Modulable Photocatalyzed Strategies for the Synthesis of α-C-Glycosyl Alanine Analogues via the Giese Reaction with Dehydroalanine Derivates

Herein, we present the α-selective Giese reaction between pyranosyl/furanosyl bromides and dehydroalanine analogues, which provides access to a library of highly valuable α-C-glycosyl alanines. The key C-glycosyl radical is generated through photocatalysis by either the new generation copper(I) complex [(DPEPhos)(bcp)Cu]PF6 or [Ru(bpy)3](BF4)2. The reactions proceed smoothly, affording the desired α-C-glycosyl alanines in up to 99% yield when diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate [Hantzsch ester (HE)] is used as an additive. N,N-Diisopropylethylamine (DIPEA) has been selected as a reductant in both protocols. A mechanistic study by means of transient absorption spectroscopy unveils a halogen-atom transfer (XAT) process in C-glycosyl radical formation.

T he C-glycosyl peptides are mimics of native glycoproteins, in which glycans are linked to amino acid moieties by C− C bonds in the anomeric position. 1 These glycoconjugates can be obtained mainly through two strategies, namely, by installing the glycosyl functionalization on the target peptide or using C-glycosyl amino acids during the peptide synthesis. 2 For example, Wang and Koh reported an elegant nickelcatalyzed C−C coupling reaction between glycosyl halides and the amino or acid functional group, which must be activated by previous chemical modification into pyridinium salts and NHPI ester, respectively. 3 Goddard-Borger and co-workers reported an interesting protocol to decorate small peptides with a glycosyl moiety by C−C bond formation between glycosyl bromide and modified tryptophan, exploiting photocatalysis. 4 Even though notably examples have been disclosed in this regard, synthesis of tailored C-glycosyl amino acids, which can be further employed in conventional peptide synthesis, represents a more flexible strategy. For example, Kooyk and Codeérecently disclosed a protocol to prepare Cmannosyl lysine derivates as building blocks for solid-phase peptide synthesis (SPPS) (Scheme 1A). 5 To date, postmodification of C-glycosyl alkyl carboxylic or carbonylic compounds remains the main strategy in any case, as proven by contributions of Dondoni and Massi, employing proline catalysis (Scheme 1B), 6 and Gagne, who achieved C-glycosyl serine synthesis through Strecker cyanation (Scheme 1C). 7 In light of that, operationally simple protocols to access these compounds are always welcome. We envisaged the possibility to exploit photocatalysis to promote the Giese reaction between pyranosyl bromide analogues with electron-poor dehydroalanine derivatives to access α-C-glycosyl alanine analogues. 8−15 Photocatalysis that involves a single-electron transfer (SET) mechanism represents a powerful approach for synthesis, 16−18 as reported in the last 2 decades. 19−26 A preliminary test has been performed by mixing compound 1a with compound 2a in the presence of 5 mol % [Ru(bpy) 3 ](BF 4 ) 2 A, N,N-diisopropylethylamine (DIPEA), and Hantzsch ester HE(1) under blue light-emitting diode (LED) irradiation (entry 1 in Table 1, Y = 50%, dr = 60:40). 2 equiv of compound 2a were employed to suppress reductive debromination. The diastereomeric ratio (dr) refers to configuration at the C-2 position, whereas the α selectivity of anomeric carbon (C-4) is always maintained thanks to the rigidity of the axial radical by the stereoelectronic effect. 27 In the absence of HE, the desired product 3aa is observed, albeit in a low yield (entry 2 in Table 1, Y = 25%, dr = 56:44) at the cost of oligomerization side products (see page S53 of the Supporting Information for details on the mechanism). 8 No reactivity was observed without DIPEA with complex A (entry 3 in Table 1, Y = 0%), and iridium(III) complex B does not show significant improvements (entry 4 in Table 1, Y = 54%, dr = 65:35). Recently, heterogeneous organic photocatalysts have gained more and more interest thanks to their green features. We tested mesoporous graphitic carbon nitride (mpg-CN) C with triethanolamine (TEOA) with unsatisfactory results (entry 5 in Table 1, Y = 10%, dr = 62:38). 