First stereoselective total synthesis of ophiocerins B and C

Article abstract of DOI:10.1055/s-2007-982579

An elegant synthesis of ophiocerins B and C is accomplished for the first time with 3R,4R,6R and 3S,4S,6R-configuration. Of these three stereogenic centers, the C-3/C-4 vic-diol was created by Sharpless asymmetric dihydroxylation, while the C-6 stereocent

Full text of DOI:10.1055/s-2007-982579

LETTER
1945
First Stereoselective Total Synthesis of Ophiocerins B and C
Synthesis
.
of
O
phioceri
S
ns
B
and
C
. Yadav,* P. Naga Lakshmi, S. J. Harshavardhan, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 5 March 2007
ber of natural products4 and shows excellent biological
activity. Owing to the challenges posed by the substitution
pattern of the tetrahydropyran ring, the synthesis of these
compounds has attracted considerable attention. There
Abstract: An elegant synthesis of ophiocerins B and C is accom-
plished for the first time with 3R,4R,6R and 3S,4S,6R-configuration.
Of these three stereogenic centers, the C-3/C-4 vic-diol was created
by Sharpless asymmetric dihydroxylation, while the C-6 stereo-
center was achieved from known chiral epoxide. The synthesis of were some precedents wherein structurally related syn-
thetic products are reported5 but the exact stereochemistry
ophiocerins B and C defined the absolute stereochemistry of these
natural products.
defined was not described. This prompted us to explore
Key words: Sharpless asymmetric dihydroxylation, ophiocerin,
tetrahydropyran derivative
the possibility of synthesizing ophiocerins B and C.
Retrosynthetic analysis of 2 and 3 revealed that both com-
pounds could be envisioned by adopting the Sharpless
asymmetric dihydroxylation for the key intermediate 7,
Ophiocerins A–C (1–3), the three diasteromeric tetrahy- which could easily be prepared from the known chiral
dropyran derivatives and ophiocerin D (4), an isocrotonyl epoxide 86 (Scheme 1).
derivative of tetrahydropyran were isolated from the
cultures of freshwater aquatic fungi Ophioceras
venezuelense (Magnaporthaceae) appear to be the first
natural products described from the genus Ophioceras.
In the present study, the vic-diol could be generated by an
asymmetric dihydroxylation, while the C-6 stereocenter
would be achieved by a known chiral epoxide. According-
ly, reduction of chiral epoxide 8 with LiAlH4 gave sec-
The isolation, structures, absolute and relative stereo-
ondary alcohol 9, which on silylation with TBDMSCl
chemical assignments of these moieties were determined
gave TBDMS ether 10 (98%, Scheme 2). The reductive
by Shearer et al. in 2005.1 Antagonistic effects among
cleavage of benzyl ether with lithium napthalenide7 af-
competing aquatic fungi have been reported from a
forded primary alcohol 11 in 94% yield. The alcohol 11
was subjected to Swern oxidation, followed by C-2 Wittig
chemical standpoint.2
Biosynthetically, compounds 1–4 (Figure 1) could be en- olefination in benzene, furnished a key intermediate 7, as
visioned to arise from either polyketide or monosaccha- trans-product in 86% yield.
ride precursors, as they bear resemblance to relatively rare
An asymmetric dihydroxylation of the TBDMS-ether 7,
triketide products such as triacetic acid lactone, as well as
with the respective AD-mix reagents resulted in the for-
to sugar-derived molecules such as deoxyhexoses, anhy-
mation of vic-diols 6a and 6b. Asymmetric dihydroxyla-
tion with AD mix-b reagent resulted in the formation of
vic-diol 6a predominantly and the diastereomeric ratio of
droglucitol, dihydropyrans, or kojic acid. The presence of
an isocrotonyl group is also somewhat unusual, although
it has been reported as a component of trichothecin and
vic-diols 6a to 6b was 98:2 while the same was 30:70 with
trichothecinols A–C isolated from Trichothecium
the AD mix-a reagent.8 However, the diols that are
oroseum, as well as in trichothecinol of plant origin, and
formed during dihydroxylation with AD-mix-a could not
in isocrotonylpterosin B isolated from the bracken fern
be separated, hence they were used as such in further
Pteridium aquilinum. The isocrotonyl moiety could arise
transformations. Both products 6a and 6b gave the target
molecules 2 and 3 in later stages. This observation was in
from early steps of polyketide or fatty acid biosynthesis.1
The substituted tetrahydropyran core3 is found in a num-
agreement with the results reported in literature.9
OH
R
OH
OH
R
OH
S
R
O
OH
OH
OH
S
4
OH
5
S
S
3
2
R
S
6
O
R
R
R
O
O
O
R
O
1
ophiocerin D (4)
ophiocerin A (1)
ophiocerin B (2)
ophiocerin C (3)
Figure 1
SYNLETT 2007, No. 12, pp 1945–1947
2
4
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982579; Art ID: D06207ST
© Georg Thieme Verlag Stuttgart · New York

