A novel method for chirospecific synthesis of 2,5-disubstituted pyrrolidines

Thaning M., Wistrand L., Stenstrøm Y., Lund H., Khan A.Z., Sandström J., Krogsgaard-Larsen P.

Koh K., Ben R.N., Durst T.

2,5-Dibromoadipic acid has been converted into the di-(R)-pantolactone ester of (S,S)-pyyrolidine-2,5-dicarboxylic acid in two steps. This compound serves as a precursor to C 2 -symmetric 2,5-disubstituted pyrrolidines. The synthesis of linear C 2 -symmetric β,β′-dihydroxyamines starting with α-bromophenylacetic acid and (S)-phenylglycine ethyl ester is also reported.

Pauly R., Sasaki N.A., Potier P.

Two different types of cyclic α-amino acids, cycloalkylglycines and N-heterocyclic α-amino acids, were prepared in optically pure form from the same chiral synthon 1-(R) (or 1-(S)) simply by altering the quantity or type of base required for anion formation. Elaboration of the heterocyclic intermediate 3 provided α,β-unsaturated N-heterocyclic α-amino acids.

Zwaagstra M.E., Meetsma A., Feringa B.L.

A new synthetic route to (2S,5S)-dimethylpyrrolidine 1, which can also be applied to the synthesis of the (2R,5R)-enantiomer, has been developed. The C2-symmetric pyrrolidine can be obtained enantiomerically pure (e.e. ⩾ 97%) in 15% overall yield starting from a mixture of isomers of 2,5-hexanediol, via a short reaction sequence using (S)-α-methylbenzylamine as a chiral auxiliary. The crystal and molecular structure of (S)-2′-phenyl-N-ethyl-(2S,5S)-dimethylpyrrolidine picrate 5, showing an antiparallel stacking of the picrate units, is also reported.

Giese B., Damm W., Wetterich F., Zeitz H.-., Rancourt J., Guindon Y.

ESR measurements and AM1 calculations show that ester substituted radicals 2 and 6 prefer conformation A as a result of allylic strain effects. But dipolar repulsion between substituents X and CO2Et In 2 and 6 has a pronounced effect on the conformation and the stereoselectivity of radicals 2 and 6.

Ezquerra J., Rubio A., Pedregal C., Sanz G., Rodriguez J.H., García Ruano J.L.

N-BOC-ethyl pyroglutamate 1 undergoes nucleophilic ring opening with lithium methyl p-tolyl sulfinyl anion delivering the p-tolylketosulfoxide 2 . Treatment of 2 with TFA gave rise to a mixture of thioesters 3a,3b . The hydrolysis of 3b afforded (2S, 5S) pirrolidine-2,5 dicarboxylic acid 5 , a constituent of the red Alga Schizymenia dubyi . Under Pummerer reaction conditions (TFAA/Pyr), 2 yielded the 5-oxo-L-pipecolic acid derivative 6 . Cis and trans pyrrolidine 2,5-dicarboxylic acids 4 and 5 were obtained by ring opening of 1 with lithium methyl p-tolyl sulfinyl anion followed by treatment with TFA and basic hydrolysis. Under Pummerer reaction conditions(TFAA/Py) 2 delivered the 5-oxo-L-pipecolic acid derivative 6 .

Moulines J., Bats J., Hautefaye P., Nuhrich A., Lamidey A.

N-tosyl-oxiraneethylamines undergo cyclization upon treatment with aqueous sodium hydroxide to afford either N-tosyl-azetidinemethanols or N-tosyl-pyrrolidin-3-ols in high yields. The change in regioselectivity of this cyclization process is quite dependent on the location of a pentamethylene substitution in the chain connecting the nitrogen with the oxirane ring.

Kitagawa O., Hanano T., Kikuchi N., Taguchi T.

The α-iodination reaction of chiral enamides 1 possessing (2R,5R)-2,5-bis(methoxymethyl)pyrrolidine as a chiral auxiliary proceeded with high diastereoselectivity in the presence of I 2 and s-collidine. The chiral iodides 2 thus obtained were converted to the α-BocNH-amides 3 without epimerization. The subsequent iodolactonization afforded trans-lactones 4 with a relatively high selectivity.

Yamamoto Y., Hoshino J., Fujimoto Y., Ohmoto J., Sawada S.

By the use of (-)-1-phenylethylamine as a chiral auxiliary, three diastereomeric isomers of 2,5-bis(methoxycarbonyl)pyrrolidine derivatives are prepared from dimethyl rac-2,5-dibromoadipate and separated by crystallization and chromatographic fractionation involving stereoselective hydrolysis. The cis isomer is recovered and epimerized to the trans counterparts. Starting from each of the two trans isomers, optically active 2,5-disubstituted [2,5-bis(methoxymethyl) and 2,5-bis(methoxymethoxymetbyl)] pyrrolidines of C 2 -symmetry are synthesized by a short route

Magaard V.W., Sanchez R.M., Bean J.W., Moore M.L.

