Enantioselective Synthesis Of β-Amino Acids Research Articles

Nickel-Catalyzed Enantioselective Synthesis of β-Amino Acids

Nickel-Catalyzed Enantioselective Synthesis of β-Amino Acids

Synthetic versatility of 2-substituted-6-methyl 2,3-dihydropyridinones in the synthesis of polyfunctional piperidine-based compounds and related β amino acid derivatives.

Chiral 2-substituted-6-methyl 2,3-dihydropyidinones 9, which can be facilely obtained from an asymmetric vinylogous Mannich reaction (VMR) with 1,3-bis-trimethysily enol ether, were used as versatile intermediates in constructing chiral polyfunctional piperidine-based compounds. The 6-methyl group of such compounds can be conveniently functionalized via alkylation and acylation reactions to provide efficient entries to the synthesis of a variety of chiral multi-substituted piperidine-based compounds. Further elaboration of the corresponding intermediates also provided access to polyfunctional indolizidine-based compounds. These methods were showcased in an asymmetric synthesis of 2,6-di-substituted piperidine compound 13, reported as the key intermediate in the synthesis of (+)-calvine and a natural alkaloid (-)-indolizidine 209D. Furthermore, selective C5 iodination of compound 9 enabled the installation of additional functional groups at this position. Finally, we demonstrated that the oxidative cleavage of 2-substituted-6-methyl-2,3-dihydropyidinones is a practical and efficient method for the enantioselective synthesis of β-amino acids, which can undergo further intra-molecular cyclization to give the corresponding chiral four-membered β-lactam derivatives.

ChemInform Abstract: Enantioselective Synthesis of β-Amino Acids. Part 2. Preparation of the Like Stereoisomers of 2-Methyl- and 2-Benzyl-3-aminobutanoic Acid.

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.

ChemInform Abstract: Enantioselective Synthesis of β-Amino Acids. Part 3. Preparation and Assignment of Configuration of 1-Benzoyl-(2S)-tert-butyl-3-methyl- perhydropyrimidin-4-one. Useful Starting Material for the Enantioselective Synthesis of α-Substitu

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.

ChemInform Abstract: Enantioselective Synthesis of β-Amino Acids. Part 10. Preparation of Novel α,α- and β,β-Disubstituted β-Amino Acids from (S)-Asparagine.

Abstract Perhydropyrimidinone ( S )- 1 is alkylated with very high diastereoselectivity to give trans products (2 S ,5 R )- 3 , (2 S ,5 R )– 4 and (2 S ,5 R )- 5 . Dialkylation of ( S )- 1 also proceeds with complete stereoselectivity to afford adducts (2 S ,5 R )- 6 , (2 S ,5 S )- 6 , (2 S ,5 R )- 7 and (2 S ,5 S )- 7 . Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2 S ,5 R )- 3 gives enantiopure α-substituted β-amino acid ( R )- 8 . Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids ( R )- or ( S )- 9 and ( R )- or ( S )- 10 . Related iminoester (2 S ,6 S )- 2 is alkylated with complete diastereoselectivity to give products (2 S ,6 S )- 11 – 13 whose hydrolysis under relatively mild conditions (2N CF 3 CO 2 H, CH 3 OH, 100°C) affords enantiopure N -benzoylated β,β-disubstituted β-amino acid esters ( S )- 14 – 16 , with intact double bonds in the olefinic substituents.

