Total synthesis of (+)-fusarisetin A

Article abstract of DOI:10.1016/j.tet.2014.08.073

Herein we report the full details of our efforts toward the application of Pauson-Khand reaction for the stereoselective construction of the trans-decalin subunit with a C16 quaternary stereocenter of fusarisetin A, which led to the asymmetric total synth

Full text of DOI:10.1016/j.tet.2014.08.073

Accepted Manuscript
Total Synthesis of (+)-Fusarisetin A
Jun Huang, Lichao Fang, Jianxian Gong, ChuangChuang Li, Zhen Yang
PII:
S0040-4020(14)01279-4
10.1016/j.tet.2014.08.073
TET 25974
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 July 2014
Revised Date: 25 August 2014
Accepted Date: 28 August 2014
Please cite this article as: Huang J, Fang L, Gong J, Li C, Yang Z, Total Synthesis of (+)-Fusarisetin A,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.08.073.
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Graphical Abstract
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Asymmetric Total Synthesis of
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(
+)-Fusarisetin A
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Jun Huang, Lichao Fang, Jiaxian Gong, Chuangchaung Li and Zhen Yang 
a
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055,
China
b Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for Molecular Science
(BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.

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Tetrahedron
journal homepage: www.elsevier.com
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Total Synthesis of (+)-Fusarisetin A
a
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a,b
Jun Huang, Lichao Fang, Jianxian Gong, ChuangChuang Li, and Zhen Yang 
a
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for Molecular Science (BNLMS),
and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
b
2 ARTICLE INFO
ABSTRACT
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Article history:
Received
Herein we report the full details of our efforts towards the application of Pauson-Khand reaction
for the stereoselective construction of the trans-decalin subunit with a C16 quaternary
stereocenter of fusarisetin A, which led to the asymmetric total synthesis of (+)-fusarisetin A.
The developed chemistry provides an alternative strategy to the intramolecular Diels-Alder
reaction that has been employed for the synthesis of trans-decalin based natural products.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
stereoselective
fusarisetin A
Pauson-Khand reaction
trans-decalin
quaternary stereocenter

Corresponding author. Tel.: +86-755-2603-2971; fax: +86-755-2603-2971; e-mail: zyang@pku.edu.cn

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1. Introduction
During the past two decades, the Pauson-Khand (PK)
6
reaction has become a powerful method for the synthesis of
Decalin moieties are widely found in a broad range of
7
complex natural product containing cyclopetenone moieties.
biologically active natural products. (+)-fusarisetin A (1 , Fig.
We envisaged that the ABC tricyclic core (cyclopentana-
phthalenone B, Figure 1) in fusarisetin A could be constructed
stereoselectively from its precursor C via an asymmetric
intramolecular PK reaction. Thus, the generated cyclopenta-
naphthalenone B could be expected to be utilized in the
1
1
)
represents the trans-decalin subunits bearing the
quaternary carbon center at C1, which was isolated from a soil
fungus Fusarium sp. FN080326 by Ahn and co-workers in
8
2
011. Biological studies revealed that (+)-fusarisetin A had
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excellent inhibitory activity on the metastasis of the
MDA-MB-231 breast cancer cells. In addition, (+)-fusarisetin
A could inhibit cell migration (7.7 µM), cell invasion (26 µM)
and acinar morphogenesis (77 µM) without significant
cytotoxicity. The relative stereochemistry of fusarisetin A was
established by X-ray crystallographic analysis, and its absolute
configuration was subsequently revised by Li et al. via the
chemical synthesis. Structurally, (+)-fusarisetin A comprises
an unprecedented pentacyclic ring system bearing ten
stereogenic centers, including two all-carbon quaternary
stereocenters. Its carbon skeleton is consist of a trans-decalin
moiety (rings A and B) and tricyclic (5/5/5) moieties (rings C,
D, E) that are both decorated with a variety of different
functionalities. Because of the impressive biological activities
and the novel structural features, several research groups have
published their efforts toward fusarisetin A, which culminated
syntheses of the decalin subunits resized in the natural
9
products, such as compound 2-5 in Fig. 1.
Previous work in our laboratories had revealed that the PK
reaction of enyne 5 represented an efficient method for
synthesis of enone 6 bearing a quaternary carbon in high yield
10
under mild conditions (Scheme 1). Herein, we report the full
details of our efforts to stereoselectively construct the
trans-decalin subunit containing the quaternary carbon center
at C16 via the intramolecular PK reaction that led to the total
synthesis of (+)-fusarisetin A.
_
____________________________________________________
2
in several successful total syntheses by the groups of Li,
3
4
Scheme 1. (TMTU)/Co (CO) -catalyzed intramolecular
2 8
Theodorakis and Gao . In general, the intramolecular
Diels-Alder reaction (IMDA) was employed to construct the
trans-decalin unit (A/B ring system).
Pauson-Khand reaction.
___________________________________________________
_
Our initial effort toward total synthesis of (+)-fusarisetin A
was motivated by developing a novel synthetic strategy for
stereoselective synthesis of the trans-decalin subunit
containing the C16 quaternary carbon center of fusarisetin A,
which could provide an alternative strategy to the
2. Results and Discussion
2.1. First generation total synthesis of fusarisetin A.
1
According to the isolation paper, our initial target was the
5
natural product enantiomer (‒)-fusarisetin A (7), and the
stereoselective construction of the cyclopentanaphthalenone
subunit 14 (Figure 2) with the expected quaternary chirality at
C16 was identified as the pivotal step in this approach.
intramolecular Diels-Alder (IMDA) reaction. Thus, the
developed chemistry would have a potential to be utilized in
the total synthesis of (+)-fusarisetin A, as well as other decalin
based natural products.
_
___________________________________________________
Fig. 2 outlines our retrosynthetic strategy for the
enantioselective total synthesis of (‒)-fusarisetin A (7). It was
envisaged that (‒)-fusarisetin A (7) could be assembled from
lactam 8 via the Dieckmann condensation reaction of
11
intermediate 8a. We reasoned that lactam 8 could be formed
1
2
via the aminolysis of 10 with aminoester 9, followed by an
intramolecular lactonization. It was not necessary to consider
the stereochemistry at the C1-position of -ketoester 10 at this
stage because the chirality at this position would be set up
naturally during the course of the subsequent Dieckmann
condensation.
It was envisaged that the -keto ester 10 could be prepared
from the epoxide ester 11 via a reductive epoxide-ring-
1
3
opening reaction followed by the oxidation of the resulting
-hydroxy ester. The epoxy ester 11 could in turn be prepared
by the epoxidation of the -unsaturated ester in 12. Given
that the Pd-catalyzed carbonylation of enol triflates has been
reported as an effective method for the conversion of ketones
to the corresponding -unsaturated esters, this approach
was used for the construction of the -unsaturated ester in
12 in a regio-controlled manner from ketone 13, which was
1
4
itself derived from cyclopentanaphthalenone 14 via
a
stereoselective 1,4-reduction. It was also expected that enyne
15, which already included the necessary chiral centers (C10
C ) could be stereoselectively transformed into
cyclopentanaphthalenone 14 via a transition metal catalyzed
Fig. 1. Decalin based bioactive natural products (a) and
general synthetic strategy (b).
_____________________________________________________
and
15

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PK reaction. The precursor enyne 15 could in turn be
constructed from aldehyde 16, which could itself be derived
from the commercially available S-(―)–carvone 17.
_____________________________________________________
TBSOTf and TMSOTf to a CH
presence of lutidine, to give enyne 15 in 90% yield.
Our attention then shifted to the Co (CO)
Cl solution of 20a in the
2 2
-mediated
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intramolecular PK reaction of enyne 15. To establish the
optimal reaction conditions, the effects of a variety of different
parameters (e.g., metal catalyst, additive, solvent, and
temperature) on the outcome of the reaction were investigated.
Several different transition metal complexes were tested,
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including PdCl in the presence of tetramethyl thiourea
TMTU) and Co (CO) under a variety of different
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(
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conditions in the presence of several different additives,
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including
ethane-1,2-diol,
molecular
sieves,
Me S,
water,
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N-methylmorpholine-N-oxide (NMO),
trimethylamine-N-oxide (TMANO),
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and TMTU.
The
results indicated that the Co (CO) -mediated PK reaction was
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the most efficient method of those tested for the
stereoselective construction of the quaternary stereogenic
center at the C position of cyclopentanaphthalenone 14.
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_
_________________________________________________
Fig. 2. Retrosynthetic analysis for the first generation
synthesis of (―)-fusarisetin A (7).
Scheme 1. Synthesis of cyclopentanaphthalenone 14.
_
_
____________________________________________________
____________________________________________________
The first phase of the synthesis required the efficient
Of the different solvents tested, including THF, benzene,
toluene and CH CN, toluene was found to provide the best
results. The temperature for the reaction was evaluated at
temperatures ranging from 70 to 130°C, with 95 C giving the
best result. Taken together, a 60% yield of product 14 was
a stoichiometric amount of
Co (CO) was used at a reaction temperature of 95 C under
preparation of 14, and the intramolecular PK reaction of enyne
15 was initially evaluated for this specific purpose. Accepting
the S-configurational assignment at the C15 chiral center in
(‒)-fusarisetin A (7), S-(―)–carvone 17 was selected as the
starting material for the synthesis. The -lithiation of 17 with
LDA (THF, -78°C, 1 h) followed by the addition of the
bromide 18 led to the formation of ketoamide 19 in 88% yield
3
o
eventually obtained when
o
2
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argon. Further treatment of 14 with K
21 in 85% yield.
CO in MeOH afforded
3
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as a single isomer (Scheme 1). The asymmetric reduction of
1
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19 with LiAlH
subsequently reacted with diethoxypropynyl lithium to afford
0a and 20b as a pair of diastereoisomers. Separation of the
generated a hydroxyl aldehyde, which was
To complete the synthesis of the fully functionalized decalin
2, we needed to establish an effective method for the
stereoselective reduction of the C6, C7 and C12, C13 double
bonds in 14, as well as a method for the removal of the
secondary alcohol at the C11-position. To achieve these goals,
a straightforward transformation was designed involving a
4
1
2
isomers was achieved at this stage by flash chromatography,
giving 20a and 20b in 52 and 17% yields, respectively.
Selective protection of the two secondary alcohols in 20a was
achieved in a one-pot reaction via the sequential addition of
2
5
transition metal catalyzed hydrogenation of the double bonds
2
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and a Barton-McCombie deoxygenation as the key steps.

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established that the desired xanthate could be formed in 30%
31
yield (69% brsm) by the treatment of 22 with NaH in THF at
0°C, followed by reaction with MeI. The resulting xanthate
was then subjected to the Barton-McCombie deoxygenation
Table 1. Optimization results of the Pauson-Khand reaction.
by the treatment with Bu SnH in toluene at 90°C for 2 h to
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give the deoxygenated product 23 in 62% yield.
_
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a
Isolated yield.
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Inspection of the 3D structure of 21 revealed that its convex
face might be more accessible than its concave face because of
its highly congested scaffold, particularly with regard to the
hydroxy group at the C11-position, which could be used to
coordinate to the transition metal and effectively deliver the
metal to the convex face for the formation of a metal-olefin
complex, leading to a stereoselective hydrogenation.
To explore the feasibility of this approach, the
hydrogenation of 21 was profiled with several different
catalysts. The initial investigations focused on the use of
2
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Crabtree’s catalyst
for this allylic alcohol-induced
hydrogenation. Unfortunately, however, no reaction occurred
and only the starting material was recovered. We then
investigated the use of a Pd/C catalyzed hydrogenation.
Although this reaction gave the desired product 22 in 44%
yield, extensive levels of over-reduction side products were
observed. Following some further investigation, Rh-catalyzed
Scheme 3. Stereoselective synthesis of ketone 13.
_____________________________________________________
Although the enantioselective synthesis of 23 had been
successfully achieved, the overall yield was low and
disappointed. With this in mind, attempts were made to
investigate the use of Danishefsky’s reductive demesylation
strategy to remove the hydroxyl group at the C11-position.
Thus, alcohol 22 was converted to the corresponding mesylate
28
hydrogenation was established as the best method for the
conversion and gave the desired product 22 in 96% yield as a
single isomer.
3
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With 22 in hand, we moved on to explore the
Barton-McCombie deoxygenation reaction. Unfortunately, this
particular synthetic transformation proved to be more
challenging than anticipated because of the sterically hindered
nature of the hydroxy group at the C11-position. Our initial
investigation of the reactions of 22 with standard
Barton-McCombie reagents such as thiocarbonyl diimidazole/
2
4 in 93% yield, and the lithium-ammonia mediated reduction
carefully tested. Unfortunately, this reaction was found to not
be chemo-selective. Furthermore, in the majority of the cases,
a mixture was obtained, presumably because as a consequence
of competitive 1,2- and 1,4-reducitons, as well as the
occurrence of demesylation. Attempts were also made to use
3
3
2
9
LiBH and LiBHEt as the reducing agent to provide product
25. Unfortunately, however, these reactions resulted only in
4 3
4-dimethylainopyridine (DMAP),
NaH/PhOCSCl and
3
0
DMAP/PhOCSCl, failed to provide the desired product.
After exploring a range of bases and alkylating agents, it was
failure.

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A recently published study indicated that the reductive
isomerization reaction of allylic systems functionalized with a
leaving group could be regioselectively achieved by a
Having established a route to the fully functionalized
ketone 27, we moved on to investigate the synthesis of the
-keto ester 10 according to the strategy outlined in Scheme 4.
Synthetically, the lithium enolate generated in situ by the
exposure of ketone 13 to LDA was allowed by reaction with
Comins’ reagent to yield the corresponding triflate, which
was subsequently subjected to a Pd-catalyzed carbonylative
esterification reaction, followed by desilylation to give 28 in
40% yield over three steps. This sequence conveniently
established the -unsaturated ester functionality necessary
for the epoxidation to 29.
Although it was anticipated that the -unsaturated ester in
8 would provide facile access to the desired epoxide 29, the
treatment of substrate 28 with a variety of different oxidative
agents, such as tert-butyl hydroperoxide (TBHP)/1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU), m-chloroperbenzoic acid
m-CPBA), and H O /NaOH, did not result in the formation
of the desired product. It was later established that epoxide 29
could be synthesized in 55% yield as single
3
4
heterogeneous Pd-catalyzed hydrogenation reaction, and this
type of reaction might involve a single electron transfer (SET)
3
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40
mechanism. With this chemistry in mind, we would like to
explore a direct synthetic transformation of acetylated allylic
4
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alcohol 26 (Scheme 3) to 23 using
a
Pd-catalyzed
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hydrogenation. To this end, substrate 21 was converted to the
corresponding acetate 26 by reaction with Ac O/Et N/DMAP
2
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in 95% yield. After experimentation, we were pleased to find
that acetylated allylic alcohol 26 could be transferred to 23 in
7
1% yield, together with its diastereoisomer in 8% yield,
2
via the Pd(OH)/C-catalyzed hydrogenation. To the best of our
knowledge, this is the first report to describe this particular
type of synthetic transformation.
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_
____________________________________________________
(
2 2
Table 2. Pd-catalyzed hydrogenation of allylic acetate.
a
a
diastereoisomer by reaction of 12 with m-CPBA in the
presence of NaHCO . No efforts were made at this stage to
3
assign the stereochemistry at the newly formed epoxide
centers because the stereochemistries at these positions would
be eliminated in the subsequent steps. It is noteworthy that a
significant amount of ketone 30 (20% yield) was also formed
during the reaction.
____________________________________________________
4
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_
_
____________________________________________________
Having successfully developed a synthesis for the efficient
construction of 23, we proceeded to investigate the synthesis
of intermediate 27 and the stereoselective installation of the
chiral centers at the C6 and C7-positions. Initially, Stryker’s
3
6
37
regent and SmI2 were evaluated for the 1,4-reduction of the
enone moiety in 23. Unfortunately, however, both of the
reactions occurred without any useful level of regio- or
stereoselectivity. A report in the literature indicated that this
type of transformation could be achieved by Pd-catalyzed
3
8
hydrogenation. To explore the synthetic feasibility of this
transformation, 23 was directly subjected to the hydrogenation
reaction with several different Pd-catalysts under a variety of
conditions. Disappointingly, none of the desired product was
ever formed, presumably because of the steric hindrance
provided by the TBS group. Following the removal of the silyl
group, however, the resulting enone proceeded smoothly
through the hydrogenation reaction in the presence of Pd/C
Scheme 4. Synthesis of keto-ester 10.
___________________________________________________
_
To install the double bond required at the C8,C9 positions
in the -keto ester 10, we first tested a direct dehydration of 13
with Burgess’ reagent [i.e. methyl N-triethylammonium-
(
strem) to afford the desired ketone 27 in 55% yield with the
39
4
6
trans-configuration across the two newly generated chiral
centers. The result suggested that the catalyst may have
coordinated to the enone moiety from the top face of 23,
leading to the formation of intermediate 28, which would have
sulfonyl)carbamate]. Unfortunately, however, the desired
dehydration product 31 could not be generated under a variety
of different conditions. In contrast, the conversion of the
hydroxyl group of 29 to the corresponding mesylate, followed
by its reaction with DBU in refluxing toluene provided the
desired product 31 in 71% over the two steps. The conversion
of 31 to the desired -keto ester 10 was completed in 65%
38a
then been subjected to the ketone-mediated epimerization to
afford ketone 27. The stereochemistry of 27 was confirmed by
the crystallographic analysis of its TBS protected derivative
4
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1
3.
yield by a SmI -mediated reduction and subsequent Dess-
2
Martin periodinane (DMP) oxidation of the resulting alcohol.

