Remote Asymmetric Induction Reactions using a E,E-Vinylketene Silyl

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Remote Asymmetric Induction Reactions using a E,E‑Vinylketene Silyl N,O‑Acetal and the Wide Range Stereocontrol Strategy for the Synthesis of Polypropionates Seijiro Hosokawa* Department of Applied Chemistry, Faculty of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan CONSPECTUS: The construction of libraries of acyclic polyketides remains a challenging topic, mostly due to the difficulties associated with finding the right balance between diversity and brevity for the synthetic routes leading to polyketides. Recently, relatively short methods have been developed and applied to the synthesis of natural products. However, these short routes often suffer from limited diversity with respect to the arrangement of functional groups and stereochemistry, as these usually require reactions that direct multiple functional groups simultaneously in one step. Therefore, methods that combine a small number of reaction steps with structural diversity remain an attractive research target for the construction of acyclic polyketide libraries. In 2004, we reported a remote asymmetric induction reaction using chiral vinylketene silyl N,O-acetal 1, which is commensurate to an antiselective vinylogous Mukaiyama aldol reaction. Ever since, this reaction has been applied to the synthesis of numerous natural products, as this synthetic route is short and efficient on account of the simultaneous introduction of both asymmetric centers and the multiply functionalized carbon chain. Recently, we have developed a variety of this remote asymmetric induction reaction based on the E,E-vinylketene N,O-acetal 1, which includes syn-selective vinylogous Mukaiyama aldol reactions, as well as alkylation, acylation, and bromination reaction. These reactions provide polypropionates in a highly stereoselective manner. The proposed transition states of these reactions are discussed in this Account. Additionally, we have developed a new short synthesis of polypropionates by combining reactions for the remote asymmetric induction and the functionalization of double bonds (wide-range stereocontrol, WRS). The remote asymmetric induction reaction simultaneously constructs the stereogenic centers at the central part of the products and introduces the α,βunsaturated imide, while the new strategy is based on the initial construction of the central part of the molecule and a subsequent functionalization of the surroundings (WRS). This strategy successfully furnished stereoisomers in a few steps, and the stereodivergent synthesis of 2,4,6-trimethyloctanoic acid derivatives was accomplished. This strategy should also be feasible to construct an acyclic polyketide library. Moreover, we applied this method to the concise synthesis of natural products. In this Account, the development of remote asymmetric induction reactions and the new WRS strategy are described. Applications of the WRS strategy as well as reactions for the stereodivergent synthesis of polypropionates and natural products are also described. The aforementioned acyclic polyketide library should be constructed in the future with the help of the WRS strategy and become a powerful tool in drug discovery.

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INTRODUCTION Recently, methods for the concise synthesis of polyketides have been developed and applied to the synthesis of natural products.1 The vinylogous Mukaiyama aldol reaction (VMAR) is one of these methods, as this reaction simultaneously constructs stereogenic centers and introduces a functionalized carbon chain.2 Therefore, VMARs have been employed as straightforward syntheses for natural products with polyketide skeletons.3 During the course of our synthetic studies on polyketides, we have developed a remote asymmetric induction type VMAR by using chiral vinylketene silyl N,O-acetal 1 (Scheme 1, TBS = tertbutyldimethylsilyl).4 The ease of preparation and handling of stable crystalline 1 encouraged us to develop various remote asymmetric induction (RAI) reactions and concise routes to © XXXX American Chemical Society

polyketides. Herein, we describe our research on the synthesis of polypropionates by RAI reactions and the wide range stereocontrol (WRS) strategy.