Preface

Abstract Organic synthesis continues to grow and develop impressively in response to new research challenges at the boundaries of structural complexity, while playing a central role in the industrial activities and applications of the chemical sciences. The International Conferences on Organic Synthesis (ICOS), which have been organized biennially around the world since 1976 under IUPAC sponsorship, faithfully reflect this growth and development. The 16th event in this series (ICOS-16) was held in Mérida, México, from 11 to 15 June 2006. The scientific program included 22 plenary and invited speakers, as well as 36 experts who participated in symposia on medicinal chemistry, organocatalysis, enantioselective synthesis of β-amino acids, organolithium compounds in organic synthesis, organic selenium and tellurium compounds in organic synthesis, and applications of microwaves in organic synthesis. In addition, almost 300 posters covering all aspects of modern organic synthesis were displayed by scientists and research scholars. The strong Latin American participation in this feature of the program, followed by those of European, North American, and Asian delegates, attested to the growing contribution of this region to chemical research in organic synthesis. Overall, the scientific program offered comprehensive and fruitful coverage of organic synthesis from a variety of different perspectives. The Mexican Academy of Sciences and the Mexican Chemical Society (celebrating its 50th Anniversary) featured as cosponsors of ICOS-16 together with IUPAC. This was the second occasion that an IUPAC-sponsored conference has been held in Mexico, the first being the 6th International Symposium on Natural Products Chemistry in Mexico City, in 1969. ICOS-16 attracted almost 500 delegates from 40 countries, mainly those of Latin America, a gratifyingly high proportion of whom were younger scientists. This issue of Pure and Applied Chemistry contains a representative selection of papers based upon lectures delivered at ICOS-16. The theme of synthesis of natural products was covered by M. Brimble (New Zealand), L. C. Dias (Brazil), and C. Gennari (Italy). Different aspects on methodology and control of chemical reactivity were presented by J. Tamariz (Mexico), S. F. Martin (USA), S. Ma (China), and Ph. Renaud (Switzerland). Organic synthesis using phosphorous was covered by R. Réau (France) and C. Nájera (Spain). The broad topic of catalysis was presented by S. Kobayashi (Japan) and C. Crudden (USA). New insights on synthesis using epoxides and aziridines were disclosed by D. Hodgson (UK) and F. McDonald (USA). Organic synthesis is a fascinating field of chemistry that has often been compared with art. The control of regio-, stereo-, and site selectivity demands deep insight into chemical reactivity as well as knowledge of new and old methodology and catalysis, and the ability to combine these creatively in sustainable processes in order to achieve specific objectives. Despite remarkable progress during recent years, efficient synthesis of specific organic compounds with tailored activities and properties will continue to challenge future generations of chemists. Further progress of organic synthesis will be covered during the next conference in this series (ICOS-17), which will take place in Korea during 2008. Thanks are due to members of the ICOS-16 Committees, to all participants, and to authors contributing to this issue. Guillermo Delgado Conference Editor

The Mannich reaction of malonates with simple imines catalyzed by bifunctional cinchona alkaloids: enantioselective synthesis of beta-amino acids.

We describe the first efficient, direct asymmetric Mannich reactions with malonates and N-Boc aryl and alkyl imines by cooperative hydrogen-bonding catalysis with a cinchona alkaloid bearing a thiourea functionality. We have also extended the scope of this reaction to beta-ketoesters. The synthetic value of this new reaction is demonstrated in the establishment of a convergent enantioselective route toward the biologically important beta-amino acids under mild and air- and moisture-tolerant conditions.

The Asymmetric Imino-aldol Approach to the Enantioselective Synthesis of β-amino acids

The Asymmetric Imino-aldol Approach to the Enantioselective Synthesis of β-amino acids

The asymmetric imino-aldol approach to the enantioselective synthesis of β-amino acids

Two approaches, based on imino-aldol additions, to the asymmetric synthesis of cyclic β-amino acids are reported. In each case a chiral auxiliary was employed attached either to the enolate or to the imine. The relative efficacy of these two synthetic methods is also briefly compared with the former still the preferred route as the latter is currently limited to the preparation ofN-sulfonyl β-amino acids.

Enantioselective synthesis of β-amino acids. Part 11: Diastereoselective alkylation of chiral derivatives of β-aminopropionic acid containing the α-phenethyl group

Several novel, chiral derivatives of β-aminopropionic acid were studied as potentially useful precursors of enantiopure α-substituted-β-amino acids. In particular, the diastereoselectivity of alkylation of ( R, R)- 2-Li enolate showed substantial stereoinduction by the bis[α-phenylethyl]amide auxiliary, leading to 80% ds in the methylation reaction. No appreciable effect upon diastereoselectivity was observed by the presence of additives (LiCl, HMPA, DMPU) in the reaction. On the other hand, stereoinduction by the α-phenylethylamino group in the methylation of ester enolate ( S)- 3-Li was lower (65% ds) under standard conditions (THF, −78°C) but improved to 81% ds in the presence of 3 equiv. of HMPA as cosolvent. ‘Matched’ and ‘mismatched’ derivatives, ( R, R, S)- 11 and ( R, R, R)- 11, respectively, were methylated via their corresponding lithium enolates. Observed diastereoselectivities generally followed the anticipated tendencies based on double stereoinduction. Thus diastereoselectivity reached 89% ds in the methylation of the matched isomer, ( R, R, S)- 11-Li.

