C O M M U N I C A T I O N S
Scheme 3. Synthesis of Neobenodine and Cetirizinea
Figure 1. Chiral sulfide 8 and the chiral sulfonium salts 9a-c and 10.
the process involves an oxidative workup, the sulfide was recovered
in over 90% yield.10 The alcohols were invariably obtained with
slightly lower enantioselectivities than the corresponding amines,
even though they are derived from a common chiral organoborane.
We believe this is caused by a very small amount of oxidation of
the borane by traces of adventitious O2, a process which gives
racemic alcohol.11 Interestingly, the higher homologation products
(12,13am, and 13an) related to 6am were isolated as a single
enantiomer and diastereomer in every case, whereas 6am itself
(from Scheme 1) was formed as a 1:1 ratio of diastereoisomers.
a Conditions: (a) 1.2 equiv of LiHMDS/THF, -78 °C; (b) H2O2/NaOH;
(c) BEt3/Me2S‚BH3; (d) H2NOSO3H.
Scheme 4. Control of Enantioselectivity
Table 2. Reactions of Chiral Sulfonium Salts 9a-c with Boranes
2a-ca
homologated boranes without significant interference from multiple
reactions of the ylide. Considering that several bonds are created
in the ylide reaction (C-C and C-B bonds), both enantiomers of
sulfide 8 are easily accessible, the sulfide can be reisolated, high
stereocontrol is achieved, and the configuration of the new
stereogenic center is predictable, we believe that this chemistry has
much future promise.
entry
R
Ar
X
product
yieldb/eec (%)
Acknowledgment. We thank EPSRC and Bristol University for
support, and Professor David Bergbreiter for useful discussions.
1
2
3
4
5
6
nBu
nBu
Et
Et
Ph
Ph
Ph
Ph
Ph
Ph
OH
NH2
OH
NH2
OH
NH2
12am
13am
12an
13an
12bo
13co
70/95
72/97d
73/96
68/97d
87/95
68/96d
Supporting Information Available: Full experimental procedures,
chemical characterization data, and enantiomeric excess determination.
This material is available free of charge via the Internet at http://
pubs.acs.org.
4-MeC6H4
4-ClC6H4
a Absolute stereochemistry of 12an was determined by comparing HPLC
data with a commercial authentic sample; others were assumed by analogy.
b Isolated yield; amines contain up to 10% higher homologated product.
These can be separated after derivatization of the amine. c The enantiomeric
excess was determined by chiral HPLC using a ChiralCel OD column.d The
enantiomeric excess was determined as its acetamide.
References
(1) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic Press:
London, 1988; p 192. (b) Hayashi, T. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. I, p 351.
(2) Matteson, D. S. Acc. Chem. Res. 1988, 21, 294.
(3) Shea, K. J. Chem.sEur. J. 2000, 6, 1113.
(4) Tufariello, J. J.; Lee, L. T. C.; Wojtkowski, P. J. Am. Chem. Soc. 1967,
89, 6804.
(5) Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S. J. Am. Chem.
Soc. 1964, 86, 3565.
(6) Brown, H. C.; Kim, K. W.; Srebnik, M.; Singaram, B. Tetrahedron 1987,
43, 4071.
A number of medicinally important compounds contain a chiral
diarylmethylamino or diarylmethylalkoxy moiety.12 Using our
methodology, access to either the alcohol or amine in high
enantiomeric excess is equally possible. For example, 12bo, which
represents a formal synthesis of the anti-inflammatory agent
neobenodine,13 was easily prepared in 87% yield and 95% ee from
sulfonium salt 9b. Cetirizine, another anti-inflammatory agent, is
also easily accessible from amine 14,14 which was made from
sulfonium salt 10c and triphenylborane in 63% yield and 96% ee
(Scheme 3).
The high enantioselectivity observed is consistent with the model
for enantiocontrol in epoxidations in which ylide conformation and
face selectivity are controlled through nonbonded interactions
(Scheme 4)15 and where rearrangement occurs with inversion at
the migrating terminus.16
(7) Brown, H. C.; Gupta, S. K.; Richard, B. J. Am. Chem. Soc. 1971, 93,
2802.
(8) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.;
Porcelloni, M.; Studly, J. R. Angew. Chem., Int. Ed. 2001, 41, 1430.
(9) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004, 37, 611.
(10) Brown, H. C.; Manual, A. K. J. Org. Chem. 1980, 45, 916.
(11) Davies, A. G.; Roberts, A. G. J. Chem. Soc. B 1967, 17.
(12) Meguro, K.; Aizawa, M.; Sohda, T.; Kawamutsu, Y.; Nagaoka, A. Chem.
Pharm. Bull. 1985, 33, 3878.
(13) Wolf, C.; Schunack, W. Arch. Pharm. (Weinheim, Ger.) 1996, 329, 87.
(14) Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.; Cossement, E.
Synthesis 1995, 766.
(15) Aggarwal, V. K.; Richardson, J. Chem. Commun. 2003, 2644.
(16) Bottoni, A.; Lombardo, M.; Neri, A.; Trombini, C. J. Org. Chem. 2003,
68, 3397.
In conclusion, we have found conditions under which semi-
stabilized sulfonium ylides react with organoboranes to furnish
JA043632K
9
J. AM. CHEM. SOC. VOL. 127, NO. 6, 2005 1643