Chanoclavine-I synthesis

Figure 11 Early scheme of chanoclavine-I synthesis from MeDMAT initiated by hydroxylation at C-10 of MeDMAT involving intermediacy of a diol. Note that the structures have been modified for the presence of the methyl group in the amino nitrogen of MeDMAT. DMAT was considered previously as precursor of chanoclavine-I...

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

In a related approach, Murakami synthesized clavicipitic acid and costaclavine [79], and later extended this chemistry to a synthesis of chanoclavine-I featuring the intramolecular Heck vinylation 240 to 241 [266], The corresponding enone failed to cyclize under these conditions. Noteworthy is that radical cyclizations, which often compete successfully with Heck reactions, were poor in this system. 

Yang described the Pd-induced cyclization of an aryl bromide onto a pendant cyano group leading to y-carbolines and related compounds [488], Genet studied the use of chiral palladium complexes in the construction of the C-ring of ergot alkaloids, a study that culminated in a synthesis of (-)-chanoclavine I [489-491]. For example, nitroindole 388 is cyclized to 389 in 57% yield and with enantioselectivities of up to 95% using Pd(OAc)2 and (S)-(-)-BINAP. 

Scheme 3. Pd-catalyzed intramolecular asymmetric allylic alkylation in Genet s synthesis of chanoclavine I (1994).

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

The synthesis of ( )-chanoclavine I by Plieninger etal.33b has now been described in detail.44... 

An intramolecular cycloaddition reaction is also a vital feature of Oppolzer s synthesis (Scheme 5).336 Here the cycloaddition reaction occurs on an unsaturated nitrone ester (39) (not isolated). Again, the aldehyde derived from oxidation of the diol (40) gave entirely the ( )-olefin on reaction with crystalline a-methoxy-carbonylethylidenetriphenylphosphorane, which allowed the synthesis of (+)-chanoclavine I (34) to be completed in an overall yield of 14% from indole-4-aldehyde. In contrast, the Horner-Emmons reaction on the aldehyde from... 

A general synthetic route from elymoclavine (56 A ) to a variety of substituted A -ergolenes, by displacement reactions on the related allylic chloride, has been developed. A rather more exciting contribution is the partial synthesis of agro-clavine (63) from chanoclavine-I (61) and isochanoclavine-I (62) (Scheme 9) the... 

Scheme 10 outlines the first recorded synthesis " of ( )-chanoclavine-I (50), which employs as essential starting material the ketone (49), prepared earlier. Agroclavine has been converted into setoclavine and isosetoclavine by incubation with crude extracts of a Claviceps species. Since the two alkaloids were also produced following incubation with boiled crude Claviceps extracts (albeit in somewhat reduced yield), most of the conversion would appear to be non-enzymic. 

Chanoclavine I, ( )-isochanoclavine I Total synthesis of 6,7-secoergolines based on the fragmentation reaction of 3-amino alcohols [19]... 

Chanoclavine I The key step of the synthesis involves the creation of the C ring by the formation of the C5-C10 bond, catalyzed by chiral palladium(O) complexes [23]... 

Chanoclavine I, ( )-dihydrosetoclavine Synthesis involves a synthetic method of 4-alkylindoles [27]... 

The synthesis of dimethylallyltryptophan (132) by a crude extract of Claviceps purpurea from tryptophan and dimethylallyl pyrophosphate recorded earlier has been reported again recently. In addition to (132), the formation of (133) was observed. (The latter compound, with unspecified stereochemistry around the double bond, has also been isolated from a C. purpurea culture ). It was found further that both (132) and (133) could act as precursors for lysergic acid amides in C. paspali cultures. Both (133) and its (Z)-isomer have been found to act as precursors for elymoclavine (137) but not chanoclavine-I (138) or agro-clavine (136), which are considered to be normal intermediates in elymoclavine biosynthesis.It may be concluded, however, from the combined evidence, that elymoclavine, lysergic acid, and related compounds may normally be formed along an alternative pathway via these allylic hydroxy-compounds. 

Yokoyama, Y., Kondo, K., Mitsuhashi, M. and Murakami, Y. (1996) Total synthesis of optically active chanoclavine-I. Tetrahedron Lett., 37, 9309-12. 

Choong TC, Shough HR (1977) The isolation and synthesis of chanoclavine-I acid. Tetrahedron Lett 3137-3138... 

The sjmthesis of (+)-chanoclavin I (582) has been achieved by a multistage route from the acetal (580) by way of the key intermediate (581) whose aliphatic double bond is readily cleaved by ozone. A third, convenient synthesis of the diterpenoid trachylo-bane (586) has been achieved by a reductive homoallylic cyclization. Reaction of the mesylate ester (583) with methylsulphinyl carbanion gives the ketone (584) and the alcohol (585). Oxidation of the crude product mixture with Jones reagent gave ketone (584) which can be reduced to trachylobane (586). ... 

Cavender and Anderson (1970) found that the synthesis of chanoclavine-I and -II from tryptophan and isopentenyl pyrophosphate was catalysed by the 60-80% ammonium sulfate precipitate obtained from the 105000 g-supernatant of a homogenate of C. purpurea. The reaction was dependent on the presence of isopentenyl pyrophosphate, methionine and ATP. Addition of a liver concentrate to the reaction was necessary, presumably to provide additional cofactors. 

Naidoo, B., Cassady, J.M., Blair, G.E. and Floss, H.G. (1970) Biosynthesis of ergot alkaloids. Synthesis of chanoclavine-I-aldehyde and its incorporation into elymoclavine by Claviceps. J. Chem. Soc. Chem. Comm., 471—472. 

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