anhydride in THF at 23 °C for 1 h furnished the synthetic
(2)-tetrahydrolipstatin 1 [[a]2D3 233.8, (c 1.4, CHCl3); lit.,1
[a]2D3 234.45, (c 1, CHCl3)]. Spectral data (IR and 400 MHz 1H
NMR) for the synthetic tetrahydrolipstatin are identical to those
reported for the natural product.1
In summary, an asymmetric synthesis of (2)-tetrahydrolip-
statin has been accomplished. A number of key features of this
synthesis are noteworthy; a Keck enantioselective allylation of
dodecanal, olefin metathesis of an acrylate ester to an
unsaturated d-lactone, elaboration of this lactone to a syn-
1,3-diol synthon and Seebach’s asymmetric alkylation of a b-
hydroxy ester.
Financial support for this work was provided by the National
Institutes of Health (GM 55600).
Notes and references
1 E. K. Weibel, P. Hadvary, E. Hochuli, E. Kupfer and H. Lengsfeld,
J. Antibiot., 1987, 40, 1081; P. Hadvary, H. Lengsfeld and H. Wolfer,
Biochem. J., 1988, 256, 357.
2 S. Hogan, A. Fleury, P. Hadvary, H. Lengsfeld, M. K. Meier, J. Triscari
and A. C. Sullivan, Int. J. Obes., 1987, 11, 35 (suppl. 3).
3 P. Hadvary, W. Sidler, W. Meister, W. Vetter and H. Wolfer, J. Biol.
Chem., 1991, 266, 2021.
4 M. L. Drent and E. A. van der Veen, Obes. Res., 1995, 3 (suppl. 4),
623S.
Scheme 3 Reagents and conditions: i, Et3N, MeOH, 23 °C, 12 h (75%); ii,
DHP, PPTS, 8 h; iii, Bu4NF, THF, AcOH, 25 °C, 5 h (60% from 7); iv,
LDA, HMPA, C6H13I, THF, 278 to 0 °C, 6 h (70% conversion, 85%); v, aq.
LiOH, 25 °C, 12 h, H+; vi, PhSO2Cl, Py, 0 °C, 8 h (84% from 11); vii, PPTS,
EtOH, reflux, 3 h (90%); viii, Cbz-Leu, DCC, DMAP (95%); ix, H2, Pd-C,
12 h; x, AcOCHO, THF, 25 °C, (87%).
5 (a) I. Paterson and V. A. Doughty, Tetrahedron Lett., 1999, 40, 393; (b)
I. Fleming and N. J. Lawrence, J. Chem. Soc., Perkin Trans. 1,, 1998,
2679; (c) B. Giese and M. J. Roth, J. Braz. Chem. Soc., 1996, 7, 243; (d)
A. Pommier, J. M. Pons, P. J. Kocienski and L. Wong, Synthesis, 1994,
1294; (e) S. Hanessian, A. Tehim and P. Chen, J. Org. Chem., 1993, 58,
7768; (f) S. C. Case-Green, S. G. Davies and C. J. R. Hedgecock,
Synlett, 1991, 781; (g) N. K. Chadha, A. D. Batcho, P. C. Tang, L. F.
Courtney, C. M. Cook, P. M. Wovkulich and M. R. Uskokovic, J. Org.
Chem., 1991, 56, 4714; (h) I. Fleming and N. J. Lawrence, Tetrahedron
Lett., 1990, 31, 3645; (i) J. Pons and P. J. Kocienski, Tetrahedron Lett.,
1989, 30, 1833; (j) P. Barbier and F. Schneider, J. Org. Chem., 1988, 53,
1218; (k) P. Barbier and F. Schneider, Helv. Chim. Acta, 1987, 70, 196;
(l) P. Barbier, F. Schneider and U. Widmer, Helv. Chim. Acta, 1987, 70,
1412.
