Showing papers on "Total synthesis published in 2010"

Organocatalytic cascade reactions as a new tool in total synthesis

Abstract: The total synthesis of natural products and biologically active compounds, such as pharmaceuticals and agrochemicals, has reached an extraordinary level of sophistication. We are, however, still far away from the 'ideal synthesis' and the state of the art is still frequently hampered by lengthy protecting-group strategies and costly purification procedures derived from the step-by-step protocols. In recent years several new criteria have been brought forward to solve these problems and to improve total synthesis: atom, step and redox economy or protecting-group-free synthesis. Over the past decade the research area of organocatalysis has rapidly grown to become a third pillar of asymmetric catalysis standing next to metal and biocatalysis, thus paving the way for a new and powerful strategy that can help to address these issues - organocatalytic cascade reactions. In this Review we present the first applications of such asymmetric organocascade reactions to the total synthesis of natural products.

Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C‐3 Position

Abstract: The 3,3′-disubstituted oxindole structural motif is a prominent feature in many alkaloid natural products, which include all kinds of tetrasubstituted carbon stereocenters, spirocyclic or not, all-carbon or heteroatom-containing. The catalytic asymmetric synthesis of the tetrasubstituted carbon stereocenter at the C-3 position of the oxindole framework integrates new synthetic methods and chiral catalysts, reflects the latest achievements in asymmetric catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. This review summarizes the recent progress in this area, and applications in the total synthesis of related bioactive compounds.

Total synthesis of celogentin C by stereoselective C-H activation.

Abstract: the most potent isolate (IC50= 0.8 mm ; IC= inhibitory concentration) from the celogentin/moroidin family, whose members possess inhibitory activity against tubulin polymerization. Its highly unusual architecture, which is characterized by the direct linkages of Trp C6 to Leu Cb, and Trp C2 to His N1 (Figure 1), and its biological activity have prompted a number of synthesis studies. Although N-linkedHis residues are known to occur in other macrocyclic peptides, the Leu-Trp linkage is extremely rare and poses a difficult synthetic challenge. To access the key Leu-Trp motif, Moody and Bentley, and Campagne et al., applied asymmetric hydrogenation conditions to dehydroamino acid precursors. Enantioand/or diastereoselectivities ranged from 1:1 to 16:1 for these 10–14 step sequences. More recently, Castle and coworkers developed a novel Knoevenagel condensation/radical conjugate addition approach to the Leu-Trp linkage. They completed the first celogentin synthesis through an elegant NCS-mediated Trp-His C N coupling by utilizing the major diastereomer product, albeit in modest enantioand diastereoselectivity. Herein, we report a highly stereoselective and efficient synthesis of celogentin C using a novel palladiumcatalyzed C H functionalization strategy. The highly constrained structure of 1 is probably assembled in vivo from the much simpler linear peptide precursor through a series of enzymatic oxidative cross-links (Figure 1). Inspired by these simple yet powerful transformations found in nature, we envisioned developing a synthetic equivalent of these processes in a direct approach to celogentin. Our synthetic strategy relied on the direct regioand stereoselective activation of the b C H bond of a Leu moiety and on the subsequent coupling of the derived C Pd species with a suitable Trp partner. The recent report by Corey et al. of the carboxamide-directed b C H functionalization of amino acids served as the starting point for our venture. Corey demonstrated that the b C H bond of the Nphthaloyl amino acid 8-aminoquinoline amide can be efficiently activated and then arylated with simple aryl iodides under Pd(OAc)2 catalysis, a procedure built on the seminal discovery of Daugulis and co-workers for the functionalization of inactivated sp C H bonds. The quinoline moiety serves as a chelating auxiliary for palladium coordination, and promotes the formation of trans-palladacycle intermediate 4. This palladium(II) intermediate presumably undergoes crosscoupling with an aryl iodide partner to provide the final arylated product which has an erythro stereochemical preference. To our delight, we were able to achieve the high-yielding and highly stereoselective 6-indolylation of N-phthaloyl leucine (Scheme 1a). Upon simple heating of precursors 2 (2.0 equiv) and 3 (1.0 equiv), with Pd(OAc)2 (0.2 equiv), and AgOAc (1.5 equiv), at 110 8C in tBuOH, the desired diastereomer 5 was formed exclusively, and the slight excess of 2 could be largely recovered. About 3% of deiodinated side product 6 was also generated. Although the quinoline carboxamide serves as an effective auxiliary in arylation chemistry, its efficient removal under mild conditions would be required for this process to become a useful tool for natural product synthesis. However, the cleavage of the amide linkage was particularly problematic, owing to both steric hindrance and the lability of the Nphthaloyl group. This phthaloyl group, which provides both bis-protection of the a-amino group and steric bias, is critical Figure 1. Celogentin C and our synthetic strategy.

