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Showing papers on "Total synthesis published in 2003"


Journal ArticleDOI
TL;DR: Alkylations with Phenols, Nitrogen Nucleophiles in AAA Total Synthesis, and Considerations for Enantioselective Allylic Alkylation are presented.
Abstract: A. Primary Alcohols as Nucleophiles 2931 B. Carboxylates as Nucleophiles 2931 C. Alkylations with Phenols 2932 IV. Nitrogen Nucleophiles in AAA Total Synthesis 2935 A. Alkylamines as Nucleophiles 2935 B. Azides as a Nucleophile 2936 C. Sulfonamide Nucleophiles 2937 D. Imide Nucleophiles 2938 E. Heterocyclic Amine Nucleophiles 2940 V. Sulfur Nucleophiles 2941 VI. Summary and Conclusions 2941 VII. Acknowledgment 2941 VIII. References 2942 I. Considerations for Enantioselective Allylic Alkylation

2,230 citations



Journal ArticleDOI
TL;DR: The first enantioselective organocatalytic Mukaiyama-Michael reaction using alpha,beta-unsaturated aldehydes has been accomplished and the use of iminium catalysis has provided a new strategy for the enantiOSElective addition of 2-silyloxy furans to unsaturated aaldehydes to generate a variety of butenolide systems.
Abstract: The first enantioselective organocatalytic Mukaiyama−Michael reaction using α,β-unsaturated aldehydes has been accomplished. The use of iminium catalysis has provided a new strategy for the enantioselective addition of 2-silyloxy furans to unsaturated aldehydes to generate a variety of butenolide systems, an important chiral synthon found among many natural isolates. The (2S,5S)-5-benzyl-2-tert-butyl-imidazolidinone amine catalyst has been found to mediate the conjugate addition of a wide variety of substituted and unsubstituted silyloxy furans to unsaturated aldehydes. A diverse range of aldehyde substrates can be accommodated in this new organocatalytic transformation. Application of this new asymmetric technology to the enantioselective total synthesis of spiculisporic acid and the corresponding 5-epi-spiculisporic acid analogue is also discussed.

349 citations


Journal ArticleDOI
TL;DR: In this article, an asymmetric synthesis of (−)-tetrodotoxin is described, which employs a number of unique transformations, foremost of which are two stereospecific C−H bond functionalization reactions.
Abstract: An asymmetric synthesis of the fugu fish poison, (−)-tetrodotoxin, is described. The route to this extraordinary target employs a number of unique transformations, foremost of which are two stereospecific C−H bond functionalization reactions. Accordingly, Rh-catalyzed carbene and nitrene C−H insertions facilitate rapid entry to the cyclohexane core of the natural product and make possible the late-stage installation of the tetrasubstituted carbinolamine center.

305 citations




Journal ArticleDOI
TL;DR: The stereocontrolled total synthesis of (-)-ephedradine A has been accomplished and features an asymmetric C-H insertion reaction, an intramolecular ester-amide exchange reaction, and a Sharpless asymmetric aminohydroxylation reaction.
Abstract: The stereocontrolled total synthesis of (−)-ephedradine A has been accomplished. The synthesis features an asymmetric C−H insertion reaction, an intramolecular ester−amide exchange reaction, and a Sharpless asymmetric aminohydroxylation reaction. Construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction.

163 citations



Journal ArticleDOI
TL;DR: This work has achieved the first asymmetric total synthesis from 2-acetoxy-tri-O-acetyl-d-glucal as a chiral starting material and selected the protective groups to accomplish the total synthesis of tetrodotoxin in an enantiomerically pure form.
Abstract: Tetrodotoxin, a toxic principle of puffer fish poisoning, is one of the most famous marine natural products because of the complex structure having many functional groups and its potent biological activity leading to death. Since the structure elucidation in 1964, this toxin has been recognized as a formidable target molecule for total synthesis. We have recently achieved the first asymmetric total synthesis from 2-acetoxy-tri-O-acetyl-d-glucal as a chiral starting material. The highly hydroxylated cyclohexane ring was constructed by Claisen rearrangement and regioselective hydroxylations of an acetone moiety and an intramolecular directed aldol condensation of the precursor having methyl ketone with dihydroxyacetone, which was synthesized through Sonogashira coupling. Installation of nitrogen functionality was unsuccessful through an attempted Overman rearrangement. We, therefore, employed a new intramolecular conjugate addition strategy between the carbamate and unsaturated ester groups. The alpha-hydroxyl lactone moiety was synthesized through an intramolecular epoxide opening by the Z-enolate of aldehyde, which was followed by oxidation-reduction of the resulting cyclic vinyl ether. The lactone was then converted to a protected ortho ester, and then gunanidinylation was followed by cleavage of the 1,2-glycol to give the fully protected tetrodotoxin. Selection of the protective groups has finally led us to accomplish the total synthesis of tetrodotoxin in an enantiomerically pure form. All the stereogenic centers were controlled with high selectivity, and the hydroxyl groups were differently protected to discriminate for the future analogue synthesis of a bioorganic program. The synthetic tetrodotoxin was purified by ion exchange chromatography and characterized to be identical with the natural compound.

