Showing papers on "Total synthesis published in 2000"

Synthesis of native proteins by chemical ligation.

Abstract: ▪ Abstract In just a few short years, the chemical ligation of unprotected peptide segments in aqueous solution has established itself as the most practical method for the total synthesis of native proteins. A wide range of proteins has been prepared. These synthetic molecules have led to the elucidation of gene function, to the discovery of novel biology, and to the determination of new three-dimensional protein structures by both NMR and X-ray crystallography. The facile access to novel analogs provided by chemical protein synthesis has led to original insights into the molecular basis of protein function in a number of systems. Chemical protein synthesis has also enabled the systematic development of proteins with enhanced potency and specificity as candidate therapeutic agents.

Evolution of a gram-scale synthesis of (+)-discodermolide

Abstract: An efficient, highly convergent, stereocontrolled total synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on gram scale. Key elements of the successful strategy include (1) elaboration of three advanced fragments from a common precursor (CP) which embodies the repeating stereochemical triad of the discodermolide backbone, (2) σ-bond installation of the Z trisubstituted olefin, exploiting a modified Negishi cross-coupling reaction, (3) synthesis of a late-stage phosphonium salt utilizing high pressure, and (4) Wittig installation of the Z disubstituted olefin and the terminal (Z)-diene.

Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B

Abstract: The synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%. The absolute stereochemistry of the C4−C12, C33−C38, and C13−C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20−C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocenter which was derived from (R)-trityl glycidol. Key fragment couplings include a stereoselective double stereodifferentiating aldol reaction, a metalated oxazole alkylation, an oxazole-stabilized Wittig olefination, and a chelation-controlled addition of the fully elaborated alkenyl metal side chain.

Total Synthesis of Leucascandrolide A

Abstract: page v Abstract Leucascandrolide A (I), a polyoxygenated marine macrolide of a new genus (Scheme I), was isolated in 1996 by Pietra and co-workers from the calcareous sponge Leucascandra caveolata. Despite intensive efforts, subsequent expeditions failed to provide additional quantities of I. The biological profile of I is characterized by strong cytotoxic activity against human cancer cell lines as well as powerful inhibition of Candida albicans. This thesis describes the total synthesis of leucascandrolide A. The synthesis planning, outlined in Scheme I, relies on the use of asymmetric synthetic methods recently developed in our laboratories and was chosen for reasons of flexibility and convergency.Leucascandrolide A (I), a polyoxygenated marine macrolide of a new genus (Scheme I), was isolated in 1996 by Pietra and co-workers from the calcareous sponge Leucascandra caveolata. Despite intensive efforts, subsequent expeditions failed to provide additional quantities of I. The biological profile of I is characterized by strong cytotoxic activity against human cancer cell lines as well as powerful inhibition of Candida albicans. This thesis describes the total synthesis of leucascandrolide A. The synthesis planning, outlined in Scheme I, relies on the use of asymmetric synthetic methods recently developed in our laboratories and was chosen for reasons of flexibility and convergency. Me O O O O OMe O Me Me O N O N O MeO H Me Me SO2Ar O Me O OR2 CO2R Me H O OR1 O O Me Me I II III O N O N O MeO H MeO

Sulfones and sulfoxides in the total synthesis of biologically active natural compounds

Abstract: Data on the use of sulfones and sulfoxides in total stereo-, regio- and enantioselective syntheses of natural compounds published over the last 15–20 years are discussed and classified into the most important types of reactions. The bibliography includes 420 references.

An Asymmetric Synthesis of the Tricyclic Core and a Formal Total Synthesis of Roseophilin via an Enyne Metathesis

Abstract: A formal synthesis of roseophilin, a novel pentacyclic structure possessing significant antitumor activity, starting from 3-cycloundecenylcarboxylic acid has been completed. The acid was converted diastereoselectively to the corresponding menthol ester via the ketene which, in turn, provided (S)-3-cycloundecenylcarboxaldehyde. Diastereoselective propargylation with propargyltriphenylstannane promoted by an asymmetric boron reagent prepared in situ from boron tribromide and the bis-p-toluenesulfonamide of (S,S)-stilbenediamine gave (1S,1‘R)-1-cycloundec-2‘-enylbut-3-yn-1-ol which set the stage for the key metathesis reaction. Platinum-catalyzed enyne metathesis via a formal [2 + 2] cycloaddition to a cyclobutene followed by conrotatory ring opening created the corresponding bicyclo[10.2.1]pentadeca-1(15),2-diene. Regioselective epoxidation of the less reactive double bond of the 1,3-diene was accomplished by 1,4-bromohydrin formation followed by base. Cuprate opening regio- and stereospecifically installed...

