A concise synthesis of (+)-pancratistatin using pinitol as a chiral building block

Article abstract of DOI:10.1016/j.tetlet.2006.03.138

A concise approach toward (+)-Pancratistatin has been achieved via 12 steps from pinitol. An ultrasound assisted arylcerium induced ring opening of cyclic sulfate was employed as a key step.

Full text of DOI:10.1016/j.tetlet.2006.03.138

Tetrahedron Letters 47 (2006) 3707–3710
A concise synthesis of (+)-pancratistatin using pinitol as a
chiral building block
Min Li,a,* Anmei Wub and Peijie Zhoub
aDepartment of Neurosciences, Georgetown University Medical Center, 4000 Reservoir Road NW, Washington, DC 20057, USA
bOrgchem Technologies, Inc. 2201 W. Campbell Park Dr, Chicago, IL 60612, USA
Received 27 February 2006; revised 20 March 2006; accepted 21 March 2006
Available online 17 April 2006
Abstract—A concise approach toward (+)-Pancratistatin has been achieved via 12 steps from pinitol. An ultrasound assisted aryl-
cerium induced ring opening of cyclic sulfate was employed as a key step.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Pancratistatin, isolated in 1984 by Dr. Pettit and
co-workers from the native Hawaiian plant Pancratium
Littorale, is an important member of the amaryllidaceae
alkaloids.1 Pancratistatin exhibits a spectrum of both
in vitro and in vivo cancer cell grow the inhibitory activ-
ity and antiviral activity.2 These include, but are not lim-
ited to the activity against murine P-5076 ovarian
sarcoma and P-388 lymphocytic leukemia. Although
the mode of action of Pancratistatin remains mysterious,
it is generally believed that Pancratistain and other ama-
ryllidaceae alkaloids are potent inhibitors of the ribo-
somal peptidyl transferases, which play vital roles in
the cell cycle from G0/G1 to S phase (Fig. 1).3
synthesis. Danishefsky’s group reported the first total
synthesis of racemic Pancratistatin in 1989.4 In 1995,
Hudlicky and co-workers accomplished the first enan-
tioselective synthesis of the natural enantiomer.5 Since
then, numerous research groups around the world have
presented their stereoselective synthesis of (+)-Pancrat-
istatin. These include research teams led by Trost and
Pulley,6 Haseltine and co-workers,7 Magnus and Seb-
hat,8 Rigby et al.,9 and Kim et al.10 So far, the most
effective strategy was developed by Trost and Pulley,
who summarized a synthesis in 13 steps with an impres-
sive overall yield of 11%.6 In 2001, Pettit et al. efforts to
modify the abundant alkaloid (+)-Narciclasine resulted
in another effective route to (+)-Pancratistatin.11
Despite the fact that many synthetic methodologies
toward (+)-Pancratistatin and its analogues12 have been
successfully developed, the construction of the trans-
fused BC ring system and the stereocontrolled installa-
tion of the hydroxyl functions remain to be challenging
for synthetic organic chemists. The supply constraint of
(+)-Pancratistatin is still a big hurdle for its therapeutic
application. Herein, we wish to report a concise synthe-
sis of (+)-Pancratistatin from pinitol.
The promising biological activity and natural paucity
has made Pancratistatin an interesting target for total
OH
HO
OH
OH
OMe
3
HO
HO
OH
OH
2
O
O
4
1
NH
5
6
OH
O
OH
We approached the synthesis of (+)-Pancratistatin by
employing a convergent synthetic strategy (Scheme 1).
According to our retrosynthetic analysis, the skeleton
of the target molecule could be constructed by coupling
two segments 1 and 2.
(+)-Pancratistatin
Pinitol
Figure 1. Structure of (+)-Pancratistatin and Pinitol.
Keywords: Pancratistatin; Stereoselective synthesis; Pinitol; Cyclic
sulfate; Arylcerium.
It is obvious that the contiguous stereogenic centers of
the C ring of (+)-Pancratistatin match exactly with
those of D-chiral-inositol. Therefore, we started
*
Corresponding author. Tel.: +1 202 687 2870; fax: +1 202 687
0617; e-mail: ml258@georgetown.edu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.138

