Stereoselective synthesis of (R)-(?) and (S)-(+)-phoracantholide I from (R)-(+)-γ-valerolactone

Article abstract of DOI:10.1016/j.tetasy.2016.05.008

A concise total synthesis of (R)-(?)-phoracantholide I 1 and (S)-(+)-phoracantholide I 2 has been developed from (R)-(+)-γ-valerolactone 6. The key steps in the synthesis of these macrolides involved enzymatic reduction of Levulinic ester 4 by asymmetric dehydrogenase, Z-selective Wittig reaction of (4-carboxybutyl)triphenylphosphonium ylide 11 with lactol 7, and cyclization of seco-acid 8 using either a Yamaguchi lactonization protocol or a Mitsunobu protocol to afford (R)-(?)-phoracantholide I and (S)-(+)-phoracantholide I respectively.

Full text of DOI:10.1016/j.tetasy.2016.05.008

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (R)-(À) and (S)-(+)-phoracantholide I
from (R)-(+)-c-valerolactone
Rajender Datrika a,b, Srinivasa Reddy Kallam a, Sandip R. Khobare a, Vikas S. Gajare a,
Muralikrishna Kommi a, Rama Mohan H. a, Siddaiah Vidavalur b, Pratap T. V. a,
⇑
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
b Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise total synthesis of (R)-(À)-phoracantholide I 1 and (S)-(+)-phoracantholide I 2 has been
developed from (R)-(+)- -valerolactone 6. The key steps in the synthesis of these macrolides involved
enzymatic reduction of Levulinic ester 4 by asymmetric dehydrogenase, Z-selective Wittig reaction of
(4-carboxybutyl)triphenylphosphonium ylide 11 with lactol 7, and cyclization of seco-acid 8 using either
a Yamaguchi lactonization protocol or a Mitsunobu protocol to afford (R)-(À)-phoracantholide I and
(S)-(+)-phoracantholide I respectively.
Received 22 April 2015
Accepted 27 May 2015
Available online xxxx
c
This article is dedicated to the memory of
Dr. Kallam Anji Reddy, the founder of Dr.
Reddy’s Laboratories Ltd.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
O
O
c-Lactones are important structural entities and valuable
building blocks in the synthesis of natural products and biologi-
cally active molecules such as pheromones, polyketides and
prostaglandins.1 Considering the high stereoselectivity during Wit-
tig reactions of the corresponding lactol of enantiomerically pure
HO
Diplodialide B
O
Recifeiolide
Diplodialide A
c
-valerolactone, the latter become very good chiral synthons in
O
O
the synthesis of natural products.2 A variety of methods are used
OH
O
O
for the synthesis of enantiomerically pure
c-lactones that either
O
use stoichiometric or catalytic chiral reagent systems3 or enzymes
as part of a greener approach for the asymmetric hydrogenation4 of
O
OCH3
c
-keto esters. With so much progress being made in the field of
asymmetric reductions of
-keto esters using enzymes,5 it has
now become quite easy to obtain the chiral alcohols that afford
enantiomerically pure -valerolactones in large quantities starting
from -keto esters. The biological activity of macrolides stems
Lasiodiplodin
(R)-(-)-Phoracantholide J
(R)-(-)-phoracantholide I
3
1
c
O
O
O
O
c
c
from the presence of a macrocyclic ring that is either medium-
sized (7- to 11-membered) or large-sized (12-membered and
larger).6 These lactones are important structural motifs in a wide
range of biologically active natural products.7 A few examples of
simple monocyclic macrolides include Recifeioltide, Diplodialide
A and B, Lasiodiplodin, Phoracantholide I and Phoracantholide J,
and Patulolide A and C (Fig. 1).
OH
O
Patulolide C
Patulolide A
Figure 1. Monocyclic macrolides.
Mantillidae is a family of small frogs of Madagascar which are
characterized by the presence of femoral glands on the ventral
sides of the shanks of the males. These glands were found to
secrete the pheromones that attract female frogs.
Phoracantholide J was identified as one of the pheromones
secreted by these glands.8 Thus phoracantholides have gained the
attention of synthetic chemists. Several syntheses of (R)-(À)- and
⇑
Corresponding author. Fax: +91 (40) 44658699.
