An efficient and chemoselective cleavage of prenyl ethers with DDQ

Article abstract of DOI:10.1055/s-2002-20480

The prenyl (Pre) protecting group tor hydroxyl functions is readily removed at room temperature with DDQ in dichloromethane-water (9:1). The reaction conditions are compatible with the presence of other ethereal functionalities such as acetonides, allyl, benzyl, TBS, TBDPS groups. We have also shown that Sdeprotection of prenyl ethers using a catalytic amount of DDQ in the presence of 3 equivalents of Mn(OAc)₃ is a good alternative for the use of a stoichiometric amount of DDQ, albeit the reaction time being longer.

Full text of DOI:10.1055/s-2002-20480

LETTER
507
An Efficient and Chemoselective Cleavage of Prenyl Ethers with DDQ
An
Efficie
e
nt and Che
a
moselective
n
Cleavage of
-
Prenyl
M
Ethers
w
ith
D
D
Q
ichel Vatèle*
Laboratoire de Chimie Organique 1, UMR 5622 CNRS, domaine scientifique de la Doua, CPE, 3 rue Victor Grignard, 69616 Villeurbanne
Cedex, France
Fax +33(472)431214; E-mail: vatele@univ-lyon1.fr
Received 12 December 2001
DDQ is also an efficient and selective reagent for the ox-
Abstract: The prenyl (Pre) protecting group for hydroxyl functions
idative deprotection of prenyl ethers (Scheme 1).
is readily removed at room temperature with DDQ in dichlor-
omethane-water (9:1). The reaction conditions are compatible with
the presence of other ethereal functionalities such as acetonides, al-
DDQ
ROH
+
lyl, benzyl, TBS, TBDPS groups. We have also shown that depro-
tection of prenyl ethers using a catalytic amount of DDQ in the
presence of 3 equivalents of Mn(OAc)3 is a good alternative for the
use of a stoichiometric amount of DDQ, albeit the reaction time be-
ing longer.
CHO
CH2Cl2-H2O (9:1)
RT, 0.75-9h
36-89%
RO
2 a-k
1 a-k
Scheme 1
Key words: DDQ, cleavage, protecting groups, ethers, oxidation
The results of this new protocol for the deprotection of
prenyl ethers are summarized in the Table.5,6 First of all,
the reaction time is very dependent on the substrate vary-
ing from 45 minutes to 9 hours.
In multistep synthesis of complex natural products con-
taining hydroxyl functions such as carbohydrates, mac-
rolides, polyether antibiotics, selection of the most
suitable protecting group for each hydroxyl group is often
decisive for the success of the synthesis. As a conse-
quence of the great importance of the protection of alco-
hols in organic synthesis, a variety of blocking techniques
has been developed.1 However, because of the increasing
complexity of the molecules synthesized containing a
multitude of functional groups, and because only few of
all the protecting groups have found wide applications,
new protecting groups with modulated reactivity and new
techniques of cleavage of existing protecting groups are
needed.
Catalytic DDQ in acetonitrile–water is known to cleave
selectively and quantitatively in 4 hours the 5,6-O-isopro-
pylidene of diacetone glucose.7 It seems that the use of
CH2Cl2–H2O as solvents allowed, albeit in moderate
yield, cleavage of the 3-O-prenyl ether of compound 1a
without noticeable 5,6-acetonide hydrolysis (entry 1).
Surprisingly, DDQ deprotects very selectively the prenyl
ether of 1-O-allyl-5-O-prenylpentane (entry 8), even
though it has been reported that under the same experi-
mental conditions primary allyl ethers are cleaved albeit
in longer time.4b The diprenyl ether of 3-(4-hydroxyphe-
nyl)-1-propanol in the presence of 1.2 equivalents of
DDQ gave the prenyl aryl ether 1k in only 36% yield. No
trace amount of the doubly deprotected compound was
detected. We have shown that this method of cleavage of
prenyl ethers is compatible with the presence of other
ethereal functions such as acetonides (entries 1–3), benzyl
(entry 3), allyl (entry 8), t-butyldimethylsilyl (entry 9) and
t-butyldiphenylsilyl (entry 10) groups.
In the course of our studies on the development of a new
generation of protecting groups based on the so-called ‘in-
tramolecular assisted removal’ principle,1a,2 we have re-
cently found that the 2-methylbut-2-enyl (prenyl) group
could be cleaved under mild conditions (iodine in dichlo-
romethane) in the presence of several other ethereal func-
tionalities. However, the yield of deprotection of prenyl
ethers in substrates containing acid-labile protecting
groups such as TBS, TBDPS, acetonides, was moderate to
low.3 Moreover, treatment of a substrate containing a pre-
nyl aryl ether with iodine did not give rise to a phenol but
instead a 2,2-dimethylchroman derivative was obtained.3
If DDQ is a mild and efficient oxidant, it has the disadvan-
tage to be expensive and removal of its by-product: 2,3-
dichloro-5,6-dicyanohydroquinone (DDQH2) is some-
times cumbersome. In order to overcome these difficul-
ties, Sharma and coworkers have reported a method for
regeneration of DDQ using Mn(OAc)3 as reoxidant.8
For all these reasons, a more general method for the re-
moval of the prenyl protecting group was needed.
We tested this protocol on one substrate: the prenyl ether
of menthol 1d. Treatment of 1d with 0.1 equivalents of
DDQ in the presence of 3 equivalents of Mn(OAc)3 2 H2O
afforded menthol in 84% yield. Although the yield of this
protocol is similar to that using a stoichiometric amount of
DDQ, the reaction time is longer (18 h versus 90 min).
2,3-Dichloro-5,6-dicyanoquinone (DDQ) is known to ox-
idatively cleave allylic ethers to , -unsaturated alde-
hydes and alcohols.4 In this communication, we show that
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0507,0509,ftx,en;G22401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Mechanistically, the oxidation/deprotection of prenyl
ethers with DDQ must follow the same pathway as that in-
volved in the cleavage of cinnamyl ethers, which has been

508
J.-M. Vatèle
LETTER
Table Oxidative Deprotection of Prenyl Ethers with DDQa in CH2Cl2–H2O (9:1)
Entry
1
Substrate
Time (h)
9
Product
Isolated yield (%)
65
O
O
O
O
O
O
O
O
OPre
OH
O
O
2a
1a
1b
2
4
89
OPre
O
OH
O
O
O
O
O
O
O
O
O
2b
OH
OH
3
4
4
68
86
PreO
PreO
O
O
O
O
OBn
OBn
O
O
1c
2c
1.5
OPre
OH
1d
2d
5
0.75
89
OH
OPre
O
O
2e
1e
6
7
1.5
1.5
78
PreO
HO
1f
2f
72b
OH
OPre
1g
2g
8
9
3
3
3
2
86
80
83
36
PreO
OAll
HO
OAll
1h
2h
HO
OTBS
PreO
OTBS
OTBDPS
2i
1i
10
11
HO
OTBDPS
PreO
2j
1j
PreO
PreO
OPre
OH
1k
2k
a 1.2 Equiv of DDQ was added except in the case of the diprenyl ether 1c (3 equiv; entry 3).
b An unidentified by-product was formed.
Synlett 2002, No. 3, 507–509 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Efficient and Chemoselective Cleavage of Prenyl Ethers with DDQ
509
well studied.4a The reaction proceeds by hydride abstrac-
tion from the activated methylene followed by trapping
the carbonium intermediates by water giving an hemiace-
tal which decomposes to furnish along with the alcohol,
DDQH2 and 3-methylbut-2-enal9 (Scheme 2).
(4) (a) Lee-Ruff, E.; Ablenas, F. J. Can. J. Chem. 1989, 67, 699.
(b) Yadav, J. S.; Chandrasekhar, S.; Sumithra, G.; Kache, R.
Tetrahedron Lett. 1996, 37, 6603. (c) Caputo, R.;Guaragna,
A.; Palumbo, G.; Pedatella, S. J. Org. Chem. 1997, 62,
9369. (d) Paterson, I.; Cowden, C. J.; Rahn, V. S.;
Woodrow, M. D. Synlett 1998, 915.
(5) General Experimental Procedure for the Cleavage of
Prenyl Ethers: To a stirred solution of the prenyl ether (1
mmol) dissolved in 9 mL of CH2Cl2 were added water and
DDQ (0.272 g; 1.2 equiv). Reaction progress was monitored
by TLC. Upon consumption of the prenyl ether, 2,3-
dichloro-5,6-dicyanohydroquinone was filtered. To the
filtrate was added a sat. NaHCO3 solution and the aq phase
was extracted twice with CH2Cl2. Drying over Na2SO4,
filtering, evaporation to dryness gave a material that was
purified by flash column chromatography using petroleum
ether–ether as eluent (2:1 ratio for compounds 2a,b, 2f and
2h–j; 1:2 for 2d, 2g and 2k; 4:1 for 2e and ether for 2c.
(6) Compounds 2a–g and 2i–k exhibited physical and spectral
