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. 2019 May 6;21(10):3644–3648. doi: 10.1021/acs.orglett.9b01069

trans-Diastereoselective Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Acetamido Benzocyclic Ketones via Dynamic Kinetic Resolution

Andrej Emanuel Cotman †,‡, Matic Lozinšek ‡, Baifan Wang †, Michel Stephan †, Barbara Mohar †,*
PMCID: PMC6750876  PMID: 31058516

Abstract

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A highly efficient enantio- and diastereoselective catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution (DKR–ATH) of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones to ent-trans-β-amido alcohols is disclosed employing a new ansa-Ru(II) complex of an enantiomerically pure syn-N,N-ligand, i.e. ent-syn-ULTAM-(CH2)3Ph. DFT calculations of the transition state structures revealed an atypical two-pronged substrate attractive stabilization engaging the commonly encountered CH/π electrostatic interaction and a new additional O=S=O···HNAc H-bond hence favoring the trans-configured products.

Asymmetric transformations comprising a dynamic kinetic resolution (DKR) step are practically very attractive since both involved enantiomers of the stereolabile racemic substrate would ideally converge to a diastereo- and enantiomerically pure product.1,2 In particular, the DKR encountered in transition-metal-catalyzed reduction of ketones, such as in asymmetric transfer hydrogenation (ATH), is a powerful one-pot protocol for “deracemization” of substrates which possess a stereolabile α-carbon by converting them into alcohols having two contiguous stereogenic centers.2 A large number of these reductions are catalyzed by enantiomerically pure ansa-Ru(II)–[ent-trans-RSO2DPEN-(η6-arene)] complexes3 (Figure 1) in the HCO2H/Et3N binary mixture, which acts as both the H-source and an adequate “racemization medium” for the intermediate en route to the final product. The substrates scope for such DKR–ATH encompasses aryl,4 perfluoroalkyl,5 or acetylenic6 ketones as well as α-substituted benzocyclic ketones. Relevant to our present work are 2-Z-1-indanones and -tetralones wherein Z = alkyl, (het)aryl, F, Cl, CO2R′, SO2Ph, C(O)Ph, SO2NHPh, and CH(OH)CF3, which furnish predominantly the corresponding enantiomeric cis-configured products under these reaction conditions.7

Figure 1.

Figure 1

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Representative ATH-efficient ansa-Ru(II) complexes of tethered (R,R)-RSO2DPEN and η6-arene ligands.

Herein we present the exceptional highly trans-selective DKR–ATH of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones using a new chiral ansa-Ru(II) complex based on ent-syn-ULTAM N,N-ligand8 (Scheme 1). Such a complex has enhanced thermal stability compared to its nontethered-type version.9 In addition, the origin of the unexpected stereochemical outcome is investigated.

Scheme 1. Synthesis of the ansa-Ru(II) Complexes C4 and Active-C4 Based on the syn-(3R,1′S)-ULTAM Ligand.

Scheme 1

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The Ru(II) complex C4 (CCDC 1905532) and its catalyst active form (active-C4) were prepared starting from enantiomerically pure syn-(3R,1′S)-ULTAM ligand following our improved procedure5a of the general one introduced by Wills for C1.10 Accordingly, its selective mono-N-alkylation at rt led to the preligand 1 (79% yield), and the shelf-stable di-μ-chlorido Ru(II) dimer 2 was readily formed (75% yield) by heating at 65 °C, in EtOH, the 1·HCl with RuCl3 hydrate. Finally, the ansa-Ru(II)–Cl complex C4 was isolated in 43% yield by treatment of 2 with i-PrNEt2 in CH2Cl2 at rt; its structure was established by single-crystal X-ray diffraction. Conveniently, the catalyst ansa-Ru(II)–H active-C4 was generated in situ by stirring the Ru(II) dimer 2 at rt for 30 min in the HCO2H/Et3N medium. Alternatively, it can be generated similarly from C4.

We have initially surveyed the suitability of a selection of ansa-Ru(II) complexes (S/C = 500) for the DKR–ATH of the reference 2-acetamido-1-indenone substrate (S1) at 60 °C in a neat HCO2H/Et3N 3:2 mixture (Table1). S1 was prepared by the Erlenmeyer azlactone synthesis followed by Friedel–Crafts intramolecular acylation.11

Table 1. Screening of ansa-Ru(II) Complexes in DKR–ATH of 2-Acetamido-1-indenone (S1)a.

