Greaney, Michael

Lam, Hon

Hulme, Alison

Ralston, Kevin John

Cancer Research UK

2015-02-23T14:37:43Z

2015-02-23T14:37:43Z

2014-11-27

Structure–activity relationships (SARs) in the disorazole family have been revealed through the biological testing of natural disorazoles and their synthetic analogues, but little is known about the contribution of the oxazole to the anti-tubulin activity of disorazole C1 I. The development of a novel Evans–Tishchenko/alkyne metathesis (ET–AM) route towards the synthesis of disorazole C1 will provide straightforward access to disorazole C1 and its heterocyclic analogues, thus allowing the contribution of the oxazole to the natural product’s bioactivity to be elucidated. Our ET–AM approach offers a highly diastereoselective and convergent means of constructing heterocyclic analogues of the disorazole C1 scaffold Het-II. It is envisaged that ET coupling of C(1)–C(9) aldehydes Het-IV to the C(10)–C(19) β-hydroxyketone V will give the key, requisite, 1,3-anti diol monoester bis-alkynes Het-III for dimerisation via an alkyne cross-metathesis/ring-closing alkyne metathesis (ACM–RCAM) reaction. Further diversification may be achieved through the synthesis of C(6)-heteroatom analogues of the C(1)–C(9) fragment Het-IV. Chapter 2 outlines efforts towards the synthesis of C(6)-amino analogues Het-VI of the C(1)–C(9) fragment IV. Elaboration of Garner’s aldehyde VIII allowed the synthesis of the N-protected C(5)–C(9) mesylate VII; an analogue of an advanced C(1)–C(9) fragment intermediate. A scalable route towards the synthesis of the C(10)–C(19) fragment V and investigations into its reactivity under ET coupling conditions are critical to the success of our ET–AM approach. Chapter 3 details convergent approaches towards the synthesis of the C(10)–C(19) β-hydroxyketone V, which centred around: (i) an olefin cross-metathesis reaction [C(11)–C(12) disconnection]; (ii) an epoxide ringopening reaction [C(12)–C(13) disconnection]; and (iii) a Mukaiyama aldol reaction [C(14)–C(15) disconnection]. Chapter 4 describes our successful linear synthesis of the β-hydroxyketone V. Gram-scale preparation of the C(10)–C(19) fragment V permitted investigation into the viability of the ET reaction as a fragment coupling strategy, the results of which are reported in Chapter 5. Although many (hetero)aryl aldehydes failed to react, the successful coupling of electron-deficient substrates allowed a contingency strategy to be explored through preparation of the mono-protected diol IX. Esterification of IX with the carboxylic acid derivative of the C(1)–C(9) oxazole has allowed generation of the C(1)–C(9)/C(10')–C(19') bis-alkyne X required for future AM investigations.

http://hdl.handle.net/1842/9954

en

The University of Edinburgh

“The Evans–Tishchenko Reaction: Scope and Applications” Ralston, K. J.; Hulme, A. N. Synthesis 2012, 44, 2310–2324. DOI: 10.1055/s-0032-1316544 http://dx.doi.org/10.1055/s-0032-1316544

Attribution-NonCommercial-ShareAlike 4.0 International

http://creativecommons.org/licenses/by-nc-sa/4.0/

disorazole C

organic chemistry

natural product synthesis

Studies towards the total synthesis of Disorazole C1 and its analogues

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy