Potential bile acid metabolites. 25. Synthesis and chemical properties of stereoisomeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids

Epimeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids and some related compounds were synthesized from chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. The key reaction involved one-step remote oxyfunctionalization of unactivated methine carbons at C-17 of CDCA and at C-14 of UDCA as their methyl ester-peracetate derivatives with dimethyldioxirane (DMDO). After dehydration of the resulting 17alpha- and 14alpha-hydroxy derivatives with POCl(3) or conc. H(2)SO(4), the respective Delta(16)- and Delta(14)-unsaturated products were subjected to hydration via hydroboration followed by oxidation to yield the 3,7,16- and 3,7,15-triketones, respectively. Stereoselective reduction of the respective triketones with tert-butylamine-borane complex afforded the epimeric 3alpha,7alpha,16- or 3alpha,7alpha,15-trihydroxy derivatives exclusively. A facile formation of the corresponding epsilon-lactones between the side chain carboxyl group at C-24 and the 16alpha- (or 16beta-) hydroxyl group in bile acids is also clarified.     

Electron ionization mass spectral fragmentation of cholestane-3beta,4alpha,5alpha-triol and cholestane-3beta,5alpha,6alpha/beta-triol bis- and tris-trimethylsilyl derivatives

The electron ionization (EI) mass spectral fragmentation of the bis- and tris-trimethylsilyl derivatives of cholestane-3beta,4alpha,5alpha-triol, cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol was investigated. The EI mass spectrum of the 3beta,4alpha-bis-trimethylsilyl derivative of cholestane-3beta,4alpha,5alpha-triol exhibits interesting fragment ions at m/z 142 and 332 resulting from the initial loss of TMSOH between the carbons 2 and 3 and subsequent retro-Diels-Alder (RDA) cleavage of the ring A. Trimethylsilyl transfer between the 4alpha- and the 5alpha-hydroxy groups acts significantly before RDA cleavage affording an ion at m/z 404. Complete silylation of cholestane-3beta,4alpha,5alpha-triol strongly stabilizes the molecule, affording an abundant molecular ion at m/z 636 and decreasing the abundance of the RDA cleavage. Loss of water (from the non-silylated 5alpha-hydroxy group) plays a very important role during the decomposition of the molecular ion of 3beta,6alpha/beta-bis-trimethylsilyl derivatives of cholestane-3beta,5alpha,6alpha/beta-triols. These derivatives appear to be very useful in assigning the configuration of the carbon 6. This assignment is based on the abundance of the fragment ions at m/z 321, 367 and 403, which are more prominent in the EI mass spectrum of the beta-isomer. In contrast, EI mass spectra of the tris-trimethylsilyl derivatives of cholestane-3beta,5alpha,6beta-triol and cholestane-3beta,5alpha,6alpha-triol differ only slightly and appear to be poorly informative.     

Conjugate addition reactions of alpha-aminoalkylcuprates with alpha, beta-alkenyl-, alpha,beta-alkynyl-, alpha,beta-beta,gamma-allenyl-, and alpha,beta-gamma,delta-dienyl carboxylic acid derivatives, nitriles, and sulfoxides

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.     

Sterically hindered C(alpha, alpha)-disubstituted alpha-amino acids: synthesis from alpha-nitroacetate and incorporation into peptides

The preparation of sterically hindered and polyfunctional C(alpha,alpha)-disubstituted alpha-amino acids (alpha alpha AAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional C(alpha,alpha)-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding C(alpha,alpha)-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PyAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).     

Functionalization of alpha,beta-unsaturated esters and ketones: a facile and highly stereoselective one-pot approach to N-protected alpha,beta-dehydroamino acid derivatives

A new, facile, and highly stereoselective protocol toward alpha,beta-dehydroamino acid derivatives has been developed. The one-pot synthesis was very convenient to perform by using the aminohalogenation reaction of alpha,beta-unsaturated esters and ketones followed by treatment with specific bases. Only two [2.2.2] bicyclic organic bases were found to be effective for this transformation. Good yields (58-68%) and excellent Z-selectivity were obtained for 12 examples. [reaction: see text]     

Low-valent niobium-mediated double activation of C-F/C-H bonds: fluorene synthesis from o-arylated alpha,alpha,alpha-trifluorotoluene derivatives

By the treatment of 0.3 molar amount of NbCl5 and LiAlH4, o-arylated alpha,alpha,alpha-trifluorotoluenes afforded fluorene derivatives in good yields. C-F bonds of the CF3 group and the neighboring ortho C-H bond were doubly activated to give the coupling products.     

