First synthesis and determination of the absolute stereochemistry of iso-cladospolide-B and cladospolides-B and C

Article abstract of DOI:10.1016/j.tetlet.2006.07.044

The syntheses of iso-cladospolide-B, cladospolide-B and cladospolide-C are reported with 4S,5S,11S-configuration. Of the three stereogenic centres, the C-4/C-5 vic-diol was created by Evans aldol condensation, while the C-11 stereocentre was created by Ja

Full text of DOI:10.1016/j.tetlet.2006.07.044

Tetrahedron Letters 47 (2006) 6537–6540
First synthesis and determination of the absolute stereochemistry
of iso-cladospolide-B and cladospolides-B and CI
G. V. M. Sharma,* K. Laxmi Reddy and J. Janardhan 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—The syntheses of iso-cladospolide-B, cladospolide-B and cladospolide-C are reported with 4S,5S,11S-configuration. Of
the three stereogenic centres, the C-4/C-5 vic-diol was created by Evans aldol condensation, while the C-11 stereocentre was created
by Jacobsen’s method. The synthesis of cladospolides 1–3 defined the absolute stereochemistry of these natural products.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Retrosynthetic analysis (Scheme 1) of 1 and 3 revealed
that both compounds could be envisioned from the
seco-acid 4, while 4 could be prepared through 5 and 6
from 5-carbon acetylenic alcohol 7. A similar consider-
ation on 2 revealed that the corresponding trans-acid 8
is the late stage intermediate, which could also be rea-
lised from 7. Thus, in the present study, the salient fea-
tures are that the vic-diol will be generated by an Evans
aldol condensation, while the C-11 stereocentre would
be obtained by Jacobsen kinetic resolution.
Cladospolide-B (1) and cladospolide-C (2) were iso-
lated1 from Cladosporium tenuissimum, while iso-clado-
spolide-B (3) was isolated2 from marine fungal species.
Based on the earlier proposals,2,3 we have synthesised
(4S,5S,11R)-1A, (4R,5R,11R)-2A and (4S,5S,11R)-3A,
besides the C-11 epimer (4R,5R,11S)-2B, whose spectral
data and optical rotation values, however, did not
match the reported data. From the preceding study4
on the synthesis of 2B, it was observed that epimerisa-
tion at C-11 significantly modified the optical rotation
from a negative value ([a]D À40.99 (c 0.3, CHCl3)) in
(4R,5R,11R)-2A to a positive value [a]D +29.4 (c 0.3,
CHCl3) in (4R,5R,11S)-2B, while the reported value
for cladospolide-C was [a]D +59.7 (c 0.4, MeOH).2
Based on this observation, it was proposed to synthesise
1–3 with 4S,5S,11S-configurations. During the course of
our synthetic studies, Carmeli and co-workers5 reported
the isolation of iso-cladospolide-B (3) from a different
Cladosporium sps. and determined the absolute stereo-
chemistry of 3 as 4S,5S,11S by Riguera’s method and
circular dichroism. Further, they proposed the same ste-
reochemical configuration for 1. Herein, we report the
first syntheses of 1–3 and the determination of their
absolute stereochemistry (Fig. 1).
Accordingly, 7 (Scheme 2) on reaction with NaH–BnBr
followed by coupling of 9 with allyl bromide gave 10
(77%), which on further treatment with m-CPBA fur-
nished racemic epoxide 11 (80%). Kinetic resolution of
racemic epoxide 11 with R,R-Jacobsen’s catalyst6 affor-
ded chiral epoxide 12 (43%) and diol 13 (40%). Reduc-
tion of epoxide 12 with LAH followed by silylation of
carbinol 14 with TBDPSCl gave TBDPS ether 15 (97%).
Catalytic hydrogenation of 15 in one-pot effected reduc-
tion of the triple bond along with debenzylation to
afford saturated alcohol 6 in 92% yield. Oxidation of
alcohol 6 with IBX and aldol condensation7 of aldehyde
16 with R-chiral auxiliary (I) furnished 17 in 65% yield.
Removal of the p-methoxybenzyl group in 17 followed
by acetonation of diol 18 afforded 19 (85%), which on
reduction with LiBH4 gave alcohol 5 (79%). Oxidation
of 5 with IBX, followed by Wittig olefination in MeOH,
furnished cis-product 21 in 80% yield. Base catalysed
hydrolysis of methyl ester 21 followed by desilylation
of 22 with HF–pyridine afforded seco-acid 4 (75%).
Macrolactonisation of 4 under Yamaguchi reaction
Keywords: Aldol condensation; vic-Diol; Jacobsen’s method; Seco-
acid; Macrolactonisation.
q IICT Communication No. 060120.
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.2006.07.044

