A facile oxidation/deprotection of electron rich silyl ethers using DDQ

Article abstract of DOI:10.1055/s-1998-1810

The selective oxidation/deprotection of allylic and benzylic silyl ethers to give aldehydes can be achieved by hydride abstraction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under neutral conditions. This reaction is possible in the presence of a variety of silyl protecting groups, as in 2 → 3, and even PMB ethers and PMP acetals, as in 14 → 15, which are normally labile under DDQ oxidation conditions.

Full text of DOI:10.1055/s-1998-1810

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915
A Facile Oxidation/Deprotection of Electron Rich Silyl Ethers Using DDQ
Ian Paterson,* Cameron J. Cowden, Volker S. Rahn and Michael D. Woodrow
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Fax +44 1223 336362; E-mail: ip100@cus.cam.ac.uk; Website: http://www-paterson.ch.cam.ac.uk
Received 29 May 1998
Abstract: The selective oxidation/deprotection of allylic and benzylic
silyl ethers to give aldehydes can be achieved by hydride abstraction
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under neutral
conditions. This reaction is possible in the presence of a variety of silyl
protecting groups, as in 2 → 3, and even PMB ethers and PMP acetals,
as in 14 → 15, which are normally labile under DDQ oxidation
conditions.
As the complexity of synthetic targets increases, so too does the need for
new protecting groups. In this respect, a large number of different silyl
ethers are now available which offer a range of reactivity based upon
1,2
either steric or electronic properties. An alternative approach is to use
the structure of the substrate to differentiate between similar protecting
groups. For example, the selective removal of one tert-
butyldimethylsilyl (TBS) ether in the presence of another is possible
using LiAlH when a nearby polar group can direct the reductive
4
3
cleavage.
4
For many years, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
5
has been used for the oxidation of allylic alcohols and, more recently,
allylic ethers to α,β-unsaturated carbonyl compounds. In our studies
towards the synthesis of aplyronine A, a 24-membered cytotoxic
6,7
8
macrolide isolated from the sea hare Aplysia kurodai, a protecting group
strategy was selected which relied heavily upon the use of silyl ethers.
For instance, in intermediate 2 silyl protection was chosen for four
hydroxyl groups. In preparation for a macrolactonisation reaction,
deprotection of the C TBS ether and then oxidation to a carboxylic acid
1
were required. Conventional methods for the selective removal of the C
1
TBS ether proved unsatisfactory and instead a novel oxidation/
Scheme 1
deprotection strategy was developed which employed DDQ under
neutral conditions.
6
despite being potentially labile to DDQ oxidation. Moreover, the
triisopropylsilyl (TIPS) ether and di-tert-butyl silylene protection
remained intact under these mild, neutral conditions.
9
In practice, treatment of substrate 2 with DDQ (1.10 equiv., CH Cl ,
2
2
10
pH7 buffer) at 0 °C for 10 min afforded the (E,E)-dienal 3 in excellent
yield (92%) with retention of double bond geometry. Hence, as well as
selective removal of the C silyl ether, oxidation to the aldehyde 3
With this initial finding, a study to ascertain the scope and generality of
this oxidation/deprotection reaction was undertaken and some of the
results are presented in Table 1. From 4 → 5 (entry 1), it is clear that
selective oxidation/deprotection of a benzylic silyl ether works well,
although this reaction was considerably slower than that for 2 → 3.
When reactions progressed slowly, addition of aqueous pH7 buffer
1
occurred which could then be transformed into the corresponding seco
acid for macrolactonisation. Notably, the p-methoxyphenyl (PMP)
acetal did not react under these oxidising conditions, highlighting the
rate difference between the allylic and benzylic hydride abstractions in
this instance. Furthermore, the two allylic methyl ethers were unaffected
Scheme 2

