Highly selective synthesis of conjugated dienoic and trienoic esters via 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- n nate bases was ≤95%, as reported earlier, the use of CsF or Bu4NF 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 ≥ Z E readily prepared in 90% selectivity. In addition to (2 ,4 )-dienoic Fig. 1. Some naturally occurring conjugated di- and oligoenes of biological CHEMISTRY esters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have been and medicinal importance. prepared in ≥98% selectivity by a newly devised Pd-catalyzed alkenylation–SG olefination tandem process. As models for conju- Over the past few decades, alkyne elementometalation reac- gated higher oligoenoic esters, all eight stereoisomers for ethyl tions (36), i.e., addition of element–metal bonds to , trideca-2,4,6-trienoate (23–30) have been prepared in ≥98% overall including hydrometalation, carbometalation, and halometalation, selectivity. has proven to be critically important in the syntheses of - containing compounds. The ultimate goal of this and related stu- highly selective synthesis ∣ Pd-catalyzed Negishi coupling dies in the authors’ group is to be able to synthesize in high yields, efficiently, and selectively (≥98%) all possible types of conjugated lkenes represent a large number of natural products of bioac- di-, tri-, and higher oligoenes. In this study, however, attention is Ative and medicinally important compounds. Of interest in focused on the following three specific aspects: (i) synthesis of this study are those containing conjugated and oligoenes all possible stereoisomers of conjugated dienoic and trienoic es- (1–11) (Fig. 1). Among numerous known methods for the synth- ters containing (E)- and/or (Z)-1,2-disubstituted alkene units via eses of including conjugated dienes and oligoenes (12, 13), alkyne elementometalation (36) –Pd-catalyzed cross-coupling of carbonyl olefination reactions, notably Wittig olefination (14) Negishi (Zn, Zr, Al) (27–31) and Suzuki (B) (32–34) versions, and its variants, such as Horner–Wadsworth–Emmons (HWE (ii) critical comparison of the Pd-catalyzed alkenylation routes hereafter) (15, 16), and Still–Gennari (SG hereafter) (17) as well with the carbonyl olefination routes represented here by mutually as Ando (18) modifications have been widely used along with re- complementary HWE (14–16) and SG (14, 17, 18) olefinations as lated Si-promoted (Peterson) (19) and S-promoted (Julia and well as Heck alkenylation (37–39), all of which are known to pro- Paris) (20) olefination reactions. As useful as these reactions are, ceed via π-addition–β-elimination and, (iii) feasibility of synergis- they often lack very high (≥98%) stereoselectivity. tic uses of Pd-catalyzed alkenylation and carbonyl olefination. In search for highly (≥98%) stereoselective alkene synthesis At this point, some comments on those closely related prior methodology, our attention was initially drawn to alkyne hydro- investigations of our own and other workers are in order. boration, which generally proceeds in >99% syn-selectivity. ≥98% Following some promising leads of Brown (21) and Zweifel and i. We recently reported highly ( ) stereoselective syntheses co-workers (22–25), we reported in 1973 a couple of highly selec- of conjugated tetra- through heptaenoic esters (40), but this tive routes to 1,4-disubstituted (E,E)- and (E,Z)-1,3-dienes (1, 3, work dealt only with their all-E isomers. 26), which appear to represent the earliest syntheses of unsym- ii. Syntheses of the (2Z,4E) and (2E,4Z) isomers of some conju- metrically substituted conjugated dienes in very high (≥97%) gated dienes by Negishi (27, 35) and Suzuki (32, 33, 35, 41) selectivity via organometallic alkenylation. alkenylations are known. Whereas Negishi coupling has uni- formly led to ≥97–98% stereoselectivity, Suzuki reported Despite highly selective and satisfactory results described ≥5% above, our continued search for a more generally applicable and stereo scrambling to varying extents ( ) for the synthesis straightforward route to conjugated di- and oligoenes led to the discovery in 1976 of the Pd-catalyzed alkenyl–alkenyl coupling Author contributions: G.W. and E.N. designed research; G.W. and S.M. performed with alkenylalanes (27) and subsequently with alkenyl derivatives research; and E.N. wrote the paper. containing Zr (28) and Zn (29), collectively known as Negishi The authors declare no conflict of interest. coupling (30, 31). Along with the subsequently developed alkenyl- This article is a PNAS Direct Submission. boron version (Suzuki coupling) (32–34), the Pd-catalyzed alkenyl– 1To whom correspondence should be addressed. E-mail: [email protected]. alkenyl coupling (35) has collectively begun establishing itself as This article contains supporting information online at www.pnas.org/lookup/suppl/ the modern “cornerstone” of alkene and oligoene synthesis. doi:10.1073/pnas.1105155108/-/DCSupplemental.

