The Crystal and Molecular Structure of 3-Oxo-17β-acetoxy-Δ4-14α-methyl-8α, 9β, 10α, 13α-estrene

The crystal and molecular structure of 3-oxo-17β-acetoxy-Δ⁴-14α-methyl-8α, 9β, 10α, 13α-estrene, C₂₁H₃₀O₃, has been determined by X-ray diffraction analysis. The crystals belong to the orthorhombic space group P2₁2₁2₁, with the cell dimensions a = 12.093 Å, b = 19.667 Å, c = 7.746 Å; Z = 4. Intensity data were collected at room temperature with an automatic four-circle diffractometer. The structure was solved by direct methods and the parameters were refined by least-squares analysis. All the hydrogen atoms were included in the refinement. The final R value was 0.038 for 1413 observed reflections. The conformation of ring A is intermediate between a half-chair and a 1, 2-diplanar form. The hydrogens at C(9) and C(10) are anti, the B/C ring junction is trans, and rings B and C adopt chair conformations. Ring D is cis fused and is halfway between C₂ and C_s forms.     

Kinetics of the reactions of cyclopropane derivatives. V. The gas-phase unimolecular reactions of 1 α-chloro-2α,3α-dimethylcyclopropane and 1α-chloro-2α,3β-dimethylcyclopropane

Thermolysis of the “all-cis” compound 1α-chloro-2α,3α-dimethylcyclopropane (A) at 550–607 K and 6–115 torr is a first-order homogeneous non-radical-chain process giving penta-1,3-diene (PD) and HCl as products. The Arrhenius parameters are log₁₀A(sec^?1) = 13.92 ± 0.08 and E = 199.6 ± 0.9 kJ/mol. The isomer with trans-methyl groups, 1α-chloro-2α,3β-dimethylcyclopropane (B) reacts by two parallel first-order processes giving as observed products trans-4-chloropent-2-ene (4CP) and PD + HCl, with log₁₀A(sec^?1) = 14.6 and 13.8, respectively, and E = 199.5 and 190.2 kJ/mol, respectively. The 4CP undergoes secondary decomposition to PD + HCl (as investigated previously). Comparison of the results for compounds (A) and (B) with those for other gas-phase and solution reactions leads to the conclusion that the gas-phase thermolyses proceed by rate-determining ring opening to form olefins which may decompose further by thermal or chemically activated reactions, and that the ring opening is a semiionic electrocyclic reaction in which alkyl groups in the 2,3-positions trans to the migrating chlorine semianion move apart, with appropriate consequences for the rate of reaction and the stereochemistry of the products.     

Destabilized carbenium ions: α-carbomethoxy-α,α-dimethyl-methyl cations

Tertiary α-carbomethoxy-α,α-dimethyl-methyl cations a have been generated by electron impact induced fragmentation from the appropriately α-substituted methyl isobutyrates 1–4. The destabilized carbenium ions a can be distinguished from their more stable isomers protonated methyl methacrylate c and protonated methyl crotonate d by MIKE and CA spectra. The loss of I^— and Br˙ from the molecular ions of 1 and 2, respectively, predominantly gives rise to the destabilized ions a, whereas loss of Cl˙ from [3]^{+ ˙} results in a mixture of ions a and c. The loss of CH₃˙ from [4]⁺˙ favours skeletal rearrangement leading to ions d. The characteristic reactions of the destabilized ions a are the loss of CO and elimination of methanol. The loss of CO is associated by a very large KER and non-statistical kinetic energy release (T₅₀ = 920 meV). Specific deuterium labelling experiments indicate that the α-carbomethoxy-α,α-dimethyl-methyl cations a rearrange via a 1,4-H shift into the carbonyl protonated methyl methacrylate c and eventually into the alkyl-O protonated methyl methacrylate before the loss of methanol. The hydrogen rearrangements exhibit a deuterium isotope effect indicating substantial energy barriers between the [C₅H₉O₂]⁺ isomers. Thus the destabilized carbenium ion a exists as a kinetically stable species within a potential energy well.     

Mass spectra of some α-substituted phenyl-α,α′-dimethoxyl ketones and their derivatives

The mass spectra of some α-substituted phenyl-α,α′-dimethoxyl ketones (compounds 1) and their 2,4-dinitrophenylhydrazones (compounds 2) and semicarbazones (compounds 3) have been studied. The characteristic fragments at m/z (M ? 73) from compounds 1, m/z (M ? 253) from compounds 2 and m/z (M ? 130) from compounds 3 are abundant and proposed to be [ArCROCH₃]⁺. Fragmentations yielding [M⁺ ? 49] from compounds 2 are abnormal and probably involve the methoxyl and nitro groups. The intense peak at m/z 130 due to [CH₃OCH₂CNNHCONH₂]⁺ from compounds 3 corresponds to α-cleavage of the molecular ion. Some other fragments from these new compounds are interpreted in this paper.     

