Epibatidine, CMI-477(enantiomer), CMI-545(racemate (exo)-isomer), CMI-488

合成路线:2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system.4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI),which was further converted into ketone (VIII).Introduction of the pyridyl group,dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa),which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb).Fletcher et al.also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

参考文献标题:Total synthesis and determination of the absolute configuration of epibatidine
文献作者:Fletcher,S.R.; Baker,R.; Chambers,M.S.; Herbert,R.H.; Hobbs,S.C.; Thomas,S.R.; Verrier,H.M.; Watt,A.P.; Ball,R.G.
参考来源:J Org Chem 1994,59(7),1771-8


合成路线:4) Szantay et al.reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions.The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane.Ring closure took place by treatment of compound (XV) with KF/Al2O3.Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII).Upon boiling in toluene,(XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII).Taking advantage of Fletcher's endo- to exo-epimerization,(XVIII) was converted into racemic epibatidine in moderate yield.The advantage of this route is that no protection and consequently no deprotection steps are involved.But the combined yield in the last two steps is only 30%.

参考文献标题:A practical route to epibatidine
文献作者:Sz醤tay,C.; Kardos-Balogh,Z.; Moldvai,I.; Sz醤tay,C.Jr.; Major-Temesv醨y,E.; Blask? G.
参考来源:Tetrahedron Lett 1994,35(19),3171-4


合成路线:15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine,which was similar to Fletcher's synthesis.However,the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions.Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI),which was dehydrated to (LXII) with Burgess reagent.Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields,respectively.Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.

参考文献标题:Total synthesis of a frog poison,(?-epibatidine,a potent non-opioid analgesic
文献作者:Okabe,K.; Natsume,M.
参考来源:Chem Pharm Bull 1994,42(7),1432-6


合成路线:16) A similar approach was described by Zhang and Trudell in a recent report:The known 7-azabicyclo[2.2.1]heptan-2-one (VIII) was conveniently synthesized by the [4+2] cycloaddition of methyl 3-bromopropynoate (LXVII) and N-BOC-pyrrole (LXVI).They modified Fletcher's synthesis rendering it more stereoselective and suitable for the preparation of (I) on a large scale.The tertiary alcohol (IX) was successfully deoxygenated by a radical reaction via its methyl oxalyl ester with Bu3SnH in the presence of AIBN.This afforded the deoxygenated product stereoselectively as the endo-isomer (Xa).

参考文献标题:A short and efficient total synthesis of (?-epibatidine
文献作者:Zhang,C.; Trudell,M.L..
参考来源:J Org Chem 1996,61(20),7189-91


合成路线:10) Albertini et al.reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII).An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX).When (XXXIX) was subjected to hydrogenation,the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL).Three standard manipulations furnished the optically pure ketone (VIII),which had already been converted to epibatidine as described by Fletcher and coworkers.

参考文献标题:Enantioselective approach to 7-azabicyclo[2.2.1]heptane ring systems using D-(-)-quinic acid as the chiral educt: Application to the formal synthesis of (+)-epibatidine
文献作者:Albertini,E.; Barco,A.; Benetti,S.; De Risi,C.; Pollini,G.P.; Zanirato,V.
参考来源:Tetrahedron Lett 1997,38(4),681-4


合成路线:The key to the total synthesis of epibatidine is to construct the 7-azabicyclo[2.2.1]heptane system.A number of papers about the syntheses of racemic epibatidine and both of its enantiomers have been published.The different methodologies for the construction of this novel ring system can be classified into four categories.1) Intramolecular nucleophilic ring closure of 1-amino-4-substituted-cyclohexane derivatives.Broka reported the first total synthesis of (?-epibatidine in 1993.The preparation of ketoaldehyde (III) was achieved as a single isomer by reaction of enal (II) with 2-(trimethylsilyloxy)-1,3-butadiene.(III) was converted into aminomesylate (IV) in 15 steps,which was heated in CHCl3 to give the mesylate salt of (I) in excellent yield.Starting from 6-chloronicotinaldehyde,epibatidine was obtained via a reaction sequence of 17 steps in an overall yield of 6%.Broka's work confirmed the correctness of the structure proposed by Daly et al.