6538
G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6537–6540
OH OH
11
5
S
S
5 S
4
S
4
OH
S
11
S
5
OH
S
S
11
O
1
S
O
O
O
1
OH
OH
4
O
1
O
iso-cladospolide B (3)
cladospolide C (2)
cladospolide B (1)
OH
OH
11
5
R
S
5 S
R
R
OH
OH
S
4
R
5
S
OH
S
11
R
11
5
O
11
1
R
R
O
O
1
O
1
4
O
OH
4
OH
4
1
OH
O
O
3A
O
2B
1A
2A
Figure 1.
OH
OH
OH
(
S
S
S
OH
OH
S
S
+
S
)
5
CO2H
O
O
O
O
O
O
3
4
1
OTPS
OTPS
(
(
)
)
5
OH
OH
OH
5
O
O
6
7
5
OH
(
S
S
OH
CO2H
)
OH
5
O
S
O
O
OH
7
O
8
2
Scheme 1.
conditions8 gave macrolide 23 in 66% yield, which on aceto-
nide hydrolysis with TiCl4 furnished cladospolide-B 1 as
the exclusive product in 85% yield, while exposure of 23
to aq AcOH (60%) gave cladospolide-B 1 and iso-clado-
spolide 3 in 52% and 20% yields, respectively.
Similarly, the optical rotation [a]D À40.9 (c 0.3, CHCl3)
observed for synthetic (4R,5R,11R)-2A and (4S,5S,11S)-
2 differs in the sign of rotation. The spectroscopic
analysis and optical rotation value were in accordance
with the reported data.
The comparable optical rotation value of synthetic
(4S,5S,11S)-3, [a]D À59.6 (c 0.3, CHCl3), with that of
the reported5 value of [a]D À61.0 (c 16.6, MeOH) thus
establishes the absolute configuration of butenolide 3
as 4S,5S,11S. Similarly, the optical rotation value of
synthetic (4S,5S,11S)-1 [a]D +24.8 (c 0.4, CHCl3), which
is comparable with the reported9 value of [a]D +26.9 (c
0.4, MeOH), confirms the absolute configuration of 1 as
4S,5S,11S.
Thus, in conclusion, taking clues from the synthesis of
the (4R,5R,11S)-isomer 2B of cladospolide C, the syn-
theses of 1, 2 and 3 were achieved with (4S,5S,11S)-con-
figuration. This study accomplished the first synthesis of
1–3 and the determination of their absolute stereochem-
istry. A further study on the synthesis of related
molecules to determine their absolute stereochemistry
is in progress.
In a further study on the synthesis of cladospolide-C 2,
aldehyde 20 (Scheme 3) was converted into trans-ester
24 (85%). Hydrolysis of ester 24 with 4 N NaOH
followed by treatment of 25 with HF–pyridine gave
seco-acid 8. Reaction of 8 with 2,4,6-trichlorobenzoyl
chloride under Yamaguchi conditions furnished macro-
lide 26, which on exposure to TiCl4 underwent facile
deprotection to afford cladospolide-C 2 in 85% yield.
The optical rotation value of synthetic (4S,5S,11S)-2,
[a]D +45.9 (c 0.4, CHCl3), was comparable with the
reported1 optical rotation [a]D +59.7 (c 0.4, MeOH).
2. Spectral data for selected compounds
2.1. Cladospolide-B (1)
Colourless solid, mp 100–102 ꢁC (lit.9 mp 98–102 ꢁC);
[a]D +24.8 (c 0.4, CHCl3); (lit.9) [a]D +26.9 (c 0.4,
1
MeOH); H NMR (300 MHz, CDCl3): d 1.26 (d, 3H,
J = 6.6 Hz, H-12), 1.17–2.05 (m, 10H, 5 · –CH2),
3.84–3.94 (m, 1H, H-5), 4.96–5.03 (m, 1H, H-11),
5.06–5.16 (m, 1H, H-4), 5.85 (dd, 1H, J = 11.9, 1.1 Hz,
H-2), 6.13 (dd, 1H, J = 12.0, 8.5 Hz, H-3); 13C NMR

