Synthesis of bis-tetrahydrofuran core of salzmanolin using intramolecular oxymercuration reaction

Article abstract of DOI:10.1007/s11164-012-0702-y

The bis-THF core of salzmanolin was commenced from d-glucose as starting material. Stereoselective bis-THF ring has been established following intramolecular oxymercuration as the key reaction. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-012-0702-y

Res Chem Intermed (2013) 39:1459–1462
DOI 10.1007/s11164-012-0702-y
Synthesis of bis-tetrahydrofuran core of salzmanolin
using intramolecular oxymercuration reaction
•
Seetaram Mohapatra Chittaranjan Bhanja
•
•
Subhendu Chakraborty Sabita Nayak
Received: 25 May 2012 / Accepted: 22 June 2012 / Published online: 12 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract The bis-THF core of salzmanolin was commenced from D-glucose as
starting material. Stereoselective bis-THF ring has been established following intra-
molecular oxymercuration as the key reaction.
Keywords Acetogenin Á Bis-THF Á Natural products Á Salzmanolin Á
Stereoselectivity Á Oxymercuration
Introduction
In recent years, the Annonaceous acetogenins have attracted immense attention due
to the remarkably wide range of biological activities like cytotoxic, antitumor,
antimalarial, pesticidal, antifeedant, and antitumor activities [1–3]. Structurally, the
acetogenins possess a bis-THF ring core flanked by two hydroxyl groups shows the
highest anticancer activity [4]. Some reports are there for the synthesis of bis-THF
ring core of acetogenins [5–8]. Salzmanolin (1) (Fig. 1), a ring hydroxylated
unsymmetrical bis-tetrahydrofuran acetogenins, was isolated from the roots of
Annona salzmanii D.C. by Queiroz et al. [9] in 2003. It shows cytotoxic activity
against a cancer cell line (KB, ED50 = 1 9 10-3 lg/mL) when compared with
normal cells (Vero, ED50 = 1 9 10-2 lg/mL). The interesting structural feature
and biological activities of 1 attracted us for its total synthesis. Initially, we focused
on the synthesis of central core of 1. Since the relative stereochemistry is reported,
S. Mohapatra (&) Á S. Chakraborty Á S. Nayak (&)
Department of Chemistry, Ravenshaw University, Cuttack 753 003, Odisha, India
e-mail: seetaram.mohapatra@gmail.com
S. Nayak
e-mail: sabitanayak18@gmail.com
C. Bhanja
Department of Chemistry, Utkal University, Bhubaneswar 751 004, Odisha, India
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S. Mohapatra et al.
trans
O
erythro
OH
threo
erythro
OH
OH
O
2
OH
OH
1
O
O
Fig. 1 Structure of salzmanolin
Fig. 2 Possible core structure
of salzmanolin
OTBS
OTBS
O
O
O
O
O
O
OH
2
3
OH
OH
OH
OTBS
OTBS
O
O
4
5
OH
OH OH
OH
OTBS
R
OH
OH
O
BnO
O
7
O
8
O
S
S
S O
OBn
S
O
O
H
H
OH
BnO
HO
6
O
O
O
9
O
O
O
O
HO
O
BnO
10
Fig. 3 Retrosynthetic analysis for mono-hydroxylated bis-tetrahydrofuran ring system of salzmanolin
on this basis we assumed few possible structures like compound 2, 3, 4, and 5
(Fig. 2). We have previously reported compound 2 [10]. Now here we have reported
benzyl protected compound 3 starting from D-glucose.
The retrosynthetic analysis for the bis-tetrahydrofuran ring system (6) is
illustrated in Fig. 3. Stereo-controlled synthesis of 8 was planned to utilize an
intramolecular oxymercuration reaction on 4-alkenol derivative 9 followed by a
second oxymercuration reaction on 7 to form the target compound 6 (Fig. 3).
The intermediate 9 was commenced from D-glucose following the known
literature procedure [11]. Having compound 9, it was planned to install the
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Synthesis of bis-tetrahydrofuran core of salzmanolin
1461
O
O
O
Ref.8
a
O
O
OH
O
HO
BnO
O
O
O
H
H
O
ClHg
BnO
O
O
11
10
9
b
O
O
O
d
c
O
H
O
H
O
O
O
H
O
O
H
H
O
O
H
BnO
BnO
HO
13
HO
BnO
12
8
Scheme 1 Reagents and conditions: a Hg(OAc)2, THF, rt, 2 h, 87 %; b O2, NaBH4, DMF, rt, 4 h, 81 %;
c (i) Na, naphthalene, THF, 0 °C, 73 % (ii) NaH, BnBr, rt, 3 h, 94 %; d (i) NaH, CS2, MeI, THF, 0 °C,
2 h, 93 %; (ii) Bu3SnH, AIBN, toluene, 90 °C, 3 h, 94 %
OH
O
OH
OH
e
g
O
O
O
O
O
O
HgCl
OBn
OBn
BnO
14
8
7
f
OTBS
OTBS
R
OH
h
g
S
S
S
O
S
O
O
O
O
OBn
OH
HgCl
OBn
6
OBn
