Enantiopure Β-amino Research Articles

Highly stereoselective ring expansion of enantiopure α-hydroxyalkyl azetidines

Stereodefined α-hydroxyalkyl azetidines, prepared in a few steps from enantiopure β-amino alcohols, are chlorinated or transformed into methanesulfonyloxymethyl derivatives in good yields. Heating of these compounds in chloroform or dimethylformamide induces a stereospecific ring enlargement to give 3-chloro or 3-methanesulfonyloxy pyrrolidines. The ease of this rearrangement depends on the nature of the migrating group (Cl − or MsO −), of the class of the starting alcohol (primary or secondary) and of the relative stereochemistry of the starting material.

Stereospecific route to enantiopure all cis-2,3,6-trisubstituted piperidines. Facile synthesis of (−)-deoxocassine and (+)-azimic acid

Reduction of the enantiopure β-amino esters 10 provides the γ-amnio alcohol 11 , which is condensed with 2,4-pentadione to afford 12 . Stepwise cyclization of 12 produced the cyclic enamine 13 , which is hydrogenated to deliver all cis-2,3,6-trisubstituted piperidine 14 . Using this reaction sequence and subsequent Baeyer–Villiger oxidation as the key step (−)-deoxocassine and (+)-azimic acid are synthesized.

N-sulfinyl beta-amino Weinreb amides: synthesis of enantiopure beta-amino carbonyl compounds. Asymmetric synthesis of (+)-sedridine and (-)-allosedridine.

[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbonyl compounds, as illustrated here by the concise enantioselective syntheses of sedum alkaloids (+)-sedridine and (-)-allosedridine.

A Novel General Route for the Preparation of Enantiopure Imidazolines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Efficient formal synthesis of the dendrobatid alkaloid, indolizidine (−)-209B

Condensation of the β-amino alcohol 7 derived from an enantiopure β-amino ester with the β-keto ester 8 provides the vinylogous urethane 9, which is cyclized to give the dehydropiperidine 10. Hydrogenation of 10 and subsequent cyclization mediated by Ph 3P/CBr 4 then afforded the bicyclic product 12, a precursor of indolizidine (−)-209B.

Reaction between N-alkylhydroxylamines and chiral enoate esters: more experimental evidence for a cycloaddition-like process, a rationale based on DFT theoretical calculations, and stereoselective synthesis of new enantiopure beta-amino acids.

The reactions between N-benzyl- and N-methylhydroxylamine and chiral enoate esters, derived from D-glyceraldehyde and (-)-verbenone, respectively, have been investigated. Theoretical calculations show that the most favorable mechanism involves the concerted cycloaddition of the hydroxylamine to the substrate. This result is in good agreement with the stereospecificity observed when the trisubstituted olefins are used. The open-chain adducts have been isolated when the processes are carried out at low temperatures and for short reaction times. These compounds evolve to the corresponding isoxazolidinones on standing at room temperature or under acid catalysis. The high pi-facial diastereoselection has been rationalized on the basis of steric effects induced by the dioxolane ring for D-glyceraldehyde derivatives or by the cyclobutane gem-dimethyl substitution for esters prepared from (-)-verbenone. As an application of these reactions, new beta-amino acids have been synthesized in a highly efficient and stereocontrolled manner.

Synthesis of enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones and N-protected 2,5-disubstituted 3-pyrrolidinones via the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters

Under the action of KHMDS in THF solvent the Dieckmann reaction of dicarbonyl compounds derived from enantiopure β-amino esters provides enantiopure N-protected 4,5-disubstituted 3-pyrrolidinones, whereas N-protected 2,5-disubstituted 3-pyrrolidinones formed in reactions mediated by tert-BuOK in DMF or toluene. Reduction of these pyrrolidinones afforded enantiopure polysubstituted pyrrolidines.

AN IMPROVED SYNTHESIS OF ENANTIOPURE β-AMINO ACIDS

An improved method for the preparation of both the enantiopure β-amino acids is presented. The diastereomer benzyl β-amino esters, obtained by stereoselective reduction of β-enamino esters, were separated and hydrogenolyzed to the free enantiopure β-amino acids.

Enantioselective synthesis of 2-substituted- N-Boc-Δ-4,5-piperidines

The title compounds were prepared through a synthetic sequence involving: (i) a reaction of the condensation product between an enantiopure β-amino alcohol and an aldehyde with allylmagnesium chloride; (ii) an N-allylation of the resulting secondary amine; (iii) a chemoselective cleavage of the β-amino alcohol residue; and (iv) a protection of the secondary amine followed by a ring closing metathesis. The advantageous use of (1 R,2 S)-norephedrine was demonstrated in these syntheses.

General route to 2,4,5-trisubstituted piperidines from enantiopure beta-amino esters. Total synthesis of pseudodistomin B triacetate and pseudodistomin F.

