J. A. Bodkin et al. / Tetrahedron Letters 44 (2003) 2869–2872
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Kupfer, E.; Maurer, R.; Meister, W.; Mercadal, Y.;
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2. (a) Lookene, A.; Skottova, N.; Olivecrona, G. J.
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Acta 1987, 70, 1412; (b) Barbier, P.; Schneider, F. Helv.
Chim. Acta 1987, 70, 196; (c) Barbier, P.; Schneider, F. J.
Org. Chem. 1988, 53, 1218; (d) Fleming, I.; Lawrence, N.
J. Tetrahedron Lett. 1990, 31, 3645; (e) 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; (f) Hanessian, S.; Tehim, A.; Chen, P. J.
Org. Chem. 1993, 58, 7768; (g) Giese, B.; Roth, M. J.
Braz. Chem. Soc. 1996, 7, 243; (h) Fleming, I.; Lawrence,
N. J. J. Chem. Soc., Perkin Trans. 1 1998, 2679; (i) Dirat,
O.; Kouklovsky, C.; Langlois, Y. Org. Lett. 1999, 1, 753;
(j) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743; (k)
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4. (a) Pons, J.-M.; Kocienski, P. Tetrahedron Lett. 1989, 30,
1833; (b) Pommier, A.; Pons, J.-M.; Kocienski, P. J.;
Wong, L. Synthesis 1994, 1294; (c) Case-Green, S. C.;
Davies, S. G.; Hedgecock, C. J. R. Synlett 1991, 781; (d)
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64, 5301; (e) Parsons, P. J.; Cowell, J. K. Synlett 2000,
107.
Scheme 4. Reagents and conditions: (a) 3 equiv. Br2 in CCl4,
MeOH/NaHCO3, rt, 20 s, quant., 5:1 trans-4:cis-4; (b)
DBPO, Ph2Se2, Bu3SnH, PhMe, 0°C, 2.5 h (63% over two
steps); (c) cbz-Leu, DCC, DMAP, CH2Cl2, DMAP, 1.5 h
(87%); (d) H2, 10% Pd–C, THF, rt, 3 h; (e) AcOCHO, ether,
rt, 20 min (76% over two steps).
The product arising from debromination of the minor
isomer, cis-4, was not observed and this may reflect the
aforementioned instability of the cis-bromolactone or
the greater ring strain associated with the cis isomer
leading to more rapid radical b-scission and destruction
of the lactone ring.
Hydroxylactone 2 was esterified with N-benzyloxycar-
bonyl- -leucine using DCC and DMAP to afford 13
L
{[h]D −23 (c 1.1, CH2Cl2); lit.3e [h]D −23.86 (c 1.06,
CHCl3)} in 87% yield.3e,h Hydrogenolysis of the benzyl-
oxycarbonyl protecting group was effected using 10%
palladium on charcoal3e,h and the crude product was
then treated with formic acetic anhydride3e,h,20 to afford
(−)-tetrahydrolipstatin 1 {[h]D −32 (c 1.8, CHCl3); lit.1b
[h]D −32 (c 1, CHCl3)} in 76% yield over two steps.
Spectral data (IR, 1H and 13C NMR) for synthetic (−)-1
are identical to those reported.3
5. Prepared from dodecanal according to the procedure of:
Takacs, J. M.; Jaber, M. R.; Clement, F.; Walters, C. J.
Org. Chem. 1998, 63, 6757.
6. All reported compounds gave satisfactory 1H, 13C, IR
and MS data.
7. Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;
Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbru¨g-
gen, H. J. Am. Chem. Soc. 1966, 88, 852.
8. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
In summary, (−)-tetrahydrolipstatin 1 was synthesised
in 12 steps and 11.3% overall yield from the unsatu-
rated ester 5. Excellent regioselectivity favouring b-lac-
tones in the bromolactonisation reaction of 3 was
afforded from the electronic bias associated with an
allylic hydroxyl group. The diastereoselectivity of this
reaction under standard conditions unexpectedly
afforded the undesired cis-b-lactone as the major
diastereomer. However, reversing the diastereoselectiv-
ity of this transformation to favour the required trans-
b-lactone (>5:1) could be achieved through the
judicious choice of experimental conditions.
9. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110,
7538.
10. Kang, S.-K.; Park, Y.-W.; Lee, D.-H.; Sim, H.-S.; Jeon,
J.-H. Tetrahedron: Asymmetry 1992, 3, 705.
11. The enantiomeric excess of the related 2-butyl ethyl ester
analogue of 10, prepared from (2E,4E) ethyl hexadeca-
2,4-dienoate by a similar sequence of asymmetric dihy-
droxylation, cyclic sulfite formation and cuprate
substitution, was determined as >90% ee by Mosher’s
ester analysis. In addition the absolute stereochemistry at
C5 was confirmed as (S) by the modified Mosher’s
method: (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kak-
isawa, H. J. Am. Chem. Soc. 1991, 113, 4092; (b) Kusumi,
T.; Hamada, T.; Ishitsuka, M. O.; Ohtani, I.; Kakisawa,
H. J. Org. Chem. 1992, 57, 1033. Additional support for
stereochemistry of 10 follows from its conversion into
(−)-tetrahydrolipstatin.
Acknowledgements
We thank the University of Sydney for financial
support.
12. Humphrey, J. M.; Aggen, J. B.; Chamberlin, A. R. J.
Am. Chem. Soc. 1996, 118, 11759.
13. Barnett, W. E.; McKenna, J. C. Tetrahedron Lett. 1971,
12, 2595.
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