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. 2025 Jun 24;147(27):24085–24094. doi: 10.1021/jacs.5c07821

Enantioselective Synthesis of 2,3-Disubstituted Azetidines via Copper-Catalyzed Boryl Allylation of Azetines

Minghui Zhu 1, Jianwei Sun 1,*
PMCID: PMC12257529  PMID: 40553580

Abstract

Disclosed here is a highly enantioselective difunctionalization of azetines for convenient access to chiral 2,3-disubstituted azetidines, a family of important scaffolds previously lacking general access. With Cu/bisphosphine as a catalyst, two versatile functionalities (boryl and allyl) were installed on azetine with concomitant construction of two new stereogenic centers. This represents a rare demonstration of Cu-catalyzed asymmetric boryl alkylation of electron-rich olefins and CC bonds in strained heterocycles. The use of allyl phosphates proved critical not only to overcome the low reactivity of the borylated alkylcuprate intermediate toward alkylation but also to avoid competing side reactions. Remarkably, in almost all cases, single isomers were obtained with complete regio-, enantio-, and diastereoselectivies on the azetidine motif as well as excellent control on the double bond configuration. The mild conditions exhibited outstanding functional group compatibility and chemoselectivity. The versatile boryl and allyl functionalities allowed for easy transformations of the products to other useful chiral azetidines previously lacking straightforward access. Control experiments and kinetic studies indicated that the reaction proceeds by a fast boryl cupration of azetine followed by rate-determining allylation via an intrinsically controlled SN2′ pathway.

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Introduction

Saturated nitrogen heterocycles represent a family of the most prevalent scaffolds in biologically active compounds. Specifically, azetidine is a uniquely privileged unit present in numerous drug candidates and natural molecules. , For example, it serves as a key pharmacophore of molecules with diverse biological activities (Scheme A). , The incorporation of this strained heterocycle is beneficial to its pharmacokinetic properties. Moreover, chiral azetidines have also served as useful chiral ligands or building blocks in asymmetric synthesis.

1. (A–C) Introduction to Chiral Azetidines and Reaction Design.

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Despite the broad utility of azetidines, methods for their synthesis have been underdeveloped as compared with the large ring homologues (e.g., pyrrolidines and piperidines), especially in enantioenriched forms. In particular, among different substitution patterns, the 2,3-disubstituted azetidines bearing two stereogenic centers are among the most challenging to construct. − For a long time, the syntheses of enantioenriched azetidines have relied on diastereomeric induction from the existing chirality in a substrate or a stoichiometric chiral auxiliary. , In contrast, direct catalytic enantioselective difunctionalization of an achiral precursor, at both the C-2 and C-3 positions with concomitant generation of two stereogenic centers, can be regarded as the most convenient approach. However, multiple challenges may be encountered in such transformations, other than achieving good reactivity. Indeed, effective controls over chemoselectivity, regioselectivity, enantioselectivity, and diastereoselectivity are all required. However, such an efficient protocol remains unavailable (Scheme B).

In continuation of our ongoing interests in the study of azetidines, we envisioned a potentially general approach to addressing the above unmet challenges (Scheme C). We hypothesized that direct enantioselective boryl allylation of azetines, a type of readily accessible substrate, would provide expedient access to diverse chiral 2,3-disubstituted azetidines since both boryl and allyl groups could be easily transformed to other functionalities. While copper-catalyzed enantioselective borylative difunctionalization of olefins has been established in various contexts, − it proved not straightforward when applied to strained rings and electron-rich olefins. − During the preparation of this manuscript, an elegant demonstration on strained cyclopropenes was reported by Liu and co-workers. However, there has been very limited success with strained heterocycles. The Brown laboratory pioneered a single example of boryl arylation of an azetine by Cu/Pd cocatalysis, but unfortunately with moderate enantioselectivity (74% ee). Compared with arylation, the formation of the C­(sp3)–C­(sp3) bond via alkylation with aliphatic electrophiles is expected to be more challenging due to low reactivity. Moreover, enantioselective difunctionalization of electron-rich double bonds (e.g., enamines and enamides) via a borylcupration mechanism remains largely unexplored in general. Herein, we report the first highly enantioselective boryl allylation of azetines, providing rapid access to diverse 2,3-disubstituted azetidines with high efficiency.

Results and Discussion

Our study began with the model reaction between azetine 1a and allylic electrophile 2a with B2pin2 as the boron source (Table ). After a comprehensive evaluation of various catalysts and reaction parameters, a combination of CuBr (10 mol %), the (S,S)-Ph-BPE ligand L1 (12 mol %), and NaO t Bu (1.5 equiv) in 1,4-dioxane at room temperature was chosen as the standard conditions. Initial evaluation of some allylic electrophiles bearing a bromide (Br), acetate (OAc), or carbonate (OBoc) leaving group resulted in essentially no desired product formation (entry 1). In these cases, boryl azetidine 1a-Bpin and allylboronate 2a-Bpin were observed as the major products, which corroborated the challenge in forming the C­(sp3)–C­(sp3) bond in this type of difunctionalization reaction on strained electron-rich olefins. Nevertheless, to our delight, further screening indicated that phosphate is an ideal leaving group, forming the desired boryl allylation product 3a in high yield with excellent enantio-, diastereo-, and regioselectivities (entries 2–3). Specifically, with dimethylphosphate as the leaving group, 3a was formed essentially quantitatively as a single isomer in an enantiopure form (entry 3). A range of chiral bisphosphines and (P,N)-ligands were also examined, but they all led to inferior results (entry 4). For example, (S)-DTBM-Segphos L3 and (R)-Phox L8 failed to give the desired product, whereas­(S)-Binap L2, (S,S)-QuinoxP L4, (R,S p )- t Bu-Josiphos L5, (S,R p )-Josiphos L6, and (S,S p )- i Pr-Phosferrox L7 led to a significant decrease in yield and/or selectivity. Notably, this reaction exhibited little sensitivity to the solvent. MTBE, THF, toluene, and DCM all gave complete control in enantio- and diastereo- and regioselectivities (>99% ee, >20:1 dr, and >20:1 rr), with a minor difference in reaction yield (entries 5–8). Similarly, different copper­(I) sources, including CuCl and Cu­(CH3CN)4BF4, maintained the high level of selectivities, albeit in slightly decreased yield (entries 9–10). The use of an alternative base, such as KO t Bu, led to a lower yield as well (entry 11). Finally, outstanding results could also be obtained at a reduced loading of catalyst/ligand, thus establishing the optimal conditions (entry 12). It is worth noting that this represents the first highly enantioselective Cu-catalyzed boryl alkylation of electron-rich olefins as well as strained heterocyclic olefins.