E-mail address: tvpratap@drreddys.com (T.V. Pratap).
http://dx.doi.org/10.1016/j.tetasy.2016.05.008
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Datrika, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.008

2
R. Datrika et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
asymmetric
O
O
dehydrogenase
HO
O
(R)
(Z)
O
(R)
ethyl levunate 4
6
8
OH
O
O
O
HO
Yamaguchi
Mitsunobu
(R)
O
(S)
O
(Z)
(R)
OH
(S)-(+)-phoracantholide I
(R)-(-)-phoracantholide I
2
1
8
Scheme 1. Retrosynthetic analysis of (R)-(À)- and (S)-(+)-phoracantholide I.
(S)-(+)-phoracantholide I 1 and 2, have been reported in the litera-
ture.9 Although these syntheses afforded the desired products in
high yield, they required the use of complex reagents, critical reac-
tion conditions and lengthy multistep synthetic sequences. Thus a
simple and scalable approach for their synthesis was sought.
As part of our efforts to synthesize macrolides of biological sig-
O
HO
O
O
(R)
OH
ylide 11
DiBAl-H
-78 °C
(R)
O
(Z)
(R)
base
OH
6
7
8
nificance using enantiomerically pure
c-valerolactone as a chiral
synthon, we herein report a facile approach for the selective total
synthesis of both (R)-(À) and (S)-(+)-phoracantholide I (1 and 2).
The retrosynthetic approach for synthesis of 1 and 2 is described
in Scheme 1. Thus 1 and 2 can be obtained either by Yamaguchi
lactonization or by Mitsunobu esterification of the seco-acid inter-
mediate (Z)-9-hydroxydec-5-enoic acid 8, a common. The interme-
diate seco-acid 8 has a Z-double bond crafted to facilitate the
intramolecular lactonization. The latter is synthesized with high
stereoselectivity via Wittig reaction of lactol 7 with (4-carboxy-
butyl)triphenyl phosphonium ylide 11. The lactol 7 intermediate
involved in the Wittig reaction can be obtained by DIBAL-H
-Br+Ph3P
OH
O
ylide 11 =
Scheme 3. Reagents and conditions: (a) DIBAL-H, DCM, À78 °C, 0.5 h, 91%; (b) 11,
Base, 0 °C, 82%.
Table 1
Z-Selective Wittig reaction condition
Lactol
Ylide 11 mol equiv
seco-acid 8
Yield (%)
Base (4.0 mol equiv)
reduction of corresponding (R)-(+)-
c-valerolactone 6. Synthesis of
O
1.0
1.0
65
61
KHMDS
NaHMDS
(R)-(+)- -valerolactone 6 can be traced to ethyl levulinate. Ethyl
c
OH
levulinate on enzymatic reduction with asymmetric dehydroge-
nase affords the corresponding enantiomerically pure alcohol 5.
1.0
2.0
2.0
2.0
1.2
59
82
74
69
56
LiHMDS
KHMDS
NaHMDS
LiHMDS
t-BuOK
7
2. Results and discussion
Our synthesis commenced with the enzymatic asymmetric
reduction of ethyl levulinate using asymmetric dehydrogenase in
presence of NADPH4 to provide alcohol 510 with high enantiomeric
excess (98.14% ee by GC).11 Lactonization of hydroxyl ester 5 using
methanolic HCl gave a lower yield, but obtained a good yield of
The Z-configuration of olefin 8 facilitates the lactonization pro-
cess by bringing the reactive sites together. The stage was now set
for the construction of macrocyclic ring. Yamaguchi lactonization
protocol14 on olefin 8 afforded lactone 9 with retention of configu-
ration of the secondary hydroxyl group while the Mitsunobu pro-
tocol15 would afford corresponding antipod 10 with inversion of
the stereogenic center.
(R)-(+)-
Amberlyst IR-120 H+ resin (Scheme 2). The obtained enantiomeri-
cally pure (R)-(+)- -valerolactone was reduced with DIBAL-H to
c-valerolactone 6 with either the use of catalytic PTSA or
c
the corresponding lactol 7. Lactol 7 upon Wittig reaction with
(4-carboxybutyl)triphenyl phosphonium ylide 1112 afforded the
Z-olefin with high stereoselectivity (Z:E = 99:1)13 and yield
(Scheme 3). The Z-selectivity and yield were studied with different
organic bases and molar equivalents of ylide (Table 1). Although all
of the bases mentioned in Table 1 afforded almost identical selec-
tivity, KHMDS afforded a higher yield when used in 4.0 equiv
against 2.0 equiv of ylide 11.
