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. 2023 Aug 28;25(35):6479–6484. doi: 10.1021/acs.orglett.3c02064

Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Lactams: Enantioselective Construction of All-Carbon Quaternary Stereocenters in Saturated Nitrogen-Containing Heterocycles

Tianyi Zhang 1, Yuji Nishiura 1, Alexander Q Cusumano 1, Brian M Stoltz 1,*
PMCID: PMC10496148  PMID: 37639656

Abstract

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Stereogenic nitrogen-containing heterocycles are ubiquitous in natural products and pharmaceutical compounds, but methods for their enantioselective construction have remained elusive. We report a general method for the asymmetric conjugate addition of arylboronic acids to β-alkyl/aryl α,β-unsaturated lactams that affords chiral β,β-disubstituted lactams. The transformation is operationally simple and air- and moisture-tolerant and uses a commercially available (S)-t-Bu-PyOx ligand. The method is high-yielding (up to 95% yield) and enantioselective (up to 97% ee) for a wide range of arylboronic acids and α,β-unsaturated lactams, including those with different ring sizes.

Asymmetric catalysis has seen significant applications in complex molecule synthesis, enabling the facile preparation of valuable enantioenriched synthetic building blocks from prochiral and racemic starting materials, especially those containing all-carbon quaternary centers.1 The enantioselective construction of all-carbon quaternary centers, while challenging due to the inherent steric demand, has become an important area of research, owing to the widespread presence of these structural motifs in natural products.2 Moreover, the incorporation of C(sp3) stereocenters into small-molecule drugs has been correlated with the clinical success of drug candidates.3 One approach toward synthesizing stereogenic centers is through asymmetric conjugate addition,4 which can be catalyzed by a wide range of transition metals including copper,5 manganese,6 nickel,7 scandium,8 and palladium.9 While many of these methodologies require the use of air- and moisture-sensitive organometallic reagents, strongly basic nucleophiles, or a combination thereof, palladium catalysis enables the use of bench-stable boronic acids and water cosolvents.9 The first Pd-catalyzed enantioselective conjugate addition of arylboronic acids to cyclic β-alkyl enones was reported by our group in 2011 and involved the use of a chiral pyridinooxazoline (PyOx) ligand (Scheme 1A).10 Soon after, the substrate scope was broadened to include lactones (Scheme 1B),11 chromones,12 4-quinolones,13 and cyclic β-aryl enones.14 While access to racemic β,β-disubstituted lactams has been demonstrated,15 there were limited examples of the enantioselective construction of lactams bearing all-carbon β-quaternary stereocenters when we commenced our investigations.

Scheme 1. Construction of All-Carbon Quaternary Centers in Cyclic Ketones, Lactones, and Lactams via Pd-Catalyzed Conjugate Addition.

Scheme 1

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N-heterocycles, common in natural products,16 pharmaceuticals,17 and new materials,18 can be accessed from lactams through exhaustive reduction, which does not allow the incorporation of quaternary centers.19 Currently, there is a lack of stereochemical complexity in most N-heterocycles in marketed drugs partly due to a lack of methods for the incorporation of stereogenic centers.20 In light of this, chiral lactams containing all-carbon β-quaternary centers would serve as synthetically valuable precursors to enantiopure γ,γ-disubstituted saturated N-heterocycles, allowing synthetic chemists to “escape from the flatland”.20 Toward the end of our studies, Baek et al. became the first to report a Pd-catalyzed asymmetric conjugate addition of arylboronic acids to α,β-unsaturated lactams (Scheme 1C).21 Herein, we report the development of a complementary palladium-catalyzed asymmetric conjugate addition of arylboronic acids to α,β-unsaturated lactams to afford β-quaternary stereogenic centers in high yield and enantioselectivity, under air- and moisture-tolerant conditions and at near-ambient temperature (Scheme 1D).

