Solvent Cage Effects in Organocobalt Corrinoid Chemistry: Thermal Homolysis of alpha- and beta-(Cyanomethyl)cobinamides(1)

The equilibrium constant for the thermal isomerization of the diastereomeric alpha- and beta-(cyanomethyl)cobinamides (NCCH(2)Cbi(+)'s) has been measured over the temperature range 70-95 degrees C. Although the beta diastereomer is the thermodynamically more stable isomer, it is favored by the entropy change, but disfavored by the enthalpy change. In the presence of >/=5 x 10(-)(3) M concentration of the radical trap 4-hydroxy-2,2,6,6,-tetramethylpiperidinyloxy (4-HTEMPO), thermolysis of either isomer leads to cob(II)inamide and the trapped NCCH(2)(*) radical (NCCH(2)-4-HTEMPO) in high yield and no isomerization can be detected. The kinetics of the 4-HTEMPO-trapped thermal homolysis of alpha- and beta-NCCH(2)Cbi(+) have been studied in anaerobic glycerol/water mixtures of varying viscosity. The observed first-order rate constants for thermolysis show the expected inverse dependence on viscosity indicating that the process is at least partially diffusion controlled. From these data, the primary rate constant, k(1), for carbon-cobalt bond homolysis and the ratio of the rate constants for in-cage recombination and diffusional separation (k(c)/k(d)) can be extracted. The enthalpies of activation for Co-C bond homolysis are identical (29.0 +/- 0.3 kcal mol(-)(1)) while the entropy of activation is 2-fold higher for the alpha diastereomer. In water, the fractional cage efficiencies, F(c), are quite small (0.12 +/- 0.01, alpha; 0.049 +/- 0.008, beta) and invariant for each complex in the temperature range 75-95 degrees C. Assuming that the rate constant for diffusional separation of the caged radical pairs is the same for both isomers, the ratio of the in-cage recombination rate constants, k(c)(alpha)/k(c)(beta), can be calculated to be 2.6 +/- 0.6. This surprising kinetic preference for the alpha diastereomer results from enthalpic stabilization of the recombination transition state for the alpha diastereomer, since the beta diastereomer is entropically favored.     

Entropy-controlled diastereoselectivity in the photocyclization of rigid derivatives of o-allylaniline

Two rigid derivatives of o-allylaniline, namely 8-allyl-2-phenyl-1,2,3,4-tetrahydroquinoline (1b) and 7-(trans-2-cinnamyl)-2-methylindoline (1c), have been chosen as suitable systems to study the potential stereoselectivity of the photocyclization process. Photolysis of 1b leads to a mixture of diastereomeric lilolidines 4 (trans/cis), while 1cproduces a mixture of 4 (trans/cis) and the tetrahydropyrrolo[3,2,1-hi]indole derivatives 5 (trans/cis). To disclose whether the diastereoselectivity could be entropy dependent, photolysis of 1b and 1c has been performed at several temperatures. In both cases, linear relationships have been observed when ln(k(t)/k(c)) (the relative reaction rate constants calculated from the diastereomeric excess) is plotted against the reciprocal temperatures. However, significant entropy-controlled diastereoselectivity has only been found for the photocyclization of 1c to 4. The fluorescence spectra of 1b,c show formation of intramolecular charge-transfer exciplexes, which is in agreement with the proposed excited-state electron-transfer mechanism for photocyclization.     

Diastereoselective Synthesis of Chiral Pyrrolidine and Piperidine Ring Systems

A diastereoselective method for the synthesis of chiral pyrrolidine and piperidine ring containing compounds was described. The protocol of bromination followed by aminocyclization furnishes an easily handled while highly efficient procedure for the intramolecular amidation of an isolated double bond. High diastereomeric excess was observed in this synthetic procedure.     

Novel Redox-Active Cyclophanes Based on 3,3'-Biindolizines: Synthesis and Chirality

The first compounds of a new series of redox-active cyclophanes were prepared by dehydrocyclization of bridged indolizines of type 1. The bridged dipyridino-compounds 2a and 2b obtained by reaction of 2 mol of lithiated alpha-picolines with dihalides were used as starting materials. Subsequent treatment of 2a,b with 2 mol of alpha-bromo ketones gave quaternary pyridinium halides. Ring closure in an alkaline medium (Chichibabin reaction) yielded the starting material for the synthesis of the macrocycles. Oxidative C-C coupling gave the diastereomeric cyclophanes of type 3. In all cases one pair of the enantiomers was obtained in excess. CV-investigations have shown that the main products are reversible redox systems. To clarify their conformations, compounds 3c, 3d/1, and3d/2 were subjected to X-ray analysis.     

gem-Diacetates as carbonyl surrogates for asymmetric synthesis. Total syntheses of sphingofungins E and F.

