Asymmetric synthesis of naturally occurring nonenolide xyolide through cross metathesis and macrolactonization reaction

Article abstract of DOI:10.1016/j.tet.2014.02.072

Asymmetric total synthesis of xyolide, a small ring macrolide is presented in this article. The synthesis is achieved through an 'E' selective cross metathesis (CM) reaction between two appropriate fragments followed by lactonization by Shiina method. One of the fragments containing 7S,8S,9R stereocenters of xyolide is accessed from n-nonanal by adopting an organocatalytic asymmetric α-aminooxylation, Z-selective Ando olefination, and substrate directed dihydroxylation reaction. The other fragments containing 4S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method.

Full text of DOI:10.1016/j.tet.2014.02.072

Tetrahedron 70 (2014) 2634e2642
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of naturally occurring nonenolide xyolide
through cross metathesis and macrolactonization reaction
*
Rohan Kalyan Rej, Anuvab Jana, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of xyolide, a small ring macrolide is presented in this article. The synthesis is
achieved through an ‘E’ selective cross metathesis (CM) reaction between two appropriate fragments
followed by lactonization by Shiina method. One of the fragments containing 7S,8S,9R stereocenters of
Received 22 January 2014
Received in revised form 15 February 2014
Accepted 24 February 2014
Available online 4 March 2014
xyolide is accessed from n-nonanal by adopting an organocatalytic asymmetric
a-aminooxylation, Z-
selective Ando olefination, and substrate directed dihydroxylation reaction. The other fragments con-
taining 4S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution)
method.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
ultimum an oomycete plant pathogen (MIC¼425
mM). Oomycetes
are lower eukaryotes, which are closely related to the golden-
brown algae, and are known to infect major food crops, causing
havoc annual losses estimated in billions of dollars worldwide.
Due to its unique structural feature and biological importance
xyolide became an instant target for the synthetic organic com-
munity, and till today two syntheses are reported for xyolide. Both
of the reported synthesis features a late stage ‘E’-selective RCM
(ring closing metathesis reaction). The metathesis precursor was
assembled by esterification reaction between properly functional-
ized carboxylic acid and alcohol fragments.10 In recent times our
group is actively engaged in the synthesis of small and medium
sized ring macrolides.11 In continuation to our effort, herein we
intend to report the asymmetric total synthesis of xyolide.
The wide and diverse range of secondary metabolites produced
by endophytes has been shown to combat pathogens and even
cancers in animals including humans.1 It is speculated that there
may be many thousands of endophytes useful to human being, but
as there are few researchers working in this field, and since due to
deforestation, many useful endophytes might be permanently lost
for medicinal use before they are discovered. It has been reasoned
that fungal endophytes isolated from tropical plants found in Am-
azonian forest would be a rich source of several medicinally im-
portant secondary metabolites.2 And this prompted the recent
isolation of xyolide a 10 membered ring nonenolide from an Am-
azonian endophytes Xylaria feejeensis by Handelsman et al.3 The
structure of xyolide was characterized through extensive NMR
analysis (1-D and 2-D) and the absolute configuration (4S,7S,8S,9R)
was determined by exciton-coupled circular dichroism measure-
ment. Close structural inspection of xyolide reveals that it contains
a 10 membered macrolide core and a C-9 alkyl (other than eMe)
appendage as its main structural components. In addition xyolide
also contain syn vicinal dihydroxy functionality (7S and 8S) and the
hydroxyl group at C-4 position is half esterified with succinic acid.
Cytospolides,4 Herbarumins,5 Stagonolide-B,6 Pinolidoxin,7 Achae-
tolide,8 and Seimatopolides (A and B)9 are few representative ex-
amples belong to this family of nonenolides having a C-9 alkyl
substitution (Fig.1) and exhibit significant biological activities, such
as antibacterial, antifungal, cytotoxic, and phytotoxic. Xyolide also
exhibit significant inhibitory activity against growth of Pythium
2. Result and discussion
We envisioned that CM reaction (cross metathesis)12 might be
an alternative option to construct the ‘E’ olefinic unsaturation at the
beginning and then macrolactonization by carboxylic acid activa-
tion protocol (such as Yamaguchi or Shiina)13 will enable us to form
the decanolide core of the target molecule. The retrosynthetic
analysis for xyolide is outlined in Scheme 1. As presented in Scheme
1, we intend to carry out a late stage macrolactonization on the
enantiopure seco-acid. The olefinic unsaturation between C-5 and
C-6 is planned to be created by a stereoselective CM reaction be-
tween two metathesis partners as presented in Scheme 1. One of
the fragment containing 4S stereocenter of xyolide will be accessed
from 1,4-butanediol through a ME-DKR (metal enzyme combined
dynamic kinetic resolution strategy),14 whereas the other fragment
consist of 7S,8S,9R stereocenters is thought to be assembled from n-
* Corresponding author. E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.072

R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
2635
O
HO2C
O
OH
OH
6
6
4
4
5
OH
OH
HO
OH HO
3
4
1
6
7
3
2
7
8
5
3
2
7
5
8
2
8
O
O
O
9
1
1
9
9
O
nC7H15
O
nC9H19
O
nC9H19
Xyolide
Seimatopolide A
Seimatopolide B
OH
4
OH
R1O
OH 3
OH
4
6
7
HO
4
6
5
3
2
7
8
6
5
8
7
3
2
O
9
5
1
O
2
OR2
1
9
8
O
1
9
OH
O
nC5H11
O
nPr
O
nC7H15
R
R
R
R
1 = Ac; R2 = H
1 = H; R2 = Ac
1 = R2 = Ac
Stagonolide-B
Achaetolide
4
6
OH
OH
OH
O
1 = R2 = H
3
7
4
6
5
3
2
7
8
5
Cytospolides A-D
2
1
8
O
9
O
1
O
9
O
(-)-Pinolidoxin
nPr
O
nPr
Herbarumin III
Fig. 1. Few representative nonenolides containing C-9 alkyl substitution (other than Me).
O
O
OH
O
O
COOH
OH
OP
Macrolactonization
HO2C
O
O
O
O
O
HO
OH
O
C7H15
C7H15
C7H15
CM
Xyolide
OH
O
O
TBDPSO
CHO
C7H15
OH
+
TBDPSO
HO
PMBO
C7H15
Organocatalytic α-aminooxylation
CHO
C7H15
Scheme 1. Retrosynthetic analysis of xyolide.
nonanal through organocatalytic asymmetric
followed by substrate directed asymmetric dihydroxylation
reaction.
a
-aminooxylation
alcohol functionality in compound 3 was achieved by coupling
enzyme-catalyzed transesterification reaction with metal-
catalyzed (ruthenium based catalyst shown in Scheme 2) racemi-
zation method.16 Isopropenyl acetate was used as the acyl donor in
the DKR reaction. The ME-DKR reaction is highly efficient for
compound 3 as it yields the corresponding acetate 4 in 90% yield
with excellent enantioselection (ee¼96%).17 This kind of ME-DKR
reaction is an excellent addition in the toolbox of a synthetic or-
ganic chemist as a variety of secondary alcohol containing enan-
tiopure synthons can be accessed by this method. We have already
explored this ME-DKR strategy for synthesizing several enantio-
pure secondary alcohol synthons for the total synthesis of related
small ring macrolides.11d,i The acetate functionality in compound 4
2.1. Synthesis of the fragment having 4S stereocenter of
xyolide
The synthesis begins with 1,4-butanediol, which on selective
monoprotection with PMB-Br afforded the corresponding alcohol 1
in 88% yield. Oxidation of alcohol 1 with DMP (Dess Martin peri-
odinane)15 afforded the corresponding aldehyde 2 in 90% yield.
