Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation - Pd-catalyzed cross-coupling

Article abstract of DOI:10.1073/pnas.1105155108

All four stereoisomers (7-10) of ethyl undeca-2,4-dienoate were prepared in ≥98% isomeric purity by Pd-catalyzed alkenylation (Negishi coupling) using ethyl (E)- and (Z)-β-bromoacrylates. Although the stereoisomeric purity of the 2Z,4E-isomer (8) prepared by Suzuki coupling using conventional alkoxide and carbonate bases was ≤95%, as reported earlier, the use of CsF or ⁿBu₄NF as a promoter base has now been found to give all of 7-10 in ≥98% selectivity. Other widely known methods reveal considerable limitations. Heck alkenylation was satisfactory for the syntheses of the 2E,4E and 2E,4Z isomers of ≥98% purity, but the purity of the 2Z,4E isomer was ≤95%. Mutually complementary Horner-Wadsworth-Emmons and Still-Gennari (SG) olefinations are also of considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer is readily prepared in ≥90% selectivity. In addition to (2Z,4E)-dienoic esters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have been prepared in ≥98% selectivity by a newly devised Pd-catalyzed alkenylation-SG olefination tandem process. As models for conjugated higher oligoenoic esters, all eight stereoisomers for ethyl trideca-2,4,6-trienoate (23-30) have been prepared in ≥98% overall selectivity.

Full text of DOI:10.1073/pnas.1105155108

Highly selective synthesis of conjugated dienoic and
trienoic esters via alkyne elementometalation–
Pd-catalyzed cross-coupling
Guangwei Wang, Swathi Mohan, and Ei-ichi Negishi1
H. C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084
Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved May 19, 2011 (received for review April 3, 2011)
All four stereoisomers (7–10) of ethyl undeca-2,4-dienoate were
prepared in ≥98% isomeric purity by Pd-catalyzed alkenylation
(Negishi coupling) using ethyl (E)- and (Z)-β-bromoacrylates.
Although the stereoisomeric purity of the 2Z,4E-isomer (8) pre-
pared by Suzuki coupling using conventional alkoxide and carbo-
nate bases was ≤95%, as reported earlier, the use of CsF or nBu4NF
as a promoter base has now been found to give all of 7–10 in
≥98% selectivity. Other widely known methods reveal consider-
able limitations. Heck alkenylation was satisfactory for the synth-
eses of the 2E,4E and 2E,4Z isomers of ≥98% purity, but the purity
of the 2Z,4E isomer was ≤95%. Mutually complementary Horner–
Wadsworth–Emmons and Still–Gennari (SG) olefinations are also
of considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer is
readily prepared in ≥90% selectivity. In addition to (2Z,4E)-dienoic
Fig. 1. Some naturally occurring conjugated di- and oligoenes of biological
esters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have been
prepared in ≥98% selectivity by a newly devised Pd-catalyzed
alkenylation–SG olefination tandem process. As models for conju-
gated higher oligoenoic esters, all eight stereoisomers for ethyl
trideca-2,4,6-trienoate (23–30) have been prepared in ≥98% overall
selectivity.
and medicinal importance.
Over the past few decades, alkyne elementometalation reac-
tions (36), i.e., addition of element–metal bonds to alkynes,
including hydrometalation, carbometalation, and halometalation,
has proven to be critically important in the syntheses of alkene-
containing compounds. The ultimate goal of this and related stu-
dies in the authors’ group is to be able to synthesize in high yields,
efficiently, and selectively (≥98%) all possible types of conjugated
di-, tri-, and higher oligoenes. In this study, however, attention is
focused on the following three specific aspects: (i) synthesis of
all possible stereoisomers of conjugated dienoic and trienoic es-
ters containing (E)- and/or (Z)-1,2-disubstituted alkene units via
alkyne elementometalation (36) –Pd-catalyzed cross-coupling of
Negishi (Zn, Zr, Al) (27–31) and Suzuki (B) (32–34) versions,
(ii) critical comparison of the Pd-catalyzed alkenylation routes
with the carbonyl olefination routes represented here by mutually
complementary HWE (14–16) and SG (14, 17, 18) olefinations as
well as Heck alkenylation (37–39), all of which are known to pro-
ceed via π-addition–β-elimination and, (iii) feasibility of synergis-
tic uses of Pd-catalyzed alkenylation and carbonyl olefination.