In the Yamaguchi lactonization (Scheme 4), dilution was found
to be one of the key factors to control the formation of dimer 12.
Therefore, studies were conducted to find appropriate dilution as
mentioned (Table 2). The dilution of 100:800 was found to give a
better ratio of monomer to dimer.
O
O
O
O
OH
O
b
a
O
O
(R)
O
HO
(R)
Yamaguchi
O
O
O
O
(Z)
(R)
O
4
5
6
O
OH
8
1
12
Scheme 2. Reagents and conditions: (a) asymmetric dehydrogenase enzyme,
NaDPH4, rt, pH: 6.8–7.2; 24 h, 74%; (b) PTSA/MeOH, rt, 20 h, 92% or Amberlyst IR-
120 resin, MeOH, rt, 40 h, 90%.
Scheme 4. Yamaguchi lactonization.
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R. Datrika et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 2
Yamaguchi cyclization
O
O
O
O
seco-Acid
Dilution* (vol)
Monomer 1 (%)
Dimer 12 (%)
8
8
8
100:100
100:400
100:800
15
65
95
85
35
5
H2-Pd/C
O
O
O
O
*
DMAP/toluene dilution versus mixed anhydride dilution.
12
13
Accordingly Yamaguchi lactonization was performed in
Scheme 6. Macrocyclic dimer of (R)-(À)-phoracantholide I; Reagents and condi-
tions: 10% Pd/C, H2, ethyl acetate, rt, 25 psi, 2 h, 82%.
100:800 dilution in the presence of 2,4,6-trichlorobenzoyl chloride,
triethylamine and DMAP to afford the unsaturated lactone 9 with
an (R)-configuration. On the other hand, lactonization in the pres-
ence of DIAD (diisopropyl azodicarboxylate) and triphenylphos-
phine afforded the corresponding unsaturated lactone 10, with
an (S)-configuration in good yield. Intermediates 9 and 10 individ-
ually when subjected to hydrogen pressure on Pd/C in ethyl acetate
furnished the title compounds (R)-(À)-phoracantholide I 1 and
(S)-(+)-phoracantholide I 2 respectively in good yield (Scheme 5).
Under these conditions, the corresponding dimeric impurity 12 is
also saturated to afford the dimeric by-product 13 (Scheme 6).
The latter was identified and characterized by spectroscopic data.
was performed at reduced pressure on a Buchi rotary evaporator.
1H and 13C NMR spectra were recorded in CDCl3 solution on a Var-
ian Gemini 200 and Brucker Avance 300 spectrometers. Chemical
shifts (d) are reported relative to TMS (d = 0.0) as an internal stan-
dard. Mass spectra were obtained on MS-EI, MS-ESI, HRMS mass
spectrometers of Agilent Technologies 1100 Series. Column chro-
matography was performed on silica gel (60–120 mesh) supplied
by Acme Chemical Co., India. TLC was performed on Merck
60 F-254 silica gel plates. IR (FT-IR) spectra were recorded either
on KBr pellets or neat as thin film or in CHCl3. Optical rotations
were recorded on a JASCO DIP-360 digital polarimeter.
3. Conclusion
4.2. Ethyl (R)-hydroxypentanoate 5
In conclusion, a highly stereoselective synthesis of (R)-(À)-
phoracantholide I 1 and (S)-(+)-phoracantholide I 2 has been
achieved in good yields. Cyclization of seco-acid 8 according to
the Yamaguchi lactonization furnished (R)-(À)-phoracantholide I
with retention of configuration while cyclization of seco-acid 8
according to the Mitsunobu lactonization furnished (S)-(+)-phora-
cantholide I with inversion of configuration. This synthesis for
these macrolides utilizes fairly inexpensive reagents and is an
environmentally friendly process. The application of this strategy
Synthesized from 50 g of Levulinic ester 4.10 Compound 5 was
obtained (37 g, 74%) as a pale yellow oil, enantiomer purity by
GC: 98.14% ee; [
a
]
24 = À12.2 (c 2.0, CHCl3); IR (Neat, cmÀ1): vmax
D
3417, 2972, 2933, 1733, 1299, 1267, 1094, 962; 1H NMR
(400 MHz, CDCl3): d 4.11 (q, 2H), 3.83 (d, 1H), 2.42 (t, 2H), 1.64
(m, 3H), 1.2 (m, 6H); 13C NMR (100 MHz, CDCl3): d 14.15, 23.47,
30.76, 33.83, 60.45, 67.31, 174.12; HRMS Calcd for C7H15O3 (M
+H+): 147.1021, found: 147.1026.
of using enantiomerically pure
c-valerolactone in the synthesis
of complex macrolides is currently underway.
