Asymmetric synthesis of (-)-tetrahydrolipstatin: an anti-aldol-based strategy.

Article abstract of DOI:10.1021/ol000070a

A stereoselective synthesis of (-)-tetrahydrolipstatin is described. The synthesis involves an asymmetric ester derived titanium enolate anti-aldol reaction, a nitro-aldol reaction to append the C-2' C(11) side chain, and a diastereoselective reduction of a beta-hydroxy ketone to an anti-1,3-diol functionality followed by its elaboration to (-)-tetrahydrolipstatin.

Full text of DOI:10.1021/ol000070a

ORGANIC
LETTERS
2000
Vol. 2, No. 16
2405-2407
Asymmetric Synthesis of
(−)-Tetrahydrolipstatin: An
anti-Aldol-Based Strategy
Arun K. Ghosh* and Steve Fidanze
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received March 28, 2000
ABSTRACT
A stereoselective synthesis of (−)-tetrahydrolipstatin is described. The synthesis involves an asymmetric ester derived titanium enolate anti-
aldol reaction, a nitro-aldol reaction to append the C-2′ C11 side chain, and a diastereoselective reduction of a â-hydroxy ketone to an anti-
1,3-diol functionality followed by its elaboration to (−)-tetrahydrolipstatin.
Tetrahydrolipstatin (1), a â-lactone, triglyceride mimic, is
the saturated analogue of lipstatin, which was isolated from
Streptomyces toxytricini in 1987.1 It is a potent and irrevers-
ible inhibitor of pancreatic lipase.1b Recently, (-)-tetrahy-
drolipstatin has been marketed in several countries as an
antiobesity agent under the name Xenical. The key to the
biological activity of 1 is the â-lactone moiety, featuring anti-
stereochemistry about the ring. The lactone has been shown
to bind irreversibly to an active site serine of pancreatic
lipase.2 Due to its biological properties, tetrahydrolipstatin
has been the subject of immense synthetic activity since its
isolation.3
selective reduction of a â-hydroxy ketone to an anti-1,3-
diol functionality. As shown in Figure 1, the key structural
As part of our continuing interest in tetrahydrolipstatin,3b
we herein report a novel, diastereoselective synthesis of (-)-
tetrahydrolipstatin. The key steps include an asymmetric ester
derived titanium enolate anti-aldol reaction, a nitro-aldol
reaction to append the C-2′ C11 side chain, and a diastereo-
Figure 1.
(1) (a) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld,
H. J. Antibiot. 1987, 40, 1081. (b) Hochuli, E.; Kupfer, E.; Maurer, R.;
Meister, W.; Mercadel, Y.; Schmidt, K. J. Antibiot. 1987, 40, 1086.
(2) (a) Hadvary, P.; Sidler, W.; Meister, W.; Vetter, W.; Wolfer, H. J.
Biol. Chem. 1991, 266, 2021. (b) Borgstrom, B. Biochem. Biophys. Acta
1988, 962, 308.
element is the sensitive â-lactone, which we envision closing
late in the synthesis. The key intermediate 2 can be prepared
10.1021/ol000070a CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/20/2000

