Showing papers on "Total synthesis published in 2001"

Stereoselective total synthesis of axially chiral natural products via biaryl lactones.

Abstract: Axially chiral natural products are rewarding synthetic targets, due to their wide distribution, diverse structures, and promising bioactivities The “lactone concept” provides an efficient strategy for the regio- and stereoselective construction of even bulky biaryls Key steps are the intramolecular coupling of the ester-prefixed molecular portions to give (mostly configurationally unstable) biaryl lactones and their stereoselective ring cleavage (usually by dynamic kinetic resolution), leading to the one oroptionallythe other atropisomeric product from the same lactone Stereoisomeric byproducts can be recycled by recyclization back to the lactone The broad applicability of the method is demonstrated in the total synthesis of selected representatives from five very different classes of natural biaryl products

Alkyne metathesis: development of a novel molybdenum-based catalyst system and its application to the total synthesis of epothilone A and C.

Abstract: Sterically hindered molybdenum(III) amido complexes of the general type [Mo{(tBu)(Ar)N} 3 ] (1), upon treatment with CH 2 Cl 2 or other halogen donors, have been converted into highly effective catalysts for all kinds of alkyne metathesis reactions. Although the actual nature of the propagating species formed in situ is still elusive, halogen transfer to the Mo center of 1 plays a decisive role in the activation of such precatalysts. It was possible to isolate and characterize by X-ray crystallography some of the resulting molybdenum halide derivatives such as 15, 16 and 20 which themselves were shown to be catalytically active. Numerous applications illustrate the performance of the catalytic system 1/CH 2 Cl 2 which operates under mild conditions and tolerates an array of polar functional groups. The wide scope allows the method to be implemented into the total synthesis of sensitive and polyfunctional natural products. Most notable among them is a concise entry into the potent anticancer agents epothilone A (86) and C (88). The macrolide core of these targets is forged by ring closing alkyne metathesis (RCAM) of diyne 113, followed by Lindlar hydrogenation of cycloalkyne 114 thus formed. Since this strategy opens a stereoselective entry into (Z)-alkene 115, the approach is inherently more efficient than previous syntheses based on conventional RCM.

Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

Abstract: A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis−Ferrier rearrangements for assembly of both the C(11−15) and C(22−26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.

Murrastifoline-F: first total synthesis, atropo-enantiomer resolution, and stereoanalysis of an axially chiral N,C-coupled biaryl alkaloid.

Abstract: The first total synthesis of the Murraya alkaloid murrastifoline-F (3), an unsymmetric, N,C-bonded heterobiarylic biscarbazole, is described. Starting from the likewise naturally occurring-but here synthetically prepared-"monomer" murrayafoline-A (6), lead tetraacetate-mediated oxidative non-phenolic biaryl coupling gives 3 as the main regioisomer. The existence of this natural product as a pair of stable atropo-enantiomers was demonstrated analytically through LC-CD investigations. Preparatively, the racemate resolution succeeded by O-demethylation, derivatization with Mosher's reagent, and chromatographic separation of the resulting diastereomers. The absolute configurations of the atropisomers were assigned by CD spectroscopy in combination with quantum chemical CD calculations at the stage of the alkaloid 3 and by ROESY experiments of the diastereomeric Mosher derivatives. In the root extract of the curry leaf plant Murraya koenigii (Rutaceae), murrastifoline-F (3) was found to exist as a 56:44 mixture in favor of the M-enantiomer, by LC-CD coupling.

The First Stereoselective Total Synthesis of Quinine

Abstract: The first entirely stereoselective total synthesis of (-)-quinine is reported.

Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction.

Abstract: A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schollkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schollkopf chiral auxiliary was chosen here for the preparation of l-tryptophans would be available from d-valine while the d-isomers required for natural product total synthesis would originate from the inexpensive l-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of l-isotryptophan 38 and l-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-d-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet−Spengler ...

