Total Synthesis of Pancratistatin Relying on the [3,3]-Sigmatropic Rearrangement

Article abstract of DOI:10.1021/jo035371n

A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene 17 was employed to construct the A and C rings with the appropr

Full text of DOI:10.1021/jo035371n

Tota l Syn th esis of P a n cr a tista tin Relyin g on th e [3,3]-Sigm a tr op ic
Rea r r a n gem en t
Hyojin Ko,† Eunkyung Kim,† J ae Eun Park,† Deukjoon Kim,‡ and Sanghee Kim*,†,‡
Natural Products Research Institute, College of Pharmacy, Seoul National University, 28 Yungun,
J ongro, 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 September 18, 2003
A new total synthesis of the antitumor alkaloid, pancratistatin (1), has been accomplished from
readily available starting materials. Claisen rearrangement of the racemic dihydropyranethylene
17 was employed to construct the A and C rings with the appropriate stereochemistry. In addition,
the Ireland-Claisen rearrangement of the enantiomerically pure 9 followed by ring-closing
metathesis provided the important intermediate 24, thus implying that our approach could yield
the enantioselective synthesis of (+)-pancratistatin. With the appropriately functionalized cyclo-
hexene 24, stereo- and regiocontrolled functional group interchanges, such as iodolactonization,
dihydroxylations, and a cyclic sulfate elimination reaction, facilitated the production of the target
natural product.
In tr od u ction
In 1984, Pettit and co-workers reported the isolation
and structure of the highly oxygenated phenanthridone
alkaloid designated (+)-pancratistatin (1, Figure 1).1 This
alkaloid exhibits high levels of in vitro and in vivo cancer
cell growth inhibitory activity and antiviral activity.2
Pancratistatin possesses six contiguous stereogenic cen-
ters in the C ring of a phenanthridone skeleton and a
trans-fused BC ring junction. Subsequently, its unique
structural features coupled with its low natural abun-
dance and promising pharmacological profiles have
prompted impressive synthetic efforts to date from a
number of laboratories. The first total synthesis of the
racemate was reported by Danishefsky in 1989,3 and the
first enantioselective 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
F IGURE 1. Structures of pancratistatin (1), narciclasine (2),
7-deoxypancratistatin (3), and lycoricidine (4).
Rigby8 have also presented new synthetic routes for (+)-
pancratistatin. Recently, Pettit achieved the synthesis of
(+)-1 from the more abundant alkaloid (+)-narciclasine
(2, Figure 1).9
Despite the numerous synthetic approaches for the
synthesis of 1 and its congeners,10 such as narciclasine
(2), 7-deoxypancratistatin (3), and lycoricidine (4), the
members of this phenanthridone alkaloid family remain
particularly attractive targets for organic synthesis. In
this paper,11 we describe full details of the stereocon-
* To whom correspondence should be addressed. Tel: 82-2-740-8913.
Fax: 82-2-762-8322.
† 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.
(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.
(6) Doyle, T. J .; Hendrix, M.; VanDerveer, D.; J avanmard, 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.
(9) Pettit, G. R.; Melody, N.; Herald, D. J . Org. Chem. 2001, 66,
2583.
(10) For a good review with citations, see: (a) Rinner, U.; Sien-
galewicz, P.; Hudlicky, T. Org. Lett. 2002, 4, 115. (b) Hudlicky, T.;
Rinner, U.; Gonzalez, D.; Akgun, H.; Schilling, S.; Siengalewicz, P.;
Martinot, T. A.; Pettit, G. R. J . Org. Chem. 2002, 67, 8726.
(11) Part of this work has been published in preliminary form, see:
Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002, 4, 1343.
(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.
10.1021/jo035371n CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/12/2003
112
J . Org. Chem. 2004, 69, 112-121

Total Synthesis of Pancratistatin
SCHEME 1. Retr osyn th etic An a lysis of
P a n cr a tista tin (1)
SCHEME 2a
trolled total synthesis of pancratistatin (1), which are
unique as compared to other previous syntheses.
Resu lts a n d Discu ssion
a
Reagents and conditions: (a) PPh3, benzene, reflux 8 h, 83%;
(b) P(OMe)3, toluene, sealed tube 180 °C, 2 h, 99%; (c) 14, 16,
n-BuLi, THF, -10 °C to rt, 1 h, 72% as a mixture of 17 and 18
(1:2.6); or 14, 16, KOH, 18-C-6, CH2Cl2, rt, 8 h, 85% as a mixture
of 17 and 18 (1:4.6); or 15, 16, LHMDS, THF, -78 °C to rt, 22 h,
60% (92% based on the recovered starting material) as a single
isomer of 17; (d) toluene, sealed tube, 250 °C, 20 h, 78%.
The initial 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 reac-
tion,12 analogous to that of Magnus et al.7 We envisioned
that the requisite cyclization precursor 5, which contains
all six of the stereocenters in the C ring, could be
stereoselectively synthesized from the simple disubsti-
tuted cyclohexene 6. The presence of a γ,δ-unsaturated
carbonyl unit in compound 6 suggested the use of a
Claisen rearrangement of 3,4-dihydro-2H-pyranylethyl-
ene 7.13 At this transformation, the relative stereochem-
istry of two substituents of the cyclohexene ring could
be controlled by the choice of the olefin configuration. The
dihydropyranylethylene 7 could be assembled from a
commercially available acrolein dimer, using a Wittig-
type reaction. On the other hand, the cyclohexene ring
of 6 could also come from the diene 8 via ring-closing
metathesis. We envisaged the diene 8 could be obtained
from an allylic ester 9 using an Ireland-Claisen rear-
rangement in which the stereochemical outcome of 8 was
significantly influenced by the reaction conditions. Fur-
ther analysis indicated that the readily available starting
materials 10 and 12, together with the commercially
available 3-butyn-2-ol (11) as a chiral source, should be
ideal synthetic precursors for the Ireland-Claisen rear-
rangement substrate 9.
Our approach commenced with the preparation of the
known phosphonium bromide 1414 from the known
bromide 13,15a as shown in Scheme 2. The bromide 13
was readily prepared from commercially available methyl
gallate via a conventional four-step sequence, following
the published procedure.15 Treatment of the obtained
phosphonium bromide 14 with n-BuLi in THF at -10 °C
formed the ylide, and then the addition of the com-
mercially available acrolein dimer 16 (1.1 equiv) provided
a mixture of olefins 18 and 17 in 72% yield with a Z/E
ratio of 2.6:1. Employing a modified Wittig reaction16
between 14 and 16 (1.1 equiv), in the presence of freshly
(14) Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R.
K.; Schmidt, J . M.; Hogan, F. J . Med. Chem. 1995, 38, 1666.
(15) (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.
(12) (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.
(13) Bu¨chi, G.; Powell, J . E., J r. J . Am. Chem. Soc. 1970, 92, 3126.
J . Org. Chem, Vol. 69, No. 1, 2004 113

Ko et al.
SCHEME 3a
disubstituted cyclohexene 22. Unfortunately, all of our
attempts with various silylating reagents, bases, and
additives18 yielded either unreacted starting material or
its silyl ketene acetal intermediate. However, when the
trans-vinyl lactone 23 was employed, the rearrangement
was accomplished efficiently to give the cis-disubstituted
cyclohexene 24. Deprotonation of 23 (LHMDS/HMPA/
THF) followed by trapping with TBSCl afforded the
corresponding silyl ketene acetal, and rearrangement of
the resulting crude material in refluxing benzene led,
after hydrolysis of the silyl ester in aqueous THF, to the
formation of 24 as the only identifiable product in 70%
overall yield.19 Access to the trans-vinyl lactone 23 was
secured by applying the PCC oxidation to trans-dihydro-
pyranethylene 17, as in the preparation of 21. Alterna-
tively, it could be prepared from its cis isomer 21 by acid-
catalyzed isomerization (CSA, CH2Cl2) at room tempera-
ture in an excellent yield (98%).
a
Reagents and conditions: (a) (i) p-TsOH, THF/H2O, 20 h, (ii)
PCC, MS 4 Å, CH2Cl2, 8 h, 80%; (b) CSA, CH2Cl2, 20 h, 98%; (c)
(i) LHMDS, TBSCl, HMPA, THF, -78 °C to rt, 5 h, (ii) benzene,
reflux, 23 h, (iii) THF/H2O (3/1), 5 h, 70%.
Through this work, in agreement with the observation
by Bu¨chi,13 we felt that dihydropyranethylene and vinyl
lactone, with a cis-oriented substituent on the aliphatic
double bond, would not undergo the Claisen rearrange-
ment under tolerable reaction conditions. As a result, we
decided to utilize a Claisen rearrangement of the trans
isomers for the total synthesis of pancratistatin. For
brevity and efficiency, the trans-dihydropyranethylene 17
would be a more desirable intermediate than the trans-
vinyl lactone 23. This issue prompted us to investigate
the selective synthesis of 17. To our satisfaction, employ-
ing the Horner-Wadsworth-Emmons reaction between
phosphonate 15 (Scheme 2) and acrolein dimer 16 (1.1
equiv) in the presence of LHMDS in THF afforded the
desired (E)-olefin 17 with very high stereoselectivity in
60% yield (92% yield based on the recovered starting
material). Only trace amounts (<1%) of the corresponding
(Z)-olefin 18 were detected in the crude 1H NMR spectra.
