Copper(II)-mediated O-arylation of protected serines and threonines

Article abstract of DOI:10.1021/ol5024689

An effective protocol toward the O-arylation of β-hydroxy-α-amino acid substrates serine and threonine has been developed via Chan-Lam cross-coupling. This Cu(II)-catalyzed transformation involves benign open-flask conditions that are welltolerated with a variety of protected (Boc-, Cbz-, Tr-, and Fmoc-) serine and threonine derivatives and various potassium organotrifluoroborates and boronic acids.

Full text of DOI:10.1021/ol5024689

Letter
pubs.acs.org/OrgLett
Open Access on 09/10/2015
Copper(II)-Mediated O‑Arylation of Protected Serines and
Threonines
Mirna El Khatib and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: An effective protocol toward the O-arylation of β-
hydroxy-α-amino acid substrates serine and threonine has been
developed via Chan−Lam cross-coupling. This Cu(II)-catalyzed
transformation involves benign open-flask conditions that are well-
tolerated with a variety of protected (Boc-, Cbz-, Tr-, and Fmoc-)
serine and threonine derivatives and various potassium organo-
trifluoroborates and boronic acids.
n nature, structural diversity in protein synthesis is achieved
with a small number of naturally occurring amino acids. In the
reaction affords the arylated product but with lowered yields. This
protocol also requires triphenylphosphine as a reagent,4b
resulting in tedious workup procedures. A new approach to the
O-arylation of serine involves the copper-mediated reaction of
nonaromatic precursors, α,β-unsaturated ketones, under aerobic
conditions (Scheme 1), affording aromatized O-arylated
I
laboratory setting, the continuing development of novel reactions
provides a much larger palette for exploring structural space, and
indeed, on this basis, peptide synthesis has gone through major
advances since the first report of peptide composition by Emil
Fisher. In fact, unnatural peptides have now become a significant
part of drug discovery efforts.1 Among other chemical
modification methods, cross-coupling reactions on peptides
and proteins have received much attention, leading to selective
formation of nonlabile linkages at residues functionally
orthogonal to natural amino acids. Various unnatural amino
acids synthesized via cross-coupling protocols can be genetically
incorporated into peptides and proteins, leading to valuable
protein modifications.2 For example, the cross-coupling of 4-
halophenylalanine, 4-boronophenylalanine, and L-tyrosine have
been successfully accomplished.3 In the same vein, β-hydroxy-α-
amino acid derivatives have been used as constructs of drugs for
the treatment of Alzheimer’s disease (Figure 1, I) or inhibition of
Scheme 1. Methods for Preparation of O-Arylated L-Serine
products. However, this protocol is substrate specific and
requires higher temperatures, affording the O-arylated L-Ser in
only 33% yield.6 Thus, development of an efficient, mild and
general method to arylate the hydroxyl position of L-serine to
access structurally complex aryl alkyl ethers in natural products
and pharmaceuticals remains a challenging goal.
This need has led to alternative methods for the synthesis of
such structural motifs.7 The direct formation of the C−O bond in
alkyl aryl ethers by metal-catalyzed arylation of aliphatic alcohols
with aryl halides is a formidable task compared to the classic
Ullman-type synthesis of diaryl ethers because of the low
reactivity of aliphatic alcohols.7,8 Investigations by Buchwald and
co-workers have shown that a reaction with Cu(I) salts in the
presence of strongly basic alkoxides, performed under refluxing
conditions, can efficiently promote the cross-coupling of aryl
halides with phenols and aliphatic alcohols,9 an alternative to the
analogous Pd-catalyzed reactions developed by Buchwald and
Hartwig.10 It is noteworthy that Buchwald’s conditions have been
used on hydroxyproline methyl esters but failed to afford the
Figure 1. Serine-containing biologically active compounds.
β-amyloid peptide release.4 Benzoxazepinone II (Figure 1) was
recently discovered as a potential target for cancer therapy.5 It is
noteworthy that compounds I and II are arylated at the O-site of
serine.
To date, there are few general methods described for the O-
arylation of L-serine. This transformation has been achieved by
nucleophilic aromatic substitution, but this protocol is limited by
the use of strong bases (NaH and KHMDS) and the need for 1-
fluoro-2-nitrobenzene substrates.4,5 Alternatively, the Mitsunobu
Received: August 20, 2014
Published: September 10, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
desired O-arylated products because of a lack of reactivity or
elimination after the resulting arylation.10g Another protocol
involves less common arylating agents such as organobismuths,
but this approach requires in situ generation of the reagents by
oxidation of the triarylbismuthine.7,11
Table 1. Optimization of Reaction Conditions with
Phenylboronic Acid and Potassium Phenyltrifluoroborate
In 1998, Chan,12 Evans,3a and Lam13 independently reported
heteroatom arylation reactions that modernized alkyl-aryl ether
synthesis. The development of this coupling reaction led to mild
transformations that took place at room temperature under
weakly basic conditions and could be carried out in an open
reaction flask. For the C−O bond-forming reactions, this was
limited primarily to phenols3b,c,13,14 with the first examples
utilizing catalytic amounts of Cu(OAc)2 reported in 2001 by
Lam.8a,13 In addition to phenols, the development of copper-
mediated C−O bond formation has flourished with the discovery
that a broad range of oxygen nucleophiles, including carboxylic
acids,15 aliphatic alcohols,8d aryloximes,16 silanols,17 N-hydrox-
yphthalimides,18 and water,2a,19 have been coupled successfully
from boron reagents using Cu(OAc)2 as the catalyst of choice.
