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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Org Lett. Author manuscript; available in PMC 2010 May 4.
Published in final edited form as:
PMCID: PMC2863135

Asymmetric Total Synthesis of the Iridoid β-Glucoside (+)-Geniposide via Phosphine Organocatalysis


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Phosphine catalyzed [3+2] cycloaddition of ethyl-2,3-butadienoate with enone (S)-3b occurs with high levels of regio- and stereocontrol to deliver the cis-fused cyclopenta[c]pyran 4 characteristic of the iridoid family of natural products. Cycloadduct 4 was converted to the iridoid glycoside (+)-geniposide in 10 steps.

The iridoids are a large family of monoterpenoid natural products structurally characterized by a highly oxygenated cis-fused cyclopenta[c]pyran ring system. 1 Members of this class embody a diverse range of biological activities,1d, 2 which has made them popular synthetic targets.3 Despite enormous progress, synthetic approaches to iridoid natural products that incorporate their natural β-glycosides remain rare due to difficulties associated with the glycosidation.4

In the course of our studies in the area of phosphine organocatalysis, 5, 6, 7, 8, 9 we explored intramolecular variants of Lu’s phosphine catalyzed [3+2] cycloaddition reported in 1995.5a, 10, 11, 12 Whereas the intermolecular cycloaddition generally provides mixtures of regio- and stereoisomeric adducts, the intramolecular cycloaddition delivers diquinanes in structurally homogenous form. As a regio- and stereocontrolled intermolecular cycloaddition of this type would be of great utility, we explored dipolarophiles possessing γ-heteroatom substitution, as in the case of enones 3, which are prepared conveniently through the Achmatowicz reaction of furfuryl alcohol. 13 It was postulated that such γ-heteroatom substitution should (a) activate the dipolarophile toward cycloaddition, (b) reinforce the inherent regiochemical bias, and (c) direct the diastereofacial selectivity of cycloaddition.

Here, we report that “Achmatowicz enones” 3 engage in regio- and stereocontrolled intermolecular [3+2] cycloaddition, thus providing direct access to the iridoid ring system 4. This methodology was applied to the synthesis of the iridoid glycoside (+)-geniposide 1,14 which displays antitumor15 and anti-inflammatory16 activity. The total asymmetric synthesis of (+)-geniposide 1 constitutes a formal synthesis of its aglycone (+)-genipin 2,17, 18 which recently has garnered attention as an effective treatment for type II diabetes (Scheme 1).19

Scheme 1
Retrosynthetic analysis of (+)-geniposide 1 and (+)-genipin 2.

Exposure of commercially available furfuryl alcohol to m-CPBA in dichloromethane delivered lactol rac-3a in 78% yield,12 which was converted to the pivalate rac-3b in 80% yield. Kinetic resolution of rac-3b was attempted under the conditions of palladium catalyzed allylic substitution employing p-nitrobenzyl alcohol as nucleophile.20 After careful optimization, it was found that chirally modified palladium catalysts arising from the combination of [(η3-C3H5)PdCl]2 (1.0 mol %) and the parent Trost ligand (3 mol %) enable recovery of the allylic pivalate (S)-3b in 92% ee in a satisfactory 70% theoretical isolated yield. Optically pure (S)-3b is readily achieved upon recrystallization from pentane. The byproduct (R)-3c was isolated in 96% theoretical isolated yield in 68% ee. Absolute stereochemistry was determined by single crystal X-ray diffraction analysis of 4,5-dichlorophthalimide adduct of (S)-3b using the anomalous dispersion method, and is consistent with the stereochemical models developed by Trost for related kinetic resolutions (Scheme 2).21

Scheme 2
Kinetic resolution of rac-3b using palladium catalyzed allylic substitution.

With (S)-3b in hand, the phosphine-catalyzed [3+2] cycloaddition was attempted using ethyl-2,3-butadienoate. Gratifyingly, using triphenylphosphine as catalyst (10 mol %) in toluene (0.2 M) at 110 °C, the desired cycloadduct 4 was obtained in 63% isolated yield after 30 minutes as a single regio- and stereoisomer, as confirmed by single crystal X-ray diffraction analysis. Note that while two equivalents of (S)-3b are used in the cycloaddition, unreacted (S)-3b was recovered in 96% isolated yield.

Installation of the α,β-unsaturated methyl ester was accomplished in a stepwise fashion. Cycloadduct 4 was converted to the cyanohydrin, which upon elimination furnished the α,β-unsaturated nitrile 5 in 60% isolated yield over two steps. Chemoselective reduction of the α,β-unsaturated ethyl ester of compound 5 using DIBAL-H delivered the allylic alcohol 6 in 62% yield. Further conversion of nitrile 6 to the methyl ester was made difficult due to the sensitivity of the enol moiety to acid, as well as the base sensitivity of the pivalate. Using the Ghaffer-Parkins catalyst, 22 hydration of nitrile 6 to the primary amide 7 was accomplished in 87% isolated yield. Nitrosation of amide 7 resulted in hydrolysis to furnish the carboxylic acid.23 During the course of this reaction the primary alcohol was converted to the acetate. Exposure of carboxylic acid to TMS-diazomethane delivered the methyl ester 8 in 74% yield over two steps.

To complete the synthesis of (+)-geniposide 1, installation of the β-glucoside was required. Quite serendipitously, it was found that upon exposure of methanolic solutions of compound 8 to Otera’s catalyst,24 acetate removal was accompanied by transfer of the pivaloyl moiety to provide lactol 9 in 73% yield as a 5:1 mixture of epimers at the anomeric carbon. Compound 9 was independently prepared from commercially available (+)-genipin 2, thus corroborating its structural assignment and providing a convenient source of forefront material. Glycosidation of lactol 9 employing the trichloroacetimidate as the glycosyl donor delivered the β-glucoside 10 in 62% yield as a single diastereomer. Global deprotection of 10 using aqueous lithium hydroxide in acetonitrile 25 provided (+)-geniposide 1 in 61% isolated yield, the spectral data of which corresponded to that of previously reported material.26

In summary, we report an asymmetric synthesis of the iridoid glucoside (+)-geniposide 1 in 14 steps. A key feature of our synthetic strategy involves rapid construction of the cis-fused cyclopenta[c]pyran iridoid ring system employing a phosphine catalyzed intermolecular [3+2] cycloaddition. Unlike typical intermolecular cycloadditions employing acrylates, fumarates and maleates, which provide adducts as mixtures of regio- and diastereoisomers, the unique structural features of γ-heteroatom substituted enones 3 combine high levels of reactivity with excellent regio- and stereocontrol.

Table 1
Conversion of (S)-3b to (+)-geniposide 1 via phosphine catalyzed [3+2] cycloaddition.a

Supplementary Material

Supplementary Data


Acknowledgment is made to the Robert A. Welch Foundation and NSF (CHE-0749016).


Supporting Information Available. Spectral data for all new compounds (1H NMR, 13C NMR, IR, HRMS). Single crystal X-ray diffraction data for the 4,5-dichlorophthalimide adduct of (S)-3a and the cycloadduct 4. This material is available free of charge via the internet at


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