Homochiral Lithium Amide Research Articles

A novel and concise synthetic access to chiral 2-substituted-4-piperidone

A novel and concise synthetic access to enantiopure chiral 2-aryl/alkyl substituted 4-piperidone has been demonstrated. This new route features two key steps: the highly diastereoselective conjugate addition of homochiral lithium amides to trans-β-substituted-α,β-unsaturated methyl esters guaranteed the enantiopurity at 2 position (de >19:1) and the intramolecular attacking of carbanions to methyl esters led to the formation of the piperidone ring. A wide range of substrates, including chiral 2-aryl and 2-alkyl-4-piperidones, were successfully synthesized with modest to high yield. Moreover, some non-chiral 3-substituted-4-piperidones were also synthesized with enhanced ring-formation yield, implicating the versatility of this method in construction of various piperidine rings.

ChemInform Abstract: An Enantioselective Deprotonation Route to a Versatile Intermediate for C-Nucleoside Synthesis.

The asymmetric transformation of ketone 1 (exo-cis-6,7-isopropylidenedioxy-8-oxabicyclo[3.2.1]octan-3-one) into optically active silyl enol ether 2 (exo-cis-6,7-isopropylidenedioxy-3-trimethylsiloxy-8-oxabicyclo[3.2.1]oct-2-ene) in up to 85% ee was achieved using the homochiral lithium amide base 6 [lithium (R,R)-bis(1-phenylethyl)amide]. Conversion of 2 into a known key intermediate 3 (methyl 2,3-O-isopropylidene-s-ribofuranosyl-acetate) for C-nucleoside synthesis was possible in a highly efficient two-step sequence.

ChemInform Abstract: Application of Homochiral Lithium Amide Base Chemistry to a Thiane Oxide System.

Treatment of the thiane oxide 6 with a homochiral lithium amide (HCLA) base 7, followed by electrophilic quench of the so-formed sulfoxide carbanion with Me3SiCl, Mel or ButCO2Et, gives the optically active products (+)-8, (+)-11 and (+)-12, respectively, in 55–60% enantiomeric excess (ee). The reaction of 6 with the HCLA base 9 can be carried out in the presence of Me3SiCl (in situ quench conditions), in which case a silylation–in situ kinetic resolution process occurs, furnishing (–)-8 in low chemical yield, in up to 69% ee. Further transformations of thiane oxides (+)-8 and (+)-11 involving reduction or removal of the ring sulfur atom were conducted, in order to establish the absolute configuration of the products. Highly stereoselective reduction of the keto sulfoxide (+)-12 was also carried out, leading ultimately to an epoxide product 20via opening of the thiane ring.

ChemInform Abstract: Enantioselective Deprotonation of Cyclohexene Oxide to (R)-2- Cyclohexen-1-ol.

The reaction of cyclohexene oxide with homochiral lithium amides, prepared from (S)-phenylglycine and (S)-valine has been studied and (R)-2-cyclohexen-1-ol 3 was prepared in a maximum of 72% ee. The optical purity was determined by 1H NMR measurement of the α-methoxy-α-(trifluoromethyl)phenyl acetic acid (MTPA) derivative of the corresponding alcohol.

ChemInform Abstract: Syntheses of Derivatives of L-Daunosamine and Its C-3 Epimer Employing as the Key Step the Asymmetric Conjugate Addition of a Homochiral Lithium Amide to tert-Butyl (E,E)-Hexa-2,4-dienoate.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric Synthesis of Piperidines and Octahydroindolizines

The conjugate addition of a homochiral lithium amide to a ξ-hydroxy-α,β-unsaturated ester, tollowed by a one-pot, ring-closure-N-debenzylation protocol has been used in the asymmetric syntheses of (S)-coniine and (R)-δ-coniceine (isolated as the corresponding hydrochloride salts) and the bicyclic core of stellettamide A.