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2
During this period of time, Li et al. disclosed their
excellent total synthesis of (‒)-fusarisetin A (7). We conceived
that the efficiency of our first generation strategy for the
synthesis of fusarisetin was not satisfied; it took 19 steps for
the preparation of key intermediate 10, representing an overall
yield of 0.6%. With this in mind, the development of a more
convenient route for the synthesis of (+)-fusarisetin A was
required.
from ketone 35, which was envisaged to be accessible from
cyclopentanaphthalenone 36 via the Pd-catalyzed stereo-
selective hydrogenation reaction, as demonstrated in Scheme
4. Overall, our retrosynthetic analysis could be traced back to
the stereoselective synthesis of cyclopentanaphthalenone 36,
which was expected could be formed via the PK reaction of
enyne 37. The key to this synthetic strategy was identified as
the development of an efficient method for the diastereo-
selective synthesis of enyne 37. It was envisaged that this
compound could be synthesized from epoxide 38 using a
regioselective nucleophilic propynylation strategy. Epoxide 38
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
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6
6
6
6
6
6
2
.1. Second generation total synthesis of fusarisetin A.
Although the first-generation strategy for the total synthesis
4
8
could be derived from a known aldehyde 39 according to a
failed to provide access to the target molecule, the chemistry
developed during the process, including the PK reaction in
particular for the stereoselective construction of cyclopenta
-naphthalenone 14, provided valuable insights for the design
of our second generation strategy for the total synthesis.
Given that the absolute configuration of the natural product
fusarisetin A had been reassigned, we therefore selected
+)-fusarisetin A (1) as our target. Retrosynthetically, the
decision was taken to apply the published protocol to
synthesize the final target (+)-fusarisetin A (1) from amide 32
via the Dieckmann-type cyclization followed by a hemi-
acetalization. It was envisaged that amide 36 could in turn be
generated via the aminolysis of the -keto ester 33 with
49
previously reported procedure.
Our synthesis started with the preparation of cyclopenta-
naphthalenone 36 (Scheme 5). Thus, nucleophilic addition of
chloroiodomethyllithium to aldehyde 39 led to the generated
of epoxide 38 as the major isomer in 72% yield, together
with the associated diastereoisomer 40 in 12% yield. The
reaction of 38 with lithium acetylide 41 at -78°C in the
presence of BF •Et O gave the requisite enyne 37 in 60%
yield. Remarkably, the PK reaction of enyne 37 proceeded
smoothly with heating in toluene (120°C) in the presence of a
stoichiometric amount of Co (CO) to give cyclopentenone 36
49
50
51
(
52
2
3
2
2
8
with the desired quaternary chiral center in 82% yield as the
2
sole isomer.
aminoester 9.
_
_
___________________________________________________
____________________________________________________
Scheme 5. Synthesis of cyclopentanaphthalenone 36.
_
____________________________________________________
We then proceeded to investigate the stereoselective
reduction of enone via the hydrogenation demonstrated in our
first generation synthetic strategy (Scheme 6). The hydroxyl
group in 36 was initially protected as the corresponding
methoxy methyl ether (MOM), followed by deprotection of its
TBS group with HF•pyridine to afford the desired product 42.
To saturate the double bond in compound 42, the material was
subjected to a Pd/C catalyzed hydrogenation under conditions
identical to those used for the formation of 27 (Scheme 3).
Interestingly, in contrast to the reaction for the formation of
27 from 23 under the same conditions, product 43 was
obtained in 89% yield as the sole isomer. The
stereochemistries at the C6 and C7-positions were the opposite
of what we expected. To account for this regioselectivity, we
hypothesized that an intramolecular hydrogen-bonding existed
between the free-hydroxyl group and the ketone group (see 3D
structure of 42a in Scheme 6), which could block the approach
Figure 3. Retrosynthetic analysis for the second generation
synthesis of (+)-fusarisetin A (1)
____________________________________________________
_
As demonstrated in the first generation synthesis, the -keto
ester 33 could be generated from epoxide 34 via a
SmI -mediated reductive epoxide-ring opening reaction
followed by oxidation of the resultant alcohol. Epoxide 34
could in turn be readily formed via the Pd-catalyzed
carbonylation and m-CPBA-mediated epoxidation reactions
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of the catalyst to the double bond from the convex face,
resulting in the formation of product 43 as the sole product.
____________________________________________________
strategy for the syntheses of trans-decalin based biologically
53
active natural products.
_
____________________________________________________
1
1
1
1
1
1
1
1
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6
Scheme 6. Synthesis of compound 43.
_
____________________________________________________
In order to generate the desired stereochemistry at C7, we
5
1
decided to use mesylate as the protecting group. We
hypothesized that the mesylate group could form a H-bonding
network with ethanol (solvent) and hydroxyl group at C5.
Therefore, 44 would likely to adopt the conformation as 44a
(see 3D structure of 44a in scheme 7).
To test this hypothesis, cyclopentanaphthalenone 36 was
treated with MsCl under basic condition, followed by
desilylation to afford 44 in 68% yield over the two steps.
Hydrogenation of 44 with Pd/C catalyst under balloon
pressure of H afforded the desired product 45 in 70% yield.
2
The structure of 45 was confirmed by X-ray crystallographic
analysis. TBS protection of the hydroxyl group in ketone 45,
followed by treatment with Comins’ reagent in the presence of
KHMDS as a base to give enol triflate 46 in 95% yield over
two steps. Esterification of 46 with Pd(Ph P) as a catalyst in
3
4
MeOH under balloon pressure of CO furnished ester 47 in
5% yield. The electron-deficient double bond in 47 was
6
epoxidized with m-CPBA in the presence of NaHCO to afford
3
the desired epoxide 48 in 75% yield. The epoxide was
demesylated by treatment with DBU in refluxing toluene,
followed by SmI mediated epoxide, and the resultant alcohol
2
was oxidized with DMP to give -keto ester 33 in 82% yield.
Thus, after reaction with the aminoester 9, amide 49 was
formed in 73% yield.
52
To complete the total synthesis, amide 49 was treated with
HF•pyridine to remove the TBS group, and the resulting keto
ester was then subjected to
a
one-pot Dieckmann
condensation/hemiacetalization process for the formation of
the DE ring of target molecule. In practice, treatment of
substrate 49 with NaOMe in MeOH resulted in the formation
of (+)-fusarisetin A (1) and (+)-C3-epi-fusarisetin A (50) in a
combined yield of 73% in a ratio of 1.4/1 (Scheme 7).
Scheme 7. Completion of the total synthesis.
_
____________________________________________________
4
. Experimental section
3. Conclusion
4.1. Synthesis of N-methoxy-N-methyl-2-((1R,6S)-3-methyl
-2-oxo-6-(prop-1-en-2-yl)cyclohex-3-en-1-yl)acetamide (19):
To a solution of S-(−)-carvone (17) (1.0 g, 1 ml, 6.66 mmol)
in dry distilled THF (20 ml) was added LDA (2 M in THF,
.66 ml, 7.32 mmol) in a dropwise manner at -78 C, and the
solution was stirred at the same temperature for 1 h. To this
solution was added bromide 18 (1.45 g, 7.99 mmol) in THF
(10 ml) slowly at -78 C, and the resultant solution was stirred
at -78 °C overnight. The reaction was quenched with a
In summary, we have developed a concise synthetic strategy
for the total synthesis of (+)-fusarisetin A in 16 steps with an
52
overall yield of 1.4 %.
The synthesis featured an
o
intramolecular Pauson-Khand reaction for the stereoselective
construction of cyclopentanaphthalenone 36, and the
Pd-catalyzed hydrogenation of allyl acetate for the stereo-
selective synthesis of the ABC tricyclic core of fusarisetin A.
The developed chemistry provides an additional synthetic
3
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1
saturated solution of NH
extracted ether (3 x 30 ml). The combined organic layers were
washed with brine (15 ml), and dried over Na SO The solvent
was removed under vacuum, and the residue was purified by a
flash chromatography on silica gel (hexane/ethyl acetate =8/1)
to give ketoamide 19 (1.44 g)as yellow oil in 86% yield; R =
Cl (50 ml), and the mixture was
EtOAc/hexanes = 1/5). H NMR (500 MHz, CDCl ) δ 5.49
3
4
(s, 1H), 5.27 (d, J = 1.0 Hz, 1H), 4.84 – 4.73 (m, 2H), 4.61
(dd, J = 7.1, 6.3 Hz, 1H), 3.95 (d, J = 5.7 Hz, 1H), 3.75 – 3.68
(m, 2H), 3.57 (m, 2H), 2.28 – 2.21 (m, 1H), 2.21 – 2.10 (m,
1H), 2.01 (dd, J = 9.0, 6.1 Hz, 1H), 1.94 (d, J = 17.4 Hz, 1H),
1.80 – 1.76 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H), 1.22 (t, J = 7.1
Hz, 6H), 0.90 (s, 9H), 0.17 (d, J = 3.1 Hz, 9H), 0.13 (d, J =
20.0 Hz, 6H); C NMR (125 MHz, CDCl ) δ 147.4, 135.0,
123.4, 112.0, 91.5, 87.6, 80.2, 76.2, 61.2, 60.8, 60.7, 45.2,
40.8, 40.2, 29.3, 25.9, 21.1, 19.8, 18.1, 15.0, 1.0, -4.2, -4.8;
HRMS (ESI) m/e 531.3298 [M+Na ] calcd for
2
4.
f
1
0
.50 (silica gel, EtOAc/hexanes = 1/2); H NMR (500 MHz,
13
CDCl ) δ 6.66 (d, J = 5.6 Hz, 1H), 4.81 (d, J = 0.8 Hz, 2H),
3
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
3
2
3
1
.72 (s, 3H), 3.16 (s, 3H), 3.06 – 2.95 (m, 1H), 2.83 – 2.70 (m,
H), 2.53 – 2.42 (m, 1H), 2.37 – 2.21 (m, 2H), 1.77 – 1.71 (m,
H), 1.69 (s, 3H); C NMR (125 MHz, CDCl ) δ 200.4,
1
3
+
3
+
73.1, 145.4, 143.1, 134.7, 113.8, 60.9, 48.3, 45.8, 32.2, 31.3,
C H NaO Si : 531.3296.
2
8
52
4
2
+
29.4, 18.1, 15.8; HRMS (ESI) m/e 252.1594 [M+H ] calcd for
C H NO : 252.1594.
+
4.4. Synthesis of compound 14. To a solution of Co (CO) (2.0
2 8
g, 5.90 mmol) in dry PhMe (300 ml) was added a solution of
compound 15 (2.5 g, 5.36 mmol) in PhMe (10 ml), and the
resultant mixture was stirred at 120 C for 15 h. After cooling
to room temperature, the reaction mixture was concentrated
under vacuum, and the residue was purified by a flash
chromatograph on silica gel (hexane:ethyl acetate = 10:1) to
give product 14 (1.63 g) as colorless oil in 60% yield; R =
0.70 (silica gel, EtOAc/hexanes = 1/3); H NMR (500 MHz,
1
4
22
3
4
3
.2. Synthesis of (1S,5S,6R)-6-(5,5-diethoxy-2-hydroxypent-
-yn-1-yl)- 2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enol (20a):
o
To a solution of ketoamide 19 (20 g, 79.7 mmol) in dry THF
o
(
300 ml) was added LiAlH (6.1 g, 159.4 mmol) at -78 C
4
carefully, and the resultant mixture was stirred at the same
temperature for 3 h. The reaction was quenched by slow
addition of a saturated sodium potassium tartrate (100 ml), and
the mixture was then stirred at room temperature for 3 h. The
f
1
CDCl ) δ 6.05 (s, 1H), 5.52 – 5.39 (m, 1H), 4.73 (dd, J = 11.8,
3
mixture was extracted CH Cl (3 x 200 ml), and the combined
5.4 Hz, 1H), 3.89 – 3.76 (m, 2H), 3.68 – 3.59 (m, 1H),3.52 –
3.38 (m, 2H), 2.57 – 2.50 (m, 1H), 2.32 (d, J = 18.7 Hz, 1H),
2.13 (d, J = 18.7 Hz, 1H), 2.05 – 1.94 (m, 1H), 1.87 (dd, J =
12.1, 5.1 Hz, 1H), 1.83 – 1.73 (m, 1H), 1.65 (s, 3H), 1.37 –
1.26 (m, 2H), 1.21 (t, J = 6.9 Hz, 6H), 1.12 (s, 3H), 0.95 (s,
10H), 0.17 (s, 9H), 0.14 (d, J = 3.0 Hz, 6H); C NMR (125
MHz, CDCl ) δ 203.9, 180.1, 135.4, 133.1, 122.8, 97.0, 77.6,
70.6, 63.4, 63.0, 50.0, 47.7, 44.9, 43.7, 41.5, 26.5, 26.0, 20.5,
20.3, 18.4, 15.5, 15.4, 1.0, -4.5, -5.1; HRMS (ESI) m/e
2
2
extracts were dried over Na SO .The solvent was removed
under vacuum, and the residue was used in next step without
further purification. To a solution of diethoxypropynyl (3.56 g,
2
4
2
7.8 mmol) in freshly distilled THF (25 ml) was added
13
n-butyllithium (2.5 M in hexane, 11.1 ml, 27.8 mmol) in a
o
dropwise manner at -78 C, and the solution was stirred at the
3
same temperature for 1 h. To this solution was a solution of
hydroxyl aldehyde (1.8 g, 9.29 mmol) in THF (5 ml), and the
resultant mixture was gradually warmed up to 0 °C, and the
mixture was continually stirred at the same temperature for 3
h. The reaction mixture was quenched by addition of a
+
+
559.3247 [M+Na ] calcd for C H NaO Si : 559.3245.
2
9
52
5
2
4
.5. Synthesis of compound 21. To a solution of 14 (1.5 g, 2.79
mmol) in MeOH (30 ml) was added K CO (0.5 g, 3.64 mmol)
at room temperature, and the mixture was for 1.5 h at the same
temperature for 1.5 h. The reaction was quenched by addition
of a saturated solution of NH Cl (20 ml), and the resultant
mixture was extracted CH Cl (3 x 20 ml). The combined
organic layers were washed with brine (10 ml), and dried over
Na SO The solvent was removed under vacuum, and the
residue was purified by a flash column chromatography on
silica gel (hexane:ethyl acetate = 8:1) to give 21 (1.04 g) as
colorless oil in 80% yield; R = 0.40 (silica gel, EtOAc/
hexanes = 1/3); H NMR (500 MHz, CDCl ) δ 6.06 (s, 1H),
5.57 – 5.36 (m, 1H), 4.75 (dd, J = 11.9, 5.4 Hz, 1H), 3.90 –
3.80 (m, 1H), 3.73 (s, 1H), 3.63 – 3.60 (m, 1H), 3.50 – 3.40
m, 2H), 2.69 – 2.65 (m, 1H), 2.32 (d, J = 18.7 Hz, 1H), 2.14
d, J = 18.7 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.92 – 1.81 (m, 1H),
.71 (s, 4H), 1.35 (tt, J = 8.5, 7.4 Hz, 2H), 1.20 (dd, J = 15.0,
.1 Hz, 7H), 1.14 (s, 3H), 0.95 (d, J = 2.7 Hz, 10H), 0.15 (d, J
3.5 Hz, 6H); C NMR (125 MHz, CDCl ) δ 204.0, 180.2,
35.2, 133.1, 122.9, 97.0, 76.0, 70.6, 63.4, 63.1, 49.9, 47.8,
saturated solution of NH
extracted CH Cl (3 x 20 ml). The combined organic layers
were washed with brine (10 ml), and dried over Na SO The
Cl (40 ml), and the mixture was
2
3
4
2
2
2
4.
solvent was removed under vacuum, and the residue was
purified by a flash column chromatography on silica gel
4
2
2
(
hexane/ethyl acetate = 15/1) to give alcohol 20a (1.54 g) as
colorless oil in 52% yield; R = 0.75 (silica gel, EtOAc/
hexanes = 1/3). H NMR (500 MHz, CDCl ) δ 5.49 (d, J = 4.0
2
4.
f
1
3
Hz, 1H), 5.29 (s, 1H), 4.81 (s, 1H), 4.78 (s, 1H), 4.54 (dd, J =
9
3
2
.0, 4.0 Hz, 1H), 3.89 (d, J = 7.4 Hz, 1H), 3.77 – 3.67 (m, 2H),
.63 – 3.52 (m, 2H), 2.20 (m, 1H), 2.17 – 2.06 (m, 1H), 2.06 –
.00 (m, 1H), 1.97 – 1.89 (m, 1H), 1.77 – 1.70 (m, 4H), 1.68 –
f
1
3
1
3
1.61 (m, 4H), 1.23 (q, J = 7.1 Hz, 6H); C NMR (125 MHz,
(
(
1
7
=
1
4
-
CDCl ) δ 146.9, 135.1, 123.4, 113.3, 91.4, 87.0, 79.6, 76.1,
3
62.1, 61.0, 47.3, 43.1, 41.5, 30.9, 19.3, 18.5, 15.0; HRMS
(ESI) m/e 345.2039 [M+Na ] calcd for
+
+
C H30NaO :
19 4
3
45.2036.
13
3
4
.3. Synthesis of tert-butyl(((S)-5,5-diethoxy-1-((1R,2S,6S)-3-
methyl-6-(prop-1-en-2-yl)-2-((trimethylsilyl)oxy)cyclohex-3-en
1-yl)pent-3-yn-2-yl)oxy)dimethylsilane (15): To a solution of
the alcohol 20a (167.0 mg, 0.519 mmol) and Et N (261 mg,
4.9, 43.3, 41.4, 26.5, 26.1, 20.4, 18.8, 18.3, 15.5, 15.4, -4.6,
4.9; HRMS (ESI) m/e 487.2851 [M+Na ] calcd for
+
-
+
3
C H NaO Si : 487.2850.
26 44 5
2.59 mmol) in dry CH Cl (15 ml) was added TBSOTf (136.9
2 2
o
mg, 0.519 mmol) at -78 C in a dropwise manner, and the
reaction mixture was stirred at the same temperature for 0.5 h.
The reaction was quenched by addition of water (50 ml), and
the mixture was extracted with ether (3 x 50 ml). The
combined organic layers were washed with brine (5 ml), and
dried over Na SO . The solvent was removed under vacuum,
4.6. Synthesis of compound 21: To a degassed solution of
alcohol 22 (0.6 g, 1.29 mmol) in PhH (15 ml) was added
Rh(PPh ) Cl (60 mg, 0.06 mmol) and NaHCO (217 mg, 2.6
mmol), and the resultant mixture was purged with hydrogen,
and then stirred at 45 C under a balloon of hydrogen for 10 h.
After the reaction, the mixture was concentrated under
vacuum, and the residue was purified by a flash column
chromatography on silica gel (hexane:ethyl acetate = 6:1) to
3
3
3
o
2
4
and the residue was purified by
chromatography on silica gel (hexane/ethyl acetate = 50/1) to
give enyne 15 (237.0 mg) in 90% yield; R = 0.95 (silica gel,
a
flash column
give 21 (578.0 mg) in 96% yield; R = 0.40 (silica gel,
f
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EtOAc/hexanes = 1/2). H NMR (500 MHz, CDCl
1H), 4.72 (dd, J = 11.8, 5.3 Hz, 1H), 3.87 – 3.77 (m, 1H), 3.67
) δ 6.07 (s,
removed under vacuum, and the residue was purified by a
3
flash column chromatography on silica gel (hexane/ethyl
–
2
1
1
1
6
3.58 (m, 1H), 3.50 – 3.39 (m, 2H), 2.79 (t, J = 7.2 Hz, 1H),
.69 – 2.51 (m, 1H), 2.32 (d, J = 18.7 Hz, 1H), 2.16 (d, J =
8.7 Hz, 1H), 1.84 – 1.74 (m, 2H), 1.69 (s, 1H), 1.52 (dd, J =
4.8, 4.6 Hz, 2H), 1.35 (dd, J = 11.3, 5.2 Hz, 1H), 1.30 (d, J =
2.1 Hz, 1H), 1.24 – 1.18 (m, 7H), 1.13 (s, 3H), 1.01 (d, J =
.5 Hz, 4H), 0.95 (s, 9H), 0.15 (d, J = 2.5 Hz, 6H); C NMR
125 MHz, CDCl ) δ 204.1, 180.1, 133.2, 97.1, 80.2, 71.2,
3.4, 63.1, 51.7, 50.4, 45.4, 43.4, 42.3, 39.8, 32.7, 27.1, 26.1,
0.4, 18.4, 18.4, 15.5, 15.4, -4.5, -4.9; HRMS (ESI) m/e
acetate = 8/1) to give the product 23 (27 mg) in 62% yield; R
f
1
= 0.80 (silica gel, EtOAc/hexanes = 1/2); H NMR (500 MHz,
CDCl ) δ 6.06 (s, 1H), 4.73 (dd, J = 11.7, 5.1 Hz, 1H), 3.89 –
3
3.76 (m, 1H), 3.70 – 3.55 (m, 1H), 3.53 – 3.34 (m, 2H), 2.32
(d, J = 18.7 Hz, 1H), 2.14 (d, J = 18.7 Hz, 1H), 2.07 – 1.94 (m,
1H), 1.75 (d, J = 12.7 Hz, 1H), 1.69 (d, J = 12.8 Hz, 1H), 1.58
(d, J = 13.0 Hz, 1H), 1.52 (d, J = 11.4 Hz, 1H), 1.37 (d, J =
10.6 Hz, 1H), 1.36 – 1.29 (m, 1H), 1.21 (dd, J = 12.0, 6.4 Hz,
13
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
(
3
6
2
4
7H), 1.11 (s, 3H), 0.95 (s, 10H), 0.89 (t, J = 8.3 Hz, 3H), 0.83
+
+
13
89.2995 [M+Na ] calcd for C H NaO Si : 489.3007.
(d, J = 9.5 Hz, 2H), 0.68 (q, J = 11.9 Hz, 1H), 0.14 (s, 6H);
C
26
46
5
NMR (125 MHz, CDCl ) δ 204.3, 180.6, 133.1, 97.1, 71.2,
3
4
(
.7. Synthesis of compound 24. To a solution of alcohol 22
50.0 mg, 0.107 mmol), DMAP (13 mg, 0.107 mmol) and
63.3, 63.0, 53.2, 50.3, 46.3, 45.5, 42.2, 36.4, 34.8, 32.5, 27.7,
26.1, 22.2, 20.4, 18.4, 15.4, 15.4, -4.5, -5.0; HRMS (ESI) m/e
+
+
Et3N (110 mg, 0.15 mL, 1.1 mmol) in CH2Cl2(3 mL) was
added MsCl (61 mg,0.54 mmol) slowly at 0 oC, and the
mixture was gradually warmed up to room temperature. After
stirring at room temperature for 2h, the reaction mixture was
quenched with water (5 mL), and resultant mixture was
extracted ether (3 x 10 mL).The combined organic layers were
washed with brine (5 mL), and dried over Na2SO4. The solvent
was removed under vacuum, and the residue was purified by a
flash column.
4
73.2059 [M+Na ] calcd for C H NaO Si : 473.3058.
26 46 4
4.9. Synthesis of compound 26. To a solution of alcohol 21
(130 mg, 0.28 mmol), DMAP (34 mg, 0.28 mmol) and Et N
(142 mg, 0.2 ml, 1.4 mmol) in CH Cl (3 ml) was added Ac O
3
2
2
2
o
(57 mg, 0.053 ml, 0.56 mmol) slowly at 0 C, and the mixture
was gradually warmed up to room temperature. After stirring
at the room temperature for 2h, the mixture was quenched by
addition of water (5 ml), and extracted ether (3 x 10 ml). The
combined organic layers were washed with brine (3 ml), and
SO4. The solvent was removed under vacuum,
flash column
chromatography on silica gel (hexane/ethyl acetate = 5/1) to
Chromatography on silica gel (hexane/ethyl acetate = 3:1) to
give product 24 (54.0 mg) in 93% yield; Rf = 0.40 (silica gel,
dried over Na
and the residue was purified by
2
1
EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl3) δ 6.05 (s,
a
1
H), 4.72 (dd, J = 11.8, 5.3 Hz, 1H), 4.12 (dd, J = 12.9, 7.2
Hz, 1H), 3.83 (dd, J = 9.0, 7.1 Hz, 1H), 3.68 –3.57 (m, 1H),
.47–3.41(m, 2H), 3.06 (s, 3H), 2.62 –2.51 (m, 1H), 2.31 (d, J
18.7 Hz, 1H), 2.18 (d, J = 18.6 Hz, 1H), 1.87 (dd, J = 13.4,
.3 Hz, 1H), 1.78 (d, J = 11.9 Hz, 1H), 1.69–1.65 (m, 1H),
.56 (dd, J = 12.9, 2.9 Hz, 1H), 1.44 (q, J = 12.2 Hz, 1H),
.25–1.20(m, 8H), 1.14 (d, J = 6.5 Hz, 4H), 1.09 (dd, J = 15.8,
.5 Hz, 5H), 0.95 (s, 9H), 0.16 (d, J = 3.4 Hz, 6H); C NMR
125 MHz, CDCl3) δ 203.5, 178.7, 133.6, 97.0, 91.4, 70.8,
63.6, 63.1, 51.6, 50.5, 45.1, 42.0, 42.0, 38.9, 38.2, 32.7, 26.8,
26.1, 20.6, 19.1, 18.4, 15.5, 15.4, -4.5, -4.9; HRMS (ESI) m/e
567.2775 [M+Na ] calcd for C26H44NaO4Si : 567.2782.
give product 26 (135 mg) in 95% yield; R = 0.60 (silica gel,
EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 6.02 (s,
f
1
3
=
3
1H), 5.65 – 5.48 (m, 1H), 5.24 (d, J = 8.8 Hz, 1H), 4.70 (dd, J
= 12.0, 5.3 Hz, 1H), 3.84 (dd, J = 9.1, 7.1 Hz, 1H), 3.67 – 3.51
(m, 1H), 3.49 – 3.35 (m, 2H), 2.33 (d, J = 18.7 Hz, 1H), 2.24 –
2.17 (m, 1H), 2.14 (d, J = 18.7 Hz, 1H), 2.10 (s, 3H), 2.01 (dd,
J = 20.7, 8.0 Hz, 1H), 1.97 – 1.85 (m, 2H), 1.55 (s, 3H), 1.45 –
1.33 (m, 2H), 1.24 – 1.15 (m, 6H), 1.14 (s, 3H), 0.93 (s, 9H),
3
1
1
4
1
3
(
1
3
0.12 (d, J = 1.7 Hz, 6H); C NMR (125 MHz, CDCl ) δ
3
203.5, 178.9, 170.9, 133.4, 132.1, 124.6, 97.0, 76.9, 70.3,
63.5, 63.2, 49.9, 47.4, 44.8, 42.6, 38.6, 26.2, 26.1, 20.7, 20.4,
18.6, 18.4, 15.4, 15.4, -4.5, -5.0; HRMS (ESI) m/e 529.2954
+
+
4.8. Synthesis of compound 23. To a solution of NaH (60 %,
9 mg, 0.48 mmol) in dry THF (4 ml) was added 22 (150 mg,
.32 mmol) slowly at 0 C, and the reaction mixture was
stirred at the same temperature for 0.5 h. To this solution was
+
+
1
0
[M+Na ] calcd for C H NaO Si : 529.2956.
28 46 6
o
4
.10. Syntheses of compounds 23 and 28. To a degassed
solution of 26 (600 mg, 1.18 mmol) in EtOH (30 ml) and
DIPEA (306 mg, 0.42 ml, 2.36 mmol) was added Pd(OH) /C
added CS (122 mg, 0.1 ml, 1.6 mmol) slowly, and the
2
resultant mixture was warmed up to room temperature, and
then stilled for 1 more hour. To this solution was MeI (227
mg, 0.1 ml, 1.6 mmol), and the resultant solution was stirred
overnight at room temperature. The reaction mixture was
quenched with a saturated solution of NH Cl, and then
extracted ether (3 x 30 ml). The combined organic layers were
washed with brine, and dried over Na SO The solvent was
removed under vacuum, and the residue was purified by a
flash column chromatography on silica gel (hexane/ethyl
acetate = 3/1) to give the product in 69% yield (based on the
recovered SM 22), together with the recovering starting
2
(
20%) (166 mg, 0.24 mmol), and the mixture was purged with
hydrogen, then stirred under a balloon pressure of hydrogen
for 2h at room temperature. After the reaction, the reaction
mixture was filtered through a pad of celite, and the filtrate
was concentrated in vacuum. The residue was purified by a
flash column chromatography on silica gel (hexane/ethyl
4
2
4.
acetate = 8/1) to give 23 (426 mg) in 71% yield; R (23)= 0.40
silica gel, EtOAc/hexanes = 1/2); and 28 (90 mg) in 15%
f
(
yield; R (28) = 0.20 (silica gel, EtOAc/hexanes = 1/2);
f
1
Compound 28: H NMR (500 MHz, CDCl ) δ 6.01 (s, 1H),
.66 (dd, J = 11.9, 5.1 Hz, 1H), 4.37 (t, J = 10.1 Hz, 1H), 3.88
3.75 (m, 1H), 3.62 – 3.51 (m, 1H), 3.46 – 3.34 (m, 2H), 2.31
d, J = 18.7 Hz, 1H), 2.16 (d, J = 18.7 Hz, 1H), 2.11 – 1.99 (m,
H), 1.81 (dd, J = 13.3, 2.8 Hz, 1H), 1.64 (d, J = 11.8 Hz, 1H),
.53 (dd, J = 14.2, 11.3 Hz, 2H), 1.32 (q, J = 12.1 Hz, 1H),
3
4
–
(
4
1
material 22 (84 mg); R = 0.60 (silica gel, EtOAc/hexanes =
f
1
/2);
To a solution of the product made above (54 mg, 0.09
mmol) in dry PhMe (6 ml) was added AIBN (3.0 mg, 0.019
mmol) and Bu SnH (57 mg, 0.051 ml, 0.19 mmol) slowly at
room temperature, and the resultant solution was heated to 90
C for 2 h with stirring. After cooling back to the room
temperature, the mixture was quenched by addition of a
saturated solution of NH Cl (6 ml), and resultant mixture was
extracted ether (3 x 10 ml). The organic layers were washed
3
1.24 – 1.16 (m, 7H), 1.12 (s, 3H), 1.08 (d, J = 13.6 Hz, 2H),
1
3
o
0.92 (s, 9H), 0.85 (d, J = 6.4 Hz, 3H), 0.11 (s, 6H); C NMR
(125 MHz, CDCl ) δ 203.7, 179.0, 170.6, 133.4, 97.0, 80.7,
70.9, 63.5, 63.1, 51.3, 50.4, 45.2, 41.6, 41.3, 37.5, 32.4, 26.8,
3
4
2
5
6.1, 20.7, 20.5, 18.4, 18.1, 15.4, -4.5, -5.0; HRMS (ESI) m/e
+
+
31.3112 [M+Na ] calcd for C H NaO Si : 531.3112.
with brine (3 ml), and dried over Na
SO
. The solvent was
28 48
6
2
4

