Lipophilic Functionalized Cobyrinic-Acid Derivatives. Part 1. Cobester α-monoacids (α,α,α,β,β,β-hexamethyl α-hydrogen Coα, Coβ-dicyanocobyrinates)

The four α,α,α, β,β,β,-hexamethyl α-hydrogen Coα, Coβ-dicyanocobyrinates 2b, d–f , with a free b-, d-, e-, and f-propionic-acid function, respectively, were prepared by partial hydrolysis of heptamethyl Coα, Coβ-dicyanocobyrinate (cobester; 1 ) in aqueous sulfuric acid. The cobester monoacids 2b, d–f were obtained as a ca. 1:1:1:1 mixture which was separated. The monoacids were purified by chromatography and isolated in crystalline form. The position of the free propionic-acid function was determined by an extensive analysis of 2b, d–f using 2D-NMR techniques; an analysis of the C,H-coupling network topology resulted in an alternative assignment strategy for cobyrinic-acid derivatives, based on pattern recognition. Additional information on the structure of the most polar of the four hexamethyl cobyrinates, of the b-isomer 2b , was also obtained in the solid state from a single-crystal X-ray analysis. Earlier structural assignments based on 1D-NMR spectra of the corresponding regioisomeric monoamides 3b, d–f (obtained from crystalline samples of the monoacids 2b, d–f ) were confirmed by the present investigations.     

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.     

Tordanone,un stéroïde replié avec une jonction de cycle A/B β-cis (5β) et B/C α-cis(8α)

Tordanone, a Twice Bent Steroid Structure with Ring A/B β-cis(5β)- and Ring B/C α-cis(8α)-Fused The 3β, 14α, 25-trihydroxy-5β, 8α-cholestan-6-one ( = tordanone; 4 ) has been prepared by stereospecific hydrogenation of 3β, 14α, 25-trihydroxy-5β-cholesta-7,22ξ-dien-6-one ( 5 ). This is the first stereospecific synthesis of a B/C cis-fused steroid belonging to the 5β, 8α -cholestane group with a H-atom at positions 5β (A/B cis-fused) and 8α. The resulting twice bent structure shows a particularly strong steric hindrance of the β-face where CH₃(18) at the C/D ring junction and H_β? C(7) of the B ring are very close to each other. Structural features and mechanistic aspects of the hydrogenation are discussed.     

Copper‐Catalyzed Bis(methoxycarbonyl)carbene Reactions of α,β‐Unsaturated Carboxamides

The [Cu(acac)₂]‐catalyzed reactions of α,β‐unsaturated carboxamides with dimethyl diazomalonate yielded dihydrofuran derivatives by a 1,5‐electrocyclic reaction at C(β), and butadiene derivatives by carbene addition reaction at C(α) (Schemes 4 and 5; Table). Phenyl substituents at the N‐atom of the amides seem to be effective on the reaction pathways (Table).     

Synthesis of β3‐Peptides and Mixed α/β3‐Peptides by Thioligation

Five β‐peptide thioesters ( 1 – 5 , containing 3, 4, 10 residues) were prepared by manual solid‐phase synthesis and purified by reverse‐phase preparative HPLC. A β‐undecapeptide ( 6 ) and an α‐undecapeptide ( 7 ) with N‐terminal β³‐HCys and Cys residues were prepared by manual and machine synthesis, respectively. Coupling of the thioesters with the cysteine derivatives in the presence of PhSH (Scheme and Fig. 1) in aqueous solution occurred smoothly and quantitatively. Pentadeca‐ and heneicosapeptides ( 8 – 10 ) were isolated, after preparative RP‐HPLC purification, in yields of up to 60%. Thus, the so‐called native chemical ligation works well with β‐peptides, producing larger β³‐ and α/β³‐mixed peptides. Compounds 1 – 10 were characterized by high‐resolution mass spectrometry (HR‐MS) and by CD spectroscopy, including temperature and concentration dependence. β‐Peptide 9 with 21 residues shows an intense negative Cotton effect near 210 nm but no zero‐crossing above 190 nm, (Figs. 2–4), which is characteristic of β‐peptidic 3₁₄‐helical structures. Comparison of the CD spectra of the mixed α/β‐pentadecapeptide ( 10 ) and a helical α‐peptide (Fig. 5) indicate the presence of an α‐peptidic 3.6₁₃ helix.     