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entry active Ru(II) cat. cosolvent trans/cis ee (%) (trans)
1 C1 – 65:35 n.d.
2 C2 – 54:46 n.d.
3 C3 – 75:25 n.d.
4 C4 – 84:16 >99.9
5 C4 DMF 82:18 n.d.
6 C4 EtOH 84:16 n.d.
7 C4 EtOAc 87:13 n.d.
8 C4 (CH2Cl)2 90:10 >99.9
9 C4 toluene 91:9 >99.9
10 C4 PhCl 91:9 (>99)b >99.9
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a

ATH of S1 (187 mg, 1.0 mmol) was carried out at 60 °C using the Ru(II) cat. (S/C = 500, 2 μmol) prepared in situ from the corresponding di-μ-chlorido Ru(II) dimer in HCO2H/Et3N 3:2 (1 mL); with a cosolvent (1 mL), less HCO2H/Et3N 3:2 (0.5 mL) was used. Conversion (100% within 3 h) and the trans/cis ratio were determined by 1H NMR, and the ee of the trans-diastereomer was determined by chiral HPLC. n.d. = not determined.

b

After upgrading by trituration with MeCN of the crude (83% total yield).

The screening revealed the outperformance of the new Ru(II) catalyst active-C4 versus the ones based on the trans-(R,R)-RSO2DPEN-type N,N-ligands, leading to an increased trans/cis diastereomeric ratio (84:16) of the 2-acetamido-1-indanol product (P1) with a perfect enantioselectivity (>99.9% ee) for both diastereomers. A further improved diastereoselectivity of up to 91:9 was attained in the presence of less polar cosolvents such as 1,2-dichloroethane, toluene, or chlorobenzene (Table 1, entries 8–10). Noteworthy, conducting this two-step reduction process at 50 °C for 3 h led to the racemic 2-acetamido-1-indanone (rac-S1′) (by chiral HPLC) in 90% yield (by 1H NMR). Continued reduction at 60 °C afforded the stereoenriched β-acetamido alcohol P1, thus clearly validating the occurrence of a DKR during the keto function reduction step. Facile trituration with MeCN of the crude product gave the stereochemically pure trans-(1S,2S)-P1 (>99.9% ee) in 83% yield. The origin of this unusual and particularly high trans-selectivity of the Ru(II) catalyst active-C4 is addressed below. These results are interesting relative to the Rh(I)-catalyzed hydrogenation of S1 by the W. Zhang group.12

Following, the Ru(II) catalyst active-C4 was applied to the ATH of a diverse set of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones (S2–S9) (Figure 2). To our delight, the substituted 1-indenones S2–S5 were reduced quantitatively within 3 h using an S/C = 500 under our standard optimized conditions (HCO2H/Et3N 3:2 in chlorobenzene at 60 °C) affording high trans/cis ratios (from 87:13 up to 92:8) with >99% ee. Trituration with MeCN of the crude yielded the enantio- and diastereochemically pure products trans-(1S,2S)-P2–P5 (Figure 3). Furthermore, the never-before-reduced 2-acetamido-3-phenyl-1-indenone (S6) underwent DKR–ATH with 95% conversion delivering trans,trans-P6 in >99% ee as the major diastereomer (dr = 81:3:4:12). Interestingly, three contiguous stereogenic carbons were created in a one-pot procedure.7c Facile single recrystallization from EtOAc afforded the virtually enantio- and diastereochemically pure trans,trans-(1S,2S,3R)-P6 (>99% ee, dr >99); its absolute configuration was confirmed by single-crystal X-ray diffraction (CCDC 1905533). Such an attained high level of trans,trans-selectivity is the result of the bias efficiency of the Ru(II) catalyst active-C4 in the reduction step giving rise to a trans-configuration at C(1)–C(2), while the one at C(3) is thermodynamically driven.13

Figure 2.

Figure 2

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Benzocyclic ketones S1–S10 explored in Ru(II)-catalyzed DKR–ATH.

Figure 3.

Figure 3

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DKR–ATH products P2–P10 derived from the corresponding benzocyclic ketones S2–S10 of Figure 2. The enantio- and diastereochemically pure products (>99% ee, dr >99, 44–83% yield) were obtained by trituration with MeCN or recrystallization from EtOAc.

Next, the racemic 2-acetamido-1-acenaphthenone (rac-S7), prepared from acenaphthoquinone by Pd/C-catalyzed hydrogenation in Ac2O of the mono-oxime, was subjected to DKR–ATH. This ketone gave the trans-diastereomer in >98% ee with a somewhat lower trans/cis ratio (84:16). Nonetheless, trituration with MeCN yielded stereochemically pure trans-(S,S)-P7.

When the focus was shifted to racemic 2-acetamido-1-tetralones rac-S8 and rac-S9, prepared from the corresponding α-tetralone by treatment with isoamyl nitrite/KOt-Bu to form the 2-oxime and then Zn in AcOH/Ac2O reduction, their ATH resulted in >99% ee (trans) with 79:21 and 77:23 trans/cis ratios, respectively.14 Gratifyingly here again, trituration with MeCN furnished the enantio- and diastereomerically pure trans-(S,S)-P8 and -P9 products.

