Convenient Synthesis of Substituted Piperidinones from α,β-Unsaturated Amides:  Formal Synthesis of Deplancheine, Tacamonine, and Paroxetine

Takasu, Kiyosei; Nishida, Naoko; Tomimura, and Akiko; Ihara, Masataka

doi:10.1021/jo050261x

Cited by 57 publications

(29 citation statements)

References 22 publications

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“…In 2005, Takasu et al reported a synthesis of racemic piperidines from a,b-unsaturated amides by an intermolecular aza-double Michael addition. 3 In the realm of organocatalysis, 4 Jorgensen and coworkers reported a Michael addition 5 of malonates to a,b-unsaturated aldehydes that could be used to obtain piperidines in only three steps in excellent yields and enantioselectivities. 6,7 In 2007, Rios and Córdova 8 reported a synthesis of pyrrolidines from 2-amidomalonates and a,b-unsaturated aldehydes, catalyzed by simple secondary amines with excellent enantioselectivities and yields.…”

Section: Introductionmentioning

confidence: 99%

Highly enantioselective organocatalytic synthesis of piperidines. Formal synthesis of (−)-Paroxetine

Valero

Schimer

Císařová

et al. 2009

Tetrahedron Letters

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Section: Introductionmentioning

confidence: 99%

Highly enantioselective organocatalytic synthesis of piperidines. Formal synthesis of (−)-Paroxetine

Valero

Schimer

Císařová

et al. 2009

Tetrahedron Letters

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“…This was then condensed with sesame in the next step of to obtain Nmethyl paroxetine, using the novel solvent sulpholane and polar solvents like DMSO, N-methyl pyrrolidone, dimethyl acetamide, 2-ethoxy ethanol or methanol. N-methyl paroxetine obtained by this method was far more superior in quality than obtained by using prior art methods [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and the overall yield was in the range of 80% to 85% with respect to the starting (-) carbinol.…”

Section: Brief Process Development Historymentioning

confidence: 99%

Developing a Commercially Viable Process for an Active Pharmaceutical Ingredient, Challenges, Myths and Reality in the Art of Process Chemistry

Dimitrova¹,

Bart²

2013

open Pro Chem J

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Process development and optimisation studies for the manufacturing process of N-methyl paroxetine was done by applying Quality by Design (QbD) principles. A normal operating range was defined for each process parameter by technique of design of experiments and knowledge of process chemistry to ensure consistent high quality of advanced intermediate and control of impurities. Initial challenges faced during early process development, were overcome by novel approach using polar aprotic solvents like sulpholane. Finally DMSO was used to improve overall impurity profile significantly.We have demonstrated a " right first time" approach to avoid failures and bitter surprises during scale up in manufacturing plant.

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“…The minor cis isomer 26 could be epimerized to 25 by treatment with NaOMe. The trans isomer 25 was reduced with LiAlH 4 to afford the piperidine 27, which had been correlated with paroxetine (28). Thus the important antidepressant was prepared in short steps.…”

Section: Aza Double Michael Reactionmentioning

confidence: 99%

“…Thus the important antidepressant was prepared in short steps. 27,28) The double Michael reaction was further applied to the syntheses of pentalenene (29), 29) pentalenic acid (30), 30) deoxypentalenic acid (31), 29) longiborneol (32), 15,31) cedrandiol (33), 32) 8,14-cedranoxide (34), 33) atisirene (35), 34,35) atisine (36), [36][37][38] estrane (37), 39) epilupinine (38), 40) and tacamonine (39) 41) (Fig. 1).…”

Section: Aza Double Michael Reactionmentioning

confidence: 99%

Syntheses of Biologically Active Natural Products and Leading Compounds for New Pharmaceuticals Employing Effective Construction of a Polycyclic Skeleton

Ihara

2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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IntroductionWhen various functional groups exist on a polycyclic skeleton, the three-dimensional relationships of the functional groups are restricted and a specific biological activity would be expected due to the rigid conformation (Chart 1). Therefore the development of an efficient method for the construction of polycyclic ring systems is highly desirable, particularly in the field of medicinal chemistry. Cascade reactions 2-7) forming a number of bonds in one operation are useful for the creation of polycyclic compounds. Many stereogenic centers can be created at the same time. A reduction in the number of reaction steps save reagents and energy and reduce waste. Therefore cascade reactions are important from the economic and green chemistry points of view. In this context, we have been studying cascade reactions under various reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions. Cascade Reaction under Polar Conditions 2.1. Double Michael ReactionThe bicyclo[2.2.2]octane skeleton is a framework of several natural products. We encountered difficulty in the stereoselective synthesis of the corresponding polycyclic systems using the intramolecular Diels-Alder reaction.8) The problem was solved by employing the intramolecular double Michael reaction, as shown in Chart 2. The treatment of cyclohexenones 1 and 3 with an a,b-unsaturated ester side chain at the 6 or 5 position with LiN(TMS) 2 provided the polycyclic bridged compounds 2 and 4 in highly stereoselective manners, respectively. 9,10) The objective products were produced via ideal transition states, fixed by the coordination with lithium ion.As a typical example of the application of this methodology, the synthesis of (Ϯ)-culumorin (13) 11) is shown in Chart Cascade reactions are useful methods for the construction of polycyclic skeletons, which are important cores for biological activities. A variety of cascade reactions carried out under multiple reaction conditions, such as pericyclic, polar, radical, and transition metal-catalyzed reaction conditions, have been investigated. Culmorin, pentalenene, pentalenic acid, deoxypentalenic acid, longiborneol, cedrandiol, 8,14-cedranoxide, atisirene, atisine, and estrane-type steroids were synthesized via the intramolecular double Michael reaction. Aza double Michael reaction was applied to the syntheses of tylophorine, epilupinine, tacamonine, and paroxetine. Furthermore, sequential Michael and aldol reactions were performed in both intramolecular and intermolecular manners, leading to the formation of polycyclic compounds fused to a four-membered ring. Synthesis of paesslerin A utilizing a multicomponent cascade reaction revealed an error in the proposed structure. Unique cascade reactions carried out under radical and transition metal-catalyzed reaction conditions were also investigated. With the combination of several cascade reactions, serofendic acids and methyl 7b b-hydroxykaurenoate, both of which have neuroprotective activity, were synthesized in a...

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Convenient Synthesis of Substituted Piperidinones from α,β-Unsaturated Amides: Formal Synthesis of Deplancheine, Tacamonine, and Paroxetine

Cited by 57 publications

References 22 publications

Highly enantioselective organocatalytic synthesis of piperidines. Formal synthesis of (−)-Paroxetine

Highly enantioselective organocatalytic synthesis of piperidines. Formal synthesis of (−)-Paroxetine

Developing a Commercially Viable Process for an Active Pharmaceutical Ingredient, Challenges, Myths and Reality in the Art of Process Chemistry

Syntheses of Biologically Active Natural Products and Leading Compounds for New Pharmaceuticals Employing Effective Construction of a Polycyclic Skeleton

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