Study of the total synthesis of (-)-exiguolide

Article abstract of DOI:10.1021/jo301066p

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.

Full text of DOI:10.1021/jo301066p

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Study of the Total Synthesis of (−)-Exiguolide
Cyril Cook, Frederic Liron, Xavier Guinchard, and Emmanuel Roulland*
́
́
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelle, CNRS, Avenue de la Terrasse, 91198, Gif-sur-Yvette,
France
S
* Supporting Information
ABSTRACT: In this article, we disclose the various routes
and strategies we had to explore before finally achieving the
total synthesis of (−)-exiguolide ((−)-1). Two first types of
approaches were set, both relying on the Trost’s domino ene−
yne coupling/oxa-Michael reaction that we choose for its
ability to control the geometry of the methylacrylate-bearing
tetrahydropyrane ring B. In our first approach, we expected to
assemble the two main fragments (C14−C21 and C1−C13)
by creating the C13−C14 bond through a palladium(0)-
catalyzed cross-coupling, but this step failed, unfortunately. In
the second approach, which was more linear, we created the
C16−C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1−C5 and C6−C21
subunits through Trost’s domino ene−yne coupling/oxa-Michael reaction. These two approaches served us to design an
ameliorated third strategy, which finally led to the total synthesis of (−)-exiguolide.
The installation of methoxycarbonylmethylidene function at C5
was made by using a Horner−Wadsworth−Emmons reaction,
which required a stoichiometric amount of a chiral
phosphonoacetate to finally deliver a Z/E mixture of products
with a relatively poor selectivity (5.8/1). This confirmed that
the construction of this structural motif is challenging and that
a better solution deserved to be found. The publication of our
own total synthesis of (−)-exiguolide ((−)-1),7 happened in
2010 concomitantly with that of Fuwa and Sasaki.8 In their
approach, a cross-metathesis reaction was used to assemble the
two main fragments, and the control of the geometry of the
methyl acrylate function of tetrahydropyrane ring A was again
made through a Horner−Wadsworth−Emmons. Since, the
same authors performed the synthesis of a series of analogues.4
In 2011, Scheidt et al. described the third total synthesis of
exiguolide (1). To achieve it, they used an interesting Prins
cyclization and again the same Horner−Wadsworth−Emmons
to build the methyl acrylate function of tetrahydropyrane ring A
(67%, Z/E: 7/1).2
INTRODUCTION
■
In 2006, the Ikegami group reported the isolation of
(−)-exiguolide ((−)-1) from the marine sponge Geodia exigua.1
This macrolide displays a number of salient motifs, which
renders this target quite attractive and challenging for synthetic
chemists. (−)-Exiguolide ((−)-1) is a 16-membered macro-
lactone bearing five C−C double bonds and seven stereogenic
centers. The macrocycle is fused with two tetrahydropyran
rings A and B, ring A bearing a methoxycarbonylmethylidene
function at C5 with a Z configuration. The control of the
geometry of this double bond represents a synthetic challenge;
furthermore, Scheidt et al.2 demonstrated that 28-(E)-
exiguolide has only minimal activity against a series of cell
lines, thus indicating Z-enoate geometry is essential for the
biological activity. When the molecule was discovered,
biological tests were performed that revealed its ability to
inhibit the fertilization of sea urchin gametes,1 a property
indicating that 1 might possess relevant anticancer activity.3
More recent studies showed that 1 is indeed endowed with
antiproliferative activity on various cell lines such as NCI-H460
human lung large cell carcinoma, on A549 human lung
adenocarcinoma cell lines significantly, and moderate growth
inhibition against PC3 prostate cancer cells, MDA-MB-231
breast cancer, and BxPC3 pancreatic cancer cells.4,2
RESULTS AND DISCUSSION
■
1. First Approach. When we started our study, the right
absolute configuration of (−)-exiguolide ((−)-1) was still
undetermined. Unfortunately we had targeted the wrong
enantiomer when we started our study of the total synthesis
of 1. As a consequence the configurations of the various
stereogenic centers of our various fragments are inverted all
along the first and second approaches. Our strategy relied on
the Trost’s domino ene−yne coupling/oxa-Michael reaction
Several total syntheses of exiguolide (1) have been published
since its discovery as well as a study of the synthesis of its
tetrahydropyranes.5 In 2008, Lee et al. reported the synthesis of
ent-exiguolide ((+)-1), the enantiomer of the naturally
occurring compound thus establishing the right absolute
configuration for this product.6 The strategy designed for this
approach featured the macrocyclization by ring closing
metathesis through formation of the C16−C17 double bond.
Received: May 30, 2012
© XXXX American Chemical Society
A
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Scheme 1. First Retrosynthetic Plan toward ent-Exiguolide ((+)-1)
Scheme 2. Synthesis of Fragment 2
catalyzed by the cationic RuII complex [CpRu(MeCN)3]PF6
(4).9 This reaction allows building the tetrahydropyrane ring of
fragment 2 while coupling fragments 7 (yne) and 8 (ene),
allowing a full control of the geometry of the vinylsilane
precursor of the acrylate double bond (C5−C28) (Scheme 1).
In this first approach we planned to assemble fragments 2 and 3
through a Pd0-catalyzed cross-coupling. We envisioned
controlling the allylic stereogenic center at C15 in intermediate
2 by substitution of the asymmetric allylic phosphate 5 by a
methylcuprate through an SN2′ process.
the Z configuration of the double bond is important, because
such geometry blocks allylic bond rotations for obvious steric
reasons (Scheme 3). Hence, the leaving group remains blocked
at one side of the average plane defined by the carbons of the
allylic system, and as a consequence its conjugated substitution
Scheme 3. SN2′ Substitution of Z Vs E Allylic Alcohols
1.2. Synthesis of Fragment 2. The synthesis of fragment 2
(Scheme 2) started with a classical syn Evans aldol reaction10
that implied aldehyde 9 and propionyloxazolidinone (S)-10 and
that led to known alcohol (+)-6.11 The latter was transformed
into the corresponding Weinreb amide12 11 and then protected
as silanyl ether 12 before being finally condensed with a lithium
acetylide to furnish ketone 13. Under Luche’s conditions,13 the
reduction of the ketone function of 13 occurred diastereose-
lectively (85:15) furnishing propargylic alcohol 14. Then, a
semihydrogenation promoted by the Lindlar catalyst14
conducted at 10 °C led very cleanly to the Z alkene 15.
Then we investigated conditions for the diastereoselective
conjugated substitution of activated Z allylic alcohol 15. Here,
B
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Table 1. SN2′ Conditions
a
entry
solvent
activation method
nucleophile
yield
b
1
2
3
4
5
6
7
8
THF
THF
Et2O
THF
THF
Et2O
Et2O
15, n-BuLi, C6F6COCl, −78 to 0 °C
15, n-BuLi, (EtO)2POCl, −78 to 0 °C
15, n-BuLi, (EtO)2POCl, −78 to 0 °C
15, n-BuLi, (EtO)2POCl, −78 °C
15, n-BuLi, (EtO)2POCl, −78 to 0 °C
15, n-BuLi, (EtO)2POCl, −78 to RT
18, n-BuLi, (EtO)2POCl, −78 to 0 °C
2MeLi, CuI, −78 to 0 °C
Me2Zn, CuCN·2LiCl, −30 to −10 °C
Me2Zn, CuCN·2LiCl, −30 to −10 °C
2MeLi, CuI, −78 °C
2MeLi, CuI, −78 to 0 °C
2MeLi, CuI, −10 °C
16, 46%
c
16, 52%
c
16, 7%
c
16, traces
c
c
16, 61−69%
16, 88−91%
c
cd
,
2MeLi, CuI, −10 °C to RT
2MeLi, CuI, −10 °C to RT
19, 97% 85:15 dr
c
cd
,
Et2O
b
18, KHMDS, (EtO)2POCl, −78 to 0 °C
19, 96% >95:5 dr
a
c
d
1
Isolated yields. Yield after PPTS promoted THP removal. One-pot procedure. dr estimated by H NMR.
Scheme 4. Tests Coupling on Fragment 2
through antiperiplanar attack of the nucleophile gives one sole
stereoisomer. The same reaction conducted on an E allylic
system would deliver a mixture of E and Z isomers having
opposite absolute configurations at the newly formed stereo-
genic center. We tried to activate alcohol 15 through the
corresponding mesylate, perfluorobenzoate or phosphate.
Unfortunately, classical conditions (MsCl, NEt3/CH2Cl2;
POCl(OEt)2, NaH/THF; POCl(OEt)2, DMAP/pyridine;
C6F6COCl, NEt3/CH2Cl215) failed to afford synthetically
useful yields of activated allylic alcohol. However, using n-
BuLi as base, we succeeded in introducing the C6F6CO leaving
group (71%), but the substitution of this leaving group led to
16 in unsatisfactory yields. So, considering that activated allylic
alcohols are sensitive species, we chose to investigate one-pot
conditions, and we also focused our attention on the cheaper
diethylphosphate leaving group. The results are presented in
Table 1. The cuprate nucleophile was prepared separately just
prior to use. We observed that methylcuprate formed from
MeLi (entries 1, 4−8) gave better yields than the one prepared
from Me2Zn (entries 2, 3). The solvent of the reaction
appeared to be important too, Et2O giving better yields than
THF (entries 6−8). One must notice that with the allylic
alcohol 187 that we synthesized in our final strategy of
synthesis,16 the use of n-BuLi led to dr erosion of the SN2′
reaction (entry 7). This was surprising because only E products
(19 and its stereoisomer at C15) were formed, indicating that
the allylic bond rotation remained well blocked in the Z allylic
system. Hence, apparently this is another process that accounts
for this dr erosion.
So, we hypothesized that the inversion of configuration
occurred at the alcohol position (C17) before the methyl-
cuprate addition. LiCl is formed when n-BuLi was used as the
base to install the phosphate leaving group, LiCl is soluble in
Et2O, and the Cl− anions may perform a SN2 (nonconjugated)
of the phosphate with inversion of configuration at C17, leading
then to Z-allylchloride 20. In the next step, the latter can
undergo a SN2′ reaction with Me2CuLi, thus accounting for the
formation of the isomer of 19. To circumvent this problem, we
used KHMDS as the base to prepare the allylic phosphate
intermediate, the byproduct being this time insoluble KCl.
Under these optimized conditions, the subsequent SN2′ step
delivered 19 in a 96% yield and as the sole detectable isomer
(entry 8). Curiously, with starting allylic alcohol 15, no isomer
of 16 was detected, which indicates that no inversion by
formation of allylic chloride occurred in that case. To explain
this, we may imagine that the OTHP protective group in 15 has
the possibility of chelating lithium ions that the OTBS group in
18 does not have, which could have important consequences on
the environment of the leaving group. Then, with 16 in hand,
the THP protecting group was removed, leading to alcohol 17,
which was then transformed into iodide 2. In order to validate
our strategy, we chose to perform Pd0-catalyzed coupling tests
involving 2 (Scheme 4). For this aim, the Negishi and the
Suzuki protocols were envisioned, which means that iodide 2
C
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Scheme 5. Synthesis of Fragment 7 and 8
Table 2. Trost Coupling Optimization
entry
solvent
additive
temperature
time (h)
yields (%)
dr syn/anti
1
2
3
4
5
6
7
8
9
acetone
CH2Cl2
CH3CN
MeOH
t-BuOH
acetone
acetone
acetone
acetone
RT
19
72
18
72
18
2
69
37
0
>2/1
<2/1
RT
reflux
RT
46
0
4/1
reflux
reflux
RT
63
4/1
n.d.
n.d.
>9/1
a
CSA (38 mol %)
AcOH (16 mol %)
AcOH (3 mol %)
3
59
b
RT
2
63
RT
2
78
a
b
Desilylated product (53%). Inseparable mixture of desired product 33 (58%) and its corresponding desilylated analogue (7%).
had to undergo a lithium−halogen exchange reaction and then
a transmetalation step prior to coupling. Following the Negishi
protocol,17 lithium derivative 21 was transmetalated as a zinc
derivative. Then Pd2(dba)3, DpePhos or PPh3, and 4-
bromoanisol were added, and the reaction medium was
refluxed overnight. But here, the only product we isolated
was deiodinated product 25. The Suzuki protocol was
performed using 9-MeO-9-BBN to transmetallate 21, and
then PdCl2(dppf), K2CO3, and 4-bromoanisol were added.
