Dzhemilev reaction for the synthesis of spiro[3.3]heptane and spiro[3.4]octanes

For the first time cycloalumination of methylenecyclobutane with the aid of Et₃Al in the presence of Cp₂ZrCl₂ leading to 6-ethyl-6-aluminaspiro[3.4]octane has been realized. The latter, without isolation, was converted into spiro[3.3]heptane, 6-thiaspiro[3.4]octane and also spiro[3.4]octan-6-ol and 6-spiro[3.4]octyl formate with high yields and selectivity.     

Proton magnetic resonance spectra of 2,6-disubstituted naphthalenes

The spectra of several 2-methyl-6-R-disubstituted naphthalenes (R=H, Me, I, NO₂, Cl, SO₂Cl, OH, OMe, COMe, Br, F and NHCOMe), have been analysed. Chemical shift and coupling constant values of these compounds are presented. The proton chemical shifts have been found to correlate with the ortho parameter, Q.     

Nuclear magnetic resonance spectra of tropic acid and some derivatives

The NMR spectra of tropic acid, its methyl ester and acetyltropic acid methyl ester were measured at 100 and 220 MHz in various solvents. The spectra were analysed by means of an iterative computer procedure. The results indicate, for all the compounds studied, a predominance of the conformation where the phenyl and hydroxyl (or acetoxyl) groups are in anti.positions to each other. The solvent and concentration effects upon the vicinal coupling constants and hence upon the position of the conformational equilibria are rather weak.     

An ab initio molecular orbital study of structures and energies of spirocompounds: spiro[3.3]heptane and spiro[3.3]hepta-1,5-diene

Ab initio molecular orbital theory with the STO-3G and 4-31G basis sets is used to determine the equilibrium geometries, enthalpies of formation, strain energies and spiro-interactions for spiro[3.3]heptane and spiro[3.3]hepta -1,5 - diene. For spiro[3.3]heptane, molecular mechanics calculations suggest that the component cyclobutane rings are puckered to a greater extent than in cyclobutane itself. For spiro[3.3]hepta - 1,5 - diene, STO-3G calculations predict that the component cyclobutene rings deviate slightly from an orthogonal arrangement. Spiro-interactions in spiro[3.3]hepta - 1,5 - diene are revealed by comparing the calculated structural parameters and strain energies with those of appropriate reference systems. The π-orbitals in spiro[3.3]hepta -1,5 -diene are predicted to be split by about 0.4 eV.     

First synthesis of 2,6-diazabicyclo[3.2.0]heptane derivatives

The first synthesis of 6-phenyl-2,6-diazabicyclo[3.2.0]heptane 1 and its orthogonally protected precursor 2 is herein reported. Our strategy enables to chemically address the two nitrogen atoms of 2,6-diazabicyclo[3.2.0]heptane core individually and selectively, thus allowing rapid access to several subsets of widely substituted fused azetidines.     

Nuclear magnetic resonance spectra of codeine and isocodeine derivatives

The NMR spectra of a spiro oxirane ( 1 ) derivative of codeinone, codeine ( 2 ), isocodeine ( 3 ), 6-methylcodeine ( 4 ) and 6-methylisocodeine ( 5 ) were compared. NOE and double-resonance experiments were used to confirm the conformation of 1 , and the configuration about C-6 of 6-methylcodeine and 6-methylisocodeine. An interchange of the chemical shifts of the olefinic protons in 1 was noted, as compared with those in all of the other compounds. This interchange could be attributed to the bond anisotropies of the oxirane moiety.     

Nuclear magnetic resonance spectra and structure of some alkyl vinyl sulphides

The NMR spectra of eight alkyl vinyl sulphides have been analyzed and the parameters compared with those obtained from an analogous series of oxygen derivatives. It is shown that a definite parallelism exists between chemical shifts and H? H coupling. Difference in absolute values have been explained by mesomeric interaction involving the ability of sulphur to accommodate a decet of electrons in its valence shell. By analogy with alkyl vinyl ethers, it is possible to predict a similar correlation between the spectral characteristics and relative reactivity of vinyl sulphides in cationic polymerization.     

Spiro[3.3]heptane as a Saturated Benzene Bioisostere**

The spiro[3.3]heptane core, with the non-coplanar exit vectors, was shown to be a saturated benzene bioisostere. This scaffold was incorporated into the anticancer drug sonidegib (instead of the meta-benzene), the anticancer drug vorinostat (instead of the phenyl ring), and the anesthetic drug benzocaine (instead of the para-benzene). The patent-free saturated analogs obtained showed a high potency in the corresponding biological assays.     

