Formal total synthesis of Palmerolide A

Article abstract of DOI:10.1016/j.tet.2015.06.036

A stereoselective formal total synthesis of the 20-membered marine macrolide Palmerolide A, a highly potent antitumor agent, is described. The key steps involved in this synthesis are reductive elimination, Sharpless asymmetric dihydroxylation, protecting

Full text of DOI:10.1016/j.tet.2015.06.036

Accepted Manuscript
Formal Total Synthesis of Palmerolide A
Bighnanshu K. Jena, Debendra K. Mohapatra
PII:
S0040-4020(15)00905-9
10.1016/j.tet.2015.06.036
TET 26871
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 February 2015
Revised Date: 6 June 2015
Accepted Date: 9 June 2015
Please cite this article as: Jena BK, Mohapatra DK, Formal Total Synthesis of Palmerolide A,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.036.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Formal total synthesis of palmerolide A
Leave this area blank for abstract info.
*
Bighnansu Jena and Debendra K. Mohapatra
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
O
O
1
1
O
O
OMOM
OMOM
H
2
0
20
Exclusively E-isomer
RCM
N
TBSO
19
19
O
7
7
EtOOC
O
OH
OH
PMBO
PMBO
O
1
5
HO
1
15
Palmerolide A (1a)
HO
11
OMOM
OMOM
1
0
10
OCONH
2
1
OCONH
2

ACCEPTED MANUSCRIPT
Graphical Abstract
Formal total synthesis of palmerolide A
Leave this area blank for abstract info.
*
Bighnanshu K. Jena and Debendra K. Mohapatra
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India
O
O
1
1
O
O
OMOM
OMOM
H
2
0
20
Exclusively E-isomer
RCM
N
TBSO
19
19
O
7
7
EtOOC
O
OH
OH
PMBO
PMBO
O
1
5
HO
1
15
Palmerolide A (1a)
HO
11
OMOM
OMOM
1
0
10
OCONH
2
1
OCONH
2

Tetrahedron
1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Formal Total Synthesis of Palmerolide A
Bighnanshu K. Jena and Debendra K. Mohapatra∗
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A stereoselective formal total synthesis of the 20-membered marine macrolide Palmerolide
A, a highly potent antitumor agent, is described. The key steps involved in this synthesis
are reductive elimination, Sharpless asymmetric dihydroxylation, protecting group
dependent ring-closing metathesis reaction, Sharpless asymmetric epoxidation, Takai
olefination and macrolactonization via Heck coupling reaction.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Palmerolide A, Macrolide, Sharpless asymmetric
dihydroxylation, Takai olefination, Ring-closing
metathesis.
1
. Introduction:
A significant number of macrocyclic natural products from
marine flora and fauna have been extensively used in past and
present for the treatment of many diseases and serve as
compounds of interest both in their natural form and as templates
for synthetic modification for the development of several novel
therapeutic agents many of which are already been marketed as
1
drugs. A natural product enters into the drug discovery process
through its potency, selectivity, and pharmacokinetic traits
required for portraying it as a clinically useful drug agent. During
2
the search for new potent drug molecules, Baker and co-workers
in 2006 reported the isolation and structural determination of
Palmerolide A, the most prominent member of Palmerolide
group, which is mainly due to its cytotoxicity, from the Antarctic
marine tunicate Synoicum adareanum. Palmerolide A is a
complex natural product comprising of a side chain containing an
enamide,
stereogenic centers, seven unsaturations with E-configuration and
0-membered macrolide ring. This natural product demonstrated
a 1,3-diene system, a carbamate moiety, five
Figure 1. Structures of originally proposed (1) and revised
Palmerolide A (1a).
2
extraordinary cytotoxic activity against the melanoma cell lines
3
UACC-62 (LC50 =18 nM) by inhibiting the proliferation of
3
Considering all these synthetic reports, a distinct retrosynthesis
vacuolar ATPase with an IC50 of 2 nM. The remarkable 10 in
7
of macrolactone core 2 including intramolecular Heck coupling,
vitro selectivity index for the melanoma cell lines prompted
further biological evaluation of the compound. These findings
coupled with the scarce natural abundance of Palmerolide A
8
intermolecular Yamaguchi reaction, protecting group dependent
ring-closing metathesis reaction for the building of fragment 3,
9
4
regioselective reductive opening of epoxide by Me Al and Takai
3
generated considerable interest in its chemical synthesis. Several
10
olefination of methyl ketone to form vinyl iodide for the
construction of C16-C23 fragment was envisioned. Different
established methodologies for the construction of intermediates
were taken up to ensure an easy access to synthesize the required
stereoisomers and other variants of Palmerolide A. As part of our
ongoing research program on the synthesis of biologically active
synthetic endeavours towards Palmerolide A led to the first total
synthesis and revision of stereochemistry by De Brabander’s
4
a
4b-d
group. Afterwards two more total syntheses by Nicolaou,
4e
5
6
and Hall, five formal syntheses and several approaches,
6
i
including ours towards Palmerolide A have been reported in the
literature.
—
——
∗
Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27193128; e-mail: mohapatra@iict.res.in

2
Tetrahedron
natural and unnatural products using protecting group
allylic alcohol 11 in 82% yield over two steps (Scheme 2). The
ACCEPTED MANUSCRIPT
11
dependent ring-closing metathesis approach, the synthesis of
macrolactone core 2 was targeted which is a late-stage
intermediate of Palmerolide A leading to a formal total synthesis
of the target molecule.
resulting alcohol was masked as its PMB-ether with PMB-Br in
presence of NaH. Desilylation of 12 by treatment with TBAF
generated primary alcohol 13 in 94% yield. The primary alcohol
1
6
13 was oxidized to corresponding aldehyde using IBX followed
by subsequent oxidation under Pinnick conditions using NaClO
furnishing acid fragment 6 in 84% yield over two steps.
2
1
7
According to the retrosynthetic analysis of Palmerolide A (1a) as
shown in Scheme 1, macrolactone core 2 could be constructed
through esterification of 3 and 4, followed by intramolecular
Heck coupling. Fragment 3 could be obtained from the 13-
membered macrolactone 5, which in turn could be prepared from
The synthesis of alcohol fragment 7 started with commercially
7
18
available 1,4-butane diol following a literature protocol, to
obtain α,β-unsaturated ester 15. The olefin was treated with
osmium tetroxide and AD-mix-α under Sharpless asymmetric
6
and 7 via coupling, followed by ring-closing metathesis
12
19
reaction of the resulting diene compound.
dihydroxylation conditions to give diol 16 (89% yield with 98%
(
DHQ)
2
PHAL, MeSO
, K Fe(CN)
6
2
NH
2
4
OTBDPS
K
2
CO
3
3
OH Ref. 15
HO
2
CO Et
t-BuOH:H
2
O (2:1), OSO
4 h, 0 oC, 89%
14
15
2
OH
O
OTBDPS
2TBDPSO
2,2-DMP, CH
2
Cl
DIBAL-H, CH
2
Cl
2
CO
2
Et
2
CO Et
0 oC, 92%, 30 min
CSA, rt, 3 h, 92%
OH
O
16
17
DMP, CH
rt, 2 h
2
Cl
2
TBDPSO
O
TBDPSO
O
AcOH:H
2
O (3:2)
OH
+
-
(
3
PPh -CH
3
) Br
50 C, 3 h, 87%
o
NaHMDS, THF
-78 oC, 4 h, 70%
O
19
O
18
yield over two steps
OH
OPMB
OTBDPS
PMBBr, NaH
2
MOMCl, i-Pr EtN
TBDPSO
TBDPSO
THF, 0 o
h, 91%
C
rt, 2 h, 85%
OH
OH
21
4
20
OPMB
OPMB
TBAF, THF
rt, 4 h, 95%
HO
OMOM
OMOM
Scheme 1: Retrosynthetic analysis of Palmerolide A.
22
7
Scheme 3. Synthesis of the alcohol fragment 7.
2
. Result and discussion
ee). Protection of the diol moiety as its acetonide 17 was
achieved by treating diol 16 with 2,2-dimethoxypropane in
presence of catalytic amount of CSA in 92% yield. The ester
group was then transformed to the corresponding terminal alkene
by a three step sequence involving reduction of 17 using DIBAL-
The synthesis of acid fragment 6 commenced with 1,5-pentane
diol 9, which was converted to epoxy alcohol 10 in 90% yield
and with 97% ee through its corresponding allylic alcohol by
treating with (+)-diethyl tartrate in presence of Ti(O Pr) and t-
BuOOH under Katsuki-Sharpless conditions. Conversion of
alcohol 10 to the corresponding iodo derivative, subsequent
reductive elimination using Zn/EtOH afforded secondary
13
i
4
14
o
H in CH Cl at −78 C to afford primary alcohol 18, which on
2
2
oxidation with Dess-Martin periodinane in CH Cl and
15
2
2
subsequent one carbon homologation with PPh =CH furnished
3
2
alkene 19 in 70% yield over three steps (Scheme 3). Removal of
isopropylidene group was effected with AcOH-H O leading to
2
20
diol 20 in 87% yield.
Selective PMB protection for the allylic hydroxyl group present
in 20 with p-methoxybenzyl bromide (PMB-Br) in presence of
NaH furnished 21 in 91% yield with 5-7% bis-PMB protected
21
product. The remaining free alcohol 21 was masked as its
MOM-ether 22 with methoxymethyl chloride (MOMCl) and
N,N-diisopropylethylamine (DIPEA) in CH Cl . Having
2
2
synthesized 6 and 7, the coupling of both the fragments was
8
initially attempted under Yamaguchi conditions which afforded
the ester 23a in low yield with the mixed anhydride as the
byproduct. Similarly, coupling in the presence of dicyclohexyl
22a-c
carbodiimide (DCC)
and 4-dimethylaminopyridine (DMAP)
Scheme 2. Synthesis of the acid fragment 6.
gave an inseparable mixture of insoluble dicyclohexyl urea along
with the product. The best result was obtained when fragments 6
22d-e
and 7 were treated with EDCI
and DMAP in CH Cl with
2 2

Tetrahedron
3
respect to purification and yield (86%) setting the stage for
conditions resulted carboxylic acid 6b in 81% yield over two
steps.
ACCEPTED MANUSCRIPT
crucial ring-closing metathesis reaction (Scheme 4).
nd
Unfortunately, refluxing the diene ester with Grubbs' 2
OH
OTBDPS OMOMTBAF, THF,
MOMCl, i-Pr
2
EtN,
generation catalyst in CH Cl2 under high dilution conditions
2
TBDPSO
OH
failed to furnish the desired product leading to complete recovery
of the starting material. We envisaged that steric congestion due
to bulky PMB-protecting group around the reacting centers might
act as a temporary constraint, preventing the ring-closing
metathesis.
1
1
2 h, r.t., 91%
24
r.t., 4 h, 93%
OMOM
OMOM IBX, DMSO, THF, r.t., 3 h
NaClO , NaH PO
HOOC
2
2
4
,
2
5
2-methyl-2-butene,
t-BuOH, H O, r.t., 2 h,
1% (over two steps)
6b
OPMB
OPMB
EDCI, DMAP
CH Cl
2 2
2
8
HOOC
+
HO
0 oC to rt
OMOM
6
7
10 h, 86%
Scheme 5. Synthesis of the acid fragment 6b.
OPG
OPG
O
O
O
The diol 20 was transformed to subunit 7b via selective
protection of allylic alcohol as a MOM ether 26 and subsequent
formation of PMB ether 27 which on desilylation with TBAF in
THF at room temperature afforded 7b in 94% yield to complete
the synthesis of alcohol fragment (Scheme 6).
Grubbs' II
1
G PO
2
G PO
O
OPG1
CH Cl , reflux
2
2
OPG2
5
a. PG = PMB
23a. PG = PMB
PG1 = PMB
PG2 = MOM
PG = PMB
1
2
PG = MOM
OTBDPS OH
OTBDPS OMOM
MOMCl, i-Pr
2
EtN
PMB-Br, NaH, THF
0 oC, 6 h, 91%
Scheme 4. RCM reaction on substrate 23a.
2
h, 0 oC, 85%
OH
OH
2
0
26
After encountering failure in the endeavor to carry out RCM
reaction, the above reaction was investigated with a set of ring-
closing metathesis precursors by only changing the protecting
group of allylic alcohol. During this process, precursors bearing
dibenzyl (di-Bn) (23b), di-tert-butyldimethylsilyl (di-TBS) (23c)
failed to produce the desired macrolactone with complete
recovery of the starting material. Surprisingly, tri-MOM diene
ester (23d) was transformed into the corresponding lactone in
OMOM
OMOM
TBAF, THF
rt, 3 h, 94%
HO
TBDPSO
OPMB
OPMB
2
7
7b
Scheme 6. Synthesis of the alcohol fragment 7b
.
The required di-MOM protected diene ester 28 was synthesized
following the earlier strategy as described in Scheme 4, which
sets the stage for crucial RCM reaction. The 13-membered
7
0% yield with 20% starting material recovery in 12 h (entry 5d,
Table 1). When the above reaction was subjected to additional 24
h, complete conversion of starting material to lactone resulted in
nd
macrolactone formation proceeded smoothly with Grubbs 2
generation catalyst under reflux conditions to afford 29 in 75%
yield with exclusive formation of E-isomer. The controlled
partial reduction of macrolactone 29 in CH Cl was efficiently
7
8% yield (entry 5e, Table 1). Taking this finding into account,
when the RCM reaction was performed on diol-diene ester 23f
under high dilution conditions, required 13-membered
macrolactone (entry 5f, Table 1) was obtained in 82% yield with
complete E-selectivity (J = 15.9 Hz) with no detectable amount
of Z-isomer. This might be due to the tolerance of Grubbs’
catalyst with activated nucleophile in the form of free allylic
alcohol group.
2
2
o
dealt with calculative amount of DIBAL-H at −78 C into
OMOM
EDCI, DMAP
CH Cl , 0 oC to rt
HOOC
+
HO
2
2
OMOM
OMOM
OPMB
6
b
7b
10 h, 84%
OMOM
Table 1 Protecting group dependent RCM for 13-membered lactone
2 2
DIBAL-H, CH Cl
Grubbs' II, CH Cl
2 O
O
2
PMBO
−78 oC, 15 min
OMOM
MOMO
reflux, 32 h, 75%
O
O
1
2
RCM
Precu
rsor
PG
PG
PG
Duration RCM
in hour) Yield( %)
Starting
Material
Recovery
(
OPMB
(5a-e)
29
28
OMOM
(%)
OMOM
2
3a
3b
PMB
Bn
PMB
Bn
MOM
MOM
MOM
24
24
24
12
36
12
0
0
100
100
100
20
0
3 2
Ph P=CHCO Et EtO
2
C
benzene, reflux, 2 h
HO
PMBO
2
HO
PMBO
OMOM
)+Br-
O
77% over two steps
2
3c
3d
3e
3f
TBS
TBS
0
OMOM
31
Cl
0 oC to rt, 2 h
(
PPh
n-BuLi, THF
−78 C, 3 h
3 3
-CH
2
MOM MOM MOM
MOM MOM MOM
70
78
82
DMP, CH
2
2
30
2
o
7
8% over two steps
OMOM
2
H
H
MOM
0
OMOM
LiOH, THF/H
2
O (3:2)
2
EtO C
Keeping in mind the formal total synthesis of Palmerolide A,
protecting groups in the fragments 6 and 7 were manipulated few
steps before esterification, which was achieved based on our
previous approach. The subunit 6b was synthesized in 3 steps,
including MOM-protection of 11 with MOMCl, DIPEA in
CH Cl and subsequent (Scheme 5) desilylation. IBX oxidation of
HOOC
PMBO
PMBO
reflux, 15 h, 95%
OMOM
OMOM
3
32
2
2
Scheme 7. Synthesis of the acid fragment 3.
primary alcohol 25 and further oxidation under Pinnick

