Enantioselective Synthesis of 2-Phenyl-9-oxabispidines

Abstract

A small selection of enantiomerically pure 2-phenyl-9-oxabispidines was synthesized in a three to five step procedure from commercially available starting materials. Ring opening of (R,R)-3-phenylglycidol with benzylamine, condensation with (S)-epichlorohydrin to the corresponding cis-2,6-bis(hydroxymethyl)-substituted morpholine intermediate, and final cyclization with a primary amine delivered the desired 2-phenyl-9-oxabispidines in good yields. The substituents at the nitrogen atoms were varied by debenzylation and subsequent alkylation.

Chiral 2‐endo‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions

“…Alternatively, purification of crude 4 by distillation (60–70 °C/0.1 mbar) is possible. The spectroscopic and analytical data of 4 were in agreement with those reported in ref 10a.…”

Chiral Bispidines

“…The 2-endo-phenyl substituted N,N¢-dimethyl-9-oxabispidine 38 73 prepared in our group did not promote the deprotonation of 11. 129 The reasons for this failure are unknown.…”

“…SiH, BF 3 •OEt 2 , CH 2 Cl 2 .Formal replacement of the remote methylene bridge in the bispidines with an ether functionality leading to 9-oxabispidines probably does not significantly change the archi-tecture of the central bicyclic system, but provides new synthetic options due to the additional heteroatom. A selection of enantiomerically pure 2-endo-phenyl-9-oxabispidines, 110-112 and 38 (Scheme 19), was prepared in our group 73. These compounds are readily available in three to five steps and 35-41% overall yield according to the following route: Ring opening of commercially available (R,R)-phenylglycidol (104) with benzylamine afforded the amino diol 105, which was treated consecutively with (S)-epichlorohydrin, potassium tert-butoxide, and methanesulfonyl chloride to give the activated morpholine 109 in a one-pot three-step reaction, via the intermediates 106-108.…”

A Flexible Route to Chiral 2-endo-Substituted 9-Oxabispidines and Their Application in the Enantioselective Oxidation of Secondary Alcohols

“…With the methylene bridge in 2 being replaced by an ether function, the 9-oxabispidines 5 are often more easily accessible than the corresponding bispidines. This has recently been demonstrated in our group by the enantioselective preparation of a set of bicyclic 2- endo -phenyl-substituted derivatives ( 5 , R = Ph; R 1 , R 2 = H, Me, Bn) from commercially available ( R , R )-phenylglycidol (3−5 steps, 35−41% yield) . A first asymmetric synthesis of the tricyclic 9-oxabispidine 6 was successfully accomplished, too …”