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In this Letter, we describe a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkyl ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr., which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields and, for many systems, the only enantioselective preparation reported to date.
Natural products and pharmaceutical compositions that possess azabicyclic ring systems 1–9 are very common; however, synthetic approaches to access these 1-azabicyclo[m.n.0]alkane systems (Fig. 1) are limited.1–8 In general, the existing strategies for the construction of azabicyclic ring systems rely on Staudinger-aza-Wittig approaches,9 7-exo-tet-cyclizations,10,11 cycloadditions ([5+2], [4+2] and [2+2+2]),12 ring-closing metathesis (RCM) strategies,13 Mitsunobu approaches14 and rearrangements (nitrone and intramolecular Schmidt rearrangements)15,16 For the larger azabicyclic ring systems, routes are very rare, and those reported lack stereocontrol.8,17
Towards the development of an enantioselective toolbox of synthetic routes to access these valuable azaheterocycles, we recently reported a novel six step approach for the rapid and enantioselective synthesis of azabicyclic systems such as 1–3 (Scheme 1).18 Here, an indium-mediated allylation of a chiral aldimine substrate 10, N-alkylation to afford 11, ring-closing metathesis (RCM) to provide 12, and finally a one-pot deprotection/acetal hydrolysis/reductive amination sequence to afford enantiopure azabicyclic ring systems 1–3.18 This methodology was then employed for the enantioselective total syntheses of (+)-grandisine D,18 cremastrine19 and amabiline.20
While this was a notable advance, we also wanted to develop a streamlined route to access the higher homologs 4–9 in an enantioselective manner. De Kimpe and co-workers recently demonstrated the asymmetric synthesis of 2-arylpyrrolidines 15 from γ-chloro N-(tert-butanesulfinyl)ketimines 13,11 and Brown and co-workers employed a related strategy for the total synthesis of (−)-tashiromine 17 and (−)-epilupinine 18 (Scheme 2, eq. 1).21
Inspired by these results and our internal efforts, we envisioned a protocol that would subject various chloroalkyl N(tert-butanesulfinyl)aldehydes 19 to an asymmetric allylation reaction to provide 20 in high diastereomeric ratio (dr).18,22,23 Deprotection and alkylation of the pyrrolidine would provide azocines 21, substrates for a ring closing metathesis reaction24 to provide general, enantioselective access to 1-azabicyclo[m.n.0]alkane cores 1–9 with an embedded olefin as a handle for further functionalization (Scheme 3).
The requisite chloroalkyl N-(tert-butanesulfinyl)aldehydes 19 were easily prepared in 92–94% yields by condensing the corresponding chloroaldehydes 22 with the Ellman (S)-tert-butanesulfinamide 23 employing CuSO4 in DCM.25,26 A subsequent indium-mediated allylation reaction affords the anticipated (R)-anti-adducts 20 in >9:1 diastereoselectivity and up to 86% yield.18,22,23 After column chromatography, single diasteromers of analogs 20 resulted, which were carried forward. Following modification of the known protocols,11,21 acid-mediated deprotection and base-induced, microwave-assisted cyclization and alkyation with the required allyl, butenyl and pentenyl bromides smoothly afforded the chiral N-alkyl azocines 21 in 63–83% yields for the three step, one-pot reaction sequence (Scheme 4).27 To enable the one-pot sequence, a number of bases, solvents and temperatures were evaluated; however, K2CO3, NaI in DMF under microwave irradiation (120 °C, 15 min) proved to be general for all substrates, even the larger 7-azocine rings.
With all of the chiral N-alkyl azocines 21 in hand, we focused on the RCM to provide the 1-azabicyclo[m.n.0]alkane systems 1–9. Initial attempt following several known reaction conditions with Grubbs II18,20,24,28,29 failed to provide the desired unsaturated 1-azabicyclo[5.4.0]tridecane core of 7. A perusal of the literature regarding RCM methods with tertiary amines, suggested that ‘protection’ of the amine by in situ generation of ammonium salts enabled facile ring-closing.29–31 Thus, treatment of 21c1 with 1.1 equivalent of camphor sulfonic acid (CSA) in 0.05 M toluene, followed by the addition of 10 mol% of Grubbs II and microwave heating for 1 hour at 100 °C, provided the unsaturated 1-azabicyclo[5.4.0]tridecane core of 7 in 70% isolated yield (Scheme 5).27 An evaluation of additional acids led to the use of trifluoroacetic acid (TFA), which was equally effective (68% yield) and allowed for simpler purification.
With a robust protocol in hand for the RCM, all of the chiral N-alkyl azocines 21 were converted, under these optimal conditions, into the desired unsaturated 1-azabicyclo[5.4.0]alkane cores 22 of 1–9 (Scheme 6). Yields for the RCM reaction averaged 70% for all the substrates 21, providing high yielding, enantioselective access to each of the key 1-azabicyclo[m.n.0]alkane systems 1–9 in short order (Fig. 2). Overall yields from the commercial aldehydes 22 ranged from 29 to 59%, and offer the synthetic and medicinal chemist a general route to access these important azabicyclic ring systems.
In summary, we have developed a novel approach for the general and enantioselective synthesis of a diverse array of small to large 1-azabicyclo[m.n.0]alkane ring systems with an embedded olefin handle for further functionalization. The stereochemistry is established via a highly diastereoselective indium-mediated allylation of an Ellman sulfinimine in greater than 9:1 dr., which is readily separable by column chromatography to afford a single diastereomer. This methodology allows for the rapid preparation of 1-azabicyclo[m.n.0]alkane ring systems that are not readily accessible through any other chemistry in excellent overall yields and, for many systems, the only enantioselective preparation reported to date.
The authors gratefully acknowledge funding from the Department of Pharmacology, Vanderbilt University Medical Center and the Warren Family & Foundation for funding the William K. Warren, Jr. Chair in Medicine
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