An enantioselective formal synthesis of (+)-(R)-α-lipoic acid by an L-proline-catalyzed aldol reaction

Article abstract of DOI:10.1055/s-2008-1032022

An efficient, highly stereocontrolled formal synthesis of (+)-(R)-α-lipoic acid was achieved, which utilizes an L-proline-catalyzed highly enantio- and diastereoselective cross-aldol reaction as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032022

PAPER
383
An Enantioselective Formal Synthesis of (+)-(R)-a-Lipoic Acid by an
L-Proline-Catalyzed Aldol Reaction
E
nantioselectiv
h
e
Formal
S
y
i
nthesis
l
of (+)
e
-(
R
)-
a
-Lipo
i
ic
A
cid Zhang,a Xiaobei Chen,b Jiangang Zhang,b Wei Wang,*a,c Wenhu Duan*a,b
a
b
c
Department of Medicinal Chemistry, School of Pharmacy, East China University of Science & Technology,
Shanghai 200237, P. R. of China
Shanghai Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences,
Graduate School of the Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131-0001, USA
Fax +1(505)2772609; E-mail: wwang@unm.edu
Received 12 September 2007; revised 7 November 2007
In recent years, small-organic-molecule-based organoca-
talysis has received considerable interest as a result of the
operational simplicity and environmental friendliness of
the technology.9–12 Organocatalyzed asymmetric process-
es are particularly attractive for the synthesis of biologi-
cally interesting chiral molecules and clinically useful
pharmaceuticals since they eliminate the use of toxic tran-
sition metals. Recently, we have successfully developed a
novel approach to the efficient total synthesis of the potent
histone deacetylases (HDACs) inhibitor, natural product
(+)-trichostatin A by employing an L-proline-catalyzed
cross-aldol reaction as the key step.12a In our continuing
effort to explore powerful asymmetric aldol reactions for
the synthesis of biologically significant molecules, herein
we described a strategy, as outlined in Scheme 1, for the
formal total synthesis of (+)-(R)-a-lipoic acid (1) from
readily available starting materials.
Abstract: An efficient, highly stereocontrolled formal synthesis of
(+)-(R)-a-lipoic acid was achieved, which utilizes an L-proline-cat-
alyzed highly enantio- and diastereoselective cross-aldol reaction as
the key step.
Key words: aldehyde, aldol reaction, ketone, lipoic acid, proline
The significance of (+)-(R)-a-lipoic acid is manifested by
its broad spectrum of biological activity (Figure 1). It is an
important growth factor, acting as a coenzyme in many bi-
ological processes found in animal tissues, plants, and
microorganisms.1 In addition, it serves as an effective
scavenger for reactive oxygen species (ROS),2 which
have been implicated in a number of pathological condi-
tions such as carcinogenesis, inflammation, ischemia-rep-
erfusion injury, and aging. Despite the fact that lipoic acid
is often used in its racemic form since the S-enantiomer
shows tolerable side effects, it has been reported that nat-
urally occurring (+)-(R)-a-lipoic acid (1) and its deriva-
tives possess more potent anti-HIV3 and antitumor4
activities than its S-counterpart and analogues. Accord-
ingly, the development of enantioselective methods for
the preparation of enantiomerically pure lipoic acid is of
particular interest from the standpoint of medicinal and
organic chemistry.5–8 Examination of the reported asym-
metric synthetic methods reveals that, generally, they rely
on using chiral auxiliaries or precursors,6 and enzymatic
reactions or kinetic resolutions;7 asymmetric synthesis
catalyzed by organometallic reagents also has been de-
scribed.8 In this communication, we wish to report the
first organocatalytic enantioselective approach to the for-
mal synthesis of (+)-(R)-a-lipoic acid by using an L-pro-
line-catalyzed cross-aldol reaction as the key step.
