Diastereoselective Total Synthesis of (±)‐Schindilactone A,Part 2: Construction of the Fully Functionalized CDEFGH Ring System

The successful synthesis of the highly complex model compound ( 2 ) of the CEFGH ring system of schindilactone A ( 1 ) is described. Several synthetic methodologies were developed and applied to achieve this goal, including ring‐closing metathesis (RCM) and Co–thiourea‐catalyzed Pauson–Khand reactions. Furthermore, two independent approaches were developed for the construction of the GH ring of model compound 2 , the key steps of which included Pd–thiourea‐catalyzed carbonylative annulation, methylation, and sequential RCM/oxa‐Michael‐addition reactions. The chemistry developed herein has provided a greater understanding of the synthesis of schindilactone A ( 1 ) and its analogous compounds of the same family.     

Formal total synthesis of (±)-cortistatin A

A second-generation synthesis of the pentacyclic core of the cortistatins, a family of rearranged steroidal alkaloids that have recently attracted much attention, is reported. The improved sequence provides access to significant quantities of this key compound, which enabled a formal total synthesis of (±)-cortistatin A by conversion to the key Nicolaou/Hirama dienone. It is anticipated that this new, robust route to the pentacyclic core will facilitate the total synthesis of a range of natural products in the cortistatin family, as well as the construction of key structural analogs to probe the promising biological activity of these important compounds.     

Methyl scanning: total synthesis of demethylasterriquinone B1 and derivatives for identification of sites of interaction with and isolation of its receptor(s)

The principle of methyl scanning is proposed for determination of the sites of interaction between biologically active small molecules and their macromolecular target(s). It involves the systematic preparation of a family of methylated derivatives of a compound and their biological testing. As a functional assay, the method can identify the regions of a molecule that are important (and unimportant) for biological activity against even unknown targets, and thus provides an excellent complement to structural biology. Methyl scanning was applied to demethylasterriquinone B1, a small-molecule mimetic of insulin. A new, optimal total synthesis of this natural product was developed that enables the family of methyl scan derivatives to be concisely prepared for evaluation in a cellular assay. The results of this experiment were used to design a biotin-demethylasterriquinone conjugate for use as an affinity reagent. This compound was prepared in tens of milligram quantities in a four-step synthesis.     

Synthesis of an octahydroindolinone scaffold for a diversity-based chemical compound library

The synthesis of a chemical compound library using diversity-oriented synthesis (DOS) is discussed. The library is structurally inspired by the Amaryllidaceae alkaloids, a family of natural products which has been known to demonstrate potent antiviral and antineoplastic activity. Highlights of this work include the rapid, high-yielding construction of the octahydroindolinone core and the solid-phase diversification of the lactam using a neutral phosphazene base.     

Synthesis, characterization and crystal structure of mesogenic compounds with an alkyloxy and a semi-perfluorinated chain. Influence of the alkyloxy chain length on molecular arrangement and molecular interactions

This paper describes the synthesis and study of the mesomorphic properties (by DSC, microscopic observation and X-ray diffraction) of three new series of semi-perfluorinated liquid crystals: 4-(2,2,3,3,4,4,4-heptafluorobutyloxycarbonyl)phenyl, 4-(2,2,3,3,4,4,5,5-octafluoropentyloxycarbonyl)phenyl, and 4-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-octyloxy-carbonyl)phenyl 4-(n-alkyloxy)benzoates. One compound of the second family crystallizes in the P1 space group with Z ' 2. The molecule adopts a slightly bent conformation with a fully extended alkyloxy and semi-perfluorinated chain in a smectic C-like structure. The comparison of the present structure is made with that of a similar compound of the first family with a longer alkyloxy chain (this latter crystallizes in the P1 space group with two independent molecules in the unit cell). Comparison of the molecular packing shows the importance of the chain lengths in the molecular arrangement and molecular interactions in both structures.     

