Toward the total synthesis of a lagunamide B analogue

Article abstract of DOI:10.1016/j.tetlet.2014.04.079

Lagunamides, isolated from a marine cyanobacterium Lyngbya majuscule found in Singapore, showed very potent activities against Plasmodium falciparum and murine leukemia cell line (P388). Herein, a concise synthetic approach toward the total synthesis of a lagunamide B analogue is discussed. Macrolactonization, HWE-olefination, and modified Crimmin's aldol are some of the key reactions featured in this synthesis.

Full text of DOI:10.1016/j.tetlet.2014.04.079

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Toward the total synthesis of a lagunamide B analogue
Sudip Pal a, Tushar Kanti Chakraborty a,b,
⇑
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10 Jankipuram Extension, Sitapur Road, Lucknow 226031, India
b Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Lagunamides, isolated from a marine cyanobacterium Lyngbya majuscule found in Singapore, showed
very potent activities against Plasmodium falciparum and murine leukemia cell line (P388). Herein, a con-
cise synthetic approach toward the total synthesis of a lagunamide B analogue is discussed. Macrolact-
onization, HWE-olefination, and modified Crimmin’s aldol are some of the key reactions featured in
this synthesis.
Received 31 March 2014
Revised 22 April 2014
Accepted 22 April 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Macrolactonization
Macrolactamization
Horner–Wadsworth–Emmons olefination
Crimmin’s aldol
2-Methyl-6-nitrobenzoic anhydride (MNBA)
Lagunamides A and B (Fig. 1), cyclic depsipeptides,1 were iso-
lated from the marine cyanobacterium Lyngbya majuscule obtained
from Pulau Hantu Besar, Singapore.2 They displayed effective anti-
18
9
20
13
N
O
O
∗
N
O
R
O
N
N
H
N
N
15
11
malarial properties, with IC50 values of 0.19 and 0.91 lM, respec-
H
O
O
N
O
O
N
3
tively, when tested against Plasmodium falciparum.3 Lagunamides
A and B also exhibited significant cytotoxic activities against
P388 murine leukemia cell lines, with IC50 value of 6.4 and
20.5 nM, respectively.4 Further, these cyanobacterial compounds5
showed moderate anti-swarming activities4 when tested against
O
O
O
O
1
HN
HN
27∗
HO
O
O
OH
O
O
∗
O
O
Hila
33
39
43
44
31
1
Pseudomonas aeruginosaPA01 6
.
Lagunamide A, R=
Lagunamide B, R=
Lagunamide A was first synthesized by Dai et al. and later by Lin
and co-workers.7 Till now there is no report on the total synthesis
of lagunamide B. Structurally, lagunamide A comprises eleven ste-
reogenic centers, whereas lagunamide B consists of ten such cen-
ters. Both have a novel polyketide moiety, one hydroxy acid unit,
Figure 1.
two
-Phe, Gly, and
A contains one normal ester group and one
But lagunamide B consists of one ,b unsaturated ester and
another allylic ester group. The challenges in the synthesis of lagu-
namide B are—(i) macrolactonization8 versus lactamization9 for
successful ring closure,10 (ii) proper protection of one ester group
over another, and (iii) synthesis of the polyketide moiety. It is
always challenging for a synthetic chemist to devise a strategic
esterification protocol for a molecule with more than one ester
L
-amino acids, and three residues of N-methyl amino acids
-Ala) in a 26-membered macrocycle. Lagunamide
,b-unsaturated ester.
(D
L
group that would facilitate selective saponification eventually
when required. Total synthesis of lagunamide A raised doubts over
the stereochemical assignments of the molecule. According to Dai
a
a
et al.,7a the molecule is having an
L-isoleucine in place of L-alloiso-
leucine and C-39 stereochemistry would be of R configuration
instead of S. This urges the revision of the assigned stereochemistry
for lagunamide B as well, since according to Tan and co-workers,4
both lagunamides A and B should have the same C-39 configura-
tion. This could only be achieved by the total synthesis of the mol-
ecule. This prompted us to devise an efficient strategy that could be
employed to prepare different isomers of the molecule and
compare their data with the reported literature. The present Letter
describes the synthesis of 1 (Fig. 1), one such analogue of
⇑
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600529.
