Keywords

11.1 Introduction

Cotylenin A (Fig. 11.1) is a diterpene glycoside isolated from the secondary metabolites of Cladosporium sp. [1]. Isolated cotylenin A regulates plant growth, induces functional and morphological differentiation in mouse (M1) and human leukemia (HL-60) cells, and causes apoptosis in many human cancer cell lines when combined with interferon-α [2]. The X-ray crystallographic analysis of a tripartite complex of cotylenin A, a 14-3-3 protein, and a phosphopeptide of H+-ATPase [3] revealed the unique bioactivity of cotylenin A.

Fig. 11.1
Chemical structures of cotylenins A, B, C, D, E, F, G, H, I, J, and R to the 1 = H. The common functional groups in the structures are O, O H, and O M e. O M e is absent only in cotylenin I and J.

Structures of cotylenins A–J

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Thus far, the bioactivities of cotylenins A-J (Fig. 11.1) [4] have not been thoroughly investigated owing to their scarcity. As mentioned above, cotylenin A exhibits promising anti-cancer activity with a unique mode of action as a “molecular glue.” However, biological studies on cotylenin A have stalled because Cladosporium sp. 501-7W, which produces cotylenin A, has lost its proliferative ability [5]. Therefore, a new source of cotylenin A must be discovered.

In this context, total synthesis is an effective method for supplying rare natural products and the derivatives or structural analogs of natural products that cannot be synthesized from natural products. After the structural elucidation of cotylenin A in 1998, only Kato et al. [6] have developed the total synthesis of cotylenol, and an aglycon of cotylenin A and total synthesis of cotylenin A has never been reported [7, 8] until our total synthesis [9, 10]. The aglycone moiety of cotylenin A has a 5–8-5 carbocyclic scaffold with a quaternary asymmetric carbon at the fused ring site, a chiral tertiary alcohol at the allylic position, four consecutive chiral carbons containing trans-1,2-diols, and a four-substituted alkene bearing an isopropyl group. In addition, a trioxabicyclo[2.2.1]heptane with methyl and epoxyethyl groups, fused to glucose and attached to the aglycon, is a structurally unusual sugar moiety. These structural features, especially the unprecedented structure of the sugar moiety, make cotylenin A unique compared to other members of the cotylenin family.

In this chapter, we describe our attempts and approaches to developing the total synthesis of cotylenin A.

11.2 Initial Synthetic Approach to Cotylenin A

11.2.1 Retrosynthetic Analysis

Scheme 11.1 shows the initial retrosynthetic analysis of cotylenin A. It can be synthesized via the glycosylation of the sugar moiety with the aglycone moiety 1. Next, as pinacol coupling can afford eight-membered carbocyclic rings, a pinacol coupling of dialdehyde 2 can afford 1,2-diol at the C8 and C9 positions [11]. However, the diastereoselectivity of the 1,2-diol could be a problem, which could be controlled by optimizing the reaction conditions. Compounds 3 and 4 could be obtained via catalytic asymmetric intramolecular cyclopropanation (CAIMCP), which was previously developed by our group [12].

Scheme 11.1
A retrosynthetic analysis of cotylenin A. The structure is broken down into simpler precursors through a series of chemical reactions including pinacol coupling, utimoto coupling, and ring-opening. Precursors include T I P S O, A X, and C A I M C P.

Initial retrosynthetic analysis of cotylenin A

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We previously synthesized chiral β-keto phosphonate 3a via CAIMCP [13]. However, we did not use 3a as an A-ring fragment owing to its low reactivity. Instead, we used α-bromoketone 3b, which we previously subjected to Utimoto coupling in the first total synthesis of ophiobolin A [14].

The C-ring fragment 4 was also prepared via CAIMCP, based on our previous report on the CAIMCP of a chiral cyclopropane derivative to afford 4 [12a].

11.2.2 Preparation of the A-ring Fragment 3b

(E)-Diazo β-keto sulfone 7, which was required for the CAIMCP step in the preparation of α-bromoketone 3b, was prepared via the procedure shown in Scheme 11.2. The stereoselective Ireland-Claisen rearrangement of but-3-en-2-ol afforded 5, which was converted to 6 by reacting with the dianion of mesityl methyl sulfone. Compound 6 underwent a diazo-transfer to afford 7. The 1H-NMR of 7 confirmed that it is a pure (E)-isomer.

Scheme 11.2
A schematic reaction pathway for synthesizing E-diazo beta-keto sulfone in three steps. 1, a sulfinate ester is converted to a beta-keto ester by reacting with n-butyllithium and mesityl methyl sulfone. 2, beta-keto is converted to a hydrazone. 3, the hydrazone is converted to the desired E-diazo beta-keto sulfone.

Preparation of (E)-diazo β-keto sulfone 7 for subsequent catalytic asymmetric intramolecular cyclopropanation (CAIMCP)

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The subsequent CAIMCP of 7 under optimized conditions afforded cyclopropane 8 in 99% yield and 91% ee (Scheme 11.3). Cyclopropane 8 was crystalline but unsuitable for X-ray crystallographic analysis. However, crystalline nitrile 9, which was prepared by the reaction of 8 with sodium cyanide, was suitable for single-crystal X-ray crystallographic analysis. Consequently, the absolute structure 9 was confirmed (Scheme 11.3).

Scheme 11.3
A 2-step synthesis of compound 9 from 7 using C A I M C P. 1, a diazo compound reacts with sodium cyanide and copper chloride in the presence of L 1 and N a B A R F in a mixture of toluene and D M S O at 100 degrees Celsius for 1 hour. 2, the mixture is heated to 50 degrees Celsius and stirred for 48 hours for a 99% yield.

