Total Synthesis and Stereochemical Assignment of Myriaporones 1, 3, and 4

Abstract

The natural products tedanolide (1 a) and 13-deoxytedanolide (1 b), which were isolated by Schmitz et al. [1] and Fusetani et al., [2] respectively, exhibit picomolar activity against a range of cancer cell lines. Their biological activity coupled with their scarcity has prompted considerable synthetic attention.[3] Our interest in these compounds stems from the isolation of a related class of natural products, the myriaporones (2 a-d), reported by Rinehart et al. in 1995. [4, 5] The myriaporones are nearly identical structurally to the C10-C23 portion of tedanolide (1 a); it is therefore possible that these two classes of compounds share the same biological receptor and have similar modes of action. As a result of their limited availability, the biology of both classes remains a mystery. Therefore, our goal is to provide material to facilitate such studies and, herein, we report the total synthesis of myriaporones 1, 3, and 4 (2 a, c, d) and the unambiguous assignment of their previously undetermined stereogenic configurations at C5 and C6.Recently, we reported the completion of the carbon skeleton of myriaporone 1 (2 a) through a stereoselective homoallenylboration and a nitrile oxide cycloaddition.[5a]Construction of myriaporone 4 (2 d) began with known alcohol 3[3c] (Scheme 1). Oxidation with IBX [6] was followed by an Evans aldol [7] reaction to set the C8 and C9 stereocenters in high yield and excellent diastereoselectivity. During the course of that work, incorporation of the epoxide at an early stage limited the scope of reaction conditions that subsequent intermediates could withstand and ultimately prevented completion of the total synthesis. Since then, Loh and Feng [3g] and Smith III et al. [3k] reported highly selective late-stage epoxidations in their efforts toward tedanolide. With these results as precedence, our focus switched to the incorporation of this particularly sensitive functional group in the penultimate step of the synthesis. Scheme 1. Synthesis of C5-epimeric isoxazolines 9 a and 9 b. Reagents and conditions: a) IBX, 95 %; b) Bu 2 BOTf, Et 3 N, 93 %; c) TBSOTf, 85 %; d) LiBH 4 ; e) TBSCl, 89 % (two steps); f) OsO 4 , NMO, 95 %; g) NaIO 4 , 84%; h) Bu 2 BOTf, Et 3 N, 99 %; i) LiBH 4 ; j) TBSCl, 92 % (two steps); k) PrNO 2 , PhNCO, 64 %; l) DDQ, 88 %; m) IBX; n) Ph 3 P= CHCH 3 , 63 % (two steps). IBX = o-iodoxybenzoic acid; Tf = trifluoromethanesulfonyl; TBS = tert-butyldimethylsilyl; NMO = N-methylmorpholine-N-oxide; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

“…Yet encouragingly, results were obtained by addition of a nickel complex or salts of copper and palladium (Table 1). Among them, it was found that only copper salts gave significant conversions without counter-anion effects (Table 1, entries [4][5][6].…”

“…[2] on treatment with various reagents, such as aryl isocyanates, [3][4][5][6][7][8][9] inorganic [10,11] and organic [12][13][14][15] chlorides or organic anhydrides, [16,17] in the presence of a dipolarophile and often a base, the isoxazole derivatives are produced besides the discarded material derived from the reagent employed [Eq. (1)].…”

The Total Synthesis of (+)‐Tedanolide—A Macrocyclic Polyketide from Marine Sponge Tedania ignis

“…For the final epoxidation we intended to use unprotected lactone 49 . When 49 was treated with substoichiometric amounts of m CPBA at −45 °C preferentially the Δ 18 allylic alcohol was epoxidized to give tedanolide ( 1 ) 31. Unfortunately a separation of 49 and epoxide 1 via column chromatography was not successful, even when RP‐18 silica gel was used.…”

A Topographically Optimized Substrate with Well‐Ordered Lattice Micropatterns for Enhancing the Osteogenic Differentiation of Murine Mesenchymal Stem Cells

“…As the proposed configuration at C10–C14 (Scheme ) was based on the comparison of NMR data,9 we prepared the C9–C17 fragment 7 (Scheme ) to provide further support for this assignment. Methyl ( S )‐3‐hydroxy‐2‐methylpropionate ( 4 ) was converted to aldehyde 5 according to our previously reported route 2a. Utilization of a reaction sequence involving an Evans anti aldol reaction,6, 11 deprotection,12 and Wittig olefination efficiently converted aldehyde 5 to the allylic alcohol 6 .…”