15
16
OTBS
Central core of
Salzmanolin
O
Si
Hg2+
O
OH
OBn
10
Fig-3 proposed mechanism
Scheme 2 Reagents and conditions: e (i) p-TSA(cat.), THF-H2O, 60 °C, 2 h, 68 %; (ii) Ph3P=CH2,
THF,0 °C-rt, 10 h 62 %; f imidazole, TBSCl, DMAP (cat.), DCM, rt, 2 h, 82 %; g Hg(OAc)2, THF, rt,
2 h, 76 %; h O2, NaBH4, DMF, rt, 4 h, 74 %
tetrahydrofuran ring of 11 diastereoselectively. Hence, the intramolecular oxym-
ercuration reaction performed on 9 using mercury (II) acetate in THF led to the
formation of 11 exclusively [12, 13]. The relative stereochemistry around the THF
ring of 11 was assigned by NOESY studies and was found to be trans. The
demercuration reaction was carried out under a stream of oxygen in the presence of
sodium borohydride in DMF to afford the primary alcohol 12, which on
debenzylation using Na/naphthalene and subsequent regioselective benzyl protec-
tion of primary alcohol provided compound 13 in good yield. After having
compound 13 in hand, we intended to deoxygenate the secondary-OH group to
achieve compound 8. For this, two-step synthesis was followed. Compound 13
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undergoes Barton–McCombie protocol provided compound 8 in good yield
(Scheme 1).
Our next concern was to set up the second tetrahydrofuran ring, and thus,
compound 4 was treated with catalytic amount of p-TSA in THF-H2O under reflux
condition afforded the hemiacetal, which after purification by silica gel column
chromatography, was subjected to one carbon homologation with Ph3P=CH2 to
produce the olefin 7 [14]. Intramolecular oxymercuration reaction of 7 using
Hg(OAc)2 in THF afforded an inseparable mixture of products 14. To achieve
diastereoselectivity, it was planned to protect the allylic alcohol selectively and then
to bring about the intramolecular oxymercuration reaction. To this end, allylic
alcohol 7 was selectively protected by the TBS group using TBSCl, imidazole in
DCM provided 15. Intramolecular oxymercuration reaction of 15 using Hg(OAc)2,
THF provided compound 16 exclusively. Demercuration of compound 16 using a
flow of O2 in NaBH4 in DMF provided the central core of salzmanolin 6 in good
yield (Scheme 2).
Conclusions
Starting from D-glucose, we have synthesized benzyl protected bis-tetrahydrofuran
core of salzmanolin using stereoselective intramolecular oxymercuration reaction as
the key step. Following the present protocol, the total synthesis of salzmanolin is
underway and will be reported in due course.
Acknowledgments S.M. thanks UGC, New Delhi, for financial support in the form of a minor research
project and S.N. thanks DST, New Delhi, for financial support in the form of fast-track Grant Regd No
61/2011.
References
1. A. Bermejo, B. Figade‘re, M.C. Zafra-Polo, I. Barrachina, E. Estornell, D. Cortes, Nat. Prod. Rep. 22,
269 (2005)
2. F.Q. Allali, X.-X. Liu, J.L. McLaughlin, J. Nat. Prod. 62, 504 (1999)
3. S.D. Jolad, J.J. Hoffman, K.H. Schram, J.R. Cole, M.S. Tempesta, G.R. Kriek, R.B. Bates, J. Org.
Chem. 47, 3151–3153 (1982)
4. V. Piccialli, T. Caserta, L. Caruso, L. Gomez-Paloma, G. Bifulco, Tetrahedron Lett. 62,
10989–11007 (2006)
5. N. Maezaki, N. Kojima, H. Tominaga, M. Yanai, T. Tanaka, Org. Lett. 5, 1411–1414 (2003)
6. L.M. Wysocki, M.W. Dodge, E.A. Voight, S.D. Burke, Org. Lett. 8, 5637–5640 (2006)
7. V. Piccialli, T. Caserta, L. Caruso, L.G. Paloma, G. Bifulco, Tetrahedron 62, 10989–11007 (2006)
8. C.L. Morris, Y. Hu, G.D. Head, L.J. Brown, W.G. Whittingham, R.C.D. Brown, J. Org. Chem. 74,
981–988 (2009)
9. F.E. Queiroz, F.R. Roblot, L.O. Vote, M.D. Paulo, R. Hocquemiller, J. Nat. Prod. 66, 755–758 (2003)
10. D.K. Mohapatra, P.R. Naidu, D.S. Reddy, S. Nayak, S. Mohapatra, E. J. Org. Chem. 6263–6268
(2010)
11. M.K. Gurjar, S. Mohapatra, U.D. Phalgune, V.G. Puranik, D.K. Mohapatra, Tetrahedron Lett. 45,
7899–7902 (2004)
12. V. Speziale, J. Roussel, A. Lattes, J. Heterocycl. Chem. 11, 771–775 (1974)
13. M. Vincens, C. Dumont, M. Vidal, Can. J. Chem. 57, 2314–2318 (1979)
14. F. Freeman, K.D. Robarge, Carbohydr. Res. 154, 270–274 (1986)
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