4
Tetrahedron
the corresponding lactol 30 followed by two carbon
vinyl iodide 43 which involved Takai olefination reaction. Thus,
ACCEPTED MANUSCRIPT
homologation which afforded the α,β-unsaturated ester 31 in 77%
yield over two steps (Scheme 7). The newly created primary
alcohol was oxidized with Dess-Martin periodinane followed by
one carbon Wittig olefination in THF to yield compound 32. The
ester functionality of 31 was saponified (Scheme 7) with LiOH in
Takai olefination of ketone with a mixture of CrCl and CHI in
2 3
THF furnished vinyl iodide 43 with moderate E:Z (>3:2) ratio in
10
78% yield. The di-TBS protected vinyl iodide 43 was subjected
to TBAF in THF to obtain 44 in 89% yield. At this stage, both
the isomers were separated by silica gel column chromatography.
Finally, selective silylation (Scheme 8) of 44 with TBSCl and
imidazole in CH Cl formed vinyl iodide 4 in 92% yield.
THF/H O (3:2) to furnish the required acid fragment 3 of
Palmerolide A.
2
2
2
The preparation of fragment 4 was initiated from known alcohol
After having achieved the synthesis of both the major fragments
3 and 4, the next target was to couple these fragments with slight
modification in protecting group to accomplish the formal
synthesis of Palmerolide A. Following Yamaguchi's method the
fragments 3 and 4 were coupled to obtain ester 45, which on
treatment with DDQ smoothly produced homoallylic alcohol 46
in 95% yield. The resulting homoallylic alcohol was masked
3
4
which was made 2 available in two steps from
3
homoproapargylic alcohol. The acetylenic bond in compound
4 was selectively reduced to furnish cis-olefin 35 through nickel
3
24
boride reduction in 89% yield. The epoxide alcohol 36 was
obtained through Sharpless asymmetric epoxidation with (+)-
25
DIPT chiral ligand from cis-olefin 35 in 96% yield and 92% ee.
The epoxide unsaturated ester 37 was prepared from optically
active epoxy alcohol in 68% yield through Swern oxidation
followed by Horner-Wadsworth-Emmons reaction. Methylative
OH
OMOM
3 6 2 3
2,4,6-Cl C H COCl, Et N
TBSO
+
HO2C
DMAP, toluene, 4 h, 93%
O
PMBO
opening of epoxide ring of 37 proceeded smoothly with Me Al in
3
4
OMOM
OTBS
I
3
presence of small amount of water to afford a single diastereomer
O
3
8 (97% de as checked by HPLC) in 91%
O
OTBS
O
DDQ, CH
2
Cl
2 2
:H O
(
19:1), pH 7 buffer
OMOM
OMOM
I MOMO
r.t., 30 min, 95%
I MOMO
OTBS
46
45
OH
OPMB
O
O
OTBS
O
O
TBSOTf
,6-lutidine
Pd(OAc)
2
K CO ,
2 3
2
OMOM
, 0 o
2
C
OMOM
MOMO
CH
1
2
Cl
h, 96%
DMF, 80 o
I MOMO
C
2
h, 60%
2
OTBS
47
OTBS
Scheme 9. Synthesis of macrocyclic core 2 of Palmerolide A.
o
using TBSOTf and 2,6-lutidine at 0 C to furnish the requisite
7
compound 47 in 96% yield. The final Heck coupling following
the procedure employed by Prasad et. al. furnished the
macrocyclic core 2 of Palmerolide A (Scheme 9), whose spectral
and analytical data were in good agreement with the reported
5a
one, which successfully completed the formal total synthesis of
Palmerolide A.
3
. Conclusion:
In conclusion, a stereocontrolled and convergent formal total
synthesis of Palmerolide A having useful biological profile has
been achieved. The key features of the synthesis were protecting
group directed RCM reaction, regioselective epoxide opening by
Me Al and macrolactonization via Heck coupling, novel Takai
3
Scheme 8. Synthesis of the alcohol fragment 4.
olefination which has not been applied for previous syntheses of
Palmerolide A for the installation of trans-vinyl iodide (C16-
C17).
9
yield. Reduction of unsaturated ester 38 with DIBAL-H in
CH Cl followed by protection of the resulting diol 39 with
2
2
TBSOTf and 2,6-lutidine afforded diTBS ether 40 in 93% yield.
4
4
. Experimental section
26
Oxidative removal of PMB ether compound 40 with DDQ in
CH Cl /H O at room temperature furnished 41 in 92% yield. The
2
2
2
.1. General Remarks:
resulting primary alcohol 41 was transformed into methyl ketone
by a three step reaction sequence involving Dess-Martin
8
Air and/or moisture sensitive reactions were carried out in
27
periodinane oxidation which furnished the corresponding
aldehyde, followed by addition of MeMgBr in THF producing
the secondary alcohol 42 in 79% yield. Subsequent oxidation
with Dess-Martin periodinane provided methyl ketone 8 in 91%
yield. The next task was the conversion of methyl ketone 8 to
anhydrous solvents under an atmosphere of argon in an oven or
flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF, benzene, toluene, diethyl ether from Na and
benzophenone; CH Cl , DMSO, DMF, hexane from CaH ;
2
2
2
MeOH, EtOH from Mg cake. Commercial reagents were used

Tetrahedron
5
without purification. Column chromatography was carried out by
−8.0 (c 0.90, CHCl ); IR (neat): 3071, 2932, 2859, 1738, 1613,
3
−1 1
ACCEPTED MANUSCRIPT
using silica gel (60–120 mesh). Specific optical rotations [α] are
1513, 1463, 1301, 1247, 1172, 1038, 926, 822 cm ; H NMR
(300 MHz, CDCl ) δ = 7.69-7.58 (m, 4H), 7.41-7.27 (m, 6H),
7.17 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.68 (m, 1H),
5.23-5.10 (m, 2H), 4.35 (AB , J = 11.5, 78.6 Hz, 2H), 3.74 (s,
D
−1
2 −1
given in 10 degcm g . Infrared spectra were recorded in
3
−
1
CHCl /neat (as mentioned) and reported in wave number (cm ).
3
1
TOF analyzer type was used for the HRMS measurement. H and
q
13
13
C NMR chemical shifts are reported in ppm downfield from
tetramethylsilane and coupling constants (J) are reported in hertz
Hz). The following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad.
3H), 3.69-3.57 (m, 3H), 1.68-1.31 (m, 6H), 1.04 (s, 9H) ppm;
C
NMR (75 MHz, CDCl ) δ = 159.0, 139.2, 135.5, 134.0, 129.4,
129.2, 127.5, 116.8, 113.7, 80.2, 69.6, 63.8, 55.1, 35.2, 32.4,
26.8, 21.7, 19.2 ppm; ESI-HRMS Calcd for C H O Na [M +
3
(
31
40
3
+
Na] 511.2644; found: 511.2623.
4
.2. (S)-7-(tert-Butyldiphenylsilyloxy)hept-1-en-3-ol (11)
To a stirred solution of epoxide 10 (5.2 g, 13.53 mmol) in
4.4. (S)-5-(4-Methoxybenzyloxy)hept-6-en-1-ol (13)
TBAF (15.77 mL, 1 M in THF, 15.77 mmol) was added to a
THF (50 mL), was added triphenylphosphine (7.1 g, 27.07
mmol), Imidazole (1.84 g, 27.07 mmol) at 0 C and stirred for 20
stirred solution of PMB ether compound (3.85 g, 7.88 mmol) in
o
o
THF (30 mL) at 0 C under N
atmosphere. The reaction mixture
2
was stirred at room temperature for 4 h. After completion of the
reaction (monitored by TLC), it was quenched with water (30
mL). The aqueous layer was extracted with ethyl acetate (3 × 30
mL). The combined organic layer was dried over anhydrous
Na SO and solvent removed under reduced pressure. The crude
min under N atmosphere. A solution of iodine (4.12 g, 16.24
mmol) in THF (20 mL) was added to the reaction mixture at 0 C
2
o
dropwise until decolourisation of reaction mixture ceases. After
completion of the reaction (monitored by TLC), it was treated
with saturated solution of sodium thiosulfate (30 mL). The
organic layer was separated and the aqueous layer extracted with
ethyl acetate (2 × 50 mL). The combined organic layer was dried
2
4
mass was purified by silica gel chromatography (EtOAc/hexane
1:4) to afford 13 (1.85 g, 94%) as a colorless liquid; Rf
=
27
(EtOAc/hexane = 1:4) 0.25. [α]D −12.6 (c 0.76, CHCl ); IR
3
over anhydrous Na SO4 and solvent removed under reduced
2
(
9
neat): 3481, 2934, 2884, 1736, 1613, 1514, 1465, 1248, 1036,
pressure. The crude Iodo compound was taken to next reaction
without purification (6.15 g).
−1 1
21, 822 cm ; H NMR (300 MHz, CDCl ) δ = 7.19 (d, J = 8.7
3
Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 5.70 (m, 1H), 5.23-5.12 (m,
2
3
H), 4.49 (d, J = 11.5 Hz, 1H), 4.22 (d, J = 11.5 Hz, 1H), 3.78 (s,
H), 3.67 (m, 1H), 3.56 (t, J = 6.2 Hz, 2H), 1.69-1.32 (m, 6H)
Activated Zn (4.07 g, 62.23 mmol) and NaI (3.73 g, 24.9 mmol)
were added to a stirred solution of crude iodo compound (6.15 g,
13
ppm; C NMR (75 MHz, CDCl ) δ = 159.0, 139.0, 130.7, 129.3,
1
HRMS Calcd for C H O Na [M + Na] 273.1466; found:
2
3
1
2.45 mmol) in MeOH (50 mL). The reaction mixture was stirred
17.1, 113.7, 80.1, 69.7, 62.7, 55.2, 35.1, 32.5, 21.5 pm; ESI-
o
+
for 3 h at 70 C. After completion of the reaction (monitored by
TLC), the reaction mass was filtered through Celite pad.
Methanol was removed under reduced pressure and the crude
mass was washed with ethyl acetate. The organic layer was
15
22
3
73.1476.
4
.5. (S)-5-(4-Methoxybenzyl)oxy)hept-6-enoic acid (6)
washed with saturated NH Cl solution (30 mL) and the aqueous
4
To a stirred solution of 2-iodoxybenzoic acid (IBX) (1.82 g, 6.5
mmol) in DMSO (10 mL), was added a solution of alcohol 13
1.42 g, 5.68 mmol) in anhydrous THF (20 mL) at room
layer was extracted with ethyl acetate (2 × 50 mL). The
combined organic layer was dried over anhydrous Na SO and
2
4
(
solvent removed under reduced pressure. The crude mass was
purified by silica gel column chromatography (EtOAc/hexane =
temperature. After stirring for 4 h, the reaction mixture was
diluted with Et O (50 mL). The solid precipitated were filtered
2
1
:4) to afford 11 (4.08 g, 81.8% over two steps) as a colorless
off and the residue was washed with Et O (60 mL). The
27
2
liquid; R (EtOAc/hexane = 1:4) 0.45. [α]D +4.7 (c 0.4, CHCl3);
f
combined filtrate and washings were successively washed with
IR (neat): 3362, 2932, 2859, 1716, 1428, 1390, 1260, 1111,
aqueous NaHCO (50 mL), brine (2 × 50 mL). The combined
−
1
1
3
9
4
22,702 cm ; H NMR (300 MHz, CDCl ) δ = 7.67-7.59 (m,
3
organic layers were dried over anhydrous Na SO and
2
4
H), 7.42-7.29 (m, 6H), 5.81 (m, 1H), 5.23-5.03 (m, 2H), 4.05
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (EtOAc/hexane = 1:4)
to afford aldehyde (1.24 g, 91%) as light yellow liquid which was
used for the next step without further purification.
(
m, 1H), 3.64 (t, J = 6.2 Hz, 2H), 1.64-1.36 (m, 6H), 1.04 (s, 9H)
13
ppm; C NMR (75 MHz, CDCl ) δ = 141.1, 135.5, 134.0, 129.5,
3
1
27.6, 114.6, 73.1, 63.7, 36.6, 32.3, 26.8, 21.6, 19.2 ppm; ESI-
+
HRMS Calcd for C H O Na [M + Na] 391.2069; found:
23
32
2
3
91.2077.
To a solution of resulting aldehyde (1.24 g, 5.0 mmol) in t-BuOH
(
15 mL), 2-methyl-2-butene (5 mL, 10 mmol, 2M solution in
4
.3. (S)-tert-Butyl(5-(4-methoxybenzyloxy)hept-6-enyloxy)-
THF) was added at room temperature. Sodium dihydrogen
phosphate (2.34 g, 15.0 mmol) and sodium chlorite (0.678 g, 7.5
mmol) were dissolved in water (15 mL) to make a clear solution
diphenylsilane (12)
o
To a solution of 11 (3.5 g, 9.50 mmol) in dry THF (45 mL), was
added NaH (0.95 g, 23.75 mmol; 60% dispersion in mineral oil)
at 0 C, and the mixture was stirred for 30 min. Then, PMB-Br
and added to the above reaction mixture at 0 C. The reaction
mixture was stirred for another 3 h at room temperature. After
completion of the reaction (monitored by TLC), the reaction
mixture was extracted with EtOAc (3 x 50 mL). The combined
organic layers were washed with brine (2 × 75 mL), dried over
anhydrous Na SO and evaporated under reduced pressure. The
crude product was purified by silica gel chromatography
(EtOAc/hexane = 3:2) to afford the desired acid 6 (1.21 g, 92%)
as a colorless oil; R (EtOAc/hexane = 3:2) 0.45. [α] −6.2 (c
1.45, CHCl ); IR (neat): 3075, 2928, 2856, 1708, 1612, 1514,
o
(1.64 g, 11.40 mmol), catalytic TBAI (0.1 g) was added and the
o
solution was stirred for additional 3 h at 50 C. After completion
of the reaction (monitored by TLC), the reaction was warmed to
0
extracted with ethyl acetate (2 × 35 mL), dried over anhydrous
Na SO4 and evaporation of the solvent was effected under
reduced pressure. The crude mass was purified by silica gel
column chromatography (EtOAc/hexane = 1:4) to afford 12 (4.22
2
4
o
C and quenched by H O drop-wise. The aqueous layer was
2
2
7
2
f
D
3
−1
1
1422, 1248, 1172, 1035 cm ; H NMR (300 MHz, CDCl ) δ =
7.18 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.3 Hz, 2H), 5.70 (m, 1H)
3
27
g, 91%) as a yellow liquid; R (EtOAc/hexane = 1:4) 0.30. [α]
f
D

6
Tetrahedron
5
.24-5.14 (m, 2H), 4.36 (AB , J = 12.1, 80.1 Hz, 2H), 3.77 (s,
filtrate and washings were successively washed with aqueous
q
ACCEPTED MANUSCRIPT
3
H), 3.69 (m, 1H), 2.3 (t, J = 6.8 Hz, 2H), 1.79-1.45 (m, 4H)
NaHCO (75 mL), H O (2 × 75 mL), brine (75 mL). The
3
2
13
ppm; C NMR (75 MHz, CDCl ) δ = 179.5, 159.0, 138.5, 130.4,
combined organic layers were dried over anhydrous Na SO and
2 4
3
1
29.3, 117.3, 113.7, 79.5, 69.6, 55.1, 34.6, 33.7, 20.5 ppm; ESI-
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (EtOAc/hexane = 1:4)
to afford (1.8 g, 89%) aldehyde as light yellow liquid which was
used for the next step without further purification.
+
HRMS Calcd for C H O Na [M + Na] 287.1259; found:
2
15
20
4
87.1256.
4
1
.6. (S)-12,12-Dimethyl-11,11-diphenyl-5-vinyl-2,4,10-trioxa-
1-silatridecane (24)
To a solution of resulting aldehyde (1.8 g, 10.47 mmol) in t-
BuOH (20 mL), 2-methyl-2-butene (10.47 mL, 20.94 mmol, 2M
solution in THF) was added at room temperature. Sodium
dihydrogenphosphate (4.9 g, 31.41 mmol) and sodium chlorite
(1.42 g, 15.70 mmol) were dissolved in water (15 mL) to make a
To a stirred solution of compound 11 (4.6 g, 12.49 mmol) in
CH Cl (45 mL), was added diisopropylethylamine (6.5 mL,
3
Methoxymethyl chloride (1.42 mL, 18.74 mmol) was added to
the reaction mixture at same temperature and allowed to stir for
1
2
2
o
7.43 mmol) and stirred for 30 min at 0 C under N atmosphere.
2
o
clear solution and added to the above reaction mixture at 0 C.
The reaction mixture was stirred for another 3 h at room
temperature. After completion of the reaction (monitored by
TLC), the reaction mixture was extracted with EtOAc (3 × 60
mL). The combined organic layer were washed with brine (100
0 h at room temperature. After completion of the reaction
(monitored by TLC), it was quenched with H O (30 mL). The
2
organic layer was separated and the aqueous layer extracted with
CH Cl (2 × 50 mL). The combined organic layer was dried over
mL), dried over anhydrous Na SO and evaporated under reduced
2 4
2
2
anhydrous Na SO and solvent removed under reduced pressure.
pressure. The crude product was purified by silica gel
2
4
The crude mass was purified by silica gel column
chromatography (EtOAc/hexane = 3:2) to afford desired acid 6b
chromatography (EtOAc/hexane = 1:4) to afford MOM ether 24
(1.79 g, 91%) as a colorless oil; R
f
(EtOAc/hexane = 3:2) 0.40.
−34.4 (c 2.4, CHCl ); IR (neat): 3082, 2935, 2890, 1712,
3
27
(
[
1
4.68 g, 91%) as a colorless liquid; R (EtOAc/hexane = 1:4) 0.40.
[α]
1419, 1150, 1097, 1033 cm ; H NMR (300 MHz, CDCl ) δ =
3
D
f
27
−1 1
α]D −15.0 (c 4.30, CHCl ); IR (neat): 2935, 2861, 1468, 1428,
3
−1 1
104, 1037, 922, 822, 704, 613, 505 cm ; H NMR (300 MHz,
5.66 (m, 1H), 5.25-5.16 (m, 2H), 4.70 (d, J = 6.8 Hz, 1H), 4.53
(d, J = 6.8 Hz, 1H), 4.00 (m, 1H), 3.37 (s, 3H), 2.41-2.35 (m,
CDCl ) δ = 7.65-7.60 (m, 4H), 7.41-7.29 (m, 6H), 5.61 (m, 1H),
3
13
5
1
1
1
3
.22-5.11 (m, 2H), 4.64 (d, J = 6.8 Hz, 1H), 4.45 (d, J = 6.8 Hz,
H), 3.93 (m, 1H), 3.63 (t, J = 6.0 Hz, 2H), 3.32 (s, 3H), 1.65-
2H), 1.82-1.50 (m, 4H) ppm; C NMR (75 MHz, CDCl
) δ =
3
179.3, 137.9, 117.5, 93.6, 76.9 , 55.4, 34.5, 33.8, 20.6 ppm; ESI-
13
+
.40 (m, 6H), 1.03 (s, 9H) ppm; C NMR (75 MHz, CDCl ) δ =
HRMS Calcd for C
211.0941.
H O Na [M + Na] 211.0940; found:
9 16 4
3
38.4, 135.5, 134.0, 129.5, 127.6, 117.1, 93.6, 77.3, 63.8, 55.4,
5.1, 32.4, 26.8, 21.7, 19.2 ppm; ESI-HRMS Calcd for
+
C H O Na [M + Na] 435.2330; found: 435.2325.
4.9. (2R,3S)-Ethyl-6-(tert-butyldiphenylsilyloxy)-2,3-dihydro
25
36
3
xyhexanoate (16)
4
.7. (S)-5-(Methoxymethoxy)hept-6-en-1-ol (25)
To a stirred mixture of K [Fe(CN) ] (26.17 g, 79.50 mmol) and
3
6
K CO (10.97 g, 79.50 mmol) in H O (132.5 mL), (DHQ) PHAL
TBAF (21.58 mL, 1 M in THF, 21.58 mmol) was added to a
2
3
2
2
(0.21 g, 0.26 mmol) was added. After being stirred for 5 min, the
stirred solution of MOM ether compound (4.45 g, 10.79 mmol)
o
α,β unsaturated ester 15 (10.5 g, 26.50 mmol) in t-BuOH (132.5
in THF (35 mL) at 0 C under N atmosphere. The reaction
2
o
mL) was added to the reaction mixture at 0 C. OsO (0.04 mL,
mixture was stirred at room temperature for 4 h. After completion
of the reaction (monitored by TLC), it was quenched with water
30 mL). The aqueous layer extracted with ethyl acetate (2 × 35
4
1
0% solution in toluene) followed by methane sulfonamide (2.51
g, 26.5 mmol) was added at same temperature. The reaction
(
o
mixture was then stirred at 0 C for 24 h and then quenched with
mL). The combined organic layer was dried over anhydrous
Na SO and solvent removed under reduced pressure. The crude
solid sodium metabisulfite (5 g). The stirring was continued for
additional 1 h and then extracted with ethyl acetate (3 × 60 mL).
The combined organic extracts were washed with saturated
2
4
mass was purified by silica gel chromatography (EtOAc/hexane
1:4) to afford 25 (1.75 g, 93%) as a colorless liquid; R
=
(
(
7
5
3
2
f
27
NaHCO solution and then with brine, dried over Na SO and
EtOAc/hexane = 1:4) 0.35. [α]D −35.9 (c 4.57, CHCl ); IR
3
2
4
3
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane =
neat): 3412, 2936, 2879, 1726, 1443, 1248, 1149, 1036, 921,
−1
1
72 cm ; H NMR (400 MHz, CDCl ) δ = 5.60 (m, 1H), 5.20-
3
1
:4) to afford 16 (10.15 g, 89%) as a colorless viscous liquid; R
.11 (m, 2H), 4.62 (d, J = 6.7 Hz, 1H), 4.44 (d, J = 6.7 Hz, 1H),
.93 (q, J = 6.7 Hz, 1H), 3.56 (t, J = 6.7 Hz, 2H), 3.31 (s, 3H),
f
27
(EtOAc/hexane = 1:4) 0.25. [α]D −7.2 (c 6.80, CHCl ); IR
3
13
(
neat): 3443, 2933, 2860, 1735, 1635, 1468, 1390, 1210, 1107,
.25 (bs, 1H), 1.64-1.32 (m, 6H) ppm; C NMR (75 MHz,
−1 1
8
4
1
21, 703 cm ; H NMR (500 MHz, CDCl ) δ = 7.63 (d, J = 5.9,
CDCl ) δ = 138.1, 117.2, 93.6, 77.2, 62.5, 55.3, 35.0, 32.4, 21.4
3
3
+
H), 7.41-7.32 (m, 6H), 4.27 (dd, J = 6.9, 14.8, 2H), 3.98 (m,
H), 3.87 (m, 1H), 3.71-3.67 (m, 2H), 2.95 (d, J = 5.9, 1H), 2.24
ppm; ESI-HRMS Calcd for C H O [M + H] 175.1328; found:
9
19
3
1
75.1321.
(
d, J = 7.9, 1H), 1.76-1.66 (m, 4H), 1.32 (t, J = 6.9 Hz, 3H), 1.04
13
(s, 9H) ppm; C NMR (75 MHz, CDCl ) δ = 173.5, 135.5, 133.6,
3
4
.8. (S)-5-(Methoxymethoxy)hept-6-enoic acid (6b)
1
29.6, 127.6, 73.4, 72.3, 63.9, 62.0, 30.6, 28.7, 26.8, 19.2, 14.2
+
ppm; ESI-HRMS Calcd for C H O SiNa [M + Na] 453.2073;
24
34
5
To a stirred solution of 2-iodoxybenzoic acid (IBX) (3.9 g,
4.0 mmol) in DMSO (20 mL), was added a solution of alcohol
4 (1.85 g, 10.75 mmol) in anhydrous THF (30 mL) at room
found: 453.2054.
1
2
4
2
.10. (4R,5S)-Ethyl-5-(3-(tert-butyldiphenylsilyloxy)propyl)-
,2-di-methyl-1,3-dioxolane-4-carboxylate (17)
temperature and stirring was continued for further 4 h. After
completion of the reaction (monitored by TLC), Et O (60 mL)
2
was added to the reaction mixture, precipitated solid was filtered
off and the residue washed with Et O (50 mL). The combined
To a stirred solution of diol 16 (9.8 g, 22.78 mmol) in CH Cl
2 2
2

