Mylène
Lang
,
Damien
Tardieu
,
Benoit
Pousse
,
Philippe
Compain
* and
Nicolas
Kern
*
Laboratoire d’Innovation Moléculaire et Applications (LIMA), UMR 7042, Université de Strasbourg/Université de Haute-Alsace/CNRS, ECPM, 25 rue Becquerel, 67087, Strasbourg, France. E-mail: philippe.compain@unistra.fr; nicolas.kern@unistra.fr
First published on 19th February 2024
Access to C,C-glycosyl amino acids as a novel class of glycomimetics is reported by means of radical generation, intermolecular addition and stereoselective reduction via a metal-induced hydrogen atom transfer (MHAT) sequence. The ‘matched’ coupling of exo-D-glycals with an enantiopure dehydroalanine bearing a (R)-configured benzyl oxazolidinone enables a singular case of two-fold diastereocontrol under iron catalysis. In the common exo-D-glucal series, the nature of the C-2 substituent was found to play a key role from both reactivity and stereocontrol aspects.
Fig. 1 Recent convergent strategies to assemble C-glycosyl amino acids from pyranosides and (C2) amino acid synthons (a) and (b) and aims of this work (c). |
In connection with our search for neo-glycoconjugates and interest in novel transformations of exo-glycals,15 we questioned the viability of an MHAT (metal-induced HAT)16,17 coupling to form C,C-glycoaminoacids, unusual adducts embedding an atypical fully substituted pseudoanomeric carbon.18 Several intramolecular cyclization strategies were examined, all of which met with failure due to the low stability of DHA-acylated exo-glycals. While an intermolecular approach first appeared daunting in terms of two-fold stereocontrol (yet unreported for Fe-HAT Baran–Giese type coupling, and including an exocyclic centre), we were curious whether the inherent low stereoinduction inferred from the pyranoside (vide supra) could be enforced. We envisioned that such a task may be achievable through the identification of an appropriate “matched” nonracemic radical acceptor, along with careful choice of the protection patterns – especially for the C-2 hydroxyl moiety, in the vicinity of subsequently formed open-shell species (Fig. 1c).
To begin to answer this question, O-benzyl-N-phthaloyl DHA-based acceptor 2a was selected (Table 1). Screening of coupling conditions (catalytic Fe(acac)3, phenylsilane and Na2HPO4 buffer in EtOH) applied to a mixture of perbenzylated exo-glycal 1a (1 equiv.) and 2a (2 equiv.) first suggested that productive radical generation from exo-glucals calls for specific dilute conditions and moderate catalyst loading (entries 1–4). Along with targeted adduct 3a, alanine imidoester 4a was identified as the main side product. Competitive reduction of C-radicophiles has been scarcely mentioned in the Fe-HAT literature,19 and may be favored here considering the captodative character of the product radical,20 partly overriding the usual cross-coupling chemoselectivity attributed to polar effects. This may also explain the use of excess electron-rich alkenes in related protocols,19,21 inconvenient with valuable exo-glycals. However, formal hydrogenation of 1a and telomerization13 were fully avoided.22 Since chromatographical separation of 3a and 4a proved tedious, base-mediated hydrolysis of the benzyl ester resulted in the epimerization of the neoformed AA stereocentre. Substitution of 2a for PMB ester 2b (entry 5, conditions [A]) allowed quantitative and epimerization-free acid-mediated dealkylation with TFA in conjunction with 1,3-dimethoxybenzene (DMB), yielding free acid 5.23 Akin to 2a, acceptor 2b appeared almost insoluble at 25 °C and sparingly at 60 °C; therefore inclusion of cosolvents was evaluated. Use of minimal EtOH in THF (16 equiv. to reach full conversion; entry 6, conditions [B]) resulted in close efficiency at the cost of reaction rate, which may be rationalized from the involvement of the alcohol in the rate-determining iron hydride generation step.15 Overall, all experiments involving achiral acceptor 2b furnished products 3 (or 5) in moderate d.r. (close to 7:3). We thus moved forward by evaluating DHA-tagged chiral oxazolidinones 2c–2h.21,24 Unlike esters, imide coupling adducts could be carefully hydrolyzed to 5 without epimerization using minimal LiOH and H2O2, enabling comparison of the