Access to N‐Substituted 2‐Pyridones by Catalytic Intermolecular Dearomatization and 1,4‐Acyl Transfer

A novel rhodium‐catalyzed dearomatization of O‐substituted pyridines to access N‐substituted 2‐pyridones has been developed. A computational study suggests a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4‐acyl migratory rearrangement from O to C. Furthermore, the chiral dirhodium complexes serve as the catalyst for the asymmetric transformation with excellent enantioselective control. DFT calculations indicate the chirality is transferred from axial chirality to the central stereogenic centre. The stronger π–π interaction and CH–π interaction account for the high enantioselectivity.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

Asymmetric Synthesis of Biaryl Atropisomers Using an Organocatalyst-Mediated Domino Reaction as the Key Step

A three-pot synthetic method that features the use of an organocatalyst as the key step was developed for the preparation of biaryl atropisomers. The first reaction is an asymmetric domino Michael–Henry reaction catalyzed by diphenylprolinol silyl ether to afford the substituted nitrocyclohexanecarbaldehyde with four stereogenic centers and one defined configuration of a stereogenic axis with excellent enantioselectivity. Removal of the central chirality from the domino products afforded biaryl atropisomers having axial chirality with excellent enantioselectivity.     

Copper-catalyzed gamma-selective and stereospecific substitution reaction of allylic carbonates with diboron: efficient route to chiral allylboron compounds

A copper-catalyzed gamma-selective and stereospecific substitution reaction of allylic carbonates with a diboron reagent affording allylboron compounds is described. Boryl group was selectively introduced at the gamma-position of the leaving carbonate group. Functionalized allylboronates that have an acetal, ester, or isolated alkene were prepared. The reaction of optically active allylic carbonates underwent complete alpha-to-gamma chirality transfer with anti-stereochemistry to produce optically active allylboronates having a boron-substituted stereogenic center.     

Intramolecular carbolithiation reactions of chiral alpha-amino-organolithium species

Enantiomerically enriched alpha-amino-organolithium species, in which the lithium atom is attached to a stereogenic carbon centre, have been found to be chemically stable at room temperature in a solvent of very low polarity and undergo intramolecular carbolithiation onto an unactivated alkene. The configurational stability of the chiral organolithium species, bearing a variety of N-alkenyl substituents, was probed by studying the enantiomeric purity of the cyclization products. With N-but-3-enyl-2-lithiopyrrolidine, cyclization to the five-membered ring is more rapid than racemization and a high yield of the pyrrolizidine alkaloid (+)-pseudoheliotridane was obtained with no loss of optical purity. In contrast, with N-pent-4-enyl-2-lithiopyrrolidine, cyclization to the six-membered ring was found to occur with significant loss of optical purity. The cyclization to the six-membered ring was determined to occur with a half-life, t(1/2) approximately 90 min at 23 degrees C. The epimerization of this organolithium species in hexane/Et2O 4:1 was calculated to have a half-life, t(1/2) approximately 30 min at 23 degrees C. Enhanced levels of enantioselectivity for the formation of the indolizidine ring system were obtained using an alkene bearing a terminal phenylthio substituent. With N-[(3-phenylthio)-prop-2-enyl]-2-lithiopyrrolidine, cyclization to the four-membered ring occurs with poor enantioselectivity at low temperature in THF but is highly enantioselective at room temperature in a solvent of very low polarity.     

Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters

A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous-flow process using a polymer-supported variant of the catalyst.     

Mechanistic investigation of enediyne-connected amino ester rearrangement. Theoretical rationale for the exclusive preference for 1,6- or 1,5-hydrogen atom transfer depending on the substrate. A potential route to chiral naphthoazepines

Memory of chirality (MOC) and deuterium-labeling studies were used to demonstrate that the cascade rearrangement of enediyne-connected amino esters 1a and 1b evolved through exclusive 1,5- or 1,6-hydrogen atom transfer, subsequent to 1,3-proton shift and Saito-Myers cyclization, depending on the structure of the starting material. These results were independently confirmed by DFT theoretical calculations performed on model monoradicals. These calculations clearly demonstrate that in the alanine series, 1,5-hydrogen shift is kinetically favored over 1,6-hydrogen shift because of its greater exergonicity. In the valine series, the bulk of the substituent at the nitrogen atom has a major influence on the fate of the reaction. N-Tosylation increases the barrier to 1,5-hydrogen shift to the benefit of 1,6-hydrogen shift. The ready availability of 1,6-hydrogen atom transfer was explored as a potential route for the enantioselective synthesis of naphthoazepines.     

Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters

A highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.     

