Total synthesis of palmyrolide A and its 5,7-epi isomers

Article abstract of DOI:10.1016/j.tet.2013.01.048

Stereoselective total synthesis of palmyrolide A, a 15-membered neuroactive macrolide, was described by adopting a synthetic strategy developed for the proposed structures, and its 5,7-epi isomers. The strategy was designed in such a way that the set of s

Full text of DOI:10.1016/j.tet.2013.01.048

Tetrahedron 69 (2013) 2419e2429
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of palmyrolide A and its 5,7-epi isomers
,
a
b
Gangarajula Sudhakar a , Karla Janardhan Reddy , Jagadeesh Babu Nanubolu
*
a Division of CPC (Organic Chemistry-II), CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
b Centre for X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective total synthesis of palmyrolide A, a 15-membered neuroactive macrolide, was described by
adopting a synthetic strategy developed for the proposed structures, and its 5,7-epi isomers. The strategy
was designed in such a way that the set of stereoisomers, which were needed for establishing the ab-
solute configuration of palmyrolide A, could be obtained from one time operation. The diastereoselective
Received 14 December 2012
Received in revised form 9 January 2013
Accepted 15 January 2013
Available online 31 January 2013
hydrogenation of exo-methylene-g-butyrolactone to a-methyl-g-butyrolactone, Yamaguchi esterfication,
and intramolecular dehydrative cyclization to form trans-enamide were the key steps involved in the
synthesis.
Keywords:
Neuroactive macrolide
Natural products
Total synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
Macrocyclization
N-Methyl enamide
1. Introduction
was reported by Maio and co-workers, which revealed the absolute
configuration of palmyrolide A5 and subsequently the second total
Marine cyanobacteria constitute a rich source of novel bioactive
secondary metabolites with unprecedented structural skeletons. A
class of macrolides with a rare N-methyl enamide, and 1,3-methyl
and tertiary butyl containing branch linked through lactone such
as laingolide (1), laingolide A (2) and madangolide (3) were isolated
from Lyngbya bouillonii.1 Structurally related neuroactive 15-
membered macrolide palmyrolide A was isolated from a marine
cyanobacterial assemblage composed of Leptolyngbya and Oscil-
latoria spp. collected from Palmyra Atoll.2 It has shown sodium
synthesis was reported very recently by Brimble and co-workers.6
In the first total synthesis, the key macrocyclization step was re-
lied on the trans-enamide formation catalysed by copper(I) iodide
and caesium carbonate where the second synthesis was achieved
using a sequential ring closing metathesis/olefin isomerization re-
action. We report herein, intramolecular dehydrative cyclization is
as a key macrocyclization step and three synthetic routes to the
macrolide: one for the proposed structures syn 4 & 4a, one for the
anti 4b & 4c, and a final for the stereoselective synthesis of pal-
myrolide A (4b) in which two fragments are derived from the same
starting material.
We envisioned that developing a synthetic strategy for the
synthesis of palmyrolide A would also be applicable in the syn-
thesis of other molecules of this class. The synthesis of palmyr-
olide A could primarily be from assembling of fragments A and
fragment B (Fig. 1) by either first intermolecular condensation to
form enamide and late-stage macrolactonization approach or
esterfication and intramolecular enamide formation sequence. At
the outset of our plan, the absolute configuration of palmyrolide A
had not yet been disclosed, thus, it was expected that the as-
sembling of fragment B with four possible stereoisomers of frag-
ment A, independently, would lead finally required number of
isomers to establish the absolute configuration of palmyrolide A.
We devised a strategy in such a way that the set of stereoisomers 4
& 4a, proposed structures of palmyrolide A,2 or 4b & 4c could be
obtained in one time operation rather than for each isomer fol-
lowing separate steps.
channel blocking activity in neuro-2a cells (IC50¼5.2
mM) without
appreciable cytotoxicity. Based on the NMR studies, planar struc-
ture was established for former molecules (1e3). While for the
palmyrolide A, in addition to the planar structure, the absolute
configuration at C(14)3 was determined as R by comparing the data
of the degradation product obtained from palmyrolide A and the
known 2-methylglutaric acid and its derivatives. As the ester hy-
drolysis was resistant in palmyrolide A, the absolute configuration
at C(5) and C(7) was not established but it was proposed2 that the
methyl at C(5) and the tert-butyl at C(7) are in syn relation as shown
in
constants.4
Impressive biological activity associated with stereochemical
4 and 4a (Fig. 1) based on carbon-proton spin-coupling
challenges stimulated the synthetic groups. The first total synthesis
* Corresponding author. Tel.: þ91 40 2719 1435; e-mail addresses: gsudhakar@
iict.res.in, gangarajulasudhakar@gmail.com (G. Sudhakar).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.048

2420
G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
O
4 & 4a
O
O
N
N
O
O
OBn
NH
OBn
NH
O
O
O
R
O
O
&
Laingolide (1) : R = CH3
Madangolide (3)
O
O
2
Laingolide A ( ) : R = H
O
1
O
O
5
5a
1
N
N
1
N
14
14
3
3
14
3
OBn
O
OBn
O
O
7
O
7
O
7
O
OEt
O
OEt
5
5
5
O
O
O
&
4a
4
4b
O
O
Original proposed structures
Revised structure
O
6a
6
O
O
1
N
1
O
OEt
NH
OBn
O
OBn
14
3
3
O
7
O
5
+
5
O
*
OH
O
OR
7
*
OH
A
B
4c
OH
O
Xc
7a
7
8
( )-
Fig. 1. Structure of laingolides (1e2), madangolide (3), proposed structures (4 & 4a),2 and
revised structure (4b),5,6 5,7-epi isomer (4c), and fragments A and B of palmyrolide A.
O
2. Results and discussion
O
OEt
OH
O
O
According to our retrosynthetic analysis shown in Scheme 1, 4
and 4a could be derived from 5 and 5a by deprotection of O-benzyl,
oxidation of primary hydroxyl and subsequent dehydrative cycli-
zation. Key intermediates 5 and 5a could be obtained from ethyl
ester hydrolysis of 6 and 6a, homologation, followed by amide
formation. The ester 6 and 6a could easily be accessible from
joining of two fragments 7 and (ꢀ)-8. Acid 7 could easily be pro-
cured from 7a by the chiral auxiliary based approach while (ꢀ)-8
10
( )-
( )-9
( )-11
Scheme 1. Retrosynthetic analysis for 4 & 4a.
a
OH
O
OH
BnO
HO
could be obtained from
lactone to lactol, 2C-Wittig reaction, and hydrogenation sequence.
The synthesis of
-butyrolactone (ꢀ)-9, in turn, was planned from
diastereoselective hydrogenation of exo-methylene- -butyr-
g
-butyrolactone (ꢀ)-9 by reduction of
12
1,6-hexanediol
g
b
g
Bn
olactone (ꢀ)-10, which could be obtained from homo allylic alcohol
(ꢀ)-11.
c
Synthesis of the first fragment 7 was begun from commercially
available 1,6-hexanediol. Controlled benzyl group protection on
1,6-hexanediol gave monobenzyl ether, which was in two-step
oxidation sequence furnished acid 12 (Scheme 2). Treatment of 12
with pivaloyl chloride and subsequent treatment with lithiated (R)-
4-benzyl-2-oxazolidinone afforded 13. Methylation of 13 at ꢁ78 ꢂC
followed by basic hydrolysis afforded 7 in 60% yield from 12 (dr
97.4:2.6 at methylation step).
N
OH
O
BnO
BnO
O
7
O
13
O
Scheme 2. Synthesis of 7. a) (i) NaH, BnBr, TBAI, THF, 12 h; (ii) (COCl)2, DMSO, Et3N,
CH2Cl2, ‒78 ꢂC, 1.5 h; (iii) NaClO2, NaH2PO4, tBuOH/2-methyl-2-butene (2:1), 2 h, 61%
(3 steps); b) Piv-Cl, Et3N, (R)-4-benzyl-2-oxazolidinone, LiCl, THF, ꢁ20 ꢂC, 4 h, 85%; c)
(i) NaHMDS, MeI, ꢁ78 ꢂC, 3 h, 75%; ii) LiOH$H2O, H2O2, THF/H2O, 3 h, 95%.
The synthesis of fragment (ꢀ)-8 (Scheme 3) was commenced
enantiomerically pure 9, which could be derived from enantio-
from (ꢀ)-11, which was synthesized by reacting trimethylace-
merically pure exo-methylene-g
-butyrolactone9 10. The racemic
taldehyde and ethyl
a
-bromomethylacrylate under Reformatsky-
(ꢀ)-9 was converted to (ꢀ)-14 in two steps such as reduction of
lactone to lactol followed by 2C-Wittig reaction. Hydrogenation of
(ꢀ)-14 produced (ꢀ)-8, which was coupled with 7 by using
Yamaguchi esterfication10 to yield inseparable diastereomers 6 & 6a
in 87% yield over two steps.
type reaction conditions reported in literature.7 Homoallylic alco-
hol (ꢀ)-11 was converted to lactone (ꢀ)-10 under acidic conditions
in quantitative yield. Hydrogenation of (ꢀ)-10 provided exclusively
one diastereomer (ꢀ)-9 in excellent yield.7c,8 Here, the racemic
(ꢀ)-9 is pivotal in the simultaneous synthesis of 4 & 4a. The
enantioselective synthesis of 4 or 4a could be achieved from
Chemoselective ester hydrolysis of 6 & 6a, as expected,11 fur-
nished acid, which was homologated to give 15 & 15a in 63% yield

G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
2421
over three steps. Treatment of 15 & 15a with DCC, HOBt, Et3N and
CH3NH2.HCl12 provided 5 & 5a, which were subjected for hydro-
genolysis followed by Swern oxidation to give expected aldehydes
16 & 16a. Finally, dehydrative cyclization13 using TFA in benzene
ꢀ
and 4 (A) MS under reflux conditions afforded the desired column
chromatographic separable cyclic products 4 & 4a (1:1.7 ratio) in
33% combined yield and 55% yield based on recovery of starting
material (brsm). Crystal structure of 4a14 confirmed the absolute
configuration of 4 and 4a, evident that there was no syn relation
between the methyl at C(5) and the tert-butyl at C(7) as for the
proposed structures of palmyrolide A.2
The simultaneous synthesis for 4b & 4c was planned from
(ꢀ)-11 (Scheme 4). Hydrogenation of (ꢀ)-11 furnished 9, a mixture
of syn and anti (1:1). Subsequently followed the same sequence of
reactions such as reduction and 2C-Wittig reaction, 9 gave 14,
which was converted to 8. Assembling of 8 with 7 delivered column
chromatographically separable syn 6 & 6a and anti 6b & 6c (syn and
anti 1:1) in 94% combined yield. The diastereomeric mixture of anti
6b & 6c was subjected to ester hydrolysis followed by the
ArndteEistert synthesis allowed the formation of homologated
carboxylic acids 15b & 15c in 63% yield (two steps). Treatment of
acids 15b & 15c with methylamine in the presence of coupling re-
agents afforded amides 5b & 5c in 94% yield. Hydrogenolysis of 5b &
5c and subsequent oxidation furnished the aldehydes 16b & 16c in
a yield of 86%. Intramolecular cyclization afforded column chro-
matographically separable diastereomers 4b & 4c (1:2 ratio) in
combined yield of 33% and 55% yield brsm. One of these di-
astereomers, 4b is identical in all respects with the palmyrolide A.