The requisite phosphonate 15 was prepared from the
bromide 13 with excess trimethyl phosphite in 99%
yield.20
powdered KOH and a catalytic amount of 18-crown-6 in
CH2Cl2 at room temperature, also gave the cis-olefin 18
and its trans isomer 17 with a Z/E ratio of 4.6:1 in 85%
yield. The yield and Z/E ratio with these reaction condi-
tions were higher than those produced by the reaction
described above, thus yielding more of the cis isomer 18,
which would give the trans-disubstituted cyclohexene 20
after a Claisen rearrangement.
Without further optimization, we investigated the
feasibility of a Claisen rearrangement of dihydropyran-
ethylenes 18 and 17. Heating the cis isomer at 250 °C in
a sealed tube did not provide any noticeable rearranged
product, and increasing the temperature higher than 300
°C resulted only in the formation of polymeric materials.
However, trans-dihydropyranethylene 17 (250 °C in a
sealed tube) cleanly provided the cis-disubstituted cyclo-
hexene 19 as a single isomer in 78% yield. As discussed
by Bu¨chi,13 this rearrangement must proceed through a
boatlike transition state, as depicted in TS I and II
(Scheme 2). The transition state of the trans isomer 17
(TS I) leads to the 1,2-cis-disubstituted cyclohexene 19
in a stereospecific manner. On the other hand, the
transition state of the cis isomer 18 (TS II), which leads
to the trans-disubstituted cyclohexene 20, suffers from
the severe nonbonded interactions between the cis-
oriented bulky aromatic ring (Ar) and the hydrogen
atoms of the dihydropyran ring, retarding the rate of
rearrangement.
To obtain a trans-disubstituted cyclohexene, we turned
our attention to the vinyl lactones 21 and 23 as alterna-
tive precursors (Scheme 3). The Claisen rearrangement
of lactonic enolates, compared to dihydropyrans, report-
edly occurs under remarkably mild conditions.17 There-
fore, we expected that the rearrangement of cis-vinyl
lactone 21 could be achieved, despite the severe non-
bonded interactions. The required cis-vinyl lactone 21
was easily prepared from the corresponding cis-dihydro-
pyranethylene 18 by oxidation with PCC in 80% yield.
With compound 21 in hand, we then employed the
cyclomutative variation of the Ireland ester enolate
Claisen rearrangement17,18 of 21 to gain the trans-
With a facile route to the large-scale preparation of the
cis-disubstituted cyclohexene 19, our study focused on the
selective introduction of the stereocenters in the C ring
(Scheme 4). First, the aldehyde group of 19 was oxidized
with NaClO2 to the corresponding carboxylic acid 24 (90%
yield), which had been synthesized by a different route
(Scheme 3). Iodolactonization of 24 under two-phase
conditions, followed by treatment of the resulting iodola-
ctone 25 with DBU in refluxing benzene, led to the
formation of the bicyclic lactone 26 with an overall yield
of 79%.21 Methanolysis of the lactone 26 with NaOMe at
room temperature for 18 h afforded an inseparable
equilibrium mixture (ca. 1:1 ratio) of hydroxy ester 27
and its C-4a epimer (pancratistatin numbering). How-
ever, when the methanolysis was carried out in refluxing
methanol for 20 h, epimerization of the methoxycarbonyl
(18) (a) Danishefsky, S.; Tsuzuki, K. J . Am. Chem. Soc. 1980, 102,
6891. (b) Turos E.; Audia, J . E.; Danishefsky, S. J . J . Am. Chem. Soc.
1989, 111, 8231. (c) Corey, E. J .; Guzman-Perez, A.; Lazerwith, S. E.
J . Am. Chem. Soc. 1997, 119, 11769.
(19) Ireland, R. E.; Daub, J . P. J . Org. Chem. 1981, 46, 478.
(20) J awad, A.; J acques, C.; Ingrid, H.-K.; Christian H.; Hugues,
M.; Robert, G. R. J . Med. Chem. 2000, 43, 560.
(21) Kobayashi, S.; Kamiyama, K. Ohno, M. J . Org. Chem. 1990,
55, 1169.
(16) Bellucci, G.; Chiappe, C.; Lo Moro, G. Tetrahedron Lett. 1996,
37, 4225.
(17) Danishefsky, S.; Funk, R. L.; Kerwin, J . F., J r. J . Am. Chem.
Soc. 1980, 102, 6889.
114 J . Org. Chem., Vol. 69, No. 1, 2004

Total Synthesis of Pancratistatin
SCHEME 4a
SCHEME 5a
a
Reagents and conditions: (a) 2-methyl-2-butene, NaClO2,
NaH2PO4, t-BuOH, H2O, 0 °C to rt, 18 h, 90%; (b) KI3, NaHCO3,
H2O, CH2Cl2, 20 h, 99%; (c) DBU, benzene, reflux, 8 h, 80%; (d)
NaOMe, MeOH, reflux, 20 h, 93%.
group was accomplished very cleanly to give 27 as the
only identifiable product in 93% yield.
With the ultimate aim of achieving the enantioselective
total synthesis of (+)-pancratistatin, we also studied the
efficient synthesis of the appropriately functionalized
cyclohexanes in their enantiomerically pure forms (Scheme
5). This synthesis began by preparing the known aryl
bromide 1022 from the commercially available 5-bromo-
3-methoxysalicylaldehyde, via a two-step sequence ac-
cording to the published procedure.7b The resulting aryl
bromide 10 was subjected to a palladium-catalyzed
Sonogashira coupling reaction23 with the commercially
available, enantiomerically pure (R)-3-butyn-2-ol ((R)-11),
in the presence of Et3N and CuI, to yield the optically
active propargylic alcohol (+)-29 in high yield (80%). In
this case, however, the reaction was very sluggish and
required a large excess of (R)-11 (6 equiv) for completion.
Reduction of the triple bond in (+)-29 with LiAlH4 in THF
stereoselectively provided the (E)-allylic alcohol (+)-30
in 75% yield. However, the high cost of the enantiomeri-
cally pure (R)-11 limited the utilization of this pathway.
Another attractive route for the synthesis of (+)-30 was
the utilization of the chiral building block (R)-28, (R)-
(E)-4-(tributylstannanyl)but-3-en-2-ol, for which we re-
cently reported an efficient enzymatic preparation
method.24 To our delight, the Stille coupling25 of aryl
bromide 10 with a slight excess of vinylstannane (R)-28
(>99% ee, 1.2 equiv), mediated by Pd(PPh3)4, successfully
gave the (E)-allylic alcohol (+)-30 in 84% yield.
a
Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N, MS 4
Å, 2 days, 80%; (b) LAH, THF, -78 °C to rt, 2 h, 75%; (c) Pd(PPh3)4,
DMF, 65 °C, 24 h, 84%; (d) 12, DCC, DMAP, CH2Cl2, 93%; (e) LDA,
HMPA, THF, TBSCl, -78 °C to rt, 77% as a mixture of 31 and 32
(6:1); (f) 33, CH2Cl2, 91% as a mixture of 24 and 22 (6:1); (g) KI3,
NaHCO3, H2O, CH2Cl2, 20 h, 76%.
HMPA/THF at -78 °C, with gradual warming to room
temperature to promote the rearrangement. After an
acidic workup, this reaction predominantly afforded the
desired acid 31, along with a minor amount of the
stereoisomer 32,28 in 77% combined yield and 6:1 selec-
tivity, as shown in Scheme 5. The relative stereochem-
istry of the newly generated stereocenters of 31 was
established by its conversion to (+)-25, and this stereo-
chemical outcome can be rationalized by invoking Ire-
land’s chairlike transition state27d geometry, as shown
in A.
The ring-closing metathesis of the inseparable mixture
of 31 and 32 with Grubbs’s catalyst29 33 in CH2Cl2 at
room temperature produced the inseparable disubstitut-
ed cyclohexenes 24 and 22, in 91% combined yield.
Iodolactonization of a mixture of 24 and 22, under the
Acylation of the resulting secondary alcohol (+)-30 with
the commercially available 5-hexenoic acid 12 under
Steglich’s DCC coupling conditions26 provided (+)-9
(93%), which was subjected to the Ireland ester enolate
Claisen rearrangement.19,27 Best results were obtained
when (+)-9 was exposed to LDA and TBSCl in 20%
(22) Shirasaka, T.; Takuma, Y.; Imaki, N. Synth. Commun. 1990,
20, 1223.
(23) (a) Sonogashira, K.; Thoda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) Morita, S.; Otsubo, K.; Matsubara, J .; Ohtani, T.;
Uchida, M. Tetrahedron: Asymmetry 1995, 6, 245.
(24) Lee, T.; Kim, S. Tetrahedron: Asymmetry 2003, 14, 1951.
(25) (a) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Geoffrey T. C.; Peter, T. C. Tetrahedron 1994, 50, 3213.
(26) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
52.
(27) (a) Ireland, R. E.; Mueller, R. H. J . Am. Chem. Soc. 1972, 94,
5897. (b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J . Am. Chem.
Soc. 1976, 98, 2868. (c) Ireland, R. E.; Norbeck, D. W. J . Am. Chem.
Soc. 1985, 107, 3279. (d) Ireland, R. E.; Wipf, P.; Armstrong, J . D. J .