4.3. (R)-(+)-c-Valerolactone 6
4. Experimental
4.1. General
Ethyl (R)-hydroxypentanoate 5 (20 g, 0.137 mol) was treated
with PTSA (0.02 g) in anhydrous methanol (200 mL) at room tem-
perature for 20 h. The reaction mass was quenched with TEA
(3.0 mL) and the solvent was evaporated. The crude residue
obtained was diluted with MTBE (240 mL) and washed with satd
NaHCO3 (240 mL). The solvent was removed under reduced pres-
Reactions were conducted under N2 in anhydrous solvents such
as DCM, THF, DMSO, CH3CN, Et2O, Toluene, and EtOAc. All reactions
were monitored by TLC (silica-coated plates and visualized under
UV light, in case of non UV-active intermediates used suitable
charring solution). Yields refer to the isolation of compounds after
chromatography and spectroscopic (1H and 13C NMR) analysis of
homogeneous material. Air-sensitive reagents were transferred
by syringe or a double-ended needle. Evaporation of the solvents
sure and the crude residue was further purified by fraction distilla-
22
tion to afford compound 6 (13 g, 92%) as a colorless oil; [
a
]
D
=
+37.05 (c 1.0, MeOH); IR (Neat, cmÀ1); vmax 2980, 1771; 1H NMR
(400 MHz, CDCl3): d 1.41 (d, J = 6.4 Hz, 3H), 1.78–1.88 (m, 1H),
2.09–2.40 (m, 1H), 2.53–2.57 (m, 2H), 4.62 (q, J = 6.4 Hz, 1H); 13C
O
O
a
b
(R)
O
O
O
HO
(R)-(-)-phoracantholide I
(R)-(-)-iso-phoracantholide J
(Z)
1
9
(R)
OH
O
O
O
8
c
d
(S)
O
(S)-(+)-iso-phoracantholide J
(S)-(+)-phoracantholide I
10
2
Scheme 5. Reagents and conditions: (a) Yamaguchi lactonization: 2,4,6-trichlorobenzoyl chloride, TEA, DMAP, toluene, 16 h, rt, 69%; (b) 10% Pd/C, H2, ethyl acetate, rt, 25 psi,
2 h, 85%; (c) Mitsunobu reaction: DIAD/TPP, 0 °C, 14 h, 63%; (d) 10% Pd/C, H2, ethyl acetate, rt, 25 psi, 2 h, 80%.
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4
R. Datrika et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
NMR (100 MHz, CDCl3): d 20.79, 28.85, 29.44, 77.09, 177.14; GC–
MS: (100, M+).
0 °C, after which seco-acid 8 (0.3 g, 1.6 mmol) was added as a dilute
solution in toluene (180 mL) over a period of 14 h. After comple-
tion of the reaction, the reaction mass was washed with water
(50 mL), and the solvent was evaporated under reduced pressure
and purified by flash chromatography to afford 10 (0.17 g, 63%):
4.4. (R,Z)-9-Hydroxydec-5-enoic acid 8
To a solution of lactone 6 (1.2 g. 0.012 mol) in DCM (24 mL) was
added 1.6 M DIBAL-H (9.6 mL, 0.014 mol) at À78 °C and reaction
mixture was stirred for 0.5 h. After completion of the reaction,
the reaction was quenched with methanol. The reaction mass
was treated with a saturated solution of sodium potassium tartrate
solution (24 mL) and stirred for 2 h at room temperature. The pro-
duct was extracted in DCM (24 mL), the combined organic layers
washed with brine and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to afford lactol 7 (1.1 g,
91%) as a colorless oil. It was used in the next stage without further
purification.
