- Enantioselective Flow Synthesis of Rolipram Enabled by a Telescoped Asymmetric Conjugate Addition-Oxidative Aldehyde Esterification Sequence Using in Situ-Generated Persulfuric Acid as Oxidant
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A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition-oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant la
- Nagy, Bence S.,Llanes, Patricia,Pericas, Miquel A.,Kappe, C. Oliver,?tv?s, Sándor B.
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- General access to C-centered radicals: Combining a bioinspired photocatalyst with boronic acids in aqueous media
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Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.
- Bloom, Steven,Chilamari, Maheshwerreddy,Immel, Jacob R.
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p. 12727 - 12737
(2020/11/18)
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- Divergent Synthesis of γ-Amino Acid and γ-Lactam Derivatives from meso-Glutaric Anhydrides
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The first divergent synthesis of both γ-amino acid and γ-lactam derivatives from meso-glutaric anhydrides is described. The organocatalytic desymmetrisation with TMSN3 relies on controlled generation of a nucleophilic ammonium azide species mediated by a polystyrene-bound base to promote efficient silylazidation. After Curtius rearrangement of the acyl azide intermediate to access the corresponding isocyanate, hydrolysis/alcoholysis provided uniformly high yields of γ-amino acids and their N-protected counterparts. The same intermediates were shown to undergo an unprecedented decarboxylation–cyclisation cascade in situ to provide synthetically useful yields of γ-lactam derivatives without using any further activating agents. Mechanistic insights invoke the intermediacy of an unconventional γ-N-carboxyanhydride (γ-NCA) in the latter process. Among the examples prepared using this transformation are 8 APIs/molecules of considerable medicinal interest.
- Connon, Stephen J.,Craig, Ryan,Smith, Simon N.
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supporting information
p. 13378 - 13382
(2020/10/02)
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- Deacetylative Amination of Acetyl Arenes and Alkanes with C-C Bond Cleavage
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The Br?nsted acid-catalyzed synthesis of primary amines from acetyl arenes and alkanes with C-C bond cleavage is described. Although the conversion from an acetyl group to amine has traditionally required multiple steps, the method described herein, which uses an oxime reagent as an amino group source, achieves the transformation directly via domino transoximation/Beckmann rearrangement/Pinner reaction. The method was also applied to the synthesis of γ-aminobutyric acids, such as baclophen and rolipram.
- Hyodo, Kengo,Hasegawa, Genna,Maki, Hiroya,Uchida, Kingo
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p. 2818 - 2822
(2019/04/25)
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- Assembling of medium/long chain-based β-arylated unnatural amino acid derivatives via the Pd(II)-catalyzed sp3 β-C-H arylation and a short route for rolipram-type derivatives
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In this paper, we report the assembling of libraries of β-arylated short/medium/long chain-based non-α-amino acid (aminoalkanoic acid) derivatives via the Pd(II)-catalyzed, bidentate directing group 8-aminoquinoline-aided sp3 β-C-H activation/arylation method. Short/medium chain-based unnatural amino acid derivatives containing an aryl group at the β-position are promising small molecules with therapeutic properties. Thus, it is necessary to enrich the libraries of short/medium/long chain-based unnatural amino acid derivatives containing an aryl group at the β-position. Considering the importance of β-arylated short/medium/long chain-based non-α-amino acid derivatives, an inclusive attention was paid to explore the Pd(II)-catalyzed sp3 β-C-H arylation of short/medium/long chain-based non-α-amino acids. Representative synthetic transformations including a short route for the assembling of rolipram and related compounds and 3-arylated GABA derivatives such as, baclofen, phenibut and tolibut were shown using selected β-C-H arylated non-α-amino acid derivatives.
- Tomar, Radha,Bhattacharya, Debabrata,Babu, Srinivasarao Arulananda
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p. 2447 - 2465
(2019/03/26)
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- Catalytic Intermolecular Carboamination of Unactivated Alkenes via Directed Aminopalladation
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An intermolecular 1,2-carboamination of unactivated alkenes proceeding via a Pd(II)/Pd(IV) catalytic cycle has been developed. To realize this transformation, a cleavable bidentate directing group is used to control the regioselectivity of aminopalladation and stabilize the resulting organopalladium(II) intermediate, such that oxidative addition to a carbon electrophile outcompetes potential β-hydride elimination. Under the optimized reaction conditions, a broad range of nitrogen nucleophiles and carbon electrophiles are compatible coupling partners in this reaction, affording moderate to high yields. The products of this reaction can be easily converted to free ?3-amino acids and ?3-lactams, both of which are common structural motifs found in drug molecules and bioactive compounds. Reaction kinetics and DFT calculations shed light on the mechanism of the reaction and explain empirically observed reactivity trends.