Synthesis of 9 from 7 via CAIMCP

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The transformation of 9 to 3b is shown in Scheme 11.4. Nitrile 9 was reduced to an aldehyde using DIBAL-H, which was further reduced to a primary alcohol using NaBH4. The primary alcohol was selectively protected to afford 10. The treatment of 10 with sodium amalgam to form an alkene, followed by regioselective bromohydrin formation and Dess-Martin oxidation, afforded the A-ring fragment 3b.

Scheme 11.4
A 3-step synthesis of the A-ring fragment 3 b. First, O T I P S reacts with D I B A L-H to reduce the carbonyl group into a primary alcohol. Second, molecule 10 reacts with N A B H 4. The third step involves converting molecule 11 to molecule 3 b with a 78% yield.

Preparation of the A-ring fragment 3b

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11.2.3 Preparation of the C-ring Fragment via the CAIMCP of α-diazo β-keto Sulfone

The retrosynthetic analysis of the C-ring fragment 4 is shown in Scheme 11.5. Fragment 4 could be prepared by the Pummerer rearrangement of sulfide 12. Compound 13, a precursor of 12, could be prepared by the reaction of formaldehyde with an enolate. The enolate could be reductively formed from sulfone 14, which could be synthesized from the reaction of phenylthiolate with cyclopropane 15. Compound 15 could be obtained from the CAIMCP of 16.

Scheme 11.5
A retrosynthetic analysis for the C-ring fragment 4 by cleaving a carbon-carbon bond between two molecules, one containing a T I P S O and a mesyl group and the other containing a phenylthiol and a mesyl group.

Retrosynthetic analysis of the C-ring fragment 4

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The first step in the synthesis of the C-ring fragment 4 was the preparation of hydroxy ketone 13 from cyclopropane 15 (>99% ee) (Scheme 11.6). Compound 15 was subjected to CAIMCP with potassium phenylthiolate to open the cyclopropane ring [15]. A reaction with samarium diiodide afforded samarium enolate, which was treated with aqueous formalin solution to afford hydroxy ketone 13.

Scheme 11.6
A 4-step synthesis of the C-ring fragment from a starting material labeled T I P S O asterisk P h S M e. The reaction scheme uses n-B U L i for a lithiation reaction, T B A F for cleavage of a silicon-oxygen bond, D M P slash N a H C O 3 for oxidation, and P h S H slash K O t-B U for nucleophilic substitution.

Preparation of the C-ring fragment 4

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Compound 13 was converted to the corresponding TIPS ether, which was reduced to an alcohol using iPrMgCl. Then, LaCl3·2LiCl [16] was used to realize the desired 1,2-addition of the ketone. Dehydration of the tertiary alcohol with thionyl chloride and pyridine and the subsequent removal of the TIPS ether afforded 14. Successive Dess–Martin oxidation of 14, double-bond isomerization under basic conditions, reduction of the aldehyde, and TIPS ether formation afforded 12. Compound 12 was subjected to Pummerer rearrangement to afford 4, which resulted in an overall yield of 37% from 16 in 12 steps. This C-ring fragment 4 was used in the coupling reaction with the A-ring fragment 3b. Owing to the low yield of 4 in this synthetic route, we developed a shorter route.

11.2.4 Preparation of the C-ring Fragment via the CAIMCP of α-diazo β-keto Ester

We explored the CAIMCP of α-diazo-β-keto esters to afford 4, as the product of the CAIMCP could be converted to the same synthetic intermediate formed during the preparation of 4 from 15 (Scheme 11.6) via ring-opening with phenyl thiolate, enol triflate formation, coupling reaction, and reduction of the ester (Scheme 11.7).

Scheme 11.7
A schematic reaction pathway of a new synthetic route for the C-ring fragment in eight steps includes reactions with P h C O O R, L D A, M e I, B r C H 2 C O O R, K O t-B u, N a H, P h S O 2 C l, T B A F, T B A F, N a N 3, and thermal decomposition to generate the alpha-diazo beta-keto ester followed by C A I M C P to form the C-ring fragment.

New synthetic route for the C-ring fragment 4 via the CAIMCP of α-diazo β-keto ester

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The CAIMCP of α-diazo-β-keto esters is generally not enantioselective owing to the low steric effect of the ester moiety [12a, 17]. Hence, we examined the CAIMCP of α-diazo-β-keto esters bearing a bulky alcohol moiety and obtained the α-diazo-β-keto ester of 2,4,6-trimethylphenol with high enantioselectivity (Scheme 11.8) [8]. Cyclopropane 18 was crystalline, and its absolute configuration was confirmed via X-ray crystallographic analysis (Scheme 11.7). Cyclopropane 18 was successively subjected to a ring-opening reaction with sodium phenylthiolate, conversion to enol triflate, and coupling with iPrMgCl and (2-Th)Cu(CN)Li [18] in a one-pot reaction to afford 19. The DIBAL-H reduction of 19 afforded 20, which is the same synthetic intermediate observed in Scheme 11.6. Thus, the C-ring fragment 4 was prepared from cyclopropane 16 with an overall yield of 48% in five flasks.

Scheme 11.8
A step-by-step chemical transformation process of C-ring fragment 4 starts with compound 17, featuring a diazo group and an ester on a benzene ring with methyl substitutions, it progresses to compound 18 through a cyclization process. Further reactions lead to Compound 19 with a phenylthiol group, then to Compound 20 after reduction.