Unsuccessful in getting the crystal structure of any of these isomers
4b & 4c, the absolute stereochemistry was confirmed only after the
report by Maio group.5a
Then we envisioned that the fragment B has the required
structural features to provide the fragment A if it is subjected to few
transformations such as homologation and introducing hydroxyl
stereocenter by the addition of tert-butyl lithium. The trans-
formations on the a-methyl acid 7 (fragment B) would lead to the
stereoselective synthesis of palmyrolide A from the same strategy
and sequence of reactions developed for its 5,7-epi isomers. Ac-
cordingly,
a-methyl acid 7 was homologated to produce methyl
ester 17,15 which was reduced to aldehyde followed by the addition
of tBuLi16 yielded 18 (Scheme 5). Hydrogenolysis of benzyl ether in
18 furnished diol 19. Upon two-step oxidation sequence 19 yielded
ketoacid that was treated with excess of diazomethane to afford
keto ester 20. Stereoselective reduction of ketone 20 using (S)-CBS
catalyst in the presence of BH3$DMS afforded the desired hydroxyl
ester 21 along with the column chromatographically separable anti
21a (dr 89:11) in 83% combined yield.17 Coupling of fragments 21
and 7 using Yamaguchi esterfication10 afforded diester 22. Che-
moselective methyl ester hydrolysis and subsequent amide for-
mation furnished 23. Hydrogenolysis of benzyl ether in 23 followed
by Swern oxidation yielded aldehyde 24. Finally, 24 was refluxed
with TFA in benzene for 3 days to get the anticipated palmyrolide A
(4b) in 33% yield and 54% yield brsm.
3. Conclusions
A unique synthetic strategy was developed for the synthesis of
all stereoisomers of palmyrolide A, which were needed for com-
parison of the data and utilized a dehydrative cyclization for mac-
rocyclization, that is, distinct from the earlier two reports. The
unreactivity of ester to hydrolysis found in palmyrolide A was
exploited to achieve chemoselective ester hydrolysis, which
Scheme 3. Synthesis of 4 and 4a. a) PTSA, toluene, 2 h, quantitative yield; b) H2, Pd/C,
EtOH, 2 h, 92%; c) (i) DIBAL-H, toluene, ꢁ78 ꢂC, 1.5 h; ii) Ph3PCHCO2Et, CH2Cl2, reflux,
2 d, 77% (2 steps); d) H2, Pd/C, EtOH, 2 h, 92%; e) 7, 2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP, THF, 12 h, 94%; f) (i) LiOH$H2O, THF/MeOH/H2O (3:1:1), 3 h; (ii) EtOCOCl,
Et3N, THF, CH2N2, 3 h; (iii) CH3CO2Ag, dioxane/H2O, ultrasound irradiation, 0.5 h, 63%
(3 steps); g) CH3NH2.HCl, DCC, HOBt, Et3N, CH2Cl2, 6 h, 94%; h) (i) H2, Pd/C, MeOH, 2 h,
93%; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢂC, 1.5 h, 92%; i) TFA, benzene, reflux, 3 d,
33% (55%, brsm). Inset: ORTEP representation of the X-ray crystal structure of 4a: the
molecular structure of 4a, with the atom-numbering scheme. Displacement ellipsoids
are drawn at the 30% probability level and H atoms are shown as small spheres of
arbitrary radius.

2422
G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
O
EtO
EtO
OH
a
BnO
HO
BnO
OCH3
OH
O
O
7
O
17
O
b
a
a
11
( )-
b
OH
O
OH
OH
9
14
8
c
BnO
c
18
19
OBn
O
OBn
d
O
OEt
O
OEt
O
O
O
OH
O
6
6a
+
&
+
e
H3CO
H3CO
7R
O
O
21
21a
(7R);
(7S)
20
6c
6b
f
d
OBn
O
OBn
NH
O
O
O
O
O
OBn
OH
O
OBn
OH
OCH3
O
g
O
O
O
+
O
O
O
O
O
O
23
22
e
15c
15b
h
O
O
OBn
NH
OBn
NH
O
O
N
NH
O
i
+
f
O
O
O
O
O
O
5b
5c
24
4b
Palmyrolide A (
)
Scheme 5. Synthesis of palmyrolide A (4b). a) (i) EtOCOCl, Et3N, THF, CH2N2, 0 ꢂC, 12 h;
(ii) CH3CO2Ag, Et3N, MeOH, 2 h, 61% (2 steps); b) (i) DIBAL-H, toluene, ꢁ78 ꢂC, 1.5 h; (ii)
tBuLi, THF, ꢁ78 ꢂC, 2 h, 69% (2 steps); c) H2, Pd/C, MeOH, 2 h, 93%; d) (i) DMP, CH2Cl2,
1 h; (ii) NaClO2, NaH2PO4, tBuOH/2-methyl-2-butene (2:1), 1 h; (iii) CH2N2 in ether,
0.5 h, 80%, (3 steps); e) (S)-CBS, toluene, 0 ꢂC, 4 h, 83%; f) 7, 2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP, THF, 12 h, 94%; g) (i) LiOH.H2O, THF/MeOH/H2O, (3:1:1), 3 h;
(ii) CH3NH2$HCl, DCC, HOBt, Et3N, CH2Cl2, 6 h, 92% (2 steps); h) (i) H2, Pd/C, MeOH, 2 h;
(ii) (COCl)2, DMSO, Et3N, CH2Cl2, ‒78 ꢂC, 1.5 h, 85% (2 steps); i) TFA, benzene, reflux, 3 d,
33% (54%, brsm).
O
O
O
NH
NH
O
O
+
O
16b
16c
g
minimized the protecting groups use in this synthesis. The crystal
structure of 4a provided additional support to the reassignment of
stereochemistry confirmed by the previous reports.
O
N
N
O
O
+
4. Experimental section
4.1. General methods
O
O
4b
4c
Anhydrous solvents were dried and distilled by standard
methods prior to use. Commercially available reagents were used
without further purification unless otherwise specified. All the re-
actions were performed under an atmosphere of nitrogen or argon
in oven-dried glassware under magnetic stirring. Column chro-
matography was carried out using silica gel (60e120 or 100e200 or
230e400 mesh) and the column was eluted with ethyl acetate/
petroleum ether or ethyl acetate. Analytical thin layer chromatog-
raphy (TLC) was performed on precoated silica gel-60 F254
Palmyrolide A
Scheme 4. Synthesis of palmyrolide A (4b) & 4c. a) H2, Pd/C, EtOH, rt, 3 h, 92%; b) (i)
DIBAL-H, toluene, ꢁ78 ꢂC, 1.5 h; (ii) PPh3CHCO2Et, CH2Cl2, 2 d, 77% (2 steps); c) 7, 2,4,6-
trichlorobenzoyl chloride, Et3N, DMAP, THF, 12 h, 94%; d) (i) LiOH$H2O, THF/MeOH/H2O
(3:1:1), 3 h; (ii) EtOCOCl, Et3N, THF, CH2N2, 3 h; (iii) CH3CO2Ag, dioxane/H2O, ultra-
sound irradiation, 0.5 h, 63% (3 steps); e) CH3NH2$HCl, HOBt, DCC, Et3N, CH2Cl2, 6 h,
94%; f) (i) H2, Pd/C, MeOH, 2 h, 94%; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢂC, 1.5 h, 92%;
g) TFA, benzene, reflux, 3 d, 55% brsm).

G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
2423
(0.5 mm) glass plates. Visualization of the spots on TLC plates was
achieved either by UV light or by staining the plates in methanolic
anisaldehyde/sulfuric acid/acetic acid or in methanol/phospho-
molybdic acid/sulfuric acid solution and charring on hot plate. 1H
NMR and 13C NMR were recorded in CDCl3 solvent on 500 MHz,
400 MHz, 300 MHz and 75 MHz, 125 MHz spectrometer, re-
spectively, at ambient temperature. Chemical shifts are reported as
CDCl3)
d
7.33e7.19 (m, 5H), 4.46 (s, 2H), 3.43 (t, J¼6.4 Hz, 2H), 2.33
(t, J¼7.5 Hz, 2H), 1.71e1.57 (m, 4H), 1.49e1.37 (m, 2H); 13C NMR
(75 MHz, CDCl3)
d 179.5, 138.2, 128.2, 127.5, 127.4, 72.6, 69.8, 33.8,
29.1, 25.5, 24.3; HRMS (ESI): calcd for C13H18O3Na [MþNa]þ
245.1153; found 245.1148.
4.1.2. (R)-4-Benzyl-3-(6-(benzyloxy)hexanoyl) oxazolidin-2-one
(13). To a stirred solution of compound 12 (19.9 g, 89.63 mmol)
in THF (224 mL) at ꢁ20 ꢂC was added Et3N (31.2 mL, 224.07 mmol)
followed by Piv-Cl (11 mL, 89.63 mmol). After stirring for 1 h at
ꢁ20 ꢂC, LiCl (5.7 g, 134.44 mmol) followed by (R)-4-benzyl-2-
oxazolidinone (15.9 g, 89.63 mmol) were added to it at the same
temperature. The stirring was continued for 1 h at ꢁ20 ꢂC and then
2 h at 0 ꢂC. It was then quenched with saturated NH4Cl solution and
extracted with EtOAc. The combined organic layers were washed
with brine, dried over Na2SO4, filtered and concentrated in vacuo.
Purification by column chromatography (10e12% EtOAc/hexane)
afforded compound 13 (29 g, 85%) as a syrupy liquid; Rf (20% EtOAc/
d
values relative to internal CHCl3 d 7.26 or TMS d
0.0 for 1H NMR
and CHCl3 d 77.0 for 13C NMR. 1H NMR data is recorded as follows:
chemical shift [multiplicity, coupling constant(s) J (Hz), relative
integral] where multiplicity is defined as: s¼singlet; d¼doublet;
t¼triplet; q¼quartet; dd¼doublet of doublet; ddd¼doublet of
double of doublet; dt¼doublet of triplet; m¼multiplet; br s¼broad
singlet. FTIR spectra were recorded on Bruker (Alpha) spectrometer.
Optical rotation values were measured on Horiba high sensitive
polarimeter using a 2 mL cell with a 10 mm path length. Mass
spectra were recorded on Micro Mass VG-7070H mass spectrom-
eter for ESI and are given in mass units (m/z). High resolution mass
spectra (HRMS) [ESIþ] were obtained using either a TOF or a double
focussing spectrometer.
hexanes) 0.5; [
a]
26.3 ꢁ28.1 (c 0.4, CHCl3); IR (Neat) nmax 2926, 2858,
D
1779, 1697, 1453, 1385, 1205, 1096, 740 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 7.34e7.15 (m, 10H), 4.60 (m, 1H), 4.47 (s, 2H), 4.19e4.09 (m,
4.1.1. 6-(Benzyloxy)hexanoic acid (12). Sodium hydride (8.13 g,
203.38 mmol) was added portion wise to a stirred solution of
hexane-1,6-diol (20 g, 169.49 mmol) in THF (507 mL) at 0 ꢂC under
nitrogen atmosphere. After the additions were completed, the re-
action mixture was stirred at 0 ꢂC for 15 min. Then benzylbromide
(20.2 mL, 169.49 mmol) was added slowly to the stirred reaction
mixture followed by the addition of TBAI (3.13 g, 8.47 mmol). After
stirring for 12 h at room temperature, the reaction mixture was
quenched at 0 ꢂC by slow addition of saturated aqueous NH4Cl
solution. THF was removed under reduced pressure and the prod-
uct was extracted from aqueous layer with EtOAc. The combined
organic layer was washed with brine, and dried over Na2SO4, fil-
tered, and concentrated in vacuo. Purification by column chroma-
tography (28e30% EtOAc/hexane) afforded 6-(benzyloxy)hexan-1-
ol (21.6 g, 72%, brsm (3 g)) as colourless oil; Rf (30% EtOAc/hexanes)
0.4; IR (Neat) nmax 3620, 2362,1693,1647,1516,1463,1352 cmꢁ1; 1H
2H), 3.46 (t, J¼6.7 Hz, 2H), 3.30 (dd, J¼13.5, 3.7 Hz, 1H), 3.01e2.80
(m, 2H), 2.69 (dd, J¼9.8, 13.5 Hz, 1H), 1.76e1.61 (m, 4H), 1.54e1.42
(m, 2H); 13C NMR (75 MHz, CDCl3)
d 173.1, 153.3, 138.5, 135.2, 129.3,
128.8, 128.2,127.5,127.4,127.2, 72.8, 70.0, 66.0, 55.0, 37.8, 35.3, 29.4,
25.6, 23.9; HRMS (ESI): calcd for C23H27NO4Na [MþNa]þ 404.1832;
found 404.1820.
