New synthetic strategies for the stereocontrolled synthesis of substituted 'skipped' diepoxides

Article abstract of DOI:10.1016/j.tet.2009.05.074

This report describes a number of new synthetic approaches toward methyl-substituted mono- and diepoxy alcohols that serve as substrates for endo-selective epoxide-opening cascades. The key transformations involve the manipulation of alkynes. Highlighted

Full text of DOI:10.1016/j.tet.2009.05.074

Tetrahedron 65 (2009) 6648–6655
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New synthetic strategies for the stereocontrolled synthesis of substituted
‘skipped’ diepoxides
*
Christopher J. Morten, Timothy F. Jamison
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Ave., 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:
Received 5 May 2009
Received in revised form 23 May 2009
Accepted 26 May 2009
Available online 3 June 2009
This report describes a number of new synthetic approaches toward methyl-substituted mono- and
diepoxy alcohols that serve as substrates for endo-selective epoxide-opening cascades. The key trans-
formations involve the manipulation of alkynes. Highlighted are the directed methylmetalation of
bishomopropargylic alcohols, the bromoallylation of alkynes, and Pd-catalyzed cross-coupling between
an alkenyl boronate ester and allylic bromides.
Ó 2009 Elsevier Ltd. All rights reserved.
Dedicated to Professor Larry E. Overman on
his receipt of the 2008 Tetrahedron Prize
and in honor of his many important con-
tributions to organic chemistry
1. Introduction
trisubstituted alkenes. The powerful Shi asymmetric epoxidation,5
in which the active catalyst is a chiral dioxirane generated in situ
Skipped dienes, also known as 1,4- or homoconjugated dienes,
are a key structural motif found in a number of important natural
products, including several leukotrienes, the omega-3 fatty acids,
insect pheremones,1 and the macrolide amphidinolide A, among
many others. Skipped polyene structures are also notable for their
proposed intermediacy in the biosynthesis of ladder polyether
natural products (such as brevetoxin B, 3, Scheme 1).
These natural products, notorious for their acute toxicity and for
the environmental destruction they wreak, have long fascinated
organic chemists due to their intriguing mixture of structural
complexity and stereochemical uniformity.2 It was Nakanishi who,
nearly 25 years ago, advanced a concise proposal for the bio-
synthesis of brevetoxin B and other ladder polyethers, a synthesis
that culminates in a cascade of regio- and stereospecific epoxide
openings.3 The appeal of this hypothesis lies in its economy. In vivo,
a single stereoselective epoxidase, chemoselective for E alkenes,
acting on polyene 1 could generate all (R,R)-‘skipped polyepoxide’
2, which could in turn undergo an all-endo cascade of epoxide-
opening cyclizations to afford brevetoxin B, 3.4
from a simple, fructose-derived ketone, has emerged as just such
a method. If asymmetric epoxidations of this type are justifiably
taken to be something of a ‘solved problem,’ the stereocontrolled
synthesis of the necessary trans-disubstituted and E-trisubstituted
alkenes (and polyenes) then becomes the primary challenge.
The difficulty of synthesizing highly substituted alkenes with
careful stereo- and regiocontrol is well documented.6 Further-
more, the construction of skipped dienes can be additionally
troublesome due to the rather delicate doubly allylic protons
found in these compounds. The pKa of 1,4-pentadiene (divinyl-
methane) in DMSO is approximately 35,7 making doubly allylic
protons sensitive to strong base, and the same C–H bonds are also
susceptible to hydrogen atom abstraction,8 which can lead to
subsequent di-p
-methane rearrangement.9 Thus the synthesis of
skipped dienes and polyenes must generally avoid very strong
bases (such as alkyllithiums) and reagents that promote single
electron processes.
1.1. Previous work
Abbreviated skipped polyenes similar to 1 can be useful sub-
strates for epoxidation and subsequent studies of biomimetic in
vitro epoxide-opening cascades. Efficient epoxidation of such
skipped polyenes would require a protocol that is reliably (R,R)- or
Strategies for skipped polyenes previously explored in our group
targeted the synthesis of trimethylsilyl (TMS)-substituted skipped
polyenes10 and all-trans-disubstituted polyenes11 from bishomo-
propargylic alcohol 4 (Scheme 2). These polyenes were then
transformed into the polyepoxy alcohols 5 and 6, respectively, with
high diastereoselectivity via Shi epoxidation. Polyepoxy alcohols 5
and 6 then underwent cascades of endo-selective epoxide openings
(accompanied by concomitant protiodesilylation in reactions of 5)
(S,S)-selective for
a wide variety of trans-disubstituted and
* Corresponding author.
E-mail address: tfj@mit.edu (T.F. Jamison).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.074

C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
6649
HO
proposed polyene precursor 1
Me
Me
Me
CHO
Me
Me
O
OH
Me
Me
H
HO
O
[O]
Me
Me
O
Me
CHO
Me
Me
O
O
H
O
O
O
O
OH
O
O
proposed polyepoxide
O
intermediate 2
Me
B
Me
H
epoxide-opening
cascade
HO
Me
CHO
Me
H
O
H
Me
O
Me
Me
O
H
O
H
H
O
O
H
O
O
brevetoxin B (3)
H
O
O
O
H
H
O
Me
H
H
H
H
Me
Scheme 1. Nakanishi’s proposed biosynthesis of brevetoxin B.
to afford THP tetrad 7, a characteristic structural subunit of the
that decorate the trisubstituted epoxides of 2 are encountered both
distal and proximal to the internal nucleophile.12 This point is crit-
ical, as the Me group can exert a rather powerful directing effect on
the regioselectivity of epoxide opening, particularly under acidic
activation.13
ladder polyether natural products.10,11
H
HO
SiMe3
We recently reported that water overcomes methyl group
directing effects in endo-selective epoxide-opening cyclizations to
enable the rapid construction of fused tetrahydropyran (THP) bi-
cycles and tricycles with the incorporation of angular Me groups.14
In that report we described the effects of Me substitution in ep-
oxide-opening reactions of diversely methyl-substituted mono-
and diepoxy alcohols 8–12 (Scheme 3). The key propargylation and
dissolving metal reactions used for diene and triene syntheses en
route to 5 and 6 were unfortunately not readily amenable to the
controlled incorporation of Me substituents into alkenes and
skipped polyenes. We were therefore obligated to develop a num-
ber of new synthetic strategies for the synthesis of 8–12. We herein
describe these strategies for the stereo- and regiocontrolled syn-
thesis of trisubstituted epoxides (and their trisubstituted alkene
precursors). Two of the key transformations highlighted in this
O
O
Me
O
O
H
SiMe3
SiMe3
5
ref. 10c
H
H
H
H
H
H
H
HO
Me
HO
O
O
O
O
O
O
H
4
H
H
7
ref. 11
H
HO
O
Me
O
O
H
6
Scheme 2. Previous polyepoxy alcohol syntheses from common intermediate 4.
