A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin

Article abstract of DOI:10.1016/j.tetlet.2013.07.125

A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin has been achieved from readily available starting materials via unified strategy employing Sharpless asymmetric dihydroxylation, ring closing metathesis, Overman rearrangement, hydrogenolysis and Bischler-Napieralski reaction in 15 purification steps with 15% overall yield.

Full text of DOI:10.1016/j.tetlet.2013.07.125

Tetrahedron Letters 54 (2013) 5562–5566
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Tetrahedron Letters
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A highly stereocontrolled asymmetric total synthesis of epimer
of (+)-7-deoxypancratistatin
a
b
b
Subhash P. Chavan a, , Sumanta Garai , Chandan Dey , Rajesh G. Gonnade
⇑
a Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
b Physical/Materials Chemistry Division, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereocontrolled asymmetric total synthesis of epimer of (+)-7-deoxypancratistatin has been
achieved from readily available starting materials via unified strategy employing Sharpless asymmetric
dihydroxylation, ringclosingmetathesis,Overmanrearrangement, hydrogenolysis andBischler–Napieralski
reaction in 15 purification steps with 15% overall yield.
Received 22 May 2013
Revised 22 July 2013
Accepted 24 July 2013
Available online 31 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amaryllidaceous alkaloids
7-Deoxypancratistatin
Epimer
Sharpless asymmetric dihydroxylation
Deoxygenation
The amaryllidaceous alkaloids are a diverse group of structur-
ally complex natural products which are used for medicinal pur-
poses dating back to at least the fourth century1 and these
alkaloids possess a wide spectrum of biological activities. In
1984, Pettit et al.,2 reported isolation of pancratistatin (1), which
was shown to display promising antineoplastic and antiviral activ-
ity. In 1989, Ghosal et al.,3 isolated the 7-deoxy compound 2,
in vitro antiviral assays of which have been shown to exhibit a bet-
ter therapeutic index than 1.
The potent biological activity and unique yet challenging struc-
tural features of these molecules possessing phenanthridone skel-
eton with four or six contiguous stereogenic centres in the C ring
and trans-fused BC-ring (C10b–C4a) have rendered them attractive
synthetic targets for organic chemists Fig. 1.
The potent biological activity of these compounds with novel
framework coupled with their low natural abundance/availability
prompted us to undertake practical synthesis of this class of com-
pounds. Several total syntheses of 7-deoxypancratistatin (2) have
been reported till date in the literature.4 The first total synthesis
of epimer of 7-deoxypancratistatin (2) has been reported by Hud-
licky and co-workers.4h,5 In this Letter we wish to describe a new
highly stereo-controlled asymmetric total synthesis of epimer of
(+)-7-deoxypancratistatin.
could be constructed by Bischler–Napieralski reaction and the ste-
reochemistry of 10b centre could be fixed via deoxygenation of ter-
tiary benzylic alcohol of intermediate 5. Allylic nitrogen
functionality could be installed via Overman rearrangement of
allylic alcohol 6. We envisioned that the requisite precursor 6,
which contains four stereocentres in the C ring, could be stereose-
lectively synthesized from diene 7 via ring closing metathesis. The
diene 7 in turn could be obtained from keto compound 8 taking
advantage of existing chiral centres to direct the other two chiral
centres to be installed. Further retrosynthetic analysis indicated
that the keto compound 8 could be synthesized from commercially
available, cheap starting material 9 via Grignard reaction followed
by Sharpless asymmetric dihydroxylation.
Accordingly, the synthesis began with the Grignard reaction of
4-bromo-1,2-(methylenedioxy)benzene 9 with succinic anhydride.
