Studies toward the total synthesis of Cytospolide E

Article abstract of DOI:10.1016/j.tet.2015.10.018

In this manuscript, we describe various approaches that we have examined towards the total synthesis of Cytospolide E. We initially attempted the RCM approach employing first and second generation Grubbs and Grubbs-Hoyeda catalysts resulting in the exclus

Full text of DOI:10.1016/j.tet.2015.10.018

Tetrahedron 71 (2015) 9088e9094
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies toward the total synthesis of Cytospolide E
*
Paresh M. Vadhadiya, Jeetendra K. Rout, C.V. Ramana
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 August 2015
Received in revised form 1 October 2015
Accepted 6 October 2015
Available online 9 October 2015
In this manuscript, we describe various approaches that we have examined towards the total synthesis of
Cytospolide E. We initially attempted the RCM approach employing first and second generation Grubbs
and GrubbseHoyeda catalysts resulting in the exclusive synthesis of the Z-isomer of Cytospolide E. With
€
the Furstner catalyst, the dimerization involving the less hindered olefin was the exclusive event. Al-
ternative approach documented is a successful cross-metathesis leading to a seco-acid with the requisite
E-configuration and undesired macrodiolide formation during the attempted Shiina’s lactonization.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Nonenolide
Yamaguchi esterification
Ring closing metathesis
Shiina lactonization
20-Membered macrodiolide
1. Introduction
Cytospolide E). Furthermore, Zhang and co-workers reported the
isolation of additional new members of this family, namely the
Nonenolides are extremely important because of their extraor-
dinary cytotoxic potential towards the cancerous cells. They also
show a broad spectrum of bioactivities such as antifungal, anti-
bacterial, antimicrofilament, and antimalarial activities. All the
nonenolides are constructed with an even number of carbon atoms
having a C-9 alkyl attachment.1 In 2011, Zhang and co-workers
reported the isolation of five new nonenolides from the fungus
Cytospora sp. obtained from the acetone extraction of the Ilex
canariensis shrub and named Cytospolides AeE.2 Cyctospolides are
characterized by an unprecedented 15 carbon atom skeleton having
a C2 methyl group, which was rarely observed in this class of nat-
ural products. The structural interpretations and absolute config-
urations were determined with the help of spectroscopic
techniques and single-crystal XRD together with the time de-
pendent (TD)-DFT calculations of CD spectra. The Cytospolides AeD
have a similar absolute configuration and vary mainly at the pres-
ence of acetate group(s) and its position. The Cytospolide E (1) is
a C2 epimer of Cytospolide D. Interestingly, it exists as a mixture of
conformers, which was confirmed by the soft pulse transfer NMR
technique and DFT calculations. During the initial bioassay tests,
these C2 epimers illustrated different cytotoxic properties against
the A549 cell line, suggesting a probable stereochemical influence
of the C2 methyl group in the growth inhibition of tumor cells (zero
Cytospolides FꢀQ and Decytospolides A and B, during their in-
vestigation on the trace compounds of the crude extract from same
fungus Cytospora sp.3
In continuation of our interest in the synthesis of the nonenolide
class of natural products using ring closing metathesis as a key
step4 and inspired with the cytotoxic activity of Cytospolide E, we
have initiated a program to synthesize Cytospolide E. While our
work was in progress, the synthesis of the Z-isomer of Cytospolide E
was documented by the Yadav,5 Nanda6 and Kamal7 groups by
employing RCM-based approaches. Interestingly, even in the case
of the synthesis of Cytospolide D, its unnatural Z-isomer was ob-
tained when RCM was used as the key skeletal construct. However,
the Kamal and Nanda groups were successful in obtaining the
naturally occurring cytospolide D with the requisite E-configura-
tion by employing the macrolactonization as the key reaction to
construct the central nonenolide core.7,8 Herein, we document the
complete details of our efforts towards the synthesis of natural
Cytospolide E culminating in various other possibilities although
they were not successful in obtaining the natural E-configured
Cytospolide E.
2. Results and discussion
activity for Cytospolide A, B and D to IC50¼7.09
mg/mL for
The key retrosynthetic disconnections for Cytospolide E (1) are
depicted in Fig. 1. Keeping the RCM as a key skeletal construct, the
diene ester 2 was identified as the key advanced intermediate,
which, in turn, could be obtained from the Yamaguchi esterification
* Corresponding author. Tel.: þ91 20 2590 2577; fax: þ91 20 2590 2629; e-mail
address: vr.chepuri@ncl.res.in (C.V. Ramana).
http://dx.doi.org/10.1016/j.tet.2015.10.018
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

P.M. Vadhadiya et al. / Tetrahedron 71 (2015) 9088e9094
9089
OR2
Me
OR
Me
OH
presence of CuI and the required alcohol fragment 3 was obtained
in 73% yield.10
2
9
O
O
O
R1O
RO
HO
Me
The synthesis of the acid fragment 4 was started by the asym-
metric aldol reaction between acrolein and Evans oxazolidinone 10
using TiCl4 and diisopropylethylamine to give an allyl alcohol 11 in
73% yield.11 The free hydroxyl group of allyl alcohol was protected
as its PMB ether employing mild reaction conditions (using silver
oxide and PMB-Cl in toluene for 26 h) in order to prevent epime-
O
O
O
Cytospolide A
(R1=H, R2=Ac)
Cytospolide C (R = Ac)
Cytospolide D ( R = H)
1
Cytospolide E ( )
Cytospolide B (R1=Ac, R2=H)
OPMB
OPMB
1
OH
rization at the a-position of the amide and hydrolysis of the chiral
PMBO
O
HO
PMBO
auxiliary. The reaction was sluggish and product 12 was isolated in
61% yield along with the unreacted 11. The oxazolidinone thereafter
was hydrolyzed under basic conditions to provide the requisite acid
4 (Scheme 2).
C5H11
C5H11O
O
4
3
2
CM
RCM
Grubbs catalyst
G-I, G-II, GH-I, GH-II
OH
O
C5H11
HO
OH
O
O
OH
C5H11
O
OH
C5H11
O
O
14
Shiina
lactonization
18
OH
RCM
Furstner catalyst
OH
O
C5H11
O
OH
O
15
HO
O
C5H11
OH
Fig. 1. Structures of Cytospolide AeE and key retrosynthetic disconnection for Cyto-
spolide E (1).
of an alcohol 3 and an acid 4. The synthesis of alcohol 3 was planned
from -glyceraldehyde and acid 4 could be accessed by means of
D
the asymmetric Evans aldol reaction of acrolein (Scheme 1).
