Showing papers on "Total synthesis published in 2013"

Chemical synthesis of proteins using peptide hydrazides as thioester surrogates

Abstract: This protocol provides a detailed procedure for the chemical synthesis of proteins through native chemical ligation of peptide hydrazides. The two crucial stages of this protocol are (i) the solid-phase synthesis of peptide hydrazides via Fmoc chemistry and (ii) the native chemical ligation of peptide hydrazides through in situ NaNO2 activation and thiolysis. This protocol may be of help in the synthesis of proteins that are not easily produced by recombinant technology and that include acid-sensitive modifications; it also does not involve the use of hazardous HF. The utility of the protocol is shown for the total synthesis of 140-aa-long α-synuclein, a protein that has an important role in the development of Parkinson's disease. The whole synthesis of the target protein α-synuclein in milligram scale takes ~30 working days.

Nine-step enantioselective total synthesis of (-)-vincorine.

Abstract: A concise and highly enantioselective total synthesis of the akuammiline alkaloid (-)-vincorine has been accomplished. A key element of the synthesis is a stereoselective organocatalytic Diels-Alder, iminium cyclization cascade sequence, which serves to construct the tetracyclic alkaloid core architecture in one step from simple achiral precursors. The challenging seven-membered azepanyl ring system is installed by way of a single electron-mediated cyclization event initiated from an acyl telluride precursor. The total synthesis of (-)-vincorine is achieved in nine steps and 9% overall yield from commercially available starting materials.

Update 1 of: macrolactonizations in the total synthesis of natural products.

Abstract: Products A. Parenty,† X. Moreau,†,§ Gilles Niel,‡ and J.-M. Campagne*,†,‡ †Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, F-91198 Gif sur Yvette, France Institut Lavoisier de Versailles, UMR CNRS 8180, Universite ́ de Versailles-Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France ‡Institut Charles Gerhardt, UMR5253, Ecole Nationale Supeŕieure de Chimie, 8 rue de l’Ecole Normale, F-34296 Montpellier, France

Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis

Abstract: Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted significant consideration as one of the most powerful synthetic tools for the carbon–carbon bond-forming reactions. The methodology has been highly successful in the stereoselective construction of a number of natural products, antibiotics, and other medicinally important compounds. The present review is focused on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.

The Impact of the Mukaiyama Aldol Reaction in Total Synthesis

Abstract: Four decades since Mukaiyama's first reports on the successful application of silicon and boron enolates in directed aldol reactions, the ability of this highly controlled carbon-carbon bond-forming method to simultaneously define stereochemistry, introduce complexity, and construct the carbon skeleton with a characteristic 1,3-oxygenation pattern has made it a powerful tool for natural product synthesis. This Minireview highlights a number of representative total syntheses that demonstrate the impact of the Mukaiyama aldol reaction and discusses the underlying mechanistic rationale that determines the stereochemical outcomes.

Construction of Vicinal All-Carbon Quaternary Stereocenters by Catalytic Asymmetric Alkylation Reaction of 3-Bromooxindoles with 3-Substituted Indoles: Total Synthesis of (+)-Perophoramidine

Abstract: Highly congested vicinal all-carbon quaternary stereocenters were generated via catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles. These catalytic reactions proceeded in excellent yields with a broad scope on either reaction partner, and with outstanding diastereo- and enantiocontrol. The newly developed method led to the total synthesis of (+)-perophoramidine in a highly efficient manner.

Intramolecular Larock Indole Synthesis: Preparation of 3,4-Fused Tricyclic Indoles and Total Synthesis of Fargesine

Abstract: A variety of common, medium, and large ring fused tricyclic indoles including the fargesine precursor (XIV) are prepared from o-iodoaniline substrates under optimized conditions A).

Copper-Catalyzed Diastereoselective Arylation of Tryptophan Derivatives: Total Synthesis of (+)-Naseseazines A and B

Abstract: A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B.

Total synthesis of daptomycin by cyclization via a chemoselective serine ligation.

Abstract: A total synthesis of daptomycin, the first natural product antibiotic launched in a generation, was achieved. This convergent synthesis relies on an efficient macrocyclization via a serine ligation to assemble the 31-membered cyclic depsipeptide. The difficult esterification by the nonproteinogenic amino acid kynurenine was accomplished via the esterification of a threonine residue by a suitably protected Trp ester, followed by ozonolysis. This synthesis provides a foundation and framework to prepare varied analogues of daptomycin to establish its structure-activity profile.