OH
OH
NH
HO
3
4
OH
OH
OH
OH
2
1
10b
4a
O
O
O
O
NH
X
O
X
O
Scheme 1 highlights the overall retrosynthetic strategy towards
(+)-7-deoxypancratistatin (2). The B ring of 7-deoxypancratistatin
3
X = OH, Narciclasine
1
X = OH, Pancratistatin
4 X = H, Lycoricidine
2 X = H, 7-Deoxypancratistatin
⇑
Corresponding author. Fax: +91 20 5892629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
Figure 1. Structures of pancratistatin (1), 7-deoxypancratistatin (2), narciclasine
(3) and lycoricidine (4).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.125

S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566
OP
5563
we were able to isolate lactone intermediate 19). The diastereose-
lectivity observed during the Grignard reaction of 14 can be ex-
plained by Cram’s chelation model11 (a, Fig. 2). After purification,
it was immediately treated under Luche reduction12 with CeCl3-
Á7H2O and NaBH4 to yield diene 16 in 95% yield as a sole observable
diastereomer (determined by 1H and 13C NMR). The stereochemis-
try at the C3 centre was surprisingly controlled by the Felkin-Anh
model (b, Fig. 2).13
OH
PO
HO
OH
OH
10b
C
10b
O
O
O
O
O
A
B
NH
Overmann
NH
Deoxygenation
reaction
O
2
5
O
Rearrangement
Bischler-Napieralski
reaction
It is well known in the literature that Ce+3 has good affinity to-
wards chelation and hence it was assumed that the Luche reduc-
tion should furnish the product as predicted by Cram’s chelation
model. Although the exact reason for the observation remains un-
clear, it can be surmised that due to the bulky size of both Ce+3 ion
and MOM group, chelation is not favourable. Cram’s chelation tran-
sition state (B) was more sterically congested as compared to Fel-
kin-Ahn transition state (C), which resulted in the hydride attack
on the less hindered face of the non-chelated transition state (C)
(Fig. 2).
OP
PO
HO
OH
OP
PO
HO
OH
O
O
O
O
7
Ring-Closing
Metathesis
6
Grignard
reaction
O
Asymmetric
dihydroxylation
Having accomplished the assembly of requisite carbon atoms
and appropriately placed functionalities, the stage was set for the
construction of the cyclohexene ring. Accordingly, the resultant
diene 16 was subjected to ring closing metathesis using Grubbs’
1st generation catalyst to gratifyingly afford substituted cyclohex-
ene advanced intermediate 17 in 96% yield. It should be empha-
sized that the synthesis of arylcyclohexene 17 is operationally
simple and it can be readily synthesized on gram scale. The sec-
ondary alcohol in arylcyclohexene 17 was selectively converted
to corresponding imidate with Cl3CCN for the ensuing Overman
rearrangement.14 Unfortunately, imidate did not undergo the
anticipated rearrangement to give the desired product 18, instead
the reaction led to the recovery of the starting imidate (Scheme 3).
The failure of the rearrangement might be attributed to the
influence of the bulky MOM group for which the b-face of double
bond was sterically congested which prevented the migration of
the imidate group (E). At this stage, we decided to invert the C3
Br
OP
O
O
O
O
O
PO
9
O
8
Scheme 1. Retrosynthetic analysis of 7-deoxypancratistatin.
O
Br
O
O
O
O
O
O
a
b
O
9
10
O
O
O
O
c
O
O
stereo-centre where
(Scheme 3, Fig. 3).
a-face was sterically less congested (F)
Br
O
O
In view of the unfavorable steric effect of the MOM group on
the rearrangement of allylic alcohol 17, it was subjected to Mits-
unobu reaction15 with p-nitrobenzoic acid to afford crude nitro-
benzoate ester which was hydrolysed with NaOMe to afford the
advanced intermediate 20 in 65% yield. It should be noted that
1-arylconduritols B and F16 have very close structural resemblance
with compounds 17 and 20, respectively, and can be potentially
readily synthesized in multi-gram scale from these compounds
17 and 20.
