Albert Padwa

Synthetic applications of furan Diels-Alder chemistry

3. Introduction Bimolecular Diels-Alder Reactions of Furans 2.1. Scope and limitations 2.1.1. Alkenes 2.1.2. Alkynes 2.1.3. Allenes 2.2. Reactive g-bonds 2.3. Catalysts and high pressure 2.4. Asymmetric Diels-Alder reactions 2.5. Total synthesis Intramolecular Diels-Alder Reactions of Furans 3.1. Scope and limitations 3.1.1. Nature of the diene 3.1.1.1. Fused furans 3.1.1.2. Vinyl furans 3.1.2. Nature of the dienophile 3.1.2.1. Alkenes 3.1.2.2. Alkynes 3.1.2.3. Ailenes 3.1.2.4. Benzynes 3.2. Mechanistic considerations 3.2.1. Substituent/structural effects 3.2.2 Catalysts 3.2.3. High-pressure reactions 3.3. Applications 3.3.1. Methodology 3.3.2. Asymmetric synthesis 3.3.3 Synthetic targets

4.9 – Intermolecular 1,3-Dipolar Cycloadditions

Cycloaddition reactions have figured prominently in both synthetic and mechanistic organic chemistry.1,2 Current understanding of the underlying principles in this area has grown from a fruitful interplay between theory and experiment.3 The monumental work of Huisgen and coworkers in the early 1960s led to the general concept of 1,3-dipolar cycloaddition.4–7 Few reactions rival this process in the number of bonds that undergo transformation during the reaction, producing products considerably more complex than the reactants. Over the years this reaction has developed into a generally useful method of five-membered heterocyclic ring synthesis, since many 1,3-dipolar species are readily available and react with a wide variety of dipolarophiles. 1,3-Dipolar cycloadditions are bimolecular in nature and involve the addition of a 1,3-dipole (1) to a multiple π-bond system (2) leading to five-membered heterocycles (3; equation 1).

Gold-Catalyzed Cycloisomerization of N-Propargylindole-2-carboxamides: Application toward the Synthesis of Lavendamycin Analogues

A series of N-propargylindole-2-carboxamides were found to undergo a AuCl 3-catalyzed cycloisomerization to give beta-carbolinones in high yield. The corresponding beta-chlorocarboline derivative was prepared and used for Pd(0)-catalyzed cross-coupling chemistry directed toward the synthesis of lavendamycin analogues.

Diastereofacial selectivity in azomethine ylide cycloaddition reactions derived from chiral α-cyanoaminosilanes

Abstract A series of α-cyanoaminosilanes has been found to act as azomethine ylide equivalents. Treatment of these compounds with silver fluoride in the presence of electron deficient olefins gives substituted pyrrolidines in high yield. The extent ofdiastereoselectivity associated with the 1,3-dipolar cycloaddition of chiral azomethine ylides with several dipolarophiles has been studied. Reasonable levels of such diastereoselectivity have been found when optically active α-cyanoaminosilanes are employed as azomethine ylide equivalents. These compounds can be prepared in multigram quantities by treating the appropriate chiral amine with chlorotrimethylsilane followed by reaction of the resulting secondary amine with formaldehyde in the presence of potassium cyanide. It was found that N-benzyl-N-cyanomethyl-N-trimethylsilylmethylamine undergoes stereospecific cycloaddition with dimethyl fumarate and maleate. The stereospecificity of the reaction is consistent with a concerted cycloaddition reaction.

