Alkaloids, free radical 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 carbazoquinodns are carbazole-3,4-quinone alkaloids and have been isolated from Streptomyces violaceus 2942-SVS3 [61]. They are strong antioxidative agents and thus represent potential drugs for the treatment of diseases initiated by oxygen-derived free radicals. We have developed an effident synthesis of carbazoquinodn C using palladium(II)-catalyzed oxidative cydization as the key step (Scheme 15.17, Table 15.2) [62]. 

The only bisbenzylisoquinoline alkaloids whose structures preclude the simple oxidative pairing mode of synthesis are those containing three diphenyl ether linkages (trilobine, isotrilobine, menisarine, normenis-arine, and micranthine). However, Barton and Cohen (10) have proposed a mechanism for the formation of the dibenzo-p-dioxin system of these alkaloids which comprises phenoxy free-radical coupling with a subsequent migration reaction. 

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... 

Cossy has reported a synthesis of a-kainic acid that establishes the stereogenic centers on a preformed pyrrolidine ring (Eq. 20) [40], Thus, ketone 57 was prepared from L-pyroglutamic acid in 11 steps. Samarium iodide-mediated cyclization of 57 gave 58 as a mixture of stereoisomers at the carbinol carbon. Dehydration gave 59, and a 6-step sequence, starting with oxidative cleavage of the double bond, provided a-kainic acid. One notable aspect of this synthesis is the use of an enamide as a free-radical acceptor in the key cyclization. This process has been used in a number of alkaloid syntheses as will be seen in the next section. 

The Ziegler group has described a creative approach to mitomycin derivatives and the related alkaloid FR-900482 that involves use of indoles as radical acceptors (Eq. 28) [62]. The key step involves cyclization of aziridinyl bromide 98 to 99 which was carried on to (+)-desmethoxymitomycin A. This reaction surely illustrates the unusual bond constructions that can be accomplished using free-radical chemistry. Interesting approaches to other indole alkaloid substructures have been reported as illustrated in Eqs. (29) [63] and (30) [64]. The former was developed in an approach to lysergic acid while the later is a model study for the synthesis of aspidosperma alkaloids. Neither of these interesting approaches has been brought to fruition. A synthesis of carbazomycin that involves an aryl radical cyclization for construction of the C3-C3a bond of an indole has also been described [65]. 

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. 

Bennasar M-L, Zulaica E, Sole D, Roca T, Garcia-Diaz D, Alonso S (2009) Total synthesis of the bridged indole alkaloid apparicine. J Org Chem 74 8359-8368 Bremner JB, Sengpracha W (2005) A free radical cyclization approach to indolo-benzodia-zocine derivatives. Tetrahedron 61 941-953... 

Pigza, J. A., Han, J. S., Chandra, A., Mutnick, D., Pink, M., Johnston, J. N. (2013). Total Synthesis of the Lycopodium Alkaloid Serratezomine A Using Free Radical-Mediated Vinyl Amination to Prepare a p-Stannyl Enamine Linchpin. 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

Similar results have been observed with heteroatomic radicals such as aminyl radical (in an example already discussed in Section VIII.3.A, Scheme 44, and more recently as an important step in the total synthesis of the alkaloid dendrobine ) and with the carboxamidyl radical. The intramolecular addition of thiyl radicals to cyclohexenes generally gives a mixture of the (Cy5) and (Cy6) products. In the same way, intramolecular addition to an unsaturated chain of a thiyl radical on a cyclohexane ring also gives a mixture of (Cy5) and (Cy6) products. This lack of selectivity is in accord with the behavior of unsaturated thiyl radicals discussed in Section VIII.4. An interesting exception of possible relevance to the biosynthetic route to cepham has been discussed in Section VIII.4.B (Scheme 58). The behavior of ethylenic aminothiols such as 107 under free radical initiation (Scheme 52, Section VIII.4.A) has been generalized to compounds such as 267, which affords 268 in 87% yield (Scheme 109). 

The methodology has been extended [68] to the total synthesis of the alkaloid lennoxanine 267 starting from the enamide 266. Subsequently an alternative methodology was also developed for lennoxanine 267 based on a 10-endo dig cyclization. The IQ-endo dig radical cyclization of the TMS-protected acetylene 268 generated the tricyclic compound 269, which was further cyclized and transformed into lennoxanine 267. The 0-endo dig radical cyclization reaction (268 269) with free acetylene was found to generate an E,Z mixture of olefins. 

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