Acid- and base-stable esters: A new protecting group for carboxylic acids

Article abstract of DOI:10.1055/s-2007-983801

An acid- and base-stable protecting group for carboxylic acids is described. The esters of (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl) methanol are stable to Bransted and Lewis acids, Bronsted bases, and a wide variety of nucleophiles; however, the esters can be conveniently deprotected by a solvolytic displacement reaction with 20% trifluoroacetic acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983801

PAPER
2513
Acid- and Base-Stable Esters: A New Protecting Group for Carboxylic Acids
A
New Protecting
G
ro
i
up for
C
c
arboxylic
h
A
cids io Kurosu,* Kallolmay Biswas, Prabagaran Narayanasamy, Dean C. Crick
Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State
University, 1682 Campus Delivery, Fort Collins, CO 80523-1682, USA
Fax +1(970)4911815; E-mail: michio.kurosu@colostate.edu
Received 16 February 2007; revised 29 May 2007
being utilized in the library productions; trityl, silyl, and
Abstract: An acid- and base-stable protecting group for carboxylic
PMB protecting groups are too labile to acids, while
acids is described. The esters of (2,6-dichloro-4-methoxyphe-
MOM, SEM, t-Bu, and ortho esters require harsh acidic
nyl)(2,4-dichlorophenyl)methanol are stable to Brønsted and Lewis
acids, Brønsted bases, and a wide variety of nucleophiles; however,
conditions for regeneration of the carboxylic acids.3 Thus,
the esters can be conveniently deprotected by a solvolytic displace- we have developed a new protecting group for carboxylic
ment reaction with 20% trifluoroacetic acid.
acids which is stable to acids, bases, and a wide variety of
nucleophiles, but can be regenerated with trifluoroacetic
acid.
Key words: acid-stable ester, base-stable ester, carboxylic acid
protecting group, chlorodiphenylmethyl esters
A diphenylmethyl ester is an acid-labile functional group
and has been utilized as a temporary protecting group for
carboxylic acids. In our experiments, diphenylmethanol
exhibited similar nucleophilicity to allylic alcohol and is
not efficiently esterified with carboxylic acids via conven-
tional carboxylic acid activation methods (i.e., DCC,
BOP-Cl, and mixed anhydride). In order to stabilize
diphenylmethyl esters by tuning electronic properties of
diphenyl moieties, several chloro-substituted diphenyl-
methyl esters were synthesized and tested for their stabil-
ity against representative acids, such as TsOH·H2O (20%
in CH2Cl2–THF), HF (10% in MeCN), BF3·OEt2 (10% in
CH2Cl2), and La(OTf)3 (10% in aq THF). Interestingly, as
summarized in Scheme 1, all (4-chlorophenyl)(4-meth-
oxyphenyl)methanols 3a–d, conveniently synthesized by
Friedel–Crafts reaction of 4-chlorobenzoyl chlorides 1
with anisoles 2, followed by sodium borohydride reduc-
tion, could be efficiently esterified using EDCI, DCC,
In connection with ongoing studies on the development of
novel drug-like MraY inhibitors,1 we have delivered a set
of small optimized libraries based on uridine-b-hy-
droxyamino acid.2 In order to efficiently generate such li-
