An expedient total synthesis of (-)-cladospolide A

Article abstract of DOI:10.1055/s-0029-1217737

A simple and efficient total synthesis of (-)-cladospolide A is described here, which involves either olefin cross metathesis or Julia-Kocienski olefination and Yamaguchi macrolactonization as key steps.

Full text of DOI:10.1055/s-0029-1217737

LETTER
2441
An Expedient Total Synthesis of (–)-Cladospolide A
S
ynthesis of (–)-C
r
ladospol
i
ide
A
shna P. Kaliappan,* Debjani Si
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received 24 June 2009
OH
5
Abstract: A simple and efficient total synthesis of (–)-cladospolide
A is described here, which involves either olefin cross metathesis or
Julia–Kocienski olefination and Yamaguchi macrolactonization as
key steps.
11
3
HO
4
OH
O
OH
O
1
2
O
Key words: olefin cross metathesis, Julia–Kocienski olefination,
O
macrolactonization, cladospolides, total synthesis
cladospolide A (1)
cladospolide B (2)
O
O
The twelve-membered macrolactone (–)-cladospolide A1
(1) was first isolated from the culture filtrate of Cladospo-
rium fulvam FI-113 along with its group member clado-
spolide B2 (2) by Isogai and co-workers in 1985
(Figure 1). Later, 1 also has been isolated from the fungus
Cladosporium tenuissimum as well as marine fungal spe-
cies I962S215 together with other family members clado-
spolide C3a and isocladospolide B,3b respectively. The
structure and absolute stereochemistry of 1 was deter-
mined as (4R,5S,11R,2E)-4,5-dihydroxy-2-decen-11-
olide by means of Mosher’s ester as well as X-ray crystal-
lographic analysis.1 While the plant growth regulator
(–)-cladospolide A inhibits root growth of lettuce seed-
lings, cladospolide B promotes the growth. Another con-
gener cladospolide C (4) has been reported to inhibit shoot
elongation of rice seedlings.2 The 4-oxo lactone, clado-
spolide D4 (5), a newly isolated species from Cladospori-
um sp. FT-0012, shows antimicrobial activity against
Mucor racemosus and Pyricularia oryazae.
HO
OH
iso-cladospolide B (3)
OH
O
O
OH
OH
O
O
O
cladospolide C (4)
cladospolide D (5)
Figure 1 Cladospolide family
thesis reaction between alkenes 10 and 12 or by Julia–
Kocienski olefination between sulfone 13 and aldehyde
11. Both the fragments 12 and 13 could be easily derived
from a common intermediate 14 which could be synthe-
sized from optically active D-ribose in few steps.
Our journey for the synthesis of (–)-cladospolide A began
with the Wittig reaction on D-ribose monoacetonide 15,
using ethyl(triphenylphosphoranylidene)acetate in the
presence of a catalytic amount of benzoic acid followed
by protection of the resultant diol as di-TBS ether afford-
ed the compound 16 in 80% yield. Saturation of the dou-
ble bond provided ester 17 which upon careful reduction
with LAH furnished the alcohol 18 in 82% yield. One car-
bon homologation to 19 was easily accomplished in 87%
yield through oxidation of alcohol 18 with PCC to corre-
sponding aldehyde followed by Wittig reaction with tri-
phenyl phosphonium methylidene (Scheme 2).
Due to their impressive biological profiles, cladospolides
have attracted the interest of synthetic chemists since their
isolation and (–)-cladospolide A has been the subject of
total synthesis5 by the groups of Mori, Ichimoto, Solladié,
and Banwell. In continuation of our interest in designing
and synthesizing natural6 and unnatural7 products, we de-
veloped interest in the synthesis of (–)-cladospolide A and
its congeners. Herein, we disclose a short and efficient
synthesis of (–)-cladospolide A.
As per our retrosynthetic analysis (Scheme 1), the mac-
rolide 1 could be easily obtained from the precursor 6,
which in turn could be synthesized from 7 through macro-
lactonization. The seco acid 7 could be traced back to
compound 8 involving Horner–Wadsworth–Emmons
reaction and compound 8 is expected to obtain from the
intermediate 9. Here, we envisioned that the key interme-
diate 9 could be constructed either by olefin cross-meta-
Fragment 19 upon exposure to key olefin cross-metathesis
reaction8 conditions with the known alkene 20 in the pres-
ence of Grubbs II catalyst9 21 (5 mol%), underwent cross-
coupling to the desired intermediate 22 as the major iso-
mer, which was then hydrogenated with Pd-C to afford
compound 23 in 42% yield over two steps (Scheme 3).
The low yield in the olefin cross-metathesis step could be
attributed to the formation of other self coupled products.
However, the possible drawbacks of olefin cross-metathe-
sis reaction have prompted us to identify an alternative
way to synthesize the intermediate 22 and it readily
SYNLETT 2009, No. 15, pp 2441–2444
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217737; Art ID: G20709ST
© Georg Thieme Verlag Stuttgart · New York

