Convergent stereospecific total synthesis of monochiral Monocillin I related macrolides

Solution‐ and Solid‐Phase Synthesis of Radicicol (Monorden) and Pochonin C

“…[3] The absolute stereochemistry of its three chiral centers was assigned by X-ray crystallography [4] and confirmed by total synthesis. [5,6] The reported biological activity initially attributed to this compound did not arouse much interest until it was reported that radicicol was a tyrosine kinase inhibitor. [7] It was later discovered that the inhibitory effect of radicicol for certain kinases stemmed from the fact that radicicol was an inhibitor of HSP90; [8,9] this molecular chaperone is necessary for the maturation and function of the kinases whose inhibition was originally observed.…”

Modular Asymmetric Synthesis of Pochonin C

“…A major criterion in such analysis is the commercial availability or ease of preparation of the fragments. Inspired by the previous work in the area, [8,9] we reasoned that the molecule could be disconnected into three fragments as shown in Scheme 2; both possible diastereoisomers of the C5 chlorine center would stem from the cis-or trans-epoxide moiety 4. Given that ring-closing metathesis (RCM) of the conjugated diene could lead to four different products (12-versus 14-membered ring and cis/trans isomers), it was reasoned that keeping the a,b-conjugated olefin masked as a thioether could prevent undesired cyclization to the 12-membered ring.…”

“…After investigating several reaction-sequence permutations, it was found that both operations could be carried out in a single step by using an excess of SO 2 Cl 2 (no overchlorination of the aromatic ring was observed). [8,23] Final deprotection of the MOM groups from 15 led to compound 1 (Table 1), which was found to have identical NMR spectra to pochonin C. [24] Importantly, treatment of compound 1 with K 2 CO 3 led to rapid and clean oxirane formation to yield compound 2, which was identical to radicicol (Scheme 5).…”

Organic Synthesis and Biological Signal Transduction

“…In addition to its activity as an antifungal antibiotic [23] and a tranquilizer, [24] radicicol was particurlarly intensively examined for its selective and potent PTK-inhibitory activity. [25] Since the natural substance is difficult to isolate, development of an efficient total synthesis (only one is published so far [26] ) provides the opportunity to produce enough material for biological and medical studies. Particular challenges for the synthesis were the construction of the 14-member macrolactone and of the conjugate dienone epoxide with a E and Z double bond.…”