Org. Chem. 1991, 56, 650.
(28) When (+)-9 was exposed to LDA and TBSCl in THF at -78 °C
with warming to room temperature, the only detectable stereoisomer
was the acid 32 (<30%).
J . Org. Chem, Vol. 69, No. 1, 2004 115

Ko et al.
SCHEME 6a
a
Reagents and conditions: (a) 1 N LiOH, THF, rt, 18 h, 99%; (b) (i) DPPA, Et3N, toluene, reflux, 15 h, (ii) NaOMe, MeOH, reflux, 0.5
h, 82%; (c) BzCl, Et3N, DMAP, CH2Cl2, rt, 15 h, 99%; (d) OsO4, NMO, THF/H2O, rt, 20 h, 96%; (e) (i) SOCl2, Et3N, CH2Cl2, 0 °C, 0.5 h,
(ii) Oxone, RuCl3‚3H2O, EtOAc/CH3CN/H2O, rt, 2 h, 83%; (f) DBU, toluene, reflux, 2 h, then H2SO4, H2O/THF, rt, 4 h, 67%; (g) OsO4,
NMO, THF/H2O, rt, 27 h, 88%; (h) (i) Ac2O, DMAP, pyridine, CH2Cl2, rt, 1 h, 77%, (ii) Tf2O, DMAP, CH2Cl2, 0 °C to 5 °C, 22 h, 78% as
a mixture of 43 and 42 (7:1); (i) BBr3, CH2Cl2, -78 to 0 °C, 1 h, 65%; (j) NaOMe, MeOH, THF, rt, 4 h, 83%.
same conditions used previously (Scheme 4), provided the
tion/regioselective rearrangement of epoxide to allylic
alcohol process.31 At this stage, it was necessary to protect
the free hydroxyl group of 35 to selectively install the
C-2 hydroxyl group on the R-face. This was accomplished
by treating compound 35 with benzoyl chloride to furnish
36 in 99% yield. Attempted epoxidations of 36 to 37 with
various reagents, such as m-CPBA and dioxiranes, were
not successful and provided only decomposed materials,
presumably due, in part, to the electron-rich nature of
iodolactone (+)-25 (76%) and unreacted 22 (13%), which
1
were now separable. The H and 13C NMR spectroscopic
data of (+)-25 (>99% ee by chiral HPLC analysis) were
identical to those of the racemate synthesized by a
different route.
Although this enantioselective pathway provided a
shorter synthetic route to the intermediate 24 with a
reasonably high overall yield, as compared to the racemic
synthesis, it was operationally more difficult for scale-
up than the racemic pathway and yielded an inseparable
mixture of diastereomers during the Ireland-Claisen
rearrangement. These issues led us to utilize the racemic
route to complete the total synthesis of pancratistatin.
With multigram quantities of 27 in hand, we began
the second stage of our synthesis of pancratistatin by
converting the ester functional group of 27 to the amine
(Scheme 6). To this end, saponification of the methyl ester
27 with LiOH was followed by a modified Curtius
rearrangement30 of the resulting acid 34 with diphen-
ylphosphoryl azide in refluxing toluene, to give a rather
stable isocyanate intermediate. This required further
treatment with NaOMe/MeOH to generate the corre-
sponding carbamate 35 in 82% overall yield.
the aromatic ring. However, dihydroxylation of the ∆2,3
-
olefin with OsO4 did occur on the desired R-face of the
molecule to produce diol 38 in an excellent yield (96%).
Thus, we decided to use 38 as an intermediate for this
transformation. To our delight, the regioselective elimi-
nation of the C-3 hydroxyl group of the diol 38, to
generate the requisite ∆3,4 unsaturation, could be achieved
by employing the cyclic sulfate elimination reaction.32
Treatment of diol 38 with thionyl chloride followed by
oxidation with RuCl3‚3H2O/Oxone33 provided the corre-
sponding cyclic sulfate 39 in 83% yield. The reaction of
cyclic sulfate 39 with DBU in refluxing toluene32a led,
after acidic workup, to the formation of the desired allylic
alcohol 40 (67% yield). Finally, routine cis-dihydroxyla-
tion of 40 with OsO4 afforded the single isomer 41 in 88%
yield, thereby completing the functionalization of the C
Initially, we explored the functional group transforma-
tion of the ∆2,3-olefin of 35 to the C-2R hydroxy ∆3,4-olefin
of 40 by employing a sequential stereoselective epoxida-
(31) For a good review of this transformation, see: Smith, J . G.
Synthesis 1984, 629.
(32) For the elimination reaction of an 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.
(33) Robins, M. J .; Lewandowska, E.; Wnuk, S. F. J . Org. Chem.
1998, 63, 7375.
(29) (a) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J . Am.
Chem. Soc. 1997, 119, 3887.
(30) (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.;
J ohnson, J . S.; Ripin, D. H. B.; Tedrow, J . S. J . Org. Chem. 1999, 64,
6411.
116 J . Org. Chem., Vol. 69, No. 1, 2004

Total Synthesis of Pancratistatin
274 (M+, 42), 165 (100); HRMS-EI (calcd for C11H15O6P)
274.0606, found 274.0609.
ring of pancratistatin. The structural assignment made
for this compound was strongly supported by its relevant
1H NMR coupling patterns and by comparing the 1H
NMR spectral data of the derived tetraacetate with those
reported by Magnus.7
(E )-6-[2-(3,4-Dih yd r o-2H -p yr a n -2-yl)vin yl]-4-m e t h -
oxyben zo[1,3]d ioxole (17). To a solution of phosphonate 15
(300 mg, 1.16 mmol) in THF (4 mL) was added LHMDS (2.0
mL, 1.0 M in THF) at -78 °C. After this mixture was warmed
to 0 °C over 1 h, acrolein dimer 16 (134 mg, 1.27 mmol) in
THF (2 mL) was added slowly. The resulting mixture was
allowed to warm to room temperature and stirred for 22 h.
The reaction was quenched with brine (6 mL) and extracted
with EtOAc (15 mL × 2). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 10:1) to give the desired compound 17 (181
mg, 60%; 92% based on the recovered starting material) as
colorless oil, along with a recovered starting material 15 (105
mg): IR (film) νmax 2924.4, 2853.0, 1736.1, 1626.1, 1508.5,
1450.6, 1429.4, 1356.1, 1319.4, 1261.6, 1240.3, 1197.9, 1136.2,
Efforts were next directed toward the Bischler-Napi-
eralski cyclization to introduce the B ring. The remaining
steps to pancratistatin required protection of the hydroxyl
groups, formation of the final lactam B ring, and protect-
ing group removal. These steps were accomplished by
employing reaction conditions analogous to those of
Magnus et al.7 Peracetylation of 41 (77%) was followed
by Banwell’s modified Bischler-Napieralski cycliza-
tion,7,12 which predominantly provided the desired prod-
uct 43, along with a minor amount of the regioisomer
42, in 78% combined yield and 7:1 regioselectivity.
Treatment of the inseparable mixture of 43 and 42 with
BBr3, to remove the C-7 methyl group protection, yielded
44 (65%) and unreacted 42, which were now separable.34
Finally, simple removal of the protecting groups with
1
1091.8, 1045.5 cm-1; H NMR (CDCl3, 300 MHz) δ 1.64-1.77
(m, 1H), 1.88-2.08 (m, 3H), 3.83 (s, 3H), 4.39 (dddd, J ) 8.4,
4.8, 2.1, 0.9 Hz, 1H), 4.67 (dddd, J ) 4.5, 2.7, 2.7, 1.2 Hz, 1H),
5.89 (s, 2H), 6.04 (dd, J ) 15.9, 6.3 Hz, 1H), 6.36 (dt, J ) 6.3,
1.8 Hz, 1H), 6.45 (dd, J ) 15.9, 1.2 Hz, 1H), 6.48 (d, J ) 1.5
Hz, 1H), 6.56 (d, J ) 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 19.4, 28.3, 56.5, 75.2, 100.1, 100.5, 101.5, 106.7, 127.8, 130.6,
131.6, 143.4, 143.5, 149.0, 149.4; MS-EI m/z (rel int) 260 (M+,
62), 203 (100), 204 (96), 165 (92); HRMS-EI (calcd for C15H16O4)
260.1049, found 260.1045.
1
NaOMe/MeOH afforded (()-1 in 83% yield, 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
total synthesis of (()-pancratistatin in 17 steps with an
overall yield of 5.8% from readily available starting
material 13. We have also developed an efficient syn-
thetic pathway to the important intermediate 24 in
enantiomerically pure form, thus showing that our ap-
proach could yield the enantioselective synthesis of (+)-
pancratistatin. Several aspects of our approach differ
significantly from other previous efforts. First, we utilized
the Claisen rearrangement/Ireland-Claisen rearrange-
ment as a key step to construct the A and C rings with
the appropriate stereochemistry. In addition, the problem
of installing six contiguous stereogenic centers in the C
ring was successfully addressed in our approach, prima-
rily due to the use of a cyclic sulfate elimination reaction.
