Alkynyliodonium salts in organic synthesis. Application to the total synthesis of (-)-agelastatin A and (-)-agelastatin B

The asymmetric total syntheses of (-)-agelastatin A and (-)-agelastatin B were accomplished in 14 steps each from (R)-epichlorohydrin. The pivotal transformation in both sequences was a sulfinate-promoted cyclization of an alkynyliodonium salt to furnish a key functionalized cyclopentene intermediate. Selective bromination in the final step led to either agelastatin A or agelastatin B, depending upon conditions.     

A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

In this article, we report a full account of our recent development of pyrroles and N‐alkoxyamides as new classes of nucleophiles for palladium‐catalyzed AAA reactions, along with application of these methodologies in the total synthesis of agelastatin A, a marine natural product with exceptional anticancer activity and other biological properties. Our method allows for access to either regioisomer of the pyrrolopiperazinones ( 6 and 19 ) with high efficiency and enantioselectivity. Note that isomer 19 was obtained via a cascade reaction through a double allylic alkylation pathway. From regioisomer 6 , the total synthesis of (+)‐agelastatin A was completed in a very short fashion (four steps from 6 ), during the course of which we developed a new copper catalyst for aziridination and an In(OTf)₃/DMSO system to oxidatively open an N‐tosyl aziridine. Starting with the other pyrrolopiperazinone 19 , a five‐step sequence has been developed to furnish a formal total synthesis of (?)‐agelastatin A. A unique feature of our syntheses is the use of two rather different strategies for the total syntheses of both enantiomers of agelastatin A using the same enantiomer of a chiral palladium catalyst.     

Alkynyliodonium salts in organic synthesis. Development of a unified strategy for the syntheses of (-)-agelastatin A and (-)-agelastatin B

The total syntheses of natural agelastatin A and agelastatin B were accomplished via a strategy that utilized an alkynyliodonium salt --> alkylidenecarbene --> cyclopentene transformation to convert a relatively simple amino alcohol derivative to the functionalized core of the agelastatin system. Subsequent manipulations delivered debromoagelastatin, which served as a precursor to both agelastatin A and agelastatin B. Alkylidenecarbene insertion chemoselectivity issues were explored en route to the final targets.     

Conformational Preferences and Absolute Configuration of Agelastatin A,a Cytotoxic Alkaloid of the Axinellid Sponge Agelas dendromorpha from the Coral Sea,via combined molecular modelling,NMR, and exciton splitting for diamide and hydroxyamide derivatives

The absolute configuration of agelastatin A ( 1 ), the major, strongly cytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5aS,5bS,8aS,9aR), as deduced from combined molecular-mechanics calculations and a novel application of exciton splitting to the bis[4-(dimethylamino)benzoyl] compounds (–)- 9 and (–)- 13 , derivatives of a diamide and a hydroxyamide, respectively. The position of the conformational equilibrium of A 1 could be finely tuned by slight molecular changes. The minor analogue, agelastatin B ( 3 ), was isolated as the trimethyl derivative (–)- 4 .     

Fighting cancer with translation inhibitors: a quantum mechanics view on the complex between the antitumor marine alkaloid agelastatin A and the yeast 80S ribosome

Structural Chemistry - The alkaloid agelastatin A (AGA) has raised great interest for its potent antitumor activity and intriguing molecular structure. This led to multifarious total syntheses and...     

A catalytic antibody against a tocopherol cyclase inhibitor

The cyclic ammonium cation 5 and its guanidinium analogue 4 are inhibitors of tocopherol cyclase. Monoclonal antibodies were raised against protein conjugates of the haptens 1-3 and screened for catalytic reactions with alkene 8, a short chain analogue of the natural substrate phytyl-hydroquinone 6, and its enol ether analogues 10a,b. Antibody 16E7 raised against hapten 3 was found to catalyze the hydrolysis of Z enol ether 10a to form hemiacetal 12 with an apparent rate acceleration of k(cat)/k(uncat)=1400. Antibody 16E7 also catalyzed the elimination of Kemp's benzisoxazole 59. The absence of cyclization in the reaction of enol ether 10a was attributed to the competition of water molecules for the oxocarbonium cation intermediate within the antibody binding pocket. Hapten and reaction design features contributing to this outcome are discussed. Antibody 16E7 provides the first example of a carboxyl group acting both as an acid in an intrinsically acid-catalyzed process and as a base in an intrinsically base-catalyzed process, as expected from first principles. In contrast to the many examples of general-acid-catalyzed processes known to be catalyzed by catalytic antibodies, the specific-acid-catalyzed cyclization of phytyl-hydroquinone 6 or its analogue 8 still eludes antibody catalysis.     

Biomimetic construction of the tetracyclic ring system of ngouniensine

2-Cyanotetrahydropyridine 9, bearing an indole-2-acetate moiety, was envisaged as a model synthetic equivalent of the dihydropyridinium cations A, which have been proposed as common biogenetic intermediates to both ngouniensine and Strychnos indole alkaloids. Lewis acid-promoted cyclization of the O-silyl ketene acetal derived from 9 led to the ngouniensine-type derivative 11.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Direct and Short Construction of the ACDE Ring System of Daphenylline

Daphenylline, a novel daphniphyllum alkaloid, boasts a fused and bridging ring system coupled with six stereogenic centers. Here we present a direct and short construction of the ACDE ring system of daphenylline from the known 3‐(2‐bromophenyl)propanal in 10 steps and 17 % overall yield. The synthesis features an iron(III)‐catalyzed aza‐Cope‐Mannich reaction, a self‐terminating 6‐exo‐trig aryl radical‐alkene cyclization and an intramolecular Friedel–Crafts acylation.     

