Chiral Lithium Amide Research Articles

Asymmetric synthesis of axially chiral benzamides and anilides utilizing planar chiral arene chromium complexes

Optically active axially chiral 2,6-disubstituted benzamides and anilides were stereoselectively prepared by utilizing planar chiral (arene)chromium complexes. Nucleophilic addition to enantiomerically pure planar chiral tricarbonyl( N, N-diethyl-2-methyl-6-formyl- (or 6-acyl)benzamide)chromium complex gave axially chiral 2-methyl-6-substituted N, N-diethyl benzamide chromium complexes with high selectivity. An alternative method for the preparation of axial chiral benzamides or anilides is an enantiotopic lithiation at the benzylic methyl of prochiral tricarbonylchromium complexes of N, N-diethyl-2,6-dimethylbenzamide and N-methyl- N-acyl-2,6-dimethylaniline with a chiral lithium amide followed by electrophilic substitution. The resulting axially chiral chromium-complexed benzamides and anilides were oxidized in air to give chromium-free axially chiral benzamides and anilides in enantiomerically enriched form without axial bond rotation at room temperature.

Lithium enolates from a (−)-quinic acid-derived cyclohexanone with a β-alkoxy leaving group: regioselective preparation and evaluation of enolate stability towards β-elimination

Deprotonation of a (−)-quinic acid-derived ketone {(2 S,3 S,4a R,8 R,8a S)-8-[( tert-butyl(dimethyl)silyl)oxy]-2,3-dimethoxy-2,3-dimethylhexahydro-1,4-benzodioxin-6(5 H)-one} using lithium hexamethyldisilazide (LHMDS) at −78 °C gave one regioisomeric enolate. The regiocontrol is governed by the axial β-silyloxy substituent and the resulting lithium enolate is stable towards β-elimination at temperatures up to −40 °C. It was found that the axial β-silyloxy group could be conveniently eliminated using 2.1 equiv of LHMDS at 0 °C for 1 h and that an equatorial β-alkoxy group was much more resistant to β-elimination. A chiral lithium amide base was used to overturn the inherent regioselectivity of ketone deprotonation with LHMDS.

Studies directed toward the synthesis of reiswigin A: Total synthesis of (±)-epi-reiswigin A

As a testing ground for the practical application of asymmetric synthesis, (–)-reiswigin A, a potent antiviral agent, was chosen as a target for total synthesis. Initial studies were undertaken to prove the viability of the key asymmetric step, enantioselective deprotonation of an intermediate meso-bicyclic ketone, using a chiral lithium amide base. Enantiomeric excesses in the range of 90%–94% were routinely obtained, even on runs as large as 10 g. Unfortunately, conversion of this key enantio-enriched intermediate to the natural product proved unsuccessful. While these studies were enroute, a parallel synthesis using the racemic compound was transformed into (±)-epi-reiswigin A.Key words: asymmetric deprotonation, synthesis, (±)-epi-reiswigin A.

Application of Chiral Lithium Amide Bases to the thia‐Sommelet Dearomatization Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A novel asymmetric route to succinimides and derived compounds: synthesis of the lignan lactone (+)-hinokinin.

A novel approach to chiral succinimides and derived compounds has been developed that involves chiral lithium amide desymmetrisation of an N-ortho-tert-butylphenyl succinimide to generate a putative atropisomeric intermediate enolate, alkylation of which enables access to the lignan lactone (+)-hinokinin.

Solution structures of chiral lithium amides with internal sulfide coordination: sulfide versus ether coordination in chiral lithium amides

A series of chiral lithium amides with chelating sulfide groups has been investigated by NMR spectroscopy. These chiral lithium amides have previously been found to mediate higher enantioselectivity in the asymmetric addition of alkyllithium reagents to aldehydes than the corresponding lithium amides containing ether groups. The chiral lithium amido sulfide chelates form homodimers in both diethyl ether and tetrahydrofuran. In diethyl ether both sulfur atoms coordinate to the same lithium while the other lithium in the dimer is solvent coordinated. Tetrahydrofuran favours equivalently solvated homodimers. Mixed dimeric complexes are formed with excess n-butyllithium in both diethyl ether and tetrahydrofuran. The structural information was obtained from observed 6Li, 15N couplings and cross peaks in the 6Li, 1H HOESY spectrum. DFT calculations at B3LYP/6-31G(d) level of theory indicate that the Li–S chelate is much less stable than the Li–O chelate. However the calculations indicate that the stability of the dimeric chelates are in agreement with the NMR results of the diethyl ether and tetrahydrofuran solutions.

