Alkaloid syntheses heterocyclic synthesis, intramolecular

The reduction of heterocyclic compounds is a versatile process of great use in the synthesis of alkaloids185. The choice of catalyst is crucial however, as illustrated by the indolizidine alkaloid synthesis shown in Scheme 34185a. The reduction of 37 to 38 proceeds with a very high degree of stereocontrol which sets up the correct framework for intramolecular cyclization to complete a short synthesis of y-lycorane 39186. 

The methodology based on nitroso DieIs-alder reaction that proved useful in the synthesis of tropane alkaloids also seemed to open an attractive route to some other alkaloids. Compared to the intramolecular imino Diels-Alder reaction (ref. Ic) the intramolecular variant of the nitroso Diels-Alder reaction has received far less attention (refs. 6b 12), despite the enormous potential it holds for alkaloid synthesis. With this in mind we proceeded to examine the application of the intramolecular nitroso Diels-Alder cycloaddition in the synthesis of alkaloids possessing saturated nitrogen heterocyclic ring systems. 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

Cyclization arising from the intramolecular photoelimination of HC1, HBr, and HI has been extensively used in the synthesis of heterocycles and alkaloids. The mechanisms of these transformations have not in many cases been thoroughly investigated. Some undoubtedly are initiated by simple homolysis of the carbon-halogen bond whereas others involve photocycliza-tion and subsequent elimination of HX. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

The retro-Diels-Alder reaction is a valuable tool for the synthesis of heterocycles <2003COR1423>. The Diels-Alder/ retro-Diels-Alder reaction of oxazoles with acetylenedicarboxylates has been extensively applied for the synthesis of 3,4-disubstituted furans. In a total synthesis of the alkaloid colchicine, such a reaction has been carried out in an intramolecular mode to yield a [ ]-annulated furan, which served as a synthetic key intermediate (Equation 30) <2000T10175>. 

Intramolecular photoelimination of HCl, HBr, and HI, often initiated by carbon-halogen bond homolysis, has again been widely used in the synthesis of heterocycles and alkaloids. 6-Acetyl-l,2-dimethoxy-4//-5,6,6a,7-tetrahydrobenzo-[rf ]thieno[2,3-g]quinoline (197), for example, has been obtained in this way by irradiation of the bromothiophen (198). " Analogous photocyclizations have been employed in the synthesis of ( + )-oliveroline, ( )-domesticine, ... 

Toth F, Kalaus G et al (2008) Synthesis of vinca alkaloids and related compounds. Part 109. An intramolecular [4+2] cycloaddition mediated biomimetic synthesis of (+-)-iboxyphyl-line. Heterocycles 75 65-76... 

Tsuda Y, Sakai Y, Nakai A, Kaneko M, Ishiguro Y, Isobe K, Taga J, Sano T (1990) Synthesis of Erythrina and Related Alkaloids. XXll. Intramolecular Cyclization Approach. (1) New Synthetic Route to Erythrinan and Related Heterocycles and Synthesis of ( )-3-Demethoxyerythratidinone. Chem Pharm Bull 38 1462... 

This reaction was initially developed by Parham in 1975 and extended primarily by Bradsher after Parham s death in 1976. It is the synthesis of aryl or heteroaryl ring fused carbocylces or heterocycles through the intramolecular reaction between a side chain electrophile and an aryl or heteroaryllithium generated from lithium-halogen exchange. Therefore, this reaction is generally known as the Parham cyclization. Occasionally, it is also referred to as the Parham reaction. J This reaction is very useful for the synthesis of alkaloids. ... 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Cyclizations of substructure type C (Figure 6.3) are also used in total synthesis of natural products bearing five-membered heterocycles, as shown by the example of (S)-camptothecin (83), a natural anticancer agent (Scheme 6.23) [71]. This pentacyclic alkaloid was synthesized in 10 steps, the last one being a 5-exo-intramolecular Mizoroki-Heck reaction. 

Additionally, Scheme 20.11 shows the versatility of Pummerer products. Under classical Pummerer conditions, heterocyclic conpounds behave as good nucleophiles, including for the production of tertiary bicyclic lactams 44. Kuhakarn et used a silicon-induced Pummerer reaction (this activation method will be explained in more detail later in this section) to generate the thionium intermediate, which was intramolecularly trapped by the lactamic nitrogen. Even when a mixture of S-stereoisomers was used, the reaction proved to be diastereoselective, and the lactam sulfide 44 was obtained as 5 1 mixture of trans cis products. Subsequent transformations led to the synthesis of a variety of bicyclic alkaloids 45-48 starting from the same sulfide lactam intermediate 44. 

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