Preparation of the C-ring fragment 4 via the CAIMCP of α-diazo β-keto ester of 2,4,6-trimethylphenol

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11.2.5 Synthesis of a C8-Epi Cotylenol Derivative via the Construction of 5–8-5 Carbocyclic Cotylenin A Scaffold by Pinacol Coupling

After synthesizing the A- and C-ring fragments, we examined their coupling (Scheme 9). As mentioned in Sect. 11.2.1, HWE coupling of 3a was unsuccessful; therefore, we used an Utimoto coupling reaction [19], which we have previously used in the first total synthesis of (+)-ophiobolin A [14]. The Utimoto coupling was expected to yield favorable results because the boron enolate generated in situ reacts mildly and efficiently with bulky aldehydes. As expected, we obtained a single isomer in high yield from the Utimoto coupling of 3b and 4 via the formation of a Zimmerman–Traxler chair-like transition state. The product was subjected to dehydration using Burgess reagent to afford the α,β-unsaturated ketone 21.

Scheme 11.9
A multi-step synthesis to construct the C 8-epi cotylenol derivative 27 is as follows. 1, conversion of starting materials 1 and 3 b into intermediate. 2, transformation of intermediate 4 into compound 22. 3, conversion of compound 22 into intermediate 24. 4, transformation of intermediate 24 into final product 27.

Synthesis of a C8-epi cotylenol derivative 27 via the construction of a 5–8-5 carbocyclic cotylenin A scaffold by pinacol coupling

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The Wittig reaction of ketone 21 with methyltriphenylphosphonium bromide and t-BuOK afforded the desired exomethylene product 22 in high yield (Scheme 11.8). During the dihydroxylation of 22, the reaction in a mixed solvent of acetone and water did not afford the desired product, and the same result was obtained when pyridine was added to accelerate the reaction. However, the reaction in a mixture of THF and water afforded the desired diol 23 in 98% yield, with a diastereomeric ratio of 8:1.

Next, we investigated the reaction conditions for the protection of the 1,2-diol in 23. Cotylenin A has a primary methyl ether and a tertiary alcohol in the A-ring moiety, and tertiary alcohols are easily dehydrated to form alkenes without protecting groups. Therefore, we selectively converted the primary hydroxy group to methyl ether at this stage and protected the tertiary hydroxy group with a trimethylsilyl group, which can be easily deprotected.

However, the selective methylation of the primary alcohol in 23 using common reagents such as methyl iodide, dimethyl sulfate, and methyl triflate did not afford the desired compound. However, the use of Meerwein reagent and bulky 2,6-di-tert-butyl-4-methylpyridine afforded the desired monomethyl ether 24 and dimethyl ether in 64% and 35% yields, respectively. To further improve the selectivity of the monomethylation, the reaction temperature was lowered to 0 °C, which furnished monomethyl 24 in 82% yield.

Next, we examined the construction of the B-ring. First, the TIPS group was removed using TBAF in THF to quantitatively yield the triol. All three hydroxy groups were protected with TMS groups using TMSCl in pyridine as the solvent. When TMSOTf was used as the reagent, the dehydration of the tertiary allylic alcohol occurred because of the Lewis acidity of TMSOTf, and the desired product was not obtained. The resulting TMS ether was treated with potassium carbonate in methanol to remove the primary TMS groups, and the resulting diol was converted into dialdehyde 25 via Dess–Martin oxidation. The pinacol coupling of dialdehyde 25 using TiCl4, Zn, and pyridine furnished an eight-membered carbocyclic ring to afford a diol product in 71% yield.

However, the 1H-NMR spectra of the diol product revealed that the configurations of the C8 and C9 positions were different from those of cotylenol. Therefore, to determine the configurations, we examined the selective oxidation and reduction of the diol and analyzed the 1H-NMR spectra of the product. The selective oxidation of the C9 hydroxy group with MnO2 and subsequent reduction with NaBH4 afforded diol 27 as a single isomer. The 1H-NMR spectrum of 27 was consistent with the same compound described in the literature, so that the structures of 26 and 27 are determined as shown in Scheme 11.9 [6b].

Notably, the configurations at the C8 and C9 positions remained almost unchanged when the reaction conditions for the pinacol coupling were varied. In addition, attempts to selectively protect one of the hydroxy groups of 28 were unsuccessful. This result was attributed to the rigid 5-8-5 carbon skeleton of cotylenol, which suggests that the stereoselective construction of the two contiguous chiral centers at C8 and C9 would be difficult via pinacol coupling. Hence, we investigated another reaction to construct the B-ring.

11.3 Revised Synthetic Approach to Cotylenin A

11.3.1 Revised Retrosynthetic Analysis of Cotylenin A

Eight-membered carbocyclic rings are generally difficult to construct owing to their transannular strain, which makes medium-membered rings special. Consequently, limited reactions are available for the effective construction of eight-membered rings. We previously realized the construction of the eight-membered ring of 29 by ring-closing metathesis (RCM) of 28 as part of the total synthesis of ophiobolin A (Scheme 11.10) [14]. This RCM strategy could be applicable to the construction of the B-ring of cotylenin A because the substrate can be easily prepared from dialdehyde 25. However, molecular modeling studies predicted that the oxidation of the C8-C9 alkene in the product would likely occur from the less-hindered side, forming a 1,2-diol with the same configuration as that in 27.

Scheme 11.10
A 3-step transformation process of organic molecules is as follows. 1, Hoveyda-Grubbs 2 catalyst and benzoquinone in toluene at 110 degrees Celsius. B n B r and N a H in D M F at 0 degrees Celsius. 3, P P T S in E t O H with a yield of 68% of the compound 29. Molecule 30 transforms in a single step using P d P P H 3 4 and P h O K in toluene.

