Silicon-Directed Regio- and Enantioselective Synthesis of α-Hydroxy-ketones Preliminary Communication

α-Silylated ketones (S)? 2 (ee ≥ 98%), easily available through silylation or silylation/alkylation from ketones 1 using the (?)-(S)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)?/(+)-(R)-1-amino-2-(methoxymethyl)pyrrolidine (RAMP)-hydrazone method, are oxidized to give α-hydroxy-ketones (R)? 5 of high enantiomeric purity (ee ≥ 98%) and in good overall yields (51-70%). The key step of the procedure is the silicon-directed diastereoselective oxidation of the corresponding silyl enol ethers of (S)? 2 , with m-chloroperbenzoic acid or 3-phenyl-2-(phenylsulfonyl)oxaziridine, followed by flash chromatography and desilylation.     

Chiral,non-racemic α-hydroxyphosphonates and phosphonic acids via stereoselective hydroxylation of diallyl benzylphosphonates

Chiral, non-racemic α-hydroxyphosphonates have been prepared in high enantiomeric excess (96–98% ee), via stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configuration of the α-hydroxyphosphonates was established from ¹H and ³¹P NMR spectroscopy of the (S)-O-methylmandelate esters. Deprotection of the diallyl α-hydroxyphosphonates under neutral conditions furnished the corresponding free phosphonic acids, retaining a high degree of stereochemical purity (90 to >98% ee).     

Mass spectra of some acyclic α,β-unsaturated aldehydes,ketones and esters

The mass spectra of a series of aliphatic acyclic α,β-unsturated aldehydes, ketones and ester have been examined. The spectra do not show evidence for McLafferty rearrangements, alkoxyl migration or for fragmentations which are dependent upon the s-trans or s-cis conformations of the compounds. There is some evidence for cis-trans isomerism about the double bond.     

Optisch aktive Alkohole aus 1,3-Dioxan-4-onen: eine praktikable Variante der enantioselektiven Synthese unter nucleophiler Substitution an Acetal-Zentren

Optically Active Alcohols from 1,3-Dioxan-4-ones. A Practical Version of Enantioselective Synthesis with Nucleophilic Substitution at Acetal Centers Secondary alcohols in enantiomeric excesses above 90% are accessible from 2-substituted 6-methyl-1,3-dioxan-4-ones (Scheme 4). The dioxanones are prepared from aldehydes and readily available (R)-or (S)-3-hydroxybutanoic acid. Treatment of the dioxanones with silyl nucleophiles or triisopropoxy(methyl)titanium in the presence of [Cl₃TiX] yields the corresponding 3-alkoxy acids in diastereoselectivities ≥ 95%. The ‘chiral auxiliary’ is removed from the alkoxy acids by treatment with LiN(i-Pr)₂ to give the secondary alcohols with ≤ 90% ee. cis/trans-Mixtures (9:1) of the dioxanones furnish products of the same configurational purity as those obtained from pure cis-isomers. In comparison with other variants of enantioselective synthese with nucleophilic substitution at acetal centers, the following advantages of the dioxanone method are noteworthy: (i) (R)- and (S)-3-hydroxybutanoic acids are both readily available; (ii) reactions are not sensitive to changes in conditions; (iii) the ‘chiral auxiliary’ is removed simply by base elimination, no oxidation is required; (iv) no chromatographic purification steps are necessary. The overall reaction described here is an enantioselective nucleophilic addition to aldehydes with concomitant dehydration of enantiomerically pure 3-hydroxybutanoic to crotonic acid.     

Enantioselective synthesis of protected α-aminoketones via electrophilic amination of α-silylketones with an oxaziridine

N-Boc protected α-aminoketones (4) of moderate enantiomeric purity were synthesised via N-Boc-3-(4-cyanophenyl)-oxaziridine (5) mediated electrophilic amination of enantiopure α-silyl ketones (2) followed by removal of the silyl directing group in the aminated products (3) with tetrabutylammonium fluoride in a buffer solution.     

