Asymmetric Transfer Hydrogenation of α-Substituted-β-Keto Carbonitriles via Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/jacs.0c13273

A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-β-keto carbonitriles is described. The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with two contiguous stereogenic centers. A wide range of α-substituted-β-keto carbonitriles were obtained in high yields (94%-98%) and excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of Ipenoxazone and Tapentadol.

Full text of DOI:10.1021/jacs.0c13273

pubs.acs.org/JACS
Communication
Asymmetric Transfer Hydrogenation of α‑Substituted-β-Keto
Carbonitriles via Dynamic Kinetic Resolution
Fangyuan Wang, Tilong Yang, Ting Wu, Long-Sheng Zheng, Congcong Yin, Yongjie Shi, Xiang-Yu Ye,
Gen-Qiang Chen,* and Xumu Zhang*
Cite This: J. Am. Chem. Soc. 2021, 143, 2477−2483
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A catalytic protocol for the enantio- and diastereoselective reduction of α-substituted-β-keto carbonitriles is
described. The reaction involves a DKR-ATH process with the simultaneous construction of β-hydroxy carbonitrile scaffolds with
two contiguous stereogenic centers. A wide range of α-substituted-β-keto carbonitriles were obtained in high yields (94%−98%) and
excellent enantio- and diastereoselectivities (up to >99% ee, up to >99:1 dr). The origin of the diastereoselectivity was also
rationalized by DFT calculations. Furthermore, this methodology offers rapid access to the pharmaceutical intermediates of
Ipenoxazone and Tapentadol.
hiral β-hydroxy carbonitriles are undoubtedly valuable
catalysts.32 Since then, the utility of reductive DKR processes
Csynthons in organic synthesis, since the cyano group is a has been further accentuated by taking advantage of
versatile precursor of amino, carbonyl, and amide groups.1−6 In
asymmetric transfer hydrogenation (ATH) with bifunctional
Ru, Rh, and Ir catalysts containing chiral N-sulfonyl-1,2-
addition, enantiomerically pure α-substituted-β-hydroxy car-
bonitrile derivatives such as 1,2-amino alcohol7−11 and 1,3-
amino alcohol12 are highly important and fundamental motifs
found in a wide variety of biologically active compounds,13,14
pharmaceuticals,15−17 chiral auxiliaries,18,19 and chiral li-
gands20−23 in asymmetric synthesis (Figure 1). In this regard,
the development of efficient method for the synthesis of these
compounds is of high significance.
diamine scaffolds.33−47
In the past few decades, tremendous attention has been
drawn to the diastereoselective construction of α-substituted-
β-hydroxy carbonitriles and many distinct approaches have
been established.48−50 Anti-selective aldol condensation
between lithiated nitriles and aldehydes provides a straightfor-
ward strategy for the construction of α-substituted-β-hydroxy
carbonitriles.51,52 However, the stereochemical outcome of the
aldol condensation is hardly controllable; a significant decrease
in selectivity is observed for linear aliphatic aldehydes. In 2001,
an efficient diastereoselective reduction of α-alkyl-β-keto
carbonitriles with TiCl4/BH3 or LiBH4/CeCl3 was reported
by Dalpozzo and co-workers, and low temperature was
necessary to achieve high diastereoselectivity (Figure 2a).53
Direct dynamic kinetic asymmetric reduction of α-substituted-
β-keto carbonitriles represents one of the most straightforward
methods for the synthesis of chiral α-substituted-β-keto
carbonitriles. Unlike other α-substituted-β-carbonyl com-
pounds, the catalytic asymmetric reduction of α-substituted-
β-keto carbonitriles has been rarely reported.7,54 In 2016,
Romano and co-workers reported the enzyme-catalyzed
reduction of α-substituted-β-keto carbonitriles, albeit with a
low yield and narrow substrate scope (Figure 2b).55 The only
example of transition-metal-catalyzed asymmetric transfer
hydrogenation was reported by Rimoldi and co-workers in
Figure 1. Examples of biologically active pharmaceuticals, chiral
ligands, and organocatalysts that can be synthesized from β-hydroxy
carbonitriles derivatives.
To date, dynamic kinetic resolution (DKR) has become an
active and important area of research in organic synthesis.