Silicon‐Based Cross‐Coupling Reactions in the Total Synthesis of Natural Products

Abstract: Unlike other variants of transition-metal-catalyzed cross-coupling reactions, those based on organosilicon donors have not been used extensively in natural product synthesis. However, recent advances such as: 1) the development of mild reaction conditions, 2) the expansion of substrate scope, 3) the development of methods to stereoselectively and efficiently introduce the silicon-containing moiety, 4) the development of a large number of sequential processes, and 5) the advent of bifunctional bis(silyl) linchpin reagents, signify the coming of age of silicon-based cross-coupling reactions. The following case studies illustrate how silicon-based cross-coupling reactions play a strategic role in constructing carbon-carbon bonds in selected target molecules.

Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity

Abstract: The first total synthesis of (+)-chaetocin has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction of diketopiperazine 10 and Co(I)-mediated reductive dimerization reaction of 12 as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogues without the sulfur functionality are inactive.

Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis.

Abstract: Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.

Simple Reagents for Direct Halonium-Induced Polyene Cyclizations

Abstract: Although there are many reagent combinations that can initiate polyene cyclizations, simple electrophilic halogen sources have not yet proven broadly effective as promoters of such processes. Herein is described a readily prepared and stable class of reagents capable of effecting such transformations for a wide range of electron-rich and -deficient terpenes derived from geraniol, farnesol, and nerol, thereby enabling the effective synthesis of a diverse array of complex chlorine-, bromine-, and iodine-containing polycyclic frameworks. Efforts to date have led to the first racemic laboratory total synthesis and structural revision of the anti-HIV natural product peyssonol A as well as an efficient and concise inaugural total synthesis of peyssonoic acid A. They have also permitted formal racemic total syntheses of aplysin-20, loliolide, K-76, and stemodin to be achieved through routes that are typically shorter, higher-yielding, and more environmentally conscious than previous efforts. Preliminary attempts to use chiral forms of the reagent class for enantioselective alkene halogenation are also described.

Total synthesis of (+)-complanadine A using an iridium-catalyzed pyridine C-H functionalization.

Abstract: The total synthesis of the Lycopodium alkaloid complanadine A, which is an unsymmetrical dimer of lycodine, was achieved by exploiting a common tetracyclic precursor Key to the success of the synthesis was the development of a late-stage site-selective C−H functionalization of a pyridine moiety to arrive at a key boronic ester intermediate

Total synthesis and absolute stereochemical assignment of (-)-communesin F.

Abstract: A concise asymmetric total synthesis of (-)-communesin F (∼6% overall yield in the longest linear sequence of 19 steps) is described. It features an unprecedented intramolecular oxidative coupling strategy for the elaboration of the requisite spiro-fused indoline moiety. Other notable elements are the use of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce the asymmetric formation of the spiro-fused indoline part, the mesylate-mediated formation of its G ring, and the introduction of the A ring at the final stage via intramolecular Staudinger reaction. This intramolecular Staudinger reaction proceeded smoothly at 80 °C, providing an additional example illustrating that twisted amides are more reactive than simple amides. Along with the total synthesis, we were able to assign the absolute configuration of natural communesin F as 6R,7R,8R,9S,11R.

