Toluene dioxygenase-mediated cis-dihydroxylation of aromatics in enantioselective synthesis. Asymmetric total syntheses of pancratistatin and 7-deoxypancratistatin, promising antitumor agents

Article abstract of DOI:10.1021/ja960596j

Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia coli JM109 (pDTG601) yields (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetonide and converted to vinylaziridines 7, 15a, 6

Full text of DOI:10.1021/ja960596j

10752
J. Am. Chem. Soc. 1996, 118, 10752-10765
Toluene Dioxygenase-Mediated cis-Dihydroxylation of
Aromatics in Enantioselective Synthesis. Asymmetric Total
Syntheses of Pancratistatin and 7-Deoxypancratistatin,
Promising Antitumor Agents1
Tomas Hudlicky,* Xinrong Tian, Kurt Ko1nigsberger, Rakesh Maurya,
Jacques Rouden, and Boreas Fan†
Contribution from the Department of Chemistry, UniVersity of Florida,
GainesVille, Florida 32611-7200
ReceiVed February 23, 1996X
Abstract: Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia
coli JM109 (pDTG601) yields (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetonide
and converted to vinylaziridines 7, 15a, 63, and 64. Our route to (+)-pancratistatin features the coupling of a higher
order cyanocuprate (derived by ortho-metalation from N,N-dimethyl-2-[(tert-butyldimethylsilyl)oxy]-3,4-(methyl-
enedioxy)benzamide) with aziridine 7 to generate 28, which contains the carbon framework of the title alkaloid.
Functional group manipulations resulted in the preparation of epoxydiol 50, which was transformed in a unique
fashion and under mild conditions (H2O/PhCO2Na) to (+)-pancratistatin, thus completing a concise synthesis of
(+)-pancratistatin in 14 steps from bromobenzene (2% overall yield). To improve this first generation attempt, a
new route was devised utilizing carbomethoxyaziridine 64 and its coupling to the cuprate of 3,4-(methylenedioxy)-
bromobenzene. The adduct was converted to (+)-7-deoxypancratistatin in a total of 11 steps from bromobenzene
(3% overall yield), and the basis for further improvement toward a practical synthesis of pancratistatin-type alkaloids
was formulated.
Introduction
The medicinal value of oil from the daffodil Narciclasus
poeticus L. in the treatment of illnesses related to cancer was
already known to physician Hippocrates of Cos2 in ancient
Grecian times, but it was not until 1877 that the first member
of the Amaryllidaceae family of alkaloids, lycorine (1, Figure
1), was isolated from Narcissus pseudonarcissus.3 Since that
time, more than 100 structurally diverse alkaloids have been
isolated from various Amaryllidaceae species. In 1958, lycorine
was shown to possess antitumor acivity.4 Lycoricidine (2) and
narciclasine (3) were discovered in 1968 in the bulbs of Lycoris
radiate.5 Sixteen years later, another highly oxygenated
phenanthridone alkaloid was extracted from Pancratium litto-
rale.6 The compound was named pancratistatin (4);7 it subse-
quently attracted considerable attention because of its spectrum
of antineoplastic activities.6c Although pancratistatin’s mech-
anism of action remains to be elucidated, that of narciclasine
Figure 1.
† Undergraduate Research Participant, Summer 1993.
X Abstract published in AdVance ACS Abstracts, October 1, 1996.
(1) Preliminary accounts of this work, performed fully (a) or in part (b)
at Virginia Polytechnic Institute and State University, have been published.
(a) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J. Am. Chem. Soc. 1995, 117,
3643. (b) Tian, X.; Maurya, R.; Ko¨nigsberger, K.; Hudlicky, T. Synlett 1995,
1125.
has been studied, and it is believed that the compound disrupts
protein biosynthesis in eukaryotes.8 Both lycoricidine and
(7) The word pancratistatin should more appropriately be spelled
pancratistatinum in correct “chemical” Latin. It implies an “all-powerful
breaker or stopper” of some activity, in this case cell division. The derivation
is of some interest here. The name of the plant translates literally as “all-
powerful from the shore of a lake” and is a Latin rendition of a Greek
word pankration, which means “victory by any and all means”. It refers to
an ancient wrestling contest which was frequently fought to the death or
unconditional surrender of one of the opponents. Barred from this match
was only the use of biting or gougingsall else was allowed. The root of
the word pankration in Greek implies power or strength (kratos) and in
Latin hurdles or obstacles. We thank Dr. Thomas MacAdoo (Virginia Tech)
for this interesting elucidation.
(2) Hartwell, J. L. Lloydia 1967, 30, 379.
(3) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske, R. H. F.,
Holmes, H. L., Eds.; Academic Press: New York, 1952; Vol. 2, Chapter
11, p 331.
(4) Fitzgerald, R.; Hartwell, J. L.; Leiter, J. J. Natl. Cancer Inst. 1958,
20, 763.
(5) Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968, 16,
1860.
(6) (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa,
Y. J. Chem. Soc., Chem. Commun. 1984, 1693. (b) Pettit, G. R.; Gaddamidi,
V.; Cragg, G. M. J. Nat. Prod. 1984, 47, 1018. (c) Pettit, G. R.; Gaddamidi,
V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.; Schmidt, J. M.; Boettner, F.
E.; Williams, M.; Sagawa, Y. J. Nat. Prod. 1986, 49, 995.
(8) (a) Carrasco, L.; Fresno, M.; Vazquez, D. FEBS Lett. 1975, 52, 236.
(b) Jimenez, A.; Sanchez, L.; Vazquez, D. FEBS Lett. 1975, 55, 53. (c)
Jimenez, A.; Santos, A.; Alonso, G.; Vasquez, D. Biochim. Biophys. Acta
1976, 425, 342. (d) Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445.
S0002-7863(96)00596-3 CCC: $12.00 © 1996 American Chemical Society

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10753
narciclasine show activities against Ehrlich carcinoma,5 but the
most promising activity resides with pancratistatin, which is
active against murine P-5076 ovarian sarcoma, as well as murine
P-388 lymphocytic leukemia.6c To date, no focused structure-
activity study has been conducted with these alkaloids, perhaps
as a consequence of the minute quantity of material available
from isolation (6.5 g of pancratistatin and 10 g of lycoricidine
were extracted from 45 kg of bulbs).6 Tests on seco-derivatives
of pancratistatin, which lack the piperonyl unit, indicated no
activity.9 The biogenesis of the alkaloids remains unconfirmed
except for the biosynthesis of narciclasine, investigated in the
early 1970s.10
aryl moiety to a suitable residue,18 but despite these efforts, no
efficient, practical preparation has materialized to date. The
chemistry of Amaryllidaceae alkaloids having antitumor activity
has recently been reviewed.19
In order to elucidate the mode of activity of pancratistatin
and its congeners and to initiate a rational design of more active
medicinal substances from these promising lead compounds, it
is essential to be able to access a large number of diversely
functionalized derivatives of the parent system. Any such
synthetic design must accommodate structural variation and
efficiently lead to the brief preparation of the target class of
compounds. A first step toward this goal has been realized by
combining biocatalytic methods for generating chirality with
new methodology of carbon-carbon bond formation. In this
article, the enantioselective syntheses of pancratistatin and
7-deoxypancratistatin are described.
The chemistry of Amaryllidaceae alkaloids is rich and
detailed, and many syntheses of lycorine and related structures
have been published.11,12 Driven by the promise of biological
activities, the synthetic community reacted to the discovery of
lycoricidine and pancratistatin with focused rigorsto date,
lycoricidine has been prepared by several groups.13 Narciclasine
has not yet been synthesized despite several attempts;14 the first
racemic preparation of pancratistatin was published by Dan-
ishefsky and Lee in 1989.15 The latter synthesis builds up the
C-ring skeleton of 4 by means of a Diels-Alder reaction
between a butadiene attached to C10a of the aromatic moiety
and â-nitrovinyl sulfone, affording a 1,4-cyclohexadiene, which
is further elaborated to the fully oxygenated alkaloid in 2%
overall yield from the diene. Two asymmetric syntheses of 4
were achieved in 1995sthe first by our group as disclosed in a
preliminary report,1a and the second by Trost and Pulley,16 who
employed Pd-catalyzed asymmetrization of a symmetric 1,4-
bis(methoxycarboxy)-2-cyclohexene with a nitrogen nucleophile,
followed by CuCN-catalyzed SN2′ substitution to introduce the
aromatic moiety. Keck et al.17 and we1b have recently published
syntheses of 7-deoxypancratistatin.17,1b Starting from readily
available D-gulono-1,4-lactone-2,3-acetonide, Keck builds up
a linear C-ring precursor and closes the crucial C10b-C4a bond
by radical addition to an oxime. The work published so far
suggests that these molecules are far more difficult to construct
than they appear at first glance. There have been several reports
of model studies concerned with the efficient attachment of the
Results and Discussion
The major difficulty with any approach to the fully oxygen-
ated Amaryllidaceae alkaloids has been in the control of
stereochemistry at C10b-C4a and in introducing (and/or
retaining) the oxygenation in the C-ring. Our approach is based
on the advantageous configuration of the cis-diol at C3-C4,
envisioned to be the controlling element of the relative and
absolute stereochemistry, introduced by toluene dioxygenase-
mediated cis-dihydroxylation of aromatic rings.20-22 The trans-
diol at C1-C2 and the trans disposition of the aryl fragment to
the C4a nitrogen suggested opening of epoxides and aziridines,
respectively, as a means for control of the configuration of the
six contiguous stereocenters in the C-ring. The initial discon-
nection assumed a convergent approach and a minimum of
functional group manipulations, as depicted in Figure 2.
The assumption that diaxial opening of the epoxide in 5 would
be accomplished with concomitant hydrolysis of the acetonide
was based on our successful performance of both of these tasks
by means of a catalytic amount of sodium benzoate in water
during the synthesis of D-chiro-inositol.23 Epoxide 5 was to
be derived from phenanthridone 6, where the â-face is blocked
by the endo-situated methyl group of the acetonide. The crucial
C-C bond formation was expected to arise from the trans
opening of the aziridine in 7 with an organometallic species
derived from the known amide 8.24 From the results obtained
in a preliminary study of the opening of aziridines of type 7
with different organometallic species,25 we were confident that
trans 1,2-opening of the vinylaziridine 7 with aromatic carbon
(9) Chre´tien, F.; Ahmed, S. Ibn.; Masion, A.; Chapleur, Y. Tetrahedron
1993, 34, 7463.
(10) (a) Fuganti, F.; Staunton, J.; Battersby, A. R. J. Chem. Soc., Chem.
Commun. 1971, 1154. (b) Fuganti, F.; Mazza, M. J. Chem. Soc., Chem.
Commun. 1971, 1388. (c) Fuganti, F.; Mazza, M. J. Chem. Soc., Chem.
Commun. 1972, 239.
(11) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, p 251.
(12) (a) Martin, S. F.; Tu, C.-Y.; Kimura, M.; Simonsen, S. H. J. Org.
Chem. 1982, 47, 3634. (b) Wang, C.-L.; Ripka, W. C.; Confalone, P. N.
Tetrahedron Lett. 1984, 25, 4613. (c) Boeckman, R. K., Jr.; Sabatucci, J.
P.; Goldstein, S. W.; Springer, D. M.; Jackson, P. F. J. Org. Chem. 1986,
51, 3740. (d) Boeckman, R. K., Jr.; Goldstein, S. W.; Walters, M. A. J.
Am. Chem. Soc. 1988, 110, 8250. (e) Ba¨ckvall, J.-E.; Andersson, P. G.;
Stone, G. B.; Gogoll, A. J. Org. Chem. 1991, 56, 2988. (f) Oppolzer, W.;
Spivey, A. C.; Bochet, C. G. J. Am. Chem. Soc. 1994, 116, 3139.
(13) (a) Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975, 2270. (b) Ohta,
S.; Kimoto, S. Chem. Pharm. Bull. 1976, 24, 2977. (c) Paulsen, H.; Stubbe,
M. Liebigs Ann. Chem. 1983, 535. (d) Paulsen, H.; Stubbe, M. Tetrahedron
Lett. 1982, 23, 3171. (e) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron
Lett. 1991, 32, 4525. (f) Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992,
114, 9694. (g) Chida, N.; Ohtsuka, M.; Ogawa, S. J. Org. Chem. 1993, 58,
4441. (h) Johnson, C. R.; Su, L. Abstract of National Organic Symposium,
Bozeman, MT, 1993. (i) Martin, S. F.; Tso, H.-H. Heterocycles 1993, 35,
85. (j) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem. Soc. 1994,
116, 5108.
(18) (a) Clark, R. D.; Souchet, M. Tetrahedron Lett. 1990, 31, 193. (b)
Thompson, R. C.; Kallmerten, J. J. Org. Chem. 1990, 55, 6076. (c) Lopes,
R. S. C.; Lopes, C. C.; Heathcock, C. H. Tetrahedron Lett. 1992, 33, 6775.
(d) Angel, S, R.; Louie, M. S. Tetrahedron Lett. 1993, 34, 4751. (e) Doyle,
T. J.; Hendrix, M.; Haseltine, J. Tetrahedron Lett. 1994, 35, 8295. (f)
Banwell, M. G.; Cowden, C. J.; Gable, R. W. J. Chem. Soc., Perkin Trans.
1 1994, 3515. (g) Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995,
36, 195. (h) Rigby, J. H.; Gupta, V. Synlett 1995, 547. (i) Doyle, T. J.;
VanDenveer, D.; Hasetline, J. Tetrahedron Lett. 1995, 36, 6197. (j) Friestad,
G. K.; Branchaud, B. P. Tetrahedron Lett. 1995, 36, 7047. (k) Gauthier, D.
R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13.
(19) Polt, R. In Organic Synthesis: Theory and Applications; Hudlicky,
T., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 3, p 109.
(20) Gibson, D. T.; Hensley, M.; Yosioka, H.; Mabry, T. J. Biochemistry
1970, 9, 1626.
(21) Gibson, D. T.; Subramaniam, V. In Microbial Degradation of
Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984;
p 181.
(22) Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989, 264, 14940.
(23) (a) Mandel, M.; Hudlicky, T. J. Org. Chem. 1993, 58, 2331. (b)
Hudlicky, T.; Mandel, M.; Rouden, J.; Lee, R. S.; Bachmann, B.; Dudding,
T.; Yost, K. Y.; Merola, J. S. J. Chem. Soc., Perkin Trans. 1 1994, 1553.
(24) (a) Iwao, M.; Reed, J. N.; Snieckus, V. J. Am. Chem. Soc. 1982,
104, 5531. (b) Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.;
Billedeau, R. J.; Snieckus, V. J. Org. Chem. 1984, 49, 742.
(14) (a) Banwell, M. G.; Cowden, C. J.; MacKay, M. F. J. Chem. Soc.,
Chem. Commun. 1994, 64. (b) Khaldi, M.; Chre´tien, F.; Chapleur, Y.
Tetrahedron Lett. 1995, 36, 3003 and references therein.
(15) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
(16) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
(17) Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995,
117, 7289.

