Asymmetric synthesis of naturally occurring (-)-seimatopolides A and B

Article abstract of DOI:10.1016/j.tet.2014.05.021

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.

Full text of DOI:10.1016/j.tet.2014.05.021

Accepted Manuscript
Asymmetric Synthesis of Naturally Occurring (-)-Seimatopolide A and B
Rohan Kalyan Rej , Pratik Pal , Samik Nanda
PII:
S0040-4020(14)00693-0
10.1016/j.tet.2014.05.021
TET 25570
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2014
Revised Date: 6 May 2014
Accepted Date: 12 May 2014
Please cite this article as: Rej RK, Pal P, Nanda S, Asymmetric Synthesis of Naturally Occurring (-)-
Seimatopolide A and B, Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.021.
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ACCEPTED MANUSCRIPT
Asymmetric Synthesis of Naturally Occurring (-)-Seimatopolide A and B
Rohan Kalyan Rej, Pratik Pal and Samik Nanda*
Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India
Tel: +91-3222-283328; Fax: +91-3222-282252; snanda@chem.iitkgp.ernet.in
Keywords: Nonenolide, Asymmetric synthesis, Cross metathesis, CBS-mediated asymmetric
reduction, asymmetric allylboration, Shiina macrolactonization.
Abstract: Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide
seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E
selective cross metathesis (CM) reaction between two suitable fragments followed by
macrolactonization reaction is the main highlight of our synthesis for the two natural products.
The fragment containing 6S,7S,9R stereocenters for seimatopolide A have been synthesized from
L-tartaric acid as a chiral pool starting material, by employing (R)-CBS mediated stereoselective
keto reduction reaction. Another fragment which is common for both the molecules, containing
the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic
resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B have been
prepared from n-decanal by adopting (R)-CBS mediated keto reduction and Brown asymmetric
allylation reaction.
Introduction
Nonanolides (known as decanolides) are biologically active secondary metabolites that contain a
ten membered macrolide core and a C-9 alkyl appendage as its main structural components
which can be broadly classified in two structural families: (i) having a C-9 methyl substitution
1
2
3
and (ii) containing higher alkyl substitution at C-9. Cytospolides, Herbarumins, Pinolidoxin
4
and Achaetolide
are few representative examples belonging to the second family of
decanolides. Recently two new decanolides seimatopolide A & B were isolated from a fungal
5
9
culture broth of Seimatosporium discosioides, which contain a C-9 nonyl (n-C H19) appendage.
1

ACCEPTED MANUSCRIPT
The structure of both the decanolides were established by extensive NMR analysis of the
corresponding Moscher’s ester. The absolute configuration of seimatopolide A was proposed to
be 3R,6R,7R,9S whereas that for seimatopolide B was 3R,6S,9S. Seimatopolides A & B have
significant biological activity, as both of them found to activate PPAR-γ receptor (peroxisome
proliferator-activated receptor γ) with EC50 values of 1.15 and 11.05 µM respectively. This
6
receptor is known for its regulatory activity of fatty acid storage and glucose metabolism. Hence
this receptor has been linked with the pathological function of several diseases such as obesity,
diabetes, atherosclerosis, and cancer. Till today, there are six total syntheses reported in the
7
7g-h
literature for seimatopolide A and two for seimatopolide B.
The absolute configuration was
7
a
7b
reassigned for both the decanolides by Reddy’s group
and Schmidt’s group
and they
proposed that the revised absolute configuration will be 3S,6S,7S,9R for seimatopolide A and
S,6R,9R for seimatopolide B (enantiomeric to the originally proposed structure; Figure-1). The
3
Schmidt group had also synthesized both the enantiomers of seimatopolide A and reassigned the
absolute configuration based on chirooptical methods. In recent times our group is actively
8
engaged in the synthesis of small and medium sized ring macrolides. In continuation to previous
effort, herein we intend to report the asymmetric total synthesis of seimatopolide A and B
through a reverse sequential strategy. The normal sequential strategy applied for seimatopolide
A/B involves esterification followed by ring closing metathesis (RCM) reaction to construct the
decanolide core as evident from the earlier reports. The strategy of altered reaction sequences
(CM followed by macrolactonization) for asymmetric synthesis of a structurally similar
8
j
decanolide xyolide was just reported.
OH
6
OH
OH
6
OH
6
4
4
4
HO
OH HO
OH
4
OH
OH
6
9
7
8
3
2
7
8
3
2
7
8
3
2
5
5
7
8
3
2
5
5
O
O
O
1
1
O
1
9
1
9
9
O
O
O
O
nC8H17
nC8H17
nC8H17
nC8H17
Seimatopolide A
3S,6S,7S,9R)
Revised structure
Seimatopolide A
(3R,6R,7R,9S)
Proposed structure
Seimatopolide B
3S,6R,9R)
Revised structure
Seimatopolide B
(
(
(3R,6S,9S)
Proposed structure
Figure-1: Structures of Seimatopolide A (Revised and proposed) and B.
2

ACCEPTED MANUSCRIPT
Result and Discussion
The previously reported synthetic strategies for seimatopolide A/B involve application of a
successful late stage E-selective RCM (ring closing metathesis) reaction in all the cases. The
RCM precursor was constructed through an esterification reaction of properly substituted alcohol
and acid. In this setup, it has been decided to carry out the synthetic efforts towards
seimatopolide A by an altered sequence of chemical reactions. We intend to apply an E-selective
CM reaction at the beginning followed by a macrolactonization method to construct the core
decanolide structure. The proposed retrosynthetic strategy is detailed in Scheme-1. It is
envisioned that macrolactonization of the seco-acid could be an alternative option to construct
7
f
the decanolide core of the target molecule seimatopolide A/B, as it was rarely attempted before.
The seco-acid in turn was planned to be accessed by an E-selective (the olefinic unsaturation
between C -C ) CM reaction of the required olefinic fragments in both the cases. For
4
5
seimatopolide A, the C
reduction of the corresponding ketone. The ketone was synthesized by an umpolung alkylation of
substituted 1,3-dithiane (derived from n-decanal) with the iodo compound derived from C
symmetric L-tartaric acid as a chiral pool. The other fragment (C -C ) was synthesized from a
9 4 9
-stereocenter in fragment (C -C ) was created by stereoselective CBS
2
-
1
5
known enantiopure alcohol, which was earlier synthesized in our group by adopting a ME-DKR
8
f
reaction of the racemic alcohol and this fragment will be used for both the decanolides. For
seimatopolide B, the stereocenter in the C (6R) position was created by stereoselective CBS
6
reduction of a vinyl ketone, which in turn was accessed from asymmetric Brown allylation
reaction from n-decanal (Scheme-1; constitutes the C (9R) stereocenter in the target molecule).
9
3

ACCEPTED MANUSCRIPT
Earlier synthesis: Normal sequence of synthetic operation: Esterification, RCM
OP2
OH
6
OP
2
4
R
OP1
R
R
OH
RCM
OP1
+
7
8
3
5
2
OP3
O
O
1
Esterification
HO
9
O
O
O
nC H
8 17
nC H
8 17
nC H
8
17
R = OH; Seimatopolide A
R = H; Seimatopolide B
This work: Reverse sequence of synthetic operation: CM, Macrolactonization
OP2
OH
OP2
R
OH
R
OP1
OP1
R
CM
+
O
OH
Macrolactonization
OP
3
CO H
2
O
OP4
nC H
nC H
8
17
8
17
nC H
8
17
R = OP2
R = OH; Seimatopolide A
R = H; Seimatopolide B
ME-DKR
OH
Asymmetric reduction
P ...P = Suitable protecting groups
1
n
OP2
HO
O
R
O
Umpolung alkylation
OTBS
S
+
O
nC H
S
9
19
I
nC H
8
17
OP2
O
O
R
Asymmetric
reduction
Weinreb
ketone synthesis
Asymmetric
allylation
OH
n-Decanal
OP3
OP3
OP3
nC H
8
17
nC H
R = H
nC H
8 17
8
17
Scheme-1: Retrosynthetic analysis of seimatopolide A and B
Synthesis of the C -C fragment for seimatopolide A/B: The synthesis starts from the known
1
5
8
f
enantiopure alcohol 1. The free alcohol group in compound 1 was protected as its MOM-ether
by treatment with MOM-Cl and DIPEA to afford compound 2 in 90% yield. The PMB-group in
9
compound 2 was deprotected with DDQ (Na-phosphate buffer; pH = 7.0) to afford alcohol 3 in
4