braries in solution, we sought a protecting group for the
carboxylic acid which can be cleaved simultaneously with
the acetonide by a volatile and mild acid such as trifluoro-
acetic acid. In addition, a protecting group for the carbox-
ylic acid should have stability to relatively strong
Brønsted and Lewis acids, bases, and a wide variety of nu-
cleophiles. Although a large number of acid-cleavable
protecting groups [i.e., trityl, TBDPS, MOM, THP, 2-(tri-
methylsilyl)ethyl, t-Bu, PMB, ortho esters, and their relat-
ed protecting groups] for carboxylic acids have been
utilized in organic syntheses, these protecting groups did
not fulfill the requirement of stability against conditions
R2
2a: R2 = R3 = H
R1
1)
R2
H
2b: R2 = Cl, R3 = H
OH
R1
2c: R2 = R3 = Cl
O
Me
R3
O
Me
R3
Cl
AlCl3, PhNO2
Cl
O
60–80%
3a: R1 = R2 = R3 = H
Cl
3b: R1 = Cl, R2 = R3 = H
3c: R1 = R2 = Cl, R3 = H
3d: R1 = R2 = R3 = Cl
1a: R1 = H
1b: R1 = Cl
2) NaBH4, MeOH
95–99%
R4CO2H, DIC,
DMAP, CH2Cl2
or R4COCl, DMAP,
CH2Cl2, 90–100%
R4
4a: R1 = R2 = R3 = H
4b: R1 = Cl, R2, R3 = H
4c: R1 = R2 = Cl, R3 = H
4d: R1 = R2 = R3 = Cl
O
R1
R2
H
O
R4 = C8H17 or 4-ClC6H4
or Boc-D-Ala
Me
R3
Cl
O
racemic or diastereomeric mixture
Scheme 1 Synthesis of the chloro-substituted diphenylmethyl esters 4a–d
SYNTHESIS 2007, No. 16, pp 2513–2516
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983801; Art ID: M00807SS
© Georg Thieme Verlag Stuttgart · New York

2514
M. Kurosu et al.
PAPER
DIC, or acid chloride methods.4 Esters 4a–c regenerated of primary and secondary amines (in aq THF at 80 °C),
the corresponding acids upon treatment with 20% TsOH NH2NH2 (in aq THF at r.t.), alkylthiols (in THF at 80 °C),
within one hour, and also were not stable with 10% HF, NaN3 (in DMF at 90 °C), H2O2/NaOH (in aq THF at r.t.),
15% TFA, 10% BF3·OEt2, and 10% La(OTf)3. Surprising- and MeMgBr (0 °C to r.t.); 3) were not enolizable with
ly, the tetrachloro-substituted diphenylmethyl esters 4d LDA, NaHMDS, KHMDS,6 and n-Bu2BOTf/DIPEA (at –
showed an unusual acid stability; no regeneration of the 78 °C to r.t.); 4) were stable under reducing conditions
acids from esters 4d was observed with 20% TsOH for such as Zn/HCl, Ag(Hg), B2H6, NaBH4 (in MeOH at
over 36 hours.
60 °C), Li(O-t-Bu)3AlH, Raney Ni, H2/RhCl(PPh3)3, and
H2/Pd–C (in EtOAc or 1,4-dioxane); 5) remained intact
under palladium-mediated coupling reaction conditions
(Suzuki–Miyaura and Heck reactions); 6) did not react
with iodine and NBS; and 7) were photolytically stable:
no change upon irradiation at 200–350 nm (in 1,4-dioxane
for 72 h).
As summarized in Table 1, esters 4d (R4 = Me or C8H17)
also exhibited excellent stability to a variety of Brønsted
and Lewis acids such as 15% TFA, 30% HF, 2 N HCl,
HBr/AcOH, TiCl4, ZnCl2, AlCl3, B(C6F5)3, BCl3, BBr3,
BF3·OEt2, TMSOTf, and La(OTf)3 at room temperature.
Moreover, esters 4d: 1) showed stability under basic con-
ditions: no saponifications were observed with NH4OH Thus, we succeeded in stabilizing the diphenylmethyl es-
(40% in aq THF–MeOH), LiOH (10% in aq THF– ter against a wide variety of acids, bases, and nucleo-
MeOH), NaOH (6 N in aq MeOH),5 TlOEt (in aq THF), philes.