10754 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
Figure 2. Disconnection approach to pancratistatin.
Scheme 1
nucleophiles would be possible. The core of our approach
would be the introduction of the 3,4-cis-diol unit of pancratistatin
in the required absolute stereochemistry by the oxidation of
halobenzene20 to diene diol 9, mediated by toluene dioxygenase
(from Pseudomonas putida 39/D), offering fast access to
aziridine 7.
Asymmetric dihydroxylation of aromatic substrates, pioneered
by Gibson et al. almost 30 years ago,20,21 has witnessed
increasing use in organic synthesis since 1988.26,27 The latest
synthetic applications have recently been reviewed28 and include
the use of recombinant E. coli JM109 (pDTG601), which
contains the information for toluene dioxygenase on a plasmid22
and allows production of diene diols in higher yields and renders
transformations of noninducing substrates easier.
Preparation of Vinylaziridines. Enantiomerically pure diols
9a,b29 were prepared by oxidation of halobenzenes 10 with
whole cells of P. putida 39/D or recombinant E. coli JM109
(pDTG601) according to the established procedure30 and stored
at -78 °C. After protection as their acetonides, dienes 11 were
used immediately to avoid dimerization through Diels-Alder
cycloaddition.31 Initially, the aziridines investigated in this study
were prepared as shown in Scheme 1. The intermediate
â-epoxide (generated from bromohydrin 12 in situ) was opened
with azide; subsequent mesylation of 13 followed by LiAlH4
reduction afforded aziridine 14. Tosylation of 14 gave tosyl-
aziridines 15 for both the chlorine (X ) Cl) and bromine (X )
Br) series. A more efficient protocol to acquire 15 and
dehalogenated derivative 7 was found by the use of Yamada’s
iodonium ylide.32 Treatment of 11a (X ) Br) or 11b (X ) Cl)
with (N-tosylimino)phenyliodinane according to Evans’s pro-
cedure33 afforded 59% and 20% overall yields of aziridines 15a
and 15b, respectively. Dehalogenation of 15a with Bu3SnH/
AIBN/THF furnished vinylaziridine 7 in 78% yield. Although
this aziridination procedure is vastly superior to the stepwise
preparation of 15, the latter has the advantage that it leads to
the free aziridines 14, which can be functionalized with groups
other than tosyl. With aziridine 7 in hand, a detailed investiga-
tion of the crucial C10a-C10b bond formation by opening of
the aziridine with suitable carbon nucleophiles was now possible.
Ring Opening of Endocyclic Vinylaziridine 7. The chem-
istry of vinylaziridines has been confined for the most part to
their use in rearrangement sequences leading to functionalized
pyrrolines.34-38 The lack of data concerning the nucleophilic
opening of vinylaziridines with carbon nucleophiles surprised
us, in view of the expected similarity of such systems to the
well-studied vinyloxiranes.34,39 There were no disclosures of
(25) Hudlicky, T.; Tian, X.; Ko¨nigsberger, K.; Rouden, J. J. Org. Chem.
1994, 59, 4037.
(26) For recent applications of cis-arene dihydrodiols in enantioselective
synthesis, see: (a) Hudlicky, T.; Nugent, T.; Griffith, W. J. Org. Chem.
1994, 59, 7944. (b) Entwistle, D. A.; Hudlicky, T. Tetrahedron Lett. 1995,
36, 2591. (c) Hudlicky, T.; Thorpe, A. J. Synlett 1994, 899. (d) Hudlicky,
T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994, 116, 5099. (e)
Reference 15j. (f) Hudlicky, T.; Abboud, K. A.; Bolonick, J.; Maurya, R.;
Stanton, M. L.; Thorpe, A. J. J. Chem. Soc., Chem.Commun. 1996, 1717.
(g) Hudlicky, T.; Abboud, K. A.; Entwistle, D. A.; Rulin, F.; Maurya, R.;
Thorpe, A. J.; Bolonick, J. Synthesis 1996, 897.
(27) For reviews on the use of cis-arene dihydrodiols as chiral synthons,
see: (a) Hudlicky, T.; Reed, J. W. In AdVances in Asymmetric Synthesis;
Hassner, A., Ed.; JAI Press: Greenwich, CT, 1995; Vol. 1, p 271. (b) Brown,
S. M.; Hudlicky, T. In Organic Synthesis: Theory and Practice; Hudlicky,
T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p 113. (c) Carless, H. A.
J. Tetrahedron: Asymmetry 1992, 3, 795. (d) Widdowson, D. A.; Ribbons,
D. W.; Thomas, S. D. Janssen Chim. Acta 1990, 8, 3. (e) Sheldrake, G. N.
In Chirality in Industry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.;
Wiley: Chichester, 1992; p 127.
(28) (a) Hudlicky, T. In ACS Symposium Series; Anastas, P. T.,
Eilliamson, T. C., Eds.; American Chemical Society: Washington, DC,
1996; Vol. 626, p 180. (b) Hudlicky, T.; Thorpe, A. J. J. Chem. Soc., Chem.
Commun. 1996, 1993.
(29) Available from Eastman Fine Chemicals, Rochester, NY, and
Genencor International, Inc., South San Francisco, CA.
(30) (a) Hudlicky, T.; Boros, E. E.; Boros, C. H. Tetrahedron: Asymmetry
1993, 4, 1365. (b) Hudlicky, T.; Boros, E. E.; Boros, C. H. Synthesis 1992,
174.
(31) (a) Pittol, C. A.; Pryce, R. J.; Roberts, S. M.; Ryback, G.; Sik, V.;
Willams, J. O. J. Chem. Soc., Perkin Trans. 1 1989, 1160. (b) Hudlicky,
T.; Boros, E. E.; Olivo, H. F.; Merola, J. S. J. Org. Chem. 1992, 57, 1026.
(c) Ley, S. V.; Redgrave, A. J.; Taylor, S. C.; Ahmed, S.; Ribbons, D. W.
Synlett 1991, 741.
(32) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975, 361.
(33) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem. 1991,
56, 6744. (b) Knight, J. G.; Muldowney, M. P. Synlett 1995, 949.
(34) Hudlicky, T.; Reed, J. W. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 899.
(35) (a) Hudlicky, T.; Seoane, G.; Price, J. D.; Gadamasetti, K. G. Synlett
1990, 433. (b) Hudlicky, T.; Luna, H.; Price, J. D.; Fan, R. J. Org. Chem.
1990, 55, 4683. (c) Hudlicky, T.; Frazier, J. O.; Seoane, G.; Tiedje, M.;
Seoane, A.; Kwart, L. D.; Beal, C. J. Am. Chem. Soc. 1986, 108, 3755.
(36) Scheiner, P. J. Org. Chem. 1967, 32, 2628.
(37) Heine, H. W. J. Am. Chem. Soc. 1963, 85, 2743.
(38) Hudlicky, T.; Sinai-Zingde, G.; Seoane, G. Synth. Commun. 1987,
17, 1155.

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10755
Table 1. Reactions of Vinylaziridine 7
Figure 3. Mechanistic rationale for vinylaziridine opening.
corresponding trends for vinylaziridines prior to our preliminary
report on parallel reactivities of vinyloxiranes and vinylaziridines
with organometallic reagents.25 Recently, several papers have
appeared describing the interaction of cuprates and other
organometallics with acyclic vinylaziridines.40 Our results
indicated that the ring opening of endocyclic vinylaziridines 7
and 15 with Grignard and cuprate reagents can be described as
either anti-1,2-addition or syn-1,4-addition. In the case of
halovinylaziridines 15, the latter process is followed by a second
1,4-addition, forming 2,4- or 4,4-disubstituted products (Figure
3). The reactions are strongly dependent on the nature of the
nucleophile and the structure of the vinylaziridine. Some
generalizations formulated during the study are delineated in
Figure 3. Whereas the reaction of an aliphatic or aromatic
cuprate or a Grignard reagent with aziridine 7 yields predomi-
nantly syn-1,4-addition,25 there is an interesting difference in
reactivity for higher order cuprates. Lithium dimethylcyano-
cuprate affords syn-1,4-addition (21, 37%), while lithium
diphenylcyanocuprate shows anti-1,2-addition (22, 70% yield;
Table 1, entries 1 and 2). Currently, we have no explanation
for this divergent reactivity. The assignment of stereochemistry
Scheme 2
1
was achieved by decoupling experiments and analysis of H-
1
NMR coupling constants, as well as H-NMR-NOE experi-
ments.
The isolation of 22, with established trans-stereochemistry,
provided a good basis for the application of this method (opening
of aziridine 7 with a higher order cyanocuprate) in the synthesis
of the title alkaloids. The aromatic portion required for
pancratistatin was synthesized according to the established
protocol by means of ortho-lithiation41 of a diethyl- or di-
methylamide species, as shown in Scheme 2. The requisite
amides were made from piperonic acid according to literature
methods.18c,24,42 Lithiation of amides 23,43 followed by quench-
ing with trimethyl borate and oxidation with H2O2, afforded
phenols 24, which were protected as either ethoxymethoxy, TBS,
or methoxy derivatives 25 using standard methods. A second
metalation, followed by cuprate formation according to Lipshutz
et al.,44 provided the required higher order cyanocuprates 26.
The addition to activated aziridine 7 gave 49%, 75%, and 72%
yields respectively of adducts 27, 28, and 29 (Table 1, entries
3-5). To our knowledge, this is the first example of a
preparation of higher order cyanocuprates via ortho-metalation
directed by the amide group. The stage was now set for the
completion of the total synthesis, as these adducts already
possess the carbon framework of the title alkaloids.
(a) trans-Amidation Route. After the successful attainment
of adduct 27, we initially chose to follow Heathcock’s trans-
amidation procedure applied in his model study45 as shown to
close the B-ring (Scheme 3). Reduction of adduct 27 with
(39) (a) Smith, J. D. Synthesis 1984, 629. (b) Marshall, J. A. Chem. ReV.
1989, 89, 1503.
(40) (a) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura,
N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994,
33, 652. (b) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875.
(41) (a) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (b)
Snieckus, V. Chem. ReV. 1990, 90, 879.
(45) Transamidation according to Heathcock:18c
(42) See also for the lithiation of diethylamides: Beak, P.; Brown, R.
A. J. Org. Chem. 1982, 47, 34.
(43) Astley, S. T.; Stephenson, G. R. J. Chem. Soc., Perkin Trans. 1
1993, 1953.
(44) Lipshutz, B. H.; Kozlowski, J. Wilhelm, R. S. J. Am. Chem. Soc.
1982, 104, 2305.

10756 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
Scheme 3
Scheme 4
sodium amalgam46 gave the free amine 30 in 20% yield, which
was subjected to a variety of conditions to accomplish the
desired ring closure to lactam 6 (R ) CH2OEt). All these efforts
met with failure, most likely because of the greatly enhanced
acidity of C10b hydrogen as compared to Heathcock’s model
compound,45 leading to elimination and epimerization.
with 1 equiv of morpholine60 and performing the reduction at
-45 °C afforded chiefly aldehyde 32a with only a trace of 32b.
Phenol 32a was protected as its benzyl ether, formed as a
mixture of aldehyde 32d and hemiaminal 33. Oxidation of this
mixture with Jones reagent provided 34, which could not be
detosylated to 35 with a variety of reagents including sodium
amalgam,46 sodium naphthalenide,61 and SmI2,62 but formed the
hemiaminal 33 instead. We believe that the lactam in 34 is
somewhat strained, thus favorizing rehybridization of the
carbonyl carbon to the sp3 state. At this point, the removal of
the tosyl group prior to the cyclization to the lactam seemed
logical.
The benzamide proved exceptionally resistant to transforma-
tion into a group more amenable to cyclization onto the amine
or tosylamide. Attempts to hydrolyze or reduce this amide met
with complete failure.51 The presence of large groups in both
ortho positions was viewed as the main reason for failure to
manipulate this group. Other ortho-metalation procedures, such
as the method of Comins et al.57 and the recently reported ortho-
metalation of lithium benzoates,58 were also attempted but did
not afford the desired products of aziridine opening.
(b) Reductive Route. Literature reports indicate that N,N-
dimethylbenzamides reduce more easily than the corresponding
diethyl derivatives.59 However, reduction of amide 28 under
conditions applied to 27 also failed. We assumed that the
smaller phenol-protecting group would allow easier approach
of reagents to the amide. Thus, the reduction of methoxy
derivative 29 (Table 1) smoothly afforded the corresponding
tertiary amine as the sole product. The sodium bis(2-methoxy-
ethoxy)aluminum hydride (SMEAH, or Red-Al) reduction of
the free phenol 31, obtained by TBAF desilylation of 28, initially
gave the desired aldehyde 32a, together with the overreduced
amine 32b and alcohol 32c (Scheme 4). Modifying SMEAH
During all these attempts, we observed that adducts 27 (R1
) CH2OEt) and 28 (R1 ) TBS) engage in atropisomerism, as
shown in Figure 4. The cuprate addition generates solely the
â-atropisomer, which isomerizes to the R-isomer during workup
and chromatography. The R-isomer shows hydrogen bonding
between the sulfonamide NH and the carboxamide carbonyl,
1
evidenced by the 3 ppm downfield shift of the NH in the H-
NMR spectrum. Three possibilities exist for the structure of
the â-isomer (â1-â3), since atropisomerism is possible not only
around the C10a-C10b bond but also for the o,o′-disubstituted
aromatic amide.63 These findings provide an explanation for
the complete lack of reactivity of the C1-C2 olefin toward
epoxidation: The carboxamide in the more stable R-form
severely restricts approach of reagents to the R-face of the
cyclohexene in 27 or 28. In addition, the deactivation by the
flanking allylic ether and aromatic moiety also may be partially
responsible for this lack of reactivity.
(46) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477. Sodium/ammonia,47 sodium/naphthalene,48
and other conditions reported for the cleavage of tosylamides49,50 were
ineffective.
(47) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311.
(48) Vigneud, V. Du.; Behrens, O. K. J. Biol. Chem. 1937, 117, 27.
(49) (a) Roemmele, R, C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367.
(b) Singer, S. P.; Sharpless, K. B. J. Org. Chem. 1978, 43, 1448. (c) Hamada,
T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986, 108, 140.
(50) Martens, J.; Scheunemann, M. Tetrahedron Lett. 1991, 32, 1417.
(51) Among others, the following reagents were attempted: KOtBu/H2O/
THF,52 LiAlH4,53 DIBAL-H/BuLi,54 SMEAH (sodium bis(methoxyethoxy)-
aluminum hydride),53,55 LiEt3BH.56
(52) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am. Chem.
Soc. 1976, 98, 1275.
(53) Brown, H.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089.
(54) Kim, S.; Ahn, K. H. J. Org. Chem. 1984, 49, 1717.
(55) Brown, H.; Tsukamoto, A. J. Am. Chem. Soc. 1959, 81, 502.
(56) Sibi, M. P.; Shankaran, K.; Alo, B. I.; Hahn, W. R.; Snieckus, V.
Tetrahedron Lett. 1987, 28, 2933.
(c) Successful Route. In an attempt to reduce the tosyl group
before closure to the lactam, we returned to adduct 28 and
acylated the tosylamide moiety with (BOC)2O following a report
on the decreased reduction potential of acyltosylamides64 and
their easy reduction to carbamates.49b Treatment of 28 with
s-BuLi at 0 °C and reaction with (BOC)2O gave a mixture of
1
at least three atropisomers, 36, as evidenced by H-NMR. It
was subsequently shown that 28R (Figure 4) was much slower
(60) Kanazawa, R.; Tokoroyama, T. Synthesis 1976, 526.
(61) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792.
(62) Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602.
(57) (a) Comins, D. L.; Brown, J. D.; Mantlo, N. B. Tetrahedron Lett.
1982, 23, 3979. (b) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1983,
24, 5465. (c) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078.
(58) Mortier, J.; Moyroud, J.; Bennetau, B.; Cain, P. A. J. Org. Chem.
1994, 59, 4042.
(63) (a) We thank Dr. Jonathan Clayden, University of Manchester, for
bringing this possibility to our attention. (b) For a recent article describing
atropisomerism in substituted biaryls, see: Kamikawa, K.; Watanabe, T.;
Uemura, M. Synlett 1995, 1040.
(64) (a) Cottrell, P. T.; Mann, C. K. J. Am. Chem. Soc. 1971, 93, 3579.
(b) Horner, L.; Singer, R. J. Tetrahedron Lett. 1969, 1545.
(59) Brown, H. C.; Kim, S. C. Synthesis 1977, 635.

