Radical cyclization of beta-aminoacrylates: synthesis of (-)-indolizidine 223AB

[reaction: see text] (-)-Indolizidine 223AB was synthesized via radical cyclization of the beta-aminoacrylate derivative of a trans-2,5-disubstituted pyrrolidine. The trans-2,5-disubstituted pyrrolidine substrate was prepared by radical cyclization of a Ses-protected beta-aminoacrylate.     

Bis(2-bromoethyl) selenium dibromide as the selenium-introducing reagent: One-pot preparation of 2,5-bis(alkoxymethyl)tetrahydroselenophenes by the cyclization of 1,5-hexadiene

The reaction of bis(2-bromoethyl)selenium dibromide (1a) with 1,5-hexadiene (2) in methanol or ethanol affords 2,5-bis(alkoxymethyl)tetrahydroselenophene-1,1-dibromides (R = CH₃ (3b), R = C₂H₅ (3c)) via 2,5-bis(bromomethyl)tetrahydroselenophene-1,1-dibromide (3a). The reaction of 1a with 2 in 1-propanol, 2-methyl-1-propanol or 1-butanol in the presence of sodium carbonate gave 2,5-bis(alkoxymethyl)tetrahydroselenophene (R = C₃H₇ (4a), R = (CH₃)₂CHCH₂ (4b) and R = C₄H₉ (4c)) via 3a. The ratios of the trans and cis isomers of 3a–3c are 3:2. In addition, the structure of trans-2,5-bis(methoxymethyl)tetrahydroselenophene-1,1-dibromide (trans-3b) was determined by X-ray crystallography.     

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.     

A novel synthetic approach to very late antigen-4 antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid via tert-butyl trans-[(4S)-Methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate as a key intermediate

This contribution describes a novel synthetic approach to very late antigen-4 (VLA-4) antagonist trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (1) via tert-butyl trans-[(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylate (2b) as a key intermediate. The synthesis, which includes n-Bu?NSO?H that catalyzed basic etherification of 12 and iodine-mediated cyclization to provide the 2,4-disubstituted pyrrolidine frame of 2b, is designed to utilize trans-4-hydroxycyclohexanecarboxylic acid (9) as a commercially available starting material.     

Coordination properties of 2,5-dimesitylpyridine: an encumbering and versatile ligand for transition-metal chemistry

To overcome the unfavorable steric pressures associated with 2,6-disubstitution in encumbering pyridine ligands, the coordination chemistry of a 2,5-disubstituted variant, namely, 2,5-dimesitylpyridine (2,5-Mes(2)py), is reported. This diaryl pyridine shows good binding ability to a range of transition-metal fragments with varying formal oxidation states and coligands. Treatment of 2.0 equiv of 2,5-Mes(2)py with monovalent Cu and Ag triflate sources generates complexes of the type [M(2,5-Mes(2)py)(2)]OTf (M = Cu, Ag; OTf = OSO(2)CF(3)), which feature long M-OTf distances and a substrate-accessible primary coordination sphere. Combination of 2,5-Mes(2)py with Cu(OTf)(2) and Pd(OAc)(2) produces four-coordinate complexes featuring cis- and trans-2,5-Mes(2)py orientations, respectively. The four-coordinate palladium complex Pd(OAc)(2)(2,5-Mes(2)py)(2) is found to resist py-ligand dissociation at room temperature in solution, but functions as a precatalyst for the aerobic C-H bond olefination of benzene at elevated temperatures. This C-H bond activation chemistry is compared with a similar Pd-based system featuring 2,6-disubstituted pyridines. 2,5-Mes(2)py also readily supports mono- and dinuclear divalent Co complexes, and the solution-phase equilibria between such species are detailed. The coordination studies presented highlight the potential of 2,5-Mes(2)py to function as an encumbering ancillary for the stabilization of low-coordinate complexes and as a supporting ligand for metal-mediated transformations.     