and DBU (10% in aq THF) at room temperature for over
24 hours; 2) showed excellent stability to nucleophiles:
esters 4d were not susceptible to the nucleophilic attacks
In order to understand the unusual stability of esters 4d
against bases and a wide variety of nucleophiles, we ana-
Table 1 Reactivities of Esters 4d (R4 = Me or C8H17) against a Variety of Reagentsq
20% TsOHa 2 N HClb 30% HFb 15% TFAc HBr/AcOH BCl3
BBr3
L
TMSOTfc AlCl3
B(C6F5)3
L
La(OTf)3
c
c
c
c
c
L
L
L
L
L
L
L
L
L
TlOEtg
NH4OHh
NH2NH2
DBUg
c
c
g
TiCl4
ZnCl2
10%
LiOH/
6 N aq
NaOHe
1 N aq NaOH, 50 °C
c
BF3·OEt2 THFd
L
L
L
L
L
Mf
L
L
L
L
H2O2/NaOHg n-Bu2NHi n-BuNH2 n-BuSHi
NaN3
MeMgBrk n-BuLi
NaHMDSm KHMDSm n-Bu2BOTfn Zn/HClo
i
j
L
L
L
L
L
L
Ml
L
L
L
L
Al(Hg)o
B2H6
NaBH4
i-Pr2AlHc LiAlH4
Li(O-t-
H2/Pd–C/EtOAc
H2/Pd–C/1,4-dioxane
H2/RhCl
(PPh3)3
k
p
k
Bu)3AlHk
L
L
L
H
H
L
L
L
L
Raney Nio
PhB(OH)2 PhCH=CH2/Pd2(dba)3/t-Bu3P·HBF4/ I2
/
NBSk
hn (200–350 nm)o
h
DIPEAk
Pd(PPh3)4/
TlOEtg
L
L
L
L
L
L
a In CH2Cl2–THF (1:1).
b In MeCN.
c In CH2Cl2.
d At 50 °C for over 1 h.
e At r.t. for over 36 h.
f 50% regeneration of 3d (see Scheme 1).
g In aq THF.
h In aq THF–MeOH.
i In THF at 80 °C.
j In DMF at 90 °C.
k In THF at r.t. for over 1 h.
l ~70% of 4d was recovered after 1 h at –78 °C.
m In THF at –78 to 0 °C for over 1 h.
n In CH2Cl2 in the presence of DIPEA.
o In 1,4-dioxane.
p In MeOH at 60 °C.
q H indicates that the protecting group is readily cleaved; M indicates that the protecting group is cleaved very slowly; L indicates that the pro-
tecting group is stable.
Synthesis 2007, No. 16, 2513–2516 © Thieme Stuttgart · New York

PAPER
A New Protecting Group for Carboxylic Acids
2515
hydrogenation reaction (H2/Pd–C in MeOH) to regenerate
the carboxylic acids (Table 1), and 2) reduced with
LiAlH4 or DIBAL-H to afford the corresponding alcohols
(R4 = C8H17 and p-ClC6H4) in high yields.
In conclusion, we have developed an acid- and base-stable
protecting group for carboxylic acids, which would be
very useful for the generation of library molecules con-
taining carboxylic acid functional groups in that: 1) the es-
ter is stable to a wide variety of nucleophiles and reagents,
and 2) the esters can be cleaved by solvolytic cleavage
with 20% trifluoroacetic acid within one hour. The novel
protecting group for carboxylic acids described here will
be useful in multistep syntheses of target molecules in-
cluding complex natural products, carbohydrates, and nu-
cleotides. It is worth mentioning that alcohol 3d could be
efficiently synthesized in only two steps (Friedel–Crafts
acylation, followed by NaBH4 reduction) using inexpen-
sive chemicals. Moreover, alcohol 3d can be regenerated,
as illustrated in Scheme 2. Thus, the new protecting group
3d should be a valuable asset not only for small-scale or-
ganic reactions but also for industrial-scale syntheses.8
Figure 1
lyzed a lowest-energy conformer of 4d (R4 = Me) by sin-
gle-crystal X-ray structure analysis (Figure 1). It was
revealed that the dihedral angles formed by the two planar
chloro-substituted benzene rings and by the –CO–O–
linkage and the ether methine proton are 83.5° and 159.8°,
respectively.7 There must be a significant electronic repul-
sion between the o-chloro atoms in the two benzene rings.