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10757
Scheme 6
Figure 4. Atropoisomerism of amides 27 and 28.
Scheme 5
°C and allowed isolation of 37, which was desilylated with
TBAF to yield 38 in 93%, Scheme 5.
Reduction of 38 to aldehyde 39 as outlined above (72% yield)
and protection of the phenol with benzyl bromide (83% yield)
afforded 40 (Scheme 5). Oxidative cyclization of this aldehyde
was then attempted under a variety of conditions. Unlike the
aldehyde 32d, compound 40 did not cyclize to the tosyllactam
41 with Jones reagent; however, sodium chlorite oxidation66,67
provided a quantitative yield of acid 42, which was immediately
methylated to afford 43 (Scheme 6). Neither the acid nor the
ester cyclized under a variety of conditionsswe judged this
reluctance to be the function of an unfavorable conformation
of the bulky BOC-protected amine and the comparative rigidness
of the C-ring bearing the acetonide.
It appeared to be necessary that the C-ring olefin should be
fully functionalized prior to the trans-amidation. The presence
of the olefin proved troublesome because it increased the acidity
of hydrogen at C10b and also appeared to restrict the confor-
mational flexibility of the C-ring. Efforts to epoxidize the C1-
C2 olefin under a host of conditions met with no success, save
the observation of complex mixtures of products.68
We therefore attempted to remove the BOC group and retain
the acetonide at the same time in order to achieve the ring
closure (Scheme 6). In an attempt to selectively cleave the
acetonide, treatment of 43 with CF3CO2H under carefully
monitored conditions revealed a mixture of 44a,b. Cyclization
of the mixture of amino esters under precedented conditions13c,d
smoothly gave a mixture of lactams 45a,b, confirming the
supposition relating to the unfavorable conformation of the
to acylate to 36, presumably because of steric congestion around
the NH of the tosylamide situated on the R-face and hindered
by the dimethylamide moiety. The mixture of atropisomers was
detosylated using Na/anthracene/DME65 to afford a mixture of
37 and 38 in a combined 82% yield. The ratio of these two
products depended on the R/â ratio of atropisomers 36 used in
the reaction, the R-form being concomitantly desilylated to
afford 38. The equilibration of 37â to 37R was slow at -78
(66) Bal. B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(67) (a) Hillis, L. R.; Ronald, R. C. J. Org. Chem. 1985, 50, 471. (b)
Ley, S. V.; Madin, A.; Monck, N. J. T. Tetrahedron Lett. 1993, 34, 7479.
(68) Conditions attempted: m-CPBA, dimethyldioxirane,69 H2O2/urea/
(CF3CO)2O,70 MO(CO)6.71
(69) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(70) Copper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533.
(65) Johnson, C. R.; Lavergne, O. J. Org. Chem. 1989, 54, 986.
(71) Duke, R. K.; Rickards, R. W. J. Org. Chem. 1984, 49, 1898.

10758 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
Figure 6.
groups. We therefore speculate that this reaction might be
unique to the enolized â-ketoamide system present in pancrat-
istatin, in which the formation of the more stable and hydrogen-
bonded phenolamide is responsible for driving the reaction to
completion. Under the reaction conditions, the formation of
O-benzyl iminoester by an intramolecular transfer could be
considered, although this may be contrary to the Beak postu-
lates.75
Figure 5. Diaxial opening of R- and â-oxiranes.
BOC-protected amine toward cyclization. Unfortunately, under
these cyclization conditions, the olefin migrated to the conju-
gated position, giving the C2 deoxynarciclasine structures 46a,b.
A fortuitous change in strategy presented itself upon analysis
of the conformations of the R- and â-epoxides of type 47sthe
assumption of trans-diaxial opening of either substrate allows
the prediction of a doubly degenerate pathway to the correct
C-ring configuration of pancratistatin in 48, as shown in Figure
5. To test this assumption, ester 43 was first subjected to acidic
conditions to remove the acetonide (HOAc/H2O/THF 2:1:1, 60
°C, 73%), and the free diol 49 was epoxidized under Sharpless
and Michaelson’s conditions (t-BuOOH/VO(acac)2, 57%),72 as
shown in Scheme 7. With the â-epoxide 50 in hand, we turned
to the conditions of epoxide hydrolysis reported for D-chiro-
inositol synthesis.23 When 50 was heated in refluxing water in
the presence of a catalytic amount of sodium benzoate, a
remarkable series of events occurred. First, the BOC group
was cleaved, instead of epoxide opening, presumably by thermal
retro-ene-type cleavage,73 giving the epoxylactam 51, as evi-
denced by NMR analysis of reaction aliquots. To our knowl-
edge, this is the first example of a thermal cleavage of the BOC
group in H2O. Second, after approximately 2 h, the hydrolysis
of the epoxide started, cleanly forming the benzyl-protected
pancratistatin 52. At this point, 1H-NMR showed four signals
corresponding to the C-ring oxomethines. The doublet at 2.89
ppm (J ) 11 Hz) was the most characteristic of these signals
and confirmed the correct configuration of H10b and the trans
relationship of H10b and H4a.
(d) Second Generation Synthesis: 7-Deoxypancratistatin.
The evaluation of our first generation synthesis required
solutions to two major problems. The first was the need to
eliminate the presence of the benzamide moiety from future
synthetic designs, because of the drastic conditions or lengthy
manipulations required for its removal. The second was the
search for a new aziridine protecting group that would alleviate
the problems encountered during the removal of the otherwise
convenient50,76 N-tosyl group. A second generation route was
conceived on the basis of the assumption that the amide carbon
of pancratistatin could also assume the function of the protecting
group of the aziridine, as shown in Figure 6. Precedent for
such transformation existed in the report by Banwell et al., who
used an activated aromatic ring as a nucleophile for an
intramolecular amide formation from a carbamate similar to
58.18f In a preliminary investigation, cuprate 59, derived from
5-bromo-1,3-benzodioxole by metal-halogen exchange (n-BuLi,
THF, -78 °C, 1 h, then CuCN, 1 h), was condensed with
aziridine 7 (BF3‚Et2O, -78 to -30 °C, 32%) to generate
tosylamide 60 (Scheme 8), which was converted to carbamate
62 by a two-step procedure consisting of treatment with s-BuLi/
(CH3OCO)2O (76%) to yield 61, followed by reduction with
sodium/anthracene (73%) as described above. This sequence
was subsequently improved by a direct synthesis of 62 via
N-carbomethoxyaziridine 63, prepared from diene acetonide 11a
by adaptation of a procedure for carbethoxyaziridination of
olefins (CH3OCONHOSO2PhNO2, base).77 The aziridination
was not without problems. A large excess of the reagent is
required, and the diene 11a is prone to Diels-Alder dimerization
during prolonged reaction times. A summary of yields and
conditions is shown in Table 2. Improvements in this procedure
will have to be attempted by investigation of different leaving
groups on the reagent (trifluoromethanesulfonate, methane-
sulfonate), as well as various basic conditions for the fragmenta-
tion of the reagent. Subsequent debromination of 63 with
Bu3SnH/AIBN/THF afforded aziridine 64 in 40-54% yield,
which was reacted with cuprate 59 to afford coupling product
62 (34% yield). The synthesis of 62 was thus achieved in just
three steps from acetonide 11a (five from bromobenzene). We
suppose that the low yields in the opening of aziridines 7 and
64 with cuprate 59, as compared to the formation of the
corresponding N,N-dialkylcarboxamides 27-29, are caused by
Third, the debenzylation of 52 to (+)-pancratistatin 4 was
observed. After 6 days, this most unusual reaction thus
furnished the title alkaloid in 51% yield from 50. Alternatively,
pure 52, isolated after 48 h of hydrolysis, was quantitatively
hydrogenated to pancratistatin 4 with H2/Pd(OH)2 in EtOAc.
1
Rf values in several solvent systems, H-NMR spectral data,
and optical rotation ([R]26D ) +41°, c 1.0, DMSO; lit.6c [R]34
D
) +48°, c 1.0, DMSO) of synthesized pancratistatin matched
well with those of an authentic sample.74 Thus, the first
enantioselective synthesis of pancratistatin was achieved, after
a somewhat arduous route, in ∼2% overall yield for the 14-
step sequence (from bromobenzene).
The observed unusual debenzylation reaction of 52 was
studied with a model compound (methyl o-(benzyloxy)benzoate)
without any evidence of cleavage of the benzyl or methyl
(75) Beak, P. Acc. Chem. Res. 1992, 25, 215.
(72) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(73) (a) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987, 52,
19. (b) Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett.
1982, 23, 465.
(74) A sample of 4 was kindly provided by Prof. G. R. Pettit of Arizona
State University.
(76) Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 613.
(77) Methyl carbamate was prepared according to the procedure for the
corresponding ethyl carbamate: Lwowski, W.; Maricich, T. J.; Mattingly,
T. W., Jr. J. Am. Chem. Soc. 1963, 85, 1200. For the aziridination,
compare: (a) Lwowski, W.; Maricich, T. J. J. Am. Chem. Soc. 1965, 87,
3630. (b) Fioravanti, S.; Loreto, M. A.; Pellacani, L.; Tardella, P. A.
Tetrahedron Lett. 1993, 34, 4353.

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10759
Scheme 7
Scheme 8
Scheme 9
observations correspond to similar difficulties experienced by
Trost and Pulley in their synthesis of pancratistatin.16 The
coupled product 62 was converted to epoxydiol 66 (HOAc/THF/
H2O, 65 °C, 94% (forming 65), then t-BuOOH, VO(acac)2,
benzene, 70 °C, 85%) and ultimately to the tetraol 67 by
refluxing in water containing a catalytic amount of sodium
benzoate (82%, Scheme 9), following our previously successful
route. Peracetylation to 68 (84%) was followed by a triflate-
catalyzed Bischler-Napieralski-type cyclization analogous to
that of Banwell et al.,18f which provided 69 in 61% yield. This
material compared well with the acetate reported by Keck et
al.17 and was deprotected (NaOMe/MeOH, 72%) to 7-deoxy-
Table 2. Synthesis of Aziridine 63
p-NO2PhSO2O- yielda
NHCO2CH3 (equiv) (%) (% remaining)
11ab
conditions
K2CO3/rt
K2CO3/rt
0.66
2
14.3
22
23
37
44
38
51
70
50
50
20
0
40
10
pancratistatin (70) [[R]25D ) +78.5° (c 0.75, DMF); lit.13c [R]20
D
K2CO3/0 °C
2
2
3
2
) +82.6° (c 1.1, DMF)] to complete the synthesis in 11 steps
from bromobenzene and an overall yield of 3%. In the next
generation attempt, redundant steps as well as the yields of
individual steps and the development of more efficient aziri-
dination reagents will have to be addressed.
K2CO3/18-crown-6
K2CO3/18-crown-6
Et3BnNCl, NaHCO3/H2O
Et3BnNCl, NaHCO3/H2O
3.7
a From diene 11a. b Amount of remaining diene 11a after disap-
pearance of the reagent. Estimated by TLC.
Conclusion and Outlook
the low stability of the lithiated species formed during the
metal-halogen exchange reaction, which therefore cannot be
warmed to -30 °C for reaction with CuCN, as described above.
This presumably led to incomplete cuprate formation. Our
A new approach to pancratistatin via enantiomerically pure
azabicyclo[4.1.0]heptenes derived from bromobenzene was
completed. The first generation synthesis was, of necessity,
quite exploratory in nature and was plagued with a number of

