Cyclization iridoid

Snider has shown that thermolysis of 2,6-dimethyl-2,7-octadienal at 350°C yielded three compounds, 365-367, having the iridoid skeleton. The lactone 368 was made by cyclization of the corresponding hydroxy acid ( 8-hydroxy-citronellic acid ), and its tert-butyldimethylsilyl enol ether rearranged in an Ireland-type Claisen rearrangement, yielding the iridoid acid 369 after removal of the silyl group with HF in acetonitrile. The latter was converted (by hydrobora-tion-oxidation) into both isomers of dihydronepetalactone (370) (erroneously considered to be unsynthesized by the authors, who clearly did not read Vol. 4, p. 497). Iridomyrmecin (371) is also accessible from 369 (Scheme 30). 

Several natural products such as cannabinoids, iridoids, indole alkaloids,fiirofuran lig-nans and other compounds have been synthesized using this methodology. Deoxyloganin (210) was obtained by condensation of the enantiomerically pure aldehyde (208) with Meldrum s acid in the presence of ethylenediammonium diacetate to give the Knoevenagel product (209), which cyclizes immediately, yielding the cycloadducts (211) and (212) in a 10 1 ratio (Scheme 40). (-)-Ajmalicine... 

The starting compound for the biosynthesis of iridoids is the mevalonic acid, and the first step seems to be common to all the structures, but they divert from the cyclization step onwards, where the iridane skeleton is formed. Dahlgreen [11] proposed three routes based on biosynthetic data and by an analysis of taxons of the reported iridoids (see scheme 1). 

Iridoids represent a class of highly oxygenated monoterpenes characterized by a c/s-fiised cyclopentapyran ring system. In principle, synthesis of such systems could be achieved by a photoreductive cyclization of S,e-unsaturated p-ketoesters. Unfortunately, unsaturated p-ketoester 101 did not lead to the ex-... 

CycUzatiou of geraniol. Treatment of geraniol (1) with this salt in CH2CI2 at 20° for 2 hours gives three new products (2), (3), and (4) in a total yield of 91%. The first two products possess the iridoid carbon skeleton. Cyclization to... 

Fig. 20.5. Proposed cyclization of iridoid monoterpenes (modified from Escher et al., 1970 used with permission of the copyright owner, the Royal Society of Chemistry, London).

M. are biosynthesized from geranyl pyrophosphate (see Terpenes) via its isomer neryl pyrophosphate (Fig.). Aliphatic M. arise by hydrolysis of the phosphate bond, or the elimination of pyrophosphate (synthesis of 3,7-dimethyloctane type). Cyclic M. usually arise by nucleophilic substitution at Cl of the neryl pyrophosphate with loss of pyrophosphate. Iridoid compounds arise from the reductive cyclization of neryl pyrophosphate. 

Titanium(ii)-chloride-induced reductive cyclization of one of the photo-adducts (43) of isoprene and methyl 2,4-dioxopentanoate produced a mixture of diastereo-meric diols (44), which are useful precursors in the synthesis of iridoids. The Lewis-acid-catalysed reaction of unsaturated carbonyl compounds such as (45) shows a strong dependence on the strength and quantity of Lewis acid used. 

Iridoids are a large and stmcturally diverse class of secondary metabolites of monoterpenoid origin [10, 11]. Their sttuc-tural parent system is the iridane skeleton, which is derived from geraniol (6) by a cyclization pathway that is mechanistically different to the cyclization reactions that are usually found in classical terpene chemistry [1, 12], Further enzymatic transformations then give the fundamental iridoid skeleton or the thereof derived secoiridoid motive (with an alternative connectivity as shown in Scheme 6.10), which often serves as a building block for the synthesis of more complex monoterpenoid indole alkaloids [1]. Noteworthy, hereby the isoprene mle is often not fulfilled anymore as the terpenoid parts of such compounds sometimes contain nine carbon atoms only due to a decarboxylation step somewhere in the sequence. Very often iridoids and secoiridoids are present as glycosides in nature. 

The total syntheses of the iridoids (-i-)-geniposide (255) and 7-deoxyloganin (256) are two illustrative cases where achiral nucleophilic organocatalysts have been successfully used to facihtate cyclization reactions of chiral starting materials. 

SCHEME 6.43 Chiral amine-catalyzed Rauhut-Currier-type cyclization in the synthesis of the iridoid (+)-mitsugashiwalactone (271). 

Geu-Flores, F., et al.. An alternative route to cyclic terpenes by reductive cyclization in iridoid biosynthesis. Nature, 2012. 492(7427) 138-142. 

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