Asymmetric Deprotonation Research Articles

Enantio‐ and Diastereoselective Synthesis of a 3,4‐Divinylpyrrolidine via Asymmetric Deprotonation and Cyclization of a 9‐Chloro‐5‐aza‐2,7‐nonadiene

Enantio‐ and Diastereoselective Synthesis of a 3,4‐Divinylpyrrolidine via Asymmetric Deprotonation and Cyclization of a 9‐Chloro‐5‐aza‐2,7‐nonadiene

Enantioselective Deprotonation of 2,6-Disubstituted Cyclohexanones with a Homochiral Magnesium Amide Base and the Observation of a Novel Kinetic Resolution Process

A recently developed homochiral magnesium amide base has been shown to be highly effective in the asymmetric deprotonation of cis-2,6-disubstituted cyclohexanones, affording excellent levels of both conversion and enantioselection (up to > 99.5 : 0.5 e.r.). In addition, a novel kinetic resolution process has been realised with the corresponding trans-disubstituted substrates, allowing access to optically enriched enol ethers and chiral ketones.

Enantioselective Synthesis of Cyclohexenylalkenes by Asymmetric Deprotonation of 4-tert-Butylcyclohexanone Followed by O-Nonaflation and Heck Couplings

Formation of (S)-4-tert-butylcyclohex-1-enyl nonaflate 4 by reaction with nonafluorobutanesulfonyl fluoride was found to be highly enantioselective both from (S)-4-tert-butyl-1-(trimethyl-siloxy)cyclohexene 3 and from the corresponding lithium enolate 2. The latter was generated by kinetic deprotonation of 4-tert-butylcyclohexanone 1 with lithium (R,R′)-bis(1-phenylethyl)amide as enantiopure base. A number of functionalized 2-(4-tert-butylcyclohex-1-enyl)alkenes 6 were prepared with roughly 90% enantiomeric excess from trimethylsilyl enol ether 3 using a one-pot nonaflation/Heck reaction sequence.

Kinetic and computational studies of the composition and structure of activated complexes in the asymmetric deprotonation of cyclohexene oxide by a norephedrine-derived chiral lithium amide†

Rational design of efficient chiral lithium amides for enantioselective deprotonations demands understanding of the origin of the selectivity. The mechanism of deprotonation of cyclohexene oxide 1 by lithium (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinylpropanamide 3, which yields (S)-cyclohex-2-en-1-ol (S)-5 in 93% enantiomeric excess in tetrahydrofuran (THF), has been investigated. Kinetics have been used to show that the reaction is first order with respect to the reagents 1 and 3, respectively. NMR investigations of a 6Li and 15N labelled isotopologue of 3 have previously shown that 3 is mainly a dimer of the lithium amide monomer in THF in the initial state. On the basis of these results it is concluded that the rate-limiting activated complexes for the epoxide deprotonation are composed of two molecules of monomer of lithium amide 3 and one molecule of epoxide. Structures and energies of unsolvated and specific THF-solvated reagents and activated complexes have been calculated using PM3 and B3LYP/6-31+G(d). The results are currently being explored for the rational design of chiral lithium amides with improved stereoselectivities.

Enantioselective deprotonation reactions using polymer-supported chiral magnesium amide bases.

Novel and readily accessible polymer-supported chiral magnesium amide reagents have been prepared and shown to be effective in the asymmetric deprotonation of a series of prochiral cyclohexanones, affording good to excellent levels of both conversion and enantiomeric ratio (up to 93:7); the Merrifield-based chiral amine species has been shown to be readily recyclable.

Asymmetric deprotonation—substitution of arenetricarbonylchromium(0) complexes: substituent controlled lithiation with the butyllithium–sparteine system

Attempted enantioselective deprotonation of fluorobenzenetricarbonylchromium(0) with ca. 1 equivalent of butyllithium/(−)-sparteine in ether–hexane at −78°C followed by a chlorotrimethylsilane quench gave the racemic ortho-substituted product. Analogous enantioselective deprotonation of anisoletricarbonylchromium(0), followed by electrophilic quench, gave the 1-(Rp)-substituted complexes in up to 77% yield with 27% e.e., but with methoxymethoxybenzenetricarbonylchromium(0), (4-triisopropylsilyloxymethyl)methoxymethoxybenzenetricarbonylchromium(0) and (N-t-butoxycarbonylaniline)tricarbonylchromium(0), the 1-(Sp)-products were formed in up to 58% yield with 92% e.e. The results are explained in terms of coordinative and non-coordinative enantioselective lithiation.

Enantioselective Reactions of Configurationally Unstable alpha-Thiobenzyllithium Compounds.

