Chiral Lithium Amide Bases Research Articles

Benzo‐fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re‐contraction of Cyclic Ureas

AbstractBenzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an ‘azatropic shift’ in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Benzo-fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re-contraction of Cyclic Ureas.

Benzo-fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1-arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring-expanded ureas with acid triggers a two-atom ring contraction-an 'azatropic shift' in which one urea nitrogen displaces the other-with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1-aryl-tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Enantioselective Intramolecular α‐Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine

AbstractA practical, transition metal‐free method allows the enantioselective synthesis of α,α‐diarylmethylamines by asymmetric α‐arylation of benzylamines. Enantioselective lithiation of N′‐aryl‐N‐benzyl‐N‐isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α‐diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an “azatropic shift” with retention of configuration, the product of which may be hydrolysed to the target amine.

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine.

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Chiral Bases as Useful Probes of Lithium Amide Reactivity

Experiments involving competition between chiral and achiral lithium amides provide a qualitative impression of the kinetics of different amide motifs in enolization reactions. The level of enantioselectivity was not diminished by the inclusion of lithium diisopropylamide (LDA; see scheme) into asymmetric enolizations mediated by a chiral lithium amide base, derived from a 1,2-diamine. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Synthesis of NS9544 Acetate

NS9544 acetate is a monoamine reuptake inhibitor that is a candidate for the treatment of neuropathic pain. After all attempts at a classical resolution of intermediate E failed, an asymmetric synthesis was undertaken in which the chirality was introduced by asymmetric deprotonation of tropinone A using the chiral lithium amide base B.

ChemInform Abstract: Useful Chiral Lactones Derived from cis-Bicyclo(3.3.0)octan-3,7-dione via Asymmetric Deprotonation.

Abstract The monoketal derived from cis-bicyclo[3.3.0]octane-3,7-dione was deprotonated using chiral lithium amide bases and the enolates were trapped as either enol acetates or trimethylsilyl enol ethers. Oxidative cleavage of the enol derivatives provided useful bicyclic lactones, the ee's of which could be determined using NMR chiral shift techniques. The lactones are also potentially useful as intermediates for asymmetric synthesis.

ChemInform Abstract: Enantioselective Opening of Spiro Epoxides Derived from cis-Bicyclo(3. 3.0)octan-3,7-dione Using Chiral Lithium Amide Bases.

The monoketal derived from cis-bicyclo[3.3.0]octane-3,7-dione was converted to epoxides 3. The meso exo epoxide was cleaved via enantioselective deprotonation using chiral lithium amide bases to provide the synthetically useful alcohol 7 with up to 76%ee. The enantiomeric excess of the alcohol was determined by 1H NMR chiral shift techniques.

ChemInform Abstract: Concerning the Synthesis and Enantioselective Rearrangements of Episulfoxides.

A novel synthesis of episulfoxides having the norbornane skeleton is possible by use of a rhodium catalyst to effect SO transfer from trans-stilbene episulfoxide to norbornene or norbornadiene. Analogous Rh2(OAc)4 catalysed sulfur transfer to these alkenes is also possible using propylene sulfide as the sulfur source. These methods did not give useful yields of products with alternative types of alkene substrate. A novel type of chiral lithium amide base reaction, involving the rearrangement of certain types of symmetrical ring-fused episulfoxides, gives alkenyl sulfoxide products in up to 88% ee. The structures of the products, including absolute stereochemistry, were assigned based on X-ray crystal structure determinations. p

Studies towards complex bridged alkaloids: regio- and stereocontrolled enolate chemistry of 2,5-diketopiperazines

The substitution of symmetrical N-protected diketopiperazines (DKPs) via enolate intermediates has been studied. The enolate reactions were highly diastereocontrolled, leading to enantiopure DKP products if chiral amino acid precursors were employed, and giving racemic products, starting with centrosymmetric DKPs, even when a chiral lithium amide base was used to generate the lithium enolate. With unsymmetrical DKPs derived from proline and either alanine, phenylalanine or valine, the enolate substitution occurred with high regio- and stereoselectivity on the proline residue. This enabled the synthesis of substituted DKPs that could be cyclised via cationic processes to give the bicyclo[2.2.2]diazaoctane core structure present in paraherquamide and stephacidin natural products.

Synthesis of Polymer‐Supported Chiral Lithium Amide Bases and Application in Asymmetric Deprotonation of Prochiral Cyclic Ketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chiral Base Mediated Transformation of Cyclic 1,3‐Diketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chiral base mediated transformation of cyclic 1,3-diketones

Treatment of certain 1,3-diketones with a chiral lithium amide base results in the formation of a non-racemic lithium mono-enolate; these intermediates can be transformed directly into chiral hydroxyketone products by reduction with DIBAL-H in high yield and with selectivities of up to 99% ee.

Enantioselective α‐Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (‐)‐Epibatidine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective α‐Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (−)‐Epibatidine

The direct asym. α-arylation of prochiral ketones has been effected using chiral lithium amide bases and diaryl iodonium salts. The methodol. has been employed in a short total synthesis of the alk ...

Asymmetric Alkylation of N-Pivaloyl-o-benzylaniline.

Abstract Alkylation of 2-methoxyethoxyphenyl phenylmethane using sec -BuLi and (−)-sparteine has been carried out in excellent yields and up to 76% ee. The use of O’Brien’s (+)-sparteine surrogate gave the opposite sense of asymmetric induction at 80% ee while the use of chiral lithium amide bases gave modest yields and ees.

The Synthesis of (−)-Isodomoic Acid C

The neuroactive algal metabolite (-)-isodomoic acid C, a kainoid amino acid, has been synthesized for the first time. Asymmetric dearomatizing cyclization of an aromatic amide using a chiral lithium amide base generates a bicyclic enone containing a pyrrolidinone ring with the relative and absolute stereochemistry of the target. A further 15 synthetic steps, including conjugate cuprate addition to the enone of a side chain precursor, a Ru-promoted oxidation of the phenyl ring to the C2-carboxylic acid substituent, a regioselective Baeyer-Villiger reaction, and an E-selective Horner-Wadsworth-Emmons reaction, elaborate the cyclization product into the target molecule.

The synthesis of bioactive indolocarbazoles related to K-252a

A range of functionalised indolocarbazoles, related to the natural product K-252a, have been prepared, starting from a readily available bridged cyclopentene. Sequences of transformations, involving initial hydroboration-oxidation to give a ketone, or by dihydroxylation and cyclic sulfate formation, enable the preparation of diverse indolocarbazole products. Issues of imide nitrogen protection for the indolocarbazole, and opportunities for asymmetric desymmetrisation of key intermediates were also explored. A novel chiral lithium amide base mediated transformation of a cyclic sulfate intermediate gave the anticipated ketone product in up to 87% ee. A number of compounds, in the form of unprotected imide substituted indolocarbazoles, were screened for biological activity and were found to be potent inhibitors of a number of kinase enzymes.

Synthesis of bioactive indolocarbazoles: synthesis, nucleophilic ring-opening and chiral base desymmetrisation of a cyclic sulfate intermediate

A number of new functionalised bridged indolocarbazole systems have been prepared by ring-opening reactions of a key cyclic sulfate intermediate, prepared from the corresponding diol by the action of sulfuryl diimidazole and DBU. The same cyclic sulfate also undergoes an unprecedented asymmetric rearrangement to a chiral ketone, on treatment with a chiral lithium amide base.

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.