Attempts directed towards the synthesis and determination of the absolute stereochemistry of iso-cladospolide-B and cladospolides-B and C

Article abstract of DOI:10.1016/j.tetlet.2006.07.043

Attempts to synthesise iso-cladospolide-B, cladospolide-B and cladospolide-C resulted in macrolides 1, 2 and 4 along with butenolide 3. Of the three stereogenic centres, the C-4/C-5 vic-diol was obtained from tartaric acid and d-glucose, while the C-11 st

Full text of DOI:10.1016/j.tetlet.2006.07.043

Tetrahedron Letters 47 (2006) 6531–6535
Attempts directed towards the synthesis and determination of
the absolute stereochemistry of iso-cladospolide-B and
cladospolides-B and CI
G. V. M. Sharma,* J. Janardhan Reddy and K. Laxmi Reddy
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 February 2006; revised 28 June 2006; accepted 10 July 2006
Available online 1 August 2006
Abstract—Attempts to synthesise iso-cladospolide-B, cladospolide-B and cladospolide-C resulted in macrolides 1, 2 and 4 along
with butenolide 3. Of the three stereogenic centres, the C-4/C-5 vic-diol was obtained from tartaric acid and D-glucose, while the
C-11 stereocentre was created by Jacobsen’s method.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
try of 36 as (4S,5S,11R)-, analogous to macrolide 1.6
Herein, we report the synthesis and attempts to deter-
mine the absolute stereochemistry of 1, 2, 3 and 4, which
is the C-11 epimer of 2 (Fig. 1).
Cladospolide-B (1) was isolated1 from Cladosporium
cladosporioides F1-113 and was found to be a plant
growth promoter. It was also isolated2 along with clado-
spolide-C (2) from Cladosporium tenuissimum. Macro-
lide 1 was found to inhibit shoot elongation of rice
seedlings (Oryza sativa L.), while 2 damages the plants
and causes necrosis. Based on the absolute configuration
of cladospolide-A3 (4R,5S,11R), the relative configura-
tions for 1 and 2 were proposed2 as (4S,5S,11R)- and
(4R,5R,11R)-, respectively. iso-Cladospolide-B (3)4 was
isolated along with 1 from the fermentation broth of
the fungal isolate I96S215 obtained from a tissue sample
of a marine sponge, and its structure was defined from
spectroscopic studies. The synthesis by Figadere and
co-workers5 has established the absolute stereochemis-
An antithetic analysis of 1 and 3 (Scheme 1) suggested
that seco-acid 5 is an appropriate late stage intermediate
which could be realised from 6, which in turn could be
accessed from 7 and 8. Thus, of the three stereogenic
centres, the vic-diol is obtained from 7, while the other
chiral centre is introduced by the Jacobsen hydrolytic
kinetic resolution method.7
Accordingly, diol 8 (Scheme 2) on reaction with
TBDPSCl gave TBDPS ether 9 (76%), which on treat-
ment with Ph3P and I2, followed by reaction of the
resulting iodide 10 with Ph3P (toluene, reflux), afforded
8
OH
OH
11
S
R
R
OH
OH
R
R
R
OH
OH
S
OH
OH
O
S
O
S
R
5
R
O
4
O
O
O
S
3
1
O
O
4
2
1
Figure 1.
Keywords: Cladosporium sps.; vic-Diol; Jacobsen’s method; Seco-acid; Mcrolactonisation.
q IICT Communication No. 060119.
*
Corresponding author. Fax: +91 40 27160387/27160757; e-mail: esmvee@iict.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.043

6532
G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6531–6535
OH
OH
O
O
R
S
S
OH
OH
O
O
O
S
O
S
R
OH
+
O
OH
5
3
1
HO
HO
CO2H
CO2H
OTPS
O
)
(
4
OBn
O
7
+
6
HO
OH
8
Scheme 1.