E-mail addresses: tushar@orgchem.iisc.ernet.in, tusharkantichakraborty@gmail.
com (T.K. Chakraborty).
http://dx.doi.org/10.1016/j.tetlet.2014.04.079
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pal, S.; Chakraborty, T. K. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.079

2
S. Pal, T. K. Chakraborty / Tetrahedron Letters xxx (2014) xxx–xxx
lagunamide B, having L L-isoleu-
-isoleucine as in lagunamide A,7a
Ph
OH
cine derived Hila (2-hydroxyisoleucic acid), and retaining the C-
39(S) stereochemistry as originally proposed.
ClH.H2N COOMe
+
BocHN
O
The molecule contains five amide and two ester bonds. Each one
of them could serve as a probable site for final cyclization. Though
macrolactamization is much more favorable process over macrol-
actonization, it was preferred to go through the latter option due
to the presence of two ester bonds. As the reactivities of the two
esters in the molecule are quite different, our retrosynthetic strat-
egy (Fig. 2) focused on the selective cleavage of one ester over the
i, ii, iii, iv
Ph
O
5
, R=Me
BocHN
N
COOR
v
N
9, R=H
O
Scheme 1. Reagents and conditions: (i) EDCI, HOBt, DIPEA, CH2Cl2, 8 h, 86%; (ii)
Ag2O, MeI, DMF, 6 h, 79%; (iii) TFA, CH2Cl2, 2 h, quant; (iv) Boc-Ala-OH, HATU,
DIPEA, CH2Cl2, 8 h, 62%; (v) LiOH, THF/MeOH/H2O, 1 h, quant.
less reactive a,b-unsaturated ester and preparing the more reactive
allyl ester in the last step of cyclization of precursor 2. The hydro-
xyl groups of the polyketide fragment should be protected with
orthogonal protecting groups so that before cyclization the allylic
alcohol could be deprotected selectively to provide the necessary
precursor molecule 2. Fragment 2 could be assembled by the
amide coupling of subtargets 3 and 4.
O
i, ii, iii
OMe
Boc-Ala-OMe
N
RHN
O
6, R=Boc
The peptidic fragment 3 could easily be obtained by coupling of
the smaller units, 5 and 6. The polyketide part of the molecule, 4
was planned to be assembled by homologation through Horner–
Wadsworth–Emmons (HWE) olefination of phosphonate 8 with
the aldehyde obtained from the protected 3,5-dihydroxy-4,6-
dimethyl-6-octanol 7.
iv
10, R=TFA.H
Ph
N
O
O
N
N
v
H
N
9
+
10
O
O
The synthesis of the peptide fragment commenced with the
11, R=Boc
NHR
COOMe
coupling of Boc-
D
-Phe-OH and HClÁH-Gly-OMe using EDCI11 and
vi
HOBt12 in CH2Cl2 in the presence of DIPEA to obtain dipeptide
Boc-D-Phe-Gly-OMe at 86% yield (Scheme 1). Dipeptide was next
12, R=TFA.H
treated with methyl iodide and silver oxide in DMF to give the
N-methylated dipeptide at 79% yield which was then deprotected
in the presence of TFA in CH2Cl2 and coupled with Boc-Ala-OH
using HATU13 and DIPEA in CH2Cl2 to generate tripeptide 5 in
62% yield. Saponification of 5 with LiOH afforded the correspond-
ing acid 9 in quantitative yield.
The commercially available Boc-Ala-OMe was converted to N-
methyl ester using methyl iodide and silver oxide in DMF in 74%
yield (Scheme 2). The N-methylated compound was deprotected
with TFA in CH2Cl2 and coupled with Boc-Ile-OH using HATU in
CH2Cl2 in the presence of DIPEA to obtain dipeptide 6 in 71% yield.
The dipeptide was then deprotected with TFA in CH2Cl2 to furnish
10 that was coupled with 9 to prepare 11 in 72% yield. Pentapep-
tide 11 (3, R = Me) was deprotected with TFA in CH2Cl2 to get the
amine salt 12.
