Showing papers on "Total synthesis published in 2012"

Pd(II)-Catalyzed Regioselective 2-Alkylation of Indoles via a Norbornene-Mediated C–H Activation: Mechanism and Applications

Abstract: A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles was developed based on a norbornene-mediated regioselective cascade C–H activation. The detailed reaction mechanism was investigated by NMR spectroscopic analyses, characterization of the key intermediate, deuterium labeling experiments, and kinetic studies. The results indicate that a catalytic cycle operates, in which an N-norbornene type palladacycle is formed as the key intermediate. Oxidative addition of alkyl bromide to the Pd(II) center in this intermediate is the rate-determining step of the reaction. The synthetic utility of this indole 2-alkylation method was demonstrated by its application in natural product total synthesis. A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in concise routes.

Rhodium(III)‐Catalyzed Intramolecular Annulation through C ? H Activation: Total Synthesis of (±)‐Antofine, (±)‐Septicine, (±)‐Tylophorine, and Rosettacin

Abstract: The mild, efficient, and practical intramolecular rhodium-catalyzed C—H/N—H bond functionalization reaction provides isoquinolones with a reverse regioselectivity compared to the reported intermolecular version.

An N-Heterocyclic Carbene/Lewis Acid Strategy for the Stereoselective Synthesis of Spirooxindole Lactones

Abstract: A cooperative catalysis approach for the enantioselective formal [3+2] addition of α,β-unsaturated aldehydes to isatins has been developed. The N-heterocyclic carbene (NHC)-catalyzed homoenolate annulations of β-aryl enals require the addition of lithium chloride for high levels of enantioselectivity. This NHC-catalyzed annulation provides efficient access to the 3-hydroxy indole skeleton and has been applied to the first eantioselective total synthesis of maremycin B.

A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition.

Abstract: Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products.[1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8–C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8.[3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 (Figure 1A),[4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B).[5] In this latter effort, the key C8–C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6.[6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.