G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6537–6540
6539
O
R
O
R
(CH2)3-OBn
12 (43%)
a, b
c
d
7
OBn
(CH2)3-OBn
11 (80%)
9 R = H (94%)
+
10 R = allyl (77%)
OH
HO
(CH2)3-OBn
13 (40%)
O
OTPSOH
( )
O
OR
OTPS
i, g
e, f
R
g, h
OBn
N
O
12
5
S
OR
6 R = CH2OH (92%)
16 R = CHO (95%)
14 R = H (96%)
15 R = OTPS (97%)
Bn
17 R = PMB (65%)
18 R = H (92%)
OR'
( )
OTPS
O
OTPS
( )
O
R
l,m,n
CO2R
j
5O
k, h
( )
5O
O
N
O
5O
O
O
21 R = Me, R' = TPS (80%)
22 R = H, R' = TPS (85%)
4 R = R' = H (75%)
Bn
5 R = CH2OH (79%)
20 R = CHO (92%)
19 (85%)
OH
OH
p or q
O
OH
o
S
S
+
S
O
O
O
O
O
O
OH
3
O
O
O
23 (66%)
1
N
O
BMPO
(R)-chiral auxiliary =
Ph
I
Scheme 2. Reagents and conditions: (a) NaH, BnBr, THF, 0 ꢁC–rt, 5 h; (b) allyl bromide, CuI, K2CO3 and TBAI, DMF, rt, 12 h; (c) m-CPBA,
CH2Cl2, rt, 10 h; (d) R,R-Jacobsen’s catalyst, H2O, rt, 12 h; (e) LAH, THF, 0 ꢁC–rt, 5 h; (f) TBDPSCl, imidazole, CH2Cl2, 0 ꢁC–rt, 3 h; (g) 10% Pd/
C, MeOH, H2, 12 h; (h) IBX, DMSO, 0 ꢁC–rt, 5 h; (i) (R)-chiral auxiliary (I), Bu2BOTf, DIPEA, CH2Cl2, 0–78 ꢁC, 4 h; (j) 2,2-DMP, CSA, 0 ꢁC–rt,
30 min; (k) LiBH4, THF–H2O (2:1), 0 ꢁC–rt, 3 h; (l) Ph3P@CHCOOMe, MeOH, 0 ꢁC–rt, 2 h; (m) 4 N NaoH, MeOH, 0 ꢁC–rt, 4 h; (n) HF–pyridine,
THF, 0 ꢁC–rt, 12 h; (o) 2,4,6-trichlorobenzoyl chloride, THF, Et3N, 0 ꢁC–rt, 8 h, DMAP, toluene, reflux, 20 h; (p) TiCl4, CH2Cl2, 0 ꢁC–rt, 2 h, 85%
exclusive 1; (q) 80% AcOH, rt, 12 h, 3, in 20% and 1 in 52%.
OR'
a, b, c
S
d
S
O
O
S
S
OH
OH
CO2R
e
20
(
)
5
S
O
O
S
O
O
O
O
24 R = Me, R' = TPS (85%)
25 R = H, R' = TPS (80%)
8 R = R' = H (75%)
26 (57%)
2 (85%)
Scheme 3. Reagents and conditions: (a) Ph3P@CHCOOMe, toluene, reflux, 4 h; (b) 4 N NaOH, MeOH, 0 ꢁC–rt, 4 h; (c) HF–pyridine, THF, 0 ꢁC–rt,
12 h; (d) 2,4,6-trichlorobenzoyl chloride, THF, Et3N, 0 ꢁC–rt, 8 h, DMAP, toluene, reflux, 20 h; (e) TiCl4, CH2Cl2, 0 ꢁC–rt, 2 h.
(75 MHz, CDCl3): d 19.6, 21.5, 24.6, 25.8, 30.5, 32.3,
