Imide Natural Products

CHAPTER 7

Imide Natural Products Justin M. Lopchuk1,2 1

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States 2 Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

7.1 INTRODUCTION The imide functionality is ubiquitous in nature and found in many structurally diverse natural products. The imides themselves are most often cyclic and the natural products containing them tend to be bioactive. Some imides, such as glutarimide, appear so frequently in highly potent, naturally occurring antibiotics, that they have come to be considered privileged scaffolds. The imide natural products covered in this chapter are grouped by a combination of the overall structural similarity of both the molecule and the type of imide itself; the groups include bisindoles, glutarimides, maleimides, polyketides, succinimides, and tetramic acids. Each individual natural product is further broken down by isolation, biological activity, and synthesis, where applicable. This chapter is not intended to provide comprehensive and exhaustive coverage of all known imidecontaining natural products. Rather, it will cover selected, representative natural products in a range of structural classes with initial isolation dates from the early 20th century up to 2018.

7.2 BISINDOLES 7.2.1 Arcyriacyanin A Isolation and Biological Activity: Arcyriacyanin A (1) is a green
blue pigment isolated from the sporangia of the slime mold Arcyria obvelata (formerly Arcyria nutans, Myxomycetes).1 The specific details of the isolation efforts appear to remain unpublished and are only mentioned in several reviews.2 Arcyriacyanin A (1) is representative member of many structurally similar bisindoylmaleimide alkaloids, including arcyriarubin A (2, a possible biogenic precursor), the isomeric arcyriaflavin A (3), and arcyroxepin A (4).3 Limited studies of the biological activity of arcyriacyanin A Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00007-2

© 2019 Elsevier Inc. All rights reserved.

255

256

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Figure 7.1

(1) showed weak inhibitory activity against a panel of 39 human cancer cell lines in addition to selective inhibition of protein kinase C and protein tyrosine kinase over protein kinase A or calmodulin-dependant protein kinase C (over 1
100 μg/mL) (Fig. 7.1).1,2 Synthesis: Despite modest biological activity, arcyriacyanin A (1) has been a popular target for total synthesis due in large part to the unsymmetrical C
C bond between the two indole heterocycles that differentiates it from compounds such as arcyriaflavin A (3), or arcyroxepin A (4). Steglich and coworkers reported the first total synthesis of arcyriacyanin A (1) by three discrete routes. Indole 5 was treated sequentially with lithium diisopropylamide (LDA) and Me3SnCl to afford stannane 6 in 76% yield. Bisindole 9 was constructed via the palladium-catalyzed crosscoupling of stannane 6 with bromoindole 7 followed by basic hydrolysis (57% over two steps). The addition of two equivalents of EtMgBr to bisindole 9 followed by heating with 3,4-dibromomaleimide (10) furnished arcyriacyanin A (1) in 41% yield (Scheme 7.1).4

Scheme 7.1

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The second approach began with the diazotation of aniline 11 followed by protection of the resulting phenol to give arene 12 (65% over two steps). The addition of dimethylformamide dimethyl acetal and catalytic amounts of pyrrolidine generated an intermediate enamine, which, upon hydrogenation, gave indole 13 in 60% yield. Indole 13 was sequentially treated with EtMgBr and bromomaleimide 14 to deliver bisindole 15. The penultimate triflate 17 was prepared in 76% yield by a two-step sequence comprised of acid-catalyzed hydrolysis and treatment with Nphenyltriflimide. An intramolecular palladium-catalyzed crosscoupling gave N-methyl arcyriacyanin A (18) in 81% yield (Scheme 7.2).4 Conversion of N-methyl arcyriacyanin A (18) to arcyriacyanin A (1) could be achieved by hydrolysis to the corresponding maleic anhydride followed by treatment with hexamethyldisilazane (HMDS).5

Scheme 7.2

Steglich and coworker’s third approach allowed for the formation of the final two C
C bonds in a single step via a domino Heck reaction. Treatment of bromomaleimide 14 with bromoindole 19 and a palladium catalyst afforded N-methyl arcyriacyanin A (18) in varying yields from 10% to 30% (Scheme 7.3).4

Scheme 7.3

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A conceptually related approach to that shown in Scheme 7.1 was reported by Tobinaga and coworkers.6 4-Aminoindole 20 was diazotized with NaNO2 and treated with potassium iodide (KI) to afford iodoindole 21 in 84% yield. A protecting group swap was accomplished by cleavage of the tosyl group with NaOH and reprotection of the nitrogen with tertbutyldimethylsilyl chloride (TBSCl) (21 - 23, Scheme 7.4).

Scheme 7.4

In order to prepare the bisindole coupling partner, indole 24 was treated with n-BuLi and triethylborane to furnish an intermediate indolyl borate (not shown); the borate was allowed to react with iodoindole 25 in the presence of a palladium catalyst to afford protected bisindole 26 in 51% yield. A two-step deprotection with tetrabutylammonium fluoride (TBAF) followed by hydrogenolysis gave bisindole 9 in 83% yield (Scheme 7.5). The tert-butyldimethylsilyl (TBS) group on iodoindole 26 allowed for a superior yield during the crosscoupling when compared to indole 21 or 22 (46% and 38% yield, respectively).

Scheme 7.5

The synthesis of arcyriacyanin A (1) was completed by the double deprotonation of bisindole 9 with 2 equiv. of MeMgI, followed by the addition of 3,4-dibromomaleimide 27 to furnish the desired product in 46% yield (Scheme 7.6). A significant solvent/temperature effect was observed for this reaction; the use of refluxing benzene instead of refluxing toluene gave the desired product 1 in only 16% yield.6

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Scheme 7.6

Steglich and coworkers recently reported another synthesis of arcyriacyanin A (1) that relies on an unusual rearrangement to form the sevenmembered ring system. Exposure of ester 28 to hot dimethyl sulfoxide (DMSO) triggered a decarboxylation to afford nitroarene 29 in 34% yield (when the reaction was run without 2,6-di-tert-butyl-4-methylphenol (BHT) yields were c. 20%). The anion of arene 29 was treated with bromomaleimide 14 to afford cyclized product 30 in 48% yield. Sequential reduction of the nitro group (via hydrogenation) and the cyano group (via diisobutylaluminum hydride (DIBAL-H)) formed the final indole ring (32, 12% yield). Pyrolysis of the Boc group gave N-methyl arcyriacyanin A (18) in 80% yield (Scheme 7.7).7 Kraus and Guo reported a formal synthesis based upon a one-pot reaction of 2-substituted indoles from 2-aminobenzyl phosphonium salts. Treatment of phosphonium salt 33 with aldehyde 34 and acetic acid

Scheme 7.7

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Scheme 7.8

under microwave conditions formed an intermediate imine; deprotonation with t-BuOK facilitated the cyclization to afford bisindole 9 in 87% yield (Scheme 7.8).8 7.2.1.1 Cladoniamides Isolation and Biological Activity: All seven members of the cladoniamides (A
G, 35
41) were isolated in 2008 by Andersen and coworkers from cultures of Streptomyces uncialis, which was found on the surface of the lichen Cladonia uncialis near the Pitt River, British Columbia.9 Initial in vitro testing showed cladoniamide G (41) was cytotoxic to human breast cancer cells (MCF-7) at 10 μg/mL.9 Cladoniamide A (35) and B (36) were later shown to be potent inhibitors of colon cancer cell line HCT-116 (IC50 of 8.8 and 10 ng/mL, respectively).10,11 A closely related natural product, BE-54017 (42), was isolated in 2000 from Streptomyces sp. A54017 and reported to have an IC50 of 0.11 μg/mL for P388 cells.12 The biosynthetic gene clusters that encode for compounds 35
42, containing a rare indolotryptoline core, have been extensively studied independently by both Brady and coworkers10 and Ryan (Fig. 7.2).13 Synthesis: Shibasaki and coworkers completed the first total synthesis of BE-54017 (42) and confirmed the absolute configuration of the alkaloid via a seven-step route starting from 5-chloroindole (43). Indole 44 was formed by stannylation of indole 43 after protection of the
NH with carbon dioxide (which also served to stabilize the subsequent α-carbanion). A carefully optimized palladium-catalyzed coupling of stannane 44 with methoxyacetyl chloride (45) furnished indole 46 in 74% yield. Treatment of indole 46 with phenylhydrazine in AcOH effected a Fisher indolization that afforded bisindole 47; since bisindole 47 proved to be unstable, it was immediately allowed to react with N-methylmaleimide (48) to give the Michael addition product 49 in 31% yield (over two steps). Indole 49 was heated to 200°C in the presence of a stoichiometric amount of palladium black to give indolocarbazole 50 in 48% yield. NMethylation of indole 50 with methyl iodide occurred in 70% yield set

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Figure 7.2

up the key dihydroxylation step. In the event, indole 51 was treated with 1.1 equiv. of OsO4 followed by a reductive workup to furnish racemic BE-54017 (42) in 37% yield. An HPLC resolution gave the pure enantiomers (Scheme 7.9).14

Scheme 7.9

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To confirm the absolute stereochemistry of BE-54017 (42), the natural product was prepared independently through cladoniamide A (35), whose absolute configuration was previously reported. Indolocarbazole 50 was dihydroxylated under the same conditions used earlier to complete the first total synthesis of cladoniamide A (35). After resolution of the enantiomers by HPLC, methylation gave (2)-BE-54017 (42), which was demonstrated to match the optical rotation of the natural product (Scheme 7.10).14

Scheme 7.10

7.3 GLUTARIMIDES 7.3.1 Cycloheximide Cycloheximide (52, also known as naramycin A or actidione) was first isolated in 1946 from Streptomyces griseus.15 It remains as one of the most famous glutarimide natural products and displays a wide variety of biological activities, including broad antibiotic, antifungal, antitumor, and amebicidal activities, as well as serving as an extremely potent rodent repellent.16 Most of the activity of cycloheximide (52) is derived from its ability to act as a protein synthesis inhibitor in eukaryotes and it is often used in experimental research studies for this purpose. Inactone (53), a closely related derivative of cycloheximide (52) was also isolated from cultures of S. griseus (Fig. 7.3).17 Actiphenol (54, also known as C-73) was first isolated concurrently from cultures of actinomycetes strain ETH 7796 and Streptomyces albulus.18 Compared to cycloheximide (52), actiphenol (54) displays minimal biological activity. Shen and colleagues have demonstrated that 52 and 54 are produced from Streptomyces sp. YIM65141 via a single biosynthetic machinery wherein actiphenol (54) may serve as the intermediate to the biosynthesis of cycloheximide (52).19 Actiketal (55) was first isolated from Streptomyces

