Double intramolecular oxymercuration: the first stereoselective synthesis of the C10-C34 fragment of asimitrin

Article abstract of DOI:10.1016/j.tetlet.2007.05.147

The first stereoselective synthesis of the C10-C34 fragment of asimitrin, a nonclassical acetogenin, has been achieved. A key feature of our approach is the application of stereoselective double intramolecular oxymercuration for the efficient preparation

Full text of DOI:10.1016/j.tetlet.2007.05.147

Tetrahedron Letters 48 (2007) 5197–5200
Double intramolecular oxymercuration: the first
stereoselective synthesis of the C10–C34 fragment of asimitrin
Debendra K. Mohapatra,* Sabita Nayak, Seetaram Mohapatra,
Mukund S. Chorghade and Mukund K. Gurjar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 2 May 2007; revised 14 May 2007; accepted 24 May 2007
Available online 31 May 2007
Abstract—The first stereoselective synthesis of the C10–C34 fragment of asimitrin, a nonclassical acetogenin, has been achieved. A
key feature of our approach is the application of stereoselective double intramolecular oxymercuration for the efficient preparation
of a mono-hydroxylated unsymmetrical bis-THF ring with two flanking hydroxyl groups. A chelation-controlled Grignard reaction
plays a pivotal role in the elaboration of a commercially available carbohydrate.
Ó 2007 Elsevier Ltd. All rights reserved.
Since the identification of the Annonaceous acetogenin
uvaricin,1 isolated from the roots of Uvaria accuminata,
as an in vivo active antitumor agent, there has been sig-
nificant interest in the isolation and biological evalua-
tion of acetogenins derived from the Annonaceae
family.2 Annonaceous acetogenins are known to be
highly potent and selective antitumor agents. More
interestingly, some members of this family have been
shown to possess the ability to combat resistance in
multi drug-resistant cancerous cells.3,4 The origin of
the selective cytotoxicity of acetogenins is believed to
result from their complexation with ubiquinone-linked
NADH oxidase present in the plasma membrane of
tumor cells. Acetogenins also bind NADH-ubiquinone
oxidoreductase (Complex I), which is a membrane
protein present in the mitochondrial electron-transport
system.5–9 Complex I has been implicated in several
diseases including idiopathic Parkinson’s disease, matu-
rity onset diabetes, stroke-like episodes, and Hunting-
ton’s disease.10 However, the precise mode of
complexation of acetogenins with the target proteins
has not been delineated. Important characteristic struc-
tural features of Annonaceous acetogenins include a
butenolide segment, one or more tetrahydrofuran rings,
and alkyl chain residues on either side.
Mucoxin, a nonclassical acetogenin, is the first of its
kind found to contain a trisubstituted hydroxylated
tetrahydrofuran ring.11 Recently, asimitrin 1 a ring-
hydroxylated unsymmetrical bis-tetrahydrofuran aceto-
genin (Fig. 1) was isolated from the seeds of Asimina
triloba.12 This novel type of acetogenin was found to
be cytotoxic selectively against prostate (PC-3) at about
10,000 times and colon adrenocarcinoma (HT-29) at
about 100 times the potency of adriamycin. Such power-
ful antitumor activity and the unique structure of 1 have
made it an attractive target similar to other classical bis-
THF acetogenins for synthetic chemists.
We have recently shown that stereoselective intramole-
cular oxymercuration can be employed effectively for the
synthesis of the bis-tetrahydrofuran ring system present
in nonclassical acetogenins with excellent selectivity.13
As a further test of this protocol for the synthesis of
the bis-tetrahydrofuran system present in asimitrin, we
describe herein the first stereoselective synthesis of the
OH
O
O
OH
OH
O
OH
O
Keywords: Acetogenins; Asimitrin; Adjacent bis-tetrahydrofuran; Int-
ramolecular oxymercuration; Chelation-controlled Grignard reaction.
asimitrin 1
Figure 1. Structure of asimitrin 1.
*
Corresponding author. Tel.: +91 20 25902627; fax: +91 20
25902629; e-mail: dk.mohapatra@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.147

