Stereoselective synthesis of β-alkylated α-amino acids via palladium-catalyzed alkylation of unactivated methylene C(sp3)-H Bonds with Primary Alkyl Halides

Article abstract of DOI:10.1021/ja406484v

We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp³)-H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.

Full text of DOI:10.1021/ja406484v

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Article
Stereoselective Synthesis of #-Alkylated #-Amino Acids
via Palladium-Catalyzed Alkylation of Unactivated
Methylene C(sp3)-H Bonds with Primary Alkyl Halides
Shu-Yu Zhang, Qiong Li, Gang He, William A Nack, and Gong Chen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja406484v • Publication Date (Web): 26 Jul 2013
Downloaded from http://pubs.acs.org on August 5, 2013
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Shu-Yu Zhang, Qiong Li, Gang He, William A. Nack, and Gong Chen*
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Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802 United States.
ABSTRACT: We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp3)−H bonds of ali-
phatic quinolyl carboxamides with -haloacetate and methyl iodide, and applications in the stereoselective synthesis of
various -alkylated -amino acids. These reactions represent the first generally applicable method for the catalytic al-
kylation of unconstrained and unactivated methylene C−H bonds with high synthetic relevance. When applied with sim-
ple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes
into the carbon scaffolds of amino acid compounds.
(AQ)-coupled propionamide 1 could be alkylated with
primary alkyl iodides such as 2 under palladium catalysis
(eq 2, Scheme 2).12 Although this alkylation reaction was
Amino acids are one of nature’s most powerful and ver-
satile building blocks for the synthesis of natural products
limited to primary C(sp3)−H bonds and proceeded in
moderate yields, it provided the foundation for our syn-
thesis of -alkylated amino acids, which relies on Pd-
catalyzed AQ-directed C(sp3)−H alkylation to install -
substituents. The success of our strategy then hinged on
the development of new reaction conditions to alkylate
less reactive 2o  C(sp3)−H bonds in a regio- and stereose-
lective fashion. In this paper, we report the development
of highly efficient palladium-catalyzed alkylations of
and biomolecules. In addition to the common proteino-
genic amino acids, nature uses post-translational modifi-
cations (PTM) to synthesize a myriad of nonproteinogen-
ic amino acids with diverse structures and functions.1
Among these modifications, alkylation at the  position of
 amino acid residues, e.g. C-methyltransferase-mediated
methylation, is particularly effective at modulating the
conformational and biophysical properties of the parent
peptide backbones (Scheme 1).2-4 These -alkylated amino
acid units contain adjacent carbon stereogenic centers
and pose significant synthetic challenge.5
Complementary to conventional synthesis strategies,
we envisioned these molecules could be expeditiously
accessed via the selective alkylation of sp3-hybridized
C−H bonds on the side chains of simple amino acid pre-
cursors.6 The Corey7 and Daugulis8 laboratories have ele-
gantly demonstrated this synthesis concept with Pd-
catalyzed auxiliary-directed acetoxylation and arylation of
the  C(sp3)−H bonds of N-Phth protected amino acids,
based on pioneering work from the Daugulis laboratory9
(eq 1, Scheme 2). However, in contrast with better devel-
oped C−H arylation and oxidation reactions, the alkyla-
tion of unactivated and nonacidic C(sp3)−H bonds re-
mains one of the most difficult transformations in organic
synthesis.10 Additionally, despite a few recent successes on
the alkylation of primary (1o) C(sp3)−H bonds of methyl
groups, alkylation of more prevalent secondary (2o)
C(sp3)−H bonds of unactivated methylene groups remains
largely undeveloped. 11-15
In a seminal 2010 paper, the Daugulis laboratory re-
ported that the -C(sp3)−H bond of 8-aminoquinoline
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Page 2 of 9
unactivated methylene C(sp3)−H bonds of aliphatic 8-
aminoquinolyl carboxamides with -haloacetate and me-
thyl iodide, and apply these reactions to the stereoselec-
tive synthesis of -alkylated -amino acids. When applied
with simple isotope-enriched reagents, they provide con-
venient and powerful means to site-selectively incorpo-
rate isotope labels into the carbon scaffolds of amino acid
compounds.
enzyme-mediated PTM
(e.g. via C-methyltransferase)
R
b
R'
1
2
3
4
5
6
7
R
H
b-alkylated
a amino acids
O
O
a
H2N
H2N
constrained rotation
around Ca - Cb
metal-catalyzed
OH
OH
functionalization of
methylene C(sp3)- H bonds
?
