Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (- )-picropodophyllin

Article abstract of DOI:10.1021/jo991582+

Described is the first catalytic, asymmetric synthesis of (-)- podophyllotoxin and its C₂-epimer, (-)picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogenmetal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate-(15) and maleate-IBF Diels- Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH₄) of 16 provides meso diol 19, which is then treated with Ac₂O, BzCl, and PhCH₂COCl to provide the corresponding meso diesters, 20- 22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro- Michael ring opening to produce dihydronaphthalene 30, in which the C₃ and C₄ stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck- type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required α-stereochemistry at C₁ is observed). The conjugate addition product is converted to (-)- picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)- podophyllotoxin, in three steps, through the introduction of a C₂- epimerization step, under Kende conditions, prior to the final conjugate addition.

Full text of DOI:10.1021/jo991582+

J . Org. Chem. 2000, 65, 847-860
847
En zym e-Assisted Asym m etr ic Tota l Syn th esis of
(-)-P od op h yllotoxin a n d (-)-P icr op od op h yllin
David B. Berkowitz,* Sungjo Choi, and J un-Ho Maeng
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588-0304
Received October 11, 1999
Described is the first catalytic, asymmetric synthesis of (-)-podophyllotoxin and its C2-epimer, (-)-
picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso
diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the
strategically late introduction of the highly oxygenated natural ring E through an arylcopper species.
The successful implementation of this approach augers well for the introduction of other
functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned
into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen-
metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical
dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate-
(15) and maleate-IBF Diels-Alder adducts (16 and 17), indicating that IBF 11 reacts about 15
times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl
maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the
desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl
acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH4)
of 16 provides meso diol 19, which is then treated with Ac2O, BzCl, and PhCH2COCl to provide the
corresponding meso diesters, 20-22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate
candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20
with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral
intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group
manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro-Michael
ring opening to produce dihydronaphthalene 30, in which the C3 and C4 stereocenters are properly
set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen
rearrangement, Heck-type cyclization, or radical cyclization), a highly diastereoselective, intermo-
lecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmag-
nesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required
R-stereochemistry at C1 is observed). The conjugate addition product is converted to (-)-
picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)-podophyllotoxin, in three
steps, through the introduction of a C2-epimerization step, under Kende conditions, prior to the
final conjugate addition.
In tr od u ction
complex that is normally present along the topoisomerase
II reaction coordinate. This results in abnormally high
concentrations of this species, actuating mutagenesis or
cell death pathways.6 Alternative mechanisms, several
of which involve reactive species derived from oxidation
(-)-Podophyllotoxin (1), an aryl tetralin lignan isolated
from the American May apple tree (Podophyllum
peltatum) and a related plant on the Indian subcontinent
(Podophyllum emodi), is a potent antimitotic, binding to
tubulin and inhibiting microtubule formation.1 There has
been renewed clinical interest in the natural product
itself, particularly for the treatment of venereal warts.2
Most notably, however, its glucosylated, 4-epi-derivative,
etoposide (2), has seen extensive application as a che-
motherapeutic, particularly for small cell lung cancer
(SCLC), advanced testicular cancer, and Kaposi’s sar-
coma.3,4 A recent report also raised the intriguing pos-
sibility of using epipodophyllotoxins as anti-HIV agents.5
The semisynthetic drug apparently has a very different
mechanism of action than its parent aglycon. Etoposide
is known to stabilize the covalent enzyme-cleaved DNA
(3) For reviews of the chemical, biological and clinical aspects of
etoposide and related epipodophyllotoxins, see: (a) Imbert, T. F.
Biochimie 1998, 80, 207-222. (b) Damayanthi, Y.; Lown, J . W. Curr.
Med. Chem. 1998, 5, 205-252. (c) Etoposide (VP-16). Current Status
and New Developments; Issell, B. F., Muggia, F. M., Carter, S. K., Eds.;
Academic Press: New York, 1984.
(4) (a) Hande, K. R. Biochim. Biophys. Acta 1998, 1400, 173-184.
(b) Pommier, Y.; Fesen, M. R.; Goldwasser, F. In Cancer Chemotherapy
and Biotherapy: Principles and Practice; Chabner, B. A., Longo, S.
L., Eds. Lippincoltt Raven: Philadephia, 1996; pp 435-461. (b) Smith,
M. A. Rubinstein, L.; Cazenave, L.; Ungerleider, R. S.; Maurer, H. M.;
Heyn, R.; Khan, F. M.; Gehan, E. J . Natl. Cancer Inst. 1993, 85, 554-
558 and references therein.
(5) Lee, C. T.-L.; Lin, V. C.-K.; Zhang, S.-X.; Zhu, X.-K.; VanVliet,
D.; Hu, H.; Beers, S. A.; Wang, Z.-Q.; Cosentino; L. M.; Morris-
Natschke, S. L.; Lee, K.-H. Bioorg. Med. Chem. Lett. 1997, 7, 2897-
2902.
(6) (a) Kingma, P, S,; Burden, D. A.; Osheroff, N. Biochemistry 1999,
38, 3457-3461. (b) Burden, D. A.; Osheroff, N. Biochim. Biophys. Acta
1998 1400, 139-154. (c) Burden, D. A.; Kingma, P. S.; Froelich-
Ammon, S. J .; Bjornsti, M.-A.; Patchan, M. W.; Thompson, R. B.;
Osheroff, N. J . Biol. Chem. 1996, 271, 29238-29244 and references
therein.
(1) King, L.; Sullivan, M. Science 1946, 104, 244-245.
(2) (a) Tyring, S.; Edwards, L.; Cherry, L. K.; Ramsdell, W. M.;
Kotner, S.; Greenberg, M. D.; Vance, J . C.; Barnum, G.; Dromgoole, S.
H.; Killey, F. P.; Toter, T. Arch. Dermatol. 1998, 134, 33-38. (b)
Claesson, U.; Lassus, A.; Happonen, H.; Hogstro¨m, L.; Siboulet, A. Int.
J . STD AIDS 1996, 7, 429-434. (c) Beutner, K. R. Curr. Probl.
Dermatol. 1996, 24, 227-232.
10.1021/jo991582+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/14/2000

848 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
of ring E, have also been put forth.7 Recently, several new
members of the etoposide family have emerged as po-
tentially superior chemotherapeutics, including the BMS
prodrug, etopophos (3),8 Nippon-Kayaku’s NK-611 (4),9
and Taiho’s TOP-53 (5),10 all of which have enhanced
water solubility, and the latter of which may hold promise
for NSCLC applications.
racemic product.12 Meyers and co-workers recorded the
first enantioselective synthesis of (-)-podophyllotoxin
wherein all stereochemical information was elegantly
derived from a chiral oxazoline-mediated construction of
the C1′-C1 bond.13a More recently, both the Charlton and
J ones groups have disclosed asymmetric Diels-Alder
approaches, disconnecting at C1-C2 and at C3-C4 and
employing a chiral ester auxiliary appended to the
dienophile.13b,c The other enantioselective entry, due to
the Vandewalle and Bhat groups, involves C3-C4 bond
formation through conjugate addition of a sulfoxide- or
dithiane-stabilized benzylic anion upon a ring D-buteno-
lide, in which a resident chiral directing group on the
butenolide13d or on the anion13e controls facial selectivity.
Philosophically, our approach16 differs from these
syntheses in two fundamental ways: (1) absolute stere-
ochemistry is to be controlled catalytically, by means of
an enzyme-catalyzed transformation upon an unnatural
substrate,17 and (2) ring E is introduced as late as
possible in the synthesis. This latter strategem is de-
signed to permit efficient structural variation in ring E
as a tool for the study of its functional role in both the
podophyllotoxin and etoposide series (Scheme 1). Ret-
rosynthetically, then, ring E is disconnected first, with
its installation envisioned to proceed either intramolecu-
larly, via an aromatic Claisen rearrangement (w X ) H2,
Y ) O, Z ) H) or a cyclization reaction (modified Heck18
or radical 6-endo-trig w X ) CH2, O; Y ) O, S; Z ) Br,
I) from 6, or intermolecularly, via conjugate addition from
7. The trans-disposed (3-alkoxymethyl-4-alkoxy)dihy-
dronaphthalene core (6 or 7) would, in turn, arise via a
retro-Michael ring opening from 8 or 9.19 If feasible, an
isobenzofuran (IBF) Diels-Alder reaction from the steri-
cally unprotected, electron-rich IBF 11 was envisioned
to be the key step in assembling the benzoxabicyclo[2.2.1]-
heptyl substructure.20,21 This would lead to a family of
advanced meso intermediates 10 to be enzymatically
Owing both to its significant clinical role and to its
intriguing structure (e.g., heavily oxygenated aromatic
core, four contiguous chiral centers, pseudoaxial ring E,
and facile epimerization at C2 and C4), podophyllotoxin
has drawn considerable attention from synthetic chem-
ists.11-16 Nearly all first generation syntheses provided
(7) (a) Sakurai, H.; Miki, T.; Imakura, Y.; Shibuya, M.; Lee, K.-H.
Mol. Pharmacol. 1991, 40, 965-973. (b) Sinha, B. K.; Eliot, H. M.;
Kalayanaraman, B. FEBS Lett. 1988, 227, 240-244. (c) Van Maanen,
J . M. S.; de Vries, J .; Pappie, D.; van der Akker, E.; Vincent, M.;
Lafleur, M.; Retel, J .; van der Greef, J .; Pinedo, H. M. Cancer Res.
1987, 47, 4658-4662 and references therein.
(13) (a) Andrews, R. C.; Teague, S. J .; Meyers, A. I. J . Am. Chem.
Soc. 1988, 110, 7854-7858. (b) Bush, E. J .; J ones, D. W. J . Chem. Soc.,
Perkin Trans. 1 1996, 151-155. (c) Charlton, J . L.; Koh, K. J . Org.
Chem. 1992, 57, 1514-1516. (d) Van Speybroeck, R.; Guo, H.; Van der
Eycken, J .; Vandewalle, M. Tetrahedron 1991, 47, 4675-4682. (e)
Hadimani, S. B.; Tanpure, R. P.; Bhat, S. V. Tetrahedron Lett. 1996,
37, 4791-4794.
(14) For recent asymmetric syntheses of building blocks toward (-)-
podophyllotoxin, see: (a) Brinksma, J .; van der Deen, H.; van Oeveren,
A.; Feringa, B. L. J . Chem. Soc., Perkin Trans. 1 1998, 4159-4163.
(b) Lautens, M.; Rovis, T. J . Org. Chem. 1997, 62, 5246-5247. (c)
Yoshida, S.; Yamanaka, T.; Miyake, T.; Moritani, Y.; Ohmizu, H.;
Iwasaki, T. Tetrahedron 1997, 53, 9585-9598.
(15) For syntheses of 4-deoxypodophyllotoxin, isopodophyllotoxin,
4-deoxyisopodophyllotoxin, and epiisopodophyllotoxin, see: (a) Han-
essian, S.; Ninkovic, S. Can. J . Chem. 1996, 74, 1880-1888. (b) Kuroda,
T.; Takahashi, M.; Kondo, K.; Iwasaki, T. J . Org. Chem. 1996, 61,
9560-9563. (c) Bogucki, D. E.; Charlton, J . L. J . Org. Chem. 1995, 60,
588-593. (d) Pelter, A.; Ward, R. S.; Qianrong, L.; Pis, J . Tetrahe-
dron: Asymmetry 1994, 5, 909-920. (e) Itoh, T.; Chika, J .-I.; Takagi,
Y.; Nishiyama, S. J . Org. Chem. 1993, 58, 5717-5723. (f) Morimoto,
T.; Chiba, M.; Achiwa, K. Tetrahedron 1993, 49, 1793-1806 (g) Choy,
W. Tetrahedron 1990, 46, 2281-2286.
(16) Berkowitz, D. B.; Maeng, J .-H.; Dantzig, A. H., Shepard, R. L.,
Norman, B. H. J . Am. Chem. Soc. 1996, 118, 9426-9427.
(17) For discussions of chemoenzymatic natural product synthesis,
see: (a) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden,
J .; Fan, B. J . Am. Chem. Soc. 1996, 118, 10752-10765. (b) J ohnson, C.
R. Tetrahedron 1996, 52, 3769-3826. (c) Mori, K. Synlett 1995, 1097-
1109.
(8) (a) de J ong, R. S.; Slijfer, E. A. M.; Uges, D. R. A.; Mulder, N.
H.; de Vries, E. G. E. Br. J . Cancer 1997, 76, 1480-1483. (b) Soni, N.;
Meropol, N. J .; Pendyala, L.; Noel, D.; Schacter, L. P.; Gunton, K. E.;
Creaven, P. J . J . Clin. Oncol. 1997, 15, 766-772. (c). Kreis, W.;
Budman, D. R.; Vinciguerra, V.; Hock, K.; Baer-J oann, I. R.; Schacter,
L. P.; Fields, S. Z. Cancer Chemother. Pharmacol. 1996, 38, 378-384.
(9) (a) Rassmann, I.; Thodtmann, R.; Mross, M.; Huttmann, A.;
Berdel, W. E.; Manegold, C.; Fiebig, H. H.; Kaeserfrolich, A.; Burk,
K.; Hanauske, A. R. Invest. New Drugs 1998, 16, 319-324. (b) Mross,
K.; Huettmann, A.; Herbst K.; Hanauske, A. R.; Schilling, T.; Manegold,
C.; Burk, K.; Hossfeld, D. K. Cancer Chemother. Pharmacol. 1996, 38
217-224.
(10) Utsugi, T.; Shibata, J .; Sugimoto, Y.; Aoyagi, K.; Wierzba, K.;
Kobunai, T.; Terada, T.; Oh-hara, T.; Tsuruo, T.; Yamada, Y. Cancer
Res. 1996, 56, 2809-2814.
(11) For reviews of synthetic approaches to the Podophyllum
lignans, see: (a) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96 and pre-
vious reviews in this series. (b) Ward, R. S. Synthesis 1992, 719-730.
(12) For syntheses of (()-podophyllotoxin, see: (a) Kraus, G. A.; Wu,
Y. J . Org. Chem. 1992, 57, 2922-2925. (b) Peterson, J . R.; Hoang, D.
D.; Rogers, R. D. Synthesis 1991, 275-277 (c) J ones, D. W.; Thompson,
A. M. J . Chem. Soc., Chem. Commun. 1987, 1797-1798. (d) Kaneko,
T.; Wong, H. Tetrahedron Lett. 1987, 28, 517-520. (e) Vyas, D. M.;
Skonezny, P. M.; J enks, T. A.; Doyle, T. W. Tetrahedron Lett. 1986,
27, 3099-3102. (f) Macdonald, D. I.; Durst, T. J . Org. Chem. 1986, 51,
4749-4750. (g) J ung, M. E.; Lowen, G. T. Tetrahedron Lett. 1986, 27,
5319-5322. (h) J ung, M. E.; Lam P. Y.; Mansuri, M. M.; Speltz, L. M.
J . Org. Chem. 1985, 50, 1087-1105. (i) Van der Eycken, J .; De Clercq,
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Kende, A. S.; King, M. L.; Curran, D. P. J . Org. Chem. 1981, 46, 2826-
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E.-I.; Luo, F.-T.; Cheng, J .-W. Tetrahedron Lett. 1988, 29, 3903-3906.
(19) For examples of retro-Michael cycloreversions in oxabicyclo-
[2.2.1]heptyl systems bearing an acidic hydrogen R to the bridgehead,
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62, 1093-1098. (b) Keay, B. A.; Rodrigo, R. Tetrahedron 1984, 40,
4597-4607.

