Unexpected highly chemoselective deprotection of the acetals from aldehydes and not ketones: TESOTf-2,6-lutidine combination

Article abstract of DOI:10.1021/ja046103p

Acetal functions are recognized as good protecting groups of carbonyl groups. Although many deprotecting methods of acetals to carbonyl functions have already been developed, there is no methodology which can deprotect acetals in the presence of ketals because the usual acidic or radical reactions occur more easily via the more stable cationic or radical intermediates from the ketals. On the other hand, this new method can proceed in a reverse manner to that described in previous reports. That is, the method can deprotect aliphatic acetals in the presence of ketals. The reaction condition is common for silylation, i.e., the TESOTf-2,6-lutidine combinations. Although the TMSOTf-2,6-lutidine combination can also deprotect acetals, it lacks chemoselectivity in deprotection of the acetals from aldehydes and ketones. The treatment of acetals with TESOTf and 2,6-lutidine in CH₂Cl₂ followed by a H₂O workup gave the corresponding aldehydes. Of course, the compounds, which have both acetal and hydroxyl functions afforded the compounds obtained by the usual silylation of an alcohol and deprotection of an acetal without any problem. However, deprotection of the ketals from ketones was not observed during the conversion reaction of acetals from aldehydes. This chemoselectivity was confirmed in the reactions of the compounds that have the acetal and ketal in the same molecule. In both cases, the acetal functions were deprotected to give aldehydes with intact ketals. Furthermore, under the conditions described here, many functional groups such as methoxy, acetoxy, allyl alcohol, and silyloxy ether are intact. This method is very mild and available for many compounds. Copyright

