Arrays of amino-acid-derived isocyanoamides are conveniently produced on a multigram scale in one step by the solventless aminolysis of the corresponding methyl esters with primary or secondary aliphatic amines. Most of the corresponding isocyanides precipitate during the reaction and can be filtered to yield highly pure, colorless, and odorless solids. They are potentially useful in the combinatorial chemistry of multicomponent reactions.
The synthesis of the potent antitumor agent, mucocin, 1, was efficiently achieved in 20 steps from
cyclododecatriene, thus confirming the proposed structure of this unusual member of the Annonaceous
acetogenins. Demonstrating the power of the “naked” carbon skeleton strategy, all seven asymmetric centers
in the key fragment of the molecule were introduced by double AE reaction followed by double AD reaction.
Simultaneous two ring closure reactions provided both the THP and THF rings in a single step.
The efficient total synthesis of asimicin, 1, and bullatacin, 2, has demonstrated the advantages of three different strategies for the synthesis of the tricyclic intermediates 6 and 7, which represent the key fragment of the bis-THF Annonaceous acetogenins. The naked carbon skeleton strategy is based on the production of all asymmetric centers by selective placement of the oxygen functions onto an unsaturated, nonfunctionalized carbon skeleton. Diversity in this approach arises from the relative timing of highly stereoselective reactions, such as the Sharpless asymmetric dihydroxylation (AD) reaction, the Kennedy oxidative cyclization (OC) with rhenium(VII) oxide, the Mitsunobu-type alcohol epimerization reaction, and the Williamson etherification reaction. The convergent strategy, which is based on the combinatorial coupling of two series of diastereomeric fragments, to produce intermediates such as 11 and 12, enjoys the advantages of both efficiency and versatility. The third approach, which is based on partially functionalized intermediates, such as 13, combines the advantages of both the linear and the convergent strategies-synthetic efficiency and diversity.
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