Asymmetric transformations comprising DKR processes are
very attractive since racemic substrates converge ideally to a
diastereo- and enantiomerically pure product in this trans-
formation.24−26 In particular, the DKR encountered in
asymmetric transfer hydrogenation (ATH) of ketones is a
powerful protocol for “deracemization” of substrates, which
possess a stereolabile α-carbon by converting them into
alcohols with two contiguous stereogenic centers.27−31 In
1989, Noyori and co-workers reported trailblazing work on the
asymmetric hydrogenation of β-keto esters using Ru−BINAP
Received: December 23, 2020
Published: February 2, 2021
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483
© 2021 American Chemical Society
2477

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Table 1. Optimization of the Reaction Conditions for the
b
DKR-ATH of 1a
Figure 2. (a−c) Previous work. (d) DKR-ATH of α-substituted-β-
keto carbonitriles.
2014; however, the enantio- and diastereoselectivity were
unsatisfactory (Figure 2c).56 As a consequence, developing
efficient synthetic routes to prepare chiral α-substituted-β-
hydroxy carbonitriles is still highly desirable. Due to the
presence of a cyano group, it is easy for the cyano group to
participate in coordination and deactivate the catalyst in
transition-metal-catalyzed hydrogenation (see Tables S1 and
S2 in the Supporting Information). To date, the DKR-ATH
strategy in reduction of α-substituted-β-keto carbonitriles
remains relatively unexplored. Herein, we disclosed an
advantageous asymmetric transfer hydrogenation of α-sub-
stituted-β-keto carbonitriles via DKR that enables formation of
α-substituted -β-hydroxy carbonitriles with high yields and
high enantio- and diastereoselectivities (up to >99% ee, up to
>99:1 dr) as well as its synthetic application in key
intermediates of Ipenoxazone and Tapentadol (Figure 2d).
We commenced our investigation by the optimization of the
reaction conditions with racemic α-methyl-β-keto carbonitriles
1a as the model substrate, and the results were depicted in
Table 1. We initially examined the transfer hydrogenation of 1a
using the commercially available TsDPEN-derived Ru, Rh, and
Ir complexes (1 mol %) in an azeotropic mixture of formic acid
and triethylamine at 25 °C in DCM; >99% conversions were
observed for all the catalyst utilized (entries 1−3). 75% ee and
66:33 dr were achieved with Noyori’s catalyst (R,R)-cat.1. The
catalyst (S,S)-cat.2 could give 2a with 98% ee albeit with only
76:24 dr. Only 48% ee was achieved for (S,S)-cat.3. Then, the
tethered catalysts were examined (entries 4−6). 94% ee, 65:35
dr, and 92% ee and 37:63 dr were achieved with the tethered
ruthenium catalyst (R,R)-cat.557 and (R,R)-cat.658 respec-
tively. To our great delight, the catalytic selectivity of tethered
rhodium catalyst (R,R)-cat.459 outperformed that of the
catalysts previously evaluated, providing (2S,3R)-α-methyl-β-
hydroxy carbonitriles 2a with >99% ee and 93:7 dr in an anti-
selective manner (entry 4).
a
Unless otherwise specified, the reactions were carried out with
catalyst/substrate (0.2 mmol) ratio of 1: 100 in 2 mL of solvent,
HCOOH/Et3N azeotropic mixture (50 μL) at 25 °C for 12 h.
b
d
f
c
HCOOH/Et3N (3:2) (50 μL). HCOOH/Et3N (1:1) (50 μL)
e
HCOOH/DBU (1:1) (50 μL). HCOOH/DIPEA (1:1) (50 μL).
The reactions were carried out with a catalyst/substrate (0.2 mmol)
g
ratio of 1:100 in 2 mL of IPA at 80 °C for 12 h. The reactions were
carried out with a catalyst/substrate (0.2 mmol) ratio of 1:100 in 2.0
mL of IPA/H2O (1.0 mL/1.0 mL), HCOONa (5 equiv), at 60 °C for
12 h. Conversions (conv.) were determined by H NMR analysis.
Enantiomeric excesses (ee) and diastereomeric ratios (dr) were
determined by HPLC analysis using a chiral stationary phase. DBU
refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; DIPEA refers to N,N-
diisopropylethylamine.
1
With the preliminary results in hand, we further examined
the effect of the solvents and the ratio of formic acid and
triethylamine on the reaction (Table 1). The solvents played
an important role in this catalytic transformation. When
MeOH and IPA were used as the solvent, 24% and 65%
conversion, 93:7 and 94:6 dr were obtained respectively
(entries 7 and 8). In contrast, when THF, 1,4-dioxane, DCM,
and EA were employed, the conversions were complete and
2478
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Scheme 1. Substrate Scope of the DKR-ATH
a
Unless otherwise specified, the reactions were carried out with catalyst/substrate (0.2 mmol) ratio of 1:100 in 2 mL of toluene, HCOOH/Et3N
1
azeotropic mixture (50 μL) at 25 °C for 12 h. Conversions (conv.) were determined by H NMR analysis. Enantiomeric excesses (ee) and
diastereomeric ratio (dr) were determined by HPLC analysis using a chiral stationary phase.