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STEREOSELECTIVE VINYLOGOUS MUKAIYAMA ALDOL REACTIONS (VMARs)

The anti-Selective VMAR

In 2004, we reported a RAI reaction using chiral vinylketene silyl N,O-acetal 1 (Scheme 1), which predominantly afforded the antiadduct 2 (Table 1).4 Various saturated, unsaturated, and Received: March 20, 2018

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DOI: 10.1021/acs.accounts.8b00125 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research Scheme 1. RAI Reaction of Vinylketene Silyl N,O-Acetal 1

Table 1. VMAR of 1 with Various Aldehydes

aromatic aldehydes can be used in this reaction and furnish the polypropionate skeleton in high stereoselectivity. Moreover, this reaction has been widely applied to the synthesis of natural products.5 A comparison between the 1H NMR and the X-ray crystallography data (Figure 1) revealed that the conformation of vinylketene silyl N,O-acetal 1 is similar in solution and in the crystalline state. In this conformation, the larger methyl group (sp3 carbon) is located trans, while the smaller olefinic H−C (sp2 carbon) resides cis to the bulky oxazolidin-2-one, which is oriented almost perpendicular to the diene plane, whereby the rotation of the oxazolidin-2-one is restricted by the presence of the tert-butyldimethylsilyl (TBS) group and the diene. Consequently, the isopropyl group is located on top of the upper face of the diene, and electrophiles may approach from the face opposite the isopropyl group (TS-1, Scheme 2), which controls the stereoselectivity of the reaction. The α-methyl group of the vinylketene silyl N,O-acetal is important for both the stability and the stereoselectivity. Scheme 3 shows 1,7-asymmetric induction reactions using terminal unsubstituted vinylketene silyl N,O-acetals 7 and 10. Tiglic acid derivative 6 was treated with sodium hexamethyldisilazide (NaHMDS) and TBSCl to obtain E-enol ether 7, while crotonic acid derivative 9 was converted to Z-enol ether 10. The VMAR of stable 7 provided 8 in excellent yield and stereoselectivity, while 10, which is unstable under acidic conditions, furnished 11 in low yield and stereoselectivity. The low yield of the reaction shown in eq 4 is due to the relative instability of 10, while the low selectivity is due to the direction of the diene chain.

Figure 1. Nuclear Overhauser effect (NOE) in CDCl3 and ORTEP drawing (thermal ellipsoids at 50% probability) of the vinylketene silyl N,O-acetal 1.

of palmerolide A (12), which exhibited 19,20-syn stereochemistry (Scheme 4).6 Both groups were furthermore able to invert the configuration of the C19 hydroxy group to obtain the corresponding derivative with C19,20-syn stereochemistry. These reports show that syn-selective VMARs represent desirable research targets,7 which prompted us to develop such reactions using vinylketene silyl N,O-acetal 1. The syn-Selective VMAR with Aldehydes

Prior to our studies on the syn-selective VMAR, the groups of Kobayashi and Yang reported that α- or β-heteroatomsubstituted aldehydes react with 1 to afford syn adducts (Scheme 5, eqs 5 and 6).7a−c Additionally, Symkenberg and Kalesse published that a 1E,3Z-vinylketene silyl N,O-acetal reacts with aldehydes to give the corresponding syn adducts (eq 7).7d

The syn-Selective VMARs

In 2007, the groups of De Brabander and Nicolaou independently used the anti-selective VMAR for total synthesis B


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Accounts of Chemical Research Scheme 2. Proposed Transition State for the RAI Reaction of 1

Scheme 4. Previously Reported Total Syntheses of Palmerolide A6a,b

When we carried out the VMAR of E,E-vinylketene silyl N,Oacetal 1 with a small amount of aldehyde at a late stage of the natural product synthesis in our laboratory, the syn adduct was obtained as the major product.7e We also discovered that the VMAR furnished the syn adduct by using an excess of TiCl4. Thus, the syn-selective VMAR was carried out using a variety of aldehydes, 1.5 equiv of 1, and 4 equiv of TiCl4 (Table 2).8 In all cases, including aromatic and saturated aldehydes, the reaction afforded the syn adducts (13) in good to high yield with excellent stereoselectivity. In the case of γ-oxygenated aldehydes k and l, the reaction proceeded slowly, and increased amounts of 1 (3 equiv) and TiCl4 (7 equiv) were required to obtain the syn adducts in good yield. Although it is clear that the stereoselectivity of the VMAR depends on the amount of Lewis acid, the exact nature of the transition state of the syn-selective reaction remains to be determined. The initial color of the reaction mixture is dark blue, while that of the anti-selective reaction exhibits a dark red color. The differences in the initial reaction color should represent a manifestation of the differences in the structure of the initial titanium complexes. As previously mentioned, the stereochemical course depends on the amount of TiCl4. The stereochemical switching is an advantage of the VMAR for the formation of polypropionate skeletons with a variety of configurations.