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 849
Sch em e 1
Sch em e 2
to be both the most convenient and the most efficient
(82% isolated yield) procedure.
Interestingly, condensation of IBF precursor 14 with
commercial dimethyl maleate (Aldrich, contains 5% dim-
ethyl fumarate) under conditions of acid catalysis pro-
duces a nearly equimolar mixture of the undesired
(chiral, racemic) fumarate cycloadduct 15 and the meso
adducts 16 (endo) and 17 (exo), derived from maleate
(Scheme 3). A control experiment established that none
of the observed 15 arose from dienophile isomerization.
Thus, careful fractional distillation of commercial dim-
ethyl maleate removed all traces of the fumarate geo-
metric isomer. Exposure of 14 to analytically pure
dimethyl maleate produced only 16 and 17 (Scheme 4).
So, one is led to the rather remarkable conclusion that
IBF 11 generated in situ reacts about 15 times faster
with dimethyl fumarate than with dimethyl maleate.
Sch em e 3
desymmetrized and then manipulated into the requisite
enolate (8 or 9).
Resu lts a n d Discu ssion
Given the projected instability of IBF 11, we chose to
target 14 as the IBF precursor from which 11 might be
generated in situ.22 Our synthesis emanates from piper-
onal and follows established procedures for its regiospe-
cific bromination and subsequent acetalization to 12.23
The hydroxymethylation of 12 was examined under a
variety of conditions. Initially, formaldehyde gas was
employed as the electrophile, but less than satisfactory
yields of 14 were obtained (Scheme 2). We then turned
to an indirect approach, using dimethylformamide as a
formyl cation equivalent, followed by borohydride reduc-
tion of aldehyde 13 (51%, two steps). In the end, the use
of solid paraformaldehyde as formaldehyde source proved
Sch em e 4
(20) This is to be contrasted with “sterically protected” IBFs such
as 1,3-diphenyl-IBF that are much more easily handled yet reactive
enough to trap alkenes with short lifetimes. For examples, see:
Friedrichsen, W. Adv. Hetereocycl. Chem. 1980, 26, 135-241.
(21) For a review of the use of isobenzofurans in natural product
synthesis, see: Rodrigo, R. Tetrahedron 1988, 44, 2093-2135.
(22) Both acid- and base-catalyzed 1,4-elimination of alkoxydihy-
droisobenzofurans to the corresponding isobenzofurans are well-
known: Tobia, D.; Rickborn, B. J . Org. Chem. 1987, 52, 2611-2615.
(23) Bromination (84% yield): (a) Conrad, P. C.; Kwiatkowski, P.
L.; Fuchs, P. L. J . Org. Chem. 1987, 52, 586-591. Acetalization (96%
yield): (b) Keay, B. A.; Plaumann, H. P.; Rajapaksa, D., Rodrigo, R.
Can J . Chem. 1983, 61, 1987-1995.
Aware that the endo product often predominates in
IBF Diels-Alder reactions with dienophiles bearing
carbonyl EWGs, we were somewhat disappointed with
the 2.8:1 endo:exo ratio obtained. However, further
examination of the literature reveals an apparent pattern
of reactivity, whereby IBFs bearing unsaturated substit-
uents at the 1- and/or 3-positions often give considerably

850 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
Sch em e 5. A Sp ectr u m of Ad va n ced m eso
Ta ble 1. En d o/Exo Selectivity in IBF Diels-Ald er
Rea ction s w ith Dim eth yl Ma lea te
In ter m ed ia tes
candidum)26a and P (Pseudomonas cepacia),26b RLE, PLE
(rabbit and pig liver esterases),26c PPL (porcine pancreatic
lipase),26d chymotrypsin,26e and penicillin acylase,26f all
of which have demonstrably broad substrate specificity
that includes at least monocyclic esters. It should be
noted that substrates 21 and 22 were targeted toward
chymotrypsin and penicillin acylase, respectively, reflect-
ing the propensity of the former enzyme for cleavage of
esters or amides derived from aromatic amino acids and
the specificity of the latter enzyme for the arylacetyl
groups.26f
We were also drawn to HLADH (horse liver alcohol
dehydrogenase) through the elegant work of J ones and
co-workers. The Toronto group has demonstrated that a
rather diverse spectrum of meso diols, including nonben-
zenoid, oxabicyclo[2.2.1]heptyl diol 23, may be efficiently
desymmetrized through HLADH-mediated four-electron
oxidation, with the participation of a nicotinamide co-
factor (Scheme 6).27
a
In these cases, single crystalline products with sharp melting
b
points were obtained. They are presumed to be endo. Ar ) 3,5-
dibromo-4-hydroxyphenyl; diethyl maleate was used as dienophile
in this case.
higher endo/exo ratios than their 1,3-unsubstituted coun-
terparts (Table 1). This may be an indication that such
1,3-IBF substituents are capable of participating in
favorable secondary orbital interactions with the car-
boxylate ester groups of the dienophile in endo IBF
Diels-Alder transition states.
For our purposes, the endo/exo mixture could nicely
be avoided by generating IBF 11 in neat dimethyl
acetylenedicarboxylate (DMAD) under HOAc catalysis
(Scheme 4), followed by catalytic hydrogenation. Under
these conditions, excellent yields of cycloadduct 18 are
reproducibly obtained, even on a 20 g scale (90%). The
excess DMAD is routinely reclaimed by distillation and
employed for subsequent cyclocondensation reactions.
Catalytic hydrogenation occurs exclusively from the less
hindered exo face in 18, as expected, providing 16, which
may be cleanly reduced to diol 19. Thus, diol 19 is
obtained from piperonal in six steps and 53% overall
yield.
Sch em e 6
En zym a tic Desym m etr iza tion . Though there are
many examples of enzymatic resolutions and desymme-
trizations of relatively simple mono- and bridged bicyclic
substrates,17b,c there are few examples of enzymatic
manipulations on polycyclic unnatural substrates, such
as the series of meso tetracycles (in the C13O5-C29O7
range) being examined here (Scheme 5). We therefore
took a “combinatorial” approach to the problem, whereby
a battery of about a dozen predominantly acyl transfer
enzymes would be screened with a range of potential
ester and alcohol substrates.25 Among the more attractive
choices for acyl transferases were lipases GC (Geotrichum
J ust over 100 screening experiments were performed
among the five meso intermediates 16 and 19-22 and
these eight enzymes. Among the variables examined were
buffer, pH, temperature, weight equivalents of enzyme,
enzyme stabilizers, and agitation method (shaking vs
magnetic stirring vs mechanical stirring). Unfortunately,
(26) (a) Murata, M.; Ikoma, S.; Achiwa, K. Chem. Pharm. Bull. 1990,
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Tetrahedron Lett. 1985, 26, 4087-4090. (d) Hemmerle, H.; Gais, H.-J .
Tetrahedron Lett. 1987, 28, 3471-3474, (e) J ones, J . B. Methods
Enzymol. 1976, 44, 831-856. (f) Holla, E. W. J . Carbohydr. Chem.
1990, 9, 113-119.
(27) (a) J ones, J . B.; Francis, C. J . Can. J . Chem. 1984, 62, 2578-
2582. (b) Grunwald, J .; Wirz, B.; Scollar, M. P.; Klibanov, A. M. J .
Am. Chem. Soc. 1986, 108, 6732-6734.
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5231-5234. (b) Meegalla, S. K.; Rodrigo, R. J . Org. Chem. 1991, 56,
1882-1888. (c) Weiss, R.; Mayer, F. Monatsh. Chem. 1937, 71, 6-9.
(d) Freslon, G.; Lepage, Y. Comptes Rendus Acad. Sci., Ser. C 1975,
280, 961-963.
(25) For a detailed account of these enzymatic desymmetrizations,
see: Berkowitz, D. B.; Maeng, J .-H. Tetrahedron: Asymmetry 1996,
7, 1577-1580.

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 851
Sch em e 7
It was discovered fortuitously that one can conduct a
sequential desilylation-hemiacetalization-oxidation se-
quence in one pot, under modified Lindgren oxidation
conditions.29 Indeed, under the original conditions of
Lindgren,29a which include sulfamic acid as Cl2 scavenger,
one isolates some of the desired lactone. Noticing this,
we chose to promote the desilylation by adding HF. In
this way, lactone 28 may be isolated in very good yield
directly from TBS-protected γ-hydroxyaldehyde 27a .
Unfortunately, however, the lactone fails to give the
desired ring-opening reaction upon incubation with a
variety of bases (NaOMe/MeOH; LDA/BF3 ‚Et2O; AlBr3/
THF; [(CH3)3Si]2NK/18-Cr-6/THF; KOtBu/DMSO). That
deprotonation indeed occurs could be established by
trapping the lactone enolate with methyl iodide.
At this point, we turned to molecular mechanics (PC
Model, MMX force field) to examine orbital overlap in
this system. Minimization of the potassium enolate of
lactone 28 gives a predicted geometry in which the
π-system is nearly orthogonal to the C1-O σ* orbital (81°
“dihedral” angle, where 0° corresponds to direct overlap
of these orbitals). Hence, it appears that the geometric
constraints imposed on an already somewhat rigid
benzoxabicyclo[2.2.1]heptyl system, by confining the eno-
late carbonyl to a γ-lactone ring, prevent the retro-
Michael reaction in 8.
HLADH (from both Sigma and Boehringer Mannheim)
failed to accept diol 19 as substrate under a large variety
of conditions, including those of Jones27a and of Klibanov.27b
However, acyl transfer chemistry was successful in
both the acylation (lipases P and GC with diol 19 and
vinyl acetate) and deacylation directions (RLE-, PLE-,
and PPL-catalyzed hydrolyses of diacetate 20).25 In the
end, the best match paired PPL with diacetate 20. Under
appropriate conditions, monoacetate 25 could be repro-
ducibly obtained in 95% ee, even on 10-20 g scales
(Scheme 7). It proved most convenient to terminate the
reaction at about two-thirds conversion to minimize diol
formation. Unreacted diacetate is then easily recycled.
Taking into account the recovered starting diacetate, this
procedure provides for an 83% yield of desymmetrized
tetracycle 25. Interestingly, the observed absolute ster-
eochemistry for 25 is opposite to that predicted by the
most comprehensive model for PPL hydrolyses of which
we are aware.25,28 This is probably because 20 is consid-
erably more complex (higher carbon count, polycyclic)
than those unnatural substrates upon which that model
is based.
On the other hand, the MMX-minimized geometry of
the corresponding “unconstrained” aldehyde-enolate (9)
indicates considerably better π-σ* overlap (63° “dihedral”
angle). In fact, treatment of 27 with base (LiHMDS,
NaHMDS, KHMDS/18-Cr-6, NaOMe/MeOH) leads to
retro-Michael ring opening. A TIPS protecting group (i.e.,
27b) is preferable to a TBS group, as the latter migrates
to the C4-O under some conditions. Reproducibly high
yields are achieved with methoxide as base (Scheme 9).
Sch em e 8. Th e La cton e En ola te F a ils to Rin g
Op en
Sch em e 9. Th e Acyclic En ola te Retr o-Mich a el
Rin g Op en s
The proper stereochemistry for (-)-podophyllotoxin has
now been set at both C3 and C4 in 30. However, that
stereochemical information is readily lost, as this 4-hy-
droxy-3-silyloxymethyl dihydronaphthalene intermediate
is quite susceptible to aromatization via elimination
under acidic conditions. Fortunately, 30 can be cleanly
protected with ether- or acetal-type protecting groups
provided that neutral to basic conditions are maintained
(Scheme 10). Aldehyde 31 can be further transformed
into several other potential Michael acceptors, with an
eye toward installing ring E via conjugate addition. Thus,
methyl ester 32 is obtained in a single step via allylic
cyanohydrin oxidation under the Corey-Ganem condi-
tions,30 or in two steps via Lindgren oxidation29 and
treatment with diazomethane. Desilylation and trans-
esterification under Ti(O-i-Pr)4 catalysis31 then provide
R,â-unsaturated lactone 33.
Ela bor a tion of Ch ir a l Mon oa ceta te 25. Having
established asymmetry, we next sought to convert the
benzoxabicyclo[2.2.1]heptyl core of monoacetate 25 into
the desired 4-hydroxydihydronaphthalene system via a
retro-Michael ring opening. In the original retrosynthetic
analysis (Scheme 1), lactone enolate 8 was to serve as
the substrate for this transformation. Monoacetate 25
could be cleanly transformed into silyl ether(s) 26a (b)
(Scheme 8). Given the possibility for racemization via
acetyl or silyl migration here, optical purity was exam-
ined by Mosher esterification. No loss of optical activity
was observed, indicating that the seven-membered tran-
sition states required for these intramolecular migrations
are not readily accessible, even under mildly basic
conditions at room temperature. The ensuing Swern
oxidation proceeds smoothly.
(29) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888-890. (b) Balkrishna, S. B.; Childers, W. E., J r.; Pinnick, H. W.
Tetrahedron 1981, 37, 2091-2096.
(30) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616-5617.
(31) Imwinkelried, R.; Schiess, M.; Seebach, D. Org. Synth. 1987,
65, 230-235.
(28) Wimmer, Z. Tetrahedron 1992, 48, 8431-8436.

852 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
Sch em e 13. Attem p ted 6-en d o-tr ig Heck
Sch em e 10. Ela bor a tion to P oten tia l Mich a el
Accep tor s
Cycliza tion
vinylogous carbonate esters) only sluggishly add aryl-
copper reagents led us to pursue several alternative
approaches to the installation of ring E in parallel to
these conjugate addition studies.
We were especially interested in the possibility of
exploiting intramolecularity and chose to examine several
potential cyclization routes. A Heck cyclization was
attractive here as ring E might be brought in through
an ester/thioester linkage to the C2-carboxyl group. It
might appear difficult to achieve such a cyclization as (i)
the migratory insertion step would have to proceed in a
6-endo-trig mode and (ii) the â-hydride elimination would
appear to be forbidden, as the Pd and the â-hydrogen
would be trans-disposed following that migratory inser-
tion. However, a Heck cyclization of this general class
has been described by Ishibashi and co-workers,19a and
Negishi’s group has reported a couple of related 5-endo-
trig Heck cyclizations.19b Ishibashi accounts for the
â-hydride elimination by proposing an isomerization from
the initial trans-Pd/â-H insertion complex to the cis
complex through the intermediacy of a Pd-enolate. Al-
ternatively, both authors use excess base, so an external
base mediated elimination cannot logically be ruled out.
The model o-bromothioester 40 could be assembled
from the corresponding acid via activation as the acyl
imidazolide. Treatment of 40 under a variety of Heck
conditions produced no cyclized products but rather gave
modest yields of either reduced starting material (Scheme
13) or lactone 33 (10% Pd(OAc)2, 20% PPh3, NaHCO3,
DMF, 80 °C). It is worthy of note that Negishi’s and
Ishibashi’s systems contain one and two sp3-carbons,
respectively, within the five- and six-membered transition
states required for their Heck cyclizations. The σ-complex
obtained after oxidative addition of PdL2 to aryl bromide
40 may not be able to achieve a geometry that permits
6-endo-trig migratory insertion.
Ap p r oa ch es to th e In tr od u ction of Rin g E. At this
point, a model study was carried out to establish the best
Michael acceptor and conditions for the projected conju-
gate addition. With the esters initially examined (Scheme
11), higher order cyanocuprates32 perform best and
addition of BF3 ‚Et2O is beneficial. Provided that freshly
prepared phenyllithium is used,33 conjugate addition of
a higher order phenylcuprate to ethyl crotonate proceeds
quite smoothly. The same conditions also lead to the
desired 1,4-adduct with the methylenedioxy-substituted
cinnamate ester 36.34 Conjugate addition was not ob-
served in these systems using (i) higher order cuprates
in the presence of TMSCl, (ii) higher order cuprates in
the absence of BF3 ‚Et2O, or (iii) lower order Gilman
cuprates.
Sch em e 11. Mod el Ar ylcu p r a te Con ju ga te
Ad d ition s
Sch em e 12. Ar om a tiza tion in th e P r esen ce of
Activa tin g Lew is Acid s
Along the same lines, it seemed reasonable to attempt
a 6-endo-trig radical cyclization on a similar system. In
light of the thiophilicity of trialkyltin radicals, we chose
to move away from the thioester. Instead, o-bromophenyl
ester 43 was constructed in a similar manner and
subjected to standard radical cyclization conditions
(Scheme 14). After 12 h at reflux, aside from recovered
starting bromoester, reduced starting material was the
only identifiable product. Apparently, hydrogen abstrac-
tion from HSnBu3 by the intermediate aryl radical is
faster than cyclization in this system.
Unfortunately, the same conditions that promote aryl-
copper addition in model system 36 lead to aromatization
in R,â-unsaturated ester 32c (Scheme 12). The realization
that such (3,4-methylenedioxy)cinnamate esters (triply
The feasibility of an aryl Claisen rearrangement was
next investigated with p-methoxyphenyl ether 45. The
allylic alcohol precursor is obtained through reduction
of R,â-unsaturated aldehyde 31b with sodium tri-
methoxyborohydride. Williamson-type conditions (on the
(32) Lipshutz, B. H.; Moretti, R.; Crow, R. Org. Synth. 1990, 69,
80-88 and references therein.
(33) Schlosser, M.: Ladenberger, V. J . Organomet. Chem. 1967, 8,
193-197.
(34) The corresponding acid is commercially available, making this
a convenient model system.