Herein, we report the first Chan−Lam cross-coupling of β-
hydroxy-α-amino acid derivatives. The results reveal an effective
and practical protocol for the formation of C−O alkyl aryl ethers
from β-hydroxy-α-amino acid substrates serine and threonine,
using benign conditions with both arylboronic acids and
aryltrifluoroborates.
In an initial attempt at arylation, the reaction of Boc-L-Ser-
OMe (1a) with both phenylboronic acid (2a) and potassium
phenyltrifluoroborate (2b) in the presence of various copper
catalysts, bases, and solvents in an open flask at room temperature
was examined (Table 1). Comprehensive results and all
screenings employed are shown in Table S1 of the Supporting
Information). The use of CuI and CuSO4·5H2O with different
catalyst loadings in the presence of Cs2CO3 and 1,10-
phenanthroline using MeCN, CH2Cl2, or toluene as solvent
was deemed ineffective (entries 1−6, Table 1). Anhydrous
Cu(OAc)2 (10 mol %) in the presence of DMAP (20 mol %)
afforded the desired product in 75% yield when 2a was utilized
(entry 7, Table 1), but not in the case of 2b (entry 7, Table 1).
The use of Cu(OAc)2 in pyridine and DMF as solvent was
ineffective with both types of boron species (entry 9, Table 1).
Fortunately, the reaction with Cu(OAc)2·H2O in the presence of
DMAP afforded the desired product with both 2a and 2b (entry
10, Table 1). We set out to examine the reaction conditions
further in the presence of Cu(OAc)2·H2O. The use of excess 2b
(2 equiv, entry 11, Table 1) was deemed ineffective, while the
most effective catalyst loading proved to be 10 mol % of
Cu(OAc)2·H2O (entries 10 and 12−13, Table 1). DMAP was
found to be superior to tetramethylguanidine, DBU, and DIPEA,
and its absence gave zero yield (entries 10, 14−16, 23, Table 1).
The addition of water (10 mol %) has no apparent effect on the
boronic acid reaction, but is believed to assist the trifluoroborate
reaction by facilitating the hydrolysis of PhBF3K. The use of
ClCH2CH2Cl at higher temperatures (60 °C) gave homocou-
pling and ether formation of 2a or 2b as major side reactions, and
thus CH2Cl2 was the solvent of choice for such transformations
(entries 17−22, Table 1).
yields of 3a (%)
catalyst
2a,
B(OH)2
2b,
BF3K
entry
(10 mol %)
base/ligand (equiv)
a
1
CuI
Cs2CO3 (3.0), 1,10-phen
(0.2)
n.r.
n.r.
b
,
20
2
CuI
Cs2CO3 (3.0), 1,10-phen
(0.1)
n.r.
n.r.
b
a
c
3
4
5
6
7
8
9
CuI
1,10-phen (0.2)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
80%
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
n.r.
n.r.
a
n.r.
DMAP (0.2)
DMAP (1.0)
py (3.0)
75%
traces
n.r.
d
21
,
10
11
12
13
14
15
16
Cu(OAc)2·
H2O
DMAP (0.2)
85%
e
8d
e
,
Cu(OAc)2·
H2O
DMAP (0.2)
DMAP (0.2)
DMAP (0.2)
traces
f
Cu(OAc)2·
H2O
65%
81%
hc
g
Cu(OAc)2·
H2O
Cu(OAc)2·
H2O
tetramethylguanidine
(0.2)
hc
Cu(OAc)2·
H2O
DBU (0.2)
hc
hc
Cu(OAc)2·
H2O
DIPEA (0.2)
DMAP (0.2)
79%
hc
70%
hc
fh
17 ,
Cu(OAc)2·
H2O
h
18
Cu(OAc)2·
H2O
n.r.
n.r.
n.r.
55%
81%
87%
n.r.
a
19
Cu(OAc)2·
H2O
DMAP (0.2)
DMAP (0.2)
DMAP (0.2)
DMAP (0.2)
n.r.
i
20
Cu(OAc)2·
H2O
60%
84%
85%
j
21
Cu(OAc)2·
H2O
k
22
Cu(OAc)2·
H2O
23
Cu(OAc)2·
H2O
n.r.
a
b
c
d
CH3CN. Toluene. CuSO4·5H2O (20 mol %). Cu(OAc)2 (150
mol %), DMF, under reflux. PhBF3K (2 equiv).8d Cu(OAc)2·H2O (5
e
f
g
h
mol %). Cu(OAc)2·H2O (20 mol %). ClCH2CH2Cl, 60 °C.
