Divergent reactions on racemic mixtures

Methods that furnish enantioenriched products are crucial in modern organic synthesis. An underutilized strategy to arrive at enantioenriched products is to perform divergent reactions on racemic mixtures, where each enantiomer of the starting material reacts with a single chiral reagent to furnish two separable, non-enantiomeric products that are enantioenriched. Stereodivergent, regiodivergent and structurally divergent reactions on racemic mixtures are discussed in this tutorial review.     

Au(I)-catalyzed annulation of enantioenriched allenes in the enantioselective total synthesis of (-)-rhazinilam

Highly stereoselective Au(I)-catalyzed pyrrole additions to enantioenriched allenes afford a unique entry to optically active heterocycles. Asymmetric quaternary carbons can be installed with concurrent heterocycle annulation utilizing this methodology. The enantioenriched allenes are conveniently obtained by catalytic asymmetric acyl halide-aldehyde cyclocondensations and SN2' ring opening of the resulting enantioenriched beta-lactones. An enantioselective total synthesis of (-)-rhazinilam highlights the potential utility of this reaction technology in target-oriented synthesis.     

Asymmetric total synthesis of rhinacanthin A

Starting from a reduced lapachol compound, the total synthesis of rhinacanthin A in both racemic and enantioenriched forms is achieved in eight steps without forming any undesired β-lapachone derivatives. For the synthesis of enantioenriched rhinacanthin A, the introduction of the asymmetric center was carried out by using the catalytic asymmetric epoxidation of an unfunctional trisubstituted olefin using Shi’s epoxidation diketal catalyst. The acidic treatment of a derived enantioenriched epoxynaphthol and the following CAN oxidation afforded the target molecule with high enantiomeric purity.     

Synthetic applications of lithiated N-Boc allylic amines as asymmetric homoenolate equivalents

Lithiation of N-(Boc)-N-(p-methoxyphenyl) allylic amines in the presence of (-)-sparteine provides asymmetric homoenolate equivalents which react with electrophiles to provide highly enantioenriched enecarbamates. Acidic hydrolysis of the enecarbamates can provide the corresponding beta-substituted aldehydes. A synthetic sequence that involves a stereocontrolled intramolecular nitrone-olefin dipolar cycloaddition has been developed for the preparation of enantioenriched 2-formyl-4-phenyl-1-aminocyclopentanes from one beta-allyl-substituted aldehyde. Further manipulations allow access to an enantioenriched beta-lactam. In another synthetic sequence, transmetalation of the lithiated intermediates and reactions with aldehyde electrophiles can be controlled to afford highly enantioenriched anti homoaldol products. Use of an anti aldehyde homoaldol product as the chiral electrophile in an iterative reaction provides a double homoaldol product containing four stereogenic centers with high diastereoselectivity and enantioselectivity. Reaction pathways are proposed to account for the observed products.     

Copper-catalyzed γ-selective and stereospecific allylic alkylation of ketene silyl acetals

Copper-catalyzed allylic alkylation of ketene silyl acetals proceeded with excellent γ-E-selectivity. Efficient α-to-γ chirality transfer with anti-selectivity occurred in the reaction of enantioenriched secondary allylic phosphates, affording enantioenriched β-branched γ,δ-unsaturated esters. Excellent functional group compatibility was observed.     

Preparation and use of enantioenriched allenylsilanes for the stereoselective synthesis of homopropargylic ethers

A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-component, Lewis acid mediated additions to in situ generated oxonium ions, resulting in enantioenriched homopropargylic ethers.     

Cu(I)-catalyzed stereospecific coupling reactions of enantioenriched α-stannylated benzyl carbamates and their application

Enantioenriched α-stannylated benzyl carbamates were used in highly stereospecific coupling reactions employing Cu(I) as catalyzing transition metal. Acid chlorides and allyl bromide derivatives were used as electrophilic coupling partners. The reaction was applied in the synthesis of two highly enantioenriched indanoles and one enantioenriched tetraline via intramolecular cyclization reactions.     

Asymmetric Synthesis of Chiral Sulfimides through the O-Alkylation of Enantioenriched Sulfinamides and Addition of Carbon Nucleophiles

Chiral sulfimides, the aza-analogues of sulfoxides, are valuable compounds in organic synthesis and medicinal chemistry. Herein, we report an efficient method for preparing chiral sulfimides from easily available enantioenriched sulfinamides. The key step of this method is a stereospecific oxygen-selective alkylation of enantioenriched sulfinamides, which is accomplished by using isopropyl iodide, K₂CO₃, and DMPU. The resulting chiral sulfinimidate esters are transformed to chiral sulfimides by the nucleophilic addition of the Grignard reagents under simple conditions. This transformation enables access to the enantioenriched diaryl or dialkyl sulfimides bearing two similar carbon substituents, which are difficult to synthesize by previous methods.     

Chiral counteranion-directed silver-catalyzed asymmetric synthesis of 1,2-dihydroisoquinolines by Friedel–Crafts alkylation reactions

The reaction of ortho-alkynylaryl aldimines and indoles catalyzed by a silver binol-derived phosphate was realized to afford a series of enantioenriched 1,2-dihydroisoquinolines in moderate to good yields and ee. An interesting phenomenon that highly enantioenriched products could be obtained from their lower ee form by silica gel column chromatography was observed, providing an easy access to the enantiopure form of the product.     

