Unlocking the Potential of Chiral DPEN: Synthetic Breakthrough and Industrialization Outlook

1,2-Diphenyl-1,2-ethanediamine, abbreviated as DPEN, has emerged as a privileged chiral scaffold due to its versatility in enantioselective catalysts design, serving as organocatalysts or ligands coordinating to metals for enantioselective transformations. For instance, the commonly used Salen ligands, Trost-type ligands, novel BIPI ligands and organocatalysts (Figure 1).[1] DPEN-derived compounds have not only been extensively employed in academic research but also adopted as cost-effective catalysts in industrial applications.

Figure 1. DPEN-based ligands and organocatalysts.[1]

Traditional synthetic route for chiral DPEN

In 1990, Salvadori and coworkers reported the synthesis of (S,S)-DPEN. The key step involved Sharpless asymmetric dihydroxylation of stilbene, which afforded the chiral diol intermediate. Subsequent tosylation of the diol, followed by azide nucleophilic substitution and LAH-mediated reduction, yielded the target compound in 32% overall yield (Figure 2a).[2a] Later, Corey and Paul developed an alternative synthetic route via a resolution-based approach (Figure 2b). [2b-c] To date, the resolution strategy remains the mainstream method for preparing DPEN-derived products. However, this approach suffers from several major drawbacks: 1) a relatively long synthetic route involving toxic or hazardous reagents; 2) Low yields 3) inevitable formation of meso-product; 4) a complicated operational process requiring steps such as salification, salt decomposition, and isomer recycling. As a result, an affordable, operationally simple and general process to access DPEN-derivatives from cheap commercially available starting materials is urgently needed.

Figure 2. Previous synthetic route or process for chiral DPEN.[2]

Original discovery and synthetic breakthrough

In 2017, Tang and co-workers originally described a chiral diboron-templated highly diastereoselective and enantioselective reductive coupling of isoquinolines, providing expedited access to a series of chiral substituted bis-isoquinolines in good yields and excellent ee’s under mild conditions (Figure 3).[3] The mechanistic investigation suggests the reaction proceeds through a concerted [3,3]-sigmatropic rearrangement.

Figure 3. Original discovery of chiral diboron-mediated reductive coupling of isoquinolines.[3]

Leveraging this mechanistic insight, Tang, Xu and co-workers successfully extended the diboron-templated reductive coupling system to imine substrates using a modified chiral diboron catalyst, delivering a wide range of chiral vicinal diamines in excellent yields and enantioselectivities (Figure 4b).[4a] Subsequently, the same strategy was applied to reductive coupling of aryl alkyl ketimines, affording a series of chiral vicinal tetrasubstituted diamines with excellent ee values and good to high yields (Figure 4c).[4b] The rational design of chiral diboron catalyst that conformationally preorganizes the substrates within their tight concerted transition states was responsible for the excellent enantioselectivities. This simple, powerful, general and practical protocol offers a cost-effective synthesis of a number of DPEN-derivatives.

Figure 4. Diboron-templated asymmetric reductive coupling of various imines or ketimines.[4]

In 2020, Tang, Xu and co-workers disclosed a highly efficient synthetic process of chiral DPEN by employing recyclable chiral diol (Figure 5a).[4a] Thus, chiral DPEN was synthesized from benzaldehyde, ammonia and tetrahydroxyldiboron as a reductant in a single step. Consequently, this scalable and cost-effective synthesis of (S,S)-DPEN was achieved in metric ton scale in ZejunPharma (Figure 5b), making the coveted chiral building blocks commercially at bulky scales. 

Figure 5. Synthesis of chiral DPEN at ZejunPharma.

Horizon Prize award

In 2024, the team of Dr. Wenjun Tang, Dr. Guangqing Xu and co-workers, were recognized to receive the Organic Chemistry Horizon Prize from Royal Society of Chemistry for developing the diboron-templated asymmetric reductive coupling (Figure 6). 

Figure 6. Horizon Prize in 2024 for discovering the diboron-templated asymmetric reductive coupling.

Chiral diamines in ZejunPharma (an enriched DPEN library with >200 species)

A wide range of chiral vicinal diamines were available using this powerful protocol. ZejunPharma can provide an array of chiral DPEN-derivatives in kilogram scale, some of which were listed in Figure 7. In addition, the derivatization of chiral DPEN with various NH protection groups were also accomplished in kilogram to metric ton scale (Figure 8). 

Figure 7. Chiral vicinal diamines produced in ZejunPharma.

Figure 8. DPEN derivatives (representative examples).