from anti-aldol adduct 3. The anti-selective aldol reaction
of ester 4 and trans-cinnamaldehyde will provide 3. Stereo-
controlled generation of such anti-aldol fragments has been
described by us recently.4
Thus, ester 4 is made from the known N-tosyl-1-amino-
2-indanol4 by coupling with octanoyl chloride in the presence
of pyridine in CH2Cl2 at 23 °C for 2 h in 92% yield after
silica gel chromatography (Scheme 1). The titanium enolate
the eluent), and diastereomerically pure 3 was subsequently
utilized for the synthesis. In a one-pot procedure, when the
above Ti-enolate was cooled to -78 °C and reacted with
excess trans-cinnamaldehyde (4 equiv) in the presence of
additional TiCl4 (2.2 equiv) and N,N′-diisopropylethylamine
(6 equiv), aldol adduct 3 was obtained exclusively in 38%
yield. However, attempts to further improve the yield were
unsuccessful.
Saponification of ester 3 was carried out by exposure to
aqueous lithium hydroperoxide in THF at 23 °C for 40 h
affording the corresponding â-hydroxy acid in 92% yield.
The chiral template 5 was fully recovered. Attempts to
protect the resulting â-hydroxy acid as a tert-butyl-1,3-
dioxan-4-one using pivalaldehyde and a variety of Brønsted
acids (CSA, PPTS, TsOH) in the presence of 4 Å molecular
sieves led only to recovered starting material.
Scheme 1a
Dioxanone 6 was however prepared efficiently utilizing
the protocol described by Crich et al.5 Thus, reaction of the
resulting â-hydroxy acid with pivalaldehyde, isopropoxy-
trimethylsilane, and TMSOTf in the presence of 4 Å
molecular sieves at -78 to -20 °C for 16 h afforded the
1,3-dioxane derivative 6 as an 11:1 mixture of diastereomers
(by 1H and 13C NMR) in 79% yield after silica gel
chromatography. This mixture was directly used for the
subsequent reaction. The relative stereochemistry of 6 was
established by NOESY experiments. As shown in Figure 2,
Figure 2.
a (a) C7H15COCl, pyridine, CH2Cl2, 23 °C, 92%; (b) TiCl4,
iPr2NEt, CH2Cl2, 0 °C to 23 °C, then Bu2BOTf, trans-cinnamal-
dehyde, CH2Cl2, -78 °C, 60%; (c) LiOOH, THF-H2O (3:1), 0
°C to 23 °C, 92%; (d) 4 Å MS, Me3CCHO, TMSOiPr, TMSOTf,
CH2Cl2, -78 °C to -20 °C, 79%; (e) O3, CH2Cl2, -78 °C, then
Ph3P, -78 °C to 23 °C, 84%; (f) nBu4N+F-, C12H25NO2, DMF,
23 °C, 82%; (g) DCC, CuCl, CH3CN, 60 °C, 80%; (h) Zn, AcOH,
THF, 0 °C, 50%; (i) CAN, HNO3, EtOH, -45 °C, 77%; (j) 4 N
HCl, THF, 23 °C, 98%; (k) CsCO3, MeOH-H2O (6:1) then BnI,
DMF, 23 °C, 60%; (l) Me4NB(OAc)3H, AcOH-CN3CN (1:1), -40
°C, 99%; (m) TIPSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 96%.
an NOE was observed between the ring C-6 hydrogen and
the C-5 alkyl chain. Also, NOEs were detected between the
ring C-5 hydrogen and the adjacent vinylic hydrogen and
between the ring C-2 and C-6 hydrogens.
Ozonolysis of 6 in CH2Cl2 at -78 °C followed by
reductive workup with Ph3P yielded the corresponding
(3) (a) Dirat, O.; Kouklovsky, C.; Langlois, Y. Org. Lett. 1999, 1, 753.
(b) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. (c) Paterson, I.;
Doughty, V. A. Tetrahedron Lett. 1999, 40, 393. (d) Fleming, I.; Lawrence,
N. J. J. Chem. Soc., Perkin Trans. 1 1998, 2679. (e) Giese, B.; Roth, M. J.
J. Braz. Chem. Soc. 1996, 7, 243. (f) Pommier, A.; Pons, J.-M.; Kocienski,
P. J.; Wong, L. Synthesis 1994, 1294. (g) Hanessian, S.; Tehim, A.; Chen,
P. J. Org. Chem. 1993, 58, 7768. (h) Case-Green, S. C.; Davies, S. G.;
Hedgecock, C. J. R. Synlett 1991, 781. (i) Chadha, N. K.; Batcho, A. D.;
Tang, P. C.; Courtney, L. F.; Cook, C. M.; Wovkulich, P. M.; Uskokovic,
M. R. J. Org. Chem. 1991, 56, 4714. (j) Fleming, I.; Lawrence, N. J.
Tetrahedron Lett. 1990, 31, 3645. (k) Pons, J.-M.; Kocienski, P. Tetrahedron
Lett. 1989, 30, 1833. (l) Barbier, P.; Schneider, F. J. Org. Chem. 1988, 53,
1218. (m) Barbier, P.; Schneider, F.; Widmer, U. HelV. Chim. Acta 1987,
70, 1412. (n) Barbier, P.; Schneider, F. HelV. Chim. Acta 1987, 70, 196.
(4) (a) Ghosh, A. K.; Fidanze, S. J. Org. Chem. 1998, 63, 6146. (b)
Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahedron Lett.
1997, 38, 7171. (c) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996,
118, 2527.
was formed by treatment of ester 4 with TiCl4 (1.2 equiv)
in CH2Cl2 at 0-23 °C for 15 min followed by addition of
N,N′-diisopropylethylamine (4 equiv) at 23 °C and stirring
of the resulting brown solution for 2 h. The resulting enolate
was cooled to -78 °C, and trans-cinnamaldehyde precom-
plexed with Bu2BOTf (1.5 equiv) was added to provide the
anti-aldol adduct 3 in 60% yield, as a mixture of anti- and
syn-diastereomers (6.1:1).4a The mixture was separated by
silica gel chromatography (20% ethyl acetate in hexanes as
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Org. Lett., Vol. 2, No. 16, 2000

