Synthesis of picropodophyllin homolactone

Article abstract of DOI:10.1016/S0040-4039(00)01136-9

Based on a Wittig olefination strategy, the first synthesis of picropodophyllin homolactone 2 is described in nine steps and 30% overall yield from podophyllotoxine 1. The relative configuration of 2 was unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work corrects the literature on the synthesis of 2. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01136-9

Tetrahedron Letters 41 (2000) 6769±6773
Synthesis of picropodophyllin homolactone
Emmanuel Roulland,a Emmanuel Bertounesque,a,* Christiane Huelb
and Claude Monnereta,*
aUMR 176 CNRS-Institut Curie, Section de Recherche, 26 rue d'Ulm, 75248 Paris Cedex 05, France
b
Â
U 350 INSERM-Institut Curie, BaÃtiment 110, Universite Paris XI, F-91405 Orsay Cedex, France
Received 24 May 2000; accepted 5 July 2000
Abstract
Based on a Wittig ole®nation strategy, the ®rst synthesis of picropodophyllin homolactone 2 is described
in nine steps and 30% overall yield from podophyllotoxine 1. The relative con®guration of 2 was
unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work
corrects the literature on the synthesis of 2. # 2000 Elsevier Science Ltd. All rights reserved.
We have been engaged in activities1 in the area of podophyllotoxin 1,2 a natural product
endowed with potent antimitotic activity. The trans-fused lactone moiety is being considered as
an important factor for displaying signi®cant cytotoxic activity,3 the cis analogues being less
potent. Less is known concerning six-membered ring lactone analogues. In 1985, Anjanamurthy
and Lokanatha Rai4 reported the synthesis of picropodophyllin homolactone 2. However, it
appeared to us that the IR absorption at 1760 cm^1 was not consistent with a d-lactone
functionality. In this communication, we describe the ®rst synthesis of picropodophyllin
homolactone 2 via a route which would accomodate a good degree of ¯exibility with respect to
the size and nature of the D-ring.
The synthesis of picropodophyllin homolactone 2 began with podophyllotoxin 1, which was
transformed into 35 (97%) through silylation (TBSOTf, 2,6-lutidine, CH2Cl2, 0ꢀC) of the benzylic
* Corresponding authors. Tel: +33-(0)1-42-34-66-55; fax: +33-(0)1-42-34-66-31; e-mail: claude.monneret@curie.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01136-9

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alcohol (Scheme 1). Subsequent hydrolysis of the g-lactone (2N NaOH, THF, 0ꢀC) a€orded the
resulting hydroxy-acid 4 (quantitative yield) with epimerization at the C2 stereocenter. Oxidation
of 4 to the low soluble lactols 5 (Dess±Martin periodinane, CH2Cl2, 25ꢀC) followed by
esteri®cation (CH3I, K2CO3, acetone, 25ꢀC) provided the desired aldehyde 6 (87% yield for the
two steps). Similar lactol compounds have been used in the asymmetrical total synthesis of
(^)-podophyllotoxin reported by Bush and Jones.6 Alternatively, according to earlier observations,7
transesteri®cation of 3 under equilibrating conditions (K2CO3 cat., MeOH, 25ꢀC) resulted in a
mixture of picropodophyllin derivative 75 (43%) and methyl picropodophyllate derivative 8
(57%). Usefully, the overall yield of 8 was improved to 86%, since it was possible to recycle (three
cycles) the undesired lactone 7 by conversion into the methyl ester 8 using the same procedure. A
Swern oxidation of the resulting alcohol also a€orded the subgoal 6. The one-carbon
homologation and the completion of the synthesis were then addressed (Scheme 2).
Scheme 1. (a) TBSOTf, 2,6-lutidine, CH2Cl2, 0ꢀC. (b) NaOH, THF/H2O, 0ꢀC. (c) Dess±Martin periodinane, CH2Cl2,
25ꢀC. (d) CH3I, K2CO3, acetone, 25ꢀC. (e) K2CO3 cat., MeOH, 25ꢀC. (f) (ClCO)2, DMSO, Et3N, CH2Cl2, ^78 to 25ꢀC
Scheme 2. (a) Ph3P+CH2OCH3 Cl^, n-BuLi, THF, ^40 to 25ꢀC. (b) 30% HClO4/H2O, Et2O, 25ꢀC. (c) NaBH4, MeOH,
25ꢀC. (d) SiO2, MeOH, re¯ux