Palladium-catalyzed, asymmetric Baeyer-Villiger oxidation of prochiral cyclobutanones with PHOX ligands

Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer-Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center.     

Generation and Application of (Diborylmethyl)zinc(II) Species: Access to Enantioenriched gem‐Diborylalkanes by an Asymmetric Allylic Substitution

We report the successful generation of (diborylmethyl)zinc(II) species by transmetallation beteween isolable (diborylmethyl)lithium and zinc(II) halide (X=Br, Cl) and their application in the synthesis of enantioenriched gem‐diborylalkanes bearing a stereogenic center at the β‐position of the diboryl groups by an asymmetric allylic substitution reaction. The reaction has a broad substrate scope, and various enantioenriched gem‐diborylalkanes can be obtained in good yields with excellent enantioselectivity. Further elaboration of the enantioenriched gem‐diborylalkanes provides access to a diverse set of valuable chiral building blocks.     

Rhodium-catalyzed asymmetric one-pot transesterification and [2 + 2 + 2] cycloaddition leading to enantioenriched 3,3-disubstituted phthalides

[structure: see text]. We have developed a cationic rhodium(I)/Solphos complex-catalyzed asymmetric one-pot transesterification and [2 + 2 + 2] cycloaddition of 1,6-diyne esters with tertiary propargylic alcohols leading to enantioenriched tricyclic 3,3-disubstituted phthalides. The present method represents a versatile new route to the synthesis of enantioenriched tricyclic 3,3-disubstituted phthalides in view of the easy access to both coupling partners.     

Palladium-catalyzed asymmetric conjugate addition of arylboronic acids to five-, six-, and seven-membered β-substituted cyclic enones: enantioselective construction of all-carbon quaternary stereocenters

The first enantioselective Pd-catalyzed construction of all-carbon quaternary stereocenters via 1,4-addition of arylboronic acids to β-substituted cyclic enones is reported. Reaction of a wide range of arylboronic acids and cyclic enones using a catalyst prepared from Pd(OCOCF(3))(2) and a chiral pyridinooxazoline ligand yields enantioenriched products bearing benzylic stereocenters. Notably, this transformation is tolerant to air and moisture, providing a practical and operationally simple method of synthesizing enantioenriched all-carbon quaternary stereocenters.     

Iron catalyzed asymmetric oxyamination of olefins

The regioselective and enantioselective oxyamination of alkenes with N-sulfonyl oxaziridines is catalyzed by a novel iron(II) bis(oxazoline) complex. This process affords oxazolidine products that can be easily manipulated to yield highly enantioenriched free amino alcohols. The regioselectivity of this process is complementary to that obtained from the analogous copper(II)-catalyzed reaction. Thus, both regioisomers of enantioenriched 1,2-aminoalcohols can be obtained using oxaziridine-mediated oxyamination reactions, and the overall sense of regiochemistry can be controlled using the appropriate choice of inexpensive first-row transition metal catalyst.     

Synthetic Applications of the beta-Lithiation of beta-Aryl Secondary Amides: Diastereoselective and Enantioselective Substitutions

The sequence of beta-lithiation and electrophilic substitution of beta-aryl secondary amides is reported. The lithiations occur regioselectively at the beta-position, and the resulting lithiated intermediates can be reacted with a wide range of electrophiles to give substituted products. Reactions of beta-lithiated amides bearing an alpha-substituent provide substituted products with high diastereoselectivity. Electrophilic substitutions of beta-lithiated N-methylamides in the presence of the chiral diamine (-)-sparteine provide highly enantioenriched products. The methodology is used to synthesize enantioenriched beta-aryl beta-substituted amides, acids, and lactones.     

Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane Reagents

We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site‐specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions.     

Asymmetric Construction of Axially Chiral 2‐Arylpyrroles by Chirality Transfer of Atropisomeric Alkenes

Axially chiral 2‐arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by organocatalytic asymmetric N‐alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2‐arylazepine atropisomers were realized through a rationally designed ene reaction.     

Reversible 1,3-anti/syn-stereochemical courses in copper-catalyzed γ-selective allyl-alkyl coupling between chiral allylic phosphates and alkylboranes

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.     

Structure and reactivity of a chiral cyclononadienone

The structure and reactivity of a highly enantioenriched dissymmetric cyclononadienone are described.     

Synthesis of highly enantioenriched hydroxy- and dihydroxy-fatty esters: substrate precursors for cytochrome P450BioI

A series of highly enantioenriched hydroxy- and dihydroxy-fatty esters were required as part of our ongoing investigation into cytochrome P450_BioI. This mediates the biosynthesis of pimelic acid via C–C bond cleavage of long chain fatty acids within Bacillus subtilis. Herein we report the synthesis of various stereoisomers of methyl 7-hydroxytetradecanoate, methyl 8-hydroxytetradecanoate, and methyl 7,8-dihydroxytetradecanoate in highly enantioenriched form, using a combination of asymmetric synthesis and a preparative enantioselective HPLC is reported.