After refluxing overnight in THF, we isolated a mixture of
desired 23 along with 24, an unexpected isomeric coupling
product (23/24: 1/1, 52%). Coupling product 24 unambigu-
ously accounts for the formation of the allyl-lithium derivative
22.
It is likely that the latter arose in the course of the metal/
halogen exchange step through a process in which lithium
derivative 21, acting here as a base, would deprotonate 25 at its
more acidic position delivering allylic lithium 22, and
regenerating then 25. Considering the rather important amount
of product 24 formed here, the above process could be catalytic
in 25. To initiate this process, only little amounts of 25 would
be necessary, the latter could come from the quench of 21 with
trace amounts of water present in THF. Despite this slightly
disappointing result, we considered that this part of our strategy
was validated, particularly since other methods could be used to
obtain the desired C14−C21 metalated fragments. Then we
started the study of the synthesis of triflate 3.
1.3. Synthesis of Fragment 3. Commercially available
methacryloyle chloride 26 was readily transformed into β,γ-
unsaturated ester 27 in a very straightforward manner via the
corresponding ketene (Scheme 5).7,18 Then, a reaction with m-
CPBA led to racemic epoxide 28, and a Jacobsen hydrolytic
kinetic resolution of racemate 28 using the (R,R)-salen-Co(III)
complex19 led to (−)-28. The epoxide function of (−)-28 was
opened by attack of an aluminum acetylide leading to the
desired homopropargylic alcohol 7. For the synthesis of β,γ-
unsaturated ketone 8, we started from lactone 29, which was
opened into its corresponding seco-ester 30.20 A Swern21
oxidation led to aldehyde 31, which under Luche’s conditions,22
led to homoallylic alcohol 32.23 Fragment 824 was finally
obtained by Swern oxidation of 32.
With yne and ene fragments (7 and 8) in hand, we searched
for suitable Trost domino ene−yne/oxa-Michael conditions.
Those originally reported by Trost (Table 2, entry 1) only led
to a mixture of 33 and its isomer at C3 (2/1) with 69% yield
after 19 h of reaction. Other solvents, CH2Cl2, MeCN, MeOH
or t-BuOH (entries 2−5), led to no reaction or only poor yield
and dr. With Trost standard conditions in refluxing acetone
(entry 6), we observed a faster reaction (2 h) delivering 33 in
63% yield and with a dr enhanced to 4/1. We added then
D
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Scheme 6. Toward Triflate 3
Scheme 7. First Retrosynthetic Plan toward ent-Exiguolide ((+)-1)
Scheme 8. Synthesis of Ene Fragment 38
various additives such as Lewis acids or Brønsted acids and
discovered conditions (entries 7, 8) in which the reaction rate
was markedly accelerated, giving good yields of products, which
had unfortunately lost their TMS groups. Finally, we set
E
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Scheme 9. Assemblage of “Yne” 7 and “Ene” 38 through Optimized Trost Reaction Conditions
Scheme 10. Third Strategy
efficient modified Trost conditions (entry 9) in which the
addition of 3 mol % of AcOH allowed the formation of 33 in
78% yield, after only 2 h of reaction (10 times faster than under
standard conditions), and with furthermore a dramatic
amelioration of the dr that climbed from 2/1 to more than
9/1. The effect of Brønsted acid is likely to help the hydrolysis
of the intermediate ruthenium enolate that is formed in the
course of the oxa-Mikael step, thus allowing the catalyst to
perform the ene−yne coupling step with a faster rate.
Having key intermediate 33 in hand, we transformed it into
alcohol 34 under Luche reduction conditions (Scheme 6). Here
unfortunately, the best observed dr was 2/1 (syn/anti). Desired
syn product 34a was treated with NIS, which led to the
substitution of the TMS group leading to iodide derivative 35.
We were delighted to obtain methyl acrylate 36 with a full
control of the double geometry through Pd0-catalyzed carbon-
ylation in methanol, thus resolving one of the most challenging
problems of this total synthesis. Lactone 37 was readily
obtained through a smooth acidic treatment with SiO2.
Compound 37 is a triester, but the most deprotonable of the
three ester functions should be the lactone. However we failed
in transforming lactone 37 neither into triflate 3 nor into the
corresponding phosphate despite numerous conditions tried
(LDA, KHMDS or n-BuLi as base, and PfNTf2 or POCl(OEt)2
as electrophile even with HMPA as cosolvent). Therefore this
disappointing result prompted us to rethink our strategy of
synthesis.
17 by a cyanide ion under Mutsunobu conditions,25 which led
to nitrile 39 (Scheme 8). Then nitrile 39 was reduced into
aldehyde 40 selectively. A Brown allylation26 of 40 was used to
control the C13 stereogenic center but it gave alcohol 41 in
only a 58% yield. The alcohol function was protected as a TIPS
ether (42) prior to the hydroboration/oxidation step that
delivered alcohol 43. Iteratively, alcohol 43 was homologated to
give nitrile 44, reduced into aldehyde 45, transformed into
homoallylic alcohol 46 and finally oxidized into β,γ-unsaturated
ketone 38 using Dess−Martin periodinane.27
We were delighted to see that the Trost reaction under our
optimized conditions allowed a fast cross-coupling of fragment
38 and 7, with a high yield (72%) and an improved dr (>9/1)
(Scheme 9), delivering 47, which is a very advanced fragment
containing almost all the carbons of the target and most of its
asymmetric centers.
Nevertheless, the global yield of this rather linear and long
sequence was too low to be compatible with the requirements
of an elegant and efficient total synthesis. Furthermore we met
trouble in having an acceptable selectivity in the transformation
of the TMS group at C28 into the corresponding iodide
derivative, the TMS at C21 being unexpectedly very reactive.
So we decided to bring various improvements and
modifications to this second strategy, which at the end led to
the third and last strategy. Meanwhile, Lee et al. had published
their synthesis of ent-exiguolide ((+)-1),6 thus establishing the
absolute configuration of natural (−)-exiguolide ((−)-1);
hence, this time in the third strategy we targeted the right
enantiomer of 1.
3. Third and Final Approach. In a final effort we designed
a more accurate and more efficient strategy toward (−)-1, the
naturally occurring enantiomer of exiguolide. Among the steps
we wanted to keep were the Trost ene−yne coupling, the
installation of the Me at C15 by an SN2′ reaction, and the Evans
aldol reaction for the starting material. One of the most
2. Second Approach. We designed a new strategy, still
relying on the Trost ene−yne coupling that would be used this
time for assembling the two main fragments of the molecule,
namely, ene 38 and yne 7 (Scheme 7).
2.1. Synthesis of Fragment 38. Starting from the alcohol 17
prepared during our first approach, we designed an iterative
strategy for the introduction of carbons C13 to C6. A first
carbon was added by substitution of the hydroxyl function of
F
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Scheme 11. Synthesis of Ene Key Fragment 49
important modifications that we choose to bring was to
introduce the side chain through cross-metathesis, rendering
the TMS at C21 no longer required in this strategy. But this
latter choice was not the best.
aluminum acetylide nucleophile;32 the more classical reaction of
the corresponding lithium acetylide in the presence of BF3 led
to decomposition.
We have shown above that a catalytic amount of acetic acid
accelerated the domino ene−yne coupling/Michael reaction
promoted by 4, and in this case, these conditions allowed a
remarkable enhancement of the diastereoselectivity. The same
conditions of cross-coupling of alkyne 48 with alkene 49 led to
tetrahydropyran 64 in a 47% yield as a 8:1 mixture of
diastereomers easily separated by HPLC. Anyway, this result
compares favorably with the 34% yield (dr not given) obtained
by Trost for his bryostatin 16 synthesis on a comparable
substrate. Furthermore one should notice that in our case, the
reaction was regioselective as the C20−C21 terminal double
bond was not engaged in the cross-coupling. The TMS group
of 64 being particularly acid sensitive, we performed its
iodolysis leading to 65, prior to the acid-promoted removal of
the two TBS protective groups and subsequent cyclization into
the hemiketal precursor of cycle B. The crude mixture of
hemiketals was subsequently reduced by Et3SiH in the presence
of BF3·OEt2 at −40 °C, affording compound 66 (dr >20:1)
now featuring the two tetrahydropyran rings A and B. After
saponification we obtained carboxylic acid 67. Then, the
methoxycarbonyl function was cleanly installed at C28 by a
Pd0-catalyzed carbonylation33 of iodinated derivative 67
furnishing the desired (Z)-α,β-unsaturated methylester 68
(92:8 Z/E mixture). We proceeded then to the macro-
lactonization step using the Yamaguchi conditions34 and
obtained macrolactone 69 in a good 74% yield (9.2% over 17
steps). The order of these steps (saponification−carbon-
ylation−macrolactonization) is rather unusual, but it was the
only way we found to make the carbonylation reaction working
in a reproducible manner.
We commenced with the synthesis of the C6−C21 fragment
49 (Scheme 10). First, we accessed the enantio-enriched
epoxide (+)-51 using the Jacobsen hydrolytic kinetic resolution
(HKR)19 on the corresponding racemic epoxide rac-51
obtained by m-CPBA epoxidation of alkene 50. Alkyne 52
was furnished by reaction of epoxide (+)-51 with lithium
trimethylsilylacetylide, followed by removal of the TMS alkyne
protective group and protection of the alcohol function. The
lithium acetylide of 52 was then condensed with known
Weinreb amide 53.28 This efficient cross-coupling step afforded
propargylic ketone 54 in 95% yield. The ketone function of 54
was reduced into alcohol 55 with a good diastereoselectivity
using Luche conditions.13 The semireduction of the alkyne
function of 55, using the Lindlar catalyst, led to Z allylic alcohol
18. As already mentioned above in section 2.1, our SN2′ one-
pot-two-step strategy was used for the control of the allylic C15
stereogenic center allowing the direct transformation of the Z
allylic alcohol 18 into the desired alkene 19 in high yield (96%)
1
and a very good transfer of chirality (dr around 95:5 by H
NMR spectroscopy). Next, the TBDPS protective group was
selectively removed under basic conditions29 affording alcohol
58, which was oxidized into aldehyde 59 under Swern
conditions.21 The latter was transformed using the Luche22
procedure into homoallylic alcohol 60 and readily oxidized by
Dess−Martin periodinane27 into β,γ-unsaturated ketone 49, the
key “ene” coupling partner of the RuII-catalyzed Trost’s ene−
yne coupling (53.4% over 11 steps from (+)-51).
On the other hand, the known “yne” partner 4830 was
accessed from trans-crotonoyl chloride 61, which was trans-
formed into β,γ-unsaturated ester 62 (Scheme 11).31 An
epoxidation by m-CPBA furnished rac-63, which was enantio-
enriched by using the Jacobsen HKR method furnishing
(+)-63.19 Finally, 48 was cleanly obtained after reaction with an
For the last step of the synthesis, it was first envisioned to
introduce the C21−C27 side chain directly by a cross-
metathesis reaction35 on alkene 69. Unfortunately, none on
the catalysts (Grubbs II and Hoveyda−Grubbs II (Scheme
G
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Scheme 12. Endgame Leading to (−)-Exiguolide (1)
12)), cross-coupling partners (i, ii,36 iii,37 and allylic alcohol
(Scheme 12)), and solvents (CH2Cl2, toluene, rt or reflux) we
tried gave any product; in all cases, the starting material 69 was
totally recovered, and not even dimers of 69 were formed. We
then reconsidered our retrosynthetic analysis, and we thought it
reasonable to expect selectivity from the OsO4 catalyzed
dihydroxylation reaction38 in favor of the C20−C21 double
bond, which is not electron-deficient and is the less hindered of
the three alkene functions of compound 69. Surprisingly we
observed a poor selectivity and identified various diols and
tetra-ols, some resulting from the unexpected dihydroxylation
of the α,β-unsaturated ester at C5−C28, the C16−C17 double
Sonogashira cross-coupling of 71 with alkyne 72,6,41 which
furnished dienyne 73. The final step of semihydrogenation led
to the targeted (−)-exiguolide (1), the characterization data of
which are identical with those reported for the naturally
occurring compound ([α]D −95.0 (c 0.28, CHCl3), lit.1
20
20
[α]D −92.5 (c 0.069, CHCl3)). We also performed the
biological evaluation of synthetic (−)-exiguolide ((−)-1) by
testing its cytotoxicity on KB cancer cells and found an IC50
value of 3.39 μM with 100 and 2% of growth cell inhibition at
10−5 and 10−6 M, respectively.