10760 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
MS (CI+) m/z (relative intensity) 400 ((M + H)+, 2), 384 (1.5), 372
(1.5), 344 (23), 314 (12), 262 (29), 244 (11), 228 (7), 187 (29), 155
(100), 108 (60), 91 (31); HRMS (CI+) calcd for C16H18BrNO4S+H
400.0218, found 400.0231.
problems in functional group manipulation. The first and the
major of these was the incorporation into the synthetic scheme
of ortho-metalation. Unfortunately, the best directing group for
this purpose proved also the most robust toward any further
transformations. To date, there are no mild procedures available
for hydrolysis of benzamides, and the main area for any
improvements in the second generation synthesis, therefore, was
a new way of generating the organometallic species for aziridine
opening without relying on the benzamide group. The second
major improvement required for the generality of the synthetic
scheme was the preparation of aziridines with groups that are
either more easily removed or play a further role in the
assembling of the carbon skeleton (i.e., CO2Me). The 14-step
approach (from bromobenzene) to pancratistatin (overall yield
2%) and the improved 11-step route to deoxypancratistatin
(overall yield 3%) described in this article represent a solid basis
for solving the supply problem for pancratistatin and its
congeners upon further optimization. The evolution of the
multigeneration design of pancratistatin synthesis also allows
for the access to the (-)-enantiomer of pancratistatin for
evaluation of potential biological activity. Because the C-ring
of pancratistatin contains symmetry elements identical to those
found in the enantiomers of pinitol78 and D-chiro-inositol,23 it
lends itself to the same design features with respect to the
antipodal compound. The concept of “latent symmetry” 27a,77
as it pertains to the preparation of (-)-pancratistatin has recently
been disclosed79 and requires only that the order of attachment
of the aryl moiety be regulated by employing either the
vinylaziridine (in the approach to the (+)-enantiomer) or the
vinyloxirane (in the approach to the (-)-enantiomer). These
and other concerns are currently being addressed in the context
of the next generation synthesis of this important alkaloid and
some of its congeners, as well as its unnatural derivatives, and
will be reported in due course.
(1R,4S,5S,6R)-3-Chloro-4,5-(isopropylidenedioxy)-7-(4′-meth-
ylphenylsulfonyl)-7-azabicyclo[4.1.0]hept-2-ene (15b). The com-
pound was obtained from 11b in 20.5% yield (from PhIdNTs)
according to method A (reaction time 18 h): Rf 0.43 (hexane/EtOAc
3:1); white solid; mp 202-203 °C (hexane/EtOAc); [R]25 -75.5° (c
D
1.54, CHCl3); IR (KBr) ν 3060, 2980, 2910, 1645, 1590, 1410 cm-1
;
1H NMR (270 MHz, CDCl3) δ 7.82 (dm, J ) 8.2 Hz, 2H), 7.37 (dm,
J ) 8.2 Hz, 2H), 6.09 (dd, J ) 4.9, 1.2 Hz, 1H), 4.65 (ddd, J ) 6.6,
1.8, 0.7 Hz, 1H), 4.30 (dd, J ) 6.6, 1.0 Hz, 1H), 3.44 (dd, J ) 6.5, 1.8
Hz, 1H), 3.34 (dt, J ) 0.6, 6.5 Hz, 1H), 2.46 (s, 3H), 1.41 (s, 3H),
1.38 (s, 3H); 13C NMR (68 MHz, CDCl3) δ 145.3 (C), 138.06 (C),
134.41 (C), 130.06 (2CH), 128.07 (2CH), 119.96 (CH), 111.72 (C),
73.04 (CH), 71.68 (CH), 37.17 (CH), 36.74 (CH), 27.51 (CH3), 26.07
(CH3), 21.74 (CH3); MS (CI+) m/z (relative intensity) 356 ((M + H)+,
3), 340 (6), 298 (27), 262 (23), 200 (36), 155 (100), 142 (36), 114
(60), 91 (43). Anal. Calcd for C16H18ClNO4: C, 54.00; H, 5.12; N,
3.94. Found: C, 53.92; H, 5.12; N, 3.86.
Method B (via Bromohydrin 12a,b). To (1S,2S)-3-chlorocyclo-
hexa-3,5-diene-1,2-diol (9b, 5.00 g, 34.11 mmol) in acetone (20 mL,
HPLC grade) were added 2,2-dimethoxypropane (30 mL) and p-
toluenesulfonic acid monohydrate (175 mg). After 20 min at room
temperature, TLC analysis indicated that no more diol 9b remained in
the reaction mixture. The reaction was quenched with saturated aqueous
NaHCO3 solution, and the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were dried with MgSO4, filtered, and
concentrated. The crude acetonide 11b was placed under high vacuum
for 15 min, and then 1,2-dimethoxyethane (140 mL) and distilled H2O
(35 mL) were added. This solution was cooled to -10 °C in an ice/
NaCl bath, and NBS (1.6 equiv based on 9b, 54.6 mmol, 9.72 g) was
added. The mixture was stirred at 0 °C for 10 h, at which point the
reaction appeared complete by TLC. To the solution was added brine
(100 mL), and the mixture was extracted with EtOAc. The EtOAc
extracts were combined and dried with MgSO4. Removal of volatiles
gave 4.20 g of crude product, which was dissolved in hot hexanes and
decanted to another flask. Upon cooling, a white precipitate formed
[this was an undesired diastereomeric bromohydrin (270 mg, 0.952
mmol, 2.8% yield from diol 9b) which was difficult to remove by
chromatography, Rf 0.30 (hexane/EtOAc 4:1)]. The solution was again
decanted, hexanes were removed to give an oily residue, and column
chromatogaphy was performed using acetone/CH2Cl2 (1:50) to give
the desired bromohydrin 12b (2.97 g, 10.5 mmol, 30.7% from diol
Experimental Section
All reactions were carried out in an argon atmosphere with standard
techniques for the exclusion of air and moisture. Glassware used for
moisture-sensitive reactions was flame-dried under vacuum. Tetrahy-
drofuran and diethyl ether were distilled from sodium benzophenone
ketyl. Dichloromethane, DMF, toluene, and TMEDA were distilled
from calcium hydride. Flash column chromatography was performed
on Merck silica gel (grade 60, 230-400 mesh). Elemental analyses
were performed by Atlantic Microlabs, Norcross, GA.
9b) as a clear oil: Rf 0.35 (hexane/EtOAc 4:1); mp 43-47 °C; [R]23
D
+ 17.2° (c 1.16, CHCl3); IR (neat) ν 3485, 3025, 3000, 2940, 1650
1
cm-1; H NMR (CDCl3) δ 6.10 (d, J ) 4.4 Hz, 1H), 4.61 (dm, J )
General Procedure for the Formation of Aziridines 15a,b.
Method A (via PhIdNTs). A mixture of 5 equiv of (1S,2S)-3-halo-
1,2-(isopropylidenedioxy)cyclohexa-3,5-diene (11a,b), 1 equiv of p-
(tosylimino)phenyliodinane (PhIdNTs), and 0.08 equiv of Cu(acac)2
in 10 mL mmol-1 of CH3CN was stirred at room temperature. After
consumption of PhIdNTs, the mixture was filtered through a pad of
silica gel and concentrated in vacuo. The crude product was recrystal-
lized from hexane/ethyl acetate.
2.27 Hz, 2H), 4.35 (dddm, J ) 9.1, 4.4, 4.2 Hz, 1H), 4.27 (m, 1H),
2.88 (d, J ) 9.1 Hz, 1H), 1.51 (s, 3H), 1.41 (s, 3H); 13C NMR (CDCl3)
δ 133.1 (C), 126.9 (CH), 112.2 (C), 78.1 (CH), 75.3 (CH), 70.2 (CH),
48.6 (CH), 27.9 (CH3), 26.4 (CH3); MS (CI, 70 eV) m/z (relative
intensity) 285 (MH+, 0.25), 283 (MH+, 0.4), 269 (40), 267 (38), 209
(65), 207 (50). Anal. Calcd for C9H12BrClO3: C, 38.12; H, 4.27.
Found: C, 38.00; H, 4.26.
The bromohydrin was treated with excess sodium azide in DMSO,
affording the azido alcohol 13b in 87% yield: [R]23 -110° (c 1.3,
(1R,4S,5S,6R)-3-Bromo-4,5-(isopropylidenedioxy)-7-(4′-meth-
ylphenylsulfonyl)-7-azabicyclo[4.1.0]hept-2-ene (15a). From 11a
(10.52 g, 45.5 mmol), 15a (1.97 g, 54% from PhIdNTs) was obtained
according to method A (reaction time 1 h): white solid; Rf 0.48 (hexane/
EtOAc 3:1); mp 206-207 °C (hexane/EtOAc); [R]25D -33.7° (c 1.05,
D
CHCl3); IR (neat) ν 3485, 3025, 3000, 2940, 2110, 1650, 1380, 1220,
1
1040 cm-1; H NMR (CDCl3) δ 5.80 (d, J ) 2.1 Hz, 1H), 4.58 (m,
2H), 4.28 (dt, J ) 8.7, 1.8 Hz, 1H), 3.82 (td, J ) 7.5, 2.1 Hz, 1H),
2.55 (d, J ) 7.5 Hz, 1H), 1.43 (s, 6H); 13C NMR (CDCl3) δ 134.2 (C),
124.0 (CH), 111.2 (C), 76.7 (CH), 76.5 (CH), 72.1 (CH), 61.0 (CH),
27.4 (CH3), 26.4 (CH3); MS (CI+) m/z (relative intensity) 246 (35,
MH+), 230 (40), 218 (100), 182 (90), 160 (50). Anal. Calcd for
C9H12ClN3O3: C, 44.00; H, 4.92; N, 17.10. Found: C, 40.08; H, 4.92;
N, 17.10.
1
CHCl3); IR (KBr) ν 3060, 2980, 2900, 1640, 1590 cm-1; H NMR
(270 MHz, CDCl3) δ 7.82 (dm, J ) 8.2 Hz, 2H), 7.37 (dm, J ) 8.2
Hz, 2H), 6.35 (dd, J ) 5.0, 1.2 Hz, 1H), 4.64 (ddd, J ) 6.5, 1.7, 0.6
Hz, 1H), 4.34 (dd, J ) 6.5, 1.2 Hz, 1H), 3.44 (dd, J ) 6.5, 1.7 Hz,
1H), 3.28 (dd, J ) 6.5, 5.0 Hz, 1H), 2.46 (s, 3H), 1.42 (s, 3H), 1.38 (s,
3H); 13C NMR (100.6 MHz, CDCl3) δ 145.1 (C), 134.1 (C), 129.92
(2CH), 129.89 (C), 127.9 (2CH), 123.9 (CH), 111.5 (C), 73.8 (CH),
71.4 (CH), 37.4 (CH), 36.4 (CH), 27.4 (CH3), 26.1 (CH3), 21.6 (CH3);
Analogous procedures provided, via the bromohydrin, bromoazido
alcohol 13a: [R]23D -93.7° (c 2.5, CHCl3); IR (CHCl3) ν 3420, 3025,
1
3000, 2940, 2110, 1650 cm-1; H NMR (CDCl3) δ 6.03 (d, J ) 2.1
Hz, 1H), 4.63 (dd, J ) 5.2, 2.1 Hz, 1H), 4.53 (dd, J ) 5.2, 2.5 Hz,
1H), 4.21 (dt, J ) 8.6, 2.0 Hz, 1H), 3.82 (td, J ) 8.7, 2.5 Hz, 1H),
2.60 (d, J ) 7.5 Hz, 1H), 1.44 (s, 3H), 1.43 (s, 3H); 13C NMR (CDCl3)
(78) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.; Price, J. D. J. Am.
Chem. Soc. 1990, 112, 9439.
(79) Hudlicky, T. Chem. ReV. 1996, 96, 3.