At this point, some comments on those closely related prior
investigations of our own and other workers are in order.
highly selective synthesis ∣ Pd-catalyzed Negishi coupling
lkenes represent a large number of natural products of bioac-
Ative and medicinally important compounds. Of interest in
this study are those containing conjugated dienes and oligoenes
(1–11) (Fig. 1). Among numerous known methods for the synth-
eses of alkenes including conjugated dienes and oligoenes (12, 13),
carbonyl olefination reactions, notably Wittig olefination (14)
and its variants, such as Horner–Wadsworth–Emmons (HWE
hereafter) (15, 16), and Still–Gennari (SG hereafter) (17) as well
as Ando (18) modifications have been widely used along with re-
lated Si-promoted (Peterson) (19) and S-promoted (Julia and
Paris) (20) olefination reactions. As useful as these reactions are,
they often lack very high (≥98%) stereoselectivity.
In search for highly (≥98%) stereoselective alkene synthesis
methodology, our attention was initially drawn to alkyne hydro-
boration, which generally proceeds in >99% syn-selectivity.
Following some promising leads of Brown (21) and Zweifel and
co-workers (22–25), we reported in 1973 a couple of highly selec-
tive routes to 1,4-disubstituted (E,E)- and (E,Z)-1,3-dienes (1, 3,
26), which appear to represent the earliest syntheses of unsym-
metrically substituted conjugated dienes in very high (≥97%)
selectivity via organometallic alkenylation.
Despite highly selective and satisfactory results described
above, our continued search for a more generally applicable and
straightforward route to conjugated di- and oligoenes led to the
discovery in 1976 of the Pd-catalyzed alkenyl–alkenyl coupling
with alkenylalanes (27) and subsequently with alkenyl derivatives
containing Zr (28) and Zn (29), collectively known as Negishi
coupling (30, 31). Along with the subsequently developed alkenyl-
boron version (Suzuki coupling) (32–34), the Pd-catalyzed alkenyl–
alkenyl coupling (35) has collectively begun establishing itself as
the modern “cornerstone” of alkene and oligoene synthesis.
i. We recently reported highly (≥98%) stereoselective syntheses
of conjugated tetra- through heptaenoic esters (40), but this
work dealt only with their all-E isomers.
ii. Syntheses of the (2Z,4E) and (2E,4Z) isomers of some conju-
gated dienes by Negishi (27, 35) and Suzuki (32, 33, 35, 41)
alkenylations are known. Whereas Negishi coupling has uni-
formly led to ≥97–98% stereoselectivity, Suzuki reported
stereo scrambling to varying extents (≥5%) for the synthesis
Author contributions: G.W. and E.N. designed research; G.W. and S.M. performed
research; and E.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: negishi@purdue.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1105155108/-/DCSupplemental.
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of ethyl (2Z,4E)-nona-2,4-dienoate (41). More recently, how-
ever, Molander and co-workers (42, 43) reported highly
stereoselective synthesis of all four stereoisomers of conju-
gated dienes via modified Suzuki coupling, although no 2,4-
dienoic esters were prepared.
respectively (Scheme 1, Eqs. 1-1 and 1-2). For the syntheses of the
(2E,4Z) and (2Z,4Z) isomers (9 and 10), (Z)-1-octenyl iodide
(14) was prepared via carbocupration (51). The desired 9 and
10 were obtained as ≥98% isomerically pure compounds in 90
and 85% yields, respectively (Scheme 1, Eqs. 1-3 and 1-4).
iii. HWE and SG olefinations and even Heck alkenylation gen-
erally require esters and related reaction-promoting groups
for satisfactory results, whereas the Pd-catalyzed alkenylation
is free from this restriction. For critical comparisons of all of
these competing processes for alkene syntheses, di- and oligo-
enoic esters were chosen as synthetic targets.
iv. In a recent attempt to synthesize all eight stereoisomers of
2,4,6-trienoic esters by Khrimian (44), two of the four isomers
containing the (Z)-γ,δ-ethenylidene group, i.e., (2E,4Z,6Z)
and (2E,4Z,6E) isomers were prepared in ca. 95% stereose-
lectivity, but the other two isomers were prepared only as
the minor (≤5%) by-products of the two mentioned above.
v. In another recent study, ethyl (2Z,4Z)-5-tributylstannylpenta-
2,4-dienoate was obtained only as the minor component of a
1∕1.8 mixture of the (2Z,4Z) and (2E,4Z) isomers by SG ole-
fination (45). A more favorable but still impure 3.5∕1 mixture
of the two isomers were obtained by Ando modification (18)
and used in the subsequent Stille coupling for a total synthesis
of (+)-sorangicin A (46).