Tetrahedron
7
(
40 mL), was added 2,2-dimethoxypropane (13.95 g, 113.89
cooled to –78 ºC. The crude aldehyde (6.3 g, 14.78 mmol) in
ACCEPTED MANUSCRIPT
mmol) and a catalytic amount of camphorsulfonic acid (264 mg)
at 0 °C. The mixture was continued to stir at room temperature
THF (25 mL) was added to the reaction mixture drop wise. The
reaction mixture was stirred at the same temperature for 4 h.
After complete consumption of the starting material (monitored
for 1 h under N atmosphere. After completion of the reaction
2
(monitored by TLC), the reaction mixture was quenched with
by TLC), the reaction was quenched with saturated NH Cl
4
saturated NaHCO solution. The aqueous layer was extracted
solution (40 mL) and warmed to room temperature. The organic
phase was separated and the aqueous phase extracted with ethyl
acetate (3 × 30 mL). The combined organic layers were washed
with brine (2 × 25 mL), dried over Na SO and concentrated.
3
with CH Cl and the combined organic solvent was dried with
2
2
anhydrous Na SO . The solvent was removed under reduced
2
4
pressure and the residue was purified by silica gel column
2
4
chromatography (EtOAc/hexane = 1:4) to give 17 (9.85 g, 92%)
Purification by silica gel column chromatography (EtOAc/hexane
27
as a yellow viscous oil; R (EtOAc/hexane = 1:4) 0.65. [α] −8.2
= 1:4) afforded the desired compound 19 (4.76 g, 70% over two
f
D
2
7
(
1
c 9.39, CHCl ); IR (neat): 3449, 2932, 2858, 1758, 1467, 1377,
steps) as a colorless liquid; R (EtOAc/hexane = 1:4) 0.25. [α]
3
f
D
−1 1
188, 1107, 704 cm ; H NMR (300 MHz, CDCl ) δ = 7.65-7.60
+4.2 (c 5.28, CHCl ); IR (neat): 2933, 2861, 1642, 1428, 1375,
3
3
−1 1
(m, 4H), 7.40-7.30 (m, 6H), 4.27-4.14 (m, 2H), 4.12-4.00 (m,
1240, 1107, 1051, 929 ,702 cm ; H NMR (500 MHz, CDCl ) δ
3
2
6
H), 3.73-3.65 (m, 2H), 1.96-1.60 (m, 4H), 1.41 (d, J = 7.9 Hz,
H) 1.29 (t, J = 7.2 Hz, 3H), 1.04 (s, 9H) ppm; C NMR (75
= 7.62 (d, J = 7.0 Hz, 4H), 7.40-7.31 (m, 6H), 5.75 (m, 1H), 5.31
(d, J = 17.0 Hz, 1H), 5.19 (d, J = 10.0 Hz, 1H), 3.91 (m, 1H),
3.70-3.58 (m, 2H), 3.61 (dt, J = 3.0, 8.0, 16.0 Hz 1H), 1.76-1.53
13
MHz, CDCl ) δ = 170.9, 135.5, 133.9, 129.5, 127.6, 110.8, 79.1,
7
ESI-HRMS Calcd for C H O SiNa [M + Na] 493.2386; found:
3
1
3
9.0, 63.4, 61.3, 29.9, 28.6, 27.2, 26.8, 25.7, 19.2, 14.1 ppm;
(m, 4H), 1.36 (d, J = 8.0 Hz, 6H), 1.04 (s, 9H) ppm; C NMR
+
(75 MHz, CDCl ) δ = 135.5, 134.0, 129.5, 127.6, 118.6, 108.5,
27
38
5
3
4
93.2373.
82.7, 80.4, 63.5, 28.9, 28.1, 27.3, 26.91, 26.85, 19.2 ppm; ESI-
+
HRMS Calcd for C H O SiNa [M + Na] 447.2331; found:
26
36
3
4
47.2330.
4
.11. ((4S,5S)-5-(3-(tert-Butyldiphenylsilyloxy)propyl)-2,2-
dimeth- yl-1,3-dioxolan-4-yl)methanol (18)
4
.13. (3S,4S)-7-(tert-Butyldiphenylsilyloxy)hept-1-ene-3,4-diol
To a stirreded solution of the ester 17 (8.2 g, 17.43 mmol) in
CH Cl (85 mL), was added DIBAL-H in toluene (21.92 mL,
(20)
2
2
1
.75 M, 38.36 mmol) dropwise at -78 °C. The solution was
A stirred solution of 19 (4 g, 9.43 mmol) in a mixture of
stirred at same temperature for 2 h under argon atmosphere. After
completion of the reaction (monitored by TLC), the reaction was
quenched by addition of saturated sodium potassium tartrate (70
mL) solution. The gelatinous mixture was stirred until two
distinct layers formed. The layers were separated, and the
aqueous layer extracted with CH Cl (3 × 60 mL). The combined
AcOH (42 mL) and H O (18 mL), was heated to 50 °C for 1.5 h.
2
After completion of reaction (monitored by TLC), the solution
o
was cooled to 0 C and saturated NaHCO solution was added
3
slowly until pH is about 4. The mixture was diluted with EtOAc
(50 mL). Then organic solvents were separated and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined
organic solvents were washed with brine solution, dried over
Na SO and concentrated under reduced pressure. The residue
2
2
organic layers were dried over Na SO4 and solvent was
2
evaporated to dryness. The residue was purified by column
2
4
chromatography (EtOAc/hexane = 1:4) to afford 18 (6.87 g,
was purified by silica gel column chromatography
27
9
2%) as colorless oil; R (EtOAc/hexane = 1:4) 0.25. [α] −8.9
(EtOAc/hexane = 1:4) to provide diol 20 (3.15 g, 87%) as a
f
D
27
(
c 6.06, CHCl ); IR (neat): 3461, 2933, 2860, 1467, 1376, 1247,
viscous liquid; R (EtOAc/hexane = 1:4) 0.40. [α] −4.9 (c 1.26,
3
f
D
−1 1
1
7
4
1
1
2
4
108, 822, 707, 506 cm ; H NMR (300 MHz, CDCl ) δ = 7.60-
CHCl ); IR (neat): 3401, 2929, 2858, 1644, 1427, 1388, 1262,
3
3
−1 1
.59 (m, 4H), 7.42-7.29 (m, 6H), 3.85 (m, 1H), 3.76-3.60 (m,
1109, 929, 703 cm ; H NMR (500 MHz, CDCl ) δ = 7.63 (d, J
3
H), 3.51 (m, 1H), 1.79-1.53 (m, 4H), 1.36 (d, J = 3.4 Hz, 6H),
= 7.0 Hz, 4H), 7.42-7.33 (m, 6H), 5.83 (m, 1H), 5.33 (d, J = 17.9
Hz, 1H), 5.21 (d, J = 10.9 Hz, 1H), 3.88 (m, 1H), 3.68 (t, J = 5.0
13
.04 (s, 9H) ppm; C NMR (75 MHz, CDCl ) δ = 135.5, 133.9,
3
13
29.5, 127.6, 108.6, 81.5, 76.7, 63.5, 62.1, 29.4, 28.9, 27.3, 27.0,
Hz, 2H), 3.45 (m, 1H), 1.54-1.30 (m, 4H) ppm; C NMR (75
+
6.9, 19.2 ppm; ESI-HRMS Calcd for C H O SiNa [M + Na]
MHz, CDCl ) δ = 137.6, 135.5, 133.5, 129.6, 127.6, 117.3, 76.3,
25
36
4
3
51.2280; found: 451.2273.
74.1, 64.1, 29.9, 28.6, 26.8, 19.1 ppm; ESI-HRMS Calcd for
+
C H O SiNa [M + Na] 407.2018; found: 407.2008.
23
32
3
4
4
.12. tert-Butyl(3-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-
-yl)- propoxy) diphenylsilane (19)
4.14. (3S,4S)-7-(tert-Butyldiphenylsilyloxy)-3-(4-methoxyben-
zyloxy)hept-1-en-4-ol (21)
To a stirred solution of primary alcohol 18 (7.0 g, 16.34
mmol) and solid anhydrous NaHCO (1.65 g, 19.61) in CH Cl
To a solution of 20 (2.1 g, 5.46 mmol) in dry THF (30 ml), was
3
2
2
o
(
60 mL) at 0 C, was added Dess-Martin periodinane (10.4 g,
added NaH (0.218 g, 5.46 mmol; 60% dispersion in mineral oil)
o
o
2
4.51 mmol). The reaction mixture was stirred at 0 C for 2 h
at 0 C and the reaction mixture was continued to stir for 30 min.
under N atmosphere. After completion of reaction (monitored by
Then, PMB-Br (0.70 g, 4.91 mmol) was added to the reaction
mixture drop-wise and was allowed to stir for additional 3 h at
same temperature. After completion of reaction, the reaction was
2
TLC), it was quenched with saturated aqueous NaHCO solution
3
(35 mL) and stirred for another 30 min. The organic layer was
separated and the aqueous layer extracted with CH Cl (2 × 60
quenched by cold H O and the aqueous layer was extracted with
2
2
2
mL). The combined organic layer was evaporated under reduced
pressure to afford a crude residue which was immediately used
for the next reaction.
ethyl acetate (2 × 25 mL) and dried over anhydrous Na SO . Solvent
was removed under reduced pressure and the residue was purified by
2 4
silica gel column chromatography (EtOAc/hexane = 1:4) to afford 21
2
7
(2.5 g, 91%) as a yellow oil; Rf (EtOAc/hexane = 1:4) 0.60. [α]D
+
11.2 (c 0.43, CHCl ); IR (neat): 3464, 2933, 2859, 1729,
Methyltriphenylphosphonium bromide (15.84 g, 44.34 mmol)
was dissolved in THF (50 mL) and cooled to –78 ºC. n-
Butyllithium (23.1 mL, 1.6 M in hexane, 36.95 mmol) was added
drop wise to the above stirred solution which turned into light
orange solution. It was then warmed to 0 ºC for 45 min and again
3
−1 1
1
471,1428, 1279, 1108, 1036, 922, 704 cm ; H NMR (300 MHz,
CDCl ) δ = 7.65-7.59 (m, 4H), 7.42-7.30 (m, 6H), 7.19 (d, J = 9.1
Hz, 2H), 6.82 (d, J = 9.1 Hz, 2H), 5.71 (m, 1H), 5.37-5.24 (m, 2H),
3
4
.55 (d, J = 11.3 Hz, 1H), 4.25 (d, J = 11.3 Hz, 1H), 3.79 (s, 3H),

