An asymmetric synthesis of hamigeran B via a Pd asymmetric allylic alkylation for enantiodiscrimination

A protocol for the asymmetric allylic alkylation of a five-membered ring ketone derivative that employs the lithium enolate in the presence of lithium alkoxides gave high yields and enantioselectivities. This product serves as a versatile intermediate as demonstrated in a convergent total synthesis of the antiviral agent hamigeran B. The sequence involves two unusual observations. In the intramolecular Heck reaction which establishes the complete ring sytem, the beta-H elimination step occurs both endocyclic (as expected) and exocyclic, the latter most surprising since it creates an exocylic tetrasubstituted double bond. In the catalytic hydrogenation, use of Pd/C gives complete selectivity for net delivery of hydrogen to the most hindered face of the substrate, whereas use of Ir black gives complete selectivity for delivery of hydrogen to the least hindered face. Such unusual behavior speaks to the unusual chemical properties associated with hamigeran B which may be relevant to its biological activity.     

Novel synthesis of CP-734432, an EP4 agonist, using Sharpless asymmetric dihydroxylation

A novel and efficient asymmetric route to CP-734432, a lactam analog of PGE2, that shows selective agonism against the EP4 receptor subtype, is reported herein. The key steps include a Heck coupling to introduce the aryl ring at C-16 and a highly diastereoselective Sharpless asymmetric dihydroxylation to set the C-15 center.     

Palladium catalyzed kinetic and dynamic kinetic asymmetric transformations of gamma-acyloxybutenolides. Enantioselective total synthesis of (+)-Aflatoxin B1 and B2a

The reaction of gamma-tert-butoxycarbonyloxy-2-butenolide with phenol nucleophiles in the presence of a Pd(0) complex with chiral ligands may be performed under conditions that favor either a kinetic resolution or a kinetic asymmetric transformation (KAT) or dynamic kinetic asymmetric transformation (DYKAT). Performing the reaction at high concentration (0.5 M) in the presence of a carbonate base favors the former, i.e., KAT; whereas, running the reaction at 0.1M in the presence of tetra-n-butylammonium chloride favors the DYKAT process. Syntheses of aflatoxin B(1) and B(2a) employs the DYKAT to introduce the stereochemistry. Starting with Pechmann condensation of the monomethyl ether of phloroglucinol, the requisite phenol nucleophile is constructed in two steps. The DYKAT proceeds with > 95% ee. A reductive Heck cyclization followed by a lanthanide catalyzed intramolecular acylation completes the synthesis of the pentacyclic nucleus in 3 steps. Reduction of the lactone provides aflatoxin B(2a) and its dehydration product B(1). This synthetic strategy creates an asymmetric synthesis of the former in only 7 steps and the latter in 9 steps. Thus, the ultimate synthetic sequence involves 3 + 5 --> 39 --> 40 --> 42 --> 43 --> 46 --> 47 --> 48 (aflatoxin B(2a)) --> 49 (aflatoxin B(1)).     

PVC-二亚乙基三胺(DETA)-Pd对Heck反应的催化性能研究

以聚氯乙烯为原料,用较简单的方法得到了聚氯乙烯二亚乙基三胺负载钯配合物(PVC-DETA-Pd).PVC-DETA-Pd具有较高的热稳定性,可以满足Heck反应所需要的高温条件.在110℃、氮气氛围,四丁基溴化铵(TBAB)做溶剂的条件下,PVC-DETA-Pd催化溴苯与苯乙烯的反应产率可以达到99%.PVC-DETA-Pd在多种缚酸剂的存在下均可有效地催化芳基溴的Heck反应,但在三丁胺中具有最好的效果.在适当的反应条件下,以PVC-DETA-Pd为催化剂,各种带取代基芳基溴、芳基氯均可以有效地与乙烯基化合物反应,反应产率>70%.PVC-DETA-Pd还具有较好的重复使用性能.     

Enantioselective Dicarbofunctionalization of Unactivated Alkenes by Palladium‐Catalyzed Tandem Heck/Suzuki Coupling Reaction

A highly enantioselective dicarbofunctionalization of unactivated alkenes was implemented by a Pd‐catalyzed asymmetric tandem Heck/Suzuki coupling reaction. This reaction represents the first example of a highly enantioselective intramolecular cyclization/cross‐coupling of olefin‐tethered aryl halides with alkyl‐, alkenyl‐ or arylboronic acids, and provides rapid access to a number of chiral compounds, such as dihydrobenzofurans, indolines, chromanes, and indanes bearing a quaternary stereocenter, in good yields with excellent enantioselectivities. The practicality of this reaction was validated in the modification of biologically complex molecules such as peptides, piperitol, CB2 receptor agonists, etc. Moreover, the synthesis of two enantiomers can be easily realized by simple change in the order of the steps in the coupling sequence.     