(b) Suzuki coupling. In our recent study on alkyne haloboration-
based alkene syntheses (52–54), we have just found that the
use of CsF or nBu4NF as a base is significantly more effective than
commonly used alkoxide and carbonate bases both in promoting
Suzuki coupling and suppressing unwanted alkenyl stereo scram-
bling. We now find the previously undescribed procedure using
CsF can suppress stereoisomerization in the synthesis of 7–10
of ≥98% stereoisomeric purity, as summarized in Scheme 2.
Critical Analysis of the Scope and Limitations of Heck Alkenylation.
Heck alkenylation (37–39) is fundamentally E selective with re-
spect to nonhalogenated terminal alkenes. Consequently, incor-
poration of a (Z)-alkenyl group via Heck alkenylation requires
the use of stereochemically preset (Z) haloalkenes. It is therefore
not practically feasible to prepare conjugated (Z,Z) alkenes by
Heck alkenylation. Another main limitation of this reaction is
that it is practically limited to those cases where certain types of
alkenes, typically some π-conjugated alkenes, including styrenes
and α,β-unsaturated carbonyl derivatives, are used (55). With
these generalizations in mind, syntheses of 7, 8, and 9 were car-
ried out. As indicated by the results summarized in Scheme 3,
both (2E,4E) and (2E,4Z) isomers (7 and 9) can be prepared
in good yields and ≥98% stereoselectivity (Scheme 3, Eqs. 3-1
and 3-2), but the synthesis of the (2Z,4E) isomer (8) has been
accompanied by stereoisomerization (Scheme 3, Eq. 3-3). We
then noted in the literature (56) that the use of styrene as non-
halogenated alkenes is stereoselective, producing the (2Z,4E)
isomers in ≥98% stereoselectivity (Scheme 3, Eq. 3-4). Thus,
stereoselectivity in these Heck reactions depends not only on re-
action conditions but also on alkene structures. The difference
between the reactions of styrenes and those of alkyl substituted
alkenes may be rationalized by invoking significant π-stabilization
of a putative benzylpalladium derivative (16) (Scheme 3, Eq. 3-5),
which suppresses stereoisomerization possibly via homoallyl-
cyclopropylcarbinyl rearrangement that can readily occur in the
absence of such stabilization (Scheme 3, Eq. 3-6).
It may be stated on the basis of those presented above that
no highly (≥98%) selective route to all eight stereoisomers of
conjugated trienoic esters has as yet been developed and that
its development is very desirable.
Results and Discussion
Highly (≥98%) Selective Synthesis of All Four Possible Stereosiomers
of 2,4-Dienoic Esters by Alkyne Elementometalation–Pd-Catalyzed Al-
kenyl–Alkenyl Cross-Coupling Tandem Processes. (a) Negishi coupling.
Although highly favorable results were well anticipated, all four
stereoisomers of ethyl 2,4-undecadienoate (7–10) were prepared
by the Negishi alkenyl–alkenyl coupling primarily to document
the yield and stereoselectivity for each of the four possible stereo-
isomers for providing a set of reference points in critical compar-
isons of various competing methods.
The experimental results are summarized in Scheme 1. Negishi
coupling of (E) and (Z) isomers of ethyl 3-bromoacrylate (11 and
12) (refs. 47 and 48, respectively) with (E)-1-octenylzirconocene
chloride (13) generated in situ via hydrozirconation (49) in >90%
yield in THF in the presence of 1 mol % of PEPPSI (15) (pyr-
idine-enhanced precatalyst preparation stabilization and initia-
tion obtained from Aldrich Chemicals Co.) (50) at 23 °C for 12 h
provided 7 and 8 of ≥98% isomeric purity in 90 and 85% yields,
Critical Analysis of the Current Scope and Limitations of HWE and SG
Olefinations for Highly (≥98%) Selective Synthesis of 2,4-Dienoic
Esters. For the synthesis of the four stereoisomers of ethyl unde-
ca-2,4-dienoates (7–10), the following eight HWE and/or SG
olefination routes may be considered (Scheme 4).
In reality, however, the following limitations and difficulties
are noted in the literature:
i. (Z)-4-phosphonocrotonic esters (20 and 22) are easily isomer-
ized when they are dealt with bases in HWE or SG conditions.