8
Tetrahedron
ACCEPTED MANUSCRIPT
3
.68-3.61 (m, 2H), 3.56-3.42 (m, 2H), 1.76-1.57 (m, 2H), 1.42-1.32
and stirred for 30 min. Alcohol 7 (1.68 g, 5.44 mmol) in CH Cl
2 2
13
(m, 2H), 1.03 (s, 9H) ppm; C NMR (75 MHz, CDCl ) δ = 159.2,
(20 mL) was slowly added to the resulting reaction mixture at the
same temperature and continued to stir for 12 h at room
temperature. After completion of the reaction (monitored by
TLC), it was quenched with water (30 mL). The organic layer
was separated and the aqueous layer extracted with CH Cl (2 ×
3
1
7
35.5, 135.4, 133.9, 130.1, 129.5, 127.6, 120.0, 113.8, 84.2, 73.1,
0.0, 63.8, 55.2, 29.7, 28.8, 28.5, 26.8 ppm; ESI-HRMS Calcd for
+
C H O SiNa [M + Na] 527.2593; found: 527.2607.
31
40
4
2
2
4
1
.15. (S)-5-((S)-1-(4-Methoxybenzyloxy)allyl)-11,11- dimethyl-
0,10-diphen yl-2,4,9-trioxa-10-silado decane (22)
50 mL). The combined organic layer was washed with brine (100
mL), dried over Na SO and the solvent was removed under
2
4
reduced pressure to give crude residue which on purification by
silica gel column chromatography (EtOAc/hexane = 1:4)
To a stirred solution of compound 21 (1.8 g, 3.57 mmol) in
CH Cl (30 mL), was added diisopropylethylamine (1.86 mL,
afforded the desired coupled product 23a (2.6 g, 86%) as a
2
2
o
27
1
0.71 mmol) and stirred for 30 min at 0 C under N atmosphere.
colorless liquid; R
1.24, CHCl
1365, 1301, 1247, 1037 cm ; H NMR (500 MHz, CDCl
f
(EtOAc/hexane = 1:4) 0.45. [α]
); IR (neat): 2952, 2935, 1738, 1613, 1514, 1465,
3
−1 1
D
−11.4 (c
2
Methoxymethyl chloride (0.41 mL, 5.35 mmol) was added to the
reaction mixture at same temperature. The reaction was
continued to stir for 10 h at room temperature. After completion
of the reaction (monitored by TLC), it was quenched with water
) δ =
3
7.17 (d, J = 8.2 Hz, 4H), 6.79 (d, J = 8.2 Hz, 4H), 5.79-5.64 (m,
2H), 5.30-5.14 (m, 4H), 4.70 (d, J = 6.4 Hz, 1H), 4.58 (d, J = 7.3
Hz, 1H), 4.53-4.45 (m,2H) 4.29-4.20 (m, 2H), 4.00 (t, J = 6.4 Hz,
2H), 3.76 (s, 6H), 3.73-3.64 (m, 2H), 3.53 (m, 1H), 3.32 (s, 3H),
2.25-2.17 (m, 2H), 1.73-1.65 (m, 3H), 1.64-1.54 (m, 5H) ppm;
(20 mL). The organic layer was separated and the aqueous layer
extracted with CH Cl (2 × 30 mL). The combined organic layer
2
2
was dried over anhydrous Na SO and solvent removed under
2
4
13
reduced pressure. The crude mass was purified by silica gel
C NMR (75 MHz, CDCl ) δ = 173.5, 159.0, 138.8, 135.2,
3
chromatography (EtOAc/hexane = 1:4) to afford 22 (1.66 g,
130.4, 129.3, 118.8, 117.2, 113.7, 97.1, 81.6, 79.8, 79.3, 70.2,
27
8
5%) as a colorless liquid; R (EtOAc/hexane = 1:4) 0.40. [α]
69.7, 64.3, 55.8, 55.2, 34.9, 34.1, 27.3, 24.8, 20.9 ppm; ESI-
f
D
+
−
5.2 (c 0.67, CHCl ); IR (neat): 2928, 2865, 1740, 1613, 1513,
HRMS Calcd for C32
579.2912.
H
44
O
8
Na [M + Na] 579.2933; found:
3
−1
1
1
463, 1247, 1173, 1037, 822, 703 cm ; H NMR (300 MHz,
CDCl ) δ = 7.67-7.60 (m, 4H), 7.42-7.30 (m, 6H), 7.19 (d, J =
3
8
.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.77 (m, 1H), 5.31-5.22
4.18. (S)-((4S,5S)-5-(tert-Butyldimethylsilyl)-4-(methoxyme-
thyl)-hept-6-enyl)-5-(tert-butyldimethylsilyl)-hept-6-enoate
(m, 2H), 4.66 (AB , J = 6.8, 30.8 Hz, 2H), 4.53 (d, J = 11.7 Hz,
q
1
H), 4.28 (d, J = 11.5 Hz, 1H), 3.79 (m, 1H), 3.77 (s, 3H), 3.62
(23c)
(t, J = 6.0 Hz, 2H), 3.55 (m, 1H), 3.32 (s, 3H), 1.76-1.44 (m, 4H),
13
1
1
7
.03 (s, 9H) ppm; C NMR (75 MHz, CDCl ) δ = 159.0, 135.5,
3
To a stirred solution of diol compound 23e (0.16 g, 0.49
mmol) in CH Cl (10 mL) was added 2,6-lutidine (0.2 mL, 1.47
34.0, 130.6, 129.5, 129.3, 127.5, 118.6, 113.7, 97.0, 81.9, 79.7,
2
2
0.1, 63.9, 55.7, 55.2, 28.5, 27.3, 26.8, 19.2 ppm; ESI-HRMS
o
mmol) followed by TBSOTf (0.31 mL, 1.47 mmol) at 0 C under
nitrogen atmosphere. The mixture was stirred for 4 h at room
temperature and then quenched with saturated aq. NaHCO3
solution (10 mL). The aqueous phase was extracted with CH Cl
+
Calcd for C H O Na [M + Na] 571.2855; found: 571.2836.
33
44
5
4
.16. (4S,5S)-5-(4-Methoxybenzyl)oxy)-4-methoxymethoxy)
2
2
hept-6-en-1-ol (7)
(3 × 15 mL), and the combined organic layer was washed with
brine (30 mL), dried over anhydrous Na SO and concentrated
under reduced pressure. The crude product was purified by
column chromatography (EtOAc/hexane: 0.5:9.5) to afford di-
2
4
To a solution of 22 (3.81 g, 6.96 mmol) in anhydrous THF (45
mL), TBAF (10.44 mL, 1 M in THF, 10.44 mmol) was added
o
drop wise at 0 C under nitrogen atmosphere. After stirring for 4
TBS ether 23c (0.235 g, 87%) as a colorless liquid; R
f
27
h at room temperature, the reaction mixture was quenched with
(EtOAc/hexane: 0.5:9.5) 0.65. [α]D −22.0 (c 1.24, CHCl ); IR
3
−1 1
saturated aqueous NaHCO solution (40 mL) and the resulting
(neat): 2924, 2854, 1729, 1633, 1459, 1253, 1169, 1038 cm ; H
3
mixture was extracted with EtOAc (3 × 60 mL). The combined
organic layers were washed with brine (100 mL), dried over
anhydrous Na SO , and concentrated under reduced pressure.
The crude residue was purified by silica gel column
chromatography (EtOAc/hexane = 2:3) to afford the desired
NMR (300 MHz, CDCl ) δ = 5.95-5.69 (m, 2H), 5.31-4.98 (m,
3
4H), 4.73 (d, J = 6.8 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.22 (m,
1H), 4.13-3.99 (m, 3H), 3.46-3.31 (m, 4H), 2.28 (t, J = 7.6 Hz,
2H), 1.81-1.45 (m, 8H), 0.9 (d, J = 2.3 Hz, 18H), 0.08-0.01 (m,
2
4
13
12H) ppm; C NMR (75 MHz, CDCl ) δ = 173.6, 141.4, 137.1,
3
alcohol 7 (2.05 g, 95%) as a colorless liquid; R (EtOAc/hexane =
115.9, 113.9, 97.3, 81.2, 74.8, 73.4, 64.3, 55.7, 37.4, 34.2, 26.3,
f
27
2
2
:3) 0.25. [α]D −5.5 (c 2.21, CHCl ); IR (neat): 3398, 2936,
863, 1735, 1612, 1513, 1459, 1301, 1248, 1173, 1035 cm ; H
25.9, 25.8, 25.1, 20.7, 18.2, 18.1, −4.4, −4.7, −4.9, −5.0 ppm;
3
−1
1
+
ESI-HRMS Calcd for C H O Si Na [M + Na] 567.3513;
28
56
6
2
NMR (300 MHz, CDCl ) δ = 7.20 (d, J = 9.1 Hz, 2H), 6.82 (d, J
found: 567.3492.
3
=
9.1 Hz, 2H), 5.78 (m, 1H), 5.35-5.25 (m, 2H), 4.69 (AB , J =
q
6
4
.8, 35.5 Hz, 2H), 4.54 (AB , J = 11.3 Hz, 2H), 3.85-3.78 (m,
q
13
4.19. (S)-((4S,5S)-4,5-Bis(methoxymethyl)hept-6-enyl)-5-
methoxy- methyl) hept-6-enoate (23d)
H), 3.64-3.55 (m, 3H), 3.36 (s, 3H), 1.71-1.41 (m, 4H) ppm;
C
(
NMR (75 MHz, CDCl ) δ = 159.0, 135.2, 130.4, 129.2, 118.7,
3
1
13.6, 97.0, 81.8, 79.5, 70.1, 62.6, 55.7, 55.1, 28.6, 27.3 ppm;
To a stirred solution of the diol 23e (0.104 g, 0.33 mmol) in
anhydrous CH Cl2 (10 mL), were added N,N-
diisopropylethylamine (0.2 mL, 1.0 mmol), and DMAP
+
ESI-HRMS Calcd for C H O SiNa [M + Na] 333.1677; found:
3
17
26
5
2
33.1666.
o
(catalytic) at 0 C. The reaction mixture was stirred for additional
4
.17. (S)-((4S,5S)-5-(4-Methoxybenzyl)oxy)-4-(methoxyme-
3
0 min. Then MOMCl (0.15 mL, 1 mmol) was added dropwise to
thoxy)-hept-6-enyl)-5-(4-methoxy benzyl)oxy) hept-6-enoate
the reaction mixture and allowed to stir for another 12 h at room
temperature. After completion of the reaction (monitored by
(23a)
TLC), it was quenched with saturated aqueous NaHCO solution
3
To a stirred solution of acid 6 (1.72 g, 6.52 mmol) in CH Cl
2
2
(10 mL). The organic layer was separated and the aqueous layer
extracted with CH Cl (3 × 10 mL). The combined organic layer
o
(
(
30 mL) at 0 C, Et N (1.2 mL, 11.96 mmol) followed by EDCI
3
2
2
2.11 g, 13.6 mmol) and DMAP (0.732 g, 6.0 mmol) were added
was washed with brine (30 mL) and dried over Na SO . The
2
4

Tetrahedron
9
residue obtained after evaporation of the solvent was purified by
A flame-dried round-bottomed flask was charged with a
ACCEPTED MANUSCRIPT
silica gel column chromatography (EtOAc/hexane: 1:4) to obtain
solution of ester 23e (0.158 g, 0.5 mmol) in CH Cl (120 mL).
2 2
the Tris-MOM ether 23d (0.125 g, 94%) as a colorless liquid; R
The solution was degassed for 20 min under argon atmosphere.
f
27
nd
(
2
EtOAc/hexane: 1:4) 0.45. [α]D −5.8 (c 2.3, CHCl ); IR (neat):
924, 2853, 1735, 1462, 1371, 1102, 1034 cm ; H NMR (300
Grubbs’ 2 generation catalyst (0.45 mg, 0.05 mmol) in CH Cl
3
2
2
−1
1
(30 mL) was subsequently added to the solution which was again
degassed for 15 min. The reaction mixture was stirred for 12 h
under refluxing conditions. After completion of the reaction
(monitored by TLC), solvent was evaporated under reduced
pressure. Purification of the crude residue by silica gel column
chromatography (EtOAc/hexane = 1:1) afforded 5e (0.119 g,
MHz, CDCl ) δ = 5.81-5.57 (m, 2H), 5.34-5.15 (m, 4H), 4.86-
3
4
3
.44 (m, 6H), 4.12-4.02 (m, 3H), 3.97 (m, 1H), 3.57 (m, 1H),
.39-3.33 (m, 9H), 2.34- 2.28 (m, 2H), 1.81-1.41 (m, 8H) ppm;
1
3
C NMR (75 MHz, CDCl ) δ = 173.5, 138.0, 134.6, 119.0,
3
1
3
17.5, 97.0, 94.1, 93.7, 79.3 , 78.6, 76.8, 64.3, 55.9, 55.6, 55.5,
2
7
4.7, 34.0, 27.3, 24.7, 20.9 ppm; ESI-HRMS Calcd for
82%) as a colorless oil; R (EtOAc/hexane = 1:1) 0.55. [α]
f
D
+
C H O Na [M + Na] 427.2307; found: 427.2319.
+16.0 (c 1.3, CHCl ); IR (neat): 3445, 2924, 2856, 1724, 1453,
3
−1 1
20
36
8
1
250, 1157, 1032 cm ; H NMR (300 MHz, CDCl ) δ = 5.79
3
(
1
3
dddd, J = 3.8, 7.6, 15.1, 15.9 Hz, 1H), 5.52 (dddd, J = 8.3, 9.8,
4
.20. (S)-((4S,5S)-5-Hydroxy-4-(methoxymethoxy)hept-6-
5.1, 17.4 Hz, 1H), 4.76-4.64 (m, 2H), 4.35-4.20 (m, 2H), 4.13-
.85 (m, 3H), 3.46-3.32 (m, 5H), 2.35-2.22 (m, 2H), 1.80-1.49
enyl) 5-hydroxy hept-6-enoate (23e
)
13
(m, 8H) ppm; C NMR (75 MHz, CDCl ) δ = 172.9, 138.1,
3
To a stirred solution of di-PMB ether 23a (2.30 g, 4.14 mmol)
1
29.6, 97.3, 83.3, 72.2, 69.5, 63.2, 55.8, 34.5, 23.4, 23.2, 19.7,
+
in CH Cl (40 mL), was added phosphate buffer (pH-7) solution
2
2
o
19.1 ppm; ESI-HRMS Calcd for C H O Na [M + Na]
3
14 24 6
(1 mL) at 0 C followed by DDQ (2.82 g, 12.42 mmol). The
11.1470; found: 311.1486.
reaction mixture was continued to stir for 2 h at room
temperature. After completion of the reaction (monitored by
TLC), it was quenched with saturated NaHCO solution (20 mL).
The organic layer was separated and the aqueous layer extracted
with CH Cl (3 × 40 mL). The combined organic layer was
washed with brine (75 mL), dried over anhydrous Na SO . The
4
.23. (5S,6S)-12,12-Dimethyl-11,11-diphenyl-5-vinyl-2,4,10-
3
trioxa-11-silatridecan-6-ol (26)
2
2
To a stirred solution of compound 20 (1.5 g, 3.9 mmol) in
2
4
solvent was removed under reduced pressure to obtain the crude
product which on purification by silica gel column
CH
Cl (30 mL), was added diisopropylethylamine (0.75 mL,
2 2
o
4.29 mmol) and stirred for 30 min at 0 C under N
atmosphere.
2
chromatography (EtOAc/hexane
=
3:7) furnished the
Methoxymethyl chloride (0.3 mL, 3.9 mmol) was added to the
reaction mixture and the stirring was continued for 2 h at same
temperature. After completion of the reaction (monitored by
TLC), it was quenched with water (20 mL). The organic layer
corresponding diol 23e (1.17 g, 90%) as a colorless oil; R
f
27
(
EtOAc/hexane = 3:7) 0.25. [α]D +2.8 (c 1.4, CHCl ); IR (neat):
3
−1
3
447, 2923, 2853, 1726, 1458, 1240, 1040, 924, 769, 607 cm ;
1
H NMR (500 MHz, CDCl ) δ = 5.89-5.78 (m, 2H), 5.35 (d, J =
was separated and the aqueous layer extracted with CH
30 mL). The combined organic layer was washed with brine (20
mL) and dried over anhydrous Na SO and solvent removed
2 2
Cl (2 ×
3
1
7.1 Hz, 1H), 5.25-5.19 (m, 2H), 5.09 (d, J = 9.8 Hz, 1H), 4.74-
.64 (m, 2H), 4.12-4.05 (m, 3H), 4.01 (t, J = 6.1 Hz, 1H), 3.45-
.39 (m, 4H), 2.33 (t, J = 7.3 Hz, 2H), 1.79-1.61 (m, 5H), 1.57-
4
3
1
1
2
2
4
under reduced pressure. The crude mass was purified by silica gel
13
.50 (m, 3H) ppm; C NMR (75 MHz, CDCl ) δ = 173.6, 140.8,
chromatography (EtOAc/hexane = 1:4) to afford 26 (1.42 g,
3
2
7
37.0, 117.1, 114.8, 97.3, 82.9, 74.6, 72.6, 64.2, 55.9, 36.2, 34.0,
7.6, 24.5, 20.7 ppm; ESI-HRMS Calcd for C H O Na [M +
85%) as a colorless liquid; R
(EtOAc/hexane = 1:4) 0.50. [α]
f D
+20.4 (c 3.67, CHCl ); IR (neat): 3464, 2933, 2859, 1729, 1471,
16
28
6
3
+
−1
1
Na] 339.1783; found: 339.1777.
1428, 1279, 1108, 1036, 922, 704, 505 cm ; H NMR (300
MHz, CDCl ) δ = 7.62 (d, J = 6.6 Hz, 4H), 7.42-7.29 (m, 6H),
3
5
1
1
.73 (m, 1H), 5.38-5.13 (m, 2H), 4.73-4.50 (m, 2H), 3.95 (bs,
H), 3.81 (m, 1H), 3.72-3.59 (m, 2H), 3.51 (m, 1H), 3.36 (s, 3H),
.82-1.44 (m, 4H), 1.03 (s, 9H) ppm; C NMR (75 MHz, CDCl3)
4
.21. (6S,9S,10S,E)-6,9,10-tris(Methoxymethoxy)oxacyclo-
tridec-7-en-2-one (5d)
13
δ = 137.2, 135.5, 134.8, 129.5, 127.6, 119.8, 93.9, 83.4, 74.8,
3.8, 55.7, 29.1, 28.6, 26.8, 19.2 ppm; ESI-HRMS Calcd for
A flame-dried round-bottomed flask was charged with a
6
solution of ester 23d (68 mg, 0.154 mmol) in CH Cl (70 mL).
2
2
+
C H SiO Na [M + Na] 451.2280; found: 451.2265.
25
36
4
The solution was degassed for 20 min under argon atmosphere.
nd
Grubbs’ 2 generation catalyst (15 mg, 0.015 mmol) in CH Cl
2
2
4
.24. (5S,6S)-6-(4-Methoxybenzyloxy)-12,12-dimethyl-11,11-
(
10 mL) was subsequently added to the solution which was again
degassed for 15 min. The reaction mixture was stirred for 48 h
under refluxing conditions. After completion of the reaction
monitored by TLC), solvent was evaporated under reduced
pressure. Purification of the crude residue by silica gel column
diphe- nyl-5-vinyl-2,4,10-trioxa-11-silatri decane (27
)
To a solution of 26 (1.2 g, 2.8 mmol) in dry THF (30 ml), was
(
added NaH (0.167 g, 4.2 mmol; 60% dispersion in mineral oil) at
o
0
C and the reaction mixture was continued to stir for 30 min.
chromatography (EtOAc/hexane = 3:7) afforded 5d (46 mg,
27
Then, PMB-Br (0.48 mL, 3.36 mmol) was added to the reaction
mixture dropwise and was allowed to stir for additional 3 h at
7
(
8%) as a colorless oil; R (EtOAc/hexane = 3:7) 0.35. [α] −4.2
f
D
c 1.1, CHCl ); IR (neat): 2924, 2854, 1729, 1458, 1219, 1149,
3
−1 1
temperature. Then, the reaction was quenched by cold H O and
1
4
4
1
1
1
3
+
097, 1033 cm ; H NMR (300 MHz, CDCl ) δ = 5.75 (dd, J =
2
3
the aqueous layer was extracted with ethyl acetate (2 × 25 mL)
.7, 15.7 Hz, 1H), 5.56 (dd, J = 8.1, 16.4 Hz, 1H), 4.82 (m, 1H),
.72-4.53 (m, 5H), 4.29-4.16 (m, 2H), 4.00 (m, 1H), 3.77 (m,
H), 3.64 (m, 1H), 3.42-3.33 (m, 9H), 2.36- 2.24 (m, 2H), 1.79-
and dried over anhydrous Na SO . Solvent was removed under
2
4
reduced pressure and the residue was purified by silica gel
13
column chromatography (EtOAc/hexane = 1:4) to afford 27 (1.39
.55 (m, 8H) ppm; C NMR (75 MHz, CDCl ) δ = 172.9, 135.2,
3
2
D
7
g, 91%) as a yellow oil; R (EtOAc/hexane = 1:4) 0.60. [α]
27.0, 96.7, 94.2, 94.0, 78.9, 78.0, 73.7, 63.4, 55.5, 55.3, 34.6,
3.7, 28.0, 23.0, 19.4 ppm; ESI-HRMS Calcd for C H O Na [M
f
+
8.0 (c 1.71, CHCl ); IR (neat): 2933, 2860, 1612, 1513, 1467,
3
−1 1
18
32
8
+
1
248, 1105, 1037, 822, 704 cm ; H NMR (400 MHz, CDCl ) δ
Na] 399.1992; found: 399.1989.
3
=
7.64-7.59 (m, 4H), 7.40-7.30 (m, 6H), 7.18 (d, J = 8.6 Hz, 2H),
6
4
.78 (d, J = 8.6 Hz, 2H), 5.73 (m, 1H), 5.29-5.21 (m, 2H), 4.72-
.40 (m, 4H), 4.09 (m, 1H), 3.76 (s, 3H), 3.64-3.56 (m, 2H),
4
.22. (6S,9S,10S,E)-6,9-Dihydroxy-10-(methoxymethoxy)
oxacyclotridec-7-en-2-one (5e)