A) Proteinogenic b-alkylated a amino acids
8
9
O
O
H2N
H2N
Ile
OH
OH
Val
10
11
12
13
14
15
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We commenced our investigation with simple AQ-
butyramide substrate 4 (eq 3, Scheme 2). Our initial trials
with iBuI 2 under the original Pd-catalyzed conditions
failed to generate any of the desired product 5. Our at-
tempts at the intramolecular C(sp3)−H alkylation of 8-I-
octanamide 6, despite optimization, provided the cy-
clized product 7 in poor yield (eq 4).16 Given the ease with
which  C−H palladation of 4 occurs in the associated
AQ-directed C−H arylation reaction system, we reasoned
that the key to this C−H alkylation reaction might be
choice of the alkyl halide electrophile, so as to efficiently
intercept the resulting palladacycle intermediate. In addi-
tion to promoting the desired alkylation of the palladacy-
cle, side reactions which neutralize alkyl iodides, includ-
ing esterification with carboxylate ligands and decompo-
sition via an E2 pathway, must be effectively suppressed.
Our recent success with Pd-catalyzed, picolinamide (PA)-
directed alkylation of 1o -C(sp3)−H bonds of aliphatic
amine substrates prompted us to evaluate the effective-
ness of -iodoacetate 9 and MeI in the AQ-directed alkyl-
ation of 2o C(sp3)−H bonds (eq 5, Scheme 2).13 To our de-
light, alkylation of 4 with 2 equiv of 9 and 2 equiv of
B) Selected naturally occurring b-methylated a amino acids
CO2H
Me
Me
Me
Me
O
O
O
O
N
H
H2N
H2N
H2N
OH
OH
OH
OH
bMe-Glu
bMe-Phe
bMe-Val
bMe-Pro
C) Selected natural products containing b-alkylated a amino acid motifs
O
N
CO2Me
O
O
H
NH
H
N
N
HN
N
N
H
O
S
N
H
O
O
O
H
Bottromycin A2
N
Br
NH
OH
O
O
Me
HO
NH SMe
N
HN
O
OH
O
N
N
H2N
H
O
N
H
H
Dihydrohymenialdisine
Maremycin A
Kainic acid
Scheme 1. Occurrence of -Alkylated  Amino Acids
Daugulis, Corey
O
Pd(OAc)2 (cat)
(AQ)
O
H
PhthN
R
o
PhthN
R
(1)
(2)
NHAQ
ArI
AgOAc or Ag2CO3 at 110 C in t-AmylOH under Ar for 6
N
H
PhI(OAc)2 or
Oxone/Mn(OAc)2/Ac2O
N
Ar (OAc)
hours proceeded to give the desired carboxymethylated
product 11 in excellent yield (eq 7, entries 4 and 6, Table
1). Application of the combination of Ag2CO3 (2 equiv)
and (BnO)2PO2H (20 mol%), originally developed for the
PA-directed C−H alkylation reaction, provided slightly
improved alkylation yield (entry 8). Addition of the radi-
cal scavenger TEMPO had little effect on the reaction
(entry 10). Product 12, bis-alkylated at both the aliphatic 
C(sp3)−H and at the ortho-C(sp2)−H position of AQ moie-
ty, was obtained as a minor side product.
Daugulis
I
2 (3 equiv)
H
O
O
b
(1 o
Pd(OAc)2 (5 mol %)
K2CO3 (2.5 equiv),
PivOH (20 mol %)
)
NHAQ
NHAQ
3 (58%)
1
t-AmylOH, 110 oC, 22 h
Our initial trial
2 (3 equiv)
b
H
O
O
(2 o
)
(3)
NHAQ
NHAQ
NHAQ
same conditions as eq 2
4
5 (not observed)
Table 1. Optimization of AQ-Directed C(sp3)−H Alkyla-
tion of Simple Aliphatic Carboxamide 4
I
Pd(OAc)2 (10 mol %)
Ag2CO3 (1 equiv)
b
(2 o
O
H
O
)
(4)
NHAQ
7 (<15%)
o-PBA (1 equiv)
t-BuOH, 110 oC, 12 h
EtO2C
b
(2 o
H
6
EtO2C
I
O
)
Our previous work
9 (2 equiv) EtO2C
O
NH CO2Et
O
(7)
Pd(OAc)2
(10 mol %)
110 oC, Ar, 6h
+
N
EtO2C
I
9 (2 equiv)
NHAQ
NHAQ
N
EtO2C
g
(1 o
Pd(OAc)2 (10 mol %)
4
NHPA
11
12
(5)
(6)
)
(PA)
(BnO)2PO2H (20 mol %)
Ag2CO3 (2 equiv)
t-AmylOH, Ar, 110 oC, 6 h
H
HN
O
solvents a
Yields (%) b
10 (88%)
entry reagents (equiv)
8
11
11
18
<2
85
46
86
12
<2
<2
<2
3
This work
R
1
2
3
4
5
6
K2CO3 (2)
A
A
A
A
T
A
H
O
O
R
X
b
(2 o
R1
R1
K2CO3 (2), PivOH (0.2)
PivOH (0.2)
AgOAc (2)
)
NHAQ
NHAQ
Pd(OAc)2 (10 mol %)
R2 R3
R2 R3
AgOAc (2)
<2
5
Scheme 2. DG-Mediated Pd-Catalyzed Alkylation of Un-
activated C(sp3)−H Bonds with Primary Alkyl Halides
Ag2CO3 (2)
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A) A possible PdII/IV manifold
7
Ag2CO3 (2), PivOH (0.2)
A
A
T
A
75
91 (85)c
67
<3
5
O-
O
1
2
3
4
5
6
7
8
8
Ag2CO3 (2), (BnO)2PO2H (0.2)
Ag2CO3 (2), (BnO)2PO2H (0.2)
Ag2CO3 (2), TEMPO (1)
O
H+
N
N
N
H
AQ
9
<2
<2
PdII
O
N
N
N
N
H
H
H
10
82
11
EtO2C
4
O
PdII
1
O (CH3)
- O
a) A: t-AmylOH, T: toluene. b) Yields are based on H-
NMR analysis of the reaction mixture after workup on a 0.2
mmol scale. c) Isolated yield.