Total Synthesis of the Thiopeptide Promothiocin A

Abstract: The thiopeptide (or thiostrepton) antibiotics are a class of sulfur-containing highly modified cyclic peptides with interesting biological activity. Described herein is the total synthesis of the thiopeptide antibiotic promothiocin A, which utilizes a modified Bohlmann−Rahtz pyridine synthesis to establish the oxazolyl−thiazole−pyridine heterocyclic centerpiece of the antibiotic. The oxazole building blocks were obtained by a dirhodium(II)-catalyzed chemoselective carbenoid N−H insertion reaction followed by cyclodehydration, and the thiazoles by the Hantzsch reaction. Two different strategies for macrocyclization were successfully employed, with the dehydroalanine side chain of the natural product being introduced in the last steps of the synthesis.

Total Synthesis of (−)‐Spirotryprostatin B and Three Stereoisomers

Abstract: A catalytic intramolecular Heck reaction, followed by capture of the resulting η(3)-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (-)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η(3)-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.

Studies on the narciclasine alkaloids: Total synthesis of (+)- narciclasine and (+)-pancratistatin

Abstract: Enantioselective total syntheses of the antitumor alkaloids, (+)-narciclasine and (+)-pancratistatin, are reported. These syntheses feature a stereo- and regiocontrolled aryl enamide photocyclization to construct a common, advanced intermediate possessing a trans-fused BC substructure. Differential functional group interchange in the C-ring of this phenanthridone core structure allows for the production of the two target natural products in enantiomerically pure form.

Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones

Abstract: With a similar mechanism of action to taxol, the title compound 1 is a particularly promising candidate for development in cancer chemotherapy This efficient synthesis, based on stereocontrolled aldol reactions, should help to overcome the scarce natural supply of 1 from the rare sponge source

Formal total synthesis of (+)-diepoxin sigma.

Abstract: The highly oxygenated antifungal anticancer natural product (+/-)-diepoxin sigma was prepared in 10 steps and in 15% overall yield from O-methylnaphthazarin. Highlights of the synthetic work include an Ullmann coupling and a possibly biomimetic oxidative spirocyclization for the introduction of the naphthalene ketal as well as the use of a retro-Diels-Alder reaction to unmask the reactive enone moiety in the naphthoquinone bisepoxide ring system. A novel highly bulky chiral binaphthol ligand was developed for a boron-mediated Diels-Alder reaction that constitutes a formal asymmetric total synthesis of (+)-diepoxin sigma.

A Novel Application of a Pd(0)-Catalyzed Nucleophilic Substitution Reaction to the Regio- and Stereoselective Synthesis of Lactam Analogues of the Epothilone Natural Products

Abstract: Several lactam analogues of the epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire three-step sequence was streamlined into a “one-pot” process for the epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactam analogue of epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.

Ring-closing alkyne metathesis. Application to the total synthesis of sophorolipid lactone.

Abstract: The first total synthesis of a major component of the microbial biosurfactant sophorolipid has been achieved This approach to the 26-membered macrolide 1 containing a Z-configured alkene group in its lipidic tether spanning the sophorose backbone is based on a ring-closing metathesis reaction of diyne 21 catalyzed by Mo[N(t-Bu)(Ar)]3 (5; Ar = 3,5-dimethylphenyl) activated in situ by CH2Cl2, followed by Lindlar reduction of the resulting cycloalkyne 22 The two β-glycosidic linkages of compound 21 were installed by means of the glucal epoxide method and a modified Koenigs−Knorr reaction promoted by AgOTf/lutidine, respectively

First Total Synthesis of the Marine Alkaloids (±)-Fasicularin and (±)-Lepadiformine Based on Stereocontrolled Intramolecular Acylnitroso-Diels−Alder Reaction

Abstract: The first total synthesis of tricyclic marine alkaloids (±)-fasicularin (2) and (±)-lepadiformine (5) was accomplished. The key common strategic element for the synthesis is the stereocontrolled intramolecular hetero-Diels−Alder reaction of an N-acylnitroso moiety to an exocyclic diene with or without bromine substitution to control the syn-facial or anti-facial selectivity, respectively, leading to the trans- or cis-fused decahydroquinoline ring systems 21 or 39 involving the simultaneous introduction of the nitrogenated quaternary center in a single step. On further elaboration of the six-membered or five-membered ring A, the trans-fused adduct 21 provided either (±)-fasicularin (2) or (±)-lepadiformine (5). The hydrochloride salt of synthetic (±)-5 was found to be identical with the isolated natural sample of lepadiformine; however, the tricyclic amino alcohol 4 having the proposed structure of lepadiformine in a nonzwitterionic form, derived from the cis-fused adduct 39, was found to be different from...

Enantioselective Construction of Vicinal Stereogenic Quaternary Centers by Dialkylation: Practical Total Syntheses of (+)- and meso-Chimonanthine.

Abstract: All three stereoisomers of the hexacyclic 3a,3a'-bispyrrolidino[2,3-b]indoline moiety found in complex indole alkaloids can be prepared, as illustrated by total syntheses of meso-chimonanthine (1) and (+)-chimonanthine (2). A rare example of high diastereoselectivity arising from the combination of a prostereogenic enolate with a chiral electrophile containing a sp(3) carbon atom is the key feature of the asymmetric synthesis of the C(2) stereoisomer.

A concise formal total synthesis of mappicine and nothapodytine B via an intramolecular hetero Diels-Alder reaction.