The reactions shown in Scheme 4, Eqs. 4-4 and 4-8, are cur-
rently very limited.
ii. Some documented unsatisfactory results (57) indicate that
the (Z)-selectivity of SG olefination is practically limited to those
cases where (Z)-α,β-alkenyl bonds are formed. Thus, those pro-
cesses shown in Scheme 4, Eqs. 4-6 and 4-8, must also be con-
sidered impractical at present.
Scheme 1. Highly selective synthesis of all four possible stereosiomers
of 2,4-dienoic esters by alkyne elementometalation–Pd-catalyzed Negishi
coupling protocol.
Scheme 2. Highly selective synthesis of all four possible stereosiomers of
2,4-dienoic esters by fluoride promoted Suzuki alkenylation.
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highly (≥98%) selective HWE olefination discussed above, SG
olefination represented by Scheme 4, Eq. 4-3, appears to be
generally ≥98% selective (17). We have indeed confirmed this
generalization by converting commercially available (E)-croto-
naldehyde (≥98% E, from TCI) and (E)-2-nonenal (97% E, from
Aldrich Chemicals Co.) to ≥98% isomerically pure ethyl (2Z,4E)-
hexa-2,4-dienoate and ethyl (2Z,4E)-undeca-2,4-dienoate (8), re-
spectively, in nearly quantitative yields by NMR. These favorable
results also promise to provide a reliable foundation for highly
(≥98%) selective syntheses of various conjugated tri- and higher
oligoenoic esters containing the (2Z,4E)-dienoic ester fragment
by Pd-catalyzed alkenylation–SG olefination tandem process
(vide infra).
Highly (≥98%) Selective Syntheses of All Eight Possible Stereoisomers
of 2,4,6-Trienoic Esters. Despite notable and promising recent
efforts (44), all eight possible stereoisomers of conjugated
2,4,6-trienoic esters do not appear to have been prepared in good
yields (≥70–80%) and ≥95% selectivity. Accordingly, we decided
to accomplish these goals through applications of the knowledge
and experience gained in the preceding sections. Specifically, we
selected the eight stereoisomers of ethyl trideca-2,4,6-trienoate
(23–30) as our target.
Scheme 3. Critical analysis of the scope and limitations of Heck alkenyla-
tion.
All Four Stereoisomers of Ethyl (4E)-Trideca-2,4,6-Trienoates (23–26).
(a) Alkyne elementometalation–Pd-catalyzed Negishi coupling proto-
col. Treatment of (E)-1-octenylzirconocene chloride (13) with
iodine in THF provided (E)-1-iodo-1-octene of ≥98% isomeric
purity in 90% yield (49), whereas its Z isomer 14 of ≥98% iso-
meric purity was prepared as described earlier in 85% yield.
Pd-catalyzed reactions of (E)- and (Z)-1-iodo-1-octenes with
ethynylzinc bromide in THF at 23 °C produced (E)- and (Z)-3-
decen-1-ynes (31 and 32) of ≥98% isomeric purity in 88% and
73% yields, respectively. Hydrozirconation (49) of (E)-3-decen-
1-yne in THF followed by addition of 11 (1 equivalent) and
1 mol % PEPPSI provided after 12 h at 23 °C the desired ethyl
(all-E)-trideca-2,4,6-trienoate (23) (Scheme 5, Eq. 5-1), of ≥98%
purity in 89% yield, whereas the use of the (Z)-3-bromoacrylic
ester (12) in place of 11 led to the formation of ≥98% pure ethyl
(2Z,4E,6E)-trideca-2,4,6-trienoate (24) in 85% yield (Scheme 5,
Eq. 5-2). In essentially the same manner, the corresponding
(2E,4E,6Z) and (2Z,4E,6Z) isomers (25 and 26) of ≥98% iso-
iii. As is known, it is cumbersome and difficult to prepare and use
(Z)-α,β-unsaturated aldehydes. Thus, for example, ethyl
(2E,4Z)-deca-2,4-dienoate (9) was prepared analogously to
that shown in Scheme 4, Eq. 4-5, involving fractional distilla-
tion, but the overall selectivity was still only 88% 2E,4Z (58).
iv. Although some highly (≥98%) stereoselective examples of
HWE reaction are known (15, 16, 57–62), it often displays
≤95%, typically 80–90%, stereoselectivity.
