key: cord-0039820-st1djxx6
authors: Isoe, Sachihiko
title: Progress in the synthesis of iridoids and related natural products
date: 2007-09-02
journal: nan
DOI: 10.1016/s1572-5995(06)80055-4
sha: 007909ae8397e78e90e4563ac0b05d77138a6e97
doc_id: 39820
cord_uid: st1djxx6

A number of iridoids and secoiridoids, which possess a wide range of biological activity, have been isolated from plants and insects—for example, dihydronepetalactone, isodihydronepetalactone, iridomyrmecin, isoiridomyrmecin, neoneptalactone, nepetalactone, actinidine (iridoid alkaloid), and dihydroactinidiolid (carotenoid metabolite), the mixture being a potent attractant for cat, have been isolated from Actinidia polygama Miq. Similarly, neomatatabiol, isoneomatatabiol, dehydroiridodiol, iridodiol, and matatabiol have been isolated from the same plant and the mixture serves as a potent attractant for lacewing. From a synthetic and biosynthetic point of view, dehydroiridodial, chrysomelidial, and iridodial are considered to be the central intermediates for the biosynthesis of other iridoids from Actinidia polygama Miq. The chemical interconversion of these iridoids is presented in the chapter. The broad diversity of both structure and biological activity exhibited by iridoids and secoiridoids has generated much interest in their general synthesis starting from a common intermediate. The chapter introduces two general methodologies for the synthesis of polyfunctional iridoids and related natural products.

The broad diversity of both structure and biological activity exhibited by iridoids and secoiridoids has generated much interest in their general synthesis starting from a common intermediate.

We have developed two general methodologies for the synthesis of polyfunctional iridoids and related natural products. One approach involves the effective utilization of tricyclo[3,3,0,02'8]octanone derivative as a building block. This methodology enabled the efficient synthesis of loganin, chrysomelidial, forthyside aglycone and other cyclopentanoid natural products. The same methodology was independently developed by Demuth et al. (4) and widely utilized for the synthesis of iridoids and polyquinanes. Similar methodology utilizing [3, 3 ,0]-octane derivatives has been known and successfully applied for the synthesis of iridoids (5) . The second approach is the effective utilization of (+)-genipin as a chiral building block whose functionality is quite fit for the synthesis of polyfuntional iridoids and related natural products. Furthermore, (+)-genipin is easily obtained by the enzymatic hydrolysis of geniposide with Cellulosin AC-40 and it can be supplied from industry in Kg scale. The altemative non-enzymatic efficient method which we developed is the hydrolysis of geniposide using hydroxymercuration followed by treatment with SnCl2 or sodium 3mercaptopropionate. The second methodology enabled the efficient synthesis of loganin, penstemide, didrovaltrate, plumericin, allamandicin, plumieride, gardenoside, garjasmin, asperuloside, cerbinal, baldrinal, secologanin, sweroside, gentiopicroside, kingiside, morronoside, sarracenin, petiodial and udoteatrial in optically active form. COjMe geniposide l)Hg(OAc)2 acetone-water ^ 2) SnCl2 or HSC2H4C02Na

COjMe genipin 2.

The increasing number of cyclopentanoid natural products and their interesting biological activity has stirred considerable interest into synthesis of such compounds. We have embarked upon the synthesis of polyfunctional iridoids via the same intermediate which may be easily obtained from an ordinary starting material. We selected tricyclo[3,3,0,02 '8] octanone as the varsatile intermediate. Tricyclo-[3,3,0,02 '8] octanone, obtained from photolysis of bicyclo [2, 2, 2] octenone or decomposition of 2-cyclopenten-l-yldiazomethylketone with cupric sulfate, was transformed with formic acid or ptoluenesulfonic acid into functionalized bicyclo [3, 3, 0] octanone, which has a distinguishable functional group in the each five membered ring and can be led into cyclopentanoid natural products via the selective conversion of the functional group. We have applied this versatile intermediate, tricyclo [3,3, 0,0^ '8] octanone towards the synthesis of polyfunctional iridoids, chrysomelidial, loganin and forsythide. 79% yield. Conversion of this acid into its acid chloride followed by treatment with ethereal diazomethane furnished the diazo ketone 3 and the decomposition of the latter with cupric sulfate in refluxing cyclohexane yielded 4-methyl-tricyclo [3,3, 