O
COOH
ref. 7e
O
1
S
S
OH
2
deoxygenation
O
OH
O
O
Baeyer–Villiger
oxidation
2
OBn
OH
1
3
OBn
4
3
aldol reaction
O
O
+
OBn
H
5
6
COOH
Scheme 1 Retrosynthetic analysis of (+)-(R)-a-lipoic acid (1)
S
S
Figure 1 (+)-(R)-a-Lipoic acid (1)
We envisioned that the target molecule 1 could be attained
from precursor lactone 2 since its racemic form has been
synthesized by Segre and co-workers (Scheme 1).5a This
disconnection raised a synthetic challenge related to the
installation of the stereogenic center in the lactone. We
were intrigued by the possibility offered by L-proline-pro-
moted cross-aldol reaction between ketone 5 and alde-
SYNTHESIS 2008, No. 3, pp 0383–0386
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032022; Art ID: M06507SS
x
x
.
x
x
.2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

384
S. Zhang et al.
PAPER
O
OH
hyde 6 to form chiral aldol adduct 4. Regioselective
Baeyer–Villiger oxidation of ketone 4 would give rise to
lactone intermediate 3, which could be reduced to 2.5a As
demonstrated, the tactics enabled us to synthesize effi-
ciently the chiral compound 2 in five steps from readily
available achiral compounds.
O
O
OBn
OBn
L-proline
(20 mol%)
OBn
+
H
+
r.t., solvent
OBn
CHO
5
4
7
6
Solvent
Yield of 4 (%)
Yield of 7 (%)
The synthesis started with commercially available com-
pounds cyclohexanone (5) and (benzyloxy)acetaldehyde
(6) (Scheme 2). Despite the fact that numerous organocat-
alyzed asymmetric aldol reactions have been devel-
oped,10–12 organocatalytic cross-aldol reactions between
cyclohexanone (5) and aldehyde 6 created a significant
challenge since the highly active aldehyde 6 readily un-
dergoes self-aldol reaction to give the product 7. As
shown in Scheme 2, under the same reaction conditions
that we used previously in N,N-dimethylformamide,12a the
desired compound 4 was obtained as the major product,
but in low yield (26%) together with a significant amount
of 7 (7%). After considerable experimentation, we were
delighted to find that the use of cyclohexanone (5) as a re-
action medium led to a dramatic improvement in the yield
of the cross-aldol reaction 4 (65%) and, at the same time,
the formation of side product 7 was minimized. Notably,
an excellent level of enantio- (>95% ee) and diastereose-
lectivity (29:1 dr) was observed based on chiral HPLC
and 1H NMR analysis.
DMF
26
65
7
–
5
Scheme 2 Optimization of L-proline-catalyzed cross-aldol reac-
tions: synthesis of b-hydroxy ketone 4
methanol to afford compound 2 by reaction of 8 under a
hydrogen atmosphere in the presence of W2 Raney nickel
for 24 hours.8f It was interesting to find that the reaction
solvent played a significant role in the conversion. When
the hydrogenation reaction was carried out in ethanol in-
stead of methanol, the reaction was not clean. Finally, the
treatment of 2 in sodium methoxide in methanol afforded
known chiral compound 9 in 91% yield. The analytical
data of the synthesized substance 9 is identical with those
reported,7g thus confirming the absolute S-configuration.
Following known synthetic sequences, compound 2 could
be converted into the target (+)-(R)-a-lipoic acid (1).7e
In conclusion, we have developed an approach to the effi-
cient synthesis of key intermediate 9, which can led to the
preparation of (+)-(R)-a-lipoic acid, in six steps from
readily available achiral starting materials. In the synthe-
sis, an L-proline-catalyzed highly enantio- and stereose-
lective cross-aldol reaction serves as the key step for the
construction of the stereogenic centers. The general strat-
egy can be explored for the synthesis of S-enantiomer of
lipoic acid and its analogues.
With compound 4 in hand, we completed the synthesis of
key intermediate 2 in four steps in a straightforward man-
ner (Scheme 3). b-Hydroxy ketone 4 was regioselectively
transformed exclusively into lactone 3 through a Baeyer–
Villiger oxidation with 3-chloroperoxybenzoic acid in
86% yield.13 Treatment of 3 with iodine/triphenylphos-
phine/imidazole furnished iodide 8.14 Deiodination and
debenzylation were achieved in a one-pot reaction in
O
O
OH
O
OH
MCPBA, NaHCO3
CH2Cl2, r.t.
OBn
OBn
86%
4
3
O
I2/Ph3P/imidazole,
toluene, reflux
H2 (1 atm), W2 Raney Ni
MeOH, r.t.