With all of these subtle variations and limitations in mind, our
attention here is mainly focused on finding and/or confirming
hard facts about those 2,4-dienoic ester syntheses shown in
Scheme 4, Eqs. 4-1 to 4-3. In contrast with frequently less than
Scheme 5. Highly selective syntheses of all four stereoisomers of ethyl
(4E)-trideca-2,4,6-trienoates (23–26) by using alkyne elementometalation–
Pd-catalyzed Negishi coupling protocol.
Scheme 4. Critical analysis of the current scope and limitations of HWE and
SG olefinations for highly selective synthesis of 2,4-dienoic esters.
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meric purity were obtained in 87% and 85% yields, respectively
(Scheme 5, Eqs. 5-3 and 5-4).
(all-E)-oligoenoic esters via Pd-catalyzed Negishi coupling–HWE
olefination strategy, however, it was confirmed that the use of
aryl and α,β-unsaturated aldehydes tended to lead to ≥98% E
selectivity (62). Prompted by these results, we examined the synth-
esis of (all-E)-trienoic ester (23) by three mutually complemen-
tary routes. However, the results summarized in Scheme 7 have
revealed yet another unexpected difficulty associated with HWE
reaction. Those reactions shown in Scheme 7, Eqs. 7-1 and 7-3,
proceeded in good yields. In sharp contrast, the reaction shown
in Scheme 7, Eq. 7-2 (63), gave the desired product 23 in less
than 5–10% yields. This reaction is under further investigation.
(b) Alkyne elementometalation–Pd-catalyzed Negishi coupling–carbo-
nyl olefination protocol. In view of the exceptionally high (≥98%)
and seemingly general stereoselectivity displayed by SG olefina-
tion for the synthesis of conjugated (2Z,4E)-di- and oligoenoic
esters, it is desirable to further explore the scope and limitations
of SG olefination along this line. On the basis of what has been
discussed in the preceding sections, combined use of Pd-catalyzed
Negishi and/or Suzuki coupling and SG olefination appears
particularly attractive. Some prototypical examples of highly
(≥98%) selective syntheses of conjugated (2Z,4E)-trienoic esters
are presented below.
All Four Stereoisomers of Ethyl (4Z)-Trideca-2,4,6-Trienoates (27–30).
(a) Alkyne elementometalation–Pd-catalyzed Negishi coupling proto-
col. The alkyne elementometalation–Pd-catalyzed Negishi cou-
pling protocol shown in Scheme 5 has provided uniformly
satisfactory routes to all four stereoisomers of ethyl (4E)-tride-
ca-2,4,6-trienoates (23–26) in three steps without generating
any detectable amounts of stereoisomers or any other isomers.
We therefore opted for reporting to the same strategy for the
syntheses of 27–30 as well by making use of both (E)- and (Z)-
3-decen-1-ynes (31 and 32, respectively) prepared in two steps as
shown in Scheme 5. Conversion of 31 into (1Z,3E)-1-iodo-
1,3-decadiene (40) was performed in two steps, as shown in
Scheme 8, via well-known terminal alkyne iodination (89% yield)
and hydroboration with dicyclohexylborane followed by protono-
lysis with HOAc in THF (75% yield) (64). Once 40 of ≥98%
stereoisomeric purity was obtained, its lithiation followed by zin-
cation and Negishi coupling with ethyl (E)- or (Z)-β-bromoacry-
late in the presence of 1 mol % of PEPPSI in THF at 23 °C
afforded the desired (2E,4Z,6E)-27 or (2Z,4Z,6E)-28 of ≥98%
stereoisomeric purity in good yield (Scheme 8).
