Strategic use of nickel(0)-catalyzed enyne-epoxide reductive coupling toward the synthesis of (-)-cyatha-3,12-diene

Article abstract of DOI:10.1016/j.tet.2008.11.086

Various situations are explored in which the nickel(0)-catalyzed enyne-epoxide reductive coupling was utilized to access key intermediates toward the total synthesis of (-)-cyatha-3,12-diene (1). Enantioenriched 3,5-dien-1-ols with a variety of functionality were obtained in a straightforward manner from easily accessible 1,3-enynes and terminal epoxides.

Full text of DOI:10.1016/j.tet.2008.11.086

Tetrahedron 65 (2009) 3270–3280
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Strategic use of nickel(0)-catalyzed enyne–epoxide reductive coupling
toward the synthesis of (ꢀ)-cyatha-3,12-diene
*
Brian A. Sparling, Graham L. Simpson, Timothy F. Jamison
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Various situations are explored in which the nickel(0)-catalyzed enyne–epoxide reductive coupling was
utilized to access key intermediates toward the total synthesis of (ꢀ)-cyatha-3,12-diene (1). Enan-
tioenriched 3,5-dien-1-ols with a variety of functionality were obtained in a straightforward manner
from easily accessible 1,3-enynes and terminal epoxides.
Received 17 September 2008
Received in revised form 24 November 2008
Accepted 26 November 2008
Available online 30 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
bearing three fused six-membered rings and a fused 5,6,6-ring
system.7,8
The cyathanes are diterpenoid fungal metabolites having
a structurally unique fused, angular tricyclic core composed of
contiguous five-, six-, and seven-membered rings.1 Many cyathanes
are known to have pronounced antifungal and antibacterial prop-
erties, and some potently induce nerve growth factor (NGF) pro-
duction in human nerve cells.2,3 In 1979, Ayer et al. hypothesized
that tricycle 1 was the common biological precursor of all cyathane
metabolites;4 22 years after the initial proposal, this compound was
isolated from the basidiomycete Hericium erinaceum YB4-6237 and
named (ꢀ)-cyatha-3,12-diene (1).5 Its potential role in cyathane
biosynthesis along with its unknown biological properties and low
abundance in nature makes cyatha-3,12-diene an attractive target
for total synthesis.
A focus of our research program has been the catalytic, multi-
component coupling reaction involving cis addition across an al-
kyne.9 Generally, we have found that use of a low-valent nickel
catalyst, an electron-rich trialkylphosphine ligand, and trie-
thylborane as a stoichiometric reductant affords reductive or
alkylative alkyne coupling in a variety of functional contexts to
form (E)-trisubstituted or tetrasubstituted olefins (Scheme 1).
Specifically, alkynes have been coupled to electrophilic double
bonds including aldehydes,10 ketones,11 and imines12 in the pres-
ence of triethylborane to form allylic alcohols and allylic amines.
Asymmetric variants of such couplings have also been developed
using chiral phosphine ligands,13 and enantioenriched
a-oxy-
aldehydes have been shown to couple with high diastereo-
selectivity to form anti-1,2-diols.14
Me
Me
H
H
OH
R3
O
Me
R4(H)
R1
Me
R3
R3
R4(H)
Me
R2
Et
1; (–)-cyatha-3,12-diene
R1
R2
NHR5
R3
cat.
NHR5
H
Ni(cod)2
+ Et3B +
Various strategies have been employed toward the synthesis of
cyathane natural products; however, all of such approaches rely on
stepwise installation of the central three rings.6 A possible alter-
native to these strategies is a transannular Diels–Alder (TADA)
reaction to form the characteristic cyathane core from a 14-mem-
bered macrocyclic triene in a single step. While a TADA reaction has
not been utilized in the synthesis of fused 5,6,7-ring systems, it has
been successfully implemented in the synthesis of tricyclic systems
R1
phosphine
R2
H
R3
R3
OH
R1
O
R2
Scheme 1.
Regioselective addition across the alkyne has been a challenge
for these intermolecular coupling reactions and several solutions
have been implemented. The presence of a trimethylsilyl group on
* Corresponding author. Tel.: þ1 617 253 1830; fax: þ1 617 253 3297.
E-mail address: tfj@mit.edu (T.F. Jamison).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.086

B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
3271
1. Cp2Zr(H)Cl, THF,
0 °C to rt, then NIS
the alkyne terminus or the presence of conjugated aryl groups and
olefins10b directs coupling to the terminal end of the alkyne. In the
olefin case, transient interaction of the conjugated -bond with the
metal center may direct the addition (Scheme 2). With this po-
tential to afford high regioselectivity and stereoselectivity, we have
implemented alkyne reductive coupling strategies toward the
synthesis of complex natural products, such as (ꢀ)-terpestacin15
and members of the amphidinolide T class.16
4
RO
2. 2.5 mol% Pd(PPh3)4,
5 mol% CuI, propyne,
pyrrolidine, –78 °C to rt
55% yield (2 steps)
p
6: R = H
TBSCl, DMAP,
Et3N, DCM
7: R = TBS
86% yield
Scheme 4.
corresponding trans-substituted vinyl iodide. This iodide was then
coupled with propyne using Sonogashira conditions21 to reliably
yield enyne 4 in multigram quantities in 55% yield over two steps.
Terminal epoxide 5 was synthesized in two steps from com-
R3
R
OH
R4
R3
cat. Ni(cod)2
cat. Bu3P
O
R2
R2
+
*
*
R4
Et3B
R1
R1
R
mercially available b-citronellene based upon an established route
L
that utilized diastereoselective iodolactonization.22
O
R4
R1 Ni
With enyne 4 and epoxide 5 readily available in multigram
quantities, the pivotal reductive coupling step was investigated
(Table 1). The presence of a phosphine catalyst was necessary for
conversion to the diene 8, and a catalyst to phosphine ratio of 1:2
gave the best results (entry 2). Long reaction times were needed to
give appreciable yield, presumably due to the unreactive nature of
the epoxide. In entries 2 and 3, a significant amount of 5 was re-
covered from the reaction. It is believed that the methyl sub-
stitution adjacent to the terminal epoxide in 5 lowered the
reactivity toward coupling. None of the enyne was recovered from
the reaction. In the presence of a nickel(0) catalyst and an electron-
rich phosphine, alkynes are known to readily dimerize and
cyclotrimerize.23 Mixtures of such polymerization products were
recovered in all these reactions.
Interestingly, when a 1:4 catalyst to phosphine ratio was used
(entry 3), 5% yield of lactone 9 was observed along with the
expected product 8. Reductive elimination of the coupling product
from the nickel catalyst may yield an unstable borinate ester, which
under extended exposure to reaction conditions formed this
cyclized product. When the reaction time was extended to 128 h
(entry 4), indeed 32% of lactone 9 was isolated. Earlier quenching of
the reaction would preclude formation of byproduct 9.
In addition to a shorter reaction time, it was also found that the
yield of the reductive coupling product could be improved by
several means. By increasing the catalyst loading to 20 mol %, it was
found that only a small excess of enyne 4 was necessary to generate
a similar yield. Sequential addition of the epoxide and then enyne
also provided a boost in yield. Perhaps the byproducts of enyne
homocoupling adversely affected the reaction through catalyst
sequestration. In summary, the reductive coupling optimization led
to reliable gram-scale production of highly functionalized in-
termediate 8 in 48% yield (Scheme 5).
*
R2
R3
Scheme 2.
R
Aside from alkyne additions to electrophilic double bonds, we
have also expanded the scope of the reductive coupling to include
additions to the electrophilic single bonds of terminal epoxides to
afford homoallylic alcohols (Schemes 1 and 2).17 Addition occurs
regioselectively to the terminal end of the epoxide and retention of
epoxide configuration is observed in the product alcohol. An oxa-
nickelacycle is proposed to be an intermediate during the fragment
coupling,18 and the use of a 1,3-enyne may impart regioselectivity
in the key bond-forming step.10b As such a coupling would afford
substrates bearing 3,5-dien-1-ol functionality in a straightforward
manner, we sought to use this transformation to rapidly access the
core of (ꢀ)-cyatha-3,12-diene.
A retrosynthetic analysis leading to the target (1) is presented in
Scheme 3. Tricyclic ketone 2 was selected as a key intermediate,
possessing the key trans-6,7 ring junction (C5 and C6), and it may
be accessed directly from 14-membered macrocyclic triene 3 via
a TADA reaction. The two adjacent stereocenters at C12 and C13,
though not present in the natural product, are the means by which
the naturally occurring enantiomer 1 will be prepared. The steri-
cally demanding TIPS group as shown should occupy a pseudoe-
quatorial position in the macrocycle and provide the only
conformation in which the methyl group of the 1,3-diene at C6 can
avoid a severe steric interaction with the groups at C13.19 To ex-
amine the conformational effects of the TIPS group, the C12 epimer
of 3 would be made as well. The 3,5-dien-1-ol present in 3 can be
conveniently accessed from the nickel(0)-catalyzed reductive cou-
pling of enyne 4 and known epoxide 5.
However, at this point difficulty was encountered in the selec-
tive removal of the TBS group at a step later in the synthesis.
Therefore an alternative, more labile protecting group was needed.
Accordingly, the triethylsilyl (TES) protecting group was selected.
Enyne 10 bearing a TES group was synthesized using the afore-
mentioned route in 47% yield over three steps from 4-pentyn-1-ol.
Using the optimized conditions of the reductive coupling of 4
and 5 afforded only 26% yield of the diene 11 from 5 and 10,
prompting further optimization efforts (Table 2). By slowing down
the addition time of the enyne from less than 1 min to 1 h (entries
1–3), the yield was improved to 41%. Further, cod was chosen as
Reported herein are the efforts toward the synthesis of 1, with
a focus on the application of the nickel(0)-catalyzed enyne–epoxide
reductive coupling in various strategic contexts.