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10761
δ 128.0 (CH), 125.0 (C), 111.0 (C), 78.0 (CH), 76.6 (CH), 71.7 (CH),
61.5 (CH), 27.4 (CH3), 26.4 (CH3); MS (CI+) m/z (relative intensity)
292 (70, MH+), 290 (70, MH+), 249 (55), 247 (55), 191 (90), 189
(90); HRMS calcd for C9H12BrN3O3+H 290.0140, found 290.0141.
Azido alcohols 13 were converted to N-tosylaziridines 15 by a
mesylation, reduction/elimination, and tosylation sequence without
isolation of any further intermediates (30-40% yield).
1.5 Hz, 1H), 4.67 (br t, J ) 4.7 Hz, 1H), 4.52 (d, J ) 8.2 Hz, 1H),
4.14 (dd, J ) 9.0, 6.0 Hz, 1H), 3.65 (q, J ) 9.0 Hz, 1H), 3.24 (dq, J
) 8.6, 1.9 Hz, 1H), 2.38 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 142.4 (C), 140.1 (C), 138.6 (C), 134.6 (CH),
129.1 (2CH), 128.61 (2CH), 128.57 (2CH), 127.14 (CH), 126.96 (2CH),
124.2 (CH), 109.93 (C), 77.58 (CH), 72.16 (CH), 58.95 (CH), 47.70
(CH), 27.79 (CH3), 25.83 (CH3), 21.41 (CH3); MS (CI+) m/z (relative
intensity) 400 (MH+, 15), 370 (23), 342 (99), 312 (19), 171 (100);
HRMS calcd for C22H25NO4S+H 400.1582, found 400.1568. Anal.
Calcd for C22H25NO4S: C, 66.14; H, 6.31; N, 3.51. Found: C, 66.05;
H, 6.36; N, 3.49.
N,N-Dimethyl-4-[(tert-butyldimethylsilyl)oxy]-1,3-benzodioxole-
5-carboxamide (25b). tert-Butyldimethylsilyl chloride (1.73 g, 11.5
mmol) in CH2Cl2 (10 mL) was added to a solution of N,N-dimethyl-
4-hydroxy-1,3-benzodioxole-5-carboxamide (24b,24 2.0 g, 9.56 mmol)
and imidazole (2.0 g, 29 mmol) in CH2Cl2 (60 mL). The solution was
stirred for 12 h at room temperature, during which time a white solid
precipitated. The mixture was washed with brine, dried over MgSO4,
and concentrated. Chromatography on silica (hexane/EtOAc 1:1)
afforded 25b (2.95 g, 95%) as a semicrystalline solid: Rf 0.60 (hexane/
EtOAc 1:1); IR (KBr) ν 2920, 2870, 2840, 1610, 1460 cm-1; 1H NMR
(270 MHz, CDCl3) δ 6.75 (d, J ) 8.0 Hz, 1H), 6.50 (d, J ) 8.0 Hz,
1H), 5.92 (s, 2H), 3.03 (s, 3H), 2.87 (s, 3H), 0.94 (s, 9H), 0.16 (br s,
6H); 13C NMR (100 MHz, CDCl3) δ 168.9 (C), 149.3 (C), 137.0 (C),
135.5 (C), 124.9 (C), 121.4 (CH), 102.8 (CH), 101.0 (CH2), 38.2 (CH3),
34.9 (CH3), 25.4 (3CH3), 18.1 (C), -4.6 (2CH3); MS (CI+) m/z (relative
intensity) 423 ((M + H)+, 52), 308 (40), 279 (12), 266 (100); HRMS
calcd for C16H25NO4Si+H 324.1631, found 324.1623.
(1R,4R,5S,6R)-4,5-(Isopropylidenedioxy)-7-(4′-methylphenylsul-
fonyl)-7-azabicyclo[4.1.0]hept-2-ene (7). A mixture of 15a (10.1 g,
25.2 mmol), tributyltin hydride (11.6 g, 39.8 mmol), and AIBN (413
mg) in THF (200 mL) was stirred at reflux. After 2 h, the mixture
was washed with excess saturated KF aqueous solution, and the organic
layer was separated and dried over Na2SO4. Removal of solvent and
column chromatography (silica gel, hexane/EtOAc 3:1) afforded 7 (6.32
g, 78%): Rf 0.37 (hexane/EtOAc 3:1); white solid; mp 106-107 °C
(hexane/EtOAc); [R]25D -183° (c 2.3, CHCl3); IR (KBr) ν 3040, 2970,
1
1601 cm-1; H NMR (270 MHz, CDCl3) δ 7.82 (d, J ) 8.2 Hz, 2H),
7.35 (d, J ) 8.0 Hz, 2H), 5.95 (ddd, J ) 10.2, 4.4, 1.7 Hz, 1H), 5.76
(dd, J ) 10.2, 2.4 Hz, 1H), 4.54 (dd, J ) 6.7, 1.5 Hz, 1H), 4.39 (dt,
J ) 6.7, 1.0 Hz, 1H), 3.37 (dd, J ) 6.5, 1.8 Hz, 1H), 3.27 (dd, J )
6.5, 4.7 Hz, 1H), 2.46 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H); 13C NMR
(68 MHz, CDCl3) δ 144.8, 134.6, 132.4, 129.8 (2C), 127.9 (2C), 120.9,
110.7, 70.6, 69.3, 36.4, 35.5, 27.8, 26.1, 21.6; MS (CI+) m/z (relative
intensity) 322 ((M + H)+, 12), 292 (11), 264 (100), 236 (44), 155
(80); HRMS (CI+) calcd for C16H19NO4S+H 322.1113, found 322.1106.
Anal. Calcd for C16H19NO4S: C, 59.80; H, 5.96; N, 4.36. Found: C,
59.90; H, 5.99; N, 4.36.
(1R,4S,5R,6S)-N-[4-Methyl-5,6-(isopropylidenedioxy)cyclohex-2-
enyl]-(4′-methylphenyl)sulfonamide (21). To a suspension of CuCN
(67 mg, 0.75 mmol) in THF (15 mL) was added a solution of
methyllithium in hexanes (1.07 mL, 1.4 M, 1.50 mmol) slowly at -78
°C. After 5 min, the turbid suspension was allowed to warm to -30
°C, stirred for 10 min, and recooled to -78 °C. Compound 7 (200
mg, 0.62 mmol), dissolved in THF (5 mL), was added, precooled, by
canula, followed by BF3‚Et2O (116 mg, 0.82 mmol). The reaction is
was stirred for 2 h at -78 °C, after which TLC indicated no more
aziridine. The mixture was quenched with dilute aqueous ammonium
chloride containing ammonia (pH 9, 10 mL), warmed to room
temperature, and extracted with EtOAc (3 × 20 mL). Drying over
sodium sulfate, concentration in vacuo, and chromatography (hexane/
EtOAc 2:1, Rf 0.36) afforded 21 (78 mg, 0.23 mmol, 37%): white
crystalline solid; Rf 0.36 (hexane/EtOAc 2:1); mp 122-123 °C (hexane/
N,N-Diethyl-4-(ethoxymethoxy)-6-{(1R,4R,5S,6R)-4,5-(isopropyl-
idenedioxy)-6-[(4′-methylphenylsulfonyl)amino]-2-cyclohexen-1-yl}-
1,3-benzodioxole-5-carboxamide (27). s-BuLi in hexane (1.28 M, 10.2
mL) was added to a solution of TMEDA (2.0 mL, 13.25 mmol) in
THF (50 mL) at -78 °C. The yellow mixture was stirred for 15 min,
and then a solution of amide 25a (3.55 g, 12.0 mmol) in THF (15 mL)
was added, precooled, by cannula. The resulting deep red solution
was stirred at -78 °C for 1 h and transferred by cannula to a round-
bottom flask charged with CuCN (538 mg, 6.0 mmol). The tannish
solution was warmed to -20 °C, furnishing a dark purple solution,
which was recooled to -78 °C, and a solution of vinylaziridine 7 (774
mg, 2.4 mmol) in THF (10 mL) was added, followed by BF3‚Et2O
(0.74 mL, 6.0 mmol). The reaction mixture was then warmed slowly
to room temperature and saturated aqueous NH4Cl solution (10 mL,
containing NH4OH, pH 8) was added. The mixture was stirred at room
temperature for 30 min, the organic layer was separated, and the aqueous
layer was extracted with EtOAc (3 × 25 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with hexane/EtOAc (3:2)
(for one atropisomer), followed by hexane/EtOAc (2:3) (for the other
atropisomer), to give 724 mg (49%) of 27 as a glassy solid.
EtOAc); [R]25 +2.5° (c 1.3, CH3OH); IR (KBr) ν 3298, 1417, 1379
D
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.79 (d, J ) 8.4 Hz, 2H), 7.30
(d, J ) 8.5 Hz, 2H), 5.67 (dt, J ) 9.5, 2.8 Hz, 1H), 5.53 (dt, J ) 9.5,
2.8 Hz, 1H), 4.82 (d, J ) 5.7 Hz, 1H), 3.85 (t, J ) 6.9 Hz, 1H), 3.77
(dd, J ) 7.2, 5.8 Hz, 1H), 3.59 (m, 1H), 2.42 (s, 3H), 2.19 (m, 1H),
1.23 (s, 3H), 1.185 (d, J ) 7.3 Hz, 3H), 1.18 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 143.5 (C), 136.9 (C), 133.5 (CH), 129.5 (2CH), 128.0
(CH), 127.5 (2CH), 109.0 (C), 79.1 (CH), 78.2 (CH), 54.9 (CH), 34.7
(CH), 27.1 (CH3), 25.0 (CH3), 21.5 (CH3), 19.1 (CH3); MS (CI+) m/z
(relative intensity) 338 (4, MH+), 280 (23), 172 (32), 109 (100); HRMS
(FAB) calcd for C17H23NO4S+H 338.1426, found 338.1438. Anal.
Calcd for C17H23NO4S: C, 60.51; H, 6.87; N, 4.15. Found: C, 60.59;
H, 6.93; N, 4.08.
(1R,2R,5R,6S)-N-[5,6-(Isopropylidenedioxy)-2-phenylcyclohex-3-
enyl]-(4′-methylphenyl)sulfonamide (22). A suspension of dry CuCN
(161 mg, 1.80 mmol) in THF (20 mL) was treated with phenyllithium
solution (1.8 M, 2.0 mL) at -78 °C. The mixture was warmed to
-10 °C with stirring to dissolve CuCN, and after cooling to -78 °C,
a solution of 7 (182 mg, 0.57 mmol) in THF (2 mL) was added,
followed by BF3‚Et2O (0.22 mL). The mixture was stirred at -78 °C
for 3 h and then quenched with aqueous NH4Cl solution (5 mL,
containing ammonia, pH 8). After being stirred at room temperature
for 30 min, the mixture was extracted with EtOAc (3 × 15 mL), and
the combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The residue was chromatographed on silica gel, eluting with
10:1 CHCl3/acetone, to give 22 (159 mg, 70%): Rf 0.36 (hexanes/
1
R-Atropisomer: H NMR (270 MHz, CDCl3) δ 7.58 (d, J ) 6.2 Hz,
1H), 7.51 (d, J ) 8.1 Hz, 2H) 7.08 (d, J ) 8.1 Hz, 2H), 6.12 (s, 1H),
6.0 (m, 2H), 5.85 (d, J ) 1.3 Hz, 1H), 5.72 (d, J ) 9.8 Hz, 1H), 5.40
(d, J ) 6.1 Hz, 1H), 5.17 (d, J ) 6.1 Hz, 1H), 4.63 (m, 1H), 4.04 (dd,
J ) 9.4, 7.1 Hz, 1H), 3.7-3.9 (m, 3H), 2.95-3.35 (m, 5H), 2.36 (s,
3H), 1.60 (s, 3H), 1.38 (s, 3H), 1.28 (t, J ) 7.1 Hz, 3H), 1.24 (t, J )
7.1 Hz, 3H), 0.95 (t, J ) 7.1 Hz, 3H); 13C NMR (68 MHz, CDCl3) δ
168.2 (C), 149.8 (C), 141.1 (C), 139.5 (C), 135.9 (C), 135.1 (C), 134.1
(CH), 132.0 (C), 128.4 (2CH), 127.0 (2CH), 125.7 (CH), 123.7 (C),
109.6 (C), 102.5 (CH), 101.4 (CH2), 95.7 (CH2), 79.3 (CH), 72.5 (CH),
65.2 (CH2), 58.3 (CH), 42.9 (CH2), 42.7 (CH), 39.6 (CH2), 27.8 (CH3),
25.9 (CH3), 21.3 (CH3), 14.8 (CH3), 14.1 (CH3), 12.7 (CH3); MS (EI)
m/z (relative intensity) 617 (M+, 20), 601 (7), 570 (30), 559 (20), 513
(7), 363 (100), 249 (28); HRMS calcd for C31H41N2O9S 617.2533, found
617.2559.
N,N-Dimethyl-4-[(tert-butyldimethylsilyl)oxy]-6-{(1R,4R,5S,6R)-
4,5-(isopropylidenedioxy)-6-[(4′-methylphenylsulfonyl)amino]-2-cy-
clohexen-1-yl}-1,3-benzodioxole-5-carboxamide (28). s-BuLi in
hexane (1.28 M, 40 mL) was added to a solution of TMEDA (7.68
mL) in THF (160 mL) at -78 °C. The yellow mixture was stirred for
10 min before cooling to -90 °C, and then a solution of amide 25b
(14.71 g, 45.47 mmol) in THF (60 mL) was added, precooled, by
cannula. The resulting deep red solution was stirred at -90 °C for 1.5
EtOAc 2:1); white solid; mp 165-167 °C (CHCl3/acetone); [R]25
D
-17.8° (c 1.07, CHCl3); IR (KBr) ν 3300, 3030, 2890, 1590 cm-1; 1H
NMR (270 MHz, CDCl3) δ 7.42 (dm, J ) 8.3 Hz, 2H), 7.24 (m, 3H),
7.09 (m, 4H), 6.00 (ddd, J ) 9.9, 3.5, 2.7 Hz, 1H), 5.87 (dd, J ) 9.9,