ACCEPTED MANUSCRIPT
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8
9
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10
4.11. Synthesis of compound 27. To a degassed solution of 23
(330 mg, 0.73 mmol) in dry THF (50 ml) was added TBAF
–78 °C. The reaction mixture was quenched with a saturated
solution of NH Cl (10 ml), and the mixture was extracted with
Et O (3 x 10 ml). The combined organic layers were washed
4
o
(1M in THF, 1.46 ml, 1.46 mmol) at 0 C, and the reaction
2
mixture was stirred at the same temperature for 0.5 h. The
reaction was quenched by addition of a saturated solution of
NH Cl (20 ml), and the mixture was extracted CH Cl (3 x 20
with brine (3 ml), and dried over Na SO The solvent was
2
4.
removed under vacuum, and the residue was purified by a
flash column chromatography on silica gel (hexane/ethyl
acetate = 20/1) to give an enol triflate (209 mg) in 85% yield;
To a stirred solution of the enol triflate (120 mg, 0.21
mmol) made above in DMF/MeOH (4 mL, VDMF/VMeOH = 1/3)
at room temperature were added Et N (0.09 mL, 0.63 mmol)
and Pd(PPh ) (48 mg, 0.04 mmol), and the resultant mixture
was heated to 50 C, and then stirred at the same temperature
for 36 hours under a CO atmosphere (1 atm). After cooling
back to room temperature, the reaction mixture was quenched
4
2
2
ml). The combined organic layers were washed with brine (5
ml), and dried over Na SO . The solvent was removed under
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
vacuum, and the residue was purified by a flash column
chromate- graphy on silica gel (hexane/ethyl acetate = 50/1) to
give the crude product.
3
3
4
o
To a degassed solution of the crude product made above
(217 mg, 0.65 mmol) in EtOH (30 ml) and Na CO (412 mg,
2
3
3.91 mmol) was added Pd/C (10%) (137 mg, 0.13 mmol), and
the mixture was first purged with hydrogen, and then stirred
under a balloon of hydrogen for 10 h at room temperature. The
reaction mixture was filtered through a pad of celite, and the
filtrate was concentrated in vacuum. The residue was purified
by a flash column chromatography on silica gel (hexane/ethyl
with a saturated solution of NH Cl (5 ml), and the mixture was
was extracted with Et O (3 x 10 ml). The combined organic
4
2
layers were washed with brine (2 ml), and dried over Na SO
2
4.
The solvent was removed under vacuum, and the residue was
purified by a flash column chromatography on silica gel
(hexane/ethyl acetate = 30/1) to give an ester (56.8 mg) in
55% yield;
To a solution of the ester made above (56.8 mg, 0.11 mmol)
in dry THF (50 ml) was added TBAF (1M in THF, 0.22 ml,
acetate = 10/1) to give 27 (33.0 mg) in 55% yield; R = 0.60
f
1
(
silica gel, EtOAc/hexanes = 1/4); H NMR (500 MHz,
CDCl ) δ 4.80 (d, J = 2.5 Hz, 1H), 4.45 (d, J = 7.2 Hz, 1H),
3
4
3
=
.07 – 3.87 (m, 1H), 3.84 – 3.70 (m, 2H), 3.67 – 3.52 (m, 1H),
.49 – 3.34 (m, 1H), 2.82 (dd, J = 10.5, 4.7 Hz, 1H), 2.68 (d, J
10.3 Hz, 1H), 2.42 (d, J = 17.1 Hz, 1H), 1.99 (d, J = 17.1
o
0.22 mmol) at 0 C, and the resultant mixture was stirred for
12 h at 50 C. The reaction mixture was quenched with a
o
Hz, 1H), 1.80 – 1.64 (m, 3H), 1.53 (dd, J = 13.0, 3.0 Hz, 1H),
1.43 – 1.32 (m, 2H), 1.28 – 1.23 (m, 3H), 1.15 (t, J = 7.0 Hz,
3H), 1.12 (d, J = 5.4 Hz, 3H), 1.08 – 1.03 (m, 1H), 1.00 – 0.94
(m, 1H), 0.86 (t, J = 5.8 Hz, 3H), 0.83 – 0.75 (m, 1H), 0.67
saturated solution of NH Cl (4 ml), and extracted with CH Cl
4
2
2
(3 x 10 ml). The combined organic layers were washed with
brine (3 mL), and dried over Na SO4. The solvent was
removed under vacuum, and the residue was purified by a
flash column chromatography on silica gel (hexane/ethyl
2
1
3
(
dd, J = 24.4, 11.9 Hz, 1H), 0.51 – 0.47 (m, 1H); C NMR
(
125 MHz, CDCl ) δ 215.8, 102.6, 66.2, 65.8, 64.6, 52.7, 52.2,
acetate = 6/1) to give alcohol 12 (37.3 mg) as colorless oil in
3
1
4
1
9.5, 44.9, 43.1, 41.5, 38.5, 36.5, 35.5, 32.5, 26.6, 22.3, 20.9,
85% yield; R = 0.10 (silica gel, EtOAc/hexanes = 1/8); H
f
+
5.1, 14.9; HRMS (ESI) m/e 361.2351 [M+Na ] calcd for
NMR (500 MHz, CDCl ) δ 6.86 (d, J = 2.1 Hz, 1H), 5.25 (d, J
= 2.3 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.86 – 3.71 (m, 6H),
.71 – 3.65 (m, 1H), 3.49 – 3.40 (m, 1H), 3.31 (d, J = 9.9 Hz,
H), 2.70 (dd, J = 9.7, 5.4 Hz, 1H), 1.75 (d, J = 12.4 Hz, 1H),
3
+
4
C H NaO : 361.2349.
2
0
34
3
1
4
.12. Synthesis of compound 13. To a solution of the crude
alcohol 27 (170 mg, 0.5 mmol), Et N (152 mg, 0.21 ml, 1.5
3
1.69 (dd, J = 8.3, 4.7 Hz, 2H), 1.51 (dd, J = 12.9, 3.1 Hz, 1H),
1.28 (t, J = 7.0 Hz, 5H), 1.18 – 1.06 (m, 8H), 0.85 (d, J = 6.5
mmol), and in dry CH Cl (10 ml) was added dropwise
2
2
o
1
3
TBSOTf (145 mg, 0.13 ml, 0.55 mmol) at -78 C, and the
result mixture was stirred at -78 C for 30 min. The reaction
Hz, 3H), 0.81 (d, J = 12.1 Hz, 1H), 0.74 – 0.60 (m, 2H);
C
o
NMR (125 MHz, CDCl ) δ 166.2, 155.5, 132.1, 101.2, 66.7,
65.3, 64.6, 51.6, 51.2, 50.9, 49.3, 48.4, 42.9, 40.1, 35.6, 35.4,
32.2, 27.5, 22.4, 19.0, 15.1, 14.9; HRMS (ESI) m/e 403.2446
3
mixture was quenched by addition of water (10 ml), and the
mixture was extracted ether (3 x 10 ml). The combined
organic layers were washed with brine (3 ml), and dried over
Na SO The solvent was removed under vacuum, and residue
+
+
[M+Na ] calcd for C22H36NaO : 403.2445.
5
2
4.
was purified by a flash column chromatography on silica gel
hexane/ethyl acetate = 30/1) to give silylether 13 (193 mg) in
4.14. Syntheses of compounds 29 and 30. To a solution of
m-CPBA (77 %, 81 mg, 0.36 mmol) and NaHCO (15 mg,
0.18 mmol) in dry ClCH CH Cl (6 ml) was added a solution
of α,β-unsaturated methyl ester 12 (35 mg, 0.09 mmol) in dry
ClCH CH Cl (3 ml) under argon, and the mixture was then
warmed up to 45 C for 12 h with stirring. The reaction was
quenched by addition of a saturated NaHSO solution (5 ml)
followed by a saturated aqueous NaHCO (5 ml), and the
(
8
3
1
5% yield; R = 0.90 (silica gel, EtOAc/hexanes = 4/1); H
f
2
2
NMR (500 MHz, CDCl ) δ 4.73 (d, J = 1.6 Hz, 1H), 4.14 –
3
4
3
.02 (m, 1H), 3.85 – 3.75 (m, 1H), 3.66 – 3.52 (m, 2H), 3.41 –
.31 (m, 1H), 2.59 (d, J = 10.2 Hz, 1H), 2.37 – 2.25 (m, 2H),
2
2
o
2.08 (d, J = 15.9 Hz, 1H), 1.68 – 1.49 (m, 4H), 1.28 (dd, J =
11.7, 3.2 Hz, 2H), 1.23 (dd, J = 8.7, 5.3 Hz, 4H), 1.15 (t, J =
7.0 Hz, 4H), 1.04 (s, 3H), 0.89 (s, 9H), 0.81 (d, J = 6.5 Hz,
3
3
mixture was extracted with CH
Cl (3 x 15 ml). The organic
2
2
3
0
H), 0.77 – 0.69 (m, 1H), 0.61 (dd, J = 24.2, 11.9 Hz, 1H),
.45 (t, J = 10.1 Hz, 1H), 0.07 (t, J = 3.4 Hz, 6H); C NMR
layers were washed with brine (5 ml), and dried over Na SO
2
4.
13
The solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 15/1) to give product 29 (20 mg, 55%) and 30 (7 mg,
(
5
2
125 MHz, CDCl ) δ 216.0, 106.5, 69.8, 65.7, 64.6, 54.9, 53.6,
3
1.5, 45.3, 44.0, 41.5, 39.3, 36.9, 36.2, 33.4, 27.3, 26.9, 23.2,
1.8, 19.1, 16.3, 16.0, -3.6, -3.7; HRMS (ESI) m/e 475.3212
20%).
+
+
1
[
M+Na ] calcd for C H NaO Si : 475.3214.
29: H NMR (500 MHz, CDCl ) δ 4.70 (d, J = 8.4 Hz, 1H),
2
6
48
4
3
4
4
9
.59 (d, J = 7.0 Hz, 1H), 3.83 – 3.78 (m, 4H), 3.77 – 3.62 (m,
H), 3.56 (dd, J = 9.0, 7.1 Hz, 1H), 3.46 (s, 1H), 3.04 (dd, J =
.4, 7.2 Hz, 1H), 1.83 (dd, J = 9.4, 5.1 Hz, 1H), 1.75 – 1.66
m, 4H), 1.58 (dd, J = 13.0, 2.9 Hz, 1H), 1.24 (t, J = 7.1 Hz,
4H), 1.18 (t, J = 7.0 Hz, 3H), 1.13 – 1.09 (m, 1H), 1.07 (s,
3H), 0.98 – 0.93 (m, 1H), 0.87 (d, J = 6.5 Hz, 4H), 0.81 – 0.70
4.13. Synthesis of compound 12. To a stirred solution of
ketone 13 (200 mg, 0.44 mmol) in THF (4 ml) at –78 °C was
added LDA (2.0 M in THF, 0.33 ml, 0.66 mmol), and the
resultant mixture was stirred for 30 min. To this solution was
added a solution of Commins' reagent (207 mg, 0.53 mmol) in
THF (4 ml), and the resultant mixture was stirred for 1 h at
(
1
3
(m, 2H); C NMR (125 MHz, CDCl ) δ 169.3, 105.1, 69.0,
3