2. Results and discussion
The synthesis of enyne 4 commenced with the protection of
commercially available 4-pentyn-1-ol (6) to its TBS ether 7 in 86%
yield (Scheme 4). Hydrozirconation of 7 using Schwartz’s reagent20
in THF followed by quenching with NIS furnished the
Me
TBSO
O
H
Me
6
Me
4
OTIPS
Me
5
12
H 13
1
O
+
H
O
OTIPS
O
OMe
Me
2
3
5
Me
Scheme 3.

3272
B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
Table 1
Reductive coupling of enyne 4 and epoxide 5
TBSO
O
4
10 mol% Ni(cod)
Me
2
Me OH
O
O
+
Bu3P
Et3B
Me
O
O
+
OMe
TBSO
OMe
TBSO
Me
9
8
Me
5
Me
Entry
Bu3P (mol %)
Time (h)
Yield of 8 (%)
Yield of 9 (%)
Recovered 5 (%)
1a
2a
3a
4b
0
20
40
20
60
60
60
0
25
23
19
0
0
5
n.d.
26
38
128
32
20
a
A mixture of 4 (3 equiv) and 5 (1 equiv) was added over <1 min to a stirring slurry of Ni(cod)2, Bu3P, and Et3B.
A mixture of 4 (1.5 equiv) and 5 (1 equiv) was added over <1 min to a stirring slurry of Ni(cod)2, Bu3P, and Et3B. After 24 h, 4 (1.5 equiv) was added.
b
O
O
O
O
+
+
TBSO
TESO
OMe
1.0 equiv 5
OMe
Me
Me
10
12
1.5 equiv 4
Me
Me
20 mol% Ni(cod)2
40 mol% Bu3P
20 mol% Ni(cod)2
40 mol% Bu3P
Me OH
O
Me OH
O
TBSO
OMe
TESO
OMe
Et3B, 14 h
48% yield
50 mol% cod
Et3B, 14 h
Me
8
Me
13
50% yield
Scheme 5.
46% recovered 12
Scheme 6.
a stabilizing additive (entries 4–6). The presence of cod may hinder
sequestration of the catalyst by enyne polymerization byproducts.
Using 50 mol % cod as an additive (entry 4) improved the yield of
the reaction to 49% with 50% recovery of epoxide 5. The coupling of
enyne 10 and epoxide 12 was also performed, which afforded
similar results for this epoxide diastereomer, yielding diene 13 in
50% yield with 46% recovery of epoxide 12 (Scheme 6).
Diene 11 was then elaborated to macrocyclic triene 3 (Scheme
7). Reduction of 11 to the corresponding diol and treatment with
excess TIPSOTf afforded the tris-silyl ether 14 in 79% yield over the
two steps. Stirring a solution of 14 with Amberlyst-15 acidic resin
for 45 min selectively removed the 1ꢁ TES group, which was oxi-
dized using Swern conditions to give aldehyde 15 in 80% yield over
two steps. Alternatively, exposure of 14 to Collins reagent afforded
15 directly via selective oxidative deprotection, albeit in only 60%
yield at 88% conversion.24
bearing terminal b-ketophosphonate and aldehyde groups. After
screening several conditions, modified Still–Gennari conditions25
provided optimal amounts of macrocyclic triene 3 in 34% over three
steps. Major byproducts of this reaction not only included the Z
isomer of 3 but also 28-membered ring dimers bearing variable
olefin geometries. In addition to problems with this macro-
cyclization, purified 3 did not convert to tricycle 2 under a variety of
thermal and Lewis acid-promoted TADA reaction conditions (Table
3). Heating a toluene solution of 3 to 200 ꢁC in a sealed tube only
provided isomers that were products of [1,5]-hydride shift (entry 2).
In reactions involving Lewis acid promotion (entries 3–5), only
decomposition was observed above the noted temperature
thresholds.
In addition to the above route, several other enyne–epoxide
coupling systems were explored. To minimize functional group
Nucleophilic addition of deprotonated methyl dimethyl phos-
phonate to aldehyde 15 followed by Dess–Martin periodinane
interconversion, it would be advantageous to install the
phosphonate prior to the reductive coupling. With this in mind,
-ketophosphonate-enyne 18 was synthesized (Scheme 8). TBS-
b-keto-
(DMP) oxidation installed
b-ketophosphonate functionality,
b
affording 16 in 54% yield over two steps. From 16, selective depro-
tection of the 1ꢁ TIPS protecting group and subsequent oxidation
afforded Horner–Wadsworth–Emmons cyclization precursor
protected enyne 4 was converted to its alcohol using acidic meth-
anol and oxidized using Swern conditions to yield aldehyde 17 in
81% yield over two steps. Exposure of 17 to a cold solution of
Table 2
Reductive coupling of enyne 10 and epoxide 5a
20 mol% Ni(cod)2
Me OH
O
O
O
40 mol% Bu3P
TESO
+
TESO
OMe
OMe
Et3B
14 h
Me
5
Me
10
11
Me
Entry
Addition time
Additive
Yield of 11 (%)
Recovered 5 (%)
of 10 (min)
1
2
3
4
5
6
<1
45
60
60
60
60
None
None
None
50 mol % cod
100 mol % cod
150 mol % cod
26
28
41
49
44
41
73
63
39
50
30
41
a
Compound 5 (1 equiv) was added to a stirring slurry of Ni(cod)2, Bu3P, Et3B, and an additive. Compound 10 was then added over the specified amount of time.

B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
3273
OTES
Me OTIPS
OTIPS
coupling reaction would be the precursor triene. TBS-protected
enyne 20 was synthesized in 27% yield over three steps from 3-
butyn-1-ol using the identical enyne synthesis methodology as
above. The TIPS analog 21 was also synthesized in 27% over three
steps.
1. LiAlH4, Et2O, 0 °C
11
2. TIPSOTf,
2,6-lutidine, DCM
79% yield (2 steps)
Me
14
1. Amberlyst-15, DCM, EtOH
2. Swern oxidation
(80% yield over 2 steps)
or
TBSO
TIPSO
Me
20
21
Me
10 equiv CrO3·2pyr, DCM, 0 °C
(60% yield at 88% conversion)
O
H
Me OTIPS
To make the requisite epoxide 26 bearing an
ester, b-citronellene (22) was converted to the known aldehyde
a
,
b
-unsaturated
OTIPS
2322 in 49% yield through monitored ozonolysis followed by
dimethylsulfide workup (Scheme 9). Wittig-type coupling of 23
with commercially available phosphorane 24 provided dienyl ester
25 in quantitative yield. Regioselective epoxidation was observed
when 25 was treated with m-CPBA, affording 26 in multigram
quantities and in 96% yield.
15
Me
1. (MeO)2P(O)Me, t-BuLi, THF, hex, –78 °C to rt
2. DMP, NaHCO3, DCM
54% yield (2 steps)
O
O
Me OTIPS
P
OMe
MeO
OTIPS
16
Me
1. HCl, MeOH
Me
Me
24
O
2. DMP, NaHCO3, DCM
3. K2CO3, 18-crown-6, PhMe (9 mM), 85 °C
O3, DCM
–78 °C
then Me2S
–78 °C to rt
49% yield
O
Ph3P
OEt
22
H
3 (34% yield over 3 steps)
DCM
Me
O
Scheme 7.
23
quant. yield
Me
1 equiv mCPBA
25
Table 3
OEt
DCM, 0 °C to rt
96% yield
1.4:1 dr (syn:anti)
Attempted TADA reaction of triene 3
Me
Me
H
Me
H
O
OTIPS
Me
conditions
OTIPS
O
26
OEt
H
O
Me
Scheme 9.
O
3
2
Me
Entry
Conditions
PhMe, 180 ꢁ
Result
With enynes 20–21 and epoxide 26 readily available, the key
reductive coupling reaction was investigated. Quite unfortunately
and unexpectedly, the reductive coupling of 21 and 26 under op-
timized conditions only afforded a trace amount of product triene
27 with recovery of enyne polymerization byproducts and
unreacted epoxide 26 (Scheme 10).
1
2
3
4
5
C
No reaction
PhMe, 200 ꢁC
Some isomerization
Decomposition
Decomposition
Decomposition
Et2AlCl, DCM, hept, ꢀ78 ꢁC to 40 ꢁ
C
BF3$OEt2, PhMe, ꢀ78 ꢁC to 30 ꢁ
SnCl4, DCM, ꢀ78 ꢁC to rt
C
tert-butyl lithium and dimethyl methylphosphonate and sub-
sequent oxidation with TPAP/NMO afforded the target enyne 18 in
50% yield over two steps. The reductive coupling of 18 and epoxide
5 gave 40% yield of the coupling product 19.
TIPSO
20 mol% Ni(cod)2
21
Me
40 mol% Bu3P
Et3B, 14 h
+
O
O
O
< 5% yield 24
OEt
1. HCl, MeOH, 0 °C
4
H
26
Me
2. Swern oxidation
81% yield (2 steps)
17
Me
Me OH
O
TIPSO
O
P
OMe
O
1. (MeO)2P(O)Me, t-BuLi,
OEt
pent, THF, –78 °C to rt
MeO
Me
27
Scheme 10.
2.TPAP,NMO,4 MS, DCM
50% yield (2 steps)
18
Me
O
This result prompted a reinvestigation of the reductive coupling
reaction. Perhaps if a different phosphine was used, the formation
of 27 could be favored over polymerization of 21. Electron-rich
trialkylphosphines, aside from facilitating reductive coupling of
terminal epoxides and 1,3-enynes, are also good ligands for cyclo-
trimerization of alkynes, especially in the 2:1 to 10:1 ratio range of
phosphine ligand to nickel(0) compound.27 Since using an electron-
poor phosphine ligand would be inhibitory to the reductive cou-
pling process, decreasing the phosphine cone angle, while keeping
the electronic nature of the ligand approximately equivalent, was
20 mol% Ni(cod)2
40 mol% Bu3P
P
OMe
Me OH
OMe
18 + 5
CO2Me
Et3B, 18 h
O
40% yield
19
Me
Scheme 8.