Study of the reaction of bulky aryllithium reagents with 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane derived from ephedrine

The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with those obtained by others. In fact, several 2,6-disubstituted aryl groups were successfully appended to the phosphorus atom, furnishing the corresponding (N-ephedrino)phosphine boranes 2a-g with dr>99:1. However, when the attack on the phosphorus atom is hindered, deprotonation on the benzylic position occurs, leading to the formation of enantiomerically pure trans-(N-methylamino)(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3). While the attack of 2,2'-dilithio-1,1'-biarenes leads to the corresponding (P-phenyl)phosphole derivatives (4i,j) and to [bis(N-ephedrino)](phenyl)phosphine-P-borane (5), the attack of 1,1'-dilithiometallocenes (M=Fe, Ru) leads to a separable diastereomeric mixture of 1,1'-bis[(N-ephedrino)(phenyl)phosphino-P-borane]metallocenes (2k,l/2k',l') with dr approximately 80:20.     

Efficient, stereoselective synthesis of trans-2,5-disubstituted morpholines

[reaction: see text] Enantio- and diastereoselective syntheses of trans-2,5-disubstituted morpholine derivatives are described. The routes are initiated by the reaction of enantiopure epoxides (2) with amino alcohols (3) and address the problem of regioselective hydroxyl activation-ring closure of the resulting amino diol adducts for (amino alcohol-derived) alkyl substituents of different steric demands.     

The nucleophilicity N index in organic chemistry

The nucleophilicity N index (J. Org. Chem. 2008, 73, 4615), the inverse of the electrophilicity, 1/ω, and the recently proposed inverse of the electrodonating power, 1/ω?, (J. Org. Chem. 2010, 75, 4957) have been checked toward (i) a series of single 5-substituted indoles for which rate constants are available, (ii) a series of para-substituted phenols, and for (iii) a series of 2,5-disubstituted bicyclic[2.2.1]hepta-2,5-dienes which display concurrently electrophilic and nucleophilic behaviors. While all considered indices account well for the nucleophilic behavior of organic molecules having a single substitution, the nucleophilicity N index works better for more complex molecules. Unlike, the inverse of the electrophilicity, 1/ω, (R(2) = 0.71), and the inverse of the electrodonating power, 1/ω? (R(2) = 0.83), a very good correlation of the nucleophilicity N index of twelve 2-substituted-6-methoxy-bicyclic[2.2.1]hepta-2,5-dienes versus the activation energy associated with the nucleophilic attack on 1,1-dicyanoethylene is found (R(2) = 0.99). This comparative study allows to assert that the nucleophilicity N index is a measure of the nucleophilicity of complex organic molecules displaying concurrently electrophilic and nucleophilic behaviors.     

Asymmetric synthesis and absolute configuration of 1-α-phenylethyl-2,5-dimethyl-4-piperidone isomers

Reaction of the methyl iodide of trans-1,2,5-trimethyl-4-piperidone with S--phenylethylamine proceeds asymmetrically and leads in 66% optical yield to the formation of the cis- and trans-diastereomeric pair of 1-(-phenylethyl)-2,5-dimethyl-4-piperidone, in which the new asymmetric centers possess the 2S,5S- and 2S,5R-configurations, respectively. According to x-ray structural analysis, the minor trans-1-(-phenylethyl)-2,5-dimethyl-4-piperidone component possesses the 2R,5S-configuration. The occurrence of asymmetric synthesis accompanying transamination was confirmed via the preparation of enantiomers of trans-2,5- and trans-1,2,5-trimethyl-4-piperidones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1641–1648, December, 1986.     

Regioselective Rh-catalyzed allylic amination/ring-closing metathesis approach to monocyclic azacycles: diastereospecific construction of 2,5-disubstituted pyrrolines

[formula: see text] Regioselective rhodium-catalyzed allylic amination followed by ring-closing metathesis, using the Grubbs' catalyst, provides an expeditious route to monosubstituted azacycles. The enantiomerically enriched allylamine 1 can also be resubjected to the reaction sequence with (R)- and (S)-2b to facilitate the diastereospecific construction of 2,5-disubstituted pyrrolines 3/4.     