An Easy and Convenient Synthesis of Optically Active β-Amino Alcohols and 1,2-Diamines. Applications in Enantioselective Deprotonation of Cyclohexene Oxide

Optically active β-dialkylamino alcohols and 1,2-diamines are not only a common structural component in a vast group of naturally occurring and synthetic molecules, but also can be widely used as versatile chiral building blocks and chiral catalysts or ligands in a variety of asymmetric synthesis, such as enantioselective dialkylzinc addition to aldehydes, enantioselective conjugated addition and enantioselective deprotonation of meso ketones and epoxides. Accordingly, many synthetic methods including aminolysis of chiral epoxides, optical resolution of their racemic mixtures and reduction of non-racemic O-acetyl mandelamides, reduction of chiral α-amino carboxamides, asymmetric reduction of α-amino ketones and aminolysis of aziridinium salts for those compounds have been reported. However, aminolysis of chiral epoxides is commonly accompanied by the formation of undesired regioisomers. The resolution method of racemic mixture suffers from providing intrinsic limitation where the maximum yield of one enantiomer from the starting material is only 50%. In the case of reduction of α-amino carboxamides, unnatural α-amino acids are not economical viable to use them as starting materials since they are expensive, but also racemization can occur in the reaction of some N-protected amino acids with dialkylamines to give α-amino carboxamides. For example, O’Brien et al. reported significant levels of racemization when N-protected phenylglycine was reacted with pyrrolidine in the presence of coupling reagent to form the corresponding α-amino carboxamide. Recently, we reported the synthesis of nearly enantiopure β-adrenergic agonists and β-hydroxy nitriles from optically active 1,2diol monotosylates 1 obtained from CBS-oxazaborolidinecatalyzed borane reduction of α-sulfonyloxyketones. We wish to report here an easy and simple method for the synthesis of nearly enantiopure β-dialkylamino alcohols 2 and 1,2-diamines 4-10 starting from 1 and their applications in enantioselective deprotonation of cyclohexene oxide using chiral lithium amides. The monotosylates 1 were directly reacted with 3 equiv. of N,N'-dialkylamines under solvent-free conditions at 40-50 C for 2-96 h to give 2 in 80-93% yield (Scheme 1). The optical purities and absolute configurations of 2 were determined by HPLC analysis using chiral columns and/or by comparing optical rotation values of the known compounds. As shown in Table 1, all the products 2 obtained have very high optical purities approaching 100% ee. To obtain chiral diamines 4-10, the reaction was carried out by treatment of 2.0 equiv. of methanesulfonyl chloride with each of the selected amino alcohols, such as 2e, 2h, 2j, and

Preparation of Protected syn‐α,β‐Dialkyl β‐Amino Acids that Contain Polar Side Chain Functionality.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine

The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short enantioselective synthesis of the drug substance paroxetine.

Application of chiral lithium amide bases to the thia-Sommelet dearomatization reaction

Thia-Sommelet dearomatization reactions of benzylsulfonium ylides can create highly congested quaternary centers. Chiral bis-lithium amide bases were shown to effect enantiotopic deprotonation of benzylsulfonium ions, leading to thia-Sommelet rearrangement. The chiral trienes were generated in up to 50% ee.

Asymmetric synthesis of the erythrinan alkaloid system using a chiral lithium amide base desymmetrisation as the key step

A new asymmetric approach to the erythrinan alkaloid system is described, which involves chiral base desymmetrisation of a ring fused imide and a 6-exo-trig radical cyclisation as the key steps.

Solid‐Phase Supported Chiral Lithium Amides Used in Deprotonation Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric synthesis of the highly potent anti-metastatic prostacyclin analogue cicaprost and its isomer isocicaprost.