Scheme 2. Reagents and conditions: (i) Ag2O, MeI, DMF, 6 h, 74%; (ii) TFA, CH2Cl2,
2 h, quant; (iii) Boc-Ile-OH, HATU, DIPEA, CH2Cl2, 8 h, 71%; (iv) TFA, CH2Cl2, 2 h,
quant; (v) EDCI, HOBt, DIPEA, CH2Cl2, 8 h, 72%; (vi) TFA, CH2Cl2, 2 h, quant.
O
O
O
O
O
O
OTBS
OH
i
ii
N
N
O
N
O
O
O
Ph
H
15
13
14
Ph
Ph
O
O
OH OTBS
O
N
OH OTBS
O
OTBS
iii
iv
v
19
Ph
O
(1:2)
O
OH OTBS
O
O
17
16
The synthesis of the polyketide fragment began with
a
N
O
H
Crimmin’s modified aldol reaction14 between the chiral auxiliary
N
O
24.8 ppm
100.8 ppm
O
O
R2
20
Ph
Ph
18
H
23.8 ppm
vi, vii
R1
H
Ph
O
Ph
O
O
N
amide bond
formation
N
H
OPiv O
O
N
OPiv OH OTBS
OPiv OH OH
ix
N
O
viii
N
H
O
N
N
O
O
O
O
O
O
O
N
OH
O
O
HN
HO
O
HN
23
22
21
MOMO
OH
O
O
Scheme 3. Reagents and conditions: (i) TiCl4, DIPEA, 1-NMP, CH2Cl2, 0 °C, 2 h, 88%
dr 97:3; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 30 min, 93%; (iii) LiBH4, THF/MeOH
(4:1), 0 °C, 1 h, 81%; (iv) pyÁSO3, Et3N, DMSO/DCM (1:0.8), 0 °C, 1 h, 93%; (v)
Bu2BOTf, DIPEA, CH2Cl2, 0 °C, 2 h, cooled to À78 °C followed by addition of 21 at
À78 °C, 2 h, 63%; (vi) LiBH4, THF/MeOH (4:1), 0 °C, 1 h, 82%; (vii) PivCl, py, CH2Cl2,
1 h, 63%; (viii) HFÁpy, THF, 2 h, 76%; (ix) 2,2-DMP, CSA, CH2Cl2, 1 h, 81%.
2
1
lactonisation
Ph
Ph
N
O
O
N
O
N
N
H
O
N
OMe
BocHN
O
O
N
O
OR
O
O
NHBoc
5
amide bond
N
NHBoc
formation
6
3
13 and tiglic aldehyde (Scheme 3). Compound 13 was treated with
TiCl4, DIPEA, and 1-methyl-2-pyrolidinone in CH2Cl2 at 0 °C to gen-
erate the corresponding enolate followed by the addition of tiglic
aldehyde at 0 °C to give compound 14 in 88% yield with a diaste-
reoselective ratio 97:3. The free allylic hydroxyl group of 14 was
treated with TBSOTf in the presence of 2,6-lutidine in CH2Cl2 to
give TBS protected compound 15 in 93% yield. Reductive removal
, R = Me, Bn
COOMe
BnO
O
BnO
O
O
O
O
P
O
MOMO
OTBS
TBSO
MOMO
OEt
O
OEt
8
4
HO
7
HWE olefination
Figure 2.
Please cite this article in press as: Pal, S.; Chakraborty, T. K. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.079

S. Pal, T. K. Chakraborty / Tetrahedron Letters xxx (2014) xxx–xxx
3
O
O
of auxiliary of TBS protected compound 15 was carried out with
i, ii
iii
lithium borohydride in THF/MeOH (4:1) at 0 °C to give the corre-
sponding alcohol 16 at 81% yield. Alcohol 16 underwent facile oxi-
dation with pyridine-sulfur trioxide complex and Et3N in a mixture
of CH2Cl2 and DMSO to give the corresponding aldehyde 17 in 93%
yield.
