Abstract
This thesis describes the use of chiral lithium amides as enantiotopic deprotonating agents and as nucleophiles in asymmetric synthesis. The chiral lithium amides were prepared from their corresponding secondary amines by reaction with butyl lithium. The syntheses of the secondary amines are described; in general (R) or (S)-1 -phenylethylamine was condensed with an aldehyde or ketone and the subsequent imine was reduced. Two new secondary amines (1R,2R,3S,4R)-2-hydroxy-3-(N-(S)-1-phenylethylamine)-2,6,6-trimethylbicyclo[3.1.1]heptane (126b) and (R,2R,3R,4R)-2- hydroxy-3-(N(R)-1-phenylethylamine)-2,6,6-trimethylbicyclo[3.1.1] heptane (126a) were synthesised and the absolute stereochemistry of 126b was determined from an X-ray crystal structure. A simple method was developed for the condensation of camphor with hindered primary amines; (R)-N-(1-phenylethyl)bomanimine (113a) and (S)-N-(1-phenylethyl)boman-imine (113b) were produced in high yield. Subsequent reduction of the C=N bond occurred diastereoselectively to give exo-(1R)-N-(1 -phenylethyl)bomanamine (119a) and endo-(1S)-N-(l-phenylethyl)bomanamine (119b); the absolute stereochemistry of 119b was confirmed from an X-ray crystallographic analysis. The enantiotopic deprotonation of 4-t-butylthiane-1,1-dioxide (pentamethylene sulphone) and subsequent reaction of the carbanion with methyl iodide and trimethylsilyl chloride was investigated. Lithium (R)-N-benzyl-1-phenylethylamide, lithium (R)-N-(1-phenylethyl)-alpha-methylbenzylamide, and lithium exo-(1R)-N-(1-phenylethyl)bomanamide failed to differentiate between the enantiotopic protons a to the SO2 function. However the lithium amide bases derived from 3-hydroxyamines showed some selectivity; deprotonation using the dianion of (1R,2S)-ephedrine or the dianion of 226b, and subsequent reaction with methyl iodide or trimethylsilyl chloride gave 2-methyl-4-t-butylthiane-1,1-dioxide or 2-trimethylsilyl-4-t-butylthiane-1,1-dioxide in 15-24% e.e. The Michael addition of lithium (R)-N-benzyl-1-phenylethylamide (30a) and lithium bis [(R)-N-(1-phenylethyl)]amide (17a) to a variety alpha,beta-unsaturated aldehydes, ketones, imines, nitriles, esters and carboxamides was investigated. The Michael addition of 30a to cinnamoyl and crotonoyl amides was found to be highly face selective (d.e. 85-96%). Addition of 30a to cinnamoyl amides followed by reaction with methyl iodide lead to two new chiral centres (72-91% d.e.) while reaction with benzaldehyde produced three new chiral centres with high diastereoselectivity (85-90% d. e.). The stereochemistry of the Michael adducts was confirmed by X-ray crystallography.