Highly diastereo- and enantioselective reagents for aldehyde crotylation

Article abstract of DOI:10.1021/ol0480731

(Chemical Equation Presented) Two new, crystalline solid, storable, and highly enantioselective reagents for aldehyde crotylation have been developed. Both (cis and trans) crotylsilane reagents are easily prepared in bulk, require trivial reaction conditi

Full text of DOI:10.1021/ol0480731

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4375-4377
Highly Diastereo- and Enantioselective
Reagents for Aldehyde Crotylation
Blaine M. Hackman, Pamela J. Lombardi, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
leighton@chem.columbia.edu
Received September 21, 2004
ABSTRACT
Two new, crystalline solid, storable, and highly enantioselective reagents for aldehyde crotylation have been developed. Both (cis and trans)
crotylsilane reagents are easily prepared in bulk, require trivial reaction conditions, and provide the homoallylic alcohol products with near
diastereo- and enantiospecificity in many cases.
For over 20 years, asymmetric aldehyde crotylation reactions
have played a prominent role in polyketide natural product
synthesis and continue to be widely employed to this day.1
The most extensively used crotylboranes developed by
Brown1d and boronate esters developed by Roush1e are type
I reagents2 in that they proceed through closed transition
states and do not require the use of an external Lewis acid.
In contrast, the versatile and highly selective chiral crotyl-
silanes developed by Panek1g,h are type II reagents that
require the use of an external Lewis acid and react through
open transition states. Crotylsilanes may be rendered type I
reagents as exemplified by the chiral Lewis base-catalyzed
addition of crotyltrichlorosilanes to aldehydes deveoped by
Denmark,3 but these reactions are not generally compatible
with aliphatic aldehydes. Our recent discovery that ring strain
presents an alternative method for creating reactive type I
allylsilane reagents4 (Scheme 1) has prompted us to inves-
Scheme 1
(1) (a) Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10. (b) Chemler, S.
R.; Roush, W. R. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; Chapter 11. (c) Ramachandran, P. V. Aldrichim.
Acta 2002, 35, 23-35. (d) Brown, H. C.; Bhat, K. S.; Randad, R. S. J.
Org. Chem. 1989, 54, 1570-1576. (e) Roush, W. R.; Ando, K.; Powers,
D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112,
6339-6348. (f) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321-2336.
(g) Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95, 1293-1316. (h) Hu,
T.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806-12815.
(i) Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003,
125, 10160-10161.
tigate whether the concept could be extended to crotylation.
Beyond this question, however, we also targeted easily
prepared, storable, crystalline solid reagents that would react
with aldehydes with excellent diastereo- and enantioselec-
tivities.
The known cis- and trans-crotyltrichlorosilanes5 were
reacted with diamine 1 in the presence of 2 equiv of 1,8-
(4) (a) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7920-7921. (b) Kubota, K.; Leighton,
J. L. Angew. Chem., Int. Ed. 2003, 42, 946-948. (c) Berger, R.; Rabbat, P.
M. A.; Leighton, J. L. J. Am. Chem. Soc. 2003, 125, 9596-9597. (d) Berger,
R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004, 126, 5686-5687.
(2) Denmark, S. E.; Weber, E. J. HelV. Chim. Acta 1983, 66, 1655-
1660.
(3) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488-
9489. (b) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951-1953.
10.1021/ol0480731 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/12/2004