We first investigated the asymmetric conjugate addition of phenylboronic acid (2) to N-tosyl protected lactam 1 utilizing conditions reported for cyclic enones by our group (entry 1, Table 1).10a An array of chiral ligands were studied (Table S1, see Supporting Information), and (S)-t-BuPyOx (4)22 was found to provide the highest level of enantioselectivity. Pairing ligand 4 with the aqueous conditions developed by the Stanley group14a afforded lactam 3 with low enantioselectivity and yield (entry 2, Table 1), likely due to ligand hydrolysis at high temperature.

Table 1. Optimization of Reaction Conditionsa.

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Entry Pd source Solvent Variations from standard conditions Yield (%)b ee (%)c
1 Pd(TFA)2 DCE NH4PF6 (30 mol %), O2,d 60 °C 49 41
2 Pd(TFA)2 H2O Na(TFA) (20 mol %), 100 °C 9 23
3 Pd(TFA)2 CHCl3 NH4PF6 (30 mol %), O2, 60 °C 25 61
4 Pd(TFA)2 CHCl3 NH4PF6 (30 mol %), O2, 40 °C 25 73
5 Pd(TFA)2 CH2Cl2 NH4PF6 (30 mol %), O2, 40 °C 68 72
6 Pd(TFA)2 CH2Cl2 NH4PF6 (30 mol %), O2, 40 h 68 78
7 Pd(TFA)2 CH2Cl2 AgOTf (24 mol %) >99 80
8 Pd(OAc)2 CH2Cl2 AgOTf (24 mol %) 92 64
9 Pd(MeCN)2Cl2 CH2Cl2 AgOTf (24 mol %) 45 71
10 Pd(TFA)2 CH2Cl2 AgOAc (24 mol %) 47 86
11 Pd(TFA)2 CH2Cl2 AgBF4 (24 mol %) >99 82
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a

Standard conditions: Reactions were performed with phenylboronic acid 2 (0.08 mmol, 4 equiv), lactam 1 (0.02 mmol), Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (4, 12 mol %), and H2O (5 equiv) in the given solvent (0.16 mL) at 30 °C for 16 h.

b

Yield was determined by 1H NMR with 1,3,5-trimethoxybenzene internal standard.

c

ee was determined by chiral SFC and absolute stereochemistry by VCD.

d

“O2” ≣ Reaction under 1 atm O2.24

The effects of solvent and reaction temperature were examined (Table S2, see Supporting Information). Replacing 1,2-dichloroethane (DCE) with chloroform as the solvent and lowering the reaction temperature (from 60 to 40 °C) led to improved enantioselectivity (Entries 3–4, Table 1). Dichloromethane was identified as the optimal solvent (entry 5, Table 1), providing product 3a in 68% yield with 72% ee. The enantioselectivity was improved by lowering the temperature to 30 °C with a longer reaction time (entry 6, Table 1). Addition of silver(I) additives, which were reported to aid in precatalyst activation through counterion abstraction,10a,11 improved the reaction yield (>99%, entries 7 and 11, Table 1) while maintaining high enantioselectivity (80–82% ee); silver tetrafluoroborate, AgBF4, provided the highest yield (>99%) and excellent enantioselectivity (82% ee) from the silver(I) salts tested (entries 7, 10, 11 in Table 1; Table S3 in Supporting Information). An array of palladium(II) precatalysts were competent in the presence of a silver(I) additive (entries 7–9, Table 1; also see Table S4 in Supporting Information), with Pd(TFA)2 providing the highest yield (>99%) and enantioselectivity (82% ee) in the presence of air and 5 equivalents of water (entry 11).23

The scope of the reaction, with respect to the N-protecting groups, was examined (Table 2). The method was found to be compatible with various N-protecting groups such as sulfonyl (3a, >99% yield, 82% ee) and benzoyl (3b–d, 65–90% yields, 79–81% ee). Substrates containing Teoc (3m) and Boc (3n) groups provided lower yields potentially due to the inherent steric bulk. Notably, high enantioselectivity (89% ee), despite a diminished yield (14%), was observed for the unprotected lactam (3o), which is uncommon due to potentially deleterious substrate coordination.23 The Troc protecting group afforded the highest yield (3f) and excellent enantioselectivity, so substrate 1f was used in subsequent substrate scope explorations.

