Design, synthesis, evaluation, and structure of vitamin D analogues with furan side chains

Based on the crystal structures of human vitamin D receptor (hVDR) bound to 1α,25-dihydroxy-vitamin D(3) (1,25 D) and superagonist ligands, we previously designed new superagonist ligands with a tetrahydrofuran ring at the side chain that optimize the aliphatic side-chain conformation through an entropy benefit. Following a similar strategy, four novel vitamin D analogues with aromatic furan side chains (3a, 3b, 4a, 4b) have now been developed. The triene system has been constructed by an efficient stereoselective intramolecular cyclization of an enol triflate (A-ring precursor) followed by a Suzuki-Miyaura coupling of the resulting intermediate with an alkenyl boronic ester (CD-side chain, upper fragment). The furan side chains have been constructed by gold chemistry. These analogues exhibit significant pro-differentiation effects and transactivation potency. The crystal structure of 3a in a complex with the ligand-binding domain of hVDR revealed that the side-chain furanic ring adopts two conformations.     

Carbon-13 NMR spectra of DDT,its analogues and related compounds

Carbon-13 NMR spectra of mono- and disubstituted aromatic compounds including DDT, its analogues, homologues, derivatives and certain model compounds have been studied. The Savitsky scheme of carbon chemical shifts in disubstituted benzenes is applicable to these compounds. The data obtained show that in mono- and disubstituted aromatic compounds containing two different substituents in the α- and β-positions of the side chain, the substituted ring carbon atom shifts follow the additivity rule and can be calculated from substituent increments. Mutual effects of substituents in the ring and in the side chains are analysed. The chlorine atoms in α-position to the phenyl ring give rise to an additive α-effect of about 25 ppm, as in perchloroalkanes. The influence of a β-chlorine atom in the side chain on the substituted carbon atom in the ring is, however, only 3 ppm as against the usual value of about 10 ppm for the β-effect in alkyl chains. Moreover, the first β-chlorine substituent has no noticeable influence on the substituted ring carbon chemical shift: the effect of 3 ppm is transferred to the para-carbon atom almost without attenuation. The ring substituted carbon atom signal shifts caused by the γ-effect of chlorine in the side chain are similar to those observed in aliphatic chains. The ortho-chlorine substituents shift the side chain α-carbon atom signal by 3.6-5.2 ppm to high field compared to para-chlorophenyl compounds. This is similar to the chlorine γ-effect in aliphatic chains.     

Heterocyclic photorearrangements. Photochemical behaviour of some 3,5-disubstituted 1,2,4-oxadiazoles in methanol at 254 nm

Photochemical behaviour of some 3,5-disubstituted 1,2,4-oxadiazoles in methanol at 254 nm has been investigated. Ring photoisomerization to the 1,3,4-oxadiazole heterocycle or formation of open chain compounds involving the nucleophilic solvent was shown to depend on the nature and the position of the substituent. Photoinduced ring closure into the benzimidazole system, involving a 3-N-phenylamino side chain sequence and a photolytic intermediate of the oxadiazole heterocycle, is also reported.     

(±)-3,4,4a,5,6,7-Hexahydro-4a-Methyl-7,7-Diphenyl-1(2H)-Naphthtlenone

The title compound was prepared in 48% overall yield using a seven-step sequence. The synthesis involves stepwise construction of a 3-formyl-3,3-diphenypropyl side chain from the double bond of 3-ethenyl-3-methylcyclohexanone followed by aldol ring closure. The approach represents a general strategy for the synthesis of a number of (±)-7,7-diary1–3,4,4a,5,6,7-hexahydro-1(2H)-naphthalenones.     

A mass spectrometric study of some triterpenes of the dammarane series

Summary 1. The mass spectra of tetracyclic triterpenes of the dammarane series with substituents at C-3, 6, and 12 and with side chains of various structures have been studied.2. The main direction of fragmentation is the formation of ions as the result of the decomposition of the side chain and of ring C, the second type of fragmentation being controlled by the structure of the side chain.Institute of Biologically Active Substances of the Far-Eastern Scientific Center of the Academy of Sciences of the USSR. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 286–294, May–June, 1971.     

