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ArticleDecember 5, 2018

Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and Squaramides
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José M. Andrés*
José M. Andrés
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
*E-mail: [email protected] (J.M.A.).
More by José M. Andrés
Alicia Maestro
Alicia Maestro
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
More by Alicia Maestro
María Valle
María Valle
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
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Isabel Valencia
Isabel Valencia
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
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Rafael Pedrosa*
Rafael Pedrosa
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
*E-mail: [email protected] (R.P.).
More by Rafael Pedrosa
http://orcid.org/0000-0002-3652-7301

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Cite this: ACS Omega 2018, 3, 12, 16591–16600

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https://doi.org/10.1021/acsomega.8b02302

Published December 5, 2018

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Abstract

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4-Vinylphenyl-substituted squaramides have been tested as organocatalysts for the diastereo- and enantioselective synthesis of trisubstituted benzopyrans via an oxa-Michael intramolecular nitro-Michael cascade reaction. Both the enantio- and diastereoselection were good to moderate, depending on the nature of the chiral scaffold in the catalyst. The diastereoselection is better for the most active catalyst because the final products epimerize at C-3 along the time. Supported squaramide sq-9 prepared by copolymerization of sq-4 with styrene and divinylbenzene is also effective in promoting the cascade reaction, and it is recoverable and reusable for five cycles maintaining the activity.

Subjects

Introduction

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Polysubstituted chromans are common frameworks in natural and synthetic molecules of biological and pharmaceutical interest, (1−5) and the synthesis of chiral structures related with these compounds has attracted a lot of work. (6−14) One of the most efficient approaches to these structures consist on the reaction of 2-substituted vinylphenol derivatives with α,β-unsaturated electrophiles. The cascade reaction starts with a Michael reaction, followed by cyclization to the final product in one step, and the organocatalyzed stereoselective version has recently received a great attention. Among these approaches, spirochromanes have been obtained by cascade reactions of ortho-hydroxynitrostyrenes (12,15) or ortho-hydroxyphenyl para-quinone methides (16) with different electrophiles. Benzopyrans with three contiguous stereocenters have been prepared by the reaction of different nitroalkenes with ortho-hydroxy chalcones, (17,18) salicylaldimines, (19,20) and sequential intermolecular–intramolecular Michael addition of nitromethane (21) or thiols. (22)

The diastereoselective synthesis of dinitro-trisubstituted benzopyrans by cascade oxa-Michael–nitro-Michael reaction of ortho-hydroxynitrostyrene and nitroalkenes was described fifteen years ago, (23) but only very recently, the enantioselective version of that process has been developed (24) by using thioureas and squaramides as catalysts in homogeneous conditions.

Immobilization of molecular catalysts provides heterogeneous materials that simplify the recovering from the reaction mixture, and recycling for batch processes (25−28) or used in flow systems. (29−32) As a part of our interest in the search for novel heterogeneous enantiopure bifunctional organocatalysts, we have recently prepared polymeric materials by copolymerization of molecular thioureas and squaramides, which are able to promote different stereoselective cascade reactions. (33) Now, we report on the stereoselective synthesis of trisubstituted benzopyrans by sequential oxa-Michael–nitro-Michael reactions catalyzed by these novel organocatalysts.

Results and Discussion

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Searching for the best experimental conditions, we started the study taking the reaction of ortho-hydroxynitrostyrene with nitrostyrene as a model reaction in different solvents. Based on our previous results, we used monomeric squaramides as catalysts with a single stereocenter derived from l-tert-leucine (sq-4, sq-5) and l-valine (sq-6, sq-7), which differ in substitution at the basic nitrogen atom. For comparative purposes, squaramide (sq-8), derived from (1R,2R)-1,2-cyclohexane diamine, and its homologous thiourea 8 were also tested as catalysts.

In the proposed reactions, four possible diastereoisomers could be formed, but only two of them, which are epimers at C-3, were detected. (2S,3S,4S)-trisubstituted benzopyran 3aa was obtained as the major stereoisomer and (2S,3R,4S)-epi-3aa as a minor one when the reaction was catalyzed by squaramides (sq-4–sq-7), prepared from l-valine or l-tert-leucine. As expected, enantiomeric compounds (2R,3R,4R)-ent-3aa and (2R,3S,4R)-ent-epi-3aa were formed in the reactions catalyzed by thiourea 8 and squaramide sq-8 obtained from (1R,2R)-1,2-cyclohexane diamine but surprisingly, ent-epi-3aa was the major diastereoisomer isolated in that case.

The preliminary experiments, collected in Table 1, show that sq-4 and sq-6, with a dimethylamino substituent, provided better results in terms of yield and stereoselectivity than their piperidyl-substituted homologs sq-5 and sq-7, respectively (compare entries 1 and 3 vs 2 and 4 in Table 1). The catalyst loading can be diminished to 2 mol % without affecting the stereoselection, although increasing the reaction time (compare entries 1 and 5 in Table 1). Different solvents were also tested and good chemical yields were obtained for all of them, but very bad stereoselection was observed for ethereal tetrahydrofuran (THF) or alcoholic (MeOH) solvents (compare entry 1 vs 6–9 in Table 1). This fact could be explained because the protic media compete with the catalysts in forming hydrogen bonds with the substrates. Squaramide sq-8 is a very active catalyst leading to ent-epi-3aa and ent-3aa in good yield after 8 h of reaction, but lower stereoselection than sq-4 and sq-6 (compare entry 11 vs 1 or 3 in Table 1), and its homologous thiourea 8 yielded the same mixture of stereoisomers but without diastereoselection and very low enantioselection (entry 10 in Table 1).

Table 1. Evaluation of Catalysts and Solvents

entry^a	catalyst	solvent	t (h)	yield (%)^b	dr^c 3aa/epi-3aa	er^c 3aa	er^c epi-3aa
1	sq-4	CH₂Cl₂	24	(81)	80:20	88:12	80:20
2	sq-5	CH₂Cl₂	24	(79)	53:47	61:39	83:17
3	sq-6	CH₂Cl₂	24	(80)	83:17	84:16	98:2
4	sq-7	CH₂Cl₂	24	(66)	60:40	60:40	76:24
5^d	sq-4	CH₂Cl₂	30	(81)	79:21	88:12	78:22
6	sq-4	CHCl₃	24	(75)	67:33	87:13	83:17
7	sq-4	PhCH₃	28	(76)	76:24	86:14	87:13
8	sq-4	THF	30	(67)	61:49	65:45	66:44
9	sq-4	MeOH	32	(65)	55:45	60:40	61:39
10	8	CH₂Cl₂	12	(77)	15:85^e	52:48^e	60:40^e
11	sq-8	CH₂Cl₂	8	(75)	20:80^e	74:26^e	72:28^e

^{^a}

Reactions were performed with 1a (0.2 mmol), 2a (0.4 mmol), and catalyst (5 mol %) in the corresponding solvent (0.6 mL) at rt.

^{^b}

Yield after purification by flash chromatography.

^{^c}

Determined by HPLC analysis on a chiral column.

^{^d}

Reaction performed with 2% of catalyst.

^{^e}

dr and er correspond to ent-3aa and ent-epi-3aa, respectively.

The scope of the reaction was initially studied by stirring, at room temperature, a mixture of ortho-hydroxynitrostyrenes with different substituents (1a–d) with two equivalents of a series of β-aryl-substituted nitroolefins (2a–e) or disubstituted nitroalkenes (2f and 2g), and 5 mol % of organocatalysts sq-4 and sq-6 in dichloromethane (DCM) as solvent (Table 2).

Table 2. Scope of the Reaction

entry^a	1a–d	2a–f	catalyst	t (h)	product (yield)^b	dr^c 3/epi-3	er^c 3	er^c epi-3
1	1a	2a	sq-9	24	3aa (70)	66:34	78:22	85:15
2^d	1a	2a	sq-9	36	3aa (65)	63:27	81:19	81:19
3	1a	2b	sq-4	16	3ab (88)	>99:<1	98:2
4	1a	2b	sq-6	16	3ab (79)	99:1	93:7
5	1a	2b	sq-9	16	3ab (86)	>99:<1	87:13
6	1a	2c	sq-4	16	3ac (84)	95:5	97:3
7	1a	2c	sq-6	16	3ac (68)	67:33	97:3	93:7
8	1a	2c	sq-8	24	3ac (75)	22:78^e	90:10^e	92:8^e
9	1a	2c	sq-9	24	3ac (72)	62:38	84:16	96:4
10	1a	2d	sq-4	72	3ad(73)	91:9	>99:<1	>99:<1
11	1a	2d	sq-6	72	3ad(70)	83:17	>99:<1	88:12
12	1a	2e	sq-4	48	3ae (85)	64:36	93:7	92:8
13	1a	2e	sq-6	48	3ae (77)	66:34	84:16	99:1
14	1a	2e	sq-9	48	3ae (79)	81:19	78:22	78:22
15	1b	2a	sq-4	72	3ba (81)	73:27	90:10	82:18
16	1b	2a	sq-9	72	3ba (70)	58:42	83:17	80:20
17	1b	2b	sq-4	18	3bb(81)	80:20	88:12	>99:<1
18	1b	2c	sq-4	20	3bc (85)	68:32	95:5	97:3
19	1b	2e	sq-4	48	3be (64)	63:37	88:12	88:12
20	1c	2a	sq-4	16	3ca (74)	79:21	96:4	>99:<1
21	1c	2a	sq-9	24	3ca (72)	77:23	82:18	85:15
22	1c	2b	sq-4	24	3cb (85)	86:14	97:3	>99:<1
23	1c	2c	sq-4	24	3cc (79)	88:12	93:7	>99:<1
24	1c	2e	sq-4	48	3ce (76)	78:22	88:12	93:7
25	1d	2a	sq-4	12	3da (65)	74:26	85:15	89:11
26	1d	2a	sq-9	20	3da (67)	67:33	83:17	87:13
27	1a	2f	sq-6	87	3af (50)	56:44	77:23	56:44

^{^a}

The reactions were performed with 1a–d (0.2 mmol), nitroolefin 2a–e (0.4 mmol), and catalyst (5 mol %) in CH₂Cl₂ (0.6 mL) at rt.

^{^b}

Isolated yield of pure compounds.

^{^c}

Determined by determined by HPLC analysis on a chiral column.

^{^d}

Reaction performed with 2% of catalyst.

^{^e}

dr and er correspond to ent-3ac and ent-epi-3ac.

We first explored the influence on the reactivity and stereoselection of the electronic nature of the aryl group in the nitrostyrenes (2a–e) acting as acceptors (entries 3–14 in Table 2). As expected, nitroolefins with electron-withdrawing groups (2b–c) are more reactive than nitrostyrene or those incorporating an electron-donating group (2d) leading to the final products in shorter reaction time. In general, the reactions occurred with good to excellent stereoselectivity, except for 2-naphthyl-derived nitroolefin 2e which led to the addition–cyclization product 3ae in good enantioselectivity but moderate diastereoselection (entries 12 and 13 in Table 2). It is noteworthy that, contrary to that previously described, (24) the reactions of nitrostyrenes with electron-withdrawing groups occur with better diastereoselection than those with electron-donating substituents (compare entries 3, 4, 6, 7 vs 10, 11). Additionally, the data show that sq-4 was the best catalyst because it provided higher yields and better stereoselection than sq-6 (compare entries 3, 6, 10, and 12 vs 4, 7, 11, and 13 in Table 2).

The reaction was extended to 2-hydroxy nitrostyrenes with different substituents at C-5 (2b–d) by using sq-4 as the catalyst (entries 15, 17–20, and 22–25 in Table 2). As a general trend, the presence of a substituent at C-5 in the phenol nucleus decreased the stereoselection, specially the diastereoselectivity, of the reaction (compare entries 15, 20, and 25 in Table 2 with entry 1 in Table 1). This behavior is independent of the electronic characteristic of the substituent (compare entries 17–19 or 22–24 vs 3, 6, 10, and 12, respectively, in Table 2).

Attempting to improve the synthetic utility of the cascade reaction, we treated to create quaternary stereocenters by reacting trisubstituted nitroolefins 2f and 2g with 1a. trans α-methyl nitrostyrene 2f reacted very slowly with 1a by using sq-6 as the organocatalyst, leading to 3af in moderate yield, very bad diastereoselection, and moderate enantioselectivity (entry 27 in Table 2). On the contrary, trans-β-trifluoromethyl nitrostyrene 2g was recovered unchanged after 144 h of stirring with 1a in the presence of the same organocatalyst. These facts are usually observed in Michael additions and could be probably due to the steric demand on the disubstituted carbon of the double bond. This kind of substitution slows down the intramolecular nitro-Michael addition in intermediate B (Scheme 1) formed in the reaction of 2f, or the first intermolecular oxa-Michael addition in the reaction of 2g.

Scheme 1. Plausible Ternary Complexes That Explain the Formation of Stereoisomers

Because our main interest was the easy recovering and recycling of the catalyst, we studied the use of squaramide sq-9 (33) that is the polymeric homolog of sq-4, as the catalyst (entries 1, 2, 5, 9, 14, 16, 21, and 26 in Table 2). These results show that the polymeric material was able to promote the stereoselective cascade process, but it was less effective than the monomeric substrate. In general, the processes need longer reaction times, and the reaction was less stereoselective.

The recyclability of polymeric squaramide sq-9 was tested in the reaction of ortho-hydroxynitrostyrene 1a with 4-fluoronitrostyrene 2b at room temperature in DCM and 5 mol % of the catalyst. The mixture of the reaction was stirred until disappearance of 1a thin-layer chromatography (TLC), and the catalyst was isolated by filtration after each cycle, and reused after washing and drying. The results summarized in Table 3 show that sq-9 can be used for five cycles maintaining the activity.

Table 3. Recyclability of Catalyst sq-9 under the Best Reaction Conditions

cycle^a	t (h)	yield (%)^b	dr^c 3ab/epi-3ab	er^c
1	16	86	>99:<1	87:13
2	16	81	>99:<1	84:16
3	16	83	>99:<1	85:15
4	18	78	>99:<1	81:19
5	18	84	>99:<1	86:14

^{^a}

The reactions were performed with 1a (0.2 mmol), nitroolefin 2b (0.4 mmol), and sq-9 (5 mol %) in 0.6 mL of DCM at rt.

^{^b}

Yields after purification by flash chromatography.

^{^c}

Determined by HPLC analysis on a chiral stationary phase.