Table 2. Substrate Scope: Variation of the Lactam N-Protecting Group. Addition of Phenylboronic Acid to Lactams (1a–o) with Different N-Protecting Groupsa.

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a

Conditions: Reactions were performed with phenylboronic acid (0.08 mmol, 4 equiv), lactams 1a–o (0.02 mmol), Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (12 mol %), AgBF4 (24 mol %), H2O (5 equiv) in CH2Cl2 (0.16 mL) at 30 °C for 16 h. Yield was determined by 1H NMR relative to 1,3,5-trimethoxybenzene internal standard. ee was determined by chiral SFC.

To investigate the nucleophile scope, a range of arylboronic acids were evaluated (Table 3). Arylboronic acids with electron-withdrawing para-substituents (5a–d) generally afforded the desired product in high yields (61–95%) and enantioselectivities (80–96%). Electron-withdrawing groups on the boronic acid reaction partner included halides (5a–b), a trifluoromethyl group (5c), and a ketone (5d). Switching to arylboronic acids bearing electron-donating para-substituents (5e–h) lowered the reaction yield (0–79%) and enantioselectivity (40–56% ee), with electron-rich aniline 4h affording none of the desired product 5h. Meanwhile, meta-substituted arylboronic acids, with either electron-donating or electron-withdrawing substituents, are compatible with the catalytic conditions and furnished the desired products in 68–94% yield and 76–93% ee (5i–k). In contrast, ortho-substituents on the arylboronic acid led to diminished yields and stereoselectivity (5l–n).25 In general, we found the nucleophile scope to be largely consistent with our group’s previous reports on the analogous cyclic enone system.10a

Table 3. Investigation of the Nucleophile Scope: Addition of Different Arylboronic Acids (4a–n) to Lactam 1fa.

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a

Conditions: Reactions were performed with phenylboronic acid 4a–n (0.20 mmol, 2.0 equiv), lactam 1f (0.10 mmol), Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (12 mol %), AgBF4 (24 mol %), H2O (0.50 mmol, 5.0 equiv) in CH2Cl2 (0.80 mL) at 30 °C for 16 h. Yields are of isolated products after column chromatography. ee was determined by chiral SFC.

Finally, α,β-unsaturated lactams varying in ring size and β-substitution pattern were examined (Table 4). The reaction remained robust for five- and seven-membered ring substrates, furnishing the corresponding products in excellent enantioselectivity and moderate to excellent yield (7a,b).26 To our knowledge, these represent the only examples of asymmetric construction of β-quaternary centers in five- and seven-membered lactams through enantioselective conjugate addition of arylboronic acids to α,β-unsaturated lactams, which are valuable synthetic building blocks for N-heterocycles.

Table 4. Asymmetric Synthesis of β,β-Disubstituted Lactamsa.

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graphic file with name ol3c02064_0008.jpg

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a

Conditions: Reactions were performed with phenylboronic acid (0.20 mmol, 2.0 equiv), lactams 6a–h (0.10 mmol), Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (12 mol %), AgBF4 (24 mol %), H2O (0.5 mmol, 5 equiv) in CH2Cl2 (0.16 mL) at 30 °C for 16 h. Yields are of isolated products after column chromatography. ee determined by chiral SFC.

b

Reaction time is 47 h.

Reactions with α,β-unsaturated lactams bearing other β-alkyl substituents, such as n-butyl and benzyl (7c,d), delivered the respective lactam products in high yield (76–86%) and enantioselectivity (83–90% ee). In addition to linear β-alkyl substitution, isopropyl (6e), cyclobutyl (6f), and cyclohexyl (6g) β-alkyl-branched substrates afforded products (7e–g) in good yields (58–91%) and enantioselectivities (61–84% ee). Moreover, preliminary studies demonstrated that α,β-unsaturated lactams bearing a β-aryl substituent (7h) were also compatible with the developed conditions. The reaction produced the desired β,β-diaryl lactam product with high enantioselectivity (90% ee) and good yield (58%). In comparison, the previous Pd-catalyzed conditions for asymmetric conjugate addition to cyclic enones developed by our group did not provide access to β,β-diaryl cyclic ketones.27