158 citations


Journal ArticleDOI
TL;DR: This method was exemplified by the first highly efficient total synthesis of natural product (-)-hinesol, which is an active ingredient of cerebral circulation and metabolism improvers.
Abstract: In one step, the skeleton of cis-spirovetivanes was constructed with high stereoselectivity by the phosphine-catalyzed [3+2] cycloaddition reaction of tert-butyl 2,3-butadienoate or 2-butynoate with 3-methyl-2-methylenecyclohexanone (5). This method was exemplified by the first highly efficient total synthesis of natural product (-)-hinesol, which is an active ingredient of cerebral circulation and metabolism improvers.

155 citations


Journal ArticleDOI
TL;DR: The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramines N, has been accomplished via intermediates 2-7, as outlined.
Abstract: The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).

Journal ArticleDOI
TL;DR: A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported, performed in the presence of four unprotected phenols, two of which reside on dichlorophenylglycines.
Abstract: A convergent diastereo- and enantioselective total synthesis of anti-HIV agent chloropeptin I is reported. Important features of the total synthesis include: (1) the use of Ti-catalyzed cyanide addition to imines to prepare a requisite amino acid moiety, (2) the discovery of the positive effect of MeOH in the Cu-mediated biaryl ether formation to afford one of the two macrocyclic peptide moieties, and (3) the discovery of the positive influence of collidine in the diastereoselective Pd-mediated cross-coupling to result in efficient formation of another macrocycle within this medicinally important molecule. This key step is performed in the presence of four unprotected phenols, two of which reside on dichlorophenylglycines.

Journal ArticleDOI
TL;DR: An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described, and the targeted clinical candidate was obtained in 55% overall yield over the longest linear sequence.
Abstract: An efficient stereoselective synthesis of the orally active NK1 receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired α-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.


Journal ArticleDOI
TL;DR: The enantioselective version of palladium-catalyzed allylic substitution, sometimes referred to as AAA (asymmetric allylic alkylation), has emerged as a powerful synthetic tool and has recently proven to be of particular value as they react with cyclic substrates of type 1 and 2.
Abstract: The enantioselective version of palladium-catalyzed allylic substitution, sometimes referred to as AAA (asymmetric allylic alkylation), has emerged as a powerful synthetic tool.[1] Since the first report of a stoichiometric AAA reaction in the 1970s,[2] it took almost 20 years of research until effective catalytic systems based on chiral ligands were developed. The major challenge in conducting such reactions enantioselectively arises from the fact that both the departure of the allylic leaving group, resulting in the formation of a cationic p-allyl–Pd complex and, in most cases, the attack of the nucleophile occur on the p face of the substrate opposite to the metal. Asymmetric induction therefore proceeds remote to the employed chiral ligands. However, some particularly successful concepts to address this issue have been devised, and over 100 catalysts have been developed.[3] Besides high levels of asymmetric induction, advantages of the AAA methodology are a broad tolerance towards functional groups and, in contrast to many other catalytic asymmetric methods, a great flexibility in the bond type to be formed. For instance, H, O, N, S, P, and C nucleophiles can be employed. Among the many new opportunities thus arising for the synthetic chemist,[4] AAA reactions of cyclic substrates of type 1 and 2 have recently proven to be of particular value as they


Journal ArticleDOI
TL;DR: The highly strained ingenane skeleton was constructed through an intramolecular cyclization reaction of an acetylene dicobalt complex followed by a rearrangement Reaction of an epoxy alcohol.
Abstract: Total synthesis of ingenol, a diterpene isolated from the genus Euphorbia, was accomplished on the basis of the novel key reactions. The highly strained ingenane skeleton was constructed through an intramolecular cyclization reaction of an acetylene dicobalt complex followed by a rearrangement reaction of an epoxy alcohol. The C(3),C(4),C(5)-triol moiety was introduced by a stereoselective double dihydroxylation reaction of a diene having C(2)−C(3) and C(4)−C(5) double bonds.

Journal ArticleDOI
TL;DR: Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues and has been shown to be important for V-ATPase inhibitory activity.
Abstract: The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a β-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.