Of the eight stereoisomers of a given conjugated triene, the (
2Z,4E,6E) and (2Z,4E,6Z) isomers were thought to be accessible
in ≥98% selectivity. To probe the feasibility of this strategy,
(2E,4E)- and (2E,4Z)-undeca-2,4-dien-1-ols (33 and 34, respec-
tively) were prepared in one step from (E)- and (Z)-1-iodo-1-oc-
tenes by their Negishi coupling catalyzed with 1 mol % of PEPPSI
with (1E)-3-diisobutylaluminoxy-1-propenyl-zirconocene chlor-
ide (35), generated in situ by successive treatment of propargyl
i
alcohol with Bu AlH-ZrCp2Cl2 (49) (Scheme 6, Eqs. 6-1 and
6-2). The desired2dienols (33 and 34) obtained in ≥98% selectivity
and 88% and 80% yields were converted to the corresponding
aldehydes in 90% and 91% yields, respectively, by MnO2 or
Dess–Martin oxidation. As anticipated, SG olefination of these
aldehydes proceeded in excellent yields to produce ≥98% iso-
merically pure conjugated trienoic esters 24 and 26, respectively,
as shown in Scheme 6, Eqs. 6-3 and 6-4. It should be noted that
the ≥98% Z geometry of the ðZÞ-C═C bond of 34 is fully retained
in 26. We also attempted earlier to synthesize 37, a close analogue
of 24, by an alternate Pd-catalyzed Negishi coupling–HWE ole-
fination route as shown in Scheme 6, Eqs. 6-5 and 6-6. Unfortu-
nately, this reaction led to an extensive stereoisomerization of the
α,β-alkenyl group, suggesting that preset ðZÞ-C═C bond in viny-
logous HWE reagents may not be retained in the olefination step.
In an early section, we discussed the generally ≤98% E selec-
tivity in HWE reaction, the typical E selectivity observed with an
alkyl aldehyde being 85–90%. In our recent work on conjugated
(b) Carbonyl olefination–Pd-catalyzed Negishi coupling protocol.
Although the syntheses of 27 and 28 summarized in Scheme 8
relying heavily on Pd-catalyzed Negishi coupling do proceed in
good yields and in high selectivity, they do require altogether five
steps in the longest linear sequences. We then noticed the avail-
ability of ≥98% stereoisomerically pure (Z)-3-iodoacrolein (65)
in two steps from commercially available ethyl propiolate. Both
HWE and SG reactions of (Z)-3-iodoacrolein proceeded in ex-
cellent yields. Although the stereoselectivity of 97% after the
HWE reaction was slightly lower than the threshold level of
≥98% we set at the outset of this investigation, simple chromato-
graphic purification improves it to ≥98%. We were further
pleased to find that the Negishi coupling of the ethyl esters of
(2E,4Z)- and (2Z,4Z)-5-iodo-2,4-pentadienoic acid (41 and 42)
with (Z)-1-octenylzinc bromide generated in situ by treatment
t
of (Z)-1-iodo-1-octene with BuLi (2 equivalents) and ZnBr2
(0.7 M equivalent) in the presence of 1 mol % of PEPPSI pro-
ceeded in 80–85% yields to give without any isomeric purification
the final two isomers, i.e., (2E,4Z,6Z)-29 and (2Z,4Z,6Z)-30, in
≥98% stereoselectivity and in good yields. Thus, a complete set of
all eight possible stereoisomers of a 2,4,6-trienoic acid ester have
been synthesized as isomerically pure compounds (Scheme 9).
Scheme 6. Highly selective synthesis of 24 and 26 by using alkyne elemen-
tomatalation–Pd-catalyzed Negishi coupling–SG olefination protocol.
Scheme 7. Critical comparision of the synthesis of (all-E)-trienoic ester (23)
by three mutually complementary HWE olefination routes.
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Scheme 8. Highly selective synthesis of ethyl (4Z,6E)-trideca-2,4,6-trienoates
(27 and 28) by using alkyne elementometalation–Pd-catalyzed Negishi
coupling protocol.
Scheme 9. Highly selective synthesis of ethyl (4Z,6Z)-trideca-2,4,6-trienoates
(29 and 30) by using carbonyl olefination–Pd-catalyzed Negishi coupling
protocol.
In this study, we deliberately chose the ethyl esters of di- and
trienoic acids so that we may readily compare our results and
methods with conventionally often-used methods, such as HWE,
SG, and Heck olefination. As is well-known, however, the Pd-
catalyzed alkenylation routes to conjugated di- and trienes, repre-
sented by Negishi and Suzuki couplings, do not require the ester
functional groups, which are either required or very desirable in
the above-mentioned olefination reactions. Although not demon-
strated in this study, we are inclined to believe and predict that, in
many other cases of the syntheses of conjugated di- and trienes,
highly satisfactory results may be obtained through the use of the
Pd-catalyzed Negishi and/or Suzuki alkenylation. Further studies
along these lines are currently ongoing in our laboratories.
Negishi or Suzuki version of Pd-catalyzed alkenylation. It is
anticipated and hoped that the study on triene syntheses reported
herein will form a reliable and useful foundation for its applica-
tions and extensions in selective syntheses of a variety of conju-
gated trienes and higher oligoenes as well.