1. Evaluation of Conditions .

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entry deviation from the “standard conditions” yield (%) ee (%) rr
1 LG = Br, OAc, and OBoc trace    
2 LG = OP(O)(OPh)2 92 98 >20:1
3 no change >95 >99 >20:1
4 L2–L8 for details, see structures
5 MTBE as a solvent 80 >99 18:1
6 THF as a solvent 79 >99 >20:1
7 toluene as a solvent 77 >99 >20:1
8 DCM as a solvent 85 >99 >20:1
9 CuCl instead of CuBr 73 >99 19:1
10 Cu(CH3CN)4BF4 instead of CuBr 80 >99 >20:1
11 KO t Bu instead of NaO t Bu 75 99 >20:1
12 CuBr (5 mol %), L1 (6 mol %) >95 >99 >20:1
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a

Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), CuBr (10 mol %), (S,S)-L1 (12 mol %), B2pin2 (0.075 mmol), 1,4-dioxane (1 mL), rt, 12 h. Yield, dr, and rr values were determined by analysis of the 1H NMR spectra of the crude reaction mixture using CH2Br2 as an internal standard. The ee value was determined by chiral HPLC analysis.

With the optimized conditions, we investigated the scope of the asymmetric boryl allylation with different 2-substituted allyl phosphates 2, which resulted in rapid access to a range of cis-2,3-disubstituted azetidines 3 with a branched allyl group (Scheme ). Allyl phosphates bearing different aryl (3a–3f) and alkenyl (3g) substituents were all effective partners in this three-component coupling. The structure and absolute configuration of product 3f were unambiguously confirmed by X-ray crystallography. In addition, the simple allyl phosphate (3l) or those bearing an alkyl substituent (3h–3k) of varying steric demand also reacted efficiently. Notably, high chemoselectivity was observed in the reactions with other heterosubstituents in the allylic position (3m–3o), as they could be potentially labile toward additional substitution. It is remarkable that the desired products were uniformly obtained as a single isomer in enantiopure forms in all these cases (>99% ee, >20:1 dr, and >20:1 rr), thus highlighting the robustness of this difunctionalization process. We also evaluated other carbon-based electrophiles, such as simple alkyl, propargyl, and aryl halides or phosphates. Unfortunately, the corresponding boryl functionalization products were not obtained (see more details in the SI).

2. Branched Allylation Scope .

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a Reaction conditions: 1a (0.4 mmol), 2 (0.6 mmol), B2pin2 (0.6 mmol), NaO t Bu (0.6 mmol), CuBr (5 mol %), (S,S)-L1 (6 mol %), 1,4-dioxane (8 mL), rt, 10 h. Isolated yield. Dr and rr values were determined by 1H NMR analysis of the crude product. The ee value was determined by HPLC on a chiral stationary phase.

The success of branched allylation further prompted us to explore the more challenging linear allylation reactions since the latter involves an additional selectivity control, i.e., E/Z ratio regarding the double bond configuration. A range of racemic allyl phosphates 4 bearing an allylic substituent (R2) were examined (Scheme ). Notably, all these cases resulted in linear allylation products 5 with good to excellent site selectivity, suggesting that the substitution was in an exclusive SN2′ fashion. Again, all the products were formed with uniformly outstanding stereoselectivity as a single enantiomer, diastereomer, and regioisomer. In the presence of an additional substituent (4i), the corresponding trisubstituted olefin 5i was also generated with high efficiency and good stereoselectivity. The mild conditions were compatible with different functional groups, including alkenes, thioethers, ethers, amines, and amides. Heterocycles could be successfully incorporated into the chiral azetidine products without an erosion in efficiency. Of note, this reaction exhibited good chemoselectivity when other CC bonds were present in the substrates. Only the electron-rich azetine motif participated in boryl allylation. Finally, our protocol also permitted the facile modification of bioactive and natural molecules. Specifically, allylic phosphates derived from abietic acid, citronellal, and majantol all resulted in the corresponding azetidines 5j–5l with good to excellent efficiency and stereoselectivities. The application in drug-like substrates and the potential to introduce azetidines in late-stage optimization of properties and potency are important.

3. Linear Allylation Scope .

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a Reaction conditions: 1a (0.4 mmol), 4 (0.6 mmol), B2pin2 (0.6 mmol), NaO t Bu (0.6 mmol), CuBr (10 mol %), (S,S)-L1 (12 mol %), 1,4-dioxane (8 mL), rt, 10 h. Isolated yield. Isolated yield. Dr, E/Z, and rr values were determined by 1H NMR analysis of the crude product. The ee value was determined by HPLC on a chiral stationary phase.