Toward the end of our studies, Baek et al. published the first method for Pd-catalyzed asymmetric conjugate addition of arylboronic acids to α,β-unsaturated lactams.21 In comparison, our method offers several complementary advances, including (1) the utilization of a commercially available chiral ligand (i.e., (S)-t-BuPyOx) that can also be synthesized on scale from simple starting materials,28,29 (2) the robustness demonstrated in the asymmetric synthesis of β,β-disubstituted lactams varying in ring size and β-alkyl and β-aryl substitution patterns, (3) tolerance of various N-protecting groups, and (4) use of near-ambient temperatures (i.e., instead of 60–70 °C).

In summary, we have developed a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to β-substituted α,β-unsaturated lactams for the asymmetric construction of all-carbon quaternary stereocenters in nitrogen-containing heterocycles. The transformation provides access to a diverse array of lactams bearing new all-carbon quaternary centers in up to 95% yield and 97% ee. This serves as the first general method for the asymmetric conjugate addition of arylboronic acids to five-, six-, and seven-membered α,β-unsaturated lactams, providing products with high enantioselectivity. Furthermore, both β-alkyl and β-aryl α,β-unsaturated lactam substrates participate in the reaction with excellent enantioinduction. The reaction applies to lactams of different ring sizes and displays broad functional group tolerance, compatible with various N-protecting groups, β-substituents, as well as arylboronic acids with various substitution patterns. The transformation proceeds at near-ambient temperature and is air- and moisture-tolerant. Key to the success of this reaction is the readily available chiral ligand, (S)-t-BuPyOx (4), rendering this catalytic system an operationally simple and practical method for enantioselective construction of lactams bearing new all-carbon quaternary stereocenters. Continuing studies of this method and its application in the context of natural product synthesis are currently ongoing and will be reported in due course.

Acknowledgments

The authors thank NIH-NIGMS (R35GM145239) and the Heritage Medical Research Institute Investigator Program for the support of our research program. The authors thank Mr. Christian Strong for NMR assistance, Dr. David VanderVelde for NMR assistance and maintenance of the Caltech NMR facility, and Dr. Scott Virgil for assistance with instrumentation and maintenance of the Caltech Center for Catalysis and Chemical Synthesis. T.Z. thanks the John Stauffer Charitable Trust for financial support. Y.N. thanks Shionogi & Co., Ltd. for a postdoctoral research fellowship.

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c02064.

  • Experimental details and NMR spectra of compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol3c02064_si_001.pdf (10.7MB, pdf)