Table 2. Optimization of AQ-Directed C(sp3)−H Alkyla-
tion of N-Phth Protected Leu 13
C- H
palladation
protonolysis
- O
N
PdII
PdII
N
I
- O
SN2 ?
EtO2C
I (L)
N
EtO2C
18
RE
(L)
9
16
Ag+
OA
I
PdIV
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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O
N
O
MeO2C
Br
EtO2C
I
PhthN
PhthN
or
NHAQ
14 (2 equiv)
9 (2 equiv)
17
NHAQ
EtO2C
(8)
CO2Et (Me: 15b)
H
Pd(OAc)2 (10 mol %), 110 oC, Ar, 20h
B) Ortho-alkylation of AQ
CO2Et
PdIV
15a bCMe-Leu
13 Leu
PdII
O
O
PdII
9
entry reagents (equiv)
solvents a
Yields (%) b
15
N
11 or 18
12
N
PdII
(?)
PdII
(?)
N
N
EtO2C
1
2
3
4
5
6
7
8
9
9 (2), AgOAc (2)
A
A
A
A
A
A
A
A
A
36
31
EtO2C
19
20
9 (2), Ag2CO3 (1)
9 (2), Ag2CO3 (1), (BnO)2PO2H (0.2)
9 (2), AgOAc (2), (BnO)2PO2H (0.2)
9 (2), Ag2CO3 (2), (BnO)2PO2H (0.2)
9 (2), Ag2CO3 (2), BINA-PO2Hc (0.2)
9 (2), Ag2CO3 (2), (PhO)2PO2H (0.2)
14 (2), Ag2CO3 (2), (BnO)2PO2H (0.2)
14 (2), Ag2CO3 (2), (BnO)2PO2H (1)
59
The exact mechanism of this Pd-catalyzed AQ-directed
Ag-promoted alkylation has not been clearly established.12
As shown in Scheme 3A, we postulate that this C−H alkyl-
45
74
46
ation reaction proceeds through
a
C−H pallada-
59
tion/coupling sequence, and that a PdII/IV manifold is op-
erative.17 Oxidative addition (OA) of 9 onto electron-rich
PdII palladacycle 16 may proceed through a SN2 pathway,
promoted by Ag+.13 The Ag+ ion could also act as a halide
scavenger, abstracting the halide ligand from PdIV inter-
mediate 17 and promoting reductive elimination (RE).18
Ag+ could also serve to remove the halide ligand from the
PdII intermediate 18 to promote the regeneration of the
more active PdII catalyst. We can only speculate on the
functional role of (BnO)2PO2H at the moment.19
(BnO)2PO2H was clearly more effective than all other car-
boxylic acid additives (e.g. PivOH, entry 7, Table 1) and
organic phosphates tested (e.g. BINA-PO2H, entry 6, Ta-
ble 2). (BnO)2PO2H could form a soluble complex with
Ag2CO3 and influence the concentration of otherwise in-
soluble Ag+ in the reaction medium. (BnO)2PO2H could
also act as a ligand (L) for palladium during the OA and
RE steps. We also suspect that (BnO)2PO2H could help
the protonolysis of the Pd-complexed alkylated interme-
diate 18, promoting the release of the product 11 and ac-
celerating the turnover of Pd catalyst. As shown in
Scheme 3B, the ortho C−H bond of the AQ group of 11 can
undergo another alkylation with 9 to form 12. We suspect
that two palladium cations are involved in this second
alkylation step. The first Pd cation complexes with alkyl-
ated substrate 11 through a strong bidentate interaction;
the second Pd is ligated through the O-imidate group and
effects the ortho-palladation and subsequent coupling
with 9, possibly through a PdII/IV manifold. A similar am-
ide-directed Pd-catalyzed ortho-methylation of arenes
with MeI was first reported by Tremont et al. in the
1970s.14a
78 (70)d
31
a) A: t-AmylOH. b) Yields are based on 1H-NMR analysis of
the reaction mixture after workup on a 0.2 mmol scale. c)
(S)-(+)-1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate; d) iso-
lated yield, > 98% ee (see Supporting Information).
