Abstract
We herein report an unprecedented strategy for the asymmetric α‐chlorination of β‐keto esters with hypervalent iodine‐based Cl‐transfer reagents using simple Cinchona alkaloid catalysts. Our investigations support an α‐chlorination mechanism where the Cinchona species serves as a nucleophilic catalyst by reacting with the chlorinating agent to generate a chiral electrophilic Cl‐transfer reagent in situ. Using at least 20 mol‐% of the alkaloid catalyst allows for good yields and enantioselectivities for a variety of different β‐keto esters under operationally simple conditions.
Highlights
Catalytic enantioselective syntheses of chiral α-chlorinated carbonyl derivatives represent important transformations, mainly because of the value of the hereby obtained enantioenriched products as building blocks or intermediates for a variety of further transformations.[1,2] In particular, these compounds can undergo highly stereospecific nucleophilic SN2type reactions allowing for the synthesis of valuable (biologically active) target molecules (Scheme 1A).[2,3] it comes as no surprise that the development of reliable enantioselective asymmetric approaches to access these targets in a catalytic fashion has been heavily investigated in the past.[2,4,5] A common synthesis strategy relies on the addition of prochiral enolate equivalents to electrophilic Cl-sources
Our group has recently reported the use of these reagents in combination with asymmetric organocatalysis[7] to access enantioenriched α-CN- and α-N3- -keto esters in good yields and with moderate enantioselectivities (Scheme 1B).[8]
We started our investigations by carrying out the α-chlorination of the tert-butyl ester 1a with the catalysts and Cl-transfer reagents depicted in Figure 1 (Table 1 gives an illustrative overview of the most significant results obtained in this screening)
Summary
Catalytic enantioselective syntheses of chiral α-chlorinated carbonyl derivatives represent important transformations, mainly because of the value of the hereby obtained enantioenriched products as building blocks or intermediates for a variety of further transformations.[1,2] In particular, these compounds can undergo highly stereospecific nucleophilic SN2type reactions allowing for the synthesis of valuable (biologically active) target molecules (Scheme 1A).[2,3] it comes as no surprise that the development of reliable enantioselective asymmetric approaches to access these targets in a catalytic fashion has been heavily investigated in the past.[2,4,5] A common synthesis strategy relies on the addition of prochiral enolate equivalents to electrophilic Cl-sources. Hypervalent iodine-based electrophile-transfer reagents have been established as powerful and broadly applicable tools in (asymmetric) organic synthesis.[6] Our group has recently reported the use of these reagents in combination with asymmetric organocatalysis[7] to access enantioenriched α-CN- and α-N3- -keto esters in good yields and with moderate enantioselectivities (Scheme 1B).[8] Simple Cinchona alkaloids[9] (i.e. Cinchonidine, CD) turned out to be the best-suited organocata-
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