Sequential C sp 3H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

Abstract: Our laboratory recently reported the synthesis of the pseudodimeric cyclobutane natural products piperarborenine B (1, Figure 1A) and piperarborenine D (proposed structure, 2) through a sequential cyclobutane C–H arylation strategy.[1,2] This led to both the concise preparation of these molecules (6–7 steps) and the structural reassignment of piperarborenine D (revised structure, 3). While the piperarborenines are the simplest examples of heterodimeric cyclobutane natural products isolated from pepper plants, a number of other heterodimers have been isolated, which all arise from a formal [2+2] cycloaddition of piperine-like monomers (4) with varying oxidation states and chain lengths.[3] Looking to extend our C–H functionalization strategy to more complex members of the family, our attention turned to the pipercyclobutanamides (5 and 6). Figure 1 Selected heterodimeric cyclobutane natural products and retrosynthesis of pipercyclobutanamide A (5) The pipercyclobutanamides were first isolated by Fujiwara and coworkers in 2001 from the fruits of the black pepper plant, Piper nigrum, though no biological activity was reported at that time.[3a] In 2006, Tezuka and coworkers reisolated pipercyclobutanamide A (5) and demonstrated a selective inhibition of cytochrome P450 2D6 (CYP2D6).[3c] These heterodimers represent a greater synthetic challenge than the piperarborenines (1,3) due to the presence of four different substituents on the cyclobutane ring. Both of these natural products contain an unusual cis unsaturated amide, and pipercyclobutanamide A (5) and B (6) contain styrene and styryl diene motifs, respectively. Viewing these molecules as an opportunity to develop cyclobutane C–H olefination chemistry, a synthetic strategy was devised and the retrosynthetic analysis of pipercyclobutanamide A (5) is shown in Figure 1B. First, the cis-alkene is transformed into an aldehyde through a stereocontrolled olefination reaction. The aldehyde could then be deconstructed to a directing group (DG) and the amide into a methyl ester using standard functional group manipulations to provide intermediate 7. Applying the strategy developed for the piperarborenines, this intermediate could be prepared through a series of epimerizations and sp3 C–H functionalizations on a desymmetrized cyclobutane dicarboxylate 8. The direct olefination of sp2 C–H bonds has been known since the seminal work of Fujiwara and Moritani in the late 1960’s,[4] but few examples exist for the direct olefination of unactivated sp3 C–H bonds.[5] During a study towards the teleocidin natural products, Sames coupled an unactivated methyl group with a vinyl boronic acid, though the sequence proceeded through a discretely isolated palladacycle.[5e] The first catalytic example was reported in 2010 by Yu and coworkers.[5a] A highly electron-deficient anilide directing group was employed to couple acrylate derivatives directly to unactivated methyl and cyclopropyl C–H bonds. Chen and coworkers later reported the coupling of cyclic vinyl iodides with methylene C–H bonds using Daugulis’ picolinamide directing group under palladium catalysis.[5d] Encouraged by this result in particular, a styrenyl iodide was chosen as the first coupling partner to examine for the synthesis of pipercyclobutanamide A (5).[6] Investigations started with the preparation of the requisite cyclobutane starting material 12 (Scheme 1). Applying the methodology developed previously for the piperarborenine natural products, methyl coumalate (9) underwent photochemical 4π electrocyclization at reduced temperature to give photopyrone 10.[7] This unstable intermediate was immediately hydrogenated and coupled to 8-aminoquinoline[8] in a single operation to give the desired C–H olefination precursor (12) in 54% overall yield. The olefination reaction was initially studied with (2-iodovinyl)benzene as a model coupling partner. The use of conditions originally developed for monoarylation (hexafluoroisopropanol (HFIP) as solvent and pivalic acid) resulted in low conversion and significant amounts of decomposition. Switching the solvent to toluene improved the reaction considerably to give bis-olefinated cyclobutane 13 as the major product in 50% isolated yield. This is in contrast to our previous work on the piperarborenines in which an epimerization event was required to allow for an efficient second C–H functionalization on the cyclobutane ring. The reason for this direct bis-olefination is unclear, but it may simply be that the vinyl iodide is smaller than the aryl iodide, leading to a more facile second reaction. Furthermore, 13 is an all-cis-cyclobutane that is quite strained and, to our knowledge, there are no other general methods for the controlled construction of this stereochemical array on a cyclobutane. Scheme 1 Total synthesis of the proposed structure of pipercyclobutanamide A (5). Reagents and conditions: a) 450-W Hanovia lamp, Pyrex filter, DCM, 15 °C, 96 h; then H2, Pt/C, 4 h; then 8-aminoquinoline (1.2 equiv), EDC (1.2 equiv), 0 to 23 °C, ... Given the modularity of this sequential C–H functionalization strategy, a monoarylation reaction could take place, followed by an olefination reaction to reach the end goal. When the standard monoarylation conditions were applied to reaction of cyclobutane 12 with 1-iodo-3,4-methylenedioxybenzene, poor conversion was observed due to methylenedioxy ring (3,4-dimethoxyiodobenzene as a coupling partner performed well). Pivalic acid proved to be an effective additive, and when the reaction was performed in tBuOH at high concentration, an acceptable monoarylation yield was obtained (54%, 1.00g scale). Due to the facile double olefination observed in the preparation of 13, monoarylated 14 was directly subjected to the C–H olefination reaction with styrenyl iodide 15. Optimizing the reaction was straightforward, employing catalytic Pd(OAc)2 in the presence of 1.5 equivalents of AgOAc with toluene as the solvent gave all-cis-cyclobutane 16 in 59% yield (480 mg scale). Pivalic acid as an additive retarded the reaction rate, and protic solvents such as t-BuOH or HFIP were inferior, giving low conversion or substantial decomposition, respectively. With the sequential functionalization product (16) in hand, the relative stereochemistry needed to be altered to the all-trans configuration found in the natural product. This was anticipated to be a facile process given the strained nature of the all-cis stereochemistry and the thermodynamically downhill path to the desired all-trans product. Experimentally, this was verified through the use of two equivalents of sodium methoxide with C-1 epimerization occurring rapidly at room temperature (< 1 min). Upon warming the reaction mixture to 45 °C, the methyl ester (C-3) epimerizes over two hours and fully hydrolyzes after the addition of aqueous sodium hydroxide to give acid 18. Without further purification, 18 was treated with excess DIBAL to transform the aminoquinoline directing group directly into an aldehyde. By employing the free carboxylic acid in this reaction, the correct oxidation state found in the natural product is maintained with the carboxylate anion acting as an innate protecting group.[9] Additionally, the direct reduction of secondary amides with DIBAL has limited precedent, and the success of this reaction is likely the result of the chelating nature of the aminoquinoline motif.[10] Furthermore, this presents a new method for the cleavage of this amide directing group that avoids the extremes of pH and heat, expanding the synthetic utility of the Daugulis methodology if found to be general. Moving forward with the crude reaction product 19, piperidine was used as both a base and a coupling partner in the reaction with T3P® (propylphosphonic anhydride) to provide amide 20 in 40–45% isolated yield over 3 steps (114 – 386 mg scale). To complete the synthesis of pipercyclobutanamide A (5), only an olefination reaction remained. This was accomplished through the use of Ando’s methodology for cis-selective unsaturated amide synthesis.[11] Treatment of aldehyde 20 with the Ando phosphonate (21) in the presence of tBuOK resulted in a ca. 5:1 cis:trans mixture of easily separable olefin isomers, giving the desired pipercyclobutanamide A (5) in 80% isolated yield (100 mg scale). Unfortunately, the 1H and 13C NMR data did not match the spectrum reported for the natural product.[12] The concise synthesis of the proposed structure of pipercyclobutanamide A (5) further demonstrates the power of C–H functionalization logic in synthesis to provide substantial amounts of complex cyclobutanes (7 steps, 5 chromatographic purifications, 5% overall yield, >100 mg prepared). The sequence features mostly skeleton-forming transforms, is protecting-group-free,[13] and has only one concession step (DIBAL reduction) leading to an ideality of 85%.[14] Salient features of the synthesis include: (1) the first example of C–H olefination on an unactivated cyclobutane ring; (2) stereocontrolled access to highly strained all-cis cyclobutanes; (3) direct conversion of aminoquinoline amides directly to aldehydes; and (4) the use of a carboxylate anion as an “innate protecting group” in an amide reduction.