4.1.3. (R)-6-(Benzyloxy)-2-methylhexanoic acid (7). To a solution of
compound 13 (29 g, 76.1 mmol) in dry THF (190 mL) at ꢁ78 ꢂC,
NaHMDS (114.2 mL, 1 M solution in THF) was added slowly drop
wise with stirring under nitrogen atmosphere. After stirring at
ꢁ78 ꢂC for 0.5 h, CH3I (14.2 mL, 228.3 mmol) was added into the
reaction mixture and stirred for an additional 3 h at ꢁ78 ꢂC. Then
the reaction mixture was quenched with saturated NH4Cl,
warmed to rt and extracted with EtOAc. The combined organic
extracts were washed with water, brine and dried over Na2SO4,
filtered and concentrated vacuo. Column chromatography (9e10%
EtOAc/hexane) gave pure (R)-4-benzyl-3-((R)-6-(benzyloxy)-2-
NMR (300 MHz, CDCl3)
J¼6.4 Hz, 2H), 3.43 (t, J¼6.4 Hz, 2H), 1.67e1.48 (m, 4H), 1.45e1.30
(m, 4H); 13C NMR (75 MHz, CDCl3)
38.4, 128.2, 127.5, 127.3, 72.7,
d 7.33e7.20 (m, 5H), 4.46 (s, 2H), 3.58 (t,
d
methylhexanoyl)oxazolidin-2-one (22.5 g, 75%) as a syrupy liq-
26.5
70.2, 62.5, 32.5, 29.5, 25.8, 25.4; HRMS (ESI); calcd for C13H20O2Na
uid; Rf (20% EtOAc/hexanes) 0.5; [
a
]
ꢁ43.8 (c 0.29, CHCl3); IR
1H
d 7.33e7.16 (m, 10H), 4.60 (m, 1H), 4.45 (s,
D
[MþNa]þ 231.1360; found 231.1353.
(Neat) nmax 2936, 2861, 1704, 1458, 1235, 1098, 698 cmꢁ1
NMR (500 MHz, CDCl3)
;
To a solution of oxalyl chloride (18.1 mL, 207.38 mmol) in dry
CH2Cl2 (460 mL) at ꢁ78 ꢂC, DMSO (29.4 mL, 414.76 mmol) was
added slowly in drop wise manner, with stirring under nitrogen
atmosphere. After 20 min stirring, compound (21.6 g, 103.69 mmol,
dissolved in 60 mL of dry CH2Cl2) was added into the reaction
mixture. After 0.5 h of stirring at ꢁ78 ꢂC, Et3N (72.1 mL,
518.45 mmol) was added and stirred for another 15 min at ꢁ78 ꢂC
and then for 15 min at 0 ꢂC. The reaction mixture was quenched
with water and extracted with EtOAc. The combined organic layers
were washed with water, brine, dried over Na2SO4, filtered and
concentrated in vacuo. The aldehyde (19.7 g, 92%) thus obtained,
was directly used after flash chromatography (5e6% EtOAc/hexane)
for the next reaction. Rf (10% EtOAc/hexane) 0.5.
2H), 4.14e4.09 (m, 2H), 3.69 (m, 1H), 3.46e3.40 (dt, J¼6.8, 2.9 Hz,
2H), 3.27 (dd, J¼12.7, 2.9 Hz, 1H), 2.70 (dd, J¼13.7, 9.8 Hz, 1H),
1.75 (m, 1H), 1.65e1.56 (m, 2H), 1.47e1.35 (m, 3H), 1.21 (d,
J¼6.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 176.9, 152.8, 138.4,
135.1, 129.2, 128.7, 128.1, 127.4, 127.2, 127.1, 72.6, 69.9, 65.7, 55.1,
37.6, 37.4, 32.9, 29.5, 23.7, 17.2; HRMS (ESI): calcd for
C24H29NO4Na [MþNa]þ 418.1994; found 418.1984.
In to a flask was added (R)-4-benzyl-3-((R)-6-(benzyloxy)-2-
methylhexanoyl)oxazolidin-2-one (22.5 g, 57.03 mmol), THF
(243 mL), water (41 mL). The homogeneous solution was cooled in
an ice bath (0 ꢂC). Hydrogen peroxide (30%, 36.7 mL, 356.43 mmol)
and lithium hydroxide (5.98 g, 142.57 mmol) were combined,
mixed, and added to the imide solution. The mixture stirred (1.5 h),
allowed to warm to ambient temp (over another 1.5 h), returned to
the ice bath, quenched with saturated sodium sulfite (giving pH 8
solution), acidified with hydrochloric acid (6 N aqueous, to pH¼1),
extracted with EtOAc, and washed with water and brine, dried over
sodium sulfate. Volatiles were removed under reduced pressure
and further purified by column chromatography (16e18% EtOAc/
hexane) to afford pure 7 (12.8 g, 95%) as a white solid product; Rf
To a solution of aldehyde in t-BuOH/2-methyl-2-butene (265 mL
(2:1)) at rt, the mixture of NaClO2 (19.9 g, 219.88 mmol) and
NaH2PO4 (26.4 g, 219.88 mmol), dissolved in minimum amount of
water, was added. After being stirred for 1 h, the solvent was re-
moved in rotatory evaporator and the residue was extracted with
EtOAc. The combined organic extracts were washed with water,
brine and dried over Na2SO4, filtered and concentrated in vacuo.
Purification by column chromatography (15% EtOAc/hexane)
afforded pure compound 12 (19.9 g, 94%) as a colourless liquid; Rf
(30% EtOAc/hexanes) 0.4; IR (Neat) nmax 2932, 2860, 1705, 1453,
(30% EtOAc/hexanes) 0.4; mp 60e62 ꢂC; [
a
]
D
26.6 ꢁ8.1 (c 1.0, CHCl3);
IR (Neat) nmax 2934, 2860, 2362, 2333, 1778, 1695, 1455, 1385, 1209,
1411, 1363, 1204, 1094, 1027, 940, 698 cmꢁ1
;
1H NMR (300 MHz,
1098, 699 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 7.34e7.19 (m, 5H),

2424
G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
4.46 (s, 2H), 3.43 (t, J¼6.7 Hz, 2H), 2.43 (m, 1H), 1.76e1.53 (m, 3H),
1.50e1.35 (m, 3H), 1.18 (d, J¼6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3)
(1.4 g, 90%) as colourless oil Rf (20% EtOAc/hexanes) 0.5, which was
used in the next step without any characterization.
d
183.0, 138.4, 128.2, 127.5, 127.4, 72.8, 69.9, 39.2, 33.1, 29.5, 23.7,
To a solution of lactol (1.4 g, 8.86 mmol) in dry CH2Cl2 (27 mL),
was added (carbethoxymethylene)triphenylphosphorane (15.5 g,
44.3 mmol). The reaction mixture was then allowed to reflux for 2
days. The reaction mixture was allowed to rt and concentrated in
vacuo. The residue was purified by column chromatography (9%
EtOAc/hexanes) to furnish unsaturated ester (ꢀ)-14 (1.73 g, 86%) as
yellow colour oil; Rf (20% EtOAc/hexanes) 0.5; IR (Neat) nmax 2927,
16.7; HRMS (ESI): calcd for C14H20O3Na [MþNa]þ 259.1304; found
259.1295.
4.1.4. Ethyl 4-hydroxy-5,5-dimethyl-2-methylenehexanoate
((ꢀ)-11). To a solution of trimethylacetaldehyde (1 g, 11.6 mmol)
in a mixture of THF (34 mL) and saturated aqueous NH4Cl (138 mL)
was added zinc dust (4.5 g, 69.6 mmol), followed by the drop wise
addition of ethyl 2-bromomethyl acrylate (2.9 g, 15.08 mmol) at
0 ꢂC. The mixture was stirred for 1 h at rt, the solids were filtered by
using sintered funnel with Celite, washed with EtOAc. The layers
were separated and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with brine and dried
with Na2SO4, filtered and concentrated in vacuo. Purification of the
residue by column chromatography (5% EtOAc/hexane) to furnish
homo allylic alcohol (ꢀ)-11 (2.18 g, 94%) as colourless liquid; Rf (10%
1707, 1648, 1516, 1464, 1368, 1283, 1180, 1077, 982 cmꢁ1
;
1H NMR
(300 MHz, CDCl3)
d
6.93 (dd, J¼15.6, 7.3 Hz, 1H), 5.77 (d, J¼15.6 Hz
1H), 4.16 (q, J¼7.1 Hz, 2H), 3.27 (dd, J¼9.6, 2.0 Hz, 1H), 2.57 (m, 1H),
1.51e1.33 (m, 2H), 1.29 (t, J¼7.1 Hz, 3H), 1.08 (d, J¼6.6 Hz, 3H), 0.89
(s, 9H); 13C NMR (75 MHz, CDCl3)
d 167.0, 155.3, 118.9, 76.9, 60.1,
37.6, 34.9, 33.3, 25.6, 17.9, 14.2; HRMS (ESI): calcd for C13H25O3
[MþH]þ 229.1798; found 229.1789.
4.1.8. Synthesis of compound ((ꢀ)-8). A solution of unsaturated
ester (ꢀ)-14 (1.7 g, 7.5 mmol) in EtOH (23 mL) was hydrogenated at
1 atmospheric balloon pressure in the presence of catalytic amount
of 10% Pd/C (170 mg) for 2 h. The mixture was then filtered through
pad of Celite, washed with EtOAc, evaporated and purified by col-
umn chromatography (10% EtOAc/hexane) to furnish the saturated
alcoholic ester (ꢀ)-8 (1.6 g, 93%) as colourless liquid; Rf (20% EtOAc/
hexanes) 0.6; IR (Neat) nmax 2957, 1736, 1516, 1371, 1258, 1173, 1099,
EtOAc/hexanes) 0.5; IR (Neat) nmax 2969,1712,1197, 1146, 674 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
6.20 (d, J¼1.5 Hz, 1H), 5.64 (d, J¼1.5 Hz,
1H), 4.26e4.16 (q, J¼6.7 Hz, 2H), 3.27 (dd, J¼9.8, 1.5, Hz 1H), 2.61
(dd, J¼13.5, 1.5 Hz, 1H), 2.14 (dd, J¼13.5, 9.8 Hz, 1H), 1.32 (t,
J¼6.7 Hz, 3H), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 167.7, 138.7,
126.9, 78.4, 60.8, 35.0, 34.9, 25.5, 14.0; HRMS (ESI): calcd for
C11H20O3Na [MþNa]þ 223.1304; found 223.1301.
1032, 669 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.10 (q, J¼7.1 Hz, 2H),
4.1.5. tert-Butyl-3-methylenedihydrofuran-2(3H)-one ((ꢀ)-10). To
a stirred solution of alcohol (ꢀ)-11 (2.18 g, 10.9 mmol) in toluene
(22 mL) at rt, was added p-toluenesulfonicacid (188 mg, 1.09 mmol)
and allowed the reaction mixture to stir at rt for 2 h. The reaction
mixture was quenched by the addition of H2O and extracted with
EtOAc. The organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by column chromatography (5% EtOAc/hexane) to furnish
unsaturated lactone (ꢀ)-10 (1.66 g, 99%) as a colourless liquid; Rf
(10% EtOAc/hexanes) 0.5; IR (Neat) nmax 2963, 1759, 1475, 1399,
3.24 (dd, J¼10.3, 1.7 Hz, 1H), 2.35e2.25 (m, 2H), 1.76e1.43 (m, 4H),
1.39e1.11 (m, 1H), 1.26 (t, J¼7.1 Hz, 3H), 0.91 (d, J¼6.2 Hz, 3H), 0.88
(s, 1H); 13C NMR (75 MHz, CDCl3)
d 174.0, 77.1, 60.2, 38.4, 34.7, 33.1,
32.1, 29.3, 25.6, 18.6, 14.1; HRMS (ESI): calcd for C13H26O3Na
[MþNa]þ 253.1774; found 253.1771.
