Published on Web 11/17/2007
Asymmetric Allylboration of Acyl Imines Catalyzed by Chiral Diols
Sha Lou, Philip N. Moquist, and Scott E. Schaus*
Contribution from the Department of Chemistry and Center for Chemical Methodology and
Library DeVelopment, Life Science and Engineering Building, Boston UniVersity, 24
Cummington Street, Boston, Massachusetts 02215
Received July 28, 2007; E-mail: seschaus@bu.edu
Abstract: Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines.
The reaction requires 15 mol % (S)-3,3′-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the
nucleophile. The reaction products are obtained in good yields (75-94%) and high enantiomeric ratios
(95:5-99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (diastereomeric ratio > 98:2)
and enantioselectivities (enantiomeric ratio > 98:2) are obtained in the reactions of acyl imines with
crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of Maraviroc,
the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of
the allylboration reaction including IR, NMR, and mass spectrometry studies indicate that acyclic boronates
are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl
imine via hydrogen bonding.
lective allyl metal additions to chiral imines.10 Innovative
catalytic approaches include the development of chiral main
group Cu-11 and Zn-promoted12 reactions as well as Pd-13 and
Zr-mediated14 allyl metal additions to imines and, more recently,
allylindium reagents generated in the presence of BINOL-
derived15 and chiral thiourea catalysts,16 which result in enan-
Introduction
Chiral homoallylic amines are valuable building blocks for
use in synthesis.1 They have found use as precursors for â-amino
acids2 and heterocycles.3 Chiral homoallylic amines have also
served as key intermediates in complex natural product synthesis
and pharmacologically relevant compounds.4 In addition, the
structural motif is also present in a variety of bioactive molecules
with wide-ranging biological properties.5
The asymmetric allylation of imines provides direct access
to chiral homoallylic amines.6 Significant progress has been
made in the development of practical approaches to these
building blocks using chiral allyl metal reagents such as allyl
silanes,7 allyl boronates,8 and boranes,9 as well as diastereose-
(6) Reviews: (a) Kleinman, E. F.; Volkmann, R. A. Additions of Nucleophilic
Alkenes to CdNR and CdNR2+. In ComprehensiVe Organic Synthesis,
Vol. 2; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; p
975. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (c)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895-1946.
(d) Bloch, R. Chem. ReV. 1998, 98, 1407-1438. (e) Alvaro, G.; Savoia,
D. Synlett 2002, 651-673. (f) Friestad, G. K.; Mathies, A. K. Tetrahedron
2007, 63, 2541-2569.
(7) (a) Panek, J. S.; Jain, N. F. J. Org. Chem. 1994, 59, 2674-2675. (b) Schaus,
J. V.; Jain, N. F.; Panek, J. S. Tetrahedron 2000, 56, 10263-10274. (c)
Berger, R.; Rabbat, P.; Leighton, J. J. Am. Chem. Soc. 2003, 125, 9596-
9597. (d) Berger, R.; Duff, K.; Leighton, J. J. Am. Chem. Soc. 2004, 126,
5686-5687.
(8) (a) Chataigner, I.; Zammattio, F.; Lebreton, J.; Villie´ras, J. Synlett 1998,
275-276. (b) Watanabe, K.; Kuroda, S.; Yokoi, A.; Ito, K.; Itsuno, S. J.
Organomet. Chem. 1999, 581, 103-107. (c) Sugiura, M.; Hirano, K.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 7182-7183. (d) Wu, T. R.;
Chong, J. M. J. Am. Chem. Soc. 2006, 128, 9646-9647.
(9) (a) Ramachandran, P. V.; Burghardt, T. E. Chem.sEur. J. 2005, 11, 4387-
4395. (b) Canales, E.; Hernandez, E.; Sodequist, J. A. J. Am. Chem. Soc.
2006, 128, 8712-8713.
(10) (a) Cook, G. R.; Maity, B. C.; Karbo, R. Org. Lett. 2004, 6, 1741-1743.
