Enantioselective total synthesis of iso-cladospolide B, cladospolide C and cladospolide B from tartaric acid

Article abstract of DOI:10.1016/j.tetasy.2011.02.018

The enantioselective synthesis of the natural products cladospolide B, cladospolide C, and iso-cladospolide B has been accomplished from tartaric acid. Key reactions in the synthetic sequence include the elaboration of a γ-hydroxy amide derived from tartaric acid via alkene cross metathesis, Yamaguchi lactonization, and ring closing metathesis.

Full text of DOI:10.1016/j.tetasy.2011.02.018

Tetrahedron: Asymmetry 22 (2011) 499–505
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective total synthesis of iso-cladospolide B, cladospolide C
and cladospolide B from tartaric acid
⇑
Kavirayani R. Prasad , Vasudeva Rao Gandi
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of the natural products cladospolide B, cladospolide C, and iso-cladospo-
lide B has been accomplished from tartaric acid. Key reactions in the synthetic sequence include the elab-
Received 23 November 2010
Accepted 17 February 2011
Available online 12 April 2011
oration of a
c-hydroxy amide derived from tartaric acid via alkene cross metathesis, Yamaguchi
lactonization, and ring closing metathesis.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
olefin in 6, with selective E- or Z-Wittig olefination and subsequent
lactonization leading to the title compounds. Allylic alcohol 6 can
be obtained from iodide 7 involving a Boord type fragmentation.
Cladospolides A–D 1–5 are 12-membered lactones isolated from
the fermented broth of cultures derived either from marine fungi or
from soil fungus.1 One of the exceptions to this macrolactone class
is iso-cladospolide B 1, isolated from Red Sea sponge Cladosporium
sp. and also from fermentation of the marine fungal species
I96S215 which is a butenolide.2 A few syntheses of individual
cladospolides3 either from chiral pool precursors or by asymmetric
synthesis are reported in the literature. Herein, we report our ef-
forts in the synthesis of cladospolides B, C, and iso-cladospolide B
Elaboration of the
c-hydroxy amide 8 via cross metathesis with
penten-2-ol was used for the synthesis of 7. The synthesis of
c
-hy-
droxy amide 8 from the bis-Weinreb amide of tartaric acid 9 is a
procedure already well established in our laboratory5 (Scheme 1).
2.1. Synthesis of (À)-iso-cladspolide B 1
At first,
c-hydroxyamide 8 was synthesized from the bis-
from
D
-tartaric acid.
Weinreb amide 9 as described earlier6 involving a controlled
Grignard reagent addition followed by a stereoselective reduction.
The secondary hydroxy group in 8 was transformed into the silyl
ether 10 involving standard reaction conditions. Olefin cross-
metathesis of 10 with (S)-and (R)-penten-2-ol in the presence of
Grubb’s second generation catalyst afforded the cross-metathesis
product 11a and 11b in 69% and 64% yield, respectively.7 Protec-
tion of the free hydroxy group in 11a and 11b as the TBS ether fol-
lowed by hydrogenation afforded the saturated amide 12a and 12b
in almost quantitative yield. Reaction of the amide 12a and 12b
with NaBH4 resulted in the primary alcohol, which was trans-
formed into the iodide 13a and 13b in good yield. Treatment of
the iodide 13a and 13b with zinc dust in refluxing ethanol fur-
nished the pivotal allylic alcohol 14a and 14b in 99% yield
(Scheme 2).8 Allylic alcohols 14a and 14b served as the precursor
for the synthesis of (À)-iso-caldospolide B 1 and (À)-cladospolide
C ent-3.
OH
Me
OH
HO
O
OH
O
O
O
(−)-iso-cladospolide B 1
(−)-cladospolide B 2
OH
OH
OH
OH
O
O
OH
O
O
O
O
O
(+)-cladospolide C 3
cladospolide A 4
cladospolide D 5
2. Results and discussion
Thus, the reaction of 14a with acryloyl chloride in the pres-
ence of Et3N yielded acryloyl ester 15 in 62% yield. Exposure of
15 to Grubbs’ second generation catalyst in toluene produced
butenolide 16 in 86% yield. Treatment of 16 with methanolic
Our approach for the synthesis of cladospolides 1–3 is based on
the elaboration of the aldehyde obtained from ozonolysis of the
HCl cleanly furnished (À)-iso-cladospolide
B 1 in 79% yield
⇑
Corresponding author. Fax: +91 8023600529.
E-mail address: prasad@orgchem.iisc.ernet.in (K.R. Prasad).
(Scheme 3).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.018

500
K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
O
O
OH
I
Me
Me
OH
1-3
3
OTBS
OTBS
OTBS
7
6
Me
N
OMe
O
Me
OMe
N
O
O
O
O
O
O
OH
N
Me
OMe
8
9
Scheme 1. Retrosynthesis for the synthesis of cladospolides 1–3.
OTBS
R
R1
Me
OTBS
O
O
O
O
TBDMSOTf/pyridine
0 °C, 1 h, 96%
(S)- or (R)-penten-2-ol
Grubbs 2nd gen cat.
CH2Cl2, Δ, 7 h
8
O
O
N
N
Me
OMe
Me
OMe
11a R = OH, R1= H 69%
10
11b R = H, R1= OH 64%
R
R1
Me
OTBS
i) TBDMSOTf/pyridine
CH2Cl2, rt, 1 h
ii) H2/Pd-C/hexane, 4 h
O
O
i) NaBH4/MeOH, 0 °C to rt, 12 h,
ii) PPh3/imidazole, I2/ toluene, Δ, 1 h
O
N
Me
OMe
12a R = OTBS, R1= H 99%
12b R = H, R1= OTBS 97%
OTBS
R1
Me
R
R1
OTBS
I
R
HO
O
O
Me
Zn dust/EtOH, 6 h, 99%
13a R = OTBS, R1= H 86%
14a R = OTBS, R1= H
14b R = H, R1= OTBS
13b R = H, R1= OTBS 84%
Scheme 2. Synthesis of key allylic alcohol unit 14a and 14b.
O
OTBS
OTBS
Me
Cl
O
Grubb's 2nd generation cat
toluene, reflux, 6 h, 86%
O
Et3N, DMAP
14a
CH2Cl2, 0 °C, 1 h
15
62%
OH
OH
Me
OTBS
OTBS
Me
O
methanolic HCl
0 °C to rt, 7 h, 79%
O
O
O
16
(−)-iso-cladospolide B 1
Scheme 3. Total synthesis of (À)-iso-cladospolide B 1.
2.2. Synthesis of (À)-cladospolide C ent-3
Wittig reaction with triethyl phosphonoacetate afforded the E-es-
ter 18 in 94% yield. Saponification of 18 with LiOH provided the hy-
droxy acid 19 in 95% yield. Macrolactonization under Yamaguchi
lactonization conditions smoothly furnished lactone 20 in 59%
yield. Deprotection of the acetonide in 20 afforded (À)-cladospo-
lide C ent-3 in 85% yield; the spectroscopic data are in complete
agreement with those reported in the literature (Scheme 4).4c
For the synthesis of (À)-cladospolide C ent-3, allylic alcohol 14a
was reacted with 2,2-dimethoxy propane in the presence of p-TSA
resulting in deprotection of the bis-silyl ether with the concomi-
tant protection of the vicinal diol to yield acetonide 17 in 86% yield.
