A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.     

Iodine atom transfer [3 + 2] cycloaddition reaction with electron-rich alkenes using N-tosyliodoaziridine derivatives as novel azahomoallyl radical precursors

Treatment of N-tosyliodoaziridine derivatives with Et(3)B efficiently produces various azahomoallyl radical (2-akenylamidyl radical) species which give oxygen-functionalized pyrrolidine derivatives through iodine atom transfer [3 + 2] cycloaddition with electron-rich alkenes such as enol ethers and ketene acetal. The present cycloaddition reaction proceeds regioselectively via C-N bond cleavage of an aziridinylalkyl radical intermediate and addition of the resulting azahomoallyl radicals to the terminal carbon of an alkene. The reaction of alkenes with the cyclohexenylamidyl radical generated from an optically active bicyclic iodoaziridine [(1S,2S,6S)-2-iodo-7-(p-toluenesulfonyl)-7-azabicyclo[4.1.0]heptane, 94% ee] also proceeds to give optically active octahydroindole derivatives (84-93% ee).     

Asymmetric transfer hydrogenation of benzaldehydes

A combined system of RuCl[(R, R)-YCH(C(6)H(5))CH(C(6)H(5))NH(2)](eta(6)-arene) (Y = NSO(2)C(6)H(4)-4-CH(3) or O) and t-C(4)H(9)OK catalyzes the asymmetric transfer hydrogenation of various benzaldehyde-1-d derivatives with 2-propanol to yield (R)-benzyl-1-d alcohols in 95-99% ee and with >99% isotopic purity. Reaction of benzaldehydes with a DCO(2)D-triethylamine mixture and the R,R catalyst affords the S deuterated alcohols in 97-99% ee.     

Expanding the Scope of Atropisomeric Monodentate P‐Donor Ligands in Asymmetric Catalysis: Hydrogen‐Transfer Reduction of α,β‐Unsaturated Acid Derivatives by Rhodium/Ph‐binepine Catalysts

A range of α,β‐unsaturated acids and esters have been selectively reduced to the corresponding saturated acid derivatives by hydrogen transfer. As the reducing agent, formic acid was used in the presence of Rh^I complexes formed with the powerful chiral ligand Ph‐binepine ( 1 ), an axially chiral binaphthalene‐type monodentate P‐donor ligand. Very high stereoselectivities (up to 97% ee) were obtained in the case of itaconic acid ( 2a ).     

Rh(I)-catalyzed formal [6 + 2] cycloaddition of 4-allenals with alkynes or alkenes in a tether

Rh(I)-catalyzed formal [6 + 2] cycloaddition of allenal 6 having an alkyne or alkene in a tether proceeded smoothly, giving 5-8- and 6-8-fused bicyclic ketone derivatives 7 in good to excellent yields. It was also found that cyclization of enantiomerically enriched (S)-6a (94% ee) gave cyclic ketone derivative (S)-7a in high yield with reasonable chirality transfer (86% ee). This result indicates that this cyclization proceeds through stereoselective formation of rhodacycle H' followed by insertion of a multiple bond.     

手性联萘基-2,2'-联吡啶及其衍生物的合成及其在不对称合成中的应用

利用Kröhnke方法,以芳基乙酮为原料一锅法简洁地合成了6-芳基-6'-溴-2,2'-联吡啶2b~2d。 通过(R)-3-(4,4,5,5-四甲基-1,3,2-二噁唑硼烷基)-2,2'-乙氧基-1,1'-联萘((R)-1)与6-溴-2,2'-联吡啶及其衍生物2a~2d的Suzuki偶联, 合成了4种手性6-[3-((R)-2,2'-二乙氧基-1,1'-联萘)基]-2,2'-联吡啶(R)-3a~3d。 将配体(R)-3a~3d应用于苯乙酮的不对称氢转移反应中,配体(R)-3a给出92%的转化率和4%的对映体过量(ee)值。     

Highly efficient rhodium/monodentate phosphoramidite catalyst and its application in the enantioselective hydrogenation of enamides and alpha-dehydroamino acid derivatives

An easily prepared and highly efficient monodentate phosphoramidite ligand derived from BINOL, (S)-2,2'-O,O-(1,1'-binaphthyl)-dioxo-N,N-diethylphospholidine, was examined in the hydrogenation of both enamides and alpha-dehydroamino acid derivatives. The catalyst provided remarkably high enantioselectivities (up to 99.6% ee for enamides and >99.9% ee for alpha-dehydroamino acid derivatives).     

Copper-catalyzed intramolecular redox reaction: Asymmetric synthesis of chiral 2-(1H-pyrrol-1-yl)-mandelic acid esters

An efficient approach to chiral α-hydroxy acid esters by Lewis acid-mediated asymmetric [1,5]-hydride shift and isomerization of 2-(3-pyrroline-1-yl)arylketone acid ester has been achieved in up to 96% yield and 94% ee. This protocol would be applied in the synthesis of chiral α-hydroxy acid derivatives with simplicity and high enantioselectivity.     