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 853
Sch em e 14. Attem p ted 6-en d o-tr ig Ra d ica l
Cycliza tion
Sch em e 16. Acyl Oxa zolin on e Mod el Ar ylcu p r a te
Con ju ga te Ad d ition s
bromide (CuBr-SMe2) and (3,4,5-trimethoxy)phenylmag-
nesium bromide (CuCN). It is important to note that for
the heavily oxygenated natural ring E, cuprate formation
must be carried at a much higher temperature (-10 f
10 °C) than for the simple phenylcopper reagent (-78
°C suffices). If 50 is introduced into a mixture of ArMgBr
and CuCN at lower temperatures (presumably prior to
cuprate formation) the reaction is not clean and produces
little to no conjugate addition product.
corresponding mesylate, with p-methoxyphenolate) failed
to give the requisite allylic ether. Eventually 45 was
produced in modest yield by a modified Mitsunobu
protocol.35 Upon attempting the Claisen rearrangement
by heating 45 to 210 °C in 1,2-dichlorobenzene in a sealed
tube, a 60% yield of aromatized product was obtained
(Scheme 15). Apparently, the formal syn elimination of
benzyl alchohol (leading to aromaticity) represents a
more favorable reaction manifold than the Claisen rear-
rangement (requiring temporary loss of aromaticity) for
this system at elevated temperatures. So, in both the
intermolecular and intramolecular approaches to ring E
installation, the sensitivity of our (4-alkoxy)dihydronaph-
thalene system to aromatization loomed large.
Sch em e 17. F a cile a n d Mod u la r In tr od u ction of
Rin g E
Apparently then, under the optimized conditions, the
R,â-unsaturated acyl oxazolidinone in 50 is chemoselec-
tively activated for 1,4-addition (Scheme 17). No aroma-
tization products are observed. Importantly, the aryl
group is introduced stereoselectively at C1, with only the
desired re face addition product being observed. This is
presumably due, in large part, to the sterically demand-
ing TIPS group, which is thought to block the si face from
attack by ArCuMgBrX. The resulting enolate is appar-
ently also protonated from the same sterically more
accessible R-face in the workup to provide 51 or 52 with
the correct relative and absolute stereochemistry for (-)-
picropodophyllin.
Sch em e 15. Attem p ted Ar om a tic Cla isen
Rea r r a n gem en t
As per design, only two steps (desilylative lactonization
and SEM deprotection) separate conjugate addition
product 52 from (-)-picropodophyllin (Schemes 18 and
19). Note that, with the natural E ring in place (i.e., 53),
only a small amount of thioether byproduct (56) ac-
companies the normal SEM deprotection product under
these modified Kim conditions.36
A Solu tion for Ster eocon tr olled Con ju ga te Ad d i-
tion a t C1. Our model work in the intermolecular
conjugate addition with conjugate additions to (3,4-
methylenedioxy)cinnnamate esters had demonstrated the
need for Lewis acid activation of the ester. However, with
Michael acceptor 32c, Lewis acids such as BF3 ‚Et2O
promote elimination across C3-C4 (presumably by acti-
vating the C4-leaving group) more efficiently than con-
jugate addition. Faced with this conundrum, we sought
to modify the Michael-acceptor functionality so as to
permit a more chemoselective activation. We surmised
that an R,â-unsaturated acyl oxazolidinone, with its
potential for bidentate metal chelation might well be
activated with milder Lewis acids (e.g., MgX2).
Sch em e 18
Indeed, treatment of model R,â-unsaturated acyl ox-
azolidinone 47 with Normant-type organocopper reagents
(Scheme 16), formed from CuX and ArMgX (1:1 stoichi-
ometry), produces excellent yields of the desired conju-
gate addition products, with both phenylmagnesium
To access (-)-podophyllotoxin, a C2 epimerization step
is introduced immediately following lactonization. Pen-
ultimate epimerization to the thermodynamically less
stable trans-lactone is a common feature of podophyllo-
toxin syntheses, from the earliest work of Gensler,12n
(35) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Fukuyama, T.;
Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985, 26, 6291-6292.
(c) Petitou, M.; Duchaussoy, P.; Choey, J . Tetrahedron Lett. 1988, 29,
1389-1390.
(36) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J . H. Synlett 1991, 183-
184.

854 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
chloride, pyridine, and diisopropylamine were distilled over
CaH2. THF, Et2O, and benzene were distilled over sodium/
benzophenone. Methanol was distilled over Mg/I2. n-Butyl-
lithium in hexanes was purchased from Aldrich and titrated
before use. Mass spectra were acquired at the Nebraska Center
for Mass Spectrometry (University of Nebraska-Lincoln) and
are reported as m/z (relative intensity). Elemental analyses
were carried out by M-H-W Labs (Phoenix, AZ) or Q-T-I Labs
(Whitehouse, NJ ).
Sch em e 19
4-(Dim et h oxy)m et h yl-5-for m yl(1,2-m et h ylen ed ioxy)-
ben zen e (13). To a solution of bromoacetal 12 (0.50 g, 1.8
mmol) in THF (8 mL) at -78 °C was added n-BuLi (1.45 mL,
1.8 mmol, 1.25 M in hexanes) dropwise via syringe. After
stirring for 1 h at 0 °C, the resulting aryllithium solution was
cooled to -78 °C,and DMF (0.87 mL, 11.2 mmol) was added.
After slowly warming to room temperature and stirring for 2
h, the reaction was poured into H2O-Et2O. The water layer
was extracted with two additional portions of Et2O, and the
combined organics were dried (Na2SO4), filtered, and concen-
trated. Flash chromatography (hexanes-Et2O-NEt3 66:33:0.5)
provided aldehyde 13 (0.25 g, 61%): 1H NMR (300 MHz, C6D6)
δ 3.00 (s, 6 H), 5.17 (s, 2 H), 5.53 (s, 1 H), 7.15 (s, 1 H), 7.52
(s, 1 H), 10.4 (s, 1 H); 13C NMR (75 MHz, C6D6) δ 52.8, 100.6,
101.9, 107.8, 107.9, 129.8, 137.6, 148.5, 152.0, 188.7; HRMS
(FAB, 3-NBA, NaI) calcd for C11H12O5Na 247.0582, obsd
247.0592.
Sch em e 20
4-(Dim eth oxy)m eth yl-5-h ydr oxym eth yl(1,2-m eth ylen e-
d ioxy)ben zen e (14). Meth od A. Aldehyde 13 (0.25 g, 1.1
mmol) was dissolved in absolute EtOH (10 mL), and the
solution was cooled to 0 °C. Sodium borohydride (0.1 g, 2.9
mmol) was added, and the reaction mixture was stirred
overnight at room temperature. The reaction was quenched
by pouring into ice/ethyl acetate, followed by acidification to
pH 6.5 with 2 N HCl. The water layer was extracted with Et2O,
and the combined organics were dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes-Et2O-
NEt3 50:50:0.5) provided the product (0.21 g, 83%): 1H NMR
(200 MHz, C6D6) δ 2.47 (t, J ) 6 Hz, 1 H), 2.97 (s, 6 H), 4.50
(d, J ) 6 Hz, 2 H), 5.29 (s, 2 H), 5.31 (s, 1 H), 6.86 (s, 1 H),
7.27 (s, 1 H); 13C NMR (125 MHz, C6D6) δ 52.8, 62.6, 101.6,
101.8, 108.4, 110.1, 130.4, 134.8, 147.5, 148.4; HRMS (EI) calcd
through the approaches of Kende12k and Meyers.13a In our
system, we find that the conditions of Kende (pyridinium
chloride quench) provide the most satisfactory results,
in terms of yield, trans:cis ratio, and reproducibility. In
the case at hand, 4-O-SEM-podophyllotoxin (53) is readily
separated from 4-O-SEM-picropodophyllin (54). The former
acetal is then deprotected smoothly to provide a sample
of the natural product that matches an authentic sample
in all respects.
Con clu sion s
for
C11H14O5 226.0841, obsd 226.0843. Anal. Calcd for
C
11H14O5: C, 58.39; H, 6.24. Found: C, 58.20; H, 6.07.
Meth od B. To a solution of bromoacetal 12 (10.0 g, 36.3
This report details the first catalytic, asymmetric
synthesis of (-)-podophyllotoxin. An IBF Diels-Alder
reaction is used to rapidly assemble a family of advanced,
tetracyclic meso intermediates of the benzoxabicyclo-
[2.2.1]heptyl variety. One of these, diacetate 20 is ef-
ficiently enzymatically desymmetrized (95% ee, 83%
corrected yield) with PPL in a mixed organic (DMSO)/
aqueous milieu. The need to synthesize, attach, and
recover a chiral auxiliary is circumvented via the use of
an inexpensive, commercially available enzyme. Key
steps in the elaboration of enzymatic product 25 into the
natural product include (i) the efficient retro-Michael ring
opening of “unconstrained” enolate 9, which unveils the
(methylenedioxy)cinnamate core, and (ii) its chemoselec-
tive and stereoselective activation, as an acyl oxazolidi-
none (50), for the introduction of ring E. Most impor-
tantly, ring E is deliberately introduced late in the
synthesis, only three steps from the final product. The
efficient installation of the highly oxygenated natural
ring E of podophyllotoxin described herein attests to the
potential of this synthetic route for structure/function
studies in this sector of the natural product.
mmol) in THF (100 mL) at -78 °C was added n-BuLi (25.0
mL, 40.6 mmol, 1.6 M in hexanes) dropwise via syringe. After
the solution was stirred for 1 h at 0 °C, a suspension of
paraformaldehyde (3.30 g, 36.7 mmol) in THF (60 mL) was
added via cannula. The reaction was warmed to room tem-
perature, stirred for 2 h, and then quenched with H2O/Et2O.
The aqueous layer was extracted with Et2O, and the combined
organics were dried (MgSO4), filtered, and concentrated. Flash
chromatography (50% EtOAc/hexanes) gave 14 (6.75 g, 82%)
with spectral characteristics as before. On a larger scale, 12
(50 g, 182 mmol) gave 14 in 72% yield (29.7 g).
Dim eth yl (1R*,2S*,3S*,4S*)-1,4-Ep oxy-6,7-m eth ylen e-
d ioxy-1,2,3,4-t et r a h yd r o-2,3-n a p h t h a len ed ica r b oxyla t e
(15) a n d m eso-(1R*,2S*,3R*,4S*)-(en d o)-isom er (16) a n d
m eso-(1R*,2R*,3S*,4S*)-(exo)-isom er (17). IBF precursor 14
(250 mg, 1.1 mmol) was dissolved in dimethyl maleate (Aldrich,
3.19 g, 22.1 mmol; contains ∼1.1 mmol dimethyl fumarate and
∼21 mmol dimethyl maleate) and glacial AcOH (0.25 mL), and
the mixture was stirred for 2 h at 80 °C. Excess dimethyl
maleate was removed by vacuum distillation. Flash chroma-
tography (33% EtOAc/hexanes) provided the major product 15
(105 mg, 31%) in a first fraction, followed by 16 (98 mg, 29%)
and 17 (37 mg, 11%) in subsequent fractions. For 15: 1H NMR
(300 MHz, CDCl3) δ 3.00 (d, J ) 4 Hz, 1 H), 3.58 (s, 3 H), 3.78
(s, 3 H), 3.83 (dd, J ) 4, 5 Hz, 1 H), 5.52 (d, J ) 5 Hz, 1 H),
5.58 (s, 1 H), 5.93 (d, J ) 2 Hz, 1 H), 5.96 (d, J ) 2 Hz, 1 H),
6.68 (s, 1H), 6.82 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 49.2,
49.4, 52.1, 52.6, 80.4, 82.9, 101.4, 101.5, 102.5, 136.1, 137.9,
146.8, 147.1, 170.2, 172.3; HRMS (FAB, ONPOE) calcd for
Exp er im en ta l Section
Gen er a l. All reactions were conducted under an argon
atmosphere using oven-dried glassware. For air- or water-
sensitive reactions, glassware was flame-dried and then al-
lowed to cool under an Ar atmosphere before use. Methylene
C
15H14O7 306.0740 [M+], obsd 306.0730.