Cyclic sulfamidates as versatile lactam precursors. An evaluation of synthetic strategies towards (-)-aphanorphine

A full account of studies which led to the efficient asymmetric synthesis of (-)-aphanorphine is reported. Two routes to the key cyclic sulfamidate intermediate are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (, and ) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) alpha-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of . These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of in 12 steps from anisaldehyde.     

The diazo route to diazonamide A: studies on the tyrosine-derived fragment

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent Pd0-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement, O-methylation and lithiation-boration. The resulting biaryl was elaborated into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with 2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone 50, albeit with poor stereocontrol.     

无配体Pd/LDH-F催化剂在Heck和Suzuki反应中的应用

 以氟离子插层的水滑石LDH-F为载体,用逐滴浸渍法制备了新型Pd/LDH-F催化剂,并用其催化溴代芳烃的Heck和Suzuki偶联反应. 用X射线衍射表征了催化剂的晶相,以等离子体发射光谱测定了溶剂中钯的流失量. 结果表明,对于Heck反应,在无配体存在和低钯用量(Pd/溴代芳烃摩尔比为0.001)的情况下, Pd/LDH-F的催化性能优于其它载体负载的Pd催化剂,显示出很高的催化活性和选择性. 在140 ℃和12 h的条件下, Pd/LDH-F催化溴苯与苯乙烯Heck反应产物的收率可达86％, 反应后催化剂经过分离,可循环使用四次其催化活性基本不变. 在DMF/水摩尔比为0.5的混合溶剂中,在室温和3 h 的条件下, Pd/LDH-F (Pd/溴代芳烃摩尔比为0.005)催化溴苯与苯基硼酸盐的Suzuki反应中,目标产物收率为99%.     

Homeopathic ligand-free palladium as a catalyst in the heck reaction. A comparison with a palladacycle

[reaction: see text] Ligand-free Pd(OAc)(2) can be used as a catalyst in the Heck reaction of aryl bromides as long as the amount of catalyst is kept between 0.01 and 0.1 mol %. At higher concentrations palladium black forms and the reaction stops. The actual catalyst is monomeric. Palladacycles merely serve as a source of ligand-free palladium in Heck reactions of aryl bromides.     

Kinetics of the Heck reactions of styrene with bromobenzene and iodobenzene in the presence of ligandless catalytic systems: A comparative study

The comparative kinetic study of the Heck reactions of styrene with iodobenzene and bromobenzene has revealed specific features of these reactions that should necessarily be taken into account for the observed data to be interpretable in the framework of a unified mechanistic conception. It has been proved for the styrene-bromobenzene reaction that benzene forms as a by-product via a heterogeneous route and catalytically active Pd(0) undergoes aggregation via an autocatalytic mechanism. The kinetics of the styrene-iodobenzene reaction indicates that benzene in this reaction forms via a homogeneous route, biphenyl forms as another by-product by a bimolecular mechanism, and excessive aryl halide concentration reduces the catalyst formation rate. A nonlinear-law mechanism is suggested for the conjugation of palladium reduction, aggregation, and oxidation in the Heck reaction. This mechanism allows the existence of a “critical” Pd(0) concentration and a “critical” formation rate of this catalytic species above which the catalytic activity begins to decrease.     

Synthesis of ceramide analogues having the C(4)-C(5) bond of the long-chain base as part of an aromatic or heteroaromatic system

Two efficient and stereoselective methods are described for the preparation of aryl and heteroaryl ceramide analogues 2 and 3. The first route involves the addition of an aryllithium or a heteroaryllithium reagent (7a or 25a, respectively) to the L-serine-derived aldehyde 4, followed by hydrolysis of the oxazolidine, liberation of the amino group, and N-acylation. The second route, which was used to prepare arylceramide analogue 2 in eight steps and 28% overall yield starting with 3-bromobenzaldehyde, utilizes a Heck reaction to afford (E)-alpha,beta-unsaturated ester 16, then osmium-catalyzed asymmetric dihydroxylation for the introduction of the desired chirality at C-2 and C-3. Regioselective alpha-azidation of alpha-O-nosyl-beta-hydroxyester 18 with sodium azide, followed by LiAlH(4) reduction of the azido and ester groups and N-acylation, complete the synthesis of arylceramide analogue 2.     

Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular heck reactions

A practical sequence involving three consecutive palladium(0)-catalyzed reactions has been developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors 10 and 11a-k are generated in one step by chemoselective Stille cross-coupling of 2'-triflato-(Z)-2-stannyl-2-butenanilide 9 with aryl or heteroaryl iodides. The pivotal catalytic asymmetric Heck cyclization step of this sequence takes place in high yield and with high enantioselectivity (71-98% ee) with the Pd-BINAP catalyst derived from Pd(OAc)(2) to construct oxindoles containing a diaryl-substituted all-carbon quaternary carbon center. A wide variety of aryl and heteroaryl substituents, including ones of considerable steric bulk, can be introduced at C3 of oxindoles in this way (Table 4). The only limitations encountered to date are aryl substituents containing ortho nitro or basic amine functionalities and the bulky N-alkyl-7-oxindolyl group. Asymmetric Heck cyclization of butenalide 22 having an o-(N-acetyl-N-benzylamino)phenyl substituent at C2 provided a approximately 1:1 mixture of amide atropisomers 23 and 24 in high yield and high enantioselectivity. These atropisomers are formed directly upon Heck cyclization of 22 at 80 degrees C, as they interconvert thermally to only a small extent at this temperature.     

Synthesis of substituted benzoxacycles via a domino ortho-alkylation/Heck coupling sequence

The synthesis of a variety of alkylidene benzoxacycles via a domino palladium-catalyzed ortho-alkylation/intramolecular Heck reaction is described. Under the optimized conditions [Pd(OAc)2 (10 mol %), P(2-Furyl)3 (20 mol %), norbornene (4 equiv), Cs2CO3 (2 equiv), CH3CN, 80 degrees C], aryl iodides with oxygen-tethered Heck acceptors are coupled with alkyl bromides (5 equiv) to generate a variety of six- and seven-membered-ring benzoxacyclic products.     

Heck reaction catalyzed by PD-modified zeolites.

[Pd]-exchanged NaY zeolites have been prepared, characterized, and applied for the first time for catalytic carbon-carbon coupling reactions. The catalysts exhibit a high activity and selectivity toward the Heck reaction of aryl bromides with olefins for small palladium concentrations (< or =0.1 mol % of Pd). The catalysts can easily be separated from the reaction mixture and reused after washing without loss in activity. No limitation to the diffusion of adducts in the zeolite cages was observed (for linear alkenes). The electronic nature of the aryl bromides and the olefins has a dominating effect on the reaction yield and selectivity. The heterogeneous catalysts quantitatively convert all types of all aryl bromide (complete conversion of bromobenzene within 30 min) and activated aryl chlorides under standard reaction conditions. Product form selectivity is observed in the Heck reaction with cyclic olefins.     

Efficient and ligand free palladium catalyst for Suzuki and Heck cross-coupling reactions

A simple and efficient system for Suzuki cross-coupling reactions was developed using a ligandless catalyst of Pd nanoclusters generated in situ from Pd(acac)₂. The cross-coupling reactions proceeded under mild reaction conditions with a high reaction rate (5 min) to give various biaryls in high yields. The system also exhibited catalytic potential for Heck reaction between aryl bromides and styrene.     

Design of highly active heterogeneous palladium catalysts for the activation of aryl chlorides in Heck reactions

In situ generation of highly active palladium species by intermediate dissolution of Pd from solid supported catalysts has been demonstrated to be a very successful approach for the activation of aryl chlorides in Heck reactions. The new ‘heterogeneous’ Pd catalysts act as reservoir for molecular Pd species with unsaturated coordination sphere in solution. Crucial Pd leaching and re-deposition onto the support can be controlled by optimization of reaction conditions and by the properties of the catalysts. Pd is re-deposited onto the support at the end of the reaction. The catalysts, palladium supported on activated carbon, on various metal oxides or fluorides and Pd complexes in zeolites, are easy to prepare, though the preparation conditions are crucial. The catalysts convert all aryl bromides completely within minutes (TON 100,000). Aryl chlorides (even deactivated ones) are converted with high yields, within 2-6 h. The catalysts belong to the most active ones in Heck reactions at all (including best homogeneous systems) and fulfill all relevant requirements for practical applications in laboratory and industry.     