Enantioselective Organocatalytic Construction of Hexahydropyrroloindole by Means of α‐Alkylation of Aldehydes Leading to the Total Synthesis of (+)‐Gliocladin C

Abstract: 12-step program: The combined use of cinchona alkaloid based amine and chiral phosphoric acid enabled the asymmetric alkylation reaction of 3-hydroxyoxindoles with aldehydes to give 3,3'-disubstituted oxindoles in excellent enantioselectivities, which allows for the enantioselective total synthesis of (+)-gliocladin C in 12 steps from 3-hydroxyoxindole with 19 % overall yield (see scheme; PMB = para-methoxybenzyl).

Total Synthesis of Indotertine A and Drimentines A, F, and G

Abstract: The pyrroloindoline alkaloids attract wide interest from the fields of chemistry, biosynthesis, and biology. From a structural perspective, they can be divided into several classes that vary in the substituent on C3a of the pyrroloindoline core, including heteroatoms, arenes, aliphatic groups, and another pyrroloindoline motif. Accordingly, a series of strategies have been developed for the synthesis of the above pyrroloindoline classes. Notably, a structurally complex aliphatic side chain linked to the C3a position is rather rare. The drimentine alkaloids (1–4, Scheme 1), which exhibit anticancer, antibacterial, antifungal, and anthelmintic properties, possess the latter substitution mode. A stereocontrolled method to form the C10b–C12 bond of the drimentine scaffold is highly desired for the synthesis of these compounds. Indotertine A (5, Scheme 1) with an unprecedented, but biosynthetically relevant, skeleton was recently discovered. The biosynthetic relationship between 3 and 5 is postulated in Scheme 1. Acidic activation of the germinal diamine moiety of 3 may generate an iminium species 6, which could undergo an iminium–olefin cyclization followed by a proton elimination of the cationic intermediate 7. Herein, we report the first total synthesis of drimentines A, G, and F (1–3), exploiting a photocatalyzed radical conjugate addition to address the problem of the C10b–C12 bond formation; a synthesis of indotertine A (5), guided by the above biosynthetic hypothesis, is also described. We first undertook a retrosynthetic analysis of drimentine G (Scheme 2). Disassembly of the diketopiperazine motif at the amide bonds followed by cleavage of the exocyclic C=C bond simplifies this molecule to core structure 8. Disconnection of the C10b–C12 bond leads to a pair of precursors (9 and 10) for an intermolecular radical conjugate addition. The former is readily available from bis(Boc-l-tryptophan) methyl ester (Boc= tert-butoxycarbonyl), whereas the latter could be derived from commercially available (+)-sclareolide (11). Scheme 1. Representative drimentine alkaloids and the postulated biosynthetic relationship between drimentine F and indotertine A.

Squaramide-catalyzed enantioselective Michael addition of masked acyl cyanides to substituted enones

Abstract: Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective Michael addition to substituted enones. The reactions are catalyzed by chiral squaramides and afford adducts in high yields (90–99%) and with excellent enantioselectivities (85–98%). The addition products are unmasked to produce dicyanohydrins that, upon treatment with a variety of nucleophiles, provide γ-keto acids, esters, and amides. The use of this umpolung synthon has enabled, in enantiomerically enriched form, the first total synthesis of the prenylated phenol (+)-fornicin C.

Enantioselective Palladium-Catalyzed Decarboxylative Allylation of Carbazolones: Total Synthesis of (−)-Aspidospermidine and (+)-Kopsihainanine A