Ring cleavage of 2 with 99% formic acid at 70-80 °C for 30 min followed by methanolysis and ketalization in the usual manner gave in 87% yield a mixture of the desired ketal (C2-8 bond cleavage) and its structural isomer (Ci_2 bond cleavage) in a ratio of 4:1 by ^H-NMR. The two isomers were easily separated by column chromatography. This desired ketal was oxidized with chromium trioxide-pyridine complex in methylene chloride to give the corresponding ketone 4 which, upon alkylation with methyl lithium in ether at -78 °C followed by treatment with p-toluenesulfonic acid in aqueous THF, afforded the ketoalcohol 5 in 81% yield. Refluxing of 5 with p-toluenesulfonyl hydrazine in methanol for 30 min produced the corresponding hydrazone in 93% yield. Treatment of this resulting hydrazone with excess n-butyl lithium in THF, followed by oxidation with osmium tetroxide in ether, and acetylation gave in 75% yield the stereoisomeric mixture of diacetates and triacetate in a ratio of 83:14:3. Diacetates were treated with phosphoryl chloride in pyridine at 50 °C for 3 h to form in 97% yield a mixture of the desired tetra-substituted olefin and tri-substituted olefin in a ratio of ca. 15:85 by ^H-NMR. Reduction of the tetrasubstituted olefin mixture with lithium aluminium hydride in ether followed by oxidation with sodium periodate in ether-water (1:1) at 4 °C for 24 h afforded chrysomelidial in excellent yields. The same oxidation of the trisubstituted olefin produced the hydrate 6, which was transformed into chrysomelidial by refluxing in 50% aqueos acetic acid in 99% yield. The diacetate was also converted to chrysomelidial by the same procedure.

Loganin was first isolated from Strychnos nux vomica and it is a widely distributed secondary plant metabolite (9) . It has proven to be an important monoterpene in plant biochemistry due to the role in the biosynthesis of indole alkaloids and other natural products (10) . We have employed the versatile intermediate 3 in the synthesis of loganin (11) (12) .

? 

We have now demonstrated the potential utility of 4-methyl-tricyclo[3,3,0,0^'^]octan-3-one 4 as a versatile intermediate in the synthesis of chrysomelidial (6) and loganin. We next describe the stereocontrolled synthesis of (±)-forsythide aglycone dimethyl ester (12) , starting from another versatile synthon, 4-methoxycarbonyl-tricyclo[3,3,0,02'^]octan-3-one (14) . Forsythide (13) is a naturally occurring iridoid glucoside isolated from the fresh leaves of Forsythia viridissima Lindl.

The 

Ozonolysis of the mixture of 17 followed by reductive workup with Zn/AcOH directly led to (+)forsythide aglycone dimethyl ester 12 after purification by preparative TLC as an oil. This was an epimeric mixture at the Ci position and was obtained in 66% yield (ratio: a-OH/p-OH=3.5/1.0 by ^H-NMR). The stereocontrolled and facile synthesis of (±)-forsythide aglycone dimethyl ester 12 was thus achieved starting from the versatile synthon 14.

3 .

Penstemide was isolated from the methanol extracts of Penstemon deutus Dongl. exLindl.

(Scrophulariaceae) by J. R. Cole et aL (14) in 1976 and its structure was revised to the present structure in 1979 (15) . On the other hand, didrovaltrate was isolated from the Valeriana Wallichii D.

C. in 1968 (16) and it's correct stereochemistry including absolute configuration was established in 1973 by Thies et aL (17) . Penstemide was found to exhibit activity against the P-388 lymphocytic leukemia test system and didrovaltrate is a very potent cytotoxic agent for the rat hepatoma cells and induces high percent definitive remissions of the Krebs II ascitic tumors (18).

Selective protection of hydroxyl groups of genipin with different protective groups followed by reduction of the methoxycarbonyl groupwith DIBAL and oxidation of resulting alcohol with BaMn04 yielded the aldehyde 18. Selective deprotection of the hemiacetal protective group followed by acylation with isovaleric acid in the presence of carbonyl diimidazole and DBU and reduction with NaBH4 furnished penstemide aglycone silylether 19 in very high yield. Glucosidation of the primary alcohol 19 followed by deprotection would lead to the synthesis of penstemide. 