We next subjected N-Phth protected amino acid sub-
strate leucine (Leu) 13 to the same carboxymethylation
reaction with 9 (eq 8, Table 2). Only a moderate yield of
15a was obtained under the same Ag2CO3-promoted con-
ditions that worked well for simple aliphatic carboxamide
4 (entries 1, 2). Gratifyingly, application of 2 equiv of
Ag2CO3 and 20 mol% of (BnO)2PO2H improved the yield
by 40% (entry 5). Additionally, we found -bromoacetate
14 to be a better electrophile than 9; application of 2 equiv
of 14, 2 equiv of Ag2CO3 and 20 mol% of (BnO)2PO2H at
o
110 C under Ar in t-AmylOH for 20 hours transformed 13
into 15b in 70% isolated yield and excellent diastereose-
lectivity (>15/1) (entry 8). Interestingly, use of 1 equiv of
(BnO)2PO2H provided significantly lower yield (entry 9).
Chiral HPLC confirmed that the chiral integrity of the -C
of Leu 13 was maintained during the C−H alkylation reac-
tion (>98% ee, see Supporting Information). The for-
mation of a five-membered palladacycle intermediate
with trans Phth-N and R configuration (see eq 10,
Scheme 5) is likely responsible for the stereoselectivity
observed in the  C−H alkylation of -substituted sub-
strates.
Scheme 3. Mechanistic Hypothesis
Scheme 4. AQ-Directed C(sp3)−H Alkylation of Simple
Aliphatic Carboxamide Substrates
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EtO2C
I
All yields are based on isolated product on a 0.2 mmol
scale: a) 3 equiv of 9 was used. b) 2 equiv of 14 was used. c) 15
mol % of Pd(OAc)2 and 5 equiv of 9 was used.
(2 equiv)
R
or MeI
H
O
1
2
3
4
5
6
7
8
O
(9)
R1
R1
Pd(OAc)2 (10 mol %)
Ag2CO3 (2 equiv)
NHAQ
NHAQ
R2 R3
R2 R3
(BnO)2PO2H (20 mol %)
t-AmylOH, 110 oC, Ar, 6-24 h
We next examined the substrate scope of this AQ-
directed C(sp3)−H alkylation with -haloacetate 9 and
MeI under the general conditions using Ag2CO3 (2
equiv)/(BnO)2PO2H (20 mol%). As shown in Scheme 4A,
excellent alkylation yields were obtained for substrates
bearing no -substituents; functionalizations of these
substrates at their methylene C(sp3)−H bonds is particu-
larly difficult due to their high structural flexibility. Car-
boxymethylation of a sterically crowded cyclopentyl sub-
strate gave 21 in 81% yield. AQ-coupled 3-
phenylpropionamide was alkylated at the benzylic posi-
tion to give 25 in 86% yield. The  methylene C(sp3)−H
bonds of 4-6 membered cyclic alkane carboxamides were
bis-alkylated with 3 equiv of 9 in excellent yield and ex-
clusive cis-diastereoselectivity (see 27, 28, 30 in Scheme
4B). In contrast, a cyclopropylcarboxamide substrate was
preferentially mono-carboxymethylated with 2 equiv of 9
to give 31, which could then be methylated with MeI to
A) Alkylation of b 2o C(sp3)- H bonds of substrates without a -substituents
EtO2C
EtO2C
Ph
EtO2C
O
O
O
PhthN
NHAQ
NHAQ
NHAQ
9
22 (78%)
23 (87%)
21 (81%)
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
EtO2C
Ph
O
O
O
Ph
NHAQ
24 (92%)
NHAQ
NHAQ
25 (84%)
26 (93%)
B) Alkylation of b 2o C(sp3)- H bonds of cyclic substrates
EtO2C
EtO2C
O
O
O
Cbz
N
NHAQ
CO2Et
NHAQ
CO2Et
NHAQ
CO2Me
28 (83%)a
27 (71%)a
29 (80%)b
O
O
O
EtO2C
NHAQ
CO2Et
NHAQ
CO2Et
NHAQ
CO2Et
30 (84%)a
32 (66%)
31 (80%)
C) Alkylation of b 1o C(sp3)- H bonds
O
O
O
NHAQ
CO2Et
EtO2C
NHAQ
EtO2C
NHAQ
EtO2C
35 (81%)c
33 (90%)
34 (60%)
Scheme 5. Pd-Catalyzed AQ-Directed Alkylation of  C(sp3)−H Bonds of Amino Acids
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O
PhthN
1
2
3
4
5
6
N
O
O
PdII
R'
X
N
PhthN
R'
PhthN
R'
H
NHAQ
R
NHAQ
R
H
(10)
(2 equiv)
H
H
Pd(OAc)2 (10 mol %), Ag2CO3 (2 equiv)
(BnO)2PO2H (20 mol %), t-AmylOH, Ar, 110 oC, 6-24 h
7
8
9
O
O
H
O
O
H
+ 14
14
PhthN
PhthN
PhthN
PhthN
NHAQ
NHAQ
NHAQ
NHAQ
CO2Me
NHAQ
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
CO2Me
NPhth
NPhth
PhthN
15 bCMe-Leu
