Double intramolecular oxymercuration: stereoselective synthesis of highly substituted bis-tetrahydrofuran

Article abstract of DOI:10.1016/j.tetlet.2006.06.049

Stereoselective intramolecular oxymercuration has been demonstrated as the key reaction for the efficient preparation of mono- and dihydroxylated unsymmetrical bis-tetrahydrofuran skeletons present in naturally occurring biologically active acetogenins us

Full text of DOI:10.1016/j.tetlet.2006.06.049

Tetrahedron Letters 47 (2006) 5943–5947
Double intramolecular oxymercuration: stereoselective synthesis
of highly substituted bis-tetrahydrofuran
Debendra K. Mohapatra,* Seetaram Mohapatra and Mukund K. Gurjar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 3 May 2006; revised 31 May 2006; accepted 8 June 2006
Available online 30 June 2006
Abstract—Stereoselective intramolecular oxymercuration has been demonstrated as the key reaction for the efficient preparation of
mono- and dihydroxylated unsymmetrical bis-tetrahydrofuran skeletons present in naturally occurring biologically active aceto-
genins using carbohydrates. These trans- and syn-selective intramolecular oxymercurations were explored in an enantioselective
synthesis of the bis-tetrahydrofuran skeleton of mucoxin.
Ó 2006 Elsevier Ltd. All rights reserved.
In recent years, the Annonaceous acetogenins have been
the focus of extensive synthetic efforts1 as a result of
O
O
O
O
H
H
H
H
H H
H
H
R1
R1
their remarkable range of biological properties such as
antitumor, antiprotozoal, antifeedant, immunosuppres-
sive, pesticidal, anthelmintic and microbial.2 In particu-
lar, the 2,5-disubstituted bis-tetrahydrofuran (classical
acetogenins 1–5) sub-group of this family has been
found to inhibit the growth of human tumor cells at
sub-micromolar levels. A large proportion of such com-
pounds are also cytotoxic to tumor cells that are resis-
tant to typical chemotherapeutic agents.3 Mucoxin 6, a
nonclassical acetogenin, is the first of its kind found to
contain a trisubstituted hydroxylated tetrahydrofuran
ring (Fig. 1).4 Recently, asimitrin 7 a ring-hydroxylated
unsymmetrical bis-tetrahydrofuran acetogenin was iso-
lated from the seeds of Asimina triloba.5 This class of
compound showed cytotoxic selectivity with 100–
10,000 times the potency compared to the classical ace-
togenins. Because of their diverse array of biological
activities and by virtue of their extremely limited avail-
ability in Nature, these compounds have attracted the
attention of synthetic organic chemists worldwide.
R
R
3 Bulladecin
4 Annonisin
5 Guanaconne
1 Rollidecin C
2 Rollidecin D
HO
OH
O
O
O
O
H
H
H
H
H
H
H
H
R1
R1
R
R
6 Mucoxin
1-7; R1 = alkyl side-chain, R = butenolide fragment
7 Asimitrin
Figure 1. Classical and non-classical acetogenins.
approaches for bis-tetrahydrofuran ring formation are
the cyclization of hydroxy-epoxides,6 hydroxy-alkenes,7
and variations of the Williamson ether synthesis.8 Proto-
cols based on Sharpless epoxidation and dihydroxyl-
ation,9 addition of chiral allenyltin reagents to
aldehydes,10 and elaboration of natural enantiopure
materials,11 have been employed for the synthesis of
the tetrahydrofuran precursors.
Stereocontrolled construction of the tetrahydrofuran
unit plays a pivotal role in the total synthesis of Anno-
naceous acetogenins. Among the more successful
We have previously reported intramolecular oxymer-
curation as an efficient method for stereoselective
formation of the tetrahydrofuran ring during an
enantioselective synthesis of the C12–C29 fragment of
amphidinolide E.12 Such ring closures have been earlier
pioneered by Evans’ and Hannessian’s groups.13
Prompted by the hydroxylated tetrahydrofuran core
present in non-classical acetogenins as well as their
Keywords: Acetogenins; Intramolecular oxymercuration; Wittig reac-
tion; Unsymmetrical bis-tetrahydrofuran; Demercuration; Barton–
McCombie deoxygenation.