Doubly diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters containing cis- and trans-dioxolane units

As part of a long-term goal directed towards the ab initio asymmetric synthesis of unnatural amino sugars, the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a range of homochiral alpha,beta-unsaturated esters containing cis- and trans-dioxolane units was investigated. These reactions resulted in "matching" and "mismatching" effects. In the "matched" cases a single diastereoisomer of the corresponding beta-amino ester (containing three contiguous stereocentres) is produced. Upon conjugate addition to a homochiral alpha,beta-unsaturated ester containing a cis-dioxolane unit, in the "mismatched" case it is the stereocontrol of the substrate which is dominant over that of the lithium amide, whilst upon addition to homochiral alpha,beta-unsaturated esters containing a trans-dioxolane unit the stereocontrol of the homochiral lithium amide is dominant. Hydrogenolytic N-deprotection of the beta-amino ester products of conjugate addition gives access to polyoxygenated beta-amino acid derivatives.

Asymmetric synthesis of 3,4-anti- and 3,4-syn-substituted aminopyrrolidines via lithium amide conjugate addition

The diastereoselective conjugate addition of homochiral lithium amides to methyl 4-(N-allyl-N-benzylamino)but-2-enoate has been used as the key step in a simple and efficient protocol for the preparation of 3,4-substituted aminopyrrolidines. This protocol provides a complementary and stereoselective route to both anti- and syn-3-amino-4-alkylpyrrolidines as well as anti- and syn-3-hydroxy-4-aminopyrrolidines, in high de and ee viabeta-amino enolate functionalisation. This methodology has been applied to the synthesis of anti-(3S,4S)- and syn-(3R,4S)-3-methoxy-4-(N-methylamino)pyrrolidine.

Asymmetric synthesis of β-amino-γ-substituted-γ-butyrolactones: double diastereoselective conjugate addition of homochiral lithium amides to homochiral α,β-unsaturated esters

Chiral alpha,beta-unsaturated esters, containing a single, gamma-stereogenic centre, show modest levels of substrate control upon conjugate addition of lithium dibenzylamide. Double diastereoselective conjugate additions of homochiral lithium N-benzyl-N-(alpha-methylbenzyl)amide to the homochiral alpha,beta-unsaturated esters display "matching" and "mismatching" effects. In each case, however, these additions proceed under the dominant stereocontrol of the lithium amide to give the corresponding beta-amino esters in high de. A remarkable reversal in stereoselectivity is noted by changing the ester functionality to an oxazolidinone. Subsequent O-deprotection and cyclisation of the resultant beta-amino adducts gives access to the corresponding beta-amino-gamma-substituted-gamma-butyrolactones in good yield and high de.

Homochiral Lithium Amides for the Asymmetric Synthesis of β‐Amino Acids.

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.

Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing ( R)-β-amino butyric acid, ( R)-β-amino pentanoic acid, ( S)-β-leucine, ( R)-β-amino octanoic acid, ( S)-β-phenylalanine, ( S)-β-tyrosine methyl ether, ( S)-β-tyrosine hydrochloride and ( S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products ( R)-β-DOPA and ( R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.

Lithium amide conjugate addition for the asymmetric synthesis of 3-aminopyrrolidines

Conjugate addition of homochiral lithium amides to methyl 4-(N-benzyl-N-allylamino)but-2-enoate, chemoselective N-deprotection and concomitant cyclisation, followed by enolate functionalisation and deprotection allows access to syn- and anti-3,4-disubstituted aminopyrrolidines in > 98% d.e. and > 98% e.e.

The Conjugate Addition of Enantiomerically Pure Lithium Amides as Homochiral Ammonia Equivalents: Scope, Limitations, and Synthetic Applications

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis of 3,4,5,6‐Tetrasubstituted Piperidin‐2‐ones by Three‐Component Coupling.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric Synthesis of 3,4,5,6-Tetrasubstituted Piperidin-2-ones by Three-Component Coupling

The asymmetric three-component coupling of α,β-unsaturated esters and alkylidene malonates initiated with a homochiral lithium amide proceeds with high levels of diastereoselectivity, with hydrogenation of the resultant α-substituted β-amino acid derivatives giving a range of differentially protected 3,4,5,6-tetrasubstituted piperidinones with four contiguous stereogenic centres.