Scheme 2. Synthesis of diene ester 2.
With both intermediates 3 and 4 in hand, our next task was their
coupling. Accordingly, Yamaguchi esterification of the olefinic acid
fragment 4 with the olefinic alcohol fragment 3 at ambient tem-
perature provided the diene ester 2 in 84% yield.12 This set the stage
for the crucial ring-closing metathesis. Treatment of 2 with the
Grubbs’ second generation catalyst in CH2Cl2 at reflux temperature
for 3 h gave the RCM product 13 with Z-geometry of the newly
forming double bond in 73% yield. The structure of 13 was ascer-
tained by its NMR spectrum. In the 1H NMR spectrum of 13, two
olefinic protons were seen to resonate at
d
5.26 (t, J¼9.9 Hz, 1H) and
5.75 (dt, J¼3.4, 11.5 Hz) ppm as well as the terminal olefinic protons
were seen to disappear. The low value of the coupling constant
J¼9.9 Hz and 11.5 Hz clearly reveals the Z-geometry of the newly
formed olefin.
Scheme 1. Synthesis of alcohol fragment 3.
The synthesis of the key alcohol fragment 3 began with the
Other attempts for the ring-closing metathesis of diene ester 2
by employing CH2Cl2 or toluene as the solvent at different tem-
peratures in combination with Grubbs’ first generation catalyst
(Ru-I) or Grubbs’ second generation catalyst (Ru-II) or Hoveydae-
Grubbs’ catalyst led to the formation of lactone 13 bearing a cis-
geometry at the newly created double bond. These results are
summarized in Table 1. Finally, the deprotection of PMB ethers of
compound 13 using TFA in CH2Cl2 at 0 ꢁC gave the Z-isomer of
Cytospolide E 14 in 75% yield. Unexpected formation of Z-isomer
may be attributed to the fact that the Z-isomer is thermodynami-
cally more stable than the E-isomer. This result is in agreement
with observations noticed by Gennari that less densely function-
alized diene with lack of functionality at the allylic position or
having functionality at only one allylic position resulted in the ex-
clusive formation of the Z-isomer of the ten-membered carbocycles
in the RCM reactions as a result of thermodynamic control.13 As
addition of 3-butenylmagnesium bromide to
D-glyceraldehyde
(prepared freshly by means of the periodate cleavage of
D-mannitol
1,2:5,6-diacetonide) to give a mixture of separable diastereomers 5
and 5a in a 4:1 ratio with 78% yield.9 The free hydroxyl group of the
required anti-alcohol 5 was protected as its PMB ether using p-
methoxy benzyl chloride (PMB-Cl) and NaH in N,N-dime-
thylformamide to afford compound 6 in 81% yield. Next, the
deprotection of the acetonide group in compound 6 in the presence
of catalytic p-TSA in methanol gave the diol 7 in 71% yield. The
selectively tosylation of the primary hydroxyl of compound 7 was
carried out using tosyl chloride and triethylamine in dichloro-
methane to afford the intermediate tosyl derivative 8 which was
further transformed to the required epoxide 9 by treating with
potassium carbonate in methanol. Finally, the regioselective
opening of epoxide 9 was carried out using n-butyl lithium in

9090
P.M. Vadhadiya et al. / Tetrahedron 71 (2015) 9088e9094
Table 1
Attempted RCM of diene ester 2 via Scheme 3
Entry
1
Catalyst
Solvent
Product/yield
First Generation
Grubbs Catalyst
Second Generation
Grubbs Catalyst
First Generation
HoveydaeGrubbs Catalyst
Second Generation
HoveydaeGrubbs Catalyst
CH2Cl2, Toluene
CH2Cl2, Toluene
CH2Cl2, Toluene
CH2Cl2, Toluene
CH2Cl2
13, 71%
13, 73%
13, 68%
13, 70%
15, 57%a
2
3
4
€
5
Furstner Catalyst
a
Isolated yield after PMB deprotection.
Scheme 4. Synthesis of macrodiolide 18.
€
After having the fully characterized seco-acid 16 in hand, the
next task was the lactonization to prepare the macrolide core.
Attempted lactonization of seco-acid using Yamaguchi lactoniza-
tion, CoreyeNicolaou lactonization methods or other coupling re-
agents such as DCC, EDCI resulted in a complex reaction mixture.
However, the Shiina lactonization using 2-methyl-6-nitrobenzoic
anhydride in the presence of DMAP proceeded smoothly to give
a 20-membered macrolide 17 in 52% yield instead of the required
10-membered nonenolide.16 The structure of 17 was confirmed by
NMR as well as HRMS. The 1H NMR and C NMR of compound 17
were found to be comparable to the expected 10 membered lac-
tone. However in HRMS, the presence of a strong peak at 1043.5865
([MþNa]þ, 100%) confirmed the presence of a 20-membered mac-
rolide structure in 17. Finally, global deprotection of the PMB groups
in macrolide 17 was carried out using TFA in dichloromethane at
0 ꢁC to give a 20-membered macrolide 18 in 72% yield. In the HRMS
spectrum of compound 18, the presence of a strong peak at
563.3550 ([MþNa]þ) indicated its dimeric structure. The NMR
spectra of 18 was characterized by the presence of two sets of
signals indicating mixture of two equilibrating conformational
isomers. However, the lack of sufficient quantity, especially in its
pure form, was the major hurdle in comprehensively assigning its
structure.
suggested by Furstner, the Grubbs catalysts, due to their higher
overall activity, are able to isomerize the cycloalkenes formed
during the course of the reaction and hence enrich the mixture in
the thermodynamically favored product. Thus, to avoid equilibra-
tion of the products initially formed,
a less reactive ruth-
eniumindenylidene complex should be used.14 Surprisingly, when
the RCM of 2 was attempted using a catalytic amount of the ruth-
eniumindenylidene complex with CH2Cl2 as solvent under reflux
conditions, the purification of the metathesis product was found to
be difficult, We subsequently subjected it for PMB deprotection
with DDQ. Surprisingly, the homo metathesis product 15 was ob-
tained as the major product. The structure of the homo metathesis
product 15 was established with the help of spectral and mass
analysis. In the 1H NMR spectrum of 15, two terminal and internal
olefinic protons of the terminal olefin moiety were seen to resonate
at
d
5.32 (br d, J¼17.4 Hz, 2H), 5.20 (br d, J¼10.4 Hz, 2H) and
5.81e5.90 ppm as a multiplet, respectively, whereas internal olefin
protons were seen to resonate at
d
5.39 (t, J¼5.0 Hz, 1.2H), 5.46 (t,
J¼3.8 Hz, 0.4H) ppm. Similarly, in the 13C NMR spectrum, the ter-
minal and internal olefinic carbons were seen to resonate at d 116.3
(t, 2C), 137.5 (d, 2C) and 129.9 (d, 2C, Major) ppm, respectively. The
structure of 15 was further supported by the presence of a peak at
m/z 591.3865 ([MþNa]þ) in the ESI-HRMS spectrum of compound
15 (Scheme 3).