ACCEPTED MANUSCRIPT
1
2
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9
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1
2
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7
8
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2
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4
5
11
67.1, 64.5, 63.5, 62.4, 52.3, 49.5, 46.6, 44.3, 43.6, 42.8, 39.5,
(m, 2H), 1.48 – 1.38 (m, 1H), 1.21 (t, J = 7.0 Hz, 6H), 1.16
36.4, 35.2, 32.2, 27.4, 22.3, 16.4, 14.8, 14.7; HRMS (ESI) m/e
– 1.07 (m, 1H), 0.92 – 0.86 (m, 6H), 0.83 – 0.76 (m, 1H), 0.76
– 0.66 (m, 1H); C NMR (125 MHz, CDCl ) δ 174.6, 131.6,
127.1, 104.3, 81.3, 63.4, 62.8, 54.0, 51.8, 48.8, 47.8, 46.3,
44.8, 42.2, 37.0, 35.8, 32.9, 25.7, 22.4, 15.1, 15.0; HRMS
+
+
13
4
3
4
4
19.2404 [M+Na ] calcd for C H NaO : 419.2404.
22 36
6
3
1
0: H NMR (500 MHz, CDCl ) δ 6.66 (d, J = 1.4 Hz, 1H),
.89 (d, J = 3.0 Hz, 1H), 3.94 – 3.84 (m, 1H), 3.78 – 3.70 (m,
H), 3.65 – 3.57 (m, 2H), 3.43 – 3.33 (m, 1H), 2.88 (d, J = 5.2
3
+
+
(ESI) m/e 381.2635 [M+H ] calcd for C H O : 381.2636.
2
2
37
5
Hz, 1H), 2.65 (dd, J = 17.6, 11.2 Hz, 1H), 1.99 (dd, J = 15.9,
To a solution of 31’ (15 mg, 0.039 mmol) in CH Cl (4 ml)
was added DMP (33 mg, 0.079 mmol) at room temperature
under N , and the resultant mixture was stirred at room
temperature for 1.5 h. The reaction was quenched by addition
of a saturated solution of NaHCO (3 ml) slowly. The mixture
was extracted with Et O (3 x 3 ml), and the combined organic
2 2
5
1
–
6
.3 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.38 (dd, J = 6.6, 3.4 Hz,
H), 1.29 (dd, J = 11.3, 3.9 Hz, 1H), 1.25 – 1.15 (m, 3H), 1.14
0.97 (m, 3H), 0.93 (dd, J = 11.4, 2.9 Hz, 1H), 0.86 (d, J =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
2
1
3
.5 Hz, 3H), 0.78 (dd, J = 24.1, 12.0 Hz, 1H); C NMR (125
3
MHz, CDCl ) δ 210.9, 165.5, 150.4, 132.4, 101.8, 63.9, 63.3,
3
2
58.6, 54.7, 51.3, 48.9, 47.1, 45.6, 44.4, 34.9, 34.8, 32.3, 27.4,
layers were washed with brine (2 ml), and dried over Na SO
2
4.
+
22.2, 20.3, 15.2, 14.9; HRMS (ESI) m/e 379.2479 [M+H ]
The solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 10/1) to give product 10 (13 mg, 87%). R = 0.86
silica gel, EtOAc/hexanes = 1/8); H NMR (500 MHz,
CDCl ) δ 5.88 – 5.77 (m, 1H), 5.52 (d, J = 10.0 Hz, 1H), 4.53
+
calcd for C22
H
O
5
: 379.2476.
35
f
4
.15. Synthesis of compound 31. To a solution of alcohol 29
1
(
(35 mg, 0.088 mmol), DMAP (11 mg, 0.088 mmol) and Et N
3
3
(
89 mg, 0.12 ml, 0.88 mmol) in CH Cl (3 ml) was added
2
2
o
(d, J = 5.0 Hz, 1H), 3.80 – 3.69 (m, 4H), 3.69 – 3.58 (m, 1H),
MsCl (1.86 g, 16.2 mmol) slowly at 0 C, and the mixture was
then warmed up to room temperature, and stirred for 30 min.
The reaction was quenched by addition of water (2 ml), and
the mixture was extracted with ether (3 x 5ml). The combined
3
2
–
1
3
2
.56 – 3.45 (m, 2H), 3.38 – 3.28 (m, 1H), 2.94 – 2.82 (m, 1H),
.22 (dd, J = 11.0, 4.7 Hz, 1H), 1.84 (t, J = 11.5 Hz, 2H), 1.78
1.68 (m, 1H), 1.54 – 1.37 (m, 3H), 1.27 (dd, J = 9.9, 3.2 Hz,
H), 1.22 – 1.16 (m, 6H), 1.14 – 1.04 (m, 1H), 1.00 – 0.96 (m,
H), 0.89 (t, J = 10.1 Hz, 4H); C NMR (125 MHz, CDCl ) δ
12.1, 170.0, 132.1, 125.5, 103.6, 63.3, 62.7, 56.5, 52.3, 52.2,
48.4, 45.4, 41.8, 38.5, 36.6, 35.4, 32.9, 25.3, 22.3, 15.2, 15.1,
15.1; HRMS (ESI) m/e 401.2298 [M+Na ] calcd for
organic layers were washed with brine, and dried over Na SO
13
2
4.
3
The solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 10/1) to give a mesylate as a crude product (35 mg,
+
8
3%);
To a solution of the mesylate made above (35 mg, 0.076
+
C
H34NaO
: 401.2298.
22
5
mmol) in PhMe (3 ml) was added DBU (200 mg, 0.2 ml, 1.31
mmol) at room temperature, and the mixture was stirred for 36
4
.17. Synthesis of compound 37. To a solution of alkyne (226
mg, 1.22 mmol) in freshly distilled THF (5 ml) was added
n-butyl lithium (0.16 mL of a 2.5 M solution in hexanes, 1.22
mmol) at -78 C in a dropwise manner, and the mixture was
stirred at the same temperature for 45 min. the mixture was
then warmed up to -10 °C for 30 min, and then cooled back to
o
h at 120 C. The reaction was quenched by addition of a
o
saturated solution of NH Cl (5 ml), and the mixture was
4
extracted with Et O (3 x 5 ml). The combined extracts were
2
dried over Na SO . The solvent was removed under vacuum,
2
4
o
and the residue was purified by a flash chromatography on
-
78 C.
silica gel (hexane/ethyl acetate =15/1) to give 31 (19 mg,
To a solution of epoxide 38 (200 mg, 1.11 mmol) in THF (5
ml) was added the solution 41 prepared above via a cannular
at -78 °C, followed by addition of BF ·OEt (0.16 ml, 1.11
mmol) within 20 min. The resultant mixture was then stirred at
78 °C for 2 h. The reaction was quenched by addition of a
saturated solution of NaHCO (10 ml), and the mixture was
extracted with ether (3 x 10 ml). The combined organic layers
were washed with brine (5 ml), and dried over Na SO The
1
6
5%); R = 0.90 (silica gel, EtOAc/hexanes = 1/2); H NMR
f
(
500 MHz, CDCl ) δ 5.73 – 5.63 (m, 1H), 5.40 (d, J = 10.1
3
3
2
Hz, 1H), 4.61 (d, J = 8.2 Hz, 1H), 3.76 (d, J = 4.4 Hz, 3H),
3
7
.73 – 3.62 (m, 2H), 3.57 – 3.49 (m, 3H), 2.73 (dd, J=10.2,
.0, 1H), 1.86 – 1.71 (m, 3H), 1.70 – 1.65 (m, 2H), 1.51 – 1.42
-
3
(
m, 1H), 1.31 – 1.23 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H), 1.14 (t,
J = 7.0 Hz, 3H), 1.02 (s, 1H), 0.99 (s, 3H), 0.91 (d, J = 6.5,
2
4.
13
3
1
4
H), 0.79 (q, J = 12.3 Hz, 1H); C NMR (125 MHz, CDCl ) δ
3
solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel. (hexane:ethyl
69.1, 131.1, 126.4, 104.9, 68.3, 63.7, 62.8, 62.0, 52.1, 49.5,
6.1, 43.5, 42.3, 41.9, 36.2, 35.3, 32.8, 26.1, 22.4, 15.2, 15.2,
acetate = 50:1) to give alcohol 37 (242 mg) as colorless oil in
+
1
15.0; HRMS (ESI) m/e 401.2298 [M+Na ] calcd for
6
0% yield; R = 0.71 (silica gel, EtOAc/hexanes = 1/6); H
f
+
5
C H NaO : 401.2298.
2
2
34
NMR (500 MHz, CDCl ) δ = 4.77 (d, J = 9.8, 2H), 4.50 (d, J =
.2, 1H), 3.79 (s, 1H), 2.46 – 2.40 (m, 1H), 2.32 – 2.26 (m,
1H), 2.12 – 2.06 (m, 1H), 1.69 (d, J = 9.4, 2H), 1.66 (s, 3H),
1.62 (d, J = 12.3, 3H), 1.56 (d, J = 11.9, 1H), 1.45 – 1.39 (m,
2H), 1.37 (s, 3H), 0.92 (d, J = 6.7, 3H), 0.89 (s, 9H), 0.10 (d, J
5.3, 6H). C NMR (126 MHz, CDCl ) δ = 148.82, 111.76,
3
6
4
.16. Synthesis of compound 10. To a solution of the 31 (20
mg, 0.05 mmol) in a mixture of THF-H O (9/1, 2 ml) was
2
deoxygenated with Ar for 10 min, followed by addition of
SmI (0.1 M in THF, 2.0 mL, 0.2 mmol). The resultant mixture
13
2
=
3
was stirred at room temperature for 1h under Ar. The reaction
was quenched by addition of a saturated solution of NaHCO3
8
3
(
4.88, 80.60, 70.11, 59.31, 48.16, 42.37, 34.93, 32.57, 32.42,
2.08, 25.98, 25.85, 24.98, 23.00, 18.42, -4.48, -4.74; HRMS
(
3 ml), and the mixture was extracted with Et O (3 x 3 ml).
+
+
2
ESI) m/e 387.2683 [M+Na ] calcd for C H NaO Si :
22 40 2
The combined organic layers were washed with brine (2 ml),
and dried over Na SO The solvent was removed under
3
87.2690.
.18. Synthesis of compound 36. To a solution of Co (CO)
2
4.
vacuum, and the residue was purified by
a
flash
4
2
8
chromatography on silica gel (hexane/ethyl acetate = 10/1) to
(286 mg, 0.839 mmol) in dry PhMe (10 ml) was added a
solution of compound 37 (278 mg, 0.762 mmol) in PhMe (10
ml) in a dropwise manner, and the resultant mixture was
stirred at 120 C for 18 h. The reaction mixture was
concentrated under vacuum, and the residue was purified by a
flash chromatograph on silica gel (hexane/ethyl acetate = 10/1)
give 31’ as a crude product (15 mg, 76%). R = 0.20 (silica
f
1
gel, EtOAc/hexanes = 1/4); H NMR (500 MHz, CDCl ) δ
3
o
5
.77 – 5.68 (m, 1H), 5.42 (d, J = 10.0 Hz, 1H), 4.46 (d, J = 4.5
Hz, 1H), 4.16 (s, 1H), 3.76 – 3.62 (m, 5H), 3.58 – 3.47 (m,
H), 2.75 (dd, J = 7.8, 5.0 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.34
s, 1H), 2.22 – 2.13 (m, 1H), 1.84 – 1.72 (m, 3H), 1.68 – 1.63
2
(

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
12
+
to give product 36 (244 mg) as colorless oil in 82% yield; R =
f
0.52 (silica gel, EtOAc/hexanes = 1/6); H NMR (500 MHz,
21.9, 14.9; HRMS (ESI) m/e 347.2214 [M+Na ] calcd for
1
+
C
H
32NaO
: 347.2193.
19
4
CDCl ) δ = 4.74 (q, J = 6.3, 1H), 3.75 – 3.64 (m, 1H), 3.28 (t,
3
4
(
(
.21. Synthesis of compound 44. To a solution of alcohol 36
J = 10.2, 1H), 2.31 (t, J = 12.2, 1H), 2.21 (s, 1H), 2.17 (d, J =
2.2 g, 5.40 mmol), DMAP (660 mg, 5.40 mmol) and Et N
1
2
6
–
.8, 2H), 1.87 (s, 1H), 1.77 (d, J = 12.7, 1H), 1.66 – 1.56 (m,
H), 1.49 – 1.37 (m, 2H), 1.30 (d, J = 3.1, 1H), 1.26 (d, J =
.5, 3H), 1.10 (s, 3H), 0.91 (d, J = 6.5, 3H), 0.85 (s, 9H), 0.63
3
3.27 g, 32.4 mmol) in CH Cl (30 ml) was added MsCl (1.86
2
2
o
g, 16.2 mmol) slowly at 0 C, and the mixture then warmed up
to rt, and then stirred for an additional 2h. The reaction was
quenched by addition of water (15 ml), and the mixture was
extracted with ether (3 x 15 ml), and the combined organic
13
0.52 (m, 1H), -0.01 (d, J = 31.7, 6H); C NMR (126 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
CDCl ) δ = 206.3, 177.9, 141.3, 75.7, 63.4, 49.9, 49.3, 44.2,
3
4
4.1, 38.6, 35.1, 34.9, 32.3, 28.1, 25.9, 24.8, 22.6, 20.1, 18.3,
+
layers were washed with brine (5 ml), and dried over Na SO .
-4.8, -4.9; HRMS (ESI) m/e 393.2815 [M+H ] calcd for
2 4
+
The solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 10/1) to give a mesylate as a crude product, which
was then dissolved in MeCN (20 ml). To this solution was
added HF (48 wt %, 9 ml) at 0°C, and the resultant mixture
was stirred at room temperature for 30 min. The reaction was
quenched by addition of a saturated solution of NaHCO (30
ml), and the mixture was extracted with CH Cl (3 x 30 ml).
The combined organic layers were washed with brine (10 ml),
and dried over Na SO The solvent was removed under
C H O Si : 393.2819.
2
3
41
3
4
(
.19. Synthesis of compound 42. To a solution of alcohol 36
500 mg, 1.27 mmol), DMAP (78 mg, 0.637 mmol) and
DIPEA (329 mg, 2.55 mmol) in CH Cl (6 ml) was added
2
2
o
MOMCl (186 mg, 2.29 mmol) slowly at 0 C, and then
warmed to room temperature, and stirred for an additional 30
min. The reaction was quenched by addition of water (3 ml),
and the mixture was extracted with ether (3 x 5 ml). The
organic layers were washed with brine (3 ml), and dried over
Na SO The solvent was removed under vacuum, and the
3
2
2
2
4.
vacuum, and the residue was purified by
a
flash
2
4.
residue was purified by a flash chromatography on silica gel
(hexane/ethyl acetate = 10/1) to give a MOM ether (501 mg,
90%).
chromatography on silica gel (hexane/ethyl acetate = 4/1) to
give alcohol 44 (1.30 g, 65% for two steps); R = 0.23 (silica
f
1
gel, EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl
) δ =
3
To a solution of the MOM ether (320 mg, 0.734 mmol)
4.72 – 4.58 (m, 1H), 4.29 – 4.19 (m, 1H), 3.45 (dd, J = 13.2,
5.2, 1H), 3.30 (d, J = 8.8, 1H), 3.05 (s, 3H), 2.61 – 2.49 (m,
1H), 2.28 – 2.17 (m, 2H), 2.10 – 2.05 (m, 1H), 1.82 – 1.71 (m,
2H), 1.71 – 1.57 (m, 2H), 1.38 (d, J = 6.7, 3H), 1.35 – 1.27 (m,
1H), 1.14 (s, 3H), 1.05 – 0.97 (m, 1H), 0.96 – 0.88 (m, 3H),
0.71 – 0.62 (m, 1H). C NMR (126 MHz, CDCl ) δ = 208.17,
made above in CH CN (5 ml) was added HF (48 wt %, 3 ml)
3
o
slowly at 0 C, and the resultant mixture was then warmed up
to rt. The reaction was quenched by addition of a saturated
solution of NaHCO (5 ml), and the mixture was extracted
3
13
with CH Cl (3 x 5 ml). The combined organic layers were
2
2
3
washed with brine (3 ml), and dried over Na SO The solvent
173.12, 140.04, 83.79, 64.03, 49.75, 48.80, 43.97, 41.23,
38.65, 38.26, 34.61, 32.02, 31.92, 28.07, 24.06, 22.49, 20.28;
2
4.
was removed under vacuum, and the residue was purified by a
flash chromatography on silica gel (hexane/ethyl acetate = 4/1)
+
+
HRMS (ESI) m/e 357.1730 [M+H ] calcd for C H O S :
1
8
29
5
to give 42 (189 mg, 80%); R = 0.36 (silica gel, EtOAc/
357.1730.
f
1
hexanes = 1/2); H NMR (500 MHz, CDCl ) δ = 4.70 (t, J =
3
4.22. Synthesis of compound 45. To a degassed solution of
7.6, 1H), 4.57 (d, J = 2.8, 1H), 3.34 (d, J = 6.9, 3H), 3.22 –
3.11 (m, 2H), 2.21 (dd, J = 18.9, 7.7, 1H), 2.16 – 2.11 (m, 2H),
1.70 (d, J = 12.9, 1H), 1.57 – 1.47 (m, 2H), 1.32 (d, J = 6.7,
3H), 1.24 (dd, J = 12.6, 3.0, 1H), 1.21 – 1.18 (m, 1H), 1.06 (s,
alcohol 44 (1.05 g, 2.95 mmol) in EtOH (30 ml) and Et N
3
(
3.92 ml, 29.5 mmol) was added Pd/C (10%) (312 mg, 0.295
mmol), and the mixture was then purged with hydrogen, and
then stirred under a balloon of hydrogen at rt for 8 h. The
mixture was filtered through a pad of celite, and the filtrate
was concentrated in vacuum. The residue was purified by a
flash chromatography on silica gel (hexane/ethyl acetate =
3
H), 0.88 (dd, J =11.7, 2.8, 1H), 0.85 (d, J = 6.5, 3H), 0.49
13
(dd, J = 24.0, 11.9, 1H). C NMR (126 MHz, CDCl ) δ =
3
2
4
1
08.4, 176.3, 138.4, 96.1, 80.8, 77.3, 77.0, 76.8, 63.7, 55.5,
9.6, 48.9, 43.9, 42.2, 38.4, 34.7, 31.9, 31.5, 27.9, 23.6, 22.3,
+
1
0/1) to give alcohol 45 (0.74 g, 70%); R = 0.25 (silica gel,
f
1
9.9; HRMS (ESI) m/e 345.2023 [M+Na ] calcd for
+
4
EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ = 4.45 –
C H NaO : 345.2036.
3
1
9
30
4
.36 (m, 1H), 3.94 – 3.84 (m, 1H), 3.00 (s, 3H), 2.44 (d, J =
4.20. Synthesis of compound 43. To a degassed solution of
alcohol 42 (180 mg, 0.558 mmol) in EtOH (10 ml) and
18.1, 1H), 2.40 – 2.31 (m, 1H), 2.24 (dd, J = 11.6, 5.4, 1H),
2.18 – 2.10 (m, 1H), 2.08 – 2.02 (m, 2H), 1.99 (d, J = 18.1,
1H), 1.76 – 1.71 (m, 1H), 1.63 – 1.54 (m, 2H), 1.37 – 1.32 (m,
1H), 1.31 (d, J = 6.4, 3H), 1.24 (s, 1H), 1.15 – 1.08 (m, 4H),
0.89 (d, J = 6.6, 3H), 0.88 – 0.78 (m, 2H), 0.68 – 0.58 (m, 1H).
C NMR (126 MHz, CDCl ) δ = 219.4, 83.2, 68.4, 54.9, 51.9,
46.5, 43.8, 41.5, 38.8, 38.8, 38.4, 34.8, 31.9, 29.9, 27.1, 22.5,
Na
.0558 mmol), and the mixture was purged with hydrogen,
and then was stirred under a balloon pressure of hydrogen for
h at rt. The reaction was worked by filtration of the reaction
CO (592 mg, 5.58 mmol) was added Pd/C (10%) (59 mg,
2
3
0
1
3
8
3
mixture then through a pad of celite, and the filtrate was
concentrated in vacuum. The residue was purified by a flash
chromatography on silica gel. (hexane/ethyl acetate = 10/1) to
+
21.3, 20.5; HRMS (ESI) m/e 359.1885 [M+H ] calcd for
+
C H O S : 359.1887.
1
8
31
5
give alcohol 43 (161 mg, 89%); R = 0.40 (silica gel, EtOAc/
f
1
4.23. Synthesis of compound 46. To a solution of the crude
alcohol 45 (591 mg, 1.65 mmol) and Et N (333 mg, 3.30
hexanes = 1/2); H NMR (500 MHz, CDCl ) δ = 4.70 (t, J =
3
7
3
.6, 1H), 4.62 – 4.48 (m, 2H), 3.34 (d, J = 6.9, 3H), 3.22 –
.11 (m, 2H), 2.21 (dd, J = 18.9, 7.7, 1H), 2.16 – 2.11 (m, 2H),
3
mmol) in dry CH Cl (10 ml) was added TBSOTf (436 mg,
2 2
o
1.65 mmol) at -78 C in a dropwise manner, and the reaction
1.70 (d, J = 12.9, 1H), 1.57 – 1.47 (m, 2H), 1.32 (d, J = 6.7,
3H), 1.24 (dd, J = 12.6, 3.0, 1H), 1.21 – 1.18 (m, 1H), 1.06 (s,
3H), 0.88 (dd, J = 11.7, 2.8, 1H), 0.85 (d, J = 6.5, 3H), 0.80
o
mixture was stirred at -78 C for 30 min. The reaction was
quenched with water (2 ml), and the mixture was extracted
with ether (3 x 5 ml). The combined organic layers were
washed with brine (3 ml), and dried over Na SO The solvent
was removed under vacuum, and the residue was purified by a
flash chromatography on silica gel. (hexane:ethyl acetate =
1
3
(dd, J = 7.0, 5.3, 1H), 0.49 (dd, J = 24.0, 11.9, 1H). C NMR
126 MHz, CDCl ) δ = 220.7, 95.9, 81.1, 68.0, 55.9, 55.7,
(
2
4.
3
5
3.4, 50.7, 46.4, 42.9, 40.2, 39.2, 34.9, 32.3, 30.7, 27.9, 22.8,

