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Catalytic Conjugate Additions of Geminal Bis(sulfone)s: Expanding the Chemistry of Sulfones as Simple Alkyl Anion Equivalents
Author(s) -
Landa Aitor,
Puente Ángel,
Santos J. Ignacio,
Vera Silvia,
Oiarbide Mikel,
Palomo Claudio
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200902094
Subject(s) - chemistry , nucleophile , enantioselective synthesis , alkyl , iminium , catalysis , sulfone , pyrrolidine , adduct , organic chemistry , addition reaction , organocatalysis , medicinal chemistry
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 α,β‐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 (β‐aryl‐substituted enals >95 % ee ; β‐alkyl substituted enals up to 94 % ee ; ee =enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding β‐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, α‐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 β‐branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral α,β‐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 .