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ratio. To assign the stereochemistry we converted both
isomers to the corresponding acetonides 10a and 10b
in a three-step sequence (Scheme 2).
Reduction with LAH in THF and debenzylation with Li
in NH3 generated the corresponding 1,3-diols which on
treatment with 2,2-DMP in acetone produced aceto-
nides 10a and 10b. 13C NMR analyses of these aceto-
nides clearly revealed the stereochemistry of the
diastereomers.9
The unrequired diastereomer 9a was converted into 9b
under standard Mitsunobu conditions to give 9b in
72% overall yield.10 Reduction of propargyl alcohol 9b
with LAH in THF resulted in trans allyl alcohol 11
which on treatment with NBS and ethyl vinyl ether
yielded bromoacetal 12 as an epimeric mixture at the
newly created acetal centre.11 The key step, stereocon-
trolled radical cyclization, was easily effected by treating
the bromoacetal 12 with a refluxing mixture of
n-Bu3SnH and catalytic AIBN in toluene to produce
the thermodynamically stable isomer 13.12 Cyclic ethyl
acetal 13, when treated with 80% AcOH in H2O resulted
in lactol 14.13 Mesylation of lactol 14 and in situ elimi-
nation was achieved by treatment with mesyl chloride
and TEA in DCM under reflux conditions14 to yield cyc-
lic vinyl ether 15, which on ozonolytic oxidative cleavage
produced aldehyde 16 which was subjected to oxida-
tion,15 without purification, with NaClO2 and 10%
NaOH solution to furnish b-hydroxy acid 17. The b-lac-
tone ring was formed using PhSO2Cl in pyridine,
followed by debenzylation and esterification with (S)-
N-formyl leucine under Mitsunobu conditions8 furnished
(ꢀ)-THL 1 (Scheme 3). The spectroscopic and physical
data of 1 were in good agreement with those reported
in the literature.16
In conclusion, an efficient total synthesis of THL 1, with
high diastereoselectivity has been achieved. We con-
structed the key intermediate 4 in two different ways
showing the flexibility of the route.
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Acknowledgements
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14. Zhang, H. C.; Daves, D. G., Jr. J. Org. Chem. 1993, 58,
2557–2560.
K.V.R. and M.S.R. thank CSIR, New Delhi for the
award of fellowships.
15. Ramesh Babu, B.; Balasubramaniam, K. K. OPPI
BRIEFS 1994, 26, 123–124.
References and notes
16. Selected data for compound 1: A white solid, Rf0.14 (20%
ethyl acetate/hexane); mp 39–41 °C (lit.3a mp 40–42 °C;)
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Widmer, U. Helv. Chim. Acta 1987, 70, 196–202; (c)
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20
20
½aꢁD ꢀ32.6 (c 0.96, CHCl3) (lit.3a½aꢁD ꢀ33 (c 0.65,
CHCl3)). 1H NMR (200 MHz, CDCl3): d 8.22 (s, 1H),
6.02 (d, 1H, J = 8.5 Hz, NH), 5.02 (m, 1H), 4.68 (m, 1H),
4.28 (m, 1H), 3.22 (dt, 1H, J = 7.6, 3.9 Hz), 2.25–2.11 (m,
1H), 2.02 (m, 1H), 1.80–1.15 (m, 33H), 0.95 (d, 6H,
J = 5.2 Hz), 0.87 (distorted t, 6H). 13C NMR (75 MHz,
CDCl3): d 171.9, 170.8, 160.7, 74.8, 72.6, 56.9, 49.7, 41.4,
38.7, 34.0, 31.9, 31.2, 29.6, 29.5, 29.4, 29.3, 29.2, 28.8, 27.7,
26.8, 25.2, 24.9, 22.8, 22.7, 22.5, 21.7, 14.1, 14.0. ESIMS:
m/z 496 [M+H]. IR (KBr): 1835, 1740, 1695 cmꢀ1. HRMS
m/z calcd for C29H54NO5 (M++H)+ 496.4004, found
496.3987.