Scheme 1. General Structures of MraY Inhibitors i
Scheme 2. Syntheses of Chlorosubstituted Diphenylmethyl
Esters and Their Stability against the Representative Acids
(Scheme 1).6 To efficiently generate such libraries in solution
or on polymer-support, we sought a protecting group or a
linker for the carboxylic acid that can be cleaved simulta-
neously with the acetonide by a volatile and mild acid such
as TFA. In addition, a protecting group (or a linker) for the
carboxylic acid should have susceptibility to relatively strong
Brønsted and Lewis acids, and a wide variety of nucleophiles.
Although a large number of acid cleavable protecting groups
(i.e., trityl, TBDPS, methoxymethyl, tetrahydropyranyl,
2-(trimethylsilyl)ethyl, tert-butyl, p-methoxybenzyl, ortho
esters, and their related protecting groups) for carboxylic
acids have been utilized in organic syntheses, these protecting
groups did not meet our needs: trityl, silyl, and MPM
protecting groups are too labile to acids being utilized in
the library production and MOM, SEM, tert-butyl, and ortho
esters require harsh acidic conditions for the regeneration
of the carboxylic acids.7 Because of the reasons mentioned
above we have developed a new protecting group for
carboxylic acid functional groups that can be selectively
cleaved by TFA but is stable to a variety of acids.
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
esterified efficiently with carboxylic acids via conventional
carboxylic acid activation methods (i.e., DCC, BOPCl, and
mixed anhydride). To stabilize diphenylmethyl esters by
tuning electronic properties of dibenzene moieties, several
chloro-substituted diphenylmethyl esters were synthesized
and tested for stability against representative acids such as
TsOH‚H2O (20% in CH2Cl2-THF), HF (10% in CH3CN),
BF3‚OEt2 (10% in CH2Cl2), and La(OTf)3 (10% in aq THF).
Interestingly, as summarized in Scheme 2 all (4-methox-
yphenyl)(chlorophenyl)methanols 4a-d, conveniently syn-
thesized by Friedel-Crafts reactions followed by NaBH4
reductions, could be efficiently esterified by using EDCI,
DCC, or acid chloride methods. The esters 4a-c regenerated
the corresponding acids by treatment with 20% TsOH within
1 h and were also not stable under 10% HF, 15% TFA, 10%
BF3‚OEt2, and 10% La(OTf)3.
a 20% in CH2Cl2-THF (1/1). b10% in CH3CN. c15% in CH2Cl2.
d10% in aq THF. H indicates the protecting group is readily cleaved.
M indicates that the protecting group is cleaved very slowly. L
indicates that the protecting group is stable. e∼5% of regeneration
of the carboxylic acids was observed after 1 h.
regeneration of the acids from the esters 4d was observed
under 20% TsOH for over 20 h. The esters 4d also exhibited
excellent stablility to 15% TFA, 10% HF, and a variety of
Lewis acids such as AlCl3, B(C6F5)3, BCl3, TMSOTf, and
La(OTf)3. Moreover, the esters 4d (1) were photolytically
stable (no change by the irradiation at 200-350 nm in DMF
for 72 h), (2) showed stability under basic conditions (no
saponifications were observed under 40% NH4OH in aq THF,
10% LiOH in aq THF-MeOH, 10% KOH in MeOH-THF,
and 10% DBU in aq THF at rt for over 12 h), and (3) showed
excellent stability to nucleophiles (the esters 4d were not
susceptible to the nucleophilic attacks of primary and
secondary amines (in aq THF at 80 °C), NH2NH2 (in aq
THF at rt), alkylthiols (in THF at 80 °C), and NaN3 (90 °C
in DMF) for over 12 h).8 However, the esters 4d slowly
reacted with 10% BF3‚OEt2 to furnish the carboxylic acids
(∼5% after 1 h) and 1,3-dichloro-2-((2,4-dichlorophenyl)-
fluoromethyl)-5-methoxybenzene. The esters 4d could con-
veniently be cleaved by using 20% TFA in CH2Cl2 to afford
the corresponding acids and the trifluoroacetate (R1, R2, and
R3 ) Cl, R4 ) CF3 in 4d).9 Thus, we succeeded in stabilizing
diphenylmethyl ester, enabling a wide range of organic
reactions for the generation of small optimized libraries of
MraY inhibitors in solution (Scheme 1). Taking advantage
of excellent chemical stability of esters of (2,6-dicholoro-
However, the tetrachloro-substituted 4-methoxydiphenyl-
methyl esters 4d showed an unusual acid stability: no
(8) The MM2 calculation of 4d (R4 ) Me) indicated that the dihedral
angle formed by two planar chloro-substituted benzenes is 76.4°. The -CO-
O- linkage and the ether methine proton would preferentially be in a
common plane. Thus, the chloro atoms at ortho positions of two benzenes
hinder the nucleophilc attack on the carbonyl group of the esters.
(9) For solvolytic displacement reactions with TFA, see: (a) Milne, J.
B. J. Chem. Non-Aqueous SolVents 1978, 5B, 1. (b) Nordlander, J. E.;
Gruetzmacher, R. R.; Miller, F. Tetrahedron Lett. 1973, 12, 927.
(6) Kurosu, M.; Narayanasamy, P.; Crick, D. C. Heterocycles 2007, 72,
in press.
(7) (a) Pearson, A. J.; Roush, W. R., Eds. Handbook of Reagents for
Organic Synthesis: ActiVating and Agents and Protecting Groups; Wiley:
New York, 1999.
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Org. Lett., Vol. 9, No. 6, 2007