Allene-alkyne cross-coupling for stereoselective synthesis of substituted 1,4-dienes and cross-conjugated trienes

Article abstract of DOI:10.1016/j.tet.2008.02.015

Titanium-mediated cross-coupling of allenic alcohols with alkynes has been investigated. Divergent reaction pathways were discovered that provide either stereodefined 1,4-dienes or substituted cross-conjugated trienes. In short, allene substitution plays

Full text of DOI:10.1016/j.tet.2008.02.015

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3437e3445
www.elsevier.com/locate/tet
Alleneealkyne cross-coupling for stereoselective synthesis of
substituted 1,4-dienes and cross-conjugated trienes
*
Heidi L. Shimp, Alissa Hare, Martin McLaughlin, Glenn C. Micalizio
Department of Chemistry, Yale Univeristy, New Haven, CT 06520-8107, USA
Received 28 December 2007; received in revised form 4 February 2008; accepted 5 February 2008
Available online 8 February 2008
Dedicated to Professor John Hartwig on his receipt of the Tetrahedron Prize
Abstract
Titanium-mediated cross-coupling of allenic alcohols with alkynes has been investigated. Divergent reaction pathways were discovered that
provide either stereodefined 1,4-dienes or substituted cross-conjugated trienes. In short, allene substitution plays a critical role in the determi-
nation of reaction pathway.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have described a variety of titanium-mediated
cross-coupling reactions for the fusion of substituted and unac-
tived p-systems (Scheme 1).3 While these coupling reactions
have provided a convergent pathway to the synthesis of stereo-
defined tetrasubstituted 1,3-dienes (1), branched allylic
systems (2) and 1,4-dienes (3), they represent only a small
The direct cross-coupling of unactivated p-systems could
represent a powerful strategy for the convergent synthesis of
complex molecules. Such processes provide an advantage
over metal-catalyzed cross-coupling reactions1 that typically
require the use of activated coupling partners (i.e., functional-
ized organometallic reagents and organic halides), as these
‘starting materials’ often require numerous stoichiometric
reactions for their preparation. While numerous examples of
metal-mediated coupling reactions of unactivated p-systems
have been described in intramolecular settings, few reports de-
scribe the success of such processes for intermolecular CeC
bond formation.2 Where, in intramolecular CeC bond forming
reactions, reactivity and selectivity are controlled by the
enforced proximity of the reacting p-systems, the analogous
bimolecular processes are significantly more complex. To
realize such intermolecular cross-coupling reactions, one must
be able to control site-selectivity (in the functionalization
of each reacting p-component) and facial selectivity, while
overcoming barriers associated with general reactivity.
alkyne–alkyne cross-coupling:
R3
HO
R1
OH
R4
R5
R5
+
R1
R4
R2
R2 R3
1
alkene–alkyne cross-coupling:
OH
R1
OH
R3
R4
R4
+
R3
R2
R1 R2
2
allylic alcohol–alkyne cross-coupling:
OH
R1
R4
R1
+
R2
R4
R3
R3
R2
3
* Corresponding author. Tel.: þ1 203 432 9403.
E-mail address: glenn.micalizio@yale.edu (G.C. Micalizio).
Scheme 1. Directed cross-coupling reactions of unactivated p-systems.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.015

3438
H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
R4
R3
sample of the potential cross-coupling reactions possible based
on the reactivity of metalep complexes.
R1
Ti
(Oi-Pr)n
R4
O
Ti
R1
(Oi-Pr)n
R4
R1
a
O
M+ –
O
or
•
+
•
H
Metal-mediated alleneealkyne cross-coupling is a relatively
underdeveloped process.4 In the context of convergent synthe-
sis of dienes, this mode of cross-coupling is known to be effec-
tive with only a limited subset of coupling partners, providing
access to di- and trisubtituted products (Scheme 2). For
example, allene hydrozirconation followed by MAO-catalyzed
allylzirconation of terminal alkynes provides a regio- and ste-
•
R2
R3
R3
A
R2
R2
9
7
B
directed
carbometalation
formal metallo-
[3,3]-rearrangement
R1
R2
R3
OH
R3
R4
R4
R1 R2
10b
R1
(i) allene hydrozirconation
R1
R2
+
H
R2
11b
•
4
(ii) MAO-catalyzed allylzirconation
of terminal alkyne
5
6
a = formation of a titanium–alkyne complex followed by introduction of the
allenic alkoxide.
b = obtained after aqueous work up.
(i) formation of titanium–alkyne
R3
complex
Scheme 3. A titanium-mediated, alkoxide-directed alleneealkyne cross-coup-
ling reaction.