(b) Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004,
69, 1415-1418. (c) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada,
T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464-3471. (d) Friestad, G. K.;
Korapala, C. S.; Ding, H. J. Org. Chem. 2006, 71, 281-289.
(11) (a) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R. G.;
Jorgensen, K. A. J. Org. Chem. 1999, 64, 4844-4849. (b) Ferraris, D.;
Young, B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.; Taggi,
A. E.; Lectka, T. J. Am. Chem. Soc. 2002, 124, 67-77. (c) Kiyohara, H.;
Nakamura, Y.; Matsubara, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2006,
45, 1615-1617. (d) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687-7691.
(12) Hamada, T.; Manabe, K.; Kobayashi, S. Angew. Chem., Int. Ed. 2003, 42,
3927-3930.
(13) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 4242-4243. (b) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 14133-14139. (c) Yamamoto, Y.; Fernandes, R. J.
Org. Chem. 2004, 69, 735-738.
(14) Gastner, T.; Ishitani, H.; Akiyama, R.; Kobayashi, S. Angew. Chem., Int.
Ed. 2001, 40, 1896-1898.
(1) Reviews: (a) Denmark, S. E.; Almstead, N. G. Allylation of Carbonyls:
Methodology and Stereochemistry. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VHC: Weinheim, Germany, 2000; Ch. 10. (b) Puentes, C.
O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39, 595-614. (c) Ding,
H.; Friestad, G. K. Synthesis 2005, 2815-2829.
(2) (a) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883-5889. (b) Robl,
J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.; Ryono, D. E.; Bird,
J. E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med. Chem. 1996,
39, 494-502.
(3) (a) Felpin, F.-X.; Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villieras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305-6312. (b) Lee, C.-L. K.; Lui,
H. Y.; Loh, T.-P. J. Org. Chem. 2004, 69, 7787-7789. (c) Goodman, M.;
Del Valle, J. R. J. Org. Chem. 2004, 69, 8945-8946.
(4) (a) Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc.
1990, 112, 2003-2005. (b) Nicolaou, K. C.; Mitchell, H. J.; van Delft, F.
L.; Rubsam, F.; Rodriguez, R. M. Angew. Chem., Int. Ed. 1998, 37, 1871-
1874. (c) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2,
1847-1850. (d) Xie, W.; Zou, B.; Pei, D. Ma, D. Org. Lett. 2005, 2775-
2777. (e) White, J. D.; Hansen, J. D. J. Org. Lett. 2005, 70, 1963-1977.
(5) (a) Lloyd, H. A.; Horning, E. C. J. Org. Chem. 1960, 25, 1959-1962. (b)
Doherty, A. M.; Sircar, I.; Kornberg, B. E.; Quin, J., III; Winters, R. T.;
Kaltenbronn, J. S.; Taylor, M. D.; Batley, B. L.; Rapundalo, S. R.; Ryan,
M. J.; Painchaud, C. A. J. Med. Chem. 1992, 35, 2-14. (c) Schmidt, U.;
Schmidt, J. Synthesis 1994, 300-304. (d) Barrow, R. A.; Moore, R. E.;
Li, L.-H.; Tius, M. A. Tetrahedron 2000, 56, 3339-3351. (e) Janjic, J.
M.; Mu, Y.; Kendall, C.; Stephenson, C. R. J.; Balachandran, R.; Raccor,
B. S.; Lu, Y.; Zhu, G.; Xie, W.; Wipf, P.; Day, B. W. Bioorg. Med. Chem.
2005, 13, 157-164. (f) Suvire, F. D.; Sortino, M.; Kouznetsov, V. V.;
Vargas, M. L. Y.; Zacchino, S. A.; Cruz, U. M.; Enriz, R. D. Bioorg. Med.
Chem. 2006, 14 1851-1862.
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10.1021/ja075204v CCC: $37.00 © 2007 American Chemical Society