5198
D. K. Mohapatra et al. / Tetrahedron Letters 48 (2007) 5197–5200
Chelation-controlled
Grignard reaction
O
O
Intramolecular
oxymercuration
HO
HO
O
OH
Ref. 14
NaH, TsCl
THF, 0 o
O
Cross-Metathesis
followed by reduction
C
O
O
O
2 h, 90%
HO
O
O
O
OH
6
7
OH
OH
O
OH
O
Intramolecular
oxymercuration
MgBr
O
O
O
O
CuCN
ether, 0 o
1 h, 81%
O
Asimitrin (1)
C
O
O
8
9
O
O
OH
Hg(OAc)2
O
O
+
O
3
O
CH2Cl2, rt
2 h, 84%
OTBS
O
O
HgCl
HgCl
O
O
5
10
(8:2)
O
O
OH
OBn
2
Scheme 2. Synthesis of 5 and 10.
tetrahydrofuran derivatives with 8:2 selectivity. Flash
silica gel column chromatography was used to obtain
pure trans- and cis-tetrahydrofurans 5 and 10. The H
OH
1
O
8
OBn
4
OTBS
O
O
O
O
O
O
O
HgCl
HO
O
O
5
6
Scheme 1. Retrosynthetic analysis.
C10–C34 fragment (incorporating the adjacent bis-tetra-
hydrofuran moiety) of asimitrin.
Our synthetic strategy towards 1 was based on a conver-
gent approach involving a cross metathesis for coupling
the bis-THF core 2 with c-lactone segment 3 as illustrated
in Scheme 1. The bis-THF core would be prepared from
1,2:5,6-di-O-isopropylidene-a-D-glucofuranose, which
plays a central role, serving not only as the source of
the C17, C19, and C20 stereocenters, but also setting
the stage for introducing the C16 and C23 stereocenters
through stereoselective intramolecular oxymercuration
and chelation-controlled Grignard reactions.
The synthetic endeavor commenced from commercially
available 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose:
the secondary hydroxyl group was converted to its
triflate derivative. Treatment with DBU resulted in
elimination of the triflate group to afford the olefin.
Hydrogenation of the resulting double bond, in the pres-
ence of Raney-Ni in ethanol at 40 psi, gave the reduced
product whose spectral and analytical data were in good
agreement with the reported values.14 Selective depro-
tection of the 5,6-O-isopropylidene group and treatment
of the resulting diol with NaH and TsCl afforded the
epoxide 8.15 Copper-catalyzed epoxide ring-opening
with allylmagnesium bromide in the presence of CuCN
furnished alcohol 9 in 81% yield (Scheme 2).16 Intra-
molecular oxymercuration of alcohol 9 with mercury(II)
acetate in dichloromethane gave a trans–cis mixture of
Figure 2. ORTEP diagrams of 5 and 10.

D. K. Mohapatra et al. / Tetrahedron Letters 48 (2007) 5197–5200
5199
and 13C NMR of compounds 5 and 10 were in good
agreement with the assigned structures.17 The relative
stereochemistry was ascertained by NOE experiments.
The structures and absolute stereochemistry were unam-
biguously confirmed by single-crystal X-ray crystallo-
graphy (Fig. 2).18
ride22 afforded compounds 13 and 14 in a 9:1 ratio. These
were separated by flash silica gel column chromatogra-
phy (Scheme 3). The chirality of the newly created sec-
ondary hydroxyl group bearing center was confirmed
by a modified Mosher’s method.23 With 13 in hand,
our next aim was to construct the trisubstituted tetra-
hydrofuran ring with requisite stereochemistry derived
from the carbohydrate moiety. At this point, it was nec-
essary to protect the hydroxyl functionality with a pro-
tecting group that would withstand the 1,2-acetonide
deprotection conditions. Thus, treatment of compound
