Iridium-Catalyzed Enantioselective C(sp3)-H Amidation Controlled by Attractive Noncovalent Interactions

Article abstract of DOI:10.1021/jacs.9b02811

While remarkable progress has been made over the past decade, new design strategies for chiral catalysts in enantioselective C(sp³)-H functionalization reactions are still highly desirable. In particular, the ability to use attractive noncovalent interactions for rate acceleration and enantiocontrol would significantly expand the current arsenal for asymmetric metal catalysis. Herein, we report the development of a highly enantioselective Ir(III)-catalyzed intramolecular C(sp³)-H amidation reaction of dioxazolone substrates for synthesis of optically enriched γ-lactams using a newly designed α-amino-acid-based chiral ligand. This Ir-catalyzed reaction proceeds with excellent efficiency and with outstanding enantioselectivity for both activated and unactivated alkyl C(sp³)-H bonds under very mild conditions. It offers the first general route for asymmetric synthesis of γ-alkyl γ-lactams. Water was found to be a unique cosolvent to achieve excellent enantioselectivity for γ-aryl lactam production. Mechanistic studies revealed that the ligands form a well-defined groove-type chiral pocket around the Ir center. The hydrophobic effect of this pocket allows facile stereocontrolled binding of substrates in polar or aqueous media. Instead of capitalizing on steric repulsions as in the conventional approaches, this new Ir catalyst operates through an unprecedented enantiocontrol mechanism for intramolecular nitrenoid C-H insertion featuring multiple attractive noncovalent interactions.

Full text of DOI:10.1021/jacs.9b02811

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Article
Iridium-Catalyzed Enantioselective C(sp3)-H Amidation
Controlled by Attractive Noncovalent Interactions
Hao Wang, Yoonsu Park, Ziqian Bai, Sukbok Chang, Gang He, and Gong Chen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02811 • Publication Date (Web): 12 Apr 2019
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Iridium-Catalyzed Enantioselective C(sp3)−H Amidation Controlled
by Attractive Noncovalent Interactions
Hao Wang,1 Yoonsu Park,2,3 Ziqian Bai,1 Sukbok Chang,2,3* Gang He,1* and Gong Chen1*
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1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
2Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
3Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
ABSTRACT: While remarkable progress has been made over the past decade, new design strategies for chiral catalysts in enantioselective
C(sp3)−H functionalization reactions are still highly desirable. In particular, the ability to use attractive non-covalent interactions for rate ac-
celeration and enantiocontrol would significantly expand the current arsenal for asymmetric metal catalysis. Herein, we report the development
of a highly enantioselective Ir(III)-catalyzed intramolecular C(sp3)−H amidation reaction of dioxazolone substrates for synthesis of optically
enriched g-lactams using a newly designed a-amino acid-based chiral ligand. This Ir-catalyzed reaction proceeds with excellent efficiency and
with outstanding enantioselectivity for both activated and unactivated alkyl C(sp3)−H bonds under very mild conditions. It offers the first
general route for asymmetric synthesis of g-alkyl g-lactams. Water was found to be a unique co-solvent to achieve excellent enantioselectivity
for g-aryl lactam production. Mechanistic studies revealed that the ligands form a well-defined groove-type chiral pocket around the Ir center.
The hydrophobic effect of this pocket allows facile stereo-controlled binding of substrates in polar or aqueous media. Instead of capitalizing on
steric repulsions as in the conventional approaches, this new Ir catalyst operates through an unprecedented enantiocontrol mechanism for
intramolecular nitrenoid C−H insertion featuring multiple attractive non-covalent interactions.
(Scheme 1a).14-19 Furthermore, in contrast to the high enantiomeric ex-
cess value (up to 99% ee) obtained for aryl substituted g-lactams, enan-
INTRODUCTION
Development of enantioselective transformations is at the forefront
of research in the transition metal-catalyzed functionalization of car-
bon-hydrogen (C−H) bonds, which can greatly augment its synthetic
utility with more precise stereocontrol.1-3 While remarkable progress
has been made over the past decade, significant challenges remain un-
addressed and new strategies for designing more effective chiral cata-
lysts is highly desirable.4-6 In general, the vast majority of the current
strategies for enantiocontrol in asymmetric metal catalysis relies on the
“blocking” mechanism, in which repulsive steric interactions are em-
ployed as a key element to destabilize the transition states, thereby min-
imizing the undesired stereoisomer.7 In contrast, enzymes typically
adopt the “promoting” mechanism via attractive non-covalent interac-
tions (e.g. hydrogen bonding, electrostatic effect, pinteractions, hydro-
phobic effect, and van der Waals forces) to stabilize the viable transi-
tion states, thus maximizing the desired stereochemical pathway under
mild conditions.7,8 However, due to the relatively weak strength and di-
rectionality, multiple non-covalent interactions need to work in con-
cert to exert strong conformational constraint, rendering it much
harder to realize for small molecule asymmetric catalysis.7,9 While ele-
ments of attractive non-covalent interactions such as H-bonding and
ion pair interactions have been utilized in metal-catalyzed C−H func-
tionalization reactions,10,11 design of enzyme-like metal catalysts for
highly enantioselective C−H functionalization invoking cooperative
non-covalent interactions has yet to be demonstrated.
