Natural Product Synthesis

DOI: 10.1002/ange.200504015

A Flexible Strategy for the Synthesis of Tri- andTetracyclic Lupin Alkaloids: Synthesis of(+)-Cytisine, (� )-Anagyrine, and(� )-Thermopsine**

Diane Gray and Timothy Gallagher*

The lupin alkaloids, which comprise a varied range ofprimarily bi-, tri-, and tetracyclic molecules based on aquinolizidine core, represent an increasingly important groupof natural products that exhibit a diverse array of properties.[1]

(�)-Cytisine (1),[2,3] which is a potent and a4b2 subtype-selective partial agonist at nicotinic acetylcholine receptors,was recently exploited successfully by Coe, O(Neill et al. asthe natural product lead for the discovery of varenicline.[4] Ina quite different realm, the potential (and also limitations) of(�)-sparteine (2) as a reagent and ligand for asymmetricsynthesis are now well established.[5–7] Many key structuralrelationships between important members of the lupinalkaloids are known.[1] For example, reduction of (+)-anagyrine (3) gives (�)-sparteine (2), while reduction of(�)-thermopsine (4), the C11 epimer of anagyrine, leads to

(�)-a- and (+)-b-isosparteine. Given this background, thedevelopment of general and therefore flexible syntheticentries to key lupin alkaloid targets becomes an attractivechallenge; earlier contributions in this area by van Tamelenand Baran[3a,d] are of particular note.

We previously reported a novel approach to (� )-cyti-sine.[8a] Although highly convergent, this chemistry hadlimitations in terms of its broader utility.[8b] Herein, we

[*] D. Gray, Prof. T. GallagherSchool of ChemistryUniversity of BristolBristol BS81TS (UK)Fax: (+44)117-929-8611E-mail: t.gallagher@bristol.ac.uk

[**] We thank Dr. Ernest Boehm (Apin Chemicals Ltd.) for an authenticsample of natural anagyrine and the EPSRC for financial support.

Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.

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report a second-generation approach that provides both amore efficient and also an asymmetric entry to cytisine.Furthermore, the core strategy focuses on establishing bothN1�C10 and C6�C7 bond constructions, which are not onlysuited to cytisine (1) but also encompass a broader range oflupin alkaloids. The more general applicability of ourapproach is demonstrated here by the synthesis of bothanagyrine (3) and thermopsine (4).

Our approach to cytisine (1) is shown in Scheme 1 andinvolves the efficient enzymatic resolution of ester 5,[8, 9] which

is readily available in a two-pot operation from simple andcommercially available starting materials. Resolution of 5 wasachieved using a-chymotrypsin to give (5R)-5 in 42% isolatedyield and with over 98% ee (as determined by chiralHPLC).[10] The acid (5S)-6 was obtained in 48% yield in64% ee, and the absolute configuration of (5R)-5 wasestablished by its conversion into (+)-cytisine[3j] (the non-natural enantiomer). Reduction of ester (5R)-5 and bromi-nation provided (5R)-7 (57% overall), and reaction of 7 with2-pyridone under basic conditions gave the N-alkylatedadduct 8 (66%), so establishing the N1�C10 linkage.

The second key feature of our strategy is formation of theC6�C7 bond, which is a structural feature common to manylupin alkaloids. Previously, this bond was set using a Pd0-mediated intramolecular a-arylation of the lactam unit,[8] butthe same C6�C7 linkage can now be made more simply.Exposure of lactam 8 to LHMDS (or LDA) led to smoothcyclization to give the internal 1,6-addition adduct 9 as asingle diastereomer (and alkene regioisomer) in 94% yield,with the stereochemistry at C6 of 9 confirmed by NOEstudies.[12] Intramolecular 1,6-additions to 2-pyridone havenot previously been reported, and indeed there are only a fewexamples known of the corresponding intermolecular pro-cess.[11] Mild oxidation of 9 gave lactam 10 in 79% yield, whichwas then converted through two steps[8] into (+)-cytisine byreduction of the lactam and debenzylation (60% yield over

two steps). In this way, non-natural (+)-cytisine ((+)-1)[13] wasobtained in 10 steps in 3.7% overall yield from commerciallyavailable materials and also allowed us to assign the absolutestereochemistry of both (5R)-5 and (5S)-6 as indicated inScheme 1.