Abstract: A six-step formal total synthesis of a natural alkaloid, mappicine (3), has been achieved. The highlight of our synthetic strategy is an intramolecular hetero Diels-Alder reaction that was used for the construction of the CD ring system of mappicine (3). In addition, it was demonstrated that the Sonogashira coupling reaction of 2-chloro-3-hydroxymethylquinoline (8c) with trimethylsilylacetylene proceeded at room temperature in excellent yield.

Enantioselective Total Synthesis of Epothilones A and B Using Multifunctional Asymmetric Catalysis

Abstract: An enantioselective total synthesis of epothilones A (1) and B (2) using multifunctional asymmetric catalysis such as a cyanosilylation of an aldehyde, an aldol reaction of an unmodified ketone with an aldehyde, and a protonation in the conjugate addition of a thiol to an α,β-unsaturated thioester has been achieved. We divided 1 and 2 into fragment A, fragment B, and fragment C. A catalytic asymmetric synthesis of fragments A and B was accomplished using a catalytic asymmetric cyanosilylation as a key step. An enantiocontrolled synthesis of fragment C was achieved in two ways. One is the use of a direct catalytic asymmetric aldol reaction of an unmodified ketone with an aldehyde as a key step, and the other utilizes a catalytic asymmetric protonation in the conjugate addition of a thiol to an α,β-unsaturated thioester as a key step. Suzuki cross-coupling of fragment A with fragment C followed by Yamaguchi lactonization as key steps led to an enantiocontrolled synthesis of epothilone A (1). On the other ha...

Recovery of carbonyl compounds from N,N-dialkylhydrazones.

Abstract: Deprotonation of enantiomerically pure hydrazones and subsequent trapping with suitable electrophiles generates new stereogenic centers with excellent stereoselectivity. To liberate the original carbonyl functionality in the final products, it is necessary to cleave the hydrazone moiety. In recent years, many reagents have been developed to regenerate carbonyl compounds from the corresponding dialkylhydrazones which are compatible with a wide range of functionalities. This has allowed the use of hydrazones in the total synthesis of complex natural products. This Account is meant to be an overview of methods which are classified as oxidative, hydrolytic, and reductive cleavage procedures.

Total Synthesis of (+)-Prelaureatin and (+)-Laurallene

Abstract: The first total syntheses of (+)-prelaureatin and (+)-laurallene are described. An asymmetric glycolate aldol addition was followed by a ring-closing metathesis to close the eight-membered ring allowing construction of the oxocene core of (+)-prelaureatin and (+)-laurallene in seven synthetic steps from (R)-benzylglycidyl ether.

A biomimetic total synthesis of (-)-spirotryprostatin B and related studies.

Abstract: The prenylated natural products spirotryprostatin A and B derived from the Trp-Pro diketopiperazine also feature an oxidative rearrangement of the indole to form a spirooxindole. Synthetically, formation of the oxindole ring was stereoselectively accomplished by reaction of the appropriate indole precursor with N-bromosuccinimide. For optimum results, the oxidation should be carried out prior to diketopiperazine cyclization. In this manner, we have synthesized the tetrahydro- and dihydro- analogues of spirotryprostatin B in four steps from L-tryptophan methyl ester. The dihydro derivative was then converted to spirotryprostatin B by unsaturation of the pyrrolidine ring to a pyrroline, thus unambiguously confirming the structure of the natural product.

Highly Regioselective Synthesis of 2,3,4-Trisubstituted 1H-Pyrroles: A Formal Total Synthesis of Lukianol A†,1

Abstract: A combined use of α-lithiation and nucleophilic substitutions of N,N-dimethyl 3,4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamide 8c led to several 2-substituted 3,4-bis(trimethylsilyl)-1H-pyrrole-1-sulfonamides. Utilizing the β-effect of a trimethylsilyl group, a highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles 23 and 34 was accomplished. The marine natural product lukianol A (3) was prepared utilizing this strategy.

The Total Synthesis of (±)-Ginkgolide B

Abstract: The total synthesis of the potent PAF antagonist ginkgolide B has been accomplished. The complex architecture of ginkgolide B which includes six rings, eleven stereogenic centers, ten oxygenated carbons, and four contiguous fully substituted carbons is a daunting challenge for chemical synthesis. The synthesis of ginkgolide B was accomplished through a stereoselective intramolecular photocycloaddition of enone 5 to construct the congested core of the molecule. The photocycloaddition substrate was prepared through technology for the construction of carboalkoxycyclopentenones previously reported from these laboratories. Regioselective cyclobutane fragmentation and further functionalization of the photoadduct 4 provided the key pentacyclic intermediate. Acid-catalyzed rearrangement and epoxide opening were key transformations in the production of ginkgolide B from the pentacyclic intermediate.

Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (- )-picropodophyllin

Abstract: Described is the first catalytic, asymmetric synthesis of (−)-podophyllotoxin and its C2-epimer, (−)-picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen−metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate− (15) and maleate−IBF Diels−Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleat...