Journal of the American Chemical Society
COMMUNICATION
Scheme 2. Preparative-Scale Reaction
useful R,R-disubstituted butyrolactone products. The remark-
able hydrogen-bond acceptor properties and silaphilicity of the
fluoride anion facilitate an efficient reaction protocol with low
catalyst loadings and high yields and selectivities. A more
complete mechanistic elucidation of this acylation reaction that
includes analysis of the basis for enantioinduction is the focus of
ongoing studies.
Scheme 3. Proposed Catalytic Cycle
’ ASSOCIATED CONTENT
S
Supporting Information. Complete experimental proce-
b
dures and characterization data for acylation products and all
isolated intermediates, H and 13C NMR spectra of acylation
1
products, HPLC traces of racemic and enantioenriched acylation
products, catalyst and silyl ketene acetal optimization data, and
crystallographic information for compound 2b. This material is
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
This work was supported by the NIH (GM-43214), a pre-
doctoral fellowship to J.A.B. from Eli Lilly, and a postdoctoral
fellowship to J.-N.D. from NSERC. We thank Dr. Shao-Liang
Zheng for crystal structure determination and Dr. Alan Hyde for
catalyst development and synthesis.
’ REFERENCES
regard.19 Furthermore, activation of the silyl ketene acetal by
fluoride or benzoate seems necessary for acylation to occur,
particularly given the complete absence of reactivity observed
with benzoyl chloride under the standard reaction conditions.20
Consistent with this hypothesis, variation of the silyl group of the
silyl ketene acetal has a measurable influence on the rate of the
reaction, with larger silyl groups leading to diminished reaction
rates. However, the identity of the silyl group has a negligible
effect on reaction enantioselectivity, indicating that it plays no
significant role in the organization of the stereoselectivity-
determining step.21 This result raises the possibility of a thiourea-
bound enolate as a key intermediate.22
(1) (a) Fersht, A. R.; Jencks, W. P. J. Am. Chem. Soc. 1969,
91, 2125–2126. (b) Fersht, A. R.; Jencks, W. P. J. Am. Chem. Coc.
1970, 92, 5432–5442.
(2) (a) Litvinenko, L. M.; Kirichenko, A. I. Dokl. Akad. Nauk. SSSR,
Ser. Khim. 1967, 176, 97–100. (b) Steglich, W.; H€ofle, G. Angew. Chem.,
Int. Ed. 1969, 8, 981.
(3) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978,
34, 2069–2076.
(4) For reviews on DMAP catalysis, see ref 3 and the following:
(a) H€ofle, G.; Steglich, W.; Vorbr€uggen, H. Angew. Chem., Int. Ed.
1978, 17, 569–583. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983,
12, 129–161. (c) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta
2003, 36, 21–27.
(5) For discussions on the mechanism of DMAP catalysis, see ref 4a
and the following: ( a) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int.
Ed. 2004, 43, 5436–5441. (b) Xu, S.; Held, I.; Kempf, B.; Mayr, H.;
Steglich, W.; Zipse, H. Chem.—Eur. J. 2005, 11, 4751–4757. (c) Held, I.;
Villinger, A.; Zipse, H. Synthesis 2005, 9, 1425–1430. (d) Lutz, V.;
Glatthaar, J.; W€urtele, C.; Serafin, M.; Hausmann, H.; Schreiner, P. R.
Chem.—Eur. J. 2009, 15, 8548–8557.
A proposed catalytic cycle that is consistent with these
observations is presented in Scheme 3. As noted, the thiourea
catalyst activates benzoyl fluoride for reaction with PPY, pre-
sumably via initial complexation to the carbonyl group of the
acyl fluoride (A). A thiourea-bound acylpyridinium/fluoride
intermediate (B) is then proposed, in which the thiourea is
associated to the fluoride anion and the catalyst arene sub-
stituent is engaged in a stabilizing interaction with the
acylpyridinium cation.15 Reaction of B with the silyl ketene
acetal likely proceeds via a pentavalent silicate intermediate23
and is proposed to be rate-determining on the basis of the
observed dependence of the overall rate on the identity of the
silyl group. However, the independence of reaction enantios-
electivity on the identity of the silyl group points to a thiourea-
bound enolate such as C as the intermediate involved in
enantiodetermining acylation.
(6) For a review on thiourea anion-binding catalysis, see: Zhang, Z.;
Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.
(7) (a) Reisman, S. E.; Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 7198–7199. (b) Klausen, R. S.; Jacobsen, E. N. Org. Lett.
2009, 11, 887–890. (c) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.;
Jacobsen, E. N. Nature 2009, 461, 968–970. (d) Knowles, R. R.; Lin, S.;
Jacobsen, E. N. J. Am. Chem. Soc. 2010, 132, 5030–5032.
(8) (a) De, C. K.; Klauber, E. G.; Seidel, D. J. Am. Chem. Soc. 2009,
131, 17060–17061. (b) Klauber, E. G.; De, C. K.; Shah, T. K.; Seidel, D.
J. Am. Chem. Soc. 2010, 132, 13624–13626. (c) Klauber, E. G.; Mittal, N.;
Shah, T. K.; Seidel, D. Org. Lett. 2011, 13, 2464–2467.
In conclusion, a highly enantioselective acylation of silyl
ketene acetals with acyl fluorides has been developed to generate
(9) For reviews on catalytic asymmetric acyl transfer reactions, see:
(a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542–547. (b) Wurz, R. P. Chem.
13874
dx.doi.org/10.1021/ja205602j |J. Am. Chem. Soc. 2011, 133, 13872–13875