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NoteOctober 16, 2023

A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks
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Aitor Maestro*
Aitor Maestro
Department of Organic Chemistry I, University of the Basque Country, UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain
Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria
*[email protected]
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https://orcid.org/0000-0003-4726-9675
Bence S. Nagy
Bence S. Nagy
Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria
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Sándor B. Ötvös
Sándor B. Ötvös
Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria
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https://orcid.org/0000-0001-6673-1744
C. Oliver Kappe*
C. Oliver Kappe
Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria
Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria
*[email protected]
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https://orcid.org/0000-0003-2983-6007

Open PDF Supporting Information (1)

The Journal of Organic Chemistry

Cite this: J. Org. Chem. 2023, 88, 21, 15523–15529

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https://doi.org/10.1021/acs.joc.3c02040

Published October 16, 2023

CC-BY 4.0 .

Abstract

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A telescoped continuous flow process is reported for the enantioselective synthesis of chiral precursors of 1-aryl-1,3-diols, intermediates in the synthesis of ezetimibe, dapoxetine, duloxetine, and atomoxetine. The two-step sequence consists of an asymmetric allylboration of readily available aldehydes using a polymer-supported chiral phosphoric acid catalyst to introduce asymmetry, followed by selective epoxidation of the resulting alkene. The process is highly stable for at least 7 h and represents a transition-metal free enantioselective approach to valuable 1-aryl-1,3-diols.

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Subjects

1-Aryl-1,3-diols 1 are important synthetic building blocks for the pharmaceutical industry. (1) They are key intermediates in the synthesis of numerous drugs, including ezetimibe (treatment of high blood cholesterol), (2) dapoxetine (premature ejaculation), (3) atomoxetine (attention deficit hyperactivity disorder), (4) and duloxetine (major depressive and anxiety disorders) (5) (Figure 1).

Figure 1. Relevant drugs synthesized from 1-aryl-1,3-diols 1.

Several synthetic routes have been developed to access optically active 1-aryl-1,3-diols using enantioselective reactions (5,6) and, most interestingly, organocatalysis. (7) While asymmetric catalytic methods are more atom-efficient and produce less waste, the high cost of chiral ligands and organocatalysts often makes chiral auxiliaries the preferred option. (2,3,8) To maximize the efficiency of existing catalytic enantioselective transformations, there has been a growing interest in the development of recyclable catalysts during the past decade. (9) In particular, chiral phosphoric acids (CPAs) have seen widespread adoption due to their versatility. (10) Numerous applications of immobilized chiral CPAs have been reported to date, highlighting their significant potential to facilitate catalyst recovery. (11)

With regard to CPA-catalyzed enantioselective reactions with potential to synthesize optically active precursors of 1,3-diols 1, Antilla and co-workers reported a highly enantioselective approach for allylboration of aldehydes using a 2,4,6-tris-isopropyl-derived CPA, (12) known as TRIP (13) (Scheme 1A). A few years later, a copolymerization-based strategy was employed to immobilize TRIP onto a polystyrene resin, and the resulting supported catalyst (PS-TRIP) was successfully applied to enantioselective allylboration reactions as a highly recyclable organocatalyst. (11) Even though some of the immobilized CPAs have been shown to be exceptionally active and robust, (11b,d) they have not been widely utilized for the enantioselective synthesis of active pharmaceutical ingredients (APIs) and related compounds. (14)

Scheme 1. (A) CPAs Used in the Enantioselective Allylboration of Aldehydes, (B) Proposed Synthetic Route to 1-Aryl-1,3-diols, and (C) Continuous Flow Setup Used for the Allylboration Step

Due to improved productivity, easier scalability, and waste reduction compared to more conventional batch procedures, telescoped continuous flow processes involving immobilized chiral catalysts have proven to be particularly useful for the multistep synthesis of optically active targets. (15) Building on our previous efforts in flow synthesis of chiral APIs and their advanced intermediates, (16) we hypothesized that merging PS-TRIP-catalyzed asymmetric allylboration with selective epoxidation of the resulting chiral alkene in an uninterrupted flow process would open a simple and efficient entry to optically active 1,3-diols as key intermediates of atomoxetine, dapoxetine, duloxetine, and ezetimibe. The planned two-step process would produce enantioenriched epoxy alcohols 5 from readily available nonchiral aldehydes, which can then be easily transformed into the desired chiral diols 1 (Scheme 1B). (17) By carefully selecting reaction conditions, we aimed to eliminate the need for any chromatographic purification, thereby facilitating larger-scale syntheses.

Our study began with optimizing the parameters of individual reaction steps. The activity of the PS-TRIP catalyst for asymmetric allylboration was explored in a flow setup consisting of two separate reagent feeds: solutions of benzaldehyde 2a (1.0 equiv) and allylboronic ester 3 (1.2 equiv). The reagent streams were pumped at a flow rate of 100 μL/min each and were combined before entering a packed bed reactor containing 0.8 g of the supported catalyst (Scheme 1C). This corresponded to a residence time on the catalyst bed of ∼15 min. Several solvents were evaluated with the purpose of making the overall process greener. (18) The effect of substrate concentration was also explored to maximize the productivity. The best results for obtaining alkene 4a were achieved in 97% yield and 90% enantiomeric excess (ee) using a substrate concentration of 0.15 M in toluene as the solvent (see Table S1 for details).

Next, various strategies were explored for the subsequent epoxidation, initially under batch conditions (Table 1). We found that hydrogen peroxide as an oxidant resulted in overoxidation of the desired chiral alcohol (5a) to the corresponding ketone 6a, making the process unsuitable for further development (Table 1, entry 1). Dimethyldioxirane (DMDO), generated from acetone and Oxone (2KHSO₅·KHSO₄·K₂SO₄) in a buffered aqueous solution, (19) showed high conversion and selectivity (Table 1, entry 2) but involved miscibility issues with toluene. To avoid solubility problems that could affect the reactivity in flow, we next evaluated organic peracids. Commercially available solutions of peracetic acid (PAA) showed high selectivity but only poor conversion (Table 1, entries 3 and 4).

Table 1. Optimization of the Epoxidation of 4a under Batch Conditions^a

entry	oxidant (equiv)	solvent	5a (%)	6a (%)
1	H₂O₂ (1.2)	2:1 acetone/H₂O	54	26
2	DMDO (2.0)	2:1 acetone/H₂O	96	1
3	PAA (4.0)	toluene	25	nd
4	PAA (8.0)	toluene	30	nd
5	mCPBA (2.0)	toluene	62	nd
6	mCPBA (3.0)	toluene	80	nd
7	mCPBA (4.0)	toluene	93	nd

^{^a}

General conditions: 4a (0.1 mmol, 1 equiv), oxidant, solvent (1.0 mL). The yields were determined by HPLC area %. nd, not detected.

Although the in situ generation of peracids under continuous flow conditions is well-known, (20) preliminary tests showed significant overoxidation to ketone 6a, probably due to the large excess of H₂O₂ required in these reactions. Therefore, we finally tested m-chloroperbenzoic acid (mCPBA) as the epoxidation agent. Gratifyingly, excellent conversion and selective epoxidation were achieved in the presence of 4.0 equiv of mCPBA, making it the preferred oxidant for further development (Table 1, entries 5–7). Although the diastereoselectivity of the epoxidation process is minimal, the late removal of the chiral center on the epoxide makes it not relevant for synthesis of diols 1. The mCPBA-mediated selective epoxidation was then transferred to continuous flow using a simple coil reactor, ensuring conversions of ≥90% within residence times of ∼10 min at 85 °C (see Table S2 for details).

Following step-by-step optimization, we combined the PS-TRIP-catalyzed asymmetric allylboration of benzaldehyde (2a) and the subsequent epoxidation in a telescoped flow sequence to access epoxy alcohol 5a, a chiral intermediate of atomoxetine and dapoxetine (Scheme 2A). Downstream to the packed bed reactor, the mCPBA feed served a double role. Apart from functioning as an epoxidation agent, it also quenched any unreacted allyl pinacol ester, thereby preventing racemic background reactions in the case of uncompleted allylboration. To safely quench any excess oxidant, the outlet of the reactor was directed into a stirred solution of Na₂S₂O₅. With the optimized setup in hand, we performed a continuous long run for 7 h. The overall process was followed by off-line HPLC with samples taken and analyzed every hour. We were pleased to find no decrease in either the conversion or enantioselectivity, showing the robustness of the process (Scheme 2B). Contrary to previous reports on enantioselective allylboration reactions, (11d,12,21) the process presented here did not require any chromatographic purification but a simple acid/base extractive workup to isolate the desired chiral adduct in sufficiently pure form.

Scheme 2. (A) Optimal Setup for the Telescoped Asymmetric Allylboration/Epoxidation Process, (B) Yields (blue) and ee (red) of 5a over Time (HPLC), and (C) Chiral Intermediates for the Synthesis of APIs

To obtain potential precursors of ezetimibe and duloxetine, the two-step flow synthesis was next attempted using 4-fluorobenzaldehyde (2b) and 2-thiophenecarboxaldehyde (2c) as the substrate, respectively (Scheme 2C). Epoxy alcohol 5b was smoothly produced from aldehyde 2b during a continuous 3 h run (90% yield, 92% ee) under conditions identical to those applied in the synthesis of 3a. In the targeted synthesis of oxirane 5c from aldehyde 2c, the epoxidation step resulted in a complex mixture, probably due to the polymerization of the thiophene ring. (22) In this case, the process was stopped after the allylboration step (performed using the setup shown in Scheme 1C; see also the Supporting Information for details) to afford alkene 4c in 99% yield and 66% ee.

To illustrate the applicability of epoxides 5 in the synthesis of 1-aryl-1,3-diols 1, we performed the ring opening of epoxide 5a in acidic media, affording triol 7a in high yield (Scheme 3). Further transformations of triols 7 to the corresponding diols 1 are known in the literature. (17)

Scheme 3. Formal Synthesis of 1-Aryl-1,3-diols 1

In summary, we have developed a telescoped continuous flow process using an immobilized CPA-mediated enantioselective allylboration as the key step followed by mCPBA-mediated selective alkene epoxidation. Our strategy consists of a transition-metal free catalytic method to access triols 7 and diols 1 in high yield and enantiocontrol by using a robust immobilized organocatalyst. By exploiting an uninterrupted flow process, we obtained chiral epoxides 5 in a simple and efficient manner, without the need for any chromatographic purification. With a cumulative residence time of <30 min, the protocol enabled a notable chemical intensification compared to earlier methodologies.

Experimental Section

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General Information

All solvents and chemicals were obtained from typical commercial vendors and used as received, without any further purification. ¹H, ¹⁹F, and ¹³C NMR spectra were recorded on a Bruker Avance III 300 MHz instrument at room temperature, in CDCl₃ as the solvent, at 300 and 75 MHz. Chemical shifts (δ) are reported in parts per million relative to the residual solvent peak (CDCl₃, ¹H, 7.26 ppm; ¹³C, 77.16 ppm). Coupling constants are reported in hertz. Multiplicity is reported with the usual abbreviations.

When required, column chromatographic purification was performed by using a Biotage Isolera automated flash chromatography system with cartridges packed with KP-SIL, 60 Å (32–63 μm particle size). Analytical thin-layer chromatography (TLC) was carried out using Merck silica gel 60 GF254 plates. Compounds were visualized by means of ultraviolet (UV) or KMnO₄.

Analytical HPLC analysis was carried out on a C18 reversed-phase (RP) analytical column (150 mm × 4.6 mm, particle size of 5 mm) at 37 °C by using mobile phases A [90:10 (v/v) water/acetonitrile with 0.1% TFA] and B (acetonitrile with 0.1% TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: linear increase from 3% to 5% B over 3 min, linear increase from 5% to 30% B over 4 min, linear increase from 30% to 100% B over 3 min, hold at 100% B for 2 min, linear decrease from 100% to 3% B over 0.5 min, and hold at 3% B for 2.5 min.

The ee of the compounds was determined by chiral HPLC or chiral GC. Chiral HPLC analysis was performed on a Shimadzu HPLC system (DGU-403 degassing unit, CTO-40S column oven, CBM20 system controller, SPD-40 UV–visible detector, LC-20AT pumps). Chiral GC analysis was performed on a Trace-GC (ThermoFisher) GC system equipped with a flame ionization detector (FID), using an Rt-BDEXse column [30 m × 0.32 mm (inside diameter) × 0.25 μm df] (Restek GmbH) and helium as a carrier gas (linear velocity of 0.5 mL min^–1). FID was used for detection, and the detector gases used for flame ionization were hydrogen and synthetic air (5.0 quality).

Optical rotation was measured in CHCl₃ (HPLC-grade) at 25 °C against the sodium D line (λ = 589 nm) on a PerkinElmer Polarimeter 341 using a 10 cm path length cell. The specific rotation was calculated with the following equation

{[α]}_{D}^{T} = \frac{100 α}{c d}

where T is the temperature in degrees Celsius, D is the sodium D line emission, α is the angle of rotation, c is the concentration of the solution in grams per 100 mL, and d is the length of the polarimeter tube in decimeters (here 1 dm). The given data were calculated as the average of three measurements. The absolute configuration was determined by comparison of the optical rotation for compound 4c, and the absolute configurations of other compounds were assigned by analogy. (12)

High-resolution mass spectra were recorded in either negative or positive mode on an Agilent 6230 TOF LC/MS instrument (G6230B) by flow injections on an Agilent 1260 Infinity Series HPLC instrument (HiP degasser G4225A, binary pump G1312B, ALS autosampler G1329B, TCC column thermostat G1316A, and DAD detector G4212B).

Equipment for the continuous flow reactions was assembled using commercially available components. Liquid streams were pumped by using Syrris Asia syringe pumps. Flow systems were pressurized by using an adjustable backpressure regulator (BPR) from Zaiput and/or by using a fixed-pressure BPR from IDEX. Reaction coils were heated by means of a conventional oil bath. Reagent feeds were streamed directly or by using injection valves and sample loops. Sample loops and reactor coils were made by using perfluoroalkoxy alkane (PFA) tubings (1/16 in. outside diameter, 0.80 mm inside diameter or 1/8 in. outside diameter, 1.58 mm inside diameter). Details of reaction setups as well as general procedures can be found in the following sections.

Synthesis of the Catalysts

The synthesis of PS-TRIP catalysts was performed following Pericàs’s procedure. (11d,g) The catalyst loading of the resin was calculated on the basis of the P elemental analysis by using the following formula:

f (\frac{mmol}{g}) = \frac{% P \times 1000}{number of P atoms \times M W (P) \times 100}

Anal. P, 0.48%; f = 0.15 mmol/g.

General Procedure for the Batch Synthesis of Racemic 4

The corresponding aldehyde (1.0 mmol, 1.0 equiv) was dissolved in 5 mL of toluene, and AllylBpin (225.1 μL, 1.2 mmol, 1.2 equiv) was added dropwise at room temperature. The reaction mixture was stirred overnight and then concentrated under vacuum. The reaction crude was purified by column chromatography on silica gel (1:0 to 7:3 hexanes/Et₂O, followed at 210 nm). The reported data match the literature.

General Procedure for the Batch Synthesis of Racemic 5

The corresponding aldehyde (1.0 mmol, 1.0 equiv) was dissolved in 5 mL of toluene, and AllylBpin (225.1 μL, 1.2 mmol, 1.2 equiv) was added dropwise at room temperature. The reaction mixture was stirred overnight, mCPBA (75% purity, 739.6 mg, 3.0 mmol, 3.0 equiv) added in one portion, and the mixture stirred overnight at room temperature. The crude reaction was quenched with 1.0 M Na₂S₂O₃ (10 mL), and the organic phase was washed with 1.0 M NaOH (3 × 10 mL), saturated NaHCO₃ (1 × 10 mL), and brine (1 × 10 mL). The organic phase was dried over MgSO₄, filtered, and concentrated.

General Procedure for the Batch Synthesis of 7

Oxirane 5a (82.1 mg, 0.5 mmol, 1.0 equiv) was dissolved in 1 mL of THF, and 1.0 M HCl (0.75 mL, 0.75 mmol, 1.5 equiv) was added dropwise. The reaction mixture was stirred for 2 h at room temperature, diluted with Et₂O (10 mL), extracted, and washed with brine (1 × 10 mL). The crude reaction mixture was purified by column chromatography on silica gel (1:0 to 1:1 hexanes/Et₂O, followed at 210 nm).

Experimental Procedure for the Telescoped Flow Synthesis of Oxiranes 5

First, 0.8 g of the PS-TRIP catalyst was loaded into an adjustable Omnifit glass column [10 mm (inside diameter)]. Prior to the reactions, the catalyst bed was swollen by pumping toluene at a rate of 200 μL/min for 30 min. Stock solutions (in toluene) of aldehyde 2a (0.30 M, 100 μL/min, 1.0 equiv) and 3 (0.36 M, 100 μL/min, 1.2 equiv) were pumped independently (overall flow rate of 200 μL/min) and combined at room temperature just before the catalyst-containing Omnifit column by using a Syrris Asia syringe pump. A check-valve was added to the exit of the packed bed reactor to avoid back flow. Then, a mCPBA^a solution in toluene (0.30 M, 400 μL/min, 4.0 equiv) was combined in the reaction coil heated to 85 °C in an oil bath.^b The system was pressurized at 5 bar by using a Zaiput BPR. The reaction outcome was quenched by collecting the mixture directly into a stirred aqueous solution of 1.0 M Na₂S₂O₃. More detailed information about the flow setup is shown in section S3 of the Supporting Information.

Workup for 1 h of the Reaction in Continuous Flow. The reaction mixture was collected over 30 mL of a 1.0 M solution of Na₂S₂O₃. The organic phase was then separated and washed with 1.0 M NaOH (3 × 50 mL), saturated NaHCO₃ (1 × 50 mL), and brine (1 × 50 mL). The organic phase was then dried over MgSO₄, filtered, and concentrated under vacuum.

Workup for 3 h of the Reaction in Continuous Flow. The reaction mixture was collected over 90 mL of a 1.0 M solution of Na₂S₂O₃. The organic phase was then separated and washed with 1.0 M NaOH (3 × 150 mL), saturated NaHCO₃ (1 × 150 mL), and brine (1 × 150 mL). The organic phase was then dried over MgSO₄, filtered, and concentrated under vacuum.

