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Abstract

A hydroxyl-directed syn-hydroboration of propargyl alcohols was developed (Scheme 1). This protocol allows for the one-pot transformations of propargyl alcohols into trisubstituted allyl alcohols. A transient linker was employed to extend the ‘reach’ of the propargyl alcohol to direct the hydroborating agent. Subsequent in situ oxidation of the borane and transition-metal catalyzed cross-couplings with alkynyl-, alkenyl-, aryl- and alkylhalides were demonstrated.
With reliable access to highly functionalized and stereodefined alkenylstannanes from previous works in our group, we sought to utilize this motif in complex molecule synthesis. Tubelactomicin A (246) was selected as an ideal target, containing an intriguing (hydroxymethyl)acrylic acid motif in the southern domain (Scheme 2). To realize our goal, a palladium catalyzed oxidative methoxy carbonylation of alkenylstannanes was developed, which provides direct access to α,β-unsaturated ester motifs in a single step. This in turn enabled a significant improvement in the route to fragment 272.
Next, we developed a methodology to convert alkenylstannanes to ketones, as this type of transformation had been previously limited to alkenylsilanes and alkenylboranes. Inspired by the well-known Chan-Lam coupling, we discovered that hydroxyl flanked alkenylstannanes could be transformed into α-acetoxy ketones in a copper-mediated process (Scheme 3). The reaction is proposed to proceed via copper species 419. Furthermore, we found that stannanes lacking an assisting hydroxyl group could be converted into the corresponding ketones utilizing copper(II) trifluoroacetate.
Additionally, a reliable and broadly applicable method for the fluorination of alkenylstannanes was developed (Scheme 4). A mild protocol employing silver diphenylphosphinate and F-TEDA-PF6 allowed access to various alkenyl fluorides. This method was then applied to the synthesis of biologically interesting peptide isosters such as 530.
Lastly, we achieved a highly convergent and efficient synthesis of 5,6-dihydrocineromycin B (615) utilizing multiple catalytic methods developed in our laboratory, namely ring-closing alkyne metathesis (RCAM), trans-selective hydrostannation, and methyl-Stille cross-coupling (Scheme 5). Furthermore, the late-stage functionalization of alkenylstannane 647 enabled divergent preparation of five additional non-natural analogs for biological evaluation.