Cob(I)alamin als Katalysator, 5. Mitteilung [1]. Enantioselektive Reduktion α,β-ungesättigter Carbonylderivate

Cob(I)alamin as Catalyst. 5. Communication [1]. Enantioselective Reduction of α,β-Unsaturated Carbonyl Derivatives The cob(I)alamin-catalyzed reduction of an α,β-unsaturated ethyl ester in aqueous acetic acid produced the (S)-configurated saturated derivative 2 with an enantiomeric excess of 21%. The starting material 1 is not reduced at pH = 7.0 in the presence of catalytic amounts of cob(I)alamin (see Scheme 2). It is shown that the attack of cob(I)alamin and not of cob(II)alamin, also present in Zn/CH₃COOH/H₂O, accounts for the enantioselective reduction observed. All the (Z)-configurated starting materials 1 , 3 , 5 , 7 , 9 and 11 have been transformed to the corresponding (S)-configurated saturated derivatives 2 , 4 , 6 , 8 , 10 and 12 , respectively. The highest enantiomeric excess revealed to be present in the saturated product 12 (32,7%, S) derived from the (Z)-configurated methyl ketone 11 (see Scheme 3 and Table 1). The reduction of the (E)-configurated starting materials led mainly to racemic products. A saturated product having the (R)-configuration with a rather weak enantiomeric excess (5.9%) has been obtained starting from the (E)-configurated methyl ketone 23 (see Scheme 5 and Table 2). The allylic alcohols 16 and 24 have been reduced to the saturated racemic derivative 17 .     

Cob (I)alamin als Katalysator. 3. Mitteilung [1]. Untersuchungen in Richtung einer enantioselektiven Reduktion α,β-ungesättigter Ester

Cob (I)alamin as Catalyst 3. Communication [1]. Examination of an Enantioselective Reduction Using α,β-Unsaturated Esters α,β-Unsaturated esters can be reduced to the corresponding saturated esters using catalytic amounts of cob (I)alamin in the presence of an excess of zinc. An enantioselective reduction has been observed starting from ethyl (Z)-3-methyl-5-phenyl-2-pentenoate (7).     

Cob(I)alamin als Katalysator. Retention der Konfiguration bei der reduktiv-protonenübertragenden Spaltung der Co,C-Bindung eines Alkylcobalamins. 7. Mitteilung [1]

Cob(I)alamin as Catalyst. 7. Communication [1]. Retention of Configuration during the Reductive Cleavage of the Co, C-Bond of an Alkylcobalamin Using catalytic amounts of cob(I)alamin (see Scheme 1) in aqueous acetic acid (?)-α-pinen ( 1 ) and (?)-β-pinen ( 2 ; s. Scheme 3) have been reduced. A large excess of metallic zinc served as electron source. The saturated products 5–8 (see Scheme 3) and the mechanistic aspects of their generation are discussed. The relative amounts of cis- ( 5 ) and trans-pinane ( 6 ) lead to the conclusion that the reductive cleavage of the Co, C-bond accompanied by H⁺ transfer in an alkylcobalamin occurs with retention of configuration. This result is in agreement with the corresponding cleavage of the Co,C-bond of an alkyl[hydroxy-diazaoctahydroporphinato]cobalt complex [9].     

Cob(I)alamin als Katalysator 2. Mitteilung [1]. Reduktion von gesättigten Nitrilen in wasserfreier Lösung

Cob (I)alamin as Catalyst 2. Communication [1]. Reduction of Saturated Nitriles in Anhydrous Solution Using cob (I)alamin as homogenous catalyst in glacial acetic acid saturated nitriles are reduced following the path of a reductive amination. The results prove the presence of an intermediate imine during the reduction of saturated nitriles with cob (I)alamine.     

Skeletal Migrations Observed during the Cob(I)alamin-Catalyzed Reduction of 4β-(tert-Butyl)-1β-(1-methylvinyl)cyclohexanecarbaldehyde

During the cob(I)alamin( 1(I) )-catalyzed reduction of 3 , intermediate formation of 2 and final generation of 4–10 was observed (see Scheme 1, cf. Tables 1 and 2). Identical products in similar ratios were generated starting from either 2 or 3 . Accepting the intermediate formation of six interconnected cobalt complexes, i.e. A–F (cf. Scheme 2), the generation of all the products observed can be explained.     