Enantioselective construction of quaternary N-heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

Abstract: The enantioselective synthesis of nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines, including the total synthesis of natural products and medicinal chemistry. In this Article, we describe the highly enantioselective palladium-catalysed decarboxylative allylic alkylation of readily available lactams to form 3,3-disubstituted pyrrolidinones, piperidinones, caprolactams and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envisage that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously used in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.

Chemoselective synthesis of ketones and ketimines by addition of organometallic reagents to secondary amides

Abstract: The development of efficient and selective transformations is crucial in synthetic chemistry as it opens new possibilities in the total synthesis of complex molecules. Applying such reactions to the synthesis of ketones is of great importance, as this motif serves as a synthetic handle for the elaboration of numerous organic functionalities. In this context, we report a general and chemoselective method based on an activation/addition sequence on secondary amides allowing the controlled isolation of structurally diverse ketones and ketimines. The generation of a highly electrophilic imidoyl triflate intermediate was found to be pivotal in the observed exceptional functional group tolerance, allowing the facile addition of readily available Grignard and diorganozinc reagents to amides, and avoiding commonly observed over-addition or reduction side reactions. The methodology has been applied to the formal synthesis of analogues of the antineoplastic agent Bexarotene and to the rapid and efficient synthesis of unsymmetrical diketones in a one-pot procedure.

Enantioselective construction of pyrroloindolines catalyzed by chiral phosphoric acids: total synthesis of (-)-debromoflustramine B.

