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

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

References

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• Preparation of 8d·HCl salt:
• 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): ν_max: 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, CH_AH_BOMe), 3.40 (3 H, s, OCH₃), 3.37 (1 H, dd, J = 9.5 and 6.5, CH_AH_BOMe), 1.23 (3 H, d, J = 6.5, CH₃). ¹³C NMR (100 MHz, CD₃OD): δ_C = 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.