Journal ArticleDOI
TL;DR: An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers which establishes the biosynthetic relationship between these two natural products.
Abstract: An asymmetric synthesis of the quinone epoxide dimer (+)-torreyanic acid (48) has been accomplished employing [4 + 2] dimerization of diastereomeric 2H-pyran monomers. Synthesis of the related monomeric natural product (+)-ambuic acid (2) has also been achieved which establishes the biosynthetic relationship between these two natural products. A tartrate-mediated nucleophilic epoxidation involving hydroxyl group direction facilitated the asymmetric synthesis of a key chiral quinone monoepoxide intermediate. Thermolysis experiments have also been conducted on a model dimer based on the torreyanic acid core structure and facile retro Diels-Alder reaction processes and equilibration of diastereomeric 2H-pyrans have been observed. Theoretical calculations of Diels-Alder transition states have been performed to evaluate alternative transition states for Diels-Alder dimerization of 2H-pyran quinone epoxide monomers and provide insight into the stereocontrol elements for these reactions.

Journal ArticleDOI
TL;DR: It is shown that the inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.
Abstract: A concise, flexible, and high yielding entry into the family of amphidinolide T macrolides, a series of cytotoxic natural products of marine origin, has been developed. All individual members, except amphidinolide T3 (3), derive from compound 39 as a common synthetic intermediate which is formed from three building blocks of similar size and complexity. The fragment coupling steps involve a highly diastereoselective SnCl(4) mediated reaction of the furanosyl sulfone derivative 11 with the silyl enol ether 18 and a palladium-catalyzed Negishi type coupling reaction between the polyfunctional organozinc reagent derived from iodide 32a and the enantiopure acid chloride 24b. The 19-membered macrocyclic ring is then formed by a high yielding ring closing metathesis (RCM) reaction of diene 33 catalyzed by the "second generation" ruthenium carbene complex 34. The efficiency of the RCM transformation stems, to a large extent, from the conformational bias introduced by the syn-syn-configured stereotriad at C12-C14 of the substrate which constitutes a key design element of the synthesis plan. The use of Nysted's reagent 38 in combination with TiCl(4) was required for the olefination of the sterically hindered ketone group in 36, whereas more conventional alkene formations were unsuccessful for this elaboration. Finally, it is shown that the inversion of a single and seemingly remote stereocenter (C12) in one of the building blocks not only affects the efficiency and stereochemical outcome of the RCM step but also exerts a significant influence on the course of the acyl-Negishi reaction, allowing a radical manifold to compete with productive cross coupling.

Journal ArticleDOI
TL;DR: 8-desbromohinckdentine A is synthesized from a 2-aryl indole by first preparing the quaternary center of the natural product and then building the seven-membered lactam and dihydropyrimidine rings onto this intermediate to form the framework of hinckerdentines A.
Abstract: Hinckdentine A is an alkaloid isolated from the bryozoan Hincksinoflustra denticulate. This natural product contains a novel and unique 11b,12,13,14,15,16-hexahydroazepino[4‘,5‘:2,3]indolo[1,2-c]quinazoline ring system that has not previously been synthesized. We have synthesized 8-desbromohinckdentine A from a 2-aryl indole by first preparing the quaternary center of the natural product and then building the seven-membered lactam and dihydropyrimidine rings onto this intermediate to form the framework of hinckdentine A.

Journal ArticleDOI
TL;DR: The evolution of a strategy culminating in an efficient, enantioselective synthesis of the potent microtubule-stabilizing agent FR182877 is described, which creates a complex pentacycle from a 19-membered macrocyclic pentaene, forming seven new stereogenic centers in a fully diastereocontrolled fashion.
Abstract: The evolution of a strategy culminating in an efficient, enantioselective synthesis of the potent microtubule-stabilizing agent FR182877 is described. Guided by a proposed biogenesis of this complex natural product, a solution emerged that involved the first reported example of a double transannular Diels-Alder reaction to fashion the key elements of its hexacyclic structure. This pivotal transformation creates a complex pentacycle from a 19-membered macrocyclic pentaene, forming seven new stereogenic centers in a fully diastereocontrolled fashion. The efficiency of the approach ultimately enabled the preparation of multigram quantities of the direct precursor of FR182877 for conversion to the relatively unstable natural product when required. The reactivity of the strained, bridgehead olefin of this secondary metabolite with biologically relevant nucleophiles is also described.


