Bicyclic Proline Research Articles

Comprehensive Strategies to Bicyclic Prolines: Applications in the Synthesis of Potent Arginase Inhibitors.

Comprehensive synthetic strategies afforded a diverse set of structurally unique bicyclic proline-containing arginase inhibitors with a high degree of three-dimensionality. The analogs that favored the Cγ-exo conformation of the proline improved the arginase potency over the initial lead. The novel synthetic strategies reported here not only enable access to previously unknown stereochemically complex proline derivatives but also provide a foundation for the future synthesis of bicyclic proline analogs, which incorporate inherent three-dimensional character into building blocks, medicine, and catalysts and could have a profound impact on the conformation of proline-containing peptides and macrocycles.

4‐(Di‐/Trifluoromethyl)‐2‐heterabicyclo[2.1.1]hexanes: Advanced Fluorinated Phenyl Isosteres and Proline analogues

AbstractA gram‐scale synthesis, physico‐chemical characterization, and lead‐likeness assessment of 4‐di/trifluoromethyl‐2‐heterabicyclo[2.1.1]hexanes as fluorinated bicyclic proline analogues and phenyl isosteres are disclosed. The key step of the synthesis included iodocyclization of fluorinated 3‐hydroxy‐/3‐aminomethyl methylenecyclobutanes; with the amino derivatives, the reaction was accompanied with carboxylation and further cyclization. Apart from the corresponding 4‐di/trifluoromethyl‐2,4‐methanoprolines, a series of fluorinated oxabicyclo[2.1.1]hexane‐derived building blocks relevant to medicinal chemistry (i. e. primary iodides, carboxylic acids, alcohols, azides, primary amines, sulfonyl chlorides, and alkynes) were prepared. For representative derivatives of the resulting fluorinated 2‐oxabicyclo[2.1.1]hexanes, pKa and logP values were measured to clarify their potential as the possible phenyl isosteres. Apart from the somewhat increased acidity, fine‐tuned lipophilicity intermediate between that of non‐fluorinated or aromatic counterparts was observed. Finally, the potential of the title building blocks was demonstrated by generation of virtual compound libraries using the LLAMA software. The resulting libraries fitted perfectly the lead‐like chemical space, had higher three‐dimensionality, and showed lower mean lead‐likeness penalty as compared to those obtained from either non‐fluorinated or aromatic derivatives.

Asymmetric Cα-Alkylation of Proline via Chirality Transfers of Conformationally Restricted Proline Derivative: Application to the Total Synthesis of (-)-Amathaspiramide F.

An efficient strategy for the asymmetric synthesis of Cα-tetrasubstituted proline derivatives from proline has been established. A nitrogen-fused bicyclic system was devised to control the stereodynamics of proline. Through N-quaternizations with allylic electrophiles followed by [2,3]-rearrangements, the bicyclic proline system delivered enantioenriched Cα-tetrasubstituted prolines. This strategy was applied to the concise total synthesis of (-)-amathaspiramide F.

Synthesis of trans-fused Octahydroisoindole-1-carboxylic Acids

trans-Fused octahydroisoindole-1-carboxylic acids are bicyclic proline analogues of potential interest in the search for new drugs. Within this work, the trans-fused octahydroisoindole system has been constructed using methyl trans-2-(hydroxymethyl)cyclohexane-1-carboxylate as the key synthetic precursor, in turn readily prepared from inexpensive cis-cyclohexane-1,2-dicarboxylic anhydride. Both the (1S*,3aR*,7aR*)- and the (1R*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acids were prepared through the Strecker reaction of methyl trans-2-formylcyclohexane-1-carboxylate as the key step. Finally, (1S*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acid was obtained with good yields in a highly stereoselective manner using (3aR*,7aR*)-octahydroisoindole-1-one as a suitable scaffold. Keywords: Amino acids, proline analogues, strecker, trans-fused ring systems, diastereoselectivity, lactamization.

Synthesis of 2-Azabicyclo[n.2.0]alkane-Derived Building Blocks

An approach to 2-azabicyclo[n.2.0]alkane derivatives (n = 1, 2), which relies on a tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence of the corresponding 2-(ω-chloroalkyl)cyclobutanones (in turn prepared by [2+2] cycloaddition of keteniminium salts and ethylene) is described. The utility of the method is demonstrated by multigram syntheses of bicyclic proline analogues, monoprotected diamines, as well as parent 2-azabicyclo[4.2.0]octane.

