A concise total synthesis of (+)-cladospolide D

Article abstract of DOI:10.1055/s-0032-1317520

A short and convergent total synthesis of (+)-cladospolide D is delineated, which involves olefin cross metathesis and furan oxidation to access the γ-oxo-α,β-unsaturated acid and Yamaguchi lactonization to construct the 12-membered ring as key steps. Copyright

Full text of DOI:10.1055/s-0032-1317520

2822▌
LETTER
lAetteCr oncise Total Synthesis of (+)-Cladospolide D
Total Synthesis of (+)-Cladospolide D
Debjani Si, Krishna P. Kaliappan*
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received: 05.09.2012; Accepted after revision: 08.10.2012
Dedicated to Professor M. Periasamy (University of Hyderabad) on the occasion of his 60th birthday
munity resulting in several syntheses of its family mem-
bers including two reports5 from our group.
Abstract: A short and convergent total synthesis of (+)-clado-
spolide D is delineated, which involves olefin cross metathesis and
furan oxidation to access the γ-oxo-α,β-unsaturated acid and Yama-
guchi lactonization to construct the 12-membered ring as key steps.
The relative and absolute stereochemistry of cladospolide
D had not been assigned until the first report on clado-
Key words: olefin cross-metathesis, Julia–Kocienski olefination, spolide D was published by Hou and co-workers who pro-
Yamaguchi lactonization, cladospolides, total synthesis
posed the structure of cladospolide D as (E)-cladospolide
D (6, Figure 2).6a Soon after their report, O’Doherty and
co-workers reassigned the C2–C3 double-bond geometry
to be Z through the synthesis of its enantiomer.6b,c
Cladospolides A–D (1–5), a family of secondary metabo-
lites isolated1–4 from different Cladosporium sp., are
known to have regulatory effects on the host plant’s
OH
growth (Figure 1). Though, it belongs to the same family,
cladospolide D (5), a 12-membered γ-oxo-lactone, diverg-
O
O
O
OH
es from other family members structurally and hence in
biological activity. Cladospolide D (5), isolated from
Cladosporium sp. FT-0012 by Omura and co-workers in
2001 along with known cladospolides A and B (1 and 2),
shows antifungal activity with IC50 values of 0.1 and
29 mg mL–1 against Mucor racemosus and Pyricularia
oryazae, respectively.4
O
O
5: cladospolide D
O
6: (E)-cladospolide D
Figure 2 Original and revised structures of cladospolide D
As a part of our ongoing research program on the synthe-
sis of biologically active natural products,7 we developed
interest in the synthesis of cladospolide family of natural
products and devised5b a flexible and unified strategy for
the synthesis of cladospolide A, B, C and isocladospolide
B. Herein, we report our collective efforts towards the
synthesis of the naturally occurring isomer of clado-
spolide D.
OH
HO
OH
O
OH
O
O
O
2: cladospolide B
1: cladospolide A
O
When we started our program on the total synthesis of
cladospolide D, the absolute stereochemistry of this mol-
ecule was not known.
O
HO
OH
OH
O
OH
OH
O
O
3: isocladospolide B
OH
OH
O
O
O
OH
HO2C
O
OH
O
O
7
O
6
8
O
5: cladospolide D
O
RO
O
O
4: cladospolide C
O
O
Figure 1 Cladospolide family
RO
OR
9
Owing to their structural diversities and appealing biolog-
ical properties, members of the cladospolide family have
attracted considerable attention from the synthetic com-
OR
10
N
N
O
S
RO
O
O
N
+
N
D
-ribose
O
O
Ph
11
SYNLETT 2012, 23, 2822–2826
12
OR
Advanced online publication: 09.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317520; Art ID: ST-2012-D0742-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of (E)-cladospolide D