91:9 to 93:7 dr were achieved (entries 9−12). For the polar
aprotic solvent DMF, only 85% conversion and 85:15 dr value
were obtained (entry 13). With the nonpolar aprotic solvent,
hexane, the conversion was very low (entry 14, <5% conv).
Pleasingly, when toluene was used in the transformation,
excellent enantio- and diastereoselectivity were obtained
2479
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(>99% ee, 96:4 dr). In addition, different ratios of triethyl-
amine and formic acid were investigated in toluene. When a
mixture of HCOOH/Et3N (3:2) or HCOOH/Et3N (1:1) was
used, lower conversion and diastereoselectivity were observed
(entries 16 and 17). Further investigation with DBU and
DIPEA in place of Et3N still yielded only moderate conversion
and diastereoselectivity (entries 18 and 19). Finally, two other
hydrogen donors were also investigated, but the activity of the
reactions was very poor (entries 20 and 21, <5% conv). The
optimal reaction conditions included (R,R)-cat.4 as catalyst,
toluene as solvent, and the azeotropic mixture of HCOOH/
Et3N as the hydrogen donor (entry 15).
Figure 3. Calculated transition states for the anti- and syn- products.
The hydrogen bonding distances are shown in Å.
Following the optimization of reaction conditions, we turned
our attention to the investigation of the substrate generality of
this DKR-ATH, and the results are illustrated in Scheme 1.
Substrates with different alkyl or aryl groups on the α position
were synthesized and subjected to the standard reaction
conditions, and the reaction proceeded smoothly to provide
the desired anti-product with high yields, excellent enantiose-
lectivities and diastereoselectivities (2a−2g, 97%−98% yield,
96:4−99:1 dr, 98%−>99% ee). Next, we evaluated the effect of
the substituents on the β position. Functional groups, such as
halides (2h−2j), trifluoromethyl (2k), methyl (2l), and
methoxy (2m) at the para position of the phenyl group were
compatible with this transformation (97%−99% yield, 98:2−
99:1 dr, 98% −>99% ee). Substrates with meta-substitution on
the phenyl group were also tolerated, and 99:1 and 95:5 dr
values were obtained respectively (2n, 2o). Moderate
enantioselectivity was obtained for the ortho-fluoro substrate,
and syn-product was produced instead of the anti-product (2p,
95% yield, 95:5 dr, and 71% ee). Moreover, the product 2q
with both the para and meta methoxy groups on the phenyl
ring was obtained with >99% ee and 99:1 dr. The current
reaction also tolerates substrates bearing 2-naphthyl, thienyl, 2-
furanyl, 2-pyridyl, and 2-indolyl groups on the β position (2r−
2u, 96%−98% yield, 90:10−>99:1 dr, >99% ee). The cyclic
compounds 1w and 1x were also suitable substrates for the
current reaction, as >99% ee and >99:1 dr were observed in
both cases (2w, 2x). Finally, the reaction of 1y and 1z, with
different β-alkyl groups (methyl and ethyl), could give anti-
products 2y and 2z with excellent enantioselectivity (>99%
ee), 93:7 dr and 81:19 dr, respectively. The absolute
configuration of 2b, 2o, 2p, and 2y was unambiguously
determined by X-ray crystallography.
With the general scope of the transformation established, we
sought to demonstrate the synthetic utilities of this method-
ology. Scheme 2 depicts 2-g-scale transformations that were
Scheme 2. Gram Scale Synthetic Utilities of the DKR-ATH
The two enantiomers of 1a could interconvert with each
other under the standard reaction conditions, and the
difference in the reactivity of the two enantiomers is the key
factor for the DKR process. In order to understand the
mechanism of DKR and rationalize the origin of diaster-
eoselectivity observed in this transformation, we calculated the
transition states for the anti- and syn- products. As shown in
Figure 3, the edge-to-face interaction between the η5-arene
fragment of the ligand and the aryl group of the substrate can
stabilize the transition state for the ketone reduction process.60
The tosyl group in the cat.4 can affect the diastereoselectivity
through its hydrogen bonding with the substrate 1a. The
hydrogen bonding strength is expected to be stronger in TSanti
(the donor−acceptor distance is 2.225 Å) than that in TSsyn
(the donor−acceptor distance is 2.274 Å), because of its
shorter donor−acceptor distance. The TSanti is calculated to be
more stable than TSsyn with the free energy difference at 2.3
kcal/mol (the electronic energy difference is 2.9 kcal/mol),
suggesting that the anti-product 2a is the major product.