R1
R3
R1
+
R2
•
4
(ii) carbometalation of allene
R2
7
8
when R1 = alkyl
E:Z varies from 64:36 to 25:75
2. Results
2.1. Synthesis of stereodefined 1,4-dienes
Scheme 2. Known pathways to 1,4-dienes based on alleneealkyne cross-
coupling.
Our studies began with examination of the cross-coupling re-
action between 2,3-butadiene-1-ol 12 and the symmetrical al-
kyne 13. As illustrated in Scheme 4, preformation of the
metalealkyne complex of 13, followed by addition of the
reoselective route to 1,4-disubstituted 1,4-dienes (4þ5/6).4d,e
For more highly substituted products, cross-coupling between
preformed titaniumealkyne complexes and monosubstituted
allenes has been reported to provide trisubstituted 1,4-dienes,
albeit with varying degrees of stereoselection (4þ7/8).4a
While cross-coupling of an alkyl substituted allene bearing
a tethered benzyl ether (R1¼(CH2)2OBn) with a symmetrical
alkyne (R2 and R3¼Bu) provides 1,4-dienes with a slight pref-
erence for the formation of the E-disubstituted olefin
(E:Z¼64:36), selectivity is a complex function of the nature
of the alkyne. For example, coupling of the same allene with
a TMS substituted alkyne provides 1,4-diene products with
a modest preference for the formation of the Z-olefin-contain-
ing 1,4-diene (E:Z¼25:75).
OPMB
OH
OPMB
OPMB
14
a
HO
+
+
(3:1)
•
OPMB
53%
OPMB
12
13
OPMB
15
a = alkyne (1.0 equiv), ClTi(Oi-Pr)3 (2.0 equiv), c-C5H9MgCl (4.0 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (0.7 equiv)
(–78 to 0 °C).
Major challenges that exist in the development of a general
alleneealkyne cross-coupling reaction include the following:
Scheme 4. A stereodefined 1,4-diene and cross-conjugated triene from an
alkoxide-directed alleneealkyne coupling.
(1) control in the functionalization of di- and trisubstituted
allenes,
(2) regioselection (for the functionalization of each p-compo-
nent: allene and alkyne), and
(3) stereoselection (in the formation of the substituted olefins
resident in the products).
lithium alkoxide of allene 12 and aqueous work-up provided
a 3:1 mixture of coupled products in 53% yield. The major com-
ponent of this mixture, identified as the stereodefined 1,4-diene
14, was accompanied by a a small amount of a cross-conjugated
triene (15). This initial result was viewed as quite promising,
as no stereoisomeric 1,4-dienes were detected in the product
mixture. Further, the stereoselection observed was consistent
with a directed CeC bond forming process in preference to a
non-directed process (the expected product from a non-directed
cross-coupling is a 1,4-diene bearing a Z-allylic alcohol;4a
not shown).
To address these issues, we initiated studies aimed at defin-
ing an alkoxide-directed alleneealkyne cross-coupling reac-
tion.5 As depicted in Scheme 3, it was anticipated that
formation of a titanium complex of 7, followed by exposure
to a preformed allenic alkoxide (9) would afford a mixed tita-
nate ester in a transient fashion. This reactive intermediate
could then rearrange via directed carbometalation (A/10)
or formal metallo-[3,3] rearrangment (B/11).6 Here, we
describe titanium-mediated cross-coupling reactions between
allenes and alkynes that provide either 1,4-dienes (10) or
cross-conjugated trienes (11) in a stereoselective fashion.
Cross-conjugated triene 15 was reasoned to be derived from
a competition between the directed carbometalation pathway
(A) and a formal metallo-[3,3] rearrangement process (B)
(Scheme 3). In considering this competing pathway, it was

H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
3439
with CeO bond breaking (C; Fig. 1),7 or by a pathway where
directed carbometalation provides an intermediate bicy-
clo[3.2.0] metallacyclopentane, which then undergoes syn
elimination (D/E/15).
OPMB
OPMB
R2
R1(Oi-Pr)
n
Ti
O
R1
R1
H2O
R2
OPMB
OPMB
H
•
[M]
H
15; R1 = H
C
If production of the cross-conjugated triene proceeded by
a pathway that involved full, or partial, CeTi bond formation
in the transition state (i.e., D), then allene substitution proxi-
mal to the alkoxide (R1¼alkyl) was anticipated to greatly im-
pact the viability of this pathway. With R1¼alkyl, progression
through D would require formation of a tertiary metalecarbon
bond, a fact which was anticipated to greatly disfavor this
pathway, and hence formation of a cross-conjugated triene. Al-
ternatively, the reaction pathway for production of 1,4-dienes
was not anticipated to be adversely affected by such substitu-
tion (see A; Scheme 3). In accord with these expectations,
cross-coupling of 2-methyl-2,3-butadiene-1-ol 16 with alkyne
13 proceeds with good efficiency, and high selectivity for the
formation of the E,E-1,4-diene 17 (Scheme 5). In this reaction,
no evidence was found for the production of a cross-conju-
gated triene, or a stereoisomeric coupling product.