Further, a route involving an intramolecular Diels–Alder (IMDA)
reaction26 was pursued in which the direct product of the reductive

3274
B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
TBSO
judged as the means by which reductive coupling would be favored
over enyne homocoupling.
1. 20 mol% Ni(cod)2,
40 mol% Me2PPh,
Et3B, 2 h
1 equiv 20
Me
Accordingly, Me2PPh was selected as a possible ligand in this
reductive coupling. This phosphine has similar electronic proper-
ties to Bu3P; however, it has a smaller cone angle (122ꢁ vs 132ꢁ).28
Additionally, Me2PPh has been shown to be effective in key alkyne–
epoxide reductive cyclizations in our syntheses of pumiliotoxins
209F and 251D.29
+
2. TIPSOTf,
2,6-lutidine, THF
O
O
OEt
62% yield (2 steps)
Me
2 equiv 26
Me OTIPS
O
Gratifyingly, the reductive coupling of 21 and 26 with the use of
Me2PPh proceeded in 21% yield of triene 27 (Scheme 11). Ketone 28
was also isolated from the reaction, which formed from metal-
mediated rearrangement of epoxide 26. Especially noteworthy was
the appearance of 21 in the crude reaction mixture by 1H NMR. In
any of the prior enyne–epoxide reductive couplings, unreacted
enyne was not recovered; mixtures of homocoupling products
were invariably isolated. Unfortunately, the dr of 27 could not be
determined due to similarities of the 1H signals of both di-
astereomers and overlap of peaks in the spectrum.
TBSO
OEt
31
Me
Scheme 12.
Interestingly, when diastereomerically pure epoxide 26a (syn-
thesized in two steps from epoxide 5) was used in a reductive
coupling with enyne 20 with identical procedures to those found in
Scheme 12, only a 43% yield of coupling product 31a was observed
(Scheme 13). This seems to suggest that the two diastereomers of
26 react at different rates in the reductive coupling reaction.
TIPSO
20 mol% Ni(cod)2
40 mol% Me2PPh
Et3B, 14 h
21
Me
27
+
TBSO
O
1. 20 mol% Ni(cod)2,
O
40 mol% Me2PPh,
1 equiv 20
Me
21% yield 27
28% yield 28
OEt
Et3B, 2 h
2. TIPSOTf,
2,6-lutidine, THF
+
26
Me
O
O
O
O
OEt
43% yield (2 steps)
28
Me
2 equiv 26a
Me
OEt
Me
Me OTIPS
O
Scheme 11.
TBSO
OEt
31a
Me
A similar yield was seen when enyne 20 was coupled with 26
under standard reductive coupling conditions to form triene 29
(Table 4, entry 1). In addition to triene 29, regioisomer 30 was also
isolated. When the reaction was run for shorter periods of time
(entries 2–3), the yield of 29 not only increased, but also greater
regioselectivity was observed. Slow decomposition of the product
during the reaction may account for the decrease in yield. It appears
that rearrangement of epoxide 26 to ketone 28 becomes a com-
peting process when using Me2PhP. With this in mind, the yield
was increased further by using a 2:1 ratio of epoxide 26 to enyne 20
(Scheme 12). In this case, it was difficult to isolate the product
triene 29 from byproduct ketone 28. This problem was circum-
vented by treatment of an isolated mixture of 28 and 29 with
TIPSOTf to afford the TIPS-protected triene 31 in 62% yield over two
steps.
Scheme 13.
Initial screening of IMDA reaction conditions with 31a failed to
produce even trace amounts of cyclization products. In order to
activate the substrate further, aldehyde 32 was prepared from 31a
by DIBAL-H reduction followed by DMP oxidation. Under a variety
of thermal, Lewis acid-promoted, and iminium-based IMDA re-
action conditions,30 32 failed to cyclize to 33 (Table 5). Heating at
300 ꢁC in a sealed tube (entry 2) or at 200 ꢁC in a microwave reactor
(entry 3) caused decomposition, and the use of several Lewis acids
promoted deprotection of the 1ꢁ TBS group (entries 5–6). Perhaps
the lack of reactivity of this and similar systems stems from in-
ability to attain the s-cis diene conformation due to severe steric
strain.
Table 4
Reductive coupling of enyne 20 and epoxide 26a
TBSO
Me
Me
Me OH
20 mol% Ni(cod)2
40 mol% Me2PPh
20
Me
TBSO
TBSO
Me
+
+
O
Et3B
OEt
EtO2C
29
O
OEt
30
OH
O
26
Me
Entry
Reaction time (h)
Recovered 20 (%)
Yield of 28 (%)
Yield of 29 (%)
Yield of 30 (%)
1
2
3
15
4
2
31b
36
40
41
32
27
39
51
12
13
9
55
a
Compound 26 (1 equiv) was added to a stirring slurry of Ni(cod)2, Me2PPh, and Et3B. Compound 20 (1.5 equiv) was then added over 30 min.
Minor homocoupling products of 20 were observed as well.
b

B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
3275
Table 5
4.2. Preparation of enynes and epoxides
4.2.1. tert-Butyldimethyl(pent-4-ynyloxy)silane (7)
Attempted IMDA reaction of trienal 32
OTBS
Me
OTBS
OHC
Me
TBSCl (18.84 g, 125 mmol, 1.05 equiv) was added to a stirring
solution of 4-pentyn-1-ol (10.00 g, 119 mmol, 1 equiv), Et3N
(24.05 g, 238 mmol, 2 equiv), and DMAP (2.91 g, 23.8 mmol,
0.2 equiv) in DCM (100 mL) at 0 ꢁC. The solution was allowed to stir
overnight and warmed to room temperature. The solution was
subsequently diluted to 250 mL DCM and washed four times with
water (200 mL each). The aqueous layers were combined and
washed with DCM (100 mL). The DCM layers were combined
and washed with brine (100 mL). Drying over MgSO4, filtration, and
concentration in vacuo afforded a clear oil. The oil was distilled at
10 Torr, 72 ꢁC to give 7 as a clear oil (20.50 g, 86% yield). 1H NMR
H
OTIPS
Me
conditions
OHC
OTIPS
32
33
Me
Entry
Conditions
PhMe, 175 ꢁ
C6H3Cl3, 330 ꢁ
Result
1
2
3
4
5
6
7
8
C
No reaction
C
Decomposition
Decomposition
Decomposition
1ꢁ TBS deprotection
1ꢁ TBS deprotection
No reaction
DMSO,
m
W, 200 ꢁC, 10 min
MeAlCl2, DCM, hex, ꢀ78 ꢁC to rt
BF3$OEt2, DCM, ꢀ78 ꢁC to ꢀ15 ꢁ
C
SnCl4, DCM, ꢀ78 ꢁC to ꢀ30 ꢁ
34, 98:2 MeCN/H2O
34, CDCl3
C
(500 MHz, CDCl3,
d
): 3.70 (t, J¼6.0 Hz, 2H), 2.28 (dt, Jt¼7.1 Hz,
Jd¼2.7 Hz, 2H), 1.93 (t, J¼2.7 Hz, 1H), 1.73 (m, 2H), 0.90 (s, 9H), 0.06
Decomposition
(s, 6H); 13C NMR (125 MHz, CDCl3,
d): 99.9, 84.4, 61.6, 31.7, 26.1,18.5,
15.0, ꢀ5.1. HRMS-ESI (m/z): [MþNa]þ calcd for C11H22O2Si,
Ph
O
221.1332; found, 221.1379.
34
NH
t-Bu
N
Me
4.2.2. (E)-tert-Butyldimethyl(oct-4-en-6-ynyloxy)silane (4)
To a stirring slurry of Schwartz’s reagent (13.61 g, 52.8 mmol,
1.05 equiv) in THF (140 mL) at 0 ꢁC was added
7 (10.00 g,
50.2 mmol, 1 equiv). The solution was warmed to room tempera-
ture, and after 100 min, the creamy white solution turned dark
green. NIS (11.87 g, 52.8 mmol, 1.05 equiv) was then dropwise
added, and the solution turned from green to bright orange to deep
red to brown black. The solution was stirred for 90 min. Volatiles
were then removed in vacuo to yield a brown-gray residue. The
residue was retaken in hexane (100 mL), passed through a plug of
silica gel (90 mL), and rinsed with hexane to give a total eluent
volume of 500 mL. The solvent was then removed in vacuo to give
a yellow oil. The yellow oil was retaken in DCM (200 mL), washed
with 1 N NaOH (75 mL), and washed with brine (75 mL). Drying
over MgSO4, filtration, and concentration in vacuo yielded 15.39 g
of a yellow oil. This oil was added to a solution of CuI (447 mg,
2.35 mmol, 0.05 equiv) and Pd(PPh3)4 (1.36 g, 1.18 mmol,
0.025 equiv) in pyrrolidine (48 mL) at ꢀ78 ꢁC. Propyne (7.5 mL,
240 mmol, 5 equiv) was bubbled through the solution and it was
stirred overnight while warming to room temperature. The solu-
tion was subsequently diluted with Et2O (200 mL) and added to ice-
cold 1 M HCl (200 mL). The layers were separated, and the organic
layer was washed twice with 1 M HCl (75 mL each) and dried over
MgSO4. The solution was then passed through a pad of silica
(100 mL) and washed with Et2O to afford a total eluent volume of
700 mL. Concentration in vacuo yielded an orange residue, which
was retaken in hexane (200 mL) and passed through a pad of silica
(100 mL) and washed with hexane to afford a total eluent volume of
700 mL. Concentration in vacuo yielded a pale yellow oil. The oil
was distilled at 2.2 Torr, 102 ꢁC to yield 4 as a clear oil (6.62 g, 55%
3. Conclusion
Within the context of studies directed toward the total synthesis
of (ꢀ)-cyatha-3,12-diene, the nickel(0)-catalyzed enyne–epoxide
reductive coupling has been shown to be effective in a variety of
contexts. Variations to the size and nature of both coupling partners
are well-tolerated, including the
a,b-unsaturated ester and
b
-ketophosphonate functionalities. Within a single step, a wide
diversity of valuable intermediates containing a 3,5-dien-1-ol was
made.