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 855
1
For 16: mp 96-99 °C; H NMR (300 MHz, CDCl3) δ 3.53
pyridine (2 mL) at 0 °C was added benzoyl chloride (0.1 mL,
0.88 mmol) dropwise via syringe. After 1 h at 0 °C, additional
benzoyl chloride (50 µL, 0.44 mmol) and DMAP (5 mg, 0.04
mmol) were added. The resulting reaction mixture was allowed
to warm to room temperature overnight, and saturated aque-
ous NaHCO3 was added. The mixture was extracted with
EtOAc, and the organics were washed with 1 N HCl and
CuSO4 (saturated aqueous). Drying (MgSO4), filtration, con-
centration, and chromatography (33% EtOAc/hexanes) yields
21 (138 mg, 75%): 1H NMR (300 MHz, CDCl3) δ 3.07-3.12
(m, 2 H), 3.60 (dd, J ) 10, 11 Hz, 2 H), 4.11 (dd, J ) 5, 11 Hz,
2 H), 5.41 (d, J ) 4 Hz, 2 H), 5.92 (d, J ) 1 Hz, 1 H), 5.98 (d,
J ) 1 Hz, 1 H), 6.81 (s, 2 H), 7.25-8.12 (m, 10 H); 13C NMR
(75 MHz, CDCl3) δ 40.1, 62.9, 81.7, 101.4, 103.2, 128.5, 129.6,
129.7, 136.1, 147.0, 166.0; HRMS (FAB, 3-NBA, NaI) calcd for
C27H22O7Na 481.1263, obsd 481.1272.
m eso-(1R*,2R*,3S*,4S*)-2,3-Bis[(2′-p h en yl)a cetoxym e-
t h yl]-1,4-ep oxy-6,7-m et h ylen ed ioxy-1,2,3,4-t et r a h yd r o-
n a p h th a len e (22). To a solution of diol 19 (50 mg, 0.2 mmol)
in CH2Cl2 (6 mL) and triethylamine (0.1 mL) at -35 °C was
added phenylacetyl chloride (58 µL, 0.44 mmol) dropwise via
syringe. The solution was warmed slowly to room temperature
over 3 h and stirred at room temperature for 12 h. Saturated
aqueous NaHCO3 was added, and then the reaction mixture
was extracted with EtOAc. The combined organic layers were
dried (MgSO4), filtered, concentrated, and chromatographed
(80% EtOAc/hexanes) to give 22 (80 mg, 82%): 1H NMR (300
MHz, CDCl3) δ 2.76-2.80 (m, 2 H), 3.14 (t, J ) 10 Hz, 2 H),
3.63 (s, 4H), 3.75 (dd, J ) 5, 11 Hz, 2 H), 5.04 (d, J ) 4 Hz, 2
H), 5.90 (d, J ) 1 Hz, 1 H), 5.95 (d, J ) 1 Hz, 1 H), 6.32 (s, 2
H), 7.27-7.40 (m, 10 H);13C NMR (75 MHz, CDCl3) δ 39.5,
41.3, 62.5, 81.2, 101.1, 102.8, 127.2, 128.6, 129.0, 133.7, 135.6,
146.5, 170.6; HRMS (FAB, 3-NBA, NaI) calcd for C29H26O7Na
509.1576, obsd 509.1594.
(s, 6H), 3.61 (dd, J ) 2, 3 Hz, 2 H), 5.41 (dd, J ) 2, 3 Hz, 2 H),
5.92 (d, J ) 2 Hz, 1 H), 5.96 (d, J ) 1 Hz, 1 H), 6.82 (s, 2 H);
13C NMR (125 MHz, CDCl3) δ 48.3, 52.3, 81.5, 101.9, 103.9,
137.2, 147.5, 170.5. Anal. Calcd for C15H14O7: C, 58.83; H, 4.61.
Found: C, 58.90; H, 4.71.
For 17: 1H NMR (300 MHz, CDCl3) δ 2.89 (s, 2 H), 3.71 (s,
6 H), 5.57 (s, 2 H), 5.93 (d, J ) 1 Hz, 1 H), 5.96 (d, J ) 1 Hz,
1 H), 6.77 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 49.7, 52.3, 81.2,
101.4, 101.6, 138.1, 147.0, 171.5; HRMS (FAB, 3-NBA, NaI)
calcd for C15H14O7Na 329.0637, obsd 329.0626.
In a control experiment, 14 (125 mg, 0.55 mmol) was treated
with pure dimethyl maleate (398 mg, 2.76 mmol; obtained by
fractional distillation) and HOAc (0.13 mL) under the above
conditions to produce 16 (87 mg, 52%) and 17 (31 mg, 18%).
No “fumarate adduct” 15 was observed in this experiment.
Dim eth yl 1,4-Dih yd r o-1,4-ep oxy-6,7-m eth ylen ed ioxy-
2,3-n a p h th a len e-d ica r boxyla te (18). The substrate (23.7 g,
105 mmol) was dissolved in excess DMAD (251 g, 1.76 mol)
and glacial AcOH (23.2 mL, 0.4 mol), and the mixture was
stirred for 2 h at 80 °C. Excess DMAD was removed by vacuum
distillation, and flash chromatography (30% EtOAc/hexanes)
gave 18 (56.4 g, 90%) as a yellow solid. On a smaller scale, 14
(5.53 g, 24.1 mmol) gave 18 in 92% yield (13.6 g): mp 117-
1
119 °C; H NMR (300 MHz, CDCl3) δ 3.79 (s, 6 H), 5.86 (s, 2
H), 5.90 (d, J ) 1 Hz, 1 H), 5.95 (d, J ) 1 Hz, 1 H), 6.95 (s, 2
H); 13C NMR (125 MHz, CDCl3) δ 53.0, 85.7, 102.2, 105.2,
141.4, 146.2, 152.5, 163.5. Anal. Calcd for C15H12O7: C, 59.21;
H, 3.98. Found: C, 59.27; H, 4.11.
Dim eth yl m eso-(1R*,2S*,3R*,4S*)-1,4-Ep oxy-6,7-m eth -
ylen ed ioxy-1,2,3,4-tetr a h yd r o-2,3-n a p h th a len ed ica r box-
yla te (16). IBF Diels-Alder product 18 (43.2 g, 0.14 mol) was
dissolved in EtOAc (300 mL), and 10% Pd/C (1.5 g) was added.
The reaction mixture was hydrogenated at 48 psi for 6 h. The
reaction mixture was filtered through Celite and concentrated
to give 16 as a white solid (43.1 g, 99%; identical to 16 produced
independently, vide supra).
(1R,2R,3S,4S)-2-Acet oxym et h yl-1,4-ep oxy-3-h yd r oxy-
m eth yl-6,7-m eth ylen edioxy-1,2,3,4-tetr ah ydr on aph th alen e
(25). A 5 L RB flask was charged with PPL (263 g, crude,
Sigma) and buffer solution (50 mM KPO4, pH 7.8, 3.5 L).
Diacetate 20 (20.0 g, 59.8 mmol) in DMSO (380 mL) was added
via a sidearm while stirring with a mechanical stirrer. The
reaction was quenched with 4 L of EtOAc after 2.5 h at room
temperature. Following centrifugation to remove insoluble
material, the organic layer was separated and washed with
water. The organics were dried over MgSO4 and concentrated.
Flash chromatography (50-80% EtOAc/hexane) gave in the
following order 20 (4.1 g, 21%); 25 [11.5 g, 66%; (83% based
on recovered 20)], and diol 19 (0.7 g, 5%). The monoacetate
25 was determined to be 95% ee by examination of the 1H NMR
m eso-(1R*,2R*,3S*,4S*)-2,3-Bis(h yd r oxym eth yl)-1,4-ep -
oxy-6,7-m eth ylen ed ioxy-1,2,3,4-tetr a h yd r on a p h th a len e
(19). To a solution of the dimethyl ester 16 (25.0 g, 82 mmol)
in Et2O (500 mL) at 0 °C was added LiAlH4 (6.2 g, 0.16 mol),
and the resulting reaction mixture was refluxed for 1 d.
Quenching was carried out by the sequential addition of H2O
(6 mL; 30 min stirring), 6.4 mL of 15% NaOH (aqueous, 6 mL,
30 min stirring), and H2O (19 mL; 30 min stirring). The
mixture was neutralized with 1 N HCl solution (100 mL),
followed by the addition of H2O (2.5 L) and extraction with
EtOAc (6.5 L). The organics were dried (Na2SO4) and concen-
trated to give 19 as a white solid (16.8 g, 82%). On a smaller
scale, 16 (4.7 g, 15 mmol) provided an 88% yield of 19 (3.4 g):
mp 177-179 °C; 1H NMR (500 MHz, CD3OD) δ 2.65-2.68
(ddd, J ) 4, 6, 9 Hz, 2 H), 2.77 (dd, J ) 9, 10 Hz, 2 H), 3.15
(dd, J ) 6, 10 Hz, 2 H), 5.24 (d, J ) 4 Hz, 2 H), 5.90 (d, J ) 1
Hz, 1 H), 5.94 (d, J ) 1 Hz, 1 H), 6.85 (s, 2 H); 13C NMR (125
MHz, C5D5N) δ 44.6, 60.1, 82.4, 101.6, 103.6, 138.2, 146.7.
Anal. Calcd for C13H14O5: C, 62.39; H, 5.64. Found: C, 62.26;
H, 5.59.
m eso-(1R*,2R*,3S*,4S*)-2,3-Bis(a cetoxym eth yl)-1,4-ep -
oxy-6,7-m eth ylen ed ioxy-1,2,3,4-tetr a h yd r on a p h th a len e
(20). To a solution of 19 (57 g, 0.23 mol) and DMAP (1.4 g,
11.4 mmol) in pyridine (750 mL) at -10 °C was added Ac2O
(69.9 g, 0.68 mol). After the mixture stirred for 16 h at room
temperature, EtOAc was added into the reaction mixture, and
the organics were washed with saturated NaHCO3 solution,
1 N HCl, and CuSO4 (aqueous, saturated). Drying (MgSO4)
and concentration provided 20 (76 g, 100%): mp 120-122 °C;
1H NMR (300 MHz, CDCl3) δ 2.05 (s, 6 H), 2.82-2.85 (m, 2
H), 3.24 (dd, J ) 10, 11 Hz, 2 H), 3.75 (dd, J ) 6, 11 Hz, 2 H),
5.26 (d, J ) 4 Hz, 2 H), 5.94 (d, J ) 1 Hz, 1 H), 5.99 (d, J ) 1
Hz, 1 H), 6.76 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.5, 40.6,
63.1, 82.2, 102.1, 103.8, 136.7, 147.6, 171.2; Anal. Calcd for
1
spectrum of its derivative Mosher ester: mp 131-134 °C; H
NMR (360 MHz, CDCl3) δ 1.43-1.58 (br. s, 1 H), 2.06 (s, 3 H),
2.77-2.84 (ddd, J ) 6, 9, 13 Hz, 2 H), 2.87 (dd, J ) 9, 10 Hz,
1 H), 3.23 (dd, J ) 10, 11 Hz, 1 H), 3.28 (dd, J ) 6, 10 Hz, 1
H), 3.76 (dd, J ) 6, 11 Hz, 1 H), 5.25 (d, J ) 4 Hz, 1 H), 5.32
(d, J ) 4 Hz, 1 H), 5.94 (d, J ) 1 Hz, 1 H), 5.98 (d, J ) 2 Hz,
1 H), 6.75 (s, 1 H), 6.83 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
21.5, 40.3, 43.8, 61.0, 63.4, 82.3, 82.4, 102.0, 103.7, 103.8, 136.7,
137.2, 147.3, 147.4, 171.5; [R]24 ) +52.6 ° (c 0.6, CHCl3);
D
HRMS (FAB, 3-NBA) calcd for C15H16O6 292.0947 [M+], obsd
292.0952. Anal. Calcd for C15H16O6: C, 61.64; H, 5.52. Found:
C, 61.72; H, 5.65.
(1S,2S,3R,4R)-2-Acetoxym eth yl-3-(ter t-bu tyl)d im eth yl-
silyloxym eth yl-1,4-ep oxy-6,7-m eth ylen ed ioxy-1,2,3,4-tet-
r a h yd r on a p h th a len e (57a ). To a solution of 25 (1.0 g, 3.4
mmol) and imidazole (0.5 g, 7.5 mmol) in DMF (10 mL) at 0
°C was added a solution of TBSCl (0.57 g, 3.8 mmol) in DMF
(10 mL), and the resulting mixture was stirred for 7 h at room
temperature. Et2O was added, and the mixture was washed
with saturated aqueous NaHCO3 and H2O. The organics were
dried (MgSO4), filtered, and concentrated to produce 57a (1.35
g, 97%) as an oil [on a large scale, 25 (8.8 g, 30 mmol) gave
57a (11.5 g, 93%)]: 1H NMR (300 MHz, CDCl3) δ -0.01 (s, 3
H), 0.00 (s, 3 H), 0.89 (s, 9 H), 2.07 (s, 3 H) 2.69-2.77 (m, 3
H), 3.10 (app t, J ) 10 Hz, 1 H), 3.27 (dd, J ) 2, 7 Hz, 1 H),
3.82 (dd, J ) 5, 11 Hz, 1 H), 5.26 (d, J ) 12 Hz, 1 H), 5.30 (d,
J ) 7 Hz, 1 H), 5.94 (d, J ) 1 Hz, 1 H), 5.97 (d, J ) 1 Hz, 1 H),
C
17H18O7: C, 61.07; H, 5.43. Found: C, 61.20; H, 5.61.
m eso-(1R*,2R*,3S*,4S*)-2,3-Bis(ben zoyloxym eth yl)-1,4-
ep oxy-6,7-m et h ylen ed ioxy-1,2,3,4-t et r a h yd r on a p h t h a -
len e (21). To a solution of diol 19 (100 mg, 0.40 mmol) in