Asymmetric synthesis of homochiral differentially protected bis-β-amino acid scaffolds

A strategy for the asymmetric synthesis of homochiral [( R, R)- or ( S, S)-], or meso-( R, S) bis-β-amino acid scaffolds, formally resulting from the stepwise conjugate addition of two differentially protected homochiral lithium amides to two α,β-unsaturated esters attached to a central arene, is demonstrated. Further manipulation enables the efficient synthesis of orthogonally protected pseudo- meso or pseudo- C 2 symmetric scaffolds via selective N-benzyl or N-allyl deprotection, enabling regio-, stereo- and chemoselective functionalisation.

Asymmetric synthesis of a homochiral differentially protected pseudo- meso bis-β-amino acid scaffold

A strategy for the asymmetric synthesis of a homochiral differentially protected pseudo- meso bis-β-amino acid scaffold utilising the conjugate addition of homochiral lithium amides and subsequent selective deprotection is demonstrated.

Transformation of arylmethylamines into alpha-aminophosphonic acids via metalated phosphoramidates: rearrangement of partly configurationally stable N-phosphorylated alpha-aminocarbanions

N-Benzyl phosphoramidate was protected at nitrogen with a TMS, p-toluenesulfonyl, Boc, lithium carboxylate, or diethoxyphosphinyl group and metalated with s-BuLi or LDA at -78 degrees C at the benzylic carbon. For the latter three protecting groups, the intermediate alpha-amino(phenylmethyl)lithiums isomerized to N-protected alpha-aminophosphonates (phosphoramidate-aminophosphonate rearrangement). (R)-N-[1-(2)H(1)]Phenylmethyl phosphoramidate in combination with Boc or (EtO)(2)P(O) was used to demonstrate that metalation occurs with a high primary kinetic isotope effect (k(H)/k(D) 13-50) and migration of the diethoxyphosphinyl group with retention of configuration at carbon. Furthermore, the short-lived carbanion lithium pairs are partly configurationally stable as the aminophosphonates formed with the two protecting groups have enantiomeric excesses of 79 and 24%, respectively. When homochiral lithium amides derived from (R)-N-isopropyl-1-phenylethylamine and (R,R)-N,N-di(1-phenylethyl)amine were used to induce a phosphoramidate-aminophosphonate rearrangement, chiral nonracemic alpha-aminophosphonates were formed (ee 26-35%). Three racemic aminophosphonates were deprotected with hot 6 M HCl and purified by ion-exchange chromatography on Dowex 50W,H(+) to exemplify the transformation of phenyl-, p-tolyl-, and (1'-naphthyl)methylamine into aminophosphonic acids via lithiated phosphoramidates.

Asymmetric synthesis of the northern segment of ephedradine C

An asymmetric synthesis of the dihydrobenzofuran segment of ephedradine C has been achieved. Key steps include a chiral oxazolidinone-mediated aldol reaction to form a β-hydroxy ester, followed by a novel debenzylation and concomitant intramolecular cyclisation with iodotrimethylsilane. An asymmetric Michael reaction with a homochiral lithium amide was used to form the third and final chiral centre. The absolute stereochemistry of these three centres was confirmed by X-ray crystal-structure determinations.

Asymmetric synthesis of the northern segment of ephedradine C. A novel dihydrobenzo[ b]furan formation

An asymmetric synthesis of the dihydrobenzo[ b]furan segment of ephedradine C has been achieved utilising a chiral oxazolidinone in an aldol reaction to form a β-hydroxy ester, followed by a novel debenzylation and concomitant intramolecular cyclisation with iodotrimethylsilane as key steps. An asymmetric Michael reaction with a homochiral lithium amide was used to form the third and final chiral centre.