Construction of eight-membered carbocyclic rings by ring-closing metathesis (RCM) of 28 in our total synthesis of ophiobolin A and intramolecular alkenylation of 30 in our total synthesis of taxol

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Notably, the intramolecular alkenylation of methyl ketone 30 afforded 31 with an eight-membered ring in the total synthesis of taxol (Scheme 11.10) [20]. Hence, we considered the intramolecular alkenylation of a methyl ketone to construct the eight-membered B-ring of cotylenin A, despite the necessity of an additional synthesis step for the substrate.

The revised retrosynthetic analysis of cotylenin A is shown in Scheme 11.11. Kato et al. reported that the desired diastereomer was preferentially formed even though the hydroxylation at the C9 position of 32 (R3 = TMS) is not highly stereoselective [6b]. Therefore, although the stereoselective hydroxylation at the C9 position of ketone 32 must be investigated, we considered ketone 32 to be a promising synthetic intermediate and investigated the intramolecular alkenylation of methyl ketone 33 to obtain 32. To synthesize methyl ketone 33, the A-ring fragment 34 was prepared from 9 (Scheme 11.4). However, a new synthetic method was developed for the C-ring fragment 35.

Scheme 11.11
A 2-step retrosynthetic analysis proposes a sequence of chemical reactions to synthesize a target molecule. First step, intramolecular alkenylation to form intermediate 35 a. Second step, glycosylation reaction to attach a sugar molecule to intermediate 35 a, resulting in cotylenin A.

Revised retrosynthetic analysis of cotylenin A

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11.3.2 Preparation of the New A-ring Fragment 34

The enolate formed by the reaction of 9 with SmI2, lithium naphthalenide, and LiDBB showed low reactivity toward aldehydes, suggesting that 9 should be transformed into α-bromo ketone 34, which could be used in Utimoto coupling. However, the enolate generated from 9 by reaction with SmI2 could not directly afford 34 (Scheme 11.12). Therefore, we investigated the preparation and reaction of the enol ether. Enol acetate 36 should be converted to 34 via bromohydrin formation; therefore, the enolate formed by the reaction of 9 with SmI2 was reacted with Ac2O [21] to afford enol acetate 36 in 20–30% yield. Hence, we explored the preparation of other enol ethers using various trapping reagents and observed that the reaction with ClP(O)(OEt)2 quantitatively afforded enol phosphate 37. The subsequent reaction of 37 with NBS in THF containing H2O afforded 34.

Scheme 11.12
A 2-step preparation process of the A-ring fragment 34 from starting material 9. In the first step, a one-task reductive enolate formation is used on molecule 9. The second step involves halogen trapping with S m l 2 in T H F at negative 78 degrees Celsius for 5 minutes followed by A c 2 O and D M A P at 20 to 30 degrees Celsius.

Preparation of the A-ring fragment 34 from 9

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11.3.3 Preparation of the New C-ring Fragment 35b

First, we developed the preparation of the iodoalkene 35a (Scheme 11.11) which corresponds to enol triflate 35b because iodoalkene is suitable for a Pd-catalyzed reaction. However, enol triflate 35b was selected because iodoalkene would react with the reactive species generated in the Utimoto coupling reaction via a radical process. Furthermore, although enol triflate is unstable under basic conditions, enol triflate 35b could be less reactive owing to the steric hindrance induced by the adjacent isopropyl group and quaternary carbon.

The enol triflate moiety of 35b was derived from the corresponding isopropyl ketone, which could be prepared by acyl radical cyclization of an aldehyde bearing a trisubstituted alkene, such as 38 (Scheme 11.13). As 38 is a known compound easily prepared from geraniol [22], we investigated the acyl radical cyclization of 38.

Scheme 11.13
A 3-step process for the preparation of the C-ring fragment 35 b from starting material 38 is as follows. First, addition of tert-butyl dimethyl silyloxy to molecule 38. Second, cyclization using P h N T f 2, L D A, and T H F at 0 degrees Celsius. Third, deprotection using a combination of 88% 3 H F E t 3 N and 89% D M P.

Preparation of the C-ring fragment 35b from 38

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The acyl radical cyclization of 38 using tert-dodecanethiol and AIBN [23] afforded a mixture of the desired 39 and the decarbonylated product derived from 38. In acyl radical cyclization, racemization may proceed via the decarbonylation and re-carbonylation of the generated acyl radical [24]. However, HPLC analysis of the derivative of 39 revealed that the optical purity of 39 was retained. Although the desired acyl radical cyclization of 38 using dodecanethiol and AIBN occurred, 39 was extremely hydrophobic, making it difficult to separate it from the unidentified by-products via silica gel column chromatography. Therefore, the product mixture was directly treated with LDA and PhNTf2 to afford enol triflate 40. The yield of the two-step process was ~ 30–40%, indicating that the reaction conditions should be optimized.

Notably, the acyl radical cyclization reactions of 38 under various conditions did not provide promising results. Hence, we explored the Cu-catalyzed radical acyl cyanation of alkenes reported by Bao et al. [25]. The reaction of 38 with CuCl, 2,2′-bipyridyl, tert-butyl hydroperoxide (TBHP), and tert-dodecanethiol in methyl tert-butyl methyl ether (TBME) afforded 39, which was converted to 40 in 54% yield (two steps). The 1H-NMR spectrum of the product mixture obtained from 38 indicated that the acyl radical reaction proceeded in ~ 90% yield (Scheme 11.13). Subsequently, the TBS group in the enol triflate 40 was removed using 3HF·Et3N. When TBAF was used for TBS removal, the CF3SO2 group migrated to afford a triflate of the primary alcohol, which further underwent intramolecular reactions [26]. Finally, the Dess–Martin reaction of the primary alcohol afforded the new C-ring fragment 35b.

