ORGANIC
LETTERS
2006
Vol. 8, No. 16
3509-3512
Highly Enantioselective Synthesis of
-Amino Alcohols
â
Thomas-Xavier Me´tro, Je´roˆme Appenzeller, Domingo Gomez Pardo,* and
Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, Ecole Supe´rieure de Physique et
de Chimie Industrielles de la Ville de Paris (ESPCI), 10 rue Vauquelin,
75231 Paris Cedex 05, France
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
Received May 9, 2006
ABSTRACT
N,N-Dialkyl-â-amino alcohols derived from r-amino acids can be rearranged enantiospecifically by using TFAA/Et3N/NaOH to give 1,2-amino
alcohols with enantiomeric excess up to 99%.
â-Amino alcohol moieties are present in a large variety of
naturally occurring and pharmacologically active molecules.1
The amino alcohol relative stereochemistry is highly impor-
tant for the biological activity of these molecules. These
entities can also be used as chiral auxiliaries in asymmetric
synthesis.2,3
Linear N,N-dialkyl-â-amino alcohols have been shown to
rearrange, via an aziridinium ion, into â-halogenoamines (on
treatment with SOCl2,4 MsCl,5 TsCl,5 SOBr2,6 CBr4/PPh3,7
DAST,8 or Deoxofluor9), into â-mesylamines (on treatment
with Ms2O10,11), and into thiocyanates (on treatment with
KSCN12). Recently we have shown that prolinols can be
rearranged enantiospecifically to give optically active pip-
eridin-3-ols, via an aziridinium intermediate, by using TFAA/
Et3N/NaOH.13,14 In this Letter, we would like to report that
these latter conditions can be applied to linear optically active
â-amino alcohols of type A to produce 1,2-amino alcohols
of type B in a very regio-, stereo-, and enantioselective
process (Scheme 1).
N,N-Dibenzyl-â-amino alcohols 2a,15 2c,5 2e,16 2f,17 2g,
and 2h18 were prepared from the commercially available
amino alcohols by using benzyl bromide (2.2 equiv) in the
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576 and references
therein.
(2) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835-
875.
(8) Hook, D. F.; Gessier, F.; Noti, C.; Kast, P.; Seebach, D. ChemBio-
Chem 2004, 5, 691-706.
(9) Ye, C.; Shreeve, J. M. J. Fluorine Chem. 2004, 125, 1869-1872.
(10) Gmeiner, P.; Junge, D.; Ka¨rtner, A. J. Org. Chem. 1994, 59, 6766-
6776.
(3) For recent examples of stereoselective synthesis of enantiopure
â-amino alcohols see: (a) Keinicke, L.; Fristrup, P.; Norrby, P.-O.; Madsen,
R. J. Am. Chem. Soc. 2005, 127, 15756-15761. (b) Cooper, T. S.; Larigo,
A. S.; Laurent, P.; Moody, C. J.; Takle, A. K. Org. Biomol. Chem. 2005,
3, 1252-1262.
(4) (a) Back, T. G.; Parvez, M.; Zhai, H. J. Org. Chem. 2003, 68, 9389-
9393. (b) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2004, 45, 3725-
3728. (c) Sivaprakasam, M.; Couty, F.; Evano, G.; Srinivas, B.; Sridhar,
R.; Rama Rao, K. Synlett 2006, 5, 781-785.
(5) Weber, K.; Kuklinski, S.; Gmeiner, P. Org. Lett. 2000, 2, 647-649
and references therein.
(11) For an interesting example of the utilization of Ms2O in the formation
of an aziridinium intermediate, see: Couturier, C.; Blanchet, J.; Schlama,
T.; Zhu, J. Org. Lett. 2006, 8, 2183-2186.
(12) Anderson, J. C.; Cubbon, R.; Harding, M.; James, D. S. Tetrahedron:
Asymmetry 1998, 9, 3461-3490.
(13) For comprehensive reviews, see: (a) Cossy, J.; Gomez Pardo, D.
Chemtracts 2002, 15, 579-605. (b) Cossy, J.; Gomez Pardo, D. Targets
Heterocycl. Syst. 2002, 6, 1-26.
(14) (a) Cossy, J.; Dumas, C.; Gomez Pardo, D. Eur. J. Org. Chem.
1999, 1693-1699. (b) Brandi, A.; Cicchi, S.; Paschetta, V.; Gomez Pardo,
D.; Cossy, J. Tetrahedron Lett. 2002, 43, 9357-9359. (c) De´champs, I.;
Gomez Pardo, D.; Karoyan, P.; Cossy, J. Synlett 2005, 1170-1172. (d)
Roudeau, R.; Gomez Pardo, D.; Cossy, J. Tetrahedron 2006, 62, 2388-
2394 and references therein.
(6) Nagle, A. S.; Salvatore, R. N.; Chong, B.-D.; Jung, K. W. Tetrahedron
Lett. 2000, 41, 3011-3014.
(7) Lehmann, T.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
2001, 11, 2863-2866.
10.1021/ol061133d CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/07/2006