Vinylmagnesium bromide addition to aldehyde 2 at ꢀ78 ꢁC fur-
nished racemic compound 3 in 82% yield. ME-DKR of secondary

2636
R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
OH
O
a
b
c
OH
OPMB
OPMB
HO
OPMB
HO
H
1
3
2
OAc
OH
OMOM
d
e
f
OPMB
OPMB
OPMB
er = 98:2
6
5
4
Ph
Ph
Ph
NHiPr
DKR catalyst
Ph
Ru
CO
CO
Cl
Scheme 2. Reagents and conditions: a) NaH, PMB-Br, TBAI, THF, 0 ꢁCdrt, 2 h, 88%; b) DMP, DCM, 0 ꢁCdrt, 1 h, 90%; c) CH2]CHMgBr, THF, ꢀ78 ꢁCdrt, 2 h, 82%; d) CAL-B, iso-
propenyl acetate, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-tetraphenylcyclopentadienyl) ruthenium (II), K2CO3, KOtBu, toluene, 90%; e) K2CO3, MeOH, 92%; f) MOM-Cl, DIPEA,
DCM, TBAI, rt, 12 h, 90%.
was then removed by treatment with K2CO3 in MeOH to yield op-
tically pure 5 in 92% yield. The free alcohol group in compound 5
was protected as its MOM ether by treatment with MOM-Cl to
furnish the compound 6 in 90% yield (Scheme 2).
highly probable due to energy considerations, as in the case of other
structures due to A1,3 strain their relative population will be ex-
tremely less. In the structure AeI of compound 8, as the b-face of
the double bond is blocked by bulky TBDPS group (even an elec-
tronic repulsion between Os]O bond and the ether oxygen of the
eOTBDPS group cannot be ruled out) hence the dihydroxylation
2.2. Synthesis of the fragment having 7S,8S,9R stereocenters
selectively occurs from the
a-face to afford compound 9 in 90%
of xyolide
yield. The diol functionality is now protected as its acetonide upon
treatment with 2,2-DMP to furnish compound 10 in 88% yield.
Partial reduction with DIBAL-H of compound 10 afforded the al-
dehyde 11 in 76% yield. Wittig olefination with Ph3PþCH3Iꢀ affor-
ded the olefin 12 in 80% yield (Scheme 3).
The synthesis was initiated from n-nonanal, which on organo-
catalytic asymmetric a
-aminooxylation with S-proline,18 followed
by cleavage of the OeN bond with CuSO4$5H2O and subsequent
protection of the free hydroxyl group with TBDPS-Cl furnished
compound 7 in 80% yield (over three steps). Ando modification19 of
HWE reaction with aldehyde 7 with (PhO)2POCH2CO2Et afforded
the corresponding ester 8 in 88% yield (Z:E¼14:1). Next substrate
directed dihydroxylation was initiated with compound 8 with
OsO4/NMO in THF:water (3:1) solvent afforded the corresponding
diol 9 with good diastereoselection (12:1). The origin of this high
selectivity can be explained from Kishi model20 as shown in
Scheme 3. In its ground state compound 8, might exist as three of
the probable conformational isomers, out of which structure AeI is
2.3. Fragment coupling by CM and completion of the
synthesis
After successful construction of both the fragments, our next job
is to couple them by cross metathesis reaction. One of the reacting
partners in CM reaction was kept constant, and compound 12 was
chosen for that purpose. Whereas for choosing the other partner
we have performed a systematic optimization with compounds 5
OTBDPS
OTBDPS
CO2Et
a
b
CHO
CHO
7; er = 97:3
8; Z:E = 14:1
OTBDPS
CO2Et
OTBDPS
CO2Et
d
c
e
O
O
HO
OH
10
9; dr = 12:1
OTBDPS
OTBDPS
f
CHO
O
O
11
O
O
12
OP
PO
n
H
H
(
)
(
)
H
nC7H15
CO2Et
H
CO2Et
H
C7H15
C7H15
n
CO2Et
TBDPSO
H
H
H
H
Preferred approach
A-III
A-II
Kishi Model for acyclic stereocontrol on dihydroxylation
A-I
Scheme 3. Reagents and conditions: (a) (i) S-proline, PhNO, DMSO, rt, 3 h; (ii) CuSO4, 0 ꢁC, 6 h; (iii) Im, TBDPS-Cl, DMAP, DCM, rt, 6 h, 80% in three steps; (b) (PhO)2POCH2CO2Et,
NaH, THF, 0 ꢁC, 88%; (c) OsO4, NMO, THF:water (3:1), 12 h, 90%; (d) 2,2-DMP, CSA, DCM, rt, 88%; (e) DIBAL-H, THF, ꢀ78 ꢁC, 76%; (f) Ph3PþCH3Iꢀ, LiHMDS, THF, 0 ꢁCdrt, 80%.

R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
2637
and 6 with HG-II (HoveydaeGrubbs Ru-based metathesis catalyst;
Scheme 4). It was observed that both the compound 5 and 6 un-
derwent CM reaction with compound 12 and furnished corre-
sponding product 13 and 14 in 65% and 32% yield, respectively with
commendable amount of stereocontrol (E:Z¼15:1; Scheme 4). It
was earlier demonstrated that compound containing a free 2ꢁ al-
lylic alcohol moiety has a rate enhancement effect in RCM re-
action.21 The reason for that high activity of compound 5 is not very
clear, but the possibility of rapid and reversible ligand exchange
As the CM reaction went smoothly as anticipated the initial
hurdle in the total synthesis is crossed. Next we have proceeded for
our desired macrolactonization method to access the nonenolide
core of xyolide. For that purpose PMB group was removed from
compound 14 by treatment with DDQ to furnish alcohol 15 in 90%
yield. Oxidation of the free hydroxyl group with DMP afforded the
corresponding aldehyde, which on subsequent oxidation under
Pinnick condition afforded compound 16 in 82% yield. Removal of
the TBDPS group in compound 16 was accomplished by treatment
OMOM
OMOM
a
OTBDPS
OPMB
OPMB
6
32% (E:Z = 15:1)
14
O
O
OTBDPS
MOM-Cl, DIPEA
NaI, 88%
O
O
12
OH
OH
OTBDPS
b
OPMB
OPMB
5
65% (E:Z = 15:1)
13
O
O
PCy
3Cl
N
N
Ru
N
N
Cl
Cl
Cl
Ru
O
Ru
O
Cl
Cl
Ph
PCy3
HG-I (C2)
G-I I (C 1)
HG-II (C3)
Scheme 4. Reagents and conditions: a) or b) HG-II (5 mol %), refluxing DCM, 24 h.
(alkoxy group replaces the Cl) and hydrogen bonding between
hydroxyl group and one of the chloride ligands cannot be ruled out.