The secondary hydroxyl group of alcohol 20 was selectively
converted to corresponding imidate by treating with Cl3CCN. With
this imidate in hand, we then tried the Overman rearrangement14
with K2CO3 in xylene under the reflux conditions and were grati-
fied to find that it worked very well as per our hypothesis. After
3 h, we obtained our desired rearranged product 21 as a single iso-
mer in 98% yield giving credence to our hypothesis. Treatment of
this bicyclic compound 21 with OsO4 afforded diol 22 as a sole iso-
lable diastereomer in 99% yield. The relative stereochemistry of
alcohol 22 was confirmed by 2D NMR study and finally by single
crystal XRD analysis.17 This stereochemical outcome can be attrib-
uted to the approach of the reagent from the b-face of the double
bond because the nearby carbamate ring and the bulky MOM
11
O
12
Scheme 2. Reagents and conditions: (a) (i) Mg, succinic anhydride, THF, 3 h, 0 °C-rt;
(ii) Me2SO4, K2CO3, acetone, 3 h, 85% (over two steps); (b) NBS, NH4OAc, CCl4, reflux,
98%; (c) Et3N, DCM, 10 min, quant.
Aryl Grignard reagent was prepared from 9 and it was quenched
with succinic anhydride to give acid and the crude acid thus ob-
tained was directly treated with Me2SO4 to give corresponding es-
ter 10 in 85% yield over two steps. Attempts to install the double
bond in one pot under IBX/DMSO6 reaction condition was unsuc-
cessful leading to recovery of starting materials. Then we decided
to introduce the olefin by stepwise addition and elimination oper-
ation. Accordingly,
with NBS to give selectively mono
Treatment of compound 11 with Et3N gave olefin 12 in quantita-
tive yield (Scheme 2).
This prochiral enone 12 was deemed to be a suitable substrate
for the installation of the chiral centres. Compound 12 was sub-
jected to Sharpless asymmetric dihydroxylation (SAD)8 to yield
chiral diol 13 in 85% yield with P98% ee.9 After screening various
literature reports on SAD we have observed that surprisingly SAD
on such type of double bond is not reported in the literature.
MOM protection of diol was smoothly performed with MOMCl to
afford di-MOM protected diol 14 in 92% yield without epimeriza-
tion.10 Ketone 14 was subjected to treatment with vinylmagne-
sium bromide to give lactol 15 in 60% yield which was found to
be unstable at room temperature (under controlled experiment
a
-bromination7 of ketone 10 was carried out
-bromoketone 11 in 98% yield.
a
group at C2 position provided steric bias for
a-face of the double
bond. After successful installation of all the requisite functional
groups around the cyclohexane ring with the desired stereochem-
istry, next task was deoxygenation of the tertiary hydroxyl group
at C10b. Towards this end, despite significant efforts, we were un-
able to get desired deoxygenated product18 under different reac-
tion conditions like hydrogenolysis (Pd/C,19 Pd(OH)2/C20 and

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S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566
Cram's chelation model
(a)
Mg+2
OMOM
R1
Ar
O
H
OMOM
R1
O
OH
H
Ar
OMOM
H
MOMO
R1
R1
Ar
Ar
BrMg
O
A
Cram's chelation model
Ce+3
(b)
CH3
O
O
O
MOMO
HO
H
H
R2
H
H
R2
-
R2
O
OMOM
O
B
MOMO
Ce+3
R2
R2
H
2
O
R
H
MOMO
H
MOMO
-
H
OH
H
C
Felkin-Anh model
Figure 2. Felkin-Anh and Cram’s chelation model transition state.
O
OMOM
OH
OMOM
O
More steric crowding
NH
MOMO
O
O
3
HO
O
H
NH
CCl3
O
2
1
H
O
O
3
O
O
O
O
O
H
O
O
b
O
CCl3
O
OH
O
a
12
OMOM
OMOM
OH
14
Less steric crowding
13
E
F
OMOM
OH
OMOM
OH
MOMO
HO
Figure 3. Effect of the MOM group on Overman rearrangement.
