Browsing Theses and Dissertations by Author "GADDIRAJU, NARENDRA VARMA"
Asymmetric Synthesis of C-1 Substituted Cocaine Analogues Using Sulfinimine (N-Sulfinyl Imine) Chemistry And Vinylaluminum Addition to Sulfinimines (N-Sulfinyl Imines) For The Asymmetric Synthesis Of Alpha-Substituted-Beta-Amino EstersDavis, Franklin A.; Andrade, Rodrigo B.; Wuest, William M.; Cannon, Kevin C. (Temple University. Libraries, 2013)Organic nitrogen containing chiral compounds are widely found in nature, and a number of them exhibit important biological and medicinal properties. The main objective of this research is to develop new methods for the asymmetric synthesis of cocaine analogues having methyl (Me), ethyl (Et), n-propyl (n-Pr), n-pentyl (n-C5H11) and phenyl (Ph) groups at the C-1 bridgehead position. The second project concerned the asymmetric synthesis of anti-α-alkyl substituted beta-amino esters, a new chiral building block, utilizing chiral sulfinimine (N-sulfinyl imine) chemistry. The easy availability and abuse of (R)-(-)-cocaine is a global problem and has resulted in many efforts aimed at the preparation of therapeutically useful cocaine analogues. However, to date analogues of cocaine for the treatment of cocaine addiction have not been reported. The requirement of a cis relationship between C-2 and C-3 substituents in the cocaine tropane skeleton where C-2 carbomethoxy group occupies the thermodynamically unfavorable axial position is the main reason for the difficulty in designing efficient asymmetric syntheses of cocaine analogues. In this study, diastereomerically pure N-sulfinyl beta-amino esters were prepared by the addition of the sodium enolate of methyl acetate to masked oxo sulfinimines, novel sulfinimines having a protected carbonyl group. Reduction of the beta-amino esters gave the corresponding beta-amino aldehydes and a Roush-Masamune modified Horner-Wadsworth-Emmons (HWE) reaction afforded the trans-N-sulfinyl alpha,beta-unsaturated delta-amino esters in good yield. Acid hydrolysis of the esters unmasked the carbonyl group and deprotected the amines resulting in an intramolecular cyclization to produce the key dehydropyrrolidines. Regioselective oxidation of the dehydropyrrolidines using catalytic methyl trioxorhenium and urea-hydrogen peroxide gave the corresponding pyrrolidine nitrones in excellent yield. On heating with the Lewis acid catalyst Al(O-t-Bu)3 the nitrones underwent a novel, stereospecific, intramolecular [3+2] cycloaddition reaction to give tricyclic isoxazolidines. Importantly, the isoxazolidine establishes the necessary cis relationship between C-2 and C-3 substituents in cocaine skeleton. The tricyclic isoxazolidines were readily converted to the N-Me quaternary ammonium salts on heating with methylmethanesulfonate and hydrogenolysis with Pd/C at 1 atm of H2 cleave the N-O bond to afford the ecgonine methyl ester, the tropane alcohol. In contrast to other C-3 (R = Me, Et, n-Pr, Ph) isoxazolidine quaternary ammonium salts, the C-3 n-C5H11 analogue did not undergo N-O bond cleavage under the hydrogenolysis conditions. This analogue rearrange to a bridged bicyclic [4.2.1]isoxazolidine. It was found that all C-3 isoxazolidine N-Me quaternary ammonium salts undergo this rearrangement on treatment with triethylamine. Fortunately, hydrogenolysis of n-C5H11 isoxazolidine quaternary ammonium salt at 4 atm of H2 cleaved the N-O bond to give the desired alcohol, ecgonine methyl ester. Benzolylation of methyl ester of ecgonine alcohols afforded the C-1 substituted cocaine analogues in 75-95% yield. This new methodology, for the first time, afforded cocaine analogues having Me, Et, n-Pr, n-C5H11 and Ph groups at the C-1 position. In another study, new methodology was devised for the asymmetric synthesis of anti-alpha-alkyl-beta-amino esters, valuable new chiral building blocks for the synthesis of beta-amino acids, beta-lactams. The aza-Morita-Baylis-Hillman (aza-MBH) reaction of various vinylaluminum/NMO reagents with N-sulfinyl imines resulted in the formation of alpha-vinyl-beta-amino esters in good yield and with 7:1 to 12:1 anti/syn selectivity. Addition of the aza-MBH reagent takes place from the least hindered direction via a nonchelation control mechanism. Hydrogenation of aza-Morita-Baylis-Hillman adducts using a cationic rhodium (I) catalyst gave anti-alpha-alkyl-beta-amino esters in good yield and high dr (10:1) and is useful new method for their preparation. The absolute configurations of the anti-alpha-alkyl-beta-amino esters were established by the oxidation of the N-sulfinyl group to a tosylate with m-CPBA, hydrolysis with LiOH and cyclization to a beta-lactam of known absolute configuration.