A new route to butane-1,2-diacetals and the development of alternative substitution patterns to facilitate differential protection of the products

Article abstract of DOI:10.1055/s-2001-18087

The utility of 2,3-dialkoxybutan-1,3-dienes as reagents for the protection of vicinal diols and α-hydroxy acids as their corresponding 1,2-diacetals is demonstrated together with their later deprotection under mild reaction conditions.

Full text of DOI:10.1055/s-2001-18087

LETTER
1793
A New Route to Butane-1,2-diacetals and the Development of Alternative
Substitution Patterns to Facilitate Differential Protection of the Products
A
NewRoute
t
to Buta
e
ne-1,2-dia
c
v
etals en V. Ley,* Patrick Michel
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cus.cam.ac.uk
Received 31 August 2001
addition of a small amount of boron trifluoride diethyl
etherate (0.25 equiv). All these reactions proceeded in rea-
sonable yields to afford products which had been de-
scribed previously (Scheme 2).2,8
Abstract: The utility of 2,3-dialkoxybutan-1,3-dienes as reagents
for the protection of vicinal diols and -hydroxy acids as their cor-
responding 1,2-diacetals is demonstrated together with their later
deprotection under mild reaction conditions.
Key words: enol ether, 1,2-diol protection -hydroxy acid protec-
tion
OMe
Ph3P HBr
OH
OH
CH2Cl2, 24h, rt
O
+
+
1
1
1
1
O
then BF3 OEt2
63 %
65 %
73 %
OMe
OMe
2
6
For some years, we have been developing the concept of
using 1,2-diacetals as a protection motif for vicinal diols
and -hydroxy acids.1,2 While this work has been exten-
sively exploited in organic synthesis programmes,3 we
have sought improvements to the process by which these
groups may be introduced and subsequently removed. 4
Ph3P HBr
OH
CH2Cl2, 24h, rt
O
Ph
O
OH
then BF3 OEt2
Ph
3
7
OMe
O
Ph3P HBr
OH
CH2Cl2, 24h, rt
Here we report the preparation of various bis-enol ether
derivatives and study their subsequent reactions to afford
1,2-diacetals some of which may be deprotected under
mild reaction conditions. Firstly we prepared the known5
methyl substituted bis-enol ether derivative 1 since we an-
ticipated that this would have similar reactivity to bis-di-
hydropyrans that had been investigated earlier.1,6
Reaction of inexpensive, commercially available, butane-
2,3-dione with methyl orthoformate in methanol contain-
ing a small amount of sulfuric acid affords 1 in reasonable
yield (Scheme 1). The reaction can be carried out on a
multigramme scale and distillation of the crude product
gives a colourless oil which can be stored at -23 °C for
long periods of time (at least two months) without notice-
able decomposition.
O
+
O
HO
OH
then BF3 OEt2
4
8
OMe
OMe
Ph3P HBr
MeO2C
MeO2C
OH
O
CH2Cl2, 3h, rt
MeO
O
+
O
MeO
then BF3 OEt2
70 %
O
OH
OMe
5
9
Scheme 2
The methyl substituted bis-enol ether 1 was also reacted
with glycolic acid 10, thioglycolic acid 11, (S)-mandelic
acid 12 and (S)-lactamide 13 in dichloromethane contain-
ing triphenylphosphonium hydrobromide to produce the
corresponding methyl substituted BDA compounds 14,
15, 16 and 17 as crystalline derivatives (Scheme 3).
HC(OMe)3
OMe
OMe
O
O
In the case of (S)-lactamide 13, diastereoisomeric prod-
ucts (1:9 ratio) were first formed in 72% yield. After one
recrystallisation, pure 17 was obtained in 51% isolated
yield. It is also important to note that our previously re-
ported method9 using butane-2,3-dione, p-toluenesulfonic
acid and methyl orthoformate fails to produce the corre-
sponding acetals in these examples.
MeOH, H2SO4
61 %
1
Scheme 1
Next the vicinal diols 2-5 were treated with 1 in dichlo-
romethane solution containing triphenylphosphine hydro-
bromide as an acid catalyst.7 The initially formed
diastereoisomeric mixtures of acetals were not isolated
but were equilibrated to the corresponding thermodynam-
ically stable butane diacetal (BDA) products 6-9 by the
Given the above successful reactions using 1, we investi-
gated the preparation of other bis enol ethers bearing dif-
ferent groups on the ether oxygen. It was envisaged that
compounds such as 18 and 19 could provide alternative
deprotection strategies for butanediacetal derivatives.
However, these compounds required a more lengthy prep-
aration. Treatment of diethyl tartrate 20 with benzyl bro-