A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid

An efficient multi-gram synthesis of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, a key chiral bicyclic proline fragment employed in the construction of the potent anti-HCV drug boceprevir, has been presented. The synthetic route commences with the readily available cis-cypermethric acid, a cheap source of the cyclopropane ring required in the targeted compound, and utilizes the cis-orientation of the 2,2-dichlorovinyl and carboxylic acid side arms, already present in the starting material, to effect a diastereoselective construction of the proline moiety.

ChemInform Abstract: Synthesis of Bicyclic Proline Derivatives by the Aza‐Cope—Mannich Reaction: Formal Synthesis of (.+‐.)‐Acetylaranotin.

AbstractSome examples concerning the key step for the approach to the desired amino acid segments are presented in the scheme.

Synthesis of bicyclic proline derivatives by the aza-Cope-Mannich reaction: formal synthesis of (±)-acetylaranotin.

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza-Cope-Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.

Synthesis of [c]‐Fused Bicyclic Proline Analogues

AbstractAn overview of synthetic methods developed to build [c]‐fused bicyclic proline analogues is presented. The focus is on the preparation of azabicycles that bear a carbocyclic ring fused to the [c] face of the pyrrolidine unit. Attention is paid both to procedures that afford the desired compounds in racemic form and to asymmetric strategies. Procedures are organized according to the size of the carbocycle that is fused to the pyrrolidine moiety. Strategies able to provide multigram quantities of enantiopure compounds that have application in the synthesis of marketed drugs are highlighted.

Solvent‐induced conformational flexibility of a bicyclic proline analogue: Octahydroindole‐2‐carboxylic acid

The conformational preferences of the N-acetyl-N'-methylamide derivatives of the four octahydroindole-2-carboxylic acid (Oic) stereoisomers have been investigated in the gas-phase and in aqueous solution using quantum mechanical calculations. In addition to the conformational effects provoked by the stereochemical diversity of Oic, which presents three chiral centers, results provide evidence of interesting and rather unusual features. The conformational preferences of the Oic stereoisomers in solution are only well described by applying a complete and systematic search process, results achieved by simple re-optimization of the gas-phase minima being very imprecise. This is because the conformational rigidity detected in the gas-phase, which is imposed by the chemical restrictions of the fused bicyclic skeleton, disappears in aqueous solution, the four stereoisomers behaving as flexible molecules in this environment. Thus, in general, the γ-turn is the only minimum energy conformation in the gas-phase while in aqueous solution the helical, polyproline-II and γ-turn motifs are energetically favored. Molecular dynamics simulations indicate that the conformational flexibility predicted by quantum mechanical calculations for the four Oic stereoisomers in solution is satisfactorily reproduced by classical force-fields.

One‐Step Synthesis of Strained Bicyclic Carboxylic and Boronic Amino Esters via Ruthenium‐Catalysed Tandem Carbene Addition/Cyclopropanation of Enynes

AbstractThe reaction of 1,6‐ and 1,7‐enynes, derived from carboxylic and boronic amino acids, with diazo compounds in the presence of the (cyclooctadiene)(pentamethylcyclopentadiene)ruthenium chloride complex [RuCl(cod)(C5Me5)] catalyst leads to the formation of strained bicyclic proline or homoproline derivatives in good yields. This catalytic transformation proceeds under mild conditions, in one step from easily accessible enynes and was applied to various protecting groups. High stereoselectivities for the created alkenyl chain and excellent diastereoselectivities for proline derivatives were obtained.

Synthesis of enantiopure ( R, R)- and ( S, S)- cis-2,3-propanoprolines

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[ b]pyrrole-6a(1 H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall synthetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino acid.

Ring closure reactions of bicyclic prolinol and prolin ester enantiomers

Starting from the of bicyclic proline ester, ethyl exo-2-azabicyclo[2.2.1]heptane-3-carboxylate (+)-5 several hydantoines and thiohydantoines were prepared by acidic ring closure of the corresponding urea or thiourea derivatives. Enantiomer (-)-5 was reduced to 2-azanorbornylmethanol 12, which was transformed to 5,8-methanooxazolo- and thiazolo[3,4-a] pyridine derivatives. The structures, stereochemistry and relative configurations of the synthesized compounds were proved by NMR.

