Stereoselective synthesis of 2,4-methanoproline homologues

The stereoselective synthesis of 2-azabicyclo[2.2.1]heptane-1-carboxylic acid and 6-azabicyclo[3.2.1]octane-5-carboxylic acid, novel rigid bicyclic proline analogues, is reported. The synthesis was performed in five steps from the corresponding 2-cycloalken-1-ones. A known approach to 2,4-methanoproline is improved. The three amino acids constitute a library of conformationally constrained proline analogues, which can be used for the design of peptidomimetics and peptide models.     

Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transformation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine.     

A facile synthesis of enantiopure 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

An efficient procedure for the preparation of enantiopure 7-benzyloxycarbonyl-7-azabicyclo[2.2.1]heptane-2-carboxylic acids is described.     

Unusually high pyramidal geometry of the bicyclic amide nitrogen in a complex 7-azabicyclo[2.2.1]heptane derivative: Theoretical analysis using a bottom-up strategy

The high pyramidalization of the bicyclic amide nitrogen found in the crystal structure of a dipeptide incorporating (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid has been investigated using quantum mechanical calculations. More specifically, a bottom-up strategy based on the study of model molecules of progressive complexity has been used. First, an appropriate quantum mechanical method has been selected by examining the distortion of the amide bond in three simple model molecules. Next, the amide distortion induced by the norbornane ring has been evaluated by considering three different 7-azabicyclo[2.2.1]heptane amides. After this, the suitability of quantum mechanical calculations to predict the effect of the substituents on the pyramidalization of the bicyclic amide nitrogen has been investigated by comparing experimental and theoretical parameters for a number of compounds. Finally, the factors responsible for amide distortion in the (1S,2S,4R)-N-benzoyl-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid derivative have been elucidated using a hierarchical approach. For this purpose, several derivatives were generated by removing or modifying the substituents attached to the 7-azanorbornane system. Results have been discussed in terms of intramolecular specific interactions.     

A novel approach to 2,4-ethanoproline

A novel approach to 2-azabicyclo[2.2.1]heptane-1-carboxylic acid (2,4-ethanoproline) is reported starting from (2S,4R)-4-hydroxyproline. The synthetic scheme consists of 10 steps and results in 22% total yield of the title compound. Enantiomeric purity of the product is checked by chiral stationary phase HPLC.     

New chiral didehydroamino acid derivatives from a cyclic glycine template with 3,6-dihydro-2H-1,4-oxazin-2-one structure: applications to the asymmetric synthesis of nonproteinogenic alpha-amino acids

New chiral (Z)-alpha,beta-didehydroamino acid (DDAA) derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one structure 11a-f have been stereoselectively prepared after condensation of chiral glycine equivalent 7 with aldehydes in the presence of K(2)CO(3) under mild solid-liquid phase-transfer catalysis reaction conditions. These new systems have been used in diastereoselective cyclopropanation reactions using Corey's ylide for the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids (ACCs) such as allo-corononamic and allo-norcoronamic acids. The hydrogenation reaction of these systems at ambient pressure in the presence of formaldehyde affords saturated oxazinones and N-methylated oxazinones which have been transformed into the N-methyl-alpha-amino acids (N-MAAs) (S)-2-(methylamino)butanoic acid and (S)-N-methylleucine. In addition, the parent alpha, beta-didehydroalanine derivative 11g has been prepared by a direct aminomethylation-elimination sequence from 7 and Eschenmoser's salt and has been used in Diels-Alder cycloaddition with endo selectivity for the synthesis of the enantiomerically pure bicyclic alpha-amino acids (-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic and (-)-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.     

Mass spectrometry in stereochemical problems. 6 — The case of mono and di-substituted norbornanes

The mass spectrometric behaviour of pairs of stereoisomeric mono- and di-substituted norbornanes, namely bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylic acid, methyl bicyclo[2.2.1]heptane-2-endo- and -exo-carboxylate, 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamidobicyclo[2.2.1]heptane-2-exo-carboxylic acid and methyl 2-exo-acetamidobicyclo[2.2.1]heptane-2-endo- and 2-endo-acetamido-bicyclo[2.2.1]heptane-2-exo-carboxylate was studied in detail with particular emphasis on characterization of the stereoisomers. The fragmentation patterns, studied with the aid of mass-analysed ion kinetic energy spectrometry, were supported by semi-empirical MO–SFC calculations, performed using the AM1 method included in the AMPAC program.     

Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate,a synthetic approach to new conformationally constrained prolines

Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several phosphoranes and the Horner–Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their utility in the synthesis of β-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has provided proline–amino acid chimeras [combinations of proline with other α-amino acids, such as l-norvaline, l-norleucine, l-α-(3-phenylpropyl)glycine or l-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure form.     

Synthesis and Stereostructure of 3-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid Diastereomers

Summary. All-endo-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid and two epimers of 3-amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid were prepared via 1,3-oxazine or γ-lactone intermediates by the stereoselective functionalization of endo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. Their structures were proved by IR and NMR spectroscopy, with the use of HMQC, HMBC, DEPT, and DIFFNOE techniques.     