Zinc-mediated asymmetric epoxidation of nitro alkenes with oxygen

The asymmetric epoxidation of nitro alkenes using oxygen in the presence of diethylzinc and N-methyl pseudo-ephedrine as a chiral additive is reported. This method provides an access to 3-substituted trans-2-nitro oxiranes of excellent diastereomeric purity (de≥98%) and with medium to good enantiomeric excesses (ee=36–82%).     

Infrared spectra and structure of substituted unsaturated carbonyl compounds: XVII. Enamino ketone and aldehyde quaternary ammonium salts

The β-trialkylammonium chloride derivatives of several α,β-unsaturated carbonyl compounds have been shown by infrared spectra to exist in the s-cis and s-trans rotational forms. The equilibrium between these two forms shifts towards the s-cis with the increasing steric requirements of the alkyl substituent linked to carbonyl. The CO and CC stretching frequencies are shifted to higher values as compared with other types of α,β-unsaturated ketones.     

Enantioselektive Synthese von Allyl-, Propargyl- und 4-En-2-inyl-aminen durch 1,2-Addition von Organocer-Reagenzien an chirale Aldimine

Enantioselective Synthesis of Allyl-, Propargyl-, and 4-En-2-ynyl-amines via 1,2-Addition of Organocerium Reagents to Chiral Aldehyde Imines (E)- and (Z)-Allyl-, propargyl-, and 4-en-2-ynyl-amines 5 and 14 , useful bifunctional building blocks and of pharmaceutical interest, are synthesized in high enantiomeric purity (e.e. ≥ 97%). Key step is the diastereoselective 1,2-addition (d.e. 86 to ≥ 98%) of organocerium reagents to chiral α,β-unsaturated aldehyde imines 3 or 8 to produce adduct amines 4 and 9 (Schemes 1 and 4, resp.). The propargylamine 9 is a substrate for Pd-catalyzed coupling with alkenyl halides to produce the enynylamine 11a and the thienyl-substituted alkynylamine 11b . The chiral auxiliary (S,S)- 2 is removed from 4 and 11 in 3 steps affording the title compounds 5 and 14 . Diastereoisomer enrichment of the hydrochloride of 6 by crystallization is possible.     

Herstellung enantiomerenreiner cis- oder trans-konfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one aus den Aminosäuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin, (S)-Methionin und (S)-Valin

Preparation of the Enantiomerically Pure cis- and trans-Configurated 2-(tert-Butyl)-3-methylimidazolidin-4-ones from the Amino Acids (S)-Alanine, (S)-Phenylalanine, (R)-Phenylglycine, (S)-Methionine, and (S)-Valine In contrast to α-hydroxy and α-mercapto carboxylic acids, simple α-amino acids do not form acetal-type derivatives ( 2 , X = NH) with pivalaldehyde. For the generation of amino-acid-derived chiral, nonracemic enolates (cf. 3 ), and hence, for the α-alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino-acid hydrochlorides were first converted to N-methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides ( 11 ). These Schiff bases could be cyclized either to trans-or to cis-imidazolidinones ( 12, 14 and 13 , respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by ¹H-NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300- or 360-MHz ¹H-NMR spectrometers.     

Synthesis of optically active α-benzyl paraconic acids and their esters and assignment of their absolute configuration

The cis- and trans-4-benzylparaconic acids and their ethyl esters were synthesized with high enantiomeric excess by hydrolysis of the corresponding diastereomeric lactonic esters using α-chymotrypsin. Thus, at low conversion values, cis- and trans-4-benzyl-5-oxo-3-tetrahydrofurancarboxylic acids were separately isolated with 99% ee and 92% ee, respectively. Both ethyl ester diastereomers were also obtained in enantiopure form. The absolute configuration of the trans-lactonic acid was assigned by ¹H NMR analysis of its ester derivatives with both enantiomers of 1-(9-anthryl)-2,2,2-trifluoroethanol, while that of the cis-lactonic acid was assigned by means of X-ray analysis of a crystalline derivative. The circular dichroism curves of the products obtained are also reported.     