Therefore, we treated a variety of acetals with E,E-vinylketene silyl N,O-acetal 1 in the presence of a Lewis acid (Table 3).9 The reactions using aromatic or α,β-unsaturated aldehyde-derived acetals furnished the corresponding syn adducts (14) in high stereoselectivity. Saturated aldehyde-derived acetals also furnished the syn adducts in good to high yield (14k−o). These results indicate that the reaction proceeds via an oxocarbenium ion. Moreover, the steric bulk of the alkyl group should influence the stereoselectivity.

The syn-Selective VMAR with Acetals

During the course of our studies on RAI reactions, we discovered that the VMAR with acetals in the presence of 1 equiv of a Lewis acid (BF3·OEt2) afforded the protected syn aldol adducts. Scheme 3. 1,7-Asymmetric Induction by VMAR

C


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Accounts of Chemical Research Table 3. VMAR of 1 with Acetalsb

Scheme 5. Previously Reported syn-Selective VMARs7

Table 2. syn-Selective VMAR Using E,E-Vinylketene Silyl N,O-Acetal 1

a

The reaction was performed in the ratio of acetal/dienol ether/ TMSOTf = 1:2:1. bAll reactions were performed in the ratio of acetal/ dienol ether/Lewis acis = 1:1:1.

Scheme 6. One-Pot Transformation of Aldehyde 15 into syn Adduct 14g

a

Performed in the ratio of aldehyde/dienol ether/TiCl4 = 1:3:7.

This reaction was also applied to the one-pot conversion of an aldehyde into the corresponding benzyl-protected syn adduct (Scheme 6). After aldehyde 15 was transformed to dibenzyl acetal g using BnOTMS and TMSOTf (0.2 equiv), TMSOTf (1.0 equiv) and 1 were added to the resulting mixture. The operation did not affect the yield and selectivity, and syn adduct 14g was obtained in high yield and stereoselectivity. According to the obtained results, we proposed a transition state for the syn selective reaction (Figure 2). The open-chain transition state would minimize steric repulsion by directing the largest group (R) and the small hydrogen to outside and the crowded area, respectively (top view A). This reaction, which

features the direct formation of the protected syn adduct, should become a powerful tool for the synthesis of natural products. D


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Accounts of Chemical Research

Figure 3. Molecular structure of TBS-protected 16 (thermal ellipsoids at 50% probability).

groups of the oxazolidone and the imide would be directed in opposing directions due to the dipole moment in 23, that is, the isopropyl group of the chiral auxiliary would cover the face below the double bond. Thus, the catalyst would approach from the face opposing the isopropyl group to give 24 as the major product. Accordingly, each olefinic moiety of the VMAR adduct would be reduced stereoselectively, which would be commensurate with a stereodivergent synthesis of reduced polypropionates. According to the hypothesis, the stereodivergent synthesis of 2,4,6-trimethyloctanoates was achieved (Scheme 9).11 Compound ent-18, the product of the VMAR between 1 and 25 was subjected to hydrogenation using the Schrock−Osborn catalyst to selectively afford ent-19. After protection of the hydroxy group as a methoxymethyl ether, a Birch reduction afforded the 2,4,6syn compound 26 in high yield and stereoselectivity via a chelating enolate intermediate. On the other hand, ent-19 was hydrogenated using palladium on alumina, which proceeded in quantitative yield and good stereoselectivity (dr = 1:6.7) on account of the dipole moment of the carbonyl groups. The major product, that is, 2,4-anti-4,6-syn product 27 was isolated by column chromatography in 87% yield. Subsequently, TBS ether ent-16 was hydrogenated using a platinum catalyst, which proceeded regio- and stereoselectively to give 4,6-anti product ent-17. Unsaturated imide ent-17 was subjected to a Birch reduction to provide 2,4-syn product 28 in 71% isolated yield. Finally, hydrogenation of ent-17 furnished 2,4,6-anti product 29 in 81% isolated yield. Therefore, all stereoisomers of 2,4,6-trimethyloctanoate were selectively obtained from a sequence of VMARs and regio- and stereoselective reductions.