R
O
O
d, e, f
a, b, c
R
OTPS
HO
OH
O
OBn
9 R = OH (76%)
10 R = I (82%)
8
O
O
6 R = CH2OTPS (75%)
13 R = CH2OH (93%)
14 R = CHO (90%)
H
OBn
11 R = Ph3P+I- (80%)
12
HO
O
O
OH
O
O
O
O
O
(
OBn
)
( )
3
(
)
3
g
3
h
+
OBn
16 (40%)
OAc
OBn
O
17 (42%)
OR'
15 (53%)
OR
(
O
)
l, m
k, f
(
)
O
O
O
O
(
)
i, j
4
3
4
16
OR
OBn
O
R
O
20 R = CH2OH (90%)
21 R = CHO (92%)
22 R = Me, R' = Ac (87%)
5 R = R' = H (84%)
18 R = H (89%)
19 R = Ac (92%)
OH
OH
S
S
OH
OH
R
n
O
O
S
O
o or p
+
O
O
R
S
O
O
O
3 (25%)
1 (55%)
23 (75%)
Scheme 2. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, 0 ꢁC, 12 h; (b) I2, Ph3P, imidazole, toluene, rt, 30 min; (c) Ph3P, toluene,
reflux, 24 h; (d) n-BuLi, dry THF, 0 ꢁC, 2 h; (e) TBAF, dry CH2Cl2, 12 h; (f) (COCl)2 dry DMSO, Et3N, CH2Cl2, À78 ꢁC, 2 h; (g) TMSOI, t-BuOK,
dry DMSO, 0 ꢁC, 1 h; (h) S,S-Jacobsen catalyst, H2O, rt, 12 h; (i) LAH, dry THF, 0 ꢁC, 1 h; (j) AcCL, Et3N, DMAP, CH2Cl2, 0 ꢁC, 2 h; (k) H2, Pd/
C, EtOAc, rt, 12 h; (l) Ph3P@CHCO2Me, MeOH, 0 ꢁC, 2 h; (m) 4 N NaOH, MeOH, rt, 4 h; (n) 2,4,6-trichlorobenzoyl chloride, Et3N, CH2Cl2,
DMAP, toluene, reflux, 24 h; (o) 80% aq AcOH, 70 ꢁC, 1 h and (p) TiCl4, dry CH2Cl2, 0 ꢁC, 2 h.
phosphonium salt 11 (80%). Wittig olefination of the
known aldehyde 12,8 (prepared from diol 7) with phos-
phonium salt 11 afforded olefin 6 (75%). Desilylation
(TBAF, CH2Cl2) of 6, followed by Swern oxidation of
alcohol 13, furnished aldehyde 14 (90%). One carbon
extension on 14 with trimethylsulfoxonium iodide
(TMSOI) (t-BuOK, DMSO) afforded the diastereoiso-
meric epoxides 15 (53%). Kinetic resolution of epoxide
15 under Jacobsen reaction conditions7 using the
(S,S)-catalyst gave epoxide 16 (40%) and diol 17
(42%). Reductive opening of epoxide 16 with LAH
afforded 18 (89%), which on acetylation followed by cat-
alytic hydrogenation of acetate 19 furnished saturated
alcohol 20 (90%). Oxidation of alcohol 20 and Wittig
reaction of aldehyde 21 with Ph3P@CHCO2Me in
MeOH afforded a,b-unsaturated ester 22 (87%) with
ities in 22 gave seco-acid 5 (84%), which on macrolac-
tonisation under Yamaguchi reaction conditions9 gave
macrolide 23 (75%). Finally, attempted deprotection of
acetonide in 23, with aq AcOH (80%) for 1 h gave
(4S,5S,11R)-butenolide 3 (25%) and (4S,5S,11R)-mac-
rolide 1 (55%) as a separable mixture of isomers. How-
ever, 23 on reaction with TiCl4 gave 1 (73%) as the
exclusive product. Besides the 1H NMR data, the optical
rotation values for 1: [a]D À95.0 (c 0.3, CHCl3) [(lit.1
[a]D +26.9 (c 0.4, MeOH); lit.2 [a]D +45.0 (c 0.4,
MeOH))] and for 3: [a]D À40.2 (c 0.3, CHCl3) [lit.4
[a]D À90.0 (c 0.23, MeOH), lit.5 [a]D À47.0 (c 0.75,
MeOH)], respectively, did not match with each other.
