Abstract
We have been interested in the reactivity of secologanin, which is transformed into more than 3000 natural products in nature and have been working on the bioinspired synthesis of several natural products using secologanin derivatives. In this chapter, we describe the total synthesis of secologanin using an organocatalytic reaction and the collective and divergent total synthesis of glycosylated monoterpenoid indole alkaloids and hetero-oligomeric iridoid glycosides through biogenetically inspired transformations from secologanin derivatives.
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Keywords
- Bioinspired reaction
- Collective synthesis
- Monoterpenoid indole alkaloid
- Hetero-oligomeric iridoid glycosides
- Organocatalytic reaction
9.1 Introduction
In the 2020s, natural products remain as attractive as ever as leads in drug discovery [1]. Novel natural products are constantly being discovered in plants, fungi, and marine organisms, investigated for their biological activities, and reported as candidate compounds for drug discovery. In recent years, analytical techniques such as NMR and X-ray crystallography have made great progress, making it possible to determine the structure of even very small amounts of natural products. As a result, reports of the isolation of new natural products have increased dramatically, but their limited supply makes detailed biological evaluation more difficult. Therefore, the importance of effective and scalable total synthesis of natural products that can only be isolated in small amounts from nature is increasing [2]. In addition, “collective synthesis” and “divergent synthesis,” in which multiple natural products are synthesized from the same intermediate, are attracting attention to prepare libraries of natural products as candidates for drug discovery [3].
Natural products are synthesized in living organisms (biosynthesis). Although biosynthetic pathways in nature are being elucidated daily, countless synthetic pathways remain to be elucidated. A fuller understanding of these pathways will better enable their reproduction chemically, which will enable the supply of natural products and their analogs. This underscores the importance of an understanding of biosynthesis among organic chemists. Many biomimetic total syntheses of natural products have been reported [4]. However, most of them mimic the biosynthetic pathway in only one step, and almost no examples of syntheses mimic the entire biosynthesis. Thus, reproducing a biosynthesis in flasks from the same intermediate to afford a “collective” and “divergent” total synthesis would be compelling. The resulting natural product library would then be evaluated for biological activity and developed into the leads of drug discovery.
This chapter details the collective total synthesis of secologanin-related natural products following the biosynthetic tree diagram, the numerous challenges we faced, and the solutions we devised [5].
9.2 Biosynthetic Tree Diagram from Secologanin
In the biosynthesis of some natural products, one key molecule leads to different scaffolds, branching out like a tree diagram from one molecule. Secologanin (1) is a monoterpene biosynthesized in plants (Fig. 9.1) [6]. Despite its small size, it has three consecutive chiral centers in a multi-substituted dihydropyran ring and several reactive functional groups. This molecule is biosynthesized within a variety of plants, including the Apocinaceae, Caprifoliaceae, Rubiaceae, and Loganiaceae families, and further diverges into more complex natural products. For example, these include monoterpenoid indole alkaloids (MTIAs, e.g., rubenine (2), cymoside (3), and ophiorine A (4)), of which a total of more than 3000 have been reported [7], and hetero-oligomeric iridoid glycosides (HOIGs, e.g., cantleyoside (5) and dipsanoside A (6)) with molecular weights exceeding 700 [8]. In particular, the biosynthesis of MTIAs is a well-known topic and is discussed in natural product chemistry textbooks [7a–e]. Theoretically, if the biosynthetic pathway that begins with secologanin (1) could be reproduced in a flask, a vast number of natural products could be easily synthesized. In fact, following the synthesis of 1, which will be described later, we achieved the synthesis of 39 natural products including 2–6 in only 4 years. These natural products are also expected to be bioactive, since many plants containing these natural products are used as folk medicines.
Secologanin and its related natural products
9.3 Concise and Scalable Total Synthesis of Secologanin
9.3.1 Retrosynthetic Analysis of Secologanin
For the collective total synthesis of secologanin-related natural products, a large supply of 1 as a starting material was required. When we began our total synthesis in 2017, no total synthesis of this molecule had been reported, despite its prominence [9].
