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Synlett 2003(3): 0365-0368
DOI: 10.1055/s-2003-37105
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enantiopure Guanidine Bases For Enantioselective Enone Epoxidations: 1, Acyclic Guanidines

Julie C. McManusa, John S. Careyb, Richard J. K. Taylor*a
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax: +44(1904)434523; e-Mail: rjkt1@york.ac.uk;
b GlaxoSmithKline Pharmaceuticals, Leigh, Tonbridge, Kent TN11 9AN, UK
Further Information

Publication History

Received 20 December 2002
Publication Date:
07 February 2003 (online)

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Abstract

A range of structurally and functionally varied enantiopure guanidines has been prepared and evaluated in the enantioselective epoxidation of 3-tert-butoxycarbonylamino-4,4-dimethoxycyclohexa-2,5-dien-1-one 1 using tert-butylhydroperoxide. Successful enantioselective epoxidations were observed and useful structure-activity data obtained, but the reactions were slow and the maximum ee observed was 30%.

Key words

enantioselective - epoxidation - enones - guanidines - stereoselectivity

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  • 15a

    (S)-1-Methoxy-2-propyl-amine (2.59 g, 29.1 mmol) was added to a solution of N,N′-di-Boc-N′′-trifluoromethanesulfonylguanidine 6 (7.59 g, 19.4 mmol) and diisopropyl(ethyl)amine (5.1 cm3, 29.3 mmol) in CH2Cl2, under argon. The reaction was at r.t. for 2 h before the solvent was removed under reduced pressure and the residue was purified by flash silica chromatography (CH2Cl2) to give N,N′-di-Boc-N′′-[(1S)-2-methoxy-1-methylethyl]guanidine 7d (6.12 g, 95%) as a white solid, mp 79-80 °C; [α]D 20 -6.5 (c 1.0, CHCl3) which was fully characterised.

  • 15b

    The Boc-protected guanidine 7d (6.05 g, 18.2 mmol) was dissolved in approx. 3 M anhyd methanolic HCl (100 cm3) and was stirred at 40 °C, under argon, for 18 h. The solvent was then removed under reduced pressure to afford N′′-[(1S)-2-methoxy-1-methylethyl]guanidine hydrochloride (8d·HCl) quantitatively (3.03 g) as a hygroscopic gum, [α]D 20 -24.3 (c 1.00, MeOH). IR (neat): νmax: 3253 and 3147 (NH), 2981 and 2934 (CH), 1640 (CN3) cm-1. 1H NMR (400 MHz, CD3OD): δ = 3.84-3.79 (1 H, m, CH), 3.47 (1 H, dd, J = 9.5 and 4.0, CHAHBOMe), 3.40 (3 H, s, OCH3), 3.37 (1 H, dd, J = 9.5 and 6.5, CHAHBOMe), 1.23 (3 H, d, J = 6.5, CH3). 13C NMR (100 MHz, CD3OD): δC = 158.3 (CN3), 76.9 (CH), 59.4 (OCH3), 48.5 (CH2), 17.4 (CH3). MS (CI): m/z = 132(100) [MH+]; HRMS (CI): Calcd for C5H14N3O: 132.1137. Found: [MH+]: 132.1132 (2.7 ppm error).

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13

All new compounds were fully characterised by 1H NMR, 13C NMR and IR spectroscopies plus HRMS or elemental analysis.

18

Chiral HPLC was carried out using a Chiralcel OJ column (25 cm × 4.6 mm) with hexane-isopropanol (98:2) as eluent at a flow rate of 1 mL/min and detection at 276 nm.