1
0
Tetrahedron
13
ACCEPTED MANUSCRIPT
3
.40-3.30 (m, 4H), 1.71-1.37 (m, 4H), 1.03 (s, 9H) ppm;
C
Grubbs’ 2nd generation catalyst (95 mg, 0.11 mmol) in CH Cl
2 2
NMR (75 MHz, CDCl ) δ = 159.1, 135.5, 135.1, 134.0, 130.8,
(60 mL) was subsequently added to the solution which was again
degassed for 15 min. The reaction mixture was stirred for 36 h
under refluxing conditions. After completion of the reaction
(monitored by TLC), solvent was evaporated under reduced
pressure. Purification of the crude residue by silica gel column
chromatography (EtOAc/hexane = 3:7) afforded 29 (0.479 g,
3
1
5
29.5, 127.6, 118.5, 113.6, 94.1, 80.6, 78.8, 72.6, 63.9, 55.5,
5.2, 28.6, 27.0, 26.8, 19.2 ppm; ESI-HRMS Calcd for
+
C H O SiNa [M + Na] 571.2855; found: 571.2836.
33
44
5
4
.25. (4S,5S)-4-(4-Methoxybenzyl)oxy)-5-(methoxymethoxy)
2
7
hept-6-en-1-ol (7b)
75%) as a colorless liquid; R
(EtOAc/hexane = 3:7) 0.25. [α]
f D
−
7.2 (c 1.65, CHCl ); IR (neat): 2930, 2884, 1731, 1513, 1458,
3
−1
1
1
1
1
4
247, 1036 cm ; H NMR (500 MHz, CDCl ) δ = 7.27 (d, J =
To a solution of 27 (3.01 g, 5.5 mmol) in anhydrous THF (30
3
2.8 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.74 (dd, J = 5.2, 15.9 Hz,
H), 5.59 (dd, J = 7.5, 15.9 Hz, 1H), 4.71-4.52 (m, 6H), 4.23-
.07 (m, 3H), 3.96 (m, 1H), 3.81 (s, 3H), 3.48 (m, 1H), 3.35 (d, J
mL), TBAF (8.25 mL, 1 M in THF, 8.25 mmol) was added drop
wise to the above stirred solution at 0 C under nitrogen
o
atmosphere. After stirring for 4 h at room temperature, the
reaction mixture was quenched with saturated aqueous NaHCO3
solution (30 mL) and the resulting mixture was extracted with
EtOAc (3 × 60 mL). The combined organic layers were washed
with brine (100 mL), dried over anhydrous Na SO , and
=
2.2 Hz, 6H), 2.28 (d, J = 4.5 Hz, 2H), 1.77-1.52 (m, 8H) ppm;
C NMR (75 MHz, CDCl ) δ = 172.8, 159.1, 134.5, 131.0,
1
3
3
1
5
29.2, 127.8, 113.7, 94.4, 94.2, 79.6, 79.0, 74.1, 72.4, 63.3, 55.3,
5.2, 34.6, 34.0, 27.5, 23.2, 19.6 ppm; ESI-HRMS Calcd for
2
4
+
C H O Na [M + Na] 475.2302; found: 475.2293.
24 36
concentrated under reduced pressure. The crude residue was
purified by silica gel column chromatography (EtOAc/hexane =
8
2
:3) to afford the desired alcohol 7b (1.6 g, 94%) as a colorless
4.28. (2E,7S,8E,10S,11S)-Ethyl-14-hydroxy-11-(4-methoxy-
benzyl)-oxy)-7,10-bis(methoxymethoxy)-tetra-deca-2,8-
dienoate (31)
27
liquid; R (EtOAc/hexane = 2:3) 0.30. [α] +6.64 (c 3.3, CHCl3);
IR (neat): 3427, 2946, 2879, 1613, 1514, 1247, 1149, 1058, 1017
cm ; H NMR (400 MHz, CDCl ) δ = 7.22 (d, J = 8.6 Hz, 2H) ,
f
D
−1 1
3
6
4
3
.82 (d, J = 8.6 Hz, 2H), 5.74 (m, 1H), 5.33-5.23 (m, 2H), 4.70-
.62 (m, 2H), 4.57-4.42 (m, 2H), 4.17 (t, J = 6.2 Hz, 1H), 3.78 (s,
H), 3.58-3.51 (m, 2H), 3.45-3.32 (m, 4H), 1.75-1.38 (m, 4H)
To a stirred solution of lactone 29 (0.231 g, 0.51 mmol) in
CH Cl , DIBAL-H (0.5 mL, 1.4M solution in toluene, 0.70
2
2
o
mmol) was added slowly (Ca. 5 min) at −78 C under nitrogen
atmosphere. The solution was stirred for 30 min at same
temperature and allowed to warm to 0 C slowly. After
13
ppm; C NMR (75 MHz, CDCl ) δ = 159.1, 134.6, 130.4, 129.6,
1
ppm; ESI-HRMS Calcd for C H O Na [M + Na] 333.1677;
found: 333.1666.
3
o
18.7, 113.7, 94.1, 80.4, 78.3, 72.6, 62.7, 55.5, 55.2, 28.8, 26.9
+
completion of the reaction (monitored by TLC), MeOH (0.3 mL)
was added slowly followed by the addition of cold aqueous
saturated sodium potassium tartrate (8 mL). The biphasic mixture
was stirred for further 2 h and then partitioned. Aqueous layer
17
26
5
4
.26. (S)-((4S,5S)-4-(4-Methoxybenzyl)oxy)-5-(methoxymeth-
oxy)-hept-6-enyl)-5-(methoxy methoxy)-hept-6-enoate (28)
was extracted with CH
Cl (3 × 20 mL). Combined organic phase
2 2
was dried over Na SO and concentrated under reduced pressure.
2
4
The crude residue (0.202 g, 87%) was used for the next step
without further purification.
The lactol compound (0.202 g, 0.45 mmol) in benzene (12 mL),
To a stirred solution of acid 6b (0.670 g, 3.56 mmol) in CH Cl
2
2
o
(
20 mL) at 0 C, Et N (0.9 mL, 6.53 mmol) followed by EDCI
3
(0.968 g, 6.23 mmol) and DMAP (0.264 g, 2.16 mmol) were
was added Ph P=CHCO Et (0.233 g, 0.67 mmol) at room
added and stirred for 30 min. Alcohol 7b (0.922 g, 2.97 mmol) in
3
2
o
temperature. The reaction mixture was heated to 80 C for 8 h.
After completion of the reaction (monitored by TLC), the
reaction mixture was concentrated under reduced pressure.
Purification by silica gel column chromatography (EtOAc/hexane
CH Cl (15 mL) was slowly added to the resulting reaction
2
2
mixture at the same temperature and continued to stir for 12 h at
room temperature. After completion of the reaction (monitored
by TLC), it was quenched with water (25 mL). The organic layer
was separated and the aqueous layer extracted with CH Cl (2 ×
=
1:4) afforded α,β-unsaturated ester 31 (0.207 g, 89%) as a
2
2
27
colorless oil; R (EtOAc/hexane = 1:4) 0.45. [α] −11.2 (c 2.2,
4
0 mL). The combined organic layer was washed with brine (75
f
D
CHCl ); IR (neat): 3418, 2925, 2856, 1715, 1613, 1514, 1463,
mL), dried over Na SO and the solvent was removed under
3
2
4
−1
1
1
8
1
248, 1032 cm ; H NMR (300 MHz, CDCl ) δ = 7.26 (d, J =
.5 Hz, 2H), 6.95 (m, 1H), 6.87 (d, J = 8.5 Hz, 2H), 5.81 (d, J =
5.7 Hz, 1H) , 5.65-5.52 (m, 2H), 4.71-4.57 (m, 4H), 4.54-4.47
reduced pressure to give crude residue which on purification by
silica gel column chromatography afforded the desired coupled
3
product 28 (1.2 g, 84 %) as a colorless liquid; R (EtOAc/hexane
f
27
(
=
m, 2H), 4.26-4.13 (m, 3H), 4.03 (m, 1H), 3.80 (s, 3H), 3.58 (t, J
5.9 Hz, 2H), 3.46 (m, 1H), 3.35 (d, J = 3.4 Hz, 6H), 2.27-2.17
=
2
2.5:7.5) 0.40. [α]D −5.3 (c 1.38, CHCl ); IR (neat): 2927,
3
−1 1
857, 1734, 1514, 1460, 1248, 1151, 1097, 1035 cm ; H NMR
1
3
(m, 2H), 1.78-1.40 (m, 8H), 1.28 (t, J = 7.2 Hz, 3H) ppm;
C
(
300 MHz, CDCl ) δ = 7.21 (d, J = 9.0 Hz, 2H), 6.81 (d, J = 8.3
3
NMR (75 MHz, CDCl ) δ = 166.7, 159.2, 148.7, 134.0, 132.0,
Hz, 2H), 5.80-5.56 (m, 2H), 5.31-5.13 (m, 4H), 4.67-4.61 (m,
3
1
6
29.5, 128.4, 121.5, 113.7, 94.3, 93.7, 80.5, 77.4, 76.1, 72.5,
3
3
1
1
7
2
5
H), 4.56-4.43 (m, 3H), 4.12 (m, 1H), 4.03-3.92 (m, 3H), 3.78 (s,
2.6, 60.1, 55.5, 55.3, 55.2, 34.9, 31.9, 28.7, 27.1, 23.8, 14.2
H), 3.40 (m, 1H), 3.32 (s, 6H), 2.28 (t, J = 7.5 Hz, 2H), 1.81-
+
13
ppm; ESI-HRMS Calcd for C H O Na [M + Na] 547.2877;
.31 (m, 8H) ppm; C NMR (75 MHz, CDCl ) δ = 173.5, 159.2,
28 44
9
3
found: 547.2871.
38.0, 134.6, 130.5, 129.6, 118.7, 117.4, 113.7,94.1, 93.7, 80.0,
8.4, 76.8, 72.6, 64.3, 55.5, 55.4, 55.2, 34.7, 34.0, 27.0, 24.9+,
0.9 ppm; ESI-HRMS Calcd for C H O Na [M + Na]
4.29. (2E,7S,8E,10R,11R)-Ethyl-11-(4-methoxybenzyl)oxy)-
7,10-bis(methoxymethoxy)penta-deca-2,8,14-trienoate (32)
26
40
8
03.26154; found: 503.26068.
4
.27. 6S,9S,10S,E)-10-(4-Methoxybenzyl)oxy)-6,9-bis(metho-
(
To a stirred solution of primary alcohol 31 (0.122 g, 0.23 mmol)
o
xymethoxy) oxacyclotridec-7-en-2-one (29)
and solid anhydrous NaHCO
3
(0.05 g) in CH
2
Cl
2
(10 mL) at 0 C,
was added Dess-Martin periodinane (0.118 g, 0.28 mmol). The
o
reaction mixture was stirred at 0 C for 3 h. After completion of
A flame-dried round-bottomed flask was charged with a solution
of ester 28 (0.681 g, 1.42 mmol) in CH Cl (400 mL). The
solution was degassed for 20 min under argon atmosphere.
reaction (monitored by TLC), it was quenched with saturated
2
2
aqueous NaHCO solution (10 mL) and stirred for another 30
3