Figure 7.3

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pulveraceus (subsp. epiderstagenes) and, though less active than cycloheximide (52), inhibits EGF-induced DNA formation in murine epithelial cells, the Con A-induced blast formation in spleen cells, and the incorporation of [3H]thymidine into EGF-stimulated Balb/MK cells (Fig. 7.3).20 Synthesis: Johnson and coworker’s synthesis of cycloheximide (52) began with cis-2,4-dimethylcyclohexanone (56), which was prepared from 2,4dimethylphenol by reduction with 10% Pd/C and hydrogen (not shown). Treatment of cyclohexanone 56 with morpholine and Dowex-50W resin in refluxing toluene for two days resulted in enamine 57 where the C2 position was epimerized to yield the trans compound. Acylation of enamine 57 with glutarimide 58 under rigorously dried conditions afforded 59, which was directly hydrolyzed to give 60 (30% yield from acid chloride 58). Reduction with PtO2 and hydrogen produced diol 61; this compound was converted to the corresponding chloroacetate 63, a strategy that resulted from a great deal of experimentation. Oxidation of the secondary alcohol furnished 64 and hydrolysis of the chloroacetate group afforded racemic cycloheximide (52). The same sequence was also used to generate the enantiopure natural product beginning with optically pure 56 (Scheme 7.11).16 The synthesis of several unnatural stereoisomers of cycloheximide (52) has also been reported.21

Scheme 7.11

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Johnson prepared actiphenol (54) in six steps beginning with commercially available dimethyl acetonedicarboxylate (65). Condensation of cyanoacetic acid (66) with 65 gave diester 67 in 54% yield. Hydrogenation of the product gave dimethyl 3-cyanomethylglutarate (68, 89% yield). Hydrolysis of glutarate 68 followed by heating furnished 3carbomethylglutarimide, which was treated with thionyl chloride to afford glutarimide 58. Acylation of 2,4-dimethylphenol (69) with 58 occurred upon heating in a solution of pyridine to afford ester 70. The final Fries rearrangement was induced by treatment with finely powdered AlCl3 and heating to 155°C to give actiphenol (54, Scheme 7.12).22

Scheme 7.12

Kiyota and coworker’s synthesis of actiketal (55) began with the palladium-catalyzed coupling of 5,7-dimethylbenzofuran (71) and dimethyl glutaconate (72), which furnished benzofuran 73 in 57% yield. The enone was selectively hydrogenated to give diester 74 in 98% yield. The glutarimide moiety was formed over a four-step sequence (62% yield) that included hydrolysis to the diacid, cyclization to the glutaric anhydride, ammonolysis to the corresponding acid amide, and finally cyclization to glutarimide 75. Oxidation of the C2
C3 double bond of benzofuran 75 delivered actiketal (55) in 33% yield (Scheme 7.13).23

7.3.2 Julocrotine, Cordiarimides, and Crotonimides Isolation and Biological Activity: Although first isolated in 1925 from Julocroton montevidensis,24 julocrotine (76) has been frequently found in many species of Croton plants, including Croton membranaceus, C. cascarilloides, C. cuneatus, and C. pullei var. glabrior Lanj.25 While the structure of

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Scheme 7.13

julocrotine (76) was first proposed on the basis of degradation studies in 1959,26 it was not confirmed until 2008 by X-ray crystallography.27 Despite being a component of trees used by native Venezuelan populations to treat gastrointestinal diseases as well as an antiinflammatory agent,28 no biological activity was known for julocrotine (76) until 2010 when it was reported to act as a potent antiproliferative agent against the promastigote and amastigote forms of Leishmania amazonensis (L.), a protozoan parasite that causes cutaneous leishmaniasis (Fig. 7.4).29 Cordiarimides A (77) and B (78) were recently isolated from the roots of Cordia globifera, collected in Nakhon Sawan Province, Thailand and represent the first instance of the isolation of glutarimide alkaloids from plants in the genus Cordia.30 Initial biological testing showed that cordiarimides A (77) and B (78) were weakly cytotoxic against the MOLT-3 cell line (145.3 and 44.5 μM, respectively) and inhibited superoxide anion radical formation in the xanthine/xanthine oxidase assay (IC50 5 54.1 and 21.7 μM, respectively). Neither compound was active against HepG2, A549, or HuCCA-1 cell lines (Fig. 7.5).30 Crotonimides A (79) and B (80) were isolated from the stems and stem bark of C. pullei var. glabrior Lanj., which was collected in the city of

Figure 7.4

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Figure 7.5

Figure 7.6

Peixe-Boi, state of Pará, Brazil (Fig. 7.6).25a Crotonimide C (81) was isolated from the roots of C. alienus, collected from the Ngong Forest in Nairobi, Kenya. No biological activity has yet been reported for the crotonimides (Fig. 7.6).31 Synthesis: The first total synthesis of julocrotine (76) was reported by Silva and Joussef via a high-yielding route (41% overall) starting from Lglutamic acid (82). Protection of the nitrogen on 82 was followed by cyclization to afford oxazolidinone 84 (94% yield over two steps). Treatment with 2-phenethylamine led to ring-opening of the oxazolidinone and the resulting product was converted to the methyl ester 85. Glutarimide formation was achieved by exposing ester 85 to pTsOH in refluxing toluene (86, 64% yield). Removal of the Cbz group via hydrogenolysis followed by coupling with (S)-2-methylbutanoic acid furnished julocrotine (76) in 75%
89% yield over two steps (Scheme 7.14).32

Scheme 7.14

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Wessjohann and coworkers reported a formal synthesis of julocrotine (76) that began with L-Cbz-glutamine (87); N,N0 -dicyclohexylcarbodiimide (DCC) coupling of 87 with N-hydroxysuccinimide (88) allowed for the cyclization to occur and afforded glutarimide 89 in 76% yield. Alkylation could be achieved with base and the appropriate alkyl bromide, but this resulted in racemization of the product (Method A, Scheme 7.15). Instead, a Mitsunobu reaction with 2-phenylethanol gave optically pure intermediate (86) in 90% yield (Method B, Scheme 7.15), which constitutes a formal synthesis of julocrotine (76). Several analogs were made from 86 via a fourcomponent Ugi reaction.33

Scheme 7.15

A closely related synthesis was concurrently reported by Huang and coworkers where L-Boc-glutamine (90) was cyclized via an N-(3dimethylaminopropyl)-N0 -ethylcarbodiimide (EDC) coupling to afford glutarimide 91 in 70% yield (Scheme 7.16). As discussed earlier, alkylation via an alkyl bromide or Mitsunobu conditions led to intermediate 92, which intercepts the previous routes to julocrotine (76).34

Scheme 7.16

Cordiarimides A (77) and B (78) were prepared by the same intermediate (91) used for the julocrotine (76) synthesis. Glutarimide 91 was alkylated with 2-bromoacetophenone (93) to give ketone 94 in 87% yield. Cleavage of the protecting group with trifluoroacetic acid (TFA) was followed by acetylation to afford cordiarimide A (77) in 83% yield over two steps. A high pressure catalytic asymmetric hydrogenation (dr 5 6:1) was realized with (S,S)-Me-DuPhos (95) and a palladium catalyst to provide cordiarimide B (78) in 95% yield (Scheme 7.17).34 Hydrogenation without phosphine 95 resulted in a 1:1 mixture of diastereomers.

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Scheme 7.17

Crotonimide A (79) and B (80) were readily synthesized from previously prepared glutarimide intermediate 92 (Scheme 7.16) via protecting group cleavage and coupling with either propionic anhydride [crotonimide A (79), 80% yield] or isobutyric anhydride [crotonimide B (80), 77% yield] (Scheme 7.18).34

Scheme 7.18

Alternatively, crotonimide A (79) was prepared from ketone 94; cleavage of the protecting group with TFA followed by coupling with propionic anhydride gave intermediate 96 in 75% yield. Complete reduction of the benzylic ketone via hydrogenation delivered crotonimide A (79) in 95% yield (Scheme 7.19).34

Scheme 7.19

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Figure 7.7

7.3.3 Lamprolobine Isolation and Biological Activity: Lamprolobine (97) was first isolated in 1968 from the leaves of Lamprolobium fruticosum Benth. (family Leguminosae), a bushy shrub commonly found in sandstone soils in northern Queensland, Australia.35 It comprised the bulk of the alkaloid material (c. 90%) found in the plant and represents an uncommon member of the quinolizidine alkaloids. Subsequently, lamprolobine (97) has been isolated from a variety of other leguminous plants, including Lupinus holosericeus, Sophora chrysophylla, S. velutina, Thermopsis villosa, and also from the root parasite Castilleja hispida.36 Epilamprolobine (98) was isolated from the fresh leaves of S. tomentosa, grown and collected in Japan.37 No significant biological activity has been reported for these compounds (Fig. 7.7). Synthesis: The first total synthesis of lamprolobine (97) was reported in 1970 by Goldberg and Lipkin.38 Diethyl ethoxymethylidenemalonate (100) was condensed with pyridine 99 to afford quinolizone 101 in 72% yield. Treatment with refluxing HCl caused hydrolysis followed by didecarboxylation to give 4-quinolizone (102). Reduction with PtO2 under hydrogen furnished 4-quinolizidone (103, 54% over two steps); further reduction with LiAlH4 gave quinolizidine (104) in quantitative yield (Scheme 7.20).38

Scheme 7.20

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Quinolizidine (104) was dehydrated with mercuric acetate in 52% yield. Treatment of 1,10-dehydroquinolizidine (105) with ethyl chloroformate and reduction with NaBH4 delivered intermediate 107 in 57% yield over two steps. Epimerization with base and reduction of the ester with LiAlH4 gave epilupinine (109, 76% over two steps). Conversion of the primary alcohol to the corresponding bromide 110 occurred in 75% yield upon treatment with PBr3. Displacement of the bromide with Npotassioglutarimide (111) afforded racemic lamprolobine (97) in 52% yield (Scheme 7.21).38

Scheme 7.21

Shortly following the first synthesis of lamprolobine (97), Wenkert and Jeffcoat published a route that began with the alkylation of nicotinonitrile (112) with 4-bromo-2-butanone ethylene ketal (113). Hydrogenation of the alkylated intermediate 114 followed by acidcatalyzed cyclization gave a separable mixture of diastereometic ketals 115 and 116. The nitrile groups were reduced to the corresponding amines with LiAlH4; Wolff
Kishner reduction subsequently removed the ketones (after hydrolysis of the ketals). Amines 117 and 118 were then treated with glutaric anhydride to furnish lamprolobine (97) and epilamprolobine (98) (Scheme 7.21).39 In the same year as the previous two syntheses (1970), Yamada, Hatano, and Matsui disclosed a route that begins with δ-valerolactam (120) and constitutes a formal synthesis of both lamprolobine (97) and epilamprolobine (98). Upon treatment with triethyloxonium fluoroborate, δ-valerolactam (120) was converted to iminoether 121 in 69% yield; this intermediate was then condensed with benzyl cyanoacetate (122) to afford

