Benzothiazines in synthesis: studies directed toward the synthesis of erogorgiaene

The use of benzothiazenes for the formal total synthesis of erogorgiaene and stereoselective total syntheses of two diastereomers of this natural product is described. In particular, the stereochemical course of a radical cyclization anticipated to give the correct relative stereochemistry for the synthesis of erogorgiaene is discussed utilizing both experimental and computational data.     

Total synthesis of pyridovericin: studies toward the biomimetic synthesis of pyridomacrolidin

[reaction: see text] The total synthesis of the novel metabolite pyridovericin 1 is reported. The synthesis of this key intermediate in our proposed biomimetic synthesis of pyridomacrolidin 2 has been accomplished in good yield from readily available 2,4-dihydroxypyridine.     

Model studies toward the synthesis of kirkine

In model studies towards the synthesis of kirkine, the carbon skeleton was constructed using a radical cascade reaction. Two different approaches towards the synthesis have been examined as well as the regioselectivity of the radical cyclisation.     

Synthetic studies directed toward the total synthesis of dolabriferol

Herein we report our results towards the total synthesis of (−)-dolabriferol, describing the synthesis of fragments C1-C9 and C10-C21. This convergent asymmetric approach relies on the use of a common Weinreb amide precursor for the preparation of both fragments, an efficient anti-aldol reaction followed by Zn(BH₄)₂ reduction to give a 1,3-syn diol, a selective oxidation of a triol under Swern conditions with concomitant lactol formation, and a diastereoselective epoxidation of an allylic alcohol with m-CPBA followed by an efficient epoxide opening with Me₂CuCNLi₂.     

Synthetic studies toward pondaplin: total synthesis of pondaplin analogues

Syntheses of synthetic analogues of pondaplin 1 have been achieved. Final macrolide construction was accomplished using a Keck macrolactonization reaction.     

Oxidative rearrangements of tricyclic vinylcyclobutane derivatives

Three tricyclic vinylcyclobutanes (3-methylenetricyclo[5.3.0.0(2,6)]decanes 1-3) have been subjected to ionization by photoinduced electron transfer in solution and by X-irradiation in Ar matrices. All three compounds undergo oxidative cycloreversion; the cleavage of the four-membered ring, however, occurs in a different direction depending on the presence of a methyl group in position 6 of the tricyclic framework. In those derivatives, cycloreversion is found to lead to 1-methyl-8-methylene-1,6-cyclodecadiene radical cations (5.+ from 1, 8.+) from 2) which upon back electron transfer yield two different hydrocarbons (6 from 5.+, 9 from 8.+), depending on the configuration around the endocyclic double bonds of the respective cyclodecadiene derivative. In the absence of a methyl group on C6, the cycloreversion leads to a radical cation complex between 1-methylenecyclopent-2-ene and cyclopentene (12.+) which appears to revert to 3 on back electron transfer. The intermediate radical cations 5.+, 8.+, and 12.+ have been identified and characterized by UV/Vis and IR spectra in Ar matrices. The mechanism of their formation is elucidated by quantum chemical calculations.     

Synthesis of 9-substituted tetrahydrodiazepinopurines: studies toward the total synthesis of asmarines

A methodology for the preparation of asmarine analogues has been developed. The asmarines are cytotoxic marine alkaloids with a unique tetrahydro[1,4]diazepino[1,2,3-g,h]purine (THDAP) structure. Three cyclization methods were applied for the preparation of the 9,9-disubstituted 10-hydroxy-THDAP system, namely, aminomercurization, iodocyclization, and acid-catalyzed cyclization. The DMPM group of the NOH functionality and cyanoethyl group of the N-9 atom were found to be the most suitable protecting groups. The structures of all compounds were mainly determined from NMR measurements including (15)N chemical shifts obtained from (15)NH HMBC spectra. The end products are at least about 1 order of magnitude less active than the natural product asmarine B.     

Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide

In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and a-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined.     

Model studies toward the total synthesis of the Lycopodium alkaloid spirolucidine

[reaction: see text] A strategy for the synthesis of the spirocyclic core of spirolucidine was explored through a model study. The diene 4a was prepared and photolyzed to give the desired [2 + 2] photoadduct 17 containing the correct relative stereochemistry corresponding to spirolucidine.     

Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: synthetic studies toward halichlorine

The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the directed 5-exo radical cyclization approach. This overall approach was successfully employed in the preparation of a functionalized aza-spirocycle.     

Synthetic studies toward the zoanthamine alkaloids: synthesis of the fully functionalized BC ring motif

A synthetic approach toward lactone 20, representing the fully functionalized BC ring motif of the zoanthamine alkaloids, has been developed and is presented herein. The challenging C9 quaternary center of 20 was installed by a Wilkinson hydrogenation of enone 17 followed by construction of an α-bromo acetal and intramolecular cyclization exclusively from the α face of the BC ring system.     

Exploratory studies toward the synthesis of the peroxylactone unit of plakortolides

Our efforts in construction the 1,2-dioxane ring of plakortolides through two approaches are described. The first one involved as a key step an acid catalyzed 6-endo ring closure of β-hydroperoxy trans-epoxides directed by a vinyl group adjacent to the epoxide function. By this route, an advanced intermediate of plakortolides was obtained in six steps and 35% overall yield. The second approach featured a 1,2-dioxane ring forming by a double opening of bis-epoxides by ethereal hydrogen peroxide. This reaction did not proceed in the expected sense and exclusive formation of hydroperoxy tetrahydropyran derivatives was observed via a tandem oxacyclization–hydroperoxidation sequence.     

Synthetic studies toward amphidinolide B1: synthesis of the C9-C26 fragment

[reaction: see text] The synthesis of the C9-C26 portion of amphidinolide B1 is described. A Fleming allylation followed by elimination was employed for the construction of the C13-C15 diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-derived alkene, in the presence of the C13-C15 diene functionality. A highly diastereoselective aldol reaction was developed to establish the C18 stereochemistry.     

Synthetic studies toward merrilactone A: a short synthesis of AB ring motif

An efficient route to the AB ring motif of merrilactone A has been established by remarkable regioselective reduction of cyclic anhydrides 3 and 8 to the γ-lactone moiety, followed by the successive Stille and Heck reactions of 1,1-dibromo-1-alkene.     

Exploratory studies toward a total synthesis of the marine ascidian metabolite perophoramidine

A strategy for a total synthesis of the marine alkaloid perophoramidine has been investigated. Key steps which have been tested include a tandem intramolecular Heck/carbonylation reaction and a stereoselective allylation of a pentacyclic δ-lactam to produce the C-4/20 vicinal quaternary centers having the requisite relative configuration of the metabolite.     

Approaches to open fullerenes: synthesis and kinetic stability of diels-alder adducts of substituted isobenzofurans and C60

We have examined the reactions of 1,3-disubstituted isobenzofurans with the fullerene C60 in the context of an approach to open a large orifice on the fullerene framework. A variety of substituted isobenzofurans (6a-h), generated from the reaction of 1,4-substituted 1,4-epoxynaphthalenes 3a-h with 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (4a) or 1,2,4,5-tetrazine (4b), were added to C60 to afford the Diels-Alder adducts 7a-h. The thermal stability of these adducts toward retro-Diels-Alder fragmentation differs greatly in solution from that in the solid state. In solution, the relatively facile retro-Diels-Alder fragmentation of monoadducts 7a and 7c, to give C60 and the free isobenzofurans 6a and 6c, have rate constants (and activation barriers) of k=9.29x10(-5) s-1 at 70 degrees C (Ea=32.6 kcal mol-1) and k=1.36x10(-4) s-1 at 40 degrees C (Ea=33.7 kcal mol-1), respectively, indicating that the addition of isobenzofurans to C60 is readily reversible at those temperatures. In the solid state, thermogravimetric analysis of adduct 7a indicates that its decomposition occurs only within the temperature range of 220-300 degrees C. As a result, these compounds can be stored at room temperature in the solid state for several weeks without significant decomposition but have to be handled within several hours in solution.     

Intramolecular cyclopropanation of glycals: studies toward the synthesis of canadensolide, sporothriolide, and xylobovide

[reaction: see text] The first examples of copper-catalyzed intramolecular cyclopropanations of glycal-derived diazoacetates are reported. The new cyclopropanes are converted into advanced intermediates for the synthesis of bislactone natural products. Synthetic highlights include the selective monodeprotection of a di-tert-butylsilylene ether and a zinc-mediated ring opening cascade reaction.     

Detailed studies of perezone rearrangements

Summary The isomerization of perezone (1) into isoperezone (2) by means of 3,4,5,6-tetrahydro-2-pyrimidinethiol afforded 6-methoxyperezone (6), the sulfide7, and the heterocycle8 as by-products. Addition of a small amount of water to the reaction system increased the yield of2 from 45 to 65%. The pathway for the formation of6,7, and8 is discussed. The reaction of2 with silica gel or withp-TsOH regioselectively yielded -isopipitzol (3) or dihydroisoperezinone (4) in 72 and 82% yield, respectively.

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Detaillierte Untersuchung von Perezon-Umlagerungen

Zusammenfassung Die Isomerisierung von Perezon (1) zu Isoperezon (2) mit 3,4,5,6-Tetrahydro-2-pyrimidinthiol ergab 6-Methoxyperezon (6), das Sulfid7 und den Heterocyclus8 als Nebenprodukte. Zugabe einer geringen Menge Wasser zum Reaktionsgemisch erhöhte die Ausbeute an2 von 45 auf 65%. Der Mechanismus der Bildung von6,7 und8 wird diskutiert. Reaktion von2 mit Kieselgel oderp-TsOH führte regioselektiv mit 72 bzw. 82% Ausbeute zu -Isopipitzol (3) oder Dihydroisoperezinon (4).