Studies towards the total synthesis of Disorazole C1 and its analogues
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Date
27/11/2014Author
Ralston, Kevin John
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Abstract
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.
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