A stereoselective approach for the total synthesis of clonostachydiol

Article abstract of DOI:10.1055/s-0028-1087296

A stereoselective synthesis of clonostachydiol is accomplished using readily available (±)-epichlorohydrin as a precursor. The synthesis involves direct and straightforward reactions such as Sharpless asymmetric epoxidation, iodination, stereoselective op

Full text of DOI:10.1055/s-0028-1087296

LETTER
2773
A Stereoselective Approach for the Total Synthesis of Clonostachydiol
S
tereosele
.
ctive
A
pproa
S
c
h
for the
T
ot
.
al Synthesis
Y
of Clonostachydio
a
l
dav,* T. Swamy, B. V. Subba Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadav@iict.res.in
Received 5 June 2008
O
O
Abstract: A stereoselective synthesis of clonostachydiol is accom-
plished using readily available ( )-epichlorohydrin as a precursor.
The synthesis involves direct and straightforward reactions such as
Sharpless asymmetric epoxidation, iodination, stereoselective
opening of epoxide with allylmagnesium chloride and Sharpless
asymmetric dihydroxylation.
O
O
HO
OH
HO
Key words: Sharpless asymmetric epoxidation, allylmagnesium
O
O
O
O
chloride, Sharpless asymmetric dihydroxylation
clonostachydiol (1)
colletol (2)
O
The cytotoxic clonostachydiol, a 14-membered bismacro-
lactone was isolated from a marine algae derived fungus.1
Fungi derived from the marine source are well-known
producers of novel and pharmacologically active second-
ary metabolites.2,3 Clonostachydiol (1) is cytotoxic, active
against Bacillus subtilis and the fungi Trichophyton men-
tagrophytes and Cladosporium resine. The promising bio-
logical activity and fascinating structure of this family of
macrolactones make them attractive synthetic targets. The
absolute and relative stereochemistry of clonostachydiol
(1) was established by Rao et al.4 Clonostachydiol (1) is
structurally similar to the colletol family (Figure 1).5
O
HO
HO
O
O
colletodiol (3)
Figure 1
The synthesis of clonostachydiol (1) began with ( )-epi-
chlorohydrin (6), which was converted into p-methoxy-
benzyl-protected glycidol ( )-76 by treating with NaH and
p-methoxybenzyl alcohol in THF at 0 °C in 82% yield.
The hydrolytic kinetic resolution7 of the racemic epoxide
( )-7 (1 equiv) with 0.55 equivalent of H2O in the pres-
ence of 0.003 mol% of (salen)Co(III)OAc complex
{(S,S)-[N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclo-
hexane-diamino]cobalt(III) acetate} gave chiral epoxide 8
in 43% yield with 98% enantiomeric excess and diol 9 in
50% yield with 92% enantiomeric excess (Scheme 2).
The extreme scarcity of the natural material together with
its novel structure prompted us to attempt the total synthe-
sis of clonostachydiol (1). Herein, we wish to report an ef-
ficient stereoselective approach for the total synthesis of
clonostachydiol (1) from commercially available ( )-epi-
chlorohydrin (6) employing the Jacobsen’s hydrolytic ki-
netic resolution, Sharpless asymmetric oxidations and
macrolactonization as the key steps. Retrosynthetic anal-
ysis of clonostachydiol (1) is depicted in Scheme 1.
The retrosynthetic analysis reveals that the target mole-
cule could be synthesized from two independent frag-
ments 4 and 5 using Yamaguchi coupling reaction
followed by Shiine’s conditions.
The chiral epoxide 8 was converted into secondary alco-
hol 9 using LAH in THF at room temperature.8 The sec-
ondary alcohol was protected as its benzyl ether 10 using
O
O
OH
OMe
O
O
HO
OH
OTBS
4
Cl
+
OBn
O
epichlorohydrin 6
OH
O
O
OMOM
5
clonostachydiol 1
Scheme 1
SYNLETT 2008, No. 18, pp 2773–2776
1
4
.1
1
.2
0
0
8
Advanced online publication: 21.10.2008
DOI: 10.1055/s-0028-1087296; Art ID: D20808ST
© Georg Thieme Verlag Stuttgart · New York

