Asymmetric syn-dihydroxylation of γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams

Various γ-substituted (2R)-N-(β,γ-enoyl)bornane-10,2-sultams have been examined in diastereoselective OsO₄ syn-dihydroxylation. In contrast to the C(α)-atom, the bornane-10,2-sultam auxiliary exerts a very poor influence on the C(β)-carbon. Spontaneous stereoselective hydrolysis of the minor diastereoisomer (3S,4S)-5c opens the way to enantiomerically pure building blocks.     

Efficient Preparation and X-Ray Structure Analyses of (2R)-N-pyruvoyl- and (2R)-N-(phenylglyoxyloyl)bornane-10,2-sultam

An efficient synthesis of the two title compounds is reported, as well as their X-ray crystal-structure analyses. A discussion based on stereoelectronic considerations rationalizes the first example of a crystalline SO₂/C(O) syn-periplanar conformer of a N-acylbornane-10,2-sultam.     

Preparation of Enantiomerically Pure β-Silylcarboxyl Derivatives by Asymmetric 1,4-Addition to N-Enoyl-sultams. Preliminary Communication

EtAlCl₂-promoted additions of organocopper reagents to camphor-derived, conjugated N-enoyl-sultams gave saturated and olefinic β-silylcarboxyl derivatives with high diastereodifferentiation. Nondestructive removal of the chiral auxiliary followed by oxidative Si-C bond cleavage furnished enantiomerically pure acetate-derived aldols and propionate-derived ‘anti’ -aldols (via silyl-directed α-methylation).     

An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

This report describes an improved synthesis of enantiomerically pure (S)‐2‐[4‐(Dimethylamino)phenyl]‐2,3‐dihydro‐N‐[2‐hydroxy‐3‐[4‐[2‐(1‐methylethoxy)‐phenyl]‐1‐piperazinyl]propyl]‐1,3‐dioxo‐1H‐isoindole‐5‐carboxamide (RWJ 69442), a potent and selective α_la‐adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification and higher enantiomeric purity. The N‐benzyl‐N—t‐butoxycarbonyl amine 6 could serve as an enantiomerically pure chiral building block for asymmetric synthesis.     

Brominations of Cyclic Acetals from α-Amino Acids and α- or β-Hydroxy Acids with N-Bromosucinimide

The preparation of novel electrophilic building blocks for the synthesis of enantiomerically pure compounds (EPC) is described. Thus, the 2-(tert-butyl)dioxolanones, -oxazolidinones, -imidazolidinones, and -dioxanones obtained by acetalization of pivalaldehyde with 2-hydroxy-, 3-hydroxy-, or 2-amino-carboxylic acids are treated with N-bromosuccinimide under typical radical-chain reaction conditions (azoisobuytyronitril/CCl₄/reflux). Products of bromination in the α-position of the carbonyl group of the five-membered-ring acetals are isolated or identified ( 2, 5 , and 8 ; Scheme 1). The dioxanones are converted to 2H, 4H-dioxinones under these conditions ( 12 , 14 , 15 , 21 , and 22 ; Schemes 2 and 3). The products can be converted to chiral derivatives of pyruvic acid (methylidene derivatives 3 and 6 ) or of 3-oxo-butanoic and -pentanoic acid ( 16 and 23 ). The mechanism of the brominations is interpreted. The conversion of serine to enactiomcrically pure dioxanones 26–28 (Scheme 4) is also discussed.     

Synthesis of a Building Block for a Nucleic-Acid Analog with a Chiral,Flexible Peptide Backbone

We present here a nine-step synthesis of the thymine-containing amino ester 1 , starting from commercially available methyl N-[(tert-butoxy)carbonyl]-L -serinate. Amino ester 1 is considered as a building block for the preparation of a new nucleic-acid analog with a chiral, flexible polyamide backbone. Key steps in the synthesis are the vitamin-B₁₂-catalyzed addition of 3-bromo-N-[(tert-butoxy)carbonyl]-L -alaninate 2 to ethyl acrylate and the homologation of the corresponding N-protected α-amino acid 4 into the β-amino ester 6 by Arndt-Eistert chemistry. The latter was found to proceed with 10% inversion of configuration at the asymmetric center in 6. Resolution to enantiomerically pure material, however, was easily achieved by simple crystallization of 1 .     