tiocontrol for the synthesis of g-lactams bearing alkyl substituents re-
mains poorly addressed.13 Recently, one of authors reported a powerful
method for synthesis of NH-free g-lactams via iridium-catalyzed intra-
molecular C−H amidation of 1,4,2-dioxazol-5-one substrates (Scheme
1b).20 These dioxazolones can easily be prepared from the correspond-
ing readily available alkyl carboxylic acids in high yields. This method
represents the first g-lactam synthesis via intramolecular nitrenoid
C−H insertion. The Ir(III) catalyst features strong electron-donating
pentamethylcyclopentadienyl and N-methyloxycarbonyl or acyl 8-
aminoquinoline ligands. More recently, an asymmetric variant of this
reaction of Ir21 and Ru catalysis22 has also been achieved by using
Noyori-type chiral 1,2-diamine ligands, affording optically active g-lac-
tams. The enantioselectivity is attributed to the transient intramolecu-
lar hydrogen bonding between the carbonyl of the substrate amide
moiety and the NH2 group of the diamine ligand. While an excellent
level of enantioselectivity was attained for the benzylic C−H amidation,
the asymmetric reaction of more demanding unactivated alkyl substi-
tuted substrates is still challenging.23-27 The insufficient enantiocontrol
might be attributed to the distant single point interaction between the
chiral induction site of the ligand and the approaching substrate.
Herein, we report the development of new chiral Ir catalysts that pos-
sess a well-defined enzyme-like chiral pocket, resulting in a more inti-
mate dioxazolone substrate/catalyst interaction. Instead of relying on
steric repulsion for enantiocontrol, this Ir asymmetric catalysis oper-
ates through multiple non-covalent interactions including hydropho-
g-Lactams are a “privileged scaffold” widely present in drug mole-
cules and natural products.12,13 While a variety of methods for the g-lac-
tams synthesis have been reported, broadly applicable strategies for en-
antioselective synthesis of g-lactams are surprisingly underdeveloped
bic effect, p-p stacking and C−H/p interactions. Remarkably, the en-
antioselectivity was
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Scheme 1. Enantioselective synthesis of g-lactams.
Page 2 of 9
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a
Rh-cat
intramolecular
carbenoid C-H insertion
asymmetric
conjugate addition
of R''-M
R''
N2
O
O
N
R
R
R
N
N
R'
H
O
R'
N
*
γ
*
O
O
Pd-cat
*
R
Cl
intramolecular
C-H alkylation
asymmetric
hydrogenation
N
H
H
(via desymmetrization)
R'
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b
Previous works
R
CO2H
readily
accessible
chiral catalyst
achiral
Ts
Ir
Ir
"diamine" ligand
Cl catalyst
N
N
Cl
H2N
N
O
(AQ)
Ar
1. NH2OH
2. CDI
O
O
R:
Ar
HN
*
alkyl, alkenyl,
alkynyl, aryl
NaBArF4, DCM, rt - 50 oC, Ar
NaBArF4, TCE, 35 o
C
intramolecular
nitrenoid C-H
insertion
R
H
H
N
R
or
This work:
O
O
O
dioxazolone
O
HN
*
via
Ir
*
Cl
N
desymmetrization
NPhth
Ar
N
^ excellent ee for alkyl
^ excellent efficiency
^ broad applicability
^ strong promotion by H2O cosolvent
^ novel amino acid-based ligand
^ new mode of enantiocontrol
O
Ar
enzyme-like chiral catalyst
with a hydrophobic pocket,
enantiocontrol via
HFIP(/H2O), 20 o
C
attractive interactions
a) Representative methods for enantioselective synthesis of g-lactams. b) Enantioselective synthesis of g-lactams via Ir-catalyzed intramolecular
C(sp3)−H amidation of dioxazolones.
As shown in Scheme 2, the benzylic C−H amidation reaction of a
model substrate 1 was investigated in the initial catalyst development.