Similarly, an antithetic analysis of (4R,5R,11R)-2
(Scheme 3) revealed that macrolactonisation of acid 24
would give 2, while 24 in turn could be envisioned from
the C-5 extended D-xylose derivative 25. Aldehyde 26
1
cis-geometry as observed from the H NMR spectrum.
Base catalysed deprotection of both the ester functional-

G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6531–6535
6533
OBn
O
(
R
R
OH
OH
R
5
O
( )
OH
R
OBz
BnO
5
O
O
OH OH
O
R
25
24
O
2
OHC
HO
O
O
( )
O
O
5
OHC
BnO
O
O
27
26
Scheme 3.
could be prepared from the known aldehyde 27,10
a
urated ester 37 with trans-geometry (J2,3 = 13.0, J3,4 =
product of D-glucose. Thus, the main strategy would
be to use the C-2/C-3 hydroxy groups as the R,R-vic-
diol system of 2, while the other stereocentre is intro-
duced by the Jacobsen method.7
5.6 Hz) in 89% yield. Exposure of ester 37 to 4 N NaOH
cleaved the benzoyl, formyl and methyl ester groups to
furnish seco-acid 24 (72%), which on Yamaguchi mac-
rolactonisation using 2,4,6-trichlorobenzoyl chloride
afforded 38 (66%). Finally, 38 on reaction with TiCl4
underwent facile debenzylation to furnish (4R,
5R,11R)-macrolide 2 (74%), whose spectral data as well
as optical rotation value [a]D À40.9 (c 0.3, CHCl3) [lit.2
[a]D +59.7 (c 0.4, MeOH)] did not match the reported
data.
Accordingly, Wittig olefination of aldehyde 27 (Scheme
4) with phosphonium salt 11 and subsequent hydro-
genation of olefin 28 afforded 29 (93%). Desilylation
(TBAF) of TPS ether 29 followed by oxidation of alco-
hol 30 gave aldehyde 26 (95%). Reaction of aldehyde 26
with trimethylsulfoxonium iodide/KOBu-t gave dia-
stereoisomeric epoxides 31 (78%), which on Jacobsen
kinetic resolution (S,S-catalyst) furnished epoxide 32
(43%) and diol 33 (41%). Reductive (LAH) opening of
32 gave alcohol 34 (81%), which on benzoylation (BzCl,
Et3N) furnished benzoate 25 (95%). Acid (60% aq
AcOH) catalysed hydrolysis of the isopropylidene group
in 25 followed by oxidative cleavage of the diol in 35
with H5IO6 afforded aldehyde 36 in 90% yield. Wittig
olefination of 36 in toluene at reflux gave the a,b-unsat-
Assuming that the stereochemical assignment of macro-
lide 2 was not correct, (4R,5R,11S)-macrolide 4, the C-
11 epimer of 2, was synthesised from 33. Thus, selective
tosylation of diol 33 (Scheme 5) was followed by reduc-
tion of monotosylate 39 with LAH to give alcohol 40
(75%). Benzoylation of 40 was followed by hydrolysis
(60% aq AcOH) of 41 to afford diol 42 (82%). Oxidative
cleavage of diol 42 and subsequent Wittig reaction of
aldehyde 43 furnished trans-product 44 (88%).
O
O
O
OHC
( )
b, c, d
O
( )
a
O
O
R
5
4
TPSO
O
O
O
BnO
BnO
BnO
28 (74%)
29 R = CH2OTPS (93%)
30 R = CH2OH (90%)
26 R = CHO (95%)
27
O
O
O
( )
5
e
( )
f
( )
O
O
O
5
5
HO
+
j
O
O
OH
BnO
O
O
O
BnO
BnO
33 (41%)
31 (78%)
32 (43%)
OBn
O
O
( )
i
( )
( )
OH
5
O
g, h
CHO
OBz OCHO
36 (90%)
5
5
32
OBz
BnO
35 (85%)
OR
BnO
OH
O
34 R = H (81%)
25 R = Bz (95%)
OBn
OH
OR
m, n
k, l
( )
CO2R
5
O
OR' OR''
O
37 R = Me, R' = Bz, R'' = CHO (89%)
24 R = R' = R'' = H (72%)
38 R = Bn (66%)
R = H (74%)
2
Scheme 4. Reagents and conditions: (a) 11, n-BuLi, dry THF, À78 ꢁC, 2 h; (b) H2, PtO2, EtOAc, rt, 12 h; (c) TBAF, dry CH2Cl2, rt,12 h; (d)
(COCl)2, dry DMSO, Et3N, CH2Cl2, À78 ꢁC, 2 h; (e) TMSOI, t-BuOK, dry DMSO, 0 ꢁC, 1 h; (f) S,S-Jacobsen catalyst, H2O, rt, 12 h; (g) LAH, dry
THF, 0 ꢁC, 1 h; (h) BzCl, Et3N, DMAP, CH2Cl2, 0 ꢁC, 2 h; (i) 60% aq AcOH, 70 ꢁC, 12 h; (j) H5IO6, EtOAc–H2O (1:1), 0 ꢁC, 1 h; (k)
Ph3P@CHCO2Me, toluene, reflux, 2 h; (l) 4 N NaOH, CH3OH, rt, 2 h; (m) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, reflux, 24 h
and (n) TiCl4, dry CH2Cl2, 0 ꢁC, 2 h.

