Protoberberines, synthesis

Maes BUW (2006) Transition-Metal-Based Carbon-Carbon and Carbon-Heteroatom Bond Formation for the Synthesis and Decoration of Heterocycles. 1 155-211 Maiti M, Kumar GS (2007) Protoberberine Alkaloids Physicochemical and Nucleic Acid Binding Properties. lO. 155-210... 

The protoberberine alkaloids (5-75) play important roles as precursors in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, inde-nobenzazepine, secoberbine, and benzo[c]phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. 

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromate afforded directly oxyche-lerythrine (232) instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient... 

Regioselective C-8—N bond cleavage of protoberberines is a crucial step for synthesis of secoberbine alkaloids (2). 

Scheme SO. Synthesis of the ochotensimine analog 288 from a phenolic protoberberine by base-induced rearrangement. Reagents a, LAH b, Mel c, HBr d, NaOH, aq EtOH e, DMSO.

Many methods have been developed so far for synthesis of protoberberine alkaloids (229). In this section interconversions of these alkaloids as well as transformations to nonnatural alkaloids are described. 

A different method using 8,14-cycloberbines was developed for synthesis of 13-methylprotoberberines (239). The Wittig reaction of the 8,14-cyclober-bines 146,442, and 339 derived from protoberberines 15,64, and 65 afforded... 

Scheme 101. Synthesis of nonnatural 2,3,10,11-tetraoxygenated protoberberines. Reagents a, hv, EtOH b, NaBH4 c, CIPO(OEt)2 d, Na, liq NH3.

Three syntheses of 6,7-secoberbines have been carried out. Two of them involved degradation of the protoberberine alkaloids (63,65), and the third was a total synthesis (69). Takao and Iwasa (63) applied the von Braun reaction to tetrahydrocoptisine (39) to obtain the 6,7-seco bromide 63, which on treatment with dimethylamine, followed by hydrolysis, gave tetrahydro-corydamine (64). This tetrahydrobase 64, which was also produced from 56 by zinc in hydrochloric acid (63), was dehydrogenated to corydamine (56) (Scheme 15). 

Total synthesis of the representative protoberberines, (+)-xylopinine 151 (equation 71) and (+)-stylopine 152 (equation 72), have been achieved using silylarene-iminium salt photochemistry128. The photochemical routes appear to be superior to alternative ground-state methods involving dipolar cyclizations. 

In recent years, dioxiranes have become workhorses for a variety of selective transformations in organic synthesis, from epoxidation of alkenes to the conversion of alcohols into fee corresponding ketones <99CJC308>. Dioxirane-mediated epoxidation continues to be the method of choice for complex substrates wife acid-sensitive functionality. Thus, fee dimethyl-dioxirane (DMD)-mediated epoxidation of the silylated stilbene lactam 159 has been reported as a key step in fee synthesis of protoberberines <99JOC877>. 

The protoberberine alkaloid, xylopinine, has been synthesized in an optically active form by Kametani et al.22 ). A key reaction in this synthesis was the photochemical cyclization of the optically active amino acid derivative 1,2,3,4-tetrahydro-6,7-dimethoxy-3-methoxycarbonyl-1 -methylene-2-veratroylisoquinoline with 1,3... 

In a projected synthesis of the protoberberine alkaloid thalictrifoline 1 the tetrahydroisoquinoline derivative 2 was treated with formaldehyde and acid under a variety of conditions. Unexpectedly, the product was the isoquinobenzoxazepine derivative 3, which was obtained in yields of 70-85% depending on the conditions used. 

N-Boc-4H-isoquinohne reacted quantitatively within 5 min with f-butyllithium in TMEDA to lead to the product silylated at the benzylic position.151 Another 4H-isoquinoline-type product has been silylated using lithium tetramethylpiperidide (LiTMP) in THF and the resulting compound has served as an intermediate in the synthesis of protoberberine.136,152 Interestingly, the intermediate lithium reagent did not react with the aldehyde group prior to silylation. A similar reaction has been done with the corresponding bromo derivative.153... 