1946
J. S. Yadav et al.
LETTER
OH
R
OH
S
OH
OH
O
O
OH
OH
R
S
OH
OH
O
O
R
R
O
O
5b
5a
ophiocerin B (2)
ophiocerin C (3)
OTBS OH
OTBS OH
OTBS
CO2Et
CO2Et
CO2Et
OH
6a
OH
6b
7
O
OBn
8
Scheme 1 Retrosynthetic analysis of ophiocerins B and C
The acetonation of diols 6a and 6b with 2,2-DMP and cat- and 5b in 85%, respectively. We envisaged a concomitant
alytic CSA resulted in 12a and 12b in 89%. Reduction of cyclization after tosylation of the 5a and 5b would occur
the ester and cleavage of the TBS ether occurred simulta- in one pot, but surprisingly, monotosylates 13a and 13b
neously with LiAlH4 at reflux conditions resulted in 5a were isolated in 90% yield using p-toluenesulfonyl
OTBS
OTBS
OH
O
c
b
d
a
OBn
OBn
OH
OBn
11
8
9
10
OH
O
O
OTBS
OTBS
g
OTBS OH
O
f
e
OH
CO2Et
CO2Et
OEt
O
O
OH
6a
7
5a
12a
OH
OH
O
OH
h
i, j
OTs
O
O
13a
2
(97%)
OH
O
O
OTBS
OTBS OH
O
OTBS
g
f
k
OH
CO2Et
CO2Et
OEt
O
O
OH
7
5b
6a + 6b
12b
OH
OH
OH
OH
O
OH
i, j
OTs
h
+
O
O
O
13b
3
2
(30%)
(70%)
Scheme 2 Reagents and conditions: (a) LiAlH4 (1 equiv), THF, 0 °C, r.t., 3–4 h, (95%); (b) TBDMSCl (1.2 equiv), imidazole (2 equiv),
CH2Cl2, 0 °C, r.t., 3 h (98%); (c) lithium (3 equiv), naphthalene (2.0 equiv), THF, r.t. to –23 °C, 3–4 h (94%); (d) (i) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C, 3 h; (ii) PPh3=CHCOOEt, (1.5 equiv), benzene, 0 °C (86%), 24 h; (e) AD mix-b, MeSO2NH2, t-BuOH–H2O (1:1), 0 °C, 24 h,
94%; (f) 2,2-DMP, CSA (cat.), 2 h, 89%; (g) LiAlH4 (3 equiv), THF, 0 °C to reflux, 7 h, 85%; (h) TsCl (1 equiv), NaH (1 equiv), THF, 0 °C,
r.t., 3–4 h (90%); (i) KOt-Bu, (3 equiv), THF, 0 °C, r.t., 3–4 h, (90%); (j) PTSA (cat.), MeOH, r.t. (97%); (k) AD mix-a, MeSO2NH2, t-BuOH–
H2O (1:1), 0 °C, 24 h, 94%.
Synlett 2007, No. 12, 1945–1947 © Thieme Stuttgart · New York