O
I
93%
79%
OBn
MeO
8
O
O
MeONa, MeOH
r.t.
O
91%
OH
OH
OH
2
9
following known
synthetic sequences
ref. 7e
COOH
1
S
S
Scheme 3 Synthesis of key intermediate lactone 2
Synthesis 2008, No. 3, 383–386 © Thieme Stuttgart · New York

PAPER
Enantioselective Formal Synthesis of (+)-(R)-a-Lipoic Acid
(S)-7-(2-Hydroxyethyl)oxepan-2-one (2)
385
Commercial reagents were used as received unless otherwise stated.
1H and 13C NMR spectra were recorded on 400 and 100 MHz NMR,
respectively, with TMS as reference.
To a soln of 8 (94 mg, 0.25 mmol) in MeOH (4 mL) was added W2
Raney Ni (0.3 g). The resulting mixture was then stirred under an
H2 atmosphere for 8 h. The mixture was filtered and washed with
MeOH. The solvent was removed under reduced pressure to give
the crude product, which was purified by flash chromatography (sil-
ica gel, petroleum ether–EtOAc, 1:1) to afford 2 (31 mg, 79%) as a
colorless oil.
(S)-2-[(R)-2-(Benzyloxy)-1-hydroxyethyl]cyclohexanone (4)
To a soln of 6 (500 mg, 3.3 mmol) in cyclohexanone (10 mL) was
added L-proline (80 mg, 0.70 mmol) and the mixture was stirred at
r.t. for 16 h. Cyclohexanone was removed under reduced pressure
at 60 °C. Flash chromatography of the residue (silica gel, petroleum
ether–EtOAc, 5:1) afforded 4 (540 mg, 65%) as a colorless oil; dr
29:1 (1H NMR); 97% ee [HPLC (Chiralcel OD-H, i-PrOH–hexane,
10:90, flow rate 1.0 mL/min, l = 220 nm): tR = 11.30 (major), 13.10
min (minor)].
[a]D23 +61.1 (c 1.28, CHCl3).
IR (KBr): 3417, 2933, 2864, 1722, 1444, 1348, 1329, 1286, 1257,
1178, 1146, 1053, 1016, 852, 694, 563 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.52 (m, 1 H), 3.81 (m, 2 H), 3.60
(s, 1 H), 2.67 (m, 2 H), 1.95 (m, 4 H), 1.82 (m, 1 H), 1.64 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 176.2, 77.0, 58.3, 38.8, 34.8,
34.6, 28.1, 22.8.
HRMS (ESI): m/z [M + Na]+ calcd for C8H14NaO3: 181.0841;
found: 181.0838.
[a]D23 –5.5 (c 0.95, CHCl3).
IR (KBr): 3460, 3030 2935, 2864, 1705, 1497, 1452, 1365, 1311,
1101, 1028, 739, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.27 (m, 5 H), 4.63–4.49 (m,
2 H), 3.93 (m, 1 H), 3.63–3.48 (m, 3 H), 2.70 (m, 1 H), 2.42–2.23
(m, 2 H), 2.09–2.00 (m, 2 H), 1.86 (m, 1 H), 1.75–1.59 (m, 2 H),
1.52–1.39 (m, 1 H).
Methyl (S)-6,8-Dihydroxyoctanoate (9)
To a soln of 2 (10 mg, 0.063 mmol) in MeOH (0.5 mL) was added
MeONa in MeOH [3 drops; Na (0.3 g) dissolved in MeOH (5 mL)]
and the mixture was stirred at r.t. for 0.5 h. The resulting mixture
was quenched with H2O and extracted with EtOAc. The organic
layer was then dried (Na2SO4), filtered, and concentrated under re-
duced pressure. Flash chromatography of the residue (silica gel,
EtOAc) afforded 9 (11 mg, 91%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 215.0, 138.0, 128.2, 127.6, 127.5,
73.3, 71.1, 70.8, 52.4, 42.5, 30.1, 27.6, 24.6.
HRMS (EI): m/z [M]+ calcd for C15H20O3: 248.1412; found:
248.1408.