2-(7-Meth oxyben zo[1,3]d ioxol-5-yl)cycloh ex-3-en eca r -
ba ld eh yd e (19). Dihydropyranethylene 17 (2.98 g, 10 mmol)
was dissolved in toluene (150 mL). This solution was trans-
ferred to a sealed tube, degassed with N2 gas, and heated at
250 °C in a sand bath for 20 h. The reaction mixture was cooled
to room temperature, evaporated, and purified by column
chromatography on silica gel (hexane/EtOAc ) 10:1) to give
aldehyde 19 (2.26 g, 78%) as a yellowish solid: mp 78-79 °C;
IR (KBr) νmax 1711.0, 1633.9, 1512.3, 1452.5, 1431.3, 1358.0,
1317.5, 1194.0, 1151.6, 1122.7, 1093.7, 1043.6 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.82-1.89 (m, 2H), 2.07-2.32 (m, 2H),
2.72 (dddd, J ) 8.1, 6.0, 6.0, 2.4 Hz, 1H), 3.85-3.90 (m, 1H),
3.87 (s, 3H), 5.77 (dddd, J ) 9.9, 4.5, 2.4, 1.8 Hz, 1H), 5.93 (s,
2H), 5.95-6.00 (m, 1H), 6.36 (d, J ) 1.5 Hz, 1H), 6.41 (dd, J
) 1.5, 0.3 Hz, 1H), 9.52 (d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 18.7, 23.5, 41.4, 50.8, 56.7, 101.4, 103.4, 109.0,
127.9, 128.7, 134.2, 134.6, 143.3, 148.9, 204.6; MS-EI m/z (rel
int) 260 (M+, 100), 232 (92), 203 (78), 178 (49), 173 (46), 152
(76); HRMS-EI (calcd for C15H16O4) 260.1049, found 260.1040.
Exp er im en ta l Section
Gen er a l Rem a r k s. All chemicals were reagent grade and
used as purchased. All reactions were performed under an
inert atmosphere of dry argon or nitrogen using distilled dry
solvents. Reactions were monitored by TLC analysis. Flash
column chromatography was carried out on silica gel (230-
400 mesh). Melting points are uncorrected. Optical rotations
were measured using sodium light (D line 589.3 nm).
(7-Met h oxyb en zo[1,3]d ioxol-5-ylm et h yl)p h osp h on ic
Acid Dim eth yl Ester (15). A mixture of bromide 1315 (90 mg,
0.37 mmol), trimethyl phosphite (0.5 mL, 4.24 mmol), and
toluene (0.5 mL) in a sealed tube was heated at 180 °C in an
oil bath for 2 h. After the mixture was cooled, the excess
trimethyl phosphite was removed in vacuo. Purification of the
residue by short flash column chromatography on silica gel
(eluent: EtOAc) gave 94 mg (99%) of 15 as colorless oil: IR
(film) νmax 1633.9, 1510.4, 1452.5, 1435.2, 1358.0, 1319.4,
1244.2, 1196.0, 1134.3, 1093.7, 1033.9 cm-1; 1H NMR (CDCl3,
300 MHz) δ 3.02 (d, J ) 21.3 Hz, 2H), 3.640 (d, J ) 10.8 Hz,
3H), 3.644 (d, J ) 10.8 Hz, 3H), 3.84 (s, 3H), 5.90 (s, 2H), 6.41-
6.43 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 31.6, 33.5, 52.7 (d,
J cp ) 6.8 Hz), 56.4, 101.3, 104.0 (d, J cp ) 6.5 Hz), 109.0 (d, J cp
) 7.4 Hz), 125.0 (d, J cp ) 9.1 Hz), 134.2 (d, J cp ) 3.7 Hz), 143.4
(d, J cp ) 3.2 Hz), 148.8 (d, J cp ) 3.2 Hz); MS-EI m/z (rel int)
2-(7-Meth oxyben zo[1,3]d ioxol-5-yl)cycloh ex-3-en eca r -
boxylic Acid (24). From 19: To a solution of aldehyde 19
(1.54 g, 5.9 mmol) in t-BuOH-H2O (1:1, 20 mL) were added
2-methyl-2-butene (60 mL, 2.0 M in THF), NaClO2 (3.2 g, 35.4
mmol), and NaH2PO4‚2H2O (1.5 g, 17.7 mmol) at 0 °C. The
reaction mixture was stirred for 18 h at room temperature. It
was concentrated until THF was removed and extracted with
EtOAc (25 mL × 3). The combined organic layers were washed
with brine, dried over Na2SO4, and evaporated under reduced
pressure. The subsequent residue was treated with hexane/
EtOAc (5:1, 20 mL). After it was stirred for 1 h, the generated
white solids were filtered, washed with hexane/EtOAc (7:1, 10
mL) twice and dried in vacuo to give carboxylic acid 24 (1.47
g, 90%) as a white solid: mp 181-182 °C; IR (KBr) νmax 2926.3,
1695.6, 1631.9, 1512.3, 1452.5, 1433.2, 1359.9, 1317.5, 1263.5,
1240.3, 1184.4, 1120.7, 1093.7, 1045.5 cm-1; 1H NMR (pyridine-
d5, 300 MHz) δ 1.95-2.19 (m, 4H), 3.06 (m, 1H), 3.68 (s, 3H),
4.09 (t, J ) 4.5 Hz, 1H), 5.81 (m, 1H), 5.84 (d, J ) 1.2 Hz,
1H), 5.85 (d, J ) 1.2 Hz, 1H), 5.89-5.93 (m, 1H), 6.82 (d, J )
1.2 Hz, 1H), 6.83 (d, J ) 1.2 Hz, 1H); 13C NMR (pyridine-d5,
75 MHz) δ 19.7, 25.2, 43.0, 45.7, 56.5, 101.6, 104.5, 110.7,
128.5, 128.9, 134.7, 135.9, 143.6, 149.1, 176.0; MS-EI m/z (rel
int) 276 (M+, 100), 230 (50), 204 (86), 203 (90), 173 (40), 152
(30); HRMS-EI (calcd for C15H16O5) 276.0998, found 276.0987.
(34) This reaction was patterned after a similar step in the Magnus
synthesis.7
J . Org. Chem, Vol. 69, No. 1, 2004 117

Ko et al.
4-Iod o-8-(7-m eth oxben zo[1,3]d ioxol-5-yl)-6-oxa bicyclo-
[3.2.1]octa n -7-on e (25). To a solution of carboxylic acid 24
(863 mg, 3.12 mmol) in CH2Cl2 (10 mL) were added 1 N
NaHCO3 solution (15 mL) and aqueous KI3 solution (40 mL,
KI: 24.3 g, 36.5 mmol, I2: 12.1 g, 16.5 mmol) at room
temperature. The mixture was stirred for 20 h and poured into
saturated aqueous Na2S2O3 solution. This reaction mixture
was extracted with EtOAc (50 mL × 2), and the combined
organic layers were washed with brine, dried over Na2SO4, and
evaporated. The crude product was purified by column chro-
matography on silica gel (hexane/EtOAc ) 1:1) to give the
iodolactone 25 (1.24 g, 99%) as colorless oil: IR (film) νmax
1784.3, 1633.9, 1512.3, 1452.5, 1325.2, 1122.7, 1091.8, 1045.5,
12 h, additional (R)-11 (0.048 mL, 0.6 mmol) was added once
more for completion. The mixture was cooled to room temper-
ature and filtrated through Celite. The filtrate was purified
by column chromatography on silica gel (CH2Cl2/MeOH ) 20:
1) to produce (+)-29 (54 mg, 80%) as yellowish oil: [R]33
)
D
+1.59 (c 2.5, CHCl3); IR (film) νmax 1624.2, 1506.5, 1448.7,
1429.4, 1352.2 1311.7, 1211.4, 1157.4, 1107.2, 1047.4 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 1.52 (d, J ) 6.6 Hz, 3H), 2.27 (br s,
1H), 3.86 (s, 3H), 4.72 (q, J ) 6.6 Hz, 1H), 5.96 (s, 2H), 6.58
(d, J ) 1.2 Hz, 1H), 6.62 (d, J ) 1.2 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 24.4, 56.5, 58.8, 83.9, 89.3, 101.7, 105.9, 111.7,
116.0, 136.1, 143.4, 148.5; MS-EI m/z (rel int) 220 (M+, 99),
205 (80), 175 (60), 147 (63), 119 (100); HRMS-EI (calcd for
1
958.7 cm-1; H NMR (CDCl3, 300 MHz) δ 1.91-2.12 (m, 3H),
C
12H12O4) 220.0736, found 220.0730.
2.31-2.45 (m, 1H), 2.78 (br s, 1H), 3.83 (s, 3H), 4.01 (s, 1H),
4.58 (t, J ) 4.8 Hz, 1H), 4.72 (d, J ) 4.2 Hz, 1H), 5.89 (s, 2H),
6.29 (d, J ) 1.5 Hz, 1H), 6.37 (d, J ) 1.5 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 24.4, 24.5, 29.1, 45.0, 50.3, 56.8, 85.3, 100.9,
101.6, 106.4, 133.8, 134.6, 143.8, 149.5, 177.1; MS-EI m/z (rel
int) 402 (M+, 100), 403 (17) 165 (21); HRMS-EI (calcd for
(R)-4-(7-Meth oxyben zo[1,3]dioxol-5-yl)bu t-3-en -2-ol ((+)-
30). From (+)-29: To a solution of (+)-29 (290 mg, 1.3 mmol)
in THF (5 mL) at -78 °C was slowly added LAH (2.8 mL, 1.0
M in Et2O). The reaction mixture was allowed to warm to room
temperature for 2 h. H2O (0.08 mL), 10% aqueous NaOH
solution (0.08 mL), and H2O (0.25 mL) were added in order to
the mixture. This resulting mixture was filtrated through a
glass funnel packed with Celite. The filtrate was extracted
with EtOAc twice, washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by column chromatog-
raphy on silica gel (hexane/EtOAc ) 4:1) to give (+)-30 (220
mg, 75%) as a colorless oil.