To a solution of ylide 11 (8.69 g, 0.019 mol) in THF (15 mL) at
0–5 °C was added 20% KHMDS (39 mL, 0.0294 mol) under an inert
atmosphere. After maintaining the temperature of the reaction at
0 °C for 10–15 min, the temperature of the reaction mass was
allowed to return to room temperature, and stirred for 15–
30 min. The reaction mass was cooled to 0 °C after which was
added lactol 7 (1.0 g, 0.01 mol) as a solution in THF (15 mL) under
an inert atmosphere. After completion of reaction, the reaction
mass was quenched with ice cold water (30 mL), and washed with
MTBE (2 Â 25 mL). The pH of the obtained aqueous layer was
adjusted to 2–3 using 3 M HCl and the product was extracted with
ethyl acetate (2 Â 25 mL). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4 and the sol-
vent was removed under reduced pressure. The crude was purified
by flash chromatography to afford 8 (1.5 g, 82%) as a colorless oil,
Colorless oil; [a]
22 = +94.2 (c 0.8, CHCl3); IR (Neat, cmÀ1); vmax
D
2999, 2966, 2934, 2914, 2873, 1724, 1658, 1224, 868; 1H NMR
(400 MHz, CDCl3): d 5.33 (m, 2H), 4.80–4.85 (m, 1H), 1.61–2.35
(m, 10H), 1.21 (d, J = 5.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
173.02, 129.60, 129.41, 70.17, 35.88, 33.63, 26.45, 24.43, 23.25,
20.27; HRMS Calcd for
169.1224.
C
10H17O2 (M+H+) 169.1229 found:
4.7. (R)-(À)-Phoracantholide I 1
To a solution of 9 (0.1 g, 0.0005 mol) in ethyl acetate (15 mL)
was added 10% Pd/C and hydrogenated at 25 psi pressure for 2 h
at room temperature. After completion of the reaction, the reaction
mass was filtered and the solvent was removed under reduced
pressure to afford pure
1 (0.085 g, 85%) as a colorless oil;
[
a
]
22 = À40.1 (c 0.5, CHCl3); [Lit.16
[a
]
D
24 = À37.3 (c 0.6, CHCl3)]; IR
D
(Neat, cmÀ1); vmax 2954, 2926, 1727, 1468, 1256, 1166, 1078,
1049; 1H NMR (400 MHz, CDCl3): d 4.98–5.02 (m, 1H), 2.45–2.51
(m, 1H), 1.91–2.20 (m, 3H), 1.71–1.79 (m, 1H), 1.35–1.60 (m,
8H), 1.26 (d, J = 6.4 Hz, 3H), 1.02–1.57 (m, 1H); 13C NMR
(400 MHz, CDCl3):19.41, 20.62, 23.39, 23.96, 24.21, 27.09, 31.33,
35.17, 72.58, 173.97; HRMS Calcd for C10H19O2 (M+H+) 171.1385
found: 171.1378.
4.8. (S)-(+)-Phoracantholide I 2
[
a
]
23 = À7.4 (c 0.53, CHCl3); IR (Neat, cmÀ1); vmax 3384, 3005,
To a solution of 10 (0.1 g, 0.0005 mol) in ethyl acetate (15 mL)
was added 10% Pd/C and hydrogenated with 25 psi for 2 h at room
temperature. After completion of the reaction, the reaction mass
was filtered and the solvent was removed under reduced pressure
D
2932, 1709, 1452, 1241, 1082, 854; 1H NMR (400 MHz, CDCl3): d
5.34–5.46 (m, 2H), 3.80 (m, 1H), 2.34 (m, 2H), 2.07 (m, 4H), 1.66
(m, 2H), 1.47–1.53 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 23.34, 23.53, 24.51, 26.31, 33.20, 38.86,
67.79, 128.95, 130.42, 179.03; HRMS Calcd for C10H19O3 (M+H+)
187.1334, found: 187.1343.
to afford pure 2 (0.08 g, 80%) as a colorless oil; [
a]
22 = +31.8 (c 0.6,
D
CHCl3); {Lit.17 22 = +34.8 (c 0.68, CHCl3)}; IR (Neat, cmÀ1); vmax
[a]
D
2954, 2926, 1727, 1468, 1256, 1166, 1078, 1049; 1H NMR
(400 MHz, CDCl3): d 4.98–5.02 (m, 1H), 2.45–2.51 (m, 1H), 1.91–
2.20 (m, 3H), 1.71–1.79 (m, 1H), 1.35–1.60 (m, 8H), 1.26 (d,
J = 6.4 Hz, 3H), 1.02–1.57 (m, 1H); 13C NMR (400 MHz,
CDCl3):19.41, 20.62, 23.39, 23.96, 24.21, 27.09, 31.33, 35.17,
72.58, 173.97; HRMS Calcd for C10H19O2 (M+H+) 171.1384 found:
171.1379.