CONCLUSION
■
39
bond remaining untouched. A mild reaction with Pb(OAc)4
No less than three approaches have been necessary to finally
achieve the total synthesis of (−)-exiguolide ((−)-1). However,
this long lasting effort gave us the occasion of developing new
relevant methodologies of synthesis, namely, the one-pot
formation and SN2′ substitution of Z-allylic phosphates, and
to apply them to total synthesis of natural product. We also
performed a study of the ene−yne Trost coupling reaction,
which led us to set optimized conditions for this powerful
finally delivered aldehyde 70 from this mixture of diols with
20% yield over two steps and partial recovery of the starting
material 69 (31%). The Takai−Utimoto40 olefination reaction
on aldehyde 70 furnished vinylic iodide derivative (−)-71 in
high yield, the enantiomer of which was previously described by
Lee.6 In the two final steps of this synthesis, we followed the
Lee’s strategy. Thus we introduced the C22−C27 side chain by
H
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(2S,3S,E)-3-(tert-Butyldimethylsilyloxy)-N-methoxy-N,2-di-
methyl-5-(trimethylsilyl)pent-4-enamide (12). To a solution of
Weinreb amide 11 (3.169 g, 12.91 mmol) and imidazole (1.58 g, 23.2
mmol) in DMF (25 mL) at room temperature was added tert-
butylchlorodimethylsilane (2.92 g, 19.4 mmol). The solution was
stirred for 3.5 h and then quenched with water (20 mL) and extracted
with Et2O. The organic layer was washed with saturated aqueous
NH4Cl and water, dried over anhydrous Na2SO4, filtered, and
concentrated under a vacuum. Purification by column chromatography
transformation. Our total synthesis approach of 1 is robust, so
relying on it we are currently developing the synthesis of
analogues in the exiguolide series. The installation of the C20−
C27 side chain was the weakness of our final approach, so we
are also currently designing a new strategy to solve this
problem.
EXPERIMENTAL SECTION
■
(Heptane/EtOAc, 10/1) gave pure Weinreb amide 12 as a colorless
20
(S)-4-Benzyl-3-((2S,3S,E)-3-hydroxy-2-methyl-5-
(trimethylsilyl)pent-4-enoyl)oxazolidin-2-one (6). To a solution
of (R)-4-benzyl-3-propionyloxazolidin-2-one (3.88 g, 16.6 mmol) in
CH2Cl2 (35 mL) at −78 °C was added slowly a 1.0 M solution of
Bu2BOTf in CH2Cl2 (16.6 mL, 16.6 mmol). Et3N (3.2 mL, 22.8
mmol) was added. The resulting yellow solution was stirred for 30 min
at −78 °C, and then 30 min at 0 °C. The mixture was then recooled to
−78 °C, and acrylaldehyde 9 (17.5 mmol) in CH2Cl2 (10 mL) was
added slowly. The resulting yellow solution was slowly warmed to −50
°C over 1.5 h. Stirring was continued at 0 °C for 30 min, and then at
room temperature for 1.5 h. The solution was then quenched by
addition of a pH 7.2 phosphate buffer solution (100 mL) added in one
portion. To this vigorously stirred mixture was added H2O2 (30%, 25
mL) while the temperature was maintained below 5 °C. The addition
of H2O2 was continued until the internal temperature was no longer
affected by the addition of oxidant. The resulting mixture was stirred
for 30 min while slowly warming to room temperature. This mixture
was then poured in a saturated aqueous NaHCO3 solution (50 mL)
and extracted with CH2Cl2. The organic phase was dried over Na2SO4,
filtered and concentrated under a vacuum to a yellow oil. The crude oil
was purified by flash column chromatography (Toluene/EtOAc, 10/1)
to give aldol 6 as a white solid (4.45 g, 70%): Rf = 0.30 (Heptane/
oil (4.645 g, 100%): Rf = 0.20 (Heptane/EtOAc, 10/1); [α]D
=
−12.9 (c 1.36, CHCl3); IR (film) ν 2955, 2857, 1663, 1247, 1059, 992,
833, 774 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.98 (dd, J = 18.6, 6.1
Hz, 1H), 5.79 (d, J = 18.6 Hz, 1H), 4.18 (dd, J = 8.6, 6.4 Hz, 1H), 3.63
(s, 3H), 3.12 (s, 3H), 2.95 (s, 1H), 1.17 (d, J = 6.7 Hz, 3H), 0.89 (s,
9H), 0.05 (s, 3H), 0.02 (s, 9H), 0.00 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 175.9, 147.8, 130.4, 77.8, 61.6, 42.7, 32.2, 26.0, 25.8, 18.4,
14.6, −1.2, −4.0, −4.6; LRMS (ESI, TOF) m/z (%) 360.5 (21) [M +
H]+, 382.5 (100) [M + Na]+, 742.0 (13) [2M + Na]+; HRMS (ESI,
TOF) m/z calcd for C17H38NO3Si2 [M + H]+ 360.2390, found
360.2378.
(5S,6S,E)-6-(tert-Butyldimethylsilyloxy)-5-methyl-1-(tetrahy-
dro-2H-pyran-2-yloxy)-8-(trimethylsilyl)oct-7-en-2-yn-4-one
(13). To a solution of 2-(prop-2-ynyloxy)tetrahydro-2H-pyran (1.1
mL, 7.5 mmol) in THF (40 mL), at −78 °C was added a 1.6 M
solution of n-BuLi in hexanes (4.7 mL, 7.5 mmol). After a 5 min
period at room temperature, the reaction medium was recooled to
−78 °C, and a solution of Weinreb amide 12 (1.351 g, 3.76 mmol) in
THF (8 mL) was added. The light yellow solution was allowed to
warm to room temperature over a 3 h period to an orange solution
and then heated at 45 °C for 1.5 h. The solution was quenched with
saturated aqueous NH4Cl solution (50 mL) and extracted with Et2O.
The organic layer was washed with saturated aqueous NH4Cl and
water, dried over anhydrous Na2SO4, filtered, and concentrated under
a vacuum. Purification by column chromatography (Heptane/EtOAc,
10/1) and drying under a vacuum to remove excess of 2-(prop-2-
ynyloxy)tetrahydro-2H-pyran gave pure propargylic ketone 13 as a
colorless oil (1.392 g, 84%): Rf = 0.46 (Heptane/EtOAc, 4/1); IR
(film) ν 2951, 2856, 2212, 1680, 1248, 1121, 1030, 833, 775 cm−1; 1H
NMR (500 MHz, CDCl3) δ 5.97 (dd, J = 18.6, 5.5 Hz, 1H), 5.87 (d, J
= 18.6 Hz, 1H), 4.82 (t, J = 3.4 Hz, 1H), 4.67−4.64 (m, 1H), 4.43 (s,
2H), 3.86−3.81 (m, 1H), 3.57−3.53 (m, 1H), 2.64 (qd, J = 6.9, 4.3
Hz, 1H), 1.86−1.53 (m, 6H), 1.13 (d, J = 6.7 Hz, 3H), 0.87 (s, 9H),
0.07 (s, 9H), 0.03 (s, 3H), −0.01 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 189.3, 146.6, 131.3, 97.3, 89.0, 84.9, 75.8, 62.2, 54.8, 54.0,
30.3, 25.9, 25.4, 19.0, 18.3, 9.6, −1.3, −3.9, −4.9; LRMS (ESI, TOF)
m/z (%) 461.2 (100) [M + Na]+; HRMS (ESI, TOF) m/z calcd for
C23H42O423NaSi2 [M + Na]+ 461.2519, found 461.2523.
(4R,5R,6S,E)-6-(tert-Butyldimethylsilyloxy)-5-methyl-1-(tet-
rahydro-2H-pyran-2-yloxy)-8-(trimethylsilyl)oct-7-en-2-yn-4-ol
(14). To a solution of propargylic ketone 13 (6.912 g, 15.75 mmol)
and CeCl3·7H2O (7.04 g, 18.9 mmol) in MeOH (100 mL) at −78 °C
was added NaBH4 (655.6 mg, 17.3 mmol, 1.1 equiv) by small portions
over 30 min. The solution was allowed to warm to 0 °C over 45 min,
and solid K2CO3 (6.53 g, 47.3 mmol, 3.0 equiv) was added. The
mixture was stirred 2 h at room temperature and then quenched by
addition of water and extracted with CH2Cl2. The organic layer was
washed with water, dried over anhydrous Na2SO4, filtered, and
concentrated under a vacuum. Column chromatography purification
(Heptane/EtOAc, 10/1) followed by preparative HPLC (Heptane/
EtOAc, 10/1) allowed the separation of the major alcohol
diastereomer 14 (5.625 g, 81%) and the minor diastereomer (416.6
mg, 6%): Rf = 0.26 (Heptane/EtOAc, 4/1); IR (film) ν 3432, 2951,
2855, 2357, 1247, 1019, 833, 774 cm−1; 1H NMR (500 MHz, CDCl3)
δ 6.05 (dd, J = 18.6, 6.1 Hz, 1H), 5.82 (d, J = 18.9 Hz, 1H), 4.81 (t, J =
3.2 Hz, 1H), 4.54−4.52 (m, 1H), 4.34−4.26 (m, 3H), 3.86−3.81 (m,
1H), 3.54−3.50 (m, 1H), 2.57 (d, J = 2.4 Hz, 0.5H), 2.56 (d, J = 2.4
Hz, 0.5H), 1.87−1.50 (m, 7H), 1.04 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H3),
0.07 (s, 9H3), 0.06 (s, 3H2), 0.00 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 147.6, 131.2, 96.9, 86.4, 81.5, 78.7, 65.6, 62.2, 62.1, 54.4,
20
EtOAc, 2/1); mp 85−87 °C; [α]D = +62.6 (c 1.04, CHCl3); IR
(film) ν 3511, 2953, 1783, 1693, 1376, 1193, 830, 693 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.36−7.28 (m, 3H), 7.21 (d, J = 7.0 Hz, 2H),
6.01 (s, 2H), 4.74−4.69 (m, 1H), 4.52−4.50 (m, 1H), 4.25−4.19 (m,
2H), 3.90−3.85 (m, 1H), 3.27 (dd, J = 13.5, 3.3 Hz, 1H), 2.92 (d, J =
3.2 Hz, 1H), 2.80 (dd, J = 13.4, 9.5 Hz, 1H), 1.22 (d, J = 7.1 Hz, 3H),
0.08 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 177.0, 153.2, 144.5,
135.2, 131.4, 129.6, 129.2, 127.6, 73.7, 66.4, 55.3, 42.5, 38.0, 10.7,
−1.2; LRMS (ESI, TOF) m/z (%) 256.1 (13) [M − C6H12OSi +
Na]+, 384.1 (100) [M + Na]+, 745.2 (16) [2M + Na]+; HRMS (ESI,
TOF) m/z calcd for C19H27NO423NaSi [M + Na]+ 384.1607, found
384.1609.
(2S,3S,E)-3-Hydroxy-N-methoxy-N,2-dimethyl-5-
(trimethylsilyl)pent-4-enamide (11). To a solution of N,O-
dimethylhydroxylamine hydrochloride (3.79 g, 38.8 mmol) in THF
(60 mL) at 0 °C was added a 2.0 M solution of trimethylaluminium in
heptane (19.1 mL, 38.2 mmol). After the end of the gaseous evolution,
the solution was allowed to warm to room temperature for 50 min. To
this solution cooled at −40 °C was added a solution of aldol 6 (4.677
g, 12.94 mmol, 1.0 equiv) in THF (30 mL). The solution was allowed
to warm to +15 °C over 2 h and stirred at this temperature for an
additional 1 h period. Then the solution was cooled to −20 °C,
quenched with a saturated aqueous Rochelle salt solution (50 mL),
and then stirred during 1 h and extracted with EtOAc. The organic
layer was washed with NH4Cl and water, dried over anhydrous
Na2SO4, filtered, and concentrated under a vacuum. Purification by
column chromatography (Heptane/EtOAc, 2/1 then 1/1) gave pure
Weinreb amide 11 as a light yellow liquid (3.179 g, 100%). Further
elution (EtOAc 100%) allowed recovery of (S)-4-benzyloxazolidin-2-
20
one 2.180 g, 95%): Rf = 0.19 (Heptane/EtOAc, 2/1); [α]D = +28.4
(c 1.36, CHCl3); IR (film) ν 3266, 2953, 1751, 1407, 1246, 836, 702
cm−1; 1H NMR (500 MHz, CDCl3) δ 6.02 (d, J = 18.9 Hz, 1H), 5.96
(dd, J = 18.9, 3.7 Hz, 1H), 4.43 (s, 1H), 3.87 (s, 1H), 3.72 (s, 3H),
3.21 (s, 3H), 2.97 (s, 1H), 1.14 (d, J = 7.0 Hz, 3H), 0.08 (s, 9H); 13C
NMR (75.5 MHz, CDCl3) δ 177.8, 145.2, 130.8, 73.7, 61.8, 39.3, 10.6,
−1.1; LRMS (ESI, TOF) m/z (%) 268.1 (100) [M + Na]+, 513.2 (92)
[2M + Na]+; HRMS (ESI, TOF) m/z calcd for C11H23NO323NaSi [M
+ Na]+ 268.1345, found 268.1358.
