Organocatalytic conversion of ribose and other protected carbohydrate derivatives into 2-deoxy-lactones

Article abstract of DOI:10.1055/s-0031-1290327

We report the simultaneous reduction of the 2-position and oxidation of the anomeric position in several protected furanosyl and pyranosyl sugar derivatives, mediated through NHC catalysis. This reaction allows the one-step access to highly valuable 2-deoxy-sugars from abundant 2-oxygenated sugar derivatives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290327

LETTER
541
Organocatalytic Conversion of Ribose and Other Protected Carbohydrate
Derivatives into 2-Deoxy-lactones
O
S
rganocatalyt
e
ic
C
onversi
b
on of Ribose
a
into 2-Deo
s
xy-lacton
t
es ian Wendeborn,* Régis Mondière, Isabelle Keller, Hannes Nussbaumer
Syngenta Crop Protection AG, Werk Stein, Schaffhauserstr., 4332 Stein, Switzerland
Fax +41(62)8660860; E-mail: sebastian.wendeborn@syngenta.com
Received 31 October 2011
has applied this principle to the synthesis of lactams, dem-
onstration that amides, carbamates, sulfonamides, and
benzylamines can act as suitable leaving groups as well.13
Abstract: We report the simultaneous reduction of the 2-position
and oxidation of the anomeric position in several protected furano-
syl and pyranosyl sugar derivatives, mediated through NHC cataly-
sis. This reaction allows the one-step access to highly valuable 2- We report here our studies demonstrating that pathway B
deoxy-sugars from abundant 2-oxygenated sugar derivatives.
can be exploited synthetically with several different car-
bohydrates in moderate to good yields.
Key words: carbenes, deoxygenation, green chemistry, isomeriza-
tion, umpolung
R2
N
In our continued interest to develop efficient reactions for
the economic derivatization and functionalization of
N
R2
1
–3
O
1
carbohydrates we asked the question whether a N-het-
erocyclic carbene (NHC) catalyst can be used to directly
functionalize the aldehyde functionality masked at the
anomeric center in sugars as a hemiacetal. NHC catalysis
is rich, but has not, to the best of our knowledge, yet been
OH
R O
OH
O
1
R O
1
OR1
R O
1
OR1
R O
R3
4
–8
applied to the derivatization of sugars. We envisioned
that reaction of a NHC and a suitable carbohydrate would
R2
R2
O
O
OH N+
N
OH OH
9
OH
1
lead to a Breslow intermediate 2 which could engage in
R3
R O
different pathways, depending on protecting groups used
N
N
1
R O
[
in particular at the C(2)–OH of the sugar] and additional
1 R2
2
R1O
1
1
OR R
R O
OR
reagents submitted to the reaction mixture. For example,
reaction of the Breslow intermediate 2 with a,b-unsaturat-
ed ketones could lead to highly valuable products such as
3
2
R2
N
5
derived from Stetter reactions at the anomeric center
N
R2
R3
O
R3
(
pathway A, exemplified for a protected furanosyl ribose
in Scheme 1). However, instead of reacting with electro-
philes, the Breslow intermediate 2 could also collapse
through b-elimination of an oxgygen leaving group at the
C(2) position of the sugar (Scheme 2, pathway B). Also
this reaction would lead to highly valuable 2-deoxy-car-
bohydrate-lactones, which are usually accessed from 2-
oxygenated carbohydrates through multistep transforma-
tions involving oxidation of the anomeric position and
radical deoxygenation of the 2-position in addition to
elaborate protecting-group manipulations to allow for the
O
OH
O
O
OH
1
R O
1
R O
1
OR1
1
OR1
R O
R O
4
5
Scheme 1 Hypothetical pathway A: Stetter reaction
In an intitial attempt 2,3,5-tribenzylated ribose was re-
acted with 0.3 equivalents of 1,3-bis-tert-butylimidazol-
-ylidene in THF. Disappointingly neither of the two dis-
cussed pathways occurred; instead b-elimination of the
C(3)–OBn group led to the clean formation of 9
1
0
desired chemoselectivity. Such reactivity (pathway B)
would have precedent in very elegant work independently
2
1
1
12
performed by Bode and Rovis who have shown that re-
actions of aldehydes containing leaving groups such as
epoxides, aziridines, and halogens or even activated car-
bon atoms in their a-positions undergo NHC-catalyzed re-
dox transfer and provide esters through subsequent
intermolecular reaction with alcohols. Recently, Gravel
(
Scheme 3). We assumed that the reported high basicity of
,3-bis-tert-butylimidazol-2-ylidene [pKa(DMSO) = 22.7]1
4–
1
1
6
may well be responsible for such outcome and that the
utilization of a less basic carbene catalyst would suppress
this competitive undesired pathway in favor of either
pathway A or B.
SYNLETT 2012, 23, 541–544
x
x
.
x
x
.
2
0
1
2
Advanced online publication: 27.01.2012
DOI: 10.1055/s-0031-1290327; Art ID: B61511ST
©
Georg Thieme Verlag Stuttgart · New York

