Photomediated ring contraction of saturated heterocycles

Abstract

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework. Herein, we describe a visible light–mediated ring contraction of α-acylated saturated heterocycles. This unconventional transformation is orthogonal to traditional ring contractions, challenging the paradigm for diversification of heterocycles including piperidine, morpholine, thiane, tetrahydropyran, and tetrahydroisoquinoline derivatives. The success of this Norrish type II variant rests on reactivity differences between photoreactive ketone groups in specific chemical environments. This strategy was applied to late-stage remodeling of pharmaceutical derivatives, peptides, and sugars.

Saturated heterocycles, especially piperidines, are among the most frequently encountered scaffolds in biologically active small molecules (1, 2). The prevalence of the piperidine scaffold in pharmaceutical and agrochemical compound libraries has resulted in increased interest in the development of methods for its site-selective derivatization (Fig. 1A) to access new chemical space. Recent advancements in C(sp³)–H functionalization have provided many powerful methods for peripheral functionalization of the piperidine framework (3–12), shifting the paradigm in late-stage functionalization. By comparison, methods that modify the piperidine skeleton are less abundant, prompting a quest for methods for this purpose. Such methods would be especially valuable for drug discovery, in which maximizing structural diversity, specifically at a late stage, is highly valued (13). To this end, we sought to develop a ring contraction of piperidines and related saturated heterocycles to carbocyclic frameworks to achieve core, rather than peripheral, modification.

Fig. 1. Approaches to piperidine diversification.

(A) Peripheral functionalization and skeletal remodeling. (B) Selected examples of ring contractions on piperidine frameworks. (C) Seminal report of Seebach and co-workers’ unusual THIQ ring contraction (20). (D) Contraction of carbohydrates reported by Suárez and co-workers (21). (E) Norrish type II approach to piperidine skeletal framework modification (this work).

Relatively few methods for piperidine ring contraction exist compared with those available for the ring contraction of carbocycles bearing functional handles. For example, in cyclohexanone derivatives alone, anionic, carbene, and cationic intermediates have all been exploited to achieve ring contraction. By contrast, for saturated nitrogen–containing heterocycles (azacycles), commonly used ring contraction strategies predominantly leverage bicyclic, quaternary-ammonium intermediates, which undergo a formal ring contraction upon attack from an exogenous nucleophile (Fig. 1B) (14, 15). More recently, we reported an approach for piperidine ring contraction through oxidative C(sp³)–N bond cleavage, wherein silver-mediated deconstructive bromination of N-benzoyl piperidines followed by intramolecular C–N bond reformation in the resulting acyclic bromoamine furnishes the corresponding N-benzoyl pyrrolidine scaffolds in two steps (Fig. 1B) (16). Although useful, these tactics are limited to piperidine-to-pyrrolidine scaffold conversions, require specific substitution patterns (14, 15), and use strongly oxidizing conditions that pose a challenge for late-stage diversification (16, 17). The ring contractions of unsaturated azacyclic systems such as pyridiniums and dihydropyridines have also been explored, for example, by using light (18, 19). However, these transformations are limited to substrates with well-recognized photoreactivity profiles.