H
H
H
H
HO
Me
HO
O
O
Me
Me
Versatile alkyne 4 was transformed into the skipped triene
precursor to 5 via the copper-mediated cross-coupling of a prop-
argyl nucleophile and a TMS-substituted alkenyl iodide.10c The
all-trans-disubstituted triene precursor to 6 was obtained from
dissolving metal reduction of a skipped triyne. Thus the two quite
differently substituted triepoxides 5 and 6 could both be straight-
forwardly derived from common intermediate 4, and both 5 and 6
cyclized to afford tetrad 7.
O
O
Me
8
9
H
HO
H
H
H
HO
Me
O
HO
H
4
O
O
Me
O
Me
O
O
H
O
Me
10
11
It is notable that the ring junctions of 7 are all hydrogen-
substituted. A cursory glance at the ladder polyether natural
products reveals that methyl (Me) substituents are also frequently
encountered at ring junctions (as in brevetoxin B (3, Scheme 1),
which bears Me groups at 5 of its 10 ring junctions). Methyl sub-
stituents also appear in 1 and 2, Nakanishi’s hypothesized poly-
epoxide and polyene precursors to brevetoxin B. The Me groups
H
H
HO
Me
O
O
Me
O
Me
12
Scheme 3. Mono- and diepoxy alcohols synthesized from bishomopropargylic
alcohol 4.

6650
C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
work, Thompson’s directed methylmetalation of alkynes15 and
Kaneda’s haloallylation of alkynes,16 have to our knowledge been
rather infrequently used in total synthesis and related applications,
but both methods have proved indispensable to our work. Fur-
thermore, all of the syntheses detailed here begin from common
intermediate 4. We believe that this work further emphasizes the
utility and versatility of alkyne 4 as a synthetic platform.
advantage, however, in carbometalation directed by the free hy-
droxyl group in 4 (Scheme 4). Thompson’s method for the directed
methylmetalation of propargylic, homopropargylic, and bishomo-
propargylic alcohols with TiCl4 and AlMe3,15 recently used in the
total synthesis of (ꢁ)-borrelidin by the Omura group,23 proved
highly effective. Methylmetalation of 4, I2 treatment, and sub-
sequent silyl protection afforded alkenyl iodide 16 in a modest 41%
yield, but with >20:1 regio- and stereoselectivity.
Alkenyl iodide 16 could be transformed into epoxide-opening
cyclizationsubstrate 8 inthreesimplestepsvia Negishi couplingwith
dimethylzinc, Shi asymmetric epoxidation (Shi AE), and TBAF-in-
duced deprotection of the TES ether (Scheme 5). The Shi asymmetric
epoxidation step proceeded with considerably lower diaster-
eoselectivity than is typically observed in Shi epoxidations of tri-
substituted alkenes. We conjecture that thispoordiastereoselectivity
arises from a mismatched relationship between the chiral dioxirane
epoxidation agent and the stereocenters of the neighboring THP ring.
However, as we have not attempted epoxidation with the antipodal
2. Results and discussion
2.1. Monoepoxide syntheses
Bishomopropargylic alcohol 4 is prepared easily on a gram scale
in five steps from 2,3-dihydropyran.17 We began our exploration
into new transformations of 4 by tackling the synthesis of mono-
epoxy alcohol 8. Compound 8 bears a proximal methyl substituent
and is therefore Me-substituted at both sides of the epoxide. Con-
sequently, we planned to approach 8 via syn-selective 1,2-difunc-
tionalization of alkyne 4 (or a protected derivative of 4).
Repeated attempts at 1,2-difunctionalization of 4 and its TBS
ether 13 via Negishi carbometalation18 resulted either in very low or
undetectable conversion under standard conditions (2 equiv AlMe3
and 1 equiv Cp2ZrCl2 in CH2Cl2 or 1,2-dichloroethane at room tem-
perature) (Scheme 4). Heating above 30 ꢀC led only to the de-
composition of starting material. Attempted methylalumination of 4
and 13 with the stoichiometric addition of water according to the
modified protocol of Wipf and Lim19 likewise led to poor conversion
and significant decomposition. Similarly, methylcupration20 of 13
was too slow to be practical. Thus the highly beguiling rapid, syn-
stereoselective methylmetalation for the eventual 1,2-dimethyla-
tion of alkynes was unfortunately but a siren’s song, leading only to
failure in our early studies.
ketone catalyst (derived from expensive
firm this hypothesis.
L-fructose), we cannot con-
H
H
H
a) Me2Zn, Pd(PPh3)4
b) Shi AE
TESO
I
HO
Me
O
Me
Me
c) TBAF
O
O
H
16
8
H
H
H
Me
O
various
Me
O
Me
HO
O
conditions
O
(ref 14)
O
Me
17
O
O
Me
O
18
Me
unsuccessful attempts at undirected carbometalation:
H
H
TBSO
Me
Scheme 5. Synthesis of monoepoxy alcohol 8; (a) Me2Zn, Pd(PPh3)4, THF/PhMe, 85%;
(b) chiral ketone 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/MeCN, 0 ꢀC,
71%, 2.8:1 dr; (c) TBAF, THF, 0 ꢀC, 94%.
TBSO
Me3Al, Cp2ZrCl2
CH2Cl2 or EDC
Al
O
O
O
H
H
With epoxy alcohol 8 in hand, we turned to the synthesis of its
isomer 9, an epoxide-opening cyclization substrate that bears
a distal Me substituent (located on the far side of the epoxide with
respect to the alcohol). This Me group was appended via alkylation
of a derivative of alkyne 4 with iodomethane to afford bishomo-
propargylic alcohol 19 (Scheme 6). As the synthetic elaboration of
internal alkyne 19 requires the incorporation of only one additional
Me group, we initially attempted to perform a hydrometalation/
methylation sequence on 19 and its silyl-protected derivatives with
Schwartz’s reagent, DIBAL, or 9-BBN, but observed in all cases low
yield, poor regioselectivity, or both.
Instead of hydrometalation, standard Thompson carbometala-
tion conditions (2.2 equiv AlMe3 and 1.1 equiv TiCl4 in CH2Cl2
at ꢁ78 ꢀC) proved best. Upon quenching with methanol, carbo-
metalation smoothly afforded trisubstituted alkene 20 in 70% yield
(79% based on recovered 19) and with no observable trace of un-
desired regio- or stereoisomers. Silyl protection, asymmetric ep-
oxidation, and deprotection then provided distally Me-substituted
epoxy alcohol 9.
13
14
not observed
H
H
TBSO
Me
TBSO
MeCu•MgBr2
Et2O/Me2S
Cu
O
H
H
13
15
not observed
successful directed carbometalation:
H
H
a) AlMe3, TiCl4;
I2
TESO
I
HO
Me
b) TESCl
O
O
H
H
4
16
Scheme 4. Carbometalation studies of 4 and 13; (a) AlMe3, TiCl4, CH2Cl2, ꢁ78 ꢀC, 2 h;
I2, Et2O; (b) TESCl, imid., DMF, 41% over two steps.
