C O M M U N I C A T I O N S
thiourea-tertiary amine catalyst. The unprecedented reaction is
highly regio- and stereoselective and practical for a broad spectrum
of substrates (generally >99% de, 96 to >99.5% ee) at room
temperature, and S/C up to 1000 could be applied without effects
on the excellent enantiocontrol. Moreover, a δ-amino acid derivative
with multiple chiral centers could be efficiently prepared from the
adduct. Further studies are actively underway to expand the scope
and application of this valuable reaction.
Acknowledgment. We are grateful for the financial support
from NSFC (Grant 20502018), Education of Ministry (Grant NCET-
05-0781), and Fok Ying Tung Education Foundation (Grant
101037).
Figure 2. The structures of various R,R-dicyanoolefins.
Table 2. Asymmetric Direct Vinylogous Mannich Reaction of
R,R-Dicyanoolefins 2 and N-Boc Aldimines 3a
entry
sub. 2
R (3)
product 4
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph (3a)
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
99
99
99
99
99
99
94
99
99
98
97
99
99
99
99
99
98
98(78)
98(78)
99
>99
99
98
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Ph (3a)
Supporting Information Available: Experimental procedures,
structural proofs including CIF files for enantiopure 4aa. This material
9
99
References
10d
11d,e
12
13
14
15
16
17
18
2j
4ja
67(32)
74(17)
99
94
99
99
99
99
99
(1) For reviews, see: (a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102. (b)
Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044. For selected recent examples, see: (c) Yoshida, T.; Morimoto, H.;
Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005,
44, 3470. (d) Enders, D.; Grondal, C.; Vrettou, M.; Raabe. G. Angew.
Chem., Int. Ed. 2005, 44, 4079. (e) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778. (f) Zhang, H.; Mifsud,
M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 9630.
(2) For reviews, see: (a) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57,
3221. (b) Martin, S. F. Acc. Chem. Res. 2002, 35, 895.
2k
2a
2a
2a
2a
2a
2a
Ph (3a)
4ka
4ab
4ac
4ad
4ae
4af
p-F-Ph (3b)
p-MeO-Ph (3c)
m-Cl-Ph (3d)
o-Cl-Ph (3e)
2-thienyl (3f)
2-furanyl (3g)
>99.5
98
4ag
96
(3) For reviews, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. ReV. 2000, 100, 1929. (b) Kalesse, M. Top. Curr. Chem. 2005,
244, 43. (c) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682.
(4) For selected examples, see: (a) Martin, S. F.; Barr, K. J. J. Am. Chem.
Soc. 1996, 118, 3299. (b) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur,
S. K. J. Am. Chem. Soc. 1999, 121, 6990. (c) Liras, S.; Lynch, C. L.;
Fryer, A. M.; Vu, B. T.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 5918.
(d) McDermott, P. J.; Stockman, R. A. Org. Lett. 2005, 7, 27.
(5) (a) Martin, S. F.; Lopez, O. D. Tetrahedron Lett. 1999, 40, 8949. (b)
Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004, 126,
11804. (c) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2006, 45, 7230.
a Reactions performed with 0.1 mmol of 2, 0.12 mmol of 3, 2 mol % of
1g in 1 mL of toluene at room temperature overnight. b Isolated yield.
c Determined by chiral HPLC analysis. The relative and absolute config-
uration of products was assigned by analogy to 4aa. d Data in bracket is of
the separable minor diastereomer. e At 0 °C in xylene for 24 h.
Scheme 1. Synthesis of Chiral δ-Lactam
(6) (a) Xue, D.; Chen, Y.-C.; Cun, L.-F.; Wang, Q.-W.; Zhu, J.; Deng, J.-G.
Org. Lett. 2005, 7, 5293. (b) Xie, J.-W.; Yue, L.; Xue, D.; Ma, X.-L.;
Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Chem. Commun. 2006, 1563.
(c) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-
C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389.
For independent work by Jørgensen, see: (d) Poulsen, T. B.; Alemparte,
C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614.