Ru-DPENs as ATH catalysts

Asymmetric transfer hydrogenation (ATH) of ketones and imines has emerged as a powerful and sustainable alternative to traditional asymmetric hydrogenation (AH) for the production of enantiomerically enriched alcohols and amines, particularly in pharmaceutical and fine chemical synthesis. Unlike AH, which requires high-pressure H₂ gas and specialized infrastructure, ATH employs safe hydrogen donors such as formic acid or HCOOH, enabling operation under mild conditions while maintaining exceptional stereochemical fidelity. Among the diverse catalytic systems developed, Noyori-type Ru(II) complexes, featuring chiral TsDPEN ligands, remain the standard catalyst for industrial-scale applications. Their dominance stems from a unique synergy of modular ligand design, unparalleled enantioselectivity, air/moisture stability, and cost-effectiveness, exemplified by their pivotal role in many cases.[5] Given the correct length of tether, the Wills group pioneered 3C-tethered Ru(II) complexes (Wills-type catalysts), where a rigid carbon chain spacer between the metal center and chiral ligand enforces precise spatial control over the transition state, significantly enhancing reactivity toward a wide range of ketones.[6a-b] Later on, Takasago's oxo-tethered Ru(II) catalysts (Takasago-type catalysts) introduced an oxygen-bridged architecture, which exhibited excellent catalytic performance for both asymmetric transfer hydrogenation and the hydrogenation of ketonic substrates under neutral conditions without any cocatalysts to give chiral secondary alcohols with high levels of enantioselectivity.[6c] These catalysts have extensively broaden the substrate compatibility but also demonstrate improved tolerance to functional groups, positioning ATH as a versatile platform for green synthesis. 

Leveraging the patented proprietary technology, ZejunPharma offers a range of Ru-DPEN complexes for asymmetric transfer hydrogenation (ATH) catalysts, scalable from kilogram to metric ton quantities (representative examples listed in Figure 9a), alongside customizable Ru catalysts tailored to specific industrial requirements (Figure 9b). These solutions are designed to address diverse manufacturing needs with precision and efficiency.

Figure 9. Ru-DPENs catalysts prepared in kilogram scale (9a) and novel Ru catalysts for customization (9b) in ZejunPharma.

Reference

[1] a) Wu, J.; Kozlowski, M.C. Catalytic Oxidative Coupling of Phenols and Related Compounds. ACS Catal. 2022, 12, 6532-6549. b) Busacca, C.A.; Grossbach, D.; So, R.C.; O'Brie, E.M.; Spinelli, E.M. Probing Electronic Effects in the Asymmetric Heck Reaction with the Bipi Ligands. Org. Lett. 2003, 5, 595-598. c) Oljira, S. B.; De Angelis, M.; Sorato, A.; Mazzoccanti, G.; Manetto, S.; D’Acquarica, I.; Ciogli, A. Catalysts, 2024; 14, 915.

[2] a) Pini, D.; Iuliano, A.; Rosini, C.; Salvadori, P. An Efficient and Practical Route to Enantiomerically Pure (+)-(1R,2R)- and (-)-(1S,2S)-1,2-Diphenylethane-1,2-Diamines. Synthesis 1990, 1990, 1023-1024. b) Saigo, K.; Kubota, N.; Takebayashi, S.; Hasegawa, M., Bull. Chem. Soc. Jpn. 1986, 59, 931. c) Pikul, S.; Corey, E. J. Organic Syntheses, 1993, 71, 22.

[3] Chen, D.; Xu, G.; Zhou, Q.; Chung, L. W.; Tang, W. Practical and Asymmetric Reductive Coupling of Isoquinolines Templated by Chiral Diborons. J. Am. Chem. Soc. 2017, 139, 9767-9770.

[4] a) Zhou, M.; Li, K.; Chen, D.; Xu, R.; Xu, G.; Tang, W. Enantioselective Reductive Coupling of Imines Templated by Chiral Diboron. J. Am. Chem. Soc. 2020, 142, 10337-10342. b) Zhou, M.; Lin, Y.; Chen, X.-X.; Xu, G.; Chung, L. W.; Tang, W. Asymmetric Synthesis of Vicinal Tetrasubstituted Diamines Via Reductive Coupling of Ketimines Templated by Chiral Diborons. Angew. Chem., Int. Ed. 2023, 62, e202300334.

[5] a) Noyori, R.; Hashiguchi, S. Asymmetric Transfer Hydrogenation Catalyzed by Chiral Ruthenium Complexes. Acc. Chem. Res. 1997, 30, 97-102. b) Wang, C.; Wu, X.; Xiao, J. Broader, Greener, and More Efficient: Recent Advances in Asymmetric Transfer Hydrogenation. Chem. Asian. J. 2008, 3, 1750-1770.

[6] a) Hannedouche, J.; Clarkson, G. J.; Wills, M. A New Class of “Tethered” Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenation Reactions. J. Am. Chem. Soc. 2004, 126, 986-987. b) Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. A Class of Ruthenium(II) Catalyst for Asymmetric Transfer Hydrogenations of Ketones. J. Am. Chem. Soc. 2005, 127, 7318-7319. c) Touge, T.; Hakamata, T.; Nara, H.; Kobayashi, T.; Sayo, N.; Saito, T.; Kayaki, Y.; Ikariya, T. Oxo-Tethered Ruthenium(II) Complex as a Bifunctional Catalyst for Asymmetric Transfer Hydrogenation and H2 Hydrogenation. J. Am. Chem. Soc. 2011, 133, 14960-14963.

ZejunPharma is dedicated to be a world-leading provider of green catalytic technologies, including structurally unique phosphorus ligands, chiral vicinal diamines, polymeric vicinal amines, as well as specialized APIs, such as naltrexone, nalmefene and chiral building blocks, catering to pharmaceutical, agrochemical and fine chemical companies or industries, as well as academia worldwide.