Enantioselective Hydrogenation of Racemic α-Arylamino Lactones to Chiral Amino Diols with Site-Specifically Modified Chiral Spiro Iridium Catalysts

Article abstract of DOI:10.1021/acs.orglett.9b01290

A protocol for highly enantioselective hydrogenation of racemic α-arylamino lactones with catalysis by site-specifically modified chiral spiro iridium complexes has been developed. With the optimized catalyst, racemic α-arylamino-γ-lactones and α-arylamino-δ-lactones could be hydrogenated to the corresponding chiral 2-amino diols with good to excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b01290

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Hydrogenation of Racemic α‑Arylamino Lactones
to Chiral Amino Diols with Site-Specifically Modified Chiral Spiro
Iridium Catalysts
Xue-Song Gu, Na Yu, Xiao-Hui Yang, An-Te Zhu, Jian-Hua Xie,* and Qi-Lin Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A protocol for highly enantioselective hydro-
genation of racemic α-arylamino lactones with catalysis by
site-specifically modified chiral spiro iridium complexes has
been developed. With the optimized catalyst, racemic α-
arylamino-γ-lactones and α-arylamino-δ-lactones could be
hydrogenated to the corresponding chiral 2-amino diols with
good to excellent enantioselectivities.
atalytic asymmetric hydrogenation of racemic carbonyl
compounds via dynamic kinetic resolution (DKR) is an
C
efficient, atom-economical way to access optically active chiral
alcohols,1 which are important building blocks in fine chemical
synthesis. For example, asymmetric hydrogenation reactions of
racemic α-substituted ketones and β-ketoesters afford chiral
secondary alcohols with two or more stereogenic centers with
high enantio- and diastereoselectivities and have been
successfully used for the synthesis of chiral drugs.1a In
addition, significant progress has recently been made in the
asymmetric hydrogenation of racemic α-substituted lactones
via DKR to afford chiral primary alcohols, although
considerable challenges remain. In 2011, Ikariya et al.2
reported the use of a ruthenium complex bearing a chiral
1,2-diamine ligand to catalyze the hydrogenation of a racemic
α-phenyl γ-lactone, albeit with low enantioselectivity (up to
32% ee). Later, we found that chiral spiro iridium complexes
(Ir-SpiroPAP) efficiently catalyze asymmetric hydrogenation of
racemic α-aryl- and alkyl-substituted δ-lactones to afford chiral
diols with up to 95% ee.3 Very recently, Zhang et al. reported
that the O-SPINOL-derived chiral spiro iridium complex Ir-O-
SpiroPAP is a highly efficient catalyst for the asymmetric
hydrogenation of racemic bridged-biaryl lactones to afford
primary alcohols with biaryl-axial chirality with excellent
enantioselectivities (up to >99% ee).4 However, all the
successful examples of asymmetric hydrogenation of racemic
α-substituted lactones via DKR reported to date have involved
δ-lactones with α-aryl or α-alkyl substituents.5
Figure 1. Typical chiral pharmaceuticals containing N-aryl-2-amino-
1,4-butyl units.
malignancies.7 SNX-0723 (2) is a brain-permeable, orally
active selective inhibitor of Hsp 90 that prevents α-synuclein
oligomerization (EC50 = 48 nM).8 Molecule 39 is a
structurally novel selective partial agonist of both the M1
and the M4 subtypes of the muscarinic acetylcholine receptor,
and molecule 410 is a potent Rho kinase inhibitor. Because of
the significance of chiral N-aryl-2-aminobutane-1,4-diols, the
development of new, efficient, reliable methods for their
stereoselective synthesis has attracted considerable research
attention.11 In this paper, we report the first example of highly
enantioselective hydrogenation of racemic α-arylamino lac-
tones via DKR, providing a novel approach to chiral N-aryl-2-
aminobutane-1,4-diols and N-aryl-2-aminopentane-1,5-diols.
We found that site-specifically modified chiral spiro iridium
complexes (Ir-SpiroPAPs) efficiently catalyze asymmetric
hydrogenation of both α-arylamino γ-lactones and α-arylamino
δ-lactones (Scheme 1).