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piperidine derivative 123 (90% yield). The benzyl-protecting group was cleaved by hydrogenolysis and the addition of acid effected the desired decarboxylation to give 2-cyanomethylenepiperidine 125 as a mixture of isomers (97% over two steps). Cyclization with methyl acrylate furnished the quinolizidine system 126 in 77% yield (Scheme 7.22).40

Scheme 7.22

The reduction of quinolizidine 126 with NaBH4 in the presence of BF3  OEt2 gave nitriles 127 and 128 as a mixture of diastereomers. Trans isomer 128 was the major product, as well as the undesired isomer, and could be epimerized to cis isomer 127 in c. 80% yield. Reduction of the nitriles with LiAlH4 gave amines 118 and 117 and completed the formal synthesis of lamprolobine (97) and epilamprolobine (98) (Scheme 7.23).40

Scheme 7.23

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The most recent synthesis of lamprolobine (97) and epilamprolobine (98) was achieved by Michael and Jungman in 1992. Upon treatment with base, thiolactam 129 underwent conjugate addition to ethyl acrylate (130) to afford ester 131 in 99% yield. After the addition of bromoacetonitrile to ester 131, exposure to triphenylphosphine and triethylamine gave vinylogous cyanamide 132 in 85% yield. A sequence of reduction of the ester, tosylation of the resulting alcohol, and displacement of the tosylate formed the quinolizidine core 135 (Scheme 7.24, 52% yield over three steps).41

Scheme 7.24

Reduction of quinolizidine 135 with PtO2 and hydrogen gave the expected cis-reduced quinolizidine 128 in good yield. The use of NaBH3CN instead gave the desired trans-reduced quinolizidine 127 as the major product, albeit with a significant amount of the other isomer 128. Compared to LiAlH4, the use of a nickel
aluminum alloy and NaOH for the nitrile reduction gave cleaner reactions and higher yields of amines 117 and 118 and completed the formal synthesis (Scheme 7.25).41

Scheme 7.25

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Enantiopure (1)-epilamprolobine (98) was prepared from (2)-lupinine (136) via a short, four-step sequence. The primary alcohol was tosylated and displaced by ammonia at high temperature to afford amine 117. Reaction of amine 117 with glutaric anhydride gave (1)-epilamprolobine (98), the antipode of the natural product (Scheme 7.26).37

Scheme 7.26

7.3.4 Sesbanimides Isolation and Biological Activity: Sesbanimides A
C (138
140) were first isolated from the seeds of Sesbania drummondi, a legume native to the Gulf Coast Plains, US.42 Investigation of these seeds, which were known to be toxic to livestock, was prompted by the discovery that their extracts had shown significant antileukemic properties. Sesbanimide A (138) was later isolated from the seeds of Sesbania vesicaria43 and S. punicea.44 The origin of the sesbanimides is likely microbial in nature; sesbanimide A (138) was most recently isolated from marine Agrobacterium strain PH-103, while sesbanimide C (140) was produced from marine Agrobacterium strain PH-A034C.45 Sesbanimide A (138), in particular, has been reported to have potent antitumor properties and immunosuppressive activity. Against KB cells, 138 displayed an in vitro ED50 of 7.7 3 1023 μg/mL and gave in vivo T/C values of 140
181 in the 0.008
0.032 mg/kg range against PS lukemia.42a Sesbanimides B (139) and C (140) displayed similar activity, but required c. 10 times higher dosage levels (Fig. 7.8).42a

Figure 7.8

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Synthesis: Given the potent biological activity of the sesbanimides, a significant amount of effort has been devoted to their synthesis. Schlessinger and Wood reported the first total synthesis of (2)-sesbanimide A (138), the antipode of the natural material.46 Their route began with aldehyde 141, a known compound that is readily prepared from D(2)-sorbitol. Aldehyde 141 was allowed to react with the sodium salt of phosphonate 142 to give α,β-unsaturated ester 143 in 87% yield. Malonate 144 was added to ester 143, which gave a 77% yield of diester 145. Glutarimide formation was achieved with NH4OH followed by heating up to 210°C (146, 68% yield over two steps). Selective hydrolysis of the primary alcohol-containing acetal was enabled by treatment of 146 with trifluoroacetic anhydride (TFAA) in acetic acid followed by a carefully pH-controlled workup; TBS protection of the secondary alcohol and DIBAL-H reduction of the primary acetate gave alcohol 147 in 84% yield over three steps. The alcohol was oxidized to the corresponding aldehyde and allowed to react with crotylstannane 149 in the presence of BF3  OEt2 to give a mixture of alcohol epimers 150 in 51% yield. Oxidation to the ketone and deprotection/cyclization formed the THF (tetrahydrofuran) ring and delivered (2)-sesbanimide A (138) in 63% yield over two steps (Scheme 7.27).46

Scheme 7.27

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Pandit and coworkers prepared both (2)-sesbanimide A (138) and (1)-sesbanimide A (138) from L- and D-xylose derivatives.47 Known aldehyde 141 was converted to α,β-unsaturated ester 152 via a Wittig reaction in 69% yield. The glutarimide ring was installed via basemediated cyclization with amide 153; the intermediate 154 was hydrolyzed with TFA and heating to trigger the decarboxylation to afford 146 in 45% yield over three steps. At this stage, one of the acetals was hydrolyzed and converted to the bis-acetate 155 (89% yield). After cleaving the acetates to reveal the diol, the alcohols were reprotected as a different acetal that could be removed under reductive conditions later in the synthesis (Scheme 7.28).

Scheme 7.28

Partial reductive cleavage of the acetal in intermediate 156 allowed for the primary alcohol to be subsequently oxidized to the corresponding aldehyde (158, 41% over two steps). Aldehyde 158 was allowed to react with allylsilane 159 in the presence of BF3  OEt2 and the resulting epimeric alcohols were oxidized to single ketone in 30% yield over two steps. A 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidation revealed the secondary alcohol and treatment of the intermediate with acid, facilitated the cyclization to afford (2)-sesbanimide A (138). An identical route was used to prepare the natural enantiomer, (1)-sesbanimide A (138) (Scheme 7.29).47 Terashima and coworkers also used L- and D-xylose derivatives as a starting point for their synthesis of both (1)-sesbanimide A (138) and

276

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Scheme 7.29

(2)-sesbanimide B (139).48 Diol 161 was readily prepared in high yield over three steps from D-xylose. The diol 161 was bis-benzylated (NaH, then BnCl) and deprotected with acid to reveal a second diol. A Wittig reaction of the hemiacetal gave ring-opened α,β-unsaturated ester 162 in 61% yield over three steps. Installation of the required acetal was readily achieved with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in dimethoxyethane (163, 79% yield). A Michael addition with the sodium salt of dimethyl malonate followed by demethoxydecarbonylation afforded diester 164 in 89% yield. A four-step sequence installed the glutarimide in 51% yield: Hydrolysis of the diester, activation of the acids with methyl chloroformate, ammonolysis to the corresponding amide acid, and dehydration to close the ring. Hydrogenolysis of the benzylprotecting groups furnished diol 166 in 95% yield (Scheme 7.30).

Scheme 7.30

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In order to protect the secondary alcohol, the primary alcohol was esterified and then reduced followed by TBS protection. Oxidation of the primary alcohol to the corresponding aldehyde was conducted under Collins conditions (167, 57% yield over four steps). A regioselective Reformatsky reaction was used to install the lactone in 73% yield; the lactone was reduced to the diol stepwise (DIBAL-H, then Luche reduction, 73% yield over two steps) and the primary alcohol protected with tertbutyl(chloro)diphenylsilane (TBDPSCl) to give alcohol 170 as a mixture of diastereomers. A final oxidation of the epimeric secondary alcohols and TBAF deprotection allowed the THF ring to cyclize and furnish (1)-sesbanimide A (138) and (2)-sesbanimide B (139) in 16% and 19% yield, respectively (Scheme 7.31).48

Scheme 7.31

A similar route was used by Koga and coworkers to prepare (1)-sesbanimide A (138) in 21 steps from D-glucose.49 Dithioacetal 171, prepared in four steps from D-glucose, was treated with base and dibromomethane to install the methylene acetal. Deprotection of the dithioacetal gave aldehyde 172 in 69% yield over two steps. A Witting reaction installed the α,β-unsaturated ester 173 in 99% yield, while the glutarimide ring was formed by reaction of the olefin with lithiated trimethylsilylacetonitrile, fluoride-promoted removal of the silyl group, hydrolysis of the nitrile to the amide, and cyclization (174, 34% yield over four steps). Treatment of the resulting product with acid gave a quantitative yield of diol 175 (Scheme 7.32). Oxidative cleavage of the diol followed by reduction gave primary alcohol 177 in 89% yield over two steps. A protecting group swap on the

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Scheme 7.32

secondary alcohol was completed in four steps (72% yield) followed by oxidation to the aldehyde to afford 148 in 95% yield constituting a formal synthesis. Coupling of aldehyde 148 with stannane 149 gave diastereomers 150 and 180 in 18% and 17% yield, respectively. As seen previously, oxidation and cyclization gave (1)-sesbanimide A (138) (Scheme 7.33).49

Scheme 7.33

Grieco and coworkers were the first group to complete a total synthesis of sesbanimide A (138) and B (139) that did not rely on sugars as their starting material.50 Lactone 183 was prepared on large scale in two steps by mixing glyoxylic acid (181) and cyclopentadiene (182) in water, followed by protection of the alcohol with chloromethyl methyl ether

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(MOMCl) (29% yield over two steps). A two-stage reduction both reduced the lactone and the olefin to diol 184 in 70% yield. The resulting primary alcohol was protected with TBSCl, followed by pyridinium chlorochromate (PCC) oxidation of the secondary alcohol to a ketone and Baeyer
Villiger oxidation to afford lactone 185 (68% yield over three steps). The enone was installed in two steps: addition of phenylselenyl chloride followed by oxidation to the corresponding sulfone and elimination (186, 70% yield over two steps). The installation of the γ-hydroxyl functionality with the correct stereochemistry required a four-step sequence. After migration of the olefin (187, 83% yield), dimethyldioxirane (DMDO) was used to generate the epoxide, which was then opened with triethylamine in dichloromethane (DCM) to afford 188 in 68% yield over two steps. (Scheme 7.34).