www.pnas.org/cgi/doi/10.1073/pnas.1105155108 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 30, 2021 of ethyl (2Z,4E)-nona-2,4-dienoate (41). More recently, how- respectively (Scheme 1, Eqs. 1-1 and 1-2). For the syntheses of the ever, Molander and co-workers (42, 43) reported highly (2E,4Z) and (2Z,4Z) isomers (9 and 10), (Z)-1-octenyl iodide stereoselective synthesis of all four stereoisomers of conju- (14) was prepared via carbocupration (51). The desired 9 and gated dienes via modified Suzuki coupling, although no 2,4- 10 were obtained as ≥98% isomerically pure compounds in 90 dienoic esters were prepared. 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 (b) Suzuki coupling. In our recent study on alkyne haloboration- for satisfactory results, whereas the Pd-catalyzed alkenylation based alkene syntheses (52–54), we have just found that the is free from this restriction. For critical comparisons of all of n use of CsF or Bu4NF as a base is significantly more effective than these competing processes for alkene syntheses, di- and oligo- commonly used alkoxide and carbonate bases both in promoting enoic esters were chosen as synthetic targets. Suzuki coupling and suppressing unwanted alkenyl stereo scram- iv. In a recent attempt to synthesize all eight stereoisomers of bling. We now find the previously undescribed procedure using 2,4,6-trienoic esters by Khrimian (44), two of the four isomers CsF can suppress stereoisomerization in the synthesis of 7–10 containing the (Z)-γ,δ-ethenylidene group, i.e., (2E,4Z,6Z) of ≥98% stereoisomeric purity, as summarized in Scheme 2. and (2E,4Z,6E) isomers were prepared in ca. 95% stereose- lectivity, but the other two isomers were prepared only as Critical Analysis of the Scope and Limitations of Heck Alkenylation. the minor (≤5%) by-products of the two mentioned above. Heck alkenylation (37–39) is fundamentally E selective with re- v. In another recent study, ethyl (2Z,4Z)-5-tributylstannylpenta- spect to nonhalogenated terminal alkenes. Consequently, incor- 2,4-dienoate was obtained only as the minor component of a poration of a (Z)-alkenyl group via Heck alkenylation requires 1∕1.8 mixture of the (2Z,4Z) and (2E,4Z) isomers by SG ole- the use of stereochemically preset (Z) haloalkenes. It is therefore fination (45). A more favorable but still impure 3.5∕1 mixture of the two isomers were obtained by Ando modification (18) not practically feasible to prepare conjugated (Z,Z) alkenes by and used in the subsequent Stille coupling for a total synthesis Heck alkenylation. Another main limitation of this reaction is of (+)-sorangicin A (46). that it is practically limited to those cases where certain types of alkenes, typically some π-conjugated alkenes, including styrenes It may be stated on the basis of those presented above that