Selective protection of the hydroxyl group of the hemiacetal of genipin followed by treatment with diphenyl disufide in the presence of tri-n-butylphosphine yielded the phenyl thioether 20. To avoid the eliminauon of the more reactive primary hydroxyl group at the stage of acylation, two isovaleryl groups were introduced by the following sequence. The hydroxyl group of the hemiacetal was acylated first by the same procedure used as that in the synthesis of penstemide aglycone, and then the primary alcohol was acylated to yield diisovalerate 22. Oxidation of phenylsulfide to phenyl sulfoxide 23 followed by Evan's rearrangement and oxidation of the resulting allylic alcohol gave the exomethylene ketone 24 in high yield. Reduction of the ketone 24 to the p-hydroxy olefin 25 followed by Sharpless oxidation afforded the p-epoxy alcohol 26. Inversion of the p-hydroxyl group to a-acetoxyl group was successfully carried out by a SN2 reaction of triflate with acetate anion in the presence of 18-Crown-6 to accompUsh the synthesis of didrovaltrate. 

The fruits of Gardenia jasminoides Ellis are a Chinese traditional medicine used for treatment of hepatitis and hemafecia. During a screening test on antifertility agents from the flowers of this plant, J-P. Gu and R-S. Xu (19) isolated garjasmin and garjasmidin. Gardenoside (20) was isolated from Gardenia jasminoides f. grandiflora and other plants. Asperuloside (21) was isolated from Asperua odorata L.. a) cat. Os04, NMO, t-BuOH:acetone:H2O=10:3:l, 85% b) 1.5 eq. TfiO, DMA?, CH2CI2; DBU, 76% c) PPTS, acetone-H20 d) 5 eq. n-Bu4NF; p-TsOH, 53% e) PPTS, acetone-H20, reflux, 50% f) TBDMSCl, Im, DMF, 93% from 28 g) 1 eq. KH, THF, 0 °C h) DCC, DMAP, CH2CI2, 85% from 30 i) PPTS, acetone:H20=3:l, reflux j) AC2O, Pyr., DMAP, 54% from 31

Garjasmin and asperuloside aglycone silylether were synthesized from genipin via gardenoside aglycone silylether (Scheme 7). Dihydroxylation of genipin disilylether (27) with osmium tetroxide followed by the selective elimination of the secondary alcohol via triflate gave disilylether of gardenoside aglycone (28) in good yield. Upon treatment of 28 with PPTS in aqueous acetone, the silyl group attached to the primary alcohol was first hydrolyzed to give gardenoside aglycone silyl ether. The prolonged reaction time, however, caused transposition of the tertiary hydroxy group to yield the desired C6 hydroxylated compounds as a mixture of stereoisomers 29 in about 3.6 to 1 ratio. This observed hydroxy transposition was significant in that the transposition of hydroxyl group in the proposed biosynthetic pathway (22) of gardenoside from geniposide proceeded in the opposite direction. The major isomer (p-hydroxy) was converted into asperuloside aglycone silylether as shown in Scheme 7. Treatment of the alcohol 30, obtained by silylation of the primary alcohol in 29, with potassium hydride in THF cleanly afforded the hydroxy acid, which was then lactonized with DCC to give the desired lactone 31. Finally hydrolysis of the silyl group to the primary alcohol followed by acetylation of the resulting alcohol completed the synthesis of asperuloside aglycone silylether. Garjasmin was synthesized from 28 by treatment with a large excess amount of TBAF (5 equiv.) followed by acidification with p-toluenesulfonic acid (p-TsOH) in 53% yield.

