Dieckmann Condensation Research Articles

Synthesis of the Novel Tetrahydropyrazolo[3,4-c]pyridin-5-one Scaffold

We report an efficient synthesis of the novel 1,4,6,7-tetra­hydropyrazolo[3,4-<i>c</i>]pyridin-5-one scaffold with the potential for incorporation of alkyl or aryl substituents at the C-3 and N-6 positions. The route utilises a Dieckmann condensation to install the lactam ring, followed by a hydrazine cyclisation to build the fused pyrazole ring.

Synthesis of Akt Inhibitor Ipatasertib. Part 1. Route Scouting and Early Process Development of a Challenging Cyclopentylpyrimidine Intermediate

Herein, the route scouting and early process development of a key cyclopentylpyrimidine ketone intermediate toward the synthesis of Akt inhibitor Ipatasertib are described. Initial supplies of the intermediate were prepared through a method that commenced with the natural product (R)-(+)-pulegone and relied on the early construction of a methyl-substituted cyclopentyl ring system. The first process chemistry route, detailed herein, enabled the synthesis of the ketone on a hundred-gram scale, but it was not feasible for the requisite production of multikilogram quantities of this compound and necessitated the exploration of alternative strategies. Several new synthetic approaches were investigated towards the preparation of the cyclopentylpyrimidine ketone, in either racemic or chiral form, which resulted in the discovery of a more practical route that hinged on the initial preparation of a highly substituted dihydroxypyrimidine compound. The cyclopentane ring in the target was then constructed through a key carbonylative esterification and subsequent tandem Dieckmann cyclization–decarboxylation sequence that was demonstrated in a racemic synthesis. This proof-of-concept was later developed into an asymmetric synthesis of the cyclopentylpyrimidine ketone, which will be described in a subsequent paper, along with the synthesis of Ipatasertib.

Synthesis of a smoothened cholesterol: 18,19-di-nor-cholesterol.

Herein, we report the first synthesis of a demethylated form of cholesterol (18,19-di-nor-cholesterol), in which the C18 and C19 methyl groups of the β-face were eliminated. Recent molecular simulations modeling 18,19-di-nor-cholesterol have suggested that cholesterol’s opposing rough β-face and smooth α-face play necessary roles in cholesterol’s membrane condensing abilities and, additionally, that specific facial preferences are displayed as cholesterol interacts with different neighboring lipids and transmembrane proteins. Inspired by these poorly characterized biochemical interactions, an extensive 18-step synthesis was completed as part of a collaborative effort, wherein synthesizing a “smoothened” cholesterol analogue would provide a direct way to experimentally measure the significance of the β-face methyl groups. Starting from known perhydrochrysenone A, the synthesis of 18,19-di-nor-cholesterol was accomplished with an excellent overall yield of 3.5%. The use of the highly stereoselective Dieckmann condensation and the employment of Evans’ chiral auxiliary were both key to ensuring the success of this synthesis.

Synthesis of a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[b]furo[3,2-d]pyridine derivative, the 5-aza analog of ramelteon

The 5-aza analog of ramelteon 3, a novel tricyclic 1,6,7,8-tetrahydro-2H-cyclopenta[b]furo[3,2-d]pyridine derivative, was synthesized by hetero-Diels–Alder reaction and chemoselective Dieckmann condensation.

Synthesis and Biological Activities of 3‐Substituted Analogues of Tenuazonic Acid

A series of tenuazonic acid analogues in which the acetyl group was replaced with electron‐withdrawing substituents have been synthesized with the aim of obtaining molecules with various bioactivities. Substituents such as cyano, sulfonyl, and amido were introduced at the 3‐position of the pyrrolidine‐2,4‐dione nucleus of tenuazonic acid. 3‐Cyano and sulfonyl pyrrolidine‐2,4‐dione compounds (2 and 6) were prepared via a Dieckmann cyclization as key step. 3‐Amido pyrrolidine‐2,4‐dione compounds (9) were prepared by a microwave‐assisted amidation reaction from corresponding 3‐carboxylate derivative. The target compounds were evaluated; their herbicidal, fungicidal, and insecticidal activities, and the preliminary bioassay data showed that some 3‐cyanopyrrolidine‐2,4‐diones 2 gave good insecticidal activity, whereas some 3‐amido compounds 9 exhibited moderate to strong fungicidal activity against Pythium dissimile at 20 mg/L.

ChemInform Abstract: New Regio‐Selective Method of Combinatorial Synthesis of Substituted Thiophenes, Thieno[3,2‐b]pyridines and Other Heterocycles via Combination of ′Domino′‐Type Reactions.