- Liu, Zhen,Wang, Yanyan,Wang, Zichen,Zeng, Tian,Liu, Peng,Engle, Keary M.
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p. 11261 - 11270
(2017/08/22)
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- Direct Catalytic Desaturation of Lactams Enabled by Soft Enolization
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A direct catalytic method is described for the α,β-desaturation of N-protected lactams to their conjugated unsaturated counterparts under mildly acidic conditions. The reaction is consistently operated at room temperature and tolerates a wide range of functional groups, showing reactivity complementary to that of prior desaturation methods. Lactams with various ring sizes and substituents at different positions all reacted smoothly. The synthetic utility of this method is demonstrated in a concise synthesis of Rolipram. In addition, linear amides also prove to be competent substrates, and the phthaloyl-protected product serves as a convenient precursor to access various conjugated carboxylic acid derivatives. Strong bases are avoided in this desaturation approach, and the key is to merge soft enolization with a Pd-catalyzed oxidation process.
- Chen, Ming,Dong, Guangbin
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supporting information
p. 7757 - 7760
(2017/06/21)
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- N-Cyanation of Secondary Amines Using Trichloroacetonitrile
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A one-pot N-cyanation of secondary amines has been developed using trichloroacetonitrile as an inexpensive cyano source. A diverse range of cyclic and acyclic secondary amines can be readily transformed into the corresponding cyanamides in good isolated yields, with the method successfully utilized in the final synthetic step of a biologically active rolipram-derived cyanamide. This approach exhibits distinct selectivity when compared to the use of highly toxic cyanogen bromide.
- Ayres, James N.,Ling, Kenneth B.,Morrill, Louis C.
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supporting information
p. 5528 - 5531
(2016/11/17)
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- Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs
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Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.
- Leyva-Perez, Antonio,Garcia-Garcia, Pilar,Corma, Avelino
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supporting information
p. 8687 - 8690
(2014/08/18)
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- From paracetamol to rolipram and derivatives: Application of deacetylation-diazotation sequences and palladium-catalyzed matsuda-heck reaction
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A six-step synthesis of the antidepressant rolipram from the popular analgetic 4-acetamidophenol (paracetamol) is described. The steps include oxidative functionalization of the aromatic core, diazonium salt formation via deacetylation-diazotation, Matsuda-Heck reaction, conjugate addition of nitromethane, and hydrogenative cyclization. Georg Thieme Verlag Stuttgart · New York.
- Schmidt, Bernd,Elizarov, Nelli,Berger, Rene,Petersen, Monibh.
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p. 1174 - 1180
(2013/06/05)
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- Synthesis of 4-substituted 1,5-dihydropyrrol-2-ones and 5,6-dihydro-1H-pyridin-2-ones by Negishi cross-coupling reactions: Short access to the antidepressant (±)-rolipram
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A straightforward access to the title compounds was established by Pd-catalyzed Negishi cross-coupling reactions of the readily available bromides 3 and 6 with various functionalized zinc reagents (71-97% yield). Georg Thieme Verlag Stuttgart.
- Albrecht, Dominik,Bach, Thorsten
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p. 1557 - 1560
(2008/02/05)
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- Conjugated addition of bis(oxazolinyl)zinc to substituted 2-nitrovinyl benzenes: an alternative synthesis of (±)-Rolipram
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In this letter we present a new 2,4,4-trimethyl-2-oxazoline anion-zinc derivative that has a remarkable thermal stability when compared with the corresponding cyanocuprate counterpart. The yields from conjugated addition to several 2-nitrovinyl benzenes are moderate to good and the reaction itself is easier to execute and cleaner. As an application, this methodology was applied to an alternative synthesis of (±)-Rolipram, a drug with several interesting biological activities.
- Oliveira, Alfredo R.M.,Villar, José A.F.P.,Simonelli, Fabio,Gariani, Rogério A.,Wosch, Celso L.,Zarbin, Paulo H.G.
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p. 1507 - 1509
(2008/02/02)
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- Catalytic four-component assembly based on allenylboronate platform: New access to privileged allylic amine structures
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We developed a novel palladium-catalyzed four-component assembly based on allenylboronate platform, by which privileged allylic amine structures can be constructed in a regioselective, stereoselective, and diversity-oriented manner. The boryl group acts not only as a useful group that can be transformed to various functional groups afterward but also as a stereochemical controller in the generation of key (π-allyl)palladium intermediates. A short synthesis of rolipram (selective phosphodiesterase-4 inhibitor) is also demonstrated. Copyright
- Tonogaki, Keisuke,Itami, Kenichiro,Yoshida, Jun-Ichi
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p. 1464 - 1465
(2007/10/03)
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- Synthesis of 4-aryl-2-pyrrolidones and β-aryl-γ-amino-butyric acid (GABA) analogues by Heck arylation of 3-pyrrolines with arenediazonium tetrafluoroborates. Synthesis of (±)-rolipram on a multigram scale and chromatographic resolution by semipreparative chiral simulated moving bed chromatography
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(Chemical Equation Presented) We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and β-aryl-γ-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.