β‐Hairpins Generated from Hybrid Peptide Sequences Containing both α‐ and β‐Amino Acids

The incorporation of the β‐amino acid residues into specific positions in the strands and β‐turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C(α) C(β) bond (θ) enhances the conformational repertoire in β‐residues. The conformational analysis of three designed peptide hairpins composed of α/β‐hybrid segments is described: Boc‐Leu‐Val‐Val‐^DPro‐β Phe ‐Leu‐Val‐Val‐OMe ( 1 ), Boc‐Leu‐Val‐β Val ‐^DPro‐Gly‐β Leu ‐Val‐Val‐OMe ( 2 ), and Boc‐Leu‐Val‐β Phe ‐Val‐^DPro‐Gly‐Leu‐β Phe ‐Val‐Val‐OMe ( 3 ). 500‐MHz ¹H‐NMR Analysis supports a preponderance of β‐hairpin conformation in solution for all three peptides, with critical cross‐strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a β‐hairpin conformation with two β‐residues occupying facing, non‐H‐bonded positions in antiparallel β‐strands. Notably, βVal(3) adopts a gauche conformation about the C(α) C(β) bond (θ=+65°) without disturbing cross‐strand H‐bonding. The crystal structure of 2 , together with previously published crystal structures of peptides 3 and Boc‐β Phe ‐β Phe ‐^DPro‐Gly‐β Phe ‐β Phe ‐OMe, provide an opportunity to visualize the packing of peptide sheets with local ‘polar segments' formed as a consequence of reversal peptide‐bond orientation. The available structural evidence for hairpins suggests that β‐residues can be accommodated into nucleating turn segments and into both the H‐bonding and non‐H‐bonding positions on the strands.     

5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成

以5-雄烯二醇为原料,用微生物转化的方法合成了两个重要的神经甾体5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇。所用菌种总枝毛霉为我们自己筛选,并首次应用于5-雄烯-3β, 7α, 17β-三醇和5-雄烯-3β, 7β, 17β-三醇的合成中。     

Umwandlung von Cardenoliden durch Mikroorganismen VI. 7β, 11α-Dihydroxydigitoxigenin und Abbau von 7β-Hydroxy-digitoxigenin zum 3β, 7β-Diacetoxy-14-hydroxy-5β, 14β, 17αH-ätiansäure-methylester. Mitteilung über Reaktionen mit Mikroorganismen [1]

Digitoxigenin ( 3 ) was transformed by a Fusarium spec. to 7β-hydroxydigitoxigenin ( 1 ) 1β, 7β-dihydroxydigitoxigenin ( 4 ) and to the hitherto unknown 7β, 11α-dihydroxydigitoxigenin ( 9 ). 7β-acetoxy-digitoxigenin ( 2 ) was degraded to methyl 3β, 7β-diacetoxy-14-hydroxy-5β, 14β, 17αH-etianate ( 11 ).     

Photochemische Reaktionen. 71. Mitteilung. Die Photoisomerisierung eines spirocyclischen α, β-Epoxyketons

On direct UV. irradiation and on triplet sensitization with acetophenone the spirocyclic epoxyketone (R)-(?)- 9 undergoes racemization (Φ^313/334 0.014, Φ^Sens 0.0060) and rearrangement to the enantiomeric spiro-β-diketones (R)-(+)- 14 (Φ^313/334 0.068, Φ^Sens 0.0037) and (S)-(?)- 14 (Φ^313/334 0.024, Φ^Sens 0.0023). The quantum yield data show that triplet reaction due to intersystem crossing is unimportant on direct irradiation, and they exclude that one common diradical intermediate of type d (Scheme 8) for the three reaction paths is involved in both the singlet and the triplet reaction. The postulate of photolytic Cα? O epoxide cleavage to intermediates of type d for the rearrangement requires that the rate of rearrangement is greater than the rate of rotation around the Cα? Cβ; bond in a given d , and that the rate difference is greater in singlet-generated d than in the triplet analogue. Reclosure of diradicals d and/or photolytic Cα? Cβ cleavage to diradical e and reclosure can account for the racemization of 9 . The optically active spiro-β-diketone 14 was found to racemize also on direct irradiation and on triplet sensitization. Furthermore, both 14 and the isomeric β-diketone 20 , which was obtained by UV. irradiation of the homocyclic epoxyketone 19 , photochemically isomerize to the enol lactones 23 and 21 , respectively.     