Tetrahedron
11
min. The organic layer was separated and the aqueous layer
resulting solution was stirred at –20 °C for a further 45 min.
ACCEPTED MANUSCRIPT
extracted with CH Cl (3 × 15 mL). The combined organic layer
Allylic alcohol 35 (8 g, 36.01 mmol) in CH Cl (320 mL) was
2
2
2 2
was evaporated under reduced pressure to afford a crude residue
which was immediately used for the next reaction.
Methyltriphenylphosphonium bromide (0.225 g, 0.63 mmol) was
dissolved in THF (10 mL) and cooled to –78 ºC. n-Butyllithium
then added and the reaction mixture was stirred at –20 °C for 24
h. After completion of the reaction (monitored by TLC), the
reaction mixture was warmed to 0 C and reaction mixture was
o
filtered through sintered funnel. Then quenched by water (57.4
mL) and stirred vigorously for 30 min. The filtrate was again
stirred along with 20% aqueous NaOH solution (14.4 mL) until
both the layers were separated. The aqueous layer was extracted
with CH Cl (3 × 40 mL). The combined organic extracts were
(0.3 mL, 1.6 M in hexane, 0.48 mmol) was added drop wise to
the above stirred solution which turned into light orange solution.
It was then warmed to 0 ºC for 45 min and again cooled to –78
ºC. The crude aldehyde (0.108 g, 0.21 mmol) in THF (5 mL) was
added to the reaction mixture drop wise. The reaction mixture
was stirred at the same temperature for 4 h. After complete
consumption of the starting material (monitored by TLC), the
2
2
dried over anhydrous Na SO and solvent was evaporated under
2
4
reduced pressure. The crude residue was purified by silica gel
column chromatography (EtOAc/hexane = 1:3) to afford pure
reaction was quenched with saturated NH Cl solution (10 mL)
and warmed to room temperature. The organic phase was
separated and the aqueous phase extracted with ethyl acetate (2 ×
epoxide 36 (8.23 g, 96%) as a colorless oil; R (EtOAc/hexane =
4
f
27
1:4) 0.20. [α]D +8.89 (c 1, CHCl ); IR (neat): 3394, 2939, 1611,
3
−1 1
1513, 1248, 1175, 1093, 1028, 819 cm ; H NMR (500 MHz,
1
5 mL). The combined organic layers were washed with brine
CDCl ) δ = 7.25 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H),
3
(
25 mL), dried over Na SO and concentrated. Purification by
4.46 (s, 2H), 3.84 (bs, 1H), 3.80 (s, 3H), 3.64 (m, 1H), 3.59 (m,
2
4
silica gel column chromatography (EtOAc/hexane = 1:4)
1H), 3.47 (dd, J = 8.1, 11.9 Hz, 1H), 3.21-3.14 (m, 2H), 3.03 (dt,
afforded the desired compound 31 (0.094 g, 78% over two steps)
J = 4.3, 8.9, 9.2 Hz, 1H), 2.06 (dq, J = 4.1, 14.7 Hz, 1H), 1.79-
27
13
as a colorless liquid; R (EtOAc/hexane = 1:4) 0.20. [α]D −10.3
1.71 (m, 1H) ppm; C NMR (75 MHz, CDCl ) δ = 159.3, 129.5,
f
3
(
1
9
c 1.5, CHCl ); IR (neat): 2925, 2851, 1723, 1511, 1457, 1248,
129.0, 113.7, 73.0, 66.2, 59.8, 55.2, 55.0, 54.7, 27.9 ppm; ESI-
3
−1
1
+
097, 1035 cm ; H NMR (500 MHz, CDCl ) δ = 7.23 (d, J =
HRMS Calcd for C H O Na [M + Na] 261.1097; found:
3
13 18
4
.0 Hz, 2H), 6.92 (m, 1H), 6.84 (d, J = 9.0 Hz, 2H), 5.82-5.70
261.1107.
(m, 2H), 5.63-5.50 (m, 2H), 4.99-4.90 (m, 2H), 4.67-4.54 (m,
4
3
2
H), 4.50-4.44 (m, 2H), 4.20-4.13 (m, 2H), 4.01 (m, 1H), 3.79 (s,
H), 3.41 (m, 1H), 3.34 (s, 7H), 2.24-2.14 (m, 2H), 2.09-2.00 (m,
H), 1.68-1.45 (m, 6H), 1.29 (t, J = 7.0 Hz, 3H) ppm; C NMR
4.32. (E)-Ethyl-3-((2S,3R)-3-(2-(4-methoxybenzyloxy)ethyl)
oxiran-2-yl)-2-methylacrylate (37)
13
(
1
7
75 MHz, CDCl ) δ = 166.6, 159.1, 148.6, 138.4, 133.8, 130.7,
30.0, 129.5, 121.6, 114.7, 113.7, 94.3, 93.6, 79.9, 77.3, 75.8,
3
To dimethyl sulfoxide (4.63 mL, 65.22 mmol) in CH Cl (40
mL), was added oxalyl chloride (3.75 mL, 43.67 mmol) drop-
2
2
2.6, 60.1, 55.5, 55.2, 35.0, 32.0, 29.9, 29.7, 23.9, 14.2 ppm;
wise at –78 °C under N atmosphere. The reaction mixture was
2
+
ESI-HRMS Calcd for C H O Na [M + Na] 543.2928; found:
5
29
44
8
stirred for 30 min before alcohol 36 (5.2 g, 21.84 mmol) in
43.2924.
CH Cl (20 mL) was added slowly. The reaction mixture was
2
2
stirred for 45 min at same temperature. Then triethylamine (15.23
mL, 109.2 mmol) was added drop-wise and allowed to stir for 1 h
at –78 °C. The reaction was allowed to stir at room temperature
for additional 1 h. After completion of the reaction (monitored by
TLC), the reaction mixture was quenched with water. The
aqueous phase was extracted with CH Cl (3 × 40 mL). The
4
.30. (Z)-5-(4-Methoxybenzyloxy)pent-2-en-1-ol (35)
To a solution of nickel acetate tetrahydrate (3.76 g, 15.11
mmol) in ethanol (75 mL), sodium borohydride was added (0.57
g, 15.11 mmol) at room temperature under H atmosphere. The
2
2
2
mixture was stirred for 30 min and then ethylene diamine (2 mL,
combined organic layers were washed with brine, dried over
Na SO and evaporated to dryness under reduced pressure. The
3
0.2 mmol) followed by alkyne 34 (20 g, 60.4 mmol) in ethanol
2
4
(
50 mL) were added at same temperature and allowed to stir for
crude aldehyde was used immediately for the next reaction
without further purification.
additional 3 h under H atmosphere. After completion of the
2
reaction (monitored by TLC), the reaction mixture was filtered
through a pad of Celite. Solvent (filtrate) was removed under
reduced pressure and the residue was purified by flash column
chromatography (EtOAc/hexane = 1:4) to provide allyl alcohol
To a stirred solution of crude aldehyde (4.43 g, 18.76 mmol) in
toluene (45 mL), was added (carbethoxyethylidene)triphenyl
phosphorane (10.2 g, 28.14 mmol) at room temperature. The
reaction mixture was heated to 90 °C for 3 h. After completion of
the reaction (monitored by TLC), the reaction mixture was
cooled to room temperature and solvent was evaporated under
reduced pressure. The residue was purified by silica gel
chromatography (EtOAc/hexane = 1:4) to afford 37 (4.74 g, 68%
3
5 (2.73 g, 89%) as a colorless oil; R (EtOAc/hexane = 1:4) 0.30.
f
IR (neat): 3398, 2936, 2861, 1611, 1513, 1360, 1247, 1090,
−1 1
1
033, 820, 575 cm ; H NMR (500 MHz, CDCl ) δ = 7.24 (d, J
3
=
8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.81 (qt, J = 1.4, 7.0, 9.5
Hz, 1H), 5.59 (qt, J = 1.1, 7.8, 9.8 Hz, 1H), 4.44 (s, 2H), 4.10 (d,
J = 7.0 Hz, 2H), 3.79 (s, 3H), 3.46 (t, J = 6.1 Hz, 2H), 2.39 (qd, J
over two steps) as a colorless oil; R (EtOAc/hexane = 1:4) 0.65.
f
27
[α]D +18.3 (c 0.9, CHCl ); IR (neat): 2959, 1711, 1513, 1461,
3
13
−1 1
=
1.2, 6.3 Hz, 2H) ppm; C NMR (75 MHz, CDCl ) δ = 159.0,
1245, 1097, 1033, 821, 566 cm ; H NMR (500 MHz, CDCl ) δ
3
3
1
30.7, 129.7, 129.2, 129.1, 113.6, 72.5, 68.5, 57.4, 55.0, 27.8
= 7.25 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.49 (dd, J =
1.4, 7.9 Hz, 1H), 4.46 (ABq, J = 11.6, 13.7 Hz, 2H), 4.25-4.15
(m, 2H), 3.80 (s, 3H), 3.67-3.57 (m, 3H), 3.38-3.34 (m, 1H), 1.96
+
ppm; ESI-HRMS Calcd for C H O Na [M + Na] 245.1148;
found: 245.1158.
13
18
3
(
d, J = 1.2 Hz, 3H), 1.95-1.79 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H)
13
4
.31. ((2S,3R)-3-(2-(4-Methoxybenzyloxy)ethyl)oxiran-2-
ppm; C NMR (75 MHz, CDCl
) δ = 166.9, 159.1, 135.0, 133.3,
3
yl)methanol (36)
130.1, 129.1, 113.7, 72.6, 66.9, 60.7, 56.7, 55.2, 53.0, 29.2, 14.1,
+
1
2.9 ppm; ESI-HRMS Calcd for C H O [M + H] 321.1696;
18 25 5
found: 321.1714.
To a suspension of thoroughly dried molecular sieves 4 Ǻ (7.2
g) in dry CH Cl (60 mL), was added Ti(OiPr) (2.87 mL, 9.7
2
2
4
mmol) followed by (+)-DET (2.42 mL, 11.52 mmol) at –20 °C
4.33. (4R,5R,E)-Ethyl-5-hydroxy-7-(4-methoxybenzyloxy)-2,4-
dimethylhept-2-enoate (38)
under N atmosphere. After stirring for 30 min, TBHP (6.5 M in
2
toluene, 13.85 mL, 90.02 mmol) was slowly added and the

1
2
Tetrahedron
To a stirred solution of epoxy unsaturated ester compound 37
then quenched with H O (25 mL) and extracted with CH Cl (2 ×
ACCEPTED MANUSCRIPT
2
2
2
(4.3 g, 13.43 mmol) in CH Cl2 (70 mL), was added
50 mL). The organic extract was washed with brine (30 mL) and
2
trimethylaluminium (67.2 mL, 134.3 mmol, 2 M in toluene) at –
0 °C under N atmosphere. The reaction mixture was allowed to
dried over Na SO and solvent removed under reduced pressure.
The residue was purified by silica gel column chromatography
2
4
4
2
stir for 30 min at the same temperature. Then, H O (1.45 mL,
(EtOAc/hexane = 1:9) to afford 40 (4.12 g, 93%) as a clear
2
27
8
0.58 mmol) was added very carefully (Caution: Me Al reacts
liquid; R (EtOAc/hexane = 1:4) 0.75. [α] +7.1 (c 2.96, CHCl3);
3
f
D
violently and may ignite upon contact with water) and slowly so
that the internal temperature did not change. After effervescence
ceased, it was allowed to stir for further 3 h at –40 °C. After
complete consumption of the starting material (shown by TLC),
IR (neat): 2955, 2931, 2857, 1613, 1513, 1465, 1251, 1090, 837,
−1 1
775 cm ; H NMR (300 MHz, CDCl ) δ = 7.24 (d, J = 8.6 Hz,
3
2H), 6.86 (d, J = 8.7 Hz, 2H), 5.26 (dd, J = 1.2, 9.8 Hz, 1H), 4.40
(dd, J = 11.4, 19.7 Hz, 2H), 3.98 (s, 2H), 3.79 (s, 3H), 3.63 (m,
1H), 3.53-3.44 (m, 2H), 2.46 (m, 1H), 1.84-1.68 (m, 2H), 1.57 (d,
J = 1.1 Hz, 3H), 0.92-0.87 (m, 21H), 0.05 (s, 6H), 0.03 (d, J = 3.2
it was quenched very slowly with saturated NH Cl (50 mL) and
4
diluted with CH Cl (100 mL). HCl (1.0 N, 50 mL) was added
2
2
13
and stirred vigorously until a clear separation of the two layers
took place. The organic layer was separated and the aqueous
layer extracted with CH Cl (2 × 80 mL). The combined organic
Hz, 6H) ppm; C NMR (75 MHz, CDCl ) δ = 159.0, 133.7,
3
130.6, 129.2, 127.7, 113.6, 73.5, 72.5, 68.7, 66.7, 55.2, 37.6,
34.6, 25.9, 18.4, 18.1, 16.4, 13.6, −4.4, −4.5, −5.2, −5.3 ppm;
2
2
+
layer was washed with brine (2 × 50 mL), dried over anhydrous
Na SO and evaporated to dryness under reduced pressure. The
ESI-HRMS Calcd for C H O Si Na [M + Na] 545.3452;
29
54
4
2
found: 545.3477.
2
4
crude mass was purified by silica gel column chromatography
EtOAc/ hexane = 1:5) to afford 38 (4.11 g, 91%) as a colorless
(
4.36. (3R,4R,E)-3,7-Bis(tert-butyldimethylsilyloxy)-4,6-
dimethylhe-pt-5-en-1-ol (41)
27
oil; R (EtOAc/hexane = 1:5) 0.55. [α] +7.7 (c 1.1, CHCl ); IR
f
D
3
(
neat): 3398, 2925, 2855, 1707, 1513, 1246, 1089, 1033, 821,
−1 1
5
2
4
3
1
3
1
3
+
58 cm ; H NMR (300 MHz, CDCl ) δ = 7.24 (d, J = 8.3 Hz,
3
To a solution of PMB protected compound 40 (2.3 g, 4.40
H), 6.88 (d, J = 8.3 Hz, 2H), 6.58 (dd, J = 1.5, 10.6 Hz, 1H),
.44 (s, 2H), 4.18 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.73-3.56 (m,
H), 3.31 (bs, 1H), 2.62-2.48 (m, 1H), 1.84 (d, J = 1.5 Hz, 3H),
.75-1.66 (m, 2H), 1.29 (t, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz,
mmol) in CH Cl :H O (19:1, 40 mL), phosphate buffer solution
2
2
2
(pH = 7) (2 mL) followed by DDQ (1.5 g, 6.60 mmol) was added
at 0 °C and allowed to stir for 2 h at room temperature. After
completion of the reaction (monitored by TLC), it was quenched
13
H) ppm; C NMR (75 MHz, CDCl ) δ = 168.1, 159.2, 143.7,
3
with saturated NaHCO (30 mL) solution. The two layers were
3
29.6, 129.3, 127.7, 113.8, 75.1, 73.0, 69.2, 60.5, 55.2, 39.7,
separated and the aqueous layer extracted with CH Cl (3 × 30
2
2
3.9, 15.6, 14.2, 12.6 ppm; ESI-HRMS Calcd for C H O Na [M
19
28
5
mL). The combined organic layer was washed with brine (2 × 30
mL), dried over anhydrous Na SO and solvent was removed
+
Na] 359.1829; found: 359.1845.
2
4
under reduced pressure to give red colored crude product which
on purification by silica gel column chromatography
(EtOAc/hexane = 1:4) to afford the desired primary alcohol 41
4
.34. (4R,5R,E)-7-(4-Methoxybenzyloxy)-2,4-dimethylhept-2-
ene-1,5-diol (39)
(
1.63 g, 92%) as a colorless liquid; R (EtOAc/hexane = 1:4) 0.25.
f
27
To a stirred solution of the ester 38 (3.2 g, 9.52 mmol) in
[α]D +5.1 (c 0.93, CHCl ); IR (neat): 3362, 2957, 2873, 1734,
1613, 1515, 1245, 1033, 821 cm ; H NMR (300 MHz, CDCl ) δ
3
−1 1
CH Cl (50 mL), was added DIBAL-H in toluene (11.42 mL,
2
2
3
1
.75 M, 19.99 mmol) dropwise at −78 °C. The solution was
= 5.20 (d, J = 9.8 Hz, 1H), 3.98 (s, 2H), 3.79 (m, 1H), 3.72-3.62
(m, 2H), 2.67-2.54 (m, 1H), 2.33 (bs, 1H), 1.87-1.75 (m, 1H),
1.72-1.63 (m, 1H), 1.61 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.89
stirred at same temperature for 2 h under N atmosphere. After
2
completion of the reaction (monitored by TLC), the reaction was
quenched by addition of saturated aqueous sodium potassium
tartrate (40 mL). The gelatinous mixture was stirred until two
distinct layers formed. The layers were separated, and the
aqueous layer extracted with CH Cl (3 × 50 mL). The combined
1
3
(m, 18H), 0.08 (d, J = 7.6 Hz, 6H), 0.04 (s, 6H) ppm; C NMR
(75 MHz, CDCl ) δ = 134.2, 126.8, 75.6, 68.5, 60.0, 37.2, 36.0,
3
25.92(3C), 25.89(3C), 18.4, 18.0, 17.5, 13.7, −4.3, −4.5, −5.2,
+
−5.3 ppm; ESI-HRMS Calcd for C H O Si [M + H] 403.3058;
2
2
21 47
3
2
organic layers washed with brine (2 × 30 mL) and dried over
Na SO and concentrated. The residue was purified by column
found: 403.3081.
2
4
chromatography (EtOAc/hexane = 1:4) to afford 39 (2.6 g, 93%)
4.37. (4R,5R,E)-4,8-Bis(tert-butyldimethylsilyloxy)-5,7-dime-
thyl-oct-6-en-2-ol (42)
27
as colorless oil; R (EtOAc/hexane = 1:4) 0.20. [α]
−10.2 (c
f
D
0
1
.63, CHCl ); IR (neat): 3384, 2950, 2865, 1612, 1513, 1457,
3
−1 1
248, 1084, 820 cm ; H NMR (300 MHz, CDCl ) δ = 7.24 (d, J
3
To a stirred solution of 41 (1.2 g, 2.98 mmol) in dry CH Cl (40
2
2
=
4
(
8.3 Hz, 2H), 6.87 (d, J = 9.0 Hz, 2H), 5.24 (d, J = 9.8 Hz, 1H),
.44 (s, 2H), 3.96 (s, 2H), 3.80 (s, 3H), 3.71-3.54 (m, 3H), 2.46
m, 1H), 1.82-1.68 (m, 2H), 1.65 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H)
mL), was added NaHCO (0.3 g, 3.57 mmol) and Dess-Martin
3
periodinane (2.53 g, 5.96 mmol) at 0 °C under N atmosphere and
2
allowed to stir for 1 h at room temperature. After completion of
the reaction (monitored by TLC), it was quenched with saturated
aqueous NaHCO (20 mL) and Na S O (10 mL) and extracted
13
ppm; C NMR (75 MHz, CDCl ) δ = 159.1, 135.0, 129.8, 129.3,
3
1
28.2, 113.7, 75.3, 72.9, 69.1, 68.5, 55.2, 38.2, 33.6, 16.2, 14.0
3
2
2
3
+
ppm; ESI-HRMS Calcd for C H O [M + H] 295.1903; found:
17
27
4
with CH Cl (2 × 35 mL). The combined organic extracts were
2 2
2
95.1918.
washed with brine (20 mL), dried over Na SO and solvent was
2
4
removed under reduced pressure furnished crude aldehyde and
used as such for the next reaction.
To a stirred solution of crude aldehyde (1.09 g, 2.72 mmol) in
4
8
.35. (8R,9R,E)-9-(2-(4-Methoxybenzyloxy)ethyl)-2,2,3,3,6,
,11,11-12,12-decamethyl-4,10-dioxa-3,11-disilatridec-6-ene
(40)
THF (30 mL) at 0 °C under N atmosphere, was added MeMgBr
2
(5.44 mL, 1 M solution in toluene, 5.44 mmol) dropwise. The
To a stirred solution of diol 39 (2.5 g, 8.50 mmol) in dry
CH Cl (40 mL), was added 2,6-lutidine (3.95 mL, 34.0 mmol)
solution was stirred for additional 2 h at room temperature. After
completion of the reaction (monitored by TLC), the reaction was
2
2
and TBSOTf (5.85 mL, 25.49 mmol) sequentially at 0 °C under
quenched by addition of saturated aqueous NH Cl (20 mL) and
4
N atmosphere and allowed to stir for 30 min. After completion
of the reaction (monitored by TLC), the reaction mixture was
extracted with ethyl acetate (2 × 35 mL). The combined organic
layers were dried over Na SO and evaporated to dryness. The
2
2
4