3708
M. Li et al. / Tetrahedron Letters 47 (2006) 3707–3710
OH
HO
OH
OMe
Br
O
O
O
O
O
O
O
O
O
O
OH
S
+
OH
NH
O
OH
NH2
OH
O
(+)-Pancratistatin
1
2
Scheme 1. Retrosynthetic analysis of (+)-Pancratistatin.
constructing the polyhydroxy subunit of (+)-Pancratist-
nucleophilic ring opening from C5 would constitute a
C ring with the exact stereochemistry as that of (+)-
Pancratistatin, we explored with great interest the intra-
molecular nucleophilic ring opening of the cyclic sulfate
8. It has been reported that cyclic sulfates ring could be
opened by diverse nucleophiles like alcohols,21 azides or
amines,22 thiols,23 halides,24 and C-nucleophiles23 as
well. In order to induce the intramolecular cyclization,
we initially employed t-BuLi to convert the aryl bromide
to the corresponding aryl lithium.23b Much disappoint-
edly, we found the reaction proceeded in a sluggish man-
ner to give a complex mixture of products. Attempts in
transforming the aryl bromide unit to its magnesium
bromide23a were unrewarding either. We postulated that
aryl lithium and aryl magnesium bromide’s abilities as
strong bases have incurred unexpected reactions such
as elimination.25 Therefore, we tried to resort to much
‘softer’ nucleophiles. It came to our attention that in
addition to aryl lithium and aryl magnesium, other aryl
nucleophiles such as aryl cerium,26 aryl cadmium,27 aryl
lithium cuprates28 have been widely used in synthetic
chemistry. Among them, organocerium compounds
were reported to possess the same activity as those of
organolithium and organomagnesium agents, but much
milder to avoid lots of side reactions.26 Inspired by these
findings, we have all the reasons to hypothesize the pos-
sibility of employing appropriate arylcerium to serve as
a nucleophile in our cyclic sulfate ring opening.
atin by employing pinitol as a building block. Using the
13
´
method reported by Martın-Lomas and co-workers,
pinitol was converted to compound 3. With compound
3 in hand, we investigated the installation of the
6a-NH2 function by modifying the 6a-OH group. The
stereoselective construction of 6a-NH2 calls for a 6b-
azide, which was usually prepared from 6a-hydroxyl
inositol derivatives via two steps.14 As an alternate, we
resorted to a one-pot transformation employing a Mits-
unobu reversion followed by an azide substitution,
which has been recently applied in the synthesis of bile
acid dimers by Aher and Pore.15 Even though the trans-
formation proceeded in a sluggish manner possibly due
to steric reasons, the azide 4 was obtained in moderate
yield. The silyl function was then removed by TBAF
and a cyclic sulfate 5 was installed to minimize the hin-
drance for the coming coupling as well as the ring open-
ing manipulation. After a Staudinger reduction,16 the
desired free amine 1 was obtained for the coupling reac-
tion (Scheme 2).
The synthesis of segment 2 was achieved via reactions
from compound 6, which was prepared according to
the procedure reported by Coleman and Gurrala.17
Compound 6 was subjected to an acid promoted PMB
deprotection,18 followed by a one-pot phosgene medi-
ated coupling reaction19 with 1 to afford amide 7 in
moderate yield. MOM protection of both the amide
and the free phenol provide 8 as the vital precursor for
ring-closure study (Scheme 3).
In order to establish the arylcerium for the ring opening
study, we explored the synthetic route as outlined in
Scheme 3, compound 8 was treated with equal equiva-
lent t-BuLi followed by addition of anhydrous CeCl3
to effect the nucleophilic ring opening.29 We were very
The cyclic sulfate has been widely used as important
intermediates in organic synthesis.20 Noticing that a
OMe
OMe
OMe
O
O
O
O
HO
HO
OH
OH
O
O
Ref 13
a
R
R
O
O
N3
OH
OH
3
4
Pinitol
b, c, d
OMe
OMe
NH2
O
O
O
O
O
O
Si
O
Si
O
O
e
S
S
R =
O
O
O
O
N3
1
5
Scheme 2. Reagents and conditions: (a) (1) PPh3, DEAD, CH3SO3H, CH2Cl2, 0 ꢁC to rt; (2) NaN3, DMF, 60 ꢁC, 72%; (b) TBAF, THF, 0 ꢁC to rt,
100%; (c) SOCl2, Et3N, CH2Cl2, 0 ꢁC; (d) NaIO4, RuCl3, aq CH3CN, 87% over two steps; (e) PPh3, aq THF, 0 ꢁC to rt, 94%.

