Stereoselective ammonium-directed epoxidation in the asymmetric syntheses of dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3

Journal article

Epoxidation of racemic trans -2-(N, N -dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl 3 CCO 2 H then m -CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans -2-(N -benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity ( > 95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1 RS,2 SR,3 SR,4 SR)-2-(N -benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF 4 as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N-H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans -2-(N -benzylamino)cyclohex-3-en-1-ol ( > 99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (-)-A-2, (-)-B-2, (-)-C-3 and (+)-F-3 ( > 98% ee in each case) from 1,3-cyclohexadiene.

Authors: Pinto, S; Davies, S; Fletcher, A; Roberts, P; Thomson, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Thieme Publishing
• Journal: Synthesis
• Volume: 50
• Issue: 1
• Pages: 64-83
• Publication date: 2017-12-12
• Acceptance date: 2017-10-10
• DOI: 10.1055/s-0036-1590948
• EISSN: 1437-210X
• ISSN: 0039-7881
• Keywords: asymmetric synthesis; regioselectivity; stereoselective synthesis; diastereoselectivity; ring-opening; epoxidation; chemoselectivity; amino alcohols