Tetrahedron
13
residue was purified by silica gel column chromatography
(
75.9, 74.2, 74.1, 68.7, 68.5, 45.1, 43.6, 37.3, 37.2, 26.0, 25.9,
ACCEPTED MANUSCRIPT
EtOAc/hexane = 1:4) to afford 42 (0.973 g, 79% over two steps)
25.3, 24.5, 18.4, 18.1, 15.9, 15.4, 13.8, 13.7, −4.1, −4.0, −4.37,
as a mixture of diastereomers; R (EtOAc/hexane = 1:4) 0.35. IR
−4.44, −5.22, −5.23 ppm; ESI- HRMS Calcd for C H IO Si N
f
23 51
2
2
+
(
neat): 3450, 2957, 2858, 1719, 1460, 1379, 1254, 1077, 836,
[M + NH ] found: 556.2497; found: 556.2483.
4
−1 1
7
9
3
3
1
0
73, 667 cm ; H NMR (300 MHz, CDCl ) δ = 5.35 (dd, J = 1.5,
3
.8 Hz, 1H), 5.13 (dd, J = 1.5, 9.8 Hz, 1H), 4.13-4.02 (m, 1H),
.99 (s, 2H), 3.97 (s, 2H), 3.95-3.87 (m, 1H), 3.80-3.73 (m, 1H),
.72-3.66 (m, 1H), 2.77-2.65 (m, 1H), 2.64-2.54 (m, 1H), 1.64-
.60 (m, 10H), 1.16 (d, J = 6.0 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H),
.97 (d, J = 6.8 Hz, 3H), 0.93-0.87 (m, 39H), 0.09-0.03 (m, 24H)
4.40. (2E,4R,5R,7E)-8-Iodo-2,4,7-trimethylocta-2,7-diene-1,5-
diol (44)
TBAF (3.34 mL, 1 M in THF, 3.344 mmol) was added to a
stirred solution of di-TBS ether compound (0.45 g, 0.836 mmol)
13
o
ppm; C NMR (75 MHz, CDCl ) δ = 134.5, 134.2, 126.7, 126.6,
3
in THF (12 mL) at 0 C under N atmosphere. The reaction
2
7
2
6.4, 76.0, 68.6, 68.4, 66.5, 64.8, 42.1, 42.0, 37.8, 37.0, 25.93,
5.90, 24.0, 23.8, 18.4, 18.02, 17.99, 16.5, 13.74, 13.70, −4.1,
mixture was stirred at room temperature for 6 h. After completion
of the reaction (monitored by TLC), it was quenched with water
−
4.2, −4.5, −4.6, −5.2, −5.3 ppm; ESI-HRMS Calcd for
(15 mL). The aqueous layer extracted with ethyl acetate (3 × 20
+
C H O Si [M + H] 417.3214; found: 417.3236.
22
49
3
2
mL), the combined organic layer was dried over anhydrous
Na SO4 and solvent removed under reduced pressure. The
residue was purified by silica gel column chromatography
2
4
.38. (4R,5R,E)-4,8-Bis(tert-butyldimethylsilyloxy)-5,7-dimet-
hyloct-6-en-2-one (8)
(EtOAc/hexane = 2:3) to afford 44 (0.23 g, 89%) as a colorless
27
liquid; R (EtOAc/hexane = 2:3) 0.30. [α] +6.2 (c 1.1, CHCl3);
f
D
To a stirred solution of secondary alcohol 42 (0.85 g, 2.04
IR (neat): 3398, 2936, 2863, 1735, 1612, 1513, 1459, 1301,
−1 1
mmol) in CH Cl anhydrous NaHCO (0.21 g, 2.45 mmol) and
1248, 1173, 1035 cm ; H NMR (500 MHz, CDCl ) δ = 6.01 (s,
2
2,
3
3
o
Dess-Martin periodinane (1.73 g, 4.08 mmol) were added at 0 C
under nitrogen atmosphere. Then the reaction mixture was stirred
for 2 h at room temperature. After completion of reaction
1H), 5.29 (d, J = 10.0 Hz, 1H), 4.02 (s,2H), 3.58-3.52 (m, 1H),
2.53-2.46 (m, 1H), 2.43 (d, J = 14.0 Hz, 1H), 2.24 (dd, J = 10.0,
14.0 Hz, 1H), 1.87 (s, 3H), 1.68 (s, 3H), 1.03 (d, J = 7.0 Hz, 3H)
13
(
monitored by TLC), the reaction mixture was quenched with
ppm; C NMR (75 MHz, CDCl ) δ = 145.3, 135.7, 127.5, 77.0,
3
saturated NaHCO (30 mL) solution. The aqueous layer was
72.8, 68.5, 44.9, 38.0, 23.9, 16.3, 14.1 ppm; ESI-HRMS Calcd
3
+
extracted with CH Cl (3 × 30 mL). The combined organic layer
for C H O INa [M + Na] 333.0322; found: 333.0321.
2
2
11 19
2
was washed with brine (2 × 20 mL), dried over anhydrous
Na SO and concentrated under reduced pressure. The crude
2
4
4.41. (2E,4R,5R,7Z)-8-Iodo-2,4,7-trimethylocta-2,7-diene-1,5-
mass was purified by silica gel chromatography (EtOAc/hexane
1:4) to afford 8 (0.77 g, 91%) as a colorless liquid; R
diol (44a)
=
f
27
27
(
2
EtOAc/hexane = 1:4) 0.65. [α]D +6.3 (c 1.8, CHCl ); IR (neat):
956, 2858, 1720, 1465, 1361, 1254, 1072, 837, 775, 668 cm ;
3
[α]D +16.5 (c 0.85, CHCl ); IR (neat): 3420, 2921, 1629, 1377,
3
−1 1
−1
1
271, 1007, 763, 670 cm ; H NMR (500 MHz, CDCl ) δ = 5.99
3
1
H NMR (300 MHz, CDCl ) δ = 5.19 (d, J = 9.8 Hz, 1H), 4.02
3
(s, 1H), 5.36 (d, J = 10.0 Hz, 1H), 4.03 (s, 2H), 3.70-3.64 (m,
(q, J = 6.0 Hz, 1H), 3.97 (s, 2H), 2.54 (d, J = 6.0 Hz, 2H), 2.51-
1
3
H), 2.60-2.53 (m, 1H), 2.42-2.35 (m, 2H), 1.96 (s, 3H), 1.72 (s,
H), 1.07 (d, J = 7.0 Hz, 3H) ppm; C NMR (75 MHz, CDCl ) δ
13
2
6
0
1
.42 (m, 1H), 2.11 (s, 3H), 1.61 (d, J = 1.5 Hz, 3H), 0.93 (d, J =
.8 Hz, 3H), 0.87 (d, J = 10.6 Hz, 18H), 0.05 (d, J = 3.0 Hz, 9H),
3
=
145.6, 135.9, 127.7, 76.4, 74.3, 68.7, 43.5, 38.8, 24.4, 16.2,
13
+
.01 (s, 3H) ppm; C NMR (75 MHz, CDCl ) δ = 207.5, 134.7,
3
14.2 ppm; ESI-HRMS Calcd for C H O INa [M + Na]
11 19 2
27.1, 72.6, 68.5, 49.5, 38.6, 31.5, 25.9, 18.4, 18.1, 16.4, 13.7,
3
33.0322; found: 333.0334.
−
4.5, −4.6, −5.3 ppm; ESI-HRMS Calcd for C H O Si Na [M +
22 46 3 2
+
Na] 437.2877; found: 437.2899.
4
2
.42. (1E,4R,5R,6E)-8-(tert-Butyldimethylsilyloxy)-1-iodo-
,5,7-trimethylocta-1,6-dien-4-ol (4)
4
1
.39. (8R,9R,E)-9-((E)-3-Iodo-2-methylallyl)-2,2,3,3,6,8,11,11,
2,12-decamethyl-4,10-dioxa-3,11-disilatridec-6-ene (43)
To a stirred solution of 41 (0.12 g, 0.387 mmol) in dry CH Cl
2
2
(
20 mL), was added imidazole (0.04 g, 0.581 mmol) followed by
Anhydrous CrCl (1.48 g, 12.06 mmol) was transferred to a
2
TBSCl (0.088 g, 0.0581 mmol) at 0 °C under N atmosphere and
allowed to stir for 1 h. After completion of the reaction
2
round bottom flask under N atmosphere and treated with THF
2
(15 mL) at room temperature. To the resulting grey suspension
(monitored by TLC), the reaction mixture was quenched with
was added a solution of ketone 8 (0.5 g, 1.2 mmol) and CHI3
saturated aqueous NH Cl (10 mL) and extracted with CH Cl (3
×
Na SO and evaporated to dryness under reduced pressure. The
crude mass was purified by silica gel column chromatography
(EtOAc/hexane = 1:4) to afford 4 (0.151 g, 92%) as a colorless
liquid; R (EtOAc/hexane = 1:4) 0.45. [α]
CHCl ); IR (neat): 3446, 2926, 2856, 1723, 1461, 1375, 1254,
1073, 839, 773, 674 cm ; H NMR (500 MHz, CDCl ) δ = 5.99
3
4
2
2
(1.32 mg, 3.36 mmol) in THF (5 mL) via cannula (2 × 2 mL
20 mL). The combined organic extracts were dried over
THF). The resulting dark red-brown mixture was stirred at room
temperature for 4 h. The reaction was quenched by addition of
2
4
H O (15 mL) and the resulting mixture was stirred for 15 min.
2
27
D
The aqueous layer was extracted with ethyl acetate (3 × 20 mL).
The combined organic extracts were washed with brine (2 × 10
+14.2 (c 1.40,
f
3
−1 1
mL), dried over Na SO and evaporated to dryness under reduced
2
4
pressure. The crude mass was purified by silica gel
(
1
s, 1H), 5.25 (d, J = 9.1 Hz, 1H), 4.01 (s, 2H), 3.51 (t, J = 9.1 Hz,
H), 2.51-2.42 (m, 2H), 2.42-2.17 (m, 1H), 1.86 (s, 3H), 1.61 (s,
3H), 1.56 (bs, 2H), 1.03 (d, J = 7.1 Hz, 3H), 0.91 (s, 9H), 0.06 (s,
chromatography (EtOAc/hexane = 1:9) to afford 43 (0.504 g,
27
7
8%) as a colorless liquid; R (EtOAc/hexane = 1:9) 0.60. [α]
f
D
13
+
15.6 (c 0.7, CHCl ); IR (neat): 3398, 2936, 2863, 1735, 1612,
3
−1 1
6H) ppm; C NMR (75 MHz, CDCl ) δ = 145.5, 135.6, 125.8,
7
ESI-HRMS Calcd for C H O ISiNa [M + Na] 447.1197;
found: 447.1186.
3
1
513, 1459, 1301, 1248, 1173, 1035 cm ; H NMR (300 MHz,
3.0, 68.2, 45.0, 38.1, 25.9, 24.0, 18.4, 16.6, 13.9, −5.2 ppm;
+
CDCl ) δ = 5.90 (d, J = 8.3 Hz, 1H), 5.29 (dd, J = 9.8, 21.9 Hz,
3
17 33 2
1
H), 3.98 (s, 2H), 3.73-3.56 (m, 1H), 2.50-2.11 (m, 3H), 1.86 (d,
J = 24.9 Hz, 3H), 1.63 (d, J = 40.8 Hz, 3H), 0.99 (d, J = 6.8 Hz,
13
3
H), 0.92-0.86 (m, 18H), 0.7-0.3 (m, 12H) ppm; C NMR (125
4
2
.43. (1Z,4R,5R,6E)-8-(tert-Butyldimethylsilyloxy)-1-iodo-
,5,7-trimethyl-octa-1,6-dien-4-ol (4a)
MHz, CDCl ) δ = 145.4, 145.0, 134.1, 133.7, 128.0, 127.4, 77.6,
3

1
4
Tetrahedron
27
[
α]D +16.6 (c 0.3, CHCl ); IR (neat): 3398, 2936, 2863,
3H), 1.70-1.48 (m, 9H), 0.95 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H),
3
ACCEPTED MANUSCRIPT
−1
1
13
1
735, 1612, 1513, 1459, 1301, 1248, 1173, 1035 cm ; H NMR
0.06 (s, 6H) ppm; C NMR (125 MHz, CDCl ) δ = 166.1, 159.2,
3
(
4
500 MHz, CDCl ) δ = 5.99 (s, 1H), 5.32 (d, J = 10.1 Hz, 1H),
.03 (s,2H), 3.65 (m, 1H), 2.56 (m, 1H), 2.39-2.36 (m, 2H), 1.95
149.0, 144.3, 138.4, 135.8, 133.9, 130.7, 129.9, 129.5, 128.1,
125.1, 121.3, 114.7, 113.7, 94.3, 93.7, 80.0, 77.4, 75.9, 74.8,
72.6, 68.1, 55.6, 55.5, 55.3, 42.2, 36.1, 35.1, 32.1, 31.9, 29.9,
25.9, 24.0, 23.9, 18.4, 16.8, 13.9, −5.2 ppm; ESI-HRMS Calcd
3
(
(
s, 3H), 1.65 (s, 3H), 1.54 (bs, 2H), 1.07 (d, J = 7.1 Hz, 3H), 0.91
s, 9H), 0.07 (s, 6H) ppm; C NMR (75 MHz, CDCl ) δ = 145.6,
13
3
+
1
−
35.8, 125.9, 74.4, 68.3, 43.5, 38.8, 25.9, 24.4, 18.4, 16.5, 13.9+,
for C H O ISiNa [M + Na] 921.3835; found: 921.3804.
44
71
9
5.2 ppm; ESI-HRMS Calcd for C H O ISiNa [M + Na]
17
33
2
4
47.1197; found: 447.1192.
4.46. (2E,7S,8E,10S,11S)-((1E,4R,5R,6E)-8-(tert-Butyldimet-
hylsilyloxy)-1-iodo-2,5,7-trimethyl-octa-1,6-dien-4-yl)-11-
hydroxy-7,10-bis(methoxy-methoxy)pentadeca-2,8,14-
trienoate (46)
4
.44. (2E,7S,8E,10S,11S)-11-(4-Methoxybenzyloxy)-7,10-
bis(meth- oxymeth oxy) pentadeca-2,8,14-trienoic acid (3)
To a stirred solution of the ester 31 (0.05 g, 0.096 mmol) in THF
To a stirred solution of PMB protected compound 45 (16 mg,
(5 mL), was added aqueous solution of LiOH (0.021 g, 0.864
0.018 mmol) in CH Cl :H O (19:1, 10 mL), 1 mL phosphate
2
2
2
mmol) at room temperature. The reaction mixture was allowed to
stir at 80 °C for 15 h. After completion of the reaction (monitored
by TLC), it was cooled to 0 °C. The reaction mixture was
acidified with 1 M HCl (until pH = 2.0) and the organic layer
separated. The aqueous layer was extracted with ethyl acetate (3
buffer solution (pH = 7) followed by DDQ (6.2 mg, 0.027 mmol)
was added at 0 °C. The reaction mixture was allowed to stir for 2
h at room temperature. After completion of the reaction
(monitored by TLC), it was quenched with saturated NaHCO (5
3
mL) solution. The two layers were separated and the aqueous
layer extracted with CH Cl (3 × 10 mL). The combined organic
×
15 mL). The combined organic layer were washed with brine
2
2
(
2 × 25 mL) and dried over anhydrous Na SO . The solvent was
layer was washed with brine (10 mL), dried over anhydrous
2
4
evaporated to dryness under reduced pressure and the crude mass
purified by silica gel column chromatography (EtOAc/hexane =
Na SO4 and evaporated under reduced pressure to give the
residue which on purification by silica gel column
chromatography (EtOAc/hexane = 1:7) afforded primary alcohol
2
1
:1) to afford 3 (0.044 g, 95%) as a colorless liquid; R
f
27
(EtOAc/hexane = 1:1) 0.25. [α]D −15.8 (c 0.4, CHCl ); IR
46 (13.3 mg, 95%) as a colorless liquid; R (EtOAc/hexane = 1:4)
3
f
27
(
neat): 3430, 2925, 2854, 1723, 1649, 1513, 1467, 1250, 1035,
0.45. [α]D +11.2 (c 0.4, CHCl ); IR (neat): 3448, 2924, 2854,
3
−1 1
−1
1
7
2
2
4
3
1
57 cm ; H NMR (300 MHz, CDCl ) δ = 7.26 (d, J = 8.3 Hz,
1719, 1652, 1258, 1097, 1033, 770 cm ; H NMR (400 MHz,
3
H), 7.11-6.99 (m, 1H), 6.87 (d, J = 8.5 Hz, 2H), 5.86-5.69 (m,
H), 5.63-5.52 (m, 2H), 5.02-4.91 (m, 2H), 4.72-4.57 (m, 4H),
.53-4.45 (m, 2H), 4.20 (t, J = 5.9 Hz, 1H), 4.08-4.00 (m, 1H),
.80 (s, 3H), 3.50-3.41 (m, 1H), 3.36 (d, J = 1.3 Hz, 6H), 2.31-
CDCl ) δ = 6.91 (dt, J = 7.0, 15.7 Hz, 1H), 5.88 (s, 1H), 5.86-
3
5.76 (m, 2H), 5.63 (m, 1H), 5.53 (m, 1H), 5.23 (d, J = 8.7 Hz,
1H), 5.03 (d, J = 15.7 Hz, 1H), 4.98-4.90 (m, 2H), 4.67 (AB , J =
q
7.0, 24.4 Hz, 2H), 4.56 (dd, J = 7.0, 15.7 Hz, 2H), 4.06-3.99 (m,
3H), 3.89 (t, J = 7.0 Hz, 1H), 3.57 (m, 1H), 3.37 (d, J = 12.2 Hz,
6H), 2.67-2.61 (m, 1H), 2.54 (bs, 1H), 2.48-2.34 (m, 2H), 2.30-
2.14 (m, 4H), 1.83 (s, 3H), 1.57-1.46 (m, 9H), 0.95 (d, J = 6.1
13
.99 (m, 4H), 1.71-1.45 (m, 6H) ppm; C NMR (75 MHz,
CDCl ) δ = 170.8, 151.5, 138.4, 133.7, 130.7, 130.0, 129.5,
3
1
5
29.4, 120.7, 114.7, 113.7, 94.2, 93.6, 79.9, 77.3, 75.8, 72.6,
13
5.53, 55.45, 55.2, 35.0, 32.1, 29.9, 29.7, 23.7 ppm; ESI-HRMS
Hz, 3H), 0.91 (s, 9H), 0.06 (s, 6H) ppm; C NMR (75 MHz,
+
Calcd for C H O Na [M + Na] 515.2617; found: 515.2615.
CDCl ) δ = 166.1, 148.9, 144.3, 138.3, 136.1, 135.8, 129.3,
27
40
8
3
1
28.1, 125.0, 121.4, 114.8, 94.0, 93.9, 80.2, 77.1, 76.2, 74.8,
4
.45. (2E,7S,8E,10S,11S)-((1E,4R,5R,6E)-8-(tert-Butyldimeth-
72.9, 68.0, 55.7, 55.5, 42.2, 36.1, 35.0, 32.0, 30.9, 29.6, 25.9,
ylsilyloxy)-1-iodo-2,5,7-trimethylocta-1,6-dien-4-yl)11-(4-
methoxybenzyloxy)-7,10-bis(methoxymethoxy)pentadeca-
24.0, 23.9, 18.4, 16.9, 13.9, −5.3 ppm; ESI-HRMS Calcd for
+
C
H
63
O
8
ISiNa [M + Na] 801.3222; found: 801.3229.
36
2
,8,14-trienoate (45)
4
.47. (2E,7S,8E,10S,11S)-((1E,4R,5R,6E)-8-(tert-Butyldime-
To a stirred solution of the acid 3 (0.49 g, 2.01 mmol) in dry
thylsilyloxy)-1-iodo-2,5,7-trimethyl-octa-1,6-dien-4-yl)-11-
(tert-butyldimethylsilyloxy)-7,10-bis(methoxymethoxy)penta
deca-2,8, 14-trienoate (47)
toluene (10 mL), Et N (0.31 mL, 4.02 mmol) followed by 2,4,6-
3
trichlorobenzoyl chloride (0.63 mL, 4.02 mmol) was added at 0
°
C under N atmosphere and continued to stir for 45 min at room
2
temperature. DMAP (1.22, 10.04 mmol) and alcohol 4 (0.45 g,
.004 mmol) dissolved in dry toluene (10 mL) was added to
To a solution of homoallylic alcohol 46 (11 mg, 0.014 mmol) in
1
CH Cl (5 mL), was added 2,6-lutidine (3.3 µL, 0.028 mmol) and
2
2
o
reaction mixture dropwise at 0 C and allowed to stir for 6 h at
room temperature. After completion of the reaction (monitored
by TLC), it was diluted with water (25 mL) and ethyl acetate (50
mL). The aqueous layer was extracted with ethyl acetate (2 × 40
mL). The combined organic layer was washed with brine (2 × 50
mL), dried over anhydrous Na SO and solvent evaporated under
TBSOTf (3.85 µL, 0.017 mmol) at 0 °C under N atmosphere.
2
The reaction mixture was allowed to stir for 30 min at same
temperature. After completion of the reaction (monitored by
TLC), the reaction mixture was then quenched with H O (5 mL).
2
The reaction mixture was diluted with CH Cl and aqueous layer
2
2
was extracted with CH Cl (2 × 10 ml). The organic layer dried
2
4
2
2
reduced pressure. The crude mass was purified by silica gel
over Na SO and solvent removed under reduced pressure. The
2 4
column chromatography (EtOAc/hexane = 1:12) to furnish 45
residue was purified by silica gel column chromatography
(
0.63 g, 93%, based on the starting alcohol) as a colorless liquid;
(EtOAc/hexane = 1:15) to afford 47 (12.1 mg, 96%) as a clear
27
27
R (EtOAc/hexane = 1:12) 0.30. [α]
+3.8 (c 0.8, CHCl ); IR
liquid; R (EtOAc/hexane = 1:15) 0.55. [α] −5.1 (c 0.7, CHCl );
f
D
3
f
D
3
−1
1
−1
(
(
neat): 2924, 2854, 1728, 1460, 1266, 1076, 772 cm ; H NMR
300 MHz, CDCl ) δ = 7.29-7.25 (m, 2H), 6.98-6.91 (m, 1H),
IR (neat): 2925, 2851, 1723, 1511, 1457, 1248, 1097, 1035 cm ;
H NMR (500 MHz, CDCl ) δ = 6.91 (dt, J = 7.0, 15.4 Hz, 1H),
1
3
3
6
5
4
4
2
.87 (d, J = 8.3 Hz, 2H), 5.88 (s, 1H), 5.84-5.71 (m, 2H), 5.64-
.55 (m, 2H), 5.23 (d, J = 9.8 Hz, 1H), 5.02-4.89 (m, 3H), 4.71-
.57 (m, 4H), 4.49 (d, J = 9.1 Hz, 2H), 4.19 (t, J = 6.0 Hz, 1H),
.08-3.98 (m, 3H), 3.81 (s, 3H), 3.50-3.40 (m, 1H), 3.36 (s, 6H),
.70-2.57 (m, 1H), 2.50-2.32 (m, 2H), 2.28-2.00 (m, 4H), 1.82 (s,
5.87 (s, 1H), 5.84-5.75 (m, 2H), 5.60 (dd, J = 6.4, 15.7 Hz, 1H),
5.54 (dd, J = 7.2, 15.7 Hz, 1H), 5.22 (d, J = 9.8 Hz, 1H), 5.03-
4.89 (m, 3H), 4.68 (d, J = 6.7 Hz, 1H), 4.64 (d, J = 6.6 Hz, 1H),
4.57 (d, J = 6.7 Hz, 1H), 4.49 (d, J = 6.7 Hz, 1H), 4.09-3.96 (m,
4H), 3.75-3.68 (m, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 2.68-2.57 (m,