3. Conclusion
In conclusion, we document various approaches toward the
total synthesis of Cytospolide E that resulted with the synthesis of
unwarranted end products. The requisite building blocks are syn-
thesized from easily available D-glyceraldehyde and acrolein by
following simple synthetic transformations. In general, the RCM
based approaches resulted in the synthesis of the Z-isomer of
Cytospolide E (with 2.02% overall yield) or when employed the
€
Furstner catalyst, the synthesis of an acyclic dimer. On the other
hand, the attempted cross-metathesis of the requisite coupling
partners and subsequent Shina’s lactonization resulted in the iso-
lation of
a 20-membered macrodiolide. Overall, these in-
vestigations reveal that Cytospolide E is a unique nonenolide target
that may not be accessed by metathesis approaches that are rou-
tinely employed for this family of natural products. Alternative
approaches to accomplish the total synthesis of Cytospolide E are
currently under progress in our laboratory.
Scheme 3. RCM of diene ester 2.
The failure in the synthesis of the natural Cytospolide E (by
following Yamaguchi esterification and the RCM strategy) led us to
think in the reverse direction of the ring closure. For that, we
intended on a cross metathesis reaction at the beginning and an
intramolecular esterification was planned at a later stage. Accord-
ing to the hypothesis, the cross metathesis in between the alcohol 3
and the acid 4 proceeded smoothly in the presence of Grubbs
second generation catalyst under reflux conditions in CH2Cl2 for
24 h to give exclusively the alkene 16 having a trans geometry in
52% yield15 (Scheme 4).
4. Experimental section
4.1. General
Air and/or moisture sensitive reactions were carried out in an-
hydrous solvents under an atmosphere of argon in oven-dried
glassware. All anhydrous solvents were distilled prior to use:
dichloromethane, 1,2-dichloroethane, DMF from CaH2; methanol

P.M. Vadhadiya et al. / Tetrahedron 71 (2015) 9088e9094
9091
from Mg cake; toluene from LAH; THF on Na/benzophenone; trie-
thylamine over KOH. Commercial reagents were used without pu-
rification. Column chromatography was carried out by using
spectrochem silica gel (60e120, 100e200, 230e400 mesh). 1H NMR
spectra were recorded on JEOL AL-400 (400 MHz), Bruker AC
200 MHz, Bruker DRX 400 MHz and Bruker DRX 500 MHz spec-
trometers, and TMS was used as an internal standard of spec-
at same temperature for 10 h. After completion, the reaction mix-
ture was neutralized with NaHCO3 and directly concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (60e70% EtOAc in petroleum ether) to
25
procure 7 (5.55 g, 71%) as a yellow oil. [
NMR (200 MHz, CDCl3):
a
]
D
3.0 (c 1.0, CHCl3); 1H
d
1.65e1.83 (m, 2H), 2.08e2.23 (m, 2H),
3.44e3.76 (m, 4H), 3.80 (s, 3H), 4.47 (d, J¼11.0 Hz, 1H), 4.55 (d,
trometers. The chemical shifts were reported in parts per million (d)
J¼10.9 Hz, 1H), 4.96e5.08 (m, 2H), 5.70e5.91 (m, 1H), 6.87 (d,
relative to internal standard TMS (0 ppm) and for CDCl3 (7.25 ppm).
The peak patterns are indicated as follows: s, singlet; d, doublet; dd,
doublet of doublet; t, triplet; m, multiplet; q, quartet. The coupling
constants, J are reported in Hertz (Hz). 13C NMR spectra were ob-
tained by JEOL AL-400 (100 MHz), Bruker DRX (125 MHz), Bruker
DRX (100 MHz) and Bruker AC (50 MHz) spectrometers and ref-
erenced to the internal solvent signals (central peak is 77.0 ppm in
CDCl3). CDCl3 or Methanol-d4 was used as an NMR solvent. High-
resolution mass spectra (HRMS) were recorded on a Thermo Sci-
entific Q-Exactive, Accela 1250 pump.
J¼8.8 Hz, 2H), 7.23e7.27 (m, 2H); 13C NMR (50 MHz, CDCl3):
d 29.3
(t), 29.5 (t), 55.1 (q), 63.3 (t), 72.0 (t), 72.7 (d), 79.5 (d), 113.7 (d, 2C),
114.8 (t), 129.4 (d, 2C), 130.1 (s), 138.2 (d), 159.1 (s) ppm; HRMS
(ESIþ) calcd for C15H22O4Na 289.1410; Found 289.1409.
4.5. (2R,3S)-2-Hydroxy-3-((4-methoxybenzyl)oxy)hept-6-en-
1-yl 4-methylbenzenesulfonate (8)
At 0 ꢁC, a solution of 7 (5 g, 18.8 mmol), triethylamine (3.1 mL,
22.5 mmol) and DMAP (Cat.) in Dry CH2Cl2 (50 mL) was treated
with p-toluenesulfonyl chloride (4 g, 20.6 mmol) and stirred at rt
for 12 h. The reaction was portioned between water (100 mL) and
CH2Cl2 (100 mL) and the aqueous layer was extracted with CH2Cl2
(100 mL). Combined organic layer was dried (Na2SO4) and con-
centrated. Purification of the crude product by column chroma-
4.2. (S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)pent-4-en-1-ol
(5)
A suspension of Mg (3.7 g, 153.7 mmol) and catalytic iodine in
dry THF (150 mL) was treated with butenyl bromide (11.7 mL,
115.7 mmol) and the contents were stirred at rt for 1 h. To this,
tography (30/35% EtOAc in petroleum ether) gave 8 (6.3 g, 80%) as
25
yellow oil. [
a
]
3.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
D
a solution of the
D
-glyceraldehyde (10 g, 76.8 mmol) in THF (50 mL)
d 1.52e1.61 (m, 1H),1.63e1.71 (m,1H), 2.02e2.11 (m,1H), 2.13e2.22
was added drop wise at 0 ꢁC and the mixture was stirred for an-
other 1 h at rt. The reaction mixture was quenched with saturated
ammonium chloride (200 mL) and extracted with ethyl acetate
(2ꢂ200 mL). The combined organic extract was dried (Na2SO4),
concentrated and the resulting crude residue was purified by silica
(m, 1H), 2.43 (s, 3H), 3.45e3.49 (m, 1H), 3.79 (s, 3H), 3.86e3.90 (m,
1H), 4.08 (dd, J¼6.3, 10.6 Hz, 1H), 4.15 (dd, J¼3.6, 10.6 Hz, 1H), 4.40
(d, J¼10.9 Hz, 1H), 4.46 (d, J¼10.9 Hz, 1H), 4.94e5.02 (m, 2H),
5.71e5.81 (m, 1H), 6.85 (d, J¼8.6 Hz, 2H), 7.17 (d, J¼8.6 Hz, 2H), 7.33
(d, J¼8.2 Hz, 2H), 7.78 (d, J¼8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
gel column chromatography (10/12% EtOAc in pet ether) afforded
d 21.6 (q), 29.0 (t), 29.2 (t), 55.2 (q), 70.8 (d), 71.3 (t), 72.1 (t), 78.0
25
5 (9 g, 63%) and 5a (2 g, 15%) as a colorless oil. [
a]
17.3 (c 1.0,
(d), 113.8 (d, 2C), 115.0 (t), 128.0 (d, 2C), 129.5 (d, 2C), 129.9 (d, 2C),
130.1 (s), 132.6 (s), 138.1 (d), 145.0 (s), 159.3 (s) ppm; HRMS (ESIþ)
calcd for C22H28O6SNa 443.1499; Found 443.1493.
