In this article the formal total synthesis of mandelalide A has been described in details. The highly convergent and flexible strategy developed for mandelalide A involved the construction of key building blocks ent-9 and 7, and their assembly to the target compound. For the synthesis and coupling of these building blocks, the Brown's crotylation, Sharpless asymmetric dihydroxylation followed by in situ Williamson type etherification, modified Prins cyclization, Masamune-Roush olefination and Heck cyclization were employed, the latter being crucial for the highly stereoselective formation of the macrocycle of mandelalide A. Initially, Julia Kocienski olefination, ring-closing metathesis reaction were investigated for the synthesis of the aglycone of the proposed structure of the mandelalide A, and found to be unsuccessful.
A practical
chemoenzymatic process has been developed for the preparation
of optically pure (S)-7-((tert-butyldiphenylsilyl)oxy)hept-1-yn-4-ol,
(S)-4. This was prepared via enantioselective
acylation of racemic homopropargylic alcohol (+/−)-4 catalyzed by Amano lipase from Pseudomonas fluorescens. The acylation reaction was studied in a packed-bed reactor (PBR)
for the production of optically pure alcohol (S)-4 in a continuous mode. The estimated kinetic parameters were V
max 3.46 (±0.17) mM/h/g and apparent K
m value, K
m,app =
582.10 (± 29.10) mM (correlation coeff. r =
0.96). At a substrate concentration of 100 mg/mL (272 mM) and a flow
rate of 0.1 mL/min, both the isomers are obtained in >95% theoretical
yield and > 99% e.e. at steady state in a PBR
with
3.6 g enzyme. The advantage of this protocol is that the enzyme can
be recycled many times. Finally, this was converted to (R)-tert-butyl((4-chloro-6-iodohept-6-en-1-yl)oxy)diphenylsilane, 3, which is the key building block for the synthesis of the
C14-C19 intermediate of eribulin.
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