Figure 2. Proposed transition state for the syn-selective VMAR with acetals.

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THE WIDE RANGE STEREOCONTROL (WRS) STRATEGY Conventionally, polyketides have been synthesized by repeated transformations of the terminal of the substrates (Scheme 7). Although this strategy affords a variety of polyketides, it is very laborious and the generation of libraries accordingly difficult and time-consuming. In order to balance the aforementioned diversity and the practicality of the synthetic routes, we developed a new strategy to synthesize polypropionates. This so-called wide range stereocontrol (WRS) strategy is based on the initial stereoselective construction of the central part of an acyclic compound using RAI reactions, before the chirality of the central or terminal part is transferred to the neighboring double bonds. Accordingly, the WRS strategy affords acyclic compounds via a short synthetic route. Stereodivergent Synthesis of Derivatives of 2,4,6-Trimethylocatanoic Acid

In the total synthesis of actinopyrone A, the absolute configuration of TBS ether 16, that is, the TBS-protected adduct of the reaction between ent-1 and tiglic aldehyde, was determined by single-crystal X-ray diffraction analysis (Figure 3).10 The molecular structure revealed that the TBS group covers one face of the olefinic moieties. Consequently, hydrogenation of 16 should proceed from the face opposite to the TBS group to provide 4,6-anti product 17 (Scheme 8; eq 8). On the other hand, a cationic catalyst might promote hydrogenation directed at the hydroxy group of adduct 18,8 which would afford 4,6-syn product 19 (eq 9). Additionally, the CC double bond of the α,β-unsaturated imide moiety is also able to undergo stereoselective reduction reactions under direction from the chiral auxiliary (eqs 10 and 11). A reduction via 21, for example, by chelation to a metal ion, would afford 22, as the isopropyl group would interfere with the protonation from the upper face. However, in the major conformation of imide 20, the carbonyl

Total Synthesis of Septoriamycin A

The strategy to construct 2,4,6-trimethylocatanoates (Scheme 9) has also been applied to the synthesis of natural products such as antileishmanial septoriamycin A.12 Using our method, we accomplished the first and efficient synthesis of septoriamycin A (Scheme 10). For that purpose, alcohol ent-19 (Scheme 9) was subjected to a Birch reduction, followed by lactonization under acidic conditions to provide δ-lactone 30. A reduction using

Scheme 7. Conventional Approach and the WRS Strategy for the Formation of Polyketides

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Scheme 8. Proposed Stereochemical Pathways for the Stereodivergent Synthesis of Reduced Polypropionates via VMARs

Scheme 9. Stereoselective Synthesis of 2,4,6-Trimethylocatanoates Using a Sequence of VMARs and Regio- and Stereoselective Reductions

Synthesis of Oxygenated Polypropionates Using Epoxide Rearrangement Reactions

DIBAL afforded the corresponding lactol, which was then 13

subjected to a Knoevenagel condensation with pyridone 32 in

In addition to the divergent synthesis of reduced polypropionates, we have investigated the divergent synthesis of oxygenated polyketides. During the course of our synthetic studies on polypropionates, epoxy alcohols attracted our attention. The chemistry of epoxy alcohols has been well-established and

the presence of amine 31. This sequence directly generated septoriamycin A as the major product of a separable mixture of C2 epimers (8:1). Septoriamycin A was thus synthesized in 35% over six steps from vinylketene silyl N,O-acetal 1. F


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Accounts of Chemical Research Scheme 10. Synthesis of Septoriamycin A