13 with BnBr in the presence of NaH afforded the benzyl
ether derivative 16 in 91% yield. Compound 16 was then
treated with p-TSA in the presence of THF and H2O
(7:3) under reflux to afford the hemiacetal, which after
purification by silica gel column chromatography was
subjected to one-carbon homologation24 with Ph3P@CH2
to produce olefin 18 in 72% yield. The allylic hydroxyl
group was selectively protected as its TBS-ether 4 in
94% yield. The requisite structural skeleton was now
set for the second intramolecular oxymercuration reac-
tion. Treatment of compound 4 with mercury(II) acetate
in dichloromethane afforded 19 as a single diastereoiso-
mer (Scheme 4). The structure of compound 19 was con-
firmed by 1H, 13C NMR, and elemental analysis and the
stereochemistry around the tetrahydrofuran ring was
assigned by NOE experiments.25
Demercuration of 5 was carried out under a stream of
oxygen in the presence of sodium borohydride to afford
the primary alcohol 11. Our next concern was to intro-
duce the alkyl side chain. To this end, the primary hydro-
xyl group of 11 was oxidized under Swern conditions19 to
afford aldehyde 12. Treatment of 12 with decylmagne-
sium bromide in the presence of CuBrÆDMS gave 13
and 14 containing a secondary hydroxyl group flanking
the THF ring with a 7:3 preponderance of the desired
isomer 13.20 To improve the selectivity, the secondary
hydroxyl group was oxidized with IBX21 in DMSO to
the keto derivative 15, which on treatment with L-Select-
(COCl)2
DMSO
O
O
O
O
CH2Cl2
O
O
O
X
12
DIEA, -78 o
2 h, 82%
C
O
O
O2, NaBH4
5 = HgCl
CuBr.DMS
Ether, -78 o
5 h, 78%
Decylmagnesium
bromide
DMF, rt,
1 h, 86%
C
11 = OH
O
O
O
+
O
Demercuration of 19 was carried out using a fast flow of
oxygen in the presence of sodium borohydride to obtain
20 in 81% yield. Finally, Swern oxidation followed by
Grignard reaction with hexenylmagnesium bromide in
the presence of CuBrÆDMS at ꢀ100 °C afforded 2 with
the secondary hydroxyl group with the required stereo-
chemistry as the exclusive product.26 The configuration
of the newly created hydroxyl center at C15 of 2 was
assigned following the modified Mosher’s method.
8
8
O
O
O
O
OH
OH
13
14
(7:3)
THF, rt
2 h, 92%
IBX
DMSO
O
O
8
O
O
O
15
THF, -100 oC, 4 h, 89%
L-Selectride
In summary, commercially available 1,2:5,6-di-O-iso-
propylidene-a-D-glucofuranose was elaborated via a
double stereoselective intramolecular oxymercuration
reaction sequence developed in our laboratories, to the
C10–C34 fragment of asimitrin in a simple and efficient
stereocontrolled manner. Total synthesis of the target
molecule is underway and will be reported in due course.
O
O
O
O
+
8
8
O
O
OH
OH
O
O
(9:1)
13
14
Scheme 3. Synthesis of 13 and 14.
O
Ph3P+CH3I-
OH
O
OH
p-TSA, THF
TBSCl, Im
O
O
O
8
8
8
H2O, refx.
2 h, 84%
n-BuLi, THF
10 h, 72%
CH2Cl2, rt
4 h, 94%
O
OBn
OR
OBn
OH
OH
O
NaH, BnBr
17
18
13 R = H
THF, 0 o
C
3 h, 91%
16 R = Bn
OTBS
HgCl
OTBS
OH
(COCl)2
DMSO
O2, NaBH4
Hg(OAc)2
OH
O
O
O
O
O
O
CH2Cl2
DMF, rt
3 h, 81%
CH2Cl2, rt
1 h, 82%
8
8
8
DIEA, -78 o
2 h, 79%
C
OBn
OBn
OBn
OTBS
4
19
20
OTBS
OH
OTBS
C6H11MgBr, CuBr.DMS
ether, -100 o
2 h, 76%
C
O
O
O
8
OBn
O
OBn
21
2
Scheme 4. Synthesis of segment 2 of asimitrin.