Like chiral alcohols, chiral amino alcohols are of great
importance in organic synthesis and medicinal chemistry,6 and
chiral 2-aminobutane-1,4-diols, particularly those with N-aryl
groups, are potentially useful synthons for chiral pharmaceut-
icals. A number of pharmaceuticals containing N-aryl-2-
aminobutane-1,4-diol moieties are shown in Figure 1. For
example, ABT-263 (navitoclax, 1), an orally bioavailable
inhibitor of Bcl-2 family of proteins, is currently in clinical
trials for treatment of small-cell lung cancer and hematological
Received: April 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Scheme 2, b). Therefore, we conducted additional experi-
ments using catalysts that were site-specifically modified at the
4-position of the pyridine ring with the hope of improving the
enantioselectivity even further.
Scheme 1. Asymmetric Hydrogenation of Racemic α-
Arylamino Lactones to Chiral Arylamino Diols
For this purpose, we prepared a series of Ir-SpiroPAP
catalysts, (R)-5j−r, bearing a dialkyl(hydroxy)methyl, diaryl-
(hydroxy)methyl, dialkylarylymethyl, or triarylmethyl group at
the pyridine 4-position. All the tested catalysts showed high
yields and good enantioselectivities in the hydrogenation of 6a
(Scheme 2, c), with (R)-5l, (R)-5m, and (R)-5o giving the
highest enantioselectivity (87% ee). These results demonstrate
that site-specific modification is a useful strategy for generating
efficient catalysts. In view of the ready availability of (R)-5l, we
used it for further optimization of the reaction conditions.
Using substrate 6a and catalyst (R)-5l, we varied the
reaction parameters (base, solvent, hydrogen pressure, and
reaction time) and evaluated their effects on the reaction
outcome (Table 1). The bases tBuOK, tBuONa, and K2CO3
To evaluate various chiral catalysts, we chose racemic α-
phenylamino γ-butyrolactone (6a) as a model substrate. Ir-
SpiroPAP catalysts 5,12 which were developed by our group,
were found to efficiently catalyze the desired hydrogenation
reaction to afford chiral N-phenyl-2-aminobutane-1,4-diol (7a,
Scheme 2). Catalyst (R)-5c (79% ee), which has a 3,5-di-tert-
Scheme 2. Evaluation of Spiro Iridium Catalysts (R)-5 for
Asymmetric Hydrogenation of 6a
a b c
, ,
Table 1. Asymmetric Hydrogenation of 6a Catalyzed by
(R)-5l
a b
,
PH2
(atm)
time
(h)
yield
c
ee
(%)
d
entry
base
S/B
solvent
(%)
1
2
3
4
5
6
7
8
tBuOK
tBuONa
K2CO3
KOH
1
1
1
1
1
1
1
5
10
20
10
10
10
10
10
nPrOH
nPrOH
nPrOH
nPrOH
MeOH
EtOH
nBuOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
10
10
10
10
10
10
10
10
10
10
30
50
10
10
6
6
24
24
6
6
6
6
6
6
2
2
24
4
92
90
83
NR
87
91
90
92
92
92
92
93
57
93
93
87
86
88
−
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
85
86
83
89
90
90
89
89
90
87
89
9
10
11
12
13
14
e
f
g
15
10
6
a
b
Optimizing the reaction conditions. Reaction conditions: 1.0 mmol
scale, (R)-5l/tBuOK/6a = 1:500:500, nPrOH (5.0 mL), 10 atm H2,
c
d
room temperature (25−30 °C). Isolated yield. Determined by
HPLC using a chiral column. The configuration of product 7a is S
determined by single-crystal X-ray diffraction analysis (see SI). At 0
°C. At 50 °C. 0.1 mol % catalyst.
e
f
g
gave comparable enantioselectivities, although K2CO3 required
a longer reaction time and gave a slightly lower yield (entries
1−3). In contrast, no reaction occurred when KOH was the
base (entry 4). We attributed this to the fact that KOH could
readily convert the lactone substrate into the corresponding
carboxylate, which is difficult to hydrogenate with most
catalysts. The solvent that gave the best enantioselectivity
was nPrOH (compare entries 1 and 5−7). Reducing the
amount of tBuOK from 1 equiv to 5 mol % (6a/tBuOK [S/B]
= 20) resulted in a slight increase in enantioselectivity (from
87% ee to 90% ee) without any obvious effect on the reaction
rate (compare entries 1 and 8−10). Increasing the H2 pressure
to 50 atm shortened the reaction time to 2 h (entries 11 and
12). Changing the reaction temperature from room temper-
ature to 0 or 50 °C had a negligible effect on the
enantioselectivity, although the reaction at 0 °C took longer
and showed a lower yield (entries 13 and 14). Comparable
a
Reaction conditions: 1.0 mmol scale, (R)-5/tBuOK/6a = 1:500:500,
nPrOH (4.0 mL), room temperature (25−30 °C), 10 atm H2, 6 h,
100% conversion. Isolated yield. Determined by HPLC using chiral
column. 24 h.
