β-C(sp3)-H Arylation of α-Hydroxy Acid Derivatives Utilizing Amino Acid as a Directing Group

Article abstract of DOI:10.1021/acs.orglett.5b02900

The Pd(II)-catalyzed arylation of unactivated β-C(sp³)-H bonds in α-hydroxy aliphatic acid with a variety of aryl iodides was developed utilizing an amino acid auxiliary as a directing group. This protocol provides access to biologically active

Full text of DOI:10.1021/acs.orglett.5b02900

Letter
pubs.acs.org/OrgLett
β‑C(sp3)−H Arylation of α‑Hydroxy Acid Derivatives Utilizing Amino
Acid as a Directing Group
Tetsuya Toba,†,‡ Yi Hu,§,‡ Anh T. Tran, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: The Pd(II)-catalyzed arylation of unactivated β-
C(sp3)−H bonds in α-hydroxy aliphatic acid with a variety of aryl
iodides was developed utilizing an amino acid auxiliary as a directing
group. This protocol provides access to biologically active β-arylated-
α-hydroxy acid derivatives.
alladium-catalyzed activation of the inert β-C(sp3)−H
Pbonds of aliphatic carboxylic acid derivatives has met with
substantial progress over the past decade with the develop-
ment of a number of directing groups such as chiral
oxazolines,1 8-aminoquinoline,2 and 2-(pyridin-2-yl)isopropyl3
as well as a variety of weakly coordinating fluorinated amide
directing groups.4
Previously, we have reported the synthesis of a variety of
unnatural amino acids via the direct β-functionalization of α-
amino acids employing the weakly coordinating perfluorinated
aryl amides5 and N-methoxyamide directing groups.6 Recently,
our group also demonstrated that C-terminal amino acids, by
coordination with Pd(II), can activate proximal β-C(sp3)−H
bonds of N-terminal amino acids in dipeptides.7 A similar
Figure 1. Some examples of biologically active β-aryl-α-hydroxy acid
derivatives.
approach has been elegantly adopted by Hong and co-workers
utilizing C-terminal amino acid amides to achieve asymmetric
β-C(sp3)−H functionalization of cyclopropane carboxylic acid
mono-N-protected amino acid (MPAA) ligands.12 Kinetic13
and computational studies14 suggest that the monomeric
Pd(II) complex coordinated by a MPAA in a bidentate
manner is highly reactive for cleaving inert C−H bonds. Our
report on the β-C(sp3)−H functionalization of di-, tri-, and
tetrapeptide compounds7 can be rationalized by the intra-
molecular amino acid constituting the peptide participating as
an internal MPAA ligand, which coordinates to Pd(II), and
promotes functionalization of the proximal β-C(sp3)−H
bonds at the N-terminus.
Based on the above findings, we turned to utilize an amino
acid auxiliary as a directing group for the functionalization of
O-protected α-hydroxy aliphatic acid derivatives. We selected
commercially available O-benzyl-D-lactic acid as the starting
material for further investigation.15 Using our previously
reported conditions for β-C(sp3)−H functionalization of di-,
tri-, and tetrapeptide compounds,7 arylation of 1a [R= (S)-i-
Pr] with 4-iodotoluene in HFIP afforded the desired product
2a in a promising 79% yield along with unreacted starting
material (Scheme 1). This result is particularly encouraging
considering that the perfluorinated aryl amide auxiliary only
derivatives.8
Although there are numerous reports describing the β-
C(sp3)−H functionalization of carboxylic acid derivatives
employing bidentate directing groups2,3,9 or weakly coordinat-
ing auxiliaries such as perfluorinated arylamides,4b examples of
β-functionalization of α-hydroxy carboxylic acids are limited.