Asymmetric aminocarbonylation of iodoalkenes in the presence of α-phenylethylamine as an N-nucleophile

Iodoalkenes, such as 2-iodo-bornene, 17-iodoandrost-16-ene, 3-methoxy-17-iodoestra-1,3,5(10),16-ene, 3β-hydroxy-20-iodopregna-5,20-diene and 3β-hydroxy-12-iodo-5α,25R-spirost-11-ene were aminocarbonylated with enantiomerically pure and racemic α-phenylethylamine as the N-nucleophile in the presence of palladium(0) catalysts. Monodentate and bidentate (chiral and achiral) phosphines were used as ligands in the catalytic system. All diastereoisomers of the corresponding carboxamides were characterised as pure stereoisomers using both α-phenylethylamine and iodoalkene in enantiomerically pure form. The diastereoisomers were obtained in moderate to high yields in a chemoselective reaction, i.e., carboxamides due to single carbon monoxide insertion were formed exclusively, with no double CO insertion leading to 2-ketocarboxamides. Diastereoselectivities of the aminocarbonylation were investigated using the N-nucleophile in racemic form by the systematic variation of the catalyst.     

Asymmetric synthesis of cyclic α-amino acid derivatives by the intramolecular reaction of magnesium carbenoid with an N-magnesio arylamine

The synthesis of pipecolic acid and homopipecolic acid derivatives was developed from ω-(2-aminophenyl)-1-chloroalkyl p-tolyl sulfoxides by treatment with i-PrMgCl. An intramolecular nucleophilic substitution reaction of a magnesium carbenoid with an N-magnesio arylamine is the key step of this reaction. Proline and pipecolic acid derivatives were also synthesized from ω-(arylamino)-1-chloroalkyl p-tolyl sulfoxides by the same chemistry. Starting from enantiomerically pure (1S,R_S)-1-chloro-3-[2-(N-methylamino)phenyl]propyl p-tolyl sulfoxide, enantiomerically pure (R)-pipecolic acid derivative was obtained. The intramolecular nucleophilic substitution reaction of the magnesium carbenoid with N-magnesio arylamine was proven to take place with inversion of the carbenoid carbon. The stereochemistry of these reactions is also discussed.     

New β-amino-α-trifluoromethyl alcohols and their exploration in the synthesis of trifluoromethylated imidazole derivatives

Racemic and enantiomerically pure β-amino-α-trifluoromethyl alcohols were obtained via sequential nucleophilic trifluoromethylation of selected α-imino ketones, derived from arylglyoxals, and subsequent removal of the MeO or Ph(Me)CH substituent, respectively, located at the N-atom. The obtained products, containing a primary amino group, were used for the synthesis of imidazole N-oxides bearing a trifluoromethyl group as a part of the N(1)-alkyl chain. Imidazole N-oxides with an electron-withdrawing ester group at C(4) underwent spontaneous isomerization under the reaction conditions, and the corresponding imidazol-2-ones derivatives were isolated as final products.     

Asymmetric Alkylations of a Sultam-Derived Glycine Equivalent: Practical preparation of enantiomerically pure α-amino acids

Alkylation of the chiral glycine derivative 2 with “activated” organohalides under ultrasound-assisted phasetransfer catalysis or with activated and nonactivated organohalides in anhydrous medium provides (mostly crystalline) alkylation products 3 . Acidic hydrolysis of the pure products 3 gives (aminoacyl)sultams 4 which by mild saponification furnish pure α-amino acids 5 in good overall yields from 2 , along with recovered auxiliary 1 (Scheme 1). Pure ω-protected α,ω-diamino acids and α-amino-ω-(hydroxyamino)acids 12–16 are readily accessible from (ω-haloacyl)sultams 3 via reaction with N-nucleophiles followed by acidic and basic hydrolyses (Scheme 2). A reliable determination of the enantiomeric purity of α-amino acids using HPLC analysis of their N-(3,5-dinitrobenzoyl)prolyl derivatives 17 is presented.     