The relative stereochemistry for compound 3aa and their epimers at C-3 (epi-3aa) were established on the basis of the values of the coupling constants of H-2, H-3, and H-3, H-4, as previously described for its 4-phenacyl-substituted homolog. (34) For 3aa, the values of the coupling constants (³J_H2,H3 = 2.5 Hz, ³J_H3,H4 = 1.8 Hz) indicate a cis relationship of the substituents at C-2 and C-3, and trans geometry for the substituents at C-3 and C-4. Additionally, absolute stereochemistry (2S,3S,4S) was established by X-ray diffraction analysis for compound 3ac (Figure 1) (35) and generalized for all compounds 3aa–de. The values of the coupling constants for the same protons (³J_H2,H3 = 6.4 Hz, ³J_H3,H4 = 4.9 Hz) also allowed the assignation of the relative stereochemistry as trans for C-2–C-3 and cis for C-3–C-4 substituents in diastereoisomer epi-3aa. In that case, the absolute configuration (2S,3R,4S) for these compounds was assigned by accepting that the stereodiscrimination in the first oxa-Michael addition occurs in the same way for the formation of both diastereoisomers.

Figure 1. X-ray structure of **3ac** (ORTEP representation at 50% probability ellipsoids).

The formation of enantiomers in the reactions promoted by catalysts derived from α-amino acids (sq-4–sq-7) and (1R,2R)-1,2-cyclohexanediamine (sq-8) is a consequence of the stereochemistry of the ternary complex formed (Scheme 1), but we were intrigued by the fact that catalysts sq-4–7 and sq-8 provided diastereoisomers 3 and ent-epi-3 as major isomers, respectively. In order to clarify that observation, we decided to study the evolution of the reaction of 1a with 2a catalyzed by sq-6 and sq-8 along the time, and the results are collected in Table 4.

Table 4. Evolution with Time of the Diastereomeric Composition of the Reaction of 1a with 2a and 2f Catalyzed by sq-8 or sq-6^a

entry	time (h)	catalyst	yield (%)^b	dr^c 3aa/epi-3aa	er 3aa^c	er epi-3aa^c
1	4	sq-6	36	45/55	82/18	95/5
2	8	sq-6	52	56/44	83/17	96/4
3	16	sq-6	77	68/32	83/17	96/4
4	24	sq-6	100	83/17	84/16	98/2
5	32	sq-6	100	85/15	83/17	96/4
6	60	sq-6	100	84/16	83/17	94/4
7	5	sq-8	83	35/65	74/26^d	72/28^d
8	8	sq-8	100	20/80	74/26^d	72/28^d
9	24	sq-8	100	53/47	76/24^d	74/26^d
10	32	sq-8	100	60/40	74/26^d	71/29^d
11	72	sq-8	100	67/33	74/26^d	73/27^d
12	96	sq-8	100	67/33	74/26^d	74/26^d
13^e	63	sq-6	58	56/44	77/23	56/44
14^e	87	sq-6	66	56/44	77/23	56/44

^{^a}

The reaction was performed with 1a (0.25 mmol), 2a (0.4 mmol), and catalyst (5 mol %) in DCM (0.6 mL) at rt.

^{^b}

Yields refer to the percent of 1a consumed in the corresponding time.

^{^c}

Measured by HPLC analysis on a chiral column.

^{^d}

er correspond to ent-3aa and ent-epi-3aa, respectively.

^{^e}

Data refer to the reaction of 2f with 1a.

The data collected in Table 4 show that both the major and the ratio of diastereoisomers are dependent on the reaction time. An additional important fact is that epi-3aa (entry 1 in Table 4) or ent-epi-3aa (entry 6) was the first formed diastereoisomer, and the ratio change along the time. For the reaction catalyzed by sq-6, the ratio of 3aa increased over time (entries 1–5 in Table 4) until the reaction finished after 24 h (entry 4). Both dr and er were maintained along the time (entries 5, 6 in Table 4). On the contrary, catalyst sq-8 is more active leading to ent-epi-3aa as a major isomer because the reaction time is shorter (entry 8). Interestingly, when the reaction mixture was stirred for longer periods of time, the epimerization of ent-epi-3aa into ent-3aa was observed, obtaining the latter as the major diastereoisomer after 72 h (entries 8–12 in Table 4), but only with negligible variations in the enantioselectivity. Interestingly, no changes in the ratio of diastereoisomers, or in the ee were observed when increasing the reaction time (compare entries 11 and 12 in Table 4). It is also interesting to note that 3aa is stable in the solid state, but it epimerizes into a mixture of 3aa/epi-3aa (58/42) by stirring a solution in DCM for 120 h without catalysts. All these data show that, in the described reaction conditions, the formation of epi-3aa is kinetically favored, but it can be transformed into thermodynamic 3aa over the time as previously described for related Michael adducts. (34,36)

The stereochemistry of the products can be explained as summarized in Scheme 1. Bifunctional squaramides are responsible of the activation of the nitroolefin by formation of hydrogen bonds, and help to deprotonate the hydroxyl group leading to ternary complexes A or C. In those complexes, the first attack occurs to the β-position of the nitroalkene on the si face in complex A or on the re face in complex C, leading to nitronates B and D, respectively. This step is responsible for the formation of the stereocenter at C-2 with configuration S in the first case and R in the second one. Intermediates B and D participate in a second intramolecular nitro-Michael addition leading to the cyclization products. The addition of the nitronate by the re face to the si face of the nitroolefin in B yields (2S,3R,4S)-epi-3. On the contrary, the cyclization from D occurs by the attack of the si face of the nitronate to the re face of the nitroalkene leading to (2R,3S,4R)-ent-epi-3. The reactions for the enantiotropic faces in complexes A and C and their intermediates (B or D) explain the formation of both enantiomers depending on the organocatalyst. The extension of the partial conversion of epi-3 into 3 or ent-epi-3 into ent-3 is dependent on the reaction time and may occur through direct epimerization by deprotonation–protonation at the stereogenic center bearing the NO₂ group at C-3. This epimerization is supported by the fact that nitroalkene 2f, without hydrogen atom at C-3 does not modify the composition of the mixture of diastereoisomers along the time (entries 13, 14 in Table 4).

Conclusions

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The described results showed that different squaramides are good catalysts that are able to promote stereoselective cascade reactions leading to enantioenriched 2,3,4-trisubstituted benzopyrans. The enantioselectivity of the process is good, but the observed diastereoselection varies from moderate to excellent. The major diastereoisomer isolated is dependent on the reaction time, and careful control of the catalysts and the reaction conditions will be necessary to obtain the desired diastereoisomers.

Experimental Section

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General Information

¹H NMR (500 MHz) and ¹³C NMR (126 MHz) spectra were recorded in CDCl₃ or (CD₃)₂CO as solvents. Chemical shifts (δ) are given from TMS, and the residual solvent resonances were taken as the internal reference. A digital polarimeter at 589 nm (sodium lamp) was used to measure the specific rotation, and concentrations are given in g per 100 mL. Fourier transform infrared peaks are reported in wave numbers, and only the most structurally important ones are provided. Silica gel (230–240 mesh) was used as support for flash chromatography. Melting points are uncorrected and were obtained in open capillary tubes. TLC analysis was carried out on silica gel 60-coated glass plates and visualized with a solution of phosphomolybdic acid. Chiral high-performance liquid chromatography (HPLC) analysis was performed on a Lux-i-Cellulose-5 analytical column (250 × 4.6 mm). Elemental analyses were performed at the Elemental Analysis Center of the Complutense University of Madrid.

Commercial compounds were used without additional purification. Solvents were dried by standard procedures. 2-(2-Nitrovinyl)phenol derivatives 1a–d (37) and nitroolefins 2e (38) and 2g (39) were prepared as previously reported. Nitroolefins 1a–d and 2f are commercially available. Chiral bifunctional thiourea 8 and squaramides sq-4–sq-8 (33) were synthesized as described previously. Racemic samples were obtained in reactions catalyzed by achiral bifunctional thiourea derived from N¹,N¹-dimethylethane-1,2-diamine (40) (5 mol %) as described for the asymmetric reactions.

Preparation of Polymeric Squaramide sq-9

To a solution of sq-4 (676 mg, 1.31 mmol) in 1-dodecanol/dry toluene 3:1 (2.5 mL), styrene (1.5 mL, 13.1 mmol), divinylbenzene (40 μL, 0.26 mmol), and azobisisobutyronitrile (85 mg, 0.52 mmol) were successively added. The mixture was deoxygenated by bubbling nitrogen, and the sealed tube was stirred for 24 h in an oil bath at 70 °C and worked-up as previously described (33) to afford 1.58 g of sq-9 as a brown solid (89% yield). IR (ATR): 2922, 2848, 1601, 1491, 807, 756 cm^–1. The effective functionalization (f = 0.44 mmol g^–1) was calculated on the basis of the elemental analysis of nitrogen (C: 83.27, H: 7.63, N: 1.87).

General Procedure for the Cascade Reaction of 2-(2-Nitrovinyl)phenol Derivatives with Nitroolefins

A mixture of nitroolefin (0.4 mmol, 1 equiv), catalyst (0.010 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol derivative (0.2 mmol, 2 equiv) in CH₂Cl₂ (0.6 mL) was stirred at rt in a Wheaton vial until the end of the reaction (TLC). The reaction mixture was chromatographed to afford the pure product. In the reaction promoted by a supported material, the catalyst was isolated by filtration and washed with MeOH. The diastereomeric and enantiomeric ratio were determined by HPLC analysis on a chiral column using mixtures of hexane/isopropanol as the eluant.

(2S,3S,4S)-3-Nitro-4-(nitromethyl)-2-phenylchromane (3aa)

Obtained as a major diastereomer in the reaction of trans-β-nitrostyrene (60 mg, 0.4 mmol, 2 equiv), catalyst sq-6 (5 mg, 0.01 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield compound 3aa (51 mg, 0.16 mmol, 80% combined yield). Yellow solid. mp 133–135 °C [lit. (24) mp 165–168 °C]. [α]_D²³ +101.2 (c 0.9, CH₂Cl₂) [lit. (24) [α]_D²² +103.1 (c 0.3, CH₂Cl₂, 94% ee, >20:1 dr)]. ¹H NMR (500 MHz, CDCl₃): δ 4.25 (m, 1H), 4.79 (dd, J₁ = 13.6 Hz, J₂ = 10.4 Hz, 1H), 4.91 (dd, J₁ = 13.6 Hz, J₂ = 4.1 Hz), 5.23 (dd, J₁ = 2.5 Hz, J₂ = 1.8 Hz, 1H), 5.36 (d, J = 2.5 Hz, 1H), 7.10 (m, 2H), 7.28 (d, J = 0.7 Hz, 1H), 7.32 (dd, J₁ = 7.4 Hz, J₂ = 0.7 Hz, 1H), 7.41–7.46 (m, 5H). HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 17.1 min (major, 2S,3S,4S), t_R = 19.7 (minor, 2R,3R,4R). (dr 83:17; er 84:16).

(2S,3R,4S)-3-Nitro-4-(nitromethyl)-2-phenylchromane (epi-3aa)

Obtained as a minor diastereomer in the reaction of trans-β-nitrostyrene, catalyst sq-6, and 2-(2-nitrovinyl)phenol 1a. ¹H NMR (500 MHz, CDCl₃): δ 4.25 (m, 1H), 4.94 (dd, J₁ = 14.5 Hz, J₂ = 6.1 Hz, 1H), 5.00 (dd, J₁ = 14.5 Hz, J₂ = 7.4 Hz, 1H), 5.28 (dd, J₁ = 6.6 Hz, J₂ = 4.6 Hz, 1H), 5.75 (d, J = 6.6 Hz, 1H), 7.05 (m, 2H), 7.09 (m, 1H), 7.31 (m, 1H), 7.36–7.43 (m, 5H). ¹³C NMR (126 MHz, CDCl₃): δ 34.5, 75.6, 75.7, 84.4, 117.5, 122.4, 126.3, 127.2, 129.1, 129.2, 129.4, 132.1, 135.6, 152.5. IR (ATR): 2930, 1716, 1552, 1487, 757, 700, 581 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₆H₁₄N₂O₅ + Na, 337.0797; found, 337.0796. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 24.2 (major, 2S,3R,4S), t_R = 55.2 (minor, 2R,3S,4R). (er >99:<1).

(2S,3S,4S)-2-(4-Fluorophenyl)-3-nitro-4-(nitromethyl)chromane (3ab)

Obtained as a major diastereomer in the reaction of (E)-1-fluoro-4-(2-nitrovinyl)benzene (67 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield compound 3ab (58 mg, 0.17 mmol, 88%). Yellow solid. mp 88–91 °C [lit. (24) mp 135–137 °C]. [α]_D²³ +110.0 (c 1.0, CH₂Cl₂) [lit. (24) [α]_D²² +114.513 (c 0.6, CH₂Cl₂, 93% ee, 13:1 dr)]. ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.46 (m, 1H), 5.17 (dd, J₁ = 15.7 Hz, J₂ = 3.8 Hz, 1H), 5.30 (dd, J₁ = 15.7 Hz, J₂ = 10.2 Hz, 1H), 5.66 (dd, J₁ = 3.3 Hz, J₂ = 2.3 Hz, 1H), 5.77 (d, J = 2.3 Hz, 1H), 7.06–7.12 (m, 2H), 7.20–7.24 (m, 2H), 7.31 (m, 1H), 7.57–7.59 (m, 1H), 7.62–7.65 (m, 2H). HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 31.9 min (major, 2S,3S,4S), t_R = 35.9 min (minor, 2R,3R,4R). (dr >99:<1; er 98:2).

(2S,3R,4S)-2-(4-Fluorophenyl)-3-nitro-4-(nitromethyl)chromane (epi-3ab)

Obtained as a minor diastereomer in the reaction of (E)-1-fluoro-4-(2-nitrovinyl)benzene, catalyst sq-4, and 2-(2-nitrovinyl)phenol 1a. ¹H NMR (500 MHz, CDCl₃): δ 4.31 (m, 1H), 4.90 (dd, J₁ = 14.6 Hz, J₂ = 6.0 Hz, 1H), 5.01 (dd, J₁ = 14.6 Hz, J₂ = 7.5 Hz, 1H), 5.24 (dd, J₁ = 7.3 Hz, J₂ = 4.7 Hz, 1H), 5.67 (d, J = 7.3 Hz, 1H), 7.03 (m, 3H), 7.11 (m, 3H), 7.37 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 34.9, 74.8, 75.7, 84.5, 116.2, 116.4, 117.6, 122.6, 127.5, 128.4, 128.5, 130.3, 131.3, 152.4. IR (ATR): 1545, 1487, 823, 755 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 0.5 mL/min, λ = 210 nm) t_R = 20.4 min (major, 2S,3R,4S), t_R = 22.2 min (minor, 2R,3S,4R).