Other attempts at 1,2-difunctionalization of 13 via silylcupration
and stannylcupration21 were also unsuccessful, with low conver-
sion observed in all cases and only stannylcupration22 yielding even
a trace of the desired adduct.
2.2. Diepoxide syntheses
It appeared that 4 and 13 were relatively inert under standard
undirected carbometalation and metallometalation conditions. In
the case of 13, the minimal alkyne reactivity may perhaps be due to
the steric demand of the neighboring bulky silyl group in the lowest
energy conformer of the molecule (alkyne and silyl ether both
equatorial). This inferred proximity could be turned to our
2.2.1. Synthesis of diepoxide 10
In general, the alkenylmetal products of carbometalation are
highly versatile and thus highly valuable, as they can be function-
alized directly in a quenching operation with a variety of simple
electrophiles (e.g., Hþ, I2, a few highly electrophilic carbon elec-
trophiles) or transmetalated to Pd or Cu and subsequently used as

C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
6651
H
H
H
H
H
HO
HO
HO
a) TMSCl
c) AlMe3, TiCl4;
H+
Me
Me
b) nBuLi; MeI;
O
O
O
+
H
Me
20
4
19
H
H
H
H
Me
d) TESCl
e) Shi AE
various
HO
O
Me
conditions
O
Me
f) TBAF
(ref. 14)
O
HO
O
H
Me
9
21
Scheme 6. Synthesis of monoepoxy alcohol 9; (a) TMSCl, HMDS, pyridine, CH2Cl2, 90%; (b) n-BuLi, Et2O; MeI; HCl(aq), 88%; (c) AlMe3, TiCl4, CH2Cl2, ꢁ78 ꢀC, 2 h, MeOH, 70% (79%
based on recovered 19); (d) TESCl, imid., DMF, 74%; (e) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/MeCN, 0 ꢀC, 78%, 5.8:1 dr; (f) TBAF, THF, 0 ꢀC, 98%.
nucleophiles in conjugate addition and cross-coupling processes.24
Unfortunately, however, Thompson carbometalation involves de-
livery of the metal to the proximal end of alkynes 4 and 19 (and Me
to the distal end). This regiochemistry precludes using trans-
metalation of the alkenylmetal and subsequent coupling for the
construction of linear skipped dienes or polyenes.
For the assembly of the linear skipped dienes necessary for the
synthesis of diepoxy alcohols 10, 11, and 12, the development of
new strategies became necessary. While terminal alkynes 4 and 13
were nearly inert to undirected carbometalation with Cu and Al/Zr
systems, we elected to try these and closely related substrates in
a catalytic halopalladation process. To our delight, halopalladation
proved straightforward and efficient.
The palladium-catalyzed haloallylation of alkynes was discov-
ered by Kaneda and co-workers.16 It has seen some use in recent
years, with notable extensions of the method reported by the Rawal
group25 and a synthetic application described by Hoye and Wang.26
It has proved invaluable to our own work. The method effects
chloro- and bromoallylation of alkynes via the proposed mecha-
transformation proved problematic in practice. Bromocrotylation is
not straightforward, as the requisite 3-bromo-1-butene is not
commercially available and isomerizes to crotyl bromide at ambi-
ent temperature.28 Chlorocrotylation with 3-chloro-1-butene was
successful, but the E/Z selectivity was only 1.7:1. Moreover, all at-
tempts to effect the cross-coupling of the isomeric alkenyl chloride
products with dimethylzinc via a Pd/P(t-Bu)3 catalyst system29
were unsuccessful.
We found more success with simple bromoallylation and sub-
sequent homologation. Bromoallylation of 26 under conditions
slightly modified from the original Kaneda conditions (dropwise
addition of the alkyne to a room temperature solution of 5 mol %
PdCl2(PhCN)2 in allyl bromide, with the addition of 5 equiv of
NaHCO330) afforded diene 28 in 88% yield, with no trace of undesired
regio- and stereoisomers (Scheme 9). Methylation of alkenyl bro-
mide 28 via Negishi coupling with dimethylzinc and a subsequent
Shi asymmetric epoxidation chemoselective for the more electron-
rich trisubstituted alkene provided epoxy alkene 29. This mono-
substituted alkene was readily and nearly quantitatively converted
PdX2(PhCN)2
- PhCN
X
R2
PdX2(PhCN)
X
β-halide
elimination
X
L2
L
Pd
X
Pd
R1
R1
X
R1
R1
1,2-insertion;
halopalladation
X
X
R2
24
+ PhCN
R2
25
PdX2(PhCN)2
22
23
X = Cl, Br
R = aryl, alkyl
L = PhCN
Scheme 7. The mechanism for haloallylation proposed by Kaneda and co-workers.
nism shown in Scheme 7.16,27 The first step is regioselective and
syn-stereoselective alkyne hallopalladation to afford alkenylpalla-
dium halide 23. After binding and 1,2 insertion of an allylic halide to
to the methylated disubstituted alkene via cross metathesis31 with
cis-2-butene32 using the Hoveyda–Grubbs second generation me-
tathesis catalyst 31 (5 mol %),33 in respectable 4.1:1 E/Z stereo-
chemical purity. While a simple Me group is added in this reaction,
cross metathesis is of course a versatile strategy that also makes
possible the appendage of more complex epoxy alkenes for the
eventual synthesis of longer epoxide chains.34 Shi epoxidation of the
resultant disubstituted alkene afforded the diepoxide in modest
(2.7:1) overall dr, but we were able to improve this to better than
20:1 dr via preparative HPLC. The choice of TBDPS as silyl protecting
group was in large part due its UV activity, which made detection on
HPLC possible. Finally, cleavage of the silyl ether afforded diepoxy
alcohol and epoxide-opening cascade substrate 10.
give 24, b-halide elimination gives diene 25.
trans-Selective halocrotylation of 26, the TBDPS ether of 4,
would provide direct access to the synthetically useful skipped
diene 27 (Scheme 8), which bears the appropriate substitution at
both the disubstituted and trisubstituted alkenes. This
a)
PdCl2(PhCN)2
H
H
H
Cl
TBDPSO
Cl
TBDPSO
O
Me
O
H
26
2.2.2. Synthesis of diepoxide 11
27
(E:Z = 1.7:1)
These results in hand, we were initially hopeful that Kaneda
haloallylation could be extended to the synthesis of diepoxy alcohol
cascade substrates 11 and 12. Both of these substrates bear a Me
Scheme 8. Chlorocrotylation of alkyne 26; (a) 3-chloro-1-butene, PdCl2(PhCN)2,
NaHCO3, THF, 87%, 1.7:1 E/Z.