11.3.4 Preparation of Methyl Ketone for Pd-Catalyzed Intramolecular Alkenylation

The as-prepared new A- (34) and C-ring (35b) fragments were then successively subjected to Utimoto coupling (Scheme 11.14) under the same conditions as those in Scheme 11.9 and a reaction with the Burgess reagent to afford 41 in 84% yield (two steps).

Scheme 11.14
A 6-step process for the preparation of methyl ketone 45 is as follows. The first step displays the conversion of benzene to methyl ketone. The second to sixth steps all involve the preparation of methyl ketone from methanol.

Preparation of methyl ketone 45

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Notably, the Wittig reaction of 41 under the conditions shown in Scheme 11.8 afforded 42 in < 35% yield, which was improved to 42% by using CeCl3 as an additive [27]. However, the yield did not increase further, despite extensive efforts. Considering that ketone 41 was recovered in all reactions and a by-product was isolated (Fig. 11.2), ketone 41 was prone to enolize in the presence of methylene phosphorane, indicating the different reactivities of ketones 41 and 21, which is shown in Scheme 11.9. Hence, we used the Takai reaction [28] to methylate 41 to afford 42 in 43% yield, which could not be improved using the reaction protocol reported by Lombardo [29]. However, the use of ZrCl4 instead of TiCl4 [30] successfully increased the yield to 91%. Notably, the exo-olefin of 42 was easily isomerized to an internal olefin when 42 was purified via silica gel column chromatography. Therefore, crude 42 was used for the subsequent dihydroxylation reaction.

Fig. 11.2
A tetrahedral molecular structure with two carbon atoms connected by a single bond. Each carbon atom forms a single bond with a hydrogen atom. The four atoms around each carbon atom are arranged in a tetrahedral manner.

Structure of a by-product of the Wittig reaction of 41

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The dihydroxylation of 42 afforded 43 in 71% yield (over two steps) with a dr ratio of 7:1. Efforts to increase the dr ratio by using various ligands for OsO4 were unsuccessful. Selective methylation of the primary alcohol of 43 and protection of the tertiary alcohol as a TMS ether afforded 44. The direct transformation of 44 to methyl ketone 45 was attempted using a variety of reagents; however, the yield was low owing to the decomposition of 44, which was ascribed to the reaction of the enol triflate moiety with the organometallic reagents. Hence, although additional steps were required, nitrile 44 was subjected to DIBAL-H reduction to afford its aldehyde, followed by reaction with MeMgBr, and the Dess–Martin reaction of the resultant alcohol successfully afforded methyl ketone 45.

11.3.5 Construction of the Eight-Membered B-ring via Pd-Catalyzed Intramolecular Alkenylation

The cyclization of methyl ketone 45 was conducted under the same reaction conditions used for the construction of the eight-membered ring in taxol [20, 31]. However, this resulted in the degradation of 45 (Scheme 11.15). Compound 30 (Scheme 11.10) obtained via Pd-catalyzed cyclization is an iodoalkene whose reactivity differs from that of enol triflate 45. Hence, the cyclization of enol triflate 45 could be different from that of 30, and the oxidative addition of enol triflate 45 and Pd may not proceed. Consequently, the reaction was conducted with PhOK and PdCl2(PCy3)2, which were ligated with more electron-rich ligands to promote oxidative addition (Scheme 11.16). The resulting product contained a mixture of 46 and its C8 epimer, indicating that epimerization occurred competitively during the cyclization. However, this epimerization was suppressed by lowering the reaction temperature to 50 °C, which afforded 46 in 95% yield.

Scheme 11.15
A chemical reaction to achieve the intramolecular alkenylation of molecule 45 under the following conditions. 1, P d P P h 3 4, P h O K, and toluene at 80 to 110 degrees Celsius. 2 and 3, P d P P h 3 4, t B u O K, toluene, C s 2 C O 3, and E t 3 N at room temperature. 4, P d C l 2 d p p f 2 C H 2 C l 2 and P h O K in toluene at 110 degrees Celsius.

Attempted intramolecular alkenylation of 45

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Scheme 11.16
A chemical reaction for the intramolecular alkenylation of compound 45 with the following reactants. T M S O, P h O K, and P d C l 2. P C y 3 2. The reaction takes place in toluene at 50 degrees Celsius and yields 95% conversion of the starting material 45 to the product 46.

Successful intramolecular alkenylation of 45

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However, the cyclization in the presence of PdCl2(PCy3)2 did not proceed when the color of the reaction solution was yellow and occurred only after a black precipitate was formed in the reaction solution. The black precipitate could be derived from Pd which was confirmed to not catalyze the cyclization. We checked whether the cyclization proceeded in the reddish-brown supernatant solution obtained after mixing PdCl2(PCy3)2 and PhOK for a certain time, and we found that the use of the reddish-brown supernatant solution including a catalytic amount of a Pd complex afforded 46. Thus, although two equivalents of PdCl2(PCy3)2 were used for the cyclization of 45, the reaction of 45 may be mediated by a catalytic amount of the Pd complex dissolved in the solution. However, the structure of the Pd complex has not yet been elucidated.

11.3.6 Stereoselective Construction of 1,2-Diol at the C8-C9 Position and Synthesis of Cotylenol

The hydroxylation of 46 at the C9 position (Scheme 11.17) using MoOPH and LiNTMS2 (LHMDS) afforded 47 and its C9 epimer in 44% and 28% yields, respectively. However, the reaction of 46 with MoOPH, LHMDS, and LiCl improved the yields of 47 and its C9 epimer to 52% and 19% yields, respectively, thereby improving the diastereoselectivity.

