Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(<i>S</i>)-Cathafoline, and (−)-Aspidophylline A

Moreno, Jesus; Picazo, Elias; Morrill, Lucas A.; Smith, Joel M.; Garg, Neil K.

doi:10.1021/jacs.5b12880

Cited by 98 publications

(55 citation statements)

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“…The target had not been synthesized previously and, more generally speaking, the akuammilines had not yet captured the full attention of the synthetic community. 28–30 This is especially noteworthy given that the akuammilines share a common biosynthetic precursor with the popular strychnos alkaloids. 31 Compound 42 also possessed interesting biological activity (i.e., promising anticancer activity against resistant cell lines) and its structure was suitably complex due to its five interconnected rings and five contiguous stereocenters.…”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

“…30a We reasoned that 42 could be accessed from 51 via a straightforward functional group manipulation. Then, in the key step, the pentacyclic core of the natural product would arise from an interrupted Fischer indolization sequence involving phenylhydrazine ( 20 ) and ketoalcohol 52 .…”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

“…By the introduction of three new rings, three new bonds, and two stereogenic centers (including the quaternary center formed in the Fischer indolization), this transformation enabled us to complete the first total synthesis of aspidophylline A ( 42 ). 30a …”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

“…Although Ben Boal initiated our efforts toward picrinine ( 43 ), he would eventually pass the torch to graduate students Joel Smith and Jesus Moreno who took the reins and completed the total synthesis. 30b,c …”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

“…This effort marked the first total synthesis of this natural product and remains the only total synthesis of 43 to date. 30b,c …”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

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Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products

Susick

Morrill

Picazo

et al. 2016

Synlett

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This account provides an overview of our laboratory’s studies of an unusual variant of the Fischer indolization reaction. We describe the discovery of the so-called ‘interrupted Fischer indolization’ and the development of the reaction from a methodological standpoint. In addition, our efforts to evaluate and apply this methodology in the context of akuammiline alkaloid total synthesis are discussed.

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Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

“…This effort marked the first total synthesis of this natural product and remains the only total synthesis of 43 to date. 30b,c …”

Section: Applications In Akuammiline Alkaloid Total Synthesismentioning

confidence: 99%

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Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products

Susick

Morrill

Picazo

et al. 2016

Synlett

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Iridium‐Catalyzed Enantioselective Indole Cyclization: Application to the Total Synthesis and Absolute Stereochemical Assignment of (−)‐Aspidophylline A

et al. 2016

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The first enantioselective total synthesis of (À)-aspidophylline A, including assignment of its absolute configuration has been accomplished. Ak ey element of the synthesis is ah ighly enantioselective indole allylic alkylation/ iminium cyclization cascade whichwas developed by employing ac ombination of Lewis acid activation and an iridium/ ligand catalyst. This strategy relies on the direct use of 2,3disubstituted indoles with secondary allylic alcohols appended at C2 and heteronucleophiles appended at C3, indoles which are easily prepared from simple starting materials under C À H activation conditions. Figure 1. Representativeakuammilinealkaloids.[*] Dr.

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Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

2016

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A new method for one-step construction of the tetracyclic core structure of the indole alkaloid (+)-minfiensine was developed utilizing a palladium-catalyzed asymmetric indole dearomatization/iminium cyclization cascade. An efficient total synthesis of (+)-minfiensine was realized using this strategy. The present method enables access to the common core structure of a series of monoterpene indole alkaloids, such as vincorine, echitamine, and aspidosphylline A.Monoterpeneindolealkaloidsconstitutealargecategoryof natural products.[1] Among them, an array of strychnos and akuammiline alkaloids are quite attractive because of their unique cagelike structure and promising biological activity (Figure 1). [1, 2] These natural products share a common core structure, the 4a,9a-heterocycle-fused tetrahydrocarbazole skeleton, which bears two adjacent quaternary stereocenters.To address the synthetic challenges posed by these complex alkaloids, the development of strategies for efficient asymmetric assembly of the core structure is in demand. During the past decade, these monoterpene indole alkaloids attracted much research interest from the synthetic community. As a result, a large number of total syntheses have been reported. [3][4][5] However, the strategies that rendered efficient asymmetric syntheses are still limited. [3a,b,d, 4d, 5b,c] For instance, for a representative member in these alkaloids, (+)-minfiensine, only two catalytic asymmetric methods have been reported to date for achieving its total synthesis (Scheme 1). [3a,b,d] Given the effort devoted to the syntheses of these important alkaloids, the discovery of efficient and flexible new strategies for asymmetric assembly of the core framework would promote advances in this field.We sought to develop a new and straightforward approach to (+)-minfiensine based on the catalytic asymmetric dearomatization of indole (Scheme 1). It is envisioned that intramolecular asymmetric allylic substitution of the indole substrate A gives the intermediate C, which upon in situ trapping of the generated iminium ion [3a-d,g, 6, 8f] affords the tetracycle D, having the desired core structure. The advantage of this design is that the exocyclic C = C bond formed by allylic alkylation largely facilitates creation of the hydroxymethyl functionality in (+)-minfiensine. To our surprise, although palladium- [7] and iridium-catalyzed [8] asymmetric allylic alkylations of indole have been well established, [9] very little effort was made to utilize the synthetic power of those protocols in Figure 1. Representative strychnos and akuammiline alkaloids and their common core structure. Scheme 1. Previous asymmetric syntheses of (+)-minfiensine and the designed asymmetric cascade cyclization strategy. Boc = tert-butoxycarbonyl, PMB = para-methoxybenzyl.

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Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)-Cathafoline, and (−)-Aspidophylline A

Cited by 98 publications

References 50 publications

Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products

Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products

Iridium‐Catalyzed Enantioselective Indole Cyclization: Application to the Total Synthesis and Absolute Stereochemical Assignment of (−)‐Aspidophylline A

Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

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Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)-Cathafoline, and (−)-Aspidophylline A

Cited by 98 publications

References 50 publications

Pardon the Interruption: A Modification of Fischer’s Venerable ­Reaction for the Synthesis of Heterocycles and Natural Products

Pardon the Interruption: A Modification of Fischer’s Venerable ­Reaction for the Synthesis of Heterocycles and Natural Products

Iridium‐Catalyzed Enantioselective Indole Cyclization: Application to the Total Synthesis and Absolute Stereochemical Assignment of (−)‐Aspidophylline A

Total Synthesis of (+)‐Minfiensine: Construction of the Tetracyclic Core Structure by an Asymmetric Cascade Cyclization

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Product

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Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products

Pardon the Interruption: A Modification of Fischer’s Venerable Reaction for the Synthesis of Heterocycles and Natural Products