*
Corresponding author. Tel.: +91 20 25902627; fax: +91 20
25902629; e-mail: dk.mohapatra@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.049

5944
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 5943–5947
pronounced activity, we became intrigued with the
possibility of using an intramolecular oxymercuration
strategy for an efficient preparation of mono- and di-
hydroxylated bis-tetrahydrofuran systems which could
be used to synthesize sufficient amounts of naturally
occurring acetogenins and/or their derivatives and cong-
eners with various side-chains, for the evaluation of bio-
logical activity (SARs).
O
:O
H
Hg
+
O
O
AcO
:O
Ph
Figure 2. Proposed mechanism.
Our retrosynthetic analysis for the dihydroxylated bis-
tetrahydrofuran ring system is illustrated in Scheme 1.
The stereocontrolled off-template construction of the
first tetrahydrofuran ring was planned to utilize an
intramolecular oxymercuration protocol on 4-alkenol
derivative 11 followed by a second one on 9 to lead to
the target compound 8.
tion at C-3 and C-4 from the carbohydrate moiety, thus,
compound 10 was treated with 20% acetic acid in the
presence of a catalytic amount of sulfuric acid under re-
flux to afford the hemiacetal, which after purification by
silica gel column chromatography was subjected to one-
carbon homologation18 with Ph3P@CH2 to produce the
olefin 9.
The known14 intermediate 11 was prepared from D-glu-
cose by a slight modification of the earlier protocol,
wherein the Grignard reaction was carried out in ether
by reverse addition of the Grignard reagent at 0 °C to
improve the diastereoselectvity (9:1) in favor of 11.
Compound 11 was isolated from the crude reaction mix-
ture by crystallization from hexane in 80% yield. The
intramolecular oxymercuration15 reaction of 11 with
mercuric chloride in water at room temperature gave a
cis–trans mixture of tetrahydrofuran derivatives with
3:1 selectivity, which was conveniently separated by
flash silica gel column chromatography to obtain the
pure cis- and trans-tetrahydrofurans 13 and 14. The ste-
reochemistry of 13 was unambiguously confirmed by
single-crystal X-ray crystallography. It is noteworthy
that treatment of compound 11 with mercury(II) acetate
in THF led to the formation of compound 14, exclu-
sively. As previously suggested,16 in THF, coordina-
tion-controlled mercurium ion formation followed by
intramolecular nucleophilic attack by the C-5 hydroxyl
group from the opposite face would lead to formation
of the trans-isomer as the sole product (Fig. 2). In the
presence of H2O, the coordination is prevented leading
to a mixture of cis- and trans-tetrahydrofuran ring sys-
tems. The demercuration17 was then carried out under
a stream of oxygen in the presence of sodium boro-
hydride to afford the primary alcohol, which on benzyl-
ation gave 10 (Scheme 2). Our next concern was to
construct the second tetrahydrofuran ring with substitu-
Now, the requisite structural skeleton was set for the
second intramolecular oxymercuration. Treatment of
compound 9 with mercury(II) acetate in dichlorometh-
ane or THF afforded 16 as the major product, while in
the presence of H2O, compound 15 was the major prod-
uct (Scheme 3). Hence, a study of the influence of H2O
was performed and Table 1 summarizes the results of
stereoselective intramolecular oxymercuration under
different reaction conditions. The stereoisomers could
be separated easily by silica gel column chromatography
1
and their purities and structures were confirmed by H,
13C NMR, elemental analysis, and the relative stereo-
chemistries
were
ascertained
using
NOESY
experiments.19
Application of this efficient protocol to the asymmetric
synthesis of the hydroxylated tetrahydrofuran skeleton
present in naturally occurring biologically active muc-
oxin 6 from compound 15 is illustrated in Scheme 4.
