Highly selective synthesis of conjugated dienoic andtrienoic esters via alkyne elementometalation–Pd-catalyzed cross-couplingGuangwei 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 wereprepared 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 nBu4NFas 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 purityof the 2Z,4E isomer was ≤95%. Mutually complementary Horner–Wadsworth–Emmons and Still–Gennari (SG) olefinations are alsoof considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer isreadily prepared in ≥90% selectivity. In addition to (2Z,4E)-dienoicesters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have beenprepared in ≥98% selectivity by a newly devised Pd-catalyzedalkenylation–SG olefination tandem process. As models for conju-gated higher oligoenoic esters, all eight stereoisomers for ethyltrideca-2,4,6-trienoate (23–30) have been prepared in ≥98% overallselectivity.

highly selective synthesis ∣ Pd-catalyzed Negishi coupling

Alkenes represent a large number of natural products of bioac-tive 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 (HWEhereafter) (15, 16), and Still–Gennari (SG hereafter) (17) as wellas Ando (18) modifications have been widely used along with re-lated Si-promoted (Peterson) (19) and S-promoted (Julia andParis) (20) olefination reactions. As useful as these reactions are,they often lack very high (≥98%) stereoselectivity.

In search for highly (≥98%) stereoselective alkene synthesismethodology, 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 andco-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 describedabove, our continued search for a more generally applicable andstraightforward route to conjugated di- and oligoenes led to thediscovery in 1976 of the Pd-catalyzed alkenyl–alkenyl couplingwith alkenylalanes (27) and subsequently with alkenyl derivativescontaining Zr (28) and Zn (29), collectively known as Negishicoupling (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 asthe modern “cornerstone” of alkene and oligoene synthesis.

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 conjugateddi-, tri-, and higher oligoenes. In this study, however, attention isfocused on the following three specific aspects: (i) synthesis ofall possible stereoisomers of conjugated dienoic and trienoic es-ters containing (E)- and/or (Z)-1,2-disubstituted alkene units viaalkyne elementometalation (36) –Pd-catalyzed cross-coupling ofNegishi (Zn, Zr, Al) (27–31) and Suzuki (B) (32–34) versions,(ii) critical comparison of the Pd-catalyzed alkenylation routeswith the carbonyl olefination routes represented here by mutuallycomplementary HWE (14–16) and SG (14, 17, 18) olefinations aswell 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 priorinvestigations of our own and other workers are in order.

i. We recently reported highly (≥98%) stereoselective synthesesof conjugated tetra- through heptaenoic esters (40), but thiswork 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 reportedstereo scrambling to varying extents (≥5%) for the synthesis

Fig. 1. Some naturally occurring conjugated di- and oligoenes of biologicaland medicinal importance.

Author contributions: G.W. and E.N. designed research; G.W. and S.M. performedresearch; 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 highlystereoselective synthesis of all four stereoisomers of conju-gated dienes via modified Suzuki coupling, although no 2,4-dienoic esters were prepared.

iii. HWE and SG olefinations and even Heck alkenylation gen-erally require esters and related reaction-promoting groupsfor satisfactory results, whereas the Pd-catalyzed alkenylationis free from this restriction. For critical comparisons of all ofthese 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 of2,4,6-trienoic esters by Khrimian (44), two of the four isomerscontaining 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 asthe 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 a1∕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 mixtureof the two isomers were obtained by Ando modification (18)and used in the subsequent Stille coupling for a total synthesisof (+)-sorangicin A (46).

It may be stated on the basis of those presented above thatno highly (≥98%) selective route to all eight stereoisomers ofconjugated trienoic esters has as yet been developed and thatits development is very desirable.

Results and DiscussionHighly (≥98%) Selective Synthesis of All Four Possible Stereosiomersof 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 fourstereoisomers of ethyl 2,4-undecadienoate (7–10) were preparedby the Negishi alkenyl–alkenyl coupling primarily to documentthe 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. Negishicoupling of (E) and (Z) isomers of ethyl 3-bromoacrylate (11 and12) (refs. 47 and 48, respectively) with (E)-1-octenylzirconocenechloride (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 hprovided 7 and 8 of ≥98% isomeric purity in 90 and 85% yields,

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 and10 were obtained as ≥98% isomerically pure compounds in 90and 85% yields, respectively (Scheme 1, Eqs. 1-3 and 1-4).

(b) Suzuki coupling. In our recent study on alkyne haloboration-based alkene syntheses (52–54), we have just found that theuse of CsF or nBu4NF as a base is significantly more effective thancommonly used alkoxide and carbonate bases both in promotingSuzuki coupling and suppressing unwanted alkenyl stereo scram-bling. We now find the previously undescribed procedure usingCsF can suppress stereoisomerization in the synthesis of 7–10of ≥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 requiresthe use of stereochemically preset (Z) haloalkenes. It is thereforenot practically feasible to prepare conjugated (Z,Z) alkenes byHeck alkenylation. Another main limitation of this reaction isthat it is practically limited to those cases where certain types ofalkenes, typically some π-conjugated alkenes, including styrenesand α,β-unsaturated carbonyl derivatives, are used (55). Withthese 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 preparedin good yields and ≥98% stereoselectivity (Scheme 3, Eqs. 3-1and 3-2), but the synthesis of the (2Z,4E) isomer (8) has beenaccompanied by stereoisomerization (Scheme 3, Eq. 3-3). Wethen 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 differencebetween the reactions of styrenes and those of alkyl substitutedalkenes may be rationalized by invoking significant π-stabilizationof a putative benzylpalladium derivative (16) (Scheme 3, Eq. 3-5),which suppresses stereoisomerization possibly via homoallyl-cyclopropylcarbinyl rearrangement that can readily occur in theabsence of such stabilization (Scheme 3, Eq. 3-6).