856 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
6.74 (s, 1 H), 6.79 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.9,
-4.8, 18.7, 21.4, 26.5, 40.3, 44.2, 61.3, 63.4, 82.4, 82.8, 101.9,
82.6, 102.0, 103.8, 103.9, 137.0, 137.6, 147.4, 147.5, 202.5;
[R]24D ) -14.2° (c 6.4, CHCl3); HRMS (FAB, 3-NBA, LiI) calcd
for C19H26O5SiLi 369.1709, obsd 369.1719.
103.6, 104.0, 136.9, 137.5, 147.1, 147.2, 171.3; [R]24 ) +9.5°
D
(c 1.7, CHCl3). Anal. Calcd for C21H30O6Si: C, 62.04; H, 7.44.
Found: C, 62.17; H, 7.04.
(1S,2R,3R,4R)-1,4-Ep oxy-2-for m yl-6,7-m eth ylen ed ioxy-
3-tr iisop r op ylsilyloxym eth yl-1,2,3,4-tetr a h yd r on a p h th a -
len e (27b). From 27a (13.9 g, 34.2 mmol), oxalyl chloride (29.0
mL, 58.1 mmol, 2.0 M in CH2Cl2), DMSO (5.34 g, 68.4 mmol)
and NEt3 (11.8 g, 116 mmol), by the same procedure as for
27a , was obtained aldehyde 27b (14.3 g, 100%): 1H NMR (300
MHz, CDCl3) δ 0.97-1.20 (m, 21 H), 2.99-3.12 (m, 2 H), 3.22
(ddd, J ) 3, 5, 8 Hz, 1 H), 3.46-3.51 (m, 1 H), 5.38 (s, 1 H),
5.40 (s, 1 H), 5.96 (d, J ) 1 Hz, 1 H), 5.98 (d, J ) 1 Hz, 1 H),
6.84 (s, 1 H), 6.85 (s, 1 H), 9.07 (d, J ) 3 Hz, 1 H); 13C NMR
(125 MHz, CDCl3) δ 12.6, 18.6, 47.3, 54.2, 62.8, 81.0, 82.7,
(1S,2S,3R,4R)-2-Acetoxym eth yl-1,4-ep oxy-6,7-m eth yl-
en ed ioxy-3-t r iisop r op ylsilyloxym et h yl-1,2,3,4-t et r a h y-
d r on a p h th a len e (57b). From 25 (14.5 g, 49.6 mmol), imida-
zole (7.4 g, 0.11 mol), and TIPSCl (11.7 mL, 54.6 mmol) in DMF
(155 mL) at 0 °C, by the procedure for 57a , was obtained 57b
(22.3 g, 100%): 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J ) 3
Hz, 18 H), 1.03-1.22 (m, 3 H), 2.06 (s, 3 H), 2.76-2.77 (m, 3
H), 3.14 (app t, J ) 10 Hz, 1 H), 3.40-3.43 (m, 1 H), 3.78 (dd,
J ) 5, 11 Hz, 1 H), 5.24 (d, J ) 4 Hz, 1 H), 5.33 (d, J ) 3 Hz,
1 H), 5.94 (d, J ) 1 Hz, 1 H), 5.97 (d, J ) 1 Hz, 1 H), 6.74 (s,
1H), 6.83 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 12.5, 18.6, 21.5,
40.2, 44.3, 61.8, 63.3, 82.3, 82.9, 101.8, 103.6, 104.1, 136.9,
137.5, 147.1, 147.2, 171.3; [R]24 D ) +3.0° (c 0.9, CHCl3); HRMS
(FAB, 3-NBA, LiI) calcd for C24H36O6SiLi 455.2442, obsd
455.2443.
102.0, 103.9, 104.0, 136.9, 137.5, 147.4, 147.5, 202.5; [R]24
)
D
-26.3° (c 0.8, CHCl3); HRMS (FAB, 3-NBA, NaI) calcd for
C22H32O5SiNa 427.1917, obsd 427.1925.
La cton e 28. To a solution of aldehyde 27a (6.1 g, 16.8
mmol) and sulfamic acid (2.1 g, 21.9 mmol) in t-BuOH (195
mL) at room temperature was added a solution of sodium
chlorite (2.0 g, 22.5 mmol) in H2O (195 mL) followed by HF
(1.6 g, concentrated aqueous). After being allowed to stir at
room temperature for 14 h, the reaction mixture was extracted
with EtOAc. The organics were dried (Na2SO4), filtered, and
concentrated. Flash chromatography (50EnDash-75% EtOAc/
hexanes) provided 28 (2.9 g, 69%): 1H NMR (300 MHz, CDCl3)
δ 3.45-3.49 (m, 1 H), 3.61-3.70 (m, 2 H), 4.19 (dd, J ) 8, 10
Hz, 1 H), 5.37 (d, J ) 5 Hz, 1 H), 5.54 (d, J ) 5 Hz, 1 H), 5.95
(d, J ) 1 Hz, 1 H), 6.01 (d, J ) 1 Hz, 1 H), 6.84 (s, 1 H), 6.85
(s, 1 H); 13C NMR (125 MHz, d6-DMSO) δ 40.8, 48.3, 67.2, 79.5,
81.5, 101.2, 102.5, 103.4, 135.3, 136.3, 146.1, 146.2, 173.9; IR-
(ATR) 1755 cm-1; [R]24 D ) +135.9° (c 2.7, CHCl3); HRMS (EI)
calcd for C13H10O5 246.0525, obsd 246.0528.
r-Meth yla ted La cton e 29. To a solution of 28 (100 mg,
0.41 mmol) in THF (1 mL) at -78 °C was added a solution of
KHMDS (820 µL of a 0.5 M solution in toluene, 0.41 mmol)
and 18-Cr-6 (108 mg, 0.41 mmol) in THF (1 mL) dropwise via
cannula. After being allowed to stir for 12 h at -78 °C and an
additional 11 h at -45 °C, ring opening was not observed by
TLC, and CH3I (255 µL, 4.1 mmol) was added. The reaction
was quenched with aqueous NaHCO3 and extracted with Et2O.
The organics were dried (Na2SO4), filtered, concentrated, and
chromatographed (33% EtOAc/hexanes) to provide a sample
of the clean methylated lactone: 1H NMR (500 MHz, CDCl3)
δ 3.28 (ddd, J ) 3, 6, 8 Hz, 1 H), 3.51 (s, 3 H), 3.58 (dd, J ) 3,
10 Hz, 1 H), 4.23 (dd, J ) 8, 10 Hz, 1 H), 5.34 (s, 1H), 5.41 (d,
J ) 5 Hz, 1 H), 5.95 (d, J ) 1 Hz, 1 H), 6.00 (d, J ) 1 Hz, 1 H),
6.82 (s, 2 H). Note: irradiation of the methyl group produced
NOEs of 3.7% at the bridgehead (H1) and of 6.6% at H3,
indicating that the lactone remains cis-endo with the methyl
group occupying an exo position. 13C NMR (125 MHz, CDCl3)
δ 46.2, 55.0, 67.1, 83.4, 85.5, 93.6, 102.4, 103.8, 104.5, 134.4,
136.4, 148.3, 172.4.
(1S,2S,3R,4R)-3-(ter t-Bu t yl)d im et h ylsilyloxym et h yl-
1,4-ep oxy-2-h yd r oxym eth yl-6,7-m eth ylen ed ioxy-1,2,3,4-
tetr a h yd r on a p h th a len e (26a ). To a solution of acetate 57a
(8.2 g, 20 mmol) in MeOH (82 mL) was added K2CO3 (557 mg,
4.0 mmol). The resulting suspension was stirred for 1.5 h at
room temperature. Dowex 50 × 8 resin (H+ form; 900 mg) was
added, and stirring was continued for 30 min. Filtration,
concentration, and flash chromatography (33% EtOAc/hex-
anes) yielded the alcohol 26a (7.0 g, 95%). On a small scale,
57a (850 mg, 2.1 mmol) gave the 26a in 97% yield (740 mg,):
1H NMR (500 MHz, CDCl3) δ 0.01 (s, 3 H), 0.02 (s, 3 H), 0.87
(s, 9 H), 2.71-2.83 (m, 2 H), 3.01 (dd, J ) 9, 10 Hz, 2 H), 3.12-
3.17 (m, 1 H), 3.20 (dd, J ) 6, 10 Hz, 1 H), 5.17 (d, J ) 4 Hz,
1 H), 5.20 (d, J ) 4 Hz, 1 H), 5.95 (d, J ) 4 Hz, 2 H), 6.72 (s,
1 H), 6.76 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ -4.9, -4.8,
18.7, 26.4, 44.4, 44.6, 61.1, 61.8, 82.0, 82.1, 101.9, 103.3, 103.4,
137.4, 137.6, 147.0, 147.1; [R]24 ) -78.8° (c 0.8, CHCl3);
D
HRMS (CI) calcd for C19H28O5Si (MH)+ 365.1706, obsd 365.1785.
(1S,2S,3R,4R)-1,4-Ep oxy-2-h yd r oxym eth yl-6,7-m eth yl-
en ed ioxy-3-t r iisop r op ylsilyloxym et h yl-1,2,3,4-t et r a h y-
d r on a p h th a len e (26b). From acetate 57b (7.10 g, 15.8 mmol)
and K2CO3 (438 mg, 3.17 mmol) in MeOH (60 mL), by the
procedure for 57a , was obtained alcohol 26b (6.43 g, 100%) as
an oil: 1H NMR (300 MHz, CDCl3) δ 0.98-1.07 (m, 21 H),
2.79-2.85 (m, 2 H), 2.97-3.11 (m, 2 H), 3.17 (dd, J ) 5, 11
Hz, 1 H), 3.31 (dd, J ) 6, 10 Hz, 1 H), 5.19 (d, J ) 4 Hz, 1 H),
5.20 (d, J ) 5 Hz, 1 H), 5.96 (s, 2 H), 6.73 (s, 1 H), 6.76 (s, 1
H); 13C NMR (75 MHz, CDCl3) δ_12.4, 18.6, 44.4, 44.5, 61.1,
62.1, 82.0, 82.1, 101.9, 103.3, 103.4, 137.3, 137.6, 147.0, 147.1;
IR (ATR) 3419 cm-1; [R]24 ) -26.8° (c 1.3, CHCl3); HRMS
D
(FAB, 3-NBA, LiI) calcd for C22H34O5SiLi 413.2336, obsd
413.2341.
(1S,2R,3R,4R)-3-(ter t-Bu t yl)d im et h ylsilyloxym et h yl-
1,4-ep oxy-2-for m yl-6,7-m et h ylen ed ioxy-1,2,3,4-t et r a h y-
d r on a p h th a len e (27a ). To a solution of oxalyl chloride (14.4
mL of a 2.0 M solution in CH2Cl2, 28.7 mmol) at -78 °C was
added a solution of DMSO (2.3 mL, 32.6 mmol) in CH2Cl2 (9.8
mL) via cannula. After 10 min of stirring at -78 °C, a solution
of 26a (6.98 g. 19.1 mmol) in CH2Cl2 (9.8 mL) was added
dropwise via cannula. After an additional 30 min at -78 °C,
a solution of NEt3 (8 mL, 57.5 mmol) in CH2Cl2 (7 mL) was
added in the same manner. The resulting reaction was allowed
to warm to -40 °C and kept there for 2 h. Et2O (500 mL) was
then added at -40 °C, and the reaction mixture was allowed
to warm to room temperature. The mixture was washed with
H2O, aqueous NH4Cl, and brine. The organics were dried (Na2-
SO4), filtered, and concentrated to produce the product 27a
(7.29 g, 100%): 1H NMR (500 MHz, CDCl3) δ -0.02 (s, 3 H),
-0.01 (s, 3 H), 0.86 (s, 9 H), 2.99 (dd, J ) 10, 19 Hz, 1 H),
3.00-3.05 (m, 1 H), 3.20 (ddd, J ) 3, 5, 8 Hz, 1 H), 3.37 (dd,
J ) 6, 9 Hz, 1 H), 5.33 (d, J ) 4 Hz, 1 H), 5.37 (d, J ) 5 Hz,
1 H), 5.95 (d, J ) 1 Hz, 1 H), 5.97 (d, J ) 2 Hz, 1 H), 6.81 (s,
1 H), 6.83 (s, 1 H), 9.06 (d, J ) 4 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ -4.9, -4.8, 18.7, 26.4, 47.1, 54.2, 62.1, 80.9,
(3R,4R)-2-F or m yl-4-h yd r oxy-6,7-(m et h ylen ed ioxy)-3-
tr iisop r op ylsilyloxym eth yl-3,4-d ih yd r on a p h th a len e (30).
To a solution of aldehyde 27b (10.5 g, 26.0 mmol) in absolute
MeOH (95 mL) at room temperature was added freshly
prepared NaOMe in MeOH (300 mL of a 60 mM solution).
After 24 h at room temperature, the reaction was monitored
by TLC,and additional NaOMe (3 × 20 mL) was added at 2 h
intervals, until no 27b remained. H2O (245 mL) was then
added, and CO2 was bubbled through the solution until the
pH reached 8 (pH paper). MeOH was removed in vacuo, and
the resulting aqueous layer was extracted with CH2Cl2. The
combined organics were dried (MgSO4), filtered, and evapo-
rated to provide analytically 30 as a white solid (9.50 g, 90%):
mp 87-89 °C; 1H NMR (500 MHz, CDCl3) δ 0.93-1.03 (m, 21
H), 1.74 (d, J ) 5 Hz, 1 H), 3.17 (app t, J ) 10 Hz, 1 H), 3.34
(ddd, J ) 2, 4, 6 Hz, 1 H), 3.80 (dd, J ) 4, 10 Hz, 1 H), 4.97
(app t, J ) 1 Hz, 1 H), 6.01 (s, 1 H), 6.02 (s, 1 H), 6.83 (s, 1 H),
6.93 (s, 1 H), 7.24 (s, 1 H), 9.61 (s, 1 H); 13C NMR (125 MHz,
CDCl3) δ 12.5, 18.5, 43.4, 62.7, 70.0, 102.4, 109.8, 110.9, 125.3,
133.8, 136.0, 145.6, 148.8, 150.7, 192.9; IR (ATR) 3395, 1674,
1645 cm-1; [R]24
) +82.0° (c 1.0, CHCl3); HRMS (FAB,
D
3-NBA) calcd for
C
22H33O5Si [(M + H)+] 405.2097, obsd