Abstract We present a novel combinatorial multicomponent regio-selective approach towards the synthesis of thieno[3,2-b]pyridines and pyridine pyrans. The methodology is based on the ‘domino’-type reaction. The high regio-selectivity in this reaction is gained by the in situ generation of the mono-potassium salt of 2-cyano-1-mercaptoethenethiolate. We also demonstrate that the use of ethyl 2-cyanoacetate in this reaction as a CH-acid leads to the termination of the domino sequence at the Dieckmann condensation step and yields novel ethyl 3-(4-cyano-3-hydroxy-5-(alkylthio)thiophen-2-yl)-3-oxopropanoate.

Synthesis of Regioisomeric Pyrido[c]azocanones from Azaindanone Derivatives

AbstractA ring enlargement reaction with methylamine gave new pyrido[2,3‐c]‐, pyrido[3,4‐c]‐ and pyrido[3,2‐c]azocanone derivatives from cyclic β‐oxo esters with a cyclopentapyridine skeleton and a 1,4‐diketone moiety. The starting materials for this ring transformation were either prepared from halogenopyridine carboxylates by Heck reaction and subsequent hydrogenation, or (halogenomethyl)pyridine carboxylates were submitted to SN reaction with diethyl malonate. Both routes were completed by Dieckmann condensation to build the cyclic β‐oxo ester structure and alkylation with phenacylbromide to install the 1,4‐diketone motif.

Regiocontrolled dieckmann condensation of 3,4-Bis(methoxycarbonylmethyl) levoglucosenone derivative

The Dieckmann condensation of 3,4-bis(methoxycarbonylmethyl) levoglucosenone derivative afforded two regioisomeric 9,11-dioxatricyclo[6.2.1.02,6]undecane derivatives at a ratio of 5: 3. The products can be used in the synthesis of iridoids.

Synthesis of Filibuvir. Part I. Diastereoselective Preparation of a β-Hydroxy Alkynyl Oxazolidinone and Conversion to a 6,6-Disubstituted 2H-Pyranone

This is the first in a series of three papers describing the identification and development of a commercial synthesis of filibuvir (1). This contribution describes development of an Evans aldol reaction to control the tertiary alcohol stereocenter, a challenging variant of that strategy in that both reacting partners were nonstandard (acetate enolate and ketone electrophile). A sequence consisting of Sonogashira coupling, acylation and hydrogenation delivered acetate 24, and Dieckmann cyclization provided β-keto lactone 2.

Synthesis of the Pentacyclic Framework of the Alkaloid Tronocarpine

AbstractA short and efficient synthesis of the pentacyclic core of the indole alkaloid tronocarpine is described. The synthetic pathway involves several easily accomplished steps, including a radical oxidative aromatic substitution reaction on the N‐tert‐butoxycarbonyl‐protected tryptamine and a xanthate, a 1,4–1,2‐nucleophilic addition between a 2,3‐disubstituted indole and an α,β‐unsaturated aldehyde, and a Ti‐mediated Dieckmann condensation. This report represents a significant advance in the quest for the first total synthesis of tronocarpine.

New regio-selective method of combinatorial synthesis of substituted thiophenes, thieno[3,2-b]pyridines and other heterocycles via combination of ‘domino’-type reactions

We present a novel combinatorial multicomponent regio-selective approach towards the synthesis of thieno[3,2-b]pyridines and pyridine pyrans. The methodology is based on the ‘domino’-type reaction. The high regio-selectivity in this reaction is gained by the in situ generation of the mono-potassium salt of 2-cyano-1-mercaptoethenethiolate. We also demonstrate that the use of ethyl 2-cyanoacetate in this reaction as a CH-acid leads to the termination of the domino sequence at the Dieckmann condensation step and yields novel ethyl 3-(4-cyano-3-hydroxy-5-(alkylthio)thiophen-2-yl)-3-oxopropanoate.

Biomimetic Synthesis of Equisetin and (+)‐Fusarisetin A

(+)-Fusarisetin A belongs to a group of acyl tetramic acid natural products that show potential anticancer activity. Equisetin, a biogenetically related acyl tetramic acid, contains the basic skeleton of (+)-fusarisetin A. We proposed that equisetin and (+)-fusarisetin A share a biosynthetic pathway that starts with naturally occurring (S)-serine and an unsaturated fatty acid. In support of this hypothesis, we have demonstrated that a cyclization sequence involving an intramolecular Diels-Alder reaction followed by a Dieckmann cyclization of polyenoylamino acid yielded equisetin. The aerobic oxidation of equisetin, promoted by either Mn(III)/O2 or a reactive oxygen species (ROS) produced by visible-light chemistry, gave peroxyfusarisetin, which could be easily reduced to (+)-fusarisetin A. We report herein detailed information on the biogenetic synthesis of equisetin and (+)-fusarisetin A.

