Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.     

Synthesis of an inherently chiral O,O′-bridged thiacalix[4]crowncarboxylic acid and its application to a chiral solvating agent

Treatment of readily available O,O′-1,1,3,3-tetraisopropyldisiloxane-1,3-diyl-bridged p-tert-butylthiacalix[4]arene (1) with tri(ethylene glycol) di-p-tosylate and subsequent desilylation gave O,O′-bridged thiacalix[4]crown 3 in an excellent yield. Mono-O-alkylation of 3 with ethyl bromoacetate, followed by optical resolution by chiral HPLC, and subsequent hydrolysis of the ester moiety gave inherently chiral O,O′-bridged thiacalix[4]crowncarboxylic acid (+)-6, which clearly discriminated enantiomeric primary amines, as well as amino esters, by ¹H NMR spectroscopy.     

Cinchona alkaloids as privileged chiral solvating agents for the enantiodiscrimination of N-protected aminoalkanephosphonates—a comparative NMR study

A series of chiral amines of increasing structural complexity, such as 1-(1-naphthyl)ethylamine, ephedrine, quinine, quinidine, 9-O-tert-butylcarbamoylquinine, and 9-O-tert-butylcarbamoylquinidine were studied as chiral solvating agents for the enantiodifferentiation of N-benzyloxycarbonyl derivatives of 1-aminoalkanephosphonic and phosphinic acids by means of ³¹P NMR spectroscopy. Among the cinchona alkaloids, that induced the most significant chemical shift non-equivalences, non-substituted quinidine exhibited the best effectiveness, excellent for analytical purposes (for example Δδ = 0.348 up to 1.008 ppm for phosphinic acid analogs). The signal separation of the diionic phosphonic acid enantiomers could be further optimized by the addition of an excess of the solvating agents. The newly obtained results appeared better when compared to the data set previously reported for the same analytes with the application of cyclodextrins.     

Resolution of inherently chiral calix[4]arenes with AABB and CDCD substitution patterns on the upper and lower rims,respectively

Proximal di-tert-butylcalix[4]arene (5,11-di-tert-butylcalix[4]arene-25,26,27,28-tetrol) 1b, obtained by direct partial removal of tert-butyl groups from p-tert-butylcalix[4]arene, gave high yields of inherently chiral derivatives upon ‘symmetry breaking’ by syn-distal di-O-alkylation or di-O-acylation in the presence of K₂CO₃. The chirality of these compounds was proven by the splitting of ¹H NMR signals in the presence of Pirkle's reagent and in some cases by HPLC enantiomeric resolution using chiral stationary phases and corroborated by mirror-image CD spectra.     

Recent advances in the use of chiral aldimines in asymmetric synthesis

Chiral N-(tert-butyl)sulfinyl aldimines easily prepared from commercially available compounds have been used as starting materials for the following processes: (i) hydrogen transfer, (ii) addition of zincates, (iii) In-promoted allylation, and (iv) addition of zinc enolates. In all cases, the final desulfinylation to yield the expected chiral α-substituted primary amines was easily performed with hydrochloric acid in an organic solvent. This methodology has been successfully applied to the preparation of chiral natural products such as alkaloids and amino acids.     

Asymmetric Baylis–Hillman reaction using sugar acrylates—synthesis of optically active α-methylene-β-hydroxy alkanoates

A study on the asymmetric Baylis–Hillman reaction of three chiral acrylates; 1,2:5,6-di-O-iso-propylidine-α-d-glucofuranose-3-acrylate 1, 2,3:5,6-di-O-iso-propylidine-α-d-mannofuranose-1-acrylate 2 and 1,2-O-iso-propylidine-5-O-tert-butyldimethylsilyl-α-d-xylofuranose-3-acrylate 3, with various aldehydes was conducted, resulting in adducts with moderate diastereoselectivity (5–40% e.e.).     

Construction of chiral α-tert-amine scaffolds via amine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety.     

Preparation of orthogonally protected (2S,3R)-2-amino-3-methyl-4-phosphonobutyric acid (Pmab) as a phosphatase-stable phosphothreonine mimetic and its use in the synthesis of polo-box domain-binding peptides

Reported herein is the first stereoselective synthesis of (2S,3R)-4-[bis-(tert-butyloxy)phosphinyl]-2-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-3-methylbutanoic acid [(N-Fmoc, O,O-(bis-(tert-butyl))-Pmab), 4] as a hydrolytically-stable phosphothreonine mimetic bearing orthogonal protection compatible with standard solid-phase protocols. The synthetic approach used employs Evans' oxazolidinone for chiral induction. Also presented is the application of 4 in the solid-phase synthesis of polo-like kinase 1 (Plk1) polo box domain (PBD)-binding peptides. These Pmab-containing peptides retain PBD binding efficacy similar to a parent pThr containing peptide. Reagent 4 should be a highly useful reagent for the preparation of signal transduction-directed peptides.     

Enantioselective synthesis of some tetrahydroisoquinoline and tetrahydro-β-carboline alkaloids

Four alkaloids: (R)-(+)-cryspine A 5, (R)-(+)-octahydroindolo[2,3-a]quinolizidine 8, (R)-(+)-harmicine 19 and (R)-(+)-desbromoarborescidine 22 were prepared via the asymmetric transfer hydrogenation reaction of a prochiral enamine (iminium salt). The enantiomeric excesses of the isolated alkaloids were determined from their ¹H NMR spectra measured in the presence of (+)-(R)-tert-butylphenylphosphinothio(seleno)ic acids as chiral solvating agents. The absolute configurations at the newly created stereogenic carbon atoms were confirmed, in all cases, by X-ray crystallography.     

