Pyrrolidine Natural Product Research Articles

Additions of Carbohydrate-Derived Alkoxyallenes to Imines and Subsequent Reactions to Enantiopure 2,5-Dihydropyrrole Derivatives

The additions of six alkoxyallenes bearing carbohydrate-derived chiral auxiliaries to imines were systematically studied. The reactions of three lithiated 1-alkoxypropa-1,2-dienes with an N-tosyl imine revealed that the diacetone fructose-derived auxiliary provided the highest diastereoselectivity of 91:9. The preferred absolute configuration of the newly formed stereogenic center was determined by subsequent ozonolysis of the allene moiety, transesterification and comparison with literature data. The analogous reactions of three axially chiral 3-nonyl-substituted 1-alkoxyallenes with these auxiliaries confirm these results and also prove that the configuration of the generated stereogenic center was only steered by the auxiliaries, whereas the chiral axis has essentially no influence. In general, four diastereomers were obtained in various portions, depending on the ratio of the two precursor allene diastereomers and on the auxiliary employed. The obtained dia­stereomeric allenyl amines were cyclized under different conditions. As expected, under basic conditions, a stereospecific cyclization occurred, whereas under silver nitrate catalysis partial isomerization at the allene stage was observed. Under both conditions the 2,5-cis-disubstituted dihydropyrroles were formed faster than the trans-isomers. Several of the 2-substituted or 2,5-disubstituted dihydropyrrole derivatives could be isolated in diastereomerically pure form and were subsequently converted into the expected pyrrolidin-3-ones by removal of the carbohydrate-derived auxiliary under acidic conditions. The desired products were obtained in good yield and with high enantiopurity. They are suitable starting materials for the synthesis of enantiopure pyrrolidine natural products.

Synthesis of bis-Phosphate Iminoaltritol Enantiomers and Structural Characterization with Adenine Phosphoribosyltransferase

Phosphoribosyl transferases (PRTs) are essential in nucleotide synthesis and salvage, amino acid, and vitamin synthesis. Transition state analysis of several PRTs has demonstrated ribocation-like transition states with a partial positive charge residing on the pentose ring. Core chemistry for synthesis of transition state analogues related to the 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) reactant of these enzymes could be developed by stereospecific placement of bis-phosphate groups on an iminoaltritol ring. Cationic character is provided by the imino group and the bis-phosphates anchor both the 1- and 5-phosphate binding sites. We provide a facile synthetic path to these molecules. Cyclic-nitrone redox methodology was applied to the stereocontrolled synthesis of three stereoisomers of a selectively monoprotected diol relevant to the synthesis of transition-state analogue inhibitors. These polyhydroxylated pyrrolidine natural product analogues were bis-phosphorylated to generate analogues of the ribocationic form of 5-phosphoribosyl 1-phosphate. A safe, high yielding synthesis of the key intermediate represents a new route to these transition state mimics. An enantiomeric pair of iminoaltritol bis-phosphates (L-DIAB and D-DIAB) was prepared and shown to display inhibition of Plasmodium falciparum orotate phosphoribosyltransferase and Saccharomyces cerevisiae adenine phosphoribosyltransferase (ScAPRT). Crystallographic inhibitor binding analysis of L- and D-DIAB bound to the catalytic sites of ScAPRT demonstrates accommodation of both enantiomers by altered ring geometry and bis-phosphate catalytic site contacts.

Palladium-Catalyzed Cross-Coupling of N-Sulfonylaziridines and Alkenylboronic Acids: Stereospecific Synthesis of Homoallylic Amines with Di- and Trisubstituted Alkenes

A palladium-catalyzed cross-coupling of 2-alkylaziridines with alkenylboronic acids to give homoallylamines is presented. The reaction is highly regioselective and stereospecific and provides convenient access to enantioenriched amines with 1,1-disubstituted, 1,2-disubstituted, and trisubstituted alkenes. The modular synthesis of a 2,5-disubstituted pyrrolidine natural product was completed in three steps and 67% overall yield.

ChemInform Abstract: Enantiodivergent Combination of Natural Product Scaffolds Enabled by Catalytic Enantioselective Cycloaddition.

