Diastereo- and enantioselective direct catalytic aldol reaction of 2-hydroxyacetophenones with aldehydes promoted by a heteropolymetallic complex: catalytic asymmetric synthesis of anti-1,2-diols

An anti-selective direct catalytic asymmetric aldol reaction of 2-hydroxyacetophenones with aldehydes is described. The reaction is catalyzed by a heteropolymetallic complex to afford anti-alpha,beta-dihydroxy ketones as the major diastereomer with excellent enantioselectivity. The use of 2-hydroxyacetophenones bearing electron-donating groups at the phenyl moiety enabled efficient transformation of the aldol products (alpha,beta-dihydroxy ketones) into the corresponding alpha,beta-dihydroxy ester derivatives via Baeyer-Villiger oxidation. A plausible reaction mechanism is also discussed based on the stereochemistry of the products.     

Multifunctional asymmetric catalysis

Two types of general and practical enantioselective catalysts, namely, bimetallic complexes and Lewis acid-Lewis base bifunctional catalysts were developed based on the concept of multifunctional catalysis. In the first part of this review, the first example of a catalytic enatioselective nitro-Mannich reaction as well as a direct catalytic enantioselective aldol reaction of 2-hydroxyacetophenone using bimetallic complexes is discussed. The new complex, composed of ytterbium, potassium, and BINOL in a ratio of 1:1:3, promoted the nitro-Mannich reaction of nitromethane with up to 91% ee. On the other hand, second generation ALB catalyzed an enantioselective and diastereoselective nitro-Mannich reaction of nitroalkanes in up to 83% ee with a diastereomeric ratio up to 7:1. Moreover, the reaction of aldehydes with 2-hydroxyacetophenone in the presence of LLB, KHMDS, and H2O selectively gave the corresponding anti-alpha,beta-dihydroxy ketones in up to 95% ee and, in the presence of the catalyst prepared from linked-BINOL and 2 eq of Et2Zn, selectively afforded the syn-alpha,beta-dihydroxy ketones in up to 86% ee. In the second part, the development of new catalysts displaying a Lewis acidity and a Lewis basicity is described. The Lewis acid of the catalyst activates aldehydes, imines, acyl quinoliniums, and ketones. At the same time, the Lewis base activates the nucleophile (TMSCN). Catalysts of this type produced a highly enantioselective cyanation of these electrophiles. Application of the catalytic enantioselective cyanosilylation of aldehydes to a total synthesis of epothilones is also described.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of glycolate-derived silyl ketene acetals to aldehydes

A catalytic system involving silicon tetrachloride and a chiral, Lewis basic bisphosphoramide catalyst is effective for the addition of glycolate-derived silyl ketene acetals to aldehydes. It was found that the sense of diastereoselectivity could be modulated by changing the size of the substituents on the silyl ketene acetals. In general, the trimethylsilyl ketene acetals derived from methyl glycolates with a large protecting group on the alpha-oxygen provide enantiomerically enriched alpha,beta-dihydroxy esters with high syn-diastereoselectivity, whereas the tert-butyldimethylsilyl ketene acetals derived from bulky esters of alpha-methoxyacetic acid provide enantiomerically enriched alpha,beta-dihydroxy esters with high anti-diastereoselecitvity.     

A beta-lactam-based stereoselective access to beta,gamma-dihydroxy alpha-amino acid-derived peptides with either alpha,beta-like or unlike configurations

A concise access to alpha,beta-dihydroxy alpha-amino acid-derived N-carboxy anhydrides (NCAs) with either like or unlike relative configuration is described. The key steps of the synthetic route are the preparation of the nonracemic 4-alkenyl beta-lactams, through either Horner-type olefination of a common 4-formyl beta-lactam or the Corey-Winter alkene synthesis applied to 4-dihydroxyalkyl beta-lactams, followed by the Sharpless AD reaction, and a subsequent ring expansion of the corresponding 4-substituted 3-hydroxy beta-lactams promoted by TEMPO. The opening of thus-prepared NCAs upon treatment with different O- and N-nucleophiles, including alpha-amino esters which lead to peptides, has also been studied under various reaction conditions.     