Various AQ-based chiral iridium catalysts were readily prepared by re-
acting stoichiometric mixture of [Cp*IrCl2]2 and AQ-coupled ligands
(L) with Na2CO3 in dichloromethane at room temperature (rt). We
were pleased to observe that the desired C−H amidation reaction of 1
proceeded smoothly in hexafluoroisopropanol (HFIP) at rt with 2.5
mol% of Ir catalyst containing the AQ-coupled Phth-protected L-tert-
leucine (Tle) ligand L7, giving g-lactam 2 in 93% yield and 80:20 er
along with 7% of carbamate 4 (entry 1). Side product 4 was presumably
formed via the addition of in situ generated isocyanate 3 with HFIP. Of
note, the catalyst system did not require any additives, and the addition
of NaBArF4 had little impact to the reactivity in HFIP (entry 2). Use of
trifluoroethanol solvent gave slightly higher er but formed more isocy-
anate side product (entry 9). In comparison, reactions in less polar sol-
vents such as dichloromethane or 1,1,2,2-tetrachloroethane (TCE)
showed significantly reduced reactivity using 2.5 mol% of catalyst. In
consistent with the previous observations,20-21 the reaction in TCE did
not proceed in the absence of sodium organoborate (entry 6), and
moderate yield of 2 (62%) along with considerable amount of isocya-
nate side product 3 (37%) was obtained using higher loading of Ir cat-
found to be significantly increased in aqueous cosolvent for g-aryl sub-
stituted substrates. This new chiral Ir catalyst system exhibits a broad
substrate scope and gives outstanding efficiency and enantioselectivity
with both activated and unactivated alkyl C(sp3)−H amidation reac-
tions. Notably, it offers the first general route for the asymmetric syn-
thesis of g-alkyl g-lactams.
RESULTS AND DISCUSSION
In the previous studies, one of authors showed that 1,4,2-dioxazol-5-
ones28 can serve as a convenient and effective precursor of N-acyl
nitrenes via a decarboxylation process to undergo directed intermolec-
ular C−H amidation reaction through an inner-sphere pathway under
Rh(III) or Ir(III) catalysis.29,30 Subsequently, it was discovered that the
reactivity of acyl nitrenoid intermediate can be tuned by the ligand on
Ir catalyst to undergo an intramolecular C−H insertion through an
outer-sphere mechanism, forming g-lactams in high yield.20 Mechanis-
tic studies revealed that the strongly electron-donating Cp* and N,N-
bidentate aminoquinoline ligands (AQ) are crucial to achieve a highly
chemoselective C−H insertion process by suppressing the competing
Curtius rearrangement pathway of Ir-carbonylnitrenoid intermediate,
which gives rise to isocyanate side products. Inspired by the pioneering
works of Davies, Hashimoto, Du Bois and others on bi-metallic rho-
dium and ruthenium-catalyzed enantioselective nitrenoid and carbe-
noid C(sp3)−H insertion reactions using carboxylic and amino acid-
derived chiral ligands,31-35 we wondered whether AQ-coupled deriva-
tives of chiral carboxylic acids might give useful level of enantiocontrol
and maintain sufficient reactivity in this monometallic Ir-catalyzed
nitrenoid C−H insertion system.
alyst (10 mol%) and 10 mol% of NaBArF (entry 8) in TCE solvent.
4
Most other solvents such as acetone or toluene gave poor results irre-
spective of the presence of NaBArF additive (see SI for details). As
4
shown in entries 10-14, surprisingly, the addition of water as a co-sol-
vent increased the reaction rate and also improved enantioselectivity
(entry 1 vs 12). Mixture of HFIP/H2O in ratios of 1:1 to 1:5 gave sim-
ilar results. A 1:2 ratio of HFIP/H2O offered the optimal balance of re-
activity and solubilizing ability (entry 12).
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Scheme 2. Development of AQ-coupled chiral carboxylic acid-based ligands for Ir-catalyzed enantioselective C−H amidation of 1.
1
2
3
4
O
O
CF3
CF3
O
H
H
C
Cp*IrLCl (2.5 mol%)
N
HN
Ph
N
Ph HN
Ph
O
O
O
HFIP, 20 oC, 12 h
O
Ph
2
4
1
initially optimized conditions
3
5
6
7
8
9
Entry
Change from initially optimized conditions
reagents (equiv)
Producta
2 [% (er)]
93 (80:20)
91 (80:20)
95 (83:17)
90 (78:22)
89 (58:42)
3
4 [%]
7
9
1
2
3
4
5
6
7
8
Ir-L7
Ir-L7; + 2.5 mol% of NaBArF
4
10
11
12
13
14
15
16
17
18
19
20
21
22
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5
Ir-L7: 2.5 ® 5 mol%
Ir-L7: 2.5 ® 1 mol%
10
11
Cat: L7 + Cp*IrCl2 (mixed in situ)
Ir-L7, HFIP ® TCE
(>90 % of 1)
50b (42% of 1)
37b
Ir-L7, HFIP ® TCE; + 2.5 mol% of NaBArF
5
4
Ir-L7: 2.5 ® 10 mol%; + 10 mol% of NaBArF ;
62 (93:7)
4
HFIP ® TCE
9
85 (88:12)
96 (90:10)
96 (95:5)
97 (96:4)
96 (93:7)
65 (86:14)
91 (96:4)
97 (96.5:3.5)
95 (97:3)
91 (91:9)
98 [96e]
(99:1)
15c
3
Ir-L7, HFIP ® trifluoroethanol
Ir-L7, HFIP ® HFIP/H2O (10/1)
Ir-L7, HFIP ® HFIP/H2O (1/1)
Ir-L7, HFIP ® HFIP/H2O (1/2)
Ir-L7, HFIP ® HFIP/H2O (1/5)
Ir-L7, HFIP ® HFIP/H2O (1/10)
Ir-L7: 2.5 ® 1 mol%; HFIP/H2O (1/2)
Ir-L7: 2.5 ® 5 mol%; HFIP/H2O (1/2)
Ir-L7, 25 oC ® 10 oC; HFIP/H2O (1/2)
Ir-L7, 25 oC ® 50 oC; HFIP/H2O (1/2)
Ir-L9 d: 2.5 mol%; HFIP/H2O (1/2)
10
11
12
13
14
15
16
17
18
19
3
3
3
15
9
3
3
7
<1
20
Ir-L9 d: 1 mol%; HFIP/H2O (1/2)
95 (98.6:1.4)
3
Results with ligands under the initially optimized conditions (entry 1)f
(AQ)
O
O
O
O
O
PhthN
AQ
PhthN
AQ
PhthN
AQ
AQ
N
N
N
O
N
N
H
MeO
H
H
H
H
O
N
γ C-H
O
L1
L2
arylation
N
AQ
68% (50:50 er)
22% (50:50 er)
N
Pd (cat)d
H
O
O
OMe
OMe
Ts
O
MeO
OMe
MeO
L9
L7
L10
90% (93:7 er)
L8
AQ
N
PhthN
AQ
98% (97:3 er)
N
93% (80:20 er)
93% (94:6 er)
N
H
H
O
O
L3
L4
PhthN
AQ
46% (48:52 er)
PhthN
AQ
34% (48:52 er)
N
H
N
H
Cl
OMe
O
N
OMe
O
O
O
N
PhthN
PhthN
AQ
PhthN
Ph
AQ
PhthN
N
N
MeO
H
N
H
H
H
N
OMe
CO2Me
97% (97:3 er)
OMe
MeO2C
L13
L14
98% (91:9 er)
L6
40% (45:55 er)
L5
56% (39:61 er)
L11
92% (80:20 er)
L12
87% (79:21 er)
a) Yields are based on 1H-NMR analysis of reaction mixture on a 0.2 mmol scale. Er was determined by HPLC using a chiral column. HFIP of 99.7%
purity was used. b) Instead of 4, isocyanate 3 was obtained. c) Carbamate of TFE was obtained. d) Cp*IrL9Cl > 99% ee. See SI for the synthesis of L8-
L10, L13 and L14 via Pd-catalyzed C−H arylation of L7 with aryl iodides. e) Isolated yield. f) Slightly higher yield and er were obtained for selected
ligands using 5 mol% of Ir catalyst. See SI for results under other reaction conditions.
In contrast to L7, ligands based on Pro (L3), Ala (L4), Phe
(L5) and Val (L6) gave significantly lower yields and er under the ini-
tially optimized conditions (entry 1). As shown with L11 and L12, sub-
stitution on the AQ moiety of L7 displayed little impact. Considering
that AQ is a well-known bidentate auxiliary in the palladium-catalyzed
b or g C−H bond functionalization reactions,36,37 we further leveraged
sp3 C−H arylation technology to modify ligand L7. Reaction of Phth-
Tle-AQ L7 with 4-iodoanisole with Pd(OAc)2 catalyst and AgOAc ad-
ditive in PhCl at 110 oC gave a separable mixture of mono-, di-, and tri-
g-arylated products L8, L9, and L10. Di-arylated ligand L9 gave further
improved C−H amidation results (98% yield, 99:1 er) in HFIP/H2O
mixed solvents (entry 19). Lowering the loading of catalyst Ir-L9 to 1
mol% also worked well (entry 20). Several other observations are note-
worthy: 1) The reaction proceeded well at further decreased tempera-
ture (10 oC) albeit at slightly lower reaction rate (entry 17); reaction at
50 oC forms more side products and with lower er (entry 18). 2) Use of
in situ mixed [Cp*IrCl2]2 with L7 gave lower yield and er (entry 5). 3)
An air atmosphere is tolerated. 4) Different C−H arylated analogs of
L7 gave variable results (see L13, L14). 5) Higher loading of catalyst
gave slightly higher er. 6) More notable improvement of performance
of L9 over L7 in terms of reactivity and enantioselectivity was observed
for certain challenging substrates (vide infra).
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Page 4 of 9
Scheme 3. Substrate scope of Ir-catalyzed enantioselective methylene C−H amidation and desymmetrization..