Solid state conformations of α,β-unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine

α,β-Unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1′-naphthyl)ethyl-O-tert-butylhydroxylamine consistently adopt a defined conformation and undergo highly diastereoselective conjugate addition reactions with lithium amide reagents. The configuration of the N-1-(1′-naphthyl)ethyl group dictates the position of the O-tert-butyl group and also the configuration adopted by the pyramidal nitrogen atom via a ‘chiral relay’ effect. Conjugate addition of lithium amide reagents to these substrates proceeds on the face opposite to both the O-tert-butyl group and nitrogen lone-pair with high levels of diastereoselectivity.     

Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Enantioselective access to (−)-indolizidines 167B, 209D, 239AB, 195B and (−)-monomorine from a common chiral synthon

An enantioselective access to (?)-indolizidine alkaloids 167B, 209D, 239AB, 195B and (?)-monomorine from a new chiral synthon is described. The use of (S)-3-(Cbz-amino)-4-(tert-butyldimethylsilyloxy)butanal, obtained from l-aspartic acid, has provided efficient access of the indolizidine frame work through a Horner–Wadsworth–Emmons reaction and reductive cyclization as the key steps.     

Palladium-catalyzed asymmetric allylic nucleophilic substitution reactions using chiral tert-butanesulfinylphosphine ligands

The asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate 3 with dimethyl malonate proceeded smoothly in the presence of lithium acetate, BSA (N,O-bis(trimethylsilyl)acetamide), [Pd(η³-C₃H₅)Cl]₂, and chiral tert-butanesulfinylphosphine ligand 2c to give the allylic alkylation product in good yield and high enantiomeric excess (up to 93% ee), while the enantioselectivities of allylic amination of 3 with various amines were moderate (up to 76% ee).     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

Domino synthesis of 2-arylbenzo[b]furans by copper(II)-catalyzed coupling of o-iodophenols and aryl acetylenes

A wide range of 2-arylbenzo[b]furans are synthesized through domino intermolecular C_(aryl)-C_(alkynyl) bond formation followed by intramolecular C_(alkynyl)-O bond forming cyclization via copper(II)-catalyzed coupling of o-iodophenols and aryl terminal acetylenes. This method requires neither expensive palladium catalyst nor oxophilic phosphine ligands, can tolerate different functional groups. The methodology is successfully utilized in formal synthesis of β-amyloid aggregation inhibitor 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl) benzofuran.     

Hg(OTf)2-Catalyzed cyclization of alkynyl tert-butylcarbonate leading to cyclic enol carbonate

Mercuric triflate was shown to be a powerful catalyst for the cyclization of alkynyl tert-butylcarbonates giving rise to cyclic enol carbonates under mild conditions. Internal alkynyl carbonate affords endo cyclization product selectively, while terminal alkynyl carbonate provides only exo cyclization product.     

Total synthesis of (R)-(+)-salsolidine by hydride addition to (R)-N-tert-butanesulfinyl ketimine

(R)-(+)-Salsolidine 1 of high enantiomeric purity was synthesized using the Pomeranz–Fritsch–Bobbitt methodology, in which the reduction (NaBH₄, DIBAL-H) of N-tert-butanesulfinyl ketimine, derived from 3,4-dimethoxyacetophenone, was the key step. The synthesis was completed in a sequence of reactions involving the removal of the chiral auxiliary, N-alkylation with 2,2-diethoxyethyl bromide and final cyclization/hydrogenolysis.     

Highly efficient NMR enantiodiscrimination of 1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane,a chiral degradation product of sevoflurane,by heptakis(2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin

The molecular basis of the efficient enantiodiscrimination of 1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane, a chiral degradation product of the inhalation anaesthetic sevoflurane, using heptakis(2,3-di-O-acetyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin as chiral selector, has been investigated by NMR spectroscopy. An interaction mechanism is proposed, which highlights the role of the functional groups on the β-cyclodextrin rims in addition to a partial molecular inclusion.     

Polyhydroxylated pyrrolizidines. Part 6: A new and concise stereoselective synthesis of (+)-casuarine and its 6,7-diepi isomer, from DMDP

A new synthesis for (+)-casuarine (1) and its 6,7-diepi isomer (15) in a stereocontrolled manner, is reported herein. An appropriately protected polyhydroxylated pyrrolidine, such as (2R,3R,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (3, protected DMDP), easily available from d-fructose, was chosen as the chiral starting material. Compounds 1 and 15 were obtained from 3, in seven steps, in a 23.2 and 20.5% overall yields, respectively.     

Intramolecular ortho-arylation of phenols utilized in the synthesis of the aporphine alkaloids (±)-lirinidine and (±)-nuciferine

A palladium-mediated intramolecular phenol ortho-arylation reaction applied to the construction of aporphine alkaloids is reported. Most significantly, the efficiency of this transformation was enhanced by the utilization of trialkylphosphine (i.e. tricyclohexylphosphine) or trialkylphosphonium salts (i.e. di-tert-butylmethyl-phosphonium tetrafluoroborate) as co-catalysts in the presence of cesium carbonate. This methodology was employed in the syntheses of the aporphine alkaloids (±)-lirinidine and (±)-nuciferine.