First total synthesis of JS isoprostane

A stereoselective Julia-Lythgoe olefination followed by an efficient 1,3-allylic transposition of the C-9 hydroxyl group of compound 13 has allowed the first total synthesis of J(2) isoprostane (1), a recently discovered member of the growing isoprostane family. This elusive compound opens up numerous new avenues for the molecular biology of cyclopentenone prostaglandins which are endowed of intriguing biological effects such as antitumor, antiinflammatory, and antiviral activities. In principle, our approach is flexible enough to allow an easy synthesis of other isoprostanes of the J family following the same methodology.     

Polycyclic ethers and an unexpected dearomatisation reaction during studies towards the bioactive alkaloid,perophoramidine

The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ether-containing precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred.     

Synthesis, structure and bonding of the hypoelectronic cluster compound Sr3Tl5

The Sr3Tl5 phase was prepared by high temperature synthesis techniques through reaction of the high purity elements in the welded Nb tubes.The structure established through X-ray structural analysis shows the compound is a good hypoelectronic trielide example of the Pu3Pd5 structural type in which skeletal electron count is lower than in a traditional Zintl phase(Cmcm,Z = 4;a = 10.604(2) ,b = 8.675(2) ,and c = 10.985(2) ;V = 1010.5(3) 3).The strontium size and the compound’s polarity appear responsible for this thallium phase crystallization in the Pu3Pd5 family type rather than the isoelectronic Sr3In5 version.A first-principle electronic structure calculation(LMTO) demonstrates that the strontium atoms participate substantially in Sr-Tl bonding in the structure.     

Design, synthesis, and evaluation of in vivo potency and selectivity of epoxysuccinyl-based inhibitors of papain-family cysteine proteases

The papain-family cathepsins are cysteine proteases that are emerging as promising therapeutic targets for a number of human disease conditions ranging from osteoporosis to cancer. Relatively few selective inhibitors for this family exist, and the in vivo selectivity of most existing compounds is unclear. We present here the synthesis of focused libraries of epoxysuccinyl-based inhibitors and their screening in crude tissue extracts. We identified a number of potent inhibitors that display selectivity for endogenous cathepsin targets both in vitro and in vivo. Importantly, the selectivity patterns observed in crude extracts were generally retained in vivo, as assessed by active-site labeling of tissues from treated animals. Overall, this study identifies several important compound classes and highlights the use of activity-based probes to assess pharmacodynamic properties of small-molecule inhibitors in vivo.     

N-Alkylation of pyrazolones with OH-protection

The synthesis of a biheterocyclic compound containing two pyrazolone sub-units, precursor of a new macrocyclic family, is described. It is shown that it is necessary to protect first the pyrazol-5-one oxygen site before condensing it with a bifunctional compound in order to obtain a selective alkylation on the heterocyclic nitrogen atom.     

Design, synthesis, and biological evaluation of estrone-derived hedgehog signaling inhibitors

The design, synthesis, and biological evaluation of new analogs of the naturally occurring compound cyclopamine, a hedgehog signaling inhibitor, are described. Structure-activity relationship studies lead to an evolving model for the pharmacophore of this medically promising compound class of anti-cancer chemotherapeutic agents.     

Convenient Preparation of 2,7,8‐Trimethyl‐6‐hydroxychroman‐2‐carboxylic Acid (γ‐Trolox)

The title chroman is useful in synthesis and as a water‐soluble analog of γ‐tocopherol, a member of the vitamin E family. This new synthesis of γ‐trolox proceeds via selective aromatic demethylation of Trolox, the more easily available 2,5,7,8‐tetramethyl homolog compound. This route is shorter than the previous synthesis, avoids the use of cyanide and methoxybutadiene, and requires no chromatography.     

7,11-epi-thyrsiferol: completion of its synthesis, evaluation of its antimitotic properties, and the further development of an SAR model

We (a) describe the completion of a total synthesis of 7,11-epi-thyrsiferol (4), (b) compare the antimitotic activities of thyrsiferol (2), Delta15,28-dehydrothyrsiferol (3), and 7,11-epi-thyrsiferol (4), (c) evaluate the synergistic behavior of the title compound and colchicine to inhibit cell proliferation, and (d) describe the results of conformational searches that provide additional insight concerning the SAR profile of the thyrsiferol family of natural products.     