The broader applicability of this synthetic strategy isexemplified for two representative tetracyclic lupin alkaloids,anagyrine (3)[14,15] and its C11 epimer thermopsine (4),[15, 16] asshown in Scheme 2 and Scheme 3. Anagyrine (3) was firstisolated in 1895 from Anagyris foetida, and previous synthe-ses of anagyrine were reported by van Tamelen and Baran,[3d]

Goldberg and Lipkin,[14a] and most recently by Padwa et al.[14b]

Our approach to 3 is shown in Scheme 2, and again it targetedthe N1�C10 and C6�C7 bonds as the key disconnections,requiring the quinolizidine-based bromide 13[17,18] as asubstrate for alkylation of 2-pyridone. Bromide 13 was

Scheme 1. Synthesis of (+)-cytisine ((+)-1). a) See Ref. [9], 56%;b) 10% Pd/C, H2 (1 atm), Na2CO3, EtOH, 95%; c) a-chymotrypsin,0.1m phosphate buffer, acetone, pH 7.4, (5R)-5 (42% yield, >98% ee)and (5S)-6 (48% yield, 64% ee after derivatization to its methyl esterfor HPLC analysis); d) LiAlH4, THF; e) PBr3, toluene, 57% overall yieldfrom (5R)-5 ; f) 2-pyridone, K2CO3, Bu4NBr, H2O, PhMe, reflux, 66%(+15% of the corresponding 2-alkoxypyridine); g) LHMDS (2 equiv),THF, 70 8C, sealed tube, 15 h, 94%; h) MnO2, CH2Cl2, 79%;i) BH3·THF, 0 8C!RT; j) Pd(OAc)2, H2 (1 atm), MeOH, HCl, 60%overall from 10. Bn=benzyl; LHMDS= lithium hexamethyldisilazide.

Scheme 2. Synthesis of (� )-anagyrine (3). a) LHMDS, EtOCH2Cl, THF,�78 8C!RT, 87%; b) KOtBu, THF, �78 8C, 84%; c) MeCO2tBu, LDA,�78 8C, THF, 68%; d) 10% Pd/C, H2 (1 atm), 100%; e) AcOH,toluene, reflux, 73%; f) LiAlH4, THF, then PBr3, toluene, 70% overallyield; g) 2-pyridone, K2CO3, Bu4NBr, H2O, toluene, reflux, 66% (+14%of the corresponding 2-alkoxypyridine); h) LDA (2 equiv), THF, roomtemperature, 3 h, 44%; i) MnO2, CH2Cl2, 76%; j) BH3·THF, 0 8C!RT,85%. LDA= lithium diisopropylamide; AcOH=acetic acid.

Scheme 3. Synthesis of (� )-thermopsine (4). a) LHMDS, (EtO2C)2C=CH2, THF, �78 8C!RT, 79%; b) TFA, CH2Cl2, THF, 0 8C, 100%;c) AcOH, toluene, reflux, 89%; d) NaCl, H2O, DMSO, 130 8C, 72 h,72%; e) LiAlH4, THF, then PBr3, toluene, 72% overall yield; f) 2-pyridone, K2CO3, Bu4NBr, H2O, toluene, reflux, 71% (+12% of thecorresponding 2-alkoxypyridine); g) LDA (2 equiv), THF, room temper-ature, 2.5 h, 26%; h) MnO2, CH2Cl2, 70%; i) BH3·THF, 0 8C!RT, 57%.TFA= trifluoroacetic acid; DMSO=dimethyl sulfoxide.

