Recent Syntheses of Epibatidine. A Review

Olivo, Horacio F.; Hemenway, Michael S.

doi:10.1080/00304940209355744

Cited by 28 publications

(10 citation statements)

References 46 publications

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“…The absolute configuration of sulfoxide (R S )-23 d prepared using ligand (R)-25 was determined by X-ray diffraction (XRD) analysis Scheme 5. Preparation of thioethers 21 a,b,c,d from p-thiocresol (20).…”

Section: Resultsmentioning

confidence: 99%

“…The first total syntheses appeared a year after the structure was revealed and epibatidine has now been prepared well over forty times 19. 20 Although the clinical promise of epibatidine was ultimately not fulfilled because of acute toxicity linked to nonselective agonism of nAChR subtypes, this compound and its analogues have become useful probes for dissecting the complexities of nAChR biology 21…”

Section: Introductionmentioning

confidence: 99%

“…The first total syntheses appeared a year after the structure was revealed and epibatidine has now been prepared well over forty times. [19,20] Although the clinical promise of epibatidine was ultimately not fulfilled because of acute toxicity linked to nonselective agonism of nAChR subtypes, this compound and its analogues have become useful probes for dissecting the complexities of nAChR biology. [21] Epibatidine was selected for this study because of its biological relevance and notoriety and our desire to demonstrate that a chain extension approach is not limited to the synthesis of linear acyclic compounds.…”

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confidence: 99%

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Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Emerson¹,

Zakharov²,

Blakemore³

2013

Chemistry A European J

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Four putative functionalized α-chloroakyllithiums RCH2CHLiCl, where R=CHCH2(18 a), CCH (18 b), CH2OBn (18 c), and CH[O(CH2)2O] (18 d), were generated in situ by sulfoxide-lithium exchange from α-chlorosulfoxides, and investigated for the stereospecific reagent-controlled homologation (StReCH) of phenethyl and 2-chloropyrid-5-yl (17) pinacol boronic esters. Deuterium labeling experiments revealed that α-chloroalkyllithiums are quenched by proton transfer from their α-chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α-deuterated α-chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid-base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b, the instability of which was attributed to a facile 1,2-hydride shift. By contrast, 18 d, a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a, 18 b, and 18 d in 16, 0, and 68% yield, respectively; α-deuterated isotopomers D-18 a and D-18 d gave yields of 33 and 79% for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (-)-epibatidine (15). One-pot double StReCH of boronate 17 by two exposures to (S)-D-18 a (≤66 % ee), followed by work-up with KOOH, gave the expected stereodiad product in 16% yield (d.r.~67:33). The comparable reaction using two exposures to (S)-D-18 d (≤90% ee) delivered the expected bisacetal containing stereodiad (R,R)-DD-48 in 40% yield (≥98% ee, d.r.=85:15). Double StReCH of 17 using (S)-D-18 d (≤90% ee) followed by (R)-D-18 d (≤90% ee) likewise gave (R,S)-DD-48 in 49% yield (≥97% ee, d.r.=79:21). (R,S)-DD-48 was converted to a dideuterated isotopomer of a synthetic intermediate in Corey's synthesis of 15.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Emerson¹,

Zakharov²,

Blakemore³

2013

Chemistry A European J

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“…To demonstrate the synthetic utility of the reaction, product 4 n was applied in the formal total synthesis of the natural alkaloid (−)‐epibatidine 6 , an analgesic approximately 200 times more potent than morphine and a highly potent agonist of the nicotinic acetylcholine receptor 21. To achieve this synthesis, a stereoselective reduction of the ketone functionality of product 4 n was performed (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Selective Access to Both Diastereoisomers in an Enantioselective Intramolecular Michael Reaction by Using a Single Chiral Organocatalyst and Application in the Formal Total Synthesis of (−)‐Epibatidine

Jensen

Weise

Dickmeiss

et al. 2012

Chemistry A European J

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Two in one: Both diastereoisomers of 4-nitro-3-substituted cyclohexanones are accessed selectively by an intramolecular Michael reaction using a single chiral aminocatalyst (see scheme). Mechanistic studies show that the reaction is selective for the cis-diastereoisomer and that the trans-diastereoisomer arises over time. DFT calculations suggest that the cis-selectivity is due to a favorable electrostatic interaction between the iminium ion and the nucleophile.

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“…Having established the asymmetric methodology for the α‐arylation of cyclic ketones, we sought to apply it to a short enantioselective synthesis of epibatidine ( 1 ; Scheme ). This alkaloid, which was isolated from the Ecuadorian poison frog Epipedobates tricolor in 1993, is 400 times more potent than morphine as an analgesic, and is also an extremely potent agonist of the nicotinic acetylcholine receptor 21. Numerous syntheses of epibatidine have since been published, most of which are racemic 22.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective α‐Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (−)‐Epibatidine

Aggarwal¹,

Olofsson

2005

Angew Chem Int Ed

145

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The enantioselective introduction of electrophiles a to carbonyl groups is a central topic in asymmetric synthesis. Although asymmetric a-alkylations have been well developed, high enantioselectivity in a-arylation of ketones has only been achieved in a very limited number of cases. These involve arylation of trisubstituted enolates using binap-Pd complexes which gives non-epimerizable, tetrasubstituted ketones. [1,2] However, this strategy cannot be used in the desymmetrization/arylation of cyclic ketones, since even if the enolate was generated enantioselectively, the ketone product would racemize the starting enolate (through proton transfer) at the high temperatures required for arylation.An alternative strategy involves a-arylation of b-ketoesters with aryl lead reagents (Scheme 1).[3] This strategy can be rendered asymmetric through 1) desymmetrization/bketoester formation, [4] 2) arylation, [3] and 3) decarboxylation and subsequent equilibration.However, a direct asymmetric arylation of cyclohexanones would clearly be superior. If this could be achieved, we envisaged that this strategy could be applied to a short asymmetric synthesis of the alkaloid (À)-epibatidine (1) (Scheme 2). Herein, we describe our success in achieving these goals.As possible electrophilic sources of aryl reagents, we considered diaryl iodonium(iii) salts since scattered reports existed of couplings with silyl enol ethers, [5] ketones, [6] and malonates, [7] albeit with varying yields. The scope and limitations of these couplings had not been investigated, and no successful asymmetric reactions have been reported. [8]

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Recent Syntheses of Epibatidine. A Review

Cited by 28 publications

References 46 publications

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Selective Access to Both Diastereoisomers in an Enantioselective Intramolecular Michael Reaction by Using a Single Chiral Organocatalyst and Application in the Formal Total Synthesis of (−)‐Epibatidine

Enantioselective α‐Arylation of Cyclohexanones with Diaryl Iodonium Salts: Application to the Synthesis of (−)‐Epibatidine

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