C O M M U N I C A T I O N S
Scheme 1 anti to syn Epimerization
Table 2. Enantioselective Addition of Imide 1 to N-Ts-iminesa
Acknowledgment. This work was supported by the EPSRC and
GlaxoSmithKline. The EPSRC Mass Spectrometry Service at the
University of Wales Swansea is also thanked for their assistance.
Supporting Information Available: Experimental procedures and
full characterization for all compounds. This material is available free
entry
R
yield (%)b
syn:antic
ee (%)d
1
2
3
4
5
6
7
8
Ph
94
96
91
94
96
86
86
98
98
85
94
95
94
99
97
98
96
63
12:88
12:88
14:86
14:86
18:82
24:76
16:84
20:80
24:76
32:68
7:93
13:87
14:86
10:90
22:78
32:68
28:72
32:68
96e
99f
99
99
99
97f
98
95
93
99f
98
90f
91g
99
97
99e
85
84
References
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-tBu-C6H4
4-MeO-C6H4
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-CN-C6H4
2-Np
(1) Viso, A.; Ferna´ndez de la Pradilla, R.; Garc´ıa, A.; Flores, A. Chem. ReV.
2005, 105, 3167.
(2) For a review on the chemistry of vicinal diamines, see; Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
(3) (a) Chowdari, N. S.; Ahmad, M.; Albertshofer, K.; Tanaka, F.; Barbas,
C. F., III. Org. Lett. 2006, 8, 2839. (b) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4564. (c) Ooi, T.; Kameda, M.; Fujii, J.-i; Maruoka, K.
Org. Lett. 2004, 6, 2397. (d) Benardi, L.; Gothelf, A. S.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583.
(4) Selected examples: (a) Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 500. (b) Saruhasi, K.; Kobayahi, S. J. Am. Chem. Soc.
2006, 128, 11232. (c) Ihori, Y.; Yamashita, Y.; Ishitani, H.; Kobayahi, S.
J. Am. Chem. Soc. 2005, 127, 15528. (d) Kobayashi, S.; Matsubara, R.;
Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125,
2507. (e) Akiyama, T.; Saitoh, Y.; Morita, H.; Fuchibe, K. AdV. Synth.
Catal. 2005, 347, 1523. (f) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Ind. Ed. 2004, 43, 1566. (g) Josephsohn, N. S.; Snapper,
M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 3734. (h) Wenzel,
A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964. (i) 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.
(5) Selected examples: (a) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu,
Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 3790. (b) Cheong, P. H.-
Y.; Zhang, H.; Thayumanavan, R.; Tanaka, F.; Houk, K. N.; Barbas, C.
F., III. Org. Lett. 2006, 8, 811. (c) Yamaguchi, A.; Matsunaga, S.;
Shibasaki, M. Tetrahedron Lett. 2006, 47, 3985. (d) Sugita, M.; Yamagu-
chi, A.; Yamigiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2005, 7, 5339. (e) Ting, A.; Lou, S.; Schaus, S. E. Org. Lett. 2006,
8, 2003. (f) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem.
Soc. 2005, 127, 11256. (g) Hayashi, Y.; Urushima, T.; Shoji, M.;
Uchimaru, T.; Shiina, I. AdV. Synth. Catal. 2005, 347, 1595. (h) Cobb,
A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84. (i) Hamashima, Y.; Sasamoto, N.; Hotta, D.;
Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int. Ed. 2005,
44, 1525. (j) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2004, 43, 4476. (k) Marigo, M.; Juhl, K.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2003, 42, 1367. (l) Trost, B. M.; Terrell, L. R. J. Am.
Chem. Soc. 2003, 125, 338.
(6) (a) Zhang, H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem.
Soc. 2006, 128, 9630. (b) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.;
Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc., 2006,
128, 1040. (c) Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006, 1760.
(7) For examples of anti-selective Mannich reactions employing hydroxyl-
substituted ketones, see: (a) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul,
V. J. Am. Chem. Soc. 2006, 128, 2778. (b) Matsunaga, S.; Kumagai, N.;
Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 4712.