Abstract: structures. The biological activities of these compounds have been well studied, the results of which have shown several promising applications, including muscle relaxants, potassium channel-blockers, and anti-cancer agents. For this reason, the total synthesis of these natural products has received considerable attention, and has been accomplished by several research groups. However, there are few examples employing catalytic asymmetric strategies to form the key pyrroloindoline substructure. Chirality at the C3 position of pyrroloindolines, bearing C N bonds, though somewhat rare, is found in several natural products, such as the recently isolated alkaloid ( )-psychotrimine (Figure 1). The total synthesis of ( )-psychotrimine by an elegant indole–aniline coupling strategy was reported by Baran et al. Also, Gouverneur et al. reported an organocatalyzed enantioselective fluorocyclization of indoles to form chiral 3-fluoropyrroloindolines, which is an interesting example of carbon–heteroatom bond formation with a pyrroloindoline substructure. However, to the best of our knowledge, the formation of a C N bond in a catalytic asymmetric strategy with a pyrroloindoline motif is not known. Development of a general catalytic method to install both carbon–carbon and carbon–nitrogen bonds in an enantioselective and controlled approach could be of interest for the preparation of chiral pyrroloindolines. Chiral phosphoric acids have proven to be efficient catalysts for many important asymmetric transformations. Despite these developments, the activation of a simple vinyl ketone as a synthetically useful electrophile is less well known, presumably owing to the expectation of poor activation. Also, there is no example of an asymmetric electrophilic amination catalyzed by chiral phosphoric acids, which is a potentially useful method for the formation of chiral compounds with these types of C N bonds. Herein, we have circumvented these limitations, and report the first example of the asymmetric formation of pyrroloindolines catalyzed by chiral phosphoric acids, thus allowing access to both the carbon–carbon and carbon–nitrogen bonds of pyrroloindoline derivatives with good yields and high selectivities. This method was then employed in the total synthesis of ( )-debromoflustramine B. The reaction of 10-carbomethoxytryptamine (1a) with methyl vinyl ketone (MVK) was selected as a model reaction to optimize the reaction conditions (Table 1). To our surprise, 1a, incorporates two MVK segments, forming 2a as a single diastereoisomer in high yield, which is believed to be generated through a double Michael addition processes. As shown in Table 1, catalyst screening in toluene at 20 8C with 4 molecular sieves (MS), indicates that catalyst PA3, which bears a 2,4,6-triisopropylphenyl group in the 3,3’ position of BINOL, is the best catalyst in terms of enantioselectivity (Table 1, entries 1–3, and entries 8–10). An improved ee of 91% was achieved by lowering the temperature to 50 8C (entry 4). With PA4 or PA5, similar selectivities were observed along with slightly lower yields (entry 3 vs. entries 5 and 6). Unsaturated PA3 could be used to deliver the product with 86 % ee and 86% yield (entry 7). Further optimization by variation of the solvent was conducted, with toluene proving to be more suitable than dichloromethane, trifluorotoluene, and ethyl acetate (entry 3 vs. entries 11–13). To our delight, a mixture of toluene and benzene furnished the product with 93% ee (Table 1, entry 14) at 20 8C. However, no further improvement was observed when the reaction was conducted at 50 8C (entry 15). When the reaction scale was increased to 1.0 mmol, the same level of Figure 1. Representative pyrroloindoline natural products.

Total synthesis of oxidized welwitindolinones and (-)-N-methylwelwitindolinone C isonitrile.

Abstract: We report the total synthesis of (−)-N-methylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.

Total synthesis of Akuammiline alkaloid (-)-vincorine via intramolecular oxidative coupling.

Abstract: An asymmetric total synthesis of the Akuammiline alkaloid (-)-vincorine (18 steps from 5-methoxytryptamine, 5% overall yield) is described. The key steps include Pd-catalyzed direct C-H functionalization of indole derivatives, organocatalyzed asymmetric Michael addition of aldehydes to alkylidene malonates, and intramolecular oxidative coupling between indole and malonate moieties.

Total Synthesis of Manzamine A and Related Alkaloids

Abstract: Total syntheses of three structurally complex marine natural products, manzamine A, ircinol A, and ircinal A, are reported. The route pivoted on the construction of a late-stage protecting-group-free pentacyclic enol triflate coupling partner, from which all three family members were accessed divergently via palladium-catalyzed reactions. The rapid synthesis of this key pentacyclic enol triflate was achieved by a highly convergent union of five fragments through a stereoselective Michael addition, a three-component nitro-Mannich lactamization cascade, an unprecedented and highly stereoselective reductive nitro-Mannich cyclization cascade, a stereoselective organometallic addition, and a Z-selective alkene ring-closing metathesis. Altogether this chemistry has allowed the shortest synthetic route to date for manzamine A (18-step longest linear sequence) via a late-stage diversification point that is ideal for future manzamine A analogue synthesis.