2442
K. P. Kaliappan, D. Si
LETTER
TBSO
O
O
O
TBSO
O
20
1
O
a
O
OH
HO
+
TBSO
O
O
O
O
O
6
7
OTBS
22
TBSO
RO
O
OTBS
19
RO
O
O
O
MesN
Cl
NMes
RO
O
OR
OR
b
TBSO
Ru
O
OR
Cl
Ph
8
9
PCy3
OTBS
OTBS
21
23
SO2Ar
Scheme 3 Reagents and conditions: a) 21 (5 mol%), toluene,
110 °C, 6 h; b) 5% Pd-C/H2, EtOH, r.t., 2 h, 42% for two steps.
RO
O
O
O
+
or
RO
RO
X
O
10 X = CH2
11 X = O
OR
OR
Thus, alcohol 18 was converted into the sulfone 24 in a
couple of steps using Mitsunobu reaction with 1-phenyl-
1H-tetrazol-5-thiol11 25, followed by oxidation of the re-
sultant sulfide (Scheme 4). Gratifyingly, Julia–Kocienski
olefination between sulfone 24 and the aldehyde 26 in the
presence of LHMDS proceeded smoothly to provide 22 in
83% yield. Having the intermediate 22 in hand in good
quantity, we proceeded further to accomplish the total
synthesis of 1. Consequently, catalytic hydrogenation of
22 to its saturated counterpart 23, followed by selective
deprotection of vicinal TBS ethers with tetrabutylammo-
nium fluoride at 0 °C afforded the diol 27 in good yield.
Oxidative cleavage of diol 27 with silica gel supported
NaIO412 furnished the corresponding aldehyde which was
immediately subjected to Horner–Wadsworth–Emmons
reaction13 to furnish trans-a,b-unsaturated ester 28 as the
major isomer in 64% yield along with its cis-isomer in
14% yield. The saponification of the trans-ester 28 with
LiOH followed by removal of the TBS ether and imple-
mentation of the key macrolactonization using Yamagu-
chi protocol14 fruitfully underwent cyclization to give the
macrolactone 6 in 71% yield. Finally, deprotection of the
acetonide was accomplished with trifluoroaectic acid15 to
afford (–)-cladospolide A (1)16 in 65% yield. The spectral
data of synthetic 1 matches with that reported earlier,5
thus confirming the accomplishment of a total synthesis of
(–)-cladospolide A.
12
13
MeO2C
O
RO
D-ribose
O
OR
14
Scheme 1 Retrosynthetic analysis of (–)-cladospolide A
EtOOC
HO
O
O
O
OH
a
b
TBSO
O
O
OTBS
15
16
EtOOC
HO
TBSO
O
O
O
O
TBSO
c
OTBS
OTBS
17
18
O
d
TBSO
O
In summary, we have successfully accomplished the total
synthesis of (–)-cladospolide A in 14 linear steps in 6%
overall yield from D-ribose monoacetonide. This ap-
proach relies on four key reactions, explicitly, either
olefin cross metathesis or Julia–Kocienski olefination
for construction of the key intermediate 22, Horner–
Wadsworth–Emmons reaction to introduce exclusively
the trans-a,b-unsaturated ester functionality and
Yamaguchi macrolactonization to furnish the twelve-
membered macrolide. This strategy is now being extended
to synthesize its other congeners.
OTBS
19
Scheme 2 Reagents and conditions: a) i) Ph3PCH=COOEt, CH2Cl2,
r.t.; ii) TBSCl, DMF, r.t., 2 h, 76% for two steps; b) 5% Pd-C/H2,
EtOH, r.t., 2 h, 90%; c) LiAlH4, Et2O, 0 °C, 15 min, 82%; d) (i) PCC,
MeCOONa, 4 Å MS, CH2Cl2, 0 °C; ii) Ph3PCH2Br, KOt-Bu, THF,
0 °C, 78% for two steps.
crossed our mind to utilize the Julia–Kocienski
olefination10 to construct the intermediate 22.
Synlett 2009, No. 15, 2441–2444 © Thieme Stuttgart · New York