Finally, the reason for the high trans-selectivity obtained in the ATH with active-C4 was investigated. By now, it is well-established that the saturation of the keto function under [Ru(trans-TsDPEN)(η6-arene)]-catalyzed ATH occurs via a six-membered pericyclic transition state (TS) involving the Ru(II)–H catalyst hydride and a proton of the N,N-ligand amino group, while the stereoselectivity is influenced by the attractive CH/π electrostatic interaction between the η6-arene and the ketone aryl group.15

Considering the nonclassical Ru(II) catalyst active-C4 structure embedding a syn-configured N,N-ligand and the cosolvent effect observed when lowering the overall polarity of the reaction medium, we contemplated the existence of an additional attractive interaction with the substrate in the TS. Most likely, it consists of a H-bond between the AcN–H of the intermediate S1′ and a proximal O atom of the sulfonamido function of active-C4. Thus, with the aim to validate this assumption, ATH using active-C4 of the racemic 2-phthalimido-1-indanone (rac-S10) (an S1′ close analog lacking the NHC(O) function) and of the simple basic α-acetamidoacetone (a linear nonaryl ketonic substrate) were carried out. Indeed, rac-S10 converted into the expected cis-configured major product (1S,2R)-P10 with a 97:3 cis/trans ratio (94% ee for cis) (Scheme 2);16,17 this is due to the outward orientation of the phthalimido group in the TS thereby minimizing the sterics as with 2-Z-1-indanones of ref (7). In the case of α-acetamidoacetone, 1-acetamido-2-propanol was obtained in an er = 85:15. These findings support the presence of an additional favorable catalyst–substrate S1′ interaction in the TS being a H-bond between O=S=O···H–NAc.

Scheme 2. Strategy for trans- or cis-β-Amino-1-indanol Using Active-C4.

Scheme 2

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Moreover, the two most plausible TS geometries were located by applying DFT calculations in chlorobenzene: “trans-TS” whereby the H-transfer from active-C4 to enantiomeric intermediate (2S)-S1′ leads to trans-(1S,2S)-P1, and “cis-TS” whereby (2R)-S1′ is transformed into cis-(1S,2R)-P1 (Figure 4). These calculations predict the “trans-TS” to be favored over the “cis-TS” by Δ = 8.8 kcal mol–1 (Ea = 16.0 vs 24.8 kcal mol–1), which is in line with the experimentally observed high trans-diastereoselectivity.18 Thus, the “trans-TS” structure is stabilized by a two-pronged catalyst ligand–substrate attractive interaction: by the H-bond (2.12 Å) between O=S=O···H–NAc and by CH/π (T-shaped geometry) favoring the (2S)-configuration with an overall trans-selectivity. In the case of “cis-TS”, the geometry with a H-bond of 2.06 Å but with the lack of a CH/π interaction is the lowest in energy.

Figure 4.

Figure 4

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Schematic orientations of S1′ enantiomers with cat. Ru(II)–H active-C4 in their TS, and the corresponding energy level from DFT calculations in chlorobenzene.

The aforementioned DKR–ATH employing active-C4 can serve to selectively prepare either of enantiomerically pure trans- or cis-β-amino-1-indanol following the deprotection of enantiomerically pure trans-(1S,2S)-P1 or cis-(1S,2R)-P10 (Scheme 2).

In conclusion, we have introduced a new enantiomerically pure ansa-RuCl[syn-ULTAM-(CH2)3Ph] complex C4 and its Ru(II)–H active-C4. A diverse series of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones were reduced via DKR–ATH to the corresponding trans-β-amido alcohols P1–P9 with up to dr = 92:8 and excellent ee’s. Facile trituration with MeCN yielded the enantio- and diastereochemically pure trans-products. DFT calculations relative to the diastereomeric TS structures revealed the existence of an atypical two-pronged attractive stabilization by CH/π interaction and by the O=S=O···H–NAc H-bond favoring the trans-products. These enantiomerically pure β-amido alcohols are valuable building blocks and amenable to further elaboration. In particular, either stereochemically pure trans- or cis-β-amino-1-indanol (deprotected trans-P1 or deprotected cis-P10) can be selectively prepared using the same catalyst and procedure.

Acknowledgments

This work was supported by the Slovenian Research Agency (Grant P1-0242). We are also grateful to Dr. Barbara Modec from the University of Ljubljana for collecting the SC-XRD data of (1S,2S,3R)-P6.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01069.

  • Experimental data, chiral HPLC chromatograms, NMR spectra for prepared compounds, computational and SC-XRD details (PDF)

Accession Codes

CCDC 1905532–1905533 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Present Address

§ Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.

Author Present Address

∥ Department of Inorganic Chemistry and Technology, Jožef Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia, and Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.

Author Present Address

⊥ Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.

Author Present Address

∇ PhosPhoenix SARL, 115, rue de l’Abbé Groult, 75015 Paris, France.

The authors declare no competing financial interest.

Supplementary Material

ol9b01069_si_001.pdf (5.9MB, pdf)

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Supplementary Materials

ol9b01069_si_001.pdf (5.9MB, pdf)

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