b
c
d
butylphenyl moiety on the P atom, gave higher enantiose-
lectivity than analogues (R)-5a (55% ee) and (R)-5b (58% ee),
which have a phenyl group and a 3,5-dimethylphenyl group,
respectively (Scheme 2, a). That is, a bulky aryl group on the P
atom enhanced the enantioselectivity of the reaction. Experi-
ments with catalysts bearing an alkyl group at various positions
on the pyridine ring revealed that a bulky tert-butyl group at
the 4-position (5h) increased the enantioselectivity to 84% ee
B
DOI: 10.1021/acs.orglett.9b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
results were obtained even when the catalyst loading was
lowered to 0.1 mol % (entry 15).
Scheme 4. Asymmetric Hydrogenation of Racemic α-
Arylamino δ-Valerolactones 8
a b c
, ,
Under the optimized conditions (Table 1, entry 9), we
hydrogenated a variety of racemic α-arylamino γ-butyrolac-
tones 6 to obtain corresponding 2-N-arylaminobutane-1,4-
diols 7 (Scheme 3). The electronic properties of the
Scheme 3. Asymmetric Hydrogenation of Racemic α-
a b c
, ,
Arylamino γ-Butyrolactones 6
a
Reaction conditions: the same as those listed in Table 1, entry 9.
Isolated yield. Determined by HPLC using chiral column. The
b
c
configuration of product 9m is S determined by single-crystal X-ray
diffraction analysis (see SI).
on either the yield or the enantioselectivity of the reaction, but
as was the case for the α-arylamino γ-butyrolactones, substrates
with an ortho-substituted aryl group showed higher enantio-
selectivities than substrates with an aryl group in the meta or
para position.
This asymmetric hydrogenation reaction could be performed
on a gram scale, and the catalyst loading could be reduced. For
example, hydrogenation of 2.37 g of racemic α-arylamino γ-
butyrolactone 6m in the presence of 0.05 mol % (S/C = 2000)
of (R)-5l produced N-arylaminobutane-1,4-diol (S)-7m in 90%
yield with 97% ee (Scheme 5). Diol (S)-7m is an ideal starting
a
Reaction conditions: The same as those listed in Table 1, entry 9.
b
c
Isolated yield. Determined by HPLC using chiral column. Boc =
tert-butoxycarbonyl; TS = p-toluenesulfonyl.
substituent on the aryl group of the substrate had no obvious
effect on the enantioselectivity, but substrates with a fluoro- or
bromo-substituted aryl group had lower reaction rates (6d, 6f,
and 6i). Substrates with an ortho-substituted aryl group (6k, 6l,
6m, and 6n) showed the highest enantioselectivity (97−98%
ee). The substrate 6p with a (6-methylpyridin-2-yl)amino
group provided the product 7p in 86% yield and 93% ee, but a
relatively higher pressure was required. When the aryl amino
group was changed to the Boc (6q) or Ts group (6r), the
hydrogenations performed well and provided the correspond-
ing products (S)-7q and (S)-7r in moderate to high yields with
comparable enantioselectivities.
Scheme 5. Gram-Scale Hydrogenation of 6m to (S)-7m and
Its Applications
Chiral N-aryl-2-aminopentane-1,5-diols are important build-
ing blocks for the synthesis of chiral 3-amino piperidines and
tetrahydropyrans,11d,e which are common structural units in
pharmaceuticals (e.g., linagliptin13 and ibrutinib14). Therefore,
we also investigated the asymmetric hydrogenation of racemic
α-arylamino δ-valerolactones 8 with catalyst (R)-5l under the
standard conditions, and the results are summarized in Scheme
4. Generally, α-arylamino δ-valerolactones showed slightly
lower reaction rates than the α-arylamino γ-butyrolactones, but
all the reactions were complete within 16 h. The electronic
properties of the substituent on the aryl group had no influence
material for constructing chiral 3-arylamino 1-aza/oxocycloal-
kanes, which are present in many chiral pharmaceuticals.15
Specifically, selective protection of the arylamino group of (S)-
7m with benzyl chloroformate generated 1,4-diol (S)-10 in
91% yield. Activation of the hydroxyl groups of (S)-10 with
methanesulfonyl chloride (MsCl) and subsequent treatment
with benzyl amine (BnNH2) gave 3-arylamino-1-pyrrolidine
C
DOI: 10.1021/acs.orglett.9b01290
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
(S)-11 in 72% yield. The N-Cbz and N-Bn protecting groups
could be removed by catalytic hydrogenation of in (S)-11 over
charcoal-supported palladium, and the resulting aliphatic
amine was selectively protected with Boc2O, yielding 3-
arylamino-1-pyrrolidine (S)-12 in 74% yield. Furthermore,
direct reaction of (S)-7m with diethyl azodicarboxylate in the
presence of PPh3 produced 3-amino-tetrahydrofuran (S)-13 in
84% yield.
