with excellent regio- and enantioselectivity.6a The extension
of this concept to simple straight-chain alkyl substituents via
the addition of the relevant organometallic reagent to
commercially available â-phenylcinnamaldehyde was ex-
pected to provide a template to allow a somewhat general
approach to the enantioselective allylic alkylation and to
avoid the need for symmetrical substrates. The alkenyl group
can then be cleaved to the aldehyde, which serves as a useful
handle for further functionalization and the benzophenone
adduct recycled via Wittig homologation. Bosnich7 was the
first to report the palladium-catalyzed allylic alkylation of
secondary â-phenylcinnamyl alcohol derivatives, in which
the trisubstituted alkene proved a particularly challenging
substrate for oxidative addition.8 Indeed, this may be the
reason this substrate has not been employed in the manner
described herein.
Table 1. Asymmetric Allylic Alkylation of the E- and
Z-Vinylogous Sulfonates 1 and 2
yield (%)c
substrate
1/2a R )
abs
eed (%) config
entry
geom.
4
5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Me
a
b
c
d
e
f
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
89
94
73
80
59
75
63
78
36
61
59
58
63
78
65
76
6
90
91
94
94
95
95
94
93
95
95
97
98
96
95
93
92
(S)
3
18
11
23
10
24
12
54
30
14
10
30
12
14
9
Et
(S)e
(S)e
(S)e
(S)e
(S)e
(S)e
(S)e
n-Pr
n-Bu
BnOCH2
BnO(CH2)2
TBSO(CH2)3
TBSO(CH2)4
g
h
The vinylogous sulfonate was developed in our laboratory
as an improved leaving group for palladium-catalyzed allylic
alkylation reactions.9 We rationalized that since the allylic
vinylogous sulfonates resemble the dibenzylidene acetone
ligand (dba), in that they have two proximal alkenes, the
metal could more easily undergo an entropically favored
oxidative addition. Furthermore, the vinylogous sulfonate
becomes a â-formyl methylsulfonate upon oxidative addition,
which was expected to influence both the catalytic turnover
and possibly the enantioselectivity through its counterion
effect.10
Indeed, treatment of the E-vinylogous sulfonate 1a,11 with
the sodium salt of dimethyl malonate and the palladium
catalyst derived from the phosphino-1,3-oxazine ligand 3,
prepared from (-)-â-pinene, furnished 4a in 89% yield with
90% enantiomeric excess in only 80 min (Table 1, Entry
a All reactions were carried out on a 0.5 mmol scale with 2 equiv of the
sodium salt of dimethyl malonate at 30 °C unless noted to the contrary.
b Reaction carried out at 20 °C. c Isolated yields. d Enantioselectivities
determined by 400 MHz 1H NMR (CDCl3) using the shift reagent (+)-
Eu(hfc)3. e Assignment made by analogy to 4a.5,13
1).12 The Z-isomer 2a11 behaved in a similar fashion,
affording a slightly higher yield due to less hydrolysis.
Table 1 summarizes the results with both E- and Z-
vinylogous sulfonates for a range of straight-chain alkyl
substituents, in which all the substrates furnished allylic
alkylation products with excellent enantioselectivity in ∼4
h (entries 3-16). In each case the major competitive side
reaction was hydrolysis to the secondary alcohol 5a, which
was easily separated and recycled. The increased hydrolysis
observed with the E-isomer is presumably the result of its
ability to adopt antiperiplanar transition state necessary for
elimination.11 It is also particularly noteworthy that the alkene
geometry of the leaving group has no appreciable effect on
the enantioselectivity, indicating that enantiodiscrimination
occurs after ionization. Therefore, the vinylogous sulfonates
have unique properties that both facilitate facile oxidative
addition to unreactive allylic systems and increase the
enantioselectivity compared with the more traditional leaving
groups often utilized for this transformation.9
(5) Evans, P. A.; Brandt, T. A. Tetrahedron Lett. 1996, 37, 9143.
(6) For examples of the enantioselective (g90% ee) Pd(0)-catalyzed
allylic alkylation of alkyl substituted allylic systems, see: (a) Dawson, G.
J.; Williams, J. M. J.; Coote, S. J. Tetrahedron: Asymmetry 1995, 6, 2535.
(b) Trost, B. M.; Radinov, R. J. Am. Chem. Soc. 1997, 119, 5962. (c)
Glorius, F.; Pfaltz, A. Org. Lett. 1999, 1, 141.
(7) Auburn, P. R.; MacKenzie, P. B.; Bosnich, B. J. Am. Chem. Soc.
1985, 107, 2033.
(8) Preliminary studies demonstrated that the nature of the leaving group
was crucial to the success of this transformation using the phosphino-1,3-
oxazine ligand 3. Treatment of the allylic acetate 6a with the sodium salt
of dimethyl malonate and the palladium catalyst derived from the phosphino-
1,3-oxazine ligand 3, failed to give any of the desired product 4a under a
variety of reaction conditions.
The absolute configuration of the allylic alkylation prod-
ucts is consistent with the model proposed by Helmchen and
others13 for 1,3-oxazoline ligands. Alkylation of the π-allyl
intermediate occurs opposite the phosphine, due to its
superior π-accepting character, providing two transition states
in which i rather than ii is responsible for the formation of
the major enantiomer (Figure 1).
This observation prompted the examination of alternative leaving groups
for this system. Treatment of the allylic carbonate 7a under similar
conditions furnished the allylic alkylation product 4a in 55% yield, albeit
with modest enantiomeric excess (82% ee). The trifluoroacetate derivative
8a proved less effective due to hydrolysis, furnishing the alcohol 5a (68%)
and the allylic alkylation product 4a in only 28% yield with 85% ee.
(9) Evans, P. A.; Brandt, T. A.; Robinson, J. E. Tetrahedron Lett. 1999,
40, 3105.
(10) For a leading reference on the effect of the metal counterion on
enantioselectivity and turnover rate, see: Burckhardt, U.; Baumann, M.;
Togni, A. Tetrahedron: Asymmetry 1997, 8, 155 and pertinent references
therein.
(12) The analogous reaction using 6a and the phosphino-1,3-oxazoline
palladium catalyst required 24 h.6a The vinylogous sulfonates of â-phenyl-
cinnamyl alcohols with aryl substituents are however particularly unstable
due to ionization of the leaving group.
(13) Spritz, J.; Kiefer, M.; Helmchen, G.; Reggelin, M.; Huttner, G.;
Walter, O.; Zsolnai, L. Tetrahedron Lett. 1994, 35, 1523 and pertinent
references therein.
(11) For the stereospecific synthesis of E- and Z-vinylogous sulfonates,
see: Meek, J. S.; Fowler, J. S. J. Org. Chem. 1968, 33, 985.
1564
Org. Lett., Vol. 1, No. 10, 1999
Evans, Andrew P.