2774
J. S. Yadav et al.
LETTER
O
NaH, anhyd THF
O
Cl
+
PMBOH
OPMB
H
H
N
N
O
6
7
Co
O
OAc
OH
O
Jacobson catalyst
HO
OPMB
OPMB
+
(S,S)-(salen)Co(III)(OAc) complex
C
[Jacobson catalyst (C)]
8
9
Scheme 2
sodium hydride and benzyl bromide in THF. Selective re- yield. Hydrolysis of ethyl ester 20 using LiOH in aqueous
moval of the p-methoxybenzyl group from compound 10 THF gave the carboxylic acid 21 in 86% yield16
using ceric ammonium nitrate in acetonitrile–water (1:1) (Scheme 4).
gave the primary alcohol. Oxidation of alcohol under
Coupling of fragments 15 and 21 was achieved by the
Swern oxidation9 conditions afforded the aldehyde, that
Yamaguchi esterification using 2,4,6-trichlorobenzoyl
was subsequently treated with (ethoxycarbonyl-
chloride and triethylamine in dichloromethane at room
methylene)triphenylphosphorane in benzene at reflux to
temperature to furnish 22 in 70% yield.17 Deprotection of
the benzyl ether from compound 22 with DDQ in CH2Cl2–
H2O gave the corresponding alcohol in 90% yield and se-
furnish E-a,b-unsaturated ester 11 in 94% yield. The ester
11 was reduced to allylic alcohol10 using DIBAL-H in
THF at –25 °C. Sharpless asymmetric epoxidation afford-
lective hydrolysis of the methyl ester with LiOH in THF–
ed the epoxy alcohol 12 in 80% yield11 and this was con-
H2O gave the seco acid in 70% yield. This seco acid was
verted into the corresponding epoxy iodide by treating
eventually cyclized via a mixed anhydride formed in situ
with iodine, triphenylphosphine and imidazole in a mix-
from 2-methyl-6-nitrobenzoic anhydride (MNBA) and
ture of diethyl ether and acetonitrile (3:1) at 0 °C. The
4-(N,N-dimethylamino)pyridine (DMAP) to give the 14-
iodo compound was converted into secondary allylic alco-
membered ring lactone in 60% yield.18 Removal of the
hol 13 by treating with activated zinc and sodium iodide
TBS and MOM groups from the bicyclic lactone using
in refluxing methanol12 and 13 was coupled with methyl
concentrated HCl in MeOH gave the target clonostachy-
acrylate in the presence of 5 mol% of the second-genera-
diol (1)19 in 85% yield (Scheme 5).
tion Grubbs catalyst in dichloromethane to afford the de-
sired trans product 14 in 92% yield.13 The secondary
OBn
OBn
O
a
b
alcohol 14 was protected as its TBS ether using tert-
butyldimethylsilyl chloride and imidazole in dichlo-
romethane at 0 °C. Finally, the removal of benzyl group
with DDQ in aqueous dichloromethane gave fragment 15
in 85% yield14 (Scheme 3).
OEt
OPMB
OPMB
O
8
10
11
OBn
OBn
c
d
The regioselective ring opening of epoxide 8 with Grig-
nard reagent, derived from magnesium metal and allyl
chloride gave a secondary alcohol that was protected with
MOMCl and DIPEA in the presence of a catalytic amount
of TBAI to afford MOM ether 16 in 92% yield. Sharpless
asymmetric dihydroxylation with AD-mix-a gave diol 17
in 88% yield with 89% diastereomeric excess15 and this
was treated with one equivalent of p-TsCl and Et3N in
dichloromethane to give the mono-tosylate in 89% yield.
This was converted into secondary alcohol 18 using LAH
in THF and 18 was protected as its benzyl ether with ben-
e
OH
OH
O
O
12
13
O
OBn
OH
f
OMe
OMe
OH
OTBS
14
15
Scheme 3 Reagents and conditions: (a) (i) LAH, THF, 85%; (ii)
NaH, BnBr, THF, 93%; (b) (i) ceric ammonium nitrate, MeCN–H2O
zyl bromide and sodium hydride in THF. Selective re- (9:1), 90%; (ii) (COCl)2, DMSO, Et3N, –78 °C, 92%; (iii)
Ph3P=CHCO2Et, benzene, reflux, 94%; (c) (i) DIBAL-H, THF, –40
to 0 °C, 85%; (ii) D-(–)-DET, Ti(Oi-Pr)4, TBHP (tert-butyl hydroper-
oxide), CH2Cl2, –20 °C, 80%; (d) (i) TPP (tetraphenylporphyrin), I2,
imidazole, CH2Cl2, 92%; (ii) Zn, NaI, MeOH, 85%; (e) methyl acry-
late, Grubbs II catalyst, CH2Cl2, 92%; (f) (i) TBDMSCl, imidazole,
CH2Cl2, 92%; (ii) DDQ, CH2Cl2–H2O (18:2), r.t., 85%.
moval of the p-methoxybenzyl group using ceric
ammonium nitrate in acetonitrile–water (1:1) gave prima-
ry alcohol 19, which was oxidized under Swern oxidation9
and Wittig olefination of the resulting aldehyde with
(ethoxycarbonylmethylene)triphenylphosphorane in re-
fluxing benzene gave olefin 20 with E geometry in 91%
Synlett 2008, No. 18, 2773–2776 © Thieme Stuttgart · New York

