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Synlett 2003(7): 1017-1021
DOI: 10.1055/s-2003-39291
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel Enantiomerically Pure Heteroleptic Magnesium Complexes for Use in Enantioselective Deprotonation Reactions

Emma L. Carswella, Douglas Hayesb, Kenneth W. Henderson*a, William J. Kerr*a, Claire J. Russella
a Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, Scotland, G1 1XL, UK
Fax: +1(547)6316652; e-Mail: khenders@nd.edu; Fax: +44(141)5484246; e-Mail: w.kerr@strath.ac.uk;
b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, England, SG1 2NY, UK
Further Information

Publication History

Received 27 March 2003
Publication Date:
20 May 2003 (online)

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Abstract

Two classes of heteroleptic magnesium complexes, alkyl­magnesium amides RMgNR2 and aryloxymagnesium amides ROMgNR2, have been prepared and subsequently shown to be efficient bases in the enantioselective deprotonation of substituted cyclic ketones. When compared with their magnesium bisamide counterparts, significantly different reactivity and selectivity profiles, including an unexpected reversal in enantioselectivity, has been observed with the new reagents.

Key words

asymmetric synthesis - chirality - magnesium amides - heteroleptic complexes

1

Present address: Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, 46556-5670, USA.

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It is also worth noting that in order to access the bisamide species, heating to reflux in THF or hexane (with two equivalents of the chiral amine) is required. [2] [9]

12

Representative experimental procedure: To a Schlenk flask, under N2, was added Bu2Mg (0.79 M solution in heptane, 1.27 mL, 1 mmol). The heptane was then removed in vacuo and replaced with THF (10 mL), followed by the addition of (R)-N-benzyl-α-methylbenzylamine 2 (0.21 mL, 1 mmol). The resultant solution was stirred at room temperature for 90 min and then cooled to -78 °C, whereupon TMSCl (0.5 mL, 4 mmol) and DMPU (0.06 mL, 0.5 mmol) were added. After stirring for 20 min at -78 °C, 4-tert-butylcyclohexanone 5a (0.123 g, 0.8 mmol) was added as a solution in THF (2 mL) over 1 h using a syringe pump. The reaction was then quenched by the addition of saturated NaHCO3 (5 mL). After warming to room temperature the reaction mixture was extracted with diethyl ether (30 mL) and washed with saturated aqueous NaHCO3 (2 × 20 mL). The combined aqueous phase was extracted with diethyl ether (2 × 20 mL), the combined organic phase dried (Na2SO4), and the solvent removed in vacuo. The reaction conversion was determined as 80% by G.C. analysis [CP SIL 19CB fused silica capillary column; carrier gas H2 (80 kPa); 45 °C (1 min)-190 °C; temperature gradient: 45°C/min; t R = 3.27 min (5a), t R = 3.69 min (6a)]. Flash column chromatography (eluting with petroleum ether) afforded (S)-4-tert-butyl-1-trimethylsiloxy-1-cyclohexene (S)-6a (0.136 g, 60%) as a clear oil which displayed an enantiomeric ratio of 86:14 {Chirasil-DEX CB capillary column; carrier gas H2 (80 kPa); 70-130 °C; temperature gradient: 1.7 °C/min;
t R = 37.66 min [(S)-6a], t R = 37.97 min [(R)-6a.]}.

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However, the reactivity of both the amide and the alkyl anions in the deprotonation reactions cannot definitively be ruled out.