Total synthesis of the CP-molecules (CP-263,114 and CP-225,917, phomoidrides B and A). 3. Completion and synthesis of advanced analogues

The completion of the total syntheses of the CP-molecules is reported. Several strategies and tactics, including the use of amide-based protecting groups for the homologated C-29 carboxylic acid and the use of an internal pyran protecting group scheme, are discussed. The endeavors leading to the design of new methods for the homologation of hindered aldehydes and to the isolation of a polycyclic byproduct (23), which inspired the development of a new series of reactions based on iodine(V) reagents, are described. In addition, the discovery and development of the LiOH-mediated conversion of CP-263,114 (1) to CP-225,917 (2) is described, and a mechanistic rationale is presented. Finally, a synthetic route to complex analogues of the CP-molecules harboring a maleimide moiety in place of the maleic anhydride is presented.     

Synthetic study on CP-263,114 (phomoidride B) by SET-mediated fragmentation

Assembly of the highly functionalized carbocyclic core of CP-263,114 has been accomplished by using radical-mediated fragmentation with lithium naphthalenide as a key step.     

Evaluation of asymmetric Diels-Alder approaches for the synthesis of the cyclohexene subunit of CP-225,917 and CP-263,114

Asymmetric synthesis of a functionalised cyclohexenone required for total synthesis of CP-225,917 and CP-263,114 is reported, using a Lewis acid-promoted Diels-Alder reaction between a 2-silyloxy-1,3-diene and a dienophile bearing an oxazolidinone auxiliary. A novel method for appendage of the exocyclic malonate unit, via cyclopropane ring opening, is also described.     

Monitoring CP-93,393 reaction mixtures by flow-injection analysis-mass spectrometry

CP-93,393 is a drug candidate at Pfizer. Flow-injection analysis-mass spectrometry (FIA-MS) was used to monitor reaction completion for CP-93,393 reaction mixtures. FIA-MS provides essentially instantaneous results, is relatively simple to operate, and is a universal system that can be used to monitor any reaction as long as the product has a molecular weight that differs from the molecular weights of the reactants. The mass spectrometer for these studies employed atmospheric pressure chemical ionization. Samples were introduced into the mass spectrometer with a flowing stream of solvent.     

An Approach to the Core Structure of CP-225,917

The complex natural product CP-225, 917 (1), which is an inhibitor of Ras fanesyl tranferase,[1～3] has at tracted much attention of several groups for its total synthesis. Our own approach is based on siloxy Cope rearrangement, which could be accomplished thermally in very good yield (99%) to from 10 to 11,[4] a model compound lacking the side arms of the natural product. Its synthetic route from 6 is shown.     

Adsorption-parallel catalytic waves of cinnamic acid in hydrogen peroxide-tetra-n-butylammonium bromide-acetate system

The mechanism of the adsorption-parallel catalytic wave of cinnamic acid (C6H5—CH = CH—COOH) in acetate buffer (pH = 4.0)-H2O2-tetra-n-butylammonium bromide (Bu4N · Br) solution was studied by the linear-sweep polarography, cyclic voltammetry and digital simulation approach. Experimental results indicate that the reduction mechanism of cinnamic acid is ECdimE' process, in which the C = C double bond of cinnamic acid first undergoes 1 e, 1H reduction to produce an intermediate free radical C6H5—CH—CH2—COOH(E), then the further reduction of the free radical in 1e,1H addition (E') occurs simultaneously with a dimerization reaction between two free radicals (Cdim). Bu4N · Br enhances the polarographic current of cinnamic acid and shifts the peak potential to positive direction. The enhancement action of Bu4N · Br is due to the adsorption of cinnamic acid induced by Bu4N species. In addition, H2O2 causes the parallel catalytic wave of cinnamic acid. The mechanism of the catalytic wave is EC' proce     

One-pot synthesis of pentacyclic diamines from quinolines by a new Zn/AcOH-promoted cascade reaction

A simple and efficient method for the one-pot synthesis of pentacyclic diamines from quinolines is described. It involves a new Zn/AcOH-promoted cascade reaction, in which two C[bond]C bonds and four to five stereogenic centers are established under mild conditions. The regiochemistry of the dimerization and cyclization step is governed by substituent effects, allowing access to a head-to-head (2, 3) or head-to-tail skeleton (4, 5).     

Stereoselective synthesis of the 6,6-spiroketal core of CP-61,405 (routiennocin)

A convergent and efficient synthesis of the 6,6-spiroketal core of the ionophore antibiotic CP-61,405 (routiennocin) is described. The synthesis required 10 steps from N-propionyl oxazolidinone (S)-8 and produced the desired spiroketal in 36% overall yield.     