(70%, dr > 15/1)
13 Leu
37 Lys
36 bCMe-Lys
(85%, dr > 15/1)
O
O
O
PhthN
PhthN
+ 14
+ PhI
NHAQ
NHAQ
MeO2C
CO2Me
H
38 bPh-Glu
(88%, dr > 15/1)a
39 bCMe-Phe
(84%, dr > 15/1)
40 Phe
O
O
O
PhthN
PhthN
+ 14
PhthN
+ 14
+ MeI
+ MeI
NHAQ
NHAQ
NHAQ
CO2Me
MeO2C
MeO2C
41 Glu
(58%)
43 bCMe-Abu
(87%, dr > 15/1)
42 bMe-Glu
(85%, dr ~ 10/1)b
O
O
+ CD3I
PhthN
PhthN
NHAQ
NHAQ
O
H
O
CD3
46 Val (90%)b
PhthN
45 Val (90%)c
PhthN
NHAQ
NHAQ
44
Ala
47
L-Abu
O
O
H
PhthN
PhthN
NHAQ
NHAQ
13CH3
49 Val (90%)b
H313C 13CH3
48 Val (90%)c
13CH3I
+
13CH3I
+
O
O
O
+ EtI
+ MeI
PhthN
+ EtI
PhthN
PhthN
NHAQ
NHAQ
NHAQ
50 Nva (51%)d
51 Ile
(90%, dr ~ 3/1)b
52 allo-Ile
(62%, dr ~ 8/1)d
O
O
PhthN
PhthN
NHAQ
+ MeI
NHAQ
+ PhI
40 Phe
54 bPh-Abu
(89%, dr > 15/1)a
53 bMe-Phe
(85%, dr ~ 10/1)b
All reactions were carried out on a 0.2 mmol scale; yields are based on isolation. a) Same reaction conditions with 2 equiv of PhI. b) 1.1
equiv of MeI was used. c) 2.2 equiv of MeI was used. d) 3 equiv of EtI and 1 equiv of Ag2CO3 was used. See Supporting Information for
experimental details.
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
give product 32 in moderate yield. Substrates derived
from propionic acid, 2-butanoic acid and ibuprofen were
carboxymethylated at the -Me position to give 33-35 un-
der the standard reaction conditions (Scheme 4C). Inter-
estingly, we observed only carboxymethylation of 1o
C(sp3)−H bond, possibly due to the newly installed ester
group coordinating to the AQ-Pd complex and inhibiting
further functionalization. Compared with MeI and -
haloacetates, other -H containing primary alkyl halides
gave low to moderate yields under the standard condi-
tions (e.g. EtI for 50, Scheme 5). The alkylation reaction
did not proceed with any secondary alkyl iodides we test-
ed.
We then applied this Pd-catalyzed C(sp3)−H alkylation
to N-Phth protected amino acid substrates. A range of
amino acid substrates bearing either aliphatic or aromatic
side chains were alkylated with 2 equiv of 14 or MeI at the
-methylene position in good to excellent yield and dia-
stereoselectivity (Scheme 5).20 Stereoinduction by the , 
trans-configured 5-member palladacycle intermediate
provided us a simple and reliable model to predict the
8
diastereoselectivity of the -alkylations.7, For instance,
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Journal of the American Chemical Society
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Lysine (Lys) 37 and phenylalanine (Phe) 40 were cleanly ylenediamine and converted into an azide group via
treatment with TfN325 (Scheme 6A). Activation of the am-
ide group of 55 with Boc2O and subsequent treatment
with LiOH/H2O2 gave the azido acid product 56 in good
yield. -Me Phe 53 could be converted to the azido acid 57
following the same sequence used for 48 (scheme 6B).
Conventionally, compound 57 can be prepared from an
anhydride derivative of enantio-enriched 3-phenylbutyric
acid using the Evans auxiliary-mediated bromination and
azidonation strategy.26 The N3 group of 57 can be reduced
to NH2 by hydrogenation and protected with Boc2O to
give the Boc-protected -Me Phe 5827 in good yield.
1
2
3
4
5
6
7
8
carboxymethylated to give 36 and 39 respectively. Alanine
(Ala) 44 was preferentially mono-carboxymethylated at
the -Me position to give a glutamic acid product (Glu)
41, similar to the reaction of our propionamide substrate
33. Glu 41 can be further methylated with MeI at the 
position to give Me-Glu 42. Glu 41 could be also arylated
with PhI under Pd-catalysis to give Ph-Glu 38, a dia-
stereomer of 39. C−H alkylation of Ala 44 under the
standard conditions with 2.2 equiv of MeI gave valine
(Val) 45 in 90% yield, which was formed through mono-
methylated intermediate L--amino butyramide (Abu) 47.
