Enantioselective Total Synthesis of (–)-Myrifabral A and B

Abstract

<p>A catalytic enantioselective approach to the myrioneuron alkaloids (–)-myrifabral A and (–)-myrifabral B is described. The synthesis was enabled by a palladium-catalyzed enantioselective allylic alkylation, that generates the C(10) all-carbon quaternary center. A key N-acyl iminium ion cyclization forged the cyclohexane fused tricyclic core, while vinyl boronate cross metathesis and oxidation afforded the lactol ring of (–)-myrifabral A. Adaptation of previously reported conditions allowed for the conversion of (–)-myrifabral A to (–)-myrifabral B.</p>

The Enantioselective Intermolecular Saegusa Allylation

“…This design facilitates the direct use of different allyls with a single pronucleophile and provides excellent yields and enantioselectivities. With the use of the Pd-PHOX system, we were able to observe intermediate C′ by 31 P NMR during the course of the reaction, leading to the conclusion that the reaction mechanism likely intersects with that of Stoltz's catalytic enantioconvergent decarboxylative allylation method. From a practicality standpoint, the racemic starting materials were all easily prepared and/or commercially available.…”

“…14,42,43 In an effort to gain insight into the reaction mechanism, we decided to run our key reaction using βketoacid 1a and allyl methyl carbonate 2i in THF-D 8 in order to make the direct comparison with 31 P NMR data published for intermediate C′ by the Stoltz group (Scheme 2). 14 Specifically, if our reaction proceeds through a similar mechanism, we reasoned that we should be able to detect intermediate C′ by 31 P NMR during the course of the reaction. Table 2.…”

“…Enantioselective Synthesis of (+)-Adalinine The study commenced by prestirring the palladium catalyst and L1 followed by addition of allyl methyl carbonate 2i (Scheme 2). Following an immediate color change and stirring for 5 min, 31 P NMR data revealed two signals corresponding to free ligand L1 (−5.95 ppm) and a new signal at 31.7 ppm. We presume this new signal at 31.7 ppm to be B′ because previous studies using allyl acetate gave a signal at 31.1 ppm in THF-D 8 .…”

“…14 A small amount of phosphine oxide was also observed after the addition of 1a and the base (27.1 ppm). 14 For comparison to the σ-allyl complexes implicated here, cationic π-allylpalladium complexes, [(t-Bu-Phox)Pd-(η3allyl)]PF 6 , have been reported and generally exhibit 31 P NMR shifts in the 20−23 ppm range. 44 Considering these data, a plausible mechanism for the title transformation is proposed (Scheme 3).…”

Symmetry-Driven Total Synthesis of Myrioneurinol

“…Several simpler bi-and tricyclic members (e.g., 1) were prepared by Bodo and coworkers 2 and others, 3 while efforts toward more complex members have proven rarer. Recent elegant syntheses of myrifabrals A and B (5)(6) by She 4 and Stoltz, 5 and that of myrioneurinol (2) by Weinreb have begun to address this challenge. 6 In continuation of our interest in alkaloid total synthesis, 7 we were drawn to myrioneurinol (2) as arguably one of the most structurally complex nondimeric Myrioneuron alkaloids.…”