Table 1 illustrates that the 1,4-diene-selective cross-coup-
ling of 1,1-disubstituted allenes with internal alkynes can be
accomplished with a variety of functionalized substrates. For
example, coupling of the methoxy-substituted allene 18
with symmetrical alkyne 13 affords the stereodefined enol
ether-containing 1,4-diene 19 in 87% yield with ꢀ20:1 selec-
tivity for the establishment of each stereodefined olefin (entry
or
R2
R1(Oi-Pr)
O
n
(Oi-Pr)n
Ti
O
R2
Ti
R2
R1
H
•
R2
H
D
E
Figure 1. Possible origins of the cross-conjugated triene product 15.
OPMB
OPMB
Me
a
OH
HO
+
•
OPMB
74%
OPMB
Me
16
13
17
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.3 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
Scheme 5. Cross-coupling of 1,1-disubstituted allenes with internal alkynes
proceeds with high levels of site-selectivity.
reasoned that the mechanism of the reaction could derive from
a pathway whereby CeC bond formation occurs in concert
Table 1
OH
OH
R3
R4
alkoxide-directed
cross-coupling
R4
•
+
R1
R1
Ph
R3
R2
R2
Entrya
Allene
Alkyne
Yield (%)
E:Zb
1,4-Diene
OH
OH
OPMB
OPMB
•
Ph
Ph
1
13
87
66
ꢀ1:20
OMe
18
OMe
19
OPMB
OH
OH
OPMB
TMS
•
Ph
2
3
ꢀ1:20
ꢀ1:20
ꢀ20:1
OMe
OMe
TMS
21c
18
20
TMS
TMS
OH
OH
•
48
62
N
Me
Me
N
16
23c
22
OH
Me Me
OH
Me Me
HO BnO
Me
OBn
•
4
OH
Me
25d
Me
Me
24
16
a
Typical reaction conditions: alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe (ꢁ78 to ꢁ30 ꢂC), cool to ꢁ78 ꢂC, then add allenyl
alkoxide (1 equiv) (ꢁ78 to 0 ꢂC).
b
Selectivity refers to the olefin formed from the allene coupling partner.
rs¼4:1.
c
d
rr¼2:1.

3440
H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
1). In a more complex example, allene 18 can be coupled to
the unsymmetrical alkyne 20 in a site- and stereoselective
manner. In this case, the 1,4-diene 21, containing both a stereo-
defined enol ether and vinylsilane, is produced in 66% yield
(entry 2). Although no evidence was found for the production
of a stereoisomeric diene or cross-conjugated triene in this re-
action, a minor isomer derived from regioisomeric functional-
ization of the TMS-alkyne was observed (rs¼4:1). This
observation speaks to the complexity of the present cross-cou-
pling reaction, where site- and stereoselective functionaliza-
tion of each unsymmetric p-system is accomplished
simultaneously.
As depicted in entry 3, the heterocycle-containing TMS-al-
kyne 22 is also a suitable substrate for this cross-coupling pro-
cess. Reaction with allene 16 provides the 1,4-diene product
23 as a single isomer (48% isolated yield). As observed previ-
ously, a minor isomer derived from regioisomeric functionali-
zation of the unsymmetrical alkyne was generated (rs¼4:1).
Finally, cross-coupling of allene 16 with the unsymmetrically
substituted internal alkyne 24 provides 1,4-diene 25 in 62%
yield (entry 4). This example demonstrates that site- and ster-
eoselective CeC bond formation proceeds with free hydroxyl
functionality tethered to each reacting p-system.
diene 28 is formed as a minor product (27:28¼3:1). This ero-
sion in selectivity, from allenic alcohol to homoallenic alco-
hol, is presumed to derive from a competition between
directed and non-directed CeC bond forming processes
(Fig. 2).
