13000
J. Am. Chem. Soc. 1998, 120, 13000-13001
Table 1. Enantioselective Catalytic Phase Transfer Alkylation
Highly Enantioselective Phase Transfer Catalyzed
Alkylation of a 3-Oxygenated Propionic Ester
Equivalent; Applications and Mechanism
E. J. Corey,* Yunxin Bo, and Jakob Busch-Petersen
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed October 12, 1998
A detailed molecular mechanism has recently been described
for the phase transfer catalyzed enantioselective alkylation of an
enolate with use of the chiral quaternary cinchonidinium salt 1a.1,2
This reaction was illustrated by a variety of examples in which a
series of (S)-R-amino acid derivatives (both natural and unnatural)
was prepared with enantioselectivities in the range 400:1 to 60:1
by alkylation of the tert-butyl glycinate-benzophenone Schiff
base.3 In the mechanistic model contact ion pairing takes place
selectively between the anionic oxygen of the enolate and just
one of the tetrahedral faces of the cationic nitrogen of 1a (for
a An excess (ca. 5 equiv) of RX was employed. b Yields refer to
chromatographically pure, isolated product 3. c Enantiopurity of 3 was
determined by chiral HPLC analysis (column: Regis Whelk-O1; elution
solvent: 20% 2-propanol-hexane). In each case it was established by
analysis of racemic 3 that the enantiomers were fully resolved.
in the presence of solid CsOH‚H2O proceeded smoothly to form
the R alkylation product 3 in good yield and in high ee (94-
98%), as summarized in Table 1. The (R)-absolute configuration
for the alkylation products, which was predicted from the
mechanistic model, was confirmed for the case of 3, R ) CH3,
by chemical correlation with (R)-(+)-2-methyl-3-tert-butyldim-
ethylsilylpropane-1,3-diol (4, R ) CH3),4 [R]25 +13.18 (c 0.19,
CHCl3), using the following sequence: (1) rDeduction of CO2t-
Bu to CH2OH with diisobutylaluminum hydride in CH2Cl2 at -78
f 0 °C over 30 min; (2) silylation with tert-butyldimethylsilyl
chloride (TBSCl)-Et3N-DMF at 23 °C for 1 h; (3) oxidation of
CdC with catalytic OsO4 and stoichiometric N-methylmorpholine
N-oxide (NMO) in 8:1 acetone-H2O at 23 °C for 24 h; (4)
oxidative C-C cleavage with Pb(OAc)4 in CH2Cl2 at 0 °C for 1
h; and (5) reduction of CHO to CH2OH with NaBH4 in CH3OH
at -40 °C. In an analogous manner 4, R ) C6H5CH2, o-C6H5-
C6H4, R ) n-C6H13 were synthesized in good overall yield from
3, R ) C6H5CH2, o-C6H5C6H4, and n-C6H13, respectively. Thus
a range of chiral 2-substituted monoprotected propane-1,3-diols,
versatile building blocks for enantioselective synthesis, can be
accessed by enantioselective phase transfer catalyzed conversion
of 2 to 3.
The general catalytic enantioselective conversion 2 f 3 has a
variety of potential applications other than to the synthesis of
chiral propane-1,3-diol derivatives, especially when a bifunctional
alkylating agent is used. Thus, starting with 3, R ) (CH2)3Cl,
the chiral tetrahydropyran 5 was produced by (1) reduction of
CO2t-Bu to CH2OH (DIBAL-H, CH2Cl2, -78 to 0 °C for 30 min,
96%) and (2) cyclization (NaH, DMF, Bu4NI at 23 °C for 2 h,
92%). Two-step oxidative cleavage of the double bond of 5 (first
cat. OsO4-NMO, then Pb(OAc)4, as above) afforded the aldehyde
6, which was converted sequentially to the corresponding alcohol
steric reasons). In addition, considerable van der Waals attraction
occurs between the enolate and a complementary binding site on
the quaternary ammonium cation within the contact ion pair. The
combination of electrostatic and van der Waals binding results
in a highly structured contact ion pair in which only one face of
the nucleophilic R carbon of the enolate is accessible to the
electrophilic alkylating species.1 This mechanistic picture provides
a logical explanation for the absolute stereochemical course of
the catalytic alkylation process and also the very high levels of
enantioselectivity which are observed. In this paper we demon-
strate that this remarkably enantioselective alkylation catalyst can
be applied to other enolates and that the enantioselectivity varies
in a predictable way with the electronic effect of remote
substituents on the enolate. In addition, we present an analysis
of the alkylation process that underscores the importance of charge
density and entropy in determining the level of enantioselectivity.
The â,γ-unsaturated ester 2 was prepared from 4,4′-bis-
(dimethylamino)benzophenone (Michler’s ketone) by the follow-
ing sequence: (1) reaction with γ-lithiated tert-butyl propiolate
(from n-BuLi on the propiolate ester in THF at -78 °C) in THF
at -15 °C for 20 h (68%); (2) catalytic reduction with 1 atm of
H2 over 5% Pd-BaSO4 at 23 °C for 20 min (91%); and (3)
dehydration with CH3SO2Cl-Et3N-4-N,N-(dimethylamino)-
pyridine in CH2Cl2 at 0 °C for 30 min (86%). Reaction of 2 in
1:1 CH2Cl2-Et2O solution containing 10 mol % of chiral
ammonium bromide 1b with various alkyl bromides or iodides
(1) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(2) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
(3) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446. (b) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoenewaldt,
E. F.; Grabowski, E. J. J. J. Org. Chem. 1987, 52, 4745. (c) O’Donnell, M.
J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. (d) O’Donnell,
M. J.; Wu, S.; Huffman, J. C. Tetrahedron 1994, 50, 4507. (e) Lipkowitz, K.
B.; Cavanaugh, M. W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181. (f) O’Donnell, M. J. et al. U.S. Patent 5,554,753, September 10, 1996.
(g) O’Donnell, M. J.; Esikova, I. A.; Mi, A.; Shullenberger, D. F.; Wu, S. In
Phase-Transfer Catalysis; Halpern, M. E., Ed.; ACS Symp. Ser. No. 659;
American Chemical Society: Washington, DC, 1997; Chapter 10.
(4) (a) Harada, T.; Hayashiya, T.; Wada, I.; Iwa-ake, N.; Oku, A. J. Am.
Chem. Soc. 1987, 109, 527. (b) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui,
K.; Fukumoto, K.; Kametani, T. J. Chem. Soc. Perkin Trans. 1 1989, 897. (c)
Marshall, J. A.; Trometer, J. D.; Cleary, D. J. Tetrahedron 1989, 45, 391.
10.1021/ja9835739 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/26/1998