Indium trichloride mediated cleavage of acetonides in the presence of acid-labile functional groups - Enhancing the synthetic utility of 1,3-dioxolanyl-substituted 1,2-oxazines

Article abstract of DOI:10.1055/s-0028-1083628

Indium trichloride in an acetonitrile-water mixture chemoselectively cleaved the isopropylidene acetals of various 1,3-dioxolanyl-substituted 1,2-oxazines as well as carbohydrate derivatives. Deprotection of acetonides can be achieved in substrates suscep

Full text of DOI:10.1055/s-0028-1083628

LETTER
2965
Indium Trichloride Mediated Cleavage of Acetonides in the Presence of
Acid-Labile Functional Groups – Enhancing the Synthetic Utility of
1,3-Dioxolanyl-Substituted 1,2-Oxazines
I
ndium Trichlo
a
ride Media
b
tedCleavag
i
e
of
A
c
a
etonide
s
n Pfrengle, Vjekoslav Dekaris, Luise Schefzig, Reinhold Zimmer, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 6 August 2008
Abstract: Indium trichloride in an acetonitrile–water mixture
chemoselectively cleaved the isopropylidene acetals of various 1,3-
dioxolanyl-substituted 1,2-oxazines as well as carbohydrate deriva-
tives. Deprotection of acetonides can be achieved in substrates sus-
ceptible for acid-induced cyclizations. Most importantly, enol ether
moieties are not attacked and the presence of glycosidic linkages or
acid-sensitive protecting groups such as tert-butyldimethylsilyl, 2-
(trimethylsilyl)ethyl, or tert-butoxycarbonyl is also tolerated.
OR1
O
O
R = (CH2)2TMS
N
O
Bn
1
Lewis acid
Brønsted
acid
?
Key words: deprotection, 1,2-oxazines, isopropylidene acetals,
Lewis acids, indium trichloride
O
O
OR1
R1O
OR2
O
OH
Bn
OH
OH
Many intermediates for the synthesis of polyhydroxylated
natural products, such as carbohydrates or nucleosides,
contain 1,2-diol units. Isopropylidene acetals also known
as acetonides are the most frequently used protecting
groups for these diols. Therefore many methods for their
formation and cleavage have been developed, typically
employing protic acids or Lewis acids.1 Only a few of
these methods allow mild and chemoselective deprotec-
tion of particularly stable isopropylidene acetals.2
N
N
O
N
O
Bn
Bn
O
2
4
3
Scheme 1 Acid-promoted transformations of 1,2-oxazine 1
when an overstoichiometric amount of InCl3 in dry
CH2Cl2 was applied.7,8 Gratifyingly, the conditions could
be optimized yielding free diol syn-4 in 84% yield
(Scheme 2) without touching the acid-sensitive enol ether
unit.9,10
During our exploration of the synthetic utility of 3,6-dihy-
dro-1,2-oxazines3 we encountered the problem to selec-
tively cleave the isopropylidene acetal of 1,2-oxazines of
type 1 without touching the other acid-sensitive functional
groups of the compound (Scheme 1). We expected this to
be a difficult task, because we had earlier discovered the
Lewis acid mediated formation of bicyclic 1,2-oxazinones
2. In this case SnCl4, TMSOTf, BF3·OEt2, Bu2BOTf, or
Et2AlCl served as suitable promoters.4 On the other hand,
treatment of 1,2-oxazines 1 with Brønsted acids like HF-
pyridine, HCl in MeOH, or DOWEX-H+ leads to forma-
tion of bicyclic tetrahydrofurans of type 3.5 Nevertheless,
we were searching for a suitable method to generate free
diols of type 4.
TMSEO
OH
TMSEO
O
InCl3 (2 equiv), H2O (4 equiv)
MeCN
OH
O
N
r.t., 2 h
84%
O
Bn
N
O
Bn
syn-4
syn-1
TMSE = (CH2)2TMS
Scheme 2 Indium trichloride mediated deprotection of 1,2-oxazine
syn-1
The use of catalytic amounts of weak Lewis acids such as
Sc(OTf)3 or SbCl3 gave no conversion of compound syn-
1. These reagents are able to perform mild and selective
deprotections of isopropylidene acetals.6 During our
screening of alternative Lewis acids for the rearrangement
of 1,2-oxazine 1 into bicyclic compound 2 we had ob-
served hydrolysis of the acetonide moiety in poor yield
Two equivalents of fairly expensive InCl3 are necessary to
perform this transformation, but since less costly reagents
failed, we considered this protocol as a useful alternative
for a general deprotection method of isopropylidene ace-
tals with additional acid-sensitive functional groups. The
deprotection of several 1,3-dioxolanyl-substituted 1,2-ox-
azines was thus investigated in more detail. Table 1 sum-
marizes the results.
SYNLETT 2008, No. 19, pp 2965–2968
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1083628; Art ID: G24708ST
© Georg Thieme Verlag Stuttgart · New York