Ala 44 can also be ethylated at the  methyl position with
EtI to give norvaline (Nva) 50 in 50% yield, which could
be subsequently methylated at the  position to give iso-
leucine (Ile) 51 in good yield and moderate diastereoselec-
tivity.
9
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
In summary, we have discovered a new set of reactions
based on the Pd-catalyzed alkylation of unactivated
methylene C(sp3)−H bonds of aminoquinolyl aliphatic
carboxamides with -haloacetate and methyl iodide.
These reactions are highly efficient, versatile, and have
broad substrate scope. These reactions represent the first
generally applicable method for the catalytic alkylation of
unconstrained and unactivated methylene C−H bonds
with high synthetic relevance. These reactions enable a
streamlined strategy for the synthesis of various natural
and unnatural amino acids, particularly -alkylated -
amino acids, starting from readily available precursors in
a diastereoselective manner following a straightforward
template. With simple isotope-enriched reagents, they
also provide a convenient and powerful solution to site-
selectively incorporate isotopes into the carbon scaffolds
of amino acid compounds. Applications of this C−H alkyl-
ation methodology in the synthesis of complex peptide
natural products containing various nonproteinogenic -
alkylated -amino acids are currently under investiga-
tion.
Abu 47 also serves as a versatile precursor for various -
methylated amino acid products bearing inverse stereo-
chemistry at the  position compared to those obtained
via AQ-directed C−H methylation. For example, carbox-
ymethylation of Abu 47 gave CMe-Glu 43. Analogous to
the synthesis of Ile 50, Abu 47 can also be ethylated with
EtI to give allo-isoleucine (allo-Ile) 52 in moderate yield
and diastereoselectivity. Arylation of 47 with PhI gave
Ph-Abu 54, a diastereomer of 53. By varying the sequence
of C−H alkylation, we can access both diastereomers of a
variety of -alkylated amino acids. Additionally, C−H
methylation of Ala 44 and Abu 47 with 13CH3I or CD3I un-
der the standard conditions gave isotope-labeled Val
products 46, 48, and 49 in excellent yield.21 These reac-
tions offer a unique and simple means for the preparation
of various site-selectively isotope-labeled amino acid
products, which are of great value in biochemical studies
of peptides and proteins.22
Scheme 6. Removal of AQ Group Under Mild Conditions
A)
1. Boc2O, DMAP,
CH3CN, rt, 92%
O
O
1. NH2C2H4NH2,
nBuOH, rt
N3
N3
NHAQ
OH
48
2. TfN3, CuSO4,
CH2Cl2, Et3N, rt,
82%, over 2 steps
2. LiOH, H2O2
THF/H2O
rt, >80%
H313C 13CH3
H313C 13CH3
Compounds 11 and 12: A mixture of carboxamide 4 (43
mg, 0.2 mmol, 1 equiv), Pd(OAc)2 (4.4 mg, 0.02 mmol, 0.1
equiv), Ag2CO3 (110 mg, 0.4 mmol, 2 equiv), (BnO)2PO2H
(11 mg, 0.2 equiv), ICH2CO2Et (86 mg, 0.4 mmol, 2 equiv)
and t-AmylOH (2 mL) in a 10 mL glass vial (purged with
Ar, sealed with PTFE cap) was stirred at 110 oC for 6 hours.
