J. Am. Chem. Soc. 1999, 121, 5075-5076
Table 1. Addition of Hexenyl Boronates to Pyrrolidine 1a
5075
Alkenyl and Aryl BoronatessMild Nucleophiles for
the Stereoselective Formation of Functionalized
N-Heterocycles
Robert A. Batey,* D. Bruce MacKay, and V. Santhakumar
Department of Chemistry, UniVersity of Toronto
Toronto, Ontario, Canada, M5S 3H6
ReceiVed NoVember 2, 1998
Nucleophilic additions to N-acyliminium ions1 constitute an
important method for the synthesis of alkaloids2 and other
biologically active nitrogen heterocycles. Intermolecular reactions
with a variety of different classes of carbon-based nucleophiles
are possible, including allylsilanes,3 other allylmetals,4 alkyl- and
arylmetals,3e,5 alkynylmetals,6 TMSCN,3d,7 isonitriles,7c enol
derivatives,3d,7c,8 and aromatics.9 While a wide variety of nucleo-
philes are known to attack N-acyliminium ions, there are few
reactions with alkenyl3e,10 or arylmetal derivatives, and we are
not aware of any reported examples of additions of organoboronic
acids or esters.11 Such additions would be attractive because
of the good air and water stability of boronic acid or ester
derivatives.12 Petasis and co-workers have recently developed a
three-component coupling reaction of alkenyl- and arylboronic
a 1.4 equiv of boronate or acid, 4 equiv of BF3‚Et2O, -78 °C, 2.5 h,
then warm to room temperature, 2.5 h. b 3 equiv of boronic acid.
acids with aldehydes and amines, for the synthesis of allylamines
and R-amino acids.13 This reaction was demonstrated not to occur
via direct addition to free iminium ions.13a However, we consid-
ered that the greater reactivity of N-acyliminium ions could enable
reaction with boronic acids and esters. We now report the first
examples of the reaction of alkenyl- and arylboronic acids and
esters with N-acyliminium ions.
* To whom correspondence may be sent (fax: 416-978-5059; e-mail:
rbatey@alchemy.chem.utoronto.ca).
(1) For recent reviews of N-acyliminium ion chemistry, see: (a) de Koning,
H.; Speckamp, W. N. In Houben-Weyl, StereoselectiVe Synthesis; Helmchen,
G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; 1995; Vol. E21, pp
1953-2009. (b) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991; Vol. 2, pp 1047-1082. (c) Volkmann, R. A. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Schreiber, S. L., Eds.;
Pergamon: Oxford, 1991; Vol. 1, pp 355-396.
3-Hydroxypyrrolidines were chosen as target structures, since
this motif is present in the polyhydroxylated indolizidine and
pyrrolizidine alkaloid families,14 which include many examples
of biologically active natural products, such as swainsonine,
castanospermine, retronecine, and australine. Pyrrolidine 1 was
therefore chosen as an N-acyliminium ion precursor. Oxidation
and protection of pyrrolidine according to the method of Kraus
and Neuenschwander gave N-Cbz-2-pyrroline.15 Dihydroxylation
using OsO4 catalysis then afforded the desired precursor 1.16
Reaction of 1 with E-hexenyl boronic acid in the absence of a
Lewis acid did not lead to the desired adducts, but instead resulted
in esterification of the boronic acid by 1. However, addition of
the Lewis acid, boron trifluoride etherate, promoted addition of
the boronic acid to give 2a (Entry 1, Table 1). Prior esterification
of the boronic acids as the corresponding boronates has a
pronounced effect on the efficacy of addition (Entries 2-6, Table
1). Use of the pinacol or diisopropyl boronates produced a slight
improvement in yield, whereas the catechol boronates were poor
substrates. Both the diethanolamine and ethylene glycol boronates
gave excellent yields of 2a. In all cases 2a was formed as a single
(2) For leading references, see: The Alkaloids, Chemistry and Biology;
Cordell, G. A., Ed.; Academic: San Diego, 1998; Vol. 50.
(3) (a) Kraus, G. A.; Neuenschwander, K. J. Chem. Soc., Chem. Commun.
1982, 134-135. (b) Thaning, M.; Wistrand, L.-G. HelV. Chim. Acta 1986,
69, 1711-1717. (c) Thaning, M.; Wistrand, L.-G. J. Org. Chem. 1990, 55,
1406-1408. (d) Renaud, P.; Seebach, D. HelV. Chim. Acta 1986, 69, 1704-
1710. (e) Arai, Y.; Fujii, A.; Ohno, T.; Koizumi, T. Chem. Pharm. Bull. 1992,
40, 1670-1672.