(S)-7-[(S)-2-(Benzyloxy)-1-hydroxyethyl]oxepan-2-one (3)
To a soln of 4 (990 mg, 4.0 mmol) in CH2Cl2 (10 mL) was added
NaHCO3 (1.01 g, 12 mmol) and MCPBA (85%, 1.63 g, 8.0 mmol)
and the mixture was stirred at r.t. for 5 h. The mixture was then fil-
tered, and the filtrate was washed sequentially with sat. aq NaHSO3,
H2O, and brine. The organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. Flash chromatography of the
residue (silica gel, petroleum ether–EtOAc, 5:1 to 1:1) afforded 3
(910 mg, 86%) as a colorless oil.
[a]D23 –3.7 (c 0.65, CHCl3) [Lit.7g [a]D25 –3.8 (CHCl3)].
IR (KBr): 3363, 2943, 1736, 1442, 1412, 1379, 1225, 1173, 1055,
1020, 989, 953, 868, 663 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.93–3.78 (m, 3 H), 3.67 (s, 3 H),
2.81–2.69 (br, 2 H), 2.34 (t, J = 7.4 Hz, 2 H), 1.73–1.60 (m, 4 H),
1.56–1.30 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 174.3, 71.5, 61.4, 51.5, 38.1,
37.2, 33.9, 24.9, 24.7.
[a]D21 +23.8 (c 2.04, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H18NaO4: 213.1103;
found: 213.1093.
IR (KBr): 3439, 2933, 2864, 1713, 1452, 1348, 1329, 1277, 1257,
1180, 1095, 1059, 1016, 741, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.28 (m, 5 H), 4.54 (m, 2 H),
4.39 (m, 1 H), 3.83 (m, 1 H), 3.59 (m, 2 H), 2.63 (m, 2 H), 2.05–1.85
(m, 3 H) 1.73–1.48 (m, 3 H).
Acknowledgment
13C NMR (100 MHz, CDCl3): d = 175.0, 137.7, 128.4, 127.8, 127.7,
This work was supported by Shanghai Basic Research Project from
the Shanghai Science and Technology Commission (Grants
06JC14080) and start-up funding from School of Pharmacy, East
China University of Science & Technology.
79.9, 73.4, 72.5, 70.1, 34.6, 30.3, 27.9, 22.8.
HRMS (EI): m/z [M]+ calcd for C15H20O4: 264.1362; found:
264.1373.
(S)-7-(1-Hydroxy-2-iodoethyl)oxepan-2-one (8)
References
To a soln of 3 (128 mg, 0.485 mmol) in toluene (8 mL) was added
imidazole (133 mg, 1.96 mmol), Ph3P (390 mg, 1.49 mmol), and I2
(250 mg, 0.98 mmol) and the mixture was stirred at reflux for 5 h.
The resulting mixture was concentrated under reduced pressure.
Flash chromatography of the residue (silica gel, petroleum ether–
EtOAc, 10:1 to 5:1) afforded 8 (170 mg, 93%) as a colorless oil.
(1) (a) Sigel, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 389.
(b) Yadav, J. S.; Mysorekar, S. V.; Garyali, K. J. Sci. Ind.
Res. 1990, 49, 400; and references cited therein.
(2) Packer, L.; Tritschler, H. J.; Wessel, K. Free Rad. Biol. Med.
1997, 22, 359.
(3) Baur, A.; Harrer, T.; Peukert, M.; Jahn, G.; Kalden, J. R.;
Fleckenstein, B. Klin. Wochenschr. 1991, 69, 722; Chem.
Abstr. 1992, 116, 207360.
[a]D21 –5.2 (c 1.77, CHCl3).
IR (KBr): 3030, 2933, 2862, 1738, 1452, 1254, 1178, 1094, 1013,
741, 698 cm–1.
(4) Bingham, P. M.; Zachar, Z. WO 0024734, 2000; Chem.
1H NMR (300 MHz, CDCl3): d = 7.39–7.29 (m, 5 H), 4.56 (m, 2 H),
4.34 (m, 2 H), 3.88 (m, 1 H), 3.73 (m, 1 H), 2.65 (m, 2 H), 2.17 (m,
1 H) 1.97 (m, 2 H), 1.75–1.53 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.0, 137.4, 128.5, 127.9, 127.7,
79.4, 73.0, 71.9, 34.7, 33.5, 33.2, 27.6, 22.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19INaO3: 397.0277;
found: 397.0246.