ACCEPTED MANUSCRIPT
8
8% yield. The primary alcohol functionality is then oxidized to carboxylic acid 4 by treatment
1
0
with BAIB/TEMPO in 88% yield (Scheme-2).
OH
OMOM
OMOM
OMOM
a
b
c
CO H
OPMB
OPMB
OH
2
4
1
2
3
Scheme-2; reagents and conditions: a) MOM-Cl, DIPEA, TBAI (cat), DCM, rt, 4 h, 90%; b)
DDQ, DCM: phosphate buffer (9:1, pH = 7.0), rt, 1 h, 88%; c) BAIB, TEMPO (cat), DCM:
water (1:1), rt, 4 h, 88%. BAIB: [Bis(acetoxy)iodo]benzene.
Synthesis of C
which was protected as its dithiane by treatment with 1,3-propanedithiol to afford compound 5 in
5% yield. Umpolung alkylation of compound 5 with known iodide (6) derived from L-tartaric
acid in presence of t-BuLi afforded compound 7 in 80% yield (brsm). The dithiane group in
4 9
-C fragment for seimatopolide A: The synthesis was initiated from n-decanal,
8
1
1
compound 7 was deprotected by using I and CaCO to afford ketone 8 in 90% yield. All the
2
3
attempts for stereoselective reduction of the carbonyl group in compound 8 (substrate directed
approach with hydride sources such as NaBH , LiBH , DIBAL-H, L-selectride) failed, as the
4
4
desired amount of stereocontrol was not achieved, we have then switched over to reagent control
1
2
approach. Stereoselective reduction of ketone 8 with (R)-CBS afforded the alcohol 9 as a sole
product. The secondary hydroxyl group was then protected as its TBS ether by treatment with
TBS-OTf and 2,6-lutidine to afford compound 10 in 88% yield. Selective deprotection of 1° TBS
1
3
group in presence of 2° TBS group was achieved by treating compound 10 with HF/pyridine
to afford compound 11 in 90% yield. Oxidation of primary hydroxyl group in compound 11 with
1
4
BAIB/TEMPO
furnished the aldehyde 12 in 86% yield. The aldehyde 12 was then
subsequently reacted with Ph P=CH to afford compound 13 in 75% yield (overall yield 26%
3
2
from n-decanal; Scheme-3). The absolute stereochemistry of compound 13 (corresponds to 6S,
1
13
7
S, 9R in seimatopolide A) was confirmed by comparing the spectroscopic data ( H/ C-NMR)
7
a
and optical rotation values with those of a known compound reported from Reddy’s group for
their synthesis of (+)-seimatopolide A.
5

ACCEPTED MANUSCRIPT
O
O
O
O
OTBS
O
OTBS
a
O
OTBS
b
c
+
S
S
S
S
6
5
O
nC H
nC H
nC H
9 19
9
19
I
9
19
8
7
OTBS
O
O
OH
O
O
OTBS
O
O
e
d
OTBS
OTBS
nC H
nC H
9
19
9
19
nC H
9 19
9
1
0
11
OH
OTBS
O
O
25
Compound 13: [α]D = -13.5 (c = 1.0, CHCl )
3
f
7a
20
Reported for ent-13: [α]
= +13.7 (c = 1.0, CHCl3)
D
nC H
9
19
12
X = O; 12
X
g
X = CH ; 13
2
Scheme-3: reagents and conditions: a) t-BuLi, -78 ˚C, THF/HMPA (10:1), 30 min, 80%; b) I2,
CaCO , THF:H O (4:1), 90%; c) (R)-CBS (20 mol%), BH .SMe , THF, -78 ˚C-rt, 6 h, 72%; d)
3
2
3
2
TBS-OTf, 2,6-lutidine, DCM, 88%; e) HF/pyridine, THF, rt, 90%; f) BAIB, TEMPO, NaHCO
DCM, rt, 2 h, 86%; g) Ph P CH I ; LHMDS, THF, 0 ˚C-rt, 4 h, 75%.
3 3
3
,
+
-
Fragment coupling and completion of the synthesis for seimatopolide A: After successful
construction of both the fragments, our next job is to couple them by cross metathesis reaction.
One of the reacting partners in CM reaction was kept constant, and compound 13 was chosen for
that purpose. Whereas for choosing the other partner we have performed a systematic
optimization with compounds 1-4 with the following Ru-based metathesis catalyst (C1-C5;
Scheme-4). It was observed that olefin 2 and 4 was sluggish in the CM reaction with olefin 13. In
all the cases starting olefin remains unreacted, which implies that both of the olefins (2 and 4) are
indeed slower in homodimerization process and belongs to Type-II olefin as mentioned by
1
5
Grubbs. In that article by Grubbs it was mentioned clearly that the prerequisite of a successful
CM reaction depends on the judicious choice of olefin partners. The best approach towards a
successful CM reaction involves reaction of an olefin (Type-I; which undergoes fast
homodimerization; compound 13 in our case) with a slow reactive olefin (Type-II, slow
homodimerization, compounds 1-4 in our case). But in our initial findings we observed that for
6

ACCEPTED MANUSCRIPT
olefins 2 and 4, when reacted with compound 13 (in presence of metathesis catalyst C1-C5), no
CM product was isolated. The compounds 1-4, all having 2˚ allylic alcohol (free in olefin 1, in
olefins 2 and 4 the alcohol is protected by suitable protecting group and in case of olefin 3,
primary alcohol is free at one terminal) moiety with a terminal olefinic functionality belongs to
type-II olefin. When compound 1 was reacted with olefin 13, we have isolated the CM product in
7
0% yield (with catalyst C3, Scheme-4). The olefin 3 with a free primary –OH group at one end,
also reacted with olefin 13 with catalyst C3, and the yield of isolated product was lower than in
the case of olefin 1 (E:Z =9:1). It is clear that greater reactivity was observed with free 2˚ allylic
alcohol moiety (in compound 1) than the protected one (compound 2 and 4). The similar
1
5
observation was also pointed out by Grubbs in his article. Even olefin 3, with a free 1˚ alcohol
is also reactive under the reaction condition. The reason was not clear, but increasing steric bulk
through protecting group might cause inertness of those olefins (2 and 4) towards CM reaction.
1
6
Similar findings were also reported by researchers, in which they have clearly demonstrated
that the presence of free 2˚ allylic alcohol moiety has a rate enhancing effect in RCM reaction.
The reason for that high activity is not very clear, but the possibility of rapid and reversible
ligand exchange (alkoxy group replaces the Cl) and hydrogen bonding between hydroxyl group
and one of the chloride ligands cannot be ruled out. The moderate reactivity (good E: Z
selectivity) of olefin 3, under the CM condition is beneficial to us in the sense that, this can be
used as one of the CM counterpart for the total synthesis of seimatopolide B.
The best results in the CM reaction (selectivity and reactivity; E: Z ~ 12:1, Table-1) were
nd
17
obtained with catalyst C3 (Hoveyda-Grubbs 2 generation catalyst; HG-II). With the catalyst
1
8
C1 (G-II), the CM product was isolated in 30% yield with poor selectivity (E: Z ~1:1).
1
9
Whereas with catalyst C2 (HG-I) no product formation was detected, indicating that NHC type
metathesis catalyst is the ideal choice for best reactivity and selectivity. The catalyst C4 (HG-II
2
0
analogue), reacts extreme slowly and high amount of catalyst (20 mol%) was required to
achieve the formation of 14 (Scheme-4, 40% isolated yield, after 80 h, E: Z ~ 8:1). The catalyst
2
1
C5 (G-II analogue) is similar in reactivity and selectivity when compared with catalyst C1.
The details for optimization of the CM reaction are presented in table-1.
7

ACCEPTED MANUSCRIPT
Table-1: Optimization of the CM conditions
b
Entry
Type-I
Type-II
Metathesis
catalyst
Catalyst
loading
Yield (%) Selectivity
a
a
olefin
olefin
(E:Z)
(mol%)
1
2
3
4
4
5
6
7
13
13
13
13
13
13
13
13
13
1
1
1
1
1
1
2
3
4
C1
5
30
nr
1:1
nr
C2
5
C3
5
70
10
40
25
nr
12:1
nr
C4
5
c
C4
20
5
8:1
1:1
nr
C5
C1-C5
C3
5
5
40
nr
9:1
nr
8
C1-C5
5
a
:
:
2 equiv of type-II olefin was taken at the beginning, additional 2 equiv was added after 30 min.
Yields refer to isolated yield after refluxing in DCM for 24 h. : After 80 h reflux in DCM. nr:
b
c
No significant reaction was observed.
8

ACCEPTED MANUSCRIPT
OMOM
OH
OMOM
OTBS O
O
OMOM
nC H
9
19
1
3
CO H
OH
2
OPMB
OPMB
2
3
4
1
OTBS O
O
a
1
3 + 1
OPMB
nC H
9
19
OH
Cross metathesis product (14)
PCy3
Cl
Ru
Cl
N
N
N
N
O
Cl
Cl
Ru
O
Ru
Cl
Cl
Ph
HG-I (C2)
PCy3
G-II (C1)
HG-II (C3)
N
N
N
N
Cl
Cl
Ru
Ru
Cl
Cl
PCy3
C5
O
C4
Scheme-4: Reagents and conditions: a) C3 (5 mol%), DCM, 24 h reflux, 70%.
After successful optimization of CM reaction, we have proceeded for the next step. The free
hydroxyl group in compound 14 was protected with MOM-Cl to furnish compound 15 in 90%
yield. Deprotection of PMB group was achieved by treating compound 15 with DDQ to afford
compound 16 in 82% yield. Oxidation of the primary alcohol group in compound 16 was
achieved with DMP to give the corresponding aldehyde, which on subsequent oxidation under
Pinnick condition afforded the carboxylic acid 17 in 82% yield (two steps). Deprotection of the
9

