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.

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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.

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.

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Enantiopure morpholine derivatives have been prepared by selenocyclofunctionalization of chiral 3-allyl-2-hydroxymethyl-substituted perhydro-1,3-benzoxazine derivatives. The cyclization occurs in high yields and diastereoselection, although the temperature of the reaction and the structure of the substituent at C-2 and the substitution pattern of the double bond can modify the regio- and stereochemistry of the final products.