Critical Analysis of the Current Scope and Limitations of HWE and SGOlefinations for Highly (≥98%) Selective Synthesis of 2,4-DienoicEsters. For the synthesis of the four stereoisomers of ethyl unde-ca-2,4-dienoates (7–10), the following eight HWE and/or SGolefination routes may be considered (Scheme 4).

In reality, however, the following limitations and difficultiesare 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 thatthe (Z)-selectivity of SG olefination is practically limited to thosecases 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 stereosiomersof 2,4-dienoic esters by alkyne elementometalation–Pd-catalyzed Negishicoupling protocol.

Scheme 2. Highly selective synthesis of all four possible stereosiomers of2,4-dienoic esters by fluoride promoted Suzuki alkenylation.

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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 tothat 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 ofHWE 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, ourattention here is mainly focused on finding and/or confirminghard facts about those 2,4-dienoic ester syntheses shown inScheme 4, Eqs. 4-1 to 4-3. In contrast with frequently less than

highly (≥98%) selective HWE olefination discussed above, SGolefination represented by Scheme 4, Eq. 4-3, appears to begenerally ≥98% selective (17). We have indeed confirmed thisgeneralization by converting commercially available (E)-croto-naldehyde (≥98% E, from TCI) and (E)-2-nonenal (97% E, fromAldrich 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 favorableresults also promise to provide a reliable foundation for highly(≥98%) selective syntheses of various conjugated tri- and higheroligoenoic esters containing the (2Z,4E)-dienoic ester fragmentby Pd-catalyzed alkenylation–SG olefination tandem process(vide infra).

Highly (≥98%) Selective Syntheses of All Eight Possible Stereoisomersof 2,4,6-Trienoic Esters. Despite notable and promising recentefforts (44), all eight possible stereoisomers of conjugated2,4,6-trienoic esters do not appear to have been prepared in goodyields (≥70–80%) and ≥95% selectivity. Accordingly, we decidedto accomplish these goals through applications of the knowledgeand experience gained in the preceding sections. Specifically, weselected the eight stereoisomers of ethyl trideca-2,4,6-trienoate(23–30) as our target.

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) withiodine in THF provided (E)-1-iodo-1-octene of ≥98% isomericpurity 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 withethynylzinc bromide in THF at 23 °C produced (E)- and (Z)-3-decen-1-ynes (31 and 32) of ≥98% isomeric purity in 88% and73% yields, respectively. Hydrozirconation (49) of (E)-3-decen-1-yne in THF followed by addition of 11 (1 equivalent) and1 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-bromoacrylicester (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-

Scheme 3. Critical analysis of the scope and limitations of Heck alkenyla-tion.

Scheme 4. Critical analysis of the current scope and limitations of HWE andSG olefinations for highly selective synthesis of 2,4-dienoic esters.

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.

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meric purity were obtained in 87% and 85% yields, respectively(Scheme 5, Eqs. 5-3 and 5-4).

(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 oligoenoicesters, it is desirable to further explore the scope and limitationsof SG olefination along this line. On the basis of what has beendiscussed in the preceding sections, combined use of Pd-catalyzedNegishi and/or Suzuki coupling and SG olefination appearsparticularly attractive. Some prototypical examples of highly(≥98%) selective syntheses of conjugated (2Z,4E)-trienoic estersare presented below.

Of the eight stereoisomers of a given conjugated triene, the (2Z,4E,6E) and (2Z,4E,6Z) isomers were thought to be accessiblein ≥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 PEPPSIwith (1E)-3-diisobutylaluminoxy-1-propenyl-zirconocene chlor-ide (35), generated in situ by successive treatment of propargylalcohol with iBu2AlH-ZrCp2Cl2 (49) (Scheme 6, Eqs. 6-1 and6-2). The desired dienols (33 and 34) obtained in ≥98% selectivityand 88% and 80% yields were converted to the correspondingaldehydes in 90% and 91% yields, respectively, by MnO2 orDess–Martin oxidation. As anticipated, SG olefination of thesealdehydes 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 thatthe ≥98% Z geometry of the ðZÞ-C═C bond of 34 is fully retainedin 26. We also attempted earlier to synthesize 37, a close analogueof 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 theα,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 analkyl aldehyde being 85–90%. In our recent work on conjugated

(all-E)-oligoenoic esters via Pd-catalyzed Negishi coupling–HWEolefination strategy, however, it was confirmed that the use ofaryl and α,β-unsaturated aldehydes tended to lead to ≥98% Eselectivity (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 haverevealed yet another unexpected difficulty associated with HWEreaction. Those reactions shown in Scheme 7, Eqs. 7-1 and 7-3,proceeded in good yields. In sharp contrast, the reaction shownin Scheme 7, Eq. 7-2 (63), gave the desired product 23 in lessthan 5–10% yields. This reaction is under further investigation.

