Extending pummerer reaction chemistry. Application to the total synthesis of (+/-)-dibromoagelaspongin

The sponge metabolite dibromoagelaspongin was synthesized in 16 steps from imidazole. The route features two successive oxidative cyclizations with complete control of regiochemistry to deliver the unusual triaminomethane core of the target. These oxidative cyclizations likely resulted from Pummerer-like processes on the imidazole-2-sulfoxide (sulfide) precursors.     

Tandem radical cyclizations with iodoaryl azides: formal total synthesis of (+/-)-aspidospermidine

An iodoazide radical cascade cyclization strategy has been used as the key step in a formal synthesis of aspidospermidine. Specifically, this step generated the alkaloid's B- and E-rings in the ethylidene-functionalized tetracycle 5. In turn, this was converted into pentacycle 25, a known advanced synthetic precursor of aspidospermidine.     

An application of the phosphine-catalyzed [4 + 2] annulation in indole alkaloid synthesis: formal syntheses of (+/-)-alstonerine and (+/-)-macroline

[reaction: see text] An application of the phosphine-catalyzed [4 + 2] annulation in the formal synthesis of alstonerine and macroline is reported. A phosphine-catalyzed [4 + 2] reaction between imine 7a and allene 8 formed the D ring of the target indole alkaloids. A subsequent intramolecular Friedel-Crafts acylation provided the C ring of the bridged tetracycle. Deprotection, followed by methylation of the bridged nitrogen, deoxygenation of the C6 ketone, and reduction of the C16 carbethoxy group provided the previously known intermediate 3.     

The total synthesis of the crinine alkaloid hamayne via a Pd[0]-catalyzed intramolecular alder-ene reaction

The racemic form of the title alkaloid, 1, has been prepared in 13 steps from the ring-fused gem-dibromocyclopropane 7. Key transformations include the thermally induced electrocyclic ring-opening of compound 7, the Pd[0]-catalyzed intramolecular Alder-ene (IMAE) reaction of the derived sulfonamide (±)-12, and the conversion of the ensuing C-3a-arylhexahydroindole (±)-16 into (±)-hamayne via a Pictet-Spengler reaction.     

Explorations in organic chemistry leading to the total synthesis of (+/-)-gelsemine

The total synthesis of (+/-)-gelsemine (1) is described. A defining phase of the effort involved recourse to a strategic oxetane ring (see compound 25). It was constructed anticipating an intramolecular displacement of the carbon (C17)-oxygen (O4) bond (see product 48). A key intermediate in the stereospecific elaboration of the oxetane linkage was enone 22, which was susceptible to two beta-face attacks leading to 24 and, thence, 25. Three sigmatropic rearrangements were employed in building the bridgehead (C20) and the spiroanilide (C7) quaternary centers en route to gelsemine.     

Studies on the total synthesis of streptazolin and its related natural products: first total synthesis of (+/-)-8alpha-hydroxystreptazolone

The intramolecular Pauson-Khand reaction of 2-oxazolone derivatives with a suitable heptynyl appendage gave exclusively the corresponding 4-hydroxy-6-substituted-9-oxa-1-azatricyclo[6.2.1.0(5,11)]undec-5-ene-7,10-diones. On the basis of this newly developed Pauson-Khand reaction of 2-oxazolone-alkyne derivatives, the first total synthesis of (+/-)-8alpha-hydroxystreptazolone was accomplished in a highly stereoselective manner. In addition, (+/-)-7-epi-8alpha-hydroxystreptazolone was also synthesized.     

First total synthesis of a novel monoterpenoid isoquinoline alkaloid, (+/-)-alangine

The structure including the stereochemistry of a novel monoterpenoid isoquinoline alkaloid, alangine, was confirmed by total synthesis via N-acyliminium cyclization to construct the isoquinoline skeleton and reductive cleavage of vinyl epoxide with Pd(0) catalyst.     

Development of the [3 + 2] annulations of cyclohexenylsilanes and chlorosulfonyl isocyanate: application to the total synthesis of (+/-)-peduncularine

The synthesis of (+/-)-peduncularine was accomplished using the [3 + 2] annulation of an allylic silane with chlorosulfonyl isocyanate to assemble the bicyclic core of the alkaloid. The stereochemistry of the annulation product was employed to control the installation of the indolylmethyl side chain at C-7 with complete stereoselectivity.     

The palladium(0) Suzuki cross-coupling reaction as the key step in the synthesis of aporphinoids

We report a flexible approach to the total synthesis of 4,5-dioxoaporphines based on the palladium(0) catalyzed Suzuki cross-coupling of phenylboronic acids with sterically hindered 2-bromo phenyl acetates or bromo phenyl acetamides, followed by sequential bicyclization of biarylacetamides promoted by oxalyl chloride/Lewis acid. The reduction of 4,5-dioxoaporphines provides a chemoselective entry to aporphines, dehydroaporphines and 4-hydroxy-dehydroaporphines. A three-steps total synthesis for (±)-O,O′-dimethylapomorphine from readily accessible precursors is also reported.     

