A Protocol for Direct Stereospecific Amination of Primary, Secondary, and Tertiary Alkylboronic Esters.

The direct, stereospecific amination of alkylboronic and borinic esters can be conducted by treatment of the organoboron compound with methoxyamine and potassium tert-butoxide. In addition to being stereospecific, this process also enables the direct amination of tertiary boronic esters in an efficient fashion.

Enantioselective Conjunctive Cross-Coupling of Bis(alkenyl)borates: A General Synthesis of Chiral Allylboron Reagents.

Palladium-catalyzed conjunctive cross-coupling is used for the synthesis of enantioenriched allylboron reagents. This reaction employs nonsymmetric bis(alkenyl)borates as substrates and appears to occur by a mechanism that involves selective activation of the less substituted alkene followed by migration of the more substituted alkene during the course of a Pd-induced metalate rearrangement.

Structure-Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis.

Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended N-acyl or O-linked alkyl/aryl group and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homologue, with the best analogs displaying nanomolar IC50 values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and dipivaloyloxymethyl (POM) prodrug esters of these compounds were made. While the added lipophilicity did not enhance Yersinia activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3-12 µg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologues from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development.

Modular, Catalytic Enantioselective Construction of Quaternary Carbon Stereocenters by Sequential Cross-Coupling Reactions.

The catalytic Suzuki-Miyaura cross-coupling with chiral γ,γ-disubstituted allylboronates in the presence of RuPhos ligand occurs with high regioselectivity and enantiospecificity, furnishing nonracemic compounds with quaternary centers. Mechanistic experiments suggest that the reaction occurs by transmetalation with allyl migration, followed by rapid reductive elimination.

Catalytic conjunctive cross-coupling enabled by metal-induced metallate rearrangement.

Transition metal catalysis plays a central role in contemporary organic synthesis. Considering the tremendously broad array of transition metal-catalyzed transformations, it is remarkable that the underlying elementary reaction steps are relatively few in number. Here, we describe an alternative to the organometallic transmetallation step that is common in many metal-catalyzed reactions, such as Suzuki-Miyaura coupling. Specifically, we demonstrate that vinyl boronic ester ate complexes, prepared by combining organoboronates and organolithium reagents, engage in palladium-induced metallate rearrangement wherein 1,2-migration of an alkyl or aryl group from boron to the vinyl α-carbon occurs concomitantly with C-Pd σ-bond formation. This elementary reaction enables a powerful cross-coupling reaction in which a chiral Pd catalyst merges three simple starting materials-an organolithium, an organoboronic ester, and an organotriflate-into chiral organoboronic esters with high enantioselectivity.

Nonracemic allylic boronates through enantiotopic-group-selective cross-coupling of geminal bis(boronates) and vinyl halides.

Under the influence of a chiral palladium catalyst, 1,1-bis(pinacolboronate) esters undergo asymmetric cross-coupling with bromoalkenes to generate nonracemic allyl boronates with high levels of enantioselectivity. The so-formed allyl boronates may be oxidized with hydrogen peroxide to provide secondary allylic alcohols or with nitrosobenzene to furnish nonracemic tertiary allylic alcohols. Mechanistic experiments suggest the operation of a pathway involving outer-sphere stereoinvertive transmetalation.

The effect of chain length and unsaturation on Mtb Dxr inhibition and antitubercular killing activity of FR900098 analogs.

Inhibition of the nonmevalonate pathway (NMP) of isoprene biosynthesis has been examined as a source of new antibiotics with novel mechanisms of action. Dxr is the best studied of the NMP enzymes and several reports have described potent Dxr inhibitors. Many of these compounds are structurally related to natural products fosmidomycin and FR900098, each bearing retrohydroxamate and phosphonate groups. We synthesized a series of compounds with two to five methylene units separating these groups to examine what linker length was optimal and tested for inhibition against Mtb Dxr. We synthesized ethyl and pivaloyl esters of these compounds to increase lipophilicity and improve inhibition of Mtb growth. Our results show that propyl or propenyl linker chains are optimal. Propenyl analog 22 has an IC50 of 1.07 µM against Mtb Dxr. The pivaloyl ester of 22, compound 26, has an MIC of 9.4 µg/mL, representing a significant improvement in antitubercular potency in this class of compounds.