Pincer ligands based on α-amino acids: V. New generation chiral receptors for the recognition of amino acid enantiomers in aqueous environment

Selective recognition of enantiomers of amino acids valine, methionine, phenylalanine, serine, and tyrosine by a binuclear copper complex with an azomethine obtained from 2,6-diformyl-4-methylphenol and L-valine was studied by means of spectrophotometry. The binding constants of individual enentiomers were estimated for valine, phenylalanine, methionine, serine, and tyrosine, and the enantioselectivity factors were evaluated. The isomers of serine and tyrosine (with respect to the first stage) were recognized with a considerable enantioselectivity (1.34 and 5.46 respectively), whereas the binding constants of valine and phenylalanine enantiomers are virtually indistinguishable.     

Memory of chirality in cascade rearrangements of enediynes

The cascade rearrangement of chiral enediynes 1c-e, involving successively 1,3-proton shift, Saito-Myers cyclization, 1,5-hydrogen atom transfer, and intramolecular coupling of the resulting biradical, proceeded at 80 °C to form tri- and tetracyclic heterocycles possessing a quaternary stereogenic center with a very high level of memory of chirality.     

Structural Diversity of Copper(I)–N‐Heterocyclic Carbene Complexes; Ligand Tuning Facilitates Isolation of the First Structurally Characterised Copper(I)–NHC Containing a Copper(I)–Alkene Interaction

The preparation of a series of imidazolium salts bearing N‐allyl substituents, and a range of substituents on the second nitrogen atom that have varying electronic and steric properties, is reported. The ligands have been coordinated to a copper(I) centre and the resulting copper(I)–NHC (NHC=N‐heterocyclic carbene) complexes have been thoroughly examined, both in solution and in the solid‐state. The solid‐state structures are highly diverse and exhibit a range of unusual geometries and cuprophilic interactions. The first structurally characterised copper(I)–NHC complex containing a copper(I)–alkene interaction is reported. An N‐pyridyl substituent, which forms a dative bond with the copper(I) centre, stabilises an interaction between the metal centre and the allyl substituent of a neighbouring ligand, to form a 1D coordination polymer. The stabilisation is attributed to the pyridyl substituent increasing the electron density at the copper(I) centre, and thus enhancing the metal(d)‐to‐alkene(π*) back‐bonding. In addition, components other than charge transfer appear to have a role in copper(I)–alkene stabilisation because further increases in the Lewis basicity of the ligand disfavours copper(I)–alkene binding.     

Furanoside diphosphines derived from d-(+)-xylose and d-(+)-glucose as ligands in rhodium-catalysed asymmetric hydroformylation reactions

Chirality transfer by furanoside diphosphines 1–3 was investigated in the Rh-catalysed asymmetric hydroformylation of prochiral olefins. In general, they induced high regioselectivities with branched aldehydes and moderate enantioselectivities of up to 58%. Improved activities were seen when a methyl substituent was introduced at C-(5) of the sugar residue. Systematic variation of the configuration at C-(5) suggests that there is a cooperative effect between stereocentres, which results in a matched combination for ligand 3 with (R)-configuration at the C-(5) stereogenic centre. Introduction of a methyl substituent at C-(5) induces a strong coordination preference. The solution structures of the species formed under hydroformylation conditions were also investigated.     

Total Synthesis of (−)-HM-3 and (−)-HM-4 Using an Asymmetric Gold-Catalyzed [3,3]-Sigmatropic Rearrangement of Sulfonium

The asymmetric total synthesis of two sesquiterpenoids, (−)-HM-3 and (−)-HM-4, isolated from a phytopathogenic fungus, has been developed using a gold-catalyzed [3,3]-sigmatropic rearrangement of sulfonium as key step. During this transformation, an excellent chirality transfer was observed between the chiral sulfoxide substrate and the newly formed quaternary stereogenic center with 96 % enantiomeric excess. The implementation of this efficient methodology allowed us to isolate the two natural products in only 7–8 chemical steps with overall yields reaching 12–16 %.     

Synergistic Kinetic Resolution and Asymmetric Propargyl Claisen Rearrangement for the Synthesis of Chiral Allenes

The asymmetric propargyl Claisen rearrangement provides a convenient entry to chiral allene motifs. Herein, we describe the development of a kinetic resolution and asymmetric rearrangement of racemic propargyl vinyl ethers. This transformation afforded chiral allene products along with the enantiomerically enriched substrate in good yields with excellent diastereo‐ and enantioselectivity. The complete chirality transfer and facially selective rearrangement enabled the simultaneous construction of an axially chiral allenic unit and a quaternary carbon stereocenter.     