LETTER
Stereoselective Approach for the Total Synthesis of Clonostachydiol
2775
OH
a
b
O
OPMB
HO
OPMB
OH
OPMB
OMOM
OMOM
8
16
17
OBn
c
e
d
OPMB
OH
OMOM
OMOM
19
18
OBn
O
OBn
O
f
OEt
OH
OMOM
OMOM
21
20
Scheme 4 Reagents and conditions: (a) (i) allyl chloride, Mg, Et2O, 90%; (ii) MOMCl, DIPEA, CH2Cl2, 92%; (b) AD-mix-a, t-BuOH–H2O,
0 °C, 88%; (c) (i) p-TsCl, Et3N, CH2Cl2, 92%; (ii) LAH, THF, 85%; (d) (i) NaH, BnBr, THF, 93%; (ii) ceric ammonium nitrate, MeCN–H2O
(9:1), 90%; (e) (i) (COCl)2, DMSO, Et3N, –78 °C, 92%; (ii) Ph3P=CHCO2Et, benzene, reflux, 91%; (f) LiOH, THF–H2O (3:1), 86%.
(3) Am-strutz, R.; Hungerbuhler, E.; Seebach, D. Helv. Chim.
Acta 198l, 64, 1796.
(4) Rama Rao, A. V.; Murthy, V. S.; Sharma, G. V. M.
Tetrahedron Lett. 1995, 36, 143.
O
O
O
O
MOMO
OTBS
HO
OH
(5) Bouz, S.; Cossy, J. Tetrahedron Lett. 2006, 47, 901.
(6) (a) Yadav, J. S.; Srihari, P. Tetrahedron: Asymmetry 2002,
15, 81. (b) Yadav, J. S.; Prakash, S. J. Tetrahedron:
Asymmetry 2005, 16, 2722. (c) Yadav, J. S.; Rajaiah, G.
Synlett 2004, 1743.
(7) (a) Tocunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobson,
E. N. Science 1997, 277, 936. (b) Schaus, S. E.; Brandes,
B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould,
A. E.; Kurrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307. (c) Yadav, J. S.; Rajaiah, G. Synlett 2004,
1743.
(8) (a) Rickborn, B.; Lamke, W. E. II J. Org. Chem. 1967, 32,
537. (b) Murphy, D. K.; Alumbaugh, R. L.; Rickborn, B.
J. Am. Chem. Soc. 1969, 91, 2649. (c) Kan, W. S.
Pharmaceutical Botany; National Research Institute of
Chinese Medicine: Taipei, 1979, 247.
(9) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(b) Marx, M.; Tidwell, T. T. J. Org. Chem. 1984, 49, 788.
(c) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(10) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
(11) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765. (b) Carreaux, F.; Favre, A.; Carboni, B.; Rouaud,
I.; Boustie, J. Tetrahedron Lett. 2006, 47, 4545.
(12) Nicolaou, K.; Duggan, M. E.; Ladduwahetty, T.
Tetrahedron Lett. 1984, 25, 2069.
a
b
15 + 21
CO2Me
OBn
O
O
22
1
Scheme 5 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP, CH2Cl2, 70%; (b) (i) DDQ, CH2Cl2–H2O
(18:2), r.t., 90%; (ii) LiOH, THF–H2O (3:1), 70%; (iii) 2-methyl-6-
nitrobenzoyl anhydride, 4-(N,N-dimethylamino)pyridine, CH2Cl2,
60%; (iv) concd HCl, MeOH, r.t., 85%.
The structure of the clonostachydiol (1) was confirmed by
comparing its spectroscopic and physical data with the
natural product and also with those in a previous synthetic
report.4 These data and specific rotation were in agree-
ment with the data reported.
In summary, we have described a highly stereoselective
synthetic route for the synthesis of clonostachydiol (1) us-
ing readily available ( )-epichlorohydrin (6) as a starting
material. The synthesis involves a sequence of reactions
including Sharpless asymmetric epoxidation, iodination,
stereoselective opening of epoxide with allylmagnesium
chloride and Sharpless asymmetric dihydroxylation
which makes for convenient scale-up. This approach is
also useful for the synthesis of other stereoisomers and for
the design of analogues.
(13) (a) Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155.
(b) Deiters, A.; Martin, S. Chem. Rev. 2004, 104, 2199.
(14) Yadav, J. S.; Chandrashekar, S.; Sumitra, G.; Rajashekar, K.
Tetrahedron Lett. 1996, 37, 6603.
(15) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa,
K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org. Chem. 1992,
57, 2768.
Acknowledgment
T.S.Y. thanks the CSIR, New Delhi for financial assistance.
(16) Thomas, J. H.; George, A. O. Org. Lett. 2002, 4, 4447.
(17) Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(18) Shiina, I.; Kubota, K.; Ibuka, R. Tetrahedron Lett. 2002, 43,
7535.
References and Notes
(19) Compound 15: [a]D +7.5 (c = 1, CDCl3). 1H NMR (300
MHz, CDCl3): d = 6.95 (dd, J = 15.8, 4.5 Hz, 1 H), 6.00 (d,
J = 15.8 Hz, 1 H), 4.25 (dd, J = 6.7, 4.5 Hz, 1 H), 3.75–3.85
(m, 1 H), 3.72 (s, 3 H), 1.15 (d, J = 6.7 Hz, 3 H), 0.95 (s,
(1) Grabley, S.; Hammann, P.; Thiericke, R.; Wink, J.; Philipps,
S.; Zeeck, A. J. Antibiot. 1993, 46, 343.
(2) MacMillan, J.; Simpson, T. J. J. Chem. Soc., Perkin Trans. 1
1973, 1487.
Synlett 2008, No. 18, 2773–2776 © Thieme Stuttgart · New York

