Abstract
A practical synthesis of a novel oxabicyclo[6.2.1]undecenetriol useful as a medicinal chemistry scaffold has been developed starting from l‐ribose. The sequence involves an oxidation/Grignard addition sequence and a challenging ring‐closing metathesis (RCM) reaction as the ring forming step. Exploration of the RCM substrate protecting groups revealed the key factor for successful nine‐membered medium ring formation to be conformational bias of the reacting alkenes of the RCM substrate by very bulky silyl ether protecting groups. The synthesis also allowed access to an epimeric triol and saturated and unsaturated variants of the nine‐membered ring. The medium ring conformation of the oxabicyclo[6.2.1]undecenetriol was determined by X‐ray crystallography and correlated to the solution state conformation by NMR experiments.
Highlights
Oxygen-containing medium rings are found in bioactive natural products such as the cladiellanes,[1] Laurencia medium ring ethers,[2] and polycyclic ethers, e.g. brevetoxin-A and ciguatoxin.[3]
ring-closing metathesis (RCM) reactions have found extensive use in the synthesis of natural products.[8,9,10,11]. This approach has been used with varying degrees of success on a broad range of substrates to overcome the challenges of medium ring and macrocycle formation.[12,13,14]
Synthesis began from the unnatural sugar, L-ribose, which was fully protected as the acetonide and diacetate 6 using literature procedures (Scheme 3).[19]
Summary
Oxygen-containing medium rings (defined as rings of 8–11 atoms) are found in bioactive natural products such as the cladiellanes,[1] Laurencia medium ring ethers,[2] and polycyclic ethers, e.g. brevetoxin-A and ciguatoxin.[3]. 2,6-Lutidine (0.071 mL, 0.61 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.11 mL, 0.49 mmol) were added to a stirred solution of (1S)- and (1R)(2R,3R,4S,5R)-2-[1-(naphthalen-2-ylmethoxy)pent-4-en-1-yl]-5-(prop2-en-1-yl)oxolane-3,4-diol (0.045 g, 0.12 mmol) in CH2Cl2 (2.0 mL) under a N2 atmosphere at room temp. Aq., 10 mL) was added to (1S)- and (1R)-1-[(3aS,4S,6R,6aR)-2,2-dimethyl-6-(prop-2-en-1-yl)-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4yl]pent-4-en-1-ol (9) (0.63 g, 2.4 mmol) and the resultant solution stirred for 20 min at room temp.
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