6 (a) K. C. Nicolaou, R. M. Rodriguez, H. J. Mitchell and F. L. van Delft,
Angew. Chem., Int. Ed., 1998, 37, 1874; (b) A. K. Ghosh, J. Cappiello
and D. Shin, Tetrahedron Lett., 1998, 39, 4651; (c) J. Cossy, D. Bauer
and V. Bellosta, Tetrahedron Lett., 1999, 40, 4187 and references cited
therein.
7 For recent reviews, see: D. L. Wright, Curr. Org. Chem., 1999, 3, 211;
R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413; S. K.
Amstrong, J. Chem. Soc., Perkin Trans. 1, 1998, 371; (d) M. Schuster
and S. Blechert, Angew. Chem., Int. Ed. Engl., 1997, 36, 2037 and
references cited therein.
23 °C for 12 h. Lactone 8 was converted to b-hydroxy ester 10
in a three step sequence involving (i) opening of the lactone ring
by exposure to Et3N in MeOH at 23 °C for 12 h, (ii) protection
of the resulting d-hydroxy methyl ester as THP ether, and (iii)
removal of the TBDMS group by treatment with Bu4NF in THF
in the presence of AcOH at 23 °C for 5 h (60% from 7). The C(2)
hexyl side chain was then introduced by an asymmetric
alkylation of the b-hydroxy ester 10 (Scheme 3). Thus, methyl
ester 10 was treated with LDA (2.2 equiv.) in the presence of
HMPA (5 equiv.) in THF at 278 °C and the reaction mixture
was warmed to 250 °C for 2 h. The resulting dianion was
cooled to 278 °C and reacted with hexyl iodide (2 equiv.) at
278 to 0 °C for 6 h to afford the alkylated product 11 in 85%
yield (based upon 30% recovery of starting material). The
removal of the THP ether group in 11 revealed excellent
diastereoselectivity (ratio 22+1 by 13C NMR).13 The ster-
eochemical course of such alkylation processes has been well-
established previously.12
8 G. E. Keck, K. H. Tarbet and L. S. Geraci, J. Am. Chem. Soc., 1993, 115,
8467; G. E. Keck and D. Krishnamurthy, Org. Synth., 1997, 75, 12.
9 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543.
Saponification of ester 11 with aqueous LiOH followed by
exposure of the resulting acid to PhSO2Cl in pyridine at 0 °C for
8 h, as described by Barbier and Schneider, afforded the b-
lactone 12 in 84% yield (from 11).5k The removal of the THP
group by treatment with PPTS in EtOH at reflux furnished the
(5S)-hydroxy b-lactone 13 [[a]2D3 214.4 (c 1.2, CHCl3)] as a
single isomer. Attempted esterification with N-formylleucine
under a variety of conditions failed to provide satisfactory
results. To complete the synthesis, N-formylleucine was
introduced by an alternate protocol as described by Uskokovic
et al.5g Esterification of 13 with Cbz-leu and DCC in the
presence of DMAP provided the Cbz derivative 14 in 95%
yield.14 Catalytic hydrogenation of 14 over 10% Pd-C followed
by N-formylation of the resulting amine with formic acetic
10 S. Takano, Y. Shimazaki, Y. Sekiguchi and K. Ogasawara, Synthesis,
1989, 539.
11 M. Miyashita, T. Suzuki and A. Yoshikoshi, Tetrahedron Lett., 1987,
28, 4293; M. Miyashita, M. Hoshino, T. Suzuki and A. Yoshikoshi,
Chem. Lett., 1988, 507.
12 D. Seebach, J. Aebi and D. Wasmuth, Org. Synth., 1985, 63, 109.
13 Alkylation of the corresponding b-hydroxy ester containing an anti-d-
benzyloxy group proceeded with excellent diastereoselectivity (40+1).
[ref. 5(e)]. Thus, the stereochemistry of the remote alkoxy group has
little influence on the stereochemical outcome of this alkylation
process.
14 All new compounds gave satisfactory spectroscopic and analytical
results.
Communication 9/04533C
1744
Chem. Commun., 1999, 1743–1744