Alkylation reactions using a galactose-based β-keto ester enolate and conversion into β-C-galactosides

Article abstract of DOI:10.1055/s-2008-1078176

A de novo approach for the synthesis of biologically important C-galactosides has been achieved via use of an acyclic galactose-derived β-keto ester. The β-keto ester enolate serves as a C-nucleophile and reacts with primary alkyl halides and Michael acceptors to generate alkylation products that can be converted into β-C-galactosides and C-disaccharide mimics with high stereoselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078176

LETTER
2475
Alkylation Reactions Using a Galactose-Based b-Keto Ester Enolate and
Conversion into b-C-Galactosides
A
lkylation Reactio
h
ns
U
sing a
G
a
a
lactose-B
n
ased
b
-Keto
a
E
ster
E
nola
n
te joy Mondal, Frank Schweizer*
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
Fax +1(204)4747012; E-mail: schweize@cc.umanitoba.ca
Received 27 May 2008
In this paper we describe a novel strategy for the synthesis
of biologically relevant b-C-galactosides via use of a ga-
lactose-based and b-keto ester derived nucleophile
(Scheme 1).
Abstract: A de novo approach for the synthesis of biologically im-
portant C-galactosides has been achieved via use of an acyclic ga-
lactose-derived b-keto ester. The b-keto ester enolate serves as a C-
nucleophile and reacts with primary alkyl halides and Michael ac-
ceptors to generate alkylation products that can be converted into b-
C-galactosides and C-disaccharide mimics with high stereoselectiv-
ity.
According to this strategy a b-keto ester derived acyclic
C-nucleophile A reacts with an electrophile (reactive
alkyl halide, Michael acceptor) to form isomeric products
B1 and B2. Acidic saponification of the tert-butyl esters B1
and B2 followed by decarboxylation produces ketone C.
Selective deprotection of C affords cyclic acetal D that
will undergo reduction to form b-C-glycoside E based on
previous literature reports.6 In order to test the outlined
strategy, access to suitably protected carbohydrate-based
b-keto ester is required. We selected galactose-derived b-
keto ester 3 as a suitable candidate based on the impor-
tance of b-galactosides in carbohydrate–protein interac-
tions.7 The allyl ether group was selected as temporary
protecting group as it is orthogonal to benzylether and
tert-butyl ester groups. The synthesis of 3 is outlined in
Scheme 2 and involves ketose 2 previously prepared on a
multigram scale from commercially available acetal 1.8
Key words: de novo approach, C-galactosides, C-nucleophile
C-Glycosides are an important class of glycomimetics, in
which the exocyclic oxygen atom of an O-glycoside is
displaced by a methylene (CH2) group. C-Glycosides ex-
hibit enhanced stability against chemical and enzymatic
hydrolysis1,2 and as such have been used as chemical
probes to study carbohydrate-mediated molecular recog-
nition in biology and medicine.3 Although numerous ef-
forts have been dedicated toward the synthesis of C-alkyl,
C-aryl glycosides, and C-oligosaccharides during the past
two decades,2–5 novel approaches with improved yields,
higher stereoselectivity, and broad applicability are still in
high demand.
OBn
OBn
O
BnO
BnO
BnO
BnO
E+
OP
–
Ot-Bu
ref. 8
O
BnO
Ot-Bu
O
O
O
BnO
OH
BnO
OH
O
A
2
1
β-keto ester
E
OBn
acidic hydrolysis, heat
– CO2
OP
Ot-Bu
ClCH2CH=CH2
NaH, DMF
BnO
BnO
BnO
BnO
O
O
Ot-Bu
87%
B1, B2
BnO
O
O
E
E
3
OP
deprotection
O
BnO
Scheme 2 Synthesis of galactose-derived b-keto ester 3
O
OH
D
C
Crucial ring opening of ketose 2 was achieved by depro-
tonation of the acetal function with sodium hydride and
subsequent trapping of the acyclic alkoxide ion with allyl
chloride. The use of allyl chloride instead of allyl bromide
as electrophile and relative short reaction times were cru-
cial in order to avoid C- and O-allylation of the generated
b-keto ester 3. Compound 3 exists predominantly in its
keto form based on 1H NMR and 13C NMR data. For in-
stance, 13C NMR shows signals at d = 204.4 ppm (C=O)
and 47.9 ppm that are consistent with the keto form.
E
reduction
E = electrophile
O
BnO
P = protecting group
E
Scheme 1 General strategy for the synthesis of b-C-glycosides
using carbohydrate-derived b-keto ester enolate A
SYNLETT 2008, No. 16, pp 2475–2478
x
x
.x
x
.2
0
0
8
Advanced online publication: 10.09.2008
DOI: 10.1055/s-2008-1078176; Art ID: S05308ST
© Georg Thieme Verlag Stuttgart · New York
With b-keto ester 3 in hands we then explored C-alkyla-
tion reactions using methyl iodide, benzyl bromide, hexyl