Cob(I)alamin als Katalysator. 6. Mitteilung [1]. Bildung und Fragmentierung von Alkylcobalaminen,ein Gleichgewichtsprozess zwischen nukleophiler Addition und reduktiver Fragmentierung

Cob(I)alamin as Catalyst. 6. Communication [1]. Formation and Fragmentation of Alkylcobalamins: the Nucleophilic Addition – Reductive Fragmentation Equilibrium Isolated olefines can be saturated using catalytic amounts of cob(I)alamin in aqueous acetic acid; as electron source an excess of zinc dust is added to the solution containing the homogeneous catalyst. During this overall hydrogenation of isolated double bonds intermediate alkylcobalamins are formed (compare e.g. Schemes 2, 4, 5, 7 and 12). Clear evidence is presented that the nucleophilic attack on the isolated double bond is carried out by cob(I)alamin and not by cob(II)alamin also present in the system (see Scheme 3b and 3c). As this catalytic saturation of olefins depends on the pH of the solution, characterized by a slow reaction at pH = 7.0 compared to the same reduction in aqueous acetic acid (see Scheme 2, 2 → 4 , and Scheme 3a), it is reasonable to accept the participation of an electrophilic attack by a proton during the generation of alkylcobalamins. – We use the term nucleophilic addition to describe the formation of alkylcobalamins from a proton, an olefin and cob(I)alamin (compare Schemes 4–7 and 12). A special sequence of experiments showed the nucleophilic addition to be regioselective. Preferentially the higher substituted alkylcobalamin revealed to be produced. Therefore, the nucleophilic addition of cob(I)alamin follows the Markownikoff rule (compare chap. 4: formation and fragmentation of β-hydroxyalkylcobalamins). Under the reaction conditions applied the intermediate alkylcobalamins can be present in base-on and base-off forms. They are known to exist as octahedral complexes and might also be stable to some extent as tetragonal-pyramidal species. In addition the base-off forms can partially be protonated at the dimethylbenzimidazole moiety in aqueous acetic acid (compare Scheme 12). From this equilibrium of intermediate alkylcobalamins three modes of decay disclosed to be possible: (i) The reductive fragmentation leading to an olefin, a proton, and cob(I)alamin is the formal retro-reaction of the nucleophilic addition (see Schemes 2, 4 and 6–12). This equilibrium of an associated alkylcobalamin and the corresponding dissociation products revealed to be a fast process compared to the reductive cleavage of the Co, C-bond cited below (s. (iii)). (ii) As the second reaction pattern an oxidative fragmentation producing an olefin, a hydroxy anion (or water, respectively) and cob (III)alamin has been observed (see Schemes 7, 8, 10 and 12). (iii) The slow reductive cleavage of the Co, C-bond, initiated by addition of electrons (see [1a] [24]), was the third reaction path observed (see Schemes 2, 4–8 and 10–12). – The stereochemistry of the three transformations originating from the intermediate alkylcobalamins is unknown up to now. The antiperiplanar pattern of the fragmentation reactions presented in the Schemes has been chosen arbitrarily (see e.g. Scheme 12).     

Competitive Formation of Ylide and Carbene Intermediates from 1π,π*-Excited α,β-Unsaturated γ,δ-Epoxyketones

Laser flash photolyses (λ = 265mm) of the γ,λ-epoxyenones 1–3, 7 and 8 , the α,β-unsaturated γ,δ-epoxy ester 6 , and the epoxytriene 9 at ambient temperature produced short-lived transients with broad absorption maxima in the visible region, which are identified as carbonyl ylides. Comparison of the rather long-wavelength absorption maxima with the results of standard PPP SCF SCI calculations suggests that some degree of twisting is present in all the ylides studied. The lifetimes of the order of hundreds of ns of these intermediates and Stern-Volmer analysis of the trapping of the carbonyl ylide derived from 2 with CH₃COOH provide conclusive evidence that the carbene products are not formed via the carbonyl-ylide intermediate (Scheme 3).     