23 Finally, compound 3aa was obtained in good yield with copper(I) complex D in dichloromethane (DCM) encouraging us to further investigate different conditions (entry 6 in Table  1, Y = 86%, dr = 55:45). 28−31 An unsatisfactory yield was obtained in water (entry 7 in Table 1, Y = 20%, dr = 50:50) and ethanol (entry 8 in Table 1, Y = 75%, dr = 55:45). The reaction does not take place in both tetrahydrofuran (THF) (entry 9 in Table 1) and toluene (entry 10 in Table 1), and only a trace amount of product was observed in EtOAc (entry 11 in Table 1). Finally, MeCN/H 2 O (2:1) (entry 13 in Table 1) provides compound 3aa in 97% yield with dr = 60:40 in only 2 h. Because of the role of HE to quench the odd-electron species as a result of the addition of the glycosyl radical to acceptor 2a (H transfer from the DHP-4 position), we tested more hindered HEs to increase the diastereoselectivity (see pages S51−S53 of the Supporting Information for details on the mechanism). Unfortunately, no improvement was observed in this regard, as reported in entries 14 and 15 in Table 1; furthermore, we observed the formation of side products as a result of the consecutive addition of compound 2a (oligomerization). Moreover, lowering the catalytic loading to 2.5% slightly decreases the yield (entry 16 in Table 1, Y = 53%, dr = 60:40). With optimized reaction conditions in hand, we moved to explore the generality of the Giese reaction. Table 2 summarizes the results that we obtained by employing the optimized conditions with photocatalyst D. With the variation of the bromide derivates, similar results were obtained for mannosyl and galactosyl derivates (3ba and 3ca), in terms of the yield and diastereoselectivity; furthermore, the lactosyl disaccharide derivative (3da) proved to be a suitable radical donor in this reaction. By variation of the acceptor, the reactivity remains the same for methyl acrylate (3ad), whereas more hindered electrophiles, such as 3-methyl substituted N,N-Boc2 dehydroalanine 2b and 3-methyl-substituted N-phenyl dehydroalanine 2c, show lower reactivity (3ab and 3ac); moreover, the tosyl-protected analogue proved to be unreactive under these conditions (3ae).
We tested some of the unreactive acceptors/donors with conditions reported in entry 1 in Table 1 (ruthenium complex A as a photocatalyst). The results are summarized in Table 3: reactions performed with peracetylated donor series (glucosyl, mannosyl, and galactosyl) afford desired products in a good yield (3fa, 3ga, and 3ha). The furanosyl analogue proves to be a suitable reagent by reacting smoothly with compound 2a (3ea). Benchmark donor 1a reacts smoothly with acetylated dehydroalanine 2f (3af) as well as the cellobiosyl donor  Reaction conditions: compound 1a (1 eq., 0.12 mmol), compound 2a (2 eq., 0.24 mmol), DIPEA (3 equiv, 0.36 mmol), HE (2 equiv, 0.24 mmol), catalyst (5 mol %, 0.006 mmol), solvent (1 mL), and blue LED (10 W). b Conversion and yield have been calculated by nuclear magnetic resonance (NMR) employing durene as the external standard. c Calculated by NMR. Probably, an intermediate featured by a coordination bond between sugar and metal is involved in the deactivation mechanism. Furthermore, the coordination between the metal center and the carboxylic group should be more favored when the substituent is −C�OCH 3 (1f) than −C�OPh (1a) for steric reasons. Furthermore, it was demonstrated that the carbonyl group could insert into the α bond of a metal acyl complex. 32 Finally, time-resolved absorption experiments were carried out to shine light on the mechanism involved in Cglycosyl radical formation. Laser excitation at 355 nm of a DCM solution containing complex A and DIPEA (0.37 M) yields a transient spectrum with a maximum at 500 nm, characteristic of the reduced complex A − (Figure 1a). 33 Table 1 Conditions) a a Reaction conditions: compounds 1f−1i (1 equiv, 0.12 mmol), compound 2a or 2f (2 equiv, 0.24 mmol), DIPEA (3 equiv, 0.36 mmol), HE (2 equiv, 0.24 mmol), complex A (5 mol%, 0.006 mmol), DCM (1 mL), blue LED (10 W), and time of 16 h. dr was calculated by NMR on the crude, and yield was calculated after the chromatography column.