D
CHCl3); 1H NMR (200 MHz, CDCl3):
d
1.34 (s, 3H), 1.40 (s, 3H),
1.42e1.65 (m, 2H), 2.03e2.16 (m, 3H), 3.75 (dt, J¼3.9, 7.9 Hz, 1H),
3.84e4.05 (m, 3H), 4.94e5.08 (m, 2H), 5.71e5.91 (m, 1H); 13C NMR
(50 MHz, CDCl3):
d
25.2 (q), 26.4 (q), 29.8 (t), 31.8 (t), 64.7 (t), 70.2
4.6. (R)-2-((S)-1-((4-Methoxybenzyl)oxy)pent-4-en-1-yl)oxir-
(d), 78.6 (d), 108.9 (s), 115.0 (t), 137.9 (d) ppm; HRMS (ESIþ) calcd
ane (9)
for C10H18O3Na 209.1148; Found 209.1147.
To a solution of 8 (3 g, 7.13 mmol), in methanol (20 mL) was
added K2CO3 (2.96 g, 21.4 mmol) at rt and stirred for 1 h. The re-
action mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
4.3. (R)-4-((S)-1-((4-Methoxybenzyl)oxy)pent-4-en-1-yl)-2,2-
dimethyl-1,3-dioxolane (6)
To a cooled solution of 5 (8 g, 42.9 mmol) in anhydrous DMF
(80 mL) were added NaH (60% dispersion in mineral oil, 2.1 g,
51.5 mmol) followed by PMB-Cl (6.4 mL, 47.2 mmol) and the con-
tents stirred at rt for 4 h. The reaction mixture was quenched with
aq Na2SO4 (200 mL) and the aqueous layer was extracted with
EtOAc (2ꢂ200 mL). The combined organic layer was washed with
brine, dried (Na2SO4) and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatogra-
phy (5e8% EtOAc in petroleum ether) to procure 6 (10.7 g, 81%) as a
chromatography (8/10% EtOAc in petroleum ether) to afford 9
25
(1.39 g, 78%) as colorless oil. [
a
]
ꢀ2.3 (c 1.0, CHCl3); 1H NMR
D
(200 MHz, CDCl3):
d
1.65e1.76 (m, 2H), 2.04e2.37 (m, 2H), 2.71 (dd,
J¼2.7, 5.3 Hz, 1H), 2.78 (dd, J¼4.0, 5.2 Hz, 1H), 2.89e2.95 (m, 1H),
3.25 (q, J¼5.6 Hz, 1H), 3.79 (s, 3H), 4.41 (d, J¼11.2 Hz, 1H), 4.59 (d,
J¼11.2 Hz, 1H), 4.94e5.06 (m, 2H), 5.70e5.90 (m, 1H), 6.87 (d,
J¼8.8 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d
29.3 (t), 31.9 (t), 45.5 (t), 53.3 (d), 55.1 (q), 71.9 (t), 77.0 (d),113.6 (d,
2C), 114.8 (t), 129.2 (d, 2C), 130.5 (s), 138.1 (d), 159.1 (s) ppm; HRMS
(ESIþ) calcd for C15H20O3Na 271.1305; Found 271.1320.
yellow oil. [
a
]
D
25 3.8 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3):
d
1.35
(s, 3H), 1.42 (s, 3H), 1.57e1.68 (m, 2H), 2.10e2.26 (m, 2H), 3.54 (q,
J¼5.2 Hz, 1H), 3.79 (s, 3H), 3.87 (t, J¼6.4 Hz, 1H), 4.10e4.13 (m, 2H),
4.50 (d, J¼11.2 Hz, 1H), 4.59 (d, J¼11.1 Hz, 1H), 4.93e5.07 (m, 2H),
5.71e5.91 (m, 1H), 6.85e6.89 (m, 2H), 7.24e7.29 (m, 2H); 13C NMR
4.7. (5S,6R)-5-((4-Methoxybenzyl)oxy)undec-1-en-6-ol (3)
At 0 ꢁC, a suspension of CuI (1.15 g, 6.0 mmol) in dry ether
(20 mL) was treated with a solution of n-butyl lithium (7.5 mL,
12.08 mmol, 1.6 M solution in Hexane) and the contents were
stirred at 0 ꢁC for 20 min. To this, a solution of the epoxide 9 (1 g,
4.03 mmol) in dry ether (5 mL) was introduced and the mixture was
stirred for another 1 h at 0 ꢁC. The reaction mixture was quenched
with cold water (50 mL) and extracted with ethyl acetate
(2ꢂ50 mL). The combined organic extract was dried (Na2SO4),
concentrated and the resulting crude product was purified by silica
gel column chromatography (12/15% EtOAc in petroleum ether) to
(50 MHz, CDCl3):
d 25.1 (q), 26.4 (q), 29.0 (t), 30.3 (t), 55.0 (q), 66.0
(t), 72.3 (t), 77.7 (d), 77.8 (d), 108.8 (s), 113.6 (d, 2C), 114.6 (t), 129.2
(d, 2C), 130.4 (s), 138.2 (d), 159.0 (s) ppm; HRMS (ESIþ) calcd for
C
18H26O4Na 329.1723; Found 329.1720.