Too unstable for asymmetric deprotonation, alpha-sulfenyl carbanions can undergo asymmetric substitution reactions with high stereoselectivity [Eq. (1)]. The key to the asymmetric induction is the dynamic kinetic resolution of the complex formed between the organolithium compound and a chiral ligand, the most effective of which were bisoxazoline derivatives.

Desymmetrisation of 4,4-disubstituted cyclohexanones by enzyme-catalysed resolution of their enol acetates

Enol acetates 3–10 derived from prochiral 4,4-disubstituted cyclohexanones can be resolved with Pseudomonas fluorescens lipase to give enantiomerically pure (>99% ee) enol esters by transesterification with n-BuOH. The product ketones are prochiral and can easily be recycled giving an overall desymmetrisation of the ketone. Highest selectivity was obtained for substrates containing a 4-cyano and 4-aryl or a 4-benzyloxy substituent. The methodology was compared to asymmetric deprotonation–enolate trapping using the chiral base (S,S)-bis(α-methylbenzyl)amide which gave low (54–64%) ee’s for this class of ketones.

(−)-Sparteine-Mediated Stereoselective Intramolecular Carbolithiation of 4-Substituted 5-Hexynyl Carbamates. Synthesis of Enantiopure 1,3-Difunctionalized Alkylidene Cyclopentanes

The stereoselective carbolithiation of alkynes with external chiral induction has been achieved for the first time by fusing the concepts of the asymmetric deprotonation (A) with s-BuLi/(−)-sparteine (s-BuLi/1) and the intramolecular carbolithiation (B). Several 4-functionalized 5-hexynyl carbamates with different terminal substituents have been prepared and efficiently cyclized providing enantiopure highly substituted alkylidene cyclopentanes. The presence of a sterically demanding substituent in the propargylic position is the essential feature of these cyclizations in order to suppress the abstraction of the remaining propargylic proton. Furthermore, in dependence on the terminal substituent, the 6-phenyl-substituted precursors undergo an intramolecular carbolithiation whereas for the 6-trimethylsilyl-substituted alkynes a subsequent migration of the O-carbamoyl group onto the vinylic carbanionic center follows.

Stereoselective total synthesis and enantioselective formal synthesis of the antineoplastic sesquiterpene quinone metachromin A

The first total synthesis of the antineoplastic marine natural product metachromin-A (1) was accomplished through a convergent synthetic approach amenable to the preparation of analogues for biological studies. The synthesis involved twelve steps in its longest sequence and sixteen steps overall. The total synthesis of the racemic metachromin-A features: (1) an efficient synthesis of the quinone intermediate 11; (2) efficient protocols for the preparation of the key fragments 5 and 6; (3) a highly regioselective Thiele-Winter acetoxylation step; and (4) a stereoselective Horner-Wadsworth-Emmons coupling reaction employing fragment 6 as a non-stabilized phosphonate as an effective partner. The metachromin-A synthesis was made formally enantioselective by the asymmetric synthesis of fragment 5 employing the methodologies developed by Simpkins (asymmetric deprotonation with a chiral nitrogenated base) and d’Angelo (enantioselective deracemization). This latter protocol furnished fragment 5 with an enantiomeric excess of ~85%, as determined by ¹H-NMR spectroscopy.

Temperature- and Electrophile-Dependent Stereocontrol: A Structural and Mechanistic Investigation of (−)-Sparteine-Mediated Asymmetric Lithiation−Substitution Sequences of N-Boc-N-(p-Methoxyphenyl)cinnamylamine

The reaction pathways for the highly enantioselective, (−)-sparteine-mediated, lithiation−substitution reactions of N-Boc-N-(p-methoxyphenyl)cinnamylamine ((E)-2) have been investigated. The solution structure of the major allyllithium intermediate has been determined by 6Li and 13C NMR to be a monomeric η3 species, endo-syn-anti-8·1. The complexes exo-syn-anti-8·1, endo-syn-syn-8·1, and exo-syn-syn-8·1 are also shown to be present in solution. The enantiodetermining step in the lithiation−silylation or lithiation−alkylation of (E)-2 can involve asymmetric deprotonation, dynamic kinetic resolution, or dynamic thermodynamic resolution. The results reported herein establish that each of these pathways can be operative. This information allows determination of the stereochemical course for each step of these reactions and permits preparation of either epimer at the new stereogenic carbon.

(−)-Sparteine-mediated stereoselective intramolecular conjugate addition reactions of dienes and enynes

Enantioenriched carbanionic pairs generated by the asymmetric deprotonation of carbamate esters with the chiral base sbutyllithium/(−)-sparteine undergo smoothly intramolecular conjugate addition reactions to dienes and enynes in high yields.