Palladium-catalyzed Heck reaction on 1-alkoxy-1,3-dienes: a regioselective gamma-arylation of alpha,beta-unsaturated carbonyl compounds

[reaction: see text] alpha,beta-Unsaturated acetals afford, in the presence of the LIC-KOR superbase, 1-alkoxybuta-1,3-dienes. These substrates cross couple with aryl derivatives in the presence of Pd catalyst (Heck conditions) in a regio- and stereoselective mode. With dialkyl acetals, the reaction affords arylated dienes; on the other hand, in the case of 1,3-dioxane derivatives, the final outcome of the process formally corresponds to the direct gamma-arylation reaction of the starting alpha,beta-unsaturated material.     

Organocatalytic asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids and derivatives

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.     

Acidity trends in alpha,beta-unsaturated alkanes, silanes, germanes, and stannanes.

The gas-phase acidity of ethyl-, vinyl-, ethynyl-, and phenyl-substituted silanes, germanes, and stannanes has been measured by means of FT-ICR techniques. The effect of unsaturation on the intrinsic acidity of these compounds and the corresponding hydrocarbons was analyzed through the use of G2 ab initio and DFT calculations. In this way, it was possible to get a general picture of the acidity trends within group 14. As expected, the acid strength increases down the group, although the acidity differences between germanium and tin derivatives are already rather small. As has been found before for amines, phosphines, and arsines, the carbon, silicon, germanium, and tin alpha,beta-unsaturated compounds are stronger acids( )than their saturated analogues. The acidifying effect of unsaturation is much larger for carbon than for Si-, Ge-, and Sn-containing compounds. The allyl anion is better stabilized by resonance than its Si, Ge, and Sn analogues, [CH(2)(-)(delta)--CH(+)(delta)(') --CH(2)(-)(delta)](-) vs [CH(2)(-)(delta)()II = CH(-)(delta)()III - XH(2)(-)(delta)()IV](-) (X = Si, Ge, Sn). The enhanced acid strength of unsaturated compounds is essentially due to a greater stabilization of the anion with respect to the neutral, because the electronegativity of the alpha,beta-unsaturated carbon group increases with its degree of unsaturation. The phenyl derivatives are systematically weaker acids than the corresponding ethynyl derivatives by 15-20 kJ mol(-)(1). Experimentally, toluene acidity is very close to that of propyne, because the deprotonation of propyne takes place preferentially at the =CH group rather than at the -CH(3) group.     

Catalytic [4+1] cycloaddition of alpha,beta-unsaturated carbonyl compounds with isocyanides

The GaCl(3)-catalyzed [4+1] cycloaddition reactions of alpha,beta-unsaturated ketones with isocyanides leading to lactone derivatives are described. While some other Lewis acids also show catalytic activity, GaCl(3) was the most efficient catalyst. The reaction is significantly affected by the structure of both the isocyanides and the alpha,beta-unsaturated ketones. Aromatic isocyanides, especially sterically demanding ones and those bearing an electron-withdrawing group, can be used, but aliphatic isocyanides cannot. The bulkiness of substituents at the beta-position of acyclic alpha,beta-unsaturated ketones is an important factor for the reaction to proceed efficiently. Generally, the more the bulky substituent, the higher is the yield. The reaction of alpha,beta-unsaturated ketones bearing geminal substituents at the beta-position gave the corresponding products in high yields. In monosubstituted derivatives, the yields are relatively low. However, substrates having a bulky substituent, such as a tert-Bu group, at the beta-position give high yields. Bulkiness is also required in cyclic alpha,beta-unsaturated ketones, but the effect is small. In alkyl vinyl ketones, the reactivity decreased with the steric bulk of the alkyl group. In aryl vinyl ketones, the presence of an electron-donating group on the aromatic ring decreases the reactivity. The success of the catalysis can be attributed to the low affinity of GaCl(3) toward heteroatoms, compared with usual Lewis acids.     

New rearrangement of 4-isoxazoline system: conversion of ketones into alpha,beta-unsaturated amides

A new rearrangement pattern of the 4-isoxazoline system is reported. The reaction, starting from 3,3-disubstituted derivatives and leading to alpha,beta-unsaturated amides, proceeds through the quaternarization of the nitrogen atom and involves the heterolytic cleavage of C(3)-N bond, assisted by the formation of a relatively stable intermediate. The overall process represents a useful conversion of ketones into alpha,beta-unsaturated amides.     

Trends in structure-toxicity relationships for carbonyl-containing alpha,beta-unsaturated compounds

Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure-toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between alpha,beta-unsaturated carbonyl compounds with the carbon-carbon double bond on the end of the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of alpha,beta-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.     