Reaction of Cα,O-dilithiooximes with functionalized carbonyl compounds. Part 2 . Reaction with α-chloroketones and α,β-unsaturated aldehydes and ketones

The reaction of Cα,O-Dilithiooximes 2 and α-chloroketones afforded 5-(hydroxymethyl)-Δ²-soxazolines 4 . α,β-Unsaturated aldehydes and ketones reacted with 2 to give the corresponding acyclic 1,2-addition products 5 . The latter were cyclized with phosphorus pentoxide to 5-vinyl-Δ²-isoxazolines 6 .     

Conjugate addition of grignard reagents to N-(α,β-unsaturated)acylpyrazoles. Diastereoselective β-alkylation using 3-phenyl-l-menthopyrazole

The conjugate additions of N-(α,β-unsaturated)acylpyrazoles were carried out by the treatment with Grignard reagents in the presence of cuprous halides. The reaction of 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3a-h occurred in higher chemical yields and with asymmetric inductions on β-position, where the addition of magnesium bromide as a Lewis acid influenced to the yields and the diastereoselectivities. In the case of α-methylated 2-(α,β-unsaturated)acyl-3-phenyl-l-menthopyrazoles 3i-n , the excellent asymmetric induction on the α-position was also observed through the diastereofacial protonation.     

Hydrolysis Reaction of N-Phosphoryl-α-, β- and γ-amino Acids Studied by HPLC

The hydrolysis reactions of N-（O,O＇diisopropyl）phosphoryl-L-α-alanine （DIPP-L-α-Ala）, N-（O,O＇diisopropyl）- phosphoryl-D-α-alanine （DIPP-D-α-Ala）, N-（O,O＇-diisopropyl）phosphoryl-β-alanine （DIPP-β-Ala） and N-（O,O＇-diisopropyl）phosphoryl-γ-amino butyric acid （DIPP-γ-Aba）, were studied by HPLC and their hydrolysis reaction kinetic equations were obtained. Under acid conditions, the reaction rate of DIPP-L-α-Ala was close to that of DIPP-D-α-Ala and the same rule was true between DIPP-β-Ala and DIPP-γ-Aba. Meantime, the reaction rate of DIPP-L/D-α-Ala was as 10 times as that of DIPP-β-Ala or DIPP-γ-Aba. Under basic conditions, the hydrolysis reactions of DIPP-β-Ala and DIPP-γ-Aba almost did not take place and the reaction rate of DIPP-L/D-α-Ala was about 1/10 of that under acid conditions. Moreover, theoretical calculation further illuminated the differences of the hydrolysis rate from the view of energy. The results would provide some helpful clues to why nature chose a-amino acids but not other kinds of analogs as protein backbones.     

Furopyridines. VIII. Molecular structure and two-dimensional NMR spectral assignment of 2,14-dimethyl-8aβ-hydroxy-7,10-dioxo-5β,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline

This paper reports the two-dimensional nmr spectral assignment and the X-ray structural determination of 2,14-dimethyl-8β-hydroxy-7,10-dioxo-5β,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline V which was obtained from 7,10-dimethyl-2β-hydroxy-14-oxo-2,3-(methanoiminoethano)-3β,4β-(propano)-3,4,5,6,7,8-hexahydro-2H-pyrano[2,3-c]pyridine IV by isomerization with hydrochloric acid. Both the compounds IV and V afforded the same dimethiodide IV -2MeI, while the configurational isomer 2,14-dimethyl-8aβ-hydroxy-7,10-dioxo-5α,6β-(propano)-6α,8α-(ethanoimino)-trans-perhydroisoquinoline III gave monomethiodide III -Mel. The structures of these methiodides were also confirmed by X-ray analysis.     