10762 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
h, and then CuCN (2.08 g, 22.75 mmol) was added. The mixture was
warmed to -20 °C over 1 h, furnishing a dark purple solution, which
was recooled to -78 °C, and a solution of vinylaziridine 7 (4.81 g
14.96 mmol) in THF (40 mL) was added, followed by BF3‚Et2O (2.8
mL). The reaction mixture was then warmed slowly to room
temperature, and saturated aqueous NH4Cl solution (100 mL, containing
aqueous ammonia, pH 8) was added. The mixture was stirred at room
temperature for 30 min, the organic layer was separated, and the aqueous
layer was extracted with EtOAc (3 × 100 mL). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The residue
was chromatographed on silica gel, eluting with hexanes/EtOAc (3:2)
(for one atropisomer), followed by hexane/EtOAc (2:3) (for the other
atropisomer), to give 6.88 g (75%) of 28 as a glassy solid. R-Atrop-
isomer: Rf 0.21 (hexane/EtOAc 1:1); [R]26D ) +33.7° (c 2.0, CHCl3);
Compound 38: Rf 0.41 (EtOAc); [R]26 -17.1° (c 1.31, CHCl3);
D
mp 133 °C (EtOAc) dec; IR (KBr) ν 3270 (broad), 2970, 2930, 1710,
1
1630 cm-1; H NMR (270 MHz, CDCl3) δ 9.73 (br s, 1H), 6.39 (m,
2H), 5.98 (d, J ) 9.6 Hz, 1H), 5.82 (m, 2H), 4.59 (t, J ) 4.2 Hz, 1H),
3.60-4.40 (m, 3H), 2.98-3.40 (m, 7H), 1.53 (s, 3H), 1.38 (s, 3H),
1.20 (s, 9H); 13C NMR (68 MHz, CDCl3) δ 169.72 (C), 155.38 (C),
149.26 (C), 136.56 (C), 136.24 (CH), 134.94 (C), 133.37 (C), 122.87
(CH), 121.13 (C), 109.35 (C), 102.08 (CH), 101.27 (CH2), 78.94 (C),
77.49 (CH), 72.35 (CH), 55.86 (CH), 44.32 (CH), 35.55 (CH3), 35.35
(CH3), 28.03 (CH3), 27.91 (3CH3), 26.06 (CH3); MS (EI) m/z (relative
intensity) 476 (M+, 6), 376 (16), 318 (30), 277 (59), 256 (20); HRMS
(EI) calcd for C24H32N2O8 476.2158, found 476.2153.
Deprotection of 37. A solution of tetrabutylammonium fluoride in
THF (1 M, 9.8 mL) was added to a solution of 37 (2.81 g, 4.76 mmol)
in THF (35 mL) at 0 °C. The resulting brown solution was stirred at
0 °C for 1.5 h, the solvent was removed in vacuo, and the residue was
chromatographed (silica gel, EtOAc) to furnish 38 (2.11 g, 93%).
6-{(1R,4R,5S,6R)-6-[(tert-Butyloxycarbonyl)amino]-4,5-(isopro-
pylidenedioxy)-2-cyclohexen-1-yl}-4-hydroxy-1,3-benzodioxole-5-
carbaldehyde (39). Sodium bis(2-methoxyethoxy)aluminum hydride
(SMEAH) in toluene (1.02 M) was modified with morpholine (1.0
equiv) at room temperature (30 min). Modified SMEAH solution (20
mL, 20 mmol) was added to a stirred solution of 38 (2.82 g, 5.9 mmol)
in THF (80 mL) at -45 °C. After 9 h, additional SMEAH solution (9
mL) was added, and the mixture was stirred for another 22 h. The
reaction was then quenched with saturated NH4Cl solution (10 mL)
and brine (10 mL). The organic phase was separated, and the aqueous
layer was extracted with EtOAc (3 × 50 mL). Drying of the combined
organic layers, concentration, and chromatography (silica gel, EtOAc)
of the residue gave aldehyde 39 as a white solid (853 mg, 72% based
on recovered 38) and recovered starting material (1.52 g): Rf 0.36
(hexane/EtOAc 3:2); mp 168 °C (hexane/EtOAc) dec; [R]25D +5.9° (c
1
IR (KBr) ν 3422, 3120, 2930, 2859, 1622, 1479 cm-1; H NMR (270
MHz, CDCl3) δ 7.62 (m, 3H), 7.09 (d, J ) 8.1 Hz, 2H), 6.26 (s, 1H),
5.9-6.05 (m, 3H), 5.79 (d, J ) 9.8 Hz, 1H), 4.58 (m, 1H), 3.99 (dd,
J ) 9.5, 6.2 Hz, 1H), 3.34 (td, J ) 10.1, 6.4 Hz, 1H), 3.10 (d, J )
10.1 Hz, 1H), 3.08 (s, 3H), 2.87 (s, 3H), 2.36 (s, 3H), 1.45 (s, 3H),
1.29 (s, 3H), 0.97 (s, 9H), 0.27 (s, 3H), 0.23 (s, 3H); 13C NMR (68
MHz, CDCl3) δ 169.08 (C), 149.68 (C), 141.14 (C), 139.89 (C), 135.93
(C), 134.71 (C), 134.58 (CH), 132.21 (C), 128.25 (2CH), 127.00 (2CH),
125.16 (CH), 123.66 (C), 109.28 (C), 101.66 (CH), 101.11 (C), 79.11
(CH), 72.53 (CH), 58.59 (CH), 42.91 (CH), 37.77 (CH), 34.90 (CH),
27.68 (CH3), 25.80 (CH3), 25.44 (3CH3), 21.94 (CH3), 17.94 (C), -4.57
(2CH3); MS (EI) m/z (relative intensity) 644 (M+, 17), 629 (27), 587
(58), 391 (100), 334 (31) 261 (28); HRMS (EI) calcd for C32H44N2O8-
SSi 644.2588, found 644.2591. Anal. Calcd for C32H44N2O8SSi: C,
59.60; H, 6.88. Found: C, 59.95; H, 6.87.
N,N-Dimethyl-4-[(tert-butyldimethylsilyl)oxy]-6-{(1R,4R,5S,6R)-
6-[N-(tert-butyloxycarbonyl)-N-[(4′-methylphenylsulfonyl)amino]]-
4,5-(isopropylidenedioxy)-2-cyclohexen-1-yl}-1,3-benzodioxole-5-
carboxamide (36). s-BuLi in hexane (1.28 M, 7.02 mL) was added
to a solution of tosylamide 28 (5.04 g, 8.17 mmol) in THF (25 mL) at
0 °C. The mixture was stirred at 0 °C for 15 min, and di-tert-butyl
dicarbonate (7.13 g, 32.67 mmol) was added. After refluxing for 4
days, the reaction mixture was quenched with brine (10 mL), the organic
layer was separated, and the aqueous phase was extracted with EtOAc
(3 × 20 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. Chromatography of the residue (silica gel,
hexane/EtOAc 3:2) afforded 4.14 g (68%) of a mixture of atropisomers
36. A pure sample for analysis could not be obtained due to the
presence of several atropisomers. The mixture was used in the next
reaction without further separation.
1.04, CHCl3); IR (KBr) ν 3360, 1650 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 10.18 (s, 1H), 6.45 (s, 1H), 6.07 (br s, 3H), 5.93 (d, J )
10.0 Hz, 1H), 4.68 (m, 2H), 4.50 (br s, 1H), 4.36 (br s, 1H), 3.31 (br
s, 1H), 1.51 (s, 3H), 1.41 (s, 3H), 1.32 (s, 9H); 13C NMR δ 193.45
(CH), 155.20 (C), 154.83 (C), 147.20 (C), 143.01 (C), 134.64 (CH),
133.02 (C), 124.62 (CH), 116.16 (C), 109.78 (C), 102.66 (CH2), 102.15
(CH), 79.85 (C), 75.85 (CH), 75.51 (CH), 72.23 (CH), 57.84 (CH),
28.22 (CH3), 28.10 (CH3), 25.81 (3CH3); MS (FAB) m/z (relative
intensity) 434 ((M + H)+, 46), 378 (16), 320 (50), 258 (46), 240 (100).
Anal. Calcd for C22H27NO8: C, 60.96; H, 6.28. Found: C, 60.91; H,
6.27.
6-[(1R,4R,5S,6R)-6-{(tert-Butyloxycarbonyl)amino]-4,5-(isopro-
pylidenedioxy)-2-cyclohexen-1-yl}-4-(phenylmethoxy)-1,3-benzo-
dioxole-5-carbaldehyde (40). Benzyl bromide (0.351 mL) was added
to a suspension of phenol 39 (853 mg, 1.97 mmol) and K2CO3 (544
mg, 3.94 mmol) in DMF (8 mL). The reaction mixture was stirred at
room temperature for 4 h and then quenched with saturated aqueous
CuSO4 solution (5 mL) and brine (5 mL). The aqueous layer was
extracted with EtOAc (3 × 15 mL), and the combined organic layers
were dried over Na2SO4. Removal of the solvent and chromatography
(silica gel, hexane/EtOAc 3:1) of the residue afforded 40 (869 mg,
83%) as a glassy solid: Rf 0.48 (hexane/EtOAc 3:2); [R]25D -86.4° (c
N,N-Dimethyl-6-{(1R,4R,5S,6R)-4-(tert-butyldimethylsilyl)-6-[(tert-
butyloxycarbonyl)amino]-4,5-(isopropylidenedioxy)-2-cyclohexen-
1-yl}-1,3-benzodioxole-5-carboxamide (37) and N,N-Dimethyl-6-
{(1R,4R,5S,6R)-6-[(tert-butyloxycarbonyl)amino]-4,5-
(isopropylidenedioxy)-2-cyclohexen-1-yl}-4-hydroxy-1,3-benzodioxole-
5-carboxamide (38). A solution of sodium anthracenide (ca. 0.6 N)
was added dropwise under Ar at -78 °C to a stirred solution of 36
(5.68 g, 7.62 mmol) in DME (30 mL) until a blue color persisted for
15 min. The reaction mixture was quenched with saturated NH4Cl
solution (5 mL), and the solvent was removed in vacuo. The residue
was taken up in EtOAc and filtered. Concentration and chromatography
of the residue (silica gel, hexane/EtOAc 2:3) gave 37 (2.81 g, 62%)
and 38 (0.75, 20%) as glassy solids.
Compound 37: Rf 0.43 (hexanes/EtOAc 1:1); [R]26D +46.2° (c 1.27,
CHCl3); IR (KBr) ν 3280, 1710, 1620, 1475 cm-1; 1H NMR (270 MHz,
CDCl3) δ 6.48 (s, 1H), 6.13 (br d, J ) 9.0 Hz, 1H), 5.98 (dt, J ) 9.7,
3.2 Hz, 1H), 5.93 (m, 2H), 5.84 (m, 2H), 4.62 (m, 1H), 3.95 (dd, J )
10.1, 5.9 Hz, 1H), 3.73 (q, J ) 10.0 Hz, 1H), 3.07 (br s, 4H), 2.85 (s,
3H), 1.61 (s, 3H), 1.39 (s, 3H), 1.24 (s, 9H), 0.96 (s, 9H), 0.23 (s, 3H),
0.15 (s, 3H); 13C NMR (68 MHz, CDCl3) δ 168.61 (C), 156.31 (C),
149.50 (C), 135.74 (C), 135.24 (CH), 134.44 (C), 132.78 (C), 125.03
(CH), 124.28 (C), 109.46 (C), 101.91 (CH), 101.04 (CH2), 78.68 (CH),
77.80 (C), 72.89 (CH), 55.34 (CH), 43.41 (CH), 37.77 (CH3), 34.81
(CH3), 28.16 (3CH3), 28.05 (CH3), 26.19 (CH3), 25.50 (3CH3), 18.07
(C), -4.30 (CH3), -4.55 (CH3); MS (CI+) m/z (relative intensity) 591
(MH+); HRMS (CI+) calcd for C30H46N2O8Si+H 591.3102, found
591.3143.
1.14, CHCl3); IR (KBr) ν 3370 (broad), 1710, 1670, 1605, 1475 cm-1
;
1H NMR (270 MHz, CDCl3) δ 10.38 (s, 1H), 7.37 (m, 5H), 6.63 (s,
1H), 6.02 (d, J ) 12.6 Hz, 2H), 6.00 (m, 1H), 5.82 (d, J ) 9.9 Hz,
1H), 5.34 (s, 2H), 4.83 (d, J ) 10.8 Hz, 1H), 4.65 (m, 2H), 4.06 (dd,
J ) 10.3, 5.1 Hz, 1H), 3.71 (q, J ) 10.4 Hz, 1H), 1.54 (s, 3H), 1.40
(s, 3H), 1.23 (s, 9H); 13C NMR (68 MHz, CDCl3) δ 192.83 (CHO),
155.54 (C), 153.82 (C), 145.59 (C), 140.88 (C), 136.30 (C), 135.69
(CH), 135.13 (C), 128.62 (2CH), 128.50 (2CH), 127.94 (CH), 124.10
(CH), 121.52 (C), 109.60 (C), 104.52 (CH), 101.85 (CH2), 78.57 (C),
77.87 (CH), 74.58 (CH2), 72.80 (CH), 56.48 (CH), 40.87 (CH), 28.15
(4CH3), 26.19 (CH3); MS (CI+) m/z (relative intensity) 524 (MH+,
76), 506 (82), 466 (61), 406 (100), 348 (25), 330 (34); HRMS (CI+)
calcd for C29H34NO8+H 524.2284, found 524.2263. Anal. Calcd for
C29H33NO8: C, 66.53; H, 6.35; N, 2.67. Found: C, 66.57; H, 6.51; N,
2.54.
Methyl 6-{(1R,4R,5S,6R)-6-[(tert-Butyloxycarbonyl)amino]-4,5-
(isopropylidenedioxy)-2-cyclohexen-1-yl}-4-(phenylmethoxy)-1,3-
benzodioxole-5-carboxylate (43). Aldehyde 40 (507 mg, 0.97 mmol)