(7) (a) Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102. (b)
Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466. (c)
Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 6700. (d) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.;
Takemoto, Y. Chem.sEur. J. 2005, 12, 466. (e) Tillman, A. L.; Ye, J.;
Dixon, D. J. Chem. Commun. 2006, 1191. (f) Song, J.; Wang, Y.; Deng,
L. J. Am. Chem. Soc. 2006, 128, 6048.
Conditions: (i) Hantzsch erster, 91%; (ii) concentrated HCl, then
(Boc)2O, K2CO3, 91%.
the highest substrate/catalyst (S/C) ratio for this type of bifunctional
organocatalysts since the pioneering work of Takemoto.8d,9d
The generality of the direct AVM was investigated with a variety
of R,R-dicyanoolefins (Figure 2) and N-Boc aldimines catalyzed
by 2 mol % of 1g at room temperature overnight (Table 2). The
reaction scope proved to be quite broad with respect to both types
of substrates. Complete diastereoselectivity (if involved) was de-
tected except the case of 2j. Excellent stereocontrol was observed
in the reactions of N-Boc benzaldimine 3a and R,R-dicyanoolefins
derived from cyclic aryl ketones (entries 1-4), acyclic aryl ketones
(entries 5-7), and cyclic aliphatic ketones (entries 8 and 9). Acyclic
aliphatic 2j gave two separable disastereomers, and a remarkable
ee (98%) was obtained for the major adduct (entry 10). In addition,
a better dr value could be attained at 0 °C (entry 11). Notably, a
simple R,R-dicyanoolefin 2k from linear aldehyde also showed high
reactivity and enantiomerically pure product was gained in quantita-
tive yield (entry 12). Furthermore, excellent results were achieved
in the asymmetric reactions of R,R-dicyanoolefin 2a and N-Boc
aryl and heteroaryl aldimines with diverse substitutions (entries 13-
18).11
(8) For reviews on thiourea catalysts, see: (a) Pihko, P. M. Angew. Chem.,
Int. Ed. 2004, 43, 2062. (b) Takemoto, Y. Org. Biomol. Chem. 2005, 3,
4299. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006,
45, 1520. (d) Connon, S. J. Chem.sEur. J. 2006, 12, 5418.
(9) For the studies from this group, see: (a) Li, B.-J.; Jiang, L.; Liu, M.;
Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (b) Liu, T.-Y.; Long,
J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org.
Biomol. Chem. 2006, 4, 2097. (c) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.;
Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem.sEur. J. 2007, 13, 319.
For other selected reports, see: (d) Okino, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2003, 125, 12672. (e) Berkessel, A.; Mukherjee, S.;
Cleemann, F.; Mu¨ller, T. N.; Lex, J. Chem. Commun. 2005, 1898. (f)
Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2005,
44, 7466. (g) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
44, 6367. (h) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 8156. (i) Inokuma, T.; Hoashi, Y.; Takemoto, Y.
J. Am. Chem. Soc. 2006, 128, 9413. (j) Wang, J.; Li, H.; Zu, L.; Jiang,
W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652.
(10) For a few examples describing high S/C (<1 mol%) organocatalysis,
see: (a) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 10012.
(b) Saaby, S.; Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126,
8120. (c) Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem., Int.
Ed. 2005, 44, 1549. (d) Terada, M.; Machioka, K.; Sorimachi, K. Angew.
Chem., Int. Ed. 2006, 45, 2254. (e) He, M.; Uc, G. J.; Bode, J. W. J. Am.
Chem. Soc. 2006, 128, 15088. (f) Ooi, T.; Takada, S.; Doda, K.; Maruoka,
K. Angew. Chem., Int. Ed. 2006, 45, 7606. (g) Terada, M.; Nakano, M.;
Ube, H. J. Am. Chem. Soc. 2006, 128, 16044.
As illustrated in Scheme 1, compound 5 with three contiguous
chiral centers was stereoselectively produced with Hantzsch ester
as the hydride reductant.6a,b Then simple hydrolysis in refluxing
concentrated HCl gave the desired δ-amino acid, which was easily
converted to the δ-lactam 6 in the presence of (Boc)2O.
(11) For R-enolizable N-Boc alkylimines the mixtures of R- and γ-addition
products were formed under the current catalytic system.
In conclusion, we have developed the first direct asymmetric
vinylogous Mannich reaction promoted by a simple bifunctional
JA068703P
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