1
2
3
4
5
6
7
H
H
O
N
R
HN
*
O
O
Cp*IrL9Cl (cat)
20 oC, 1-12 h
O
O
R
or
O
standard conditionsa
[A]: 2.5 mol% of cat, HFIP/H2O (1:2)
[B]: 2.5 mol% of cat, HFIP
H
HN
*
N
O
O
*
H
8
9
Benzylic, allylic, propargylic C-H amidation
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HN
HN
HN
HN
HN
Br
I
F3C
O2N
7
6
5
8
9
X-ray of 9
85% (99.5:0.5 er) [A]
>95% (99.5:0.5 er) [A]
35% (87:13 er) [B]
47% (93:7 er) [A]
68% (96:4 er) {30%}b [Ca]
84% (99.6:0.4 er) [A]
95% (98.5:1.5 er) [A]
91% (98:2 er) [A, 1 mol% of cat]
O
O
O
O
O
O
HN
HN
HN
HN
HN
HN
Ph
MeO
F
Me
11
15
10
12
13
14
tracee,f [A or B]
41% (98:2 er) {52} [A]
89% (99.5:0.5 er) [Ca]
tracee [A or B]
26% (91:9 er) [Da]
tracee [A or B]
68% (99.2:0.8 er) [Ca,g
90% (99:1 er)c [A]
]
46% (86:14 er) [Da]
>95% (99.1:0.9 er)c [A]
84% (97.5:2.5 er) [Da]
Unactivated alkyl C-H amidation
I
O
O
O
O
O
O
HN
HN
HN
HN
HN
HN
Ph
16
20
18
19
17
21
80% (98:2 er) [A]
45% (97:3 er)c {52}b 70% (99.5: 0.5 er)c{26}b
89% (99.3:0.7 er)c
44% (88:12 er) [B]
65% (98:2 er) {30} [Ca]
85% (99.4:0.6 er)
[B, 1 mol% of cat, 1h]
91% (99.3:0.7 er)c [B, 48h]
52% (88:12 er) [Da]
[B]
[B]
[B, 48h]
O
O
O
H
O
N
HN
11
HN
HN
7
8
5
25
22 (from myristic acid)
87% (99.8:0.2 er)c [B]
23
24 (from erucic acid)
88% (99.7:0.3 er)c [B]
95% (99.5:0.5 er)
[B, 1 mol% of cat]
88% (99.5:0.5 er)c [B, 36h]
Methylene desymmetrization
O
O
O
O
O
O
HN
*
HN
*
HN
*
HN
*
HN
HN
*
*
Ph
Ph
27d
26d
28d
30d
29-cisd
29-transd
+
89% (99.5:0.5 er)c [B]
>95% (96:4 er) [A]
92% (99.6:0.4 er) [B]
(> 19:1 dr)
>95% (99.7:0.3 er)
[A, 1 mol% of cat]
(>19:1 dr)
>95% (98.6:1.4 er)c [B]
43% (98:2 er)c
50% (98:2 er)c
(> 19:1 dr)
[B]
(9:1 dr)
Transformations of γ-lactams
O
i. Boc2O, DMAP
ii. LiOH, H2O2, THF
i. MeI, KOH, toluene
ii. LAH, THF
NHBoc
HN
N
CO2H
93%, over 2 steps
13
13
13
78%, over 2 steps
32 (99.4:0.6 er)
31 (from stearic acid)
88% (99.5:0.5 er)
[B, 1 mol% of cat, 2 gram scale]
33 bgugaineh
a) Yields are based on isolated yields on a 0.2 mmol scale reaction under standard conditions A, B under ambient air atmosphere. Additional conditions
C: 5 mol% of catalyst, HFIP, D: 10 mol% of catalyst, 10 mol% of NaBArF4 in TCE solvent. er values were based on chiral HPLC analysis. b) Yield of
carbamate side product in {} for selected reactions. c) er was measured based on the N-Cbz protected derivatives. d) Absolute stereochemistry was not
determined. e) Poor conversion of starting material was observed. f) The reaction solution changed from colorless to bright yellow upon mixing starting
material with catalyst. g) 5 mol% of NaBArF4 was added. h) a 99:1 er was obtained for its N-benzyl analog. See SI for details..
Substrate scope. With the optimized conditions (A, 2.5
mol% of Ir-L9 in HFIP/H2O) for benzylic C−H amidation in hand, we
next examined the scope of this chiral g-lactam synthesis with various
dioxazolone substrates (Scheme 3). As exemplified by 5, the use of
HFIP/H2O (1:2) solvents consistently gave better yield and enantiose-
lectivity than HFIP solvent alone (conditions B, 2.5 mol% of Ir-L9 in
HFIP). Functional groups such as CF3 (6), NO2 (7) and halogens (8,
9) on phenyl ring were tolerated. The absolute stereochemistry of
iodo-containing product 9 was confirmed by X-crystallographic analy-
sis. Certain electron-withdrawing/polar groups such as NO2 (7) on
phenyl ring significantly reduced the reactivity. For these substrates, 5
mol% of catalyst in HFIP solvent (conditions C) was required to obtain
reasonable yield of g-lactam products along with the increased amount
of carbamate side product while enantioselectivity of the reactions was
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Journal of the American Chemical Society
largely unaffected. Notably, product 11 carrying a methoxyphenyl
for details). Such conformational stability of Tle-ligated catalysts can
be explained by the rotational restriction of bonds connected to the Ca
1
2
3
4
5
6
7
8
group was formed in poor yield under the standard conditions in either
HFIP or HFIP/H2O solvents. In contrast, switching the solvent to
center due to the strongly favored staggered conformation between Ca
and Cb. The high stability of Cp*IrL7Cl catalyst in H2O could be ex-
plained by the tight N,N-bidentate chelation of AQ to the Ir center.