Facile route to 3,5-disubstituted morpholines: enantioselective synthesis of O-protected trans-3,5-bis(hydroxymethyl)morpholines

[reaction: see text] (3R,5R)-1 R1 & R2 = TBDPS, (3S,5R)-2 R1 = Bn,R2 = TBDPS, (3S,5S)-3 R2 & R2 = Bn. trans-3,5-Bis(benzyl/tert-butyldiphenylsilyloxymethyl)morpholines, promising candidates for the C(2)-symmetric class of chiral reagents, were prepared with excellent optical purity. A key step in the synthesis is the coupling of a serinol derivative with 2,3-O-isopropylideneglycerol triflate or its equivalent. This methodology was extended to the synthesis of chiral trans-3-(benzyloxymethyl)-5-(tert-butyldiphenylsilyloxymethyl)morpholine, a potentially useful chiral building block.     

Chelating diamide based rate enhancement of intramolecular alkene hydroaminations catalyzed by a neutral Sc(III) complex

[reaction: see text] Neutral scandium amido complexes are viable catalysts for intramolecular alkene hydroamination. Catalytic activity is strongly coupled to the electronic character of the Sc(III) ligand environment with chelating diamide coordination providing a precatalyst possessing substantially improved activity and superb distereoselectivity in the synthesis of trans-2,5-disubstituted pyrrolidines.     

Palladium-catalyzed synthesis of tetrahydrofurans from gamma-hydroxy terminal alkenes: scope, limitations, and stereoselectivity

A new, stereoselective synthesis of substituted tetrahydrofurans via Pd-catalyzed reactions of aryl and vinyl bromides with gamma-hydroxy terminal alkenes is described. This transformation affords trans-2,5- and trans-2,3-disubstituted tetrahydrofurans with up to >20:1 dr. This methodology also provides access to bicyclic and spirocyclic tetrahydrofuran derivatives in good yield with 10-20:1 dr. The scope and limitations of these transformations are discussed in detail, as are the effect of substrate sterics and electronics on yield and stereoselectivity. A proposed mechanism of these transformations is presented along with a model that rationalizes the stereochemical outcome of the reactions.     

Cross-coupling of organomanganese derivatives of 3-sulfolenes with allyl and propargyl bromides; a simple synthesis of functionalized 1,3-dienes

Reactions of organomanganese compounds RMnCl (R=3-sulfolen-2-yl or 5-methyl-3-sulfolen-2-yl) with allyl or propargyl bromides afford the corresponding 2-substituted or 2,5-disubstituted 3-sulfolenes in high yields. Thermolysis of the cross-coupling products results in 1,3,6-trienes or l,3-dien-6-ynes.All = allyl.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 106–113, January, 1994.     

Kinetic resolution of chiral aminoalkenes via asymmetric hydroamination/cyclisation using binaphtholate yttrium complexes

Chiral binaphtholate yttrium aryl complexes are highly active and enantioselective catalysts for the asymmetric hydroamination of aminoalkenes, as well as the kinetic resolution of alpha-substituted 1-aminopent-4-enes to give trans-2,5-disubstituted pyrrolidines with good enantiomeric excess and high k(rel).     

Direct synthesis of (imine)platinum(II) complexes by iminoacylation of ketoximes with activated organonitrile ligands