2966
F. Pfrengle et al.
LETTER
Table 1 Isopropylidene Acetal Cleavage Using Indium Trichloride and Water in Acetonitrilea
Entry
1
Substrate
Product
Time (h)
Yieldb (%)
TMSEO
OH
TMSEO
O
OH
OH
OH
O
O
O
2
84
81
70c
80
58c
81
N
N
N
O
Bn
O
Bn
O
syn-4
syn-1
TMSEO
O
OH
TMSEO
O
2
3
4
5
6
2
N
Bn
Bn
O
ent-syn-4
ent-syn-1
TMSEO
OH
TMSEO
8
N
N
O
Bn
O
Bn
anti-4
anti-1
MeO
OH
MeO
O
OH
O
O
O
2
N
N
O
Bn
O
Bn
O
syn-15
syn-5
MeO
OH
MeO
OH
OH
8
N
N
N
O
Bn
O
Bn
O
anti-15
anti-5
MeO
OH
MeO
2.5
N
O
Boc
O
O
Boc
16
6
O
O
P
P
EtO
EtO
EtO
O
OH
O
EtO
O
OH
7
3
97
N
N
O
Bn
O
Bn
7
17
Ph
Ph
O
OH
8
9
3
3
87
63
O
OH
N
N
O
O
Bn
O
Bn
18
8
9
OH
OH
O
N
O
N
Bn
O
Bn
19
Synlett 2008, No. 19, 2965–2968 © Thieme Stuttgart · New York

LETTER
Indium Trichloride Mediated Cleavage of Acetonides
2967
Table 1 Isopropylidene Acetal Cleavage Using Indium Trichloride and Water in Acetonitrilea (continued)
Entry
10
Substrate
Product
Time (h)
3
Yieldb (%)
58d
TMSEO
HO
OH
Bn
TMSEO
HO
O
OH
O
N
N
O
O
Bn
20
10
MeO
OH
Bn
OH
MeO
O
O
OH
O
11
12
3
4
88
N
OH
O
Bn
O
N
O
O
21
11
OH
O
HO
Ph
H
55d,e
Ph
H
N
N
EtO
O
EtO
O
22
12
OMe
OMe
O
O
13
18
85f
O
HO
O
HO
O
O
HO
OH
23
13
OMe
OMe
O
O
O
14
18
50d,e
TBSO
O
O
TBSO
O
HO
OH
24
14
a Conditions: InCl3 (2 equiv), H2O (4 equiv), MeCN, r.t.
b Yields after purification by column chromatography.
c Reaction was conducted at 0 °C.
d Conversion was not complete.
e InCl3 (3 equiv) was used.
f Purification by recrystallization.
Treatment of 1,2-oxazines 1 and 5–11 with indium Encouraged by these results we investigated the deprotec-
trichloride in acetonitrile and in the presence of water fur- tion of more stable isopropylidene acetals exemplified by
nished free diols 4 and 15–21 in moderate to excellent 1,2-oxazine 1212 and rhamnose derivatives 1313 and 14
yields. Acid-labile functional groups such as enol ether (entries 12–14). We obtained the free diols 22–24 in mod-
moieties (Table 1, entries 1–6, 11) and enol phosphate erate to good yields, however, longer reaction times were
(entry 7) survived the procedure essentially untouched. required. It is highly remarkable that the second acetal
Protective groups like 2-(trimethylsilyl)ethyl (entries 1–3, moiety in these products is not attacked under the reaction
10) or tert-butoxycarbonyl group (entry 6) are also stable. conditions. In the sterically hindered acetonide of 14 the
The hydrolysis of both isopropylidene acetals of 1,2-ox- tert-butyldimethylsilyl protecting group in direct proxim-
azine 11 proceeds cleanly without formation of cycliza- ity to the diol group also survived, although the yield of
tion products (entry 11).11
product 24 is only 50% (entry 14).
Synlett 2008, No. 19, 2965–2968 © Thieme Stuttgart · New York