The best results in the CM reaction (selectivity and reactivity;
E:Zw15:1) were obtained with catalyst C3 (HoveydaeGrubbs sec-
ond generation catalyst; HG-II).22 With the catalyst C1 (G-II),23 the
CM product was isolated in 30% yield with poor selectivity
(E:Zw1:1). Whereas with catalyst C2 (HG-I)24 no product formation
was detected, indicating that NHC type Ru-based metathesis cata-
lyst is the ideal choice for best reactivity and selectivity.
with TBAF in THF as a solvent to the seco-acid 17 in 88% yield. The
acid 17 on macrolactonization under Shiina condition13 as shown in
Scheme 5 afforded the corresponding nonenolide core of xyolide 18
in 68% yield. Selective deprotection of MOM group was achieved by
treating the compound 18 with silica supported KHSO425 to furnish
compound 19 in 86% yield. Compound 19 was then treated with
succinic anhydride, DCC, and DMAP to afford the half ester 20 in
90% yield. Finally deprotection of the acetonide functionality was
accomplished by treating compound 20 with 2 N HCl in THF solvent
OMOM
OMOM
OTBDPS
OPMB
OTBDPS
a
OH
b
14
O
O
O
O
15
OMOM
COOH
OMOM
c
OTBDPS
OH
O
d
COOH
O
O
17
16
O
O
O
O
OMOM
OH
O
O
COOH
O
COOH
OH
O
e
O
O
f
g
O
O
O
O
O
O
O
OH
O
C7H15
O
C7H15
C7H15
C7H15
20
18
19
Xyolide
Overall yield = 5% from n-nonanal
Scheme 5. Reagents and conditions: (a) DDQ, DCM:phosphate buffer (19:1), 1 h, rt, 90%; (b) (i) DMP, DCM, rt, 2 h, (ii) NaClO2, NaH2PO4, tBuOH, 2-methyl-2-butene, H2O, rt, 4 h, 82%
in two-step; (c) TBAF, THF, 40 ꢁC, 3 h, 88%; (d) MNBA (2-methyl-6-nitro benzoic anhydride), DIPEA (diisopropylethyl amine), DMAP, toluene, 60 ꢁC, 24 h, 68%; (e) silica supported
KHSO4, DCM, rt, 4 h, 86%; (f) succinic anhydride, DCC, DMAP, 90%, rt, DCM, 24 h; (g) 2 N HCl, THF, rt, 12 h, 85%.

2638
R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
to furnish the target molecule xyolide in 85% yield (Scheme 5;
overall yield¼5% from n-nonanal).
(m, 4H). 13C NMR (50 MHz, CDCl3)
70.0, 62.4, 55.2, 29.9, 26.6.
d: 159.2, 130.2, 129.4, 113.8, 72.6,
3. Conclusions
4.1.2. 4-(4-Methoxy-benzyloxy)-butyraldehyde
(2). Alcohol
1
(2.10 g, 10 mmol) was taken in dry DCM (40 ml) and cooled to 0 ꢁC.
Dess Martin Periodinane (DMP) (4.45 g, 10.5 mmol) was then added
and the reaction mixture was warmed to room temperature over
1 h. The reaction mixture was then quenched with Na2S2O3 and
saturated NaHCO3 solution successively and stirred for further
20 min. The resulting solution was then extracted with DCM. The
organic extract was then dried with MgSO4, filtered, and the solvent
was removed in vacuo. The crude residue was purified by flash
column chromatography (EtOAc:hexane¼1:5) to afford the com-
pound 2 (1.87 g) in 90% yield.
In conclusion, an asymmetric total synthesis of naturally oc-
curring nonenolide xyolide is presented in this article. The syn-
thetic strategy delineated in this article employs a successful
application of ‘E’ selective CM reaction for the construction of re-
quired olefinic geometry in the target molecule followed by
a macrolactonization reaction by Shiina protocol. In general the
reported synthetic strategies for these type of small ring macrolides
with an inbuilt unsaturation (Z or E), involve application of a suc-
cessful late stage selective RCM (ring closing metathesis) reaction in
all the cases. This altered sequence of chemical reaction, for ex-
ample, CM followed by macrolactonization reported by us in this
article could serve as an efficient strategy for the construction of
small ring macrolide natural products in near future. We are cur-
rently exploring this strategy for the total synthesis of several
structurally related naturally occurring small ring macrolides.
Rf¼0.3 (EtOAc:hexane¼1:5). 1H NMR of compound 2 (200 MHz,
CDCl3)
d
: 9.78 (s, 1H), 7.26 (d, J¼8.6 Hz, 2H), 6.90 (d, J¼8.6 Hz, 2H),
4.43 (s, 2H), 3.81 (s, 3H), 3.49 (t, J¼6.2 Hz, 2H), 2.58e2.50 (m, 2H),
1.98e1.91 (m, 2H). 13C NMR (50 MHz, CDCl3)
d: 202.4, 159.2, 130.3,
129.3, 113.8, 72.6, 68.8, 55.2, 40.9, 22.5.
4.1.3. 6-(4-Methoxybenzyloxy)hex-1-en-3-ol (3). Aldehyde 2 (5 g,
24 mmol) was taken in 40 ml of anhydrous THF. Solution of
vinylmagnesium bromide (freshly prepared from vinyl bromide
and Mg metal, 36 mmol) was added to it at ꢀ78 ꢁC. The reaction
mixture was kept at the same temperature for 1 h, after that time
saturated NH4Cl solution was added to it. The solution was then
extracted with EtOAc, and the organic layer was washed with water
and brine. The organic layer was dried (MgSO4) and evaporated to
afford the crude alcohol. Purification of the crude product by silica
gel chromatography (EtOAc:hexane¼1:3) afforded the racemic al-
cohol 3 (4.65 g) in 82% yield.
4. Experimental section
4.1. Materials and methods
All oxygen and/or moisture-sensitive reactions were carried out
under N2 atmosphere in glassware that had been flame-dried un-
der a vacuum (w0.5 mmHg) and purged with N2 prior to use. Un-
less otherwise stated, materials were obtained from commercial
suppliers and used without further purification. CAL-B (immobi-
lized on acrylic resin) was purchased from SigmaeAldrich Co, USA.
THF and diethyl ether were distilled from sodium benzophenone
ketyl. Dichloromethane (DCM), dimethylformamide (DMF), and
dimethylsulfoxide (DMSO) were distilled from calcium hydride.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates with UV light, ethanolic
anisaldehyde, and phosphomolybdic acid/heat as developing
agents. Silicagel 100e200 mesh was used for column chromatog-
raphy. Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. NMR spectra were
recorded on 400 & 200 MHz spectrometers at 25 ꢁC in CDCl3 using
Rf¼0.3 (EtOAc:hexane¼1:3).
4.1.4. (S)-6-(4-Methoxybenzyloxy)hex-1-en-3-yl acetate (4). In
a 50 ml round-bottom flask attached with a grease free high vac-
uum
stopcock,
chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-
tetraphenylcyclopentadienyl) ruthenium (II) (DKR catalyst, 84 mg,
0.136 mmol) was taken. The flask was successively charged with
alcohol 3 (0.80 g, 3.4 mmol) in 10 ml dry toluene, Na2CO3 (180 mg,
3.4 mmol), CAL-B (25 mg), and KOtBu (19 mg, 0.17 mmol) followed
by isopropenyl acetate (0.58 ml, 5 mmol). The reaction mixture was
then stirred at room temperature under argon atmosphere for al-
most 8 h. After completion of the reaction the mixture was filtered
off and the solvent was evaporated to afford the crude acetate,
which was subsequently purified by silica gel column chromatog-
raphy (EtOAc:hexane¼1:10) to afford the pure acetate 4 (83 mg) in
TMS as the internal standard. Chemical shifts are shown in d.
13C
NMR spectra were recorded with a complete proton decoupling
environment. The chemical shift value is listed as dH and dC for 1H
and 13C, respectively. Mass spectrometric analysis was performed
in the CRF, IIT-Kharagpur (TOF analyzer). Optical rotations were
measured on a digital polarimeter. HPLC analysis was performed
with CHIRALPAK AD-H & OJ-H (Daicel) column by using UVevis
detector.
90% yield.