Scheme 11. Synthetic Route to the C24−C40 Segment 33 of Aculeximycin

applied widely to the synthesis of natural products.14 For the synthetic studies on the antibiotic aculeximycin15 (Scheme 11), we employed rearrangement reactions of epoxy alcohols. We hypothesized that the C24−C40 segment 33 could be synthesized by an aldol condensation between the C33−C40 segment 34 and the C25−C32 segment 35 (Scheme 11)16 and that it should be possible to generate these oligoketides in a concise manner using a combining of VMAR (Scheme 1) and two kinds of epoxide rearrangement reactions (Scheme 12). One of the rearrangement reactions is the semipinacol rearrangement (path a), while the other is the epoxide−carbonyl isomerization (path b). In contrast to path a, that is, Jung’s method,17 path b has not been applied yet to natural product synthesis; nevertheless, an appropriate use of these reactions should allow access to a variety of polyketides. The synthesis of C33−C40 segment 34 started from vinylketene silyl N,O-acetal 36 (Scheme 13). The RAI reaction with 36 and butanal 37 provided 38 in high yield and excellent selectivity. After the reduction that afforded allylic alcohol 39, epoxidation14a and protection furnished TBS-protected epoxy alcohol 40 in high selectivity. Subsequent treatment of 40 with TMSOTf in the presence of Hünig’s base promoted the semipinacol rearrangement to give aldehyde 34. On the other hand, C25−C32 segment 35 was synthesized (Scheme 14) using a VMAR of terminal unsubstituted diene 7 and tiglic aldehyde 25 in the presence of H2O.18 The thus obtained allylic alcohol 41 was subjected to a vanadium-mediated epoxidation that afforded epoxy alcohol 42,14b which was treated with the Lewis acid t-Bu2Si(OTf)2 to promote the epoxidecarbonyl rearrangement. The resulting anti β-hydroxy-α-methyl ketone 43 was subsequently protected as PMB ether 35. The coupling of two segments and the construction of C24− C40 segment 33 are shown in Scheme 15. The lithium enolate of 35 was treated with aldehyde 34 to give an aldol adduct, which was further converted into the α,β-unsaturated ketone 44 in a sequential mesylation/elimination in one pot. A Luche reduction of 44 proceeded stereoselectively to yield the desired isomer 45. Removal of TMS group under acidic conditions furnished diol 46, which was separated from other stereoisomers including derivatives of the stereoisomer of 35 by column chromatography. After protection of the diol as methoxymethyl ethers, the ester

Scheme 12. Epoxide-Opening Hydride Shift Reactions That Afford Aldols

group was converted into an ethyl ketone moiety to generate C24−C40 segment 33. Thus, we discovered an efficient synthesis of the C24−C40 segment of aculeximycin by combination of VMARs and epoxide rearrangement reactions. This synthesis represents an efficient and straightforward route to medium-sized oxygenated polypropionates. G


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Accounts of Chemical Research Scheme 13. Synthesis of C33−C40 Segment 34

Scheme 15. Coupling of Segments and Synthesis of C24−C40 Segment 33

Scheme 14. Synthesis of C25−C32 Segment 35

Scheme 16. Acylation of E,E-Vinylketene N,O-Acetal 1

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including pivalate (g), benzoate (h), and carbonate (i), were able to furnish 47b (R = Et) in good to high yields. Additionally, acid anhydride 48, which contains a stereogenic center at the α position, was also subjected to the reaction (Scheme 17). The reaction furnished adduct 49 as a single isomer, which proves that the reaction did not include a ketene intermediate.

THE ACYLATION REACTION As described in Tables 1 and 2, we have developed syn- and antiselective VMARs using E,E-vinylketene silyl N,O-acetal 1, which suggests that the stereochemistry of the δ position is affected by the amount of TiCl4, while the γ position remains unaffected under the applied reaction conditions. These results led us to the conclusion that the acylation reaction of 1 should proceed in high stereoselectivity. After examining various acylating reagents and Lewis acids, we found that acid anhydrides in the presence of SnCl4 afforded the best results for the formation of adduct 47 in high yield as a single isomer (Scheme 16).19 Subsequently, various acid anhydrides were subjected to the optimized conditions (Table 4). Saturated acid anhydrides, except sterically hindered pivalic anhydride, afforded the corresponding adducts in good yields. Unsaturated acid anhydrides provided the adduct in moderate yield, while benzoic anhydride or cyclic glutaric anhydride (f) did not react with 1, which suggests that the chelation of SnCl4 by the acid anhydride is necessary for the reaction to proceed. Mixed anhydrides,