Concise and Stereocontrolled Synthesis of the Tetracyclic Core of Daphniglaucin C

The tetracyclic core of daphniglaucin C was prepared from the known 4-keto-N-Boc methyl-l-prolinate in 15 steps with a cumulative yield of 14.7%. The key steps toward this core motif feature a reductive double bond transposition from an unactivated tertiary allylic alcohol, a Pd-catalyzed Stille coupling, and Dieckmann cyclizations.

Convenient synthesis of novel N-(5-allyl-7,7-difluoro)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides

Abstract 5-Allyl-7,7-difluoro-2-(2,4-difluorophenyl)-6-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-amine represents a fluorinated heterocyclic scaffold, potentially attractive. It was synthesized via Michael addition, Mannich reaction of the difluorinated ethyl bromoacetate with a benzotriazole derivative, followed by a Dieckmann condensation. Starting from simple materials, this efficient route which gives access to novel functionalized N-(5-allyl-7,7-dihalo)-4,5,6,7-tetrahydro-2H-indazol-3-yl)-carboxymides, was explored and adapted for parallel synthesis, resulting in a compound library.

Synthetic Studies on the Bis-Anthraquinoid Core of the Angelimicins

Bidirectional Hauser and Michael–Dieckmann annulation strategies for the preparation of bis-anthraquinoid framework of the angelimicin family of natural products are explored, using cyclohex-2-enone and biphenyl Michael donors, which are prepared from 1,2,5-trimethoxy-3-methylbenzene. The Hauser annulations are not productive, but the Michael–Dieckmann reactions proceed in 40% yield. Attempts to aromatize these biphenyl cycloadducts proved unsuccessful. This result differs from the success reported in another study of the same reaction. In contrast, aromatization of the related monomeric Michael–Dieckmann cycloadduct proceeds smoothly.

Chiral Bicyclic Tetramates as Non‐Planar Templates for Chemical Library Synthesis

Chemoselective Dieckmann cyclization reactions may be used on oxazolidine and thiazolidine templates derived from various aldehydes to access bicyclic tetramates, which have potential as templates for chemical library construction. Bioassay against Staphylococcus aureus and Escherichia coli showed that these systems have little or no intrinsic antibacterial bioactivity.

Process R&amp;D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development

Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

Two Approaches toward the Formal Total Synthesis of Oseltamivir Phosphate (Tamiflu): Catalytic Enantioselective Three-Component Reaction Strategy and l-Glutamic Acid Strategy

Two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized L-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies used Dieckmann condensation to construct a six-membered ring core, after which manipulation of the functional groups and protecting groups accessed Corey's intermediate for the synthesis of oseltamivir phosphate. While the first synthesis was accomplished via four purification steps in 25.7% overall yield, albeit with moderate optical purity (76% ee), the second strategy achieved the synthesis via six purification steps in 19.8% overall yield with perfect enantiocontrol.

4-Hydroxy-1,1′-bis[(S)-1-phenylethyl]-5,5′,6,6′-tetrahydro-3,4′-bipyridine-2,2′(1H,1′H)-dione

The title bis-piperidine, C26H28N2O3, was unexpectedly obtained via a dimerization mechanism promoted by acetic acid when performing the Dieckmann cyclization of a chiral amido ester. The S,S configuration was assigned by reference to the enanti­omerically pure starting material. In the mol­ecule, two core heterocycles are linked by a σ bond. One ring includes a keto–enol group, while the other presents an enone functionality. Both rings present a conformation inter­mediate between envelope and screw-boat, and the dihedral angle between the mean planes passing through the rings [48.9 (1)°] is large enough to avoid hindrance between ring substituents. The enol tautomeric form in one ring favors the formation of strong inter­molecular O—H⋯O=C hydrogen bonds. The resulting one-dimensional supra­molecular structure features single-stranded helices running along the 21 screw axis parallel to [100].

KI-catalysed synthesis of 4-methylcatechol dimethylacetate and fragrant compound Calone 1951®

AbstractSynthesis of the fragrant compound Calone 1951® from 4-methyl catechol and methyl bromoacetate entails three successive reactions: the Williamson reaction, Dieckmann condensation, and hydrolysis-decarboxylation reaction. In this paper, the synthesis of 4-methylcatechol dimethylacetate (MCDA) via the Williamson reaction by adding KI as catalyst was investigated. It was found that the addition of an appropriate amount of KI can significantly increase the product yield due to generation of methyl iodoacetate via the reaction between KI and methyl bromoacetate. The synthesised MCDA as well as Calone 1951® were first characterised by melting points, HPLC, IR, and NMR analyses. Next, the effect of the key operating factors on MCDA synthesis by the Williamson reaction was investigated and the optimum operating conditions were obtained via a group of orthogonal experiments. The verification experiments demonstrated that, under the optimum operating conditions, the MCDA yield could be increased from 78.5 % to 95.4 % by the addition of an appropriate amount of KI; the corresponding yield of Calone 1951® increased to 68 %.