Highly enantioselective rhodium-catalyzed hydrogenation of beta-dehydroamino acid derivatives using monodentate phosphoramidites

New and very easily accessible monodentate phosphoramidite ligands have been developed that lead to excellent ee's and full conversions in the hydrogenation of (E)- and (Z)-beta-dehydroamino acid derivatives with both aliphatic and aromatic side chains. Particularly, two different catalytic systems were established for (E)-beta-(acylamino)acrylates (98-99% ee) and (Z)-beta-(acylamino)acrylates (92-95% ee) based on phosphoramidites 2 and 3, respectively.     

Enantioselective synthesis of (2-pyridyl)alanines via catalytic hydrogenation and application to the synthesis of L-azatyrosine

[reaction: see text] A novel method for the synthesis of (2-pyridyl)alanines 2a-b was developed by converting (2-pyridyl)dehydroamino acid derivatives 1a-b to the corresponding N-oxides 3a-b followed by asymmetric hydrogenation using (R,R)-[Rh(Et-DUPHOS)(COD)]BF(4) [(R,R)-6] catalyst and subsequent N-oxide reduction in 80-83% ee. This methodology was applied to the total synthesis of L-azatyrosine [(+)-12], an antitumor antibiotic, starting from (5-benzyloxy)-2-pyridylmethanol (7), in >96% enantiomeric purity.     

Direct organocatalytic asymmetric aldol reactions of alpha-amino aldehydes: expedient syntheses of highly enantiomerically enriched anti-beta-hydroxy-alpha-amino acids

[reaction: see text] A simple and efficient method for the synthesis of highly enantiomerically enriched beta-hydroxy-alpha-amino acid derivatives has been developed. Direct asymmetric aldol reactions of a glycine aldehyde (aminoacetaldehyde) derivative have been performed under organocatalysis using l-proline or (S)-5-pyrrolidine-2-yl-1H-tetrazole. The reactions afforded anti-beta-hydroxy-alpha-amino aldehydes in good yield with high diastereoselectivity (dr up to >100:1) and high enantioselectivity (up to >99.5% ee), which were easily transformed into beta-hydroxy-alpha-amino acid derivatives.     

Enantioselective reduction of benzofuryl halomethyl ketones: asymmetric synthesis of (R)-bufuralol

Enantioselective reduction of representative 2-(bromoacetyl)- and 2-(chloroacetyl)benzofurans with (−)-B-chlorodiisopinocampheylborane and by transfer hydrogenation with formic acid/triethylamine in the presence of RhCl[R,R-TsDPEN](C₅Me₅) is described. Transfer hydrogenation of the chloro ketones produced the corresponding chlorohydrins of ⩾95% ee. (R)-Bufuralol of 96% ee was prepared from the corresponding chloro ketone by transfer hydrogenation–substitution.     

Asymmetric transfer hydrogenation of aryl ketones catalyzed by salt-free two samarium centers supported by a chiral multidentate alkoxy ligand

[reaction: see text] We synthesized a chiral multidentate ligand, (R,R,R,R)-N,N,N',N'-tetra(2-hydroxy-2-phenylethyl)-1,3-xylylene diamine [(R)-2], which can support two metals at adjacent positions. Asymmetric transfer hydrogenation of acetophenone and its derivatives was conducted by using salt-free bimetallic lanthanoid complexes of (R)-2, and the combination of two samarium atoms and (R)-2 was found to be the best catalyst system for asymmetric transfer hydrogenation of aryl ketones in high enantioselectivity (up to >99% ee).     

A novel chiral phosphinediamine ligand and asymmetric hydrogenation of acrylic acid derivatives

A novel chiral phosphinediamine ligand (PN₂) was prepared from (S)-1-phenylethylamine and dichloroisopropylphosphine. The rhodium-PN₂ catalyst utilizing selective ligation of the amino unit and electrostatic interaction between the ligand and a substrate gave high enantioselectivities up to 92% ee in asymmetric hydrogenations of acrylic acid derivatives.     

Synthesis of fluorinated glutamic acid derivatives via vinylalumination

A variety of structural types of fluorinated allylic acetates, prepared by vinylalumination of fluorinated aldehydes, were reacted with the benzophenone imine of glycine tert-butyl ester to provide 4-(fluorobenzylidenyl)- and 4-(fluoroalkylidenyl) glutamic acid derivatives in 61-96% yield. The 4-(4-fluorobenzylidenyl) glutamic acid derivative was hydrolyzed to give the 4-(4-fluorobenzylidenyl)pyroglutamate and then hydrogenated to the 4-(4-fluorobenzyl)pyroglutamate. The catalytic enantioselective conjugate addition-elimination of the benzophenone imine of glycine tert-butyl ester with the fluorinated allylic acetates prepared from fluoral, pentafluorobenzaldehyde, and 2,6-difluorobenzaldehyde provided the corresponding 4-(fluoroalkylidenyl)- and 4-(fluorobenzylidenyl) glutamic acid derivatives in 42, 45 and 80% ee, respectively.     