References

  1. a Jacobsen E. N.; Pfaltz A.; Yamamoto H.. Comprehensive Asymmetric Catalysis: Supplement 1; Springer Science & Business Media, 2003; Vol. 1. [Google Scholar]; b Mikami K.; Lautens M.. New Frontiers in Asymmetric Catalysis; John Wiley & Sons, 2007. [Google Scholar]
  2. a Denissova I.; Barriault L. Stereoselective Formation of Quaternary Carbon Centers and Related Functions. Tetrahedron 2003, 59, 10105–10146. 10.1016/j.tet.2003.10.039. [DOI] [Google Scholar]; b Douglas C. J.; Overman L. E. Catalytic Asymmetric Synthesis of All-Carbon Quaternary Stereocenters. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367. 10.1073/pnas.0307113101. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Christoffers J.; Baro A. Stereoselective Construction of Quaternary Stereocenters. Adv. Synth. Catal. 2005, 347, 1473–1482. 10.1002/adsc.200505165. [DOI] [Google Scholar]; d Trost B. M.; Jiang C. Catalytic Enantioselective Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006, 2006 (3), 369–396. 10.1055/s-2006-926302. [DOI] [Google Scholar]; e Mohr J. T.; Stoltz B. M. Enantioselective Tsuji Allylations. Chem. - Asian J. 2007, 2, 1476–1491. 10.1002/asia.200700183. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Cozzi P. G.; Hilgraf R.; Zimmermann N. Enantioselective Catalytic Formation of Quaternary Stereogenic Centers. Eur. J. Org. Chem. 2007, 2007, 5969–5994. 10.1002/ejoc.200700318. [DOI] [Google Scholar]; g Liu Y.; Han S.-J.; Liu W.-B.; Stoltz B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751. 10.1021/ar5004658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. a Lovering F.; Bikker J.; Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem. 2009, 52, 6752–6756. 10.1021/jm901241e. [DOI] [PubMed] [Google Scholar]; b Lovering F. Escape from Flatland 2: complexity and promiscuity. MedChemComm 2013, 4, 515–519. 10.1039/c2md20347b. [DOI] [Google Scholar]
  4. Hawner C.; Alexakis A. Metal-Catalyzed Asymmetric Conjugate Addition Reaction: Formation of Quaternary Stereocenters. Chem. Commun. 2010, 46, 7295–7306. 10.1039/c0cc02309d. [DOI] [PubMed] [Google Scholar]
  5. Copper-catalyzed asymmetric conjugate addition:; a Feringa B. L. Phosphoramidites: Marvellous Ligands in Catalytic Asymmetric Conjugate Addition. Acc. Chem. Res. 2000, 33, 346–353. 10.1021/ar990084k. [DOI] [PubMed] [Google Scholar]; b Müller D.; Hawner C.; Tissot M.; Palais L.; Alexakis A. Creation of Quaternary Stereogenic Centers via Copper-Catalyzed Asymmetric Conjugate Addition of Alkenyl Alanes to α, β-Unsaturated Cyclic Ketones. Synlett 2010, 2010, 1694–1698. 10.1055/s-0029-1219958. [DOI] [Google Scholar]; c Martin D.; Kehrli S.; d’Augustin M.; Clavier H.; Mauduit M.; Alexakis A. Copper-Catalyzed Asymmetric Conjugate Addition of Grignard Reagents to Trisubstituted Enones. Construction of All-Carbon Quaternary Chiral Centers. J. Am. Chem. Soc. 2006, 128, 8416–8417. 10.1021/ja0629920. [DOI] [PubMed] [Google Scholar]
  6. Mitsunuma H.; Shibasaki M.; Kanai M.; Matsunaga S. Catalytic Asymmetric Total Synthesis of Chimonanthine, Folicanthine, and Calycanthine through Double Michael Reaction of Bisoxindole. Angew. Chem., Int. Ed. 2012, 51, 5217–5221. 10.1002/anie.201201132. [DOI] [PubMed] [Google Scholar]