Trisubstituted allenes are also useful substrates in this ster-
eoselective cross-coupling reaction. As depicted in Scheme 7,
coupling of allene (ꢃ)-29 with the symmetrical alkyne 13 pro-
OPMB
OPMB
Me
OH
a
HO
+
OPMB
•
53%
OPMB
Me
Me Me
30
(+ 31% of cross-conjugated triene)
29
13
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
Scheme 7. Cross-coupling of trisubstituted allenes with internal alkynes.
vides the highly substituted, stereodefined E,E-1,4-diene 30 in
53% yield. While the yield of the substituted diene is sufficient
to render this reaction useful for the synthesis of highly
substituted 1,4-dienes, unlike previously described cross-cou-
plings, this reaction produces a significant amount of cross-
conjugated triene (31%).
While allenic alkoxides uniformly provide 1,4-diene prod-
ucts with high levels of stereoselection in coupling reactions
with internal alkynes (regio- and diastereoselection is
ꢀ20:1), the homoallenic alkoxide derived from 26 does not
provide high levels of stereoselection in cross-coupling reac-
tions with alkyne 13 (Scheme 6). Whereas the 1,4-diene 27
is the major product in this coupling reaction, the isomeric
2.2. Convergent synthesis of stereodefined poly-substituted
cross-conjugated trienes
OPMB
OPMB
2.2.1. Background to the utility of cross-conjugated trienes
in complex molecule synthesis
Cross-conjugated trienes are a functional group with great
potential in complex molecule synthesis.8 Since Blomquist
and Verdol’s synthesis of 2-vinyl-1,3-butadiene (32), and sub-
sequent demonstration of its diene-transmissive DielseAlder
reaction with maleic anhydride,9 many have explored the po-
tential of cross-conjugated trienes in carbocycle and heterocy-
cle construction (Scheme 8).4h,10
OH Me
Me
OPMB
OPMB
27
a
•
+
OPMB
+
(3:1)
64%
HO
Me
OPMB
26
13
HO
28
a = alkyne (1.4 equiv), ClTi(Oi-Pr)3 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
Despite great interest in the use of this reactive structural
motif, barriers still exist in the preparation of highly
substituted and stereodefined cross-conjugated trienes.
Whereas cyclic cross-conjugated trienes are accessible via
Scheme 6. Cross-coupling of homoallenic alcohols with alkynes leads to
diminished stereoselection.
R
O
Ti
(Oi-Pr)n
Me
R
•
R
Me
OH
+ –O
Me
R
M
R
E,E-1,4-diene
directed
carbometalation
+
•
O– +
M
R
(Oi-Pr)n
R
Me
Ti
R
26
13
Me
HO
R
•
R
non-directed
Z,E-1,4-diene
carbometalation
Figure 2. Competition between directed and non-directed carbometalation.

H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
3441
Blomquist and Verdol, 1955:
AcO OAc
O
OPMB
O
OPMB
OPMB
O
O
a
maleic
HO
+
•
OPMB
O
anhydride
81%
Me
Me
O
31
32
33
35
34
13
Scheme 8. Synthesis of 2-vinyl-1,3-butadiene and its diene-transmissive
DielseAlder reaction with maleic anhydride.
a = alkyne (1.4 equiv), Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe
(–78 to –30 °C), cool to –78 °C, then add lithium alkoxide of allene (1 equiv)
(–78 to 0 °C).
metal-mediated cycloisomerization processes,11 the synthesis
of acyclic cross-conjugated trienes is limited to the preparation
of a small subset of sparsely substituted trienes.9,12 In such
processes, issues concerning stereoselection in the generation
of the substituted olefins of the cross-conjugated triene are
pronounced.
Based on the potential utility of substituted cross-conju-
gated trienes in complex molecule synthesis, and the lack of
general convergent pathways for their synthesis, we focused
our attention on optimizing the alleneealkyne cross-coupling
reaction for the synthesis of stereodefined cross-conjugated
trienes.
Scheme 9. Coupling of (ꢃ)-2,3-pentadiene-1-ol 34 with alkyne 13.
isopropyl-substituted allenic alcohol 36 with alkyne 13 pro-
vides the substituted triene 37 in 69% yield with ꢀ20:1 selec-
tivity for the formation of each stereodefined trisubstituted
olefin. Entry 2 demonstrates that this convergent coupling re-
action can be employed to generate tetrasubstituted olefins. In
this case, triene 39 can be prepared as a single isomer in 62%
yield.
Aside from controlling olefin geometry and site-selectivity
in allene-functionalization, one can also control site-selectivity
in the functionalization of unsymmetrical alkynes. As illus-
trated in entry 3, the branched alkyne 40 can be selectively
coupled to allene 36. In this reaction, CeC bond formation oc-
curs preferentially distal to the branched architecture of alkyne
40, and affords cross-conjugated triene 41 in 57% yield
(rs¼3:1, E:Z ꢀ20:1). The stereochemistry of these products
was assigned on the basis of spectroscopic data, as depicted
for 37 (Fig. 4).