Enantioselective functionalisation of the C-2' position of 1,2,3,4,5-pentamethylazaferrocene via sparteine mediated lithiation: potential new ligands for asymmetric catalysis

The s-BuLi-sparteine base combination deprotonated the C-2' position of 1,2,3,4,5-pentamethylazaferrocene and subsequent reaction with a range of electrophiles gave C-2 substituted products in 76-93% yield and approximately 80% ee. The products could be recrystallised to enrich ee's to >90%. Resubjection of the initial addition products ( approximately 80% ee) to the deprotonation conditions led to a kinetic resolution to give products with >90% ee and superior overall yields compared to recrystallisation for the cases where the electrophiles were Ph2CO, MeI and Ph2S2. Transmetallation of the 2-lithiopentamethylazaferrocene ( approximately 80% ee) with ZnCl2 allowed palladium catalysed cross coupling with a variety of C-2 haloaryl, heteroaryl and vinyl groups to give some novel C-2' substituted pentamethylazaferrocene derivatives in 61-77% yield in 80% ee. Potential N,N-chelate ligands were recrystallised to >95% ee. A novel C2-symmetric bis-pentamethylazaferrocene could be synthesised by an iron catalysed oxidative coupling of the enatioenriched C-2 lithio derivative and in the presence of a PhMe-Et2O solvent mixture proceeded in 97% ee.     

Gold(I)-catalyzed intramolecular amination of allylic alcohols with alkylamines

A 1:1 mixture of (1)AuCl [1 = P(t-Bu)(2)o-biphenyl] and AgSbF(6) catalyzes the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. Gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee, 95% de) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield with 96% ee, consistent with the net syn addition of the amine relative to the departing hydroxyl group.     

Rh-catalyzed asymmetric hydrogenation of gamma-phthalimido-substituted alpha,beta-unsaturated carboxylic acid esters: an efficient enantioselective synthesis of beta-aryl-gamma-amino acids

A series of chiral beta-aryl-gamma-amino acid ester derivatives were synthesized in high enantioselectivities (93-97% ee) via the Rh-catalyzed asymmetric hydrogenation of gamma-phthalimido-alpha,beta-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine-aminophosphine ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram with high enantioselectivities.     

Synthesis of β-amino acid derivatives via copper-catalyzed asymmetric 1,4-reduction of β-(acylamino)acrylates

A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.     

Stereoselective synthesis of highly enantioenriched (E)-allylsilanes by palladium-catalyzed intramolecular bis-silylation: 1,3-chirality transfer and enantioenrichment via dimer formation

Highly enantioenriched (E)-allylsilanes have been synthesized from optically active allylic alcohols on the basis of Pd-catalyzed intramolecular bis-silylation followed by highly stereospecific Si-O elimination reactions. The method involves three steps: 1) O-disilanylation of the allylic alcohols with chlorodisilanes, 2) intramolecular bis-silylation in the presence of a 1,1,3,3-tetramethylbutyl isocyanide/[Pd(acac)2] (acac = acetylacetonate) catalyst at 110 degrees C, and 3) treatment of the reaction mixture with organolithium reagents. The overall transformation proceeds with nearly complete conservation of the enantiopurity of the starting allyl alcohols by transposition of the C=C bond. For instance, (R)-(E)-3-decen-2-ol (99.6-99.7 % ee) produced (S)-(E)-4-(organosilyl)-2-decene of 98.8-99.4 % ee for a variety of silyl groups, including Me3Si, Me2PhSi, tBuMe2Si, Et3Si, and iPr3Si. In the bis-silylation step, the initially formed trans-1,2-oxasiletanes immediately dimerize to stereoselectively give 1,5-dioxa-2,6-disilacyclooctanes, which are isolated in high yield by carrying out the reaction at 70 degrees C. The eight-membered ring compounds undergo thermal extrusion of (E)-allylsilanes in high yield at 110 degrees C, along with formation of 1,3-dioxa-2,5-disilacyclohexane derivatives. These in turn undergo a Peterson-type elimination by treatment with nucleophiles such as BuLi and PhLi to give the (E)-allylsilanes. All of the steps involved in the sequence proceed with extremely high stereoselectivity and stereospecificity, leading to almost complete 1,3-chirality transfer through the overall transformation. The dimerization step, which forms diastereomeric intermediates, allows the synthesis of a highly enantioenriched allylsilane (99.4 % ee) from an optically active allylic alcohol with lower enantiopurity (79.2 % ee) by enrichment of enantiopurity. A general method for the determination of the enantiomeric excesses of (E)-allylsilanes is also described in detail.