The present three-component coupling reaction permitted the convenient introduction of two versatile functionalities to the azetidine ring with complete absolute and relative stereocontrol. To further demonstrate its synthetic utility, we performed a gram-scale synthesis of azetidine 3e by the optimized protocol (Scheme ). Notably, the loading of CuBr and (S,S)-L1 could be further reduced to 1 and 1.2 mol %, respectively, to achieve equally high efficiency and stereoselectivity (Scheme A). Next, some transformations of 3e were performed. The Zweifel olefination of the boronate unit in 3e with a vinyl Grignard reagent followed by ring-closing metathesis provided expedient access to enantiopure azabicyclo[3.2.0]­heptane 6, a skeleton of significant medicinal value. The versatile boronate unit in 3e could be easily transformed to other functionalities. For example, arylation with furan could be achieved with high stereospecificity in the presence of the in situ lithiated furan and NBS. Furthermore, homologative oxidation with CH2Br2 and n-BuLi smoothly afforded alcohol 8. Alternatively, direct oxidation could lead to a secondary alcohol, which easily underwent bromination to form 9. The boronate could be efficiently converted to potassium trifluoroborate salt 10. A Pd-catalyzed Heck coupling with PhI was also successfully implemented, leading to exclusive C–C bond formation at the olefin terminal position but not at the Bpin unit. It could be envisioned that these molecules could serve as precursors to other functionalized azetidines after simple transformations. Notably, no erosion in the high enantiopurity was observed in these transformations.

4. (A, B) Larger-Scale Reaction and Synthetic Applications .

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a Reagents and conditions: (a) (vinyl)­MgBr, I2, NaOMe, −78 °C to rt; the Grubbs II catalyst, DCM, 60 °C. (b) Furan, n-BuLi, NBS, −78 °C to rt. (c) CH2Br2, n-BuLi, THF, −78 °C to rt; NaBO3 ·4H2O, THF/H2O, rt. (d) NaBO3 ·4H2O, THF/H2O, rt; PPh3, CBr4, toluene, 100 °C. (e) KHF2, MeOH/H2O, rt. (f) Pd­(dppf)­Cl2, PhI, Ag2O, Cs2CO3, THF/H2O, 80 °C. (g) BnBr, NaH, THF, 0 °C to rt. (h) the Grubbs II catalyst, CH2CHOTMS, toluene, 120 °C; K2OsO4 ·2H2O, NaIO4, NMO, t BuOH, H2O, rt. (i) NaClO2, NaH2PO4, H2O2, MeCN, rt.

Our protocol can also provide access to advanced intermediates toward natural molecules (Scheme B). For example, a large-scale synthesis of 3l followed by in situ oxidation delivered enantiopure 3-hydroxylazetidine 12. After protection as a benzyl ether 13, isomerization and oxidative cleavage of the double bond resulted in aldehyde 14. Further oxidation then provided carboxylic acid 15, an advanced intermediate leading to various stereoisomers of mugineic acids, known as phytosiderophores to facilitate iron uptake in plants.

Next, we performed experiments to gain some insight into the reaction mechanism (Figure ). The addition of TEMPO did not affect the high efficiency, suggesting that this may not be a radical pathway (Figure A). The use of deuterated allylic electrophile 2b-d 2 resulted in 3b-d 2 with exclusive deuterium incorporation at the terminal position, indicating that this substitution is an intrinsic SN2′ process, but not by an SN2 pathway or via reductive elimination of a π-allyl species, which would lead to a mixture (Figure B). Furthermore, the product ee values showed a linear correlation with those of the ligand, thus consistent with the formation of a 1:1 adduct of the copper salt with the chiral bidentate ligand that dictates the enantio-determining bond formation (Figure C). Kinetic studies were also studied, which indicated that this process exhibits zeroth order in azetine and B2pin2, but first order in electrophile 2a and the catalyst (Figure D).

1.

1

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(A–E) Mechanistic studies and the proposed mechanism.

Based on these observations, we proposed a possible mechanism (Figure E). The reaction begins by forming Cu­(I)/bisphosphine complex I. Subsequent ligand exchange driven by the formation of a stable boronate t BuO-Bpin generates the Cu-Bpin species II, which undergoes migratory insertion to the double bond of azetine 1a to form the key alkyl cuprate III. The latter step is highly regioselective, with Bpin added exclusively to the 3-position. The syn-addition mechanism governs complete diastereoselectivity. The chiral catalyst also provides effective facial discrimination. Moreover, according to the kinetic data, this step is fast and thermodynamically favorable. This can also be regarded as fast saturation of the limiting Cu-Bpin species by azetine 1a, resulting in pseudo zeroth order in 1a. The subsequent C–C bond formation proceeds by nucleophilic attack to the less hindered terminal of the allylic electrophile in an SN2′ fashion, which is a slow step due to the low reactivity of the sterically hindered alkyl cuprate bearing an adjacent nitrogen atom. Therefore, the proper choice of an allylic phosphate electrophile is critical to ensure sufficient reactivity and to avoid competing protonation that would lead to 1a-Bpin. It is also worth mentioning that the high reactivity of the azetine substrate is also critical to avoid direct addition of Cu-Bpin species II to the allylic electrophile, which would lead to side product 2-Bpin. This also explains the high chemoselectivity even in the presence of other CC bonds in the substrates.

Conclusions

In summary, we have developed the first highly enantioselective direct difunctionalization of azetines for convenient access to chiral 2,3-disubstituted azetidines, a family of important scaffolds previously lacking general access. It also represents a rare demonstration of Cu-catalyzed asymmetric boryl alkylation of (heterosubstituted) electron-rich olefins and CC bonds in strained heterocycles, despite the broad utility of this powerful olefin difunctionalization strategy. With the proper choice of a chiral bisphosphine ligand and allyl electrophiles, two versatile functionalities (boryl and allyl) were installed on the valuable azetidine ring with concomitant construction of two new stereogenic centers. The use of allyl phosphates proved critical not only to overcome the low reactivity of the borylcupration intermediate toward alkylation but also to avoid the side reactions such as direct functionalization of the allyl electrophile without involving azetine. It is remarkable that, in almost all the cases, single isomers were obtained with complete control over chemo-, regio-, enantio-, and diastereoselectivities in the azetidine motif as well as excellent control over the double bond configuration in the allyl group. The mild conditions exhibited outstanding functional group compatibility as well, leaving regular CC bonds intact and thus showing great potential in facile modification of complex natural and drug molecules. The boryl and allyl units can be easily converted to other functionalities, thereby leading to other chiral azetidines that are not straightforward to access before. Control experiments and kinetic studies indicated that the reaction proceeds by a fast borylcupration of azetine followed by rate-determining allylation via an intrinsically controlled SN2′ pathway. Further extension of this efficient protocol is expected to address other challenges in organic synthesis.