MOMO
3
10b
O
O
c
d
O
O
O
OMOM
OMOM
OH
16
MOMO
15
MOMO
HO
OMOM
O
O
OMOM
OH
b
O
O
a
MOMO
HO
O
17
MOMO
HO
NH
3
20
1
21
O
O
f
e
O
O
HN
CCl3
O
OMOM
OH
OMOM
OH
18
17
O
MOMO
MOMO
10b
OMOM
O
O
c
OH
O
O
OH
O
MOMO
NH
NH2
10b
O
O
O
O
O
23
22
19
Scheme 3. Reagents and conditions: (a) (i) (DHQD)2PHAL, OSO4, K3[Fe(CN)6],
K2CO3, tBuOH:H2O (1:1), 4 days, 85%, P98% ee; (b) MOM-Cl, DIPEA, DCM, reflux,
92%; (c) vinylmagnesium bromide (2 equiv), THF, 0 °C, 60%; (d) CeCl3Á7H2O, NaBH4,
MeOH, 0 °C, 15 min, 95%; (e) Grubbs’ 1st generation catalyst, DCM, reflux, 4 h, 96%;
(f) (i) CCl3CN, DBU, DCM, 0 °C, 30 min; (ii) K2CO3, xylene, reflux.
22
Scheme 4. Reagents and conditions: (a) (i) Bu3P, DEAD, p-NO2C6H4CO2H, toluene,
0 °C, 5 h; (ii) NaOMe, MeOH, 0 °C, 2 h, 65% (over two steps); (b) (i) CCl3CN, DBU,
DCM, 0 °C, 30 min; (ii) K2CO3, xylene, reflux, 3 h, 98%; (c) OsO4, NMO, CH3CN–H2O
(9:1), rt, 3 days, 99%.
Raney Ni21) ionic hydrogenation22 (Et3SiH/BF3ÁOEt2 and Et3SiH/
TFA) and Birch reduction23 (Scheme 4).
The above results indicated that the carbamate ring is very sta-
ble and is highly resistant under the above reaction conditions.
This finding prompted us to activate the carbamate ring. Accord-
ingly, the diol of compound 22 was protected as its acetonide fol-
lowed the treatment with dimethyldicarbonate to furnish
compound 24 where the carbamate ring was activated. With the

S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566
5565
Table 1
OAc
NH
OH
NH
Deoxygenation of activated carbamate
AcO
HO
OAc
OAc
OH
OH
Entry
Reaction conditions
Producta
O
O
O
O
a
b
26
1
2
3
4
5
6
7
Pd(OH)2, CH3COOH, H2, EtOH
Pd(OH)2, H2, EtOH
Pd/C, CH3COOH, H2, EtOH
Pd/C, H2, EtOH
cis Stereochemistry
cis Stereochemistry
cis Stereochemistry
cis Stereochemistry
Complex reaction mixture
Complex reaction mixture
SMb was recovered
O
28
O
27
Epimer of (+)-7-deoxypancratistatin
Li, liq. NH3, THF
BF3ÁOEt2/TFA, Et3SiH, DCM
Scheme 6. Reagents and conditions: (a) Tf2O, DMAP, DCM, À5 °C, 16 h, 70%; (b)
Raney Ni, H2, EtOH, reflux
K2CO3, MeOH, rt, overnight, 85%.
a
Relative stereochemistry at C4a–C10b centres.
Starting material.
b
from inexpensive, commercially and easily available starting mate-
rials in 15% overall yield after 15 purification steps which is the
highest overall yield reported so far. We have synthesized an ad-
vanced intermediate 20 on multi-gram scale which can be elabo-
rated for the efficient synthesis of different 1-arylconduritols and
Lycrocidine (4). Synthesis of other related natural products and
the evaluation of biological activity of 1-arylconduritols and epi-
mer of (+)-7-deoxypancratistatin (28) are under progress and will
be reported in due course.
activated compound 24 in hand, our next aim was to carry out the
deoxygenation reaction in order to fix the desired stereochemistry
at C10b centre (Table 1). Hydrogenolysis of compound 24 gratify-
ing furnished the deoxygenated compound as a single diastereo-
mer, however, with cis stereochemistry leading to the formation
of product 25 (entries 1–4). Under ionic hydrogenation and Birch
reduction conditions, it resulted in a complex reaction mixture (en-
tries 5 and 6). Under Raney nickel reduction conditions, we failed
to get deoxygenated product (entry 7). Although the desired trans
stereochemistry at C4a–C10b centre as required to obtain (+)-7-
deoxypancratistatin (2) could not be achieved under these reaction
conditions, an advanced intermediate 22, bearing the exact re-
quired stereochemistry at C4a–C10b for the synthesis of (+)-7-
deoxypancratistatin (2) was obtained in good yields. We believe
that by proper choice of reagents and reaction conditions, interme-
diate 22 can be converted to (+)-7-deoxypancratistatin (2).