(4) (a) Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S. J. Org. Chem.
1988, 53, 3865-3868. (b) Onoue, H.; Narisada, M.; Uyeo, S.; Matsumura,
H.; Okada, K.; Yano, T.; Nagata, W. Tetrahedron Lett. 1979, 3867-3870.
(c) Kise, N.; Yamazaki, H.; Mabuchi, T.; Shono, T. Tetrahedron Lett. 1994,
35, 1561-1564.
(5) (a) Yamada, J.; Satoˆ, H.; Yamamoto, Y. Tetrahedron Lett. 1989, 30,
5611-5614. (b) Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1990, 44,
707-710. (c) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991, 47, 573-582.
(d) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995, 60, 5011-
5015. (e) Comins, D. L.; Foley, M. A. Tetrahedron Lett. 1988, 29, 6711-
6714. (f) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron
1991, 47, 1311-1328. (g) Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y.
Tetrahedron Lett. 1990, 31, 6385-6386. (h) Hanson, G. J.; Russell, M. A.
Tetrahedron Lett. 1989, 30, 5751-5754.
1
diastereomer (>98:2 cis:trans by H NMR).17
The reaction is amenable to a range of alkenyl- and arylbor-
onates, producing exclusively the cis-2,3-substituted products
(Table 2).18 Simple alkyl- and phenyl-substituted E-alkenyl
boronates give adducts having an E-alkene geometry (Entries 1-3,
Table 2). The alkene stereochemistry is maintained in the products,
(6) (a) Lundkvist, J. R. M.; Wistrand, L.-G.; Hacksell, U. Tetrahedron Lett.
1990, 31, 719-722. (b) Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119,
3409-3410.
(7) (a) Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1989, 43, 290-
295. (b) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima,
S. Tetrahedron 1994, 50, 6221-6238. (c) Irie, K.; Aoe, K.; Tanaka, T.; Saito,
S. J. Chem. Soc., Chem. Commun. 1985, 633-635.
(12) (a) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer-Verlag: Berlin, 1995. (b) Pelter, A.; Smith, K.; Brown, H. C. Borane
Reagents; Academic: London, 1988.
(8) (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981,
103, 1172-1176. (b) Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.;
Makino, A. J. Org. Chem. 1984, 49, 300-304. (c) Pilli, R. A.; Russowsky,
D. J. Org. Chem. 1996, 61, 3187-3190.
(13) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583-
586. (b) Petasis, N. A.; Zaviolov, I. A. J. Am. Chem. Soc. 1997, 119, 445-
446. (c) Petasis, N. A.; Goodman, A.; Zaviolov, I. A. Tetrahedron 1997, 53,
16463-16470.
(9) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Takata, J. Chem. Lett. 1981,
1121-1124. (b) Martin, S. F.; Barr, K. J. J. Am. Chem. Soc. 1996, 118, 3299-
3300.
(14) For leading references, see: Casiraghi, G.; Zanardi, F.; Rassu, G.;
Spanu, P. Chem. ReV. 1995, 95, 1677-1716.
(10) For alkenylcopper reagents see ref 3d, and: (a) Germon, C.; Alexakis,
A.; Normant, J. F. Synthesis 1984, 40-43. (b) Thaning, M.; Wistrand, L.-G.
Acta Chem. Scand. 1992, 46, 194-199. (c) McClure, K. F.; Renold, P.; Kemp,
D. S. J. Org. Chem. 1995, 60, 454-457. (d) Martin, S. F.; Chen, H.-J.;
Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S.
Tetrahedron 1996, 52, 7251-7264. For alkenylsilanes, see: (e) Angst, C.
Pure Appl. Chem. 1987, 59, 373-380.
(11) For an interesting example of the reaction of an allylborane with an
N-acylimine, see: Rossi, T.; Biondi, S.; Contini, S.; Thomas, R. J.; Marchioro,
C. J. Am. Chem. Soc. 1995, 117, 9604-9605.
(15) Kraus, G. A.; Neuenschwander, K. J. Org. Chem. 1981, 46, 4791-
4792.
(16) During the course of this study Correia and co-workers reported this
dihydroxylation reaction. Asymmetric dihydroxylation and asymmetric
epoxidation/hydrolysis reactions gave low to moderate enantioselectivity,
see: Sugisaki, C. H.; Carroll, P. J.; Correia, C. R. D. Tetrahedron Lett. 1998,
39, 3413-3416.
(17) The diastereomer of 2a was prepared via Mitsonobu reaction (see
Supporting Information), and was not found in crude reaction mixtures.
10.1021/ja983801z CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/15/1999