Tetrahedron
H), 2.48-2.32 (m, 2H), 2.27-1.98 (m, 4H), 1.82 (s, 3H), 1.72-
.35 (m, 9H), 0.94 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H),
15
1
1
0
Omura, S., Ed.; Academic Press: San Diego, 2002; pp 57-98; (c)
ACCEPTED MANUSCRIPT
Higa, T.; Tanaka, J. Stud. Nat. Prod. Chem. 1997, 19 (Part E), 549;
(d) For an extensive review on the total synthesis of bioactive marine
macrolides, see: Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95,
2041; (e) Parenty, A.; Moreau, X.; Niel, G.; Campagne, J.-M. Chem.
Rev. 2013, 113, PR1−PR40 and references therein.
(a) Diyabalanage,T.; Amsler, C. D.; McClintock, J. B.; Baker, B. J. J.
Am. Chem. Soc. 2006, 128, 5630; (b) Leber, M. D.; Baker, B. J.
Tetrahedron Lett. 2007, 48, 8009.
Xie, X. S.; Padron-Perez, D.; Liao, X.; Wang, J.; Roth, M. G.; De
Brabander, J. K. J. Biol. Chem. 2004, 279, 19755.
(a) Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem.
Soc. 2007, 129, 6386; (b) Nicolaou, K. C.; Guduru, R.; Sun, Y. P.;
Banerji, B.; Chen, D. Y. K. Angew. Chem. Int. Ed. 2007, 46, 5896;
13
.07 (d, J = 6.3 Hz, 6H), 0.06 (s, 6H) ppm; C NMR (125 MHz,
CDCl ) δ = 166.1, 149.1, 144.3, 138.7, 135.8, 133.8, 129.6,
3
1
5
2
25.0, 121.3, 114.4, 94.5, 93.6, 78.9, 77.2, 75.8, 74.8, 73.5, 68.0,
5.47, 55.44, 42.2, 36.1, 35.1, 32.1, 31.7, 29.6, 25.92(3C),
2.
5.88(3C), 24.0, 23.9, 18.4, 18.1, 16.9, 13.9, −4.3, −4.7, −5.2
+
ppm; ESI-HRMS Calcd for C H O NISi [M + NH ] 910.4539;
42
81
8
2
4
3
4
.
.
found: 910.4600.
4
.48. (3E,8S,9E,11S,12S,15E,17E,20R)-12-(tert-Butyldimet-
hylsilyloxy)-20-((R,E)-5-(tert-butyldimethylsilyloxy)-4-methyl
pent-3-en-2-yl)-8,11-bis(methoxymethoxy)-18-methyloxacyclo
icosa-3,9,15,17-tetraen-2-one (2)
(
c) Nicolaou, K. C.; Sun, Y. P.; Guduru, R.; Chen, D. Y. K. J. Am.
Chem. Soc. 2008, 130, 3633; (d) Nicolaou, K. C.; Leung, Y. C. G.;
Dethe, D. H.; Guduru, R.; Sun,Y. P.; Lim, C. S.; Chen, D. Y. K. J.
Am. Chem. Soc. 2008, 130, 10019; (e) Penner, M.; Rauniyar, V.;
Kasper, L. T.; Hall, D. G. J. Am. Chem. Soc. 2009, 131, 14216.
(a) Prasad, K. R.; Pawar, A. B. Org. Lett. 2011, 13, 4252; (b) Pawar,
A. B.; Prasad, K. R. Chem. Eur. J. 2012, 18, 15202; (c) Pujari, S. A.;
Gowrisankar, P.; Kaliappan, K. P. Chem. Asia. J. 2011, 6, 3137; (d)
Gowrisankar, P.; Pujari, S. A.; Kaliappan, K. P. Chem. Eur. J. 2010,
16, 5858; (e) Jägel, J.; Maier, M. E. Synthesis 2009, 2881; (f) Lisboa,
Marilda P.; Jones, David M.; Dudley, Gregory B. Org.
Lett. 2013, 15, 886.
(a) Lisboa, P. M.; Jeong-Im, H. J.; Jones, D. M.; Dudley, G. B.
Synlett 2012, 1493; (b) Jones, D. M.; Dudley, G. B. Synlett 2010,
223; (c) Leber, M. D.; Baker, B. J. Tetrahedron 2010, 66, 1557; (d)
Prasad, K. R.; Pawar, A. B. Synlett 2010, 1093; (e) Kaliappan, K. P.;
Gowrisankar, P. Synlett 2007, 1537; (f) Cantagrel, G.; Cantagrel, C.;
Cossy, Cantagrel J. Synlett 2007, 2983; (g) Chandrasekhar, S.;
Vijeender, K.; Chandrasekhar, G.; Reddy, C. R. Tetrahedron:
Asymmetry 2007, 18, 2473; (h) Jägel, J.; Scmauder, A.; Binanzer, M.;
Maier, M. E. Tetrahedron 2007, 63, 13006; (i) Jena, B. K.;
Mohapatra, D. K. Tetrahedron Lett. 2013, 54, 3415; (j) Wen, Z.-K.;
Xu, Y.-H.; Loh, T.-P. Chem. Eur. J. 2012, 18, 13284.
To a stirred solution of vinyl iodide 47 (9.7 mg, 0.011 mmol) in
5
6
.
.
dry DMF (5 mL), was added K CO (12.6 mg, 0.09 mmol) and
2
3
Pd(OAc) (3 mg, 0.014 mmol) at room temperature under Ar
2
o
atmosphere. The reaction mixture was heated to 65 C and
continued to stir for 5 h at same temperature. After complete
consumption of the starting material (monitored by TLC), the
reaction mixture was cooled to room temperature and quenched
with water (2 mL). The aqueous layer was extracted with ethyl
2
acetate (3 × 5 mL), washed with brine (5 mL), dried over Na SO4
and concentrated under reduced pressure. The crude mass was
purified by silica gel column chromatography (EtOAc/hexane =
1
(
(
1
:4) to afford 2 (5 mg, 60%) as a viscous liquid; R
f
27
EtOAc/hexane = 1:4) 0.55. [α]D −121.6 (c 0.4, CHCl ); IR
3
neat): 2928, 2856, 2310, 1720, 1655, 1531, 1465, 1255, 1102,
−1 1
036, 836, 775 cm ; H NMR (500 MHz, CDCl ) δ = 6.82 (ddd,
3
J = 4.7, 10.4, 15.3 Hz, 1H), 6.10 (dd, J = 11.1, 14.7 Hz, 1H), 5.73
7.
(a) Jaegel, J.; Maier, M. E. Synthesis 2009, 2881; (b) Negishi, E.-I.
Bull. Chem. Soc. Jpn. 2007, 80, 233; (c) Link, J. T. Org. React. 2002,
0, 157; (d) Bhatt, U.; Chirstmann, M.; Quitschalle, M.; Cluas, E.;
Kalesse, M. J. Org. Chem. 2001, 66, 1885. Formation of only the
E,E-diene is observed within detectable (HECK Coupling) limits by
NMR. For recent approaches involving intramolecular Heck reaction
in macrolactone synthesis, see: (e) Li, P.; Li, J.; Arikan, F.;
Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Am. Chem. Soc. 2009,
(
(
(
1
4
1
1
dd, J = 1.2, 15.6 Hz, 1H), 5.68 (dd, J = 3.0, 15.7 Hz, 1H), 5.63
d, J = 10.3 Hz, 1H), 5.51-5.46 (m, 1H), 5.45-5.38 (m, 1H), 5.23
dd, J = 1.1, 9.9 Hz, 1H), 4.95-4.89 (m, 1H), 4.69 (d, J = 6.7 Hz,
H), 4.63 (s, 2H), 4.50 (d, J = 6.7 Hz, 1H), 4.17-4.09 (m, 1H),
.01 (s, 2H), 3.99-3.92 (m, 1H), 3.67 (dddd, J = 1.5, 4.4, 9.8,
4.0 Hz, 1H), 3.37 (s, 3H), 3.36 (s, 3H), 2.64-2.57 (m, 1H), 2.27-
.95 (m, 6H), 1.80-1.40 (m, 12H), 0.95 (d, J = 6.6 Hz, 3H), 0.92
6
1
31, 11678; (f) Menche, D.; Hassfeld, J.; Li, J.; Rudolph, S. J. Am.
(
s, 9H), 0.91(s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H) ppm;
Chem. Soc. 2007, 129, 6100; (g) Menche, D.; Hassfeld, J.; . Li, J.;
Mayer, K.; Rudolph, S. J. Org. Chem. 2009, 74, 7220; (h) Li, P.; Li,
J.; Arikan, F.; Ahlbrecht, W.; Dieckmann, M.; Menche, D. J. Org.
Chem. 2010, 75, 2429.
Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
1
3
C NMR (125 MHz, CDCl ) δ = 166.4, 148.8, 135.5, 132.5,
3
1
7
3
31.9, 130.4, 129.9, 128.1, 126.5, 125.5, 121.1, 95.6, 93.2, 78.1,
7.2, 74.6, 74.0, 68.2, 55.5, 55.3, 43.9, 36.8, 35.8, 33.2, 33.0,
8
9
1
.
0.5, 25.9, 25.0, 18.4, 18.1, 17.3, 16.4, 13.9, −4.5, −4.7, −5.2
+
ppm; ESI-HRMS Calcd for C H O NSi [M + NH ] 782.5417;
42
80
8
2
4
.
Pfaltz, A.; Mattenberger, A. Angew. Chem., Int. Ed. Engl. 1982, 21,
found: 782.5401.
7
1.
0.
Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408.
(a) Mohapatra, D. K.; Pattanayak, M. R.; Das, P. P.; Pradhan,T. R.;
Yadav, J. S. Org. Biomol. Chem. 2011, 9, 5630; (b) Mohapatra, D.
K.; Reddy, D. P.; Dash, U.; Yadav, J. S. Tetrahedron Lett. 2011, 52,
51; (c) Mohapatra, D. K.; Sahoo, G.; Ramesh, D. K.; Rao, J. S.;
Sastry, G. N. Tetrahedron Lett. 2009, 50, 5636; (d) Mohapatra, D.
K.; Dash, U.; Naidu, P. R.; Yadav, J. S. Tetrahedron Lett. 2009, 50,
129; (e) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.;
Chorghade, M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett.
2007, 48, 2621.
(a) Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed. 2006, 45,
086; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199; (c)
Acknowledgements
11.
We are thankful to the Director, CSIR-IICT and HoD, NPCD,
for their kind support and encouragement. The authors thank
CSIR, New Delhi for financial support as part of XII Five Year
plan programme under title ORIGIN (CSC-0108). DKM thanks
the Council of Scientific and Industrial Research (CSIR), New
Delhi, India, for a research grant (INSA Young Scientist Award
Scheme). B.K.J. is thankful to the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the financial
assistance in the form of fellowship.
1
2
12.
6
Grubbs, R. H. Tetrahedron 2004, 60, 7117; (d) Prunet, J. Angew.
Chem. Int. Ed. 2003, 42, 2826; (e) Love, J. A. In Handbook of
Metathesis; Grubbs, R. H. Ed. Wiley-VCH: Weinheim, Germany,
Supplementary data
2
003; pp 296; (f) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org.
34, 18; (g) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; (h)
Maier, M. E. Angew. Chem. Int. Ed. 2000, 39, 2073; (i) Grubbs, R.
H.; Chang, S. Tetrahedron 1998, 54, 4413; (j) Armstrong, S. K. J.
Chem. Soc., Perkin Trans. 1 1998, 371.
1
3.
Ruiz, J. M.; Afonso, M. M.; Palenzuela, J. A. Molecules 2007, 12,
194.
References and Notes
1
1
4.
5.
Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
Reddy, L. V. R.; Sagar, R.; Shaw, A. K. Tetrahedron Lett. 2006, 47,
1
.
(a) Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329
and references therein; (b) Ishibashi, M. Macrolide Antibiotics;
1
753.

1
6
Tetrahedron
1
6.
Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
ACCEPTED MANUSCRIPT
1
7.
(a) Balkrishna, S. B.; Childers, Jr. W. E.; Pinnick, H. W. Tetrahderon
1
5
981, 37, 2091; (b) Dalcanale, E.; Montanari, F. J. Org. Chem. 1986,
1, 567.
1
1
8.
9.
Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55, 14013.
Kolb, H. C.; VanNiewenzie, M. S.; Sharpless, K. B. Chem. Rev.
1
994, 94, 2483.
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2
2
0.
1.
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Yang, J.-H.; Liu, J.; Hsung, R. P. Org. Lett. 2008, 10, 2525.
Seepersaud, M.; Al-bed, Y. Tetrahedron Lett. 2000, 41, 7801.
(a) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589; (b)
Mikolajczyk, M.; Kielbasin´ ski, P. Tetrahedron 1981, 37, 233; (c)
Neises, B.; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17, 522.
(
(
d) Nozaki, S.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1982, 55, 2165;
e) Sheehan, J. C.; Preston, J.; Cruickshank, P. A. J. Am. Chem. Soc.
1
965, 87, 2492.
2
2
2
2
2
3.
4.
5.
6.
7.
Srihari, P.; Prem Kumar, B.; Subbarayudu, K.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 6977.
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Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
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Tetrahedron 1986, 42, 3021.
(a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess,
D. B.; Martin, J. C. J. Am.Chem. Soc. 1991, 113, 7277.

ACCEPTED MANUSCRIPT
Supporting Information
Formal Total Synthesis of Palmerolide A
†
*,†
Bighnanshu K. Jena and Debendra K. Mohapatra
†
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500 007, INDIA; mohapatra@iict.res.in
*
Corresponding author. Tel.: +91-40-27193128; fax: +91-40-27160512
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