合成路线:2) Fletcher and his group also utilized an intramolecular displacement to construct the azabicycloheptane ring system.4-Benzylamino-1,2-epoxycyclohexane (V) was cyclized in N-methyl-pyrrolidone upon heating to yield the exo-alcohol (VI),which was further converted into ketone (VIII).Introduction of the pyridyl group,dehydration and catalytic hydrogenation resulted primarily in the endo-isomer (Xa),which could be epimerized using t-BuOK to afford the more stable exo-isomer (Xb).Fletcher et al.also succeeded in separating the enantiomers of (VII) as their Mosher ester and in establishing the absolute configuration of (I) as (1R,2R,4S).

合成路线:3) Corey's group published a stereocontrolled route to both enantiomers of epibatidine through HPLC separation of N-(trifluoroacetyl)epibatidine using chiral columns.A Diels-Alder reaction between (Z)-alpha,beta-unsaturated ester (XI) and 1,3-butadiene furnished the cis-4,5-disubstituted cyclohexene (XII),which was converted to the vicinal dibromide (XIII).Upon treatment with t-BuOK,(XIII) underwent intramolecular nucleophilic substitution to give compound (XIV) with the azabicyclo[2.2.1]heptane ring system.

合成路线:4) Szantay et al.reported a practical route to epibatidine by using commonly available starting materials under convenient reaction conditions.The alpha,beta-unsaturated ketone (XV) was synthesized by Wittig reaction of 6-chloronicotinaldehyde and the appropriate phosphorane.Ring closure took place by treatment of compound (XV) with KF/Al2O3.Reduction of the keto group followed by mesylation and subsequent reduction of the nitro group afforded amine (XVII).Upon boiling in toluene,(XVII) was immediately transformed into the undesired endo-isomer of epibatidine (XVIII).Taking advantage of Fletcher's endo- to exo-epimerization,(XVIII) was converted into racemic epibatidine in moderate yield.The advantage of this route is that no protection and consequently no deprotection steps are involved.But the combined yield in the last two steps is only 30%.

合成路线:5) Later on,Szantay's group modified the above described procedure based on a polarity reversal approach (8).Compound (XVI) was thus converted to the ring closure precursor (XIX) in 7 steps.Base-catalyzed ring closure of (XIX) afforded racemic epibatidine.

合成路线:6) Nakai et al.used 3-lithio pyridine as a nucleophile to attack ketone (XX),yielding the tertiary alcohol (XXI) stereoselectively.Reductive elimination of the hydroxyl group followed by oxidation and acid hydrolysis gave N-oxide (XXII),which was treated with POCl3 to produce (I) and (XXIII) in low yields.

合成路线:7) Sestanj and his coworkers succeeded in synthesizing epibatidine by a conjugate addition intramolecular displacement strategy.Conjugate addition of higher order cyanocuprate (XXIV) to alpha,beta-unsaturated ketone (XXV) obtained the ketone (XXVI),which was converted to (XXVII) in 60% overall yield.Under Mitsunobu conditions with DEAD and PPh3 as reagents,only the beta-amino-tosylate cyclized to give the epibatidine ring system.

合成路线:8) Ko and his coworkers employed the [4+2] addition reaction of 1-(2-chloro-5-pyridyl)cyclohexa-2,4-diene (XXIX) with singlet oxygen to form the bicyclic peroxide (XXX) as the key step.(XXX) was converted to azidomesylate (XXXI) in 42% overall yield.Based on Broka's epibatidine synthesis,(?-(I) was obtained through reduction and intramolecular displacement.

合成路线:9) The first asymmetric synthesis of (-)-epibatidine was disclosed by Trost and Cook through a Pd-catalyzed desymmetrization of cis-dibenzoyloxy-2-cyclohexene (XXXII) and a Pd-catalyzed cross-coupling reaction.Dibenzoate (XXXII) was reacted with trimethylsilylazide in the presence of a Pd catalyst with chiral phosphine ligands to give ent-(XXXIII) in excellent yield and e.e.(XXXIII) was converted to vinyl bromide (XXXIV),which was coupled with the stable organostannane (XXXV) through a Pd(0)-catalyzed reaction to give enone (XXXVI).Reduction of the double bond and carbonyl,O-mesylation of the resulting amido alcohol and finally heating of the crude amino mesylate in acetonitrile produced (-)-epibatidine.

