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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC 2010 April 2.
Published in final edited form as:
PMCID: PMC2753232
NIHMSID: NIHMS103275

Asymmetric Synthesis of Substituted Tropinones using the Intramolecular Mannich Cyclization Reaction and Acyclic N-Sulfinyl β-Amino Ketone Ketals

Abstract

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Sulfinimine-derived, enantiopure N-sulfinyl β-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with (Boc)2O/DMAP afford substituted tropinones in good yield.

The continuing interest in the synthesis and biosynthesis of the tropane alkaloids, the 8-azabicyclo[3.2.1]octane ring system, is because of the significant biological properties of several members of this class of heterocycles including (−)-cocaine (1) and atropine (2) (Figue 1).1 The impetus for most of the synthetic studies has been the search for useful cocaine-type analogs, (antagonists and agonists). Many syntheses of cocaine analogs employ advanced starting materials such as tropinone and cocaine itself.2 Other procedures to access the tropane skeleton include cycloadditon and intramolecular nucleophilic substitution reactions, Michael addition reactions, iminium ion cyclizations, and ring-closing metathesis procedures.3 Relatively few of these methods are asymmetric.3

Figure 1
Important Tropanes.

Rapoport prepared (−)-1 from glutamic acid using an intramolecular nucleophilic substitution reaction to form the tropane ring.4 Cha prepared (+)-cocaine (1) by desymmetrization of tropinone using a chiral lithium base and an aldol reaction to install the axial carbomethoxy group.5 Most asymmetric syntheses of this ring system employ some type of a cycloaddition reaction.3,6,7,8,9,10 For example, Mans and Pearson synthesized (+)-cocaine (1) in 86% ee using a 2-azaallyllithium [3+2] cycloaddition reaction to prepare a meso-pyrrolidine dialdehyde which was then subjected to an asymmetric proline-catalyzed intramolecular enol-exo-aldol reaction.3a Recently Reddy and Davies described the enantioselective synthesis of substituted tropanes using a rhodium-catalyzed [4+3] cycloaddition reaction of vinyldiazoacetates with N-Boc pyrroles.10a With few exceptions10 most syntheses are multi-step, low overall yielding procedures which do not provide easy access to ring substituted examples, particularly at the bridge-head positions of the tropane skeleton. We describe here the application of acyclic N-sulfinyl β-amino ketone ketals and the intramolecular Mannich cyclization reaction for the asymmetric synthesis of substituted tropanones.

The acid catalyzed intramolecular Mannich cyclization reaction between an N-sulfinyl β-amino ketone and an aldehyde is an important method for the asymmetric synthesis of stereodefined substituted piperidines (Figure 2).11,12,13 We employed this protocol in highly efficient asymmetric syntheses of the trisubstituted piperidine, (−)-nupharamine,14 and indolizidine alkaloids (−)-209B15 and (−)-223A.16 Enantiopure N-sulfinyl β-amino ketones are prepared by reaction of Grignard reagents with N-sulfinyl β-amino Weinreb amides.17,18 We reasoned that substituted tropinones would result if the Mannich cyclization were to occur at a pyrrolidine ring iminium ion that is also attached to the ketone unit. Hydrolysis of an acyclic N-sulfinyl β-amino ketone ketal could generate such a dehydropyrrolidine species, which under acidic conditions, would form an iminium ion that could cyclize to the tropinone (Figure 2).19

Figure 2
Intramolecular Mannich Cyclizations.

Treatment of masked oxo sulfinimines (S)-(+)-1a (R = Ph) and (S)-(+)-1b (R = Me) with an excess of the sodium enolate of methyl acetate gave mixtures of the β-amino ester 2 and the desired N-sulfinyl δ-amino β-ketoester ketals (SS,S)-(+)-3.20 In these cases the solution was recooled to −78 °C and an additional 5 equivalents of the enolate was added, affording (SS,S)-(+)-3a and (SS,S)-(+)-3b in 69% and 80% isolated yields, respectively. This contrasts with earlier studies where δ-amino β-ketoesters were prepared in excellent yield and high de by reaction of sulfinimines with an excess of the sodium enolate.21

When the N-sulfinyl δ-amino β-ketoester ketals (SS,S)-(+)-3 were treated with 3 N HCl/MeOH in THF at rt for 3 h the tropinone was not formed, but rather the dehydropyrrolidines (S)-(+)-4a and (S)-(−)-4b in 80 and 66% yields, respectively (Scheme 1). Evidence for the formation of 4, rather than the isomeric tropinone, is the presence of the imino carbons at δ 171–179 ppm in 13C NMR in addition to the keto and ester carbons at δ 200–210 and δ 165 ppm, respectively. In the 1H NMR spectra, the Me protons in (−)-4b appear downfield at δ 2 ppm compared to δ 1.0–1.3 ppm for these protons in the corresponding tropinones (see below). Suprisingly, when (S)-(+)-4a was hydrogenated (Pd-C) at 100 psi for 8 h hydroxy dehydropyrrolidine (+)-5 was formed as a single isomer in 60–70% yield (Scheme 1).22 Evidence for the reduction of keto group rather than the imine is the presence of the imino carbon at δ 171 ppm and the absence of the keto carbon at δ 201 ppm.