OH
O
OBn
O
O
P
NH2
OH
25
OEt
OEt
HO
26
BnO
Chiral auxiliary 18 was treated with nBu2BOTf and DIPEA at 0 °C
and stirred for 2 h. After that the mixture was cooled to À78 °C and
aldehyde 17 was added at the same temperature. The reaction was
stirred for 2 h and worked up. This led to the formation of two iso-
mers with major compound 20 and minor compound 19, in 2:1
ratio, in 63% yield. To understand the stereochemistry of the newly
generated center of the alcohol, major stereoisomer 20 was sub-
jected to reductive removal of the chiral auxiliary with lithium
borohydride followed by selective protection of the primary alco-
hol over secondary one with pivaloyl chloride to produce com-
pound 21 at 63% yield. Next, silyl protection was removed with
HFÁpy in THF to obtain 22 at 76% yield. Both the hydroxyls of 22
were then protected with the acetonide group to prepare 23 in
81% yield. 13C NMR spectrum of the 23 (acetonide Me d 23.8 and
24.8 ppm, ketal carbon d 100.8 ppm) concluded the anti orientation
of the 1,3-diol for the major isomer 20.15
O
O
BnO
O
O
P
OEt
O
MOMO
OTBS
iv
OEt
O
8
4
HO
O
O
O
MOMO
OTBS
v
vi
27
Ph
N
O
O
N
N
N
H
viii or ix
O
O
O
O
degraded products
HN
COOMe
MOMO
OR
O
28
, R=TBS
vii
Major isomer 20 was then protected as MOM-ether, using
MOMCl in the presence of DIPEA in CH2Cl2, in 81% yield (Scheme 4)
followed by deprotection with lithium borohydride in THF/MeOH
(4:1) at 0 °C to give the corresponding alcohol 7 at 85% yield. Alco-
hol 7 underwent facile oxidation with pyridine-sulfur trioxide
complex and Et3N in a mixture of CH2Cl2 and DMSO to give the cor-
responding aldehyde 23 in 93% yield.
29, R=H
Scheme 5. Reagents and conditions: (i) Ref. 16; (ii) Ref. 17; (iii) DIC, DMAP, CH2Cl2,
83%; (iv) 23, LiCl, DIPEA, ACN, 20 h, 59%; (v) PdCl2, Et3N, Et3SiH, CH2Cl2, 15 min; (vi)
12, EDCI, HOBt, DIPEA, CH2Cl2, 8 h, 34%; (vii) HFÁpy, THF, 2 h, 63%; (viii) LiOH, THF/
MeOH/H2O, 1 h, degraded products; (ix) Me3SnOH, DCE, 80 °C, 12 h, degraded
products.
For phosphonate ester fragment 8, L-Ile was treated with NaNO2
solution in 1 M H2SO4 at 0 °C for 5 days (Scheme 5).16 During the
addition of NaNO2 solution to the reaction mixture and during
the reaction period, the internal temperature of the reaction was
Ph
Ph
O
O
O
N
O
N
N
H
N
iv
i, ii
N
H
N
11
kept below 5 °C. It led to the formation
a-hydroxy acid 24 with
N
O
O
N
O
iii
O
O
O
retention in configuration. Now, -hydroxy acid was reacted with
a
COOBn
HN
COOBn
NHR
MOMO
OR
BnBr in the presence of DBU in ACN to give the benzyl protected a-
30, R=Boc
hydroxy ester 25.17
O
The a-hydroxy ester 25 was coupled with 2-(diethoxyphospho-
31, R=TFA.H
32, R=TBS
33, R=H
v
ryl)propanoic acid 26 using DIC and a catalytic amount of DMAP in
CH2Cl2. The reaction yielded phosphonate compound 8 in 83%
yield. Compound 8 was coupled with 23 in the presence of LiCl
and DIPEA in ACN to give fragment 4 in 59% yield. Next, the
Ph
N
O
N
O
N
Ph
N
N
O
N
H
O
O
N
O
vii
O
O
a
,b-unsaturated ester 4 was hydrogenated with PdCl2 and Et3SiH
H
N
HN
COOR
OH
O
O
in the presence of Et3N in CH2Cl218 to afford the free acid 27 which
was coupled with 12 to give 28 in 34% yield. Compound 28 was
treated with HFÁpy complex in THF to give the linear seco acid
29 in 63% yield. Compound 29 was treated with LiOH in
THF/MeOH/H2O for selective deprotection of the methyl ester.
But it led to complete degradation of the compound.
MOMO
O
O
HN
O
MOMO
O
O
O
33, R=Bn
2, R=H
vi
34
Subsequently, 29 was treated with Me3SnOH in DCE at 80 °C for
12 h to get the seco-acid 2.19 But even in this reaction, several spots
were generated, as seen in the TLC, indicating degradation of the
molecule.
