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Title: Studies towards the total synthesis of phorboxazoles A and B
Author: Arnott, E. A.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
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The Thesis describes work directed towards the total synthesis of phorboxazoles A(1) and B(2), marine macrolides recently isolated from an Indian Ocean sponge of the genus Phorbas which show potent cytostatic activity with S-phase arrest (mean NCI GI50 < 1.6 nM). (Fig. 0909A) Our convergent disconnection strategy required a central C20-C32 fragment (6) containing five stereocentres. The C23-C26 stereotetrads of (E)-enoates 194 and 205 were established with 97% ds using a stereoselective boron-mediated anti anti aldol reaction between (E)-aldehyde 22 and (S)-ketone 23 or 40, followed by substrate-directed 1,3-anti reduction using (inter alia) Evans-Tishchenko reduction. HWE olefination to 194 was followed by methanolysis to give tetrahydropyran ester 18 in 14% yield over 7 steps. The diastereoselectivity of the intramolecular hetero-Michael cyclisation (60% ds at C22) was later improved to 80% ds by subjecting 205 to an alternative reduction-oxidation procedure to afford aldehyde 6 in 26% yield over 8 steps. (Fig. 0909B) Hemiacetals 246 and 253 were synthesised from 211 to demonstrate the viability of the planned C32-C33 disconnection via metallation of the oxazole 2-methyl position. In order to achieve the desired deprotonation at the 2-methyl site, it proved necessary to block the 5-position of the oxazole ring (C30) with a TMS group, achieved in 70% yield using an in situ anion-trapping method. It was also advantageous to protect the C20 hydroxyl with a TBS group prior to 2-methyl functionalisation, giving 253 in 77% yield. Model studies using acetonide 159 revealed that using a δ-lactone rather than an aldehyde as the electrophile gave higher and more reproducible yields, with the additional advantage of direct access to the desired hemiacetal functionality (e.g. δ-valerolactone for 246 and 253). (Fig. 0909C) In order to investigate the feasibility of the intended C19-C20 olefination, a range of C15-C19 olefination reagents were synthesised from bromide 258, after using radical chemistry to functionalise the oxazole 2-methyl group of 104. In model Horner-Wadsworth-Emmons (HWE) reactions leading to olefin 267, diisopropylphosphonate 268 provided better (E)-selectivity than diethylphosphonate 266, which gave only 50% ds with MHMS (M = Li, Na, or K). For 266, use of KHMDS/18-crown-6 increased the E:Z ratio to 75:25, but this was surpassed by the tributylphosphonium ylide derived from 276, which afforded 267 in 88% ds. (Fig. 0909D) The same Wittig conditions were applied to C20-C32 fragment 6 to produce C15-C32 olefin 256 in 91% yield with 89% ds in favour of (E)-256. The convenience of the in situ phosphonium salt formation and the low basicity of the corresponding ylide makes this a promising fragment coupling reaction for use in a future total synthesis of the phorboxazoles.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available