Demercuration of 15 under a stream of oxygen in the
presence of sodium borohydride, followed by selective
protection of the primary hydroxyl group as its TBS
ether afforded compound 18. With 18 in hand, it was
then obligatory to remove the secondary oxygen func-
tion from C-4 of the tetrahydrofuran moiety following
the Barton–McCombie protocol via the xanthate 19
and treatment with tributylstannane to produce 20 in
excellent yield. Cleavage of the silyl ether using TBAF
OH
BnO
OH
BnO
O
O
O
OH
H
H
H
H
H
H
OH
OBn
OBn
9
8
O
O
O
O
O
OH
HO
O
O
H
OBn
H
BnO
O
O
O
O
O
BnO
12
11
10
Scheme 1. Retrosynthetic analysis.

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 5943–5947
5945
O
O
O
OH
O
O
Ref. 14
a
HO
O
O
H
O
H
O
O
(for 13+14)
HgCl
O
O
BnO
O
BnO
11
13
b
12
+
(for 14)
OH
BnO
O
e,f
c,d
O
O
O
H
H
O
H
H
O
OH
H
OBn
H
HgCl
OBn
O
O
BnO
BnO
9
10
14
Scheme 2. Reagents and conditions: (a) HgCl2, H2O, rt, 1 h, (13:14 = 3:1), (90%); (b) Hg(OAc)2, THF, rt, 2 h, only 14, (87%); (c) O2, NaBH4, DMF,
rt, 4 h (81%); (d) NaH, BnBr, rt, 3 h (94%); (e) 20% CH3COOH, H2SO4 (cat.), 80 °C, 7 h (78%) and (f) Ph3P@CH2, THF, rt, 4 h (88%).
OH
BnO
OH
BnO
OH
BnO
a
+
O
O
O
O
O
H
H
OBn
OH
H
H
H
H
OBn
H
H
H
H
HgCl
HgCl
OBn
15
16
9
Scheme 3. Second stereoselective oxymercuration under different reaction conditions (Table 1).
Table 1. Results from the intramolecular oxymercuration under different reaction conditions
Entry
9 (equiv)
Conditions
Ratio 15:16
Yielda (%)
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
Hg(OAC)2 (1.5 equiv), CH2Cl2, rt, 3 h
Hg(OAC)2 (1.5 equiv), THF, rt, 4 h
Hg(OAC)2 (1.5 equiv), H2O–THF (2:1), rt, 3 h
HgCl2 (1.5 equiv), H2O–THF (2:1), rt, 2 h
HgCl2 (1.5 equiv), H2O, rt, 2 h
5:95
5:95
85:15
87:13
95:5
92
89
90
87
92
91
HgCl2 (1.5 equiv), THF, rt, 2 h
14:86
a Isolated yield.
OH
OH
BnO
OH
BnO
BnO
a
c
b
O
O
O
O
O
H
O
H
H
H
OBn
H
H
H
H
OBn
H
H
H
H
OH
HgCl
OTBS
OBn
17
18
15
O
SMe
BnO
BnO
BnO
e
d
S
O
O
O
H
O
O
O
H
H
H
OBn
H
OBn
H
H
H
H
H
OBn
H
H
OTBS
OTBS
OH
19
20
21
Scheme 4. Reagents and conditions: (a) O2, NaBH4, DMF, rt, 4 h (86%); (b) imidazole, TBSCl, rt, 5 h (92%); (c) NaH, CS2, MeI, THF, 0 °C, 2 h
(93%); (d) Bu3SnH, AIBN, toluene, 90 °C, 3 h (94%) and (e) TBAF, THF, rt, 3 h (89%).
in THF at room temperature afforded the target unsym-
metrical bis-tetrahydrofuran with requisite stereochem-
istry and functionality. This substance is now ready
for connecting to the other subunits of mucoxin 6.
aration of various functionalized bis-tetrahydrofuran
derivatives, which are subunits of polyether antibiotics
and acetogenins, using a strategy involving stereoselec-
tive intramolecular oxymercuration as the key step. An
application of the strategy has been demonstrated by
synthesizing the unsymmetrical bis-tetrahydrofuran
skeleton of mucoxin with appropriate stereochemistry
In conclusion, starting from D-glucose, we have demon-
strated an efficient stereocontrolled routes for the prep-

5946
D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 5943–5947
13. (a) Hanessian, S.; Cooke, N. G.; Dettoff, B.; Sakito, Y. J.
