Search

The opening of the bridging ether of 8-oxabicyclo[3,2.1]oct-6-ene systems fused to a five-membered carbocycle is accomplished by choosing the five-membered ring witth a double bond conjugated to the oxabicycle. Data indicate that the double bond either mediates a 1,6-addition reaction or stabilizes the carbanion.

The regioselective synthesis of isoquino(1,2-b)(3)benzazepines or homoprotoberberines using 11-membered stilbene lactams as key intermediates has been undertaken. The lactams were prepared by the intramolecular addition of an aryl radical to a trimethylsilylacetylene. The homoprotoberberines are formed when the amide of both lactams is reduced to an amide functionality and results in a regioselective (7,6)-transannular cyclization.

One of the challenges of modern organic synthesis is coming up with high efficiency in terms of maximized target-relevant molecular complexity and minimal synthetic steps. One option is the manipulation of the rich oxygenation pattern of the cycloadducts, which suggest an immediate entry to cis-2,5-disubstituted tetrahydrofurans by oxidative cleavage of the carbocycle. The results showed that the rich oxygenation and conformational rigidity of the oxabicyclic (5C + 2C) pyrone-alkene adducts offers rich unique opportunities for speeding up the synthesis of tetrahydrofurans.

Fused 6,7,5-tricarboxylic compounds have been synthesized by one-pot coupling of an intramolecular thermal (5C + 2C) pyrone-alkene cycloaddition to a (4C + 2C) Diels-Alder reaction. The compounds consist of a 1,4-oxa-bridge in the seven-membered carbocycle and undergoes transformation involving the net formation of four carbon-carbon bonds. Three new cycles and at least five new stereocenters are also formed during the transformation. Deoxygenated and aromatized products can be formed by opening the oxa-bridge through reaction of the adducts with samarium diiodide and trimethylsilyl triflate.

Silylated stilbene lactams were synthesized by intramolecular addition of an aryl radical to a trimethylsilylacetylene and subsequently converted into protoberberines via dimethyldioxirane epoxidation and acid-catalyzed cyclization of the epoxysilane with HCl. The nonsilylated trans- and cis-stilbene analogues were treated with dimethyldioxirane to produce 13-hydroxytetrahydroprotoberbirines and 13a-hydroxy-13-ketotetrahydroprotoberberines as the major compounds.

A novel method for the synthesis of annelated 3- and 3,3''-substituted bipyridines and terpyridines was developed based on the utilization of Co(I) complexes as catalysts for the formation of the pyridine nuclei. The synthetic process was characterized by the CpCo(CO)2-catalyzed cocyclization of 5-hexanenitrile and unsubstituted 2-ethynylpyridine. The irradiation of the intermediate product led to the formation of a mixture of 2,2'-bipyridine and its 3,2'-bipyridine isomer.

3-Hydroxy-pyridone in 58% yield was produced by the reaction of methylamine and allyl thioether which was derived from the addition of chloropyrone with allylmercaptan and triethylamine. The pyridone that was derived from the chemical reaction was utilized to develope a second pyridone product. The pyridone did not undergo thermal pyrone-alkene cycloaddition due to its aromatic characteristics. Cycloadditions with 4-unsubstituted oxydopyridinium ylides exhibited chemical reactions with high regioselectivity.

The alkaloid (+/-)-clavizepine was prepared from dibenzopyranazepine in nine steps in 17% overall yield. 2,3-Dihydroxybenzaldehyde formed aldehyde after benzylation. Treatment of the aldehyde with 1,3-propanedithiol produced a phenolic dithioketal, which gave a coupled product after -nBuLi treatment and alkylation. Ullman reaction produced a complex mixture of products that formed alkenes by reduction with Raney nickel. Debenzylation of the hydroxylated alkenes gave a phenolic compound which afforded a cyclic compound after treatment with acetic acid. Catalytic hydrogenation of the cyclic compound, reductive cleavage and N-methylation, in that order, gave the amine resembling the structure of (+/-)-clavizepine.

Pyrrolinediones were reacted with two benzyne molecules to produce 4-phenylisoquinolones. Subsequentreaction of the bromopyrrolinedione produced the bromoadduct, phenylated adductand a minor unexpected compound. Results showed a more complex mechanism than those previously cited. New mechanisms for the reaction are suggested. Variation in the R2 groups resulted in corresponding variations in the reactionmechanisms.