Chiral Induction by Elimination-Coupled Lithium–Ene Reaction: Synthesis of (+)-(3R,4R)-1,2-Dihydromultifidene

Cyclization of the alkadienyl carbamates 1 to the cis-divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (−)-sparteine-induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium–ene reaction and an Sn′ reaction.

Chiral Induction by Elimination-Coupled Lithium-Ene Reaction: Synthesis of (+)-(3R,4R)-1,2-Dihydromultifidene.

Cyclization of the alkadienyl carbamates 1 to the cis-divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (-)-sparteine-induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium-ene reaction and an Sn ' reaction.

Chiral Induction by Elimination-Coupled Lithium-Ene Reaction: Synthesis of (+)-(3R,4R)-1,2-Dihydromultifidene

Cyclization of the alkadienyl carbamates 1 to the cis-divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (-)-sparteine-induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium-ene reaction and an Sn ' reaction.

Asymmetric Syntheses of N-Boc 2-Substituted Pyrrolidines and Piperidines by Intramolecular Cyclization

Asymmetric lithiation-substitutions by n-BuLi/(−)-sparteine with the N-Boc-N-(3-halopropyl)allylamines 1−4 provide the N-Boc-2-alkenylpyrrolidines (S)-5, (S)-6, and (S)-7 in yields of 31−93% with enantiomeric ratios (ers) from 65:35 to 90:10. These reactions are shown to involve an initial asymmetric deprotonation, but the enantiodetermining step is a subsequent asymmetric cyclization under the influence of the chiral ligand. Extension to formation of a piperidine is illustrated by reaction of N-Boc-(4-chlorobutyl)cinnamylamine (9) to afford (S)-N-Boc-2-(trans-β-styryl)piperidine ((S)-10) in 68% yield with an enantiomeric ratio (er) of 84:16. Analogous reactions with epoxide ring openings of N-Boc-N-(oxaalkenyl)benzylamines 11 and 12 afford the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)pyrrolidine (13) in 67% yield with a diastereomeric ratio (dr) of 50:50 and ers of 97:3 and 95:5 and the corresponding N-Boc-2-phenyl-3-(hydroxymethyl)piperidine (14) in 29% yield with a dr of 86:14 and ers of 81:19 and...

Enantioselective deprotonation of 4-tert-butylcyclohexanone by conformationally constrained chiral lithium amide bases

Conformationally rigid chiral lithium amides based on a tetrahydroisoquinoline motif have been prepared bearing a range of substituents at C1 and C3. These bases were tested in the asymmetric deprotonation reaction of 4-tert-butylcyclohexanone. Although the 1-substituted tetrahydroisoquinolines gave low enantioselectivity, the chiral bases containing a nitrogen heterocycle at C3 were found to induce high enantioselectivity (81% ee) in the presence of HMPA.

New Chiral Ligands with Nonstereogenic Chirotopic Centers for Asymmetric Synthesis.

Pseudo-C2 -symmetrical ligands have been prepared efficiently: The attachment of the chiral alkyl group to the heteroatom (P or N) through a nonstereogenic, chirotopic carbon center facilitates their synthesis as the configuration at this carbon atom no longer needs to be controlled. Two such ligands were combined, for example, in the base 1, which is especially useful for asymmetric deprotonation of prochiral ketones [Eq. (a)].

(−)-Sparteine-mediated stereoselective intramolecular carbolithiation of alkynes

The asymmetric deprotonation mediated by the chiral base s-butyllithium/(−)-sparteine of 4-substituted 5-hexynyl carbamates permits the synthesis of enantioenriched carbanionic pairs which undergo a regioselective 5- exo- dig ring closure with the triple bond acting as an internal electrophile. The functionalized five-membered rings are formed with complete stereoselectivity in high yields.

Stereoselective reactions. 29. Lithium-hydrogen interchange between achiral tridentate lithium amides and chiral bidentate amines. An approach to catalytic enantioselective deprotonation

1H-NMR spectral studies have shown that lithium-hydrogen interchange between a chiral bidentate amine ( (R)- 3b ) and an achiral tridentate lithium amide ( 5a) occurs rapidly in THF, favoring the exclusive formation of a chiral bidentate lithium amide ( (R)- 2b ) at equilibrium. This finding was applied to catalytic asymmetric deprotonation of prochiral 4-substituted cyclohexanones ( 1) using 0.3 equivalent of (R)- 3b in the presence of 2.4 equivalents of 5a in THF in the presence of DABCO and HMPA.