A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.
A practical synthesis of 11-membered C 2 -symmetric binaphthyl ketone (R)-1, a catalyst for asymmetric epoxidation, was developed. (±)-1,1'-Binaphthyl-2,2'-dicarboxylic acid [(±)-6] was efficiently resolved by (R)-(-)-1-cyclohexylethylamine to give (R)-6 in >99% ee and in 38% yield. Condensation of the acid chloride derived from (R)-6 with 1,3-dihydroxyacetone dimer at 60-70 °C provided the desired chiral ketone (R)-1 in 61-63% yield without need for high dilution techniques.
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...
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