Ruthenium-catalyzed hydrogen transfer from 4-aminobutanol to butadiene results in the pairwise generation of 3,4-dihydro-2H-pyrrole and an allylruthenium complex, which combine to form products of imine anti-crotylation. In couplings of 1-substituted-1,3-dienes, novel C2 regioselectivity is observed. As corroborated by deuterium labeling studies, kinetically preferred hydrometalation of the terminal olefin of the 1-substituted-1,3-diene delivers a 1,1-disubstituted π-allylruthenium complex that isomerizes to a thermodynamically more stable monosubstituted π-allylruthenium complex, which undergoes imine addition with allylic inversion through a closed transition structure. Direct ruthenium-catalyzed diene hydroaminoalkylations with pyrrolidine also are described.
The direct metal-catalyzed [1,3]-transposition of allylic alcohols and allylic silyl ethers is a synthetically useful isomerization process that occurs via [3,3]-sigmatropic rearrangement induced by high oxidation state oxometal complexes. The isomerization requires only a catalytic amount of promoter, and high chirality transfer can be achieved. Thus, it bears a significant potential to become a powerful tool in multistep synthesis. Although [1,3]-transposition of allylic alcohols has been known since the late 1960s, the development of synthetically useful protocols that allow for a high level of regio- and stereoselectivity control and their synthetic applications have emerged only recently. This tutorial review summarizes recently developed regioselective [1,3]-transpositions of allylic alcohols and silyl ethers and their applications to natural product synthesis.
β-Ketonitriles bearing a quaternary carbon at the 2-position were prepared through Rh-catalyzed addition of aryl boronic acids to 2,2-disubstituted malononitriles. In contrast to the previously described transnitrilative cyanation of aryl boronic acids with dialkylmalononitriles, the present reaction avoids retro-Thorpe collapse of the intermediate addition product through the use of a milder base. The reaction was amenable to a variety of aryl boronic acids and disubstituted malononitriles, providing a diverse array of β-ketonitriles. The products could be further derivatized to valuable chiral α,α-disubstituted-β-aminonitriles through addition reactions to the corresponding N-tert-butanesulfinyl imines.
An asymmetric total synthesis of (-)-amphidinolide V was accomplished. The synthesis features a base-catalyzed alkynyl silane alcoholysis/ring-closing enyne metathesis sequence for facile construction of a 1,3-diene motif. A diene RCM followed by a ring-contractive allylic transposition of cyclic silyl ethers was incorporated for the stereoselective installation of a functionalized 1,5-diene subunit. An efficient proline-mediated direct cross-aldol condensation of two advanced aldehyde intermediates was utilized for the construction of a key α,β-unsaturated epoxyaldehyde. This total synthesis demonstrates the prowess of metal-catalyzed transformations in complex molecule synthesis.
The synthesis and biological evaluation of chromane-containing bryostatin analogues WN-2 to WN-7 and the previously reported salicylate-based analogue WN-8 are described. Analogues WN-2 to WN-7 are prepared through convergent assembly of the chromane-containing Fragment B-I with the “binding domain” Fragment A-I or its C26-des-methyl congener, Fragment A-II. The synthesis of Fragment B-I features enantioselective double C-H allylation of 1,3-propane diol to form the C2-symmetric diol 3 and Heck cyclization of bromodiene 5 to form the chromane core. The synthesis of salicylate WN-8 is accomplished through the union of Fragments A-III and B-II. The highest binding affinities for PKCα are observed for the C26-des-methyl analogues WN-3 (Ki = 63.9 nM) and WN-7 (Ki = 63.1 nM). All analogues, WN-2 to WN-8, inhibited growth of Toledo cells, with the most potent analogue being WN-7. This response, however, does not distinguish between phorbol ester-like and bryostatin-like behavior. In contrast, while many of the analogues contain a conserved C-ring in the binding domain and other features common to analogues with bryostatin-like properties, all analogues evaluated in the U937 proliferation and cell attachment assays displayed phorbol ester-like and/or toxic behavior, including WN-8, for which “bryostatin-like PKC modulatory activities” previously was suggested solely based on PKC binding. These results underscore the importance of considering downstream biological effects, as tumor suppression cannot be inferred from potent PKC binding.
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