(2S,3S,4S)-2-(4-Chlorophenyl)-3-nitro-4-(nitromethyl)chromane (3ac)

Obtained as a major diastereomer in the reaction of (E)-1-chloro-4-(2-nitrovinyl)benzene (73 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield compound 3ac (58 mg, 0.16 mmol, 84%). Yellow solid. mp 122–124 °C [lit. (24) mp 139–141 °C]. [α]_D²³ +71.6 (c 1.0, CH₂Cl₂) [lit. (24) [α]_D²² +98.2 (c 1.0, CH₂Cl₂, 92% ee, >20:1 dr)]. ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.26 (m, 1H), 4.78 (dd, J₁ = 13.5 Hz, J₂ = 10.4 Hz, 1H), 4.91 (m, 1H), 5.20 (m, 1H), 5.32 (d, J = 2.3 Hz, 1H), 7.08 (m, 1H), 7.11 (m, 1H), 7.28 (m, 1H), 7.31–7.37 (m, 3H), 7.42 (m, 2H). HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 95:5, 1.0 mL/min, λ = 210 nm) t_R = 27.3 min (major, 2S,3S,4S), t_R = 31.7 min (minor, 2R,3R,4R). (dr 95:5; er 97:3).

(2S,3R,4S)-2-(4-Chlorophenyl)-3-nitro-4-(nitromethyl)chromane (epi-3ac)

Obtained as a minor diastereomer in the reaction of (E)-1-chloro-4-(2-nitrovinyl)benzene, catalyst sq-4, and 2-(2-nitrovinyl)phenol 1a. ¹H NMR (500 MHz, CDCl₃): δ 4.27 (m, 1H), 4.92 (dd, J₁ = 14.6 Hz, J₂ = 6.0 Hz, 1H), 5.00 (dd, J₁ = 14.5 Hz, J₂ = 7.5 Hz 1H), 5.23 (dd, J₁ = 7.0 Hz, J₂ = 4.7 Hz, 1H), 5.69 (d, J = 7.0 Hz, 1H), 7.03 (m, 2H), 7.32 (m, 3H), 7.39 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 34.7, 74.9, 75.6, 84.3, 116.9, 117.6, 122.7, 127.4, 127.8, 129.5, 130.3, 134.0, 135.7, 152.3. IR (ATR): 1546, 1489, 820, 755 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₆H₁₃ClN₂O₅ + Na, 371.0408; found, 371.0406. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 95:5, 1.0 mL/min, λ = 210 nm) t_R = 13.8 min (major, 2S,3R,4S), t_R = 38.9 min (minor, 2R,3S,4R). (er 74:26).

(2S,3S,4S)-2-(4-Methoxyphenyl)-3-nitro-4-(nitromethyl)chromane (3ad)

Obtained as a major diastereomer in the reaction of (E)-1-methoxy-4-(2-nitrovinyl)benzene (72 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield compound 3ad (50 mg, 0.15 mmol, 73%). Yellow solid. mp 176–178 °C [lit. (24) mp 198–199 °C]. [α]_D²³ +109.1 (c 1.0, CH₂Cl₂) [lit. (24) [α]_D²² +147.5 (c 0.2, CH₂Cl₂, >99% ee, >20:1 dr)]. ¹H NMR (500 MHz, (CD₃)₂CO): δ 3.82 (s, 3H), 4.40 (m, 1H), 5.17 (m, 1H), 5.28 (m, 1H), 5.58 (d, J = 2.5 Hz, 1H), 5.67 (m, 1H), 6.99 (m, 2H), 7.06 (m, 2H), 7.31 (m, 1H), 7.47 (m, 2H), 7.55 (m, 1H). HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 34.9 min (major, 2S,3S,4S), t_R = 37.2 min (minor, 2R,3R,4R). (dr 91:9; er >99:<1).

(2S,3S,4S)-2-(Naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3ae)

Obtained as a major diastereomer in the reaction of (E)-2-(2-nitrovinyl)naphthalene (38) (80 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield compound 3ae (61 mg, 0.17 mmol, 85%). Yellow solid. mp 107–110 °C [lit. (24) mp 172–175 °C]. [α]_D²³ +115.1 (c 1.0, CH₂Cl₂) [lit. (24) [α]_D²² +125.0 (c 0.1, CH₂Cl₂, >99% ee, >20:1 dr)]. ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.51 (dd, J₁ = 10.2 Hz, J₂ = 3.8 Hz, 1H), 5.22 (dd, J₁ = 15.6 Hz, J₂ = 3.8 Hz, 1H), 5.39 (dd, J₁ = 15.6 Hz, J₂ = 10.1 Hz, 1H), 5.79 (dd, J₁ = 2.4 Hz, J₂ = 1.0 Hz, 1H), 5.94 (d, J = 2.3 Hz, 1H), 7.13 (m, 2H), 7.35 (m, 1H), 7.56 (m, 2H), 7.60–7.62 (m, H), 7.71 (m, H), 7.94–7.99 (m, 3H), 8.13 (m, 1H). HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 24.7 min (major, 2S,3S,4S), t_R = 31.4 min (minor, 2R,3R,4R). (dr 64:36; er 93:7).

(2S,3R,4S)-2-(Naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (epi-3ae)

Obtained as a minor diastereomer in the reaction of (E)-2-(2-nitrovinyl)naphthalene, catalyst sq-4, and 2-(2-nitrovinyl)phenol 1a. ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.47 (dt, J₁ = 7.5 Hz, J₂ = 4.9 Hz, 1H), 5.25 (dd, J₁ = 15.7 Hz, J₂ = 5.2 Hz, 1H), 5.40 (dd, J₁ = 15.7 Hz, J₂ = 7.5 Hz, 1H), 5.91 (dd, J₁ = 6.7 Hz, J₂ = 4.6 Hz, 1H), 6.17 (d, J = 6.7 Hz, 1H), 7.07 (m, 2H), 7.33–7.37 (m, 2H), 7.54–7.58 (m, 2H), 7.70 (m, 1H), 7.71–7.96 (m, 2H), 8.00 (m, 1H), 8.07 (m, 1H). ¹³C NMR (126 MHz, (CD₃)₂CO): δ 34.4, 75.5, 75.6, 84.3, 116.9, 118.3, 122.0, 123.8, 126.6, 126.7, 126.8, 127.7, 128.1, 128.8, 129.5, 133.1, 133.6, 133.9, 153.0. IR (ATR): 1554, 1485, 829, 747 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₂₀H₁₆N₂O₅ + Na, 387.0958; found, 387.0953. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 34.0 min (major, 2S,3R,4S), t_R = 82.6 min (minor, 2R,3S,4R). (er 92:8).

(2S,3S,4S)-6-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (3ba)

Obtained as a major diastereomer in the reaction of trans-β-nitrostyrene (60 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b (36 mg, 0.2 mmol, 1 equiv) to yield compound 3ba (53 mg, 0.16 mmol, 81%). Yellow solid. mp 125–127 °C. [α]_D²³ +119.3 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 2.34 (s, 3H), 4.21 (ddd, J₁ = 10.5 Hz, J₂ = 4.1 Hz, J₃ = 1.6 Hz), 4.76 (dd, J₁ = 13.6 Hz, J₂ = 10.5 Hz, 1H), 4.90 (dd, J₁ = 13.6 Hz, J₂ = 4.0 Hz, 1H), 5.19 (m, 1H), 5.31 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 7.06 (m, 1H), 7.12 (m, 1H), 7.40–7.45 (m, 5H). ¹³C NMR (126 MHz, CDCl₃): δ 20.7, 37.0, 73.3, 78.5, 84.1, 115.4, 117.8, 125.6, 128.6, 128.9, 129.2, 130.6, 132.3, 134.6, 151.9. IR (ATR): 1552, 1503, 818, 757, 704 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₇H₁₆N₂O₅ + Na, 351.0997; found, 351.0958. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 14.1 min (major, 2S,3S,4S), t_R = 18.1 min (minor, 2R,3R,4R). (dr 73:27; er 90:10).

(2S,3R,4S)-6-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (epi-3ba)

Obtained as a minor diastereomer in the reaction of trans-β-nitrostyrene, catalyst sq-4, and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b. ¹H NMR (500 MHz, CDCl₃): δ 2.30 (s, 3H), 4.20 (m, 1H), 4.93 (dd, J₁ = 14.6 Hz, J₂ = 6.0 Hz, 1H), 5.00 (dd, J₁ = 14.5 Hz, J₂ = 7.5 Hz, 1H), 5.26 (dd, J₁ = 6.7 Hz, J₂ = 4.6 Hz, 1H), 5.71 (d, J = 6.6 Hz, 1H), 6.87 (s, 1H), 6.92 (d, 1H, J = 8.3 Hz), 7.10 (m, 1H), 7.35–7.42 (m, 5H). ¹³C NMR (126 MHz, CDCl₃): δ 20.6, 34.5, 75.6, 75.7, 84.6, 116.7, 117.3, 126.2, 127.3, 129.2, 129.5, 130.8, 131.9, 135.7, 150.3. HRMS (ESI-QTOF) m/z: calcd for C₁₇H₁₆N₂O₅ + Na, 351.0997; found, 351.0959. IR (ATR): 1554, 1497, 816, 751, 694 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 23.9 min (major, 2S,3R,4S), t_R = 54.7 min (minor, 2R,3S,4R). (er 82:18).

(2S,3S,4S)-2-(4-Fluorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (3bb)

Obtained as a major diastereomer in the reaction of trans-4-fluoro-β-nitrostyrene (67 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b (36 mg, 0.2 mmol, 1 equiv) to yield compound 3bb (55 mg, 0.16 mmol, 81%). Yellow solid. mp 99–101 °C. [α]_D²³ +137.5 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 2.32 (s, 3H), 4.20 (m, 1H), 4.72 (dd, J₁ = 14.5 Hz, J₂ = 5.9 Hz, 1H), 4.86 (dd, J₁ = 14.5 Hz, J₂ = 7.5 Hz, 1H), 5.14 (m, 1H), 5.26 (d, J = 6.7 Hz, 1H), 6.95 (m, 1H), 7.10 (m, 4H), 7.38 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 20.6, 36.9, 72.7, 78.4, 84.1, 115.3, 115.9 (d, J = 21.8 Hz), 117.7, 127.4, 127.5, 128.6, 130.4 (d, J = 3.1 Hz); 130.6, 132.4, 151.7, 161.7, 164.2. IR (ATR): 2920, 1603, 1554, 1513, 829, 751 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 12.5 min (major, 2S,3S,4S), t_R = 15.5 min (minor, 2R,3R,4R). (dr 80:20; er 88:12).

(2S,3R,4S)-2-(4-Fluorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (epi-3bb)

Obtained as a minor diastereomer in the reaction of trans-4-fluoro-β-nitrostyrene, catalyst sq-4, and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b. ¹H NMR (500 MHz, CDCl₃): δ 2.30 (s, 3H), 4.25 (m, 1H), 4.90 (dd, J₁ = 14.6 Hz, J₂ = 5.8 Hz, 1H), 5.01 (dd, J₁ = 14.6 Hz, J₂ = 7.6 Hz, 1H), 5.21 (dd, J₁ = 7.3 Hz, J₂ = 4.7 Hz, 1H), 5.63 (d, J = 7.3 Hz, 1H), 6.91 (m, 2H), 7.09 (m, 3H), 7.36 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 20.6, 34.9, 74.8, 75.7, 84.7, 116.2 (d, J = 21.9 Hz), 116.6, 117.3, 124.5, 127.6, 128.4 (d, J = 8.4 Hz), 128.8, 131.0, 132.2, 150.2. HRMS (ESI-QTOF) m/z: calcd for C₁₇H₁₅FN₂O₅ + Na, 369.0863; found, 369.0861. IR (ATR): 1605, 1556, 1497, 819, 751, 694 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 21.7 min (major, 2S,3R,4S), t_R = 60.7 min (minor, 2R,3S,4R). (er >99:<1).

(2S,3S,4S)-2-(4-Chlorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (3bc)

Obtained as a major diastereomer in the reaction of trans-4-chloro-β-nitrostyrene (73 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b (36 mg, 0.2 mmol, 1 equiv) to yield compound 3bc (62 mg, 0.17 mmol, 85%). Yellow solid. mp 137–139 °C. [α]_D²³ +154.1 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 2.34 (s, 3H), 4.21 (m, 1H), 4.5 (dd, J₁ = 13.5 Hz, J₂ = 10.5 Hz, 1H), 4.91 (dd, J₁ = 13.5 Hz, J₂ = 4.0 Hz, 1H), 5.17 (t, J = 2.1 Hz, 1H), .29 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.07 (m, 1H), 7.12 (m, 1H), 7.36 (m, 2H), 7.41 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 20.6, 37.0, 72.7, 78.4, 83.9, 115.3, 117.8, 127.0, 128.6, 129.1, 130.7, 132.5, 133.1, 135.1, 151.6. IR (ATR): 1554, 1493, 812, 690, 515 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₇H₁₅ClN₂O₅ + Na, 385.0597; found, 385.0562. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 13.9 min (major, 2S,3S,4S), t_R = 19.7 min (minor, 2R,3R,4R). (dr 68:32; er 95:5).

(2S,3R,4S)-2-(4-Chlorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (epi-3bc)

Obtained as a minor diastereomer in the reaction of trans-4-chloro-β-nitrostyrene, catalyst sq-4, and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b. ¹H NMR (500 MHz, CDCl₃): δ 2.30 (s, 3H), 4.22 (m, 1H), 4.91 (dd, J₁ = 14.6 Hz, J₂ = 5.8 Hz, 1H), 5.00 (dd, J₁ = 14.6 Hz, J₂ = 7.6 Hz, 1H), 5.21 (dd, J₁ = 7.0 Hz, J₂ = 4.6 Hz, 1H), 5.65 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 7.32–7.37 (m, 6H). ¹³C NMR (126 MHz, CDCl₃): δ 20.6, 34.7, 74.8, 75.6, 84.5, 116.6, 117.3, 127.5, 127.8, 129.4, 131.0, 132.2, 134.1, 135.6, 150.1. HRMS (ESI-QTOF) m/z: calcd for C₁₇H₁₅ClN₂O₅ + Na, 385.0597; found, 385.0562. IR (ATR): 1554, 1497, 817, 754, 696 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 25.5 min (major, 2S,3R,4S), t_R = 64.7 min (minor, 2R,3S,4R). (er 97:3).