Note that the epoxidation step was not suitable for the synthesis of compound 5c due to the undesired polymerization of the thiophene in the reaction. (22) In contrast to compounds 5a and 5b, in which colorless or pale yellow solutions were observed, during the synthesis of 5c, a black precipitate is formed in the case of 4c and mCPBA, leading to the clogging of the system and a complex mixture of byproducts.

Therefore, the 3 h run for the synthesis of 4c was performed by collecting the allylation product of 2a and 3 just after the packed bed reactor, using the optimal reaction conditions for the allylboration reaction (Table 1, entry 6). The reaction outcome was quenched by collecting directly into a stirred 1.0 M Na₂S₂O₃ (90 mL), and the organic phase was extracted in toluene, dried over MgSO₄, filtered, and concentrated. The reaction crude was purified by column chromatography on silica gel (1:0 to 7:3 hexanes/Et₂O, followed at 210 nm).

Characterization Data of 4, 5, and 7

(R)-1-(Thiophen-2-yl)but-3-en-1-ol (4c)

The product was synthesized using the flow procedure and collected for 3 h after the steady state, affording 0.82 g (99%) of the product as a colorless oil. The reported data match the literature: (12) ¹H NMR (300 MHz, CDCl₃) δ 7.27 (dd, J = 4.2, 2.2 Hz, 1H), 7.05–6.96 (m, 2H), 5.85 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.25–5.14 (m, 2H), 5.00 (td, J = 6.5, 2.7 Hz, 1H), 2.70–2.56 (m, 2H), 2.37 (bs, 1H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 147.9, 134.0, 126.7, 124.7, 123.8, 118.9, 69.5, 43.9; HRMS (TOF+) m/z [2M + K]⁺ calcd for C₁₆H₂₀O₂S₂K 347.0537, found 347.0571;

{[α]}_{589}^{25} = \frac{100 \times + 0.246}{1.07 \times 1} = + 22.99

(c = 1.07 in CHCl₃). Literature data for (S)-4c (96% ee): −12.33 (c = 1.07 in CHCl₃). (12) For chiral GC-FID analysis, the oven was heated to 60 °C before injection of the sample and held at that temperature for 1.0 min after the injection. Then, the temperature was increased to 130 °C at a rate of 5.0 °C/min and held for 10.0 min. The temperature was then increased to 145 °C at a rate of 3.0 °C/min and held for 1.0 min. t_R = 28.4 (minor) and 28.5 min (major).

(1R)-2-(Oxiran-2-yl)-1-phenylethan-1-ol (5a)

The product was synthesized using the telescoped flow procedure and collected for 7 h after the steady state, affording 1.99 g (95%) of the product as a yellowish oil (mixture of diastereomers): ¹H NMR (300 MHz, CDCl₃) δ 7.52–7.28 (m, 10H), 5.11–4.83 (m, 2H), 3.18 (dtd, J = 6.8, 4.0, 2.7 Hz, 1H), 3.03 (dtd, J = 7.0, 4.1, 2.8 Hz, 1H), 2.84 (dd, J = 4.8, 4.0 Hz, 1H), 2.76 (dd, J = 4.8, 4.0 Hz, 1H), 2.62 (dd, J = 4.8, 2.8 Hz, 1H), 2.51 (dd, J = 5.0, 2.8 Hz, 1H), 2.42 (bs, 1H). 2.22–2.01 (m, 2H), 1.97–1.75 (m, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 144.2, 143.9, 128.7, 128.7, 127.9, 127.8, 125.9, 125.7, 72.9, 71.9, 50.4, 50.1, 47.2, 46.9, 41.9, 41.4; HRMS (TOF+) m/z [M + H]⁺ calcd for C₁₀H₁₂O₂H 165.0910, found 165.0902;

{[α]}_{589}^{25} = \frac{100 \times + 0.323}{1.05 \times 1} = + 30.76

(c = 1.05 in CHCl₃); HPLC (AD-H, 5/95 i-PrOH/n-heptane, flow rate of 1.0 mL/min, oven temperature of 12 °C, λ = 210 nm): t_R = 18.5 (diastereomer 1, major), 20.5 (diastereomer 2, major), 21.7 (diastereomer 1, minor), and 23.3 min (diastereomer 2, minor).

(1R)-1-(4-Fluorophenyl)-2-(oxiran-2-yl)ethan-1-ol (5b)

The product was synthesized using the telescoped flow procedure and collected for 3 h after the steady state, affording 0.89 g (90%) of the product as a yellowish oil (mixture of diastereomers): ¹H NMR (300 MHz, CDCl₃) δ 7.37–7.27 (m, 4H), 7.09–6.95 (m, 4H), 4.94–4.81 (m, 2H), 3.12 (dtd, J = 6.8, 4.0, 2.8 Hz, 1H), 2.94 (dtd, J = 7.0, 4.1, 2.7 Hz, 1H), 2.88 (s, 2H), 2.78 (dd, J = 4.8, 4.1 Hz, 1H), 2.72 (dd, J = 4.9, 4.0 Hz, 1H), 2.56 (dd, J = 4.8, 2.8 Hz, 1H), 2.46 (dd, J = 4.9, 2.7 Hz, 1H), 2.15–1.93 (m, 2H), 1.87–1.65 (m, 2H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 162.3 (d, J = 245.6 Hz), 162.2 (d, J = 245.4 Hz), 139.9 (d, J = 3.1 Hz), 139.7 (d, J = 3.2 Hz), 127.5 (d, J = 8.2 Hz), 127.3 (d, J = 8.1 Hz), 115.4 (d, J = 21.4 Hz), 115.4(2) (d, J = 21.4 Hz), 72.1, 71.1, 50.3, 50.0, 47.1, 46.9, 41.9, 41.4; ¹⁹F NMR (282 MHz, CDCl₃) δ −114.7, −115.0; HRMS (TOF+) m/z [M]⁺ calcd for C₁₀H₁₁FO₂H 182.0743, found 182.0095;

{[α]}_{589}^{25} = \frac{100 \times + 0.386}{1.02 \times 1} = + 37.84

(c = 1.02 in CHCl₃); HPLC (AD-H, 2/98 i-PrOH/n-heptane, flow rate of 1.0 mL/min, oven temperature of 12 °C, λ = 210 nm): t_R = 37.7 (diastereomer 1, major), 40.9 (diastereomer 2, major), 43.0 (diastereomer 1, minor), and 45.1 min (diastereomer 2, minor).

(4R)-4-Phenylbutane-1,2,4-triol (7a)

The general procedure was followed, affording 72.0 mg (79%) of the product as a yellowish oil (mixture of diastereomers). The reported data match the literature: (23) ¹H NMR (300 MHz, CDCl₃) δ 7.50–7.20 (m, 10H), 5.06 (t, J = 6.0 Hz, 1H), 4.97 (dd, J = 8.8, 4.4 Hz, 1H), 4.18–3.99 (m, 2H), 3.69–3.47 (m, 4H), 3.45–2.53 (m, 4H), 2.11–1.84 (m, 4H); ¹³C{¹H} NMR (75 MHz, CDCl₃) δ 144.1, 143.9, 128.8, 128.7, 128.1, 127.8, 125.8, 125.6, 74.5, 72.0, 71.5, 69.0, 50.0, 49.7, 42.7, 42.1; HRMS (TOF-) m/z [M – H]⁻ calcd for C₁₀H₁₃O₃ 181.0870, found 181.0879;

{[α]}_{589}^{25} = \frac{100 \times + 0.231}{0.99 \times 1} = + 23.33

(c = 0.99 in CHCl₃); HPLC (AD-H, 5/95 i-PrOH/n-heptane, flow rate of 1.0 mL/min, oven temperature of 12 °C, λ = 210 nm): t_R = 24.7 (diastereomer 1, major), 26.1 (diastereomer 21, minor), 33.2 (diastereomer 2, minor), and 38.5 min (diastereomer 2, major).

Data Availability

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The data underlying this study are available in the published article and its Supporting Information.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02040.

General procedures and characterization data (PDF)

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Corresponding Authors
- Aitor Maestro - Department of Organic Chemistry I, University of the Basque Country, UPV/EHU, Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria; https://orcid.org/0000-0003-4726-9675; Email: [email protected]
- C. Oliver Kappe - Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria; https://orcid.org/0000-0003-2983-6007; Email: [email protected]
Authors
- Bence S. Nagy - Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria
- Sándor B. Ötvös - Institute of Chemistry, University of Graz, NAWI Graz, A-8010 Graz, Austria; Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), A-8010 Graz, Austria; https://orcid.org/0000-0001-6673-1744
Funding
Open Access is funded by the Austrian Science Fund (FWF).
Notes
The authors declare no competing financial interest.

Acknowledgments

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A.M. acknowledges funding from the Department of Education of the Basque Government (postdoctoral program). The authors thank the Austrian Science Fund (FWF) for financial support through Project P 34397-N. The authors thank Helmar Wiltsche from the TU Graz for the elemental analysis. A preprint of this manuscript was previously uploaded to chemRxiv. (24)

Additional Notes

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^a During the long run reaction, a color change in the mCPBA stock solution was observed, going from a colorless solution to a slightly yellow solution, indicating partial degradation. To avoid a potential conversion decrease during the epoxidation step, a new mCPBA solution was prepared after 5 h.

^b Higher temperatures resulted in degradation of the mCPBA and led to undesired byproducts.

References

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This article references 24 other publications.

