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Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated δ C–H Cyanation
Article
Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation Zuxiao Zhang, Xin Zhang, David A. Nagib [email protected]
HIGHLIGHTS Remote d C–H functionalization of amines with a carbonyl equivalent (i.e., a nitrile) Regio- and enantioselective interception of an intramolecular H-atom transfer (HAT) Interrupted Hofmann-Lo¨fflerFreytag reaction entailing enantioselective C–C formation Asymmetric synthesis of b aryl piperidines from acyclic amines
Zhang and colleagues describe a new method that enables the asymmetric synthesis of piperidines, which are commonly found in many drugs, including the anti-cancer agent, niraparib. The piperidine ring is formed from simple, linear amines by a new catalytic reaction that replaces a single C–H bond with a C–C bond. The positional and three-dimensional selectivity of this transformation was enabled by developing a copper catalyst to harness a radical relay mechanism.
Zhang et al., Chem 5, 1–8 December 12, 2019 ª 2019 Elsevier Inc. https://doi.org/10.1016/j.chempr.2019.09.010
Please cite this article in press as: Zhang et al., Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.010
Article
Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation Zuxiao Zhang,1 Xin Zhang,1 and David A. Nagib1,2,*
SUMMARY
The Bigger Picture
Piperidines are the most prevalent heterocycle found in medicines. Yet, although they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Lo¨ffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio-, and enantioselective d C–H cyanation of acyclic amines described here, incorporates a carbonyl equivalent selectively at the d position. This d C–H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for d C–C formation is presented, as well as conversion of the resulting enantioenriched d-amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other stereoselective d C–H functionalizations.
One of the most prevalent motifs found in medicines is the piperidine ring. However, its selective, asymmetric synthesis remains a challenge. For example, access to anti-cancer drug, niraparib, requires wasteful resolution of symmetric mixtures. In this article, we describe a new method to convert simple, linear amines, such as those found in plasticizers, to more complex asymmetric products by selectively transforming one of its C–H bonds. The newly installed dcyano group can then be manipulated in a variety of ways, including to form asymmetric piperidine rings. Several medicinally relevant products are now accessible by this approach, which also enables the first asymmetric synthesis of the anticancer drug, niraparib.
INTRODUCTION Since the landmark synthesis of nicotine over a century ago, N to C radical relays have enabled the conversion of acyclic amines to pyrrolidines.1,2 This d C–H amination, which occurs by an entropically and enthalpically favored 1,5-hydrogen atom transfer (HAT), robustly affords d regioselective C–N formation and access to five-membered heterocycles.3 Cognizant of the medicinal importance of corresponding six-membered heterocycles,4 we endeavored to leverage this robust, regioselective HAT mechanism to also enable selective access to chiral piperidines. To illustrate the importance of this ongoing challenge, the synthesis of anti-cancer drug, niraparib, necessitated chemical, physical, and enzymatic resolutions to control its C3 stereocenter (Figure 1A).5,6 As a streamlined alternative, Pd-catalyzed,7 remote C–H arylations have been developed to directly access g8- or b9substituted piperidines, albeit only racemically (Figure 1B). Looking toward a complementary, radical-mediated method for remote C–H functionalization of acyclic amines, we sought to employ an Hofmann-Lo¨ffler-Freytag (HLF) reaction mechanism, which typically affords pyrrolidines3,10 (Figure 1B). However, recently, the first examples of d C–C formation have been enabled by intercepting this radical translocation to afford acyclic, d-functionalized amides.11–20 Nonetheless, development of enantioselective methods for termination of an HAT pathway remains an ongoing challenge21–24—both for the classic d C–H amination as well as for recent interrupted methods for d C–H functionalization. In fact, with the exception of a single example of d C–H arylation from our lab (65% ee),25 all known remote C–H functionalizations via N-radical relays are racemic.
Chem 5, 1–8, December 12, 2019 ª 2019 Elsevier Inc.
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Figure 1. Chiral Piperidine Synthesis (A) State-of-art methods for preparing piperidines in medicines are racemic. (B) Remote C–H functionalizations of amines are racemic. (C) Asymmetric a C–H functionalizations via HAT. (D) Proposed catalytic, asymmetric d C–H cyanation of amines.