4.5. (R,Z)-10-Methyl-4,5,9,10-tetrahydro-3H-oxecin-2(8H)-one 9
To a solution of seco-acid 8 (0.25 g, 0.0013 mol) in dry THF
(12.5 mL) were added TEA (1.35 g, 0.013 mol) and 2,4,6-trichloro
benzoylchloride (1.95 g, 0.008 mol) at 0 °C under inert conditions
and stirred for 2 h at 0 °C. The solid suspension was removed by fil-
tration, further diluted with 200 mL of dry toluene, transferred to
an addition vessel under inert atmosphere and then added slowly
to a solution of DMAP (1.64 g, 0.013 mol) and toluene (25 mL) in a
separate reaction flask at 25 °C over a period of 16 h. After comple-
tion of the reaction, it was diluted with ethyl acetate (50 mL) and
washed with 1 M HCl (250 mL) and brine. The organic layer
obtained was evaporated and then purified by flash chromatogra-
4.9. (4Z,8R,14Z,18R)-8,18-Dimethyl-1,9-dioxacyclooctadeca-
4,14-diene-2,10-dione 12
Pale yellow colored solid: Mp: 42.9 °C; IR (KBr, cmÀ1); vmax
2999, 2966, 2934, 2914, 2873, 1724, 1658, 1224, 868; 1H NMR
(400 MHz, CDCl3): d 1.20 (d, J = 6.4 Hz, 6H), 1.50–1.77 (m, 8H),
2.02–2.36 (m, 12H), 4.85–4.91 (m, 2H), 5.32–5.40 (m, 4H); 13C
NMR (100 MHz, CDCl3): 173.05, 129.64, 129.44, 70.20, 35.92,
33.68, 26.49, 24.47, 23.28, 20.29; HRMS Calcd for C20H33O4 (M
+H+): 337.2379 found: 337.2374.
phy to afford 9 (0.15 g, 69%) as colorless oil; [
a
]
23 = À56.3 (c 0.53,
D
CHCl3); IR (Neat, cmÀ1); vmax 2999, 2966, 2934, 2914, 2873,
1724, 1658, 1224, 868; 1H NMR (400 MHz, CDCl3): d 5.33 (m,
2H), 4.80–4.85 (m, 1H), 1.61–2.35 (m, 10H), 1.21 (d, J = 5.9 Hz,
3H); 13C NMR (100 MHz, CDCl3): 173.02, 129.60, 129.41, 70.17,
35.88, 33.63, 26.45, 24.43, 23.25, 20.27; HRMS Calcd for C10H17O2
(M+H+) 169.1229 found: 169.1237.
4.10. (8R,18R)-8,18-Dimethyl-1,9-dioxacyclooctadecane-2,10-
dione 13
Pale yellow colored solid: Mp: 40.7 °C; IR (KBr, cmÀ1); vmax
2930, 2856, 1729, 1253, 1015; 1H NMR (400 MHz, CDCl3): d 1.18
(d, J = 6.3 Hz, 6H), 1.26–1.69 (m, 24H), 2.22–2.36 (m, 4H), 4.90–
4.94 (m, 2H); 13C NMR (100 MHz, CDCl3): 20.33, 24.99, 25.11,
28.48, 29.25, 29.32, 34.62, 35.91, 70.30, 173.36; HRMS Calcd for
4.6. (S,Z)-10-Methyl-4,5,9,10-tetrahydro-3H-oxecin-2(8H)-one 10
To a solution of triphenylphosphine (1.7 g, 6.4 mmol) in toluene
(60 mL) at 0 °C was added DIAD (1.3 g, 6.4 mmol) dropwise under
an inert atmosphere. The resultant mixture was stirred for 2 h at
C
20H37O4 (M+H+) 341.2692 found: 341.2698.
Please cite this article in press as: Datrika, R.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.05.008

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Acknowledgments
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The authors would like to thank Dr. Vilas Dahanukar and Dr.
Reddy’s Laboratories for continued support. We also thank the
Analytical Department of Dr. Reddy’s Laboratories, for providing
the analytical support.
DRL IPD communication No: IPDO IPM-00501.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.05.
008.
References and notes
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