28
Rf¼0.5 (EtOAc:hexane¼1:10). [
a
d
]
ꢀ6.8 (c 0.4, CHCl3). 1H NMR
D
of compound 4 (200 MHz, CDCl3)
: 7.25 (d, J¼8.6 Hz, 2H), 6.89 (d,
J¼8.6 Hz, 2H), 5.77 (ddd, J¼6.2, 10.4, 17.4 Hz, 1H), 5.29e5.13 (m, 3H),
4.42 (s, 2H), 3.79 (s, 3H), 3.44 (t, J¼5.6 Hz, 2H), 2.04 (s, 3H),
4.1.1. 4-(4-Methoxy-benzyloxy)-butan-1-ol (1). Butane 1,4 diol
(10 g, 111 mmol) was taken in 200 ml of dry THF. NaH (60% dis-
persion in mineral oil, 4.44 g, 111 mmol) was added to it portion
wise at 0 ꢁC. The reaction mixture was then stirred at 0 ꢁC for 1 h.
TBAI (5 mmol) was added to it followed by addition of 4-
methoxybenzyl bromide. The reaction mixture was stirred further
for 2 h at room temperature. Water was added carefully to the
reaction mixture to quench any excess of NaH. The reaction mixture
was then extracted with large volume of EtOAc, washed with brine.
It was then dried with MgSO4, filtered, and the solvent was re-
moved in vacuo. The crude residue was purified by flash column
chromatography (EtOAc:hexane¼1:3) to afford the compound 1
(20.51 g) in 88% yield.
1.72e1.60 (m, 4H). 13C NMR (50 MHz, CDCl3)
d: 170.4, 159.2, 136.4,
130.6, 129.3, 116.8, 113.8, 74.6, 72.6, 69.5, 55.3, 30.9, 25.5, 21.3.
4.1.5. (S)-6-(4-Methoxybenzyloxy)hex-1-en-3-ol (5). To a solution
of acetate compound 4 (834 mg, 3.0 mmol) in methanol was added
K2CO3 (125 mg, 0.9 mmol) at room temperature and stirred for
1.5 h. After that time methanol was evaporated and water was
added to the solution. The solution was then extracted with ethyl
acetate. The organic extracts were then washed with brine and
dried over MgSO4. The organic solution was then concentrated in
rotary evaporator and purified by column chromatography
(EtOAc:hexane¼1:10) to furnish the (S) alcohol 5 (651 mg) in 92%
yield.
Rf¼0.3 (EtOAc:hexane¼1:3). 1H NMR of compound 1 (200 MHz,
CDCl3)
d
: 7.26 (d, J¼8.6 Hz, 2H), 6.88 (d, J¼8.6 Hz, 2H), 4.45 (s, 2H),
Rf¼0.3 (EtOAc:hexane¼1:3). [
a
]
28 þ9.9 (c 0.4, CHCl3). 1H NMR of
D
3.80 (s, 3H), 3.64 (t, J¼6.0 Hz, 2H), 3.50 (t, J¼6.0 Hz, 2H), 1.74e1.64
compound 5 (200 MHz, CDCl3)
d: 7.28 (d, J¼8.4 Hz, 2H), 6.90 (d,

R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
2639
J¼8.4 Hz, 2H), 5.88 (ddd, J¼5.8, 10.4, 16.4 Hz, 1H), 5.27e5.07 (m,
2H), 4.46 (s, 2H), 4.16e4.10 (m, 1H), 3.81 (s, 3H), 3.53e3.47 (m, 2H),
evaporated to afford the unsaturated ester (Z:E¼14:1), which was
further purified by flash chromatography (EtOAc:hexane¼1:100) to
afford pure 8 (4.2 g) in 88% yield.
1.71e1.61 (m, 4H). 13C NMR (50 MHz, CDCl3)
d: 159.2, 141.2, 130.3,
129.4, 114.4, 113.8, 72.6, 70.0, 55.3, 34.3, 25.8. HRMS (ESI) for
Rf¼0.3 (EtOAc:hexane¼1:30). [
a
]
28 þ1.1 (c 1.1, CHCl3). 1H NMR of
D
C
14H20O3Na [MþNa]þ, calculated: 259.1309; found: 259.1312.
compound 8 (200 MHz, CDCl3)
d
: 7.69e7.62 (m, 4H), 7.43e7.27 (m,
6H), 6.17 (dd, J¼8.2, 11.6 Hz, 1H), 5.48 (d, J¼11.6 Hz, 1H), 5.40e5.31
(m, 1H), 4.00 (q, J¼7.0 Hz, 2H), 1.69e1.52 (m, 2H), 1.31e1.19 (m,
11H), 1.18e1.09 (m, 11H), 0.92e0.86 (m, 3H). 13C NMR (50 MHz,
4.1.6. (S)-1-Methoxy-4-((4-(methoxymethoxy)hex-5-enyloxy)
methyl)benzene (6). To a solution of alcohol 5 (505 mg, 2.14 mmol)
in DCM, diisopropyl ethyl amine (0.6 ml, 3.21 mmol) was added at
CDCl3) d: 165.7, 152.5, 136.0, 134.4, 134.3, 129.6, 127.6, 127.5, 117.9,
0
ꢁC and stirred for 15 min at the same temperature. MOM-Cl
70.1, 60.0, 37.6, 31.9, 29.7, 29.3, 27.2, 24.8, 22.8, 19.5, 14.2. HRMS
(0.2 ml, 2.56 mmol) and tetra-n-butyl ammonium iodide (10 mg)
was then added to the reaction mixture and stirred for additional
12 h at room temperature. Water was added to the reaction mixture
and extracted with DCM. The organic extract was then washed with
water and brine. The organic solvent was dried over MgSO4, con-
centrated, and purified by silica gel column chromatography
(EtOAc:hexane¼1:10) to afford the desired product 6 (539 mg) in
(ESI) for
467.3016.
C
29H42O3Si [MþH]þ, calculated: 467.2981; found:
4.1.9. (R,E)-Ethyl 4-(tert-butyldiphenylsilyloxy)undec-2-enoate
(8). 1H NMR of compound 8 (200 MHz, CDCl3)
: 7.71e7.61 (m,
d
4H), 7.45e7.36 (m, 6H), 6.88 (dd, J¼5.2, 15.6 Hz, 1H), 5.91 (d,
J¼15.2 Hz, 1H), 4.37e4.32 (m, 1H), 4.18 (q, J¼7.0 Hz, 2H), 1.43e1.40
(m, 2H), 1.34e1.14 (m, 11H), 1.10e1.00 (m, 11H), 0.92e0.86 (m, 3H).
90% yield.
28
Rf¼0.4 (EtOAc:hexane¼1:10). [
a
d
]
þ8.6 (c 0.3, CHCl3). 1H NMR
13C NMR (50 MHz, CDCl3)
d: 166.8, 150.4, 136.0, 134.2, 133.8, 129.9,
D
of compound 6 (200 MHz, CDCl3)
: 7.28 (d, J¼8.4 Hz, 2H), 6.88 (d,
127.8, 120.3, 72.7, 60.4, 37.0, 31.9, 29.5, 29.2, 27.2, 24.1, 22.8, 19.6,
28
J¼8.4 Hz, 2H), 5.73 (ddd, J¼7.6, 9.8, 17.6 Hz, 1H), 5.26e5.17 (m, 2H),
4.72 (d, J¼6.6 Hz, 1H), 4.55 (d, J¼6.6 Hz, 1H), 4.46 (s, 2H), 4.07e4.00
(m, 1H), 3.81 (s, 3H), 3.52e3.43 (m, 2H), 3.38 (s, 3H), 1.73e1.61 (m,
14.4, 14.2. [
a
]
þ4.1 (c 1.1, CHCl3).