Scheme 7.34

Inversion of the γ-hydroxyl group to furnish alcohol 189 was realized via a Misunobu reaction in 75% yield. The methylene acetal 190 was isolated in 45% yield after a short reaction time with BF3  OEt2. The glutarimide ring was installed in three steps beginning with the conjugate addition of silyl ketene acetal 191 to the α,β-unsaturated lactone 190. The intermediate ester 192 was converted to bis-amide 193 upon exposure to ammonia in methanol; the ring-closing event occurred after heating to 259°C for 50 minutes to afford glutarimide 194 in 28% yield over three steps. After two protecting group manipulations, the attempt to silylate the secondary alcohol 195 resulted in tricyclic silyl ether 196 in near quantitative yield. A two-step redox operation converted the pivaloate to the required aldehyde 197 in 79% yield (Scheme 7.35).50

280

Imides

Scheme 7.35

The Schlessinger protocol (discussed earlier) was used to convert aldehyde 197 into a mixture of alcohols 198 and 199. The remainder of the synthesis follows previous route: Collins oxidation of the secondary alcohols to the corresponding ketones, followed by acidic hydrolysis of the silyl ethers and cyclization to afford racemic sesbanimide A (138) and B (139) (Scheme 7.36).50

Scheme 7.36

Panek and colleagues reported an asymmetric formal synthesis of (1)-sesbanimide A (138) based upon several key transformations, including a diastereoselective catalytic osmylation and chelation-controlled nucleophilic addition of vinyl Grignard reagents to forge three of the stereocenters.51 α,β-Unsaturated aldehyde 200 was treated with a lithiated silane to afford alcohol 201, which was subsequently oxidized to ketone

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202 (27% yield over two steps). Asymmetric reduction of ketone 202 with a chiral borane furnished secondary alcohol 203 in 76% yield and 92% ee. Acetylation followed by a diastereoselective osmium-catalyzed dihydroxylation in the presence of trimethylamine N-oxide (TMNO) afforded diol 205 in 92% yield with 4.0
4.4:1 anti:syn selectivity. Sequential protections of the diol as silyl and methoxymethyl (MOM) ethers gave intermediate 206 in 94% yield over two steps. The acetate was subsequently cleaved with DIBAL-H to reveal the secondary alcohol, which was then oxidized to furnish ketone 207 (86% yield over two steps). A selective hydrogenoloysis was achieved whereby the acyl silane functionality was converted to aldehyde 208 in 84% yield, while leaving the benzyl-protecting group untouched (Scheme 7.37).

Scheme 7.37

The addition of vinylmagnesium bromide to aldehyde 208 was achieved with good yield and diastereoselectivity (86%, 5:1 ratio). The reaction conditions were critical: High dilution and fast addition times for the Grignard reagent were found to give the best stereocontrol. Deprotection of the silyl group revealed the diol 210, which was converted to the required methylene acetal with bromochloromethane (211, 55% over three steps). Ozonolysis transformed the olefin into an aldehyde, which was allowed to react in a Wittig reaction to give α,β-unsaturated ester 212 in 74% yield. Conjugate addition and cyclization of t-butyl acetimidoacetate with 212 afforded glutarimide 213. Decarboxylation of the extraneous ester gave precursor 214 in 63% yield over two steps. A final

282

Imides

Scheme 7.38

three-step sequence of protecting group manipulations completed the formal synthesis of (1)-sesbanimide A (138) as advanced intermediate 216 intercepts Terashima’s route described earlier (Scheme 7.38).51 Honda and coworkers reported a formal synthesis of sesbanimides A (138) and B (139).52 The key step begins the synthesis and involves the chelation-controlled aldol reaction of a tetronic acid derivative 218 with glyceraldehyde derivative 217. The resulting alcohol was protected with chlorotriethylsilane (TESCl) to afford optically active lactone 219. Reduction of the olefin and a protecting group swap was achieved in three steps to furnish protected polyol 220 in 95% yield. The cyclic acetal was cleaved with TFA and the resulting diol oxidatively cleaved with sodium periodate. The newly revealed aldehyde was reduced to the corresponding alcohol with NaBH4 and protected with TBDPSCl (221, 58% yield over four steps). Lactone 221 was reduced to lactol 222 with DIBAL-H in 90% yield. Ring-expansion was achieved by the addition of thioacetal 223 and treatment of the intermediate with acid to give spirocycle 224 in 83% yield. The thioacetal was removed with sodium periodate to return lactone 225 in quantitative yield. A sequence of selenide addition
elimination installed the required olefin (226, 87% yield) and exposure of the α,β-unsaturated lactone 226 to BF3  OEt2 afforded methylene acetal 190 in 83% yield. This intermediate intercepts Grieco’s route and constitutes a formal synthesis of sesbanimides A (138) and B (139) (Scheme 7.39).52

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283

Scheme 7.39

7.3.5 Streptimidone Isolation and Biological Activity: Steptimidone (227) was first isolated from the cultures of a Streptomyces sp. in 195953 and has since been identified as a component in the culture broths and mycelial mats of Micromonospora coerulea strain Ao58.54 9-Methylsteptimidone (228) has been isolated from both Streptomyces sp. S-885 and E/887.55 As with the structurally similar cycloheximide (52), both natural products inhibit protein synthesis in eukaryotic cells and exhibit antiyeast, antifungal, antiprotozoal, and herbicidal activity.53,54 In contrast to cycloheximide (52), steptimidone (227) has not shown plant phytotoxicity in some studies, making it a candidate as a plant chemotherapeutic.54 The antiviral activity of 9methylsteptimidone (228) against poliovirus, vesicular stomach virus, and the Newcastle disease virus has also been reported (Fig. 7.9).55b Synthesis: The synthesis of steptimidone (227) and its diastereomers was reported by Kiyota and coworkers in 2000.56 Enantiopure ester 229 was converted by a known procedure to benzyl ether 230.57 Oxidation of the primary alcohol gave the corresponding aldehyde, which was treated with MeMgI to give a diastereomeric mixture of alcohols 231 in 73% yield. Protection of the alcohol with a silyl group followed by hydrogenolysis gave alcohol 233. The alcohol was oxidized to an aldehyde and

284

Imides

Figure 7.9

treated with phosphane oxide 234 to afford diene 235 in 67% yield. Removal of the TBS group with TBAF and oxidation with Dess
Martin periodinane furnished ketone 237 (Scheme 7.40).

Scheme 7.40

Intermediate ketone 237 was treated with LDA to form the required enolate, which then was allowed to react with aldehyde 238; the reaction resulted in a mixture of two unnatural diastereomers of streptimidone 239 and 240 in 28% and 19% yield, respectively (Scheme 7.41).

Scheme 7.41

Natural streptimidone (227) and the final unnatural diastereomer of streptimidone 242 were prepared in an analogous fashion from ester 229 using benzyl ether 241 as an intermediate (Scheme 7.42). From these synthetic studies it was reported that the natural stereochemical configuration of streptimidone (227) is required for antifungal activity.56

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285

Scheme 7.42

7.4 MALEIMIDES 7.4.1 Farinomalein Isolation and Biological Activity: Farinomalein A (243) was first isolated from the entomopathogenic fungus Paecilomyces farinosus HF599.58 The producing strain of fungus, in turn, was itself isolated from a lepidopteran larval cadaver collected on Mt. Tsukuba, Ibaraki, Japan. Farinomalein A (243) and its methyl ester 244 along with farinomaleins C
E (245
247) were also isolated from an unidentified endophytic fungus gathered from the inner tissues of healthy leaves of the mangrove plant (Avicennia marina, Oman).59 A closely related derivative, pestalotiopsoid A (248), was isolated from the endophytic fungus Pestalotiopsis sp. found on the Chinese mangrove plant Rhizophora mucronata.60 Farinomalein A (243) has potent activity against the plant pathogen Phytophthora sojae P6497 (5 μg/disk),58 while the methyl ester 244 has moderate cytotoxic activity against the mouse lymphoma cell line L5178Y (4.4 μg/mL).59 A subsequent study of synthetically prepared farinomaleins A (243), C
E (245
247), and various analogs showed that a lipophilic ester group enhanced antifungal potency against Cladosporium cladosporioides (e.g., 243 at 5 μg vs 245 at 0.5 μg) (Fig. 7.10).61

Figure 7.10

286

Imides

Synthesis: Farinomalein A (243) was first prepared by Miles and Yan via a short, three-step sequence starting from isovaleraldehyde (249).62 γ-Hydroxybutenolide 250 was synthesized in 10 g batches in 65%
75% yield and exists in equilibrium with a small amount of open chain tautomer 251. Oxidation with Dess
Martin periodinane furnished anhydride 252; the crude intermediate was then treated directly with either β-alanine (253) or 254 to furnish farinomalein A (243) and farinomalein A methyl ester (244) (64% and 58% over two steps, respectively) (Scheme 7.43).

Scheme 7.43

Dallavalle and coworkers reported a more scalable route that intercepts the intermediate γ-hydroxybutenolide 252.63 A Horner
Wadsworth
Emmons reaction of butyrate 255 with triethylphosphonate 256 gave diester 258 in 80% yield. Hydrolysis with LiOH followed by cyclization with TFAA gave γ-hydroxybutenolide 252 in near quantitative yield over two steps to complete the formal synthesis (Scheme 7.44).

Scheme 7.44

Farinomalein C (245) and D (246) were readily prepared in good yield from farinomalein A (243) by esterification with the appropriate alcohol (92% yield and 54% yield over two steps, respectively) (Scheme 7.45).61 The same authors prepared farinomalein E (247), though the requisite alcohol requires seven steps to prepare (not shown).