Metathesis in natural product synthesis : strategies, substrates and catalysts

Abstract: Preface SYNTHESIS OF NATURAL PRODUCTS CONTAINING MEDIUM-SIZE CARBOCYCLES BY RING-CLOSING ALKENE METATHESIS Introduction Formation of Five-Membered Carbocycles by RCM Formation of Six-Membered Carbocycles by RCM Formation of Seven-Membered Carbocycles by RCM Formation of Eight-Membered Carbocycles by RCM Formation of Nine-Membered Carbocycles by RCM Formation of 10-Membered Carbocycles by RCM Conclusion NATURAL PRODUCTS CONTAINING MEDIUM-SIZED NITROGEN HETEROCYCLES SYNTHESIZED BY RING-CLOSING ALKENE METATHESIS Introduction Five-Membered Nitrogen Heterocycles Six-Membered Nitrogen Heterocycles Seven-Membered Nitrogen Heterocycles Eight-Membered Nitrogen Heterocycles Conclusion SYNTHESIS OF NATURAL PRODUCTS CONTAINING MEDIUM-SIZE OXYGEN HETEROCYCLES BY RING-CLOSING ALKENE METATHESIS Introduction General RCM Approaches to Medium Rings Laurencin Eunicellins/Eleutherobin Helianane Octalactin A Microcarpalide and the Herbarums Marine Ladder Toxins Conclusion PHOSPHOROUS AND SULFUR HETEROCYCLES VIA RING-CLOSING METATHESIS: APPLICATION IN NATURAL PRODUCT SYNTHESIS Introduction Synthesis and Reactivity of Sulfones Derived from RCM Total Synthesis of the Originally Proposed Structure of (?)-Mycothiazole Synthesis and Reactivity of Phosphates from RCM Applications of Phosphate Tethers in the Synthesis of Dolabelide C Conclusion SYNTHESIS OF NATURAL PRODUCTS CONTAINING MACROCYCLES BY ALKENE RING-CLOSING METATHESIS Introduction Organization of the Chapter Macrocyclic Polyketides Terpenoids Macrocyclic Lipids Macrocyclic Glycolipids Conclusions and Outlook SYNTHESIS OF NATURAL PRODUCTS AND RELATED COMPOUNDS USING ENE-YNE METATHESIS Introduction Synthesis of Natural Products and Related Compounds Using Ene-Yne Metathesis Synthesis of Natural Products and Related Compounds Using Ene-Yne Cross-Metathesis (CM) Synthesis of Natural Products Using Skeletal Reorganization RING-CLOSING ALKYNE METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction Alkyne Metathesis Ring-Closing Alkyne Metathesis Applications of RCAM in Natural Product Synthesis Conclusions TEMPORARY SILICON-TETHERED RING-CLOSING METATHESIS REACTIONS IN NATURAL PRODUCT SYNTHESIS Introduction Temporary Silicon-Tethered Ring-Closing Metathesis Reactions Conclusions and Outlook METATHESIS INVOLVING A RELAY AND APPLICATIONS IN NATURAL PRODUCT SYNTHESIS Introduction Early Relay Metathesis Discoveries Examples of Relay Metathesis Directed at Targets Other tan Natural Products Examples of Relay Metathesis Motivated by Natural Product Synthesis Examples of Relay Metatheses Thwarted in Achieving the Desired Outcome Conclusion CROSS-METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction Functionalization of Olefins Appending a Side Chain Couplings Cascade Processes Involving CM Ene-Yne CM Alkyne CM Conclusion and Perspectives CASCADE METATHESIS IN NATURAL PRODUCT SYNTHESIS Introduction RCM-CM Sequences Ene-Yne-Ene RCM-RCM ROM-CM Sequences RCM-ROM Sequences - Ring-Rearrangement Metathesis (RRM) RCM-ROM Sequences Combined with Other Metathesis Reactions Conclusions and Outlook CATALYTIC ENANTIOSELECTIVE OLEFIN METATHESIS AND NATURAL PRODUCT SYNTHESIS Introduction Total Synthesis of Natural Products with Enantiomerically Pure Chiral Olefin Metathesis Catalysts Bearing a C2-Symmetric Diolate Ligand Enantioselective Synthesis of Quebrachamine through an Exceptionally Challenging RCM Reaction Synthesis of Baconipyrone C by Ru-Catalyzed Enantioselective ROCM Conclusions and Future Outlook METATHESIS REACTIONS IN SOLID-PHASE ORGANIC SYNTHESIS Introduction Metathesis-Based Cyclorelease Reaction Ring-Closing Metathesis (RCM) Intraresin Dimerization Restricting Peptide Conformation through Cyclization Cross-Metathesis on Solid Phase Ene-Yne Metathesis on Solid Phase Conclusion

Enantioselective synthesis of pyrroloindolines by a formal [3 + 2] cycloaddition reaction.