The Michael addition reaction of enantiopure beta-amino esters with methyl acrylate followed by Dieckmann condensation and enol silylation affords the enol ethers 6, which are hydrogenated with catalysis by Raney-Ni at 80 atm and 80 degrees C to provide 2,4, 5-trisubstituted piperidines with high diastereoselectivity. In this case Ni-H attacks the C-C double bond from the direction of the 2-alkyl group to provide the products in which 2,4,5-trisubstrited groups are all cis to each other. While hydrogenation of enol ether 13 without a N-Boc protecting group gives the product 15 in which the 4-hydroxy group and 5-ester moiety are trans to the 2-alkyl group. By using the diastereoselective hydrogenation products 9d and 9e as key intermediates, pseudodistomin B triacetate and pseudodistomin F are synthesized. The key steps for these transformations include Curtius rearrangement and Julia olefination.

β-Amino ester route to tussilagine, isotussilagine and (−)-petasinecine

Condensation of enantiopure β-amino ester 2a with methyl pyruvate provides two diastereoisomers 3 and 4. Both 3 and 4 are subjected to hydrogenation followed by cyclization producing pyrrolidinones 5 and 8. From 5 and 8 isotussilagine and tussilagine are obtained respectively, by using a Mitsunobu reaction as a key step. In a similar manner, (–)-petasinecine is synthesized from the condensation product of 2b with ethyl glyoxalate.

β-Peptides: a surprise at every turn

β-Peptides, i.e. oligomers of β-amino acids, containing as few as six residues may form surprisingly stable helices, with half-lives for the H/D exchange of the central NH protons of up to several days. Furthermore, these β-peptides (carrying the side chains of familiar α-amino acids such as Ala, Val, Leu, Phe, Lys in the 2- and/or 3-position of their 3-amino carboxylic moieties) have been shown to be stable to common peptidases for at least two days. In this article, a brief account of the results obtained since we started work in this area in early 1995 is given. The synthesis of enantiopure β-amino acids can be achieved by homologation of α-amino acids. The greater structural variability of β-amino acids leads to an even greater multitude of possible β-peptide primary and secondary structures. Circular dichroism, NMR and X-ray investigations have unveiled helical, pleated-sheet and tubular arrangements of linear and cyclic β-peptides composed of up to twelve β-amino acids. The prospects for the use of β-peptides as drugs, the construction of large, enzymatically-active β-proteins and their interaction with the natural, α-peptidic counterparts are discussed.

Catalytic enantioselective conjugate additions using enantiopure β-amino disulfides and β-amino thiolates

The enantioselective conjugate addition of diethylzinc to chalcone catalysed by nickel(II) using an enantiopure β-amino thiolate 2 or β-amino disulfide 1 to achieve ee's of up to 50% is described.

ChemInform Abstract: Approach to Highly Enantiopure β‐Amino Acid Esters by Using Lipase Catalysis in Organic Media.

AbstractChemInform 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.

Approach to highly enantiopure β-amino acid esters by using lipase catalysis in organic media

Ethyl esters of ten alicyclic β-aminocarboxylic acids were resolved by lipase catalysis in organic solvents. The resolution was based on acylation of the amino group at the R -stereogenic centre with various 2,2,2-trifluoroethyl esters. An increase in the hydrophobic nature of the acyl donor enhanced the enantioselectivity and reactivity in the case of lipase SP 526 from Candida antarctica , while the opposite effect was observed with lipase PS from Pseudomonas cepacia . An unexceptional enantioselectivity enhancement was observed when 2,2,2-trifluoroethyl chloroacetate was used in the case of lipase PS catalysis. Ethyl esters of ten alicyclic β-aminocarboxylic acids were resolved by lipase catalysis in organic solvents.

Stereoselective Reduction of Enantiopure β-Enamino Esters by Hydride: A Convenient Synthesis of Both Enantiopure β-Amino Esters

The reduction of enantiopure β-enamino esters 1 with sodium triacetoxyborohydride in acetic acid is described. This occurs with good diastereo- and enantioselectivity to yield β-amino esters 2 and 3 (after hydrogenolysis of the N-chiral group). A model is reported for the origin of the stereoselectivity through an enol ester−diacetoxyborohydride 6, which affords the intramolecular reduction. By choosing the appropriate chiral amine, this procedure allows a straightforward preparation of both the enantiopure β-amino esters and derivatives with known biological activity, using readily available starting materials and inexpensive reagents and conditions.

Biocatalytic resolution of β-fluoroalkyl-β-amino acids

N-Phenylacetyl derivatives of β-fluoroalkyl-β-alanines 6 were synthesized and biocatalytically resolved to the corresponding enantiopure β-amino acids 7,9 with the aid of penicillin acylase (EC 3.5.1.11) from Escherichia coli. In substrates 6 the enantioselectivity of the biocatalytic process was practically uninfluenced by the nature of the fluoroalkyl chain. Thus, β-fluoroalkyl-β-alanines 7,9 bearing short (R = CF 3, CHF 2) or long [C 3F 7, H(CF 2)4] chains were prepared in high enantiomeric parity. The ( R)-enantiomer was the fast-reacting enantiomer in all cases.

An Enzymatic Entry to Enantiopure β-Amino Acids

An Enzymatic Entry to Enantiopure β-Amino Acids