Our retrosynthetic analysis is shown in Scheme 9.1. We planned to construct the aldehyde of 1 using a hydroboration/oxidation the alkyne. The terminal double bond would be installed by sulfoxide elimination. We would set the two anomeric centers using a Schmidt glycosylation. The key intermediate, dihydropyran 8, would be constructed using a thioester-selective reduction (Fukuyama reduction) of 10 [10], followed by a spontaneous cyclization reaction from bisaldehyde intermediate 9. We hypothesized that the chiral centers α and β to the aldehyde of 10 could be set using an organocatalytic asymmetric Michael reaction using ene-yne compound 11 and the sulfide-containing aldehyde 12. The anticipated synthetic challenges at this stage were (1) stereoselective construction of the bisacetal structure during installation of the β-glucose, (2) thioester-selective reduction in the presence of several reduction-sensitive functional groups (alkyne, ester, aldehyde, β-acrylate residue, and acetal), (3) induction of stereoselectivity in an organocatalytic asymmetric Michael reaction.
Retrosynthetic analysis of secologanin
9.3.2 Stereoselectivity of Organocatalytic Michael Reaction
The total synthesis of secologanin (1) was initiated based on this retrosynthetic analysis. The first key reaction was the organocatalytic asymmetric Michael reaction (Fig. 9.2). Initially we prepared the Michael acceptor 16 with an alkyl side chain derived from a malonic acid half thioester and carried out an asymmetric Michael reaction with butanal as a model substrate using a diphenylprolinol silyl ether catalyst 14 (Fig. 9.2b). The reaction proceeded smoothly, and the Michael adduct 17 was obtained in high yield and high enantioselectivity. However, the product was not the desired anti-adduct. Instead, we observed the syn-adduct using many reaction conditions, including using various additives. Isomerization of the products was also investigated without success. Usually, in the transition state of asymmetric Michael reactions using secondary amine catalysts, the largest functional group is in an anti-relationship with the catalyst, and the relatively less bulky functional group is in a gauche-relationship. Thus, in the case of substrate 16, the catalyst and alkyl side chain are in an anti-relationship, and the syn adduct is preferred as the product. The solution to the problem of diastereoselectivity was to change the alkyl side chain of substrate 16 to an alkyne. This is because alkynes are sp hybridized and are sterically less bulky than sp2 and sp3 centers (sp < sp2 < sp3). Therefore, when substrate 13 with an enyne motif is employed, the alkyne sidechain is sterically less bulky and is in a gauche-relationship with the catalyst, which favors the anti-adduct (Fig. 9.2a). When substrate 13 (prepared in one step from commercially available 3-trimethylsilylpropynal by Knoevenagel condensation) and butanal were stirred with 3 mol% of catalyst 14, the anti-adduct was obtained as the predominant diastereomer. A similar anti-selective Michael addition reaction using an alkyne as a substrate was reported by Hong et al. [11]. Although substrate 13 is an E/Z mixture, the stereochemistry was completely controlled, indicating that the methoxycarbonyl and ethyl thiocarbonyl groups are not distinguished in the transition state.