Polymerization of α-methylene-N-methylpyrrolidone

α-Methylene-N-methylpyrrolidone (α-MMP) was synthesized and homopolymerized by bulk and solution methods. The poly(α-MMP) is readily soluble in water, methanol, methylene chloride, and dipolar aprotic solvents at room temperature. Thermogravimetric analysis of poly(α-MMP) showed a 10% weight loss at 330°C in air. The kinetics of α-MMP homopolymerization and copolymerization were investigated in acetonitrile, using azobisisobutyronitrile (AIBN) as an initiator. The rate of polymerization R_p could be expresed by R_p = k[AIBN]^0.49[α-MMP]^1.3. The overall activation energy was calculated to be 84.1 kj/mol. The relative reactivity ratios of α-MMP (M₂) copolymerization with methyl methacrylate (r₁ = 0.59, r₂ = 0.26) in acetonitrile were obtained. Applying the Q-e scheme led to Q = 2.18 and e = 1.77. These Q and e values are larger than those for acrylamide derivatives.     

A Chirally Stable,Atropoisomeric, Cα‐Tetrasubstituted α‐Amino Acid: Incorporation into Model Peptides and Conformational Preference

A variety of model peptides, including four complete homologous series, to the pentamer level, characterized by the recently proposed binaphthyl‐based, axially chiral, C^α‐tetrasubstituted, cyclic α‐amino acid Bin, in combination with Ala, Gly, or Aib residues, was synthesized by solution methods and fully characterized. The solution conformational propensity of these peptides was determined by FT‐IR absorption and ¹H‐NMR techniques. Moreover, the molecular structures of the free amino acid (S)‐enantiomer and an N^α‐acylated dipeptide alkylamide with the heterochiral sequence ‐(R)‐Bin‐Phe‐ were assessed in the crystal state by X‐ray diffraction. Taken together, the results point to the conclusion that β‐bends and 3₁₀ helices are preferentially adopted by Bin‐containing peptides, although the fully extended conformation would also be adopted in solution by the short oligomers to some extent. We also confirmed the tendency of (R)‐Bin to fold a peptide chain into right‐handed bend and helical structures. The absolute configuration of the Bin residue(s) was correlated with the typically intense exciton‐split Cotton effect of the ¹B_b binaphthyl transition near 225 nm.     

Radical-initiated homo- and copolymerization of α-methylene-γ-butyrolactone

The kinetics of α-methylene-γ-butyrolactone (α-MBL) homopolymerization was investigated in N,N-dimethylformamide (DMF) with azobis(isobutyronitrile) as initiator. The rate of polymerization (R_p) was expresed by R_p = k[AIBN]^0.54[α-MBL]^1.1 and the overall activation energy was calculated as 76.1 kJ/mol. Kinetic constants for α-MBL polymerization were obtained as follows: k_p/k_t^1/2 = 0.161 L^1/2 mol^?1/2·s^?1/2; 2fk_d = 2.18 × 10^?5 s^?1. The relative reactivity ratios of α-MBL(M₂) copolymerization with styrene (r₁ = 0.14, r₂ = 0.87) were obtained. Applying the Q–e scheme led to Q = 2.2 and e = 0.65. These Q and e values for α-MBL are higher than those for MMA     

Atomic Xα calculations based on EHFS(α) = Eexp

The total energies and one-electron energies for first- and second-row atoms were calculated by using the Hartree–Fock and the Hartree–Fock-Slater Hamiltonian with X_α orbitals, u_i(α_exp); α was parametrized from E^HFS (α_exp) = E^exp. The E^HF (α_exp) total energies are always higher than the Hartree–Fock energies for the atoms. The relation of the calculated ionization potential to the experimental ionization potential depends on the α used to define u_i(α), α_exp, or α_HF.     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

Synthesis of Phenanthrene Derivatives through the Reaction of an α,α‐Dicyanoolefin with α,β‐Unsaturated Carbonyl Compounds

Phenanthrene derivatives were prepared by reacting an α,α‐dicyanoolefin with different α,β‐unsaturated carbonyl compounds resulting from Wittig reaction of ninhydrin and phosphanylidene or condensation of barbituric acid and an aldehyde. The easy procedure, mild and metal‐catalyst free, reaction conditions, good yields, and no need for chromatographic purifications are important features of this protocol. The structures of the product of type 3 and 5 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 1).     

