Biogenetically Inspired Approach to the <i>Strychnos </i>Alkaloids. Concise Syntheses of (±)-Akuammicine and (±)-Strychnine

Itô, Masayuki; Clark, C.; Mortimore, Michael; Goh, Jane Betty; Martin, Stephen F.

doi:10.1021/ja010935v

Cited by 153 publications

(67 citation statements)

References 36 publications

(76 reference statements)

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“…1). 13,14 The allylation of yohimbine (12) was also highly diastereoselective, providing a single allylation product (13) roughly equal amounts of the two diastereomeric allylated products 15 (Eq. 3).…”

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed β-Allylation of 2,3-Disubstituted Indoles

2008

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Given the prevalence of the indole nucleus in biologically active compounds, the direct C3-functionalization of 2,3-disubstituted indoles represents an important problem. Described is a general, high-yielding method for the palladium-catalyzed β-allylation of carba-and heterocycle fused indoles, including complex natural product substrates.Indoles and indole-derived heterocycles are prevalent structural motifs in natural products, medicinal compounds, and organic materials. 1 Given their importance, much effort has been directed toward the development of methods for the selective functionalization of the indole nucleus at the N1, C2, and C3 sites. 2 A particularly difficult transformation is the electrophilic attack at C3 on 3-substituted indoles to produce indolenines containing a new carbon-carbon bond and a quaternary stereocenter. Indolenine units can be found within natural products, as biogenetic precursors to indole alkaloids, and as pivotal intermediates in total syntheses. 3,4 Traditional methods for β-functionalization of indoles, which take advantage of the ambident character of indoles or indole anions, have limitations. 5 Not only is alkylation of C3-substituted indoles difficult, but the strong, nucleophilic bases (e.g. Grignard reagents, NaNH 2 ) typically used for such transformations restrict their scope due to functional group incompatibility. In the course of our studies toward the total synthesis of complex alkaloids, we required a mild, functional group-tolerant method for the introduction of an allyl group regioselectively on a β-carboline substrate (e.g. 1, Scheme 1). While the literature records methods for the palladium-catalyzed β-allylation of simple indoles, 6 the direct allylation of hindered, 2,3-disubstituted indoles, such as 1, remains an unsolved problem. 7 We report here a general, high-yielding method for the palladium-catalyzed allylation of carba-and heterocycle fused indoles, including highly functionalized complex natural product substrates. 8 In initial studies, we examined the effectiveness of published methods for the palladiumcatalyzed indole allylation using 1,2,3,4-tetrahydrocarbazole (3) as a challenging substrate and allyl methyl carbonate (4) as the allyl source (Table 1, Entries 1-4). 6,7,9 The modest yields obtained using these protocols, prompted us to explore other catalyst systems for this transformation. 10 Some of the many conditions examined during this optimization process are shown in Table 1. Pd 2 (dba) 3 was quickly determined to be a suitable source of the catalytically active palladium species (Entries 5-11). With regard to phosphine ligands, hindered alkyl phosphines gave the allylated product in fair to good yields, whereas triphenylphosphine (Entry 5) and trifurylphosphine (Entry 11) gave the best yields of 5. Significantly, the rate of the reaction was found to considerably faster with trifurylphosphine than with triphenylphosphine. 11 Additionally, under these conditions, none of the Nallylated product was observed. Reduction in the amoun...

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Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed β-Allylation of 2,3-Disubstituted Indoles

2008

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“…The synthesis of lactone 2 was initiated by N-acylation of the D-phenylglycine-derived oxazolidinone 8 15 with the known 4-benzyloxy-2-butenoic acid (7), 18 3 ), in 88% yield in two steps (Scheme 2). Conjugate addition of MeMgBr to the α,β-unsaturated imide 9 was carried out according to Hruby conditions 15 in the presence of CuBr·SMe 2 in THF/Me 2 S/CH 2 Cl 2 (-78 → -30 °C) to produce a mixture of 1,4-adducts, 10 and its C2 epimer 11, in 97% yield in a ratio of 94:6 as determined by 500 MHz 1 H NMR.…”

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confidence: 99%

Stereoselective synthesis of a C1–C6 fragment of pinnatoxin A via a 1,4-addition/alkylation sequence

Nakamura

Kikuchi

Hashimoto

2008

Tetrahedron: Asymmetry

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Abstract-A C1-C6 fragment of pinnatoxin A, (5S,6R)-5,6-dimethyl-3-methyleneoxepan-2-one, which features a γ,δ-trans-dimethylsubstituted α-methylene lactone, has been synthesized in an optically pure form from ethyl (E)-4-benzyloxy-2-butenoate through an auxiliary-based conjugate addition and alkylation reaction. The excellent diastereoselectivity (98:2) observed in the alkylation reaction would be a result of stereocontrol from both the adjacent stereocenter and the chiral oxazolidinone.

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“…The first total synthesis of strychnine, one of the most significant achievements in the history of organic synthesis, was reported by Woodward in 1954. 37,38) Nearly 40 years after Woodward's pioneering work, a number of groups reported the total synthesis, [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] four of which culminated in an enantioselective synthesis of the natural enantiomer. 41,42,44,45,47,48,52) As summarized in Bonjoch's excellent review, 34) the major stumbling blocks in the synthesis are the generation of the spirocenter at C7 and the assembly of the bridged framework (CDE core ring).…”

Section: )mentioning

confidence: 99%

“…Finally, removal of the acetyl group provided the crude Wieland-Gumlich aldehyde, which was converted to (Ϫ)-strychnine (4) by the established method. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] 2-2. Development of the Stable, Storable, and Reusable Asymmetric Catalyst La-O-linked-BINOL Complex for a Catalytic Asymmetric Michael Reaction [22][23][24] The ALB complex is a highly efficient catalyst for the Michael reaction of malonates to cyclic enones.…”

Section: )mentioning

confidence: 99%

Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

Ohshima

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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I present herewith enantioselective total syntheses of several bioactive natural products, such as (؊)-strychnine, (؉)-decursin, (؊)-cryptocaryolone diacetate, (؊)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with coworkers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (؊)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La-O-linked-BINOL complex. Further extension of the reaction using b b-keto ester as a Michael donor was achieved with the development of a La-NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (؉)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La-BINOL-Ph 3 As‫؍‬O (1 : 1 : 1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of a a,b b-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of a a,b b-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding a a,b b-epoxy morpholinyl amides. Highly catalyst-controlled enantio-or diastereoselective epoxidation of the a a,b b-unsaturated morpholinyl amides, coupled with diastereoselective reduction of b b-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (؊)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of a a,b b-epoxy amides to the corresponding a a-and b b-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (؊)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their str...

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Biogenetically Inspired Approach to the Strychnos Alkaloids. Concise Syntheses of (±)-Akuammicine and (±)-Strychnine

Cited by 153 publications

References 36 publications

Palladium-Catalyzed β-Allylation of 2,3-Disubstituted Indoles

Palladium-Catalyzed β-Allylation of 2,3-Disubstituted Indoles

Stereoselective synthesis of a C1–C6 fragment of pinnatoxin A via a 1,4-addition/alkylation sequence

Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

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