The first enantioselective total synthesis of
antifungal agent Sch 38516, also known as fluvirucin B1,
is
described. The synthesis includes a convergent asymmetric
preparation of amine 17 and acid 18, which are
then
united to afford diene 62. Metal-catalyzed
transformations play a crucial role in the synthesis of the latter
moiety.
Of particular note are the diastereo- and enantioselective
Zr-catalyzed alkylations, a tandem Ti- and Ni-catalyzed
process that constitutes a hydrovinylation reaction, and a Ru-catalyzed
alcohol oxidation to afford carboxylic acid
18. The requisite carbohydrate 38 is
synthesized in a highly diastereo- and enantioselective fashion.
Optical purity
of the carbohydrate moiety arises from the use of the asymmetric
dihydroxylation method of Sharpless;
diastereochemical control is achieved through a selective dipolar [3
+ 2] cycloaddition with a readily available
amine serving as the chiral auxiliary. Union of the appropriately
outfitted carbohydrate 71 and diene 62 through
an
efficient and diastereoselective glycosylation is followed by a
remarkably efficient Mo-catalyzed macrocyclization
that proceeds readily at room temperature.
Zirconocene dichloride catalyzes the addition of ethylmagnesium halides to chiral allylic and homoallylic alcohols and ethers in an efficient manner. These transformations proceed with high levels of regio-and stereocontrol; with the appropriate choice of the neighboring heteroatom substituent (alcohol vs ether), either of the two diastereotopic faces of a chiral alkene can be selectively functionalized. Experimental data described indicate that the regio-and stereoselective outcomes of catalytic carbomagnesation of acyclic substrates are unique. Simple addition of zirconacyclopropanes to unsaturated alcohols and ethers proceeds without stereoselection and affords the derived metallacyclopentanes either with no regiocontrol or with a completely opposite sense of regiochemistry compared to that obtained under the catalytic conditions. A detailed mechanistic scheme is provided that accounts for all the characteristics of a zirconium-catalyzed ethylmagnesation reaction. The proposed paradigm includes a biszirconocene complex as its centerpiece; intermediacy of the bimetallic complex is supported by rate studies and readily accounts for the observed selectivities. The proposed mechanistic hypothesis rationalizes (i) the requirement for excess EtMgCl, (ii) the necessity for the presence of a Lewis basic heteroatom, and (iii) the reason for the highly regioselective rupture of the intermediate metallacyclopentane.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.