Synthesis of enantiomerically pure quaternary glutamic acids via chemo- and diastereoselective alkylation of (5S)-3-([2-meth-oxycarbonyl]ethyl)-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one

Laurence M Harwood,Michael G B Drew,Archie Jahans,Simon N G Tyler,Iain D Macgilp,Charles Rees

doi:10.3998/ark.5550190.0001.514

Abstract

The imine moiety of (5S)-3-((2-methoxycarbonyl)ethyl)-5-phenyl-5,6-dihydro-2H-1,4- oxazin-2-one 2 undergoes highly diastereocontrolled reduction and Lewis acid-mediated chemo- and diastereoselective nucleophilic addition of Grignard reagents. Subsequent dismantling of the cyclic template permits ready access to enantiomerically pure glutamic acid analogues.

Highlights

We have previously reported the formation of a–substituted amino acid derivatives, via an approach in which enantiomerically pure 3–substituted 5–phenyl–5,6–dihydro-2H–1,4– oxazin–2–one 1a, prepared by cyclisation of (2S)–phenylglycinol with α-keto ester derivatives, underwent diastereocontrolled nucleophilic attack by Grignard reagents using Lewis acid activation to facilitate chemoselection between the imine and lactone functionalities.[2]
The chemoselectivity demonstrated by substrates 1 in our studies is complementary to that observed by Molinski on related substrates in the absence of Lewis acid, when phenylmagnesium bromide was shown to react via initial attack at the lactone of the 5,6–dihydro-2H–1,4–oxazin–2–one system.[3]
In contrast to our previously observed moderate diastereoselection in the hydrogenation of 3–ethyl–5–phenyl–5,6–dihydro–2H–1,4–oxazin–2–one,ii[v] hydrogenation furnished the 3,5–syn–disubstituted tetra-Hydrooxazinone 3 in higher than 94% d.e. according to integration of the proton NMR spectrum of the crude reaction mixture, the pure major diastereomer being isolated in 89% recrystallised yield

Summary

Introduction

We have previously reported the formation of a–substituted amino acid derivatives, via an approach in which enantiomerically pure 3–substituted 5–phenyl–5,6–dihydro-2H–1,4– oxazin–2–one 1a, prepared by cyclisation of (2S)–phenylglycinol with α-keto ester derivatives, underwent diastereocontrolled nucleophilic attack by Grignard reagents using Lewis acid activation to facilitate chemoselection between the imine and lactone functionalities.[2]. Subsequent degradation of the cyclic template using our standard conditions [H2/Pd(OH)2–C, aq MeOH, TFA2] furnished a two component mixture shown to consist of glutamic acid and pyroglutamic acid Heating this mixture in 5M HCl (conditions known not to cause racemisation [vi]) afforded pure D–glutamic acid 4 in 97% isolated yield {[α]D23 = –22.6 (c 0.31, H2O); lit for L– enantiomer [vii] [α]D22= +24.4 (c 6.0, H2O)} (Scheme 2). This overall conversion can be considered to constitute a biomimetic pathway, since L–glutamic acid is synthesised in vivo by reductive amination of 2–oxoglutarate in the presence of glutamate dehydrogenase.[8]

H Ph N ii

Findings

13. X–ray crystallographic data for 5a