conducted. First, under the standard conditions, gram-scale 1d
was converted to the desired product (S,S)-2d in 99% yield,
>99% ee, and 99:1 dr. The target product 4d was obtained in
high yield with undiminished enantioselectivity (>99% ee)
after platinum-catalyzed hydration61 and simultaneous Hoff-
man degradation and ring-closing cascade.62 Notably, the
chiral compound 4d can be transformed into Ipenoxazone in
just one step according to the reported procedure (Scheme
2a).63 The DKR-ATH reaction of 1o was also conducted on a
gram scale, and 2o was obtained with 98% yield, 99% ee, and
95:5 dr. The dr value could be increased to 99:1 after a simple
recrystallization. Subsequent reduction of the cyano group with
LiAlH4, N-methylation with formalin, and oxidation with Dess-
Martin periodinane proceeded smoothly to give the vital
intermediate 6o in high yield. Tapentadol can be easily
2480
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
accessed via intermediate 6o according to the reported
procedure (Scheme 2b).64
Yongjie Shi − Department of Chemistry, Southern University
of Science and Technology, Shenzhen, People’s Republic of
China
Xiang-Yu Ye − Department of Chemistry, Southern University
of Science and Technology, Shenzhen, People’s Republic of
China; orcid.org/0000-0002-7299-5815
In summary, we have successfully developed a highly
efficient dynamic kinetic resolution strategy for the asymmetric
transfer hydrogenation of β-keto carbonitriles, providing the
corresponding α-substituted-β-keto carbonitriles with high
enantio- and diastereoselectivities (up to >99% ee and up to
>99:1 dr). The origin of the diastereoselectivity was also
rationalized by DFT calculations. In addition, the synthetic
utilities of the transformation were demonstrated by the gram-
scale synthesis of key intermediates of Ipenoxazone and
Tapentadol. Further synthetic applications and theoretical
investigations on the current transformations are underway in
our laboratory, and the results will be reported in due course.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13273
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
X.Z. is indebted to Southern University of Science and
Technology (start-up fund), Shenzhen Science and Technol-
ogy Innovation Committee (Nos. KQTD20150717103157174
and JSGG20170821140353405), Key-Area Research and
Development Program of Guangdong Province (No.
2020B010188001), Innovative Team of Universities in
Guangdong Province (No. 2020KCXTD016), and National
Natural Science Foundation of China (No. 21991113).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13273.
Experimental procedures, spectral data, and NMR
spectra for all compounds (PDF)
Accession Codes
REFERENCES
■
CCDC 2013113, 2013116, 2013520, 2013878, and 2015445
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.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.
(1) Seo, M. H.; Lee, Y. Y.; Goo, Y. M. A new method for the
preparation of β-hydroxy nitriles; transformation of 3-bromo-2-
isoxazolines to β-hydroxy nitriles by treatment of alkanethiolates.
Synth. Commun. 1994, 24, 1433−1439.
(2) Wade, P. A.; Bereznak, J. F. Sulfonylisoxazolines: reliable
intermediates for the preparation of β-hydroxy nitriles. J. Org. Chem.
1987, 52, 2973−2977.
(3) Ankati, H.; Zhu, D.; Yang, Y.; Biehl, E. R.; Hua, L. Asymmetric
synthesis of both antipodes of β-hydroxy nitriles and beta-hydroxy
carboxylic acids via enzymatic reduction or sequential reduction/
hydrolysis. J. Org. Chem. 2009, 74, 1658−1662.
AUTHOR INFORMATION
■
Corresponding Authors
̀
̈
(4) Pamies, O.; Backvall, J.-E. Efficient Lipase-Catalyzed Kinetic
Resolution and Dynamic Kinetic Resolution of β-Hydroxy Nitriles.
Correction of Absolute Configuration and Transformation to Chiral
β-Hydroxy Acids and γ-Amino Alcohols. Adv. Synth. Catal. 2002, 344,
947−952.
Gen-Qiang Chen − Shenzhen Grubbs Institute, Department of
Chemistry, and Academy for Advanced Interdisciplinary
Studies, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0003-2276-
6800; Email: chengq@sustech.edu.cn
Xumu Zhang − Shenzhen Grubbs Institute and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0001-5700-
0608; Email: zhangxm@sustech.edu.cn
(5) Kanda, T.; Naraoka, A.; Naka, H. Catalytic Transfer Hydration
of Cyanohydrins to α-Hydroxyamides. J. Am. Chem. Soc. 2019, 141,
825−830.
