Isoiridomyrmecin synthesis

The application of this chemistry to the synthesis ofterpene natural products such as (—)-mitsugashiwalactone and (+)-isoiridomyrmecin [15] (Scheme 9.5) involved low-valent iron-catalyzed Alder-ene reactions in key steps in these synthesis. 

An analogous cycloaddition involving benzene and vinyl acetate (Scheme 20) also provides rapid access to simple bicyclo[3.3.0]octanes, which have many synthetic uses as illustrated in part by their value in a straightforward synthesis of isoiridomyrmecin (150). 

Wender and co-workers have continued their elegant use of the meta photocycloaddition of ethylenes to arenes as the key step in the synthesis of several naturally occurring compounds. The major product from irradiation of benzene and vinyl acetate is the 1-endo acetate of (36), and using this as the starting material, the total synthesis of the ant defensive secretion, isoiridomyrmecin (50), has been accomplished in seven further steps." There... 

S. Ito et al. utilized the aza-Claisen rearrangement of carboxamide enolates for the enantioselective total synthesis of (-)-isoiridomyrmecin, which is a constituent of Actinidia polygama and exhibits unique bioactivity. The rearrangement of the (S,S) stereoisomer was conducted under standard conditions, and the product was isolated as a single [R,R) stereoisomer in 77% yield. 

Eight- to sixteen-step syntheses of isoiridomyrmecin and verbenalol,763 iridomyr-mecin764 allodolicholactone (first synthesis), iridomyrmecin and its iso-epimer785 and sarracenin766 have been reported. 

Thus, Cid and Pombo-Villar have also described the synthesis of (-)-a-skytanthine (201) and (+)-epi-dihydrotecomanine (202) from the common intermediate 200 (195). Treatment of200with (4-toluenesulfonyl)hydrazide and in situ reduction with sodium cyanoborohydride afforded the piperi-done 203 in 44% yield. Debenzylation with Li-NH3 followed by reduction of the lactam 204 [which is formally an aza-analog of (+)-isoiridomyrmecin (205)] with UAIH4 gave 206, and iV-methylation under Eschweiler-Clarke conditions afforded (-)-a-skytanthine (201) (Scheme 12) (195). 

Another application of the stereoselective tandem cyelization is the synthesis of isoiri-domyrmecin from an acyclic precursor97. Reductive cyelization of 4-bromo-5-methyl-l-trimethylsilyl-8-decen-l-yne gives a mixture of four bicyclic products in a ratio of 47 44 5 4. Conversion to the bicyclic ketone, an intermediate in the synthesis of isoiridomyrmecin, shows the potential utility of this approach in natural product synthesis. 

This abnormal insertion mode was applied in a total synthesis of the natural product ( )-isoiridomyrmecin 197 in seven steps starting from 2,3-butadienyl bromide (Scheme 57). ... 

Hofferberth et al. reported diastereoselective synthesis of several ant-associated iridoids, namely, nepetalactol (85), dolichodial (86), dihydronepetalactone (87), and isoiridomyrmecin (88), from citronellal (89) using common laboratory reagents (Scheme 97.8) [115]. 

Clark et al. (1959) proposed citronellal (V) as a precursor, and were able to synthesize isoiridomyrmecin (II) from this acyclic monoterpenoid as shown below some iridomyrmecin (I) was undoubtedly formed as well, although it was not isolated. In the laboratory synthesis, the aldehyde grouping was protected during the allylic oxidation this would be unnecessary in an enzymatic oxidation. The second step is an intramolecular Michael addition, yielding iridodial (III), the immediate precursor to iridomyrmecins (I and II) in all three schemes. The final step is an intramolecular Cannizzaro reaction. 

Schollhom B, Mulzer J. Stereocontrolled formation of three contiguous stereogenic centers by free radical cylization. Synthesis of (+)-iridomyrcecin and (—)-isoiridomyrmecin. Formal synthesis of 8-skythantine. Eur. J. Org. Chem. 2006 (4) 901-908. 

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