Formal total synthesis of ovalcin by carbohydrate approach

Article abstract of DOI:10.1055/s-2007-970767

A formal total synthesis of ovalcin is described herein starting from readily available sugar ribose with selective zinc-mediated ring-opening reaction and Grubbs olefin metathesis as the key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970767

992
LETTER
Formal Total Synthesis of Ovalcin by Carbohydrate Approach
Total
S
ynt
h
hesis of
O
va
i
lcin llu Singh Yadav,* Sreedhar Pamu, Dinesh Chandra Bhunia, Srihari Pabbaraja
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: yadavpub@iict.res.in
Received 6 August 2006
AGM 1470 and enhanced potency compared to fumagil-
lin. The significant stability and biological activity of
ovalcin have attracted many synthetic organic chemists to
design new methods for accessing them. Corey et al.6
were the first to report the total synthesis of racemic as
well as chiral ovalcin and these reports were followed by
several other syntheses for chiral ovalcin.7
Abstract: A formal total synthesis of ovalcin is described herein
starting from readily available sugar ribose with selective zinc-me-
diated ring-opening reaction and Grubbs olefin metathesis as the
key steps.
Key words: angiogenesis, metathesis, ring opening, epoxidation
As part of our ongoing research program for the synthesis
of natural products having biological activity,8 we herein
describe the formal total synthesis of ovalcin. Our syn-
thetic approach is based on the chiron approach and utiliz-
es two key steps: an olefin metathesis reaction and the
zinc-mediated ring-opening reaction to afford the chiral
olefinic alcohol.
During recent years, abnormal angiogenesis has been
recognized as a common feature for many proliferative
diseases including diabetic retinopathy, psoriasis, rheu-
matoid arthritis, and cancer.1 Thus it has become increas-
ingly important to inhibit angiogenesis as one of the
alternative promising methods for cancer therapy.2
Towards these studies, in 1990 an antibiotic fumagillin (1,
Figure 1) was reported to have potent antiangiogenitic
activity.3 The high toxicity and instability associated with
1 has limited its usage. Simultaneously, a semi-synthetic
drug TNP-4704 (2, also known as AGM 1470) was devel-
oped with more potency compared to fumagillin, but also
suffered from low stability. These instabilities have made
medicinal chemists search for a stable and potent drug.
During the course of those investigations, ovalcin (3), iso-
lated from cultures of Pseudorotium ovalis5 stock, was
found to be non-toxic, non-inflammatory and stable at
room temperature for years bearing equal potency as
Our retrosynthetic approach revealed a key intermediate
4, which could be easily prepared by olefin metathesis of
5, which in turn is obtained from D-ribose via a sequence
of reactions (Scheme 1).
Accordingly, commercially available D-(–)-ribose was
protected as its 2,3-O-isopropylidene derivative and the
primary hydroxyl group was protected as a tert-butyldi-
methylsilyl ether 7 with TBDMSCl and imidazole. The
resulting compound 7 was converted into compound 8
according to the known procedure.9 Compound 8 was pro-
tected as its PMB ether 9 with p-methoxybenzyl bromide.
Me
O
O
Me
O
O
O
Me
O
O
OMe
O
OMe
O
OH
OMe
H
OH
O
N
Cl
O
O
O
fumagillin (1)
ovalcin (3)
AGM 1470 (2)
Figure 1
OH
Me
O
O
O
O
I
OPMB
OBn
OH
OH
D-(–)-ribose
O
O
OMe
OMe
OMe
Me Me
O
OTES
OTES
3
5
6
4
Scheme 1 Retrosynthesis
SYNLETT 2007, No. 6, pp 0992–0994
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-970767; Art ID: D24006ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Ovalcin
993
O
O
OH
TBDMSO
OH
TBDMSO
d
c
a, b
D-ribose
O
O
O
O
7
Me Me
Me Me
8
O
O
O
HO
OPMB
TBDMSO
OPMB
I
OPMB
f
e
O
O
O
O
O
O
Me Me
Me Me
9
10
Me Me
6
OH
OBn
OPMB
OPMB
g
h
O
O
O
O
Me Me
Me Me
11
12
Scheme 2 Reagents and conditions: (a) 2,2-dimethoxypropane, acetone, PTSA, r.t., 72%; (b) TBDMSCl, imidazole, CH2Cl2, r.t., 98%; (c)
Me2SO=CH2, DMSO, 20 °C, 60%; (d) NaH, PMBBr, Et2O, 0 °C to r.t., 3 h, 97%; (e) TBAF, THF, 30 min 98%; (f) I2, TPP, imidazole, toluene,
reflux, 2 h, 99%; (g) Zn, EtOH, reflux, 2 h, 95%; (h) NaH, BnBr, THF, 0 °C to r.t. 12 h, 85%.