data in accordance with those described in the literature.
New compound 2h gave spectroscopic and analytical data in
agreement with the assigned structure. 1H NMR (CDCl3, 200
MHz): = 1.28–1.72 (6 H, m), 2.55 (1 H, s, OH), 3.39 (t, 2
H, J = 6.3 Hz, CH2OAll), 3.58 (t, 2 H, J = 6.4 Hz, CH2OH),
3.93 (dt, 2 H, J = 5.6 and 1.4 Hz, CH2-CH=CH2), 5.12 (brd,
1 H, J = 10 Hz, CH=CH2), 5.22 (dq, 1 H, J = 17 Hz and 1.5
Hz, CH=CH2), 5.88 (ddd, 1 H, J = 5.6, 10 and 17 Hz,
CH=CH2); 13C NMR (CDCl3, 50.3 MHz): = 22.4, 29.4,
32.4, 62.5, 70.3, 71.8, 116.8, 134.9. Anal. Calcd for
C8H16O2: C, 66.63; H, 11.18. Found: C, 66.55; H, 11.22.
(7) Garcia Fernandez, J. M.; Ortiz Mellet, C.; Moreno Marin,
A.; Fuentes, J. Carbohydr. Res. 1995, 274, 263.
H2O
+
DDQH-
DDQ
+
RO
RO
H
O
DDQH2
ROH
+
+
CHO
RO
Scheme 2
In summary, the use of DDQ in dichloromethane–water
provides a mild and efficient means of removing prenyl
ethers and enhances its usefulness as a protecting group.
The mild cleavage conditions broadens the synthetic ap-
plications of prenyl ethers and the high selectivity ob-
served in the presence of other functionalities extends its
utility as an orthogonal protecting group.
References
(1) See for example: (a) Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 3rd ed.; John
Wiley: New York, 1999. (b) Kocienski, P. J. Protecting
Groups; Thieme: Stuggart, 1994. (c) Ziegler, T. Protecting
Group Strategies for Carbohydrates, In Carbohydrate
Chemistry; Booms, G. J., Ed.; Blackie Academic and
Professional: Glasgow, 1998, 21.
(8) (a) Sharma, G. V. M.; Lavanya, B.; Mahalingam, A. K.;
Krishna, P. R. Tetrahedron Lett. 2000, 41, 10323.
(b) Sharma, G. V. M.; Rakesh, n. Tetrahedron Lett. 2001, 42,
5571.
(9) This , -unsaturated aldehyde was isolated and has
spectroscopic data in accord with those described in the
literature: Vani, P. V. S. N.; Chida, A. S.; Srinivasan, R.;
Chandrasekharam, M.; Singh, A. K. Synth. Commun. 2001,
31, 219.
(2) Patek, M. Int. J. Pept. Protein Res. 1993, 42, 97.
(3) Vatèle, J.-M. Synlett 2001, 1989.
Synlett 2002, No. 3, 507–509 ISSN 0936-5214 © Thieme Stuttgart · New York