D
4.1.10. (2R,3S,4R)-Ethyl 4-(tert-butyldiphenylsilyloxy)-2,3-
dihydroxyundecanoate (9). The TBDPS-protected ester 8 (8.31 g,
17.84 mmol) was taken in THF:H2O (3:1), OsO4 (0.05 M, 17.9 ml,
0.89 mmol), and NMO (3.13 g, 26.76 mmol) was added at room
temperature and stirred for 12 h, after which saturated solution of
NaHSO3 (2.7 g, 26.76 mmol) was added and the solution was fur-
ther stirred for 2 h. The organic layer was extracted with ethyl
acetate, washed with brine, and dried over MgSO4. Then it was
evaporated to dryness to afford the crude diol, which was further
purified by flash chromatography (EtOAc:hexane¼1:5) to afford
pure 9 (8.1 g) in 90% yield.
4H). 13C NMR (50 MHz, CDCl3)
d: 159.2, 138.4, 130.8, 129.3, 117.3,
113.8, 93.8, 72.6, 69.9, 55.5, 55.3, 32.1, 25.8. HRMS (ESI) for
C
16H24O4Na [MþNa]þ, calculated: 303.1572; found: 303.1584.
4.1.7. (R)-2-(tert-Butyldiphenylsilyloxy)nonanal
(7). n-Nonanal
(256 mg, 2 mmol) was added at room temperature to a vial con-
taining nitrosobenzene (107 mg, 1 mmol) and a catalytic amount of
(S)-proline (11 mg, 10 mol %) in DMSO (4.0 ml). After 3 h reaction
time, the temperature was lowered to 0 ꢁC, followed by dilution
with anhydrous MeOH (5.0 ml) and catalytic amount of
CuSO4$5H2O (75 mg, 30 mol %). The reaction mixture was then
stirred at this temperature for 6 h and then quenched by addition of
aqueous NH4Cl. The aqueous phase was extracted three times with
EtOAc. The combined organic layers were dried with MgSO4, which
was subsequently removed by filtration. The solvent was removed
under reduced pressure.
Rf¼0.4 (EtOAc:hexane¼1:5). [
a
]
28 þ3.5 (c 1.0, CHCl3). 1H NMR of
D
compound 9 (200 MHz, CDCl3)
d
: 7.72e7.69 (m, 4H), 7.45e7.36 (m,
6H), 4.27e4.14 (m, 3H), 3.98e3.92 (m, 1H), 3.66e3.62 (m, 1H),
1.72e1.56 (m, 2H),1.29e1.22 (m, 7H),1.21e0.97 (m,15H), 0.87e0.80
(m, 3H). 13C NMR (50 MHz, CDCl3)
d: 173.6, 136.1, 136.0, 133.9, 130.1,
129.9, 127.9, 127.7, 74.0, 73.5, 72.2, 61.8, 33.4, 31.8, 29.3, 29.1, 27.2,
24.9, 22.7, 19.6, 14.3, 14.2. HRMS (ESI) for C29H44O5SiNa [MþNa]þ,
calculated: 523.2855; found: 523.2857.
Rf¼0.5 (EtOAc:hexane¼1:40).
The crude aldehyde (3.52 g, 22.3 mmol) was taken in anhydrous
DCM (60 ml) and cooled to 0 ꢁC. Imidazole (2.27 g, 33.45 mmol) and
DMAP (100 mg, 0.81 mmol) were added to the reaction mixture
followed by the addition of TBDPS-Cl (7 ml, 26.76 mmol). The re-
action mixture was allowed to warm to room temperature for 6 h,
after which water was added to it and the organic layer was washed
with brine and dried over MgSO4. Evaporation and purification by
silica gel column chromatography (EtOAc:hexane¼1:40) yielded
4.1.11. (4R,5S)-Ethyl 5-((R)-1-(tert-butyldiphenylsilyloxy)octyl)-2,2-
dimethyl-1,3-dioxolane-4-carboxylate (10). Compound 9 (1.94 g,
4 mmol) was taken in 20 ml of dry DCM. 2,2-Dimethoxypropane
(DMP, 1.5 ml, 12 mmol) was added to it followed by addition of
catalytic amount of CSA (0.45 mmol, 122 mg). The reaction mixture
was then stirred at room temperature for overnight. Water was
added to the reaction mixture. Then it was extracted with DCM and
washed with brine. The organic layer was dried over MgSO4 and
evaporated to dryness. The product was purified by silica gel col-
umn chromatography (EtOAc:hexane¼1:20) to afford the com-
pound 10 (1.9 g) in 88% yield.
the mono TBDPS-protected aldehyde 7 (633 mg) in 80% yield.
Rf¼0.5 (EtOAc:hexane¼1:40). [
a]
ꢀ5.1 (c 0.9, CHCl3). 1H NMR
28
D
of compound 7 (200 MHz, CDCl3)
d
: 9.60 (d, J¼1.4 Hz,1H), 7.68e7.63
(m, 4H), 7.46e7.35 (m, 6H), 4.04 (t, J¼5.8 Hz, 1H), 1.62e1.57 (m, 2H),
1.27e1.13 (m, 19H), 0.91e0.85 (m, 3H). 13C NMR (50 MHz, CDCl3)
d:
204.1, 136.0, 135.9, 133.3, 130.1, 127.9, 78.2, 33.0, 31.8, 29.6, 29.1, 27.1,
24.2, 22.7, 19.5, 14.2. HRMS (ESI) for C25H36O2SiNa [MþNa]þ, cal-
culated: 419.2382; found: 419.2385.
Rf¼0.6 (EtOAc:hexane¼1:10). [
a
]
28 þ1.3 (c 1.4, CHCl3). 1H NMR of
D
compound 10 (200 MHz, CDCl3)
d
: 7.74e7.67 (m, 4H), 7.41e7.26 (m,
6H), 4.42e4.39 (m, 1H), 4.31e4.20 (m, 1H), 3.99e3.87 (m, 2H),
3.76e3.67 (m, 1H), 1.40 (s, 6H), 1.20e1.12 (m, 12H), 1.11e1.00 (m,
4.1.8. (R,Z)-Ethyl 4-(tert-butyldiphenylsilyloxy)undec-2-enoate
(8). To a solution of ethyl (diphenylphosphono) acetate (3.4 g,
10.7 mmol) in THF (40 ml) was added NaH (60%, 513 mg,
12.84 mmol) at 0 ꢁC. After 15 min the aldehyde 7 (4.23 g,
10.7 mmol) in THF (10 ml) was added, and the resulting mixture
was gradually warmed to the room temperature. After completion
of the reaction as indicated by TLC analysis, water was added to the
reaction mixture. Then it was extracted with ethyl acetate and
washed with brine. The organic layer was dried over MgSO4 and
12H), 0.91e0.84 (m, 3H). 13C NMR (50 MHz, CDCl3)
d: 170.3, 136.3,
134.7, 134.6, 129.4, 129.2, 127.4, 127.1, 110.7, 81.3, 76.1, 72.5, 61.0,
34.1, 31.9, 29.8, 29.3, 27.3, 26.5, 25.5, 25.1, 22.8, 19.9, 14.2, 14.0.
HRMS (ESI) for C32H48O5SiNa [MþNa]þ, calculated: 563.3168;
found: 563.3172.
4.1.12. (4R,5S)-5-(R)-1-((tert-Butyldiphenylsilyloxy)octyl)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde (11). The compound 10
(1.51 g, 2.8 mmol) was taken in dry DCM (10 ml) and cooled to

2640
R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
ꢀ78 ꢁC. Solution of DIBAL-H (1 M in DCM, 2.8 ml) was added to it
for a period of 30 min. The reaction was stirred for further 2 h at the
same temperature and then warmed to ꢀ20 ꢁC and quenched with
dry methanol and stirred for further 1.5 h. Then it was extracted
with ethyl acetate, washed with brine, and dried over MgSO4. The
organic extract was evaporated to dryness to afford the crude
product, which was then purified by silica gel column chromatog-
raphy (EtOAc:hexane¼1:20) to afford the compound 11 (1.05 g) in
76% yield.
HRMS (ESI) for C43H62O6SiNa [MþNa]þ, calculated: 725.4213;
found: 725.4210.
4.2.2. tert-Butyl((R)-1-((4S,5S)-5-((S,E)-6-(4-methoxybenzyloxy)-3-
(methoxymethoxy)hex-1-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)octy-
loxy)diphenylsilane (14). 1H NMR of compound 14 (400 MHz,
CDCl3) d: 7.73e7.71 (m, 4H), 7.40e7.33 (m, 6H), 7.31e7.24 (m, 2H),
6.89e6.87 (m, 2H), 5.41 (dd, J¼6.2, 15.6 Hz, 1H), 5.32 (dd, J¼8.0,
15.6 Hz, 1H), 4.49 (d, J¼6.8 Hz, 1H), 4.44 (s, 2H), 4.38 (d, J¼7.2 Hz,
1H), 4.32 (t, J¼6.8 Hz, 1H), 4.11 (t, J¼7.0 Hz, 1H), 3.88e3.85 (m, 1H),
3.81 (s, 3H), 3.65e3.63 (m, 1H), 3.40e3.37 (m, 2H), 3.31 (s, 3H),
1.66e1.60 (m, 4H), 1.54e1.36 (m, 12H), 1.34e1.19 (m, 6H),
1.21e1.09 (m, 9H), 0.90e0.86 (m, 3H). 13C NMR (100 MHz, CDCl3)
Rf¼0.5 (EtOAc:hexane¼1:15). 1H NMR of compound 11
(200 MHz, CDCl3)
7.40e7.37 (m, 6H), 4.44e4.38 (m, 1H), 4.33e4.27 (m, 1H), 3.83 (q,
J¼5.6 Hz, 1H), 1.33e1.07 (m, 8H), 1.06e0.87 (m, 19H), 0.86e0.80 (m,
d
: 9.66 (d, J¼2.8 Hz, 1H), 7.80e7.67 (m, 4H),
3H). 13C NMR (50 MHz, CDCl3)
d: 201.1, 136.2, 134.4, 134.1, 129.6,
d: 159.1, 136.2, 136.1, 134.5, 134.3, 130.6, 129.2, 129.0, 127.2, 126.9,
127.6, 127.5, 110.7, 81.2, 81.0, 71.5, 33.3, 31.8, 29.3, 29.1, 27.1, 25.6,
25.0, 22.7, 19.6, 14.2.
113.7, 108.3, 93.7, 80.8, 78.0, 75.5, 72.1, 69.7, 55.4, 55.2, 33.1, 32.1,
31.7, 29.8, 29.7, 29.1, 28.0, 27.2, 25.7, 25.3, 24.8, 22.6, 19.6, 14.1.
Rf¼0.5 (EtOAc:hexane¼1:10). [
a
]
28 ꢀ1.9 (c 0.2, CHCl3). HRMS (ESI)
D
4.1.13. tert-Butyl (R)-1-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-
for
C
45H66O7SiNa [MþNa]þ, calculated: 769.4474; found:
4-yl)octyloxy)diphenylsilane) (12). To
a suspension of methyl-
769.4481.
triphenylphosphonium iodide (646 mg, 1.6 mmol) in dry THF (2 ml)
was added LiHMDS (1.0 M solution in THF, 1.6 ml) at 0 ꢁC. The
yellow mixture was then stirred at 0 ꢁC for 15 min. A solution of the
aldehyde 11 (397 mg, 0.8 mmol) in 1 ml of THF was added to the
reaction mixture. The yellow suspension was stirred at room tem-
perature for further 1 h. After completion of the reaction, as in-
dicated by TLC analysis, the reaction was quenched with water and
the layers were separated. It was then extracted with ether and
the organic layer was washed with brine. It was then dried with
MgSO4, filtered, and the solvent was removed in vacuo. The
crude residue was purified by flash column chromatography
(EtOAc:hexane¼1:30) to afford the compound 12 (316 mg) in 80%
4.2.3. (S,E)-6-((4S,5S)-5-((R)-1-(tert-Butyldiphenylsilyloxy)octyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-(methoxymethoxy)hex-5-en-1-ol
(15). Compound 14 (292 mg, 0.4 mmol) was taken in 3 ml of DCM/
H2O (19:1). DDQ (90 mg, 0.4 mmol) was added to it in one portion.
The reaction mixture was stirred at room temperature for 1 h. The
reaction mixture was then filtered off, and the filtrate was washed
with saturated NaHCO3 solution, water, and brine. The organic layer
was dried (MgSO4) and evaporated in vacuo to afford the crude
product. Purification of the crude residue by silica gel column
chromatography (EtOAc:hexane¼1:3) afforded the desired product
15 (225 mg) in 90% yield as an oil.
yield.
Rf¼0.5 (EtOAc:hexane¼1:5). [
a
]
28 ꢀ1.3 (c 0.3, CHCl3). 1H NMR of
D
28
Rf¼0.5 (EtOAc:hexane¼1:30). [
a
]
D
þ1.7 (c 1.0, CHCl3). 1H NMR
compound 15 (200 MHz, CDCl3)
d: 7.77e7.73 (m, 4H), 7.45e7.30 (m,
of compound 12 (200 MHz, CDCl3)
d: 7.79e7.76 (m, 4H), 7.42e7.36
6H), 5.49e5.30 (m, 2H), 4.53 (d, J¼6.6 Hz, 1H), 4.46e4.32 (m, 2H),
4.18e4.11 (m, 1H), 3.95e3.91 (m, 1H), 3.67e3.62 (m, 3H), 3.35 (s,
3H), 1.58e1.49 (m, 4H), 1.33e1.26 (m, 13H), 1.22e0.92 (m, 15H),
(m, 6H), 5.70e5.52 (m, 1H), 5.21e5.07 (m, 2H), 4.39e4.32 (m, 1H),
4.21e4.14 (m, 1H), 3.81e3.71 (m, 1H), 1.32e1.11 (m, 14H), 1.10e0.94
(m, 10H), 0.91e0.88 (m, 3H). 13C NMR (50 MHz, CDCl3)
d
: 136.4,
0.88e0.87 (m, 3H). 13C NMR (50 MHz, CDCl3)
d: 136.1, 134.4, 133.9,
134.8, 129.4, 129.2, 127.8, 127.3, 127.1, 118.7, 108.5, 81.0, 79.3, 72.2,
33.2, 31.9, 29.6, 29.2, 28.1, 27.4, 25.4, 25.0, 22.8, 19.8, 14.2. HRMS
(ESI) for C31H46O3SiNa [MþNa]þ, calculated: 517.3113; found:
517.3100.
129.2, 129.0, 127.1, 126.9, 108.3, 93.7, 80.7, 77.9, 75.4, 72.1, 62.6, 55.5,
33.1, 31.9, 31.6, 29.6, 29.0, 28.4, 28.0, 27.1, 25.3, 24.8, 22.5, 19.6, 14.0.
HRMS (ESI) for C37H58O6SiNa [MþNa]þ, calculated: 649.3900;
found: 649.3912.