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prepared through diastereoselective 1,4-addition[19] of theenolate derived from tert-butyl acetate to the a,b-unsaturatedester 11, which was available in two steps from racemic ethylN-benzyl homopipecolate. N-Debenzylation of the 1,4-addi-tion adduct and then acid-mediated cyclization led to 12, andreduction of the ester and bromination provided the requisitebromide 13. Again, this intermediate underwent clean N-alkylation with 2-pyridone, and cyclization of 14 under basicconditions proceeded to give 15 in 44% yield. This step servesto complete the tetracyclic core of anagyrine as a singlediastereomer, with the relative stereochemistry at C6 thatcorresponds to that required for sparteine, as again deter-mined by NOE studies.[20] Oxidation of 15, followed byselective reduction of lactam 16 then gave (� )-anagyrine (3),which we were able to compare directly with an authenticsample of the natural product.[21]

The synthesis of (� )-thermopsine (4) was achieved byapplication of the same strategy. The only significant require-ment here was for the epimeric quinolizidine derivative20,[17, 18] which was prepared efficiently as shown in Scheme 3.The key stereocenters were established by addition of theenolate derived from (� )-17 to freshly prepared diethylmethylenemalonate to give adduct 18 as a single diastereo-mer. The stereochemical outcome of this key step wasconsistent with that reported for the corresponding allylationreaction, as reported by Knight and co-workers.[22] Cleavageof the Boc residue from 18 and thermally induced cyclizationwere followed by selective ester cleavage and decarboxyla-tion to give 19, the structure and relative stereochemistry ofwhich was confirmed by single-crystal X-ray analysis.[23]

Conversion of 19 into bromide 20 followed by N-alkylationof 2-pyridone gave 21. This intermediate underwent base(LDA)-induced cyclization to provide 22 in 26% yield.[24, 25] Inthe same fashion as described for anagyrine, oxidation of 22and subsequent reduction of the lactam in 23 gave (� )-thermopsine (4). Although an authentic sample of thermop-sine was not available, we were able to compare spectroscopicdata for our synthetic material with that available in theliterature[15c,d] and our crystallographic assignment of ester 19underpins this conclusion.

In summary, we have disclosed a synthetic strategy that isbroadly applicable to representative lupin alkaloids, withsyntheses of anagyrine (3) and thermopsine (4) also consti-tuting formal routes to sparteine (2) and a- and b-isospar-teines, respectively. More significantly, however, the chemis-try that we have described is highly convergent, concentratingas it does on two key and common bonds within the core ofthese target structures. This approach also offers newopportunities to develop novel and significantly differentvariants of important targets, including both cytisine andsparteine, which will complement currently available meth-ods. Our primary objective has been to validate the viabilityof the basic synthetic strategy, but asymmetric entries are alsoimportant and are being pursued.[18] However, the corner-stone of this new approach is the intramolecular 1,6-additionof a mono- or bicyclic lactam enolate to an N-alkylatedpyridone as exemplified by 8!9 (94%), 14!15 (44%), and21!22 (26%). Such 1,6-addition processes are without directprecedent, and this step needs to be examined in more detail

as it is clearly sensitive to the steric environment of thesubstrate.[25] This type of process has applications elsewhere,and further studies to understand more fully, optimize, andextend the scope of this process are underway.[26]

Received: November 11, 2005Published online: March 7, 2006

.Keywords: alkaloids · cyclization · natural products ·nucleophilic addition · synthetic methods

[1] N. J. Leonard in The Alkaloids, Vol. 3 (Eds: R. H. F. Manske,H. L. Holmes), Academic Press, New York, 1953, p. 120; H. C. S.Wood, R. Wrigglesworth in Rodd�s Chemistry of CarbonCompounds, Vol. IV, part H (Ed: S. Coffey), Elsevier, Amster-dam, 1978, chap. 38, p. 285; K. A. Aslanov, Y. K. Kushmuradov,A. S. Sadykov in The Alkaloids, Vol. 31 (Ed: A. Brossi),Academic Press, New York, 1997, p. 117.

[2] H. Ing, J. Chem. Soc. 1932, 2778; A. Partheil,Arch. Pharm. 1894,232, 161. For a recent overview of nicotinic pharmacologyrelevant to cytisine, see: A. A. Jensen, B. Frølund, T. Lijefors, P.Krogsgaard-Larsen, J. Med. Chem. 2005, 48, 4705.