Ozonolysis of the olefin in 17 furnished the aldehyde, which upon

K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
501
i) O3/O2, Me2S, NaHCO3
CH2Cl2:MeOH
−78 °C to 0 °C, 3 h
ii) (EtO)2P(O)CH2CO2Et
NaH, THF, 0 °C, 1 h, 94 %
O
OH
Me
2,2-dimethoxypropane
p-TSA, CH2Cl2, Δ, 1 h
86%
O
14a
17
Me
Me
OH
O
O
O
O
LiOH, THF:H2O
rt, 20 h, 95%
O
OH
O
OH
19
OEt
18
OH
OH
TFA
CH3CN:H2O
0 °C to rt
O
O
2,4,6-trichlorobenzoyl
chloride, Et3N/DMAP
toluene, Δ, 12 h, 59%
O
2 h, 85%
O
O
O
20
−
3
( )-cladospolide C ent-
Scheme 4. Total synthesis of (À)-cladospolide C ent-3.
i) O3/O2, Me2S, NaHCO3
CH2Cl2:MeOH
−78 °C to 0 °C, 3 h
ii) Ph3P=CH-CO2Et, MeOH
−78 °C to −15 °C
O
OH
Me
O
2,2-dimethoxypropane
p-TSA, CH2Cl2, Δ, 1 h
86%
14b
21
4 h, 82% for two steps
O
O
OH
Me
HO
ref. 3f
O
OH
O
O
EtO
22
(−)-cladospolide B 2
Scheme 5. Formal total synthesis of (À)-cladospolide B 2.
2.3. Synthesis of (À)-cladospolide B 2
fication. THF was freshly distilled over Na-benzophenone ketyl.
Melting points are uncorrected. Unless stated otherwise, all the
reactions were performed under an inert atmosphere. Unless sta-
ted otherwise, all NMR spectra were recorded in CDCl3.
For the synthesis of (À)-cladospolide B 2, alcohol 14b was trea-
ted with 2,2-dimethoxy propane in the presence of p-TSA to fur-
nish acetonide 21 in 86% yield. Ozonolysis of the olefin in 21
gave an aldehyde, which was subjected to a Wittig reaction to yield
the Z-ester 22 as the major product in 82% yield.9 Since the conver-
sion of 22 to (À)-cladospolide B 2 is already reported in the litera-
ture,3f the present sequence constitutes a formal total synthesis of
cladospolide B 2 (Scheme 5).
4.2. Preparation of (4S,5S)-N-methoxy-5-((S)-1-(tert-butyl-
dimethyl-silanyloxy)pent-4-enyl)-N,2,2-trimethyl-1,3-
dioxolane-4-carboxamide 10
To a stirred ice-cooled solution of 8 (1 g, 3.7 mmol) in dry dichlo-
romethane (10 mL) was added pyridine (0.6 mL, 7.4 mmol) at 0 °C.
After 10 min, TBDMSOTf (1 mL, 4.4 mmol) was introduced dropwise
to the reaction mixture at 0 °C. The progress of the reaction was
monitored by TLC and after the reaction was complete (ꢀ1 h), it
was poured into ice-cooled water (10 mL) and extracted with EtOAc
(2 Â 20 mL). The combined EtOAc extracts were washed with brine
(10 mL) and dried (Na2SO4). Evaporation of the solvent and silica gel
column chromatography of the residue using petroleum ether/
EtOAc (4:1) as an eluent yielded 10 (1.38 g, 96%) as a colorless oil.
3. Conclusion
In conclusion, an enantiodivergent total synthesis of iso-
cladospolide B and cladospolide C and a formal approach to the
total synthesis of cladospolide B from D-tartaric acid have been
reported. Key reactions en route to the target compounds include
olefin cross metathesis, Yamaguchi lactonization, and ring closing
metathesis.
[a
]
D = +9.1 (c 0.8, CHCl3). IR (neat) 2955, 1674, 1457, 1257,
776 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.81 (ddt, J = 16.8, 10.3,
.
4. Experimental
4.1. General
6.5 Hz, 1H), 5.02 (d, J = 17.0 Hz, 1H), 4.95 (d, J = 10.2 Hz, 1H), 4.72
(s, 1H), 4.57 (s, 1H), 3.84 (dt, J = 9.0, 4.8 Hz, 1H), 3.75 (s, 3H), 3.21
(s, 3H), 2.26–1.76 (m, 2H), 1.75–1.46 (m, 2H), 1.45 (s, 3H), 1.43 (s,
3H), 0.87 (s, 9H), 0.07(s, 6H). 13C NMR (100 MHz, CDCl3): d 170.4
(Cq), 138.4 (CH), 114.6 (CH2), 111.0 (Cq), 80.0 (CH), 72.3 (CH), 71.5
(CH), 61.8 (CH3), 32.2 (CH3), 32.0 (CH2), 29.8 (CH2), 27.0 (CH3),
26.2 (CH3), 25.8 (CH3, 3C), 18.1 (Cq), À4.48 (CH3), À4.54 (CH3).
HRMS: m/z for C19H37NO5Si+Na, calcd: 410.2339; found: 410.2333.
Column chromatography was performed on silica gel, Acme
grade 100–200 mesh. TLC plates were visualized either with UV
in an iodine chamber, or with phosphomolybdic acid spray, unless
noted otherwise. Unless stated otherwise, all reagents were pur-
chased from commercial sources and used without additional puri-

502
K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
4.3. Preparation of (4S,5S)-5-((1S,7S)-7-hydroxy-1-(tert-butyl-
dimethyl-silanyloxy)oct-4-enyl)-N-methoxy-N,2,2-trimethyl-
1,3-dioxolane-4-carboxamide 11a
(CH3, 3C), 25.7 (CH3, 3C), 25.6 (CH2), 23.7 (CH3), 18.0 (Cq, 2C),
À4.5 (CH3), À4.6 (CH3, 2C), À4.8(CH3). HRMS: m/z for C28H59NO6-
Si2+Na calcd: 584.3779; found: 584.3770.
Performing the reaction with 11b yielded 12b in 97% yield:
To a solution of 10 (0.5 g, 1.28 mmol) and (S)-(+)-4-penten-2-ol
(0.17 g, 1.93 mmol) in dry CH2Cl2 (128 mL) was added Grubbs’ 2nd
generation catalyst (0.06 g, 0.07 mmol) under a nitrogen atmo-
sphere. The reaction mixture was refluxed for 7 h under a nitrogen
atmosphere. Evaporation of the solvent and purification of the
resulting residue by silica gel column chromatography using petro-
leum ether/EtOAc (6:4) as eluent afforded 11a (0.4 g, 69%) as a light
[
a
]
D = +3.7 (c 1.8, CHCl3). IR (neat) 2930, 1676, 1380, 1072,
775 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.74–5.26 (m, 2H), 4.78
.
