Iridoids total synthesis

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

Since neonepetalactone is closely related to the iridoids described above, the total synthesis followed the same procedure (Scheme 1.2.14) leading to the desired natural product in 55% overall yield and excellent de and ee values of >96%. 

The conversion of a bicyclo[2.2.1]octenone derivative to the corresponding bicyclo[3.3.0]octenone, a common intermediate in the total synthesis of several iridoid monoterpenes, was achieved by N.C. Chang et al. The target was obtained by sequential application of the Corey-Chaykovsky epoxidation, Demjanov rearrangement and a photochemical [1,3]-acyl shift. 

Trost has used a,a-disulfenylated lactones as enolate precursors. As shown in equation (23), a,a-di-(phenylthio)- v-butyrolactone is treated sequentially with ethylmagnesium bromide and acetaldehyde to obtain -hydroxy lactone (8) in virtually quantitative yield. Oxidation of the phenylthio group and subsequent elimination of the resulting sulfoxide provides the unsaturated hydroxy lactone (9). The process was employed with more complex lactones in a total synthesis of iridoids. The method fails with a,a-di-sulfenylated ketones unless a catalytic amount of copper(I) bromide is included in the reaction mixture. 

Monosubstituted norbornenones may also be used as precursors for stereoselective rearrangements provided that the 7-substituent has a syn orientation to the carbonyl group. For example, dimethyl acetal 40 is used in the total synthesis of the iridoid monoterpene ( + )-dimethyl secologanoside 0-methyl ether (43)1068 as well as the synthesis of the civ-fused hydrindanone 471069. 

Terpenes.- The first total synthesis of the biologically active marine natural product metachromin A (241) has been achieved using an ( )-stereoselective olefination with the phosphonate (240) as the key step. The olefination reaction of the a-cyanophosphonate (242) with ( , )-farnesal (243) has been studied under a wide variety of conditions with a view to optimising (Z)-stereoselectivity.Excellent (Z)-stereoselectivity was achieved and the resulting procedure applied to a stereoselective synthesis of plaunotol (244). Epimerisation and P-elimination of base-sensitive substrates can cause problems in phosphonate- and phosphine oxide-based olefinations. Such reactions have been excluded in a recent report of enantiospecific syntheses of iridoid monoterpene lactones by intramolecular phosphonate-olefination through the use of mild bases such as DBU and di(wopropyl)ethyl amine/lithium chloride. 

Baeyer-VUliger oxidation. The Baeyer-Villiger oxidation of 1 to 2 was used ill one step in a total synthesis of ( )-sarracenin (3), an iridoid monoterpene. riic oxidation was carried out in CH2CI2 in the presence of sodium bicarbonate, which approximately doubles the rate of reaction." This method is credited to >r. I . S. Slotter (private communication). 

The iridoid natural products contain a functionally and stereochemically rich scaffold, which has inspired chemists to design a diverse range of strategies for their construction. Biichi and coworkers reported the first total synthesis of the iridoid aglycone ( )-genipin (25) in 1967 (Scheme 5). Pivotal to... 

Based on our experiences with the NHC-catalyzed synthesis of dihydropyra-nones, we thought it conceivable that ot,p-unsaturated enol ester 51a could be converted to the iridoid cyclopenta[c]pyran core (i.e., 52a) (Scheme 11). In turn, it was envisaged that the required unsaturated enol ester 51a could be prepared via acylation of methyl formyl acetate (53a) with enantioenriched acyl chloride 54. The NHC-catalyzed rearrangement would only prove viable if it proceeded with chemoselectivity, due to the presence of additional ester functionality in enol ester 51a, and stereoselectively, to provide the correct diastereomer of 52a for the natural product. Although it was unclear whether these selectivities could be achieved, or whether the reaction would proceed with substrates annulated about the a,p-unsaturation, it was envisaged that this study would, at the very least, allow the limitations of the NHC catalysis to be examined. From the iridoid core 52a, completion of the total synthesis would require the chemo- and stereoselective reduction of the lactone to the lactol, followed by glycosylation. 