Starting from this experimentally-obtained conformation, density
functional theory (DFT) calculations were carried out to estimate the
relevant energetics and the enantiocontrol in a reaction of model sub-
strate 1.
TCE, increasing the loading of Ir (10 mol%), and adding NaBArF
4
(conditions D) afforded 84% yield and 97:3 er. Not surprisingly, steric
congestion around the reactive center resulted in decreased reactivity
and enantioselectivity, as seen in the formation of 10. As shown in the
formation of 13 and 14, allylic or propargylic substrates challenging to
diamine-Ir catalyst system21 gave g-vinyl or alkynyl g-lactams in excel-
lent yield and outstanding er in HFIP/H2O solvents. Synthesis of 15
bearing a phenyl alkynyl substituent required higher loading of catalyst
(5 mol%) and HFIP solvent.
9
As outlined in Scheme 4b and 4c, the reaction likely starts
with an dissociation of chloride anion from neutral Cp*IrL7Cl, form-
ing a cationic Ir(III) species I with an open coordination site. Due to
the high polarity and strong Cl- solvating ability of HFIP38 or H2O, the
dissociation takes place even in the absence of the Cl- scavenger such as
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As shown by 16-25, we were pleased to observe that cycliza-
tion at the unactivated aliphatic C−H bonds proceeded with excellent
yield and enantioselectivity in HFIP solvent under conditions B, thus
forming various g-lactams carrying aliphatic g-alkyl substituents. Simi-
lar to the reactions of g-alkynyl substituted substrates, substrates bear-
ing short g-alkyl group (e.g. 16) worked well in HFIP/H2O solvents
whereas longer alkyl groups showed diminished reactivity and worked
better in HFIP. It is worth mentioning that highly enantioselective syn-
thesis of such g-lactams (>95% ee) remains challenging using existing
methods.13 Many of these substrates can be easily prepared from read-
ily available aliphatic carboxylic acids. Functional groups such as iodo
(21), terminal and internal alkenes (23, 24) and alkynes (25) were tol-
erated. A simplest g-alkyl γ-lactam product 16 was prepared in 91%
yield and 99.3:0.7 er. Product 22, derived from a natural compound
myristic acid, was prepared in 87% yield and with 99.6% ee. Products 21
and 25 were prepared in excellent yield and with excellent er using 1
mol% of catalyst.
NaBArF .20 The optimized structure of I is very similar to the Cl-bound
4
Ir-L7 catalyst. The electrostatic potential map (EPM) of I showed that
the AQ, Cp* and Phth groups form a well-organized chiral pocket fea-
turing a cationic Ir center buried in a hydrophobic groove with the top
end blocked by the Cp* plane. Driven by the coordination of N of di-
oxazolone to the Ir center and the hydrophobic effect,38 apolar sub-
strate 1 dissolved in the polar reaction medium (HFIP or mixed
HFIP/H2O) readily enters the chiral pocket of I to form a sub-
strate/catalyst complex II, which then undergoes decarboxylation to
form an Ir-carbonylnitrenoid intermediate III with an energy barrier of
23.3 kcal/mol (Scheme 4b). In comparison to III, its diastereomer III’
with the alkyl group pointing toward Cp* is much less stable by 5.6
kcal/mol, possibly due to the steric clash with Cp* (see SI for the struc-
ture of III’). As the key stage, subsequent intramolecular C−H inser-
tion of III takes place through a 6-membered chair-like transition state
III-TSR or III-TSS, which is supposedly the enantioselectivity-deter-
mining step. Indeed, traversing III-TSS that eventually gives (S)-con-
figured lactam product is kinetically more favored than the process
traversing III-TSR by nearly 3 kcal/mol, which is consistent with the
experimentally observed enantiomeric excess (94% ee, Scheme 4c).
Because of the high polarity of the amide group and its weaker com-
plexation ability with Ir center, the final γ-lactam product can readily
be released from the pocket, thus regenerating the catalytic species I.