- Garcia, Ariel L. L.,Carpes, Marcos J. S.,De Oca, Antonio C. B. M.,Dos Santos, Marco A. G.,Santana, Cesar C.,Correia, Carlos Roque D.
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p. 1050 - 1053
(2007/10/03)
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- Synthesis of (±)-rolipram
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A facile synthesis of rolipram via stepwise [3+2] annulation and desulfonated hydrolysis was reported. Base-induced coupling/cyclization reactions of α-sulfonylacetamide with (Z)-2-bromoacrylic ester yielded three contiguous centers on the pyroglutamate system with trans-trans orientation as the one-pot key step.
- Chang, Meng-Yang,Sun, Pei-Pei,Chen, Shui-Tein,Chang, Nein-Chen
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p. 1865 - 1872
(2007/10/03)
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- γ-Lactam synthesis via C-H insertion: Elaboration of N-benzyl protecting groups for high regioselectivity toward the total synthesis of rolipram
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(Matrix presented) By intramolecular C-H insertion of α-diazo-α -(phenylsulfonyl)acetamides, γ-lactams such as the antidepressant agent rolipram were efficiently synthesized in a highly regioselective manner. N-Benzyl moieties were elaborated as amide protecting groups to enhance regioselectivity in C-H activation as well as chemoselectivity over addition reactions.
- Yoon, Cheol Hwan,Nagle, Advait,Chen, Chiliu,Gandhi, Drashti,Jung, Kyung Woon
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p. 2259 - 2262
(2007/10/03)
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- First highly regio- and diastereoselective [3+2] cycloaddition of chiral nonracemic Fischer carbene complexes with azomethine ylides: An enantioselective synthesis of (+)-Rolipram
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A new procedure for the synthesis of 1,3,4-trisubstituted and 1,4-di-substituted pyrrolidin-2-one derivatives in an enantioselective fashion is reported. The 1,3-dipolar cycloaddition of (±)-menthol and (-)-8-phenylmenthol derived Fischer alkoxy alkenyl carbene complexes with in situ generated functionalized azomethine ylides gives the corresponding cycloadducts as chelated tetracarbonyl Fischer carbene complexes. Only one regioisomer is detected in all cases, and the diastereoselectivity of the reaction is very high when (-)-8-phenylmenthol derived carbenes are employed. Oxidation and further transformation of the cycloadducts provide an easy access to pyrrolidin-2-ones. The anti-inflammatory and antidepressant drug (+)-Rolipram is readily prepared in four steps in a 20% overall yield by taking advantage of this newly developed methodology.
- Barluenga, Jose,Fernandez-Rodriguez, Manuel A.,Aguilar, Enrique,Fernandez-Mari, Felix,Salinas, Alejandro,Olano, Bernardo
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p. 3533 - 3544
(2007/10/03)
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- A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid
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A stereoselective synthesis of (R)-(-)-rolipram from L-glutamic acid is described. The key step is a stereoselective Michael addition of an arylcuprate to a modified pyroglutamic derivative which acts as the template to induce the stereoselectivity. Facile manipulation of the enantiomerically pure Michael product afforded the expected therapeutic agent.
- Diaz, Adolfo,Siro, Jorge G.,García-Navío, José L.,Vaquero, Juan J.,Alvarez-Builla, Julio
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p. 559 - 562
(2007/10/03)
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- 4-(Polyalkoxy phenyl)-2-pyrrolidones
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4-(Polyalkoxyphenyl)-2-pyrrolidones of the formula STR1 wherein R1 and R2 each are hydrocarbon of up to 18 carbon atoms at least one being other than methyl, a heterocyclic ring, or alkyl of 1-5 carbon atoms substituted by halogen, OH, COOH, alkoxy, alkoxycarbonyl or an amino group; R' is H, alkyl, aryl or acyl; and X is O or S; possess neuropsychotropic activity. The compounds wherein X is O can be produced by saponifying and decarboxylating a corresponding 2-pyrrolidone-3-carboxylic acid alkyl ester or cyclizing a corresponding 3-phenyl-4-amino-butyric acid or alkyl ester thereof. The pyrrolidones can be converted to the corresponding thiopyrrolidones by reaction with phosphorous pentasulfide in the presence of base.
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