We sought to develop a complementary and mechanistically distinct approach to piperidine ring contraction that could also be applied to a wide range of saturated heterocycles to provide access to underexplored, skeletally diverse substrates. We drew inspiration from an unusual transformation reported by Seebach and co-workers (Fig. 1C), in which an α-carboxyl tetrahydroisoquinoline (THIQ) derivative (1a) underwent contraction to the corresponding indane scaffold (2a) under strongly basic conditions. This transformation features a curious endo-to-exocyclic nitrogen atom transposition, giving rise to a β–amino acid structural motif (20). Despite its novelty, only two examples were reported, and the requisite strongly basic conditions limit its potential application to skeletal modification of drug-like molecules bearing base-reactive functional groups. A more functional-group-compatible, albeit similarly specific, variant of this type of transformation was reported by Suárez and co-workers for α-diketonyl sugars (e.g., 1b), which undergo light-mediated ring contraction with a subsequent hemiketalization to give fused [5,5] ring systems (i.e., 2b) (Fig. 1D) (21, 22). Notably, the α-diketone moiety required for the reaction is derivatized in the resulting product. Our design of a complementary ring contraction sought broad functional group compatibility and a widened scope beyond α-diketonyl-derived sugars. Herein, we report the visible light–mediated ring contraction of α-acylated cyclic piperidines to furnish cis-1,2–disubstituted cyclopentane scaffolds (Fig. 1E) and the extension of this method to other saturated heterocycles including tetrahydropyrans and thianes. The success of these Norrish type II transformations hinged on predicted (and observed) photophysical differences between the ketone groups in the starting substrates and products (vide infra). An asymmetric variant of this transformation is also described.

Development of photomediated ring contraction

We commenced our studies by focusing on piperidine ring contractions (Fig. 2A). We envisioned that upon irradiation, α-acylated precursors such as I, in which the aroyl group is disposed pseudoaxially to avoid pseudo A^1,3-like strain (23), would undergo excitation and intersystem crossing to afford II in the triplet state. A subsequent Norrish type II 1,5-hydrogen atom transfer (HAT) would yield the corresponding 1,4-diradical (III), which would undergo homolytic C–N bond fragmentation, leading to imine-enol IV. The desired cyclopentane product would then result from an intramolecular enol attack on the tethered imine (Mannich reaction) to afford cyclopentane V. Under photoirradiation, however, we also recognized the potential for undesired reactivity (Fig. 2B), especially further reactivity of the reaction product (V) to form additional excited species such as VI.

Fig. 2. Reaction development.

(A) Proposed mechanism for piperidine ring contraction. (B) Potential undesired side reactivity through Norrish type I and Norrish–Yang cyclization processes. (C) Reaction optimization for light-mediated ring contraction. Reactions were performed on a 0.05 mmol scale. Relative stereochemistry is depicted. *Yields were determined by ¹H NMR integration using Ph₃CH as an internal standard. †Diastereomeric ratio (d.r.) was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude mixture. ‡Reaction was performed on a 1-g scale in flow, with an isolated yield of major diastereomer reported. §High throughput experimentation (HTE) conducted to identify 3-cyanoumbelliferone. Conversion was determined by liquid chromatography–mass spectrometry analysis.

In principle, the success of the reaction would depend on subtle differences in reactivity between the starting material (I) and the reaction product (V; an anticipated “photostationary” state), because both bear a photoreactive phenyl ketone that could participate in Norrish-type processes (see VI). In their studies (Fig. 1D), Suárez and co-workers had achieved success primarily because a photostationary state was reached upon hemiketalization of the α-diketone in the product (21, 22). We envisioned that even though chemical transformation of the photoreactive moiety would not be realized upon product formation in our case, differences in the n→π* photoabsorption profiles of I and V could arise by virtue of an intramolecular H-bond that is established in V. As is well known for spatially forbidden n→π* transitions, increased polarity in the local environment can lead to a hypsochromic (blue) shift for λ_max (24), which we anticipated would lead to differences in the photoreactivity of I and V. Additionally, we recognized that other photochemical processes could outcompete our desired ring contraction reaction. For example, although more prominent for dialkyl ketones, Norrish type I C–C bond homolysis from the triplet excited state (i.e., II) could lead to the formation of undesired alkyl-acyl radical pairs (see VII) (24). Another possible complication could arise after 1,5-hydrogen atom abstraction, in which radical recombination of diradical III could occur to give the corresponding [3.1.1]-bicycle (VIII), i.e., a Norrish–Yang cyclization. We imagined that a Norrish type II C–N fragmentation of III (to ultimately afford V) would outcompete a Norrish–Yang cyclization on the basis of an anticipated unfavorable conformational bias against ring closure to azetidinol VIII and a slower rate for intersystem crossing to the requisite singlet diradical for cyclobutanol C–C bond formation (25).

