Studies on the biosynthesis of phomoidride B (CP-263,114): evidence for a decarboxylative homodimerization pathway

[reaction: see text]. Feeding experiments using a deuterium labeled C16 maleic anhydride and whole cell culture of ATCC 74256 led to the isolation of phomoidride B with deuterium incorporation at C(7) and C(19) as determined by 2H NMR and electrospray mass spectrometry. This result is in accord with a decarboxylative homodimerization of the C16 maleic anhydride as a key biosynthetic step leading to phomoidride B.     

Investigations into the production and interconversion of phomoidrides A-D

[structure: see text] Fermentation of ATCC 74256 led to the isolation and identification of C7 epimers of phomoidride A (CP-225,917) and phomoidride B (CP-263,114). We suggest the names phomoidrides C and D for these new fermentation products. Studies on the effect of pH on the distribution of phomoidrides A-D suggest phomoidride B (CP-263,114) is the first-formed secondary metabolite and the source of the remaining three phomoidrides.     

Synthetic study of phomoidride B (CP-263,114); utilization of the oxidopyrylium [5 + 2] cycloaddition

The highly functionalized core structure of phomoidride B (CP-263,114) was pursued by using intermolecular oxidopyrylium-alkene cyclization as one of the key steps.     

An approach to the synthesis of the phomoidrides

The phomoidrides are a structurally fascinating family of natural products which possess moderate inhibitory activity against Ras farnesyl transferase and squalene synthase. Since their discovery they have inspired a great deal of attention from synthetic chemists. Our own work, culminating in an efficient synthesis of the fully elaborated tetracyclic core of phomoidrides B and D, is described herein. The synthesis relies on a late stage tandem reaction involving a novel carbonylation reaction that delivers the strained bicyclic pseudoester system, which strain in turn drives a highly efficient silyloxy-Cope rearrangement that delivers the tetracyclic core of phomoidrides B and D. Several examples of this powerful tandem reaction are presented that document its tolerance of significant structural variation. The application of this methodology to the synthesis of a phomoidride D precursor lacking only the maleic anhydride is described, and the prospects for the completion of a total synthesis are discussed.     

Total synthesis of dapiramicin B

The first total synthesis of dapiramicin B, a nucleoside antibiotic, is described. The characteristic N-glycoside linkage in dapiramicin B was effectively constructed by way of the Pd-catalyzed coupling reaction of a heptopyranosylamine with a bromopyrrolopyrimidine derivative.     

Total synthesis of (+)-lysergic acid

A stereocontrolled total synthesis of (+)-lysergic acid (1) is achieved using three metal-catalyzed methodologies for the construction of three key rings. Highlights of the synthesis include Pd-catalyzed indole synthesis to form the B ring, a RCM reaction to form the D ring, and an intramolecular Heck reaction to form the C ring.     

In situ generation of vinyl allenes and its applications to one-pot assembly of cyclohexene, cyclooctadiene, 3,7-nonadienone, and bicyclo[6.4.0]dodecene derivatives with palladium-catalyzed multicomponent reactions

A novel tandem Pd-catalyzed cross-coupling and [4 + 4] cycloaddition sequence allows the rapid synthesis of eight-membered carbocycles starting from alpha-bromovinyl arenes and propargyl bromides in one reaction vessel. It is noteworthy that four components are assembled into one molecule via this procedure. In contrast to alpha-bromovinyl arenes, alpha-bromovinyl alkanes afforded tandem cross-coupling and homo [4 + 2] cycloaddition products. Subjecting an equimolar mixture of alpha-bromostyrene and 2-bromo-1-octene to propargyl bromides furnished the tandem Pd-catalyzed cross-coupling and hetero [4 + 2] cycloaddition product. Exposure of equimolar mixtures of alpha-bromovinyl arenes to allenylindium resulted in tandem a Pd-catalyzed cross-coupling and hetero [4 + 4] cycloaddition products. Synthesis of vinylallene from the reaction of vinyl triflate with allenylindium followed by Pd-catalyzed carbon monoxide insertion reaction gave the corresponding 3,7-nonadienone product via tandem Pd-catalyzed cross-coupling and [4 + 4 + 1] annulation. Tandem Pd-catalyzed cross-coupling, [4 + 4] cycloaddition, and [4 + 2] cycloaddition provided the rapid synthesis of bicyclo[6.4.0]dodecene derivatives starting from alpha-bromovinyl arenes, propargyl bromides, and dienophiles in one operation, in which five components were integrated into one molecule.     