(2S,3S,4S)-6-Methyl-2-(naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3be)

Obtained as a major diastereomer in the reaction of (E)-2-(2-nitroethenyl)-naphthalene (38) (80 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-methyl-2-(2-nitrovinyl)phenol 1b (36 mg, 0.2 mmol, 1 equiv) to yield compound 3be (48 mg, 0.13 mmol, 64%). Yellow solid. mp 98–100 °C. [α]_D²³ +126.7 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 2.36 (s, 3H), 4.26 (m, 1H), 81 (m, 1H), 4.95 (dd, J₁ = 13.4 Hz, J₂ = 4.1 Hz, 1H), 5.31 (m, 1H), 5.48 (d, J = 2.3 Hz, 1H), 7.05 (m, 1H), 7.09 (m, 1H), 7.14 (m, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.53 (m, 2H), 7.86–7.94 (m, 4H). ¹³C NMR (126 MHz, CDCl₃): δ 20.7, 37.1, 73.4, 78.6, 84.0, 115.5, 117.8, 122.6, 125.2, 126.6, 126.7, 127.8, 128.7, 128.8, 130.6, 131.9, 132.3, 133.1, 133.5, 151.9. IR (ATR): 2924, 1603, 1550, 812 cm^–1. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 18.7 min (major, 2S,3S,4S), t_R = 28.4 min (minor, 2R,3R,4R). (dr 62:38; er 88:12).

(2S,3S,4S)-6-Bromo-3-nitro-4-(nitromethyl)-2-phenylchromane (3ca)

Obtained as a major diastereomer in the reaction of trans-β-nitrostyrene (60 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-bromo-2-(2-nitrovinyl)phenol 1c (49 mg, 0.2 mmol, 1 equiv) to yield compound 3ca (58 mg, 0.15 mmol, 74%). Yellow solid. mp 93–96 °C. [α]_D²³ +109.6 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 4.23 (m, 1H), 4.76 (dd, J₁ = 13.7 Hz, J₂ = 10.4 Hz, 1H), 4.89 (dd, J₁ = 13.7 Hz, J₂ = 4.1 Hz, 1H), 5.19 (m, 1H), 5.32 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 9.4 Hz, 1H), 7.38–7.45 (m, 7H). ¹³C NMR (126 MHz, CDCl₃): δ 36.7, 73.4, 78.1, 83.6, 114.8, 117.9, 119.8, 125.5, 129.0, 129.4, 131.1, 132.9, 133.9, 153.1. IR (ATR): 1550, 1481, 816 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₆H₁₃BrN₂O₅ + Na, 414.9897; found, 414.9904. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 18.7 min (major, 2S,3S,4S), t_R = 21.7 min (minor, 2R,3R,4R). (dr 79:21; er 96:4).

(2S,3S,4S)-6-Bromo-2-(4-fluorophenyl)-3-nitro-4-(nitromethyl)chromane (3cb)

Obtained as a major diastereomer in the reaction of trans-4-fluoro-β-nitrostyrene (67 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-bromo-2-(2-nitrovinyl)phenol 1c (49 mg, 0.2 mmol, 1 equiv) to yield compound 3cb (68 mg, 0.17 mmol, 83%). Yellow solid. mp 138–141 °C. [α]_D²³ +112.5 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.50 (dd, J₁ = 10.1 Hz, J₂ = 3.6, 1H), 5.22 (dd, J₁ = 15.9 Hz, J₂ = 3.6 Hz, 1H), 5.32 (dd, J₁ = 16.0 Hz, J₂ = 10.2 Hz, 1H), 5.69 (dd, J₁ = 2.4 Hz, J₂ = 1.0 Hz, 1H), 5.81 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 7.22 (m, 2H), 7.47 (m, 1H), 7.63 (m, 2H), 7.83 (m, 1H). ¹³C NMR (126 MHz, (CD₃)₂CO): δ 36.1, 72.4, 76.8, 84.7, 113.7, 115.3 (d, J = 21.9 Hz), 119.2, 120.0, 128.1 (d, J = 8.5 Hz), 131.6, 131.7, 131.8, 132.1, 153.6, 161.8 (d, J = 245.5 Hz). IR (ATR): 2920, 1550, 1513, 816, 661 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₆H₁₂BrFN₂O₅ + Na, 432.9797; found, 432.9810. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 15.2 min (major, 2S,3S,4S), t_R = 16.7 min (minor, 2R,3R,4R). (dr 86:14; er 97:3).

(2S,3S,4S)-6-Bromo-2-(4-chlorophenyl)-3-nitro-4-(nitromethyl)chromane (3cc)

Obtained according to general procedure, using trans-4-chloro-β-nitrostyrene (0.4 mmol, 73 mg, 2 equiv), catalyst sq-4 (0.01 mmol, 0.05 equiv), and (E)-4-bromo-2-(2-nitrovinyl)phenol compound 1c (49 mg, 0.2 mmol, 1 equiv) to yield compound 3cc (68 mg, 0.16 mmol, 79%). mp 226–228 °C. [α]_D²³ +9.3 (c 1.0, CHCl₃). ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.50 (m, 1H), 5.22 (dd, J₁ = 15.9 Hz, J₂ = 3.6 Hz, 1H), 5.32 (dd, J₁ = 16.0 Hz, J₂ = 10.1 Hz, 1H), 5.71 (m, 1H), 5.82 (d, J = 2.4, 1H), 7.05 (d, J = 8.8 Hz, 1H), 7.45–7.49 (m, 3H), 7.60 (m, 2H), 7.82 (m, 1H). ¹³C NMR (126 MHz, (CD₃)₂CO): δ 36.1, 72.4, 76.8 (CH₂), 84.52, 113.8, 119.2, 120.0, 127.7, 128.6, 131.8, 132.1, 134.1, 134.55, 153.5. IR (ATR): 1697, 1550, 1481, 808, 641 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₁₆H₁₂BrClN₂O₅ + Na, 448.9497; found, 448.9516. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 17.1 min (major, 2S,3S,4S), t_R = 19.7 min (minor, 2R,3R,4R). (dr 88:12; er 93:7).

(2S,3S,4S)-6-Bromo-2-(naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3ce)

Obtained as a major diastereomer in the reaction of (E)-2-(2-nitroethenyl)-naphthalene⁴¹ (80 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-bromo-2-(2-nitrovinyl)phenol 1c (49 mg, 0.2 mmol, 1 equiv) to yield compound 3ce (67 mg, 0.15 mmol, 76%). Yellow solid. mp 129–131 °C. [α]_D²³ +98.9 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, (CD₃)₂CO): δ 4.54 (dd, J₁ = 10.2 Hz, J₂ = 3.6 Hz, 1H), 5.27 (dd, J₁ = 15.9 Hz, J₂ = 3.6 Hz, 1H), 5.40 (dd, J₁ = 15.9 Hz, J₂ = 10.2 Hz, 1H), 5.81 (dd, J = 2.5 Hz, 1.0 Hz, 1H), 5.97 (d, J = 1.4 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.50 (dd, J₁ = 8.7 Hz, J₂ = 2.4 Hz, 1H), 7.56 (m, 2H), 7.71 (dd, J₁ = 8.6, J₂ = 1.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.94–7.99 (m, 3H), 8.12 (s, 1H). ¹³C NMR (126 MHz, (CD₃)₂CO): δ 36.2, 73.1, 76.9, 84.7, 113.7, 119.3, 120.2, 123.4, 125.1, 126.5, 126.6, 127.7, 128.1, 128.2, 131.8, 132.1, 133.0, 133.1, 133.5, 153.7. IR (ATR): 1697, 1550, 1481, 816, 747 cm^–1. HRMS (ESI-QTOF) m/z: calcd for C₂₀H₁₅BrN₂O₅ + Na, 465.0099; found, 465.0068. HPLC: (Lux i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 24.0 min (major, 2S,3S,4S), t_R = 30.9 min (minor, 2R,3R,4R). (dr 78:22; er 88:12).

(2S,3S,4S)-6-Chloro-3-nitro-4-(nitromethyl)-2-phenylchromane (3da)

Obtained as a major diastereomer in the reaction of trans-β-nitrostyrene (60 mg, 0.4 mmol, 2 equiv), catalyst sq-4 (5 mg, 0.01 mmol, 0.05 equiv), and (E)-4-chloro-2-(2-nitrovinyl)phenol 1d (40 mg, 0.2 mmol, 1 equiv) to yield compound 3da (45 mg, 0.13 mmol, 65%). Yellow solid. mp 71–73 °C. [α]_D²³ +115.0 (c 1.0, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ 4.23 (m, 1H), 4.77 (m, 1H), 4.89 (dd, J₁ = 13.7 Hz, J₂ = 4.0 Hz, 1H), 5.20 (dd, J₁ = 2.5 Hz, J₂ = 1.7 Hz, 1H), 5.32 (d, J = 2.4 Hz, 1H), 7.05 (d, J = 9.3 Hz, 1H), 7.06–7.46 (m, 7H). ¹³C NMR (126 MHz, CDCl₃): δ 36.8, 73.5, 78.1, 83.6, 119.5, 125.5, 127.7, 128.1, 129.0, 129.4, 130.0, 131.9, 133.9, 152.6. IR (ATR): 2924, 1550, 816, 755, 698 cm^–1. HPLC: (Lux-i-Cellulose-5, n-hexane/isopropanol = 90:10, 1.0 mL/min, λ = 210 nm) t_R = 16.8 min (major, 2S,3S,4S), t_R = 18.6 min (minor, 2R,3R,4R). (dr 74:26; er 85:15).

(2S,3S,4S)-3-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (3af) (24)

Obtained as a major diastereoisomer in the reaction of trans α-methyl-β-nitrostyrene (65 mg, 0.4 mmol, 2 equiv), catalyst sq-6 (10 mg, 0.02 mmol, 0.10 equiv), and 2-(2-nitrovinyl)phenol 1a (33 mg, 0.2 mmol, 1 equiv) to yield the products (30 mg, 0.1 mmol, 50%) as an inseparable mixture of 3af and epi-3af. ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.29 (m, 12H), 7.17–7.16 (m, 1H) (major), 7.07–6.98 (m, 5H), 5.75 (s, 1H) (major), 5.59 (s, 1H) (minor), 5.17 (dd, J = 8.1 Hz, J = 2.9 Hz, 1H) (minor), 5.11 (dd, J = 15.2 Hz, J = 6.3 Hz, 1H) (major), 4.88 (dd, J = 15.2 Hz, J = 5.6 Hz, 1H) (major), 4.73 (dd, J = 14.6 Hz, J = 8.2 Hz, 1H) (minor), 4.44 (dd, J = 14.7 Hz, J = 3.1 Hz, 1H) (minor), 4.14 (t, J = 5.9 Hz, 1H) (major), 1.63 (s, 3H) (major), 1.40 (s, 3H) (minor). HPLC: (Lux i-Amylose-1, n-hexane/isopropanol = 97:3, 1.0 mL/min, λ = 210 nm) t_R = 14.5 min (major, 2S,3R,4S), t_R = 15.2 (minor, 2R,3S,4R). (er 56:44), t_R = 18.1 min (minor, 2R,3R,4R), t_R = 20.0 (major, 2S,3S,4S). (dr 56:44; er 77:23).

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¹H NMR and ¹³C NMR spectra for new compounds, X-ray crystallographic data for 3ac, copy of IR spectra for polymeric squaramide 9, and copies of the HPLC chromatograms (PDF)

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Author Information

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Corresponding Authors
- José M. Andrés - Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain; Email: [email protected]
- Rafael Pedrosa - Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain; http://orcid.org/0000-0002-3652-7301; Email: [email protected]
Authors
- Alicia Maestro - Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
- María Valle - Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
- Isabel Valencia - Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Paseo de Belén 7, 47011 Valladolid, Spain
Notes
The authors declare no competing financial interest.

Acknowledgments

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The authors thank the Ministerio de Economía of Spain (Project FEDER-CTQ2014-59870-P) and Junta de Castilla y León (Projects FEDER-VA115P17 and VA149G18) for financial support. The aid in the X-ray diffraction determinations provided by Prof. J. A. Miguel is also acknowledged.

