tions,8 and less enantioselective catalytic examples were
reported.9,10 Up to now, only three highly enantioselective
catalytic examples of Brassard’s diene with aldehydes have
been reported. Two of them are Schiff base-metal complex
systems reported by our group,11 and the other is a TADDOL
system reported by Ding’s group.12 However, all of the
examples are mainly restricted to aromatic aldehydes13 and
to the best of our knowledge, the major huddle in this area
lies in a lack of high enantioselectivity for aliphatic alde-
hydes.14 Herein, we reported our efforts on the development
of the catalytic enantioselective HDA reaction of Brassard’s
diene with aliphatic aldehydes, as well as the one-step
enantioselective synthesis of (R)-(+)-kavain and (S)-(+)-
dihydrokavain.
Our studies started with the reaction of Brassard’s diene
1 with hexanal 2a as a model reaction. After some experi-
mentation, we focused our attention on the well-known
BINOL-Ti(IV) complexes,15 which have been extensively
studied as effective chiral Lewis acid catalysts. The first trial
by simple mixing (R)-BINOL and Ti(i-PrO)4 in situ in the
ratio of 1:1 and 2:1 gave the results of 35% yield and 26%
ee (Table 1, entry 1) and 10% yield and 66% ee (Table 1,
Table 1. HDA Reaction of Brassard’s Diene with Hexanal
Catalyzed by (R)-BINOL-Ti(IV) Complexesa
(R)-BINOL:
catalyst
reaction yield
ee
entry Ti(i-PrO)4:4b loading (mol %) time (h) (%)b (%)c
1
2
3d
4
5
6
7
1:1:0
2:1:0
1:1:1 (4a)
1:1:1
2:1:1
10
10
10
10
10
15
15
48
48
48
48
48
35
10
51
57
20
55
74
26
66
72
71
23
83
83
1:1:1
1:1:1
48
115
(2) For a review, see: (a) Boucard, V.; Broustal, G.; Campagne, J. M.
Eur. J. Org. Chem. 2007, 225. (b) Dieter, R. K.; Guo, F. Org. Lett. 2006,
8, 4779. (c) Tiseni, P. S.; Peters, R. Angew. Chem., Int. Ed. 2007, 46, 5325.
(d) D’Annibale, A.; Ciaralli, L.; Bassetti, M.; Pasquini, C. J. Org. Chem.
2007, 72, 6067. (e) You, Z. W.; Jiang, Z. X.; Wang, B. L.; Qing, F. L. J.
Org. Chem. 2006, 71, 7261. (f) Creech, G. S.; Kwon, O. Org. Lett. 2008,
10, 429. (g) Esteban, J.; Costa, A. M.; Go´mez, AÅ .; Vilarrasa, J. Org. Lett.
2008, 10, 65. (h) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2.
(i) Bonazzi, S.; Gu¨ttinger, S.; Zemp, I.; Kutay, U.; Gademann, K. Angew.
Chem., Int. Ed. 2007, 46, 8707.
(3) For some reviews on the hetero-Diels-Alder reaction, see: (a)
Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558. (b) Jørgensen, K.
A. Eur. J. Org. Chem. 2004, 2093. (c) Kagan, H. B.; Riant, O. Chem. ReV.
1992, 92, 1007. (d) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (e)
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668. (f) Johnson, J. S.; Evans, D. A.
Acc. Chem. Res. 2000, 33, 325. (g) Lin, L. L.; Liu, X. H.; Feng, X. M.
Synlett 2007, 2147.
a All reactions were performed with hexanal (0.25 mmol) and diene 1
(0.375 mmol) in 1.0 mL toluene at 28 °C. b Isolated yield. c Enantioselec-
tivities were determined by GC analysis. d Additive was 4a.
entry 2), respectively. Although a modest improvement, the
BINOL-Ti(IV) system showed the potential for asymmetric
HDA reaction of Brassard’s diene. In order to improve the
yield and enantioselectivity, additives were introduced into
the (R)-BINOL-Ti(IV) system (for details, see Supporting
Information). To our delight, when 4-pycolyl chloride 4a
was added to the BINOL-Ti(IV) (1:1) complex, both the
yield and enantioselectivity improved drastically (Table 1,
entry 3 vs entry 1). Considering the stability, 4a was replaced
by commercially available 4-pycolyl chloride hydrochloride
4b with results maintained (57% yield and 71% ee, Table 1,
entry 4). However, when 4b was added to the BINOL-
Ti(IV) (2:1) complex, the enantioselectivity sharply dropped
(Table 1, entry 5 vs entry 2). Further improvement of the ee
(83% ee) was achieved after increasing the catalyst loading
from 10 to 15 mol % (Table 1, entry 6), and the yield was
also improved to 74% by prolonging the reaction time to
115 h (Table 1, entry 7).
Under the optimized conditions, the substrate scope of this
reaction system was then examined with other aliphatic
aldehydes. As shown in Table 2, this catalyst system was
efficient for a majority of aliphatic aldehydes, including
nonbranched (Table 2, entries 1-4), branched (Table 2, entry
5), cyclo- (Table 2, entry 6), and R,â-unsaturated (Table 2,
entry 7) aliphatic aldehydes, leading to the corresponding
6-substituted 4-methoxy-5,6-dihydropyran-2-ones in 46-
79% yields with 81-88% ee. For aromatic aldehydes, such
as benzaldehyde, 87% ee was also obtained when the reaction
was performed at 0 °C.
(4) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911.
(5) (a) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 4647.
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M., Jr.; Fritsch, N.; Clardy, J. J. Am. Chem. Soc. 1979, 101, 7001. (d) Larson,
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(8) Togni, A. Organometallics 1990, 9, 3106.
(9) For examples of Danishefsky-type diene with two-fold substitution
at terminus, see: (a) Danishefsky, S.; Pearson, W. H.; Harvey, D. F.; Maring,
C. J.; Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256. (b) Danishefsky,
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J. Org. Chem. 2005, 70, 8533.
(10) For example of highly enantioselective aza-Diels-Alder reaction
of Brassard’s diene with imines, see: Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2006, 45, 4796.
(11) (a) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y. Z.; Feng, X. M.; Zhang,
G. L. Org. Lett. 2004, 6, 2185. (b) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y.
Z.; Feng, X. M. Eur. J. Org. Chem. 2005, 3542. (c) Lin, L. L.; Fan, Q.;
Qin, B.; Feng, X. M. J. Org. Chem. 2006, 71, 4141.
(12) Du, H. F.; Zhao, D. B.; Ding, K. L. Chem. Eur. J. 2004, 10, 5964.
(13) A 69% ee was obtained for 3-phenylpropionaldehyde in the
TADDOL system.12.
(15) For reviews, see: (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV.
2003, 103, 3155. (b) Brunel, J. M. Chem. ReV. 2005, 105, 857. (c) Duthaler,
R. O.; Hafner, A. Chem. ReV. 1992, 92, 807. (d) Ramo´n, D. J.; Yus, M.
Chem. ReV. 2006, 106, 2126.
(14) Less than 10% ee was obtained by Feng’s catalyst, (+)-Eu(hfc)3,
or Jacobsen’s catalyst.6
1312
Org. Lett., Vol. 10, No. 6, 2008