4. Experimental
4.1. General information
Unless otherwise noted, all reactions were performed under an
argon atmosphere with rigid exclusion of moisture from reagents
and glassware. THF was freshly distilled over sodium/benzophe-
none ketyl. DCM was distilled from calcium hydride. Anhydrous
pyrrolidine was used as purchased from Aldrich. Ni(cod)2 was pur-
chased from Strem Chemicals, Inc., stored under nitrogen atmo-
sphere, and used without further purification. Analytical thin-layer
chromatography (TLC) was performed using EM Science silica gel 60
F254 plates and developed using UV light (254 nm) and aqueous ceric
ammonium molybdate (CAM) stain. Liquid chromatography was
performed using a forced flow (flash chromatography) of the in-
dicated solvent system on Silicycle silica gel (230–400 mesh).1H and
13C NMR spectra were recorded on a Varian Inova 500 MHz spec-
trometer in CDCl3 and analyzed using iNMR version 0.6.2. Chemical
shifts in 1H NMR spectra are reported in parts per million (ppm) on
yield over two steps). 1H NMR (300 MHz, CDCl3,
d): 6.05 (m, 1H),
5.45 (d, J¼17.4 Hz, 1H), 3.61 (t, J¼6.3 Hz, 2H), 2.15 (m, 2H), 1.94 (d,
J¼2.2 Hz, 3H), 1.60 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H); 13C NMR
(125 MHz, CDCl3, d): 143.0, 110.3, 84.4, 78.6, 62.5, 32.1, 29.5, 26.2,
18.5, 4.4, ꢀ5.1. IR (NaCl, thin film, cmꢀ1): 2929, 2857, 1744, 1472,
1361, 1256, 1103, 955, 837, 776. HRMS-ESI (m/z): [MþNa]þ calcd for
C14H26OSi, 261.1645; found, 261.1654.
the
d scale from an internal standard of residual chloroform
(7.27 ppm). Data are reported as follows: chemical shift, multiplicity
(s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet and
br¼broad), coupling constant in hertz (Hz), and integration.
Chemical shifts of 13C NMR spectra are reported in parts per million
4.2.3. (R)-Methyl 4-((R)-oxiran-2-yl)pentanoate (7)
Synthesized according to a literature procedure.22
from the central peak of CDCl3 (77.23 ppm) on the d scale. IR spectra
were recorded on a Perkin–Elmer 2000 FT-IR. High resolution mass
spectra (HRMS) were obtained on a Bruker Daltonics APEXII 3
Fourier Transform Mass Spectrometer by Ms. Li Li of the Massa-
chusetts Institute of Technology, Department of Chemistry In-
strumentation Facility.
4.2.4. (E)-Triethyl(oct-4-en-6-ynyloxy)silane (10)
Using the identical procedure for the synthesis of 7, the reaction
of TESCl (31.4 mL,187 mmol) and 4-pentyn-1-ol (15.00 g,178 mmol)
with Et3N (49.6 mL, 357 mmol) and DMAP (4.35 g, 35.7 mmol) in
DCM (600 mL) afforded triethyl(pent-4-ynyloxy)silane as a clear oil

3276
B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
after distillation at 2.8 Torr, 57 ꢁC (35.32 g, >99% yield). Using the
identical procedure for the synthesis of 4, the reaction of trie-
thyl(pent-4-ynyloxy)silane (14.86 g, 74.9 mmol), Schwartz’s re-
agent (20.27 g, 78.7 mmol), and NIS (9.83 g, 78.7 mmol) in THF
(245 mL) afforded the corresponding vinyl iodide. The reaction of
this oil and propyne (12 mL, 244 mmol) with Pd(PPh3)4 (1.41 g,
1.23 mmol) and CuI (464 mg, 2.44 mmol) in pyrrolidine (49 mL)
afforded 10 as a clear oil after distillation at 2.8 Torr, 87 ꢁC (8.48 g,
(dq, Jd¼15.8 Hz, Jq¼1.6 Hz, 1H), 3.80 (d, JH–P¼11.3 Hz, 6H), 3.09 (d,
JH–P¼22.8 Hz, 2H), 2.71 (t, J¼7.3 Hz, 2H), 2.37 (dt, Jd¼7.3 Hz,
Jt¼7.1 Hz, 2H), 1.92 (d, J¼1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3,
d)
200.5 (JC–P¼6.2 Hz), 140.4, 111.2, 84.9, 74.9, 53.0 (JC–P¼6.4 Hz), 42.9,
41.3 (JC–P¼128.0 Hz), 26.5, 4.1. HRMS-ESI (m/z): [MþNa]þ calcd for
C11H17O4P, 267.0757; found, 267.0751.
4.2.8. (E)-tert-Butyl(hept-3-en-5-ynyloxy)dimethylsilane (20)
47% yield over two steps). 1H NMR (500 MHz, CDCl3,
d
): 6.05 (dt,
Using the identical procedure for the synthesis of 7, the reaction
of TBSCl (10.45 g, 69.4 mmol) and 3-butyn-1-ol (5.0 mL, 66.1 mmol)
with Et3N (18.5 mL, 132 mmol) and DMAP (1.61 g, 13.2 mmol) in
DCM (220 mL) afforded (but-3-ynyloxy)(tert-butyl)dimethylsilane
as a clear oil after distillation at 5 Torr, 39 ꢁC (8.74 g, 72% yield).
Using the identical procedure for the synthesis of 4, the reaction of
(but-3-ynyloxy)(tert-butyl)dimethylsilane (4.00 g, 21.7 mmol),
Schwartz’s reagent (5.87 g, 22.8 mmol), and NIS (2.85 g,
22.8 mmol) in THF (72 mL) afforded the corresponding vinyl iodide.
The reaction of this oil and propyne (5 mL, 71 mmol) with
Pd(PPh3)4 (412 mg, 0.36 mmol) and CuI (136 mg, 0.71 mmol) in
pyrrolidine (14 mL) afforded 20 as a clear oil after distillation at
5 Torr, 98 ꢁC (1.81 g, 37% yield over two steps). 1H NMR (500 MHz,
Jd¼15.8 Hz, Jt¼7.4 Hz, 1H), 5.45 (dq, Jd¼15.8 Hz, Jq¼2.1 Hz, 1H), 3.61
(t, J¼6.4 Hz, 2H), 2.15 (m, 2H), 1.94 (d, J¼2.1 Hz, 3H), 1.61 (m, 2H),
0.96 (t, J¼7.9 Hz, 9H), 0.60 (q, J¼7.9 Hz, 6H); 13C NMR (125 MHz,
CDCl3, d): 143.0,110.3, 84.4, 78.5, 62.2, 32.2, 29.5, 7.0, 6.6, 4.6. HRMS-
ESI (m/z): [MþNa]þ calcd for C14H26OSi, 261.1645; found, 261.1650.
4.2.5. (R)-Methyl 4-((S)-oxiran-2-yl)pentanoate (12)
Synthesized according to a literature procedure.22
4.2.6. (E)-Oct-4-en-6-ynal (17)
Concentrated HCl (0.3 mL) was added dropwise to a solution of
4 (1.80 g, 7.55 mmol) in MeOH (30 mL). After stirring for 1 h, sat-
urated aqueous NaHCO3 (50 mL) was added. Volatiles were re-
moved in vacuo and the resulting solution was extracted thrice
with EtOAc (50 mL each). The aqueous layer was saturated with
NaCl and the extraction procedure was repeated. The EtOAc layers
were combined, dried over Na2SO4, and concentrated in vacuo to
CDCl3,
d
): 6.04 (dt, Jd¼15.9 Hz, Jt¼7.2 Hz, 1H), 5.50 (dq, Jd¼15.9 Hz,
Jq¼2.2 Hz, 1H), 3.64 (t, J¼6.7 Hz, 2H), 2.30 (dt, Jd¼7.2 Hz, Jt¼6.7 Hz,
1H), 1.94 (d, J¼2.2 Hz, 3H), 0.89 (s, 9H), 0.05 (s, 6H); 13C NMR
(125 MHz, CDCl3, d): 139.7, 111.9, 84.7, 78.5, 62.6, 36.8, 26.1, 18.5, 4.4,
ꢀ5.1. HRMS-ESI (m/z): [MþNa]þ calcd for C13H24OSi, 247.1489;
afford a crude oil (958 mg). DMSO (710
mL, 10 mmol, 2.3 equiv) was
found, 247.1487.
added dropwise to a solution of oxalyl chloride (623
mL, 7.5 mmol,
1.75 equiv) in DCM (25 mL) at ꢀ78 ꢁC, and the resulting solution
was stirred for 15 min. A portion of this oil (531 mg, 4.28 mmol,
1 equiv) in DCM (3 mL) was added dropwise to this solution and
stirred for 30 min. Et3N (1.52 g, 15 mmol, 3.5 equiv) was added
dropwise, and the solution was warmed to room temperature over
1 h. The solution was diluted with water (30 mL) and extracted
with DCM (4ꢂ25 mL). The organic extracts were combined, washed
with water (30 mL), brine (30 mL), dried over MgSO4, and con-
centrated in vacuo to yield an oil. Flash column chromatography
(300 mL silica, 8:2 hexane/EtOAc) afforded 17 (485 mg, 81% yield
4.2.9. (E)-(Hept-3-en-5-ynyloxy)tri-iso-propylsilane (21)
Using the identical procedure for the synthesis of 7, the reaction
of TIPSCl (8.02 g, 41.6 mmol) and 3-butyn-1-ol (3.0 mL, 39.6 mmol)
with Et3N (11 mL, 79.3 mmol) and DMAP (0.97 g, 7.9 mmol) in DCM
(132 mL) afforded (but-3-ynyloxy)tri-iso-propylsilane as a clear oil
(8.40 g, >99% yield). Using the identical procedure for the synthesis
of 4, the reaction of (but-3-ynyloxy)tri-iso-propylsilane (3.67 g,
17.3 mmol), Schwartz’s reagent (4.67 g, 18.1 mmol), and NIS (2.27 g,
18.1 mmol) in THF (60 mL) afforded the corresponding vinyl iodide.