Organocatalytic Michael reaction stereoselectivity
9.3.3 Scalable Total Synthesis of Secologanin
With optimized conditions for the asymmetric Michael reaction in hand, we moved on to the total synthesis of 1 (Scheme 9.2). We used a sulfide-containing aldehyde 12 to enable installation of a terminal double bond in the late stage. The reaction proceeded with very high stereoselectivity, and anti-adduct 10 was obtained. Subsequently, a thioester-selective reduction reaction developed by Fukuyama et al. was attempted. This reaction showed excellent functional group selectivity and was not impacted by the presence of the sulfide seven atoms from the center being reduced. Thus, the thioester moiety was reduced to an aldehyde selectively, resulting in the formation of bisaldehyde intermediate 9 in situ. The 3-oxopropanate motif in 9 was readily converted to an enol by tautomerization and cyclized to dihydropyran 8 spontaneously (76% over two steps). The glycosylation reaction, which had raised concerns about stereoselectivity, worked well with the standard Schmidt glycosylation reaction [12]. Thus, when compound 8 was treated with imidate-functionalized glucose tetraacetate 18 in the presence of BF3-Et2O, the stereochemistry of the newly generated bisacetal moiety was completely controlled, and the desired glycosylated compound 7 was obtained as a single isomer. The hemiacetal of 8 is in rapid equilibrium, and the sterically preferred α-oriented hydroxyl group reacts with glycosyl donors selectively. In addition, the glycosyl donor reacts selectively on the β-face due to the neighboring effect of the acetyl group at the C2 position. This kinetic-controlled stereoselectivity dramatically improved the efficiency of the total synthesis of 1. Substrate 20 for hydroboration was then prepared by removing the silyl group that had been attached to the terminal alkyne. When tetrabutylammonium fluoride (TBAF) was used in this reaction, the acetyl groups on the glucose chain were removed by the water contained in the reagent. Therefore, tetrabutylammonium difluorotriphenylsilicate (TBAT), which can be handled under anhydrous conditions, was used.
Dihydropyran ring construction and stereoselective sugar chain insertion
What remained for the chemical transformation from compound 20 to 1 was the construction of the aldehyde by hydroboration/oxidation, the construction of the terminal alkene by elimination, and the removal of the four acetyl groups by hydrolysis. The non-catalyzed hydroboration reaction of terminal alkynes did not proceed with boron reagents such as 9-BBN. After several experiments with derivatives, it was clear that the reaction was inhibited by the presence of glycosidic chains. The problem might have been that the boron reagent could not approach the reaction site due to steric hindrance. Finally, the addition of a catalytic amount of Schwartz's reagent promoted this reaction efficiently (Scheme 9.3) [13].
Completion of the total synthesis of secologanin
In the subsequent oxidation reaction, under standard conditions, i.e., NaOH and H2O2 in water, the undesired removal of the acetyl groups from the sugar chain proceeded. Unexpectedly, with this substrate 20, the oxidation reaction proceeded without the addition of sodium hydroxide, which is usually required. In addition, these reaction conditions not only prevented the undesired removal of the acetyl groups but also allowed the oxidation of the sulfide necessary for the next elimination reaction to proceed. Then, sulfoxide elimination of 21 was promoted by heating in the presence of trimethyl phosphate to provide the key intermediate secologanin tetraacetate (22) in our bioinspired total synthesis [14]. The total yield of 22 was 25% on a decagram scale over seven steps from commercially available 3-trimethylsilylpropynal. Finally, the acetyl group was removed by hydrolysis accompanied by temporary protection of the aldehyde to achieve the first total synthesis of secologanin (1) [5a].
9.4 Collective Total Synthesis of Glycosylated Monoterpenoid Indole Alkaloids
As described in the introduction, secologanin (1) is an important constituent of the monoterpenoid indole alkaloids (Scheme 9.4) [7]. In biosynthesis, 1 is converted to 5-carboxystrictosidine (23) and strictosidine (24) by an enzymatic Pictet–Spengler cyclization with tryptophan or tryptamine. Intermediates 23 and 24 lead to more than 3000 alkaloids. Most of them involve the cleavage of the sugar chains of 23 and 24, but some alkaloids have been found in which the sugar chains are maintained. We have thus far achieved the total syntheses of 33 MTIAs using this bioinspired strategy. In this chapter, we present the total synthesis of glycosylated MTIAs.