Similarly, entries 4e7 demonstrate that selective functional-
ization of silyl-substituted alkynes is possible.8 In these cases,
the cross-conjugated triene products 43, 45, 46 and 48 can be
generated in >70% yield, with high levels of stereoselection
(regioselection with respect to alkyne functionalization¼4:1).
The stereoselectivity observed in these reactions is consis-
tent with CeC bond formation occurring anti to the distal
alkyl substituent of the allene via geometry B (Scheme 3).
To further explore the validity of this model, the cross-coup-
ling reaction of a diastereomerically pure chiral allene,
bearing a secondary hydroxyl directing group, with a sym-
metrical alkyne was investigated (Scheme 10). Coupling of
allene 49 with alkyne 13 provides triene 50 in 50% yield.
The observed stereoselection is consistent with reaction by
way of a boat-like geometry H,3d where CeC bond forma-
tion occurs anti to the terminal butyl substituent of the
allene, with the allenic substituent (R1) occupying an
equatorial position.
2.2.2. Synthesis of cross-conjugated trienes
The decreased regioselection observed in cross-coupling of
trisubstituted allene 29 with alkyne 13 could be derived from
a destabilization of the transition state for directed carbometa-
lation in pathway F (Fig. 3). This destabilization would likely
be based on the required build-up of non-bonded 1,2-steric in-
teractions in the development of the intermediate bicy-
clo[3.3.0] metallacycle. Cross-coupling by CeC bond
formation at the central carbon of the allene would avoid these
destabilizing interactions, yet would require the formation
(partial or full, depending on the mechanism) of a tertiary met-
alecarbon bond (G). Following this analysis, we reasoned that
the reaction pathway for cross-coupling of allenes with
alkynes could be diverted from the production of 1,4-dienes
to stereodefined cross-conjugated trienes if the requirement
of generating a tertiary metalecarbon bond was removed,
while retaining the substitution at the terminus of the allene.
In line with this expectation, we were pleased to find that
coupling of (ꢃ)-2,3-pentadiene-1-ol 34 with alkyne 13 affords
the stereodefined cross-conjugated triene 35 (41% post HPLC;
Scheme 9). Although this unoptimized coupling reaction did
not proceed with high efficiency, no evidence was found for
the production of a 1,4-diene.
A variety of substituted allenes and alkynes can be em-
ployed in this site- and stereoselective cross-conjugated triene
synthesis. As depicted in entry 1 of Table 2, coupling of the
The highly substituted cross-conjugated trienes produced
from this cross-coupling reaction have great potential for
(Oi-Pr)n
O
Ti
R
Me
(Oi-Pr)n
Ti
cross-conjugated
triene
O
R
Me
vs.
1,4-diene
R
H
•
Me
R
F
G
Me
non-bonded steric
interaction
Figure 3. Competition between directed carbometalation and formal metallo-[3,3] rearrangement with trisubstituted allenes.

3442
H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
Table 2
R3
R3
R1
R4
R2
OH
titanium-mediated
+
•
cross-coupling
R1 R2
E:Zb
R4
Entrya
Allene
Alkyne
Yield (%)
69
rsc
Product
OPMB
OH
OH
1
13
ꢀ20:1
d
iPr
•
36
OPMB
OPMB
iPr
37
Me
•
Me
2
3
13
62
d
d
OPMB
Me
Me
39
38
Me Me
Me Me Me
OH
OH
i-Pr
i-Pr
•
57d
ꢀ20:1
3:1
Me
TESO
40
OBn
OBn
HO
i-Pr
36
41
R
BnO
OBn
•
R
i-Pr
4
5
36
42; R¼TMS
44; R¼TIPS
75
82
ꢀ20:1
ꢀ20:1
4:1
4:1
43; R¼TMS
45; R¼TIPS
R
PMBO
R
Me
Me
OH
OPMB
•
Me
Me
6
7
a
38
20; R¼TMS
47; R¼TIPS
71
74
d
d
4:1
4:1
46; R¼TMS
48; R¼TIPS
Typical reaction conditions: alkyne (1.4 equiv), ClTi(Oi-Pr)3 or Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.2 equiv), PhMe (ꢁ78 to ꢁ30 ꢂC), cool to ꢁ78 ꢂC, then
add allenyl alkoxide (1 equiv) (ꢁ78 to 0 ꢂC).
b
Refers to the establishment of the substituted olefin derived from the allene (the other stereodefined olefin, derived from the alkyne is formed as a single
isomer).
c
Refers to the site of alkyne functionalization.