References

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Catalytic Synthesis of 2H-Chromenes
Majumdar, Nilanjana; Paul, Nanda D.; Mandal, Sutanuva; de Bruin, Bas; Wulff, William D.
ACS Catalysis (2015), 5 (4), 2329-2366CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
A review. 2H-Chromenes (2H-1-benzopyran derivs.) display a broad spectrum of biol. activities. The 2H-chromene substructure is an important structural motif present in a variety of medicines, natural products, and materials showing unique photophys. properties. Hence, the structural importance of the benzopyran moiety has elicited a great deal of interest in the field of org. synthesis and chem. biol. to develop new and improved synthesis of these mol. skeletons. This review gives an up-to-date overview of different catalytic methodologies developed for the synthesis of 2H-chromenes and is structured around the three main approaches applied in catalytic 2H-chromene synthesis: (I) catalysis with (transition) metals, (II) metal-free Bronsted and Lewis acid/base catalysis, which includes examples of nonenantioselective organocatalysis, and (III) enantioselective organocatalysis. The section in which the metal-catalyzed reactions are discussed describes different ring-closing strategies based on (transition) metal catalysis, including a few enantioselective approaches. For most of these reactions, plausible mechanisms are delineated. Moreover, synthesis of some natural products and medicinally important drugs are included. Specific advantages and disadvantages of the several synthetic methodologies are discussed. The review focuses on catalytic 2H-chromene synthesis. However, for a complete overview, synthetic routes involving some stoichiometric steps and reactions producing ring-scaffolds that are closely related to 2H-chromenes are also included.
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Hu, N.; Li, K.; Wang, Z.; Tang, W. Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantioselective Palladium-Catalyzed Alkene Aryloxyarylation Reactions. Angew. Chem., Int. Ed. 2016, 55, 5044, DOI: 10.1002/anie.201600379
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Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantioselective Palladium-Catalyzed Alkene Aryloxyarylation Reactions
Hu, Naifu; Li, Ke; Wang, Zheng; Tang, Wenjun
Angewandte Chemie, International Edition (2016), 55 (16), 5044-5048CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A highly enantioselective alkene aryloxyarylation led to the high-yielding formation of a series of 1,4-benzodioxanes, 1,4-benzooxazines, and chromans contg. quaternary stereocenters with excellent enantioselectivity. The sterically bulky and conformationally well defined chiral monophosphorus ligand I or II was responsible for the high reactivity and enantioselectivity of these transformations. The application of this method to the synthesis of the chiral chroman backbone of α-tocopherol was demonstrated.
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Mao, H.; Lin, A.; Tang, Y.; Shi, Y.; Hu, H.; Cheng, Y.; Zhu, C. Organocatalytic oxa/aza-Michael-Michael Cascade Strategy for the Construction of Spiro [Chroman/Tetrahydroquinoline-3,3′-oxindole] Scaffolds. Org. Lett. 2013, 15, 4062, DOI: 10.1021/ol401595g
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Organocatalytic oxa/aza-Michael-Michael Cascade Strategy for the Construction of Spiro [Chroman/Tetrahydroquinoline-3,3'-oxindole] Scaffolds
Mao, Haibin; Lin, Aijun; Tang, Yang; Shi, Yan; Hu, Hongwen; Cheng, Yixiang; Zhu, Chengjian
Organic Letters (2013), 15 (16), 4062-4065CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A new useful and effective chiral amine-catalyzed oxa- and aza-Michael-Michael cascade methodol. for the construction of enantiomerically enriched indolinones spiro-fused with chromans or tetrahydroquinolines is reported. By employing suitable organocatalysts depending on the different Michael donors (Ar-OH/Ar-NHR), the processes offered excellent stereocontrol (dr >20:1, >99% ee) under mild conditions [e.g., protected methyleneindolinone I + (E)-2-(2-nitrovinyl)phenol in presence of squaramide-cinchona bifunctional catalyst afforded II (72% yield, 92% ee)].
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Zheng, W.; Zhang, J.; Liu, S.; Yu, C.; Miao, Z. Asymmetric synthesis of spiro[chroman-3,3′-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael-Michael cascade strategy with bifunctional amine-thiourea organocatalysts. RSC Adv. 2015, 5, 91108, DOI: 10.1039/c5ra17792h
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Asymmetric synthesis of spiro[chroman-3,3'-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael-Michael cascade strategy with bifunctional amine-thiourea organocatalysts
Zheng, Weiping; Zhang, Jiayong; Liu, Shuang; Yu, Chengbin; Miao, Zhiwei
RSC Advances (2015), 5 (111), 91108-91113CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
An efficient chiral bifunctional amine-thiourea catalyzed cascade oxa-Michael-Michael addn. of 4-alkenyl pyrazolin-3-ones I [R2 = CH3, C6H5; R3 = 2-ClC6H4, 3-O2NC6H4, 2-furyl, etc.; R4 = H, CH3] to (E)-2-(2-nitrovinyl)phenol R1CH=CHNO2 [R1 = 2-hydroxybenzen-1-yl, 2-hydroxynaphthalen-1-yl, 2-hydroxy-4-methoxybenzen-1-yl, etc.] for the synthesis of chiral heterocyclic systems contg. spiro[chroman-3,3'-pyrazol] scaffolds, e.g., II(R = H, 5,6-C4H4, 7-MeO, etc.) has been developed. This reaction afforded the desired products, e.g., II in high to excellent yields (up to 98%) with moderate to high enantioselectivities (up to 99%) and diastereoselectivities (up to 20:1) under low catalyst (15 mol%) concn. This catalytic asym. reaction provides an efficient route toward the synthesis of chiral spiro[chroman-3,3'-pyrazol] derivs., e.g., II contg. three contiguous stereocenters which possess potential pharmaceutical activities.
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Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds. Angew. Chem., Int. Ed. 2016, 55, 12104, DOI: 10.1002/anie.201606947
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Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds
Zhao, Kun; Zhi, Ying; Shu, Tao; Valkonen, Arto; Rissanen, Kari; Enders, Dieter
Angewandte Chemie, International Edition (2016), 55 (39), 12104-12108CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
An asym. organocatalytic domino oxa-Michael/1,6-addn. reaction of ortho-hydroxyphenyl-substituted para-quinone methides and isatin-derived enoates was developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4-phenyl-substituted chromans bearing spiro-connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99% ee).
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Zhu, Y.; Li, X.; Chen, Q.; Su, J.; Jia, F.; Qiu, S.; Ma, M.; Sun, Q.; Yan, W.; Wang, K.; Wang, R. Highly Enantioselective Cascade Reaction Catalyzed by Squaramides: the Synthesis of CF₃-Containing Chromanes. Org. Lett. 2015, 17, 3826, DOI: 10.1021/acs.orglett.5b01799
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Saha, P.; Biswas, A.; Molleti, N.; Singh, V. K. Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst. J. Org. Chem. 2015, 80, 11115, DOI: 10.1021/acs.joc.5b01751
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Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst
Saha, Prasenjit; Biswas, Arnab; Molleti, Nagaraju; Singh, Vinod K.
Journal of Organic Chemistry (2015), 80 (21), 11115-11122CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A highly enantioselective synthesis of chiral chroman derivs. via an oxa-Michael-Michael cascade reaction has been developed using a bifunctional thiourea organocatalyst [e.g., trans-2-hydroxychalcone + trans-β-nitrostyrene → I (72% yield, dr 83:17, ee > 99%) in presence of cinchona alkaloid-derived thiourea]. The products were obtained with excellent enantioselectivities (up to >99%), good yields (up to 95%), and diastereoselectivities (up to 5:1).
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Wang, X.-F.; An, J.; Zhang, X.-X.; Tan, F.; Chen, J.-R.; Xiao, W.-J. Catalytic Asymmetric Aza-Michael–Michael Addition Cascade: Enantioselective Synthesis of Polysubstituted 4-Aminobenzopyrans. Org. Lett. 2011, 13, 808, DOI: 10.1021/ol1031188
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Catalytic Asymmetric Aza-Michael-Michael Addition Cascade: Enantioselective Synthesis of Polysubstituted 4-Aminobenzopyrans
Wang, Xu-Fan; An, Jing; Zhang, Xiao-Xiao; Tan, Fen; Chen, Jia-Rong; Xiao, Wen-Jing
Organic Letters (2011), 13 (4), 808-811CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
A catalytic asym. aza-Michael-Michael addn. cascade of anilines to nitroolefin enoates in the presence of chiral bifunctional thiourea catalysts has been disclosed. This reaction provides a mild and efficient approach to polysubstituted chiral 4-aminobenzopyrans, e.g., I bearing three consecutive stereocenters in high yields with excellent stereoselectivities.
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Jia, Z.-X.; Luo, Y.-C.; Cheng, X.-N.; Xu, P.-F.; Gu, Y.-C. Organocatalyzed Michael-Michael Cascade Reaction: Asymmetric Synthesis of Polysubstituted Chromans. J. Org. Chem. 2013, 78, 6488, DOI: 10.1021/jo400476b
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Organocatalyzed Michael-Michael Cascade Reaction: Asymmetric Synthesis of Polysubstituted Chromans
Jia, Zhen-Xin; Luo, Yong-Chun; Cheng, Xi-Na; Xu, Peng-Fei; Gu, Yu-Cheng
Journal of Organic Chemistry (2013), 78 (13), 6488-6494CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
An enantioselective cascade Michael-Michael reaction between chalcones enolates and nitromethane catalyzed by a bifunctional thiourea is developed. This reaction provides a mild but efficient approach to chiral benzopyrans bearing three consecutive stereocenters, e.g. I, in high yields with excellent stereoselectivities, and the benzopyrans can be easily transformed to the corresponding tricyclic product, e.g. II.
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Wang, X.-F.; Hua, Q.-L.; Cheng, Y.; An, X.-L.; Yang, Q.-Q.; Chen, J.-R.; Xiao, W.-J. Organocatalytic Asymmetric Sulfa-Michael/Michael Addition Reactions: A Strategy for the Synthesis of Highly Substituted Chromans with a Quaternary Stereocenter. Angew. Chem., Int. Ed. 2010, 49, 8379, DOI: 10.1002/anie.201004534
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Organocatalytic asymmetric sulfa-Michael/Michael addition reactions: a strategy for the synthesis of highly substituted chromans with a quaternary stereocenter
Wang, Xu-Fan; Hua, Qiu-Lin; Cheng, Ying; An, Xiao-Lei; Yang, Qing-Qing; Chen, Jia-Rong; Xiao, Wen-Jing
Angewandte Chemie, International Edition (2010), 49 (45), 8379-8383, S8379/1-S8379/71CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A series of highly substituted chromans were obtained from chiral thiourea catalyzed asym. double Michael addn. of thiols to (E)-Et 3-(2-((E)-2-nitropropen-1-yl)phenoxy)acrylate derivs. The optimized reaction conditions involves thiourea I catalyzed cascade Michael addn. in dichloromethane to produce the desired products, e.g. II in excellent diastereoselectivity (> 95:5 d.r,) and high enantiomeric excess (89-92 % ee).
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Yao, C.-F.; Jang, Y.-J.; Yan, M.-C. An easy and efficient synthesis of 3-nitrochromans. Tetrahedron Lett. 2003, 44, 3813, DOI: 10.1016/s0040-4039(03)00776-7
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There is no corresponding record for this reference.
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Tang, C.-K.; Feng, K.-X.; Xia, A.-B.; Li, C.; Zheng, Y.-Y.; Xu, Z.-Y.; Xu, D.-Q. Asymmetric synthesis of polysubstituted chiral chromans via an organocatalytic oxa-Michael-nitro-Michael domino reaction. RSC Adv. 2018, 8, 3095, DOI: 10.1039/c7ra13525d
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Asymmetric synthesis of polysubstituted chiral chromans via an organocatalytic oxa-Michael-nitro-Michael domino reaction
Tang, Cheng-Ke; Feng, Kai-Xiang; Xia, Ai-Bao; Li, Chen; Zheng, Ya-Yun; Xu, Zhen-Yuan; Xu, Dan-Qian
RSC Advances (2018), 8 (6), 3095-3098CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A catalytic asym. method for the synthesis of (2S,3S,4S)-2-(alkyl/phenyl)-3-nitro-4-(nitromethyl)chromanes such as I [R1 = H, 6-Br, 8-OMe, etc; R2 = n-Bu, Ph, 2-naphthyl, etc.] via squaramide-catalyzed oxa-Michael-nitro-Michael domino reaction of 2-hydroxynitrostyrenes with trans-β-nitroolefins with excellent enantioselectivities (up to 99% ee), diastereoselectivities (up to >20 : 1 dr) and moderate to good yields (up to 82%) was developed.
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Gruttadauria, M.; Giacalone, F.; Noto, R. Supported proline and proline-derivatives as recyclable organocatalysts. Chem. Soc. Rev. 2008, 37, 1666, DOI: 10.1039/b800704g
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Supported proline and proline-derivatives as recyclable organocatalysts
Gruttadauria, Michelangelo; Giacalone, Francesco; Noto, Renato
Chemical Society Reviews (2008), 37 (8), 1666-1688CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. In the last eight years, l-proline and l-proline derivs., such as substituted prolinamides or pyrrolidines, were successfully used as organocatalysts in several reactions. In this crit. review the authors summarized the immobilization procedures of such organocatalysts highlighting their application, recoverability and reusability (86 refs.).
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Kristensen, T. E.; Hansen, T. Polymer-Supported Chiral Organocatalysts: Synthetic Strategies for the Road Towards Affordable Polymeric Immobilization. Eur. J. Org. Chem. 2010, 2010, 3179, DOI: 10.1002/ejoc.201000319
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Itsuno, S.; Hassan, M. M. Polymer-immobilized chiral catalysts. RSC Adv. 2014, 4, 52023, DOI: 10.1039/c4ra09561h
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Polymer-immobilized chiral catalysts
Itsuno, Shinichi; Hassan, Md. Mehadi
RSC Advances (2014), 4 (94), 52023-52043CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
A review: Polymer immobilization of chiral catalysts has progressed extensively over the past years. Recent intensive development of chiral organocatalysts resulted in the identification of numerous highly active catalysts, which are, however, still far less effective than transition metal catalysts. Sepn. of relatively large amts. of organocatalysts from the reaction mixt. causes problems during product isolation. In the case of chirally modified metal catalysts, recovery of valuable metal species and suppression of metal leaching are perpetually important requirements in the design of environmentally friendly chem. processes. Various types of chiral organocatalysts and metal catalysts have been immobilized as pendant groups onto the side chains of polymer supports. Another important polymer immobilization technique is the incorporation of a chiral catalyst into its main chain, with several types of chiral catalyst monomers having been copolymd. with achiral monomers for their prodn. Recently, the synthesis of chiral main-chain polymeric catalysts has progressed extensively. Moreover, many examples of polymer-immobilized catalysts exhibit higher enantioselectivities in comparison to those of the corresponding low-mol.-wt. catalysts. The development of these polymer-immobilized chiral catalysts, which have largely been reported in the last five years, is reviewed in this article.
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Altava, B.; Burguete, M. I.; García-Verdugo, E.; Luis, S. V. Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst. Chem. Soc. Rev. 2018, 47, 2722, DOI: 10.1039/c7cs00734e
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Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst
Altava, Belen; Burguete, M. Isabel; Garcia-Verdugo, Eduardo; Luis, Santiago V.
Chemical Society Reviews (2018), 47 (8), 2722-2771CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. Pos. effects of the polymeric support on the performance of supported chiral catalysts, in terms of activity, stability and selectivity-enantioselectivity, have been reported when the support is properly selected and optimized opening the way to the design of more efficient catalytic systems.
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Tsubogo, T.; Ishiwata, T.; Kobayashi, S. Asymmetric Carbon-Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts. Angew. Chem., Int. Ed. 2013, 52, 6590, DOI: 10.1002/anie.201210066
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Asymmetric Carbon-Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts
Tsubogo, Tetsu; Ishiwata, Takanori; Kobayashi, Shu
Angewandte Chemie, International Edition (2013), 52 (26), 6590-6604CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Catalytic asym. carbon-carbon bond-forming reactions provide one of the most efficient ways to synthesize optically active compds., and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover no. (TON) is often lower than that of some other reactions, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous-flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asym. C-C bond-forming reactions under continuous-flow conditions with chiral heterogeneous catalysts.
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Puglisi, A.; Benaglia, M.; Chiroli, V. Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems. Green Chem. 2013, 15, 1790, DOI: 10.1039/c3gc40195b
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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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Zhao, D.; Ding, K. Recent Advances in Asymmetric Catalysis in Flow. ACS Catal. 2013, 3, 928, DOI: 10.1021/cs300830x
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Recent Advances in Asymmetric Catalysis in Flow
Zhao, Dongbo; Ding, Kuiling
ACS Catalysis (2013), 3 (5), 928-944CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
A review. Asym. catalysis in flow has been attracting much attention very recently because of the potential advantages over its batchwise counterpart, such as high-throughput screening and synthesis, easy automation with the integration of on-demand reaction anal., little or no reaction workup, and potential long-term use of the catalysts in the case of heterogeneous catalysis. Homogeneous asym. catalysis performed in a microreactor has demonstrated successful examples in fast catalyst screening, integrated inline/online anal., microflow photocatalysis, multistep transformation with unstable intermediates, and potential for lower catalyst loading or homogeneous catalyst recycling. Since heterogeneous asym. catalysis serves as a better way than its homogeneous analog for catalyst sepn. and recycling, this Review Article summarizes recent development via different catalyst immobilization methods, such as covalent support, a self-supported method, an adsorption method, and H-bonding, electrostatic or ionic interaction, and nonconventional media, as well. In addn., biocatalysis, including enzyme-catalyzed kinetic resoln. and transformation, in flow will be discussed either in homogeneous or heterogeneous mode.
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Munirathinam, R.; Huskens, J.; Verboom, W. Supported Catalysis in Continuous-Flow Microreactors. Adv. Synth. Catal. 2015, 357, 1093, DOI: 10.1002/adsc.201401081
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Supported Catalysis in Continuous-Flow Microreactors
Munirathinam, Rajesh; Huskens, Jurriaan; Verboom, Willem
Advanced Synthesis & Catalysis (2015), 357 (6), 1093-1123CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The recent developments in performing heterogeneous catalysis in continuous-flow microreactors was summarized. Three different types, namely, (i) packed-bed, (ii) monolithic, and (iii) wall-coated approaches were discussed to implement various kinds of catalysts in a microreactor. In addn., the applications of these supported catalysts to perform a variety of org. reactions were described. Furthermore, advantages of catalytic microreactors over classical batch reactors on one or more aspects of the reaction, such as rate, conversion, selectivity, and enantioselectivity were presented.
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Andrés, J. M.; Maestro, A.; Valle, M.; Pedrosa, R. Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4H-Chromenes. J. Org. Chem. 2018, 83, 5546, DOI: 10.1021/acs.joc.8b00567
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Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4H-Chromenes
Andres, Jose M.; Maestro, Alicia; Valle, Maria; Pedrosa, Rafael
Journal of Organic Chemistry (2018), 83 (10), 5546-5557CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
Nonracemic vinylbenzyloxyaryl-substituted thioureas and squaramides and the styrene and divinylbenzene copolymers of a nonracemic vinylbenzyloxyaryl-substituted thiourea and squaramide were prepd. as catalysts for the diastereoselective and enantioselective tandem Mannich and cyclocondensation reactions of α-amino sulfones I (R = H, Me, Br, Cl, O2N) with nitrostyrenes (E)-R1CH:CHNO2 (R1 = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 2-naphthyl) and phenylsulfonylacetonitrile to yield arylbenzopyrans II (R = H, Me, Br, Cl, O2N; R1 = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 2-naphthyl) and III (R = H, Me, Br, Cl) in up to >99:1 dr and er. The styrene and divinylbenzene copolymers with a nonracemic vinylbenzyloxyaryl-substituted thiourea and squaramide were stereoselective catalysts for the enantioselective tandem Mannich and cyclocondensation reactions and were recovered and reused for five cycles.
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Korotaev, V. Y.; Kotovich, I. V.; Barkov, A. Y.; Kutyashev, I. B.; Kodess, M. I.; Sosnovskikh, V. Y. Uncatalyzed, highly stereoselective addition of α-morpholinostyrene to 3-nitro-2-(trihalomethyl)-2 H -chromenes. Synthesis of trans - cis - and trans - trans -3-nitro-4-phenacyl-(2-trihalomethyl)chromanes. Tetrahedron 2016, 72, 216, DOI: 10.1016/j.tet.2015.11.036
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CCDC 1858605 contains the crystallographic data for compound ent-8a. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
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Pedrosa, R.; Manzano, R.; Andrés, J. M. Direct Experimental Evidence for the Epimerization of Diastereoisomers in the Enantioselective Organocatalyzed Michael Addition of Acetoacetates to Nitroolefins. Synlett 2011, 2203, DOI: 10.1055/s-0030-1261139
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Hoveyda, H. R.; Marsault, E.; Gagnon, R.; Mathieu, A. P.; Vézina, M.; Landry, A.; Wang, Z.; Benakli, K.; Beaubien, S.; Saint-Louis, C.; Brassard, M.; Pinault, J.-F.; Ouellet, L.; Bhat, S.; Ramaseshan, M.; Peng, X.; Foucher, L.; Beauchemin, S.; Bhérer, P.; Veber, D. F.; Peterson, M. L.; Fraser, G. L. Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic. J. Med. Chem. 2011, 54, 8305, DOI: 10.1021/jm2007062
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Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic
Hoveyda Hamid R; Marsault Eric; Gagnon Rene; Mathieu Axel P; Vezina Martin; Landry Annick; Wang Zhigang; Benakli Kamel; Beaubien Sylvie; Saint-Louis Carl; Brassard Martin; Pinault Jean-Francois; Ouellet Luc; Bhat Shridhar; Ramaseshan Mahesh; Peng Xiaowen; Foucher Laurence; Beauchemin Sophie; Bherer Patrick; Veber Daniel F; Peterson Mark L; Fraser Graeme L
Journal of medicinal chemistry (2011), 54 (24), 8305-20 ISSN:.
High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.
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Huang, P.; Li, Y.; Fu, X.; Zhang, R.; Jin, K.; Wang, W.; Duan, C. Silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes with CF3SO₂Na. Tetrahedron Lett. 2016, 57, 4705, DOI: 10.1016/j.tetlet.2016.09.016
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Silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes with CF3SO2Na
Huang, Ping; Li, Yaming; Fu, Xinmei; Zhang, Rong; Jin, Kun; Wang, Wenxin; Duan, Chunying
Tetrahedron Letters (2016), 57 (42), 4705-4708CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
A novel and convenient approach to the synthesis of substituted β-trifluoromethyl styrenes (E)-RCH=CHCF3 (R = 2,4-Cl2C6H3, 4-O2NC6H4, naphthalen-2-yl, etc.) via a silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes (E)-RCH=CHNO2 with CF3SO2Na under relatively mild conditions has been developed. This protocol delivered excellent stereoselectivity and showed wide substrate tolerance.
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Shen, Y.; Lai, X.; Zha, G.; Liu, W.; Xu, Y.; Sun, P.; Xia, T.; Shen, Y. Enantioselective Michael Addition of Pyrazolin-5-ones to β-CF₃-β- Disubstituted Nitroalkenes Catalyzed by Squaramide Organocatalyst. Synlett 2016, 27, 1983, DOI: 10.1055/s-0035-1561460
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Thiourea/Proline Derivative-Catalyzed Synthesis of Tetrahydrofuran Derivatives: A Mechanistic View
Opalka, Suzanne M.; Steinbacher, Jeremy L.; Lambiris, Brandon A.; McQuade, D. Tyler
Journal of Organic Chemistry (2011), 76 (16), 6503-6517CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
A thiourea/proline deriv.-catalyzed synthesis of linear α-substituted THF/pyran derivs. starting with lactol substrates is presented. This study demonstrates the utility and potential complications of using (thio)urea/proline cocatalysis as each of these catalysts is necessary to provide the obsd. reactivity, but a time-dependent decrease in enantioselectivity is obsd. New mechanistic insights into (thio)urea/proline cocatalysis are presented.