Scheme 6. Reagents and conditions: (i) LiOH, THF/MeOH/H2O, 1 h, quant; (ii)
PhCH2OCOCl, Et3N, DMAP, CH2Cl2, 4 h, 78%; (iii) TFA, CH2Cl2, 2 h, quant; (iv) 27,
EDCI, HOBt, DIPEA, CH2Cl2, 8 h, 35%; (v) HFÁpy, THF, 2 h, 61%; (vi) PdCl2, Et3N, Et3SiH,
CH2Cl2, 15 min; (vii) MNBA, DIPEA, CH2Cl2, 48 h; low yield.
To overcome these problems, it was decided to try an ester
protecting group that could be hydrolyzed under mild conditions.
Pentapeptide 11 was saponified with LiOH in THF/MeOH/H2O to
prepare the corresponding acid and was treated with benzylchlo-
roformate in Et3N and DMAP catalyst in CH2Cl2 to give the benzyl
ester 30 in 78% yield (Scheme 6). Pentapeptide benzyl ester 30 was
deprotected with TFA in CH2Cl2 to prepare amine salt 31 and cou-
pled with 27 to give 32 in 35% yield.20
Compound 32 was treated with HFÁpy complex in THF to give
the intermediate 33 in 61% yield.21 Compound 33 carried a labile
benzyl ester, in place of methyl ester, that was expected not to give
any problem while deprotecting using the same conditions used
above for 29. As a result, compound 33 was treated with bases—
(i) LiOH in THF/MeOH/H2O, and (ii) Me3SnOH in DCE at 80 °C for
7 h—to furnish the target acid 37. But in both cases, the degraded
products were observed albeit in less quantities. As an alternative
MOMO
O
OTBS
MOMO
OTBS
iii
i, ii
20
HO
23
7
Scheme 4. Reagents and conditions: (i) MOMCl, DIPEA, CH2Cl2, 0 °C, 1 h, 81%; (ii)
LiBH4, THF, 0 °C, 1 h, 85%; (iii) pyÁSO3, Et3N, DMSO/DCM (1:0.8), 0 °C, 1 h, 93%.
Please cite this article in press as: Pal, S.; Chakraborty, T. K. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.079

4
S. Pal, T. K. Chakraborty / Tetrahedron Letters xxx (2014) xxx–xxx
7. (a) Dai, L.; Chen, B.; Lei, H.; Wang, Z.; Liu, Y.; Xu, Z., et al Chem. Commun. 2012,
8697; (b) Huang, W.; Ren, R.-G.; Dong, H.-Q.; Wei, B.-G.; Lin, G.-Q. J. Org. Chem.
2013, 78, 10747.
8. Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006, 106, 911.
9. Davies, J. S. J. Pept. Sci. 2003, 9, 471.
10. Wen, S.; Packham, G.; Ganesan, A. J. Org. Chem. 2008, 73, 9353.
11. Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26, 2525.
12. König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
method, compound 33 was treated with PdCl2 and Et3SiH in the
presence of Et3N in CH2Cl2 to afford the seco acid 2. The reaction
was fairly clean with very negligible degraded products observed
in the TLC.
Compound 2 was subjected to Mitsunobu cyclization with TPP
and DEAD in THF.22 But the expected product could not be isolated.
ESI mass spectra of the crude and worked-up product did not show
any peak at the desired region. Compound 2 was also tried to be
cyclized with 2-chloro-N-methylpyridinium iodide23 in the pres-
ence of DIPEA in ACN under highly diluted conditions, but again
failed to provide the desired result.
13. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
14. Crimmins, M. T.; She, J. Synlett 2004, 1371.
15. (a) Rychnovsky, S. D.; Skalitxky, D. J. Tetrahedron Lett. 1990, 31, 945; (b) Evans,
D. A.; Rieger, D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099.
16. Pettit, G. R.; Hu, S.; Knight, J. C.; Chapuis, J. C. J. Nat. Prod. 2009, 72, 372.
17. Uesusuki, S.; Watanabe, B.; Yamamoto, S.; Otsuki, J.; Nakagawa, Y. Biosci.
Biotechnol. Biochem. 2004, 68, 1097.
