Component-Based Syntheses of Trioxacarcin A, DC-45-A1, and Structural Analogs

The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1, and structural analogs by latestage, stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogs that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogs arising from modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells

Synthesis of Cortistatins A, J, K, and L

The cortistatins are a recently identified class of marine natural products characterized by an unusual steroidal skeleton and have been found to inhibit differentially the proliferation of various mammalian cells in culture by an unknown mechanism. We describe a comprehensive route for the synthesis of cortistatins from a common precursor, which in turn is assembled from two fragments of similar structural complexity. Cortistatins A and J, and for the first time, K and L, have been synthesized in parallel processes from like intermediates prepared from a single compound. With the identification of facile laboratory transformations linking intermediates in the cortistatin L synthetic series with corresponding intermediates to cortistatins A and J, we have been led to speculate that somewhat related paths might occur in nature, offering potential sequencing and chemical detail for cortistatin biosynthetic pathways.Chemistry and Chemical Biolog

A Method for the Preparation of Differentiated transtrans-1,2-Diol Derivatives with Enantio- and Diastereocontrol

We describe a synthetic sequence that allows for the preparation of optically active $trans$-1,2-diol monosilyl ether derivatives from ketones, providing a new means for retrosynthetic simplification of differentiated diol and polyol targets. The sequence involves silyl enol ether formation, Shi asymmetric epoxidation, and then regio- and stereospecific addition of hydride, methide, or higher alkylide. The tactical combination presented has not been integrated in synthetic problem solving, so far as we are aware, but has promise for broad application.Chemistry and Chemical Biolog

Evidence for aminoglycoside participation in thiol activation of neocarzinostatin chromophore. Synthesis and reactivity of the epoxy dienediyne core

The reaction of the chromophore subunit (1) of the natural antitumor antibiotic neocarzinostatin with methyl thioglycolate produces an NMR-observable intermediate, assigned as 2, which decays with a half-life of ~2 h at -38 °C to form the putative biradical 3. While the latter rearrangement is striking, perhaps no less so is the thiol addition step (1 → 2), which occurs readily at -70 °C in acetic acid-tetrahydrofuran (1:9, t_(1/2) ≃ 1.5 h, 0.2 M thiol). Reported herein are (1) the assembly of the full core functionality of neocarzinostatin chromophore in a synthetic system and (2) the preparation of a nonbasic derivative of the chromo-phore itself. Experiments with these synthetic materials provide strong evidence that thiol activation of 1 is facilitated dramatically through participation of the carbohydrate amino group as an internal base

A New and Unusual Pathway for the Reaction of Neocarzinostatin Chromophore with Thiols. Revised Structure of the Protein-Directed Thiol Adduct

Neocarzinostatin (holo-NCS) is an antitumor antibiotic comprising a nonprotein chromophore component (1) and a 113- amino acid carrier protein (apo-NCS). Goldberg and coworkers first demonstrated that the reaction of the isolated chromophore (1) with thiols in the presence of double-stranded DNA leads to DNA cleavage by a free-radical mechanism. The pathway shown in Scheme 1 was later proposed to account for this activity, a proposal that is now supported by a considerable body of evidence. In 1992, Saito and co-workers showed that the reaction of holo-NCS with small thiols, such as β-mercaptoethanol (BME), takes a different course, to form a product that is formally a 1:1:1 adduct of thiol, 1, and water. Structure 2 was proposed for this adduct, along with the mechanistic pathway shown in Scheme 2. Complicating the analysis was the fact that 2 was an inseparable mixture of two components, present in equal parts

A convergent synthetic route to the tunicamycin antibiotics. Synthesis of (+)-tunicamycin V

The tunicamycins are a family of natural products represented generally by structure 1, wherein R indicates one of several long-chain branched, linear, saturated or unsaturated acyl substituents. They elicit a considerable range of biological responses including antimicrobial, antifungal, antiviral, and antitumor activities. Their ability to function as potent inhibitors of oligosaccharide synthesis in eukaryotic cells has established them as unique biochemical probes of the role of glycosylation on protein structure and function. In this work, we describe a concise synthetic route to the tunicamycins, illustrated by the preparation of (+)-tunicamycin V (1-V)

Observations of Global and Local Infall in NGC 1333

We report ``infall asymmetry'' in the HCO$^+$ (1--0) and (3--2) lines toward NGC 1333, extended over $\sim 0.39 {\rm pc}^2$, a larger extent than has been reported be fore, for any star-forming region. The infall asymmetry extends over a major portion of the star-forming complex, and is not limited to a single protostar, or to a single dense core, or to a single spectral line. It seems likely that the infall asymmetry represents inward motions, and that these motions are physically associated with the complex. Both blue-asymmetric and red-asymmetric lines are seen, but in both the (3--2) and (1--0) lines of HCO$^+$ the vast majority of the asymmetric lines are blue, indicating inward motions. The (3--2) line, tracing denser gas, has the spectra with the strongest asymmetry and these spectra are associated with the protostars IRAS 4A and 4B, which most likely indicates a warm central source is affecting the line profiles. The (3--2) and (1--0) lines usually have the same sense of asymmetry in common positions, but their profiles differ significantly, and the (1--0) line appears to trace motions on much larger spatial scales than does the (3--2) line. Line profile models fit the spectra well, but do not strongly constrain their parameters. The mass accretion rate of the inward motions is of order 10$^{-4}$ M$_\odot$/yr, similar to the ratio of stellar mass to cluster age.Comment: 28 pages, 11 figures, 1 colour figur

Pseudoephenamine: A Practical Chiral Auxiliary for Asymmetric Synthesis

Pseudoephenamine is shown to be a versatile chiral auxiliary for asymmetric synthesis. It is free from regulatory restrictions and exhibits remarkable stereocontrol in alkylation reactions, especially those that form quaternary carbon centers. Amides derived from pseudoephenamine exhibit a high propensity to be crystalline substances and provide sharp, well-defined peaks in NMR spectra.Chemistry and Chemical Biolog

Methodological advances permit the stereocontrolled construction of diverse fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a

a b s t r a c t Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of compounds in this important family of therapeutic agents. In the key transformation and an important extension of the powerful MichaeleClaisen cyclization (AB plus D) approach to the construction of fully synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon center can be assembled by highly stereocontrolled coupling reactions of b-substituted AB enones and otoluate ester anion D-ring precursors. Novel and versatile b-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 1 (the key precursor to fully synthetic tetracyclines) into a diverse range of b-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a b-methyl ester-substituted AB enone. A C5aeC11a-bridged cyclopropane tetracycline precursor was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged cyclopropane intermediate served as (further) diversifiable branch-points, allowing maximally expedient synthesis of C5a-substituted tetracyclines by final-step diversification