(s, 1H), 4.63 (s, 1H), 4.15–3.55 (m, 5H), 3.27 (s, 3H), 2.62–1.81
(m, 4H), 1.77–1.55 (m, 2H), 1.51 (s, 3H), 1.49 (s, 3H), 1.17 (d,
J = 6.0 Hz, 3H), 0.94 (s, 9H), 0.93 (s, 9H), 0.11 (s, 6H), 0.10 (s, 6H).
13C NMR (100 MHz, CDCl3): d 170.5 (Cq), 131.9 (CH), 127.3 (CH),
111.0 (Cq), 80.1 (CH), 72.3 (CH), 71.7 (CH), 68.8 (CH), 61.8 (CH3),
43.0 (CH2), 37.5 (CH2), 32.6 (CH2), 32.3 (CH3), 28.8 (CH2), 27.0
(CH3), 26.2 (CH3), 25.8 (CH3, 6C), 23.4 (CH3), 18.1 (Cq, 2C), À4.5
(CH3, 2C), À4.7 (CH3, 2C). HRMS: m/z for C28H57NO6Si2+Na, calcd:
584.3779; found: 584.3774.
brown oil. [a]D = +10.3 (c 1.8, CHCl3); IR (neat) 3464, 2956, 1671,
1473, 837 cmÀ1. 1H NMR (400 MHz, CDCl3) for a mixture of E/Z iso-
mers: d 5.54 (td, J = 15.5, 6.4 Hz, 1H), 5.47 (td, J = 12.5, 6.1 Hz, 1H),
4.71 (s, 1H), 4.56 (s, 1H), 3.87–3.76 (m, 2H), 3.75 (s, 3H), 3.21 (s,
3H), 2.35–1.89 (m, 4H), 1.85 (br s, 1H), 1.75–1.51 (m, 2H), 1.43
(s, 3H), 1.42 (s, 3H), 1.18 (d, J = 6.2 Hz, 3H), 0.86 (s, 9H), 0.05 (s,
6H). 13C NMR (100 MHz, CDCl3) for a mixture of E/Z isomers: d
170.4 (Cq), 133.8 (CH), 132.4 (CH), 126.6 (CH), 125.7 (CH), 111.0
(Cq), 79.8 (CH), 72.4 (CH), 71.4 (CH), 67.6 (CH), 67.1 (CH), 61.9
(CH), 42.6 (CH2), 37.1 (CH2), 32.6 (CH2), 32.3 (CH3), 28.9 (CH3),
27.0 (CH3), 26.2 (CH3), 25.8 (3C, CH3), 23.7 (CH2), 22.7 (CH3), 18.1
(Cq), À4.5 (CH3, 2C). HRMS: m/z for C22H43NO6Si+Na, calcd:
468.2757; found: 468.2754.
4.5. Preparation of (4R,5S)-4-((1S,7S)-1,7-bis(tert-butyl-
dimethyl-silanyloxy)octyl)-5-(iodomethyl)-2,2-dimethyl-1,3-
dioxolane 13a
In a single necked round bottomed flask equipped with a mag-
netic stirrer bar and a guard tube was placed a solution of amide
12a (0.32 g, 0.56 mmol) in MeOH (6 mL). Next, NaBH4 (0.11 g,
3 mmol) was introduced into the reaction mixture portion wise
at 0 °C. The reaction mixture was slowly warmed up to room tem-
perature and stirred overnight at the same temperature. After the
reaction was complete (TLC), most of the methanol was removed
under reduced pressure; water (10 mL) was added to the reaction
mixture and extracted with EtOAc (3 Â 10 mL). The combined or-
ganic layers were washed with brine (5 mL), and dried over
Na2SO4. Evaporation of the solvent followed by silica gel column
chromatography of the crude residue with petroleum ether/EtOAc
(9:1) as eluent gave the alcohol (0.28 g, 96%) as a colorless oil.
Performing the reaction with (R)-pentene-2-ol furnished 11b in
64% yield: [
a]
D = +4.2 (c 3.5, CHCl3). IR (neat): mmax 3403, 2931,
1665, 1256, 776 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 5.75–5.25
(m, 2H), 4.76 (s, 1H), 4.62 (s, 1H), 3.98–3.62 (m, 5H), 3.26 (s, 3H),
2.49–2.15 (m, 4H), 1.91 (br s, 1H), 1.79–1.35 (m, 8H), 1.23 (d,
J = 6.2 Hz, 3H), 0.92 (s, 9H), 0.10 (s, 6H). 13C NMR (100 MHz, CDCl3):
d 170.5 (Cq), 133.8 (CH), 126.6 (CH), 111.0 (Cq), 79.9 (CH), 72.4
(CH), 71.5 (CH), 67.3 (CH), 62.0 (CH3), 42.6 (CH2), 32.6 (CH2), 32.3
(CH3), 28.9 (CH2), 27.1 (CH3), 26.3 (CH3), 25.9 (CH3, 3C), 22.7
(CH3), 18.2 (Cq), À4.4 (CH3, 2C). HRMS: m/z for C22H43NO6Si+Na,
calcd 468.2757; found 468.2735.
[a
]
D = À4.3 (c 1.9, CHCl3); IR (neat) 3477, 2933, 1464, 1254, 835,
775 cmÀ1 1H NMR (400 MHz, CDCl3): d 4.22–3.99 (m, 1H), 3.97–
.
3.59 (m, 5H), 2.55–2.38 (m, 1H), 1.76–1.25 (m, 16H), 1.17 (d,
J = 6.0 Hz, 3H), 0.97 (s, 9H), 0.95 (s, 9H), 0.14 (s, 6H), 0.11 (s, 6H).
13C NMR (100 MHz, CDCl3): d 108.6 (Cq), 80.7 (CH), 77.0 (CH),
72.0 (CH), 68.6 (CH), 62.9 (CH2), 39.7 (CH2), 32.5 (CH2), 29.8
(CH2), 27.1 (CH3), 27.0 (CH3), 26.2 (CH2), 25.9 (CH3, 6C), 25.7
(CH2), 23.8 (CH3), 18.2 (Cq), À4.2 (CH3), À4.4 (CH3), À4.7 (CH3),
À4.7 (CH3). HRMS: m/z for C26H56O5Si2+Na calcd: 527.3564; found:
527.3563.
To a solution of the alcohol obtained above (0.25 g, 0.49 mmol)
in dry toluene (6 mL) were added PPh3 (0.39 g, 1.47 mmol), imidaz-
ole (0.1 g, 1.47 mmol), and iodine (0.19 g, 0.74 mmol), under an ar-
gon atmosphere at room temperature. The reaction mixture was
then stirred at reflux for 1 h. After the reaction was complete
(TLC), it was cooled to room temperature and poured into water
(10 mL) and extracted with ether (3 Â 10 mL). The combined ether
layers were washed with brine (5 mL), a saturated solution of so-
dium thiosulfate (5 mL), water (5 mL) and dried over Na2SO4. Evap-
oration of the solvent followed by silica gel column
chromatography of the crude residue with petroleum ether/ether
(95:5) as eluent afforded 13a (0.25 g, 84%) as a colorless oil.