I
dx.doi.org/10.1021/jo301066p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
45.4, 30.4, 26.0, 25.5, 19.24, 19.21, 18.3, 9.3, −1.3, −3.7, −4.8; LRMS
(ESI, TOF) m/z (%) 463.3 (100) [M + Na]+; HRMS (ESI, TOF) m/
z calcd for C23H44O423NaSi2 [M + Na]+ 463.2676, found 463.2664.
(2Z,4S,5R,6S,7E)-6-(tert-Butyldimethylsilyloxy)-5-methyl-1-
(tetrahydro-2H-pyran-2-yloxy)-8-(trimethylsilyl)octa-2,7-dien-
4-ol (15). To a solution of propargylic alcohol 14 (3.057 g, 6.94
mmol) in EtOAc (80 mL) at room temperature was added Lindlar
palladium catalyst (452 mg) and freshly distilled quinoline (640 μL).
The solution was purged and placed under hydrogen atmosphere (1
atm) at 0 °C and then stirred strongly at 10 °C for 1.5 h. The mixture
was filtered on a thin silica pad and washed with EtOAc. The organic
layer was concentrated under a vacuum. Purification by column
chromatography (Heptane/EtOAc, 10/1) afforded allylic alcohol 15 as
a colorless oil (2.672 g, 87%): Rf = 0.33 (Heptane/EtOAc, 4/1); IR
(film) ν 3469, 2952, 2856, 2363, 1620, 1248, 1022, 833, 774 cm−1; 1H
NMR (500 MHz, CDCl3) δ 6.044 (dd, J = 18.9, 6.3 Hz, 0.5H), 6.040
(dd, J = 18.9, 6.3 Hz, 0.5H), 5.82 (d, J = 18.6 Hz, 1H), 5.75−5.59 (m,
2H), 4.67−4.61 (m, 2H), 4.36 (dd, J = 12.5, 5.5 Hz, 0.5H), 4.25−4.23
(m, 1H), 4.21−4.16 (m, 1H), 4.07 (dd, J = 12.7, 5.1 Hz, 0.5H), 3.88−
3.83 (m, 1H), 3.55−3.48 (m, 1H), 2.91 (d, J = 2.1 Hz, 0.5H), 2.83 (d,
J = 2.1 Hz, 0.5H), 1.85−1.51 (m, 7H), 0.97 (d, J = 7.0 Hz, 3H), 0.90
(s, 9H), 0.07 (s, 9H), 0.06 (s, 3H), 0.01 (s, 3H); 13C NMR (75.5
MHz, CDCl3) δ 147.9, 135.7, 134.8, 130.8, 127.7, 127.1, 98.5, 97.5,
79.8, 79.6, 70.4, 70.1, 63.6, 62.8, 62.33, 62.26, 45.3, 45.1, 30.8, 30.7,
26.0, 25.6, 19.5, 18.3, 8.0, 7.9, −1.3, −3.6, −4.7; LRMS (ESI, TOF) m/
z (%) 465.2 (100) [M + Na]+; HRMS (ESI, TOF) m/z calcd for
C23H46O423NaSi2 [M + Na]+ 465.2832, found 465.2809.
1H), 5.73 (d, J = 18.6, Hz, 1H), 5.40 (dd, J = 15.6, 8.2 Hz, 1H), 5.15
(dd, J = 15.6, 8.2 Hz, 1H), 3.88 (dd, J = 6.1 Hz, 1H), 3.47−3.42 (m,
1H), 3.25 (t, J = 9.5 Hz, 1H), 2.32−2.21 (m, 2H), 1.55 (s, 1H), 0.98
(d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
9H), 0.03 (s, 3H), −0.01 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
147.5, 134.9, 132.8, 130.8, 79.8, 67.1, 43.8, 40.2, 26.1, 18.5, 16.6, 16.2,
−1.2, −4.0, −4.7; LRMS (ESI, TOF) m/z (%) 379.3 (100) [M +
Na]+; HRMS (ESI, TOF) m/z calcd for C19H40O223NaSi2 [M + Na]+
379.2448, found 379.2465.
tert-Butyl((1E,3S,4R,5E,7R)-8-iodo-4,7-dimethyl-1-
(trimethylsilyl)octa-1,5-dien-3-yloxy)dimethylsilane (2). To a
solution of dienol 17 (495.0 mg, 1.39 mmol) and imidazole (624 mg,
9.2 mmol) in CH2Cl2 (10 mL) at 0 °C was added a solution of PPh3
(910 mg, 3.5 mmol) and I2 (881 mg, 3.5 mmol) prepared 10 min
before in CH2Cl2 (10 mL) at 0 °C. The yellow solution was stirred 16
h at room temperature, and then 70−200 μm silica (1.5 g) was added.
The solvent was removed giving a powder, and purification by column
chromatography (Heptane/EtOAc, 20/1) gave iodide 2 (629.0 mg,
20
97%): Rf = 0.68 (Heptane/EtOAc, 10/1); [α]D = +18.9 (c 0.92,
CHCl3); IR (film) ν 2953, 2927, 2855, 1620, 1461, 1360, 1247, 832,
773, 691, 670, 612 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.93 (dd, J =
18.6, 6.1 Hz, 1H), 5.73 (d, J = 18.6 Hz, 1H), 5.45 (dd, J = 15.6, 7.6 Hz,
1H), 5.25 (dd, J = 15.6, 7.3 Hz, 1H), 3.89 (dd, J = 5.8, 5.5 Hz, 1H),
3.17 (dd, J = 9.5, 5.5 Hz, 1H), 3.06 (dd, J = 9.5, 7.3 Hz, 1H), 2.35−
2.27 (m, 1H), 2.23−2.16 (m, 1H), 1.09 (d, J = 6.4 Hz, 3H), 0.96 (d, J
= 7.0 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H);
13C NMR (75.5 MHz, CDCl3) δ 147.9, 133.9, 132.8, 130.1, 79.7, 43.3,
tert-Butyl((1E,3S,4R,5E,7R)-4,7-dimethyl-8-(tetrahydro-2H-
pyran-2-yloxy)-1-(trimethylsilyl)octa-1,5-dien-3-yloxy)-
dimethylsilane (16). To a solution of allylic alcohol 15 (1.476 g, 3.33
mmol) in Et2O (3.5 mL) at −78 °C was added a 1.6 M solution of n-
BuLi in hexanes (2.9 mL, 4.7 mmol), followed by diethyl
chlorophosphate (725 μL, 5.0 mmol), and this reaction mixture was
stirred 1 h at 0 °C. A solution of Me2CuLi in Et2O (extemporaneously
prepared by the addition of a 1.6 M solution of MeLi in Et2O (4.6 mL,
7.3 mmol, 2.2 equiv) to a suspension of CuI (698.3 mg, 3.7 mmol, 1.1
equiv) in Et2O (3 mL) at 0 °C) was added at −10 °C to the solution
of allylic phosphate. After 40 min of stirring at −10 °C, the reaction
was quenched by addition of a saturated aqueous NH4Cl solution (5
mL) and of aqueous NH3 (5 mL). The mixture became dark blue and
was then extracted with CH2Cl2. The organic layer was washed with
saturated aqueous NH4Cl and water, dried over anhydrous Na2SO4,
filtered, and concentrated under a vacuum. Purification by column
chromatography (Heptane/CH2Cl2, 2/1, then Heptane/EtOAc, 10/1)
gave diene 16 (1.343 g, 91%) as a colorless oil: Rf = 0.61 (Heptane/
EtOAc, 4/1); IR (film) ν 2954, 2856, 1621, 1248, 1032, 833, 773
cm−1; 1H NMR (500 MHz, CDCl3) δ 5.92 (dd, J = 18.7, 5.9 Hz, 1H),
5.71 (d, J = 18.9 Hz, 1H), 5.43 (dd, J = 15.6, 7.0 Hz, 0.5H), 5.42 (dd, J
= 15.6, 7.0 Hz, 0.5H), 5.34 (dd, J = 15.6, 6.7 Hz, 0.5H), 5.31 (dd, J =
15.6, 6.7 Hz, 0.5H), 4.59−4.56 (m, 1H), 3.88−3.83 (m, 2H), 3.64 (dd,
J = 9.5, 5.8 Hz, 0.5H), 3.51−3.45 (m, 1.5H), 3.29 (dd, J = 9.5, 5.8 Hz,
0.5H), 3.14 (dd, J = 9.2, 7.6 Hz, 0.5H), 2.44−2.37 (m, 1H), 2.20−2.14
(m, 1H), 1.86 1.50 (m, 6H), 1.02 (d, J = 6.8 Hz, 1.5H), 1.01 (d, J = 6.8
Hz, 1.5H), 0.94 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 9H), 0.02 (s,
3H), −0.03 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 148.2, 132.9,
132.8, 132.3, 132.2, 129.7, 99.2, 98.6, 79.8, 72.9, 72.5, 62.3, 62.2, 43.3,
37.0, 36.9, 30.8, 26.1, 25.7, 19.7, 19.6, 18.5, 17.5, 17.4, 15.43, 15.40,
−1.1, −4.0, −4.7; LRMS (ESI, TOF) m/z (%) 463.2 (100) [M +
Na]+; HRMS (ESI, TOF) m/z calcd for C24H48O323NaSi2 [M + Na]+
463.3040, found 463.3052.
38.9, 26.1, 21.0, 18.5, 15.9, 15.5, −1.1, −3.9, −4.6; LRMS (ESI, TOF)
m/z (%) 489.2 [M + Na]+; HRMS (ESI, TOF) m/z calcd for
C19H39IO23NaSi2 [M + Na]+ 489.1482, found 489.1483.
tert-Butyl((1E,3S,4R,5E,7S)-8-(4-methoxyphenyl)-4,7-dimeth-
yl-1-(trimethylsilyl)octa-1,5-dien-3-yloxy)dimethylsilane (23).
tert-Butyl((1E,3S,4R,5E)-7-(4-methoxyphenyl)-4,7-dimethyl-1-
(trimethylsilyl)octa-1,5-dien-3-yloxy)dimethylsilane (24). To a
solution of iodide 2 (91.7 mg, 0.20 mmol) in Et2O (3 mL) at −78 °C
was added a 1.7 M solution of t-BuLi in pentane (250 μL, 0.4 mmol),
followed 10 min later by the addition of a 1.0 M solution of B-
methoxy-9-borabicyclo[3.3.1]nonane in hexane (462 μL, 0.46 mmol)
and THF (3 mL). The solution was allowed to warm to room
temperature, and then an aqueous solution of K3PO4 (200 μL, 3.0 M,
0.6 mmol) was added, followed by the addition of 4-bromoanisol (49.2
μL, 0.4 mmol) and PdCl2(dppf) (7.2 mg, 0.01 mmol). Et2O was
removed, and the mixture was refluxed for 3 h and then stirred at room
temperature for 63 h. The reaction was quenched with water and
extracted with Et2O. The organic layer was washed with brine and
water, dried over anhydrous Na2SO4, filtered, and concentrated under
a vacuum. Purification by column chromatography (Heptane/CH2Cl2,
10/1, then 5/1) gave a nonseparable mixture of product 23 and the
isomer byproduct 24 (1:1, 45.8 mg, 52%). Data for the 1:1 mixture of
1
23 and 24: Rf = 0.31 (Heptane/CH2Cl2, 5/1); H NMR (500 MHz,
CDCl3) δ 7.25 (d, J = 8.8 Hz, 2H, HAr), 7.05 (d, J = 8.6 Hz, 2H, HAr),
6.84−6.80 (m, 4H, HAr), 5.95 (dd, J = 18.3, 5.8 Hz, 1H, H2), 5.92 (dd,
J = 18.3, 5.8 Hz, 1H, H2), 5.74 (d, J = 18.5 Hz, 1H, H1), 5.71 (d, J =
18.7 Hz, 1H, H1), 5.56 (d, J = 15.7 Hz, 1H, H5), 5.37 (d, J = 7.8 Hz,
1H, H6), 5.35−5.33 (m, 2H, H5, H6), 3.89 (t, J = 5.9 Hz, 1H, H3), 3.86
(t, J = 5.6 Hz, 1H, H3), 3.79 (s, 6H, OCH3), 2.62 (dd, J = 13.0, 5.7 Hz,
1H, H8a), 2.38 (dd, J = 12.9, 8.1 Hz, 1H, H8a), 2.36−2.28 (m, 1H, H7),
2.26−2.19 (m, 1H, H4), 2.19−2.12 (m, 1H, H4), 1.33 (s, 6H, H8b),
0.98 (d, J = 6.7 Hz, 3H, H9 or H10), 0.94 (d, J = 6.9 Hz, 3H, H9 or
H10), 0.91 (d, J = 6.6 Hz, 3H, H9 or H10), 0.89 (s, 18H,
SiMe2C(CH3)3), 0.05 (s, 9H, Si(CH3)3), 0.04 (s, 9H, Si(CH3)3),
0.02 (s, 3H, SitBu(CH3)2), 0.00 (s, 3H, SitBu(CH3)2), −0.01 (s, 3H,
SitBu(CH3)2), −0.03 (s, 3H, SitBu(CH3)2).
