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. 2024 Jul 22;26(31):6546–6550. doi: 10.1021/acs.orglett.4c02013

Diastereoselective [3 + 2] Cycloaddition between Tertiary Amine N-Oxides and Substituted Alkenes to Access 7-Azanorbornanes

Alexander H Cocolas †, Aiden M Lane †, Benjamin S Musiak †, Eric J Chartier †, Derek A Bedillion †, Sarah L Hejnosz †, Jeffrey J Rohde ‡, Paul A Lummis †, Jeffrey D Evanseck †, Thomas D Montgomery †,*
PMCID: PMC11320637  PMID: 39038111

Abstract

graphic file with name ol4c02013_0004.jpg

We have developed a diastereoselective synthesis of 43 novel 7-azanorbornanes using tertiary amine N-oxides and substituted alkenes. Our method uses an efficient [3 + 2] cycloaddition, starting from either commercially available or easily accessible precursors to generate yields up to 97% and diastereomeric ratios up to >20:1. Density functional theory (DFT) calculations were performed, suggesting that the observed diastereoselectivity is likely due to steric considerations.

Small lipophilic molecules with bridged stereocenters have gained popularity as potential drug targets.1,2 Moreover, motifs that exhibit spherical or highly rigid characteristics have demonstrated a high propensity to be more selective than primarily planar scafolds.3−5 7-Azanorbornanes (7-azabicyclo[2.2.1]heptanes) generally score high in both of these metrics due to their biological and pharmacological relevance.6−13 Naturally occurring epibatidine (1), and its synthetic derivatives (2 and 3) have demonstrated biological relevance by binding to the α4β2 subunit of the nicotinic acetylcholine receptor (nAChR) at nanomolar concentrations (Scheme 1A).14,15 Recently, the Fujii group expanded the utility of 7-azanorbornanes, demonstrating agonism at the growth hormone secretagogue receptor (GHSR)16 along with the κ- and δ-opioid receptors.9,10

Scheme 1. 7-Azanorbornane Relevance and Syntheses.

Scheme 1

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Given the importance of these scaffolds, several approaches have been employed to generate the 7-azanorbornane core. The most developed method utilizes a Diels–Alder [4 + 2] cycloaddition between N-protected pyrroles and alkynes, followed by hydrogenation (Scheme 1B).17−21 This method installs multiple substituents onto the 7-azanorbornane ring but requires 3 to 6 steps and frequently suffers from poor diastereoselectivity. Another effective tactic uses a leaving group-assisted intramolecular cyclization approach (Scheme 1C);22−30 this transannular route is more stereoselective but requires 6 to 11 steps to set the desired stereocenters and isolate the product. Armstrong (3-steps 36% overall yield)31,32 and Pandey (5-steps 40–46% overall yield)33−35 demonstrated alternative methods to generate exo-7-azanorbornanes with a limited substrate scope.

While these approaches are undoubtably effective at generating the bicyclic core, a more concise method that selectively generates endo-7-azanorbornanes remains absent in the literature. This work aims to fill this gap as endo-7-azanorbornanes can be isolated in an efficient and diastereoselective manner by coupling tertiary amine N-oxides with substituted alkenes in three total steps and up to 88% overall yield (Scheme 1D).

The use of tertiary amine N-oxides as precursors for [3 + 2] cycloadditions was originally reported by Roussi where they demonstrated the formation of various pyrrolidines.36−41 Later work by Davoren expanded this area through use of various stilbenes.42 Previously, we probed this chemistry computationally43 and established a synthetic method producing 1,2-diamines and imidazolidines by coupling tertiary amine N-oxides with silyl imines.44 We present here our most recent studies into the reaction of pyrrolidine N-oxides with substituted alkenes to give endo-7-azanorbornanes in good yields and high diastereoselectivities.

From the optimization of reaction conditions (Supporting Information (SI), Table S1), we observed an excellent level of conversion of 9a to 7-azanorbornane 10a. The major diastereomer (19:1 dr) could be either the endo10ea or the exo11ea (Scheme 2). Density functional theory (DFT)45,46 calculations produced the predicted distance from the benzylic proton to the nearest CH3 from the tert-butyl group (Figure 1A). A minimized ground state structure of 10aa showed a minimum distance of 2.07 Å and an average distance of 3.04 Å, whereas for 11aa these distances were 4.34 and 4.78 Å, respectively. A NOESY experiment showed a strong interaction between the well resolved tert-butyl and benzylic peaks, giving strong evidence for the assignment of 10aa as the major stereoisomer. We performed similar analyses on compounds 10ab, 10ea, 10 lb, and 10mb, observing the same strong correlation in each. A crystal structure of 10mb was obtained following the addition of tetrafluoroboric acid to generate [10mb•H]BF4 which confirmed the assigned diastereoselectivity (Figure 1B).

Scheme 2. Substrate Scope.