The Type 2 Intramolecular Diels–Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes

Abstract: Anti-Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities The type 2 intramolecular Diels-Alder (IMDA) reaction provides a one-step entry into this fascinating class of molecules The reaction has made available numerous anti-Bredt alkenes for structural and chemical studies X-ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions More recently, the type 2 intramolecular Diels-Alder reaction and the resulting anti-Bredt alkenes have found application in organic synthesis The constraints resulting from the connectivity in the Diels-Alder precursor creates a strong regio- and stereochemical bias in the cycloaddition step The end result of this bias is the stereoselective synthesis of highly substituted six-membered rings The reaction also achieves a facile synthesis of seven- and eight-membered rings in a single step from acyclic precursors The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products

Total Synthesis of (−)‐Salicylihalamide

Abstract: A concise total synthesis of the potent cytotoxic marine natural products salicylihalamide A and B (la, b) is reported. Key steps of our approach were the asymmetric hydrogenation reactions of β-keto esters 18 and 32 catalyzed by [((S)-BINAP)Ru-Cl 2 ] 2 .NEt 3 and the cyclization of the macrolide core by ring closing olefin metathesis (RCM) using the "second-generation" ruthenium carbene complex 24 as the catalyst which bears an imidazol-2-ylidene ligand. The E/Z ratio obtained in this macrocyclization reaction was determined by the protecting groups at the remote phenolic OH group of the cyclization precursor. The elaboration of the resulting cycloalkene 37 into the final target involved a CrCl 2 -mediated synthesis of vinyliodide 49 which, after deprotection, did undergo a copper-catalyzed cross-coupling process with the (Z,Z)-configurated carboxamide 42 to form the labile enamide moiety of 1. Compound 42 was derived from a palladium-catalyzed Negishi coupling between butynylzinc chloride and 3-iodoacrylate 39 followed by a Lindlar reduction of enyne 40 thus obtained and a final aminolysis of the ester group.

Asymmetric Total Synthesis of ent-(−)-Roseophilin: Assignment of Absolute Configuration

Abstract: An asymmetric total synthesis of ent-(-)-roseophilin (1), the unnatural enantiomer of a novel naturally occurring antitumor antibiotic, is described. The approach enlists a room temperature heterocyclic azadiene inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (7) with the optically active enol ether 6 bearing the C23 chiral center followed by a reductive ring contraction reaction for formation of an appropriately functionalized pyrrole ring in a key 1,2,4,5-tetrazine --> 1,2-diazine --> pyrrole reaction sequence. A Grubbs' ring closing metathesis reaction was utilized to close the unusual 13-membered macrocycle prior to a subsequent 5-exo-trig acyl radical-alkene cyclization that was used to introduce the fused cyclopentanone and complete the preparation of the tricylic ansa-bridged azafulvene core 32. Condensation of 32 with 33 under the modified conditions of Tius and Harrington followed by final deprotection provided (22S,23S)-1. Comparison of synthetic (22S,23S)-1 ([alpha](25)(D), CD) with natural 1 established that they were enantiomers and enabled the assignment of the absolute stereochemistry of the natural product as 22R,23R. Surprisingly, ent-(-)-1 was found to be 2-10-fold more potent than natural (+)-1 in cytotoxic assays, providing an unusually rewarding culmination to synthetic efforts that provided the unnatural enantiomer.

Total synthesis of cytochrome b562 by native chemical ligation using a removable auxiliary