(2R,3E,5R,6S,7E)-6-(tert-Butyldimethylsilyloxy)-2,5-dimethyl-
8-(trimethylsilyl)octa-3,7-dien-1-ol (17). A solution of diene 16
(73.5 mg, 0.17 mmol) and PPTS (4.2 mg, 0.02 mmol) in MeOH (5
mL) was refluxed for 1.5 h. Some solid NaHCO3 was added to
neutralize the reaction mixture, which was then filtered and washed
with EtOAc, and concentrated under a vacuum. Purification by column
chromatography (Heptane/EtOAc, 20/1) gave dienol 17 (50.7 mg,
tert-Butyl((1E,3S,4R,5E)-4,7-dimethyl-1-(trimethylsilyl)octa-
1,5-dien-3-yloxy)dimethylsilane (25). To a solution of iodide 2
(38.7 mg, 0.08 mmol) in Et2O (0.6 mL) at −78 °C was added a 1.7 M
solution of t-BuLi in pentane (100 μL, 0.2 mmol). Ten minutes later, a
solution of ZnCl2 in THF (180 μL, 0.5 M, 0.09 mmol) was added. The
reaction mixture was allowed to warm to room temperature, and then
40 min later 4-bromoanisol (16 μL, 0.12 mmol) was added followed
20
85%): Rf = 0.35 (Heptane/EtOAc, 4/1); [α]D = +6.5 (c 1.07,
CHCl3); IR (film) ν 3350, 2955, 2857, 1620, 1461, 1248, 1028, 832,
1
773 cm−1; H NMR (500 MHz, CDCl3) δ 5.92 (dd, J = 18.6, 6.1 Hz,
J
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The Journal of Organic Chemistry
Featured Article
by a solution of Pd2(dba)3 (2.3 mg, 2.5 μmol) and PPh3 (3.3 mg, 0.012
mmol) in THF (0.5 mL). Et2O was removed, and the mixture was
refluxed for 19 h. The reaction was quenched by addition of water and
extracted with AcOEt. The organic layer was washed with water, dried
over anhydrous Na2SO4, filtered, and concentrated under a vacuum.
The crude oil contained 4-bromoanisol and product 25: Rf = 0.62
(Heptane/CH2Cl2, 5/1); 1H NMR (500 MHz, CDCl3) δ 5.93 (dd, J =
18.7, 5.9 Hz, 1H), 5.71 (d, J = 18.7 Hz, 1H), 5.35−5.25 (m, 2H), 3.86
(dd, J = 6.1, 5.6 Hz, 1H), 2.25−2.18 (m, 1H), 2.18−2.10 (m, 1H),
0.95 (d, J = 6.7 Hz, 6H), 0.94 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.05
(s, 9H), 0.02 (s, 3H), −0.02 (s, 3H).
(3S)-tert-Butyl 3,4-Epoxybutanoate ((−)-28). To a solution of
tert-butyl but-3-enoate 27 (10 g, 70.4 mmol) in CH2Cl2 (100 mL) was
added m-CPBA (24.0 g, 97.4 mmol, 1.4 equiv) in one portion at 0 °C.
The reaction mixture was allowed to warm to room temperature and
stirred for 16 h. The white precipitate was filtered off, and the filtrate
concentrated under a vacuum. The residue was distilled under a
7.3 Hz, 2H), 1.80 (br s, 1H), 1.78−1.68 (m, 2H), 1.65−1.55 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 174.4, 62.4, 51.7, 33.8, 32.2, 21.2.
Methyl 5-Oxopentanoate (31). To a solution of oxalylchloride
(1.4 mL, 15.0 mmol) in CH2Cl2 (15 mL) at −78 °C was added
dropwise a solution of DMSO (2.3 mL, 29.9 mmol) in CH2Cl2
(15.mL). The reaction mixture was stirred for 10 min, and then a
solution of alcohol 30 (1.80 g, 13.6 mmol) in CH2Cl2 (15 mL) was
added, and the reaction mixture was stirred for 30 min. Et3N (10.1 mL,
72.5 mmol) was added, and the reaction mixture was allowed to warm
to room temperature. The reaction mixture was then hydrolyzed with
saturated aqueous NH4Cl and extracted with EtOAc. The organic
phase was dried over Na2SO4, filtered and concentrated under a
vacuum. The residue was distilled bulb to bulb under a vacuum
1
yielding aldehyde 31 (1.68 g, 95%) as a colorless oil: H NMR (300
MHz, CDCl3) δH (ppm) 9.78 (t, J = 1.3 Hz, 1H, CHO), 3.68 (s, 3H,
CO2CH3), 2.54 (dt, J = 7.3, 1.3 Hz, 2H, H4), 2.38 (t, J = 7.3 Hz, 2H,
H2), 1.96 (quint, J = 7.2 Hz, 2H, H3); 13C NMR (75 MHz, CDCl3) δC
(ppm) 201.7, 173.5, 43.1, 33.1, 17.5.
vacuum using a bulb to bulb Buchi oven affording the racemic epoxyde
̈
Methyl 5-Hydroxyoct-7-enoate (32). A flask fitted with a reflux
condenser was charged with a saturated aqueous NH4Cl solution (8.0
mL), THF (1.5 mL) and aldehyde 31 (1.04 g, 8.0 mmol).
Allylbromide (1.4 mL, 16.1 mmol) was added, followed by Zn dust
(1.17 g, 17.9 mmol), which led to a very exothermic evolution. After
20 min the reaction was completed, and the mixture was diluted with
water and 2 N HCl and extracted with EtOAc. The organic phase was
dried over Na2SO4, filtered, concentrated under a vacuum, and purified
by column chromatography (Heptane/EtOAc, 4/1) giving homoallylic
28 as a colorless oil (8.2 g, 75%). To a flask open to air and charged
with (S,S)-Co(II) salen (19.5 mg, 0.03 mmol) in toluene (2 mL) was
added AcOH (20 μL, 0.4 mmol). The solution, initially red, turned
brown within a few seconds and was stirred in open air for 45 min
before being concentrated under a vacuum. Racemic epoxyde 28
(998.2 mg, 6.3 mmol, 1 equiv) was added neat, the mixture was cooled
to 0 °C, and water (63 μL, 3.5 mmol, 0.55 equiv) was added dropwise,
while the temperature was controlled, which must stay below 15 °C.
After the end of the addition, the reaction mixture was allowed to
warm to room temperature (water bath was used to ensure
temperature remained around 20 °C). The solution was stirred in
air for 18 h and was then directly distilled under a vacuum in a bulb to
1
alcohol 32 (900 mg, 65%) as a colorless oil: H NMR (300 MHz,
CDCl3) δ 5.89−5.75 (m, 1H), 5.16−5.11 (m, 2H), 3.67 (s, 3H),
3.67−3.62 (m, 1H), 2.36 (t, J = 7.3 Hz, 2H), 2.20−2.10 (m, 1H),
1.86−1.66 (m, 3H), 1.55−1.43 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 174.3, 134.8, 118.5, 70.4, 51.8, 42.1, 36.3, 34.1, 21.2; MS (ESI, TOF)
m/z 195 (M + Na); HRMS (ESI, TOF) m/z calcd for C9H16O323Na
[M + Na]+ 195.0997, found 195.0996.
bulb Buchi oven affording enantiomerically enriched (ee determined at
̈
the next step on product 7) (S)-epoxyde (−)-28 (389 mg, 43%) as a
20
colorless oil: bp 26−30 °C/0.01 mbar; [α]D = −4.15 (c 0.92,
1
CHCl3); IR (film) ν 2977, 2930, 1726, 1367, 1256, 1151 cm−1; H
Methyl 5-Oxooct-7-enoate (8). A solution of oxalylchloride
(0.84 mL, 0.6 mmol, 1.17 equiv) in CH2Cl2 (20 mL) was cooled to
−78 °C, and a solution of DMSO (1.4 mL, 19.7 mmol) in CH2Cl2 (20
mL) was added dropwise. The reaction mixture was stirred for 10 min,
and then a solution of alcohol 32 (1.41 g, 8.2 mmol) in CH2Cl2 (15
mL) was added dropwise. The solution was stirred for 20 min before
introduction of Et3N (6.0 mL, 43.0 mmol). The mixture was stirred at
−78 °C for 4 h before being poured into a saturated aqueous NH4Cl
solution and extracted with CH2Cl2. The organic phase was dried over
Na2SO4, filtered, concentrated under a vacuum and purified by column
chromatography (Heptane/EtOAc, 9/1) giving homoallylic ketone 8
(1.10 g, 79%) as a colorless oil: IR (film) ν 2952, 2359, 1732, 1713,
NMR (300 MHz, CDCl3) δ 3.28−3.22 (m, 1H), 2.83 (t, J = 4.5 Hz,
1H), 2.57−2.53 (m, 2H), 2.48 (d, J = 6.0 Hz, 1H), 1.47 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 169.9, 81.5, 48.5, 46.9, 39.5, 28.3; MS (EI)
m/z 145 (M − Me), 139, 102; HRMS (ESI, TOF) m/z calcd for
C8H14O323Na [M + Na]+ 181.0841, found 181.0858.
(5R)-tert-Butyl 3-Hydroxy-6-(trimethylsilyle)hex-5-ynoate
(7). To a solution of trimethylsilylacetylene (450 μL, 3.2 mmol) in
toluene (5 mL) was added at 0 °C a 1.6 M solution of n-BuLi in
hexanes (2.0 mL, 3.2 mmol). The reaction mixture was stirred for 30
min, and a 1.0 M solution of Et2AlCl in heptane (3.2 mL, 3.2 mmol)
was added, and then stirring was continued for 40 min. Epoxyde
(−)-28 (389 mg, 2.46 mmol) was then added, and the reaction was
stirred for 2 h before being quenched by addition of water and
extracted with EtOAc, dried over Na2SO4, filtered and concentrated
under a vacuum. Purification by column chromatography (Heptane/
EtOAc, 4/1) gave homopropargylic alcohol 7 (504 mg, 80%) as a
colorless oil: [α]D20 = −25.5 (c 1.41, CHCl3); IR (film) ν 3449, 2961,
2359, 2175, 1726, 1248, 1147, 837 cm−1; 1H NMR (300 MHz,
CDCl3) δH (ppm) 4.15−4.07 (m, 1H), 3.13 (d, J = 3.0 Hz, 1H), 2.62−
2.55 (m, 1H), 2.50−2.39 (m, 3H), 1.47 (s, 9H), 0.16 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 171.9, 102.4, 87.6, 81.4, 66.7, 41.1, 28.1,
27.7, 28.1, 27.7, 0.0; MS (EI) m/z 257 (M + H), 201, 183, 167, 161,
145, 140; HRMS (ESI, TOF) m/z calcd for C13H24O323NaSi [M +
Na]+ 279.1392, found 279.1376. Determination of enantiomeric excess
by chiral HPLC: column AD-H 5 μm (4.6 × 150 mm), hexane/iso-
propanol, 98/2, 1 mL/min; tR(R) = 5.578 min; tR(S) = 5.995 min.