C
15H15IO5) 401.9964, found 401.9948.
8-(7-Meth oxyben zo[1,3]d ioxol-5-yl)-6-oxa bicyclo[3.2.1]-
oct-3-en -7-on e (26). The iodolactone 25 (1.24 g, 3.08 mmol)
was dissolved in benzene (20 mL) and added DBU (0.5 mL,
3.34 mmol). The mixture was heated to reflux for 8 h and then
cooled to room temperature. The precipitate was filtered off
and filterate was diluted with EtOAc. This solution was
washed with 1 N HCl aqueous solution and brine, dried over
Na2SO4, and evaporated. The subsequent residue was treated
with hexane/EtOAc (2:1, 10 mL). After 2 min, it gave rise to
precipitate and solidified. After it was stirred for 1 h, the
generated white solids were filtered, washed with hexane/
EtOAc (3:1, 5 mL) twice, and dried in vacuo to give 26 (668
mg, 80%) as a white solid: mp 142-144 °C; IR (KBr) υmax
1765.0, 1633.9, 1516.2, 1460.3, 1433.3, 1371.5, 1327.1, 1250.0,
1199.8, 1147.8, 1130.4, 1093.7, 1041.7 cm-1; 1H NMR (CDCl3,
300 MHz) δ 2.54 (m, 1H), 2.65 (m, 1H), 2.94 (br s, 1H), 3.38
(s, 1H), 3.81 (s, 3H), 4.69 (dt, J ) 5.7, 0.9 Hz, 1H), 5.83-5.86
(m, 1H), 5.88 (s, 2H), 6.26-6.32 (m, 1H), 6.33 (d, J ) 1.5 Hz,
1H), 6.38 (d, J ) 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ
30.9, 44.8, 50.6, 56.7, 78.0, 101.1, 101.5, 106.5, 130.1, 130.5,
134.1, 134.6, 143.8, 149.4, 178.5; MS-EI m/z (rel int) 274 (92),
246 (60), 178 (100); HRMS-EI (calcd for C15H14O5) 274.0841,
found 274.0852.
5-Hydr oxy-6-(7-m eth oxyben zo[1,3]dioxol-5-yl)cycloh ex-
3-en eca r boxylic Acid Meth yl Ester (27). The mixture of
olefinic lactone 26 (1.49 g, 5.43 mmol) and NaOMe/MeOH (55
mL, 0.5 M in MeOH) was heated to reflux for 20 h and then
cooled to room temperature. The reaction was quenched with
saturated aqueous NH4Cl solution (20 mL) and extracted with
EtOAc (25 mL × 3). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated. The resulting
residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 3:2) to give 27 as yellowish oil (1.55 g,
93%): IR (film) νmax 3520.4, 1732.2, 1633.9, 1510.4, 1433.2,
1315.6, 1194.0, 1138.1, 1091.8, 1043.6 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.48 (d, J ) 3.6 Hz, 1H), 2.34 (m, 1H), 2.52 (m,
1H), 3.07 (dd, J ) 12.3, 3.3 Hz, 1H), 3.22 (ddd, J ) 12.3, 10.8,
5.1 Hz, 1H), 3.53 (s, 3H), 3.89 (s, 3H), 4.11 (br s, 1H), 5.94-
5.97 (m, 4H), 6.44 (d, J ) 1.5 Hz, 1H), 6.48 (d, J ) 1.5 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 30.1, 38.9, 48.3, 51.5, 56.4,
66.6, 101.3, 102.5, 107.8, 127.5, 128.7, 134.1, 134.4, 143.4,
148.8, 175.4; MS-EI m/z (rel int) 306 (M+, 7), 236 (100), 205
(20); HRMS-EI (calcd for C16H18O6) 306.1103, found 306.1104.
From 10: To a solution of (R)-2824 (1.3 g, 3.6 mmol) in DMF
(10 mL) were added aryl bromide 10 (566 mg, 2.45 mmol) and
Pd(PPh3)4 (283 mg, 0.25 mmol) under N2 atmosphere. The
mixture was heated to 65 °C for 24 h. After the mixture was
cooled to room temperature, it was washed with 10% aqueous
KF solution and extracted with EtOAc four times. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated. The residue was purified by column
chromatography on silica gel (hexane/EtOAc ) 3:1) to give the
desired compound (+)-30 (460 mg, 84%) as colorless oil: [R]20
D
) +91.2 (c 3.4, CHCl3); IR (film) νmax 3379.6, 1626.1, 1510.4,
1450.6, 1431.3, 1356.1, 1321.4, 1238.4, 1197.9, 1136.2, 1091.8,
1045.5, 964.5 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.34 (d, J )
6.6 Hz, 3H), 1.94 (br s, 1H), 3.88 (s, 3H), 4.44 (ddq, J ) 6.6,
0.9, 6.3 Hz, 1H), 5.94 (s, 2H), 6.08 (dd, J ) 15.6, 6.3 Hz, 1H),
6.42 (d, J ) 16.2 Hz, 1H), 6.51 (d, J ) 1.5 Hz, 1H), 6.58 (d, J
) 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 23.4, 56.5, 68.7,
100.0, 101.4, 106.6, 129.0, 131.6, 132.3, 134.9, 143.5, 149.0;
MS-EI m/z (rel int) 222 (M+, 92), 179 (100), 165 (48), 149 (38);
HRMS-EI (calcd for C12H14O4) 222.0892, found 222.0895.
(R)-Hex-5-en oic Acid 3-(7-Meth oxyben zo[1,3]d ioxol-5-
yl)-1-m eth yla llyl Ester ((+)-9). To a solution of (+)-30 (1.05
g, 4.7 mmol) in CH2Cl2 (12 mL) were added hexenoic acid 12
(0.67 mL, 5.6 mmol), DMAP (0.17 g, 1.4 mmol), and DCC (1.36
g, 6.6 mmol) at 0 °C. The reaction mixture was stirred for 2 h
at room temperature followed by dilution with hexane. The
generated white precipitate was removed by filtration through
Celite. The residue was purified by column chromatography
on silica gel (hexane/EtOAc ) 15:1) to give (+)-9 (1.4 g, 93%)
as a colorless oil: [R]20 ) +89.9 (c 3.6, CHCl3); IR (film) νmax
D
1730.3, 1626.1, 1510.4, 1450.6, 1431.3, 1358.0, 1319.4, 1242.3,
1199.8, 1138.1, 1093.7, 1043.6 cm-1 1H NMR (CDCl3, 300
;
MHz) δ 1.38 (d, J ) 6.6 Hz, 3H), 1.73 (m, 2H), 2.09 (m, 2H),
2.32 (t, J ) 7.5 Hz, 2H), 3.89 (s, 3H), 4.95-5.05 (m, 2H), 5.55
(ddq, J ) 6.9, 0.9, 6.6 Hz, 1H), 5.77 (dddd, J ) 17.1, 10.2, 6.6,
6.6 Hz, 1H), 5.95 (s, 2H), 6.51 (dd, J ) 15.9, 6.9 Hz, 1H), 6.47
(d, J ) 15.6 Hz, 1H), 6.52 (d, J ) 1.5 Hz, 1H), 6.60 (d, J ) 1.2
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.4, 24.0, 33.0, 33.8,
56.5, 70.7, 100.0, 101.5, 106.9, 115.3, 127.6, 131.2, 131.3, 135.1,
137.6, 143.5, 149.1, 172.7; MS-EI m/z (rel int) 318 (M+, 75),
319 (17), 222 (100), 221 (64), 205 (88), 179 (70), 175 (90);
HRMS-EI (calcd for C18H22O5) 318.1467, found 318.1468.
(R)-4-(7-Meth oxyben zo[1,3]dioxol-5-yl)bu t-3-yn -2-ol ((+)-
29). To the predried mixture of bromide 10 (70 mg, 0.3 mmol),
copper iodide (6 mg, 0.03 mmol), dichlorobis(triphenylphos-
phine)palladium(II) (21 mg, 0.03 mmol), and molecular sieves
4 Å (200 mg) were added triethylamine (3 mL) and (R)-(+)-3-
butyn-2-ol ((R)-11) (0.048 mL, 0.6 mmol). The mixture was
heated to 60 °C for 24 h, and then (R)-11 (0.048 mL, 0.6 mmol)
was added again. After the reaction mixture was heated for
(2RS,3S)-2-Bu t-3-en yl-3-(7-m eth oxyben zo[1,3]d ioxol-5-
yl)h ex-4-en oic Acid ((2R,3S)-31 a n d (2S,3S)-32). To a
stirred solution of (+)-9 (300 mg, 0.94 mmol) in THF (11 mL)
and HMPA (4.4 mL) was added TBSCl (213 mg, 1.4 mmol) in
118 J . Org. Chem., Vol. 69, No. 1, 2004

Total Synthesis of Pancratistatin
THF (3 mL). After the mixture was cooled to -78 °C, LDA
(3.8 mL, 0.5 M in THF) was slowly added. The reaction mixture
was slowly warmed to room temperature and stirred for 15 h.