Supplementary Material

ja5c07821_si_001.pdf (9.6MB, pdf)

Acknowledgments

We thank the National Natural Science Foundation of China (22271242 and 22471232), the Hong Kong Research Grants Council (C6012-21G, 16309321, 16304322, 16309722, 16309023, and 16310924), and Innovation and Technology Commission (ITC-CNERC14SC01) for financial support. M.Z. thanks the Hong Kong Scholars Program for financial support.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c07821.

  • Additional experimental and computational details and spectroscopic data of all compounds (PDF)

The authors declare no competing financial interest.

References

  1. a Vitaku E., Smith D. T., Njardarson J. T.. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014;57:10257–10274. doi: 10.1021/jm501100b. [DOI] [PubMed] [Google Scholar]; b Heravi M. M., Zadsirjan V.. Prescribed Drugs Containing Nitrogen Heterocycles: An Overview. RSC Adv. 2020;10:44247–44311. doi: 10.1039/D0RA09198G. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Marshall C. M., Federice J. G., Bell C. N., Cox P. B., Njardarson J. T.. An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023) J. Med. Chem. 2024;67:11622–11655. doi: 10.1021/acs.jmedchem.4c01122. [DOI] [PubMed] [Google Scholar]; d Gupta P., Mahajan N.. Biocatalytic Approaches towards the Stereoselective Synthesis of Vicinal Amino Alcohols. New J. Chem. 2018;42:12296–12327. doi: 10.1039/C8NJ00485D. [DOI] [Google Scholar]; e Hargaden G. C., Guiry P. J.. Recent Applications of Oxazoline-Containing Ligands in Asymmetric Catalysis. Chem. Rev. 2009;109:2505–2550. doi: 10.1021/cr800400z. [DOI] [PubMed] [Google Scholar]
  2. Reviews of azetidines in medicinal chemistry:; a Wang D. X., Booth H., Lerner-Marmarosh N., Osdene T. S., Abood L. G.. Structure-Activity Relationships for Nicotine Analogs Comparing Competition for [3H]­Nicotine Binding and Psychotropic Potency. Drug Dev. Res. 1998;45:10–16. doi: 10.1002/(SICI)1098-2299(199809)45:1<10::AID-DDR2>3.0.CO;2-G. [DOI] [Google Scholar]; b St. Jean D. J. Jr., Fotsch C.. Mitigating Heterocycle Metabolism in Drug Discovery. J. Med. Chem. 2012;55:6002–6020. doi: 10.1021/jm300343m. [DOI] [PubMed] [Google Scholar]; c Bauer M. R., Fruscia P., Lucas S. C. C., Michaelides I. N., Nelson J. E., Storer R. I., Whitehurst B. C.. Put a Ring on It: Application of Small Aliphatic Rings in Medicinal Chemistry. RSC Med. Chem. 2021;12:448–471. doi: 10.1039/d0md00370k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Selected examples of azetidine-containing natural and bioactive molecules:; a Shioiri T., Hamada Y., Matsuura F.. Total Synthesis of Phytosiderophores. Tetrahedron. 1995;51:3939–3958. doi: 10.1016/0040-4020(94)01096-I. [DOI] [Google Scholar]; b Maetani M., Zoller J., Melillo B., Verho O., Kato N., Pu J., Comer E., Schreiber S. L.. Synthesis of a Bicyclic Azetidine with in Vivo Antimalarial Activity Enabled by Stereospecific, Directed C­(sp3)-H Arylation. J. Am. Chem. Soc. 2017;139:11300–11306. doi: 10.1021/jacs.7b06994. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Tao Y., Remillard D., Vinogradova E. V., Yokoyama M., Banchenko S., Schwefel D., Melillo B., Schreiber S. L., Zhang X., Cravatt B. F.. Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1. J. Am. Chem. Soc. 2022;144:18688–18699. doi: 10.1021/jacs.2c08964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. For a review and selected example on azetidines in asymmetric synthesis:; a Milton J. P., Fossey J. S.. Azetidines and Their Applications in Asymmetric Catalysis. Tetrahedron. 2021;77:131767–131781. doi: 10.1016/j.tet.2020.131767. [DOI] [Google Scholar]; For an example as chiral ligands:; b Zhang Z., Li M., Zi G.. Synthesis of New Chiral cis-3-Hydroxyazetidines and Their Application in Diethylzinc Addition to Aldehydes. Chirality. 2007;19:802–808. doi: 10.1002/chir.20470. [DOI] [PubMed] [Google Scholar]
  5. Leading reviews on the synthesis of azetidines:; a Brandi A., Cicchi S., Cordero F. M.. Novel Syntheses of Azetidines and Azetidinones. Chem. Rev. 2008;108:3988–4035. doi: 10.1021/cr800325e. [DOI] [PubMed] [Google Scholar]; b Bott T. M., West F. G.. Preparation and Synthetic Applications of Azetidines. Heterocycles. 2012;84:223–264. doi: 10.3987/rev-11-sr(p)9. [DOI] [Google Scholar]; c Antermite D., Degennaro L., Luisi R.. Recent Advances in the Chemistry of Metallated Azetidines. Org. Biomol. Chem. 2017;15:34–50. doi: 10.1039/C6OB01665K. [DOI] [PubMed] [Google Scholar]; d Mehra V., Lumb I., Anand A., Kumar V.. Recent Advances in Synthetic Facets of Immensely Reactive Azetidines. RSC Adv. 2017;7:45763–45783. doi: 10.1039/C7RA08884A. [DOI] [Google Scholar]; e Reidl T. W., Anderson L. L.. Divergent Functionalizations of Azetidines and Unsaturated Azetidines. Asian J. Org. Chem. 2019;8:931–945. doi: 10.1002/ajoc.201900229. [DOI] [Google Scholar]; f Zadsirjan V., Soleimani F.. Recent Advances in the Synthesis of Azetidines. Tetrahedron. 