Abstract: (R)-BINOL•SnCl_4 was found to catalyze a formal [3 + 2] cycloaddition reaction between C(3)-substituted indoles and 2-amidoacrylates to provide pyrroloindolines. A variety of pyrroloindolines were prepared with high enantioselectivity in one step from simple precursors. This methodology is expected to facilitate the total synthesis of pyrroloindoline alkaloids, an important class of biologically active natural products.

Enantioselective Synthesis of (−)‐Englerins A and B

Abstract: 1 was found to be 1–2 orders of magnitude more potent than taxol against certain cancer cell lines. In contrast, ( )englerin B (2), lacking the glycolate at C10, was much less active and selective. An elegant total synthesis of the enantiomer of 1 from the naturally occurring terpene trans,cis-nepetalactone by the research group of Christmann established the absolute configuration of these guaianes as shown in Scheme 1. Recently, our research group has developed the gold(I)catalyzed [2+2+2] alkyne/alkene/carbonyl cycloaddition of 1,6-enynes bearing a carbonyl group in which two C C and one C O bonds are formed in a domino process. As has been shown in gold(I)-catalyzed reactions of enynes, this reaction is stereospecific. Furthermore, we have recently found that a propargylic stereocenter bearing an OR group exerts an exquisite stereocontrol in the cyclization process, which has been applied in the total synthesis of the oxatricyclic sesquiterpenes (+)-orientalol F (3) and ( )pubinernoid B (4). This cyclization is faster than the intramolecular 1,5-migration of propargylic OR groups that occurs in related systems. We planned to use the gold-catalyzed domino reaction for the synthesis of 1 and 2 from a 1,6-enyne 5 that is substituted by OR groups at the propargylic and allylic positions (Scheme 2). However, the allylic OR’ group would confer

General Approach to Epipolythiodiketopiperazine Alkaloids: Total Synthesis of (+)-Chaetocins A and C and (+)-12,12′-Dideoxychetracin A

Abstract: A highly stereoselective and systematic strategy for the introduction of polysulfides in the synthesis of epipolythiodiketopiperazines is described. We report the first total synthesis of dimeric epitri- and epitetrathiodiketopiperazines.

Total synthesis of (±) maoecrystal V.

Abstract: A concise first total synthesis of (±) maoecrystal V (1) is reported. The synthesis features a Wessely oxidative dearomatization of a phenol, an intramolecular Diels-Alder reaction, and a Rh-catalyzed O-H bond insertion as key steps.

Total Synthesis of (−)-Mersicarpine

Abstract: The total synthesis of (-)-mersicarpine was achieved in 10 steps from a known ketoester. Our synthesis features an Eschenmoser-Tanabe-type fragmentation to synthesize an alkyne unit containing a quaternary carbon center, a facile construction of the indole skeleton via a combination of a Sonogashira coupling and a gold(III) catalyzed cyclization, as well as a one-pot process to arrange the cyclic imine and the hemiaminal moieties. Our synthesis unambiguously confirmed the reported structure of (-)-mersicarpine including the absolute configuration.

Transition-metal-catalyzed cycloadditions for the synthesis of eight-membered carbocycles.

Abstract: Eight-membered carbocycles are found in a wide variety of natural products that exhibit a broad range of biological and medicinal activities (cf. the most potent anticancer drug, taxol). However, the synthesis of eight-membered carbocycles is quite challenging as traditional approaches are met with entropic and enthalpic penalties in the ring-forming transition states. These negative effects can be totally or partially avoided with the implementation of transition-metal-catalyzed/mediated cycloadditions. In this Focus Review, examples of elegant and efficient metal-catalyzed and some metal-mediated cycloadditions (including Ni- catalyzed [4+4] and Rh-catalyzed [4+2+2] and [5+2+1] reactions) are presented to illustrate this. Application of these cycloaddition reactions in total synthesis is also presented to show the significance of these reactions in addressing challenges in natural product synthesis.