6652
C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
a)
PdCl2(PhCN)2
H
H
H
H
H
Br
TBDPSO
Br
TBDPSO
TBDPSO
b) Me2Zn, Pd(PPh3)4
c) Shi AE
Me
O
O
O
O
H
26
28
29
H
H
H
H
H
H
H
various
d)
HO
Me
HO
Me
O
conditions
cat. 31
O
N
N
Mes
Mes
e) Shi AE
f) TBAF
(ref. 14)
O
O
Me
O
Me
30
O
Cl
10
Ru
O
Cl
iPr
31
Scheme 9. Synthesis of diepoxide 10; (a) allyl bromide, PdCl2(PhCN)2, NaHCO3, rt, 88%; (b) Me2Zn, Pd(PPh3)4, THF/PhMe; (c) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/
MeCN, 0 ꢀC, 48% over two steps, 4:1 dr; (d) cis-2-butene, Hoveyda–Grubbs second generation catalyst 31, CH2Cl2, 4.1:1 E/Z; (e) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/
MeCN, 0 ꢀC, 90% over two steps, 2.7:1 overall dr; (f) TBAF, THF, 98%.
substituent on the distal side (the endo site of attack) of the epoxide
closer to the THP ring. Unfortunately, bromoallylation of internal
alkyne 32 unexpectedly proceeded with a reversal of regiose-
lectivity as compared to that observed with terminal alkyne 26 such
that undesired regioisomer 33 predominated (Scheme 10).
Ultimately, for the synthesis of diepoxide 11, we took recourse to
the hydrometalation/cross-coupling strategy first investigated for
the preparation of distally trisubstituted monoepoxide 9. Hydro-
zirconation of 32 with Cp2Zr(H)Cl (Schwartz’s reagent) proceeded
in good yield, but the regioselectivity of addition across the alkyne
was nearly 1:1, and separation of the resultant regioisomers after
either iodinolysis of the C–Zr bond or transmetalation to Zn and
quench with carbon electrophiles proved troublesome.
found that these conditions represented a reasonable com-
promise, as longer reaction times and higher temperatures led
to lower mass recovery. While poor conversion is a drawback of
this transformation, unreacted 32 could be recovered and
recycled. Furthermore, the stereochemistry of addition was
cleanly syn, the regioselectivity was 2.0:1 in favor of the de-
sired 35 over the undesired 36, and, most important, the two
regioisomeric pinacolate esters were readily separable by col-
umn chromatography.
After purification, alkenyl boronate ester 35 was cross-coupled
with allyl bromide via Pd-catalyzed conditions adapted from those
developed by Miyaura and co-workers.37 The addition of 2 equiv of
water was found to improve the reaction rate substantially, pre-
a)
PdCl2(PhCN)2
H
H
H
H
H
Br
TBDPSO
Me
RO
TBDPSO
Br
+
Br
O
O
O
H
32
Me
Me
33 (R=TBDPS)
34
47%
undesired
22%
desired
Scheme 10. Bromoallylation of internal alkyne 32; (a) allyl bromide, PdCl2(PhCN)2, NaHCO3, THF, 69%, 2.2:1 33/34 regioselectivity.
Uncatalyzed hydroboration of 32 with pinacolborane was so
slow as to be entirely impractical, but the addition of catalytic
quantities (0.1 equiv) of Cp2Zr(H)Cl and triethylamine accord-
ing to the modification of Wang and co-workers35 to the
method developed by Pereira and Srebnik36 improved the re-
action rate (Scheme 11). However, even with Cp2Zr(H)Cl ca-
talysis and upon heating the hydroboration reaction mixture to
60 ꢀC for 28 h, conversion of starting alkyne 32 to pinacolates
35 and 36 was typically only 60–80%. While less than ideal, we
sumably by effecting in situ hydrolysis of the boronate ester to the
more reactive boronic acid. Bidentate bisphosphine ligands like
dppe and the best ligand identified, dppf, were found to improve
reaction rate as compared to those with monodentate ligands such
as PPh3, PCy3, or Buchwald ligands.38
The crude diene was carried into Shi epoxidation (again
chemoselective for the more electron-rich trisubstituted olefin
over the monosubstituted) to afford epoxy alkene 37. Cross
metathesis of 37 with cis-2-butene again proceeded in excellent
H
H
H
H
H
TBDPSO
RO
TBDPSO
TBDPSO
pinB
a) nBuLi; MeI
b) HBpin
Me
pinB
Me
+
Cp2Zr(H)Cl
Et3N
O
O
O
O
H
H
H
Me
26
32
35
36 (R = TBDPS)
H
H
H
H
H
Me
H
H
c)
various
Br
e)
TBDPSO
O
HO
HO
Me
O
conditions
PdCl2(dppf)
cat. 31
35
O
(ref. 14)
f) Shi AE
g) TBAF
K3PO4, H2O
d) Shi AE
O
O
O
Me
O
O
H
38
H
Me
Me
37
11
Scheme 11. Synthesis of diepoxy alcohol 11; (a) n-BuLi, THF, MeI, 99%; (b) HBpin, Cp2Zr(H)Cl, Et3N, 60 ꢀC, 44% (2.0:1 mixture of regiosiomers 35 and 36, 60% based on recovered 32);
(c) allyl bromide, PdCl2(dppf), K3PO4, H2O, THF; (d) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/MeCN, 0 ꢀC, 53% over two steps, 3:1 dr; (e) cis-2-butene, catalyst 31,
CH2Cl2, 4.2:1 E/Z; (f) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/MeCN, 0 ꢀC, 85% over two steps, 1.5:1 overall dr; (g) TBAF, THF, 95%.

C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
6653
Me
Me
Me
Me
H
H
H
H
H
a)
TBDPSO
Br
TBDPSO
Me
TBDPSO
PdCl2(dppf)
K3PO4, H2O
b) Shi AE
O
Me
Me
+
B
O
O
O
Me
O
O
H
Me
Me
39
Me
35
40
inseparable by
column chromatography
H
H
H
H
H
various
TBDPSO
TBDPSO
O
HO
c) TBAF
conditions
Me
Me
Me
O
Me
+
O
O
(ref. 14)
Me
O
Me
O
O
H
Me
Me
Me
41
42
12
readily separable by
column chromatography
H
H
Me
H
H
HO
Me
O
O
O
H
43
Scheme 12. Synthesis of diepoxy alcohol 12; (a) prenyl bromide, PdCl2(dppf), K3PO4, H2O, THF, 75%, 2.5:1 39/40; (b) 18, Oxone, n-Bu4NHSO4, K2CO3, Na2B4O7 buffer, DMM/MeCN,
ꢀC, 65% (yield of 42 based on 39), 3.5:1 dr; (c) TBAF, THF, 92%.
