Stereoselective Bromination−Suzuki Cross-Coupling of Dehydroamino Acids To Form Novel Reverse-Turn Peptidomimetics:  Substituted Unsaturated and Saturated Indolizidinone Amino Acids

Abstract

A general and efficient methodology has been developed to prepare the C4-substituted dipeptide reverse-turn mimetics unsaturated (9a, 10a) and saturated (11a) azabicyclo[4.3.0] alkane amino acid derivatives. The side chain was introduced by bromination of dehydroamino acid intermediates followed by Suzuki coupling. Hydrogenation of the bicyclic dehydroamino acid 9a afforded saturated bicyclic lactam 11a. This approach can be further explored for the synthesis of a variety of such beta-turn mimetics with aryl and alkyl side chain functionalities. [reaction: see text]

Crystal structure ofN-(tert-butoxycarbonyl)glycyl-(Z)-β-bromodehydroalanine methyl ester [Boc–Gly–(β-Br)(Z)ΔAla–OMe]

“…One of the interesting classes of such mimetics are -bromo-dehydroamino acids and their derivatives, which are usually obtained by radical halogenation of dehydroamino acids using Nbromosuccinimide (NBS). This reaction proceeds in two steps, namely by halogenation of dehydroamino acids, which gives -bromo-imines, followed by tautomerization to the desired products upon treatment with an amine (Coleman & Carpenter, 1993;Zhang et al, 2002). -Bromo-dehydroamino acid derivatives are useful substrates in coupling reactions with alkynes (Singh et al, 2003) or organoboranes (Collier et al 2002;Zhang et al, 2002).…”

“…This reaction proceeds in two steps, namely by halogenation of dehydroamino acids, which gives -bromo-imines, followed by tautomerization to the desired products upon treatment with an amine (Coleman & Carpenter, 1993;Zhang et al, 2002). -Bromo-dehydroamino acid derivatives are useful substrates in coupling reactions with alkynes (Singh et al, 2003) or organoboranes (Collier et al 2002;Zhang et al, 2002). Further asymmetric hydrogenation of their double bound allows non-proteinogenic -amino acids and their derivatives to be obtained.…”

α,β-Dehydroamino Acids

“…The HWE reaction is the key step in the synthesis of bturn mimic 13 (Scheme 4, bottom) [41][42][43] and (S,S)-or mesodiaminopimelic acid reported by Hruby. 44 Pyridine-containing amino acids, such as L-azatyrosine (16) were prepared by Adamczyk using the HWE reaction with subsequent hydrogenation (Scheme 5).…”

“…Synthesis of isodityrosine using the commercially available HWE reagent 7; 40 synthetic route to b-turn mimic 13 (bottom)[41][42][43] Preparation of pyridine-containing amino acids according to Adamczyk[45][46][47][48] a,b-Dehydroamino esters with axial chirality prepared by Cativiela and Su49,50 …”

Tryptophan Analogues with Fixed Side‐Chain Orientation: Expanding the Scope

“…These methods often intend to influence the conformational pattern of side chains but not their overall number. Significantly harsher conformational locks are local side-chain-to-backbone cyclizations [4] or bicyclic dipeptides [5] that often go at the expense of side-chain functional groups because the combination of local backbone rings and side-chain functionality requires much synthetic effort [6] or is restricted to hydroxy substituents. [7] Instead of losing side-chain functionality to achieve a severe conformational restriction, we recently proposed doubly functionalized asymmetric β-branched amino acids as local conformational locks.…”