Am. Chem. Soc. 1990, 112, 5276–5290; (b) Evans, D. A.;
Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am.
Chem. Soc. 1990, 112, 5290–5313.
14. Bertrand, P.; Sukkari, H. E.; Gesson, J. P.; Renoux, B.
Synthesis 1999, 330–335.
and functionality starting from compound 12 in fifteen
steps with 17% overall yield. Following the present
protocol, the total syntheses of acetogenins are under-
way and will be reported in due course.
15. (a) Speziale, V.; Roussel, J.; Lattes, A. J. Heterocycl.
Chem. 1974, 11, 771–775; (b) Vincens, M.; Dumont, C.;
Vidal, M. Can. J. Chem. 1979, 57, 2314–2318.
16. (a) Thaisrivongs, S.; Seebach, D. J. Am. Chem. Soc. 1983,
105, 7407–7413; (b) Giese, B.; Bartmann, D. Tetrahedron
Lett. 1985, 26, 1197–1200; (c) Garavelas, A.; Mavropou-
los, I.; Perlmutter, P.; Westman, G. Tetrahedron Lett.
1995, 36, 463–466; (d) Bratt, K.; Garavelas, A.; Perlmut-
ter, P.; Westmann, G. J. Org. Chem. 1996, 61, 2109–2117.
17. Sih, J. C.; Graber, D. R. J. Org. Chem. 1982, 47, 4919–
4927.
Acknowledgments
S.M. thanks CSIR, New Delhi, for financial support in
the form of a research fellowship. We thank Dr. P. R.
Rajmohan for providing the NMR data.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
06.049.
18. Freeman, F.; Robarge, K. D. Carbohydr. Res. 1986, 154,
270–274.
25
19. Analytical and spectral data of compound 9: ½aꢀD ꢁ10.7 (c
2.4, CHCl3); 1H NMR (200 MHz, CDCl3) d 7.34–7.25 (m,
10H), 5.97 (qd, 1H, J = 5.6, 10.5 Hz), 5.39 (dt, 1H,
J = 1.6, 17.2 Hz), 5.22 (dt, 1H, J = 1.6, 10.5 Hz), 4.69 (s,
2H), 4.54 (s, 2H), 4.41–4.32 (m, 1H), 4.28–4.14 (m, 2H),
3.59 (t, 1H, J = 3.8 Hz), 3.47–3.43 (m, 3H), 2.11–1.72 (m,
4H). 13C NMR (50 MHz, CDCl3) d 138.1, 137.9, 128.3,
128.2, 128.0, 127.7, 127.6, 127.5, 127.4, 116.2, 82.2, 78.9,
78.4, 74.3, 73.2, 72.6, 72.5, 72.1, 28.4, 28.0. Anal. Calcd for
C24H30O5: C, 72.34; H, 7.59%. Found: C, 72.30; H, 7.52%.
References and notes
1. Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina,
I.; Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269–
303, and references therein.
2. (a) Tormo, J. R.; Gallardo, T.; Gonzalez, M. C.;
Bermenjo, A.; Cabedon, N.; Andrew, I.; Estornell, W.
Curr. Top. Phytochem. 1999, 2, 69–90; (b) Johnson, H. A.;
Oberlies, N. H.; Alali, F. Q.; McLaughlin, J. L. Bio. Act.
Nat. Prod. 2000, 173–183.
25
Analytical and spectral data of compound 15: ½aꢀD ꢁ23.1
1
(c 2.3, CHCl3); H NMR (500 MHz, CDCl3) d 7.35–7.26
3. (a) Oberlies, N. H.; Croy, V. L.; Harrison, M. L.;
McLaughlin, J. L. Cancer Lett. 1997, 115, 73–79; (b)
Oberlies, N. H.; Chang, C.-J.; McLaughlin, J. L. J. Med.
Chem. 1997, 40, 2102–2106.
4. Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416–
1429.
5. Kim, E. J.; Suh, K. M.; Kim, D. H.; Jung, E. J.; Seo, C. S.;
Son, J. K.; Woo, M. H.; McLaughlin, J. L. J. Nat. Prod.
2005, 68, 194–197.
6. THF’s from hydroxy epoxides: (a) Hoye, T. R.; Tan, L.
Tetrahedron Lett. 1995, 36, 1981–1984, and references
cited therein for the earlier work; (b) Naito, H.; Kawa-
hara, E.; Maruta, K.; Maeda, M.; Sasaki, S. J. Org. Chem.
1995, 60, 4419–4427; (c) Sinha, S. C.; Sinha, S. C.; Keinan,
E. J. Org. Chem. 1999, 64, 7067–7073.
7. THF’s from hydroxyalkenes: (a) Sinha, S. C.; Sinha, A.;
Sinha, S. C.; Keinan, E. J. Am. Chem. Soc. 1997, 119,
12014–12015, and references cited therein for the earlier
work; (b) Hu, Y.; Brown, R. C. D. Chem. Commun. 2005,
5636–5637, and references cited therein for the earlier
work.
8. THF’s via Williamson type etherification: (a) Yazbak, A.;
Sinha, S. C.; Keinan, E. J. Org. Chem. 1998, 63, 5863–
5868; (b) Emde, U.; Koert, U. Eur. J. Org. Chem. 2000,
1889–1904.
9. Recent reviews on the synthesis of THF acetogenins: (a)
Figadere, B. Acc. Chem. Res. 1995, 28, 359–365; (b) Koert,
U. Synthesis 1995, 115–132; (c) Hoppe, R.; Scharf, H.-D.
Synthesis 1995, 1447–1464; (d) Casiraghi, G.; Zanardi, F.;
Battistini, L.; Rassu, G.; Appendino, G. Chemtracts:Org.
Chem. 1998, 11, 803–827.
10. Marshall, J. A.; Jiang, H. J. Org. Chem. 1999, 64, 971–975.
11. THF’s from enantiopure natural precursors: (a) Koert, U.
Tetrahedron Lett. 1994, 35, 2517–2520; (b) Yao, Z.-J.; Wu,
Y. L. J. Org. Chem. 1995, 60, 1170–1176.
(m, 10H), 4.67 (d, 1H, J = 12.4 Hz), 4.53 (d, 2H,
J = 2.3 Hz), 4.45 (d, 1H, J = 12.4 Hz), 4.27 (q, 1H,
J = 7.8 Hz), 4.23–418. (m, 2H), 3.85 (dd, 1H, J = 4.1,
7.8 Hz), 3.76–3.71 (m, 2H), 3.57 (dd, 1H, J = 5.9,
10.1 Hz), 3.46 (dd, 1H, J = 4.6, 10.1 Hz), 2.19 (dd, 1H,
J = 6.8, 11.9 Hz), 2.10 (dd, 1H, J = 3.2, 11.9 Hz), 1.97–
1.91 (m, 1H), 1.82–1.76 (m, 1H), 1.68–1.60 (m, 1H), 1.42–
1.33 (m, 1H). 13C NMR (125 MHz, CDCl3) d 138.1, 137.1,
128.7, 128.6, 128.4, 128.3, 127.9, 127.7, 85.1, 84.7, 83.1,
81.6, 78.2, 78.0, 73.4, 72.7, 71.6, 29.7, 28.6, 28.0. Anal.