Biosynthesis of 5-carboxystrictosidine and strictosidine
9.4.1 Total Syntheses of 5-Carboxystrictosidine and Rubenine
Following the biosynthesis, we first aimed for the first asymmetric total synthesis of 5-carboxystrictosidine (23) (Scheme 9.5). Thus, the Pictet–Spengler reaction was performed with synthetic 22 and tryptophan methyl ester (25) in the presence of trifluoroacetic acid (TFA) [15]. The reaction proceeded quantitatively, and the stereochemistry at the C3 position was controlled as the S configuration with moderate selectivity. After hydrolysis of the four acetyl groups and the methyl ester, the total synthesis of 5-carboxystricrosidine (23) was achieved. The NMR of 23, which has an amino acid moiety, is very sensitive to pH, and careful adjustment of pH was necessary to match it with the NMR of the natural product.
Total syntheses of 5-carboxystrictosidine and rubenine
The next synthetic target was rubenine (2), which has six contiguous rings, one of which is a strained seven-membered ring [16]. For the key reaction, we decided to use a bioinspired reaction in which rings are formed sequentially by a domino sequence. The aldehyde of key intermediate 22 was converted to acetal 27 using 1,2-phenylenedimethanol (26), which can be removed by hydrogenation. Stereoselective epoxidation of the terminal double bond of compound 27 was extremely difficult. Because of its steric hindrance, the terminal double bond is unreactive. In addition, in some cases, the double bond of the β-acrylate residue was oxidized. After several attempts, we found that treatment with mCPBA using 1,1,1,3,3,3-hexafluoroisopropaol (HFIP) as the solvent resulted in site-selective epoxidation and gave a slight preference for a product with the desired stereochemistry. mCPBA might be activated in situ by HFIP which is a weakly acidic solvent [17]. The subsequent hydrogenation reaction converted the acetal to an aldehyde to obtain compound 28. Next, our optimized Pictet–Spengler reaction conditions were applied to compound 28. The reaction proceeded stereoselectively (C3S:C3R = 2.5:1). Furthermore, when the crude mixture of intermediate 29 was loaded on silica gel for purification, the cyclization reaction from the secondary amine at the N4 position proceeded. Thus, the N4 position of the C3S intermediate 29 attacked the C18 position, and the desired seven-membered ring product 30 was obtained as the major product in a 60% yield over two steps. On the other hand, the six-membered ring intermediate resulting from the attack to the C19 position was converted to the byproduct 31 via lactonization (8%). Finally, after the removal of the acetyl groups of 30, the crude material was heated in the presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) to construct the lactone ring, achieving the first total synthesis of rubenine (2) [5a]. Note that the reaction proceeded without any problem with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the final step, but it was difficult to separate the highly polar product 2 and DBU. On the other hand, DBN could be efficiently removed by heating under reduced pressure.
9.4.2 Discovery of Diastereoselective Pictet–Spengler Cyclization and Total Syntheses of Strictosidine and Strictosamide
Next, the total synthesis of strictosidine (24), another biosynthetically important intermediate, was commenced (Scheme 9.6). For the completion of this total synthesis, a Pictet–Spengler cyclization reaction controlling the C3 position was required. We initially considered using an asymmetric Pictet–Spengler reaction catalyzed by a chiral phosphoric acid or thiourea but decided not to invest in this line of research due to the likely challenge introduced by the presence of many hydrogen-bond-accepting functional groups such as the sugar ring in secologanin derivative 22. The moderate diastereoselectivity observed in the total synthesis of 5-carboxystrictosidine (23) with tryptophan derivative 25 inspired us to use α-cyanotryptamine (32) in the total synthesis of 24. Surprisingly, the simple tryptophan derivative 32 was not previously reported, however, it could be synthesized from tryptophan in three steps (see details in Ref. [5b]). In addition, crystals of 32 were stable to storage in air at room temperature.