Formal Synthesis of Khafrefungin

On the basis of the acylation reaction presented in the previous section, we planned a concise synthesis of the polypropionate khafrefungin (Scheme 18), a potent antifungal agent.20 The total synthesis of khafrefungin has been achieved by Kobayashi in 2001 and by our group in 2007.21,22 Our synthesis started from methyl (R)-β-hydroxyisobutyrate, and 14 steps were required to obtain polypropionate segment 50 (Scheme 18).24 However, we have recently established an alternative route to carboxylic acid 50, using RAI reactions and the WRS strategy. We anticipated that carboxylic acid 50 could be constructed by coupling aldehyde 52 and ketone ent-47b, both of which could be derived from E,E-vinylketene silyl N,O-acetals (Scheme 18). H


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Accounts of Chemical Research Table 4. Acylation Reactions of 1 with Various Acid Anhydrides

Scheme 19. Synthesis of Aldehyde 52

Scheme 20. Formal Synthesis of Khafrefungin Using RAI and WRS Strategies

Scheme 17. Acylation of 1 with Chiral Acid Anhydride 48

Scheme 18. Retrosynthetic Analysis of Khafrefungin

position did not occur via this synthetic route. The synthesis is straightforward, that is, the longest linear sequence to polypropionate 50 requires seven steps from commercially available aldehyde 53. The present acylation method should thus become a powerful tool for concise synthetic routes to polypropionates.

We started the synthesis from the selective cross aldol condensation between decanal 53 and propanal 54 (Scheme 19). The resulting unsaturated aldehyde, 55, was then subjected to the VMAR, followed by TBS protection to give anti adduct 56 as a single isomer. Subsequently, 56 was hydrogenated using Adam’s catalyst to give 12S isomer 57 as the major isomer (dr = 6:1, isolated yield of 57 60%),11 which was submitted to DIBALH reduction to generate aldehyde 52. On the other hand, ent-47b was prepared by a RAI-type acylation using ent-1 (Scheme 20). The adduct ent-47b was coupled with aldehyde 52 by an aldol condensation using SnCl4 and triethylamine to directly yield α,β,γ,δ-unsaturated ketone 58. The hydrolysis of 58 afforded carboxylic acid 50, that is, the polyketide segment of khafrefungin. Epimerization at the C4

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ALKYLATION REACTIONS Fully reduced polypropionates that do not contain any oxygen in the side chain are frequently encountered in natural products.23 The alkylation of E,E-vinylketene silyl N,O-acetal 1 would provide a straightforward method to construct fully reduced polypropionates, while VMARs furnish adducts that require an additional deoxygenation sequence. In order to establish RAItype alkylations, we examined the reaction between 1 and a variety of alkyl iodides. Although n-Pr-I did not afford any adduct, activated iodides reacted with 1 in the presence of silver(I) trifluoroacetate (AgTFA) and BF3·OEt224 to provide γ-alkylated I


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Accounts of Chemical Research compounds 59 (Table 5).25 Allylic, benzyl, and propargyl iodides furnished the adducts in good yield and high stereoselectivity. Table 5. Reactions between 1 and Alkyl Iodides in the Presence of AgTFA and BF3·OEt2

Figure 4. Chemical structure of PDIM.

Scheme 22. Retrosynthetic Analysis of Mycocerosic Acid

a

We started the synthesis from the RAI reaction of 1 and dibenzyl acetal 65 (Scheme 23).25 After imide 66 was converted to the unstable allyl iodide 64, this was immediately submitted to the alkylation reaction. The reaction between 64 and 1 in the presence of AgOTf furnished 63 in good yield and excellent stereoselectivity. The subsequent Birch reduction promoted both the reduction of the α,β-unsaturated imide and the removal of the benzyl group. In this reaction, 2-methylbenzimidazole 67 can serve as a bulky proton source to construct the C2 position of 68 in excellent stereoselectivity. Other previously reported bulky proton sources such as 2,6-di-t-butylphenol27,27a and 2pyridone27b furnished 68 in low to moderate stereoselectivity due to their high acidity. The stereoselective reduction of the internal olefin of 68 was accomplished by a hydroxy group directed hydrogenation using a Schrock−Osborn catalyst to produce all-syn 69 in high yield and excellent stereoselectivity. Oxidation of the primary alcohol was followed by a Kocienski olefination to produce olefin 71, which underwent hydrogenation to afford saturated imide 72. Hydrolysis of 72 provided a product whose spectral data were identical to those of previously reported mycocerosic acid.28 Therefore, mycocerosic acid has been synthesized in ten steps from 1, which demonstrates the synthetic utility of this method, which includes a RAI-type alkylation and a Birch reduction via protonation using 2-methylbenzimidazole for the synthesis of reduced polypropionates.

