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Title: Studies towards the total synthesis of neolaulimalide and laulimalide and synthesis of novel laulimalide analogues
Author: Hutchinson, J. K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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Neolaulimalide (1) and laulimalide (2) are structurally related cytotoxic marine polyketides belonging to the microtubule-stabilising family of anti-cancer agents. Our approach toward the laulimalides is based on the highly convergent synthesis of a common advanced intermediate 3 which, it was imagined, could be used to obtain both natural products. It was envisaged that the synthesis of 3 would feature a similar strategy to that of Paterson’s second generation route to laulimalide. The key fragment coupling would be mediated by an asymmetric reagent-controlled boron aldol reaction between methyl ketone 4 and aldehyde 5, followed by a macrolactonisation under Mitsunobu conditions to construct the macrocycle. The central dihydropyran moiety of the C1-C14 methyl ketone 4 was constructed using an asymmetric Jacobsen’s Hetero-Diels-Alder (HDA) reaction between aldehyde 6 and Danishefsky’s diene (7). The C13-C28 aldehyde was assembled from an aldol addition/elimination reaction between pyran aldehyde 8, itself constructed using a ring-closing metathesis approach from (R)-glycidol, and methyl ketone 10 (derived from (S)-malic acid). Difficulties were encountered when performing the key Mitsunobu macrolactonisation reaction upon advanced seco-acid substrates, in which the sterically-hindered allylic alcohol underwent exclusive SN2’-type displacement to deliver the corresponding rearrangement products. The prepared laulimalide analogues 12, 13 and 14 were tested for biological activity, displaying reduced microtubule-stabilising activity and cytotoxicity when compared with the natural product data. a revised strategy towards the laulimalides was therefore envisaged that hinged on a Yamaguchi macrolactonisation protocol in which the unwanted SN2’-type side-reaction would be avoided.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available