Catalytic asymmetric 1,4-addition reactions using alpha,beta-unsaturated N-acylpyrroles as highly reactive monodentate alpha,beta-unsaturated ester surrogates

Synthesis and application of alpha,beta-unsaturated N-acylpyrroles as highly reactive, monodentate ester surrogates in the catalytic asymmetric epoxidation and Michael reactions are described. alpha,beta-Unsaturated N-acylpyrroles with various functional groups were synthesized by the Wittig reaction using ylide 2. A Sm(O-i-Pr)(3)/H(8)-BINOL complex was the most effective catalyst for the epoxidation to afford pyrrolyl epoxides in up to 100% yield and >99% ee. Catalyst loading was successfully reduced to as little as 0.02 mol % (substrate/catalyst = 5000). The high turnover frequency and high volumetric productivity of the present reaction are also noteworthy. In addition, a sequential Wittig olefination-catalytic asymmetric epoxidation reaction was developed, providing efficient one-pot access to optically active epoxides from various aldehydes in high yield and ee (96-->99%). In a direct catalytic asymmetric Michael reaction of hydroxyketone promoted by the Et(2)Zn/linked-BINOL complex, Michael adducts were obtained in good yield (74-97%), dr (69/31-95/5), and ee (73-95%). This represents the first direct catalytic asymmetric Michael reaction of unmodified ketone to an alpha,beta-unsaturated carboxylic acid derivative. The properties of alpha,beta-unsaturated N-acylpyrrole are also discussed. Finally, the utility of the N-acylpyrrole unit for further transformations is demonstrated.     

Direct asymmetric organocatalytic Michael reactions of alpha,alpha-disubstituted aldehydes with beta-nitrostyrenes for the synthesis of quaternary carbon-containing products

[reaction: see text] Direct asymmetric catalytic Michael reactions have been performed using chiral-amine/acid bifunctional catalysts. Performed with 0.3 equiv of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and 0.3 equiv of trifluoroacetic acid as the catalyst, the reaction of alpha,alpha-dialkylaldehydes with (E)-beta-nitrostyrene provided the alpha,alpha-dialkyl Michael products in up to 96% yield with up to 91% ee. With respect to enantioselectivity, l-proline was a poor catalyst of this class of Michael reactions.     

In Process Citation

By means of suitable chemical reactions, formaldehyde is obtained from 1,2-diols, hexitols, primary alpha-amino alcohols, 2-nitro-1-hydroxy aliphatic compounds, the méthylène group in R-CHCH(2) and 17-ketolsteroids, and converted into a dihydrolutidine derivative which is then determined by fluorimetry. The formation of dihydro-pyridine derivatives also allows the fluorimetric determination of primary alkylamines, nitriles and aliphatic aldehydes. Aldehydes with an alpha-methylene group and 2-deoxysugars can be determined by forming fluorescent quinaldines. The fluorescent compound obtained by condensing glyoxylic acid with resorcinol allows the determination of alpha,beta-dihydroxy and hexuronic acids after a periodate oxidation. The fluorimetric determination of phenols is achieved by converting them into coumarins.     

Iridium complex-catalyzed allylic amination of allylic esters

Iridium complex-catalyzed allylic amination of allylic carbonates was studied. The solvent strongly affected the catalytic activity. The use of a polar solvent such as EtOH is essential for obtaining the products in high yield. The reaction of (E)-3-substituted-2-propenyl carbonate and 1-substituted-2-propenyl carbonate with pyrrolidine in the presence of a catalytic amount of [Ir(COD)Cl](2) and P(OPh)(3) (P/Ir = 2) gave a branch amine with up to 99% selectivity. Both secondary and primary amines could be used for this reaction. When a primary amine was used, selective monoallylation occurred. No diallylation product was obtained. The reaction of 1,1-disubstituted-2-propenyl acetate with amines exclusively gave an alpha,alpha-disubstituted allylic amine. This reaction provides an alternative route to the addition of an organometallic reagent to ketimines for the preparation of such amines. The reaction of (Z)-3-substituted-2-propenyl carbonate with amines gave (Z)-linear amines with up to 100% selectivity. In all cases, no (E)-linear amine was obtained. The selectivities described here have not been achieved in similar palladium complex-catalyzed reactions.     

