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

Article abstract of DOI:10.1021/acs.orglett.9b01069

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/πelectrostatic interaction and a new additional O=S=O···HNAc H-bond hence favoring the trans-configured products.

Full text of DOI:10.1021/acs.orglett.9b01069

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
trans-Diastereoselective Ru(II)-Catalyzed Asymmetric Transfer
Hydrogenation of α‑Acetamido Benzocyclic Ketones via Dynamic
Kinetic Resolution
‡,∥
Andrej Emanuel Cotman,†,‡,§ Matic Lozinsek,
Baifan Wang,†,⊥ Michel Stephan,†,∇
̌
and Barbara Mohar*,†,∇
†National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
‡
̌
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia
S
* Supporting Information
ABSTRACT: A highly efficient enantio- and diastereoselec-
tive 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.
symmetric transformations comprising a dynamic kinetic
resolution (DKR) step are practically very attractive since
predominantly the corresponding enantiomeric cis-configured
products under these reaction conditions.7
A
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 (Fig-
ure 1) in the HCO2H/Et3N binary mixture, which acts as
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.
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.
Figure 1. Representative ATH-efficient ansa-Ru(II) complexes of
tethered (R,R)-RSO2DPEN and η6-arene ligands.
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
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
Received: March 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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%
Scheme 1. Synthesis of the ansa-Ru(II) Complexes C4 and
Active-C4 Based on the syn-(3R,1′S)-ULTAM Ligand
1
yield (by H 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
the Erlenmeyer azlactone synthesis followed by Friedel−Crafts
intramolecular acylation.11
Figure 2. Benzocyclic ketones S1−S10 explored in Ru(II)-catalyzed
DKR−ATH.
Table 1. Screening of ansa-Ru(II) Complexes in DKR−ATH
a
of 2-Acetamido-1-indenone (S1)
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 chlor-
obenzene 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
entry active Ru(II) cat.
cosolvent
trans/cis
65:35
ee (%) (trans)
1
2
3
4
5
6
7
8
9
C1
C2
C3
C4
C4
C4
C4
C4
C4
C4
−
−
−
−
n.d.
n.d.
n.d.
>99.9
n.d.
n.d.
n.d.
>99.9
>99.9
>99.9
54:46
75:25
84:16
82:18
84:16
87:13
90:10
91:9
DMF
EtOH
EtOAc
(CH2Cl)2
toluene
PhCl
b
10
91:9 (>99)
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
1
determined by H NMR, and the ee of the trans-diastereomer was
b
determined by chiral HPLC. n.d. = not determined. 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 diastereose-
lectivity of up to 91:9 was attained in the presence of less polar
cosolvents such as 1,2-dichloroethane, toluene, or chloroben-
zene (Table 1, entries 8−10). Noteworthy, conducting this
Figure 3. 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.
B
DOI: 10.1021/acs.orglett.9b01069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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
Scheme 2. Strategy for trans- or cis-β-Amino-1-indanol
Using Active-C4
Next, the racemic 2-acetamido-1-acenaphthenone (rac-S7),
prepared from acenaphthoquinone by Pd/C-catalyzed hydro-
genation 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
Figure 4. 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.
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.
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.
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 diaster-
eochemically pure trans-products. DFT calculations relative to
the diastereomeric TS structures revealed the existence of an
atypical two-pronged attractive stabilization by CH/π inter-
action 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
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
C
DOI: 10.1021/acs.orglett.9b01069
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cl complex or the initial di-μ-chlorido Ru(II) dimer is the precursor
of the corresponding Ru(II)−H active catalyst.
cis-P10) can be selectively prepared using the same catalyst
and procedure.
(4) Selected articles: (a) Seashore-Ludlow, B.; Saint-Dizier, F.;
Somfai, P. Org. Lett. 2012, 14, 6334−6337. (b) Xu, F.; Zacuto, M. J.;
Kohmura, Y.; Rosen, J.; Gibb, A.; Alam, M.; Scott, J.; Tschaen, D. Org.
