Enantioselective Synthesis of β‐Amino Acids. Part 13. Diastereoselective Alkylation of Dianions Derived from Chiral Analogues of β‐Aminopropanoic Acid Containing the α‐Phenylethyl Group.

Abstract

Dedicated to Professor Dieter Seebach, in appreciation for his example as a person and as a scientist.Inexpensive acryloyl chloride was converted in 91% overall yield to two derivatives of b-alanine, (R,R,R)-6 and (R,R,S)-6, containing two chiral auxiliaries. C-Alkylation of (R,R,R)-and (R,R,S)-6 via a dianion derivative, was performed by direct metallation with 2.2 equiv. of lithium hexamethyldisilazane (LHMDS) in THF at À 788. C-Alkylation of (R,R,S)-6-Li 2 (−matched× pair of chiral auxiliaries) afforded the mono-alkylated products 8 ± 11 in 29 ± 96% yield and 54 ± 95% stereoselectivity. Employment of LiCl as an additive generally increased stereoselectivities, whereas the effect of HMPA as a cosolvent was erratic. Chemical correlation of the major diastereoisomer from the alkylation reactions with (S)-a-alkyl-b-alanine (12 ± 15) showed that addition of the electrophile preferentially takes place on the enolate×s Si-face. This conclusion is also supported by molecular-modeling studies (ab initio HF/3-21G), which indicate that the lowest-energy conformation for (R,R,S)-6-Li 2 presents the more sterically hindered Re-face of the enolate. The theoretical studies also predict a determining role for NÀLiÀO chelation in (R,R,S)-6-Li 2 , giving rise to an interesting −ion-triplet× configuration for the dilithium dianion.Introduction. ± Because of the enormous importance of amino acids and peptides in stereospecific biological interactions [1], a truly remarkable amount of research has been dedicated to the asymmetric synthesis of chiral amino acids [2]. Among the methods available for the preparation of enantiomerically enriched a-amino acids, those making use of chiral derivatives of glycine [3] have been particularly successful. Among these, Seebach×s chiral imidazolidinone A represents a prominent substrate and pioneering concept (Scheme 1) [4].More recently, motivated by the efficiency of the a-phenylethylamino moiety as a chiral auxiliary [5] and by the advantageous effect of C 2 -symmetric substrates in asymmetric synthesis [6], we successfully explored −open-chain× glycinamides of type B and C as substrates in the preparation of enantiomerically pure a-amino acids [7].During the last few years, the preparation of b-amino acids has emerged as an important and challenging synthetic endeavor, partly because they are components of a variety of natural products, such as taxol [8], the dolastatins [9], and many others [10]. Furthermore, a number of open-chain [11] or cyclized [12] b-amino acids display interesting pharmacological properties and give rise to stabilized helical peptides with enhanced resistance to enzymatic degradation [13].

The Alkylation of Carbanions

“…Further useful dianions can be generated from ketones (C=C(OM)CM or C=C(OM)CCM) [138][139][140][141][142], carboxylic acids (C=C(OM) 2 ) [143][144][145], succinic acid derivatives ((C=C(OM)OR) 2 ) [146], alkynes (MC"CCM, MC"CC-OM) [147][148][149][150][151][152][153][154][155], imidazoles [156], thiophenes [157,158], b-alanine derivatives (MN-CC=C(OM)X) [159], 3-nitropropanoates [160,161], 3-hydroxypropanoates [162,163], 2-hydroxyethylsulfones [164,165], arenes [166][167][168], allenes [169], thioamides [170], and sulfonamides (MC-SO 2 NM [171]; R 2 NSO 2 -CM 2 [172]). If the nucleophilic sites in the polyanion have different chemical hardness, regioselective alkylation can be achieved by selecting a soft or a hard electrophile (second reaction, Scheme 5.13).…”