[3] For previous syntheses of cytisine, see ref. [8] and: a) E. E.van Tamelen, J. S. Baran, J. Am. Chem. Soc. 1955, 77, 4944; b) F.Bohlmann, A. English, N. Ottawa, H. Sander, W. Weise, Chem.Ber. 1956, 89, 792; c) T. R. Govindachari, S. Rajadurai, M.Subramanian, B. S. Thyagarajan, J. Chem. Soc. 1957, 3839;d) E. E. van Tamelen, J. S. Baran, J. Am. Chem. Soc. 1958, 80,4659; e) B. T. O(Neill, D. Yohannes, M. W. Bundesmann, E. P.Arnold, Org. Lett. 2000, 2, 4201; f) J. W. Coe, Org. Lett. 2000, 2,4205; g) P. Nshimyumukiza, D. Cahard, J. Rouden, M. C. Lasne,J. C. Plaquevent, Tetrahedron Lett. 2001, 42, 7787; h) D. Stead, P.O(Brien, A. J. Sanderson, Org. Lett. 2005, 7, 4459; for asym-metric routes to cytisine, see: i) B. Danieli, G. Lesma, D.Passarella, A. Sacchetti, A. Silvani, A. Virdis, Org. Lett. 2004,6, 493; for the synthesis of (+)-cytisine, see: j) T. Honda, R.Takahashi, H. Namiki, J. Org. Chem. 2005, 70, 499.

[4] a) J. W. Coe, M. G. Vetelino, C. G. Bashore, M. C. Wirtz, P. R.Brooks, E. P. Arnold, L. A. Lebel, C. B. Fox, S. B. Sands, T. I.Davis, D. W. Schulz, H. Rollema, F. D. Tingley, B. T. O(Neill,Bioorg. Med. Chem. Lett. 2005, 15, 2974; b) J. W. Coe, P. R.Brooks, M. G. Vetelino, M. C. Wirtz, E. P. Arnold, J. H. Huang,S. B. Sands, T. I. Davis, L. A. Lebel, C. B. Fox, A. Shrikhande,J. H. Heym, E. Schaeffer, H. Rollema, Y. Lu, R. S. Mansbach,L. K. Chambers, C. C. Rovetti, D. W. Schulz, F. D. Tingley, B. T.O(Neill, J. Med. Chem. 2005, 48, 3474. Varenicline (Champix)has recently been granted a priority review by the US FDA andis currently in late-stage clinical trials as a smoking cessationagent.

[5] a) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376; Angew.Chem. Int. Ed. Engl. 1997, 36, 2283; b) T. Schutz, Synlett 2003,901.

[6] For the synthesis, evaluation, and computational aspects ofsparteine mimics, see: a) M. J. Dearden, C. R. Firkin, J. P. R.Hermet, P. O(Brien, J. Am. Chem. Soc. 2002, 124, 11870; b) M. J.Dearden, M. J. McGrath, P. O(Brien, J. Org. Chem. 2004, 69,5789; c) P. O(Brien, K. B. Wiberg, W. F. Bailey, J. P. R. Hermet,M. J. McGrath, J. Am. Chem. Soc. 2004, 126, 15480; d) P. W.Phuan, J. C. Ianni, M. C. Kozlowski, J. Am. Chem. Soc. 2004, 126,15473.

[7] For asymmetric syntheses of sparteine, see: a) B. T. Smith, J. A.Wendt, J. Aube, Org. Lett. 2002, 4, 2577; b) J. P. R. Hermet, M. J.McGrath, P. O(Brien, D. W. Porter, J. Gilday, Chem. Commun.2004, 1830; a number of approaches to racemic sparteine havealso been reported; see: T. Buttler, I. Fleming, S. Gonsior, B. H.

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Kim, A. Y. Sung, H. G. Woo, Org. Biomol. Chem. 2005, 3, 1557,and references therein.