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Abstract
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Scheme 1
Scheme 1. Plausible Ternary Complexes That Explain the Formation of Stereoisomers
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Figure 1
Figure 1. X-ray structure of 3ac (ORTEP representation at 50% probability ellipsoids).
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References
This article references 40 other publications.
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  Khan, S.; Shukla, S.; Sinha, S.; Lakra, A. D.; Bora, H. K.; Meeran, S. M. Centchroman suppresses breast cancer metastasis by reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling. Int. J. Biochem. Cell Biol. 2015, 58, 1, DOI: 10.1016/j.biocel.2014.10.028
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  Centchroman suppresses breast cancer metastasis by reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling
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  International Journal of Biochemistry & Cell Biology (2015), 58 (), 1-16CODEN: IJBBFU; ISSN:1357-2725. (Elsevier Ltd.)
  Metastatic spread during carcinogenesis worsens disease prognosis and accelerates the cancer progression. Therefore, newer therapeutic options with higher specificity toward metastatic cancer are required. Centchroman (CC), a female oral contraceptive, has previously been reported to possess antiproliferative and proapoptotic activities in human breast cancer cells. Here, we investigated the effect of CC-treatment against breast cancer metastasis and assocd. mol. mechanism using in vitro and in vivo models. CC significantly inhibited the proliferation of human and mouse mammary cancer cells. CC-treatment also inhibited migration and invasion capacities of highly metastatic MDA-MB-231 and 4T1 cells, at sub-IC50 concns. Inhibition of cell migration and invasion was found to be assocd. with the reversal of epithelial-to-mesenchymal transition (EMT) as obsd. by the upregulation of epithelial markers and downregulation of mesenchymal markers as well as decreased activities of matrix metalloproteinases. Exptl. EMT induced by exposure to TGFβ/TNFα in nontumorigenic human mammary epithelial MCF10A cells was also reversed by CC as evidenced by morphol. changes and modulation in the expression levels of EMT-markers. CC-mediated inhibition of cellular migration was, at least partially, mediated through inhibition of ERK1/2 signaling, which was further validated by using MEK1/2 inhibitor (PD0325901). Furthermore, CC-treatment resulted in suppression of tumor growth and lung metastasis in 4T1-syngeneic mouse model. Collectively, our findings suggest that CC-treatment at higher doses specifically induces cellular apoptosis and inhibits cellular proliferation; whereas at lower doses, it inhibits cellular migration and invasion. Therefore, CC could further be developed as an effective drug candidate against metastatic breast cancer.
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  Fridén-Saxin, M.; Seifert, T.; Malo, M.; da Silva Andersson, K.; Pemberton, N.; Dyrager, C.; Friberg, A.; Dahlén, K.; Wallén, E. A. A.; Grøtli, M.; Luthman, K. Chroman-4-one and chromone based somatostatin β-turn mimetics. Eur. J. Med. Chem. 2016, 114, 59, DOI: 10.1016/j.ejmech.2016.02.046
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  Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives
  Masesane, Ishmael B.; Desta, Zelalem Yibralign
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  A review. Reported methods for the synthesis of chromane derivs. through the reaction of salicylaldehyde and enolates was discussed. The enolates and their equiv. involved in the reactions discussed in this article were derived from ketones, nitroalkanes, malononitrile and α,β-unsatd. compds.
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  Hou, W.; Zheng, B.; Chen, J.; Peng, Y. Asymmetric Synthesis of Polysubstituted 4-Amino- and 3,4-Diaminochromanes with a Chiral Multifunctional Organocatalyst. Org. Lett. 2012, 14, 2378, DOI: 10.1021/ol300798t
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  Bhanja, C.; Jena, S.; Nayak, S.; Mohapatra, S. Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines. Beilstein J. Org. Chem. 2012, 8, 1668, DOI: 10.3762/bjoc.8.191
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  Organocatalytic tandem Michael addition reactions: a powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines
  Bhanja, Chittaranjan; Jena, Satyaban; Nayak, Sabita; Mohapatra, Seetaram
  Beilstein Journal of Organic Chemistry (2012), 8 (), 1668-1694, No. 191CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
  A review. Enantioselective organocatalysis has become a field of central importance within asym. chem. synthesis and appears to be efficient approach toward the construction of complex chiral mols. from simple achiral materials in one-pot transformations under mild conditions with high stereocontrol. This review addresses the most significant synthetic methods reported on chiral amine-catalyzed tandem Michael conjugate addn. of heteroatom-centered nucleophiles to α,β-unsatd. compds. followed by cyclization reactions for the enantioselective construction of functionalized chiral chromenes, thiochromenes and 1,2-dihydroquinolines in optically enriched forms found in a myriad of bioactive natural products and synthetic compds.
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  Yang, W.; Yang, Y.; Du, D.-M. Squaramide-Tertiary Amine Catalyzed Asymmetric Cascade Sulfa-Michael/Michael Addition via Dynamic Kinetic Resolution: Access to Highly Functionalized Chromans with Three Contiguous Stereocenters. Org. Lett. 2013, 15, 1190, DOI: 10.1021/ol400025a
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  The domestication of ortho-quinone methides
  Bai, Wen-Ju; David, Jonathan G.; Feng, Zhen-Gao; Weaver, Marisa G.; Wu, Kun-Liang; Pettus, Thomas R. R.
  Accounts of Chemical Research (2014), 47 (12), 3655-3664CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
  A review. An ortho-quinone methide (o-QM) is a highly reactive chem. motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biol. importance, it is surprising how few applications within org. synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the prepn. of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature. About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temp. from readily available salicylaldehydes, particularly OBoc derivs. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addn. of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent β-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temp. levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions. This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate addns. that led to unbranched or branched ortho-alkyl substituted phenols and Diels-Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addn., the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels-Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.
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  Building Up Quarternary Stereocenters of Chromans by Asymmetric Redox Organocatalysis: A New Entry to Vitamin E
  Netscher, Thomas
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  A review of the enantioselective synthesis of chroman skeleton and α-tocopherol using an organocatalyst.
12. 12
  Zheng, B.; Hou, W.; Peng, Y. Asymmetric oxa-Michael-aza-Henry Cascade Reaction of 2-Hydroxyaryl-Substituted α-Amido Sulfones and Nitroolefins Mediated by Chiral Squaramides. ChemCatChem 2014, 6, 2527, DOI: 10.1002/cctc.201402236
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  Catalytic Synthesis of 2H-Chromenes
  Majumdar, Nilanjana; Paul, Nanda D.; Mandal, Sutanuva; de Bruin, Bas; Wulff, William D.
  ACS Catalysis (2015), 5 (4), 2329-2366CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  A review. 2H-Chromenes (2H-1-benzopyran derivs.) display a broad spectrum of biol. activities. The 2H-chromene substructure is an important structural motif present in a variety of medicines, natural products, and materials showing unique photophys. properties. Hence, the structural importance of the benzopyran moiety has elicited a great deal of interest in the field of org. synthesis and chem. biol. to develop new and improved synthesis of these mol. skeletons. This review gives an up-to-date overview of different catalytic methodologies developed for the synthesis of 2H-chromenes and is structured around the three main approaches applied in catalytic 2H-chromene synthesis: (I) catalysis with (transition) metals, (II) metal-free Bronsted and Lewis acid/base catalysis, which includes examples of nonenantioselective organocatalysis, and (III) enantioselective organocatalysis. The section in which the metal-catalyzed reactions are discussed describes different ring-closing strategies based on (transition) metal catalysis, including a few enantioselective approaches. For most of these reactions, plausible mechanisms are delineated. Moreover, synthesis of some natural products and medicinally important drugs are included. Specific advantages and disadvantages of the several synthetic methodologies are discussed. The review focuses on catalytic 2H-chromene synthesis. However, for a complete overview, synthetic routes involving some stoichiometric steps and reactions producing ring-scaffolds that are closely related to 2H-chromenes are also included.
14. 14
  Hu, N.; Li, K.; Wang, Z.; Tang, W. Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantioselective Palladium-Catalyzed Alkene Aryloxyarylation Reactions. Angew. Chem., Int. Ed. 2016, 55, 5044, DOI: 10.1002/anie.201600379
  14
  Synthesis of Chiral 1,4-Benzodioxanes and Chromans by Enantioselective Palladium-Catalyzed Alkene Aryloxyarylation Reactions
  Hu, Naifu; Li, Ke; Wang, Zheng; Tang, Wenjun
  Angewandte Chemie, International Edition (2016), 55 (16), 5044-5048CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A highly enantioselective alkene aryloxyarylation led to the high-yielding formation of a series of 1,4-benzodioxanes, 1,4-benzooxazines, and chromans contg. quaternary stereocenters with excellent enantioselectivity. The sterically bulky and conformationally well defined chiral monophosphorus ligand I or II was responsible for the high reactivity and enantioselectivity of these transformations. The application of this method to the synthesis of the chiral chroman backbone of α-tocopherol was demonstrated.
15. 15
  Mao, H.; Lin, A.; Tang, Y.; Shi, Y.; Hu, H.; Cheng, Y.; Zhu, C. Organocatalytic oxa/aza-Michael-Michael Cascade Strategy for the Construction of Spiro [Chroman/Tetrahydroquinoline-3,3′-oxindole] Scaffolds. Org. Lett. 2013, 15, 4062, DOI: 10.1021/ol401595g
  15
  Organocatalytic oxa/aza-Michael-Michael Cascade Strategy for the Construction of Spiro [Chroman/Tetrahydroquinoline-3,3'-oxindole] Scaffolds
  Mao, Haibin; Lin, Aijun; Tang, Yang; Shi, Yan; Hu, Hongwen; Cheng, Yixiang; Zhu, Chengjian
  Organic Letters (2013), 15 (16), 4062-4065CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A new useful and effective chiral amine-catalyzed oxa- and aza-Michael-Michael cascade methodol. for the construction of enantiomerically enriched indolinones spiro-fused with chromans or tetrahydroquinolines is reported. By employing suitable organocatalysts depending on the different Michael donors (Ar-OH/Ar-NHR), the processes offered excellent stereocontrol (dr >20:1, >99% ee) under mild conditions [e.g., protected methyleneindolinone I + (E)-2-(2-nitrovinyl)phenol in presence of squaramide-cinchona bifunctional catalyst afforded II (72% yield, 92% ee)].
16. 16
  Zheng, W.; Zhang, J.; Liu, S.; Yu, C.; Miao, Z. Asymmetric synthesis of spiro[chroman-3,3′-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael-Michael cascade strategy with bifunctional amine-thiourea organocatalysts. RSC Adv. 2015, 5, 91108, DOI: 10.1039/c5ra17792h
  16
  Asymmetric synthesis of spiro[chroman-3,3'-pyrazol] scaffolds with an all-carbon quaternary stereocenter via a oxa-Michael-Michael cascade strategy with bifunctional amine-thiourea organocatalysts
  Zheng, Weiping; Zhang, Jiayong; Liu, Shuang; Yu, Chengbin; Miao, Zhiwei
  RSC Advances (2015), 5 (111), 91108-91113CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  An efficient chiral bifunctional amine-thiourea catalyzed cascade oxa-Michael-Michael addn. of 4-alkenyl pyrazolin-3-ones I [R2 = CH3, C6H5; R3 = 2-ClC6H4, 3-O2NC6H4, 2-furyl, etc.; R4 = H, CH3] to (E)-2-(2-nitrovinyl)phenol R1CH=CHNO2 [R1 = 2-hydroxybenzen-1-yl, 2-hydroxynaphthalen-1-yl, 2-hydroxy-4-methoxybenzen-1-yl, etc.] for the synthesis of chiral heterocyclic systems contg. spiro[chroman-3,3'-pyrazol] scaffolds, e.g., II(R = H, 5,6-C4H4, 7-MeO, etc.) has been developed. This reaction afforded the desired products, e.g., II in high to excellent yields (up to 98%) with moderate to high enantioselectivities (up to 99%) and diastereoselectivities (up to 20:1) under low catalyst (15 mol%) concn. This catalytic asym. reaction provides an efficient route toward the synthesis of chiral spiro[chroman-3,3'-pyrazol] derivs., e.g., II contg. three contiguous stereocenters which possess potential pharmaceutical activities.
17. 17
  Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds. Angew. Chem., Int. Ed. 2016, 55, 12104, DOI: 10.1002/anie.201606947
  17
  Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds
  Zhao, Kun; Zhi, Ying; Shu, Tao; Valkonen, Arto; Rissanen, Kari; Enders, Dieter
  Angewandte Chemie, International Edition (2016), 55 (39), 12104-12108CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  An asym. organocatalytic domino oxa-Michael/1,6-addn. reaction of ortho-hydroxyphenyl-substituted para-quinone methides and isatin-derived enoates was developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4-phenyl-substituted chromans bearing spiro-connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99% ee).
18. 18
  Zhu, Y.; Li, X.; Chen, Q.; Su, J.; Jia, F.; Qiu, S.; Ma, M.; Sun, Q.; Yan, W.; Wang, K.; Wang, R. Highly Enantioselective Cascade Reaction Catalyzed by Squaramides: the Synthesis of CF₃-Containing Chromanes. Org. Lett. 2015, 17, 3826, DOI: 10.1021/acs.orglett.5b01799
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19. 19
  Saha, P.; Biswas, A.; Molleti, N.; Singh, V. K. Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst. J. Org. Chem. 2015, 80, 11115, DOI: 10.1021/acs.joc.5b01751
  19
  Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst
  Saha, Prasenjit; Biswas, Arnab; Molleti, Nagaraju; Singh, Vinod K.
  Journal of Organic Chemistry (2015), 80 (21), 11115-11122CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A highly enantioselective synthesis of chiral chroman derivs. via an oxa-Michael-Michael cascade reaction has been developed using a bifunctional thiourea organocatalyst [e.g., trans-2-hydroxychalcone + trans-β-nitrostyrene → I (72% yield, dr 83:17, ee > 99%) in presence of cinchona alkaloid-derived thiourea]. The products were obtained with excellent enantioselectivities (up to >99%), good yields (up to 95%), and diastereoselectivities (up to 5:1).
20. 20
  Wang, X.-F.; An, J.; Zhang, X.-X.; Tan, F.; Chen, J.-R.; Xiao, W.-J. Catalytic Asymmetric Aza-Michael–Michael Addition Cascade: Enantioselective Synthesis of Polysubstituted 4-Aminobenzopyrans. Org. Lett. 2011, 13, 808, DOI: 10.1021/ol1031188
  20
  Catalytic Asymmetric Aza-Michael-Michael Addition Cascade: Enantioselective Synthesis of Polysubstituted 4-Aminobenzopyrans
  Wang, Xu-Fan; An, Jing; Zhang, Xiao-Xiao; Tan, Fen; Chen, Jia-Rong; Xiao, Wen-Jing
  Organic Letters (2011), 13 (4), 808-811CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
  A catalytic asym. aza-Michael-Michael addn. cascade of anilines to nitroolefin enoates in the presence of chiral bifunctional thiourea catalysts has been disclosed. This reaction provides a mild and efficient approach to polysubstituted chiral 4-aminobenzopyrans, e.g., I bearing three consecutive stereocenters in high yields with excellent stereoselectivities.
21. 21
  Jia, Z.-X.; Luo, Y.-C.; Cheng, X.-N.; Xu, P.-F.; Gu, Y.-C. Organocatalyzed Michael-Michael Cascade Reaction: Asymmetric Synthesis of Polysubstituted Chromans. J. Org. Chem. 2013, 78, 6488, DOI: 10.1021/jo400476b
  21