Polymerization of styrene oxide catalyzed by a diethylzinc/α-pinene oxide system

Styrene oxide (SO) was polymerized with a diethylzinc/α-pinene oxide (ZnEt₂/α-PiO) catalyst system under various conditions. Polystyrene oxide (PSO) thus obtained had a regular head-to-tail and isotactic structure. The number-average molecular weight reached 4.07 × 10⁴, and the molecular weight distribution was 5.7 (M_w/M_n). The glass-transition temperature of PSO was about 47 to 50 °C, depending on the molecular weight. The molar ratio of ZnEt₂ to α-PiO, 2 : 1, led to a high molecular weight of PSO in an 89.2% yield within 72 h. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4640–4645, 1999     

Kupplung von Peptiden mit C-terminalen α,α-disubstituierten α - Aminosäuren via Oxazol-5(4H)-one

Peptide-Bond Formation with C-Terminal α,α-Disubstituted α - Amino Acids via Intermediate Oxazol-5(4H)-ones The formation of peptide bonds between dipeptides 4 containing a C-terminalα,α-disubstituted α-amino acid and ethyl p-aminobenzoate ( 5 ) using DCC as coupling reagent proceeds via 4,4-disubstituted oxazol-5(4H)-ones 7 as intermediates (Scheme 3). The reaction yielding tripeptides 6 (Table 2) is catalyzed efficiently by camphor-10-sulfonic acid (Table 1). The main problem of this coupling reaction is the epimerization of the nonterminal amino acid in 4 via a mechanism shown in Scheme 1. CSA catalysis at 0° suppresses completely this troublesome side reaction. For the coupling of Z-Val-Aib-OH ( 11 ) and Fmoc-Pro-Aib-OH ( 14 ) with H-Gly-OBu¹ ( 12 ) and H-Ala-Aib-NMe₂ ( 15 ), respectively, the best results have been obtained using DCC in the presence of ZnCl₂ (Table 3).     

Aminocyclopentitol Inhibitors of α‐L‐Fucosidases

Aminocyclopentitol analogs of α‐L ‐fucose were synthesized stereoselectively from D ‐ribose. Alkyl substituents were attached at the NH₂ group to mimic the glycosidic leaving group. The resulting (alkylamino)cyclopentitols inhibited α‐L ‐fucosidases selectively with inhibition constants in the range of K_i=10⁻⁷ M . Comparisons with stereoisomers and acyclic analogs showed that this inhibition only occurs with N‐alkyl substitution and proper configuration at the cyclopentane, as expected for transition‐state‐analog‐type inhibition. These observations were supported by molecular‐modeling comparisons between inhibitor and transition state.     

α-D-Glycosyl-Substituted α,α-D-Trehaloses with (1 → 4)-Linkage: Syntheses and NMR Investigations

Two symmetrical trehalose glycosyl ‘acceptors’ 4 and 6 were prepared and three of the unsymmetrical type, 8 , 10 , and 11 . Glucosylation of symmetrical ‘acceptor’ 4 gave a higher yield of trisaccharide (44%) than protect ve-group manipulation, namely via selective debenzylidenation 2 → 9 or monoacetylation 2 → 5 which proceeded in moderate yields (33–34%). A comparison of catalysts in the cis-glucosylation of trehalose ‘acceptor’ 10 with tetra-O-benzyl-β-D -glucopyranosyl fluoride 13 profiled triflic anhydride ((Tf)₂O) as a new reactive promoter yielding 92% of trisaccharide 14 , deblocking gave the target saccharide α-D -glucopyranosyI-( 1 → 4 )-α,α-D -trehalose. ¹H-NMR spectra of most compounds were analyzed extensively. The use of the ID TOCSY technique is advocated for its time efficiency, if needed supplemented by ROESY experiments.     