6534
G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6531–6535
O
O
( )
O
( )
O
( )
5
a
d
OH
b, c
O
5
TsO
5
33
OH
BnO
OBz
BnO
O
OR
OH
42 (82%)
O
BnO
40 R = H (75%)
41 R = Bz (78%)
39 (71%)
OBn
CHO
OBn
R
S
OH
OR
( )
h, i
e
( )
f,g
CO2R
5
5
OR' OR''
O
OBz OCHO
R
44 R = Me, R' = Bz, R'' = CHO (88%)
45 R = R' = R'' = H (81%)
43 (87%)
O
46 R = Bn (79%)
4 R = H (74%)
Scheme 5. Reagents and conditions: (a) p-TsCl, Et3N, CH2Cl2, 0 ꢁC, 12 h; (b) LAH, dry THF, 0 ꢁC, 1 h; (c) BzCl, Et3N, DMAP, CH2Cl2, 0 ꢁC, 2 h;
(d) 60% aq AcOH, 70 ꢁC, 12 h; (e) H5IO6, EtOAc:H2O (1:1), 0 ꢁC, 1 h; (f) Ph3P@CHCO2Me, toluene, reflux, 2 h; (g) 4 N NaOH, CH3OH, rt, 2 h; (h)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, reflux, 24 h and (i) TiCl4, dry CH2Cl2, 0 ꢁC, 2 h.
One-pot base (NaOH) catalysed deprotection of all the
ester groups in 44 gave seco-acid 45, which under Yama-
guchi reaction conditions underwent smooth macro-
lactonisation to afford 46 (79%). Exposure of 46 to
TiCl4 furnished macrolide 4 (74%), whose spectral data
also did not match with the reported data for clado-
spolide-C; however, the optical rotation value [a]D
+29.7 (c 0.3, CHCl3) [lit.2 [a]D +59.7 (c 0.4, MeOH)]
was observed with a positive sign.
187 (94), 151 (26), 127 (100), 55 (44); HRMS (ESI):
m/z calculated for C12H21O4 [M+H]+ 229.1439, found
229.1430.
Lactone 3: Colourless syrup, [a]D À40.2 (c 0.3, CHCl3);
1
lit.4 [a]D À90.0 (c 0.23, MeOH); H NMR (400 MHz,
CDCl3) d: 1.13 (d, 3H, J = 6.2 Hz, H-12), 1.22–1.61
(m, 10H, 5 · –CH2), 3.70 (m, 1H, H-11), 3.77 (m, 1H,
H-5), 5.07 (q, 1H, J = 1.8 Hz, H-4), 6.16 (dd, 1H,
J = 5.8, 2.0 Hz, H-2), 7.63 (dd, 1H, J = 5.8, 1.4 Hz,
H-3); 13C NMR (125 MHz, CDCl3) d: 23.2, 26.1, 26.7,
30.6, 34.0, 40.2, 68.4, 71.8, 88.4, 122.6, 157.1, 175.9;
IR (KBr): 1175, 1262, 1715, 3520 cmÀ1; FABMS: (m/z,
%): 251 (M++23, 42), 167 (17), 149 (18), 109 (100);
HRMS (ESI): m/z calculated for C12H21O4 [M+H]+
229.1439, found 229.1433.
