Synthesis of anisomycin

The triflate of (39) has been converted into the pyrrolidine (4 directly by treatment with ammonia. The 6-configuration, inappropriate for a synthesis of anisomycin, was expected, assuming that displacement of the triflate group is the first stage in the reaction. We have so far been unable to rearrange the 6-isomer (45) into the required a-series. This work is being continued. 

SCHEME 35. Richardson s total synthesis of (—)-anisomycin with Ram Bhatt, John Moffatt, and Julian Verheyden (and others) at Syntex in 1975. 

Another impressive example is the synthesis of ( + )-anisomycin, the unnatural enantiomer, in 88-90% ee and 22% overall yield, the key step being an asymmetric alkylation of 2,5-dihydro-1//-pyrrole44. ... 

The ready availability of both enantiomers of (1) has greatly enhanced its value as a synthetic intermediate. The pheromone (S)-(—)-ipsenol (2), prepared in 16% overall yield in four steps from (/ )-( ), is just one of many examples of this utility. In practice, either isomer can sometimes be used by adjusting the order of addition of the groups at C-1 and C-3. The synthesis of (—)-anisomycin (3) illustrates this point. ... 

The asymmetric alkylation of A -pyrroline has been used in the synthesis of anisomycin in 90% ee using a formamidine chiral auxiliary, as shown in Scheme 22. ... 

Synthesis from a-mannitol An enantioconvergent synthesis of (-)-anisomycin... 

The structure and relative stereochemistry of anisomycin were firstly investigated chemically [10] and then determined by X-ray crystallographic analysis [25]. The absolute stereochemistry was estabhshed as (2R,3S,4S) by chemical correlation with L-tyrosine [10-12]. The activity and structural features of anisomycin have attracted the attention of several synthetic organic chemists to produce synthetic routes to anisomycin and its analogues. Few routes have been achieved with good stereoselectivity, while others have an inherent problem in separating unwanted isomers [26-90]. Herein, we report a new development in the synthesis of anisomycin and its analogues. 

A nitrone-based approach to the enantioselective total synthesis of (-)-anisomycin (1) has been developed from (3S,4S)-l-benzylpyrrolidine-3,4-diol (89), which was obtained from L-tartaric acid (Scheme 10) [29]. l-Tartaric acid was converted to pyrrolidine 89 [79] by condensation with benzylamine and then reduction with NaBH4/BF3 Et20. 

Another approach for the total synthesis of anisomycin derivatives from (+)-tartaric acid has been reported via the N -benzyl tartarimide (95) (Scheme 11) [89]. Thus, (+)-tartaric acid was refluxed with benzyl amine in a xylene solution to give 95, which was subjected to reaction with the Grignard reagent of anisyl chloride in THF to give the keto-amide 96 in 55% yield. 

A total synthesis of (-)-anisomycin (1) from malimide has been achieved by a highly regio and trans stereoselective reductive alkylation of (S)-M,0-dibenzyl malimide 117 (Scheme 14) [85]. Reductive alkylation of (S)-lM,0-dibenzyl malimide 117, prepared from (S)-malic acid [86], with p-methoxybenzylmagnesium chloride gave the a-hydroxylactam 118 as a di-astereomeric mixture. Hydroxylactam 118 in the presence of 3 equivalents of boron trifluoride etherate was reduced with excess of triethylsilane to yield predominantly trans-119 in 94.8% yield. Catalytic hydrogenation of 119 afforded 120 in quantitative yield which was reduced to pyrrolidine 121 in 90%... 

A synthesis of the intermediate 39 used in Scheme 4 for the synthesis of anisomycin (1) has been developed from D-mannitol (Scheme 18) [76,77] by its conversion to the commercially available (E)-imsaturated ester (4S)-... 

Chiral intermediates for the synthesis of (-)-anisomycin (1) and (+)-anisomycin (anti-1) (153), (R)-2-(p-methoxyphenyl)methyl-2,5-dihydro-pyrrole (142) and its (S)-isomer (+)-187, have been efficiently synthesized from D-tyrosine and L-tyrosine, respectively (Scheme 20) [28]. D-tyrosine was converted to 0-methyl D-tyrosine methyl ester (182) [72-75] which was treated with di-tert-butyl dicarbonate to protect the amino group. Subsequent reduction of the ester group with sodium borohydride in the presence of lithium chloride furnished the alcohol 183. Swern oxidation of 183 followed by chain extension with the anion derived from bis(2,2,2-trifluoroethyl)(ethoxycarbonylmethyl)-phosphonate afforded (Z)-Q ,/0-unsaturated ester (184), which was used immediately without purification to avoid or minimize any possible racemization of the chiral center. Reduction of the ester group of 184 with diisobutylaluminium hydride afforded the alcohol 185 which after mesylation followed by intramolecular cyclization gave the desired 2,5-dihydropyrrole derivative 186. Removal of the tert-butyloxycarbonyl group was achieved by treatment with trifuoroacetic acid to give (-)-142 in 62% overall yield from 182. The (S)-2,5-dihydropyrrole (-l-)-187 was also prepared in the same manner starting from L-tyrosine. Since (-l-)-187 had been transformed into (-l-)-anisomycin (anti-1) (153), (-)-142 could also be transformed to the (-)-anisomycin (1) [26,66]. 

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