(6) Norder, A.; Warren, S. A.; Herdtweck, E.; Huber, S. M.; Bach, T.
Diastereotopos-differentiation in the Rh-catalyzed amination of
benzylic methylene groups in the α-position to a stereogenic center.
J. Am. Chem. Soc. 2012, 134, 13524−13531.
Authors
(7) Kamal, A.; Khanna, G. B.; Krishnaji, T.; Ramu, R. A new facile
chemoenzymatic synthesis of levamisole. Bioorg. Med. Chem. Lett.
2005, 15, 613−615.
(8) Zandbergen, P.; Brussee, J.; van der Gen, A.; Kruse, C. G.
Stereoselective synthesis of β-hydroxy-α-amino acids from chiral
cyanohydrins. Tetrahedron: Asymmetry 1992, 3, 769−774.
(9) Lu, W.; Chen, P.; Lin, G. New stereoselective synthesis of
thiamphenicol and florfenicol from enantiomerically pure cyanohy-
drin: a chemo-enzymatic approach. Tetrahedron 2008, 64, 7822−
7827.
(10) Schwarz, J. L.; Kleinmans, R.; Paulisch, T. O.; Glorius, F. 1,2-
Amino Alcohols via Cr/Photoredox Dual-Catalyzed Addition of α-
Amino Carbanion Equivalents to Carbonyls. J. Am. Chem. Soc. 2020,
142, 2168−2174.
(11) Meng, J.; Gao, M.; Lv, H.; Zhang, X. Highly enantioselective
hydrogenation of omicron-alkoxy tetrasubstituted enamides catalyzed
by a Rh/(R,S)-JosiPhos catalyst. Org. Lett. 2015, 17, 1842−1845.
(12) Facchetti, G.; Gandolfi, R.; Fuse, M.; Zerla, D.; Cesarotti, E.;
Pellizzoni, M.; Rimoldi, I. Simple 1,3-diamines and their application as
Fangyuan Wang − School of Chemistry and Chemical
Engineering, Harbin Institute of Technology, Harbin, People’s
Republic of China; Department of Chemistry, Southern
University of Science and Technology, Shenzhen, People’s
Republic of China
Tilong Yang − Department of Chemistry, Southern University
of Science and Technology, Shenzhen, People’s Republic of
China; orcid.org/0000-0002-9126-8840
Ting Wu − College of Innovation and Entrepreneurship,
Southern University of Science and Technology, Shenzhen,
People’s Republic of China
Long-Sheng Zheng − Department of Chemistry, Southern
University of Science and Technology, Shenzhen, People’s
Republic of China
Congcong Yin − Department of Chemistry, Southern
University of Science and Technology, Shenzhen, People’s
Republic of China
2481
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
ligands in ruthenium(II) catalysts for asymmetric transfer hydro-
genation of aryl ketones. New J. Chem. 2015, 39, 3792−3800.
(13) Gohil, V. M.; Sheth, S. A.; Nilsson, R.; Wojtovich, A. P.; Lee, J.
H.; Perocchi, F.; Chen, W.; Clish, C. B.; Ayata, C.; Brookes, P. S.;
Mootha, V. K. Nutrient-sensitized screening for drugs that shift
energy metabolism from mitochondrial respiration to glycolysis. Nat.
Biotechnol. 2010, 28, 249−255.
(14) Woo, J. C. S.; Cui, S.; Walker, S. D.; Faul, M. M. Asymmetric
syntheses of a GPR40 receptor agonist via diastereoselective and
enantioselective conjugate alkynylation. Tetrahedron 2010, 66, 4730−
4737.
(15) Bandyopadhyay, A.; Malik, A.; Kumar, M. G.; Gopi, H. N.
Exploring β-hydroxy γ-amino acids (statines) in the design of hybrid
peptide foldamers. Org. Lett. 2014, 16, 294−297.
(16) Pohjala, L.; Utt, A.; Varjak, M.; Lulla, A.; Merits, A.; Ahola, T.;
Tammela, P. Inhibitors of alphavirus entry and replication identified
with a stable Chikungunya replicon cell line and virus-based assays.
PLoS One 2011, 6, No. e28923.
(17) Kim, Y.; Ha, H. J.; Yun, S. Y.; Lee, W. K. The preparation of
stable aziridinium ions and their ring-openings. Chem. Commun. 2008,
4363−4365.