Radical polymerization of N-phenyl-α-methylene-β-lactam

N-phenyl-α-methylene-β-lactam (PML), a cyclic analog of N,N-disubstituted methacrylamides which do not undergo radical homopolymerization, was synthesized and polymerized with α,α′-azobis (isobutyronitrile) (AIBN) in solution. Poly (PML) (PPML) is readily soluble in tetrahydrofuran, chloroform, pyridine, and polar aprotic solvents but insoluble in toluene, ethyl acetate, and methanol. PPML obtained by radical initiation is highly syndiotactic (rr = 92%), exhibits a glass transition at 180°C, and loses no weight upto 330°C in nitrogen. The kinetics of PML homo-polymerization with AIBN was investigated in N-methyl-2-pyrrolidone. The rate of polymerization (R_p) can be expressed by R_p = k[AIBN]^0.55[PML]^1.2 and the overall activation energy has been calculated to be 87.3 kJ/mol. Monomer reactivity ratios in copolymerization of PML (M₂) with styrene (M₁) are r₁ = 0.67 and r₂ = 0.41, from which Q and e values of PML are calculated as 0.60 and 0.33, respectively.     

Preparation and Mechanism of Solvolysis of N-Hydroxy-α-oxobenzeneethanimidoyl Chloride,a 2-(Hydroxyimino)-1-phenylethan-1-one Derivative: Molecular Structure of α-Oxo-oximes (=α-(Hydroxyimino) Ketones)

Acid-catalyzed methanolysis of N-hydroxy-α-oxobenzeneethanimidoyl chloride ( 1 ), a 2-(hydroxyimino)-1-phenylethan-1-one derivative obtained in one step from acetophenone, leads to a constant ratio of methyl α-oxobenzeneacetate ( 2 ) and methyl α-(hydroxyimino)benzeneacetate ( 3 ). ¹³C(α) Labelled [¹³C]- 1 affords ¹³C(α) labelled [¹³C]- 3 , thus discarding the hypothesis of its formation via 1,2-arene migration. The reported sequence opens a novel approach to phenylglyoxylic and mandelic acid esters (=α-oxobenzeneacetic and α-hydroxybenzeneacetic acid esters), from acetophenone. The molecular structures of 1 and 3 were determined by X-ray structure analysis and compared with previously reported crystallographic data of α-oxo-oximes (=α-(hydroxyimino) ketones) 4 and 6 – 8 . The unique stereoelectronic characteristics of the α-oxo-oxime moiety are discussed. All α-oxo-oximes share the following structural characteristics: (E)-configuration of the oxime C=N−OH bond (i.e. OH and C=O trans), the s-trans conformation of the oxo and imino moieties about the C(α)-C(=NOH) single bond, and intermolecular H-bonding. They differ from the isostructural β-diketone enols by the absence of resonance-assisted intramolecular H-bonding.     

Geiparvarin Analogues: Synthesis and Anticancer Evaluation of α-Methylidene-γ-butyrolactone-Bearing Coumarins

To determine some of the structural features of geiparvarin that account for its cytostatic activity in vitro, certain geiparvarin analogues modified in the furan-3(2H)-one moiety and the alkenyloxy substituent were synthesized and tested against the growth of 60 human cancer cell lines derived from nine cancer-cell types. These compounds demonstrated a strong growth-inhibitory activity against leukemia cell lines but were relatively inactive against non-small-cell lung cancers and CNS cancers. Comparison of the mean log GI₅₀ values of γ-[(E)-1-methylprop-1-enyl]-α-methylidene-γ-butyrolactones 7 – 9 revealed that 7-[(E)-3-(2,3,4,5-tetrahydro-4-methylidene-5-oxofuran-2-yl)but-2-enyloxy]-2H- 1-benzopyran-2-one ( 8 ; −5.47) was more active than its 6-substituted counterpart 7 (−5.21) and its 3-chloro-4-methyl derivative 9 (−5.31) and had a potency similar to that of geiparvarin (log GI₅₀=−5.41). These results indicated that the furan-3(2H)-one moiety of geiparvarin could be replaced by an α-methylidene-γ-butyrolactone unit without losing the anticancer potency, and that the best substitution site at the coumarin moiety was C(7). The alkenyloxy substituent of 8 was also replaced by a methoxy substituent. Among these α-methylidene-γ-butyrolactones, 7-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-phenylfuran-2-yl)methoxy]-2H-1-benzopyran-2-one ( 11 ) was the most potent with a mean log GI₅₀ value of −5.83 and a range value of 132 (10^2.12).     

