Solid-Phase Total Synthesis of Scytalidamide A

The first total synthesis of the natural cyclic heptapeptide scytalidamide A was achieved on solid phase using two different resins, a phenylalanine silane resin and a 4-methoxybenzaldehyde backbone linker resin. The synthetic product confirms the structure of the natural product reported in the preceding paper in this issue (Tan, L. T.; Cheng, X. C.; Jensen, P. R.; Fenical, W. J. Org. Chem. 2003, 68, 8767)

Stereospecific Total Syntheses of Proteasome Inhibitors Omuralide and Lactacystin

Omuralide, a transformation product of the microbial metabolite lactacystin, was the first molecule discovered as a specific inhibitor of the proteasome and is unique in that it specifically inhibits the proteolytic activity of the 20S subunit of the proteasome without inhibiting any other protease activities of the cell. The total syntheses of omuralide and (+)-lactacystin are reported. An important key intermediate is synthesized at an early stage, which allows analogues of these two natural products to be made readily

Electronic Effects of Peripheral Substituents at Porphyrin Meso Positions

Porphyrins are stable molecules with a macrocyclic conjugated system and often peripheral substituents. This unique structure makes the electronic properties of the four meso-carbons (the methine bridges) nearly identical. Replacement of the weakly electron-polarizing 2,4-vinyl groups of protoporphyrin IX with strongly electron-polarizing acetyl groups not only leads to much lower meso-carbon reactivities toward electrophilic aromatic substitution but also results in a significant meso-selectivity (the β- and γ-meso-positions become much more nucleophilic (basic) than the α- and δ-meso-positions). To further investigate the relationship between the porphyrin meso-carbon reactivities and the peripheral substituents, two monoacetylporphyrin analogues also were synthesized. This investigation not only leads to empirical rules for predicting porphyrin meso-carbon selectivities but also provides important models for theoretical calculations of porphyrin aromaticity

Traceless Solid-Phase Synthesis of Chiral 3-Aryl <i>β</i>-Amino Acid Containing Peptides Using a Side-Chain-Tethered <i>β</i>-Amino Acid Building Block

A general method for the attachment of a chiral aromatic side-chain-containing β-amino acid to a polymer support using a traceless silyl linkage strategy has been developed. Using this building block, solid-phase synthesis was carried out to obtain tripeptide analogues with the aromatic ring either unsubstituted or halogenated (Br, I) at the position of the silyl group. The building blocks could generate libraries of peptidomimetics or cyclic peptides containing β-amino acids with nonpolar side chains

A New Class of Conformationally Rigid Analogues of 4-Amino-5-halopentanoic Acids, Potent Inactivators of γ-Aminobutyric Acid Aminotransferase

Recently, we found (Qiu, J.; Pingsterhaus, J. M.; Silverman, R. B. J. Med. Chem. 1999, 42, 4725−4728) that conformationally rigid analogues of the GABA aminotransferase (GABA-AT) inactivator vigabatrin were not inactivators of GABA-AT. To determine if this is a general phenomenon of GABA-AT inactivators, several mono- and di-halogen-substituted conformationally rigid analogues (7−15) of other GABA-AT inactivators, 4-amino-5-halopentanoic acids, were synthesized as potential inactivators of GABA-AT. Four of them, (+)-7, (−)-9, (+)-10, and (+)-15, were inactivators, although not as potent as the corresponding open-chain analogues. The maximal inactivation rate constants, kinact, for the fluoro- and bromo-substituted analogues were comparable, indicating that cleavage of the C−X bond is not rate determining. Consistent with that observation is the finding that [3-2H]-10 exhibits a deuterium isotope effect on inactivation of 3.3, suggesting that C−H bond cleavage is the rate-determining step. The rate of inactivation of GABA-AT by the fluorinated analogue 7 is 1/15 that of inactivation by the corresponding open-chain analogue, 4-amino-5-fluoropentanoic acid (3a). Whereas inactivation by 3a releases only one fluoride ion, inactivation by 7 releases 148 fluoride ions, accounting for the less efficient inactivation rate. Inactivation leads to covalent attachment of 2 equiv of inactivator after gel filtration; upon urea denaturation, 1 equiv of radioactivity remains bound to the enzyme. This suggests that, unlike the open-chain anlogue, the conformationally rigid analogue becomes, at least partially, attached to an active-site residue. It appears that the conformational constraint has a larger effect on inactivators that inactivate by a Michael addition mechanism than by an enamine mechanism