Design of a new axially chiral molecule by conformational fixation: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide and its heavier analogues

We have designed a new axially chiral bis(sulfoxide) molecule with conformational rigidity: 2,6-dithiaspiro[3.3]heptane 2,6-dioxide 2a. This molecule has axial asymmetry due to two puckered thietane ring systems. The lone pairs on the sulfur show a strong s-character, which was expected to result in a high barrier to racemization, that is, inversion at the sulfur. We confirmed this prediction by calculations and experimentation. The lone pairs of the sulfur in 2a are sp^1.00 and the enthalpy of activation (ΔH³) for inversion is 47.5 kcal/mol (B3LYP/6-31G(d)). The ¹H NMR spectra of 2a showed two doublets and two doubled doublet peaks, which resulted from the rigidity of the four-membered ring frameworks without flipping. We separated the enantiomers of 2a by HPLC with a chiral stationary phase column to observe a set of complementary peaks. We also calculated the diselena- and ditellura congeners and confirmed that they also show axial chirality.     

Synthons for syntheses of spiro[2.4]heptane analogues of prostaglandins

Methods for the preparation of synthons for syntheses of spiro[2.4]heptane analogues of prostaglandins are described. Two of them (1a and1b) enable the syntheses of 11-deoxy-type compounds and were prepared from spiro[2.4]heptan-4-one (3) which after transformation into the 5-phenylthio-,-unsaturated ketone5 was subjected to conjugate addition of organocuprate reagent6. The third synthon (2)-a potential intermediate in syntheses of complete spiro[2.4]heptane analogues of prostaglandins-was prepared from the bicyclic ketone10 byBaeyer-Villiger oxidation followed by epoxidation.

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Ausgangsverbindungen für die Synthese von Prostaglandin-analogen Spiro[2.4]heptanen

Zusammenfassung Es werden Synthesewege für Spiro[2.4]hepane als Analoge zu Prostaglandinen beschrieben. Zwei davon (1a und1b) ermöglichen die Synthese von Verbindungen des 11-Deoxy-Typs; sie wurden aus Spiro[2.4]heptan-4-on (3) dargestellt, das nach der Umwandlung zum 5-phenylthio-,-ungesättigten Keton5 einer konjugierten Addition von Organocuprat-Reagens6 unterworfen wurde. Das dritte (2), ein potentielles Zwischenprodukt in der Synthese von vollständigen Spiro[2.4]heptan-Analogen zu Prostaglandinen, wurde aus dem bicyclischen Keton10 durchBaeyer-Villiger-Oxidation gefolgt von einer Epoxidierung dargestellt.

     

1-Azaspiro[3.3]heptane as a Bioisostere of Piperidine**

1-Azaspiro[3.3]heptanes were synthesized, characterized, and validated biologically as bioisosteres of piperidine. The key synthesis step was thermal [2+2] cycloaddition between endocyclic alkenes and the Graf isocyanate, ClO₂S−NCO, to give spirocyclic β-lactams. Reduction of the β-lactam ring with alane produced 1-azaspiro[3.3]heptanes. Incorporation of this core into the anesthetic drug bupivacaine instead of the piperidine fragment resulted in a new patent-free analogue with high activity.     

Electron impact mass spectrometry of some 2,11-diaza[3.3]cyclophane derivatives

The most significant mass spectral features of thirteen title compounds are discussed with the aid of high-resolution mass measurements and metastable peak analysis. The decomposition patterns of the compounds investigated are strongly affected by N-substitution and by methyl substituents ortho to the bridging chains (ortho effects). A unique feature connected with symmetrical macrocycles, bearing at least two ortho methyl substituents on each phenyl ring, is the presence in their spectra of diagnostically important peaks, corresponding to [M ? RNH₂]⁺˙ and [M ? 2RNH₂]⁺˙ (R = Ts, H, CH₃). These daughter ions are proposed to be associated with the formation of cage compounds (multibridged cyclophanes), generated by an intramolecular [4 + 4] cycloaddition reaction of unstable linear bis-(o-xylylene) precursors.     

Nuclear magnetic resonance and the conformation of some derivatives of Michler's ketone

¹H NMR spectra are reported for Michler's ketone and twenty of its derivatives, along with ¹³C chemical shifts for five of the compounds. ¹H chemical shifts show only small changes with increasing substitution at the sterically hindered 2-position. Estimates of the dihedral angle between the benzene ring and C? CO? C planes have been obtained from the chemical shifts of C?O and 4-C for ketones 1, 3, 5, 15 and 16 . These angles are both internally consistent and very similar to dihedral angles determined by other methods for corresponding compounds in the benzophenone series.     

Carbon-13 magnetic resonance spectra and the stereochemistry of some substituted bicyclo[2.1.1]hexanes

Using selective deuteriation and broad-band and off-resonance proton decoupling techniques, complete signal assignments are made for the ¹³C NMR spectra of a number of ketones and unsaturated esters with the bicyclo[2.1.1]hexane ring systems.     

Mass-spectrometric investigation of some 2,6-dimethyloxazolo[4,5-d]pyrimidine derivatives

The fragmentation of the molecular ions of 4-chloro- and 4-alkylamino -2,6-dimethyloxazolo[4,5-d]pyrimidines involves splitting out or fragmentation of the substituent in the 4 position or cleavage of the oxazole ring. The compositions of the fragment ions were determined on the basis of the high-resolution mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1255–1258, September, 1982.