0
yield and good stereoselectivity (4.2:1 E/Z), and the resulting
disubstituted alkene was subjected to another Shi epoxidation
to afford the diepoxide in disappointing 1.5:1 overall dr. The
1.5:1 mixture of diastereomers was enhanced to greater 9:1
diastereopurity via preparative HPLC, and final TBAF depro-
tection gave diepoxy alcohol and cascade substrate 11 in ex-
cellent yield.
All air-sensitive reactions were performed under an oxygen-free
atmosphere of argon with rigid exclusion of moisture from reagents
and glassware. Dichloromethane was either distilled from calcium
hydride or purified via an SG Water USA solvent column system.
Tetrahydrofuran (THF) was either distilled from a blue solution of
benzophenone ketyl or purified via an SG Water USA solvent col-
umn system. Triethylamine was purified via an SG Water USA sol-
vent column system. Allyl bromide was purified by filtration
through basic alumina before use. K3PO4 was oven-dried overnight
before use. Chiral ketone 18, used in Shi asymmetric epoxidation,
2.2.3. Synthesis of diepoxide 12
The synthesis of the third and final diepoxy alcohol cascade
substrate 12, which bears methyl substituents on both epoxides,
intercepted the synthesis of 11 at alkenyl boronate ester 35
(Scheme 12). Cross-coupling of 35 with prenyl bromide (rather
than allyl) proceeded in similarly good 75% overall yield, but the
was prepared from D-fructose according to the procedure of Vidal-
Ferran and co-workers.39 All other reagents and solvents were used
as obtained, without further purification.
coupling, which goes through an unsymmetrical
p-allyl in-
termediate, resulted in a 2.5:1 mixture of the desired SN2 product
39 along with undesired SN20 product 40.
4.2. Preparation of alkenyl iodide 16 by carbometalation
These diene isomers were inseparable by column chromatog-
raphy, but Shi epoxidation proved chemoselective yet again, ep-
oxidizing both trisubstituted alkenes in 39, but leaving untouched
the monosubstituted olefin in 40 to give a readily separable mixture
of monoepoxide 41 and diepoxide 42 (65% yield based on 39, 3.5:1
dr). The diastereopurity of 42 was improved via preparative HPLC,
and samples of ꢂ15:1 dr were subjected to TBAF deprotection to
afford diepoxy alcohol 12.
To a solution of bishomopropargylic alcohol 4 (265 mg,
1.89 mmol) in CH2Cl2 (20 mL) at ꢁ78 ꢀC was added slowly a 2 M
solution of AlMe3 in hexanes (2.08 mL, 4.16 mmol). This solution was
warmed for 3 min by removing the flask from its cold bath to ensure
complete deprotonation. After recooling to ꢁ78 ꢀC, a 1 M solution of
TiCl4 in CH2Cl2 (2.08 mL, 2.08 mmol) was added dropwise. The so-
lutionwas stirred 2 h at ꢁ78 ꢀC and then quenched with a solution of
I2 (2.4 g, 9.45 mmol) in Et2O (20 mL). The reaction flask was then
wrapped in foil and allowed to warm to room temperature for 10 h.,
at which point H2O (2 mL) was added. The quenched reaction solu-
tion was diluted with Et2O (100 mL) and washed with aqueous 3 M
NaHSO3 (40 mL) until the organic layer was colorless. The aqueous
layer was extracted with Et2O (3ꢃ40 mL), andthe combined organics
were washed with satd NaCl, dried over MgSO4, and concentrated in
vacuo. The crude alkenyl iodide was carried forward without puri-
fication; Rf¼0.72 (50% EtOAc in hexanes), UV active.
3. Conclusion
We have developed synthetic routes to trisubstituted mono-
and diepoxides 8–12, which serve as substrates in endo-selective
epoxide-opening cyclizations and cascades. The longest of these
routes (the synthesis of 11) is eight steps from known homo-
propargylic alcohol 4. We believe that these transformations
highlight the remarkable versatility of common intermediate 4.
Further exploration into new methods for the stereocontrolled
construction of skipped polyenes and epoxide chains is ongoing in
our laboratory.
Upon dissolution of this crude in DMF (1 mL), imidazole (322 mg,
4.73 mmol) and TESCl (380 mL, 342 mg, 2.27 mmol) were added, and
the solution was stirred 2 h at room temperature. The reaction
mixture was applied directly to column of SiO2 and chromato-
graphed (2% EtOAc in hexanes) to afford 16 (310 mg, 0.78 mmol, 41%
over two steps), which was isolated along with some silylated
4. Experimental
4.1. General
bishomopropargylic alcohol (43 mg, 0.17 mmol). Rf of 16¼0.60 (10%
22
EtOAc in hexanes), UV active; [
a
]
ꢁ19.2 (c 4.0, CHCl3).
D
IR (thin film, NaCl) 2955, 2876, 1461, 1415, 1274, 1239, 1127, 1102,
1004 cmꢁ1
.
Full experimental details for compounds 4, 8–12, 16–17, 19–21,
26, 28–30, 32, 35, 37–38, and 42–43 are available in Supplementary
data to Ref. 14.
1H NMR (500 MHz, CDCl3)
3.90–3.85 (m, 1H), 3.39–3.28 (m, 3H), 3.04 (app d, J¼14.8 Hz, 1H),
2.41 (dd, J¼14.8, 9.1 Hz, 1H), 2.02 (m, 1H), 1.75 (d, J¼6.3 Hz, 3H),
d
5.64 (app qt, J¼6.3, 0.7 Hz, 1H),

6654
C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
1.68–1.62 (m, 2H), 1.54–1.44 (m, 1H), 0.96 (t, J¼7.9 Hz, 9H), 0.59 (q,
and Schwartz’s reagent (41 mg, 0.16 mmol). The resulting slurry
was heated to 60 ꢀC and stirred vigorously for 28 h while protected
from light. After cooling, the crude reaction mixture was filtered
through a short pad of SiO2 (100% Et2O) and concentrated in vacuo
to a heavy oil containing a 2:1 mixture of pinacolate 35 (Rf¼0.36,
10% EtOAc in hexanes) and its regioisomer 36 (Rf¼0.38, 10% EtOAc
in hexanes), along with unreacted 32, traces of a proton quench
product, and borate and other impurities. These were separated via
careful column chromatography (gradient 3% to 5% EtOAc in hex-
anes) to afford 35 (235 mg, 0.45 mmol, 29%; 39% based on re-
J¼7.8 Hz, 6H); 13C NMR (125 MHz, CDCl3)
d 131.5, 107.3, 81.3, 70.8,
68.1, 47.8, 33.8, 25.8, 22.5, 7.1, 5.3.
HRMS (ESI) m/z calcd for C15H29IO2Si (MþNa)þ: 419.0874,
found: 419.0893.