In a) AC2O, Pyr., CH2CI2, 92% b) Pd(PPh3)4, Ph3P, THF; MeCOCH2C02Me, NaH,THF, quant, c) 2,2-Dimethyl-l,3-propanediol, p-TsOH, CgHe, 86% d) cat. OSO4, NMO, t-BuOH-acetone-H20, --50% e) NaOMe, MeOH, 94% f) (CF3S02)20/DMAP/CH2Cl2; DBU, 90% g) Ph3CBF4, CH2CI2, 78% h)PhSeBrorPhSeCl,DMAP,CH2Cl2 i) H2O2, CH2CI2, 80% from 35 j) n-Bu4NF, 2 eq. AcOH, THF, quant, k) Et3SiH, TFA, 0 °C, 18 h, 40% 1) EtgSiH, TFA, it, 20 h Scheme 8 Inoue et al. (28) succeeded in the synthesis of plumieride (24) from lO-dehydrogardenoside tetraacetate and ethylacetoacetate by a biomimetic route in 1979. In our synthesis of plumericin and allamandicin, plumierde which was thought to be a biogenetic precursor (29) was selected as the key intermediate. We first attempted the coupling of genipin with methyl acetoacetate. Selective protection of the hydroxyl group of genipin hemiacetal followed by acetylation produced allyl acetate 32. Palladium % allyl complex mediated coupling reaction (30) of ally lace tate with sodium salt of methylacetoacetate produced the coupling product 33 in quantitative yield. Protection of the ketone as an acetal followed by reaction with osmium tetroxide yielded the dihydroxy compound 34. Both lactonization and dehydration proceeded in high yield by the treatment of 34 with sodium methoxide followed by treatment with trifluoromethanesulfonic anhydride, 4-dimethylaminopyridine and DBU.

It is noteworthy that the use of trifluoromethane sulfonyl chloride gave the chloride by substitution.

Difficulty in a similar dehydration was reported in the synthesis of plumericin by Trost (31) .

Deprotection of the acetal protecting group proceeded well on treatment with tritylfluoroborate. The introduction of phenylselenyl group and selenoxide elimination also proceeded nicely to give an unsataurated keto lactone 36 (32) . Reduction of the keto lactone 36 with triethylsilane in trifluoroacetic acid (33) furnished a mixture of plumieride aglycone silylether (41) and its epimer 42 (60:40) in 78% yield (Scheme 9). Desilylation of 36 with tetrabutylammonium flouoride (TBAF) in the presence of 2 equiv. of acetic acid followed by Michael addition of the alcohol produced the tetracyclic ether 37 in quantitative yield. The final step is the stereoselective reduction of the keto group to give allamandicin. After many fruitless attempts, it was found that this reaction was best performed by the reduction with triethylsilane in CF3CO2H at 0 °C to accomplish the synthesis of (+)-allamandicin. In this case (+)-^/?/-allamandicin (38) and (+)-iso-allamandicin (39) were aslo obtained. Any reductions in basic conditions gave fruidess results. When this reduction was carried out at room temperature, a mixture of (+)-plumericin and (+)-iso-plumericin (40) (75:25) were obtained in 50% yield. Dehydration of a mixture of allamandicin and ^p/-allamandicin (38) (75: 25) with phosphoryl chloride afforded a mixture of (+)-plumericin and (+)-iso-plumericin (40) needed to obtain 43 more conveniently and efficiently. We therefore tried to find a more efficient synthetic route to get this key compound.

The silylation of genipin with t-butyldimethylsilyl chloride in the presence of imidazole gave the monosilyl ether 47 quantitatively (Scheme 10). For the subsequent dehydration, we then tried to convert the hydroxy group of 47 into several leaving groups. However it was difficult to get compounds with leaving groups on the hemiacetal carbon, because of the instability of intermediates.

We found that the thioimidazolide (40) yield. It seemed that this cyclopentadieno[c]pyran ring system was very unstable in the presence of nucleophiles under acidic or basic conditions. We found that in the presence of a primary amine such as benzylamine, 43 quickly reacted with 2 equivalents of amine to give unknown derivatives.

However in the case of over 5 equivalents of benzylamine, an 0/N exchange very quickly occurred to give a cyclopenta[c]pyridine derivative (52) (Scheme 11). This result was also found in baldrinal.

(41) To our surprise, cerbinal did not show any cytotoxicity against several human carcinomas. 5 eq. PhCH2NH2 THF,rt a very short time

As described above we have developed a general method for the efficient synthesis of cerbinal involving a cyclopentadieno[c]pyran ring system. Using cerbinal as a building block, we have successfully achieved the synthesis of baldrinal. This synthetic scheme helped us to gain a lot of information about the chemical properties and biological activities of this unique aromatic system. This synthetic scheme may be applied to the synthesis of 45 and 46 as well as an unnatural 10 n iridoids to investigate their structure-activity relationship in their biological activities, especially their antitumor activity.