The reaction of this oil and propyne (1.5 g, 40 mmol) with
Pd(PPh3)4 (206 mg, 0.18 mmol) and CuI (68 mg, 0.36 mmol) in
pyrrolidine (7.1 mL) afforded 21 as a clear oil (1.13 g, 27% yield over
over two steps). 1H NMR (500 MHz, CDCl3,
d): 9.77 (t, J¼1.3 Hz, 1H),
6.02 (dt, Jd¼15.8 Hz, Jt¼7.0 Hz, 1H), 5.49 (dq, Jd¼15.8 Hz, Jq¼1.6 Hz,
1H), 2.55 (dt, Jt¼6.7 Hz, Jd¼1.3 Hz, 2H), 2.41 (dt, Jd¼7.0 Hz,
two steps). 1H NMR (500 MHz, CDCl3,
d
): 6.08 (dt, Jd¼15.9 Hz,
Jt¼6.7 Hz, 2H), 1.92 (d, J¼1.6 Hz, 3H); 13C NMR (125 MHz, CDCl3,
d
):
Jt¼7.2 Hz, 1H), 5.51 (dq, Jd¼15.9 Hz, Jq¼2.1 Hz, 1H), 3.71 (t, J¼6.8 Hz,
2H), 2.34 (dt, Jd¼7.2 Hz, Jt¼6.8 Hz, 1H), 1.94 (d, J¼2.1 Hz, 3H), 1.05–
201.5, 140.4, 111.6, 85.4, 76.9, 43.0, 25.5, 4.3. HRMS-ESI (m/z):
[MþNa]þ calcd for C8H10O, 145.0624; found, 145.0629.
1.10 (m, 21H); 13C NMR (125 MHz, CDCl3,
d): 139.8, 111.8, 84.7, 78.5,
62.9, 37.0, 18.2, 12.2, 4.4. HRMS-ESI (m/z): [MþNa]þ calcd for
4.2.7. (E)-Dimethyl 2-oxonon-5-en-7-ynylphosphonate (18)
C16H30OSi, 289.1958; found, 289.1954.
A solution of t-BuLi in pentane (1.7 M, 9.36 mL, 15.92 mmol,
4 equiv) was added dropwise over 10 min to THF (117 mL) at
ꢀ78 ꢁC. Dimethyl methylphosphonate (2.47 g, 19.9 mmol, 5 equiv)
was added dropwise over 10 min and the solution was stirred for
45 min to give a colorless solution. A solution of 17 (485 mg,
3.98 mmol, 1 equiv) in THF (3 mL) was added dropwise over 10 min
and the solution was stirred at ꢀ78 ꢁC for 2 h. Brine (40 mL) was
added by syringe and the solution was warmed to room tempera-
ture over 1 h. Volatiles were removed in vacuo, and the residue was
diluted with water (100 mL) and extracted thrice with EtOAc
(75 mL each). The organic extracts were combined, washed with
brine (100 mL), dried over Na2SO4, and concentrated in vacuo to
yield a residue. The residue, NMO (932 mg, 7.96 mmol, 2 equiv),
and 4 Å MS (2 g) were taken up in DCM (45 mL). TPAP (70 mg,
0.2 mmol, 0.05 equiv) was added and the solution was stirred for
16 h. The solution was then filtered through a plug of silica (100 mL)
and rinsed with EtOAc. The eluent was concentrated in vacuo to
yield a residue. Flash column chromatography (200 mL silica, 1:9
hexane/EtOAc) afforded 18 (486 mg, 50% yield over two steps). 1H
4.2.10. (R,E)-Ethyl 6-methylocta-2,7-dienoate (25)
b
-Citronellene (10.8 mL, 59 mmol,1 equiv) was taken up in DCM
(120 mL) and cooled to ꢀ78 ꢁC while bubbling oxygen through the
solution. Ozone was then bubbled through the solution
(w0.7 mmol/min) for 75 min. Oxygen and then argon were bub-
bled through the solution for 10 min each. Me2S (10.9 mL,
148 mmol, 2.5 equiv) was added, and the solution was allowed to
stir overnight and warmed to room temperature. The solution was
then concentrated at 40 Torr to yield a white residual oil. Short-
path distillation of the oil at 40 Torr, 59–61 ꢁC afforded aldehyde
2322 as a clear oil (3.27 g). To a solution of 23 (3.27 g, 29.2 mmol,
1 equiv) in DCM (97 mL) was added (carbethoxymethylene)-
triphenyl phosphorane (10.16 g, 29.2 mmol, 1 equiv). The solution
was stirred overnight and then concentrated in vacuo to an oily,
white residue. Flash column chromatography (300 mL, 95:5 hex-
ane/EtOAc) afforded 25 as a clear oil (5.32 g, 49% yield over two
steps). 1H NMR (500 MHz, CDCl3,
1H), 5.82 (d, J¼15.6 Hz, 1H), 4.94–5.00 (m, 2H), 4.19 (q, J¼7.1 Hz,
2H), 2.14–2.21 (m, 3H), 1.45 (m, 2H), 1.29 (t, J¼7.1 Hz, 3H), 1.01 (d,
d
): 6.96 (dt, Jd¼15.6 Hz, Jt¼6.9 Hz,
NMR (500 MHz, CDCl3,
d): 5.99 (dt, Jd¼15.8 Hz, Jt¼7.1 Hz, 1H), 5.48

B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
3277
J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3,
d
): 168.8, 149.3, 143.8,
11 as a clear oil (132 mg, 49% yield) along with 7 (53 mg, 50% re-
covery). 1H NMR (500 MHz, CDCl3,
121.4, 113.5, 60.2, 37.4, 34.8, 30.0, 20.3, 14.4. HRMS-ESI (m/z):
[MþNa]þ calcd for C11H18O2, 205.1199; found, 205.1205.
d): 6.24 (dd, J1¼15.0 Hz,
J2¼10.8 Hz, 1H), 5.87 (d, J¼10.8 Hz, 1H), 5.62 (dt, Jd¼15.0 Hz,
Jt¼7.4 Hz, 1H), 3.65 (s, 3H), 3.60 (t, J¼6.5 Hz, 2H), 3.53 (m, 1H), 2.41
(m, 1H), 2.31 (m, 1H), 2.24 (m, 1H), 2.14 (m, 2H), 2.00 (m, 1H), 1.87
(m, 1H), 1.74 (s, 3H), 1.55–1.64 (m, 1H), 1.49 (m, 1H), 0.94 (t,
J¼8.0 Hz, 9H), 0.91 (d, J¼6.8 Hz, 3H), 0.58 (q, J¼8.0 Hz, 6H); 13C
4.2.11. (R,E)-Ethyl 6-(oxiran-2-yl)hept-2-enoate (26)
To a solution of 25 (1.09 g, 6.0 mmol, 1 equiv) in DCM (12 mL) at
0 ꢁC was portionwise added m-CPBA (ꢃ77% purity, 1.34 g,
29.2 mmol, 1 equiv). The solution was stirred overnight and
warmed to room temperature. The solution was then diluted with
EtOAc (50 mL) and treated with saturated aqueous NaHCO3 (25 mL)
and 1 M NaOH (25 mL). The layers were separated and the aqueous
layer was washed thrice with EtOAc (50 mL each). The organic
extracts were combined, dried over MgSO4, filtered, and concen-
trated in vacuo to yield a clear oil. Flash column chromatography
(150 mL silica, 8:2 hexane/EtOAc) afforded 26 as a clear oil (1.14 g,
96% yield, 1.4:1 dr syn(26a)/anti(26b)). 1H NMR (500 MHz, CDCl3,
NMR (125 MHz, CDCl3, d): 174.6,133.6,132.7,128.6,126.5, 72.3, 62.4,
51.8, 44.5, 38.2, 32.7, 32.2, 29.4, 27.7, 16.7, 15.3, 7.0, 4.6. HRMS-ESI
(m/z): [MþNa]þ calcd for C22H42O4Si, 421.2745; found, 421.2749.