Tandem methodology for heterocyclic synthesis

Tandem methodology for heterocyclic synthesis represents a powerful approach for the rapid buildup of molecular complexity from potentially simple starting materials. Work from our laboratory has shown that the rhodium(II)-catalyzed cyclization cascade of alpha-diazo imides represents an effective method for the synthesis of a variety of heterocyclic systems. As an extension of these studies, we became interested in using a linked Pummerer/N-acyliminium ion cyclization sequence since we felt that this combination offers unique opportunities for the assemblage of complex target molecules. A synthetic method that combines transformations of different reaction types significantly broadens the scope of such procedures in synthetic chemistry. Alpha-thiocarbocations generated from the Pummerer reaction of beta-phenylsulfinylmethyl-alpha, beta-unsaturated amides can be intercepted by the adjacent amido group to produce transient amino-substituted furans which undergo subsequent Diels–Alder cycloadditions. Using this domino amido Pummerer/Diels–Alder cascade, we were able to assemble novel polycyclic systems in a single operation. The key step in the process involves the generation of a reactive N-acyliminium ion by fragmentation of an amino-substituted [4+2]-cycloadduct. The successful synthesis of a number of alkaloids by this sequence of reactions reveals the usefulness and importance of this unique domino cascade. Application of the process for the preparation of the stenoma alkaloid stenine was recently carried out in our laboratory.

General Access to the Vinca and Tacaman Alkaloids Using a Rh(II)-Catalyzed Cyclization/Cycloaddition Cascade

The total synthesis of several members of the vinca and tacaman classes of indole alkaloids has been accomplished. The central step in the synthesis consists of an intramolecular [3+2]-cycloaddition reaction of an alpha-diazo indoloamide which delivers the pentacyclic skeleton of the natural product in excellent yield. The acid lability of the oxabicyclic structure was exploited to establish the trans-D/E ring fusion of (+/-)-3H-epivincamine (3). Finally, a base induced keto-amide ring contraction was utilized to generate the E-ring of the natural product. A variation of the cascade sequence of reactions used to synthesize (+/-)-3H-epivincamine was also employed for the synthesis of the tacaman alkaloids (+/-)-tacamonine and (+/-)-apotacamine.

Heteroaryl cross-coupling as an entry toward the synthesis of lavendamycin analogues: a model study

ABC analogues of the antitumor antibiotic lavendamycin, which contain the key metal chelation site and redox-active quinone unit essential for biological activity, were prepared via the palladium(0)-catalyzed cross-coupling reaction of various 2-haloheteroaromatics with 2-stannylated pyridines and quinolines. Using the Stille reaction, 2-bromo substituted quinolines and 1-bromoisoquinolines were found to undergo efficient coupling with 2-pyridinylstannanes to provide unsymmetrical heterobiaryl derivatives. While the Stille reaction using the reverse coupling partners (i.e., 2-quinolinylstannanes and haloheteroaromatics) had not received much attention in the literature, we found that this alternative coupling reaction efficiently provided several new heterobiaryl derivatives. The gold-catalyzed intramolecular cycloisomerization of N-(prop-2-ynyl)-1H-indole-2-carboxamide smoothly afforded a beta-carbolinone derivative that was subsequently used for a Pd(0)-catalyzed cross-coupling directed toward the synthesis of lavendamycin analogues.

Significance of the anomeric effect on the configurational stability of cyclopropyl carbanions

Abstract The effect of an electron withdrawing group adjacent to cyclopropyl carbanion has been studied. The facility with which carbanion interconversion occurs can be attributed to the existence of the anomeric effect.

Copper-catalyzed amidations of bromo substituted furans and thiophenes

The CN cross-coupling reaction between aromatic halides and amides has now been applied to 2- and 3-substituted bromofurans and bromothiophenes. Catalytic CuI in the presence of N,N′-dimethylethylenediamine as a ligand and K3PO4 or K2CO3 as the base furnished 2- and 3-substituted amidofurans and thiophenes ranging from 11 to 99% depending on the particular amide source used.

A General Synthetic Entry to the Pentacyclic Strychnos Alkaloid Family, Using a [4 + 2]-Cycloaddition/Rearrangement Cascade Sequence

The total synthesis of (+/-)-strychnopivotine, (+/-)-tubifolidine, (+/-)-strychnine, and (+/-)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s- trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels-Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (+/-)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (+/-)-strychnine. The total synthesis of (+/-)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.