Convenient methods for the synthesis of highly functionalized and naturally occurring chiral allenes

A convenient two step procedure to access highly functionalized chiral allenes using chiral N-methylcamphanyl piperazine derivatives is described. In this transformation, chiral propargylamines are obtained in 79–96% yields with up to 99:1 dr by the CuBr catalyzed reactions of chiral piperazine derivatives with 1-alkynes and aldehydes containing functional groups, which are converted into chiral allenes in the presence of zinc bromide, affording the chiral allenes in 59–85% yields and with up to 99% ee. The antifungal agent Sapium japonicum and an allene precursor intermediate for the synthesis of the pheromone of the male dried bean beetle 15 are obtained in 72–78% yields and with up to 98% ee following this methodology.     

Synthesis of hindered chiral guanidine bases starting from (S)-(N,N-dialkyl-aminomethyl)pyrrolidines and BrCN

An efficient method for the preparation of hindered chiral guanidines using cyanogen bromide is described. The reaction between BrCN and vicinal diamines derived from (S)-2-(N,N-dialkyl-aminomethyl)-pyrrolidines provides chiral substituted cyanamides. The cyanamide derivatives reacted with secondary amines in hexafluoroisopropanol at reflux to form chiral hindered guanidines, which were isolated in good to excellent yields (70–96%). The chiral guanidines were prepared in an effort to design sophisticated chiral guanidine catalysts for asymmetric synthesis.     

Enantioselective synthesis of multifunctionalized 4H-pyran derivatives using bifunctional thiourea-tertiary amine catalysts

A series of novel chiral multifunctionalized 4H-pyran derivatives were easily accessed via the one-pot asymmetric Michael addition-cyclization reaction between malononitrile and β,γ-unsaturated α-keto esters catalyzed by chiral bifunctional thiourea-tertiary amine catalysts. With the optimized reaction conditions, the desired products were obtained with 50–68% yields and 72–88% ees.     

Synthesis of the functionalized spiro[indoline-3,5′-pyrroline]-2,2′-diones via three-component reactions of arylamines,acetylenedicarboxylates, and isatins

In the presence of p-toluenesulfonic acid as the catalyst the three-component reactions of arylamines, acetylenedicarboxylates, and isatins showed very interesting molecular diversity. When equal amount of arylamine was used, the three-component reaction resulted in the high yields of functionalized 3′-hydroxyspiro[indoline-3,5′-pyrroline]-2,2′-dione derivatives. On the other hand the functionalized 3′-N-arylaminospiro[indoline-3,5′-pyrroline]-2,2′-diones were also successfully prepared in satisfactory yields by using 2 M arylamine in the reaction.     

Chiral Diels–Alder reaction between cyclopentadiene and nitroso derivatives: thermal isomerisation/racemisation of the adducts

Cyclopentadiene nitroso adducts 1a and ent-1a were synthesised in good yields and good enantiomeric excess from chiral chloro-nitroso derivatives 4 and 5 in the d-mannose and d-ribose series, respectively. The thermal racemisation of these adducts occurred below room temperature. Some other chiral Diels–Alder nitroso adducts were prepared in the d-mandelic, l-prolinol and d-O-methylprolinol series and their thermal isomerisation was specified according to the N-substitution. A simple synthesis of the chiral amido-cyclopentenol (+)-2b, an important precursor for biological interesting compounds, is presented from ent-1a.     

Diastereomeric process-based chiral resolution of helical quinone derivatives using (−)-menthyl chloroformate

Diastereomeric resolution of helically distorted polycondensed bisphenols (1,1′-bibenzo[c]phenanthrene-2,2′-diols: HEBPOLs) 2a–b was conducted utilizing (1R)-(?)-menthyl chloroformate as a chiral resolving agent. Subsequent manipulation produced highly optically pure [>99% enantiomeric excess (ee)] quinone derivatives (P) and (M)-1a–b in very good yields. The absolute configuration of each product was confirmed based on circular dichroism (CD) spectra and X-ray crystal structure analysis.     

Highly enantioselective Michael/cyclization tandem reaction between dimedone and isatylidene malononitriles

A highly enantioselective Michael/cyclization tandem reaction between dimedone and isatylidene malononitriles has been developed. With 5?mol% of bifunctional organocatalyst C15, chiral spiro[2-amino-4H-pyran-oxindole] derivatives were obtained in excellent yields (97–99%) with excellent enantioselectivities (up to?>?99% ee).     