2968
F. Pfrengle et al.
LETTER
(9) Typical Procedure for the InCl3-Mediated Hydrolysis of
Isopropylidene Acetals – Conversion of syn-1 into syn-4
1,2-Oxazine syn-1 (6.00 g, 15.3 mmol), InCl3 (6.68 g, 30.6
mmol), and H2O (1.10 mL, 61.2 mmol) were dissolved in
MeCN (230 mL), and the mixture was stirred for 3 h at r.t.
After addition of H2O and CH2Cl2 the layers were separated
and the aqueous layer was extracted 2 times with CH2Cl2.
The combined organic layers were dried with MgSO4,
filtered, and concentrated. Column chromatography (silica
gel, EtOAc–hexane = 1:4) provided 4.50 g (84%) syn-4 as
colorless oil.
In conclusion, the presented method for deprotection of
isopropylidene acetals not only enhances the synthetic
utility of 1,2-oxazines, which is already presented in sev-
eral reports,14 but it also constitutes a powerful procedure
for the chemoselective deprotection of particularly stable
acetonides. We are convinced that the new protocol may
serve as a ‘last resource’ method for the deprotection of
other difficult substrates.
Acknowledgment
Analytical Data for (1¢S,3S)-1-{-2-Benzyl-4-(2-trimethyl-
silylethoxy)-3,6-dihydro-2H[1,2]oxazin-3-yl}ethan-1,2-
diol
Support by the Fonds der Chemischen Industrie (PhD fellowship for
F. Pfrengle), the Deutsche Forschungsgemeinschaft (SFB 765), and
the Bayer Schering Pharma AG is most gratefully acknowledged.
We thank J. Diab and M. Medvecky for experimental help and Dr.
A. Al-Harrasi for preliminary results.
[a]D22 +43.6 (c 0.81, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 0.04 (s, 9 H, SiMe3), 0.96–1.10 (m, 2 H, CH2Si), 2.84 (s,
1 H, OH), 3.04 (dd, J = 6.6, 1.6 Hz, 1 H, 3-H), 3.59 (s, 1 H,
OH), 3.63 (dd, J = 11.8, 4.7 Hz, 1 H, 2¢-H), 3.74 (dd,
J = 11.8, 3.6 Hz, 1 H, 2¢-H), 3.78–3.83 (m, 1 H, OCH2),
3.86–3.90 (m, 2 H, OCH2, 1¢-H), 3.93 (d, J = 13.2 Hz, 1 H,
NCH2), 4.17 (dd, J = 15.3, 3.6 Hz, 1 H, 6-H), 4.20 (d,
J = 13.2 Hz, 1 H, NCH2), 4.47 (dt, J = 15.3, 1.9 Hz, 1 H,
6-H), 4.81 (dd, J = 3.6, 1.9 Hz, 1 H, 5-H), 7.24–7.37 (m, 5
H, Ph) ppm. 13C NMR (126 MHz, CDCl3): d = –1.3 (q,
SiMe3), 17.5 (t, CH2Si), 56.9 (t, NCH2), 60.5 (t, C-6), 62.2
(d, C-3), 64.4 (t, C-2¢), 64.5 (t, OCH2), 72.0 (d, C-1¢), 91.7
(d, C-5), 127.8, 128.4, 129.0, 136.3 (3 d, s, Ph), 148.4 (s, C-
4) ppm. IR (film): 3460 (OH), 3090–2840 (=C–H, C–H),
1680 (C=C) cm–1. ESI-TOF: m/z calcd for [M + H]+:
352.1939; found: 352.2002. Anal. Calcd for C18H29NO4Si
(351.5): C, 61.50; H, 8.32; N, 3.98. Found: C, 61.37; H, 8.49;
N, 4.12.
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Synlett 2008, No. 19, 2965–2968 © Thieme Stuttgart · New York