2025;169:134383–134398. doi: 10.1016/j.tet.2024.134383. [DOI] [Google Scholar]; g Jaiswal S., Arya N., Kishore D., Dwivedi J., Sharma S.. Exploring Azetidine-Containing Heterocycles: From Green Synthesis to Applications. Tetrahedron. 2025;81:134491–134507. doi: 10.1016/j.tet.2025.134491. [DOI] [Google Scholar]; h Mughal H., Szostak M.. Recent Advances in the Synthesis and Reactivity of Azetidines: Strain-Driven Character of the Four-Membered Heterocycle. Org. Biomol. Chem. 2021;19:3274–3286. doi: 10.1039/D1OB00061F. [DOI] [PubMed] [Google Scholar]; i Burns S. M., McClure T. J., Parikh S. G., Schindler C. S.. Synthesis and Biological Activity of Penaresidins A and B, Penazetidine A, and Related Analogues. Synthesis. 2025;57:571–596. doi: 10.1055/s-0043-1763676. [DOI] [Google Scholar]
  6. For selected examples of nonenantioselective synthesis of azetidines:; a Fawcett A., Murtaza A., Gregson C. H. U., Aggarwal V. K.. Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines. J. Am. Chem. Soc. 2019;141:4573–4578. doi: 10.1021/jacs.9b01513. [DOI] [PubMed] [Google Scholar]; b Tyler J. L., Noble A., Aggarwal V. K.. Four-Component Strain-Release-Driven Synthesis of Functionalized Azetidines. Angew. Chem., Int. Ed. 2022;61:e202214049. doi: 10.1002/anie.202214049. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Jaiswal V., Mondal S., Singh B., Singh V. P., Saha J.. Cation-Promoted Strain-Release-Driven Access to Functionalized Azetidines from Azabicyclo[1.1.0] Butanes. Angew. Chem., Int. Ed. 2023;62:e202304471. doi: 10.1002/ange.202304471. [DOI] [PubMed] [Google Scholar]; d Hsu C.-M., Lin H.-B., Hou X.-Z., Tapales R. V. P., Shin C.-K., Miñoza S., Tsai Y.-S., Tsai Z.-N., Chan C.-L., Liao H.-H.. Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization. J. Am. Chem. Soc. 2023;145:19049–19059. doi: 10.1021/jacs.3c06710. [DOI] [PubMed] [Google Scholar]; e Symes O. L., Ishikura H., Begg C. S., Rojas J. J., Speller H. A., Cherk A. M., Fang M., Leung D., Croft R. A., Higham J. I., Huang K., Barnard A., Haycock P., White A. J. P., Choi C., Bull J. A.. Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery. J. Am. Chem. Soc. 2024;146:35377–35389. doi: 10.1021/jacs.4c14164. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Rodríguez R., Corti V., Rizzo L., Visentini S., Bortolus M., Amati A., Natali M., Pelosi G., Costa P., Dell’Amico L.. Radical Strain-Release Photocatalysis for the Synthesis of Azetidines. Nat. Catal. 2024;7:1223–1231. doi: 10.1038/s41929-024-01206-4. [DOI] [Google Scholar]
  7. Selected examples of the synthesis of azetidines from enantioenriched precursors and/or with stoichiometric chiral auxiliaries:; a Hanessian S., Bernstein N., Yang R.-Y., Maguire R.. Asymmetric Synthesis of L-Azetidine-2-Carboxylic Acid and 3-Substituted Congeners-Conformationally Constrained Analogs of Phenylalanine, Naphthylalanine, and Leucine. Bioorg. Med. Chem. Lett. 1999;9:1437–1442. doi: 10.1016/S0960-894X(99)00218-8. [DOI] [PubMed] [Google Scholar]; b Pradhan T. K., Krishnan K. S., Vasse J.-L., Szymoniak J.. Access to Enantiomerically Enriched cis-2,3-Disubstituted Azetidines via Diastereoselective Hydrozirconation. Org. Lett. 2011;13:1793–1795. doi: 10.1021/ol200323r. [DOI] [PubMed] [Google Scholar]; c Lenagh-Snow G. M. J., Araujo N., Jenkinson S. F., Rutherford C., Nakagawa S., Kato A., Yu C.-Y., Weymouth-Wilson A. C., Fleet G. W. J.. Inhibition of Nonmammalian Glycosidases by Azetidine Iminosugars Derived from Stable 3,5-Di-O-triflates of Pentoses. Org. Lett. 2011;13:5834–5837. doi: 10.1021/ol2024482. [DOI] [PubMed] [Google Scholar]; d Hodgson D. M., Mortimer C. L., McKenna J. M.. Amine Protection/α-Activation with the tert-Butoxythiocarbonyl Group: Application to Azetidine Lithiation-Electrophilic Substitution. Org. Lett. 2015;17:330–333. doi: 10.1021/ol503441d. [DOI] [PubMed] [Google Scholar]; e Marichev K. O., Wang K., Dong K., Greco N., Massey L. A., Deng Y., Arman H., Doyle M. P.. Synthesis of Chiral Tetrasubstituted Azetidines from Donor-Acceptor Azetines via Asymmetric Copper­(I)-Catalyzed Imido-Ylide [3 + 1]-Cycloaddition with Metallo-Enolcarbenes. Angew. Chem., Int. Ed. 2019;58:16188–16192. doi: 10.1002/anie.201909929. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Delany P. K., Hodgson D. M.. Synthesis and Homologation of an Azetidin-2-yl Boronic Ester with α-Lithioalkyl Triisopropylbenzoates. Org. Lett. 2019;21:9981–9984. doi: 10.1021/acs.orglett.9b03901. [DOI] [PubMed] [Google Scholar]; g Ma X., Zhao H., Binayeva M., Ralph G., Diane M., Zhao S., Wang C.-Y., Biscoe M. R.. A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters. Chem. 2020;6:781–791. doi: 10.1016/j.chempr.2020.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Kratena N., Gökler T., Maltrovsky L., Oburger E., Stanetty C.. A Unified Approach to Phytosiderophore Natural Products. Chem. - Eur. J. 2021;27:577–580. doi: 10.1002/chem.202004004. [DOI] [PMC free article] [PubMed] [Google Scholar]; i Zelch D., Russo C. M., Ruud K. J., O’Reilly M. C.. A General and Scalable Method toward Enantioenriched C2-Substituted Azetidines Using Chiral tert-Butanesulfinamides. J. Org. Chem. 2024;89:15137–15144. doi: 10.1021/acs.joc.4c01908. [DOI] [PMC free article] [PubMed] [Google Scholar]; j Bielecki, M. ; Nassir, M. ; Sharma, H. A. ; Truax, N. J. ; Raheja, N. ; Thompson, T. M. ; Ewing, T. E.-H. ; Melillo, B. ; Cravatt, B. F. ; Baran, P. S. . Enantiocontrolled Azetidine Library Synthesis via Strain-Release Functionalization of 1-Azabicyclobutanes. J. Am. Chem. Soc. 2024. 10.1021/jacs.5c07227. [DOI] [PubMed] [Google Scholar]
  8. Other catalytic enantioselective approaches (not difunctionalization together with generation of two stereogenic centers):; a Reiners F., Joseph E., Nißl B., Didier D.. Stereoselective Access to Azetidine-based α-Amino Acids and Applications to Small Peptide Synthesis. Org. Lett. 2020;22:8533–8537. doi: 10.1021/acs.orglett.0c03131. [DOI] [PubMed] [Google Scholar]; b Qian L.-L., Hu Y.-C., Min X.-T., Yang S.-N., Shen B.-X., Wan B., Chen Q.-A.. CPA-Catalyzed Multicomponent Reaction of Anilines, Aldehydes, and Azetidinones: Rapid Access to Enantiopure-fused Azetidines. Chem. Catal. 2022;2:2024–2033. doi: 10.1016/j.checat.2022.05.023. [DOI] [Google Scholar]; c Miller D., Lal R. G., Marchetti L. A., Arnold F. H.. Biocatalytic One-Carbon Ring Expansion of Aziridines to Azetidines via a Highly Enantioselective [1, 2]-Stevens Rearrangement. J. Am. Chem. Soc. 2022;144:4739–4745. doi: 10.1021/jacs.2c00251. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Boddy A. J., Sahay A. K., Rivers E. L., White A. J. P., Spivey A. C., Bull J. A.. Enantioselective Phase-Transfer-Catalyzed Synthesis of Spirocyclic Azetidine Oxindoles. Org. Lett. 2024;26:2079–2084. doi: 10.1021/acs.orglett.4c00358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Our efforts in azetidine chemistry:; a Wang Z., Sheong F. K., Sung H. H. Y., Williams I. D., Lin Z., Sun J.. Catalytic Enantioselective Intermolecular Desymmetrization of Azetidines. J. Am. Chem. Soc. 2015;137:5895–5898. doi: 10.1021/jacs.5b03083. [DOI] [PubMed] [Google Scholar]; b Qian D., Chen M., Bissember A. C., Sun J.. Counterion-Induced Asymmetric Control in Ring-Opening of Azetidiniums: Facile Access to Chiral Amines. Angew. Chem., Int. Ed. 2018;57:3763–3766. doi: 10.1002/anie.201712395. [DOI] [PubMed] [Google Scholar]
  10. For a review and selected examples of azetine synthesis:; a Gatazka M. R., McFree E. C., Ng C. H., Wearing E. R., Kiw Y. M., Schindler C. S.. New Strategies for the Synthesis of 1- and 2-Azetines and Their Applications as Value-Added Building Blocks. Org. Biomol. Chem. 2022;20:9052–9068. doi: 10.1039/d2ob01812h. [DOI] [PMC free article] [PubMed] [Google Scholar]; For selected examples:; b Baumann A. N., Eisold M., Music A., Haas G., Kiw Y. M., Didier D.. Methods for the Synthesis of Substituted Azetines. Org. Lett. 2017;19:5681–5684. doi: 10.1021/acs.orglett.7b02847. [DOI] [PubMed] [Google Scholar]; c Marichev K. O., Dong K., Massey L. A., Deng Y., Angelis L. D., Wang K., Arman H., Doyle M. P.. Chiral Donor-Acceptor Azetines as Powerful Reactants for Synthesis of Amino Acid Derivatives. Nat. Commun. 2019;10:5328–5338. doi: 10.1038/s41467-019-13326-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. For leading reviews:; a Whyte A., Torelli A., Mirabi B., Zhang A., Lautens M.. Copper-Catalyzed Borylative Difunctionalization of π-Systems. ACS Catal. 2020;10:11578–11622. doi: 10.1021/acscatal.0c02758. [DOI] [Google Scholar]; b Hemming D., Fritzemeier R. P., Westcott S. A., Santos W. L., Steel P. G.. Copper-Boryl Mediated Organic Synthesis. Chem. Soc. Rev. 2018;47:7477–7494. doi: 10.1039/C7CS00816C. [DOI] [PubMed] [Google Scholar]