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proved to be detrimental to the yield, probably because of competitive
4
aqueous decomposition of DDQ. The oxidation/deprotection of silyl
ether 6a (entry 2) was again slower, indicating the beneficial effect of
the diene unit. However, a good yield of enal 7 was obtained when TES
ether 6b was used instead. In both these cases, selective deprotection of
the allylic silyl group was achieved. The final entry in the table, 8 → 9,
indicates that enones can also be formed using the DDQ oxidation.
Scheme 3
In summary, the selective oxidation/deprotection of allylic and benzylic
silyl ethers is possible by hydride abstraction with DDQ under neutral
conditions. In favourable cases, this reaction is even possible in the
presence of PMB ethers and PMP acetals which are normally labile
11
under these conditions. This transformation should find application in
the synthesis of a variety of complex polyoxygenated natural products.
Acknowledgements: We thank the EPSRC (GR/K54052) and Merck
for support. VSR was a participant in the ERASMUS/ SOCRATES
programme.
References and Notes
(1) For a recent review on silyl ethers and their selective deprotection,
see: Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(2) Kocienski, P. J. Protecting Groups; Thieme: New York, 1994.
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley-Interscience: New York, 1991.
(3) de Vries, E. F. J.; Brussee, J.; van der Gen, A. J. Org. Chem. 1994,
59, 7133.
(4) Buckle, D. R. Encyclopaedia of Reagents for Organic Synthesis,
Vol 3, Paquette, L. (ed), John Wiley & Sons, Chichester, 1995,
1699. For a review of oxidation reactions using DDQ, see: Walker,
D.; Hiebert, J. D. Chem. Rev. 1966, 66, 153.
(5) Braude, E. A.; Linstead, R. P.; Wooldridge, K. R. J. Chem. Soc.
1956, 3070. More recently, a reaction catalytic in DDQ has been
reported: Cacchi, S.; La Torre, F.; Paolucci, G. Synthesis 1978,
848.
In Scheme 2, three more complex substrates having further silyl and/or
PMB (p-methoxybenzyl) protecting groups were submitted to the DDQ-
mediated oxidation/deprotection reaction. Reaction of diene 10 with
DDQ selectively removed the allylic TBS ether in the presence of three
other silyl protecting groups, with simultaneous oxidation to the
aldehyde 11 (82%). Again, the diene unit is beneficial in accelerating
the reaction. Treatment of allylic silyl ether 12 with DDQ gave enal 13
(88%), with the other silyl ethers surviving unscathed. Finally, in an
attempt to compare the rate of allylic hydride abstraction with that for
(6) Lee-Ruff, E.; Ablenas, F. J. Can. J. Chem. 1989, 67, 699. Caputo,
R.; Guaragna, A.; Palumbo, G.; Pedatella, S. J. Org. Chem. 1997,
62, 9369. Wang, W.; Li, T.; Attardo, G. J. Org. Chem. 1997, 62,
6598.
(7) The deprotection/oxidation of allylic and benzylic silyl ethers with
DDQ has been reported on two occasions that we are aware:
(a) Narasimhan, N. S.; Bapat, C. P. J. Chem. Soc. Perkin Trans. 1
1984, 1435. (b) Piva, O.; Amougay, A.; Pete, J.-P. Tetrahedron
Lett. 1991, 32, 3993. In the first instance, it is likely that the acid-
labile trimethylsilyl group is removed before oxidation. In the
second case, irradiation with UV light was necessary to give good
yields of α,β-unsaturated carbonyl compounds. For a review of
other methods of silyl ether oxidation/deprotection, see: Muzart, J.
Synthesis, 1993, 11.
11
benzylic abstraction, substrate 14 was treated with DDQ (1.0 equiv.).
While 14 has both a PMB ether and a PMP acetal, selective formation of
the dienal 15 was accomplished in 96% yield, indicating that allylic
hydride abstraction is favoured.
Our preferred mechanism for this process involves hydride removal
from the activated methylene followed by loss of the silyl group, cf.
Scheme 3. An alternative mechanism would involve silyl ether cleavage
followed by oxidation of the allylic alcohol. While DDQ has been
(8) Yamada, K.; Ojika, M.; Ishigaki, T; Yoshida, Y.; Ekimoto, H.;
Arakawa, M. J. Am. Chem. Soc. 1993, 115, 11020. Ojika, M.;
Kigoshi, H.; Ishigaki, T.; Tsukada, I.; Tsuboi, T.; Ogawa, T.;
Yamada, K. J. Am. Chem. Soc. 1994, 116, 7441.
12
reported to deprotect silyl ethers under aqueous conditions, this is
likely to result from the reaction of DDQ with water leading to acidic
(9) Typical procedure for the oxidation/deprotection of allylic silyl
13
conditions. In this respect, the pH of an aqueous solution of DDQ has
ethers with DDQ: Freshly recrystallised (CH Cl ) DDQ (83 mg,
2
2
13b
been measured at <2.2 after 6 h. As the oxidation of compound 2, for
0.36 mmol, 1.1 equiv.) was added to a cooled (0 °C), stirred two-
phase solution of silyl ether 2 (380 mg, 0.33 mmol) in CH Cl (10
instance, takes place within 10 min at 0 °C in the presence of pH7
buffer, the two-step mechanism of silyl ether hydrolysis followed by
allylic alcohol oxidation is unlikely. Furthermore, the substantial rate
acceleration for pentadienyl silyl ethers, e.g. 2 and 14, relative to simple
allylic ones can be best rationalised by hydride abstraction occurring
first.
2
2
mL) and pH7 buffer (1 mL). After 10 min, TLC analysis indicated
that the reaction had gone to completion and NaHCO (sat. aq.)
3
(10 mL) was added. The phases were separated, then the aqueous
phase was extracted with Et O (3 x 10 mL) and the combined
2
organic layers were dried (MgSO ), filtered and concentrated.
4