M. Li et al. / Tetrahedron Letters 47 (2006) 3707–3710
3709
O
O S
O
O
OMe
O
Br
O
Br
Br
O
O
O
O
a, b
Cl
NH
O
O
c
O
O
OPMB
OH
O
Mg
6
7
OH
NH
O
O S
O
OMe
HO
OH
OH
O
HO3SO
O
O
OMe
Br
O
O
O
O
O
e
d
N
O
NMOM
O
MOMO
OH
O
O
O
O
O
MOM
MOM
(+)-Pancratistatin
9
8
Scheme 3. Reagents and conditions: (a) CH3CO2H, 100 ꢁC, 4 h, 97%; (b) MgBr2ÆOEt2, COCl2, ether, 0 ꢁC, 1, 64%; (c) K2CO3, MOMCl, DMF, rt,
84%; (d) t-BuLi, CeCl3, ultrasound, THF, À78 ꢁC to rt, 72%; (e) (1) BBr3, CH2Cl2, À78 to 0 ꢁC, 1 h; (2) MeOH, À78 to 0 ꢁC, 2 h, 52%.
Antiviral Agents; Chu, C. K., Culter, H. G., Eds.; Plenum:
New York, 1992; pp 121–135.
fortunate to obtain the highly desired 9 in 76% after
recovering 20% of the starting material 8. To the best
of our knowledge, this is the first ring opening of cyclic
sulfate by organocerium. Further optimization led us to
find that when the reaction was performed in an ultra-
sonic bath,30 the yield was improved with all the
compound 8 consumed and the reaction time was short-
ened as well.31 After securing the both the skeleton and
the stereochemistry of the target, we explored the depro-
tection of 9. This proceeded uneventfully, but it is worth
mentioning that maintaining the reaction temperature
below 0 ꢁC and controlling the reaction time are vital
to realize global deprotection without jeopardizing the
methylenecatechol unit.32,10
3. (a) Mutsuga, M.; Kojima, K.; Yamashita, M.; Ohno, T.;
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In summary, a concise synthesis of (+)-Pancratistatin33
was accomplished via 12 steps from pinitol and an read-
ily available compound 6 by employing an arylcerium
induced ring opening of cyclic sulfate 8 as the key step.
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31. Procedure for the ring opening reaction: A solution of 8
(300 mg, 0.48 mmol) in anhydrous THF (5 mL) was
cooled to À78 ꢁC and t-BuLi (2.5 M in hexanes, 0.19 mL,
0.48 mmol) was added dropwise. The resulting pale-yellow
solution was allowed to stir at the same temperature for
30 min, before a suspension of anhydrous CeCl3 (125 mg)
in THF (1 mL)29 was added. The mixture was stirred at
À78 ꢁC for 2 h and allowed to warm up slowly to room
temperature. The flask was then placed in an ultrasonic
bath (Bransonic 2210) at room temperature. The reaction
was monitored by TLC until 8 was fully consumed
(approximately 4 h). Saturated aqueous NH4Cl solution
(2 mL) was added and the mixture was extracted with
ethyl acetate (15 mL · 3). The organic layer was com-
bined, washed with brine (15 mL · 3) and dried over
Na2SO4. After concentrating under reduced pressure, the
residue was purified by flash column chromatography
(Rf = 0.27, hexanes/ethyl acetate 2:3) to give 9 (188 mg,
72%) as an off-white solid.
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33. (+)-Pancratistatin (6.1 mg) was obtained as an off-white
solid. 1H NMR (300 MHz, DMSO-d6) d 13.06 (s, 1H),
7.51 (s, 1H), 6.48 (d, J = 1.0 Hz, 1H), 6.05 (d, J = 1.1 Hz,
1H), 6.02 (d, J = 1.0 Hz, 1H), 5.35 (s, 1H), 5.05–5.07 (m,
2H), 4.84 (s, 1H), 4.27 (m, 1H), 3.95 (dd, J1 = 7.4 Hz,
J2 = 4.0 Hz, 1H), 3.84 (s, 1H), 3.68–3.72 (m, 2H), 2.95 (d,
J = 11.2 Hz, 1H). 13C NMR (75 MHz, DMSO-d6)
d 169.82, 152.30, 145.64, 140.01, 131.94, 107.73, 101.95,
97.93, 73.50, 70.42, 70.21, 68.76, 50.68, 29.20.