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

Abstract

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 n Bu4NF 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 HornerWadsworth-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.highly selective synthesis | Pd-catalyzed Negishi coupling A lkenes represent a large number of natural products of bioactive 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 syntheses 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 related 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 hydroboration, 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 selective routes to 1,4-disubstituted (E,E)-and (E,Z)-1,3-dienes (1, 3, 26), which appear to represent the earliest syntheses of unsymmetrically 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 alkenylboron version (Suzuki coupling) (32-34), the Pd-catalyzed alken...

Antiallergic Phorbol Ester from the Seeds of Aquilaria malaccensis

“…The geometry of the double bonds was assigned by coupling constants in 1 H NMR. The NMR data were in agreement with those of (2 Z ,4 E ,6 E )-ethyl tetradeca-2,4,6-trienoate [ 25 ]. The fatty acid moiety was attached to phorbol backbone at C-12 by virtue of HMBC correlation from H-12 to C-1′ ( δ C 166.3).…”

Kinetic resolution of racemic allylic alcohols via iridium-catalyzed asymmetric hydrogenation: scope, synthetic applications and insight into the origin of selectivity

“…With 5 and 7 in hand, we then focused on coupling the two fragments corresponding to the geometry of the target inthomycins. Firstly, using a modified version of Negishi's method, 24 enyne 5 was subjected to hydrozirconation and then coupled with 7 to give the triene 8 in good yield with excellent stereoselectivity. After desilylation of 8 , we obtained the reported alcohol 9 21 b,c with over 99% ee, thus achieving the formal total synthesis of (3 S )-inthomycin B.…”

Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes

“…As an alternative to the Suzuki cross-coupling, Negishi developed a series of strategies for the alkyne elementometalation/Pd-catalysed alkenyl–alkenyl cross-coupling tandem processes. For example, all four stereoisomers of ethyl 2,4-undecadienoate can be prepared in high selectivity by the Negishi alkenyl–alkenyl coupling ( Scheme 6 ) [ 57 ]. On the one hand, Negishi coupling of ( E ) and ( Z ) isomers of ethyl 3-bromoacrylate with in situ generated ( E )-1-octenylzirconocene chloride afforded (2 E ,4 E )- and (2 Z ,4 E )-dienes in good yields and excellent diastereoisomeric ratio.…”