Enamide photocyclization

The aroylation of l-aIkyl-3,4-dihydroisoquinolines produces enamides which readily undergo photocyclization to oxoberberine derivatives. The reaction is analogous to the hexatriene-cyclohexadiene rearrangement and proceeds most favorably (50-807o yield) when the irradiations are performed on degassed solutions  

If the aroyl group is ortho substituted by the group R, that group is eliminated in the reaction as HR, and electron redistribution affords an 8-oxoproto-berberine. In the absence of an ortho substituent (R = H), a 1,5 hydride shift occurs and the product is an 8-oxotetrahydroprotoberberine. 

In a study of the mechanism and stereochemistry of the enamide photo-cyclization, Lenz has demonstrated that ethylidene and benzylidene isoquinoline enamides cyclize stereospecifically from the Z-isomer to yield 13-substituted oxoberberines in which the 13-substituent is quasi-axial and the C-13 and C-14 hydrogens are in a cis relationship.  

Photocyclization of the enamide 11 followed by lithium aluminum hydride reduction provided a short preparation of the tetrahydroprotoberberine xylo-pinine in excellent yield.  

The 13-methyltetrahydroprotoberberine base cavidine was synthesized by aroylation of a l-ethyl-3,4-dihydroisoquinoline followed by enamide photo-cyclization which gave, in addition to the desired product 13, an undesired side product 12. Subsequent two-step reduction of 13 aflforded cavidine 

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A new total synthesis of flavopereirine perchlorate (148) has been reported by Ninomiya et al. (109) via enamide photocyclization. Harmalane (150) was acy-lated with 3-methoxyethacryloyl chloride to enamide 151 which was irradiated in benzene solution without purification to yield the unstable lactam 152. The latter was treated with hydrochloric acid, resulting in dehydrolactam 153 in a yield of 35% from harmalane (150). Lithium aluminum hydride reduction of 153, followed by dehydrogenation, afforded flavopereirine (148), isolated as its perchlorate (109). 

Simple synthesis of demethoxycarbonyloxogambirtannine (347) was reported by Ninomiya and co-workers (188) via enamide photocyclization. N-Benzoyla-tion of harmalane (150) afforded enamide 348, which could be photocyclized to 347 in 37% yield. 

Attempts have been made for the enantioselective synthesis of (—)-yohim-bane. Kametani et al. (216) reported the total synthesis of key intermediate (-)-368 starting from L-tryptophan, using enamide photocyclization. However, the optical purity of (—)-17-methoxyhexadehydroyohimbane obtained was only 17% owing to the partical racemization of intermediates throughout the reaction sequence. 

The total synthesis of ( )-yohimbine via regioselective functionalization of 18,19-dehydroyohimbinone (434) has been reported by Ninomiya et al. (231). Key intermediate 434 was prepared by enamide photocyclization of 432, fol-... 

Photochemistry of Carboxylic Acid Derivatives J. D. Coyle, Chem. Rev., 1978,78,97-123. Application of Enamide Photocyclization to the Synthesis of Natural Products I. Ninomiya, Heterocycles, 1974, 2, 105-123. 

When the normal enamide photocyclization is disfavored, other reaction pathways can be observed13. For example, irradiation of enamide 27 leads to the formation of the expected cyclization product 28 (equation 8). 

Ninomiya and Naito established an enantioselective variant of their enamide photocyclization based on chiral proton donors. The enamide photocyclization... 

In a more recent study, the enamide photocyclization with very similar photosubstrates was examined in the presence of chiral amino alcohols and chiral amines as asymmetric inductors [47]. The achieved enantioselectivities are in the same range as the ones reported by Ninomiya and Naito, but in this approach the asymmetric induction was more effective for the cis products. In cyclopentane at — 40°C, 0.1 equivalents of the most effective inductor, (— )-ephedrine (entity, gave the cis cyclization products with up to 37% ee and the trans products with only 2% ee. The role of the chiral inductor as a Br0nsted acid was supported by flash photolysis experiments. The presence of the chiral amino alcohol led to an increase in the rate of disappearance of a transient that was assigned to the primary cyclization intermediate of type 29, i.e., the chiral inductor accelerates the protonation/deprotonation sequence that reestablishes the aromatic ring. 

The first observation was N— C acyl migration on irradiation of N-acylenamines (4-10). However, when A-benzoylenamines were irradiated, a new photocyclization reaction was discovered (9,10), and since has been developed for use as a synthetic tool with general applicability to the synthesis of various alkaloids. As a result, it is now firmly established as enamide photocyclization. 

Started in the late 1960s, studies on enamide photocyclization and its application to the synthesis of alkaloids have been successfully accumulated and have achieved a number of total syntheses of various types of isoquinoline and indole alkaloids and related heterocyclic compounds (11). 

This expectation was visualized through a number of examples of enamide photocyclization and the results obtained clearly suggest that this... 

After 10 years of research on enamide photocyclization, it has now been established that any type of enamide can undergo smooth photocyclization to afford the corresponding lactam in good yields. The characteristic points of their photocyclizations are summarized as follows ... 

Enamide photocyclization is basically of a nonoxidative nature, yielding the lactam isomeric to the starting enamide. 

Clearly these structures show the superiority of enamide photocyclization as a useful synthetic method for the synthesis of alkaloids. 

Several reviews on enamide photocyclization (11-13) and photochemical synthesis of isoquinoline alkaloids (14) have been published. 