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 857
405.2096. Anal. Calcd for C22H32O5Si: C, 65.31; H, 7.97.
Found: C, 65.45; H, 7.98.
(3R ,4R )-6,7-Me t h yle n e d ioxy-3-t r iisop r op ylsilyloxy-
m e t h yl-4-(2′-t r im e t h ylsilyle t h oxy)m e t h oxy-3,4-d ih y-
d r on a p h th a len e-2-ca r boxylic Acid (42). To a solution of
aldehyde 31c (3.5 g, 6.5 mmol) in t-BuOH (130 mL) and
2-methyl-2-butene (35 mL) at room temperature was added a
solution of NaClO2 (5.4 g, 60 mmol) and NaH2PO4 (5.4 g) in
H2O (60 mL). After being allowed to stir at room temperature
overnight, the reaction mixture was extracted with Et2O, dried,
and concentrated. Flash chromatography (10-30% EtOAc/
hexanes) provided the title acid (3.6 g, 100%). [On a larger
scale, 31c (15.0 g, 28 mmol) gave the same acid in excellent
(3R,4R)-4-Allyloxy-2-h yd r oxym et h yl-6,7-m et h ylen e-
d ioxy-3-tr iisop r op ylsilyloxym eth yl-3,4-d ih yd r on a p h th a -
len e (31a ). To a solution of aldehyde 30 (3.1 g, 7.74 mmol) in
DMF (50 mL) at 0 °C was added NaH (372 mg of a 60%
dispersion, 9.29 mmol) followed by allyl bromide (740 µL, 8.51
mmol) via syringe. The resulting mixture was allowed to stir
for 3 h at 0 °C and an additional 0.5 h at room temperature.
The reaction mixture was diluted in Et2O and then washed
with aqueous NaHCO3 and H2O. The organics were dried
(MgSO4), filtered, concentrated, and chromatographed (25%
EtOAc/hexanes) to give 31a (2.4 g, 71%): 1H NMR (300 MHz,
CDCl3) δ 0.93-1.03 (m, 21 H), 3.05 (app t, J ) 10 Hz, 1 H),
3.45 (ddd, J ) 1, 4, 6 Hz, 1 H), 3.69 (dd, J ) 4, 10 Hz, 1 H),
3.97 (dd, J ) 1, 6 Hz, 2 H), 4.69 (s, 1 H), 5.15-5.28 (m, 2 H),
5.78-5.92 (m, 1 H), 6.01 (d, J ) 1 Hz, 1 H), 6.03 (d, J ) 1 Hz,
1 H), 6.83 (s, 2 H), 9.59 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
12.5, 18.6, 40.2, 61.8, 69.6, 75.2, 102.3, 109.9, 111.8, 118.2,
126.3, 131.0, 135.6, 136.4, 145.9, 148.7, 150.2, 193.0; HRMS
(FAB, 3-NBA, NaI) calcd for C25H36O5SiNa 467.2230, obsd
467.2242.
1
yield (14.8 g, 95%).] H NMR (500 MHz, CDCl3) δ 0.00 (s, 9
H), 0.92-1.12 (m, 23 H), 3.13 (app t, J ) 10 Hz, 1 H), 3.38
(ddd, J ) 1, 5, 6 Hz, 1 H), 3.47-3.65 (m, 2 H), 3.78 (dd, J ) 4,
10 Hz, 1 H), 4.61 (d, J ) 7 Hz, 1 H), 4.67 (d, J ) 7 Hz, 1 H),
4.97 (d, J ) 2 Hz, 1 H), 5.99 (d, J ) 1 Hz, 1 H), 6.01 (d, J ) 1
Hz, 1 H), 6.80 (s, 1 H), 6.88 (s, 1 H), 7.63 (s, 1 H); 13C NMR
(125 MHz, CDCl3) δ -0.8, 12.6, 18.6, 18.7, 43.2, 62.0, 65.7,
72.6, 92.4, 102.2, 109.9, 112.0, 125.8, 126.5, 129.4, 139.1, 148.6,
149.6, 172.9; IR (ATR) 3854, 1676 cm-1; [R]24 ) +78.3° (c
D
1.6, CHCl3); HRMS (FAB, 3-NBA, NaI) calcd for C28H46O7Si2-
Na 573.2680, obsd 573.2677.
Meth yl (3R,4R)-6,7-Meth ylen ed ioxy-3-tr iisop r op ylsi-
lyloxym eth yl-4-(2′-tr im eth ylsilyleth oxy)m eth oxy-3,4-d i-
h yd r on a p h t h a len e-2-ca r boxyla t e (32c). To a solution of
N-methyl-N-nitroso urea (4.26 g, 41.4 mol) in Et2O (35 mL)
was added a precooled (at 0 °C) solution of KOH (6.3 g, 108.6
mmol) in H2O (18 mL). Then the Et2O solution was warmed
to 30-40 °C. The CH2N2 thereby formed was distilled directly
into a solution of the acid 42 (1.44 g, 2.62 mmol) in Et2O (50
mL) and MeOH (30 mL) at 0 °C for 40 min, followed by
quenching of excess CH2N2 with HOAc. Concentration pro-
duced the methyl ester 32c (1.48 g, 100%): 1H NMR (500 MHz,
CDCl3) δ -0.01 (s, 9 H), 0.91-1.05 (m, 23 H), 3.06 (app t, J )
10 Hz, 1 H), 3.37 (ddd, J ) 2, 4, 6 Hz, 1 H), 3.46-3.51 (m, 1
H), 3.57-3.62 (m, 1 H), 3.74-3.80 (m, 4 H), 4.59 (d, J ) 7 Hz,
1 H), 4.64 (d, J ) 7 Hz, 1 H), 4.97 (s, 1 H), 5.97 (d, J ) 1 Hz,
1 H), 5.99 (d, J ) 2 Hz, 1 H), 6.77 (s, 1 H), 6.87 (s, 1 H), 7.52
(s, 1 H); 13C NMR (125 MHz, CDCl3) δ -0.8, 12.5, 18.6, 18.7,
43.5, 52.3, 62.0, 65.6, 72.6, 92.4, 102.1, 109.7, 112.0, 126.3,
126.7, 128.8, 137.1, 148.5, 149.2, 167.8; [R]24 D ) +97.3° (c 1.2,
CHCl3); HRMS (FAB, 3-NBA, NaI) calcd for C29H48O7Si2Na
587.2836, obsd 587.2848.
La cton e 33. To a solution of 32a (910 mg, 1.9 mmol) in
THF (20 mL) at 0 °C was added TBAF (2.1 mL of a 1.0 M
solution in THF, 2.1 mmol). After being allowed to stir for 4 h
at 0 °C, the reaction mixture was quenched with aqueous
NaHCO3. The H2O layer was extracted with Et2O. The
combined organics were dried (MgSO4), filtered, and concen-
trated to produce an oil. A solution of this oil and titanium-
(IV) isopropoxide (116 µL, 0.38 mmol) in benzene (200 mL)
was refluxed on a Dean Stark apparatus for 16 h. The reaction
mixture was concentrated and chromatographed (25% EtOAc/
hexanes) to produce 33 (268 mg, 50%): 1H NMR (300 MHz,
CDCl3) δ 3.34 (ddd, J ) 3, 9, 12 Hz, 1 H), 4.15-4.25 (m, 3 H),
4.61 (d, J ) 14 Hz, 1 H), 4.81 (app t, J ) 9 Hz, 1 H), 5.27-
5.40 (m, 2 H), 5.94-5.99 (m, 1 H), 6.00 (d, J ) 2 Hz, 1 H), 6.02
(d, J ) 2 Hz, 1 H), 6.79 (s, 1 H), 7.10 (s, 1 H), 7.27 (d, J ) 3
Hz, 1 H).
(3R,4R)-4-Ben zyloxy-2-for m yl-6,7-m et h ylen ed ioxy-3-
tr iisopr opylsilyloxym eth yl-3,4-dih ydr on aph th alen e (31b).
To a solution of 30 (350 mg, 0.87 mmol) in DMF (5.5 mL) at
-10 °C were added sequentially NaH (42 mg of a 60%
dispersion, 1.04 mmol) and benzyl bromide (113 µL, 0.95
mmol). The resulting reaction mixture was allowed to warm
to room temperature overnight. The mixture was diluted with
Et2O and then washed with aqueous NaHCO3 and H2O. The
organics were dried (MgSO4), filtered, and concentrated to
produce 31b (428 mg, 100%): 1H NMR (360 MHz, CDCl3) δ
0.86-0.99 (m, 21 H), 3.05 (app t, J ) 10 Hz, 1 H), 3.51-3.56
(m, 1 H), 3.69 (dd, J ) 4, 10 Hz, 1 H), 4.50 (s, 2 H), 4.71 (s, 1
H), 6.02 (s, 1 H), 6.03 (s, 1 H), 6.71 (s, 1 H), 6.84 (s, 1 H), 7.24-
7.33 (m, 6 H), 9.61 (s, 1 H).
(3R,4R)-2-Hyd r oxym eth yl-6,7-m eth ylen ed ioxy-3-tr iiso-
pr opylsilyloxy-m eth yl-4-(2′-tr im eth ylsilyleth oxy)m eth oxy-
3,4-d ih yd r on a p h th a len e (31c). To a solution of 30 (7.0 g,
17 mmol) in CH2Cl2 (140 mL) at 0 °C were added sequentially
diisopropylethylamine (9.0 mL, 52 mmol) and SEM chloride
(4.6 mL, 26 mmol). The resulting reaction mixture was allowed
to warm slowly to room temperature overnight and then
poured into aqueous NaHCO3. The aqueous layer was further
extracted with CH2Cl2. After drying (MgSO4), filtering, and
evaporating, the crude product was purified by SiO2 chroma-
tography (10% EtOAc/hexanes) to provide 13 (8.6 g, 93%): 1H
NMR (360 MHz, CDCl3) δ 0.00 (s, 9 H), 0.91-1.04 (m, 23 H),
3.07 (app t, J ) 10 Hz, 1 H), 3.41 (ddd, J ) 2, 4, 6 Hz, 1 H),
3.46-3.62 (m, 2 H), 3.70 (dd, J ) 5, 10 Hz, 1 H), 4.58 (d, J )
7 Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H), 4.98 (d, J ) 1 Hz, 1 H),
6.01 (d, J ) 2 Hz, 1 H), 6.02 (d, J ) 1 Hz, 1 H), 6.84 (s, 1 H),
6.90 (s, 1 H), 7.23 (s, 1 H), 9.60 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ -0.8, 12.5, 18.6, 18.7, 41.1, 61.8, 65.7, 72.3, 92.4,
102.4, 109.9, 112.1, 126.3, 130.7, 136.5, 145.7, 148.7, 150.2,
192.9; IR (ATR) 1674 cm-1; [R]24 ) +37.7° (c 0.9, CHCl3).
D
Anal. Calcd for C28H46O6Si2: C, 62.88; H, 8.67. Found: C,
63.00; H, 8.49.
Met h yl (3R,4R)-4-Allyloxy-6,7-m et h ylen ed ioxy-3-t r i-
isop r op ylsilyloxym eth yl-3,4-d ih yd r on a p h th a len e-2-ca r -
boxyla te (32a ). To a solution of 31a (50 mg, 0.11 mmol) in
MeOH (1.5 mL) at room temperature were added NaCN (30
mg, 0.60 mmol) and freshly prepared MnO2 (207 mg, 2.39
mmol). The resulting reaction mixture was allowed to stir for
20 h. The reaction mixture was concentrated, and H2O was
added. The mixture was extracted with Et2O, and the organics
were dried (MgSO4), filtered, concentrated, and chromato-
graphed (25% EtOAc/hexanes) to yield 32a (39 mg, 74%): 1H
NMR (360 MHz, CDCl3) δ 0.99-1.07 (m, 21 H), 3.04 (app t, J
) 10 Hz, 1 H), 3.41 (ddd, J ) 2, 4, 6 Hz, 1 H), 3.75 (dd, J ) 4,
10 Hz, 1 H), 3.79 (s, 3 H), 3.91-3.99 (m, 2 H), 4.68 (d, J ) 2
Hz, 1 H), 5.15-5.28 (m, 2 H), 5.83-5.90 (m, 1 H), 5.98 (d, J )
1 Hz, 1 H), 6.00 (d, J ) 2 Hz, 1 H), 6.76 (s, 1 H), 6.80 (s, 1 H),
7.51 (s, 1 H).
(()-Eth yl 3-P h en ylbu ta n oa te (35). To a deoxygenated
solution of CuCN (358 mg, 4.0 mmol) in Et2O (6 mL) at -78
°C was added a solution of a freshly prepared PhLi (672 mg,
8.0 mmol) in Et2O (4.8 mL). The resulting reaction mixture
was allowed to stir for 1.5 h at -78 °C. BF3‚Et2O (541 µL, 4.4
mmol) and ethyl trans-crotonate (34, 62 µL, 0.5 mmol) were
added sequentially at -78 °C. The resulting mixture was
allowed to warm to -30 °C overnight and then poured into
aqueous NH4Cl. The aqueous layer was further extracted with
Et2O. After drying (MgSO4), filtering and evaporating, the
crude product was purified by SiO2 chromatography (33%
EtOAc/hexanes) to provide 35 (72 mg, 75%): 1H NMR (360
MHz, CDCl3) δ 1.10 (t, J ) 7 Hz, 3 H), 1.22 (d, J ) 7 Hz, 3 H),
2.48 (dd, J ) 15, 29 Hz, 1 H), 2.51 (dd, J ) 15, 28 Hz, 1 H),
3.15-3.25 (m, 1 H), 4.00 (q, J ) 7 Hz, 2 H), 7.09-7.29 (m, 5
H).

858 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
Meth yl (2E)-(3′,4′-Meth ylen ed ioxy)cin n a m a te (36). The
title methyl ester 36 was obtained with freshly prepared
CH2N2 as described for 32c. (2E)-(3′,4′-Methylenedioxy)cin-
namic acid (Aldrich, 2.7 g, 14.1 mmol) gave 36 in 99% yield
(2.9 g): 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 3 H), 6.00 (s, 2
H) 6.25 (d, J ) 16 Hz, 1 H), 6.80 (d, J ) 8 Hz, 1 H), 6.98-7.02
(m, 2 H), 7.59 (d, J ) 16 Hz, 1 H).
ether layer was dried (MgSO4) and concentrated. Chromatog-
raphy (25% EtOAc/hexanes) yielded reduction product 41 (4
mg, 22%): 1H NMR (360 MHz, CDCl3) δ 0.96-1.12 (m, 21 H),
3.11 (app t, J ) 10 Hz, 1 H), 3.48 (br dd, J ) 6, 10 Hz, 1 H),
3.88 (dd, J ) 6, 10 Hz, 1 H), 4.01-4.06 (m, 2 H), 4.78 (br s, 1
H), 5.21 (d, J ) 10.5 Hz, 1 H),), 5.30 (d, J ) 18 Hz, 1 H), 5.90
(m, 1 H), 6.02-6.07 (br s, 2 H), 6.81 (s, 1 H), 6.85 (s, 1 H),
7.41-7.54 (m, 3 H), 7.66 (s, 1 H), 7.68-7.75 (m, 2 H).
(()-Meth yl (3′,4′-Meth ylen ed ioxy)-3-p h en yl-2,3-d ih y-
d r ocin n a m a te (37). To a deoxygenated solution of CuCN (179
mg, 2.0 mmol) in Et2O (3 mL) at -78 °C was added a solution
of a freshly prepared PhLi (336 mg, 4.0 mmol) in Et2O (3.1
mL). The reaction mixure was allowed to stir for 1.5 h at -35
°C. After the reaction mixture was cooled to -78 °C, BF3 ‚Et2O
(271 µL, 2.2 mmol) and a solution of 36 (52 mg, 0.3 mmol) in
Et2O (2 mL) were added sequentially at -78 °C. The resulting
reaction mixture was allowed to warm to -35 °C overnight
and then stirred at room temperature for 12 h. Aqueous NH4-
Cl was added, and the aqueous layer was extracted with Et2O.
The combined organics were dried (MgSO4), filtered, and
concentrated. Flash chromatography (33% EtOAc/hexanes)
and MPLC (acetone/CHCl3/hexanes 4:63:33) provided the
adduct 37 (36 mg, 50%): 1H NMR (360 MHz, CDCl3) δ 3.00
(d, J ) 8 Hz, 2 H), 3.59 (s, 3 H), 4.47 (t, J ) 8 Hz, 1 H), 5.89
(s, 2 H), 6.68 (s, 1 H), 6.71 (d, J ) 1 Hz, 2 H), 7.15-7.30 (m,
5 H).
2′′-Br om op h en yl (3R,4R)-6,7-Meth ylen ed ioxy-3-tr iiso-
pr opylsilyloxym eth yl-4-(2′-tr im eth ylsilyleth oxy)m eth oxy-
3,4-d ih yd r on a p h th a len e-2-ca r boxyla te (43). To a solution
of acid 42 (255 mg, 0.46 mmol) in THF (1 mL) at room
temperature was added CDI (83 mg, 0.51 mmol). After 3 h at
room temperature, the reaction mixture was partitioned
between Et2O and H2O. The H2O layer was back-extracted
with Et2O. The combined organics were dried and evaporated
to provide the acyl imidazolide, which was taken forward
without further purification. To a solution of 2-bromophenol
(87 µL, 0.75 mmol) in THF (2 mL) at 0 °C was added KHMDS
(1.5 mL of a 0.5 M solution in toluene, 0.75 mmol). The
resulting mixture was allowed to stir 1 h at 0 °C prior to
dropwise addition of a solution of acyl imidazolide (275 mg,
0.46 mmol) in THF (1 mL) via cannula. The reaction mixture
was allowed to warm to room temperature over 7 h and then
quenched with aqueous NaHCO3. The H2O layer was extracted
with Et2O. The combined organics were dried, filtered, con-
centrated, and chromatographed (25% EtOAc/hexanes) to
produce 43 (63 mg, 20%): 1H NMR (300 MHz, CDCl3) δ 0.00
(s, 9 H), 0.96-1.02 (m, 23 H), 3.17 (app t, J ) 10 Hz, 1 H),
3.46-3.67 (m, 3 H), 3.97 (dd, J ) 4, 10 Hz, 1 H), 4.63 (d, J )
7 Hz, 1 H), 4.70 (d, J ) 7 Hz, 1 H), 5.06 (d, J ) 1 Hz, 1 H),
6.01 (d, J ) 1 Hz, 1 H), 6.02 (d, J ) 1 Hz, 1 H), 6.85 (s, 1 H),
6.91 (s, 1 H), 7.21-7.62 (m, 4 H), 7.82 (s, 1 H).
P h en yl (3R,4R)-6,7-Meth ylen ed ioxy-3-tr iisop r op ylsi-
lyloxym eth yl-4-(2′-tr im eth ylsilyleth oxy)m eth oxy-3,4-d i-
h yd r on a p h th a len e-2-ca r boxyla te (44). To a mixture of 43
(20 mg, 28 µmol) and AIBN (0.5 mg, 2.8 µmol) in dry PhMe
(750 µL) was added Bu3SnH (8.1 mg, 28 µmol) in dry PhMe
(100 µL), and the resulting reaction mixture was refluxed for
12 h. The reaction was quenched with NaHCO3 solution,
extracted with Et2O, dried (MgSO4), filtered, and concentrated.
Flash chromatography (20% Et2O/hexanes) provided 44 (5 mg,
28%) and recovered 43 (5 mg, 25%). For 44:1H NMR (360 MHz,
CDCl3) δ -0.02-0.03 (br s, 9 H), 0.95-1.03 (br s, 23 H), 3.18
(app t, J ) 9.5 Hz, 1 H), 3.44-3.51 (m, 1 H), 3.52-3.67 (m, 2
H), 3.87-3.93 (dd, J ) 5, 10 Hz, 1 H), 4.65 (d, J ) 7 Hz, 1 H),
4.71 (d, J ) 7 Hz, 1 H), 5.05 (br s, 1 H), 6.01-6.04 (m, 2 H),
6.85 (s, 1 H), 6.93 (s, 1 H), 7.16 (d, J ) 8 Hz, 2 H), 7.24 (app
t, J ) 8 Hz, 1 H), 7.40 (app t, J ) 8 Hz, 2 H).
(3R,4R)-4-Ben zyloxy-2-h yd r oxym eth yl-6,7-m eth ylen e-
d ioxy-3-tr iisop r op ylsilyloxym eth yl-3,4-d ih yd r on a p h th a -
len e (58). To a solution of 31b (520 mg, 1.1 mmol) in EtOH
(18 mL) at 0 °C was added NaB(OCH3)3H (184 mg, 1.5 mmol).
The resulting mixture was allowed to warm to room temper-
ature over 9 h and then quenched with aqueous NaHCO3. The
mixture was extracted with Et2O. The organic layers were
dried (MgSO4), filtered, and concentrated to produce the 58
(453 mg, 87%): 1H NMR (360 MHz, CDCl3) δ 0.96-1.11 (m,
21 H), 2.40 (br., 1 H), 2.92-2.96 (m, 1 H), 3.28 (dd, J ) 8, 10
Hz, 1 H), 3.56 (dd, J ) 6, 10 Hz, 1 H), 4.25 (d, J ) 1 Hz, 2 H),
4.42 (d, J ) 2 Hz, 1 H), 4.49 (s, 1 H), 4.51 (s, 1 H), 5.95 (s, 2
H), 6.42 (s, 1 H), 6.64 (s, 2 H), 7.25-7.32 (m, 5 H).
(3R,4R)-4-Ben zyloxy-2-(4′-m et h oxy)p h en oxym et h yl-
6,7-m eth ylen ed ioxy-3-tr iisop r op ylsilyloxym eth yl-3,4-d i-
h yd r on a p h th a len e (45). To a solution of 58 (30 mg, 0.06
mmol) in THF (1 mL) was added p-methoxyphenol (45 mg,
0.36 mmol), Ph3P (41 mg, 0.16 mmol), and diethylazodicar-
boxylate (25 µL, 0.16 mmol). The resulting reaction mixture
was heated to 80 °C for 13 h. The reaction mixture was cooled,
concentrated, and chromatographed (25% EtOAc/hexanes) to
give 45 (10 mg, 28%): 1H NMR (360 MHz, CDCl3) δ 0.92-
1.05 (m, 21 H), 2.98 (ddd, J ) 2, 5, 7 Hz, 1 H), 3.73 (app t, J
) 10 Hz, 1 H), 3.66-3.82 (m, 4 H), 4.48 (dd, J ) 7 Hz, 2 H),
4.59 (d, J ) 2 Hz, 1 H), 4.60 (d, J ) 1 Hz, 2 H), 5.94 (d, J ) 1
Hz, 1 H), 5.95 (d, J ) 2 Hz, 1 H), 6.50 (s, 1 H), 6.64 (s, 1 H),
Meth yl
6,7-Meth ylen ed ioxy-3-tr iisop r op ylsilyloxy-
m eth yl-n a p h th a len e-2-ca r boxyla te (38). Attempts to per-
form conjugate additions upon R,â-unsaturated ester 32c,
under the conditions used to synthesize 37 (or indeed, incuba-
tion of 32c with BF3 ‚Et2O at -78 °C in Et2O) led only to the
isolation of aromatized product 38: 1H NMR (360 MHz, CDCl3)
δ 1.6-1.19 (m, 21 H), 3.93 (s, 3 H), 5.30 (s, 2 H), 6.05 (s, 2 H),
7.14 (s, 1 H), 7.16 (s, 1 H), 8.11 (s, 1 H), 8.36 (s, 1 H).
(3R,4R)-4-Allyloxy-6,7-m eth ylen ed ioxy-3-(tr iisop r op yl-
silyloxy)m et h yl-3,4-d ih yd r on a p h t h a len e-2-ca r b oxylic
Acid (39). Following the same procedure as for the synthesis
of 42 (vide supra) acid 39 (311 mg, 100%) was synthesized from
aldehyde 31a (300 mg, 0.67 mmol): 1H NMR (360 MHz, CDCl3)
δ 0.97-1.08 (m, 21 H), 3.10 (app t, J ) 10 Hz, 1 H), 3.41(ddd,
J ) 2, 5, 6 Hz, 1 H), 3.78 (dd, J ) 5, 10 Hz, 1 H), 3.98 (app d,
J ) 6 Hz, 2 H), 4.68 (d, J ) 1 Hz, 1 H), 5.16-5.29 (m, 2 H),
5.82-5.93 (m, 1 H), 6.00 (d, J ) 2 Hz, 1 H), 6.01 (d, J ) 1 Hz,
1 H), 6.79 (s, 1 H), 6.82 (s, 1 H), 7.62 (s, 1 H).
2′-Br om oth iop h en yl (3R,4R)-4-Allyloxy-6,7-m eth ylen e-
d ioxy-3-tr iisop r op ylsilyloxym eth yl-3,4-d ih yd r on a p h th a -
len e-2-ca r boxyla te (40). To a solution of 39 (100 mg, 0.22
mmol) in THF (500 µL) at room temperature was added
carbonyl diimidazole (CDI, 39 mg, 0.24 mmol). The resulting
reaction mixture was allowed to stir 2.5 h at room temperature
and then concentrated. The crude product was dissolved in
Et2O and extracted with H2O to remove imidazole. The
organics were dried (MgSO4), filtered, and concentrated to
produce the imidazolide.
To a deoxygenated solution of 2-bromothiophenol (22 µL,
0.21 mmol) in THF (500 µL) at 0 °C was added KHMDS (430
µL of a 0.5 M solution in toluene, 0.21 mmol). The resulting
reaction mixture was allowed to stir 1 h at 0 °C. Then a
solution of the imidazolide in THF (500 µL) was added, via
cannula. The reaction was stirred for 3.5 h at 0 °C and then
quenched with aqueous NaHCO3. The H2O layer was extracted
with Et2O. The combined organics were dried, filtered, con-
centrated, and chromatographed (20% EtOAc/hexanes) to yield
40 (99 mg, 73%): 1H NMR (360 MHz, CDCl3) δ 0.85-1.04 (m,
21 H), 3.15 (app t, J ) 10 Hz, 1 H), 3.50 (ddd, J ) 2, 5, 6 Hz,
1 H), 3.83 (dd, J ) 5, 10 Hz, 1 H), 3.99 (app d, J ) 6 Hz, 2 H),
4.71 (d, J ) 2 Hz, 1 H), 5.16-5.30 (m, 2 H), 5.82-5.93 (m, 1
H), 6.01 (d, J ) 2 Hz, 1 H), 6.03 (d, J ) 2 Hz, 1 H), 6.82 (s, 1
H), 6.85 (s, 1 H), 7.25-7.72 (m, 4 H), 7.65 (s, 1 H).
Th iop h en yl (3R,4R)-4-Allyloxy-6,7-m eth ylen ed ioxy-3-
t r iisop r op ylsilyloxym et h yl-3,4-d ih yd r on a p h t h a len e-2-
ca r boxyla te (41). o-Bromothioester 40 (20 mg, 32 µmol) was
incubated with PdCl2(PPh3)2 (5 mg, 6 µmol), PPh3 (10 mg, 38
µmol), and K2CO3 (9 mg, 64 µmol) in DMF (300 µL) under Ar
at 75 oC for 24 h. After cooling to room temperature, the
reaction mixture was partitioned between H2O and Et2O. The