The o-chloro atom in the dichlorophenyl moiety is located
toward the carbonyl ester plane. Thus, the chloro atoms at
the o-positions in the two benzene rings hinder nucleo-
philic attack at the ester carbonyl from both the re- and si-
faces. In addition, the 3,5-dichloro atoms in the anisole
moiety attenuate an electron-donating character of the
methoxy group. Therefore, esters 4d would exhibit stabil-
ity against bases, nucleophiles, and acids. To the best of
our knowledge this is the first example of esters which are
stable to both acids and bases. Esters 4d could be conve-
niently cleaved using 20% trifluoroacetic acid in dichlo-
romethane to afford the corresponding acids (R4CO2H)
and the trifluoroacetate 5a in quantitative yields. The tri-
fluoroacetate 5a also survived most acidic conditions test-
ed in Table 1 and SiO2, but could be easily cleaved with
aqueous ammonia in tetrahydrofuran–methanol within
three hours to regenerate 3d in quantitative yield
(Scheme 2). Alternatively, esters 4d were 1) cleaved by a
IR absorptions on NaCl plates were run on a Perkin Elmer FT-IR
1
1600 spectrometer. H NMR spectral data were obtained using
Varian 300 MHz and 400 MHz instruments. The residual solvent
signal was utilized as an internal reference. 13C NMR spectral data
were obtained using a Varian 100 MHz spectrometer. Chemical
shifts were reported in parts per million (ppm) downfield from
TMS, using the middle resonance of CDCl3 (77.0 ppm) as an inter-
nal standard. For all NMR spectra, d values are given in ppm and J
values in Hz. Mass spectra were obtained at Colorado State Univer-
sity’s Central Instrument Facility. Reagents and solvents are com-
mercial grade and were used as supplied. Reaction vessels were
flame-dried or oven-dried and cooled under an inert atmosphere
when necessary.
2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol
(3d)
Anhyd AlCl3 (4.5 g, 33.9 mmol) was placed in a round-bottom flask
and PhNO2 (150 mL) was added. At –78 °C, 2,4-dichlorobenzoyl
chloride (1b) (4.7 mL, 33.9 mmol) and 3,5-dichloroanisole (2c) (5.0
g, 28.2 mmol) were added. The reaction mixture was kept at –78 °C
for 1 h, then warmed to r.t. over 24 h. The mixture was diluted with
Et2O (50 mL) at 0 °C and the reaction was quenched with 1 N
NaOH (~30 mL); the mixture was vigorously stirred until a white
precipitate had been formed. The precipitates were filtered and
R4
O
O
Cl
H
Cl
O
HO
R4
Cl
20% TFA
+
R5
CH2Cl2
quant.
Me
H
Cl
Cl
Cl
O
O
4d
R4 = C8H17 or 4-ClC6H4
or Boc-D-Ala
Me
Cl
Cl
O
racemic or diastereomeric mixture
5a: R5 = CF3CO
3d: R5 = H
NH4OH,
THF–MeOH
quant.
Scheme 2 Solvolytic displacement reaction with trifluoroacetic acid
Synthesis 2007, No. 16, 2513–2516 © Thieme Stuttgart · New York

2516
M. Kurosu et al.
PAPER
washed with CH2Cl2 (50, 30, and 20 mL). The combined organic
solvents were dried (Na2SO4), filtered, and concentrated under re-
duced pressure (~10 mmHg). Purification by silica gel chromatog-
raphy (hexanes–CHCl3, 4:1) provided (2,6-dichloro-4-
methoxyphenyl)(2,4-dichlorophenyl)methanone (8.3 g, 85%) as a
white powder.
TLC (hexanes–EtOAc, 5:1) provided a diastereomeric mixture of
the title (2R)-propanoate (34 mg, 92%) as a solid.