Intramolecular Pd-catalyzed carbocyclization, Heck reactions, and aryl-radical cyclizations with planar chiral arene tricarbonyl chromium complexes

(o-butenylhalobenzene)Cr(CO)(3) complexes were synthesized by diastereoselectve allylmetal additions to o-halo benzaldehyde complexes. The addition of allylZnBr proved particularly convenient and clean. The complexes undergo intramolecular Pd-catalyzed cyclizations (Heck reactions) without decomplexation and/or alkene isomerization. In complexes with a benzylic stereogenic center, the diastereoselectivity of the alkene carbopalladation is governed by the planar chirality of the complex rather than by the benzylic stereogenic center in the side chain. This reaction outcome can be rationalized by the geometry of the arene plane vs that of the Pd coordination plane in the transition step of the alkene carbopalladation step. An alternative cyclization procedure involves the generation of a Cr(CO)(3)-coordinated arene radical from the bromo and iodo complexes. Intramolecular aryl-radical cyclization affords indan complexes. The transition metal arene pi-bond remains intact during this process.     

Synthesis and application of quinazoline-oxazoline-containing (quinazox) ligands

A practical synthesis of potentially tridentate P,N,N-ligands containing two stereogenic elements incorporated into the axially chiral Quinazolinap and centrally chiral 2-oxazoline subunits is reported. The application of these novel hybrid ligands in Pd(0)-catalyzed asymmetric allylic alkylation revealed the matched and mismatched diastereomer, dominant stereogenic element, as well as the effect of the oxazoline R substituent on the level of enantioselectivity (ee's up to 81%). [structure: see text]     

Asymmetric Fluorinative Dearomatization of Tryptophol Derivatives by Chiral Anion Phase‐Transfer Catalysis

An asymmetric fluorinative dearomatization reaction of tryptophol derivatives was developed via chiral anion phase‐transfer catalysis. Various fluorinated furoindolines were obtained in moderate to excellent yields and enantioselectivity in the presence of Selectfluor. The preliminary mechanistic studies suggested the existence of an in situ formed tryptophol boronic ester plays a critical role in determining the enantioselectivity. This method features the facile introduction of a fluorine atom in a highly enantioselective manner and construction of two contiguous quaternary stereogenic centers.     

Synthesis of allenes from allylic alcohol derivatives bearing a bromine atom using a palladium(0)/diethylzinc system

A general and efficient synthesis of allenes using a palladium(0)/diethylzinc system is described. Treatment of mesylates or trichloroacetates of (E)- or (Z)-2-bromoalk-2-en-1-ols with diethylzinc in the presence of a catalytic amount of palladium(0) affords allenes bearing an aminoalkyl, alkyl, or aryl substituent(s) in good to high yields. No transfer of chirality from the stereogenic center carrying the mesyloxy group to the allene was observed.     

Chiral Cooperativity: The Effect of Distant Chiral Centers in Ferrocenylamine Ligands upon Enantioselectivity in the Gold(I)-Catalyzed Aldol Reaction

Long-range chiral cooperativity in enantiomerically pure ferrocenylamine ligands containing both planar and multiple centers of chirality (multiple stereogenic C-atoms) was demonstrated in the Au^I-catalyzed reaction of aldehydes and isocyanoesters. Synthetic methodology was developed for the synthesis of ferrocenylamine ligands with two and three chiral centers of known absolute configuration in the C-side chain in addition to the planar chirality of the molecule. The diastereo- and enantioselectivity of the Au^I-catalyzed formation of the trans- and cis-dihydrooxazoles 5 and 6 , respectively, from benzaldehyde ( 1 ) and methyl isocyanoacetate ( 2 ) depend upon the sequence of chirality (absolute configuration of the chiral centers) in the side chain of the ferrocenylamine ligands. Particularly significant effects were observed upon the enantioselectivity for the minor cis-dihydrooxazole 6 , for which, in certain cases, resulted in a change in the enantiomeric dihydrooxazole 6 produced in excess with a change in the absolute configuration of a distant chiral center. Significant effects upon diastereo- and enantioselectivity were observed when chiral ferrocenylamine ligands containing free OH groups were utilized. Using ligands containing a free OH group gave 6 with an absolute configuration opposite to that produced by the corresponding ester and carbamate derivatives. The possible mechanisms for the transmission of chiral information in the proposed stereoselective transition state (TS) was discussed, including both the formation of a stereogenic N-atom and steric effects based upon Newman's rule of six.     

Total synthesis of (R)-tylophorine by using an asymmetric hydrogenation of the allyl alcohol

An efficient synthesis of naturally occurring (R)-tylophorine is described. The alkaloid was prepared in seven steps from a known phenanthryl aldehyde with an overall yield of 14.2%. Asymmetric hydrogenation of an allyl alcohol was employed as a key step for installing a stereogenic center with good enantioselectivity (77% ee), and the ee value of the ω-chloro alcohol was improved to 95% by recrystallization. After azidation and oxidation of the enantio-enriched ω-chloro alcohol to the precursor of the Schmidt reaction, the chirality transfer in the stereospecific 1,2-migration furnished the chiral carbon in the alkaloid. Finally, a one-pot deformylation/Pictet-Spengler cyclization completed the total synthesis of (R)-tylophorine.