Abstract: We have completed the total chemical synthesis of cytochrome b562 and an axial ligand analogue, [SeMet7]cyt b562, by thioester-mediated chemical ligation of unprotected peptide segments. A novel auxiliary-mediated native chemical ligation that enables peptide ligation to be applied to protein sequences lacking cysteine was used. A cleavable thiol-containing auxiliary group, 1-phenyl-2-mercaptoethyl, was added to the α-amino group of one peptide segment to facilitate amide bond-forming ligation. The amine-linked 1-phenyl-2-mercaptoethyl auxiliary was stable to anhydrous hydrogen fluoride used to cleave and deprotect peptides after solid-phase peptide synthesis. Following native chemical ligation with a thioester-containing segment, the auxiliary group was cleanly removed from the newly formed amide bond by treatment with anhydrous hydrogen fluoride, yielding a full-length unmodified polypeptide product. The resulting polypeptide was reconstituted with heme and folded to form the functional protein molecule. Synthetic wild-type cyt b562 exhibited spectroscopic and electrochemical properties identical to the recombinant protein, whereas the engineered [SeMet7]cyt b562 analogue protein was spectroscopically and functionally distinct, with a reduction potential shifted by ≈45 mV. The use of the 1-phenyl-2-mercaptoethyl removable auxiliary reported here will greatly expand the applicability of total protein synthesis by native chemical ligation of unprotected peptide segments.

Total synthesis of tricyclic azaspirane derivatives of tyrosine: FR901483 and TAN1251C.

Abstract: A solution to the long-standing problem presented by the oxidative cyclization of a phenolic 3-arylpropionamide to a spirolactam has been developed in this laboratory via oxazoline chemistry. This research was motivated by our interest in some novel tricyclic azaspirane natural products formally derived from tyrosine, such as FR901483 and TAN1251C. In this paper, we disclose full details of the total synthesis of these substances.

FR901464: Total Synthesis, Proof of Structure, and Evaluation of Synthetic Analogues

Abstract: The natural product FR901464 (1) was isolated by the Fujisawa Pharmaceutical Co. and shown to have intriguing biological properties including impressive antitumor activity. In this paper we describe the first total synthesis of 1 in full detail. A chiral building block synthetic strategy was used to assemble the target: optically active components were generated using asymmetric catalytic reactions, and these fragments were coupled together at a late stage in a convergent synthesis. In particular, a versatile, asymmetric hetero-Diels-Alder (HDA) reaction was developed in the context of this synthesis and used with great effectiveness for the preparation of the two densely functionalized pyran rings. The flexible nature of the synthetic route also allowed us to prepare a series of analogues of 1. These compounds were used to prove the relative stereochemistry of the natural product as well as to probe the importance of certain structural features of FR901464 with regard to biological activity.

First and second generation total synthesis of the teicoplanin aglycon.

Abstract: Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key in...

Synthesis and absolute stereochemistry of roseophilin.

Abstract: The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of the natural product as 22R,23R. Cyclopentenone (+)-12 was prepared in 78% yield and 86% ee in the key step.

Enantioselective total synthesis of a potent antitumor antibiotic, fredericamycin A.

Abstract: The asymmetric total synthesis of both enantiomers of the potent antitumor antibiotic fredericamycin A (1) is detailed based on the protocol for the construction of its peri-hydroxy polyaromatic skeleton bearing the chirality at the spiro carbon via a strong base-induced cycloaddition of suitably substituted homophthalic anhydrides (AB-ring unit) with an optically active CDEF-ring unit. Particular attention has been given to the novel synthesis of the optically active spiro carbon center by a stereospecific rearrangement of optically active benzofuzed-trans-epoxy acylates leading to spirocyclopentane-1,1‘-indane systems. This method is quite useful for the construction of an optically active spiro compound and was applied to the synthesis of the optically pure CDEF-ring unit of 1. Cycloaddition of the optically pure CDEF-ring unit to AB-ring units prepared via benzyne afforded two natural and unnatural-type hexacyclic compounds, which were converted to natural and unnatural enantiomers of synthetic 1, and...

Total synthesis of microtubule-stabilizing agent (-)-laulimalide.

