A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry.

Article abstract of DOI:10.1039/b312245j

A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picrop

Full text of DOI:10.1039/b312245j

A concise stereocontrolled formal total synthesis of (±)-podophyllotoxin
using sulfoxide chemistry†
Mike Casey* and Claire M. Keaveney
Chemistry Department, the Centre for Synthesis and Chemical Biology, and the Conway Institute of
Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
E-mail: mike.casey@ucd.ie; Fax: +353 1 716 2127; Tel: +353 1 716 2420
Received (in Cambridge, UK) 2nd October 2003, Accepted 17th November 2003
First published as an Advance Article on the web 5th December 2003
A short stereoselective formal total synthesis of ( )-podophyllo-
toxin has been carried out from a sulfoxide, using a one-pot
tandem conjugate addition/aldol/electrophilic aromatic sub-
stitution reaction to form a tetralin, which was converted into
picropodophyllin in two steps.
Addition of racemic tert-butyl sulfoxide 2 to ethyl g-(t-
butyldiphenylsilyloxy)crotonate 3,‡ and addition of 3,4,5-trime-
thoxybenzaldehyde to the intermediate enolate, afforded diaster-
eomerically pure adduct 4 in 64% yield (Scheme 2), along with a
second diastereomer (4%) and some untrapped conjugate adduct.
The relative stereochemistry of the four new centres formed in this
step was assigned on the basis of earlier results,5 and the NMR data
for the carbinol proton (d 4.88 ppm, Jab 3.7 Hz).10 The syn/anti
diastereoselectivity of the aldol reaction was higher than found in
related systems,3 indicating that some remote asymmetric induction
enhanced the usually weak syn selectivity.
Following the precedent of Vandewalle,11 it was found that
tosylation of the aldol product 4 resulted in spontaneous cyclisation
below room temperature to give the tetralin 5 in 38% yield.§
Moreover, in situ tosylation of the alkoxide formed by the
conjugate addition/aldol sequence, followed by warming to room
The natural product podophyllotoxin 1 possesses significant anti-
tumour activity, and is in clinical use as an antiviral agent.1
However, its most important use is as the precursor for the anti-
cancer agents etoposide, etopophos, and teniposide.1 Such is the
success of these drugs that the wild plant populations from which
podophyllotoxin is harvested are declining,2 and there is much
interest in exploring alternative sources. Chemical synthesis is one
option, but although several total syntheses have been reported,3
and new approaches continue to appear,4 there is still a need for
more efficient routes.
Synthetic strategies involving conjugate addition of acyl anion
equivalents to butenolides, followed by aldol condensation, and
tetralin formation provide particularly flexible and concise routes to
podophyllotoxin and analogues.3 The use of a sulfoxide-stabilised
anion as the nucleophile in the conjugate addition was attractive
because of the potential to use an enantiomerically pure sulfoxide to
carry out an asymmetric synthesis (Scheme 1). However, although
excellent asymmetric induction can indeed be obtained in conjugate
additions of sulfoxide-stabilised anions,5 we and others found that
cyclic electrophiles could not be used.5,6 The report of an
exceptionally short asymmetric synthesis of podophyllotoxin, that
relied on conjugate addition of a sulfoxide to butenolide,7 ran
counter to these observations. We attempted to repeat the published
procedure, but did not obtain the reported addition product. We
therefore proceeded with an alternative route that utilised an acyclic
unsaturated ester as the precursor for the D ring of podophyllotoxin,
and now report the results of the first phase in the development of
this route, which culminated in a particularly short synthesis of
(±)-picropodophyllin 9, a known precursor for podophyllo-
toxin.8,9
Scheme 1
Scheme
2 Reagents and conditions: (i) LDA, THF, 278 °C; 3;
3,4,5-trimethoxybenzaldehyde; (ii) LDA, THF, 278 °C; tosyl chloride,
278 °C to rt; (iii) LDA, THF, 278 °C; ethyl g-(t-butyldiphenylsilyloxy)-
crotonate; 3,4,5-trimethoxybenzaldehyde; tosyl chloride, 278 °C to rt; (iv)
TBAF, THF, rt; (v) Tf2O, collidine, CH2Cl2, 278 to 0 °C; H2O.
† Electronic supplementary information (ESI) available: experimental
details for the preparation of compounds 2, 4, 5, 6, 7, 8, 9, and 12. See http:
//www.rsc.org/suppdata/cc/b3/b312245j/
184
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 – 1 8 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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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.
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37, 4791. A second puzzling feature of this synthesis is the reported
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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.
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Scheme 3
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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.
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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