Abstract
Polypropionates—motifs with alternating methyl and hydroxy groups—are important segments of many natural products possessing high bioactivity and therapeutic value. Synthetic access to these structures remains an area of intensive interest, focusing on the establishment of the contiguous stereocentres and a desire for operational simplicity. Here we report an efficient strategy for the stereoselective assembly of polypropionates with three or four stereocentres through a three-step relay process that include Diels–Alder reaction, silylenol ether hydrolysis and Baeyer–Villiger oxidation. The stereochemistry and functionality of the resulting polypropionates depend on the substitution pattern of the diene and dienophile substrates of the Diels–Alder cycloaddition. More importantly, the relay sequence is effectively performed in one pot, and the product could potentially undergo the same sequence for further elaboration. Finally, the C1–C9 segment of the macrolide etnangien is constructed with four of the six stereogenic centres established using the relay sequence.
Highlights
Polypropionates—motifs with alternating methyl and hydroxy groups—are important segments of many natural products possessing high bioactivity and therapeutic value
Motivated by the intensive interest towards the expedient synthesis of polypropionates, we devise an alternative stereoselective strategy from simple and readily available precursors. This approach involves sequential Diels–Alder cycloaddition of silylenol ethers and enones acting as the respective dienes and dienophiles, silylenol ether hydrolysis to afford a cyclic ketone and Baeyer–Villiger oxidation to enable double oxygen insertions with stereoretention at key positions
Previous studies have demonstrated the strong effect of the terminal substitution of dienes and dienophiles in the exo- and endo-stereochemical outcome of the Diels–Alder reaction[20, 21]
Summary
Polypropionates—motifs with alternating methyl and hydroxy groups—are important segments of many natural products possessing high bioactivity and therapeutic value Synthetic access to these structures remains an area of intensive interest, focusing on the establishment of the contiguous stereocentres and a desire for operational simplicity. Motivated by the intensive interest towards the expedient synthesis of polypropionates, we devise an alternative stereoselective strategy from simple and readily available precursors This approach involves sequential Diels–Alder cycloaddition of silylenol ethers and enones acting as the respective dienes and dienophiles, silylenol ether hydrolysis to afford a cyclic ketone and Baeyer–Villiger oxidation to enable double oxygen insertions with stereoretention at key positions. The relay sequence provides a suitable access into polypropionates with three or four contiguous stereocentres both in stepwise and one-pot manner Using this procedure, the synthesis of the C1–C9 segment of the macrolide natural product etnangien is successfully demonstrated
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