Iridium complex-catalyzed [2+2+2] cycloaddition of alpha,omega-diynes with monoynes and monoenes

[reaction: see text] [Ir(cod)Cl]2/DPPE was found to be a new catalyst for the cycloaddition of alpha,omega-diynes with monoynes to give polysubstituted benzene derivatives in high yields. Internal monoynes as well as terminal monoynes could be used. The reaction tolerates a broad range of functional groups such as alcohol, amine, alkene, ether, halogen, and nitrile. The reaction of 1,6-octadiyne derivatives with 1-alkynes gives ortho products and meta products. The regioselectivity could be controlled by the choice of ligand. The reaction with DPPE was meta selective, with meta selectivity of up to 82%. The reaction with DPPF was ortho selective, with ortho selectivity of up to 88%. We propose a mechanism to account for this regioselective cycloaddition. [Ir(cod)Cl](2)/DPPE also catalyzed the cycloaddition of alpha,omega-diynes with 2,5-dihydrofuran to give bicyclic cyclohexadiene derivatives. The reaction with 2,3-dihydrofuran and n-butyl vinyl ether gave benzene derivatives instead of cyclohexadiene derivatives. We also propose a mechanism to account for this novel aromatization that includes cleavage of the C-O bond.     

Zn粉作为催化剂前体催化对甲苯磺酰胺/二溴海因与烯烃的区域选择性和立体选择性氨溴加成反应

Zn粉作为催化剂前体, 在反应中可被原位氧化成高效Zn(Ⅱ)-催化剂. 在该催化剂催化下, 以对甲苯磺酰胺和1,3-二溴-5,5-二甲基乙内酰脲(二溴海因)为氮源/卤素源, 二氯甲烷作溶剂, 建立了烯键上的高度区域选择和立体选择性氨溴加成反应新体系. 该方法在室温下可高产率地制得邻位氨基溴的加成产物, 最高收率可达99%. 实验结果表明, 当与双键直接相连的苯环对位有强给电子基团(CH₃O)时, 反应收率高, 并可得到唯一的氨溴加成产物(α-溴-β-氨基); 当与双键直接相连的苯环对位有强拉电子基团(NO₂)或弱拉电子基团(如Br和F)时, 该反应的产率相对较低, 但也能制得另一个唯一的氨溴加成产物异构体(α-氨基-β-溴型). 本文考察了20种不同结构底物的氨溴加成反应情况, 产物结构经过¹H NMR、¹³C NMR和元素分析确证, 并探讨了该反应的机理.     

exo-selective asymmetric Diels-Alder reaction catalyzed by diamine salts as organocatalysts

[reaction: see text] A novel binaphthyl-based diamine (R)-2 was designed and synthesized. A protonic acid-(R)-2 salt catalyst has the advantage of exhibiting unprecedented high exo selectivity in the asymmetric Diels-Alder reaction of alpha,beta-unsaturated aldehydes. For instance, the reaction between cinnamaldehyde and cyclopentadiene in the presence of 12 mol % of binaphthyl-based diamine (R)-2 and 10 mol % of p-TsOH.H(2)O in alpha,alpha,alpha-trifluorotoluene at -20 degrees C gave the corresponding exo cycloadduct with 92% ee as a major diastereomer (exo/endo = 13/1).     

Rhodium(II,II) dimer as an efficient catalyst for aziridination of sulfonamides and amidation of steroids

[reaction: see text] Unsaturated sulfonamides underwent direct intramolecular aziridination catalyzed by Rh(2)(OAc)(4) with PhI(OAc)(2) and Al(2)O(3) to give the corresponding aziridine products in excellent yields (up to 98%) and with good to excellent conversions. High turnovers (up to 1375) were achieved. The intermolecular rhodium-catalyzed amidation of cholesteryl acetate with PhI=NTs or PhI(OAc)(2)/NH(2)R as the nitrogen source exhibited both excellent regio- and alpha-selectivity (alpha/beta ratio up to 9:1).     

Alpha-amidation of cyclic ethers catalyzed by simple copper salt and a mild and efficient preparation method for alpha,omega-amino alcohols

Copper(II) trifluoromethanesulfonate catalyzed the amidation of cyclic ethers with iminoiodanes under mild conditions (CH2Cl2, 40 degrees C) with good yields (up to 86% based on 97% conversion) and selectivity (only alpha-amino products were found). Subsequently, the tosylamidated products could undergo a reductive ring-opening reaction to give alpha,omega-amino alcohols.     