Inspired by the pioneering work of Liu and Stahl on asymmetric a C–H functionalizations through a benzylic HAT mechanism (Figure 1C),26,27 we proposed the d C–C formation could also be rendered asymmetric to afford enantioenriched, remote stereocenters by intercepting a regioselective 1,5-HAT. Specifically, we envisioned an enantioselective d C–H cyanation of amines may provide access to a distal carbonyl surrogate (Figure 1D). Subsequent reduction of this d-amino nitrile could then unmask a d-aldehyde stereocenter and facilitate cyclization to enantioenriched piperidines. In this strategy, acyclic amines and cyanide would afford chiral piperidines by an atypical (5+1) synthetic disconnection. Importantly, we were cognizant that the chiral Cu catalyst must be involved in the C–C bond-forming event in order to impart enantiocontrol on this d C–H cyanation. Otherwise, this might lead to a background racemic reaction.28 If successful, we envisioned this approach for stereoselective interception of an intramolecular HAT based on N-centered radicals could enable the asymmetric synthesis of a wide variety of remotely functionalized amines and heterocycles.
RESULTS AND DISCUSSION Strategy To enable our design of an enantioselective d C–H cyanation of amines (Figure 2A), we proposed a chiral Cu complex could serve as a catalyst to both initiate and intercept the radical relay. For this approach to successfully preclude d C–H amination, we hypothesized a competent pathway (Figure 2B) would require the radical precursor, N-fluoro amide A, to not engage a Cu(I) catalyst until after transmetalation by Me3SiCN has first occurred (Scheme S9). The resultant, more reducing Cu(I)CN may then selectively reduce the N–F bond to afford an N-centered radical B, which can facilitate HAT.29 Upon regioselective translocation of N to C radicals via 1,5-HAT, d C-radical C may be reversibly intercepted30 by the oxidized Cu(II)
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1Department
of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
2Lead
Contact
*Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.09.010
Please cite this article in press as: Zhang et al., Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.010
Figure 2. Enantioselective d C–H Cyanation (A) Catalytic, asymmetric d C–H cyanation. (B) Proposed Cu-catalyzed mechanism. (C) Development of highly asymmetric reaction. a a amide (0.1 mmol), 3% Cu(OTf)2 , 7.5% L*, Me 3 SiCN (1.8 equiv), solvent (0.05 M), 18 h, 23 C. b 20:1 MeCN:DMAc. c 10.5:1 MeCN: DMAc, 4.25% Cu(OTf) 2 , 6.75% L5. Isolated yields. Enantiomeric excess (ee) determined by HPLC. >20:1 d regioselectivity observed in all cases. See Tables S1–S4 and Scheme S1 for more details.
CN to form remote organocopper complex D.31 Lastly, stereoselective reductive elimination of D may provide enantioselective C–C formation to yield d C–H cyanation (E) along with the regenerated Cu(I) catalyst. Discovery To test our hypothesis that intercepting an N-radical relay may enable enantioselective d C–H cyanation, we combined Me3SiCN and N-fluoro-tosylamide with a pre-stirred complex of Cu(OTf)2 and bisoxazoline ligand L0 at room temperature (Figure 2C). Among all solvents investigated (e.g., benzene [PhH], dichloromethane [DCM], and acetonitrile [MeCN]), only dimethylacetamide (DMAc) facilitated conversion of the starting material, albeit with an unclean reaction profile (30% yield, entries 1 and 2). However, co-solvent mixtures appear to attenuate undesired reaction pathways. For example, 9:1 mixtures of either PhH:DMAc or MeCN:DMAc provide desired d-amino nitrile 1 in modest yield and selectivity (entries 3 and 4). Cognizant that excess CN anion in solution may displace the chiral ligand from Cu to result in a racemic background reaction (as elucidated in the enantioselective cyanotrifluoromethylation of alkenes),32,33 we probed the effect of increased concentration of the bidentate ligand (entries 5–8). After extensive investigation, we determined the ideal Cu:L ratio for this C–H cyanation to be 3% Cu(OTf)2 and 7.5% L—affording 83% ee with L1 (entry 7). Finally, while L0 has been shown to afford high selectivity in the intermolecular variant,6 our observation that the cis-1-amino-2-indanol catalyst backbone affords greater enantioselectivity for this d C–H cyanation encouraged us to explore a broader set of such ligands (Figure 2C, bottom row). In this regard, we found that a cyclopropane spacer (L1) between the oxazolines affords 84% ee. Furthermore, incorporating a bis-Bn umbrella (L5) to cover the
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Figure 3. Enantioselective, Copper-Catalyzed d C–H Cyanation via Radical Relaya a amide (0.2 mmol), Cu(OTf) 2 (3–4.5 mol %), L1 or L5 (7.5 mol %), Me 3 SiCN (1.8 equiv) in MeCN:DMAc (0.05 M) for 16–20 h at 23 C. Isolated yields. Enantiomeric excess (ee) determined by HPLC. >20:1 d regioselectivity in all cases.
