Application of palladium-catalyzed allylic arylation to the synthesis of a (±)-7-deoxypancratistatin analogue

Article abstract of DOI:10.1021/ol061070z

(Chemical Equation Presented) Palladium-catalyzed coupling of an aryl siloxane and an allylic carbonate proceeded in good yield to give an adduct that was converted to an analogue of (±)-7-deoxypancratistatin.

Full text of DOI:10.1021/ol061070z

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4183-4186
Application of Palladium-Catalyzed
Allylic Arylation to the Synthesis of a
(±)-7-Deoxypancratistatin Analogue
Krupa H. Shukla, Debra J. Boehmler, Suzanne Bogacyzk, Bridget R. Duvall,
William A. Peterson, William T. McElroy, and Philip DeShong*
Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
deshong@umd.edu
Received May 2, 2006
ABSTRACT
Palladium-catalyzed coupling of an aryl siloxane and an allylic carbonate proceeded in good yield to give an adduct that was converted to an
analogue of ( )-7-deoxypancratistatin.
±
The natural products pancratistatin (1), 7-deoxypancratistatin
(2), and their analogues have been shown to possess antiviral
and antitumor activity under high dosage conditions (Figure
1).1 The biological activity of these compounds and their
synthetic targets. Controlling the stereochemistry of the dense
array of oxygenated functionality on ring C and the trans-
fused BC-ring junction have proven to be the key elements
in the previous syntheses of this family of lycorane
derivatives.1d,2
We have previously reported the coupling of silicate anions
with allylic esters in the presence of a palladium(0) catalyst
to provide homostyrene derivatives.3 These couplings are
stereospecific, occurring with inversion of configuration and
(2) (a) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829-
4837. (b) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143-
10144 (c) Gauthier, D. R.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13-
16. (d) Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard, S.; Haseltine,
J. Tetrahedron 1997, 53, 11153-11170. (e) Magnus, P.; Sebhat, I. K.
Tetrahedron 1998, 54, 15509-15524. (f) Rigby, J. H.; Maharoof, U. S.
M.; Mateo, M. E. J. Am. Chem. Soc. 2000, 122, 6624-6628. (g) Pettit, G.
R.; Melody, N.; Herald, D. L. J. Org. Chem. 2001, 66, 2583-2587. (h)
Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343-1345. (i)
Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Org. Chem. 1999, 64, 4465-
4476. (j) Nadein, O. N.; Kornienko, A. Org. Lett. 2004, 6, 831-834. (k)
Pandey, G.; Murugan, A.; Balakrishnan, M.; Chem. Commun. 2002, 624-
625. (l) Grubb, L. M.; Dowdy, A. L.; Blanchette, H. S.; Friestad, G. K.;
Branchaud, B. P. Tetrahedron Lett. 1999, 40, 2691-2694. (m) Mehta, G.;
Mohal, N. Tetrahedron Lett. 1998, 39, 3281-3284. (n) Banwell, M. G.;
Cowden, C. J. Aust. J. Chem. 1994, 47, 2235-2254. (o) Bala´zs, L.; Ka´das,
I.; To¨ke, L. J. Heterocycl. Chem. 1998, 35, 343-348. (p) Angle, S. R.;
Louie, M. S. Tetrahedron Lett. 1993, 34, 4751-4754. (q) Lopes, R. S. C.;
Lopes, C. C.; Heathcock, C. H. Tetrahedron Lett. 1992, 33, 6775-6778.
(r) Clark, R. D.; Souchet, M. Tetrahedron Lett. 1990, 31, 193-196. (s)
Moser, M.; Sun, X.; Hudlicky, T. Org. Lett. 2005, 7, 5669-5672. (t) Rinner,
U.; Hudlicky, T. Synlett. 2005, 3, 365-387 and references therein. (u)
Håkansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Chem. Eur. J.
2006, 12, 3243-3253.
Figure 1. Structures of pancratistatin and 7-deoxypancratistatin.
stereochemical complexity have made them challenging
(1) (a) 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, 995-1002. (b) Ghosal, S.; Singh, S.; Kumar, Y.; Srivastava,
R. S. Phytochemistry 1989, 28, 611-613. (c) Gabrielsen, B.; Monath, T.
P.; Huggins, J. W.; Kefauver, D. F.; Pettit, G. R.; Groszek, G.; Hollingshead,
M.; Kirsi, J. J.; Shannon, W. M.; Schubert, E. M.; DaRe, J.; Ugarkar, B.;
Ussery, M. A.; Phelan, M. J. J. Nat. Prod. 1992, 55, 1569-1581. (d)
Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun, H.; Schilling, S.; Sien-
galewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002, 67, 8726-
8743 and references therein. (e) McNulty, J.; Mao, J.; Gibe, R.; Mo, R.;
Wolf, S.; Pettit, G. R.; Herald, D. L.; Boyd, M. R. Bioorg. Med. Chem.
Lett. 2001, 11, 169-172.
10.1021/ol061070z CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/25/2006