Diastereoselective and enantiospecific synthesis of gamma-substituted alpha,beta-unsaturated nitriles from O-protected allylic cyanohydrins

gamma-Functionalized alpha,beta-unsaturated nitriles are prepared diastereoselectively and enantiospecifically from enantioenriched cyanohydrin-O-phosphates and carbonates derived from alpha,beta-unsaturated aldehydes, either by palladium or iridium-catalyzed nucleophilic allylic substitution reactions with different nucleophiles. Appropriate reaction conditions for dibenzylamine, benzylamine, sodium azide, NaOAc, tetra-n-butylammonium acetate (TBAA), the corresponding sodium salts of phenol and N-hydroxysuccinimide and the carbonucleophile sodium dimethyl malonate are described. Different substituted O-protected cyanohydrins, such as carbonates and phosphates, derived from crotonaldehyde, (E)-hex-2-enal, oct-2-enal, 2-methylbut-2-enal, and cinnamaldehyde are used as allylic substrates. The substitution takes place with total retention of the configuration for the (E)-gamma-functionalized nitriles and with inversion of the configuration for the Z-isomers. In general, cyanohydrin-O-phosphates are the materials of choice to get the highest E-diastereoselectivity. Dibenzylamine is the best nucleophile for the synthesis of gamma-nitrogenated alpha,beta-unsaturated nitriles in the presence of either palladium or iridium catalysts when aliphatic compounds and cinnamaldehyde derivative are used (up to 98% dr). For the synthesis of gamma-oxygenated alpha,beta-unsaturated nitriles sodium or TBAA the reagents are selected to avoid epimerizations in up to 76% dr. Finally, the Tsuji-Trost reaction with sodium malonate works only under palladium catalysis in up to 70% dr.     

Organocatalytic asymmetric epoxidation reactions in water-alcohol solutions

The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.     

Catalytic asymmetric nitroaldol (Henry) reaction with a zinc-Fam catalyst

Ferrocenyl-substituted aziridinylmethanol (Fam-1) was used as a catalyst with zinc for the asymmetric nitroaldol (Henry) reaction. This catalyst worked with a variety of aldehydes (aromatic, aliphatic, alpha,beta-unsaturated, and heteroaromatic) and alpha-ketoesters to give the nitroaldol product in up to 97% yield and 91% ee. The chiral ligand can be recovered and recycled without losing its activity.     

Direct catalytic asymmetric aldol reaction of hydroxyketones: asymmetric Zn catalysis with a Et(2)Zn/linked-BINOL complex

Full details of our newly developed catalyses with asymmetric zinc complexes as mimics of class II zinc-containing aldolase are described. A Et(2)Zn/(S,S)-linked-BINOL complex was developed and successfully applied to direct catalytic asymmetric aldol reactions of hydroxyketones. A Et(2)Zn/(S,S)-linked-BINOL 1 = 2/1 system was initially developed, which efficiently promoted the direct aldol reaction of 2-hydroxy-2'-methoxyacetophenone (7d). Using 1 mol % of (S,S)-linked-BINOL 1 and 2 mol % of Et(2)Zn, we obtained 1,2-dihydroxyketones syn-selectively in high yield (up to 95%), good diastereomeric ratio (up to 97/3), and excellent enantiomeric excess (up to 99%). Mechanistic investigation of Et(2)Zn/(S,S)-linked-BINOL 1, including X-ray analysis, NMR analysis, cold spray ionization mass spectrometry (CSI-MS) analysis, and kinetic studies, provided new insight into the active oligomeric Zn/(S,S)-linked-BINOL 1/ketone 7d active species. On the basis of mechanistic investigations, a modified second generation Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 with molecular sieves 3A (MS 3A) system was developed as a much more effective catalyst system for the direct aldol reaction. As little as 0.1 mol % of (S,S)-linked-BINOL 1 and 0.4 mol % of Et(2)Zn promoted the direct aldol reaction smoothly, using only 1.1 equiv of 7d as a donor (substrate/ligand = 1000). This is the most efficient, in terms of catalyst loading, asymmetric catalyst for the direct catalytic asymmetric aldol reaction. Moreover, the Et(2)Zn/(S,S)-linked-BINOL 1 = 4/1 system was effective in the direct catalytic asymmetric aldol reaction of 2-hydroxy-2'-methoxypropiophenone (12), which afforded a chiral tetrasubstituted carbon center (tert-alcohol) in good yield (up to 97%) and ee (up to 97%), albeit in modest syn-selectivity. Newly developed (S,S)-sulfur-linked-BINOL 2 was also effective in the direct aldol reaction of 12. The Et(2)Zn/(S,S)-sulfur-linked-BINOL 2 = 4/1 system gave aldol adducts anti-selectively in good ee (up to 93%). Transformations of the aldol adducts into synthetically versatile intermediates were also described.     

