C O M M U N I C A T I O N S
Scheme 2. Meyers Dearomatization Approach to
(-)-Podophyllotoxina
25. Following conversion into thionocarbonate 26, exposure to tris-
(trimethylsilyl)silane gave aryl tetrahydronaphthalene lactone 27
in 40% yield. Fleming-Tamao oxidation17 of the benzyl silane gave
the alcohol, which was immediately oxidized to ketone 28. Finally,
Pd(0)-mediated deallylation-decarboxylation afforded (-)-isopi-
cropodophyllone 4.
In summary, an efficient and conceptually novel strategy for the
stereocontrolled synthesis of aryl tetrahydronaphthalene lactone
lignans has been developed. The late point of convergence instills
true modularity in this approach, thereby facilitating SAR studies
and inviting the application of combinatorial protocols. Work toward
this end, in addition to optimization studies on the carboxyarylation
reaction and further applications of this methodology, is under
investigation in this laboratory.
Acknowledgment. The authors thank Professors Lew Mander
and Athel Beckwith (ANU) and Professor Gary Molander (Uni-
versity of Pennsylvania) for helpful discussions, and the Australian
Research Council for funding.
a (a) PhMe2SiLi (5.0 equiv), THF, -78 °C, 3 h, then allylchloroformate
(7.5 equiv), -78 °C f 25 °C; (b) KHCO3 (0.7 equiv), K2CO3 (2.5 equiv)
MeOH-H2O, 25 °C, 55 min, 30% of 23, 57% of 22 over two steps; (c)
MeOTf (2.0 equiv), CH2Cl2, 25 °C, 2 h, then NaBH4 (4.0 equiv) THF-
MeOH, 25 °C, 30 min, then (COOH)2‚2H2O (5.1 equiv), THF-H2O, 25
°C, 16 h, 100% over three steps; (d) Bu3SnH (2.0 equiv), SiO2, PhMe, 80
°C, 10 h, 79%; (e) 16 (1.1 equiv), pyridine (2.0 equiv), CH2Cl2, 25 °C, 2
h, 99%; (f) (Me3Si)3SiH (1.1 equiv), AIBN (0.6 equiv added over 14 h),
PhH, 80 °C, 14 h, 40%; (g) BF3‚2AcOH (9.0 equiv), CH2Cl2, sealed tube,
50 °C, 27 h, then m-CPBA (6.9 equiv), KF (1.2 equiv), DMF, 25 °C, 1 h,
then Dess-Martin periodinane (1.8 equiv), CH2Cl2, 25 °C, 30 min, 60%
based on recovered 27 over three steps; (h) Pd(OAc)2 (4 equiv), PPh3 (8.0
equiv), HCO2H (40 equiv), NEt3 (50 equiv), THF, 25 °C, 43 min, 100%.
Supporting Information Available: Key experimental procedures,
characterization data, and 1H and 13C NMR spectra of new compounds
(PDF). This material is available free of charge via the Internet at
References
(1) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75 and references therein.
(2) Imbert, T. F. Biochimie 1998, 80, 207.
(3) (a) Damayanthi, Y.; Lown, J. W. Curr. Med. Chem. 1998, 5, 205. (b)
Bohlin, L.; Rosen, B. Drug DiscoVery Today 1996, 1, 343.
(4) Reviews: (a) Ward, R. S. Synthesis 1992, 719. (b) Ward, R. S. Tetrahedron
1990, 46, 5029.
(5) Total syntheses of (-)-podophyllotoxin: (a) Andrews, R. C.; Teague, S.
J.; Meyers, A. I. J. Am. Chem. Soc. 1988, 110, 7854. (b) Van Speybroeck,
R.; Guo, H.; Van der Eycken, J.; Vandewalle, M. Tetrahedron 1991, 47,
4675. (c) Charlton, J. L.; Koh, K. J. Org. Chem. 1992, 57, 1514. (d) Bush,
E. J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1996, 151. (e) Hadimani,
S. B.; Tanpure, R. P.; Bhat, S. V. Tetrahedron Lett. 1996, 37, 4791. (f)
Berkowitz, D. B.; Choi, S.; Maeng, J.-H. J. Org. Chem. 2000, 65, 847.