Desilylation of compound 9 with TBAF afforded alcohol TES ether 14 at the allylic position at low temperature and
10 which was further converted into iodide 6 with iodine, simultaneously as the methyl ether 15 with methyl iodide.
triphenylphosphine and imidazole.10 By applying the Compound 15 on PMB deprotection with DDQ provided
commonly used protocol for zinc-mediated ring-opening primary alcohol 16 which was oxidized to aldehyde 17
reaction11 compound 11 was obtained in good yields.14 under Swern conditions.12 Vinylation of the aldehyde 17
The resulting free alcohol 11 was masked with NaH and afforded allyl alcohol 5 which could be used for the
benzyl bromide as its benzyl ether 12 (Scheme 2).
metathesis reaction to access the required basic skeleton.
Thus compound 5 was subjected to metathesis using
Grubbs’ first-generation catalyst13 to afford compound 18
(Scheme 3).
Deprotection of the acetonide group from compound 12
was achieved with PTSA in methanol to give diol 13. The
diol 13 was selectively protected as the corresponding
OBn
OH
OH
OPMB
b
c
a
OPMB
OPMB
O
O
OH OBn
OTES OBn
OMe
Me Me
12
14
13
OMe
OMe
e
CHO
OH
d
f
OPMB
OTES OBn
OTES OBn
OTES OBn
16
17
15
O
OH
O
OBn
OMe
OMe OH
OBn
OMe
OH
i
h
g
OMe
OTES OBn
OTES
OTES
OTES
5
19
18
20
Me
O
O
O
OH
OH
OMe
ref. 7b
OH
j
k
OMe
OMe
O
OTES
OTES
21
4
3
Scheme 3 Reagents and conditions: (a) PTSA, MeOH, r.t., 30 min, 98%; (b) TESCl, imidazole, 0 °C, 1 h, 84%; (c) NaH, MeI, THF, 0 °C to
r.t., 4 h, 95%; (d) DDQ, CH2Cl2–H2O (8:2), r.t., 2 h, 61%; (e) TPAP, NMO, CH2Cl2, r.t., 1 h, 80%; (f) vinylmagnesium bromide, THF, r.t., 90
min, 75%; (g) (Cy3P)2Cl2Ru=CHPh (10 mol%), CH2Cl2, r.t., 2 h, 98%; (h) IBX, DMSO, CH2Cl2, r.t., 1 h, 69%; (i) Pd(OH)2, THF, H2 atm 87%;
(j) MePPh3I, t-BuOK, THF, 0 °C to r.t., 5 h, 87%; (k) MCPBA, CH2Cl2, 0 °C to r.t., 3 h, 85%.
Synlett 2007, No. 6, 992–994 © Thieme Stuttgart · New York

994
J. S. Yadav et al.
LETTER
(6) (a) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107,
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(b) Barton, D. H. R.; Bath, S.; Billington, D. C.; Gero, S. D.;
Quiclet-Sire, B.; Samadi, M. J. Chem. Soc., Perkin Trans. 1
1995, 1551. (c) Bath, S.; Billington, D. C.; Gero, S. D.;
Quiclet-Sire, B.; Samadi, M. J. Chem. Soc., Chem. Commun.
1994, 1495.
(8) For recent works, see: (a) Yadav, J. S.; Prathap, I.; Tadi, B.
P. Tetrahedron Lett. 2006, 47, 3773. (b) Yadav, J. S.;
Srinivas, R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603.
(c) Yadav, J. S.; Raju, A. K.; Rao, P. P.; Rajaiah, G.
Tetrahedron: Asymmetry 2005, 16, 3283. (d) Yadav, J. S.;
Prakash, S. J.; Gangadhar, Y. Tetrahedron: Asymmetry
2005, 16, 2722. (e) Yadav, J. S.; Reddy, M. S.; Prasad, A. R.