It was acidified to pH 2-3 with 1 N HCl aqueous solution and
extracted with EtOAc twice. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography on silica gel
(hexane/EtOAc ) 3:1) to give inseparable 31 and 32 (232 mg,
77%) as colorless oil. 1H NMR analysis of crude reaction
mixture indicated a 6:1 mixture of two stereoisomers 31 and
32, respectively: IR (film) νmax 2937.9, 1705.2, 1633.9, 1510.4,
1452.5, 1433.2 cm-1; 1H NMR of a major 31 (CDCl3, 300 MHz)
δ 1.28-1.39 (m, 1H), 1.51-1.59 (m, 1H), 1.61 (d, J ) 5.2 Hz,
3H), 1.88-2.11 (m, 2H), 2.64 (ddd, J ) 10.8, 10.8, 3.6 Hz, 1H),
3.28 (dd, J ) 10.5, 7.8 Hz, 1H), 3.90 (s, 3H), 4.92-5.01 (m,
2H), 5.45-5.74 (m, 3H), 5.94 (s, 2H), 6.33 (d, J ) 1.2 Hz, 1H),
6.37 (d, J ) 1.5 Hz, 1H); 13C NMR of a major 31 (CDCl3, 75
MHz) δ 17.8, 29.7, 31.5, 51.3, 52.1, 56.6, 101.3, 101.5, 107.4,
115.4, 126.7, 131.8, 133.8, 136.5, 137.3, 143.6, 149.1, 181.2;
MS-EI m/z (rel int) 318 (M+, 17), 205 (100), 175 (92), 147 (31);
HRMS-EI (calcd for C18H22O5) 318.1467, found 318.1464.
(1RS,2S)-2-(7-Meth oxyben zo[1,3]d ioxol-5-yl)cycloh ex-
3-en eca r boxylic Acid ((1R,2S)-24 a n d (1S,2S)-22). To a
solution of the inseparable mixture of 31 and 32 (100 mg, 0.31
mmol) in CH2Cl2 was added Grubbs’s catalyst 33 (12.8 mg,
0.016 mmol). The reaction mixture was stirred for 1 h at room
temperature and concentrated. The crude residue was purified
by column chromatography on silica gel (hexane/EtOAc ) 5:2)
to give 22 and desired compound 24 (79 mg, 91%) as white
solids. 1H NMR analysis of clude reaction mixture indicated a
1:6 mixture of two stereoisomers 22 and 24, respectively.
(1R,4R,5S,8R)-4-Iod o-8-(7-m eth oxyben zo[1,3]d ioxol-5-
yl)-6-oxa bicyclo[3.2.1]octa n -7-on e ((+)-25). To a solution
of carboxylic acid 24 and 22 (88.5 mg, 0.32 mmol) in CH2Cl2
(2 mL) were added 1 N NaHCO3 aqueous solution (1.5 mL)
and KI3 aqueous solution (4 mL, KI:2.5 g, 37 mmol, I2:1.1 g,
16 mmol) at room temperature. The mixture was stirred for
20 h and poured into saturated aqueous Na2S2O3 solution. This
reaction mixture was extracted with EtOAc (10 mL × 2). The
combined organic layers were washed with brine, dried over
Na2SO4, and evaporated. The crude product was purified by
column chromatography on silica gel (hexane/EtOAc ) 1:1) to
separate the iodolactone (+)-25 (98 mg, 76%) as colorless oil
and unreacted compound 22. The enantiopurity was deter-
mined by chiral HPLC analysis (CHIRALCEL OD-H, hexane/
2-propanol (99.5:0.5, v/v), flow rate: 0.5 mL/min, retention
time: 44.7 min (+)-isomer, detected at 254 nm): [R]20D ) +69.3
(c 2.0, CHCl3).
carboxylic acid 34 (1.04 g, 3.6 mmol), triethylamine (1.49 mL,
10.7 mmol), and diphenylphosphoryl azide (2.3 mL, 10.6 mmol)
in toluene (42 mL) was stirred at room temperature for 20 min
until the solution was clear. This reaction mixture was heated
slowly to reflux for 15 h and cooled to room temperature. Then
the mixture was diluted with EtOAc. It was washed with
saturated aqueous NH4Cl solution and brine and dried over
Na2SO4. This crude product was evaporated and chromato-
graphed on a silica gel column (hexane/EtOAc ) 3:2) to give
isocyanate intermediate (IR 2442, 1691 cm-1). This intermedi-
ate was dissolved in MeOH (40 mL), and NaOMe (0.33 mg,
6.1 mmol) was added. The reaction mixture was heated to
reflux for 30 min and then cooled to room temperature. The
reaction was quenched with saturated aqueous NH4Cl solution
and diluted with EtOAc. It was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The resulting
residue was purified by column chromatography (hexane/
EtOAc ) 3:2) to give colorless syrup 35 (938 mg, 82%): IR
(film) νmax 3321.7, 1699.4, 1512.3, 1286.6, 1134.3, 1059.0 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.95 (m, 1H), 2.71 (dt, J ) 17.4,
4.2 Hz, 1H), 2.79 (dd, J ) 12.0, 3.3 Hz, 1H), 3.52 (br s, 3H),
3.81 (s, 3H), 4.12 (t, J ) 3.3 Hz, 1H), 4.23 (br s, 1H), 4.39 (br
d, J ) 8.1 Hz, 1H), 5.84 (dt, J ) 4.5, 1.8 Hz, 2H), 5.88 (s, 2H),
6.40-6.42 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 33.3, 44.0,
51.1, 51.2, 55.6, 67.7, 100.4, 102.2, 107.5, 126.7, 128.2, 131.6,
133.4, 142.7, 148.1, 155.6; MS-EI m/z (rel int) 321 (M+, 4), 251
(48), 228 (100), 219 (32), 127 (27); HRMS-EI (calcd for C16H19
NO6) 321.1212, found 321.1212.
-
Ben zoic Acid 6-(7-Met h oxyb en zo[1,3]d ioxol-5-yl)-5-
m eth oxyca r bon yla m in ocycloh ex-2-en yl Ester (36). To a
solution of methyl ester 35 (677 mg, 2.11 mmol) in dry CH2-
Cl2 (30 mL) was added DMAP (77 mg, 0.63 mmol), triethyl-
amine (0.88 mL, 6.31 mmol), and benzoyl chloride (0.47 mL,
4.05 mmol). The reaction mixture was stirred at room tem-
perature for 15 h. Then, it was diluted with EtOAc and washed
with 1 N HCl and saturated aqueous NaHCO3 solution. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by column chromatog-
raphy (hexane/EtOAc ) 3:2) to give 36 (893 mg, 99%) as
colorless oil: IR (film) νmax 1711.0, 1535.5, 1340.7, 1269.3,
1111.1, 1057.1 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.05 (dd, J
) 18.9, 9.6 Hz, 1H), 2.81 (dt, J ) 17.7, 3.6 Hz, 1H), 2.99 (dd,
J ) 12.0, 3.6 Hz, 1H), 3.53 (br s, 3H), 3.55 (s, 3H), 4.52 (br s,
2H), 5.56 (t, J ) 3.9 Hz, 1H), 5.78 (d, J ) 1.5 Hz, 1H), 5.80 (d,
J ) 1.5 Hz, 1H), 5.82-5.94 (m, 2H), 6.39 (s, 2H), 7.31-7.37
(m, 2H), 7.43-7.49 (m, 1H), 7.89-7.93 (m, 2H); 13C NMR
(CDCl3, 75 MHz) δ 34.2, 45.9, 50.2, 52.1, 56.1, 70.9, 101.3,
103.5, 108.2, 124.9, 128.3, 129.5, 130.1, 131.1, 131.6, 132.9,
134.3, 143.3, 148.6, 156.6, 165.3; MS-EI m/z (rel int) 425 (M+,
5-Hydr oxy-6-(7-m eth oxyben zo[1,3]dioxol-5-yl)cycloh ex-
3-en eca r boxylic Acid (34). To a solution of ester 27 (1.0 g,
3.26 mmol) in THF (15 mL) was added 1 N LiOH aqueous
solution (20 mL). After being stirred at room temperature for
18 h, the solution was acidified to pH 2 with 1 N HCl aqueous
solution. It was diluted with EtOAc. The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(25 mL × 3). The combined organic layers were washed with
brine, dried over Na2SO4, and evaporated. The crude product
was purified by column chromatography on silica gel (hexane/
EtOAc ) 3:2) to give 34 (952 mg, 99%) as a white solid: mp
195 °C dec; IR (KBr) νmax 3468.3, 1726.5, 1633.9, 1512.3,
1450.6, 1433.2, 1186.3, 1143.9, 1099.5, 1039.7 cm-1; 1H NMR
(pyridine-d5, 300 MHz) δ 2.74 (m, 2H), 3.44 (dd, J ) 12.3, 3.6
Hz, 1H), 3.74 (s, 3H), 3.82 (ddd, J ) 12.0, 9.0, 6.9 Hz, 1H),
4.46 (t, J ) 4.5 Hz, 1H), 5.77 (d, J ) 1.2 Hz, 1H), 5.78 (d, J )
1.2 Hz, 1H), 5.91-5.97 (m, 1H), 6.22-6.29 (m, 1H), 6.97 (d, J
) 1.2 Hz, 1H), 7.08 (d, J ) 1.2 Hz, 1H); 13C NMR (pyridine-d5,
75 MHz) δ 31.3, 40.7, 49.6, 56.5, 67.0, 101.3, 104.0, 109.9,
127.4, 130.7, 134.2, 137.5, 143.7, 149.1, 178.0; MS-EI m/z (rel
int) 292 (M+, 15), 274 (34), 244 (68), 222 (100), 178 (33); HRMS-
EI (calcd for C15H16O6) 292.0947, found 292.0946.