Complex target-oriented total synthesis in the drug discovery process: the discovery of a highly promising family of second generation epothilones

The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.     

Asymmetric [C + NC + CC] coupling entry to the naphthyridinomycin natural product family: formal total synthesis of cyanocycline A and bioxalomycin β2

A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin β2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin β2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).     

Efficient and Facile Synthesis of ( ± )-Salvirecognine

Salvirecognine (7) is a diterpene isolated from Salvia recognita[1] which has been the subject of continued and growing interest, due to the range of biological activities shown by many members of this family. [2] In order to study further relationships between the structure and biological activity of the diterpene compounds and as an extension of diterpenoid synthesis in our laboratory, [3,4] the first total synthesis of the title compound was achieved by an efficient and facile route (Scheme 1).     

Synthetic studies on amipurimycin: total synthesis of a thymine nucleoside analogue

Amipurimycin, a member of the complex peptidyl nucleoside family of antibiotics, is a Streptomyces-derived potent antifungal agent. The mechanism of action of amipurimycin, however, remains undetermined. Additionally, there are no reports on the total synthesis or structure-activity relationships (SAR) of this potentially useful bioactive compound. In a study aimed at the total synthesis and SAR studies of this natural product, the present research reports the development of a synthetic route to the central pyranosyl amino acid core of amipurimycin and its further elaboration, culminating in the synthesis of a unique thymine analogue. Utilizing a d-serine-derived dihydroaminopyrone as a strategic building block, the synthesis involves de novo construction of the fully functionalized C-3-branched carbohydrate amino acid core, followed by glycosidic attachment of thymine at C-1, and peptidic linking of the C-6 amine with the 1,2-aminocyclopentane carboxylic acid side chain.     

Synthesis of aurachin D and isoprenoid analogues from the myxobacterium Stigmatella aurantiaca

Aurachins, a family of isoprenoid quinoline alkaloids isolated from the myxobacterium Stigmatella aurantiaca, possess multiple interesting bioactivities and were subject of intensive studies of biosynthesis. In this Letter, we describe the efficient few step total synthesis of the parent compound aurachin D and two isoprenoid analogues via Conrad–Limpach cyclization. The main antimicrobial and cytotoxic profiles of these derivatives were explored.     

The total synthesis of coleophomones B, C, and D

Members of the coleophomone family of natural products all possess several intriguing and challenging architectural features, as well as exhibit unusual biological activity. They, therefore, constitute attractive targets for synthesis. In this Article, we describe the total synthesis of coleophomones B (2), C (3), and D (4). The highly strained and congested 11-membered macrocycle of coleophomones B (2) and C (3) was constructed using an impressive olefin metathesis reaction. Furthermore, both of the requisite geometric isomers of the Delta(16,17) within the macrocycle could be accessed from a common precursor, facilitating a divergence that lent the coleophomone B (2)/C (3) synthesis an unusually high degree of efficiency. The synthesis of coleophomone D (4) confirmed that it exists as a dynamic mixture of isomeric forms with a different aromatic substitution pattern from the other family members.     

Synthesis,Structure and Photophysical Properties of a New Class of Inherently Chiral Boron(III) Chelates—The tert-Leucine Complexes

A new family of boron(III) chelates is introduced whereby molecular chirality, confirmed by circular dichroism, is imported during synthesis such that isolation of the diastereoisomers does not require separation procedures. The photophysical properties of two members of the family have been examined: the N,O,O-salicylaldehyde-based derivative shows pronounced intramolecular charge-transfer character in fluid solution and is weakly fluorescent, with a large Stokes shift. The corresponding 2-methylamino-benzaldehyde-derived N,N,O-chelate absorbs and fluoresces in the visible region with a much smaller Stokes shift. Orange fluorescence is also observed for this compound as a cast film. Temperature-dependence studies show that decay of the fluorescent state is weakly activated but emission is less than quantitative at 77 K. Quite rare for boron(III)-based chelates, this derivative undergoes intersystem crossing to form a meta-stable triplet-excited state. X-ray crystal structures are reported for both compounds, along with simulated ECD spectra.