  Organocatalyzed Michael-Michael Cascade Reaction: Asymmetric Synthesis of Polysubstituted Chromans
  Jia, Zhen-Xin; Luo, Yong-Chun; Cheng, Xi-Na; Xu, Peng-Fei; Gu, Yu-Cheng
  Journal of Organic Chemistry (2013), 78 (13), 6488-6494CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  An enantioselective cascade Michael-Michael reaction between chalcones enolates and nitromethane catalyzed by a bifunctional thiourea is developed. This reaction provides a mild but efficient approach to chiral benzopyrans bearing three consecutive stereocenters, e.g. I, in high yields with excellent stereoselectivities, and the benzopyrans can be easily transformed to the corresponding tricyclic product, e.g. II.
22. 22
  Wang, X.-F.; Hua, Q.-L.; Cheng, Y.; An, X.-L.; Yang, Q.-Q.; Chen, J.-R.; Xiao, W.-J. Organocatalytic Asymmetric Sulfa-Michael/Michael Addition Reactions: A Strategy for the Synthesis of Highly Substituted Chromans with a Quaternary Stereocenter. Angew. Chem., Int. Ed. 2010, 49, 8379, DOI: 10.1002/anie.201004534
  22
  Organocatalytic asymmetric sulfa-Michael/Michael addition reactions: a strategy for the synthesis of highly substituted chromans with a quaternary stereocenter
  Wang, Xu-Fan; Hua, Qiu-Lin; Cheng, Ying; An, Xiao-Lei; Yang, Qing-Qing; Chen, Jia-Rong; Xiao, Wen-Jing
  Angewandte Chemie, International Edition (2010), 49 (45), 8379-8383, S8379/1-S8379/71CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A series of highly substituted chromans were obtained from chiral thiourea catalyzed asym. double Michael addn. of thiols to (E)-Et 3-(2-((E)-2-nitropropen-1-yl)phenoxy)acrylate derivs. The optimized reaction conditions involves thiourea I catalyzed cascade Michael addn. in dichloromethane to produce the desired products, e.g. II in excellent diastereoselectivity (> 95:5 d.r,) and high enantiomeric excess (89-92 % ee).
23. 23
  Yao, C.-F.; Jang, Y.-J.; Yan, M.-C. An easy and efficient synthesis of 3-nitrochromans. Tetrahedron Lett. 2003, 44, 3813, DOI: 10.1016/s0040-4039(03)00776-7
  There is no corresponding record for this reference.
24. 24
  Tang, C.-K.; Feng, K.-X.; Xia, A.-B.; Li, C.; Zheng, Y.-Y.; Xu, Z.-Y.; Xu, D.-Q. Asymmetric synthesis of polysubstituted chiral chromans via an organocatalytic oxa-Michael-nitro-Michael domino reaction. RSC Adv. 2018, 8, 3095, DOI: 10.1039/c7ra13525d
  24
  Asymmetric synthesis of polysubstituted chiral chromans via an organocatalytic oxa-Michael-nitro-Michael domino reaction
  Tang, Cheng-Ke; Feng, Kai-Xiang; Xia, Ai-Bao; Li, Chen; Zheng, Ya-Yun; Xu, Zhen-Yuan; Xu, Dan-Qian
  RSC Advances (2018), 8 (6), 3095-3098CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A catalytic asym. method for the synthesis of (2S,3S,4S)-2-(alkyl/phenyl)-3-nitro-4-(nitromethyl)chromanes such as I [R1 = H, 6-Br, 8-OMe, etc; R2 = n-Bu, Ph, 2-naphthyl, etc.] via squaramide-catalyzed oxa-Michael-nitro-Michael domino reaction of 2-hydroxynitrostyrenes with trans-β-nitroolefins with excellent enantioselectivities (up to 99% ee), diastereoselectivities (up to >20 : 1 dr) and moderate to good yields (up to 82%) was developed.
25. 25
  Gruttadauria, M.; Giacalone, F.; Noto, R. Supported proline and proline-derivatives as recyclable organocatalysts. Chem. Soc. Rev. 2008, 37, 1666, DOI: 10.1039/b800704g
  25
  Supported proline and proline-derivatives as recyclable organocatalysts
  Gruttadauria, Michelangelo; Giacalone, Francesco; Noto, Renato
  Chemical Society Reviews (2008), 37 (8), 1666-1688CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. In the last eight years, l-proline and l-proline derivs., such as substituted prolinamides or pyrrolidines, were successfully used as organocatalysts in several reactions. In this crit. review the authors summarized the immobilization procedures of such organocatalysts highlighting their application, recoverability and reusability (86 refs.).
26. 26
  Kristensen, T. E.; Hansen, T. Polymer-Supported Chiral Organocatalysts: Synthetic Strategies for the Road Towards Affordable Polymeric Immobilization. Eur. J. Org. Chem. 2010, 2010, 3179, DOI: 10.1002/ejoc.201000319
  There is no corresponding record for this reference.
27. 27
  Itsuno, S.; Hassan, M. M. Polymer-immobilized chiral catalysts. RSC Adv. 2014, 4, 52023, DOI: 10.1039/c4ra09561h
  27
  Polymer-immobilized chiral catalysts
  Itsuno, Shinichi; Hassan, Md. Mehadi
  RSC Advances (2014), 4 (94), 52023-52043CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
  A review: Polymer immobilization of chiral catalysts has progressed extensively over the past years. Recent intensive development of chiral organocatalysts resulted in the identification of numerous highly active catalysts, which are, however, still far less effective than transition metal catalysts. Sepn. of relatively large amts. of organocatalysts from the reaction mixt. causes problems during product isolation. In the case of chirally modified metal catalysts, recovery of valuable metal species and suppression of metal leaching are perpetually important requirements in the design of environmentally friendly chem. processes. Various types of chiral organocatalysts and metal catalysts have been immobilized as pendant groups onto the side chains of polymer supports. Another important polymer immobilization technique is the incorporation of a chiral catalyst into its main chain, with several types of chiral catalyst monomers having been copolymd. with achiral monomers for their prodn. Recently, the synthesis of chiral main-chain polymeric catalysts has progressed extensively. Moreover, many examples of polymer-immobilized catalysts exhibit higher enantioselectivities in comparison to those of the corresponding low-mol.-wt. catalysts. The development of these polymer-immobilized chiral catalysts, which have largely been reported in the last five years, is reviewed in this article.
28. 28
  Altava, B.; Burguete, M. I.; García-Verdugo, E.; Luis, S. V. Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst. Chem. Soc. Rev. 2018, 47, 2722, DOI: 10.1039/c7cs00734e
  28
  Chiral catalysts immobilized on achiral polymers: effect of the polymer support on the performance of the catalyst
  Altava, Belen; Burguete, M. Isabel; Garcia-Verdugo, Eduardo; Luis, Santiago V.
  Chemical Society Reviews (2018), 47 (8), 2722-2771CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. Pos. effects of the polymeric support on the performance of supported chiral catalysts, in terms of activity, stability and selectivity-enantioselectivity, have been reported when the support is properly selected and optimized opening the way to the design of more efficient catalytic systems.
29. 29
  Tsubogo, T.; Ishiwata, T.; Kobayashi, S. Asymmetric Carbon-Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts. Angew. Chem., Int. Ed. 2013, 52, 6590, DOI: 10.1002/anie.201210066
  29
  Asymmetric Carbon-Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts
  Tsubogo, Tetsu; Ishiwata, Takanori; Kobayashi, Shu
  Angewandte Chemie, International Edition (2013), 52 (26), 6590-6604CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Catalytic asym. carbon-carbon bond-forming reactions provide one of the most efficient ways to synthesize optically active compds., and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover no. (TON) is often lower than that of some other reactions, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous-flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asym. C-C bond-forming reactions under continuous-flow conditions with chiral heterogeneous catalysts.
30. 30
  Puglisi, A.; Benaglia, M.; Chiroli, V. Stereoselective organic reactions promoted by immobilized chiral catalysts in continuous flow systems. Green Chem. 2013, 15, 1790, DOI: 10.1039/c3gc40195b
  30
  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.
31. 31
  Zhao, D.; Ding, K. Recent Advances in Asymmetric Catalysis in Flow. ACS Catal. 2013, 3, 928, DOI: 10.1021/cs300830x
  31
  Recent Advances in Asymmetric Catalysis in Flow
  Zhao, Dongbo; Ding, Kuiling
  ACS Catalysis (2013), 3 (5), 928-944CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
  A review. Asym. catalysis in flow has been attracting much attention very recently because of the potential advantages over its batchwise counterpart, such as high-throughput screening and synthesis, easy automation with the integration of on-demand reaction anal., little or no reaction workup, and potential long-term use of the catalysts in the case of heterogeneous catalysis. Homogeneous asym. catalysis performed in a microreactor has demonstrated successful examples in fast catalyst screening, integrated inline/online anal., microflow photocatalysis, multistep transformation with unstable intermediates, and potential for lower catalyst loading or homogeneous catalyst recycling. Since heterogeneous asym. catalysis serves as a better way than its homogeneous analog for catalyst sepn. and recycling, this Review Article summarizes recent development via different catalyst immobilization methods, such as covalent support, a self-supported method, an adsorption method, and H-bonding, electrostatic or ionic interaction, and nonconventional media, as well. In addn., biocatalysis, including enzyme-catalyzed kinetic resoln. and transformation, in flow will be discussed either in homogeneous or heterogeneous mode.
32. 32
  Munirathinam, R.; Huskens, J.; Verboom, W. Supported Catalysis in Continuous-Flow Microreactors. Adv. Synth. Catal. 2015, 357, 1093, DOI: 10.1002/adsc.201401081
  32
  Supported Catalysis in Continuous-Flow Microreactors
  Munirathinam, Rajesh; Huskens, Jurriaan; Verboom, Willem
  Advanced Synthesis & Catalysis (2015), 357 (6), 1093-1123CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. The recent developments in performing heterogeneous catalysis in continuous-flow microreactors was summarized. Three different types, namely, (i) packed-bed, (ii) monolithic, and (iii) wall-coated approaches were discussed to implement various kinds of catalysts in a microreactor. In addn., the applications of these supported catalysts to perform a variety of org. reactions were described. Furthermore, advantages of catalytic microreactors over classical batch reactors on one or more aspects of the reaction, such as rate, conversion, selectivity, and enantioselectivity were presented.
33. 33
  Andrés, J. M.; Maestro, A.; Valle, M.; Pedrosa, R. Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4H-Chromenes. J. Org. Chem. 2018, 83, 5546, DOI: 10.1021/acs.joc.8b00567
  33
  Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4H-Chromenes
  Andres, Jose M.; Maestro, Alicia; Valle, Maria; Pedrosa, Rafael
  Journal of Organic Chemistry (2018), 83 (10), 5546-5557CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  Nonracemic vinylbenzyloxyaryl-substituted thioureas and squaramides and the styrene and divinylbenzene copolymers of a nonracemic vinylbenzyloxyaryl-substituted thiourea and squaramide were prepd. as catalysts for the diastereoselective and enantioselective tandem Mannich and cyclocondensation reactions of α-amino sulfones I (R = H, Me, Br, Cl, O2N) with nitrostyrenes (E)-R1CH:CHNO2 (R1 = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 2-naphthyl) and phenylsulfonylacetonitrile to yield arylbenzopyrans II (R = H, Me, Br, Cl, O2N; R1 = Ph, 4-ClC6H4, 4-FC6H4, 4-MeOC6H4, 2-naphthyl) and III (R = H, Me, Br, Cl) in up to >99:1 dr and er. The styrene and divinylbenzene copolymers with a nonracemic vinylbenzyloxyaryl-substituted thiourea and squaramide were stereoselective catalysts for the enantioselective tandem Mannich and cyclocondensation reactions and were recovered and reused for five cycles.
34. 34
  Korotaev, V. Y.; Kotovich, I. V.; Barkov, A. Y.; Kutyashev, I. B.; Kodess, M. I.; Sosnovskikh, V. Y. Uncatalyzed, highly stereoselective addition of α-morpholinostyrene to 3-nitro-2-(trihalomethyl)-2 H -chromenes. Synthesis of trans - cis - and trans - trans -3-nitro-4-phenacyl-(2-trihalomethyl)chromanes. Tetrahedron 2016, 72, 216, DOI: 10.1016/j.tet.2015.11.036
  There is no corresponding record for this reference.
35. 35
  CCDC 1858605 contains the crystallographic data for compound ent-8a. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
  There is no corresponding record for this reference.
36. 36
  Pedrosa, R.; Manzano, R.; Andrés, J. M. Direct Experimental Evidence for the Epimerization of Diastereoisomers in the Enantioselective Organocatalyzed Michael Addition of Acetoacetates to Nitroolefins. Synlett 2011, 2203, DOI: 10.1055/s-0030-1261139
  There is no corresponding record for this reference.
37. 37
  Hoveyda, H. R.; Marsault, E.; Gagnon, R.; Mathieu, A. P.; Vézina, M.; Landry, A.; Wang, Z.; Benakli, K.; Beaubien, S.; Saint-Louis, C.; Brassard, M.; Pinault, J.-F.; Ouellet, L.; Bhat, S.; Ramaseshan, M.; Peng, X.; Foucher, L.; Beauchemin, S.; Bhérer, P.; Veber, D. F.; Peterson, M. L.; Fraser, G. L. Optimization of the Potency and Pharmacokinetic Properties of a Macrocyclic Ghrelin Receptor Agonist (Part I): Development of Ulimorelin (TZP-101) from Hit to Clinic. J. Med. Chem. 2011, 54, 8305, DOI: 10.1021/jm2007062
  37
  Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic
  Hoveyda Hamid R; Marsault Eric; Gagnon Rene; Mathieu Axel P; Vezina Martin; Landry Annick; Wang Zhigang; Benakli Kamel; Beaubien Sylvie; Saint-Louis Carl; Brassard Martin; Pinault Jean-Francois; Ouellet Luc; Bhat Shridhar; Ramaseshan Mahesh; Peng Xiaowen; Foucher Laurence; Beauchemin Sophie; Bherer Patrick; Veber Daniel F; Peterson Mark L; Fraser Graeme L
  Journal of medicinal chemistry (2011), 54 (24), 8305-20 ISSN:.
  High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.
38. 38
  Huang, P.; Li, Y.; Fu, X.; Zhang, R.; Jin, K.; Wang, W.; Duan, C. Silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes with CF3SO₂Na. Tetrahedron Lett. 2016, 57, 4705, DOI: 10.1016/j.tetlet.2016.09.016
  38
  Silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes with CF3SO2Na
  Huang, Ping; Li, Yaming; Fu, Xinmei; Zhang, Rong; Jin, Kun; Wang, Wenxin; Duan, Chunying
  Tetrahedron Letters (2016), 57 (42), 4705-4708CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
  A novel and convenient approach to the synthesis of substituted β-trifluoromethyl styrenes (E)-RCH=CHCF3 (R = 2,4-Cl2C6H3, 4-O2NC6H4, naphthalen-2-yl, etc.) via a silver(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes (E)-RCH=CHNO2 with CF3SO2Na under relatively mild conditions has been developed. This protocol delivered excellent stereoselectivity and showed wide substrate tolerance.
39. 39
  Shen, Y.; Lai, X.; Zha, G.; Liu, W.; Xu, Y.; Sun, P.; Xia, T.; Shen, Y. Enantioselective Michael Addition of Pyrazolin-5-ones to β-CF₃-β- Disubstituted Nitroalkenes Catalyzed by Squaramide Organocatalyst. Synlett 2016, 27, 1983, DOI: 10.1055/s-0035-1561460
  There is no corresponding record for this reference.
40. 40
  Opalka, S. M.; Steinbacher, J. L.; Lambiris, B. A.; McQuade, D. T. Thiourea/Proline Derivative-Catalyzed Synthesis of Tetrahydrofuran Derivatives: A Mechanistic View. J. Org. Chem. 2011, 76, 6503, DOI: 10.1021/jo200838v
  40
  Thiourea/Proline Derivative-Catalyzed Synthesis of Tetrahydrofuran Derivatives: A Mechanistic View
  Opalka, Suzanne M.; Steinbacher, Jeremy L.; Lambiris, Brandon A.; McQuade, D. Tyler
  Journal of Organic Chemistry (2011), 76 (16), 6503-6517CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
  A thiourea/proline deriv.-catalyzed synthesis of linear α-substituted THF/pyran derivs. starting with lactol substrates is presented. This study demonstrates the utility and potential complications of using (thio)urea/proline cocatalysis as each of these catalysts is necessary to provide the obsd. reactivity, but a time-dependent decrease in enantioselectivity is obsd. New mechanistic insights into (thio)urea/proline cocatalysis are presented.
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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02302.
- ¹H NMR and ¹³C NMR spectra for new compounds, X-ray crystallographic data for 3ac, copy of IR spectra for polymeric squaramide 9, and copies of the HPLC chromatograms (PDF)
- ao8b02302_si_001.pdf (4.9 MB)
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Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and SquaramidesClick to copy article linkArticle link copied!