5
42
S. Wendeborn et al.
LETTER
R2
R2
from D and DBU at 50 °C (Table 1, entry 12). The use of
KOt-Bu or Hünig’s base instead of DBU resulted in either
no reaction or lower conversions. Those optimized condi-
tions allowed the isolation of 8a in 68% yield.
OH OH N+
OH OH
N
1
1
R O
R O
N
N
R2
R2
1
OR1
R O
1
R O
2
RO–
6
Table 1 Reaction Conditions for the Synthesis of 8aa
BnO
O
BnO
O
OH
conditions
O
R2
N+
BnO
OBn
BnO
OH O
1a
8a
1
R O
O
O
1
Entry NHCb Based
R O
N
Solvent
Temp Time Conv.
(°C)
24
90
70
50
90
90
90
50
90
90
24
50
(h)
20
16
24
20
7
(%)e
R2
1
1
R O
R O
R2
7
8
Ac
1
2
3
4
5
6
7
8
9
0
–
THF
75
N
A¢
B
DBU
PhMe
DCE
10
N
R2
i-Pr NEt
0
2
Scheme 2 Pathway B: Bode–Rovis reaction
B
KOt-Bu
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
0
C
C
C
D
D
D
D
D
i-Pr NEt
50
2
We therefore screened reaction conditions involving the
following catalysts and precatalysts (Figure 1). The reac-
tion conditions screened are summarized in Table 1.
DBU
16
24
20
7
40
i-Pr NEt
50
2
Cl–
KOt-Bu
0
50
•
•
+
i-Pr NEt
2
N
N
N
N
1
i-Pr NEt
24
16
16
30
2
A
A'
BF4–
F
11
DBU
DBU
20
F
Cl–
N
N
1
2
100 (68)f
Cl–
N+
N
N+
N
a
b
c
d
e
f
N+
F
Reaction conditions screened for conversion of 1a into 8a.
.1 equiv.
.3 equiv.
.08 equiv
Based on crude H NMR, the remainder being starting material.
Isolated yield of 8a on a 400 mg scale.
0
0
0
F
F
D
S
C
B
1
Figure 1 List of screened catalysts and precatalysts
Reaction of 1a with catalyst A provided 8a in satisfactory Applying the optimized reaction conditions to other pen-
conversion at ambient temperature. Reaction with in situ tose and hexose derivatives allowed for the preparation of
generated carbene catalyst (A¢ and DBU) succeeded, how- several C(2)-deoxy-lactones. Results are summarized in
ever, with very low conversion (Table 1, entry 2). The cat- Scheme 4. Both, C(2)-benzyl ethers and C(2,3)-ketals
alyst generated from thiazolium B and either Et N or KOt- were suitable leaving groups allowing for deoxygenation
3
Bu resulted in no reaction (Table 1, entries 3 and 4), while of the C(2)-position with concomitant oxidation of the
C in the presence of either Hünig’s base or KOt-Bu gave anomeric C(1) in several sugar derivatives. In the case of
conversion in the range of 50% (Table 1, entries 5–7). C(2,3)-ketals (14 and 16) the corresponding C(3) free al-
Longer reaction times did not further improve overall con- cohols were isolated. In the case of 16, the reaction pro-
1
version, suggesting catalyst deactivation. Gratifyingly, ceeded with 50% conversion, as judged by H NMR of the
1
00% conversion was observed with the catalyst derived crude reaction mixture. The low isolated yield of 17 may
••
N
N
O
O
O
OH
O
OH
(
0.3 equiv)
BnO
BnO
BnO
THF, r.t., 1 h
00% conversion
BnO
OBn
BnO
8a
not observed
OBn
observed
1
1a
9
Scheme 3 Undesired b-elimination with 1,3-bis-tert-butylimidazol-2-ylidene
Synlett 2012, 23, 541–544
© Thieme Stuttgart · New York