Investigation of Pd leaching from supported Pd catalysts during the Heck reaction

Palladium supported on amorphous silica, mercapto-functionalized silica, amine functionalized silica, and zeolite Y has been studied as a catalyst in the Heck reaction of iodobenzene with butyl acrylate in the presence of triethylamine base and dimethylformamide solvent. Trapping of soluble Pd with poly(4-vinylpyridine), hot filtration tests during the batchwise Heck reaction, and reaction tests of effluents from a fixed bed continuous reactor support the conclusion that leached Pd is the active phase in the Heck reaction for all of the catalysts tested. Two different paths of Pd leaching that depend on the chemical state of the Pd were elucidated in this study. Oxidative addition of aryl halide to reduced Pd caused leaching of samples containing metallic particles. However, for a zeolite Y sample containing unreduced cationic Pd, the presence of triethylamine base was required to leach Pd into solution. These two paths of Pd leaching are consistent with the generally accepted mechanism of the Heck reaction.     

Callipeltoside a: total synthesis,assignment of the absolute and relative configuration,and evaluation of synthetic analogues

The total synthesis of the novel antitumor agent callipeltoside A, as well as several analogues, is accomplished and allows assignment of the stereochemistry not previously established. A convergent strategy is employed wherein the target is dissected into three units-the core macrolactone, the sugar callipeltose, and a cyclopropyl bearing chain. The strategy for the synthesis of the macrolactone derives from employment of diastereoselective aldol reactions that emanate from an 11 carbon piece. The stereochemistry of the latter derives from the chiral pool and two asymmetric reactions-a ketone reduction using CBS-oxazaborolidine and a Pd catalyzed asymmetric allylic alkylation (AAA). The novelty of the latter protocol is its control of regioselectivity as well as absolute configuration. The trisubstituted olefin is generated using an alkene-alkyne coupling to create a trisubustituted olefin with complete control of geometry. The excellent chemo- and regioselectivity highlights the synthetic potential of this new ruthenium catalyzed process. The macrolactonization employs in situ formation of an acylketene generated by the thermolysis of a m-dioxolenone. Two strategies evolved for attachment of the side chain-one based upon olefination and a second upon olefin metathesis. The higher efficiency of the latter makes it the method of choice. A novel one pot olefin metathesis-Takai olefination protocol that should be broadly applicable is developed. The sugar is attached by a glycosylation by employing the O-trichloroacetimidate. This route provided both C-13 epimers of the macrolactone by using either enantiomeric ligand in the Pd AAA reaction. It also provided both trans-chlorocyclopropane diastereomers of callipeltoside A which allows the C-20 and C-21 configuration to be established as S and R, respectively. The convergent nature of the synthesis in which the largest piece, the macrolatone, require only 16 linear steps imparts utility to this strategy for the establishment of the structure-activity relationship. Initial biological testing demonstrates the irrelevance of the chloro substituent and the necessity of the sugar.     

Concise enantioselective total syntheses of (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine and (+)-norchelidonine by a Pd II-catalyzed ring-opening strategy

New enantioselective syntheses of the B/C hexahydrobenzo[c]phenanthridine alkaloids (+)-homochelidonine, (+)-chelamidine, (+)-chelidonine, (+)-chelamine, and (+)-norchelidonine are described. Our rapid and convergent route to this class of natural products involved the development and application of a Pd II-catalyzed asymmetric ring-opening reaction of a meso-azabicyclic alkene with an aryl boronic acid as the key step. By screening a variety of functionalized ortho-substituted aryl boronic acids, chiral ligands and reaction conditions we were able to prepare the requisite cis-1-amino-2-aryldihydronaphthalenes in high yield and in up to 90 % ee. Early attempts to complete the synthesis of (+)-homochelidonine using an N-Boc azabicyclic alkene are described in full. The successful route required a protecting group alteration followed by B ring formation and then stereoselective installation of the C-11 syn-hydroxy group by regioselective epoxide ring-opening using a hydride source. Ring-opening of the same epoxide intermediate with water ultimately led to the synthesis of (+)-chelamidine. The same strategy was then used to synthesize the other structurally similar B/C hexahydrobenzo[c]phenanthridine alkaloids, (+)-chelidonine, (+)-chelamidine, and (+)-norchelidonine.     

Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.