Stereoselective Total Synthesis of (±)-Alstoscholarisine E

Wood, Michael D.; Klosowski, Daniel W.; Martin, Stephen F.

doi:10.1021/acs.orglett.9b04093

Cited by 13 publications

(3 citation statements)

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“…The first of these doors led to applications of the VMR and related nucleophilic additions to iminium ions as key skeletal constructions for alkaloid synthesis. The broad utility of these reactions is reflected by their applications to the syntheses of a number of skeletally diverse alkaloids, including pumiliotoxin 251D, 10 croomine, 11 rugulovasine A, 12,13 citrinadin A, 14 and alstoscholarisine E 15 (Figure 1) as well as N-methylwelwitindolinone C isothiocyanate 16 and actinophyllic acid. 17 Bioactive natural products, which have long played an important role in synthetic organic chemistry and drug discovery, have traditionally been restricted to secondary metabolites.…”

Section: Natural Productsmentioning

confidence: 99%

Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Martin

2022

Acc. Chem. Res.

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Section: Natural Productsmentioning

confidence: 99%

Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Martin

2022

Acc. Chem. Res.

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“…The first application of Vaska's complex to reductive aminal formation was reported by the Martin group as the final step in the synthesis of the indole alkaloid (±)-alstoscholarisine E (Scheme 27). 82 Starting from triamine 14, they synthesized intermediate 15 in six steps. Exposure of 15 to the reported stoichiometric reductive conditions (DIBAL-H, or Schwartz's reagent) proved unsuccessful.…”

Section: Recent Applications In the Synthesis Ofmentioning

confidence: 99%

Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products

et al. 2020

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The tertiary amide is a ubiquitous functional group and plays an irreplaceable role in medicinal chemistry. Its robust nature has meantin the pastthat selective manipulation of this motif remained elusive. The reductive activation through hydrosilylation of tertiary amidesusing Vaska’s complex (IrCl(CO)(PPh3)2)has emerged as a powerful strategy for the chemoselective transformation of amides into reactive enamines and iminium ions. Furthermore, these synthetically valuable species can be accessed in the presence of traditionally more reactive functional groups. This approach to amide reductive activation via hydrosilylation has been exploited in a range of downstream C–C bond forming processes and has seen significant applications in total synthesis, enabling streamlined routes for the synthesis of complex natural product architectures. This perspective covers the development of this synthetic strategy, from initial hydrosilylation studies to its flourishing use in the reductive functionalization of amide-containing molecules, both simple and complex.

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“…It is equally applicable for the elaboration of simple building blocks into valuable products and for expediting natural product synthesis. − To this end, Vaska’s complex (IrCl(CO)(PPh 3 ) 2 ), in conjunction with TMDS (1,1,3,3-tetramethyldisiloxane) as a terminal reductant, has come to the fore as an effective system for generating iminium ions in situ, via the hydrosilylation of tertiary amide and lactam reactants (Scheme A) . The mild reaction conditions, exquisite chemoselectivity, and broad functional group tolerance of this approach have contributed to its growing application as a synthetic strategy in the elaboration of simple building blocks and in late-stage functionalization of complex molecular architectures including alkaloid natural products …”

Section: Introductionmentioning

confidence: 99%

Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

et al. 2020

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A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska's complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction's efficiency. Scheme 1. α-Functionalization strategies for amine synthesis from tertiary amides Scheme 3. Optimization studies for (A) Vaska's catalyzed amide hydrosilylation. (B) The photocatalytic reductive coupling of the silyl hemiaminal intermediate with DHA derivative. stituted structures delivered tertiary amine products, although a steric increase vs. reaction efficiency trend was observed. 19 Intramolecular Cyclization. We recognized the opportunity that this tandem amide activation protocolthrough tethering an alkene acceptor to the alkyl chain of the amide starting material-could be suitably leveraged towards the synthesis of complex heterocyclic amine frameworks. Accordingly, model substrates bearing a pendant α,β-unsaturated ester (1s-1t) were prepared, but initial studies demonstrated that these motifs did not readily undergo hydrosilylation using Vaska's catalyst (only around 80% conversion was achieved after 8 hours of reaction time), and furthermore significant quantities of over reduction side-product were isolated following the photocatalytic step. 20 Nevertheless, these initial challenges were circumvented when a derivative of Vaska's complex bearing triphenylphosphite ligands-previously reported by Nagashima 21-was employed in the hydrosilylation step instead (Scheme 5). Pleasingly, clean conversion to a stable silyl hemiaminal species was achieved within one hour, and subsequent subjection to the optimized photoredox conditions delivered the desired cyclic pyrrolidine (4s) and piperidine (4t) products in good yields. Scheme 5. Extension of the Vaska-photoredox system for reductive cyclization of tertiary amides Secondary Amide Activation. Recent endeavors by Chida and Sato, and Huang have demonstrated the utility of [Ir(COE)2Cl]2 complex in conjunction with Et2SiH2 reductant for the nucleophilic reductive functionalization of secondary amide building blocks, affording the corresponding α-branched secondary amine products. 4e,f Scheme 6. Reverse polarity, photocatalytic reductive functionalization of seconda...

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Stereoselective Total Synthesis of (±)-Alstoscholarisine E

Cited by 13 publications

References 50 publications

Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products

Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium-Catalyzed Hydrosilylation and Single Electron Transfer Strategy

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