2776
J. S. Yadav et al.
LETTER
9 H), 0.10 (s, 3 H), 0.06 (s, 3 H). 13C NMR (50 MHz,
CDCl3): d = 166.4, 147.4, 121.6, 75.6, 70.2, 51.3, 25.6, 18.0,
–4.6. IR (Neat): 3452, 2928, 2885, 1714, 1642, 1412, 1225,
915 cm–1. MS (ESI): m/z = 297 [M + Na+]. HRMS: m/z calcd
for C13H26O4SiNa: 297.1498; found: 297.1491.
129.4, 123.5, 97.2, 77.0, 76.1, 72.5, 55.0, 34.5, 32.2, 23.6.
MS (ESI): m/z = 309 [M+ + 1], 331 [M+ + Na]. HRMS: m/z
calcd for C17H24O5Na: 331.1521; found: 331.1519.
Compound 1: [a]D +101 (c = 1, MeOH). 1H NMR (300
MHz, CDCl3): d = 6.85 (dd, J = 14.3, 4.3 Hz, 1 H), 6.78 (dd,
J = 15.1, 6.1 Hz, 1 H), 6.08 (d, J = 14.3 Hz, 1 H), 5.95 (d,
J = 15.1 Hz, 1 H), 4.90–4.98 (m, 1 H), 4.15–4.25 (m, 2 H),
3.85–3.95 (m, 1 H), 1.55–1.68 (m, 4 H), 1.25 (d, J = 6.0 Hz,
3 H, Me), 1.25 (d, J = 6.0 Hz, 3 H, Me). IR (Neat): 3350,
2984, 2918, 1709, 1643, 1252, 1175 cm–1. LCMS: m/z = 307
[M+ + Na].
Compound 21: [a]D +7.5 (c = 0.6, CDCl3). 1H NMR (300
MHz, CDCl3): d = 7.22–7.35 (m, 5 H), 6.90 (dd, J = 15.6, 6.2
Hz, 1 H), 5.95 (d, J = 15.6 Hz, 1 H), 4.50–4.62 (m, 2 H), 4.45
(d, J = 6.6 Hz, 2 H), 4.06–4.15 (m, 1 H), 3.45–3.55 (m, 1 H),
3.35 (s, 3 H), 1.50–1.75 (m, 4 H), 1.20 (d, J = 6.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.4, 152.2, 130.0, 129.6,
Synlett 2008, No. 18, 2773–2776 © Thieme Stuttgart · New York

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