Protoberberine alkaloids 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. 

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. 

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). 

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. 

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. 

Coyle and Bryant have reported the efficient synthesis of a triazabicyclo[3.3.0]octane system by the photocyclization of hydantoin derivatives. Thus irradiation of (295), synthesized by standard Mannich procedures, afforded the bicyclooctanes (296) in moderate to good yields. The process, akin to Norrish Type II behaviour, is a 1,6-hydrogen transfer followed by bonding in the resultant biradical (297). The bis-Mannich base compound (298) also photocyclizes, yielding (299). Coyle and his co-workers have also successfully applied the known reactivity of phthalimides to yield polycyclic compounds. Thus irradiation of (300) affords the cyclized compound (301). This can be converted into the protoberberine alkaloid skeleton (302) by treatment with aqueous HCl. The crown ether analogues (303) and (304) have... 

A recent synthesis of deoxythalidastine by Bradsher and Andrew 93a) has confirmed its proposed structure as XXXVII. Thus, thalid-astine joins berberastine as the second fully characterized protoberberine alkaloid having a C-5 hydroxyl function. The evidence cited does not rigorously exclude the possibility of locating the hydroxyl at the C-6 position. 

Several new approaches to the synthesis of the tetracyclic ring system of the protoberberine alkaloids have been developed in the last 10 years. 

A second general method for the synthesis of the protoberberine alkaloids has been described by Battersby et al. (116). The method, which utilizes a 1,2-dihydroquinoline as a key intermediate, has been used to synthesize ( + )-norcoralydine (XXXIX R = CH3) and (+ )-coreximine (LXXIX), as illustrated for the latter in Chart III. 

When using the appropriate tetramethoxyisoquinolinium salt LXXXII (R = 0CH3), the protoberberine base norcoralydine (119) was obtained in 39% yield by this method. In contrast to the results obtained in the synthesis of 2,3-dimethoxyberbine, the intermediate isocarbostyril LXXXIII (R = 0CH3) was quite stable to acid and could be readily isolated. Attempts to induce the cyclization of this compound with acid were unsuccessful. The above method constitutes the most efficient synthetic route to the protoberberine alkaloids so far devised. 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

Photocyclisation of 1 -benzylidene-2-formyl-6-methoxy-7-benzyloxy-3,4-di-hydroisoquinoline is the key step in the synthesis of bharatamine, a natural racemic protoberberine alkaloid, and thermolysis of l-biaryl-5-morpholino-v-triazolines (134) gives the amidines (135) which will undergo photocyclisation to the 6-alkylphenanthridines (136) following morpholine elimination. These 6-alkylphenanthridines can also be synthesised, but with lower... 

The phthalides occur in several natural products . They are also intermediates for the synthesis of a variety of natural products like naphthols, anthraquinone natural products, anthracyclic antibiotics, the phthalide isoquinolines, protoberberine alkaloids etc. 

In connection with the synthesis of protoberberine alkaloids, Marsden and MacLean have investigated the addition of phthalide enolates to 3,4-dihydroisoquinolines. These reactions are an extension of the previously described work of Dodsworth et involving phthalide additions to acyclic imines... 

A one-step synthesis of the protoberberine alkaloid karachine (18), employing a presumed Mannich reaction of 4-methyl-2-trimethylsilyloxy-2,4-pentadiene with berberine, has been detailed by Stevens and Pruitt.154 It is plausible that the initial step of the one-flask reaction sequence leading to karachine is, in fact, a [4+ + 2] cycloaddition of the quaternary aromatic salt, berberine chloride, with the terminal electron-rich olefin of the silyloxydiene [Eq. (70)]. 

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