upper portion of the catalyst and decrease the bidentate bite angle affords 90% ee. Yields were further improved in these two cases (to 93%) by using less DMAc co-solvent to further minimize undesired reactivity. Notably, only d regioselectivity was observed in all cases (>20:1). Synthetic Evaluation Having developed a catalytic, asymmetric d C–H cyanation, we then sought to investigate the utility and scope of this radical relay mechanism (Figure 3). To this end, we subjected a wide array of amines with varying electronics on the sulfonamide (1 and 2) as well as at the 4-aryl substituent (3–16). Given the likely role of the 4-aryl group in stabilizing a benzyl radical that engages the Cu catalyst in enantioselective C–C bond formation, we were especially curious about its generality. Fortunately, we found that both electron-releasing (OMe, NPhth, and Me) as well as electron-withdrawing (F, CN, CF3, CO2Et, and SO2NR2) groups are well-tolerated, affording d-amino nitriles with 86%–93% ee. We were also pleased to find that these substituents could be placed anywhere on the arene (ortho, meta, and para) without any significant effect on stereoselectivity. Moreover, functional groups that can be further modified were also tolerated (Cl 5 and CO2Et 10). Additionally, a bis-CF3 arene (14), polyarene (naphthalene 15), and heteroarene (thiophene 16) were incorporated in this radical relay reaction. Finally, a more geometrically constrained ortho-alkyl benzamide facilitates HAT and provides the a-benzyl nitrile in good yield and enantioselectivity (17).
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Figure 4. Mechanistic Probes for Chemo- and Regio-Selectivity
Selectivity Probes Given the robust stereoselectivity observed, we next turned our attention to a deeper exploration of the chemo- and regio-selectivity of this HAT-mediated reaction by including weaker C–H bonds (gray circles) within various molecular probes (Figure 4). An initial competition between multiple benzylic C–H bonds within a single molecule illustrates the propensity for d selectivity (>20:1) via intra- versus intermolecular26 HAT—and exclusively 1,5 over 1,6-HAT (18-19). Although the enantioselectivity of Ts-amide 18 is slightly lower than the parent system (87% versus 90% ee), the more sterically crowded and rigid ortho-benzamide 19 affords even higher selectivity than its parent amide (95% versus 93% ee). We next tested the robustness of the 1,5-HAT mechanism by including two benzylic C–H bonds at d and ε positions in a benzo-fused bicycle (20). In this case, 1,5-HAT fully outcompetes 1,6-HAT affording a single isomer (>20:1 d) in high diastereoselectivity (16:1 dr). However, when a significant thermodynamic bias (8 kcal/mol) is incorporated to override 1,5-HAT (21; benzylic ε C–H, 90 kcal/mol; versus secondary d C–H, 98 kcal/mol),34 then both intramolecular HAT events become kinetically comparable, affording a mixture of both isomers (1:1.3 d:ε). Conversely, addition of an extra methylene to examine a 1,5- versus 1,7-HAT competition (22) results in exclusive d selectivity (>20:1)—even outcompeting the bias for benzylic over secondary C–H abstraction. When a completely aliphatic amine is used (23), wherein the a-amino C–H is at least 15 kcal/mol weaker than the d methylenic C–H, the d isomer is exclusively observed, albeit not enantioselectively (11% ee). In the same vein, amines bearing a-oxy and allylic C–H bonds (24–26) undergo this regioselective radical relay to afford d-amino nitriles in >20:1 rr but with low enantioselectively (< 10% ee) (a-amido C–H, < 83 kcal/mol; a-oxy C–H, 94 kcal/mol; allylic C–H, 83 kcal/mol).34 To further illustrate the synthetic utility of this regioselective, 1,5-HAT mechanism, we subjected an amine with multiple benzylic C–H bonds (S18) to both a and d C–H cyanation conditions (Figure 5). In the presence of a free N–H amide, the a C–H cyanation reaction26 is significantly inhibited, affording minimal conversion (14% yield, >80% recovered starting material; see Schemes S10 and S11 for more details). Moreover, a 1:1 mixture of isomers is observed between the d-amino nitrile and the cyclopentyl nitriles (iso-18). This contrasts with the single regio- and stereoisomer observed using our newly developed d C–H cyanation conditions (72% yield, >20:1 d selectivity, 87% ee).