4.3.3. (4R,5R,7E,9E)-Methyl 5-hydroxy-4,7-dimethyl-13-
(triethylsilyloxy)trideca-7,9-dienoate (13)
Using the optimized procedure for the synthesis of 11, the re-
action of 10 (1.13 g, 4.74 mmol, 1.5 equiv) and 12 (503 mg,
3.18 mmol, 1 equiv) with Ni(cod)2 (174 mg, 0.63 mmol, 0.2 equiv),
d
): 6.90–6.98 (m, 1H), 5.79–5.85 (m, 1H), 4.17 (q, J¼7.1 Hz, 2H), 2.76
Bu3P (316
4 equiv), and cod (194
a clear oil (631 mg, 50% yield) along with recovered 12 (230 mg,
46% recovery). 1H NMR (500 MHz, CDCl3,
m
L, 1.26 mmol, 0.4 equiv), Et3B (1.85 mL, 12.64 mmol,
(26b, m, 2H), 2.70 (26a, m, 2H), 2.53 (26b, m, 1H), 2.46 (26a, m, 1H),
2.20–2.31 (m, 2H), 1.71 (26a, m, 1H), 1.56 (26b, m, 1H), 1.45 (26a, m,
1H), 1.35 (26b, m, 1H), 1.30–1.34 (26a, m, 1H), 1.27 (t, J¼7.1 Hz, 3H),
1.03 (26a, d, J¼6.8 Hz, 3H), 0.97 (26b, d, J¼6.9 Hz, 3H); 13C NMR
mL, 1.58 mmol, 0.5 equiv) afforded 13 as
d): 6.26 (dd, J1¼15.0 Hz,
J2¼10.8 Hz, 1H), 5.88 (d, J¼10.8 Hz, 1H), 5.64 (dt, Jd¼15.0 Hz,
Jt¼7.0 Hz,1H), 3.68 (s, 3H), 3.64 (m,1H), 3.62 (t, J¼6.5 Hz, 2H), 2.32–
2.42 (m, 2H), 2.08–2.22 (m, 4H), 1.87 (m, 1H), 1.76 (s, 3H), 1.61–1.66
(m, 2H), 1.54 (m, 2H), 0.96 (t, J¼8.0 Hz, 9H), 0.93 (d, J¼6.5 Hz, 3H),
(125 MHz, CDCl3, d): 166.8, 166.7, 149.0, 149.0, 121.8, 121.7, 60.4,
60.3, 57.0, 56.7, 46.9, 45.8, 36.0, 35.6, 33.2, 31.9, 29.8, 29.8, 18.1, 17.0,
16.0, 14.4. HRMS-ESI (m/z): [MþNa]þ calcd for C11H18O3, 221.1148;
found, 221.1147.
0.60 (q, J¼8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3,
d): 174.6, 133.5,
132.8, 128.3, 126.6, 71.6, 62.4, 51.8, 45.0, 37.8, 32.7, 32.3, 29.4, 28.5,
16.7, 13.9, 7.0, 4.6. HRMS-ESI (m/z): [MþNa]þ calcd for C22H42O4Si,
421.2745; found, 421.2750.
4.3. Optimized reductive coupling procedures
4.3.1. (4R,5S,7E,9E)-Methyl 13-(tert-butyldimethylsilyloxy)-5-
hydroxy-4,7-dimethyltrideca-7,9-dienoate (8)
4.3.4. (4R,5S,7E,9E)-Methyl 14-(dimethoxyphosphoryl)-5-hydroxy-
4,7-dimethyl-13-oxotetradeca-7,9-dienoate (19)
In a glovebox, a 10 mL teardrop flask was charged with Ni(cod)2
(70 mg, 0.25 mmol, 0.2 equiv) and Bu3P (126
mL, 0.51 mmol,
In a glovebox, a 10 mL teardrop flask was charged with Ni(cod)2
0.4 equiv). The flask was sealed with a rubber septum and electrical
tape. Outside the box and under a positive pressure of argon, Et3B
(0.74 mL, 5.1 mmol, 4 equiv), 5 (198 mg, 1.25 mmol, 1 equiv), and 4
(452 mg, 1.90 mmol, 1.5 equiv) were sequentially added. The black
reaction mixture was stirred overnight for 14 h. The reaction mix-
ture was then exposed to air, diluted with EtOAc (5 mL), and stirred
vigorously for 2 h, whereupon the solution turned from black to
clear yellow. The solution was then concentrated in vacuo to a yel-
low oil. Flash column chromatography (100 mL silica, 95:5 hexane/
EtOAc/9:1 hexane/EtOAc) afforded 8 as a slight yellow oil
(9 mg, 33
flask was sealed with a rubber septum and electrical tape. Outside
the box and under a positive pressure of argon, Et3B (97 L,
0.66 mmol, 4 equiv) was added followed by a mixture of 5 (26 mg,
0.16 mmol, 1 equiv) and 18 (42 mg, 0.17 mmol, 1.1 equiv). The so-
lution was stirred for 18 h. The solution was diluted with Et2O,
exposed to air for 1 h, and was subjected directly to flash column
chromatography (EtOAc/99:1 EtOAc/MeOH) to yield 19 (26 mg,
mmol, 0.2 equiv) and Bu3P (14 mL, 66 mmol, 0.4 equiv). The
m
40% yield). 1H NMR (500 MHz, CDCl3,
d
): 6.28 (dd, J1¼15.1 Hz,
J2¼11.2 Hz, 1H), 5.87 (d, J¼11.2 Hz, 1H), 5.59 (dt, Jd¼15.1 Hz,
Jt¼7.2 Hz, 1H), 3.80 (d, JH–P¼11.2 Hz, 6H), 3.76–3.79 (m, 1H), 3.68 (s,
3H), 3.52–3.57 (br m, 1H), 3.10 (d, JH–P¼22.8 Hz, 2H), 2.74 (t,
J¼7.3 Hz, 2H), 2.42–2.48 (br m, 2H), 2.40 (t, J¼6.4 Hz, 2H), 2.22–2.28
(br m, 2H), 1.77 (s, 3H), 1.99–2.05 (br m, 2H), 1.85–1.92 (br m, 1H),
(241 mg, 48% yield). 1H NMR (300 MHz, CDCl3,
d): 6.25 (dd,
J1¼15.0 Hz, J2¼10.8 Hz, 1H), 5.88 (d, J¼10.8 Hz, 1H), 5.63 (dt,
Jd¼15.0 Hz, Jt¼7.4 Hz, 1H), 3.67 (s, 3H), 3.61 (t, J¼6.4 Hz, 2H), 3.55
(m, 1H), 1.40–2.43 (m, 14H), 0.92 (d, J¼6.6 Hz, 3H), 0.89 (s, 9H), 0.04
(s, 6H); 13C NMR (125 MHz, CDCl3,
d): 174.5, 133.5, 132.7, 128.4,
0.93 (d, J¼6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3,
d): 201.3 (JC–
126.5, 72.3, 62.6, 51.7, 44.4, 38.1, 32.6, 32.1, 29.3, 27.6, 26.1, 16.6, 15.2,
14.3, ꢀ5.2. HRMS-ESI (m/z): [MþNa]þ calcd for C22H42O4Si,
421.2745; found, 421.2734.
¼6.1 Hz), 174.6, 133.9, 131.2, 128.1, 127.5, 72.4, 53.3 (JC–P¼6.4 Hz),
P
51.8, 44.5, 43.9, 41.6 (JC–P¼128.1 Hz), 38.2, 32.1, 27.7, 26.8, 16.8, 15.3.
HRMS-ESI (m/z): [MþNa]þ calcd for C19H33O7P, 427.1856; found,
427.1854.
4.3.2. (4R,5S,7E,9E)-Methyl 5-hydroxy-4,7-dimethyl-13-
(triethylsilyloxy)trideca-7,9-dienoate (11)
4.3.5. (R,2E,9E,11E)-Ethyl 7-hydroxy-6,9-dimethyl-14-(tri-iso-
propylsilyloxy)tetradeca-2,9,11-trienoate (27)
In a glovebox, a 10 mL teardrop flask was charged with Ni(cod)2
(35 mg, 0.13 mmol, 0.2 equiv) and Bu3P (63
mL, 0.25 mmol,
In a glovebox, a 10 mL teardrop flask was charged with Ni(cod)2
0.4 equiv). The flask was sealed with a rubber septum and electrical
tape. Outside the box and under a positive pressure of argon, Et3B
(0.37 mL, 2.5 mmol, 4 equiv), cod (39 mL, 0.32 mmol, 0.5 equiv), and
(14 mg, 0.050 mmol, 0.2 equiv) and Me2PhP (14 mL, 0.10 mmol,
0.4 equiv). The flask was sealed with a rubber septum and electrical
tape. Outside the box and under a positive pressure of argon, Et3B
(0.15 mL, 1.0 mmol, 4 equiv) and 26 (50 mg, 0.25 mmol, 1 equiv)
were added sequentially. Compound 21 (101 mg, 0.34 mmol,
1.5 equiv) was added dropwise over 30 min. The black reaction
mixture was stirred overnight. The reaction mixture was diluted
with EtOAc (5 mL), exposed to air, and then stirred vigorously for
1 h, whereupon the solution turned from black to clear yellow. The
solution was then concentrated in vacuo to a brown oil. Flash col-
umn chromatography (100 mL silica, 95:5 hexane/EtOAc/8:2
5 (106 mg, 0.67 mmol, 1 equiv) were added sequentially. Com-
pound 10 (226 mg, 0.95 mmol, 1.5 equiv) was added dropwise over
approximately 1 h. The black reaction mixture was stirred over-
night for 14 h. The reaction mixture was diluted with EtOAc (5 mL),
exposed to air, and then stirred vigorously for 30 min, whereupon
the solution turned from black to clear yellow. The solution was
then concentrated in vacuo to a yellow-green oil. Flash column
chromatography (150 mL silica, 95:5/9:1 hexane/EtOAc) afforded

3278
B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
hexane/EtOAc) afforded 27 (25 mg, 21% yield) as a clear oil along
with 28 (14 mg, 28% yield) as a clear oil. 1H NMR (500 MHz, CDCl3,
in DCM (6 mL) were added TIPSOTf (0.68 mL, 2.5 mmol, 3.1 equiv)
and 2,6-lutidine (0.63 mL, 5.4 mmol, 6.8 equiv). The solution was
stirred for 4 h. Water (9 mL) was then added and the solution was
stirred for 10 min. The solution was then acidified with 1 N HCl
(3 mL) and extracted thrice with DCM (10 mL each). The organic
extracts were combined, washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Flash column chro-
matography (200 mL silica, 98:2 hexane/EtOAc) afforded 547 mg
(79% yield over two steps) of 14 as a clear oil. 1H NMR (500 MHz,
d
): 6.98 (dt, Jd¼15.7 Hz, Jt¼6.6 Hz, 1H), 6.31 (dd, J1¼15.1 Hz,
J2¼11.5 Hz, 1H), 5.89 (d, J¼11.5 Hz, 1H), 5.84 (d, J¼15.7 Hz, 1H), 5.67
(dt, Jd¼15.1 Hz, Jt¼7.5 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.73 (t,
J¼6.8 Hz, 2H), 3.64 (m, 1H), 3.54 (br m, 1H), 2.36 (dt, Jt¼6.8 Hz,
Jd¼7.0 Hz, 2H), 2.20 (m, 2H), 2.11 (m, 1H), 1.90 (m, 1H), 1.84 (m, 1H),
1.77 (s, 3H), 1.36 (m, 1H), 1.29 (t, J¼7.1 Hz, 3H), 1.03–1.10 (m, 22H),
0.93 (d, J¼6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3,
d) 166.7, 166.7,
149.4, 149.3, 133.1, 133.1, 130.1, 130.0, 128.4, 128.2, 128.0, 128.0,
121.4, 121.4, 72.3, 72.1, 71.6, 63.3, 60.2, 60.2, 45.7, 44.9, 44.4, 38.0,
37.5, 36.8, 35.9, 33.1, 31.5, 30.7, 30.1, 29.7, 18.1, 16.6, 15.9, 15.1, 14.4,
13.9, 13.8, 12.1. HRMS-ESI (m/z): [MþNa]þ calcd for C27H50O4Si,
489.3371; found, 489.3380.
