An approach to the enantiocontrolled synthesis of pseudomonic acids via a novel mono—claisen rearrangement

A short, efficient approach to a key chiral intermediate for the synthesis of pseudomonic acids A and C is delineated.Pseudomonic acids A($\text{1a}$), B($\text{1b}$), and C($\text{2}$) are members of a novel of “C-glycopyranoside” antimicrobial agents which have recently attracted synthetic attetion.² Presently, we wish to report a short efficient stratedy towards the total synthesis of opticaly active pseudomonic acids. The sequence is highlighted by a novel controlled mono-Claisen rearrangement and a highly regioselective π-allylpalladium mediated displacement.Diacetyl-(L)-arabinal ($\text{3}$)³ was converted to the bis-ketenesilylacetal $\text{4}$ and warmed to 60°C according to the Ireland ester-enolate Claisen rearrangement method.⁴ Over a period of ≈5h, smooth conversion to a major rearranged product $\text{5}$ was observed by 300 MHz NMR. The identity of $\text{5}$ was confirmed by direct desilylation and methylation (KF, KHCO₃, H₂O, HMPA, CH₃I). After flash chromatography, compound $\text{7}$ was isolated in 55% overall yield from $\text{3}$. Careful inspection of the crude methylation product revealed the presence of ≈5% doubly rearranged product $\text{6}$.The rearrangement of $\text{4}$ to $\text{5}$ is a unique example of a selective mono-Claisen rearrangement in which the rate of a second similar Claisen rearrangement ($\text{5}$ → $\text{6}$) is much slower under the reaction conditions. Although the reasons for this interesting selectivity are unclear at this time,⁵ in practice, the mono-Claisen rearrangement obviates the need for selective differentiation of the two hydroxyl groups, a difficult task at best, in this case.Palladium mediated allylic acetate displacement provided an ideal method for introduction of a second chemodifferentiated side chain with allylic retention and retention of stereochemistry. Alkylation of $\text{7}$ with sodiothylmalonate using 5 mole % Pd(O)dppe₂⁶ was unusually facile (<45 min, 25°C, THF). After semi-preparative HPLC, essentially a single regio- and stereoisomer was isolated in 96% yield.⁷ Structure $\text{8}$ was confirmed by extensive ¹H-NMR decoupling, as well as an off-resonance ¹³C-NMR experiment. In particular, H₁ (δ 4.53) was coupled vicinally to H₆ and H₆′ (5 Hz, 8 Hz) and H₂ (1.5 Hz), and allylically to H₃ (2 Hz). In contrast, H₄ (δ 2.78) was coupled to H₇ (10 Hz), H_5e and H_5a (1.8 Hz, 4 Hz), H₃ (5 Hz), and H₂ (<1 Hz). In addition, H₁ and H₄ exhibited a small long range coupling constant (J = <1 Hz). The coupling constants rule out

regioisomer $\text{9}$ and are fully consistent with the indicated conformation, which minimizes 1,3-diaxial-like interactions.Finally, catalytic osmylation of $\text{8}{}^8$ gave a single cis-diol $\text{10}$ in nearly quantitative yield. Appending of suitably functionalized side chains to provide an enantiocontrolled synthesis of pseudomonic acids A($\text{1a}$) and C($\text{2}$) is in progress.^9,10