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
13
4:1) to give the silylether 46 (701 mg, 90%); R
= 0.85 (silica
gel, EtOAc/hexanes = 1/1); H NMR (500 MHz, CDCl ) δ =
.40 – 4.31 (m, 1H), 4.00 (d, J = 4.7, 1H), 3.00 (s, 3H), 2.38 –
2.99 (s, 3H), 2.59 – 2.53 (m, 1H), 2.30 – 2.24 (m, 1H), 2.05
f
1
(d, J = 1.9, 1H), 1.75 – 1.67 (m, 3H), 1.57 – 1.51 (m, 1H), 1.46
(d, J = 3.4, 1H), 1.24 (d, J = 5.1, 1H), 1.21 (d, J = 6.3, 3H),
1.12 – 1.08 (m, 1H), 1.05 (s, 3H), 0.92 – 0.89 (m, 4H), 0.88 (s,
9H), 0.85 (s, 2H), 0.76 – 0.68 (m, 1H), 0.05 (s, 6H); C NMR
(126 MHz, CDCl ) δ = 169.41, 83.90, 68.45, 67.56, 62.12,
52.47, 48.09, 42.85, 42.62, 42.32, 40.89, 38.88, 38.21, 34.64,
31.72, 29.84, 27.56, 26.03, 22.55, 21.64, 18.18, 15.80, -4.67,
-4.70; HRMS (ESI) m/e 531.2802 [M+H ] calcd for
3
4
2
–
1
.31 (m, 2H), 2.29 – 2.20 (m, 1H), 2.10 (d, J = 10.7, 1H), 2.07
1.97 (m, 2H), 1.93 (d, J = 17.0, 1H), 1.72 (d, J = 12.8, 1H),
.62 – 1.54 (m, 2H), 1.31 (d, J = 6.3, 4H), 1.09 (s, 4H), 0.88
1
3
3
(d, J = 6.5, 3H), 0.85 (s, 9H), 0.83 – 0.78 (m, 2H), 0.61 (q, J =
13
1
2
3
2.0, 1H), 0.04 (s, 6H); C NMR (126 MHz, CDCl ) δ =
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
+
16.5, 83.8, 68.2, 55.4, 53.2, 45.9, 43.6, 41.2, 38.9, 38.5, 38.4,
4.8, 31.9, 29.8, 26.9, 26.0, 22.6, 21.5, 20.5, 18.2, -4.2, -4.7;
+
C H O SSi : 531.2806.
2
6
47
7
+
+
HRMS (ESI) m/e 473.2759 [M+H ] calcd for C H O SSi :
2
4
45
5
4.26. Synthesis of compound 33. To a solution of 48 (67 mg,
.13 mmol) in PhMe (3 ml) was added DBU at rt, and the
resultant mixture was stirred at 120 C for 48 h. The reaction
was quenched by addition of a saturated solution of NH Cl (5
ml), and the mixture was extracted with Et O (3 x 5 ml). The
4
73.2751.
0
o
4
.24. Synthesis of compound 47. To a stirred solution of
ketone 46 (780 mg, 1.65 mmol) in THF (5 ml) at –78 °C was
added KHMDS (1.0 M in THF, 3.30 mmol, 3.30 ml), and the
resultant mixture was then stirred at the same temperature for
4
2
combined extracts were dried over Na SO . The solvent was
2
4
1
h. To this solution was added a solution of Commins' reagent
removed under vacuum, and the residue was purified by a
flash column chromatography on silica gel to give an olefin as
a crude product.
To a solution of the above residue in THF-H O (5 ml, 9/1)
was deoxygenated with Ar for 10 min, followed by addition of
SmI (0.1 M in THF, 2.5 ml, 0.25 mmol). The resultant
mixture was stirred at rt under Ar for 1h. The reaction was
(966 mg, 2.47 mmol) in THF (2 ml), and the resultant mixture
was stirred at –78 °C for 1 h. The reaction mixture was
quenched by addition of a saturated solution of NH Cl (6 ml),
4
2
and the mixture was extracted with Et O (3 x 5 ml). The
2
combined organic layers were washed with brine (2 ml), and
dried over Na SO The solvent was removed under vacuum,
2
2
4.
and the residue was purified by a flash chromatography on
silica gel (hexane/ethyl acetate = 20/1) to give a triflate (270
mg, 0.446 mmol), which was then dissolved in a mixed
solvent of DMF/MeOH (12 ml, 1/3). To this solution was
added Et N (0.18 ml, 1.34 mmol) and Pd(PPh ) (106 mg,
quenched by addition of a saturated solution of NaHCO
(5
3
ml), and the mixture was extracted with Et O (3 x 5 ml). The
combined organic layers were washed with brine (3 ml), and
dried over Na SO The solvent was removed under vacuum,
and the residue was purified by a flash chromatography on
silica gel (hexane/ethyl acetate = 10/1) to give an alcohol (40
mg, 0.092 mmol), which was then dissolved in CH Cl (4 ml).
To this solution was added DMP (77 mg, 0.183 mmol) at rt
under N , and the resultant mixture was stirred at rt for 1.5 h.
The reaction was quenched by addition of a saturated solution
of NaHCO (5 ml), and the mixture was then extracted with
Et O (3 x 5 ml). The combined organic layers were washed
with brine (2 ml), and dried over Na SO The solvent was
removed under vacuum, and the residue was purified by a
flash chromatography on silica gel (hexane/ethyl acetate
=25/1) to give product 33 (25 mg) in 46% yield for three steps.
R = 0.86 (silica gel, EtOAc/hexanes = 1/8); H NMR (500
MHz, CDCl ) δ = 5.64 (d, J = 9.7, 1H), 5.41 (d, J = 10.0, 1H),
4.13 (d, J = 3.9, 1H), 4.00 (d, J = 4.2, 1H), 3.69 (s, 3H), 2.69 –
2.57 (m, 1H), 2.32 – 2.19 (m, 2H), 2.12 (d, J = 10.1, 1H), 1.76
(d, J = 11.3, 3H), 1.66 (d, J = 10.9, 2H), 1.42 (s, 1H), 1.25 (s,
1H), 1.22 (d, J = 6.3, 3H), 1.12 (t, J = 10.0, 1H), 0.89 (s, 15H),
2
2
4.
3
3 4
o
0
.0892 mmol), and the resultant mixture was heated to 50 C,
and stirred for 12 h under a CO atmosphere (1 atm). The
reaction was quenched by addition of a saturated solution of
NH Cl (10 ml), and the mixture was extracted with Et O (3 x
2
2
4
2
2
1
0 ml). The combined organic layers were washed with brine,
and dried over Na SO The solvent was removed under
2
4.
3
vacuum, and the
residue was purified by a flash
2
chromatography on silica gel (hexane/ethyl acetate = 10/1) to
2
4.
give product 47 (149 mg) in 65% yield; R = 0.62 (silica gel,
f
1
EtOAc/hexanes = 1/4); H NMR (500 MHz, CDCl
) δ = 6.70
3
(s, 1H), 4.57 (d, J = 6.1, 1H), 4.40 (d, J = 5.6, 1H), 3.68 (s,
1
3
2
1
1
3
0
H), 2.98 (s, 3H), 2.76 (d, J = 8.1, 1H), 2.44 (d, J = 7.1, 1H),
.19 (d, J = 14.0, 1H), 2.02 (d, J = 12.0, 1H), 1.94 – 1.85 (m,
H), 1.69 (d, J = 12.7, 1H), 1.59 (d, J = 11.1, 1H), 1.51 (d, J =
1.3, 1H), 1.31 (s, 1H), 1.24 (t, J = 10.9, 2H), 1.19 (d, J = 6.3,
H), 1.07 (s, 3H), 0.96 (t, J = 10.9, 1H), 0.86 (d, J = 6.2, 3H),
.79 (s, 9H), 0.69 – 0.59 (m, 1H), -0.07 (d, J = 48.0, 6H).
f
3
13
C
13
NMR (126 MHz, CDCl ) δ = 166.2, 152.8, 134.8, 85.1, 66.4,
0.75 – 0.66 (m, 1H), 0.07 (d, J = 6.2, 6H). C NMR (126
MHz, CDCl ) δ = 174.9, 132.1, 127.5, 81.3, 69.1, 55.0, 52.9,
51.9, 47.2, 46.0, 45.3, 42.3, 37.2, 35.9, 33.1, 29.8, 26.1, 25.9,
22.6, 21.4, 18.3, 15.4, -4.3, -4.5; HRMS (ESI) m/e 435.2923
3
5
2
5
5.1, 51.3, 48.2, 46.6, 42.8, 40.6, 39.4, 38.8, 34.9, 32.7, 32.0,
3
7.7, 25.9, 22.8, 22.5, 19.4, 18.1, -4.0, -5.2; HRMS (ESI) m/e
+
+
15.2850 [M+H ] calcd for C H O SSi : 515.2857.
2
6
47
6
+
+
[M+H ] calcd for C H O Si : 435.2925.
2
5
43
4
4
.25. Synthesis of compound 48. To a mixture of m-CPBA
(283 mg, 1.63 mmol) and NaHCO (69 mg, 0.816mmol) in dry
4.27. Synthesis of compound 49. To a stirred solution of 33 (20
mg, 0.046 mmol) and DMAP (29 mg, 0.23 mmol) in toluene
(1 mL) was added 7 (113 mg, 0.46 mmol) at room
temperature, and the mixture was heated to 90 C, and then
stirred for 30 h. The reaction mixture was concentrated under
3
ClCH CH Cl (6 ml), was added a solution of α,β-unsaturated
2
2
methyl ester 47 (210 mg, 0.408 mmol) in dry CH Cl (2 ml)
2
2
o
under argon at room temperature, and the resultant mixture
o
was heated to 45 C, and then stirred for 12 h, the reaction
mixture was quenched by addition of a saturated solution of
NaHSO (5 ml). The mixture was extracted with Et O (3 x 5
vacuum, and the residue was purified by
a
flash
chromatography on silica gel (hexane/ethyl acetate = 20/1) to
give product 49 (22 mg, 73%). R = 0.55 (silica gel,
EtOAc/hexanes = 1/8); H NMR (500 MHz, CDCl ) δ = 5.91 –
5.82 (m, 1H), 5.46 (t, J = 8.5, 1H), 5.00 – 4.91 (m, 1H), 4.17 –
4.06 (m, 1H), 4.04 – 3.95 (m, 1H), 3.92 – 3.84 (m, 1H), 3.66
(s, 3H), 3.32 (s, 3H), 2.90 – 2.79 (m, 1H), 2.60 – 2.42 (m, 1H),
2.41 – 2.32 (m, 1H), 1.77 (d, J = 4.3, 2H), 1.66 (d, J = 13.6,
1H), 1.61 – 1.56 (m, 1H), 1.52 – 1.46 (m, 1H), 1.43 – 1.36 (m,
3
2
ml), and the combined organic layers were washed with brine
(2 ml), and dried over Na SO The solvent was removed under
f
1
2
4.
3
vacuum, and the residue was purified by
chromatography on silica gel (hexane/ethyl acetate = 15/1) to
give product 48 (162 mg) in 75% yield; R = 0.46 (silica gel,
EtOAc/hexanes = 1/4); H NMR (500 MHz, CDCl ) δ = 4.41 –
a
flash
f
1
3
4
.33 (m, 1H), 4.04 – 3.96 (m, 1H), 3.76 (s, 3H), 3.35 (s, 1H),