5), 251 (26), 228 (100), 219 (23); HRMS-EI (calcd for C23H23
NO7) 425.1475, found 425.1485.
-
Ben zoic Acid 2,3-Dih yd r oxy-6-(7-m eth oxyben zo[1,3]-
d ioxol-5-yl)-5-m et h oxyca r b on yla m in ocycloh exyl E st er
(38). To a solution of 36 (220 mg, 0.52 mmol) in THF (4 mL)
was added N-methylmorpholine N-oxide (91 mg, 0.77 mmol)
in H2O (1 mL) and OsO4 (0.2 mL, 4% in H2O). The reaction
mixture was stirred at room temperature for 20 h. The reaction
was quenched with saturated aqueous NaHSO3 solution and
extracted with EtOAc (15 mL × 3). The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated. This crude product was chromatographed on
silica gel column (hexane/EtOAc ) 2:3) to give colorless syrup
38 (228 mg, 96%): IR (film) νmax 3373.8, 1693.7, 1635.8, 1537.4,
1452.5, 1280.9, 1111.1, 1066.7, 1026.2 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.85 (dd, J ) 12.3, 2.4 Hz, 1H), 2.35-2.40 (m,
1H), 2.77 (br s, 1H), 3.18 (dd, J ) 12.0, 2.7 Hz, 1H), 3.42 (br
s, 1H), 3.57 (s, 6H), 4.15 (m, 2H), 4.39 (m, 1H), 4.79 (d, J )
8.4 Hz, 1H), 5.42 (t, J ) 3.0 Hz, 1H), 5.83 (d, J ) 1.5 Hz, 1H),
5.85 (d, J ) 1.5 Hz, 1H), 6.42 (m, 2H), 7.41-7.46 (m, 2H),
7.54-7.60 (m, 1H), 7.96-8.00 (m, 2H); 13C NMR (CDCl3, 75
MHz) δ 35.7, 46.1. 47.0, 52.1, 56.1, 67.4, 69.2, 76.1, 101.2,
103.1, 107.7, 128.6, 129.3, 129.6, 131.9, 133.5, 134.2, 143.3,
[5-Hydr oxy-6-(7-m eth oxyben zo[1,3]dioxol-5-yl)cycloh ex-
3-en yl]ca r ba m ic Acid Meth yl Ester (35). The mixture of
J . Org. Chem, Vol. 69, No. 1, 2004 119

Ko et al.
148.6, 156.6, 165.1; MS-EI m/z (rel int) 459 (M+, 1), 244 (12),
228 (43), 122 (100); HRMS-EI (calcd for C23H25NO9) 459.1529,
found 459.1517.
1H), 3.58 (s, 3H), 3.77 (br d, J ) 7.2 Hz, 1H), 4.01 (m, 1H),
4.15 (br s, 1H), 4.21 (dd, J ) 6.3, 3.3 Hz, 1H), 4.71 (dd, J )
21.9, 10.2 Hz, 1H), 4.80 (d, J ) 3.9 Hz, 1H), 5.20 (m, 1H), 5.82
(dd, J ) 2.7, 1.2 Hz, 2H), 6.10 (br d, J ) 9.6 Hz, 1H), 6.45 (d,
J ) 1.5 Hz, 1H), 6.62 (br s, 1H), 7.47-7.53 (m, 2H), 7.59-7.64
(m, 1H), 8.07-8.10 (m, 2H); 13C NMR (acetone-d6, 75 MHz) δ
47.0, 51.0, 51.7, 56.2, 70.3, 72.7, 74.4, 77.5, 101.8, 103.9, 109.2,
129.3, 129.5, 130.4, 131.6, 133.7, 134.3, 144.0, 149.2, 158.3,
165.6; MS-EI m/z (rel int) 475 (M+, 5), 260 (48), 232 (35), 207
(31), 105 (100); HRMS-EI (calcd for C23H25NO10) 475.1478,
found 475.1498.
Ben zoic Acid 5-(7-Met h oxyb en zo[1,3]d ioxol-5-yl)-6-
m eth oxyca r bon yla m in o-2,2-d ioxoh exa h yd r o-2λ6-ben zo-
[1,3,2]d ioxa th iol-4-yl Ester (39). Triethylamine (0.17 mL,
1.22 mmol) and thionyl chloride (55 µL, 0.75 mmol) were added
to a solution of ester 38 (230 mg, 0.50 mmol) in CH2Cl2 (6 mL)
at 0 °C. After 30 min, this reaction mixture was added to H2O
(6 mL) and extracted with EtOAc (15 mL × 2). The combined
organic layers were dried over Na2SO4 and concentrated. This
crude cyclic sulfite was dried in vacuo for 3 h and dissolved in
CH3CN/EtOAc/H2O (6 mL, 2:1:1). To the resulting solution
were added RuCl3‚3H2O (2 mg, 9.6 µmol) and Oxone (870 mg,
1.4 mmol). After the reaction mixture was stirred at room
temperature for 2 h, it was diluted with EtOAc and washed
with saturated NaHSO3 solution. The organic layer was dried
over Na2SO4, concentrated, and purified by column chroma-
tography on silica gel (hexane/EtOAc ) 3:2) to give cyclic
sulfate 39 (216 mg, 83%) as a colorless syrup: IR (film) νmax
Ben zoic Acid 2,3,4-Tr iacetoxy-7-m eth oxy-6-oxo-1,2,3,4,-
4a ,5,6,11b-octa h yd r o[1,3]d ioxolo[4,5-j]p h en a n th r id in -1-
yl Ester (42 a n d 43). To a mixture of triol 41 (36 mg, 76 µmol),
pyridine (0.2 mL, 2.5 mmol), and DMAP (5 mg, 0.04 mmol) in
CH2Cl2 (2 mL) was added Ac2O (0.1 mL, 1.1 mmol). After being
stirred at room temperature for 1 h, the reaction mixture was
evaporated and purified by column chromatography on silica
gel in hexane/EtOAc (1:1) to yield triacetate (35 mg, 77%). To
a stirred solution of the resulting triacetate (19 mg, 32 µmol)
and DMAP (20 mg, 0.16 mmol) in CH2Cl2 (2 mL) at 0 °C was
added trifluoromethanesulfonic anhydride (45 µL, 0.27 mmol).
After the resulting mixture was stirred at 5 °C for 22 h, it
was poured into saturated aqueous NaHCO3 solution and
extracted with EtOAc (10 mL × 3). The combined organic
layers were washed with 0.5 M HCl solution and brine, dried
over Na2SO4, and concentrated. This mixture was dissolved
in THF (2 mL) and 2 M HCl (0.2 mL) and stirred at room
temperature for 5 h. The reaction mixture was partitioned
between saturated aqueous NaHCO3 and EtOAc (10 mL × 3).
The combined organic layers were washed with brine, dried
over Na2SO4, and concentrated. The crude product was purified
by column chromatograpyh on silica gel (hexane/EtOAc ) 1:5)
to give an inseparable mixture of 43 and 42 (14 mg, 78%, 7:1)
1716.8, 1635.8, 1514.3, 1452.5, 1392.7, 1265.4, 1211.4 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 2.28 (dt, J ) 14.1, 9.3 Hz, 1H),
2.89 (dt, J ) 14.1, 6.0 Hz, 1H), 3.17 (dd, J ) 11.4, 2.1 Hz, 1H),
3.62 (s, 6H), 4.46-4.60 (m, 2H), 5.09 (dd, J ) 4.8, 2.7 Hz, 1H),
5.26 (ddd, J ) 11.1, 9.6, 6.0 Hz, 1H), 5.71 (t, J ) 2.7 Hz, 1H),
5.89 (d, J ) 1.5 Hz, 1H), 5.91 (d, J ) 1.2 Hz, 1H), 6.39 (d, J )
1.5 Hz, 1H), 6.44 (d, J ) 1.5 Hz, 1H), 7.47-7.52 (m, 2H), 7.61-
7.67 (m, 1H), 7.97-8.01 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ
29.7, 33.8, 44.9, 46.2, 52.4, 56.2, 70.7, 77.9, 80.1, 101.6, 102.8,
107.8, 128.2, 128.6 128.9, 129.3, 129.8, 134.2, 143.7, 149.2,
164.1; MS-EI m/z (rel int) 527 (M+, 2), 253 (31), 112 (52), 105
(100); HRMS-EI (calcd for C23H23NO11S) 521.0992, found
521.09827.
Ben zoic Acid 2-Hydr oxy-6-(7-m eth oxyben zo[1,3]dioxol-
5-yl)-5-m eth oxycar bon ylam in ocycloh ex-3-en yl Ester (40).