Despite the potential challenges associated with side reactions and overreactions of our phenyl ketone substrate, on the basis of the anticipated differences in absorptivity for I and V, we reasoned that tuning the wavelength of light could selectively promote the desired reactivity while minimizing the photoreactivity of the resulting products. Gratifyingly, photoirradiation of 3a using a 400-nm blue LED lamp provided 1,2-disubstituted cyclopentane 4a in 73% yield at room temperature (Fig. 2C, entry 1). Empirically, the photomediated ring contraction proceeded best with a 400-nm-wavelength light source; longer wavelength irradiation (centered at 450 nm; lower energy) did not result in any conversion, whereas shorter wavelength light sources (e.g., centered at 385 nm; higher energy), which more closely aligned with the calculated and measured absorptivity curves of both product and starting material, led to competing nonspecific oligomerization. Sulfonyl groups on the piperidine nitrogen were especially effective in providing the desired product in good to high yields, presumably enhancing the intramolecular H-bond in 4a that accounts for its stability under the reaction conditions. Other electron-withdrawing groups on the piperidine nitrogen, such as benzoyl, Boc, or pivaloyl (Fig. 2C, entries 2 to 4), resulted in lower yields of the ring contraction product. The choice of solvent was also critical. Benzene, which can enhance H-bonding in 4a, gave the highest yields and diastereoselectivity (26). Other solvents, such as methanol (Fig. 2C, entry 5), acetonitrile (Fig. 2C, entry 6), toluene (Fig. 2C, entry 7), and trifluorotoluene (Fig. 2C, entry 8), led to diminished yields and lower diastereoselectivity. Given the toxicity concerns of using benzene, we have also identified p-xylene as a serviceable solvent alternative (Fig. 2C, entry 9; see the supplementary materials for full solvent screen, and select substrates using p-xylene as the solvent). Lowering the concentration of the substrate also led to improvements in yield; a concentration of 0.05 M, which presumably slows the rate of competing unproductive intermolecular side reactions, was determined to be optimal. From these observations, we identified an optimized set of conditions for sulfonyl derivatives of the piperidine substrates, which afforded 4a in 84% isolated yield and high diastereoselectivity (Fig. 2C, entry 13). The reaction could be performed at gram scale under continuous (flow) conditions (Fig. 2C, entry 14; see the supplementary materials for additional details). For substrates bearing other protecting groups, such as amide and carbamate substrates, we observed reduced conversion to the desired product. This observation was intriguing because, ostensibly, the photoreactive phenyl ketone group in the starting substrates was conserved. We posited that changing the group on nitrogen (e.g., sulfonyl to acyl or carbamoyl) could lead to discrete differences in the triplet state energy of the phenyl ketone. We hypothesized that a photosensitizer or photocatalyst could improve the efficacy of the reaction, and thus we initiated a screen of 46 known photosensitizers and photocatalysts using amide substrate 3n. 3-Cyanoumbelliferone (IX; Fig. 2C, entry 16) emerged as an effective additive that improved the efficiency of the reaction: Piperidine 3m, 3o, 3s, and 3t were converted to their corresponding cyclopentylamines with improved yields (average of 11% increase, vide infra). The observed effect appeared to be subtle and substrate dependent. Efforts to further understand the role of cyanoumbelliferone IX are ongoing.