Electronic spectra of α,β-unsaturated carbonyl compounds—II : An evaluation of increments characteristic of structural features of β-oxy-α,β-unsaturated ketones

By comparing UV spectra of β-alkoxy-α,β-unsaturated ketones of established steric structure, spectral constants characteristic of the cis/trans configuration change and s-cis/s-trans and O-s-cis/O-s-trans conformation changes have been evaluated. These are: Δλ^cis_trans = 0, Δλ^s-cis_s-trans = 8 nm and Δλ^O-s-trans_O-s-cis = 6 nm. A comparison of cis-s-cis enol ethers with the parent enols yielded the increment for the intramolecular (“chelating”) H-bond, Δγ_chel = 24 nm. The methanol-induced bathochromic shift has been found to depend strongly on s-cis/s-trans isomerism. The substituent increments have been shown to be dependent on the degree of substitution in the reference molecule. The results obtained have been summarized in a set of spectral increments complementing the basic system of Woodward and the Fiesers.     

Enantioselective synthesis of HIV protease inhibitor amprenavir via Co-catalyzed HKR of 2-(1-azido-2-phenylethyl)oxirane

A short and efficient enantioselective synthesis of the HIV protease inhibitor amprenavir 1 (99% ee) as well as a formal synthesis of saquinavir 3 have been achieved in high enantiomeric purity starting from commercially available materials. Our strategy mainly comprises a Co-catalyzed two-stereocentred hydrolytic kinetic resolution (HKR) of racemic 2-(1-azido-2-phenylethyl)oxirane as the chirality inducing step. Also presented is a concise synthesis of (S)-3-hydroxytetrahydrofuran 4, the key structural feature, in high enantiomeric purity (98% ee).     

Conformational studies by nuclear magnetic resonance. VII—The direct observation of rotational isomers in some enamino carbonyl compounds and their thione derivatives by carbon magnetic resonance

Carbon-13 magnetic resonance spectra of the s-cis and s-trans rotamers of enamino ketones and thiones of the general formula \documentclass{article}\pagestyle{empty}\begin{document}${\rm X =}\mathop {\rm C}\limits^{\rm 1} {\rm (}\mathop {\rm R}\limits^{\rm 1} {\rm)}\mathop {\rm C}\limits^{\rm 2} {\rm H =}\mathop {\rm C}\limits^{\rm 3} {\rm HN}\mathop {{\rm R}_{\rm 2}}\limits^{\rm 4}$\end{document} (where × = O or S and R-1, R-4 = alkyl) have been obtained. With dimethylaminoacrolein and its thione analogue, restricted rotation could only be observed in the latter. The chemical shift differences between rotamers and homologues are attributed to changes in conjugation and to induced bond polarisation, both these factors resulting from steric strain. In particular, nonplanar deformations of the s-trans rotamers are deduced from their C-2 chemical shift values.     

Enzymatic desymmetrization of cis-1,3-cyclohexanedicarboxylic acid diesters

cis-1,3-Cyclohexanedicarboxylic acid (1,3-CHDA) monoesters were prepared in high overall yield and high enantiomeric purity using a three step process from cis/trans-1,3-CHDA. The asymmetry is induced by an enzymatic hydrolytic desymmetrization of a meso cis-1,3-CHDA diester. A judicious choice of ester substituents and enzyme can provide >80% overall yield of either enantiomer in >94% ee.     

A pilot-scale synthesis of (1R)-trans-2-(2,3-dihydro-4-benzofuranyl)cyclopropanecarboxylic acid: a practical application of asymmetric cyclopropanation using a styrene as a limiting reagent

Asymmetric cyclopropanation of styrene 1 (as the limiting reagent) was demonstrated using excess ethyl diazoacetate and catalytic Ru(ip-Pybox). Selective hydrolysis of the resulting 90:10 trans:cis mixture of cyclopropane 4 generated cyclopropyl acid 2 as a 96:4 trans:cis mixture with 84% e.e. for the trans-cyclopropane. Further purification and enantiomeric enrichment was achieved by diastereoselective crystallization with (+)-dehydroabeitylamine to afford the (R,R)-isomer with ≥99.9% e.e in 60–65 M% yield starting from styrene 1.     

