Practical Enzymatic Production of Carbocycles.

The Pd-catalyzed carbon-carbon bond formation pioneered by Heck in 1969 has dominated medicinal chemistry development for the ensuing fifty years. As the demand for more complex three-dimensional active pharmaceuticals continues to increase, preparative enzyme-mediated assembly, by virtue of its exquisite selectivity and sustainable nature, is poised to provide a practical and affordable alternative for accessing such compounds. In this minireview, we summarize recent state-of-the-art developments in practical enzyme-mediated assembly of carbocycles. When appropriate, background information on the enzymatic transformation is provided and challenges and/or limitations are also highlighted.

Nonenzymatic lipid mediators, neuroprostanes, exert the antiarrhythmic properties of docosahexaenoic acid.

Neuroprostanes are lipid mediators produced by nonenzymatic free radical peroxidation of docosahexaenoic acid (DHA). DHA is associated with a lower atherosclerosis risk, suggesting a beneficial role in cardiovascular diseases. The aim of this study was to investigate the influence of DHA peroxidation on its potentially antiarrhythmic properties (AAP) in isolated ventricular cardiomyocytes and in vivo in post-myocardial infarcted mice. Calcium imaging and biochemical experiments indicate that cardiac arrhythmias induced by isoproterenol are associated with Ca(2+) leak from the sarcoplasmic reticulum after oxidation and phosphorylation of the type 2 ryanodine receptor (RyR2) leading to dissociation of the FKBP12.6/RyR2 complex. Both oxidized DHA and 4(RS)-4-F4t-NeuroP prevented cellular arrhythmias and posttranslational modifications of the RyR2 leading to a stabilized FKBP12.6/RyR2 complex. DHA per se did not have AAP. The AAP of 4(RS)-4-F4t-NeuroP was also observed in vivo. In this study, we challenged the paradigm that spontaneously formed oxygenated metabolites of lipids are undesirable as they are unconditionally toxic. This study reveals that the lipid mediator 4(RS)-4-F4t-neuroprostane derived from nonenzymatic peroxidation of docosahexaenoic acid can counteract such deleterious effects through cardiac antiarrhythmic properties. Our findings demonstrate 4(RS)-4-F4t-NeuroP as a mediator of the cardioprotective AAP of DHA. This discovery opens new perspectives for products of nonenzymatic oxidized ω3 polyunsaturated fatty acids as potent mediators in diseases that involve ryanodine complex destabilization such as ischemic events.

Synthesis of the pentacylic core of (+)-salvileucalin B.

A concise preparation of the prochiral pentacyclic core of (+)-salvileucalin B is presented. The key feature in the synthesis is the Cu-catalyzed intramolecular cyclopropanation of a symmetrical indane-derived α-diazo ß-keto ester. This symmetry is carried through the remainder of the synthesis. This practical approach could allow the ready preparation of derivatives for further chemical and biological studies of this class of natural products.

Cyclohexanones by Rh-mediated intramolecular C-H insertion.

Some long chain α-aryl α-diazo ketones under Rh catalysis cyclize efficiently to the corresponding cyclohexanones. This is in marked contrast to the cyclizations of α-diazo ß-ketoesters, which consistently deliver cyclopentanone products.

Construction of the tricyclic A-B-C core of the Veratrum alkaloids.

Organocatalyzed enantioselective allylation of 2-iodocyclohexenone followed by methylation and oxy-Cope rearrangement delivered enantiomerically enriched 2-methyl 3-allyl cyclohexanone, which engaged in acid-catalyzed Robinson annulation to give the bicyclic enone. Subsequent elaboration of the pendant allyl group into an α-diazo ß-keto ester set the stage for Rh-mediated cyclization to deliver the tricyclic A-B-C core of the Veratrum alkaloids.

A piperidine chiron for the Veratrum alkaloids.

A Veratrum piperidine chiron was prepared over 11 steps (7.9% yield) from (-)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented.

-NH- termination of the Si(111) surface by wet chemistry.

For over a quarter of a century the hydrogen-terminated Si(111) single-crystalline surface has been the gold standard as a starting point for silicon surface modification chemistry. However, creating a well-defined and stable interface based on Si-N bonds has remained elusive. Despite the fact that azides, nitro compounds, and amines do lead to the formation of surface Si-N, each of these modification schemes produces additional carbon- or oxygen-containing functional groups that in turn react with the surface itself, leaving contaminants that affect the interface properties for any further modification protocols. We describe the preparation of a Si(111) surface functionalized predominantly with Si-NH-Si species based on chlorination followed by the room temperature ammonia treatment utilizing NH(3)-saturated tetrahydrofuran (THF). The obtained surface has been characterized by infrared spectroscopy and X-ray photoelectron spectroscopy. This analysis was supplemented with DFT calculations. This newly characterized surface will join the previously established H-Si(111) and Cl-Si(111) surfaces as a general starting point for the preparation of oxygen- and carbon-free interfaces, with numerous potential applications.

