Use this URL to cite or link to this record in EThOS:
Title: Asymmetric synthesis of polycyclic heterocycles & application to the synthesis of comosidine
Author: Ball, Jennifer Claire
ISNI:       0000 0004 2725 123X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
This work demonstrates the use of a Diels-Alder/retro Diels-Alder approach using a chiral anthracene auxiliary to control the stereochemistry of subsequent reactions. A range of N-substituted maleimide cycloadducts have been prepared and asymmetric transformations undertaken to give N-acyliminium ion precursors. N-Acyliminium ions have been formed under standard conditions and a range of nucleophiles used to form tertiary and quaternary stereocentres. For the synthesis of polycyclic heterocycles, a N-[2-(6-methoxypyridin-2-yl)ethyl] cycloadduct was prepared in 3 steps from commercially available starting materials. Asymmetric transformations were carried out; reduction and Grignard addition to form hydroxy-lactams both in high yield with high selectivity. The N-acyliminium ion was then formed for both systems but unfortunately, due to the inherent electron poor nature of the pyridine ring, even with an activating methoxy group, no ring formation occurred and side products predominated. For the synthesis of natural product comosidine, a N-(3,4-dimethoxyphenylpropyl)maleimide cycloadduct was prepared in high yield and a range of nucleophiles added to prepare hydroxy-lactam analogues. When subjected to Friedel-Crafts conditions in an attempt to form a 7 membered ring, no cyclisation took place. In fact, intramolecular Friedel-Crafts additions were shown to be highly dependent on the ring size that is being formed when using a dimethoxyphenyl group as nucleophile. Indeed the 6 membered ring is the only size that will form. Attempts to make 5, 7 and 8 membered rings by this method are not viable, and computational studies show the desired FriedelCrafts products are relatively less stable than the alkenes that are indeed formed experimentally for the 7 and 8 ring analogues. Intermolecular Friedel-Crafts reactions have also been undertaken using nucleophiles such as furan, thiophene and indole, accessing tertiary stereocentres (seven examples in 54 - 100% yield) and quaternary stereo centres (five examples in 50 - 100% yield). Retro Diels-Alder reaction of furan addition cycloadduct containing a quaternary stereocentre yielded a substituted maleimide derivative in 100% yield and 97% enantiomeric excess. This demonstrates the use of this strategy to construct quaternary stereo genic centres. A further attempt to prepare comosidine used a Parham cyclisation; using an aryl iodide to form the desired 7 membered ring. This proved to be very successful and gave the corresponding hydroxy-lactam in high yield. Addition of carbon nucleophiles such as silyl enol ethers, were then tested on a range of substituted N-acyliminium ions to prove the overall methodology before application to the natural product. Three examples with tertiary stereocentres were prepared in 97 - 98% yield and four examples with quaternary stereocentres formed in 78 - 95% yield, exclusively. The nature of the Nacyliminium ion itself has found to be very important. If the iminium ion is unstabilised, nucleophilic addition is relatively facile. However, if a stabilising group is attached such as a phenyl ring, attack is much more difficult and harsher reaction conditions are needed. The N-acyliminium ion formed for comosidine was found to be very stable and therefore would not react with any nucleophile tested. Several ideas to overcome the stability and unreactivity of very electron rich N-acyliminium ions have been investigated. Finally, the formal synthesis of (+)-hygrine has been completed by use of the methodology; using addition of acetone to the N-acyliminium ion formed from Nmethylmaleimide hydroxy-lactam in 100% yield. Other steps including cycloreversion, hydrogenation and amide reduction gave the enantioenriched protected natural product in 7 steps from 9-(1-methoxyethyl) anthracene auxiliary and N-methyl maleimide.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available