Highly satisfactory procedures for the Pd-catalyzed cross coupling of aryl electrophiles with in situ generated alkynylzinc derivatives

[reaction: see text] Two new and very efficient procedures (Procedures A and B) are reported for the Pd-catalyzed cross coupling of aryl electrophiles with terminal alkynes via their in situ conversion into alkynylzinc derivatives. Procedure A is particularly valuable in cases where electron-deficient alkynes are used, while Procedure B is operationally simple and very satisfactory in less demanding cases.     

Syntheses of all-methylated ellagitannin, isorugosin B and rugosin B

Ellagitannins possess a wide range of biological activities and remarkable structural diversity, which commonly include an axially chiral biaryl unit. This paper describes syntheses of all-methylated versions of isorugosin B and rugosin B, which are regioisomeric, ellagitannin-related compounds. The key features of these syntheses involve the construction of an axially chiral biaryl function on a sugar moiety through a Pd-catalyzed intramolecular biaryl coupling reaction, Bringmann’s atroposelective lactone opening reaction, and a two-step ester formation. This is the first synthetic approach for generating ellagitannins featuring a valoneoyl group.     

Carbenylative amination with N-tosylhydrazones

A Pd-catalyzed reaction of vinyl iodides and N-tosylhydrazones that assembles η(3)-allyl ligands through carbene insertion is demonstrated. Intramolecular trapping with nitrogen nucleophiles generates good yields of cinnamyl and pentadienyl amines like those found in alkaloid natural products. Carbenylative amination was the key reaction to complete the synthesis of the alkaloid caulophyllumine B. Migratory insertion was biased to provide allylamines with optical purity up to 64% ee, but in a lower yield.     

Palladium-catalyzed preparation of vinylallenes from 2-bromo-1,3,5-trienes via an alkylidene-pi-allylpalladium-mediated formal SN2" pathway

[Structure: see text] A novel Pd-catalyzed reaction to prepare conjugated vinylallenes from 2-bromo-1,3,5-triene and a soft nucleophile via a formal SN2" pathway was developed. The reaction proceeds via alkylidene-pi-allylpalladium and allenyl-pi-allylpalladium intermediates, and a dynamic process involving the two palladium intermediates played important roles in determining the selectivity of the Pd-catalyzed reaction. The reaction was extended to an asymmetric counterpart, and an axially chiral vinylallene was obtained with up to 81% ee.     

Pd-catalyzed direct arylation of polyfluoroarenes on water under mild conditions using PPh3 ligand

We report a Pd-catalyzed direct arylation of polyfluoroarenes with aryl iodides. The advantages of this reaction are its high reaction efficiency, excellent functional group compatibility, mild reaction conditions (70 °C), inexpensive PPh(3) ligand, and use of pure water as reaction medium. The usefulness of this reaction has also been demonstrated by rapid preparation of highly functionalized polyfluoroarenes via iterative Pd-catalyzed C-H bond functionalization.     

Regio- and stereoselective introduction of 15β-hydroxy group and side chains to steroids by the palladium-catalyzed reaction of 1,3-diene monoepoxide

The Pd-catalyzed reaction of 1,3-diene monoepoxides with carbonucleophiles is applied to the regio- and stereoselective introduction of 15β-hydroxy group and side chains to steroid nuclei. 3β-Hydroxyandrost-5-en-17-one (15) was converted to 15,16β-epoxy-Δ¹⁷⁽²⁰⁾ isoheptylidene steroid 20 and ethylidene steroid 21. The former was subjected to the Pd-catalyzed reaction with dimethyl malonate and then converted to 15β-hydroxycholesterol (29). Similarly, 15β-hydroxyisocholesterol (32) was obtained from the ethylidene steroid 21 using the Pd-catalyzed reaction of methyl 3-oxo-5-methylhexanoate (24) as a key reaction.     

Palladium catalyzed bicyclization of 1,8-diiodonaphthalene and tertiary propargylic alcohols to phenalenones and their applications as fluorescent chemosensor for fluoride ions

Phenalenone derivatives were efficiently constructed from 1,8-diiodonaphthalene and tertiary propynols via a one-pot domino reaction which eventually included Pd-catalyzed Sonogoshira coupling, Pd-catalyzed allylic oxidation and Pd-catalyzed C(sp(2))-H activation. Moreover, the synthesized phenalenone derivative presented a practical application as a fluorescent chemosensor for fluoride anion with high sensitivity and selectivity.     