Phosphorylinitrile oxides. 7. Quantum chemical study of the dimerization of nitrile oxides

A semiempirical MNDO calculation was carried out for the singlet potential energy surface for the dimerization of acetonitrile oxide leading to dimethylfuroxane. The dimerization of nitrile oxides proceeds by a two-step mechanism. The rate-limiting step is formation of a dinitrosoethylene intermediate. A semiempirical AMI calculation was carried out to study the effect of phosphoryl substituents on formation of the transition state of the rate-limiting step in the dimerization of dimethoxyphosphorylnitrile oxide. Independently of the initial orientation of the two phosphorylnitrile oxide molecules, a gauche-oriented dimerica species is formed in the first step in the dimerization. There is hardly any specific effect ofthe phosphoryl substituents in the first step of phosphorylnitrile oxide dimerization.Communication 6, see ref. [1].Kazan State Technological University, 420015 Kazan, and Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1269–1273, September, 1994. Original article submitted August 5, 1994.     

Design and synthesis of a 1 alpha,25-dihydroxyvitamin D3 dimer as a potential chemical inducer of vitamin D receptor dimerization

[formula: see text] A dimer comprising two 1 alpha,25-dihydroxyvitamin D3 units linked by an alkyl side chain at C-11 was synthesized with a view to the simultaneous binding of two vitamin D receptor (VDR) molecules and the consequent induction of VDR dimerization. The short, convergent synthesis uses a stereoselective cuprate addition to introduce the linking side chain and a key ruthenlum olefin metathesis as the dimerization step.     

Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A

Marinomycins A-C (1-3), and their monomeric analogues monomarinomycin A (m-1) and iso-monomarinomycin A (m-2), were synthesized by a convergent strategy from key building blocks ketophosphonate 5, aldehyde 6, and dienyl bromide carboxylic acid 7. The first attempt to construct marinomycin A [1, convertible to marinomycins B (2) and C (3) by light] by direct Suzuki-type dimerization/cyclization of boronic acid dienyl bromide 4 led to premature ring closure to afford, after global desilylation, monomarinomycin A (m-1) and iso-monomarinomycin A (m-2) in good yield and only small amounts (< or =2%) of the desired product. A subsequent stepwise approach based on Suzuki-type couplings improved considerably the overall yield of marinomycin A (1), and hence of marinomycins B (2) and C (3). Alternative direct dimerization approaches based on the Stille and Heck coupling reactions also led to monomarinomycins A (m-1 and m-2), but failed to deliver useful amounts of marinomycin A (1).     

Structural,electrochemical, and adsorption studies of Ni and Zn benzylimidazole coordination polymers with terephthalate linkers

Two coordination polymers, [Ni(bim)₂(L1)(H₂O)₂] _n (CP-1) and [Zn(bim)(L1)(Cl)] _n (CP-2) (bim = 1-benzylimidazole, L1 = terephthalic acid), were synthesized and characterized by physicochemical and spectroscopic methods. The Ni(II) center in CP-1 is octahedral, while the Zn(II) center in CP-2 is tetrahedral. CP-1 and CP-2 were used to modify carbon paste electrodes to assess their effect on the electrochemical behavior of ferricyanide. The redox reactions of ferricyanide on both electrodes proved to be reversible and diffusion controlled, with ferricyanide diffusion coefficients for CP-1 and CP-2 of 1.88 × 10⁵ and 3.44 × 10⁵ cm² s^?1, respectively. These coordination polymers were also investigated for their adsorption behavior toward two dyes: Chicago sky blue and methylene blue. CP-1 and CP-2 both rapidly adsorbed the anionic Chicago sky blue dye by different intermolecular interactions; in contrast, the cationic methylene blue dye was adsorbed to a lesser extent. The adsorption of these CPs depends on the charge but not the size of the dye. Addition of methanolic potassium nitrate solution caused the release of the adsorbed dyes.     

Evolution of a synthetic approach to CP-263,114

[structure: see text] Three different approaches to the carbocyclic core of CP-263,114 are presented that illustrate a strategic evolution from an oxy-Cope rearrangement to variants of the Wharton fragmentation.     

Theoretical investigation of carboranylpyrrole structures and the thermal resistance and conducting properties of carboranylpyrrole polymers

The carboranylpyrrole polymers are functional materials with superior thermal resistance and conducting performances. The carboranylpyrrole structures and Laplacian bond order (LBO) of carborane moiety, as well as the thermal resistance and conducting properties of carboranylpyrrole dimers or polymers, were investigated theoretically. The ¹¹B NMR chemical shifts of 3-(2-methyl-o-carboranyl)alkyl-1H-pyrrole monomers (CP-1 to CP-5) were calculated and analyzed. The average LBO values of some characteristic chemical bonds in the carborane cages of CP-1 to CP-5 molecules were calculated. It is found that the average LBO values of carborane moieties change slightly with the increase in alkyl chain length. The temperature resulting in about 15–20 % weight loss for CP-1, CP-3, CP-4 and CP-5 polymers is predicted to be more than 700 °C. Apart from the C–C bonds in carborane moieties of 3-(2-R-o-carboranyl)propyl-1H-pyrrole (R = CH₂OH, CH₂OCH₃, CN, COCl, Ph) substituents, the LBO values of other bonds in these cages change slightly relative to that in the molecule of 3-(2-methyl-o-carboranyl)propyl-1H-pyrrole (CP-3). The C–C bond LBO values in the carborane cages of these substituents with electron-donating groups (R = CH₂OH, CH₂OCH₃) are bigger than that in CP-3, while those values in those substituents with electron-withdrawing groups (R = CN, COCl, Ph) are smaller than that in CP-3. The polymerization activity calculated for CP-1 to CP-5 monomers increases with the increase in alkyl chain length. The calculated orbital energy gap (?E _LUMO?HOMO) of CP-1 to CP-5 dimers decreases with the increase in alkyl chain length, and accordingly, the electronic conductivity has the potential to increase. In addition, the calculated band gaps of CP-1 to CP-5 dimers cell models also decrease with the increase in alkyl chain length.     