(8) (a) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4365. (b) Also see ref 3d.
9
10
11
12
13
14
15
16
17
18
2-thiophenyl
3-furyl
2-N-Ts-indolyl
(E)-cinnamyl
cyclohexyl
cyclopropyl
C5H11
a Conditions; imide 1 (1.0 equiv), imine (2.0 equiv), Mg(ClO4)2 (10 mol
%), 10 (11 mol %), DIPEA (20 mol %), CH2Cl2, -78 °C, 24 h. b Isolated
yields. c Determined by 1H NMR spectroscopy of crude reaction mixtures.
d Determined by chiral HPLC using Chiracel OD column, of anti-isomer.
e Absolute configuration established by X-ray diffraction study. All others
assigned by analogy. f ee measured on ethyl ester derivative. g ee measured
on isopropyl ester derivative.
Ts)-indolyl-derived imines demonstrates that heteroaromatic imines
can be successfully employed (entries 12-14). The indole-derived
imine provides a potentially useful â-amino-tryptophan derivative.13
The methodology is not limited to aromatic imines; addition of
imide 1 to the N-Ts imine generated from cinnamaldehyde
proceeded smoothly (entry 15). The cyclohexyl-derived imine
delivered the Mannich adduct in 98% yield with 99% ee, although
the smaller cyclopropyl- and hexyl-derived imines showed reduced
enantioselectivity (entries 16-18). In all cases the anti-diastereomer
was obtained as the major product. This selectivity is opposite that
observed in the additions of imide 1 to the corresponding aryl
aldehydes9 and presumably originates from the tosyl group of the
E-configured imines forcing coordination of the Lewis acid syn to
the imine substituent.14 Control experiments established that the
diasteromer ratios are constant throughout the reaction.
The in situ protection of the anti-diamines as the corresponding
cis-cyclic thioureas provided an opportunity to access the syn-
Mannich diastereomers. For example, conversion of imide 4 to ester
11 provides a substrate suitable for R-epimerization; treatment of
ester 11 with DBU results in the formation of the trans-substituted
thiourea 12, corresponding to the syn-Mannich adduct (Scheme 1).
In conclusion, we have developed a new enantioselective route
to anti-configured protected R,â-diamino acids using a direct
enantioselective Mannich reaction. A variety of aryl-, heteroaryl-,
alkenyl-, and alkyl-derived imines can all be employed. Conversion
(9) (a) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M. J.; John,
M. P. Angew. Chem., Int. Ed. 2005, 44, 1543. (b) Willis, M. C.; Piccio,
V. J.-D. Synlett 2002, 1625.
(10) For examples of the use of a chiral version of 1 in diastereoselective aldol
additions, see: (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986,
108, 6757. (b) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1987, 109,
7151. (c) Lago, M. A.; Samanen, J.; Elliot, J. D. J. Org. Chem. 1992, 57,
3493. (d) Boger, D. L.; Colletti, S. L.; Honda, T.; Menezes, R. F. J. Am.
Chem. Soc. 1994, 116, 5607.
(11) McManus, H. A.; Guiry, P. J. Chem. ReV. 2004, 104, 4151.
(12) (a) Kanemasa, S.; Oderaotoshi, Y.; Yamamoto, H.; Tanaka, J.; Wada, E.;
Curran, D. P. J. Org. Chem. 1997, 62, 6454. (b) Iserloh, U.; Oderaotoshi,
Y.; Kanemasa, S.; Curran, D. P. Org. Synth. 2003, 80, 46.
(13) (a) Fueloep, F.; Martinek, T. A.; Toth, G. K. Chem. Soc. ReV. 2006, 35,
323. (b) Sewald, N. Angew. Chem. Int. Ed. 2003, 42, 5794.
(14) For a review of enantioselective additions to imines, see: Kobayashi, S.;
Ishitani, H. Chem. ReV. 1999, 99, 1069.
i
of the products to their Pr-ester derivatives allows epimerization
to the syn-diastereomers.
JA073473F
9
J. AM. CHEM. SOC. VOL. 129, NO. 35, 2007 10633