4.3. Preparation of trisubstituted alkene 20
by carbometalation
To a of bishomopropargylic alcohol 19 in CH2Cl2 (10 mL) at 0 ꢀC
was added slowly a 2 M solution of AlMe3 in hexanes (0.96 mL,
1.93 mmol). This solution was stirred for 3 min and then recooled to
ꢁ78 ꢀC. A 1 M solution of TiCl4 in CH2Cl2 (0.96 mL, 0.96 mmol) was
added dropwise. The solution was stirred 2 h at ꢁ78 ꢀC and then
quenched with cold MeOH (1 mL), upon which the solution turned
pale yellow. The solution was diluted with Et2O (10 mL) and
washed with a saturated solution of Rochelle’s salt (10 mL). The
aqueous layer was extracted with Et2O (3ꢃ20 ml), dried over
MgSO4, and concentrated in vacuo, and this crude product was
purified by column chromatography (25% EtOAc in hexanes) to
covered 32) in >20:1 regioisomeric purity along with unreacted 32
22
(163 mg, 26%); [
a
]
D
ꢁ2.1 (c 1.9, CDCl3).
IR (thin film, NaCl) 3072, 2932, 2246, 1632, 1472, 1428, 1371,
1301, 1103 cmꢁ1
1H NMR (500 MHz, CDCl3)
.
d
7.71–7.67 (m, 4H), 7.45–7.36 (m,
6H), 6.43 (app tq, J¼6.4, 1.5 Hz, 1H), 3.81–3.76 (m, 1H), 3.45–3.39
(m, 1H), 3.30–3.24 (m, 2H), 2.81–2.75 (m, 1H), 2.08–2.00 (m, 1H),
1.82–1.77 (m,1H),1.63 (d, J¼1.5 Hz, 3H),1.49–1.38 (m, 3H),1.27 (app
s,12H),1.04 (s, 9H); 13C NMR (125 MHz, CDCl3)
d 143.43,136.1,136.1,
134.9, 133.9, 129.9, 129.7, 127.9, 127.6, 83.3, 82.4, 72.6, 67.9, 33.6,
32.1, 27.2, 25.8, 25.1, 25.0, 19.5, 14.5 (no signal was observed for the
boron-bound carbon).
afford 20 as a colorless oil (105 mg, 0.62 mmol, 70%): Rf¼0.38 (30%
22
EtOAc in hexanes); [
a
]
D
ꢁ19.4 (c 1.2, CDCl3). Some unreacted 19
(16 mg, 0.10 mmol, 12%) was also recovered.
HRMS (ESI) m/z calcd for C31H46BO4Si (MþNa)þ: 543.3089,
found: 543.3089.
IR (thin film, NaCl) 3412, 2928, 2855, 1451, 1376, 1340, 1277,
1095, 1036, 944 cmꢁ1
.
1H NMR (500 MHz, CDCl3)
d
5.29 (app t, J¼7.0 Hz, 1H), 3.94–3.89
4.6. Preparation of diepoxide 42 by Pd-catalyzed
cross-coupling and Shi AE
(m, 1H), 3.42–3.30 (m, 2H), 3.08 (ddd, J¼8.7, 7.2, 4.5 Hz, 1H), 2.52
(app dt, J¼15.0, 5.8 Hz,1H), 2.24 (app dt, J¼15.0, 7.0 Hz,1H), 2.10 (m,
1H), 1.73 (s, 3H), 1.72–1.64 (m, 5H), 1.40 (dddd, J¼17.4, 11.3, 6.3,
[1,10-Bis(diphenylphosphino)ferrocene]
dichloropalladium(II)
5.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
67.9, 32.8, 31.6, 26.1, 25.7, 18.2.
d
134.1, 120.5, 82.4, 70.9,
(PdCl2(dppf)) (73 mg, 0.10 mmol) was added to a flame-dried, cooled
sealed tube. K3PO4 (1.83 g, 8.63 mmol) was added, and the tube was
pumped under high vacuum and backfilled with argon three times.
Alkenyl boronate 35 (600 mg, 1.15 mmol) was then added as a solu-
tion in dry THF (2 mL). The mixture was allowed to stir under Ar for
HRMS (ESI) m/z calcd for C10H18O2 (MþNa)þ: 193.1199, found:
193.1194.
4.4. Preparation of alkenyl bromide 28 by bromoallylation
5 min. Degassed water (42 mg, 42
sparging) was then added, followed immediately by prenyl bromide
(859 mg, 666 L, 5.76 mmol). The sealed tub was capped, and the
mL, 2.3 mmol, degassed via
To PdCl2(PhCN)2 (40 mg, 0.11 mmol) and NaHCO3 (880 mg,
10.5 mmol) was added allyl bromide (9 mL,105 mmol). The resulting
solution was stirred 15 min at room temperature. Alkyne 26 (795 mg,
2.1 mmol) as a solution in THF (2 mL) was then added dropwise at
ambient temperature via syringe pump over 90 min. After addition
the reaction mixture was stirred a further 30 min, directly concen-
trated in vacuo, and chromatographed (gradient 2% to 3% to 5% EtOAc
m
slurry was heated to 80 ꢀC and stirred vigorously for 42 h. After
cooling and dilutionwith Et2O (5 mL), the crude product was filtered
through SiO2 (washed with Et2O) and concentrated in vacuo to yield
a 2.5:1 mixture of 39 and 40. These inseparable diene isomers were
purified away from phosphine and other impurities via column
chromatography (gradient 2% to 3% EtOAc in hexanes) to give a 2.5:1
mixture of 39/40 (400 mg, 0.86 mmol, 75% combined yield, Rf¼0.63,
10% EtOAc in hexanes). This mixture was carried forward into Shi
epoxidation without further purification.
in hexanes) to afford alkenyl bromide 28 (920 mg, 1.84 mmol, 88%):
22
Rf¼0.54 (10% EtOAc in hexanes); [
a
]
ꢁ11.5 (c 27.0, CDCl3).
D
IR (thin film, NaCl) 3072, 3011, 2933, 2858, 1639, 1472, 1428,
1362, 1218, 1127, 1103, 1048 cmꢁ1
1H NMR (500 MHz, CDCl3)
.