aldehyde. The aldehyde was treated with 1-nitrododecane6
in DMF at 23 °C for 24 h in the presence of a catalytic
amount (10 mol %) of nBu4N+F- to provide the correspond-
ing nitro aldol products 7 as a mixture of diastereomers in
82% isolated yield. The resulting mixture of diastereomers
without further separation was then subjected to Seebach’s
dehydration conditions with DCC and CuCl in acetonitrile
at 60 °C for 18 h.7 The nitroalkene 8 was isolated as a
mixture (E/Z, 1:1.7) of isomers in 80% yield. The nitroalkene
was then reduced to oxime 9 with zinc and acetic acid in
THF at 0 °C for 15 min.8 The resulting oxime 9 was
oxidatively hydrolyzed with ceric ammonium nitrate in the
presence of nitric acid in ethanol at -45 °C to provide ketone
10 as a single isomer.9,10
Scheme 2a
a (a) H2, Pd(OH)2, EtOAc-MeOH (4:1), 23 °C, 99%; (b)
PhSO2Cl, pyridine, 0 °C, 74%; (c) nBu4N+F-, AcOH, THF, 0 °C,
70%; (d) Ph3P, N-formyl-L-leucine, DIAD, THF, 23 °C, 90%.
Attempts to reduce this ketone directly under a variety of
reaction conditions resulted in a mixture of diastereomers
1
with low selectivity (ca. 1.2:1 by H NMR). We have
therefore elected to utilize Evans’ hydroxyl directed stereo-
controlled reduction of â-hydroxy ketones to deliver the C-2′
stereocenter diastereoselectively.11 Thus, dioxanone 10 was
first hydrolyzed using Seebach’s conditions to provide the
free â-hydroxy acid.12 The resulting acid was esterified with
CsCO3 and benzyl iodide to furnish benzyl ester 11 in 59%
yield (two steps). â-Hydroxy ketone 11 was then subjected
to anti-selective reduction using Evans’ protocol.11 Treatment
of 11 with Me4NB(OAc)3H in a mixture (1:1) of MeCN and
AcOH at -40 °C for 24 h provided the anti-1,3-diol 12
diastereoselectively (selectivity 22:1 by 500 MHz 1H NMR
and 13C NMR analysis) in near quantitative yield. The
mixture was used directly for the next reaction. Selective
protection of the more accessible C-5 hydroxyl group was
carried out with TIPSOTf and 2,6-lutidine in CH2Cl2 at -78
°C for 2.5 h to obtain the monoprotected TIPS ether 13 as
a single isomer (by 1H and 13C NMR) in 96% yield.
However, the use of TBSOTf for this protection was much
less selective; the corresponding C-5 and C-3 monoprotected
silyl ethers were formed as a 3:1 mixture.
mixture of ethyl acetate and methanol (4:1) in the presence
of Pearlman’s catalyst provided â-hydroxy acid 14 in 99%
yield. Exposure of the acid to PhSO2Cl in pyridine at 0 °C
for 48 h afforded â-lactone 15 in 74% isolated yield. The
removal of the TIPS protecting group was effected by
treatment of 15 with nBu4N+F- and AcOH in THF at 0 °C
for 4 h to provide the known lactone 16 ([R]23D -42 (c 0.19,
CHCl3); lit.3m [R]20 -41.4 (c 0.5, CHCl3)) in 70% yield.3n
D
To complete the synthesis, lactone 16 was exposed to
known3a Mitsunobu esterification conditions using N-formyl-
L-leucine, Ph3P, and diisopropyl azodicarboxylate to furnish
(-)-tetrahydrolipstatin 1 ([R]23D -33 (c 0.06, CHCl3); lit.3m
[R]20D -33 (c 0.36, CHCl3)) in 90% yield. Spectral data (IR,
1H NMR and 13C NMR) for synthetic (-)-1 are identical to
that reported for the natural product.
In conclusion, a diastereoselective synthesis of (-)-
tetrahydrolipstatin is described. The key steps involve an
asymmetric ester derived titanium enolate anti-aldol reaction,
a nitro aldol reaction, and a diastereoselective reduction of
a â-hydroxy ketone. Three of the four asymmetric centers
(C-3, C-4, and C-2′) of (-)-1 were set by asymmetric
synthesis. The current route is easily amenable to the
synthesis of other stereoisomers and structural variants of
(-)-tetrahydrolipstatin.
Protected ether 13 was converted to tetrahydrolipstatin as
shown in Scheme 2. Catalytic hydrogenation of 13 in a
(5) (a) Crich, D.; Jiao, X.-Y.; Brunko, M. Tetrahedron 1997, 53, 7127.
(b) Kurihara, M.; Miyata, N. Chem. Lett. 1995, 263. (c) Tsunoda, T.; Suzuki,
M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357.
(6) The 1-nitrododecane was conveniently prepared by oxidation of the
corresponding amine with MCPBA in CH2Cl2 at reflux for 1 h (78% yield).
For a similar reaction, see: Gilbert, K. E.; Borden, W. T. J. Org. Chem.
1979, 44, 659.
(7) Knochel, P.; Seebach, D. Synthesis 1982, 1017.
(8) Baer, H. H.; Rank, W. Can. J. Chem. 1972, 50, 1292.
(9) Bird, J. W.; Diaper, D. G. M. Can. J. Chem. 1969, 47, 145.
(10) All new compounds gave satisfactory analytical and spectroscopic
data.
Acknowledgment. Financial support for this work was
provided by the National Institutes of Health (GM 55600).
We thank Mr. Chunfeng Liu for preliminary experimental
assistance and Dr. John Harwood for NMR experiments.
Supporting Information Available: 1H NMR and 13C
NMR spectra for compounds 3-16. This material is available
free of charge via the Internet at http://pubs.acs.org.
(11) (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Org. Chem.
1988, 53, 3560. (b) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986,
27, 5939.
(12) Pietzonka, T.; Seebach, D. Chem. Ber. 1991, 124, 1837.
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