Cob(I)alamin-Catalyzed Skeletal Migrations Observed during the Reduction of 4β-(tert-Butyl)-1α-(1-methylvinyl)cyclohexanecarbaldehyde

The cob(I) alamin (1(I)) -catalyzed² transformation of the aldehyde 2 has been studied (cf. Table 1). Kinetic examinations showed a rapid isomerization of 2 to 3 (cf. Fig. 1 and 2). From the transformations in glacial AcOH, the two cyclopropanols 5 and 7 were isolated as main products (cf. Tables 1–3 and Fig. 1 and 2). Using large amounts of 1(I) , the aldehyde 4 was very slowly transformed. Accepting the intermediate formation of 6 interconnected Co-complexes, i. e. A , B , C , D , E and F (cf. Scheme), the generation of all the products observed can be explained.     

Von der basenkatalysierten Ringöffnung von 2H-Azirinen zu einer α-Alkylierungsmethode von primären Aminen

From a Base Catalyzed Ring Opening of 2H-Azirines to an α-Alkylation Method of Primary Amines It is shown that fluorene-9′-spiro-2-(3-phenyl-2H-azirine) ( 1 ) on treatment with various alcohols in the presence of the corresponding alkoxide ions yields N-(9′-fluorenyl)benzimidates 2a-d (Scheme 1). 2,2,3-Triphenyl-2H-azirine ( 3 ) reacts with methanol in a similar manner (Scheme 2). Benzimidates 2a (Scheme 3), 8 (Scheme 4) and and 10 (Scheme 5) can easily be deprotonated by butyllithium (BuLi) or lithium diisopropylamide (LDA) in tetrahydrofuran (THF) to 1-methoxy-2-aza-allylanions, that can be alkylated, at C(3), exclusively, by various electrophiles (e.g. R-X(X = I, Br), RCHO or methyl acrylate (see also Scheme 6)). As the acidic hydrolyses (1N HCl) of benzimidates 9 and 11 leads to the corresponding α-alkylated free amines 15 and 18 (Scheme 7 and 8), benzoyl derivatives 16 and 19 are obtained from the hydrolysis under basic conditions. On the other hand, it is observed that a catalyzed Chapman rearrangement of 9 and 11 results in the formation of N-benzoyl-N-methyl derivatives 17 and 20 (Scheme 7 and 8). The described reactions offer a simple method for the α-alkylation of activated primary amines.     

Cob(I)alamin as Catalyst. 8th Communication. Cob(I)alamin and Heptamethyl Cob(I)yrinate During the Reduction of α,β-Unsaturated Carbonyl Derivatives

Hydrogen bonds as presented in Figure 2 cannot account for the enantioselective attack of cob(I)alamin ( 4 ( I )) or heptamethyl cob(I)yrinate ( 5 ( I )) on one of the two enantiotopic faces of the substrates. The attack of the strongly nucleophilic 3d orbital is preferentially directed to the re-side of the starting materials with (Z)-configuration and leads, after the highly stereoselective reductive cleavage of the Co, C bond, to saturated products with (S)-configuration in varying enantiomeric excesses (see Schemes 1, 3 and Table 1).     

Thermodynamic trans-Effects of the Nucleotide Base in the B12 Coenzymes

The thermodynamic effects of the nucleotide coordination on the Co-C bond strengths in the B ₁₂ coenzymes were analyzed. Methyl group transfer reactions from methylcob( III )inamides to cob( II )inamides and cob( I )inamides in neutral aqueous solution were used in equilibration experiments to determine the effect fo the intramolecular coordination of the nucleotide function on the Co-C bond dissociation energies of methylcob( III )alamin ( 4 ). In the equilibrium between 4 , cob( I )inamide ( 11 ), cob( I )alamin ( 10 ) and methylcob( III )inamide 6 (Scheme 2), 4 and 11 were found to predominate ( 4 + 11 ? 10 + 6 , equilibrium constant K_I/III≈0.004), while the equilibrium between 4 , cob( II )inamide 9 , cob( II )alamin ( 5 ), and 6 (Scheme 1) proved to be well balanced ( 4 + 9 ? 5 + 6 , equilibrium constant K_II/III=0.60). These equilibrium values indicate the nucleotide coordination to stabilize the Co–C bond in 4 both against homolysis (slight effect) and against nucleophilic heterolysis (considerable effect). They reflect a stabilization of the complete corrins 4 and 5 by the nucleotide coordination, which is also indicated for 4 and 5 by their (nucleotide) basicity. The latter information, where available for other organocobalamins, allows the analysis of the thermodynamicnucleotide trans effect there as well: e.g. in coenzyme B ₁₂ ( 1 ), the nucleotide coordination is found this way to weaken the Co–C bond towards homolysis by ca. 0.7 kcal/mol.     