Methyl 5-Hydroxypentanoate (30). To a flask charged with δ-
valerolactone (15.0 g, 150.0 mmol) in MeOH (300 mL) was added
concentrated sulphuric acid (0.8 mL, 15.0 mmol), and the reaction
mixture was refluxed for 21 h. Solid NaHCO3 was added, and the
solution was filtered and partially concentrated under a vacuum. Water
was added, and the mixture was extracted with EtOAc, dried over
Na2SO4, filtered and concentrated under a vacuum. It yielded the
1
1638, 1435, 1198, 1169 cm−1; H NMR (300 MHz, CDCl3) δ 5.98−
5.85 (m, 1H), 5.21−5.11 (m, 2H), 3.68 (s, 3H), 3.17 (dt, J = 7.2, 1.7
Hz, 2H), 2.53 (t, J = 7.5 Hz, 2H), 2.34 (d, J = 7.5 Hz, 2H), 1.96−1.85
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 208.0, 173.8, 130.7, 119.1,
51.2, 48.0, 41.2, 33.2, 19.0; MS (EI) m/z 170 (M+), 129, 101; Anal.
Calcd for C9H14O3 C 63.51; H 8.29, found C 63.50; H 8.45.
Methyl 6-((2S,6R,Z)-6-(2-tert-Butoxy-2-oxoethyl)-4-
((trimethylsilyl)methylene)tetrahydro-2H-pyran-2-yl)-5-oxo-
hexanoate (33). To a solution of homoallylic ketone 8 (654.0 mg,
3.85 mmol) and homopropargylic alcohol 7 (1.568 g, 6.1 mmol) in
acetone (4 mL) were added [CpRu(MeCN)3]PF6 (127.8 mg, 0.29
mmol) and AcOH (7 μL, 0.12 mmol). The reaction mixture was
stirred at room temperature for 1.5 h. The solvents were then
evaporated under a vacuum, and the residue was purified by HPLC
(Heptane/EtOAc, 8/1, 23 bar, 30 mL/min) giving tetrahydropyran 33
20
(1.28 g, 78%) as a colorless oil: [α]D = +15.3 (c 1.05, CHCl3); IR
1
(film) ν 2933, 2358, 2339, 1702, 1407, 918 cm−1; H NMR (300
MHz, CDCl3) δ 5.28 (s, 1H), 3.84−3.78 (m, 1H), 3.70−3.65 (m, 1H),
3.66 (s, 3H), 2.64 (dd, J = 8.2, 15.4 Hz, 1H), 2.52 (t, J = 8.2 Hz, 1H),
2.49−2.48 (m, 1H), 2.46−2.45 (m, 1H), 2.41 (dd, J = 4.7, 15.4 Hz,
1H), 2.34−2.30 (m, 3H), 2.18 (d, J = 12.9 Hz, 1H), 2.05 (t, J = 12.0
Hz, 1H), 1.91−1.84 (m, 4H), 1.44 (s, 9H3), 0.10 (s, 9H3); 13C NMR
(75 MHz, CDCl3) δ 208.2, 173.9, 170.2, 151.9, 124.6, 80.8, 75.2, 75.1,
51.7, 49.4, 45.2, 42.9, 42.6, 39.3, 33.2, 28.3, 18.8, 0.5; MS (EI) m/z 426
1
expected hydroxyester 30 (16.93 g, 85%) as a colorless oil: H NMR
(300 MHz, CDCl3) δ 3.67 (s, 3H), 3.65 (t, J = 6.2 Hz, 2H), 2.37 (t, J =
K
dx.doi.org/10.1021/jo301066p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(M+), 370, 282, 226, 181, 129, 101; Anal. Calcd for C22H38O6Si C
61.94; H 8.98. Found C 62.46; H 9.14.
71.1, 51.5, 51.0, 42.6, 42.2, 36.6, 34.9, 33.9, 28.0, 20.9; MS (ESI, TOF)
m/z 437 ([M + Na]+); HRMS (ESI, TOF) m/z calcd for
C21H34O823Na [M + Na]+ 437.2151, found 437.2144.
(5R)-Methyl 6-((2S,6R,Z)-6-(2-tert-Butoxy-2-oxoethyl)-4-((tri-
methyl-silyl)methylene)tetrahydro-2H-pyran-2-yl)-5-hydroxy-
hexanoate (34a). (5S)-Methyl 6-((2S,6R,Z)-6-(2-tert-Butoxy-2-
oxoethyl)-4-((trimethyl-silyl)methylene)tetrahydro-2H-pyran-
2-yl)-5-hydroxyhexanoate (34b). To a solution of tetrahydropyran
33 (845.0 mg, 1.98 mmol) and CeCl3·7H2O (734.7 mg, 1.97 mmol) in
MeOH (5 mL) was added NaBH4 (81.5 mg, 2.2 mmol, 1.1 equiv) at 0
°C in small portions. The reaction mixture was stirred at 0 °C for 1 h
and then diluted with water and extracted with EtOAc. The organic
layer was dried over Na2SO4, filtered and concentrated under a
vacuum. HPLC purification (Heptane/EtOAc, 5/1, 36 bar, 20 mL/
min) allowed separation of diastereomer 34a (460 mg, 54%) and
diastrereoisomer 34b (263 mg, 31%). Data for 34a: [α]D20 = +22.9 (c
0.94, CHCl3); IR (film) ν 3524, 2949, 2358, 2339, 1728, 1622, 1366,
1246, 1153, 1131 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.26 (s, 1H),
3.86−3.81 (m, 1H), 3.79−3.68 (m, 1H), 3.66 (s, 3H), 3.64−3.57 (m,
1H), 2.51 (dd, J = 8.0 Hz, 15.3 Hz, 1H), 2.42−2.39 (m, 2H), 2.33 (t, J
= 7.4 Hz, 1H), 2.11 (d, J = 6.5 Hz, 2H), 1.94 (t, J = 12.5 Hz, 2H),
1.81−1.65 (m, 2H), 1.62−1.56 (m, 2H), 1.54−1.37 (m, 2H), 1.46 (s,
9H), 0.10 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.4, 170.3, 151.9,
124.5, 81.3, 80.4, 75.1, 71.6, 51.6, 45.8, 42.8, 42.6, 39.4, 36.9, 34.2,
28.3, 21.1, 0.5; MS (ESI, TOF) m/z 451 ([M + Na]+); HRMS (ESI,
TOF) m/z calcd for C22H40O623NaSi [M + Na]+ 451.2492, found
tert-Butyl 2-((2R,6S,Z)-4-(2-Methoxy-2-oxoethylidene)-6-
(((R)-6-oxotetrahydro-2H-pyran-2-yl)methyl)tetrahydro-2H-
pyran-2-yl)acetate (37). To a solution of alcohol 36 (66 mg, 0.16
mmol) in toluene (3 mL) was added silica (59.4 mg). The suspension
was refluxed for 26 h and then filtered and concentrated under a
vacuum. Column chromatography purification (Heptane/EtOAc, 2/1)
gave lactone 37 (44 mg, 72%) as a colorless oil: [α]D20 = +48.5 (c 0.70,
1
CHCl3); IR (film) ν 2949, 1714, 1650, 1366, 1239, 1150 cm−1; H
NMR (500 MHz, CDCl3) δ 5.70 (s, 1H), 4.54−4.46 (m, 1H), 3.85 (d,
J = 13.9 Hz, 1H), 3.79−3.66 (m, 1H), 3.69 (s, 3H), 3.62−3.55 (m,
1H), 2.62−2.51 (m, 1H), 2.50−2.38 (m, 3H), 2.25−2.16 (m, 2H),
2.11−1.70 (m, 7H), 1.66−1.50 (m, 2H), 1.45 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 171.9, 170.1, 166.8, 156.0, 115.3, 80.8, 74.6, 74.1,
51.2, 42.6, 42.3, 41.5, 35.1, 29.6, 29.5, 28.2, 27.2, 18.7; MS (ESI, TOF)
m/z 405 ([M + Na]+); HRMS (ESI, TOF) m/z calcd for
C20H30O723Na [M + Na]+ 405.1889, found 405.1889.
(3S,4E,6R,7S,8E)-7-(tert-Butyldimethylsilyloxy)-3,6-dimethyl-
9-(trimethylsilyl)nona-4,8-dienenitrile (39). To a solution of
alcohol 17 (584.9 mg, 1.64 mmol) in Et2O (9 mL) at room
temperature was added PPh3 (1.720 g, 6.6 mmol), and then DEAD
(1.0 mL, 6.6 mmol), and acetone cyanohydrin (375 μL, 4.1 mmol).
The solution was then stirred for 5 h at room temperature, quenched
by addition of water and extracted with CH2Cl2. The organic phase
was washed with water, dried over anhydrous Na2SO4 and filtered.
DEAD (0.2 mL, 1.3 mmol, 0.8 equiv) was added to consume the
excess of PPh3, and then the organic layer was concentrated under a
vacuum. The crude oil was purified by column chromatography
(Heptane/EtOAc, 40/1) to give nitrile 39 (451.0 mg, 75%): Rf = 0.42
20
451.2524. Data for 34b: [α]D = +18.1 (c 1.28, CHCl3); IR (film) ν
3484, 2949, 2359, 1729, 1622, 1247, 1152, 1132 cm−1; 1H NMR (300
MHz, CDCl3) δ 5.26 (s, 1H), 3.88−3.80 (m, 1H), 3.74−3.63 (m, 1H),
3.68 (s, 3H), 2.82 (d, J = 4.6 Hz, 1H), 2.53−2.42 (m, 2H), 2.39 (d, J =
5.0 Hz, 1H), 2.36−2.31 (m, 2H), 2.18 (t, J = 11.6 Hz, 1H), 2.07 (d, J =
13.1 Hz, 1H), 1.93 (t, J = 12.4 Hz, 1H), 1.84−1.73 (m, 1H), 1.72−
1.56 (m, 4H), 1.55−1.40 (m, 2H), 1.46 (s, 9H), 0.10 (s, 9H); 13C
NMR (75 MHz, CDCl3) δ 174.3, 170.5, 152.4, 124.4, 81.1, 76.4, 75.2,
68.4, 51.6, 45.2, 42.7, 41.9, 39.4, 36.4, 34.2, 28.3, 21.6, 0.5; MS (ESI,
TOF) m/z 451 ([M + Na]+); HRMS (ESI, TOF) m/z calcd for
C22H40O623NaSi [M + Na]+ 451.2492, found 451.2476.
20
(Heptane/EtOAc, 10/1); [α]D = +2.6 (c 1.06, CHCl3); IR (film) ν
1
2956, 2856, 1458, 1248, 1107, 836, 775, 668 cm−1; H NMR (500
MHz, CDCl3) δ 5.91 (dd, J = 18.7, 6.0 Hz, 1H), 5.73 (d, J = 18.6 Hz,
1H), 5.50 (dd, J = 15.6, 7.3 Hz, 1H), 5.32 (dd, J = 15.6, 7.0 Hz, 1H),
3.89 (dd, J = 5.5, 5.2 Hz, 1H), 2.56−2.48 (m, 1H), 2.34 (dd, J = 16.5,
6.1 Hz, 1H), 2.27 (dd, J = 16.5, 7.0 Hz, 1H), 2.24−2.18 (m, 1H), 1.14
(d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
9H), 0.02 (s, 3H), −0.02 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
147.6, 134.2, 131.6, 130.3, 118.8, 79.5, 43.1, 33.8, 26.1, 25.2, 20.0, 18.4,
15.3, −1.1, −4.0, −4.7; LRMS (ESI, TOF) m/z (%) 388.2 (100) [M +
Na]+; HRMS (ESI, TOF) m/z calcd for C20H39NO23NaSi2 [M + Na]+
388.2468, found 388.2476.