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Abstract

Introduction

Results and Discussion

Scheme 1

Figure 1

Conclusions

Experimental Section

General Information

Preparation of Polymeric Squaramide sq-9

General Procedure for the Cascade Reaction of 2-(2-Nitrovinyl)phenol Derivatives with Nitroolefins

(2S,3S,4S)-3-Nitro-4-(nitromethyl)-2-phenylchromane (3aa)

(2S,3R,4S)-3-Nitro-4-(nitromethyl)-2-phenylchromane (epi-3aa)

(2S,3S,4S)-2-(4-Fluorophenyl)-3-nitro-4-(nitromethyl)chromane (3ab)

(2S,3R,4S)-2-(4-Fluorophenyl)-3-nitro-4-(nitromethyl)chromane (epi-3ab)

(2S,3S,4S)-2-(4-Chlorophenyl)-3-nitro-4-(nitromethyl)chromane (3ac)

(2S,3R,4S)-2-(4-Chlorophenyl)-3-nitro-4-(nitromethyl)chromane (epi-3ac)

(2S,3S,4S)-2-(4-Methoxyphenyl)-3-nitro-4-(nitromethyl)chromane (3ad)

(2S,3S,4S)-2-(Naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3ae)

(2S,3R,4S)-2-(Naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (epi-3ae)

(2S,3S,4S)-6-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (3ba)

(2S,3R,4S)-6-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (epi-3ba)

(2S,3S,4S)-2-(4-Fluorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (3bb)

(2S,3R,4S)-2-(4-Fluorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (epi-3bb)

(2S,3S,4S)-2-(4-Chlorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (3bc)

(2S,3R,4S)-2-(4-Chlorophenyl)-6-methyl-3-nitro-4-(nitromethyl)chromane (epi-3bc)

(2S,3S,4S)-6-Methyl-2-(naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3be)

(2S,3S,4S)-6-Bromo-3-nitro-4-(nitromethyl)-2-phenylchromane (3ca)

(2S,3S,4S)-6-Bromo-2-(4-fluorophenyl)-3-nitro-4-(nitromethyl)chromane (3cb)

(2S,3S,4S)-6-Bromo-2-(4-chlorophenyl)-3-nitro-4-(nitromethyl)chromane (3cc)

(2S,3S,4S)-6-Bromo-2-(naphthalen-2-yl)-3-nitro-4-(nitromethyl)chromane (3ce)

(2S,3S,4S)-6-Chloro-3-nitro-4-(nitromethyl)-2-phenylchromane (3da)

(2S,3S,4S)-3-Methyl-3-nitro-4-(nitromethyl)-2-phenylchromane (3af) (24)

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Abstract

Scheme 1

Figure 1

References

Supporting Information

Supporting Information

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Diastereo- and Enantioselective Syntheses of Trisubstituted Benzopyrans by Cascade Reactions Catalyzed by Monomeric and Polymeric Recoverable Bifunctional Thioureas and Squaramides
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