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10763
was dissolved in t-BuOH (24 mL) and 2-methyl-2-butene (6.6 mL,
85% purity). A solution of sodium chlorite (1.18 g, 10.43 mmol) and
potassium dihydrogen phosphate (1.07 g, 7.86 mmol) in H2O (10 mL)
was added dropwise over a 10 min period. The yellow solution was
stirred overnight at room temperature. Volatiles were removed under
high vacuum, brine (3 mL) was added to the residue, and the aqueous
layer was extracted with EtOAc (4 × 20 mL). The organic extract
was dried over Na2SO4, and the crude acid 42 was treated with excess
diazomethane. Removal of the solvent and chromatography (silica gel,
hexane/EtOAc 3:2) gave the methyl ester 43 (526 mg, 98%) as a glassy
solid: Rf 0.40 (hexane/EtOAc 3:2); [R]25D +17.1° (c 1.07, CHCl3); IR
(KBr) ν 3370, 1705, 1620; 1H NMR (270 MHz, CDCl3) δ 7.26-7.39
(m, 5H), 6.54 (s, 1H), 5.84-5.99 (m, 4H), 5.21 (s, 2H), 4.94 (br s,
1H), 4.63 (t, J ) 4.4 Hz, 1H), 4.01 (br s, 1H), 3.79 (s, 3H), 3.73 (q, J
) 10.1 Hz, 1H), 3.36 (br s, 1H), 1.61 (s, 3H), 1.40 (s, 3H), 1.27 (s,
9H); 13C NMR (68 MHz, CDCl3) δ 168.14 (C), 155.51 (C), 150.56
(C), 139.46 (C), 136.99 (C), 135.80 (C), 135.19 (CH), 134.01 (C),
128.29 (CH), 127.94 (2CH), 127.63 (2CH), 124.22 (CH), 121.42 (C),
109.56 (C), 103.29 (CH), 101.48 (CH2), 78.67 (C), 77.37 (CH), 74.27
(CH2), 72.54 (CH), 55.52 (CH), 52.09 (CH3), 43.84 (CH), 29.58 (4CH3),
26.06 (CH3); MS (FAB) m/z (relative intensity) 554 (MH+, 8), 440
(19), 346 (13). Anal. Calcd for C30H35NO9: C, 65.09; H, 6.37; N,
2.53. Found: C, 65.29; H, 6.61; N, 2.34.
methanol) dec; [R]26 +40.9° (c 1.0, DMSO), lit.6c [R]34 + 48° (c
D
D
1.0, DMSO); 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.51 (s,
1H), 6.48 (s, 1H), 6.05 (d, J ) 1.0 Hz, 1H), 6.02 (d, J ) 1.0 Hz, 1H),
5.35 (d, J ) 4 Hz, 1H), 5.09 (d, J ) 6 Hz, 1H), 5.03 (d, J ) 6 Hz,
1H), 4.84 (d, J ) 7.5 Hz, 1H), 4.27 (m, 1H), 3.95 (q, J ) 3.6 Hz, 1H),
3.84 (m, 1H), 3.74 (m, 2H), 2.96 (d, J ) 11.5 Hz, 1H).
N-[(1R,2R,5R,6S)-2-(1,3-Benzodioxol-5-yl)-5,6-(isopropylidene-
dioxy)cyclohex-3-en-1-yl]-4-methylbenzenesulfonamide (60). n-BuLi
(1.9 M in hexane, 10 mL) was added to a solution of 5-bromo-1,3-
benzodioxole (16.6 mmol) in THF (65 mL) at -78 °C. The reaction
mixture was stirred for 40 min at -78 °C, and CuCN (744 mg, 8.3
mmol) was added. After the mixture was stirred at -78 °C for 1 h, a
solution of aziridine 7 (1.27 g, 3.95 mmol) in THF (10 mL) was added,
followed by BF3‚Et2O (0.4 mL). The reaction mixture was allowed to
warm slowly to room temperature with stirring, and saturated aqueous
NH4Cl solution (10 mL) was added. The organic layer was separated,
and the aqueous phase was extracted with EtOAc (4 × 10 mL). The
combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was chromatographed (silica gel,
CH2Cl2/acetone 12:1) to give tosylamide 60 (552 mg, 32%) as a white
solid: mp 75-76 °C (CH2Cl2/acetone); [R]22D +44.6° (c 1.16, CHCl3);
1
IR (KBr) ν 3260, 1480 cm-1; H NMR (200 MHz, CHCl3) δ 7.43 (d,
J ) 8.2 Hz, 2H), 7.09 (d, J ) 8.2 Hz, 2H), 6.49 (m, 3H), 5.95 (m,
3H), 5.76 (dd, J ) 9.9, 1.6 Hz, 1H), 5.34 (d, J ) 8.5 Hz, 1H), 4.61 (t,
J ) 4.5 Hz, 1H), 4.13 (dd, J ) 9.1, 6.0 Hz, 1H), 3.51 (q, J ) 9.2 Hz,
1H), 3.13 (br d, J ) 9.8 Hz, 1H), 2.38 (s, 3H), 1.50 (s, 3H), 1.35 (s,
3H); 13C NMR (50 MHz, C6D6) δ 147.87 (C), 146.86 (C), 141.57 (C),
140.58 (C), 135.10 (CH), 135.02 (C), 129.02 (2CH), 126.93 (2CH),
124.30 (CH), 122.28 (CH), 109.88 (C), 109.20 (CH), 108.38 (CH),
100.74 (CH2), 78.18 (CH), 72.72 (CH), 59.62 (CH), 47.51 (CH), 28.31
(CH3), 26.28 (CH3), 21.11 (CH3); HRMS (EI) calcd for C23H25NO6S
443.1403, found 443.1416. Anal. Calcd for C23H25NO6S: C, 62.28;
H, 5.68; N, 3.18. Found: C, 62.11; H, 5.91; N, 3.05.
Methyl 6-{(1R,4R,5S,6R)-6-[(tert-Butyloxycarbonyl)amino]-4,5-
dihydroxy-2-cyclohexen-1-yl}-4-(phenylmethoxy)-1,3-benzodioxole-
5-carboxylate (49). Methyl ester 43 (488 mg, 0.88 mmol) was
dissolved in a mixture of acetic acid, THF, and H2O (2:1:1, 8 mL),
and the solution was heated at 60 °C for 3 h. The solvent was removed
in vacuo, and the residue was subjected to chromatography (hexane/
EtOAc 1:4) to afford the 4,5-diol 49 (324 mg, 73%) as a white solid:
Rf 0.19 (hexane/EtOAc 2:3); mp 129-131 °C (hexane/EtOAc); [R]25
D
+73.7° (c 0.91, CHCl3); IR (KBr) ν 3270, 3360, 3290, 1715, 1695,
1
1620 cm-1; H NMR (270 MHz, CDCl3) δ 7.27-7.40 (m, 5H), 6.61
(s, 1H), 6.15 (br s, 1H), 5.97 (m, 3H), 5.59 (d, J ) 9.1 Hz, 1H), 5.29
(d, J ) 11.3 Hz, 1H), 5.18 (d, J ) 11.3 Hz, 1H), 4.83 (br s, 1H), 4.23
(t, J ) 3.3 Hz, 1H), 3.87 (m, 1H), 3.73 (s, 3H), 3.61 (m, 1H), 3.31 (br
s, 1H), 3.29 (d, J ) 10.2 Hz, 1H), 1.38 (s, 9H); 13C NMR (68 MHz,
CDCl3) δ 168.83 (C), 158.68 (C), 151.08 (C), 139.38 (C), 136.92 (C),
136.10 (C), 134.91 (C), 132.75 (CH), 128.40 (2CH), 128.13 (CH),
127.80 (2CH), 126.98 (CH), 120.88 (C), 103.60 (CH), 101.72 (CH2),
80.03 (C), 74.86 (CH), 74.39 (CH2), 66.68 (CH), 54.66 (CH), 52.50
(CH3), 45.02 (CH), 28.29 (3CH3); MS (FAB) m/z (relative intensity)
514 (MH+, 6), 414 (40), 382 (6), 256 (7); HRMS calcd for C27H31-
NO9+H 514.2077, found 514.2165. Anal. Calcd for C27H31NO9: C,
63.15; H, 6.08; N, 2.73. Found: C, 62.48; H, 6.19; N, 2.57.
N-[(1R,2R,5R,6S)-2-(1,3-Benzodioxol-5-yl)-5,6-(isopropylidene-
dioxy)cyclohex-3-en-1-yl]-N-(methoxycarbonyl)-4-methylbenzene-
sulfonamide (61). s-BuLi (1.68 mL, 1.85 mmol) was added to a
solution of tosylamide 60 (745 mg, 1.68 mmol) in THF (5 mL) at 0
°C. The reaction mixture was stirred for 5 min, and then dimethyl
pyrocarbonate (0.8 mL, 7.5 mmol) was added. After being stirred at
room temperature for 10 h, the reaction was quenched with aqueous
NH4Cl (10 mL), and the mixture was extracted with EtOAc (3 × 20
mL). The organic layers were combined and washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The residue
was chromatographed (silica gel, hexane/EtOAc 2:1) to give urethane
61 (642 mg, 76%): white solid; Rf 0.32 (hexane/EtOAc); mp 98-99
°C (hexane/EtOAc); [R]24D +59.7° (c 1.24, CHCl3); IR (KBr) ν 2990,
1725, 1480 cm-1; 1H NMR (200 MHz, CHCl3) δ 7.26 (d, J ) 8.2 Hz,
2H), 7.09 (d, J ) 8.2 Hz, 2H), 6.77 (d J ) 7.7 Hz, 1H), 6.63 (m, 2H),
5.96 (m, 4H), 4.83 (m, 2H), 4.62 (t, J ) 10.2 Hz, 1H), 4.14 (d, J )
Methyl 6-{(1R,2R,3S,4S,5S,6R)-6-[(tert-Butyloxycarbonyl)amino]-
5,6-epoxy-3,4-dihydroxycyclohex-1-yl}-4-(phenylmethoxy)-1,3-ben-
zodioxole-5-carboxylate (50). tert-Butyl hydroperoxide in decane (5
M, 0.45 mL) was added to a solution of 49 (280 mg, 0.55 mmol) and
vanadyl acetylacetonate (7 mg, 0.026 mmol) in benzene (10 mL). After
being stirred for 2 h at 60 °C, the reaction mixture was concentrated
under reduced pressure and subjected to chromatography (hexane/
EtOAc 1:5) to afford epoxide 50 (129 mg, 53% yield based on
recovered starting material) as a glassy solid and recovered starting
material (42 mg): Rf 0.18 (hexane/EtOAc 1:4); [R]25D +28.6° (c 1.48,
10.9 Hz, 1H), 3.62 (s, 3H), 2.36 (s, 3H), 1.69 (s, 3H), 1.46 (s, 3H); 13
C
NMR (50 MHz, CDCl3) δ 152.38 (C), 148.01 (C), 147.00 (C), 143.61
(C), 137.20 (C), 136.69 (CH), 134.49 (C), 128.63 (2CH), 128.54 (2CH),
123.11 (CH), 121.87 (CH), 110.39 (C), 109.04 (CH), 108.56 (CH),
100.98 (CH2), 73.24 (CH), 73.12 (CH), 63.32 (CH), 53.23 (CH), 43.47
(CH3), 27.64 (CH3), 25.89 (CH3), 21.51 (CH3); HRMS (EI) calcd for
C25H27NO8S 501.1457, found 501.1459.
CHCl3); IR (KBr) ν 3380, 1705, 1615 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 7.27-7.40 (m, 5H), 7.04 (s, 1H), 5.99 (d, J ) 2.3 Hz, 2H),
5.68 (br d, J ) 7.3 Hz, 1H), 5.24 (AB, J ) 11.3 Hz, ∆δ ) 0.07 ppm,
2H), 4.28 (t, J ) 5.0 Hz, 1H), 3.83 (m, 4H), 3.35-3.46 (m, 3H), 3.07
(d, J ) 10.9 Hz, 1H), 1.33 (s, 9H); 13C NMR (68 MHz, CDCl3) δ
168.72 (C), 158.06 (C), 151.18 (C), 139.47 (C), 136.86 (C), 136.42
(C), 132.46 (C), 128.37 (2CH), 128.12 (CH), 127.82 (2CH), 121.31
(C), 103.52 (CH), 101.73 (CH2), 79.85 (C), 74.46 (CH), 74.39 (CH2),
66.28 (CH), 58.09 (CH), 52.70 (CH), 52.46 (CH3), 50.49 (CH), 43.29
(CH), 29.23 (3CH3); MS (FAB) m/z (relative intensity) 530 ((M +
H)+, 17), 474 (6), 430 (53); HRMS calcd for C27H31NO10+H 530.2026,
found 530.2050.
Pancratistatin (4). A suspension of epoxide 50 (109 mg, 0.21
mmol) and sodium benzoate (1 mg) in water (8 mL) was stirred at 100
°C for 6 days. The mixture was then concentrated and subjected to
chromatography (chloroform/methanol 4:1) to afford pancratistatin (35
mg, 51%): Rf 0.40 (chloroform/methanol 4:1); mp 260 °C (chloroform/
Methyl N-[(1R,2R,5R,6S)-2-(1,3-Benzodioxol-5-yl)-5,6-(isopropyl-
idenedioxy)cyclohex-3-en-1-yl]carbamate (62). Method A. Na/
anthracene was added to a stirred solution of tosylamide 61 (554 mg,
1.08 mmol) in DME (11 mL) at -78 °C until a blue color persisted.
The reaction was quenched with brine (5 mL), and the reaction mixture
was extracted with EtOAc (4 × 15 mL). The combined organic layers
were dried over MgSO4 and concentrated, and the residue was
chromatographed (silica gel, hexane/EtOAc 3:2) to give 62 (261 mg,
69%): white solid; Rf 0.30 (hexane/EtOAc 3:2); mp 190-191 °C
(hexane/EtOAc); [R]25D +83.8° (c 1.23, CHCl3); IR (KBr) ν 3321, 1725,
1536, 1480; 1H NMR (400 MHz, CDCl3) δ 6.73 (d, J ) 7.9 Hz, 1H),
6.66 (d, J ) 1.7 Hz, 1H), 6.62 (dd, J ) 7.8, 1.7 Hz, 1H), 5.98 (m, 1H),
5.93 (m, 2H), 5.90 (m, 1H), 4.67 (t, J ) 4.9 Hz, 1H), 4.59 (br s, 1H),
4.39 (br s, 1H), 3.54 (s, 3H), 3.40 (m, 1H), 1.53 (s, 3H), 1.40 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 156.46 (C), 147.68 (C), 146.45 (C),
136.00 (CH), 134.73 (C), 123.46 (CH), 121.40 (CH), 109.56 (C), 108.35