Origin of selectivity of tsuji-trost allylic alkylation of lactones: highly ordered transition States with lithium-containing enolates

We report computational investigations on the mechanism and the selectivity of Pd-catalyzed allylic alkylation of γ-valerolactone. Density functional calculations using the B3LYP functional are performed on the selectivity-determining nucleophilic addition step of this reaction. The B3LYP results of commonly assumed pathways fail to reproduce the observed selectivity of the reaction. Therefore, alternative pathways are considered for the nucleophilic addition step, to explain the experimentally established role of the additives LiCl and lithium diisopropyl amide (LDA) in the Pd-catalyzed reaction. These pathways involve different approaches of the enolate toward the η(3) -allylpalladium complex that are mainly guided by stabilizing Cl(δ-) ???Li(δ+) ???O(enolate) interactions in the transition state. In the calculations, the experimentally observed trans-product selectivity for the prototypical reaction with (S)-BINAP ligands is found only when assuming the addition of a "mixed" Li-enolate/LiCl adduct to the η(3) -allylpalladium complex. This mechanism provides a reasonable explanation for the experimental results and sheds light on the role of LiCl in the reaction. The analysis of the different transition-state models allows us to identify steric and electronic factors that stabilize or destabilize the relevant diastereomeric transition states. Calculations for different combinations of substrates (γ-valerolactone and δ-caprolactone) and catalysts (with (R)- and (S)-BINAP ligands) reproduce the experimentally observed selectivities well and thus provide further support for the proposed mechanism.     

Highly efficient and selective synthesis of conjugated triynes and higher oligoynes of biological and materials chemical interest via palladium-catalyzed alkynyl-alkenyl coupling

Iteration of a Pd-catalyzed reaction of alkynyl- and oligoynylzincs with (E)-ICH=CHCl followed by metalation-termination with electrophiles(E) has provided a linear route to conjugated tri- and tetraynes, and Pd-catalyzed monoalkynylation of 1,1-dibromoenynes accompanied by dehydrobromination has provided a convergent route to conjugated tri- , tetra- , and pentaynes. Both display unprecedented high efficiency and selectivity. [reaction: see text]     

Process research on arylnaphthalene lignan aza-analogues: a new palladium-catalyzed benzannulation of α,β-bisbenzylidenesuccinic acid derivatives

The discovery of a new Pd-catalyzed benzannulation reaction of bisbenzylidenesuccinimide during process research on arylnaphthalene lignan aza-analogues is described. An extension of the Pd-catalyzed benzannulation to the regiospecific synthesis of various arylnaphthalene lignan aza-analogues utilizing classical Stobbe condensation is included.     

Palladium-catalyzed intra-molecular olefin insertion reaction of α-alkenyl-α-acyloxytrialkylsilane. Synthesis of optically active carbocycle

Pd-catalyzed intra-molecular olefin insertion/carbonylation reaction of optically active α-alkenyl-α-acyloxysilanes is described. The reactions proceeded in a stereoselective manner to give five- and six-membered optically active carbocycles having (E)-vinylsilane in their side chains. Under CO condition, optically active carbocycles containing one-carbon homologated side chain were produced by Pd-catalyzed tandem olefin insertion-carbonylation reaction.     

A new route to methyl (R,E)-(-)-tetradeca-2,4,5-trienoate (pheromone of Acanthoscelides obtectus) utilizing a palladium-catalyzed asymmetric allene formation reaction

[reaction: see text] A formal total synthesis of the sex attractant of male dried bean beetle, methyl (R,E)-(-)-tetradeca-2,4,5-trienoate, was achieved by a new efficient route utilizing the Pd-catalyzed asymmetric allene synthesis reaction. It was found that the atropisomeric biaryl bisphosphine (R)-segphos showed better enantioselectivity than (R)-binap in the Pd-catalyzed reaction for preparing alkyl-substituted axially chiral allenes.     

Synthesis and mesomorphic behaviour of new discotic liquid crystalline compounds containing triphenylamine as a core moiety via Sonogashira coupling

Design and synthesis of cholesterol based disk-like liquid crystalline compounds using triphenylamine as a core moiety have been achieved by Pd-catalyzed cross-coupling reaction. The newly synthesized compounds exhibit a cholesteric phase with fingerprint texture as well as oily texture. In the low temperature region, there is a signature of smectic B with characteristic dendritic and mosaic textures. The mesogenic properties were characterized by polarizing microscopy, differential scanning calorimetry and HRXRD studies.