Scope of the photomediated ring contraction

With optimized conditions in hand, the scope of the visible-light mediated ring contraction was explored (Fig. 3A). The generality of the group on the nitrogen atom was investigated first. Arylsulfonyl-derivatized piperidines featuring electron-withdrawing substituents, such as ketones (e.g., 3h), esters (e.g., 3i), and halogens (3e to 3g), led to good to modest yields of the respective ring-contracted products. Likewise, arylsulfonyl-derivatized piperidines bearing electron-donating groups such as ethers (e.g., 3c and 3d) were also competent in the ring contraction transformation. The presence of a p-nitro substituent (3j) resulted in the complete recovery of starting material, likely resulting from photoquenching (27–29). Although arylsulfonyl substituents on the piperidine nitrogen led to the highest ring contraction product yields, substrates bearing acyl (e.g., 3m to 3p), carbamoyl (3q), and urea-type groups (e.g., 3r and 3s) on the nitrogen also led to successful ring contraction in the presence of cyanoumbelliferone (IX) (Fig. 3A).

Fig. 3. Scope of substrates in piperidine ring contraction.

Reaction conditions: Starting material (0.2 mmol), benzene (0.05 M), 400 nm LED, 18 to 24 hours. Isolated yields reported and relative stereochemistry are shown. Diastereomeric ratio was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. (A) Scope of protecting groups in ring contraction. *Additive IX (30 mol%) was added to the reaction mixture. †0.2 mmol scale trials conducted in the absence of additive IX. (B) Scope of aryl ketone in ring contraction. ‡Ring-opened product after a subsequent Norrish type II process is also observed. §(With N-Ts) Norrish–Yang azetidinol product observed in 12% (19% brsm). ¶(With N-Ts) Reaction irradiated with a medium-pressure mercury lamp for 24 hours. (C) Scope of heterocyclic core in ring contraction. #Reaction conducted on a 0.14 mmol scale. **Reaction conducted on a 0.11 mmol scale. ††Selected examples conducted on a 0.05 mmol scale using p-xylene (0.05 M) as a solvent. Yield was determined by ¹H NMR integration using Ph₃CH as an internal standard (see the supplementary materials for more details).

Phosphoramidite-containing substrates (3t and 3u) were also competent, providing the cyclopentane products in yields comparable to those observed for substrates bearing a sulfonyl group. In these cases, the phosphoramidyl group is easily removed under acidic conditions (30). The efficacy of the additive was also found to vary depending on the substrate, with the conversion of 3q to 4q being minimally affected upon adding IX. Here, the persisting low yield likely involves reduced productive hydrogen atom transfer because of a preference for an unproductive conformation of the starting material (see the supplementary materials for more details).

Next, we investigated the scope of the ring contraction with respect to the nature of the α-aroyl group (Fig. 3B). Here, the reaction was shown to be sensitive to sterics, with p-methyl substitution (5a) giving rise to higher yields and diastereoselectivity compared with the isomeric o-methyl–substituted 5b. Aryl ketones featuring electron-donating substituents, such as ethers (5c) and thioethers (5d), led to good yields and diastereoselectivity for the desired product. Halogen-containing α-aryl-ketone 5e was also competent in the ring contraction chemistry, affording an additional functional handle for modification after ring contraction. By comparison, electron-withdrawing groups such as p-CN and p-CF₃ (e.g., 5f and 5g) led to the formation of the desired product in modest yield and lower diastereoselectivity. This is likely the result of the increased acidity of the α-keto-proton in the product, which could undergo epimerization. On the basis of our calculations, epimerization through a retro–Mannich-Mannich pathway is unlikely (vide infra). Additionally, in the case of substrate 5g, we observed an ensuing ring opening of the product through Norrish type II cleavage, evidencing the potential overreactivity of the cyclopentane products in some cases (see the supplementary materials for more details). Other aromatic ketones were also examined. For example, extended aromatic systems such as naphthalenyl ketones (5h) performed comparably, as did heteroaromatics such as thiophenyl ketones (see 5k). Although the conditions identified were optimized for α-aroyl groups, several substrates bearing non–aryl-substituted ketones also participated successfully in the ring contraction transformation. Specifically, the desired products were observed for an alkynyl C(sp)–bearing substrate (5l) and a vinyl C(sp²)–bearing substrate (5m). In the case of 5l, the substantial decrease in yield can be attributed to a competing Norrish–Yang cyclization process leading to an azetidinol side product (see the supplementary materials for more details). Using more forcing, higher-energy (mercury lamp) irradiation, alkyl C(sp³)–substituted ketone 5n was converted to 6n in 25% yield, highlighting, even in this case, the differential reactivity of the ketone groups in the starting material and product.