Scheme 11.17
A multi-step process to synthesize cotylenol starting with T M S O and M e O on a six-membered carbon ring, reacting with L H M D S and L I C l forms intermediate 46 at negative 50 degrees Celsius. Conversion to intermediate 47 yields a minor byproduct. Treatment with M e 4 N B H O A c 3 in C H 3 C N produces intermediate 48 in 80% yield.

Total synthesis of cotylenol

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Subsequently, the reduction of α-hydroxy ketone 47 was examined. Reduction in the presence of NaBH(OAc)3 and Me4NBH(OAc)3 [32] stereoselectively produces a trans-1,2-diol from a cyclic α-hydroxy ketone, afforded 48 but exhibited poor reproducibility in terms of yield and stereoselectivity [6]. This lack of reproducibility was attributed to the low solubility of the reagents in the solvents. Hence, reagents with more lipophilic ligands were used to improve the solubility of the reductant. Notably, the reduction with Me4NBH(O2CiPr)3, which was readily prepared from Me4NBH4 and iPrCO2H, afforded trans-1,2-diol 48 in 80% yield as a single diastereomer. The high reproducibility and stereoselectivity of the reduction reaction can be ascribed to the ligand (O2CiPr), which enhances the solubility of the reagent and the steric effect on the transition state, which favorably affords 48. Incidentally, Me4NBH(O2CiPr)3 was ~ 10 times more soluble in THF than Me4NBH(OAc)3. The reduction of 47 using Me4NBH(O2CiPr)3 afforded cyclic borates. Hence, trimethylolethane, which is known to form chelates with boronates by ligand exchange, was used in the reduction workup of Me4NBH(O2CiPr)3 to isolate trans-1,2-diol 48. Finally, the TMS group in 48 was removed using TBAF to afford cotylenol. The spectroscopic data of the synthesized cotylenol were identical to those of the natural product [33].

11.4 Synthesis of the Sugar Moiety in Cotylenin A

The sugar moiety of cotylenin A is different from that of all other cotylenins, and its synthesis had not been reported until our report on the first total synthesis of cotylenin A. This could be attributed to the highly oxidized, unprecedented structure of the sugar, which comprises a trioxabicyclo[2.2.1]heptane and an epoxide. This sugar moiety contains acid-sensitive functional groups and is therefore unstable in acids, making its synthesis challenging. The trioxabicyclo[2.2.1]heptane is fused to the THP ring, which is likely a glucose derivative because the sequence of the chiral carbon atoms in the THP ring is the same as that in glucose. The sugar moiety of cotylenin A could be synthesized by coupling glucose-derived hydroxyketone 49 with epoxyaldehyde 50 (Scheme 11.18). Therefore, considering the glycosylation reaction of the aglycone moiety with the acid-sensitive sugar moiety, we initially assembled thioglycoside 49 and epoxyaldehyde 50 to synthesize a sugar moiety that could be glycosylated under mild conditions.

Scheme 11.18
A reaction for the initial retrosynthetic analysis of the sugar moiety in cotylenin A through glycosylation. The central focus is on the sugar moiety which is being introduced into the molecule. The involved glycosyl donor is the sugar source and the glycosyl acceptor is the molecule receiving the sugar.

Initial retrosynthetic analysis of the sugar moiety

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Hydroxyketone 49 was synthesized as shown in Scheme 11.19. Benzylation of known compound 51 [34], followed by regioselective reduction of p-methoxybenzylidene acetal to afford 52, methylation of the primary alcohol of 52, removal of the PMB group using DDQ to afford 53, Dess–Martin oxidation, and removal of the TBS group furnished 49. The low yield of the TBS group removal was due to the tendency of 49 to dimerize.

Scheme 11.19
A chemical synthesis pathway for the preparation of compound 49. The first step involves converting compound 51, which has a hydroxyl group, to compound 52, which has a methoxy group. The second step involves converting compound 52 to compound 49 using p- P T S A and methanol at room temperature.

Preparation of 49

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Epoxy aldehyde 50a was prepared from the known compound 54 [35] (Scheme 11.20). Compound 54 was subjected to Payne rearrangement in the presence of tBuSH under basic conditions, affording a β-hydroxy sulfide [36]. The subsequent reaction of the sulfide with Meerwein’s reagent afforded the sulfonium salt, which on treatment with a base afforded epoxide 55 [36]. The benzyl group of 55 was removed by hydrogenolysis to afford 1,2-diol. Oxidation of the primary alcohol of the 1,2-diol with various reagents was attempted. However, the product, hydroxyaldehyde, was highly water-soluble and easily dimerized. Therefore, the 1,2-diol was converted to bis-TMS ether, followed by Swern oxidation to obtain 50a  [37].

Scheme 11.20
A chemical reaction pathway for the preparation of compound 50 a. The pathway starts with compound B n O with B U S H in T H F at negative 78 degrees Celsius and goes through eight steps to form compound 50 a.

Preparation of 50a

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Next, the coupling of 49 and 50a was examined under acidic conditions, which led to the dimerization of 49 to furnish 56 and 57 (Scheme 11.21). This could be attributed to the steric hindrance of the TMS ether of the adjacent tertiary alcohol on the carbonyl group of the aldehyde. Therefore, the less-hindered 50b was used, which formed 56 and 57 but not the desired product.

Scheme 11.21
A chemical reaction for the attempted coupling of compounds 49 and 50 in two attempts. The first attempt uses compound 50 a where Y is the trimethylsilyl group. The second attempt uses compound 50 b where Y is the acetyl group. The reactants of both attempts are in T H F at negative 78 degrees Celsius.

