1-Azabicyclic ring systems having angular substituents adjacent to nitrogen are structural motifs found in a variety of alkaloid natural products and biologically active agents.1 Despite the presence of these moieties in compounds of interest, few general methods have been reported for their enantioselective synthesis.2 In this report, we describe a general enantioselective synthesis of such 1-azabicyclic frameworks that introduces a new strategy for achieving dynamic kinetic resolution in the formation of C–C bonds.
Previously, we described the construction of racemic 1-azabicyclic products such as octahydroindole 4 by a novel sequence in which the less-stable isomer 3 of a cationic 2-aza-Cope equilibration is trapped by dimedone (eq 1).3 During investigations of the reaction mechanism, we observed that deuterium was incorporated from MeOD into the angular 3a position of product 4, signifying that the starting iminium cation 2 rapidly equilibrated with enamonium isomer 1. Such a rapid pre-equilibrium suggested that introduction of a non-racemic stereocenter into the homoallylic side chain of precursor 2 might result in a dynamic kinetic resolution to deliver largely one enantiomer of the 1-azabicyclic product.4
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The proposed dynamic kinetic resolution was first explored with substrates having a substituent at the homoallylic carbon of the side chain of the starting iminium ion 2.4 A phenyl substituent provided the highest degree of chirality transfer, although chirality transfer was not complete. However, complete transfer of chirality from a non-racemic side chain was realized when a phenyl substituent was incorporated at the allylic carbon.5
The optimized sequence that was developed is summarized for the synthesis of octahydrocyclopenta[b]pyrrole 8 in Scheme 1. The carboxylic acid derived from ketal ester 5, which is available in two steps from cyclopentanone,3,4 was coupled with enantioenriched amine 6, and the resulting amide was reduced with lithium aluminum hydride to give secondary homoallylic amine 7 in 61% yield over 3 steps.6 (R)-2-Phenyl-3-butenamine (6, 99% ee) is available on multigram scale from molybdenum-catalyzed asymmetric allylic substitution of cinnamyl methyl carbonate with dimethyl sodiomalonate,7 followed by conventional elaboration of the product to the primary amine.6 Aminoketal 7 was heated at 120 °C for 30 min with 1 equiv of CF3CO2H (TFA), 2.5 equiv of dimedone and 0.1 equiv of morpholine in the absence of solvent to provide azabicyclic amine 8, which was converted to its Cbz derivative to facilitate purification and analysis. In this way, azabicyclic carbamate 9 was obtained in 89% yield and 99% ee, indicating complete transfer of chirality from the allylic stereocenter. To emphasize the synthetic utility of the reaction, the transformation of aminoketal 7 was conducted on a 1-gram scale to furnish heterocycle 8 in 99% ee and 87% yield.8
Scheme 1.
Enantioselective Synthesis of 1-Azabicyclo[3.3.0]octane 8
The scope of this enantioselective synthesis can be seen in the results summarized in Table 1. Angularly substituted octahydroindole 10, decahydrocyclohepta[b]pyrrole 11, and octahydrocyclopenta[b]pyridine 12 were all formed in good yields and 99% ee, as exclusively the cis stereoisomers (entries 2–4). Diastereoselection was lower in the formation of decahydroquinoline 13 (cis:trans = 1.7:1), with the readily separable stereoisomers each generated in 99% ee (entry 5). Methyl-substituted cis-octahydroindole 14 was formed exclusively as the all-cis stereoisomer (81% yield and 99% ee) from a precursor that was a mixture of four diastereomers (entry 6); this result established that both carbons adjacent to the ketal in the starting carbocyclic ring can be epimerized by iminium ion/enamonium equilibration.3 The absolute configuration of 1-azabicyclic product 12 was established by single crystal analysis of the corresponding secondary amine hydrobromide salt and that of products 9 and 10 by chemical correlation;6 absolute configurations of other products were assigned by analogy.
Table 1.