ACCEPTED MANUSCRIPT
TBS group with TBAF/THF afforded the seco-acid 18 in 85% yield. Macrolactonization of the
2
3
24
acid 18 under Yamaguchi and Shiina conditions afforded the decanolide core 19 in 62% and
8% yield respectively. Finally deprotection of acetonide and MOM groups were achieved by
treating compound 19 with 2M HCl in THF to afford the target molecule seimatopolide A
Scheme-5; overall yield = 5% from n-decanal). The spectral data of our synthesized
6
(
1
13
7a-b
seimatopolide A ( H/ C-NMR) matches perfectly with those of reported one. Optical rotation
2
8
value {[α]D = -27.4 (c = 0.05, MeOH)} also matches perfectly with those of literature value as
reported by Schmidt’s group and Reddy’s group in their respective synthesis of (-)-seimatopolide
A, having absolute configuration 3S, 6S, 7S, 9R.
O
O
O
OH
OMOM
b
O
O
OMOM
c
O
a
OTBS
OPMB
OTBS
OTBS
1
5
16
OPMB
OH
nC H
nC H
9
9
19
19
nC H
9
19
1
4
OH
O
O
HO
O
OH
OMOM
OMOM
O
e
g
or f
O
O
OP
CO H
2
nC H
19
O
nC H
O
9
9
19
nC H
9
19
1
9
(-)-Seimatopolide A
P = TBS; 17
P = H; 18
d
Scheme-5: Reagents and conditions: a) MOM-Cl, DIPEA, DCM, 90%; rt, 8 h; b) DDQ, DCM:
phosphate buffer (9:1, pH = 7.0), rt, 2 h, 82%; c) (i) DMP, NaHCO , DCM, rt, 2 h, (ii) NaClO
NaH PO , t-BuOH, 2-methyl-2-butene, H O, rt, 4 h, 82% in two step; d) TBAF, THF, rt, 6h,
5%; e) 2,4,6-trichlorobenzoylchloride, DIPEA, DMAP, toluene, 60 ˚C, 24 h, 62%; f) MNBA
3
2
,
2
4
2
8
˚
(2-methyl-6-nitro benzoic anhydride), DIPEA (diisopropylethyl amine), DMAP, toluene, 60 C,
2
4 h, 68%; g) 2M HCl, THF, rt, 12 h, 80%.
1
0

ACCEPTED MANUSCRIPT
Synthesis of C
4
-C
9
fragment for seimatopolide B: The synthesis was commenced from n-
2
5
decanal, which on asymmetric allylation by Brown method afforded the alcohol 20 in 88%
yield with excellent enantioselection (er>99%). Protection of the free alcohol group with
TBDPS-Cl afforded compound 21 in 92% yield. Hydroboration of compound 21 with BH
3 2
.SMe
followed by oxidation with NaOH/H O furnished alcohol 22 in 82% yield. Oxidation of alcohol
2
2
2
2 with BAIB/TEMPO afforded corresponding carboxylic acid 23 in88% yield. Acid 23 is then
coupled with N,O-dimethylhydroxyl amine in presence of EDC.HCl and Et N to afford the
3
2
6
corresponding Weinreb amide 24 in 90% yield. Vinylmagnesium bromide addition on amide
4 at -78 ˚C afforded the ketone 25 in 90% yield. Stereoselective ketone reduction with (R)-CBS
2
afforded the alcohol 26 (dr ~ 15:1). Protection of the free hydroxyl group with MOM-Cl in
presence of DIPEA afforded the protected MOM ether 27 in 86% yield (Scheme-6). The
absolute stereochemistry of compound 26 (3R, 6R which corresponds to 6R, 9R stereocenters in
the natural product seimatopolide B) was confirmed by converting 26 into a known compound
1
13
2
8 and comparing the spectroscopic data ( H/ C-NMR) and optical rotation values with those of
7
g
that reported by Reddy et al for their synthesis of (+)-seimatopolide B.
1
1

ACCEPTED MANUSCRIPT
OH
a
b
d
c
n-Decanal
OH
OTBDPS
OTBDPS
20
21
2
2
nC H
nC H
9 19
9
19
nC H
9
19
O
O
O
Me
N
OH
e
OMe
f
g
OTBDPS
OTBDPS
OTBDPS
2
3
2
4
25
nC H
9
19
nC9H19
nC H
9 19
OH
OMOM
B
)2
h
OTBDPS
OTBDPS
26
27
(
-)-allyldiisopinocamphenylborane
nC9H19
(Ipc BAllyl)
nC H
2
9
19
i,j
OPMB
R
This work: [α]D25 = +16.6 (c = 1.0, CHCl3)
Reported:7g [α]D20 = +16.8 (c = 1.0, CHCl3)
OH
R
28
nC9H19
2
Scheme-6: Reagents and conditions: a) (-)-Ipc BAllyl, 88%; b) Imidazole, TBDPS-Cl, DCM,
rt, 4 h, 92%; c) BH :SMe , THF, H O , NaOH, 2 h, 82%; d) BAIB, TEMPO, DCM:H O (1:1), 3
3
2
2
2
2
h, rt, 88%; e) MeNH(OMe).HCl, Et N, DCC, rt, 6 h, 90%; f) CH =CHMgBr, THF, -78 ˚C-rt, 2
3
2
h, 90%; g) (R)-CBS (20 mol%), BH .SMe , THF, -78 ˚C-rt, 6 h, 75%; h) MOM-Cl, DIPEA,
3
2
1
2

ACCEPTED MANUSCRIPT
3
DCM, TBAI, rt, 86%; (i) PMB-imidate, Sc(OTf) , -10°C, 15 min, 85%; (j) TBAF, THF, rt,
6
h,95%.
Fragment coupling and completion of the synthesis for seimatopolide B: With compound 27
in our hand, we next proceeded for the CM reaction with the previously synthesized compound
3
. Cross metathesis reaction of compound 27 with 3 proceeded smoothly as anticipated with
catalyst C3 (HG-II) in refluxing DCM solvent afforded compound 29 (75%, E: Z = 15:1).
Oxidation of the free alcohol functionality with BAIB/TEMPO afforded corresponding
carboxylic acid 30 in 85% yield. Deprotection of the TBDPS group in compound 30 was
achieved by treating with TBAF in THF to furnish the seco-acid 31. Macrolactonization of the
crude seco-acid 31 under Shiina condition afforded the decanolide 32 in 72% yield. Finally
deprotection of both the MOM groups were achieved by treating compound 32 with 2M HCl to
furnish seimatopolide B as a white solid in 82% yield (Scheme-7; overall yield = 10.6% from n-
1
13
decanal). The spectral data of our synthesized seimatopolide B ( H/ C-NMR) matches perfectly
7
g
28
with those of reported one. Optical rotation value {[α]D = -13.4 (c = 0.02, MeOH)} also
matches perfectly with those of literature value as reported by Reddy’s group in the synthesis of
(-)-seimatopolide B, having absolute configuration 3S, 6R, 9R.
OMOM
OMOM
MOMO
MOMO
OMOM
OH
OMOM
a
b
c
+
OP
OP
OP
OH
3
CO H
2
3
0
2
7
29
C8H17
C H
8 17
C H
8
17
P = TBDPS
OH
MOMO
OMOM
OMOM
CO H
d
e
OH
OMOM
O
OH
O
2
O
3
1
32
O
C H
8
17
C H
8
17
C H
8 17
(
-)-Seimatopolide B
Scheme-7: Reagents and conditions: a) C3 (5 mmol%), DCM, 24 h reflux, 75%; b) BAIB,
TEMPO, DCM:H O (1:1), 85% c) TBAF, THF, rt, 4 h, d) MNBA (2-methyl-6-nitro benzoic
2
o
anhydride), DIPEA (diisopropylethyl amine), DMAP, toluene, 60 C, 24 h, 72%; e) 2M HCl,
THF, rt, 12 h, 82%.
1
3

ACCEPTED MANUSCRIPT
Conclusion:
In conclusion we have achieved a short and flexible asymmetric synthesis of the naturally
occurring decanolide (-)-seimatopolide A and B starting from easily available starting materials.
Our reported synthesis of seimatopolide A and B is different and unique from other reported
synthesis, as we have exploited a cross metathesis reaction to construct the E-olefinic
unsaturation in the target molecule. The strategy of altered sequence of chemical reactions (CM
followed by macrolactonization) adopted by us had not been explored earlier for the synthesis of
such decanolides. In future, we will try to explore the strategy for the total synthesis of such
structurally related macrolides.
Experimental section:
Materials and methods: All oxygen and/or moisture-sensitive reactions were carried out under
N atmosphere in glassware that had been flame-dried under a vacuum (~0.5 mmHg) and purged
2
with N prior to use. Unless otherwise stated, materials were obtained from commercial suppliers
2
and used without further purification. THF and diethyl ether were distilled from sodium
benzophenone ketyl. Dichloromethane (DCM) and HMPA were distilled from calcium hydride.
Ru-based metathesis catalysts were purchased commercial suppliers and used as obtained.
Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates with UV light, ethanolic anisaldehyde, and phosphomolybdic acid/heat as developing
agents. Silicagel 100-200 mesh was used for column chromatography. Yields refer to
1
chromatographically and spectroscopically homogeneous materials unless otherwise stated. H
NMR spectra were obtained at 200 or 400 MHz in CDCl or pyridine-d with CHCl (δ = 7.26
3
5
3
ppm) or pyridine (δ = 7.22 ppm) as internal standards. Coupling constants (J) are reported in
hertz (Hz) and the resonance multiplicity abbreviations used are: s, singlet; d, doublet; t, triplet;
q, quartet; dt, doublet of triplets; dd, doublet of doublets; ddd, doublet of doublet of doublets; m,
13
multiplet; ov = overlapped multiplets. C NMR spectra were recorded at 50 or 100 MHz in
CDCl or pyridine-d with CDCl (δ = 77.23 ppm) and pyridine (δ = 135.9 ppm) as internal
3
5
3
1
13
standards. The chemical shift value is listed as δ and δ for H and C, respectively. Mass
H
C
spectroscopic analysis was performed in the CRF, IIT-Kharagpur (TOF analyzer). Optical
1
4