To this mixture (400 mg, 0.86 mmol) in 2:1 v/v DMM/MeCN
(23.2 mL) was added a 0.05 M solution of Na2B4O7$10H2O in 4ꢃ10ꢁ4
Na2EDTA (15.5 mL), n-Bu4HSO4 (75 mg, 0.22 mmol), and chiral ke-
tone 18 (222 mg, 0.86 mmol). This biphasic mixture was stirred vig-
orously at 0 ꢀC. To this mixture was added, simultaneously over
30 min via syringe pump, a solution of Oxone (1.06 g, 1.73 mmol) in
4ꢃ10ꢁ4 Na2EDTA (7.75 mL) and a 0.89 M solution of K2CO3 (7.75 mL,
6.9 mmol). After the K2CO3 and Oxone solutions had been added, the
resulting mixture was stirred an additional 20 min., at which point it
was diluted with EtOAc (25 mL). The aqueous layer was extracted
with EtOAc (3ꢃ25 mL), and the combined organics werewashed with
satd NaCl, dried over MgSO4, and concentrated in vacuo to provide
desired diepoxide 42 and diastereomers. Compound 40 was partially
oxidized under these conditions to monoepoxide 41 (Rf¼0.77, 20%
EtOAc in hexanes). Column chromatography (15% EtOAc in hexanes)
afforded diepoxide 42 in 3.5:1 overall dr as a colorless oil (276 mg,
0.56 mmol, 65% (49% yield over two steps), Rf¼0.54 (20% EtOAc in
hexanes))contaminatedwithasmallquantityofketone18. Diepoxide
42wasfurtherpurifiedviapreparativeHPLC(SupelcoSUPELCOSILLC-
d
7.87 (app t, J¼8.4 Hz, 4H), 7.56–7.46
(m, 6H), 5.92 (dddd, J¼16.5,10.1, 6.2, 6.2 Hz,1H), 5.85 (app t, J¼6.8 Hz,
1H), 5.22(dd, J¼17.1,1.7 Hz,1H), 5.13 (dd, J¼10.1,1.5 Hz,1H), 3.92–3.87
(m, 1H), 3.71 (app td, J¼9.2, 1.5 Hz, 1H), 3.55 (ddd, J¼10.2, 9.1, 4.6 Hz,
1H), 3.39 (apptd, J¼11.3, 2.7 Hz,1H), 3.32 (app d, J¼14.7 Hz,1H), 3.13–
3.02 (m, 2H), 2.43 (dd, J¼14.8, 10.0 Hz, 1H), 2.05–2.00 (m, 1H), 1.70–
1.62(m,1H),1.60–1.48(m, 2H),1.23(s, 9H);13CNMR(125 MHz,CDCl3)
d
135.9,135.9,134.9,134.3,133.5,129.9,129.7,127.8,127.6,126.0,115.5,
80.0, 71.9, 67.6, 44.5, 35.8, 33.5, 27.1, 25.5, 19.3.
HRMS (ESI) m/z calcd for C27H35BrO2Si (MþNa)þ: 521.1482,
found: 521.1489.
4.5. Preparation of alkenyl boronate ester 35
by hydroboration
Alkyne 32 (616 mg, 1.56 mmol) was added to a dry, cooled
sealed tube. The tube was pumped under high vacuum and then
backfilled with argon three times. Pinacolborane (287
mL, 253 mg,
1.98 mmol) was added, followed by Et3N (22 L, 16 mg, 0.16 mmol)
m
SI 20 mm achiral SiO2 column, 5 mm particle size; 99.5:0.5 hexanes/

C.J. Morten, T.F. Jamison / Tetrahedron 65 (2009) 6648–6655
6655
Me-substituted epoxides under acidic conditions, see: (f) Xiong, Z.; Corey, E. J.
J. Am. Chem. Soc. 2000, 122, 9328.
14. Morten, C. J.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 6678.
15. (a) Schiavelli, M. D.; Plunkett, J. J.; Thompson, D. W. J. Org. Chem. 1981, 46, 807;
(b) Ewing, J. C.; Ferguson, G. S.; Moore, D. W.; Shultz, F. W.; Thompson, D. W.
J. Org. Chem. 1985, 50, 2124.
16. (a) Kaneda, K.; Kawamoto, F.; Fujiwara, Y.; Imanaka, T.; Teranishi, S. Tetrahedron
Lett. 1974, 12, 1067; (b) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.;
Teranishi, S. J. Org. Chem. 1979, 44, 55.
17. A racemic synthesis of 4 was reported by Bowman and McDonald: (a) Bowman,
J. L.; McDonald, F. E. J. Org. Chem. 1998, 63, 3680; (þ)-4, the enantiomer of 4, has
been prepared by the Nakata group: (b) Matsuo, G.; Hinou, H.; Koshino, H.;
Suenaga, T.; Nakata, T. Tetrahedron Lett. 2000, 41, 903; (c) Suzuki, K.; Nakata, T.
Org. Lett. 2002, 4, 2739. A previous asymmetric synthesis of 4 by the Jamison
group is reported in Ref. 10a. We report a streamlined gram-scale synthesis of 4,
requiring five steps from 2,3-dihydropyran, in Supplementary data to Ref. 14.
18. Initial report: (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252;
Successful carbometallation in the presence of free hydroxyl groups: (b) Rand,
C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E.-I. J. Org. Chem. 1981, 46, 4093;
Recent review: (c) Negishi, E.-I. Dalton Trans. 2005, 827.
i-PrOH, 20 mL/min; tR of desired diastereomer¼11.9 min) to afford 42
22
free of 20 and in 15:1 to 20:1 overall dr (depending on batch); [
a]
D
(for a sample in 20:1 dr) ꢁ7.5 (c 3.3, CDCl3).
IR (thin film, NaCl) 3072, 2958, 2930, 2857, 1590, 1472, 1462,
1428, 1379, 1102 cmꢁ1
.
1H NMR (500 MHz, CDCl3)
d
7.71–7.66 (m, 4H), 7.46–7.41 (m,
2H), 7.40–7.36 (m, 4H), 3.85–3.80 (m, 1H), 3.43 (ddd, J¼9.3, 4.8,
4.5 Hz, 1H), 3.29 (app td, J¼9.3, 2.5 Hz, 1H), 2.93 (app t, J¼6.1 Hz,
1H), 2.89 (app t, J¼6.0 Hz, 1H), 2.11 (ddd, J¼14.4, 6.4, 2.7 Hz, 1H),
1.85–1.80 (m, 1H), 1.77–1.73 (m, 2H), 1.60 (ddd, J¼14.9, 9.5, 5.8 Hz,
1H), 1.51–1.39 (m, 3H), 1.33 (app s, 6H), 1.27 (s, 3H), 1.04 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 136.1,136.1,134.7,133.6,130.0,129.8,127.9,
127.7, 81.4, 72.5, 67.9, 61.3, 61.2, 58.8, 58.0, 38.2, 33.5, 31.8, 27.2,
25.6, 24.9, 19.5, 19.0, 17.3.
HRMS (ESI) m/z calcd for C30H42O4Si (MþNa)þ: 517.2745, found:
517.2751.
19. Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
20. Marfat, A.; McQuirk, P. R.; Helquist, P. Tetrahedron Lett. 1978, 19, 1363.
21. For
a general review of the 1,2-difunctionalization of alkynes via metal-
Acknowledgements
lometalation, see: (a) Beletskaya, I.; Moberg, C. Chem. Rev. 1999, 99, 3435; For
a recent review of silylcupration, see: (b) Barbero, A.; Pulido, F. J. Acc. Chem. Res.