  12. Pioneering studies by Hoveyda and co-workers:; a Meng F., Jang H., Jung B., Hoveyda A. H.. Cu-Catalyzed Chemoselective Preparation of 2-(Pinacolato)­Boron-Substituted Allylcopper Complexes and their In-Situ Site-, Diastereo-, and Enantioselective Additions to Aldehydes and Ketones. Angew. Chem., Int. Ed. 2013;52:5046–5051. doi: 10.1002/anie.201301018. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Meng F., McGrath K. P., Hoveyda A. H.. Multifunctional Organoboron Compounds for Scalable Natural Product Synthesis. Nature. 2014;513:367–374. doi: 10.1038/nature13735. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Meng F., Haeffner F., Hoveyda A. H.. Diastereo- and Enantioselective Reactions of Bis­(pinacolato)­diboron, 1,3-Enynes, and Aldehydes Catalyzed by an Easily Accessible bisphosphine-Cu Complex. J. Am. Chem. Soc. 2014;136:11304–11307. doi: 10.1021/ja5071202. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Meng F., Li X., Torker S., Shi Y., Shen X., Hoveyda A. H.. Catalytic Enantioselective 1,6-Conjugate Additions of Propargyl and Allyl Groups. Nature. 2016;537:387–393. doi: 10.1038/nature19063. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Li X., Meng F., Torker S., Shi Y., Hoveyda A. H.. Catalytic Enantioselective Conjugate Additions of (pin)­B-Substituted Allylcopper Compounds Generated in situ from Butadiene or Isoprene. Angew. Chem., Int. Ed. 2016;55:9997–10002. doi: 10.1002/anie.201605001. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Jang H., Romiti F., Torker S., Hoveyda A. H.. Catalytic Diastereo- and Enantioselective Additions of Versatile Allyl Groups to N-H Ketimines. Nat. Chem. 2017;9:1269–1275. doi: 10.1038/nchem.2816. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Lee J., Radomkit S., Torker S., Del Pozo J., Hoveyda A. H.. Mechanism-Based Enhancement of Scope and Enantioselectivity for Reactions Involving a Copper-Substituted Stereogenic Carbon Centre. Nat. Chem. 2018;10:99–108. doi: 10.1038/nchem.2861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. For selected other examples of copper-catalyzed borylative functionalization of CC bonds:; a Liu P., Fukui Y., Tian P., He Z.-T., Sun C.-Y., Wu N.-Y., Lin G.-Q.. Cu-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Enynes. J. Am. Chem. Soc. 2013;135:11700–11703. doi: 10.1021/ja404593c. [DOI] [PubMed] [Google Scholar]; b Matsuda N., Hirano K., Satoh T., Miura M.. Regioselective and Stereospecific Copper-Catalyzed Aminoboration of Styrenes with Bis­(pinacolato)­diboron and O-Benzoyl-N,N-dialkylhydroxylamines. J. Am. Chem. Soc. 2013;135:4934–4937. doi: 10.1021/ja4007645. [DOI] [PubMed] [Google Scholar]; c Jia T., Cao P., Wang B., Lou Y., Yin X., Wang M., Liao J.. A Cu/Pd Cooperative Catalysis for Enantioselective Allylboration of Alkenes. J. Am. Chem. Soc. 2015;137:13760–13763. doi: 10.1021/jacs.5b09146. [DOI] [PubMed] [Google Scholar]; d Jiang L., Cao P., Wang M., Chen B., Wang B., Liao J.. Highly Diastereo- and Enantioselective Cu-Catalyzed Borylative Coupling of 1,3-Dienes and Aldimines. Angew. Chem., Int. Ed. 2016;55:13854–13858. doi: 10.1002/anie.201607493. [DOI] [PubMed] [Google Scholar]; e Yeung K., Ruscoe R. E., Rae J., Pulis A. P., Procter D. J.. Enantioselective Generation of Adjacent Stereocenters in a Copper-Catalyzed Three-Component Coupling of Imines, Allenes, and Diboranes. Angew. Chem., Int. Ed. 2016;55:11912–11916. doi: 10.1002/anie.201606710. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Kim N., Han J. T., Ryu D. H., Yun J.. Copper-Catalyzed Asymmetric Borylallylation of Vinyl Arenes. Org. Lett. 2017;19:6144–6147. doi: 10.1021/acs.orglett.7b03022. [DOI] [PubMed] [Google Scholar]; g Han J., Zhou W., Zhang P.-C., Wang H., Zhang R., Wu H.-H., Zhang J.. Design and Synthesis of WJ-Phos, and Application in Cu-Catalyzed Enantioselective Boroacylation of 1,1-Disubstituted allenes. ACS Catal. 2019;9:6890–6895. doi: 10.1021/acscatal.9b02080. [DOI] [Google Scholar]; h Han J. T., Kim S.-T., Baik M.-H., Yun J.. Direct Stereoconvergent Allylation of Chiral Alkylcopper Nucleophiles with Racemic Allylic Phosphates. Chem. - Eur. J. 2020;26:2592–2596. doi: 10.1002/chem.201905361. [DOI] [PubMed] [Google Scholar]; i Manna S., Dherbassy Q., Perry G. J. P., Procter D. J.. Enantio- and Diastereoselective Synthesis of Homopropargyl Amines by Copper-Catalyzed Coupling of Imines, 1,3-Enynes, and Diborons. Angew. Chem., Int. Ed. 2020;59:4879–4882. doi: 10.1002/anie.201915191. [DOI] [PMC free article] [PubMed] [Google Scholar]; j Fiorito D., Liu Y., Besnard C., Mazet C.. Direct Access to Chiral Secondary Amides by Copper-Catalyzed Borylative Carboxamidation of Vinylarenes with Isocyanates. J. Am. Chem. Soc. 2020;142:623–632. doi: 10.1021/jacs.9b12297. [DOI] [PubMed] [Google Scholar]; k Wu F.-P., Holz J., Yuan Y., Wu X.