Bnl (1.5 equiv) and AgTFA (1.2 equiv)were employed.

In order to investigate the reaction mechanism, Z-allyl iodide 60 was used as an electrophile in the alkylation (Scheme 21). The Scheme 21. Alkylation of 1 with Z-Allyl Iodide 60

reaction proceeded at −90 °C and provided a 1.2:1 mixture of Zisomer 61 and E-isomer 62. Additionally, ethyl iodoacetate did not afford the corresponding adduct (not shown in Scheme 21). These results suggest that the reaction involves cation intermediates.

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BROMINATION REACTIONS In the previous sections, RAI-type C−C bond-forming reactions have been discussed. Here, we turn our attention to the induction of heteroatoms at the γ-position of vinylketene silyl N,O-acetal 1. After examining various conditions, we found that treatment of 1 with Br2 and BCl3 provided bromide 73 as a single isomer in high yield (Scheme 24),29 whereby the order of addition of the reagents was of pivotal importance. The addition of Br2 to a mixture of 1 and BCl3 provided 73 in excellent selectivity, while

Total Synthesis of Mycocerosic Acid

This alkylation reaction was then applied to the synthesis of mycocerosic acid, which is a component of phthiocerol dimycocerosate (PDIM), a virulent factor of Mycobacterium tuberculosis (Figure 4).26 As shown in Scheme 22, we hypothesized that the target molecule could be obtained from the regio- and stereoselective reductions of two olefins of imide 63, which could be synthesized by the stereoselective alkylation between allyl iodide 64 and vinylketene silyl N,O-acetal 1. J


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Accounts of Chemical Research Scheme 23. Synthesis of Mycocerosic Acid Based on a RAItype Alkylation and Stereoselective Reductions

Figure 5. Proposed transition states for general nucleophilic reactions (eq 12) and the RAI-type bromination reaction (eq 13).

the chiral auxiliary, which would interfere with the approach of the electrophile from the lower face of the diene (Figure 5; eq 13). Consequently, Br2 should approach from the upper face of the diene (TS-3), which would provide 73 with a 4R configuration. With allylic bromide 73 in hand, we examined derivatization reactions to introduce heteroatoms (Scheme 25). Nucleophiles including azides, acetates, and thioacetates substituted the bromide smoothly in the presence of crown ether to afford 75, 76, and 77, respectively. In the absence of crown ether, each reaction showed partial epimerization to give a diastereoisomer

Scheme 24. Remote Asymmetric Bromination of 1 Using BCl3 and Br2

Scheme 25. Substitution Reactions of 73 To Introduce Heteroatoms at the γ-Position

the addition of 1 into a mixture of Br2 and BCl3 afforded 73 only in moderate selectivity (90%, dr = 3.9:1). Product 73 exhibits the opposite stereochemistry at the C4 position relative to the products of previously presented reactions, which indicates that the bromination proceeds in a stereoselective manner different from previously presented reactions. Figure 5 shows the reaction mechanisms of the general nucleophilic reactions and the bromination reaction. In previously presented reactions, the electrophile approaches from the lower face of the diene (TS-2) to avoid any steric repulsion with the isopropyl group (eq 12). On the other hand, bromination reactions afforded 73 as the predominant isomer, which indicates that the reactions proceeded from the upper face of the diene, as BCl3 should coordinate to the carbonyl oxygen of K


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Accounts of Chemical Research mixture of substituted products, which indicates that the generated bromide may react with allylic bromide 73 to afford the epimerized bromide.