4.4. Preparation of (4S,5S)-5-((1S,7S)-1,7-bis(tert-butyl-
dimethyl-silanyloxy)octyl)-N-methoxy-N,2,2-trimethyl-1,3-
dioxolane-4-carboxamide 12a
To a pre-cooled solution of 11a (0.35 g, 0.78 mmol) in dry
CH2Cl2 (5 mL) was added pyridine (0.13 mL, 1.6 mmol) at 0 °C.
After 10 min, TBDMSOTf (0.21 mL, 0.94 mmol) was introduced
dropwise to the reaction mixture at 0 °C. The progress of the reac-
tion was monitored by TLC and after the reaction was complete
(ꢀ1 h), it was poured into ice-cold water (10 mL) and extracted
with EtOAc (2 Â 10 mL). The combined EtOAc extracts were
washed with brine (10 mL) and dried (Na2SO4). Evaporation of
the solvent and silica gel column chromatography of the resulting
residue using petroleum ether/EtOAc (9:1) as eluent yielded
TBDMS ether (0.41 g, 93%) as a colorless oil.
To a solution of the TBDMS ether (0.35 g, 0.62 mmol) (obtained
above) in hexane (4 mL) was added 10% palladium on activated
charcoal (60 mg) under an argon atmosphere. The reaction mixture
was stirred for 4 h under a hydrogen atmosphere. It was then fil-
tered through a short pad of Celite and the Celite pad was washed
with ether (10 mL). Evaporation of the solvent followed by silica
gel column chromatography of the residue using petroleum
ether/EtOAc (9:1) as eluent furnished 12a (0.35 g, 99%) as a color-
[a]
D = +10.3 (c 0.6, CHCl3). IR (neat): mmax 2929, 1471, 1254, 1067,
774 cmÀ1 1H NMR (400 MHz, CDCl3): d 3.98–3.87 (m, 1H), 3.85–
.
3.63 (m, 3H), 3.42 (dd, J = 10.6, 4.2 Hz, 1H), 3.25 (dd, J = 10.6,
5.8 Hz, 1H), 1.74–1.56 (m, 2H), 1.54–1.22 (m, 14H), 1.11 (d,
J = 6.1 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H),
0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): d 109.2 (Cq), 82.9 (CH),
75.7 (CH), 71.9 (CH), 68.6 (CH), 39.7 (CH2), 33.0 (CH2), 29.8 (CH2),
27.6 (CH3), 27.3 (CH3), 26.0 (CH2), 25.93 (CH3, 3C), 25.92 (CH3,
3C), 25.7 (CH2), 23.8 (CH3), 18.2 (Cq), 18.1 (Cq, 2C), 7.7 (CH2),
À4.0 (CH3), À4.4 (CH3), À4.6 (CH3), À4.7 (CH3). HRMS: m/z for
less oil. [
a
.
]
D = +9.6 (c 1.8, CHCl3); IR (neat) 2928, 2856, 1677, 1463,
775 cmÀ1
1H NMR (400 MHz, CDCl3): d 4.73 (s, 1H), 4.56 (s, 1H),
3.92–3.65 (m, 5H), 3.22 (s, 3H), 1.65–1.16 (m, 16H), 1.11 (d,
J = 6.0 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.05 (s, 6H).
13C NMR (100 MHz, CDCl3): d 170.4 (Cq), 110.9 (Cq), 80.1 (CH),
72.3 (CH), 72.1 (CH), 68.5 (CH), 61.7 (CH3), 39.6 (CH2), 32.7 (CH2),
32.2 (CH3), 29.8 (CH2), 29.7 (CH2), 26.9 (CH3), 26.1 (CH3), 25.8
C26H55IO4Si2+Na, calcd: 637.2581; found: 637.2580.

K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
503
Performing the reaction with 12b afforded 13b in 86% yield.
D = À11.6 (c 1.3, CHCl3). IR (neat): 2954, 1372, 1255, 1067,
J = 17.1 Hz, 10.2 Hz, 1H), 5.96–5.72 (m, 2H), 5.41–5.10 (m, 3H),
3.85–3.61 (m, 2H), 1.49–1.13 (m, 10H), 1.10 (d, J = 6.0 Hz, 3H),
0.84 (s, 18H), 0.05 (s, 3H), 0.03 (s, 3H), 0.00 (s, 6H). 13C NMR
(75 MHz, CDCl3): d 165.2 (Cq), 133.0 (CH), 130.8 (CH), 128.7
(CH2), 117.6 (CH2), 77.0 (CH), 72.7 (CH), 68.6 (CH), 39.7 (CH2),
32.6 (CH2), 29.8 (CH2), 29.7 (CH2), 25.9 (CH3, 3C), 25.8 (CH3, 2C),
25.7 (CH3), 25.0 (CH2), 23.8 (CH3), 18.1 (Cq), 18.0 (Cq), À4.4 (CH3,
2C), À4.6 (CH3), À4.7 (CH3). HRMS: m/z for C26H52O4Si2+Na, calcd:
507.3302; found: 507.3300.
[a]
774 cmÀ1 1H NMR (400 MHz, CDCl3): d 3.90 (dd, J = 11.6, 5.8 Hz,
.
1H), 3.84–3.65 (m, 3H), 3.42 (dd, J = 10.6, 4.2 Hz, 1H), 3.26 (dd,
J = 10.6, 5.8 Hz, 1H), 1.74–1.51 (m, 2H), 1.49–1.16 (m, 14H), 1.11
(d, J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.10 (s, 3H), 0.08 (s,
3H), 0.05 (s, 6H). 13C NMR (100 MHz, CDCl3): d 109.1 (Cq), 82.9
(CH), 75.6 (CH), 71.8 (CH), 68.6 (CH), 39.6 (CH2), 32.9 (CH2), 29.8
(CH2), 27.6 (CH3), 27.3 (CH3), 25.9 (CH3, 6C), 25.7 (CH2), 23.8
(CH3), 18.1 (Cq, 2C), 7.7 (CH2), À4.0 (CH3), À4.4 (CH3), À4.6
(CH3), À4.7 (CH3). HRMS: m/z for C26H55IO4Si2+Na, calcd:
637.2581; found: 637.2587.
4.8. Preparation of (S)-5-((1S,7S)-1,7-bis(tert-butyl-dimethyl-
silanyloxy)octyl)furan-2(5H)-one 16
4.6. Preparation of (3S,4S,10S)-4,10-bis(tert-butyl-dimethyl-
silanyloxy)undec-1-en-3-ol 14a
To a solution of the acryloyl ester 15 (0.05 g, 0.1 mmol) in 2 mL
toluene was added Grubbs’ 2nd generation catalyst (0.008 g,
0.01 mmol) in 2 mL of toluene and stirred under reflux for 6 h. It
was then cooled to room temperature and most of the toluene
was evaporated off. Column chromatography of the resultant resi-
due using petroleum ether/EtOAc (9:1) as eluent afforded 16 in
To a solution of the iodide 13a (0.22 g, 0.35 mmol) in absolute
ethanol was added activated zinc dust (0.19 g, 2.9 mmol) (6 mL)
at room temperature and stirred at reflux. The progress of the reac-
tion was followed by TLC. After completion of the reaction (ꢀ1 h),
it was filtered through a short pad of Celite and the Celite pad was
washed with ether (2 Â 10 mL). Evaporation of the solvent fol-
lowed by silica gel column chromatography of the crude residue
with petroleum ether/EtOAc (9:1) as eluent furnished 14a
86% (0.04 g) yield. [
a]
D = À80.7 (c 0.8, CHCl3). IR (neat): mmax
2930, 1789, 1760, 1255, 1074, 774 cmÀ1
.