4.1.9. Synthesis of compounds 6 & 6a. A solution of acid 7 (600 mg,
2.54 mmol) in dry THF (50 mL) was cooled to 0 ꢂC under N2. Then,
triethylamine (0.9 mL, 6.34 mmol) and 2,4,6-trichlorobenzoyl
chloride (0.8 mL, 5.08 mmol) were added drop wise, followed by
stirring at rt for 2 h. Subsequently, a solution of alcohol (ꢀ)-8
(584 mg, 2.54 mmol) and DMAP (775 mg, 6.34 mmol) in dry THF
(26 mL) was added drop wise at 0 ꢂC. The mixture was then stirred at
rt for 12 h. Reaction mixture was quenched with water and extracted
with EtOAc, washed with brine, dried over sodium sulfate. Volatiles
were removed under reduced pressure and purification by column
chromatography (4e5% EtOAc/hexanes) afforded inseparable di-
astereomeric mixture 6 & 6a (dr 1:1, 1.04 g, 94%) as a colourless
liquid; Rf (10% EtOAc/hexanes) 0.5; IR (Neat) nmax 2963, 2866, 1730,
1338, 1280, 1249, 1131, 995, 813 cmꢁ1
6.18 (t, J¼2.9 Hz, 1H), 5.58 (t, J¼2.9 Hz, 1H), 4.18 (t, J¼7.3 Hz, 1H),
2.85 (m, 1H), 2.70 (m, 1H), 0.95 (s, 9H); 13C NMR (75 MHz, CDCl3)
;
1H NMR (500 MHz, CDCl3)
d
d
170.3, 135.0, 121.4, 84.4, 34.0, 28.6, 24.4; HRMS (ESI): calcd for
C9H15O2 [MþH]þ 155.1066; found 155.1064.
4.1.6. Synthesis of compound ((ꢀ)-9). A solution of lactone (ꢀ)-10
(1.66 g, 10.77 mmol) in EtOH (32 mL) was hydrogenated at 1 at-
mospheric balloon pressure in the presence of catalytic amount of
10% Pd/C (161 mg) for 2 h. The mixture was then filtered through
pad of Celite, washed with EtOAc, evaporated and purified by col-
umn chromatography (6% EtOAc/hexane) to afford exclusively syn
product (ꢀ)-9 (1.54 g, 92%) as a colourless liquid; Rf (10% EtOAc/
hexanes) 0.5; IR (Neat) nmax 2964, 2877, 1766, 1459, 1368, 1168,
1461, 1370, 1256, 1169, 1031, 738 cmꢁ1 1H NMR (500 MHz, CDCl3)
;
d
7.32e7.19 (m, 5H), 4.80 (dd, J¼10.0, 1.0 Hz, 1H), 4.45 (s, 2H), 4.07
(2q, J¼7.0 Hz, 2H), 3.42 (t, J¼6.0 Hz, 2H), 2.40 (m, 1H), 2.27e2.19 (m,
2H), 1.69 (m, 1H), 1.63e1.43 (m, 5H), 1.42e1.33 (m, 3H), 1.28 (m, 1H),
1.24 (2t, J¼7.0 Hz, 3H),1.15 (2d, J¼7.0 Hz, 3H), 0.91 (2d, J¼6.0 Hz, 3H),
1048, 994, 931 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.07 (dd, J¼10.9,
0.88 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 176.3, 173.6, 138.5, 128.2,
5.4 Hz, 1H), 2.68 (m, 1H), 2.28 (ddd, J¼12.4, 8.5, 5.4 Hz, 1H), 1.60 (m,
127.4, 127.3, 77.6, 72.7, 70.0, 60.1, 39.8, 36.7, 36.6, 34.4, 34.3, 33.3,
32.9, 32.0, 29.5, 29.0, 25.8, 23.9, 18.5, 17.3, 17.2, 14.1; HRMS (ESI):
calcd for C27H44O5Na [MþNa]þ 471.3081; found 471.3075.
1H), 1.27 (d, J¼7.1 Hz, 3H), 0.95 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
179.3, 85.4, 35.7, 32.8, 31.7, 24.6, 14.6; HRMS (ESI): calcd for
C9H17O2 [MþH]þ 157.1223; found 157.1223.
4.1.10. Synthesis of compounds 15 & 15a. The ester compounds 6 &
6a (1.04 g, 2.39 mmol) were taken in THF:MeOH:H2O (3:1:1,
7.5 mL), LiOH$H2O (401 mg, 9.56 mmol) was added at 0 ꢂC and the
reaction was allowed to stir for 3 h. The reaction mixture was
acidified to pH 2 with 1 N HCl and the residue was extracted with
EtOAc, washed with H2O and brine, organic layer dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (16e18% EtOAc/
hexane) to afford the acid (984 mg, 98%) as a colourless liquid; Rf
(30% EtOAc/hexanes) 0.3; IR (Neat) nmax 3648, 2933, 2866, 1709,
4.1.7. Synthesis of compound ((ꢀ)-14). To a solution of lactone
(ꢀ)-9 (1.54 g, 9.87 mmol) in toluene at ꢁ78 ꢂC was added DIBAL-H
(7.9 mL, 1.5 M solution in toluene). The reaction mixture was stirred
for 0.5 h at that temperature and was quenched by the addition of
methanol (2 mL). The reaction mixture was then allowed to warm
up to rt and diluted with EtOAc added saturated solution of sodium
potassium tartrate (15 mL) and stirred for 1 h, filtered. The com-
pound was extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Column
chromatography purification (11% EtOAc/hexanes) afforded lactol
1460, 1370, 1169, 1099, 960, 932 cmꢁ1 1H NMR (300 MHz, CDCl3)
;

G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
2425
d
7.37e7.23 (m, 5H), 4.83 (dd, J¼10.5, 1.5 Hz, 1H), 4.51 (d, J¼7.5 Hz,
(130 mg) for 2 h. The mixture was then filtered through pad of
Celite, washed with EtOAc, evaporated and purified by column
chromatography (75e80% EtOAc) to afford the alcohol (476 mg,
93%) as colourless liquid; Rf (EtOAc) 0.4; IR (Neat) nmax 3302, 2929,
2H), 3.47 (t, J¼6.8 Hz, 2H), 2.43 (m, 1H), 2.32 (t, J¼6.7 Hz, 2H),
1.77e1.46 (m, 6H), 1.45e1.19 (m, 5H), 1.15 (d, J¼6.7 Hz, 3H), 0.92 (m,
3H), 0.88 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 179.3, 178.7, 176.5,
176.4, 138.4, 138.1, 128.3, 127.7, 127.6, 127.5, 127.4, 77.7, 72.7, 72.6,
70.0, 69.9, 40.0, 39.9, 36.8, 34.5, 34.4, 33.5, 33.4, 32.8, 32.7, 31.7,
29.5, 29.4, 28.9, 28.8, 25.9, 24.0, 18.6, 17.5, 17.4; HRMS (ESI): calcd
for C25H40O5Na [MþNa]þ 443.2768; found 443.2755.
2867, 1724, 1647, 1549, 1461, 1372, 1163, 1070, 957 cmꢁ1 1H NMR
;
(500 MHz, CDCl3)
d
5.71 (br,1H), 4.81 (dd, J¼10.5,1.6 Hz,1H), 3.61 (t,
J¼6.4 Hz, 2H), 2.78 (s, 3H), 2.45 (m, 1H), 2.23 (br s, 1H), 2.12 (t,
J¼7.2 Hz, 2H), 1.71 (m, 1H), 1.66e1.49 (m, 4H), 1.47e1.35 (m, 2H),
1.28 (m, 1H), 1.24e1.13 (m, 7H), 0.89 (d, J¼6.4 Hz, 3H), 0.86 (s, 9H);
To the acid compound (984 mg, 2.34 mmol) in dry THF (10 mL),
triethylamine (0.4 mL, 2.81 mmol) and ethylchloroformate
(0.25 mL, 2.57 mmol) were added sequentially at ꢁ15 ꢂC, stirring
was continued for 15 min at the same temperature, then the so-
lution was warmed up to 0 ꢂC. A solution of diazomethane in
diethyl ether was added slowly at 0 ꢂC. Slightly yellow colour so-
lution was allowed to reach rt and was stirred for a further 3 h.
Excess diazomethane was decomposed by drop wise addition of
CH3CO2H. The mixture was washed with aq NaHCO3, aq NH4Cl and
brine solution. The organic layer was dried over Na2SO4, filtered,
and evaporated in vacuo, to afford diazo ketone (726 mg, 70%) as
yellow colour oil. Rf (20% EtOAc/hexanes) 0.4.
13C NMR (75 MHz, CDCl3)
d 176.8, 176.3, 174.1, 174.0, 78.0, 77.9, 62.3,
62.2, 40.5, 39.7, 37.7, 37.6, 36.9, 36.6, 36.4, 34.4, 33.6, 33.5, 32.6, 32.5,
29.4, 26.1, 25.8, 23.6, 23.4, 18.9, 17.6; HRMS (ESI): calcd for
C20H40O4N [MþH]þ 358.2951; found 358.2953.
To a solution of oxalyl chloride (0.2 mL, 2.66 mmol) in dry
CH2Cl2 (4 mL) at ꢁ78 ꢂC, DMSO (0.4 mL, 5.32 mmol) was added
slowly in drop wise manner, with stirring under nitrogen atmo-
sphere. After 20 min stirring, alcoholic compound (476 mg,
1.33 mmol), dissolved in dry CH2Cl2 (3 mL) was added in to the
reaction mixture. After 0.5 h of stirring at ꢁ78 ꢂC, Et3N (0.7 mL,
6.65 mmol) was added and stirred for another 15 min at ꢁ78 ꢂC and
then for 15 min at 0 ꢂC. The reaction mixture was quenched with
water and extracted with EtOAc. The combined organic layers were
washed with water, brine, dried over Na2SO4, filtered, and con-
centrated in vacuo, further purified by flash column chromatogra-
phy (60e65% EtOAc/hexanes) to furnish the aldehydes 16 & 16a
(435 mg, 92%) as colourless liquid; Rf (EtOAc) 0.6; IR (Neat) nmax
The resulted diazo ketone (726 mg, 1.64) was dissolved in di-
oxane/water (5:1, 16 mL). After addition of silver acetate (27 mg,
0.164 mmol), the mixture was sonicated using an ultrasound
cleaning bath for 0.5 h. The reaction progress was monitored by TLC.
After completion of the reaction, the solution was acidified to pH 2
with 1 N HCl and extracted with EtOAc, the combined organic layers
were washed with water, brine solution and dried over Na2SO4,
concentrated in vacuo and further purified by column chromatog-
raphy (20% EtOAc/hexane) to afford acids 15 & 15a (662 mg, 93%) as
a colourless liquid; Rf (30% EtOAc/hexanes) 0.4; IR (Neat) nmax 3620,
2960, 2867,1707,1516,1168,1103, 956, 692 cmꢁ1; 1H NMR (300 MHz,
2960, 1721, 1641, 1552, 1460, 1407, 1372, 1162, 1067, 958, 752 cmꢁ1
1H NMR (300 MHz, CDCl3)
9.77 (m, 1H), 5.74 (br, 1H), 4.83 (dd,
;
d
J¼10.5, 0.7 Hz, 1H), 2.80 (m, 3H), 2.52e2.40 (m, 3H), 2.17e2.09 (m,
2H),1.79e1.48 (m, 6H),1.48e1.13 (m, 5H),1.18 (d, J¼7.5 Hz, 3H), 0.90
(d, J¼6.0 Hz, 3H), 0.88 (m, 9H); 13C NMR (75 MHz, CDCl3)
d 202.0,
CDCl3)
d
7.38e7.27 (m, 5H), 4.83 (dd, J¼10.5,1.5 Hz,1H), 4.50 (s, 2H),
201.9, 175.7, 175.6, 173.6, 77.7, 43.2, 39.5, 39.3, 37.4, 37.3, 36.4, 36.3,
34.0, 32.5, 28.9, 25.8, 25.5, 23.0, 22.9, 19.4, 18.5, 17.1; HRMS (ESI):
calcd for C20H37O4NNa [MþNa]þ 378.2614; found 378.2612.
