Iridium-catalyzed asymmetric hydrogenation of racemic β-keto lactams via dynamic kinetic resolution

Article abstract of DOI:10.1021/acs.orglett.6b03397

A highly efficient Ir-catalyzed asymmetric hydrogenation of racemic β-keto lactams via dynamic kinetic resolution (DKR) for the synthesis of optically active β-hydroxyl lactams has been described. With the Ir-SpiroSAP catalyst, a series of racemic β-keto lactams including β-keto γ-, δ-, and ?-lactams were hydrogenated to chiral β-hydroxy lactams in high yields (87-99%) with excellent enantio- and diastereoselectivity (83-99.9% ee, syn/anti: 97:3->99:1) at low catalyst loading under mild reaction conditions. This efficient method has been successfully applied in the synthesis of the chiral intermediate of fluoroquinolone antibiotic premafloxacine.

Full text of DOI:10.1021/acs.orglett.6b03397

Letter
pubs.acs.org/OrgLett
Iridium-Catalyzed Asymmetric Hydrogenation of Racemic β‑Keto
Lactams via Dynamic Kinetic Resolution
Deng-Hui Bao,† Xue-Song Gu,† Jian-Hua Xie,*,† and Qi-Lin Zhou*,†,‡
†State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A highly efficient Ir-catalyzed asymmetric hydrogenation of racemic β-keto lactams via dynamic kinetic resolution
(DKR) for the synthesis of optically active β-hydroxyl lactams has been described. With the Ir-SpiroSAP catalyst, a series of
racemic β-keto lactams including β-keto γ-, δ-, and ε-lactams were hydrogenated to chiral β-hydroxy lactams in high yields (87−
99%) with excellent enantio- and diastereoselectivity (83−99.9% ee, syn/anti: 97:3−>99:1) at low catalyst loading under mild
reaction conditions. This efficient method has been successfully applied in the synthesis of the chiral intermediate of
fluoroquinolone antibiotic premafloxacine.
he development of catalytic asymmetric reactions that are
both highly efficient and selective is an important and
asymmetric hydrogenation of racemic α-acyl lactams 1 with
chiral spiro iridium catalysts SpiroSAP for the synthesis of chiral
β-hydroxy lactams 2.
T
challenging task in organic synthesis. The Ru(diphosphine)-
catalyzed asymmetric hydrogenation of racemic α-substituted
β-ketoesters via dynamic kinetic resolution (DKR), initiated by
The hydrogenation of racemic 1-benzyl-3-acetylpyrrolidin-2-
one (1a) was initially performed under the reaction conditions
of 10 atm of H2, t-BuOK as a base in MeOH at S/C = 1000.
The catalyst (R)-3 gave 100% conversion within 0.5 h with
moderate enantioselectivity (syn-isomer, 76% ee; anti-isomer,
29% ee) and syn/anti-selectivity (syn/anti = 80:20) (Table 1,
entry 1). Gratifyingly, the catalyst (R)-4 bearing a 1,3-dithiane
moiety shows very high activity and enantioselectivity in the
hydrogenation of 1a. The hydrogenation was completed within
0.5 h and afforded (3S,1′R)-2a in 100% conversion with 99.7%
ee and >99:1 syn/anti-selectivity (entry 2). The absolute
configuration of (3S,1′R)-2a was determined by X-ray
diffraction analysis of its single crystal (see Supporting
Information (SI)). The effect of solvent on the reaction was
examined with catalyst (R)-4. The hydrogenations in EtOH
and n-PrOH gave comparable conversion and selectivity, but
required a longer reaction time (entries 3 and 4). However, the
reaction in i-PrOH was slow (31% conversion after 4 h, entry
5). No hydrogenation was observed in toluene (entry 6). The
hydrogenation reaction also proceeded smoothly with KOH,
NaOH, or K2CO3 as a base, affording 2a with excellent enantio-
and diastereoselectivity (entries 8−10). However, low con-
versions were observed in the reactions using t-BuONa,
Na2CO3, or Et3N as a base (entries 7, 11, and 12). When the
Noyori1 and Genet 2
̂
, has been demonstrated to be an efficient
and reliable method for the synthesis of chiral β-hydroxy esters