stereochemical course with reactions of 2b. First, (R)-configured isopropyl derivative 2c underwent addition with lower diastereoselectivity (entry 7). Phenyl analog 2d only led to traces of the coupling adduct, while isobutyryl analog 2e reacted poorly with the glycosyl radical without impacting stereoinduction (entries 8 and 9). Gratifyingly, a ‘matched’ case was disclosed with benzyl surrogate 2f (i.e. Evans’ auxiliary,25 entry 10), which reacted efficiently and induced good diastereocontrol (88:12) under conditions [A]. As the stereodetermining redox termination step involves the protic solvent,26 system [B] with minimal EtOH was evaluated and induced a slight enhancement (entry 11). Since acceptor 2f displayed better solubility in THF, decreasing the reaction temperature to 25 °C allowed even higher control but with lower efficiency (entry 12). Consecutively, the (S)-enantiomer 2g was probed to be ‘mismatched’ (entry 13). The gem-dimethyl surrogate of the optimal auxiliary27 acted as a potent inductor, but the apparent lower stability of parent acceptor 2h only enabled moderate yields (entry 14). The observation that all auxiliaries and conditions afforded the same major diastereoisomer of 5 stands in line with previous reports involving pyranosides, where the degree but not the direction of stereoselectivity could be influenced.13,14 Furthermore, closer examination of related work12 reveals that stereoinduction in the termination step is usually lower for pyranosides bearing equatorial O- or N-functionality at C-2. In contrast to mannosides or 2-deoxy derivatives for example, their orientation may partly impede the population of a favorable conformer for stereoselective termination (vide infra). A series of exo-D-glucals diversely protected at C-2 were thus examined (Fig. 2a).‡ With relatively bulky silyl groups (1b & 1c) negligible conversions were observed while DHA reduction predominated. The solvolytically unstable free-hydroxyl derivative 1d only led to the corresponding adduct 6 in low yield and d.r. Pleasingly, stable and less hindered methoxymethyl (MOM) derivative 1e led to the highest yield and stereoselectivity (94:6) observed. Orthogonal removal of the auxiliary in 7 and acid-mediated lactonization to 8 were straightforward and allowed unambiguous assignment of the (R)-configuration of the AA by 1H NOESY analysis. In view of the importance of 2-amino-C-glycosides,28 coupling of the seldom (2-acetamido)exo-glycal291f could be achieved in moderate yield and stereoselectivity, granting with adduct 9 a first entry to 2-amido-C,C-glycosidic motifs. Considering these results, we speculate that (1) steric impediment of the olefin in 1 is detrimental to radical generation; (2) alongside competitive processes efficiency is also correlated to the chemical stability of the often sensitive exo-glycal; and (3) high stereoselectivities are obtained when the C-2 position of the sugar is relatively unhindered. As mentioned above, if the optimized acceptor and conditions enable enforcement of two-fold stereocontrol in the D-gluco series, extension to related important pyranosides should be feasible. This was probed with exo-D-mannal 1g and exo-D-galactal 1h, whose corresponding coupling adducts 10 and 11 were successfully isolated after direct hydrolysis (Fig. 2b). As notable, selective MOM protection at C-2 was not mandatory here to achieve high control. The (very) decent chemical yields obtained from these fragile, electron-rich terminal exo-glycals again testify of the relative mildness of the Fe-HAT conditions. Although optimized for pyranosides, the protocol also allowed the efficient conversion of furanoside 1i into adduct 12 with significant control at the AA centre (Fig. 2c). The main limitations concern trisubstituted15 and electronically deactivated difluoroolefins,30 which do not undergo MHAT at a sufficient rate with respect to DHA derivatives (Fig. 2d). On the other hand, sulfonylhydrazone acceptors used for reductive alkylation31 either seem to: (1) lack sufficient reactivity towards tertiary glycosyl radicals (alkylsulfonyl derivatives), whose reduction thus leads to formal alkene hydrogenation, or (2) undergo nonselective fragmentation (arylsulfonyl derivatives).