2004, 37, 817; For a recent review of stannylcupration, see: (c) Barbero, A.;
Pulido, F. J. Chem. Soc. Rev. 2005, 34, 913.
This work was supported by the NIGMS (GM72566). C.J.M.
thanks the George Bu¨chi Summer Graduate Fellowship for fellow-
ship support. Li Li (MIT) acquired HRMS data. We are grateful also to
Dr. Jeffery A. Byers, Dr. Aaron Van Dyke, Ivan Vilotijevic, and Brian S.
Underwood (all of MIT) for many helpful discussions. Without their
insights this work would not have been possible.
22. The conditions that effected a trace of the desired product were taken from:
Barbero, A.; Cuadrado, P.; Flemin, I.; Gonzalez, A. M.; Pulido, F. J.; Rubio, R.
J. Chem. Soc., Perkin Trans. 1 1993, 1657.
23. Nagamitsu, T.; Takano, D.; Fukuda, T.; Otoguro, K.; Kuwajima, I.; Harigaya, Y.;
Omura, S. Org. Lett. 2004, 6, 1865.
24. For a few examples of the manifold potential electrophilic quenches and
transmetalation possibilities open to alkenylaluminum and alkenylcopper
species, including conjugated additions, transmetalation to Pd, and subsequent
cross-coupling, see: (a) Marfat, A.; McQuirk, P. R.; Kramer, R.; Helquist, P. J.
J. Am. Chem. Soc. 1977, 99, 253; (b) Okukado, N.; Negishi, E.-I. Tetrahedron Lett.
1978, 27, 2357; (c) Matsushita, H.; Negishi, E.-I. J. Am. Chem. Soc. 1981, 103, 2882;
(d) Williams, D. R.; Shamin, K. Org. Lett. 2005, 7, 4161; (e) DeBergh, J. R.; Spivey,
K. M.; Ready, J. M. J. Am. Chem. Soc. 2008, 130, 7828.
´
References and notes
1. Wilson, S. R.; Zucker, P. A. J. Org. Chem. 1988, 53, 4682.
2. Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew. Chem., Int. Ed. 2008, 47, 7182.
3. (a) Nakanishi, K. Toxicon 1985, 23, 473; (b) Lee, M. S.; Qin, G.-w.; Nakanishi,
K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6234; (c) Shimizu, Y. In Natural
Toxins: Animal, Plant, and Microbial; Harris, J. B., Ed.; Clarendon: Oxford,
1986; p 123.
25. (a) Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4317; (b) Thadani, A. N.; Rawal,
V. H. Org. Lett. 2002, 4, 4321.
26. Hoye, T. R.; Wang, J. J. Am. Chem. Soc. 2005, 127, 6950.
27. Ba¨ckvall, J.-E.; Nilsson, Y. I. M.; Gatti, R. G. P. Organometallics 1995, 14, 4242.
28. Winstein, S.; Young, W. G. J. Am. Chem. Soc. 1936, 58, 104.
29. Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719.
30. The addition of NaHCO3 was found to improve yield slightly. Remarkably,
a trace of silyl ether cleavage was observed in the absence of this base, pre-
sumably due to a small quantity of HBr in solution.
31. For discussions of improving the stereoselectivity and reactivity of cross me-
tatheses, see: (a) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder,
R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58; (b)
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360; For a recent review, see: (c) Connon, S. J.; Blecher, S. Angew. Chem.,
Int. Ed. 2003, 42, 1900.
4. Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45, 4406.
5. (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119,
11224; (b) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-X.; Shi, Y. J. Org. Chem.
1998, 63, 2948; (c) Shi, Y. Acc. Chem. Res. 2004, 37, 488.
6. (a) Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis; Cam-
bridge: Cambridge, UK, 2006; pp 105–158; (b) Preparation of Alkenes, A Practical
Approach; Williams, J. M. J., Ed.; Oxford: New York, NY, 1996; (c) Flynn, A. B.;
Ogilvie, W. W. Chem. Rev. 2007, 107, 4698.
7. Bordwell, F. G.; Drucker, G. E.; Fried, H. E. J. Org. Chem. 1981, 46, 632.
8. The bond dissociation energy of the doubly allylic C–H bonds in 1,4-pentadiene
is quite low; it has been measured at 68.5 kcal/mol. See: McMahon, T. B.;
Kebarle, P. J. Am. Chem. Soc. 1974, 96, 5940.
32. Patel, J.; Mujcinovic, S.; Jackson, W. R.; Robinson, A. J.; Serelis, A. K.; Such, C.
Green Chem. 2006, 8, 450.
33. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
9. Hixson, S. S.; Mariano, P. S.; Zimmerman, H. E. Chem. Rev. 1973, 73, 531.
10. (a) Heffron, T. P.; Jamison, T. F. Org. Lett. 2003, 5, 2339; (b) Heffron, T. P.; Trenkle,
J. D.; Jamison, T. F. Tetrahedron 2003, 59, 8913; (c) Simpson, G. L.; Heffron, T. P.;
Merino, E.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1056.
34. Van Dyke, A. R; Jamison, T. F Angew. Chem., Int. Ed. 2009, 48, 4430.
35. Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahedron Lett. 2005, 46, 8777.
36. Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127.
37. Ishiyama, T.; Yamamoto, M.; Miyaura, N. Chem. Lett. 1996, 25, 1117.
38. For an overview of the bulky, electron-rich biaryl phosphines developed by the
Buchwald group, see: (a) Mauger, C. C.; Mignani, G. A. Aldrichimica Acta 2006,
39, 17; (b) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599; (c) Fors,
B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130,
13552 and references therein.
11. Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189.
12. In Scheme 1, distal Me groups are shown in red and proximal in blue, for clarity.
13. For examples of highly endo-regioselective intramolecular opening of distally
Me-substituted epoxides under acidic conditions, see: (a) Bravo, F.; McDonald,
F. E.; Neiwert, W. A.; Do, B.; Hardcastle, K. I. Org. Lett. 2003, 5, 2123; (b) Bravo,
F.; McDonald, F. E.; Neiwert, W. A.; Hardcastle, K. I. Org. Lett. 2004, 6, 4487; (c)
Valentine, J. C.; McDonald, F. E.; Neiwert, W. A.; Hardcastle, K. I. J. Am. Chem.
Soc. 2005, 127, 4586; (d) Wan, S.; Gunaydin, H.; Houk, K. N.; Floreancig, P. E.
J. Am. Chem. Soc. 2007, 129, 7915; (e) Morimoto, Y.; Nishikawa, Y.; Ueba, C.;
Tanaka, T. Angew. Chem., Int. Ed. 2006, 45, 810; For a canonical example of
39. Nieto, N.; Molas, P.; Benet-Buchholz, J.; Vidal-Ferran, A. J. Org. Chem. 2005, 70,
10143.
highly
exo-regioselective
intramolecular
opening
of
proximally