Catalytic Conjugate Additions of Geminal Bis(sulfone)s: Expanding the Chemistry of Sulfones as Simple Alkyl Anion Equivalents

Abstract

The value of cyclic gem-bis(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bond-forming reactions is demonstrated. The 1,4-type nucleophilic additions of bis(sulfone) 4 to alpha,beta-unsaturated ketones take place by assistance of catalytic guanidine base. On the other hand, pyrrolidines are able to catalyze the conjugate addition of 4 to both enones and enals, likely by means of iminium ion activation. Upon exploration of the best chiral pyrrolidine catalyst, it has been found that the addition of 4 to enals catalyzed by diphenylprolinol silyl ether 10 proceeds with very high enantioselectivity (beta-aryl-substituted enals >95% ee; beta-alkyl substituted enals up to 94% ee; ee = enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding beta-methyl aldehydes, as well as the derived alcohols, acetals, and methyl esters after simple (Mg, MeOH) well-established protocols. Application of the procedure to the synthesis of biologically relevant phenethyl building blocks is shown. Most interestingly, alpha-alkylation of initially obtained bis(sulfone) adducts can be done even with less reactive alkylating reagents, such as long linear-chain or branched-chain alkyl halides. Accordingly, upon the desulfonation process, a general, experimentally simple and highly enantioselective access to beta-branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral alpha,beta-unsaturated aldehydes derived from citronellal as the Michael acceptor partners. In these instances, the sense of the conjugate addition of 4 is controlled by the chirality of the pyrrolidine catalyst, thus allowing for a stereochemically predictable access to 1,3-dimethyl arrays, such as those present in deoxygenated polyketide-type natural products. The intramolecular variation of this technology by using doubly unsaturated aldehyde-ester 22 illustrated the site selectivity of the procedure and its potential for tandem processes leading to highly substituted polycyclic systems, such as 24.

A Theoretical and Experimental Study of the Effects of Silyl Substituents in Enantioselective Reactions Catalyzed by Diphenylprolinol Silyl Ether

“…Although excellent enantioselectivity was obtained with cinnamaldehydes, enantioselectivity decreased with aliphatic enals (90.0:10.0 enantiomeric ratio (e.r.) in the reaction of crotonaldehyde) 23c. Aleman and co‐workers reported the reaction using diphenylprolinol TMS ether ( 1 ) in the presence of LiOAc in THF, and excellent enantioselectivities were obtained in most of the reactions except for crotonaldehyde, which afforded the product in 90.0:10.0 e.r 23a.…”

Peptide‐Catalyzed Desymmetrization of an Achiral Ferrocenyl Compound To Induce Planar Chirality

“…Effect of cyclization for the enantioselectivity of 4. was mainly converted into the diastereomers of 5. [18] After examining the reaction conditions, the addition of benzoic acid [19] was found to be effective for obtaining cyclic compound 5 as a major product (Scheme 4).…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…The sulfone was used as an activated methylene compound in the Michael reaction of a,b-unsaturated aldehydes reported by Palomo and co-workers in 2009 [49] The screening of iminium catalysts revealed that silyl ether 13a was effective in the reaction of sulfone and cinnamaldehyde with good yield and excellent enantioselectivity (Scheme 23).…”