Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity.

The total synthesis and evaluation of a key systematic series of vinblastines that incorporate the first deep-seated changes to the substituent at C4 are detailed. The synthetic approach features an expanded and redefined scope of a 1,3,4-oxadiazole [4 + 2]/[3 + 2] cycloaddition cascade in which electronically mismatched electron-deficient trisubstituted alkenes and unactivated trisubstituted alkenes were found to productively initiate the cycloaddition cascade with tethered electron-deficient 1,3,4-oxadiazoles. Such cycloaddition cascades were used to directly introduce altered C4 substituents, providing the basis for concise total syntheses of a series of C4 modified vindolines and their subsequent single-step incorporation into the corresponding synthetic vinblastines in routes as short as 8-12 steps.

Total Synthesis of the 7,10-Epimer of the Proposed Structure of Amphidinolide N, Part II: Synthesis of C17-C29 Subunit and Completion of the Synthesis.

The total synthesis of 7,10-epimer of the proposed structure of amphidinolide N was accomplished. The requisite chiral C17-C29 subunit was assembled stereoselectively via Keck allylation, Shi epoxidation, diastereoselective 1,3-reduction, and a later oxidative synthesis of the THF framework. The C1-C13 and C17-C29 subunits were successfully coupled using a Enders RAMP "linchpin" as the C14-C16 three carbon unit, thereby controlling the chirality at C14 and C16.

Total Synthesis of the 7,10-Epimer of the Proposed Structure of Amphidinolide N, Part I: Synthesis of the C1-C13 Subunit.

Amphidinolide N, the structure of which has been recently revised, is a 26-membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10-epimer of the proposed structure of amphidinolide N, we have synthesized the C1-C13 subunit enantio- and diastereoselectively.

Transannular Diels-Alder/1,3-dipolar cycloaddition cascade of 1,3,4-oxadiazoles: total synthesis of a unique set of vinblastine analogues.

A powerful tandem [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles initiated by a transannular [4 + 2] cycloaddition is detailed. An impressive four rings, four carbon-carbon bonds, and six stereocenters are set on each site of the newly formed central six-membered ring in a cascade thermal reaction that proceeds at temperatures as low as 80 °C. The resulting cycloadducts provide the basis for the synthesis of unique analogues of vinblastine containing metabolically benign deep-seated cyclic modifications at the C3/C4 centers of the vindoline-derived subunit of the natural product.

Practical syntheses of proposed and revised manzacidin B and their congeners.

A concise and highly stereoselective total synthesis of manzacidin B and its congeners has been developed following chelation-controlled syn-epoxidation and Lewis acid catalyzed intramolecular regioselective epoxide ring opening to generate the quarternary amine center. Elaboration of the triol moiety to the target molecule was achieved in good overall yield, representing practical total syntheses of manzacidin B and its congeners. From the XRD, NMR, and analytical data, the correct structure of natural manzacidin B, (4R,5R,6R)-6, was confirmed.

Organocatalytic, enantioselective intramolecular [6+2] cycloaddition reaction for the formation of tricyclopentanoids and insight on its mechanism from a computational study.

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether.

Total synthesis and determination of the absolute configuration of FD-838, a naturally occurring azaspirobicyclic product.

The first asymmetric total synthesis of FD-838, a naturally occurring azaspirobicyclic product, has been accomplished allowing determination of its absolute stereochemistry.

Synthesis of spirocycles via ring closing metathesis of heterocycles carrying gem-diallyl substituents obtained via ring opening of (halomethyl)cyclopropanes with allyltributyltin.

In the presence of allyl tri-n-butyltin--AIBN, cyclopropylmethyl bromides/xanthates undergo ring-opening reaction with concomitant formation of geminal diallyl derivatives in good yields. The ring closing metathesis reactions on geminal diallyl derivatives with Grubbs' catalyst provided spirocyclopentenyl products. Combination of these two methodologies has been applied to the synthesis of mono-, bis-cyclopentyl-carbohydrates as well as spirocyclopentylproline derivatives.