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Figure 5. Comparison between a and d C–H Cyanations
Synthetic Utility To illustrate the synthetic utility of these enantioenriched d-amino nitriles, we then investigated the reactivity of the latent carbonyls within these products (Figure 6). After synthesis at a 2 mmol scale (94% yield, 90% ee), 1 could either be reduced to 1,5-diamine 27 (via BH3) or hydrolyzed to d-amino amide 28 (via H2O2)—affording products with high enantiospecificity in both cases (80%–99% es). In the hopes of harnessing the proposed d aldehyde, 1 was also reduced by iBu2Al-H. Upon cyclization of the transiently generated d-amino aldehyde, the resultant hemiaminal 29 was then subjected to additional reactions. In the simplest case, reduction of hemiaminal 29 by Et3SiH affords (S)-3-phenylpiperidine 30 in 99% es. Noting the challenge of stereoselectively preparing such useful heterocyclic building block by other means, we then explored the generality of this synthetic route. To our delight, (S)-3-substituted piperidines containing thiophene (31), naphthalene (32), para-sulfonamide (33), and bis-CF3 arene (34) were all readily prepared by this double reduction sequence with excellent stereospecificity (up to 99% es). Finally, other nucleophiles could also be combined with hemiaminal 29, including allylsilane, which affords (2S,3S)-2-allyl-3-phenylpiperidine 35 in 3:1 dr and 99% es. As further demonstration of the synthetic utility of this enantioselective d C–H cyanation, we also completed a formal synthesis of the anti-cancer drug, niraparib, which had previously only been prepared racemically or by enzymatic resolution (Figure 7).5,6 Subjecting the enantioenriched d-amino nitrile 7 to deprotection and reduction affords the para-NH2 (S)-3-arylpiperidine 36 in 50% yield and >99% es. The kilogram-scale synthesis of niraparib has already been reported from this deprotected aniline.5,6
Figure 6. Synthesis of Enantioenriched Heterocycles from Acyclic Amines via d-Amino Nitriles
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Figure 7. Formal, Asymmetric Synthesis of Anti-cancer Drug, Niraparib
Conclusions In summary, an enantioselective d C–H cyanation has been developed by intercepting an N-centered radical relay with a chiral Cu catalyst. The resultant, enantioenriched d-amino nitriles, represent the first examples of a highly asymmetric variant of an HLF reaction. The utility of these remotely functionalized amines was showcased by the synthesis of a family of chiral piperidines. Mechanistic probes for the chemo-, regio-, and enantio- selectivity of this HAT pathway also provide insights to enable future applications of this enantioselective strategy for other radical-mediated, remote C–H functionalizations.
EXPERIMENTAL PROCEDURES Full experimental procedures are provided in the Supplemental Information. See Schemes S2–S8 and Figures S1–S172 for synthesis and characterization of new compounds and Table S5 for exceptions.
SUPPLEMENTAL INFORMATION Supplemental Information can be found online at https://doi.org/10.1016/j.chempr. 2019.09.010.
ACKNOWLEDGMENTS We thank the National Institutes of Health (NIH R35 GM119812) and the National Science Foundation (NSF CAREER 1654656) for financial support.
AUTHOR CONTRIBUTIONS Z.Z. designed, discovered, and optimized the enantioselective d C–H cyanation. Z.Z. and X.Z. designed, performed, and analyzed all experiments probing reaction scope, selectivity, and synthetic utility. All authors contributed to writing this manuscript.