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The enol ether functionality of 9 was stereoselectivity incorporated (84% overall yield, E:Z
1
ratio=60:40 by H NMR analysis) by treating 6 with methoxymethylenetriphenylphosphonium
chloride and n-BuLi.8 A subsequent hydrolysis of 9 (30% HClO4/H2O, Et2O, 25ꢀC) a€orded an
inseparable 1:5 mixture of the stable g-lactols 10 (55%). This transformation accomplished not
only the two deprotection operations, but also the unwanted epimerization at C4. Attempts to
avoid the acidic removal of the TBS ether protecting group by the method of Yamamoto9
(TBAF, BF3±Et2O) also led to 10, but in low yield. Sequential reduction (NaBH4, MeOH, 25ꢀC)
of 10 and acidic treatment of the resultant diol gave a mixture of the anticipated10 g-lactone 11
(83%), encompassing a neopodophyllotoxin-like structure,11 and hydroxy-ester 12 (9%). The
utility of 1112 as a viable intermediate in the synthesis of 2 was not examined. Consequently, we
chose to subject aldehyde 6 to a Wittig methylenation (76%) in order to suppress the problematic
acidic hydrolysis of the enol ether 9 (Scheme 3).
Scheme 3. (a) Ph3P+CH3 I^, n-BuLi, THF, ^78ꢀC. (b) TBAF, THF, 25ꢀC. (c) 9-BBN, THF then 30% H2O2/H2O,
phosphate bu€er, pH 7, MeOH, 25ꢀC. (d) NaOH, THF/H2O, 0ꢀC. (e) DCC, 4-DMAP, THF, 25ꢀC
Attempted direct alkene hydroboration of 13 by means of conventional reagents (9-BBN, BH3/
SMe2) failed to provide the desired TBS ether analogue of 15. However, diol 15 was conveniently
prepared in 56% overall yield by deprotection of the sterically hindered TBS ether and
subsequent hydroboration (9-BBN, THF, 25ꢀC) of the ole®n 14. The coupling constants of 15
(J1,2=8.9, J2,3=3.5 and J3,4=4.4 Hz) were similar to those found for methyl picropodophyllate.13
The synthesis was then completed by saponi®cation of 15, giving the crude d-hydroxy-acid,
which was immediately treated with DCC and 4-DMAP to a€ord the desired d-lactone 214 in
84% overall yield. The structure of 2 was established unambiguously on the basis of a spectroscopic
analysis (1H NMR (400 MHz), 1D, 2D NOESY; 13C NMR (100 MHz); IR) and molecular
modeling. This product was clearly di€erent from that described earlier4 by comparison of their
melting points and spectroscopic data (1H NMR, IR). The IR absorption at 1741 cm^1 indicated
the presence of a d-lactone functionality. A Monte Carlo search (SYBYL 6.5/Tripos force ®eld)
gave the lowest energy conformations as A and B respectively, for the cis-lactone 2 and the trans-
isomer 16 (Fig. 1). The vicinal coupling constants (H-1, H-2, H-3, H-4) and the observed NOESY
(absence of H-2/H-4 and H-3/H-12a interactions, strong H-2/H-12a NOESY) con®rm structure 2
for the synthesized lactone, in good agreement with a conformation such as A. These data allow
us to exclude structure 16.