LETTER
Synthesis of (–)-Cladospolide A
2443
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N
NPh
O
O
N
HO
O
O
N
TBSO
S
a, b
O2
TBSO
OTBS
18
24
OTBS
TBSO
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O
O
TBSO
TBSO
O
22
OTBS
26
O
O
O
O
HO
f, g
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OTBS
EtO
OTBS
27
OH
O
28
O
O
HS
N
N
h–j
k
1
N
N
O
Ph
25
O
6
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Scheme 4 Reagents and conditions: a) 25, Ph3P, DIAD, THF,
–20 °C, 92%; b) (NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, r.t., 88%; c)
LiHMDS, THF, –78 °C, 26, 83%; d) 5% Pd-C/H2, EtOH, r.t., 2 h,
84%; e) TBAF (1 M soln in THF), THF, 0 °C, 2 h, 80%. f) silica supp.
NaIO4, CH2Cl2, 0 °C, 1 h; g) (OEt)2P(O)CH2COOEt, LiCl, DIPEA,
THF, 6 h, 64% for two steps; h) LiOH, THF–MeOH–H2O, 4 h, 93%;
i) TBAF (1 M soln in THF), THF, 55 °C, 81%; j) 2,4,6-trichloroben-
zoyl chloride, Et3N, 2 h, then DMAP, toluene, reflux, 8 h, 71%; k)
TFA, MeCN–H2O, 0 °C, 1 h, 65%.
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Acknowledgment
KPK thanks CSIR, New Delhi, for the financial support and SAIF,
IIT Mumbai for spectral facilities. DS thanks CSIR for a fellowship.
References and Notes
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(16) Spectral Data for Selected Compounds
20
Compound 22: Rf = 0.28 (2% EtOAc in hexane); [a]D
–27.6 (c 0.50, CHCl3). IR (neat): 3020, 2931, 1657, 1216,
1045, 669 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.45–5.42
(2 H, m), 4.09–4.05 (3 H, m), 3.80–3.74 (1 H, m), 3.66 (1 H,
dd, J = 11.3, 4.8 Hz), 2.13–2.03 (4 H, m), 1.63–1.53 (2 H,
m), 1.40 (3 H, s), 1.31 (3 H, s), 1.10 (3 H, d, J = 6.1 Hz), 0.90
(9 H, s), 0.88 (9 H, s), 0.86 (9 H, s), 0.11 (3 H, s), 0.08 (3 H,
s), 0.06 (6 H, s), 0.04 (3 H, s), 0.03 (3 H, s). 13C NMR (100
MHz, CDCl3): d = 132.0, 127.2, 107.8, 77.4, 76.4, 72.6,
68.8, 65.3, 43.0, 30.1, 29.1, 28.4, 26.0, 25.96, 25.90, 23.3,
18.4, 18.1, –3.5, –4.5, –4.6, –4.7, –5.3, –5.4.
(2) Hirota, A.; Sakai, H.; Isogai, A. Agric. Biol. Chem. 1985, 49,
731.
(3) (a) Fujii, Y.; Fukuda, A.; Hamasaki, T.; Ichimoto, I.;
Nakajima, H. Phytochemistry 1995, 40, 1443. (b) Smith,
C. J.; Abbanat, D.; Bernan, V. S.; Maiese, W. M.;
Greenstein, M.; Jampa, J.; Tahir, A.; Ireland, C. M. J. Nat.
Prod. 2000, 63, 142.
(4) Zhang, H.; Tomoda, H.; Tabata, N.; Miura, H.; Namikoshi,
M.; Yamaguchi, Y.; Masuma, R.; Omura, S. J. Antibiot.
2001, 54, 635.
20
Compound 23: Rf = 0.26 (2% EtOAc in hexanes); [a]D
–29.7 (c 0.66, CHCl3). IR (neat): 3021, 2930, 2858, 2640,
1380, 1216, 1044, 669 cm–1. 1H NMR (400 MHz, CDCl3):
d = 4.08–4.04 (2 H, m), 3.79–3.73 (3 H, m), 3.68–3.64 (1 H,
m), 1.65–1.24 (10 H, complex m), 1.39 (3 H, s), 1.30 (3 H,
(5) Synthesis of (–)-cladospolide A: (a) Maemoto, S.; Mori, K.
Chem. Lett. 1987, 109. (b) Mori, K.; Maemoto, S. Liebigs
Ann. Chem. 1987, 863. (c) Ichimoto, I.; Sato, M.; Kirihata,
Synlett 2009, No. 15, 2441–2444 © Thieme Stuttgart · New York