  7. Nickel-catalyzed asymmetric conjugate addition:; a Chen J.; Chen J.; Xie Y.; Zhang H. Enantioselective Total Synthesis of (−)-Stenine. Angew. Chem., Int. Ed. 2012, 51, 1024–1027. 10.1002/anie.201106587. [DOI] [PubMed] [Google Scholar]; b Evans D. A.; Seidel D. Ni(II)–Bis[(R,R)-N,N‘-Dibenzylcyclohexane-1,2-Diamine]Br2 Catalyzed Enantioselective Michael Additions of 1,3-Dicarbonyl Compounds to Conjugated Nitroalkenes. J. Am. Chem. Soc. 2005, 127, 9958–9959. 10.1021/ja052935r. [DOI] [PubMed] [Google Scholar]; c Evans D. A.; Mito S.; Seidel D. Scope and Mechanism of Enantioselective Michael Additions of 1, 3-Dicarbonyl Compounds to Nitroalkenes Catalyzed by Nickel (II)–Diamine Complexes. J. Am. Chem. Soc. 2007, 129, 11583–11592. 10.1021/ja0735913. [DOI] [PubMed] [Google Scholar]; d Ouchi H.; Asahina A.; Asakawa T.; Inai M.; Hamashima Y.; Kan T. Practical Total Syntheses of Acromelic Acids A and B. Org. Lett. 2014, 16, 1980–1983. 10.1021/ol500529w. [DOI] [PubMed] [Google Scholar]; e Nakamura A.; Lectard S.; Hashizume D.; Hamashima Y.; Sodeoka M. Diastereo-and Enantioselective Conjugate Addition of α-Ketoesters to Nitroalkenes Catalyzed by a Chiral Ni(OAc)2 Complex under Mild Conditions. J. Am. Chem. Soc. 2010, 132, 4036–4037. 10.1021/ja909457b. [DOI] [PubMed] [Google Scholar]; f Sun Z.; Zhou M.; Li X.; Meng X.; Peng F.; Zhang H.; Shao Z. Catalytic Asymmetric Assembly of Octahydroindolones: Divergent Synthesis of Lycorine-type Amaryllidaceae Alkaloids (+)-α-Lycorane and (+)-Lycorine. Chem. - Eur. J. 2014, 20, 6112–6119. 10.1002/chem.201400178. [DOI] [PubMed] [Google Scholar]; g Li X.; Peng F.; Zhou M.; Mo M.; Zhao R.; Shao Z. Catalytic Asymmetric Synthesis of 1, 3-Enyne Scaffolds: Design and Synthesis of Conjugated Nitro Dienynes as Novel Michael Acceptors and Development of a New Synthetic Methodology. Chem. Commun. 2014, 50, 1745–1747. 10.1039/C3CC48951E. [DOI] [PubMed] [Google Scholar]
  8. Scandium-catalyzed asymmetric conjugate addition:; a Li L.; Yang Q.; Wang Y.; Jia Y. Catalytic Asymmetric Total Synthesis of (−)-Galanthamine and (−)-Lycoramine. Angew. Chem., Int. Ed. 2015, 54, 6255–6259. 10.1002/anie.201411338. [DOI] [PubMed] [Google Scholar]; b Liu X.; Lin L.; Feng X. Chiral N,N′-Dioxides: New Ligands and Organocatalysts for Catalytic Asymmetric Reactions. Acc. Chem. Res. 2011, 44, 574–587. 10.1021/ar200015s. [DOI] [PubMed] [Google Scholar]; c Liu X.; Lin L.; Feng X. Chiral N, N′-Dioxide Ligands: Synthesis, Coordination Chemistry and Asymmetric Catalysis. Org. Chem. Front. 2014, 1, 298–302. 10.1039/c3qo00059a. [DOI] [Google Scholar]
  9. a Lu X.; Lin S. Pd(II)-Bipyridine Catalyzed Conjugate Addition of Arylboronic Acid to α,β-Unsaturated Carbonyl Compounds. J. Org. Chem. 2005, 70, 9651–9653. 10.1021/jo051561h. [DOI] [PubMed] [Google Scholar]; b Lin S.; Lu X. Cationic Pd(II)/Bipyridine-Catalyzed Conjugate Addition of Arylboronic Acids to β, β-Disubstituted Enones: Construction of Quaternary Carbon Centers. Org. Lett. 2010, 12, 2536–2539. 10.1021/ol100767u. [DOI] [PubMed] [Google Scholar]; c Wu L.; Shen J.; Yang G.; Zhang W. Recent Advances in the Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids to Electron-Deficient Olefins. Tetrahedron Lett. 2018, 59, 4055–4062. 10.1016/j.tetlet.2018.10.013. [DOI] [Google Scholar]
  10. a Kikushima K.; Holder J. C.; Gatti M.; Stoltz B. M. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Five-, Six-, and Seven-Membered β-Substituted Cyclic Enones: Enantioselective Construction of All-Carbon Quaternary Stereocenters. J. Am. Chem. Soc. 2011, 133, 6902–6905. 10.1021/ja200664x. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Holder J. C.; Zou L.; Marziale A. N.; Liu P.; Lan Y.; Gatti M.; Kikushima K.; Houk K. N.; Stoltz B. M. Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted Cyclic Enones: Insights from Computation and Experiment. J. Am. Chem. Soc. 2013, 135, 14996–15007. 