Total Synthesis of the Bridged Indole Alkaloid Apparicine

Bennasar, M.‐Lluïsa; Zulaica, Ester; Solé, Daniel; Roca, Tomas; García-Díaz, Davinia; Alonso, Sandra

doi:10.1021/jo901986v

Cited by 66 publications

(19 citation statements)

References 60 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Performed in refluxing dichloromethane, compounds 82a and b resulted, the newly established C=C bond staying where formed . However, according to the transformation depicted at the bottom of Scheme , this location of the C=C bond was disfavored when exposure to the Grubbs‐II catalyst in refluxing toluene provided an opportunity for the migration . When the dihydroazepine moiety contained an N ‐Ts group, this migration was unidirectional and “clockwise” (→ iso ‐ 82a ) .…”

Section: An Rcm/isomerization Approach To Compound 11dmentioning

confidence: 99%

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

et al. 2020

View full text Add to dashboard Cite

Four homoallyl ortho-vinylaryl ketones (10a-d) -1,8dienes of sorts -were prepared by several approaches. In the presence of 1-2 mol-% Grubbs-II catalyst, they ring-closed to give 6,7-dihydrobenzocyclohepten-5-ones (11a-d) in 90-96 % yield. With SeO 2 the parent compound (11a) delivered benzocyclohepten-5-one (13a) and/or selenium-containing compounds (18)(19)(20)(21)(22) but no more than traces of 6,7-benzotropolone (5a). However, 5a was accessible from compound 11a via the sodium enolate and allowing it to react with a stream of oxygen [a] Scheme 1. Top: our previously established ring-closing olefin metathesis ("RCM")/ketal hydrolysis route to type-5 6,7-benzotropolones. [9] Underneath: regiocomplementary processings of a type-4 RCM product via the dibromide 7 and the bromoolefins 7 or iso-7 by cross-couplings and hydrolyses giving type-8 or type-iso-8 6,7-benzotropolones, respectively. [10] The Arican routes of Scheme 1 have a major drawback, though, namely the harsh conditions required for hydrolyzing a type-4 ketal in the last step: Liberating the enol required refluxing with 10 equiv. of tosic acid and 100 equiv. of water in acetonitrile for 1 h -2 d. [9,10] These conditions were applicable to certain type-9 or type-iso-9-ketals, as well ( Figure 2). When their substituent R was Et, Ph, CO 2 Me or CO 2 Et, such hydrolyses also proceeded well. [9] However, when their substituent R was CH=CH-CO 2 iPr (in 9a or iso-9a), HC=CH 2 (in 9c or iso-9c) or C≡C-SiMe 3 (in iso-9c) the substrate vanished under hydrolysis conditions without delivering any benzotropolone. [9,10] The C≡C-SiMe 3 -containing ketal 9b was an in-between-case: Its hydrolysis released a benzotropolone as expected but the sidechain R had been converted into C(=O)-CH 3 . [10] Eur.2930 Scheme 2. Can 6,7-benzotropolones 5 be reached via an RCM/oxidation route rather than via the RCM/hydrolysis route of Scheme 1? A 4-e 2 oxidation 11 → 5 would be required overall, but two 2-e 2 oxidations 11 → 12 and 12 → 5 might be used as an alternative. 5.We wondered whether step 2 might be disadvantaged vs. a dehydration delivering the benzotropone 13. While 13 looks like a dead-end at first, it might be re-routable towards 5. This is because unsubstituted benzotropone (13, all R = H) gave unsubstituted benzotropolone (5, all R = H) by endoperoxide formation and an ensuing reduction with thiourea. [11] Consequently, benzotropones 13 appeared as conceivable intermediates of our Scheme-2 strategy towards benzotropolones. A Modified Synthesis of 6,7-BenzotropoloneOur proof-of-principle benzotropolone synthesis by the approach of Scheme 1 delivered the parent compound 5a and is shown in Scheme 3 and Scheme 5. Scheme 3 advances to the RCM product and Scheme 5 supplements its oxidation. Scheme 3. Reaching the RCM product 11a, our synthetic precursor of unsubstituted benzotropolone (5a).Our synthesis began by a salt-free Wittig methylidenation of ortho-bromobenzaldehyde (14, Scheme 3). [12] The resulting ortho-bromostyrene (15) was treated sucessively with nBuLi and the...

show abstract

Section: An Rcm/isomerization Approach To Compound 11dmentioning

confidence: 99%

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In the first total synthesis of (±)‐apparicine (Scheme c), the tricyclic ABC substructure of the indole alkaloid was also achieved from an acyl selenide. The radical acceptor is a bromovinyl unit that increases both the efficiency and endo regioselectivity of the ring closure.…”

Section: From Carboxylic Acid Derivativesmentioning

confidence: 99%

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

Bonjoch

Diaba

2020

Eur J Org Chem

View full text Add to dashboard Cite

The usefulness of radical reactions in alkaloid synthesis is reviewed from the perspective of the functional groups embedded in the molecular structure of synthetic intermediates, that act as precursors of carbon‐centered radicals in the construction of new C–C bonds. The functional groups featured are alkenes, alkynes, halides (alkyl, vinyl, aryl), xanthates, sulfides, selenides, aldehydes, ketones, carboxylic acid derivatives (selenoesters, haloacetamides), β‐dicarbonyl compounds, and α‐heterosubstituted nitrogen‐compounds. The use of nitrogen‐centered radicals for C–N bond formation is also covered. Among the variety of radical processes applied, the most predominant are the hydride reductive method (Sn, Si), atom transfer radical reactions (Cu, Ru, B), and single‐electron transfer radical reactions promoted by Sm, Ni, Fe, Mn, Ti, and Ag. This review showcases the role radical reactions have played in the recent development of new strategies in alkaloid synthesis, as well as the implementation of new radical procedures in demanding substrates.

show abstract

“…Due to their unique structure and potentially useful biological activity, the total synthesis of 5-nor stemmadenine alkaloids has been reported by Bennasar et al [ 39 , 40 ], Micalizio [ 37 ], and Takayama [ 41 ] (Scheme 2 ). In addition, synthetic work on the 1-azabicyclo[4.2.2]decane skeleton core has been published by Joule [ 42 , 43 ] and Weinreb’s group [ 44 ] (Scheme 3 ).…”

Section: Synthesis Studiesmentioning

confidence: 99%

“…In addition, synthetic work on the 1-azabicyclo[4.2.2]decane skeleton core has been published by Joule [ 42 , 43 ] and Weinreb’s group [ 44 ] (Scheme 3 ). A recent report of the total synthesis of (±)-apparicine ( 2 ) by Bennasar and co-workers [ 39 , 40 ] detailed an approach which utilized an intramolecular Heck reaction. Micalizio and Takayama [ 37 , 41 ] reported the total syntheses of conolidine ( 6 ), which could be derived from an iminium ion under intramolecular Mannich reaction.…”

Section: Synthesis Studiesmentioning

confidence: 99%

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

et al. 2016

View full text Add to dashboard Cite

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin–Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

show abstract

Total Synthesis of the Bridged Indole Alkaloid Apparicine

Cited by 66 publications

References 60 publications

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

6,7‐Benzotropolone Syntheses Based on Ring‐Closing Metatheses and Four‐Electron Oxidations

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

Contact Info

Product

Resources

About