Beitrag zur Massenspektrometrie substituierter α, ω-Alkandiamine. 29. Mitteilung über massenspektrometrische Untersuchungen

Contribution to the mass spectrometry of substituted α,ω-alkane diamines The main mass spectral fragmentation pattern of compounds of types 1 to 4 is discussed. After loss of C₆H₅ · CH₂ · from the molecular ion the acid correspondin to the N,N-disubstituted residue is splitted off. The mechanism of this fragmentation reaction depends on the member of CH₂-groups between the two nitrogen atoms (Schemes 1 and 3) and on the substitution pattern of both nitrogens (Scheme 2).     

Photochemische Reaktionen 111. Mitteilung [1] Zur Photochemie α, β-ungesättigter γ, δ-Epoxyester I: Singulett- versus Triplettreaktivität

On triplet excitation (E)- 2 isomerizes to (Z)- 2 and reacts by cleavage of the C(γ), O-bond to isomeric δ-ketoester compounds ( 3 and 4 ) and 2,5-dihydrofuran compounds ( 5 and 19 , s. Scheme 1). - On singulet excitation (E)- 2 gives mainly isomers formed by cleavage of the C(γ), C(δ)-bond ( 6–14 , s. Scheme 1). However, the products 3–5 of the triplet induced cleavage of the C(γ), O-bond are obtained in small amounts, too. The conversion of (E)- 2 to an intermediate ketonium-ylide b (s. Scheme 5) is proven by the isolation of its cyclization product 13 and of the acetals 16 and 17 , the products of solvent addition to b . - Excitation (λ = 254 nm) of the enol ether (E/Z)- 6 yields the isomeric α, β-unsaturated ε-ketoesters (E/Z)- 8 and 9 , which undergo photodeconjugation to give the isomeric γ, δ-unsaturated ε-ketoesters (E/Z)- 10 . - On treatment with BF₃O(C₂H₅)₂ (E)- 2 isomerizes by cleavage of the C(δ), O-bond to the γ-ketoester (E)- 20 (s. Scheme 2). Conversion of (Z)- 2 with FeCl₃ gives the isomeric furan compound 21 exclusively.     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

Chiral Acylsilanes in Organic Synthesis. Part 3. Silicon-directed stereoselective preparation and Ireland ester-enolate rearrangement of O-acyl-substituted α-silylated allyl alcohols

Stereocontrolled addition of alk-1-enylmetal reagents to the chiral (alkoxymethyl)-substituted acylsilanes (±)- 6 gave rise to α-silylated allyl alcohols, which were converted to the corresponding acetates or propionates 11–16 (Scheme 2). Deprotonation and silylation with Me₃SiCl afforded – in an Ireland ester-enolate-accelerated Claisen rearrangement – stereoselectively αδ-silylated γδ-unsaturated carboxylic acids 18–24 (Scheme 4). The Me₃Si groups in α-position to the COOH group of these compounds were removed chemoselectively in presence of the chiral silyl group in δ-position by treatment with Bu₄NF · 3 H₂O or Et₃N · 3 HF (→ 27–32 ; Scheme 5). The reaction sequence allows a novel stereocontrolled access to chiral C-frameworks possessing a vinylsilane moiety with its full reaction potential.     

Stereochemistry of the Methyl Group in (R)‐3‐Methylitaconate Derived by Rearrangement of 2‐Methylideneglutarate Catalysed by a Coenzyme B12‐Dependent Mutase

2‐Methylideneglutarate mutase is an adenosylcobalamin (coenzyme B₁₂)‐dependent enzyme that catalyses the equilibration of 2‐methylideneglutarate with (R)‐3‐methylitaconate. This reaction is believed to occur via protein‐bound free radicals derived from substrate and product. The stereochemistry of the formation of the methyl group of 3‐methylitaconate has been probed using a `chiral methyl group'. The methyl group in 3‐([²H₁,³H]methyl)itaconate derived from either (R)‐ or (S)‐2‐methylidene[3‐²H₁,3‐³H₁]glutarate was a 50 : 50 mixture of (R)‐ and (S)‐forms. It is concluded that the barrier to rotation about the C−C bond between the methylene radical centre and adjacent C‐atom in the product‐related radical [^.CH₂CH(⁻O₂CC=CH₂)CO₂⁻] is relatively low, and that the interaction of the radical with cob(II)alamin is minimal. Hence, cob(II)alamin is a spectator of the molecular rearrangement of the substrate radical to product radical.     

