C O M M U N I C A T I O N S
Table 3. Aldol Reactions Catalyzed by 2 or 3a
Table 1. Evaluation of Catalysts for the anti-Mannich-type and
syn-Aldol Reactionsa
yieldb
(%)
drc
syn:anti
eed
(%)
entry
R1
R2
product
catalyst
1
2
H
p-NO2C6H4
5
2
3
3
2
3
3
2
3
3
2
3
3
2
3
3
3
75
>95
83
65
81
78
67
89
80
60
78
69
70
87
78
78
15:1
18:1
18:1
7:1
7:1
14:1
7:1
3:1
12:1
5:1
5:1
7:1
90
98
97
92
92
94
84
82
92
86
80
93
86
80
86
94
time
(h)
yieldb
(%)
drc
anti:syn
eed
anti/syn
entry
product
catalyst
3e
4
H
p-ClC6H4
p-BrC6H4
p-CNC6H4
1-naphthyl
p-NO2C6H4
13
14
15
16
17
1
2
3
4
5
6
7
4
4
4
4
4
5
5
5
5
5
L-Trp (1)
L-Ser
L-Thr (2)
3
O-tBu-L-Tyr
L-Trp (1)
L-Ser
L-Thr (2)
3
4
28
48
22
22
18
22
16
48
24
75
77
74
85
50
80
75
88
5:1
3:1
2:1
8:1
3:1
1:2.5
1:2
1:3
1:18
1:3
87/68
75/33
66/14
94/56
75/45
5/40
10/50
0/62
58/98
14/50
5
6e
7
H
8
9e
10f
11
12e
13
14
15e
16
H
8
9e
10e
>95
71
H
8:1
10:1
6:1
O-tBu-L-Tyr
a Reaction was performed in DMSO at 25 °C except as indicated. See
Supporting Information. b Isolated yield. c Determined by NMR of unpu-
rified product. d Determined by chiral-phase HPLC. e Reaction performed
in NMP at 4 °C.
Me
12:1
a See Supporting Information for conditions. b Isolated yield. c Deter-
mined by 1H NMR of isolated products. d Determined by chiral-phase HPLC
for syn-product. e Reaction in NMP-water (9:1). f Reaction time 96 h.
Table 2. Mannich and Mannich-type Reactions Catalyzed by 1
or 3a
Acknowledgment. This research was supported by The Skaggs
Institute for Chemical Biology.
Note Added after ASAP Publication. Ref 10 was corrected on
December 21, 2006.
Supporting Information Available: Experimental details, product
characterization, and X-ray structure of 5. This material is available
yieldb
(%)
drc
anti:syn
eed
(%)
entry
R1
R2
product
catalyst
1e
2
3
4
5
6
7
8
9
H
p-NO2C6H4
4
1
3
1
3
1
3
1
3
1
1
1
1
95
85
83
78
89
71
85
76
75
72
67
70
12:1
>15:1
>10:1
9:1
>10:1
>10:1
>10:1
>10:1
4:1
95
98
90
90
93
94
92
91
77
53
91
96
H
H
H
p-CNC6H4
p-BrC6H4
p-ClC6H4
6
7
8
References
(1) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-
VCH: Weinheim, Germany, 2003, and references therein.
(2) (a) Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Ohshima, T.;
Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466. (b) Kumagai,
N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto, S.;
Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169. (c)
Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 4712. (d) Matsunaga, S.; Yoshida, T.; Morimoto, H.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777. (e) Sugita,
M.; Yamaguchi, A.; Yamagiwa, N.; Handa, S.; Matsunaga, S.; Shibasaki,
M. Org. Lett. 2005, 7, 5339. (f) Trost, B. M.; Ito, H.; Silcoff, E. R. J.
Am. Chem. Soc. 2001, 123, 3367. (g) Trost, B. M.; Terrell, L. R. J. Am.
Chem. Soc. 2003, 125, 338. (h) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778.
H
H
H
Me
C6H4
9
10
11
12
10
11e,f
12e
p-MeOC6H4
CO2Et
p-NO2C6H4
1.3:1
2:1
>19:1
a See Supporting Information for conditions. b Isolated yield. c Deter-
mined by 1H NMR of isolated products. d Determined by chiral-phase HPLC
for anti-product. e Preformed imine was used. f Reaction was performed at
25 °C.
(3) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386. (b) Sakthivel,
K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123,
5260. (c) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1842. (d) Notz, W.; Watanabe, S.;
Chowdari, N. S.; Zhong, G.; Betancort, J. M.; Tanaka, F.; Barbas, C. F.,
III. AdV. Synth. Catal. 2004, 346, 1131.
(entry 12). To the best of our knowledge, there are no other reports
concerning direct asymmetric reactions with 1-hydroxy-2-butanone.
Aldol reactions catalyzed by 2 and 3 were also optimized, and
the reactions were performed in NMP and NMP-water (9:1) at 4
°C (Table 3). Desired syn-diols were obtained with high dr (up to
18:1) and ee (up to 98% ee). Both dr and ee increased with the
addition of water in many cases (entries 5, 8, and 11 vs 6, 9, and
12). The aldol reaction of 1-hydroxy-2-butanone catalyzed by 3
also afforded excellent results (entry 16).
The absolute configuration of anti-4 obtained from the 1-cata-
lyzed reaction and of syn-5 obtained from the 3-catalyzed reaction
was determined to be (3R,4R)-4 and (3R,4S)-5, respectively (see
Supporting Information); these results are in accord with our
predicted transition states H and I (Scheme 1).
In summary, we have developed simple and efficient routes to
highly enantiomerically enriched anti-1,2-amino alcohols and syn-
1,2-diols through direct asymmetric Mannich, Mannich-type, and
aldol reactions involving unmodified R-hydroxyketones catalyzed
by primary amine-containing amino acids. These results provide
additional support for our original hypothesis suggesting that amino
acid catalysis played a key role in prebiotic chemistry facilitating
the asymmetric synthesis of the molecules of life.10 Further studies on
the full scope of these reactions will be reported in the near future.
(4) (a) Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K. N.; Tanaka,
F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040. (b) Zhang, H.;
Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128,
9630.
(5) For other anti-Mannich reactions involving organocatalysis, see: (a) Kano,
T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem. Soc. 2005,
127, 16408. (b) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjaersgaard, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296.
(6) The â-proline-catalyzed reaction afforded 4 in good yield (91%) but with
moderate dr (∼1:1) and ee (50% ee for the anti-isomer).
(7) Hoffmann, T.; Zhong, G.; List, B.; Shabat, D.; Anderson, J.; Gramatikova,
S.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 1998, 120, 2768.
(8) For (Z)-enamine intermediates between primary amines and alkanones,
see: (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(b) Tsogoeva, S. B.; Wei, S. Chem. Commun. 2006, 1451. For compu-
tational studies of a hydroxyacetone enamine, see: (c) Bahmanyar, S.;
Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273.
(9) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 496. (b) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III.
Tetrahedron Lett. 2004, 45, 325. (c) Cordova, A.; Zou, W.; Ibrahem, I.;
Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586. (d)
Bassan, A.; Zou, W.; Reyes, E.; Himo, F.; Cordova, A. Angew. Chem.,
Int. Ed. 2005, 44, 7028. (e) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem.
Commun. 2006, 2801.
(10) Chowdari, N. S.; Ramachary, D. B.; Cordova, A.; Barbas, C. F., III.
Tetrahedron Lett. 2002, 43, 9591.
JA0677012
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J. AM. CHEM. SOC. VOL. 129, NO. 2, 2007 289