Total syntheses of strictosidine and strictosamide using a diastereoselective Pictet–Spengler reaction
First, the Pictet–Spengler reaction was performed using secologanin derivative 22 and (S)-32 derived from l-tryptophan. The reaction proceeded quickly (3 min) and the desired cyclization was obtained quantitatively. Unexpectedly, the diastereoselectivity was poor (3S:3R = 1.5:1). On the other hand, when (R)-32 derived from d-tryptophan was employed, the diastereoselectivity was dramatically improved (3S:3R ⇒10:1) while maintaining its high reactivity. The cyano group at C5 of the cyclized product 33 was removed by treatment with acetic acid/methanol followed by reduction of the resulting imine in situ to give strictosidine tetraacetate (34) (more than 1 g of 34 was prepared). This two-step sequence is an alternative method to strictosidine synthase, which completely controls the C3 stereochemistry in the biosynthesis [18]. Finally, the removal of the acetyl groups of the sugar chain was performed to achieve the total synthesis of the natural product 24. The total yield of 24 was 20% over 10 steps [5b].
The determination of the stereochemistry of the C3 position generated by the Pictet–Spengler reaction was challenging at the stage of compound 33. Finally, we determined the stereochemistry at the C3 position after preparing a rigid pentacyclic natural product, strictosamide (35), via a two-step transformation from 34. Comparison of CD spectra of 35, which strongly reflect the stereochemistry of the C3 position, proved to be an extremely useful tool (For substrates with an open C ring, such as compound 24, comparison of CD spectra is known to be ineffective in determining the stereochemistry at the C3 position) [19].
9.4.3 Mechanistic Insight into the Pictet–Spengler Reaction Diastereoselectivity
We wanted to know why different stereoselectivity was observed with α-cyanotryptamine and with tryptophan methyl ester. We also wanted to know which structure motif of secologanin was required to induce diastereoselectivity. Therefore, the Pictet–Spengler reaction was performed with various derivatives of secologanin to observe the diastereoselectivity in each product (Fig. 9.3, syntheses of secologanine derivatives; see ref [5b]). The reaction was first performed with secologanin methyl ether. The diastereoselectivity of the product was very high, and it was clear that the sugar chain did not affect the selectivity (compound 36). Similarly, the terminal double bond at C18–19 had no effect on selectivity (compound 37). On the other hand, diastereoselectivity decreased to 2.7:1 when the methoxycarbonyl group at C22 was removed (compound 38). Clearly, the carbonyl group improved the diastereoselectivity. The influence of the stereochemistry at the C15, 20, and 21 positions of secologanin on diastereoselectivity was studied. No decrease in the diastereoselectivity of the Pictet–Spengler reaction was observed when the isomers at C20 and C21 were used (compounds 39, 40, and 41). On the other hand, the diastereoselectivity was lost when the reaction was carried out using the stereoisomer at C15. In summary, it is clear that the relative configuration of C5 (cyano group) and C15 and the presence of the carbonyl group at C22 are essential for diastereoselectivity of this Pictet–Spengler reaction.
Pictet–Spengler reaction with (R)-32 and secologanin derivatives
In addition to the above experiments, the transition states in each substrate were analyzed using DFT calculations (Fig. 9.4). When (R)-α-cyanotryptamine was used, a unique eight-membered ring was formed via a hydrogen bond between the proton on the iminium ion and the carbonyl group at C22. Then, nucleophilic attack from indole came from the β-face on the eight-membered ring. On the other hand, when tryptophan methyl ester was used as a substrate, the proton of the iminium ion hydrogen bonded with the methoxycarbonyl group of the adjacent tryptophan, forming a five-membered ring. Thus, cyanotryptamine and tryptophan form hydrogen bonds at different sites, and the reactions proceed through distinct transition states [5b].