Organic Letters pubs.acs.org/OrgLett
Letter nature of the photoreaction involving the DIPEA electron donor. 34 On the other hand, upon the addition of compound 1a, the transient absorption at 500 nm undergoes a progressive decay with kinetics, which are dependent upon the concentration of sugar (Figure 1b). This can be taken as an indication of the occurrence of a bimolecular electron transfer process from photogenerated complex A − to compound 1a. The decays can be analyzed using pseudo-first-order kinetics, and a bimolecular rate constant of 1.7 × 10 6 M −1 s −1 can be calculated ( Figure S30 of the Supporting Information). This low value is consistent with a highly activated SET, in agreement with the expected endergonicity of the electron transfer process from complex A − to compound 1a. Interestingly, the maximum amount of photogenerated complex A − species (prompt positive signal in Figure 1b; see also Figure S31 of the Supporting Information for further details) is always lower when sugar 1a is present in the photolyzed solution. This experimental evidence can be explained by considering a fast reaction between the DIPEA • radical and compound 1a outcompeting the reaction with ground-state complex A molecule. According to Leonori and co-workers, α-aminoalkyl radicals from tertiary amines are able to efficiently generate alkyl radicals from alkyl halides through a halogen-atom transfer (XAT) mechanism. Similar results were observed in transient absorption experiments carried out with the iridium-(III) complex B (see Figures S32−S36 of the Supporting Information for further details). The same conclusions can be transposed to copper(I) complex D. Unfortunately, this latter complex gives less efficient excited-state quenching by DIPEA ( Figure S37 of the Supporting Information). Thus, we can propose a detailed photoreaction mechanism, which is depicted in Scheme 2. 35,36 Photoreaction is initiated with reductive quenching of the photocatalyst excited state (PC*) by DIPEA to form PC − , which is then involved in a SET process with compound 1a affording intermediate I. This undergoes a mesolytic cleavage, providing the anomeric radical analogue II, which is then sequestrated by compound 2a to produce intermediate III and subsequently compound 3aa by hydrogen abstraction (path a). According to the photophysical results discussed above, an additional pathway could in parallel occur, in which the αaminoalkyl radical IV abstracts the bromide atom from compound 1a affording intermediate II (path b). Mechanistically, XAT is initiated by the α-amino radical, generated by DIPEA and PC*; thus, it cannot be excluded that the glycosyl radical is directly involved in the quenching of PC − . We should consider that, only in the case of photocatalysts B and D, photoreaction could in principle proceed even in the absence of DIPEA because parallel generation of PC − can also be triggered by reductive quenching of excited PC* by HE (see Figures S33 and S38 of the Supporting Information). The low conversion experimentally observed (see entry 33 in Table S3 of the Supporting Information for details) thus suggests that path a is not very efficient, likely associated with the slow rates of the SET between PC − and compound 1a. This evidence supports the critical requirement of the DIPEA electron donor to achieve high product yields and the relevance of path b toward the profitable generation of intermediate II and the final product.
In conclusion, we have developed a straightforward route to access α-C-glycosyl alanine analogues by the photocatalyzed Giese reaction. Two protocols have been disclosed: one involves the copper(I) complex D in the MeCN/H 2 O mixture affording the desired product in a very fast reaction time (2 h), with the common ruthenium(II) photocatalyst A being employed when this procedure does not work as a result of substrate inhibition. A small library of α-C-glycosyl alanine analogues was reported, and photocatalyst substrate-dependent inhibition has been investigated by NMR experiments. Finally, photophysical measurements were performed to elucidate the mechanism involved, unveiling a profitable XAT mechanism occurring in parallel with the established SET process.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.

* sı Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c01660. FAIR data, including the primary NMR FID files, for compounds 1−13 (ZIP) Materials and methods, optimization of reaction conditions, characterization data, synthetic procedures, and additional mechanistic experiments (PDF)