The phosphane catalyzed [3+2] cycloaddition between aUenoates and activated alkenes have attracted extensive attention since its discovery [95, 96]. Recently, in 2009, Krische and his co-worker reported a phosphane-catalyzed [3+2] cycloaddition of ethyl-2,3-butadienoate 237 with an enone 238 to give the cis-fused cyclopenta[c]pyran 239. They applied this methodology to the total synthesis of the iridoid p-glucoside (+)-geniposide 240, Scheme 3.77 [97], Alternatively, phosphane-catalyzed [3+2] annulation of aUenoates with aldehydes, affording 2-alky-lidenetetrahydrofurans, was reported by He and his co-workers [98]. 

The potential importance of the iridoid family of compounds was aheady mentioned previously in this volume (see Scheme 48 and 126). The Lupton group has reported recently the total synthesis of the natural product 7-deoxyloganin (625) 521). Synthesis of the bicyclic core was achieved by a NHC (626)-catalyzed rearrangement of the precursor 627 to furnish the lactone 628 in reasonable yield and with full transfer of stereo-information (Scheme 129), thus giving access to 625 after just three further steps. 

Jones RA, Krische MJ (2009) Asymmetric Total Synthesis of the Iridoid P-Glucoside (+)-Geniposide via Phosphine Organocatalysis. Org Lett 11 1849... 

MacMillan et al. reported total synthesis of iridoids, brasoside (71), and littoralisone (72), in 13 steps in 13% overall yield [102]. Both these iridoids were isolated earlier from Verbena littoralis, and littoralisone (72) was demonstrated to be the active agent for increased NGF-induced neurite outgrowth in PC12D cells [103]. They synthesized the iridolactone aglucone (73) using (-) citronellol (74) as starting material via the intermediate, formyl enal (74a). Proline-catalyzed intramolecular Michael addition of the formyl enal was the key step of their synthesis (Scheme 97.4). 

Recently, Vidari et al. synthesized 9-deoxygelsemide (75), which was isolated earlier from Gelsemium elegans by Takayama et al. [104, 105]. The key synthetic steps were the variant Woodward-Prevost reaction for installation of characteristic cis-a-l,2-dioxygenated system at C-6 and C-7, and construction of the dihydropyran ring via formylation of y-lactone. The total synthesis of the iridoid was achieved in 11 steps and 6.6% overall yield from enantiomerically pure lactone (76) (Scheme 97.5). 

Jones RA, Krische MJ (2(X)9) Asymmetric total synthesis of the iridoid P-glucoside (-1-)-geniposide via phosphine organocatalysis. Org Lett 11 1849-1851... 

Monoterpenes and iridoids are important classes of secondary metabolites, and their biosynthesis as well as total synthesis approaches to access these compounds has attracted the interest of chemists for a long time. This overview will summarize the most important biosynthesis pathways and in addition will illustrate how one of the most important recent developments in organic chemistry, asymmetric organocatalysis, contributed in the development of total synthesis approaches toward these compounds. Therefore, a comprehensive introduction to asymmetric organocatalysis will be given as well. However, it should be noted that the applicability of this methodology to the synthesis of natural products is of course not only limited to monoterpenes and iridoids but holds much promise for other classes of primary and secondary metabolites as well. 

ORGANOCATALYSIS IN THE TOTAL SYNTHESIS OF IRIDOIDS AND MONOTERPENOID INDOLE ALKALOIDS... 

SCHEME 6.40 Phosphine-catalyzed [3-h2] cycloaddition in the total synthesis of the iridoid 3-glucoside (+)-geniposide (255). 

Monoterpenes and iridoids are very important natural products, and the biosynthetic pathways toward these compounds are nowadays well understood. We choose this class of secondary metabolites to highlight the potential of asymmetric organocatalysis for the total synthesis of complex natural products. Asymmetric organocatalysis has been one of the most exciting fields in organic chemistry over the last decades, and we hope that we have been able to illustrate how diverse and powerful this methodology can be with respect to different activation modes that are possible and different substance classes that can be easily accessed thereby. 

SCHEME 7.50 Application of cycloisomerization of trienes in the total synthesis of iridoids. 

Kato, N., Takeshita, H., Tanaka, S., and Kataoka, H. (1989) Lactol-regulated silyloxy-Cope rearrangement and its application to the total synthesis of dictymal, an aldehyde possessing an iridoid dimeric structure./. Chem. Soc. Perkin Trans. L, 1833-1840. 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

---