Total synthesis of marine natural products without using protecting groups

Abstract

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups--the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less. Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups.

Direct B‐Alkyl Suzuki–Miyaura Cross‐Coupling of Trialkyl‐ boranes with Aryl Bromides in the Presence of Unmasked Acidic or Basic Functions and Base‐Labile Protections under Mild Non‐Aqueous Conditions

“…[31] The smooth coupling of 4-bromoaniline, a problematic substrate, was illustrative of the scope of this protocol (entry 11). Furthermore, our protocol also worked well with substrates bearing highly electron-donating amine functions and nitrogen heterocycle (entries [12][13][14].…”

“…[13] A systematic study on the direct B-alkyl Suzuki coupling in the presence of acidic functions proper (e.g., carboxylic acids and phenols) is lacking. [14] Besides, basic functions such as amines might interfere with transition metal catalysis.…”

Selective chemical reactions in supercritical carbon dioxide, water, and ionic liquids

“…Switching from an organic solvent to scCO 2 , water, or an ionic media can result in: (1) recycling and reusing the catalyst; (2) increasing the solubility and the stability of the catalyst; (3) increasing the reactivity and the selectivity of some specific reactions; (4) increasing the efficiency of the reaction (e.g. E-factor (282)), synthesis without protections (283,284), and with minimum reaction steps); (5) exploring new reactivities; and finally (6) improving the design to decrease toxic wastes and byproducts. The unusual chemical and physical properties of scCO 2 such as low toxicity, easy separations, variable density, low viscosity, low surface tension, nonflammability, and naturally abundancy is well established.…”

Green chemistry for chemical synthesis

“…Recently, progress has been made on this subject. For example, Baran et al (44) have reported a total synthesis of a natural product without any protecting groups. Another instance is the efficient synthesis of (ϩ)-3-deoxy-D-glycero-D-galactononulosonic acid (KDN) by using the indium-mediated allylation reaction in water reported by Chan and Li (Scheme 9) (45).…”