Full text of DOI:10.1021/ja046103p

Published on Web 09/02/2004
Unexpected Highly Chemoselective Deprotection of the Acetals from
Aldehydes and Not Ketones: TESOTf-2,6-Lutidine Combination
Hiromichi Fujioka,* Yoshinari Sawama, Nobutaka Murata, Takashi Okitsu, Ozora Kubo,
Satoshi Matsuda, and Yasuyuki Kita*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received July 1, 2004; E-mail: fujioka@phs.osaka-u.ac.jp; kita@phs.osaka-u.ac.jp
Acetal functions are recognized as good protecting groups of
carbonyl functions and are widely used in synthetic organic
chemistry. They are tolerant under neutral and basic conditions.
Acidic conditions are usually used for their deprotection, and under
these conditions, acetals from ketone functions are usually depro-
tected more easily than the acetals from aldehyde functions due to
Table 1. Study on Silylating Reagents for Deprotection of Acetal
1a
1
the stability of the cation intermediates. On the other hand, an
example of selective deprotection of the acetals from aldehyde
functions in the presence of ketals from ketones is unprecedented,
to the best of our knowledge, although many methods for the
deprotection of acetals from aldehydes and ketones under neutral
2
or mild conditions have been recently developed. We present here
a new method, which can selectively deprotect acetals, not ketals.
The method is the use of combinations of trimethylsilyltriflate
a
Equivalent of 2,6-lutidine is 1.5 times the silylating reagent. b Reaction
(TMSOTf)-2,6-lutidine or triethylsilyltriflate (TESOTf)-2,6-lu-
was carried out at room temperature for 24 h.
tidine. Trialkylsilyltriflates are more often recognized as one of
the most powerful reagents for the trialkylsilylation of hindered
hydroxyl functions such as tert-alcohols. When we treated the
Table 2. Deprotection of Various Acetals
3
acetal 1a with TMSOTf-2,6-lutidine for producing compound 3a
(R ) TMS), to our surprise, even the use of 1.2 equiv of TMSOTf
afforded a small amount of the aldehyde 2a (R ) TMS), and
the use of 2.0 equiv of TMSOTf gave 2a in a quantitative yield
(Table 1, runs 1, 2). This was an unexpected result. 2a (R ) TMS)
must be obtained by the deprotection of an acetal in addition to
the usual silylation of the tert-alcohol. TESOTf is also effective
for the deprotection of the acetal to give 2a (R ) TES) in an
4
excellent yield (run 3), whereas TMSCl gave the only silyl acetal
3a (R ) TMS) and TESCl did not work at all (runs 4, 5). The use
of TfOH resulted in no reaction, and no deprotection of the acetal
occurred, which showed that the TfOH formed in the reaction
mixture by silylation of the hydroxyl group could not deprotect
the acetal (run 6).
This deprotection of the acetal was applied to the simple acetal
1b, which has only the acetal function without the hydroxyl group
(
see Table 2). A non-basic condition proved that a base is necessary.
i
3 2
Among the bases examined here (2,6-lutidine, Et N, Pr NEt,
pyridine, 2-picoline, 4-DMAP, 2,6-di-tert-butylpyridine), 2,6-
lutidine proved to be the base of choice to give aldehyde 2b. The
as above (first formation of polar spot and then H O treatment
affording 2b). On the other hand, for dioxane 1d, TMSOTf was
effective for the deprotection to give the aldehyde 2b although it
2
i
5
reaction using Pr
2
NEt afforded the enol ether, nonpolar spot. On
the other hand, the reaction using 2,6-lutidine first gave the polar
compound. TLC can monitor the progress of the reaction. Com-
needed a longer reaction time (3.0 h) (run 5), whereas TESOTf
afforded the enol ether 4, which was less polar on TLC (R value
f
pound 1b first afforded a very polar spot (R
EtOAc as the developing solvent within 0.5 h, and then the H
workup afforded compound 2b (R value 0.65 by hexane-CH Cl
1/1)). 1H NMR also monitored the progress of the reaction
Supporting Information).
Other kinds of acetals were next examined (Table 2). For acyclic
f
value 0.0) even using
0.95 by hexane-CH Cl (1/1)) and isolated after workup in place
of aldehyde 2b (run 6). The methoxyl and acetoxy group tolerated
the conditions (runs 7, 8).
The most characteristic feature of our method, the high chemose-
lectivity, is shown in Scheme 1. The 1-to-1 mixture of 1g and 1h
afforded the deprotected aldehyde 2e from 1g with intact 1h. This
result confirmed the deprotection of the acetal from the aldehyde
faster than that of the ketal from the ketone. This result is very
interesting, since ketals are usually deprotected faster than acetals
2
2
2
O
f
2
2
(
(
acetal and dioxolane (1b and 1c), both TMSOTf and TESOTf were
effective for producing the aldehyde 2b, respectively, within 0.5 h
(runs 1-4). The behaviors of the reaction mixtures were the same
11800
9
J. AM. CHEM. SOC. 2004, 126, 11800-11801
10.1021/ja046103p CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Chemoselective Deprotection
Scheme 2
9
scyphostatin synthesis. Although compound 11 has acid-labile tert-
butyldimethylsilyloxy and allyl alcohol units in addition to an acetal
unit, this method gave 12 in one step from 11 in high yield (82%).
In conclusion, we have developed an unprecedented, unexpected,
and remarkably highly chemoselective deprotection method of
acetals. This methodology can selectively deprotect acetals in the
presence of ketals, although this chemoselectivity is difficult to
achieve by other previously reported methods. The structures of
the polar components formed during the reactions are now under
investigation. The reaction conditions are usually used for the
silylation of hydroxyl functions. This report cautions chemists who
intend to silylate the hydroxy function of the compounds with the
acetal group from an aldehyde.
Table 3. Chemoselective Deprotection of the Compounds Having
Acetal and Ketal Units in the Same Molecule
Supporting Information Available: General reaction procedure
using TMSOTf-2,6-lutidine and TESOTf-2,6-lutidine condition;
experimental details of the reaction of 5 with TESOTf-2,6-lutidine
(
Scheme 1) and the transfer of 11 to 12 (Scheme 2), and the physical
1
data of 6, 10a-10e (Table 3), and 12; H NMR study of the transfer
from 1b to 2b; speculation of the reaction mechanism. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(
1) (a) Greene, T. W.; Wuts, P. G. ProtectiVe Groups in Organic Synthesis,
3
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(
2) For selected recent examples on deacetalization, see: (a) Ates, A.; Gautier,
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a
Method A: 2.0 equiv of TESOTf, 3.0 equiv of 2,6-lutidine. Method
(3) For review of TMSOTf, see: Emde, H.; Domsch, D.; Feger, H.; Frick,
U.; G o¨ ts, A.; Hergott, H. H.; Hofmann, K.; Kober, W.; Kr a¨ geloh, K.;
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B: 3.0 equiv of TESOTf, 4.0 equiv of 2,6-lutidine.
due to the stabilization of the cationic intermediates by the alkyl
group.6 This tendency was totally clarified in the reaction of
compound 5, which has ketal and acetal units in the same molecule.
Our method selectively gave the ketal aldehyde 6 in good yield,
whereas the other representative methods such as aqueous p-TsOH
treatment and TMSI treatment did not give any deacetalized product
(4) For intramolecular transacetalization of MOM ether by identical conditions,
see: (a) Durharm, T. B.; Blanchard, N.; Savall, B. M.; Powell, N. A.;
Roush, W. R. J. Am. Chem. Soc. 2004, 126, 9307. (b) Powell, N. A.;
Roush, W. R. Org. Lett. 2001, 3, 453. See Supporting Information.
(
5) The enol ether (A) was obtained.
6
. It is noteworthy that the result obtained by our method is
7,8
completely different from the one using p-TsOH or TMSI.
Table 3 shows that our chemoselective deprotecting method is
available for various compounds having acetal and ketal units in
the same molecule. In the case of 9a, the â-methoxy group remained
without elimination (run 1). This shows that this method is very
mild. In the cases of 9b,c with a hydroxyl function, silylation of
the hydroxyl function occurred with chemoselective deprotection
of the acetal under this condition as shown (runs 2, 3). This
chemoselective deprotection was also observed in steroid systems
For the formation of enol ethers, see: (a) Rychnovsky, S. D.; Kim, J.
Tetrahedron Lett. 1991, 32, 7219. (b) Gassman, P. G.; Burns, S. J. J.
Org. Chem. 1988, 53, 5574.
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Chem. Soc. 1955, 77, 5590.
7) Jung, M. E.; Andrus, W. A.; Ornstein, P. L. Tetrahedron Lett. 1977, 4175.
8) For the examples where aliphatic ketals are deprotected selectively in the
presence of aliphatic acetals, see: (a) Entry 8 of Table 1 in ref 2f; (b)
Ukaji, Y.; Koumoto, N.; Fujisawa, T. Chem. Lett. 1989, 1623.
9) Total synthesis of scyphostatin is in progress, and the preparation of 11
will be presented soon. Compare Fujioka, H.; Kotoku, N.; Sawama, Y.;
Nagatomi, Y.; Kita, Y. Tetrahedron Lett. 2002, 43, 4825.
(
(
(
(
(runs 4, 5).
This method proved to be very useful for obtaining compound
12 (Scheme 2). Compound 12 is a key intermediate for our
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J. AM. CHEM. SOC.
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