are highly regioselective; a model has been proposed to
explain the high regioselectivity observed in the coupling.
We were interested to determine the scope and limitation of
this coupling strategy by synthesizing diol 3, an analogue
of 7-deoxypancratistatin. Based on precedent, coupling of
allylic carbonate 5 with aryl siloxane 6 would occur with
inversion of configuration to join the A and C rings and
establish the requisite trans-BC ring juncture. Ring B would
be constructed by a Bischler-Napieralski cyclization (Scheme
1).
a Pd(0) catalyst gave the allylic arylated coupling products
4 and 9, respectively, in 81% yield as a 1:1.6 mixture of re-
gioisomers. In this instance, the allylic coupling had occurred
with complete inversion of stereochemistry as expected but
had not displayed regioselectivity for the desired isomer.
On the basis of previous investigations of regioselectivity
in cyclohexenyl systems, formation of a mixture of regio-
isomeric coupling products 4 and 9 was anticipated.7 Using
the model developed in our laboratory, the π-allyl Pd
complex derived from allylic carbonate 5 formed on the face
opposite from the departing carbonate group (Scheme 3).
Scheme 1. Retrosynthesis
Scheme 3. Explanation for Observed Regioselectivity of
Coupling Products 4 and 9
Allylic carbonate 5 was prepared as shown in Scheme 2.
Scheme 2. Synthesis of Carbamate 4
The resulting “symmetrical” Pd complex 10 does not have
substituents on the face of the π-complex which has Pd
attached. Accordingly, subsequent reductive elimination of
the aryl group from silicon would occur with equal proclivity
at the 1 and 3 positions. Under these circumstances, modest
regioselectivity was anticipated. The role of electronic factors
on the regioselectivity of the coupling reaction was unknown,
but results from Szabo´8 indicated that the coupling reaction
would favor carbamate 9, as was ultimately observed in the
experiment. Surprisingly, when the benzyl carbamate (Cbz)
analogue of 5 was used as coupling partner with the siloxane
6, the yield of coupled products (Cbz analogues of 4/9)
dramatically decreased.
The mixture of regioisomeric carbamates 4 and 9 was
subjected to Bischler-Napieralski cyclization using P2O5 and
POCl3/Me3SiOSiMe3 (1:1), and only regioisomer 4 under-
went cyclization to provide lactam 11 (Scheme 4).9 The
Friedel-Crafts cyclization was completely regioselective,
giving only the desired tricycle. None of the regioisomeric
tricycle was observed, in analogy with the results of
Magnus.10
Diels-Alder reaction of cyclohexadiene with the acyl nitroso
dienophile (generated in situ) gave hydroxamate 7.4 The
hydroxamate underwent reductive N-O bond cleavage with
molybdenum hexacarbonyl to form allylic alcohol-carbam-
ate 8,5 followed by acylation with ethyl chloroformate to
give carbonate-carbamate 5. Coupling of carbonate 5 with
electron-rich aryl siloxane 66 in the presence of TBAF and
Previous syntheses of pancratistatin and its analogues had
shown that C-ring alkenes were significantly less reactive
(6) Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449-7455.
(7) Hoke, M. E.; Brescia, M.-R.; Bogacyzk, S.; DeShong, P.; King, B.
W.; Crimmins, M. T. J. Org. Chem. 2002, 67, 327-335.
(8) Jonasson, C.; Kritikos, M.; Ba¨ckvall, J.-E.; Szabo´, K. Chem. Eur. J.
2000, 6, 432-436 and references therein.
(9) Chern, M.-S.; Li, W.-R. Tetrahedron Lett. 2004, 45, 8323-8326.
(10) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341-
5342.
(3) (a) Brescia, M.-R.; DeShong, P. J. Org. Chem. 1998, 63, 3156-
3157. (b) Correia, R.; DeShong, P. J. Org. Chem. 2001, 66, 7159-7165.
(c) Bogaczyk, S. Ph.D. Dissertation, University of Maryland, College Park,
MD, 2002.
(4) Jenkins, N. E.; Ware, R. W.; Atkinson, R. N.; King, S. B. Synth.
Commun. 2000, 30, 947-953.
(5) Tranmer, G. K.; Tam, W. Org. Lett. 2002, 4, 4101-4104.
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Org. Lett., Vol. 8, No. 19, 2006