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Scheme 7.45

7.4.2 Pencolide Isolation and Biological Activity: Pencolide was first isolated in 1963 from cultures of Penicillium multicolor Grigorrieva
Manilova and Poradielova (NRRL 4036).64 Although the stereochemical assignment was initially proposed to be (E),65 this was later corrected to (Z) by Olsen and coworkers.66 Subsequent isolations of pencolide (260) have been reported from P. sclerotiorum (Serra do Cipó National Park, Brazil)67 and P. citreonigrum (Joao Pessoa, State of Paraíba, Brazil).68 The biological activity of pencolide is still unclear. Takahashi and coworkers reported moderate activity (c. 13
17 mm zones of inhibition with 100 μg/disk) against Streptococcus pyogenese, Staphylococcus aureus, Salmonella typhimurium, Escherichia coli, and Candida albicans67; however, Cichewicz and coworkers observed no activity against 10 Gram-negative and Gram-positive bacteria and 5 fungi (including many of the same previously reported species) at up to 135 μg/disk (Fig. 7.11).68 Synthesis: Inspired by a biosynthetic proposal, Strunz and Ren prepared pencolide (260) in one step by mixing L-threonine (261) and anhydride 262 at 150°C for 3 hours to furnish pencolide (260) in 42% yield (Scheme 7.46). Racemic threonine could also be used in the reaction with similar results (260, 41% yield).69

Figure 7.11

Scheme 7.46

288

Imides

Figure 7.12

7.5 POLYKETIDES 7.5.1 Dorrigocin A and B Isolation and Biological Activity: Dorrigocins A (263) and B (264) were isolated in 1994 by researchers in Abbott Laboratories from a culture of Streptomyces platensis subsp. rosaceus strain AB1981F-75 (originally collected from soil on the Dorrigo plateau in New South Wales, Australia).70 Dorrigocin A (263) was reported to reverse the morphology of rastransformed NIH/3T3 cells; instead of inhibiting prenylation of protein synthesis, 263 inhibits the carboxylmethyltransferase in K-ras transformed cells.71 Shen and coworkers have demonstrated that dorrigocins A (263) and B (264) are not, strictly speaking, natural products, but instead shunt metabolites of isomigrastatin (Fig. 7.12).72 Synthesis: No total syntheses of dorrigocins A (263) and B (264) have been completed, though various analogs and congeners have been reported.73 Brazidec and coworkers prepared the C1
C13 fragment of 2,3-dihydrodorrigocin A (279) in a stereoselective fashion over 14 linear steps in a 2% overall yield.74 6-Bromohexanoic acid (265) was converted via a previously published route to sulfone 266, which was subjected to a Julia
Kocieñski olefination with aldehyde 267 in 76% yield as a 1:1 mixture of (E:Z) isomers. A 9:1 ratio of isomers [in favor of (E)] was obtained for olefin 269 after exposure to 2,20 -azobis(2-methylpropionitrile) (AIBN) and thiophenol. Deprotection of the silyl ether revealed the primary alcohol, which was subsequently oxidized with Dess
Martin periodinane to afford aldehyde 271 in 71% yield over two steps (Scheme 7.47). An aldol reaction was used to couple aldehyde 271 with chiral auxiliary 272 in 74% yield with excellent selectivity. The resulting secondary

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Scheme 7.47

alcohol was protected as the methoxymethyl ether (274, 79% yield), and the auxiliary removed with LiBH4 in methanol to furnish the primary alcohol in 70% yield. As before, the alcohol was oxidized to the corresponding aldehyde 275 with Dess
Martin periodinane in 86% yield (Scheme 7.48).74

Scheme 7.48

Diester 277 was prepared in 66% yield via the coupling of aldehyde 275 with stabilized phosphorilidene 276. Reduction of the ethyl ester followed by acidic hydrolysis of the t-butyl ester completed the synthesis of the C1
C13 fragment of 2,3-dihydrodorrigocin A (279) in 16% yield over the final two steps (Scheme 7.49).74

290

Imides

Scheme 7.49

7.5.2 Isomigrastatin Isolation and Biological Activity: Isomigrastatin (280) was isolated from S. platensis strain NRRL 18993 by Kosan Bioscience in 2002, a species that also produces migrastatin (281) and dorrigocins A (263) and B (264) (Fig. 7.13).75 Isomigrastatin (280) is extremely unstable, both hydrolytically and thermally. Elegant studies by Shen and coworkers demonstrated that isomigrastatin (280) is the “true” natural product produced by Streptomyces sp. and that migrastatin (281) and dorrigocins A (263) and B (264) are shunt metabolites, formed by hydrolytic or thermal degradation of 280.72 Conversion to migrastatin (281) occurs via a 3,3-sigmatropic rearrangement (Pathway 1, starred carbon added for clarity) in the presence of water or heat. Hydrolysis of the ester involving migration of the olefin (Pathway 2) leads to dorrigocin A (263), while direct attack of water on the ester itself (Pathway 3), gives dorrigocin B (264) (Fig. 7.14).76 Synthesis: Despite the structural similarity between isomigrastatin (280) and migrastatin (281), Danishefsky and coworker’s routes toward the two

Figure 7.13

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Figure 7.14

compounds bear little resemblance, especially in the later stages.77 Lactol 284 was prepared from dihydropyrone 282 as discussed in the migrastatin (281) synthesis (see Scheme 7.62). Treatment of lactol 284 with 3chloroperbenzoic acid (mCPBA) afforded epoxide 284 in 43% yield; reductive ring-opening with LiBH4 gave diol 286 in excellent yield. Transient protection of the primary alcohol allowed for the preparation of MOM ether 287 in 75% yield over three steps (Scheme 7.50).

Scheme 7.50

Glutarimide Wittig reagent 290 was prepared in a straightforward manner from aldehyde 238. Wittig reagent 288 was mixed with aldehyde

292

Imides

238 to afford intermediate 289 in 70% yield. Reduction of the enone proceeded smoothly to give glutarimide Wittig reagent 290 in 95% yield (Scheme 7.51).77

Scheme 7.51

After oxidation of alcohol 287 to an intermediate aldehyde, Wittig reagent 290 was added to furnish enone 291 in 83% yield. The stereochemistry of the next reduction proved critical because the pending cuprate addition was found to occur with high antiselectivity. A stereoselective CBS reduction, followed by TBS protection, gave the required protected alcohol 292, with approximately 10:1 selectivity. Addition of the cuprate to allylic epoxide 292 afforded the desired diastereomer of allylic alcohol 293 in 80% yield (Scheme 7.52).77

Scheme 7.52

Esterification of allylic alcohol 293 with racemic carboxylic acid 294 proceeded with high kinetic resolution, giving an 8:1 mixture of diastereomers (at the selenide position) in 95% yield. The TBS group was

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293

Scheme 7.53

cleaved with HF  pyridine to reveal the secondary alcohol, which was subsequently oxidized to the corresponding ketone. The MOM group was removed to provide the ring-closing metathesis (RCM) precursor 296 in 68% yield over three steps. The ruthenium-catalyzed ring-closing metathesis afforded 21% of the desired (E) isomer, along with 36% of the (Z) isomer. Oxidation
elimination of the selenide gave the (E) isomer with good selectivity and completed the total synthesis of isomigrastatin (280) in 93% yield. Treatment of isomigrastatin (280) with trimethylphosphine rapidly and quantitatively isomerized the enone olefin from (E) to (Z), supporting the notion that 298 is more stable than 280 (Scheme 7.53).77

7.5.3 Lactimidomycin Isolation and Biological Activity: Lactimidomycin (299) was originally isolated by researchers at Bristol
Meyers Squibb in 1992 from the culture broth of Streptomyces amphibiosporus R310-104 (ATCC 53964).78 Initial

294

Imides

Figure 7.15

biological testing revealed 299 prolonged the survival time of mice transplanted with experimental tumors as well as some antifungal activity.78 Further studies showed that lactimidomycin (299) inhibits DNA and protein biosynthesis.79 Some reports suggest 299 is a potent cell migration inhibitor,80 while others report that no significant cell migration inhibition occurs at subtoxic doses.81 More recently, the mechanism of action for lactimidomycin (299) was reported to involve preventing binding of tRNA by 299 itself binding at the E-site of tRNA (specifically targeting the first elongation cycle) (Fig. 7.15).82 Synthesis: The only two total syntheses of lactimidomycin (299) reported to date have both been by Fürstner and coworkers, utilizing ring-closing alkyne metathesis as the key step.81,83 Treatment of ester 300 with LDA and methyl iodide, followed by protection with TESCl gave α-methyl ester 301 in excellent yield. After reduction of the ester to the aldehyde, olefination afforded α,β-unsaturated ester 302 in 92% yield over two steps. A two-step redox operation furnished α,β-unsaturated aldehyde 303 (77% yield), which was subjected to an aldol reaction with chiral auxiliary 304. The chiral auxiliary was converted to Weinreb amide 305 before being reduced to aldehyde 306 (Scheme 7.54).83b

Scheme 7.54

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Aldehyde 306 was converted to two different alkyne precursors: Alkyne 308 with Ohira
Bestman reagent 307 in 44% yield over three steps, and enyne 310 via Julia olefination with sulfone 309 in 59% yield over two steps (Scheme 7.55).83b

Scheme 7.55

Alkyne 308 proved unproductive in the ring-closing alkyne metathesis; only dimerization and oligomerization products were observed. In contrast, enyne 310, after coupling with acid 311 to afford diyne 312, smoothly underwent the desired ring-closing metathesis giving macrolide 314 in 95% yield. The reaction was even successful on gram-scale, delivering 1.2 g of 314 in 84% yield. The required (E) olefin was installed via a hydrosilylation/protodesilylation event in 64% yield over two steps. Conversion of the ketone to enone was achieved via selenation followed by oxidation
elimination (64% yield over two steps). One further oxidation with Dess
Martin periodinane furnished ketone 317 in 87% yield (Scheme 7.56).83b All that remained was to install the glutarimide moiety. In order to obtain the desired selectivity in the aldol reaction of ketone 317 with aldehyde 238, borane 318 was required. While other conditions led to unappealing mixtures, borane gave 318 as a single diastereomer. Deprotection under buffered fluoride conditions completed the synthesis of lactimidomycin (299) in 60% yield over three steps (Scheme 7.57).83b In a later effort Fürstner and coworkers used 1,3-diene 319 with catalyst 320 in order to improve the route surrounding the ring-closing event. The catalyst and position of the silyl group in 319 was critical to the outcome of the reaction; upon exposure to the reaction conditions 1,3-diene 319 was converted to a 95:5 mixture of macrolides 321 and 322 in 76%
78% yield, favoring the desired product. Macrolide 321 was deprotected and desilylated in 74% yield over two steps to intercept their own

296

Imides

Scheme 7.56

Scheme 7.57

previous route and constitutes a formal synthesis of lactimidomycin (299) (Scheme 7.58).83a Nagorny and coworkers completed a formal synthesis of lactimidomycin (299) that relied on a zinc-mediated Horner
Wadsworth
Emmons

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297

Scheme 7.58

macrocyclization. The reaction was successful on a fairly large scale (423 mg) in 93% yield and gave only minor amounts (c. 3%) of dimerized product (which was a concern based upon model studies). Deprotection of the TBS group completed the formal synthesis. The same group has prepared numerous analogs and reported that compounds lacking the glutarimide side chain were significantly less toxic to human mammary epithelial cells (Scheme 7.59).84

Scheme 7.59

Nagasawa and Kuwahara used a key Stille coupling to forge the bond between vinyl iodide 324 and stannane 325 in 89% yield. The macrocyclization was successful after hydrolysis of the ester and exposure of the intermediate acid to Yamaguchi macrocyclization conditions. Treatment of selenide 328 with NaIO4 not only promoted the elimination (to give the enone), but also removed the TES group to complete the formal synthesis of lactimidomycin (299) (Scheme 7.60).85 Li and Georg are the most recent group to complete a formal synthesis of lactimidomycin (299). The key macrocyclization of advanced