Substituted piperidines and several other saturated heterocycles were then examined for their propensity to undergo this type of ring contraction (Fig. 3C). Single substituents at the γ-position were tolerated (see 7a), imparting stereocontrol. Benzannulated substrates such as tetrahydroisoquinoline 7b successfully underwent the ring contraction transformation, providing the corresponding amino indane scaffolds (i.e., 8b) in good yields and under mild conditions. Additionally, upon irradiation of substrates containing a morpholine scaffold, the tetrahydrofuran heterocycle (8c) was formed. The ring contraction methodology was also extended beyond azacyclic frameworks to α-acylated thiane and tetrahydropyran derivatives. These were also competent substrates, leading to the formation of cyclopentane thiol and alcohol products (see 8d to 8h), respectively. In the case of 7d, formation of the resulting thiol (8d) could be viewed as the unveiling of a covalent modifier upon photoirradiation.

Finally, we turned our attention toward the application of the ring contraction methodology to biologically active small molecules to demonstrate the potential for late-stage derivatization of drug candidates. Upon irradiation, MDMC (9a, stimulant), rimiterol (9b, bronchodilator), cathinone (9c, DAT reuptake inhibitor) (31), and mefloquine (9d, anti-malarial) derivatives underwent contraction to their corresponding cyclopentane isomers (Fig. 4A). In the case of 9d, a ring-opened aldehyde side product was also observed, potentially arising from hydrolysis of the imine intermediate before Mannich-type ring closure. We speculate that these events were likely due to the electron-deficient bis-trifluoromethylquinoline group in 9d. The ring contraction transformation was also leveraged in peptide diversification (Fig. 4B). Here, glycine-containing peptide 11 was converted to the corresponding amino cyclopentane (12), unveiling an H-bond donor. In this example, irradiation converts the α-peptide grouping to the corresponding β-amino ketone, accomplishing a nonintuitive peptide modification. Prospective applications include unveiling peptide-turn mimics upon irradiation.

Fig. 4. Applications toward biologically relevant compounds.

(A) Selected examples of bioactive drug molecule contraction. (B) Ring contraction–mediated peptide editing (see the supplementary materials for more details). (C) Sugar editing enabled by targeted “digestion.” Reaction conditions: Starting material (0.2 mmol), benzene (0.05 M), 400 nm LED, 24 hours. Isolated yields reported and relative stereochemistry are shown. Diastereomeric ratio was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. *Reaction conducted on a 0.1 mmol scale, where yield was determined by ¹H NMR integration using Ph₃CH as an internal standard and d.r. was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. †Ring-opened product also observed in 4.5% yield (see the supplementary materials for more details).

Because of the participation of cyclic ether derivatives in these light-mediated ring contractions, we also explored this rearrangement in sugar editing (Fig. 4C). When subjected to 400-nm irradiation conditions, D-galactose–derived bis-acetonide 13 gave isomeric ring–opened product 14. Here, the enol resulting from the Norrish type II ring opening presumably tautomerizes to the aryl ketone and does not engage the lactone carbonyl group, offering a powerful targeted “digestion” of sugar derivatives.