In addition to the above enantioselective methylene C−H
amidation, desymmetrization of substrates carrying two symmetric
methylene groups also worked well to form more complex g-lactams
carrying consecutive stereogenic centers. For instance, desymmetriza-
tion of benzylic methylenes of either acyclic or cyclic substrates gave
products 26 and 27 in high yield, and excellent er and dr under the con-
ditions A or B. Reaction of cyclopentylmethyl dioxazolone gave a cis-
fused product 28 in 76% yield, 99% ee, and >19:1 dr. Reaction of cyclo-
hexylmethyl dioxazolone gave a diastereomeric mixture of 29-cis and
29-trans in excellent er. A gram-scale reaction of stearic acid-derived
dioxazolone gave 31 in 88% yield and 99% ee under the conditions B
with 1 mol% of catalyst. Boc activation of 31 followed by the treatment
with LiOH provided Boc-protected g-amino stearic acid 32 in 93%
yield. A two-step sequence of N-methylation of 31 with MeI and reduc-
tion with lithium aluminum hydride (LAH) gave enantioenriched nat-
ural product bgugaine 33 in four steps and 66% overall yield from com-
mercially available stearic acid.
Structural analysis of the transition state III-TS revealed
that the γ-phenyl substrate 1 is fully confined in the chiral pocket of cat-
alyst by multiple noncovalent interactions with the AQ and Phth
planes. The phenyl group of 1 builds a p stacking interaction with the
AQ plane in both III-TSS and III-TSR. The steric repulsion between
the γ-Phe and Phth groups was found to be insignificant. In contrast, a
Cγ(sp3)−H/p attractive interaction between the aliphatic skeleton of
substrate and Phth group is observed in both transition states with a
H/p distance of 2.59 Å in III-TSS and 2.86 Å in III-TSR.40-42 An extra
Ca(sp3)−H/p interaction with a longer H/p distance of 3.02 Å is ob-
served in III-TSS. Noncovalent interaction (NCI) plot analysis re-
vealed that a van der Waals repulsion between the carbonyl O of sub-
strate and carbonyl O of Phth with an O-O distance of 3.12 Å also con-
tributes to the destabilization of III-TSR. Such interaction is absent in
III-TSS. As shown in Scheme 4c, a ∆∆G≠ of 2.21 kcal/mol was ob-
tained for the corresponding transition states III-TSS-Me and III-TSR-
Me of the reaction of γ-methyl substrate, offering similarly high enan-
tioselectivity (product 16, see SI for the details of DFT calculations).
In comparison to 1, the γ-methyl substrate does not form p-stacking
Mechanistic study. Intrigued by the superior performance
of the new catalytic system in partially aqueous media, we sought to un-
derstand the origin of reactivity and enantioselectivity using the ligand
Phth-Tle-AQ L7. The structure of the Ir catalyst carrying L7 was con-
firmed by X-ray crystallography, as shown in Scheme 4a. Interestingly,
the planar phthalimide group of Phth-Tle-AQ is positioned in a close
proximity to the AQ group with the Ca−H bond pointing toward the
Cp* ring. In contrast to the existence of a diastereomeric mixture of Ir
catalysts ligated by amino acid ligands carrying a sterically less demand-
ing side chain such as Phth-Ala-AQ (L4, b-monosubstituted) and
Phth-Val-AQ (L6, b-disubstituted), catalysts containing Tle (b-trisub-
stituted) or arylated Tle ligands, e.g. L7 and L9, exist as a single dia-
stereomer in solution phase, as confirmed by 1H-NMR analysis (see SI
interaction with the AQ group. However, the attractive C−H/p inter-
actions with the Phth group remain operative likely leading to the en-
antiocontrol in the C−H insertion step.43
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Journal of the American Chemical Society
Page 6 of 9
Scheme 4. Mechanistic studies of Ir-catalyzed enantioselective C−H amidation of 1 with Cp*IrL7Cl.
1
2
3
a
b
II-TS
ΔG
(25.04)
(kcal/mol)
4
5
6
7
8
9
III-TSR
(1.30)
III-TSS
(-1.60)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
X-ray structure of
I
II
Cp*IrL7Cl
EPM of I
(0.0)
(1.73)
H
Me
Me
O
III
O
Cα
(-13.41)
N
I +PDT
N
Me
O
L7 in Ir-L7
c
O
+
O
N
N
H
Ir
(R)-pdt
O
tBu
N
H
N
H
O
O
O
O
O
Ph
H
O
O
+
O
N
Ir
+
Ir
O
+
Ir
N
tBu
N
O
tBu
N
N
- CO2
N
N
substrate 1
N
III-TSR (1.30)
N
O
N
N
O
O
O
O
Ph
I
III
II
Ph
+
O
Ir
tBu
O
N
N
N
H
H
N
(S)-pdt
H
Ph
O
O/O replusion
III-TSS (-1.60)
C-H / π
3.15 Å
3.12 Å
3.02 Å
2.59 Å
2.80 Å
2.74 Å
2.69 Å
2.83 Å
2.86 Å
III-TSR (1.30)
III-TSR-Me (5.82)
III-TSS-Me (3.61) favored
III-TSS (-1.60) favored
γ-Me substrate
γ-Ph substrate 1
ΔΔG‡ = 2.90 kcal/mol
ΔΔG‡ = 2.21 kcal/mol
a, X-ray structure of catalyst Cp*IrL7Cl and calculated structure (electrostatic potential map) of intermediate I. b, Calculated energy profiles for the
reaction of 1. DFT calculations were performed at the PCM (water) M06/{SDD, 6-311+G**}//B3LYP/{LANL2DZ, 6-31G**} level of theory, See SI
for details. c, Proposed reaction pathways and stereochemical model with substrate 1 (g-Phe) and calculated transition state structures for the enanti-
odetermining C−H insertion step for g-Phe and g-methyl substrates.