ACCEPTED MANUSCRIPT
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2H), 1.34 – 1.30 (m, 2H), 1.28 (s, 2H), 1.25 (s, 3H), 1.23 (d, J
= 6.4, 3H), 1.20 – 1.15 (m, 1H), 0.88 (d, J = 7.9, 18H), 0.08 –
(Grant Nos. JCYJ20130329180217059, GJHS20120628101
-219325, ZYC201105170335A, ZYC201105170358A).
1
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6
.04 (m, 12H). C NMR (126 MHz, CDCl ) δ = 213.8, 169.7,
3
68.8, 131.3, 127.2, 69.5, 62.2, 60.4, 55.4, 52.8, 51.8, 51.3,
4.6, 41.7, 37.9, 36.6, 35.3, 34.8, 32.9, 29.7, 25.9, 25.7, 25.3,
3.2, 22.3, 18.1, 15.2, -3.9, -4.9, -5.6, -5.7; HRMS (ESI) m/e
References and notes
1
2
.
.
Jang, J.-H.; Asami, Y.; Jiang, J.-P.; Kim, S.-O.; Shin, S.-S.;
Hashizume, D.; Muroi, M.; Saito, T.; Oh, H.; Kim. B. Y.; Osada,
H.; Ahn, J. S. J. Am. Chem. Soc. 2011, 133, 6865.
Deng, J.; Zhu, B.; Lu, Z.-Y.; Yu, H.-X.; Li, A. J. Am. Chem. Soc.
2012, 134, 920.
(a) Xu, J.; Caro-Diaz, J. E.; Trzoss, L.; Theodorakis, E. A. J. A.
Chem. Soc. 2012, 134, 5072. (b) Xu, J.; Caro-Diaz, E. J. E.;
Lacoske, M. H.; Hung, C.-I.; Jamora, C.; Theodorakis, E. A.
Chem. Sci. 2012, 3, 3378. (c) Caro-Diaz, E. J. E.; Aung, A.; Xu,
J.; Varghese, S.; Theodorakis,E. A. Org. Chem. Front. 2014, 1,
135.
(a) Yin, J.; Wang, C.; Kong, L.-L.; Cai, S.-J.; Gao, S.-H. Angew.
Chem. Int. Ed. 2012, 51, 7786. (b) Yin, J.; Kong, L. L.; Wang, C.;
Shi, Y. B.; Cai, S. J.; Gao, S. H. Chem. Eur. J. 2013, 19, 13040.
+
+
50.4275 [M+H ] calcd for C H NO Si : 650.4267.
3
5
46
6
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
4
.28. Syntheses of (+)-fusarisetin A (1) and C3-epi-(+)-
fusarisetin A (50). To a solution of disilylether 49 (9 mg,
0.0138 mmol) in AcOH/THF/H O (2.5 ml, 3:1:1) was added
3.
2
o
HF (1 ml, 48 wt %) slowly at 0 C, and the mixture was then
warmed up to rt, and stirred for an additional 30 min. The
reaction was quenched by addition of a saturated solution of
NaHCO (5 ml), and extracted with CH Cl (3 x 5 ml). The
3
2
2
combined organic layers were washed with brine (2 ml), and
dried over Na SO The solvent was removed under vacuum,
4
.
2
4.
and the residue was purified chromatography on silica gel
CH Cl /acetone, from 10/1 to 4/1) to give a diol (5 mg, 0.012
(c) Yin, J.; Gao, S.-H. Synlett 2014, 25, 1.
(
2
2
5.
For the synthesis of fusarisetin A, see reference 2-4; For the
references for the synthesis of superstolides A, see: Chen, L.;
Hua, Z.; Li, G.; Jin, Z. Org. Lett.2011, 13, 3580. Selected
references for the synthesis of chlorothricolide see: (b) Roush, W.
R.; Hall, S. E. J. Am. Chem. Soc. 1981, 103, 5200. (c) Snider, B.
B.; Burbaum, B. W. J. Org. Chem. 1983, 48, 4370. (d)
Boeckman, Jr. R. K.; Barta, T. E. J. Org. Chem. 1985, 50, 3421.
e) Marshall, J. A.; Grote, J.; Audia, J. E. J. Am. Chem. Soc.
987, 109, 1186. (f) Takeda, K.; Igarashi, Y.; Okazaki, K.;
Yoshis, E.; Yamaguchi, K. J. Org. Chem. 1990, 55, 3431. (g)
Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457.
(h) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120,
mmol, 86%), which was then dissolved in dry MeOH. To this
solution was added NaOMe (0.5 M in MeOH, 0.12 ml, 0.06
o
mmol) slowly at 0 C, and the mixture was stirred at the same
temperature for 10 min. After stirring at room temperature for
1 h, the reaction was quenched by addition of a saturated
solution of NH
5 ml). The combined organic layers were washed with brine,
and dried over Na SO The solvent was removed under
Cl (0.5 ml), and mixture was extracted EA (3 x
4
(
1
2
4.
vacuum, and the residue was purified by
a
flash
chromatography on silica gel (CH Cl /acetone from 10/1 to
2
2
4
/1) to give (+)-fusarisetin A (1) (2.0 mg, 43%); and
7
411. (i) Boeckman, Jr. R. K.; Shao, P.; Wrobleski, S. T.;
C3-epi-(+)-fusarisetin A (50) (1.4 mg, 30%).
Boehmler, D. J.; Heintzelma, G. R.; Barbosa, A. J. J. Am. Chem.
Soc. 2006, 128, 10572. Fortotal synthesis of equsetin, see: (j)
Turos, E.; Audia, J. E.; Danishefsky, S. J. J. Am. Chem. Soc.
1989, 111, 8231. (k) .Yuki, K.; Shindo, M.; Shishido, K.
Tetrahedron Lett. 2001, 42, 2517. (l) Burke, L. T.; Dixon, D. J.;
Ley, S. V.; Rodriguez, F. Org. Lett. 2000, 2, 3611.
(a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J.
Chem. Soc. Perkin Trans. 11973, 977. (b) Khand, I. U.; Knox, G.
R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc. D.: Chem.
Commun. 1971, 36a. For reviews on the Pauson−Khand reaction:
R (+)-fusarisetin A (1) = 0.28 (silica gel, CH Cl /acetone =
f
2
2
1
1
5
/4). H NMR (500 MHz, MeOD) δ = 5.85 – 5.75 (m, 1H),
.57 (d, J = 9.9, 1H), 4.35 (q, J = 12.5, 6.3, 1H), 3.90 – 3.81
(m, 2H), 3.59 (t, J = 5.0, 1H), 2.87 – 2.81 (m, 1H), 2.68 (dd, J
=
10.9, 4.6, 1H), 1.88 (d, J = 13.1, 2H), 1.75 (d, J = 12.8, 1H),
6
.
1.58 – 1.48 (m, 3H), 1.46 (d, J = 6.5, 3H), 1.14 – 1.07 (m, 1H),
0.98 (d, J = 7.9, 4H), 0.93 (t, J = 5.9, 3H), 0.84 (d, J = 11.9,
1H). C NMR (126 MHz, MeOD) δ = 214.1, 172.1, 133.6,
1
3
(
a) Pauson, P. L. Tetrahedron 1985, 41, 5855. (b) Schore, N. E.
126.9, 109.7, 79.7, 76.5, 71.7, 61.8, 56.4, 55.3, 44.7, 43.3,
Org. React. 1991, 40, 1. (c) Schore, N. E. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, p 1037. (d) Schore, N. E. Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G.A.,
Wilkinson, G., Eds.; Elsevier: New York, 1995; Vol. 12, p
703.(e) Jeong, N. Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany,
3
4
9.1, 38.0, 34.3, 29.9, 26.6, 22.9, 17.8, 14.4; HRMS (ESI) m/e
+
+
12.2089 [M+Na ] calcd for C H NNaO : 412.2079.
22 31
5
R (C3-epi-(+)-fusarisetin A (50) = 0.20 (silica gel, CH Cl /
acetone = 1/4). H NMR (500 MHz, MeOD) δ = 5.79 (s, 1H),
f
2
2
1
5
3
2
1
.55 (d, J = 9.9, 1H), 4.35 – 4.25 (m, 1H), 4.00 – 3.93 (m, 1H),
.79 – 3.71 (m, 1H), 3.68 – 3.59 (m, 1H), 2.97 (s, 3H), 2.82 –
.73 (m, 1H), 2.64 (d, J = 10.8, 1H), 1.86 (d, J = 13.5, 2H),
.74 (d, J = 11.3, 1H), 1.57 (d, J = 12.6, 1H), 1.51 – 1.44 (m,
H), 1.43 (d, J = 6.4, 3H), 1.09 (dd, J = 20.7, 8.5, 1H), 0.98 (d,
1
297.
998; pp 560. (h) Chung, Y. K. Coord. Chem. Rev. 1999, 188,
7
.
(a) Xiao, Q.; Ren, W. W.; Chen, Z. X.; Sun, T. W.; Li, Y.; Ye, Q.
D.; Gong, J. X.; Meng, F. K.; You, L.; Liu, Y. F.; Zhao, M. Z.;
Xu, L. M.; Shan, Z. H.; Shi, Y.; Tang, Y. F.; Chen, J. H.; Yang,
Z. Angew. Chem. Int. Ed. 2011, 50, 7373. (b) Turlington, M.;
Du, Y.; Ostrum, S. G.; Santosh, V.; Wren, K.; Lin, T.; Sabat, M.;
Pu, L. J. Am. Chem. Soc. 2011, 133, 11780. (c) Hayashi, Y.;
Inagaki, F.; Mukai, C. Org. Lett. 2011, 13, 1778. (d) Plummer, C.
Soheili, W. A.; Leighton, J. L. Org. Lett. 2012, 14, 2462. (e)
Darses, B.; Michaelides, I. N.; Sladojevich, F.; Ward, J. W.;
Rzepa, P. R.; Dixon, D. J. Org. Lett.2012, 14, 1684.(f) Liu, Q.;
Yue, G.; Wu, N.; Lin, G.; Li, Y.; Quan, J.; Li, C.-C.; Wang, G.;
Yang, Z. Angew. Chem. Int. Ed. 2012, 51, 12072.
2
1
3
J = 6.9, 4H), 0.92 (d, J = 6.5, 3H), 0.85 – 0.78 (m, 1H).
C
NMR (101 MHz, MeOD) δ = 213.5, 172.4, 133.5, 126.8,
109.7, 79.7, 76.8, 70.8, 60.4, 55.6, 54.9, 44.5, 43.2, 39.1, 37.9,
36.4, 34.2, 28.9, 26.5, 22.8, 17.4, 14.1; HRMS (ESI) m/e
+
+
4
12.2089 [M+Na ] calcd for C H NNaO : 412.2079.
22 31 5
Supplementary Material
Experimental procedures, spectral and other characterization
data can be found in the online version at ???.
8
9
.
.
(a) Schore, N. E.; Croudace, M. C. J. Org. Chem. 1981, 46,
5
436.
For asymmetric version controlled by a chiral fragment present
at the substrate, see: (b) Marco-Costelles, J.; Ruiz, J.
Tetrahedron Lett. 1998, 55, 919. (c) Kaneda, K.; Honda, T.
Tetrahedron 2008, 64, 11589. (d) Jia, X.; Williams, R. M.
Tetrahedron: Asymmetry 2008, 19, 2901. For asymmetric
version controlled by an external chiral promoter, see: (e) O’Neil,
I. A.; Miller, N. D.; Barkley, J. V.; Low, C. M. R.; Kalindjian, S.
Acknowledgments
This work was supported by the NSF of China (Grant no.
2
2
1372016), 973 Program (Grant Nos. 2010CB83201 and
012CB722602), and Shenzhen Basic Research Program

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Trans. I 1975, 1574.
2

ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Supporting Information
Asymmetric Total Synthesis of (+)-Fusarisetin A
a
a
a
a
a,b
Jun Huang, Lichao Fang, Jianxian Gong, Chuang chuang Li and Zhen Yang
a
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University
Shenzhen Graduate School, Shenzhen, 518055, China.
b
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing
National Laboratory for Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences,
Peking University, Beijing, 100871, China.
E-mail: licc@pku.edu.cn, zyang@pku.edu.cn
Tel: +86 755 2603 2971;
Fax: + 86 10 6275 9105
Table of Contents:
General
Information …………………………………………………………………………………………….S2
Experimental Procedures …………….…………………………………………………………....S3-21
NMR Spectra …………………………………………………………………………...……..…. S22-97

ACCEPTED MANUSCRIPT
General Information
All reactions were carried out under a nitrogen atmosphere with dry solvents under anhydrous
conditions, unless otherwise noted. All the chemicals were purchased commercially, and used without
further purification. Anhydrous THF and dioxane were distilled from sodium-benzophenone, and
dichloromethane was distilled from calcium hydride. Yields refer to chromatographically, unless
otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Tsingdao
silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of
phosphomolybdic acid and cerium sulfate, and heat as developing agents. Tsingdao silica gel (60,
particle size 0.040–0.063 mm) was used for flash column chromatography.
Reagents were purchased at the highest commercial quality and used without further purification,
1
13
unless otherwise stated. NMR spectra were recorded on either a Brüker Advance 400 ( H: 400 MHz, C:
1
13
1
00 MHz), Brüker Advance 500 ( H: 500 MHz, C 125 MHz). Mass spectrometric data were obtained
using Bruker Apex IV RTMS. The following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad.

ACCEPTED MANUSCRIPT
Synthesis of Compound 19:
To a solution of S- (―)-carvone (17) (1.0 g, 1 mL, 6.66 mmol) in dry distilled THF (20 mL) was added LDA (2 M
o
in THF, 3.66 mL, 7.32 mmol) in a dropwise manner at -78 C, and the solution was stirred at the same temperature for
o
1
h. To this solution was added bromide 18 (1.45 g, 7.99 mmol) in THF (10mL) slowly at -78 C, and the resultant
solution was stirred at -78 °C overnight. The reaction was quenched with a saturated solution of NH Cl (50 mL), and
4
the mixture was extracted ether (3 x 30 mL). The combined organic layers were washed with brine (15 mL), and dried
ocer Na SO The solvent was removed under vacuum, and the residue was purified by a flash chromatography on
2
4.
silica gel (hexane/ethyl acetate =8/1) to give ketoamide 19 (1.44 g)as yellow oil in 86% yield; R = 0.50 (silica gel,
f
1
EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 6.66 (d, J = 5.6 Hz, 1H), 4.81 (d, J = 0.8 Hz, 2H), 3.72 (s, 3H),
3
3
1
1
.16 (s, 3H), 3.06 – 2.95 (m, 1H), 2.83 – 2.70 (m, 2H), 2.53 – 2.42 (m, 1H), 2.37 – 2.21 (m, 2H), 1.77 – 1.71 (m, 3H),
1
3
.69 (s, 3H); C NMR (125 MHz, CDCl ) δ 200.4, 173.1, 145.4, 143.1, 134.7, 113.8, 60.9, 48.3, 45.8, 32.2, 31.3, 29.4,
3
+
+
8.1, 15.8; HRMS (ESI) m/e 252.1594 [M+H ] calcd for C H NO : 252.1594.
1
4
22
3
Synthesis of Compound 20a:
To a solution of ketoamide 19 (20.0 g, 79.7 mmol) in dry THF (300 mL) was added LiAlH (6.1 g, 159.4 mmol) at
4
o
-
78 C carefully, and the resultant mixture was stirred at the same temperature for 3 h. The reaction was quenched by
slow addition of a saturated sodium potassium tartrate (100 mL), and the mixture was then stirred at room temperature
for 3 h. The mixture was extracted CH Cl (3 x 200 mL), and the combined extracts were dried over Na SO .The
2
2
2
4
solvent was removed under vacuum, and the residue was used in next step without further purification.
To a solution of diethoxypropynyl (3.56 g, 27.8 mmol) in freshly distilled THF (25 mL) was added n-butyllithium
o
(
2.5 M in hexane, 11.1 mL, 27.8 mmol) in a dropwise manner at -78 C, and the solution was stirred at the same
temperature for 1 h. To this solution was a solution of hydroxyl aldehyde (1.8 g, 9.29 mmol) in THF (5 mL ), and the
resultant mixture was gradually warmed up to 0 °C, and the mixture was continually stirred at the same temperature for
3
h. The reaction mixture was quenched by addition of a saturated solution of NH Cl (40 mL), and the mixture was
4
extracted CH Cl (3 x 20 mL). The combined organic layers were washed with brine (10 mL), and dried over Na SO
4.
2
2
2
The solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel
(
hexane/ethyl acetate = 15/1) to give alcohol 20a (1.54 g) as colorless oil in 52% yield; R = 0.75 (silica gel,
f
1
EtOAc/hexanes = 1/3). H NMR (500 MHz, CDCl ) δ 5.49 (d, J = 4.0 Hz, 1H), 5.29 (s, 1H), 4.81 (s, 1H), 4.78 (s, 1H),
3
4
2
6
1
.54 (dd, J = 9.0, 4.0 Hz, 1H), 3.89 (d, J = 7.4 Hz, 1H), 3.77 – 3.67 (m, 2H), 3.63 – 3.52 (m, 2H), 2.20 (m, 1H), 2.17 –
.06 (m, 1H), 2.06 – 2.00 (m, 1H), 1.97 – 1.89 (m, 1H), 1.77 – 1.70 (m, 4H), 1.68 – 1.61 (m, 4H), 1.23 (q, J = 7.1 Hz,
1
3
H); C NMR (125 MHz, CDCl ) δ 146.9, 135.1, 123.4, 113.3, 91.4, 87.0, 79.6, 76.1, 62.1, 61.0, 47.3, 43.1, 41.5, 30.9,
3
+
+
9.3, 18.5, 15.0; HRMS (ESI) m/e 345.2039 [M+Na ] calcd for C H NaO : 345.2036.
1
9
30
4
Synthesis of Compound 15:

ACCEPTED MANUSCRIPT
To a solution of the alcohol 20a (167.0 mg, 0.519 mmol) and Et N (261 mg, 2.59 mmol) in dry CH Cl (15 mL)
3
2
2
o
was added TBSOTf (136.9 mg, 0.519 mmol) at -78 C in a dropwise manner, and the reaction mixture was stirred at the
same temperature for 0.5 h. The reaction was quenched by addition of water (50 mL), and the mixture was extracted
with ether (3 x 50 ml). The combined organic layers were washed with brine (5 mL), and dried over Na SO . The
2
4
solvent was removed under vacuum, and the residue was purified by a flash column chromatography on silica gel
(
hexane/ethyl acetate = 50/1) to give enyne 15 (237.0 mg) in 90% yield; R = 0.95 (silica gel, EtOAc/hexanes = 1/5).
f
1
H NMR (500 MHz, CDCl ) δ 5.49 (s, 1H), 5.27 (d, J = 1.0 Hz, 1H), 4.84 – 4.73 (m, 2H), 4.61 (dd, J = 7.1, 6.3 Hz,
3
1H), 3.95 (d, J = 5.7 Hz, 1H), 3.75 – 3.68 (m, 2H), 3.57 (m, 2H), 2.28 – 2.21 (m, 1H), 2.21 – 2.10 (m, 1H), 2.01 (dd, J
=
9.0, 6.1 Hz, 1H), 1.94 (d, J = 17.4 Hz, 1H), 1.80 – 1.76 (m, 2H), 1.73 (s, 3H), 1.68 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H),
1
3
0.90 (s, 9H), 0.17 (d, J = 3.1 Hz, 9H), 0.13 (d, J = 20.0 Hz, 6H); C NMR (125 MHz, CDCl ) δ 147.4, 135.0, 123.4,
3
1
12.0, 91.5, 87.6, 80.2, 76.2, 61.2, 60.8, 60.7, 45.2, 40.8, 40.2, 29.3, 25.9, 21.1, 19.8, 18.1, 15.0, 1.0, -4.2, -4.8; HRMS
+
+
(ESI) m/e 531.3298 [M+Na ] calcd for C H NaO Si : 531.3296.
28 52 4 2
Synthesis of Compound 14:
To a solution of Co (CO) (2.0 g, 5.90 mmol) in dry PhMe (300 mL) was added a solution of compound 15 (2.5 g,
2
8
o
5
.36 mmol) in PhMe (10 mL), and the resultant mixture was stirred at 120 C for 15 h. After cooling to room
temperature, the reaction mixture was concentrated under vacuum, and the residue was purified by a flash
chromatograph on silica gel (hexane:ethyl acetate = 10:1) to give product 14 (1.63 g) as colorless oil in 60% yield; R =
f
1
0
.70 (silica gel, EtOAc/hexanes = 1/3); H NMR (500 MHz, CDCl ) δ 6.05 (s, 1H), 5.52 – 5.39 (m, 1H), 4.73 (dd, J =
3
11.8, 5.4 Hz, 1H), 3.89 – 3.76 (m, 2H), 3.68 – 3.59 (m, 1H),3.52 – 3.38 (m, 2H), 2.57 – 2.50 (m, 1H), 2.32 (d, J = 18.7
Hz, 1H), 2.13 (d, J = 18.7 Hz, 1H), 2.05 – 1.94 (m, 1H), 1.87 (dd, J = 12.1, 5.1 Hz, 1H), 1.83 – 1.73 (m, 1H), 1.65 (s,
3
H), 1.37 – 1.26 (m, 2H), 1.21 (t, J = 6.9 Hz, 6H), 1.12 (s, 3H), 0.95 (s, 10H), 0.17 (s, 9H), 0.14 (d, J = 3.0 Hz, 6H);
13
C NMR (125 MHz, CDCl ) δ 203.9, 180.1, 135.4, 133.1, 122.8, 97.0, 77.6, 70.6, 63.4, 63.0, 50.0, 47.7, 44.9, 43.7,
3
+
41.5, 26.5, 26.0, 20.5, 20.3, 18.4, 15.5, 15.4, 1.0, -4.5, -5.1; HRMS (ESI) m/e 559.3247 [M+Na ] calcd for
+
C H NaO Si : 559.3245.
29
52
5
2
Synthesis of Compound 21:

ACCEPTED MANUSCRIPT
To a solution of 14 (1.5 g, 2.79 mmol) in MeOH (30 mL) was added K CO (0.5 g, 3.64 mmol) at room
2
3
temperature, and the mixture was for 1.5 h at the same temperature for 1.5 h. The reaction was quenched by addition of
a saturated solution of NH Cl (20 mL), and the resultant mixture was extracted CH Cl (3 x 20 mL). The combined
4
2
2
organic layers were washed with brine (10 mL), and dried over Na SO The solvent was removed under vacuum, and
2
4.
the residue was purified by a flash column chromatography on silica gel (hexane:ethyl acetate = 8:1) to give 21 (1.04 g)
1
as colorless oil in 80% yield; R = 0.40 (silica gel, EtOAc/hexanes = 1/3); H NMR (500 MHz, CDCl ) δ 6.06 (s, 1H),
f
3
5.57 – 5.36 (m, 1H), 4.75 (dd, J = 11.9, 5.4 Hz, 1H), 3.90 – 3.80 (m, 1H), 3.73 (s, 1H), 3.63 – 3.60 (m, 1H), 3.50 – 3.40
(m, 2H), 2.69 – 2.65 (m, 1H), 2.32 (d, J = 18.7 Hz, 1H), 2.14 (d, J = 18.7 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.92 – 1.81 (m,
1
0
4
H), 1.71 (s, 4H), 1.35 (tt, J = 8.5, 7.4 Hz, 2H), 1.20 (dd, J = 15.0, 7.1 Hz, 7H), 1.14 (s, 3H), 0.95 (d, J = 2.7 Hz, 10H),
13
.15 (d, J = 3.5 Hz, 6H); C NMR (125 MHz, CDCl ) δ 204.0, 180.2, 135.2, 133.1, 122.9, 97.0, 76.0, 70.6, 63.4, 63.1,
3
+
9.9, 47.8, 44.9, 43.3, 41.4, 26.5, 26.1, 20.4, 18.8, 18.3, 15.5, 15.4, -4.6, -4.9; HRMS (ESI) m/e 487.2851 [M+Na ]
+
calcd for C H NaO Si : 487.2850.
2
6
44
5
Synthesis of Compound 22:
To a degassed solution of alcohol 21 (600.0 mg, 1.29 mmol) in PhH (15 mL) was added Rh(PPh ) Cl (60.0 mg,
3
3
0
.06 mmol) and NaHCO (217.0 mg, 2.6 mmol), and the resultant mixture was purged with hydrogen, and then stirred
3
o
at 45 C under a balloon of hydrogen for 10 h. After the reaction, the mixture was concentrated under vacuum, and the
residue was purified by a flash column chromatography on silica gel (hexane:ethyl acetate = 6:1) to give 22 (578.0 mg)
1
in 96% yield; R = 0.40 (silica gel, EtOAc/hexanes = 1/2). H NMR (500 MHz, CDCl ) δ 6.07 (s, 1H), 4.72 (dd, J =
f
3
1
1.8, 5.3 Hz, 1H), 3.87 – 3.77 (m, 1H), 3.67 – 3.58 (m, 1H), 3.50 – 3.39 (m, 2H), 2.79 (t, J = 7.2 Hz, 1H), 2.69 – 2.51
m, 1H), 2.32 (d, J = 18.7 Hz, 1H), 2.16 (d, J = 18.7 Hz, 1H), 1.84 – 1.74 (m, 2H), 1.69 (s, 1H), 1.52 (dd, J = 14.8, 4.6
Hz, 2H), 1.35 (dd, J = 11.3, 5.2 Hz, 1H), 1.30 (d, J = 12.1 Hz, 1H), 1.24 – 1.18 (m, 7H), 1.13 (s, 3H), 1.01 (d, J = 6.5
(
1
3
Hz, 4H), 0.95 (s, 9H), 0.15 (d, J = 2.5 Hz, 6H); C NMR (125 MHz, CDCl ) δ 204.1, 180.1, 133.2, 97.1, 80.2, 71.2,
3
6
4
3.4, 63.1, 51.7, 50.4, 45.4, 43.4, 42.3, 39.8, 32.7, 27.1, 26.1, 20.4, 18.4, 18.4, 15.5, 15.4, -4.5, -4.9; HRMS (ESI) m/e
+
+
89.2995 [M+Na ] calcd for C H NaO Si : 489.3007.
26
46
5
Synthesis of Compound 24:
To a solution of alcohol 22 (50.0 mg, 0.107 mmol), DMAP (13 mg, 0.107 mmol) and Et N (110 mg, 0.15 mL, 1.1
3
o
mmol) in CH Cl (3 mL) was added MsCl (61 mg, 0.54 mmol) slowly at 0 C, and the mixture was gradually warmed
2
2
up to room temperature. After stirring at room temperature for 2h, the reaction mixture was quenched with water (5
mL), and resultant mixture was extracted ether (3 x 10 mL). The combined organic layers were washed with brine (5
mL), and dried over Na SO The solvent was removed under vacuum, and the residue was purified by a flash column
2
4.

ACCEPTED MANUSCRIPT
chromatography on silica gel (hexane:ethyl acetate = 3:1) to give product 24 (54.0 mg) in 93% yield; R = 0.40 (silica
f
1
gel, EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 6.05 (s, 1H), 4.72 (dd, J = 11.8, 5.3 Hz, 1H), 4.12 (dd, J =
3
1
1
1
4
1
1
2.9, 7.2 Hz, 1H), 3.83 (dd, J = 9.0, 7.1 Hz, 1H), 3.68 – 3.57 (m, 1H), 3.47 – 3.41 (m, 2H), 3.06 (s, 3H), 2.62 – 2.51 (m,
H), 2.31 (d, J = 18.7 Hz, 1H), 2.18 (d, J = 18.6 Hz, 1H), 1.87 (dd, J = 13.4, 3.3 Hz, 1H), 1.78 (d, J = 11.9 Hz, 1H),
.69 – 1.65 (m, 1H), 1.56 (dd, J = 12.9, 2.9 Hz, 1H), 1.44 (q, J = 12.2 Hz, 1H), 1.25 – 1.20 (m, 8H), 1.14 (d, J = 6.5 Hz,
1
3
H), 1.09 (dd, J = 15.8, 4.5 Hz, 5H), 0.95 (s, 9H), 0.16 (d, J = 3.4 Hz, 6H); C NMR (125 MHz, CDCl ) δ 203.5,
3
78.7, 133.6, 97.0, 91.4, 70.8, 63.6, 63.1, 51.6, 50.5, 45.1, 42.0, 42.0, 38.9, 38.2, 32.7, 26.8, 26.1, 20.6, 19.1, 18.4, 15.5,
+
+
5.4, -4.5, -4.9; HRMS (ESI) m/e 567.2775 [M+Na ] calcd for C H NaO Si : 567.2782.
2
6
44
4
Synthesis of Compound 23:
To a solution of NaH (60 %, 19 mg, 0.48 mmol) in dry THF (4 mL) was added 22 (150 mg, 0.32 mmol) slowly at
o
0
0
C, and the reaction mixture was stirred at the same temperature for 0.5 h. To this solution was added CS (122 mg,
2
.1 mL, 1.6 mmol) slowly, and the resultant mixture was warmed up to room temperature, and then stilled for 1 more
hour. To this solution was MeI (227 mg, 0.1 mL, 1.6 mmol), and the resultant solution was stilled overnight at room
temperature. The reaction mixture was quenched with a saturated solution of NH Cl, and then extracted ether (3 x 30
4
mL). The combined organic layers were washed with brine, and dried over Na SO The solvent was removed under
2
4.
vacuum, and the residue was purified by a flash column chromatography on silica gel (hexane/ethyl acetate = 3/1) to
give the product in 69% yield (based on the recovered SM 22), together with the recovering starting material 22 (84
mg); R = 0.60 (silica gel, EtOAc/hexanes = 1/2);
f
To a solution of the product made above (54.0 mg, 0.09 mmol) in dry PhMe (6 mL) was added AIBN (3.0 mg,
0
.019 mmol) and Bu SnH (57.0 mg, 0.051 mL, 0.19 mmol) slowly at room temperature, and the resultant solution was
3
o
heated to 90 C for 2 h with stirring. After cooling back to the room temperature, the mixture was quenched by addition
of a saturated solution of NH Cl (6 mL), and resultant mixture was extracted ether (3 x 10 mL). The organic layers
4
were washed with brine (3 mL), and dried over Na SO . The solvent was removed under vacuum, and the residue was
2
4
purified by a flash column chromatography on silica gel (hexane/ethyl acetate = 8/1) to give the product 23 (27.0 mg)
1
in 62% yield; R = 0.80 (silica gel, EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 6.06 (s, 1H), 4.73 (dd, J =
f
3
1
1.7, 5.1 Hz, 1H), 3.89 – 3.76 (m, 1H), 3.70 – 3.55 (m, 1H), 3.53 – 3.34 (m, 2H), 2.32 (d, J = 18.7 Hz, 1H), 2.14 (d, J =
8.7 Hz, 1H), 2.07 – 1.94 (m, 1H), 1.75 (d, J = 12.7 Hz, 1H), 1.69 (d, J = 12.8 Hz, 1H), 1.58 (d, J = 13.0 Hz, 1H), 1.52
d, J = 11.4 Hz, 1H), 1.37 (d, J = 10.6 Hz, 1H), 1.36 – 1.29 (m, 1H), 1.21 (dd, J = 12.0, 6.4 Hz, 7H), 1.11 (s, 3H), 0.95
1
(
(
1
3
s, 10H), 0.89 (t, J = 8.3 Hz, 3H), 0.83 (d, J = 9.5 Hz, 2H), 0.68 (q, J = 11.9 Hz, 1H), 0.14 (s, 6H); C NMR (125 MHz,
CDCl ) δ 204.3, 180.6, 133.1, 97.1, 71.2, 63.3, 63.0, 53.2, 50.3, 46.3, 45.5, 42.2, 36.4, 34.8, 32.5, 27.7, 26.1, 22.2, 20.4,
3
+
+
1
8.4, 15.4, 15.4, -4.5, -5.0; HRMS (ESI) m/e 473.2059 [M+Na ] calcd for C H NaO Si : 473.3058.
26 46 4
Synthesis of Compound 26:

ACCEPTED MANUSCRIPT
To a solution of alcohol 21 (130.0 mg, 0.28 mmol), DMAP (34 mg, 0.28 mmol) and Et N (142 mg, 0.2 mL, 1.4
3
o
mmol) in CH Cl (3 mL) was added Ac O (57 mg, 0.053 mL, 0.56 mmol) slowly at 0 C, and the mixture was
2
2
2
gradually warmed up to room temperature. After stirring at the room temperature for 2h, the mixture was quenched by
addition of water (5 mL), and extracted ether (3 x 10 mL). The combined organic layers were washed with brine (3
mL), and dried over Na SO The solvent was removed under vacuum, and the residue was purified by a flash column
2
4.
chromatography on silica gel (hexane/ethyl acetate = 5/1) to give product 26 (135 mg) in 95% yield; R = 0.60 (silica
f
1
gel, EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 6.02 (s, 1H), 5.65 – 5.48 (m, 1H), 5.24 (d, J = 8.8 Hz, 1H),
3
4
.70 (dd, J = 12.0, 5.3 Hz, 1H), 3.84 (dd, J = 9.1, 7.1 Hz, 1H), 3.67 – 3.51 (m, 1H), 3.49 – 3.35 (m, 2H), 2.33 (d, J =
8.7 Hz, 1H), 2.24 – 2.17 (m, 1H), 2.14 (d, J = 18.7 Hz, 1H), 2.10 (s, 3H), 2.01 (dd, J = 20.7, 8.0 Hz, 1H), 1.97 – 1.85
1
(m, 2H), 1.55 (s, 3H), 1.45 – 1.33 (m, 2H), 1.24 – 1.15 (m, 6H), 1.14 (s, 3H), 0.93 (s, 9H), 0.12 (d, J = 1.7 Hz, 6H);
1
4
3C NMR (125 MHz, CDCl ) δ 203.5, 178.9, 170.9, 133.4, 132.1, 124.6, 97.0, 76.9, 70.3, 63.5, 63.2, 49.9, 47.4, 44.8,
3
+
2.6, 38.6, 26.2, 26.1, 20.7, 20.4, 18.6, 18.4, 15.4, 15.4, -4.5, -5.0; HRMS (ESI) m/e 529.2954 [M+Na ] calcd for
+
C H NaO Si : 529.2956.
28
46
6
Synthesis of Compound 23 and 28:
To a degassed solution of 26 (600.0 mg, 1.18 mmol) in EtOH (30 mL) and DIPEA (306 mg, 0.42 mL, 2.36 mmol)
was added Pd(OH) /C (20%) (166 mg, 0.24 mmol), and the mixture was purged with hydrogen, then stirred under a
2
balloon of hydrogen for 2h at room temperature. After the reaction, the reaction mixture was filtered through a pad of
Celite, and the filtrate was concentrated in vacuum. The residue was purified by a flash column chromatography on
silica gel (hexane/ethyl acetate = 8/1) to give 23 (426.0 mg) in 71% yield; R (23) = 0.40 (silica gel, EtOAc/hexanes =
f
1
/2); and 28 (90 mg) in 15% yield; R (28) = 0.20 (silica gel, EtOAc/hexanes = 1/2);
f
1
Compound 28: H NMR (500 MHz, CDCl ) δ 6.01 (s, 1H), 4.66 (dd, J = 11.9, 5.1 Hz, 1H), 4.37 (t, J = 10.1 Hz, 1H),
3
3
2
.88 – 3.75 (m, 1H), 3.62 – 3.51 (m, 1H), 3.46 – 3.34 (m, 2H), 2.31 (d, J = 18.7 Hz, 1H), 2.16 (d, J = 18.7 Hz, 1H),
.11 – 1.99 (m, 4H), 1.81 (dd, J = 13.3, 2.8 Hz, 1H), 1.64 (d, J = 11.8 Hz, 1H), 1.53 (dd, J = 14.2, 11.3 Hz, 2H), 1.32 (q,
J = 12.1 Hz, 1H), 1.24 – 1.16 (m, 7H), 1.12 (s, 3H), 1.08 (d, J = 13.6 Hz, 2H), 0.92 (s, 9H), 0.85 (d, J = 6.4 Hz, 3H),
1
3
0
4
.11 (s, 6H); C NMR (125 MHz, CDCl ) δ 203.7, 179.0, 170.6, 133.4, 97.0, 80.7, 70.9, 63.5, 63.1, 51.3, 50.4, 45.2,
3
+
1.6, 41.3, 37.5, 32.4, 26.8, 26.1, 20.7, 20.5, 18.4, 18.1, 15.4, -4.5, -5.0; HRMS (ESI) m/e 531.3112 [M+Na ] calcd for
+
C H NaO Si : 531.3112.
28
48
6
Synthesis of Compound 27:

ACCEPTED MANUSCRIPT
To a degassed solution of 23 (330 mg, 0.73 mmol) in dry THF (50 mL) was added TBAF (1M in THF, 1.46 mL,
o
1
.46 mmol) at 0 C, and the reaction mixture was stirred at the same temperature for 0.5 h. The reaction was quenched
by addition of a saturated solution of NH Cl (20 mL), and the mixture was extracted CH Cl (3 x 20 mL). The
4
2
2
combined organic layers were washed with brine (5 mL), and dried over Na SO . The solvent was removed under
2
4
vacuum, and the residue was purified by a flash column chromatography on silica gel (hexane/ethyl acetate = 50/1) to
give the crude product.
To a degassed solution of the crude product made above (217.0 mg, 0.65 mmol) in EtOH (30 mL) and Na CO3
2
(412.0 mg, 3.91 mmol) was added Pd/C (10%) (137.0 mg, 0.13 mmol), and the mixture was first purged with hydrogen,
and then stirred under a balloon of hydrogen for 10 h at room temperature. The reaction mixture was filtered through a
pad of Celite, and the filtrate was concentrated in vacuum. The residue was purified by a flash column chromatography
on silica gel (hexane/ethyl acetate = 10/1) to give 27 (33.0 mg) in 55% yield; R = 0.60 (silica gel, EtOAc/hexanes =
f
1
1
/4); H NMR (500 MHz, CDCl ) δ 4.80 (d, J = 2.5 Hz, 1H), 4.45 (d, J = 7.2 Hz, 1H), 4.07 – 3.87 (m, 1H), 3.84 – 3.70
3
(
m, 2H), 3.67 – 3.52 (m, 1H), 3.49 – 3.34 (m, 1H), 2.82 (dd, J = 10.5, 4.7 Hz, 1H), 2.68 (d, J = 10.3 Hz, 1H), 2.42 (d, J
17.1 Hz, 1H), 1.99 (d, J = 17.1 Hz, 1H), 1.80 – 1.64 (m, 3H), 1.53 (dd, J = 13.0, 3.0 Hz, 1H), 1.43 – 1.32 (m, 2H),
.28 – 1.23 (m, 3H), 1.15 (t, J = 7.0 Hz, 3H), 1.12 (d, J = 5.4 Hz, 3H), 1.08 – 1.03 (m, 1H), 1.00 – 0.94 (m, 1H), 0.86 (t,
=
1
1
3
J = 5.8 Hz, 3H), 0.83 – 0.75 (m, 1H), 0.67 (dd, J = 24.4, 11.9 Hz, 1H), 0.51 – 0.47 (m, 1H); C NMR (125 MHz,
CDCl ) δ 215.8, 102.6, 66.2, 65.8, 64.6, 52.7, 52.2, 49.5, 44.9, 43.1, 41.5, 38.5, 36.5, 35.5, 32.5, 26.6, 22.3, 20.9, 15.1,
3
+
+
1
4.9; HRMS (ESI) m/e 361.2351 [M+Na ] calcd for C H NaO : 361.2349.
20 34 4
Synthesis of Compound 13:
To a solution of the crude alcohol 27 (170.0 mg, 0.5 mmol), Et N (152 mg, 0.21 mL, 1.5 mmol), and in dry
3
o
CH Cl (10 mL) was added dropwise TBSOTf (145 mg, 0.13 mL, 0.55 mmol) at -78 C, and the result mixture was
2
2
o
stirred at -78 C for 0.5h. The reaction mixture was quenched by addition of water (10 mL), and the mixture was
extracted ether (3 x 10 mL). The combined organic layers were washed with brine (3 mL), and dried over Na SO The
2
4.
solvent was removed under vacuum, and residue was purified by a flash column chromatography on silica gel
(
hexane/ethyl acetate = 30/1) to give silylether 13 (193.0 mg) in 85% yield; R = 0.90 (silica gel, EtOAc/hexanes = 4/1);
f
1
H NMR (500 MHz, CDCl ) δ 4.73 (d, J = 1.6 Hz, 1H), 4.14 – 4.02 (m, 1H), 3.85 – 3.75 (m, 1H), 3.66 – 3.52 (m, 2H),
3
3
1
.41 – 3.31 (m, 1H), 2.59 (d, J = 10.2 Hz, 1H), 2.37 – 2.25 (m, 2H), 2.08 (d, J = 15.9 Hz, 1H), 1.68 – 1.49 (m, 4H),
.28 (dd, J = 11.7, 3.2 Hz, 2H), 1.23 (dd, J = 8.7, 5.3 Hz, 4H), 1.15 (t, J = 7.0 Hz, 4H), 1.04 (s, 3H), 0.89 (s, 9H), 0.81
(
d, J = 6.5 Hz, 3H), 0.77 – 0.69 (m, 1H), 0.61 (dd, J = 24.2, 11.9 Hz, 1H), 0.45 (t, J = 10.1 Hz, 1H), 0.07 (t, J = 3.4 Hz,
1
3
6
3
4
H); C NMR (125 MHz, CDCl ) δ 216.0, 106.5, 69.8, 65.7, 64.6, 54.9, 53.6, 51.5, 45.3, 44.0, 41.5, 39.3, 36.9, 36.2,
3
+
+
3.4, 27.3, 26.9, 23.2, 21.8, 19.1, 16.3, 16.0, -3.6, -3.7; HRMS (ESI) m/e 475.3212 [M+Na ] calcd for C H NaO Si :
2
6
48
4
75.3214.