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An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-dapoxetine, a selective serotonin reuptake inhibitor (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.
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A simple and convenient method was reported for the prepn. of optically active β-hydroxy-β-arylpropionates I (R1 = Ph, 4-MeOC6H4, 4-O2NC6H4, 2,4-Cl2C6H3, 2-furyl, etc.; R2 = Me, Et, Me2CH, n-Bu), δ-hydroxy-δ-aryl-β-oxo-pentanoates II and their butyryl derivs. via Candida Rugosa lipase-catalyzed hydrolysis. The optically active products were used as precursors in synthesis of some chiral pharmaceuticals, such as fluoxetine and tomoxetine, and polysubstituted dihydropyrans.
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Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J. P.; Ben Hassine, B.; Genêt, J. P. Enantioselective Hydrogenation of β-Keto Esters Using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications. Adv. Synth. Catal. 2003, 345 (1–2), 261– 274, DOI: 10.1002/adsc.200390021
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Advanced Synthesis & Catalysis (2003), 345 (1+2), 261-274CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compds. Using a simple and straightforward in situ catalyst prepn., the conditions were optimized using mol. hydrogen. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atm. and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asym. hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.
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6
Selected examples related to transition-metal catalysis:
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Copper-Catalyzed Stereospecific Hydroboration of Internal Allylic Alcohols
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European Journal of Organic Chemistry (2019), 2019 (44), 7367-7371CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
An effective Cu-catalyzed stereospecific hydroboration of aliph. and arom. 1,1,2-trisubstituted internal allylic alcs. was reported. This reaction proceeded via a silyl ether transient protection of allylic alcs. and subsequent stereospecific hydroboration. Followed by an oxidative workup, an array of acyclic, cyclic and heterocyclic 1,3-diols was synthesized in good to excellent yields with good functional group tolerance and excellent diastereomeric ratios (> 20:1).
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(b) Fernández, E.; Pietruszka, J.; Frey, W. Palladium-Catalyzed Synthesis of Enantiomerically Pure α-Substituted Allylboronic Esters and Their Addition to Aldehydes. J. Org. Chem. 2010, 75 (16), 5580– 5589, DOI: 10.1021/jo1008959
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Palladium-catalyzed synthesis of enantiomerically pure α-substituted allylboronic esters and their addition to aldehydes
Fernandez, Enrique; Pietruszka, Joerg; Frey, Wolfgang
Journal of Organic Chemistry (2010), 75 (16), 5580-5589CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Tartrate-derived boronic esters I can be subjected to palladium-catalyzed carbonyl allylations with SnCl2 to obtain enantiomerically pure α-substituted allylboronic esters II (R = Ph, 3,4-C6H4F2, C6F5, furfural, CO2Et, PhCHCH, PhCH2CH2, iPr, iBu, c-C6H11, H) and III (R = C6F5, furfural, CO2Et, PhCHCH, iPr, c-C6H11, H). The reaction proceeds regioselectively and with high, simple diastereoselectivity to form anti-products. Their addn. to aldehydes yields enantiomerically enriched homoallylic alcs. e. g. IV. Synthesis, characterization, and a mechanistic rational is presented here.
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(c) Peng, F.; Hall, D. G. Preparation of α-Substituted Allylboronates by Chemoselective Iridium-Catalyzed Asymmetric Allylic Alkylation of 1-Propenylboronates. Tetrahedron Lett. 2007, 48 (18), 3305– 3309, DOI: 10.1016/j.tetlet.2007.02.124
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Preparation of α-substituted allylboronates by chemoselective iridium-catalyzed asymmetric allylic alkylation of 1-propenylboronates
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Chiral α-substituted allylic boronates are attractive reagents that add to aldehydes with very high stereoselectivity. This study examd. the feasibility of an improved method of prepn. based on the catalytic asym. allylic alkylation of simple 3-hydroxy-1-propenylboronate derivs. with malonate anions. Whereas palladium catalysis failed in promoting the desired process, iridium catalysis led to a regioselective formation of the desired, branched allylboronates with up to 84% ee using a chiral monophosphoramidite ligand. This allylation reagent adds to aldehydes with high chirality transfer. A diastereoselective alkoxycyclization on the resulting homoallylic alcs. allows a sepn. of the epimeric E/Z isomers.
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(d) Wang, S.; Rodríguez-Escrich, C.; Fan, X.; Pericàs, M. A. A Site Isolation-Enabled Organocatalytic Approach to Enantiopure γ-Amino Alcohol Drugs. Tetrahedron 2018, 74 (29), 3943– 3946, DOI: 10.1016/j.tet.2018.04.022
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A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs
Wang, Shoulei; Rodriguez-Escrich, Carles; Fan, Xinyuan; Pericas, Miquel A.
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An efficient approach was developed for enhancing the reactivity of benzaldehyde in the cross-aldol reaction with acetaldehyde resulting from the deoligomerization of paraldehyde. The tandem process was mediated by the dual polymer supported catalytic system, which operated under site isolation conditions in a recyclable manner. The strategy reported herein involved temporary conversion of benzaldehyde into η6-benzaldehyde Cr(CO)3 circumvented the limitations. Asym. synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrated the benefits of this strategy.
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Selected examples of biocatalysis:
(e) Chênevert, R.; Fortier, G.; Rhlid, R. B. Asymmetric Synthesis of Both Enantiomers of Fluoxetine via Microbiological Reduction of Ethyl Benzoylacetate. Tetrahedron 1992, 48 (33), 6769– 6776, DOI: 10.1016/S0040-4020(01)89866-5
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Asymmetric synthesis of both enantiomers of fluoxetine via microbiological reduction of ethyl benzoylacetate
Chenevert, Robert; Fortier, Genevieve; Bel Rhlid, Rachid
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Microbiol. redn. of Et benzoylacetate by bakers' yeast (Saccharomyces cerevisiae), Beauveria sulfurescens or Geotrichum candidum afforded Et (S)-3-hydroxy-3-phenylpropionate (I) in high optical yield. This enantiomerically pure alc. was converted into both enantiomers of fluoxetine II. Thus, I reacted with MeNH2 and 4-ClC6H4CF3 to give (S)-II. Treating I with 4-HOC6H4CF3 and MeNH2 gave (R)-II. The product resulting from the bakers' yeast redn. had ee values (87-93%) lower than the 100% value erroneously attributed in earlier studies.
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(f) Ramos, A. de S.; Ribeiro, J. B.; Vazquez, L.; Fiaux, S. B.; Leite, S. G. F.; Ramos, M. da C. K. V.; Neto, F. R. de A.; Antunes, O. A. C. Immobilized Microorganisms in the Reduction of Ethyl Benzoylacetate. Tetrahedron Lett. 2009, 50 (52), 7362– 7364, DOI: 10.1016/j.tetlet.2009.10.068
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Immobilized microorganisms in the reduction of ethyl benzoylacetate
Ramos, Aline de Souza; Ribeiro, Joyce Benzaquem; Vazquez, Leonardo; Fiaux, Sorele Batista; Leite, Selma Gomes Ferreira; Ramos, Maria da Conceicao Klaus V.; Radler de Aquino Neto, Francisco; Antunes, O. A. C.
Tetrahedron Letters (2009), 50 (52), 7362-7364CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
The enantioselective redn. of Et benzoylacetate (EBA) into Et (S)-3-hydroxy-3-phenylpropanoate (S-HPPE) by nine yeast strains and three filamentous fungi strains is described. The conversion obtained was in the range 0-89% and the enantiomeric excess was 100% in many cases. Conversion levels were higher when the redn. was performed with microorganisms immobilized in calcium alginate and enantioselectivity remained excellent. Some reaction's conditions of bioredn. by immobilized cells of Rhodotorula rubra were studied using a 25-2 fractional factorial design.
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7
Selected examples:
(a) Qiao, Y.; Chen, Q.; Lin, S.; Ni, B.; Headley, A. D. Organocatalytic Direct Asymmetric Crossed-Aldol Reactions of Acetaldehyde in Aqueous Media. J. Org. Chem. 2013, 78 (6), 2693– 2696, DOI: 10.1021/jo302442g
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Organocatalytic Direct Asymmetric Crossed-Aldol Reactions of Acetaldehyde in Aqueous Media
Qiao, Yupu; Chen, Qiankun; Lin, Sirong; Ni, Bukuo; Headley, Allan D.
Journal of Organic Chemistry (2013), 78 (6), 2693-2697CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A new diarylprolinol-based catalyst I, which contains a dioctylamino group, in the presence of a newly developed ionic liq. supported (ILS) benzoic acid II as cocatalyst, is shown to be an effective catalytic system for the asym. direct crossed-aldol reaction of acetaldehyde in aq. media using brine. For the reactions studied, the catalyst loading could be reduced to 5 mol %; high yields (up to 97%) and high enantioselectivities (up to 92% ee) were also achieved for a wide variety of arom. aldehydes.
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(b) Wang, Y.; Huang, G.; Hu, S.; Jin, K.; Wu, Y.; Chen, F. Enantioselective β-Hydroxy Thioesters Formation via Decarboxylative Aldol Reactions of Malonic Acid Half Thioesters with Aldehydes Promoted by Chloramphenicol Derived Sulfonamides. Tetrahedron 2017, 73 (34), 5055– 5062, DOI: 10.1016/j.tet.2017.05.066
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7b
Enantioselective β-hydroxy thioesters formation via decarboxylative aldol reactions of malonic acid half thioesters with aldehydes promoted by chloramphenicol derived sulfonamides1
Wang, Yafeng; Huang, Guanxin; Hu, Sha; Jin, Kaijun; Wu, Yan; Chen, Fener
Tetrahedron (2017), 73 (34), 5055-5062CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
A highly enantioselective synthesis of chiral β-hydroxy thioesters that uses a decarboxylative aldol reaction of malonic acid half thioesters and aldehydes catalyzed by a chloramphenicol base-derived bifunctional organocatalyst is reported. The resulting chiral β-hydroxy thioesters were obtained in high yields (up to 82%) with good to excellent enantioselectivities (up to 94% ee). The synthetic application of the methodol. is illustrated by the asym. synthesis of the selective serotonin reuptake inhibitor dapoxetine.
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(c) Schreyer, L.; Kaib, P. S. J.; Wakchaure, V. N.; Obradors, C.; Properzi, R.; Lee, S.; List, B. Confined Acids Catalyze Asymmetric Single Aldolizations of Acetaldehyde Enolates. Science 2018, 362, 216– 219, DOI: 10.1126/science.aau0817
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Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates
Schreyer, Lucas; Kaib, Philip S. J.; Wakchaure, Vijay N.; Obradors, Carla; Properzi, Roberta; Lee, Sunggi; List, Benjamin
Science (Washington, DC, United States) (2018), 362 (6411), 216-219CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Reactions that form a product with the same reactive functionality as that of one of the starting compds. frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliph. and arom. acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-mol. catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mol % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.
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8
Selected examples:
(a) Khatik, G. L.; Khurana, R.; Kumar, V.; Nair, V. A. Asymmetric Induction by (S)-4-Isopropyl-1-Phenylimidazolidin-2-Thione in Titanium-Mediated Aldol Reactions and Its Application in Enantioselective Synthesis of (R)-Baclofen. Synthesis 2011, 19, 3123– 3132, DOI: 10.1055/s-0030-1260187
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(b) Fernandes, A. A. G.; Leonarczyk, I. A.; Ferreira, M. A. B.; Dias, L. C. Diastereoselectivity in the Boron Aldol Reaction of α-Alkoxy and α,β-Bis-Alkoxy Methyl Ketones. Org. Biomol. Chem. 2019, 17 (12), 3167– 3180, DOI: 10.1039/C9OB00358D
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8b
Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones
Fernandes, Alessandra A. G.; Leonarczyk, Ives A.; Ferreira, Marco A. B.; Dias, Luiz Carlos
Organic & Biomolecular Chemistry (2019), 17 (12), 3167-3180CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
In this work, using DFT calcns., we investigated the 1,4 and 1,5 asym. induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy Me ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theor. calcns. revealed the origins of the 1,4 asym. induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.
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(c) Le Sann, C.; Muñoz, D. M.; Saunders, N.; Simpson, T. J.; Smith, D. I.; Soulas, F.; Watts, P.; Willis, C. L. Assembly Intermediates in Polyketide Biosynthesis: Enantioselective Syntheses of b-Hydroxycarbonyl Compounds. Org. Biomol. Chem. 2005, 3, 1719– 1728, DOI: 10.1039/b419492f
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8c
Assembly intermediates in polyketide biosynthesis: enantioselective syntheses of β-hydroxycarbonyl compounds
Le Sann, Christine; Munoz, Dulce M.; Saunders, Natalie; Simpson, Thomas J.; Smith, David I.; Soulas, Florilene; Watts, Paul; Willis, Christine L.
Organic & Biomolecular Chemistry (2005), 3 (9), 1719-1728CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
A versatile approach for the enantioselective synthesis of functionalized β-hydroxy N-acetylcysteamine thiol esters, such as I, has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone II using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted δ-lactones.
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9
Some reviews:
(a) Fulgheri, T.; Della Penna, F.; Baschieri, A.; Carlone, A. Advancements in the Recycling of Organocatalysts: From Classical to Alternative Approaches. Curr. Opin. Green Sustain. Chem. 2020, 25, 100387, DOI: 10.1016/j.cogsc.2020.100387
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(b) Susam, Z. D.; Tanyeli, C. Recyclable Organocatalysts in Asymmetric Synthesis. Asian J. Org. Chem. 2021, 10 (6), 1251– 1266, DOI: 10.1002/ajoc.202100165
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Recyclable Organocatalysts in Asymmetric Synthesis
Susam, Zeynep Dilsad; Tanyeli, Cihangir
Asian Journal of Organic Chemistry (2021), 10 (6), 1251-1266CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This survey summarizes the studies that have been done so far to enlight the subject of recyclable organocatalysts for the synthesis of asym. compds. and headlights cover-up silica supported organocatalysts, polymer supported organocatalysts, magnetic nanoparticle supported organocatalysts, gold nanoparticle supported organocatalysts, ionic liqs. organocatalysts and fluorous supported organocatalysts.
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10
Some recent reviews:
(a) del Corte, X.; Martínez de Marigorta, E.; Palacios, F.; Vicario, J.; Maestro, A. An Overview of the Applications of Chiral Phosphoric Acid Organocatalysts in Enantioselective Additions to C = O and C = N Bonds. Org. Chem. Front. 2022, 9 (22), 6331– 6399, DOI: 10.1039/D2QO01209J
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An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to C:O and C:N bonds
del Corte, Xabier; Martinez de Marigorta, Edorta; Palacios, Francisco; Vicario, Javier; Maestro, Aitor
Organic Chemistry Frontiers (2022), 9 (22), 6331-6399CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
A review. Chiral phosphoric acids (CPAs) have been used as efficient organocatalysts since the first examples were reported 18 years ago by Akiyama and Terada. Although they were originally developed for enantioselective addns. to imines, a wide reaction scope has been demonstrated using this type of catalyst. In this review, the known applications of CPA for enantioselective addns. to CO and CN bonds are covered.
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(b) Pálvölgyi, Á. M.; Scharinger, F.; Schnürch, M.; Bica-Schröder, K. Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations. Eur. J. Org. Chem. 2021, 2021 (38), 5367– 5381, DOI: 10.1002/ejoc.202100894
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10b
Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations
Palvolgyi, Adam Mark; Scharinger, Fabian; Schnuerch, Michael; Bica-Schroder, Katharina
European Journal of Organic Chemistry (2021), 2021 (38), 5367-5381CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Herein, recent developments in the field of organocatalytic asym. transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asym. catalysis relies on metal-free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asym. redn. of α,β-unsatd. carbonyl compds., imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asym. transfer hydrogenations.
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(c) Xia, Z.-L.; Xu-Xu, Q.-F.; Zheng, C.; You, S.-L. Chiral Phosphoric Acid-Catalyzed Asymmetric Dearomatization Reactions. Chem. Soc. Rev. 2020, 49 (1), 286– 300, DOI: 10.1039/C8CS00436F
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10c
Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions
Xia, Zi-Lei; Xu-Xu, Qing-Feng; Zheng, Chao; You, Shu-Li
Chemical Society Reviews (2020), 49 (1), 286-300CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. The recent development of chiral phosphoric acid (CPA)-catalyzed asym. dearomatization reactions is reviewed. A wide array of electron-rich arenes (indoles, phenols, naphthols, benzothiophenes, benzofurans, etc.) and electron-poor arenes (pyridines, quinolines, isoquinolines, etc.) has been proved reactive towards various reaction partners in the presence of a CPA catalyst, enabling asym. dearomatization reactions that lead to structurally-diverse polycyclic mols. The reactions are grouped according to the roles of the arenes in the reactions (as nucleophiles or electrophiles) and the types of reaction partners. This review closes with a personal perspective on the dynamic research area of asym. dearomatization reactions by CPAs.
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Recent examples:
(a) Lai, J.; Fianchini, M.; Pericas, M. A. Development of Immobilized Spinol-Derived Chiral Phosphoric Acids for Catalytic Continuous Flow Processes. Use in the Catalytic Desymmetrization of 3,3-Disubstituted Oxetanes. ACS Catal. 2020, 10 (24), 14971– 14983, DOI: 10.1021/acscatal.0c04497
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11a
Development of Immobilized SPINOL-Derived Chiral Phosphoric Acids for Catalytic Continuous Flow Processes. Use in the Catalytic Desymmetrization of 3,3-Disubstituted Oxetanes
Lai, Junshan; Fianchini, Mauro; Pericas, Miquel A.
ACS Catalysis (2020), 10 (24), 14971-14983CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