3.46 (t, J¼6.6 Hz, 2H), 2.43 (m,1H), 2.35e2.25 (m, 2H),1.77e1.47 (m,
6H), 1.48e1.18 (m, 7H), 1.15 (d, J¼6.9 Hz, 3H), 0.90 (d, J¼5.8 Hz, 3H),
0.87 (s, 9H); 13C NMR (125 MHz, CDCl3):
d 179.2, 176.4, 138.4, 128.2,
ꢀ
127.5, 127.4, 77.9, 72.7, 70.0, 39.9, 39.8, 37.4, 36.8, 34.5, 34.4, 34.1,
33.4, 29.5, 29.1, 25.9, 23.9, 22.2, 18.8, 17.3; HRMS (ESI): calcd for
C26H43O5 [MþH]þ 435.3150; found 435.3146.
4.1.13. Synthesis of 4 & 4a. A dried 4 (A) (1.07 g) molecular sieves
powder was taken in dry benzene (540 mL) under nitrogen, to this
reaction mixture, compounds 16 & 16a (200 mg, 0.56 mmol) in
benzene (20 mL) was cannulated, then trifluoroaceticacid (0.2 mL,
2.59 mmol) was added slowly drop wise to above reaction mixture
at rt, and then it was refluxed for 3 days. The solids were filtered out,
extracted with EtOAc. The combined organic layers were washed
with saturated NaHCO3, brine solution and dried over Na2SO4, fil-
tered, and concentrated in vacuo, further purified by column chro-
matography (11e13% EtOAc/hexanes) to afford the separable cyclic
products 4 as a liquid, 4a as a white gummy solid in 1:1.7 (4:4a) ratio
(62 mg, 55%, brsm (81 mg)). Rf (25% EtOAc/hexanes) 0.4.
4.1.11. Synthesis of compounds 5 & 5a. To a stirred solution of acid
compounds 15 & 15a (662 mg, 1.52 mmol) in dry CH2Cl2 (6 mL),
HOBt (214 mg, 1.58 mmol) was added followed by DCC (326 mg,
1.58 mmol). After 5 min, to this solution, methylamine hydrochlo-
ride (113 mg, 1.67 mmol) and triethylamine (0.3 mL, 2.28 mmol)
were added subsequently. The mixture was stirred at rt for 6 h. The
precipitated dicyclohexyl urea was removed by subsequent tritu-
ration with cold ethyl acetate and filtration. The EtOAc solution was
washed with 1 N HCl, saturated NaHCO3, and brine, dried over
Na2SO4, filtered and concentrated, further purified by column
chromatography (30e32% EtOAc/hexane) to afford the amide
compounds 5 & 5a (634 mg, 94%) as yellow colour oil; Rf (50%
EtOAc/hexanes) 0.4; IR (Neat) nmax 3302, 2929, 2867, 1724, 1647,
1549, 1461, 1372, 1163, 1070, 957 cmꢁ1; 1H NMR (300 MHz, CDCl3)
26.1
4.1.13.1. Data of compound 4. [
a
]
þ45.5 (c 0.56, CHCl3); IR
D
(Neat) nmax 2924, 1726, 1677, 1646, 1516, 1463, 1393, 1175, 1078, 940,
688 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
6.66 (d, J¼14.2 Hz, 1H), 5.14
(dt, J¼14.2, 7.1 Hz, 1H), 4.86 (dd, J¼10.2, 1.5 Hz, 1H), 3.07 (s, 3H),
2.63e2.53 (m, 2H), 2.46 (m, 1H), 2.22 (m, 1H), 2.12 (m, 1H), 1.89 (m,
1H), 1.82e1.55 (m, 4H), 1.38e1.24 (m, 3H), 1.20 (d, J¼7.1 Hz, 3H), 1.17
(m, 1H), 0.94 (d, J¼6.3 Hz, 3H), 0.91 (s, 9H); 13C NMR (75 MHz,
d
7.38e7.28 (m, 5H), 5.62 (br s,1H), 4.82 (dd, J¼10.5,1.5 Hz,1H), 4.50
(s, 2H), 3.47 (2t, J¼6.8 Hz, 2H), 2.76 (2d, J¼5.3 Hz, 3H), 2.43 (m, 1H),
2.14e2.04 (m, 2H), 1.76e1.46 (m, 6H), 1.45e1.19 (m, 7H), 1.16 (d,
CDCl3)
d 175.6, 172.6, 130.9, 113.0, 78.9, 37.9, 36.5, 36.3, 34.8, 33.8,
J¼7.5 Hz, 3H), 0.91e0.85 (m,12H); 13C NMR (75 MHz, CDCl3)
d
176.4,
32.9, 30.7, 27.6, 27.1, 26.0, 22.6, 20.5, 17.4; HRMS (ESI): calcd for
176.3, 173.7, 173.6, 138.4, 132.9, 132.8, 129.4, 128.2, 127.5, 127.4, 78.1,
78.0, 72.7, 70.1, 64.8, 64.7, 40.0, 39.8, 37.7, 37.6, 36.8, 36.7, 36.6, 34.5,
34.4, 33.4, 33.3, 33.2, 29.6, 29.5, 29.4, 29.3, 29.2, 28.6, 26.1, 25.9,
24.0, 23.9, 23.4, 23.4, 23.3, 23.2, 18.9, 17.4, 17.4; HRMS (ESI): calcd
for C27H46O4N [MþH]þ 448.3421; found 448.3423.
C20H36O3N [MþH]þ 338.2689; found 338.2689.
4.1.13.2. Data of compound 4a. Rf (20% EtOAc/hexanes) 0.4; mp
25.8
40e42 ꢂC: [
a]
ꢁ41.2 (c 0.16, CHCl3); IR (Neat) nmax 2923, 1727,
D
D
1673, 1645, 1516, 1462, 1387, 1334, 1167, 931 cmꢁ1
(500 MHz, CDCl3)
4.7 Hz, 1H), 4.78 (dd, J¼9.5, 0.8 Hz, 1H), 3.07 (s, 3H), 2.64 (dt, J¼13.4,
7.9 Hz, 1H), 2.52 (m, 1H), 2.33e2.21 (m, 2H), 2.16 (m, 1H), 1.92 (m,
1H), 1.76e1.67 (m, 2H), 1.44e1.32 (m, 2H), 1.28e1.20 (m, 3H), 1.23
;
1H NMR
d
6.68 (d, J¼13.4 Hz, 1H), 4.87 (ddd, J¼13.4, 10.3,
4.1.12. Synthesis of compounds 16 & 16a. The compounds 5 & 5a
(634 mg,1.43 mmol), in dry methanol (6 mL) were hydrogenated by
using 1 atmospheric balloon pressure in the presence of 20% Pd/C

2426
G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
(d, J¼7.1 Hz, 3H), 1.14 (m,1H), 0.94 (d, J¼4.7 Hz, 3H), 0.87 (s, 9H); 13
C
acids of 6b & 6c in a similar manner as compounds (15 & 15a). The
crude product was purified by column chromatography (20%
EtOAc/hexane) to afford acids (15b & 15c) (207 mg, 65% over two
steps) as a colourless liquid.
NMR (75 MHz, CDCl3)
d 175.8, 172.1, 129.8, 110.2, 78.6, 38.4, 36.9,
35.2, 34.8, 31.7, 31.6, 29.7, 29.0, 27.9 25.8, 23.2, 19.5, 19.3; HRMS
(ESI): calcd for C20H36O3N [MþH]þ 338.2689; found 338.2689.
4.1.14. Synthesis of compound (9). A solution of homo allylic alcohol
(ꢀ)-11 (245 mg, 1.225 mmol) in ethanol (4 mL) was hydrogenated
at 1 atmospheric balloon pressure in the presence of catalytic
amount of 10% Pd/C (50 mg) for 3 h. The mixture was then filtered
through pad of Celite, washed with EtOAc, evaporated and purified
by column chromatography (6% EtOAc/hexane) to afford 9 (syn:anti
1:1) product (176 mg, 92%) as a colourless liquid; Rf (10% EtOAc/
hexanes) 0.5; IR (Neat) nmax 2864, 1766, 1459, 1368, 1168, 1048,
4.1.19. Data of acids of 6b & 6c. The acids were prepared from 6b &
6c (335 mg, 0.747 mmol) in a similar manner as acids of 6 & 6a. The
crude product was purified by column chromatography (20%
EtOAc/hexane) to afford acids 6b & 6c (308 mg, 98%) as a colourless
liquid; Rf (30% EtOAc/hexanes) 0.4; IR (Neat) nmax 3648, 2961, 2868,
1722, 1458, 1370, 1169, 1100, 935, 697 cmꢁ1
CDCl3)
;
1H NMR (300 MHz,
d
7.39e7.23 (m, 5H), 4.83 (m, 1H), 4.50 (m, 2H), 3.46 (t, J¼6.4,
2H), 2.43 (m, 1H), 2.38e2.18 (m, 2H), 1.89 (m, 1H), 1.77e1.55 (m,
3H), 1.49e1.28 (m, 7H), 1.15 (d, J¼6.9 Hz, 3H), 0.91e0.86 (m, 12H);
994 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
4.22 (dd, J¼7.9, 6.6 Hz, 1H),
4.07 (dd, J¼10.9, 5.6 Hz, 1H), 2.76e2.60 (m, 2H), 2.34e2.18 (m, 2H),
1.82 (m, 1H), 1.60 (m, 1H), 1.32e1.25 (m, 6H), 0.95 (s, 9H), 0.94 (s,
13C NMR (75 MHz, CDCl3)
d 179.5, 179.3, 176.3, 138.4, 138.3, 128.2,
127.6, 127.5, 127.4, 77.9, 72.7, 70.0, 39.9, 39.8, 37.1, 34.6, 34.5, 33.4,
33.3, 31.6, 30.1, 29.5, 29.2, 29.1, 25.8, 23.9, 20.2, 17.4, 17.2; HRMS
(ESI): calcd for C25H40O5Na [MþNa]þ 443.2768; found 443.2746.
9H); 13C NMR (75 MHz, CDCl3)
d (180.3, 179.5, 85.7, 85.6, 36.0, 34.8,
34.0, 33.0, 31.9, 30.5, 24.8, 24.8, 16.5, 14.8); HRMS (ESI): calcd for
C9H17O2 [MþH]þ 157.1223; found 157.1222.
4.1.20. Data of 15b & 15c. Rf (30% EtOAc/hexanes) 0.4; IR (Neat) nmax
4.1.15. Synthesis of compound (14). Compound 14 was prepared
from 9 (176 mg,1.13 mmol) in a similar manner as compound (ꢀ)-14.