In 2010, Shabashov and Daugulis reported a single example of
β-arylation of benzyl protected lactic acid employing a 2-
methylthioaniline auxiliary.10 More recently, Baudoin’s group
has elegantly utilized silyl ketene acetals for the migrative
arylation to deliver β-arylated α-hydroxy carboxylic esters,
albeit with loss of chirality at the α-position.11 Herein, we
report the arylation of unactivated β-C(sp3)−H bonds in α-
hydroxy acid derivatives that utilizes an amino acid auxiliary as
a directing group to deliver various 2-hydroxy-3-arylpropionic
acids with high stereochemical integrity. We envisaged that
this protocol would facilitate access to a variety of 2-hydroxy-
3-arylpropionic acids, which are frequently found building
blocks in several pharmaceuticals and biologically active
compounds (Figure 1), from readily available lactic acid
feedstock.
We have previously disclosed a diverse range of C−H bond
activation reactions that are either enabled or accelerated by
Received: October 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02900
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 1. Scope of Amino Acids as the Auxiliaries
Table 1. Selected Data from Optimization Study
a
entry
[Ag]
[base]
KF
yield (%)
1
2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgF
79
70
21
58
51
75
59
76
7
KHCO3
K2HPO4
LiF
3
4
5
NaHCO3
CsF
6
7
None
KF
8
9
Ag3PO4
Cu(OAc)2
AgOAc
AgOAc
KF
10
KF
0
b
11
KF
76
66
69
69
71
77
78
85
c
12
KF
d
13
14
15
AgOAc
KF
e
AgOAc
KF
f
a
AgOAc
AgOAc
AgOAc
KF
Reaction conditions: substrate (0.1 mmol), 4-Me-C6H4I (2 equiv),
Pd(OAc)2 (10 mol %), AgOAc (2 equiv), KF (3 equiv), HFIP (1 mL),
g
16
KF
KF
KF
h
b
100 °C, 24 h. The yields were determined by 1H NMR analysis of the
crude reaction mixture using CH2Br2 as an internal standard.
17
h
e
18
AgOAc
a
The yields were determined by 1H NMR analysis of the crude
b
c
d
gave the desired arylation product in 50% yield despite
extensive optimization. As a control experiment, the
corresponding amino ester was not reactive.
products using CH2Br2 as an internal standard. 120 °C. 16 h. 1.5
equiv. 3 equiv. 2 equiv. Pd(OAc)2 (5 mol %). 4-Me-C6H4I (3
equiv)
e
f
g
h
The effect of the directing groups was then investigated.
Further screening of the amino acid auxiliary revealed match/
mismatch effects. Specifically, in the arylation of D-lactic acid
with 4-iodotoluene, the L-valine auxiliary (1a) afforded a
higher yield of the desired product (2a: 79%, Scheme 1) than
the D-valine counterpart (2b: 38%, Scheme 1). The yield for
L-isoleucine (1d) was comparable to 1a, while the smaller L-
alanine (1c) or bulkier L-phenylalanine (1e) decreased the
yield. Achiral glycine (1g) gave a higher yield than its gem-
dimethyl analogue (1f).
Encouraged by these results, systematic screening was
performed using 1a as model substrate. Representative
screening results are shown in Table 1 (see the Supporting
Information for comprehensive screening tables). Solvent
screening led us to discover polar, weakly acidic hexafluor-
oisopropanol (HFIP) as the solvent of choice. Although salts
of other cations were also effective to some extent, potassium
was apparently the best cation, for it generally gave higher
yields than other salts (entries 1−6).16 The reaction also
proceeded in the absence of base, albeit with lower yield
(entry 7). Counteranions also played an important role with
fluoride being the best anion (entry 1) while phosphate anion
was shown to have a detrimental effect on yield (entries 3, 9).
Substitution of Cu(OAc)2 for AgOAc completely suppressed
the reaction (entry 10), demonstrating the necessity of the
silver source. It has been postulated in the literature that silver
salts play dual roles. First, the reaction of the alkylpalladium-
(II) with ArI is often promoted by Ag(I) salts. Second, Ag(I)
can act as iodide scavengers, thereby preventing catalyst
poisoning resulting from accumulation of iodide anions in the
reaction mixture17 and resulting in an increase in turnover
number.18 From the screening results, the best combination of
the reagents were found to be Pd(OAc)2, AgOAc, and KF in
HFIP.