Yield after deprotection with TBAF (see supplementary data for details).
d
nOe
provides the cycloadduct 52 in 50% yield (endo:exo¼6:1;
creased reactivity of (Z)-dienes in DielseAlder reactions.13
OPMB
Scheme 11). This reactivity pattern is consistent with the de-
OPMB
HH
OPMB
OPMB
H
H
nOe
Me Me
3. Conclusion
i-Pr
37
The cross-coupling of allenic alcohols with alkynes can be
accomplished in a highly regio- and stereoselective manner.
Applying an alkoxide-directed coupling reaction, tetrasubsti-
tuted 1,4-dienes are prepared by titanium-mediated coupling
of 1,1-disubstituted allenes with internal alkynes. In these
cases, stereoselection is consistent with the proposition that
these processes proceed through the formation of bicy-
clo[3.3.0] metallacyclopentenes, protonation of which affords
1,4-dienes 55 (Scheme 12). Alternatively, alkoxide-directed
cross-coupling of 1,3-disubstituted allenes with internal al-
kynes provides a general strategy for the synthesis of
Figure 4. Stereochemical assignment of the cross-conjugated triene products
was accomplished by analysis of NOE data as depicted for 37.
facilitating the syntheses of complex carbocyclic and heterocy-
clic ring systems via site- and stereoselective cycloaddition pro-
cesses. Whereas the reactivity of less-substituted acyclic cross-
conjugated trienes is difficult to control in bimolecular [4þ2]
cycloadditions, as multiple cycloadditions often predomina-
te,4h,9,10,12 the substituted trienes generated here cleanly
undergo mono-cycloaddition with activated dienophiles. For ex-
ample, heating a toluene solution of 37 with maleimide 51

H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
3443
stereoselection?
R3
R3
R2
R3
R3
OH
R1 *
cross-coupling
H
R1
R3
R3
+
+
•
or
R1
R2
H
R2
Bu
H
H
(i-PrO)n
Ti
Bu
H
R2
R2
OH
OPMB
a
O
BnO
•
13
R1
H
•
50%
OPMB
H
Bu
BnO
49
H
(E) 50
a = alkyne 9 (1.4 equiv), Ti(Oi-Pr)4 (2.1 equiv), c-C5H9MgCl (4.3 equiv), PhMe (–78 to –30 °C), cool to –78 °C, then add allenyl alkoxide
(1 equiv) –78 °C to 0 °C.
Scheme 10. Alleneealkyne coupling for the synthesis of stereodefined tetrasubstituted cross-conjugated trienes.
OPMB
tetrahydrofuran were distilled from sodium/benzophenone ke-
tyl before use. Diethyl ether was used after passing through an
activated alumina column. Titanium(IV) isopropoxide was
used after distillation of the commercially available reagent.
ClTi(Oi-Pr)3 was purchased as a 1 M solution in hexanes
from Aldrich and was used without further analysis or purifi-
cation. All other commercially available reagents were used as
received.
OPMB
PMBO
O
O
H
OPMB
PhMe
+
N Me
N Me
90 °C
50%
i-Pr
H
O
O
i-Pr
52
37
51
dr = 6:1
Scheme 11. Thermal intermolecular site- and stereoselective DielseAlder
reaction of a trisubstituted cross-conjugated triene and an activated dienophile.
