The 1-azabicyclo[3.1.0]-hex-2-ylidene)glycinate system like 3 is an important fragment involved in antitumor antibiotics, azinomycins 1,2) A (1), B (2) (carzinophilin 3,4) ). We already reported 5) an efficient synthetic method for (pyrrolidin-2-ylidene)glycinates 5a and 5b, which are the basic skeleton of unique unsaturated cyclic dehydro amino acid 3, by intramolecular-1,3-dipolar cyclic addition of azide and olefin as a key reaction using azide 4a and 4b. Recently, several synthetic studies 6,7) and investigation of biological properties of carzinophilin and its related synthetic products have been reported 8) and it is mentioned there that a five-membered unsaturated dehydro amino acid part like 3 has an important role in the biological activity of carzinophilin. Our work concerning the intramolecular 1,3-dipolar cyclic addition of azide and olefin would serve to construct (pyrrolidine-2-ylidene)glycinates, which are the key compounds for 3.In this paper, further application of this cyclic reaction was investigated to see if this method could be widely used to synthesize other (pyrrolidin-2-ylidene)glycinate and glycinamide. We chose newly an amide 4c which has an azinomycin A related functional group (RϭNHCH 2 COCH 3 ) and another ester 4d as substrates of azide. Intramolecular cyclic reaction of azide and olefin occurred in both cases of 4c and 4d and afforded cyclic dehydro amino acid 5c and 5d in high yield. Considering both the results obtained in a preliminary report 5) and that obtained in this paper, this reaction was revealed to be applicable for various esters 4a, 4b, 4d (RϭOMe, O t Bu, allyl) and also amide 4d (RϭNHCOCH 3 ). It is remarkable that the reaction occurred in the amide 4d, which is presumed to have poor reactivity in this cyclic reaction considering the already described reaction mechanism, 5) because the amide group does not have enough electronwithdrawing force, hence it is difficult to construct the triazoline ring which is an important intermediate 5) for intramolecular 1,3-dipolar cyclic addition of azide and olefin.In addition, the conversion of methyl (E)-(pyrrolidine-2-ylidene)glycinate 5a, which was already synthesized by us, 5) to the key compound 6a and 6b for the precursor of aziridine construction for 3 was developed. These results will serve for the construction of 3. Results and DiscussionOur synthetic strategy for 5c and 5d is described below (Chart 1). Compound 8, which was already synthesized via aldehyde 7 according to the procedure described in our previous paper, 5) would afford unsaturated carboxylic acid 9 by hydrolysis of the methyl ester 8. Acid 9 would be converted to the amide 10, which would give the alcohol 11. Compound 11 would be converted to (pyrrolidine-2-ylidene)glycinamide 5c conveniently via azide by intramolecular 1,3-dipolar cyclic addition of azide olefin in a similar manner as described in a preliminary report. 5) Acid 9 would also afford allyl ester 12, which would give the alcohol 13. Compound 13 would be cyclized to (pyrrolidine-2-ylidene)glyc...
Construction of (Pyrrolidine-2-ylidene)glycinate and Glycinamides. -Pyrrolidineylidene glycine-amide (XII) and glycinate, which are important fragments of antitumor antibiotics, are synthesized from arabinal (I) utilizing the title reaction, cf. (XI)→(XII), as a key reaction. Initial Horner-Emmons reaction of (I) with reagent (II), followed by condensation of hydrolysis product (V) and amino alcohol (VI) yields, after oxidation of amide alcohol (VII), the desired ketone (VIII). The removal of the Tbs-protecting group is carried out by using pyridine as a mixed solvent to prevent Z-E isomerization by strong acid hydrogen fluoride. Alcohol (IX) is obtained as mixture of conformational isomers. The monochloromethanesulfonyl group is the appropriate leaving group for conversion of (IX) to azide. -(KONDA-YAMADA*, Y.; ASANO, K.; SATOU, T.; MONMA, S.; SAKAYANAGI, M.; SATOU, N.; TAKEDA, K.; HARIGAYA, Y.; Chem. Pharm. Bull. 53 (2005) 5, 529-536; Sch. Pharm. Sci., Kitasato Univ., Minato, Tokyo 108, Japan; Eng.) -H. Hoennerscheid 46-195
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