-F.. Copper-Catalyzed Carbonylative Synthesis of β-Boryl Amides via Boroamidation of Alkenes. CCS Chem. 2021;3:2643–2654. doi: 10.31635/ccschem.020.202000579. [DOI] [Google Scholar]; l Akiyama S., Oyama N., Endo T., Kubota K., Ito H.. A Copper­(I)-Catalyzed Radical-Relay Reaction Enabling the Intermolecular 1,2-Alkylborylation of Unactivated Olefins. J. Am. Chem. Soc. 2021;143:5260–5286. doi: 10.1021/jacs.1c02050. [DOI] [PubMed] [Google Scholar]; m Fan Z., Ye M., Wang Y., Qiu J., Li W., Ma X., Yang K., Song Q.. Enantioselective Copper-Catalyzed sp2/sp3 Diborylation of 1-Chloro-1-Trifluoromethylalkenes. ACS Cent. Sci. 2022;8:1134–1144. doi: 10.1021/acscentsci.2c00339. [DOI] [PMC free article] [PubMed] [Google Scholar]; n Byun S., Farah O., Wise H. R., Katchmar A., Cheong P. H.-Y., Scheidt K. A.. Enantioselective Copper-Catalyzed Borylative Amidation of Allenes. J. Am. Chem. Soc. 2022;144:22850–22857. doi: 10.1021/jacs.2c10507. [DOI] [PubMed] [Google Scholar]; o Zhang S., Li L., Li D., Zhou Y.-Y., Tang Y.. Catalytic Regio- and Enantioselective Boracarboxylation of Arylalkenes with CO2 and Diboron. J. Am. Chem. Soc. 2024;146:2888–2894. doi: 10.1021/jacs.3c12720. [DOI] [PubMed] [Google Scholar]; p Gui Y.-Y., Chen X.-W., Mo X.-Y., Yue J.-P., Yuan R., Liu Y., Liao L.-L., Ye J.-H., Yu D.-G.. Cu-Catalyzed Asymmetric Dicarboxylation of 1,3-Dienes with CO2 . J. Am. Chem. Soc. 2024;146:2919–2927. doi: 10.1021/jacs.3c14146. [DOI] [PubMed] [Google Scholar]
  14. Simlandy A. K., Lyu M.-Y., Brown M. K.. Catalytic Arylboration of Spirocyclic Cyclobutenes: Rapid Access to Highly Substituted Spiro­[3.n] Alkanes. ACS Catal. 2021;11:12815–12820. doi: 10.1021/acscatal.1c03491. For a racemic borylcupration of strained olefins followed by functionalization: [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gao C., Tang K., Yang X., Gao S., Zheng Q., Chen X., Liu J.. Cu-Catalyzed Diastereo-and Enantioselective Synthesis of Borylated Cyclopropanes with Three Contiguous Stereocenters. J. Am. Chem. Soc. 2025;147:3360–3370. doi: 10.1021/jacs.4c14158. [DOI] [PubMed] [Google Scholar]
  16. For examples of enantioselective borylcupration of strained olefins followed by protonation:; a Parra A., Amenós L., Guisán-Ceinos M., López A., García Ruano J. L., Tortosa M.. Copper-Catalyzed Diastereo- and Enantioselective Desymmetrization of Cyclopropenes: Synthesis of Cyclopropylboronates. J. Am. Chem. Soc. 2014;136:15833–15836. doi: 10.1021/ja510419z. [DOI] [PubMed] [Google Scholar]; b Guisán-Ceinos M., Parra A., Martín-Heras V., Tortosa M.. Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach. Angew. Chem., Int. Ed. 2016;55:7083–7086. doi: 10.1002/ange.201601976. [DOI] [PubMed] [Google Scholar]; c Clement H. A., Boghi M., McDonald R. M., Bernier L., Coe J. W., Farrell W., Helal C. J., Reese M. R., Sach N. W., Lee J. C., Hall D. G.. High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates. Angew. Chem., Int. Ed. 2019;58:18576–18580. doi: 10.1002/ange.201909308. [DOI] [PubMed] [Google Scholar]; d Nguyen K., Clement H. A., Bernier L., Coe J. W., Farrell W., Helal C. J., Reese M. R., Sach N. W., Lee J. C., Hall D. G.. Catalytic Enantioselective Synthesis of a cis-β-Boronyl Cyclobutylcarboxyester Scaffold and Its Highly Diastereoselective Nickel/Photoredox Dual-Catalyzed Csp3-Csp2 Cross-Coupling to Access Elusive trans-β-Aryl/Heteroaryl Cyclobutylcarboxyesters. ACS Catal. 2021;11:404–413. doi: 10.1021/acscatal.0c04520. [DOI] [Google Scholar]
  17. Trammel G. L., Kannangara P. B., Vasko D., Datsenko O., Mykhailiuk P., Brown M. K.. Arylboration of Enecarbamates for the synthesis of Borylated Saturated N-Heterocycles. Angew. Chem., Int. Ed. 2022;61:e202212117. doi: 10.1002/anie.202212117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Armstrong R. J., Aggarwal V. K.. 50 Years of Zweifel Olefination: A Transition-Metal-Free Coupling. Synthesis. 2017;49:3323–3336. doi: 10.1055/s-0036-1589046. [DOI] [Google Scholar]
  19. a Ji J., Schrimpf M. R., Sippy K. B., Bunnelle W. H., Li T., Anderson D. J., Faltynek C., Surowy C. S., Dyhring T., Ahring P. K., Meyer M. D.. Synthesis and Structure-Activity Relationship Studies of 3,6-Diazabicyclo[3.2.0]­heptanes as Novel α4β2 Nicotinic Acetylcholine Receptor Selective Agonists. J. Med. Chem. 2007;50:5493–5508. doi: 10.1021/jm070755h. [DOI] [PubMed] [Google Scholar]; b Schmid M., Steiner O., Fasshold L., Goessler W., Holl A.-M., Kühn K.-D.. The Stability of Carbapenems Before and After Admixture to PMMA-Cement Used for Replacement Surgery Caused by Gram-Negative Bacteria. Eur. J. Med. Res. 2020;25:34. doi: 10.1186/s40001-020-00428-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

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