(-)-Podophyllotoxin and (-)-Picropodophyllin
J . Org. Chem., Vol. 65, No. 3, 2000 859
6.67 (s, 1 H), 6.79-6.90 (m, 4 H), 7.23-7.30 (m, 5 H); MS (FAB,
3-NBA, NaI) 625 (5, [M + Na]+), 517 (10), 199 (100).
lyleth oxy)m eth oxy-3,4-d ih yd r on a p h th a len e (50). To a
solution of starting acid 42 (9.28 g, 16.9 mmol) in THF (45
mL) at room temperature was added CDI (3.01 g, 18.5 mmol),
whereupon gas evolution was immediately observed. After 3
h at room temperature, the reaction mixture was partitioned
between Et2O and H2O. The combined organics were dried and
evaporated to provide the crude acyl imidazolide, which was
taken forward without further purification. To a deoxygenated
solution of 2-oxazolidinone (1.91 g, 21.9 mmol) in THF (100
mL) at -78 °C was added n-BuLi (17.7 mL of a 1.24 M solution
in hexanes, 17.7 mmol). The resulting reaction mixture was
allowed to stir for 1 h at -78 °C. Then a solution of acyl
imidazolide (10.1 g, 16.9 mmol) in THF (80 mL) was added,
dropwise, via cannula at -78 °C. After 4.5 h at -78 °C, the
reaction mixture was diluted with Et2O and then extracted
with H2O. The organic layer was dried (MgSO4), filtered,
concentrated, and chromatographed (hexanes/EtOAc/NEt3 67:
33:0.5) to yield 50 (6.66 g, 64%): mp 110-112 °C; 1H NMR
(500 MHz, CDCl3) δ -0.01 (s, 9 H), 0.93-1.03 (m, 23 H), 3.22
(app t, J ) 10 Hz, 1 H), 3.44 (ddd, J ) 2, 6, 7 Hz, 1 H), 3.52
(app dt, J ) 6, 10 Hz, 1 H), 3.61 (app dt, J ) 6, 11 Hz, 1 H),
3.71 (app dd, J ) 6, 10 Hz, 1 H), 3.95 (ddd, J ) 6, 8, 10 Hz, 1
H), 4.09-4.15 (m, 1 H), 4.37-4.44 (m, 2 H), 4.60 (d, J ) 7 Hz,
1 H), 4.68 (d, J ) 7 Hz, 1 H), 4.94 (d, J ) 2 Hz, 1H), 5.96 (d,
J ) 2 Hz, 1 H), 5.98 (d, J ) 1 Hz, 1 H), 6.74 (s, 1 H), 6.86 (s,
1 H), 7.12 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ -0.78, 12.5,
18.6, 18.7, 43.7, 44.7, 62.4, 62.8, 65.6, 71.7, 92.3, 102.2, 109.9,
112.0, 126.2, 127.1, 128.7, 138.0, 148.6, 149.4, 154.2, 170.2;
IR (ATR) 1781, 1663 cm-1; [R]24 D ) +69.9° (c 3.0, CHCl3). Anal.
Calcd for C31H49NO8Si2: C, 60.06; H, 7.97; N, 2.26. Found: C,
60.19; H, 7.70; N, 2.32.
2-(4′-Meth oxy)p h en oxym eth yl-6,7-(m eth ylen ed ioxy)-3-
tr iisop r op ylsilyloxym eth yl-n a p h th a len e (46). Aryl benzyl
ether 45 (8 mg, 13 µmol) was heated to 210 oC in o-dichlo-
robenzene (600 µL) in a sealed vessel for 1.5 h. After evapora-
tion of solvent, flash chromatography (25% EtOAc/hexanes)
provided aromatized product 46 (4 mg, 60%): 1H NMR (360
MHz, CDCl3) δ 0.95-1.14 (m, 21 H), 3.77 (s, 3 H), 4.99 (s, 2
H), 5.18 (s, 2 H), 6.04 (s, 2 H), 6.84 (d, J ) 8 Hz, 1 H), 6.93 (d,
J ) 8 Hz, 1 H), 7.10 (s, 1 H), 7.13 (s, 1 H), 7.71 (s, 1 H), 7.78
(s, 1 H).
N-(3′,4′-Meth ylen ed ioxy)-(2E)-cin n a m oyloxa zolid in o-
n e (47). To a solution of 3,4-(methylenedioxy)cinnamic acid
(5.0 g, 26.0 mmol) in THF (70 mL) at room temperature was
added CDI (4.6 g, 28.6 mmol). After being allowed to stir at
room temperature overnight, the reaction mixture was con-
centrated. The organics were dissolved in EtOAc (100 mL),
washed with H2O (4 × 100 mL), concentrated, and used
directly without further purification. To a solution of 2-ox-
azolidone (1.8 g, 20.6 mmol) in THF (80 mL) at -78 °C was
added KHMDS (41 mL of a 0.5 M solution in PhMe, 20.6
mmol). The resulting reaction mixture was allowed to stir for
30 min at 78 °C. Then a solution of acyl imidazolide (3.8 g,
15.6 mmol) in CH2Cl2 (100 mL) was added via cannula at -78
°C. The resulting mixture was allowed to warm to room
temperature slowly for 16 h and quenched with aqueous
NaHCO3. The H2O layer was extracted once with CH2Cl2. The
combined organic layers were dried, concentrated, and chro-
matographed (66% EtOAc/hexanes) to yield 47 (2.3 g, 56%):
1H NMR (300 MHz, CDCl3) δ 4.10 (t, J ) 8 Hz, 2 H), 4.42 (t,
J ) 8 Hz, 2 H), 5.99 (s, 2 H), 6.79 (d, J ) 8 Hz, 1 H), 7.07 (dd,
J ) 2, 8 Hz, 1 H), 7.12 (d, J ) 2 Hz, 1 H), 7.69 (d, J ) 16 Hz,
1 H), 7.75 (d, J ) 16 Hz, 1 H).
(()-N-[-3-(3′,4′-Met h ylen ed ioxy)p h en yl-3-p h en ylp r o-
p a n oyl]oxa zolid in on e (48). To a deoxygenated solution of
CuBr-Me2S (43 mg, 0.21 mmol) in THF (400 µL) and Me2S
(400 µL) at -78 °C was added PhMgBr (287 µL of a 1.0 M
solution in THF, 0.29 mmol). The resulting mixture was
allowed to stir for 1 h at 78 °C, whereupon a solution of 47
(24 mg, 0.09 mmol) in THF (450 µL) was added via cannula.
After 2 h at -20 °C, aqueous NH4Cl was added, followed by
Et2O. After further extraction of the aqueous layer wih Et2O,
the combined organics were dried (MgSO4), filtered, and
concentrated. Flash chromatography (50% EtOAc/hexanes)
yielded 48 (30 mg, 100%): 1H NMR (300 MHz, CDCl3) δ 3.70
(d, J ) 8 Hz, 2 H), 3.91 (t, J ) 8 Hz, 2 H), 4.33 (t, J ) 8 Hz,
2 H), 4.60 (t, J ) 8 Hz, 1 H), 5.90 (s, 2 H), 6.69-6.77 (m, 3 H),
7.24-7.30 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 40.7, 42.4,
45.9, 62.0, 100.9, 108.3, 108.4, 120.6, 126.5, 127.6, 128.5, 137.5,
143.6, 146.1, 147.7, 153.5, 171.3.
(()-N-[-3-(3′,4′-Met h ylen ed ioxy)p h en yl-3-(3′′,4′′,5′′-t r i-
m eth oxy)p h en ylp r op a n oyl]oxa zolid in on e (49). To a sus-
pension of CuCN (87 mg, 0.96 mmol) in THF (3 mL) at 5 °C
was added 3,4,5-trimethoxyphenylmagnesium bromide37 (3.26
mL of a 0.3 M solution in THF). The resulting mixture was
allowed to stir for 1 h at 5 °C, whereupon a solution of 47 (63
mg, 0.24 mmol) in THF (5 mL) was added via cannula. After
0.5 h at 5 °C, aqueous NH4Cl solution was added, followed by
Et2O. After further extraction of the aqueous layer with Et2O,
the combined organics were dried (MgSO4), filtered, and
evaporated. Chromatography (33% EtOAc/hexanes) yielded 49
(87 mg, 84%): 1H NMR (300 MHz, CDCl3) δ 3.54 (dd, J ) 7,
17 Hz, 1 H), 3.76 (dd, J ) 7, 17 Hz, 1 H), 3.78 (s, 3 H), 3.81 (s,
3 H), 3,91 (t, J ) 8 Hz, 2 H), 4.34 (t, J ) 8 Hz, 2 H), 4.51 (t,
J ) 7 Hz, 1 H), 5.89 (s, 2 H), 6.47 (s, 2 H), 6.70-6.78 (m, 3 H);
13C NMR (75 MHz, CDCl3) d 40.5, 42.4, 46.3, 56.0, 60.6, 61.9,
100.8, 104.6, 108.0, 108.1, 120.3, 136.4, 137.2, 139.1, 146.1,
147.6, 153.0, 153.5, 171.2; HRMS (FAB, 3-NBA, NaI) calcd for
(1R,2S,3R,4R)-6,7-Meth ylen edioxy-2-(N-oxazolidin on yl)-
ca r bon yl-1-p h en yl-3-tr iisop r op ylsilyloxym eth yl-4-(2′-tr i-
m eth ylsilyleth oxy)m eth oxy-1,2,3,4-tetr a h yd r on a p h th a -
len e (51). To a suspension of CuCN (1.62 g, 18.1 mmol) in
THF (17 mL) and Me2S (17 mL) at -78 °C was added PhMgBr
(21.5 mL of a 1.0 M solution in Et2O). The resulting mixture
was allowed to stir for 1.5 h at -78 °C, whereupon a solution
of 50 (1.40 g, 2.26 mmol) in THF (12.5 mL) was added via
cannula. After 3 h at -40 °C, aqueous NH4Cl was added,
followed by Et2O. After further extraction of the aqueous layer
with Et2O, the combined organics were dried (MgSO4), filtered,
and evaporated. Chromatography (25% EtOAc/hexanes) yielded
51 (1.23 g, 78%): 1H NMR (360 MHz, CDCl3) δ 0.04 (s, 9 H),
0.96-1.06 (m, 23 H), 2.70-2.75 (m, 1H), 3.49 (dd, J ) 9, 10
Hz, 1 H), 3.60-3.67 (m, 1 H), 3.75 (dd, J ) 5, 11 Hz, 1 H),
3.81-3.91 (m, 3 H), 4.19-4.31 (m, 2 H), 4.44 (d, J ) 11 Hz, 1
H), 4.80-4.86 (m, 2 H), 4.87 (d, J ) 3 Hz, 1 H), 4.93 (d, J ) 7
Hz, 1 H), 5.81 (d, J ) 1 Hz, 1 H), 5.86 (d, J ) 1 Hz, 1 H), 6.22
(s, 1 H), 6.73 (s, 1 H), 7.21-7.23 (m, 5 H); 13C NMR (125 MHz,
CDCl3) δ -0.7, 12.6, 18.6, 18.8, 42.4, 43.4, 44.0, 45.6, 61.5, 62.4,
65.7, 73.0, 93.1, 101.5, 110.0, 110.6, 127.1, 127.8, 129.0, 130.2,
133.6, 145.7, 146.7, 148.3, 153.2, 174.4; IR (ATR) 1784, 1695
cm-1; [R]24 ) -106.9° (c 3.6, CHCl3). Anal. Calcd for C37H55
-
D
NO8Si2: C, 63.67; H, 7.94; N, 2.01. Found: C, 63.72; H, 7.78;
N, 1.86.
(1R,2S,3R,4R)-6,7-Meth ylen edioxy-2-(N-oxazolidin on yl)-
ca r b on yl-3-t r iisop r op ylsilyloxym e t h yl-1-(3′,4′,5′-t r i-
m et h oxy)p h en yl-4-(2′′-t r im et h ylsilylet h oxy)m et h oxy-
1,2,3,4-tetr a h yd r on a p h th a len e (52). To a suspension of
CuCN (0.52 g, 5.81 mmol) in THF (10 mL) at 10 °C was added
(3,4,5-trimethoxy)phenylmagnesium bromide37 (19.3 mL of a
0.3 M solution in THF). The resulting mixture was allowed to
stir for 1 h at 10 °C, whereupon a solution of 50 (0.45 g, 0.73
mmol) in THF (10 mL) was added via cannula. After 2.5 h at
10 °C, the reaction was worked up as for 51. Chromatography
(10-30% EtOAc/hexanes) yielded 52 (0.49 g, 85%): 1H NMR
(500 MHz, CDCl3) δ 0.02 (s, 9 H), 0.97-1.01 (m, 5 H), 0.98 (d,
J ) 4 Hz, 18 H), 2.63-2.67 (m, 1 H), 3.50 (dd, J ) 9, 10 Hz, 1
H), 3.62 (dt, J ) 7,10 Hz, 1H), 3.76 (s, 6 H), 3.80 (s, 3 H), 4.28-
4.32 (m, 3 H), 4.81 (d, J ) 7 Hz, 1 H), 4.87-4.90 (m, 3 H), 5.85
(d, J ) 1 Hz, 1 H), 5.88 (d, J ) 1 Hz, 1 H), 6.32 (s, 1 H), 6.44
(s, 2 H), 6.75 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ -1.4, 12.0,
17.9, 18.1, 41.8, 42.8, 44.0, 44.4, 56.1, 60.8, 61.7, 65.1, 72.7,
92.6, 100.9, 106.5, 109.1, 110.0, 127.3, 132.4, 136.5, 140.2,
C
22H23NO8Na 452.1321, obsd 452.1324.
(3R,4R)-6,7-Meth ylen ed ioxy-2-(N-oxa zolid in on yl)ca r -
b on yl-3-t r iisop r op ylsilyloxym e t h yl-4-(2′-t r im e t h ylsi-
(37) Koza´k, I.; Kronra´d, L.; Procha´zka, M. J . Labelled Compd.
Radiopharm. 1978, 15, 401-405.