5,5-Dimethylproline was designed to induce a cis -peptide bond when incorporated into peptides. In a model dipeptide, it exists 90% as the cis isomer. A convenient synthesis of Boc- DL -5,5-dimethylproline methyl ester is described. This conformationally-constrained amino acid may be expected to exist predominantly in the cis peptide bond isomer when into peptides. The peptide bond in the model peptide Boc-Phe-Me 2 Pro-OMe is shown to be 90% in the cis isomer.

Langlois N., Rojas A.

(2S, 5S) pyrrolidine-2,5-dicarboxylic acid 1 was synthesized from (5S) N-methoxycarbonyl-5-ethoxyethoxy-methyl pyrrolidin-2-one 2 by a simple and efficient way. 1

Genicot C., Ghosez L.

Amide 3 derived from N-tosylsarcosine and (2R,5R)-dimethylpyrrolidine was converted into keteniminium salt 4 which readily cycloadded to olefins. Hydrolysis of the adducts yielded cyclobutanones which were regiospecifically oxidized to gamma-lactones 7. High enantioselectivities were observed with 1,2-cis-disubstitued olefins.

Ghosez L., Genicot C., Gouverneur V.

Abstract

Rosset S., Célérier J.P., Lhommet G.

We describe enantioselective syntheses of 2,5-disubstituted pyrroline and pyrrolidine with unsaturated radical, starting from (S)-pyroglutamic acid.

Gouverneur V., Ghosez L.

2-azadienes 1 which are readily prepared from acyl chlorides react with high facial selectivity with the chiral carbamoyl nitroso dicnophile 2. Reduction and hydrolysis of the adducts yield enantiomerically pure amino acids.

Borah M., Saikia A.K.

Walker D., Rogier D.

Thiomorpholine and thiomorpholine 1,1-dioxide are important building blocks in medicinal chemistry research, and some analogues containing these moieties have entered human clinical trials. Analogues containing bridged bicyclic thiomorpholines have also shown interesting biological profiles. 3-Thia-6-azabicyclo[3.1.1]heptane, 3-thia-8-azabicyclo[3.2.1]octane, and their corresponding 1,1-dioxide counterparts were prepared as novel bicyclic thiomorpholine building blocks. Each heterocycle was synthesized from an inexpensive starting material by straightforward chemistry.

Arimitsu S., Kato D., Maruoka K.

Although alkyl sulfonates are commonly used for alkylating agents, there are very few reports on phase-transfer-catalyzed asymmetric alkylation with alkyl sulfonates. Herein, we report that the asymmetric reaction using glycine Schiff base 1 and optically pure epoxy triflates op-2 proceeded smoothly in the presence of phase-transfer catalyst (S,S)-4a to furnish γ,δ-epoxy-α-amino acids 3 in good yield with high enantioselectivity.

Atta A.K., Pathak T.

Pentosyl and hexosyl acyclic vinyl sulfones having a suitably positioned leaving group reacted with externally delivered carbon, nitrogen, oxygen, and sulfur nucleophiles to afford a series of five-membered carbocycles and heterocycles in a diastereoselective fashion. This diversity-oriented synthetic method generates a wide range of chirally pure cyclic compounds from easily accessible starting materials and reagents.

Alonso D.A., Ájera C.N.

Abstract The use of sulfones in organic chemistry, acting as an auxiliary group, is still a very important synthetic strategy, especially for the formation of carbon‐carbon single and double bonds. Once the synthetic objective is achieved, the sulfone gruop is usually removed from the molecule. This removal most commonly involves a reductive desulfonylation process with either replacement of the sulfone by hydrogen, or a process that results in the formation of a carbon‐carbon double bond when a β‐hydroxy or β‐alkoxy sulfone is employed. This chapter is devoted to the replacement of the sulfone group by a hydrogen (reductive desulfonylation reactions), and reductive elimination reactions of Julia‐type substrates (Julia‐Lythgoe olefination process). The chapter addresses the full scope, generality, limitations, and synthetic applications of these reactions. The literature through most of 2007 is covered.

Chênevert R., Jacques F., Giguère P., Dasser M.

The enzymatic desymmetrization of various meso-N-Boc-2,5-cis-disubstituted pyrrolidines and pyrrolines compounds by ester hydrolysis or transesterification provided the corresponding monoesters in high enantiomeric excess.

