Design of a new axially chiral molecule by conformational fixation: 2,6-diphospha- and 2,6-diarsaspiro[3.3]heptanes

We have designed a new axially chiral diphosphine that shows conformational rigidity: 2,6-diphosphaspiro[3.3]heptane 2a. This molecule has axial asymmetry due to puckering of the two phosphetane ring systems. Although its nitrogen congener 2,6-diazaspiro[3.3]heptane 1a is easily racemized, 2,6-diphosphaspiro[3.3]heptane 2a does not racemize at ambient temperature because the lone pairs on the phosphorus atoms have a strong s-character, which results in a high barrier to inversion at the phosphorus, that is, a high barrier to racemization. We also calculated the properties of the diarsa congener 3a and predicted that it also exhibits axial chirality and that it can be separated into enantiomers at ambient temperature.     

A dynamic NMR study of sulphur inversion in transition metal complexes of 2,6-dithiaspiro[3.3]heptane (2,6-DTSH), 2,6-DTSH-2-oxide and 2,6-DTSH-2,2-dioxide

The following complexes were synthesised [W(CO)₅L¹], [{W(CO)₅}₂L¹], [W(CO)₅L²], [W(CO)₅L³], [{PdCl₂(PPh₃)}₂L¹], [PdCl₂(PPh₃)L²] and [PdCl₂(PPh₃)L³] where L¹=2,6-dithiaspiro[3.3]heptane (2,6-DTSH), L²=2,6-DTSH-2-oxide and L³=2,6-DTSH-2,2′-dioxide. In solution these complexes exhibit pyramidal inversion of the metal-coordinated sulphur atom(s), rates and activation energies of which were evaluated by total NMR bandshape analysis. ΔG³ values were in the range 45–50 kJ mol⁻¹. These magnitudes are discussed in terms of ring geometry distortions and sulphur lone pair interactions.     

Nuclear magnetic resonance spectra of some 2,6-disubstituted spiro[3.3]heptane derivatives

Analysis of the full splitting pattern of the 100 MHz ¹H-NMR spectra of diethyl - 2,6 -dibromospiro[3.3]heptane - 2,6 - dicarboxylate (3) in chloroform and benzene and the 220 MHz ¹H-NMR spectrum of dimethylspiro[3.3]heptane - 2,6 - dicarboxylate (2) in naphthalene has been carried out. Puckering of the cyclobutane rings is revealed. Reasonable agreement with an X-ray study on Fecht acid (1) and with the data from the ¹C-NMR spectra of compounds 2 and 3 has been obtained. The temperature dependency of the ¹H-NMR spectra of 2, 3 and the symmetrically substituted tetraethylspiro[3.3]heptane - 2,2,6,6 - tetracarboxylate (4) has been investigated and is discussed in terms of conformational interconversion.     

Design of a new molecule that exhibits observable CD spectra under σ-σ* excitation: 2,6-Disilyl-2,6-disilaspiro[3.3]heptanes

Abstract

We previously designed and prepared the first molecules to exhibit observable CD spectra by n-σ* excitation, 2,6-dithiaspiro[3.3]heptane 2,6-dioxide. Spiro[3.3]heptane frameworks possess axial asymmetry due to puckering of 2 four-membered rings; the ring bonds are rich in p-character due to acute bond angles, which lowers the σ* energy levels. In contrast, the lone pairs are rich in s-character, which results in a good donor with conformational fixation. We expected that, instead of lone pairs as donating orbitals, the use of σ-electron-donating Si-Si bonds should result in UV absorption in the observable range (>180?nm), so that the Cotton effect could appear, at least partially, in that range. We designed 2,6-disilyl-2,6-disilaspiro[3.3]heptanes as models, and performed theoretical calculations to confirm our idea.     

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.     

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.     

Conformation of dithia[3.3]- and [2.2] azuleno(2,6)pyridinophanes

Four azuleno(2,6)pyridinophanes (1–4) were synthesized and their conformations were found by NMR spectroscopy to be very similar to those of the corresponding azulenometacyclophanes. A transverse conformational change was observed for [2.2](5,7)azuleno(2,6)pyridinophane.     

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.     

Expanding the azaspiro[3.3]heptane family: synthesis of novel highly functionalized building blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design.     

2,6-Diazaspiro[3.3]heptanes: synthesis and application in Pd-catalyzed aryl amination reactions

A concise and scalable synthesis of a 2,6-diazaspiro[3.3]heptane building block is reported. The usefulness of this structural surrogate of piperazine is shown in arene amination reactions yielding a variety of N-Boc- N'-aryl-2,6-diazaspiro[3.3]heptanes.     

