Stereoselective deprotonation of tropinone and reactions of tropinone lithium enolate

Abstract

MAREK MAJEWSKI AND GUO-ZHU ZHENG. Can. J. Chem. 70, 261 8 (1992). Tropinone (6) was deprotonated with lithium diisopropylamide and with chiral lithium amides (18)(19)(20)(21)(22)(23)(24) and the resulting enolates (two enantiomers) were treated with electrophiles. The aldol reaction with benzaldehyde and deuteration were both diastereoselective. The former yielded only one isomer (exo, anti) of the aldol 8a; the latter proceeded from the exo face. This selectivity permitted us to probe the deprotonation of tropinone with lithium amides; it was concluded that the reaction involves predominantly the exo axial protons. The reaction of tropinone enolate with ethyl chloroformate led, via a ring opening, to the cycloheptenone derivative 9. The reaction with methyl cyanoformate yielded, in the presence of silver acetate and acetic acid, the P-ketoester 8b; however, in the absence of these additives, and especially when 12-crown-4 was added to the enolate, a ring opening leading to the pyrrolidine derivative 10 occurred instead. Deprotonation of tropinone with chiral lithium amides proceeded with modest enantioselectivity. A synthesis of non-racemic anhydroecgonine via this strategy allowed establishing the absolute stereochemistry of deprotonation.MAREK MAJEWSKI et Guo-ZHU ZHENG. Can. J. Chem. 70, 2618Chem. 70, (1992 On a dtprotonk la tropinone (6) a l'aide du diisopropylamidure de sodium et des amidures de lithium chiraux (18-24) et l'on a trait6 les Cnolates qui se sont formts (deux knantiomkres) avec des klectrophiles. La reaction aldolique avec le benzaldkhyde ainsi que la deuttration sont toutes les deux diastkrkosClectives; la premikre ne fournit qu'un isomtre (exo, anti) de l'aldol 8a alors que la dernikre se produit par la face exo. Cette sklectivitt a permis d'examiner la dtprotonation de la tropinone avec des amidures de lithium; on en a conclu que la rtaction implique principalement les protons axiaux exo. La rkaction de l'knolate de tropinone avec le chloroformate d'kthyle conduit, par le biais d'une ouverture de cycle, au dCrivC cycloheptknone 9. La rtaction avec le cyanoformate de mtthyle, rkaliste en presence d'acttate d'argent et d'acide acCtique, conduit au p-cCtoester 8b; toutefois, lorsque cette addition est rtaliste en l'absence de ces additifs et particulikrement lorsqu'on ajoute de l'Cther 12-couronne-4 21 l'knolate, il se produit plut6t une ouverture de cycle conduisant au dtrivt de la pyrrolidine 10. La dkprotonation de la tropinone sous I'influence d'amidures de lithium se produit avec une knantiosklectivitt modeste. Une synthkse de I'anhydroecgonine non-rackmique a l'aide de cette stratCgie a permis d'ktablir la stCrtochimie absolue de la dkprotonation.[Traduit par la rkdaction] Introduction strategy suitable for the construction of a number of tropane alkaloids (6) in a stereoselective manner.

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers

“…Knowing that in tropinone the axial α-protons are deshielded versus the equatorial protons by ca. 0.5 ppm [12,25], we were also able to identify positively, within the pairs of interconverting isomeric TBDMS ethers, the isomer with exo and endo side chain (equatorial and axial α-CH, respectively). On the basis of the observed exo – endo isomerization, and trends in NMR data changes upon isomerization, we were fairly certain of the assigned stereochemistry of the new isomer as exo , syn - 3 .…”

“…exo , anti -2-[Hydroxy(phenyl)methyl]-8-methyl-8-azabicyclo[3.2.1]octan-3-one ( exo , anti -3) [3–4 12] Colorless solid; mp 118–121 °C (decomp. ); 1 H NMR δ 7.32–7.25 (m, 5H), 5.23 (d, J = 3.1 Hz, 1H), 3.61–3.59 (m, 1H), 3.50–3.47 (m, 1H), 2.86 (ddd, J = 15.6 Hz, 4.6 Hz, 1.5 Hz, 1H), 2.47 (s, 3H), 2.45–2.42 (m, 1H, eq-H at C-2), 2.33 (dt, J = 15.6 Hz, 1.9 Hz, 1H), 2.21–2.12 (m, 1H), 1.69–1.53 (m, 1H); R f 0.50 (10% MeOH/DCM).…”

“…1) were synthesized by enantioselective deprotonation with lithium amide bases followed by diastereoselective aldol reaction with aldehydes [10–11]. In all the aldol reactions promoted by achiral (LDA [5,12]) or by chiral lithium amides (e.g., lithium bis(1-phenylethyl)amide [4–5] or Koga’s amide [3]), including amides immobilized on a polymeric carrier [13–14], the major products had the exo , anti configuration (Scheme 1). …”

Tropane alkaloids from Erythroxylum emarginatum

“…Anhydroecgonine methyl ester, the principal alkaloid of this plant, was originally isolated from the seeds of E. coca in 1941 [3]. The absolute configurations were determined to be the 1R and 5S forms based on optical rotation [2][3][4].…”

Bicyclic β-amino acids

“…190 Later, reaction of lithium enolate of tropinone with methyl cyanoformate was used, which allowed improving the yield of 385 to 82%. 191 Using the chiral base 387 for the generation of enolate allowed for performing of this reaction in enantioselective manner, so that (1R,5S) (unnatural) isomer of 385 was obtained with 93% ee. 192 One more related enantioselective approach to the β-ketoesters of the type 385 relied on asymmetric dealkoxycarbonylation of diester 388, catalyzed by porcine liver esterase (PLE) (Scheme 95).…”