3. For various reasons, it is very desirable to explore and develop
Pd-catalyzed alkenylation–carbonyl olefination synergy. In
view of the superior features associated with SG olefination
in the synthesis of (2Z,4E)-dienoic esters (vide supra), its
applicability to the synthesis of conjugated trienoic esters has
been probed. Both (2Z,4E,6E)- and (2Z,4E,6Z)-tri-deca-2,4,6-
trienoic ethyl esters (24 and 26) were prepared in high yields
and ≥98% stereoselectivity by Pd-catalyzed alkenylation–SG
olefination tandem processes.
Conclusions
1. As a preliminary step, critical analysis and evaluation of
selected Pd-catalyzed alkenylation and carbonyl olefination
reactions were made with regard to the syntheses of all four
stereoisomers of ethyl undeca-2,4-dienoate (7–10). Negishi
alkenylation is uniformly applicable and highly satisfactory for
preparing all four isomers 7–10 in >80% yields and ≥98% se-
lectivity (Scheme 1). By using CsF or nBu4NF as a base, Suzuki
alkenylation permits the synthesis of ethyl (2Z, 4E)-undeca-
2,4-dienoate (8) in ≥98% selectivity, and that the other three
stereoisomers are also preparable in ≥98% selectivity.
The other protocols are significantly more limited in scope
and selectivity.
Materials and Methods
General. All experiments were conducted in flame-dried glassware under ar-
gon atmosphere. THF and diethyl ether were dried and distilled from sodium/
benzophenone under nitrogen. ZnBr2 was flame-dried under vacuum prior
to use. Details for the synthesis of all four stereoisomers (7–10) of ethyl un-
deca-2,4-dienoate and all eight stereoisomers (23–30) of ethyl trideca-2,4,6-
trienoate, as well as their spectroscopic data, are available in SI Appendix.
Representative Procedure for Hydrozirconation–Pd-Catalyzed Negishi Coupling
Protocol. To a solution of ZrCp2Cl2 (0.438 g, 1.5 mmol) in THF (4.5 mL) was
added dropwise a solution of iBu2AlH (1.5 mL, 1.0 M solution in hexane,
1.5 mmol) at 0 °C in dark under argon atmosphere, and the resulting suspen-
sion was stirred at 0 °C for 30 min followed by the addition of a solution of
1-octyne (0.19 mL, 1.3 mmol) in THF (2 mL). The reaction mixture was warmed
to 23 °C and stirred at 23 °C for 30 min. To a solution of ethyl (E)-3-bromoa-
crylate (0.179 g, 1.0 mmol) and PEPPSI (7 mg, 0.01 mmol) in THF (3 mL) was
added the above reaction mixture, and the resulting reaction mixture was
stirred at 23 °C for 12 h. The reaction mixture was quenched with water and
extracted with ether (2 × 20 mL). The combined organic layers were dried
over anhydrous MgSO4, filtered, and concentrated to give crude product
with ≥98% isomeric purity determined by 1H NMR. Flash chromatography
(silica gel, 5% ethyl acetate in hexanes) afforded 0.188 g of (2E, 4E)-ethyl
undeca-2, 4-dienoate (7) in 90% yield with ≥98% 2E, 4E isomeric purity
determined by 1H NMR.
A systematic investigation of HWE and SG olefinations for
the synthesis of 2,4-dienoic esters has confirmed the following:
i. (2E,4E)-Dienoic esters are readily preparable in good yields.
However, their steroisomeric purity is generally 85–90%, and
a very high (≥98%) level of stereoselectivity is observable only
with α,β-unsaturated aldehydes including aryl aldehydes and
certain (2E)-alkenals as well as with some sterically hindered
alkyl aldehydes.
ii. SG olefination appears to be satisfactory for preparing various
(2Z,4E)-di- and -oligoenoic esters in high yields and ≥98%
selectivity.
iii. SG olefination has thus far remained unsatisfactory for the
preparation of (2Z,4Z)-dienoic esters.
2. One of the most notable advances made in this study is the
synthesis of all eight stereoisomers of ethyl trideca-2,4,6-trien-
oate (23–30) in good yields and ≥98% selectivity by using the
ACKNOWLEDGMENTS. We thank the National Institutes of Health (GM 36792)
and Purdue University for support of this research. We also thank Sigma-
Aldrich, Albemarle, and Boulder Scientific for their support.
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