An improved synthetic route to 1alpha,25-dihydroxyvitamin D2 involves the nucleophilic attack of stannylacetylene on a pregnyl dioxanone, obtained from a dinorcholanol and (3R)-3-hydroxybutyric acid. The attack cleaves the ketone's dioxo-ring and installs the acetylene. Conversion of the resulting alcohol into a ketone and construction of the triene by cross-coupling with a cyclohexenylinyne leads to the target 1alpha,25-dihydroxyvitamin D2.

Aunique synthetic route to C-25 analogues of 1alpha,25-dihydroxyvitamin D3 involves the ultrasound induced conjugate addition of an iodo triflate to electron-deficient olefins under aqueous conditions. The triflate is prepared in three steps from the Inhoffen-Lythgoe diol. The vinyl triflate adducts of the zinc-copper induced sonochemical step then undergo a dienyne convergent process to yield the various C-25 derivatives of 1alpha,25-(OH)2-D3.

Intermolecular benzyne cycloaddition (IBC) is a convergent, regioselective, flexible approach to the synthesis of benzophenanthridines. The process involves the use of pyrrolinediones as aza diene equivalents in the cycloaddition reactions with arynes. The use of IBC in the synthesis of 2,3,8,9- and 2,3,7,8-tetrasubstituted alkaloids leads to the preparation of nitidine, avicine and chelerythrine.

Ashort, simple and efficient synthesis of benzophenathridine alkaloids is described. The process involves a convergent Diels-Alder reaction between a tricyclic alpha-pyrone obtained from phthalimide and arynes derived from the aprotic diazotization of anthranilic acids. It is applied to the synthesis of antineoplastic benzophenanthridines such as nitidine, which is prepared from 4,5-dioxyanthranilic acid.

The preparation of 1-(OPPh2)ethenyl-2-(Me)-5-(OTBS)-cyclohexane and of its enantiomer provides the A-ring fragment for the convergent syntheses of dihydrotachysterol2 (DHT2), its 25-hydroxy analogue (25-OH-DHT2), 10(R),19-dihydro-(5E)-3-epivitamin D2 and the latter's 19-dihydroxy analogue. The cyclohexane is obtained in 32% yield from the Ganem reaction of (+)- and (-)-carvone followed by a seven-step process involving a stereo-directing ozonolysis. From the A-ring fragment, DHT2 is prepared in 74% yield and 25-OH-DHT2 in 84% yield. The enantiomer produces the two epivitamins D2 in 70% and 80% yields.

Trans-hydrindanol and trans-hydrindanone served as precursors in the synthesis of the CD and side-chain fragments of vitamin D metabolites and analogues. An enedione and a tosylate compound provided the starting materials for the corresponding syntheses of the hydrindanol and the hydrindanone. The key procedure in the hydrindanol synthesis involved Wilkinson catalyst-mediated hydrogenation of the hydrindenol intermediates which led to the formation of the desired trans-product in 65% yield. Both hydrindanol and hydrindanone compounds produced the diol form of the CD fragment in 81% and 80% yields, respectively.

A new high-yielding synthetic route to phthalides involves a Parham-type ring formation with the use of a carbamate as an internal electrophilic trap. The addition (at -95 degrees C) of tert-butyllithium to o-bromocarbamates in a tetrahydrofuran solution causes a metal-halogen interchange, yielding the ortho-lithiated intermediates which are trapped on their side chain. The synthetic technique also leads to lactones that may be used as precursors to aristocularine alkaloids.

Organolithiums undergo conjugated addition to the exocyclic double bond of o-styryl oxazolines. In contrast, m-styryl oxazolines are known to undergo nucleophilic substitution and addition. Alkyllithiums form o-oxazolyl alkyl benzenes while phenyllithium forms dihydrostilbenes, both in very high (70-95%) yields. ortho-3,6-Methoxy substituents enhance the reactions by stabilizing the benzylic anion. On the other hand, alkyl Grignards give very poor yields while heavier Grignards and softer lithium anions do not react at all.