4.4. (2R,3S)-3-((4-Methoxybenzyl)oxy)hept-6-ene-1,2-diol (7)
At 0 ꢁC, p-TSA (500 mg, 2.94 mmol) was added to a solution of 6
(9 g, 29.4 mmol) in dry MeOH (80 mL) and the contents was stirred

9092
P.M. Vadhadiya et al. / Tetrahedron 71 (2015) 9088e9094
25
afford 3 (900 mg, 73%) as yellow oil. [
a
]
D
ꢀ9.2 (c 1.0, CHCl3); 1H
(Na2SO4) and evaporated under reduced pressure. The crude
product was purified by silica gel column chromatography (8/10%
EtOAc in petroleum ether) to procure diene ester 2 (900 mg, 84%) as
NMR (200 MHz, CDCl3):
d
0.89 (t, J¼6.7 Hz, 3H), 1.30e1.80 (m, 9H),
1.98e2.36 (m, 3H), 3.35 (td, J¼3.5, 9.0 Hz, 1H), 3.81 (s, 3H),
3.81e2.84 (m, 1H), 4.45 (d, J¼11.0 Hz, 1H), 4.55 (d, J¼11.0 Hz, 1H),
4.94e5.06 (m, 2H), 5.70e5.90 (m, 1H), 6.88 (d, J¼8.7 Hz, 2H), 7.27
25
a light yellow oil. [
CDCl3):
a]
ꢀ8.0 (c 1.0, CHCl3); 1H NMR (500 MHz,
D
d
0.85 (t, J¼6.6 Hz, 3H), 1.20 (d, J¼7.0 Hz, 3H), 1.22e1.25 (m,
(d, J¼6.8 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d
13.9 (q), 22.5 (t), 25.7
2H), 1.47e1.79 (m, 8H), 2.01e2.08 (m, 1H), 2.17e2.25 (m, 1H), 2.63
(quin, J¼7.0 Hz, 1H), 3.41 (td, J¼3.2, 8.9 Hz, 1H), 3.78 (s, 3H), 3.78 (s,
3H), 3.97 (t, J¼7.2 Hz, 1H), 4.27 (d, J¼11.2 Hz, 1H), 4.31 (d, J¼10.8 Hz,
1H), 4.50 (d, J¼11.3 Hz, 1H), 4.58 (d, J¼11.0 Hz, 1H), 4.93e5.00 (m,
2H), 5.06 (td, J¼3.3, 9.3 Hz, 1H), 5.24e5.28 (m, 2H), 5.72e5.83 (m,
2H), 6.83e6.85 (m, 4H), 7.20e7.26 (m, 4H); 13C NMR (125 MHz,
(t), 27.7 (t), 29.8 (t), 31.8 (t), 32.0 (t), 55.1 (q), 71.3 (t), 71.4 (d), 81.0
(d), 113.7 (d, 2C), 114.6 (t), 129.3 (d, 2C), 130.4 (s), 138.5 (d), 159.1 (s)
ppm; HRMS (ESIþ) calcd for
C19H30O3Na 329.2087; Found
329.2081.
4.8. (S)-4-Benzyl-3-((2S,3R)-3-((4-methoxybenzyl)oxy)-2-
CDCl3): d 13.0 (q), 14.0 (q), 22.5 (t), 25.4 (t), 29.5 (t), 29.8 (t), 30.0 (t),
methylpent-4-enoyl)oxazolidin-2-one (12)
31.6 (t), 45.4 (d), 55.2 (q), 55.2 (q), 70.2 (t), 71.8 (t), 74.8 (d), 79.3 (d),
81.2 (d), 113.7 (d, 2C), 113.7 (d, 2C), 114.8 (t), 118.7 (t), 129.2 (d, 2C),
129.5 (d, 2C), 130.5 (s), 130.7 (s), 136.4 (d), 138.4 (d), 159.0 (s), 159.1
(s), 173.9 (s) ppm; HRMS (ESIþ) calcd for C33H47O6 539.3367; Found
539.3378.
To a solution of alcohol 11 (2 g, 6.91 mmol) in toluene (20 mL)
was added PMB-Cl (1.9 mL, 13.82 mmol) followed by Ag2O (3.2 g,
13.82 mmol) at rt. Then the reaction mixture was stirred at room
temperature for 26 h and reaction mixture was filtered over Celite,
concentrated under reduced pressure. The resulting crude product
was purified by the column chromatography (230e400 silica gel,
4.11. (3S,4R,9S,10R,Z)-4,9-Bis((4-methoxybenzyl)oxy)-3-
methyl-10-pentyl-3,4,7,8,9,10-hexahydro-2H-oxecin-2-one (13)
10% EtOAc in pet ether) to give 12 (600 mg, 61%) as a colorless oil
25
along with recovered starting material 700 mg [
a
]
ꢀ25.7 (c 2.0,
To a solution of diene ester 2 (100 mg, 0.18 mmol) in dry CH2Cl2
(30 mL), second gen. Grubbs’ catalyst (31 mg, 0.04 mmol) was
added and the mixture was degassed under an argon atmosphere
thoroughly. The reaction mixture was heated at 40 ꢁC for 3 h and
the solvent was removed under reduced pressure. The residue was
D
CHCl3); 1H NMR (200 MHz, CDCl3)
d
1.24 (d, J¼6.8 Hz, 3H), 2.71 (dd,
J¼13.3, 9.7 Hz, 1H), 3.25 (dd, J¼13.3, 3.2 Hz, 1H), 3.77 (s, 3H),
3.88e4.12 (m, 4H), 4.25 (d, J¼11.7 Hz, 1H), 4.37e4.51 (m, 1H), 4.55
(d, J¼11.7 Hz, 1H), 5.24e5.33 (m, 2H), 5.83 (ddd, J¼16.1, 9.0, 7.3 Hz,
1H), 6.84 (d, J¼8.7 Hz, 2H), 7.16e7.37 (m, 7H) ppm; 13C NMR
purified by column chromatography (10/12% EtOAc in petroleum
25
(50 MHz, CDCl3)
d
12.5 (q), 37.7 (t), 42.2 (d), 55.2 (q), 55.5 (d), 65.8
ether) giving macrolide 13 (69 mg, 73%) as a colorless liquid. [
a]
D
(t), 69.8 (t), 80.2 (d), 113.6 (d, 2C), 118.8 (t), 127.2 (d), 128.9 (d, 2C),
129.4 (d, 2C), 129.5 (d, 2C), 130.3 (s), 135.3 (s), 136.0 (d), 153.1 (s),
159.0 (s), 174.3 (s) ppm; HRMS (ESIþ) calcd for C24H27O5NNa
432.1781; Found 432.1777.