[8] a) C. Botuha, C. M. S. Galley, T. Gallagher, Org. Biomol. Chem.2004, 2, 1825; b) We have already examined the feasibility ofextrapolating this first-generation synthetic approach to ther-mopsine (4). However, problems were encountered in both theN-alkylation of 6-bromo-2-pyridone using bromide 20 to estab-lish the N1�C10 linkage: O-alkylation predominated. This resultprovided the motivation to find more straightforward solutionsto the formation of the N1�C10 and C6�C7 bonds.

[9] G. R. Cook, L. G. Beholz, J. R. Stille, J. Org. Chem. 1994, 59,3575.

[10] Felluga et al. reported the enzymatic resolution of a series of N-substituted pyrrolidinone analogues of 5 : F. Felluga, G. Pitacco,M. Prodan, S. Pricl, M. Visintin, E. Valentin, Tetrahedron:Asymmetry 2001, 12, 3241. The enantiomeric excess of ester(5R)-5 was determined by chiral HPLC (Chiralcel OJ column)using racemic 5 as a standard. The enantiomeric excess of acid(5S)-6 was determined by its conversion into ester (5S)-5 usingHCl in MeOH. We have observed the same sense of asymmetricdifferentiation, that is, selective hydrolysis of (5S)-5 to (5S)-6, asseen by Felluga et al. in the five-membered lactam series.

[11] For rare examples of intermolecular 1,6-additions of alkyllithium derivatives to 2-pyridones that lack additional activating(electron-withdrawing) substituents, see: a) P. Meghani, J. A.Joule, J. Chem. Soc. Perkin Trans. 1 1988, 1; b) E. W. Thomas, J.Org. Chem. 1986, 51, 2184; an interesting photochemical 1,6-addition to 2-pyridone has been suggested to involve electrontransfer and radical coupling; see: N. Sakurai, S. Ohmiya, J.Chem. Soc. Chem. Commun. 1993, 297.

[12] Characterization data for all compounds reported herein areavailable in the Supporting Information. NOE experiments werecarried out to determine the stereochemistry of 9. Irradiation ofC6-H showed an enhancement of both C8-Hax (2.8%) and C10-Hax (6.2%). Irradiation of C8-Hax showed an enhancement ofboth C6-H (9.1%) and C10-Hax (4.8%).

[13] Natural (�)-cytisine is commercially available, and we used acommercial sample of it to compare with our synthetic material.A lack of information in the literature as to the pharmacologicalprofile of (+)-cytisine[26] prompted our interest in this enantio-mer as our initial target, and (+)-cytisine is currently underevaluation as a nicotinic ligand. Optical rotation data forsynthetic (+)-cytisine were recorded: [a]20

D =++ 120 (c= 0.1,EtOH); (literature values: for (�)-1 [a]D=�110 (c= 0.5,EtOH)[13a] ; for (+)-1 [a]D=++ 113.5 (c= 0.3, EtOH)[3j]).a) Y.-H. Wang, J.-S. Li, H. Kubo, K. Higashiyama, H. Komiya,S. Ohmiya, Chem. Pharm. Bull. 1999, 47, 1308.

[14] The first synthesis of anagyrine was reported by van Tamelenand Baran,[3d] who exploited related chemistry to synthesisecytisine[3a-d] and thermopsine[3d] . For later routes to anagyrine,see: a) S. I. Goldberg, A. H. Lipkin, J. Org. Chem. 1972, 37, 1823;b) A. Padwa, T. M. Heidelbaugh, J. T. Kuethe, J. Org. Chem.2000, 65, 2368.

[15] The crystal structure reported supposedly for anagyrine (A. U.Rahman, A. Pervin, M. I. Choudhary, N. Hasan, B. Sener, J. Nat.Prod. 1991, 54, 929) corresponds, in fact, to thermopsine, and thishas been the subject of a query note placed on the file in theCambridge Crystallographic Data Centre. The authors of theoriginal paper, however, have not commented on this apparenterror. There has been some dispute over the stereochemicalassignments of anagyrine and thermopsine; for a discussion ofthe issues involved, see: a) D. S. Rycroft, D. J. Robins, I. H.Sadler,Magn. Reson. Chem. 1991, 29, 936; b) Z. M. Liu, L. Yang,Z. J. Jia, J. H. Chen, Magn. Reson. Chem. 1992, 30, 511. Thisproblem has since been resolved and the original assignmentsconfirmed: c) D. J. Robins, D. S. Rycroft, Magn. Reson. Chem.1992, 30, 1125; d) B. Mikhova, H. Duddeck,Magn. Reson. Chem.

