Organocatalytic asymmetric assembly reactions for the syntheses of carbohydrate derivatives by intermolecular Michael-Henry reactions

Abstract

Given the significance of carbohydrates in life, medicine, and industry, the development of simple and efficient de novo methods to synthesize carbohydrates are highly desirable. Organocatalytic asymmetric assembly reactions are powerful tools to rapidly construct molecules with stereochemical complexity from simple precursors. Here, we present a simple and robust methodology for the asymmetric synthesis of pyranose derivatives with taloand manno-configurations from simple achiral precursors through organocatalytic asymmetric intermolecular Michael-Henry reaction sequences. In this process, (tert-butyldimethylsilyloxy)acetaldehyde 1 was successfully utilized in two ways: as a donor in a highly selective anti-Michael reaction and as an acceptor in a consecutive Henry reaction. Varied nitroolefins served as Michael acceptors and varied aldehydes substituted for 1 as Henry acceptors providing for the construction of a wide range of carbohydrates with up to 5 stereocenters. In these reactions, a catalyst-controlled Michael reaction followed by a substrate-controlled Henry reaction provided 3,4-dideoxytalose derivatives 6 in a highly stereoselective manner. The Henry reaction was affected by addition of a simple base such as triethylamine: A complex chiral base was not necessary. 3,4-Dideoxymannose derivatives 7 were produced by simply changing the base from triethylamine to 1,8-diazabicyclo[5.4.0]undec-7-ene. Extension of this methodology to a syn-Michael initiated sequence was also successful. A mechanistic discussion is provided to explain the unusual substrate-induced stereoselectivity of the Henry reaction.amine-thiourea catalyst | asymmetric reaction | carbohydrates | Michael reaction | organocatalysis C arbohydrates are one of the most important classes of organic molecules and play diverse and essential roles in life, medicine, and industry. Since Emil Fischer's structural elucidation and synthesis of carbohydrates more than a century ago (1), carbohydrate synthesis has continued to challenge synthetic chemists. Robust, simple, direct, and highly stereoselective methods to carbohydrate synthesis remain largely elusive and the development of such methodologies is a driving force in synthetic chemistry. Indeed, our discovery of the proline catalyzed intermolecular aldol reaction (2, 3) and other related reactions (4, 5) were made possible by our development of antibody aldolases as synthetic tools for carbohydrate synthesis (6, 7). In the decade since this discovery, organocatalysis has emerged as a promising route to a wide range of chiral molecules (4,5,(8)(9)(10)(11). Our studies in organocatalysis prompted us (5,(12)(13)(14) and later others (15, 16) to develop cascade reactions and one-pot synthetic approaches toward the synthesis of complex molecules containing multiple stereocenters with the aim of producing robust and operationally simple approaches to the synthesis complex asymmetric molecules like carbohydrates. We have classified reactions of this type broadly as organocatalytic asymmetric assembly r...

A Simple Recipe for Sophisticated Cocktails: Organocatalytic One‐Pot Reactions—Concept, Nomenclature, and Future Perspectives

“…Recently, Barbas and co-workers reported two closely related TypeA-2-2C1X procedures targeting sugar and iminosugar derivatives (Scheme 5). [19] Both procedures are based on an initial anti-selective conjugate addition of the silylprotected hydroxyacetaldehyde 13 b to nitroalkenes 14 in the presence of a bifunctional amino-thiourea organocatalyst 22. From the resulting common nitroalkane intermediate 23, two divergent approaches, a Henry and an aza-Henry reaction, may be applied for the stereoselective formation of 3,4-deoxy sugar 24 and iminosugar 26 derivatives, respectively.…”

Acetaldehyde: A Small Organic Molecule with Big Impact on Organocatalytic Reactions

“…During the reaction, small amounts of the d ‐ manno ‐isomer 55 were observed, due to the base‐promoted epimerization at the C4 position of compound 54 . Interestingly, the maximum yield of 3,4‐dideoxy‐ d ‐mannose derivative 55 as C4‐epimer was achieved by treatment with DBU (Scheme ) …”

Evolution of asymmetric organocatalysis: multi- and retrocatalysis

“…The use of DBU (237) as base catalyst under otherwise identical conditions led to a complete epimerization at the stereogenic center bearing the nitro group thus afforded the corresponding 3,4-dideoxy-D-mannose derivatives epi-235 (Scheme 36; only the cyclized form was observed). 97 Except for 2,6-dichloronitrostyrene, all previously tested nitroolefins were applicable affording products epi-235 via the anti-Michael/syn-Henry/epimerization reaction sequence. To increase the utility of the reaction other aldehydes were tested as acceptors for the Henry reaction.…”