IR (film): 1615, 1610 cm–1
1H NMR (400 MHz, CDCl3): d = 7.45 (m, 2 H), 7.36 (m, 2 H), 7.23
(m, 4 H), 7.06 (m, 2 H), 6.81 (m, 2 H), 5.03 (m, 1 H), 4.44 (m, 1 H),
3.73 (s, 3 H), 3.70 (s, 3 H), 1.43 (s, 18 H), 1.37 (d, J = 7.2 Hz, 3 H),
1.15 (d, J = 6.4 Hz, 3 H)
13C NMR (100 MHz, CDCl3): d = 170.9, 159.4, 136.4, 136.2, 135.9,
134.4, 134.1, 134.0, 133.9, 133.6, 130.3, 129.5, 129.4, 126.3, 122.6,
122.5, 121.7, 111.1, 79.9, 69.8, 56.2, 56.1, 49.2, 28.3, 18.9, 18.5
IR (film): 1619, 1584, 1553, 1400, 1309 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 8.2 Hz, 1 H), 7.54 (d,
J = 2.1 Hz, 1 H), 7.37 (dd, J = 8.1, 2.1 Hz, 1 H), 6.95 (s, 2 H), 3.87
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.6, 163.8, 142.0, 138.3, 137.7,
136.4, 130.3, 129.9, 127.8, 122.9, 118.4, 117.9, 114.6, 56.1.
HRMS–FAB: m/z [M + Na]+ calcd for C22H23Cl4O5NNa:
544.02280; found: 544.02282
HRMS–FAB: m/z [M + Na]+ calcd for C14H8Cl4O2Na: 370.91761;
found: 370.91765.
Typical Procedure for the Deprotection
The ester of 3d was dissolved in 20% TFA in CH2Cl2 (0.3 M) and
kept for 1 h at r.t. All volatiles were evaporated in vacuo to provide
the carboxylic acid and 5a. The carboxylic acid was separated from
5d by a silica-gel plug (hexanes–EtOAc, 10:1 to CHCl3–MeOH,
5:1) or a back-extraction procedure [solvent system: EtOAc–H2O
(for the extraction of 5d under a basic conditions (NaHCO3),
CHCl3–H2O (for the extraction of the carboxylic acid under an acid-
ic conditions (dil. HCl)].
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone
(1.0 g, 2.8 mmol) was dissolved in MeOH (15 mL) and cooled to
0 °C. NaBH4 (318 mg, 8.4 mmol) was added to the mixture. The re-
action was quenched with aq NH4Cl (15 mL) and the mixture was
extracted with EtOAc (100, 30, and 20 mL). The combined extracts
were washed with brine (15 mL), dried (Na2SO4), and concentrated
under reduced pressure. Purification by silica gel chromatography
(hexanes–EtOAc, 5:1) provided 3d (980 mg, 97%) as a white pow-
der.
IR (film): 3482, 1438, 1410, 1325 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 1 H), 7.38 (d,
J = 3.0 Hz, 1 H), 7.31 (dd, J = 8.2, 3.0 Hz, 1 H), 6.91 (s, 2 H), 6.61
(d, J = 2.1 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 137.8, 136.3, 133.9, 133.0,
130.5, 129.6, 129.6, 128.0, 126.6, 115.4, 115.4, 70.2, 55.9.
This paper is dedicated to Professor Yoshito Kishi (Harvard Univer-
sity) on the occasion of his 70th birthday. We thank the National In-
stitutes of Health (NIAID grants AI049151, AI018357, and
AI06357) and Colorado State University for generous financial sup-
port.
HRMS–FAB: m/z [M + Na]+ calcd for C14H10Cl4O2Na: 372.93326;
found: 372.93327.
References
(1) Dini, C. Curr. Top. Med. Chem. 2005, 5, 1221.
(2) (a) Kurosu, M.; Narayanasamy, P.; Crick, D. C.
