Radical Cyclizations in Alkaloid Synthesis

The photolysis of arenediazonium salts has been widely used for intramolecular cyclizations in the synthesis of 1-phenylethylisoquinoline alkaloids by Kametani and Fukumoto (review 1972). An example is the photolysis of the diazonium ion 10.73, which resulted in the formation of O-benzylandrocymbine (10.74) (Kametani et al., 1971). The mechanism of this cyclization is obviously quite complex, since the carbon (as cation or radical ) to which the diazonio group is attached in 10.73 does not react with the aromatic CH group, but with the tertiary carbon (dot in 10.73), forming a quinone-like ring (10.74). In our opinion the methyl cation released is likely to react with the counter-ion X- or the solvent. 

The synthesis of tacamonine, an indole alkaloid of the Iboga type, was accomplished in both racemic and homochiral forms, by incorporating a classical 6-exo-trig radical cyclization in the key step of the synthesis (Reaction 7.57) [52], The cyclization produced piperidinone in a 72% yield as a diaster-eomeric mixture. 

Tacamonine, an indole alkaloid of the Iboga type, isolated from Tabermemontana eglandulosa, the root of which is used to treat snake bites in Zaire, bears structural similarity to the Hunteria alkaloids, eburnamonines, which possess vasodilator and hypotensive activities. Its synthesis in racemic and homochiral form was accomplished by incorporating a classic 6-exo-trig radical cyclization in the key step of the synthesis (Scheme 6)71. The radical precursor 6 was constructed in a 7-step synthesis by starting from racemic or chiral propane-1,3-diol. The radical cyclization of 6 produced the piperidinone in 72% yield as a diastereomeric mixture, which was then transformed into tacamonine. 

Scheme 2. Nickel powder promoted 5-endo-trig radical cyclization in erythrina alkaloid synthesis...

Chapter 4 by J.J. Li reviews radical cyclization reactions in the total synthesis of indole alkaloids. The use of free radical chemistry in the synthesis of alkaloids has grown markedly because of the mild reaction conditions, tolerance of a wide variety of functional groups, and the good stereoselectivities. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

The most complex application of this methodology to a problem in alkaloid synthesis is that of gelsemine shown in Scheme 4 [16]. Treatment of free radical cyclization precursor 27 (12 steps from commercially available materials) with TBTH gave 31 in 64% yield. The stereochemical outcome at C16 indicates that this... 

Free-radical cyclizations in which oxime ethers behave as free-radical acceptors were first noted in the 1980s [68], and a good review of the field has been published [69]. This methodology has seen use in the field of alkaloid synthesis, and the aforementioned review nicely presents many of these accomplishments. This chapter will be restricted to studies directed toward what the author considers to be targets of reasonable structural complexity. 

This chapter has attempted to present a thorough overview of alkaloid syntheses in which free-radical cyclizations have played a pivotal role. It is not meant to be a comprehensive review, but focusses on syntheses in which nitrogen plays a clear role in the cyclization process, either as an attenuator of radical reactivity (Sections 4,1.2 and 4.1.3), a tether (Section 4.1.4), or a radical acceptor (Section 4.1.5). Several other notable alkaloids syntheses have been reported in which carbocyclizations play the pivotal role and introduction of nitrogen is secondary, for example Sha s syntheses of (-)-dendrobine [76] and (-t-)-paniculatine [77], and Clive s synthesis of (+)-fredericamycin [78]. Syntheses in which nitrogen-centered radicals play a critical role are also known, such as the Zard synthesis of (—)-dendrobine [79]. My apologies to these authors for not elaborating on their fine contributions, to authors who have nicely used intermolecular radical addition reactions in alkaloid synthesis, and to others whose contributions may have escaped my attention. 

Finally, it is my hope that this chapter illustrates that attempts to use free-radical cyclization reactions in alkaloid synthesis have led to the development of interesting chemistry and the pursuit of some creative and, sometimes, very direct approaches to complex natural products. 

The synthetic utility of radical cyclization was used as the key step in a four-step synthesis of the natural product (d,0-epilupinine (134b, a quinolizidine alkaloid) (75CB1043) from methyl nicotinate (146). Thus, l-(4-bromobutyl)-3-methoxycarbonyl-l,4,5,6-tetrahydropyridine (140), obtained from methyl nicotinate (146), was cyclized to 141 (43%), which on reduction with LiAlH4 in THF provided 134b in 95% yield (89T5269). 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

Another effective combination of two radical cyclization steps has been demonstrated by Sha and coworkers during the course of the first total synthesis of (+)-paniculatine (3-24), a natural alkaloid belonging to the subclass of Lycopodium alkaloids [13]. 3-24 has a unique tetracyclic scaffold with seven stereogenic centers [14]. Although no special features of (+)-paniculatine have so far been documented, other Lycopodium alkaloids are reported to be potent acetylcholinesterase inhibitors, or show promising results in the treatment of Alzheimer s disease [15]. When... 

Scheme 3.62. Domino radical hydrogen abstraction-cyclization procedure in the synthesis towards Aspidosperma alkaloids.

The radical-based strategy has invaded the field of A-containing heterocycles. Cyclizations mediated by silyl radicals have been introduced as the key step in the synthesis of alkaloids and pharmacologically active compounds, with many advantages both in terms of selectivity and bio-compatibility. Some of the most significant and innovative examples are described in this section. 

The plan for a tandem cyclization as the key step in the synthesis of morphine alkaloids has been successfully performed [95]. Three examples are given in Scheme 7.10. Specifically, the initially formed aryl radical, generated by bromine abstraction from compound 74, underwent a tandem cyclization to construct the desired carbocyclic skeleton. Depending on the nature of the Z substituent to the double bond, the product radicals either abstracted hydrogen from silane (Z = C02Me or CN) or eliminated thiyl radical (Z = SPh). 

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