Herman Ziffer

The absolute stereochemistry of several cis-dihydrodiols microbially produced from substituted benzenes

Abstract The absolute stereochemistry of a series of 3-substituted cis -dihydrodiols obtained by microbial oxidation of toluene, ethylbenzene, chlorobenzene, and biphenyl has been assigned from chemical and spectrophotometric studies. ϱ-Halogenated toluenes also have been investigated as substrates in these oxidations, and the corresponding cis -dihydrodiols isolated. Implications from the observation that some of the cis -dihydrodiols are racemic are discussed. Oxidation of an olefin, (±)-3-methylcyclohexene, by these microorganisms leads only to cis -diols whose absolute stereochemistry about the hydroxyl-bearing carbons is the same as that found for the cis -dihydrodiols formed from the aromatic substrates.

Optical activity of non-planar conjugated dienes—I : Homoannular cisoid dienes

Abstract A review is given of the results obtained so far in the investigation of the optical rotatory dispersion or circular dichroism of a number of non-planar homoannular cisoid dienes. The findings agree in every instance with the predictions of a theoretical rule connecting the sign of the Cotton effect with the chirality of the diene; two seeming exceptions can be explained through detailed conformational analysis. The rule can therefore serve as a reliable basis for stereochemical studies on this class of dienes. As expected theoretically, the amplitudes of the Cotton effects produced by these inherently dissymmetric chromophores are very high, values up to 100,000 deg mol−1 having been found. However, steroidal 1,3-dienes form a separate group characterized by comparatively low amplitudes, in many instances associated with a distinctive shape of the curve.

Optical activity of non-planar conjugated dienes—II : Transoid dienes

Abstract Earlier work1 has demonstrated that the sign of the Cotton effect associated with the longest wavelength electronic trnsition of a non-planar cisoid diene is determined by the helical sense of the diene system. The theoretical treatment has now been extended to non-planar transoid dienes and experimentally verified by determining the sign of the Cotton effect associated with a transoid diene (3-acetoxy-Δ8,14-cholestadiene) of unequivocal absolute configuration and skew sense. The optical rotatory dispersion of seven other transoid dienes has been determined and in all cases but one the sign of the measured Cotton effect agrees with the prediction.

Evidence for an enantioselective pumiliotoxin 7-hydroxylase in dendrobatid poison frogs of the genus Dendrobates.

Dendrobatid poison frogs readily accumulate alkaloids from diet into skin, where such compounds serve as a chemical defense against predators. Arthropods seem to be the source of decahydroquinolines (DHQs), several izidines, coccinellines, spiropyrrolizidines, pumiliotoxins (PTXs), and allopumiliotoxins (aPTXs). A DHQ iso-223F, and PTX (+)-251D were fed to poison frogs of the dendrobatid genera Dendrobates, Epipedobates, and Phyllobates. The two alkaloids were accumulated in skin unchanged except for the three species of Dendrobates, where ≈80% of accumulated PTX (+)-251D was stereoselectively hydroxylated to aPTX (+)-267A. The unnatural enantiomer PTX (-)-251D was accumulated efficiently when fed to Dendrobates auratus, but was not hydroxylated. The enantiomers of PTX 251D and their desmethyl analogs were synthesized from N-Boc-protected (-)- and (+)-proline methyl esters. Both PTX (+)-251D and aPTX (+)-267A proved to be potent convulsants in mice, with (+)-267A being ≈5-fold more toxic than (+)-251D. Both alkaloids were hyperalgesic at the site of injection. The unnatural PTX (-)-251D caused no overt effect in mice. Thus, the evolutionary development of a pumiliotoxin 7-hydroxylase would have provided frogs of the genus Dendrobates with a means of enhancing the antipredator potency of ingested PTXs.

Molecular vibrations of quinones—I. Fermi resonance involving the carbonyl stretch in p-benzoquinone and its isotopic derivatives

Abstract Infrared spectra in the region 1550–1700 cm −1 are reported for p -benzoquinone, four of its deuterated derivatives and two derivatives containing O 18 . Changes in the spectra with isotopic substitution and with solvent demonstrate conclusively the presence of Fermi resonance in quinone, quinone- d 4 and quinone-2,5- d 2 . A “hot band”, suggested recently as accounting for one of the three bands in this region in ordinary quinone, does not appear in the isotopic species.

Synthesis and antimalarial activities of base-catalyzed adducts of 11-azaartemisinin

A series of N-substituted 11-azaartemisinins were prepared in high yield employing base-catalyzed additions to an amide nitrogen of olefins and terminal acetylenes conjugated with electron withdrawing groups (EWGs). When the terminal acetylene was conjugated with carbomethoxy, N,N-dimethyl amide or carbonyl groups, the E-adducts resulted. A mixture of E- and Z-adducts were obtained when the EWG was a nitrile. In vitro antimalarial activities of each compound were determined against two drug-resistant strains of Plasmodium falciparum. Many of the compounds prepared were several times more active than artemisinin.

2-Amino-3-(methylamino)propanoic acid (BMAA) bioavailability in the primate

2-Amino-3-(methylamino)-propanoic acid (BMAA) is a low potency excitatory amino acid present in the cycad plant that has been proposed as a factor in the high incidence of amyotrophic lateral sclerosis-parkinsonism dementia (ALS-PD) in the western Pacific region. We employed stable isotopic forms of BMAA to assess the oral bioavailability of this compound in cynomolgous monkeys (n = 3). The stable isotope labeled BMAA ([15N]-BMAA) was injected i.v. at the same time that the unlabeled compound was administered orally. Both forms of BMAA were then quantified in a 48h urine sample by gas chromatography-mass spectrometry (GC/MS). Following oral dosing, 80% of the administered BMAA was absorbed into the systemic circulation; thus, oral bioavailability was high and other routes of administration could not result in significantly higher circulating levels of BMAA for a given administered dose.

The photochemistry of 3,5-disubstituted 1,4-dihydropyridines

Abstract On irradiation, 1,4-dihydropyridines have been shown to undergo three types of reaction: disproportionation, isomerization and dimerization. The presence of 2,6-substituents inhibits these reactions except in the case of 3a which undergoes disproportionation. The diester 10 and diketone 11 yield mixtures of the corresponding 1,2-isomers and photodimers. The structure and stereochemistry of the dimers derived from 10 have been established by X-ray and NMR methods to be head-to-tail anti, 17, and head-to-tail syn, 16. The latter compound cyclizes to the cage isomer 15 upon further irradiation.

Acid catalyzed michael additions to artemisitene

A series of 14-substituted-artemisinin and 9-epiartemisinin derivatives was prepared by a titanium-tetrachloride catalyzed addition of trimethylsilyl enol ethers to artemisitene. Several compounds were four to seven times more active than artemisinin against Plasmodium falciparum.

A photochemical rearrangement of β,γ-unsaturated cyclic ketones

Abstract Irradiation of the β,γ-unsaturated cyclic ketones I and IV results in an unusual rearrangement yielding the conjugated cyclopropyl ketones IIa and Va. The structures of the photoproducts were deduced from their spectroscopic properties and proved by converting the photoproducts to compounds of known structure. The photoproduct Va has been converted to a 10α methyl A-nor steroid. A possible mechanism for the reaction is discussed.