Dioxane. O2 balloon.22 O2 balloon, H2O (0.01 equiv). hc =
i
j
k
homocoupling.
the reaction was unaffected by steric factors but was more
sensitive to the electronic nature of the boron substrate as
demonstrated by the yields.
Strongly electron-donating substituents with p-methyl (3c), p-
ethyl (3h), p-isopropyl (3i), p-tert-butyl (3j), and p-N,N-
dimethylamino (3k) afforded O-arylated L-serines in high yields.
Electron-withdrawing substituents were also tolerated under the
reaction conditions but gave lower yields, as in 3,5-
trifluoromethyl (3e), p-trifluoromethyl (3m), and the m-nitrile
(3l) substituted products. Both methyl and benzyl esters were
examined, revealing that benzyl esters afford better yields (3f vs
Under the conditions developed, the scope and limitations of
this coupling were evaluated (Schemes 2 and 3). Various aryl and
heteroaryltrifluoroborates and boronic acids as well as a series of
serine derivatives with different protecting groups and ester
derivatives of L-Ser (Scheme 2) were employed. Several
protecting groups, Boc- (3a−e), Cbz- (3f−3p, 3s), Tr-(3q),
and the base-sensitive Fmoc- (3r) were well-tolerated. In general,
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Organic Letters
Letter
and dibenzothiophene (3n). However, the use of thiophenes and
furans was detrimental, and no cross-coupling was observed
when using organoboron reagents incorporating these ring
systems. Instead, such substrates afforded unreacted starting
materials and homocoupling as major side-products, especially at
higher reaction temperatures.
Scheme 2. Substrate Scope of O-Arylation of L-Serine
Derivatives
We next turned our attention to applying this method to L-
threonine (Scheme 3). With these substrates as well, the reaction
conditions developed proved highly suitable and, most
importantly, afforded single diastereomers with no epimerization
observed. Both Boc- (5a) and Cbz- (5b−5g) protecting groups
were employed and also proved to be well-tolerated.
Surprisingly, the reaction of Cbz-L-Ser-L-Thr-OMe 6 with 2
equiv of the phenyltrifluoroborate gave a single mono-O-arylated
product 7 in 22% yield (eq 1). The mass spectral fragmentation
pattern of the product indicated that arylation took place
selectively at the L-serine site (see Supporting Information). The
use of dichloroethane at 60 °C led to more homocoupling and
ether formation of the corresponding phenyltrifluoroborate, with
no significant change in product formation.
In addition, we examined the reaction conditions using the
phenolic OH of L-tyrosine as the nucleophile, and indeed, the
reaction of Boc-L-Tyr-OMe 8 afforded the desired product 9 in
42% yield (eq 2).
a
Ar/HetAr-BXn = B(OH)2 was utilized, and no water was added to the
reaction.
Scheme 3. Substrate Scope of O-Arylation of L-Threonine
Derivatives
We also studied the side-products of this transformation.
Interestingly, the reaction affords ethers of the corresponding
boron reagents (Scheme 4), particularly with organoborons
Scheme 4. Ether Formation from the Corresponding Boron
Reagents
possessing electron-donating groups. The side-product ether 10
was obtained when the reaction was run under the same
conditions but in the absence of the amino acid. We believe that
this is the result of copper(II)-promoted oxidation of ArBF3K23
with subsequent participation of the resulting phenol in the cross-
coupling.
Finally, the reaction performed under argon, in the absence of
air/oxygen, with (4-isopropylphenyl)boronic acid did not
progress and afforded no product after 48 h.
a
Ar/HetAr-BXn = B(OH)2 was utilized, and no water was added to the
reaction.
3g). Using bulky protecting groups, such as the trityl group in 3q,
as well as o-methyl (3m) and m-methyl (3k) substituents seemed
tohave noeffect on the yield of the reaction. Although resulting in
very low yields, we were pleased to observe that the reaction
works with some heterocycles, including N-methylindole (3o)
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Letter
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novel unnatural β-aryloxy-α-amino acid derivatives. This new
Cu(II)-catalyzed transformation involves mild conditions (rt,
open flask) and is well-tolerated with a variety of protected (Boc-,
Cbz-, Tr-, and Fmoc-) serine and threonine derivatives and
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and product characterizations, 1H and
13C NMR spectra, mass spectral fragmentation for 7, and Table
S1. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*(G.A.M.) E-mail: gmolandr@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM-081376).
Frontier Scientific is acknowledged for their generous donation
of potassium organotrifluoroborates and boronic acids. Dr.
Rakesh Kohli (University of Pennsylvania) is acknowledged for
acquisition of HRMS spectra.
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