Lett. 2014, 16, 5422−5425. (c) Son, S.-M.; Lee, H.-K. J. Org. Chem.
2014, 79, 2666−2681. (d) Monnereau, L.; Cartigny, D.; Scalone, M.;
Ayad, T.; Ratovelomanana-Vidal, V. Chem. - Eur. J. 2015, 21, 11799−
11806. (e) Sun, G.; Zhou, Z.; Luo, Z.; Wang, H.; Chen, L.; Xu, Y.; Li,
S.; Jian, W.; Zeng, J.; Hu, B.; Han, X.; Lin, Y.; Wang, Z. Org. Lett.
2017, 19, 4339−4342. (f) Xiong, Z.; Pei, C.; Xue, P.; Lv, H.; Zhang,
X. Chem. Commun. 2018, 54, 3883−3886.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01069.
■
S
Experimental data, chiral HPLC chromatograms, NMR
spectra for prepared compounds, computational and SC-
XRD details (PDF)
̌
(5) (a) Sterk, D.; Stephan, M.; Mohar, B. Org. Lett. 2006, 8, 5935−
5938. (b) Mohar, B.; Stephan, M.; Urleb, U. Tetrahedron 2010, 66,
4144−4149.
Accession Codes
CCDC 1905532−1905533 contain the supplementary crys-
tallographic 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.
(6) Fang, Z.; Wills, M. J. Org. Chem. 2013, 78, 8594−8605.
(7) For DKR−ATH of 2-Z-1-indanones and -tetralones wherein Z =
̌
́
alkyl, see: (a) Kisic, A.; Stephan, M.; Mohar, B. Adv. Synth. Catal.
2015, 357, 2540−2546. (b) Morris, J. C.; McErlean, C. S. P. Org.
Biomol. Chem. 2016, 14, 1236−1238. (c) Cotman, A. E.; Modec, B.;
Mohar, B. Org. Lett. 2018, 20, 2921−2924. For Z = het(aryl), see:
(d) Peach, P.; Cross, D. J.; Kenny, J. A.; Mann, I.; Houson, I.;
Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron 2006, 62, 1864−
1876. (e) Vyas, V. K.; Bhanage, B. M. Org. Lett. 2016, 18, 6436−6439.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: moharbarbara@yahoo.com.
ORCID
́
For Z = F or Cl, see: (f) Ros, A.; Magriz, A.; Dietrich, H.; Fernandez,
R.; Alvarez, E.; Lassaletta, J. M. Org. Lett. 2006, 8, 127−130. For Z =
̌
CO2Me, see: (g) Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron:
Asymmetry 2002, 13, 2605−2608. (h) Rast, S.; Modec, B.; Stephan,
M.; Mohar, B. Org. Biomol. Chem. 2016, 14, 2112−2120. For Z =
CO2Et, see: (i) Ros, A.; Magriz, A.; Dietrich, H.; Lassaletta, J. M.;
Andrej Emanuel Cotman: 0000-0003-2528-396X
̌
Matic Lozinsek: 0000-0002-1864-4248
́
Michel Stephan: 0000-0002-3781-4011
Barbara Mohar: 0000-0001-5393-7030
Fernandez, R. Tetrahedron 2007, 63, 7532−7537. For Z = SO2Ph,
see: (j) Ding, Z.; Yang, J.; Wang, T.; Shen, Z.; Zhang, Y. Chem.
Commun. 2009, 5, 571−573. For Z = SO2NHPh, see: (k) Geng, Z.;
Wu, Y.; Miao, S.; Shen, Z.; Zhang, Y. Tetrahedron Lett. 2011, 52,
907−909. For Z = C(O)Ph, see: (l) Wu, Y.; Geng, Z.; Bai, J.; Zhang,
Y. Chin. J. Chem. 2011, 29, 1467−1472. For Z = CH(OH)CF3, see:
(m) Cotman, A. E.; Cahard, D.; Mohar, B. Angew. Chem., Int. Ed.