5200
D. K. Mohapatra et al. / Tetrahedron Letters 48 (2007) 5197–5200
(s, 3H), 1.32 (s, 3H); 13C NMR (50 MHz, CDCl3) 112.8,
Acknowledgments
106.2, 82.5, 80.6, 77.8, 38.0, 36.6, 33.6, 29.1, 27.6, 26.5;
Anal. Calcd for C12H19O4HgCl: C, 31.16; H, 4.11.
Found: C, 31.38; H, 4.25. Analytical and spectral data
S.N. and S.M. thank the CSIR, New Delhi, for the
financial support in the form of a research fellowship.
We also thank Dr. Mohan M. Bhadbhade and Dr. P.
R. Rajmohanan for the X-ray crystallographic assis-
tance and NMR data, respectively.
25
of 10. ½aꢁD +21.4 (c 0.9, CH2Cl2); IR (CHCl3): 3024,
1
1639, 1392, 1376, 1217, 1044 cmꢀ1; H NMR (200 MHz,
CDCl3): d 5.77 (d, J = 4.0 Hz, 1H), 4.70 (m, 1H), 4.39
(m, 1H), 4.11 (q, J = 7.5 Hz, 1H), 4.01 (m, 1H), 2.39 (m,
1H), 2.21–2.11 (m, 3H), 1.89 (m, 1H), 1.84 (m, 1H), 1.74
(s, 1H), 1.57 (s, 3H), 1.41 (m, 1H), 1.31 (s, 3H); 13C
NMR (50 MHz, CDCl3) 112.7, 106.3, 83.1, 81.4, 80.5,
78.6, 38.5, 34.9, 34.1, 28.2, 27.4, 26.3; Anal. Calcd for
C12H19O4HgCl: C, 31.16; H, 4.11. Found: C, 31.24; H,
4.17.
References and notes
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1113–1120.
18. Crystallographic data for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
645458 for 5 and CCDC 645459 for 10. 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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25
25. Analytical and spectral data of 19. ½aꢁD ꢀ8.86, (c 1.3,
CH2Cl2); IR (CHCl3): 3059, 3025, 1869, 1802, 1747, 1668,
1601, 1583, 1492, 979, 964, 748 cmꢀ1; 1H NMR (200 MHz,
CDCl3): d 7.25–7.14 (m, 5H), 4.65 (d, J = 11.6 Hz, 1H),
4.49 (d, J = 11.6 Hz, 1H), 4.22–4.13 (m, 2H), 4.05–3.89
(m, 2H), 3.74 (m, 1H), 3.54 (m, 1H), 2.24–2.03 (m, 2H),
1.94–1.77 (m, 3H), 1.72–1.51 (m, 3H), 1.15 (s, 18H), 0.85
(s, 9H), 0.79 (t, J = 5.5 Hz, 3H), 0.03 (s, 6H); 13C NMR
(50 MHz, CDCl3): 139.3, 128.2, 127.9, 127.3, 82.8, 81.1,
80.8, 80.5, 80.4; 73.6, 73.5, 38.7, 31.9, 29.7, 29.6, 29.4, 28.7,
26.3, 25.9, 25.9, 22.7, 18.5, 14.2, ꢀ4.4; Anal. Calcd for
C33H57O4SiHgCl: C, 50.76; H, 7.30. Found: C, 50.82; H,
7.48.
14. Horton, D.; Roski, J. P.; Norris, P. J. Org. Chem. 1996,
61, 3783–3793.
25
15. Analytical and spectral data of 8. ½aꢁD ꢀ37.77 (c 1.0,
CH2Cl2); IR (CHCl3) 1597, 1495, 1454 cmꢀ1 1H NMR
;
(200 MHz, CDCl3) d 5.83 (d, J = 3.7 Hz, 1H), 4.75 (ddd,
J = 1.2, 3.7, 5.3 Hz, 1H), 3.82 (ddd, J = 3.0, 7.3, 10.3 Hz,
1H), 3.35 (m, 1H), 2.81 (t, J = 4.0 Hz, 1H), 2.58 (dd,
J = 2.6, 4.8 Hz, 1H), 2.22 (dd, J = 5.6, 8.5 Hz, 1H), 2.14
(m, 1H), 1.57 (s, 3H), 1.34 (s, 3H); 13C NMR (50 MHz,
CDCl3) d 112.3, 106.7, 82.4, 80.3, 53.6, 44.5, 34.1, 27.0,
25.9; Anal. Calcd for C9H14O4: C, 58.06; H, 7.52. Found:
C, 58.32; H, 7.74.
25
26. Analytical and spectral data of 2. ½aꢁD ꢀ10.94 (c 0.4,
CH2Cl2); IR (CHCl3): 3480, 2976, 2940, 1640, 1598 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 7.35–7.29 (m, 4H), 7.23
(m, 1H), 5.79 (m, 1H), 4.97 (m, 1H), 4.90 (m, 1H), 4.72 (d,
J = 11.6 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.43 (q,
J = 6.2 Hz, 1H), 4.09–4.04 (m, 2H), 3.82 (m, 1H), 3.75 (m,
1H), 3.62 (ddd, J = 3.6, 6.8, 11.0 Hz, 2H), 2.15 (m, 1H),
2.07–2.03 (m, 2H), 2.00–1.87 (m, 3H), 1.82 (m, 1H), 1.68
(m, 1H), 1.52–1.37 (m, 7H), 1.30–1.22 (m, 17H), 0.90 (s,
9H), 0.88 (t, J = 6.8 Hz, 3H), 0.08 (s, 6H); 13C NMR
(50 MHz, CDCl3): 139.3, 139.0, 128.2, 127.8, 127.3, 114.2,
83.7, 82.9, 81.1, 80.3, 79.5, 73.4, 73.2, 70.4, 38.0, 33.9, 33.5,
32.0, 31.9, 29.7, 29.6, 29.4, 29.2, 28.8, 26.0, 25.9, 25.8, 25.5,
22.7, 18.0, 14.1, ꢀ4.3, ꢀ5.0; Anal. Calcd for C39H68O5Si:
C, 72.67; H, 10.55. Found: C, 72.83; H, 10.37.
16. Reddy, P. P.; Yen, K.-F.; Uang, B.-J. J. Org. Chem. 2002,
67, 1034–1035.
25
17. Analytical and spectral data of 5. ½aꢁD ꢀ16.5 (c 0.6,
CH2Cl2); IR (CHCl3): 3017, 1637, 1383, 1374, 1215,
1031 cmꢀ1 1H NMR (200 MHz, CDCl3): d 5.75 (d,
;
J = 3.9 Hz, 1H), 4.71 (m, 1H), 4.40 (m, 1H), 4.32 (q,
J = 7.7 Hz, 1H), 3.95 (m, 1H), 2.39 (dd, J = 5.5, 12.0 Hz,
1H), 2.23–2.07 (m, 5H), 1.88 (m, 1H), 1.71 (s, 1H), 1.56