1H NMR (300 MHz,
CDCl3): d 7.41 (dd, J = 5.7, 1.5 Hz, 1H), 6.11 (dd, J = 5.7, 2.1 Hz,
1H), 4.94 (td, J = 3.6, 1.8 Hz, 1H), 4.05–3.81 (m, 1H), 3.79–3.65
(m, 1H), 1.51–1.24 (m, 10H), 1.10 (d, J = 6.0 Hz, 3H), 0.85 (s, 9H),
0.84 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H), À0.01 (s, 3H).
13C NMR (75 MHz, CDCl3): d 172.9 (Cq), 154.1 (CH), 122.6 (CH2),
85.4 (CH), 72.0 (CH), 68.5 (CH), 39.6 (CH2), 32.4 (CH2), 29.7 (CH2),
25.9 (CH3, 3C), 25.7 (CH3, 3C), 25.61 (CH2), 25.55 (CH2), 23.8
(CH3), 18.1 (Cq), 18.0 (Cq), À4.4 (CH3), À4.5 (CH3), À4.6 (CH3),
À4.7 (CH3). HRMS: m/z for C24H48O4Si2+Na, calcd: 479.2989;
found: 479.2983.
(0.16 g, 100%) as a colorless oil. [
m
a]D = +2.5 (c 1.2, CHCl3). IR (neat):
max 3473, 2931, 1463, 1255, 774 cmÀ1. 1H NMR (400 MHz, CDCl3):
d 5.90 (ddd, J = 16.8, 10.5, 5.7 Hz, 1H), 5.37 (d, J = 17.4 Hz, 1H), 5.24
(d, J = 10.5 Hz, 1H), 4.12–3.91 (m, 1H), 3.89–3.65 (m, 1H), 3.63 (dd,
J = 10.8, 5.0 Hz, 1H), 2.40 (d, J = 6.2 Hz, 1H), 1.65–1.27 (m, 10H),
1.17 (d, J = 6.0 Hz, 3H), 0.97 (s, 9H), 0.95 (s, 9H), 0.14 (s, 3H), 0.13
(s, 3H), 0.11 (s, 3H), 0.10 (s, 3H). 13C NMR (100 MHz, CDCl3): d
138.9 (CH), 116.2 (CH2), 75.6 (CH), 74.5 (CH), 68.8 (CH), 39.9
(CH2), 33.9 (CH2), 30.2 (CH2), 26.2 (CH3, 3C), 26.1 (CH3, 3C), 26.0
(CH2), 25.3 (CH2), 24.1 (CH3), 18.2 (Cq, 2C) À4.0 (CH3), À4.2
(CH3), À4.3 (CH3), À4.5 (CH3). HRMS: m/z for C23H50O3Si2+Na,
calcd: 453.3196; found: 453.3193.
4.9. Preparation of (À)-iso-cladospolide B 1
To an ice-cold solution of lactone 16 (27 mg, 0.6 mmol) in meth-
anol (1.5 mL) was added methanolic HCl (4 mL) at 0 °C. The reac-
tion mixture was slowly allowed to return to room temperature
and stirred at the same temperature. Progress of the reaction was
monitored by TLC. After the reaction was complete (ꢀ7 h), the sol-
vent was evaporated off. Silica gel column chromatography of the
resulting residue using EtOAc as eluent furnished (À)-iso-cladospo-
Performing the reaction with 13b afforded 14b in 99% yield.
[
a]
D = À10.4 (c 1.8, CHCl3). IR (neat) 3462, 2898, 1472, 1067,
774 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.84 (ddd, J = 16.5, 10.5,
.
5.7 Hz, 1H), 5.31 (d, J = 17.2 Hz, 1H), 5.17 (d, J = 10.5 Hz, 1H),
4.05–3.87 (m, 1H), 3.82–3.73 (m, 1H), 3.57 (dd, J = 10.5, 4.6 Hz,
1H), 2.35 (d, J = 6.0 Hz, 1H), 1.67–1.19 (m, 10H), 1.11 (d,
J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H),
0.04 (s, 6H). 13C NMR (100 MHz, CDCl3): d 138.6 (CH), 115.9
(CH2), 75.3 (CH), 74.2 (CH), 68.5 (CH), 39.6 (CH2), 33.6 (CH2), 29.9
(CH2), 25.9 (CH3, 6C), 25.7 (CH2), 25.0 (CH2), 23.8 (CH3), 18.1 (Cq,
2C), À4.3 (CH3), À4.4 (CH3), À4.5 (CH3), À4.8 (CH3). HRMS: m/z
for C23H50O3Si2+Na, calcd: 453.3196; found: 453.3193.
lide B 1 (10 mg, 79%) as a colorless oil. [
Lit.3c
D = À61.6 (c 0.5, MeOH). IR (neat): mmax 3402, 2857, 1747,
1600, 1463, 828 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.46 (d,
a]
D = À63.3 (c 1, MeOH);
[a]
.
J = 5.8, 1H), 6.18 (dd, J = 6.0, 1.4 Hz, 1H), 5.15–4.91 (m, 1H), 3.87–
3.69 (m, 2H), 2.32–1.89 (br s, 2H), 1.75–1.21 (m, 10H), 1.80 (d,
J = 6.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 172.9 (Cq), 153.8
(CH), 122.5 (CH), 86.1 (CH), 71.5 (CH), 67.9 (CH), 39.0 (CH2), 32.9
(CH2), 29.2 (CH2), 25.4 (CH2), 25.3 (CH2), 23.4 (CH3). HRMS: m/z
for C12H20O4+Na, calcd: 251.1259; found 251.1265.
4.7. Preparation of (3S,4S,10S)-4,10-bis(tert-butyl-dimethyl-
silanyloxy)undec-1-en-3-yl acrylate 15
4.10. Preparation of (S)-7-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-
To an ice-cold solution of 14a (0.10 g, 0.23 mmol) in CH2Cl2
(4 mL) was added DMAP (0.03 g, 0.23 mmol) and Et3N (0.1 mL,
0.69 mmol) and stirred for 15 min at 0 °C. Acryloyl chloride
(0.06 mL, 0.69 mmol) was introduced into the reaction mixture
dropwise at 0 °C and stirred at the same temperature for 0.5 h.