(5R)-Methyl 6-((2S,6R,Z)-6-(2-tert-Butoxy-2-oxoethyl)-4-
(iodomethylene)tetrahydro-2H-pyran-2-yl)-5-hydroxyhexa-
noate (35). A solution of 34a (90 mg, 0.21 mmol) in CH3CN (3 mL)
was protected from light and cooled to 0 °C, and then NIS (78.6 mg,
0.35 mmol) was added, and the reaction was stirred at 0 °C for 25 min.
The reaction mixture was hydrolyzed by addition of a solution of
sodium thiosulfate and extracted with EtOAc. The organic layer was
dried over Na2SO4, filtered and concentrated under a vacuum. Column
chromatography (Heptane/EtOAc, 4/1) gave the desired vinyl iodide
(3S,4E,6R,7S,8E)-7-(tert-Butyldimethylsilyloxy)-3,6-dimethyl-
9-(trimethylsilyl)nona-4,8-dienal (40). To a solution of nitrile 39
(446.5 mg, 1.22 mmol) in CH2Cl2 (10 mL) at −78 °C was added a 1.0
M solution of di-iso-butylaluminium hydride in heptane (2.4 mL, 2.4
mmol). The solution was allowed to warm to 0 °C over 1.75 h and
stirred at this temperature for 30 min. The solution was quenched at 0
°C by adding a saturated aqueous solution of Rochelle salt, stirred for
2.5 h, and extracted with CH2Cl2. The organic layer was washed with
water, dried over anhydrous Na2SO4, filtered, and concentrated under
a vacuum to give aldehyde 40 (425.5 mg, 95%): Rf = 0.46 (Heptane/
EtOAc, 10/1); [α]D = +21.0 (c 1.03, CHCl3); IR (film) ν 2954, 2928,
2856, 1729, 1247, 833, 774 cm−1; 1H NMR (500 MHz, CDCl3) δ 9.71
(s, 1H), 5.90 (dd, J = 18.6, 5.9 Hz, 1H), 5.71 (d, J = 18.6 Hz, 1H), 5.40
(dd, J = 15.6, 7.3 Hz, 1H), 5.32 (dd, J = 15.6, 6.7 Hz, 1H), 3.86 (dd, J
= 5.5, 5.2 Hz, 1H), 2.75−2.67 (m, 1H), 2.40 (ddd, J = 15.9, 7.0, 1.8
Hz, 1H), 2.31 (ddd, J = 15.9, 7.0, 2.1 Hz, 1H), 2.21−2.14 (m, 1H),
1.04 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.05
(s, 9H), 0.01 (s, 3H), −0.03 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ
202.8, 147.8, 133.7, 132.6, 130.1, 79.6, 50.6, 43.2, 31.8, 26.1, 20.8, 18.4,
15.5, −1.2, −4.0, −4.7; LRMS (ESI, TOF) m/z (%) 391.2 (51) [M +
Na]+, 423.3 (100) [M + MeOH + Na]+; HRMS (ESI, TOF) m/z
calcd for C20H40O223NaSi2 [M + Na]+ 391.2465, found 391.2472.
(4S,6S,7E,9R,10S,11E)-10-(tert-Butyldimethylsilyloxy)-6,9-di-
methyl-12-(trimethylsilyl)dodeca-1,7,11-trien-4-ol (41). To a
solution of (−)Ipc2BOMe (772.4 mg, 2.4 mmol, 2.2 equiv) in Et2O
(5 mL) at 0 °C was added a 1.0 M solution of allylmagnesium bromide
in Et2O (2.4 mL, 2.4 mmol, 2.2 equiv). The solution was allowed to
20
35 (100 mg, 99%) as a colorless oil: [α]D = +49.1 (c 1.07, CHCl3);
IR (film) ν 3521, 2947, 1726, 1367, 1264, 1151, 1134 cm−1; 1H NMR
(500 MHz, CDCl3) δ 5.99 (s, 1H), 3.86−3.70 (m, 2H), 3.66 (s, 3H),
3.61−3.53 (m, 1H), 3.47 (m, 1H), 2.70 (dt, J = 1.8, 13.7 Hz, 1H), 2.52
(dd, J = 15.6, 6.5 Hz, 1H), 2.45 (dd, J = 4.3, 15.3 Hz, 1H), 2.39−2.36
(m, 1H), 2.33 (t, J = 7.4 Hz, 2H), 2.07 (t, J = 12.2 Hz, 1H), 1.88 (t, J =
12.5 Hz, 1H), 1.80−1.57 (m, 5H), 1.53−1.39 (m, 2H), 1.46 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 174.4, 170.1, 145.1, 81.5, 79.5, 74.7,
74.4, 71.3, 51.7, 43.2, 42.33, 42.30, 40.9, 36.9, 34.1, 28.3, 21.1; MS
(ESI, TOF) m/z 505 ([M + Na]+); HRMS (ESI, TOF) m/z calcd for
C19H31IO623Na [M + Na]+ 505.1063, found 505.1082.
(5R)-Methyl 6-((2S,6R,Z)-6-(2-tert-Butoxy-2-oxoethyl)-4-(2-
methoxy-2-oxoethylidene)tetrahydro-2H-pyran-2-yl)-5-hy-
droxyhexanoate (36). To a solution of vinyl iodode 35 (75 mg, 0.16
mmol) in MeOH (3 mL) were added PdCl2(dppf) (5.9 mg, 8.1 μmol)
and Et3N (43 μL, 0.31 mmol). The reaction flask was purged with CO,
and the reaction mixture was refluxed under vigorous stirring for 45
min. After cooling to room temperature, the reaction mixture was
concentrated under a vacuum. Column chromatography (Heptane/
EtOAc, 2/1) gave the desired ester 36 (48 mg, 75%) as a brown oil: IR
1
(film) ν 3526, 2948, 1714, 1650, 1149 cm−1; H NMR (300 MHz,
CDCl3) δ 5.70 (s, 1H), 3.85 (dd, J = 1.9, 13.7 Hz, 1H), 3.84−3.78 (m,
3H), 3.69 (s, 3H), 3.66 (s, 3H), 3.48 (s, 1H), 2.53−2.43 (m, 3H), 2.33
(t, J = 7.3 Hz, 3H), 2.16 (d, J = 6.4 Hz, 3H), 1.89 (t, J = 12.5 Hz, 1H),
1.80−1.58 (m, 8H), 1.54−1.39 (m, 6H), 1.46 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 174.1, 170.0, 166.6, 155.5, 115.1, 81.2, 79.5, 74.5,
L
dx.doi.org/10.1021/jo301066p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
warm to room temperature and stirred for 1.5 h leading to the
formation of a white precipitate. After cooling down to −78 °C, a
solution of aldehyde 40 (368.7 mg, 1.22 mmol, 1.0 equiv) in Et2O (10
mL) at 0 °C was added, and the resulting solution was stirred at −78
°C for 1 h, 30 min at 0 °C, and then 45 min at room temperature. The
solution was cooled at 0 °C and quenched by addition of H2O2 30% (6
mL) and 2 N aqueous NaOH (6 mL). The resultant mixture was
stirred at room temperature for 16 h and then extracted with Et2O.
The organic layer was washed with water, dried over anhydrous
Na2SO4, filtered and concentrated under a vacuum. HPLC purification
(Heptane/EtOAc, 30/1; 40 mL/min) allowed separation of the two
diastereomers (dr 93/7, by 1H NMR) and gave homoallylic alcohol 41
CDCl3) δ 148.1, 137.2, 135.9, 130.9, 129.7, 79.8, 70.4, 63.5, 43.3, 43.0,
33.4, 33.0, 29.5, 27.4, 26.1, 22.9, 20.7, 18.5, 18.4, 15.3, 12.8, −1.1, −4.0,
−4.6; LRMS (ESI, TOF) m/z (%) 607.4 (100) [M + Na]+; HRMS
(ESI, TOF) m/z calcd for C32H68O323NaSi3 [M + Na]+ 607.4374,
found 607.4365.
(5S,7S,8E,10R,11S,12E)-11-(tert-Butyldimethylsilyloxy)-7,10-
dimethyl-5-(triisopropylsilyloxy)-13-(trimethylsilyl)trideca-
8,12-dienenitrile (44). To a solution of alcohol 43 (166.0 mg, 0.28
mmol) and PPh3 (297.6 mg, 1.1 mmol, 4.0 equiv) in Et2O (2 mL) at
room temperature was added DEAD (185 μL, 1.2 mmol), and acetone
cyanohydrin (80 μL, 0.9 mmol). The reaction mixture was then stirred
for 15 h at room temperature, concentrated and then purified by
column chromatography (Heptane/CH2Cl2, 10/1, 6/1 and 2/1) to
give nitrile 44 (122.0 mg, 72%): Rf = 0.11 (Heptane/CH2Cl2, 10/1);
20
(261.5 mg, 58%): Rf = 0.36 (Heptane/EtOAc, 10/1); [α]D = +18.0
(c 1.12, CHCl3); IR (film) ν 3380, 2954, 2924, 2857, 1462, 1248, 833,
20
1
774 cm−1; H NMR (500 MHz, CDCl3) δ 5.95 (dd, J = 18.6, 5.8 Hz,
[α]D = +0.1 (c 1.09, CHCl3); IR (film) ν 2954, 2928, 2865, 1462,
1248, 836, 775, 677 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.92 (dd, J
= 18.6, 5.9 Hz, 1H), 5.72 (d, J = 18.6 Hz, 1H), 5.35 (dd, J = 15.6, 7.0
Hz, 1H), 5.26 (dd, J = 15.6, 7.0 Hz, 1H), 3.96−3.92 (m, 1H), 3.87 (t, J
= 5.5 Hz, 1H), 2.39−2.31 (m, 2H), 2.18−2.09 (m, 2H), 1.81−1.40 (m,
9H), 1.05 (s, 18H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H),
0.89 (s, 9H), 0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 148.0, 135.7, 131.1, 129.8, 79.8, 69.8, 43.8, 43.0,
35.4, 33.5, 26.1, 20.8, 20.3, 18.4, 17.7, 15.4, 12.9, −1.1, −4.0, −4.6;
LRMS (ESI, TOF) m/z (%) 616.4 (100) [M + Na]+; HRMS (ESI,
TOF) m/z calcd for C33H67NO223NaSi3 [M + Na]+ 616.4377, found
616.4388.
1H), 5.86−5.78 (m, 1H), 5.75 (d, J = 18.9 Hz, 1H), 5.38 (dd, J = 15.6,
7.6 Hz, 1H), 5.22 (dd, J = 15.6, 8.2 Hz, 1H), 5.13 (d, J = 4.6 Hz, 1H),
5.10 (s, 1H), 3.90 (dd, J = 5.2, 4.9 Hz, 1H), 3.72−3.67 (m, 1H), 2.39−
2.31 (m, 1H), 2.27−2.12 (m, 3H), 1.46−1.33 (m, 2H), 0.99 (d, J = 6.7
Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 9H), 0.02 (s,
3H), −0.02 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 147.6, 135.5,
135.1, 132.0, 129.9, 118.0, 79.6, 68.7, 44.2, 43.3, 42.5, 33.9, 26.1, 21.9,
18.5, 15.9, −1.1, −4.0, −4.7; LRMS (ESI, TOF) m/z (%) 433.3 (100)
[M + Na]+; HRMS (ESI, TOF) m/z calcd for C23H46O223NaSi2 [M +
Na]+ 433.2934, found 433.2947.