Abstract: The Aspidosperma alkaloids represent the largest family of monoterpenoid indole alkaloids, with more than 250 members isolated from various biological sources. Because of their structural and stereochemical complexity, their central biosynthetic role in plants, and their interesting biological activity, Aspidosperma alkaloids have attracted attention from the synthetic community for over 40 years and have remained a focus of extensive research activity to the present day. Aspidospermidine (Scheme 1), the archetypal member, is among the most highly sought Aspidosperma alkaloid targets. Because it comprises the basic skeletal features of this family of natural products, particularly the complex and characteristic pentacyclic ABCDE framework, it has been the primary target of most syntheses toward Aspidosperma alkaloids and has served as the ideal proving ground for the development of new synthetic methods and strategies. 4] Since the 1960s, aspidospermidine has been synthesized by over 40 research groups in racemic and nonracemic forms. The majority of these syntheses follow one of the following three synthetic strategies: 1) the Fischer indole approach used by Stork and co-workers, 2) the indoloquinolizidine rearrangement approach used by Harley-Mason and co-workers, and 3) E-ring-closing approach. Despite the numerous successful syntheses of aspidospermidine, there are only few reports on the employment of catalytic asymmetric strategies. In 2002, Rawal and co-workers reported an elegant catalytic enantioselective total synthesis of (+)-aspidospermidine. In this approach, a highly enantioselective Diels–Alder reaction between 1-amino-3-siloxydiene and 2-ethylacrolein catalyzed by the chiral Cr–salen complex developed by Jacobsen was exploited to form the C ring, which bears a quaternary carbon center at C4, and subsequently the DABE ring system was formed sequentially (the E-ring-closing approach). Recently, MacMillan and coworkers described an impressive organocatalytic asymmetric total synthesis of (+)-aspidospermidine based on a cascade Diels–Alder/cyclization sequence. The development of a general, efficient, and conceptually new strategy for the catalytic enantioselective total synthesis of aspidospermidine still remains important and challenging. We sought to develop a general catalytic asymmetric strategy for the synthesis of aspidospermidine and related natural products in a concise and divergent manner. In this regard, we selected kopsihainanine A, a member of the Kopsia alkaloid family, which has not been synthesized in asymmetric form, as our second target to demonstrate the feasibility of our strategy. Structurally, aspidospermidine and kopsihainanine A contain a common functionalized tetracyclic framework that features a hydrocarbazole core with a crucial all-carbon quaternary stereogenic center (Scheme 1). In addition to the formation of this all-carbon quaternary stereogenic center, another key challenge for the divergent asymmetric synthesis is the cis-fused C/D ring in aspidospermidine and several other members of the family of Aspidosperma alkaloids (such as limaspermidine, cylindrocarine, minovincine, and vincadifformine), whereas the C’/D’ ring in kopsihainanine A is trans-fused (Scheme 1). To achieve our challenging goal, we developed a diversityoriented retrosynthetic analysis (Scheme 2). We planned to form both the cis-fused C/D ring in aspidospermidine and the trans-fused C’/D’ ring in kopsihainanine A from the common Scheme 1. Selected Aspidosperma and Kopsia alkaloids. The core structure of these alkaloids is the piperidine-fused hydrocarbazole ring system.

Catalytic Enantioselective Michael Addition of α-Aryl-α-Isocyanoacetates to Vinyl Selenone: Synthesis of α,α-Disubstituted α-Amino Acids and (+)- and (−)-Trigonoliimine A

Abstract: Be like Mike: The title reaction in the presence of the catalyst 1 afforded Michael adducts in excellent yields and enantioselectivities. The adducts were readily converted into alpha,alpha’-disubstituted alpha-amino acids. The enantioselective total synthesis of both (+)- and (-)-trigonoliimine A was accomplished using one of the Michael adducts derived from this methodology.

Total Synthesis of Maoecrystal V: Early-Stage C–H Functionalization and Lactone Assembly by Radical Cyclization

Abstract: A total synthesis of the unusual ent-kaurane maoecrystal V is described. The synthesis strategy features a counterintuitive early disconnection of the lactone subunit to a polycyclic enol ether intermediate in order to preserve the central tetrahydrofuran ring until the beginning stages of the synthesis. This strategy enables an application of C–H functionalization at the early phase of the synthesis during the construction of a dihydrobenzofuran intermediate.

A concise total synthesis of (+)-scholarisine A empowered by a unique C-H arylation.

Abstract: The structurally unique akuammiline alkaloid (+)-scholarisine A was synthesized in 14 steps from a known enone (15 steps from commercial materials) through a route empowered by a unique C-H arylation reaction to forge its polycyclic core. Additional key steps include a pyrone Diels-Alder reaction and a radical cyclization/Keck allylation to fashion the core cage polycycle and one of the molecule's quaternary centers, as well as the use of a carefully positioned pendant hydroxyl group to facilitate the chemoselective reduction of an extremely unreactive lactam in the presence of a readily reduced lactone.

