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

Emma L. Carswell; Douglas Hayes; Kenneth W. Henderson; William J. Kerr; Claire J. Russell

doi:10.1055/s-2003-39291

LETTER

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

Emma L. Carswell^a, Douglas Hayes^b, Kenneth W. Henderson*^a, William J. Kerr*^a, Claire J. Russell^a
^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

Abstract

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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

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References

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

<A NAME="RD07203ST-2">2</A> Henderson KW. Kerr WJ. Moir JH. Tetrahedron 2002, 58: 4573

For recent reviews, see:

<A NAME="RD07203ST-3A">3a</A> O’Brien P. J. Chem. Soc., Perkin Trans. 1 2001, 95

<A NAME="RD07203ST-3B">3b</A> O’Brien P. J. Chem. Soc., Perkin Trans. 1 1998, 1439

<A NAME="RD07203ST-3C">3c</A> Simpkins NS. Pure Appl. Chem. 1996, 68: 691

<A NAME="RD07203ST-4">4</A> Henderson KW. Mulvey RE. Clegg W. O’Neil PA. Polyhedron 1993, 12: 2535

<A NAME="RD07203ST-5">5</A> Zhang M. Eaton PE. Angew. Chem. Int. Ed. 2002, 41: 2169

<A NAME="RD07203ST-6">6</A> Henderson KW. Allan JF. Kennedy AR. Chem. Commun. 1997, 1149

<A NAME="RD07203ST-7">7</A> Ashby EC. Willard GF. J. Org. Chem. 1978, 43: 4094

During the preparation of this manuscript two articles have appeared detailing the use of chiral alkylmagnesium amides in enantioselective alkylation of aldehydes and in the asymmetric reduction of aryl trifluoromethylketones:

<A NAME="RD07203ST-8A">8a</A> Yong KH. Taylor NJ. Chong JM. Org. Lett. 2002, 4: 3553

<A NAME="RD07203ST-8B">8b</A> Yong KH. Chong JM. Org. Lett. 2002, 4: 4139

<A NAME="RD07203ST-9">9</A> Henderson KW. Kerr WJ. Moir JH. Chem. Commun. 2000, 479

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]

For related discussions on replacing HMPA as an additive see:

<A NAME="RD07203ST-11A">11a</A> O’Neil IA. Lai JYQ. Wynn D. Chem. Commun. 1999, 59

<A NAME="RD07203ST-11B">11b</A> Mukhopadhyay T. Seebach D. Helv. Chim. Acta 1982, 65: 385

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.]}.

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

<A NAME="RD07203ST-14">14</A> Henderson KW. Kerr WJ. Moir JH. Synlett 2001, 1253

<A NAME="RD07203ST-15">15</A> Eaton PE. Lee CH. Xiong Y. J. Am. Chem. Soc. 1989, 111: 8016

<A NAME="RD07203ST-16">16</A> For a recent review of catalytic enantioselective deprotonations see: Eames J. Eur. J. Org. Chem. 2002, 393