2444
K. P. Kaliappan, D. Si
LETTER
J = 6.4 Hz), 0.98–0.92 (1 H, m). 13C NMR (100 MHz,
CDCl3): d = 166.9, 145.1, 124.3, 109.4, 79.5, 76.4, 72.7,
33.3, 30.7, 28.1, 27.9, 25.4, 21.8, 20.0, 18.3.
(–)–Cladospolide A (1): Rf = 0.19 (50% EtOAc in hexanes);
mp 90–92 °C; [a]D20 –40.4 (c 0.50, CHCl3). IR (KBr): 3437,
2927, 2870, 1713, 1651, 1462, 1377, 1269, 1165, 1021, 880
cm–1. 1H NMR (400 MHz, CDCl3): d = 6.80 (1 H, dd,
J = 16.0, 5.5 Hz), 6.20 (1 H, dd, J = 16.0, 1.5 Hz), 5.15–5.08
(1 H, m), 4.55–4.53 (1 H, m), 3.65 (1 H, ddd, J = 9.1, 1.8, 1.2
Hz), 1.81–1.11 (9 H, complex m), 1.27 (3 H, d, J = 6.4 Hz),
0.90–0.84 (1 H, m). 13C NMR (100 MHz, CDCl3): d = 167.9,
145.5, 122.2, 74.6, 72.9, 72.8, 32.3, 30.6, 28.1, 25.0, 22.5,
18.9.
s), 1.09 (3 H, d, J = 6.1 Hz), 0.90 (9 H, s), 0.87 (9 H, s), 0.85
(9 H, s), 0.10 (3 H, s), 0.07 (3 H, s), 0.05 (6 H, s), 0.037 (3
H, s), 0.033 (3 H, s). 13C NMR (100 MHz, CDCl3): d =
107.7, 76.6, 72.6, 68.5, 65.3, 39.6, 30.0, 29.8, 28.4, 26.1,
26.0, 25.96, 25.90, 23.8, 18.4, 18.2, 18.1, –3.5, –4.4, –4.7,
–4.8, –5.3, –5.4. HRMS (EI): m/z calcd for [C32H70O5Si3 +
Na]+ : 641.4429; found: 641.4412.
20
Compound 6: Rf = 0.34 (10% EtOAc in hexanes); [a]D
–12.7 (c 0.83, CHCl3). IR (neat): 3020, 2937, 2401, 1712,
1382, 1216, 1023, 669 cm–1. 1H NMR (400 MHz, CDCl3):
d = 6.96 (1 H, dd, J = 15.7, 9.1 Hz), 6.05 (1 H, d, J = 15.8
Hz), 5.08–5.15 (1 H, m), 4.68 (1 H, dd, J = 8.8, 6.4 Hz), 4.10
(1 H, ddd, J = 7.9, 6.1, 1.8 Hz), 1.73–1.61 (2 H, m), 1.54–
1.20 (7 H, m), 1.48 (3 H, s), 1.34 (3 H, s), 1.27 (3 H, d,
Synlett 2009, No. 15, 2441–2444 © Thieme Stuttgart · New York

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