and α,β-unsaturated carbonyl derivatives, are used (55). With no highly (≥98%) selective route to all eight stereoisomers of these generalizations in mind, syntheses of 7, 8, and 9 were car- conjugated trienoic esters has as yet been developed and that ried out. As indicated by the results summarized in Scheme 3, its development is very desirable. both (2E,4E) and (2E,4Z) isomers (7 and 9) can be prepared in good yields and ≥98% stereoselectivity (Scheme 3, Eqs. 3-1 Results and Discussion and 3-2), but the synthesis of the (2Z,4E) isomer (8) has been Highly (≥98%) Selective Synthesis of All Four Possible Stereosiomers accompanied by stereoisomerization (Scheme 3, Eq. 3-3). We of 2,4-Dienoic Esters by Alkyne Elementometalation–Pd-Catalyzed Al- then noted in the literature (56) that the use of styrene as non- kenyl–Alkenyl Cross-Coupling Tandem Processes. (a) Negishi coupling. halogenated alkenes is stereoselective, producing the (2Z,4E) Although highly favorable results were well anticipated, all four isomers in ≥98% stereoselectivity (Scheme 3, Eq. 3-4). Thus, stereoisomers of ethyl 2,4-undecadienoate (7–10) were prepared stereoselectivity in these Heck reactions depends not only on re- by the Negishi alkenyl–alkenyl coupling primarily to document action conditions but also on alkene structures. The difference the yield and stereoselectivity for each of the four possible stereo- between the reactions of styrenes and those of alkyl substituted isomers for providing a set of reference points in critical compar- alkenes may be rationalized by invoking significant π-stabilization isons of various competing methods. of a putative benzylpalladium derivative (16) (Scheme 3, Eq. 3-5), The experimental results are summarized in Scheme 1. Negishi which suppresses stereoisomerization possibly via homoallyl- coupling of (E) and (Z) isomers of ethyl 3-bromoacrylate (11 and cyclopropylcarbinyl rearrangement that can readily occur in the 12) (refs. 47 and 48, respectively) with (E)-1-octenylzirconocene absence of such stabilization (Scheme 3, Eq. 3-6). chloride (13) generated in situ via hydrozirconation (49) in >90% yield in THF in the presence of 1 mol % of PEPPSI (15) (pyr- Critical Analysis of the Current Scope and Limitations of HWE and SG idine-enhanced precatalyst preparation stabilization and initia- Olefinations for Highly (≥98%) Selective Synthesis of 2,4-Dienoic tion obtained from Aldrich Chemicals Co.) (50) at 23 °C for 12 h Esters. For the synthesis of the four stereoisomers of ethyl unde- 7–10 provided 7 and 8 of ≥98% isomeric purity in 90 and 85% yields, ca-2,4-dienoates ( ), 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 Scheme 2. Highly selective synthesis of all four possible stereosiomers of coupling protocol. 2,4-dienoic esters by fluoride promoted Suzuki alkenylation.