Abstr. 2000, 132, 3081921.
(5) For examples of racemic syntheses of lipoic acid, see:
(a) Segre, A.; Viterbo, R.; Parisi, G. J. Am. Chem. Soc. 1957,
79, 3503. (b) Tsuji, J.; Yasuda, H.; Mandai, T. J. Org. Chem.
1978, 43, 3606. (c) Menon, R. B.; Kumar, M. A.;
Ravindranathan, T. Tetrahedron Lett. 1987, 28, 5313.
(d) Crevisy, C.; Herbage, B.; Marrel, M.-L.; Toupet, L.;
Gree, R. Eur. J. Org. Chem. 1998, 1949. (e) Chavan, S. P.;
Synthesis 2008, No. 3, 383–386 © Thieme Stuttgart · New York

386
S. Zhang et al.
PAPER
2004, 37, 580. (e) Jarvo, E. R.; Miller, S. J. Tetrahedron
Shivsankar, K.; Pasupathy, K. Synthesis 2005, 1297.
(6) For examples of using chiral auxiliaries or precursors for
asymmetric syntheses of lipoic acid, see: (a) Brookes, M.
H.; Golding, B. T.; Howes, D. A.; Hudson, A. T. J. Chem.
Soc., Chem. Commun. 1983, 1051. (b) Elliott, J. D.; Steele,
J.; Johnson, W. S. Tetrahedron Lett. 1985, 26, 2535.
(c) Rama Rao, A. V.; Mysorekar, S. V.; Gurjar, M. K.;
Yadav, J. S. Tetrahedron Lett. 1987, 28, 2183. (d) Brookes,
M. H.; Golding, B. T.; Hudson, A. T. J. Chem. Soc., Perkin
Trans. 1 1988, 9. (e) Silks, L. A. III; Peng, J.; Odom, J. D.;
Dunlap, R. B. J. Chem. Soc., Perkin Trans. 1 1991, 2495.
(7) For examples of enzymatic reactions for asymmetric
syntheses of lipoic acid, see: (a) Brooks, D. W.; Kellogg, R.
P.; Cooper, C. S. J. Org. Chem. 1987, 52, 192. (b)Gopalan,
A. S.; Jacobs, H. K. Tetrahedron Lett. 1989, 30, 5705.
(c) Dasaradhi, L.; Fadnavis, N. W.; Bhalerao, U. T. J. Chem.
Soc., Chem. Commun. 1990, 729. (d) Gopalan, A. S.;
Jacobs, H. K. J. Chem. Soc., Perkin Trans. 1 1990, 1897.
(e) Adger, B.; Bes, M. T.; Grogan, G.; McCague, R.;
Pedragosa-Moreau, S.; Roberts, S. M.; Villa, R.; Wan, P. W.
H.; Willetts, A. J. J. Chem. Soc., Chem. Commun. 1995,
1563. (f) Laxmi, Y. R. S.; Lyengar, D. S. Synthesis 1996,
594. (g) Bezbarua, M. S.; Saikia, A. K.; Barua, N. C.; Kalita,
D.; Ghosh, A. C. Synthesis 1996, 1289. (h) Adger, B.; Bes,
M. T.; Grogan, G.; McCague, R.; Pedragosa-Moreau, S.;
Roberts, S. M.; Villa, R.; Wan, P. W. H.; Willetts, A. J.
Bioorg. Med. Chem. 1997, 5, 253. (i) Fadnavis, N. W.;
Babu, R. L.; Vadivel, S. K.; Deshpande, A. A.; Bhalerao, U.
T. Tetrahedron: Asymmetry 1998, 9, 4109.
(8) For examples of asymmetric syntheses of lipoic acid
catalyzed by organometallic reagents, see: (a) Page, P. C.
B.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc., Chem.
Commun. 1986, 1408. (b) Page, P. C. B.; Rayner, C. M.;
Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1990, 1615.
(c) Zimmer, R.; Hain, U.; Berndt, M.; Gewald, R.; Reissig,
H.-U. Tetrahedron: Asymmetry 2000, 11, 879.