A mixture of cyclic sulfate 39 (140 mg, 0.27 mmol) and DBU
(0.1 mL, 0.67 mmol) in toluene (5 mL) was heated to reflux
for 2 h. After the reaction mixture was cooled to room
temperature, to it were added 10% aqueous H2SO4 solution
(0.5 mL) and THF (4.5 mL). It was stirred for 4 h at room
temperature, and then the reaction mixture was diluted with
EtOAc. It was washed with saturated aqueous NaHCO3
solution and brine. The organic layer was dried over Na2SO4
and concentrated. The crude product was purified by silica gel
column chromatography (hexane/EtOAc ) 1:1) to give allylic
alcohol 40 (79.4 mg, 67%) as a colorless oil: IR (film) νmax
3364.2, 1705.2, 1635.8, 1514.3, 1452.5, 1269.3 cm-1; 1H NMR
(acetone-d6, 300 MHz) δ 3.41 (dd, J ) 10.8, 1.8 Hz, 1H), 3.51
(s, 3H), 3.63 (s, 3H), 4.15 (m, 1H), 4.69 (d, J ) 5.1 Hz, 1H),
4.93 (t, J ) 9.6 Hz, 1H), 5.27 (br s, 1H), 5.83-5.88 (m, 3H),
5.95 (dd, J ) 10.2, 1.8 Hz, 1H), 6.38 (d, J ) 9.3 Hz, 1H), 6.50
(d, J ) 1.2 Hz, 1H), 6.60 (d, J ) 0.9 Hz, 1H), 7.50-7.57 (m,
2H), 7.62-7.68 (m, 1H), 8.02-8.05 (m, 2H); 13C NMR (acetone-
d6, 75 MHz) δ 45.1, 49.2, 51.9, 56.4, 65.9, 78.3, 102.0, 103.2,
108.9, 128.0, 129.5, 130.2, 130.3, 131.0, 133.9, 134.1, 135.1,
144.2, 149.7, 157.5, 165.7; MS-EI m/z (rel int) 441 (M+, 9), 298
as a white solid: IR (film) νmax 1749.6, 1658.9, 1257.7 cm-1
;
1H NMR of a major 43 (CDCl3, 300 MHz) δ 1.81 (s, 3H), 2.09
(s, 3H), 2.20 (s, 3H), 3.49 (dd, J ) 12.9, 1.8 Hz, 1H), 4.05 (s,
3H), 4.37 (dd, J ) 12.6, 10.8 Hz, 1H), 5.23 (dd, J ) 10.8, 3.3
Hz, 1H), 5.34 (t, J ) 3.0 Hz, 1H), 5.50 (t, J ) 3.0 Hz, 1H), 5.80
(m, 1H), 5.94 (s, 2H), 6.40 (m, 1H), 6.42 (s, 1H), 7.40-7.45 (m,
2H), 7.55-7.61 (m, 1H), 7.98-8.01 (m, 2H); MS-EI m/z (rel
int) 569 (M+, 16), 344 (22), 284 (32), 260 (16), 105 (100); HRMS-
EI (calcd for C28H27NO12) 569.1533, found 569.1527.
Ben zoic Acid 2,3,4-Tr ia cetoxy-7-h yd r oxy-6-oxo-1,2,3,4,-
4a ,5,6,11b-octa h yd r o[1,3]d ioxolo[4,5-j]p h en a n th r id in -1-
yl Ester (44). To a solution of 42 and 43 (13 mg, 0.023 mmol)
in CH2Cl2 (2 mL) at -78 °C was added BBr3 (60 µL, 1 M in
CH2Cl2, 0.06 mmol). The reaction mixture was warmed to 0
°C and stirred for 30 min. Then, 10% NH4OH aqueous solution
(2 mL) was added at 0 °C. After being stirred for 20 min, the
reaction mixture was extracted with EtOAc (10 mL × 3). The
combined organic layers were washed with brine, dried, and
concentrated. The residue was purified by silica gel column
chromatography (hexane/EtOAc ) 1:1) to give unreacted 42
and the desired compound 44 (7.2 mg, 65%) as white solid:
mp 152 °C dec; IR (film) νmax 1755.4, 1674.4, 1624.2, 1601.1,
1464.1, 1369.6, 1340.7, 1271.2, 1234.6 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.83 (s, 3H), 2.11 (s, 3H), 2.20 (s, 3H), 3.56 (ddd,
J ) 13.2, 2.7, 0.9 Hz, 1H), 4.47 (dd, J ) 13.2, 10.8 Hz, 1H),
5.25 (dd, J ) 10.8, 3.6 Hz, 1H), 5.36 (t, J ) 3.0 Hz, 1H), 5.52
(t, J ) 3.0 Hz, 1H), 5.82 (br s, 1H), 5.97 (d, J ) 1.5 Hz, 1H),
6.01 (d, J ) 1.5 Hz, 1H), 6.22 (br s, 1H), 6.30 (d, J ) 0.9 Hz,
1H), 7.40-7.46 (m, 2H), 7.56-7.62 (m, 1H), 8.00-8.02 (m, 2H),
12.33 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 20.4, 20.7, 20.8,
39.5, 48.6, 66.4, 66.8, 67.6, 71.6, 96.8, 102.4, 107.2, 128.5, 128.8,
130.0, 131.5, 133.5, 133.8, 146.6, 149.4, 153.3, 164.9, 168.2,
169.1, 170.0; MS-EI m/z (rel int) 555 (M+, 40), 274 (94), 105
(33), 244 (87), 228 (31), 105 (100); HRMS-EI (calcd for C23H23
NO8) 441.1424, found 441.1414.
-
Ben zoic Acid 2,3,4-Tr ih yd r oxy-6-(7-m eth oxyben zo[1,3]-
d ioxol-5-yl)-5-m eth oxyca r bon yla m in ocycloh exyl Ester
(41). To a solution of allylic alcohol 40 (40 mg, 91 µmol) in
THF (2 mL) was added N-methylmorpholine N-oxide (16 mg,
0.14 mmol) in H2O (0.5 mL) and OsO4 (0.2 mL, 4% in H2O).
The reaction mixture was stirred at room temperature for 27
h. The reaction was quenched with saturated aqueous NaHSO3
solution and extracted with EtOAc (10 mL × 5). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated. This crude product was chromatographed on a
silica gel column in EtOAc to give triol 41 (37.9 mg, 88%) as
a colorless oil: IR (film) νmax 3366.1, 1699.4, 1635.8, 1539.3,
(100); HRMS-EI (calcd for
555.1378.
C27H25NO12) 555.1377, found
(()-P a n cr a tista tin (1). To a solution of 44 (7.2 mg, 13
µmol) in THF (2 mL) was added NaOMe (0.4 mL, 0.5 M in
MeOH). After being stirred at room temperature for 4 h, the
1
1512.3, 1452.5, 1273.1 cm-1; H NMR (acetone-d6, 300 MHz)
δ 3.45 (s, 3H), 3.49 (d, J ) 2.7 Hz, 1H), 3.53 (d, J ) 2.4 Hz,
120 J . Org. Chem., Vol. 69, No. 1, 2004

Total Synthesis of Pancratistatin
reaction was quenched with saturated aqueous NH4Cl solution
(2 mL). This mixture was extracted with EtOAc (10 mL × 7)
and the combined organic layers were dried over Na2SO4,
concentrated, and purified by column chromatography on silica
gel (EtOAc/MeOH ) 15:1) to give (()-pancratistatin (3.5 mg,
83%) as a white solid: mp 263-264 °C dec; IR (KBr) υmax
325 (M+, 100), 247 (49), 206 (67), 205 (68); HRMS-EI (calcd
for C14H15NO8) 325.0798, found 325.0784.
Ack n ow led gm en t. This work was supported by a
grant (1999-2-21500-001-3) from the Basic Research
Program of the Korea Science & Engineering Founda-
tion.
3420.1, 1672.4, 1628.1, 1468.0, 1358.0, 1084.1, 1047.4 cm-1
;
1H NMR (DMSO-d6, 300 MHz) δ 2.96 (d, J ) 10.8 Hz, 1H),
3.66-3.72 (m, 2H), 3.84 (m, 1H), 3.95 (dd, J ) 7.2, 3.6 Hz,
1H), 4.27 (m, 1H), 4.82 (d, J ) 7.5 Hz, 1H), 5.05 (d, J ) 5.7
Hz, 1H), 5.08 (d, J ) 5.7 Hz, 1H), 5.36 (d, J ) 4.2 Hz, 1H),
6.02 (d, J ) 0.9 Hz, 1H), 6.05 (d, J ) 1.2 Hz, 1H), 6.48 (d, J )
0 0.9 Hz, 1H), 7.51 (br s, 1H), 13.06 (s, 1H); 13C NMR (DMSO-
d6, 75 MHz) δ 29.2, 50.7, 68.7, 70.2, 70.4, 73.5, 97.9, 101.9,
107.7, 131.9, 135.9, 145.6, 152.2, 169.7; MS-EI m/z (rel int)
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for the syntheses of 18, 21, 23, and 24; copies of H
NMR and 13C NMR spectra of compounds 1, 9, 17, 19, 23-26,
34, 36, 40, 41, and 44, as well as mixtures of 22 and 24, 31
and 32; chiral HPLC analysis data of (+)-25. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O035371N
J . Org. Chem, Vol. 69, No. 1, 2004 121