with two contiguous stereocenters.3 Hattori et al.4 expanded
this method to the asymmetric hydrogenation of racemic α-
acetyl γ-lactam, 1-benzyl-3-acetylpyrrolidin-2-one to optically
active β-hydroxy γ-lactam and provided an enantioselective
approach to 2-(N-imidoylpyrrolidinyl) carbapenems, which
shows higher activity than imipenem against Staphylococcus
aureus (MRSA). Subsequently, researchers of Pfizer5 and Eli
Lilly6 used Ru-catalyzed asymmetric hydrogenation of racemic
α-acyl γ-lactams via DKR for the preparation of pyrrolidine-
containing chiral drugs such as PF-00951966, a novel broad-
spectrum fluoroquinolone antibiotic,7 and serotonin norepi-
nephrine reuptake inhibitors (Scheme 1).8 However, the
catalyst loading is still high (S/C < 300) and the substrate
scope of reaction needs improvement.9
Recently, we developed several chiral spiro iridium catalysts
bearing P−N−N type ligands SpiroPAP (3)10 and P−N−S
type ligands SpiroSAP (4),11 which are extremely efficient for
the asymmetric hydrogenation of β-keto esters to optically
active β-hydroxy esters.10c,11 When we evaluated these spiro
iridium catalysts for the hydrogenation of racemic α-acyl
lactams to β-hydroxy lactams, we found that the catalyst Ir-(R)-
SpiroSAP ((R)-4) shows excellent selectivities (up to 99.9% ee,
>99:1 syn/anti-selectivity) with turnover numbers (TON) up
to 5000 (Scheme 1). We herein describe the catalytic
Received: November 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03397
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(98−99.9% ee) and syn/anti-selectivity (syn/anti: 98:2−>99:1)
(Table 2, entries 1−12). Changing protecting group at the N-
atom of lactam substrates has a strong effect on the reaction
rate, but has little effect on the selectivity of the reaction.
However, no hydrogenation reaction was observed when
nonprotected lactams were used. The reaction exhibits good
tolerance for the functional groups. The substrates containing
an olefin (1h) and an ester group (1i and 1k) also gave desired
products in high yield and selectivities (entries 8, 9, and 11).
Because the hydroxyl and ester groups in 2i easily form a
lactone in acidic workup, the hydrogenation product of γ-
lactam 1i is a lactone−lactam, 1-benzyl-3-(5-oxotetrahydro-
furan-2-yl)pyrrolidin-2-one (2i, entry 9). The β-keto δ-lactams
1m−q can also be hydrogenated to the corresponding β-
hydroxy δ-lactams 1m−q in high yield (96−99%) with
excellent diastereoselectivity (syn/anti = 97:3−99:1) and
enantioselectivity (98−99.9% ee) (entries 13−17). However,
the β-keto-ε-lactam (1r) showed lower enantioselectivity (83%
ee) in the hydrogenation reaction (entry 18). In addition, the
catalyst (R)-4 is also efficient for the asymmetric hydrogenation
of racemic acyclic β-keto amides such as N,N-dibenzyl-2-
methyl-3-oxobutanamide, resulting in the corresponding β-
hydroxy amide in a high yield (98%, 24 h) with good syn-
selectivity (syn/anti: 89:11), however, with low enantioselec-
tivity (syn-isomer, 44% ee, anti-isomer, 5% ee) (see SI).
The β-keto lactams were able to epimerize through an enol
intermediate under basic conditions, which is why the
asymmetric hydrogenation lactams 1 via DKR can be achieved.
To answer if the hydrogenation of β-keto lactam 1 occurs on its
ketone or enol form, we performed a hydrogenation of rac-1a
with D2 under identical reaction conditions (Scheme 2). The
1H NMR analysis showed that the hydrogenation product
contains 72% deuterium at the 1′-position and 7% deuterium at
the α-position of lactam. This result supported that the
hydrogenation of β-keto lactams 1 occurs on its ketone form
(Scheme 2, a). The minor deuteration at the α-position of
lactam came from the hydrogen−deuterium exchange of
substrate under the reaction conditions.
