Enantioselective Desymmetrization ofmeso-Decalin Diallylic Alcohols by a New Zr-Based Sharpless AE Process: A Novel Approach to the Asymmetric Synthesis of PolyhydroxylatedCelastraceae Sesquiterpene Cores

Abstract

Crude plant extracts of the Celastraceae have been valued since antiquity for their stimulant, appetite suppressive, antiarthritic, antibacterial, insect repellent, and memoryrestorative properties. [1] Pervasive among the secondary metabolites isolated from this class of plants is a large family of polyhydroxylated sesquiterpene esters having a dihydro-bagarofuran skeleton. [2] Many members of this family, partic-ularly esters of three polyhydroxylated agarofurans: euonyminol, 4b-hydroxyalatol, and 14-deoxyalatol, exhibit significant biological activity. These include: triptogelins A-1/A-6 [3a] and celhin A [3b] (antitumor), wilfortrine [4] (immunosuppressive), wilforine [5] (insecticidal), and celangulin [6a] and cathedulins E-3/E-4/E-5 [6b] (insect antifeedant). Additionally, hypoglaunine B and related macrocyclic lactone derivatives of euonyminol have recently been shown to display significant anti-HIV activity [7] (Scheme 1). A B RO RO OR OR OR OH RO RO OR OR OR OH O HO HO OH OH X 1 O OH H X 2 X 4 X 3 AcO AcO OAc O AcO O OAc H O OH O N O OH O O O euonyminol: X 1 ,X 2 ,X 3 ,X 4 = OH 4β-hydroxyalatol: X 1 ,X 3 = OH, X 2 ,X 4 = H 14-deoxyalatol: X 1 ,X 2 ,X 3 ,X 4 = H epoxidative enantioselective desymmetrization hypoglaunine B 4 14 Scheme 1. Desymmetrization strategy. R protecting group, Ac acetyl.One striking feature of the three core structures common to these natural products is a symmetric array of hydroxyl groups on the top face of their ªnorthernº periphery. We were intrigued by the possibility of exploiting this symmetry to facilitate their synthesis. In particular, we identified epoxide B as a pivotal intermediate for the preparation of all the core structures and we envisaged that a two-directional synthesis of meso-diallylic alcohol A followed by epoxidative enantioselective desymmetrization [8] would provide an efficient route to this intermediate (Scheme 1). Here we describe how the successful implementation of this plan required the development of a Zr-based Sharpless asymmetric epoxidation (AE) process for tertiary diallylic alcohols.At the outset of our work, only one trans-decalinic diallylic alcohol had been reported. [9] In view of this limited precedent, and the potentially labile nature of the structure, we opted to evaluate the feasibility of our strategy on simple model system 5 (Scheme 2). Epoxide 1 was prepared from naphthalene by Birch reduction (Na/NH 3 ; 74 % yield) then epoxidation (CH 3 CO 3 H; 87 % yield). [10] Ring opening with Et 2 AlCN, [11] followed by completely diastereoselective epoxidation and trans-diaxial ring opening with Me 3 Al gave triol 4. Selective mesylation then anti elimination in neat DBU furnished the requisite diallylic alcohol 5. This alcohol was prone to partial [1,3]-allylic rearrangement to give the corresponding conjugated dienyl alcohol on silica, but could be obtained pure after chromatography on grade 1 basic alumina.Sharpless AE [12] with either catalytic [13] or stoichiometric [13] amounts of Ti(OiPr) 4 /d-(À)-diisopropyl tartrate (DIPT) pro-...

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