A family of C2-sym. 1,1'-spirobiindane-7,7'-diol (SPINOL) derivs. contg. polymerizable styryl units has been prepd. through a highly convergent approach. Radical copolymn. of these monomers with styrene has allowed the synthesis of a family of immobilized SPINOL-derived chiral phosphoric acids (SPAs) where the combination of the restricted axial flexibility of the SPINOL units and the existence of extended and adaptable chiral walls adjacent to them leads to enhanced stereocontrol in catalytic processes. The optimal immobilized species (Cat f) brings about the catalytic desymmetrization of 3,3-disubstituted oxetanes in up to 90% yield with up to >99% enantioselectivity, exhibiting a very high recyclability (no decrease in conversion or enantioselectivity after 16, 16-h runs). To exploit these characteristics, a continuous flow process has been implemented and operated for the sequential prepn. of 17 diverse enantioenriched products. The suitability of the flow setup for gram scale prepns. (20 mmol scale), the stability of Cat f for long periods of time with intermittent use in flow, and its deactivation/reactivation by treatment with pyridine/hydrochloric acid in dioxane have been demonstrated. D. functional theory has been employed to provide a rational justification of the deep effect on enantioselectivity arising from the presence of sterically bulky substituents at the 6,6'-positions of the SPINOL unit. The main structural features of Cat f have subsequently been incorporated to the design of a simplified homogeneous analog available in a straightforward manner (Cat g) that performs the benchmark desymmetrization reaction with similar yields and enantioselectivities as Cat f, providing a convenient alternative for cases when single use in soln. is sought.
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(b) Huang, X. Y.; Zheng, Q.; Zou, L. M.; Gu, Q.; Tu, T.; You, S. L. Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions. ACS Catal. 2022, 12 (8), 4545– 4553, DOI: 10.1021/acscatal.2c00397
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11b
Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions
Huang, Xian-Yun; Zheng, Qingshu; Zou, Lei-Ming; Gu, Qing; Tu, Tao; You, Shu-Li
ACS Catalysis (2022), 12 (8), 4545-4553CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
Knitting rigid arom. building blocks using external crosslinkers has been developed into an effective strategy for the synthesis of porous polymers in recent years. Here, the authors report the synthesis of porous chiral phosphoric acids by this strategy. Moreover, these porous chiral phosphoric acids were found to enable highly enantioselective dearomatization reactions. Remarkably, after being reused for 10 runs, no obvious loss in catalytic activity and selectivity was obsd. The features of high reactivity, selectivity, stability, and recyclability of these hyper-crosslinked porous chiral phosphoric acids are significant for practical catalyst design.
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(c) Chen, X.; Jiang, H.; Li, X.; Hou, B.; Gong, W.; Wu, X.; Han, X.; Zheng, F.; Liu, Y.; Jiang, J.; Cui, Y. Chiral Phosphoric Acids in Metal–Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity. Angew. Chem., Int. Ed. 2019, 58 (41), 14748– 14757, DOI: 10.1002/anie.201908959
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11c
Chiral Phosphoric Acids in Metal-Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity
Chen, Xu; Jiang, Hong; Li, Xu; Hou, Bang; Gong, Wei; Wu, Xiaowei; Han, Xing; Zheng, Fanfan; Liu, Yan; Jiang, Jianwen; Cui, Yong
Angewandte Chemie, International Edition (2019), 58 (41), 14748-14757CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Chiral phosphoric acids are incorporated into indium-based metal-org. frameworks (In-MOFs) by sterically preventing them from coordination. This concept leads to the synthesis of three chiral porous 3D In-MOFs with different network topologies constructed from three enantiopure 1,1'-biphenol-phosphoric acid derived tetracarboxylate linkers. More importantly, all the uncoordinated phosphoric acid groups are periodically aligned within the channels and display significantly enhanced acidity compared to the non-immobilized acids. This facilitates the Bronsted acid catalysis of asym. condensation/amine addn. and imine redn. The enantioselectivities can be tuned (up to >99% ee) by varying the substituents to achieve a nearly linear correlation with the concns. of steric bulky groups in the MOFs. DFT calcns. suggest that the framework provides a chiral confined microenvironment that dictates both selectivity and reactivity of chiral MOFs.
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(d) Clot-Almenara, L.; Rodríguez-Escrich, C.; Osorio-Planes, L.; Pericas, M. A. Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes. ACS Catal. 2016, 6 (11), 7647– 7651, DOI: 10.1021/acscatal.6b02621
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11d
Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes
Clot-Almenara, Lidia; Rodriguez-Escrich, Carles; Osorio-Planes, Laura; Pericas, Miquel A.
ACS Catalysis (2016), 6 (11), 7647-7651CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
The widely applicable TRIP phosphoric acid catalyst I has been immobilized on polystyrene using a copolymn.-based strategy. The resin (PS-TRIP) has proven to be highly active and enantioselective in the asym. allylboration of aldehydes. Moreover, it has shown to be extremely robust, as it can be reused for 18 times, after which it still retained its activity. Lastly, to further prove the benefits of the immobilization, a continuous flow expt. spanning 28 h has been carried out with very high yields and ee's.
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(e) Zhang, Y.; Zhang, Z.; Ma, S.; Jia, J.; Xia, H.; Liu, X. Hypercrosslinking Chiral Brønsted Acids into Porous Organic Polymers for Efficient Heterogeneous Asymmetric Organosynthesis. J. Mater. Chem. A 2021, 9 (45), 25369– 25373, DOI: 10.1039/D1TA07449K
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11e
Hypercrosslinking chiral Bronsted acids into porous organic polymers for efficient heterogeneous asymmetric organosynthesis
Zhang, Yuwei; Zhang, Zhenwei; Ma, Si; Jia, Ji; Xia, Hong; Liu, Xiaoming
Journal of Materials Chemistry A: Materials for Energy and Sustainability (2021), 9 (45), 25369-25373CODEN: JMCAET; ISSN:2050-7496. (Royal Society of Chemistry)
A construction strategy for directly immobilizing the axially chiral phosphoric acid into hypercrosslinked polymers by a one-pot Friedel-Crafts alkylation reaction was developed. The obtained chiral polymers have high porosity, excellent stability and tailorable catalytic centers, and display excellent activity, enantioselectivity and recyclability for asym. transfer hydrogenation.
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(f) Li, S.; Zhang, J.; Chen, S.; Ma, X. Semi-Heterogeneous Asymmetric Organocatalysis: Covalent Immobilization of BINOL-Derived Chiral Phosphoric Acid (TRIP) to Polystyrene Brush Grafted on SiO2 Nanoparticles. J. Catal. 2022, 416, 139– 148, DOI: 10.1016/j.jcat.2022.10.021
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11f
Semi-heterogeneous asymmetric organocatalysis: Covalent immobilization of BINOL-derived chiral phosphoric acid (TRIP) to polystyrene brush grafted on SiO2 nanoparticles
Li, Shan; Zhang, Jianing; Chen, Shaoqi; Ma, Xuebing
Journal of Catalysis (2022), 416 (), 139-148CODEN: JCTLA5; ISSN:0021-9517. (Elsevier Inc.)
Reduced mass transfer and tedious immobilization of expensive chiral organocatalyst are two bottlenecks for the large-scale synthesis of optically active mols. in heterogeneous asym. organocatalysis. Here, a quasi-homogeneous organocatalysis is achieved by anchoring BINOL-derived phosphoric acid (TRIP) to polystyrene (PS) brush grafted on SiO2 nanoparticles via one-pot, effectively improving mass transfer due to the open stretching of TRIP-anchored PS brush in toluene. The PS brush enables TRIP to catalyze asym. allylation in significantly higher yields and enantioselectivities than PS-supported TRIP, and in slightly higher yields than homogeneous TRIP. The sparser grafting d. of PS brush is more conducive to the swelling of PS brush, leading to the faster mass transfer of reactants from the top to end of PS brush. Overall, the one-pot anchoring of TRIP to PS brush combines the advantages of homogeneous and heterogeneous organocatalysis, providing an ideal strategy for solving the two bottlenecks in heterogeneous asym. organocatalysis.
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(g) Clot-Almenara, L.; Rodríguez-Escrich, C.; Pericàs, M. A. Desymmetrisation of: Meso -Diones Promoted by a Highly Recyclable Polymer-Supported Chiral Phosphoric Acid Catalyst. RSC Adv. 2018, 8 (13), 6910– 6914, DOI: 10.1039/C7RA13471A
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11g
Desymmetrisation of meso-diones promoted by a highly recyclable polymer-supported chiral phosphoric acid catalyst
Clot-Almenara, Lidia; Rodriguez-Escrich, Carles; Pericas, Miquel A.
RSC Advances (2018), 8 (13), 6910-6914CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A polystyrene-supported BINOL-derived chiral phosphoric acid was applied to the desymmetrisation of meso-diones to produce enantioenriched cyclohexenones such as I [R = Me, Et, Ph, Bn, etc.;]. The catalytic resin has proven highly active and robust, giving rise to Hajos-Parrish or Wieland-Miescher type products in good yields and enantioselectivities, while allowing for extended recycling.
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Jain, P.; Antilla, J. C. Chiral Brønsted Acid-Catalyzed Allylboration of Aldehydes. J. Am. Chem. Soc. 2010, 132 (34), 11884– 11886, DOI: 10.1021/ja104956s
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Chiral Bronsted Acid-Catalyzed Allylboration of Aldehydes
Jain, Pankaj; Antilla, Jon C.
Journal of the American Chemical Society (2010), 132 (34), 11884-11886CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
A new high-yielding and highly enantioselective chiral Bronsted acid-catalyzed allylboration of aldehydes RCHO (R = Ph, 4-ClC6H4, PhCH2, cyclohexyl, 2-thienyl, 1-naphthyl, etc.) with allyl pinacol boronate is described. The reaction is shown to be highly general, with a broad substrate scope that covers aryl, heteroaryl, α,β-unsatd., and aliph. aldehydes. The reaction conditions are also shown to be effective for the catalytic enantioselective crotylation of aldehydes. The high reactivity of the allylboronate is suggested to be due to protonation of the boronate oxygen by the chiral phosphoric acid catalyst.
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Hoffmann, S.; Seayad, A. M.; List, B. A Powerful Brønsted Acid Catalyst for the Organocatalytic Asymmetric Transfer Hydrogenation of Imines. Angew. Chem., Int. Ed. 2005, 44 (45), 7424– 7427, DOI: 10.1002/anie.200503062
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A powerful Bronsted acid catalyst for the organocatalytic asymmetric transfer hydrogenation of imines
Hoffmann, Sebastian; Seayad, Abdul Majeed; List, Benjamin
Angewandte Chemie, International Edition (2005), 44 (45), 7424-7427CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A 1 mol% loading of a chiral binaphthalene phosphoric acid catalyst converts arom. and aliph. imines into the amines in high yields and enantioselectivities if treated with Hantzsch dihydropyridine.
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Some reviews:
(a) Merad, J.; Lalli, C.; Bernadat, G.; Maury, J.; Masson, G. Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals. Chem. - Eur. J. 2018, 24 (16), 3925– 3943, DOI: 10.1002/chem.201703556
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14a
Enantioselective Bronsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals
Merad, Jeremy; Lalli, Claudia; Bernadat, Guillaume; Maury, Julien; Masson, Geraldine
Chemistry - A European Journal (2018), 24 (16), 3925-3943CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The present report attempts to provide an overview of enantioselective total or formal syntheses designed around Bronsted acid-catalyzed transformations. To demonstrate the versatility of the reactions promoted and the diversity of the accessible motifs, this minireview draws a systematic parallel between methods and retrosynthetic anal. The manuscript is organized according to the main reaction types and the nature of newly-formed bonds.
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(b) Hughes, D. L. Highlights of the Recent Patent Literature: Focus on Asymmetric Organocatalysis. Org. Process Res. Dev. 2022, 26 (8), 2224– 2239, DOI: 10.1021/acs.oprd.2c00139
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14b
Highlights of the Recent Patent Literature: Focus on Asymmetric Organocatalysis
Hughes, David L.
Organic Process Research & Development (2022), 26 (8), 2224-2239CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
A review. Contributions in asym. organocatalysis from the patent literature since 2018, including reactions catalyzed by Cinchona alkaloids as free base and quaternary salts, phosphonium salts, proline-derived catalysts, and chiral phosphoric acids were explored. Examples of processes employing asym. organocatalysis for the industrial prepn. of pharmaceutical intermediates were highlighted.
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Selected reviews:
(a) Ötvös, S. B.; Kappe, C. O. Continuous Flow Asymmetric Synthesis of Chiral Active Pharmaceutical Ingredients and Their Advanced Intermediates. Green Chem. 2021, 23 (17), 6117– 6138, DOI: 10.1039/D1GC01615F
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15a
Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates
Otvos Sandor B; Kappe C Oliver; Otvos Sandor B; Kappe C Oliver
Green chemistry : an international journal and green chemistry resource : GC (2021), 23 (17), 6117-6138 ISSN:1463-9262.
Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein.
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(b) Jiao, J.; Nie, W.; Yu, T.; Yang, F.; Zhang, Q.; Aihemaiti, F.; Yang, T.; Liu, X.; Wang, J.; Li, P. Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges. Chem. - Eur. J. 2021, 27, 4817– 4838, DOI: 10.1002/chem.202004477
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15b
Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges
Jiao, Jiao; Nie, Wenzheng; Yu, Tao; Yang, Fan; Zhang, Qian; Aihemaiti, Feierdaiweisi; Yang, Tingjun; Liu, Xuanyu; Wang, Jiachen; Li, Pengfei
Chemistry - A European Journal (2021), 27 (15), 4817-4838CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. This minireview summarizes the most recent reports (2017-2020) on continuous-flow synthesis of functional mols. Notably, several complex active pharmaceutical ingredients (APIs) have been prepd. by the continuous-flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous-flow chem. for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.
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(c) Ferlin, F.; Lanari, D.; Vaccaro, L. Sustainable Flow Approaches to Active Pharmaceutical Ingredients. Green Chem. 2020, 22 (18), 5937– 5955, DOI: 10.1039/D0GC02404J
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(d) Rodríguez-Escrich, C.; Pericàs, M. A. Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts. Chem. Rec. 2019, 19 (9), 1872– 1890, DOI: 10.1002/tcr.201800097
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15d
Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts
Rodriguez-Escrich, Carles; Pericas, Miquel A.
Chemical Record (2019), 19 (9), 1872-1890CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)
Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green prodn. of enantioenriched compds. To further increase the green profile of this approach, the use of solid-supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli- to multi-gram amts. of chiral product with a reduced footprint set-up. Herein, we will present the efforts devoted in our lab. towards the immobilization of chiral catalysts and their use in single-pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal-based catalysts constitute our current toolkit of supported species for enantioselective catalysis.
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(e) Masuda, K.; Ichitsuka, T.; Koumura, N.; Sato, K.; Kobayashi, S. Flow Fine Synthesis with Heterogeneous Catalysts. Tetrahedron 2018, 74 (15), 1705– 1730, DOI: 10.1016/j.tet.2018.02.006
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15e
Flow fine synthesis with heterogeneous catalysts
Masuda, Koichiro; Ichitsuka, Tomohiro; Koumura, Nagatoshi; Sato, Kazuhiko; Kobayashi, Shu
Tetrahedron (2018), 74 (15), 1705-1730CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
A review. This review aims to summarize recent developments in continuous-flow reactions with heterogeneous catalysts for synthesis of fine chems.
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(f) Britton, J.; Raston, C. L. Multi-Step Continuous-Flow Synthesis. Chem. Soc. Rev. 2017, 46 (5), 1250– 1271, DOI: 10.1039/C6CS00830E
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15f
Multi-step continuous-flow synthesis
Britton, Joshua; Raston, Colin L.
Chemical Society Reviews (2017), 46 (5), 1250-1271CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. This review article focused on multi-step continuous-flow methodol., which had applications in synthesis of active pharmaceutical ingredients, natural products, and commodity chems. This review described the advancements while highlighted the rapid progress, benefits, and diversification of this expanding field.
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(g) Puglisi, A.; Benaglia, M.; Chiroli, V. Stereoselective Organic Reactions Promoted by Immobilized Chiral Catalysts in Continuous Flow Systems. Green Chem. 2013, 15 (7), 1790– 1813, DOI: 10.1039/c3gc40195b
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15g
Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems
Puglisi, Alessandra; Benaglia, Maurizio; Chiroli, Valerio
Green Chemistry (2013), 15 (7), 1790-1813CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
A review. The immobilization of the catalyst on a support with the aim of facilitating the sepn. of the product from the catalyst, and thus the recovery and recycling of the latter, can be regarded as an important improvement for a catalytic process. However, a system where a catalyst must not be removed from the reaction vessel is even more attractive: in continuous flow methods the immobilized catalyst permanently resides in the reactor where it transforms the entering starting materials into the desired products. The retention of the catalytic species inside the reaction vessel can be achieved by different techniques ranging from ultrafiltration through a MW-selective membrane to immobilization on different supports. In this review the authors will discuss the most significant examples of stereoselective reactions promoted by immobilized chiral catalysts and performed under continuous flow conditions, with particular attention to the more recent contributions of the last few years.
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For general reviews on continuous flow chemistry, see also:
(h) Capaldo, L.; Wen, Z.; Noël, T. A Field Guide to Flow Chemistry for Synthetic Organic Chemists. Chem. Sci. 2023, 14, 4230– 4247, DOI: 10.1039/D3SC00992K
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15h
A field guide to flow chemistry for synthetic organic chemists
Capaldo, Luca; Wen, Zhenghui; Noel, Timothy
Chemical Science (2023), 14 (16), 4230-4247CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
A review. Flow chem. has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show that several of the benefits of microreactor technol. can be exploited to push the boundaries in org. synthesis and to unleash unique reactivity and selectivity. By "lifting the veil" on some of the governing principles behind the obsd. trends, we hope that this review will serve as a useful field guide for those interested in diving into flow chem.
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(i) Gérardy, R.; Emmanuel, N.; Toupy, T.; Kassin, V. E.; Tshibalonza, N. N.; Schmitz, M.; Monbaliu, J. C. M. Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges. Eur. J. Org. Chem. 2018, 2018 (20), 2301– 2351, DOI: 10.1002/ejoc.201800149
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15i
Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges
Gerardy, Romaric; Emmanuel, Noemie; Toupy, Thomas; Kassin, Victor-Emmanuel; Tshibalonza, Nelly Ntumba; Schmitz, Michael; Monbaliu, Jean-Christophe M.
