Construction of highly substituted stereodefined dienes by cross-coupling of α-allenic acetates

Article abstract of DOI:10.1002/ejoc.200600721

The assembly of highly substituted dienes remains a challenge for organic chemistry. This work represents a strategy for the construction of highly substituted 1,3-dienes by means of a Tsuji-Trost cross coupling between α-allenic acetates and organozinc reagents. The reaction is high yielding, and installs a trisubstituted olefin with E/Z selectivities up to 95:5 favoring the (E) product. A cheap, commercially available palladium precatalyst and a ligand are used to control the E/Z selectivity. Furthermore, an interesting reversal in selectivity is noted in which appropriate choice of ligand may be used to control the outcome of the reaction and favor the (Z) product. Thirteen examples are described, highlighting the substrate scope of the reaction. It is hoped that the straight-forward reaction conditions and high selectivity will make this reaction of broad use in natural product chemistry. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600721

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600721
Construction of Highly Substituted Stereodefined Dienes by Cross-Coupling of
α-Allenic Acetates
John S. Schneekloth Jr.,[a] Mathieu Pucheault,[b] and Craig M. Crews*[a–c]
Keywords: Cross-coupling / Allenes / Alkenes
The assembly of highly substituted dienes remains a chal-
lenge for organic chemistry. This work represents a strategy
tivity is noted in which appropriate choice of ligand may be
used to control the outcome of the reaction and favor the (Z)
for the construction of highly substituted 1,3-dienes by means product. Thirteen examples are described, highlighting the
of a Tsuji–Trost cross coupling between α-allenic acetates
and organozinc reagents. The reaction is high yielding, and
installs a trisubstituted olefin with E/Z selectivities up to 95:5
favoring the (E) product. A cheap, commercially available
palladium precatalyst and a ligand are used to control the
E/Z selectivity. Furthermore, an interesting reversal in selec-
substrate scope of the reaction. It is hoped that the straight-
forward reaction conditions and high selectivity will make
this reaction of broad use in natural product chemistry.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
compounds to form highly substituted, stereodefined (E)-
dienes (Scheme 1). Furthermore, we report a dramatic, li-
gand-dependent reversal of E/Z selectivity in the reaction.
The reaction is high yielding and tolerant to a wide variety
of organozinc nucleophiles as well as to the nature of the
allenic acetate. Previous work in this area has been sparse,
although there have been other isolated reports of coupling
organoboron or organozinc reagents with allenic ace-
tates.[10–14] Specifically, this work represents the first at-
tempt to install a stereodefined diene containing a differen-
tially functionalized trisubstituted olefin by cross coupling
of an allenic acetate.[15,16]
Introduction
The synthesis of highly substituted 1,3-dienes remains an
important challenge in synthetic chemistry. In addition to
being useful substrates for Diels–Alder cycloadditions,
highly substituted dienes are prevalent in a number of bio-
logically active polyketide-based natural products such as
amphidinolide B[1] and galbonolide B[2] (Figure 1). While
a variety of methods are available for constructing dienes
through the formation of sp2–sp2 carbon–carbon bonds,[3–5]
these methods are not always useful in complex systems.[6]
Surprisingly, there are few robust methods available to con-
struct dienes with the substitution pattern shown in Fig-
ure 1.[7] As part of a program directed towards the total
synthesis of amphidinolide B,[8,9] we reported that an α-all-
enic acetate could be used in a palladium-catalyzed cross-
coupling reaction with an organometallic reagent to form
a highly substituted stereodefined 1,3-diene.[8] Due to the
success of this early observation, we sought to develop this
reaction into a general method for the construction of a
variety of highly substituted stereodefined dienes. Herein
we report a general method for the efficient, stereoselective
coupling of α-allenic acetates with a variety of organozinc
[a] Departments of Chemistry, Yale University,
New Haven, CT 06520, USA
E-mail: craig.crews@yale.edu
[b] Departments of Molecular, Cellular, and Developmental
Biology,
Yale University, New Haven, CT 06520, USA
[c] Departments of Pharmacology, Yale University,
New Haven, CT 06520, USA
Figure 1. Natural products containing the E-substituted s-cis-diene
motif.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
40
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 40–43