The crude product was purified by column chromatography (9%
EtOAc/hexanes) to furnish unsaturated ester 14 (195 mg, 77% over
two steps) as yellow colour oil; Rf (20% EtOAc/hexanes) 0.5; IR (Neat)
nmax 3489, 2960, 2873, 1709, 1650, 1471, 1369, 1276, 1177, 1037,
3620, 2959, 1722, 1458, 1369, 1168, 1102, 959, 670 cmꢁ1 1H NMR
;
(500MHz,CDCl3)d7.34e7.22(m, 5H),4.81(m,1H), 4.49(s,2H), 3.46(t,
J¼7.0 Hz, 2H), 2.43 (m,1H), 2.38e2.24 (m, 2H),1.70 (m,1H),1.65e1.58
(m, 3H), 1.55e1.45 (m, 2H), 1.44e1.29 (m, 6H), 1.15 (d, J¼7.0 Hz, 3H),
1.07 (m, 1H), 0.90e0.84 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 179.1,
176.4, 138.5, 128.2, 127.5, 127.4, 78.1, 72.8, 70.1, 40.0, 39.8, 37.2, 34.6,
34.5, 34.1, 33.4, 29.6, 29.2, 25.9, 23.9, 21.8, 20.5,17.3; HRMS (ESI): calcd
for C26H42O5Na [MþNa]þ 457.2924; found 457.2935.
985 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
6.99 (dd, J¼15.8, 7.5 Hz, 1H),
6.81 (dd, J¼15.8, 9.0 Hz, 1H), 5.83 (dd, J¼15.8, 10.5 Hz, 2H), 4.19 (m,
4H), 3.31 (dd, J¼9.8, 3.0 Hz, 1H), 3.15 (dd, J¼9.8, 3.0 Hz, 1H),
2.73e2.50 (m, 2H), 1.70 (br s, 1H), 1.54e1.35 (m, 4H), 1.33e1.25 (t,
J¼7.1 Hz, 6H),1.09 (t, J¼6.8 Hz, 6H), 0.89 (s, 9H), 0.88 (s, 9H); 13C NMR
4.1.21. Synthesis of compounds 5b & 5c. The diastereomers 5b & 5c
were prepared from 15b & 15c (207 mg, 0.476 mmol) in a similar
manner as compounds 5 & 5a. The crude product was purified by
column chromatography (30e32% EtOAc/hexane) to afford the am-
ide compounds 5b & 5c (200 mg, 94%) as yellow colour oil; Rf (50%
EtOAc/hexanes) 0.4; IR (Neat) nmax 3304, 2941, 2867,1724,1647,1547,
(75 MHz, CDCl3)
d 166.9, 166.7, 155.2, 153.8, 120.4, 118.7, 76.9, 76.8,
60.1, 37.8, 37.4, 34.8, 34.7, 33.6, 33.2, 25.5, 25.4, 20.7,17.8,14.1; HRMS
(ESI): calcd for C13H24O3Na [MþNa]þ 251.1617; found 251.1608.
4.1.16. Synthesis of compound (8). Compound 8 was prepared from
14 (195 mg, 0.855 mmol) in a similar manner as compound (ꢀ)-8.
The crude product was purified by column chromatography (10%
EtOAc/hexanes) to furnish saturated alcoholic ester (8) (183 mg,
93%) as yellow colour oil; Rf (20% EtOAc/hexanes) 0.6; IR (Neat) nmax
3495, 2957, 2872, 1730, 1469, 1372, 1183, 1099, 664 cmꢁ1; 1H NMR
1462, 1368, 1167, 671 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 7.37e7.24
(m, 5H), 6.12 (br s,1H), 4.75 (dd, J¼9.0, 3.0 Hz,1H), 4.49 (s, 2H), 3.46 (t,
J¼6.4 Hz, 2H), 2.79 (m, 3H), 2.45 (m, 1H), 2.21e1.99 (m, 2H), 1.88 (m,
1H), 1.80e1.56 (m, 4H), 1.53e1.20 (m, 7H), 1.16, (m, 3H), 1.02 (m, 1H),
0.89e0.85 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 176.9, 174.1, 138.5,
138.4, 128.2, 127.5, 127.4, 78.7, 72.8, 70.0, 40.0, 39.9, 37.6, 36.0, 34.5,
34.4, 33.8, 33.4, 29.6, 28.7, 26.1, 25.8, 23.9, 22.8, 20.7,17.3; HRMS (ESI):
calcd for C27H46O4N [MþH]þ 448.3421; found 448.3424.
(300 MHz, CDCl3)
d
4.13 (q, J¼7.1 Hz, 4H), 3.32 (m, 2H), 2.44e2.22 (m,
4H), 1.94e1.81 (m, 2H), 1.75e1.49 (m, 4H), 1.42e1.15 (m, 4H), 1.26 (t,
J¼7.1 Hz, 6H), 0.97e0.89 (m, 6H), 0.89 (m, 9H), 0.89 (m, 9H); 13C NMR
(75 MHz, CDCl3)
d
174.0, 173.8, 76.7, 76.5, 60.0, 59.9, 38.6, 38.2, 34.6,
4.1.22. Synthesis of 16b & 16c. Compounds 16b & 16c were pre-
pared from 5b & 5c (200 mg, 0.447 mmol) via alcohols of 5b & 5c in
a similar manner as compounds 16 & 16a. The crude product was
purified by column chromatography (60e65% EtOAc/hexanes) to
afford 16b & 16c (137 mg, 92%) as colourless liquid.
32.9, 31.9, 31.5, 29.8, 29.2, 29.1, 25.5, 20.4, 18.4, 13.9; HRMS (ESI):
calcd for C13H26O3Na [MþNa]þ 253.1774; found 253.1772.
4.1.17. Synthesis of compounds 6b & 6c. The diastereomers 6b & 6c
were prepared from 7 (188 mg, 0.795 mmol) & 8 (183 mg, 0.795) in
a similar manner as compounds 6 & 6a. The crude product was
purified by column chromatography (4e5% EtOAc/hexanes) to af-
ford inseparable diastereomeric mixture 6b & 6c (dr 1:1, 335 mg,
94%) as a colourless liquid; Rf (10% EtOAc/hexanes) 0.5; IR (Neat)
4.1.23. Data of alcohols of 5b & 5c. Alcohols were prepared from 5b
& 5c (200 mg, 0.447 mmol). The crude product was purified by
column chromatography (75e80% EtOAc/hexanes) to afford alco-
hols (150 mg, 94%) of 5b & 5c as colourless liquid; Rf (EtOAc) 0.4; IR
(Neat) nmax 3620, 3304, 2941, 2863, 1724, 1648, 1548, 1462, 1371,
nmax 2927, 2857, 1731, 1459, 1370, 1250, 1168, 1100, 694 cmꢁ1
NMR (300 MHz, CDCl3)
;
1H
d
7.38e7.24 (m, 5H), 4.81 (dd, J¼9.0, 3.0 Hz,
1165, 1070, 961, 673 cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 6.32e6.11
1H), 4.49 (s, 2H), 4.11 (q, J¼7.1 Hz, 2H), 3.46 (t, J¼6.4 Hz, 2H), 2.43
(m, 1H), 2.36e2.12 (m, 2H), 1.83 (m, 1H), 1.77e1.55 (m, 3H),
1.53e1.29 (m, 7H), 1.25 (t, J¼7.1 Hz, 3H), 1.16 (d, J¼6.9 Hz, 3H), 0.88
(br s, 1H), 4.78 (m, 1H), 3.64 (t, J¼6.2 Hz, 2H), 2.83e2.78 (m, 3H),
2.47 (m, 1H), 2.23e1.88 (m, 3H), 1.82e1.66 (m, 2H), 1.64e1.22 (m,
10H), 1.18 (d, J¼7.0 Hz, 3H), 1.0 (m, 1H), 0.91e0.84 (m, 12H); 13C
(m, 12H); 13C NMR (75 MHz, CDCl3)
d
176.3, 173.8, 138.5, 128.2,
NMR (75 MHz, CDCl3) d 176.9, 176.7, 174.0, 173.8, 78.4, 78.3, 62.1,
127.5, 127.4, 78.0, 72.8, 70.1, 60.1, 39.9, 39.8, 37.1, 34.6, 34.5, 33.4,
33.3, 30.4, 29.6, 29.4, 25.9, 2423.9, 20.3, 17.3, 14.1; HRMS (ESI): calcd
for C27H44O5Na [MþNa]þ 471.3081; found 471.3067.
62.0, 40.0, 39.8, 37.5, 37.4, 36.1, 36.0, 34.5, 34.4, 33.2, 33.1, 32.4, 32.3,
28.7, 26.0, 25.8, 23.4, 23.0, 22.8, 20.6, 17.6, 17.5, 17.3; HRMS (ESI):
calcd for C20H40O4N [MþH]þ 358.2951; found 358.2954.
4.1.18. Synthesis of compounds (15b & 15c). The diastereomers (15b
& 15c) were prepared from (6b & 6c) (335 mg, 0.747 mmol) via
4.1.24. Data of 16b & 16c. Rf (EtOAc) 0.6; IR (Neat) nmax 3414, 2956,
2923, 1727, 1647, 1559, 1462, 1367, 1259, 1165, 1076, 960 cmꢁ1 1H
;

G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
2427
NMR(300MHz,CDCl3)
d
9.77(m,1H),6.06(brs,1H), 4.77(m,1H), 2.81
DIBAL-H (22.2 mL, 1.5 M solution in toluene), the reaction mixture
was stirred for 10 min at that temp and was quenched by the ad-
dition of methanol (6.7 mL). The reaction mixture was then allowed
to warm up to rt and diluted with EtOAc, added saturated solution of
sodium potassium tartrate (80 mL) and stirred for 1 h, filtered. The
compound was extracted with EtOAc, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. Flash
column chromatography purification (5% EtOAc/hexanes) afforded
aldehyde (7 g, 90%) as colourless oil; Rf (10% EtOAc/hexanes) 0.5.
To a solution of aldehyde (7 g, 29.89 mmol) in dry THF (75 mL)
was added tert-BuLi (30 mL, 1.5 M solution in pentane) at ꢁ78 ꢂC,
and the mixture was stirred for 2 h under argon. The reaction
mixture was poured into aqueous solution of NH4Cl at 0 ꢂC,
extracted with EtOAc. The combined organic layers were washed
with water, brine solution and dried over Na2SO4, filtered, and
concentrated in vacuo. Purified by column chromatography (8e9%
EtOAc/hexanes) to furnish the required alcohol 18 (6.7 g) as yellow
(d, J¼4.5 Hz, 3H), 2.51e2.43 (m, 3H), 2.23e2.02 (m, 2H),1.83e1.59 (m,
4H),1.54e1.35 (m, 6H),1.21e1.17 (m, 3H),1.02 (m,1H), 0.92e0.86 (m,
12H); 13C NMR (75 MHz, CDCl3)
d 202.0, 176.4, 173.9, 78.7, 43.6, 39.9,
37.5, 36.0, 34.4, 32.8, 28.8, 26.1, 25.8, 22.8, 20.7, 19.7, 17.4, 17.3; HRMS
(ESI): calcd for C20H38O4N [MþH]þ 356.2795; found 356.2797.
4.1.25. Synthesis of 4b (palmyrolide A) & 4c. Compound 4b (pal-
myrolide A) & 4c were prepared from 16b & 16c (120 mg, 0.337) in
a similar manner as compounds 4 & 4a. The crude product was
purified by column chromatography (13e15% EtOAc/hexanes) to
afford the separable cyclic products 4b & 4c as a colourless liquid in
1:2 ratio (38 mg, 55% combined yield, brsm (48 mg)); Rf (20%
EtOAc/hexanes) 0.4.