2of6 ∣ www.pnas.org/cgi/doi/10.1073/pnas.1105155108 Wang et al. Downloaded by guest on September 30, 2021 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- All Four Stereoisomers of Ethyl (4E)-Trideca-2,4,6-Trienoates (23–26). tion. (a) Alkyne elementometalation–Pd-catalyzed Negishi coupling proto- col. Treatment of (E)-1-octenylzirconocene chloride (13)with CHEMISTRY iii. As is known, it is cumbersome and difficult to prepare and use iodine in THF provided (E)-1-iodo-1- of ≥98% isomeric (Z)-α,β-unsaturated aldehydes. Thus, for example, ethyl 14 ≥98% 9 purity in 90% yield (49), whereas its Z isomer of iso- (2E,4Z)-deca-2,4-dienoate ( ) was prepared analogously to meric purity was prepared as described earlier in 85% yield. that shown in Scheme 4, Eq. 4-5, involving fractional distilla- Pd-catalyzed reactions of (E)- and (Z)-1-iodo-1- with tion, but the overall selectivity was still only 88% 2E,4Z (58). ethynylzinc bromide in THF at 23 °C produced (E)- and (Z)-3- iv. Although some highly (≥98%) stereoselective examples of decen-1-ynes (31 and 32)of≥98% isomeric purity in 88% and HWE reaction are known (15, 16, 57–62), it often displays 73% yields, respectively. Hydrozirconation (49) of (E)-3-decen- ≤95%, typically 80–90%, stereoselectivity. 1-yne in THF followed by addition of 11 (1 equivalent) and With all of these subtle variations and limitations in mind, our 1 mol % PEPPSI provided after 12 h at 23 °C the desired ethyl attention here is mainly focused on finding and/or confirming (all-E)-trideca-2,4,6-trienoate (23) (Scheme 5, Eq. 5-1), of ≥98% hard facts about those 2,4-dienoic ester syntheses shown in purity in 89% yield, whereas the use of the (Z)-3-bromoacrylic Scheme 4, Eqs. 4-1 to 4-3. In contrast with frequently less than 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-

Scheme 5. Highly selective syntheses of all four stereoisomers of ethyl Scheme 4. Critical analysis of the current scope and limitations of HWE and (4E)-trideca-2,4,6-trienoates (23–26) by using alkyne elementometalation– SG olefinations for highly selective synthesis of 2,4-dienoic esters. Pd-catalyzed Negishi coupling protocol.

Wang et al. PNAS Early Edition ∣ 3of6 Downloaded by guest on September 30, 2021 meric purity were obtained in 87% and 85% yields, respectively (all-E)-oligoenoic esters via Pd-catalyzed Negishi coupling–HWE (Scheme 5, Eqs. 5-3 and 5-4). olefination strategy, however, it was confirmed that the use of aryl and α,β-unsaturated aldehydes tended to lead to ≥98% E (b) Alkyne elementometalation–Pd-catalyzed Negishi coupling–carbo- selectivity (62). Prompted by these results, we examined the synth- nyl olefination protocol. In view of the exceptionally high (≥98%) esis of (all-E)-trienoic ester (23) by three mutually complemen- and seemingly general stereoselectivity displayed by SG olefina- tary routes. However, the results summarized in Scheme 7 have tion for the synthesis of conjugated (2Z,4E)-di- and oligoenoic revealed yet another unexpected difficulty associated with HWE esters, it is desirable to further explore the scope and limitations reaction. Those reactions shown in Scheme 7, Eqs. 7-1 and 7-3, of SG olefination along this line. On the basis of what has been proceeded in good yields. In sharp contrast, the reaction shown discussed in the preceding sections, combined use of Pd-catalyzed in Scheme 7, Eq. 7-2 (63), gave the desired product 23 in less Negishi and/or Suzuki coupling and SG olefination appears than 5–10% yields. This reaction is under further investigation. particularly attractive. Some prototypical examples