2476
D. Mondal, F. Schweizer
LETTER
bromide, and hexyl iodide as representative electrophiles, mide, n-hexyl iodide, or n-hexyl bromide as electrophiles
cesium carbonate as a base, and DMSO as solvent.9 We (Table 1). O-Alkylated products were obtained in the case
selected two reaction conditions (method A and B) to con- of monoalkylated products 6a and 6b (C/O ratio = 1:1)
trol the formation of mono- and dialkylated products and 8a and 8b. However, using hexyl iodide (C/O
(Table 1).
ratio = 4.5:1) instead of hexyl bromide (C/O ratio = 2.6:1)
reduced O-alkylation in products 8a and 8b. In all cases
the mono- and di-C-alkylated products could be separated
by flash chromatography. After chromatographic separa-
tion the diastereomeric mixtures 4a and 4b, 6a and 6b, 8a
and 8b as well as the di-C-alkylated products 5, 7, and 9
were converted into ketones 10–15 (Scheme 3) after ester
saponification with TFA and decarboxylation in toluene.
Table 1 Formation of Mono- and Dialkylated Products
Alkyl halide (RX) Mono/dib
Methoda Yield (%)c
MeI
4a,b/5 = 78:22
A
B
A
B
A
B
A
B
89b
78b
50d
76b
74d
80b
65d
79b
4a,b/5 = 3:97
6a,b/7 = 82:18
6a,b/7 = 5:95
8a,b/9 = 85:15
8a,b/9 = 8:92
8a,b/9 = 87:13
8a,b/9 = 10:90
PhCH2Br
C6H13I
C6H13Br
Deprotection of the O-allyl ether was achieved by expo-
sure to palladium chloride in a solvent mixture containing
sodium acetate–water–acetic acid10 to produce acetals 16–
21 in 78–89% yield (Scheme 3). All acetals except 21 ex-
isted in the cyclized form. Compound 21 existed as a 1:1
mixture containing cyclic and the acyclic keto forms in
CDCl3. It is apparent that the bulkiness of the substituents
R1 and R2 in compound 21 destabilize sterically the cyclic
form. Lewis acid (BF3·OEt2) catalyzed reductive dehy-
droxylation using triethylsilane13 in 1,2-dichloroethane
converted acetals 16–21 exclusively into the b-C-galacto-
sides 22–27 in 86–92% yield. The b-C-glycosidic linkage
in compounds 22–27 was confirmed from the vicinal di-
axial coupling constant 3JH1,H2 > 9.0 Hz (Scheme 3).
a Method A: RX (1.3 equiv), Cs2CO3 (1.4 equiv), DMSO, r.t., 1 h;
method B: RX (3.5 equiv), Cs2CO3 (4.0 equiv), DMSO, 50 °C, 3 h.
b Determined by isolation.
c C-Alkylated products (mono and di).
d Determined by NMR.
In order to explore the reactivity of deprotonated galac-
tose-derived b-keto ester 3 towards other classes of elec-
trophiles, we studied Michael addition reactions to a,b-
unsaturated carbonyl compounds.11 We were particularly
interested in selecting Michael acceptors that display
structural similarities to carbohydrates. Michael adducts
of this type may find use as glycomimetics.7b Initially, we
studied the 1,4-Michael addition reaction of 3 to 2-cyclo-
hexenone using potassium carbonate in 1:1 mixture of
Method A reflects conditions for the synthesis of
monoalkylated products while method B was used to pre-
pare dialkylated products. For instance, the mono-C-
methyl-substituted b-keto esters 4a,b were formed exclu-
sively as a mixture of two diastereomers in 89% yield
(method A) while the di-C-methyl-substituted ester 5 was
obtained as a single diastereomer in 78% yield (method
B). Comparable yields were obtained for di-C-benzylated
product 7 and di-C-hexylated product 9 using benzyl bro-
OBn
BnO
OBn
RX , Cs2CO3
DMSO, method A or
method B
BnO
BnO
R1
R1 R2
1. TFA, CH2Cl2, 0 °C
2. toluene, 80 °C
O
O
Ot-Bu
BnO
R2
3
BnO
BnO
O
O
O
4a,b: R1 = Me, R2 = H
10: R1 = Me, R2 = H, 67%
11: R1, R2 = Me, 63%
5: R1, R2 = Me
6a,b: R1 = Bn, R2 = H
7: R1, R2 = Bn
8a,b: R1 = C6H13, R2 = H
9: R1, R2 = C6H13
12: R1 = Bn, R2 = H, 62%
13: R1, R2 = Bn, 59%
14: R1 = C6H13, R2 = H, 69%
15: R1, R2 = C6H13, 65%
OBn
OBn
H2
BnO
BnO
R1
BnO
R1
PdCl2, NaOAc
AcOH, H2O
O
BF3⋅OEt2, Et3SiH
DCE, 0 °C
O
BnO
R2
R2
BnO
OH
BnO
H1
22: R1 = Me, R2 = H, 87%
16: R1 = Me, R2 = H, 82%
17: R1, R2 = Me, 87%
23: R1, R2 = Me, 92%
24: R1 = Bn, R2 = H, 86%
25: R1, R2 = Bn, 89%
26: R1 = C6H13, R2 = H, 89%
27: R1, R2 = C6H13, 88%
18: R1 = Bn, R2 = H, 78%
19: R1, R2 = Bn, 84%
20: R1 = C6H13, R2 = H, 81%
21: R1, R2 = C6H13, 89%
Scheme 3 Synthesis of alkyl b-C-galactosides via alkylation (see also Table 1)
Synlett 2008, No. 16, 2475–2478 © Thieme Stuttgart · New York