A molecular mechanics force field for the cobalt corrinoids

A force field for the cobalt (III) corrinoids (derivatives of vitamin B₁₂) for use with a modified version of the molecular mechanics program 2(87) has been developed empirically around 19 cobalt corrinoid crystal structures. Bond lengths, bond angles and torsional angles are reproduced with r.m.s. differences of 0.01 Å, 2.4 °, and 4.2 °, respectively, within the standard deviation of the mean of these parameters found in the solid state. The axial ligand occupying the lower coordination site in the cobalamins, 5,6-dimethylbenzimidazole, is shown to have very limited rotational freedom and is constrained by the downward-pointing b and d propionamide side chains of the corrin ring. Strain-energy profiles for rotation of the side chains of the corrin ring show the existence of several local energy minima and this explains the observed variability in the orientations of these side chains in the solid state. The known change in conformation which occurs in the C ring when the e side chain is epimerized from the lower to the upper face of the corrin ring in cyano-13-epicobalamin is correctly predicted, provided the starting conformation of the C ring is unbiased. A study of cyano-8-epicobalamin indicates that an analogous conformational change does not occur in the B ring and the epimerized d side chain assumes an equatorial orientation relative to the corrin ring. Parameters for the Co---C bond in alkylcobalamins were developed and the structure of methyl- and adenosylcobalamin are accurately reproduced. An examination of the strain energy consequences of rotation of the adenosyl ligand about the Co---C bond identifies a number of low-energy conformations at least two of which, in which adenosyl lies over the “southern” and “eastern” portions of the corrin ring, respectively, have been previously deduced from NMR observations. Coordinated neopentyl in neopentylcobalamin is much more hindered to rotation about the Co---C bond and the lowest conformation finds two γ(C) atoms straddling the upwardly projecting C46 methyl group of the corrin.     

New flexible synthesis of pyrazoles with different,functionalized substituents at C3 and C5

Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3 and varying alkyl and aryl substituents attached to carbon 5 are presented. Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at C5 is reported here, starting by coupling protected alkynols with acid chlorides RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5-substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic substitution reactions, the chlorides are useful precursors to other polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)- and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The significance of the ligands made here is that by placing a ligating side chain on a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton will be available for hydrogen bonding, depending on the steric environment created by R at C5.     

Total synthesis of (-)-hennoxazole A

An enantioselective, convergent, total synthesis of the antiviral marine natural product (-)-hennoxazole A has been completed in 17 steps, longest linear sequence, from serine methyl ester and in 9 steps from an achiral bisoxazole intermediate. Elaboration of a thiazolidinethione allowed for rapid assembly of the pyran-based ring system. Key late-stage coupling was effected by deprotonation of the bisoxazole methyl group, followed by alkylation with an allylic bromide side chain segment. [structure: see text]     

Dynamic mechanical properties of poly-α-olefins containing ring structures in side chains

Dynamic loss modulus curves have been determined over a temperature range beginning at liquid nitrogen temperature for poly-α-olefin polymers containing various ring structures, i.e., phenyl, cyclohexyl, cyclopentyl, and naphthyl, in the side chain. Glass transition and appropriate secondary relaxation temperatures were observed for each polymer. Separation of each pendant ring structure from the main backbone chain by successive additions of methylene units results in lower glass-transition temperatures. Comparison of polymers with similar side chains and different ring structures shows that the respective glass-transition temperatures decrease in the order naphthyl > cyclohexyl > phenyl > cyclopentyl. Secondary relaxation peaks were obtained at about ?150°C for polymers containing the cyclohexyl and cyclopentyl rings. A similar peak was observed for the polymer possessing a phenyl ring separated from the main chain backbone by two methylene units. The comparable polymer containing the naphthyl ring structure exhibited a broad secondary relaxation peak centered at ?20°C. The polymers possessing cyclohexyl rings separated from the main chain backbone by one or two methylene units had an additional low temperature peak at ?80°C. The molecular mechanism associated with this relaxation may be related to intramolecular transformations of the cyclohexyl ring between its “chair–chair” conformations.     

Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.     

PMR spectra of certain chalcones and their heterocyclic analogs

The PMR spectra of chalcone and some of its derivatives and heterocyclic analogs have been measured, the signals have been assigned to certain atomic groupings and the trans configuration of the molecules has been established. We show that the conductivity of the electronic effects increases from the furan ring to the thiophene and selenophene rings. The effect of a carbonyl group in heteroaromatic systems on the proton signals from a methyl group in the side chain is markedly less than it is on the proton signals from the ring.     

Pharmacologically interesting compounds—I: High resolution mass spectra of phenothiazines

The mass spectra of twenty-six commercially available medicinal phenothiazines have been determined at high resolution. In each compound, the side chain attached to the 10-position of the phenothiazine ring contains nitrogen and fission of the C? C bond α to this nitrogen gives in most cases the base peak. Some of the compounds are also substituted at the 2-position and this substituent generally remains intact, though some substituents such as acetyl, propionyl, methoxyl and methylthio can undergo fragmentation. Fragmentations fall into three groups; those which give ions representing a part of the side chain; those which give ions representing the intact phenothiazine ring with part of the side chain attached; those which give ions representing a partially fragmented ring system.     