4.2.4. (S,E)-6-((4S,5S)-5-((R)-1-(tert-Butyldiphenylsilyloxy)octyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-(methoxymethoxy)hex-5-enoic
acid (16). Alcohol 15 (187 mg, 0.3 mmol), was taken in dry DCM
(10 ml) and cooled to 0 ꢁC. Dess Martin Periodinane (DMP) (259 mg,
0.4 mmol) was then added and warmed to room temperature over
2 h. The reaction mixture was quenched with Na2S2O3 and satu-
rated NaHCO3 solution successively and stirred for further 20 min.
The organic solution was then dried with MgSO4, filtered, and the
solvent was removed in vacuo to afford the crude aldehyde, which
was used subsequently for the next step.
4.2. General procedure for cross metathesis
Olefin 12 (492 mg, 1 mmol) was taken in a flame-dried round-
bottom flask and the 2ꢁ allylic alcohol (5/6, 2 mmol) in DCM (10 ml)
was added to it. HoveydaeGrubbs catalyst (HG-II; 31 mg,
0.05 mmol) was then added to the reaction solution under inert
atmosphere. The light green solution was then refluxed for 24 h
under argon atmosphere and then it was concentrated in vacuo to
afford dark brown oil. Purification of this residue on silica gel by
flash chromatography (EtOAc:hexane¼1:20) afforded the com-
pound 13/14 in 65% and 32%, respectively as a yellow oil.
To a solution of the crude aldehyde (180 mg, 0.3 mmol) in tert-
butanol (8 ml), 2-methyl-2-butene (4 ml) was added dropwise,
then
a solution of sodium phosphate monobasic (153 mg,
4.2.1. (S,E)-1-((4S,5S)-5-((R)-1-(tert-Butyldiphenylsilyloxy)octyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-6-(4-methoxybenzyloxy)hex-1-en-
1.28 mmol) and sodium chlorite (232 mg, 2.56 mmol) in water
(4 ml) was added. The solution was stirred for 4 h at room tem-
perature, then ethyl acetate and water was added to the reaction
mixture. The aqueous layer was extracted twice with EtOAc. The
combined organic layers were washed with water and brine and
dried with MgSO4. Concentrated and purified by column chroma-
tography (EtOAc:hexane¼1:2) to afford the carboxylic acid 16
3-ol (13). 1H NMR of compound 13 (200 MHz, CDCl3)
d: 7.76e7.73
(m, 4H), 7.40e7.30 (m, 8H), 6.92e6.88 (m, 2H), 5.41e5.35 (m, 2H),
4.34e4.28 (m, 3H), 4.17e4.09 (m, 1H), 3.88e3.85 (m, 1H), 3.81 (s,
3H), 3.65e3.63 (m, 1H), 3.42e3.35 (m, 2H), 1.70e1.61 (m, 4H),
1.54e1.36 (m, 12H), 1.34e1.09 (m, 15H), 0.92e0.88 (m, 3H). 13C
NMR (100 MHz, CDCl3)
d
: 159.2, 136.1, 136.1, 134.5, 134.3, 130.6,
(157 mg) in 82% yield.
28
129.2, 129.0, 127.2, 126.9, 113.7, 108.4, 80.8, 78.1, 75.5, 72.1, 69.7,
Rf¼0.3 (EtOAc:hexane¼1:3). [
a
]
þ0.9 (c 0.2, CHCl3). 1H NMR
D
55.4, 33.1, 32.1, 31.6, 29.8, 29.5, 29.1, 28.0, 27.2, 25.7, 25.3, 24.9, 22.6,
of compound 16 (200 MHz, CDCl3) d: 7.77e7.73 (m, 4H),
28
19.5, 14.1. Rf¼0.3 (EtOAc:hexane¼1:10). [
a
]
ꢀ3.9 (c 0.4, CHCl3).
7.44e7.30 (m, 6H), 5.43e5.40 (m, 2H), 4.49 (d, J¼7.0 Hz, 1H),
D

R.K. Rej et al. / Tetrahedron 70 (2014) 2634e2642
2641
4.41e4.32 (m, 2H), 4.18e4.11 (m, 1H), 3.97e3.94 (m, 1H),
3.67e3.62 (m, 1H), 3.34 (s, 3H), 2.44e2.36 (m, 2H), 1.78e1.70 (m,
2H), 1.35e1.30 (m, 9H), 1.29e1.21 (m, 9H), 1.20e1.00 (m, 9H),
(m, 2H), 1.55 (s, 3H), 1.38 (s, 3H), 1.34e1.21 (m, 10H), 0.88e0.84 (m,
3H). 13C NMR (50 MHz, CDCl3)
: 175.0,128.1,126.6,109.3, 78.5, 75.7,
70.1, 33.6, 31.9, 31.8, 31.2, 29.4, 29.2, 28.4, 26.2, 24.5, 22.6, 14.0.
HRMS (ESI) for C19H32O5Na [MþNa]þ, calculated: 363.2145; found:
363.2148.
d
0.93e0.86 (m, 3H). 13C NMR (50 MHz, CDCl3)
d: 178.2, 136.4,
134.7, 133.5, 129.9, 129.5, 129.3, 127.4, 127.1, 108.6, 94.0, 81.0, 78.0,
74.7, 72.3, 55.8, 33.4, 31.9, 30.3, 29.9, 29.3, 28.2, 27.4, 25.5, 25.0,
22.8, 19.8, 14.3. HRMS (ESI) for C37H56O7SiNa [MþNa]þ, calcu-
lated: 663.3692; found: 663.3677.
4.2.8. 4-((3aR,4R,9S,11aS,E)-4-Heptyl-2,2-dimethyl-6-oxo-
4,6,7,8,9,11a-hexahydro-3aH-[1,3]dioxolo[4,5-c]oxecin-9-yloxy)-4-
oxobutanoic acid (20). Succinic anhydride (22 mg, 0.22 mmol) was
taken in dry DCM (2 ml). DCC (61 mg, 0.3 mmol), DMAP (5 mg), and
alcohol 19 (50 mg, 0.15 mmol) were sequentially added to the re-
action mixture. The reaction mixture was kept at room temperature
for 24 h. DCM was evaporated and the crude ester was purified by
flash chromatography (EtOAc:hexane¼1:10) to afford the ester 20
(60 mg) in 90% yield.
4.2.5. (S,E)-6-((4S,5R)-5-((R)-1-Hydroxyoctyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-(methoxymethoxy)hex-5-enoic
acid
(17). Compound 16 (128 mg, 0.2 mmol) was taken in dry THF
(2 ml). TBAF (1 M in THF, 0.4 ml, 0.4 mmol) was added to the so-
lution, and the reaction mixture was then stirred for 3 h at 40 ꢁC.
THF was then evaporated, and water (2 ml) was added to it, the
reaction mixture was extracted with EtOAc (50 ml), the organic
layer was washed with NaHCO3 and brine, and dried (Na2SO4). It
was purified by flash chromatography (EtOAc:hexane¼1:1) to af-
ford compound 17 (70 mg) in 88% yield.
