Angewandte
Chemie
lectivity for such a conjugate addition, which involves a
sterically highly hindered Michael donor and a sterically
hindered and electronically relatively weak Michael acceptor,
has proven to be a significant challenge. In spite of its
synthetic potential for the direct enantioselective creation of
adjacent all-carbon quaternary and tertiary stereocenters, to
our knowledge there were only three examples of conjugate
additions of trisubstituted carbon nucleophiles to b-substi-
tuted enones in synthetically useful stereoselectivity. All three
tions for a wide range of a-substituted b-ketoesters as well as
an unprecedented wide range of enones, the current reaction
represents an advance of both conceptual and synthetic
significance for the development of catalytic asymmetric
conjugate additions. Investigations are currently under way to
fully define the scope and understand the mechanism of the
reaction.
literature examples, reported by Sodeoka[5] and Jacobsen,[7] Experimental Section
Preparative-scale synthesis of tert-butyl 1-oxo-2-(3-oxobutyl)-2-
used a trans-acyclic enone as the Michael acceptor and were
promoted by chiral metal complexes.
indancarboxylate 4Ba: a,b-Unsaturated ketone 3a (1.02 mL,
12.5 mmol) was added dropwise to a solution of QD-1c (24.0 mg,
0.05 mmol) and b-ketoester 2B (1.16 g, 5.0 mmol) in CH2Cl2
(10.0 mL) at room temperature. The resulting clear solution was
Table 3 summarizes the results obtained for the conjugate
addition of ketoesters 2 to b-substituted enones 5a–c
catalyzed by cinchona alkaloids 1b and 1c. High enantiose-
lectivity and diastereoselectivity as well as excellent yields
could be attained for conjugate additions with both five- and
six-membered cyclic enones (Table 3, entries 1–3). To the best
stirred at roomtemperature for 3 h, when
consumed as indicated by TLC analysis. The reaction mixture was
concentrated under vacuumand subjected to chromatography (SiO
2B was completely
,
2
hexanes/EtOAc 10:1) to give the desired 1,4-adduct 4Ba as a colorless
oil (1.51 g, > 99% yield, 97% ee). The enantiomeric
excess was determined by HPLC (Daicel Chiralcel OJ,
Table 3: Construction of adjacent quaternary–tertiary stereocenters by enantiose-
lective and diastereoselective conjugate addition of b-ketoester to b-substituted
a,b-unsaturated ketones.[a]
hexanes/isopropyl alcohol (90:10), 1.00 mLminÀ1, l =
220 nm, tr (major) = 27.9 min, tr (minor) = 33.8 min).
1H NMR (400 MHz, CDCl3): d = 7.76 (d, J = 8.0 Hz,
1H), 7.62 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.47 (d, J =
8.0 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 3.61 (d, J =
17.2 Hz, 1H), 3.01 (d, J = 17.2 Hz, 1H), 2.68–2.47 (m,
2H), 2.21–2.16 (m, 2H), 2.13 (s, 3H), 1.39 ppm (s, 9H);
13C NMR (100 MHz, CDCl3): d = 207.6, 202.7, 170.1,
152.6, 135.2, 127.7, 126.3, 124.6, 81.9, 59.8, 38.8, 37.9,
29.8, 28.3, 27.2 ppm; IR (CHCl3): n˜ = 2978, 2932, 1733,
1715, 1607, 1368, 1153 cmÀ1
.
After the 1,4-adduct was collected, the column was
washed with methanol to allow the recovery of QD-1c
in NMR spectroscopically pure form(23 mg, 96%).
Entry Ketoester Enone Catalyst (mol%) t [h] Yield [%][b] d.r.[c] ee [%][d]
1[e]
2
2B
2F
2B
2F
5a
5a
5b
5c
QD-1b (10)
Q-1c (20)
QD-1b (20)
Q-1c (20)
12 99
95
96:4[f] 98
93:7 95
2
3[g]
4
120 87
20 83
93:7 85
Received: July 28, 2005
Published online: December 30, 2005
86:14 99 (94[h])
[a] Unless otherwise specified, the reaction was performed by treatment of 2
(0.3 mmol) with 5 (0.75 mmol, 2.5 equiv) and catalyst (20 mol%) in CH2Cl2
(0.3 mL). [b] Yield of isolated product. [c] Unless otherwise specified, d.r. values
were determined by HPLC. [d] For the major diastereomer of 6. [e] The reaction
was performed with 2B (0.3 mmol) and 5a (0.7 mmol, 2.5 equiv). [f] Determined
Keywords: alkaloids · conjugate addition ·
diastereoselectivity · enantioselectivity · enones
.
1
by H NMR analysis of crude products. [g] The reaction was performed with 2B
(0.3 mmol) and 5b (0.7 mmol, 2.5 equiv). [h] For the minor diastereomer of 6.
[1] For reviews covering catalytic enantioselective
conjugate additions of b-ketoesters to enones,
see: a) M. Yamaguchi in Comprehensive Asym-
metric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H.
of our knowledge, these represent the first examples of a
highly enantioselective and diastereoselective catalytic con-
jugate addition of a trisubstituted carbon nucleophile to a
cyclic enone. Remarkably, excellent enantioselectivity and
useful diastereoselectivity could also be attained with the
trans-acyclic enone 5c. Relative to the conjugate additions
with vinyl ketones 3, these reactions require a longer reaction
time and higher catalyst loading (Table 3, entry 4). Impor-
tantly, the reaction can be conveniently performed at room
temperature and the catalysts are easily recyclable in greater
than 95% yield.[13]
In conclusion, we have demonstrated the feasibility of
using a chiral organic catalyst to mediate a highly efficient and
general conjugate addition of a-substituted b-ketoesters to
a,b-unsaturated ketones. By giving high stereoselectivity with
easily accessible catalysts under operationally simple condi-
Yamamoto), Springer, Heidelberg, 2003, Suppl. 1 to Chap. 31.2,
p. 151; b) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102,
2187 – 2209; c) N. Krause, A. Hoffmann-Röder, Synthesis 2001,
171 – 196; d) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033 –
8061; for reviews on an enantioselective construction of all-
carbon quaternary stereocenters, see: e) C. J. Douglas, L. E.
Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363 – 5367; f) J.
Christoffers, A. Baro, Angew. Chem. 2003, 115, 1726 – 1728;
Angew. Chem. Int. Ed. 2003, 42, 1688 – 1690; g) J. Christoffers,
Chem. Eur. J. 2003, 9, 4862 – 4867; h) J. Christoffers, A. Mann,
Angew. Chem. 2001, 113, 4725 – 4732; Angew. Chem. Int. Ed.
2001, 40, 4591 – 4597; i) E. J. Corey, A. Guzman-Perez, Angew.
Chem. 1998, 110, 402 – 415; Angew. Chem. Int. Ed. 1998, 37, 388 –
401.
[2] H. Wynberg, R. Helder, Tetrahedron Lett. 1975, 4057 – 4060.
[3] For an example of enantioselective conjugate addition of a-
methyl a-cyanoacetate to vinyl ketones or acrolein, see: M.
Angew. Chem. Int. Ed. 2006, 45, 947 –950
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