A Stereoselective Synthesis of (R)-(-)-rolipram from L-Glutamic Acid

Dı́az, Adolfo; Siro, Jorge G.; Garcia‐Navio, J. L.; Vaquero, Juan J.; Alvárez‐Builla, Julio

doi:10.1055/s-1997-3182

Cited by 30 publications

(15 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Deprotection to obtain (R)-Rolipram was performed in 78% overall yield by treatment of 7j (90% ee) with TFA-CH 2 Cl 2 (1:1), followed by heating with Et 3 N in toluene solution at reflux (Scheme 2). 14 Comparison of the optical rotation of the product 2 {[a] D -27.4 (c = 0.1, MeOH)} with literature data proved the absolute configuration to be R. 3 In conclusion, we have developed straightforward and efficient enantioselective syntheses of (-)-(R)-Baclofen and (-)-(R)-Rolipram using as key steps Rh-catalyzed additions of arylboronic acids to 4-aminobut-2,3-enoic acid derivatives. -4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2 9, 28.7, 38.1, 41.7, 45.3, 60.3, 80.1, 128.6, 128.8, 132.6, 133.9, 139.6, 171.4 = 13.8, 28.1, 38.3, 42.2, 45.5, 60.2, 79.1, 126.8, 127.4, 128.5, 141.1, 155.6, 171.7. Anal.…”

Section: Entrymentioning

confidence: 95%

See 1 more Smart Citation

Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids

Becht¹,

Meyer²,

Helmchen

2003

Synthesis

View full text Add to dashboard Cite

Highly enantioselective syntheses of two important gaminobutyric acid (GABA) analogues, the antispastic drug (-)-(R)-Baclofen and the antidepressant agent (-)-(R)-Rolipram, are reported. Key-steps in both syntheses are the Rh-catalyzed asymmetric 1,4-additions of arylboronic acids to 4-aminobut-2,3-enoic acid derivatives.Because of the crucial importance of g-aminobutyric acid (GABA) in various nervous system functions, GABA analogues are of great interest in medicinal chemistry. 1 For example, the strongly lipophilic b-substituted analogue 4-amino-3-(4-chlorophenyl)butyric acid (1, Baclofen) is until now the only available selective agonist of the GABA B receptor. 2 Of particular interest is the cyclic GABA analogue 4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-one (2, Rolipram), known for its potent inhibitor activity of the cardiac cyclic AMP phosphodiesterase, found in brain tissue. 3 It has been disclosed that for both compounds the (R)-enantiomers are responsible for the pharmacological activities. 2,3 Therefore, short and efficient syntheses of the enantiomerically pure GABA analogues (R)-Baclofen and (R)-Rolipram are of great interest.Several stereoselective syntheses of (R)-Baclofen 4 and (R)-Rolipram 3,5 have already been reported. Some of these syntheses require more than ten steps and proceed generally with a relatively low overall yield. In this paper, we describe shorter and more efficient syntheses of these compounds from a common precursor based on asymmetric catalysis (Scheme 1). 6 Key steps of our syntheses are Rh(I)-catalyzed asymmetric conjugate additions of arylboronic acids to the substrates 3a-c (Scheme 2). Scheme 1 Scheme 2 Downloaded by: York University libraries. Copyrighted material.

show abstract

Section: Entrymentioning

confidence: 95%

“…Calcd for C 20 H 18 ClNO 4 : C,64.61;H,4.88;N,3.77. Found: C,64.39;H,4.87;N,3.75. Ethyl 4-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) 14.0, 38.7, 40.1, 43.1, 60.5, 115.3, 115.6, 123.3, 129.2, 129.3, 131.8, 134.0, 136.0, 168.1, 171.3.…”

Section: Entrymentioning

confidence: 99%

Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids

Becht¹,

Meyer²,

Helmchen

2003

Synthesis

View full text Add to dashboard Cite

show abstract

“…Although a mixture of trans and cis pyroglutamic acid esters 4 were formed in the reaction (Table 2), both of them can be readily converted into bioactive 4-substituted pyrrolidin-2-ones with the same absolute configuration via tert-butyl group removal and subsequent Barton decarboxylation. [14] For example, Alzheimers drug (S)-Rolipram [15] (11) can be synthesized with high enantiopurity from a mixture of trans-4 m and cis-4 m via the reaction sequence (Scheme 4 b).…”

Section: Angewandte Chemiementioning

confidence: 99%

Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis

Zhou

Song

et al. 2021

Angew Chem Int Ed

View full text Add to dashboard Cite

Direct α‐functionalization of NH2‐free glycinates with relatively weak electrophiles such as α,β‐unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α‐C of glycinate 1 a with α,β‐unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14–96 % yields with 81–97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4‐substituted pyrrolidin‐2‐ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert‐butyl group removal and subsequent Barton decarboxylation.

show abstract

“…For execution of the reactions described in Scheme 4, we used as substrate N-benzyl-3-pyrrolin-2-one(8), which was previously obtained [1]. Thus, the treatment of 8 with TMSCl followed by reaction with the Grignard reagent PhMgBr and CuBr·SMe 2 [11][12][13] generated a product identified by 1 H NMR, IR, and LRMS as the hemiaminal 9. The compound 10, identified by 1 H NMR, was obtained by hydrogenation of 8 with hydrogen and the Pearlman catalyst Pd(OH) 2 /C [14].…”

Section: Evaluation Of the Reactivity Of N-benzyl-3-pyrrolin-2-one Inmentioning

confidence: 99%

2-Pyrrolidinones and 3-Pyrrolin-2-ones: A Study on the Chemical Reactivity of These Structural Moieties

Alves

2011

Organic Chemistry International

View full text Add to dashboard Cite

show abstract

A Stereoselective Synthesis of (R)-(-)-rolipram from L-Glutamic Acid

Cited by 30 publications

References 2 publications

Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids

Enantioselective Syntheses of (-)-(R)-Rolipram, (-)-(R)-Baclofen and Other GABA Analogues via Rhodium-Catalyzed Conjugate Addition of Arylboronic Acids

Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis

2-Pyrrolidinones and 3-Pyrrolin-2-ones: A Study on the Chemical Reactivity of These Structural Moieties

Contact Info

Product

Resources

About