Heterocycles 2007, 72, 339. (b) Kurosu, M.; Mahapatra, S.;
Narayanasamy, P.; Crick, D. C. Tetrahedron Lett. 2007, 48,
799. (c) Kurosu, M.; Biswas, K.; Crick, D. C. Org. Lett.
2007, 9, 1141. (d) Kurosu, M.; Crick, D. C. Tetrahedron
Lett. 2006, 47, 5325.
(3) (a) Handbook of Reagents for Organic Synthesis: Activating
Agents and Protecting Groups; Pearson, A. J.; Roush, W. R.,
Eds.; Wiley: New York, 1999. (b) Greene, T. W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley & Sons: New York, 1999.
(4) The nucleophilicity of diphenylmethanol may be increased
due to: 1) introduction of the methoxy group at the 4-posi-
tion, and 2) stereoelectronic effects of the chloro substituents
on the aromatic rings.
(5) 50% regeneration of 3d was observed with 1 N aq NaOH at
50 °C for one hour.
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl
Nonanoate; Typical Procedure for the Esterification of 3d
To a stirred soln of alcohol 3d (148 mg, 0.42 mmol) in CH2Cl2 (3.0
mL) was added n-nonanoic acid (84 mg, 0.53 mmol), DIC (98 mL,
0.60 mmol), and DMAP (146 mg, 1.2 mmol). After 3 h at r.t., the
reaction was quenched with 0.5 N HCl (3 mL) and the mixture was
extracted with EtOAc (30 mL). The combined extracts were washed
with aq NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), and
concentrated under reduced pressure. Purification by silica gel chro-
matography (hexanes–EtOAc, 20:1 to 10:1) provided the title
nonanoate (194 mg, 0.39 mmol, 94%) as an oil.
IR (film): 1615, 1428, 1315 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49 (s, 1 H), 7.36 (m, 2 H), 7.21
(m, 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 6.80 (d, J = 2.1 Hz, 1 H), 3.72
(s, 3 H), 2.42 (t, J = 1.8 Hz, 2 H), 1.28 (m, 12 H), 0.89 (t, J = 6.7 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 172.3, 159.4, 136.2, 135.6, 134.6,
134.0, 133.5, 130.1, 129.4, 126.2, 122.5, 122.3, 111.1, 68.5, 56.2,
34.1, 31.7, 29.2, 29.1, 29.0, 24.8, 22.6, 14.1.
(6) No deuterium exchange at the a-position of the esters upon
quenching with CD3OD and aldol reactions with
benzaldehyde were observed.
HRMS–FAB: m/z [M + Na]+ calcd for C23H26Cl4O3Na: 513.05338;
found: 513.05340.
(7) The –CO–O– linkage and the ether methine proton showed
a deviation of 20.2° out of a preferential common plane.
(8) We have synthesized a variety of esters with N-protected
D- or L-amino acids. Significant separation of signals for a
diastereomeric mixture of esters at the a-position of the
carbonyl group is observed in the 1H NMR spectra; however,
so far no separation of the diastereomers of 4d has been
observed on TLC. These characteristics may be applied to
the determination of the stereochemistry of unknown
a-chiral carboxylic acids by using optically pure 3d. The
synthesis of (+)-3d and (–)-3d will be reported elsewhere.
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl
(2R)-2-(tert-Butoxycarbonylamino)propanoate
To a stirred soln of alcohol 3d (25 mg, 0.071 mmol) in CH2Cl2 (1.0
mL) was added Boc–D-Ala–OH (20 mg, 0.11 mmol), DIC (26 mL,
0.17 mmol), and DMAP (27 mg, 0.22 mmol). After 3 h at r.t., the
reaction was quenched with 0.5 N HCl (1 mL) and the mixture was
extracted with EtOAc (15 mL). The combined extracts were washed
with aq NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated under reduced pressure. Purification by preparative
Synthesis 2007, No. 16, 2513–2516 © Thieme Stuttgart · New York