mide and sodium hydride gave the dialkylated product 21
in 67% yield. Correspondingly, similar reaction of 20 with
allyl bromide gave 22 (68%). Reduction of the ester
Synlett 2001, No. 11, 26 10 2001. Article Identifier:
1437-2096,E;2001,0,11,1793,1795,ftx,en;D19201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1794
S. V. Ley, P. Michel
LETTER
as a representative diol, with either 18 or 19 under the pre-
viously established conditions, gave the products 27 and
28 respectively (Scheme 5).
OMe
O
Ph3P HBr
O
OH
OH
O
+
1
O
CH2Cl2, 3h, rt
83 %
OMe
OMe
10
14
OR
O
O
OH
OH
OR
OR
Ph3P HBr
O
O
OH
SH
Ph3P HBr
O
+
O
CH2Cl2, 24h
O
+
+
1
1
57 %
S
CH2Cl2, 3h, rt
OR
OMe
OMe
18 R = Bn
19 R = Allyl
25 R = Bn 95 %
26 R = Allyl 82 %
10
11
15
O
Ph3P HBr
O
OH
OH
OR
MeO2C
MeO2C
OH
Ph3P HBr
OR
OR
O
O
Ph
51 %
OMe
CH2Cl2, 24h, rt
O
MeO
MeO
CH2Cl2, 24h
O
+
O
Ph
OMe
then BF3 OEt2
O
OH
12
16
OR
MeO
O
O
O
NH2
+
18 R = Bn
19 R = Allyl
27 R = Bn 90 %
28 R = Allyl 87 %
5
Ph3P HBr
H
H
N
N
1
+
:
O
O
Me
CH2Cl2, 24h, rt
Me
OH
Scheme 5
OMe
1
OMe
Me
13
9
recryst.
in hexane
OMe
Since deprotection of the methyl substituted butane diac-
etal functionality normally requires strongly acidic condi-
tions such as aqueous trifluoroacetic acid,11 we wished to
exploit the protecting group opportunities presented by
these new benzyl and allyl substituted derivatives.
O
H
N
Me
51 %
O
17
OMe
For example, reduction of 27 and 28 with lithium alumin-
ium hydride gave the diols 29 and 30. The benzyl substi-
tuted diol 29 was reacted firstly with one equivalent of
sodium hydride followed by t-butyldimethylsilyl chloride
and subsequently with methoxymethyl chloride (MO-
MCl) and Hünig’s base to give 31 in 74% overall yield.
The 1,2-diacetal in 31 was then removed selectively by
hydrogenolysis with hydrogen and Pd/C (Merck) in ethyl
Scheme 3
groups in 21 and 22 using lithium aluminium hydride, fol-
lowed by conversion to the bis-tosylate 23 and 24 using p-
toluenesulfonyl chloride, proceeded in a straightforward
manner.10 These reactions were commonly performed on
scales of more than 20 g. Finally, elimination of 23 and 24 acetate to give the syn-diol 32 in 74% yield. Similarly, 30
through treatment with potassium t-butoxide in THF gave
the corresponding substituted bis-enol ethers 18 and 19
(Scheme 4).
OR
OR
O
LiAlH4
MeO
MeO
HO
HO
As with the previous methyl substituted bis-enol ether 1,
we found that both the benzyl derivative 18 and the allyl
substituted compound 19 react well with -hydroxy acids
and diols to afford the corresponding protected products.
In order to illustrate these reactions, glycolic acid 10 was
treated with triphenylphosphine hydrobromide in methyl-
ene chloride in the presence of 18 or 19 to give the substi-
tuted products 25 and 26. Reaction of dimethyl tartrate 5,
O
O
O
O
THF
O
OR
OR
29 R = Bn 70 %
30 R = Allyl 84 %
27 R = Bn
28 R = Allyl
OBn
1) NaH,TBSCl
MOMO
TBSO
29
74 %
O
O
2) MOMCl
iPr2EtN
31
OBn
OH
Pd/C (Merck)
H2, EtOAc
MOMO
74 %
EtO2C
EtO2C
OH
OH
EtO2C
EtO2C
OR
OR
OTBS
73 %
NaH, RBr
THF
32
OH
OAllyl
1) NaH,TBSCl
2) NaH, BnBr
21 R = Bn 67 %
22 R = Allyl 68 %
20
BnO
TBSO
30
O
O
33
OAllyl
OH
OR
OR
OR
OR
1) LiAlH4
TsO
TsO
t-BuOK
THF
2) TsCl, pyr
1) Ir(cod)(PPh2Me)2PF6
71 %
OTBS
BnO
2) O3, CH2Cl2/MeOH
3) THF, NaHCO3
23 R = Bn 69 %
24 R = Allyl 66 %
18 R = Bn 93 %
19 R = Allyl 68 %
OH
34
Scheme 4
Scheme 6
Synlett 2001, No. 11, 1793–1795 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Route to Butane-1,2-diacetals
1795
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was converted to 33 by reaction with t-butyldimethylsilyl
chloride followed by treatment with benzyl bromide in
73% overall yield. Isomerisation of diallyl 33 by
Ir(cod)(PPh2Me)2PF6 followed by ozonolysis and basic
hydrolysis gave the syn-diol 34 in 71% yield (Scheme 6).
12
These reactions demonstrate clearly additional opportuni-
ties that can arise by using these new complementary 1,2-
diacetal protection methods.
(4) Lainé, D.; Fujita, M.; Ley, S. V. J. Chem. Soc., Perkin Trans.
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Acknowledgement
We thank the BBSRC (to PM) and the Novartis Research Fel-
lowship (to SVL) for financial support.
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Synlett 2001, No. 11, 1793–1795 ISSN 0936-5214 © Thieme Stuttgart · New York