68.1, 73.8, 74.5, 121.5, 149.0, 166.8; IR (KBr): 1075,
1282, 1350, 1635, 1715, 2940, 3320 cmÀ1; ESIMS:
(m/z, %): 229 (M++1, 35), 167 (58), 149 (24), 109
(100); HRMS (ESI): m/z calcd for C12H21O4 [M+H]+
229.1439, found 229.1436.
3.0 Hz, H-3); 13C NMR (75 MHz, CDCl3): d 20.5,
24.2, 24.5, 27.4, 32.1, 34.4, 74.3, 76.6, 77.8, 124.2,
145.6, 166.2; IR (KBr): 850, 1170, 1265, 1635, 1710,
2925, 3518 cmÀ1; FABMS: (m/z, %): 251 (M++23, 12),
187 (94), 151 (26), 127 (100), 55 (44); HRMS (FABMS):
m/z calcd for C12H21O4 [M+H]+ 229.1439, found
229.1432.
2.2. Cladospolide-C (2)
2.3. iso-Cladospolide-B (3)
Colourless solid, mp 90–92 ꢁC; (lit.1 mp 90–91 ꢁC); [a]D
+45.9 (c 0.4, CHCl3); lit.1 [a]D +59.7 (c 0.4, MeOH); 1H
NMR (300 MHz, CDCl3): d 1.25 (d, 3H, J = 6.0 Hz, H-
12), 1.15–1.90 (m, 10H, 5 · CH2), 3.45–3.57 (m, 1H, H-
5), 4.15–4.22 (m, 1H, H-4), 5.15–5.25 (m, 1H, H-11),
6.12 (d, 1H, J = 14.9 Hz, H-2), 7.08 (dd, 1H, J = 14.9,
Colourless syrup, [a]D À59.6 (c 0.3, CHCl3); (lit.5 [a]D
1
À61.0 (c 16.6, MeOH)); H NMR (500 MHz, CDCl3):
d 1.19 (d, 3H, J = 5.8 Hz, H-12), 1.22–1.61 (m, 10H,
5 · –CH2), 3.70 (m, 1H, H-11), 3.77 (m, 1H, H-5),
4.97 (q, 1H, J = 1.8 Hz, H-4), 6.18 (dd, 1H, J = 5.8,

6540
G. V. M. Sharma et al. / Tetrahedron Letters 47 (2006) 6537–6540
1.5 Hz, H-2), 7.54 (dd, 1H, J = 5.8, 1.3 Hz, H-3); 13C
NMR (75 MHz, CDCl3): d 23.5, 26.8, 26.5, 30.4, 34.8,
40.3, 68.6, 71.9, 88.0, 122.3, 157.4, 175.8; IR (KBr):
1175, 1262, 1638, 1715, 3520 cmÀ1; FABMS: (m/z, %):
251 (M++23, 42), 167 (17), 149 (18), 109 (100); HRMS
(FABMS): m/z calcd for C12H21O4 [M+H]+ 229.1439,
found 229.1435.
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Acknowledgements
K.L.R. and J.J.R. are thankful to the UGC and CSIR,
New Delhi, India, for financial support.
References and notes
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jima, J. Phytochemistry 1995, 40, 1443–1446.