ACCEPTED MANUSCRIPT
Synthesis of Compound 12:
To a stirred solution of ketone 13 (200.0 mg, 0.44 mmol) in THF (4 mL) at –78 °C was added LDA (2.0 M in THF,
0.33 mL, 0.66 mmol), and the resultant mixture was stirred for 0.5 h. To this solution was added a solution of
Commins' reagent (207 mg, 0.53 mmol) in THF (4 mL), and the resultant mixture was stirred for 1 h at –78 °C. The
reaction mixture was quenched with a saturated solution of NH Cl (10 mL), and the mixture was extracted with Et O
4
2
(
3 x 10 mL). The combined organic layers were washed with brine (3 mL), and dried over Na SO The solvent was
2 4.
removed under vacuum, and the residue was purified by a flash column chromatography on silica gel (hexane/ethyl
acetate = 20/1) to give enol triflate (209.0 mg) in 85% yield;
To a stirred solution of enol triflate (120.0 mg, 0.21 mmol) in DMF/MeOH (4 mL, VDMF/VMeOH = 1/3) at room
temperature were added Et N (0.09 mL, 0.63 mmol) and Pd(PPh ) (48.0 mg, 0.04 mmol), and the resultant mixture
3
3 4
o
was heated to 50 C, and then stirred at the same temperature for 36 hours under a CO atmosphere (1 atm). After
cooling back to room temperature, the reaction mixture was quenched with a saturated solution of NH Cl (5 mL), and
4
the mixture was was extracted 3x with Et O (3 x 10 mL). The combined organic layers were washed with brine (2 mL),
2
and dried over Na SO The solvent was removed under vacuum, and the residue was purified by a flash column
2
4.
chromatography on silica gel (hexane/ethyl acetate = 30/1) to give ester product (56.8 mg) in 55% yield;
To a solution of ester product made above (57.0 mg, 0.11 mmol) in dry THF (50 mL) was added TBAF (1M in
o
o
THF, 0.22 mL, 0.22 mmol) at 0 C, and the resultant mixture was stirred for 12 h at 50 C. The reaction mixture was
quenched with a saturated solution of NH Cl (4 mL), and extracted 3x with CH Cl (3 x 10 mL). The combined organic
4
2
2
layers were washed with brine (3 mL), and dried over Na SO The solvent was removed under vacuum, and the
2
4.
residue was purified by a flash column chromatography on silica gel (hexane/ethyl acetate = 6/1) to give alcohol 12
1
(
37.3 mg) as colorless oil in 85% yield; R = 0.10 (silica gel, EtOAc/hexanes = 1/8); H NMR (500 MHz, CDCl ) δ
f
3
6
3
8
0
6
.86 (d, J = 2.1 Hz, 1H), 5.25 (d, J = 2.3 Hz, 1H), 5.20 (d, J = 7.2 Hz, 1H), 3.86 – 3.71 (m, 6H), 3.71 – 3.65 (m, 1H),
.49 – 3.40 (m, 1H), 3.31 (d, J = 9.9 Hz, 1H), 2.70 (dd, J = 9.7, 5.4 Hz, 1H), 1.75 (d, J = 12.4 Hz, 1H), 1.69 (dd, J =
.3, 4.7 Hz, 2H), 1.51 (dd, J = 12.9, 3.1 Hz, 1H), 1.28 (t, J = 7.0 Hz, 5H), 1.18 – 1.06 (m, 8H), 0.85 (d, J = 6.5 Hz, 3H),
13
.81 (d, J = 12.1 Hz, 1H), 0.74 – 0.60 (m, 2H); C NMR (125 MHz, CDCl ) δ 166.2, 155.5, 132.1, 101.2, 66.7, 65.3,
3
4.6, 51.6, 51.2, 50.9, 49.3, 48.4, 42.9, 40.1, 35.6, 35.4, 32.2, 27.5, 22.4, 19.0, 15.1, 14.9; HRMS (ESI) m/e 403.2446
+
+
[M+Na ] calcd for C H NaO : 403.2445.
22 36 5
Synthesis of Compound 29 and 30:
To a solution of m-CPBA (77 %, 81.0 mg, 0.36 mmol) and NaHCO (15 mg, 0.18 mmol) in dry ClCH CH Cl (6
3
2
2
mL) was added a solution of α,β -unsaturated methyl ester 12 (35.0 mg, 0.09 mmol) in dry ClCH CH Cl (3 mL) under
2
2

ACCEPTED MANUSCRIPT
o
argon, and the mixture was then warmed up to 45 C for 12 h with stirring. The reaction was quenched by addition of a
saturated NaHSO solution (5 mL) followed by a saturated aqueous NaHCO (5 mL), and the mixture was extracted
3
3
with CH Cl (3 x 15 mL). The organic layers were washed with brine (5 mL), and dried over Na SO The solvent was
2
2
2
4.
removed under vacuum, and the residue was purified by a flash chromatography on silica gel (hexane/ethyl acetate =
1
5/1) to give product 29 (20.0 mg, 55%) and 30 (7.0 mg, 20%).
1
2
9: H NMR (500 MHz, CDCl ) δ 4.70 (d, J = 8.4 Hz, 1H), 4.59 (d, J = 7.0 Hz, 1H), 3.83 – 3.78 (m, 4H), 3.77 –
3
3
1
1
1
1
.62 (m, 4H), 3.56 (dd, J = 9.0, 7.1 Hz, 1H), 3.46 (s, 1H), 3.04 (dd, J = 9.4, 7.2 Hz, 1H), 1.83 (dd, J = 9.4, 5.1 Hz, 1H),
.75 – 1.66 (m, 4H), 1.58 (dd, J = 13.0, 2.9 Hz, 1H), 1.24 (t, J = 7.1 Hz, 4H), 1.18 (t, J = 7.0 Hz, 3H), 1.13 – 1.09 (m,
1
3
H), 1.07 (s, 3H), 0.98 – 0.93 (m, 1H), 0.87 (d, J = 6.5 Hz, 4H), 0.81 – 0.70 (m, 2H); C NMR (125 MHz, CDCl ) δ
3
69.3, 105.1, 69.0, 67.1, 64.5, 63.5, 62.4, 52.3, 49.5, 46.6, 44.3, 43.6, 42.8, 39.5, 36.4, 35.2, 32.2, 27.4, 22.3, 16.4, 14.8,
+
+
4.7; HRMS (ESI) m/e 419.2404 [M+Na ] calcd for C H NaO : 419.2404.
2
2
36
6
1
3
0: H NMR (500 MHz, CDCl ) δ 6.66 (d, J = 1.4 Hz, 1H), 4.89 (d, J = 3.0 Hz, 1H), 3.94 – 3.84 (m, 1H), 3.78 –
3
3.70 (m, 4H), 3.65 – 3.57 (m, 2H), 3.43 – 3.33 (m, 1H), 2.88 (d, J = 5.2 Hz, 1H), 2.65 (dd, J = 17.6, 11.2 Hz, 1H), 1.99
(dd, J = 15.9, 5.3 Hz, 2H), 1.79 – 1.65 (m, 4H), 1.38 (dd, J = 6.6, 3.4 Hz, 1H), 1.29 (dd, J = 11.3, 3.9 Hz, 1H), 1.25 –
1
1
4
.15 (m, 3H), 1.14 – 0.97 (m, 3H), 0.93 (dd, J = 11.4, 2.9 Hz, 1H), 0.86 (d, J = 6.5 Hz, 3H), 0.78 (dd, J = 24.1, 12.0 Hz,
1
3
H); C NMR (125 MHz, CDCl ) δ 210.9, 165.5, 150.4, 132.4, 101.8, 63.9, 63.3, 58.6, 54.7, 51.3, 48.9, 47.1, 45.6,
3
+
+
4.4, 34.9, 34.8, 32.3, 27.4, 22.2, 20.3, 15.2, 14.9; HRMS (ESI) m/e 379.2479 [M+H ] calcd for C H O : 379.2476.
2
2
35
5
Synthesis of Compound 31:
To a solution of alcohol 29 (35.0 mg, 0.088 mmol), DMAP (11 mg, 0.088 mmol) and Et N (89 mg, 0.12 mL, 0.88
3
o
mmol) in CH Cl (3 mL) was added MsCl (1.86 g, 16.2 mmol) slowly at 0 C. The mixture was warmed up to room
2
2
temperature, and then stirred for 0.5 h. The reaction was quenched by addition of water ( 2 mL), and the mixture was
extracted with ether (3 x 5mL). The combined organic layers were washed with brine, and dried over Na SO The
2
4.
solvent was removed under vacuum, and the residue was purified by a flash chromatography on silica gel (hexane/ethyl
acetate = 10/1) to give the mesylate a crude product (35.0 mg, 83%);
To a solution of the mesylate made above (35 mg, 0.076 mmol) in PhMe (3 mL) was added DBU (200 mg, 0.2
o
mL, 1.31 mmol) at room temperature, and the mixture was stirred for 36 h at 120 C. The reaction was quenched by
addition of a saturated solution of NH Cl (5 mL), and the mixture was extracted with Et O (3 x 5 mL). The combined
4
2
extracts were dried over Na SO . The solvent was removed under vacuum, and the residue was purified by a flash
2
4
chromatography on silica gel (hexane/ethyl acetate =15/1) to give 31 (19.0 mg, 65%); R = 0.90 (silica gel,
f
1
EtOAc/hexanes = 1/2); H NMR (500 MHz, CDCl ) δ 5.73 – 5.63 (m, 1H), 5.40 (d, J = 10.1 Hz, 1H), 4.61 (d, J = 8.2
3
Hz, 1H), 3.76 (d, J = 4.4 Hz, 3H), 3.73 – 3.62 (m, 2H), 3.57 – 3.49 (m, 3H), 2.73 (dd, J=10.2, 7.0, 1H), 1.86 – 1.71 (m,
3
1
1
H), 1.70 – 1.65 (m, 2H), 1.51 – 1.42 (m, 1H), 1.31 – 1.23 (m, 2H), 1.21 (t, J = 7.0 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H),
1
3
.02 (s, 1H), 0.99 (s, 3H), 0.91 (d, J=6.5, 3H), 0.79 (q, J = 12.3 Hz, 1H); C NMR (125 MHz, CDCl ) δ 169.1, 131.1,
3
26.4, 104.9, 68.3, 63.7, 62.8, 62.0, 52.1, 49.5, 46.1, 43.5, 42.3, 41.9, 36.2, 35.3, 32.8, 26.1, 22.4, 15.2, 15.2, 15.0;
+
+
HRMS (ESI) m/e 401.2298 [M+Na ] calcd for C H NaO : 401.2298.
22
34
5

ACCEPTED MANUSCRIPT
Synthesis of Compound 10:
To a solution of the 31 (20.0 mg, 0.05 mmol) in a mixture of THF-H O (9/1, 2 mL) was deoxygenated with Ar for
2
1
0 min, followed by addition of SmI (0.1 M in THF, 2.0 mL, 0.2 mmol). The resultant mixture was stirred at room
2
temperature for 1h under Ar. The reaction was quenched by addition of a saturated solution of NaHCO (3 mL), and the
3
mixture was extracted with Et O (3 x 3 mL). The combined organic layers were washed with brine (2 mL), and dried
2
over Na SO The solvent was removed under vacuum, and the residue was purified by a flash chromatography on
2
4.
silica gel (hexane/ethyl acetate = 10/1) to give 31’ as a crude product (15.0 mg, 76%). R = 0.20 (silica gel,
f
1
EtOAc/hexanes = 1/4); H NMR (500 MHz, CDCl ) δ 5.77 – 5.68 (m, 1H), 5.42 (d, J = 10.0 Hz, 1H), 4.46 (d, J = 4.5
3
Hz, 1H), 4.16 (s, 1H), 3.76 – 3.62 (m, 5H), 3.58 – 3.47 (m, 2H), 2.75 (dd, J = 7.8, 5.0 Hz, 1H), 2.61 – 2.53 (m, 1H),
2
6
.34 (s, 1H), 2.22 – 2.13 (m, 1H), 1.84 – 1.72 (m, 3H), 1.68 – 1.63 (m, 2H), 1.48 – 1.38 (m, 1H), 1.21 (t, J = 7.0 Hz,
1
3
H), 1.16 – 1.07 (m, 1H), 0.92 – 0.86 (m, 6H), 0.83 – 0.76 (m, 1H), 0.76 – 0.66 (m, 1H); C NMR (125 MHz, CDCl )
3
δ 174.6, 131.6, 127.1, 104.3, 81.3, 63.4, 62.8, 54.0, 51.8, 48.8, 47.8, 46.3, 44.8, 42.2, 37.0, 35.8, 32.9, 25.7, 22.4, 15.1,
+
+
1
5.0; HRMS (ESI) m/e 381.2635 [M+H ] calcd for C H O : 381.2636.
22 37 5
To a solution of 31’ (15.0 mg, 0.039 mmol ) in CH Cl (4 mL) was added DMP (33.0 mg, 0.079mmol) at room
2
2
temperature under N , and the resultant mixture was stirred at room temperature for 1.5 h. The reaction was quenched
2
by addition of a saturated solution of NaHCO (3 mL) slowly. The mixture was extracted with Et O (3 x 3 mL), and the
3
2
combined organic layers were washed with brine (2 mL), and dried over Na SO The solvent was removed under
2
4.
vacuum, and the residue was purified by a flash chromatography on silica gel (hexane/ethyl acetate = 10/1) to give
1
product 10 (13.0 mg, 87%). R = 0.86 (silica gel, EtOAc/hexanes = 1/8); H NMR (500 MHz, CDCl ) δ 5.88 – 5.77 (m,
f
3
1
3
1
H), 5.52 (d, J = 10.0 Hz, 1H), 4.53 (d, J = 5.0 Hz, 1H), 3.80 – 3.69 (m, 4H), 3.69 – 3.58 (m, 1H), 3.56 – 3.45 (m, 2H),
.38 – 3.28 (m, 1H), 2.94 – 2.82 (m, 1H), 2.22 (dd, J = 11.0, 4.7 Hz, 1H), 1.84 (t, J = 11.5 Hz, 2H), 1.78 – 1.68 (m, 1H),
.54 – 1.37 (m, 3H), 1.27 (dd, J = 9.9, 3.2 Hz, 1H), 1.22 – 1.16 (m, 6H), 1.14 – 1.04 (m, 1H), 1.00 – 0.96 (m, 3H), 0.89
13
(t, J = 10.1 Hz, 4H); C NMR (125 MHz, CDCl ) δ 212.1, 170.0, 132.1, 125.5, 103.6, 63.3, 62.7, 56.5, 52.3, 52.2, 48.4,
3
+
45.4, 41.8, 38.5, 36.6, 35.4, 32.9, 25.3, 22.3, 15.2, 15.1, 15.1; HRMS (ESI) m/e 401.2298 [M+Na ] calcd for
+
C H NaO : 401.2298.
22
34
5
Synthesis of Compound 37:
To a solution of alkyne (226.0 mg, 1.22 mmol) in freshly distilled THF (5 mL) was added n-butyllithium (0.16 mL
o
of a 2.5 M solution in hexanes, 1.22 mmol) at -78 C in a dropwise manner, and the mixture was stirred at the same
o
temperature for 45 min. the mixture was then warmed up to -10 °C for 30 min, and then cooled back to -78 C.
To a solution of epoxide 38 (200mg, 1.11 mmol) in THF (5 mL) was added the solution 45 prepared above via a

ACCEPTED MANUSCRIPT
cannular at -78 °C, followed by addition of BF ·OEt (0.16 mL, 1.11 mmol) within 20 min. The resultant mixture was
3
2
then stirred at -78 °C for 2 h. The reaction was quenched by addition of a saturated solution of NaHCO (10 mL), and
3
the mixture was extracted with ether (3 x 10 mL). The combined organic layers were washed with brine (5 mL), and
dried over Na SO The solvent was removed under vacuum, and the residue was purified by a flash chromatography
2
4.
on silica gel. (hexane:ethyl acetate = 50:1) to give alcohol 37 (242.2 mg) as colorless oil in 60% yield; R = 0.71 (silica
f
1
gel, EtOAc/hexanes = 1/6); H NMR (500 MHz, CDCl ) δ = 4.77 (d, J = 9.8, 2H), 4.50 (d, J = 6.2, 1H), 3.79 (s, 1H),
3
2
1
.46 – 2.40 (m, 1H), 2.32 – 2.26 (m, 1H), 2.12 – 2.06 (m, 1H), 1.69 (d, J = 9.4, 2H), 1.66 (s, 3H), 1.62 (d, J = 12.3, 3H),
13
.56 (d, J = 11.9, 1H), 1.45 – 1.39 (m, 2H), 1.37 (s, 3H), 0.92 (d, J = 6.7, 3H), 0.89 (s, 9H), 0.10 (d, J = 5.3, 6H). C
NMR (126 MHz, CDCl ) δ = 148.82, 111.76, 84.88, 80.60, 70.11, 59.31, 48.16, 42.37, 34.93, 32.57, 32.42, 32.08,
3
+
+
2
3
5.98, 25.85, 24.98, 23.00, 18.42, -4.48, -4.74; HRMS (ESI) m/e 387.2683 [M+Na ] calcd for C H NaO Si :
22 40 2
87.2690.
Synthesis of Compound 36:
To a solution of Co (CO) (286.0 mg, 0.839 mmol) in dry PhMe (10 mL) was added a solution of compound 37
2
8
o
(
278.0 mg, 0.762 mmol) in PhMe (10 mL) in a dropwise manner, and the resultant mixture was stirred at 120 C for 18
h. The reaction mixture was concentrated under vacuum, and the residue was purified by a flash chromatograph on
silica gel (hexane/ethyl acetate = 10/1) to give product 36 (243.5 mg) as colorless oil in 82% yield; R = 0.52 (silica gel,
f
1
EtOAc/hexanes = 1/6); H NMR (500 MHz, CDCl ) δ = 4.74 (q, J = 6.3, 1H), 3.75 – 3.64 (m, 1H), 3.28 (t, J = 10.2,
3
1
1
0
4
H), 2.31 (t, J = 12.2, 1H), 2.21 (s, 1H), 2.17 (d, J = 1.8, 2H), 1.87 (s, 1H), 1.77 (d, J = 12.7, 1H), 1.66 – 1.56 (m, 2H),
.49 – 1.37 (m, 2H), 1.30 (d, J = 3.1, 1H), 1.26 (d, J = 6.5, 3H), 1.10 (s, 3H), 0.91 (d, J = 6.5, 3H), 0.85 (s, 9H), 0.63 –
13
.52 (m, 1H), -0.01 (d, J = 31.7, 6H). C NMR (126 MHz, CDCl ) δ = 206.27, 177.98, 141.34, 75.68, 63.35, 49.85,
3
9.27, 44.20, 44.10, 38.61, 35.10, 34.99, 32.27, 28.10, 25.99, 24.78, 22.64, 20.13, 18.29, -4.84, -4.94; HRMS (ESI)
+
+
m/e 393.2815 [M+H ] calcd for C H O Si : 393.2819.
23
41
3
Synthesis of Compound 42:
To a solution of alcohol 36 (500.0 mg, 1.27 mmol), DMAP (78.0 mg, 0.637 mmol) and DIPEA (329.0 mg, 2.55
o
mmol) in CH Cl (6 mL) was added MOMCl (186.0 mg, 2.29 mmol) slowly at 0 C, and then warmed to room
2
2
temperature, and stirred for an additional 30 min. The reaction was quenched by addition of water (3 mL), and the
mixture was extracted with ether (3 x 5 mL). The organic layers were washed with brine (3 mL), and dried over
Na SO The solvent was removed under vacuum, and the residue was purified by a flash chromatography on silica gel
2
4.