diagnostic of a syn relationship between the two protons.
Protons H10b and H4a of 13 exhibit a 13 Hz coupling constant
which is indicative of a trans diaxial relationship. These
coupling constant values are in accord with the coupling
observed (2 Hz) for protons H1 and H10b and (13 Hz) for
protons H10b and H4a respectively in 14.
Scheme 4. Cyclization and Installation of trans-Diol
To synthesize pancratistatin (1) or 7-deoxypancratistatin
(2) by this approach, it would be necessary to couple
carbonate 15 with arylsiloxane 6 in analogy with the reactions
described above (Scheme 5). Unlike the model system with
Scheme 5. Preliminary Studies Related to Couplings of
Pancratistatin and 7-Deoxypancratistatin
than normal, so we were not surprised when epoxidation of
the double bond achieved using m-CPBA11 gave a mixture
of diastereomeric epoxides 12 in low yield (15-30%).
Attempts to improve the yield of epoxides using more
reactive epoxidation reagents led to extensive decomposition
of the alkene. In principle, the stereoselectivity in the
epoxidation reaction was of no consequence since the diaxial
opening of each epoxide should be regiospecific and give
only trans-diol 13.
allylic carbonate 5 that gave no regioselectivity in the
coupling (Schemes 2 and 3), fully functionalized carbonate
15 was expected to couple with high regioselectivity based
on the model developed in our previous studies and shown
in Scheme 3. However, repeated attempts to effect coupling
between carbonate 15 and siloxane 6 were unsuccessful; no
traces of the desired adduct 16 were detected. Generally, the
allylic carbonate was recovered unchanged from the reaction
indicating that π-allyl complex formation had not occurred.
Under forcing conditions using allyl palladium chloride dimer
as the catalyst, aryl ether 17 was isolated in 10% yield. The
structure of ether 17 was confirmed by X-ray crystallographic
analysis. Formation of aryl ethers in these coupling reactions
is unprecedented and a logical mechanistic rationale for the
formation of the ether product is under investigation.
A more direct method of introducing the trans-diol
functionality was successful: one-pot trans-dihydroxylation
with hydrogen peroxide in formic acid (presumably via the
epoxide) gave diol 13 in 51% yield.12 The initial product of
the reaction is a mixture of alcohol-formates (from opening
of the expoxide) which is hydrolyzed immediately to give
the desired diol. Purification of diol 13 by a variety of normal
or reverse-phase methods led to extensive loss of product.
The most efficient purification method ultimately involved
an extraction-precipitation regime.
The relative stereochemistry of diol 13 was confirmed by
1
Failure of carbonate 15 to undergo the allylic arylation
reaction can be attributed to steric congestion of the â face
of the alkene, the face on which the transition metal must
reside, by the methyl group of the isopropylidene protecting
group on the diol moiety. Carbonate 15 is conformationally
rigid and adopts a clamshell like conformation that places
this methyl group almost directly over the alkene, thus
blocking π-allyl formation. Presumably, replacement of the
diol protecting with groups that allow conformational mobil-
ity (i.e., MOM, etc.) should result in efficient allylic
arylations. These studies will be reported in due course.
COSY experiments and correlation to published H NMR
data of the benzoate of the 7-deoxypancratistatin derivative
(14).13 For example, the coupling constant J1,10b for tricycle
13 is 2 Hz (Figure 2). The small coupling constant is
Acknowledgment. The generous financial support of the
National Institutes of Health, National Cancer Institute is
(11) Castillo, P.; Rodriguez-Ubis, J. C.; Rodriguez, F. Synthesis 1986,
839-840.
(12) Kelly, T. R. J. Org. Chem. 1972, 37, 3393-3397.
(13) Paulsen, H.; Stubbe, M. Liebigs Ann. Chem. 1983, 535-556.
Figure 2. Relative stereochemistry was confirmed from correlation
with H NMR coupling constants.
1
Org. Lett., Vol. 8, No. 19, 2006
4185

acknowledged (CA 82169). We thank Dr. Yiu-Fai Lam and
Mr. Noel Whittaker (University of Maryland) for their
assistance obtaining NMR and mass spectral data, respec-
tively. We thank Dr James Fettinger (University of Maryland)
for X-ray crystallographic analysis of ether 17.
Supporting Information Available: Synthetic procedures
and spectroscopic data for compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061070Z
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