DECLARATION OF INTERESTS The authors declare no competing interests. Received: July 25, 2019 Revised: August 23, 2019 Accepted: September 18, 2019 Published: October 17, 2019
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Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation Zuxiao Zhang, Xin Zhang, David A. Nagib [email protected]
HIGHLIGHTS Remote d C–H functionalization of amines with a carbonyl equivalent (i.e., a nitrile) Regio- and enantioselective interception of an intramolecular H-atom transfer (HAT) Interrupted Hofmann-Lo¨fflerFreytag reaction entailing enantioselective C–C formation Asymmetric synthesis of b aryl piperidines from acyclic amines
Zhang and colleagues describe a new method that enables the asymmetric synthesis of piperidines, which are commonly found in many drugs, including the anti-cancer agent, niraparib. The piperidine ring is formed from simple, linear amines by a new catalytic reaction that replaces a single C–H bond with a C–C bond. The positional and three-dimensional selectivity of this transformation was enabled by developing a copper catalyst to harness a radical relay mechanism.
Zhang et al., Chem 5, 1–8 December 12, 2019 ª 2019 Elsevier Inc. https://doi.org/10.1016/j.chempr.2019.09.010
Please cite this article in press as: Zhang et al., Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.010
Article
Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation Zuxiao Zhang,1 Xin Zhang,1 and David A. Nagib1,2,*
SUMMARY
The Bigger Picture
Piperidines are the most prevalent heterocycle found in medicines. Yet, although they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Lo¨ffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio-, and enantioselective d C–H cyanation of acyclic amines described here, incorporates a carbonyl equivalent selectively at the d position. This d C–H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for d C–C formation is presented, as well as conversion of the resulting enantioenriched d-amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio-selectivity of this HAT mechanism are also included to enable extension to other stereoselective d C–H functionalizations.
One of the most prevalent motifs found in medicines is the piperidine ring. However, its selective, asymmetric synthesis remains a challenge. For example, access to anti-cancer drug, niraparib, requires wasteful resolution of symmetric mixtures. In this article, we describe a new method to convert simple, linear amines, such as those found in plasticizers, to more complex asymmetric products by selectively transforming one of its C–H bonds. The newly installed dcyano group can then be manipulated in a variety of ways, including to form asymmetric piperidine rings. Several medicinally relevant products are now accessible by this approach, which also enables the first asymmetric synthesis of the anticancer drug, niraparib.
INTRODUCTION Since the landmark synthesis of nicotine over a century ago, N to C radical relays have enabled the conversion of acyclic amines to pyrrolidines.1,2 This d C–H amination, which occurs by an entropically and enthalpically favored 1,5-hydrogen atom transfer (HAT), robustly affords d regioselective C–N formation and access to five-membered heterocycles.3 Cognizant of the medicinal importance of corresponding six-membered heterocycles,4 we endeavored to leverage this robust, regioselective HAT mechanism to also enable selective access to chiral piperidines. To illustrate the importance of this ongoing challenge, the synthesis of anti-cancer drug, niraparib, necessitated chemical, physical, and enzymatic resolutions to control its C3 stereocenter (Figure 1A).5,6 As a streamlined alternative, Pd-catalyzed,7 remote C–H arylations have been developed to directly access g8- or b9substituted piperidines, albeit only racemically (Figure 1B). Looking toward a complementary, radical-mediated method for remote C–H functionalization of acyclic amines, we sought to employ an Hofmann-Lo¨ffler-Freytag (HLF) reaction mechanism, which typically affords pyrrolidines3,10 (Figure 1B). However, recently, the first examples of d C–C formation have been enabled by intercepting this radical translocation to afford acyclic, d-functionalized amides.11–20 Nonetheless, development of enantioselective methods for termination of an HAT pathway remains an ongoing challenge21–24—both for the classic d C–H amination as well as for recent interrupted methods for d C–H functionalization. In fact, with the exception of a single example of d C–H arylation from our lab (65% ee),25 all known remote C–H functionalizations via N-radical relays are racemic.
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Please cite this article in press as: Zhang et al., Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.010
Figure 1. Chiral Piperidine Synthesis (A) State-of-art methods for preparing piperidines in medicines are racemic. (B) Remote C–H functionalizations of amines are racemic. (C) Asymmetric a C–H functionalizations via HAT. (D) Proposed catalytic, asymmetric d C–H cyanation of amines.