Thus, even though the syntheses of 1, 2 and 3 along with
4 were achieved from two chiral synthons with vic-diols
from tartaric acid and D-glucose, the absolute stereo-
chemistry of the target natural products could not be
determined. From the observed change in the sign of
rotation in 4, it was proposed to attempt the synthesis
of 1, 2 and 3 with the 4S,5S,11S-configuration.11
Macrolide 4: Colourless solid, mp 80–82 ꢁC; [a]D +29.7
1
(c 0.3, CHCl3); H NMR (300 MHz, CDCl3) d: 1.21
2. Spectral data for selected compounds
(d, 3H, J = 6.5 Hz, H-12), 1.20–1.82 (m, 10H,
5 · CH2), 3.34–3.41 (m, 1H, H-5), 3.98–4.05 (m, 1H,
H-4), 4.70–4.92 (m, 1H, H-11), 6.08 (d, 1H,
J = 9.3 Hz, H-2), 6.98 (dd, 1H, J = 9.3, 5.3 Hz, H-3);
13C NMR (75 MHz, CDCl3) d: 22.8, 26.2, 26.6, 30.8,
35.0, 41.2, 68.5, 72.2, 88.5, 122.6, 155.8, 174.3; IR
(KBr): 1170, 1265, 1710, 3518 cmÀ1; FABMS: (m/z,
%): 251 (M++23, 32), 187 (94), 151 (26), 127 (100), 55
(44); HRMS (ESI): m/z calculated for C12H21O4
[M+H]+ 229.1439, found 229.1431.
Macrolide 1: Colourless solid, mp 105–110 ꢁC (lit.2 mp
109–110 ꢁC); [a]D À95.0 (c 0.5, CHCl3); lit.2 [a]D +45.0
1
(c 0.4, MeOH); H NMR (300 MHz, CDCl3) d: 1.29
(d, 3H, J = 6.0 Hz, H-12), 1.17–2.05 (m, 10H, 5 ·
–CH2), 3.82 (dd, 1H, J = 9.0, 5.2 Hz, H-5), 4.89 (dq,
1H, J = 10.5, 1.5, 6.0 Hz, H-11), 5.24 (t, 1H,
J = 8.3 Hz, H-4), 5.80 (d, 1H, J = 12.0 Hz, H-2), 6.12
(dd, 1H, J = 9.0, 8.3 Hz, H-3); 13C NMR (125 MHz,
CDCl3) d: 19.7, 21.2, 24.1, 25.7, 30.6, 32.0, 67.4, 73.8,
74.4, 121.6, 148.7, 165.9; IR (KBr): 1075, 1282, 1350,
1635, 1715, 2940, 3320 cmÀ1; FABMS: (m/z, %): 251
(M++23, 22), 167 (28), 149 (12), 109 (100); HRMS
(ESI): m/z calculated for C12H21O4 [M+H]+ 229.1439,
found 229.1429.
Acknowledgements
J.J.R. and K.L.R. are thankful to the CSIR and UGC,
New Delhi, India, for financial support.
Macrolide 2: Colourless solid, mp 80–85 ꢁC (lit.2 mp 90–
91 ꢁC); [a]D À40.9 (c 0.3, CHCl3); lit.2 [a]D +59.7 (c 0.4,
1
MeOH); H NMR (400 MHz, CDCl3) d: 1.27 (d, 3H,
References and notes
J = 6.0 Hz, H-12), 1.15–1.90 (m, 10H, 5 · CH2), 3.99–
4.04 (m, 1H, H-5), 4.40–4.30 (m, 1H, H-4), 5.10–5.20
(m, 1H, H-11), 6.08 (d, 1H, J = 8.0 Hz, H-2), 6.98 (dd,
1H, J = 8.0, 2.8 Hz, H-3); 13C NMR (75 MHz, CDCl3)
d: 20.8, 22.4, 25.5, 31.4, 31.8, 38.2, 39.3, 64.9, 72.5,
124.8, 144.0, 174.3; IR (KBr): 850, 1170, 1265, 1710,
2925, 3518 cmÀ1; FABMS: (m/z, %): 251 (M++23, 12),
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