298

Imides

Scheme 7.60

intermediate 330 was a copper-catalyzed ene-yne coupling/alkyne reduction tandem reaction. Interestingly, if the enone was installed prior to the ring-closing event, complete decomposition of the starting material occurred. Presumably, the increased flexibility afforded with vinyl iodide 330 allowed the reaction to occur smoothly, giving the macrolide in 83% yield. Deprotection with TBAF completed the formal synthesis of lactimidomycin (299) in 91% yield with a 93:7 mixture of epimers at the chiral center of the ester (Scheme 7.61).86

Scheme 7.61

7.5.4 Migrastatin Isolation and Biological Activity: Migrastatin (281) was first isolated by Imoto and coworkers from the cultured broth of Streptomyces sp. MK929-43F187 and later found in cultures of S. platensis strain NRRL 18993.75 Migrastatin (281) was reported to inhibit the spontaneous migration of human esophageal cancer EC17 cells independently of either cytotoxicity

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299

Figure 7.16

or the inhibition of protein synthesis. More recent studies have continued to support the potent inhibition of tumor cell migration of 281, while showing it has no effect on the biosyntheses of DNA, RNA, or protein in the same cells.87 Much like the dorrigocins, migrastatin (281) was found to be a shunt metabolite of isomigrastatin (Fig. 7.16).72 Synthesis: Given the potent biological activity of migrastatin (281), many reports have been published disclosing the synthesis of simplified analogs73,88 along with approaches toward its core structure.89 In this section, only the two completed total syntheses will be discussed in detail.90,91 Danishefsky and coworker’s synthesis of migrastatin (281) began with the DIBAL-H reduction of commercially available diester 331 to the corresponding dialdehyde; the intermediate was immediately treated with divinylzinc to afford diol 332 in a diasteroselective fashion (75% yield). Following methylation of the diol, the acetonide was cleaved with acid to furnish diol 333 in 80% yield. Glycol cleavage of 333 with Pb (OAc)4 gave aldehyde 334, which proved sensitive to handling, and so was directly treated with diene 335 in a chelation-controlled Lewis acid
catalyzed diene aldehyde cyclocondensation. This sequence afforded dihydropyrone 282 in 75% yield over two steps as a single diastereomer. Luche reduction converted the enone to an allyic alcohol; this was followed by a Ferrier rearrangement that transposed the
OH to furnish lactol 284. Reductive ring-opening furnished diol 336 in 44% yield over two steps from enone 282. Several protecting group manipulations and an oxidation afforded aldehyde 338 (Scheme 7.62).90 Adduct 339 was the exclusive product formed from the aldol reaction between aldehyde 338 and chiral auxiliary 272 (67% yield). The resulting secondary alcohol was protected with TESCl and the auxiliary cleaved with LiBH4 (340, 83% yield over two steps). To ultimately install the

300

Imides

Scheme 7.62

glutarimide ring, alcohol 340 was converted to phosphonate 341 followed by the Masamune
Roush variant of the Horner
Wadsworth
Emmons reaction with aldehyde 238 to forge enone 342 in 57% yield over two steps (Scheme 7.63).90

Scheme 7.63

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301

Enone 342 was reduced in a conjugate fashion by treatment with Stryker reagent, followed by selective cleavage of the TES group to give alcohol 343 in 82% yield. A Yamaguchi esterification allowed for the joining of acid 344 with alcohol 343 in 66% yield. The total synthesis of migrastatin (281) was completed following a ring-closing metathesis (70% yield) and deprotection (Scheme 7.64).90

Scheme 7.64

The only other total synthesis of migrastatin (281) to date was achieved by Reymond and Cossy. Methyl ester 346 was deprotected with acid and selectively protected on the primary alcohol with TBDPSCl to afford alcohol 347 in 67% yield over two steps. O-Methylation and reduction of the ester gave alcohol 348. Swern oxidation converted the alcohol to an aldehyde; direct treatment of the crude intermediate with stannane 349 furnished olefin 350 in 87% yield with a dr of 90:10. Esterification of the secondary alcohol followed by ring-closing metathesis gave α,β-unsaturated lactone 354 in 52% yield over two steps (Scheme 7.65).91

302

Imides

Scheme 7.65

Reductive ring-opening of lactone 354 gave diol 355 in 74% yield. Both alcohols were TBS protected followed by selective cleavage of the silyl group on the primary allylic alcohol to afford 356 in 56% yield over two steps. After oxidation of the allylic alcohol to α,β-unsaturated aldehyde 357, a selective crotylation with complex 358 and TES protection of the resulting alcohol delivered diene 359 in 72% yield. Oxidative cleavage of the terminal olefin was accomplished chemoselectively via a two-step sequence to furnish aldehyde 360 in 80% yield over two steps (Scheme 7.66).91

Scheme 7.66

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303

Treatment of aldehyde 360 with vinylmagnesium chloride followed by oxidation of the resulting alcohol installed the vinyl ketone (361, 73% yield over two steps). A ruthenium-catalyzed crossmetathesis of vinyl ketone 361 with glutarimide 363 gave intermediate 364 in 32% yield after 72 hours. Hydrogenation of the enone proceeded smoothly in excellent yield (Scheme 7.67).91

Scheme 7.67

Selective deprotection of the TES group in glutarimide 365 proceeded in 80% yield and was followed by Yamaguchi esterification with diene 366 to afford advanced intermediate 367 in 74% yield. A sequence of TBDPS deprotection, oxidation of the primary alcohol to an aldehyde, and olefination under Takai conditions delivered triene 345 in 44% yield over three steps, and intercepts a late-stage intermediate from Danishefsky’s route, thus constituting a formal synthesis of migrastatin (281) (Scheme 7.68).91

304

Imides

Scheme 7.68

7.6 SUCCINIMIDES 7.6.1 Methyllycaconitine Isolation and Biological Activity: Methyllycaconitine (368) is a complex C19 diterpenoid alkaloid that has been isolated from various Delphinium species, including D. brownii and D. elatum.92 It is highly toxic to both mammals and insects, and plants in this class are routinely responsible for a significant number of cattle deaths in North America.93 Given the toxicity of methyllycaconitine (368), its use is limited to a chemical and biological probe rather than a pharmaceutical or agrochemical. Methyllycaconitine (368) is considered to be the most potent nonprotein antagonist of the neuronal nicotinic acetylcholine receptor (nAChR) known; as such, most of the studies around 368 are in this arena and have implications in the treatment of various cognitive and neurodegenerative diseases (Fig. 7.17).94 Synthesis: Although no total syntheses of methyllycaconitine (368) have been reported, several groups have prepared analogs, synthesized subunits, or made attempts toward the overall core.95 A semisynthesis via the acylation of lycoctonine (372) was reported by Blagbrough and coworkers in 1994.96 The asymmetric hydrogenation of itaconic acid (369)

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305

Figure 7.17

gave chiral diacid 370 in 72% yield and .90% ee. Treatment of the diacid 370 with acetyl chloride furnished the optically active anhydride 371 (Scheme 7.69).96

Scheme 7.69

Lycoctonine (372) was regioselectively acylated with isatoic anhydride (373), which gave an isomeric mixture of half-acid amides that were not isolated (not shown). The mixture was treated with anhydride 371 followed by the addition of N,N0 -carbonyldiimidazole (CDI) to afford methyllycaconitine (368) in 55% yield (Scheme 7.70).96

Scheme 7.70

7.6.2 Palasimide Isolation and Biological Activity: Palasimide (374) was isolated in 1990 from the pods of Butea monosperma, a deciduous tree native to the tropical and subtropical regions of India and Southeast Asia.97 The tree is an abundant

306

Imides

Figure 7.18

source of natural products, including various flavonoids, alkaloids, and terpenoids. The root, bark, leaves, flowers, fruit, and seeds are frequently used by local populations for medicinal purposes; for example, the roots and leaves are effective for diseases of the eye, while the bark is used for dysentery and ulcers.98 Although no biological studies have been reported for palasimide (374) itself, palasonin (375, isolated from seeds of the same tree), has been shown to have anthelmintic properties (Fig. 7.18).99 Synthesis: All synthetic work toward palasimide (374) was undertaken and completed before its isolation and while actually targeting palasonin (375). Palasimide (374) was first prepared by semisynthesis in 1967 by Bochis and Fisher as a means to confirm the structure of palasonin (375).100 Later, Meinwald and coworkers completed a total synthesis of palasimide (374) en route to palasonin (375).101 Anhydride 376 and furan underwent a Diels
Alder reaction in the presence of hydrogen and Pd/C to afford adduct 377 in 69% yield. Subsequent conversion to the N-phenylimide derivative and reduction with NaBH4 gave a mixture of diols 378 and 379 (49% and 10% yield, respectively). A selective oxidation of the secondary alcohols was achieved with cerium-catalyzed conditions and stoichiometric KBrO3. The primary alcohol of imide 380 was converted to the corresponding iodide by mesylation and displacement with NaI in 69% yield over two steps. Radical dehalogenation of iodide 381 furnished palasimide (374) in 96% yield (Scheme 7.71).101

Scheme 7.71

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307

Shortly thereafter, Dauban and coworkers reported a two-step synthesis of palasonin (375) that serves as a formal synthesis of palasimide (374). Anhydride 382 and furan engaged in a high-yielding Diels
Alder reaction when exposed to 8 kbar of pressure for 138 hours. Reduction of the resulting olefin under hydrogen with 10% palladium on carbon gave palasonin (375) in 99% yield (Scheme 7.72).102

Scheme 7.72

7.6.3 Salfredins C1
C3 Isolation and Biological Activity: Salfredins C1 (384), C2 (385), and C3 (386) were isolated from the fermentation broth of Crucibulum sp. RF-3817 by Kamigauchi and coworkers as part of a screening program for identifying pharmacologically active microbial products. The salfredins were thus identified as novel aldose reductase inhibitors. In particular, they were tested for inhibitory activity against rat lens aldose reductase where salfredin C2 (385) was found to be the most potent of the group (Fig. 7.19).103 Synthesis: To date, no syntheses have been reported for salfredins C1
C3 (384
386). The total synthesis of salfredin B11, a nonnitrogencontaining coumarin derivative, has been reported.