The equivalent of an asymmetric addition to a carbonyl group with a stabilized anion is accomplished by discriminating between the enantiotopic C-O single bonds of a gem-diacetate. In this way, enantioselective total syntheses of two antifugal agents, sphingofungins E and F, have been accomplished. The synthetic strategy is based on a series of catalytic processes whereby all of the chiral centers are created with high stereoselectivities. The first two stereocenters are introduced by an asymmetric allylic alkylation reaction of gem-diacetate 9 with azlactone 10. The complex of Pd(0) and ligand 14 efficiently catalyzes this key reaction, which differentiates both the enantiotopic leaving groups of a gem-diacetate and enantiotopic faces of the enolate of an azlactone in high enantiomeric excess and diastereomeric excess. From these two stereocenters, the configurations of the remaining two centers are set by a diastereoselective Os(VIII)-catalyzed dihydroxylation reaction with excellent stereocontrol. The trans-alkene is established by Cr(II)-mediated olefination, and a subsequent B-alkyl Suzuki coupling reaction conjoins the polar head unit and the nonpolar, 13-carbon lipid tail. The efficiency of our strategy is illustrated by the completion of syntheses of sphingofungins F and E in 15 and 17 steps, and in 17% and 5% overall yields, respectively.     

Enantioselective Total Syntheses of (−)‐Rhazinilam, (−)‐Leucomidine B,and (+)‐Leuconodine F

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd‐catalyzed decarboxylative cross‐coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7 , respectively. The former was converted into (?)‐rhazinilam, while the latter was converted into (?)‐leucomidine B and (+)‐leuconodine F. A substrate‐directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self‐induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.     

Enantioselective Total Syntheses of (−)‐Rhazinilam, (−)‐Leucomidine B,and (+)‐Leuconodine F

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd‐catalyzed decarboxylative cross‐coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7 , respectively. The former was converted into (−)‐rhazinilam, while the latter was converted into (−)‐leucomidine B and (+)‐leuconodine F. A substrate‐directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self‐induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.     

Seasoning materials chemistry by using a well-matured organic concept

The concept "introduction of allylic 1,3-strain (A(1,3)-strain) to photochromism" originated from the experience of total synthesis of natural products about 18 years ago, when the author was a post doc. It was first applied to synthetic organic reactions, then it was successfully employed in the diastereoselective photochromic reactions of diarylethenes. A diastereomeric excess of the photoreaction was 88 % for the first example, and it was improved to 94 % by the recent operation of rational molecular tailoring.     

Highly diastereoselective reduction of ferrocene bis-imines with methyllithium and the formation of C2-symmetric Zr complexes

Alkylation of ferrocene bis-imines Fc[N=C(H)Ar]2 (Ar = Ph, p-Tol) with MeLi was found to proceed in a highly diastereoselective fashion producing the C2-symmetric ferrocene diamines Fc[NC(H)(Me)Ar]2-H2 with 90% diastereomeric excess. This process allowed for the synthesis of C2-symmetric zirconium complexes Fc[NC(Me)Ar]ZrBn2.     

Highly diastereoselective Diels-Alder reaction using a chiral auxiliary derived from levoglucosenone

[reaction: see text] A new chiral auxiliary derived from levoglucosenone is reported. The compound is obtained by a cycloaddition reaction with 9-methoxy methylanthracene followed by a diastereoselective reduction of the C-2 keto function. The auxiliary has been used as a chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene. The results showed excellent diastereomeric excess even at room temperature when the reaction was promoted by Et(2)AlCl as the Lewis acid.     

Diastereoselective synthesis of cyclosaligenyl-nucleosyl-phosphotriesters

A diastereoselective synthesis of cycloSal-phosphotriesters (cycloSal=cycloSaligenyl) based on chiral auxiliaries has been developed that allows the synthesis of single diastereomers of the cycloSal-pronucleotides. In previously described synthesis routes, the cycloSal-compounds were always obtained as 1:1 diastereomeric mixtures that could be separated in only rare cases. However, it was shown that the diastereomers have different antiviral activity, toxicity, and hydrolysis stabilities. Here, first a chiral thiazoline derivative was used to prepare nonsubstituted and 5-methyl-cycloSal-phosphotriesters in 48 and ≥95% de (de=diastereomeric excess). However, this approach failed to give the important group of 3-substituted cycloSal-nucleotides. Therefore, two other chiral groups were discovered that allowed the synthesis of (R(P))- and (S(P))-3-methyl-cycloSal-phosphotriesters as well. The antiviral activity was found to be five- to 20-fold different between the two individual diastereomers, which proved the importance of this approach.     