(18) Murakami, K.; Sasano, Y.; Tomizawa, M.; Shibuya, M.; Kwon,
E.; Iwabuchi, Y. Highly enantioselective organocatalytic oxidative
kinetic resolution of secondary alcohols using chiral alkoxyamines as
precatalysts: catalyst structure, active species, and substrate scope. J.
Am. Chem. Soc. 2014, 136, 17591−17600.
(19) Sarabia, F.; Vivar-Garcia, C.; Garcia-Castro, M.; Martin-Ortiz, J.
Cyclic sulfur ylides derived from Gleason-type chiral auxiliaries for the
asymmetric synthesis of epoxy amides. J. Org. Chem. 2011, 76, 3139−
3150.
(20) Pradeep, C. P.; Das, S. K. Coordination and supramolecular
aspects of the metal complexes of chiral N-salicyl-β-amino alcohol
Schiff base ligands: Towards understanding the roles of weak
interactions in their catalytic reactions. Coord. Chem. Rev. 2013,
257, 1699−1715.
drogenation of alpha-Acetamido Benzocyclic Ketones via Dynamic
Kinetic Resolution. Org. Lett. 2019, 21, 3644−3648.
(32) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura,
M.; Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.;
Kumobayashi, H. Stereoselective hydrogenation via dynamic kinetic
resolution. J. Am. Chem. Soc. 1989, 111, 9134−9135.
(33) Steward, K. M.; Corbett, M. T.; Goodman, C. G.; Johnson, J. S.
Asymmetric synthesis of diverse glycolic acid scaffolds via dynamic
kinetic resolution of alpha-keto esters. J. Am. Chem. Soc. 2012, 134,
20197−20206.
(34) Kumaraswamy, G.; Narayana Murthy, A.; Narayanarao, V.;
Vemulapalli, S. P.; Bharatam, J. Enantioselective synthesis of delta-/
gamma-alkoxy-beta-hydroxy-alpha-alkyl-substituted Weinreb amides
via DKR-ATH: application to the synthesis of advanced intermediate
of (−)-brevisamide. Org. Biomol. Chem. 2013, 11, 6751−6765.
(35) Kumaraswamy, G.; Narayanarao, V.; Shanigaram, P.;
Balakishan, G. Diastereoselective synthesis of an advanced inter-
mediate of the crocacin family using asymmetric transfer hydro-
genation-DKR and Marshall allenylation as key reactions. Tetrahedron
2015, 71, 8960−8964.
(36) Fang, L.; Liu, S.; Han, L.; Li, H.; Zhao, F. Ruthenium-Catalyzed
Synthesis of cis-2,3-Dihydrobenzofuran-3-ols by Aqueous Transfer
Hydrogenation via Dynamic Kinetic Resolution. Organometallics
2017, 36, 1217−1219.
(37) Jeran, M.; Cotman, A. E.; Stephan, M.; Mohar, B. Stereopure
Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic
Kinetic Resolution-Asymmetric Transfer Hydrogenation. Org. Lett.
2017, 19, 2042−2045.
(38) 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. Highly
Enantioselective Synthesis of syn-beta-Hydroxy alpha-Dibenzylamino
Esters via DKR Asymmetric Transfer Hydrogenation and Gram-Scale
Preparation of Droxidopa. Org. Lett. 2017, 19, 4339−4342.
(39) Zheng, D.; Zhao, Q.; Hu, X.; Cheng, T.; Liu, G.; Wang, W. A
dynamic kinetic asymmetric transfer hydrogenation-cyclization
tandem reaction: an easy access to chiral 3,4-dihydro-2H-pyran-
carbonitriles. Chem. Commun. 2017, 53, 6113−6116.
(40) Kim, H. R.; Achary, R.; Lee, H. K. DBU-Promoted Dynamic
Kinetic Resolution in Rh-Catalyzed Asymmetric Transfer Hydro-
genation of 5-Alkyl Cyclic Sulfamidate Imines: Stereoselective
Synthesis of Functionalized 1,2-Amino Alcohols. J. Org. Chem.
2018, 83, 11987−11999.
(41) Zheng, L. S.; Ferard, C.; Phansavath, P.; Ratovelomanana-Vidal,
V. Rhodium-mediated asymmetric transfer hydrogenation: a diaster-
eo- and enantioselective synthesis of syn-alpha-amido beta-hydroxy
esters. Chem. Commun. 2018, 54, 283−286.
(42) Rolt, A.; O’Neill, P. M.; Liang, T. J.; Stachulski, A. V. Synthesis
of MeBmt and related derivatives via syn-selective ATH-DKR. RSC
Adv. 2019, 9, 40336−40339.