(d) Upadhya, T. T.; Nikalje, M. D.; Sudalai, A. Tetrahedron
Lett. 2001, 42, 4891. (e) Zimmer, R.; Peritz, A.; Czerwonka,
R.; Schefzig, L.; Reissig, H.-U. Eur. J. Org. Chem. 2002,
3419. (f) Chavan, S. P.; Praveen, C.; Ramakrishna, G.;
Kalkote, U. R. Tetrahedron Lett. 2004, 45, 6027. (g) Bose,
D. S.; Fatima, L.; Rajender, S. Synthesis 2006, 1863.
(9) For selected recent reviews of organocatalysis, see:
(a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40,
3726. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138. (c) List, B. Tetrahedron 2002, 58, 5573.
(d) Notz, W.; Tanaka, F.; Barbas, C. F. III Acc. Chem. Res.
2002, 58, 2481. (f) Special issue on Asymmetric
Organocatalysis: Acc. Chem. Res. 2004, 37, 487.
(10) For L-proline-promoted aldol reactions, see: (a) List, B.;
Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122,
2395. (b) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798. (c) Enders, D.; Grondal, C.
Angew. Chem. Int. Ed. 2005, 44, 1210. (d) Casas, J.;
Engqvist, M.; Ibrahem, I.; Kaynak, B.; Córdova, A. Angew.
Chem. Int. Ed. 2005, 44, 1343. (e) Pan, Q.; Zou, B.; Wang,
Y.; Ma, D. Org. Lett. 2004, 6, 1009. (f) Northrup, A. B.;
MacMillan, D. W. C. Science 2004, 305, 1752. (g) Suri, J.
T.; Ramachary, D. B.; Barbas, C. F. III Org. Lett. 2005, 7,
1383.
(11) For selected examples of aldol reactions catalyzed by proline
derivatives, see: (a) Mase, N.; Tanaka, F.; Barbas, C. F. III
Angew. Chem. Int. Ed. 2004, 43, 2420. (b) Sakthivel, K.;
Notz, W.; Bui, T.; Barbas, C. F. III J. Am. Chem. Soc. 2001,
123, 5260. (c) Nakadai, M.; Saito, S.; Yamamoto, H.
Tetrahedron 2002, 58, 8167. (d) Tang, Z.; Jiang, F.; Yu, L.-
T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D.
J. Am. Chem. Soc. 2003, 125, 5262. (e) Mangion, I. K.;
Northrup, A. B.; MacMillan, D. W. C. Angew. Chem. Int.
Ed. 2004, 43, 6722. (f) Krattiger, P.; Kovasy, R.; Revell, J.
D.; Ivan, S.; Wennemers, H. Org. Lett. 2005, 7, 1101.
(g) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
(h) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Ley, S.
V. Org. Biomol. Chem. 2005, 3, 84. (i) Wang, W.; Li, H.;
Wang, J. Tetrahedron Lett. 2005, 46, 5077. (j) Hayashi, Y.;
Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji,
M. Angew. Chem. Int. Ed. 2006, 45, 958. (k) Dziedzic, P.;
Zou, W.; Hafren, J.; Córdova, A. Org. Biomol. Chem. 2006,
4, 38. (l) Chimni, S. S.; Mahajan, D.; Babu, V. V. S.
Tetrahedron Lett. 2005, 46, 5617. (m) Bellis, E.; Vasilatou,
K.; Kokotos, G. Synthesis 2005, 2407. (n) Chen, J.-R.; Lu,
H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org. Lett.
2005, 7, 4543.
(12) (a) Zhang, S.-L.; Duan, W.-H.; Wang, W. Adv. Synth. Catal.
2006, 348, 1228; and other examples using L-proline-
catalyzed aldol reactions in natural product synthesis for
total synthesis. (b) Mangion, I. K.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2005, 127, 3696. (c) Pihko, P. M.; Erkkila,
A. Tetrahedron Lett. 2003, 44, 7607.
(13) Molander, G. A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216.
(14) Akita, H.; Chen, C. Y.; Kato, K. Tetrahedron 1998, 54,
11011.
Synthesis 2008, No. 3, 383–386 © Thieme Stuttgart · New York