Scheme 27. Synthesis of Lactone Segment 79

Total Synthesis of Pellasoren A

After having established a stereoselective synthesis of γheteroatom-substituted α,β-unsaturated imides, we planned its application in a short synthesis of an antitumor agent, pellasoren A (Scheme 26).30 Pellasoren A has been synthesized by Kalesse Scheme 26. Retrosynthetic Analysis of Pellasoren A Using RAI Reactions

Scheme 28. Synthesis of Tetraene Segment 78 and Total Synthesis of Pellasoren A

et al. and its absolute structure has been determined.30 The structure and bioactivity of pellasoren A prompted us to establish a concise synthetic route using the method presented in the previous section. Our synthetic route to pellasoren A is shown in Scheme 26. The target molecule was divided to two segments, amide segment 78 and lactone segment 79. The former should be obtained from the coupling of carboxylic acid 8030 and amine 81, which might be derived from azide 75. Lactone segment 79 could be prepared via our reduced polypropionate synthesis using the VMAR of 1. The synthesis of lactone segment 79 is shown in Scheme 27.29 The VMAR of 1 with aldehyde 8231 provided adduct 83 in high stereoselectivity. Subsequent treatment of 83 with sodium in liquid ammonia promoted a Birch reduction, and the resulting enolate was protonated in a stereoselective manner using 6725 as a bulky proton source. The crude product afforded lactone segment 79 under acidic conditions. The synthesis of amide segment 78 and the total synthesis of pellasoren A are shown in Scheme 28. Treatment of azide 75, prepared via the previously presented remote asymmetric halogenation, with triphenylphosphine in the presence of water furnished the corresponding amine, which was immediately acylated in situ with 80 to yield amide 84. Reduction of the imide moiety of 84 with DIBAL afforded aldehyde 85 in high yield. Aldehyde 85 was subjected to a subsequent allylation and Peterson olefination by treatment with an allylborane that was prepared from allene 86 and 9-BBN.32 The reaction proceeded smoothly and stereoselectively to directly afford amide segment 78. Finally, an olefin metathesis between 78 and 79 generated pellasoren A as a single isomer. Thus, the total synthesis of pellasoren A was achieved in six steps of the longest linear sequence from vinylketene silyl N,O-acetal 1.

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CONCLUSION AND OUTLOOK Remote asymmetric induction (RAI) reactions for E,E-vinylketene silyl N,O-acetal 1 including syn- and anti-selective vinylogous Mukaiyama aldol reactions (VMARs), acylations, alkylations, and the introduction of heteroatoms have been developed and used for the synthesis of polypropionates. These reactions should become powerful tools for the efficient construction of polyketide skeleton via the simultaneous introduction of stereogenic centers and functionalized carbon chains. On the other hand, the wide range stereocontrol (WRS) strategy, which is based on the initial construction of the central part of the carbon chain, followed by a functionalization of the olefin moiety, contributes to the increased diversity of the L


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products accessible. As discussed in this Account, the combination of the RAI reactions and the WRS strategy have led to concise syntheses of a variety of polypropionates. In the future, the construction of polyketide libraries should thus become significantly less laborious, which could help to promote the discovery of new bioactive compounds and might induce a paradigm shift in drug discovery.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Seijiro Hosokawa: 0000-0002-8036-532X Notes

The author declares no competing financial interest. Biography Seijiro Hosokawa received his B.S. and M.S. degrees from Hokkaido University under the supervision of Professor Haruhisa Shirahama. In 1996, he completed his Ph.D. at Nagoya University under the supervision of Professor Minoru Isobe. After one year of postdoctoral research at Nagoya University (Professor Minoru Isobe) and another year at the Scripps Research Institute (Professor K. C. Nicolaou), he was appointed Assistant Professor in the group of Professor Susumu Kobayashi at Tokyo University of Science. In 2003, he joined the group of Professor Kuniaki Tatsuta at Waseda University, where he was promoted to Associate Professor in 2007. Since 2011, he has been presiding over his own laboratory, where he focuses on the development of new synthetic methods and their application to natural product synthesis.

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ACKNOWLEDGMENTS The author is grateful for financial support from The NOVARTIS Foundation (Japan) for the Promotion of Science, The Kurata Memorial Hitachi Science and Technology Foundation, The Naito Foundation, The Sumitomo Foundation, and MEXT (Japan).

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REFERENCES

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Remote Asymmetric Induction Reactions using a E,E-Vinylketene Silyl

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