Total synthesis of guanacastepene a: a route to enantiomeric control

[reaction: see text] The goal of the total synthesis of guanacastepene A served as a focus to bring together several chemical inquiries. One involved the synthesis of fused 5,7-hydrazulenones (see structure 20). Another issue had to do with the mechanistic intermediates in reductive cyclizations (see 17 to 18 and 19). The total synthesis required a mastery of an intramolecular Knoevenagel condensation of a beta,gamma-unsaturated ketone (see compound 41). Actually, cyclization was best accomplished when the terminal double bond of 41 was first converted to an epoxide. Further issues related to the stereochemistry at C5 and, rather surprisingly, the propensity for beta-face acetoxylation at C13. Crystallographic verification of the assigned beta-stereochemistry at C13 is provided. Finally, a route to optically active material is provided (see compound 20). A key element in this construction was an enantioselective addition of isopropenyl cuprate to 2-methylcyclopentenone (see compound 99).     

Synthesis of a C8 oxygenated pyranonaphthoquinone: a useful precursor to dimeric pyranonaphthoquinones

The synthesis of a pyranonaphthoquinone bearing an oxygenated substituent at C8 is reported. The oxygen substituent at C8 provides a key functionality for use as a homocoupling precursor for the synthesis of a dimeric pyranonaphthoquinone.     

Rearrangement of a pyranone to a benzothiazole

The conversion of 2-chloromethyl-5-methoxy-4H-pyran-4-one to 2-amino-5-hydroxy-6-methoxybenzothiazole hydrochloride under mild reaction conditions has been observed. The synthesis of the identical benzothiazole by an alternate unequivocal method is also reported.     

Diastereoselective phenol para-alkylation: access to a cross-conjugated cyclohexadienone en route to resiniferatoxin

We document a route for the synthesis of a densely functionalized spiro-fused 2,5-cyclohexadienone as an intermediate for the synthesis of resineferatoxin. The strategy is based on an unprecedented diastereoselective, intramolecular phenol para-alkylation to a cross-conjugated cyclohexadienone. In the course of these synthetic studies we developed rapid access to a chiral nitrile possessing a quaternary stereocenter and disclose an unusual acetal rearrangement from a dioxane, which favors the corresponding dioxepane.     

Approach to geminally alkylated azaphthalans via a consecutive double desilylation-alkylation reaction: application to a synthesis of cerpegin

A new approach to geminally alkylated azaphthalans and an application of this chemistry to the synthesis of the pyridone alkaloid, cerpegin, is reported.     

An N-acyliminium cyclization approach to a total synthesis of (+)-cylindricine C

[reaction: see text] Details of problems and solutions encountered during the development of an enantioselective total synthesis of (+)-cylindricine C are described here. The total synthesis itself was accomplished in 8 steps, featuring an N-acyliminium cyclization strategy, the seldom-used Wharton rearrangement, and a key epimerization at C5.     

A modified approach to the phomoidrides: synthesis of a late-stage intermediate containing a key carbon quaternary stereocenter

A previously developed approach to the synthesis of the phomoidrides has been modified to incorporate all necessary carbon atoms prior to the key tandem carbonylation/Cope rearrangement reaction. This modification necessitated the synthesis of a challenging all-carbon quaternary stereocenter, which in turn rendered ineffective several reactions from the original synthesis. An oxidative radical cleavage of a spirocyclopropane ring system was developed that accomplishes the synthesis of the quaternary center, and a regioselective double hydroboration reaction was devised that provides an alternate approach to a key sequence of functional group interconversions, where the originally developed route was found to be ineffective.     

Development of a general approach to the synthesis of a library of isoflavonoid derivatives

Isoflavonoids are a class of organic compounds that act primarily as antioxidants. They are produced almost exclusively by various members of the bean family including soybeans, tofu, peanuts, chick peas, and alfalfa. The antioxidant characteristics that isoflavonoids exhibit help hinder the progression of certain cancers, primarily breast, prostate, and colon cancer. We have developed a three-five step synthesis for obtaining a suite of isoflavonoid derivatives. The synthesis involves an enamine formation, a ring closure and halogenation, a Suzuki coupling, and finally a global deprotection to obtain the respective isoflavonoid derivatives.     

Pd-catalyzed carbonylative lactamization: a novel synthetic approach to FR900482

An asymmetric synthesis of the benzazocine core of FR900482 has been achieved in 15 steps from 3,5-dinitro-p-toluic acid. Key features of the synthesis include an enantioselective N-methylephedrine-mediated zinc acetylide addition to a highly enolizable arylacetaldehyde and a novel Pd-catalyzed carbonylative lactamization to form an eight-membered ring. [reaction--see text]     

The Knight route to cyclopiazonic acid: enantioselective synthesis of a key intermediate

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides thapsigargin and artemisinin. Inhibitors of SERCA hold promise as novel anticancer and antimalarial drugs. Since its structure elucidation three racemic syntheses of α-cyclopiazonic acid have been published. We report now the first enantioselective and high yielding synthesis of a key-intermediate of the Knight synthesis, currently the most efficient route to CPA. Our synthesis is based on a diastereoselective 1,4-cuprate addition followed by an enolate azidation of an indolylacrylic acid modified with the Evans auxiliary.     