Enantioselective Synthesis of Substituted 1-Azabicyclics
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|---|---|---|---|---|---|---|---|
| Entry | m | n | R1 | R2 | Product | Yield (%) | ee (%)a |
| 1 | 1 | 1 | H | H | 9 | 89 | 99 |
| 2 | 2 | 1 | H | H | 10 | 82 | 99 |
| 3 | 3 | 1 | H | H | 11 | 79 | 99 |
| 4 | 1 | 2 | H | H | 12b | 89 | 99 |
| 5 | 2 | 2 | H | H | 13b | 86c | 99d |
| 6 | 2 | 1 | H | Me | 14b | 81 | 99 |
| 7e | 2 | 1 | Me | H | 15b | 48 | 99 |
Enantiomeric excess was determined by enantioselective HPLC.
Relative configuration was determined by NOESY data.
A 1.7:1 mixture of cis and trans stereoisomers.
For both diastereomers.
Time was 1 h.
The success of the dynamic kinetic resolution to form 1-azabicyclic products 9–14 suggested that this strategy could be employed to kinetically resolve aminoketals containing an additional substituent R1. This possibility was demonstrated in the formation of cis-octahydroindole 15, in which both angular carbons are fully substituted, in 48% yield (Table 1, entry 7).
Our current understanding of this new approach to dynamic kinetic resolution derives from the following experiments. When the reaction of aminoketal 7 was carried out in deuterated methanol (1 equiv TFA, 120 °C, sealed tube), azabicyclic product d3-9 was produced, as expected for rapid iminium ion/enamonium equilibration.3 Product d3-9 was also formed when azabicyclooctane 8 was allowed to react with 3 equiv of paraformaldehyde (1 equiv TFA, 120 °C, MeOD, sealed tube) in the absence of dimedone for 24 h, followed by addition of dimedone and conversion to the Cbz derivative; this result establishes that in the absence of dimedone iminium ion isomers 16 and 17 equilibrate under the reaction conditions (eq 2). However, trapping with dimedone is irreversible, as attempted reaction of secondary amine 8 with the formaldehyde/dimedone adduct9 (1 equiv TFA, 120 °C, MeOD, 20 h, sealed tube; CbzCl) provided azabicyclooctanyl carbamate 9 devoid of deuterium.
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In light of these results, we propose the following mechanism (Scheme 2). Reaction of aminoketal 7 with TFA establishes a rapid pre-equilibration between iminium ion diastereomers 18 and 20 and enamonium ion 19.10 The cationic 2-aza-Cope rearrangement occurs more slowly and preferentially from iminium ion diastereomer 18 by favored chair transition structure 21. Dimedone irreversibly traps the thermodynamically less-stable iminium ion product 16 to give 1-azabicyclic product 8 in high enantiomeric purity, more rapidly than formaldiminium ion 16 reverts to the equilibrium mixture of cations 18, 19 and 20.11
Scheme 2.
Proposed Mechanism of Dynamic Kinetic Resolution
To highlight some potential uses of this family of enantiopure amines, several products were converted in high yield to previously unknown β-amino acids, potentially valuable inputs for the synthesis of peptidomimetics and scaffolds for medicinal chemistry (eq 3).12
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A useful enantioselective synthesis of angularly substituted 1-azabicyclic molecules is reported that delivers the product amines in exceptionally high enantiopurity. This synthesis introduces a new strategy for dynamic kinetic resolution in which a rapid tautomeric equilibration of diastereomeric iminium cations is combined with a diastereoselective sigmatropic rearrangement. Experiments to further develop the scope of this method and obtain a deeper understanding of its mechanism are currently underway.
Supplementary Material
Acknowledgments
The NIH Neurological Disorders & Stroke Institute (NS-12389) and Takeda Pharmaceutical Co. supported this research. NMR, mass spectra, and X-ray analyses were obtained at UC Irvine using instrumentation acquired with the assistance of NSF and NIH Shared Instrumentation programs. We thank Zach Aron, University of Indiana, for suggestions and early experiments.
Footnotes
Supporting Information Available: Experimental details; copies of 1H and 13C NMR spectra of new compounds and of HPLC traces used to determine ee; a scheme showing all potential chair and boat topography aza-Cope rearrangements of 18 and 20, and a CIF file. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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