Scheme 1
Synthesis of N-Sulfinyl δ-Amino β-Ketoester Ketals and Their Hydrolysis.

Reaction of imine (S)-(+)-4a with (Boc)2O and a catalytic amount of DMAP resulted in formation of enol carbonate (S)-(+)-6 in 70% yield. The vinylic proton at δ 5.9 ppm in the 1H NMR and the dehydropyrrolidine carbon at δ 175 ppm in the 13C NMR support this structural assignment. NOE studies are consistent with the E-geometry for (+)-6. Importantly, when (S)-(−)-4b was treated with (Boc)2O/cat.-DMAP, the Mannich cyclization resulted in tropinone (+)-7 in excellent yield (Scheme 2). However, (+)-7 was formed as a 70:30 inseparable mixture of tropinones that are epimeric at C-2. The major epimer is assigned as having the C-2 carbomethoxy group in the axial position in analogy to the related tropinone reported by Thomas et al. in their racemic approaches to the alkaloid stemofoline.19 It is likely that the imino phenyl group in (S)-(+)-4a sterically inhibits the Mannich cyclization.

Scheme 2
Mannich Cyclization of Dehydropyrrolidines.

To further define the scope of the Mannich cyclization of dehydropyrrolidine ketone, the keto moiety was next varied. Masked oxo Weinreb amides (SS,S)-(+)-8 and (SS,2R,3S)-(+)-9 were prepared in good yield and high d.r. by reaction of (S)-(+)-1b with the potassium enolate of N-methoxy-N-methylacetamide17a and the lithium enolate of N-methoxy-N-methylpropylamide,17b respectively (Scheme 3).

Scheme 3
Synthesis of β-Amino Ketone ketals.

Treatment of the Weinreb amides (SS,S)-(+)-8 and (SS,2R,3S)-(+)-9 with benzylmagnesium chloride gave ketones (SS,S)-(+)-10, and (SS,3R,3S)-(+)-12 in excellent yield, while ethylmagnesium chloride with (SS,2S,3S)-(+)-8 gave ketone (SS,3S)-(+)-11 in good yield (Scheme 3).

As expected, reacting ketones 10–12 with 3 N HCl-MeOH in THF gave the corresponding dehydropyrrolidine ketones 13–15 in good yield (Scheme 4). When (S)-(+)-13 was treated with (Boc)2O/cat.-DMAP, the enol carbonate (S)-(+)-16 resulted in 77% yield (Scheme 4). There was no reaction of (S)-(+)-14 with (Boc)2O/cat.-DMAP. However, reaction with p-nitrobenzoyl chloride (p-NO2-Bz-Cl) and 1.1 equiv of DMAP, to generate a more electrophilic acyliminium ion species, failed to give the tropinone, but gave the isomeric enamide (S)-(+)-17 in 70% yield. Evidence for the enamide structure comes from HMQC experiments which show the enamide proton at 4.97 ppm and the carbon attached to it at 112.8 ppm. The quaternary C-N carbon is coupled to the vinyl hydrogen. The pyrrolidine Me and C-2 protons are broadened due to the amide rotamers. Under acidic conditions the enamide hydrolysis product, (R)-(−)-18, was also formed. This product is apparently formed in the work-up because it was not detected in the crude reaction mixture.

Scheme 4
Mannich Cyclization of Dehydropyrrolidine Ketones.

Remarkably, (3R,4S)-(+)-15 gave tropinone (+)-19 as a single isomer in 60% yield with (Boc)2O/cat.-DMAP and with p-nitrobenzoyl chloride/DMAP a 95% yield of tropinone (−)-20 was formed. NOE studies suggest a syn relationship between C-2 and C-4 protons where the Ph and Me substituents occupy the equatorial positions in (+)-19 and (−)-20. These results were confirmed by an X-ray crystal structure of (−)-20 (see Supporting Information).

In (S)-(+)-13 the bulky phenyl group may inhibit the Mannich cyclization favoring enol carbonate formation. In (S)-(+)-14 enamide formation is apparently much faster than enolizaton due to the greater acidity of the intermediate pyrrolidine C-2 acyliminium ion proton (Scheme 4). However, the fact that (3R,4S)-(+)-15 gave tropinone (+)-19 in good yield suggests that other factors may be of importance in determining whether the intermediate acyliminium ion forms the enol carbonate, deportonates or undergoes the Mannich cyclization. One thought is that the alpha-Me group in (+)-15 somehow inhibits enol carbonate formation favoring the Mannich cyclization.

In summary, sulfinimine-derived N-sulfinyl β-amino ketone ketals and the intramolecular Mannich cyclization reaction represent a valuable new method for the asymmetric synthesis of substituted tropinones including those having substituents at the bridgehead positions.

Supplementary Material

1_si_001

2_si_002

3_si_003

4_si_004

5_si_005

Click here to view.(12K, crtext)

Acknowledgment

We thank Dr. Charles DeBrosse, Director of Temple NMR facilities, for aid with the NOE experiments. This work was supported by a grant from the National Institutes of General Medicinal Sciences (GM 57870) and and Boehringer Ingelheim Pharmaceuticals, Inc.

Footnotes

Supporting Information Available: Full experimental and spectroscopic data for all new compounds are provided. X-Ray data, ORTEP and CIF for compound (S)-(−)-20 is provided. This material is available free of charge via the World Wide Web at http://pubs.acs.org.

References

1. For reviews see: O'Hagan D. Nat. Prod. Rep. 2000;17:435. [PubMed]
Humphrey AJ, O’Hagan D. Nat. Prod. Rep. 2001;18:494–502. [PubMed]
2. For a review of these methods see: Singh S. Chem. Rev. 2000;100:925. [PubMed]
3. For an excellent summary of these reactions see: (a) Mans DM, Pearson WH. Org. Lett. 2004;6:3305. [PubMed] (b) Mans DM. Ph.D. Thesis. Ann Arbor, MI, USA: Univ. Michigan; 2004. Aza-Bridged Bicyclic Amines From (2-Azaallyl)stannanes and the Total Synthesis of (+)-Cocaine.
4. Lin R, Castells J, Rapoport H. J. Org. Chem. 1998;63:4069.
5. Lee JC, Lee K, Cha JK. J. Org. Chem. 2000;65:4773. [PubMed]
6. Takahashi T, Kitano K, Hagi T, Nihonmatsu H, Koizumi T. Chem. Lett. 1989:597.
7. Takahashi T, Fujii A, Sugita J, Hagi T, Kitano K, Arai Y, Koizumi T, Shiro M. Tetrahedron: Asymmetry. 1991;2:1379.
8. Pham VC, Charlton JL. J. Org. Chem. 1995;60:8051.
9. Rigby JH, Pigge FC. J. Org. Chem. 1995;60:7392.
10. (a) Reddy RP, Davies HML. J. Am. Chem. Soc. 2007;129:10312. [PubMed] (b) Antoline JE, Hsung RP, Huang J, Song Z, Li G. Org. Lett. 2007;9:1275. [PubMed]
11. Davis FA. J. Org. Chem. 2006;71:8993. [PubMed]
12. For related studies using aldehydes and β-aminoketals see: (a) Abrunhosa-Thomas I, Roy O, Barra M, Besset T, Chalard P, Troin Y. Synlett. 2007:1613. (b) Al-Sarabi AE, Bariau A, Gabant M, Wypych J-C, Chalard P, Troin Y. ARKIVOC. 2007:119. (c) Bariau A, Canet J-L, Chalard P, Troin Y. Tetrahedron: Asymmetry. 2005;16:3650.
13. For reviews on the Mannich reaction see: (a) Speckamp WN, Hiemstra H. Tetrahedron. 1985;41:4367. (b) Arend M, Westermann B, Risch N. Angew. Chem. Int. Ed. 1998;37:1044.
14. Davis FA, Santhanaraman M. J. Org. Chem. 2006;71:4222. [PubMed]
15. Davis FA, Yang B. Org. Lett. 2003;5:5011. [PubMed]
16. Davis FA, Yang B. J. Am. Chem. Soc. 2005;127:8398. [PubMed]
17. (a) Davis FA, Nolt MB, Wu Y, Prasad KR, Li D, Yang B, Bowen K, Lee SH, Eardley JH. J. Org. Chem. 2005;70:2184. [PubMed] (b) Davis FA, Song M. Org. Lett. 2007;9:2413. [PubMed]
18. Davis FA, Gaspari PM, Nolt B, Xu P. J. Org. Chem. 2008;73:9619. [PubMed]
19. In racemic approaches to the alkaloid stemofoline Thomas et. al. used a similar approach and observed the rearrangement of a depyrrolidine to a tropinone. Baylis AM, Davies MPH, Thomas E. J. Org. Biomol. Chem. 2007;5:3139. [PubMed]
20. For applications of masked oxo sulfinimines in asymmetric synthesis see: (a) Davis FA, Zhang H, Lee SH. Org. Lett. 2001;3:759. [PubMed] (b) Davis FA, Lee SH, Xu H. J. Org. Chem. 2004;69:3774. [PubMed] (c) Ref. 18.
21. (a) Davis FA, Chao B, Fang T, Szewcsyk JM. Org. Lett. 2000;2:1041. [PubMed] (b) Davis FA, Chao B, Rao A. Org. Lett. 2001;3:3169. [PubMed] (c) Davis FA, Fang T, Chao B, Burns DM. Synthesis. 2000:2106.
22. For leading references to the catalyytic hydrogenation of β-ketoesters see: Thomassigny C, Greck C. Tetrahedron: Asymmetry. 2004;15:199.