European Journal of Organic Chemistry (2018), 2018 (20-21), 2301-2351CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
This review intends to provide the reader with a clear and concise overview of how preparative continuous flow org. chem. could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chem. has enabled significant advances for the manufg. of pharmaceuticals, as well as for biomass valorization toward a biosourced chem. industry. Examples related to pharmaceutical prodn. are herein focused on (a) the implementation of flow chem. to reduce the occurrence of drug shortages, (b) continuous flow manufg. of orphan drugs, (c) continuous flow prepn. of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufg. of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform mols. Besides pos. impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technol. within the actual context of terrorism and drug abuse.
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Recent references:
(a) Ötvös, S. B.; Pericàs, M. A.; Kappe, C. O. Multigram-Scale Flow Synthesis of the Chiral Key Intermediate of (−)-Paroxetine Enabled by Solvent-Free Heterogeneous Organocatalysis. Chem. Sci. 2019, 10 (48), 11141– 11146, DOI: 10.1039/C9SC04752B
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16a
Multigram-scale flow synthesis of the chiral key intermediate of (-)-paroxetine enabled by solvent-free heterogeneous organocatalysis
Otvos Sandor B; Kappe C Oliver; Pericas Miquel A; Pericas Miquel A; Kappe C Oliver
Chemical science (2019), 10 (48), 11141-11146 ISSN:2041-6520.
The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (-)-paroxetine is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free organocatalytic conjugate addition followed by a telescoped reductive amination-lactamization-amide/ester reduction sequence. Due to the efficient heterogeneous catalysts and the solvent-free or highly concentrated conditions applied, the flow method offers key advances in terms of productivity and sustainability compared to earlier batch approaches.
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(b) Ötvös, S. B.; Llanes, P.; Pericàs, M. A.; Kappe, C. O. Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut. Org. Lett. 2020, 22 (20), 8122– 8126, DOI: 10.1021/acs.orglett.0c03100
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16b
Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut
Otvos Sandor B; Kappe C Oliver; Otvos Sandor B; Kappe C Oliver; Llanes Patricia; Pericas Miquel A; Pericas Miquel A
Organic letters (2020), 22 (20), 8122-8126 ISSN:.
The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type addition facilitated by a polystyrene-supported heterogeneous organocatalyst under neat conditions followed by in situ-generated performic acid-mediated aldehyde oxidation. Simple access to valuable optically active substances is provided with key advances in terms of productivity and sustainability compared to those of previous batch approaches.
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(c) Nagy, B. S.; Llanes, P.; Pericas, M. A.; Kappe, C. O.; Ötvös, S. B. Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant. Org. Lett. 2022, 24 (4), 1066– 1071, DOI: 10.1021/acs.orglett.1c04300
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16c
Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence using in Situ-Generated Persulfuric Acid as Oxidant
Nagy, Bence S.; Llanes, Patricia; Pericas, Miquel A.; Kappe, C. Oliver; Oetvoes, Sandor B.
Organic Letters (2022), 24 (4), 1066-1071CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asym. conjugate addn.-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group redn. and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.
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Selected references:
(a) Bosset, C.; Angibaud, P.; Stanfield, I.; Meerpoel, L.; Berthelot, D.; Guérinot, A.; Cossy, J. Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans. J. Org. Chem. 2015, 80 (24), 12509– 12525, DOI: 10.1021/acs.joc.5b02371
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17a
Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans
Bosset, Cyril; Angibaud, Patrick; Stanfield, Ian; Meerpoel, Lieven; Berthelot, Didier; Guerinot, Amandine; Cossy, Janine
Journal of Organic Chemistry (2015), 80 (24), 12509-12525CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
An iron-catalyzed cyclization of hydroxy allylic derivs. into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodn. equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.
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(b) Couty, S.; Meyer, C.; Cossy, J. Gold-Catalyzed Cycloisomerizations of Ene-Ynamides. Tetrahedron 2009, 65 (9), 1809– 1832, DOI: 10.1016/j.tet.2008.10.108
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17b
Gold-catalyzed cycloisomerizations of ene-ynamides
Couty, Sylvain; Meyer, Christophe; Cossy, Janine
Tetrahedron (2009), 65 (9), 1809-1832CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
The gold-catalyzed cycloisomerizations of 1,6-ene-ynamides proceed under mild conditions and lead to cyclobutanones from terminal or trimethylsilyl substituted ynamides, or to carbonyl compds. bearing a 2,3-methanopyrrolidine subunit from substrates possessing a propargylic alc. moiety. High diastereoselectivities are obsd. with 1,6-ene-ynamides having a stereocenter at the α or β position of the nitrogen atom.
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(c) Lee, Y.; Shabbir, S.; Jeong, Y.; Ban, J.; Rhee, H. Formal Synthesis of Fesoterodine by Acid-Facilitated Aromatic Alkylation. Bull. Korean Chem. Soc. 2015, 36 (12), 2885– 2889, DOI: 10.1002/bkcs.10592
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17c
Formal Synthesis of Fesoterodine by Acid-Facilitated Aromatic Alkylation
Lee, Youngeun; Shabbir, Saira; Jeong, Yuri; Ban, Jaeyoung; Rhee, Hakjune
Bulletin of the Korean Chemical Society (2015), 36 (12), 2885-2889CODEN: BKCSDE; ISSN:0253-2964. (Wiley-VCH Verlag GmbH & Co. KGaA)
The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzaldehyde from Et benzoylacetate by Friedel-Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the redn. of the ketoester to a 1,3-diol, diisopropylamine substitution, and Friedel-Crafts alkylation, followed by redn. and chiral resoln.
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(d) Fernandes, A. A. G.; Leonarczyk, I. A.; Ferreira, M. A. B.; Dias, L. C. Diastereoselectivity in the Boron Aldol Reaction of α-Alkoxy and α,β-Bis-Alkoxy Methyl Ketones. Org. Biomol. Chem. 2019, 17 (12), 3167– 3180, DOI: 10.1039/C9OB00358D
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17d
Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones
Fernandes, Alessandra A. G.; Leonarczyk, Ives A.; Ferreira, Marco A. B.; Dias, Luiz Carlos
Organic & Biomolecular Chemistry (2019), 17 (12), 3167-3180CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
In this work, using DFT calcns., we investigated the 1,4 and 1,5 asym. induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy Me ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theor. calcns. revealed the origins of the 1,4 asym. induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.
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Some reviews about green solvents:
(a) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice. Chem. Soc. Rev. 2010, 39 (1), 301– 312, DOI: 10.1039/B918763B
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18a
Green Chemistry: Principles and Practice
Anastas, Paul; Eghbali, Nicolas
Chemical Society Reviews (2010), 39 (1), 301-312CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. Green Chem. is a relatively new emerging field that strives to work at the mol. level to achieve sustainability. The field has received widespread interest in the past decade due to its ability to harness chem. innovation to meet environmental and economic goals simultaneously. Green Chem. has a framework of a cohesive set of Twelve Principles, which have been systematically surveyed in this crit. review. This article covers the concepts of design and the scientific philosophy of Green Chem. with a set of illustrative examples. Future trends in Green Chem. are discussed with the challenge of using the Principles as a cohesive design system (93 refs.).
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(b) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 Selection Guide of Classical- and Less Classical-Solvents. Green Chem. 2016, 18 (1), 288– 296, DOI: 10.1039/C5GC01008J
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18b
CHEM21 selection guide of classical- and less classical-solvents
Prat, Denis; Wells, Andy; Hayler, John; Sneddon, Helen; McElroy, C. Robert; Abou-Shehada, Sarah; Dunn, Peter J.
Green Chemistry (2016), 18 (1), 288-296CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
A selection guide of common solvents has been elaborated, based on a survey of publically available solvent selection guides. In order to rank less classical solvents, a set of Safety, Health and Environment criteria is proposed, aligned with the Global Harmonized System (GHS) and European regulations. A methodol. based on a simple combination of these criteria gives an overall preliminary ranking of any solvent. This enables in particular a simplified greenness evaluation of bio-derived solvents.
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For a review about dioxiranes, see:
(a) Murray, R. W. Dioxiranes. Chem. Rev. 1989, 89 (5), 1187– 1201, DOI: 10.1021/cr00095a013
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19a
Chemistry of dioxiranes. 12. Dioxiranes
Murray, Robert W.
Chemical Reviews (Washington, DC, United States) (1989), 89 (5), 1187-201CODEN: CHREAY; ISSN:0009-2665.
A review with >70 refs.
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For references related to the use of DMDO in flow, see:
(b) Ahlqvist, G. P.; Burke, E. G.; Johnson, J. A.; Jamison, T. F. Continuous Dimethyldioxirane Generation for Polymer Epoxidation. Polym. Chem. 2021, 12 (4), 489– 493, DOI: 10.1039/D0PY01676D
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19b
Continuous dimethyldioxirane generation for polymer epoxidation
Ahlqvist, Grace P.; Burke, Eileen G.; Johnson, Jeremiah A.; Jamison, Timothy F.
Polymer Chemistry (2021), 12 (4), 489-493CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
Post-polymn. modification of commodity polymers yields new applications for materials already produced industrially. Incorporation of small amts. of epoxides into unsatd. polymers such as polybutadiene expands their use for grafting and compatibilization applications, but controlled epoxidn. of these polymers in a safe, scalable manner presents a challenge. Herein we describe the development of a reactor for the continuous flow generation and use of dimethyldioxirane (DMDO) and its application to the low-level epoxidn. of unsatd. polymers. A continuous stirred tank reactor (CSTR) prevents reactor clogging by allowing solid ppts. to settle, enabling the pumping of a homogeneous soln. of oxidant. Modification of relative concns., flow rates, and temps. achieves variable epoxidn. levels. This method has been demonstrated on gram scale.
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(c) Cossar, P. J.; Baker, J. R.; Cain, N.; McCluskey, A. In Situ Epoxide Generation by Dimethyldioxirane Oxidation and the Use of Epichlorohydrin in the Flow Synthesis of a Library of β-Amino Alcohols. R. Soc. Open Sci. 2018, 5, 171190, DOI: 10.1098/rsos.171190
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19c
In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols
Cossar, Peter J.; Baker, Jennifer R.; Cain, Nicholas; McCluskey, Adam
Royal Society Open Science (2018), 5 (4), 171190/1-171190/22CODEN: RSOSAV; ISSN:2054-5703. (Royal Society)
The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcs. The limitation was encountered in the prodn. of analogs of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol was a potential antibiotic lead. The in-situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidn. abrogates this limitation and afforded facile accessed to structurally diverse β-amino alcs. Comp.1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol was readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in-situ generation of DMDO, with olefin epoxidn. in typically good yields and a flow mediated ring opening aminolysis to form an expanded library of β-amino alcs., resulting in modest to excellent yields. Alternatively flow coupling of epichlorohydrin with phenols (22%-89%) and a Bi(OTf)3 catalyzed microwave ring opening with amines afforded a select range of β-amino alcs., but with lower levels of aminolysis regiocontrol than the sequential flow approach.
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Recent references about peracid generation in flow:
(a) Nagy, B. S.; Fu, G.; Hone, C. A.; Kappe, C. O.; Ötvös, S. B. Harnessing a Continuous-Flow Persulfuric Acid Generator for Direct Oxidative Aldehyde Esterifications. ChemSusChem 2023, 16 (2), e2022018, DOI: 10.1002/cssc.202201868
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There is no corresponding record for this reference.
(b) Prieschl, M.; Ötvös, S. B.; Kappe, C. O. Sustainable Aldehyde Oxidations in Continuous Flow Using in Situ-Generated Performic Acid. ACS Sustain. Chem. Eng. 2021, 9 (16), 5519– 5525, DOI: 10.1021/acssuschemeng.1c01668
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There is no corresponding record for this reference.
21
Selected examples about enantioselective allylboration and related reactions:
(a) Yang, X.; Pang, S.; Cheng, F.; Zhang, Y.; Lin, Y.-W.; Yuan, Q.; Zhang, F.-L.; Huang, Y.-Y. Enantioselective Synthesis of 1,3-Disubstituted 1,3- Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid. J. Org. Chem. 2017, 82 (19), 10388– 10397, DOI: 10.1021/acs.joc.7b01856
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21a
Enantioselective Synthesis of 1,3-Disubstituted 1,3-Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid
Yang, Xing; Pang, Shuai; Cheng, Feng; Zhang, Yue; Lin, Ya-Wei; Yuan, Quan; Zhang, Fang-Lin; Huang, Yi-Yong
Journal of Organic Chemistry (2017), 82 (19), 10388-10397CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The first chiral Bronsted acid-catalyzed asym. cascade allylboration/oxo-Michael reaction between o-formyl chalcones and allylboronate has been successfully discovered, which afforded chiral 1,3-disubstituted 1,3-dihydroisobenzofurans, e.g. I, with a yield, diastereoselective ratio (dr) and enantioselective excess (ee) up to 94%, 2.5:1, and 98%, resp. In addn., 2,3-dienylboronic pinacol ester was also applied into this cascade reaction with good catalytic results.
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(b) Jain, P.; Wang, H.; Houk, K. N.; Antilla, J. C. Brønsted Acid Catalyzed Asymmetric Propargylation of Aldehydes. Angew. Chem., Int. Ed. 2012, 51 (6), 1391– 1394, DOI: 10.1002/anie.201107407
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21b
Bronsted acid-catalyzed asymmetric propargylation of aldehydes
Jain, Pankaj; Wang, Hao; Houk, Kendall N.; Antilla, Jon C.
Angewandte Chemie, International Edition (2012), 51 (6), 1391-1394, S1391/1-S1391/41CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A Bronsted acid-catalyzed propargylation of aldehydes with allenylboronate is described. Corresponding homopropargylic alcs. were obtained using this methods.
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(c) Wang, M.; Khan, S.; Miliordos, E.; Chen, M. Enantioselective Allenylation of Aldehydes via Brønsted Acid Catalysis. Adv. Synth. Catal. 2018, 360 (23), 4634– 4639, DOI: 10.1002/adsc.201801080
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21c
Enantioselective Allenylation of Aldehydes via Bronsted Acid Catalysis
Wang, Mengzhou; Khan, Shahriar; Miliordos, Evangelos; Chen, Ming
Advanced Synthesis & Catalysis (2018), 360 (23), 4634-4639CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
An enantioselective allenylation of aldehydes catalyzed by a chiral, nonracemic phosphoric acid was reported. Under the developed conditions, 1,1'-disubstituted allenic alcs. were obtained in 64-98% yields with 88-99% ee. Computational studies were conducted to probe the origin of asym. induction. Mechanistic studies suggest that the pinacol moiety of the propargylboronate is crit. to the enantioselectivity of the reaction that was supported by exptl. data.
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Treiber, A. Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation. J. Org. Chem. 2002, 67 (21), 7261– 7266, DOI: 10.1021/jo0202177
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22
Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation
Treiber, Alexander
Journal of Organic Chemistry (2002), 67 (21), 7261-7266CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
The oxidn. of thiophene (1) with peracids in a strongly acidic environment yielded thiophen-2-one (4) as the product of an apparent direct hydroxylation of the thiophene arom. ring together with the anticipated thiophene-S-oxide dimers as the main products. Formation of the latter dimers can be rationalized in a straightforward manner by initial oxidn. at the sulfur atom of thiophene (1) to yield thiophene-S-oxide followed by subsequent dimerization in a Diels-Alder type reaction. Trapping expts. in the presence of a competing dienophile indicated that thiophen-2-one (4) did not originate from the monomeric thiophene-S-oxide but was the product of an independent reaction pathway. The extent of thiophen-2-one (4) formation correlated with the acidity of the reaction medium and was suppressed in the presence of water, the latter presumably acting as a competing base. As evidenced by the use of 2,5-dideuterated thiophene (1-D), its mechanism of formation involved a 1,2-hydride shift, a feature commonly described in the peracid-mediated epoxidn. of arom. hydrocarbons and indicative for the occurrence of cationic intermediates. In agreement with all these observations we propose a mechanism involving initial protonation of thiophene followed by nucleophilic attack of the peracid in position 2 of the thiophene ring. Intramol. epoxidn. may lead to the formation of thiophene 2,3-epoxide as a highly reactive intermediate that then undergoes heterolytic ring opening and a 1,2-hydride shift to yield thiophen-2-one (4) after a final, acid-catalyzed, isomerization of the double bond.
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23
Gamedze, M. P.; Maseko, R. B.; Chigondo, F.; Nkambule, C. M. Serendipitous Synthesis of 3-Hydroxy Tetrahydrofurans from Tin Catalyzed Sulfonylation of Acyclic 1,2,4-Triols. Tetrahedron Lett. 2012, 53 (44), 5929– 5932, DOI: 10.1016/j.tetlet.2012.08.110
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23
Serendipitous synthesis of 3-hydroxytetrahydrofurans from tin catalyzed sulfonylation of acyclic 1,2,4-triols
Gamedze, Makhosazana P.; Maseko, Rejoice B.; Chigondo, Fidelis; Nkambule, Comfort M.
Tetrahedron Letters (2012), 53 (44), 5929-5932CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu2SnO (5 mol %) results in cyclization and the formation of 3-hydroxytetrahydrofurans (56-85%) while the anti-1,2,4-triols react to give C1-O-sulfonyl derivs. in good yields (66-83%) and the cyclization product in poor yield (5-12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary hydroxyl followed by an intramol. tin acetal rearrangement to a 1,3-stannylene which then undergoes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.
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24
Maestro, A.; Nagy, B. S.; Ötvös, S. B.; Kappe, C. O. A Telescoped Continuous Flow Enantioselective Process to Access Chiral Intermediates of Atomoxetine, Dapoxetine, Duloxetine and Ezetimibe. chemRxiv 2023, DOI: 10.26434/chemrxiv-2023-93llx
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Cite this: J. Org. Chem. 2023, 88, 21, 15523–15529