ACCEPTED MANUSCRIPT
rotations were measured on a JASCO digital polarimeter. HPLC analysis was performed with
CHIRALPAK AD-H (Daicel) column by using UV-Vis detector.
(S)-1-methoxy-4-((3-(methoxymethoxy)pent-4-enyloxy)methyl)benzene (2):
To a solution of alcohol 1 (2.0 g, 9.01 mmol) in DCM (20 ml), diisopropyl ethyl amine (4.71
˚
mL, 27.03 mmol) was added at 0 C and stirred for 15 min at the same temperature. MOM-Cl
(1.2 mL, 18.02 mmol) and tetra-n-butyl ammonium iodide (10 mg) was then added to the
reaction mixture and stirred for additional 4 h at room temperature. Water was added to the
reaction mixture and extracted with DCM, the organic solution was then washed with water and
4
brine. The organic extracts were dried over MgSO , concentrated and purified by silica gel
column chromatography (EtOAc: hexane = 1:10) to afford the desired product 2 (2.15 g, 8.1
mmol) with 90% yield.
f
R = 0.4 (EtOAc: hexane = 1:10).
2
8
[
α]D = +8.6 (c = 0.3, CHCl3).
1
H NMR of Compound 2 (200 MHz, CDCl ) δ: 7.27 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz,
3
2
H), 5.70 (ddd, J = 16.8, 10.0, 7.4 Hz, 1H), 5.26-5.16 (m, 2H), 4.70 (d, J = 6.6 Hz, 1H), 4.54 (d,
J = 6.6 Hz, 1H), 4.43 (s, 2H), 4.20 (q, J = 7.2 Hz, 1H), 3.80 (s, 3H), 3.60-3.41 (m, 2H), 3.35 (s,
3
H), 1.90-1.75 (m, 2H).
1
3
C NMR (50 MHz, CDCl
5.6, 55.4, 35.8.
3
) δ: 159.3, 138.3, 130.7, 129.4, 117.3, 113.9, 94.1, 74.7, 72.8, 66.4,
5
+
HRMS (ESI) for C H O Na [M + Na] , calculated: 289.1416; found: 289.1423.
1
5
22
4
(S)-3-(methoxymethoxy)pent-4-en-1-ol (3):
Compound 2 (1.8 g, 6.42 mmol) was taken in 20 mL of DCM: phosphate buffer (9:1). DDQ (1.6
g, 7.07 mmol) was added to it in one portion. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was then filtered off, and the filtrate was washed with
5
% NaHCO solution, water and brine. The organic layer was dried (over MgSO ) and
3 4
evaporated. Purification by silica gel column chromatography (EtOAc: hexane = 1:3) afforded
the desired product 3 (0.82 g, 5.64 mmol) in 88% yield.
1
5

ACCEPTED MANUSCRIPT
f
R = 0.4 (EtOAc: hexane = 1:3)
2
8
[
α]D = -112.6 (c = 1.6, CHCl3).
1
H NMR of Compound 3 (200 MHz, CDCl ) δ: 5.72 (ddd, J = 17.4, 10.1, 7.2 Hz, 1H), 5.28-5.18
3
(m, 2H), 4.70 (d, J = 6.6 Hz, 1H), 4.55 (d, J = 6.6 Hz, 1H), 4.25 (q, J = 7.0 Hz, 1H), 3.84-3.79
(m, 2H), 3.35 (s, 3H), 2.66 (brs, 1H), 1.84-1.76 (m, 2H).
1
3
C NMR (50 MHz, CDCl
3
) δ: 137.5, 117.4, 93.9, 76.2, 59.9, 55.6, 37.6.
+
HRMS (ESI) for C
7
H
14
O
3
Na [M + Na] , calculated: 169.0841; found: 169.0851.
(S)-3-(methoxymethoxy)pent-4-enoic acid (4):
To a solution of above alcohol 3 (300 mg, 2.05 mmol) in DCM: H O (1:1, 8 mL) were added
2
TEMPO (92 mg, 0.61 mmol) and BAIB (1.97 g, 6.15 mmol). After stirring at room temperature
for 4 h, the reaction mixture was diluted with DCM (10 mL) and then washed with saturated
aqueous Na S O (10 mL). The organic layer was dried over MgSO , filtered, and the filtrate was
2
2
3
4
concentrated under reduced pressure to give the crude carboxylic acid. The crude product was
further purified by flash column chromatography (EtOAc: hexane = 1:2) to furnish the pure acid
4
(288 mg, 88%) as a colorless oil.
R
f
= 0.3 (EtOAc: hexane = 1:1).
2
8
[
α]D = -57.4 (c = 1.3, CHCl3).
1
3
H NMR of Compound 4 (200 MHz, CDCl ) δ: 7.68 (brs, 1H), 5.71 (ddd, J = 17.4, 10.0, 7.4 Hz,
1
2
H), 5.32-5.18 (m, 2H), 4.66 (d, J = 7.0 Hz, 1H), 4.54-4.45 (m, 2H), 3.32 (s, 3H), 2.69-2.45 (m,
H).
1
3
C NMR (50 MHz, CDCl
3
) δ: 176.0, 136.5, 118.5, 93.9, 73.8, 55.6, 40.9.
+
HRMS (ESI) for C
7
H
12
O
4
Na [M + Na] , calculated: 183.0633; found: 183.0634.
tert-butyl(((4S,5S)-2,2-dimethyl-5-((2-nonyl-1,3-dithian-2-yl)methyl)-1,3-dioxolan-4-
yl)methoxy)dimethylsilane (7):
The dithiane 5 (3 g, 12.20 mmol) was dissolved in a mixture of THF: HMPA (10:1, 30 mL) and
cooled to -78 °C. t-BuLi (18.7 mL, 1.3 M in pentane, 24.40 mmol) was then added to the
solution and five min later a precooled solution of the iodide 6 (5.63 g, 14.6 mmol) in THF:
1
6

ACCEPTED MANUSCRIPT
HMPA (10:1, 30 mL) was added via double ended needle. After 20 min, the reaction was
quenched with a saturated solution of NH Cl and warmed to room temperature. The solution was
4
then diluted with ether (200 mL) and washed successively with water (50 mL) and brine (50
4
mL). The organic extract was dried over MgSO , filtered and concentrated. Purification by
column chromatography (EtOAc: hexane = 1:20) afforded the product 7 (4.9 g, 9.76 mmol, 80%)
as a colourless liquid.
R = 0.3 (EtOAc: hexane = 1:20).
f
2
8
[
α]D = -10.1 (c = 0.9, CHCl3).
1
3
H NMR of Compound 7 (200 MHz, CDCl ) δ: 4.20 (t, J = 8.0 Hz, 1H), 3.85-3.66 (m, 3H), 2.93-
2
1
.66 (m, 4H), 2.13-1.86 (m, 4H), 1.39 (s, 3H), 1.36 (s, 3H), 1.43-1.27 (m, 16H), 0.91-0.85(m,
2H), 0.08 (s, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 108.8, 81.0, 77.2, 63.7, 52.7, 41.0, 39.3, 31.8, 29.7, 29.5, 29.4,
3
2
9.3, 27.2, 26.9, 26.0, 25.9, 25.3, 23.8, 22.6, 18.4, 14.0, -5.3.
+
HRMS (ESI) for C26
H O
52 3
S
2
SiNa [M + Na] , calculated: 527.3025; found: 527.3028.
1
-((4S,5S)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)undecan-2-
one (8):
Dithiane 7 (1.7 g, 3.37 mmol) was dissolved in THF: H O (4:1, 40 mL) and then cooled to 0 ˚C.
2
Iodine (2.54 g, 10.11 mmol) and CaCO
reaction mixture at the same temperature. The reaction mixture was then allowed to stir for 30
min at room temperature, after that it was quenched with saturated Na (20 mL) solution.
3
(3.37 g, 33.7 mmol) was added successively to the
2 2 3
S O
The aqueous phase was separated and extracted with EtOAc. The combined organic extracts
were washed with brine, dried over anhydrous MgSO , and concentrated in vacuo. The crude
4
residue was purified by column chromatography (EtOAc: hexane = 1:15) to furnish ketone 8
(1.25 g, 3.03 mmol, 90%) as a colorless oil.
R
f
= 0.3 (EtOAc: hexane = 1:15)
2
8
[
α]D = 5.6 (c = 0.4, CHCl3).
1
H NMR of Compound 8 (200 MHz, CDCl ) δ: 4.35-4.26 (m, 1H), 3.82-3.63 (m, 3H), 2.69 (d, J
3
=
6.0 Hz, 2H), 2.45 (t, J = 7.4 Hz, 2H), 1.37(s, 6H), 1.36-1.25 (m, 14H), 0.90-0.88 (m, 12H),
0
.05 (s, 6H).
1
7