Reversed regioselectivity in aryl radical additions to enamides and enamines can also be observed with aryl substituents on the alkene [86]. This cyclization type has been successfully applied in the synthesis of protoberberines and the pavine alkaloids. Argemonine (39) was obtained from a 6-exo cyclization of 40 passing through a well-stabilized benzylic radical (Scheme 15). 

Benzylic desilylation and destannation have been often used in the alkylation of electron-poor aromatics (see Sect. 2.1.3), but are obviously useful in other contexts, a particularly well developed example being the benzylation of iminium salts for the synthesis of new heterocycles [236-238], including protoberberine alkaloids (Scheme 45) [239],... 

Several applications of this methodology have appeared from Mariano s group, however, we will demonstrate the synthetic potential of this discovery by citing here the two most important examples. Synthesis of ( +) Xylopinine (205), a protoberberine alkaloid, has been performed [161] from the photocyclisation of 204 in methanol. Similarly, a erythrane ring system (207) has been constructed [162] from the photoreactions of 206. Some other interesting aspects of this chemistry have been related to a novel Pictet-Spengler [163] type cyclisation and the chemistry of allene cation radicals [164]. 

The phenanthridine skeleton is synthesized by photocyclization of the enamides prepared from cyclohexanonimines and benzoyl chlorides (17,18). The benzo[c]phenanthridine skeletons are formed from the enamides prepared from 2-tetralonimines and benzoyl chlorides (19,20). More conveniently, the skeletons of protoberberine alkaloids are readily synthesized from the enamides prepared by simple acylation of 1 -methyl-3,4-dihy-droisoquinolines with benzoyl chlorides (21-24). This berbine synthesis is one of the most typical examples of the application of enamide photocyclization to alkaloid synthesis and can be further extended to the facile synthesis of the skeletons of the yohimbine group of indole alkaloids (25,26). 

There are two types of enamides readily available for the simple synthesis of protoberberine alkaloids via the route involving photocyclization. One is the 2-acyl-1-benzylideneisoqui noline-type enamide that has a stilbene structure in the molecule and is known to undergo a six -electron conrota-tory electrocyclic cyclization to a dihydrophenanthrene and subsequent dehydrogenation (103), and thus provides a useful synthetic route to apor-phine alkaloids. The second is the 2-aroyl-l-methyleneisoqui noline-type enamide that gives the 8-oxoberbine in good yields on irradiation. 

Total synthesis of protoberberine alkaloids via the route involving enamide photocyclization consists of nonoxidative photocyclization of the 2-aroyl-l-methylene-3,4-dihydroisoquinolines and the subsequent metal-hydride reduction of the photocyclized lactams. This simple combination of reactions for alkaloid synthesis provides one of the most convenient synthetic routes to this group of popular alkaloids. 

Xylopinine. Among many popular protoberberine alkaloids, xylopinine has been of interest to synthetic chemists because of its pharmacological activity (112). Three groups (21,23,29-32,44,107) have independently described total synthesis of this alkaloid Ninomiya et al. (16) and Kametani et al. (66) succeeded in the asymmetric synthesis of this alkaloid by enamide photocyclization. 

Recently, Castedo et al. (137) studied enamide photocyclization for aporphine synthesis and modified Cava s procedure (135 -137) after consideration of the reaction course and structural requirement for the exclusive formation of aporphine. Castedo s group concluded that an enamide should have a forced m-stilbene geometry, in order to avoid an undesired mode of cyclization leading to protoberberine-type compounds and also to avoid a facile conversion to oxoaporphines after cyclization. 

In a pair of back-to-back papers, the author and co-workers first reported the isolation and characterization of thalibealine (70), a novel tetrahydro-protoberberine-aporphine dimeric alkaloid from Thalictrum wangii,143 That report was followed by a paper reporting the synthesis of thalprezwalskinone (71) and a revision of the structure of that alkaloid.144... 

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