Configuration-Odor Relationships in 5β-Ambrox

The four possible A/B cis-fused diastereoisomers of Ambrox® have been synthesized and their configurations and conformations established by X-ray and NMR analysis. Only 5β-ambrox (= 1,2,3a,4,5,5β,6,7,8,9,9a,9bα-dodecahydro-3aβ,6,6,9aβ-tetramethylnaphtho[2,1-b]furan; 5 ) has an odor quality comparable to Ambrox®. The 1,3-synperiplanar/diaxial conformation of the substituents at C(8) ( = C(3a)) and C(10) (= C(9a)) has thus been confirmed to be a compulsory structure element for the particular odor.     

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).     

Studies on furan derivatives IV. A simple preparation of α-substituted β-(5-nitro-2-furyl)ethynyls from α-substituted β-(5-nitro-2-furyl)vinylamines

α-Substituted β-(5-nitro-2-furyl)ethynyls were conveniently prepared by the deamination of α-substituted β-(5-nitro-2-furyl)vinylamines. Also the application of this reaction toward α,β-bis(p-nitrophenyl)vinylamine was examined and afforded α,β-bis(p-nitrophenyl)ethynyl as the main product.     

β‐Peptide Conjugates: Syntheses and CD and NMR Investigations of β/α‐Chimeric Peptides,of a DPA‐β‐Decapeptide,and of a PEGylated β‐Heptapeptide

β³‐Peptides consisting of six, seven, and ten homologated proteinogenic amino acid residues have been attached to an α‐heptapeptide (all d‐ amino acid residues; 4 ), to a hexaethylene glycol chain (PEGylation; 5c ), and to dipicolinic acid (DPA derivative 6 ), respectively. The conjugation of the β‐peptides with the second component was carried out through the N‐termini in all three cases. According to NMR analysis (CD₃OH solutions), the (M)‐3₁₄‐helical structure of the β‐peptidic segments was unscathed in all three chimeric compounds (Figs. 2, 4, and 5). The α‐peptidic section of the α/β‐peptide was unstructured, and so was the oligoethylene glycol chain in the PEGylated compound. Thus, neither does the appendage influence the β‐peptidic secondary structure, nor does the latter cause any order in the attached oligomers to be observed by this method of analysis. A similar conclusion may be drawn from CD spectra (Figs. 1, 3, and 5). These results bode well for the development of delivery systems involving β‐peptides.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.     

Theoretical Prediction of Substituent Effects on the Intrinsic Folding Properties of β‐Peptides

A systematic conformational analysis on blocked β‐amino acids as constituents of β‐peptides by ab initio MO theory reveals that the conformer pool of β‐peptide monomers is essentially determined by the conformation of simple submonomer fragments. The influence of single and multiple substitutions at the C(α) and C(β) backbone atoms on the intrinsic folding properties of the monomers was estimated both in the single‐molecule approximation and in a polar solvent continuum, applying a quantum‐chemical SCRF model. Substitution at C(β) has a higher impact on the β‐amino acid conformation than a substitution at C(α). It can be shown that the conformations of important periodic secondary structures in β‐peptides belong to the conformer pool of the monomers, even for those secondary‐structure elements where H‐bond formation appears only in longer sequences. Rules for design of special secondary‐structure types by selection of an actual substituent pattern in the β‐amino acid constituents have been derived within the monomer approach.     

On the Reactivity of (−)‐(R)‐Carvone and (−)‐4aα,7α,7aβ‐Nepetalactone: Synthesis of New Heterocycles

The 1,3‐dipolar cycloaddition of 4‐chlorobenzonitrile oxide to the unsaturated system of (?)‐(R)‐carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with NH₂OH to yield a new heterocycle, observed for the first time. On the other hand, the addition of 4‐chlorobenzonitrile oxide to the unsaturated lactone (?)‐4aα,7α,7aβ‐nepetalactone gave, in a good yield, also a new heterocycle, again obtained for the first time. The terpenoid (?)‐(R)‐carvone and iridoid (?)‐4aα,7α,7aβ‐nepetalactone were isolated from Moroccan species Mentha viridis (L.) and Nepeta tuberosa (L.), respectively. The new heterocycles obtained were identified by combination of chromatographic and spectroscopic methods.