Calculated transition states of diastereoselective Pictet–Spengler reactions
9.4.4 Bioinspired Total Synthesis of Cymoside
Cymoside (3), a monoterpenoid indole alkaloid found in Chimarrhis cymosa (Rubiaceae) in 2015, contains an interesting hexacyclic skeleton that includes a unique propellane-type structure (Fig. 9.1 and Scheme 9.7) [20]. Furthermore, it contains eight asymmetric centers, including three contiguous quaternary chiral centers, not including the sugar moiety. In addition, the natural product 3 is an extremely rare molecule with a tris-acetal structure that includes sugar chains. Its total synthesis appears daunting due to the crowded caged structure. However, when we considered the biosynthesis of 3, we realized that this molecule is an oxidized derivative of strictosidine (24). In 2020, the Vincent group achieved a total synthesis of 3 with a biogenetically inspired strategy similar to ours [21]. Scheme 9.7 shows a very simple conversion from a derivative of 24 to 3 following its biosynthetic pathway. To realize the proposed bioinspired reaction, a stereoselective insertion of a hydroxyl group at the C7 of the indole ring was required. Strictosidine derivative 33, bearing a cyano group, was chosen as a substrate. In addition, we avoided protecting the secondary amine at N4 to match more closely the biosynthesis. After several trials, the desired domino reaction proceeded using pretreatment of substrate 33 with TFA followed by adding mCPBA. Thus, the otherwise oxidizable amine at the N4 position was protected by TFA by forming a salt in situ. The resulting TFA salt forms a hydrogen bonding network that allows mCPBA to approach from the β-face of the indole and insert a β-OH at C7 selectively [22]. The resulting intermediate 44 has an α-hydroxyimine moiety and a β-acrylate moiety, and a formal [3+2] cyclization reaction proceeded. The reaction was initiated by stereoselective oxa-Michael addition from the 7-OH to C17 followed by a stereoselective Mannich reaction from C16 to C2 to form the rigid dihydrofuran ring containing four contiguous chiral centers. Subsequently, the unique tris-acetal structure was constructed. Finally, the total synthesis of 3 was achieved through decyanation and removal of the acetyl groups. This 11-step synthesis was accomplished with an overall yield of 7% [5b].
Total synthesis of cymoside
9.4.5 Bioinspired Total Synthesis of Ophiorines A and B
Ophiorines A (4) and B (48) are pentacyclic alkaloids from Ophirrhiza species (Rubiaceae) (Fig. 9.1) [23]. Structurally, they belong to β-carboline-type MTIAs which are aromatized on the C-ring, and they have a bicyclo ring structure containing an N,O-acetal moiety. Furthermore, they are rare natural products that form a unique intramolecular counterionic structure consisting of a pyridine ring and a carboxylic acid in the same molecule. Since its isolation in 1985, there have been no examples of total synthesis or synthetic studies until we completed them. Initially, oxidation of the C-ring of strictosidine tetraacetate (34) was examined to construct the β-carboline motif. Various oxidants such as DDQ and KMnO4 were examined, but the sugar chains and β-acrylate residue did not survive under the reaction conditions. Therefore, we decided to use the elimination reaction of a cyano group of compound 33 (Scheme 9.8). Thus, when 33 was treated with acetic acid in methanol, the expected decyanation followed by spontaneous air oxidation proceeded to construct the desired β-carboline 46 (lyaloside tetraacetate) (60 h, 83%). Interestingly, treatment of compound 33 with only acetic acid does not afford decyanation; methanol was essential for the decyanation reaction, although the reason is unclear. Successful decyanation was achieved under Brønsted acid conditions, but the reaction required more than 2 days. Therefore, we investigated Lewis acid conditions. Inexpensive silver nitrate worked well, yielding compound 46 in 94% yield in 20 h. Removal of the four acetyl groups of 46 provided lyaloside (47) in excellent yield. A conversion from the natural product 47 to ophiorines A and B using the bioinspired reaction was achieved in water. In addition, since natural products are ionic molecules, the addition of salt as a stabilizer was examined. Thus, when the highly polar compound 47 was heated in water in the presence of ammonium acetate, a bioinspired Michael reaction proceeded, followed by hydrolysis of the methoxycarbonyl group, resulting in ophiorines A (4) and B (48) with an intramolecular counterionic structure (4:48 = 1.7:1, 75%, 11 steps total) [5h].
