Catalytic enantioselective olefin metathesis in natural product synthesis. Chiral metal-based complexes that deliver high enantioselectivity and more

Abstract

Chiral olefin metathesis catalysts enable chemists to access enantiomerically enriched small molecules with high efficiency; synthesis schemes involving such complexes can be substantially more concise than those that would involve enantiomerically pure substrates and achiral Mo alkylidenes or Ru-based carbenes. The scope of research towards design and development of chiral catalysts is not limited to discovery of complexes that are merely the chiral versions of the related achiral variants. A chiral olefin metathesis catalyst, in addition to furnishing products of high enantiomeric purity, can offer levels of efficiency, product selectivity and/or olefin stereoselectivity that are unavailable through the achiral variants. Such positive attributes of chiral catalysts (whether utilized in racemic or enantiomerically enriched form) should be considered as general, applicable to other classes of transformations.

Scheme 1

Enantioselective synthesis of antifungal agent fluvirucin B₁ through a late-stage macrocyclic Mo-catalyzed RCM.

Scheme 2

Total synthesis of aspidospermine through catalytic diastereoselective RCM.

Scheme 3

Total synthesis of (−)-longithorone A involving a diastereoselective enyne RCM. The silylether-bearing stereogenic carbon centers, installed for control of planar stereogenicity and subsequently removed, are highlighted.

Scheme 4

Control of atropisomerism in total syntheses of rac-coleophomones B and C. Ar = pBrC₆H₄; Mes = 2,4,6-Me₃C₆H₂.

Scheme 5

Synthesis of (+)-endo-brevicomin through enantioselective RCM.

Scheme 6

Total synthesis of coniine through enantioselective RCM.

Scheme 7

Synthesis of africanol through an enantioselective ring-opening/ring-closing metathesis (RORCM) reaction. Ar = 2,4,6-(iPr)₃C₆H₂, TBS = t-butyldimethylsilyl

Scheme 8

Enantioselective synthesis of the lactone fragment of HIV-protease inhibitor tipranivir through a Mo-catalyzed ring-opening/ring-closing metathesis (RORCM) reaction. Ar = 2,4,6-(iPr)₃C₆H₂

Scheme 9

Catalyst development spurred by total synthesis: A stereogenic-at-Mo complex as a highly effective chiral catalyst developed for enantioselective RCM in total synthesis of quebrachamine.

Scheme 10

Total synthesis of baconipyrone C through an enantioselective Ru-catalyzed ring-opening/cross-metathesis (ROCM) reaction. PMB = pmethoxybenzyl; Mes = 2,4,6-Me₃C₆H₂

Scheme 11

A stereogenic-at-Mo complex serving as a uniquely efficient RCM catalyst.

Scheme 12

A racemic stereogenic-at-Ru catalyst used to promote sequence-selective polymerization; success of this strategy is due to energy differences between the two carbene diastereomers of the chiral complex.

Scheme 13

Chiral olefin metathesis catalysts are not only valuable for obtaining enantiomerically enriched products; they can also offer other types of selectivity. Mes = 2,4,6-Me₃-C₆H_2.

Scheme 14

Chiral Pd- and Cu-based complexes generate product-selectivity, site-selectivity and efficiency levels that are superior to those afforded by the corresponding achiral catalysts.

Scheme 15

Natural product synthesis often underlines significant deficiencies in catalyst development, as indicated by an inefficient cross-metathesis reaction in an enantioselective synthesis of elenic acid.