LETTER
Total Synthesis of (+)-Cladospolide D
2823
Hence, our initial objective was to assign the absolute ste- zole-5-thiol 15,10 followed by oxidation of the resultant
reochemistry through its total synthesis. However, during sulfide (Scheme 2). Subsequently, the Julia–Kocienski
the early phase of our studies, Hou and co-workers olefination between sulfone 16 and aldehyde 1711 oc-
reported6a the first total synthesis as well as the absolute curred smoothly to give the desired alkene which, after
stereochemical assignment of (+)-cladospolide D, and so, hydrogenation, provided the key intermediate 18. Remov-
we set macrolide 6 as our revised synthetic target. Thus, al of the primary TBS ether proceeded uneventfully to af-
according to our retrosynthetic analysis, we envisaged ford alcohol 19 which, upon Swern oxidation followed by
that macrolide 6, the oxolactone, could be synthesized Horner–Wadsworth–Emmons reaction,12 resulted in the
from the corresponding diol 7 through selective oxidation trans-α,β-unsaturated ester 20 in good yield. Hydrolysis
of an allylic alcohol (Scheme 1), the macrolide 7 being of ester 20 with LiOH and cleavage of the TBS ether with
obtained from hydroxy acid 8 through lactonization. Seco TBAF at elevated temperature afforded the hydroxy acid
acid 8 could be derived through homologation from com- 8. Yamaguchi lactonization13 of acid 8 and subsequent de-
pound 9, which in turn, could be accessed from alkene 10. protection of the acetonide moiety under acidic
Thus, based on our previous experience we planned a conditions14 successfully afforded the macrolactone 7.
Julia–Kocienski olefination8 between aldehyde 11 and However, to our surprise, all our attempts to achieve se-
sulfone 12 to access alkene 10, and the sulfone 12 could lective oxidation led to overoxidation along with C–C
well be derived from D-ribose.
bond cleavage.
During this course of our research, O’Doherty and co-
workers reported6b,c their work on cladospolide D, reas-
signing the C2–C3 double-bond geometry to be Z. Fur-
thermore, they also reported their difficulties associated
with the selective oxidation of the allylic alcohol in ent-
cladospolide D, supporting our observations in the syn-
thetic studies of cladospolide D.
HO
O
O
O
O
O
ref. 9
HO
a, b
OTBS
OH
14
13
N
N
O
S
O
O
O
O
d
N
c
Nevertheless, in our quest to complete the total synthesis
of natural cladospolide D, we revised our strategy to one
that uses a protection–oxidation–deprotection sequence,
as used by O’Doherty and co-workers.
N
O
Ph
TBSO
OTBS
OTBS
18
16
O
O
O
O
e
f, g
O
TBSO
EtO2C
O
OR
O
OH
O
OH
TBSO
OH
OH
OH
19
20
O
O
O
21
5
MnO2
or
22
OH
OH
O
O
h, i
PDC
or
AgCO3–Celite
O
O
O
OH
HO2C
D-ribose
OH
HO2C
23
O
OR
O
8
O
7
RO
24
OH
O
N
N
Scheme 3 Retrosynthetic analysis of (Z)-cladospolide D
TBSO
N
SH
N
O
O
Ph
15
Hence, we expected that cladospolide D (5), the oxolac-
tone, could be synthesized from the precursor 21 through
oxidation of allylic alcohol 21 (Scheme 3). The allylic al-
cohol 21 could be traced to diol 22 through selective pro-
tection of one of the alcohols. Again the macrolactone 22
could be constructed from hydroxy acid 23, and acid 23
could, in turn, be obtained from D-ribose-derived key in-
termediate 24 in a few steps.
17
O
6
Scheme 2 Reagents and conditions: (a) 15, Ph3P, DIAD, THF,
–20 °C, 90%; (b) (NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, r.t., 80%;
(c) i) 17, LiHMDS, THF, –78 °C; ii) H2/Pd–C, EtOH, 50% (2 steps);
(d) TBAF, THF, 0 °C, 90%; (e) i) (COCl)2, DMSO, Et3N, CH2Cl2,
–78 °C; ii) (OEt)2P(O)CH2CO2Et, LiCl, DIPEA, THF, 69% (2 steps);
(f) LiOH, THF–MeOH–H2O, 85%; (g) TBAF, THF, 60 °C, 75%;
(h) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP, toluene,
reflux, 71%; (i) TFA, MeCN–H2O, 62%.
Thus, alcohol 19, upon oxidation followed by Wittig reac-
tion with ethyl(triphenylphosphoranylidene) acetate at
low temperature,14 resulted in the formation of cis-α,β-un-
saturated ester 25 in 70% yield (Scheme 4). Deprotection
of the secondary silyl ether with HF–pyridine complex
and hydrolysis of ester with LiOH afforded the hydroxy
acid 23 in good yield.
Thus, we began our synthetic journey with the conversion
of D-ribose monoacetonide 13 into alcohol 14.9 The alco-
hol 14 was then transformed into sulfone 16 in a two-step
sequence via Mitsunobu reaction with 1-phenyl-1H-tetra-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2822–2826

