temperature, resulted in a one-pot conversion of the sulfoxide 2 into
the tetralin 5!
completing the formal total synthesis of (±)-podophyllotoxin. The
spectroscopic data for our product were identical to those reported
for picropodophyllin.9
The yield of tetralin was low (27%), mainly because of
competing formation of a second product in similar amounts. The
side product was unstable and it could not be characterised, but it
clearly was a diastereoisomer of the aldol product 4 and the Jab
value of 7.0 Hz indicated that it was the anti aldol 12 (Scheme 3).
We suggest that the benzylic carbocation 10, formed from the
tosylate, undergoes two competing cyclisations, one involving
nucleophilic attack by the arene to give the desired tetralin 5, and
the second involving attack by the sulfoxide to give a sulfonium salt
11.12,13 Assuming that the latter cyclisation occurred with the same
sense of diastereoselectivity as the tetralin formation, hydrolysis of
the sulfonium salt with inversion at the benzylic centre would then
account for the formation of side product 12. Use of other
sulfonylating agents, solvents and conditions did not improve the
yield of the tetralin 5. Although further work clearly is required, the
one-pot formation of the tetralin 5 with complete control of
diastereoselectivity is a notable development.
In conclusion, we have carried out a novel and exceptionally
short synthesis of (±)-picropodophyllin. The high level of asym-
metric induction by the sulfoxide, and the facile replacement of the
sulfinyl group, are key features of this highly convergent and
flexible route. Use of a g-alkoxycrotonate rather than a butenolide
required an extra step, i.e. the deprotection lactonisation. However,
it provided the picropodophyllin stereochemistry directly, so that
only one epimerisation is required for conversion into (±)-podo-
phyllotoxin. Work on optimisation of the tetralin formation, and on
use of an enantiopure sulfoxide,15 is underway.
Notes and references
‡ Prepared by Wittig reaction of glycolaldehyde dimer and silylation. Use
of a bulky protecting group is essential to the success of the aldol reaction,
presumably because it prevents intramolecular coordination of the oxygen
to the enolate counterion.
Treatment of the silyloxy ester 5 with TBAF gave the lactone 6
in 71% yield (Scheme 2). Lactonisation appears to be greatly
facilitated by the cis relationship of the alcohol and ester groups in
the tetralin. Conversion of the C–S bond of the benzylic sulfoxide
into a C–O bond was the only step remaining. Reaction of sulfoxide
6 with triflic anhydride and collidine, according to the method of
Berkowitz,14 did effect activation of the sulfoxide, but the product
was the cyclic sulfide 7 rather than picropodophyllin. Presumably,
the trifloxy sulfonium salt 13 underwent nucleophilic substitution
by the activated arene, which was held in close proximity in the
relatively rigid cis lactone structure, to give sulfonium salt 14, and
loss of isobutene then gave sulfide 7 (Scheme 4).
This unwanted cyclisation was avoided by changing the order of
the steps (Scheme 2). Treatment of the unlactonised sulfoxide 5
with triflic anhydride, followed by water, gave the desired benzylic
alcohol 8. The potential to replace the sulfinyl group with
nucleophiles to provide diverse podophyllotoxin analogues is an
advantageous feature of this route.14 Desilylation of the crude
product 8 with TBAF was accompanied by spontaneous lactonisa-
tion to afford (±)-picropodophyllin 9 in 38% yield from 5,
§ The t-butyldimethylsilyl analogue of silyloxy ester 4 was easily converted
into the corresponding lactone, but attempts to form the tetralin subsequent
to lactonisation were unsuccessful.
1 Y. Damayanthi and J. W. Lown, Curr. Med. Chem., 1998, 5, 205.
2 C. Canel, R. M. Moraes, F. E. Dayay and D. Ferreira, Phytochemistry,
2000, 54, 115.
3 For reviews see: R. S. Ward, Synthesis, 1992, 719; R. S. Ward, Nat.
Prod. Rep., 1999, 16, 75.
4 D. B. Berkowitz, S. Choi and J.-H. Maeng, J. Org. Chem., 2000, 65,
847; L. Charrault, V. Michelet and J.-P. Genet, Tetrahedron Lett., 2002,
43, 4757; G. Poli and G. Giambastiani, J. Org. Chem., 2002, 67, 9456;
J. Clayden, M. N. Kenworthy and M. Helliwell, Org. Lett., 2003, 5, 831;
U. Engelhardt, A. Sarkar and T. Linker, Angew. Chem., Int. Ed., 2003,
42, 2487; A. J. Reynolds, A. J. Scott, C. I. Turner and M. S. Sherburn,
J. Am. Chem. Soc., 2003, 125, 12108.
5 M. Casey, A. C. Manage and R. S. Gairns, Tetrahedron Lett., 1989, 30,
6919; M. Casey, R. S. Gairns, G. M. Geraghty, C. J. Kelly, P. J. Murphy
and A. J. Walker, Synlett, 2000, 1721; Z. Appelbe, M. Casey, C. M.
Keaveney and C. J. Kelly, Synlett, 2002, 1404.
6 F. E. Ziegler and J. A. Schwarz, J. Org. Chem., 1978, 43, 985; J. H.
Dodd, R. S. Garigipati and S. M. Weinreb, J. Org. Chem., 1982, 47,
4045; S. Nakamura, H. Takemoto, Y. Ueno, T. Toru, T. Kakumoto and
T. Hagiwara, J. Org. Chem., 2000, 65, 469.
7 S. B. Hadimani, R. P. Tanpure and S. V. Bhat, Tetrahedron Lett., 1996,
37, 4791. A second puzzling feature of this synthesis is the reported
formation of podophyllotoxin, albeit in poor yield, by cyclisation of a
benzylic alcohol, a reaction that generally gives the picropodophyllin
stereochemistry highly selectively3.
8 W. J. Gensler and C. D. Gatsonis, J. Org. Chem., 1966, 31, 4004; A. S.
Kende, M. Logan King and D. P. Curran, J. Org. Chem., 1981, 46,
2826.
9 R. C. Andrews, S. J. Teague and A. I. Meyers, J. Am. Chem. Soc., 1988,
110, 7854.
Scheme 3
10 T. Nakata and T. Oishi, Tetrahedron Lett., 1980, 21, 1641.
11 J. Van der Eycken, P. De Clercq and M. Vandewalle, Tetrahedron,
1986, 42, 4297.
12 For a closely related cyclisation, but with a different mode of hydrolysis
of the sulfonium salt, see S. Raghavan and M. A. Rasheed, Tetrahedron:
Asymmetry, 2003, 14, 1371.
13 A similar mechanism, involving reversible formation of sulfonium ions,
could account for the formation of ‘retrolactones’ in cyclisations of
analogous sulfides: A. Pelter, R. S. Ward, M. C. Pritchard and I. T. Kay,
J. Chem. Soc., Perkin Trans 1, 1988, 1615.
14 D. B. Berkowitz, S. Choi, D. Bhuniya and R. K. Shoemaker, Org. Lett.,
2000, 2, 1149.
15 Enantiopure t-butyl sulfoxides are readily available: D. A. Cogan, G.
Liu, K. Kim, B. J. Backes and J. A. Ellman, J. Am. Chem. Soc., 1998,
120, 8011.
Scheme 4
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 – 1 8 5
185