Sydnones as Masked Hydrazines for Heterocycle Formation: Reactions of 3-(2-substituted phenyl)sydnones with HCl

In general, reaction of 3-(2-substituted phenyl)sydnones with HCl gives products derived from cleavage of the sydnone ring to the corresponding hydrazine and subsequent cyclization to the side chain. In one case, 3-(2-aminophenyl)sydnone ( 43 ), the product obtained, l-amino-lH-benzimidazole ( 47 ), apparently results from nucleophilic interception by the side chain prior to complete cleavage of the sydnone ring.     

Total and Semi‐Syntheses of Antimicrobial Thuggacin Derivatives

The total and semi‐synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A–C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi‐synthetic O‐methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17–C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.     

Synthesis of 4-phenylethoxyquinazoline Fungicides/Insecticides

Recently, 4-phenylethoxyquinzoline and its analogues have been found to have both fungicidal and insecticidal activities. The synthesis of these compounds involves the construction of the quinazoline ring, preparation of the side chain, and coupling the side chain with 4-chloroquinazoline and its analogs.     

A Short Sequence for the Iterative Synthesis of Fused Polyethers

A simple and efficient four‐step sequence for the synthesis of fused polyether arrays has been developed. Cyclic ethers are installed by sequential alkynyl ether formation, carbocupration, ring‐closing metathesis and hydroboration with acidic workup. Crucially, the alkene required for the subsequent ring formation by ring‐closing metathesis is present in the substrate but is masked in the form of a vinylic silane, which prevents competitive metathesis of the side chain. Generation of the reactive alkene from the unreactive vinylic silane is accomplished by hydroboration and subsequent acid‐mediated Peterson elimination of the intermediate hydroxysilane.     

Synthesis of amino acid-derived cyclic acyl amidines for use in beta-strand peptidomimetics

The acyl amidine represented by the 4,5-dihydro-2(3H)-pyrazinone ring system 2 is isosteric to the vinylogous amide of the 1,2-dihydro-3(6H)-pyridinone 1, but its assembly from separate amine and amide components enables ready incorporation of an amino acid side chain with correct regio- and stereochemistry. beta-Strand peptidomimetics incorporating amino acid analogues based on 2 have recently been shown to be potent, protease-resistant ligands to a PDZ protein-interaction domain. Two routes to the protected dipeptide analogue 3 are described.     

Specific and nonspecific interactions in a molecule with flexible side chain: 2-phenylethanol and its 1:1 complex with argon studied by high-resolution UV spectroscopy

Using high-resolution resonance-enhanced two-photon ionization spectroscopy in combination with genetic-algorithm-based computer-aided rotational fit analysis and ab initio quantum chemistry calculations we determined the conformational structure and transition moment orientation in 2-phenylethanol and its 1:1 clusters with argon. The results clearly demonstrate that the gauche structure of 2-phenylethanol, which is stabilized by the intramolecular pi-hydrogen bond between the folded side chain and the benzene ring, is the most abundant in the cold molecular beam. In this conformer the transition moment is rotated by 18 degrees from the short axis of the aromatic ring. Two distinct 1:1 complexes of 2-phenylethanol with argon in a cis- and trans-configuration with respect to the side chain have been found. Employing the Kraitchman [Am. J. Phys. 21, 17 (1953)] analysis we have found that the structure of the 2-phenylethanol moiety and the orientation of the transition moment do not change after the complexation with argon within the experimental accuracy. From the measured band intensities we conclude that in addition to the dispersion interaction of the argon atom with the aromatic ring a hydrogen-bond-type interaction with the terminal -OH group of the side chain stabilizes the cis-structure of the 1:1 complex of 2-phenylethanol with argon.     

Silver complexes of peptidomimetic polyazapyridinophanes. The influence of the bonding cavity size and the nature of side chains

Several peptidomimetic macrocycles containing a pyridine spacer and ring sizes ranging from 15 to 17 have been efficiently synthesized starting from valine and phenylalanine. The complexes formed have been investigated by potentiometry and NMR. Log K values show that phenylalanine derivatives are consistently more stable than valine derivatives , whilst macrocycles with ring sizes of 16 members are the most appropriate for the complexation. The NMR data, in combination with molecular modeling, allow rationalization of the structure of the complexes formed and the participation of the aromatic rings from the side chain of phenylalanine in pi-Ag+ interactions to be discarded.     

29Si N.M.R. investigations of polysiloxanes

A number of side chain liquid crystal polysiloxanes prepared from both homo-and co-polymeric backbones have been studied by ²⁹Si N.M.R. and the chemical shifts assigned. Partly mesogenated poly(hydrogenmethylsiloxanes) have been similarly studied and chemical shift assignments made for sequence distributions. The data should prove helpful in studies of compositional variation in preparations of side chain copolymeric polysiloxanes.