Highly Substituted Stereodefined Dienes
SHORT COMMUNICATION
Table 1. Reaction optimization.
Entry [Pd][a]
Ligand
Solvent
Conv. E/Z Ratio
(%)[b]
1
2
[Pd(PPh3)4]
–
–
–
THF
THF
100
0
55:45
n/a
3
4
5
6
7
8
9
10
11
12
13
14
15
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(allyl)Cl2]
dppp
dppf
dppp
THF
THF
THF
THF
51
100
23
86:14
84:16
79:21
86:14
88:12
77:23
59:41
91:9
84:16
89:11
90:10
90:10
92:8
Scheme 1. Cross coupling of α-allenic acetates with organozinc
compounds and proposed reaction mechanism.
[Pd(MeCN)2Cl2] dppp
34
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
[Pd2dba3]
dppp
PCy3
PBu3
BINAP
dppf
dppf
dppf
dppf
dppf
THF
100
100
100
100
88
89
83
100
THF
THF[c]
THF
Results and Discussion
THF
MeCN
CH2Cl2
toluene
We anticipated that allenic acetates would behave like al-
lylic acetates in that a π–σ–π-type isomerization could oc-
cur, and appropriate modulation of reaction conditions
could give rise to either the E- or Z-substituted product
(Scheme 1). Initially, we sought mild reaction conditions, as
it was postulated that high reaction temperatures would
likely lead to lower E/Z selectivity. Palladium-catalyzed
Tsuji–Trost[17] and Negishi[18] type cross-coupling reactions
typically proceed under mild conditions, and it was ex-
pected that by fine tuning the reaction conditions the steric
toluene[c] 100
[a] 5 mol-% of palladium catalyst was used. [b] Conversion mea-
sured by 1H NMR after 12 h of reaction time. [c] Reaction con-
ducted at 0 °C. Cooling the reaction to –20 °C was found to slow
the reaction considerably, with little increase in selectivity.
Having optimized the reaction to produce 2a, we next
difference between the methyl group and R1 could be ex- looked to vary the nature of the organozinc reagent
ploited to generate a large selectivity favoring the (E)-sub- (Table 2). We observed good selectivity irrespective of the
stituted product over the (Z)-substituted isomer. Toward nature of the organozinc compound (Table 2).[21] Good
this end, we synthesized the substrate 1a, bearing methyl chemical yield and E/Z selectivity were observed when 1
and cyclohexyl substituents on the α-allenic carbon, which was coupled with alkyl-, vinyl-, and arylzinc halides, as well
was hoped to exhibit a moderate selectivity.
as with dialkylzinc compounds. An alkynylzinc organome-
The experiments described in Table 1 detail this optimi- tallic reacted with good selectivity, but only moderate yield.
zation. As the SN2’ reaction of allenic acetates has been In all cases, the E/Z selectivity was high, with a typical yield
reported previously,[19] it was important to determine that of greater than 80%. A benzylzinc partner was also found
the reaction was in fact catalyzed by palladium, and not to be effective (entry 12).
proceeding through
a
direct substitution mechanism.
We next examined the effect of the R1 substituent
Table 1, Entry 2, verifies that the reaction only occurs in (Table 2). Coupling of phenethylzinc bromide with a variety
the presence of catalyst. While our initial experiment using of substituted α-allenic acetates revealed that the reaction
[Pd(PPh3)4] achieved high conversion, E/Z selectivity was is tolerant to a variety of functionalities. Use of a second
poor. In order to examine the effect of varying the ligand, branched R1 substituent afforded a product with good yield
we screened a variety of monodentate and bidentate phos- and high selectivity (Entry 7). Electron-poor aryl and
phane ligands.[20] Trialkyl and triarylphosphanes generally phenyl substituents are also easily obtained with excellent
afforded high conversion, but lower selectivity (Entries 8, yield and selectivity (entries 9–11). Even when R1 is isobutyl
9). Uniformly, bidentate ligands induced a higher E/Z selec- (Entries 8, 12, and 13), the subtle steric difference between
tivity than even the bulkiest monodentate ligands. Wide bite methyl and isobutyl substituents can be exploited to obtain
angle ligands such as dppp and dppf afforded the highest the (E) product with reasonable selectivity.
E/Z ratio. Screening a variety of palladium precursors re-
Although most ligands tested favored the (E)-substituted
vealed that [Pd2dba3] was the most effective in terms of diene product, this was not the case for every example. As
selectivity. Examining a variety of solvents indicated that described in Scheme 2, the coupling reaction underwent a
generation of the catalyst in toluene, followed by addition dramatic reversal of selectivity when the bulky biaryl phos-
of the organozinc reagent in THF afforded the best overall phane ligand 4 developed by Buchwald and co-workers was
selectivity. Finally, conducting the reaction at 0 °C for 12 h used.[22] While the overall yield of the reaction was still
afforded diene 2a in 85% isolated yield with an optimized high, the major product isolated from the reaction was the
E/Z selectivity of 92/8.
(Z)-substituted diene in a ratio of 74:26. This effect is not
Eur. J. Org. Chem. 2007, 40–43
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
41

J. S. Schneekloth, J., M. Pucheault, C. M. Crews
SHORT COMMUNICATION
Table 2. Substrate scope of the cross-coupling reaction.
[a] Organozinc bromides were used as an 0.5  solution in THF. [b] Me2Zn and Et2Zn were used as a 1.0  solution in THF. [c] The
alkynylzinc triflate was prepared from the corresponding alkyne and zinc(II) triflate with Et3N as an 0.1  solution in THF.
limited to 1; several other substrates tested under identical of organozinc nucleophiles to prepare several highly substi-
conditions also slightly favored the (Z) isomer (Scheme 2). tuted, stereodefined dienes. The reaction is highly tolerant
Although the mechanistic implications of this result are un- to the nature of the organozinc species, and high selectivity
clear, it raises the possibility that the intermediate is formed is observed with several differentially substituted allenic
by a different mechanism, which can be controlled to favor acetates. The reaction proceeds with a cheap, commercially
the thermodynamically less stable (Z) product.
available catalyst precursor and ligand. Depending on the
In conclusion, we have reported a highly selective cross- ligand used, it is possible to control the reaction to favor
coupling reaction between α-allenic acetates and a variety highly the (E)-substituted product, or slightly favor the (Z)
42
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 40–43

Highly Substituted Stereodefined Dienes
SHORT COMMUNICATION
Supporting Information (see also the footnote on the first page of
this article): General procedures for the preparation of α-allenic
acetates, full spectroscopic data for 1a–e and diene products de-
scribed in Table 2.
Acknowledgments
The authors would like to thank Professors John Wood and Glenn
Micalizio for helpful discussion during the preparation of the ma-
nuscript. J. S. S. thanks the American Chemical Society, Division
of Medicinal Chemistry and Aventis Pharmaceuticals for a predoc-
toral fellowship. M. P. thanks the Human Frontier Science Program
Organization for a cross-disciplinary postdoctoral fellowship. We
thank the NIH (GM062120) for funding.
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Received: August 16, 2006
Published Online: November 21, 2006
Eur. J. Org. Chem. 2007, 40–43
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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