Tetrahedron Lett. 2005, 46, 2133.
The allylic alcohol 18 was converted into enone 19 with
iodoxybenzoic acid. One-pot reduction of the a,b-unsat-
urated olefin and deprotection of the benzyl ether was
achieved with Pd(OH)2 under hydrogen atmosphere to
afford the compound 20. A one-carbon Wittig reaction on
the ketone with methyltriphenylphosphonium iodide
yielded olefin 21. Epoxidation of the olefin with MCPBA
afforded the known key intermediate 4.14 This intermedi-
ate has already been converted into ovalcin in a further
few steps as reported earlier by Barton et al.7b Thus we
have accomplished a formal total synthesis of ovalcin.
In conclusion, we have described an efficient formal total
synthesis of ovalcin by a chiron approach. Since all the
reactions are high-yielding, this strategy could be applied
to a multigram-scale synthesis of the key intermediate
which can be derivatized further for synthesis of several
other analogues to probe their biological activities.
(9) Fréchou, C.; Dheilly, L.; Beaupère, D.; Uzan, R.; Demailly,
G. Tetrahedron Lett. 1992, 33, 5067.
(10) Garegg, J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866.
Acknowledgment
(11) (a) Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990.
For applications and modified procedures, see: (b) Ferrier,
R. J.; Furneaux, R. H.; Prasit, P.; Tyler, P. C.; Brown, K. L.;
Gainsford, G. J.; Diehl, W. J. Chem. Soc., Perkin Trans. 1
1983, 1621. (c) Ferrier, R. J.; Prasit, P. J. Chem. Soc., Perkin
Trans. 1 1983, 1645. (d) Ferrier, R. J.; Schmidt, P.; Tyler, P.
C. J. Chem. Soc., Perkin Trans. 1 1985, 301. (e) Nicolaou,
K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron Lett.
1984, 25, 2069. (f) Yadav, J. S.; Reddy, B. V. S.; Srinivasa
Reddy, K. Tetrahedron 2003, 59, 5333.
Two of us (S.P. and D.C.B.) thank CSIR, New Delhi for financial
assistance.
References and Notes
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(14) Selected Spectroscopic Data
Compound 4: colorless oil; [a]D –57 (c 2.1 CHCl3), lit7b [a]D
–60.0 (c 1.28, CHCl3). IR (CHCl3): 3458, 1452, 1380, 1247,
1114, 1014, 981 cm–1. 1H NMR (300 MHz, CDCl3): d = 4.30
(s, 1 H), 4.02 (d, J = 9.0 Hz, 1 H), 3.44 (s, 3 H), 3.06 (d,
J = 4.5 Hz, 1 H), 3.03 (d, J = 2.2 Hz, 1 H), 2.57 (d, J = 5.2
Hz, 1 H), 2.23 (td, J = 5.4 Hz, 1 H), 1.99 (br s, 1 H, OH), 1.73
(m, 2 H), 1.35 (m, 1 H), 0.97 (t, 9 H), 0.61 (q, 6 H). 13C NMR
(75 MHz, CDCl3): d = 85.23, 67.52, 66.76, 59.95, 57.71,
50.06, 28.90, 26.20, 6.74, 4.88. MS–FAB: m/z = 260 [M+].
Compound 11: colorless oil; [a]D –13.0 (c 2.5, CHCl3). IR
(CHCl3): 3476, 2934, 1613, 1514, 1458, 1301, 1173, 931,
758 cm–1. 1H NMR (200 MHz, CDCI3): d = 7.22 (d, J = 8.5
Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 5.96 (m, 1 H), 5.24 (m, 2
H), 4.51 (m, 1 H), 4.43 (d, J = 1.5 Hz, 2 H), 4.17 (dd, J = 3.1,
7.0 Hz, 1 H), 3.77 (s, 1 H), 3.66 (m, 1 H), 3.40 (d, J = 5.4 Hz,
1 H), 2.17 (d, J = 5.4 Hz, 1 H), 1.48 (s, 3 H), 1.35 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.30, 134.08, 130.00,
129.40, 119.45, 113.80, 108.67, 79.01, 68.76, 52.24, 27.18,
24.95. MS–FAB: m/z = 308 [M+].
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Synlett 2007, No. 6, 992–994 © Thieme Stuttgart · New York