Stereoselective synthesis of trisubstituted (E,E)-1,3-dienes by the site-selective reductive cross-coupling of internal alkynes with terminal alkynes: a fragment coupling reaction for natural product synthesis.
A highly selective convergent coupling reaction is described between alkynes for the synthesis of stereodefined trisubstituted (E,E)-1,3-dienes-structural motifs commonly found embedded in the skeletons of bioactive polyketide-derived natural products. While numerous multistep processes for the synthesis of this stereodefined functional group exist, the current method represents a significant advance as it does not require stereodefined olefinic coupling partners (vinyl halide or vinyl organometallic); it proceeds by a single convergent C-C bond-forming event (avoiding multistep methods based on carbonyl olefination) and is tolerant of a diverse array of functional groups including free hydroxyls. Through a systematic study of titanium-mediated reductive cross-coupling reactions of internal alkynes with terminal alkynes, a fragment coupling reaction of great utility in natural product synthesis has emerged. Here, use of a proximal hydroxy group to control regioselection in the functionalization of a preformed titanacyclopropene has led to the establishment of a highly selective bimolecular coupling process, where C-C bond formation occurs in concert with the establishment of two stereodefined alkenes. Compared to the body of literature known for related metal-mediated coupling reactions, the current work defines a powerful advance, achieving site-selective bimolecular C-C bond formation without the need for using TMS-alkynes or conjugated alkynes. Overall, complex 1,3-dienes relevant for the synthesis of polyketide-derived natural products of varying stereochemistry were prepared with typically >or=20:1 selectivity, defining the important role of an alkoxide directing group located delta to preformed titanacyclopropenes.
Perez
Lark J
LJ
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Shimp
Heidi L
HL
Micalizio
Glenn C
GC
D000466:Alkadienes / Q000138:chemical synthesis* / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry; D001685:Biological Factors / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
D000466:Alkadienes; D000480:Alkynes; D001685:Biological Factors