Catalytic selective cyclizations of aminocyclopropanes: formal synthesis of aspidospermidine and total synthesis of goniomitine.

Abstract: Mild Control: Selective cyclization of aminocyclopropanes on the N1 or C3 positions of indole was achieved by tuning the catalyst and solvent. The new strategy was applied to the formal synthesis of aspidospermidine and the total synthesis of goniomitine in 13 steps and 11% overall yield. The first studies on the bioactivity of goniomitine demonstrated significant cytotoxicity against several tumor cell lines (IC50: 150-400 nM).

High‐Yielding Synthesis of the Anti‐Influenza Neuraminidase Inhibitor (−)‐Oseltamivir by Two “One‐Pot” Sequences

Abstract: The efficient asymmetric total synthesis of (―)-oseltamivir, an antiviral reagent, has been accomplished by using two "one-pot" reaction sequences, with excellent overall yield (60 % ) and only one required purification by column chromatography. The first one-pot reaction sequence consists of a diphenylprolinol silyl ether mediated asymmetric Michael reaction, a domino Michael reaction/ Horner―Wadsworth―Emmons reaction combined with retro-aldol/Horner― Wadsworth―Emmons reaction and retro Michael reactions, a thiol Michael reaction, and a base-catalyzed isomerization. Six reactions can be successfully conducted in the second one-pot reaction sequence; these are deprotection of a tert-butyl ester and its conversion into an acyl chloride then an acyl azide, Curtius rearrangement, amide formation, reduction of a nitro group into an amine, and a retro Michael reaction of a thiol moiety. A column-free synthesis of (—)—oseltamivir has also been established.

Asymmetric Total Synthesis of Vindorosine, Vindoline, and Key Vinblastine Analogues

Abstract: Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels−Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C−C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ6,7-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our us...

Silver Nanoparticle-Catalyzed Diels−Alder Cycloadditions of 2′-Hydroxychalcones

Abstract: Metal nanoparticles are currently being employed as catalysts for a number of classical chemical transformations. In contrast, identification of novel reactions of nanoparticles, especially toward the synthesis of complex natural products and derivatives, is highly underdeveloped and represents a bourgeoning area in chemical synthesis. Herein, we report silica-supported silver nanoparticles as solid, recyclable catalysts for Diels-Alder cycloadditions of 2'-hydroxychalcones and dienes in high yield and turnover number. The use of silver nanoparticle catalysts is further demonstrated by the total synthesis of the cytotoxic natural product panduratin A employing a highly electron-rich dienophile and Lewis acid sensitive diene.

Hypervalent Iodine Chemistry: Modern Developments In Organic Synthesis

Abstract: and General Aspects.- Reactivities, Properties and Structures.- Preparation of Hypervalent Iodine Compounds.- C-C-Bond Forming Reactions.- C-Heteroatom-Bond Forming Reactions.- Heteroatom-Heteroatom-Bond Forming Reactions.- Oxidations and Rearrangements.- Synthetic Applications (Total Synthesis and Natural Product Synthesis).

Asymmetric Total Synthesis of Vindoline

Abstract: A concise asymmetric total synthesis of (−)-vindoline (1) is detailed based on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which the tether linking the initiating dienophile and oxadiazole bears a chiral substituent that controls the facial selectivity of the initiating Diels−Alder reaction and sets absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduces three rings and four C−C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. Implementation of the approach also required the development of a unique ring expansion reaction to provide a six-membered ring suitably functionalized for introduction of the Δ(6, 7)-double bond found in the core structure of vindoline and defined our use of a protected hydroxymethyl group as the substituent used to cont...

Enantioselective Synthesis of (+)-Cephalostatin 1

Abstract: This Article describes an enantioselective synthesis of cephalostatin 1. Key steps of this synthesis are a unique methyl group selective allylic oxidation, directed C−H hydroxylation of a sterol at C12, Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization.

Total Synthesis and Biological Evaluation of the Resveratrol-Derived Polyphenol Natural Products Hopeanol and Hopeahainol A

Abstract: The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2), whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A (3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported cytotoxic potencies of hopeanol (2).