Enantiopure Guanidine Bases for Enantioselective Enone Epoxidations: 2, Cyclic Guanidines

Abstract

A range of structurally and functionally varied enantiopure cyclic and bicyclic 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. Encouraging enantiomeric excesses were observed (up to 60%). Low enantiomeric excesses were also observed with 2-methylnaphthoquinone and trans-chalcone.

Key words

enantioselective - epoxidation - enones - guanidines - stereoselectivity

References

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• Preparation of 6b. HCl salt:
• 9a

  (R)-(-)-2-Phenylglycinol (189 mg, 1.38 mmol) was added to a solution of di-tert-butyl-2-[(trifluoromethanesulfonyl)imino]dihydro-1,3(2H,4H)-pyrimidinecarboxylate 10 (300 mg, 0.69 mmol) and diisopropyl(ethyl)amine (0.24 cm³, 1.38 mmol) in CH₂Cl₂ (4 cm³), under a nitrogen atmosphere. The solution was stirred at r.t. for 18 h before the solvent was removed under reduced pressure and the residue purified by flash silica chromatography (CH₂Cl₂:MeOH, 50:1) to afford di-tert-butyl-2-[(1R)-2-hydroxy-1-phenylethylimino]dihydro-1,3(2H,4H)-pyrimidinecarboxylate 11 (208 mg, 71%) as a clear gum, [α]_D ²⁰ +18.7 (c 1.25, CHCl₃) which was fully characterised.

• 9b

  The Boc-protected guanidine 11 (200 mg, 0.48 mmol) was dissolved in approx. 3 M anhyd. methanolic HCl (20 cm³) and was stirred at r.t., under nitrogen, for 18 h. The solvent was then removed under reduced pressure to afford N-[(1S)-1-phenyl-2-hydroxyethyl]-N-tetrahydro-2(1H)-pyrimidinylideneaminehydrochloride 6b. HCl quantitatively (124 mg) as a gum, [α]_D ²⁰ -40.9 (c 1.0, MeOH). IR(neat): ν_max = 3365 (OH), 3029 and 2096 (CH), 1695 (CN₃) cm^-1. MS (CI): m/z = 220 (100) [MH⁺], 202 (21), 138 (27), 100 (25), 75 (31). HRMS (CI): Calcd for C₁₂H₁₈N₃O: 220.1450. Found: [MH⁺]: 220.1456 (-2.7 ppm error), which gave consistent ¹H and ¹³C NMR spectra.

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• Michael Additions:
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8

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

11

Rapid hydrolysis to DMPU occurred; a one-pot variant was also unsuccessful.

13

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.