7.2 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3):
d
0.85 (t, J¼6.9 Hz, 3H),
1.25e1.28 (m, 5H), 1.30 (d, J¼6.9 Hz, 3H), 1.45e1.55 (m, 4H),
2.01e2.08 (m, 2H), 2.34e2.39 (m, 1H), 2.53e2.60 (m, 1H), 3.30 (dt,
J¼2.2, 7.2 Hz, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 4.20e4.27 (m, 2H), 4.44
(s, 2H), 4.52 (d, J¼11.8 Hz, 1H), 4.99e5.02 (m, 1H), 5.25 (t, J¼10.1 Hz,
1H), 5.73 (dt, J¼3.6, 11.8 Hz, 1H), 6.85e6.88 (m, 4H), 7.20e7.23 (m,
4.9. (2S,3R)-3-((4-Methoxybenzyl)oxy)-2-methylpent-4-enoic
acid (4)
4H); 13C NMR (125 MHz, CDCl3):
d 13.9 (q), 15.3 (q), 22.5 (t), 24.6 (t),
24.7 (t), 30.2 (t), 31.5 (t), 31.6 (t), 47.7 (d), 55.3 (q), 55.3 (q), 70.1 (t),
70.5 (t), 75.0 (d, 2C), 79.9 (d), 113.7 (d, 2C), 113.7 (d, 2C), 128.2 (d),
129.1 (d, 2C), 129.5 (d, 2C), 130.6 (s, 2C), 135.6 (d), 159.1 (s), 159.1 (s),
172.8 (s) ppm; HRMS (ESIþ) calcd for C31H42O6Na 533.2874; Found
533.2866.
To a solution oxazolidinone 12 (450 mg, 1.1 mmol) in THF:H2O
(4:1 mL) was added LiOH.H2O (92 mg, 2.2 mmol) followed by 30%
H2O2 in water (149 mg, 0.5 mL, 4.4 mmol) at 0 ꢁC. The reaction
mixture was stirred at rt for 3 h. After completion of reaction, the
reaction mixture was neutralized with 2N HCl and the aqueous
layer was washed with CH2Cl2 (3ꢂ20 mL), concentrated, and pu-
rified by column chromatography (100e200 silica gel, 4% MeOH in
4.12. (3S,4R,9S,10R,Z)-4,9-Dihydroxy-3-methyl-10-pentyl-
3,4,7,8,9,10-hexahydro-2H-oxecin-2-one (14)
CH2Cl2) to give acid 4 (165 mg, 60%). [
NMR (200 MHz, CDCl3)
a
]
25 ꢀ43.2 (c 1.0, CHCl3); 1H
D
d
1.20 (d, J¼7.1 Hz, 3H), 2.69 (quin, J¼6.9 Hz,
To an ice cooed solution of 13 (50 mg, 97.91
mmol) in dry CH2Cl2
1H), 3.80 (s, 3H), 4.01 (dd, J¼7.6, 5.9 Hz, 1H), 4.32 (d, J¼11.4 Hz, 1H),
4.58 (d, J¼11.4, 1H), 5.27e5.37 (m, 2H), 5.79 (ddd, J¼16.9, 10.6,
7.8 Hz, 1H), 6.86 (d, J¼8.7 Hz, 2H), 7.23 (d, J¼8.7 Hz, 2H) ppm; 13C
(2 mL) was added TFA (15
m
L) and stirred for 2 h at 0 ꢁC. The reaction
mixture was concentrated under reduced pressure, and the
resulting residue was purified on silica gel column (30/35% EtOAc
NMR (50 MHz, CDCl3)
d
12.1 (q), 44.5 (d), 55.2 (q), 70.2 (t), 80.5 (d),
in petroleum ether) to furnish 14 (20.0 mg, 75%) as a white solid.
25
113.8 (d, 2C), 119.7 (t), 129.4 (d, 2C), 129.8 (s), 135.1 (d), 159.2 (s),
178.6 (s) ppm; HRMS (ESIþ) calcd for C14H18O4 Na 273.1097; Found
273.1094.
mp: 157e160 ꢁC; [
a]
15.2 (c 1.0, CHCl3); 1H NMR (400 MHz,
D
CDCl3):
d
0.87 (t, J¼6.5 Hz, 3H), 1.29e1.36 (m, 6H), 1.38 (d, J¼6.7 Hz,
3H), 1.55e1.62 (m, 2H), 1.76e1.85 (m, 1H), 1.92e2.03 (m, 2H),
2.47e2.55 (m, 1H), 2.73 (dq, J¼3.7, 12.2 Hz, 1H), 3.79 (br s, 1H), 4.62
(t, J¼9.5 Hz, 1H), 5.11 (td, J¼3.7, 8.3 Hz, 1H), 5.35 (dt, J¼1.5, 10.9 Hz,
4.10. (5S,6R)-5-((4-Methoxybenzyl)oxy)undec-1-en-6-yl
(2S,3R)-3-((4-methoxybenzyl)oxy)-2-methylpent-4-enoate (2)
1H), 5.73 (dt, J¼3.5, 11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 13.9
(q), 14.9 (q), 22.4 (t), 25.2 (t), 25.3 (t), 30.9 (t), 31.3 (t), 31.4 (t), 49.1
(d), 69.5 (d), 74.3 (d), 77.7 (d), 129.9 (d), 133.9 (d), 174.7 (s) ppm;
HRMS (ESIþ) calcd for C15H26O4Na 293.1723; Found 293.1722.
To a solution of acid 4 (500 mg, 2.0 mmol) in dry THF (10 mL),
2,4,6-trichlorobenzyl chloride (0.37 mL, 2.40 mmol) followed by
N,N-diisopropylethylamine (2 mL, 11.49 mmol) were added and the
mixture was stirred for 2 h at ambient temperature. After com-
pletion of mixed anhydride formation as indicated by TLC, DMAP
(488 mg, 4.0 mmol) and a solution of alcohol 3 (612 mg, 2.0 mmol)
in THF (5 mL) was introduced and the contents were stirred for 16 h
at rt. The reaction mixture was quenched with cold water (20 mL)
and extracted with ethyl acetate (2ꢂ30 mL). The combined organic
phase was washed with aq NaHCO3 solution and water, dried
4.13. (6R,7S,14S,15R,E)-7,14-Dihydroxyicos-10-ene-6,15-diyl
(2S,20S,3R,30R)-bis(3-hydroxy-2-methylpent-4-enoate) (15)
To a solution of diene ester 2 (100 mg, 0.18 mmol) in dry CH2Cl2
(30 mL), furstner’ catalyst (18 mg, 0.02 mmol) was added and the
mixture was degassed under an argon atmosphere thoroughly. The
reaction mixture was heated at 40 ꢁC for 12 h and the solvent was

P.M. Vadhadiya et al. / Tetrahedron 71 (2015) 9088e9094
9093
removed under reduced pressure. A solution of resulting crude CM
product (70 mg, 0.07 mmol) and DDQ (76 mg, 0.33 mmol) in
CH2Cl2-water (3 mL, 18:1) was stirred for 3 h at room temperature.