2824
D. Si, K. P. Kaliappan
LETTER
O
O
O
Accordingly, we proposed that the cladospolide D motif
27 could be constructed from the corresponding (E)-lac-
tone 28 through the photoisomerization6b,c of the double
bond, and the lactone 28 would be obtained from the hy-
droxyacid 29 (Scheme 5). Thus, an oxidation of furan 30
would be appropriate to access the seco acid 29 and, for
generating alkene 31, we proposed utilizing olefin cross
metathesis16 between alkenes 33 and 32 which in turn
would be accessible from furfural 34.
a
b, c
O
TBSO
OH
TBSO
CO2Et
25
19
f
d, e
HO
O
HO
O
OH
OH
HO2C
23
O
O
OTBS
O
O
Thus, our amended synthesis of cladospolide D (5) com-
menced with the conversion of furfural into optically pure
alcohol (R)-35.17 The alcohol (R)-35 was then protected as
its TBS ether 36 before being exposed to the known al-
kene 3718 for olefin cross metathesis with Grubbs’ sec-
ond-generation catalyst 38 and CuI19 in refluxing Et2O
(Scheme 6). It was heartening to see the formation of
cross-metathesis product along with the formation of
some dimerized products of the individual alkenes. Thus,
for the ease of purification, the mixture of alkenes was hy-
drogenated, and the required ester 39 was isolated in 65%
yield over two steps. It is worth mentioning that increased
duration of the hydrogenation effected overreduction, fur-
nishing the tetrahydrofuran as the sole product.
22
26
Scheme 4 Reagents and conditions: (a) i) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C; ii) Ph3PCHCO2Et, MeOH, –78 °C, 70% (2 steps);
(b) HF–pyridine, THF, 0 °C, 82%; (c) LiOH, THF–H2O, 98%; (d)
2,4,6-trichlorobenzoyl chloride, Et3N, 2 h, then DMAP, toluene, 90
°C, 2 h, 60%; (e) TFA, MeCN–H2O, 0 °C, 1 h, 90%; (f) TBSCl, im-
idazole, CH2Cl2.
The hydroxy acid 23 under Yamaguchi conditions lac-
tonized successfully to the macrolactone 23a which, upon
deprotection of acetonide under acidic conditions, fur-
nished diol 22 in 54% yield. To our dismay, diol 22 could
not be selectively protected by TBSCl and imidazole to
the desired product 26. We reasoned that the higher reac-
tivity of the allylic alcohol may well be the reason for this
problem and so did not proceed further in this sequence.
ref. 17
a
OHC
O
O
O
All the ineffective endeavors as well as failure of our end-
game plan to cladospolide D aided us to devise a complete
different strategy towards cladospolide D exploiting the
chemistry of furan as a masked 1,4-diketone. Literature
precedents available on the conversion of 2-substituted
and 2,5-disubstituted furans into γ-oxo-α,β-unsaturated
carbonyls led us to propose to fabricate the (Z)-1,4-dike-
tone present in cladospolide D motif from the oxidation of
an appropriate furan.15
OH
OTBS
36
34
35
O
H
c, d
b
O
OTBS
O
OTBS
OH
g
OCOPh
39
40
e, f
O
O
OTBS
cladospolide D (5)
OR2
O
O
O
OR2
41
O
OH
O
O
O
O
O
MesN NMes
O
28
Cl
PhOCO
37
Ru
5
27
Cl
Ph
PCy3
O
38
OH
O
OR2
O
Scheme 6 Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2,
0 °C, 83%; (b) i) 37, 38 (2 mol%), CuI, Et2O, reflux, 10 h; ii) H2,
Pd/C, EtOAc–MeOH, 65% (2 steps); (c) DIBAL-H, Et2O, –30 °C,
80%; (d) NBS, NaHCO3, acetone–H2O, –15 °C, then furan, –15 °C,
pyridine, r.t., 5 h, 76%; (e) NaClO2, NaH2PO4, 2-methyl-2-butene,
THF–H2O, 0 °C, 95%; (f) 2,4,6-trichlorobenzoyl chloride, Et3N,
THF, 2 h, then DMAP, toluene, 100 °C, 8 h, 25%; (g) HF–MeCN, 0
°C to r.t., 56%.
OR2
OH
OR1
29
30
O
OR1
OR2
32
+
O
OR2
OHC
O
34
31
The cleavage of benzoate ester 39 was easily accom-
plished by treatment with DIBAL-H, and the key oxida-
tion of furan with NBS proceeded efficiently to furnish
the desired aldehyde 40 as the sole product in 76% yield.
Further oxidation of aldehyde 40 to acid 40a was carried
out smoothly under Pinnik conditions20 and this was then
OR1
33
Scheme 5 Revised retrosynthetic analysis of cladospolide D
Synlett 2012, 23, 2822–2826
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of (+)-Cladospolide D
2825
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lactone 41 with concomitant isomerization of the α,β-un-
saturated double bond, albeit in low yield. We presume
that the E–Z isomerization of the α,β-unsaturated 12-
membered system might be a result of transannular steric
strain, favoring the Z-isomer over the E.21 Moreover, the
isomerization might perhaps be facilitated by the expo-
sure to silica gel or the mildly basic conditions6b,c of the
Yamaguchi lactonization. Finally, we removed the silyl
ether under acidic conditions6b,c to accomplish the total
synthesis of cladospolide D (5)22 in eight steps in the lon-
gest linear sequence, starting from enantiomerically en-
riched furfuryl alcohol (R)-35. The spectroscopic data of
synthetic 5 matched those reported6b,c except for the spe-
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20
MeOH) {reported for ent-5: [α]D –57 (c 0.1, MeOH)}.
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In conclusion, we have accomplished the total synthesis
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Acknowledgment
We thank the DST, New Delhi for financial support. KPK thanks
DST for the award of Swarnajayanti fellowship. DS thanks CSIR,
New Delhi for a fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2822–2826