Journal ArticleDOI
TL;DR: A modular approach to the total synthesis of fURAquinocins culminated in the total syntheses of furaquinocin A, B, and E.
Abstract: A modular approach to the total synthesis of furaquinocins culminated in the total syntheses of furaquinocin A, B, and E. A Pd-catalyzed dynamic kinetic asymmetric transformation (DYKAT) on carbonates derived from Baylis-Hillman adducts, followed by a reductive Heck cyclization allows the enantio- and diastereoselective construction of dihydrobenzofuran 32. Introduction of a double unsatured side chain via Horner-Wadsworth-Emmons reaction and assembly of the naphthoquinone with squaric acid based methodology leads to furaquinocin E. The use of differentially substituted squaric acid derivatives allows the synthesis of three analogues of furaquinocin E. The additional stereocenters in furaquinocin A and B can be introduced with a diastereoselective Sakurai allylation. The stereoselective elongation of the side chain is possible using cross metathesis or ring closing metathesis. The obtained late-stage intermediates were successfully transformed to furaquinocin A and B.

Journal ArticleDOI
TL;DR: A total synthesis of (+)-phomactin A is described using a B-alkyl Suzuki macrocyclization to incorporate the isolated trisubstituted olefin.
Abstract: A total synthesis of (+)-phomactin A is described using a B-alkyl Suzuki macrocyclization to incorporate the isolated trisubstituted olefin. This macrocyclization was accomplished with the sensitive hydrated furan ring in place. (R)-(+)-pulegone was used to establish the highly substituted cyclohexene core of the molecule.

Journal ArticleDOI
TL;DR: This first successful implementation of a cascade epoxy alcohol cyclization for the synthesis of marine polycyclic ether toxins proceeds in 39 steps and 4% overall yield.
Abstract: A convergent biomimetic synthesis of hemibrevetoxin B from d-glucal and d-arabinose utilizes an electrophile-promoted cascade anti-Baldwin cyclization of an epoxy alcohol. The epoxy alcohol arises from a palladium-catalyzed coupling of a highly functionalized organozinc compound and an alkenyl iodide, which serve as two chiral building blocks of similar size and complexity. This first successful implementation of a cascade epoxy alcohol cyclization for the synthesis of marine polycyclic ether toxins proceeds in 39 steps and 4% overall yield.

Journal ArticleDOI
TL;DR: The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative.
Abstract: (-)-Nakadomarin A is a member of manzamine alkaloid isolated from a marine sponge and have a unique hexacyclic structure. The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative. The synthesis established the structure of nakadomarin A including absolute configuration.

Journal ArticleDOI
TL;DR: The synthesis of deoxylaulimalide demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity.
Abstract: Three different routes are described for the synthesis of deoxylaulimalide (3), which is the immediate precursor of the marine sponge metabolite laulimalide (1). These routes mainly differ with respect to their ring closing step. Thus, route 1 uses a Still-Gennari olefination, route 2 a Yamaguchi lactonization, and route 3 an intramolecular allylsilane-aldehyde addition for establishing the macrocyclic structure. The unprotected deoxy derivative 3 was subjected to Sharpless' asymmetric epoxidation (SAE). With (R,R)-tartrate the 16,17-epoxide laulimalide (1) is formed selectively, whereas (S,S)-tartrate generates the 21,22-epoxide 142. This demonstrates the high reagent control involved in the SAE process, which in this case is used to achieve high stereo- and regioselectivity. Laulimalide and some derivatives thereof have been tested with respect to antitumor activity and compared to standard compounds paclitaxel and epothilone B.

Journal ArticleDOI
TL;DR: Dramatic solvent effects observed in the macrolactonization reaction suggest that hydrogen-bonding effects play a critical role in the biologically active marine natural product leucascandrolide A.
Abstract: The total synthesis of the biologically active marine natural product leucascandrolide A is reported. A convergent strategy is employed, allowing for the rapid assembly of the macrolide moiety. Key steps of our approach include the diastereoselective addition of a zinc alkynilide to (R)-isopropylidene glyceraldehyde, the enantioselective copper(I) fluoride catalyzed aldol addition of a TMS-dienolate to crotonaldehyde, and the formation of a 2,6-trans-substituted tetrahydropyran by selenium-mediated intramolecular cyclization. Moreover, dramatic solvent effects observed in the macrolactonization reaction suggest that hydrogen-bonding effects play a critical role. An improved route to a key intermediate of our synthesis is documented.

Journal ArticleDOI
TL;DR: The development of a new method for the enantioselective synthesis of disubstituted gamma-butyrolactones and the formal total synthesis of (-)-methylenolactocin and (-)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties.
Abstract: The development of a new method for the enantioselective synthesis of disubstituted γ-butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (−)-roccellaric acid, (−)-nephrosteranic acid and (−)-protopraesorediosic acid, and the formal total synthesis of (−)-methylenolactocin and (−)-protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)-catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)-catalyzed, intermolecular cross metathesis reactions.