LETTER
Organocatalytic Conversion of Ribose into 2-Deoxy-lactones
543
be explained by acid-catalyzed conversion into its pyrano- and 16 no elimination of hydroxide occurred. Addition of
1
7
syl derivative. By contrast, acetylated sugars were not methyl vinyl ketone to the reaction mixture derived from
suitable substrates for this redox-transfer reaction. The 22 did not lead to the desired Stetter product.
1
8
known NHC-catalyzed transacetylation took place in-
stead and produced 20, the peracetylated derivative.
OH OH Mes
N
O
O
OH
O
O
OH
D (0.1 equiv)
BnO
N
BnO
BnO
BnO
BnO
DBU (0.08 equiv)
BnO
+N
OH OH
OBn
PhMe, 50 °C, 23 h
HO
OH
2
1
OBn
D (0.1 equiv)
OBn
m/z = 468
DBU (0.08 equiv)
1
1
0
11
7% isolated yield
5
PhMe, 50 °C, 24 h
O
OH
O
O
D (0.1 equiv)
Mes
OH OH OH
BnO
BnO
BnO
DBU (0.08 equiv)
N
O
OH
OH
O
N
OBn
PhMe, 50 °C, 15 h
then 90 °C, 44 h
BnO
+N
OBn
O
O
OH
OBn
2
Ph
O
1
3
a
OH
Ph
53% conversion
2
2
m/z = 496
R
Scheme 5 Adduct formation observed by LC–ESMS between
ribose or glucose derivatives not protected in the C(2)-position and
catalyst generated from D
R
D (0.1 equiv)
R
R
O
DBU (0.08 equiv)
O
O
O
O
O
O
OH
PhMe, 90 °C, 18 h
In summary, we have shown that sugars can be oxidized
to the corresponding lactones with simultaneous reduc-
tion of the C(2)-position through a catalytic NHC-mediat-
ed reaction. This reaction allows for a particular efficient
access to C(2)-deoxygenated lactones from carbohy-
drates. While a free C(1)–OH is required, the C(2)–OH
group has to be protected, like for example by a benzyl
ether or an acetal. The proposed Breslow intermediate
could be observed by mass spectrometry with substrates
containing a free C(2)–OH, however, their engagement in
Stetter reactions failed.
HO
isolated yield
5a R = Me 74%
O
R
O
1
R
1
4a,b
15b R,R = -(CH2)5- 77%
D (0.1 equiv)
O
O
O
OH
DBU (0.08 equiv)
HO
HO
HO
PhMe, 50 °C, 16 h
50% conversion
O
O
1
7
1
3% isolated yield
16
O
O
AcO
AcO
OAc
O
OH
19
Acknowledgment
D (0.1 equiv)
AcO
AcO
not observed
+
DBU (0.08 equiv)
We thank Armando Cicchetti and Philipp Wirz for conducting some
of the experiments, Dr. Katharina Gaus and Dr. Leonhard Hagmann
for spectroscopic support, and Dr. Raphaël Dumeunier for insight-
ful discussions. We thank Prof. Jeffrey Bode for suggesting some of
the reaction conditions reported in Table 1 during a consulting dis-
cussion with Syngenta in February 2011.
OAc
PhMe, 90 °C, 44 h
O
OAc
OAc
AcO
AcO
1
8
OAc
OAc
2
0
5
8% conversion
Scheme 4 Redox transfer between C(1) and C(2) of pentose and References and Notes
hexose derivatives. a Separation from remaining starting material not
possible.
(
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(
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©
Thieme Stuttgart · New York
Synlett 2012, 23, 541–544

5
44
S. Wendeborn et al.
LETTER
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1
1
H NMR (400 MHz, DMSO-d ): d = 2.22 (dd, J = 17.61,
6
2.20 Hz, 1 H), 2.81 (dd, J = 17.79, 6.42 Hz, 1 H), 3.47–3.62
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Synlett 2012, 23, 541–544
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
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