Entry | Acceptor | Solvent(s)/conc. (M) | t (h) | Yield (%)/product | d.r.b |
---|---|---|---|---|---|
a Estimated yield by 1H NMR (isolated material contaminated with 4a). b Determined by 1H NMR analysis of partly purified 3a or pure 5. c 20 mol% [Fe]. d Formation of unseparable side products. e Isolated yield after acidic hydrolysis to 5. f 16 equiv. EtOH as additive. g Confirmed by HPLC. h At 25 °C. [A] & [B]: optimal conditions. | |||||
1 | 2a | EtOH (0.1) | 1.5 | 60 (3a)a | 69:31 |
2 | 2a | EtOH (0.01) | 16 | 52 (3a)a | 71:29 |
3 | 2a | EtOH (0.03) | 4 | 77 (3a)a | 73:27 |
4c | 2a | EtOH (0.03) | 2 | 40 (3a)ad | nd |
5 [A] | 2b | EtOH (0.03) | 4 | 76 (5)e | 69:31 |
6 [B] | 2b | THF (0.03)f | 16 | 66 (5)e | 71:29 |
7 | 2c | EtOH (0.03) | 4 | 50 (5)e | 58:42 |
8 | 2d | EtOH (0.03) | 4 | Traced | nd |
9 | 2e | EtOH (0.03) | 4 | 21 (5)e | 70:30 |
10 [A] | 2f | EtOH (0.03) | 4 | 75 (5)e | 88:12g |
11 [B] | 2f | THF (0.03)f | 16 | 82 | 92:8g |
12h | 2f | THF (0.03)f | 16 | 45 | 96:4g |
13 | 2g | EtOH (0.03) | 4 | 67 | 74:26 |
14 | 2h | EtOH (0.03) | 4 | 31 | 93:7g |
Based on our results and taking account of Poli & Holland's studies,26 a tentative model for the stereocontrolled formation of the AA centre may be envisioned from two perspectives (Fig. 3). Following generation of an iron(III) enolate via inner-sphere electron transfer from Fe(II)(acac)2 species (a), a nonchelated model – expectable considering a moderately Lewis acidic and coordinatively saturated Fe(III) complex – may explain the preference for si-face ‘concerted’ protonation from a metal-bound EtOH molecule leading to the (R)-configuration while accounting for the effect of substituents at C-2, in close vicinity of the aryl moiety presented by the auxiliary. Additional shielding of the re-face is imposed by the angular methyl group, while the flat phthalimide can partly rotate to minimize steric interactions with the former methyl and the auxiliary, also restricting the rotation of the pseudoanomeric C–C bond. Similar considerations may apply to a proton-coupled electron transfer process (b), in which a conjugated π-type radical in its ground state would adopt a similar planar geometry, poised to undergo stereoselective PCET from alcohol-bound Fe(II) species.
Fig. 3 Proposed models for stereoselective termination via SET/protonation (a) or proton-coupled electron transfer (b) in the D-gluco series. |
In conclusion, a novel entry to rare C,C-glycosyl amino acids was established. Guided by a systematic study of substituents and auxiliary effects, high two-fold stereocontrol was achieved in the direct assembly of exo-glycals with dehydroalanine acceptors, representing a first case using the MHAT intermolecular coupling pathway. Further development of new catalytic stereocontrolled reactions of exo-glycals is underway and will be reported in due course.
NK gratefully acknowledges support from Unistra (IDEX grant W19RAT27). ML and DT thank the French Ministry of Research (MRT fellowships). Dr E. Wasielewski and M. Chessé are thanked for their support. Dr X. Bugaut is thanked for insightful discussions.
Footnotes |
† Electronic supplementary information (ESI) available: Experimental details including synthesis and characterization. See DOI: https://doi.org/10.1039/d3cc06249j |
‡ Due to the varying polarities of adducts, from this stage the auxiliary was cleaved only if required for an easier purification. |
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