An efficient and general method for resolving cyclopropene carboxylic acids

A general method is described for the resolution of cycloprop-2-ene carboxylic acids via diastereomeric N-acyloxazolidines prepared from enantiomerically pure oxazolidinones. Although a number of oxazolidinones were shown to resolve cyclopropene carboxylic acids, the oxazolidinones of S-phenylalaninol, S-phenylglycine and (1S,2R)-cis-1-amino-2-indanol are optimal in terms of resolving power and cost effectiveness. Separations were performed using simple flash chromatography, and because there is typically a large difference in R_f values it is possible to separate gram quantities of pure diastereomers in a single chromatogram. The cycloprop-2-ene carboxylic acids that can be resolved include those that are substituted at the 1-position by H, Ph, α-naphthyl, CO₂Me, CH₂OMOM, and trans-styryl; alkene substituents include Me, n-alkyl, Ph and tethered alkynes. Remarkably, 2-methyl-3-propylcycloprop-2-ene carboxylic acid can also be resolved with ease. The relative configurations of four diastereomerically pure oxazolidines were determined by X-ray crystallography. Reduction of the N-acyloxazolidinones with LiBH₄ give enantiomerically pure derivatives of 3-hydroxymethylcyclopropene that react with either MeMgCl or vinylMgCl and catalytic CuI to give enantiomerically pure products of syn-addition.     

Asymmetric Dihydroxylations of β-Substituted N-(α,β-Enoyl)bornane-10,2-sultams

Pure (E)- or (Z)-enoylsultams 2 were Oxidized with OsO₄/N-Methylmorpholine N-oxide in a stereospecific and highly π-face-selective manner. Acetalization of the resulting 1,2-diols furnished, after purification, the stable, crystalline acetals 6 in >99% d.e. and in 63–74% overall yield from 2 . Reductive or hydrolytic cleavage of 6 gave enantiomerically pure alcohols 8 or carboxylic acids 9 with recovery of the sultan auxiliary 1 .     

Towards Substrate–Reagent Interaction of Lochmann–Schlosser Bases in THF: Bridging THF Hides Potential Reaction Site of a Chiral Superbase

The metalation of N,N-dimethylaminomethylferrocene in THF by the superbasic mixture of ⁿBuLi/KO^tBu proceeds readily at low temperatures to afford a bimetallic Li₂K₂ aggregate containing ferrocenyl anions and tert-butoxide. Starting from an enantiomerically enriched ortho-lithiated aminomethylferrocene, an enantiomerically pure superbase can be prepared. The molecular compound exhibits superbasic behavior deprotonating N,N-dimethylbenzylamine in the α-position and is also capable of deprotonating toluene. Quantum chemical calculations provide insight into the role of the bridging THF molecule to the possible substrate–reagent interaction. In addition, a benzylpotassium alkoxide adduct gives a closer look into the corresponding reaction site of the Lochmann–Schlosser base that is reported herein.     

Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the Preparation of β3‐Oligopeptides by Iterative α‐Keto Acid?Hydroxylamine (KAHA) Ligations

A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of β³‐oligopeptides via α‐keto acid? hydroxylamine (KAHA) ligation is presented. This one‐pot synthetic method utilizes in situ generated nitrones bearing gulose‐derived chiral auxiliaries for the asymmetric 1,3‐dipolar cycloaddition with methyl 2‐methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers bearing diverse side chains (proteinogenic and non‐proteinogenic) can be synthesized in either configuration (like‐ and unlike‐configured). The scalable and enantioselective synthesis of the isoxazolidine monomers enables the use of the synthesis of β³‐oligopeptides via iterative α‐keto acid? hydroxylamine (KAHA) ligation.     

Novel selenium-containing non-natural diamino acids

The general synthesis of a new class of non-natural diamino acids, 2-amino-3-[(2′-aminoalkyl)seleno]propanoic acids, or Se-(aminoalkyl)selenocysteines, is reported. Under the conditions devised, enantiopure N-Boc-protected β-l-iodoamines, which are readily generated from proteinogenic α-amino acids, were treated with the selenolate anion obtained from NaBH₄ splitting of the Se-Se bond in commercial l-selenocystine. The Se-alkylation products were enantiomerically pure and the reaction is high yielding (92-98%), without any detectable traces of accompanying by-products.     