An efficient strategy has been established for the enantiodivergent synthesis of natural product inspired compounds embodying both tropane and pyrrolidine natural product fragments. This strategy includes the enantioselective kinetic resolution of racemic tropanes by means of a copper(I)-catalyzed [3+2] cycloaddition and allows the preparation of two enantiopure products in a one-pot reaction in high yield and with high diastereo- and enantioselectivity by using one chiral catalyst.

Enantiodivergent Combination of Natural Product Scaffolds Enabled by Catalytic Enantioselective Cycloaddition

AbstractAn efficient strategy has been established for the enantiodivergent synthesis of natural product inspired compounds embodying both tropane and pyrrolidine natural product fragments. This strategy includes the enantioselective kinetic resolution of racemic tropanes by means of a copper(I)‐catalyzed [3+2] cycloaddition and allows the preparation of two enantiopure products in a one‐pot reaction in high yield and with high diastereo‐ and enantioselectivity by using one chiral catalyst.

Enantiodivergent Combination of Natural Product Scaffolds Enabled by Catalytic Enantioselective Cycloaddition.

An efficient strategy has been established for the enantiodivergent synthesis of natural product inspired compounds embodying both tropane and pyrrolidine natural product fragments. This strategy includes the enantioselective kinetic resolution of racemic tropanes by means of a copper(I)-catalyzed [3+2] cycloaddition and allows the preparation of two enantiopure products in a one-pot reaction in high yield and with high diastereo- and enantioselectivity by using one chiral catalyst.

Enantioselective Route to β-Silyl-δ-keto Esters by Organocatalyzed Regioselective Michael Addition of Methyl Ketones to a (Silylmethylene)malonate and Their Use in Natural Product Synthesis

The direct Michael addition of alkyl methyl ketones through the acetyl methyl terminal to diethyl {[dimethyl(phenyl)silyl]methylene}malonate was catalyzed by the (S)-N-(pyrrolidin-2-ylmethyl)pyrrolidine/trifluoroacetic acid combination with high yield and excellent regio- and enantioselectivity. The ketone adducts can easily undergo de-ethoxycarbonylation to give β-silyl-δketo esters with excellent synthetic potential. This has been demonstrated by the synthesis of a suitably substituted β-silyl-δ-keto ester as an advanced intermediate for a chiral hydroxylated pyrrolidine natural product, (+)-preussin. Silicon-controlled diastereoselective reduction of the ketone functionality of β-silyl-δ-keto esters followed by lactonization of the resulting hydroxy esters gave disubstituted δ-valerolactones. Advanced intermediates for the antipodes of natural products, namely (+)-massoialactone and (+)-mevinolin analogue, and natural products, namely (-)-tetrahydrolipstatin and (+)-5-hexadecanolide, have been achieved.

Chemical Predisposition in Synthesis: Application to the Preparation of the Pyrrolidine Natural Products, Plakoridines A and B.

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Chemical predisposition in synthesis: application to the preparation of the pyrrolidine natural products, plakoridines A and B

The pyrrolidine natural products, plakoridines A and B, as well as an array of unnatural analogues, have been prepared using a five-step synthetic sequence modelled on a biogenetic theory. The key transformation involves a ‘Mannich/Michael/internal-redox’ cascade, which proceeds in yields of 31–63%.

Asymmetric synthesis of 2-substituted butane-1,4-diols by hydrogenation of homochiral fumaramide derivatives

Diastereoselective hydrogenation of homochiral fumaramides 1 derived from (2 R)-Oppolzer’s sultam was observed by analysis of the 1H NMR spectra of the succinamide mixtures with de’s of 77–88%. Reduction of these succinamides using LiAlH 4 gave the corresponding (2 S)-butane-1,4-diols and established that addition of hydrogen takes place selectively on the re-face of fumaramides 1. The stereoselectivity was confirmed by estimating the ee’s from the 19F NMR spectra of the Mosher’s diesters of the diols. This methodology was applied to the synthesis of selected pyrrolidine natural products in homochiral form.

.alpha.-Amino carbanions. Preparation, metalation, and alkylation of enamidines. Synthesis of piperidine and pyrrolidine natural products and homologation of carbonyl compounds

.alpha.-Amino carbanions. Preparation, metalation, and alkylation of enamidines. Synthesis of piperidine and pyrrolidine natural products and homologation of carbonyl compounds