Model Studies for Heme Oxygenase-Catalyzed Porphyrin Meso Hydroxylation

Nonenzymatic model studies based on a porphyrin analogue (2,4-diacetyldeuteroporphyrin) that avoid the steric effect complications of the heme oxygenase active site were carried out to determine the polarity of the ferric hydroperoxide attacking species. Mass spectral and deuterium-labeling experiments indicate that the porphyrin meso positions that are at higher π-electron densities in ferric 2,4-diacetyldeuteroporphyrin are selectively attacked. This supports an electrophilic aromatic substitution mechanism for the heme oxygenase-catalyzed porphyrin meso hydroxylation

Rapid, High-Yield, Solid-Phase Synthesis of the Antitumor Antibiotic Sansalvamide A Using a Side-Chain-Tethered Phenylalanine Building Block

A 10-step solid-phase synthesis of the cytotoxic depsipeptide sansalvamide A (1) has been accomplished in an overall yield of 67% with >95% purity employing polymer-bound phenylalanine building block 2. Both the N- and C-termini of 2 are extended followed by on-resin head-to-tail macrocyclization of the linear peptide in a high yield. This should be a general stategy for the synthesis of diverse libraries of cyclic peptides and depsipeptides that contain exclusively phenylalanine and other hydrophobic side chains

Monoamine Oxidase B-Catalyzed Reactions of <i>cis</i>- and <i>trans</i>-5-Aminomethyl-3-(4-Methoxyphenyl)dihydrofuran-2(3<i>H</i>)-ones. Evidence for a Reversible Redox Reaction

Monoamine oxidase B (MAO B) was previously shown to catalyze the decarboxylation of cis- (1) and trans-5-(aminomethyl)-3-(4-methoxyphenyl)dihydrofuran-2(3H)-one hydrochloride (2) (Silverman, R. B.; Zhou, J. J. P.; Ding, C. Z.; Lu, X. J. Am. Chem. Soc. 1995, 117, 12895−12896). By [14C]-labeling of the aryl methoxyl group, it is now shown that the decarboxylated product is 4-(4-methoxyphenyl)butanal (7), which is in the same oxidation state as the substrate. Two other products are produced, 4-carboxy-4-(4-methoxyphenyl)butanal (8), and 5-formyl-3-(4-methoxyphenyl)dihydrofuran-2(3H)-one (9). Only 9 is an oxidation product; 7 and 8 are in the same oxidation state as the substrate (1 or 2). No products are detected under strictly anaerobic conditions. All of these products can be rationalized as arising from the formation of an α-carbon radical, generated either by single-electron amine oxidation and loss of a proton or direct hydrogen atom abstraction to 10 (Scheme ). This intermediate then can undergo second electron oxidation and hydrolysis of the iminium ion to give 9 (the normal oxidation product). However, it also can suffer either homolytic C−O bond cleavage, decarboxylation, and electron return from the active site to give 7 or heterolytic cleavage and electron return from the active site to give 8. 5-(4-Methoxyphenyl)tetrahydrofuran-2-ol (14), an oxidation product from the intermediate that leads to 7, is not detected. These results suggest that MAO B can catalyze reversible redox reactions

Direct Amination of γ-Halo-β-ketoesters with Anilines

The direct amination of α-haloacetoacetates with anilines is described. Compared to existing methods, this simple protocol provides an attractive strategy to prepare diverse γ-anilino-β-ketoesters in one step. Good to excellent yields of the amination products were obtained under robust conditions, providing versatile and useful scaffolds

Efficient Solid-Phase Synthesis of Compounds Containing Phenylalanine and Its Derivatives via Side-Chain Attachment to the Polymer Support

Efficient Solid-Phase Synthesis of Compounds Containing Phenylalanine and Its Derivatives via Side-Chain Attachment to the Polymer Suppor