Finally, success was achieved when compound 2 was subjected
to the Shiina cyclization method24 using 2-methyl-6-nitrobenzoic
anhydride (MNBA) in the presence of DIPEA and a catalytic amount
of DMAP in CH2Cl2 at high dilution that gave a product which was
isolated and showed an ESI mass peak at m/z 906 [M+Na]+. But the
yield was very low. As a result, it was becoming very difficult to get
the final compound in sufficient quantities for purification, spectral
characterization, and further work. Work is now in progress to
improve the yields of some of the steps, especially the macrocycli-
zation step, and complete the total synthesis of the target
molecule.
In conclusion, we have been able to devise a synthetic protocol
for the synthesis of lagunamide B with a careful choice of an
appropriate ester protecting group. At the end, its selective
removal keeping the other ester intact allowed us to successfully
construct the macrocyclic framework of this depsipeptide using
lactonization strategy rather than lactamization approach.
18. Rupprecht, K. M.; Baker, J. B.; Davis, A. A.; Hodges, P. J.; Kinneary, J. F.
Tetrahedron Lett. 1998, 39, 233.
19. Nicolaou, K. C.; Anthony, A. E.; Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem., Int.
Ed. 2005, 44, 1378.
20. Synthesis of 32: To a stirred solution of 4 (450 mg, 0.74 mmol) in CH2Cl2 (3 mL),
Et3N (0.15 mL, 1.1 mmol), PdCl2 (7 mg, 0.04 mmol), and Et3SiH (0.2 mL,
1.1 mmol) were sequentially added at 0 °C. After stirring for 15 min at 0 °C,
the reaction mixture was quenched with saturated NH4Cl solution and diluted
with EtOAc (60 mL), washed with 1 N HCl (25 mL), water (25 mL), brine
(25 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to
afford crude acid 27 as a yellow liquid. To a stirred solution of 30 (630 mg,
0.89 mmol) in CH2Cl2 (6 mL) at 0 °C, trifluoroacetic acid (3 mL) was added and
stirring was continued for 2 h at room temperature. The reaction mixture was
then concentrated in vacuo to get the trifluoroacetate salt 31. To a stirred
solution of 27 in dry CH2Cl2 (10 mL) at 0 °C, HOBtÁH2O (169 mg, 1.1 mmol) and
EDCI (213 mg, 1.1 mmol) were sequentially added. After 10 min, 31, dissolved
in dry CH2Cl2 (5 mL), was added to the reaction mixture followed by the
addition of DIPEA (0.4 mL, 2.2 mmol). After stirring for 8 h at room
temperature, the reaction mixture was diluted with EtOAc (125 mL), washed
with 1 N HCl (2 Â 75 mL), saturated NaHCO3 (2 Â 75 mL), water (75 mL), brine
(75 mL), dried (anhydrous Na2SO4), filtered, and concentrated in vacuo.
Purification by silica gel column chromatography (SiO2, 50% EtOAc in
petroleum ether eluant) afforded compound 32 (286 mg, 35%) as pale yellow
liquid. Rf = 0.5 (SiO2, 60% EtOAc in petroleum ether). 1H NMR (300 MHz, CDCl3):
d 7.29–7.15 (m, 10H), 7.06 (d, J = 7.8 Hz, 1H), 6.89 (m, 1H), 6.61 (d, J = 8.6 Hz,
1H), 5.75–5.65 (m, 1H), 5.38–5.31 (m, 2H), 5.17 (d, J = 12.2 Hz, 1H), 5.10 (d,
J = 12.2 Hz, 1H), 5.01–4.97 (m, 1H), 4.87–4.71 (m, 1H), 4.63 (d, J = 7.0 Hz, 1H),
4.52 (d, J = 7.0 Hz, 1H), 3.69 (d, J = 9.2 Hz, 1H), 3.44–3.40 (m, 1H), 3.31 (s, 3H),
3.24–2.70 (m, 5H), 3.03 (s, 3H), 3.00 (s, 3H), 2.88 (s, 3H), 2.39–2.28 (m, 1H),
2.21–2.15 (m, 1H), 2.05–1.96 (m, 4H), 1.88–0.79 (m, 8H), 1.84 (s, 3H), 1.58 (d,
J = 6.2 Hz, 3H), 1.57 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.89–
0.79 (m, 10H), 0.88 (s, 9H), 0.03 (s, 3H), À0.05 (s, 3H). MS (ESI): m/z (%): 1128
(100) [M+Na]+, HRMS (ESI): calcd for C60H95N5O12SiNa 1128.6639 [M+Na]+,
found 1128.6637.