Abstract: An enantioselective first total synthesis of laulimalide (1) is described. Laulimalide, a remarkably potent antitumor macrolide, has been isolated from the Indonesian sponge Hyattella sp. and the Okinawan sponge Fasciospongia rimosa. Laulimalide represents a new class of antitumor agents with significant clinical potential. The synthesis is convergent and involved the assembly of C3−C16 segment 4 and C17−C28 segment 5 by Julia olefination. The sensitive C2−C3 cis-olefin functionality was installed by Yamaguchi macrolactonization of a hydroxy alkynic acid followed by hydrogenation of the resulting alkynoic lactone over Lindlar's catalyst. Initial attempts of intramolecular Still's variant of Horner−Emmons olefination between the C19-phosphonocetate and C3-aldehyde provided a 1:2 mixture of cis- and trans-macrolactones. The trans-isomer was photoisomerized to a mixture of cis- and trans-isomers. The other key steps involved ring-closing olefin metathesis to construct both dihydropyran units, stereoselective...

Total synthesis and determination of the absolute configuration of frondosin B.

Abstract: Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.

Synthesis of Medium-Sized Ring Lactams

Abstract: Medium-sized ring lactams (7- to 15-membered) find widespread use in organic chemistry as key intermediates in the synthesis of more complex structures or as core structures in natural product or pharmaceutically important compounds. Until now, the generation of such rings is still a challenge in organic synthesis. During the past decade an increasing interest has focused on the generation of cyclic peptides as well as hairpin and β-turn mimics and the medium-sized rings were thought to represent suitable fragments. Furthermore, a range of complex natural products is characterized by such lactam structure and their total synthesis is a broad field for organic chemists to test new strategies and to develop new methods.

Total synthesis and biological evaluation of the nakijiquinones.

Abstract: The Her-2/Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. The nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of the nakijiquinones may display inhibitory properties toward other receptor tyrosine kinases involved in cell signaling and proliferation. Here, we describe the first enantioselective synthesis of the nakijiquinones. Key elements of the synthesis are (i) the reductive alkylation of a Wieland−Miescher-type enone with a tetramethoxyaryl bromide, (ii) the oxidative conversion of the aryl ring into a p-quinoid system, (iii) the regioselective saponification of one of the two vinylogous esters incorporated therein, and (iv) the selective introduction of different amino acids via nucleophilic conversion of the remaining vinylogous ester into the corresponding vinylogous amide. The correct stereochemistry and substitution patterns are completed by conversion of two keto gr...

Total Synthesis of Colombiasin A.

Abstract: Colombian corals of the species Pseudopterogorgia elisabethae produce the title compound, colombiasin A (1). This structurally novel, biologically active tetracyclic compound has now been synthesized for the first time in racemic form. Preliminary studies toward the asymmetric total synthesis of both enantiomers indicate that the determination of the absolute stereochemistry can be expected soon.

Discovery through total synthesis: a retrospective on the himastatin problem.

Abstract: A total synthesis of a structure proposed for himastatin was accomplished. The non-identity of the fully synthetic material with himastatin necessitated a revision of the assigned structure. Confirmation of the revised stereostructure was subsequently confirmed through total synthesis. Among the achievements during this effort were i) stereospecific routes to both anti-cis and syn-cis pyrrolindoline substructures; ii) a practical synthesis to 5-hydroxypiperazic acid in enantiomerically pure form; iii) a Stille coupling leading to a complex bi-indole moiety, and iv) efficient protecting group management throughout the evolving depsipeptide domain. The outlines for a biological pharmacophore have been delineated. The alternating D- and L-substituents in the 6-mer as well as the biaryl linkage connecting the two identical subunits are critical for maintaining biological activity. This pattern is simulated in another antibiotic, and suggests a possible structural trend for future SAR investigations.

A Novel and Highly Stereoselective Intramolecular Formal [3+3] Cycloaddition Reaction of Vinylogous Amides Tethered with α,β-Unsaturated Aldehydes: A Formal Total Synthesis of (+)-Gephyrotoxin.

Abstract: Complex piperidinyl heterocycles (for example, 2) were accessed by using a novel intramolecular formal [3+3] cycloaddition reaction of vinylogous amides tethered with enals (for example, 1). This method has been applied to a formal total synthesis of (+)-gephyrotoxin (3).