Direct catalytic asymmetric Mannich-type reaction of hydroxyketone using a Et2Zn/linked-BINOL complex: synthesis of either anti- or syn-beta-amino alcohols

Full details of a direct catalytic asymmetric Mannich-type reaction of a hydroxyketone using a Et2Zn/(S,S)-linked-BINOL complex are described. By choosing the proper protective groups on imine nitrogen, either anti- or syn-beta-amino alcohol was obtained in good diastereomeric ratio, yield, and excellent enantiomeric excess using the same zinc catalysis. N-Diphenylphosphinoyl (Dpp) imine 3 gave anti-beta-amino alcohols in anti/syn = up to >98/2, up to >99% yield, and up to >99.5% ee, while Boc-imine 4 gave syn-beta-amino alcohols in anti/syn = up to 5/95, up to >99% yield, and up to >99.5% ee. The high catalyst turnover number (TON) is also noteworthy. Catalyst loading was successfully reduced to 0.02 mol % (TON = up to 4920) for the anti-selective reaction and 0.05 mol % (TON = up to 1760) for the syn-selective reaction. The Et2Zn/(S,S)-linked-BINOL complex exhibited far better TON than in previous reports of catalytic asymmetric Mannich-type reactions. Mechanistic studies to clarify the reason for the high catalyst efficiency as well as transformations of Mannich adducts are also described.     

Development of a new reaction system for the synthesis of highly optically active alpha,gamma-substituted gamma-butyrolactones

A highly useful method for the synthesis of optically active alpha,gamma-substituted gamma-butyrolactones has been developed. The SmI(2)-induced reductive coupling of chiral 2-alkyl acrylates derived from isosorbide with ketones in the presence of (1S)-(-)-2,10-camphorsultam as a proton source give the chiral alpha,gamma-substituted gamma-butyrolactones in good yields and high enantiomeric purities (up to >99% ee for trans and 75% ee for cis). The reaction system has been investigated with various ketones, and it is demonstrated that this system is very effective for trans-alpha,gamma-substituted gamma-butyrolactones. Both the chiral auxiliary and the hindered proton source in this system are necessary for the observed excellent ee values of the products. The absolute configuration of the trans products is assigned on the basis of the X-ray crystal structure.     

Synthesis of a hydroxyethylene isostere of the tripeptide Arg-Gly-Leu via a convergent acyl-like radical addition strategy

[reaction: see text] A hydroxyethylene isostere of the tripeptide Arg-Gly-Leu, representing an important fragment of a novel cyclic-peptide-based uPA inhibitor, was synthesized in few steps employing as the key step a samarium diiodide promoted coupling of either the 4-thiopyridyl ester of N(alpha)-Fmoc- or N(alpha)-Cbz-protected L-ornithine with the N-acryloyl derivative of L-leucine methyl ester. Epimerization under the coupling conditions at the chiral center in the alpha-position to the ketone was demonstrated not to take place. A stereoselective reduction of the Cbz-protected aminoketone obtained from this radical reaction was promoted by the same single-electron reducing agent in the presence of methanol providing the syn-amino alcohol with a diastereoselectivity of 85:15. With the use of lithium tri-tert-butoxyaluminum hydride in methanol, the corresponding anti-isomer was obtained almost exclusively. Subsequent elaboration of the ornithine moiety in the anti-isomer by introduction of the guanidine group followed by hydrolysis of the C-terminal ester bond and protection of the alcohol as its tert-butyldimethylsilyl ether provided the desired tripeptide mimic. The long reaction times required for the radical addition reactions with N(delta)-Boc-L-ornithine (up to 5 days) led to a short study where a series of 4-thiopyridyl esters of Cbz-protected amino acids were reacted with two acrylates. Whereas N(delta)-Boc-L-ornithine, alanine, phenylalanine, proline, and leucine all provided the aminoketone in 43-79% yield, valine only afforded traces of the coupling product.