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https://doi.org/10.1021/acs.joc.3c02040

Published October 16, 2023

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Abstract
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Figure 1
Figure 1. Relevant drugs synthesized from 1-aryl-1,3-diols 1.
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Scheme 1
Scheme 1. (A) CPAs Used in the Enantioselective Allylboration of Aldehydes, (B) Proposed Synthetic Route to 1-Aryl-1,3-diols, and (C) Continuous Flow Setup Used for the Allylboration Step
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Scheme 2
Scheme 2. (A) Optimal Setup for the Telescoped Asymmetric Allylboration/Epoxidation Process, (B) Yields (blue) and ee (red) of 5a over Time (HPLC), and (C) Chiral Intermediates for the Synthesis of APIs
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Scheme 3
Scheme 3. Formal Synthesis of 1-Aryl-1,3-diols 1
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References
This article references 24 other publications.
1. 1
  Vardanyan, R.; Hruby, V. Synthesis of Best-Seller Drugs; Elsevier, 2016. DOI: 10.1016/C2012-0-07004-4
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2. 2
  Goyal, S.; Thakur, A.; Sharma, R.; Gangar, M.; Patel, B.; Nair, V. A. Stereoselective Alkylation of Imines and Its Application towards the Synthesis of β-Lactams. Asian J. Org. Chem. 2016, 5 (11), 1359– 1367, DOI: 10.1002/ajoc.201600339
  2
  Stereoselective alkylation of imines and its application towards the synthesis of β-lactams
  Goyal, Sandeep; Thakur, Anamika; Sharma, Ratnesh; Gangar, Mukesh; Patel, Bhautikkumar; Nair, Vipin A.
  Asian Journal of Organic Chemistry (2016), 5 (11), 1359-1367CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)
  (S)-4-Isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one was evaluated as a chiral auxiliary for asym. acetate and propionate Mannich-type reactions, by generation of the titanium enolates, affording excellent yields and stereoselectivities. The application of the auxiliary was exemplified in the stereoselective synthesis of ezetimibe (I).
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3. 3
  Khatik, G. L.; Sharma, R.; Kumar, V.; Chouhan, M.; Nair, V. A. Stereoselective Synthesis of (S)-Dapoxetine: A Chiral Auxiliary Mediated Approach. Tetrahedron Lett. 2013, 54 (45), 5991– 5993, DOI: 10.1016/j.tetlet.2013.08.059
  3
  Stereoselective synthesis of (S)-dapoxetine: A chiral auxiliary mediated approach
  Khatik, Gopal L.; Sharma, Ratnesh; Kumar, Varun; Chouhan, Mangilal; Nair, Vipin A.
  Tetrahedron Letters (2013), 54 (45), 5991-5993CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  An imidazolidin-2-one chiral auxiliary mediated acetate aldol reaction was explored in the enantioselective synthesis of (S)-dapoxetine, a selective serotonin reuptake inhibitor (SSRI). The diastereoselective aldol adduct was transformed to highly enantiopure (S)-dapoxetine with overall good yield.
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4. 4
  Xu, C.; Yuan, C. Candida Rugosa Lipase-Catalyzed Kinetic Resolution of β-Hydroxy- β-Arylpropionates and δ-Hydroxy-δ-Aryl-β-Oxo-Pentanoates. Tetrahedron 2005, 61 (8), 2169– 2186, DOI: 10.1016/j.tet.2004.12.059
  4
  Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy-β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates
  Xu, Chengfu; Yuan, Chengye
  Tetrahedron (2005), 61 (8), 2169-2186CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)
  A simple and convenient method was reported for the prepn. of optically active β-hydroxy-β-arylpropionates I (R1 = Ph, 4-MeOC6H4, 4-O2NC6H4, 2,4-Cl2C6H3, 2-furyl, etc.; R2 = Me, Et, Me2CH, n-Bu), δ-hydroxy-δ-aryl-β-oxo-pentanoates II and their butyryl derivs. via Candida Rugosa lipase-catalyzed hydrolysis. The optically active products were used as precursors in synthesis of some chiral pharmaceuticals, such as fluoxetine and tomoxetine, and polysubstituted dihydropyrans.
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5. 5
  Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J. P.; Ben Hassine, B.; Genêt, J. P. Enantioselective Hydrogenation of β-Keto Esters Using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications. Adv. Synth. Catal. 2003, 345 (1–2), 261– 274, DOI: 10.1002/adsc.200390021
  5
  Enantioselective hydrogenation of β-keto esters using chiral diphosphine-ruthenium complexes: Optimization for academic and industrial purposes and synthetic applications
  Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J. P.; Ben Hassine, B.; Genet, J. P.
  Advanced Synthesis & Catalysis (2003), 345 (1+2), 261-274CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compds. Using a simple and straightforward in situ catalyst prepn., the conditions were optimized using mol. hydrogen. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atm. and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asym. hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.
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6. 6
  Selected examples related to transition-metal catalysis:
  (a) Ji, E.; Meng, H.; Zheng, Y.; Ramadoss, V.; Wang, Y. Copper-Catalyzed Stereospecific Hydroboration of Internal Allylic Alcohols. Eur. J. Org. Chem. 2019, 2019 (44), 7367– 7371, DOI: 10.1002/ejoc.201901435
  6a
  Copper-Catalyzed Stereospecific Hydroboration of Internal Allylic Alcohols
  Ji, Enhui; Meng, Haiwen; Zheng, Yue; Ramadoss, Velayudham; Wang, Yahui
  European Journal of Organic Chemistry (2019), 2019 (44), 7367-7371CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An effective Cu-catalyzed stereospecific hydroboration of aliph. and arom. 1,1,2-trisubstituted internal allylic alcs. was reported. This reaction proceeded via a silyl ether transient protection of allylic alcs. and subsequent stereospecific hydroboration. Followed by an oxidative workup, an array of acyclic, cyclic and heterocyclic 1,3-diols was synthesized in good to excellent yields with good functional group tolerance and excellent diastereomeric ratios (> 20:1).
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  (b) Fernández, E.; Pietruszka, J.; Frey, W. Palladium-Catalyzed Synthesis of Enantiomerically Pure α-Substituted Allylboronic Esters and Their Addition to Aldehydes. J. Org. Chem. 2010, 75 (16), 5580– 5589, DOI: 10.1021/jo1008959
  6b
  Palladium-catalyzed synthesis of enantiomerically pure α-substituted allylboronic esters and their addition to aldehydes
  Fernandez, Enrique; Pietruszka, Joerg; Frey, Wolfgang
  Journal of Organic Chemistry (2010), 75 (16), 5580-5589CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Tartrate-derived boronic esters I can be subjected to palladium-catalyzed carbonyl allylations with SnCl2 to obtain enantiomerically pure α-substituted allylboronic esters II (R = Ph, 3,4-C6H4F2, C6F5, furfural, CO2Et, PhCHCH, PhCH2CH2, iPr, iBu, c-C6H11, H) and III (R = C6F5, furfural, CO2Et, PhCHCH, iPr, c-C6H11, H). The reaction proceeds regioselectively and with high, simple diastereoselectivity to form anti-products. Their addn. to aldehydes yields enantiomerically enriched homoallylic alcs. e. g. IV. Synthesis, characterization, and a mechanistic rational is presented here.
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  (c) Peng, F.; Hall, D. G. Preparation of α-Substituted Allylboronates by Chemoselective Iridium-Catalyzed Asymmetric Allylic Alkylation of 1-Propenylboronates. Tetrahedron Lett. 2007, 48 (18), 3305– 3309, DOI: 10.1016/j.tetlet.2007.02.124
  6c
  Preparation of α-substituted allylboronates by chemoselective iridium-catalyzed asymmetric allylic alkylation of 1-propenylboronates
  Peng, Feng; Hall, Dennis G.
  Tetrahedron Letters (2007), 48 (18), 3305-3309CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  Chiral α-substituted allylic boronates are attractive reagents that add to aldehydes with very high stereoselectivity. This study examd. the feasibility of an improved method of prepn. based on the catalytic asym. allylic alkylation of simple 3-hydroxy-1-propenylboronate derivs. with malonate anions. Whereas palladium catalysis failed in promoting the desired process, iridium catalysis led to a regioselective formation of the desired, branched allylboronates with up to 84% ee using a chiral monophosphoramidite ligand. This allylation reagent adds to aldehydes with high chirality transfer. A diastereoselective alkoxycyclization on the resulting homoallylic alcs. allows a sepn. of the epimeric E/Z isomers.
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  (d) Wang, S.; Rodríguez-Escrich, C.; Fan, X.; Pericàs, M. A. A Site Isolation-Enabled Organocatalytic Approach to Enantiopure γ-Amino Alcohol Drugs. Tetrahedron 2018, 74 (29), 3943– 3946, DOI: 10.1016/j.tet.2018.04.022
  6d
  A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs
  Wang, Shoulei; Rodriguez-Escrich, Carles; Fan, Xinyuan; Pericas, Miquel A.
  Tetrahedron (2018), 74 (29), 3943-3946CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  An efficient approach was developed for enhancing the reactivity of benzaldehyde in the cross-aldol reaction with acetaldehyde resulting from the deoligomerization of paraldehyde. The tandem process was mediated by the dual polymer supported catalytic system, which operated under site isolation conditions in a recyclable manner. The strategy reported herein involved temporary conversion of benzaldehyde into η6-benzaldehyde Cr(CO)3 circumvented the limitations. Asym. synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrated the benefits of this strategy.
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  Selected examples of biocatalysis:
  (e) Chênevert, R.; Fortier, G.; Rhlid, R. B. Asymmetric Synthesis of Both Enantiomers of Fluoxetine via Microbiological Reduction of Ethyl Benzoylacetate. Tetrahedron 1992, 48 (33), 6769– 6776, DOI: 10.1016/S0040-4020(01)89866-5
  6e
  Asymmetric synthesis of both enantiomers of fluoxetine via microbiological reduction of ethyl benzoylacetate
  Chenevert, Robert; Fortier, Genevieve; Bel Rhlid, Rachid
  Tetrahedron (1992), 48 (33), 6769-76CODEN: TETRAB; ISSN:0040-4020.
  Microbiol. redn. of Et benzoylacetate by bakers' yeast (Saccharomyces cerevisiae), Beauveria sulfurescens or Geotrichum candidum afforded Et (S)-3-hydroxy-3-phenylpropionate (I) in high optical yield. This enantiomerically pure alc. was converted into both enantiomers of fluoxetine II. Thus, I reacted with MeNH2 and 4-ClC6H4CF3 to give (S)-II. Treating I with 4-HOC6H4CF3 and MeNH2 gave (R)-II. The product resulting from the bakers' yeast redn. had ee values (87-93%) lower than the 100% value erroneously attributed in earlier studies.
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  (f) Ramos, A. de S.; Ribeiro, J. B.; Vazquez, L.; Fiaux, S. B.; Leite, S. G. F.; Ramos, M. da C. K. V.; Neto, F. R. de A.; Antunes, O. A. C. Immobilized Microorganisms in the Reduction of Ethyl Benzoylacetate. Tetrahedron Lett. 2009, 50 (52), 7362– 7364, DOI: 10.1016/j.tetlet.2009.10.068
  6f
  Immobilized microorganisms in the reduction of ethyl benzoylacetate
  Ramos, Aline de Souza; Ribeiro, Joyce Benzaquem; Vazquez, Leonardo; Fiaux, Sorele Batista; Leite, Selma Gomes Ferreira; Ramos, Maria da Conceicao Klaus V.; Radler de Aquino Neto, Francisco; Antunes, O. A. C.
  Tetrahedron Letters (2009), 50 (52), 7362-7364CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  The enantioselective redn. of Et benzoylacetate (EBA) into Et (S)-3-hydroxy-3-phenylpropanoate (S-HPPE) by nine yeast strains and three filamentous fungi strains is described. The conversion obtained was in the range 0-89% and the enantiomeric excess was 100% in many cases. Conversion levels were higher when the redn. was performed with microorganisms immobilized in calcium alginate and enantioselectivity remained excellent. Some reaction's conditions of bioredn. by immobilized cells of Rhodotorula rubra were studied using a 25-2 fractional factorial design.
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7. 7
  Selected examples:
  (a) Qiao, Y.; Chen, Q.; Lin, S.; Ni, B.; Headley, A. D. Organocatalytic Direct Asymmetric Crossed-Aldol Reactions of Acetaldehyde in Aqueous Media. J. Org. Chem. 2013, 78 (6), 2693– 2696, DOI: 10.1021/jo302442g
  7a
  Organocatalytic Direct Asymmetric Crossed-Aldol Reactions of Acetaldehyde in Aqueous Media
  Qiao, Yupu; Chen, Qiankun; Lin, Sirong; Ni, Bukuo; Headley, Allan D.
  Journal of Organic Chemistry (2013), 78 (6), 2693-2697CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A new diarylprolinol-based catalyst I, which contains a dioctylamino group, in the presence of a newly developed ionic liq. supported (ILS) benzoic acid II as cocatalyst, is shown to be an effective catalytic system for the asym. direct crossed-aldol reaction of acetaldehyde in aq. media using brine. For the reactions studied, the catalyst loading could be reduced to 5 mol %; high yields (up to 97%) and high enantioselectivities (up to 92% ee) were also achieved for a wide variety of arom. aldehydes.
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  (b) Wang, Y.; Huang, G.; Hu, S.; Jin, K.; Wu, Y.; Chen, F. Enantioselective β-Hydroxy Thioesters Formation via Decarboxylative Aldol Reactions of Malonic Acid Half Thioesters with Aldehydes Promoted by Chloramphenicol Derived Sulfonamides. Tetrahedron 2017, 73 (34), 5055– 5062, DOI: 10.1016/j.tet.2017.05.066
  7b
  Enantioselective β-hydroxy thioesters formation via decarboxylative aldol reactions of malonic acid half thioesters with aldehydes promoted by chloramphenicol derived sulfonamides1
  Wang, Yafeng; Huang, Guanxin; Hu, Sha; Jin, Kaijun; Wu, Yan; Chen, Fener
  Tetrahedron (2017), 73 (34), 5055-5062CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  A highly enantioselective synthesis of chiral β-hydroxy thioesters that uses a decarboxylative aldol reaction of malonic acid half thioesters and aldehydes catalyzed by a chloramphenicol base-derived bifunctional organocatalyst is reported. The resulting chiral β-hydroxy thioesters were obtained in high yields (up to 82%) with good to excellent enantioselectivities (up to 94% ee). The synthetic application of the methodol. is illustrated by the asym. synthesis of the selective serotonin reuptake inhibitor dapoxetine.
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  (c) Schreyer, L.; Kaib, P. S. J.; Wakchaure, V. N.; Obradors, C.; Properzi, R.; Lee, S.; List, B. Confined Acids Catalyze Asymmetric Single Aldolizations of Acetaldehyde Enolates. Science 2018, 362, 216– 219, DOI: 10.1126/science.aau0817
  7c
  Confined acids catalyze asymmetric single aldolizations of acetaldehyde enolates
  Schreyer, Lucas; Kaib, Philip S. J.; Wakchaure, Vijay N.; Obradors, Carla; Properzi, Roberta; Lee, Sunggi; List, Benjamin
  Science (Washington, DC, United States) (2018), 362 (6411), 216-219CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Reactions that form a product with the same reactive functionality as that of one of the starting compds. frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert-butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliph. and arom. acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-mol. catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mol % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.
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8. 8
  Selected examples:
  (a) Khatik, G. L.; Khurana, R.; Kumar, V.; Nair, V. A. Asymmetric Induction by (S)-4-Isopropyl-1-Phenylimidazolidin-2-Thione in Titanium-Mediated Aldol Reactions and Its Application in Enantioselective Synthesis of (R)-Baclofen. Synthesis 2011, 19, 3123– 3132, DOI: 10.1055/s-0030-1260187
  There is no corresponding record for this reference.
  (b) Fernandes, A. A. G.; Leonarczyk, I. A.; Ferreira, M. A. B.; Dias, L. C. Diastereoselectivity in the Boron Aldol Reaction of α-Alkoxy and α,β-Bis-Alkoxy Methyl Ketones. Org. Biomol. Chem. 2019, 17 (12), 3167– 3180, DOI: 10.1039/C9OB00358D
  8b
  Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones
  Fernandes, Alessandra A. G.; Leonarczyk, Ives A.; Ferreira, Marco A. B.; Dias, Luiz Carlos
  Organic & Biomolecular Chemistry (2019), 17 (12), 3167-3180CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  In this work, using DFT calcns., we investigated the 1,4 and 1,5 asym. induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy Me ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theor. calcns. revealed the origins of the 1,4 asym. induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.
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  (c) Le Sann, C.; Muñoz, D. M.; Saunders, N.; Simpson, T. J.; Smith, D. I.; Soulas, F.; Watts, P.; Willis, C. L. Assembly Intermediates in Polyketide Biosynthesis: Enantioselective Syntheses of b-Hydroxycarbonyl Compounds. Org. Biomol. Chem. 2005, 3, 1719– 1728, DOI: 10.1039/b419492f
  8c
  Assembly intermediates in polyketide biosynthesis: enantioselective syntheses of β-hydroxycarbonyl compounds
  Le Sann, Christine; Munoz, Dulce M.; Saunders, Natalie; Simpson, Thomas J.; Smith, David I.; Soulas, Florilene; Watts, Paul; Willis, Christine L.
  Organic & Biomolecular Chemistry (2005), 3 (9), 1719-1728CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  A versatile approach for the enantioselective synthesis of functionalized β-hydroxy N-acetylcysteamine thiol esters, such as I, has been developed which allows the facile incorporation of isotopic labels. It has been shown that a remarkable reversal of selectivity occurs in the titanium mediated aldol reaction of acyloxazolidinone II using either (S)- or (R)-tert-butyldimethylsilyloxybutanal. The aldol products are valuable intermediates in the synthesis of 4-hydroxy-6-substituted δ-lactones.
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9. 9
  Some reviews:
  (a) Fulgheri, T.; Della Penna, F.; Baschieri, A.; Carlone, A. Advancements in the Recycling of Organocatalysts: From Classical to Alternative Approaches. Curr. Opin. Green Sustain. Chem. 2020, 25, 100387, DOI: 10.1016/j.cogsc.2020.100387
  There is no corresponding record for this reference.
  (b) Susam, Z. D.; Tanyeli, C. Recyclable Organocatalysts in Asymmetric Synthesis. Asian J. Org. Chem. 2021, 10 (6), 1251– 1266, DOI: 10.1002/ajoc.202100165
  9b
  Recyclable Organocatalysts in Asymmetric Synthesis
  Susam, Zeynep Dilsad; Tanyeli, Cihangir
  Asian Journal of Organic Chemistry (2021), 10 (6), 1251-1266CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This survey summarizes the studies that have been done so far to enlight the subject of recyclable organocatalysts for the synthesis of asym. compds. and headlights cover-up silica supported organocatalysts, polymer supported organocatalysts, magnetic nanoparticle supported organocatalysts, gold nanoparticle supported organocatalysts, ionic liqs. organocatalysts and fluorous supported organocatalysts.
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10. 10
  Some recent reviews:
  (a) del Corte, X.; Martínez de Marigorta, E.; Palacios, F.; Vicario, J.; Maestro, A. An Overview of the Applications of Chiral Phosphoric Acid Organocatalysts in Enantioselective Additions to C = O and C = N Bonds. Org. Chem. Front. 2022, 9 (22), 6331– 6399, DOI: 10.1039/D2QO01209J
  10a
  An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to C:O and C:N bonds
  del Corte, Xabier; Martinez de Marigorta, Edorta; Palacios, Francisco; Vicario, Javier; Maestro, Aitor
  Organic Chemistry Frontiers (2022), 9 (22), 6331-6399CODEN: OCFRA8; ISSN:2052-4129. (Royal Society of Chemistry)
  A review. Chiral phosphoric acids (CPAs) have been used as efficient organocatalysts since the first examples were reported 18 years ago by Akiyama and Terada. Although they were originally developed for enantioselective addns. to imines, a wide reaction scope has been demonstrated using this type of catalyst. In this review, the known applications of CPA for enantioselective addns. to CO and CN bonds are covered.
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  (b) Pálvölgyi, Á. M.; Scharinger, F.; Schnürch, M.; Bica-Schröder, K. Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations. Eur. J. Org. Chem. 2021, 2021 (38), 5367– 5381, DOI: 10.1002/ejoc.202100894
  10b
  Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations
  Palvolgyi, Adam Mark; Scharinger, Fabian; Schnuerch, Michael; Bica-Schroder, Katharina
  European Journal of Organic Chemistry (2021), 2021 (38), 5367-5381CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Herein, recent developments in the field of organocatalytic asym. transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asym. catalysis relies on metal-free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asym. redn. of α,β-unsatd. carbonyl compds., imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asym. transfer hydrogenations.
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  (c) Xia, Z.-L.; Xu-Xu, Q.-F.; Zheng, C.; You, S.-L. Chiral Phosphoric Acid-Catalyzed Asymmetric Dearomatization Reactions. Chem. Soc. Rev. 2020, 49 (1), 286– 300, DOI: 10.1039/C8CS00436F
  10c
  Chiral phosphoric acid-catalyzed asymmetric dearomatization reactions
  Xia, Zi-Lei; Xu-Xu, Qing-Feng; Zheng, Chao; You, Shu-Li
  Chemical Society Reviews (2020), 49 (1), 286-300CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. The recent development of chiral phosphoric acid (CPA)-catalyzed asym. dearomatization reactions is reviewed. A wide array of electron-rich arenes (indoles, phenols, naphthols, benzothiophenes, benzofurans, etc.) and electron-poor arenes (pyridines, quinolines, isoquinolines, etc.) has been proved reactive towards various reaction partners in the presence of a CPA catalyst, enabling asym. dearomatization reactions that lead to structurally-diverse polycyclic mols. The reactions are grouped according to the roles of the arenes in the reactions (as nucleophiles or electrophiles) and the types of reaction partners. This review closes with a personal perspective on the dynamic research area of asym. dearomatization reactions by CPAs.