1998, 36, 779. Mikhova and Duddeck[15d] report a comprehensivelisting of 13C NMR data for lupin alkaloids, including bothanagyrine and thermopsine.

[16] Earlier syntheses of thermopsine were reported by van Tamelenand Baran[3d] and Bohlmann et al. (F. Bohlmann, E. Winterfeldt,H. Overwien, H. Pagel, Chem. Ber. 1962, 95, 944).

[17] A number of different approaches to racemic quinolizidinesesters and halides 12/19 and 13/20, respectively, have alreadybeen reported[17a–h] , but attempts to produce asymmetric variantsof these have had limited success.[17h] New synthetic approachesto both 12 and 19 have been outlined herein (Schemes 2 and 3)with the longer term aim of using these routes to provideenantiomerically pure substrates. These studies are currentlyunderway.[18] a) F. Bohlmann, E. Winterfeldt, H. Laurent, W.Ude, Tetrahedron 1963, 19, 195; b) T. Kappe, Monatsh. Chem.1967, 98, 1852; c) B. Lal, D. N. Bhedi, H. Dornauer, N. J.De Souza, J. Heterocycl. Chem. 1980, 17, 1073; d) M. L. Brem-merr, S. M. Weinreb, Tetrahedron Lett. 1983, 24, 261; e) M. Ihara,T. Kirihara, K. Fukumoto, T. Kametani, Heterocycles 1985, 23,1097; f) M. Ihara, T. Kirihara, A. Kawaguchi, M. Tsuruta, K.Fukumoto, J. Chem. Soc. Perkin Trans. 1 1987, 1719; g) T.Nagasaka, H. Yamamoto, H. Hayashi, H. Kato, M. Kawaida, K.Yamaguchi, F. Hamaguchi, Heterocycles 1989, 29, 1209; h) M. J.Wanner, G. J. Koomen, Tetrahedron 1991, 47, 8431; i) E. D.Edstrom, Tetrahedron Lett. 1991, 32, 5709.

[18] Methyl homopipecolate, the starting material used in Schemes 2and 3, is now available in enantiomerically pure form by eitheran efficient homologation process[18a] or by enzymatic resolu-tion.[18b] a) D. Gray, C. ConcellLn, T. Gallagher, J. Org. Chem.2004, 69, 4849; b) C. Pousset, R. Callens, M. Haddad, M.LarchevÞque, Tetrahedron: Asymmetry 2004, 15, 3407.

[19] O(Brien and co-workers reported a related diastereoselective1,4-addition reaction in their synthesis of (+)-sparteine.[7b] Thisreaction used an N-a-methylbenzyl moiety to induce a verymodest level of diastereoselectivity in a cyclization reactionleading to the piperidine ring. For a related alkylative cyclizationstrategy also based on N-a-methylbenzyl as a chiral-directinggroup that generates a very similar intermediate to that used byO(Brien and co-workers, see: D. N. A. Fox, D. Lathbury, M. F.Mahon, K. C. Molloy, T. Gallagher, J. Am. Chem. Soc. 1991, 113,2652.

[20] NOE experiments were carried out to determine the stereo-chemistry of 15. Irradiation of C6-H showed an enhancement ofC10-Hax (3.9%). Enhancement of C8-Hax was also observed butwas complicated because this signal overlapped with C13-Hax

and C13-Heq. As a result, selective irradiation of C8-Hax was notpossible. Irradiation of C10-Hax showed an enhancement of bothC6-H (7.9%) and C8-Hax, although the latter enhancementcould not be quantified.