Kim B.H., Lee H.B., Hwang J.K., Kim Y.G.

The conjugate addition of thioacetic acid to methacrylamides with chiral C 2 -symmetric trans -2,5-disubstituted pyrrolidines afforded the addition products in excellent stereoselectivities (>99% de) and good yields (80–90%). The high selectivity was attributed mainly to the steric effect of the chiral auxiliaries. The cyclic nature of the chiral auxiliaries seemed also important for both the stereoselectivity and the reaction rate. Acidic hydrolysis of the adduct containing (2 R ,5 R )-bis(methoxymethyl)pyrrolidine gave ( S )-3-mercapto-2-methylpropanoic acid, a key intermediate for captopril, in 98% ee and 96% yield. The chiral auxiliary was recovered in the demethylated form of N -Boc-(2 R ,3 R )-bis(hydroxymethyl)pyrrolidine in 90% yield.

Donohoe T.J., Freestone G.C., Headley C.E., Rigby C.L., Cousins R.P., Bhalay G.

[reaction: see text] The partial reduction of 2,5-pyrrole diester 1 followed by enantioselective protonation in situ to furnish synthetically useful building blocks is described. An enantiomeric excess of up to 74% was achieved using (-)-ephedrine and related analogues as chiral proton sources. The pyrroline product obtained could be recrystallized to give enantiomerically pure material.

Aggarwal V.K., Sandrinelli F., Charmant J.P.

trans-(2S,5S)-(1,1-Diphenylmethyl)pyrrolidine has been prepared from the corresponding diester in four steps and 54% overall yield. Key steps involve the nucleophilic addition of an organomagnesiun reagent to a carbonyl compound promoted by cerium(III) chloride and the reductive removal of benzylic trimethylsilyloxyl groups with Me3SiCl–NaI–MeCN and water.

Wang Q., Sasaki N.A., Riche C., Potier P.

Treatment of (2S)-1-O-benzylglycerol-2,3-bistriflate (2) with the trilithiated species of chiral building blocks 5−7 provided 2,3,5-trisubstituted pyrrolidines that were subjected to reductive desulfonylation to give trans-2,5-disubstituted pyrrolidines 11−13, respectively. The same reaction sequence with the (2R)-bistriflate 4 and trilithiated 5 afforded the cis isomer 19. This two-step synthetic mehodology can furnish any one of the four possible diastereomers of enantiopure 2,5-disubstituted pyrrolidines in 60−72% overall yields.

Nájera C., Yus M.

Wang Q., AndréSasaki N., Potier P.

Treatment of readily available chiral building block 1 with (2R)-2,3-O-isopropylideneglyceraldehyde (5) provides a new route for asymmetric synthesis of 2,4-disubstituted pyrrolidines. Several proline-amino acid chimeras: proline-leucine, proline-lysine, proline-arginine and proline-glutamic acid, are synthesized in highly diastereomerically pure forms.

Wang Q., Sasaki N.A., Potier P.

A new strategy for asymmetric synthesis of 2,4-disubstituted pyrrolidines is described, starting from readily available chiral building blocks 1 and (2 R )-2,3- O -isopropylideneglycealdehyde ( 6 ). An efficient synthesis of enentiomerically pure compounds 2 and 3 was developed starting from chiral synthon 1

Alonso D.A., Costa A., Mancheño B., Nájera C.

The lithiation of N -benzyl- β -tosylethanamine ( 10a ) and N -benzyl- α -phenyl- β -tosylethanamine ( 10b ) with n -butyllithium at −78°C leads to monoanions 11a and 11b , respectively. Intermediates 11 react with different monoelectrophiles (D 2 O, alkyl halides, and carbonyl compounds) at the α-position with respect to the sulfone, and with dielectrophiles (1,3-, 1,4-dihalides, α-bromoacetates, and α-chloroketones) to afford the corresponding 6, 7, and 5-membered nitrogen heterocycles. The benzoazepine derivative 13ae , obtained by reaction of 11a with 4,5-bis(chloromethyl)-1,2-dimethoxybenzene, are transformed into the inmediate precursor 24 of capsazepine 25 an antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. Cyclic β-amino sulfone: N -benzyl-3-tosylpiperidine ( 13aa ) suffers lithiation at the axial position reacting with electrophiles to give compounds 27 . In the case of the Michael addition to methyl crotonate the corresponding adducts are converted into 1-azabicyclo[3.3.1]nonan-2-one derivatives. Finally, base-induced dehydrosulfinylation, reductive desulfonylation, and Julia's methylenation are studied with some representative derivatives.

Sasaki N.A., Dockner M., Chiaroni A., Riche C., Potier P.