Attempted coupling of 49 and 50

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Consequently, we explored another synthetic method for the sugar moiety. Watson et al. refluxed a benzene solution of hydroxyketone 58 with p-TsOH to obtain 60 bearing a trioxabicyclo[2.2.1]heptane moiety in 97% yield (Scheme 11.22) [38]. This reaction likely involves transannular dehydration via the intermediate 1,4-dioxane derivative 59 to produce 60 bearing a trioxabicyclo[2.2.1]heptane moiety.

Scheme 11.22
A chemical reaction for the formation of trioxabicyclo heptane derivative 59. It exhibits p-T s O H and benzene as the reagents with reflux conditions for the reaction. The yield for this reaction is indicated as 97%.

Formation of the trioxabicyclo[2.2.1]heptane derivative 59 via the dimerization of 58

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As the transannular dehydration of 59 afforded 60, we hypothesized that 61 could be synthesized by the transannular acetal exchange of 62, which could be produced from 63 (Scheme 11.23). Therefore, we synthesized 66 (Scheme 11.24) via the intermolecular acetal exchange reaction [39] of 64 [40] with 65, which was in turn obtained by removing TBS from the methyl ether of 52. Compound 66 was subjected to DIBAL-H reduction and sharpless asymmetric epoxidation to afford 67. Successive Payne rearrangement with TBAF [41] and reaction with CDI afforded cyclic carbonate 68. The removal of the PMB group of 68 using DDQ, followed by Parikh–Doering oxidation afforded 62 in 19% yield. Notably, the oxidation of one of the diastereomers of the starting material was slow, and 39% of the unreacted diastereomer was recovered. This could be attributed to the intramolecular hydrogen bonding of 68a or the steric hindrance derived from its shape, which may reduce the reactivity of the secondary alcohol.

Scheme 11.23
A retrosynthetic analysis of the sugar moiety of cotylenin A. The molecule is divided into 3 sections, with the leftmost section labeled sugar moiety containing 6 carbon atoms, 5 oxygen atoms, and 3 C H 3 O. It features a cyclic structure between carbon atoms 61 and 62 and 2 P h S.

Retrosynthetic analysis of the sugar moiety of cotylenin A via transannular acetal exchange

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Scheme 11.24
A multi-step reaction scheme for the preparation of compound 62 starts with reacting a compound with o t o l 3 P, T E S O T, and C H 2 C L 2 at 0 degrees Celsius for 1.5 hours. After passing all the steps, the scheme yields compounds 65, 66, 67, 62, and 68 a with different yields.

Preparation of 62

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Next, we attempted to obtain 61 from the transannular acetal exchange reaction of 62 (Scheme 11.25). However, 61 was not produced. The structure of 59 (Scheme 11.22) was symmetric, and its reaction proceeded even if a cation was generated from either hemiketal. In addition, the six-membered ring containing two hemiketals in 59 is flexible and is likely to undergo conformational changes, which could be favorable for the reaction. However, in the case of 62, the structure of the trans-fused glucose ring was less flexible and may not form an oxa-bridged ring.

Scheme 11.25
A reaction attempts to synthesize compound 61 through a transannular acetal exchange reaction. Molecule 62 serves as the starting material. The target molecule 61 shares the same core structure as 62 but the positions of the methoxy groups are reversed.

Attempted transannular acetal exchange for the synthesis of 61

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Notably, the hemithioacetal in hydroxyketone 49 decomposed during isolation, which makes the optimization of the reaction conditions difficult. Hence, we synthesized hydroxyketones without a hemithioacetal by removing the dimethyl ketal of 69 using p-TsOH and acetone (Scheme 11.26). However, the reaction yielded 70a as a mixture of isomers. The reaction of 69 with pivaldehyde in the presence of p-TsOH afforded hemiketal 70b as a diastereomeric mixture in 48% yield.

Scheme 11.26
A reaction scheme where molecule 69 reacts with acetone and pivalaldehyde in an acid-catalyzed process to form a hemiketal molecule, 70 a or 70 b, depending on the functional groups attached to the starting molecule 69.

Formation of hemiketal 70 via the acid-catalyzed reaction of 69 with acetone and pivalaldehyde

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The reaction of an aldehyde with hydroxyketone 49 could produce a hemiketal which is similar to 70b in Scheme 11.26. An epoxy aldehyde could be suitable because it has low steric hindrance and is expected to form an oxa-bridged ring through an intramolecular reaction of the hemiketal generated by the reaction with 49. As we obtained aldehyde 71 (Scheme 11.27), which would afford the desired configuration of the sugar moiety, we explored the reaction of 49 with 71.

Scheme 11.27
A 2-step reaction scheme of synthesizing compound 74 from starting materials 49 and 71 with the help of T B A F. Step 1 involves compounds 49 and 71 with triethylamine as the base in dichloromethane at 0 degrees Celsius for one hour. In step 2, compound 72 is converted to the target molecule 74 through a series of reactions.

Synthesis of 74 via the reaction of 49 and 71

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However, as the products of the reaction of 49 with 71 contain acid-sensitive epoxides and acetals, we employed basic conditions based on the dimerization of hydroxyketones under basic conditions [42]. However, only the starting material was detected during TLC monitoring. Nevertheless, as 70 is formed from 69, we believed that 72 must have formed, which was confirmed via 1H-NMR. Therefore, unlike 70, 72 was unstable and was converted into the starting material.

