Hexahydropyrrolo[2,3-b ]indole alkaloids of biological relevance: proposed biosynthesis and synthetic approaches

The hexahydropyrrolo[2,3-b ]indole alkaloids represent a diverse family of structurally complex tryptamine derived alkaloids isolated from a widespread series of natural sources. A hexahydropyrrolo[2,3-b ]indole ring having a carbon substituent at C-3 a is the defining structural feature of a diverse collection of natural products. The structural complexity of the hexahydropyrrolo[2,3-b ]indole alkaloids makes them a particularly elusive and at the same time, appealing target for total synthetic effort. In this review article, we discuss on the biosynthetic proposal as well as key efforts on the total syntheses of naturally occurring complex hexahydropyrrolo[2,3-b ]indole alkaloids.


Introduction
Nitrogen containing heterocycles are omnipresent in bioactive compound of both natural and synthetic origin.In this regard, the hexahydropyrrolo [2,3-b]indole alkaloids are a subset of tryptamine derived tricyclic structures (also known as cyclotryptamine alkaloids) with an all-carbon stereogenic center at the pseudobenzylic position.These cyclotryptamine alkaloids are important building blocks in the total synthesis of natural products, as well as for the development of new drugs. 1Architecturally intriguing C-3 alkylated hexahydropyrrolo [2,3-b]indole alkaloids (1a-r, Figures 1 and 2) are an important class of indole alkaloids which are found in an array of natural products. 1A subset of methylated, prenylated and reverse-prenylated hexahydropyrrolo [2,3-b]indole natural products exhibit a broad spectrum of biological activities. 2 The characteristic molecular architecture and promising medicinal value has prompted the development of a number of methods to access such motifs, with numerous studies particularly in the area of pyrrolidinoindoline syntheses.

Biological Profile of Hexahydropyrrolo[2,3-b]indole Alkaloids
The history of ()-physostigmine (1d) and pharmacological effects has been reviewed independently by Holmstedt, 36 Somani 37 and Triggle 38 .()-Physostigmine (1d) alkaloids isolated from West African perennial shrub Physostigma venenosum. 39][45] The role of physostigmine (1d) in the central cholinergic nervous system in memory processes was summarized by Deutsch in 1971 and in 1983. 46,479][50] Another new analgesic drug (-)-eseroline (1b) can be derived from (-)-physostigmine (1d), after hydrolysis of N-methyl carbamyl group. 51Eseroline (1b) as a free base is quite unstable and is easily oxidized, 52 whereas its salts with acids like salicylic, fumaric, tartaric etc. are stable even in solution in presence of antioxidant agents.4][55][56] Unlike the latter compound, however, eseroline (1b) is devoid of anticholinesterase activity 57 and its analgesic effect is not antagonized by atropine.In agreement with the findings of Bartolini 58 and Ireson 59 eseroline (1b), a physostigmine (1d) derivative, proved to be a potent analgesic as evidenced by the hot plate test with rats.It has about the same order of potency as morphine.Among these derivatives of physostigmine, the most attractive compound, ()-phenserine (1e), is a dual AChE and -amyloid precursor protein (-APP) inhibitor being developed to treat mild to moderate Alzheimer's disease.Therefore, phenserine may represent an important new catalog of compounds for treatment of AD, with the goal of developing potential Alzheimer's pharmacotherapeutics (Figure 1), 60,61 Flustramines, isolated from the Bryozoa Flusta foliacea, are a family of marine alkaloids with characteristic prenylated or reverse prenylated hexahydropyrrolo [2,3-b]indole backbone.3][64] ()-Pseudophrynaminol (1o) was isolated from the skin of the Australian frog Pseudophryne coriacea and emerge as a potent inhibitor of ganglionic and neuromuscular nicotinic receptor-channels (Figure 2). 65,66nother class of biologically active indole alkaloid like ()-ardeemin (1l), ()-N-acetylardeemin (1m) and ()-fructigenine A (1n) display promising bioactivities towards life-threatening diseases.Where as fructigenine A (1n) has growth-inhibitory activity against Avena coleoptile and leukemia L-5178Y cells 26 and Nacetylardeemin (1m) is one of the most potent known agents for reversal of multiple drug resistance (MDR), as measured against KBV-1 (vinblastine resistant) tumor cell lines. 27Thus, 5-N-acetylardeemin would be termed a naturally occurring MDR reversal agent (Figure 1). 67The biological activities of these compounds have been well studied, the results of which have shown several promising applications, including muscle relaxants, potassium channel-blockers and anti-cancer agents.For this reason, the total synthesis of these natural products has received considerable attention, and has been accomplished by several research groups.
In 2012, Zhang et.al. have 104 developed a stereocontrolled copper catalyzed Intramolecular alkylation of o-bromoanilides bearing a chiral sulfinyl amide unit to synthesize the precursors for the total synthesis of flustramine as well as pseudophrynamine alkaloids (Scheme 29).Next, in presence of different alkyl bromide copper mediated strategy completed the synthesis of targated molecules 25c and 25d.Treatment of these key intermediates 25c and 25d with HCl and MeOH afforded amine compounds 25e and 25f with 88% and 85% yield, respectively (Scheme 29).Further, DIBAL-H reduction followed by benzyl group deprotection under Birch reduction provided pseudophrynaminol (1o) and debromoflustramine E (1h) with 85% and 98% yield, respectively (Scheme 29).

Scheme 30. Ir Catalyzed reverse Prenylated pyrroloindoline synthesis by Carreira et al.
In 2014, Carreira and co-workers 105 have developed a direct C3 selective reverse prenylation of tryptamine derivative (9j).The methodology employs a readily accessible Ir-catalyst and a simple dimethyl allyl carbonate as precursor for the prenyl group with a variety of 3-substituted-1H-indoles as substrates, involving the formation of vicinal quaternary centers (Scheme 30).The diastereoselective reaction with tryptophan methyl ester enables access to a adaptable hexahydropyrrolo [2,3-b]indole intermediate, which they used as precursor for the stereoselective synthesis of ()-aszonalenin (9k) and ()-brevicompanine B (9l) (Scheme 30).

Conclusions
This review is intended to provide an overview of the complex hexahydropyrrolo [2,3-b]indole alkaloids where biosynthetic relationship and synthetic approaches to this family of alkaloids have been discussed elaborately.The fascinating molecular architecture of the members of this natural product family has stimulated the interest of numerous synthetic chemists which has led to a number of creative synthetic approaches and beautiful total syntheses.Although, the biological activities of only a few numbers of hexahydropyrrolo [2,3b]indole alkaloids are reported, the exhaustive biological potential of the majority of hexahydropyrrolo [2,3b]indole alkaloids has yet to be evaluated.The knowledge from biological stidues would be useful in screening these products for therapeutic applications.