Recent Advances in the Enantioselective Synthesis of β-Amino Acids

Abstract: The introductory section of this review presents some of the currently most compelling β-amino acid targets, according to their structural types: (α and β-aryl substituted, olefinic and alkynyl, α,α- and α,β-disubstituted, 'cyclic and conformationally restricted, fluorine­ containing, and phosphonic analogous β-amino acids. The main section highlights some of the very new (1996-1998), promising methodology for the enantioselective synthesis of β-amino acids, with especial emphasis on catalytic and enzymatic processes, as well as methods based on "chiral pool", "self-regeneration of stereogenic centers", diastereoselective nucleophilic additions to prochiral double bonds, and enantioselective reactions in the presence of chiral additives.

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from ( S)-asparagine

Perhydropyrimidinone ( S)- 1 is alkylated with very high diastereoselectivity to give trans products (2 S,5 R)- 3, (2 S,5 R)– 4 and (2 S,5 R)- 5. Dialkylation of ( S)- 1 also proceeds with complete stereoselectivity to afford adducts (2 S,5 R)- 6, (2 S,5 S)- 6, (2 S,5 R)- 7 and (2 S,5 S)- 7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2 S,5 R)- 3 gives enantiopure α-substituted β-amino acid ( R)- 8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids ( R)- or ( S)- 9 and ( R)- or ( S)- 10. Related iminoester (2 S,6 S)- 2 is alkylated with complete diastereoselectivity to give products (2 S,6 S)- 11– 13 whose hydrolysis under relatively mild conditions (2N CF 3CO 2H, CH 3OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters ( S)- 14– 16, with intact double bonds in the olefinic substituents.

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2( S)- tert-butyl-3-methylperhydropyrimidin-4-one [1, 2

Double alkylation of enantiopure N, N-acetal pyrimidinone ( S)- 1, a masked chiral derivative of β-alanine prepared from ( S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2 S,5 R)- 6, (2 S,5 S)- 6, (2 S,5 R)- 7, and (2 S,5 S)- 7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids ( R)- 8, ( S)- 8, ( R)- 9, and ( S)- 9 in very good yields.

Enantioselective synthesis of β-amino acids. 7. Preparation of enantiopure α-substituted β-amino acids from 1-benzoyl-2( S)- tert-butyl-3-methylperhydropyrimidin-4-one. 1,2

Inexpensive natural α-amino acid L-asparagine was efficiently converted to either ( R)- or ( S)- α-alkylated β-amino acids in enantiomerically pure state. The key intermediate in this protocol is the enantiopure N, N-acetal pyrimidinone (S)- 1 , a masked chiral derivative of β-alanine.

Enantioselective synthesis of β-amino acids. 6. High 1,2-stereoinduction in the preparation of enantiopure 2( R)-hydroxy-3( R)- N-benzoylamino-3-phenylpropionic acid ( like stereoisomer of taxol's side chain)

The remarkably high 1,2-stereoinduction encountered in the hydroxylation of 1-benzoyl-3-methyl-6( S)-phenylperhydropyrimidin-4-one [ (S)- 2 ] allows for the preparation of enantiopure N-benzoyl (2 R,3 R)-3-phenylisoserine, the like stereoisomer of taxol's C-13 side chain.

Asymmetric synthesis of sulfinimines: applications to the synthesis of nonracemic .beta.-amino acids and .alpha.-hydroxyl .beta.-amino acids

Asymmetric oxidation of sulfenimines 1 affords sulfinimines 2 (88-90% ee) which are chiral ammonia imine synthons useful in the enantioselective synthesis of β-amino acids and α-hydroxy-β-amino acids such as the C-13 side chain of taxol (2R,3S)-7

Enantioselective synthesis of β-amino acids based on BINAP—ruthenium(II) catalyzed hydrogenation

BINAP—Ru(II) catalyzed hydrogenation of β-substituted ( E)-β-(acylamino)acrylic acids allows efficient enantioselective synthesis of β-amino acids. The Z double bond isomers which possess an intramolecular hydrogen bond between amide and ester groups are more reactive but are hydrogenated with poor enantioselectivity. BINAP—Rh(I) complexes afford only moderate stereoselectivity with the opposite sense of enantioselection.