Mild cleavage of aryl mesylates: Methanesulfonate as potent protecting group for phenols

Article abstract of DOI:10.1021/ol049514j

A mild protocol for the chemoselective deprotection of aryl methanesulfonates is described. The transformation can be conducted on highly functionalized substrates and renders the methanesulfonate a useful, previously underutilized protecting group for phenols.

Full text of DOI:10.1021/ol049514j

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1513-1514
Mild Cleavage of Aryl Mesylates:
Methanesulfonate as Potent Protecting
Group for Phenols
Tobias Ritter, Kyrill Stanek, Igor Larrosa, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received March 15, 2004
ABSTRACT
A mild protocol for the chemoselective deprotection of aryl methanesulfonates is described. The transformation can be conducted on highly
functionalized substrates and renders the methanesulfonate a useful, previously underutilized protecting group for phenols.
Phenols are widely occurring subunits in natural products
(e.g., aromatic steroids, canabinoids, macrolides, quinones,
alkaloids, and iridoids), small-molecule pharmaceuticals (e.g.,
chloramphenicol, epinephrine, ethynylestradiol, and tamox-
ifen), and materials.1-3 The most commonly employed
protection regimens include methyl or benzyl ethers, with
the former requiring harsh reagents or conditions for its
removal. Methyl and arylsulfonates have also been employed
as protecting groups;4 however, these are generally avoided
because of the vigorous conditions required for their removal
that are often at odds with other functionality. In this paper,
we expand the utility of methanesulfonate as a protecting
group for phenols through the observation that they can be
conveniently removed in a broad range of substrates upon
exposure of methanesulfonate phenyl esters to lithium
diisopropylamide (LDA) (eq 1). The mildness of the pro-
cedure is evident in the wide range of functionality that is
compatible with the deprotection conditions.5
As phenol protecting groups, mesylates display ideal
characteristics, namely, their facile and high-yielding intro-
duction using inexpensive MsCl along with their high
stability to a variety of conditions.4
As shown in Table 1, treatment of a broad range of aryl
mesylates in THF with 1.6 equiv of LDA within a temper-
ature range of -78 to +23 °C furnishes the corresponding
alcohols in 57-96% yield.6 Both electron-rich and electron-
deficient phenols participate in the reaction as well as
mesylated hydroxypyridines and -quinolines (entries 10 and
11). Of additional significance, the N-methanesulfonamide
of 4-quinolone undergoes rapid deprotection at 0 °C in 72%
yield (entry 12).
(1) (a) Steglich, W.; Fugmann, B.; Lang-Fugmann, S. Naturstoffe;
Thieme, Stuttgart, 1997. (b) Lednicer, D. Strategies for Organic Drug
Synthesis and Design; Wiley: New York, 1998.
(2) Pu, L. Chem. ReV. 2004, 104, 1687-1716.
The mesylate of a phenol renders the aromatic ring
considerably less electron-rich. We have exploited this
(3) For recent examples, see the following. (a) Dynemicin: Myers, A.
G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem.
Soc. 1997, 119, 6072-6094. (b) Ecteinascidin: Endo, A.; Yanagisawa, A.;
Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124,
6552-6554. (c) Vancomycin: Evans, D. A.; Wood, M. R.; Trotter, B. W.;
Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998,
37, 2700-2704.
(5) To the best of our knowledge only one example has been reported
where a methanesulfonate is used as phenol protecting group and deprotected
with LDA. However, no indication of the generality is provided. See ref
3c.
(6) Preliminary results in our laboratories suggest that the corresponding
p-toluenesulfonates also participate in this desulfonation reaction.
(4) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
10.1021/ol049514j CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/01/2004

Table 1. Deprotection of Arylmethanesulfonates (See eq 1)a
Scheme 1
handling and purification of the electron-rich cinnamyl
bromides (e.g., 3 and 4) proved difficult due to decomposi-
tion. The instability of electron-rich benzyl and cinnamyl
halides is to be expected as a consequence of their known
propensity to undergo ionization. In this respect, the rate of
solvolysis of p-methoxybenzyl chloride in aqueous acetone
at 60 °C is 104 faster than that of benzyl chloride.8 In contrast,
the mesylated cinnamyl bromide 5 proved to be a stable,
conveniently handled material that was amenable to meta-
lation. Thus, treatment of 5 with Zn in DMF at 0 °C furnished
an intermediate allylic zinc species which underwent addition
to aldehyde 6 to give 41% yield of 7 after desilylation. After
a sequence of steps, 7 was converted into compounds 1 and
2 (entries 13 and 14), which underwent deprotection in good
yield. It is noteworthy that the phenolic mesylate in 2
smoothly undergoes chemoselective deprotection in good
yield in the presence of an aliphatic mesylate ester.
In summary, we have demonstrated the efficient, chemose-
lective deprotection of aryl methanesulfonates with LDA to
afford the corresponding phenols in up to 95% yield. The
use of mesylates to stabilize cinnamyl and benzyl halides
derived from electron-rich aromatics expands the opportuni-
ties to use more complex organometallic reagents in the
synthesis of natural products. Due to low cost, efficient
introduction, stability, and convenient removal under condi-
tions that are tolerant of a wide range of functionality, this
protecting group should find numerous future applications
in academic and industrial processes.
Acknowledgment. We thank the Swiss National Science
Foundation and the F. Hoffmann-La Roche Ltd as well as
Merck & Co., Inc., and Eli Lilly and Company. T.R. thanks
the Fonds der Chemischen Industrie for a Kekule´ Fellowship.
a 1.6 equiv per phenolic mesylate group of LDA in THF was used. b 6
equiv of LDA was used. c 4 equiv of LDA was used.
Supporting Information Available: Experimental details
and characterization for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
noteworthy feature in the context of our interest in the total
synthesis of resiniferatoxin 8 (Scheme 1). In our efforts to
improve upon our previously reported route, we were
interested in effecting the metalation of a cinnamyl bromide
for subsequent coupling with aldehyde 6.7 However, the
OL049514J
(7) Jackson, S. R.; Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira,
E. M. Angew. Chem., Int. Ed. 2001, 40, 2694-2697.
(8) Simonetta, M.; Favini, G. J. Chem. Soc. 1954, 1840-1844.
1514
Org. Lett., Vol. 6, No. 9, 2004