Synthesis and Stereostructure of 3-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid Diastereomers

All-endo-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid and two epimers of 3-amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid were prepared via 1,3-oxazine or γ-lactone intermediates by the stereoselective functionalization of endo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. Their structures were proved by IR and NMR spectroscopy, with the use of HMQC, HMBC, DEPT, and DIFFNOE techniques.     

Incorporation of Ahc into model dipeptides as an inducer of a beta-turn with a distorted amide bond. Conformational analysis

The proline residue of dipeptides Ser-Pro and Pro-Ser has been replaced by 7-azabicyclo[2.2.1]heptane-1-carboxylic acid (Ahc), a conformationally restricted analogue of proline that is capable of mimicking distorted amides. The conformational analysis of the new peptides in the solid state revealed that the Ahc-Ser sequence displays a type I beta-turn, which includes a distorted amide bond. In contrast, the Ser-Ahc sequence exists in a nonfolded structure.     

Liquid-phase combinatorial synthesis of alicyclic beta-lactams via Ugi four-component reaction

[reaction: see text] Alicyclic beta-lactams were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction (U-4C-3CR), starting from alicyclic beta-amino acids such as cis-2-aminocyclohexanecarboxylic acid, cis-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues. A six-membered mixture-based combinatorial library of beta-lactams was also generated.     

Use of enantiomerically pure 7-azabicyclo[2.2.1]heptan-2-ol as a chiral template for the synthesis of aminocyclitols

Using enantiopure 7-azabicyclo[2.2.1]heptane-2-ol, the synthesis of cis- as well as trans-2-aminocyclohexanols, dihydroconduramine E-1, and ent-conduramine F-1 has been described.     

Synthesis of 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, a rigid non-chiral analogue of 2-aminoadipic acid

A non-chiral, rigid 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, an analogue of 2-aminoadipic acid, has been synthesized in six steps from dimethyl-meso-2,5-dibromohexanedioate in 28% total yield. A key step in the synthesis is double alkylation of a dimethyl pyrrolidine-2,5-dicarboxylate by 1-bromo-2-chloroethane.     

Stabilisation of the type I β-turn conformation by a bicyclic analogue of proline

A highly constrained analogue of l-proline, (1S,2S,4R)-2-phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid, has been incorporated into a model dipeptide. X-Ray diffraction analysis has shown that, in the solid state, this constrained peptide adopts a type I β-turn whereas the analogous dipeptide sequence incorporating l-proline has been shown to accommodate a βII-turn disposition. Attractive interactions involving the middle NH group and either the aromatic rings or the pyramidalised bicycle nitrogen seem to play a role in the stabilisation of the βI-turn conformation observed.     

Structural analysis of three methyl N-phosphorylated 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylates

Both exo and endo isomers of (±)-methyl N-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate and (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate were dihydroxylated with OsO₄. The unexpected formation of (±)-methyl 5,6-dihydroxy-N-diphenylphosphoryl-2-azabicyclo[2.2.1]heptane-3-endo-carboxylate from (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-endo-carboxylate is discussed based on NMR analyses and experimental observations. The two N-diphenylphosphoryl dihydroxybicycles are analyzed in terms of their crystalline structure by X-ray crystallography.     

High-Performance liquid chromatographic separation of enantiomers of unusual amino acids possessing cycloalkane or cycloalkene skeletons on a chiral crown ether containing stationary phase

Summary Direct reversed-phase high-performance liquid chromatographic methods were developed for the separation and identification of the enantiomers of mono- and bicyclic racemic β-amino acids:cis- andtrans-2-aminocyclopentane-1-carboxylic acids,cis- andtrans-2-aminocyclohexane-1-carboxylic acids,cis- andtrans-2-amino-4-cyclohexene-1-carboxylic acids,diendo- anddiexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acids anddiendo- anddiexo-3-amino-5-bicyclo[2.2.1]heptene-2-carboxylic acids. Enantioseparation was carried out by the application of a chiral stationary phase, Crownpak CR(+). The conditions of separation were optimized by changing the temperature, the flow rate and the pH of the mobile phase. Presented at: Balaton Symposium on High-Performance Separation Methods, Siófok, Hungary, September 3–5, 1997.     

Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1]heptadienes using tandem radical addition-homoallylic radical rearrangement

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.     

Enantiopure synthesis of all four stereoisomers of carbapenam-3-carboxylic acid methyl ester

The retro-Dieckmann reaction has been used as a stereodivergent synthetic tool on N-Boc-7-azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl ester to obtain enantiopure trans- and cis-5-(carboxymethyl)pyrrolidine-2-carboxylic acid methyl esters. These disubstituted pyrrolidines have been used as starting materials to develop concise and straightforward syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters. In this way, we have confirmed unequivocally the stereochemistry of two carbapenams isolated from strains of Serratia and Erwinia species.     

(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸的合成

以(R)-(+)-α-甲基苄胺为原料,依次经缩合,Diels-Alder反应,还原,Cbz-保护和水解反应,合成了抗丙肝新药HCV NS3/4A蛋白酶拟肽类抑制剂的重要中间体——(1R,3S,4S)-2-苄氧羰基-2-氮杂双环[2.2.1]庚烷-3-羧酸,总收率66%,其结构经1H NMR和ESI-MS确证。