After the reaction was complete (TLC), it was poured into water
(5 mL) and extracted with EtOAc (2 Â 10 mL). The combined or-
ganic layers were washed with saturated sodium bicarbonate solu-
tion (5 mL), brine (5 mL) and dried (Na2SO4). Evaporation of the
solvent followed by silica gel column chromatography of the crude
residue with petroleum ether/ether (95:5) as eluent resulted in the
dioxolan-4-yl)heptan-2-ol 17
To a solution of 14a (0.2 g, 0.46 mmol) in dry CH2Cl2 (4 mL) was
added p-TSA (0.13 g, 0.7 mmol) and 2,2-dimethoxy propane
(0.11 mL, 0.92 mmol) under argon atmosphere and refluxed for
3.5 h. After the reaction was complete (TLC), it was cooled to room
temperature. Solid K2CO3 (0.09 g) was introduced and stirred for
15 min at room temperature. The reaction mixture was filtered
through a short pad of Celite and the Celite pad was washed with
EtOAc (2 Â 10 mL). Evaporation of the solvent followed by silica gel
column chromatography of the crude residue with petroleum
ether/EtOAc (6:4) as eluent yielded 17 (0.09 g, 86%) as a pale yel-
acryloyl ester 15 (0.07 g, 62%) as a colorless oil. [
CHCl3). IR (neat):
max 3080, 2932, 1728, 1529, 1273, 720 cmÀ1. 1H
NMR (300 MHz, CDCl3): d 6.39 (d, J = 17.4 Hz, 1H), 6.11 (dd,
a]
D = À16.3 (c 0.8,
m
low oil. [
a]
D = +4.6 (c 2.0, CHCl3). IR (neat): mmax 3418, 2861,
1371, 1017, 874 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 5.79 (ddd,

504
K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
J = 17.4, 10.2, 7.4 Hz, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.23 (d,
J = 10.2 Hz, 1H), 3.96 (t, J = 8.0 Hz, 1H), 3.77 (dd, J = 11.5, 5.8 Hz,
1H), 3.66 (td, J = 8.2, 6.0 Hz, 1H), 1.73–1.26 (m, 17H), 1.16 (d,
J = 6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 135.4 (CH), 118.8
(CH), 108.5 (Cq), 82.7 (CH), 80.6 (CH), 68.0 (CH), 39.2 (CH2), 31.7
(CH2), 29.6 (CH2), 27.2 (CH3), 26.9 (CH3), 26.0 (CH2), 25.5 (CH2),
23.4 (CH3). HRMS: m/z for C14H26O3+Na, calcd: 265.1780; found:
265.1782.
4.13. Preparation of (3aS,8S,13aS,E)-2,2,8-trimethyl-
9,10,11,12,13,13a-hexahydro-3aH-[1,3]dioxolo[4,5-e]
[1]oxacyclododecin-6(8H)-one 20
To a solution of acid 19 (52 mg, 0.18 mmol) and Et3N (0.03 mL,
0.22 mmol) in dry THF (0.9 mL) was added 2,4,6-trichlorobenzoyl
chloride (0.03 mL, 0.2 mmol) dropwise under an argon atmosphere
at room temperature. The reaction mixture was stirred at room
temperature for 2 h, followed by dilution with dry toluene
(22 mL) and was then added dropwise to a refluxing solution of
DMAP (710 mg, 5.8 mmol) in dry toluene (54 mL). After the addi-
tion, the mixture was refluxed for 10 h, and then concentrated in
vacuum. The residue was dissolved in EtOAc (30 mL) and washed
with 1 M HCl (20 mL), saturated NaHCO3 (5 mL) and brine
(5 mL), dried over Na2SO4. Evaporation of the solvent followed by
silica gel column chromatography of the resulting residue using
petroleum ether/ether (9:1) as eluent furnished macrolactone 20
4.11. Preparation of (E)-ethyl 3-((4S,5S)-5-((S)-6-
hydroxyheptyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate 18
Ozone was bubbled through a pre cooled (À78 °C) solution of 17
(40 mg, 0.16 mmol) in a mixture of CH2Cl2/MeOH (4:1, 5 mL) con-
taining solid NaHCO3 (15 mg) until the pale blue color persisted.
Excess ozone was flushed off with oxygen and Me2S (0.2 mL) was
added. The reaction mixture was warmed up to 0 °C and stirred
at the same temperature for 3 h. It was then concentrated under
reduced pressure and filtered through a short pad of Celite and
the Celite pad was washed with EtOAc (10 mL). Evaporation of
the solvent yielded the crude aldehyde, which was subjected to
the next reaction without further purification.
To an ice cold suspension of NaH (16 mg, 0.41 mmol) in THF
(1 mL) was added triethyl phosphonoacetate (0.08 mL, 0.41 mmol)
in THF (2 mL) dropwise at 0 °C and stirred for 0.5 h at the same
temperature. The solution of the crude aldehyde (50 mg,
0.16 mmol) (obtained above) in THF (2 mL) was slowly introduced
at 0 °C and the reaction mixture was stirred for 0.5 h at the same
temperature. After completion of the reaction, it was quenched
with saturated NH4Cl (5 mL) and extracted with EtOAc
(2 Â 10 mL). The combined organic layers were washed with brine
(5 mL), and dried over Na2SO4. Evaporation of solvent followed by
silica gel column chromatography of the crude residue with petro-
leum ether/EtOAc (6:4) as eluent afforded 18 (0.46 mg, 94%) as a
(30 mg, 59%). [
a]
D = À6.3 (c 1.5, MeOH). IR (neat) 2984, 1723,
1381, 1163, 858 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 6.79 (dd,
J = 15.8, 9.6 Hz, 1H), 6.24 (d, J = 15.7 Hz, 1H), 5.29–4.78 (m, 1H),
4.05 (t, J = 9.0 Hz, 1H), 3.92 (ddd, J = 11.3, 8.6, 4.2 Hz, 1H), 2.15–
1.76 (m, 1H), 1.75–1.55 (m, 4H), 1.54–0.98 (m, 14H). 13C NMR
(100 MHz, CDCl3): d 166.6 (Cq), 143.8 (CH), 125.9 (CH), 109.2
(Cq), 80.3 (CH), 80.0 (CH), 75.4 (CH), 35.3 (CH2), 29.4 (CH2), 27.8
(CH2), 27.1 (CH3), 26.8 (CH3), 25.1 (CH2), 24.9 (CH2), 20.6 (CH3).
HRMS: m/z for C15H24O4+Na, calcd: 291.1572; found: 291.1577.