Inspired by the pioneering work of Liu and Stahl on asymmetric a C–H functionalizations through a benzylic HAT mechanism (Figure 1C),26,27 we proposed the d C–C formation could also be rendered asymmetric to afford enantioenriched, remote stereocenters by intercepting a regioselective 1,5-HAT. Specifically, we envisioned an enantioselective d C–H cyanation of amines may provide access to a distal carbonyl surrogate (Figure 1D). Subsequent reduction of this d-amino nitrile could then unmask a d-aldehyde stereocenter and facilitate cyclization to enantioenriched piperidines. In this strategy, acyclic amines and cyanide would afford chiral piperidines by an atypical (5+1) synthetic disconnection. Importantly, we were cognizant that the chiral Cu catalyst must be involved in the C–C bond-forming event in order to impart enantiocontrol on this d C–H cyanation. Otherwise, this might lead to a background racemic reaction.28 If successful, we envisioned this approach for stereoselective interception of an intramolecular HAT based on N-centered radicals could enable the asymmetric synthesis of a wide variety of remotely functionalized amines and heterocycles.
RESULTS AND DISCUSSION Strategy To enable our design of an enantioselective d C–H cyanation of amines (Figure 2A), we proposed a chiral Cu complex could serve as a catalyst to both initiate and intercept the radical relay. For this approach to successfully preclude d C–H amination, we hypothesized a competent pathway (Figure 2B) would require the radical precursor, N-fluoro amide A, to not engage a Cu(I) catalyst until after transmetalation by Me3SiCN has first occurred (Scheme S9). The resultant, more reducing Cu(I)CN may then selectively reduce the N–F bond to afford an N-centered radical B, which can facilitate HAT.29 Upon regioselective translocation of N to C radicals via 1,5-HAT, d C-radical C may be reversibly intercepted30 by the oxidized Cu(II)
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1Department
of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
2Lead
Contact
*Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.09.010
Please cite this article in press as: Zhang et al., Chiral Piperidines from Acyclic Amines via Enantioselective, Radical-Mediated d C–H Cyanation, Chem (2019), https://doi.org/10.1016/j.chempr.2019.09.010
Figure 2. Enantioselective d C–H Cyanation (A) Catalytic, asymmetric d C–H cyanation. (B) Proposed Cu-catalyzed mechanism. (C) Development of highly asymmetric reaction. a a amide (0.1 mmol), 3% Cu(OTf)2 , 7.5% L*, Me 3 SiCN (1.8 equiv), solvent (0.05 M), 18 h, 23 C. b 20:1 MeCN:DMAc. c 10.5:1 MeCN: DMAc, 4.25% Cu(OTf) 2 , 6.75% L5. Isolated yields. Enantiomeric excess (ee) determined by HPLC. >20:1 d regioselectivity observed in all cases. See Tables S1–S4 and Scheme S1 for more details.
CN to form remote organocopper complex D.31 Lastly, stereoselective reductive elimination of D may provide enantioselective C–C formation to yield d C–H cyanation (E) along with the regenerated Cu(I) catalyst. Discovery To test our hypothesis that intercepting an N-radical relay may enable enantioselective d C–H cyanation, we combined Me3SiCN and N-fluoro-tosylamide with a pre-stirred complex of Cu(OTf)2 and bisoxazoline ligand L0 at room temperature (Figure 2C). Among all solvents investigated (e.g., benzene [PhH], dichloromethane [DCM], and acetonitrile [MeCN]), only dimethylacetamide (DMAc) facilitated conversion of the starting material, albeit with an unclean reaction profile (30% yield, entries 1 and 2). However, co-solvent mixtures appear to attenuate undesired reaction pathways. For example, 9:1 mixtures of either PhH:DMAc or MeCN:DMAc provide desired d-amino nitrile 1 in modest yield and selectivity (entries 3 and 4). Cognizant that excess CN anion in solution may displace the chiral ligand from Cu to result in a racemic background reaction (as elucidated in the enantioselective cyanotrifluoromethylation of alkenes),32,33 we probed the effect of increased concentration of the bidentate ligand (entries 5–8). After extensive investigation, we determined the ideal Cu:L ratio for this C–H cyanation to be 3% Cu(OTf)2 and 7.5% L—affording 83% ee with L1 (entry 7). Finally, while L0 has been shown to afford high selectivity in the intermolecular variant,6 our observation that the cis-1-amino-2-indanol catalyst backbone affords greater enantioselectivity for this d C–H cyanation encouraged us to explore a broader set of such ligands (Figure 2C, bottom row). In this regard, we found that a cyclopropane spacer (L1) between the oxazolines affords 84% ee. Furthermore, incorporating a bis-Bn umbrella (L5) to cover the
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Figure 3. Enantioselective, Copper-Catalyzed d C–H Cyanation via Radical Relaya a amide (0.2 mmol), Cu(OTf) 2 (3–4.5 mol %), L1 or L5 (7.5 mol %), Me 3 SiCN (1.8 equiv) in MeCN:DMAc (0.05 M) for 16–20 h at 23 C. Isolated yields. Enantiomeric excess (ee) determined by HPLC. >20:1 d regioselectivity in all cases.
