一、 不對稱合成(–)-Shikimic Acid二、 探索(–)-Ovalicin的合成途徑

Abstract

Asymmetric Synthesis of (–)-Shikimic Acid The synthesis commenced with commercially available cheap L-tartaric acid or its derivative dimethyl 2,3-O-isopropylidenetartrate. Exposure of the tartarate with DIBAL-H followed by a highly diastereoselective divinyl zinc addition to the in situ generated dialdehyde, afforded the desired vinyl carbinol (82% yield). For formation of the six-membered ring and installation of the epoxide unit, we envisioned acid-promoted isomerization of the trans fused-ring in RCM product followed by epoxidation. Expectedly, ring-closing metathesis of vinyl carbinol with Grubbs’ 2nd generation catalyst followed by TFA-promoted isomerization of the in situ generated trans diol and epoxidation with mCPBA resulted in efficient formation of the desired epoxide. A significant advantage of this one-pot transformation is that no resolution steps are required, and because of it’s C2 symmetry before a shift of acetonide protecting group, there is no loss in yield due to the formation of diastereomers. Acylation of the cis diol with acetoxyisobytryl bromide led to trans bromoacetate as the only product. Selective cleavage of the acetate was achieved by treatment with LiBH4 to provide the desired bromohydrin in 89% yield. Subsequent mesylation of the hydroxyl group followed by treatment with DBU in refluxing DME furnished the epoxyvinyl bromide. With unsaturated epoxide in hand, the stage was set for regiocontrolled reductive cleavage of epoxide by SN2 chemistry. Most gratifyingly, exposure of vinylepoxide to LiAlH4 in ether at 0 oC for 15 min smoothly and exceedingly cleanly effected the desired cleavage to lead to unsaturated bromo alcohol in 88% yield. Elaboration of bromo alcohol to (–)-shikimic acid was initiated by treatment with tBuLi followed by quenching with CO2 and removal of the acetal protecting group with HOAc/H2O producing (–)-shikimic acid, which was characterized as its triacetate derivative. Synthetic Studies toward (–)-Ovalicin The synthesis commenced with commercially available cheap D-tartaric acid or its derivative dimethyl 2,3-O-isopropylidenetartrate. Exposure of the tartarate with DIBAL-H followed by a highly diastereoselective divinyl zinc addition to the in situ generated dialdehyde, afforded the desired vinyl carbinol (83% yield). Formation of the six-membered ring called for an acid-promoted isomerization of the trans fused-ring in RCM product. Expectedly, ring-closing metathesis of vinyl carbinol with Grubbs’ 2nd generation catalyst followed by TFA-promoted isomerization of the in situ generated trans diol resulted in efficient formation of the desired cis diol. Selective benzylation of the unsaturated vicinal diol was achieved by treatment with Bu2SnO, tetrabutylammonium iodide, and benzyl bromide to afford benzyloxy alcohol in high yield and good regioselectivity (>6:1). Protection of the hydroxyl group as methyl ether followed by HOAc/H2O promoted removal of the acetal protecting group provided the unsaturated cis diol in excellent yield. Conditions for oxidizing the allylic alcohol to the corresponding enone have been screened, and the PDC-DMF mediated oxidation at 0 oC afforded unsaturated ketone in 66% yield. Conjugate reduction of enone with H2/Pd/C and nucleophilic addition of the CH2N2 to the carbonyl group yielded epoxy alcohol. Subsequent oxidation of the hydroxy group was achieved by treating with Dess-Martin periodinane to afford epoxy ketone in 91% yield. Finally, elaboration of epoxy ketone to (–)-ovalicin called for the cleavage of the benzyl ether, coupling of epoxy ketone with alkenyllithium, selective epoxidation of C-C double bond, and oxidation of the hydroxy group. We found that the disclosed protocol reported by Samadi et al. is well suited for this task.