7.6.4 Versimide and Violaceimides A
E Isolation and Biological Activity: Versimide (387) was isolated by Brown in 1970 as a metabolite from the mold Aspergillis versicolor.104 More recently it has been isolated from the insect fungus Gibellula sp. BCC36964.105 Versimide (387) was originally reported to have insecticidal properties104

Figure 7.19

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Imides

Figure 7.20

Figure 7.21

and has since been demonstrated to be cytotoxic to various cancerous and noncancerous cell lines, including MCF-7 (IC50 5 3.59 μg/mL), KB (IC50 5 4.83 μg/mL), NCI-H187 (IC50 5 1.89 μg/mL), and Vero (IC50 5 2.49 μg/mL) (Fig. 7.20).105 Violaceimides A
E (388
390) were recently isolated from the sponge-associated fungus Aspergillus violaceus strain WZXY-m64-17, which was collected from the South China Sea. Violaceimides A (388) and B (388-OMe) were found to selectively inhibit the growth of human leukemia U937 and human colorectal cancer cell HCT-8, while displaying low cytotoxicity toward Vero cells (Fig. 7.21).106 Synthesis: The first published synthesis of versimide (387) was reported by Atkins and Kay.107 The sodium salt of succinimide 391 was allowed to react with dimethyl bromomalonate (392) to afford intermediate 393. After forming an anion at the activated tertiary carbon of 393, chloromethyl methyl sulfide (394) was added to give alkylated succinimide 395. Oxidation with KMnO4 converted the sulfide to the corresponding sulfone in intermediate 396; subsequent heating in the presence of KI effected the elimination of the sulfone and CO2 to furnish versimide (387) in 81% yield (Scheme 7.73).107 Brown and Smale achieved a two-step total synthesis of versimide (387), albeit in a lower-yielding sequence than described earlier.108 Serine methyl ester hydrochloride (397) was treated with anhydride 371 in the

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309

Scheme 7.73

presence of Et3N in refluxing dioxane to afford succinimide 398 in 26% yield. Elimination of the alcohol was completed with anhydrous potassium hydrogen sulfate in refluxing N,N0 -dimethylformamide (DMF), which gave versimide (387) in 21% yield (Scheme 7.74).108 No syntheses of violaceimides A
E (388
390) have been reported to date.

Scheme 7.74

7.7 TETRAMIC ACIDS 7.7.1 Malyngamides Isolation and Biological Activity: The malyngamides are a large class (. 35 members) of amide-containing fatty acids isolated primarily from marine cyanobacteria of the genus Lyngbya (recently reclassified as Moorea spp.).109 Several malyngamides have also been isolated from the extracts of sea hares, molluscs known to sequester toxic metabolites from their diet, and include malyngamides O and P (from Stylocheilus longicauda)110 and malyngamides S and X (from Bursatella leachii).111,112 As a group, the

310

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malyngamides display a wide range of biological activity, including anticancer, antiinflammatory, antimalarial, antitubercular, and toxicity to fish and crustaceans. A small subset of the malyngamides contain an imide functionality in the form of a N-acyl tetramic acid. Malyngamides A (399) and B (401) were first isolated in 1978 from shallow-water varieties of a marine blue-green alga, Lyngbya majuscula (Kahala Beach, Oahu, Hawaii).113 Subsequent studies showed that malyngamides A (399) and B (401) may have an antifeedant effect in some species of reef fish.114 Isomalyngamides A (400) and B (402), which differ from malyngamides A (399) and B (401) only by the conformation of the chloromethylene group, were isolated in 1999 in the same location (L. majuscula, Kahala Beach, Oahu, Hawaii).115 These compounds were found to be lethal to the crayfish Procambarus clarkii when administered by intraperitoneal injection. Notably, it appears that over the course of a decade the major constituents of L. majuscula have shifted from malyngamides A (399) and B (401) to isomalyngamides A (400) and B (402). The cause of this change is currently unclear (Fig. 7.22).115 Malyngamides Q (403) and R (404) were isolated from the lipid extract of the marine cyanobacterium L. majuscula, collected near Sakatia Island, Madagascar.116 Malyngamide Q (403) could not be subjected to biological studies since it decomposed shortly after characterization; however, malyngamide R (404) was shown to be moderately toxic to brine shrimp (LD50 5 18 ppm). Malyngamide X (405) was isolated from the sea hare B. leachii, which was collected from Sichang Island in the Gulf of Thailand.117 Initial biological testing of compound 405 showed moderate cytotoxicity against oral human epidermoid carcinoma of the nasopharynx (ED50 5 8.20 μM), human small cell lung cancer (ED50 5 4.12 μM), and

Figure 7.22

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311

Figure 7.23

breast cancer cell lines (ED50 5 7.03 μM), antitubercular activity against Mycobacterium tuberculosis H37Ra strain (MIC 5 80 μM) and antimalarial activity against Plasmodium falciparum K1 multidrug-resistant strain (ED50 5 5.44 μM) (Fig. 7.23). Malyngamide 4 (406) was isolated from the extracts of L. majuscula (renamed Moorea producens) collected from the Red Sea near Jeddah, Saudi Arabia.118 It was found to be modestly active against lung carcinoma (ED50 5 40 μM), colorectal cancer (ED50 5 50 μM), and breast adenocarcinoma (ED50 5 44 μM) cell lines and possessed weak antitubercular activity against M. tuberculosis H37Rv (17% inhibition at 12.5 μg/mL). The most recently disclosed (and currently unnamed) malyngamide 407 was isolated from M. producens (Kahala Beach, Oahu, Hawaii).119 Unique among the compounds in its class, malyngamide 407 has a free hydroxyl group at C7 (instead of OMe). This is suggested to explain at least some of the significant drop in potency when comparing 407 to isomalyngamides A (400) and B (402) in mouse L1210 leukemia cells (IC50 5 2900, 130, and 30 μM for 407, 400, and 402, respectively) and lethal toxicity to the shrimp Palaemon paucidens (LD100 5 33.30, 4.25, and 1.70 mg/kg for 407, 400, and 402, respectively) (Fig. 7.24). Synthesis: Of the imide-containing malyngamides described earlier, only Q (403), R (404), and X (405) have succumbed to total synthesis. Cao and coworkers recently reported an enantioselective convergent route to malyngamides O, P, Q (403), and R (404).120 Ethyl 4-chloro-3oxobutanoate (408) was converted to azide 409 by treatment with NaN3 in aqueous acetone (78% yield). Hydrogenation of the azide and protection of the resulting amine afforded ketone 410 in 71% yield. Both the ester and ketone were reduced in the presence of DIBAL-H and the

312

Imides

Figure 7.24

primary alcohol was selectively protected with TBDPSCl (411, 68% yield over two steps). A 2-iodoxybenzoic acid (IBX) oxidation followed by a Wittig reaction gave vinyl chloride 412 in 72% yield over two steps with a 3:1 (Z:E) ratio for the olefin. Methylation of the Boc-protected amine furnished key intermediate 413 in 99% yield (Scheme 7.75).

Scheme 7.75

The tetramic acid moiety 416 was prepared in seven steps as shown in Scheme 7.76. Serine (397) was sequentially protected on both the amine and alcohol to give 414 in 90% yield over two steps. The pyrrolidone ring was formed by treatment of acid 414 with Meldrum’s acid followed by heating with MeOH; a Mitsunobu reaction followed by cleavage of

Scheme 7.76

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313

the Boc group with TFA afforded pyrrolidone 415t in 42% yield over four steps. A final acetylation provided building block 416 in 81% yield (Scheme 7.76).120 Intermediate 412 (prepared in Scheme 7.75) was deprotected and coupled with acid 417 in 86% yield over two steps. Reprotection of the nitrogen (93% yield) followed by TBAF-mediated deprotection of the alcohol (85% yield) gave amide 420 (Scheme 7.77).120

Scheme 7.77

Intermediate 421, destined to become malyngamide R (404), was prepared in an analogous fashion from vinyl chloride 413. A sequence of Boc deprotection, DCC coupling with acid 417, and deprotection of the silyl ether gave intermediate 421 in 85% yield over three steps (Scheme 7.78).120

Scheme 7.78

After oxidation of the primary alcohol to the corresponding aldehyde with IBX, vinyl chlorides 422 and 423 were treated with TiCl4 in the presence of pyrrolidine 416, which allowed the aldol reaction to occur, giving a diastereomeric mixture of alcohols [56% when R 5 Me (424), 57% when R 5 Boc (425), over two steps]. IBX oxidation of the secondary alcohols afforded ketones 426 and 427 in 73%
75% yield (Scheme 7.79).120

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Scheme 7.79

The total synthesis of malyngamide R (404) was completed in 52% yield by treatment of penultimate intermediate 426 with trimethyl orthoformate and catalytic sulfuric acid to both convert the ketone to the required methyl enol ether and cleave the TBS group (Scheme 7.80).120

Scheme 7.80

The total synthesis of malyngamide Q (403) was completed in a similar fashion. After conversion of the ketone to the methyl enol ether with concomitant removal of the TBS group, treatment with Mg(ClO4)2 facilitated the Boc deprotection to afford malyngamide Q (403) in 40% yield over three steps (Scheme 7.81).120

Scheme 7.81

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315

Isobe and coworkers completed the first total synthesis of malyngamide X (405) by a convergent route that allows for the rapid assembly of a series of structural analogs.112 Epoxide 428 was opened with a cuprate reagent derived from C6H13MgBr; the intermediate alcohol 429 was converted to the corresponding epoxide 430 after treatment with base (90% yield over two steps). The lithium acetylide of alkyne 431 opened epoxide 430 to give enantiopure alcohol 432 in 98% yield. Methylation of the secondary alcohol was achieved in 71% yield by treatment of 432 with MeI in a mixture of NaH
DMSO. The alkyne was reduced under dissolving metal conditions to afford the trans olefin; cleavage of the protecting group gave alcohol 434 in 81% yield over two steps. A final oxidation completed the synthesis of the fatty acid portion of the natural product (Scheme 7.82).112

Scheme 7.82

The required pyrrolidone ring was prepared in a similar fashion to the route shown in Scheme 7.76. Protected valine 435 was treated with Meldrum’s acid to form the ring, while Mitsunobu conditions converted the free hydroxyl group to the corresponding methyl ether. Deprotection of the amide and acylation of the nitrogen gave pyrrolidone 438 in 68% yield over four steps. Pyrrolidone 438 was converted to the (Z)-enolate by treatment with n-Bu2BOTf; once formation was complete, the addition of Boc-alaninal (439) and Et2AlCl allowed the aldol reaction to proceed and furnished the antiselective product 440 in 44% yield. Deprotection and coupling with amino acid 441 afforded peptide 442 in

316

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82% yield. The synthesis of malyngamide X (405) was completed in 44% yield with a final deprotection and coupling with previously prepared acid 417 (Scheme 7.83).112