合成路线:10) Albertini et al.reported a formal synthesis of epibatidine utilizing the enantiopure cyclohexanone (XXXVIII) as a convenient starting material which was easily available from D-(-)quinic acid (XXXVII).An important step in this synthesis was the regioselective intramolecular nucleophilic ring opening of the vicinal diol cyclic sulfate (XXXIX).When (XXXIX) was subjected to hydrogenation,the azido group was converted into an amino group and an internal displacement took place spontaneously to form the inner salt (XL).Three standard manipulations furnished the optically pure ketone (VIII),which had already been converted to epibatidine as described by Fletcher and coworkers.

合成路线:11) Hassner and Belostotskii reported a simple synthesis of 7-alkyl-7-azabicyclo[2.2.1]heptanes.The starting aminoalcohols which were easily available from the monoethylene ketal of 1,4-cyclohexanedione (XLI) were treated with triphenylphosphine-carbon tetrachloride,leading to 7-alkyl-7-azabicyclo[2.2.1]heptanes (XLIII) in good yields.Recently,Davis et al.described the microbial hydroxylations of (XLIII) using the fungi Beauveria bassiana,Rhizopus nigricans,Aspergillus ochraceus and Rhizopus arrhizus as the primary organisms.Though the enantioselectivity was not high enough,these results demonstrated the potential of microbiological oxygenations to deliver enantioselective reactions.

合成路线:12) Reaction of N-substituted-pyrrole derivatives with activated dienophiles.Retrosynthetic analysis revealed that the [4+2] cycloaddition reaction between pyrrole and dienophiles should be a general method for the synthesis of the 7-azanorborane ring system.Unfortunately,pyrrole is not a good diene for the Diels-Alder reactions.Pyrrole and its derivatives readily undergo Michael addition upon treatment with dienophiles,and the resulting 7-aza[2.2.1]bicycloheptenes are thermodynamically unstable.In order to stablize the resultant products and accelerate the cycloaddition reaction,N-protected pyrroles with a decreased aromaticity of the pyrrole ring are usually used as diene components and acetylene equivalents are used as dienophiles.In 1993 Shen et al.first reported a 4-step synthesis of racemic epibatidine.A Diels-Alder reaction of N-carbomethoxypyrrole (XLV) and phenylsulfonyl(6-chloro-3-pyridyl)acetylene (XLVI) afforded the adduct (XLVII) in 70% yield.Desulfonation and concomitant reduction of conjugated double bond with sodium amalgam resulted in a mixture of 1:2 ratio of exo-(XLVIII) to endo-(XLVIII).

合成路线:13) Later on Carroll and Kotian modified Shen's route by replacement of N-carbomethoxypyrrole with N-(t-carbobutoxy)pyrrole in order to avoid the drastic reaction condition in the deprotection step.However,there was the problem of competing retro Diels-Alder reaction of the cycloadduct (L) and dechlorination.Therefore,the selective reduction of the least substituted double bond of (L) was carried out first.Desulfonation and simultaneous reduction of (LI) with amalgam obtained a 1:2 mixture of exo-(LII) and endo-(LII) analogous to Shen's report.The endo-isomer was epimerized to the exo-isomer in 46% yield using Fletcher's procedure.Finally,deprotection of the BOC group under mild conditions produced (I) in nearly quantitative yield.

合成路线:14) It is noteworthy that Regan et al.described a very concise synthesis of racemic epibatidine.The key step was a reductive Pd-catalyzed Heck-type coupling of the known starting materials olefin (LVI) and 2-chloro-5-iodopyridine (LVII).The desired exo-isomer (LVIII) was formed stereoselectively.