of highly (≥98%) selective syntheses of conjugated (2Z,4E)-trienoic esters All Four Stereoisomers of Ethyl (4Z)-Trideca-2,4,6-Trienoates (27–30). are presented below. (a) Alkyne elementometalation–Pd-catalyzed Negishi coupling proto- Of the eight stereoisomers of a given conjugated triene, the ( col. The alkyne elementometalation–Pd-catalyzed Negishi cou- 2Z,4E,6E) and (2Z,4E,6Z) isomers were thought to be accessible pling protocol shown in Scheme 5 has provided uniformly in ≥98% selectivity. To probe the feasibility of this strategy, satisfactory routes to all four stereoisomers of ethyl (4E)-tride- (2E,4E)- and (2E,4Z)-undeca-2,4-dien-1-ols (33 and 34, respec- ca-2,4,6-trienoates (23–26) in three steps without generating tively) were prepared in one step from (E)- and (Z)-1-iodo-1-oc- any detectable amounts of stereoisomers or any other isomers. tenes by their Negishi coupling catalyzed with 1 mol % of PEPPSI We therefore opted for reporting to the same strategy for the with (1E)-3-diisobutylaluminoxy-1-propenyl-zirconocene chlor- syntheses of 27–30 as well by making use of both (E)- and (Z)- ide (35), generated in situ by successive treatment of propargyl 3-decen-1-ynes (31 and 32, respectively) prepared in two steps as i 31 with Bu2AlH-ZrCp2Cl2 (49) (Scheme 6, Eqs. 6-1 and shown in Scheme 5. Conversion of into (1Z,3E)-1-iodo- 6-2). The desired dienols (33 and 34) obtained in ≥98% selectivity 1,3-decadiene (40) was performed in two steps, as shown in and 88% and 80% yields were converted to the corresponding Scheme 8, via well-known terminal alkyne iodination (89% yield) aldehydes in 90% and 91% yields, respectively, by MnO2 or and with dicyclohexylborane followed by protono- Dess–Martin oxidation. As anticipated, SG olefination of these lysis with HOAc in THF (75% yield) (64). Once 40 of ≥98% aldehydes proceeded in excellent yields to produce ≥98% iso- stereoisomeric purity was obtained, its lithiation followed by zin- merically pure conjugated trienoic esters 24 and 26, respectively, cation and Negishi coupling with ethyl (E)- or (Z)-β-bromoacry- as shown in Scheme 6, Eqs. 6-3 and 6-4. It should be noted that late in the presence of 1 mol % of PEPPSI in THF at 23 °C the ≥98% Z geometry of the ðZÞ-C═C bond of 34 is fully retained afforded the desired (2E,4Z,6E)-27 or (2Z,4Z,6E)-28 of ≥98% in 26. We also attempted earlier to synthesize 37, a close analogue stereoisomeric purity in good yield (Scheme 8). 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- (b) Carbonyl olefination–Pd-catalyzed Negishi coupling protocol. nately, this reaction led to an extensive stereoisomerization of the Although the syntheses of 27 and 28 summarized in Scheme 8 α,β-alkenyl group, suggesting that preset ðZÞ-C═C bond in viny- relying heavily on Pd-catalyzed Negishi coupling do proceed in logous HWE reagents may not be retained in the olefination step. good yields and in high selectivity, they do require altogether five In an early section, we discussed the generally ≤98% E selec- steps in the longest linear sequences. We then noticed the avail- tivity in HWE reaction, the typical E selectivity observed with an ability of ≥98% stereoisomerically pure (Z)-3-iodoacrolein (65) alkyl aldehyde being 85–90%. In our recent work on conjugated 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%.Wewerefurther 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- Scheme 7. Critical comparision of the synthesis of (all-E)-trienoic ester (23) tomatalation–Pd-catalyzed Negishi coupling–SG olefination protocol. by three mutually complementary HWE olefination routes.

