Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

Abstract

A group of naturally occurring substances containing nitrogen is widely distributed in plants as well as in fungi, animal, marine organisms, and insects, and many exhibit significant biological activity. These natural products with a huge variety of chemical structures include antibiotics, antitumor agents, immunostimulants, drugs affecting the cardiovascular and central nervous systems, analgesics etc. The diverse activities and low natural abundance of this group of natural products when coupled with their molecular complexity warrant development of new and efficient synthetic methods and strategy for the total synthesis of these products, in particular alkaloids. The purpose of this review is to describe some of our achievements in the total synthesis of the naturally-occurring bases including the Dendrobatid alkaloids pumiliotoxin B and allopumiliotoxin A, the anitibiotic streptazolin, the tricyclic marine alkaloids isolated from the ascidians such as fasicularin, lepadiformine, and cylindricine C, and the dimeric monoterpene alkaloid incarvillateine as well as the formal total synthesis of the spirocyclic marine alkaloids halichlorine and pinnaic acid, which are isolated from the Japanese marine sponge and the Okinawan bivalve, respectively.

Synthesis of (–)‐(S)‐Norlaudanosine, (+)‐(R)‐O,O‐Dimethylcoclaurine, and (+)‐(R)‐Salsolidine by Alkylation of an α‐Aminonitrile

“…K 2 CO 3 solution (9 mL) and water (6 mL) were added and the mixture was extracted with ethyl acetate (3 ϫ 10 mL). The combined organic layers were dried with Na 2 SO 4 and the solvent was removed in vacuo to furnish a slightly brown oil (514 mg), which was purified by column chromatography (silica, eluent petroleum ether/EtOAc/Et 2 + (100 %). These data are in accordance with the values reported in the literature.…”

“…[1] Both synthetic compounds and natural products containing nitrogen frequently exhibit potent biological activities. [2] An example is the large group of tetrahydroisoquinoline alkaloids, several members of which have become classical targets for the development of new synthetic methodologies. [3][4][5][6][7] Here we report on a short asymmetric approach to α-branched secondary amines and its application to the synthesis of 1-substituted 1,2,3,4-tetrahydrosioquinoline alkaloids.…”

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

“…That the wide range of biological activities possessed by these molecules have attracted much attention of synthetic organic chemists, and numerous approaches have been reported [7–9]. Pumiliotoxin 251D (PTX 251D) ( 2 ) is the first structurally defined member of pumiliotoxins, a class of dendrobatid alkaloids isolated from Ecuadorean poisonous frog, Dendrobares tricolor in 1980 [10].…”

New One-Pot Methodologies for the Modification or Synthesis of Alkaloid Scaffolds

“…These reactions have numerous applications in the field of total synthesis of natural products, particularly in avoiding the costly protection/deprotection processes and purification of intermediates [2–6]. The importance of these reactions to the organic synthesis community is illustrated by the numerous reviews that have discussed different aspects of these reactions [2–11]. Most of these reviews discuss one-pot reactions that were developed during the total synthesis of selected examples of natural products (either as designed or serendipitous developments) such as Nicolaou’s [4–6] and Tietze’s reviews [2,3].…”

“…Synthesis of heterocycles by one-pot methodologies were discussed in detail in Padwa’s reviews [9,10]. Specific reviews on the construction of alkaloids are not found with the exception of Kobayashi’s review that discussed new methodologies developed for the total synthesis of some select examples of alkaloids [11]. …”