2826
D. Si, K. P. Kaliappan
LETTER
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(22) Experimental Details and Spectral Data for Selected
Compounds
1018 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.75 (d, J = 12.5
Hz, 1 H), 6.25 (d, J = 12.5 Hz, 1 H), 4.94–4.89 (m, 1 H), 4.33
(dd, J = 7.5, 3.8 Hz, 1 H), 1.97–1.89 (m, 1 H), 1.79–1.24 (m,
9 H), 1.28 (d, J = 6.1 Hz, 3 H), 0.94 (s, 9 H), 0.11 (s, 3 H),
0.10 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 203.4, 166.5,
133.7, 130.8, 76.4, 74.1, 33.5, 30.5, 26.4, 26.0, 25.9, 22.3,
21.3, 20.2, 18.3, 14.3, –4.5,–4.9. ESI-HRMS: m/z calcd for
C18H33O4Si: 341.2148; found: 341.2152.
(+)-Cladospolide D (5)6b,c
To a plastic flask was added lactone 41 (8 mg, 0.023 mmol)
and 5% HF in MeCN (26 μL) at r.t. The reaction mixture was
stirred for 8 h, and then EtOAc was added to dilute the
reaction solution. The reaction mixture was washed with
NaHCO3, extracted with EtOAc (3 × 5 mL), dried over
anhyd. Na2SO4, filtered, and evaporated under reduced
pressure to leave the crude product which was then purified
using silica gel column chromatography (12% EtOAc in
hexanes) to give cladospolide D (5.3 mg, 56%) as a colorless
oil. Rf = 0.25 (10% EtOAc in hexanes); [α]D20 +55.1 (c 0.1,
MeOH). IR (neat): 3468, 2930, 2854, 1725, 1462, 1101,
1012 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.42 (d, J = 13.4
Hz, 1 H), 6.31 (d, J = 13.4 Hz, 1 H), 5.26–5.21 (m, 1 H),
4.68–4.65 (m, 1 H), 3.20 (d, J = 5.5 Hz, 1 H), 1.96–1.92 (m,
1 H), 1.71–1.64 (m, 3 H), 1.52–1.28 (m, 6 H), 1.30 (d, J =
6.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 203.6, 165.3,
133.4, 131.1, 73.6, 71.6, 33.3, 31.2, 23.1, 21.7, 21.6, 20.8.
ESI-HRMS: m/z calcd for C12H18O4Na: 249.1103; found:
249.1104.
(5R,11S,Z)-5-(tert-Butyldimethylsilyloxy)-11-
methylcyclododec-2-ene-1,4-dione (41)
To a stirred solution of hydroxy acid 40a (60 mg, 0.20
mmol) and Et3N (55 μL, 0.40 mmol) in anhyd THF (5 mL)
was added 2,4,6-trichloroenzoyl chloride (40 μL, 0.26
mmol) at 0 °C, and the resulting mixture was stirred for a
further 2 h. The reaction mixture was then diluted with
anhyd toluene (10 mL), was added to a refluxing solution of
DMAP (51 mg, 0.40 mmol) in toluene (60 mL) at a rate of 3
mL/h and was refluxed for further 8 h. The resulting mixture
was cooled to r.t., quenched with a sat. NaHCO3 solution
(20 mL), and the aqueous layer was extracted with EtOAc
(3 × 20 mL). The combined organic fractions were washed
with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (8% EtOAc in hexanes) to afford
macrolactone 41 (17 mg, 25%) as an oily liquid. Rf = 0.30
(10% EtOAc in hexanes); [α]D20 +72.5 (c 0.9, CHCl3). IR
Synlett 2012, 23, 2822–2826
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