Total synthesis of neurymenolide A based on a gold-catalyzed synthesis of 4-hydroxy-2-pyrones.

Abstract: Treat me gently: for a selective synthesis of the unusually sensitive cyclophanic α-pyrone neurymenolide A, the chosen catalysts must be able to distinguish between six different sites of unsaturation, without scrambling any of the skipped π systems. This challenge was met with a new gold-catalyzed pyrone synthesis in combination with a molybdenum-catalyzed ring-closing alkyne metathesis.

Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis

Abstract: From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.

Enantioselective total synthesis of (+)-ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation

Abstract: In this study we performed the total synthesis of the terpene indole alkaloid (+)-ibophyllidine through a pathway involving asymmetric phosphine catalysis, with our novel L-4-hydroxyproline-derived chiral phosphine mediating the key [3 + 2] annulation. Hydrogenation of the [3 + 2] adduct allowed the rapid formation of the stereochemically dense pyrrolidine ring of (+)-ibophyllidine in excellent yield with exceptionally high levels of both diastereo- and enantioselectivity. We constructed the remainder of the pentacyclic skeleton through an intramolecular alkylation and an intramolecular aza-Morita–Baylis–Hillman reaction.

Concise Total Synthesis of (+)-Gliocladins B and C.

Abstract: The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel–Crafts-based strategy to provide an efficient multigram-scale access to the C3-(3′-indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first-generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C.

Total Synthesis of (±)-Maoecrystal V

Abstract: The total synthesis of racemic maoecrystal V has been accomplished. Key steps include an intramolecular Diels–Alder cyclization to rapidly construct the core system from simple starting materials and the creation of the A–C ring trans-fusion through intramolecular delivery of a hydrogen to the hindered β-face of the ring system.

Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8'-epi-ent-rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery of new antiviral and antimalarial agents.

Abstract: An improved sulfenylation method for the preparation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines from diketopiperazines has been developed. Employing NaHMDS and related bases and elemental sulfur or bis[bis(trimethylsilyl)amino]trisulfide (23) in THF, the developed method was applied to the synthesis of a series of natural and designed molecules, including epicoccin G (1), 8,8′-epi-ent-rostratin B (2), gliotoxin (3), gliotoxin G (4), emethallicin E (5), and haematocin (6). Biological screening of selected synthesized compounds led to the discovery of a number of nanomolar antipoliovirus agents (i.e., 46, 2,2′-epi-46, and 61) and several low-micromolar anti-Plasmodium falciparum lead compounds (i.e., 46, 2,2′-epi-46, 58, 61, and 1).

Nature-Inspired Total Synthesis of (−)-Fusarisetin A

Abstract: A concise, protecting group-free total synthesis of (−)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(−)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.

Total synthesis of (±)-communesin F via a cycloaddition with indol-2-one.

Abstract: A concise total synthesis of (±)-communesin F has been completed in 15 linear steps from 4-bromotryptophol in an overall yield of 6.7%. A key step features the cycloaddition of indol-2-one with 3-(2-azidoethyl)-4-bromoindole and facilitates the rapid construction of the lower aminal-containing tetracyclic core of the natural product.

Enantioselective total synthesis of (-)-acetylaranotin, a dihydrooxepine epidithiodiketopiperazine.

Abstract: The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (−)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (−)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family.

Total Synthesis of (+)-Scholarisine A

Abstract: An effective total synthesis and assignment of the absolute configuration of the architecturally challenging compound (+)-scholarisine A has been achieved via a 20-step sequence. Highlights include a reductive cyclization involving a nitrile and an epoxide, a modified Fischer indole protocol, a late-stage oxidative lactonization, and an intramolecular cyclization leading to the indolenine ring system of (+)-scholarisine A.