Molecular Dynamics-Based Models Explain the Unexpected Diastereoselectivity of the Sharpless Asymmetric Dihydroxylation of Allyl D-Xylosides

Abstract

The catalytic asymmetric dihydroxylation of several allyl 2‐O‐benzyl‐α‐D‐xylosides with AD‐mix β and PYR(DHQD)2 shows almost no diastereofacial selectivity if the 3‐ and 4‐OH groups are unprotected or acetylated. Acetal, benzyl ethers and benzoyl esters enhance the diastereoselectivity, in the opposite sense to that predicted by the “AD mnemonic”, which is completely lost using AD‐mix α. In an attempt to understand this behaviour, computational studies of the asymmetric dihydroxylation (AD) of olefins using Sharpless' and Corey's catalysts have been carried out using molecular dynamics. A three‐step algorithm was developed taking advantage of the enzyme‐like behaviour of catalyst‐olefin systems and applied using an ESFF force field. To validate our approach, the first sampling step procedure was then refined and performed using a modified CVFF force field. This led to a U‐shaped model in good agreement with that proposed by Corey for the AD of allyl 4‐methoxybenzoates, which brings to the fore a role for the methoxy group. This model also accounts for the observed enantioselectivity of styrene dihydroxylation. When applied to the AD of allyl xylosides using AD‐mix β, our model accounts well for the observed diastereoselectivity. Both synthetic and modelling results confirmed that aromatic groups on the olefin could be involved in π‐π stacking interactions with the aromatic rings of the catalyst and should be important, if not a prerequisite, to achieve high enantio‐ and diastereoselectivity.

Electronic Records Research Working Meeting, May 28‐30, 1997: A Report from the Archives Community

“…We believe this type of interaction is important for high diastereoselectivity. Interestingly, this finding is in excellent agreement with the conclusions recently put forward to explain the unexpected diastereoselectivity of the Sharpless asymmetric dihydroxylation of allyl D ‐xylosides,53 which highlight the essential role of aromatic or, more generally, large lipophilic (hydrophobic) moieties of the substrate and catalyst in interactions leading to preferential stabilization of one diastereomeric intermediate.…”

Comprehensive Synthesis of Substrates, Intermediates, and Products of the Sulfoglycolytic Embden–Meyerhoff–Parnas Pathway

“…Direct substitution of the bromide with sodium sulfite in water afforded the known allyl α- d -sulfoquinovoside 10 . , While prior syntheses employ KMnO 4 to dihydroxylate this alkene, , we were inspired by related work using catalytic OsO 4 and Me 3 NO 19 to adopt a ligand-catalyzed Sharpless dihydroxylation, which provides a rate enhancement for the oxidation of terminal alkenes versus osmium tetroxide alone . We were, however, aware of the limited ability of chiral catalysts used in related transformations of unprotected allyl α-glycosides to impart any meaningful diastereoselectivity on the dihydroxylation reaction . While preliminary experiments with commercially available AD-mix reagents provided a successful transformation, we had difficulty purifying the highly polar SQGro products from the large amounts of salts derived from the potassium ferricyanide co-oxidant.…”

Toward a computational tool predicting the stereochemical outcome of asymmetric reactions: Development of the molecular mechanics‐based program ACE and application to asymmetric epoxidation reactions

“…[ 33, 34 ] The unexpected sense of diastereoselectivity was first explained by means of a molecular mechanics method. [ 35 ] An improved protocol was then applied to a large set of substrates, including carbohydrate derivatives, with substantial predictive power. [ 36, 37 ] More recently, we reported the development of a preliminary version of a computational tool, namely asymmetric catalyst evaluation (ACE, version 1.0) that was found to accurately predict the stereochemical outcome of asymmetric Diels Alder cycloadditions and proline‐catalyzed aldol reactions.…”