(43) Luo, Z.; Wang, Z.; Sun, G.; Jian, W.; Jiang, F.; Luan, B.; Li, R.;
Zhang, L. Ruthenium-Catalyzed Highly Enantioselective Synthesis of
cis-3-Quinuclidinols via DKR Asymmetric Transfer Hydrogenation.
Org. Lett. 2020, 22, 4322−4326.
(44) Fan, D.; Liu, Y.; Jia, J.; Zhang, Z.; Liu, Y.; Zhang, W. Synthesis
of Chiral α-Aminosilanes through Palladium-Catalyzed Asymmetric
Hydrogenation of Silylimines. Org. Lett. 2019, 21, 1042−1045.
(45) Vyas, V. K.; Clarkson, G. J.; Wills, M. Sulfone Group as a
Versatile and Removable Directing Group for Asymmetric Transfer
Hydrogenation of Ketones. Angew. Chem., Int. Ed. 2020, 59, 14265−
14269.
(46) Westermeyer, A.; Guillamot, G.; Phansavath, P.;
Ratovelomanana-Vidal, V. Synthesis of Enantioenriched β-Hydroxy-
γ-Acetal Enamides by Rhodium-Catalyzed Asymmetric Transfer
Hydrogenation. Org. Lett. 2020, 22, 3911−3914.
(47) Vyas, V. K.; Bhanage, B. M. Kinetic Resolution Driven
Diastereo- and Enantioselective Synthesis of cis-β-Heteroaryl Amino
Cycloalkanols by Ruthenium-Catalyzed Asymmetric Transfer Hydro-
genation. Org. Lett. 2016, 18, 6436−6439.
(21) Pu, L.; Yu, H. B. Catalytic asymmetric organozinc additions to
carbonyl compounds. Chem. Rev. 2001, 101, 757−824.
(22) Zahrt, A. F.; Athavale, S. V.; Denmark, S. E. Quantitative
Structure-Selectivity Relationships in Enantioselective Catalysis: Past,
Present, and Future. Chem. Rev. 2020, 120, 1620−1689.
(23) Beletskaya, I. P.; Najera, C.; Yus, M. Stereodivergent Catalysis.
Chem. Rev. 2018, 118, 5080−5200.
(24) Zhang, Y.; Zhang, Y.; Ramstrom, O. Dynamic covalent kinetic
resolution. Catal. Rev.: Sci. Eng. 2020, 62, 66−95.
(25) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in
Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-
Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and
Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117,
4528−4561.
(26) Seo, C. S. G.; Morris, R. H. Catalytic Homogeneous
Asymmetric Hydrogenation: Successes and Opportunities. Organo-
metallics 2019, 38, 47−65.
(27) Steward, K. M.; Gentry, E. C.; Johnson, J. S. Dynamic kinetic
resolution of alpha-keto esters via asymmetric transfer hydrogenation.
J. Am. Chem. Soc. 2012, 134, 7329−7332.
(28) Krabbe, S. W.; Johnson, J. S. Asymmetric total syntheses of
megacerotonic acid and shimobashiric acid A. Org. Lett. 2015, 17,
1188−1191.
(29) Ratovelomanana-Vidal, V.; Phansavath, P.; Echeverria, P.-G.;
Ayad, T. Recent Developments in Asymmetric Hydrogenation and
Transfer Hydrogenation of Ketones and Imines through Dynamic
Kinetic Resolution. Synthesis 2016, 48, 2523−2539.
(30) Vyas, V. K.; Bhanage, B. M. Ru-Prolinamide-Catalyzed
Asymmetric Transfer Hydrogenation of Racemic β-Heterosubstituted
Cycloalkanones Driven by Dynamic Kinetic Resolution. Asian J. Org.
Chem. 2018, 7, 346−349.
(31) Cotman, A. E.; Lozinsek, M.; Wang, B.; Stephan, M.; Mohar, B.
trans-Diastereoselective Ru(II)-Catalyzed Asymmetric Transfer Hy-
2482
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(48) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M.
Direct catalytic aldol-type reactions using RCH2CN. Org. Lett. 2003,
5, 3147−3150.
(49) Goto, A.; Endo, K.; Ukai, Y.; Irle, S.; Saito, S. Rh(I)-catalyzed
aldol-type reaction of organonitriles under mild conditions. Chem.
Commun. 2008, 2212−2214.
(50) Chakraborty, S.; Patel, Y. J.; Krause, J. A.; Guan, H. A robust
nickel catalyst for cyanomethylation of aldehydes: activation of
acetonitrile under base-free conditions. Angew. Chem., Int. Ed. 2013,
52, 7523−7526.