10.1021/ja401713g. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Boeser C. L.; Holder J. C.; Taylor B. L.; Houk K. N.; Stoltz B. M.; Zare R. N. Mechanistic Analysis of an Asymmetric Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted Cyclic Enones. Chem. Sci. 2015, 6, 1917–1922. 10.1039/C4SC03337J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gottumukkala A. L.; Matcha K.; Lutz M.; de Vries J. G.; Minnaard A. J. Palladium-Catalyzed Asymmetric Quaternary Stereocenter Formation. Chem. - Eur. J. 2012, 18, 6907–6914. 10.1002/chem.201200694. [DOI] [PubMed] [Google Scholar]
  12. Baek D.; Ryu H.; Ryu J. Y.; Lee J.; Stoltz B. M.; Hong S. Catalytic Enantioselective Synthesis of Tetrasubstituted Chromanones via Palladium-Catalyzed Asymmetric Conjugate Arylation Using Chiral Pyridine-Dihydroisoquinoline Ligands. Chem. Sci. 2020, 11, 4602–4607. 10.1039/D0SC00412J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Holder J. C.; Marziale A. N.; Gatti M.; Mao B.; Stoltz B. M. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Heterocyclic Acceptors. Chemistry (Weinheim an der Bergstrasse, Germany) 2013, 19, 74. 10.1002/chem.201203643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. a Van Zeeland R.; Stanley L. M. Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β,β-Disubstituted Enones in Aqueous Media: Formation of Bis-Benzylic and Ortho -Substituted Benzylic Quaternary Centers. ACS Catal. 2015, 5, 5203–5206. 10.1021/acscatal.5b01272. [DOI] [Google Scholar]; b Kadam A. A.; Ellern A.; Stanley L. M. Enantioselective, Palladium-Catalyzed Conjugate Additions of Arylboronic Acids to Form Bis-Benzylic Quaternary Stereocenters. Org. Lett. 2017, 19, 4062–4065. 10.1021/acs.orglett.7b01825. [DOI] [PubMed] [Google Scholar]
  15. Chen M.; Rago A. J.; Dong G. Platinum-Catalyzed Desaturation of Lactams, Ketones, and Lactones. Angew. Chem., Int. Ed. 2018, 57, 16205–16209. 10.1002/anie.201811197. [DOI] [PubMed] [Google Scholar]
  16. Cordell G. A.The Alkaloids. In The Alkaloids: Chemistry and Biology; Elsevier, 2010; Vol. 69, p iv. [Google Scholar]
  17. Joule J. A.; Mills K.. Heterocyclic Chemistry; John Wiley & Sons, 2008. [Google Scholar]
  18. a Anton A.; Baird B. R.. Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed.; Wiley, 2006; Vol. 19. [Google Scholar]; b Schlack P. Polymerizable Lactams. Pur. Appl. Chem. 1967, 15, 507–524. 10.1351/pac196715030507. [DOI] [Google Scholar]; c Nylon Plastics; Kohan M. I., Ed.; Interscience, 1973. [Google Scholar]
  19. Examples of accessing N-heterocycles in total synthesis (nonexhaustive):; a Li Z.; Li J.; Yang N.; Chen Y.; Zhou Y.; Ji X.; Zhang L.; Wang J.; Xie X.; Liu H. Gold(I)-Catalyzed Cascade Approach for the Synthesis of Tryptamine-Based Polycyclic Privileged Scaffolds as A1-Adrenergic Receptor Antagonists. J. Org. Chem. 2013, 78, 10802–10811. 10.1021/jo4017887. [DOI] [PubMed] [Google Scholar]; b Wang Y.-T.; Long X.-Y.; Ding X.; Fan S.-R.; Cai J.-Y.; Yang B.-J.; Zhang X.-F.; Luo R.; Yang L.; Ruan T.; Ren J.; Jing C.-X.; Zheng Y.-T.; Hao X.-J.; Chen D.-Z. Novel Nucleocapsid Protein-Targeting Phenanthridine Inhibitors of SARS-CoV-2. Eur. J. Med. Chem. 2022, 227, 113966 10.1016/j.ejmech.2021.113966. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Fan-Chiang T.-T.; Wang H.-K.; Hsieh J.-C. Synthesis of Phenanthridine Skeletal Amaryllidaceae Alkaloids. Tetrahedron 2016, 72, 5640–5645. 10.1016/j.tet.2016.07.065. [DOI] [Google Scholar]; d Chisholm D. R.; Zhou G.