Calcd for C24H29O5HgCl: C, 45.50; H, 4.61%. Found: C,
45.64; H, 4.59%. Analytical and spectral data of com-
25
pound 16: ½aꢀD ꢁ19.4 (c 1.7, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.35–7.24 (m, 10H), 4.61–4.55 (m, 2H), 4.52 (s,
2H), 4.43 (d, 1H, J = 11.9 Hz), 4.28 (q, 1H, J = 7.6 Hz),
4.24–4.17 (m, 1H), 4.13–4.07 (m, 2H), 3.87 (d, 1H,
J = 4.0 Hz), 3.55 (dd, 1H, J = 5.8, 10.1 Hz), 3.46 (dd,
1H, J = 4.27, 10.1 Hz), 3.12 (br s, 1H), 2.05 (dd, 1H,
J = 7.0, 12.0 Hz), 2.02–1.93 (m, 2H), 1.78 (dd, 1H, J = 3.7,
12.0 Hz), 1.74–1.62 (m, 2H), 1.52–1.41 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 138.1, 137.7, 128.5, 128.4, 127.9,
127.7, 127.5, 85.3, 82.7, 79.4, 78.6, 77.9, 74.2, 73.4, 72.8,
72.3, 28.7, 28.0, 27.9. Anal. Calcd for C24H29O5HgCl: C,
45.50; H, 4.61%. Found: C, 45.57; H, 4.72%. Analytical
25
and spectral data of compound 17: ½aꢀD ꢁ13.6 (c 2.4,
CHCl3); 1H NMR (500 MHz, CDCl3) d 7.31–7.26 (m,
10H), 4.65 (d, 1H, J = 11.9 Hz), 4.53 (s, 2H), 4.41 (d, 1H,
J = 11.9 Hz), 4.32 (br s, 1H), 4.29 (q, 1H, J = 8.3 Hz), 4.19
(m, 1H), 3.92 (dd, 1H, J = 4.6, 7.8 Hz), 3.89 (q, 1H,
J = 4.1 Hz), 3.83 (dd, 1H, J = 1.8, 4.1 Hz), 3.78 (dd, 1H,
J = 3.7, 12.0 Hz), 3.71 (dd, 1H, J = 4.1, 11.6 Hz), 3.53 (dd,
1H, J = 5.0, 10.1 Hz), 3.46 (dd, 1H, J = 5.0, 10.1 Hz), 3.25
(br s, 1H), 3.06 (br s, 1H), 2.04–1.95 (m, 2H), 1.76–1.68
(m, 1H), 1.56–1.49 (m, 1H); 13C NMR (125 MHz, CDCl3)
d 138.2, 137.5, 128.4, 128.3, 127.9, 127.8, 127.6, 127.5,
86.2, 85.2, 83.0, 78.1, 75.4, 73.3, 72.5, 71.4, 62.6, 28.6, 28.2.
Anal. Calcd for C24H30O6: C, 69.54; H, 7.30%. Found: C,
69.46; H, 7.24%. Analytical and spectral data of
12. Gurjar, M. K.; Mohapatra, S.; Phalgune, U. D.; Puranik,
V. G.; Mohapatra, D. K. Tetrahedron Lett. 2004, 45,
7899–7902.

D. K. Mohapatra et al. / Tetrahedron Letters 47 (2006) 5943–5947
5947
25
compound 21: ½aꢀD ꢁ45.9 (c 2.6, CHCl3); 1H NMR
9.8 Hz), 2.54 (br s, 1H), 2.20–2.07 (m, 3H), 2.03–1.96 (m,
1H), 1.82–1.73 (m, 1H), 1.59–1.48 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 138.4, 137.5, 128.4, 128.3, 127.8,
127.7, 127.6, 127.5, 85.5, 79.1, 78.9, 78.4, 78.1, 73.4, 72.6,
70.7, 64.4, 32.2, 28.8, 28.5. Anal. Calcd for C24H30O5: C,
72.34; H, 7.59%. Found: C, 72.30; H, 7.66%.
(400 MHz, CDCl3) d 7.35–7.25 (m, 10H), 4.59 (d, 1H,
J = 11.6 Hz), 4.55 (s, 2H), 4.36 (dt, 1H, J = 6.5, 9.8 Hz),
4.29 (d, 1H, J = 11.6 Hz), 4.26–4.16 (m, 2H), 4.04–4.01
(m, 1H), 3.84 (dd, 1H, J = 2.5, 11.6 Hz), 3.67 (dd, 1H,
J = 4.0, 7.8 Hz), 3.60–3.54 (m, 2H), 3.48 (dd, 1H, J = 5.3,