To improve the protocol further, we evaluated the effects of
temperature, reaction time, and chemical equivalents of the
reagents on the efficiency of the arylation reaction. Raising the
temperature did not affect the yield (Table 1, entry 11), while
decreasing the reaction time, AgOAc, or KF reduced the yield
(entries 12, 13, and 15, respectively). It was also found that
while excess aryl iodide alone did not improve the yield
(entry 17), a simultaneous increase of both iodide and AgOAc
gave rise to the highest yield (entry 18). It was also possible
to lower the Pd(OAc)2 loading to 5 mol %, albeit with a small
reduction in yield (entry 16). For further information, see
Table S2, entry 31, in the Supporting Information).
With the optimized conditions in hand, the scope of the
coupling partners was then explored (Scheme 2). In general,
substrate 1a was arylated with a wide range of aryl iodides in
moderate to good yields. Both electron-donating and electron-
withdrawing groups at either the meta or para positions of the
aryl iodides were tolerated. Aryl iodides with ortho
substituents gave lower yields, presumably due to the steric
hindrance, since a small o-F substituent on the aryl iodide was
well tolerated (12). Under the present reaction conditions, p-
bromotoluene was not reactive. To demonstrate the scalability
of this protocol, a gram-scale synthesis (4.0 mmol) of 2a was
performed. We were pleased to find that the desired product
could be obtained in 70% isolated yield.
Removal of the auxiliary group was accomplished in high
yield through an N-nitrosylation/hydrolysis sequence (Scheme
3). Thus, 2a was esterified with TMSCHN2 to afford 18 in
97% yield, which was treated with NaNO2 in AcOH/Ac2O to
give the acid 19 in 72% yield (91% based on recovered
starting material). Alternatively, 2a could be heated in
concentrated HCl/1,4-dioxane to give free α-hydroxy acid
17 in 70% yield. These two routes provide orthogonal
B
DOI: 10.1021/acs.orglett.5b02900
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 2. Scope of Coupling Partners for Pd-Catalyzed β-Arylation of α-Hydroxy Acids
a
Reaction conditions: substrate (0.2 mmol), ArI (3 equiv), Pd(OAc)2 (10 mol %), AgOAc (3 equiv), KF (3 equiv), HFIP (0.1 M), 100 °C, 24 h.
Isolated yields. The reaction was carried out on a 4.0 mmol scale.
b
c
ASSOCIATED CONTENT
Scheme 3. Removal of the Amino Acid Auxiliary
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02900.
Experimental procedures, detailed optimization data,
and characterization of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yu200@scripps.edu.
Present Addresses
†(T.T.) Medicinal Chemistry Function, Asubio Pharma Co.,
Ltd.
methods to access differently protected β-aryl-α-hydroxy acid
derivatives without erosion in the stereochemistry with acids
17 and 19 being obtained in 99% ee as determined by
analytical chiral HPLC.
§(Y.H.) College of Biotechnology and Pharmaceutical
Engineering, Nanjing Tech University.
Author Contributions
‡T.T. and Y.H. contributed equally.
In summary, we have developed an arylation procedure for
unactivated β-C(sp3)−H bonds in α-hydroxy acid derivatives
directed by a commercially available amino acid auxiliary. The
reaction proceeded with a wide range of aryl iodides to deliver
biologically important β-aryl-α-hydroxy acids in moderate to
good yields with high stereochemical integrity. The amino
acid auxiliary demonstrated superior reactivity to the
perfluorinated aryl amide counterpart while also allowing for
efficient removal using two complementary methods to afford
differentially protected β-aryl-α-hydroxy acids. Further re-
search for expanding the scope of this β-C(sp3)−H
functionalization protocol is currently underway in our
laboratories.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support.
We thank Asubio Pharma Co., Ltd. for financial support to
T.T., Nanjing Tech University and Jiangsu Provincial
Department of Education for the visiting scholar fellowship
to Y.H., and The University of Sydney for postdoctoral
funding to A.T.T.
C
DOI: 10.1021/acs.orglett.5b02900
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Organic Letters
Letter
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DOI: 10.1021/acs.orglett.5b02900
Org. Lett. XXXX, XXX, XXX−XXX