Scheme 1. Asymmetric Hydrogenation of Racemic β-Keto γ-
Lactams via DKR
catalyst loading was decreased from 0.1 to 0.02 mol % (S/C =
5000) the reaction still gave full conversion with 99.4% ee and
95:5 syn/anti-selectivity at 50 atm of H2 pressure (initial) and
20 h (entry 13).
Under the optimal reaction conditions, a variety of racemic γ-
lactams with different α-acyl groups 1a−l were hydrogenated to
the corresponding optically active chiral β-hydroxyl γ-lactams
2a−i in high yield (88−96%) with excellent enantioselectivity
a
Table 1. Asymmetric Hydrogenation of 1a: Optimization of Reaction Conditions
b
c
c
entry
cat.
solvent
base
time (h)
conv (%)
syn/anti
ee (%)
d
1
(R)-3
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
(R)-4
MeOH
MeOH
EtOH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
0.5
0.5
2
100
100
100
100
31
80:20
>99:1
>99:1
>99:1
98:2
76 (29)
99.7
98
2
3
4
n-PrOH
i-PrOH
toluene
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2.5
4
97
5
97
6
15
4
<5
−
−
7
85
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
95:5
99.3
99.7
99.1
99.6
99.5
99.9
99.4
8
0.5
1.5
0.6
4
100
100
100
52
9
NaOH
K2CO3
Na2CO3
Et3N
10
11
12
4
88
e
13
KOH
20
100
a
Reaction conditions: 1.0 mmol scale, [1a] = 1.0 M, 1.0 μmol catalyst, [base] = 0.1 M, 1.0 mL of solvent, room temperature (25−30 °C).
b
c
d
1
Determined by H NMR spectroscopy. The ee value of syn-isomer, determined by HPLC using a Chiralcel AD-H column. The ee value of the
e
anti-isomer is in parentheses. 5.0 mmol scale, S/C = 5000, 50 atm of H2 (initial).
B
DOI: 10.1021/acs.orglett.6b03397
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Letter
a
Table 2. Asymmetric Hydrogenation of Racemic α-Acyl Lactams 1 with (R)-4
b
c
d
entry
1
R1
R2
Bn
n
time (h)
yield (%)
syn/anti
ee (%)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Me
Me
Et
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3
0.5
8
94
92
95
95
94
90
91
95
88
91
88
96
96
97
97
99
91
87
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98:2
99.7
99.9
99.9
99.6
99.7
99.9
98
PMP
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
0.5
3
n-Pr
Bn
2
Cy
3
e
7
1g
1h
1i
i-Bu
24
24
4
f
8
g
Me2CCH(CH2)2
99
9
MeO2C(CH2)2
C6H5
99.9
99.9
99.9
99.4
99.6
99.9
98
10
11
1j
4
1k
1l
4-MeOCOC6H4
2-furyl
12
20
4
e
12
98:2
13
1m
1n
1o
1p
1q
1r
Me
99:1
h
14
n-Pr
24
24
24
24
24
>99:1
97:3
h
15
Bn
h
16
C6H5
98:2
98
e
17
3-ClC6H4
Me
>99:1
97:3
99
h
18
83
a
b
c
d
Reaction conditions were the same as those described in Table 1, entry 8. Isolated yield. Determined by HPLC. The ee value of syn-isomer,
e
f
g
h
determined by HPLC. 50 atm. 0.2 mol % of (R)-4, 50 atm. Lactone-lactam product was obtained after acidic workup. 0.5 mol % of (R)-4, 50 atm
of H2.
Scheme 2. Hydrogenation of rac-1a with D2
Scheme 3. Enantioselective Synthesis of (S)-N-Methyl-1-
((R)-pyrrolidin-3-yl)ethan-1-amine (9)
To demonstrate the utility of this highly efficient method, we
used the hydrogenation product (3S,1′R)-2a to synthesize (S)-
N-methyl-1-((R)-pyrrolidin-3-yl)ethan-1-amine (9, Scheme 3),
a key chiral intermediate to access fluoroquinolone antibiotic
premafloxacin.12 The reduction of γ-lactam (3S,1′R)-2a (99.7%
ee, syn/anti > 99:1) with Red-Al was followed by a Mitsunobu
reaction to yield azide 6 in 94% yield. Azide 6 was reduced with
LiAlH4, and the resulting amine reacted with ethyl
chloroformate to afford carbamate 7 in 64% yield. The
reduction of carbamate 7 with LiAlH4 and removal of the
benzyl protecting group by hydrogenation with Pd(OH)2/C
produced chiral intermediate 9 in 71% yield. Thus, we
accomplished the enantioselective synthesis of (S)-N-methyl-
1-((R)-pyrrolidin-3-yl)ethan-1-amine (9) in 43% overall yield.