An asymmetric synthesis of the anti-metastatic prostacyclin analogue cicaprost and a formal one of its isomer isocicaprost by a new route are described. A key step of these syntheses is the coupling of a chiral bicyclic C6-C14 ethynyl building block with a chiral C15-C21 omega-side chain amide building block with formation of the C14-C15 bond of the target molecules. A highly stereoselective reduction of the thereby obtained C6-C21 intermediate carrying a carbonyl group at C15 of the side chain was accomplished by the chiral oxazaborolidine method. The chiral phosphono acetate method was used for the highly stereoselective attachment of the alpha-side chain to the bicyclic C6-C21 intermediate carrying a carbonyl group at C6. Asymmetric syntheses of the bicyclic C6-C14 ethynyl building blocks were carried out starting from achiral bicyclic C6-C12 ketones by using the chiral lithium amide method. In the course of these syntheses, a new method for the introduction of an ethynyl group at the alpha-position of the carbonyl group of a ketone with formation of the corresponding homopropargylic alcohol was devised. Its key steps are an aldol reaction of the corresponding silyl enol ether with chloral and the elimination of a trichlorocarbinol derivative with formation of the ethynyl group. In addition, a new aldehyde to terminal alkyne transformation has been realized. Its key steps are the conversion of an aldehyde to the corresponding 1-alkenyl dimethylaminosulfoxonium salt and the elimination of the latter with a strong base. Two basically different routes have been followed for the synthesis of the enantiomerically pure C15-C21 omega-side chain amide building block. The first is based on the chiral oxazolidinone method and features a highly stereoselective alkylation of (4R)-N-acetyl-4-benzyloxazolidin-2-one, and the second encompasses a malonate synthesis of the racemic amide and its efficient preparative scale resolution by HPLC on a chiral stationary phase containing column.

Preparation of protected syn-alpha,beta-dialkyl beta-amino acids that contain polar side chain functionality.

We report the synthesis of syn-alpha,beta-dialkyl beta-amino acid derivatives suitably protected for solid-phase synthesis that give rise to residues containing positively charged lysine-like side chains. These amino acids, as well as syn-alpha,beta-dialkyl beta-amino acids that contain diverse hydrophobic side chains, are prepared in good de and ee. The key step in this route involves Davies's protocol for the conjugate addition of a chiral lithium amide to alpha,beta-unsaturated tert-butyl esters (Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 9, 1141). syn-alpha,beta-Dialkyl beta-amino acids are interesting building blocks because of their sheet-forming propensity and because of their presence in bioactive compounds.

Chiral Lithium Amide Base Mediated Rearrangement of meso‐Cyclohexene Oxides: Asymmetric Synthesis of Amino‐ and Aziridinocyclohexenols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Solid-phase supported chiral lithium amides used in deprotonation reactions

The lithium salt of polymer supported phenylethyl amine showed surprisingly high enantioselectivity in the asymmetric deprotonation reaction of cyclohexene oxide. The polymer supported chiral lithium amide base also proved to be more reactive compared to the free chiral lithium amide base. This is a new insight in the development and mechanism of chiral lithium amide bases used in asymmetric reactions.

Syntheses of Natural Products and Biologically Active Compounds by Means of Enantioselective Deprotonation Strategy

AbstractFor Abstract see ChemInform Abstract in Full Text.

Lithium diisopinocampheylamide: a new and highly effective chiral catalyst in the enantioselective deprotonation of meso-epoxides

α-Pinene based novel chiral lithium amides have been used for the catalytic enantioselective deprotonation of cyclohexene oxide. An enantiomeric excess of up to 95% for ( R)-2-scyclohexen-1-ol was achieved with lithium (−)- N, N-diisopinocampheylamide. A systematic study shows that the isopinocampheyl moiety plays an important role in achieving high enantioselectivity.

Asymmetric total synthesis of the proposed structure of the medicinal alkaloid jamtine using the chiral base approach.

[reaction: see text] A highly step-economic asymmetric synthesis of the tetracyclic structure assigned to the medicinal alkaloid jamtine has been accomplished using a chiral lithium amide base desymmetrization of a ring-fused imide. The structure synthesized appears to be different from that of the natural product originally reported.

Chiral lithium amide base-mediated rearrangement of meso-cyclohexene oxides: asymmetric synthesis of amino- and aziridinocyclohexenols.

Two different chiral lithium amide base routes for the synthesis of amino- and aziridino-containing cyclohexenols have been explored. The first strategy involved the diastereoselective preparation of novel meso-aziridinocyclohexene oxides and their subsequent enantioselective rearrangement using chiral bases. In this approach, the diphenylphosphinoyl nitrogen protecting group proved optimal and aziridinocyclohexenols of 47-68% ee were obtained. Of particular note was the smooth rearrangement of the epoxide to an allylic alcohol in the presence of an aziridine: under optimised chiral base conditions, the aziridine remained essentially unaffected. A second more straightforward strategy for introduction of an amino functionality was also investigated: (1S,4R,5S)- and (1R,4R,5S)-4,5-bis(tert-butyldimethylsilyloxy)cyclohex-2-enols, readily prepared in > 95% ee using a chiral base approach, were subjected to Mitsunobu substitution using a sulfonamide and Overman rearrangement.