Computational insight

To gain insight into the proposed mechanism and origin of stereoselectivity for these photomediated ring contractions, we performed a computational study for the reaction of N-tosyl piperidine derivative 3b (Fig. 5A). All of the quantum chemical calculations in the transition state modeling presented were performed using the Gaussian 16 program (32). Geometry optimizations and frequency calculations were performed at the M06–2X/6–31+G** level of theory with the SMD model for implicit solvation by benzene (see the supplementary materials for more details) (33–35). We initially postulated that the positional selectivity for 1,5-HAT could be attributed to the greater hydricity and lower bond dissociation energy of the α-amino hydrogen atom (Fig. 5A, ³3b → ³A). Using density functional theory (DFT) calculations, we found that the more hydridic and polarity matched α-piperidinyl hydrogen atom had a HAT transition state 9.0 kcal/mol lower in energy than the potentially competing C–H abstraction at the γ-position (36, 37). The calculations also revealed a conformational preference in the transition state for the N–S bond wherein maximal separation is maintained between the carbonyl and sulfonyl oxygens (see the supplementary materials for more details).

Fig. 5. Computational studies on ring contraction mechanism.

(A) Reaction profile for the piperidine ring contraction. (B) Experimentally and computationally (normalized) determined absorption profiles for the starting material (3b) and product (4b). (C) Imine-enol geometries and transition states calculated for the diastereoselective ring closure.

We also reasoned that the diastereoselective formation of the cis-disposed amino cyclopentane products (e.g., 4b) would potentially result from a series of noncovalent interactions such as π-stacking and H-bonding in the transition state for the Mannich-type ring closure. Computed transition state structures support the Mannich-type cyclization/C–C bond formation proceeding in concert with proton transfer from the enol moiety to the N-tosyl group, consistent with the proposal by Suárez and co-workers for the aldol-type cyclization in hexopyranose carbohydrates (22). Three scenarios could be envisaged that qualitatively support the experimentally observed diastereoselectivity (Fig. 5C, top right). In the first scenario, only the (E/Z) imine–enol is productive. This geometry arises when fragmentation of diradical intermediate ³A occurs faster than acyl bond rotation (Fig. 5A, see ³A orange bond). Alternatively, if interconversion of the (Z) and (E) forms for both the enol (C=C) and the imine (C=N) bonds is facile, then all four possible imine–enol double-bond geometries can be accessed in the Mannich cyclization. However, the requisite triplet 1,4-diradical conformer that would afford the (Z)-imine (Ts-axial) is high in energy, and the contributions from a (Z)-imine geometry to the stereochemical outcome are expected to be negligible (see the supplementary materials for a complete discussion). We propose, therefore, that the most likely scenario is one in which the diradical is long-lived enough to allow acyl bond rotation and subsequent sampling of both enol diastereomers (38, 39). In this scenario, only the (E/Z) and (E/E) imine–enols are accessible and the energy differences between TS-1–4 would determine the stereochemical outcome. The Boltzmann average of these four transition states predicted a ratio of 14:1 in favor of the cis cyclopentane isomer, in good agreement with the experimentally determined 12:1 ratio. The cis diastereoselectivity mainly originates from the energy difference between TS-3 and TS-4, which could be rationalized by a shorter and presumably stronger H-bond, as well as a more staggered arrangement of substituents about the forming C–C bond in TS-3 (Fig. 5C, ¹B→¹4b). The overall transformation of N-tosyl piperidine 3b to either cyclopentane product was calculated to be exergonic (−4.2 kcal mol⁻¹ for the 4b compared with −3.3 kcal mol⁻¹ for the trans-isomer of 4b).