Enantioselective,copper(I)-catalyzed three-component reaction for the synthesis of β,γ-alkynyl α-amino acid derivatives

The first catalytic asymmetric three-component reaction of ethyl glyoxylate, para-anisidine, and aliphatic, aromatic alkynes catalyzed by CuOTf·0.5C₆H₆/pybox 7 has been developed. The protocol provided the corresponding chiral β,γ-alkynyl α-amino acid derivatives in good yields and 66–74% ee.     

Synthesis of new homochiral 2,3-dialkylpiperazines derived from (R)-(−)-phenylglycinol

The synthesis of four new 2,3-dialkylpiperazines in yields of 70–99% using (R)-(−)-phenylglycinol as a chiral inductor is described. The synthesis involved reduction of the oxazino–oxazine type derivatives obtained by condensation of glyoxal and phenylglycinol to give hydroxyethylenediamine precursors which were further condensed with glyoxal, butanedione and 1-phenyl-1,2-propanedione and then reduced to provide the corresponding piperazines. The stereochemical outcome is determined by the configuration of the bisoxazolidine precursors, which is in turn dictated by steric effects exerted by the substituents on the five membered ring. The structures of five derivatives were established by X-ray analysis.     

Stereoselective Lewis acid promoted Kharasch-type addition of 3-bromoacetyl-2-oxazolidinones to norbornadiene

Ytterbium trifluoromethanesulfonate promoted radical atom-transfer addition of 3-bromoacetyl-2-oxazolidinones to norbornadiene afforded stereoselectively the corresponding 5-exo-3-bromo-5-nortricycleneacetic acid derivatives in good yields. Following clean tri(trimethylsilyl)silane reduction of the bromides, 3-exo-nortricycleneacetic acid derivatives were obtained with excellent diastereoselectivities (90–96% de) when using the chiral 4-isopropyl- and 4-benzyl-substituted 2-oxazolidinone auxiliaries. The stereochemistry of the studied compounds was investigated by 1D and 2D NMR spectroscopy.     

Synthesis of chiral calix[4]arenes bearing tartaric ester moieties

The synthesis of chiral calix[4]arenes with tartaric acid ester moieties has been achieved by the reactions of tartaric ester chloroacetates with calix[4]arenes in moderate yields. All the chiral calix[4]arene derivatives are in a cone conformation according to the ¹H NMR doublet–doublet pattern of the protons of the methylene groups between the phenol rings. The results of NMR and specific rotations indicate that the molecules have C₂ symmetry with asymmetric features.     

Asymmetric Morita–Baylis–Hillman reaction of chiral glyoxylates

The first Morita–Baylis–Hillman reaction of chiral glyoxylic acid derivatives, i.e. N-glyoxyloyl-(2R)-bornane-10,2-sultam and (−)-8-phenylmenthyl glyoxylate is described. The reaction with cyclic α,β-unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride. The adducts were obtained with very high diastereoisomeric excess (over 95% d.e.) and typical yields of 78%. The absolute configuration of the newly created stereogenic center was established by X-ray crystallographic analysis.     

cis–trans Enantiomerism in the Diels–Alder cycloadducts of 6-arylfulvenes with maleic anhydride: resolution of the exo adducts via the N-((1S)-1-(naphth-1-yl)ethyl)imide derivatives: assignment of the absolute configurations based on the crystal structure of an imide diastereomer

A new case of the uncommon cis–trans enantiomerism is presented. The titled anhydride adducts were prepared in good yields by the known reaction of three 6-arylfulvenes with maleic anhydride (aryl = phenyl, p-tolyl and p-anisyl). The exo adducts were converted to the corresponding imides by reaction with (1S)-1-(naphth-1-yl)ethylamine in ∼80% yields, and the resulting diastereomeric imides separated by silica gel column chromatography. They were hydrolysed and recyclised to the chiral anhydrides, in ‘one-pot’ with 10% NaOH–EtOH, followed by treatment with 2 M HCl, in ∼40% yields. The titled anhydrides were thus obtained in homochiral form, in enantiomeric purities (generally) of ∼90% as indicated by chiral HPLC. The chiral anhydrides were also converted to the corresponding imides (presumably stereospecifically), by treatment with ammonia solution in excellent yields. The crystal structure of one of the above diastereomeric imides (derived from 6-phenylfulvene) was determined, and based on the known (S)-configuration of the naphthylethylamine moiety, the ‘configurations’ of the original anhydride adducts were assigned.     