ACCEPTED MANUSCRIPT
1
3
C NMR (50 MHz, CDCl
3
) δ: 208.4, 108.9, 80.4, 74.8, 63.5, 46.4, 43.5, 31.8, 29.6, 29.3, 29.2,
2
9.1, 27.1, 26.8, 25.8, 23.4, 22.6, 18.2, 14.0, -5.4.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 437.3063; found: 473.3025.
2
3
46
4
(R)-1-((4S,5S)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)undecan-2-ol (9) :
To a stirred solution of (R)-2-methyl-CBS-oxazaborolidine (0.3 mL of a 1.0 M solution in
toluene, 0.3 mmol) in THF (0.6 mL) at -78 ˚C under N atmosphere was added BH .DMS
2
3
complex (1 mL of a 2 M solution in THF, 2.0 mmol) followed by the addition of a solution of 8
660 mg, 1.59 mmol) in THF (3 mL). After 6 h, H O (5 mL) was added and the mixture was
(
2
allowed to warm to room temperature. The aqueous phase was extracted with diethyl ether (2 ×
5 mL), and the combined organic phases were washed with H O, then brine and dried over
2
2
anhydrous MgSO The crude residue was purified by column chromatography (EtOAc: hexane
4
.
=
1:10) to give 9 (476 mg, 1.14 mmol, 72%) as a colorless oil.
R = 0.2 (EtOAc: hexane = 1:10).
f
2
D
8
[α]
= -18.6 (c = 1.1, CHCl
3
).
1
H NMR of Compound 9 (200 MHz, CDCl ) δ: 4.15-4.09 (m, 1H), 3.83-3.64 (m, 4H), 1.77 (t, J
3
=
5.8 Hz, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.35-1.25 (m, 16H), 0.90-0.80 (m, 12H), 0.05 (s, 6H).
1
3
3
C NMR (50 MHz, CDCl ) δ: 108.5, 80.3, 76.9, 69.0, 63.7, 39.3, 37.4, 31.8, 29.6, 29.5, 29.2,
2
7.2, 26.7, 25.8, 25.6, 22.6, 18.2, 14.0, -5.5, -5.6.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 439.3219; found: 439.3224.
2
3
48
4
tert-butyl((R)-1-((4S,5S)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)undecan-2-yloxy)dimethylsilane (10):
2
,6-Lutidine (492 mg, 4.6 mmol) was added to a solution of compound 9 (1.0 g, 2.3 mmol) in
anhydrous DCM (20 mL) at room temperature. After stirring for 15 min TBS-OTf (1.05 mL, 4.6
mmol) was added to the reaction vessel and stirred for 1h at room temperature. After completion
of the reaction, water was added to the reaction mixture and the organic layer was washed with
excess water and brine. The organic layer was dried (MgSO ) and evaporated to dryness to
4
1
8

ACCEPTED MANUSCRIPT
afford the crude silylated compound, which was purified by silica gel chromatography (EtOAc:
hexane = 1:30) to give 10 (1.09 g, 90%) as a colorless oil.
R = 0.2 (EtOAc: hexane = 1:40).
f
2
D
8
[α]
= -6.6 (c = 0.2, CHCl
3
).
1
H NMR of Compound 10 (200 MHz, CDCl ) δ: 4.08-3.88 (m, 2H), 3.79-3.57 (m, 3H), 1.75-
3
1
.71 (m, 2H), 1.42 (s, 3H), 1.39 (s, 3H), 1.36-1.27 (m, 16H), 0.92-0.89 (m, 21H), 0.05 (s, 12H).
1
3
3
C NMR (50 MHz, CDCl ) δ: 108.6, 82.0, 75.6, 70.1, 63.4, 41.6, 36.6, 32.1, 30.0, 29.8, 29.5,
2
7.6, 27.1, 26.1, 25.3, 22.9, 18.5, 18.3, 14.3, -4.2, -4.3, -5.1, -5.2.
+
HRMS (ESI) for C H O Si Na [M + Na] , calculated: 553.4084; found: 553.4085.
2
9
62
4
2
((4S,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)undecyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)methanol (11):
To the solution of silyl ether 10 (520 mg, 1 mmol) in THF (8 mL) in a plastic vial was added
pyridine buffered HF/pyridine solution (8 mL, prepared from 5 mL THF + 2 mL pyridine and 1
mL HF/pyridine). The reaction was stirred at room temperature for 12 h before being quenched
with saturated aqueous Na CO (15 mL). The mixture was extracted with EtOAc (20 mL x 3).
2
3
The combined organic layer was then washed with saturated aqueous NaCl (10 mL), dried over
MgSO and concentrated under reduced pressure. Purification by flash chromatography (EtOAc:
4
hexane = 1:10) afforded alcohol 11 (374 mg, 0.9 mmol) as a colourless oil.
R = 0.2 (EtOAc: hexane = 1:10).
f
2
8
[
α]D = -20.9 (c = 1.0, CHCl3).
1
3
H NMR of Compound 11 (200 MHz, CDCl ) δ: 4.06-3.96 (m, 1H), 3.82-3.63 (m, 4H), 1.80-
1
.72 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 1.35-1.23 (m, 16H), 0.90-0.80 (m, 12H), 0.04 (s, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 109.2, 81.3, 79.6, 71.3, 63.7, 40.5, 37.5, 32.0, 29.8, 29.7, 29.4,
3
2
7.3, 27.0, 26.0, 25.6, 22.8, 18.4, 14.2, -5.3, -5.4.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 439.3219; found: 439.3224.
2
3
48
4
1
9

ACCEPTED MANUSCRIPT
(4R,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)undecyl)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde (12) :
To a solution of above alcohol 11 (341 mg, 0.82 mmol) in dry DCM (4 mL) were added TEMPO
3
(12 mg, 0.08 mmol), BAIB (263 mg, 0.82 mmol) and NaHCO (68 mg, 0.82 mmol). After
stirring at room temperature for 2 h, the reaction mixture was diluted with DCM (5 mL) and then
washed with saturated aqueous Na S O (5 mL). The organic layer was dried over MgSO ,
2
2
3
4
filtered, and the filtrate was concentrated under reduced pressure to give the crude aldehyde 12
which was used for the next step without further purification.
R = 0.2 (EtOAc: hexane = 1:15).
f
1
3
H NMR of Compound 12 (200 MHz, CDCl ) δ: 9.70-9.63 (m, 1H), 4.24-4.14 (m, 1H), 3.98-
3
1
.84 (m, 2H), 1.81-1.75 (m, 2H), 1.45 (s, 3H), 1.40 (s, 3H), 1.38-1.25 (m, 16H), 0.88-0.86 (m,
2H), 0.04 (s, 6H).
1
3
C NMR (50 MHz, CDCl
3
) δ: 200.6, 111.1, 85.1, 73.6, 68.9, 40.4, 38.3, 32.0, 30.0, 29.8, 29.7,
2
9.5, 27.4, 26.3, 26.0, 24.6, 22.8, 18.2, 14.2, -4.0, -4.6.
Tert-butyl((R)-1-((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)undecan-2-
yloxy)dimethylsilane (13):
To a suspension of methyltriphenylphosphonium iodide (646 mg, 1.6 mmol) in dry THF (5 mL)
˚
was added LiHMDS (1.0 M solution in THF, 1.6 mL) at 0 C. The yellow mixture was stirred at
°
0
C for 15 min. A solution of the aldehyde 12 (331 mg, 0.8 mmol) in 2 mL of THF was added to
the reaction mixture. The yellow suspension was stirred at room temperature for further 4 h.
After that the reaction was quenched with addition of water, and the layers were separated and
4
extracted with 25 mL of ether, washed with brine. It was then dried with MgSO , filtered, and
the solvent was removed in vacuo. The crude residue was purified by flash column
chromatography (EtOAc: hexane = 1:30) to afford the compound 13 (247 mg, 0.6 mml) in 75%
yield.
R = 0.3 (EtOAc: hexane = 1:30).
f
2
8
[
α]D = -13.5 (c = 1.0, CHCl3).
2
0