A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.     

Indole synthesis by radical cyclization of o-alkenylphenyl isocyanides and its application to the total synthesis of natural products

Development of indole synthesis by tin-mediated radical cyclization of o-alkenylphenyl isocyanide is described. Upon heating o-alkenylphenyl isocyanide in the presence of tri-n-butyltin hydride and AIBN, 2-stannyl-3-substituted indole was formed via 5-exo-trig cyclization of the imidoyl radical intermediate. After acidic workup, 3-substituted indoles were isolated. For substrates bearing simple alkyl groups, a substantial amount of tetrahydroquinoline derivatives were generated through 6-endo-trig cyclization. This undesired cyclization was suppressed by using an excess amount (five equivalents based on o-alkenylphenyl isocyanide) of ethanethiol instead of tri-n-butyltin hydride. The 2-stannylindole intermediates proved to be a suitable substrate for Stille coupling, giving 2,3-disubstituted indoles in a one-pot procedure. In addition, the 2-stannylindole intermediates could be converted to 2-iodoindoles by treatment with iodine or N-iodosuccinimide. The 2-iodoindoles thus obtained served as good substrates for Heck reactions, Stille couplings, Suzuki couplings, and palladium-mediated carbonylations, to afford a variety of 2,3-disubstituted indoles. The utility of this protocol was demonstrated by application to synthetic studies on gelsemine and discorhabdin A, and the total synthesis of an aspidosperma alkaloid, (-)-vindoline.     

New synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues

[reaction: see text] A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4 --> 5.     

Controlling the regiochemistry of radical cyclizations

This review describes the results of our recent studies on the control of the regiochemistry of radical cyclizations. N-vinylic alpha-chloroacetamides generally cyclized in a 5-endo-trig manner to give five-membered lactams, whereas 4-exo-trig cyclization occurred when the cyclized radical intermediates were highly stabilized by an adjacent phenyl or phenylthio group to afford beta-lactams. The 5-exo or 6-exo cyclization of aryl radicals onto the alkenic bond of enamides could be shifted to the corresponding 6-endo or 7-endo mode of cyclization by a positional change of the carbonyl group of enamides. The 6-endo- and 7-endo-selective aryl radical cyclizations were applied to radical cascades for the synthesis of alkaloids such as phenanthroindolizidine, cephalotaxine skeleton, and lennoxamine. The 5-exo-trig cyclization of an alkyl radical onto the alkenyl bond of enamides could also be shifted to the 6-endo mode by a positional change of the carbonyl group of enamides. The 6-endo- selective cyclization was applied to the radical cascade to afford a cylindricine skeleton. Other examples of controlling the regiochemistry of radical cyclizations and their applications to the synthesis of natural products are also discussed.     

Biomimetic total synthesis of (+)-gelsemine

Challenging: (+)-gelsemine was synthesized from (R,R)-aziridine 1 in 25 steps with approximately 1 % overall yield. A multistep, one-pot enol-oxonium cyclization cascade was used to construct, simultaneously, the E ring, F ring, C3 stereocenter, and C7 quaternary stereocenter. This synthesis using the enol-oxonium cyclization reaction as a key step to make the cage structure has demonstrated the proposed biosynthetic pathway of the gelsemine family.     

Head-to-tail oxime cyclization of oligodeoxynucleotides for the efficient synthesis of circular DNA analogues

A convenient strategy for the synthesis of the analogue of cyclic oligodeoxyribonucleotides is presented. The cyclization of the oligonucleotide was accomplished through intramolecular oxime bond formation between a 5'-oxyamine moiety and a 3'-aldehydic group.     

A Unified Approach for the Assembly of Atisine‐ and Hetidine‐type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C

A tetracyclic dinitrile was synthesized in twelve steps from cyclohex‐2‐en‐1‐one by using a chelation‐triggered conjugate addition to a γ‐hydroxy‐substituted α,β‐unsaturated nitrile and an oxidative dearomatization/Diels–Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen‐atom‐transfer reaction of the tetracyclic dinitrile, Pd/C‐catalyzed reductive cyclization, and subsequent functional group manipulation.     

Asymmetric formal total synthesis of the stemofoline alkaloids: the evolution,development, and application of a catalytic dipolar cycloaddition cascade

A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-d-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama–Itô cyclization, and a useful modification of the Barton decarboxylation protocol.     

Reaction Mechanism for the Dual Gold‐Catalyzed Synthesis of Dibenzopentalene: A DFT Study

A wide range of gold‐catalyzed reactions based on a dual activation mechanism has recently been reported in the literature. Herein, we present a computational investigation of the mechanism for the formation of dibenzopentalenes from 1‐ethynyl‐2‐(phenylethynyl)benzene. Transition states have been found, which substantiate the dual activation mechanism previously published and furthermore point towards a continuous presence of two gold moieties throughout the mechanistic cycle, an observation of high importance for all reactions in the field of dual activation. The initial activation of the diyne has been shown to proceed via an intermolecular transfer of a cationic gold catalyst from the thermodynamically preferred geminal‐σ,π‐acetylide complex to the active non‐geminal analogue. Furthermore, the regioselectivity of a 5‐endo versus a 6‐endo cyclization has been addressed, and the 5‐endo cyclization was found to be most favorable both thermodynamically and with regard to the activation barrier.     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

Total Syntheses of Daphenylline,Daphnipaxianine A,and Himalenine D

We report the total syntheses of daphenylline ( 1 ), daphnipaxianine A ( 5 ), and himalenine D ( 6 ), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom‐transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring‐expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1 . The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.