4.14. Preparation of cladospolide C ent-3
To an ice-cold solution of macrolactone 20 (20 mg, 0.07 mmol)
in CH3CN/H2O (2:1, 1.5 mL) was added TFA (0.1 mL) dropwise at
0 °C. The reaction mixture was slowly warmed to room tempera-
ture and stirred for 2 h at the same temperature. Solid NaHCO3
was added and stirred for 10 min at room temperature. It was fil-
tered through a short pad of Celite and the Celite pad was washed
with EtOAc (10 mL). The combined organic layers were washed
with brine (1 Â 3 mL), dried over Na2SO4. Evaporation of the sol-
vent followed by silica gel column chromatography of the resulting
residue using EtOAc as eluent afforded ent-3 (13 mg, 85%) as a col-
colorless oil. [
a]
D = À7.1 (c 1.2, CH2Cl2). IR (neat): mmax 3437,
2984, 1722, 1371, 1036 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 6.83
(dd, J = 15.6, 5.8 Hz, 1H), 6.08 (d, J = 15.6 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 4.14–4.06 (m, 1H), 3.88–3.55 (m, 2H), 1.76–1.64
(m, 4H), 1.50–1.20 (m, 16H), 1.15 (d, J = 6.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 165.9 (Cq), 144.0 (CH), 122.6 (CH), 109.3
(Cq), 80.5 (CH), 80.1 (CH), 67.9 (CH), 60.5 (CH2), 39.1 (CH2), 31.8
(CH2), 29.4 (CH2), 27.2 (CH3), 26.5 (CH3), 25.8 (CH2), 25.4 (CH2),
23.4 (CH3), 14.1 (CH3). HRMS: m/z for C17H30O5+Na, calcd:
337.1991; found: 337.1992.
orless solid. Mp: 91–92 °C. [
a
]
D = À58.7 (c 0.5, MeOH); lit.4c
[a]D = +58.2 (c 0.5, MeOH for the enantiomer). IR (KBr) 3401,
2932, 1718, 1260, 1033 cmÀ1 1H NMR (400 MHz, CDCl3): d 6.82
.
(dd, J = 15.7, 9.4 Hz, 1H), 6.05 (d, J = 15.8 Hz, 1H), 4.96 (dqd,
J = 12.6, 6.2, 3.9 Hz, 1H), 3.98 (t, J = 8.0 Hz, 1H), 3.69–3.25 (m,
1H), 2.54 (br s, 2H), 1.85–1.12 (m, 10H), 1.30 (d, J = 6.4 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 166.8 (Cq), 145.4 (CH), 124.4 (CH),
77.5 (CH), 76.5 (CH), 74.4 (CH), 33.9 (CH2), 32.1 (CH2), 27.3 (CH2),
24.5 (CH2), 24.0 (CH2), 20.8 (CH3).
4.12. Preparation of (E)-3-((4S,5S)-5-((S)-6-hydroxyheptyl)-2,2-
dimethyl-1,3-dioxolan-4-yl) acrylic acid 19
To a solution of the hydroxy ester 18 (0.08 g, 0.25 mmol) in THF/
H2O (4:1, 4 mL) was added LiOH (0.05 g, 1.3 mmol) at room tem-
perature and stirred for 20 h at the same temperature. The progress
of the reaction was monitored by TLC and after reaction was com-
plete, it was diluted with water (5 mL), neutralized with dil HCl
(pH 3) and extracted with EtOAc (3 Â 10 mL). The combined organ-
ic layers were washed with brine (5 mL), and dried (Na2SO4). Most
of the solvent was removed under reduced pressure and silica gel
column chromatography of the resulting residue using EtOAc as
4.15. Preparation of (R)-7-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-
dioxolan-4-yl)heptan-2-ol 21
To a solution of 14b (0.18 g, 0.42 mmol) in dry CH2Cl2 (4 mL) was
added p-TSA (0.12 g, 0.63 mmol) and 2,2-dimethoxy propane
(0.1 mL, 0.84 mmol) under an argon atmosphere and refluxed for
3.5 h. After the reaction was complete (TLC), it was cooled to room
temperature. Solid K2CO3 (0.09 g), was introduced and stirred for
15 min at room temperature. The reaction mixture was filtered
through a short pad of Celite and the Celite pad was washed with
EtOAc (2 Â 10 mL). Evaporation of the solvent followed by silica
gel column chromatography of the crude residue with petroleum
ether/EtOAc (6:4) as eluent yielded 21 (0.09 g, 89%) as a pale yellow
eluent afforded 19 (0.07 g, 95%) as a colorless oil. [
1.1, CHCl3). IR (neat) 3437, 2934, 1704, 1373, 980 cmÀ1
(400 MHz, CDCl3): 6.93 (dd, J = 15.5, 5.6 Hz, 1H), 6.12 (d,
a]
D = À14.8 (c
.
1H NMR
d
J = 15.5 Hz, 1H), 5.61 (br s, 2H), 4.20–4.02 (m, 1H), 3.95–3.55 (m,
2H), 1.74–1.26 (m, 16H), 1.17 (d, J = 6.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 170.1 (Cq), 146.2 (CH), 122.1 (CH), 109.5
(Cq), 80.5 (CH), 80.1 (CH), 68.2 (CH), 38.9 (CH2), 31.9 (CH2), 29.5
(CH2), 27.2 (CH3), 26.6 (CH3), 25.8 (CH2), 25.4 (CH2), 23.2 (CH3).
HRMS: m/z for C15H26O5+Na, calcd: 309.1678; found: 309.1677.
oil. [
a
]
D = À8.7 (c 0.7, CHCl3). IR (neat) 3420, 2861, 1371, 1018,
874 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 5.80 (ddd, J = 17.4, 10.2,
7.2 Hz, 1H), 5.35 (d, J = 17.1 Hz, 1H), 5.23 (d, J = 10.2 Hz, 1H), 3.97
(t, J = 7.9 Hz, 1H), 3.77 (td, J = 12.6, 6.3 Hz, 1H), 3.72–3.50 (m, 1H),

K. R. Prasad, V. R. Gandi / Tetrahedron: Asymmetry 22 (2011) 499–505
505
1.75–1.23 (m, 16H), 1.17 (d, J = 6.1 Hz, 3H). 13C NMR (100 MHz,
References
CDCl3): d 135.5 (CH), 118.7 (CH2), 108.4 (Cq), 82.7 (CH), 80.6 (CH),
68.0 (CH), 39.2 (CH2), 31.7 (CH2), 29.6 (CH2), 27.3 (CH3), 26.9
(CH3), 26.0 (CH2), 25.6 (CH2), 23.5 (CH3). HRMS: m/z for
1. Cameron, J. S.; Abbanat, D.; Bernan, V. S.; Maiese, W. M.; Greenstein, M.; Jompa,
J.; Tahir, A.; Ireland, C. M. J. Nat. Prod. 2000, 63, 142.
2. Gesner, S.; Cohen, N.; Ilan, M.; Yarden, O.; Carmeli, S. J. Nat. Prod. 2005, 68, 1350.
3. For the synthesis of the revised structure of iso-cladospolide B 1 see: (a) Sharma,
G. V. M.; Reddy, J. J.; Reddy, K. L. Tetrahedron Lett. 2006, 47, 6531; (b) Sharma, G.
V. M.; Reddy, J. J.; Reddy, K. L. Tetrahedron Lett. 2006, 47, 6537; (c) Ferrié, L.;
Reymond, S.; Capdevielle, P.; Cossy, J. Synlett 2007, 2891; For other syntheses of
the structure of iso-cladospolide B see: (d) Trost, B. M.; Aponick, A. J. Am. Chem.
Soc. 2006, 128, 3931; (e) Srihari, P.; Bhasker, E. V.; Harshavasdhan, S. J.; Yadav, J.