ACCEPTED MANUSCRIPT
1
H NMR of Compound 13 (200 MHz, CDCl
3
) δ: 5.87-5.70 (m, 1H), 5.29-5.21 (m, 2H), 3.96-
3
.78 (m, 3H), 1.43-1.27 (m, 8H), 1.25-1.01 (m, 16H), 0.89-0.80 (m, 12H), 0.12-0.06 (m, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 135.3, 119.0, 108.7, 83.1, 77.4, 69.3, 39.2, 38.5, 32.1, 30.1, 29.8,
3
2
9.7, 29.5, 27.6, 27.1, 26.1, 24.7, 22.8, 18.2, 14.3, -4.0, -4.5.
+
HRMS (ESI) for C24
H O
48 3
SiNa [M + Na] , calculated: 435.327; found: 435.3259.
General procedure for cross metathesis reaction:
Olefin 13 (412 mg, 1 mmol) was taken in a flame-dried round-bottom flask, the 2˚ allylic alcohol
nd
(
1/2/3/4, 2 mmol) in DCM (10 mL) was added to it, followed by Hoveyda-Grubbs 2 generation
catalyst (HG-II, C3, 31 mg, 0.05 mmol). An additional 2 equiv of olefin (1-4) was added to the
reaction mixture after 30 min. The light green solution which was then refluxed for 24 h under
argon atmosphere and then it was concentrated in vacuo to give dark brown oil. Purification of
this residue on silica gel by flash chromatography afforded the desired compound as yellow oil.
(S,E)-1-((4S,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)undecyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)-5-(4-methoxybenzyloxy)pent-4-en-1-ol (14):
R = 0.3 (EtOAc: hexane = 1:2).
f
2
8
[
α]D = -4.2 (c = 0.9, CHCl3).
1
H NMR of Compound 14 (400 MHz, CDCl ) δ: 7.24 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz,
3
2
1
1
H), 5.83 (dd, J = 15.2, 5.2 Hz, 1H), 5.64 (dd, J = 15.2, 7.2 Hz, 1H), 4.44 (s, 2H), 4.41-4.36 (m,
H), 3.94-3.90 (m, 1H), 3.86-3.81 (m, 2H), 3.80 (s, 3H), 3.70-3.66 (m, 1H), 3.65-3.60 (m, 1H),
.82-1.77 (m, 2H), 1.59-1.51 (m, 2H), 1.44-1.39 (m, 2H), 1.40 (s, 3H), 1.37 (s, 3H), 1.30-1.23
(m, 14H), 0.90-0.84 (m, 12H), 0.05 (s, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 159.4, 137.6, 130.1, 129.5, 127.0, 114.0, 108.6, 82.2, 77.4, 73.1,
3
7
1
1.1, 69.3, 68.2, 55.4, 39.1, 38.5, 36.5, 32.1, 30.1, 29.8, 29.5, 27.6, 27.1, 26.1, 24.7, 22.8, 18.3,
4.3, -4.0, -4.4.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 629.4213; found: 629.4210.
3
5
62
6
2
1

ACCEPTED MANUSCRIPT
Tert-butyl((R)-1-((4S,5S)-5-((S,E)-5-(4-methoxybenzyloxy)-3-(methoxymethoxy)pent-1-
enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)undecan-2-yloxy)dimethylsilane (15):
To a solution of alcohol 14 (600 mg, 1 mmol) in anhydrous DCM, diisopropyl ethyl amine (0.24
°
mL, 1 mmol) was added at 0 C and stirred for 15 min at the same temperature. MOM-Cl (0.078
mL, 1 mmol) and tetra-n-butyl ammonium iodide (TBAI, catalytic) was then added to the
reaction mixture and stirred for additional 8 h at room temperature. Water was added to the
reaction mixture and extracted with DCM, washed with water and brine. The organic extracts
were dried over MgSO , concentrated and purified by silica gel column chromatography
4
(EtOAc: hexane = 1:10) to afford the desired product 15 (585 mg, 0.9 mmol) with 90% yield.
R
f
= 0.3 (EtOAc: hexane = 1:3).
2
8
[
α]D = -17.9 (c = 0.8, CHCl3).
1
H NMR of Compound 15 (400 MHz, CDCl ) δ: 7.25 (d, J = 7.6 Hz, 2H), 6.85 (d, J = 7.6 Hz,
3
2
1
1
1
H), 5.63 (ov, 2H), 4.63 (d, J = 6.4 Hz, 1H), 4.50 (d, J = 6.4 Hz, 1H), 4.41 (s, 2H), 4.23-4.21 (m,
H), 3.94-3.91 (m, 1H), 3.85-3.83 (m, 3H), 3.79 (s, 3H), 3.58-3.50 (m, 2H), 3.32 (s, 3H), 1.88-
.81 (m, 2H), 1.53-1.50 (m, 2H), 1.45-1.42 (m, 2H), 1.40 (s, 3H), 1.37 (s, 3H), 1.36-1.25 (m,
4H), 0.90-0.80 (m, 12H), 0.04 (s, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 159.1, 134.2, 130.5, 129.8, 129.2, 113.7, 108.6, 94.0, 81.8, 77.3,
3
7
2
3.1, 72.6, 69.0, 66.2, 55.4, 55.2, 39.0, 38.3, 35.7, 31.9, 29.8, 29.6, 29.5, 29.3, 27.4, 26.9, 25.8,
4.4, 22.6, 18.0, 14.1, -4.2, -4.6.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 650.4476; found: 650.4465.
3
7
66
7
(S,E)-5-((4S,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)undecyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-(methoxymethoxy)pent-4-en-1-ol (16):
Compound 15 (590 mg, 0.9 mmol) was taken in 5 mL of DCM: phosphate buffer (9:1). DDQ
(
204 mg, 0.9 mmol) was then added to it in one portion. The reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was then filtered off, and the filtrate was washed with
% NaHCO solution, water and brine. The organic layer was dried (MgSO ) and evaporated.
5
3
4
2
2

ACCEPTED MANUSCRIPT
Purification by silica gel column chromatography (EtOAc: hexane = 1:3) afforded the desired
product 16 (391 mg, 0.73 mmol) in 82% yield
R = 0.2 (EtOAc: hexane = 1:3).
f
2
8
[
α]D = -58.6 (c = 1.3, CHCl3).
1
3
H NMR of Compound 16 (400 MHz, CDCl ) δ: 5.68-5.65 (ov, 2H), 4.65 (d, J = 6.4 Hz, 1H),
4
3
1
.53 (d, J = 6.4 Hz, 1H), 4.28 (q, J = 6.4 Hz, 1H), 3.94 (t, J = 6.8 Hz, 1H), 3.85-3.70 (m, 4H),
.37 (s, 3H), 1.83-1.79 (m, 2H), 1.53-1.51 (m, 2H), 1.43-1.41 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H),
.35-1.25 (m, 14H), 0.88-0.86 (m, 12H), 0.04 (s, 6H).
1
3
C NMR (50 MHz, CDCl ) δ: 133.8, 130.2, 108.9, 94.3, 81.8, 77.6, 75.2, 69.3, 60.1, 55.8, 39.3,
3
3
8.5, 37.9, 32.1, 30.1, 29.8, 29.5, 27.6, 27.1, 26.1, 24.7, 22.8, 18.2, 14.3, -3.9, -4.4.
+
HRMS (ESI) for C29
H O
58 6
SiNa [M + Na] , calculated: 553.3900; found:553.3900.
(S,E)-5-((4S,5S)-5-((R)-2-(tert-butyldimethylsilyloxy)undecyl)-2,2-dimethyl-1,3-dioxolan-4-
yl)-3-(methoxymethoxy)pent-4-enoic acid (17):
°
Alcohol 16 (159 mg, 0.3 mmol), was taken in dry DCM (10 mL) and cooled to 0 C. Dess Martin
Periodinane (DMP, 259 mg, 0.4 mmol) was then added to the reaction mixture. The solution was
then warmed to room temperature over 2 h. The reaction mixture was quenched with Na S O
3
2
2
3
and saturated NaHCO solution successively and stirred for further 20 minutes. The organic
solution was then dried with MgSO , filtered, and the solvent was removed in vacuo to furnish
4
the crude aldehyde.
The crude aldehyde was taken in t-BuOH (2 mL) and 2-methyl-2-butene (1 mL) was added to it
dropwise followed by the addition of a solution of sodium phosphate monobasic (38.4 mg, 0.32
mmol) and sodium chlorite (58 mg, 0.64 mmol) in water (1 mL). The solution was stirred for 4 h
at room temperature, then ethyl acetate and water was added to the reaction mixture. The
aqueous layer was extracted twice with EtOAc and the combined organic layers were washed
4
with water and brine, dried (MgSO ). The organic solvent was concentrated and purified by
silica gel column chromatography (EtOAc: hexane = 1:2) to afford the carboxylic acid 17 in 82%
yield.
2
3