upper portion of the catalyst and decrease the bidentate bite angle affords 90% ee. Yields were further improved in these two cases (to 93%) by using less DMAc co-solvent to further minimize undesired reactivity. Notably, only d regioselectivity was observed in all cases (>20:1). Synthetic Evaluation Having developed a catalytic, asymmetric d C–H cyanation, we then sought to investigate the utility and scope of this radical relay mechanism (Figure 3). To this end, we subjected a wide array of amines with varying electronics on the sulfonamide (1 and 2) as well as at the 4-aryl substituent (3–16). Given the likely role of the 4-aryl group in stabilizing a benzyl radical that engages the Cu catalyst in enantioselective C–C bond formation, we were especially curious about its generality. Fortunately, we found that both electron-releasing (OMe, NPhth, and Me) as well as electron-withdrawing (F, CN, CF3, CO2Et, and SO2NR2) groups are well-tolerated, affording d-amino nitriles with 86%–93% ee. We were also pleased to find that these substituents could be placed anywhere on the arene (ortho, meta, and para) without any significant effect on stereoselectivity. Moreover, functional groups that can be further modified were also tolerated (Cl 5 and CO2Et 10). Additionally, a bis-CF3 arene (14), polyarene (naphthalene 15), and heteroarene (thiophene 16) were incorporated in this radical relay reaction. Finally, a more geometrically constrained ortho-alkyl benzamide facilitates HAT and provides the a-benzyl nitrile in good yield and enantioselectivity (17).
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Figure 4. Mechanistic Probes for Chemo- and Regio-Selectivity
Selectivity Probes Given the robust stereoselectivity observed, we next turned our attention to a deeper exploration of the chemo- and regio-selectivity of this HAT-mediated reaction by including weaker C–H bonds (gray circles) within various molecular probes (Figure 4). An initial competition between multiple benzylic C–H bonds within a single molecule illustrates the propensity for d selectivity (>20:1) via intra- versus intermolecular26 HAT—and exclusively 1,5 over 1,6-HAT (18-19). Although the enantioselectivity of Ts-amide 18 is slightly lower than the parent system (87% versus 90% ee), the more sterically crowded and rigid ortho-benzamide 19 affords even higher selectivity than its parent amide (95% versus 93% ee). We next tested the robustness of the 1,5-HAT mechanism by including two benzylic C–H bonds at d and ε positions in a benzo-fused bicycle (20). In this case, 1,5-HAT fully outcompetes 1,6-HAT affording a single isomer (>20:1 d) in high diastereoselectivity (16:1 dr). However, when a significant thermodynamic bias (8 kcal/mol) is incorporated to override 1,5-HAT (21; benzylic ε C–H, 90 kcal/mol; versus secondary d C–H, 98 kcal/mol),34 then both intramolecular HAT events become kinetically comparable, affording a mixture of both isomers (1:1.3 d:ε). Conversely, addition of an extra methylene to examine a 1,5- versus 1,7-HAT competition (22) results in exclusive d selectivity (>20:1)—even outcompeting the bias for benzylic over secondary C–H abstraction. When a completely aliphatic amine is used (23), wherein the a-amino C–H is at least 15 kcal/mol weaker than the d methylenic C–H, the d isomer is exclusively observed, albeit not enantioselectively (11% ee). In the same vein, amines bearing a-oxy and allylic C–H bonds (24–26) undergo this regioselective radical relay to afford d-amino nitriles in >20:1 rr but with low enantioselectively (< 10% ee) (a-amido C–H, < 83 kcal/mol; a-oxy C–H, 94 kcal/mol; allylic C–H, 83 kcal/mol).34 To further illustrate the synthetic utility of this regioselective, 1,5-HAT mechanism, we subjected an amine with multiple benzylic C–H bonds (S18) to both a and d C–H cyanation conditions (Figure 5). In the presence of a free N–H amide, the a C–H cyanation reaction26 is significantly inhibited, affording minimal conversion (14% yield, >80% recovered starting material; see Schemes S10 and S11 for more details). Moreover, a 1:1 mixture of isomers is observed between the d-amino nitrile and the cyclopentyl nitriles (iso-18). This contrasts with the single regio- and stereoisomer observed using our newly developed d C–H cyanation conditions (72% yield, >20:1 d selectivity, 87% ee).
