Scheme 1. Direct Organocatalytic Tandem Asymmetric
Desymmetrization/O-N Bond Heterolysis
Table 1. Optimization of Direct Organocatalytic Tandem ADS
and O-N Bond Heterolysis of Highly Substituted Prochiral
Spirotrione 1aa
catalyst
(20 mol
%)
product
solvent
(0.3 M)
Ph-NdO
(equiv) (°C) (h)
T
t
(5a) yield eec
entry
(%)b
(%)
Our tandem approach complements previous R-aminoxyla-
tion of simple ketones catalyzed by L-proline.4
1d
2d
4
4
DMSO
(bmim)PF6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
0.5
25 54
25 54
25 54
25 24
25 24
25 24
25 44
25 20
<3
<2
<2
42
50
60
72
51
85
76
30
We initiated our studies of the ADS/O-N bond reduction
reaction by screening a number of known and novel
organocatalysts for the R-hydroxylation of highly substituted
spirotrione 1a5 by nitrosobenzene 2. Representative results
are shown in Table 1. L-Proline 4 catalyzed the formation
of R-hydroxy ketone 5a in very poor yields in DMSO and
[bmim]PF6 solvents (Table 1, entries 1 and 2). The bifunc-
tional catalyst diamine 3b/TFA6 also generated 5a in very
poor yields in DMSO (Table 1, entry 3). In contrast to this
result, L-proline 4 afforded 5a as a single diastereomer in
CH3CN with >99% enantiomeric excess (ee); however, the
yield of 5a was moderate (42%, Table 1, entry 4). Interest-
ingly, L-proline catalysis in aprotic/nonpolar solvents (CHCl3
and CH2Cl2) provided 5a in good yields with >99% ee and
diastereomeric excess (de) (Table 1, entries 5 and 6).
Tetrazole-based catalyst 3a7 also furnished the R-hydroxy
ketone 5a in moderate to good yields with excellent ee and
3d 3b/TFAe DMSO
4f
5f
6f
7
8
9
4
4
4
3a
3a
4
3a
4
CH3CN
CHCl3
>99
>99
>99
>99
>99
>99
>99
>99
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
4
4
4
24
24
24
10
11g
a Reactions were carried out in solvent (0.3 M) with indicated equivalents
of nitrosobenzene relative to the prochiral ketone 1a in the presence of 20
mol % catalyst. b Yield refers to the column-purified product. c Ee deter-
mined by CSP-HPLC analysis. d Unreacted prochiral ketone 1a (80-85%)
was isolated. e 1:1 mixture of 3b and trifluoroacetic acid. f Unreacted
prochiral ketone 1a (30-40%) was isolated. g Aminoxy ketone 6a (15%)
was isolated along with unreacted prochiral ketone 1a (70%).
de (Table 1, entries 7 and 8). The optimal conditions for
L-proline 4 catalysis were 4 °C in CH2Cl2 with 3 equiv of
nitrosobenzene 2 and furnished R-hydroxy ketone 5a in 85%
yield, >99% ee, and de (Table 1, entry 9).8 In these tandem
reactions, product 5a was accompanied by trans-azoxyben-
zene 7 and unreacted prochiral spirotrione 1a, and no
R-aminoxy ketone 6a was observed (Table 1).
(4) (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250. (b)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808-10809. (c) Momiyama, N.; Torii, H.; Saito,
S.; Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374-5378.
(d) Bogevig, A.; Sundeen, H.; Cordova, A. Angew. Chem., Int. Ed. 2004,
43, 1109-1112. (e) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M.
Angew. Chem., Int. Ed. 2004, 43, 1112-1115. (f) Merino P.; Tejero, T.
Angew. Chem., Int. Ed. 2004, 43, 2995-2997. (g) Hayashi, Y.; Yamaguchi,
J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293-8296. (h)
Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem.
2004, 69, 5966-5973. (i) Co´rdova, A.; Sunde´n, H.; Bøgevig, A.; Johansson,
M.; Himo, F. Chem. Eur. J. 2004, 10, 3673-3684. (j) Yamamoto, Y.;
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962-5963.
(k) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed.
2004, 43, 3317-3321. (l) Wang, W.; Wang, J.; Hao, Li., Liao, L.
Tetrahedron Lett. 2004, 45, 7235-7238. (m) Hayashi, Y.; Yamaguchi, J.;
Hibino, K.; Sumiya, T.; Urushima, T.; Shoji, M.; Hashizume, D.; Koshino,
H. AdV. Synth. Catal. 2004, 346, 1435. (n) Cheong, P. H. Y.; Houk, K. N.
J. Am. Chem. Soc. 2004, 126, 13912-13913.
The proposed mechanism for stereospecific synthesis of
chiral alcohol 5a through reaction of prochiral spirotrione
1a and nitrosobenzene 2 is illustrated in Scheme 2. Chiral
L-pyrrolidine-tetrazole 3a or L-proline 4 catalyze the dia-
stereospecific in situ generation of enamine 9 from spirot-
rione 1a. Subsequent (Re-face)4n nucleophilic addition to
nitrosobenzene 2 furnishes the R-aminoxy ketone 6a, which
immediately undergoes addition to excess nitrosobenzene 2
followed by rearrangement of intermediate 12 into R-hydroxy
(5) All prochiral spirotriones 1 were prepared using the newly developed
“organo-click chemistry” technique; see: Ramachary, D. B.; Barbas, C.
F., III. Chem. Eur. J. 2004, 10, 5323-5331.
(6) The 3b/trifluoroacetic acid (TFA) catalyst system was shown to be
highly effective in the asymmetric aldol and Michael reactions. Due to the
insolubility of salt 3b/TFA in other solvents, we used only DMSO as a
solvent in our tandem ADS/O-N bond heterolysis studies. For details of
catalyst 3b/TFA in asymmetric catalysis, see: (a) Mase, N.; Thayumanavan,
R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527-2530. (b) Mase,
N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem., Int. Ed. 2004, 43, 2420-
2423. (c) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369-
4372. (d) Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.; Barbas,
C. F., III. J. Org. Chem. 2004, 69, 5838-5849. (e) Nakadai, M.; Saito, S.;
Yamamoto, H. Tetrahedron 2002, 58, 8167-8177. (f) Sakthivel, K.; Notz,
W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260-5267.
(g) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III.
Tetrahedron Lett. 2001, 42, 199-201.
(7) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558-560.
(b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983-1986. (c) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84-96. (d) Hartikka, A.; Arvidsson, P. Tetrahedron: Asymmetry 2004, 15,
1831-1834. (e) Cobb, A. J. A.; Longbottom, D. A.; Shaw, D. M.; Ley, S.
V. Chem. Commun. 2004, 16, 1808-1809. (f) Thayumanavan, R.; Tanaka,
F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541-3544. (g) For application
in total synthesis of BIRT-377, see: Chowdari, N. S.; Barbas, C. F., III.
Org. Lett. 2005, 7, 867-870.
(8) Relative stereochemistry of product 5a was established by NMR
analysis of the 3,5-dinitrobenzoate derivative of 5a (eq S1, see Supporting
Information).
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Org. Lett., Vol. 7, No. 8, 2005