Abstract
Nonproteinogenic a,a-disubstituted-a-amino acids have attracted considerable attention because of their utility as conformational modifiers of biologically active peptides and as enzyme inhibitors. Typical methods for asymmetric synthesis of them involve chiral auxiliary-based enolate chemistry (ref. 1). However, the most straightforward strategy for the synthesis would involve direct asymmetric a-alkylation of parent a-amino acids in the absence of additional chiral sources such as chiral auxiliaries, chiral ligands, or even chiral catalysts. Since both L- and D-a-amino acids are readily commercially available, the synthetic route shown in Scheme 1 seems most attractive for the purpose. However, this process usually gives racemic a-alkylated products from either L- or D-a-amino acid because the enolate formation eliminates the chiral information of C(2) and an achiral enolate common to both L- and D-series is formed (A = B). If enolate intermediates enable to memorize the chiral information at C(2) of the starting materials, L- and D-a-amino acids would give optically active L- and D- (or D- and L-) a,a-disubsituted a-amino acids via intrinsically chiral enolate intermediates A and B, respectively. In this paper, we describe asymmetric a-alkylation of a-amino acid derivatives via the synthetic route
Highlights
Memory of ChiralityNonproteinogenic ƒ¿, ƒ¿-disubstituted-a-amino attracted of considerable their utility active for as peptides their chemistry.2,3 for of the the parent electrophiles, or route purpose.and an lity), from either If and D
Memory of Nonproteinogenic ƒ¿, ƒ¿-disubstituted-a-amino attracted of considerable their utility active for as peptides their chemistry.2,3 for of the the parent electrophiles, or route purpose
Asymmetric transformations based on dynamic chirality of the enolate structure are shown below
Summary
Nonproteinogenic ƒ¿, ƒ¿-disubstituted-a-amino attracted of considerable their utility active for as peptides their chemistry. for of the the parent electrophiles, or route purpose. Asymmetric transformations based on dynamic chirality of the enolate structure are shown below. Chiral nonracemic enolates of type 1 and 2 are expected to exist under particular conditions, their half-lives to racemization are usually too short to effect the actual asymmetric reactions. In order to realize an asymmetric transformation via the chiral enolate of type 1, we designed a chiral ketone 3 that would generate an axially chiral enolate 5 with relatively long half-life to racemization due to the restricted rotation of the C(1)-C(2) bond (Scheme 2). N-MOM-N-Boc in a highly of examin entries a solvent the further shown addition with property conditions 2, methyl induction sources, chemical selected lithium by asymmetric chiral substituents with followed low result treatment high of external.
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