Having identified the critical stereo-steering role of Phth
group, additional control experiments were designed to corroborate
computational insights. As shown in Scheme 5, analogous ligands of L7
bearing different N-protecting groups were prepared and subjected to
the reaction of 1 under standard conditions A. Replacing Phth group of
L7 with more flexible benzamide (Bz, L18) or carbamate (Cbz, L19)
gave significantly diminished reactivity and enantioselectivity which fa-
vors the opposite direction possibly under the influence of the steric ef-
fect. In contrast, benzo-fused imide analogs with large arene moieties
(L15-L17) gave comparable results to Phth. These results are in line
with the stereoelectronic effect of the Phth group in the current enan-
tiocontrol model.
In summary, we have developed a highly efficient and broadly ap-
plicable method for the asymmetric synthesis of g-lactams via Ir-cata-
lyzed enantioselective C(sp3)−H amidation of dioxazolone substrates.
The catalyst is equipped with a newly designed a-amino acid-based
chiral ligand, and the Cp*, AQ and Phth groups were elucidated to form
a well-defined chiral pocket around the Ir center. The hydrophobic ef-
fect of the pocket allows facile binding of substrates in polar or aqueous
media. The new synthetic procedure is operationally simple under
mild conditions, providing excellent yields with outstanding enantiose-
lectivity for both activated and unactivated alkyl C(sp3)−H bonds. It
can effect both enantioselective methylene C−H amidation and point
desymmetrization. Instead of capitalizing on steric repulsions , this new
enzyme-like Ir catalyst operates through a rarely precedented enantio-
control mechanism for C-H functionalization featuring
Conclusion
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Journal of the American Chemical Society
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1
2
3
4
5
6
7
8
O
H
H
Cp*IrLCl (2.5 mol%)
HN
HFIP/H2O (1:2), 20 oC, 12 h
N
Ph
O
O
Ph
O
1
2
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Br
Br
O
O
O
Br
O
O
O
N
AQ
N
AQ
N
AQ
Br
N
N
H
N
H
H
O
O
O
9
L16
90% (95:5 er)
L15
91% (92:8 er)
L7
10
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97% (96:4 er)
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BnO
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O
AQ
N
H
N
N
H
H
O
O
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catalyst /Noyori type chiral diamine ligand appeared: Xing, Q.; Chan, C.
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γ-Lactams Formation by Intramolecular C–H Amidation of 1,4,2-Diox-
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L17
L18
L19
87% (94:6 er)
32% (32:68 er)
25% (34:66 er)
Scheme 5. Performance of L7 analogs with different N-protecting
groups. Yields are based on 1H-NMR analysis of reaction mixture on
a 0.2 mmol scale. Er was determined by HPLC using a chiral column.
multiple attractive non-covalent interactions.
ASSOCIATED CONTENT
Detailed synthetic procedures, compound characterization, NMR spec-
tra, X-ray crystallographic data, and computational details are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr, hegang@nankai.edu.cn, gongchen@nan-
kai.edu.cn. The authors declare no competing financial interest.
ACKNOWLEDGMENT
G.C. thanks NSFC-21672105, NSFC-21421062, Laviana, China Post-
doctoral Science Foundation (2018M640225), and the Fundamental
Research Funds for the Central Universities (No. 63191318) for finan-
cial support of the experimental part of this work. G.C. dedicates this
work to the 100th anniversary of Nankai University. S.C. thanks the In-
stitute for Basic Science (IBS-R010-D1) in Republic of Korea for finan-
cial support.
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from numbers to insights. Chem. Soc. Rev. 2018, 47, 1142.
43. Bond distances between the g C-H and the aminoquinoline of III-TSR-
Me and III-TSS-Me were around 3.0 Å, implying weak C-H/p interac-
tions between the substrate and the AQ plane. However, due to the sim-
ilar intensity of the interactions, they are not expected to be critical in
the energetics related to the enantio-determining step.
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Ir
Cl
N
O
O
NPhth
Ar
R:
N
HN
*
alkyl, alkenyl,
alkynyl, aryl
O
H
H
R
Ar
N
R
O
O
(1-2.5 mol%)
up to 99.6 ee%
for alkyl
or
O
HFIP(/H2O), 20 oC
dioxazolone
intramolecular
nitrenoid C-H insertion
HN
*
via
*
desymmetrization
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