4.2. Representative procedure for the stereoselective
synthesis of 1,4-dienes
OH
R1
R2
R1
R3
titanium-mediated
cross-coupling
R3
+
+
HO
HO
R2
•
4.2.1. Synthesis of (2E,5Z)-8-(4-methoxybenzyloxy)-5-
(2-(4-methoxybenzyloxy)ethyl)-2-methylocta-2,5-dien-1-ol,17
To a ꢁ78 ꢂC solution of alkyne 13 (200 mg, 0.56 mmol) in
3.7 mL of PhMe were added 850 mL of ClTi(Oi-Pr)3 (1.0 M
in hexanes, 0.85 mmol) and 860 mL of c-C5H9MgCl (1.96 M in
Et2O, 1.69 mmol) dropwise via a gas-tight syringe. The result-
ing clear, yellow solution turned dark reddish brown while
warming slowly to ꢁ30 ꢂC over 1 h. The reaction mixture
was stirred at ꢁ30 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To
a separate ꢁ78 ꢂC solution of allene 16 (69 mg, 0.39 mmol)
in 1.0 mL PhMe was added 160 mL of nBuLi (2.45 M in hex-
anes, 0.39 mmol) dropwise via gas-tight syringe. The resulting
solution was stirred for 15 min, removed from the cold bath,
and added to the ꢁ78 ꢂC titanium solution dropwise via can-
nula. After warming slowly to 0 ꢂC over 2 h, the reaction was
quenched with 5 mL of satd NH4Cl solution. The mixture
was warmed to room temperature before extracting with EtOAc
(3ꢄ15 mL). The combined organic layer was washed with satd
NaHCO3 solution (1ꢄ30 mL), brine (1ꢄ30 mL) and dried over
anhydrous Na2SO4. Flash column chromatography of the crude
material (20% EtOAc/hexanes, then 50% EtOAc/hexanes) pro-
vided 127 mg (74%) of diene 17 as a clear, colorless oil. A
small portion was further purified by HPLC [EtOAc/hexanes:
gradient from 35% to 55% (0e20 min, 25 mL/min) on a Micro-
sorb (Si 80-120-C5 H410119) column] to obtain a sample for
analytical characterization. 1H NMR (400 MHz, CDCl3)
d 7.26e7.23 (m, 4H), 6.89e6.85 (m, 4H), 5.42e5.37 (m,
1H), 5.24 (t, J¼7.1 Hz, 1H), 4.42 (s, 2H), 4.41 (s, 2H), 4.00
(d, J¼5.8 Hz, 2H), 3.80 (s, 3H), 3.80 (s, 3H), 3.46e3.39 (m,
53
54
55
R2
R3
R3
titanium-mediated
cross-coupling
•
R2
R1
R1
H
56
54
57
Scheme 12. Alleneealkyne cross-coupling for the synthesis of 1,4-dienes or
cross-conjugated trienes.
substituted cross-conjugated trienes 57. These stereodefined
substituted cross-conjugated trienes are useful intermediates
in the synthesis of complex polycyclic systems, as they un-
dergo site- and stereoselective mono [4þ2] cycloaddition
with activated dienophiles. Overall, these highly site-selective
cross-coupling reactions provide stereoselective convergent
access to structural motifs that are anticipated to be of great
utility in the synthesis of complex molecules. Research di-
rected at exploring these processes, both mechanistically and
in the context of target-oriented synthesis, is underway.
4. Experimental section
4.1. General experimental information
All reactions were conducted in flame-dried glassware un-
der nitrogen using anhydrous solvents. Toluene and

3444
H.L. Shimp et al. / Tetrahedron 64 (2008) 3437e3445
4H), 2.75 (d, J¼7.3 Hz, 2H), 2.34 (dt, J¼14.7, 7.6 Hz, 2H),
2.33 (t, J¼7.3 Hz, 2H), 1.64 (s, 3H), 1.34 (t, J¼6.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 159.1, 136.6, 136.0, 130.6,
130.5, 129.21, 129.16, 123.8, 123.1, 113.7, 77.2, 72.5, 69.8,
68.8, 68.6, 55.2, 35.7, 31.1, 28.6, 13.6; IR (thin film, NaCl)
3433, 2907, 2857, 1613, 1513, 1464, 1360, 1302, 1173, 1093,
1035, 802 cmꢁ1; LRMS (EI, Na) calcd for C27H36O5Na,
463.26 m/z (MþNa); observed, 463.3 m/z (MþNa)þ.
(GM80266). H.L.S. acknowledges support from BMS in the
form of a graduate student fellowship.
Supplementary data
Complete experimental details for all preparative proce-
dures along with spectral data for all products are provided.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2008.02.015.
4.3. Representative procedure for the stereoselective
synthesis of cross-conjugated trienes
References and notes
1. For a recent review of palladium-catalyzed cross-coupling in total synthe-
sis, see: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442e4489.
4.3.1. Synthesis of (3E,5E)-1-(4-methoxybenzyloxy)-(4-
(2-methoxybenzyloxy)ethyl)-5-vinyl-7-methyl-3,5-octadiene, 37
To a ꢁ78 ꢂC solution of alkyne 13 (200 mg, 0.56 mmol) in
3.7 mL of PhMe was added 850 mL of ClTi(Oi-Pr)3 (1.0 M
in hexanes, 0.85 mmol) and 860 mL of c-C5H9MgCl (1.96 M
in Et2O, 1.68 mmol) dropwise via a gas-tight syringe. The re-
sulting clear, yellow solution turned dark reddish brown while
warming slowly to ꢁ30 ꢂC over 1 h. The reaction mixture was
stirred at ꢁ30 ꢂC for 1 h and then cooled to ꢁ78 ꢂC. To a sep-
arate ꢁ78 ꢂC solution of allene 36 (44 mg, 0.39 mmol) in
1.0 mL PhMe was added 160 mL of nBuLi (2.45 M in hexanes,
0.39 mmol) dropwise via gas-tight syringe. The resulting solu-
tion was stirred for 15 min, removed from the cold bath, and
added to the ꢁ78 ꢂC titanium solution dropwise via cannula.
