A Condensed, Scalable Synthesis of Racemic Koningic Acid.

The natural product koningic acid (KA) is a selective covalent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical node in the glycolysis pathway. While KA is available commercially, sources are limited and its cost becomes rapidly prohibitive beyond the milligram scale. Additionally, a practical and flexible synthetic route to KA and analogs remains to be developed. Here we detail a new route that is operationally safer, scalable and offers a five-step reduction in the previously reported longest linear sequence.

A Covalent Cysteine-Targeting Kinase Inhibitor of Ire1 Permits Allosteric Control of Endoribonuclease Activity.

The unfolded protein response (UPR) initiated by the transmembrane kinase/ribonuclease Ire1 has been implicated in a variety of diseases. Ire1, with its unique position in the UPR, is an ideal target for the development of therapies; however, the identification of specific kinase inhibitors is challenging. Recently, the development of covalent inhibitors has gained great momentum because of the irreversible deactivation of the target. We identified and determined the mechanism of action of the Ire1-inhibitory compound UPRM8. MS analysis revealed that UPRM8 inhibition occurs by covalent adduct formation at a conserved cysteine at the regulatory DFG+2 position in the Ire1 kinase activation loop. Mutational analysis of the target cysteine residue identified both UPRM8-resistant and catalytically inactive Ire1 mutants. We describe a novel covalent inhibition mechanism of UPRM8, which can serve as a lead for the rational design and optimization of inhibitors of human Ire1.

Solid-Phase Parallel Synthesis of Functionalised Medium-to-Large Cyclic Peptidomimetics through Three-Component Coupling Driven by Aziridine Aldehyde Dimers.

The first solid-phase parallel synthesis of macrocyclic peptides using three-component coupling driven by aziridine aldehyde dimers is described. The method supports the synthesis of 9- to 18-membered aziridine-containing macrocycles, which are then functionalized by nucleophilic opening of the aziridine ring. This constitutes a robust approach for the rapid parallel synthesis of macrocyclic peptides.

Modular assembly of purine-like bisphosphonates as inhibitors of HIV-1 reverse transcriptase.

Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis.

Discovery of thienopyrimidine-based inhibitors of the human farnesyl pyrophosphate synthase--parallel synthesis of analogs via a trimethylsilyl ylidene intermediate.

Thienopyrimidine-based bisphosphonates were identified as a new class of nitrogen-containing bisphosphonate (N-BP) inhibitors of the human farnesyl pyrophosphate synthase (hFPPS). Analogs were prepared via cyclization of 2-(1-(trimethylsilyl)ethylidene)malononitrile to 2-amino-4-(trimethylsilyl)thiophene-3-carbonitrile in the presence of elemental sulfur. Direct ipso-iododesilylation of this intermediate led to selective iodination at Cß of the sulfur atom in high efficiency. The synthetic protocols developed were used in the parallel synthesis of structurally diverse thieno[2,3-d]pyrimidin-4-amine-based bisphosphonate inhibitors of hFPPS.

Rhodium-catalyzed tandem vinylcyclopropanation of strained alkenes.

This communication reports an unusual rhodium-catalyzed 1,6-addition of a dienylboronate ester to highly strained alkenes. The resulting vinylcyclopropane-fused tricyclic products were produced in moderate to good yields. Preliminary mechanistic studies are also presented.

Addition of bifunctional organoboron reagents to strained alkenes. Carbon-carbon bond formation with Rh(I) catalysis in aqueous media.

Arylboronate esters bearing a pendant Michael-type acceptor olefin undergo transmetalation with a rhodium-based catalytic complex to generate a functionalized organorhodium intermediate that can cyclize onto strained olefins in good to excellent yields. The catalytic system involves the use of an electron-rich, sterically bulky ligand to stabilize the organorhodium intermediate and reduce the incidence of protodeboronation in aqueous media.

The zero-plus first metatarsal and its relationship to bunion deformity.

The relationship between first metatarsal length and hallux valgus (HV) deformity was examined. Retrospectively, 210 randomly selected radiographic files were reviewed between 1988 and 1993. The morbid population consisted of 110 feet with HV deformities. The control population consisted of 100 healthy feet (no deformity). Seventy-seven percent of the patients with HV deformity had a first metatarsal length that was equal to or longer than the second metatarsal. This was defined as a zero-plus first metatarsal. Only 28% of the control population had this same proportion in length. Thus, prevalence of zero-plus first metatarsal was significantly associated with HV formation (chi(2)(1) = 51.15, P <.001). The mean first metatarsal protrusion distance was significantly higher in the bunion population (+1.58 mm) than in the control patients (-2.05 mm) (P <.001). The distribution of head shape differed significantly between the patients with HV and control patients; patients with HV had predominantly round heads (91%) and the control patients had predominantly square and square with a ridge heads (80%) (chi(2)(2) = 107.7, P <.001). All zero-plus first metatarsals in the HV population had a round first metatarsal head. Only 7.1% of the control patients had a round head with a zero-plus metatarsal. There was a positive relationship between the protrusion distance of the first metatarsal and the severity of the intermetatarsal angle, particularly in those patients with intermetatarsal angles ranging from 13 degrees to 20 degrees (P <.01). It was concluded that a zero-plus first metatarsal is a significant etiologic factor in the development of bunion deformity and should be part of the preoperative evaluation.

Mild procedure for the catalytic bis(stannylation) of alkynes with hexaalkylditins.

[reaction: see text] Bis(stannylation) of terminal alkynes is achieved through the use of a palladium-isonitrile catalyst complex using a hexaalkylditin as a stannyl group transfer reagent in an atom-efficient and mild catalytic process. Functional group tolerance is good, allowing the presence of amine, carbamate, silyl, ester, and ether moieties. An activated internal alkyne also underwent bis(stannylation) in moderate yield, allowing access to symmetrical bis(alkenyl)stannanes.

Diastereoselective formation of indanes from arylboronate esters catalyzed by rhodium(I) in aqueous media.

[reaction: see text] Arylboronate esters bearing a pendant Michael-acceptor alkene can add to norbornene and cyclize to give indane systems in yields ranging from 62% to 95% with high diastereomeric excess (>20:1). The reaction is performed in an organic/aqueous emulsion and catalyzed using [Rh(COD)Cl]2 with t-Bu-amphos chloride, a sterically bulky, electron-rich, water-soluble phosphine ligand.