Felkin-Anh preference, affording a 55:45 mixture of the
syn and anti adducts 11a and 10a (Table 1). When the
Scheme 2. Preparation of Vinylmetal Reagents 2a-ca
Table 1. Additions of Vinylzinc Reagent 8 to the
(S)-Aldehydes 9a and 9b
a (a) Cp2ZrCl2, AlMe3, CH2Cl2, H2O; (b) I2 (74%, 2-steps); (c)
t-BuLi; (d) MgBr2.
R
ligand
yield, %
10:11a
3 involved in situ addition of aldehyde 1 to the carbo-
alumination product, vinylalane 2c. However, the selectivity
of this process was no better than that observed with the
Grignard reagent 2b.
TBS (9a )
TBS (9a )
TBS (9a )
Bn(9b)
Bn (9b)
Bn (9b)
none
74
70
70
77
68
70
45:55
>90:10
<10:90
75:25
95:5
75:25
Li(1R,2S)-NMEb
Li(1S,2R)-NMEb
none
Li(1R,2S)-NMEb
Li(1S,2R)-NMEb
At this stage in our investigation, hoping to enhance the
substrate preference for anti addition to aldehyde 1, we
decided to explore the use of a chiral ligand in the addition
reaction. Additions of diorganozinc reagents to aldehydes
catalyzed by chiral ligands have been extensively studied
since Noyori’s original discovery of the reaction in 1986.5
The overwhelming majority of those studies were directed
toward chiral ligand development with diethyl or dimethyl-
zinc and simple achiral aldehydes.6 In 1991 Oppolzer and
Radinov reported a more synthetically useful variant of this
reaction employing vinylzinc bromide reagents in which the
lithium alkoxide derived from (1S,2R)-N-methylephedrine
serves as a chiral ligand.7 These reactions proceed through
a chiral zinc complex and require a stoichiometric amount
of the ligand. However, recovery of the chiral ligand is easily
achieved through extraction of the reaction mixture with acid.
Furthermore both enantiomers of N-methylephedrine are
readily available in high optical purity.
a 1H NMR integration. b Li-NME
(PhCH(OLi)CH(NMe2)CH3).
) lithio N-methylephedrine
addition was conducted in the presence of the lithio derivative
of (1R,2S)-N-methylephedrine, the anti adduct 10a predomi-
nated by >90:10. Use of the enantiomeric N-methylephedrine
reversed this product ratio in favor of the syn adduct 11a.
Addition of the zinc reagent 8 to the (S)-benzyloxy propanal
9b11 in the absence of chiral ligand afforded mainly the
chelation-controlled anti adduct 10b (75:25). This preference
was increased to 95:5 when the addition was conducted in
the presence of the (1R,2S) ligand (matched case). In the
presence of the enantiomeric ligand the addition afforded a
75:25 mixture favoring the chelation-derived anti isomer 10b.
The stereochemistry of the foregoing adducts was confirmed
by H NMR analysis of the O-methyl mandelic esters.12
1
To date additions of this type have not generally been
utilized in natural product synthesis despite the relative
simplicity of the methodology and the reported high levels
of enantioselectivity.8 Moreover, only a few studies have
addressed the issue of diastereoselectivity resulting from
additions of organozinc reagents of any kind to chiral
aldehydes.9 In view of the potential of this methodology for
applications in complex synthesis, we decided to examine
reactions of vinylzinc reagents related to 2 with prototype
chiral aldehydes. Our initial studies were conducted with the
vinylzinc reagent 8, prepared as shown in Scheme 3, from
the TBS ether analogue 6 of vinyl iodide 5.
Reactions of the vinylzinc reagent 8 with the chiral aldehydes
12a and 12b, derived from (S)-ethyl lactate, were examined
next. The TBS-protected aldehyde 12a13 afforded a 65:35
mixture of adducts favoring the Felkin-Anh/Cornforth
(5) Kitamura, M.; Suga, S.; Kawal, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071.
(6) For a recent comprehensive review, see: Pu. L.; Yu, H.-B. Chem.
ReV. 2001, 101, 757.
(7) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1991, 32, 5777.
(8) An intramolecular version of the reaction was employed by Oppolzer
in reported syntheses of (R)-(-)-muscone and (+)-aspercilin, two relatively
simple macrocylic natural products. Oppolzer, W.; Radinov, R. N. J. Am.
Chem. Soc. 1993, 115, 1593. Oppolzer, W.; Radinov, R. N.; De Brabander,
J. Tetrahedron Lett. 1995, 36, 2607. See also: Layton, M. E.; Morales, C.
A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773.
(9) Soai, K.; Hatanaka, T.; Yamashita, T. J. Chem. Soc., Chem. Commun.
1992, 927. Soai, K.; Shimada, C.; Takeuchi, M.; Itabashi, M. J. Chem.
Soc., Chem. Commun. 1994, 567. Watanabe, M.; Komota, M.; Nishimura,
M.; Araki, S.; Butsugan, Y. J. Chem. Soc., Perkin Trans. 1 1993, 2193.
(10) Roush, W. R.; Palkowitz , A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
Scheme 3. Preparation of the Vinylzinc Reagent 8
(11) Marshall, J. A.; Yu, R. H.; Perkins, J. H. J. Org. Chem. 1995, 60,
5550.
(12) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. D. J. Org. Chem. 1986, 51, 2370.
(13) Massad, S.; Hawkins, L. D.; Baker, D. C. J. Org. Chem. 1983, 48,
5188.
Addition of the zinc reagent 8 to TBS-protected (S)-3-
hydroxy-2-methylpropanal 9a10 proceeded with a slight
446
Org. Lett., Vol. 6, No. 3, 2004