P(III) vs P(V): A P(V) Reagent for Thiophosphoramidate Linkages and Application to an Asymmetric Synthesis of a Cyclic Dinucleotide STING Agonist.

A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.

Zinc Acetate-Promoted Buchwald-Hartwig Couplings of Heteroaromatic Amines.

Zinc salts have been shown to promote the Buchwald-Hartwig coupling of azaindoles and azaindazoles with heteroaryl chlorides to provide the corresponding 1-aryl-1H-azaindoles and 1-aryl-1H-azaindazoles. The substrate scope and mechanistic aspects of this reaction were explored.

Evaluation of HIV-1 inhibition by stereoisomers and analogues of the sesquiterpenoid hydroquinone peyssonol A.

Peyssonol A, a brominated natural product with documented anti-HIV-1 activity, was synthesized racemically along with 6 isomers and 15 truncated analogues and synthetic precursors. These compounds were screened in a cell-based assay against a recombinant HIV-1 strain to investigate structure-activity relationships. The results obtained suggest that both the aliphatic and aromatic domains of peyssonol A are responsible for its potency, while the stereochemical configuration of the substituents on the aliphatic domain, including their bromine atom, are largely irrelevant. Although none of the analogues tested were as potent as the parent natural product, several exhibited greater therapeutic indices due to reduced cytotoxicity, noting that nearly all compounds tested were measurably cytotoxic.

Concise synthetic approaches for the Laurencia family: formal total syntheses of (±)-laurefucin and (±)-E- and (±)-Z-pinnatifidenyne.

Herein is presented a cohesive strategy to rapidly fashion diverse members of the lauroxocane family of natural products, leading to the shortest syntheses of any member to date. These efforts include racemic formal total syntheses of laurefucin and E- and Z-pinnatifidenyne as well as a facile preparation of the oxocene core of 3E-dehydrobromolaurefucin. The key elements of the design are novel diastereoselective ring-expanding bromoetherifications of tetrahydrofurans triggered by a unique bromonium source (BDSB, Et(2)SBr·SbBrCl(5)) and strategically positioned nucleophilic traps, where altering the identity and position of these traps affords diverse functionality on the eight-membered ring backbone. Its biogenetic relevance is also discussed in light of the range of substrates that successfully undergo this key rearrangement.

A general strategy for the stereocontrolled preparation of diverse 8- and 9-membered Laurencia-type bromoethers.

A unique procedure to effect a ring-expanding bromoetherification process is described, wherein tetrahydrofurans and tetrahydropyrans are smoothly transformed into 8- and 9-membered bromoethers in a regio- and stereocontrolled manner through the use of BDSB (bromodiethylsulfonium bromopentachloroantimonate). These products resemble the cores of the Laurencia C15 acetogenins. In light of the generality and effectiveness of the approach, this work provides a unique strategy for their laboratory preparation and may implicate a possible biosynthesis pathway.

Simple reagents for direct halonium-induced polyene cyclizations.

Although there are many reagent combinations that can initiate polyene cyclizations, simple electrophilic halogen sources have not yet proven broadly effective as promoters of such processes. Herein is described a readily prepared and stable class of reagents capable of effecting such transformations for a wide range of electron-rich and -deficient terpenes derived from geraniol, farnesol, and nerol, thereby enabling the effective synthesis of a diverse array of complex chlorine-, bromine-, and iodine-containing polycyclic frameworks. Efforts to date have led to the first racemic laboratory total synthesis and structural revision of the anti-HIV natural product peyssonol A as well as an efficient and concise inaugural total synthesis of peyssonoic acid A. They have also permitted formal racemic total syntheses of aplysin-20, loliolide, K-76, and stemodin to be achieved through routes that are typically shorter, higher-yielding, and more environmentally conscious than previous efforts. Preliminary attempts to use chiral forms of the reagent class for enantioselective alkene halogenation are also described.

Polymerization of enantiopure monomers using syndiospecific catalysts: a new approach to sequence control in polymer synthesis.

The ring-opening polymerization of a mixture of enantiomerically pure but different monomers using an yttrium complex as initiator proceeds readily at room temperature to give the corresponding highly alternating polyester.