Stereocontrolled Total Synthesis of Pancratistatin

Article abstract of DOI:10.1021/ol0256419

(Matrix Presented) A new total synthesis of the antitumor alkaloids, pancratistatin (1), has been accomplished from readily available staring materials. The Claisen rearrangement of dihydropyranethylene 5 was employed to construct the A and C rings. Stere

Full text of DOI:10.1021/ol0256419

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1343-1345
Stereocontrolled Total Synthesis of
Pancratistatin
Sanghee Kim,*,†,‡ Hyojin Ko,† Eunkyung Kim,† and Deukjoon Kim‡
Natural Products Research Institute, Seoul National UniVersity, 28 Yungun, Jongro,
Seoul 110-460, Korea, and College of Pharmacy, Seoul National UniVersity, San 56-1,
Shilim, Kwanak, Seoul 151-742, Korea
pennkim@snu.ac.kr
Received January 30, 2002
ABSTRACT
A new total synthesis of the antitumor alkaloids, pancratistatin (1), has been accomplished from readily available staring materials. The
Claisen rearrangement of dihydropyranethylene 5 was employed to construct the A and C rings. Stereo- and regiocontrolled functional group
interchange, such as iodolactonization, dihydroxylations, and a cyclic sulfate elimination reaction, allows for the production of the target
natural product.
Pancratistatin (1, Figure 1) is a highly oxygenated phenan-
thridone alkaloid, which was isolated from the roots of
promising pharmacological profile, low natural abundance,
and unique structural features, as it contains six contiguous
stereogenic centers in the C ring of a phenanthridone
skeleton. The first total synthesis of the racemate was
reported by Danishefsky in 1989,3 and the first enantio-
selective synthesis of the natural enantiomer was recorded
by Hudlicky in 1995.4 In the same year, Trost presented an
enantioselective synthesis with a high overall yield.5 Since
then, Haseltine,6 Magnus,7 and Rigby8 have also presented
(2) (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. (b) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.;
Kevauver, D. F.; Pettit, G. R.; Groszek, G.; Holingshead, 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. (c) Gabrielsen, B.; Monath, T.
P.; Huggins, J. W.; Kirsi, J. J.; Holingshead, M.; Shannon, W. M.; Pettit.
G. R. In Natural Products as AntiViral Agents; Chu, C. K., Cutler, H. G.,
Eds.; Plenum: New York, 1992; pp 121-135.
Figure 1. Structures of pancratistatin (1) and narciclasine (2).
Pancratium littorale by Pettit and co-workers in 1984.1 This
alkaloid exhibits a high level of in vitro and in vivo cancer
cell growth inhibitory activity and antiviral activity.2 The
significant synthetic interest in pancratistatin stems from its
(3) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
(4) Tian, X.; Hudlicky, T.; Ko¨nigsberger, K. J. Am. Chem. Soc. 1995,
117, 3643.
(5) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
(6) Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard, S.; Haseltine,
J. Tetrahedron 1997, 53, 11153.
(7) (a) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341.
(b) Magnus, P.; Sebhat, I. K. Tetrahedron 1998, 54, 15509.
(8) (a) Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655.
(b) Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc.
2000, 122, 6624.
† Natural Products Research Institute.
‡ College of Pharmacy.
(1) (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.
10.1021/ol0256419 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/21/2002