S. Synthesis 2006, 4041; (f) Pandey, S. K.; Kumar, P. Tetrahedron Lett. 2005, 46,
6625; (g) Franck, X.; Vaz Araujo, M. E.; Jullian, J.-C.; Hocquemiller, R.; Figadere,
B. Tetrahedron Lett. 2001, 42, 2801.
4. For earlier syntheses of cladospolides B and C see: (a) Prasad, K. R.; Gandi, V. R.
Tetrahedron: Asymmetry 2010, 21, 275; (b) Xing, Y.; O’Doherty, G. A. Org. Lett.
2009, 11, 1107; (c) Chou, C.-Y.; Hou, D.-R. J. Org. Chem. 2006, 71, 9887; For earlier
syntheses of cladospolide A see: (d) Reddy, Ch. R.; Rao, N. N. Tetrahedron Lett.
2009, 50, 2478; (e) Austin, K. A. B.; Banwell, M. G.; Loong, D. T. J.; Rae, A. D.;
Willis, A. C. Org. Biomol. Chem. 2005, 3, 1081; (f) Rajesh, K.; Suresh, V.; Selvam, J.
J. P.; Rao, C. B.; Venkateswarlu, Y. Synthesis 2010, 1381; (g) Kaliappan, K.; Si, D.
Synlett 2010, 2441; Maemoto, S.; Mori, K. Chem. Lett. 1987, 109; (h) Banwell, M.
G.; Loong, D. T. J. Org. Biomol. Chem. 2004, 2, 2050; (i) Banwell, M. G.; Jolliffe, K.
A.; Loong, D. T. J.; McRae, K. J.; Vounatsos, F. J. Chem. Soc., Perkin Trans. 1 2002,
22; (j) Solladié, G.; Almario, A. Tetrahedron: Asymmetry 1995, 6, 559; (k) Solladié,
G.; Antonio, A. Pure Appl. Chem. 1994, 66, 2159; (l) Ichimoto, I.; Sato, M.; Kirihata,
M.; Ueda, H. Chem. Express 1987, 2, 495; (m) Mori, K.; Maemoto, S. Liebigs Ann.
Chem. 1987, 863; For synthesis of cladospolide D; see: (n) Xing, Y.; O’Doherty, G.
A. Org. Lett. 2009, 11, 1107; (o) Xing, Y.; Penn, J. H.; O’Doherty, G. A. Synthesis
2009, 2847; (p) Lu, K.-J.; Chen, C.-H.; Hou, D.-R. Tetrahedron 2009, 65, 225.
C14H26O3+Na calcd 265.1780; found 265.1777.
4.16. Preparation of (Z)-ethyl 3-((4S,5S)-5-((R)-6-
hydroxyheptyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate 22
Ozone was bubbled through a pre cooled (À78 °C) solution of 21
(0.05 g, 0.2 mmol) in a mixture of CH2Cl2/MeOH (4:1, 5 mL) con-
taining solid NaHCO3 (15 mg) until the pale blue color persisted.
Excess ozone was flushed off with oxygen and Me2S (0.2 mL) was
added. The reaction mixture was warmed up to 0 °C and stirred
at the same temperature for 3 h. It was then concentrated under
reduced pressure, filtered through a short pad of Celite, and the
Celite pad was washed with EtOAc (10 mL). Evaporation of the sol-
vent yielded the crude aldehyde which was subjected to the next
reaction without further purification.
To a solution of the crude aldehyde (obtained above) (0.07 g,
0.2 mmol) in dry MeOH (3 mL) was added (carbethoxymethyl-
ene)triphenyl phosphorane (0.17 g, 0.5 mmol) at À78 °C under a
nitrogen atmosphere. The reaction mixture was slowly warmed
up to À15 °C and stirred for 4 h at the same temperature. The p
of the reaction was followed by TLC. After completion of the reac-
tion (ꢀ3 h), most of the solvent was removed under reduced pres-
sure. Silica gel column chromatography of the resulting residue
using petroleum ether/EtOAc (6:4) as eluent afforded 22 (0.052 g,
5. For a general approach to the synthesis of
Prasad, K. R.; Chandrakumar, A. Tetrahedron 2007, 63, 1798; For recent
application of -keto amides derived from tartaric acid in natural product
c-keto amides from tartaric acid see:
c
synthesis see: (a) Prasad, K. R.; Pawar, A. B. Synlett 2010, 1093; (b) Prasad, K. R.;
Pawar, A. B. ARKIVOC 2010, 39; (c) Prasad, K. R.; Gandi, V. R.; Nidhiry, J. E.; Bhat,
K. S. Synthesis 2010, 2521; (d) Prasad, K. R.; Gandi, V. R. Synlett 2009; (e) Prasad,
K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2; (f) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2916; (g) Prasad, K. R.; Swain, B. Tetrahedron: Asymmetry 2008,
19, 1134; (h) Prasad, K. R.; Chandrakumar, A. J. Org. Chem. 2007, 72, 6312; (i)
Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71, 3643.
82%) as a colorless oil. [
a]
D = +31.4 (c 1.1, CHCl3). IR (neat) 3420,
.
2860, 1723, 1193, 875 cmÀ1
1H NMR (400 MHz, CDCl3): d 6.16
(dd, J = 11.8, 8.8 Hz, 1H), 5.97 (d, J = 11.7 Hz, 1H), 5.30 (t,
J = 8.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.95–3.52 (m, 2H), 1.85–
1.23 (m, 19H), 1.21 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d 165.5 (Cq), 145.5 (CH), 123.1 (CH2), 109.2 (Cq), 81.0 (CH), 76.1
(CH), 68.1 (CH), 60.5 (CH2), 39.2 (CH2), 32.0 (CH2), 29.6 (CH2),
27.4 (CH3), 27.1 (CH3), 25.9 (CH2), 25.6 (CH2), 23.5 (CH3), 14.2
(CH3). HRMS: m/z for C17H30O5+Na, calcd: 337.1991; found:
337.1995.
6. Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 850.
7. In all cross metathesis reactions of 10, with penten-2-ol, the formation of a
minor amount of the dimer resulting from dimerization of penten-2-ol was also
observed. The E/Z ratio of the product olefin in 11a and 11b is inconclusive from
NMR. However, stereochemistry of the olefin is of no consequence as it is
saturated in the next step involving hydrogenation.
8. (a) Swallen, L. C.; Boord, C. E. J. Am. Chem. Soc. 1930, 52, 651; For application of
this strategy in the synthesis of allylic alcohols, see: (b) Schneider, C.; Kazmaier,
U. Synthesis 1998, 1314; (c) Ramarao, A. V.; Reddy, E. R.; Joshi, B. V.; Yadav, J. S.
Tetrahedron Lett. 1987, 28, 6497.
9. Wittig olefination of the aldehyde derived from 22 leading to 23 was performed
according to the literature procedure described for similar compound. See Ref.
3f. The Z/E ratio of the product was found to be ꢀ9:1 by 1H NMR. For Z-
predominant Wittig olefinations with glyceraldehyde acetonide see: Minami,
N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 1109; For a review on Wittig
olefination reactions see: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.
Acknowledgments
We thank the Department of Science and Technology (DST),
New Delhi for funding. K.R.P. is a swarnajayanthi fellow of DST,
New Delhi. V.R.G. thanks the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for a senior research fellowship.