Chain dynamics in microgels: poly(N-vinylcaprolactam-co-N-vinylpyrrolidone) microgels as examples

Microgels are highly swollen colloids built up of flexible cross-linked chains. We studied the static and dynamic light scattering (LS) behavior of thermosensitive microgels based on N-vinylcaprolactam and N-vinylpyrrolidone prepared by precipitation copolymerization in H2O (CP-1) and D2O (CP-2). Striking differences in behavior were observed in the two solvents. In both cases the angular dependence of static LS could reasonably well be described by a soft sphere model (J. Polym. Sci., Polym. Phys. Ed. 1982, 20, 157) with small deviations at large qRg. At temperatures larger than the collapse temperatures, the CP-1 sample in water started to aggregate whereas the CP-2 sample in D2O showed no association and developed the expected change toward hard sphere behavior. Dynamic LS permitted the determination of internal or segmental mobility. A remarkable shift toward large qRg was found for CP-1 compared to the behavior of linear chains. The dynamic behavior is clearly displayed in a plot of Gamma*(q) = (Gamma1(q)/q3)(eta0/kT), with Gamma1(q) the first cumulant of the field time correlation function and the common meaning of the other parameters. A long range of hard sphere behavior indicated the suppression of internal modes, but at large qRg the swollen microgel CP-1 in water displayed internal motions with a spectrum similar to that of Zimm relaxations. No internal mobility could be detected with the CP-2 sample in D2O. The behavior is in agreement with observations in the literature. The differences in the two similar solvents were attributed to the poorer solvent quality of D2O.     

Improved synthetic methods of CP-060S,a novel cardioprotective drug

Two synthetic methods of CP-060S, (−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one (−)-1, have been developed. The first method involved preparative HPLC resolution of bromo-intermediate 4. The second one involved resolution of 1 by crystallization of the corresponding diastereomeric salt.     

Structural aspects of two-stage dimerization in an ionic C60 complex with bis(benzene)chromium: Cr(C6H6)2.C60.C6H4Cl2

Single crystals of the ionic C60 complex with bis(benzene)chromium: {Cr(I)(C6H6)2(.+)}.(C60.-)).C6H4Cl2 (1) were obtained. The crystal structure of 1 shows the presence of monomeric C60.- radical anions at 250 K and the formation of single-bonded (C60-)2 dimers at 90 K. The dimerization is realized in two types of the C60.-) pairs with different interfullerene center-to-center distances of 10.052 and 10.279 A arranged in zigzag chains along the a-direction. As a result, two symmetrically independent (C60-)2 dimers found in 1 at 90 K have different environments, intercage C-C bond lengths and C60- center-to-center distances. Such differences should provide different thermal stability of these dimers and result in the appearance of two stages at the dimerization. Indeed, according to SQUID measurements, the magnetic moment of 1 decreases stepwise at the dimerization in two temperature ranges at 240-200 and 200-160 K.     

Novel synthesis of CP-734432, an EP4 agonist, using Sharpless asymmetric dihydroxylation

A novel and efficient asymmetric route to CP-734432, a lactam analog of PGE2, that shows selective agonism against the EP4 receptor subtype, is reported herein. The key steps include a Heck coupling to introduce the aryl ring at C-16 and a highly diastereoselective Sharpless asymmetric dihydroxylation to set the C-15 center.     

Synthetic study of phomoidride B (CP-263,114); utilization of the oxidopyrylium [5 + 2] cycloaddition

The highly functionalized core structure of phomoidride B (CP-263,114) was pursued by using intermolecular oxidopyrylium-alkene cyclization as one of the key steps.     

Total synthesis of epoxyquinols A, B, and C and epoxytwinol A and the reactivity of a 2H-pyran derivative as the diene component in the Diels-Alder reaction

Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCl(4)-mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6pi-electrocyclization, and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction composed of oxidation, 6pi-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6pi-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized by a similar cascade reaction composed of the four successive steps: oxidation, imine formation, 6pi-azaelectrocyclization, and Diels-Alder dimerization.