Fluorous Parallel Synthesis of a Piperazinedione-Fused Tricyclic Compound Library

A fluorous-linker-assisted solution-phase protocol has been developed and applied to parallel synthesis of a piperazinedione-fused tricyclic compound library. The one-pot [3 + 2] cycloaddition of fluorous amino esters, aldehydes, and maleimides afforded bicyclic proline derivatives. The intermediates were subjected to N-acylation with chloroacetyl chloride, followed by displacement reactions with amines. Linker cleavage with concomitant lactamization yielded the final products. Microwave heating was employed to facilitate several reaction steps and fluorous solid phase extraction (F-SPE) was employed to purify the intermediates. During the method development, a small library containing sixteen analogs was prepared. The optimized conditions were applied to the synthesis of a production library containing ninety analogs.

Convenient synthesis of an enantiomerically pure bicyclic proline and its N-oxyl derivatives

An enantiomerically pure bicyclic proline derivative was prepared by cis-selective allylation and diastereospecific intramolecular alkylation starting from d-pipecolinic acid. In addition, enantiomerically pure azabicyclo N-oxyls derived from the bicyclic proline worked well as catalysts for the enantioselective electrooxidation of racemic sec-alcohols to afford optically active sec-alcohols in moderate enantiomeric purity.

Bicyclic proline analogues as organocatalysts for stereoselective aldol reactions: an in silico DFT study

Density functional theory has been employed in investigating the efficiency of a series of bicyclic analogues of proline as stereoselective organocatalysts for the aldol reaction. Three classes of conformationally restricted proline analogues, as part of either a [2.2.1] or [2.1.1] bicyclic framework, have been studied. Transition states for the stereoselective C-C bond formation between enamines derived from [2.2.1] and [2.1.1] bicyclic amino acids and p-nitrobenzaldehyde, leading to enantiomeric products, have been identified. Analysis of the transition state geometries revealed that the structural rigidity of catalysts, improved transition state organization as well as other weak interactions influence the relative stabilities of diastereomeric transition states and help contribute to the overall stereoselectivity in the aldol reaction. These bicyclic catalysts are predicted to be substantially more effective in improving the enantiomeric excess than the widely used organocatalyst proline. Enantiomeric excesses in the range 82-95% are predicted for these bicyclic catalysts when a sterically unbiased substrate such as p-nitrobenzaldehyde is employed for the asymmetric aldol reaction. More interestingly, introduction of substituents, as simple as a methyl group, at the ortho position of the aryl aldehyde bring about an increase in the enantiomeric excess to values greater than 98%. The reasons behind the vital energy separation between diastereomeric transition states has been rationalized with the help of a number of weak interactions such as intramolecular hydrogen bonding and Coulombic interactions operating on the transition states. These predictions could have wider implications for the rational design of improved organocatalysts for stereoselective carbon-carbon bond-forming reactions.

Synthesis of a Bicyclic Proline Analogue from l-Ascorbic Acid

The efficient synthesis of a bicyclic α-amino acid from L-ascorbic acid is presented. The synthetic procedure is a three-step process involving an S N 2 reaction of an amino acetal with an L-ascorbic acid derivative, followed by protection of the amine as a Fmoc urethane, and acid-promoted trans-acetalization to give the title compound. Inversion of the configuration at the stereocenter of the precursor derived from L-ascorbic acid allowed the formation of the corresponding bicyclic α-amino acid bearing the carboxylic group in the 2-exo configuration. Such Fmoc-protected α-amino acids can be considered as bicyclic mimetics of proline, and are particularly suited for solid-phase peptidomimetic chemistry.

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.

Inhibitors of Hepatitis C Virus NS3.4A Protease: P2 Proline Variants

A series of novel bicyclic proline P2 scaffold based tetrapeptide inhibitors were designed and prepared. Given their relatively small size, these compounds exhibited exceptional binding affinities and good cellular potencies for HCV protease. One of the best analogues, tricyclic based P2 scaffold 12, had an affinity for HCV with a Ki of 37 nM and cell activity IC50 of 200 nM.

Solid-phase synthesis of α-substituted proline hydantoins and analogs

The manual solid-phase preparation of racemic α-substituted bicyclic proline hydantoins and analogs, which can potentially contain up to four sites of structural diversity (ring size and substitution on the ring or at the ring fusion), is described. Key steps involved alkylation of aldimines of resin-bound amino acids with α,ω-dihaloalkanes and intramolecular displacement of the halide to generate α-substituted prolines and homologs. After formation of resin-bound ureas by reaction of these sterically-hindered secondary amines with isocyanates, base-catalyzed cyclization/cleavage yielded the desired hydantoin products.