Rf¼0.4 (EtOAc:hexane¼1:10). [
a
]
d
28 þ31.2 (c 0.5, CHCl3). 1H NMR
D
of compound 20 (400 MHz, CDCl3)
: 5.91 (dd, J¼3.2, 15.2 Hz, 1H),
5.63 (dd, J¼2.4, 8.8 Hz, 1H), 5.29e5.18 (m, 1H), 4.96e4.88 (m, 1H),
4.72e4.67 (m, 1H), 3.98 (dd, J¼4.4, 9.6 Hz, 1H), 2.77e2.55 (m, 4H),
2.40e2.28 (m, 2H), 2.19e1.99 (m, 4H), 1.54 (s, 3H), 1.36 (s, 3H),
Rf¼0.1 (EtOAc:hexane¼1:2). [
a
]
28 þ9.9 (c 0.2, CHCl3). 1H NMR of
D
compound 17 (200 MHz, CDCl3)
d
: 5.43e5.33 (m, 2H), 4.50e4.45
1.34e1.18 (m, 10H), 0.88e0.84 (m, 3H). 13C NMR (50 MHz, CDCl3)
d:
(m, 1H), 4.43e4.29 (m, 2H), 4.12e4.09 (m, 1H), 3.95e3.92 (m, 1H),
3.64e3.56 (m, 1H), 3.27 (s, 3H), 2.38e2.34 (m, 2H), 1.73e1.70 (m,
2H), 1.38e1.26 (m, 9H), 1.25e1.15 (m, 9H), 0.87e0.84 (m, 3H). 13C
177.3, 174.1, 171.3, 128.2, 123.7, 109.4, 78.5, 76.9, 75.5, 71.0, 31.9, 31.7,
30.9, 30.5, 29.3, 29.1, 28.9, 28.5, 28.4, 26.1, 24.4, 22.6, 14.0. HRMS
(ESI) for
463.2284.
C
23H36O8Na [MþNa]þ, calculated: 463.2290; found:
NMR (50 MHz, CDCl3) d: 178.2, 108.6, 94.0, 81.0, 78.0, 74.8, 72.3,
55.8, 33.5, 31.9, 30.3, 29.9, 29.3, 28.2, 27.5, 25.5, 25.0, 22.8,19.8, 14.3.
HRMS (ESI) for C21H38O7Na [MþNa]þ, calculated: 425.2515; found:
425.2518.
4.2.9. 4-((5S,8S,9S,10R,E)-10-Heptyl-8,9-dihydroxy-2-oxo-
3,4,5,8,9,10-hexahydro-2H-oxecin-5-yloxy)-4-oxobutanoic acid (xyo-
lide). To a solution of compound 20 (26 mg, 0.06 mmol) in THF
(5 ml), HCl (1 ml, 2 M) was added at room temperature and stirred
for 12 h. Water was added to the reaction mixture and it was
extracted with ethyl acetate. The organic layer was washed with
NaHCO3 and brine. It was then dried over MgSO4, concentrated in
a rotary evaporator, and purified by silica gel column chromatog-
raphy (EtOAc:hexane¼1:1) to afford the target molecule xyolide
4.2.6. (3aR,4R,9S,11aS,E)-4-Heptyl-9-(methoxymethoxy)-2,2-
dimethyl-7,8,9,11a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]oxecin-6(4H)-
one (18). To a solution of MBNA (46 mg, 0.13 mmol), DIPEA
(0.181 ml, 1.05 mmol), and DMAP (15 mg, 0.12 mmol) in toluene
(35 ml) at room temperature was added a solution of seco-acid 17
(41 mg, 0.1 mmol) in toluene (15 ml). After that the reaction mix-
ture was stirred for 24 h at 60 ꢁC, then cooled to room temperature
and quenched by adding saturated aqueous NaHCO3 solution. The
organic solution was then successively washed with water, brine,
and dried over MgSO4. The organic solvent was evaporated to fur-
nish the crude product, which was purified by silica gel column
chromatography (EtOAc:hexane¼1:20) to afford the lactone 18
(26 mg) in 68% yield.
(21 mg) in 85% yield.
28
Rf¼0.3 (EtOAc:hexane¼2:1). [
a
]
D
þ10.1 (c 0.8, CHCl3). 1H NMR
of Xyolide (400 MHz, CDCl3)
d
: 5.86 (dd, J¼1.8, 15.4 Hz, 1H), 5.50
(ddd, J¼1.4, 9.6, 15.4 Hz, 1H), 5.18e5.10 (m, 1H), 4.99 (td, J¼1.8,
9.6 Hz, 1H), 4.52e4.49 (m, 1H), 3.60 (dd, J¼1.8, 9.6 Hz, 1H), 2.67 (t,
J¼6.2 Hz, 2H), 2.62 (t, J¼5.8 Hz, 2H), 2.40e2.31 (m, 1H), 2.12e1.98
(m, 3H), 1.91e1.82 (m, 1H), 1.57e1.48 (m, 1H), 1.37e1.17 (m, 10H),
Rf¼0.3 (EtOAc:hexane¼1:10). [
a
]
d
28 þ11.9 (c 0.3, CHCl3). 1H NMR
0.88 (t, J¼6.8 Hz, 3H). 13C NMR (50 MHz, CDCl3)
d: 176.5,174.5,171.6,
D
of compound 18 (200 MHz, CDCl3)
: 5.84 (dd, J¼3.8, 15.4 Hz, 1H),
132.6, 123.5, 76.4, 73.5, 72.5, 70.8, 31.7, 31.5, 31.2, 29.6, 29.4, 29.3,
29.1, 28.8, 24.5, 22.6, 14.0. HRMS (ESI) for C20H32O8Na [MþNa]þ,
calculated: 423.1982; found: 423.1978.
5.38e5.24 (m, 2H), 4.75 (d, J¼6.6 Hz, 1H), 4.56 (d, J¼6.6 Hz, 1H),
4.43e4.36 (m, 1H), 4.17e4.08 (m, 2H), 3.38 (s, 3H), 2.45e2.23 (m,
4H), 1.71e1.60 (m, 2H), 1.44 (s, 3H), 1.38 (s, 3H), 1.32e1.10 (m, 10H),
0.90e0.87 (m, 3H). 13C NMR (50 MHz, CDCl3)
d: 175.0, 133.9, 130.0,
Acknowledgements
108.2, 94.2, 79.0, 78.2, 77.8, 68.9, 55.6, 32.9, 31.9, 31.4, 29.9, 29.4,
29.3, 28.9, 26.1, 25.5, 22.8, 14.2. HRMS (ESI) for C21H36O6Na
[MþNa]þ, calculated: 407.2409; found: 407.2412.
Financial support from CSIR-India is gratefully acknowledged
(Grant: 02(0020)/11/EMR-II). We are also thankful to DST-India
(IRPHA) for NMR instrument. One of the authors R.K.R. is thank-
ful to CSIR-India for providing research fellowship.
4.2.7. (3aR,4R,9S,11aS,E)-4-Heptyl-9-hydroxy-2,2-dimethyl-
7,8,9,11a-tetrahydro-3aH-[1,3]dioxolo[4,5-c]oxecin-6(4H)-one
(19). To a solution of compound 18 (69 mg, 0.18 mmol) in dry DCM
(10 ml) was added activated KHSO4$SiO2 (0.68 g, 4.3 mmol). The
reaction mixture was stirred for 4 h at room temperature then fil-
tered through a plug of cotton wool and washed with ethyl acetate
until the filtrate dripped clear. The filtrate was concentrated in
vacuo to give a black residue. Purification of the residue by flash
column chromatography using (EtOAc:hexane¼1:10) afforded al-
Supplementary data
Copies of 1H, 13C NMR spectra of all compounds, and HPLC
chromatogram of racemic and enantiopure 3 and 7 is provided.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.072.
cohol 19 (52 mg, 86%) as a yellow oil.
28
Rf¼0.4 (EtOAc:hexane¼1:5). [
a
]
þ39.9 (c 0.2, CHCl3). 1H NMR
D
d
References and notes
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: 5.82 (dd, J¼3.2, 15.8 Hz, 1H),
5.66 (dd, J¼1.6, 8.4 Hz, 1H), 4.96e4.90 (m, 1H), 4.70e4.67 (m, 1H),
4.21e3.98 (m, 2H), 2.37e2.31 (m, 2H), 2.09e2.01 (m, 2H), 1.85e1.74
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