August 1998
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Flash chromatography (20% EtOAc/hexanes) afforded the
(1H, m, 17-CH), 1.59-1.53 (4H, m, 10-CH, 11-CH H , 12-CH ),
A B 2
aldehyde 3 as a colourless oil (314 mg, 92%).
1.48-1.41 (2H, m, 18-CH ),1.45 (3H, s, 14-CCH ), 1.20 (3H, d, J
2 3
= 6.9 Hz, 10-CHCH ), 1.09 (3H, m, OSi(CH(CH ) ) ), 1.06 (18H,
(10) All new compounds gave spectroscopic data in agreement with the
3
3 2 3
d, J = 5.1 Hz, OSi(CH(CH ) ) ), 1.03 (3H, d, J = 6.8 Hz, 26-
assigned structures. Compound 3 had: IR (thin film) 1710, 1642
3 2 3
-1
1
CHCH ), 0.99 (18H, s, Si(C(CH ) ) ), 0.85 (3H, d, J = 6.5 Hz, 24-
cm ; H NMR δ (500 MHz, CDCl ) 9.55 (1H, d, J = 7.9 Hz,
3
3 3 2
3
CHCH ), 0.84 (3H, d, J = 7.2 Hz, 17-CHCH ), 0.81 (3H, d, J =
CHO), 7.36 (2H, d, J = 8.7 Hz, ArH), 7.09 (1H, dd, J = 15.4, 10.8
Hz, 3-CH), 6.87 (2H, d, J = 8.7 Hz, ArH), 6.43 (1H, dd, J = 15.2,
10.8 Hz, 4-CH), 6.30 (1H, ap. dt, J = 15.2, 6.8 Hz, 5-CH), 6.10
(1H, dd, J = 15.4, 6.8 Hz, 2-CH), 5.78 (1H, ap. dt, J = 15.5, 6.6
Hz, 21-CH), 5.67 (1H, s, CHAr), 5.31 (1H, ap. t, J = 7.1 Hz, 15-
CH), 5.29 (1H, dd, J = 15.5, 8.4 Hz, 20-CH), 4.04 (1H, m, 23-
CH), 4.02 (1H, dd, J = 9.6, 6.3 Hz, 7-CH), 3.90 (1H, dd, J = 9.6,
3
3
13
6.8 Hz, 8-CHCH ); C NMR δ (62.9 MHz, CDCl ) 193.8, 159.8,
3
3
151.9, 142.3, 134.7, 132.1, 132.0, 131.5, 130.7, 130.7, 128.0,
127.3, 113.6, 94.9, 88.3, 81.0, 79.1, 78.5, 76.8, 76.6, 63.6, 55.7,
55.6, 55.3, 42.6, 39.0, 38.8, 34.9, 34.4, 34.1, 33.6, 32.1, 29.8,
29.6, 28.8, 28.1, 28.0, 27.6, 27.4, 19.8, 18.1, 15.2, 14.2, 13.8,
13.0, 12.0, 10.2.
5.7 Hz, 27-CH H ), 3.80 (1H, m, 25-CH), 3.80 (3H, s, OCH ),
(11) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
A
B
3
3.63 (1H, dd, J = 10.0, 1.0 Hz, 9-CH), 3.59-3.54 (2H, m, 19-CH
and 27-CH H ), 3.37 (1H, ap.t, J = 7.0 Hz, 13-CH), 3.24 (3H, s,
Tetrahedron 1986, 42, 3021.
A
B
(12) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin
Trans. 1 1992, 2997.
OCH ), 3.14 (3H, s, OCH ), 3.08 (1H, ap.dt, J = 15.6, 6.8 Hz, 6-
3
3
CH H ), 2.53 (1H, ap.dt, J = 15.6, 6.3 Hz, 6-CH H ), 2.36-2.28
A
B
A B
(13) (a) Oku, A.; Kinugasa, M.; Kamada, T. Chem Lett. 1993, 165.
(b) Tanemura, K.; Suzuki, T.; Horaguchi, T. Bull. Chem. Soc. Jpn.
1994, 67, 290.
(2H, m, 24-CH and 22-CH H ), 2.21 (1H, ddd, J = 14.2, 6.8, 3.1
A
B
Hz, 22-CH H ), 2.08 (1H, ap. dt, J = 14.0, 6.5 Hz, 16-CH H ),
A
B
A B
1.88 (1H, m, 26-CH), 1.83 (1H, ap. dt, J = 14.0, 7.8 Hz, 16-
CH H ), 1.73 (1H, m, 8-CH), 1.66 (1H, m, 11-CH H ), 1.63
A
B
A B