The reaction mixture was cooled to room temperature
and concentrated in vacuo. The resulting residue was pu-
rified by silica gel flash chromatography to give the alkyl-
ated product 11 in 85 % isolated yield (Rf = 0.5, 25 %
55
56
B)
O
1. Pd/C, NH4HCO2
MeOH, rt
2. Boc2O, NaOH,
H2O, rt
O
O
PhthN
same
sequence
BocHN
N3
NHAQ
OH
OH
for 48
64%
82 %
53
57
58
Evans auxilairy-mediated
a -bromindation, azidonation
(ref 26)
1
EtOAc in hexanes). H NMR (CDCl3, 300 MHz, ppm): δ
O
O
O
9.83 (s, 1 H), 8.79-8.76 (m, 2 H), 8.16-8.13 (m, 1 H), 7.55-
7.24 (m, 3 H), 4.14 (dd, J = 14.1 and 7.2 Hz, 2 H), 2.71-2.62
(m, 2 H), 2.54-2.43 (m, 2 H), 2.36-2.29 (m, 1 H), 1.25 (t, J =
59
13
7.2 Hz, 3 H), 1.13 (d, J = 6.3 Hz, 3 H); C NMR (CDCl3, 75
MHz, ppm) δ 172.4, 170.3, 148.1, 138.3, 136.3, 134.4, 127.9,
127.3, 121.6, 121.4, 116.4, 60.3, 44.6, 40.9, 28.1, 19.8, 14.2;
HRMS: calculated for C17H21N2O3 [M+H+]: 301.1552; found:
301.1553; Compound 12 (Rf = 0.5, 35 % EtOAc in hexanes):
The amide-linked AQ group of the amino acid products
can be removed under mild conditions using our previ-
24
ously reported protocol.23,
For example, the N-Phth
group of 13C-labeled Val 48 can be deprotected with eth-
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Journal of the American Chemical Society
1H NMR (CDCl3, 300 MHz, ppm): δ 9.87 (s, 1 H), 8.81-8.71
Compound 56: A mixture of compound 55 (44 mg, 0.16
1
2
3
4
5
6
7
8
(m, 2 H), 8.36 (dd, J = 8.7 and 1.2 Hz, 1 H), 7.52-7.43 (m, 2
H), 4.18-4.08 (m, 4 H), 3.98 (s, 2 H), 2.66 (dd, J = 9.6 and
3.6 Hz, 2 H), 2.51-2.46 (m, 2 H), 2.36-2.33 (m, 1 H) 1.28-1.18
(m, 6 H), 1.13 (d, J = 6.6 Hz, 3 H); 13C NMR (CDCl3, 75
MHz, ppm) δ 172.5, 171.3, 170.4, 147.9, 138.6, 134.1, 133.0,
129.1, 127.0, 124.6, 121.6, 116.0, 61.1, 60.4, 44.7, 41.0, 38.4,
28.2, 19.9, 14.3, 14.2; HRMS: calculated for C21H27N2O5
[M+H+]: 387.1920; found: 387.1922.
mmol, 1 equiv), Boc2O (106 mg, 0.48 mmol, 3 equiv) and
DMAP (40 mg, 0.32 mmol, 2 equiv) in anhydrous CH3CN
(1 mL) was stirred at room temperature for 6 hours. The
resulting residue was concentrated in vacuo and then pu-
rified by silica gel flash chromatography to give product
55a in 92 % yield (54 mg, Rf = 0.60, 25% EtOAc in hex-
1
anes). H NMR (CDCl3, 300 MHz, ppm): δ 8.87 (d, J = 3.0
Hz, 1 H), 8.16 (d, J = 8.1 Hz, 1 H), 7.82 (dd, J = 7.5 and 1.5
Hz, 1 H), 7.59-7.51 (m, 2 H), 7.41 (dd, J = 8.4 and 4.2 Hz, 1
H), 5.09 (br, 1 H), 2.52-2.38 (m, 1 H), 1.41 (t, J = 6.0 Hz, 1.5
H), 1.32 (t, J = 6.0 Hz, 1.5 H), 1.21 (s, 9 H). 0.99 (t, J = 6.0
9
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
13
Compound 48: A mixture of carboxamide 44 (69 mg,
0.2 mmol, 1 equiv), Pd(OAc)2 (4.4 mg, 0.02 mmol, 0.1
equiv), Ag2CO3 (110 mg, 0.4 mmol, 2 equiv), (BnO)2PO2H
(11 mg, 0.2 equiv), 13CH3I (63 mg, 0.44 mmol, 2.2 equiv)
and t-AmylOH (2 mL) in a 10 mL glass vial (purged with
Ar, sealed with PTFE cap) was stirred at 110 oC for 3 hours.
The reaction mixture was cooled to room temperature
and concentrated in vacuo. The resulting residue was pu-
rified by silica gel flash chromatography to give the alkyl-
ated product 48 in 90 % yield (Rf = 0.50, 35 % EtOAc in
Hz, 1.5 H), 0.90 (t, J = 6.0 Hz, 1.5 H); C NMR (CDCl3, 75
MHz, ppm) δ 173.5, 152.5, 150.4, 143.9, 136.3, 135.9, 128.8,
128.6, 128.3, 126.0, 121.6, 83.3, 67.7, 31.4, 27.5, 19.9 (13C), 17.9
(13C); HRMS: calculated for C1713C2H24N5O3 [M+H+]:
372.1946; found: 372.1949; Compound 55a (37 mg, 0.1
mmol, 1 equiv) was dissolved in THF/H2O (1 mL, 3:1), Li-
OH•H2O (8 mg, 0.2 mmol, 2 equiv) and 30% H2O2 (0.5
mmol, 5 equiv) were then added at 0 oC. The reaction was
stirred at room temperature for 3 hours and Na2SO3 (1
mmol, 10 equiv) was added. The reaction mixture was
diluted with EtOAc (2 mL), acidified with 0.5 M aq. HCl,
and extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo. The
resulting residue was purified by silica gel flash chroma-
tography to give compound 56 (14 mg, >80%) (Rf = 0.40,
1
hexanes). H NMR (CDCl3, 300 MHz, ppm): δ 10.58 (s, 1
H), 8.86-8.75 (m, 2 H), 8.14-8.12 (m, 1 H), 7.89 (dd, J = 5.7
and 3.3 Hz, 2 H), 7.73 (dd, J = 5.4 and 3.0 Hz, 2 H), 7.51-
7.44 (m, 3 H), 4.72-4.67 (m, 1 H), 3.28-3.19 (m, 1 H), 1.44 (t,
J = 6.0 Hz, 1.5 H), 1.20 (t, J = 6.0 Hz, 1.5 H), 1.02 (t, J = 6.0
13
1
Hz, 1.5 H), 0.78 (t, J = 6.0 Hz, 1.5 H); C NMR (CDCl3, 75
in 50% EtOAc in hexanes). H NMR (CDCl3, 300 MHz,
MHz, ppm) δ 168.1, 166.8, 148.5, 136.1, 134.2, 131.6, 127.9,
127.2, 123.6, 121,9, 121.6, 117.0, 63.2, 27.3, 20.4 (13C), 19.6
(13C); HRMS: calculated for C2013C2H20N3O3 [M+H+]:
376.1572; found: 376.1573.
