I. Reactions of cyclopropanones with alkyl azides. II. Double conjugate additions of bis-nucleophiles to quinone monoketals: Formal total synthesis of (+/-)-gelsemine

• Main Author: Grecian, Scott A
• Format: Dissertation
• Language: English
• Subjects: chemistry, organic

The Lewis acid-mediated reactions of substituted cyclopropanone acetals with alkyl azides were examined. When cyclopropanone acetal was treated with alkyl azides, N-substituted 2-azetidinones and ethyl carbamate products were obtained, arising from azide addition to the carbonyl, followed by ring expansion or rearrangement, respectively. When 2,2-dimethylcyclopropanone acetals were reacted with azides in the presence of BF3*OEt2, the products obtained were alpha-amino-alpha'-diazomethyl ketones, which arose from C2-C3 bond cleavage of the corresponding cyclopropanone, giving oxyallyl cations, that were captured by azides. Aryl-substituted cyclopropanone acetals, when subjected to these conditions, afforded [1,2,3]oxaborazoles exclusively, which were also the result of C2-C3 bond rupture, azide capture and then loss of nitrogen. In the reactions of n-hexyl-substituted cyclopropanone acetals with alkyl azides, a mixture of 2-azetidinones and regioisomeric [1,2,3]oxaborazoles were obtained. A computational study was performed to investigate the regioselectivity of azide addition in these processes.
A series of cyclohexa-2,5-dienone monoketals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of catalytic KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. When ethyl acetoacetate was used as a nucleophile, [3.3.1]bicyclic products were obtained in good yields. The regiochemistry of conjugate addition was dependent on the cyclohexa-2,5-dienone monoketal substitution.
When cyclohexa-2,5-dienone monoketals were treated with the lithium dianion of ethyl 3-nitropropionate, followed by mild acid, [3.2.1]bicyclooctanones were generated in preparatively useful yields. One of these adducts was regioselectively acylated and subjected to an intramolecular Heck reaction, which established the spirooxindole. One of these Heck reaction products was manipulated into advanced intermediates previously used by Fukuyama and coworkers in their total syntheses of (+/-)- and (+)-gelsemine. Attempts to form gelsemine's pyrrolidinyl ring through intramolecular cyclization techniques are described.