4.1.25.1. Data of palmyrolide A (4b). Rf (25% EtOAc/hexanes) 0.4;
[
a]
26.5 ꢁ28.6 (c 0.52, CHCl3); IR (Neat) nmax 2924, 2855, 1725, 1674,
D
1644, 1462, 1374, 1246, 1177, 1124, 1073, 940 cmꢁ1
;
1H NMR
colour oil; Rf (15% EtOAc/hexanes) 0.5; [
a
]
26 þ20.0 (c 0.1, CHCl3); IR
D
(500 MHz, CDCl3)
d
6.47 (d, J¼14.1 Hz, 1H), 5.27 (dt, J¼14.1, 7.5 Hz,
(Neat) nmax 3436, 2929, 2860, 1631, 1454, 1363, 1104, 733 cmꢁ1; 1H
1H), 4.88 (dd, J¼11.3, 1.8 Hz, 1H), 3.04 (s, 3H), 2.48 (m, 1H),
2.43e2.33 (m, 2H), 2.33e2.23 (m, 2H), 1.86e1.71 (m, 3H), 1.71e1.53
(m, 2H), 1.48 (m, 1H), 1.42e1.31 (m, 2H), 1.21 (d, J¼7.5 Hz, 3H), 1.06
(m, 1H), 0.90 (d, J¼6.6 Hz, 3H), 0.86 (s, 9H); 13C NMR (75 MHz,
NMR (300 MHz, CDCl3) d 7.37e7.24 (m, 5H), 4.51 (s, 2H), 3.48 (t,
J¼6.4 Hz, 2H), 3.28 (m, 1H), 1.73e1.52 (m, 5H), 1.50e0.99 (m, 4H),
0.94 (d, J¼6.8 Hz, 3H), 0.88 (s, 9H); 13C NMR (75 MHz, CDCl3)
d
138.6,128.3,127.6,127.4, 77.5, 77.2, 72.8, 70.4, 39.2, 38.8, 38.1, 35.3,
CDCl3):
d
175.3, 172.9, 130.6, 117.3, 76.9, 38.8, 35.6, 35.2, 34.5, 34.4,
34.8, 34.7, 30.0, 29.9, 29.5, 25.7, 25.6, 23.6, 23.4, 20.9, 18.8; HRMS
32.8, 31.7, 29.3, 26.9, 26.0, 24.3, 20.6, 16.8; HRMS (ESI): calcd for
(ESI): calcd for C19H32O2Na [MþNa]þ 315.2294; found 315.2282.
C20H36O3N [MþH]þ 338.2689; found 338.2690.
4.1.28. (5R)-5,8,8-Trimethylnonane-1,7-diol (19). The compound 18
(6.7 g, 22.9 mmol), in dry methanol (69 mL) was debenzylated by
using 1 atmospheric H2 balloon pressure in the presence of 20% Pd/C
(1.34 g) for 2 h. The mixture was then filtered through pad of Celite,
washed with EtOAc, evaporated and purified by column chromatog-
26.2
4.1.25.2. Data of 4c. [
a]
þ4.3 (c 0.46, CHCl3); IR (Neat) nmax
D
2959, 2928, 1726, 1672, 1645, 1463, 1386, 1336, 1171, 1123,
934 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
6.62 (d, J¼14.1 Hz, 1H), 4.91
(ddd, J¼14.1, 9.4, 5.6 Hz,1H), 4.83 (dd, J¼9.4,1.9 Hz,1H), 3.04 (s, 3H),
2.59e2.41 (m, 3H), 2.31 (m, 1H), 2.19 (m, 1H), 1.98 (m, 1H), 1.78 (m,
1H), 1.65e1.53 (m, 2H), 1.48e1.38 (m, 3H), 1.34 (m, 1H), 1.25 (d,
J¼7.5 Hz, 3H), 0.98 (m, 1H), 0.87 (d, J¼6.6 Hz, 3H), 0.85 (s, 9H); 13C
raphy (25e28%EtOAc/hexanes)toafforddiolproduct19 (4.3g,93%)as
26.2
colourless liquid; Rf (40% EtOAc/hexanes) 0.4; [
a
]
þ8.8 (c 0.48,
D
CHCl3); IR (Neat) nmax 3361, 2935, 1693, 1626, 1516, 1465, 1112,
NMR (75 MHz, CDCl3)
d
175.3, 172.7, 129.7, 110.0, 76.3, 37.1, 36.4,
983 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
3.65 (t, J¼6.5 Hz, 2H), 3.29 (m,
35.3, 34.1, 33.4, 30.9, 29.6, 29.4, 27.3, 25.8, 24.8, 19.9, 19.1; HRMS
1H), 1.71e1.53 (m, 2H), 1.52e1.15 (m, 6H), 1.07 (m, 1H), 0.95 (d,
(ESI): calcd for C20H36O3N [MþH]þ 338.2689; found 338.2692.
J¼7.0 Hz, 3H), 0.89 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 77.4, 62.8, 39.1,
38.7, 38.0, 35.1, 34.8, 34.7, 32.9, 29.8, 29.5, 25.6, 23.1, 22.9, 20.9, 18.9;
4.1.26. (R)-Methyl 7-(benzyloxy)-3-methylheptanoate (17). The
compound 7 (12.8 g, 54.1 mmol) was dissolved in dry THF (216 mL),
triethylamine (9 mL, 64.92 mmol) and ethylchloroformate (7.8 mL,
59.5 mmol) were added sequentially at ꢁ15 ꢂC. Stirring was con-
tinued for 15 min at the same temp, and then the solution was
warmed up to 0 ꢂC. A solution of diazomethane in diethyl ether was
added slowly at 0 ꢂC, slightly yellow colour solution was stirred for
a further 12 h at 0 ꢂC. Excess of diazomethane was decomposed by
drop wise addition of CH3CO2H. The mixture was washed with satd
NaHCO3, satd NH4Cl and brine solution. The organic layer was dried
over Na2SO4, filtered, and evaporated in vacuo.
HRMS(ESI):calcdforC12H26O2Na [MþNa]þ 225.1825;found225.1821.
4.1.29. (R)-Methyl 5,8,8-trimethyl-7-oxononanoate (20). To a stirred
solution of diol 19 (4.3 g, 21.25 mmol) in CH2Cl2 (65 mL) was added
DMP (Dess-Martin periodinane, 19.8 g, 46.75 mmol) at 0 ꢂC and the
resulted solution was stirred at rt for 1 h. Then the reaction mixture
was quenched with 1:1 mixture of saturated NaHCO3 solution and
saturated Na2S2O3 solution and stirred for 15 min to get clear so-
lution, and then aqueous layer was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and purified by flash column chromatography (5%
EtOAc/hexanes) to furnish the aldehyde (3.7 g) as colourless liquid;
Rf (10% EtOAc/hexanes) 0.5.
To a solution of aldehyde (3.7 g,18.65 mmol) in t-BuOH/2-methyl-
2-butene (2:1, 52 mL) at rt, NaClO2 (3.9 g, 42.89 mmol) and NaH2PO4
(5.1 g, 42.89 mmol), were dissolved in minimum amount of water,
were added. After being stirred for 1 h, the solvent was removed in
rotatory evaporator and the residue was extracted with EtOAc. The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by column
chromatography (18e20% EtOAc/hexane) afforded pure acid com-
pound (3.75 g, 94%) as a colourless liquid; Rf (30% EtOAc/hexanes) 0.4.
To a stirred solution of acid (3.7 g, 17.26 mmol) in dry ether
(42 mL), was added CH2N2 in ether solution at 0 ꢂC, stirring was
continued for 0.5 h at the same temp. Excess of diazomethane was
decomposed by drop wise addition of CH3CO2H, extracted with
EtOAc. The combined organic layers were washed with water, brine
solution and dried over Na2SO4, filtered, and concentrated in vacuo.
To a solution of a-diazo ketone (9.6 g, 36.9 mmol) in anhydrous
CH3OH (520 mL) was added drop wise a solution of silver acetate
(1.85 g, 11.07 mmol) in triethylamine (41.1 mL, 0.29 mmol) under
nitrogen. The mixture was stirred at rt for 2 h. The solvent was
evaporated, and the residue was purified by column chromatog-
raphy (5% EtOAc/hexane). Rf (10% EtOAc/hexane) 0.5; [
a
]
26.5 þ8.1 (c
D
0.58, CHCl3); IR (Neat) nmax 2932, 2856, 1739, 1516, 1460, 1365, 1201,
1164, 696 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 7.37e7.24 (m, 5H),
4.50 (s, 2H), 3.65 (s, 3H), 3.46 (t, J¼6.6 Hz, 2H), 2.30 (dd, J¼14.3,
6.6 Hz, 1H), 2.11 (dd, J¼14.3, 8.8 Hz, 1H), 1.95 (m, 1H), 1.65e1.54 (m,
2H), 1.47e1.28 (m, 3H), 1.21 (m, 1H), 0.93 (d, J¼6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d 173.7, 138.5, 128.3, 127.5, 127.4, 72.8. 70.2, 51.3,
41.5, 36.4, 30.2, 29.8, 23.5 19.6; HRMS (ESI): calcd for C16H24O3
[MþNa]þ 287.1627 found 287.1648.
4.1.27. (5R)-9-(Benzyloxy)-2,2,5-trimethylnonan-3-ol (18). To a so-
lution of ester 17 (8.8 g, 33.3 mmol) in toluene at ꢁ78 ꢂC was added

2428
G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
Purified by column chromatography (5% EtOAc/hexanes) to furnish
d
7.38e7.24 (m, 5H), 6.09 (br s, 1H), 4.75 (dd, J¼9.8, 2.2 Hz, 1H), 4.50
the required ester 20 (3.8 g, 97%) as yellow colour oil; Rf (10% EtOAc/
(s, 2H), 3.46 (t, J¼6.4 Hz, 2H), 2.80 (d, J¼4.5 Hz, 3H), 2.45 (m, 1H),
2.21e2.01 (m, 2H), 1.83e1.57 (m, 6H), 1.53e1.33 (m, 5H), 1.26 (m,
1H), 1.16 (d, J¼7.5 Hz, 3H), 1.01 (m, 1H), 0.91e0.84 (m, 12H); 13C
25.8
hexanes) 0.5; [
a
]
ꢁ7.1 (c 0.6, CHCl3); IR (Neat) nmax 2958, 1739,
1H NMR
3.66 (s, 3H), 2.43e2.35 (m, 2H), 2.35e2.24 (m,
D
1704, 1464, 1365, 1249, 1198, 1167, 1060, 670 cmꢁ1
(500 MHz, CDCl3)
;
d
NMR (75 MHz, CDCl3): d 176.9, 173.9, 138.4, 128.2, 127.5, 127.4, 78.6,
2H), 2.06 (m, 1H), 1.71e1.54 (m, 2H), 1.29 (m, 1H), 1.17 (m, 1H), 1.12
72.8, 70.0, 40.0, 37.6, 36.0, 34.4, 33.4, 33.0, 29.6, 28.7, 26.1, 25.9, 24.0,
22.8, 20.8, 17.4; HRMS (ESI): calcd for C27H45O4NNa [MþNa]þ
470.3240; found 470.3223.
(s, 9H), 0.87 (d, J¼6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 215.3,
174.0, 51.4, 44.1, 43.6, 36.1, 34.0, 28.1, 26.2, 22.4, 19.6; HRMS (ESI):
calcd for C13H24O3Na [MþNa]þ 251.1623; found 251.1618.
4.1.34. Data of acid of 22. Acid of 22 was prepared from 22 (888 mg,
1.98 mmol) in a similar manner as 15 & 15a. The crude product was
purified by column chromatography (16e18% EtOAc/hexanes) to
4.1.30. (5R,7R)-Methyl 7-hydroxy-5,8,8-trimethylnonanoate (21). To
a stirred solution of (S)-CBS catalyst (1 M solution in toluene, 5 mL,
4.98 mmol) in dry toluene (34 mL), was added BH3.Me2S (1.6 mL,
16.6 mmol) at 0 ꢂC drop wise under nitrogen. After stirring for
10 min at 0 ꢂC, a solution of ketone 20 (3.8 g, 16.6 mmol) in 8 mL of
toluene was cannulated and stirring was continued for 4 h at the
same temperature. After completion, the reaction mixture was
quenched by careful drop wise addition of MeOH (60 mL), diluted
with saturated NH4Cl, stirred for 1 h and then extracted with EtOAc.