CCDC 1910496 and 1910508 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.
In order to understand why the site-specifically modified
chiral spiro iridium complexes gave higher enantioselectivity
and the stereochemistry of the hydrogenation, we proposed a
preliminary mechanism involving a metal−ligand bifunctional
interaction between the catalyst and substrate (a precyclic six-
membered transition state)1a according to the crystal structure
of Ir-SpiroPAP12b (Figure 2). For avoiding the steric
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhxie@nankai.edu.cn.
ORCID
Jian-Hua Xie: 0000-0003-3907-2530
Qi-Lin Zhou: 0000-0002-4700-3765
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21532003, 21871152, and 21790332) and the “111”
project (B06005) of the Ministry of Education of China for
financial support. This paper is dedicated to the 100th
anniversary of Nankai University.
REFERENCES
■
(1) (a) Ohkuma, T.; Noyori, R. In The Handbook of Homogeneous
Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH:
Weinheim, 2007; p 1105. (b) Pellissier, H. Recent developments in
dynamic kinetic resolution. Tetrahedron 2011, 67, 3769−3802.
(c) Xie, J.-H.; Zhou, Q.-L. Catalytic Asymmetric Hydrogenation of
Substituted Ketones and Aldehydes via Dynamic Kinetic Resolution:
Efficient Approach to Chiral Alcohols. Aldrichimica Acta 2015, 48,
33−39. (d) Echeverria, P.-G.; Ayad, T.; Phansavath, P.;
Ratovelomanana-Vidal, V. Recent Developments in Asymmetric
Hydrogenation and Transfer Hydrogenation of Ketones and Imines
through Dynamic Kinetic Resolution. Synthesis 2016, 48, 2523−2539.
(2) Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi, A.; Himizu, A.;
Ikariya, T. Catalytic Hydrogenation of Carboxamides and Esters by
Well-Defined Cp*Ru Complexes Bearing a Protic Amine Ligand. J.
Am. Chem. Soc. 2011, 133, 4240−4242.
Figure 2. Stereochemistry of the hydrogenation of 6a.
interaction between the N-phenyl group of the substrate 6a
and the bulky substituent at the 4-position of the pyridine ring
of the catalyst (R)-5l, TS1 is a more favorable transition state
than TS2, yielding the hemiacetal 1416 with a 2S configuration.
Then, the hemiacetal 14 was converted to aldehyde (S)-15 and
followed by a hydrogenation to afford (S)-7a.
In conclusion, we have achieved the first asymmetric
hydrogenation of racemic α-arylamino lactones via DKR for
the synthesis of optically active chiral 2-arylamino diols. With
catalysis by site-specifically modified chiral spiro iridium
complex (R)-5l, a series of α-arylamino γ-butyrolactones and
α-arylamino δ-valerolactones were hydrogenated under mild
conditions to afford the corresponding chiral 2-arylamino diols
in high yields with good to excellent enantioselectivities. This
reaction, which could be performed on a gram scale at low H2
pressure, provides a practical method for the enantioselective
synthesis of chiral drugs and natural products containing 3-
arylamino-1-aza/oxo-cycloalkane moieties.
(3) Yang, X.-H.; Yue, H.-T.; Yu, N.; Li, Y.-P.; Xie, J.-H.; Zhou, Q.-L.
Iridium-catalyzed asymmetric hydrogenation of racemic α-substituted
lactones to chiral diols. Chem. Sci. 2017, 8, 1811−1184.