Pd-Catalyzed Chemoselective Catellani Ortho-Arylation of Iodopyrroles: Rapid Total Synthesis of Rhazinal

Abstract: A Pd-catalyzed chemoselective Catellani reaction of iodopyrroles was developed. The rare chemoselectivity between two different aryl halides was realized by optimizing the kinetics of the different steps of this multicomponent process. The new developed method led to the rapid synthesis of rhazinal in a highly efficient manner.

Pd-catalyzed asymmetric β-hydride elimination en route to chiral allenes.

Abstract: We wish to report our preliminary results on the discovery and development of a catalytic, asymmetric β-hydride elimination from vinyl Pd(II)-complexes derived from enol triflates to access chiral allenes. To achieve this, we developed a class of chiral phosphite ligands that demonstrate high enantioselectivity, allow access of either allene enantiomer, and are readily synthesized. The methodology is demonstrated on over 20 substrates, and application to the formal asymmetric total synthesis of the natural product, (+)-epibatidine, is also provided.

Allylic Oxidations in Natural Product Synthesis

Abstract: Although C–H oxidation of hydrocarbons is generally difficult, allylic C–H oxidation is relatively simple and predictable, even on a preparative scale, because active species generated at the allylic position are stabilized by the double bond. Therefore, allylic oxidation has been employed in natural product synthesis, and a variety of reagents and conditions for allylic oxidation have been reported. However, reagents and conditions suitable for natural product synthesis are limited in terms of efficiency and chemo-, regio-, and stereoselectivity, owing to the structural and characteristic diversity of natural products. This review addresses allylic oxidations, highlighting reagents and conditions that meet the requirements for natural product synthesis. 1 Introduction 2 Selenium Reagents 2.1 Selenium Dioxide 2.2 Diphenyldiselenide–Iodoxybenzene 3 Chromium(VI) Reagents 3.1 Chromic Acid and Chromate Ester 3.2 Chromium Trioxide–3,5-Dimethylpyrazole (CrO3·3,5-DMP) 3.3 PCC and PDC 4 Transition-Metal Reagents 5 Others 6 Conclusion

Access to the akuammiline family of alkaloids: total synthesis of (+)-scholarisine A.

Abstract: The planning and implementation of an enantioselective total synthesis of (+)-scholarisine A is presented. Key tactics employed include a novel cyclization, consisting of a nitrile reduction coupled with concomitant addition of the resultant amine to an epoxide; a modified Fischer indolization; an oxidative lactonization of a diol in the presence of an indole ring; and a late-stage cyclization to complete the caged ring scaffold. The development of a possible "retro-biosynthetic" approach to other members of the akuammiline alkaloid family is also described.

Enantioselective total synthesis of hyperforin.

Abstract: A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization was used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.

Enantioselective Total Syntheses of Leuconolam–Leuconoxine–Mersicarpine Group Monoterpene Indole Alkaloids

Abstract: A unified strategy allowing enantioselective total syntheses of (−)-mersicarpine, (−)-scholarisine G, (+)-melodinine E, (−)-leuconoxine, and (−)-leuconolam from a common cyclohexenone derivative was reported. The Suzuki–Miyaura reaction was used to couple two simple fragments incorporating the key elements for total synthesis, and unprecedented oxidation/reduction/cyclization processes were developed that converted the substituted cyclohexenone to either a mersicarpine or leuconoxine skeleton. In a reverse biomimetic synthesis fashion, (+)-melodinine E was converted to (−)-leuconolam under acidic conditions.

Phosphine Organocatalysis in the Synthesis of Natural Products and Bioactive Compounds

Abstract: During the last few years, synthetic methods based on phosphine organocatalysis have experienced extremely fast developments. This short overview is intended to demonstrate that these methods can afford suitable tools for the constitution of either focused or diversity-oriented-synthesis (DOS) inspired libraries of small molecules for biological screening. It also reports selected examples where these organocatalytic methods have been used conveniently as key steps in the formal or total synthesis of complex natural products. Especially, synthetic applications of the inter- and intramolecular cyclizations of unsaturated substrates have been considered in this review.

Lewis Acid Catalyzed Formal Intramolecular [3+2] Cross-Cycloaddition of Cyclopropane 1,1-Diesters with Alkenes: General and Efficient Strategy for Construction of Bridged [n.2.1] Carbocyclic Skeletons

Abstract: The title reaction is successfully developed, and applied to the total synthesis of the tetracyclic diterpenoids phyllocladanol (XX) and phyllocladene (XXI).