Sparteine-Mediated Deprotonation Research Articles

Diastereoselective Lithiation of N-Silyl-Protected (S)-Tetrahydro-1H-pyrrolo[1,2-c]imidazol-3(2H)-one

An L-proline-derived imidazolone protected with an N-triethylsilyl (N-TES) group undergoes diastereoselective lithiation–electrophile quench to give C5-substituted products with syn stereochemistry. Unlike the previous N-t-Bu analogues, the N-TES derivatives may be easily N-desilylated to give secondary ureas that serve as precursors to N-phenyl chiral bicyclic guanidines. INTRODUCTION The stereoselective synthesis of variously substituted pyrrolidines by lithiation–substitution reactions continues to evolve as a valuable tool in synthetic chemistry. Based initially on (–)-sparteine-mediated deprotonation on N-Boc pyrrolidine (1, Scheme 1) reported by Beak and coworkers, recent advances in ligand design have allowed for the synthesis of enantiomeric products, or the use of sub-stoichiometric amounts of ligand under dynamic thermodynamic resolution conditions. It is also now possible to install aryl and vinyl substituents with retention of stereochemical integrity of the chiral carbanion. As part of efforts to find alternate syntheses of chiral reagents with a pyrroloimidazol(in)e framework, we reported previously the diastereoselective lithiation–substitution of t-Bu protected urea 4 to afford a series of C5-substituted products with syn stereochemistry. This approach was modeled on Beak’s observation of syn-selective lithiation–substitution in chiral cyclic carbamate 6. 9 Although lithiation of urea 4 was effective for providing diastereomerically enriched imidazolinones, it posed two challenges for development of a more general approach leading to variously N-substituted pyrroloimidazolinium salt precatalysts: First, the synthesis of 4 from L-proline-derived Cbz-proteced t-Bu amide 3 gave inconsistent yields upon scale-up. Second, removal of the N-t-Bu group from the C5-substituted products 5 required prolonged exposure to refluxing trifluoroacetic acid, which posed stability issues for substituents in certain HETEROCYCLES, Vol. 88, No. 1, 2014 347

Enantioselective, (−)-sparteine-mediated deprotonation of geranyl and neryl N, N-diisopropylcarbamate: configurational stability of the intermediate lithium compounds

( E)/( Z)-Isomeric allylic carbamate esters were deprotonated by n-butyllithium/(−)-sparteine in toluene. Trapping experiments with chlorotrimethylsilane afforded the α-substitution products, with ( R)-configuration, revealing that the pro-S proton is removed predominantly to form the corresponding ( S)-lithium·(−)-sparteine derivatives; k S / k R >15:1 and >7:1, respectively. A slow ( S)→( R)-epimerization occurs at −78 °C ( T 1/2>60 min). The allylic double bond is stable to ( Z)–( E) isomerization under these conditions.

Asymmetric Synthesis of 2‐Alkenyl‐1‐cyclopentanols via Tin—Lithium Exchange and Intramolecular Cycloalkylation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric synthesis of 2-alkenyl-1-cyclopentanols via tin-lithium exchange and intramolecular cycloalkylation.

[reaction: see text] We report a method for the synthesis of chiral cyclopentanes using tin-lithium exchange and cycloalkylation reactions. The sec-butyllithium/(-)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishes a highly enantioenriched stannane as a stable carbanion equivalent. It was transformed into suitable cyclization precursors, which underwent tin-lithium exchange and stereoselective cycloalkylation when reacted with n-butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic resolution was observed with a higher substituted stannane.

Kinetics and mechanism of the (-)-sparteine-mediated deprotonation of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine.

The (-)-sparteine-mediated asymmetric lithiation-substitution of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine ((E)-5) to afford gamma-substituted enantiomerically enriched products 6 is reported. The solution structure for the lithiated intermediate 8.1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, alpha-lithio, eta(1)-coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale; competitive electrophilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectroscopy provide pseudo-first-order rate constants for reactions with a variety of concentrations of amine, (-)-sparteine, and n-BuLi. The reaction is first order in amine and zero order in 1:1 base--ligand complex. When the concentration of n-BuLi is varied independently of (-)-sparteine concentration, the reaction rate exhibits an inverse dependence on n-BuLi concentration. The deuterium isotope effect for the reaction was determined to be 86 at -75 degrees C, a result consistent with C--H bond breaking in the rate-determining step and indicative of tunneling. A reaction pathway involving a prelithiation complex is supported by kinetic simulations.

Chiral diamines. Part 3: Effect of ligand structure on the enantioselective deprotonation of N-Boc-pyrrolidine with i-PrLi: a computational comparison of (−)-sparteine and ( S, S)-1,2-bis( N, N-dimethylamino)cyclohexane

The deprotonation N-Boc-pyrrolidine by i-PrLi–( S, S)-1,2-bis( N, N-dimethylamino)cyclohexane has been studied at the HF/3-21G and B3P86/6-31G* theoretical levels. The two lowest energy complexes of the N-Boc-pyrrolidine– i-PrLi–diamine ligand, as well as the transition states leading to proton transfer, were found to be similar in both geometry and energy in accord with experimental findings. The results are compared to those for the analogous but enantioselective (−)-sparteine-mediated deprotonation.

Diastereoselective Lithiation and Substitution of (S)-N-Benzylprolinol and rac-N-Benzylpiperidine-2-methanol via the Carbamate Esters: Kinetic Resolution by Means of (-)-Sparteine-Mediated Deprotonation

Diastereoselective Lithiation and Substitution of (S)-N-Benzylprolinol and rac-N-Benzylpiperidine-2-methanol via the Carbamate Esters: Kinetic Resolution by Means of (-)-Sparteine-Mediated Deprotonation

Efficient Desymmetrization ofmeso-cis-1,2-Cyclohexanedimethanol with Differentiation between Diastereotopic and Enantiotopic C−H Bonds by (−)-Sparteine-Mediated Deprotonation

A powerful nonenzymatic desymmetrization of a meso-diol, coupled with an efficient diastereoselective C–C bond formation at one of the enantiotopic sites is reported. The key step consists of the selection by sec-butyllithium/(−)-sparteine between enantiotopic and diastereotopic groups in the deprotonation step [Eq. (a)]. Kinetic resolutions of desymmetrized racemates (El = [D1] or Me3Sn) also were achieved.

Convenient Synthesis of Enantiomerically Enriched β-Cyclopropylalaninol Derivatives by Kinetic Resolution via (-)-Sparteine-Mediated Deprotonation

Convenient Synthesis of Enantiomerically Enriched β-Cyclopropylalaninol Derivatives by Kinetic Resolution via (-)-Sparteine-Mediated Deprotonation