Enantioselective Synthesis of cis- and trans-Cycloheptyl β-Fluoro Amines by Sequential aza-Henry Addition/Ring-Closing Metathesis

Abstract

The synthesis of 7-membered carbocyclic β-fluoroamines is accomplished by a combination of the enantioselective aza-Henry reaction of aliphatic N-Boc imines and ring-closing metathesis. Use of reductive denitration gives both diastereomers of the β-fluoro amine carbocycle, each with high enantiomeric excess.

Graphical Abstract

β-Fluoroamines are codified tools in drug development^1,2 and organocatalysis,³ stimulating a wide range of methods to prepare this functional group.^4,5,6,7,8 β-Fluoroamines can stabilize specific conformations of acyclic chains,⁹ while also affecting the amine’s basicity¹⁰ and ability to engage in hydrogen bonding interactions.¹¹ Conformational effects of β-fluoroamines in rings may be less pronounced than those in acyclic arrays, but precision control of stereoelectronic effects between fluorine and amine can be achieved.^12,13,14 Methods for formation of cyclic β-fluoroamines have lagged behind those of their acyclic counterparts,¹⁵ and often fail to provide all possible stereoisomers when both fluorine and amine reside at chiral carbons.¹⁶ Access to both diastereomers and their mirror images is desired in medicinal chemistry where β-fluoroamines are used to optimize several lead properties, including potency and pharmacokinetics.¹¹ Despite this clear promise and synthetic need, cycloheptyl β-fluoroamines have long had few solutions for their synthesis.^17,18,19

Among the leading methods, α-fluorination of cyclic ketones and subsequent reductive amination leads to β-fluoroamines based on stereocontrolled C-F bond formation and diastereocontrolled C-N bond formation by reduction.²⁰ Carbocycles with a fused aziridine ring are precursors to anti-β-fluoroamines, including enantioenriched materials, through ring-opening reactions.²¹ Despite this progress, the preparation of cyclic β-fluoroamines from acyclic precursors has not been reported. Such an approach could offer the convergency of carbon-carbon bond formation and the potential to reach a range of ring sizes. We targeted β-fluoroamines embedded in 7-membered carbocyclic rings due to the significance of these cycloheptyl rings in biologically active natural products, and their potential integration into small molecule therapeutics.^22,23,24 Figure 1 outlines the design to source these cycloheptyl rings from unsaturated aldehyde (3) and nitroalkane (4) starting points. This offers two major points of convergency, one in the use of an aza-Henry reaction to forge the central carbon-carbon bond of the vic-fluoroamine as intermediate 2,²⁵ and the second in the application of ring-closing metathesis (RCM) to establish the 7-membered ring.^26,27,28,29 We report the successful realization of this strategy, providing the cis- and trans-vic-fluoroamines of saturated carbocyclic 7-membered rings in high enantiomeric excess.

Figure 1.

Retrosynthesis plan: Enantioselective synthesis of cis- and trans-β-fluoroamines of 7-membered carboycles.

The forging of the carbon-cabon bond that supports the β-fluoroamine through an aza-Henry addition was not without concern since the electrophilic N-Boc imine is subject to tautomerization to the N-Boc enamide. Numerous methods have been developed for the enantioselective aza-Henry reaction,³⁰ but relatively few have been applied to enolizable aliphatic N-Boc imines,³¹ and even fewer with α-fluoro nitroalkanes.²⁵ α-Fluoronitroalkanes can be less reactive than their non-fluorinated counterparts,^25,32 but they are readily prepared by α-fluorination of nitroalkanes such as 4.^33,34 Application of a nonracemic quaternary ammonium salt (7) and phase transfer catalysis, a combination developed by Palomo,^31e provided an effective means to synthesize doubly unsaturated β-fluoro amine syn-2 (Scheme 1). Initial attempts to effect this conversion were unsuccessful, an outcome that was ultimately traced to the use of 1–2 equivalents of α-fluoronitroalkane. It was found that 4–5 equivalents were necessary to deliver the desired addition product in a reasonable reaction time. Palomo has hypothesized that nitronate not only serves in the role of nucleophile, but also as the base that effects elimination to the N-Boc imine.^31d Once optimized, this addition led to a good yield (83%) of α-fluoro-β-amino-nitroalkanes 2. The major addition product (8.8:1 dr) was determined to be the less common syn-diastereomer,^30,31 as we recently noted in a more general study,³⁵ produced in high enantiomeric excess (94% ee). Importantly, the minor anti-diastereomer was produced in 90–92% ee. High ee for both diastereomers is one of two requirements for success of the synthesis strategy. The second requirement is that both diastereomers are homochiral at the secondary amine, as this would allow the diastereomers to converge during subsequent denitration of a diastereomeric mixture (vide infra). For this study, the diastereomers were separated at this stage for ease of characterization.