Scheme 1
Scheme 2a
a new synthesis of (+)-pancratistatin. Recently, Pettit
achieved the synthesis of (+)-1 from the more abundant
alkaloid (+)-narciclasine (2, Figure 1).9 In this Letter, we
wish to report our successful approach to the synthesis of
(()-pancratistatin.
The strategy of our synthesis is presented in Scheme 1.
The B ring of the phenanthridone skeleton would be
constructed at a relatively late stage of the synthesis by
employing the Bischler-Napieralski reaction.7,10 The req-
uisite cyclization precursor 3, which contains the six ste-
reocenters in the C ring, could be stereoselectively synthe-
sized from the cis-disubstituted cyclohexene 4. The presence
of a γ,δ-unsaturated carbonyl unit in compound 4 suggested
the use of a Claisen rearrangement of 3,4-dihydro-2H-
pyranylethylene 5.11
The synthesis began by preparing the known bromide 612
from the commercially available methyl gallate via a
conventional four-step sequence. Treatment of 6 with excess
trimethyl phosphite provided phosphonate 7 in 97% yield
(Scheme 2).13 Employing the Honer-Wadsworth-Emmons
reaction between 7 and commercially available acrolein
dimer 8 (1.1 equiv) in the presence of LHMDS in THF
afforded the desired (E)-olefin 5 with very high stereo-
selectivity in 60% yield (92% yield based on the recovered
starting material).14 Only trace amounts (<1%) of the
corresponding (Z)-olefin were detected in the crude NMR
spectra. The Claisen rearrangement of dihydropyranethylene
5 (250 °C in a sealed tube) provided the cis-disubstituted
cyclohexene 4 as a single isomer in 78% yield. As discussed
by Bu¨chi,11 this rearrangement must proceed through a
boatlike transition state.
a (a) P(OMe)3, toluene, sealed tube, 180 °C, 2 h, 97%; (b) 8,
LHMDS, THF, 0 °C to rt, 22 h, 60% (92% based on the recovered
starting material); (c) toluene, sealed tube, 250 °C, 20 h, 78%; (d)
NaClO2, NaH2PO4‚2H2O, 2-methyl-2-butene, THF, tBuOH, H2O,
rt, 18 h, 90%; (e) (i) KI3, aqueous NaHCO3, CH2Cl2, rt, 20 h, (ii)
DBU, benzene, reflux, 8 h, 78%; (f) NaOMe, MeOH, reflux, 20 h,
93%; (g) 1N LiOH, THF, rt, 18 h, 99%; (h) (i) DPPA, Et3N, toluene,
reflux, 15 h, (ii) NaOMe, MeOH, reflux, 0.5 h, 82%.
With the appropriately functionalized cyclohexene 4 in
hand, our study focused on the selective introduction of the
stereocenters in the C ring. First, the aldehyde group of 4
was oxidized with NaClO2 to the corresponding carboxylic
acid 9 in 90% yield. Iodolactonization of 9 under two-phase
conditions followed by treatment of the resulting iodolactone
with DBU in refluxing benzene led to the formation of the
bicyclic lactone 10 with an overall yield of 78%.15 Metha-
nolysis of the lactone 10 with NaOMe at room temperature
for 18 h afforded an inseparable equilibrium mixture (ca.
1:1 ratio) of hydroxy ester 11 and its C-4a epimer (pancrat-
istatin numbering). However, when the methanolysis was
carried out in refluxing methanol for 20 h, epimerization of
the methoxycarbonyl group was accomplished very cleanly
to give 11 as the only identifiable product in 93% yield.
Saponification of the methyl ester 11 with LiOH was
followed by a modified Curtius rearrangement16 of the
resulting acid 12 with diphenylphosphoryl azide in refluxing
toluene to give a rather stable isocyanate intermediate that
required further treatment with NaOMe/MeOH to generate
the corresponding carbamate 13 in 82% overall yield.
The final C-ring functional group processing of 13
proceeded as follows (Scheme 3). At this stage, it was
necessary to protect the free hydroxyl group of 13 to
(9) Pettit, G. R.; Melody, N.; Herald, D. J. Org. Chem. 2001, 66, 2583.
(10) (a) Banwell, M. G.; Cowden, C. J.; Gable, R. W. J. Chem. Soc.,
Perkin Trans. 1 1994, 3515. (b) Fodor, G.; Nagibandi, S. Tetrahedron 1980,
36, 1279.
(11) Bu¨chi, G.; Powell, J. E., Jr. J. Am. Chem. Soc. 1970, 92, 3126.
(12) (a) Lalami, K.; Dhal, R.; Brown, E. Heterocycles 1988, 27, 1131.
(b) For an efficient preparation of the corresponding alcohol from methyl
gallate, see: Pettit, G. R.; Singh, S. B. Can. J. Chem. 1987, 65, 2390.
(13) Jawad, A.; Jacques, C.; Ingrid, H.-K.; Christian H.; Hugues, M.;
Robert, G. R. J. Med. Chem. 2000, 43, 560.
(14) Wittig reaction between the corresponding phosphonium bromide
and acrolein dimer 8 in the presence of KOH and 18-crown-6 ether in CH2-
Cl2 provided a mixture of olefins with a Z/E ratio of 5:1 in 85% yield.
(15) Kobayashi, S.; Kamiyama, K. Ohno, M. J. Org. Chem. 1990, 55,
1169.
(16) (a) Shin, K. J.; Moon, H. R.; George, C.; Marquez, V. E.J. Org.
Chem. 2000, 65, 2172. (b) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.;
Johnson, J. S.; Ripin, D. H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64,
6411.
1344
Org. Lett., Vol. 4, No. 8, 2002