To this was added aqueous sodium bicarbonate solution (5 mL), and
the contents were partitioned between water and CH2Cl2. The
aqueous layer was extracted with CH2Cl2 (5 mL), and the combined
organic layer was dried over Na2SO4 and concentrated. The residue
was purified by silica gel chromatography (60/70% EtOAc in pe-
2H), 4.54 (d, J¼10.9 Hz, 2H), 4.99e5.00 (m, 2H), 5.50 (dd, J¼8.7,
15.7 Hz, 2H), 5.62 (td, J¼5.6,15.2 Hz, 2H), 6.82e6.85 (m, 8H), 7.21 (d,
J¼8.1 Hz, 8H); 13C NMR (100 MHz, CDCl3):
d 14.0 (q, 2C), 14.1 (q, 2C),
22.5 (t, 2C), 25.3 (t, 2C), 28.0 (t, 2C), 29.3 (t, 2C), 30.3 (t, 2C), 31.7 (t,
2C), 46.0 (d, 2C), 55.2 (q, 4C), 69.3 (t, 2C), 71.3 (t, 2C), 74.2 (d, 2C),
78.7 (d, 2C), 81.2 (d, 2C), 113.7 (d, 4C), 113.7 (d, 4C), 128.2 (d, 2C),
129.2 (d, 4C), 129.4 (d, 4C), 130.4 (s, 2C), 130.6 (s, 2C), 135.5 (d, 2C),
159.0 (s, 2C), 159.2 (s, 2C), 173.3 (s, 2C) ppm; HRMS (ESIþ) calcd for
troleum ether) to give 15 (30 mg, 57%) as yellow syrup. [
a
]
25 28.6 (c
C62H84O12Na 1043.5855; Found 1043.5865.
D
0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d
0.87 (t, J¼6.7 Hz, 6H), 1.15
(d, J¼7.1 Hz, 6H), 1.24e1.26 (m, 14H), 1.44e1.52 (m, 6H), 2.16e2.34
(m, 4H), 2.62e2.68 (m, 2H), 3.64e3.72 (m, 2H), 4.47 (s, 2H),
4.88e4.93 (m, 2H), 5.20 (d, J¼10.5 Hz, 2H), 5.32 (d, J¼17.2 Hz 2H),
5.39 (t, J¼5.0 Hz, 1.2H), 5.46 (t, J¼3.8 Hz, 0.4H), 5.81e5.90 (m, 2H);
4.16. (3S,4R,5E,9S,10R,13S,14R,15E,19S,20R)-4,9,14,19-
Tetrahydroxy-3,13-dimethyl-10,20-dipentyl-1,11-
dioxacycloicosa-5,15-diene-2,12-dione (18)
13C NMR (100 MHz, CDCl3):
d 10.4 (q, 2C), 14.0 (q, 2C), 22.5 (t, 4C,
To an ice cooed solution of 17 (20 mg, 19.58
mmol) in dry CH2Cl2
Major), 22.6 (t, 2C, Minor), 23.4 (t, 2C, Minor), 25.4 (t, 2C), 28.9 (t,
2C, Minor), 29.7 (t, 2C, Major), 31.3 (t, 4C, Minor), 31.6 (t, 4C, Major),
45.2 (d, 2C, Minor), 45.3 (d, 2C, Major), 71.9 (d, 2C, Major), 72.5 (d,
2C, Minor), 73.2 (d, 2C, Minor), 73.3 (d, 2C, Major), 77.9 (d, 2C), 116.3
(t, 2C, Major), 116.4 (t, 2C, Minor), 129.9 (d, 2C, Major), 130.0 (d, 2C,
Minor), 137.5 (d, 2C, Major), 138.5 (d, 2C, Minor), 175.2 (s, 2C) ppm;
HRMS (ESIþ) calcd for C32H56O8Na 591.3867; Found 591.3865.
(2 mL) was added TFA (10 L) and stirred for 2 h at rt. The reaction
mixture was concentrated under reduced pressure, and the
resulting residue was purified on silica gel column (3/4% MeOH in
m
CH2Cl2) to furnish macrolide 18 (7.6 mg, 72%) as a white-cream
25
solid. mp: 68e71 ꢁC; [
a
]
26.3 (c 0.3, CHCl3); 1H NMR (500 MHz,
D
CDCl3):
d
0.85 (t, J¼7.3 Hz, 6H), 1.18e1.32 (m, 22H), 1.57e1.69 (m,
4H), 2.00e2.03 (m, 4H), 2.76e2.92 (m, 2H), 3.40e3.45 (m, 1H, Mi-
nor), 3.62e3.67 (m, 2H, Major), 4.08e4.13 (m, 2H), 4.87e4.96 (m,
2H), 4.96e5.0 (m, 1H, Minor), 5.59e5.66 (m, 2H), 5.77e5.85 (m,
4.14. (2S,3R,8S,9R,E)-9-Hydroxy-3,8-bis((4-methoxy-benzyl)
oxy)-2-methyltetradec-4-enoic acid (16)
2H); 13C NMR (100 MHz, CDCl3):
d 13.5 (q, 2C, Minor), 13.8 (q, 2C,
Major), 14.0 (q, 2C, Minor), 14.1 (q, 2C, Major), 22.4 (t, 2C, Minor),
22.7 (t, 2C, Major), 25.3 (t, 2C, Minor), 25.6 (t, 2C, Major), 28.1 (t, 2C,
Minor), 28.5 (t, 2C, Major), 28.9 (t, 2C, Minor), 29.4 (t, 2C, Major),
30.1 (t, 2C, Minor), 30.4 (t, 2C, Major), 31.4 (t, 2C, Minor), 31.5 (t, 2C,
Major), 45.6 (d, 2C, Minor), 46.7 (d, 2C, Major), 72.5 (d, 2C, Minor),
73.1 (d, 2C, Major), 73.9 (d, 2C, Minor), 74.4 (d, 2C, Major), 75.8 (d,
2C, Minor), 77.9 (d, 2C, Major), 129.2 (d, 2C, Major), 130.5 (d, 2C,
Minor),130.8 (d, 2C, Major),131.6 (d, 2C, Minor),174.5 (s, 2C, Major),
174.7 (s, 2C, Minor) ppm; HRMS (ESIþ) calcd for C30H52O8Na
563.3554; Found 563.3550.