Secologanin was isolated from Lonicera morrowii A. Gray (kingimboku) by Mitsuhashi et al.

in 1970 (42) and has considerable biosynthetic significance, because it is the common nonnitrogenous precursor to a vast and diverse array of indole alkaloids (43) . Secologanin is biosynthesized via loganin by C7.8 cleavage of the five membered ring.

The biomimetic fragmentation approach to the synthesis of secologanin has been employed by L. F. Tietze (44) and J. J. Partridge (45) . We have applied the oxidative fragmentation of y-hydroxy alkylstannane with lead tetraacetate, which was previously developed in our laboratory, (46) to the synthesis of brefeldin A.

The monosilyl ether 53 was obtained from genipin by disilylation of the primary hydroxyl group and the hemiacetal, followed by selective desilylation of the primary hydroxyl group with PPTS in 98% yield. This simple procedure was very useful for both regioselective and stereoselective protection of the hydroxy group of the hemiacetal in genipin. Allylic rearragement of the free hydroxyl group of 55 was achieved by Evans rearrangement. (47) Thus 53 was converted to a thioether, which was oxidized to give the sulfoxide. Thermal rearrangement of the resulting sulfoxide proceeded smoothly to give the alcohol 54, which was subjected to oxidation, yielding the exomethylene ketone 55.

It is well known that trialkylstannyl lithium normally adds to a,p-unstaurated ketone to give the formal 1,4-adduct in excellent yield (48) . MeOH, NaI04, rt, 72% k) NaBH4, MeOH, rt 1) cat. NaOMe, hv, sens., 74%

Gentiopicroside, which is the principal bitter glucoside of common gentians, was isolated in 1862 (51) and has been widely used as stomachic or antidote from ancient times. The instability of the gentiopicroside made its structure elucidation extremely difficult (52) . Inoue suggested that gentiopicroside could be biosynthesized via sweroside and swertiamarin (53) . Secologanin aglycone silylether (58) Secologanin, kingiside, morronoside and sweroside have been isolated from Lonicera morrowii A. Gray by Souzu and Mitsuhashi (42, 56) . Considering the fact that these four glucosides coexist in the same plant, these compounds are supposed to be biogenetically close congeners as suggested by Inoue (22) . Since kingiside is biosynthesized via secologanin, we therefore attempted first to synthesize kingiside aglycone-0-silyl ether (64) from secologanin aglycone silylether (58) .

Secologanin aglycone silylether (58) was oxidized to give the corresponding carboxylic acid.

PhSeBr was found to be an excellent reagent for lactonization. Deselenylation of the selenolactone with triphenylstannane gave a lactone, which was assigned as ^p/-kingiside aglycone silylether (69) .

Selenolactonization under equilibrium conditions ensured the formation of the thermodynamically more stable selenolactone (57) . In order to control Cg stereochemistry, we tried an alternative route. NATURAL PRODUCTS RELATED TO IRIDOIDS Udoteal, a marine linear diterpene, is considered to be a key intermediate for the biosynthesis of petiodial, udoteatrial, halimedatrial, halimedalactone and halitunal having an iridoid framework. On the other hand, seco-manoalide, a sesterterpene having a y-hydroxy butenolide ring, is considered to be formed from a linear sesterterpene whose functionality is very similar to udoteal. It may be possible to think that synthetic seco-manoalide analogue, which is a remarkable phospholipase A2 inhibitor, will be isolated in the future. (-)-Petiodial was isolated from the marine algae, Udotea petiolata, collected in Naples (58) and from Udotea Flabellum (59) in Cambean independently. This monocyclic diterpenoid dialdehyde shows significant biological activities against several marine bacteria, inhibits of cell division in fertilized sea urchin eggs, and is toxic to herbivorous damselfish causing death within one hour. Besides petiodial, the diterpenoids udoteatrial (60) and halimedatrial (61) have been reported possessing similar structures. The absolute configuration of these compounds has not been determined, and in the case of petiodial the relative stereochemistry has also not been reported yet. In the biosynthesis of these diterpenoids, the corresponding linear diterpene udoteal, isolated from the algae, was suggested to be the biogenetic precursors (61) . In this section the first efficient synthesis (62) of optically active petiodial and determination of its absolute structure (65, 7R) has been described. Next the absolute stereochemistry of another asymmetric center at C7 of 78 was determined as follows. Reduction of the mixture of (+)-petiodial (78) and its diastereoisomer 79 obtained above with LiAlH(t-BuO)3 (64) afforded the corresponding diols which were isolated respectively in a ratio of 3:2. The major alcohol 80 was reconverted into (+)-petiodial This syntheses also confirmed that the biogenetic precursor of petiodial is not an iridoid, but it could be a linear diterpene udoteal. The synthetic method employed here could be expanded to get various analogues involving different side chain. These compounds might show much better biological activities than those of petiodial. From this successful synthesis we can expand our research fields into more complicated diterpenes involving a cyclopentene ring system.