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11. 11
  Recent examples:
  (a) Lai, J.; Fianchini, M.; Pericas, M. A. Development of Immobilized Spinol-Derived Chiral Phosphoric Acids for Catalytic Continuous Flow Processes. Use in the Catalytic Desymmetrization of 3,3-Disubstituted Oxetanes. ACS Catal. 2020, 10 (24), 14971– 14983, DOI: 10.1021/acscatal.0c04497
  11a
  Development of Immobilized SPINOL-Derived Chiral Phosphoric Acids for Catalytic Continuous Flow Processes. Use in the Catalytic Desymmetrization of 3,3-Disubstituted Oxetanes
  Lai, Junshan; Fianchini, Mauro; Pericas, Miquel A.
  ACS Catalysis (2020), 10 (24), 14971-14983CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  A family of C2-sym. 1,1'-spirobiindane-7,7'-diol (SPINOL) derivs. contg. polymerizable styryl units has been prepd. through a highly convergent approach. Radical copolymn. of these monomers with styrene has allowed the synthesis of a family of immobilized SPINOL-derived chiral phosphoric acids (SPAs) where the combination of the restricted axial flexibility of the SPINOL units and the existence of extended and adaptable chiral walls adjacent to them leads to enhanced stereocontrol in catalytic processes. The optimal immobilized species (Cat f) brings about the catalytic desymmetrization of 3,3-disubstituted oxetanes in up to 90% yield with up to >99% enantioselectivity, exhibiting a very high recyclability (no decrease in conversion or enantioselectivity after 16, 16-h runs). To exploit these characteristics, a continuous flow process has been implemented and operated for the sequential prepn. of 17 diverse enantioenriched products. The suitability of the flow setup for gram scale prepns. (20 mmol scale), the stability of Cat f for long periods of time with intermittent use in flow, and its deactivation/reactivation by treatment with pyridine/hydrochloric acid in dioxane have been demonstrated. D. functional theory has been employed to provide a rational justification of the deep effect on enantioselectivity arising from the presence of sterically bulky substituents at the 6,6'-positions of the SPINOL unit. The main structural features of Cat f have subsequently been incorporated to the design of a simplified homogeneous analog available in a straightforward manner (Cat g) that performs the benchmark desymmetrization reaction with similar yields and enantioselectivities as Cat f, providing a convenient alternative for cases when single use in soln. is sought.
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  (b) Huang, X. Y.; Zheng, Q.; Zou, L. M.; Gu, Q.; Tu, T.; You, S. L. Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions. ACS Catal. 2022, 12 (8), 4545– 4553, DOI: 10.1021/acscatal.2c00397
  11b
  Hyper-Crosslinked Porous Chiral Phosphoric Acids: Robust Solid Organocatalysts for Asymmetric Dearomatization Reactions
  Huang, Xian-Yun; Zheng, Qingshu; Zou, Lei-Ming; Gu, Qing; Tu, Tao; You, Shu-Li
  ACS Catalysis (2022), 12 (8), 4545-4553CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  Knitting rigid arom. building blocks using external crosslinkers has been developed into an effective strategy for the synthesis of porous polymers in recent years. Here, the authors report the synthesis of porous chiral phosphoric acids by this strategy. Moreover, these porous chiral phosphoric acids were found to enable highly enantioselective dearomatization reactions. Remarkably, after being reused for 10 runs, no obvious loss in catalytic activity and selectivity was obsd. The features of high reactivity, selectivity, stability, and recyclability of these hyper-crosslinked porous chiral phosphoric acids are significant for practical catalyst design.
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  (c) Chen, X.; Jiang, H.; Li, X.; Hou, B.; Gong, W.; Wu, X.; Han, X.; Zheng, F.; Liu, Y.; Jiang, J.; Cui, Y. Chiral Phosphoric Acids in Metal–Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity. Angew. Chem., Int. Ed. 2019, 58 (41), 14748– 14757, DOI: 10.1002/anie.201908959
  11c
  Chiral Phosphoric Acids in Metal-Organic Frameworks with Enhanced Acidity and Tunable Catalytic Selectivity
  Chen, Xu; Jiang, Hong; Li, Xu; Hou, Bang; Gong, Wei; Wu, Xiaowei; Han, Xing; Zheng, Fanfan; Liu, Yan; Jiang, Jianwen; Cui, Yong
  Angewandte Chemie, International Edition (2019), 58 (41), 14748-14757CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Chiral phosphoric acids are incorporated into indium-based metal-org. frameworks (In-MOFs) by sterically preventing them from coordination. This concept leads to the synthesis of three chiral porous 3D In-MOFs with different network topologies constructed from three enantiopure 1,1'-biphenol-phosphoric acid derived tetracarboxylate linkers. More importantly, all the uncoordinated phosphoric acid groups are periodically aligned within the channels and display significantly enhanced acidity compared to the non-immobilized acids. This facilitates the Bronsted acid catalysis of asym. condensation/amine addn. and imine redn. The enantioselectivities can be tuned (up to >99% ee) by varying the substituents to achieve a nearly linear correlation with the concns. of steric bulky groups in the MOFs. DFT calcns. suggest that the framework provides a chiral confined microenvironment that dictates both selectivity and reactivity of chiral MOFs.
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  (d) Clot-Almenara, L.; Rodríguez-Escrich, C.; Osorio-Planes, L.; Pericas, M. A. Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes. ACS Catal. 2016, 6 (11), 7647– 7651, DOI: 10.1021/acscatal.6b02621
  11d
  Polystyrene-Supported TRIP: A Highly Recyclable Catalyst for Batch and Flow Enantioselective Allylation of Aldehydes
  Clot-Almenara, Lidia; Rodriguez-Escrich, Carles; Osorio-Planes, Laura; Pericas, Miquel A.
  ACS Catalysis (2016), 6 (11), 7647-7651CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  The widely applicable TRIP phosphoric acid catalyst I has been immobilized on polystyrene using a copolymn.-based strategy. The resin (PS-TRIP) has proven to be highly active and enantioselective in the asym. allylboration of aldehydes. Moreover, it has shown to be extremely robust, as it can be reused for 18 times, after which it still retained its activity. Lastly, to further prove the benefits of the immobilization, a continuous flow expt. spanning 28 h has been carried out with very high yields and ee's.
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  (e) Zhang, Y.; Zhang, Z.; Ma, S.; Jia, J.; Xia, H.; Liu, X. Hypercrosslinking Chiral Brønsted Acids into Porous Organic Polymers for Efficient Heterogeneous Asymmetric Organosynthesis. J. Mater. Chem. A 2021, 9 (45), 25369– 25373, DOI: 10.1039/D1TA07449K
  11e
  Hypercrosslinking chiral Bronsted acids into porous organic polymers for efficient heterogeneous asymmetric organosynthesis
  Zhang, Yuwei; Zhang, Zhenwei; Ma, Si; Jia, Ji; Xia, Hong; Liu, Xiaoming
  Journal of Materials Chemistry A: Materials for Energy and Sustainability (2021), 9 (45), 25369-25373CODEN: JMCAET; ISSN:2050-7496. (Royal Society of Chemistry)
  A construction strategy for directly immobilizing the axially chiral phosphoric acid into hypercrosslinked polymers by a one-pot Friedel-Crafts alkylation reaction was developed. The obtained chiral polymers have high porosity, excellent stability and tailorable catalytic centers, and display excellent activity, enantioselectivity and recyclability for asym. transfer hydrogenation.
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  (f) Li, S.; Zhang, J.; Chen, S.; Ma, X. Semi-Heterogeneous Asymmetric Organocatalysis: Covalent Immobilization of BINOL-Derived Chiral Phosphoric Acid (TRIP) to Polystyrene Brush Grafted on SiO2 Nanoparticles. J. Catal. 2022, 416, 139– 148, DOI: 10.1016/j.jcat.2022.10.021
  11f
  Semi-heterogeneous asymmetric organocatalysis: Covalent immobilization of BINOL-derived chiral phosphoric acid (TRIP) to polystyrene brush grafted on SiO2 nanoparticles
  Li, Shan; Zhang, Jianing; Chen, Shaoqi; Ma, Xuebing
  Journal of Catalysis (2022), 416 (), 139-148CODEN: JCTLA5; ISSN:0021-9517. (Elsevier Inc.)
  Reduced mass transfer and tedious immobilization of expensive chiral organocatalyst are two bottlenecks for the large-scale synthesis of optically active mols. in heterogeneous asym. organocatalysis. Here, a quasi-homogeneous organocatalysis is achieved by anchoring BINOL-derived phosphoric acid (TRIP) to polystyrene (PS) brush grafted on SiO2 nanoparticles via one-pot, effectively improving mass transfer due to the open stretching of TRIP-anchored PS brush in toluene. The PS brush enables TRIP to catalyze asym. allylation in significantly higher yields and enantioselectivities than PS-supported TRIP, and in slightly higher yields than homogeneous TRIP. The sparser grafting d. of PS brush is more conducive to the swelling of PS brush, leading to the faster mass transfer of reactants from the top to end of PS brush. Overall, the one-pot anchoring of TRIP to PS brush combines the advantages of homogeneous and heterogeneous organocatalysis, providing an ideal strategy for solving the two bottlenecks in heterogeneous asym. organocatalysis.
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  (g) Clot-Almenara, L.; Rodríguez-Escrich, C.; Pericàs, M. A. Desymmetrisation of: Meso -Diones Promoted by a Highly Recyclable Polymer-Supported Chiral Phosphoric Acid Catalyst. RSC Adv. 2018, 8 (13), 6910– 6914, DOI: 10.1039/C7RA13471A
  11g
  Desymmetrisation of meso-diones promoted by a highly recyclable polymer-supported chiral phosphoric acid catalyst
  Clot-Almenara, Lidia; Rodriguez-Escrich, Carles; Pericas, Miquel A.
  RSC Advances (2018), 8 (13), 6910-6914CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A polystyrene-supported BINOL-derived chiral phosphoric acid was applied to the desymmetrisation of meso-diones to produce enantioenriched cyclohexenones such as I [R = Me, Et, Ph, Bn, etc.;]. The catalytic resin has proven highly active and robust, giving rise to Hajos-Parrish or Wieland-Miescher type products in good yields and enantioselectivities, while allowing for extended recycling.
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12. 12
  Jain, P.; Antilla, J. C. Chiral Brønsted Acid-Catalyzed Allylboration of Aldehydes. J. Am. Chem. Soc. 2010, 132 (34), 11884– 11886, DOI: 10.1021/ja104956s
  12
  Chiral Bronsted Acid-Catalyzed Allylboration of Aldehydes
  Jain, Pankaj; Antilla, Jon C.
  Journal of the American Chemical Society (2010), 132 (34), 11884-11886CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  A new high-yielding and highly enantioselective chiral Bronsted acid-catalyzed allylboration of aldehydes RCHO (R = Ph, 4-ClC6H4, PhCH2, cyclohexyl, 2-thienyl, 1-naphthyl, etc.) with allyl pinacol boronate is described. The reaction is shown to be highly general, with a broad substrate scope that covers aryl, heteroaryl, α,β-unsatd., and aliph. aldehydes. The reaction conditions are also shown to be effective for the catalytic enantioselective crotylation of aldehydes. The high reactivity of the allylboronate is suggested to be due to protonation of the boronate oxygen by the chiral phosphoric acid catalyst.
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13. 13
  Hoffmann, S.; Seayad, A. M.; List, B. A Powerful Brønsted Acid Catalyst for the Organocatalytic Asymmetric Transfer Hydrogenation of Imines. Angew. Chem., Int. Ed. 2005, 44 (45), 7424– 7427, DOI: 10.1002/anie.200503062
  13
  A powerful Bronsted acid catalyst for the organocatalytic asymmetric transfer hydrogenation of imines
  Hoffmann, Sebastian; Seayad, Abdul Majeed; List, Benjamin
  Angewandte Chemie, International Edition (2005), 44 (45), 7424-7427CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A 1 mol% loading of a chiral binaphthalene phosphoric acid catalyst converts arom. and aliph. imines into the amines in high yields and enantioselectivities if treated with Hantzsch dihydropyridine.
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14. 14
  Some reviews:
  (a) Merad, J.; Lalli, C.; Bernadat, G.; Maury, J.; Masson, G. Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals. Chem. - Eur. J. 2018, 24 (16), 3925– 3943, DOI: 10.1002/chem.201703556
  14a
  Enantioselective Bronsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals
  Merad, Jeremy; Lalli, Claudia; Bernadat, Guillaume; Maury, Julien; Masson, Geraldine
  Chemistry - A European Journal (2018), 24 (16), 3925-3943CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The present report attempts to provide an overview of enantioselective total or formal syntheses designed around Bronsted acid-catalyzed transformations. To demonstrate the versatility of the reactions promoted and the diversity of the accessible motifs, this minireview draws a systematic parallel between methods and retrosynthetic anal. The manuscript is organized according to the main reaction types and the nature of newly-formed bonds.
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  (b) Hughes, D. L. Highlights of the Recent Patent Literature: Focus on Asymmetric Organocatalysis. Org. Process Res. Dev. 2022, 26 (8), 2224– 2239, DOI: 10.1021/acs.oprd.2c00139
  14b
  Highlights of the Recent Patent Literature: Focus on Asymmetric Organocatalysis
  Hughes, David L.
  Organic Process Research & Development (2022), 26 (8), 2224-2239CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
  A review. Contributions in asym. organocatalysis from the patent literature since 2018, including reactions catalyzed by Cinchona alkaloids as free base and quaternary salts, phosphonium salts, proline-derived catalysts, and chiral phosphoric acids were explored. Examples of processes employing asym. organocatalysis for the industrial prepn. of pharmaceutical intermediates were highlighted.
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15. 15
  Selected reviews:
  (a) Ötvös, S. B.; Kappe, C. O. Continuous Flow Asymmetric Synthesis of Chiral Active Pharmaceutical Ingredients and Their Advanced Intermediates. Green Chem. 2021, 23 (17), 6117– 6138, DOI: 10.1039/D1GC01615F
  15a
  Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates
  Otvos Sandor B; Kappe C Oliver; Otvos Sandor B; Kappe C Oliver
  Green chemistry : an international journal and green chemistry resource : GC (2021), 23 (17), 6117-6138 ISSN:1463-9262.
  Catalytic enantioselective transformations provide well-established and direct access to stereogenic synthons that are broadly distributed among active pharmaceutical ingredients (APIs). These reactions have been demonstrated to benefit considerably from the merits of continuous processing and microreactor technology. Over the past few years, continuous flow enantioselective catalysis has grown into a mature field and has found diverse applications in asymmetric synthesis of pharmaceutically active substances. The present review therefore surveys flow chemistry-based approaches for the synthesis of chiral APIs and their advanced stereogenic intermediates, covering the utilization of biocatalysis, organometallic catalysis and metal-free organocatalysis to introduce asymmetry in continuously operated systems. Single-step processes, interrupted multistep flow syntheses, combined batch/flow processes and uninterrupted one-flow syntheses are discussed herein.
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  (b) Jiao, J.; Nie, W.; Yu, T.; Yang, F.; Zhang, Q.; Aihemaiti, F.; Yang, T.; Liu, X.; Wang, J.; Li, P. Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges. Chem. - Eur. J. 2021, 27, 4817– 4838, DOI: 10.1002/chem.202004477
  15b
  Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges
  Jiao, Jiao; Nie, Wenzheng; Yu, Tao; Yang, Fan; Zhang, Qian; Aihemaiti, Feierdaiweisi; Yang, Tingjun; Liu, Xuanyu; Wang, Jiachen; Li, Pengfei
  Chemistry - A European Journal (2021), 27 (15), 4817-4838CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. This minireview summarizes the most recent reports (2017-2020) on continuous-flow synthesis of functional mols. Notably, several complex active pharmaceutical ingredients (APIs) have been prepd. by the continuous-flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous-flow chem. for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.
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  (c) Ferlin, F.; Lanari, D.; Vaccaro, L. Sustainable Flow Approaches to Active Pharmaceutical Ingredients. Green Chem. 2020, 22 (18), 5937– 5955, DOI: 10.1039/D0GC02404J
  There is no corresponding record for this reference.
  (d) Rodríguez-Escrich, C.; Pericàs, M. A. Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts. Chem. Rec. 2019, 19 (9), 1872– 1890, DOI: 10.1002/tcr.201800097
  15d
  Catalytic Enantioselective Flow Processes with Solid-Supported Chiral Catalysts
  Rodriguez-Escrich, Carles; Pericas, Miquel A.
  Chemical Record (2019), 19 (9), 1872-1890CODEN: CRHEAK; ISSN:1528-0691. (Wiley-VCH Verlag GmbH & Co. KGaA)
  Sustainability concerns are the wind in the sails for the development of novel, more selective catalytic processes. Hence, chiral catalysts play a crucial role in the green prodn. of enantioenriched compds. To further increase the green profile of this approach, the use of solid-supported catalytic species is appealing due to the reduced generation of waste, as well as the possibility of reusing the precious catalyst. Even more attractive is the implementation of flow processes based on these immobilized catalysts, a flexible strategy that allows to generate from milli- to multi-gram amts. of chiral product with a reduced footprint set-up. Herein, we will present the efforts devoted in our lab. towards the immobilization of chiral catalysts and their use in single-pass, highly enantioselective, flow processes. Proline, diarylprolinols, other aminocatalysts, squaramides, thioureas, phosphoric acids and even chiral ligands and metal-based catalysts constitute our current toolkit of supported species for enantioselective catalysis.
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  (e) Masuda, K.; Ichitsuka, T.; Koumura, N.; Sato, K.; Kobayashi, S. Flow Fine Synthesis with Heterogeneous Catalysts. Tetrahedron 2018, 74 (15), 1705– 1730, DOI: 10.1016/j.tet.2018.02.006
  15e
  Flow fine synthesis with heterogeneous catalysts
  Masuda, Koichiro; Ichitsuka, Tomohiro; Koumura, Nagatoshi; Sato, Kazuhiko; Kobayashi, Shu
  Tetrahedron (2018), 74 (15), 1705-1730CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  A review. This review aims to summarize recent developments in continuous-flow reactions with heterogeneous catalysts for synthesis of fine chems.
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  (f) Britton, J.; Raston, C. L. Multi-Step Continuous-Flow Synthesis. Chem. Soc. Rev. 2017, 46 (5), 1250– 1271, DOI: 10.1039/C6CS00830E
  15f
  Multi-step continuous-flow synthesis
  Britton, Joshua; Raston, Colin L.
  Chemical Society Reviews (2017), 46 (5), 1250-1271CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. This review article focused on multi-step continuous-flow methodol., which had applications in synthesis of active pharmaceutical ingredients, natural products, and commodity chems. This review described the advancements while highlighted the rapid progress, benefits, and diversification of this expanding field.
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  (g) Puglisi, A.; Benaglia, M.; Chiroli, V. Stereoselective Organic Reactions Promoted by Immobilized Chiral Catalysts in Continuous Flow Systems. Green Chem. 2013, 15 (7), 1790– 1813, DOI: 10.1039/c3gc40195b
  15g
  Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems
  Puglisi, Alessandra; Benaglia, Maurizio; Chiroli, Valerio
  Green Chemistry (2013), 15 (7), 1790-1813CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
  A review. The immobilization of the catalyst on a support with the aim of facilitating the sepn. of the product from the catalyst, and thus the recovery and recycling of the latter, can be regarded as an important improvement for a catalytic process. However, a system where a catalyst must not be removed from the reaction vessel is even more attractive: in continuous flow methods the immobilized catalyst permanently resides in the reactor where it transforms the entering starting materials into the desired products. The retention of the catalytic species inside the reaction vessel can be achieved by different techniques ranging from ultrafiltration through a MW-selective membrane to immobilization on different supports. In this review the authors will discuss the most significant examples of stereoselective reactions promoted by immobilized chiral catalysts and performed under continuous flow conditions, with particular attention to the more recent contributions of the last few years.
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  For general reviews on continuous flow chemistry, see also:
  (h) Capaldo, L.; Wen, Z.; Noël, T. A Field Guide to Flow Chemistry for Synthetic Organic Chemists. Chem. Sci. 2023, 14, 4230– 4247, DOI: 10.1039/D3SC00992K
  15h
  A field guide to flow chemistry for synthetic organic chemists
  Capaldo, Luca; Wen, Zhenghui; Noel, Timothy
  Chemical Science (2023), 14 (16), 4230-4247CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  A review. Flow chem. has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show that several of the benefits of microreactor technol. can be exploited to push the boundaries in org. synthesis and to unleash unique reactivity and selectivity. By "lifting the veil" on some of the governing principles behind the obsd. trends, we hope that this review will serve as a useful field guide for those interested in diving into flow chem.
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  (i) Gérardy, R.; Emmanuel, N.; Toupy, T.; Kassin, V. E.; Tshibalonza, N. N.; Schmitz, M.; Monbaliu, J. C. M. Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges. Eur. J. Org. Chem. 2018, 2018 (20), 2301– 2351, DOI: 10.1002/ejoc.201800149