LETTER
Synthesis of Ophiocerins B and C
1947
(4) Nicolau, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: Weinheim, 1996.
chloride and NaH in THF. Finally, the cyclization was
attempted with various bases like NaH, K2CO3, DBU, and
pyridine. None of them was found to be successful.
Interestingly, the desired cyclization was achieved using
KOt-Bu (3 equiv) in THF. Accordingly, treatment of 13a
with KOt-Bu (3 equiv) in THF gave the cyclized products
2 (97%) after the removal of acetonide. Similarly, 13b
furnished 3 (70%) and 2 (30%) in respective manner.
Ophiocerin B (2) is a yellow liquid with optical rotation
(5) (a) Ichimoto, I.; Tatsumi, C. Agric. Biol. Chem. 1964, 28,
723. (b) Rosenthal, A.; Abson, D. Can. J. Chem. 1965, 43,
1318. (c) Minami, T.; Moriyama, A.; Hanaoka, M. Synlett
1995, 663. (d) Carpintero, M.; Bastida, A.; Garcia-Junceda,
E.; Jimenez-Barbero, J.; Fernandez-Mayoralas, A. Eur. J.
Org. Chem. 2001, 4127. (e) König, W. A.; Lutz, S.;
Mischnick-Luebbecke, P.; Brassat, B.; Wenz, G. J.
Chromatogr. 1988, 447, 193. (f) Garegg, P. J.; Lindberg, B.;
Konradsson, P.; Kvarnstrom, I. Carbohydr. Res. 1988, 176,
145.
(6) Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C.
Tetrahedron Lett. 2001, 42, 4907.
(7) Liu, H. J.; Yip, J. Tetrahedron Lett. 1997, 38, 2253.
(8) Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett.
2002, 4, 647.
25
[a]D –34.0 (c 0.25, CH2Cl2) and ophiocerin C (3) is a
25
white solid with optical rotation [a]D +42.2 (c 0.1,
CH2Cl2).10 The spectroscopic analyses and optical
rotation values were in accordance with the data reported
in literature.2
In summary, we have described an elegant synthesis of
both ophiocerins B and C in a stereoselective manner
using the Sharpless dihydroxylation as a key step. This
study accomplished the total synthesis of 2 and 3. Syn-
thesis of ophiocerin A with configuration 3R,4S,6R can be
achieved by an asymmetric dihydroxylation of a key inter-
mediate, i.e. cis-olefin 7, with AD mix-b reagent and sub-
sequent chemical transformations described herein. This
work is in progress.
(9) (a) Chattopadhyay, A.; Salaskar, A. J. Chem. Soc., Perkin
Trans. 1 2002, 785. (b) Salaskar, A.; Sharma, A.;
Chattopadhyay, S. Tetrahedron: Asymmetry 2006, 17, 325.
(10) Spectroscopic Data for Target Molecules
25
Ophiocerin B (2): pale yellow oil; [a]D –34.0 (c 0.25,
CH2Cl2). IR (neat): nmax = 3388, 1452, 1380, 1266, 1079,
1004 cm–1. 1H NMR (500 MHz, CDCl3): d = 3.99 (br s, 1 H),
3.97 (dd, 1 H, J = 1.6, 12.4 Hz), 3.85 (ddq, 1 H, J = 2.6, 6.3,
12.0 Hz), 3.73 (dd, 1 H, J = 2.3, 12.2 Hz), 3.47 (br s, 1 H,),
2.21 (d, 1 H, J = 8.0 Hz), 1.81 (ddd, 1 H, J = 3.1, 11.3, 14.3
Hz), 1.64–1.59 (m, 2 H) 1.18 (d, 3 H, J = 6.0 Hz). 13C NMR
(75 MHz, CDCl3): d = 68.4, 68.2, 67.4, 67.2, 36.0, 21.1. ESI-
MS: m/z = 155 [M + Na]+. HRMS: m/z calcd for C6H12O3Na:
155.0684 [M+ + Na]; found: 155.0691.
Acknowledgment
P.N.L. and S.J.H. thank CSIR New Delhi for the award of
fellowships.
Ophiocerin C (3): white solid, mp 80–82 °C; [a]D25 +42.2 (c
0.1, CH2Cl2). IR (neat): nmax = 3413, 1460, 1380, 1262, 1136,
1080, 1006 cm–1. 1H NMR (500 MHz, CDCl3): d = 3.98 (dd,
1 H, J = 5.3, 11.4 Hz), 3.61–3.47 (m, 3 H), 3.16 (dd, 1 H,
J = 9.8, 11.3 Hz), 2.10–2.05 (br s, 1 H), 2.02–1.97 (m, 2 H),
1.37 (ddd, 1 H, J = 11.3, 11.3, 12.8 Hz), 1.20 (d, 3 H, J = 6.4
Hz). 13C NMR (75 MHz, CDCl3): d = 73.4, 72.6, 72.4, 69.6,
40.5, 21.2. ESI-MS: m/z = 155 [M + Na]+. HRMS: m/z calcd
for C6H12O3Na: 155.0684 [M+ + Na]; found: 155.0691.
References and Notes
(1) Reategui, R. F.; Gloer, J. B.; Campbell, J.; Shearer, C. A.
J. Nat. Prod. 2005, 68, 701; and references cited therein.
(2) Oh, H.; Gloer, J. B.; Shearer, C. A. J. Nat. Prod. 1999, 62,
497.
(3) (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.;
Marini-Bettolo, G. B. Gazz. Chim. Ital. 1964, 287.
(b) Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz.
Chim. Ital. 1965, 95. (c) Aragao Craveiro, A.; da Costa
Prado, A.; Gottlieb, O. R.; Welerson de Albuquerque, P. C.
Phytochemistry 1970, 9, 1869. (d) Alcântara, A. F. de C.;
Souza, M. R.; Pilo-Veloso, D. Fitoterapia 2000, 71, 613.
Synlett 2007, No. 12, 1945–1947 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.