(4) Chen, G.-Q.; Lin, B.-J.; Huang, J.-M.; Zhao, L.-Y.; Chen, Q.-S.;
Jia, S.-P.; Yin, Q.; Zhang, X. Design and Synthesis of Chiral oxa-
Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric Reduction of
Bringmann’s Lactones with Molecular H2. J. Am. Chem. Soc. 2018,
140, 8064−8068.
(5) Asymmetric hydrogenations involved in the hydrogenation of
esters, see: (a) Liu, C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.; Zhou, Q.-L.
Asymmetric Hydrogenation of α,α’-Disubstituted Cycloketones
through Dynamic Kinetic Resolution: An Efficient Construction of
Chiral Diols with Three Contiguous Stereocenters. Angew. Chem., Int.
Ed. 2013, 52, 593−596. (b) Yang, X.-H.; Xie, J.-H.; Liu, W.-P.; Zhou,
Q.-L. Catalytic Asymmetric Hydrogenation of δ-Ketoesters: Highly
Efficient Approach to Chiral 1,5-Diols. Angew. Chem., Int. Ed. 2013,
52, 7833−7836. (c) Yang, X.-H.; Wang, K.; Zhu, S.-F.; Xie, J.-H.;
Zhou, Q.-L. Remote Ester Group Leads to Efficient Kinetic
Resolution of Racemic Aliphatic Alcohols via Asymmetric Hydro-
genation. J. Am. Chem. Soc. 2014, 136, 17426−17429. (d) Arai, N.;
Namba, T.; Kawaguchi, K.; Matsumoto, Y.; Ohkuma, T. Chemo-
selectivity Control in the Asymmetric Hydrogenation of γ- and δ-Keto
Esters into Hydroxy Esters or Diols. Angew. Chem., Int. Ed. 2018, 57,
1386−1389.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01290.
Synthesis and characterization of detailed experimental
procedures (PDF)
D
DOI: 10.1021/acs.orglett.9b01290
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(6) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and
Applications; Wiley-VCH: Weinheim, 2010.
pyrrolidines. J. Org. Chem. 2004, 69, 8893−8902. (b) LoGrasso, P. V.;
Feng, Y. Rho Kinase (ROCK) Inhibitors and Their Application to
Inflammatory Disorders. Curr. Top. Med. Chem. 2009, 9, 704−723.
(c) Orliac, A.; Routier, J.; Burgat Charvillon, F.; Sauer, W. H. B.;
Bombrun, A.; Kulkarni, S. S.; Gomez Pardo, D.; Cossy, J.
Enantioselective Synthesis and Physicochemical Properties of
Libraries of 3-Amino- and 3-Amidofluoropiperidines. Chem.Eur. J.
2014, 20, 3813−3824 and refs 8−10 .
(16) Takebayashi, S.; Bergens, S. H. Facile Bifunctional Addition of
Lactones and Esters at Low Temperatures. The First Intermediates in
Lactone/Ester Hydrogenations. Organometallics 2009, 28, 2349−2351
and ref 4 .
(7) Park, C.-M.; Bruncko, M.; Adickes, J.; Bauch, J.; Ding, H.;
Kunzer, A.; Marsh, K. C.; Nimmer, P.; Shoemaker, A. R.; Song, X.;
Tahir, S. K.; Tse, C.; Wang, X.; Wendt, M. D.; Yang, X.; Zhang, H.;
Fesik, S. W.; Rosenberg, S. H.; Elmore, S. W. Discovery of an Orally
Bioavailable Small Molecule Inhibitor of Prosurvival B-Cell
Lymphoma 2 Proteins. J. Med. Chem. 2008, 51, 6902−6915.
(8) Putcha, P.; Danzer, K. M.; Kranich, L. R.; Scott, A.; Silinski, M.;
Mabbett, S.; Hicks, C. D.; Veal, J. M.; Steed, P. M.; Hyman, B. T.;
Mclean, P. J. Brain-Permeable Small-Molecule Inhibitors of Hsp90
Prevent α-Synuclein Oligomer Formation and Rescue α-SynucleinIn-
duced Toxicity. J. Pharmacol. Exp. Ther. 2010, 332, 849−857.
(9) Sumiyoshi, T.; Enomoto, T.; Takai, K.; Takahashi, Y.; Konishi,
Y.; Uruno, Y.; Tojo, K.; Suwa, A.; Matsuda, H.; Nakako, T.; Sakai, M.;
Kitamura, A.; Uematsu, Y.; Kiyoshi, A. Discovery of Novel N-
Substituted Oxindoles as Selective M1 and M4Muscarinic Acetylcho-
line Receptors Partial Agonists. ACS Med. Chem. Lett. 2013, 4, 244−
248.
