Chiral 1,3-perhydrobenzoxazines 1, 2, and 9-14, prepared by condensation of 8-(benzylamino)menthol with different aldehydes, react with alkylmagnesium bromides and trimethylaluminum leading to the open amino alcohols 3a-d, 4a-d, and 15-20 in excellent chemical yields and good to excellent diastereomeric excess. The sequential elimination of the menthol appendage by heating with P(2)O(5) and the benzyl group by hydrogenolysis lead to primary amines 7a-d, 8a-d, and 27-30 in excellent chemical yields and ee. The addition of the alkyl group from the Grignard derivatives and the methyl group from the trimethylaluminum occurs from opposite sides of the heterocycle, yielding the final primary amines with the same stereochemistry.
[2+2] photocycloadditions involving chiral 3-acryloyl-2-vinylperhydro-1,3-benzoxazines derived from (-)-8-aminomenthol are highly diastereoselective reactions. The facial selectivity depends on the type of substitution at the vinyl double bond, and always leads to cis-fused bicyclic derivatives. The de is good for compounds with one substituent at the outer carbon of the double bond at C-2, but only one diastereomer is formed in cyclizations of compounds with two substituents at that position. The elimination of the menthol appendage gives enantiopure 3-azabicyclo[3.2.0]heptanes.
[reaction: see text] Condensation of N-substituted glycines with chiral 3-allyl-2-formyl perhydro-1,3-benzoxazines forms an azomethine ylide that cyclizes to give octahydropyrrolo[3,4-b]pyrrole derivatives. The [3 + 2] dipolar cycloadditions are stereoespecific leading to a single diastereoisomer. The chemical yields are dependent on the reaction temperature and the presence or absence of a base.
Stereochemical aspects of the intramolecular Diels−Alder reaction on perhydro-1,3-benzoxazines
derived from (−)-8-aminomenthol bearing α,β-unsaturated amides and the dienic component
attached at C-2 are described. The thermal cyclization of 2-(2‘-furyl) derivatives 2, 6, and 7
exclusively afforded mixtures of exo adducts. The product selectivity was highly dependent on the
solvent of the reaction. In CH2Cl2, the kinetic products 3, 8, and 9 always predominated, whereas
in hexane or toluene, less polar solvents, the thermodynamic adducts 4, 10, and 11 were formed as
major diastereoisomers. In cyclizations catalyzed with equimolar or 2-fold excess of Lewis acid,
the kinetic stereiosomers were predominant. Some Lewis acids catalyzed the reaction, but
diethylaluminum chloride was the most effective. The cyclization on the perhydro-1,3-benzoxazine
13, bearing an open dienic component, was much less stereoselective, and a mixture of two exo and
two endo possible stereoisomers were formed. Elimination of the menthol appendage in two steps
by reductive ring opening of the N,O-acetal moiety and oxidation−elimination yielded enantiomerically pure tetrahydroisoindoline derivatives.
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