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Figure 5. Comparison between a and d C–H Cyanations
Synthetic Utility To illustrate the synthetic utility of these enantioenriched d-amino nitriles, we then investigated the reactivity of the latent carbonyls within these products (Figure 6). After synthesis at a 2 mmol scale (94% yield, 90% ee), 1 could either be reduced to 1,5-diamine 27 (via BH3) or hydrolyzed to d-amino amide 28 (via H2O2)—affording products with high enantiospecificity in both cases (80%–99% es). In the hopes of harnessing the proposed d aldehyde, 1 was also reduced by iBu2Al-H. Upon cyclization of the transiently generated d-amino aldehyde, the resultant hemiaminal 29 was then subjected to additional reactions. In the simplest case, reduction of hemiaminal 29 by Et3SiH affords (S)-3-phenylpiperidine 30 in 99% es. Noting the challenge of stereoselectively preparing such useful heterocyclic building block by other means, we then explored the generality of this synthetic route. To our delight, (S)-3-substituted piperidines containing thiophene (31), naphthalene (32), para-sulfonamide (33), and bis-CF3 arene (34) were all readily prepared by this double reduction sequence with excellent stereospecificity (up to 99% es). Finally, other nucleophiles could also be combined with hemiaminal 29, including allylsilane, which affords (2S,3S)-2-allyl-3-phenylpiperidine 35 in 3:1 dr and 99% es. As further demonstration of the synthetic utility of this enantioselective d C–H cyanation, we also completed a formal synthesis of the anti-cancer drug, niraparib, which had previously only been prepared racemically or by enzymatic resolution (Figure 7).5,6 Subjecting the enantioenriched d-amino nitrile 7 to deprotection and reduction affords the para-NH2 (S)-3-arylpiperidine 36 in 50% yield and >99% es. The kilogram-scale synthesis of niraparib has already been reported from this deprotected aniline.5,6
Figure 6. Synthesis of Enantioenriched Heterocycles from Acyclic Amines via d-Amino Nitriles
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Figure 7. Formal, Asymmetric Synthesis of Anti-cancer Drug, Niraparib
Conclusions In summary, an enantioselective d C–H cyanation has been developed by intercepting an N-centered radical relay with a chiral Cu catalyst. The resultant, enantioenriched d-amino nitriles, represent the first examples of a highly asymmetric variant of an HLF reaction. The utility of these remotely functionalized amines was showcased by the synthesis of a family of chiral piperidines. Mechanistic probes for the chemo-, regio-, and enantio- selectivity of this HAT pathway also provide insights to enable future applications of this enantioselective strategy for other radical-mediated, remote C–H functionalizations.
EXPERIMENTAL PROCEDURES Full experimental procedures are provided in the Supplemental Information. See Schemes S2–S8 and Figures S1–S172 for synthesis and characterization of new compounds and Table S5 for exceptions.
SUPPLEMENTAL INFORMATION Supplemental Information can be found online at https://doi.org/10.1016/j.chempr. 2019.09.010.
ACKNOWLEDGMENTS We thank the National Institutes of Health (NIH R35 GM119812) and the National Science Foundation (NSF CAREER 1654656) for financial support.
AUTHOR CONTRIBUTIONS Z.Z. designed, discovered, and optimized the enantioselective d C–H cyanation. Z.Z. and X.Z. designed, performed, and analyzed all experiments probing reaction scope, selectivity, and synthetic utility. All authors contributed to writing this manuscript.
DECLARATION OF INTERESTS The authors declare no competing interests. Received: July 25, 2019 Revised: August 23, 2019 Accepted: September 18, 2019 Published: October 17, 2019
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