Efficient, stereoselective synthesis of trans-2,5-disubstituted morpholines

Organic Letters

Volumn 6, Issue 6, 2004, Pages 1045-1047

  Lanman, Brian A ^a   Myers, Andrew G ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYL GROUP; AMINOALCOHOL; EPOXIDE; HYDROXYL GROUP; MORPHOLINE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; ENANTIOSELECTIVITY; RING CLOSING METATHESIS; STEREOCHEMISTRY;

AMINO ALCOHOLS; EPOXY COMPOUNDS; MOLECULAR STRUCTURE; MORPHOLINES; STEREOISOMERISM;

EID: 1642486447     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol049861t     Document Type: Article

References (20)

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4. Lanman, B. A.; Myers, A. G. Manuscript in preparation.
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15. The undesired cis-2,6-disubstituted morpholine is presumed to have arisen by a sequence involving reversible aziridinium ion formation. Tosylate-mediated opening of the aziridinium ion at the more substituted terminus followed by ring closure would proceed with net retention of configuration at the methyl-bearing center while effecting its transfer from the 5-to the 6-position of the cyclic product.
16. The 2-nitrobenzenesulfonamide (nosyl) protective group (Fukuyama, T.; Jow, C-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373-6374) was found not to be a viable substitute for the N-tosyl protective group in the synthesis of 9, as it was not stable toward the conditions of attempted cyclization (cf. 7 → 8, Scheme 1; nosyl cleavage occurred, forming a mixture of 2-nitrophenyl ethers as products).
17. We acknowledge Dr. Jonathan White for conducting the synthesis of 9 on a 20-g scale.
18. The 1,5-bis-O-tosylate formed during the synthesis of 15 did not react under the cyclization conditions; it was readily separated from 16 by flash column chromatography on silica gel.
19. Cooper, K. A.; Dhar, M. L.; Hughes, E. D.; Ingold, C. K.; MacNulty, B. J.; Woolf, L. I. J. Chem. Soc. 1948, 2043-2049.
20. Sodium naphthalenide/tetrahydrofuran was used in lieu of sodium/ ammonia in order to avoid competing Birch reduction of the aromatic ring.