Asymmetric oxidation catalyzed by myoglobin mutants

The sperm whale myoglobin active site mutants (L29H/H64L and F43H/H64L Mb) have been shown to catalyze the asymmetric oxidation of sulfides and olefins. Thioanisole, ethyl phenyl sulfide, and cis-β-methylstyrene are oxidized by L29H/H64L Mb with more than 95% enantiomeric excess (% ee). On the other hand, the F43H/H64L mutant transforms trans-β-methylstyrene into the trans-epoxide with 96% ee. The dominant sulfoxide product in the incubation of alkyl phenyl thioethers is the R isomer; however, the mutants afford dominantly the S isomer of aromatic bicyclic sulfoxides. The results help us to rationalize the difference in the preferred stereochemistry of the Mb mutant-catalyzed reactions. Furthermore, the Mb mutants exhibit an improvement in the oxidation rate up to 300-fold with respect to wild type.     

Conformations of dibenzylideneacetone: An IR spectroscopic study

The conformational analysis of dibenzylideneacetone has been carried out using IR spectroscopy. Appearance of a triplet C=O band is attributed to the coexistence of three conformers viz s-cis, cis, s-cis, trans and nonplanar s-trans, trans in contrast to the earlier findings which showed the existence of only two conformers. The relative proportions of the conformers are in the order s-cis, trans> nonplanar s-trans, trans> s-cis, cis in less polar solvents and nonplanar s-trans, trans> s-cis, trans> s-cis, cis in more polar solvents.     

Enantioselective Formation of Bicyclic Lactones by Rhodium-Catalyzed Intramolecular CH-insertion reactions

The decomposition of cyclohexyl diazoacetate ( 5a ) in the presence of the chiral [Rh₂{(2S)-mepy}₄] catalyst leads to a 3:1 cis/trans mixture of bicyclic lactone 6a with an enantiomeric excess of 95–97% (cis) and 90% (trans). The conformationally rigid tert-butyl derivatives 5b and 5c afford, in the presence of the same catalyst, 6b and 6c , respectively, via insertion into the equatorial C? H bonds exclusively, with ee's of ca. 95%. A remarkable degree of induction (92–95%) results in the lactone 6g upon decomposition of 1-isopropyl-2-methylpropyl diazoacetate ( 5g ). The diazoacetates derived from 1-methylcyclohexanol, cyclopentanol and 1-methylcyclopentanol ( 5d–f ) afford under similar conditions insertion products with higher diastereoselectivity, but significantly lower enantioselectivity. Other dirhodium catalysts are less efficient.     

Synthesis, reactions and structural features of monofluorinated cyclopropanecarboxylates

Monofluorinated cyclopropanecarboxylates are available in racemic or optically active form by transition metal-catalyzed reactions of vinylfluorides with diazoacetates. From α-fluorostyrene and tert-butyl diazoacetate in the presence of 2 mol% of an enantiopure bis(oxazoline) copper complex, a 81:19 mixture of tert-butyl trans- and cis-2-fluoro-2-phenylcyclopropanecarboxylates was obtained with high enantiomeric excess (ee) of 93 or 89%, respectively. The corresponding racemic ethylesters were used as starting materials for the synthesis of carboxamides, of the cis- and trans-isomers of analogues of tranylcypromine, an anti-depressive drug and several of its homologous fluorinated cyclopropylmethyl and cyclopropylethyl amines. Corresponding enantiopure cyclopropylmethanols and several of their derivatives were synthesized also. Solid state structures of a selection of these compounds were examined by X-ray crystallography. Particularly, the cis-configurated fluorinated phenylcyclopropane derivatives showed extremely close intermolecular CH?FC contacts. The shortest of such distances (2.17 Å) was found in the N-(4-bromophenyl)carbamate of (1S,2R)-(2-fluoro-2-phenylcyclopropyl)methanol.     

Carbohydrates as chiral auxiliaries in enantioselective synthesis of four stereoisomers of optically active α,γ-substituted γ-butyrolactones

Using several easily accessed and inexpensive chiral auxiliaries derived from carbohydrates, all four stereoisomers of the optically active α,γ-substituted γ-butyrolactones were obtained respectively in high enantiomeric purities (up to 96% ee for trans and up to >99% ee for cis) by the SmI₂-induced reductive coupling reaction in the presence of a proton source.