Scheme 2

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Expanded substrate scope found in SI, Scheme S1. (a) Reactions carried on a 0.4 mmol scale. Conditions: N-oxide (1.0 equiv) alkene (0.5 equiv), LDA (3.0 equiv), dry THF (0.1M), −78 °C to RT, N2. Isolated yields were reported. (b) Carried out on a 7.0 mmol scale. (c) LDA (4.5 equiv).

Figure 1.

Figure 1

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(A) Minimized ground state for 10aa using M062x/jul-cc-pvTz. (B) X-ray structure of [10mb•H]BF4 (CD CCDC 2352512). Hydrogen atoms and BF4– anion omitted for clarity.

With optimized conditions in hand, we examined the substrate scope (Scheme 2, SI, Scheme S1). To selectively generate 7-azanorboranes, pyrrolidine N-oxides containing tert-butyl, adamantyl, and tert-octyl were used. Our baseline reaction using styrene afforded good yields with an average isolated yield of 91% (10a); 10aa was run on a gram scale, demonstrating scalability. Para-substituted alkyl groups (10b and 10c) demonstrated an average of 87% isolated yield. Biphenyl 10d, carbazole 10m, and naphthyl 10n, were well tolerated with modest to excellent yields. Electron-rich para-4-OMe 10e afforded an average yield of 95%, whereas meta-4-OMe 10p gave an average yield of 83%, presumably due to lower electronic contribution of the meta position. Phenol 10f gave only modest yields, although this could be improved by using a silyl protecting group (10g and 10l). Polysubstituted compounds 10k and 10o worked well, with the 2,4,6-trimethyl substrate 10o having comparable isolated yields as the 4-Me (10d). Across these substrates we noticed a strong correlation between ortho substitution and improved diastereotopic ratios (10c and 10k compared to 10l and 10o). As we observed in our prior work, electron-deficient substrates were tolerated but gave lower isolated yields (10h and 10i). Reactions starting with 4-fluorostyrene showed significant degradation under the reaction conditions, partially explaining the poor yields. From the reaction mixture, along with expected 10h we observed 10f by 1H NMR and HRMS, showing a halogen to hydroxyl conversion. Examination of nonfluoro halogens showed similar issues and gave no meaningful amounts of halogenated products. Excitingly, boronic acid (10j) and alkyl (10q) containing substrates were also tolerated.

To overcome the limitations of our substrate scope and demonstrate the versatility of these products, we subjected 7-azanorbornanes 10aa, 10bc and 10gb to additional transformations (SI, Scheme S2). While strong electron withdrawing groups were not generally compatible with this chemistry, 10aa was successfully nitrated (S1). 10gb was subjected to TBAF deprotection followed by exposure to Tf2O installing the pseudohalogen47 triflate group (S2) in excellent yield over two steps. The tert-octyl N-protecting group was cleaved in the presence of BCl3, affording free amine (S3).

The mechanism of this reaction is expected to be analogous to our previous studies with generation of an azomethine ylide.43,44 Of greater interest to this work was an explanation for the diastereotopic selectivity for the endo product. We postulate that this is due to steric considerations since we saw a universal increase in d.r. going from tButyl to the more hindered tOctyl functional group (Scheme 2). Additionally, ortho-substituted products (10l and 10o) yielded some of the highest diastereomeric ratios. These experimental observations agreed with computational calculations performed using M06-2X45 with Dunning’s correlation consistent complete basis sets.46,48 Analysis of transition structures for both the endo and exo pathways predicted an 18:2 diastereomeric ratio for 10aa, giving good agreement with experimental results (SI, Table S3).

In summary we developed a diastereoselective [3 + 2] cycloaddition between pyrrolidine N-oxides and substituted alkenes, generating 43 novel 7-azanorbornanes. This work makes use of easily accessible or commercially available starting materials. Finally, using both experimental observations and computational calculations we postulate a reasonable mechanism for the high diastereoselectivity.

Acknowledgments

Support from the National Institutes of Health (1-R15 GM148917-01) is gratefully acknowledged. Support from the National Science Foundation for computational resources (CHE-1726824), and summer student support through the REU program (M.H., CHE-2244151). The authors thank Dr. Alex Veinot (Western University) and Dr. Jennifer Aitken (Duquesne University) for their helpful discussion regarding the single crystal X-ray diffraction analysis.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c02013.

  • Detailed experimental procedures, compound characterization data, copies of NMR spectra for new compounds, and computational data (PDF)

  • FAIR Data, including the primary NMR FID files, for compound(s) 8a–8c, 10aa–10qa, tBu pyrrolidine, and toctyl pyrrolidine (ZIP)

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Jeffrey J. Rohde was added as an author July 26, 2024.

Supplementary Material

ol4c02013_si_001.zip (112.7MB, zip)
ol4c02013_si_002.pdf (7.3MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol4c02013_si_001.zip (112.7MB, zip)
ol4c02013_si_002.pdf (7.3MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

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