  15i
  Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges
  Gerardy, Romaric; Emmanuel, Noemie; Toupy, Thomas; Kassin, Victor-Emmanuel; Tshibalonza, Nelly Ntumba; Schmitz, Michael; Monbaliu, Jean-Christophe M.
  European Journal of Organic Chemistry (2018), 2018 (20-21), 2301-2351CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
  This review intends to provide the reader with a clear and concise overview of how preparative continuous flow org. chem. could potentially impact on current important societal challenges. These societal challenges include health/well-being and sustainable development. Continuous flow chem. has enabled significant advances for the manufg. of pharmaceuticals, as well as for biomass valorization toward a biosourced chem. industry. Examples related to pharmaceutical prodn. are herein focused on (a) the implementation of flow chem. to reduce the occurrence of drug shortages, (b) continuous flow manufg. of orphan drugs, (c) continuous flow prepn. of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufg. of peptide-based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform mols. Besides pos. impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technol. within the actual context of terrorism and drug abuse.
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16. 16
  Recent references:
  (a) Ötvös, S. B.; Pericàs, M. A.; Kappe, C. O. Multigram-Scale Flow Synthesis of the Chiral Key Intermediate of (−)-Paroxetine Enabled by Solvent-Free Heterogeneous Organocatalysis. Chem. Sci. 2019, 10 (48), 11141– 11146, DOI: 10.1039/C9SC04752B
  16a
  Multigram-scale flow synthesis of the chiral key intermediate of (-)-paroxetine enabled by solvent-free heterogeneous organocatalysis
  Otvos Sandor B; Kappe C Oliver; Pericas Miquel A; Pericas Miquel A; Kappe C Oliver
  Chemical science (2019), 10 (48), 11141-11146 ISSN:2041-6520.
  The catalytic enantioselective synthesis of the chiral key intermediate of the antidepressant (-)-paroxetine is demonstrated as a continuous flow process on multi-gram scale. The critical step is a solvent-free organocatalytic conjugate addition followed by a telescoped reductive amination-lactamization-amide/ester reduction sequence. Due to the efficient heterogeneous catalysts and the solvent-free or highly concentrated conditions applied, the flow method offers key advances in terms of productivity and sustainability compared to earlier batch approaches.
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  (b) Ötvös, S. B.; Llanes, P.; Pericàs, M. A.; Kappe, C. O. Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut. Org. Lett. 2020, 22 (20), 8122– 8126, DOI: 10.1021/acs.orglett.0c03100
  16b
  Telescoped Continuous Flow Synthesis of Optically Active γ-Nitrobutyric Acids as Key Intermediates of Baclofen, Phenibut, and Fluorophenibut
  Otvos Sandor B; Kappe C Oliver; Otvos Sandor B; Kappe C Oliver; Llanes Patricia; Pericas Miquel A; Pericas Miquel A
  Organic letters (2020), 22 (20), 8122-8126 ISSN:.
  The two-step flow asymmetric synthesis of chiral γ-nitrobutyric acids as key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut is reported on a multigram scale. The telescoped process comprises an enantioselective Michael-type addition facilitated by a polystyrene-supported heterogeneous organocatalyst under neat conditions followed by in situ-generated performic acid-mediated aldehyde oxidation. Simple access to valuable optically active substances is provided with key advances in terms of productivity and sustainability compared to those of previous batch approaches.
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  (c) Nagy, B. S.; Llanes, P.; Pericas, M. A.; Kappe, C. O.; Ötvös, S. B. Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant. Org. Lett. 2022, 24 (4), 1066– 1071, DOI: 10.1021/acs.orglett.1c04300
  16c
  Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence using in Situ-Generated Persulfuric Acid as Oxidant
  Nagy, Bence S.; Llanes, Patricia; Pericas, Miquel A.; Kappe, C. Oliver; Oetvoes, Sandor B.
  Organic Letters (2022), 24 (4), 1066-1071CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asym. conjugate addn.-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group redn. and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.
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17. 17
  Selected references:
  (a) Bosset, C.; Angibaud, P.; Stanfield, I.; Meerpoel, L.; Berthelot, D.; Guérinot, A.; Cossy, J. Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans. J. Org. Chem. 2015, 80 (24), 12509– 12525, DOI: 10.1021/acs.joc.5b02371
  17a
  Iron-Catalyzed Synthesis of C2 Aryl- and N-Heteroaryl-Substituted Tetrahydropyrans
  Bosset, Cyril; Angibaud, Patrick; Stanfield, Ian; Meerpoel, Lieven; Berthelot, Didier; Guerinot, Amandine; Cossy, Janine
  Journal of Organic Chemistry (2015), 80 (24), 12509-12525CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  An iron-catalyzed cyclization of hydroxy allylic derivs. into tetrahydropyrans possessing an N-heteroaryl at C2 is disclosed. The reaction proceeds with good yield and in high diastereoselectivity in favor of the more stable isomer. The diastereoselectivity results from an iron-induced reopening of the tetrahydropyrans, allowing a thermodn. equilibration. The method allows access to a variety of 2,6-disubstituted as well as 2,4,6-trisubstituted tetrahydropyrans that could be considered as attractive scaffolds for the pharmaceutical industry.
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  (b) Couty, S.; Meyer, C.; Cossy, J. Gold-Catalyzed Cycloisomerizations of Ene-Ynamides. Tetrahedron 2009, 65 (9), 1809– 1832, DOI: 10.1016/j.tet.2008.10.108
  17b
  Gold-catalyzed cycloisomerizations of ene-ynamides
  Couty, Sylvain; Meyer, Christophe; Cossy, Janine
  Tetrahedron (2009), 65 (9), 1809-1832CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
  The gold-catalyzed cycloisomerizations of 1,6-ene-ynamides proceed under mild conditions and lead to cyclobutanones from terminal or trimethylsilyl substituted ynamides, or to carbonyl compds. bearing a 2,3-methanopyrrolidine subunit from substrates possessing a propargylic alc. moiety. High diastereoselectivities are obsd. with 1,6-ene-ynamides having a stereocenter at the α or β position of the nitrogen atom.
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  (c) Lee, Y.; Shabbir, S.; Jeong, Y.; Ban, J.; Rhee, H. Formal Synthesis of Fesoterodine by Acid-Facilitated Aromatic Alkylation. Bull. Korean Chem. Soc. 2015, 36 (12), 2885– 2889, DOI: 10.1002/bkcs.10592
  17c
  Formal Synthesis of Fesoterodine by Acid-Facilitated Aromatic Alkylation
  Lee, Youngeun; Shabbir, Saira; Jeong, Yuri; Ban, Jaeyoung; Rhee, Hakjune
  Bulletin of the Korean Chemical Society (2015), 36 (12), 2885-2889CODEN: BKCSDE; ISSN:0253-2964. (Wiley-VCH Verlag GmbH & Co. KGaA)
  The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzaldehyde from Et benzoylacetate by Friedel-Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the redn. of the ketoester to a 1,3-diol, diisopropylamine substitution, and Friedel-Crafts alkylation, followed by redn. and chiral resoln.
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  (d) Fernandes, A. A. G.; Leonarczyk, I. A.; Ferreira, M. A. B.; Dias, L. C. Diastereoselectivity in the Boron Aldol Reaction of α-Alkoxy and α,β-Bis-Alkoxy Methyl Ketones. Org. Biomol. Chem. 2019, 17 (12), 3167– 3180, DOI: 10.1039/C9OB00358D
  17d
  Diastereoselectivity in the boron aldol reaction of α-alkoxy and α,β-bis-alkoxy methyl ketones
  Fernandes, Alessandra A. G.; Leonarczyk, Ives A.; Ferreira, Marco A. B.; Dias, Luiz Carlos
  Organic & Biomolecular Chemistry (2019), 17 (12), 3167-3180CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
  In this work, using DFT calcns., we investigated the 1,4 and 1,5 asym. induction in boron enolate aldol reactions of α-alkoxy and α,β-bisalkoxy Me ketones. We evaluated the steric influence of alkyl substituents at the α position and the stereoelectronic influence of the oxygen protecting groups at the α and β positions. Theor. calcns. revealed the origins of the 1,4 asym. induction in terms of the nature of the β-substituent. The synergistic effect between the α,β-syn and α,β-anti-bisalkoxy stereocenters was elucidated. In the presence of the β-alkoxy center, the reaction proceeds through the Goodman-Paton 1,5-stereoinduction model, experiencing a minor influence of the α-alkoxy center.
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18. 18
  Some reviews about green solvents:
  (a) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice. Chem. Soc. Rev. 2010, 39 (1), 301– 312, DOI: 10.1039/B918763B
  18a
  Green Chemistry: Principles and Practice
  Anastas, Paul; Eghbali, Nicolas
  Chemical Society Reviews (2010), 39 (1), 301-312CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. Green Chem. is a relatively new emerging field that strives to work at the mol. level to achieve sustainability. The field has received widespread interest in the past decade due to its ability to harness chem. innovation to meet environmental and economic goals simultaneously. Green Chem. has a framework of a cohesive set of Twelve Principles, which have been systematically surveyed in this crit. review. This article covers the concepts of design and the scientific philosophy of Green Chem. with a set of illustrative examples. Future trends in Green Chem. are discussed with the challenge of using the Principles as a cohesive design system (93 refs.).
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  (b) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 Selection Guide of Classical- and Less Classical-Solvents. Green Chem. 2016, 18 (1), 288– 296, DOI: 10.1039/C5GC01008J
  18b
  CHEM21 selection guide of classical- and less classical-solvents
  Prat, Denis; Wells, Andy; Hayler, John; Sneddon, Helen; McElroy, C. Robert; Abou-Shehada, Sarah; Dunn, Peter J.
  Green Chemistry (2016), 18 (1), 288-296CODEN: GRCHFJ; ISSN:1463-9262. (Royal Society of Chemistry)
  A selection guide of common solvents has been elaborated, based on a survey of publically available solvent selection guides. In order to rank less classical solvents, a set of Safety, Health and Environment criteria is proposed, aligned with the Global Harmonized System (GHS) and European regulations. A methodol. based on a simple combination of these criteria gives an overall preliminary ranking of any solvent. This enables in particular a simplified greenness evaluation of bio-derived solvents.
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19. 19
  For a review about dioxiranes, see:
  (a) Murray, R. W. Dioxiranes. Chem. Rev. 1989, 89 (5), 1187– 1201, DOI: 10.1021/cr00095a013
  19a
  Chemistry of dioxiranes. 12. Dioxiranes
  Murray, Robert W.
  Chemical Reviews (Washington, DC, United States) (1989), 89 (5), 1187-201CODEN: CHREAY; ISSN:0009-2665.
  A review with >70 refs.
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  For references related to the use of DMDO in flow, see:
  (b) Ahlqvist, G. P.; Burke, E. G.; Johnson, J. A.; Jamison, T. F. Continuous Dimethyldioxirane Generation for Polymer Epoxidation. Polym. Chem. 2021, 12 (4), 489– 493, DOI: 10.1039/D0PY01676D
  19b
  Continuous dimethyldioxirane generation for polymer epoxidation
  Ahlqvist, Grace P.; Burke, Eileen G.; Johnson, Jeremiah A.; Jamison, Timothy F.
  Polymer Chemistry (2021), 12 (4), 489-493CODEN: PCOHC2; ISSN:1759-9962. (Royal Society of Chemistry)
  Post-polymn. modification of commodity polymers yields new applications for materials already produced industrially. Incorporation of small amts. of epoxides into unsatd. polymers such as polybutadiene expands their use for grafting and compatibilization applications, but controlled epoxidn. of these polymers in a safe, scalable manner presents a challenge. Herein we describe the development of a reactor for the continuous flow generation and use of dimethyldioxirane (DMDO) and its application to the low-level epoxidn. of unsatd. polymers. A continuous stirred tank reactor (CSTR) prevents reactor clogging by allowing solid ppts. to settle, enabling the pumping of a homogeneous soln. of oxidant. Modification of relative concns., flow rates, and temps. achieves variable epoxidn. levels. This method has been demonstrated on gram scale.
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  (c) Cossar, P. J.; Baker, J. R.; Cain, N.; McCluskey, A. In Situ Epoxide Generation by Dimethyldioxirane Oxidation and the Use of Epichlorohydrin in the Flow Synthesis of a Library of β-Amino Alcohols. R. Soc. Open Sci. 2018, 5, 171190, DOI: 10.1098/rsos.171190
  19c
  In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of β-amino alcohols
  Cossar, Peter J.; Baker, Jennifer R.; Cain, Nicholas; McCluskey, Adam
  Royal Society Open Science (2018), 5 (4), 171190/1-171190/22CODEN: RSOSAV; ISSN:2054-5703. (Royal Society)
  The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of β-amino alcs. The limitation was encountered in the prodn. of analogs of 1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol was a potential antibiotic lead. The in-situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidn. abrogates this limitation and afforded facile accessed to structurally diverse β-amino alcs. Comp.1-(4-nitrophenoxy)-3-((2-((4-(trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol was readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in-situ generation of DMDO, with olefin epoxidn. in typically good yields and a flow mediated ring opening aminolysis to form an expanded library of β-amino alcs., resulting in modest to excellent yields. Alternatively flow coupling of epichlorohydrin with phenols (22%-89%) and a Bi(OTf)3 catalyzed microwave ring opening with amines afforded a select range of β-amino alcs., but with lower levels of aminolysis regiocontrol than the sequential flow approach.
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20. 20
  Recent references about peracid generation in flow:
  (a) Nagy, B. S.; Fu, G.; Hone, C. A.; Kappe, C. O.; Ötvös, S. B. Harnessing a Continuous-Flow Persulfuric Acid Generator for Direct Oxidative Aldehyde Esterifications. ChemSusChem 2023, 16 (2), e2022018, DOI: 10.1002/cssc.202201868
  There is no corresponding record for this reference.
  (b) Prieschl, M.; Ötvös, S. B.; Kappe, C. O. Sustainable Aldehyde Oxidations in Continuous Flow Using in Situ-Generated Performic Acid. ACS Sustain. Chem. Eng. 2021, 9 (16), 5519– 5525, DOI: 10.1021/acssuschemeng.1c01668
  There is no corresponding record for this reference.
21. 21
  Selected examples about enantioselective allylboration and related reactions:
  (a) Yang, X.; Pang, S.; Cheng, F.; Zhang, Y.; Lin, Y.-W.; Yuan, Q.; Zhang, F.-L.; Huang, Y.-Y. Enantioselective Synthesis of 1,3-Disubstituted 1,3- Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid. J. Org. Chem. 2017, 82 (19), 10388– 10397, DOI: 10.1021/acs.joc.7b01856
  21a
  Enantioselective Synthesis of 1,3-Disubstituted 1,3-Dihydroisobenzofurans via a Cascade Allylboration/Oxo-Michael Reaction of o-Formyl Chalcones Catalyzed by a Chiral Phosphoric Acid
  Yang, Xing; Pang, Shuai; Cheng, Feng; Zhang, Yue; Lin, Ya-Wei; Yuan, Quan; Zhang, Fang-Lin; Huang, Yi-Yong
  Journal of Organic Chemistry (2017), 82 (19), 10388-10397CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The first chiral Bronsted acid-catalyzed asym. cascade allylboration/oxo-Michael reaction between o-formyl chalcones and allylboronate has been successfully discovered, which afforded chiral 1,3-disubstituted 1,3-dihydroisobenzofurans, e.g. I, with a yield, diastereoselective ratio (dr) and enantioselective excess (ee) up to 94%, 2.5:1, and 98%, resp. In addn., 2,3-dienylboronic pinacol ester was also applied into this cascade reaction with good catalytic results.
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  (b) Jain, P.; Wang, H.; Houk, K. N.; Antilla, J. C. Brønsted Acid Catalyzed Asymmetric Propargylation of Aldehydes. Angew. Chem., Int. Ed. 2012, 51 (6), 1391– 1394, DOI: 10.1002/anie.201107407
  21b
  Bronsted acid-catalyzed asymmetric propargylation of aldehydes
  Jain, Pankaj; Wang, Hao; Houk, Kendall N.; Antilla, Jon C.
  Angewandte Chemie, International Edition (2012), 51 (6), 1391-1394, S1391/1-S1391/41CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A Bronsted acid-catalyzed propargylation of aldehydes with allenylboronate is described. Corresponding homopropargylic alcs. were obtained using this methods.
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  (c) Wang, M.; Khan, S.; Miliordos, E.; Chen, M. Enantioselective Allenylation of Aldehydes via Brønsted Acid Catalysis. Adv. Synth. Catal. 2018, 360 (23), 4634– 4639, DOI: 10.1002/adsc.201801080
  21c
  Enantioselective Allenylation of Aldehydes via Bronsted Acid Catalysis
  Wang, Mengzhou; Khan, Shahriar; Miliordos, Evangelos; Chen, Ming
  Advanced Synthesis & Catalysis (2018), 360 (23), 4634-4639CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An enantioselective allenylation of aldehydes catalyzed by a chiral, nonracemic phosphoric acid was reported. Under the developed conditions, 1,1'-disubstituted allenic alcs. were obtained in 64-98% yields with 88-99% ee. Computational studies were conducted to probe the origin of asym. induction. Mechanistic studies suggest that the pinacol moiety of the propargylboronate is crit. to the enantioselectivity of the reaction that was supported by exptl. data.
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22. 22
  Treiber, A. Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation. J. Org. Chem. 2002, 67 (21), 7261– 7266, DOI: 10.1021/jo0202177
  22
  Mechanism of the Aromatic Hydroxylation of Thiophene by Acid-Catalyzed Peracid Oxidation
  Treiber, Alexander
  Journal of Organic Chemistry (2002), 67 (21), 7261-7266CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  The oxidn. of thiophene (1) with peracids in a strongly acidic environment yielded thiophen-2-one (4) as the product of an apparent direct hydroxylation of the thiophene arom. ring together with the anticipated thiophene-S-oxide dimers as the main products. Formation of the latter dimers can be rationalized in a straightforward manner by initial oxidn. at the sulfur atom of thiophene (1) to yield thiophene-S-oxide followed by subsequent dimerization in a Diels-Alder type reaction. Trapping expts. in the presence of a competing dienophile indicated that thiophen-2-one (4) did not originate from the monomeric thiophene-S-oxide but was the product of an independent reaction pathway. The extent of thiophen-2-one (4) formation correlated with the acidity of the reaction medium and was suppressed in the presence of water, the latter presumably acting as a competing base. As evidenced by the use of 2,5-dideuterated thiophene (1-D), its mechanism of formation involved a 1,2-hydride shift, a feature commonly described in the peracid-mediated epoxidn. of arom. hydrocarbons and indicative for the occurrence of cationic intermediates. In agreement with all these observations we propose a mechanism involving initial protonation of thiophene followed by nucleophilic attack of the peracid in position 2 of the thiophene ring. Intramol. epoxidn. may lead to the formation of thiophene 2,3-epoxide as a highly reactive intermediate that then undergoes heterolytic ring opening and a 1,2-hydride shift to yield thiophen-2-one (4) after a final, acid-catalyzed, isomerization of the double bond.
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23. 23
  Gamedze, M. P.; Maseko, R. B.; Chigondo, F.; Nkambule, C. M. Serendipitous Synthesis of 3-Hydroxy Tetrahydrofurans from Tin Catalyzed Sulfonylation of Acyclic 1,2,4-Triols. Tetrahedron Lett. 2012, 53 (44), 5929– 5932, DOI: 10.1016/j.tetlet.2012.08.110
  23
  Serendipitous synthesis of 3-hydroxytetrahydrofurans from tin catalyzed sulfonylation of acyclic 1,2,4-triols
  Gamedze, Makhosazana P.; Maseko, Rejoice B.; Chigondo, Fidelis; Nkambule, Comfort M.
  Tetrahedron Letters (2012), 53 (44), 5929-5932CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu2SnO (5 mol %) results in cyclization and the formation of 3-hydroxytetrahydrofurans (56-85%) while the anti-1,2,4-triols react to give C1-O-sulfonyl derivs. in good yields (66-83%) and the cyclization product in poor yield (5-12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary hydroxyl followed by an intramol. tin acetal rearrangement to a 1,3-stannylene which then undergoes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.
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24. 24
  Maestro, A.; Nagy, B. S.; Ötvös, S. B.; Kappe, C. O. A Telescoped Continuous Flow Enantioselective Process to Access Chiral Intermediates of Atomoxetine, Dapoxetine, Duloxetine and Ezetimibe. chemRxiv 2023, DOI: 10.26434/chemrxiv-2023-93llx
  There is no corresponding record for this reference.
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A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building BlocksClick to copy article linkArticle link copied!

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Synthesis of the Catalysts

General Procedure for the Batch Synthesis of Racemic 4

General Procedure for the Batch Synthesis of Racemic 5

General Procedure for the Batch Synthesis of 7

Experimental Procedure for the Telescoped Flow Synthesis of Oxiranes 5

Characterization Data of 4, 5, and 7

(R)-1-(Thiophen-2-yl)but-3-en-1-ol (4c)

(1R)-2-(Oxiran-2-yl)-1-phenylethan-1-ol (5a)

(1R)-1-(4-Fluorophenyl)-2-(oxiran-2-yl)ethan-1-ol (5b)

(4R)-4-Phenylbutane-1,2,4-triol (7a)

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Figure 1

Scheme 1

Scheme 2

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A Telescoped Continuous Flow Enantioselective Process for Accessing Intermediates of 1-Aryl-1,3-diols as Chiral Building Blocks
Click to copy article linkArticle link copied!