C2-Symmetric bicyclo[3.3.1]nona-2,6-diene and bicyclo[3.3.2]deca-2,6-diene: new chiral diene ligands based on the 1,5-cyclooctadiene framework

As a new type of C₂-symmetric chiral diene ligands, which coordinate to a metal by their 1,5-cyclooctadiene framework, we prepared 2,6-disubstituted bicyclo[3.3.1]nona-2,6-diene (bnd*) and bicyclo[3.3.2]deca-2,6-diene (bdd*), and examined their catalytic activity and enantioselectivity for rhodium-catalyzed asymmetric 1,4-addition to α,β-unsaturated ketones and 1,2-addition to N-sulfonylimines. High enantioselectivity of the Ph-bnd* ligand was observed in the addition of phenylboroxine to N-tosylimine and N-4-nitrobenzenesulfonylimine of 4-chlorobenzaldehyde to give phenyl(4-chlorophenyl)methylamines in high enantiomeric excess (98–99% ee).     

Synthesis of chiral 2-furyl and 3-nitro-7-oxabicyclo[2.2.1]heptane derivatives from sugars

Asymmetric Diels–Alder reactions between 2-methylfuran and chiral (E)-1,2-dideoxy-1-nitroalkenes derived from d-mannose and d-galactose were carried out at room temperature, under 13 kbar pressure. The processes were completely regioselective, and only the four adducts with penta-O-acetyl-1′-C-(4-methyl-3-nitro-7-oxabicyclo[2.2.1]hept-5-en-2-yl)pentitols structures were formed in each case. These adducts, as well as those arising from cycloadditions of the same nitroalkenes and furan, have been converted into chiral derivatives, such as 2-furyl substituted 1-nitrosugars, 2-glyco-4-methyl-3-nitro-7-oxabicyclo[2.2.1]heptanes, and 5,6-exo-epoxy-2-glyco-3-nitro-7-oxabicyclo[2.2.1]hept-5-enes.     

Intramolecular hydrogen abstraction promoted by N-radicals: synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems

Homochiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems can be synthesized by reaction of specifically protected phosphoramidate derivatives of carbohydrates with (diacetoxyiodo)benzene or iodosylbenzene and iodine. The reaction mechanism goes through homolytic fragmentation of a hypothetical iodoamide intermediate. The N-radicals so generated participate in an intramolecular hydrogen abstraction reaction (IHA) to give the aforementioned bicycles.     

A quantum chemical study of tricyclo[3.2.0.0]heptane: a new hypothetical molecule with unusual spatial structure. Similarities and differences with syn- and anti-tricyclo[3.2.0.0]heptanes

HF and MP2 calculations with the 6-31G^∗∗ and 6-311G^∗∗ basis sets for the titled molecules and those at MP2/cc-pVTZ level for the hypothetical tricyclo[3.2.0.0^1,3]heptane indicate that the latter molecule should have a carbon atom with highly unusual configuration strongly departing from the tetrahedral one. Both analysis of vibrational frequencies of this molecules and comparison of its energy with those of known isomeric syn- and anti- tricyclo[3.2.0.0^2,4]heptanes as well as the DFT analysis of its plausible decomposition routes performed at the DFT level indicate that it could be a plausible synthetic target.     

Synthesis and conformational properties of 5,7-disubstituted [3.3] Metacyclo (2,5) thiophenophane-1,12-diones

The title compounds showed unique conformational equilibria which were dependent upon the substituents in the 5,7-positions, the predominant conformers being in a $\text{syn}$ O,S,O-$\text{cis}$,$\text{cis}$ conformation with a highly deformed thiophene-2,5-dicarbonyl moiety.     

Design,synthesis and structure determination of new inherently chiral para-bromoalkoxycalix[4]arenes

The preparative method for the synthesis of inherently chiral para-bromoalkoxycalix[4]arenes based on para-bromination, stepwise regioselective debenzoylation and the following alkylation of the readily available 25-propoxy-26,27-dibenzoyloxycalix[4]arene with propyl bromide or (R)-N-(1-phenylethyl)bromoacetamide has been developed. Three types of the inherently chiral calix[4]arenes in cone or partial cone conformations with asymmetrical (_AHHH^HBHH, _AAHH^HBHH, _AHBH^HCHH) substitution of both upper and lower rims have been obtained in racemic, diastereomerically pure or enantiomerically pure forms. Their structure and the absolute configuration have been determined by NMR and X-ray.     

Design of a novel inherently chiral calix[4]arene for chiral molecular recognition

A newly designed inherently chiral calix[4]arene was synthesized and resolved to an optically pure form. Enantiomeric recognition ability of the chiral calix[4]arene was examined using 1H NMR experiments with mandelic acid. In addition, the chiral calix[4]arene was applied to asymmetric reactions, as an organocatalyst.