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Palladium-catalyzed asymmetric allylic alkylation: insights, application toward cyclopentanoid and cycloheptanoid molecules, and the total synthesis of several daucane sesquiterpenes

Citation

Bennett, Nathan Bruce (2013) Palladium-catalyzed asymmetric allylic alkylation: insights, application toward cyclopentanoid and cycloheptanoid molecules, and the total synthesis of several daucane sesquiterpenes. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:06102013-121027424

Abstract

The asymmetric construction of quaternary stereocenters is a topic of great interest in the organic chemistry community given their prevalence in natural products and biologically active molecules. Over the last decade, the Stoltz group has pursued the synthesis of this challenging motif via a palladium-catalyzed allylic alkylation using chiral phosphinooxazoline (PHOX) ligands. Recent results indicate that the alkylation of lactams and imides consistently proceeds with enantioselectivities substantially higher than any other substrate class previously examined in this system. This observation prompted exploration of the characteristics that distinguish these molecules as superior alkylation substrates, resulting in newfound insights and marked improvements in the allylic alkylation of carbocyclic compounds.

General routes to cyclopentanoid and cycloheptanoid core structures have been developed that incorporate the palladium-catalyzed allylic alkylation as a key transformation. The unique reactivity of α-quaternary vinylogous esters upon addition of hydride or organometallic reagents enables divergent access to γ-quaternary acylcyclopentenes or cycloheptenones through respective ring contraction or carbonyl transposition pathways. Derivatization of the resulting molecules provides a series of mono-, bi-, and tricyclic systems that can serve as valuable intermediates for the total synthesis of complex natural products.

The allylic alkylation and ring contraction methodology has been employed to prepare variably functionalized bicyclo[5.3.0]decane molecules and enables the enantioselective total syntheses of daucene, daucenal, epoxydaucenal B, and 14-p-anisoyloxydauc-4,8-diene. This route overcomes the challenge of accessing β-substituted acylcyclopentenes by employing a siloxyenone to effect the Grignard addition and ring opening in a single step. Subsequent ring-closing metathesis and aldol reactions form the hydroazulene core of these targets. Derivatization of a key enone intermediate allows access to either the daucane sesquiterpene or sphenobolane diterpene carbon skeletons, as well as other oxygenated scaffolds.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:allylation, alkylation, methodology, natural product, total synthesis, palladium
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Reisman, Sarah E. (chair)
  • Hsieh-Wilson, Linda C.
  • Fu, Gregory C.
  • Virgil, Scott C.
  • Stoltz, Brian M.
Defense Date:7 June 2013
Record Number:CaltechTHESIS:06102013-121027424
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:06102013-121027424
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7883
Collection:CaltechTHESIS
Deposited By: Nathan Bennett
Deposited On:03 Jul 2014 20:42
Last Modified:03 Jul 2014 20:42

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