Some properties of poly-α-piperidone

The high molecular weight polymer of α-piperidone, which had been unobtainable with the use of alkali metal, trialkyl aluminum, or Grignard reagent as catalyst, was prepared with M–AlEt₃, (where M is alkali metal), MAlEt₄ or KAlEt₃ (piperidone) as catalyst and N-acyl-α-piperidone as initiator. From the determination of the behavior of the solution viscosity of poly-α-piperidone in m-cresol at 30°C. the value of 0.27 for the Huggins constant was obtained. Examination of the correlation between the number-average molecular weight, determined by endgroup titration, and the intrinsic viscosity gave a somewhat small value for the endgroup COOH. This may be considered due to the consumption of N-acyl-α-piperidone by a propagating polymer in the course of polymerization. The thermal stabilities of the polyamides, nylons 4, 5, and 6, was in the order nylons 6 > 5 > 4 according to differential thermal and thermogravimetric analyses, Poly-α-piperidone, which has a reduced viscosity of 0.7, shows a melting point of 270°C.. which was expected from the zigzag pattern of the correlation between melting points and numbers of CH₂ groups for polyamino-acid polymers.     

Preparation of N-Fmoc-Protected β2- and β3-Amino Acids and their use as building blocks for the solid-phase synthesis of β-peptides

N-Fmoc-Protected (Fmoc = (9H-fluoren-9-ylmethoxy)carbonyl) β-amino acids are required for an efficient synthesis of β-oligopeptides on solid support. Enantiomerically pure Fmoc-β³-amino acids β³: side chain and NH₂ at C(3)(= C(β)) were prepared from Fmoc-protected (S)- and (R)-α-amino acids with aliphatic, aromatic, and functionalized side chains, using the standard or an optimized Arndt-Eistert reaction sequence. Fmoc-β²- Amino acids (β² side chain at C(2), NH₂ at C(3)(= C(β))) configuration bearing the side chain of Ala, Val, Leu, and Phe were synthesized via the Evans' chiral auxiliary methodology. The target β³-heptapeptides 5–8 , a β³- pentadecapeptide 9 and a β²-heptapeptide 10 were synthesized on a manual solid-phase synthesis apparatus using conventional solid-phase peptide synthesis procedures (Scheme 3). In the case of β³-peptides, two methods were used to anchor the first β-amino acid: esterification of the ortho-chlorotrityl chloride resin with the first Fmoc-β-amino acid 2 (Method I, Scheme 2) or acylation of the 4-(benzyloxy)benzyl alcohol resin (Wang resin) with the ketene intermediates from the Wolff rearrangement of amino-acid-derived diazo ketone 1 (Method II, Scheme 2). The former technique provided better results, as exemplified by the synthesis of the heptapeptides 5 and 6 (Table 2). The intermediate from the Wolff rearrangement of diazo ketones 1 was also used for sequential peptide-bond formation on solid support (synthesis of the tetrapeptides 11 and 12 ). The CD spectra of the β²- and β³-peptides 5 , 9 , and 10 show the typical pattern previously assigned to an (M) 3₁ helical secondary structure (Fig.). The most intense CD absorption was observed with the pentadecapeptide 9 (strong broad negative Cotton effect at ca. 213 nm); compared to the analogous heptapeptide 5 , this corresponds to a 2.5 fold increase in the molar ellipticity per residue!     

Polymerization of α-piperidone with M–AlEt3, MAlEt4, or KAlEt3(piperidone) as catalysts and N-acetyl-α-piperidone as initiator

Low-temperature polymerization of α-piperidone was carried out by using MAlEt₄, KAlEt₃(piperidone), and M–AlEt₃ (where M is Li, Na, or K) as catalysts and N-acetyl-α-piperidone as initiator. The behavior in polymerization of these catalysts was superior to alkali metal or aluminum triethyl, and a polymer having an intrinsic viscosity of 0.8 dl./g. was obtained. Polymerization results and infrared analyses of the metal salts of lactams suggest that a complex, the structure of which was analogous to the one formed from M–AlEt₃, is formed in the case of the alkali metal piperidonate–ethyl aluminum dipiperidonate catalyst system and that it is changed to another complex having a different composition and lower catalytic activity by heat treatment. The infrared absorption band of the metal salts of lactams and of KAlEt₃(piperidone) at 1570–1590 cm.^?1, which is attributable to the C?N group in enolate form, may be considered to be related to the catalytic activities of alkali metals and the polymerizabilities of lactams. Such special catalysts as MAlEt₄, alkali metal–AlEt₃, or KAlEt₃(piperidone) are supposed to suppress the consumption, by alkali metal, of N-acyl-α-piperidone group of growing polymer end. A prolonged polymerization required for obtaining a high molecular weight polymer, even when such catalysts are used, is ascribable to a greater difficulty in re-forming lactam anion from α-piperidone, the basicity of which is higher than that of the other lactams.