-L.; Pohl E.; Valentine R.; Whiting A. Practical Synthetic Strategies toward Lipophilic 6-Iodotetrahydroquinolines and -Dihydroquinolines. Beilstein J. Org. Chem. 2016, 12, 1851–1862. 10.3762/bjoc.12.174. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Scharnagel D.; Goller J.; Deibl N.; Milius W.; Breuning M. The Enantioselective Total Synthesis of Bisquinolizidine Alkaloids: A Modular “Inside-Out” Approach. Angew. Chem., Int. Ed. 2018, 57, 2432–2435. 10.1002/anie.201712852. [DOI] [PubMed] [Google Scholar]; f Zhou S.; Junge K.; Addis D.; Das S.; Beller M. A Convenient and General Iron-Catalyzed Reduction of Amides to Amines. Angew. Chem., Int. Ed. 2009, 48, 9507–9510. 10.1002/anie.200904677. [DOI] [PubMed] [Google Scholar]; g Uludag N.; Sanda M.; Asutay O.; Coskun N. New Route to 20-Deethyldasycarpidone by Ring-Closure with DDQ. Org. Prep. Proced. Int. 2014, 46, 551–558. 10.1080/00304948.2014.963458. [DOI] [Google Scholar]
  20. Sercel Z. P.; Sun A. W.; Stoltz B. M. Synthesis of Enantioenriched Gem-Disubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. Org. Lett. 2021, 23, 6348–6351. 10.1021/acs.orglett.1c02134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Baek D.; Ryu H.; Hahm H.; Lee J.; Hong S. Palladium Catalysis Featuring Attractive Noncovalent Interactions Enabled Highly Enantioselective Access to β-Quaternary δ-Lactams. ACS Catal. 2022, 12, 5559–5564. 10.1021/acscatal.2c00541. [DOI] [Google Scholar]
  22. Brunner H.; Obermann U. Asymmetrische Katalysen, 45. Enantioselektive Hydrosilylierung von Ketonen mit [Rh(COD)Cl]2/Pyridinyloxazolin-Katalysatoren. Chem. Ber. 1989, 122, 499–507. 10.1002/cber.19891220318. [DOI] [Google Scholar]
  23. Shockley S. E.; Holder J. C.; Stoltz B. M. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Cyclic Electrophiles. Org. Process Res. Dev. 2015, 19, 974–981. 10.1021/acs.oprd.5b00169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yang G.; Zhang W. A Palladium-Catalyzed Enantioselective Addition of Arylboronic Acids to Cyclic Ketimines. Angew. Chem., Int. Ed. 2013, 52, 7540–7544. 10.1002/anie.201302861. [DOI] [PubMed] [Google Scholar]
  25. Heterocyclic boronic acids (nitrogen- and sulfur-containing) remain challenging nucleophiles to date, inert to our catalytic conditions despite various optimization attempts.
  26. No reaction was observed with either the eight-membered conjugate acceptor or 1,2-oxadinone acceptor, both of which remain challenging substrates for future explorations.
  27. Holder J. C.; Goodman E. D.; Kikushima K.; Gatti M.; Marziale A. N.; Stoltz B. M. Synthesis of Diverse β-Quaternary Ketones via Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Cyclic Enones. Tetrahedron 2015, 71, 5781–5792. 10.1016/j.tet.2014.11.048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Holder J.; Shockley S. E.; Wiesenfeldt M. P.; Shimizu H.; Stoltz B. M. Preparation of (S)-tert-ButylPyOx and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids. Org. Synth. 2015, 92, 247–266. 10.15227/orgsyn.092.0247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Aranda C.; Cornejo A.; Fraile J. M.; García-Verdugo E.; Gil M. J.; Luis S. V.; Mayoral J. A.; Martinez-Merino V.; Ochoa Z. Efficient Enhancement of Copper-Pyridineoxazoline Catalysts through Immobilization and Process Design. Green Chem. 2011, 13 (4), 983–990. 10.1039/c0gc00775g. [DOI] [Google Scholar]

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Supplementary Materials

ol3c02064_si_001.pdf (10.7MB, pdf)

Data Availability Statement

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

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