The combined organic layers were washed with water, brine and
dried over Na2SO4, and filtered. Purified by column chromatogra-
phy (12e14% EtOAc/hexanes) to furnish alcohol 21 and 21a (3.2 g)
(dr 89:11) as colourless liquid.
afford
(5R,7R)-7-(((R)-6-(benzyloxy)-2-methylhexanoyl)oxy)-
5,8,8-trimethylnonanoic acid (842 mg, 98%) as colourless oil; Rf
26.2
(30% EtOAc/hexanes) 0.3; [
nmax 3437, 2961, 2938, 1727, 1709, 1631, 1459, 1366, 1262, 1198, 1167,
960, 696 cmꢁ1; 1H NMR (300 MHz, CDCl3)
7.37e7.24 (m, 5H), 4.81
a
]
þ36.4 (c 0.53, CHCl3); IR (Neat)
D
d
(dd, J¼7.0, 4.3 Hz, 1H), 4.50 (s, 2H), 3.46 (t, J¼6.6 Hz, 2H), 2.43 (m,
1H), 2.37e2.26 (m, 2H), 1.78e1.24 (m, 12H), 1.15 (d, J¼7.0 Hz, 3H),
1.06 (1H), 0.94e0.83 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 179.1,
176.4, 138.5, 128.3, 127.5, 127.4, 78.1, 72.8, 70.1, 40.0, 37.2, 34.6, 34.5,
34.1, 33.4, 29.6, 29.2, 25.9, 24.0, 21.8, 20.5, 17.3; HRMS (ESI): calcd
for C26H42O5Na [MþNa]þ 457.2929; found 457.2927.
4.1.30.1. Data of 21. Rf (20% EtOAc/hexanes) 0.4; [
a
]
25.9 þ45.2 (c
4.1.35. Data of alcohol of 23. The alcohol of 23 was prepared from
23 (809 mg,1.82 mmol) in a similar manner as alcohol of 5 & 5a. The
crude product was purified by column chromatography (75e80%
EtOAc) to furnish the (R)-(3R,5R)-2,2,5-trimethyl-9-(methyl-
amino)-9-oxononan-3-yl-6-hydroxy-2-methylhexanoate (553 mg,
D
0.21, CHCl3); IR (Neat) nmax 3619, 2954, 1739, 1516, 1463, 1366, 1257,
1201,1169, 1071, 671 cmꢁ1; 1H NMR (300 MHz, CDCl3)
d 3.67 (s, 3H),
3.27 (dd, J¼10.0, 1.5 Hz, 1H) 2.40e2.22 (m, 2H), 1.80e1.32 (m, 6H),
1.24e1.0 (m, 2H), 0.95 (d, J¼6.6 Hz, 3H), 0.88 (s, 9H); 13C NMR
(75 MHz, CDCl3)
d
174.2, 77.4, 51.4, 39.0, 34.9, 34.8, 34.2, 29.6, 25.6,
92%) as colourless liquid; Rf (EtOAc) 0.4; [
a
]
27 þ40.0 (c 0.58, CHCl3);
D
22.2, 20.8; HRMS (ESI): calcd for C13H26O3Na [MþNa]þ 253.1774;
IR (Neat) nmax 3620, 3301, 2934, 1707, 1647, 1516, 1463, 1372, 1164,
found 253.1765.
1070, 959, 669 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d 6.02 (br s, 1H),
4.78 (dd, J¼9.9, 2.2 Hz, 1H), 3.64 (t, J¼6.6 Hz, 2H), 2.81 (d, J¼5.5 Hz,
3H), 2.47 (m, 1H), 2.20e2.05 (m, 2H), 1.80e1.64 (m, 4H), 1.62e1.54
(m, 2H), 1.52e1.33 (m, 5H), 1.28 (m, 1H), 1.18 (d, J¼6.6 Hz, 3H), 1.01
4.1.31. (5R,7S)-Methyl 7-hydroxy-5,8,8-trimethylnonanoate (21a). Rf
26.3
(20% EtOAc/hexanes) 0.4; [
a
]
þ53.6 (c 0.13, CHCl3); IR (Neat)
D
nmax 3613, 2947, 1737, 1510, 1473, 1352, 1257, 1169, 1071, 680 cmꢁ1
1H NMR (300 MHz, CDCl3)
3.67 (s, 3H), 3.29 (dd, J¼10.4, 2.1 Hz,
1H) 2.31 (t, J¼7.5 Hz, 2H), 1.76e1.56 (m, 3H), 1.39e1.13 (m, 4H),
0.91e0.87 (m, 12H); 13C NMR (125 MHz, CDCl3)
174.3, 77.2, 51.4,
;
(m, 1H), 0.91e0.85 (m, 12H); 13C NMR (75 MHz, CDCl3)
d 176.8,
d
174.0, 78.5, 62.3, 40.1, 37.5, 36.1, 34.4, 33.3, 32.4, 28.7, 26.1, 25.9,
23.5, 22.9, 20.7, 17.3; HRMS (ESI): calcd for C20H40O4N [MþH]þ
358.2951; found 358.2939.
d
38.6, 37.7, 34.8, 34.3, 29.3, 25.6, 22.4, 18.8; HRMS (ESI): calcd for
C13H26O3Na [MþNa]þ 253.1774; found 253.1770.
4.1.36. (R)-(3R,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl 2-methyl-6-oxohexanoate (24). The compound 24 was prepared
from alcohol of 23 (605 mg, 1.69 mmol) in a similar manner as 16 &
16a. The crude product was purified by flash column chromatog-
raphy (60e65% EtOAc/hexanes) to afford 24 (553 mg, 92%) as col-
4.1.32. (5R,7R)-Methyl
7-(((R)-6-(benzyloxy)-2-methylhexanoyl)
oxy)-5,8,8-trimethylnonanoate (22). The compound 22 was pre-
pared from 7 (500 mg, 2.115 mmol) & 21 (487 mg, 2.115) in a similar
manner as compounds 6 & 6a. The crude product was purified by
column chromatography (4e5% EtOAc/hexanes) to afford 22
ourless liquid; Rf (EtOAc) 0.6; [
a
]
26 þ39.1 (c 0.23, CHCl3); IR (Neat)
D
nmax 3414, 2956, 2923, 1727, 1647, 1559, 1462, 1367, 1259, 1165, 1076,
(888 mg, 94%) as a colourless liquid; Rf (10% EtOAc/hexanes) 0.5;
960 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 9.77 (s, 1H), 6.01 (br s, 1H),
26.5
[
a]
þ43.9 (c 0.37, CHCl3); IR (Neat) nmax 2963, 2866, 1739, 1727,
4.78 (dd, J¼8.8, 3.3 Hz, 1H), 2.81 (d, J¼4.4 Hz, 3H), 2.50e2.43 (m,
3H), 2.15 (m,1H), 2.09 (m,1H),1.80e1.59 (m, 4H),1.52e1.36 (m, 5H),
1.26 (m, 1H), 1.19 (d, J¼7.7 Hz, 3H), 1.02 (m, 1H), 0.91e0.84 (m, 12H);
D
1516, 1462, 1167, 1104, 671 cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
7.37e7.27 (m, 5H), 4.81 (dd, J¼6.7, 4.9 Hz, 1H), 4.49 (s, 2H), 3.66 (s,
3H), 3.46 (t, J¼6.6 Hz, 2H), 2.43 (m, 1H), 2.35e2.19 (m, 2H),
1.76e1.56 (m, 4H), 1.56e1.26 (m, 8H), 1.15 (d, J¼7.0 Hz, 3H), 1.05 (m,
13C NMR (75 MHz, CDCl3)
d 202.0, 176.4, 173.9, 78.7, 43.6, 39.9, 37.5,
36.0, 34.4, 32.8, 28.8, 26.1, 25.8, 22.8, 20.7, 19.7, 17.3; HRMS (ESI):
1H), 0.91e0.85 (m, 12H); 13C NMR (75 MHz, CDCl3)
d
176.3, 174.1,
calcd for C20H38O4N [MþH]þ 356.2795; found 356.2781.
138.6, 128.2, 127.5, 127.4, 78.0, 72.8, 70.1, 51.3, 40.0, 37.2, 34.7, 34.5,
34.2, 33.4, 29.6, 29.2, 25.9, 24.0, 22.0, 20.5, 17.3; HRMS (ESI): calcd
for C27H44O5Na [MþNa]þ 471.3081; found 471.3056.
4.1.37. Palmyrolide A (4b). Palmyrolide A (4b) was prepared from 24
(100 mg, 0.28 mmol) in a similar manner as 4 & 4a. The crude product
was purified by column chromatography (14e15% EtOAc/hexanes) to
afford Palmyrolide A (4b) (27 mg, 54%, brsm(47 mg))ascolourless oil.
4.1.33. (R)-(3R,5R)-2,2,5-Trimethyl-9-(methylamino)-9-oxononan-3-
yl-6-(benzyloxy)-2-methylhexanoate (23). The compound 23
(842 mg, 1.94 mmol) was prepared from acid of 22 in a similar
manner as 5 & 5a. The crude product was purified by column
chromatography (30e32% EtOAc/hexanes) to afford 23 (809 mg,
Acknowledgements
This work was financially supported by the Department of Sci-
ence and Technology (DST) New Delhi, India (Grant No. SR/S1/OC-
16/2010). The author (K.J.R.) wishes to thank UGC, New Delhi, India
for the award of research fellowship.
94%) as a yellow colour oil; Rf (50% EtOAc/hexanes) 0.4; [
a
]
26.1 þ43.3
D
(c 0.41, CHCl3); IR (Neat) nmax 3302, 2940, 2865, 1725, 1648, 1547,
1460, 1368, 1168, 1103, 698 cmꢁ1 1H NMR (300 MHz, CDCl3)
;

G. Sudhakar et al. / Tetrahedron 69 (2013) 2419e2429
2429
8. (a) Kennedy, J. W. J.; Hall, D. G. J. Org. Chem. 2004, 69, 4412e4428; (b) Du-
meunier, R.; Marko, I. E. Tetrahedron Lett. 2000, 41, 10219e10222.
Supplementary data
ꢁ
9. Similar exo-methylene-g-butyrolactone in enantiomerically pure form was
A supplementary data file (1H and 13C NMR) of the synthesized
compounds. Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2013.01.048.
reported by us (Ref. 7c), and some selected references of others: (a) Huang, L.;
Wang, Q.; Liu, X.; Jiang, H. Angew. Chem., Int. Ed. 2012, 51, 5696e5700; (b)
Suzuki, T.; Atsumi, J.; Sengoku, T.; Takahashi, M.; Yoda, H. J. Organomet. Chem.
2010, 695, 128e136; (c) Rauniyar, V.; Hall, D. G. J. Org. Chem. 2009, 74,
ꢁ
4236e4241; (d) Chataigner, I.; Zammattio, F.; Lebreton, J.; Viillieras, J. Tetra-
€
hedron 2008, 64, 2441e2455; (e) Adam, W.; Groer, P.; Moller, C. R. S. Tetrahe-
dron: Asymmetry 2000, 11, 2239e2243; (f) Komatsu, Y.; Sasaki, F.; Takei, S.;
Kitazume, T. J. Org. Chem. 1998, 63, 8058e8062.
References and notes
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11. Chemoselectivity was expected based on the stability of ester group at C(13) of
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Estevez, R. J.; Castedo, L. Tetrahedron 1995, 51, 10801e10810.
14. (a) CCDC 905005 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html. (b) Interestingly, we also found the X-ray crystal structure for
racemate (ꢀ)-4a, which might be obtained from epimerization at C(14) of 4.
CCDC 905006 contains the supplementary crystallographic data for this paper.
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15. (a) Patil, N. T.; Tilekar, J. N.; Dhavale, D. D. J. Org. Chem. 2001, 66, 1065e1074; (b)
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