Design, Development, and Scale-Up of a Selective meso-Epoxide Desymmetrization Process

Abstract

A pilot-plant scale desymmetrization of the cyclic meso-epoxide 4b, using a chiral lithium amide prepared from symmetrical diamine 17, was designed and implemented to provide allylic alcohol 3b in high yield and greater than 99% ee. This chiral alcohol was converted to ketone 2b, a key intermediate in a new asymmetric synthesis of LY459477. Chiral diamine 17 was prepared from a readily available chiral precursor, (R)-rmethylbenzylamine, and could be recovered from the reaction mixture and reused. Studies performed to probe the mechanism of the rearrangement reaction of epoxide 4b showed that diamine 17 provided an optimal combination of selectivity and scaleability for this process.

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

“…Recently, Varie et al 208 reported a pilot-plant desymetrization of the cyclic meso -epoxide 507a using a chiral lithium amide prepared from ( R , R )-diamine 508 and n -BuLi to give the allyl alcohol (1 S ,4 R )- 509 in 72% yield and 99.3% ee. However, treatment of meso -epoxide 507b under identical conditions gave the allyl alcohol (1 S ,4 S )- 510 in only 3% yield and 48% ee (Scheme 105).…”

Synthesis of complex unnatural fluorine-containing amino acids

“…The synthesis of 4-fluoro-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 108 was reported by Monn and co-workers in 2013 for the purpose of carrying out biological studies ( Scheme 24 ) [ 95 ]. Initial reduction of ketone 105 , a versatile intermediate prepared from enone 103 [ 96 ], resulted in the formation of β-carbinol 106 [ 97 ]. Further treatment with DAST allowed successful installation of a fluorine atom on the α-face of the bicyclohexane structure at the C4 position ( 107 ).…”

Advances in the Chemistry of Chiral Lithium Amides

“…Deprotonation reactions involving a stoichiometric (or more) amount of CLA, and thus in the absence of an achiral amide, continued to be explored in the same period (Scheme 10.2). Some of the reactions studied in this context include the rearrangements of (i) bis-protected meso-4,5-dihydroxycyclohexene oxides 110 (using CLAs 18b, 41-47, 56a,c, 58 or 69, 2 equiv, ee up to 95%), precursors of conduritol derivatives known for their antibiotic and antileukemic activity (Scheme 10.2, first line) [4d]; (ii) spiro epoxide fused cis-bicyclo [3.3.0]octanes 111 (using CLAs 4b, 18a, or 58, 2 equiv, ee up to 80%) (Scheme 10.2, second line) [15]; (iii) meso-aziridinocyclohexene oxides 112 (using CLAs 46a, 56a, 58, 60, or 69, 1.2 equiv, ee up to 68%) (Scheme 10.2, third line) [16]; and (iv) substituted cyclopentene oxides 113 (using CLAs 5a, 18a, 21, 22a, 24a, 25, 26, 27, 46a, 56, or 69, 2-3 equiv, ee up to 93%) (Scheme 10.2, fourth line) [17,18]. Working with solid-phase supported CLAs (99 and 100) on cyclohexene oxide also proved to be successful (ee up to 91%) [19].…”