Subsequently, hemiacetal 72 was converted to TMS ether 73, whose structure was confirmed by 1H-NMR. Compound 73 was treated with TBAF, and the expected cyclization generated 74 bearing a trioxabicyclo[2.2.1]octane. If the benzyl ether next to the hydroxy group in 74 is a tosylate, it can be converted to the corresponding epoxide bearing the correct stereochemistry under basic conditions. This synthetic approach (Scheme 11.27) could be applicable to the synthesis of the sugar moiety of cotylenin A.

We investigated the coupling conditions for 49 and epoxy-aldehyde-bearing tosylate 75 (Scheme 11.28). The reaction of 49 with 75 afforded a mixture of hemiacetals 77a and 77b at 20–25 °C in acetonitrile with 1 equiv. of CSA. The concentration (2 M) of the reaction mixture was crucial for the formation of 77a and 77b. However, similar to 72, 77a and 77b were unstable. Both 77a and 77b were not detected during TLC analysis but were identified as a 1:1 mixture in 1H-NMR analysis. Notably, when the mixture of 77a and 77b was diluted to 0.1 M with acetonitrile, 77a and 77b disappeared, and the equilibrium shifted to 49 and 75. This result indicates that the 2 M concentration of the reaction mixture is crucial for the formation of 77a and 77b, suggesting that the aggregation of products may have shifted the equilibrium toward the product.

Scheme 11.28
A synthesis reaction of sugar moiety fragment 79. Step 1 involves intermolecular acetalization between compound 49 and H O A c catalyzed by C S A, yielding compound 76. Step 2 displays the intramolecular acetalization of compound 76, resulting in compound 79.

Successful synthesis of the sugar moiety fragment 79 via the reaction of 49 with 75

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The epoxide ring-opening reaction by the internal attack of the hydroxy group of 77a proceeded slowly, even with acid catalysis, and 78 was formed 24 h after the start of the reaction. After 48 h, the yield of 78 did not change, which could be attributed to the configuration of the C1″ position and a consequent slow interconversion of 77a and 77b.

Compound 78 could not be sufficiently purified by silica gel column chromatography and contained inseparable impurities; therefore, it was treated directly with NaH to afford epoxide 79 (23% yield from 49 and 75). The sequential conversion from 49 and 75 to 79 involved the formation of four carbon–oxygen bonds to furnish a reasonable yield of 23%. This synthetic procedure required only two flasks, which is advantageous, and could be scaled up to the gram scale.

11.5 Glycosylation and Completion of the First Total Synthesis of Cotylenin A

Next, the glycosylation of 79 was investigated (Scheme 11.29). The C8 hydroxy group of 48 was more reactive than the C9 hydroxy group, likely because of steric hindrance, and the reaction of 48 with Ac2O afforded 80 in 59% yield (77% brsm). The glycosylation of 80 and 79 using common reagents such as Tf2O and MeOTf resulted in the degradation of 79. The desired compound 81 was obtained under Crich’s conditions [43], but in low yield. Hence, glycosylation was attempted with various reagents. Compound 81 was obtained in moderate yield via the formation of a sulfonium ylide of 80 in the presence of the catalyst Rh2(oct)4 and the subsequent glycosylation catalyzed by Brønsted acid, which was previously reported by Wan et al. [44]. However, 81 could not be separated from a trace amount of impurities with silica gel column chromatography. Consequently, the crude product was directly used in the next three reactions.

Scheme 11.29
A reaction for the final steps in the first total synthesis of cotylenin A. The key step is glycosylation, which involves attaching a sugar molecule which is the glycosyl donor to an aglycone molecule which is the glycosyl acceptor.

Glycosylation and completion of the first total synthesis of cotylenin A

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The C8 acetate of 81 was difficult to remove by hydrolysis but could be removed by reaction with methyl lithium at low temperatures. Finally, the TMS group was removed using TBAF, and the benzyl group was removed by hydrogenolysis to afford cotylenin A.

All the spectroscopic data for the synthesized cotylenin and naturally occurring cotylenin A were consistent [1], thus validating the first enantioselective total synthesis of cotylenin A. To the best of our knowledge, we reported the specific rotation of cotylenin A for the first time in the literature.

11.6 Conclusion

Herein, we described the first successful enantioselective total synthesis of cotylenin A in detail. Our synthetic approach to cotylenin A was convergent and featured the synthesis of an aglycon moiety using two chiral fragments containing a five-membered carbon ring. Synthetic studies on the aglycon moiety of cotylenin A revealed B-ring formation by intramolecular pinacol coupling between the C8 and C9 positions. However, arranging contiguous asymmetric carbons at the C8 and C9 positions after introducing two hydroxy groups is difficult. Hence, we developed a revised synthesis of the aglycon moiety via the alkenylation of methyl ketones, which required two new chiral fragments. The A-ring fragment was prepared using catalytic asymmetric intramolecular cyclopropanation (CAIMCP), which we previously developed. The C-ring fragment was prepared by the acyl radical cyclization of a known aldehyde, which was obtained by the sharpless asymmetric epoxidation of geraniol and subsequent rearrangement. The radical generation method using a copper catalyst and TBHP was effective for acyl radical reactions. The A- and C-ring fragments were effectively assembled using the Utimoto coupling reaction. A highly stereoselective reduction of α-hydroxyketone in the B-ring with Me4NBH(O2CiPr)3 afforded the desired trans-1,2-diol. Terminating successive reversible acetalizations via irreversible epoxide ring-opening reactions led to the first successful synthesis of a structurally unprecedented sugar moiety. Glycosylation was difficult because of the steric hindrance around the C9 hydroxy group of the aglycon; however, the desired product was successfully obtained under the reaction conditions reported by Wan et al. Even though the yield of cotylenin A could be improved by optimizing the low-yielding steps, our total synthesis could increase the supply of cotylenin A for further studies.