Total syntheses of ophiorines A and B
9.5 Collective Total Synthesis of Hetero-Oligomeric Iridoid Glycosides
The dried root of Dipsacus asper (Caprifoliaceae) is a well-known folk medicine used for bone maladies such as fractures, osteoporosis, and rheumatoid arthritis [24]. In addition, these oligomers are expected to be biologically active components of folk medicine [8]. To synthesize many of these HOIGs, it was necessary to prepare large quantities of loganin or its derivatives. Loganin (49) is found in plants of the families Rutaceae, Caprifoliaceae, Loganiaceae, Gentianaceae, and Apocynaceae [25]. It is a representative of iridoid glycosides with various biological activities such as anti-inflammatory activity [26]. In biosynthesis, loganin (49) is the precursor of secologanin (1) and forms a terminal double bond and an aldehyde by enzymatic oxidative cleavage at C7-8 positions [27]. Having already succeeded in the gram-scale synthesis of 1, we planned to synthesize 49 by the reverse-biosynthetic strategy, i.e., the reductive ring-closing reaction of 1. If this strategy succeeded, we could supply both 1 and 49, to allow the efficient collective total synthesis of HOIGs (Scheme 9.9).
Synthetic strategy of hetero-oligomeric iridoid glycosides
9.5.1 Total Syntheses of Loganin and Cantleyoside
We next undertook the synthesis of 49 using reductive ring closure (Scheme 9.10). Thus, secologanin tetraacetate (22) was treated with various one-electron reductants. After several trials with metal reductants, we found SmI2 was a suitable reductant with good diastereoselectivity to provide cyclized products in 93% yield (dr at C7 = 3:1; loganin tetraacetate (50) was isolated in 70% yield). In this reaction, the stereochemistry at C8 was controlled completely (formation of the other diastereomer would involve a steric clash by positioning the terminal olefin methylene over the dihydropyran ring). 50 was successfully converted to natural product loganin (49) via solvolysis.
Total syntheses of loganin and cantleyoside
Once the total syntheses of secologanin (1) and loganin (49) were completed, cantleyoside (5) was chosen as the next synthetic target. Cantleyoside (5) is a heterodimeric iridoid glycoside with a C7 secondary alcohol of 49 and a C11 carboxylic acid of 1 connected via an ester. To accomplish this, we synthesized secologanic acid derivative 51 from compound 22. First, we converted the aldehyde of 22 to an acetal with ethylene glycol, followed by hydrolysis of the acetyl and methoxycarbonyl groups and re-acetylation of the sugar chain to give 51 in high yield. The dehydration-condensation reaction of compounds 50 and 51 was accomplished by heating with EDCI and DMAP. The acetal of the resulting dimeric compound was subsequently cleaved to an aldehyde to afford cantleyoside octaacetate (52). The esterification reaction requires four of the five alcohols of loganin to be protected, with only C7 exposed. Although naturally occurring loganin (49) is commercially available, selectively distinguishing the C7 alcohol from the glucosyl alcohols was not a chemically viable approach. Thus, a reductive cyclization reaction of 1 was essential for the total synthesis of 5.
The first total synthesis of cantleyoside (5) was achieved by removing the acetyl groups from compound 52 (total 11 steps via 50, total yield 12%).
9.5.2 Bioinspired Total Synthesis of Dipsanoside A, Dipsaperine, and (3R,5S)-5-Carboxyvincosidic Acid 22-Loganin Ester
Many natural products are derived from cantleyoside (5) (Fig. 9.1 and Scheme 9.11). For example, dipsanoside A (6) is a dimer of 5 derived from an aldol condensation. We corrected the stereochemistry of 6 based on our synthesis; see details in ref 5f [8c]. Dipsaperine (53) and (3R,5S)-5-carboxyvincosidic acid 22-loganin ester (54) are derived from a Pictet–Spengler condensation with 5 and tryptophan, and they are diastereomers at C3. Recently, aldol condensations mediated by amino acids such as proline have been extensively investigated [29]. Sometimes, the structures of certain natural products offer clues to the biosynthesis of other natural products. The structures of 53 and 54 offer the tantalizing clue that 6 could be derived from a tryptophan-mediated aldol reaction of 5. Based on our strong interest in these biosynthetic pathways, we decided to test chemically whether this pathway was viable. Indeed, when one equivalent of l-tryptophan and 52 were stirred in DMF for 4 days, the anticipated E-selective aldol condensation reaction proceeded, yielding dipsanoside A hexadecaacetate in 81% yield. After hydrolysis, the first total synthesis of dipsanoside A (6) was achieved (total 12 steps, total yield 8%).