Acknowledgements
The authors wish to thank DST, New Delhi for JC Bose Fellow-
ship (T.K.C.; DST No: SR/S2/JCB-30/2007), CSIR, New Delhi for
research fellowship (S.P.) and the SAIF division of CSIR-CDRI for
analytical support.
Supplementary data
21. Synthesis of 33: To a stirred solution of 32 (286 mg, 0.26 mmol) in dry THF
(3 mL), HFÁpyridine complex (1 mL) at 0 °C was added. The reaction was
monitored using TLC. After stirring for 2 h at 0 °C, the reaction mixture was
quenched with aqueous saturated NaHCO3 solution and diluted with EtOAc
(125 mL), washed with 1 N HCl (50 mL), water (50 mL), brine (50 mL), dried
(anhydrous Na2SO4), filtered and concentrated in vacuo. Purification by silica
gel column chromatography (SiO2, 50% EtOAc in petroleum ether eluant)
afforded compound 33 (157 mg, 61%) as pale yellow liquid. Rf = 0.5 (SiO2, 70%
EtOAc in petroleum ether). 1H NMR (300 MHz, CDCl3): d 7.33–7.20 (m, 10H),
6.88 (m, 2H), 6.67 (d, J = 8.9 Hz, 1H), 5.69–5.67 (m, 1H), 5.57–5.55 (m, 1H),
5.34–5.33 (m, 1H), 5.17 (d, J = 12.0 Hz, 1H), 5.10 (d, J = 12.1 Hz, 1H), 5.01 (m,
2H), 4.81–4.76 (m, 2H), 4.66 (s, 2H), 4.24–4.13 (m, 2H), 3.77–3.66 (m, 2H),
3.41–3.32 (m, 1H), 3.38 (s, 3H), 3.04 (s, 3H), 3.01 (s, 3H), 2.85 (s, 3H), 3.15–2.80
(m, 5H), 2.49 (m, 2H), 2.41–2.33 (m, 2H), 2.05–2.00 (m, 4H), 1.88 (s, 3H), 1.64
(d, J = 3.09 Hz, 3H), 1.56 (s, 3H), 1.41–1.06 (m, 6H), 1.06–0.73 (m, 12H). MS
(ESI): m/z (%): 1014 (100) [M+Na]+, HRMS (ESI): calcd for C54H82N5O12
992.5954 [M+H]+, found 992.5931.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.
079.
References and notes
1. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the ‘Gold Book’), 1997.
2. Sethubathi, G. V. B.; Prabu, V. A. Curr. Res. J. Biol. Sci. 2010, 2, 24.
3. (a) Rich, S. M.; Leendertz, F. H.; Xu, G.; Lebreton, M.; Djoko, C. F.; Aminake, M.
N., et al Proc. Natl. Acad. Sci. 2009, 106, 1490; (b) Perkins, D. J.; Were, T.;
Davenport, G. C.; Kempaiah, P.; Hittner, J. B.; Ong’Echa, J. M. Int. J. Biol. Sci. 2011,
7, 1427.
4. Tripathi, T. F.; Puddick, J.; Prinsep, M. R.; Rottmann, M.; Tan, L. T. J. Nat. Prod.
2010, 73, 1810.
5. Costa, M.; Rodrigues, J. C.; Fernandes, M. H.; Barros, P.; Vasconcelos, V.;
Martins, R. Mar. Drugs 2012, 10, 2181.
22. Liao, X.; Wu, Y.; De Brabander, J. K. Angew. Chem., Int. Ed. 2003, 42, 1648.
23. Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 5, 49.
24. Shiina, I.; Fukui, H.; Sasaki, A. Nat. Protoc. 2007, 2, 2312.
6. Balcht, A.; Smith, Raymond Informa Health Care 1994, 83.
Please cite this article in press as: Pal, S.; Chakraborty, T. K. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.079