The metal-mediated iminoacylation of ketoximes R1R2C=NOH (1a R1 = R2 = Me; 1b R1 = Me, R2 = Et; 1c R1R2 = C4H8; 1d R1R2 = C5H10) upon treatment with the platinum(II) complex trans-[PtCl2(NCCH2CO2Me)2] 2a with an organonitrile bearing an acceptor group proceeds under mild conditions in dry CH2Cl2 to give the trans-[PtCl2{NH=C(CH2CO2Me)ON=CR1R2}2] 3a-d isomers in moderate yield. The reaction of those ketoximes with trans-[PtCl2(NCCH2Cl)2] 2b under the same experimental conditions gives a 1 : 1 mixture of the isomers trans/cis-[PtCl2{NH=C(CH2Cl)ON=CR1R2}2] 3e-h and 4e-h in moderate to good yield. These reactions are greatly accelerated by microwave irradiation to give, with higher yields (ca. 75%), the same products which were characterized by IR and 1H, 13C and 195Pt NMR spectroscopies, FAB-MS, elemental analysis for the stable trans isomers, and X-ray diffraction analysis (3f). The diiminoester ligand in 3a was liberated upon reaction of the complex with a diphosphine.     

AlCl3-promoted highly regio- and diastereoselective [3 + 2] cycloadditions of activated cyclopropanes and aromatic aldehydes: construction of 2,5-diaryl-3,3,4-trisubstituted tetrahydrofurans

The AlCl(3)-catalyzed [3 + 2] cycloaddition reaction of diethyl trans-2,3-disubstituted cyclopropane-1,1-dicarboxylates and aromatic aldehydes was carried out under mild conditions to provide a series of diethyl 2,5-diaryl-4-benzoyltetrahydrofuran-3,3-dicarboxylates in moderate to good yields with excellent diastereoselectivities. While common 2,5-cis products were obtained with electron-neutral or electron-poor aryl aldehydes, the much less common 2,5-trans products were obtained in excellent diastereoselectivities when electron-rich aryl aldehydes were used. The relative configurations of those typical products were confirmed by X-ray crystallographic analyses.     

9-Borabicyclo[3.3.2]decanes and the asymmetric hydroboration of 1,1-disubstituted alkenes

The syntheses of the optically pure asymmetric hydroborating agents 1 (a, R = Ph; b, R = TMS) in both enantiomeric forms are reported. These reagents are effective for the hydroboration of cis-, trans- and trisubstituted alkenes. More significantly, they exhibit unprecedented levels of selectivity in the asymmetric hydroboration of 1,1-disubstituted alkenes (28-92% ee), a previously unanswered challenge in the nearly 50 year history of this reagent-controlled process. For example, the hydroboration of alpha-methylstyrene with 1a produces the corresponding alcohol 6f in 78% ee (cf., Ipc2BH, 5% ee). Suzuki coupling of the intermediate adducts 5 produces the nonracemic products 7 very effectively (50-84%) without loss of optical purity.     

The Bip method, based on the induced circular dichroism of a flexible biphenyl probe in terminally protected -Bip-Xaa*- dipeptides, for assignment of the absolute configuration of beta-amino acids

An induced axial chirality of the biphenyl core of the Bip (2',1':1,2;1',2':3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid) residue in the terminally protected dipeptides Boc-Bip-beta-Xaa*-OMe (beta-Xaa* = L-beta(3)-HAla, L-beta(3)-HVal, L-beta(3)-HLeu, L-beta(3)-HPro, trans-(1S,2S)-ACHC, trans-(1R,2R)-ACHC, trans-(1S,2S)-ACPC, trans-(1R,2R)-ACPC) resulted in an induced circular dichroism, revealing the usefulness of the Bip method for a reliable and fast assignment of the absolute configuration of chiral beta-amino acids. Remarkably, the Bip method was also applied to the unique spin-labeled, cyclic, beta-amino acids cis/trans-beta-TOAC and trans-POAC. In particular, this study allowed the assignment of the unknown absolute configurations of the enantiomers of the latter compound.     

Asymmetric synthesis of trans-2,5-disubstituted pyrrolidines from enantiopure homoallylic amines. Synthesis of pyrrolidine (-)-197B

Iodocyclization of sulfinimine-derived enantiopure homoallylic sulfonamides affords trans-2,5-disubstituted 3-iodopyrrolidines and represents valuable methodology for the asymmetric synthesis of this important heterocyclic ring system.