Catalytic Asymmetric Formation of δ‐Lactones by [4+2] Cycloaddition of Zwitterionic Dienolates Generated from α,β‐Unsaturated Acid Chlorides

Abstract

d-Lactones are subunits of numerous natural and unnatural products that display a wide range of biological activity. In many cases they show high efficacy as antibacterial, [1] antiviral (HIV protease inhibitors), [2] anticancer, [3] immunosuppressive, [4] or cholesterol-lowering agents (HMGR inhibitors). [5] For example, the majority of statin drugs such as Lipitor and Zocor, the worlds best-selling drugs in 2004, contain a bhydroxy-d-lactone moiety or the corresponding open-chain dhydroxy carboxylate form. [6] In addition, d-lactones are very useful building blocks for the synthesis of bioactive compounds. [7] Many approaches, most often multistep procedures, have been elaborated for the preparation of d-lactones. [8] The most direct route to a,b-unsaturated d-lactones is based on hetero-Diels-Alder (HDA) reactions. [9] In order to generate directly the desired oxidation state, a vinylketene equivalent such as a vinylketene acetal is required as the diene component. It has been reasoned though that twofold substitution at the butadiene terminus has a deleterious effect upon the enantioselectivity of HDA reactions, thus explaining why these dienes have been less frequently used in asymmetric HDA reactions than Danishefsky-type dienes. [10] Up to now, only three highly enantioselective, catalytic HDA-based methodologies using a vinylketene acetal have been reported, [11][12][13] which are all restricted to the use of Brassard-type dienes (1,3dialkoxy-1-(trimethylsiloxy)butadienes) [14] and aromatic aldehydes [15] and which all require long reaction times (48-72 h) to provide useful yields.We present herein a new concept for the synthesis of a,bunsaturated d-lactones 6 which circumvents the preformation, isolation, and purification of moisture-and acid-sensitive vinylketene acetals. Our work was based on the hypothesis that substituted vinylketenes 2 should be formed in situ by dehydrohalogenation of a,b-unsaturated acid chlorides 1 (Scheme 1). [16] Vinylketenes are known to be inherently unstable species, [17] but they might be trapped and at the same time activated as a diene component of a Diels-Alder reaction by an enantiopure tertiary amine, thus forming an enantiomerically pure zwitterionic dienolate 4. This type of species was supposed to be reactive enough, in an s-cis conformation, to undergo [4+2] cycloadditions with aldehydes, by either a stepwise or a concerted mechanism. Our investigations were inspired by the tertiary-amine-catalyzed asymmetric synthesis of b-lactones from ketene via zwitterionic enolate intermediates. [18] Because of the considerable homology of 4 to vinylketene acetals, the intermediate formation of these dienolates was anticipated to overcome the pronounced tendency of vinylketenes to preferentially undergo [2+2] cycloaddition reactions. [19] 3,4-Dimethylpent-2-enoyl chloride (1 a; R 1 = iPr) and trichloroacetaldehyde (chloral, 5 a; R 2 = CCl 3 ) were chosen as model substrates for the development of this process. Initial experiments in acetonitrile at À15 8C using stoichiometric ...

Organocatalyzed Cycloadditions

“…Peters and co-workers developed a tertiary amine-catalyzed enantioselective [4 + 2] cycloaddition of a,b-unsaturated acid chlorides 76a-e and electron-poor aldehyde chloral (77) to provide d-lactones 79a-e, Scheme 3.27 [42]. Vinylketene, which was formed in situ by dehydrohalogenation of a,b-unsaturated acid chloride …”

“…It was noteworthy to use water-saturated nitromethane as the reaction solvent. The adduct 41 was transformed to a tetracycle with the skeleton of the ring A-D of daphnicyclidin-Type alkaloids (42).…”

Cycloaddition and Electrocyclic Reactions of Vinylketenes, Allenylketenes, and Alkynylketenes

“…Vinylketenes, generated in situ by dehydrochlorination, react with trichloroacetaldehyde in the presence of Sn(OTf) 2 and O-trimethylsilylquinidine as a chiral catalyst to afford δ-lactones such as 123 in good yields and with high enantiomeric purity (Scheme 142). 156,157,32 Reaction in the presence of MeOD provides the methyl ester with partial deuterium incorporation. This result is interpreted as showing the involvement of both a vinylketene intermediate and a route that involves displacement of chloride by the amine catalyst followed by deprotonation to afford a dienolate intermediate, which leads to lactone products without a vinylketene intermediate.…”

“…The isomeric benzoquinones (±)-O-methylperezone (156) and (±)-Omethylisoperezone (157) are synthesized from the same cyclobutenedione 155 (Scheme 165). 106 Addition of 2-propenyllithium, cyclobutenone ring opening, electrocyclization, and a final oxidation affords product 156 via the dienylketene.…”

Cinchona Alkaloids and their Derivatives as Chirality Inducers in Metal‐Promoted Enantioselective Carbon–Carbon and Carbon–Heteroatom Bond Forming Reactions

“…It is worth to note that, while Nelsons protocol (i.e., the combination of a cinchona alkaloid with a lithium salt) provides the cis-b-lactone products, the use of lanthanide and pseudolanthanide triflates as cocatalysts, in some cases, affords the trans isomers in high diastereoselectivity. The sense of the diastereoselectivity depends on the substitution of the acid Very recently, a similar bifunctional catalyst system (metal triflates and cinchona alkaloid) was successfully applied by Peters and coworkers for the synthesis of b-sultones (Scheme 4.17) [40] and chiral a,b-unsaturated d-lactones [41].…”