Enantioselective Synthesis of Euonyminol

Abstract

We describe an enantioselective total synthesis of the nonahydroxylated sesquiterpenoid euonyminol, the dihydro-βagarofuran nucleus of the macrocyclic terpenoid alkaloids known as the cathedulins. Key features of the synthetic sequence include a highly diastereoselective intramolecular alkene oxyalkylation to establish the C10 quaternary center, an intramolecular aldol− dehydration to access the tricyclic scaffold of the target, a tandem lactonization−epoxide opening to form the trans-C2−C3 vicinal diol residue, and a late-stage diastereoselective α-ketol rearrangement. The synthesis provides the first synthetic access to enantioenriched euonyminol and establishes a platform to synthesize the cathedulins.

Development of an Enantioselective Synthesis of (−)-Euonyminol

“…Unfortunately, while the 1,2-addition to the alkynyl aldehyde 39 proceeded to form the desired configuration at C1 (see 39 → 41, Scheme 4a), the 1,2-addition to the ketoaldehyde 55 was more challenging (Table 2). 14 Treatment of 55 with a variety of nucleophiles, including vinyllithium, vinylmagnesium bromide, and ethynylmagnesium bromide, resulted in the recovery of the starting material (entries 1−5). Fortunately, when ethynylmagnesium bromide was used as nucleophile and lanthanum chloride was used as additive, the 1,2-addition product 56 was obtained in 94% yield and with >20:1 diastereoselectivity at C1 ( 1 H NMR analysis; entry 6).…”

“…However, despite extensive efforts aimed at achieving this transformation, we were unsuccessful (Table 3). 14 For example, when the iron-based catalyst (Fe-PDP) developed by Chen and White was employed, 33 we observed only the selective oxidation of the primary methoxymethyl ether group without any oxidation at C8 (entries 1−2). Similarly, the use of small dioxiranes oxidants (DMDO or TFDO) 34 did not result in any productive C−H oxidation.…”

“…The compounds 1−2, 24 −25, 32−34, 36, 36a, 54−58, 61− 62, 64, 77−82, 85, and 91−92 were prepared according to published procedures. 14 The methoxymethyl ether 21, 21 the Shi ketone S1, 22 the N-xanthylamide S11, 17a and the N-bromoamide S12 17b were prepared according to published procedures.…”

“…NMR spectroscopic data for the unsaturated ketone 64 obtained in this way were in agreement with those previously reported. 14 Synthesis of the Diol 83.…”

“…We recently disclosed a synthetic route to (−)-euonyminol (1) from (R)-carvone. 14 We envision that, with further refinement, this route may serve as an entry to the cathedulins. Here we describe in full the development of our successful synthetic strategy including several alternative approaches to the target and new improvements in streamlining the synthesis including a shorter, higher-yielding strategy to construct the trans-decalin ring of 1.…”