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Figure 1.
Compounds 10, 11 and 2 displayed low activities in vitro against L1210 (IC50 values in mM: 10,
23.5; 11, 21; 2, 1.3; 1, 0.007).
In summary, the ®rst synthesis of 2 has been achieved from podophyllotoxin 1 in nine steps and
30% overall yield. Moreover, our route should allow the construction of podophyllotoxin
analogues including D-rings of various sizes and degrees of substitution, from the key
intermediate 6. Such an approach is currently under investigation.
Acknowledgements
This work was ®nancially supported by the Centre National de la Recherche Scienti®que and
the Institut Curie. We also thank the Laboratoires Servier, France, for biological evaluations.
References
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von Wartburg, A. Liebigs Ann. Chem. 1965, 681, 207±224. Charlton, J. L.; Koh, K. J. Org. Chem. 1992, 57, 1514±
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25
D
12. Analytical data for compound 11. Mp: 88±90ꢀC; ‰ꢀŠ +42 (c 0.4; CHCl3); IR (CDCl3) 3628, 2938, 1769 cm^1; H
1
NMR (300 MHz, CDCl3) ꢁ 1.43 (t, 1H, J=4.7 Hz, OH), 1.62 (m, 1H, H-11a), 1.81 (m, 1H, H-11b), 2.78 (d, 1H,

6773
J=1.1 Hz, H-2), 2.86 (t, 1H, J=7.3 Hz, H-3), 3.72 (m, 2H, H-12a, H-12b), 3.78 (s, 6H, OMe), 3.84 (s, 3H, OMe),
4.41 (d, 1H, J=1.1 Hz, H-1), 5.10 (d, 1H, J=1.0 Hz, H-4), 5.94 (d, 1H, J=1.2 Hz, OCH2O), 5.99 (d, 1H, J=1.2
Hz, OCH2O), 6.31 (s, 2H, H-20, H-60), 6.49 (s, 1H, H-8), 6.75 (s, 1H, H-5); MS (DCI/NH3) m/z 429 [M+H]+, 446
[M+NH4]+.
13. Gordaliza, M.; Castro, M. A.; Miguel del Corral, J. M.; Lopez-Vazquez, M. L.; Garcõa, P. A.; San Feliciano, A.;
Garcõa-Gravalos, M. D.; Broughton, H. Tetrahedron 1997, 53, 15743±15760.
25
14. Analytical data for compound 2. Mp: 197±198ꢀC (hexane/EtOAc), lit.:4 144±146ꢀC; ‰ꢀŠ ^114 (c 0.1; CHCl3); IR
D
(CDCl3) 3800±3400, 2932, 1741, 1591 cm^1; 1H NMR (400 MHz, CDCl3) ꢁ 2.09±2.19 (m, 2H, H-11a, H-11b), 2.43
(bs, 1H, OH), 2.53 (m, 1H, H-3), 3.01 (dd, 1H, J=6.4, 2.9 Hz, H-2), 3.79 (s, 6H, OMe), 3.84 (s, 3H, OMe), 4.26±
4.35 (m, 1H, H-12a), 4.38 (d, 1H, J=9.6 Hz, H-4), 4.43±4.51 (m, 1H, H-12b), 4.64 (d, 1H, J=2.9 Hz, H-1), 5.91±
5.94 (degenerated m, 2H, OCH2O), 6.30 (s, 2H, H-20, H-60), 6.43 (s, 1H, H-8), 7.00 (s, 1H, H-5); 13C NMR (100
MHz, CDCl3) quaternary carbons not speci®cally assigned ꢁ 24.9 (C-11), 34.2 (C-3), 43.6 (C-1), 46 (C-2), 56 (2C,
OMe), 60.7 (1C, OMe), 66 (C-12), 71.4 (C-4), 101 (OCH2O), 105.8 (C-5), 105.9 (2C, C-20, C-60), 109.4 (C-8), 128,
131.5, 137, 136.8 (quaternary carbons C-10, C-40, C-4a, C-8a), 146.9, 147.4 (quaternary carbons C-6, C-7), 153.2
(2C, C-30, C-50), 173 (CˆO); MS (DCI/NH3) m/z 446 [M+NH4]+.