合成路线:15) Natsume's approach to epibatidine was to construct the basic skeleton of (I) by condensation of N-protected 7-azabicyclo[2.2.1]heptan-2-one with 5-lithio-2-chloropyridine,which was similar to Fletcher's synthesis.However,the azabicycloheptanone (LX) was derived from the Diels-Alder adduct (LIX) of 1-(p-toluenesulfonyl)pyrrole and dimethyl acetylenedicarboxylate through a standard sequence of reactions.Reaction of (LX) with 5-lithio-2-methoxypyridine gave (LXI),which was dehydrated to (LXII) with Burgess reagent.Catalytic hydrogenation of (LXII) over palladium-on-charcoal in 2-propanol/water (12:1) containing 1% HCl afforded (LXIII) and (LXIV) in 22% and 72% yields,respectively.Treatment of (LXIV) with POCl3/DMF obtained (LXV) in 70% yield.

合成路线:16) A similar approach was described by Zhang and Trudell in a recent report:The known 7-azabicyclo[2.2.1]heptan-2-one (VIII) was conveniently synthesized by the [4+2] cycloaddition of methyl 3-bromopropynoate (LXVII) and N-BOC-pyrrole (LXVI).They modified Fletcher's synthesis rendering it more stereoselective and suitable for the preparation of (I) on a large scale.The tertiary alcohol (IX) was successfully deoxygenated by a radical reaction via its methyl oxalyl ester with Bu3SnH in the presence of AIBN.This afforded the deoxygenated product stereoselectively as the endo-isomer (Xa).

合成路线:17) Pandey et al.reported an efficient synthesis of epibatidine via [3+2] cycloaddition of nonstabilized azomethine ylide and substituted 6-chloro-3-vinylpyridine.The precursor (LXX) was obtained in 73% yield from N-BOC pyrrolidine (LXIX) by standard manipulations.The [3+2] cycloaddition between (LXX) and alpha,beta-unsaturated ester (LXXI) furnished cycloadduct (LXXII) stereoselectively.Decarboxylation followed by reductive N-debenzylation converted (LXXII) into (I) in 78% overall yield.

合成路线:18) Ring contraction of the tropinone skeleton via a Favorskii rearrangement.Bai et al.utilized the readily available tropinone (LXXIII) as a starting material.Compound (LXXIV),which could be obtained from (LXXIII) in one step,was brominated with cupric bromide to give the monobromide (LXXV).Without separation of the two isomers,both isomers (LXXV) underwent Favorskii rearrangement to yield the expected ester (LXXVI).The key intermediate (LXXVII) was then obtained by selenation of (LXXVI) followed by selenoxide elimination.A palladium-catalyzed Heck-type coupling of (LXXVII) and 2-chloro-5-iodopyridine (LVII) furnished the exo-isomer (LXXVIII) stereoselectively in 56% yield.Conversion of (LXXVIII) to (I) was achieved by radical decarboxylation of the corresponding thiohydroxamic ester followed by cleavage of the carbamate with iodotrimethyl silane.

合成路线:19) Intramolecular cyclization of substituted proline derivatives.Rapoport et al.developed an asymmetric methodology which had potential for the enantiospecific synthesis of (+)- and (-)-epibatidine.The triflate (LXXIX) was readily synthesized from levulinic acid in 3 straightforward steps.Alkylation of S-thiolactam (LXXX) prepared from L-glutamic acid with triflate (LXXIX),followed by sulfide contraction provided the carbamate (LXXXI).(LXXXI) was then converted into keto acid (LXXXII).(LXXXII) was decarboxylated and the resulting iminium ions were subjected to intramolecular cyclization to give a mixture of trans-2,3-disubstituted-7-azabicyclo[2.2.1]heptanes (LXXXIII) and (LXXXIV).This mixture was selectively converted into (+)- and (-)-N-BOC-7-azabicyclo[2.2.1]heptane-2-ones (VIII),which are versatile intermediates for the enantiospecific synthesis of (+)- and (-)-epibatidine.

参考文献标题:Epibatidine
文献作者:Bai,D.; Xu,R.; Zhu,X.
参考来源:Drugs Fut 1997,22(11),1210

###############################################################################################################################################################################################################################################################