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 uniformlysatisfactory routes to all four stereoisomers of ethyl (4E)-tride-ca-2,4,6-trienoates (23–26) in three steps without generatingany detectable amounts of stereoisomers or any other isomers.We therefore opted for reporting to the same strategy for thesyntheses 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 asshown in Scheme 5. Conversion of 31 into (1Z,3E)-1-iodo-1,3-decadiene (40) was performed in two steps, as shown inScheme 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 °Cafforded the desired (2E,4Z,6E)-27 or (2Z,4Z,6E)-28 of ≥98%stereoisomeric purity in good yield (Scheme 8).

(b) Carbonyl olefination–Pd-catalyzed Negishi coupling protocol.Although the syntheses of 27 and 28 summarized in Scheme 8relying heavily on Pd-catalyzed Negishi coupling do proceed ingood yields and in high selectivity, they do require altogether fivesteps 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. BothHWE and SG reactions of (Z)-3-iodoacrolein proceeded in ex-cellent yields. Although the stereoselectivity of 97% after theHWE 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 furtherpleased 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 treatmentof (Z)-1-iodo-1-octene with tBuLi (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 purificationthe 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 ofall eight possible stereoisomers of a 2,4,6-trienoic acid ester havebeen 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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In this study, we deliberately chose the ethyl esters of di- andtrienoic acids so that we may readily compare our results andmethods 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 esterfunctional groups, which are either required or very desirable inthe above-mentioned olefination reactions. Although not demon-strated in this study, we are inclined to believe and predict that, inmany other cases of the syntheses of conjugated di- and trienes,highly satisfactory results may be obtained through the use of thePd-catalyzed Negishi and/or Suzuki alkenylation. Further studiesalong these lines are currently ongoing in our laboratories.

Conclusions1. As a preliminary step, critical analysis and evaluation of

selected Pd-catalyzed alkenylation and carbonyl olefinationreactions were made with regard to the syntheses of all fourstereoisomers of ethyl undeca-2,4-dienoate (7–10). Negishialkenylation is uniformly applicable and highly satisfactory forpreparing all four isomers 7–10 in >80% yields and ≥98% se-lectivity (Scheme 1). By using CsF or nBu4NF as a base, Suzukialkenylation permits the synthesis of ethyl (2Z, 4E)-undeca-2,4-dienoate (8) in ≥98% selectivity, and that the other threestereoisomers are also preparable in ≥98% selectivity.The other protocols are significantly more limited in scopeand selectivity.A systematic investigation of HWE and SG olefinations forthe 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%, anda very high (≥98%) level of stereoselectivity is observable onlywith α,β-unsaturated aldehydes including aryl aldehydes andcertain (2E)-alkenals as well as with some sterically hinderedalkyl 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 thepreparation of (2Z,4Z)-dienoic esters.

2. One of the most notable advances made in this study is thesynthesis of all eight stereoisomers of ethyl trideca-2,4,6-trien-oate (23–30) in good yields and ≥98% selectivity by using the

Negishi or Suzuki version of Pd-catalyzed alkenylation. It isanticipated and hoped that the study on triene syntheses reportedherein 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 developPd-catalyzed alkenylation–carbonyl olefination synergy. Inview of the superior features associated with SG olefinationin the synthesis of (2Z,4E)-dienoic esters (vide supra), itsapplicability to the synthesis of conjugated trienoic esters hasbeen probed. Both (2Z,4E,6E)- and (2Z,4E,6Z)-tri-deca-2,4,6-trienoic ethyl esters (24 and 26) were prepared in high yieldsand ≥98% stereoselectivity by Pd-catalyzed alkenylation–SGolefination tandem processes.

Materials and MethodsGeneral. 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 priorto 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 CouplingProtocol. To a solution of ZrCp2Cl2 (0.438 g, 1.5 mmol) in THF (4.5 mL) wasadded 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 of1-octyne (0.19 mL, 1.3 mmol) in THF (2 mL). The reactionmixture was warmedto 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) wasadded the above reaction mixture, and the resulting reaction mixture wasstirred at 23 °C for 12 h. The reaction mixture was quenched with water andextracted with ether (2 × 20 mL). The combined organic layers were driedover anhydrous MgSO4, filtered, and concentrated to give crude productwith ≥98% isomeric purity determined by 1H NMR. Flash chromatography(silica gel, 5% ethyl acetate in hexanes) afforded 0.188 g of (2E, 4E)-ethylundeca-2, 4-dienoate (7) in 90% yield with ≥98% 2E, 4E isomeric puritydetermined by 1H NMR.

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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Scheme 8. Highly selective synthesis of ethyl (4Z,6E)-trideca-2,4,6-trienoates(27 and 28) by using alkyne elementometalation–Pd-catalyzed Negishicoupling 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 couplingprotocol.

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