Synthesis of the reported structure of trans-africanan-1α-ol.

A trisubstituted cyclopentane chiron has been prepared by dynamic kinetic reduction of a pulegone-derived ß-keto ester. This chiron served as the starting material for the synthesis of the reported structure of the tricyclic sesquiterpene trans-africanan-1α-ol. The synthetic material was not congruent with the natural product.

Enantioselective conjugate allylation of cyclic enones.

Enantioselective organocatalytic 1,2-allylation of a cyclic enone followed by anionic oxy-Cope rearrangement delivered the ketone as a mixture of diastereomers. This appears to be a general method for the net enantioselective conjugate allylation of cyclic enones.

Aliphatic C-H to C-C conversion: synthesis of (-)-cameroonan-7α-ol.

In the course of a synthesis of the tricyclic sesquiterpene (-)-cameroonan-7α-ol from the acyclic (+)-citronellal, seven aliphatic C-H bonds were converted to C-C bonds, and three rings and four new stereogenic centers were established.

Synthesis of (-)-Astrogorgiadiol.

Astrogorgiadiol is a naturally occurring Vitamin D analogue that, in cell culture, downregulates the production of the cytokine osteopontin (OPN). OPN has been implicated in virulent asthma, and OPN knockout mice do not develop osteoporosis. As we have pursued whole animal studies with astrogorgiadiol, we have increased the scale of the synthesis. We report an improved preparation of the A-ring synthon and the scale-up of the diasteromerically pure D-ring/sidechain chiron.

Conjugate addition of lithiated methyl pyridines to enones.

Preparatively useful conjugate addition of lithiated methyl pyridines to cyclic and acyclic enones is reported. Addition of 2-picoline to 3-penten-2-one led to a concise synthesis of the alkaloids (+/-)-senepodine G and (+/-)-cermizine C.

Intramolecular [1 + 4 + 1] cycloaddition: establishment of the method.

Structurally complex and physiologically active natural products often include bicyclic and polycyclic ring systems having defined relative and absolute configuration. Approaches that allow the construction of more than one carbocyclic ring at a time have proven valuable, in particular those that allow at the same time the control of an array of new stereogenic centers. One of the most general and most widely used protocols has been the intramolecular Diels-Alder [4 + 2] cycloaddition, in which a single stereogenic center between the diene and the dienophile can control the relative and absolute configuration of the product. We report a two-step [1 + 4 + 1] procedure for bicyclic and polycyclic construction, based on the cyclization of an omega-dienyl ketone. This is complementary to, and will likely be as useful as, the intramolecular Diels-Alder cycloaddition.

A divergent synthesis of the delta(13)-9-isofurans.

A stereodivergent total synthesis of the Delta(13)-9-isofurans has been developed. The four core substituted tetrahydrofurans were prepared by the Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation followed by cascade cyclization. The relative configuration at C-8 was inverted by oxidation followed by immediate L-Selectride reduction. The relative configuration of the C-15 diastereomers was assigned by (S)-Binol/LAH/EtOH reduction of the corresponding enone. This synthesis of the Delta(13)-9-isofurans will provide sufficient material for further investigation of their biological activity.

Synthesis of (+)-coronafacic acid.

An enantioselective synthesis of (+)-coronafacic acid has been achieved. Rhodium-catalyzed cyclization of an alpha-diazoester provided the intermediate cyclopentanone in high enantiomeric purity. Subsequent Fe-mediated cyclocarbonylation of a derived alkenyl cyclopropane gave a bicyclic enone that then was hydrogenated and carried on to the natural product.

Preparation of the Major Urinary Metabolite of (-)-Prostaglandin E(2).

The best way to measure whole body production of the locally acting hormone prostaglandin E(2) (PGE(2)) is to assess the accumulation of the major urinary metabolite, PGE(2) U (M). A practical preparation of this delicate diacid is described. This synthetic PGE(2)U(M) will enable production of the antibodies that will be used to quantify this key metabolite.

One Carbon Homologation of Halides to Benzyl Ethers.

The preparation of one carbon homologated benzyl ethers from alkyl and aromatic halides is reported. The coupling reaction is rapid and efficient at room temperature.

Convenient access to bicyclic and tricyclic diazenes.

Heating the tosylhydrazone of an omega-alkenyl ketone or aldehyde to reflux in toluene in the presence of K(2)CO(3) delivered the bicyclic diazene. Irradiation of the diazene converted it to the cyclopropane. This appears to be a generally useful method for the construction of substituted cyclopentanes and cyclohexanes.

Convenient synthetic route to an enantiomerically pure FMOC alpha-amino acid.

A strategy for the facile alpha-amination of carboxylic acid menthyl esters is described. The resulting diastereomers, readily separable, can be individually carried on to each enantiomer of the FMOC alpha-amino acid. A variety of unnatural side chains were compatible with this approach. The menthyl ester was easily removed from the FMOC alpha-amino acid without racemization.