ACCEPTED MANUSCRIPT
f
R = 0.3 (EtOAc: hexane = 1:1).
2
D
8
[α]
= -27.9 (c = 1.0, CHCl
3
).
1
H NMR of Compound 17 (200 MHz, CDCl ) δ: 5.75-5.72 (ov, 2H), 4.66 (d, J = 6.8 Hz, 1H),
3
4
1
.57-4.54 (m, 2H), 3.99-3.77 (m, 3H), 3.35 (s, 3H), 2.65-2.59 (m, 2H), 1.57-1.41 (m, 8H), 1.40-
.30 (m, 16H), 0.91-0.85 (m, 12H), 0.06 (s, 6H).
1
3
C NMR (100 MHz, CDCl ) δ: 175.1, 132.3, 130.9, 108.7, 93.9, 81.4, 77.2, 72.2, 69.0, 55.5,
3
4
0.7, 39.0, 38.2, 31.8, 29.8, 29.6, 29.5, 29.4, 27.3, 26.8, 25.8, 24.5, 22.8, 18.0, 14.0, -4.2, -4.6.
+
HRMS (ESI) for C29
H O
56 7
SiNa [M + Na] , calculated: 567.3692; found: 567.3682.
(S,E)-5-((4S,5S)-5-((R)-2-hydroxyundecyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
(
methoxymethoxy)pent-4-enoic acid (18):
To a solution of 17 (144 mg, 0.24 mmol) in dry THF ( 2 mL) was added TBAF (1.0 M in THF,
.5 mmol, 0.5 mL) at room temperature and stirring was continued for 6 h. The reaction was
0
quenched by the addition of saturated aqueous NH Cl (10 mL), the layers were separated and the
4
aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed
with water and brine, dried (MgSO ). The organic solvent was concentrated and purified by
4
silica gel column chromatography (EtOAc: hexane = 1:2) to afford the carboxylic acid 18 (82
mg, 0.196 mmol) in 85% yield.
R = 0.2 (EtOAc: hexane = 1:1).
f
2
8
[
α]D = -17.9 (c = 1.0, CHCl3).
1
H NMR of Compound 18 (400 MHz, CDCl ) δ: 5.73-5.71 (ov, 2H), 4.66 (d, J = 6.8 Hz, 1H),
3
4
2
1
.55 (d, J = 6.8 Hz, 1H), 4.54-4.50 (m, 1H), 3.96-3.92 (m, 1H), 3.87-3.79 (m, 2H), 3.34 (s, 3H),
.66 (dd, J = 15.6, 8.4 Hz, 1H), 2.58 (dd, J = 15.6, 8.4 Hz, 1H), 1.54-1.50 (m, 2H), 1.40 (s, 3H),
.37 (s, 3H), 1.30-1.20 (m, 16H), 0.88-0.84 (m, 3H).
1
3
C NMR (100 MHz, CDCl ) δ: 174.6, 133.7, 129.5, 108.9, 94.3, 81.2, 78.1, 73.5, 68.8, 55.4,
3
3
7.9, 37.7, 31.8, 29.7, 29.6, 29.3, 26.8, 25.6, 22.6, 14.3.
+
HRMS (ESI) for C23
H O
42 7
Na [M + Na] , calculated: 453.2828; found: 453.2810.
2
4

ACCEPTED MANUSCRIPT
(3aS,5R,9S,11aS,E)-9-(methoxymethoxy)-2,2-dimethyl-5-nonyl-4,5,8,9-tetrahydro-3aH-
[1,3]dioxolo[4,5-d]oxecin-7(11aH)-one (19):
Yamaguchi procedure:
To a solution of seco-acid 18 (43 mg, 0.1 mmol) in dry toluene (5 mL) were added 2,4,6-
°
trichlorobenzoyl chloride (0.18 mL, 1.0 mmol) and diisopropyl ethylamine (0.4 mL) at 25 C.
The mixture was stirred for 15 h at this temperature. The solution was then diluted by addition of
dry toluene (5 mL) and it was added through a syringe pump slowly to the solution of DMAP
°
(
122 mg, 1.0 mmol) in toluene (50 mL) at 60 C over 24 h. The reaction was stirred for an
additional 24 h at the same temperature and quenched by adding saturated aqueous NH Cl
4
4
solution. The organic solution was successively washed with water, brine and dried over MgSO .
The organic solvent was evaporated and purified by silica gel column chromatography (EtOAc:
hexane = 1:20) to afford the lactone 19 (25 mg) in 62% yield.
Shiina procedure:
To a solution of MNBA (46 mg, 0.13 mmol) and DMAP (15 mg, 0.12 mmol) in toluene (35 mL)
at room temperature was added a solution of seco-acid 18 (43 mg, 0.1 mmol) in toluene (15 mL).
After that the reaction mixture was stirred for 24 h and quenched by adding saturated aqueous
NaHCO solution. The organic solution was successively washed with water, brine and dried
3
over MgSO
chromatography (EtOAc: hexane = 1:20) to afford the lactone 19 (28 mg) in 68% yield.
= 0.4 (EtOAc: hexane = 1:15).
4
. The organic solvent was evaporated and purified by silica gel column
R
f
2
D
8
[α]
= +17.9 (c = 1.0, CHCl
3
).
1
H NMR of Compound 19 (400 MHz, CDCl ) δ: 5.86 (d, J = 15.6 Hz, 1H), 5.68 (dd, J = 15.6,
3
9
.2 Hz, 1H), 5.01-4.98 (m, 1H), 4.69 (s, 2H), 4.63-4.61 (m, 1H), 4.06 (t, J = 8.8 Hz, 1H), 3.64 (t,
J = 8.8 Hz, 1H), 3.40 (s, 3H), 2.67 (d, J = 12.0 Hz, 1H), 2.49 (dd, J = 12.0, 4.0 Hz, 1H), 2.07 (d,
J = 15.6 Hz, 1H), 1.93-1.86 (m, 1H), 1.50-1.47 (m, 2H), 1.39 (s, 6H), 1.30-1.20 (m, 14H), 0.86
(t, J = 6.8 Hz, 3H).
1
3
C NMR (100 MHz, CDCl ) δ: 169.6, 136.1, 127.6, 108.2, 94.6, 83.3, 81.5, 74.8, 72.8, 55.6,
3
4
3.7, 36.7, 36.0, 31.9, 29.5, 29.4, 27.2, 27.0, 25.3, 22.8, 14.2.
2
5

ACCEPTED MANUSCRIPT
+
HRMS (ESI) for C23
H O
40 6
Na [M + Na] , calculated: 435.2723; found: 435.2732.
Seimatopolide A:
To a solution of ring closing compound 19 (20 mg, 0.048 mmol) in THF (2 mL) was added HCl
1 mL, 2M) at room temperature and stirred for 12 h. Water was added to the reaction mixture
and it was extracted with ethyl acetate. The organic layer was washed with NaHCO and brine. It
(
3
was then dried over MgSO , concentrated in a rotary evaporator and purified by silica gel
4
column chromatography (EtOAc: hexane = 2:1) to afford the target molecule seimatopolide A
(13 mg, 0.038 mmol) in 80% yield as a white solid.
R = 0.4 (EtOAc: hexane = 2:1).
f
2
8
[
α]D = -27.4 (c = 0.05, MeOH).
1
H NMR (400 MHz, pyridine-d
5
) δ 6.46 (dd, J = 16.0, 9.6 Hz, 1H), 6.14 (dd, J = 16.0, 3.2 Hz,
1
8
1
H), 5.14 (dt, J = 6.8, 6.5 Hz, 1H), 4.98-4.97 (m, 1H), 4.40 (t, J = 9.2 Hz, 1H), 3.97 (dd, J = 8.8,
.4 Hz, 1H), 2.86 (dd, J =11.6, 3.2 Hz, 1H), 2.74 (dd, J = 12.0, 4.0 Hz, 1H), 2.30−2.24 (m, 2H),
.68-1.66 (m, 1H), 1.57-1.55 (m, 1H), 1.40−1.15 (m, 14H), 0.86 (t, J = 7.2 Hz, 3H).
1
3
C NMR (100 MHz, pyridine-d ) δ: 170.7, 136.8, 128.3, 79.9, 77.4, 73.7, 67.5, 44.9, 42.5, 37.7,
5
3
2.4, 30.2, 30.2, 30.1, 29.9, 25.8, 23.3, 14.6.
+
HRMS (ESI) for C H O Na [M + Na] , calculated: 351.2142; found: 351.2146.
1
8
32
5
(R)-tridec-1-en-4-ol (20):
(
-)-Allyldiisopinocamphenylborane (Ipc B-Allyl, 25 mmol, 1.0 M solution in pentane, 25 mL)
2
was cooled to -78 ˚C, and 3.90 g (25 mmol) of decanal in diethyl ether (100 mL) was added to
the solution dropwise with stirring. The reaction mixture was then stirred for 1 h at -78 ˚C and
then allowed to warm up to 25 ˚C. It was then treated with 18.3 mL (55 mmol) of 3N NaOH and
1
5 mL of 30% H O , and the contents were refluxed for 1 h. The organic layer was then
2 2
4
separated and washed with water (15 mL) and brine (15 mL) and dried over anhydrous MgSO .
The organic solvent was then concentrated in rotary evaporator to yield the crude product, which
was then purified by silica gel column chromatography (EtOAc: hexane = 1:10) to furnish the
compound 20 (4.3 g, 22 mmol) in 88% yield.
R = 0.3 (EtOAc: hexane = 1:20)
f
2
6