In conclusion, we have developed a highly efficient Ir-
catalyzed asymmetric hydrogenation of racemic β-keto lactams
via DKR for the synthesis of optically active β-hydroxyl lactams.
With the Ir-SpiroSAP catalyst, a series of racemic β-keto
lactams including β-keto γ-, δ-, and ε-lactams were hydro-
genated to chiral β-hydroxy lactams in high yields with excellent
enantio- and diastereoselectivity at a low catalyst loading under
mild reaction conditions. This reaction provides an efficient and
practical method for the synthesis of chiral β-hydroxyl lactams
with two contiguous stereocenters.
C
DOI: 10.1021/acs.orglett.6b03397
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Stangeland, E.; Saito, D. R.; Hughes, A.; Schmidt, J.; Van
Dyke, P.; Patterson, L. J. U.S. Pat. Appl. Publ. 2011, US 20110009465
A1 20110113; Theravance Inc., San Francisco, CA, 2011. (b) Dreyfus,
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03397.
■
S
Experiment procedures and the characterizations of the
substrates and products (PDF)
Crystallographic data (CIF)
́
Richards, S. J.; Rincon, J. A.; Seest, E. P.; Shah, J.; Shaojuan, J.;
Simmons, R. M. A.; Stephenson, G. A.; Tromiczak, E. G.; Thompson,
L. K.; Walter, M. W.; Weber, W. W.; Zarrinmayeh, H.; Thomas, C. E.;
Joshi, E.; Iyengar, S.; Johansson, A. M. ACS Med. Chem. Lett. 2013, 4,
560.
AUTHOR INFORMATION
Corresponding Authors
■
(9) For Ru-catalyzed asymmetric hydrogenation and transfer
hydrogenation of racemic α-substituted β-keto amides via DKR, see:
(a) Son, S.-M.; Lee, H.-K. J. Org. Chem. 2013, 78, 8396. (b) Araya, I.;
Kiyota, K.; Nagao, M. U.S. patent 2013/217893 A1, 2013. (c) Limanto,
J.; Krska, S. W.; Dorner, B. T.; Vazquez, E.; Yoshikawa, N.; Tan, L.
Org. Lett. 2010, 12, 512. (d) Lynch, D.; Deasy, R. E.; Clarke, L.-A.;
Slattery, C. N.; Khandavilli, U. B. R.; Lawrence, S. E.; Maguire, A. R.;
Magnus, N. A.; Moynihan, H. A. Org. Lett. 2016, 18, 4978.
(10) For a review, see: (a) Xie, J.-H.; Zhou, Q.-L. Huaxue Xuebao
2014, 72, 778. For papers, see: (b) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.;
Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2011, 50, 7329.
(c) Xie, J.-H.; Liu, X.-Y.; Yang, X.-H.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-
L. Angew. Chem., Int. Ed. 2012, 51, 201. (d) Yang, X.-H.; Xie, J.-H.; Liu,
W.-P.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2013, 52, 7833. (e) Yang, X.-
H.; Xie, J.-H.; Zhou, Q.-L. Org. Chem. Front. 2014, 1, 190. (f) Yang, X.-
H.; Wang, K.; Zhu, S.-F.; Xie, J.-H.; Zhou, Q.-L. J. Am. Chem. Soc.
2014, 136, 17426.
*E-mail: jhxie@nankai.edu.cn.
*E-mail: qlzhou@nankai.edu.cn.
ORCID
Jian-Hua Xie: 0000-0003-3907-2530
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China,
and the “111” project (B06005) of the Ministry of Education of
China for financial support.
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DOI: 10.1021/acs.orglett.6b03397
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