Asymmetric synthesis of 3-substituted indole derivatives containing tetrahydrothiophene via cascade sulfa-Michael/Michael additions catalyzed by a chiral squaramide catalyst

The organocatalyzed enantioselective cascade sulfa-Michael/Michael addition reaction of (E)-3-mercapto-2-butenoic acid esters to (E)-3-aryl-2-(indol-3-ylcarbonyl)acrylonitriles has been developed. This process was promoted by a chiral squaramide catalyst to afford chiral 3-substituted indole derivatives containing tetrahydrothiophene with three contiguous stereocenters in excellent diastereoselectivities (up to >20:1 dr) with moderate to good yields and enantioselectivities (up to 93%, 89% ee).     

A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes

A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a–e and 9h–j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65–91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (?)-8a-epi-swainsonine (4) and (?)-8,8a-di-epi-swainsonine (5) have been achieved.     

Asymmetric domino Michael–Henry reaction of 1,2-diones with nitroolefins catalyzed by a chiral bisoxazolidine–Ni(acac)2 complex

The asymmetric domino Michael–Henry reaction of 1,2-cyclohexadione with nitroolefins catalyzed by chiral ligand bisoxazolidine 1 and Ni(acac)₂ has been developed. This process provided highly functionalized chiral bicycle[3,2,1] octane derivatives with the generation of four new stereogenic centers in high yields (76–99%), and with excellent enantioselectivities (up to 99%) and good diastereoselectivities (up to 9:1) under mild reaction conditions. The procedure presented is simple and makes this method suitable for practical use.     

Application of novel enantiopure hydroxymethyl-substituted pyridine derivatives in asymmetric catalysis

The synthetic modification of enantiopure hydroxymethyl-substituted pyridine derivatives leading to novel chiral ligands is described. A set of these pyridine derivatives was examined as ligands in asymmetric transformations such as enantioselective alkylations or alkynylations of aldehydes, the asymmetric copper-catalyzed Henry reaction and the asymmetric allylation of benzaldehyde with allyl(trichloro)silane. This first screening revealed that several of the pyridine derivatives prepared are effective ligands affording high yields and good enantioselectivities. The asymmetric alkylation of aldehydes with diethylzinc provided yields of up to 93% with an enantiomeric excess of up to 88%. The asymmetric Henry reaction was also efficiently catalyzed by one of the prepared ligands affording (S)-2-nitro-1-phenylethanol in 68% yield and with 70% ee.     

Highly diastereoselective reactions of 2-lithiated indoles with chiral N-tert-butanesulfinyl aldimines for the synthesis of chiral (2-indolyl) methanamine derivatives

Nucleophilic addition reactions of 2-lithiated N-phenylsulfonylindoles with (R)-N-tert-butanesulfinyl aldimines provided chiral (2-indolyl) methanamine derivatives in moderate to good yields (up to 100%) with excellent diastereoselectivities (>99:1), in which no additional Lewis acids were required.     

Synthesis of chiral norbornane derivatives as γ-amino alcohol catalysts: the effect of the functional group positions on the chirality transfer

Starting from (1S,4R) chiral ketone (+)-6, we developed a synthetic route to the synthesis of new chiral γ-amino alcohols (+)- and (−)-syn-2-amino-7-hydroxy norbornane derivatives with excellent yields and enantiomeric excesses (up to 99%). These compounds were tested as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde presenting moderate results. The results obtained, compared with others previously reported, showed that the relative disposition of the amino and hydroxyl groups on C(2) and C(7) positions, play an important role in the catalytic activity.     

Formation of chiral aryl ethers from enantiopure amine or alcohol substrates

Three methods for the preparation of chiral aryl ethers are demonstrated. N,N-Disulfonylimide derivatives are used in the stereoselective formation of aryl ethers from chiral amines. Nucleophilic attack of aryloxide anions on the cyclic N,N-disulfonylimide derivative of (S)-1-phenylethylamine afforded the (R)-1-phenylethyl phenyl and 2-naphthyl ethers with 83–87 and 70–79% inversion of configuration, respectively. The results are compared with results from alternative methods for the preparation of homochiral aryl ethers from chiral alcohols with complete retention and inversion of configuration, respectively.