ACCEPTED MANUSCRIPT
2
D
8
[α]
= +5.9 (c = 1.8, CHCl
3
).
1
H NMR of Compound 20 (200 MHz, CDCl ) δ: 5.84 (ddd, J = 14.2, 10.4, 7.0 Hz, 1H), 5.15-
3
5
1
.11 (m, 2H), 3.67-3.61 (m, 1H), 2.33-2.27 (m, 1H), 2.17-2.04 (m, 1H), 1.47-1.26 (m, 2H), 1.25-
.03 (m, 14H); 0.89-0.86 (m, 3H).
1
3
C NMR (50 MHz, CDCl ) δ: 134.8, 117.7, 70.6, 41.8, 36.7, 31.8, 29.6, 29.5, 29.4, 29.2, 25.5,
3
2
2.5, 13.9.
+
HRMS (ESI) for C13
H
26ONa [M + Na] , calculated: 221.1881; found: 221.1875.
(R)-tert-butyldiphenyl(tridec-1-en-4-yloxy)silane (21):
°
Alcohol 20 (4.3 g, 22 mmol) was taken in anhydrous DCM (60 mL) and cooled to 0 C.
Imidazole (3.03 g, 44 mmol) and DMAP (100 mg) were added to the reaction mixture followed
by the addition of TBDPS-Cl (7 mL, 26 mmol). The reaction mixture was then allowed to warm
at room temperature for 4 h, after which water was added to it and the organic layer was
4
extracted with DCM, washed with brine and dried over MgSO . The organic solvent was
concentrated in rotary evaporator and the crude product was purified by silica gel column
chromatography (EtOAc: hexane = 1:40) to afford the TBDPS-protected compound 21 (8.8 g,
2
0.24 mmol) in 92% yield.
R = 0.6 (EtOAc: hexane = 1:20)
f
2
D
8
[α]
3
= +8.1 (c = 1.0, CHCl ).
1
H NMR of Compound 21 (200 MHz, CDCl ) δ: 7.72-7.67 (m, 4H), 7.47-7.32 (m, 6H), 5.79
3
(ddd, J = 14.2, 10.4, 7.0 Hz, 1H), 4.99-4.90 (m, 2H), 3.82-3.71 (m, 1H), 2.24-2.16 (m, 2H),
1
.46-1.38 (m, 2H), 1.36-1.11 (m, 14H), 1.07 (s, 9H), 0.92-0.86 (m, 3H).
1
3
C NMR (50 MHz, CDCl ) δ: 136.0, 135.1, 134.6, 129.5, 127.5, 116.7, 72.9, 41.1, 36.1, 32.0,
3
2
9.6, 27.1, 24.9, 22.8, 19.4, 14.2.
+
HRMS (ESI) for C H OSiNa [M + Na] , calculated: 459.3058; found: 459.3065.
2
9
44
(R)-4-(tert-butyldiphenylsilyloxy)tridecan-1-ol (22):
°
BH
3 2
.SMe (5.5 mL, 2.0 M in THF, 11 mmol) was added to a cooled (0 C) solution of compound
2
1 (4.36 g, 10 mmol) in THF (20 ml). The mixture was stirred for an additional 2 h and then
2
7

ACCEPTED MANUSCRIPT
2 2
quenched with EtOH followed by the addition of 3 M aqueous NaOH (4 mL) and 30% H O (4
mL). The mixture was stirred vigorously for 3.5 h and 10% aqueous Na S O (3 mL) was added
2
2
3
to it. It was then extracted with ether and washed with brine. The organic solvent was dried
MgSO ), concentrated and purified by silica gel column chromatography (EtOAc: hexane = 1:5)
to provide the alcohol 22(3.72 g, 8.2 mmol) with 82% yield.
= 0.3 (EtOAc: hexane = 1:5).
(
4
R
f
2
8
[
α]D = +7.3 (c = 0.4, CHCl3).
1
H NMR of Compound 22 (200 MHz, CDCl ) δ: 7.70-7.66 (m, 4H), 7.47-7.34 (m, 6H), 3.79-
3
3
.74 (m, 1H), 3.61-3.52 (m, 2H), 1.61-1.43 (m, 6H), 1.26-1.13 (m, 14H), 1.06 (s, 9H), 0.92-0.85
(m, 3H).
1
3
C NMR (50 MHz, CDCl ) δ: 135.9, 134.4, 129.4, 127.4, 72.9, 63.0, 36.0, 32.3, 31.8, 29.5, 29.4,
3
2
9.2, 27.8, 27.0, 24.9, 22.6, 19.3, 14.0.
+
HRMS (ESI) for C H O SiNa [M + Na] , calculated: 477.3154; found: 477.3165.
2
9
46
2
(R)-4-(tert-butyldiphenylsilyloxy)tridecanoic acid (23):
To a solution of above alcohol 22 (3.6 g, 8 mmol) in H O: DCM (1/1, 32 mL) were added
2
TEMPO (357 mg, 2.4 mmol) and BAIB (7.69 g, 24 mmol). After stirring at room temperature
for 3 h, the reaction mixture was diluted with DCM (100 mL) and then washed with saturated
2 2 3 4
aqueous Na S O (40 mL). The organic layer was dried over MgSO , filtered, and the filtrate was
concentrated under reduced pressure to give the crude carboxylic acid, which was further
purified by flash column chromatography (silica gel, EtOAc: hexane = 1:2) to furnish the acid 23
(3.29 g, 88%) as a colorless oil.
R = 0.3 (EtOAc: hexane = 1:1)
f
2
8
[
α]D = +8.1 (c = 0.3, CHCl3).
1
3
H NMR of Compound 23 (200 MHz, CDCl ) δ: 7.75-7.71 (m, 4H), 7.47-7.30 (m, 6H), 3.82 (t, J
=
5.4 Hz, 1H), 2.45 (t, J = 7.8 Hz, 2H), 1.88-1.80 (m, 2H), 1.47-1.40 (m, 2H), 1.35-1.15 (m,
1
4H), 1.11 (s, 9H), 0.97-0.90 (m, 3H).
1
3
C NMR (50 MHz, CDCl
3
) δ: 180.2, 135.8, 134.4, 134.0, 129.5, 129.4, 127.5, 127.4, 72.0, 36.1,
3
1.8, 30.6, 29.4, 29.2, 27.0, 24.8, 22.6, 19.3, 14.0.
2
8

ACCEPTED MANUSCRIPT
+
HRMS (ESI) for C29
H O
44 3
SiNa [M + Na] , calculated: 491.2957; found: 491.2959.
(R)-4-(tert-butyldiphenylsilyloxy)-N-methoxy-N-methyltridecanamide (24):
Triethylamine (0.36 mL, 2.6 mmol) was added to a solution of acid 23 (936 mg, 2.0 mmol) in
DCM (12 mL). To this solution N,O-dimethylhydroxylamine hydrochloride (0.25 g, 2.6 mmol),
4
-dimethylaminopyridine (0.26 g, 2.8
mmol) and 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (0.47 g, 2.5 mmol) was sequentially added at room
temperature. The resulting mixture was stirred at room temperature for 6 h. After the completion
of the reaction the organic solution was washed successively with 1M hydrochloric acid (20
mL), brine (20 mL), saturated aqueous NaHCO (20 mL) and brine (20 mL). The organic layer
3
4
was dried (MgSO ) and concentrated in vacuo to afford the crude amide as yellow oil. The crude
product was then purified by chromatography (silica gel, hexanes: EtOAc = 1:2) to afford the
title compound 24 (919 mg, 90%) as a colorless oil.
R = 0.3 (EtOAc: hexane = 1:2).
f
2
8
[
α]D = +3.4 (c = 0.3, CHCl3).
1
3
H NMR of Compound 24 (200 MHz, CDCl ) δ: 7.73-7.68 (m, 4H), 7.43-7.34 (m, 6H), 3.84-
3
2
.76 (m, 1H), 3.58 (s, 3H), 3.14 (s, 3H), 2.55-2.33 (m, 2H), 1.88-1.76 (m, 2H), 1.46-1.40 (m,
H), 1.39-1.16 (m, 14H), 1.08 (s, 9H), 0.93-0.86 (m, 3H).
1
3
3
C NMR (50 MHz, CDCl ) δ: 174.6, 135.8, 134.5, 134.2, 129.4, 127.4, 127.3, 72.9, 60.9, 36.5,
3
1.8, 30.7, 29.5, 29.4, 29.2, 27.0, 24.8, 22.6, 19.3, 14.0.
+
HRMS (ESI) for C H NO SiNa [M + Na] , calculated: 534.3379; found: 534.3382.
3
1
49
3
(R)-6-(tert-butyldiphenylsilyloxy)pentadec-1-en-3-one (25):
A 1.0 M solution of vinylmagnesium bromide in THF (8.57 mL, 8.57 mmol) was added to a
stirred solution of 24 (1.4 g, 2.85 mmol) in anhydrous THF (10 mL) at -78 ˚C under N . The
2
mixture was stirred at -78 ˚C for 2 h and then it was quenched with saturated aq. NH Cl (5 mL)
4
solution. The organic solution was extracted with EtOAc (3 × 20 mL). The combined organic
extracts were washed with brine (1 × 30 mL), and then dried over MgSO . The organic solution
4
was filtered and concentrated to afford the crude product. The residue was purified by column
2
9