After warming slowly to ꢁ30 ꢂC over 1 h, the reaction was
quenched with 5 mL of satd NH4Cl solution. The mixture
was warmed to room temperature before extracting with
EtOAc (3ꢄ15 mL). The combined organic layer was washed
with satd NaHCO3 solution (1ꢄ30 mL), brine (1ꢄ30 mL)
and dried over anhydrous Na2SO4. Flash column chromatogra-
phy of the crude material (5% EtOAc/hexanes, then 7.5%
EtOAc/hexanes) provided 121 mg (69%) of triene 37 as a clear,
2. For recent reviews of such metal-mediated coupling, see: (a) Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
2002; p 512; (b) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43,
3890e3908; (c) Trost, B. M.; Toste, F. D.; Pinkerson, A. B. Chem. Rev.
2001, 101, 2067e2096; (d) Buchwald, S. L.; Nielsen, R. B. Chem. Rev.
1988, 88, 1047e1058.
3. For alkyneealkyne cross-coupling, see: (a) Ryan, J.; Micalizio, G. C.
J. Am. Chem. Soc. 2006, 128, 2764e2765; (b) Shimp, H. L.; Micalizio,
G. C. Org. Lett. 2005, 7, 5111e5114; For alkeneealkyne cross-coupling,
see: (c) Reichard, H. A.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46,
1440e1443; For allylic alcoholealkyne cross-coupling, see: (d)
Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 15112e
15113; For alkyneeimine cross-coupling, see: (e) McLaughlin, M.;
Takahashi, M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46,
3912e3914; For alkeneeimine cross-coupling, see: (f) Takahashi, M.;
Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514e7516.
4. For examples of metal-mediated cross-coupling of allenes and alkynes,
see: (a) Hideura, D.; Urabe, H.; Sato, F. Chem. Commun. 1998, 271e
272; (b) Tanaka, R.; Sasaki, M.; Sato, F.; Urabe, H. Tetrahedron Lett.
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1
colorless oil. H NMR (400 MHz, CDCl3) d 7.26e7.21 (m,
4H), 6.88e6.83 (m, 4H), 6.53 (dd, J¼17.4, 10.6 Hz, 1H),
5.36 (t, J¼7.3 Hz, 1H), 5.15 (d, J¼10.1 Hz, 1H), 5.13e5.06
(m, 2H), 4.42 (s, 2H), 4.37 (s, 2H), 3.78 (s, 3H), 3.78 (s, 3H),
3.46 (t, J¼7.1 Hz, 2H), 3.36 (t, J¼7.3 Hz, 2H), 2.74e2.65
(m, 1H), 2.51 (t, J¼7.6 Hz, 2H), 2.42 (dt, J¼14.1, 7.3 Hz,
2H), 0.95 (d, J¼6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 159.1, 159.0, 138.7, 138.5, 138.1, 132.6, 130.7, 130.6,
129.2, 129.1, 126.6, 116.4, 113.69, 113.65, 72.44, 72.39, 69.7,
68.7, 55.21, 55.20, 30.2, 28.8, 26.9, 23.1; IR (thin film, NaCl)
2957, 2864, 1613, 1513, 1464, 1360, 1302, 1248, 1173, 1097,
1037, 820 cmꢁ1; LRMS (EI, Na) calcd for C29H38O4Na,
473.28 m/z (MþNa); observed, 473.5 m/z (MþNa)þ.
5. For a preliminary account, see: Shimp, H. L.; Micalizio, G. C. Chem.
Commun. 2007, 4531e4533.
6. For an example of such a metal-mediated alkylation with allylic transpo-
sition, see Ref. 3d.
7. (a) Vogel, E.; Ott, K. H.; Gajek, K. Liebigs Ann. Chem. 1961, 644,
172e188; (b) Doering, W.; von, E.; Roth, W. R. Tetrahedron 1963, 19,
715e737; For an example of a metallo-[3,3] rearrangement for isomeriza-
tion of allylic alcohols, see: (c) Chabardes, P.; Kuntz, E.; Varagnat, J.
Tetrahedron 1977, 33, 1775e1783.
Acknowledgements
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We gratefully acknowledge financial support of this work
by the American Cancer Society (RSG-06-117-e01), the
American Chemical Society (PRF-45334-G1), the Arnold
and Mabel Beckman Foundation, Boehringer Ingelheim, Eli
Lilly & Co., and the National Institutes of Health e NIGMS
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