diazabicyclo[5.4.0]undec-7-ene (DBU) to give reagents 2 and
3 (Scheme 2). We have been able to develop this procedure
crotylated by reagent 2, establishing that the reagent has
limited tolerance for steric hindrance. Notwithstanding these
caveats, reagent 2 is a highly effective and enantioselective
reagent that may be prepared in bulk and employed using
trivial experimental conditions.
A survey of the performance of reagent 3 was then carried
out with the same set of aliphatic, aromatic, and R,â-
unsaturated aldehydes (Table 2). In every case, the anti
Scheme 2
Table 2. Anti-Selective Aldehyde Crotylation with (R,R)-3
such that it may be easily carried out on large (e.g., ∼30 g)
scale, with isolation of the reagents accomplished by simple
crystallization. We note that this is a slightly modified, and
improved, version of our previously reported method4b for
the synthesis of the allyl reagent. For all three reagents, the
procedure reported here should be considered the method
of choice.
A survey of the performance of reagent 2 was carried out
with a variety of aliphatic, aromatic, and R,â-unsaturated
aldehydes (Table 1). In every case, the syn diastereomer was
entry
R
yield (%)
eea (%)
1
2
3
4
5
6
7
8
PhCH2CH2
(CH3) 2CHCH2
Cy
BnOCH2
PMBOCH2CH2
Ph
81
71
68
83
82
54
60
52
98
97
97
99
99
93
96
94
p-CF3C6H4
(E)-PhCHdCH
a Enantiomeric excess determined by chiral GLC or HPLC.
Table 1. Syn-Selective Aldehyde Crotylation with (R,R)-2
diastereomer was produced with at least good (>15:1), and
in most cases excellent (>25:1), diastereoselectivity. As was
observed with reagent 2, the yields were generally good,
although the yields with aromatic and R,â-unsaturated
aldehydes tend to be somewhat lower than with aliphatic
aldehdyes. Also as was observed with reagent 2, reagent 3
was found to be incompetent to crotylate very sterically
hindered aldehydes such as pivalaldehyde. These caveats
aside, reagent 3 is a highly effective and enantioselective
reagent that may be prepared in bulk and employed using
trivial experimental conditions.
Reagents 2 and 3 are moisture-sensitive, and care must
be taken to exclude moisture if they are stored for any length
of time. We have found that they possess unlimited shelf
life if stored in an inert atmosphere glovebox. In dry
environments, they may be handeled in air, but repeated
exposure to air does cause some degradation over time.
The choice of p-bromobenzyl groups for the diamine
substituents was guided not by enantioselectivity (other
groups provide similar levels of selectivity) but by the fact
that they (uniquely, among the groups screened) confer the
much desired property of crystallinity on reagents 2 and 3.
This crystallinity comes at a price, however, in that the
bromine atoms result in reagents of high molecular weight
(569). This raises reasonable concerns about atom economy,
and it was therefore desirable to establish that the diamine
controller could be readily recovered in high yield. The
reaction of reagent 2 with dihydrocinnamaldehyde (15.6
mmol) was carried out under the standard conditions (Scheme
entry
R
yield (%)
eea (%)
1
2
3
4
5
6
7
8
PhCH2CH2
(CH3) 2CHCH2
Cy
BnOCH2
PMBOCH2CH2
Ph
83
70
67
82
73
67
61
67
97
96
97
96
96
95
96
95
p-CF3C6H4
(E)-PhCHdCH
a Enantiomeric excess determined by chiral GLC or HPLC.
produced with at least good (>15:1), and in most cases
excellent (>25:1), diastereoselectivity. The yields were
generally good, although it was observed that the yields with
aromatic and R,â-unsaturated aldehydes tend to be lower than
with aliphatic aldehdyes. Pivalaldehyde was not successfully
(5) (a) Tsuji, J.; Hara, M.; Ohno, K. Tetrahedron 1974, 30, 2143-2146.
(b) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1-C3. (c)
Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989, 30, 1099-1102.
(d) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y.
Tetrahedron 1997, 53, 3513-3526.
4376
Org. Lett., Vol. 6, No. 23, 2004

be easily recovered in high yield. Current efforts are focused
on improving the efficiency and scope of the reaction with
sterically hindered aldehydes and on the discovery of lower
molecular weightsbut still crystalline solidsvariants of these
reagents.
Scheme 3
Acknowledgment. The National Institutes of Health
(National Institute of General Medical Sciences, R01
GM58133) is acknowledged for financial support of this
work. We are grateful to Merck Research Laboratories and
Amgen for financial support. We gratefully acknowledge the
support of Pfizer in the form of a Diversity in Organic
Chemistry Fellowship to P.J.L.
3). Following chromatographic purification of the product,
the column was simply flushed with EtOAc/hexanes/Et3N
(1:1:0.1) to provide recovered diamine 1 in 90% yield.
We have developed the cis- and trans-crotylsilane reagents
2 and 3 and demonstrated their use in highly enantioselective
syn- and anti-selective aldehyde crotylation reactions, re-
spectively. The reagents are easily prepared in bulk and are
storable crystalline solids, the crotylation reactions are
experimentally trivial, and the chiral diamine controller may
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0480731
Org. Lett., Vol. 6, No. 23, 2004
4377