Synthesis of Reactive Intermediates for Natural Cyclopentane Derivatives from (−)-Quinic Acid: Preparation of 11α-hydroxy-13-oxaprostanoic acid

We describe a flexible, stereocontrolled synthesis of enantiomerically pure substituted cyclopentenes and cyclopentanes - including 11α-hydroxy-13-oxaprostanoic acid 20 - (?)-quinic acid via an acyclic precursor 6 by an intramolecular aldolisation-dehydration reaction.     

Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform: practical synthesis of α-tribromomethyl amines

The unprecedented nucleophilic tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically pure α-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By changing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.     

Investigations into the cine-Amination of 4-Substituted-5-bromopyrimidines by potassium amide in liquid ammonia

The cine-amination of some 4-R-5-bromopyrimidines (t-butyl, phenyl, methoxyl, piperidine, methyl, methylamino, anilino, amino) by potassium amide in liquid ammonia has been studied. Evidence is presented that the conversion into the corresponding 4-substituted-6-aminopyrimidines can proceed in part via an S_N(ANRORC) mechanism, involving an open-chain intermediate, provided that the substituent at C-4 does not contain an acidic proton in the α-position to the pyrimidine ring. 5-Bromo-4-piperidinopyrimidine yields the tele-amination product, 2-amino-4-piperidinopyrimidine, alongside the 6-amino derivative. It is proven that the tele-amination does not proceed via an S_N(ANRORC) mechanism.     

Enzymatic Resolution of O‐(Methoxymethyl)‐Protected Tropane‐diols

A convenient synthetic route to enantiomerically pure tropane‐diol building blocks is described. The reaction sequence started from tropenone derivatives 1 , which were dihydroxylated to give 6,7‐dihydroxytropanone derivatives 2 . After introduction of the methoxymethyl (MOM) protecting group in diol 2a , a lipase‐mediated resolution of the resulting racemic mono‐MOM ether (±)‐ 5d with vinyl acetate and vinyl trifluoroacetate gave the acetates (?)‐ 6d and (?)‐ 6f , respectively, with 96–99% ee, and MOM ether (+)‐ 5d with up to 89% ee. Deacetylation of (?)‐ 6d afforded quantitatively MOM ether (?)‐ 5d with 99% ee, the absolute configuration of which was assigned via the modified Mosher method to be (R) at C(6). Enzymatic treatment of unprotected diol 2a with vinyl trifluoroacetate or alkoxycarbonylation resulted in the formation of C_s‐symmetrical products 9 and 12 rather than the desired desymmetrized derivatives.     

Enantiomeric Enrichments via the Self‐Disproportionation of Enantiomers (SDE) by Achiral,Gravity‐Driven Column Chromatography: a Case Study Using N‐(1‐Phenylethyl)acetamide for Optimizing the Enantiomerically Pure Yield and Magnitude of the SDE

This work explores the self‐disproportionation of enantiomers (SDE) via achiral, gravity‐driven column chromatography as typically used in laboratory settings for the purpose of enantiomeric enrichment using N‐(1‐phenylethyl)acetamide (PEA) as a case study. The major finding of this work is the very large magnitude of the SDE for PEA across a variety of conditions and broad range of starting ee values, thereby facilitating a simple, reliable, and predictable means of obtaining enantiomerically pure samples. For example, starting with a sample of PEA of ee as low as 28%, a single column run yielded an enantiomerically pure sample (>99.9% ee) from the first fractions and a significantly enantiomerically depleted sample (<17% ee) from the final fractions. An assessment of SDE via achiral, gravity‐driven column chromatography was also rendered with regard to the differing objectives that workers might target – a large magnitude of the SDE, obtaining an optimum sample of desired ee, or preparative‐scale separation of the excess enantiomer. Overall, it can be considered that the SDE phenomenon via achiral, gravity‐driven column chromatography – readily applicable in the usual laboratory settings – is a simple and convenient method for enantiomeric enrichment with a high degree of proficiency. Advantages of SDE via achiral, gravity‐driven column chromatography over conventional fractional recrystallization for the enantiomeric enrichment of amides/amines, and applicable also to many other classes of compounds as well, are discussed.