Bioinspired dimerization and Pictet–Spengler reaction toward total syntheses of hetero-oligomeric iridoid glycosides
On the other hand, when compound 52 and l-tryptophan methyl ester (25) were stirred in the presence of TFA, the Pictet–Spengler reaction proceeded to give the desired cyclized product in 98% yield (3S:3R = 2:1). After a similar hydrolysis, the first total syntheses of 53 and 54 were achieved.
In the above syntheses, tryptophan mediates an aldol condensation under neutral conditions and behaves as a substrate in the Pictet–Spengler reaction under acidic conditions. We suspect that this is similar to the events occurring in the actual biosynthesis. Inhibition of the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts was found in the synthetic 6, 53, and 54 (IC50 value; 6 = 5.9 μM, 53 = 12.8 μM, 54 = 6.6 μM) [29]. In addition, these compounds were not cytotoxic. Therefore, these natural products may be responsible for the efficacy (bonesetting) in folk medicine [5f].
9.6 Conclusion
We successfully achieved a collective total synthesis of 39 natural products, including glycosylated monoterpenoid indole alkaloids (MTIAs) and hetero-oligomeric iridoid glycosides (HOIGs) via bioinspired transformations, initiated by the first total synthesis of secologanin (1). The key strategy of our secologanin synthesis was a rapid and stereoselective construction of the secologanin scaffold through an anti-selective organocatalytic Michael reaction/Fukuyama reduction/spontaneous cyclization/Schmidt glycosylation sequence, and we obtained a key intermediate, secologanin tetraacetate (22), on a decagram scale in seven steps. First, Pictet–Spenglar cyclization with l-tryptophan methyl ester (25) or (R)-α-cyanotryptamine (32) using 22 proceeded via different transition states but in the same 3S stereoselectivity to give 5-carboxystrictosidine (23) and strictosidine (24), respectively. These biosynthetic intermediates of MTIAs were converted into complex alkaloids, including rubenine (2) and cymoside (3), via bioinspired transformation on the highly reactive secologanin reaction sites. Elimination of the cyano group, which had been installed from cyanotryptamine, and subsequent autoxidation rapidly constructed the β-carboline structure, and β-carboline-type glycosylated monoterpenoid indole alkaloids including lyaloside (47) and ophiorines A (4) and B (48) were provided in the common synthetic route. On the other hand, loganin (49), the biosynthetic precursor of secologanin (1), was synthesized from 22 via a reverse-biogenetically inspired transformation (reductive cyclization). These iridoid monomers were condensed via hetero-oligomerization to HOIGs including dipsanoside A (6) and dipsaperine (53), and these larger natural products were found to inhibit RANKL-induced formation of multinuclear osteoclasts.
Although these biogenetically inspired transformations are now one of the common strategies in the total synthesis of natural products, there are actually not many examples of derivation to different groups of natural products using a common intermediate. This is because of the difficulty of setting up and synthesizing key highly reactive intermediates. We were fortunate to encounter secologanin and were able to use it to efficiently construct a natural product library. It is our mission as synthetic organic chemists to continue to further extend the branches of the tree diagram.
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Sakamoto, J., Ishikawa, H. (2024). Collective Total Synthesis of Secologanin-Related Natural Products. In: Nakada, M., Tanino, K., Nagasawa, K., Yokoshima, S. (eds) Modern Natural Product Synthesis. Springer, Singapore. https://doi.org/10.1007/978-981-97-1619-7_9
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