2016, 55, 5294−5298.
Present Addresses
§
̌
̌
Faculty of Pharmacy, University of Ljubljana, Askerceva 7,
1000 Ljubljana, Slovenia.
Department of Inorganic Chemistry and Technology, Jozef
Stefan Institute, Jamova cesta 39, 1000 Ljubljana, Slovenia, and
Faculty of Chemistry and Chemical Technology, University of
∥
̌
(8) syn-ULTAM = syn-3-(α-aminobenzyl)-benzo-γ-sultam (acces-
sible in both enantiomeric forms). For its preparation, see:
(a) Refernce 7h. (b) Jeran, M.; Cotman, A. E.; Stephan, M.;
Mohar, B. Org. Lett. 2017, 19, 2042−2045.
(9) Noteworthy, ATH of benchmark substrates 1-indanone and α-
tetralone using our new tethered Ru(II)−[syn-(3R,1’S)-ULTAM-
(CH2)3Ph] complex (active-C4) with an S/C = 1000 at 60 °C was
complete within 4.5 h furnishing 98% ee (R) for both (see Supporting
Information), while with the nontethered complex [Ru(syn-(3R,1′S)-
ULTAM)(p-cymene)] with an S/C = 200 was required for full
conversion within 4 h at 40 °C giving 99% ee (R) for 1-indanol or 1-
tetralol.7h Note, this nontethered-type version has a short lifetime at
60 °C which is unsuitable for the quantitative CC and CO
reductions of S1.
(10) Jolley, K. E.; Zanotti-Gerosa, A.; Hancock, F.; Dyke, A.;
Grainger, D. M.; Medlock, J. A.; Nedden, H. G.; Le Paih, J. J. M.;
Roseblade, S. J.; Seger, A.; Sivakumar, V.; Prokes, I.; Morris, D. J.;
Wills, M. Adv. Synth. Catal. 2012, 354, 2545−2555.
(11) Zhang, Z.; Hu, Q.; Wang, Y.; Chen, J.; Zhang, W. Org. Lett.
2015, 17, 5380−5383.
(12) By contrast, asymmetric hydrogenation of S1 catalyzed by 1%
Rh(I)-(3H-QuinoxP*) in dioxane proceeded stereoselectively in the
absence of DKR with reduction of only the CC bond at 3 atm of
H2 (92% ee for S1′), or both CC and CO under 20 atm of H2
(trans/cis = 93:7, 94% ee for trans-P1). For this, see: Hu, Q.; Chen, J.;
Zhang, Z.; Liu, Y.; Zhang, W. Org. Lett. 2016, 18, 1290−1293.
(13) Noteworthy, under DKR−ATH (using Ru(II) cat. active-C4)
of 2-methoxycarbonyl-3-phenyl-1-indanone (keto/enol = 88:12) and
2,3-diphenyl-1-indenone leading to dr = 57:43:0:0 (quant, 97% ee for
major, >99% ee for minor) and 34:41:25:0 (quant), respectively, very
̌
Ljubljana, Vecna pot 113, 1000 Ljubljana, Slovenia.
⊥Department of Chemistry and Chemical Biology, Rutgers
University, Piscataway, NJ 08854, USA.
PhosPhoenix SARL, 115, rue de l’Abbe Groult, 75015 Paris,
France.
Notes
∇
́
The authors declare no competing financial interest.
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.
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■
̈
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D
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Letter
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(14) In the literature, stereochemically pure trans-(R,R)-P8 was
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acylation of (R)-homotyrosine followed by diastereoselective
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ee was obtained employing the PipSO2DPEN-based catalyst active-
C3.
(18) Gas-phase DFT calculations similarly predicted the “trans-TS”
to be favored over the “cis-TS” by Δ = 7.3 kcal mol−1 (Ea = 11.1 vs
18.4 kcal mol−1).
E
DOI: 10.1021/acs.orglett.9b01069
Org. Lett. XXXX, XXX, XXX−XXX