Applications of dihydroarenediols to chemoenzymatic synthesis : approaches to total synthesis of morphine alkaloids

The present studies describe, as a primary goal, our recent progess toward the synthesis of morphine alkaloids from aromatic precursors. Model substrates were synthesized which allowed investigation into Diels-Alder, radical cascade, and palladium-catalyzed bond-forming reactions as possible routes to the morphine alkaloid skeleton. As a secondary objective, three separate series of aromatic substrates were subjected to whole-cell oxidation with Escherichia coli JM 109 (pDTG601), a recombinant organism over-expressing the enzyme toluene dioxygenase. Included in this study were bromothioanisoles, dibromobenzenes, and cyclopropylbenzene derivatives. The products of oxidation were characterized by chemical conversion to known intermediates. The synthetic utility of one of these bacterial metabolites, derived from oxidation of o-dibromobenezene, was demonstrated by chemical conversion to (-)conduritol E.

Palladium and platinum complexes of vitamin Bâ

Palladium and platinum complexes of pyridoxamine, pyridoxine and pyridoxal have been prepared. The structures of the complexes PtCI2PM.H20, trans-PdC12 (PN)2 and [PLH+ ]2[PtC16] 2- ,H20 have been determined by use of single crystal x-ray studies. The compounds PdC12PH, trans-PdC12 (PN) 2 , cis-PdCI2 (PN)2 and cis PdC12 (PL)2 were also studied by use of carbon-13 nmr spectroscopy. All the complexes have also been characterised by use of infrared spectral studies. In the complexes, PtCI2PM.H20 and PdC12PM, the ligand pyridoxamine is chela ted to the metal through the aminomethyl nitrogen and the phenolate oxygen atoms whereas in the complexes, trans-PdCI2 (PN)2' cis-PdCI2 (PN)2 and cis-PdC12 (PL)2 the vitamin B6 ligands are coordinated to the metal through the pyridine ring nitrogen. The compounds [PLH+ ]2[PtCI6] 2- .H20 and [PMH2] 2+ [PdCI4] 2- .H20have no direct metal-ligand bonding, In all the complexes, the metal maintains a square planar coordination except in [PLH +] 2[PtCI6] 2- ,H20 where the metal is octahedrally coordinated. PH pyridoxamine [PMH ] 2+ = diprotonated pyridoxamine 2 PN = pyridoxine PL pyridoxal PLH+ protonated pyridoxal

Phospha-adamantanes as ligands for palladium-catalyzed cross-coupling reactions

New and robust methodologies have been designed for palladium-catalyzed crosscoupling reactions involving·a novel·class oftertiary phosphine ligand incorporating a phospha-adamantane framework. It has been realized that bulky, electron-rich phosphines, when used as ligands for palladium, allow for cross-coupling reactions involving even the less reactive aryl halide substrates with a variety of coupling partners. In an effort to design new ligands suitable for carrying out cross-coupling transformations, the secondary phosphine, 1,3,5,7-tetramethyl-2,4,8-trioxa-6phosphaadamantane was converted into a number of tertiary phosphine derivatives. The ability of these tertiary phosphaadamantanes to act as effective ligands in the palladiumcatalyzed Suzuki cross-coupling was examined. 1,3,5,7-Tetramethyl-6-phenyl-2,4,8trioxa- 6-phosphaadamantane (PA-Ph) used in combination with Pdz(dba)3permitted the reaction of an array of aryl iodides, bromides and chlorides with a variety arylboronic acids to give biaryls in good to excellent yields. Subsequently, palladium complexes of PA-Ph were prepared and isolated in high yields as air stable palladium bisphosphine complexes. Two different kinds of crystals were isolated and upon characterization revealed two complexes, Pd(PA-Ph)z.dba and Pd(PA-Ph)zOz. Preliminary screening for their catalytic activity indicated that the former is more reactive than the latter. Pd(PAPh) z.dba was applied as the catalyst for Sonogashira cross-coupling reactions of aryl iodides and bromides and in the reactions of aryl bromides and chlorides with ketones to give a-arylated ketones at mild temperatures in high yields.

The nucleophillic substitution of various chloroanthraquinones of their possible rearrangement via aryne intermediates

The work in this thesis deals mainly with nucleophilic substitution of chloroanthraquinones as a route to various starting materials which might rearrange, via aryne intermediates to afford fused-ring heterocy1ic carboxylic acids. 1-Amino-5-chloroanthraquinone was successfully prepared by reacting 1,5-dichloroanthraquinone with sodium aZide in ref1uxing dimethylsulfoxide (DMSO). It could also be prepared from the same starting material by reaction with ammonia (gas) in DMSO in the presence of potassium fluoride. Treatment of l-amino-5-chloroanthraquinone with potassium amide in liquid ammonia or with potassium t-butoxide in t-butylbenzene returned mainly starting material, although in the latter case some 1-amino-5-hydroxyanthraquinone was also isolated. 1-Hydroxy-5-chloroanthraquinone was ultimately prepared by diazotization of the amino-analog. It was recovered almost quantitatively after treatmenu'with potassium amide in liquid ammonia. The reaction with potassium t-butoxide in t-buty1benzene was anomalous and gave 1-hydroxyanthraquinone as the only iso1able product. Acridines were successfully prepared by the action of 70% sulfuric acid on 1,5-bis(p-toluidino)-anthraquinone and 1-p-toluidino-5- ch10roanthraquinone, and in the latter case, cleavage to give an acridinecarboxylate was attempted. Substituted anthraquinones reacted with sodium azide in sulfuric acid to give azepindiones by -NH insertion. Methods for separating and identifying isomeric mixtures of these compounds were examined. Attempted decarbonylation of selected azepindiones to give acridones gave mainly what were thought to be amino-benzophenone derivatives. Chloroanthraquinones were found to react with hexamethylphosphoramide (HMPA) to give mixtures of the dimethylamino- and methylaminoderivatives. Under the same conditions halogeno-nitrobenzenes and nitrophenols were substituted to give the appropriate dimethyl aminobenzenes, except in two cases. 3-Chloronitrobenzene reacted anomalously to give a small amount of 3,3'-dichloroazobenzene and a trace of 4-dimethylamino-nitrobenzene. Pentachlorophenol reacted to give a pentachlorophenylphosphorodiamidate in good yield.

Modifications to the Suzuki reaction and mechanistic insights on the NBS mediated cleavage of benzylidene acetals /

One of the most challenging tasks for a synthetic organic chemist today, is the development of chemo, regio, and stereoselective methodologies toward the total synthesis of macromolecules. r . The objective of my thesis was to develop methodologies towards this end. The first part of my project was to develop highly functionalized chirons from D-glucose, a cheap, chiral starting material, to be utilized in this capacity. The second part of the project dealt with modifying the carbon-carbon bond forming Suzuki reaction, which is utilized quite often as a means of combining molecular sub units in total synthesis applications. As previously stated the first area of the project was to develop high value chirons from D-glucose, but the mechanism of their formation was also investigated. The free radical initiated oxidative fragmentation of benzylidene acetals was investigated through the use of several test-case substrates in order to unravel the possible mechanistic pathways. This was performed by reacting the different acetals with N-bromosuccinimide and benzoyl peroxide in chlorobenzene at 70^C in all cases. Of the three mechanistic pathways discussed in the literature, it was determined, from the various reaction products obtained, that the fragmentation of the initial benzylic radical does not occur spontaneously but rather, oxidation proceeds to give the benzyl bromide, which then fragments via a polar pathway. It was also discovered that the regioselectivity of the fragmentation step could be altered through incorporation of an allylic system into the benzylidene acetal. This allows for the acquisition of a new set of densely functionalized. chiral, valuable synthetic intermediates in only a few steps and in high yields from a-Dglucose. The second part of the project was the utilization of the phosphonium salt room temperature ionic liquid tetradecyltrihexylphosphonium chloride (THPC) as an efficient reusable medium for the palladium catalyzed Suzuki cross-coupling reaction of aryl halides, including aryl chlorides, under mild conditions. The cross-coupling reactions were found to proceed in THPC containing small amounts of water and toluene using potassium phosphate and 1% Pd2(dba)3. Variously substituted iodobenzenes, including electron rich derivatives, reacted efficiently in THPC with a variety of arylboronic acids and afforded complete conversion within 1 hour at 50 ^C. The corresponding aryl bromides also reacted under these conditions with the addition of a catalytic amount of triphenylphosphine that allowed for complete conversion and high isolated yields. The reactions involving aryl chlorides were considerably slower, although the addition of triphenylphosphine and heating at 70 ^C allowed high conversion of electron deficient derivatives. Addition of water and hexane to the reaction products results in a triphasic system in which the top hexane phase contained the biaryl products, the palladium catalyst remained fully dissolved in the central THPC layer, while the inorganic salts were extracted into the lower aqueous phase. The catalyst was then recycled by removing the top and bottom layers and adding the reagents to the ionic liquid which was heated again at 50 ^C; resulting in complete turnover of iodobenzene. Repetition of this procedure gave the biphenyl product in 82-97% yield (repeated five times) for both the initial and recycled reaction sequences.

Phospha-adamantane ligands and phosphorous ionic liquids for palladium-catalyzed cross-coupling reactions /

New and robust methodologies have been designed for palladiumcatalyzed cross-coupling reactions involving a library of novel tertiary phosphine ligands incorporating a phospha-adamantane framework. The secondary phosphine, l,3,5,7-tetramethyl-2,4,8-trioxa-6-phospha-adamantane was converted into a small library of tertiary phosphine derivatives and the ability of these tertiary phosphaadamantanes to act as effective ligands in the palladium-catalyzed amination reaction and p-alkyl-Suzuki cross-coupling was examined. l,3,5,7-Tetramethyl-6- phenyl-2,4,8-trioxa-6-phosphaadamantane (PA-Ph) used in combination with Pd2(dba)3 CHCI3 facilitated the reaction of an array of aryl iodides, bromides and chlorides with a variety secondary and primary amines to give tertiary and secondary amines respectively in good to excellent yields. 8-(2,4-Dimethoxyphenyl)- l,3,5,7-tetramethyl-2,4,6-trioxa-8-phospha-tricyclo[3.3.1.1*3,7*]decane used in combination with Pd(0Ac)2 permitted the reaction of an array of alkyl iodides, and bromides with a variety aryl boronic acids and alkyl 9-BBN compounds in good to excellent yields. Subsequent to this work, the use of phosphorous based ionic liquids, specifically tetradecyltrihexylphosphonium chloride (THPC), in the Heck reaction provided good to excellent yields in the coupling of aryl iodides and bromides with a variety of olefins.

New-England Palladium Vol. XLII No. 49- December 17, 1813

A four page, semi-weekly paper that was published from 1803 to 1814.

New-England Palladium Vol. XLI No. 40- May 18, 1813

A four page, semi-weekly paper that was published from 1803 to 1814.

New-England Palladium Vol. 40 No. 33- October 23, 1812

A four page, semi-weekly paper that was published from 1803 to 1814.