CDCl3,
d
): 6.21 (dd, J1¼15.0 Hz, J2¼10.8 Hz, 1H), 5.81 (d, J¼10.8 Hz,
1H), 5.54 (dt, Jd¼15.0 Hz, Jt¼7.4 Hz, 1H), 3.92 (dt, Jt¼6.6 Hz,
Jd¼2.5 Hz, 1H), 3.68 (t, J¼6.5 Hz, 2H), 3.62 (t, J¼6.5 Hz, 2H), 2.15 (m,
4H), 1.73 (s, 3H), 1.56–1.70 (m, 5H), 1.46 (m, 2H), 1.10–1.19 (m, 4H),
1.05–1.07 (m, 36H), 0.97 (t, J¼8.0 Hz, 9H), 0.94 (d, J¼6.8 Hz, 3H),
0.61 (q, J¼8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3,
d): 133.6, 132.0,
4.4. (2E,6R,7S,9E,11E)-Ethyl 14-(tert-butyldimethyl silyloxy)-
6,9-dimethyl-7-(tri-iso-propylsilyloxy)tetra
deca-2,9,11-trienoate (31a)
127.7, 127.1, 75.2, 64.0, 62.5, 43.8, 38.4, 32.9, 31.6, 29.4, 28.0, 18.5,
18.3, 17.2, 15.5, 13.2, 12.2, 7.0, 4.6. HRMS-ESI (m/z): [MþNa]þ calcd
for C39H82O3Si3, 705.5464; found, 705.5476.
In a glovebox, a 10 mL teardrop flask was charged with Ni(cod)2
4.5.2. (4E,6E,9S,10R)-7,10-Dimethyl-9,13-bis(tri-iso-
(62 mg, 0.23 mmol, 0.2 equiv) and Me2PhP (64
mL, 0.45 mmol,
propylsilyloxy)trideca-4,6-dienal (15)
0.4 equiv). The flask was sealed with a rubber septum and electrical
tape. Outside the box and under a positive pressure of argon, Et3B
(0.66 mL, 4.5 mmol, 4 equiv) and 26a (446 mg, 2.25 mmol, 2 equiv)
were added sequentially. Compound 20 (300 mg, 1.13 mmol,
1 equiv) was added dropwise over approximately 30 min. The black
reaction mixture was stirred for 2 h. The reaction mixture was di-
luted with EtOAc (5 mL), exposed to air, and then stirred vigorously
for 1 h, whereupon the solution turned from black to clear yellow.
The solution was then concentrated in vacuo to a brown oil. Flash
column chromatography (500 mL silica, 95:5 hexane/EtOAc/8:2
hexane/EtOAc) afforded a crude mixture containing 29a, which was
retaken in THF (10 mL). To this solution was added TIPSOTf
(0.39 mL, 1.5 mmol) and 2,6-lutidine (0.27 mL, 2.3 mmol). The so-
lution was stirred overnight. Water (5 mL) was added and the layers
were separated. The aqueous layer was washed thrice with EtOAc
(5 mL each). The organic extracts were combined, dried over
Na2SO4, filtered, and concentrated in vacuo to yield a clear oil. Flash
column chromatography (400 mL silica, 97:3 hexane/EtOAc) affor-
ded 31a as a clear oil (284 mg, 43% yield). 1H NMR (500 MHz, CDCl3,
In a glovebox, CrO3 (123 mg, 1.23 mmol, 10 equiv) was placed in
a 20 mL screw-top vial. The vial was sealed with a septum and
electrical tape. Outside the box and under a positive pressure of
argon, DCM (1.8 mL) and pyridine (199 mL, 2.46 mmol, 20 equiv)
were added to yield a heterogeneous orange slurry, which was
stirred for 30 min. This solution was added to a solution of 14
(84 mg, 0.12 mmol, 1 equiv) in DCM (1 mL) at 0 ꢁC. The red solution
was stirred for 11 h. The solution was then diluted with DCM
(10 mL) and washed with 1 N HCl (2 mL), saturated aqueous
NaHCO3 (4 mL), water (4 mL), and brine (2 mL). The organic layer
was then dried over Na2SO4 and passed through a pad of SiO2
(20 mL), rinsing with EtOAc to give a total eluent volume of 50 mL.
The eluent was concentrated in vacuo to an orange oil. Flash col-
umn chromatography (35 mL silica, 98:2 hexane/EtOAc) afforded
36 mg (60% yield based on recovered 14) of 15 as a clear oil along
with 10 mg (12% recovery) of 14 as a clear oil. 1H NMR (500 MHz,
CDCl3,
d
): 9.78 (t, J¼1.0 Hz, 1H), 6.25 (dd, J1¼15.0 Hz, J2¼10.8 Hz,
1H), 5.80 (d, J¼10.8 Hz,1H), 5.52 (dt, Jt¼6.8 Hz, Jd¼15.0 Hz,1H), 3.92
(dt, Jt¼5.9 Hz, Jd¼1.9 Hz, 1H), 3.67 (t, J¼6.2 Hz, 2H), 2.54 (m, 2H),
2.43 (m, 2H), 2.15 (m, 2H), 1.73 (s, 3H), 1.60 (m, 2H), 1.44 (m, 2H),
1.16 (m, 1H), 1.04–1.07 (m, 42H), 0.94 (d, J¼6.8 Hz, 3H); 13C NMR
d
): 6.97 (dt, Jd¼15.5 Hz, Jt¼6.8 Hz, 1H), 6.25 (dd, J1¼15.1 Hz,
J2¼11.8 Hz, 1H), 5.82 (d, J¼15.5 Hz, 1H), 5.80 (d, J¼11.8 Hz, 1H), 5.55
(dt, Jd¼15.1 Hz, Jt¼7.1 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.92 (dt,
Jt¼6.6 Hz, Jd¼2.5 Hz, 1H), 3.64 (t, J¼6.8 Hz, 2H), 2.26–2.34 (m, 3H),
2.17 (m, 2H), 2.11 (m, 1H), 1.73 (s, 3H), 1.62 (m, 1H), 1.52 (m, 1H), 1.27
(t, J¼7.1 Hz, 3H), 1.02–1.10 (m, 28H), 0.95 (d, J¼7.1 Hz, 3H), 0.90 (s,
(125 MHz, CDCl3, d): 202.3, 135.0, 129.5, 128.1, 127.1, 75.1, 64.0, 43.8,
43.7, 38.5, 31.5, 28.1, 25.7, 18.5, 18.3, 17.3, 15.3, 13.1, 12.2. HRMS-ESI
(m/z): [MþNa]þ calcd for C33H66O3Si2, 589.4443; found, 589.4426.
9H); 13C NMR (125 MHz, CDCl3,
d): 167.4, 150.2, 134.0, 129.4, 129.0,
4.5.3. Dimethyl (5E,7E,10S,11R)-8,11-dimethyl-2-oxo-10,14-bis-
128.1, 121.8, 74.4, 63.8, 60.8, 45.4, 37.7, 37.3, 32.1, 31.3, 26.6, 19.0,
17.5, 16.0, 15.0, 13.7, 13.4, ꢀ4.5. HRMS-ESI (m/z): [MþNa]þ calcd for
C33H64O4Si2, 603.4235; found, 603.4226.
(tri-iso-propylsilyloxy)tetradeca-5,7-dienylphosphonate (16)
To
a solution of dimethyl methylphosphonate (626 mL,
5.86 mmol, 5 equiv) in THF (26.6 mL) cooled to ꢀ78 ꢁC was added
a solution of n-BuLi in hexane (2.5 M, 1.87 mL, 4.69 mmol, 4 equiv).