Insight into the selective reactivity of the starting material compared with the product under the reaction conditions was also supported by the DFT-calculated and empirically measured absorption profiles of 3b and 4b. Even though the calculated λ_max values for the starting material and product (Fig. 5B, top) did not differ markedly, we observed secondary absorption peaks associated with the expected n→π* occurring from 300 to 375 nm (Fig. 5B, bottom). Here, a hypsochromic shift was observed for amino cyclopentane product 4b relative to starting piperidine 3b, likely accounting for the selective excitation of the starting material. Also observed empirically was an overall decrease in absorptivity for the product (e.g., ε₃₄₀ = 48.0 L cm⁻¹ mol⁻¹ for 3b versus ε₃₂₀ = 19.2 L cm⁻¹ mol⁻¹ for 4b). Although predictions and rationalizations of photochemical processes tend to focus on λ_max values, in our system, irradiation at λ_max would have led to indiscriminate reaction of both the starting materials and products. By focusing on the secondary, n→π* absorption region of 300 to 375 nm, we were able to modulate the reactivity of the ketone group that is conserved in both the starting material and product by exploiting subtle differences in the absorbance wavelengths and extinction coefficients (see the supplementary materials for more details) (40). The emission spectrum of the 400-nm light source slightly overlaps with the wavelength of light absorbed by the starting material but negligibly with the product. However, the empirically established optimal use of a commercially acquired 400-nm blue LED light source remains to be fully reconciled with the measured absorption values.

Toward a general asymmetric variant

Our insights into the observed diastereoselectivity for these transformations, which arises from highly organized transition states of an achiral imine-enol intermediate (as revealed from our calculations), combined with the successes of other powerful enantioselective photomediated processes (41, 42), inspired us to pursue enantioselective variants. We observed the formation of racemic product 4b when enantioenriched 3b was subjected to the ring contraction conditions, confirming that in this formal radical polar crossover the imine–enol intermediate is achiral. Therefore, we could circumvent the inherent challenges associated with stereocontrol of radical intermediates by effecting enantioselective closure of the achiral imine-enol intermediate under a two-electron reaction manifold (43). Given the ample literature precedent and predictive models for chiral phosphoric acid–catalyzed reactions of imines, we postulated that rate enhancement of the Mannich step would occur after imine protonation and attendant deprotonation of the enol, leading to an organized transition state favoring attack on one enantioface (see Fig. 6 and the supplementary materials for more details). The combination of H-bonding and ion pairing that would be realized in this case was anticipated to yield enantioenriched Mannich products (Fig. 6) (44–48).

Fig. 6. Development of an asymmetric ring contraction variant.

*Reaction conducted on a 0.05 mmol scale in which yields were determined by ¹H NMR integration using Ph₃CH as an internal standard and d.r. was determined by ¹H NMR integration of resonances corresponding to diastereomers in the crude. For the major diastereomer, e.r. was determined by SFC analysis. †10 mol% (R)-TRIP (CPA1) used as chiral phosphoric acid. ‡10 mol% (R)-XYL-SPA (CPA2) used as chiral phosphoric acid.

Consistent with this hypothesis, ring contraction of 3b with 10 mol% of (R)-TRIP (CPA1) as an additive provided (−)-4b in 92:8 enantiomeric ratio (e.r.) 84% enantiomeric excess (ee) with yields and diastereoselectivity consistent with those obtained under the standard reaction conditions for the formation of the racemate; using the SPINOL-derived phosphoric acid (R)-XYL-SPA (CPA2) gave (+)-4b in 95:5 e.r. (90% ee). Enantioselectivity, albeit modest, was also observed for amide, urea, THIQ, morpholine, and tetrahydropyran derivatives, giving rise to the enantioenriched products 4m, 4s, 8b, 8c, 8e, and 8g, respectively.

Conclusion

Using a Norrish type II reaction, we have established a versatile method for the scaffold remodeling of piperidines as well as other saturated heterocycles. The overall transformation is robust, and the conditions tolerate a wide range of functional groups. Key to the success of these transformations is the “photo-protection” of a pendant ketone group in the product through intramolecular H-bonding, an observation supported by our experimental and computational findings. This reaction has been rendered enantioselective using chiral phosphoric acids.

Data and materials availability:

All reported data can be found in the manuscript or the supplementary materials. Requests for additional materials should be directed to the corresponding authors. X-ray crystallographic data for 3a, 4a, 4m, 9a, 10a, and (−)-4b (CCDC 2061160, 2061161, 2061162, 2061169, 2061170, and 2071240, respectively) are available from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/).