10764 J. Am. Chem. Soc., Vol. 118, No. 44, 1996
Hudlicky et al.
(CH), 108.08 (CH), 100.86 (CH2), 76.18 (CH), 72.33 (CH), 57.08 (CH),
51.80 (CH), 45.81 (CH3), 28.13 (CH3), 25.87 (CH3); HRMS (CI) calcd
for C18H21NO6+H+ 348.1447, found 348.1508. Anal. Calcd for
C18H21NO6: C, 62.24; H 6.09; N, 4.03. Found: C, 62.01; H, 6.01; N,
3.91.
134.90 (CH), 127.89 (CH), 122.80 (CH), 109.64 (CH), 108.85 (CH),
102.18 (CH2), 73.63 (CH), 67.98 (CH), 56.11 (CH), 52.34 (CH), 50.26
(CH3); HRMS (FAB) calcd for C15H17NO6+H+ 308.1134, found
308.1188. Anal. Calcd for C15H17NO6: C, 58.62; H, 5.58; N, 4.56.
Found: C, 58.93; H, 5.59; N, 4.50.
Method B: from Aziridine 64. n-BuLi (2.5 M in hexane, 0.425
mL) was added to a solution of 5-bromo-1,3-benzodioxole (213 mg,
1.06 mmol) in THF (10 mL at -78 °C. The reaction mixture was
stirred for 50 min at -78 °C, and CuCN (48 mg, 0.53 mmol) was
added. After the mixture was stirred at -78 °C for 90 min, a solution
of aziridine 64 (50 mg, 0.22 mmol) in THF (10 mL) was added,
precooled by a cannula, followed by BF3‚Et2O (0.067 mL, 0.53 mmol).
The reaction mixture was allowed to warm up to -60 °C over 2 h, or
until TLC analysis indicated complete consumption of aziridine 64.
Saturated NH4Cl solution (10 mL) was added, the mixture warmed up
to room temperature, the organic layer separated, and the aqueous phase
extracted with EtOAc (4 × 10 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The
residue was chromatographed (silica gel, CH2Cl2/acetone 12:1) to give
carbamate 62 (23 mg, 30%) as a white solid.
Methyl N-[(1R,2R,3R,4R,5S,6S)-2-(1,3-Benzodioxol-5-yl)-5,6-di-
hydroxy-3,4-epoxycyclohex-1-yl]carbamate (66). VO(acac)2 (25 mg,
0.07 mmol) was added to a solution of olefin 65 (351 mg, 1.14 mmol)
and t-BuOOH (5 M, 1.14 mL) in benzene (20 mL), and the mixture
was heated at 70 °C for 3 h. The solvent was evaporated, and the
residue was chromatographed (silica gel, CHCl3/MeOH 8:1) to give
epoxide 66 (315 mg, 85%): white solid; Rf 0.26 (CHCl3/CH3OH 8:1);
mp 194-195 °C (CHCl3/MeOH); [R]25 +68.0° (c 0.9, MeOH); IR
D
(KBr) ν 3305, 2980, 2880, 1680, 1535, 1480 cm-1; 1H NMR (200 MHz,
CD3OD) δ 6.96 (d, J ) 1.5 Hz, 1H), 6.84 (dd, J ) 7.9, 1.5 Hz, 1H),
6.72 (d, J ) 7.9 Hz, 1H), 5.90 (s, 2H), 4.25 (t, J ) 5.1 Hz, 1H), 3.78
(t, J ) 10.7 Hz, 1H), 3.46 (s, 3H), 3.38 (m, 3H), 3.08 (d, J ) 10.9 Hz,
1H); 13C NMR (50 MHz, CD3OD) δ 159.71 (C), 149.09 (C), 148.19
(C), 135.16 (C), 123.32 (CH), 109.99 (CH), 108.86 (CH), 102.22 (CH2),
73.17 (CH), 67.68 (CH), 59.36 (CH), 54.29 (CH), 52.33 (CH), 51.93
(CH3), 48.39 (CH); HRMS (FAB) calcd for C15H17NO7+H+ 324.1083,
found 324.1044. Anal. Calcd for C15H17NO7: C, 55.73; H 5.30; N,
4.33. Found: C, 55.76; H, 5.49; N, 4.18.
Methyl N-[(1R,2R,3R,4S,5S,6S)-2-(1,3-Benzodioxol-5-yl)-3,4,5,6-
tetrahydroxycyclohexyl]carbamate (67). Sodium benzoate (6 mg)
was added to epoxide 66 (214 mg, 0.62 mmol) and water (5 mL), and
the mixture was heated at 100 °C under argon for 7 days. Water was
removed in vacuo, and the residue was chromatographed (silica gel,
CHCl3/MeOH 6:1) to give aryl aminocyclitol 67 (173 mg, 82%): white
solid; Rf 0.22 (CHCl3/CH3OH 6:1); mp 86 °C (CHCl3/CH3OH) dec;
[R]24D -1.73° (c 1.21, MeOH); IR (KBr) ν 3400, 2900, 1695; 1H NMR
(200 MHz, CD3OD) δ 6.87 (d, J ) 1.6 Hz, 1H), 6.77 (dd, J ) 8.0, 1.6
Hz, 1H), 6.70 (d, J ) 8.0 Hz, 1H), 5.87 (m, 2H), 4.32 (m, 1H), 4.03
(m, 2H), 3.74 (m, 2H), 3.49 (s, 3H), 3.30 (s, 1H), 3.14 (dd, J ) 12.2,
2.0 Hz, 1H); 13C NMR (50 MHz, CD3OD) δ 159.91 (C), 148.61 (C),
147.53 (C), 134.93 (C), 123.69 (CH), 110.86 (CH), 108.56 (CH), 101.96
(CH2), 76.02 (CH), 73.47 (CH), 73.35 (CH), 71.84 (CH), 52.29 (CH),
51.30 (CH3), 48.3 (CH); HRMS (CI) calcd for C15H20NO8+H 342.1188,
found 342.1144.
Methyl (1R,4S,5S,6R)-3-Bromo-4,5-(isopropylidenedioxy)-7-
azabicyclo[4.1.0]hept-2-ene-7-carboxylate (63). To (1S,2S)-3-bro-
mocyclohexa-3,5-diene-1,2-diol (9a, 1.15 g, 6.02 mmol) in dichlo-
romethane (40 mL) were added 2,2-dimethoxypropane (1.15 g, 11.0
mmol) and p-TsOH (25 mg). After being stirred for 60 min at room
temperature, the turbid solution was washed with 1 N NaOH (2 × 25
mL) and brine (25 mL). The solution was dried over Na2SO4 and
concentrated in vacuo to afford the pure acetonide 11a (1.30 g). A
solution of NaHCO3 (1.28 g, 15.2 mmol) in water (17 mL) was added
to a solution of acetonide 11a (1.30 g), methyl (p-nitrophenylsulfonyl)-
oxycarbamate (3.09 g, 11.2 mmol), and benzyltriethylammonium
chloride (0.28 g, 1.22 mmol) in dichloromethane (25 mL) and stirred
vigorously for 16 h at room temperature. After phase separation, the
aqueous phase was extracted twice with dichloromethane, and the
combined organic phases were washed with water, dried over MgSO4
and concentrated in vacuo. The residue was chromatographed (silica
gel, hexane/EtOAc 80:20) to afford pure aziridine 63 (0.648 g, 38%
from the acetonide) as a white solid: mp 97-99 °C (ethyl ether); [R]25
D
+30.0° (c 1.66, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.48 (dd, J )
5.0, 1.4 Hz, 1H), 4.90 (ddd, J ) 6.1, 1.9, 0.8 Hz, 1H), 4.38 (dd, J )
6.3, 1.4 Hz, 1H), 3.75 (s, 3H), 3.20 (dd, J ) 5.8, 1.6 Hz, 1H), 2.98 (t,
J ) 4.9 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.9, 128.3, 125.7, 111.2, 73.8, 72.2, 53.9, 35.3, 34.9, 27.5,
26.1; HRMS calcd for C11H15NBrO4 304.0184, found 304.0185. Anal.
Calcd for C11H14BrNO4: C, 43.44; H, 4.63; N, 4.60. Found: C, 43.64;
H, 4.73; N, 4.55.
Methyl N-[(1R,2R,3R,4S,5S,6S)-2-(1,3-Benzodioxol-5-yl)-3,4,5,6-
tetraacetoxycyclohexyl]carbamate (68). Aryl aminocyclitol 67 (40
mg) was dissolved in pyridine (1 mL) and acetic anhydride (1 mL),
and the mixture was stirred at room temperature for 16 h. The solvent
was evaporated in vacuo, and the residue was chromatographed (silica
gel, hexane/EtOAc 1:1) to furnish tetraacetate 68 (50 mg, 84%): white
solid; Rf 0.43 (hexane/EtOAc 2:3); mp 109-110 °C (hexane/EtOAc);
Methyl (1R,4R,5S,6R)-4,5-(Isopropylidenedioxy)-7-azabicyclo-
[4.1.0]hept-2-ene-7-carboxylate (64). To a degassed solution of
bromide 63 (500 mg, 1.64 mmol) in THF (50 mL) at reflux were added
tributyltin hydride (574 mg, 1.97 mmol) and AIBN (50 mg, 0.304
mmol), and the solution was heated under reflux until TLC (hexane/
EtOAc 3:1) indicated no remaining starting material (∼60 min). The
mixture was concentrated in vacuo, followed by chromatography
(hexane/EtOAc 3:1), to afford 64 (302 mg, 82%; average yield range:
[R]25 +14.1° (c 0.86, CHCl3); IR (KBr) ν 3360, 2950, 1740, 1520
D
cm-1; 1H NMR (200 MHz, CDCl3) δ 6.72 (m, 3H), 5.93 (s, 2H), 5.35
(s, 1H), 5.23 (m, 1H), 5.09 (m, 2H), 4.70 (m, 1H), 4.40 (br d, J ) 9.0
Hz, 1H), 3.54 (s, 3H), 3.22 (d, J ) 11.4 Hz, 1H), 2.18 (s, 6H), 2.02 (s,
6H); 13C NMR (50 MHz, CDCl3) δ 170.53 (C), 169.33 (C), 168.82
(C), 168.25 (C), 156.56 (C), 147.74 (C), 146.96 (C), 129.58 (C), 122.19
(CH), 109.06 (CH), 108.16 (CH), 101.02 (CH2), 72.06 (CH), 71.11
(CH), 68.71 (CH), 68.09 (CH), 52.19 (CH), 48.07 (CH3), 47.20 (CH),
20.79 (2CH3), 20.62 (2CH3); HRMS (CI) calcd for C23H27NO12+H
510.1611, found 510.1543. Anal. Calcd for C23H27NO12: C, 54.22;
H 5.34; N, 2.75. Found: C, 54.49; H, 5.41; N, 2.57.
40-50%) as an oil: Rf 0.30 (hexane/EtOAc 3:1); [R]22 -94° (c 1.0,
D
1
CHCl3); IR (CH2Cl2 film) 1734 cm-1; H NMR (300 MHz, CDCl3) δ
6.06 (ddd, J ) 10.0, 4.4, 1.7 Hz, 1H), 5.71 (dm, J ) 10.0 Hz, 1H),
4.80 (dm, J ) 6.6 Hz, 1H), 4.43 (dt, J ) 6.6, 2.0 Hz, 1H), 3.74 (s,
3H), 3.14 (dd, J ) 5.9, 2.0 Hz, 1H), 2.96 (t, J ) 5.1 Hz, 1H), 1.39 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 162.4, 130.9, 122.6, 110.4, 70.9,
70.1, 53.8, 34.6, 33.2, 27.8, 26.1.
(1R,2S,3S,4S,4aR,11bR)-1,2,3,4-Tetraacetoxy-1,3,4,4a,5,10b-hexahy-
dro-1,3-dioxolo[4,5-j]phenanthridin-6-(2H)-one (69). Freshly dis-
tilled Tf2O (121 mg, 0.432 mmol) was added at 0 °C to a solution of
tetraacetate 68 (44 mg, 0.864 mmol) and DMAP (32 mg, 0.259 mmol)
in CH2Cl2 (2 mL). The mixture was stirred at 5 °C for 16 h, the solvent
was removed in vacuo, and then THF (2 mL) and aqueous HCl (0.2
mL, 2 N) were added, and the mixture was stirred at room temperature
for 5 h. Neutralization with aqueous NaHCO3, extraction with EtOAc
(3 × 15 mL), drying of the organic phase over MgSO4, and
concentration afforded a residue, which was chromatographed (silica
gel, hexane/EtOAc 1:1) to furnish the cyclized product 69 (25 mg,
61%): white solid; Rf 0.50 (hexane/EtOAc 1:2); mp 232-238 °C
(hexane/EtOAc); [R]25D +75.2° (c 1.2, CHCl3); IR (KBr) ν 3330, 2920,
1750, 1665 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 6.59 (s,
1H), 6.56 (s, 1H), 6.03 (m, 2H), 5.58 (m, 1H), 5.47 (t, J ) 2.9 Hz,
Methyl N-[(1R,2R,5R,6S)-2-(1,3-Benzodioxol-5-yl)-5,6-dihydroxy-
cyclohex-3-en-1-yl]carbamate (65). Acetonide 62 (465 mg, 1.34
mmol) in AcOH/THF/H2O (2:1:1; 5 mL) was heated at 65 °C for 3 h.
The solvent was evaporated in vacuo, and the residue was recrystallized
from EtOAc/methanol to give diol 65 (390 mg, 94%) as a white solid:
Rf 0.35 (CHCl3/CH3OH 8:1); mp 200-201 °C (EtOAc/MeOH); [R]25
D
+107.7° (c 1.22, MeOH); IR (KBr) ν 3400, 3320, 3300, 2868, 1690,
1
1535 cm-1; H NMR (200 MHz, CD3OD) δ 6.72 (m, 3H), 5.89 (m,
3H), 5.65 (dd, J ) 9.9, 2.0 Hz, 1H), 4.61 (s, 1H), 4.21 (t, J ) 4.3 Hz,
1H), 3.74 (m, 1H), 3.60 (m, 1H), 3.50 (m, 3H), 3.30 (m, 3H); 13C NMR
(50 MHz, CD3OD) δ 159.85 (C), 149.12 (C), 147.91 (C), 137.29 (C),

Syntheses of Pancratistatin and 7-Deoxypancratistatin
J. Am. Chem. Soc., Vol. 118, No. 44, 1996 10765
1H), 5.23 (t, J ) 2.7 Hz, 1H), 5.20 (dd, J ) 3.5, 10.8 Hz, 1H), 4.30
(dd, J ) 12.8, 11.0 Hz, 1H), 3.46 (dd, J ) 13.0, 2.7 Hz, 1H), 2.16 (s,
3H), 2.11 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.03 (C), 169.77 (C), 169.04 (C), 168.27 (C), 165.07 (C),
151.77 (C), 147.25 (C), 131.52 (C), 123.32 (C), 108.44 (CH), 103.68
(CH), 101.86 (CH3), 71.53 (CH), 67.67 (CH), 66.92 (CH), 66.32 (CH),
48.21 (CH), 39.46 (CH), 20.79 (CH3), 20.76 (CH3), 20.62 (CH3), 20.59
(CH3); HRMS (CI) calcd for C22H23NO11+H 478.1349, found 478.1351.
Deoxypancratistatin (70). Sodium methoxide (0.5 M in methanol,
1.1 mL) was added to a solution of tetraacetate 69 (26 mg, 0.054 mmol)
in THF (1 mL). The reaction mixture was stirred at room temperature
for 10 h, and saturated NH4Cl aqueous solution (2 mL) was added.
The aqueous layer was extracted exhaustively with EtOAc, and the
organic layer was dried over Na2SO4. Concentration and column
chromatography (silica gel, CHCl3/CH3OH 4:1) gave deoxypancrat-
Acknowledgment. The authors thank the National Science
Foundation (CHE-9315684 and CHE-9521489), Genencor
International, Inc., TDC Research, Inc., and The University of
Florida for generous financial support. The authors also thank
Prof. G. E. Keck (University of Utah) for the kind provision of
1
TLC, [R]D, and H-NMR data of the tetraacetate of 7-deoxy-
pancratistatin, as well as Prof. G. R. Pettit (Arizona State
University) for a sample of (+)-pancratistatin. Stefan Schilling,
Dr. Paul Higgs, and Dr. Josie Reed are thanked for additional
experimental work and for editing the manuscript, respectively.
Supporting Information Available: Experimental proce-
dures and key physical data for compounds 29, 30, 31, 32a,
32d, 33, and 34 (3 pages). See any current masthead page for
ordering and Internet access instructions.
istatin 70 (12 mg, 72%): Rf 0.30 (CHCl3/CH3OH 4:1); mp 306-309
1
°C; [R]25 +78.5° (c 0.75, DMF); H NMR (400 MHz, DMSO-d6) δ
D
7.30 (s,1H), 6.90 (s, 1H), 6.84 (s, 1H), 6.06 (s, 2H), 5.36 (d, J ) 4.0
Hz, 1H), 5.07 (d, J ) 5.8 Hz, 1H), 5.05 (d, J ) 6.1 Hz, 1H), 4.77 (d,
J ) 7.5 Hz, 1H), 4.31 (m, 1H), 3.97 (q, J ) 3.5 Hz, 1H), 3.84 (m,
1H), 3.72 (m, 2H), 2.97 (d, J ) 12.0 Hz, 1H).
JA960596J