Since the enamide A affords the dehydrolactam E on irradiation in the presence of iodine, and no conversion from D to E is observed under nonoxidative conditions, the nonoxidative nature of the original enamide photocyclization is clearly established (Scheme 4). 

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). 

As a result of studies on the enamide photocyclization under nonoxida-tive conditions, this type of photocyclization of Ar-a,/ -unsaturated acylena-mines becomes one of the most useful and prolific methodologies for the synthesis of alkaloids as shown in the following section. 

In addition to the works on enamide photocyclization described in this chapter, there are some interesting reports on the mechanistic study (46,47) and also on the application of nonoxidative cyclization to the synthesis of pharmacologically active heterocyclic compounds (39,48-52). 

The structure of this cyclic intermediate B, which contains an immonium structure, suggests the possibility of undergoing a facile reduction by hydride, if present during the course of photocyclization. This expectation was visualized as expected on the various enamides and therefore opened up a new phase of the application of enamide photocyclization (15) (Scheme 16). 

The use of a chiral hydride complex has been central to the asymmetric reduction of ketones such as acetophenone (58). A number of excellent chiral metal hydride complexes have been introduced by many researchers, including Noyori (59,60), Meyers (61), Mukaiyama (62,63), Terashima (64,65), and others (58). It is apparent that there is a close similarity in structure between acetophenone and the proposed intermediate in enamide photocyclization, therefore suggesting the possibility of undergoing photocyclization in an asymmetric manner. 

Furthermore, an asymmetric synthesis of natural xylopinine (20) by the route involving reductive photocyclization was successfully accomplished (16). Independently, Kametani et al. reported another asymmetric total synthesis of natural xylopinine via the route involving a diastereo-differen-tiated photocyclization of the chiral enamide (19) under nonoxidative conditions (66). Therefore, it is now established that enamide photocyclization is a reaction capable of not only undergoing a wide variety of cycliza-tions under various conditions but also having a high quality (Scheme 22). 

The use of enamide photocyclization in the synthesis of Amaryllidaceae alkaloids has remained a basic study and so far limited only to the synthesis of the skeletons of lycorine and crinine, as well as intermediates in the total synthesis of haemanthidine and nortazettine, and some of the degradation products of these alkaloids. 

Regiochemistry of enamide photocyclization in this synthesis can also be controlled by the use of an ortho substituent that acts as an eliminating group on cyclization to the root of the substituent. Thus, the omethoxyl and bromo groups are used for this regioselective cyclization as exemplified by a number of total syntheses of alkaloids (19,20) (Scheme 37). 

Corynoline, 12-Hydroxycorynoline, and 11-Epicorynoline. By taking the reported interconversions (97-99) of the corynoline group of alkaloids into consideration, Ninomiya et al. (85,86,100-102) accomplished the first total synthesis of most of the corynoline group 114, 116, and 117 by applying enamide photocyclization. They first prepared two important key intermediates, the lactam 109 and the amine 110, which were proved to be the... 

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. 

Kametani et al. (66) also succeeded in the asymmetric synthesis of xylopinine by applying 1,3-asymmetric induction to enamide photocyclization. Acylation of L-3,4-dimethoxyphenylalanine, followed by the Bischler-Na-pieralski cyclization of the resulting amide, gave the chiral 3,4-dihyroiso-quinoline 159, which was then acylated to afford the chiral enamide 19. 

Successful berbine synthesis summarized in Section IV,C prompted Nin-omiya s group (25,26,117,118) to extend enamide photocyclization to har-malane, therefore giving rise to a novel and facile synthesis of polycyclic heterocycles such as the yohimbine group of compounds. Before reductive photocyclization was introduced, the use of nonoxidative photocyclization with indole alkaloids was limited to simple systems and those possessing a large degree of aromaticity. 

Yohimbine. Ninomiya et al. (118) reported a formal total synthesis of yohimbine by applying enamide photocyclization. Harmalane was acylated with 4-methoxy-3-methoxycarbonylbenzoyl chloride to yield the enamide 198, which was found to be so unstable that it was irradiated without purification. Of two photocyclized products thus obtained, 199 in 32% yield and 200 in 5% yield, the latter product was identical to a known key intermediate (119) of yohimbine when their spectral data were compared (Scheme 76). 

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. 

Corunnine, Nandazurine, ( )-Caaverine, ( )-Isoboldine, ( )-Thalicmi-dine, and ( )-Domesticine. Relative to the aporphine synthesis by enamide photocyclization, Kupchan and O Brien (141) have developed the oxidative photochemical synthesis of aporphine alkaloids. 

Sophisticated physical techniques have had a major impact on alkaloid research, particularly on the determination of novel structures. Progress in this area will be reviewed periodically, and the chapter on Elucidation of Structural Formula, Configuration, and Conformation of Alkaloids by X-Ray Diffraction is the first of a series of such reviews. Attention is given to chemical methodology, found to be most valuable in alkaloid synthesis, presented here in the chapter on Application of Enamide Photocyclization in Alkaloid Synthesis. Of a more traditional nature is the presentation of alkaloid classes, which have not been reviewed for many years and where considerable new material has accumulated. Hence, two chapters, namely, The Imidazole Alkaloids, last reviewed in Vol. Ill (1953) and Ipecac Alkaloids and (3-Carboline Congeners, reviewed in Vol. XIII (1971), are included. 

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