The solution was stirred for 30 min at ꢀ78 ꢁC. A solution of 15
(664 mg, 1.17 mmol, 1 equiv) in THF (2 mL) was slowly added fol-
lowed by two THF rinses (1 mL each). The solution was allowed to
stir overnight while warming to room temperature. The yellow
solution was poured onto aqueous pH 7 phosphate buffer (20 mL)
and diluted with EtOAc (20 mL). The layers were separated and the
aqueous layer was washed thrice with EtOAc (10 mL each). The
organic extracts were combined, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude material was retaken in DCM
(11.7 mL), and DMP (1.49 g, 3.52 mmol, 3 equiv) and NaHCO3
(984 mg, 11.7 mmol,10 equiv) were added. After stirring for 20 min,
saturated aqueous Na2S2O3 (15 mL) was added. After stirring for
1 h, the layers were separated and the aqueous layer was washed
four times with EtOAc (10 mL each). The organic extracts were
combined and dried over Na2SO4. Filtration and concentration in
4.5. Elaboration of reductive coupling products
4.5.1. (8E,10E,13S,14R)-3,3-Diethyl-19,19-di-iso-propyl-11,14,20-
trimethyl-13-(tri-iso-propylsilyloxy)-4,18-dioxa-3,19-
disilahenicosa-8,10-diene (14)
To a solution of 11 (402 mg, 1.01 mmol, 1 equiv) in Et2O (26 mL)
at 0 ꢁC was added dropwise a solution of LiAlH4 in Et2O (1 M,
2.0 mL, 2.02 mmol, 2 equiv). The solution was stirred for 35 min at
0 ꢁC. Water (76
(230
m
L), 15% (w/w) aqueous NaOH (76
mL), and water
m
L) were sequentially added. The solution was allowed to
warm to room temperature and stir for an additional 10 min. The
solution was then filtered, rinsed with Et2O, and concentrated in
vacuo. Flash column chromatography (200 mL Florisil, 8:2 hexane/
EtOAc/7:3 hexane/EtOAc) afforded 286 mg of the intermediate
diol. To a solution of this intermediate (286 mg, 0.80 mmol,1 equiv)

B.A. Sparling et al. / Tetrahedron 65 (2009) 3270–3280
3279
vacuo yielded a yellow oil. Flash column chromatography (110 mL
silica, 3:7 hexane/EtOAc/1:3 hexane/EtOAc) afforded 630 mg (54%
yield over 2 steps) of 16 as a slightly yellow oil. 1H NMR (500 MHz,
45 min and the layers were separated. The aqueous layer was
washed twice with Et2O (5 mL each). The organic extracts were
combined, dried over MgSO4, filtered, and concentrated in vacuo to
a clear oil. Flash column chromatography (75 mL silica, 3:1 hexane/
EtOAc) afforded 154 mg (68% yield) of the intermediate allylic al-
cohol as a clear oil. To a solution of this alcohol (133 mg, 0.25 mmol,
1 equiv) in DCM (12 mL) were added DMP (209 mg, 0.49 mmol,
2 equiv) and NaHCO3 (207 mg, 2.47 mmol, 10 equiv). The solution
was stirred for 2 h and then treated with saturated aqueous
Na2S2O3 (5 mL). The layers were separated and the aqueous layer
was washed twice with DCM (5 mL each). The organic extracts
were combined, dried over MgSO4, filtered, and concentrated in
vacuo to a clear oil. Flash column chromatography (80 mL silica, 4:1
hexane/EtOAc) afforded 126 mg (94% yield, 64% yield over two
CDCl3,
d
): 6.22 (dd, J1¼15.0 Hz, J2¼10.8 Hz, 1H), 5.77 (d, J¼10.8 Hz,
1H), 5.48 (dt, Jd¼15.0 Hz, Jt¼7.5 Hz, 1H), 3.90 (dt, Jt¼6.3 Hz,
Jd¼2.6 Hz,1H), 3.67 (t, J¼6.5 Hz, 3H), 3.78 (d, JH–P¼11.2 Hz, 4H), 3.66
(t, J¼6.5 Hz, 2H), 3.09 (d, JH–P¼22.7 Hz, 2H), 2.70 (t, J¼7.6 Hz, 2H),
2.37 (m, 2H), 2.13 (m, 2H),1.71 (s, 3H),1.60 (m, 2H),1.43 (m, 2H),1.11–
1.17 (m, 1H), 1.02–1.06 (m, 42H), 0.92 (d, J¼6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3,
d): 201.4 (JC–P¼6.4 Hz), 134.7, 129.7, 127.9, 127.2,
75.1, 64.0, 53.2 (JC–P¼6.4 Hz), 44.2, 43.7, 42.0 (JC–P¼127.8 Hz), 38.4,
31.5 (m), 28.1 (m), 26.9, 18.4, 18.2, 17.3, 15.4, 13.1, 12.2. HRMS-ESI
(m/z): [MþNa]þ calcd for C36H73O6PSi2, 711.4576; found, 711.4602.
4.5.4. (2E,6R,7S,9Z,11E)-6,9-Dimethyl-7-(tri-iso-propylsilyloxy)-
cyclotetradeca-2,9,11-trienone (3)
steps) of 32 as a clear oil. 1H NMR (500 MHz, CDCl3,
d): 9.49 (d,
J¼7.9 Hz, 1H), 6.83 (dt, Jd¼15.5 Hz, Jt¼7.1 Hz, 1H), 6.25 (dd,
J1¼15.0 Hz, J2¼10.9 Hz,1H), 6.13 (dd, J1¼15.5 Hz, J2¼7.9 Hz,1H), 5.80
(d, J¼10.9 Hz, 1H), 5.55 (dt, Jd¼15.0 Hz, Jt¼7.1 Hz, 1H), 3.95 (dt,
Jt¼6.2 Hz, Jd¼2.0 Hz, 1H), 3.65 (t, J¼6.7 Hz, 2H), 2.43 (m, 1H), 2.32
(m, 2H), 2.22 (m, 2H), 1.73 (s, 3H),1.59 (m, 2H), 1.39 (m, 1H), 1.08 (m,
1H), 1.05–1.08 (m, 21H), 0.98 (d, J¼6.8 Hz, 3H), 0.90 (s, 9H), 0.06 (s,
To a solution of 16 (106 mg, 0.15 mmol) in MeOH (5 mL) cooled
to 0 ꢁC was added concentrated HCl (three drops). The solution was
stirred for 30 min at 0 ꢁC and then for 45 min at room temperature.
Water (2 mL) and saturated aqueous NaHCO3 (6 mL) were added.
The solution was extracted four times with Et2O (5 mL each). The
organic extracts were combined, dried over Na2SO4, filtered, and
concentrated in vacuo to give a clear oil. Flash column chroma-
tography (30 mL silica, 1:9 hexane/EtOAc) afforded 66 mg (83%
yield) of the intermediate primary alcohol as a clear oil. To a solu-
tion of this alcohol (183 mg, 0.34 mmol, 1 equiv) in DCM (18.7 mL)
were added DMP (437 mg, 1.03 mmol, 3 equiv) and NaHCO3
(288 mg, 3.43 mmol, 10 equiv). After stirring for 100 min, saturated
aqueous Na2S2O3 (10 mL) and saturated aqueous NaHCO3 (10 mL)
were added. The layers were separated and the aqueous layer was
washed four times with DCM (10 mL each). The organic extracts
were combined, dried over Na2SO4, filtered, and concentrated in
vacuo to yield a white residue. Flash column chromatography
(75 mL silica, 4:96 hexane/EtOAc/2:98 hexane/EtOAc) afforded
163 mg (90% yield) of the intermediate aldehyde as a clear oil. To
6H); 13C NMR (125 MHz, CDCl3,
d): 194.4, 159.4, 133.5, 133.2, 129.1,
128.5, 127.8, 75.0, 63.3, 44.6, 37.1, 36.8, 31.2, 31.1, 29.1, 26.2, 18.5,
17.2, 15.9, 13.1, ꢀ5.0. HRMS-ESI (m/z): [MþNa]þ calcd for
C31H60O3Si2, 559.3973; found, 559.3985.
Acknowledgements
This work was supported by the NIGMS (GM-063755). B.A.S.
thanks the MIT Undergraduate Research Opportunities Program
(UROP) for funding, including the Thomas A. Spencer Endowed
UROP Fund and the Paul E. Gray Endowed Fund for UROP. We are
grateful to Ms. Li Li for obtaining mass spectrometric data for all
new compounds (MIT, Department of Chemistry Instrumentation
Facility, which is supported in part by the NSF (CHE-9809061 and
DBI-9729592) and the NIH (1S10RR13886-01)).
a solution of this aldehyde (47 mg, 88 mmol, 1 equiv) in PhMe
(9.5 mL) were added oven-dried K2CO3 (61 mg, 0.44 mmol, 5 equiv)
and 18-crown-6 (116 mg, 0.44 mmol, 5 equiv). After 45 min of
stirring, the solution was submerged into an oil bath preheated to
85 ꢁC, and the solution was stirred overnight at that temperature.
The reaction mixture was then cooled to room temperature and
washed twice with saturated aqueous NH4Cl (5 mL each) and once
with brine (5 mL). The aqueous extracts were combined and
washed twice with EtOAc (10 mL each). The organic extracts were
combined, dried over Na2SO4, filtered, and concentrated in vacuo to
yield a yellow oil. Flash column chromatography (30 mL silica, 99:1
hexane/EtOAc) afforded a complex mixture of olefin isomers and
dimers, but 16 mg (45% yield, 34% over three steps) of 3 was iso-
References and notes
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d): 6.74 (m, 1H), 6.21 (dd,
J1¼15.3 Hz, J2¼10.5 Hz, 1H), 6.06 (d, J¼16.0 Hz, 1H), 5.79 (d,
J¼10.5 Hz, 1H), 5.56 (dt, Jd¼15.3 Hz, Jt¼7.0 Hz, 1H), 4.01 (m, 1H),
2.63 (m, 2H), 2.30–2.40 (m, 4H), 2.12 (m, 1H), 1.71 (s, 3H), 1.58 (m,
1H), 1.48 (m, 1H), 1.41 (m, 1H), 1.28 (m, 1H), 1.02–1.06 (m, 21H), 0.95
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3280
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