Elatenyne is a small dibrominated natural product first isolated from Laurencia elata. The structure of elatenyne was originally assigned as a pyrano[3,2-b]pyran on the basis of NMR methods. Total synthesis of the originally proposed pyrano[3,2-b]pyran structure of elatenyne led to the gross structure of the natural product being reassigned as a 2,2'-bifuranyl. The full stereostructure of this highly flexible small molecule was subsequently predicted by Boltzmann-weighted DFT calculations of (13)C NMR chemical shifts for all 32 potential diastereomers, with the predicted structure being in accord with the proposed biogenesis outlined below. Herein we report two complementary total syntheses of elatenyne, which confirm the computer-predicted stereostructure. Additionally, the total syntheses of (E)-elatenyne and a related 2,2'-bifuranyl, laurendecumenyne B, are reported. This work has not only allowed the full structure determination of all of these natural products but also provides excellent supporting evidence for their proposed biogenesis. The total synthesis of elatenyne demonstrates that DFT calculations of (13)C NMR chemical shifts coupled with biosynthetic postulates, comprise a very useful method for distinguishing among large numbers of highly flexible, closely related molecules.

The first total synthesis of an (E)-cladiellin diterpene, (-)-cladiella-6,11-diene-3-ol (1), was accomplished featuring an intramolecular amide enolate alkylation-intramolecular Diels-Alder strategy. In addition, a highly stereo-, regio-, and chemoselective synthetic strategy for other members of the cladiellin diterpenes such as (+)-polyanthellin A (2), (-)-cladiell-11-ene-3,6,7-triol (3), and (-)-deacetoxyalcyonin acetate (4) was developed utilizing the synthetic (E)-cladiellin 1 as a common intermediate by taking advantage of the unique chemical properties of its C(6)-(E)-oxatricyclic skeleton.

The first asymmetric total syntheses of the dihalogenated medium-sized dioxabicyclic marine natural products (+)-3-(Z)-isolaureatin (1) and (+)-3-(Z)-laureatin (2) have been accomplished. Notable features of the highly stereo-, regio-, and chemoselective syntheses of these alpha,alpha'-trans-oxocene natural products include an intramolecular amide enolate alkylation to construct the alpha,alpha'-cis-oxocene, novel "lone pair-lone pair interaction-controlled" epimerizations to the alpha,alpha'-trans-oxocenes, various strategies for stereoselective introduction of halogen atoms, and novel olefin cross-metatheses for construction of the (Z)-enyne systems.

The first and highly stereoselective asymmetric total syntheses of eight-membered ring ether marine natural products (+)-3-(E)-pinnatifidenyne and (+)-3-(Z)-pinnatifidenyne have been accomplished. Notable features of our syntheses include a novel and efficient construction of oxocene 5 by a highly stereo- and regioselective internal alkylation and direct ketone synthesis of ketone 16 from the alpha-alkyloxy amide moiety in oxocene 5.

The first asymmetric total synthesis of (-)-laurefucin (1), a unique C-15 acetogenin with a 2,8-dioxabicyclo[5.2.1]decane skeleton, has been accomplished in nine steps in 31% overall yield from known oxocene 10. Highlights of the highly stereoselective synthesis include a novel organoselenium-mediated biomimetic hydroxyetherification.

[reaction: see text] A new iterative strategy for the synthesis of unsymmetrically substituted polyynes has been developed. The starting bromoalkyne is homologated by one acetylene unit through palladium-catalyzed cross-coupling with a TIPS-protected terminal acetylene and a subsequent in situ one-pot AgF-mediated desilylative bromination. The utility of this new synthetic method is demonstrated by its application to the total synthesis of (S)-(E)-15,16-dihydrominquartynoic acid.

[structure: see text] The first asymmetric total synthesis of a potential antitumor phenanthroindolizidine alkaloid, (-)-antofine, is described. An important feature of this synthesis is the creation of a stereogenic center by using enantioselective catalytic phase transfer alkylation, affording an unnatural alpha-amino acid derivative, together with a ring closing metathesis for pyrrolidine ring construction.

The asymmetric total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, (-)-antofine and (-)-cryptopleurine, are described. An efficient synthetic pathway to the key intermediate 12, in enantiomerically pure form, was achieved by using a chiral building block (R)-9 and the Overman rearrangement with a total transfer of chirality. The problem of constructing the pyrrolidine and piperidine rings was successfully addressed, primarily by using a ring-closing metathesis reaction and a cross-metathesis reaction, respectively.