Scheme 1.

Catalyzed aza-Henry additions leading to ring-closing metathesis substrates for β-fluoro cycloheptylamine synthesis (top) and conformational analysis of fluorocycloheptene 8 (bottom).

The doubly terminal unsaturation of 2 allowed immediate application of ring-closing metathesis to construct the cycloheptenyl carbocycle. In the event, treatment with 5 mol % Grubbs II catalyst led to a single cycloheptene isomer 8 in 94% yield. Assignment of relative stereochemistry to this aza-Henry reaction major diastereomer was accomplished by advanced NMR experiments (HSQC, HMBC) to first assign all protons in 8, and then analyzed by ¹H-¹H NOESY (Scheme 1).³⁶ Particularly helpful was a HOESY (¹⁹F-¹H) experiment that indicated that the fluorine and NH were proximal. Additionally, the combination of H7β crosspeaks with fluorine and NH corroborated this relationship. Coupling constants were both consistent with NOESY data, and suggestive of a conformation wherein the fluorine is axial and NHBoc is equatorial: C3(Hα) and C1(H) both exhibited large couplings to fluorine (³J_HF = 34.7 Hz and 25.8 Hz, respectively), relative to the smaller coupling of C3(Hβ) = ³J_HF = 8.6 Hz.³⁷ This configurational assignment and conformation hypothesis was further supported by acquisition of an X-ray crystal structure for 8 (Scheme 1).

Use of 10 mol % dichloro-para-benzoquinone (DCBQ) substantially enhanced the selectivity of the RCM for a single product.³⁸ On scales up to 6 mmol, this reaction profile was maintained. The success of the overall procedure was replicated by targeting a benzo-fused cycloheptyl amine (11, Scheme 2). This procedure followed the approach for 8, except for the preparation of the α-amido sulfone 9 from ortho-vinyl benzaldehyde.³⁹ A chiral bis(amidine) (BAM) catalyst was applied to the aza-Henry step, leading to the β-amino-α-fluoronitroalkane in 76% yield and good stereoselection (8:1 dr, 92% ee (major)).³⁵ Notably, only 1.2 equivalents of the nitroalkane were needed to achieve good yield. The adduct was immediately subjected to RCM, providing benzocycloheptene 11 in 97% yield. An X-ray quality crystal yielded to analysis, revealing a similar fluorine-axial conformation (Scheme 2).

Scheme 2.

Catalyzed aza-Henry additions and ring-closing metathesis to prepare 11.

Cycloheptenyl amine 8 was reductively denitrated, leading to a minimal preference for the syn-β-fluoroamino cycloheptene (cis-12) in an 83% yield for the diastereomers (Scheme 3).⁴⁰ Access to both diastereomers was an advantage of this approach, further enhanced by their straightforward separation using standard flash chromatography. Although each diastereomer was a solid, neither yielded to single-crystal formation. The relative configuration for each diastereomer 12 was therefore assigned using a combination of 2D NMR experiments for which key elements are summarized in Figure 2.³⁶ A conformation in which the NHBoc-substituent is positioned equatorial was indicated by HOESY/NOESY for cis-12 and trans-12 as summarized and depicted in Figure 2. On gram-scale, this step and the subsequent hydrogenation could be applied to deliver stereoisomerically pure vic-β-fluoro amines 1 in protected form and good overall yield (Scheme 3). Overall, this synthesis required only 5 steps from a commercially available aldehyde and α-fluorinated allyl nitromethane.

Scheme 3.

Reductive denitration of 9 and subsequent hydrogenation to prepare N-protected β-fluoro cycloheptylamines 14.

Figure 2.

Assignment of relative configuation to enantioenriched β-fluoroamines 8.

In conclusion, an approach to 7-membered carbocyclic β-fluoroamines has been developed, leveraging the enantioselective aza-Henry and ring-closing metathesis reactions in sequence. A non-stereocontrolled reductive denitration provided the discrete β-fluoroamine functionality as a pair of readily-separated diastereomers that were advanced in parallel. The fully saturated β-fluoroamines were then prepared by hydrogenation. These results provide access to the parent cycloheptene and cycloheptane β-fluoro amines, and a potentially more general platform, to explore ring-size homologues, for therapeutic development.

Data Availability Statement:

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