Scheme 7.83

7.7.2 Palau’imide Isolation and Biological Activity: Palau’imide (443) was isolated from a “mixed collection” of Lyngbya sp. NIH309. The combined collection sites in Palau include Short Dropoff, Big Dropoff, Lighthouse Channel, Ngerkuul Pass, and Ngerkuul Lagoon. Palau’imide (443) was only found in the Lyngbya extracts collected in Palau and was absent from the same organism collected in Guam. Initial biological testing revealed that Palau’imide (443) is cytotoxic to KB and LoVo cells (IC50 of 1.4 and 0.36 μM, respectively) (Fig. 7.25).121

Figure 7.25

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317

Synthesis: The first total synthesis of Palau’imide (443) was completed by Huang and coworkers and served to establish the stereochemistry of the C20 methyl group, which was still ambiguous after isolation.122 Synthesis of pyrrolidone 450 began with the conversion of methyl 2methylacetoacetate (444) to methyl enol ether 445 in 80% yield over two steps via treatment with trimethyl orthoester and catalytic sulfuric acid followed by thermolysis of the intermediate acetal. Allylic bromination with N-bromosuccinimide (NBS) proceeded to give 446 in 86% yield. Phenylglycine derivative 447, serving as a chiral auxiliary, was heated with bromide 446 to afford tetramate derivative 448 in 78% yield. Formation of the anion with t-BuLi and quenching with benzyl bromide gave intermediate 449 in 62% yield; the diastereoselectivity was approximately 6:1 in favor of the desired product, while the positional selectivity (the desired C5 position vs reaction at C3) was approximately 4:1. Finally, the auxiliary was cleaved via a ceric ammonium nitrate (CAN)-mediated oxidation to furnish pyrrolidone 450 in 80% yield (Scheme 7.84).122

Scheme 7.84

After activation with C6F5OH, valine derivative 451 was coupled with pyrrolidone 452 in 85% yield. The synthesis of Palau’imide (443) was completed after deprotection of the amine and the EDC-mediated coupling of acid 455 (67% over two steps) (Scheme 7.85).122 Pettus and coworkers completed a formal synthesis of Palau’imide (443) by developing a mild route to 3-methyl tetramic acid derivatives. After protection, phenylglycine derivative 457 was coupled with

318

Imides

Scheme 7.85

2-bromopropionyl bromide to afford a diastereomeric mixture of amides 459 in 42% yield over two steps. The key cyclization was achieved with SmI2 followed by diazomethane and maintains a high proportion of the original enantiopurity. The methodology is suitable for a range of C5 derivatives (e.g., phenyl, isopropyl, sec-butyl). In this way pyrrolidone was prepared in 65% yield with an er of 92:8. After cleavage of the protecting group a recrystallization delivered fully enantiopure intermediate 452 and completed the formal synthesis of Palau’imide (443) (Scheme 7.86).123

Scheme 7.86

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319

Figure 7.26

7.7.3 Sintokamides Isolation and Biological Activity: Sintokamides A
E (461
465) were isolated by Andersen and coworkers in 2008 from specimens of the sponge Dysidea sp., collected near Palau Sintok, Karimunjawa archipelago, Indonesia.124 Sintokamide A (461) was found to act as an antagonist of androgen receptor with a unique mode of activity, which has implications in the treatment of prostate cancer (Fig. 7.26).125 Synthesis: Sintokamide C (463) was the first member of the class to succumb to total synthesis.126 The route began with known acid 467, which has been previously prepared over a nine-step sequence starting with L-glutamic acid (82). Tetramic acid 468 was synthesized in 70% yield by treatment of acid 467 with DCC and Meldrum’s acid, followed by heating in EtOAc. The addition of diazomethane afforded the methyl enol ether 469; subsequent exposure to TFA gave the amide 470 in 69% yield over two steps (Scheme 7.87).126 Construction of amino acid derivative 477 began with a Horner
Wadsworth
Emmons olefination of aldehyde 472 with phosphonate 471 in 72% yield. After hydrogenation of the enone, amide 474

320

Imides

Scheme 7.87

was treated with sodium bis(trimethylsilyl)amide(NaHMDS) to form the corresponding enolate; the addition of methyl iodide gave intermediate 475 in 68% yield with high diastereoselectivity. The chiral auxiliary was reductively cleaved and the resulting alcohol protected with TBDPSCl. After treatment with acid, alcohol 476 was isolated in 71% yield over three steps. A 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-[bis(acetoxy)iodo]benzene (BAIB) oxidation converted the primary alcohol to the corresponding carboxylic acid 477 in 85% yield (Scheme 7.88).126

Scheme 7.88

Carboxylic acid 477 was protected as the benzoate, treated with TFA to reveal the free amine, and acylated to furnish amide 479 in 83% yield over three steps. Several further protecting group and activating manipulations gave amide 481 in three steps (Scheme 7.89).126

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321

Scheme 7.89

Upon treatment with lithium bis(trimethylsilyl)amide (LiHMDS), tetramic acid 470 was acylated with amide 481 to afford advanced intermediate 482 in 71% yield. The silyl groups were cleaved with HF  pyridine and the resulting diol oxidized to the corresponding dialdehyde (484, 55% yield over two steps). Both aldehydes were chlorinated using triphenyl phosphate and chlorine in 77% yield. A final deprotection furnished sintokamide C (463) in 73% yield (Scheme 7.90).126

Scheme 7.90

The only other total synthesis of the sintokamides reported to date is a unified, protecting group-free approach by Zakarian and coworkers that

322

Imides

allowed for the preparation of three members of the class.127 The route began with the asymmetric ruthenium-catalyzed trichloromethylation of oxazolidinone 486, which gave the desired product 487 in 96% yield and .98:2 dr. The chiral auxiliary was removed with LiAlH4 (78% yield) and the resulting alcohol was converted to the corresponding nitrile via a nucleophilic displacement to afford 489 in 75% yield over two steps. After reduction of the nitrile to a primary amine, it was transformed into sulfinimine 490, which served to direct the subsequent Lewis acid
catalyzed cyanation that furnished intermediate 491 in 73% yield over three steps (dr . 95:5). The sulfinimine moiety was cleaved via hydrolysis and the resulting free amine acylated with succinimide derivative 492 (Scheme 7.91).127

Scheme 7.91

Dichloromethyl building block 499 was prepared in a similar manner to 493, albeit with minor modifications. The asymmetric rutheniumcatalyzed dichloromethylation of oxazolidinone 486 proceeded in 64% yield with complete stereoselectivity. Instead of LiAlH4, NaBH4 was used for the removal of the chiral auxiliary and iododehydroxylation was employed to assist with installing the nitrile (496, 43% over three steps). Cyanation was achieved again via sulfinimine 497, but with a slightly lesser dr of 87:13 (86% yield). Hydrolysis of the chiral auxiliary afforded free amine 499 in 88% yield (Scheme 7.92).127 Chlorinated building blocks 499 and 493 were coupling using EDC in 91% yield and the methyl ester hydrolyzed with LiOH to give peptidic intermediate 500. Treatment with Meldrum’s acid, isopropyl chloroformate (501), and 4-(dimethylamino)pyridine (DMAP), followed by thermolysis and methylation crafted the tetramic acid moiety and completed

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323

Scheme 7.92

the synthesis of sintokamide A (461) in 48% yield, along with 24% of the epimer 503 (Scheme 7.93).127

Scheme 7.93

Sintokamides B (462) and E (465) were accessed in a similar fashion. Amines 505 and 506 were coupled with acid 493 in 91% and 92% yield, respectively. Installation of the tetramic acid portion completed the synthesis over three further steps to give sintokamides B (462) and E (465) in 60% (dr 5 . 95:5) and 65% yield (dr 5 67:33), respectively (Scheme 7.94).127

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Scheme 7.94

LIST OF ABBREVIATIONS AIBN BAIB BHT BINAP BPPM CAN CbzCl CDI CSA DBU DCC DCE DCM DDQ DEAD DIAD

2,20 -Azobis(2-methylpropionitrile) [Bis(acetoxy)iodo]benzene 2,6-Di-tert-butyl-4-methylphenol (1,10 -Binaphthalene-2,20 -diyl)bis(diphenylphosphine) (2S,4S)-1-tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine Ceric ammonium nitrate Benzyl chloroformate N,N0 -Carbonyldiimidazole Camphor-10-sulfonic acid 1,8-Diazabicyclo[5.4.0]undecane N,N0 -Dicyclohexylcarbodiimide 1,2-Dichloroethane Dichloromethane 2,3-Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate

Imide Natural Products

DIBAL-H DMAP DMDO 1,2-DME DMF DMSO DMTMM dppp EDC HOAt HOBt HMDS HMPA IBX (2)-(Ipc) 2BCl IPCC KHMDS LDA LiHMDS mCPBA MOMCl MS MsCl NaHMDS NBS NMM NMO PCC PfpOH PTSA (S)-Me-CBS TBAF TBAI TBDPSCl TBDPSOTf TBSCl TBSOTf TEMPO TESCl TFA TFAA THF TMNO TMSCl TMSCN TMSOTf TsCl

Diisobutylaluminum hydride 4-(Dimethylamino)pyridine Dimethyldioxirane 1,2-Dimethoxyethane N,N0 -Dimethylformamide Dimethyl sulfoxide 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 1,3-Bis(diphenylphosphino)propane N-(3-Dimethylaminopropyl)-N0 -ethylcarbodiimide 1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole Hexamethyldisilazane Hexamethylphosphoramide 2-Iodoxybenzoic acid (2)-Diisopinocampheylchloroborane Isopropenyl chloroformate Potassium bis(trimethylsilyl)amide Lithium diisopropylamide Lithium bis(trimethylsilyl)amide 3-Chloroperbenzoic acid Chloromethyl methyl ether Molecular sieves Methanesulfonyl chloride Sodium bis(trimethylsilyl)amide N-Bromosuccinimide 4-Methylmorpholine 4-Methylmorpholine N-oxide Pyridinium chlorochromate 2,2,3,3,3-Pentafluoro-1-propanol p-Toluenesulfonic acid (S)-2-Methyl-CBS-oxazaborolidine Tetrabutylammonium fluoride Tetrabutylammonium iodide tert-Butyl(chloro)diphenylsilane tert-Butyldimethylsilyl trifluoromethanesulfonate tert-Butyldimethylsilyl chloride tert-Butyldimethylsilyl trifluoromethanesulfonate 2,2,6,6-Tetramethylpiperidine 1-oxyl Chlorotriethylsilane Trifluoroacetic acid Trifluoroacetic anhydride Tetrahydrofuran Trimethylamine N-oxide Trimethylsilyl chloride Trimethylsilyl cyanide Trimethylsilyl trifluoromethanesulfonate p-Toluenesulfonyl chloride

325

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