Efficient 1,3-Asymmetric Inductions during Nucleophilic Additions to Imine and Iminium Ion Derivatives

Abstract

Two new b-amino alcohols have been synthesized by a reaction between an organolithium compound 1 involving an allylsilane moiety with either an imine or an oxazolidine derived from (S)-phenylglycinol. These reactions occurred in good yields and with high diastereoselectivity. Both amino-alcohols were engaged in cyclization reaction with glyoxal to afford in two steps highly functionalized bicyclic lactones.Key words: organolithium reagent, asymmetric synthesis, b-amino alcoholsThe addition of organometallic reagents to imines derived from phenylglycinol has recently begun to attract interest of chemists. 1 Pioneering works of Takahashi et al. 2 reported the diastereoselective addition of chiral imines and 1,3-oxazolidines with MeMgBr and MeLi. This study prompted many groups to synthesize by this way chiral amines, 3 optically pure b-amino alcohols 4 and various natural and non-natural products. 5 This interesting process is not restricted to such simple organometallic reagents. This Letter relates the reaction of b-amino alcohols-derived substrates with [2-((trimethylsilyl)methyl)prop-2-enyl]lithium 1, which has been recently synthesized by Livinghouse and Ryter, 6 from an allyl selenide. Kang et al. 7 described the reactivity of an analogous reagent with various aldimines which afford racemic piperidines.In the course of our studies aimed at extending our methodology that leads to derivatives of pipecolic acid, 8 amino alcohols presenting both a second chiral center and an allylsilane side-chain were required. Chiral imine 2 and oxazolidine 3 were obtained quantitatively by stirring (S)-phenylglycinol at room temperature with the corresponding aldehyde in the presence of MgSO 4 . The structure of the products was established by 1 H NMR. The main product derived from benzaldehyde was the trans imine 2 as already described. 2a The propanal-derived oxazolidine 3 was obtained as a mixture which was epimeric at C-2 (60/ 40). 9 Subsequent addition of the organolithium reagent 1 on the chiral compounds 2 and 3 10 afforded b-amino alcohols 4 and 5 respectively in good yields and with high diastereoselectivity (see Scheme 1 and Table 1). As shown in the Table 1, allowing the reaction mixtures to reach room temperature resulted in lower yields; this can be ascribed to the instability of the anionic intermediates prior to the hydrolytic workup.Scheme 1 a) TMSCH 2 C(=CH 2 )CH 2 Li (1), THF, -78 to -20°C. Table 1 Reactions of the Lithium Derivative 1 with Compounds 2 and 3.These two new b-amino alcohols 4 and 5 were engaged in cyclization reaction 11 with glyoxal to test, on the one hand, whether our already described methodology could be extended to those new substrates and, on the other hand, to establish the absolute configurations of the stereogenic centers (Scheme 2). Scheme 2 a) CHOCHO, THF/H 2 O, 93% and 95% from 4 and 5 respectively; b) COCl 2 , DMSO, NEt 3 , 70% for 8 and 93% for 9. Li TMS 1 N OH Ph R N H O Ph R OH NH TMS Ph R 2 (R=Ph) 3 (R=Et) 4 (R=Ph) 5 (R=Et) a a N O Ph R H OH N O Ph R H O 4 (R=Ph) 5 (R=Et) a b ...

Recent Developments in the Ring‐Chain Tautomerism of 1,3‐Heterocycles

“…[41] The additions of {2-[(trimethylsilyl)methyl]prop-2-enyl}lithium to (S)-phenylglycinol-derived oxazolidines (90) also afforded β-amino alcohols 91 with high diastereoselectivities (Scheme 29). [42] Scheme 29 Probably because of a slow tautomeric equilibration process, an open (A) and two C-2-epimeric cyclic (B and C) tautomers of the condensation product 92 derived from (R)-phenylglycinol and 2,2,2-trifluoroacetophenone could be isolated. When compounds 92AϪC were treated with various organolithium reagents, N-substituted amino alcohol derivatives 93 or 94 were obtained with moderate to excellent diastereoselectivities.…”

Parallel Solid-Phase Synthesis and Structural Characterization of a Library of Highly Substituted Chiral 1,3-Oxazolidines

“…1,3-Oxazolidines are remarkably versatile molecules having found use as chiral auxiliaries, , as intermediates for more complex chiral heterocycles, − and as prodrugs for improving the pharmacokinetic profile of certain β -amino alcohol pharmacophores . They are ideally suited as scaffolds for combinatorial library generation because they have a rigid core that possesses four sites for the incorporation of diversity elements and can be synthesized with a high degree of chiral integrity (Figure A).…”

Asymmetric Syntheses of New Functionalized β-Amino Alcohols via Diastereoselective Addition of Organometallic Reagents onto Oxazolidines

“…Pioneering works in this field have been concerned with the diastereoselective addition of alkyl or aryllithium reagents onto oxazolidines derived from amino alcohol and especially from phenylglycinol. As part of a program aimed at emphasizing the efficiency of asymmetric syntheses of pipecolic acid derivatives from functionalized β-amino alcohols, we have recently explored the reactions between unsaturated organolithium reagents and oxazolidines 1 .…”