A degassed solution of acid 4 (50 mg, 0.2 mmol), alcohol 3
(122 mg, 0.4 mmol) and Grubbs’ second gen. catalyst (33 mg,
0.04 mmol) in dichloromethane (30 mL) was heated under reflux
under argon for 96 h and concentrated. The residue was purified by
column chromatography (4e5% MeOH in CH2Cl2) to afford 16
(55 mg, 52%) as yellow oil along with self-dimerization products of
alcohol 3 (55 mg, 47%) and 4 (18 mg, 38%). [
a
]
25 ꢀ20.8 (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3):
d
0.89 (t, J¼6.9 Hz, 3H), 1.16 (d, J¼7.2 Hz,
3H), 1.29e1.35 (m, 5H), 1.36e1.55 (m, 4H), 1.63e1.75 (m, 1H),
2.04e2.17 (m, 1H), 2.21e2.29 (m,1H), 2.67 (quin, J¼6.3 Hz,1H), 3.34
(td, J¼3.7, 8.6 Hz, 1H), 3.73e3.79 (m, 1H), 3.79 (s, 6H), 3.89 (dd,
J¼6.1, 8.3 Hz, 1H), 4.29 (d, J¼11.4 Hz, 1H), 4.44 (d, J¼11.2 Hz, 1H),
4.54 (d, J¼11.6 Hz, 2H), 5.36 (dd, J¼8.8, 15.4 Hz, 1H), 5.67 (td, J¼6.8,
15.4 Hz, 1H), 6.85e6.89 (m, 4H), 7.21 (d, J¼8.4 Hz, 2H), 7.26 (d,
Acknowledgements
We thank CSIR (India) for funding this project (12 FYP ORIGIN
program, CSC0108) and for a fellowship to PMV and JKR.
J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d 12.5 (q), 14.0 (q), 22.6
(t), 25.9 (t), 28.0 (t), 28.4 (t), 31.8 (t, 2C), 44.6 (d), 55.2 (q, 2C), 69.8
(t), 71.4 (d), 71.5 (t), 80.5 (d), 81.0 (d), 113.8 (d, 2C), 113.8 (d, 2C),
126.9 (d), 129.4 (d, 2C), 129.5 (d, 2C), 129.7 (s), 130.3 (s), 136.7 (d),
159.2 (s), 159.3 (s), 176.9 (s) ppm; HRMS (ESIþ) calcd for
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.10.018.
C
31H44O7Na 551.2979; Found 551.2972.
References and notes
4.15. (3S,4R,5E,9S,10R,13S,14R,15E,19S,20R)-4,9,14,19-
Tetrakis((4-methoxybenzyl)oxy)-3,13-dimethyl-10,20-
dipentyl-1,11-dioxacycloicosa-5,15-diene-2,12-dione (17)
1. (a) Drager, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep. 1996, 13,
365e375; (b) Ferraz, H. M. C.; Bombonato, F. I.; Longo, L. S. Synthesis 2007,
3261e3285; (c) Riatto, V. B.; Pilli, R. A.; Victor, M. M. Tetrahedron 2008, 64,
2279e2300.
2. Lu, S.; Kurtan, T.; Yang, G. J.; Sun, P.; Mandi, A.; Krohn, K.; Draeger, S.; Schulz, B.;
Yi, Y. H.; Li, L.; Zhang, W. Eur. J. Org. Chem. 2011, 5452e5459.
3. Lu, S.; Sun, P.; Li, T. J.; Kurtan, T.; Mandi, A.; Antus, S.; Krohn, K.; Draeger, S.;
Schulz, B.; Yi, Y. H.; Li, L.; Zhang, W. J. Org. Chem. 2011, 76, 9699e9710.
4. (a) Ramana, C. V.; Khaladkar, T. P.; Chatterjee, S.; Gurjar, M. K. J. Org. Chem.
2008, 73, 3817e3822; (b) Giri, A. G.; Mondal, M. A.; Puranik, V. G.; Ramana, C. V.
Org. Biomol. Chem. 2010, 8, 398e406; (c) Vadhadiya, P. M.; Puranik, V. G.;
Ramana, C. V. J. Org. Chem. 2012, 77, 2169e2175; (d) Vadhadiya, P. M.; Ramana,
C. V. Tetrahedron Lett. 2014, 55, 6263e6265.
A solution of seco-acid 16 (40 mg, 75.6 mmol) in dry toluene
ꢀ
(20 mL), was added to the stirred solution of molecular sieves (4A,
1g), DMAP (27 mg, 0.22 mmol) and 2-Methyl-6-Nitrobenzoic an-
hydride (20 mg, 0.06 mmol) in dry toluene (20 mL) using syringe
pump (0.8 mL/h). After the addition was complete it was stirred for
another 6 h at rt. The reaction mix was diluted with ethyl acetate
and was filtered. The organic phase was washed with satd NaHCO3,
brine, dried and concentrated. The residue was purified by column
5. Yadav, J. S.; Pandurangam, T.; Kumar, A. S.; Reddy, P. A. N.; Prasad, A. R.; Reddy,
B. V. S.; Rajendraprasad, K.; Kunwar, A. C. Tetrahedron Lett. 2012, 53,
6048e6050.
6. Rej, R. K.; Nanda, S. Eur. J. Org. Chem. 2014, 860e871.
7. Kamal, A.; Balakrishna, M.; Reddy, P. V.; Rahim, A. Tetrahedron: Asymmetry 2014,
chromatography (20/25% EtOAc in petroleum ether) giving
25
macrolide 17 (20 mg, 52%) as a yellow liquid. [
a
]
13.9 (c 1.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3):
d
0.85 (t, J¼7.3 Hz, 6H), 1.19 (d,
25, 148e155.
J¼6.7 Hz, 6H), 1.25e1.32 (m, 16H), 1.40e1.46 (m, 2H), 1.65e1.72 (m,
2H),1.95e2.02 (m, 2H), 2.24e2.31 (m, 2H), 2.71 (quin, J¼7.4 Hz, 2H),
3.36e3.38 (m, 2H), 3.71 (t, J¼7.8 Hz, 2H), 3.77 (s, 6H), 3.77 (s, 6H),
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