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Highly Selective Synthesis of Conjugated Dienoic and Trienoic Esters Via Alkyne Elementometalation– Pd-Catalyzed Cross-Coupling

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Highly Selective Synthesis of Conjugated Dienoic and Trienoic Esters Via Alkyne Elementometalation– Pd-Catalyzed Cross-Coupling 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- 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 alkynes, 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 alkene- 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 dienes 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 alkenes 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.
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