Toward the Development of a Structurally Novel Class of Chiral Auxiliaries:  Diastereoselective Aldol Reactions of a (1R,2S)-Ephedrine-Based 3,4,5,6-Tetrahydro-2H-1,3,4-oxadiazin-2-one

Abstract

[reaction: see text] Asymmetric aldol addition reactions have been conducted with (1R,2S)-ephedrine-derived 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (2). Diastereoselectivities range from 75:25 to 99:1 for the formation of the crude non-Evans syn adducts 8a-h. The facial selectivity of the enolate is directed by the stereogenic N(4)-methyl substituent. Aldol adduct 8a is readily cleaved by acid hydrolysis to afford (2S,3S)-3-hydroxy-2-methyl-3-phenylpropionic acid (9) in >95% ee.

(5S,6R)-5-Methyl-6-phenyl-4-propyl-1,3,4-oxadiazinane-2-thione

“…Other oxadiazinanones, but no oxadiazinanthiones, have been reported and studied. The oxadiazinanone structures previously reported by Hitchcock and co-workers all contain a carbonyl group attached at the N3 position, which is believed to have an impact on the ring conformation (Burgeson et al, 2004;Casper, Blackburn et al, 2002;Casper, Burgeson et al, 2002;Ferrence et al, 2003;Hitchcock et al, 2001Hitchcock et al, , 2004Hitchcock et al, , 2008Squire et al, 2005;Szczepura et al, 2004).…”

“…For related compounds, see: Burgeson et al (2004) ;Casper, Blackburn et al (2002) ;Casper, Burgeson et al (2002); Cremer & Pople (1975); Ferrence et al (2003); Hitchcock et al (2001Hitchcock et al ( , 2004; Rodrigues et al (2005Rodrigues et al ( , 2006; Squire et al (2005); Szczepura et al (2004). For structural analysis, see: Boeyens (1978); Bruno et al (2004); Cremer & Pople (1975); Spek (2009 Hydrogen-bond geometry (Å , ).…”

“…A Mogul (Bruno et al 2004) geometry check showed all non-H bond angles and distances to be normal. X-ray crystal structural data obtained for the oxadiazinan-2-thione proved to be interesting in the context of comparing it to related oxadiazinanone structures (Casper, Burgeson et al, 2002).…”

Synthesis, reactivity and conformational stability of an l-phenylalanine derived oxadiazinanone

“…[1][2][3][4][5][6] The oxadiazinanones that have been synthesized have been derived from the Ephedra alkaloids, namely (1R,2S)-ephedrine, 1-4 (1R,2S)-norephedrine, 5,6 and (1S,2S)-pseudoephedrine 7 (Chart 1). We have demonstrated the utility of (1R,2S)-ephedrine and (1R,2S)-norephedrine derived oxadiazinanones as chiral auxiliaries in the asymmetric aldol addition.…”

“…We have demonstrated the utility of (1R,2S)-ephedrine and (1R,2S)-norephedrine derived oxadiazinanones as chiral auxiliaries in the asymmetric aldol addition. [1][2][3][4][5][6] Based on the observed diastereoselectivities from these studies, as well as computational studies and 1 H NMR studies, the ephedrine and norephedrine derived oxadiazinanones are considered to be conformationally and, consequently, configurationally stable at the N 4 -nitrogen.…”