778
Chem. Pharm. Bull. 64, 778–784 (2016)
Vol. 64, No. 7
Special Collection of Papers
This article is dedicated to Professor Satoshi Ōmura in celebration of his 2015 Nobel Prize.
Regular Article
Additional Nucleophile-Free FeCl3-Catalyzed Green Deprotection of
2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids
Yoshinari Sawama,* Masahiro Masuda, Akie Honda, Hiroki Yokoyama, Kwihwan Park,
Naoki Yasukawa, Yasunari Monguchi, and Hironao Sajiki*
Gifu Pharmaceutical University; 1–25–4 Daigaku-nishi, Gifu 501–1196, Japan.
Received February 22, 2016; accepted March 10, 2016
The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally
achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections
of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively
catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols
and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling
mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a
precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the
sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtra-
tion.
Key words deprotection; alcohol; carboxylic acid; 2,4-dimethoxyphenylmethyl (DMPM) protecting-group;
iron catalyst; self-cleaving mechanism
The protection/deprotection method is important and the ethers without the addition of nucleophiles30) [Chart 1, (e)].
deprotection under mild conditions associated with perfect We now report the extensive results of the FeCl3-catalyzed
tolerance of the non-target functional groups can be a power- deprotection method of 2,4-dimethylphenylmethyl (DMPM)-
ful tool to effectively construct the target molecules in organic protected alcohols without purification using silica-gel column
reactions.1) The 4-methoxyphenylmethyl (MPM) group and chromatography together with a novel application for the de-
its derivatives are widely utilized as the protecting group of protection of 2,4-DMPM-protected carboxylic acids. Because
alcohols, and the various deprotection methods have been 2,4-DMPM-protected alcohols were found to be preferentially
developed.1–21) 4-MPM ethers are generally deprotected by the deprotected in comparison with 4-MPM-protected alcohols in
use of a stoichiometric amount of oxidants [2,3-dichloro-5,6- the reported methods (DDQ,1,31) the combination of CeCl3 and
dicyano-p-benzoquinone (DDQ)2,3) and ceric ammonium NaI10) or Ph3C·BF419)), the synthetic route via the 2,4-DMPM-
nitrate (CAN)4,5)], Pd/C-catalyzed hydrogenation under atmo- protected alcohol could be adapted in the efficient synthesis
spheric hydrogen gas1) or the combination of a stoichiometric of target molecules (e.g., total syntheses of natural prod-
amount of nucleophiles and the catalytic or stoichiometric ucts).19,31,32) However, the problems of side-products derived
Lewis acids6–17) [Chart 1, (a)–(d)]. However, the stoichiomet- from 2,4-DMPM group, which should be separated by silica-
ric byproducts derived from 4-MPM protective groups (e.g., gel column chromatography, have been unsolved.
anisaldehydes, and toluene derivatives) and the acidic residues
The 4-MPM-protected 1-decanol (1a) effectively underwent
derived from reagents when using DDQ and CAN should be deprotection in the presence of 5mol% of FeCl3 without any
removed from the reaction mixture by the purification pro- additional nucleophile in CH2Cl2 at room temperature to pro-
cess using silica-gel column chromatography. In addition, a duce the mother alcohol (2a) and many side-products derived
stoichiometric amount of Ph3C·BF418,19) and the chlorosulfonyl from the 4-MPM moiety, which should be separated by silica-
isocyanate (CSI)–NaOH combination20) has also been used gel column chromatography (Eq. 1). Since benzyl (Bn) ether
for the deprotection of the 4-MPM ether. Although a catalytic was tolerant under the FeCl3-catalyzed conditions, the che-
method using ZrCl4 in CH3CN has been developed for the de- moselective deprotection of the 4-MPM protective group of 1b
protection of the 4-MPM ether, silica-gel column chromatog- could be accomplished (Eq. 2). Meanwhile, the deprotection of
raphy purification is necessary to remove the undefined side- 3,4-DMPM also efficiently proceeded to form the correspond-
products.21) We have found that the widely used iron(III) chlo- ing deprotected alcohol (2a) and an inseparable mixture of the
ride (FeCl3) could effectively activate the benzylic position corresponding cyclic trimer, tetramer, pentamer and hexamer
and achieved various reactions accompanied by the cleavage (m/z; 478.1934, 623.2623, 773.3293, 923.3951 [M+Na]+)33–35)
of the benzylic C–O bond to construct unique skeletons.22–29) of the 3,4-DMPM protective group, which were detected and
Furthermore, we have recently developed the FeCl3-catalyzed determined by an electrospray ionization (ESI)/MS spectral
self-cleaving deprotection method of various types of MPM analysis (Eq. 3, the chart is in the Supplementary Materials).
*To whom correspondence should be addressed. e-mail: sawama@gifu-pu.ac.jp; sajiki@gifu-pu.ac.jp
© 2016 The Pharmaceutical Society of Japan