Enantiotopos-differentiating (-)-sparteine-mediated gamma-deprotonation of 1-alkenyl carbamates: DFT calculations verify the observed stereoselectivity

The enantioselective lithiation/gamma-deprotonation of three 1-alkenyl N,N-diisopropylcarbamates 6 by alkyllithium/(-)-sparteine has been modeled by the DFT method B3LYP/6-31G(d). The results of these calculations predict the preferential removal of the gamma-pro-R proton from the precomplexes 7 to give the (S)-lithio derivates 8. The calculations also indicate the necessity of an anion-stabilizing substituent (Ph, -CC-Ph) in the alpha-position of the substrate. These data are in excellent concordance with the experimental results. It is demonstrated that the formation and the properties of lithium carbanions are predictable with high accuracy by standard quantum chemical calculations if these species are monomeric and rigidified to some extent by chelation.     

Enantioselective carbanion cyclization of 5-alkenyl carbamates induced by asymmetric lithiation with s-butyllithium/(−)-sparteine system

Treatment of (E)-6-phenyl-5-hexenyl carbamates with s-BuLi/(−)-sparteine is shown to afford the trans-1,2-disubstituted cyclopentane derivatives in high % ee, along with the bicyclo[3.1.0]hexanes (bicyclization products).     

An enantioenriched vanadium phosphonate generated via asymmetric chiral amplification of crystallization from achiral sources showing a single-crystal-to-single-crystal dehydration process

By using an asymmetrical 2-carboxyphenylphosphonate ligand (2-cpp(3-)), a chiral layered vanadium compound (VO)(3)(2-cpp)(2)(H(2)O)(6)·H(2)O (1) is isolated. The bulk sample is enantioenriched due to symmetry breaking on crystallization. Partial release of the coordination water molecules upon heating leads to a single-crystal-to-single-crystal transformation to compound [(VO)(3)(2-cpp)(2)(H(2)O)(4)] (1a) which is centrosymmetric.     

Reagent-controlled asymmetric homologation of boronic esters by enantioenriched main-group chiral carbenoids

[reaction: see text] Putative enantioenriched carbenoid species, (R)-1-chloro-2-phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generated in situ by sulfoxide ligand exchange from (-)-(R(S),R)-1-chloro-2-phenylethyl p-tolyl sulfoxide (8), effected the stereocontrolled homologation of boronic esters. sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approaching that of sulfoxide 8 in examples employing Li-carbenoid 26.     

Asymmetric gamma-deprotonation and homoaldol reaction of 1,3-dien-2-yl carbamates: stereo- and regiochemistry

[reaction: see text] Lithium compounds 7 are configurationally stable intermediates obtained by deprotonation of 1,3-dien-2-yl carbamates 6 with n-butyllithium/(-)-sparteine with a high degree of enantiotopic differentiation at the gamma-position. They react with electrophiles regioselectively giving highly enantioenriched products. Starting with different isomers or changing the double-bond geometries in 6 leads to either of the enantiomers.     

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D₂O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C–H bond rather than the α-C–D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

A strategy of combining H/D-Ex and azomethine ylide-involved 1,3-DC was developed for the construction of α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation.     

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.     

Additions of enantioenriched allenylzinc and indium reagents to lactic aldehyde ethers

Allenylzinc and indium reagents were generated in situ through Pd(0)-catalyzed metalation of (R)- and (S)-3-butyn-2-ol methanesulfonate with Et(2)Zn and InI. These reagents add to the benzyl and TBS ethers of (S)-lactic aldehyde to afford diastereomeric stereotriads in moderate to high yield. The (S)/(S) combination afforded the anti,anti adducts with 94:6-100:0 diastereoselectivity. The (R)/(S) combination was mismatched, affording a mixture of anti,syn and syn,anti adducts in diastereomeric ratios of ca. 80:20-85:15. Addition of the racemic allenylmetal reagents to the (S)-lactic aldehyde ethers afforded the products of matched and mismatched pairings in equal amount.     

Asymmetric addition of achiral organomagnesium reagents or organolithiums to achiral aldehydes or ketones: a review

The enantioselective preparation of chiral secondary and tertiary alcohols via addition of an achiral organomagnesium reagent or an organolithium to an achiral aldehyde or ketone in a chiral medium is reviewed. The review is written in chronological order and contains 113 references to literature through late 2008.     

Absolute asymmetric synthesis by nucleophilic carbonyl addition using chiral crystals of achiral amides

Reaction of the chiral crystals of the achiral amides with n-butyllithium in toluene at -80 degrees C gave optically active alcohols in 17-84% ee.     

Asymmetric synthesis of di- and trisubstituted pyrrolidinones via zirconium-mediated intramolecular coupling of N-3-alkenyl carbamates

N-3-Alkenyl carbamates, which are readily available in enantiomerically pure form, undergo a stereoselective intramolecular coupling under the effect of a Cp₂ZrCl₂/2n-BuLi reagent. The influence of the carbamate structure on the stereoselectivity was tested. The reaction gives an easy access to various di- and trisubstituted enantiopure pyrrolidinones.     

Regio- and enantioselective copper-catalyzed addition of dialkylzinc reagents to cyclic 2-alkenyl aziridines

The reactions of some organocopper reagents with cyclic 2-alkenyl aziridines were examined. The stereoselectivity of the addition reaction of dialkylzinc can be strongly influenced by the use of phosphoramidites as ligands for copper. Chiral copper complexes of 2,2′-binaphthyl-based phosphoramidites were shown to be highly effective catalysts for the regio- (S_N2′) and anti-stereoselective addition of dialkylzinc reagents to these compounds according to a kinetic resolution protocol. The corresponding new cyclic allylic amine reaction products were obtained with a good enantioselectivity (83% ee).