Hypervalent iodine-mediated vicinal syn diazidation: application to the total synthesis of (+/-)-dibromophakellstatin

[reaction: see text] The total synthesis of (+/-)-dibromophakellstatin is described. The molecule is constructed from a key syn-diazide, formed by a hypervalent iodine-mediated diazidation of a dihydrodipyrrolopyrazinone ring structure.     

First total synthesis of (+/-)-strychnofoline via a highly selective ring-expansion reaction

An efficient synthesis of the antitumor alkaloid (+/-)-strychnofoline is documented. Key to the development of the highly convergent strategy delineated is the coupling of a cyclic imine with spiro[cyclopropan-1,3'-oxindole], which takes place in a highly diastereoselective manner. The ability to conduct annulation reactions of spirocyclopropyloxindoles with functionalized cyclic imines provides new avenues for the preparation of this important class of biologically active structures.     

A concise total synthesis of (+/-)-alantrypinone by a novel hetero-Diels-Alder reaction

[reaction: see text] An efficient total synthesis of (+/-)-alantrypinone (1) and its 17-epi isomer (17) has been accomplished employing a novel aza-Diels-Alder reaction as the key step. The reaction sequence comprises 8 steps starting from anthranilic acid and proceeds in 13.5% overall yield. An interesting anionic equilibration between 1 and its epimer 17 has also been discovered.     

Total synthesis of (+/-)-gleenol and (+/-)-axenol via a functionalized spiro[4.5]decane

Total synthesis of the biologically important axane sesquiterpenes, gleenol (1) and axenol (2), was accomplished through a readily available spiro[4.5]decane. The key features of the synthesis of 1 and 2 include Claisen rearrangement to afford the multi-functionalized spiro[4.5]decane 4 as a single diastereomer in excellent yield, installation of the C7 isopropyl group via ketene dithioacetal instead of direct alkylation and a diastereoselective reduction of ketone under the Birch conditions.     

A new and efficient method for o-quinone methide intermediate generation: application to the biomimetic synthesis of the benzopyran derived natural products (+/-)-lucidene and (+/-)-alboatrin

Lucidene and alboatrin are complex benzopyran derived natural products. A key step in their biogenesis may involve a hetero Diels-Alder cycloaddition between an o-quinone methide intermediate with a simple, or activated tri-substituted olefin. Experimental evidence is provided to support this hypothesis, with the biomimetic synthesis of both (+/-)-lucidene and (+/-)-alboatrin successfully achieved using a new and efficient method for o-quinone methide generation.     

芳樟醇全合成的新方法

本文报道了两种新的、简便的(±)-芳樟醇全合成的方法,一种方法是以γ-乙酰基丙醇为原料,经三步反应得到产物,总得率59%,另一种方法是以1,3-丙二醇为原料,经六步反应得到产物总得率12%。     

Efficient route to 4a-methyltetrahydrofluorenes: a total synthesis of (+/-)-dichroanal B via intramolecular Heck reaction

An efficient new route based on intramolecular Heck cyclization of the diene 11 was developed to prepare the 4a-methyltetrahydrofluorene diterpenoids and utilized for the total synthesis of (+/-)-dichroanal B with significantly improved overall yield.     

A novel stereocontrolled approach to eudesmanolides: total synthesis of (+/-)-gallicadiol and (+/-)-isogallicadiol

[reaction: see text] A novel approach for the stereocontrolled synthesis of eudesmanolides was developed based on a quasi-biomimetic strategy starting from a functionalized oxabicyclic template, as shown above, by which the first total syntheses of gallicadiol (6) and isogallicadiol (7) were achieved. The key elements of the synthesis include: (1) a facile and stereospecific synthesis of a functionalized epoxy aldehyde intermediate; (2) a mild Lewis acid-mediated stereoselective ene cyclization; and (3) a stereocontrolled gamma-lactonization.     

A stereoselective approach to the azaspiro[5.5]undecane ring system using a conjugate addition/dipolar cycloaddition cascade: application to the total synthesis of (+/-)-2,7,8-epi-perhydrohistrionicotoxin

An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (+/-)-2,7,8-epi-PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the beta-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-PHTx (4) in five additional steps. Utilizing this tandem conjugate addition/dipolar cycloaddition cascade, we have also successfully synthesized azaspiro[5.5]undecane 36, which had previously been converted into (+/-)-perhydrohistrionicotoxin (2), thereby completing a formal total synthesis of this alkaloid.     

Synthesis of the lipophilic antifolate piritrexim via a palladium(0)-catalyzed cross-coupling reaction

[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling reaction between 2-amino-3-cyano-4-methyl-5-bromopyridine and 2,5-dimethoxybenzylzinc chloride to form 2-amino-4-methyl-5-(2,5-dimethoxybenzyl)nicotinonitrile. To complete the synthesis, the amino group is replaced by a more reactive bromine atom via nonaqueous diazotization with tert-butyl nitrite, and the resultant bromo nitrile is cyclized with guanidine.