860 J . Org. Chem., Vol. 65, No. 3, 2000
Berkowitz et al.
146.2, 147.6, 152.6, 153.0, 173.8; IR (ATR) 1783, 1693 cm-1
;
the reaction was quenched by the addition of aqueous NaHCO3
(5 mL) and extracted with CH2Cl2. The combined organics were
dried (MgSO4), filtered, and concentrated. Flash chromatog-
raphy (25-50% EtOAc/hexanes) gave 56 (4 mg, 8%) in a first
fraction and 55 (30 mg, 65%) in a second fraction. For 55: 1H
NMR (500 MHz, CDCl3) δ 2.49 (bs, 1 H), 2.68-2.73 (m, 1 H),
3.21 (dd, J ) 5, 9 Hz, 1 H), 3.80 (s, 6 H), 3.84 (s, 3 H), 4.07 (d,
J ) 5 Hz, 1 H), 4.40 (dd, J ) 6, 10 Hz, 1 H), 4.46 (d, J ) 9 Hz,
1 H), 4.50 (dd, J ) 2, 10 Hz, 1 H), 5.90 (d, J ) 1 Hz, 1 H), 5.92
[R]24 ) -98.1° (c 1.02, CHCl3). Anal. Calcd for C40H61NO11
-
D
Si2: C, 60.96; H, 7.80; N, 1.78. Found: C, 60.55; H, 7.59; N,
1.52.
(1R,2S,3R,4R)-4-O-(2-Tr im et h ylsilylet h oxy)m et h ylp i-
cr op od op h yllin (53). To a solution of 52 (285 mg, 362 µmol)
in THF (5 mL) at room temperature was added TBAF (0.92
mL of a 1.0 M solution in THF). The resulting reaction mixture
was heated at 40-50 °C for 5 h. After cooling to room
temperature, the volatiles were evaporated in vacuo. The
residue was taken up in dry PhH-CHCl3 (1:1; 10 mL) and
concentrated to azeotropically remove H2O and promote the
lactonization of any γ-hydroxy acid present. This procedure
was repeated twice. Then the crude product was partitioned
between CH2Cl2 and aqueous NH4Cl. After further extraction
of the aqueous layer with CH2Cl2, the crude product was
subjected to SiO2 chromatography (10-30% EtOAc/hexanes)
to provide 53 (123 mg, 62%): 1H NMR (500 MHz, CDCl3) δ
0.02 (s, 9 H), 0.90-1.01 (m, 2 H), 2.91-2.96 (m, 1 H), 3.24
(dd, J ) 5, 10 Hz, 1 H), 3.60 (dt, J ) 7,10 Hz 1 H), 3.71-3.76
(m, 1 H), 3.79 (s, 6H), 3.82 (s, 3H), 4.14 (d, J ) 5 Hz, 1 H),
4.32 (dd, J ) 4, 10 Hz, 1 H), 4.41 (dd, J ) 7, 10 Hz, 1 H), 4.51
(d, J ) 7 Hz, 1 H), 4.76 (d, J ) 7 Hz, 1 H), 4.79 (d, J ) 7 Hz,
1 H), 5.91 (d, J ) 1 Hz, 1 H), 5.92 (d, J ) 1 Hz, 1 H), 6.40 (s,
1 H), 6.44 (s, 2 H), 6.85 (s, 1 H); 13C NMR (125 MHz, CDCl3)
δ -1.5, 18.1, 40.9, 44.7, 45.2, 56.1, 60.8, 65.9, 70.1, 74.9, 94.1,
101.2, 105.7, 107.1, 109.5, 129.0, 131.2, 136.9, 139.0, 146.8,
(d, J ) 1 Hz, 1 H), 6.34 (s, 1 H), 6.44 (s, 2 H), 7.03 (s, 1 H); 13
C
NMR (125 MHz, CHCl3) δ 42.6, 44.0, 45.4, 56.2, 60.9, 69.3,
69.8, 101.2, 105.4, 105.8, 109.1, 130.6, 132.2, 137.1, 139.3,
147.0, 147.3, 153.6, 177.9; IR (ATR) 3472, 1769 cm-1; [R]24
D
) -10.0° (c 0.3, CHCl3); HRMS (FAB, 3-NBA) calcd for
C22H22O8 414.1315 [M+], obsd 414.1324. For 56: 1H NMR (500
MHz, CDCl3) δ 1.29 (t, J ) 8 Hz, 3 H), 2.61 (br q, J ) 2, 8 Hz,
2 H), 2.89-2.98 (m, 1 H), 3.11 (dd, J ) 4, 8 Hz, 1 H), 3.73 (d,
J ) 8 Hz, 1 H), 3.79 (s, 6 H), 3.83 (s, 3 H), 4.25 (d, J ) 4 Hz,
1 H), 4.37-4.40 (m, 2H), 5.91 (d, J ) 1 Hz, 1 H), 5.93 (d, J )
1 Hz, 1 H), 6.40 (s, 2 H), 6.41 (s, 1 H), 7.18 (s, 1 H); IR (ATR)
1770 cm-1; [R]24
) 139.2° (c 0.05, CHCl3); HRMS (FAB,
D
3-NBA) calcd for C24H26O7S 458.1399 [M+], obsd 458.1399.
(-)-P od op h yllotoxin (1). trans-Lactone 54 (71 mg, 0.13
mmol) was taken up in Et2O (4 mL) and PhH (1 mL). MgBr2‚
Et2O complex (61 mg 0.24 mmol) was added under Ar. To the
resulting solution at 0 °C was added EtSH (29 µL, 0.39 mmol)
dropwise, via syringe. After 2 h at 0 °C and 6 h at room
temperature, additional MgBr2‚Et2O (30 mg, 0.12 mmol) and
EtSH (15 µL, 0.2 mmol) were added, as before. After 3 h, the
reaction was quenched by the addition of aqueous NaHCO3 (5
mL) and extracted with CH2Cl2. The combined organics were
dried (MgSO4), filtered, and concentrated. Flash chromatog-
raphy (25-50% EtOAc/hexanes) gave 1 (44 mg, 81%), identical
in all respects to an authentic sample of the natural product:
1H NMR (500 MHz, CDCl3) δ 2.00 (bs, 1 H), 2.72-2.80 (m, 1
H), 2.83 (dd, J ) 4, 14 Hz, 1 H), 3.75 (s, 6 H), 3.80 (s, 3 H),
4.08 (appt, J ) 10 Hz, 1 H), 4.58-4.61 (m, 2 H), 4.76 (d, J )
10 Hz, 1 H), 5.96 (d, J ) 1 Hz, 1 H), 5.98 (d, J ) 1 Hz, 1 H),
6.36 (s, 2 H), 6.50 (s, 1 H), 7.10 (s, 1 H); 13C NMR (125 MHz,
CHCl3) δ 40.8, 44.1, 45.3, 56.3, 60.7, 71.3, 72.8, 101.4, 106.3,
108.5, 109.8, 131.2, 133.2, 135.4, 137.4, 147.7, 147.8, 152.6,
147.6, 153.3, 178.0; IR (ATR) 1773 cm-1; [R]24 ) +61.3° (c
D
0.75, CHCl3). Anal. Calcd for C28H36O9Si: C, 61.74; H, 6.66.
Found: C, 61.53; H, 6.91.
(1R ,2R ,3R ,4R )-4-O-(2′-Tr im e t h ylsilyle t h oxy)m e t h -
ylp od op h yllotoxin (54). A solution of LDA (4.15 mL of a 0.27
M solution in THF, 1.1 mmol) was prepared at 0 °C and then
cooled to -78 °C. A solution of 53 (200 mg, 0.37 mmol) in THF
(5 mL) was then added dropwise via cannula at -78 °C. After
this solution stirred for 90 min at -78 °C, a suspension of
freshly prepared pyridinium hydrochloride (297 mg, 2.57
mmol) in THF (3 × 2 mL) was added. The transfer was effected
in three portions owing to the limited solubility of the salt in
THF. After allowing the reaction mixture to come to room
temperature, it was poured into saturated NH4Cl (aqueous,
10 mL) and CHCl3 (20 mL). Following a second extraction with
CHCl3, the organics were dried (MgSO4), filtered, concentrated,
and chromatographed (10-30% EtOAc/hexanes) to give 54 (93
mg, 47%), in a first fraction, followed by diastereomeric lactone
53 (91 mg, 46%). For 54: 1H NMR (500 MHz, CDCl3) δ 0.01
(s, 9 H), 0.91-0.97 (m, 2 H), 2.81 (dd, J ) 5, 14 Hz, 1 H), 2.86-
2.95 (m, 1H), 3.68 (dt, J ) 1, 8 Hz, 2 H), 3.73 (s, 6 H), 3.79 (s,
3 H), 4.11 (appt, J ) 9 Hz, 1 H), 4.56 (d, J ) 5 Hz, 1 H), 4.60
(dd, J ) 7, 9 Hz, 1 H), 4.68 (d, J ) 9 Hz, 1 H), 4.83 (d, J ) 8
Hz, 1 H), 4.89 (d, J ) 8 Hz, 1 H), 5.94 (s, 1 H), 5.95 (s, 1 H),
6.37 (s, 2 H), 6.49 (s, 1 H), 6.98 (s, 1 H); 13C NMR (125 MHz,
CDCl3) δ -1.5, 18.1, 38.9, 43.9, 45.6, 56.1, 60.7, 66.1, 71.9, 79.4,
94.9, 101.4, 107.1, 108.0, 109.6, 131.1, 131.7, 135.3, 136.9,
147.5, 147.7, 152.5, 174.2; IR (ATR) 1779 cm-1; [R]24D ) -95.7°
(c 1.1, CHCl3). Anal. Calcd for C28H36O9Si: C, 61.74; H, 6.66.
Found: C, 61.43; H, 6.59. HRMS (FAB, 3-NBA) calcd for
174.4; IR (ATR) 3710, 1770 cm-1; [R]24 ) -101.7° (c 0.55,
D
EtOH) {lit. [R]24 ) -102.1° (c 0.529, EtOH)13b and [R]22
)
D
D
-104 (c 0.36, EtOH)13a}; HRMS (FAB, 3-NBA) calcd for
C
22H22O8 414.1315 [M+], obsd 414.1299.
Ack n ow led gm en t . Financial support from the
American Cancer Society (RPG-96-001-03-CDD) is grate-
fully acknowledged. D.B.B. is an Alfred P. Sloan Re-
search Fellow (1997-2001). J .-H.M. thanks the UNL
Center for Biotechnology for a fellowship. We thank Dr.
Richard K. Shoemaker for assistance with NMR experi-
ments and Dr. Ron Cerny (Nebraska Center for Mass
Spectrometry) for high resolution mass spectra. This
research was facilitated by grants for NMR and GC/
MS instrumentation from the NIH (SIG 1-S10-RR06301)
and the NSF (CHE-93000831), respectively.
C
28H36O9Si 544.2128 [M+], obsd 544.2148.
(-)-P icr op od op h yllin (55). cis-Lactone 53 (75 mg, 0.14
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra for compounds 13-22; 25; 26a ,b; 27a ,b; 28-
30; 31c; 32a ,c; 33; 35-44; 46-56; 57a ,b; and 58, as well as
comparison spectra of synthetic and authentic (-)-podophyl-
lotoxin (1). This material is available free of charge via the
Internet at http://pubs.acs.org.
mmol) was taken up in Et2O (4 mL) and PhH (1 mL). MgBr2‚
Et2O complex (64 mg, 0.25 mmol) was added under Ar
atmosphere in a glovebag. To the resulting solution at 0 °C
was added EtSH (31 µL, 0.41 mmol) dropwise, via syringe.
After 2 h at 0 °C and 6 h at room temperature, additional
MgBr2‚Et2O (32 mg, 0.13 mmol) and EtSH (15 µL, 0.2 mmol)
were added, as before. After 3 h (0 °C f room temperature),
J O991582+