ppm): δ 3.79 (br, 1 H), 2.29-2.19 (m, 1 H), 1.30-1.21 (m, 3 H),
0.88-0.79 (m, 3 H); 13C NMR (CDCl3, 75 MHz, ppm) δ
176.4, 67.7, 30.9, 19.4 (13C), 17.7 (13C); HRMS: calculated for
C313C2H10N3O2 [M+H+]: 146.0840; found: 146.0843.
Compound 55: A mixture of compound 48 (75 mg, 0.2
mmol, 1 equiv) and ethylenediamine (120 mg, 2 mmol, 10
equiv) in nBuOH (2 mL) was stirred at room temperature
for 12 hours. The reaction mixture was concentrated in
vacuo and the resulting residue was purified by silica gel
flash chromatography (10% MeOH in CH2Cl2) to give the
free amine intermediate. The amine intermediate was
dissolved in CH2Cl2 (2 mL). CuSO4 (1 mg, 0.006 mmol,
0.03 equiv), TfN325 (~0.6 M in CH2Cl2, ~4 equiv), and Et3N
(0.6 mmol, 3 equiv) were added and the mixture was
stirred at room temperature for 4 hours. Water was added
and the mixture was extracted with CH2Cl2. The organic
layer was dried over anhydrous Na2SO4 and concentrated
in vacuo. The resulting residue was purified by silica gel
flash chromatography to give the compound 55 in 82%
Additional experimental procedures and spectroscopic data
for all new compounds are supplied. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
guc11@psu.edu
We gratefully thank The Pennsylvania State University, NSF
(CAREER CHE-1055795), and ACS-PRF (51705-DNI1) for fi-
nancial support of this work.
1
yield (2 steps, Rf = 0.70, 25% EtOAc in hexanes). H NMR
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and 1.5 Hz, 1 H), 8.83-8.80 (m, 1 H), 8.20 (dd, J = 8.4 and
1.5 Hz, 1 H), 7.59-7.49 (m, 3 H), 4.10 (dd, J = 7.5 and 4.5
Hz, 1 H), 2.57-2.53 (m, 1 H), 1.42 (dd, J = 6.6 and 5.1 Hz, 1.5
H), 1.28 (dd, J = 6.0 and 5.1 Hz, 1.5 H), 1.00 (dd, J = 6.6 and
5.1 Hz, 1.5 H), 0.86 (dd, J = 6.6 and 5.4 Hz, 1.5 H); 13C NMR
(CDCl3, 75 MHz, ppm) δ 167.7, 148.6, 138.7, 136.3, 133.6,
128.0, 127.2, 122.3, 121.7, 116.7 71.5, 32.4, 19.7 (13C), 17.1 (13C);
HRMS: calculated for C1213C2H16N5O [M+H+]: 272.1422;
found: 272.1427.
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Journal of the American Chemical Society
Page 8 of 9
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2
3
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5
6
7
8
6 was previously reported by us: Feng, Y.; Wang, Y.; Land-
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stable PdIV complex. However, alternative mechanisms in-
volving Pd intermediates of different oxidation states cannot
be completely ruled out for this CH alkylation reaction sys-
tem.
18. Preliminary results from our computational investigation of
Pd-catalyzed PA-directed CH arylation indicates that the
iodide is exchanged with an OAc ligand prior to the PdIV in-
termediate undergoing reductive elimination.
9
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
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60
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occur as a minor side reaction for certain structurally con-
strained substrates.
o
21. Methylation reactions of most substrates at 80 C gave simi-
lar result.
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mild
conditions
at rt
13CH3I (2.2 equiv)
O
O
H
O
PhthN
H
PhthN
N3
N
H
NHAQ
OH
H313C 13CH3
Pd(OAc)2 (10 mol %)
(BnO)2PO2H (0.2 equiv)
Ag2CO3 (2 equiv)
N
H313C 13CH3
Val (90%)
H
(AQ)
Ala
t-AmylOH, 110 oC, Ar, 20 h
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