With cis deoxygenated product 25 in hand, it was carried for-
ward to accomplish the total synthesis of epimer of 7-deoxypanc-
ratistatin. Accordingly, acetonide and MOM groups were globally
deprotected in one-pot by addition of 2–3 drops of concd HCl in
MeOH. Then the free hydroxyl groups were protected with acetic
anhydride to yield tetraacetate 26 in 97% yield. The relative stereo-
chemistry and structure were confirmed by XRD analysis24
(Scheme 5).
Acknowledgments
S.G. thanks CSIR, New Delhi, India, for a fellowship and S.P.C.
acknowledges funding from NCL in-house projects [MLP 017226
and MLP012726]. We thank Dr. Rahul Banerjee, CSIR-NCL for
X-ray analysis and we also thank the Director, CSIR-NCL for this
facility.
References and notes
1. Hartwell, J. L. Lloydia 1967, 30, 379.
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McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289; (c) Hudlicky, T.;
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Gonzalez, D.; Akgun, H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G.
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A.; McElroy, W. T.; DeShong, P. Org. Lett. 2006, 8, 4183; (l) Hakansson, A. E.;
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9. Enantiomeric excess (% ee) was determined by Chiral HPLC analysis (Chiralcel
OJ-H (250 Â 4.6 mm), mobile phase:isopropanol:pet ether = 40:60, wave
length = 254 nm, flow rate = 0.5 ml/min).
10. Enantiomeric excess (% ee) was determined by Chiral HPLC analysis (Kromasil
5-Amy Coat (250 Â 4.6 mm), mobile phase:isopropanol:n-hexane = 5:95, wave
length = 254 nm, flow rate = 1 ml/min).
The carbamate 26 was treated with Tf2O and DMAP under mod-
ified the Bischler–Napieralski protocol25 for the construction of the
B ring to afford compound 27. Finally, global removal of all four
acetate groups was achieved by treatment with K2CO3 in MeOH
to furnish epimer of (+)-7-deoxypancratistatin (28) (Scheme 6).
The absolute stereochemistry of 28 was assigned by comparison
of the reported optical rotations.5,4h
In summary, we have completed a new and potentially practical
synthetic route to the epimer of (+)-7-doxypancratistatin starting
OMOM
OMOM
MOMO
MOMO
O
O
10b
10b
4a
4a
HN
O
O
O
O
O
O
O
O
b
a
O
O
22
N
24
O
25
O
OAc
AcO
OAc
10b
4a
O
OAc
O
Table 1
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Am. Chem. Soc. 1981, 103, 5454.
HN
O
26
26
O
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Scheme 5. Reagents and conditions: (a) (i) Me2C(OMe)2, cat. PTSA, DCM, 0 °C, 1 h;
(ii) dimethyldicarbonate, Et3N, DMAP, DCM, 1 h, rt, 97%; (b) (i) concd HCl (2–3
drops), MeOH, rt, 4 h; (ii) Ac2O, pyridine, rt, overnight, 97%.

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S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 5562–5566
15. (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380; (b)
Mitsunobu, O. Synthesis 1981, 1.
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Tetrahedron 1990, 46, 3715.
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17. Crystallographic data (excluding structure factors) for the structures have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 918587. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (Fax:
+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).
18. Previously Pettit and co-workers (Pettit, G.R. Melody, N. Herald, D.L. Knight, J.C.
Chapuis, J.-C. J. Nat. Prod. 2007, 70, 417) were also unable to get the correct
stereochemistry at C10b centre by a radical deoxygenation reaction for the
synthesis of pancratistatin.
23. Small, G. H.; Minnella, A. E.; Hall, S. S. J. Org. Chem. 1975, 40, 3151.
24. Crystallographic data (excluding structure factors) for the structures have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 918586. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. (Fax:
+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.Uk).
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