In order to explore the anticancer activity/selectivity of
Apoptolidin analogues, we report preparation of four
C-19,20 diols to test the possibility of avoiding the undesir-
able trans-acylative ring expansion equilibrium which attends
the natural isomer.5a
The synthesis6 of hemiacetals 5 and 6 begins with 1,2-
addition of the lithium acetylides prepared by the method
of Corey et al.7 on dibromides 28 and 38 to lactone ester
4.8,9 The reaction affords inseparable ∼1:1 anomeric hemi-
acetals 5 and 6 in 75 and 80% yields, with ∼15-20%
unreacted 4 and proton quenched acetylene being recovered
(Scheme 1). Careful control of reaction temperature and
reagent stoichiometry is essential to avoid â-elimination of
the silyloxy group and/or addition to the methyl ester.
Benzene and cyclohexane were good solvents, but hexane
gave a much slower reaction rate, while ethyl acetate and
methanol favored over-reduction. Interestingly, the 1:1
anomeric mixtures of hemiacetals 6 and 7 largely isomerized
to â-anomers (Z)-8 and 9 during the hydrogenation. Protec-
tion of hemiacetal 8 led to methoxyacetal 10 by the action
of PPTS in methanol (Scheme 2).
Scheme 2. Sulfide Oxidation and Semi-hydrogenation
Scheme 1. Addition of Acetylenic Anions to Lactone 4
Seminal contributions of the Donohoe group at Oxford,12
describing the ability of allylic and homoallylic alcohols to
direct osmylation, inspired our extension of this effect to
the chemistry of allylic hemiacetals. Treatment of (Z)-allylic
lactol 8 using the Oxford stoichiometric OsO4/TMEDA/
CH2Cl2 protocol13 at low temperature provided a 9:1 mixture
of diols 11/14 in near quantitative yield. Upjohn dihydroxy-
lation14 using catalytic OsO4 and NMO in aqueous acetone
at room temperature for 12 h produced 95% yield of diols
11/14 in a less selective 3:1 ratio. Attempts to employ the
Sharpless alkaloid catalyzed AD protocol on the hemiacetals
led to no reaction, even after several days at room temper-
ature.15 By way of comparison, methoxyacetal 10 afforded
less than 25% of dihydroxylated methoxyacetals 13/16 with
minimal selectivity under both conditions. The stereochem-
istry of diol 11 was verified by X-ray.8 As anticipated, the
effect of the side chain terminus was minimal, with TBS
ether (Z)-9 showing a 4:1 preference in favor of diol 12 using
the Upjohn method (Table 1). Stereochemistry of this
Numerous efforts10 at semi-hydrogenation of alkyne 5 failed,
presumably due to catalyst poisoning by the phenyl sulfide
moiety. Therefore, 5 was oxidized11 to sulfone 7, which is
easily reduced to allylic hemiacetal (Z)-8 in 85% yield under
a hydrogen balloon using catalytic Pd-BaSO4 and quinoline.
(3) (a) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.;
Weyershausen, B.; Mitchelle, H. J.; Wei, H.; Guntupalli, P.; Hepworth,
D.; Sugita, K. J. Am. Chem. Soc. 2003, 125, 15433. (b) Nicolaou, K. C.;
Li, Y.; Sugita, K.; Monenschein, H.; Guntupalli, P.; Mitchelle, H. J.;
Fylaktakidou, K. C.; Vourloumis, D.; Giannakakou, P.; O’Brate, A. J. Am.
Chem. Soc. 2003, 125, 15443 and references cited therein. (c) Wehlan, H.;
Dauber, M.; Fernaud, M. T. M.; Schuppan, J.; Mahrwald, R.; Ziemer, B.;
Garcia, M. E. J.; Koert, U. Angew. Chem., Int. Ed. 2004, 43, 4597. (d)
Daniel, P. T.; Koert, U.; Schuppan, J. Angew. Chem., Int. Ed. 2006, 45,
872 and references cited therein. (e) Wu, B.; Liu, Q.; Sulikowski, G. A.
Angew. Chem., Int. Ed. 2004, 43, 6673 and references cited therein. (f)
Crimmins, M. T.; Christie, H. S.; Chaudhary, K.; Long, A. J. Am. Chem.
Soc. 2005, 127, 13810. (g) Chen, Y.; Evarts, J. B.; Torres, E.; Fuchs, P. L.
Org. Lett. 2002, 4, 3571. (h) Abe, K.; Kato, K.; Arai, T.; Rahim, M. A.;
Sultana, I.; Matsumura, S.; Toshima, K. Tetrahedron Lett. 2004, 45, 8849.
(i) Chang, S. S.; Xu, J.; Loh, T. P. Tetrahedron Lett. 2003, 44, 4997. (j)
Paquette, W. D.; Taylor, R. E. Org. Lett. 2004, 6, 103.
Table 1. Dihydroxylation of (Z)- 8, 9, and 10
(4) (a) Wender, P. A.; Gulledge, A. V.; Jankowski, O. D.; Seto, H. Org.
Lett. 2002, 4, 3819. (b) Pennington, J. D.; Williams, H. J.; Salomon, A. R.;
Sulikowski, G. A. Org. Lett. 2002, 4, 3823.
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substrate
R
conditionsa
% yieldb
ratioc
(7) Corey, E. J. Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(8) See Supporting Information for additional information. An improved
preparation of lactone 4 is provided.
(9) Torres, E.; Chen, Y.; Kim, I. C.; Fuchs, P. L. Angew. Chem., Int.
Ed. 2003, 42, 3124.
(10) (a) Brunet, J. J.; Gallois, P.; Caubere, P. J. Org. Chem. 1980, 45,
1937. (b) Sondengam, B. L.; Charles, G.; Akam, T. M. Tetrahedron Lett.
1980, 44, 1069. (c) Koviach, J. L.; Chappell, M. D.; Halcomb, R. L. J.
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43, 1801.
8
8
9
10
10
H
H
H
CH3
CH3
A
B
B
A
B
quant
95
95
<25d
<25d
9:1 (11/14)
3:1 (11/14)
4:1 (12/15)
1.5:1 (13/16)
1.5:1 (13/16)
a Condition A: OsO4 (1 equiv), TMEDA (1.1 equiv), CH2Cl2, -78 °C
to rt, 12 h. Condition B: OsO4 (5 mol %), NMO (3 equiv), acetone-H2O
(4:1), rt, 12 h. b Isolated yield. c Determined by 1H NMR. d The remainder
of the mixture is recovered starting material.
2446
Org. Lett., Vol. 9, No. 13, 2007