(51) Zhou, J. J. P.; Zhong, B.; Silverman, R. B. Improved Procedure
for the Synthesis of Substituted β-Hydroxy Nitriles. J. Org. Chem.
1995, 60, 2261−2262.
(52) Carlier, P. R.; Lo, K. M.; Lo, M. M. C.; Lo, P. C. K.; Lo, C. W.
S. Synthetic Optimization and Structural Limitations of the Nitrile
Aldol Reaction. J. Org. Chem. 1997, 62, 6316−6321.
(53) Dalpozzo, R.; Bartoli, G.; Bosco, M.; De Nino, A.; Procopio, A.;
Sambri, L.; Tagarelli, A. An Efficient Diastereoselective Reduction of
α-Alkyl-β-keto Carbonitriles with TiCl4/BH3 or LiBH4/CeCl3 to syn-
or anti-α-Alkyl-β-hydroxy Carbonitriles. Eur. J. Org. Chem. 2001,
2001, 2971−2976.
(54) Rimoldi, I.; Facchetti, G.; Nava, D.; Contente, M. L.; Gandolfi,
R. Efficient methodology to produce a duloxetine precursor using
whole cells of Rhodotorula rubra. Tetrahedron: Asymmetry 2016, 27,
389−396.
(55) Contente, M. L.; Serra, I.; Molinari, F.; Gandolfi, R.; Pinto, A.;
Romano, D. Preparation of enantiomerically enriched aromatic β-
hydroxynitriles and halohydrins by ketone reduction with recombi-
nant ketoreductase KRED1-Pglu. Tetrahedron 2016, 72, 3974−3979.
(56) Zerla, D.; Facchetti, G.; Fuse, M.; Pellizzoni, M.; Castellano, C.;
Cesarotti, E.; Gandolfi, R.; Rimoldi, I. 8-Amino-5,6,7,8-tetrahydro-
quinolines as ligands in iridium(III) catalysts for the reduction of aryl
ketones by asymmetric transfer hydrogenation (ATH). Tetrahedron:
Asymmetry 2014, 25, 1031−1037.
(57) Matharu, D. S.; Morris, D. J.; Kawamoto, A. M.; Clarkson, G. J.;
Wills, M. A stereochemically well-defined rhodium(III) catalyst for
asymmetric transfer hydrogenation of ketones. Org. Lett. 2005, 7,
5489−5491.
(58) 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.
(59) Echeverria, P.-G.; Férard, C.; Phansavath, P.; Ratovelomanana-
Vidal, V. Synthesis, characterization and use of a new tethered Rh(III)
complex in asymmetric transfer hydrogenation of ketones. Catal.
Commun. 2015, 62, 95−99.
(60) Touge, T.; Sakaguchi, K.; Tamaki, N.; Nara, H.; Yokozawa, T.;
Matsumura, K.; Kayaki, Y. Multiple Absolute Stereocontrol in
Cascade Lactone Formation via Dynamic Kinetic Resolution Driven
by the Asymmetric Transfer Hydrogenation of Keto Acids with Oxo-
Tethered Ruthenium Catalysts. J. Am. Chem. Soc. 2019, 141, 16354−
16361.
(61) Xing, X.; Xu, C.; Chen, B.; Li, C.; Virgil, S. C.; Grubbs, R. H.
Highly Active Platinum Catalysts for Nitrile and Cyanohydrin
Hydration: Catalyst Design and Ligand Screening via High-
Throughput Techniques. J. Am. Chem. Soc. 2018, 140, 17782−17789.
(62) Zhou, Y.; Jermaks, J.; Keresztes, I.; MacMillan, S. N.; Collum,
D. B. Pseudophedrine-Derived Myers Enolates: Structures and
Influence of Lithium Chloride on Reactivity and Mechanism. J. Am.
Chem. Soc. 2019, 141, 5444−5460.
(63) Masaki, M.; Shinozaki, H. A new class of potent centrally acting
muscle relaxants: pharmacology of oxazolidinones in rat decerebrate
rigidity. Br. J. Pharmacol. 1986, 89, 219−228.
(64) Zhang, G.; Fang, S.; Jia, Y.; Gao, F.; Yuan, X.; He, H.; Tang, Y.
Process for preparation of Tapentadol intermediate. CN106674029 A,
2017.
2483
https://dx.doi.org/10.1021/jacs.0c13273
J. Am. Chem. Soc. 2021, 143, 2477−2483