4of6 ∣ www.pnas.org/cgi/doi/10.1073/pnas.1105155108 Wang et al. Downloaded by guest on September 30, 2021 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 In this study, we deliberately chose the ethyl esters of di- and protocol. trienoic acids so that we may readily compare our results and methods with conventionally often-used methods, such as HWE, Negishi or Suzuki version of Pd-catalyzed alkenylation. It is SG, and Heck olefination. As is well-known, however, the Pd- anticipated and hoped that the study on triene syntheses reported catalyzed alkenylation routes to conjugated di- and trienes, repre- herein will form a reliable and useful foundation for its applica- sented by Negishi and Suzuki couplings, do not require the ester tions and extensions in selective syntheses of a variety of conju- functional groups, which are either required or very desirable in gated trienes and higher oligoenes as well. the above-mentioned olefination reactions. Although not demon- 3. For various reasons, it is very desirable to explore and develop strated in this study, we are inclined to believe and predict that, in Pd-catalyzed alkenylation–carbonyl olefination synergy. In many other cases of the syntheses of conjugated di- and trienes, view of the superior features associated with SG olefination highly satisfactory results may be obtained through the use of the in the synthesis of (2Z,4E)-dienoic esters (vide supra), its Pd-catalyzed Negishi and/or Suzuki alkenylation. Further studies applicability to the synthesis of conjugated trienoic esters has CHEMISTRY along these lines are currently ongoing in our laboratories. been probed. Both (2Z,4E,6E)- and (2Z,4E,6Z)-tri-deca-2,4,6- 24 26 Conclusions trienoic ethyl esters ( and ) were prepared in high yields and ≥98% – 1. As a preliminary step, critical analysis and evaluation of stereoselectivity by Pd-catalyzed alkenylation SG selected Pd-catalyzed alkenylation and carbonyl olefination olefination tandem processes. reactions were made with regard to the syntheses of all four 7–10 Materials and Methods stereoisomers of ethyl undeca-2,4-dienoate ( ). Negishi General. All experiments were conducted in flame-dried glassware under ar- alkenylation is uniformly applicable and highly satisfactory for gon atmosphere. THF and diethyl ether were dried and distilled from sodium/ 7–10 >80% ≥98% preparing all four isomers in yields and se- benzophenone under nitrogen. ZnBr2 was flame-dried under vacuum prior n lectivity (Scheme 1). By using CsF or Bu4NF as a base, Suzuki to use. Details for the synthesis of all four stereoisomers (7–10) of ethyl un- alkenylation permits the synthesis of ethyl (2Z,4E)-undeca- deca-2,4-dienoate and all eight stereoisomers (23–30) of ethyl trideca-2,4,6- 2,4-dienoate (8)in≥98% selectivity, and that the other three trienoate, as well as their spectroscopic data, are available in SI Appendix. stereoisomers are also preparable in ≥98% selectivity. The other protocols are significantly more limited in scope 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 and selectivity. i A systematic investigation of HWE and SG olefinations for added dropwise a solution of Bu2AlH (1.5 mL, 1.0 M solution in hexane, the synthesis of 2,4-dienoic esters has confirmed the following: 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 i. (2E,4E)-Dienoic esters are readily preparable in good yields. 1- (0.19 mL, 1.3 mmol) in THF (2 mL). The reaction mixture was warmed However, their steroisomeric purity is generally 85–90%, and to 23 °C and stirred at 23 °C for 30 min. To a solution of ethyl (E)-3-bromoa- a very high (≥98%) level of stereoselectivity is observable only crylate (0.179 g, 1.0 mmol) and PEPPSI (7 mg, 0.01 mmol) in THF (3 mL) was with α,β-unsaturated aldehydes including aryl aldehydes and added the above reaction mixture, and the resulting reaction mixture was certain (2E)-alkenals as well as with some sterically hindered stirred at 23 °C for 12 h. The reaction mixture was quenched with water and 2 × 20 alkyl aldehydes. extracted with ether ( mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to give crude product ii. SG olefination appears to be satisfactory for preparing various 1 ≥98% with ≥98% isomeric purity determined by H NMR. Flash chromatography (2Z,4E)-di- and -oligoenoic esters in high yields and (silica gel, 5% ethyl acetate in hexanes) afforded 0.188 g of (2E,4E)-ethyl selectivity. undeca-2, 4-dienoate (7) in 90% yield with ≥98% 2E,4E isomeric purity iii. SG olefination has thus far remained unsatisfactory for the determined by 1H NMR. preparation of (2Z,4Z)-dienoic esters. 2. One of the most notable advances made in this study is the ACKNOWLEDGMENTS. We thank the National Institutes of Health (GM 36792) synthesis of all eight stereoisomers of ethyl trideca-2,4,6-trien- and Purdue University for support of this research. We also thank Sigma- oate (23–30) in good yields and ≥98% selectivity by using the Aldrich, Albemarle, and Boulder Scientific for their support.

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