[21] A sample of natural anagyrine was kindly provided by Dr.Ernest Boehm (Apin Chemicals Ltd.) and used for comparisonpurposes (1H and 13C NMR spectroscopic data and TLC). Wewere able to correlate 1H and 13C NMR data for syntheticanagyrine (and synthetic thermopsine) with that reported byRobins et al.,[15a,c] and Mikhova and Duddeck.[15d] The region ofthe 13C NMR spectra[15d] displaying the resonances for C7�C15for these two isomers is quite distinct, and full details areavailable in the Supporting Information.

[22] C. Morley, D. W. Knight, A. C. Share, J. Chem. Soc. Perkin Trans.1 1994, 2903; for related diastereoselective alkylations involvingN-benzyl piperidines, see: S. Ledoux, J. P. CNlNrier, G. Lhommet,Tetrahedron Lett. 1999, 40, 9019; S. Ledoux, E. Marchalant, J. P.CNlNrier, G. Lhommet, Tetrahedron Lett. 2001, 42, 5397.

[23] Crystal data for lactam 19 : C11H17NO3, Mr= 211.26, colorlessplate, 0.50O 0.50 O 0.10 mm3, MoKa radiation (l= 0.71073 P) wasused, and intensity data were collected as w scans (frames, 0.38width, 2qmax= 508); a multiscan absorption correction (G. M.

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Sheldrick, SADABS v2.03, University of GQttingen, Germany,2003) was applied, (m= 0.094 mm�1, Tmax= 1.00, Tmin= 0.94), thestructure was solved and refined by standard techniques (G. M.Sheldrick, SHELXS-97, University of GQttingen, Germany,1990 ; G. M. Sheldrick, SHELXL-97, University of GQttingen,Germany, 1997); triclinic crystal system, a= 9.3234(19), b=10.175(2), c= 11.724(2) P, a= 88.69(3), b= 75.71(3), g=88.28(3)8, V= 1077.2(4) P3, 1= 1.303, T= 173(2) K, spacegroup P1̄, Z= 4, Rint= 0.0456 (for 10271 measured reflections),273 parameters were used in the refinement, hydrogen atomswere constrained to ideal geometries and refined with displace-ment parameters equal to 1.5 times (methyl H atoms) or1.2 times (all other H atoms) Ueq of their parent atom; largestdifference electron density map features were + 0.192,�0.191 eP�3, R1= 0.0423 [for 2532 unique reflections with> 2s(I)], wR2= 0.0994 (for all 3787 unique reflections).CCDC 289282 contains the supplementary crystallographicdata for this paper. These data can be obtained free of chargefrom the Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data request/cif.

[24] NOE experiments were carried out to determine the stereo-chemistry of 22. Irradiation of C6-H showed an enhancement ofboth C8-Hax (2.2%) and C10-Hax (3.4%). Irradiation of C10-Hax

showed an enhancement of both C6-H (4.4%) and C8-Hax

(3.2%).[25] For cyclization to occur, there is a requirement that the enolates

derived from bicyclic lactams 14 and 21 maintain the pyridonesubstituent associated with C1 (quinolizidine numbering) in anaxial environment. Interestingly, the crystal structure of bicycliclactam 19 (see Supporting Information) shows the CO2Mesubstituent at C1 to be orientated in a pseudoequatorialenvironment, and, significantly, the cyclization of 21 (derivedfrom 19 and which leads to thermopsine) is the least efficient ofthose we have examined to date. However, at this time, thefactors that moderate the efficiency and scope of this reactionhave not yet been defined, and the processes reported hereremain unoptimized.

[26] Note added in proof: The activity of (+)-cytisine at thea4b2* nicotine acetylcholine receptor labeled with [3H]-epiba-tidine has been determined: Ki= 0.79� 0.30 mm for (+)-cytisineversus Ki= 3.0� 0.65 nm for (�)-cytisine. This low level ofactivity could also be attributed to a small (ca. 0.4%) level ofcontamination by (�)-cytisine as a consequence of the kineticresolution step involved. We thank Professor Susan Wonnacottand Neal Innocent (University of Bath) for this determination.

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