Synthetic strategies to epoxydiynes and a key synthon of the neocarzinostatin chromophore

We present herein our recent efforts towards the synthesis of epoxydiynes which represent an unusual structural feature of the neocarzinostatin chromophore. A number of different routes to these epoxydiynes have been explored with varying success. Ultimately a concise and convergent approach was developed, which involved the addition of an allenyl zinc bromide to propargylic ketones/aldehydes followed by epoxide formation. This new protocol enabled us to synthesise a fully elaborated epoxydiyne which will find application for our studies towards the total synthesis of the NCS chromophore.     

Development of a new traceless aniline linker for solid-phase synthesis of azomethines. Application to parallel synthesis of a rod-shaped liquid crystalline library

A new traceless linker was developed to synthesize a library of 42 compounds possessing an azomethine linkage using combinatorial solid-phase parallel synthesis. The loading of the substrates on a solid support and cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process under mild conditions, respectively. Thioesters with a hydroxy group on the central core exhibited liquid crystalline properties with the widest transition temperatures in the library.     

Addition of difluoromethyl radicals to glycals: a new route to alpha-CF2-D-glycosides

The synthesis of synthetically useful alpha-CF2-glycosides by radical addition of ethyl bromodifluoroacetate onto 2-benzyloxyglycals is described. The methodology provides an access to alpha-O-glycoside mimics and, potentially, to valuable alpha-O-glycoconjugate analogues.     

Directed evolution of new glycosynthases from Agrobacterium beta-glucosidase: a general screen to detect enzymes for oligosaccharide synthesis

BACKGROUND: Oligosaccharide synthesis is becoming increasingly important to industry as diverse therapeutic roles for these molecules are discovered. The chemical synthesis of oligosaccharides on an industrial scale is often prohibitively complex and costly. An alternative, that of enzymatic synthesis, is limited by the difficulty of obtaining an appropriate enzyme. A general screen for enzymes that catalyze the synthesis of the glycosidic bond would enable the identification and engineering of new or improved enzymes. RESULTS: Glycosynthases are nucleophile mutants of retaining glycosidases that efficiently catalyze the synthesis of the glycosidic linkage by condensing an activated glycosyl fluoride donor with a suitable acceptor sugar. A novel agar plate-based coupled-enzyme screen was developed (using a two-plasmid system) and used to select an improved glycosynthase from a library of mutants. CONCLUSIONS: Plate-based coupled-enzyme screens of this type are extremely valuable for identification of functional synthetic enzymes and can be applied to the evolution of a range of glycosyl transferases.     

The Synthesis of Warfarin Using a Reconfigurable-Reactor Platform Integrated to a Multiple-Variable Optimization Tool

Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug-flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart-cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high-level of confidence in analytical measurements, which are obtained without operator intervention.     

A practical route to enantiopure 3-hydroxy-pyrrolidines: application to a straightforward synthesis of (−)-bulgecinine

A practical synthesis of enantiopure substituted 3-hydroxy-pyrrolidines is reported. In four steps, starting from commercially available amino acids as chiral educts, this method allows for an efficient preparation of a variety of 3-hydroxy-pyrrolidines, as well as 3-hydroxy-piperidines and azepanes. Application of this methodology for a straightforward asymmetric synthesis of (−)-bulgecinine is also described.     

Ambident effect of a p-sulfinyl group for the introduction of two carbon substituents to phenol rings: a convergent synthesis of diverse benzofuran neolignans

A convergent synthesis of diversely substituted benzofuran neolignans (8) is described employing a single p-sulfinyl group on the phenols (3) as an ambident functional group for two types of carbon-carbon bond-forming reactions: (i) the direct synthesis of the dihydrobenzofuran skeletons through an aromatic Pummerer-type reaction and (ii) the ipso-substitution of the sulfur functional group by carbon substituents through a ligand exchange reaction.     

Synthesis of a trimeric gp120 epitope mimic conjugated to a T-helper peptide to improve antigenicity

A fully synthetic trivalent mimotope of gp120 conjugated to pan allelic HLA DR binding epitope was prepared using solid-phase peptide synthesis and optimized copper-catalyzed azide-alkyne cycloaddition. The methodology efficiently provides chemically uniform heteromultimeric peptide constructs with enhanced binding, avidity, and specificity toward an established HIV-neutralizing human antibody, MAb b12. The versatile synthetic strategy serves as a powerful platform for the development of synthetic peptides as potential HIV-1 vaccine candidates.     

De novo synthesis of a D-galacturonic acid thioglycoside as key to the total synthesis of a glycosphingolipid from Sphingomonas yanoikuyae

A concise synthesis of a differentially protected D-galacturonic acid (D-GalA) thioglycoside and the construction of a potent immunomodulating glycosphingolipid are described. The key steps of the synthesis are an Evans aldol reaction between a C4 aldehyde and a PMB-protected glycolyloxazolidinone as well as a tandem-PMB-deprotection/cyclization to thioglycosides. The key glycosylation step is optimized by varying the anomeric leaving group, the activating agent, and the solvent system.     

Transannular rearrangement of activated 2,5-diketopiperazines: a key route to original scaffolds

An efficient and original stereocontrolled transannular rearrangement starting from activated 2,5-diketopiperazines has been developed, an opportunity for the medicinal chemistry field, which requests access to novel biological scaffolds. This powerful ring contraction, which can be related to a stereoselective aza-version of the Chan rearrangement, allows for example the one-step synthesis of various tetramic acids, access to 2-disubstituted statins, or the synthesis of relevant lactam-constrained dipeptide mimetics using a TRAL-RCM sequence.