Open Access
Majireck, Max Michael
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
May 03, 2011
Committee Members:
  • Steven M Weinreb, Dissertation Advisor
  • Scott Trent Feldman, Committee Member
  • Steven M Weinreb, Committee Chair
  • Raymond Lee Funk, Committee Member
  • Michael Anthony Hickner, Committee Member
  • indole
  • total synthesis
  • Michael addition
  • Nitrosoalkene
  • alkaloid
An efficient procedure for the alkylation of nitrosoalkenes has been developed in which an array of potassium ester enolates were found to add in Michael fashion to various nitrosoalkenes generated via the Denmark protocol from ƒÑ-chloro-O-TBS ketoximes and ƒÑ-chloro-O-TBS aldoximes. Using this methodology, a number of different ƒÑ-alkylated oxime constructs were synthesized including systems which contain vicinal quaternary centers. A total synthesis of the structurally unique monoterpene indole alkaloids angustilodine (167), alstilobanine A (169), and alstilobanine E (168) has been initiated. Initial exploratory studies identified indole-2-acetate ester enolates as suitable nucleophiles for conjugate additions to 3-piperidone derived nitrosoalkenes. The Michael adduct 266, which contains the indole-piperidine substructure found in alkaloids 167-169, was prepared from the conjugate addition of the monoanion of indole-2-acetate 218 to the 3-piperidone derived nitrosoalkene 265. However, subsequent functionalization of the indole C-3 was found to be difficult. A more convergent and highly efficient reaction was developed, which employed the conjugate addition of the dianion derived from 2,3-disubstituted indole 286, containing an oxoacetate moiety at the indole C-3, to nitrosoalkene 265 to prepare Michael adduct 315 in nearly quantitative yield. Additionally, an efficient stepwise deoxygenation sequence was developed to reduce the ketone in 3-oxoacetate 315 after all attempts to directly reduce this moiety in the related system 291 failed. Attempted conversion of the indole containing oxime 325 to ketone 326 using standard deoximation reactions led to low yields and/or product degradation. Therefore, a mild protocol for the reductive deoximation of ketoxime pivalates was developed and was found to be compatible with the indole containing ketoxime pivalates 354 and 359 as well as various other model ketoxime pivalates. Ketone 360 was subsequently converted to the key keto-acid 361 which was subjected to Romo¡¦s intramolecular aldol lactonization conditions to stereoselectively form pentacyclic ƒÒ-lactone 362 which contains the cis-azadecalin ring system found within the alkaloids 167-169. Numerous strategies have been examined for installing a C-17 hydroxymethyl group and completing the total synthesis of alkaloids 167-169. It was discovered that intermolecular alkylation of the enolate derived from indole ester 374 with formaldehyde produces the hydroxymethyl compound 393 containing the undesired stereochemistry at C-17. On the other hand, the C-17 carbon could be installed with the proper stereochemistry via a silicon-tethered intramolecular ester enolate alkylation to provide the cyclic siloxane 408. However, numerous attempts to oxidize siloxane 408 and its derivatives to a hydroxymethyl compound under standard Fleming-Tamao conditions failed. Preliminary experiments using the Woerpel modification to the Fleming-Tamao oxidation on cyclic siloxane 449 have identified this reaction to be potentially useful for generation of the C-17 hydroxymethyl unit. Future optimization and implementation of this procedure will provide the late stage intermediate triol 463, which will be used to complete the total synthesis of angustilodine (167) and alstilobanine E (168). A Barton-McCombie deoxygenation of the primary alcohol in cyclic siloxane 449 will produce siloxane 469, which should undergo a similar oxidation en route to a total synthesis of alstilobanine A (169).