Direct Enantioselective Conjugate Addition of Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries

Abstract

Michael addition is a premier synthetic method for carbon–carbon and carbon–heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B.

10‐Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)‐Dragmacidin D

“…Attempts to obtain the α-methylation product with CH 3 I and LDA or n -BuLi as the enolization reagents only led to decomposition of the starting material (Table 1, entries 1, 2). 9a A clean methylation was observed with LiN(SiMe 3 ) 2 (entry 3). We postulated decomposition with the more basic reagents was due to competitive lithiation of the arene C—H bond of 8 at the C3 position forming benzyne species.…”

“…This transformation was to be followed by Friedel-Crafts-type direct arylation with 6-bromoindole under acidic conditions, also utilized in the Itami/Yamaguchi synthesis.6 Bromoaniline 5 for the Larock indole synthesis was to arise from precursor 7 , identifying 4-methoxy-2-bromoacetic acid 8 as a straightforward starting material for its preparation by our direct alkylation method with the readily available tetramine ( R )- 1TA as the stereodirecting reagent (Scheme 1). 9 One of the challenging objectives was the preservation of the stereogenic center in 7 through the remaining operation of the synthesis.…”

“…Intact lithium amide ( R )- TALi 2 is a critical part of the chiral aggregate for stereoselective alkylation. 9b Investigation of various readily available amines drew our attention to t -Bu(Me 3 Si)NH, which in our assessment stroke the right balance between steric bulk to prevent C3 lithiation and basicity (p K a = 33 for t -BuNHSiMe 3 ; p K a = 37 for i -Pr 2 NH). 12 A preliminary experiment supported this assessment (entry 5).…”

Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries

“…The free carboxy group in the resulting products can be readily converted to amines as well as a variety of heterocycles, alcohols, esters, amides, or nitriles. The requisite enediolates, produced by the double deprotonation of carboxylic acids, have been largely neglected as intermediates in organic synthesis 24,25 despite their high nucleophilicity and formal symmetry the eliminates the problem of stereoselective enolization. Enediolate dianions are also expected to form mixed aggregates with lithium amide-based stereodirecting auxiliaries.…”

Diastereoselective Synthesis of γ-Lactones through Reaction of Enediolates with α,β-Unsaturated Sulfoxonium Salts

“…Proposed New Method for Diastereoselective γ-Lactone Synthesis enantioselectivity. 9 In this paper, we report that the reaction of lithium enediolates with vinylsulfoxonium salts provides an efficient and highly diastereoselective route to γ-lactones.…”