(10) Iwakubo, M.; Takami, A.; Okada, Y.; Kawata, T.; Tagami, Y.;
Sato, M.; Sugiyama, T.; Fukushima, K.; Taya, S.; Amano, M.;
Kaibuchi, K.; Iijima, H. Design and synthesis of rho kinase inhibitors.
Bioorg. Med. Chem. 2007, 15, 1022−1033.
(11) Selected papers for the synthesis of optically active 2-
aminobutane-1,4-diols, see: (a) Lee, S.-J.; Ahn, J.-G.; Seo, J.; Ha,
H.-J.; Cho, C.-W. Organocatalytic enantioselective synthesis of acyclic
pyrimidine nucleosides by aza-Michael reaction Org. Org. Biomol.
Chem. 2018, 16, 9477−9486. (b) Lukesh, J. C., III; Palte, M. J.;
Raines, R. T. A Potent, Versatile Disulfide-Reducing Agent from
Aspartic Acid. J. Am. Chem. Soc. 2012, 134, 4057−4059. (c) Molinaro,
C.; Bulger, P. G.; Lee, E. E.; Kosjek, B.; Lau, S.; Gauvreau, D.;
Howard, M. E.; Wallace, D. J.; O’Shea, P. D. CRTH2 Antagonist MK-
7246: A Synthetic Evolution from Discovery through Development. J.
̈
Org. Chem. 2012, 77, 2299−2309. (d) Jorres, M.; Schiffers, I.;
Atodiresei, I.; Bolm, C. Asymmetric Michael Additions of α-
Nitrocyclohexanone to Aryl Nitroalkenes Catalyzed by Natural
Amino Acid-Derived Bifunctional Thioureas. Org. Lett. 2012, 14,
4518−4521. (e) Suhartono, M.; Schneider, A. E.; Durner, G.; Gobel,
̈
̈
M. W. Synthetic Aromatic Amino Acids from a Negishi Cross-
Coupling Reaction. Synthesis 2010, 2010, 293−303. (f) Ito, M.; Koo,
L. W.; Himizu, A.; Kobayashi, C.; Sakaguchi, A.; Ikariya, T.
Hydrogenation of N-Acylcarbamates and N-Acylsulfonamides Cata-
lyzed by a Bifunctional [Cp*Ru(PN)] Complex. Angew. Chem., Int.
Ed. 2009, 48, 1324−1327.
(12) For review, see: (a) Xie, J.-H.; Zhou, Q.-L. Magical chiral spiro
ligands. Huaxue Xuebao 2014, 72, 778−797. For selected papers, see:
(b) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. An
Additional Coordination Group Leads to Extremely Efficient Chiral
Iridium Catalysts for Asymmetric Hydrogenation of Ketones. Angew.
Chem., Int. Ed. 2011, 50, 7329−7332. Xie, J.-H.; Liu, X.-Y.; Yang, X.-
H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Chiral Iridium Catalysts
Bearing Spiro Pyridine-Aminophosphine Ligands Enable Highly
Efficient Asymmetric Hydrogenation of β-Aryl β-Ketoesters. Angew.
Chem., Int. Ed. 2012, 51, 201−203.
(13) Eckhardt, M.; Landkopf, E.; Mark, M.; Tadayyon, M.; Thomas,
L.; Nar, H.; Pfrengle, W.; Guth, B.; Lotz, R.; Sieger, P.; Fuchs, H.;
Himmelsbach, F. 8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-
methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-
dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally
Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes. J.
Med. Chem. 2007, 50, 6450−6453.
(14) Honigberg, L. A.; Smith, A. M.; Sirisawad, M.; Verner, E.;
Loury, D.; Chang, B.; Li, S.; Pan, Z.; Thamm, D. H.; Miller, R. A.;
Buggy, J. J. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-
cell activation and is efficacious in models of autoimmune disease and
B-cell malignancy. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 13075−
13080.
(15) (a) Jean, L.; Rouden, J.; Maddaluno, J.; Lasne, M.-C.
Palladium-Mediated Arylation of 3-Aminopiperidines and 3-Amino-
E
DOI: 10.1021/acs.orglett.9b01290
Org. Lett. XXXX, XXX, XXX−XXX