The unique monocyclic diterpenoid trialdehyde udoteatrial (84) (60) isolated from marine algae Udotea flabellum, was reported to show antimicrobial activity against Staphylococcus aureus and Candida albicans. Since all three substituents on the cyclopentane ring are in cis relationship, udoteatrial is known to exist as a form of the mono-hydrate.

Although the relative stereostructure of natural udoteatrial hydrate (85) was confirmed as (25*, J/?*, (5/?*, 7/?*) by synthesis of the racemic form (67), its absolute configuration has remained uncertain.

Since udoteotrial hydrate (85) could be considered to consist of the iridoid carbon framework and geranyl side chain, we decided to investigate the synthesis of 85 starting from genipin to demonstrate the usefulness of genipin as a chiral building block as well as to confirm the absolute configuration of 85. In this section, the synthesis (68) of the optically active 85 and the absolute configuration of natural udoteatrial hydrate is described.

To introduce the geranyl side chain into the iridoid carbon framework, the tricyclic exomethylene lactone 86 was designated to be the key intermediate. The problem upon introduction of the geranyl side chain was the stereocontrol of the newly formed stereogenic center at C7. Since it seemed, however, that the side chain in 85 occupied the thermodynamically stable a-configuration, it was considered that base catalyzed isomerization could control the stereochemistry at C7 after introduction of the side chain into 86. To support this assumption, semiempirical calculations (PM3) (69) of simplified analogues derived from 86 did show that the a-isomer were more stable than the p-isomer. On the other hand, assay of in vitro cytotoxicity of these analogues afforded significant results. Thus, the compounds possessing the homogeranyl side chain (97, 98 and 99) were found to be cytotoxic against KB human oral epidermoid carcinoma and human lung carcinoma A-549 as summarized in the Table (72) . Compound 97 was the most toxic among the analogues examined at concentration of 4x10"^ |ig/ml. The effect of side chain was apparent from the fact that the methyl derivatives were much less toxic relative to compounds 97, 98

and 99 (73) . Furthermore, 97 having the acetate in an axial orientation at C19 exhibited at least 4 fold enhanced cytotoxicity than those having equatorial acetates. From the stereoelectronic point of view, it was suggested that compounds with the better leaving ability of the acetoxy group showed stronger cytotoxicity, although the mechanism of the inhibition of cell growth of these compounds was not understood at all. This observation suggested that the generation of oxonium species by elimination of the acetoxy group might be relevant for the exhibition of cytotoxicity of these compounds. Such oxonium species may act as alkylating agents as is well known in the case of iminium species generated in the naphthyridinomycin/saframycin class of antitumor antibiotics. 

All iridoids and related natural products which are described in Figure 4 and Figure 5 have two or three aldehydes or equivalent functionalities such as enol ether or hemiacetal groups.

These functionalities may play a major role for the display of biological and pharmacological activities. We have synthesized the silyl ether of iridoid aglycones in those cases where the natural products are glucosides, because the real biological activity should be revealed by the aglycone having the aldehyde functionality, which is prepared by desilylation in nearly neutral conditions. The iridoid molecules are reminiscent of a large number of known biologically active dialdehydes such as polygodial, warburganal and manoalide. 

Hyeon in

Proc. Nat. Acad. Sci

95 (1973) 540; b)

Brazilian-Sino Symposium on Chemistry and Pharmacology of Natural Products

Biosynthesis of Iridoids and Secoiridoids, Progress in the Chemistry of Organic Natural Products

Canonica supposed a wrong structure

Inoue revised the structure in 1968: H. Inoue etal

Synthesis of dl-petiodial: B. M. Trost

Advances in Organic Chemistry, Methods and Results

Increase of cytotoxicity by substitution with longer alkyl chain was sometimes observed. For a recent example, see