Highly stereoselective oxy-Michael additions to alpha,beta-disubstituted nitro olefins: asymmetric synthesis of pseudo-norephedrine derivatives and THP* protected alpha-hydroxy ketones

The "naked" anion of (S)-6-methyl delta lactol undergoes efficient oxy-Michael addition to alpha,beta-disubstituted nitro olefins to give the THP* protected Henry products with excellent (95-->98% de) stereocontrol at the beta-position and moderate (up to 3 : 1) stereocontrol at the alpha-position in favour of the syn-diastereoisomer. Nitro group reduction with in situN-Boc protection and THP* removal provides alpha,beta-disubstituted ethanolamine derivatives, while treatment with tetrapropylammonium perruthenate gives THP* protected alpha-hydroxy ketone derivatives in high diasteromeric excess.     

Regioselective Heck couplings of alpha,beta-unsaturated tosylates and mesylates with electron-rich olefins

[chemical reaction: see text]. Highly regioselective Heck couplings of alpha,beta-unsaturated tosylate and mesylate derivatives with N-acyl N-vinylamines and vinyl ethers were achieved. Several 2-alkoxy-1,3-dienes and 2-acylamino-1,3-butadienes were synthesized in good yields using 1.5 mol % of Pd2(dba)3, 3 mol % of DPPF, and diisopropylethylamine in dioxane. When working with alpha,beta-unsaturated ketones and esters, this method provides a less costly alternative to similar couplings using a triflate electrophile.     

Enantioselective formal hydration of alpha,beta-unsaturated imides by Al-catalyzed conjugate addition of oxime nucleophiles

The (salen)Al-catalyzed asymmetric conjugate addition of salicylaldoxime to alpha,beta-unsaturated imides is the key step in an efficient and highly enantioselective two-step formal hydration of these electron-deficient olefins. This reaction constitutes the first example of an enantioselective conjugate addition of an oxygen-centered nucleophile to alpha,beta-unsaturated carboxylic acid derivatives. Application of this method to chiral, nonracemic substrates revealed a high level of catalyst-induced diastereoselectivity, underscoring its potential utility for polyketide natural product synthesis.     

Three component coupling of alpha-iminoesters via umpolung addition of organometals: synthesis of alpha,alpha-disubstituted alpha-amino acids

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.     

Iridium complex-catalyzed [2+2+2] cycloaddition of alpha,omega-diynes with monoynes and monoenes

[reaction: see text] [Ir(cod)Cl]2/DPPE was found to be a new catalyst for the cycloaddition of alpha,omega-diynes with monoynes to give polysubstituted benzene derivatives in high yields. Internal monoynes as well as terminal monoynes could be used. The reaction tolerates a broad range of functional groups such as alcohol, amine, alkene, ether, halogen, and nitrile. The reaction of 1,6-octadiyne derivatives with 1-alkynes gives ortho products and meta products. The regioselectivity could be controlled by the choice of ligand. The reaction with DPPE was meta selective, with meta selectivity of up to 82%. The reaction with DPPF was ortho selective, with ortho selectivity of up to 88%. We propose a mechanism to account for this regioselective cycloaddition. [Ir(cod)Cl](2)/DPPE also catalyzed the cycloaddition of alpha,omega-diynes with 2,5-dihydrofuran to give bicyclic cyclohexadiene derivatives. The reaction with 2,3-dihydrofuran and n-butyl vinyl ether gave benzene derivatives instead of cyclohexadiene derivatives. We also propose a mechanism to account for this novel aromatization that includes cleavage of the C-O bond.     

Highly efficient chromatographic resolution of alpha,alpha'-dihydroxybiaryls

[graph: see text] Separation factors as high as 115 were observed for the chromatographic resolution of many alpha,alpha'-dihydroxybiaryls with a single chiral stationary phase made from readily available amino acid derivatives. The stationary phase works well for biphenyl-type compounds. It works extremely well for larger bis-aromatic compounds, such as binaphthyl-type compounds.     

New and efficient syntheses of alpha-iodo-alpha,alpha-difluoro- and beta-iodo-alpha,alpha,beta,beta-tetrafluorocarboxylic acid derivatives as useful building blocks for making functional fluoro compounds

Perfluoroolefins reacted with I-Cl and ClSO(3)H under mild conditions to give R(F)CFICF(2)OSO(2)Cl, which could be readily converted into various alpha-iodo-perfluorocarboxylic acid derivatives or telomerized with tetrafluoroethylene to I(CF(2)CF(2))(n)()OSO(2)Cl. Ring-opening reaction of perfluoroalkoxypentafluorocyclopropane with iodine at 240 degrees C produced ICF(2)CF(2)COF, which was quenched by alcohol, water, or NH(3) to give beta-iodo-alpha,alpha,beta,beta-tetrafluorocarboxylic acid derivatives. These functional fluorinated iodides can be used as building blocks for making selectively fluorinated compounds.