Highly Efficient Asymmetric Conjugate Additions of Aldehydes with Vinyl Sulfones Using a Sulfonamide Organocatalyst

Abstract

A sulfonamide organocatalyst promotes the asymmetric conjugate addition of branched aldehydes to vinyl sulfones to afford the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee.All-carbon quaternary stereocenters are ubiquitous motifs in many natural products and bioactive compounds; however, relatively harsh conditions are needed for their construction and the electrophile-nucleophile combinations are limited due to their steric hindrance. Therefore, stereoselective formation of carbon-carbon bonds for the construction of all-carbon quaternary stereocenters is one of the most challenging research themes in organic synthesis. 1 Synthetic methods for compounds with quaternary stereogenic centers using an organocatalyst have attracted considerable attention, particularly in the field of green chemistry. 2 1,1-Bis(benzenesulfonyl)ethylene (9) is a good Michael acceptor and reacts with various carbonyl compounds as a nucleophile in the presence of organocatalysts to afford valuable addition products. 3 In particular, the conjugate additions of branched aldehydes with 9 enable the effective construction of chiral all-carbon quaternary centers. However, despite the importance of effective synthetic methods, successful conjugate additions of branched aldehydes to vinyl sulfone 9 for the construction of all-carbon quaternary stereogenic center have rarely been reported. 4 We investigated organocatalysts that can effectively promote this reaction under mild conditions. On the other hand, we have recently reported that β-aminosulfonamide organocatalysts 1-5 (Figure 1), which are easily prepared from L-phenylalanine or L-valine, inexpensive natural amino acids, are good organocatalysts for the direct asymmetric aldol reaction in water. 5 In addition, we also have reported an asymmetric Michael reaction of aldehydes with maleimides using a primary amine thiourea organocatalyst derived from L-phenylalanine. 6 To further demonstrate the effectiveness of organocatalysts derived from L-phenylalanine or L-valine, we attempted additional applications for the stereoselective construction of all-carbon quaternary centers using organocatalysts. Herein, we would like to report highly efficient conjugate additions of branched aldehydes 10 to vinyl sulfone 9 using novel organocatalyst 6.We examined the β-aminosulfonamide organocatalysts 1-5 that we reported for the direct aldol reactions, 5 as shown in Table 1. With the exception of 1, high enantioselectivities were obtained (entries 1-5). Trifluoromethanesulfonamide 5, derived from L-valine, was the most suitable catalyst for the conjugate addition with vinyl sulfone 9, although 2 and 3, derived from L-phenylalanine, were superior to 5 for the direct aldol reactions. 5d Furthermore, to develop a more powerful organocatalyst, we attempted to prepare novel organocatalyst 6, which enhanced the acidity of the sulfonamide group by the introduction of the perfluorobutyl group that has strong electron-withdrawing characteristics (Scheme 1). T...

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…The SuFEx reactions typically use common sulfonylation conditions (Et 3 N, CH 2 Cl 2 ); [130,[136][137][138][139] also, ammonia [140][141][142][143][144][145] or aliphatic amines [146][147][148][149][150][151] can act both as reagents and as bases (Scheme 15A). One more important modification includes reaction of sulfonyl halides and aliphatic N-silylamines in refluxing in MeCN.…”

Bifunctional Sulfonamide as Hydrogen Bonding Catalyst in Catalytic Asymmetric Reactions: Concept and Application in the Past Decade

“…The methods that highly effective organocatalysis of Michael addition between aldehydes and vinyl sulfones were developed in Miura's group, while the conjugate addition for conducting all-carbon quaternary stereocenters was rarely studied before 2011 (Scheme 23). [61,62] Two β-aminosulfonamides 28 [61] and 34 [62] with bulky fluoroalkyl group were added into the reaction system with TFA as additive. 28 gave excellent yield (up to 99 %) and enantioselectivity (up to 95 % ee) in m-xylene, while 34 promoted reaction with similar results (up to 100 % and 94 % ee) under dichloroethane condition.…”

Perfluoroalkanesulfonamide Organocatalysts for Asymmetric Conjugate Additions of Branched Aldehydes to Vinyl Sulfones

“…In addition, we have reported a method for the synthesis of both enantiomeric aldol products in water using sulfonamide organocatalysts 1 [46] and 2 [47,48], prepared from l -phenylalanine. Very recently, we reported in a preliminary communication that perfluoroalkanesulfonamides 5 and 6 catalyze the conjugate additions of branched aldehydes to vinyl sulfone 11 to give the corresponding adducts with excellent stereoselectivities [49]; however, development of a protocol for recovery and reuse of 5 and 6 is yet to be reported. Herein, we describe the full details of the conjugate additions of branched aldehydes to vinyl sulfone using 6 and novel fluorous sulfonamide 7 (Figure 1).…”