For a recent synthesis of epi-podophyllotoxin, see: Engelhardt, U.; Sarkar,
A.; Linker, T. Angew. Chem., Int. Ed. 2003, 42, 2487.
(6) Atta-ur-Rahman; A. M.; Choudhary, M. I.; Habib-ur-Rehman, K. M. H.
Phytochemistry 1995, 40, 427.
(7) (a) Mander, L. N.; Sherburn, M. S. Tetrahedron Lett. 1996, 37, 4255. (b)
Bachi, M. D.; Bosch, M.; Denenmark, D.; Girsh, D. J. Org. Chem. 1992,
57, 6803. For other examples of addition reactions of Barton-McCombie
intermediates: Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem.
Soc. 2003, 125, 1492 and references therein.
(8) Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L. Tetrahedron Lett.
1986, 27, 4957.
(9) Clark, R. D.; Jahangir. J. Org. Chem. 1989, 54, 1174.
(10) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(11) Prepared from thiophosgene and 3,4,5-trimethoxyphenol according to the
standard procedure: Barton, D. H. R.; Blundell, P.; Dorchak, J.; Jang, D.
O.; Jaszberenyi, J. C. Tetrahedron 1991, 47, 8969.
dienolate of crotonyl oxazolidinone 12 and 6-vinyl piperonal 11.9
After protection as the corresponding silyl ether 13 and reductive
removal of the auxiliary, ring-closing metathesis of alcohol 14 with
first generation Grubbs catalyst10 gave the dihydronaphthalene-2-
methanol 15 in excellent yield. Exposure to the chlorothionoformate
derivative of 3,4,5-trimethoxyphenol 1611 proceeded smoothly. We
were delighted to find that tris(trimethylsilyl)silane promoted the
conversion of thionocarbonate 17 into alkene carboxyarylation
product 18 in 38% yield.12 Desilylation with buffered TBAF and
oxidation with PCC gave (+)-isopicropodophyllone, which under-
went acid-catalyzed transesterification to give methyl ester 19. This
compound was converted into (+)-podophyllotoxin ent-1 through
the reported5d three-step sequence involving selective epimerization
at C-3, stereoselective ketone reduction, and trans-lactone forma-
tion.
The enantiomeric series was accessed by Meyers’ elegant
naphthalene dearomatization chemistry.13 Thus, stereoselective
nucleophilic addition of dimethylphenylsilyl-lithium to valine-
derived 2-naphthyl oxazoline 20,14 followed by aza-enolate trapping
with allyl chloroformate, furnished adduct 22 as a single diastere-
oisomer, within the limits of detection. This reaction was unexpect-
edly accompanied by C-6 SNAr product 21. Oxazoline 22 was
converted into aldehyde 24,15 which was in turn reduced16 to alcohol
(12) Efforts to optimize this reaction are under way. Thus far, better results
have been obtained with (Me3Si)3SiH than with Bu3SnH.7
(13) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(14) Prepared from 2-naphthoic acid (Teague, S. J.; Roth, G. P. Synthesis 1986,
427) under modified Vorbruggen conditions: Vorbruggen, H.; Krolik-
iewicz, K. Tetrahedron Lett. 1981, 22, 4471.
(15) Degnan, A. P.; Meyers, A. I. J. Org. Chem. 2000, 65, 3503.
(16) Fung, N. Y. M.; de Mayo, P.; Schauble, J. H.; Weedon, A. C. J. Org.
Chem. 1978, 43, 3977.
(17) Jones, G.; Landais, Y. Tetrahedron 1996, 52, 7599.
JA0376588
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12109