The regioselective elimination of the C-3 hydroxyl group to
generate the requisite ∆3,4 unsaturation was achieved by
employing the cyclic sulfate elimination reaction.17 Treatment
of diol 16 with thionyl chloride followed by oxidation with
RuCl3‚3H2O/Oxone18 provided the corresponding cyclic
sulfate 17 in 83% yield. The reaction of cyclic sulfate 17
with DBU in refluxing toluene17a led, after acidic workup,
to the formation of the desired allylic alcohol 18 (67% yield).
Routine cis-dihydroxylation of 18 with OsO4 afforded the
single isomer 19 in 88% yield, thereby completing the
functionalization of the C ring of pancratistatin. The structural
assignment made for this compound was strongly supported
by its relevant 1H NMR coupling patterns and by comparing
Scheme 3a
1
the H NMR spectral data of the derived tetraacetate with
those reported by Magnus.7
The remaining steps to pancratistatin required protection
of the hydroxyl groups, formation of the final lactam B ring,
and protecting group removal and were accomplished by
employing reaction conditions analogous to those of Magnus
et al.7 Peracetylation of 19 (77%) was followed by a
Banwell’s modified Bischler-Napieralski cyclization,7,10
which provided predominantly the desired product 20, along
with a minor amount of the regioisomer 21 in 78% combined
yield and 7:1 regioselectivity. Treatment of an inseparable
mixture of 20 and 21 with BBr3 to remove the C-7 methyl
group protection yielded 22 (65%) and unreacted 21, which
were now separable.19 Finally, simple removal of protecting
groups with NaOMe/MeOH afforded (()-1 in 83% yield,
1
of which H and 13C NMR spectral data were in good
agreement with those reported.1,3-10
In conclusion, we have accomplished the stereoselective
synthesis of (()-pancratistatin from readily available starting
materials. We utilized the Claisen rearrangement of dihy-
dropyranethylene 5 to construct the A and C rings, and
subsequent iodolactonization, dihydroxylations, and cyclic
sulfate elimination reactions to install six contiguous ste-
reogenic centers in the C ring.
Acknowledgment. This work was supported by a grant
(1999-2-21500-001-3) from the Basic Research Program of
the Korea Science & Engineering Foundation.
a (a) BzCl, Et3N, DMAP, CH2Cl2, rt, 15 h, 99%; (b) OsO4, NMO,
THF/H2O, rt, 20 h, 96%; (c) (i) SOCl2, Et3N, CH2Cl2, 0 °C, 0.5 h,
(ii) Oxone, RuCl3‚3H2O, EtOAc/CH3CN/H2O, rt, 2 h, 83%; (d)
DBU, toluene, reflux, 2 h, then H2SO4, H2O/THF, rt, 4 h, 67%; (e)
OsO4, NMO, THF/H2O, rt, 27 h, 88%; (f) (i) Ac2O, DMAP,
pyridine, CH2Cl2, rt, 1 h, 77%,(ii) Tf2O, DMAP, CH2Cl2, 0 to 5
°C, 22 h, 78%; (g) BBr3, CH2Cl2, -78 to 0 °C, 1 h, 65%; (h)
NaOMe, MeOH, THF, rt, 4 h, 83%.
Supporting Information Available: Full experimental
procedures and spectral data of new compounds and 1H NMR
and 13C NMR spectra of compounds 1, 4, 5, 12, 14, 19, and
22. This material is available free of charge via the Internet
at http://pubs.acs.org.
selectively install the C-2 hydroxyl group on the R-face. This
was accomplished by reacting compound 13 with benzoyl
chloride to furnish 14 in 99% yield. Attempted epoxidation
of 14 to 15 with various regents such as mCPBA and
dioxiranes was not successful, providing only decomposed
materials. However, dihydroxylation of the ∆2,3-olefin with
OsO4 did occur on the R-face of the molecule to produce
diol 16 in 96% yield. The stereochemistry of 16 was
tentatively assigned as R, on the basis of steric considerations.
OL0256419
(17) For an elimination reaction of R-nonactivated cyclic sulfate, see:
(a) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J.
Am. Chem. Soc. 1999, 121, 296. (b) Kim, C. U.; Lew, W.; Williams, M.
A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P. A.; Mendel, D. B.; Laver, W.
G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451. (c) Schaub, C.; Mu¨ller,
B.; Schmidt, R. R. Eur. J. Org. Chem. 2000, 1745.
(18) Robins, M. J.; Lewandowska, E.; Wnuk, S. F. J. Org. Chem. 1998,
63, 7375.
(19) This reaction patterned after a similar step in the Magnus synthesis.7
Org. Lett., Vol. 4, No. 8, 2002
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