pH-sensitive C-ON bond homolysis of alkoxyamines of imidazoline series with multiple ionizable groups as an approach for control of nitroxide mediated polymerization

Recently, a new concept of pH-switchable agents for reversible addition-fragmentation chain transfer (RAFT) polymerization has been introduced by Benaglia et al. (J. Am. Chem. Soc.2009, 131, 6914-6915). In this paper we extended the concept of pH-switchable mediators to nitroxide mediated polymerization (NMP) by employing nitroxides with basic or acidic groups as controlling agents. Four alkoxyamines, the derivatives of 2-(4-(dimethylamino)-2-ethyl-5,5-dimethyl-2-(pyridin-4-yl)-2,5-dihydro-1H-imidazol-1-oxyl and 2-(2-carboxyethyl)-5,5-diethyl-2,4-dimethyl-2,5-dihydro-1H-imidazol-1-oxyl, have been prepared. The influence of pH on alkoxyamine homolysis rate constants (k(d)) and on the nitroxide-alkyl radical recombination rate constants (k(c)) was studied. All alkoxyamines under study as well as the parent nitroxides have several basic groups, which under pH variation can undergo consecutive protonation. It was shown that the k(d) value under basic conditions are significantly (up to 15-fold) higher than in acidic solution at the same temperature, whereas the k(c) value in basic solutions decrease by a factor of 2 only. The efficiency of NMP is known to be dependent on k(d) and k(c), both constants being dependent on the monomer structure; therefore the performance of NMP of different monomers in the controlled mode requires different conditions. It is shown that the pH value crucially affects the polymerization regime, changing it from the controlled to the uncontrolled mode. The controlled regime of NMP of different hydrophilic monomers (sodium 4-styrenesulphonate and acrylamide) in aqueous solution under mild conditions (90 °C) can be achieved using the same alkoxyamine by the variation of the pH value. The chain length of polymers depends on pH value during the polymerization.     

A new class of versatile chiral-bridged atropisomeric diphosphine ligands: remarkably efficient ligand syntheses and their applications in highly enantioselective hydrogenation reactions

A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereoselective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to the catalytic enantioselective hydrogenations of alpha- and beta-ketoesters (C=O bond reduction), 2-(6'-methoxy-2'-naphthyl)propenoic acid, alkyl-substituted beta-dehydroamino acids (C=C bond reduction), and N-heteroaromatic compounds (C=N bond reduction). An excellent level of enantioselection (up to 99.9% ee) has been attained for the catalytic reactions. In addition, the significant ligand dihedral angle effects on the Ir-catalyzed asymmetric hydrogenation of N-heteroaromatic compounds were also revealed.     

Selectivity of biohydroxylation with Beauveria bassiana of trans-2-fluorocycloalkyl N-phenylcarbamates

Biohydroxylation with Beauveria bassiana of racemates and the pure enantiomers of trans-2-fluorocyclohexyl- 3 and trans-2-fluorocycloheptyl N-phenylcarbamates 6 were investigated and compared with results found for the corresponding nonfluorinated parent compounds. In all cases, mixtures of diastereomeric products hydroxylated in the 4-position were isolated, besides products of p-hydroxylation of the aromatic ring and succeeding compounds derived from these primary reaction products. The regioselectivity of hydroxylation by this fungus is not changed by a single fluorine substituent attached closely to the electron-rich anchoring group in the trans-2-position. There is a different influence on the diastereoselectivity of hydroxylation depending on the absolute configuration of the fluorinated substrates. While the transformation of the (S,S)-2-fluorocycloalkyl N-phenylcarbamates is not diastereoselective giving almost 1:1 mixtures of cis- and trans-4-hydroxyl compounds, the corresponding reactions of the (R,R)-isomers led preferentially to the products trans-hydroxylated in the 4-position. The transformation of the racemic fluorinated six-membered N-phenylcarbamate 3 led to products having a very small enantiomeric excess. The fluorine substituent slightly increased the enantioselectivity of transformation of the racemic seven-membered substrate 6 compared to the C(s)()-symmetric nonfluorinated carbamate. Thus, the fluorine substituent in the trans-2-position in these examples did not change the regioselectivity but rather influenced the stereochemistry of biotransformation, depending on the absolute configuration of the substrate and ring size.     

Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous catalysis: mechanistic aspects

The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was studied over supported rhodium and ruthenium catalysts at room temperature and a pressure of 5 MPa. The reaction was diastereoselective with the predominant formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric excess (de) of up to 96%. The most stable conformation was determined by means of a combination of modelling calculations, NMR spectroscopy and X-ray structural determination. In this conformation, the carbonyl group of the pyroglutamate auxiliary shields one face of the aromatic ring. The observed selectivity may thus be explained by a preferential adsorption at the unshielded face which avoids steric repulsion by the C=O group to result in a cis hydrogenation. The addition of an amine, the nature of the support (alumina or active carbon) or of the metal (Rh or Ru) were shown to give additional stabilisation of the adsorption at the unshielded face to increase the diastereoisomeric excess.     

Diastereoselective yang photocyclization reactions in solution. synthesis of enantiopure azetidin-3-ol derivatives

[reaction: see text] Chiral 2-acyl-3-allyl- or 2-acyl-3-benzyl-substituted perhydro-1,3-benzoxazines readily cyclized under irradiation to azetidin-3-ol derivatives. The diastereoselectivity of the cyclization is dependent on the nature of the substituents at the nitrogen atom. N-allyl-substituted derivatives yielded only two of the four possible diastereomers in moderate to good diastereomeric excess. The cyclization of N-benzyl derivatives was totally diastereoselective leading to a single diastereomer. The elimination of the menthol appendage lead to enantiopure 2,3-disubstituted azetidin-3-ol derivatives.     

Novel Chiral Auxiliary for Attempted Resolution of Key Roxifiban Intermediate: A Simple Diastereoselective Coupling Approach for the Synthesis of Roxifiban

This article describes a simple method for the synthesis of roxifiban, a potent glycoprotein GP IIb‐IIIa receptor antagonist, by a diastereoselective coupling approach to give >99.9% optical purity. We have also described an attempt to resolve the key synthetic intermediate by diastereomeric ester formation. Although we have been able to separate two diastereomeric esters, the removal of the chiral auxiliary led to partial racemization.     

High Diastereoselection of a Dissymmetric Capsule by Chiral Guest Complexation

Encapsulation of chiral guests in the dissymmetric capsule 1?4 BF₄ formed diastereomeric supramolecular complexes G ? 1?4 BF₄ ( G : guest). When chiral guests 2 a – q were encapsulated within the dissymmetric space of the self‐assembled capsule 1?4 BF₄, circular dichroism (CD) was observed at the absorption bands that are characteristic of the π–π* transition of the bipyridine moiety of the capsule, which suggests that the P and M helicities of the capsule are biased by the chiral guest complexation. The P helicity of diastereomeric complex (S)‐ 2 l ? 1?4 BF₄ was determined to be predominant, based on CD exciton coupling theory and DFT calculations. The diastereoselectivity was highly influenced by the ester substituents, such that benzyl ester moieties were good for improving the diastereoselectivity. A diastereomeric excess of 98 % was achieved upon the complexation of 2 j . The relative enthalpic and entropic components for the distereoselectivity were obtained from a van’t Hoff plot. The enthalpic components were linearly correlated with the substituent Hammett parameters (σ_p⁺). The electron‐rich benzyl ester moieties generated donor–acceptor π–π stacking interactions with the bipyridine moiety, which resulted in a significant difference in energy between the predominant and subordinate diastereomeric complexes.     

Cyclopropane-aldehyde annulations at quaternary donor sites: stereoselective access to highly substituted tetrahydrofurans

A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3 + 2)-annulation of quaternary donor site cyclopropanes and aldehydes is described. The reaction is catalyzed by Sn(OTf)(2), SnCl(4), or Hf(OTf)(4) in yields up to 95% and diastereomeric ratios as high as 99:1.     

Photolysis and recombination of adenosylcobalamin bound to glutamate mutase

Ultrafast spectroscopic measurements are used to determine the kinetics of homolysis and recombination for adenosylcobalamin bound in the active site of glutamate mutase. These are the first such measurements on an adenosylcobalamin-dependent enzyme. A short-lived intermediate is formed prior to formation of the cob(II)alamin radical. This intermediate was not observed upon photolysis of adenosylcobalamin in free solution. The intrinsic rate constant for geminate recombination for adenosylcobalamin bound to glutamate mutase is 1.08 +/- 0.10 ns-1, only 16% smaller than the rate constant measured in free solution, 1.39 +/- 0.06 ns-1, suggesting the protein does not greatly perturb the stability of the cobalt-carbon bond upon binding the coenzyme.