Methyl 4‐O‐β‐d‐galactopyranosyl α‐d‐mannopyranoside methanol 0.375‐solvate

Methyl β‐d ‐galactopyranosyl‐(1→4)‐α‐d ‐mannopyranoside methanol 0.375‐solvate, C₁₃H₂₄O₁₁·0.375CH₃OH, (I), was crystallized from a methanol–ethanol solvent system in a glycosidic linkage conformation, with ϕ′ (O5_Gal—C1_Gal—O1_Gal—C4_Man) = −68.2 (3)° and ψ′ (C1_Gal—O1_Gal—C4_Man—C5_Man) = −123.9 (2)°, where the ring is defined by atoms O5/C1–C5 (monosaccharide numbering); C1 denotes the anomeric C atom and C6 the exocyclic hydroxymethyl C atom in the βGalp and αManp residues, respectively. The linkage conformation in (I) differs from that in crystalline methyl α‐lactoside [methyl β‐d ‐galactopyranosyl‐(1→4)‐α‐d ‐glucopyranoside], (II) [Pan, Noll & Serianni (2005). Acta Cryst. C 61 , o674–o677], where ϕ′ is −93.6° and ψ′ is −144.8°. An intermolecular hydrogen bond exists between O3_Man and O5_Gal in (I), similar to that between O3_Glc and O5_Gal in (II). The structures of (I) and (II) are also compared with those of their constituent residues, viz. methyl α‐d ‐mannopyranoside, methyl α‐d ‐glucopyranoside and methyl β‐d ‐galactopyranoside, revealing significant differences in the Cremer–Pople puckering parameters, exocyclic hydroxymethyl group conformations and intermolecular hydrogen‐bonding patterns.     

Chemie der α-Aminonitrile 1. Mitteilung Einleitung und Wege zu Uroporphyrinogen-octanitrilen

Chemistry of α-Aminonitriles I: Introduction and Pathways to Uroporphyrinogen-octanitriles. An introduction to experimental studies on the chemistry of α-aminonitriles potentially relevant to the problems of prebiotic chemistry is presented. The framework of conditions wherein the investigation is chosen to be carried out implies both molecular oxygen and - whenever feasible - water to be excluded from reaction conditions. This study focusses on 2-amino-2-propenenitrile ( 3 ) (Scheme 6) as central starting material of reaction sequences which aim at the nitrile forms of proteinogenic amino acids as well as at the aza forms of building blocks of biological cofactor molecules as their targets (Scheme 5). Schemes 13,16,23 as well as 25 and 26 summarize reaction sequences by which 3 is transformed within the defined framework of conditions into the thermodynamic (statistically controlled) mixture of the four isomeric uroperphyrinogen-octanitriles 57–60 . HPLC's of such mixtures document the dominance of the least symmetrical isomer whose constitutional pattern of peripheral substituents happens to be the one percent in all biological porphinoids. Preparative procedures for the synthesis of 3 (Scheme 9), the β,β-disubstituted pyrrol-nitriles 30,53 and 54 (Scheme 19) as well as the porphyrinogenoctakis(propionitrile) and-octakis(acetonitrile) 65 and 66 , respectively (Scheme 24) are given.     

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).     

Protolytic Opening of Two Diastereoisomeric Cyclopropanols

Cob(I) alamin ( 1(I) )-catalyzed reduction of the aldehyde 2 led to the two crystalline cyclopropanols 3 and 4 (see Scheme 2). The protolytic ring-opening starting from 3 produced the saturated aldehydes 6 and 7;8 was formed in traces only (see Scheme 3). The protolysis starting from 3 led, therefore, mainly to retention of configuration at the spiro C-atom ( 7 ); ring-opening with inversion was observed in traces only ( 8 ). Starting from 4 , the protolysis produced 9 and 7 ; the absence of 8 showed this protolysis to proceed 9 and 7 ; the absence of 8 showed this protolysis to proceed exclusively with inversion of configuration at the spiro center. Of the p-bromobenzoate 5 (cf. Scheme 2) the structure has been determined by X-ray analysis.