(5S,6R,9S,11S,E)-11-Allyl-13,13-diisopropyl-2,2,3,3,6,9,14-
heptamethyl-5-((E)-2-(trimethylsilyl)vinyl)-4,12-dioxa-3,13-dis-
ilapentadec-7-ene (42). To a solution of homoallylic alcohol 41
(240.6 mg, 0.59 mmol) and 2,6-lutidine (140 μL, 1.2 mmol) in
CH2Cl2 (2 mL) at 0 °C was added TIPSOTf (190 μL, 0.7 mmol). The
solution was stirred at 0 °C for 2 h, quenched at 0 °C with water and
extracted with CH2Cl2. The organic layer was washed with saturated
aqueous NH4Cl, dried over anhydrous Na2SO4, filtered, and
concentrated under a vacuum. Purification by column chromatography
(Heptane/CH2Cl2, 30/1) gave triene 42 (323.5 mg, 97%): Rf = 0.48
(Heptane/CH2Cl2, 10/1); [α]D20 = +13.2 (c 1.12, CHCl3); IR (film) ν
(5S,7S,8E,10R,11S,12E)-11-(tert-Butyldimethylsilyloxy)-7,10-
dimethyl-5-(triisopropylsilyloxy)-13-(trimethylsilyl)trideca-
8,12-dienal (45). To a solution of nitrile 44 (117.2 mg, 0.20 mmol)
in CH2Cl2 (2 mL) at −78 °C was added a 1.0 M solution of
diisobutylaluminium hydride in heptane (395 μL, 0.4 mmol). The
solution was allowed to warm to 0 °C over 1.5 h and was stirred at 0
°C for 2 h. The solution was quenched at 0 °C by addition of a
saturated aqueous Rochelle salt solution, stirred for 1.5 h and extracted
with CH2Cl2. The organic phase was washed with water, dried over
anhydrous Na2SO4, filtered, and concentrated under a vacuum to give
aldehyde 45 (118 mg, 100%): Rf = 0.52 (Heptane/EtOAc, 7/1);
1
2954, 2865, 2358, 1462, 1248, 1060, 835, 774, 676 cm−1; H NMR
20
[α]D = +6.3 (c 1.08, CHCl3); IR (film) ν 2954, 2928, 2865, 1731,
(500 MHz, CDCl3) δ 5.93 (dd, J = 18.6, 5.8 Hz, 1H), 5.91−5.82 (m,
1H), 5.71 (d, J = 18.9 Hz, 1H), 5.35 (dd, J = 15.6, 6.7 Hz, 1H), 5.26
(dd, J = 15.6, 7.0 Hz, 1H), 5.05 (d, J = 3.4 Hz, 1H), 5.02 (s, 1H),
3.94−3.89 (m, 1H), 3.86 (t, J = 5.5 Hz, 1H,), 2.34−2.12 (m, 4H),
1.73−1.34 (m, 5H), 1.06 (s, 18H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J
= 6.7 Hz, 3H), 0.89 (s, 9H), 0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H);
13C NMR (75.5 MHz, CDCl3) δ 148.1, 135.9, 135.1, 130.9, 129.7,
116.9, 79.8, 70.4, 44.1, 43.1, 41.8, 33.2, 32.1, 26.1, 22.9, 21.1, 18.4,
15.4, 12.9, −1.1, −4.0, −4.6; LRMS (ESI, TOF) m/z (%) 589.4 (100)
[M + Na]+; HRMS (ESI, TOF) m/z calcd for C32H66O223NaSi3 [M +
Na]+ 589.4268, found 589.4270.
1462, 1248, 1059, 836, 775, 668 cm−1; 1H NMR (500 MHz, CDCl3) δ
9.76 (s, 1H), 5.92 (dd, J = 18.6, 5.8 Hz, 1H), 5.72 (d, J = 18.6 Hz, 1H),
5.36 (dd, J = 15.6, 6.7 Hz, 1H), 5.27 (dd, J = 15.6, 7.0 Hz, 1H), 3.93−
3.86 (m, 2H), 2.44−2.40 (m, 1H), 2.19−2.13 (m, 2H), 1.76−1.35 (m,
10H), 1.05 (s, 18H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H),
0.89 (s, 9H), 0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 202.8, 148.1, 135.8, 131.0, 129.8, 79.8, 70.3,
44.3, 43.9, 43.0, 36.2, 33.4, 26.1, 20.9, 18.4, 17.0, 15.4, 12.9, −1.1, −4.0,
−4.6; LRMS (ESI, TOF) m/z (%) 619.5 (5) [M + Na]+, 651.5 (100)
[M + MeOH + Na]+; HRMS (ESI, TOF) m/z calcd for
C34H72O423NaSi3 [M + MeOH + Na]+ 651.4636, found 651.4639.
(8S,10S,11E,13R,14S,15E)-14-(tert-Butyldimethylsilyloxy)-
10,13-dimethyl-8-(triisopropylsilyloxy)-16-(trimethylsilyl)-
hexadeca-1,11,15-trien-4-ol (46). To a solution of crude aldehyde
45 (0.20 mmol) in Et2O (2 mL) at 0 °C was added a 1.0 M solution of
allylmagnesium bromide in Et2O. The solution was stirred at 0 °C for
2.25 h and at room temperature for 1 h, and then quenched by
addition of a saturated aqueous NH4Cl solution (60 μL). A white
precipitate appeared, and the mixture was filtered over a silica pad. The
crude product was purified by column chromatography (Heptane/
EtOAc, 25/1, 20/1 and 15/1) to give homoallylic alcohol 46 (65.4 mg,
52%): Rf = 0.37 (Heptane/EtOAc, 7/1); IR (film) ν 2928, 2864, 1462,
1248, 1058, 993, 835, 774, 675 cm−1; 1H NMR (500 MHz, CDCl3) δ
5.93 (dd, J = 18.6, 5.9 Hz, 1H), 5.87−5.79 (m, 1H), 5.71 (d, J = 18.6
Hz, 1H), 5.36 (dd, J = 15.6, 6.7 Hz, 1H), 5.27 (dd, J = 15.6, 6.7 Hz,
1H), 5.15 (br s, 1H), 5.12 (s, 1H), 3.89−3.85 (m, 2H), 3.65 (br s,
1H), 2.34−2.28 (m, 1H), 2.21−2.11 (m, 3H), 1.73−1.38 (m, 12H),
1.05 (s, 18H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.89
(s, 9H), 0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H); 13C NMR (75.5
MHz, CDCl3) δ 148.1, 136.0, 135.9, 130.8, 129.7, 118.3, 79.8, 70.8,
70.7, 44.1, 43.0, 42.0, 37.3, 37.0, 33.4, 26.1, 21.1, 20.4, 18.4, 15.4, 13.0,
−1.1, −4.0, −4.6; LRMS (ESI, TOF) m/z (%) 661.5 (100) [M +
(4S,6S,7E,9R,10S,11E)-10-(tert-Butyldimethylsilyloxy)-6,9-di-
methyl-4-(triisopropylsilyloxy)-12-(trimethylsilyl)dodeca-7,11-
dien-1-ol (43). A solution of triene 42 (173.7 mg, 0.31 mmol) and
solid 9-BBN (41.1 mg, 0.4 mmol) in THF (2 mL) was stirred at room
temperature for 17.5 h. Solid 9-BBN dimer (11.2 mg, 0.05 mmol) was
added, and the solution was stirred at room temperature for 4 h, and
then it was heated at 40 °C for 2 h. Then H2O2 30% (1 mL), 3 N
aqueous NaOH (1 mL) and EtOH (1 mL) were added, and the
mixture was stirred at room temperature for 1 h. After extraction by
CH2Cl2, the organic phase was washed with saturated aqueous
Na2S2O3 and water, dried over anhydrous Na2SO4, filtered, and
concentrated under a vacuum. Purification by column chromatography
(Heptane/CH2Cl2, 30/1 then 10/1 and Heptane/EtOAc 20/1 then
10/1) gave alcohol 43 (134.0 mg, 75%): Rf = 0.62 (Heptane/EtOAc,
20
1/1); [α]D = 0.00 (c 1.05, CHCl3); IR (film) ν 3328, 2928, 2864,
1462, 1248, 1056, 835, 774, 675 cm−1; 1H NMR (500 MHz, CDCl3) δ
5.93 (dd, J = 18.6, 5.8 Hz, 1H), 5.72 (d, J = 18.6 Hz, 1H), 5.36 (dd, J =
15.6, 7.0 Hz, 1H), 5.28 (dd, J = 15.6, 6.7 Hz, 1H), 3.99−3.95 (m, 1H),
3.87 (t, J = 5.5 Hz, 1H), 3.67−3.59 (m, 2H), 2.42−2.40 (m, 0.5H),
2.18−2.10 (m, 2H), 1.89−1.86 (m, 0.5H), 1.65−1.38 (m, 9H), 1.07 (s,
18H), 0.94 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H),
0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H); 13C NMR (75.5 MHz,
M
dx.doi.org/10.1021/jo301066p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Na]+; HRMS (ESI, TOF) m/z calcd for C36H74O323NaSi3 [M + Na]+
661.4844, found 661.4844.
ACKNOWLEDGMENTS
■
We thank CNRS for its financial support. We thank Dr. Yves
Janin (Institut Pasteur, Paris) for all the fruitful scientific
discussions we used to have.
(8S,10S,11E,13R,14S,15E)-14-(tert-Butyldimethylsilyloxy)-
10,13-dimethyl-8-(triisopropylsilyloxy)-16-(trimethylsilyl)-
hexadeca-1,11,15-trien-4-one (38). To a solution of homoallylic
alcohol 46 (59.4 mg, 0.093 mmol) in CH2Cl2 (1 mL) at room
temperature was added Dess−Martin periodinane (59.1 mg, 0.14
mmol). The solution was stirred for 2 h, and then more Dess−Martin
periodinane (31.0 mg, 0.073 mmol) was added. The solution was
stirred for another 1.5 h, quenched by addition of a saturated aqueous
NaHCO3 solution and Na2S2O3, and then extracted with CH2Cl2. The
organic phase was washed with saturated aqueous NaHCO3 and
Na2S2O3, dried over anhydrous Na2SO4, filtered, and concentrated
under a vacuum. The crude product was purified by column
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(m, 2H), 5.71 (d, J = 18.6 Hz, 1H), 5.36 (dd, J = 15.7, 6.8 Hz, 1H),
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tert-Butyl-2-((2R,6S,Z)-6-((6S,8S,9E,11R,12S,13E)-12-(tert-bu-
tyldimethylsilyloxy)-8,11-dimethyl-2-oxo-6-(triisopropylsily-
loxy)-14-(trimethylsilyl)tetradeca-9,13-dienyl)-4-
((trimethylsilyl)methylene)tetrahydro-2H-pyran-2-yl)acetate
(47). A solution of homoallylic ketone 38 (38.9 mg, 0.061 mmol),
homoallylic alcohol 7 (25.0 mg, 0.1 mmol), [CpRu(MeCN)3]PF6 (1.9
mg, 4.3 μmol) and AcOH (0.1 μL, 1.8 μmol) in acetone (200 μL) was
stirred at room temperature for 5.5 h. The mixture was then filtered
over a silica pad, and the crude oil was purified by column
chromatography (Heptane/Et2O, 50/1 and 40/1, then Heptane/
EtOAc, 30/1 and 20/1) to give tetrahydropyran 47 (39.1 mg, 72%): Rf
20
= 0.49 (Heptane/EtOAc, 10/1); [α]D = +9.4 (c 0.89, CHCl3); IR
(film) ν 2953, 2865, 1731, 1623, 1462, 1366, 1248, 1062, 993, 834,
774, 675 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.93 (dd, J = 18.6, 5.8
Hz, 1H), 5.71 (d, J = 18.9 Hz, 1H), 5.36 (dd, J = 15.8, 6.7 Hz, 1H),
5.28 (s, 1H), 5.27 (dd, J = 15.3, 7.0 Hz, 1H), 3.89−3.79 (m, 3H),
3.70−3.65 (m, 1H), 2.66 (dd, J = 15.6, 7.6 Hz, 1H), 2.50−2.37 (m,
5H), 2.33 (dd, J = 14.7, 6.1 Hz, 1H), 2.20−2.13 (m, 3H), 2.03 (t, J =
12.2 Hz, 1H), 1.88 (t, J = 12.2 Hz, 1H), 1.65−1.36 (m, 9H), 1.44 (s,
9H), 1.05 (s, 18H), 0.94 (s, 3H), 0.92 (s, 3H), 0.89 (s, 9H), 0.10 (s,
9H), 0.04 (s, 9H), 0.02 (s, 3H), −0.02 (s, 3H2); 13C NMR (75.5 MHz,
CDCl3) δ 208.8, 170.2, 152.0, 148.1, 135.9, 130.8, 129.7, 124.5, 80.7,
79.8, 75.1, 70.6, 49.1, 45.1, 44.2, 44.0, 43.0, 39.3, 36.5, 33.3, 28.2, 26.1,
21.0, 18.6, 18.4, 15.4, 12.9, 0.4, −1.1, −4.0, −4.6; LRMS (ESI, TOF)
m/z (%) 915.6 (100) [M + Na]+; HRMS (ESI, TOF) m/z calcd for
C49H96O623NaSi4 [M + Na]+ 915.6182, found 915.6149.
ASSOCIATED CONTENT
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* Supporting Information
1H and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
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emmanue.roulland@icsn.cnrs-gif.fr.
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