LETTER
Alkylation Reactions Using a Galactose-Based b-Keto Ester Enolate
2477
O
DMF and acetonitrile at room temperature. Products 28a–
d were obtained as a mixture containing all four stereoiso-
mers in a combined yield of 87%. Exposure to trifluoro-
acetic acid in dichloromethane at 0 °C for three hours
followed by decarboxylation in toluene at 80 °C afforded
an inseparable mixture of two diastereomers 29a and 29b
in a combined yield of 58%. Deallylation using palladi-
um(II) chloride in a solvent mixture containing sodium
acetate–water–acetic acid produced acetals 30 and 31
(1:1) in a combined yield of 88% yield after chromato-
graphic separation. Lewis acid catalyzed reductive dehy-
droxylation of 30 and 31 using Et3SiH and BF3·OEt2 at
0 °C in 1,2-dichloroethane afforded stereoselectively b-
C-galactosides 32 (3J1,2 = 9.4 Hz) and 33 (3J1,2 = 9.3 Hz),
respectively, in 91% and 93% yield (Scheme 4).
O
O
O
OBn
BnO
BnO
K2CO3
DMF–AcCN (1:1)
O
Ot-Bu
O
O
3
90%
BnO
O
O
34a,b
O
O
OBn
O
1. TFA, CH2Cl2, 0 °C
2. toluene, 80 °C
PdCl2, NaOAc
AcOH, H2O
BnO
BnO
O
53%
82%
BnO
O
35
O
O
OBn
BnO
O
O
BF3⋅OEt2, Et3SiH
O
DCE, 0 °C
O
O
BnO
85%
BnO
OH
36
OBn
K2CO3
BnO
DMF–AcCN (1:1)
3
O
O
O
Ot-Bu
87%
BnO
OBn
OBn
O
OBn
BnO
BnO
BnO
BnO
ref.13
O
O
O
O
28a–d
OR
OBn
BnO
BnO
BnO
OBn
37
38
1. TFA, CH2Cl2, 0 °C
2. toluene, 80 °C
BnO
Scheme 5 Synthesis of a b-C-disaccharide mimic via 1,4-Michael
addition to levoglucosenone
O
O
BnO
58%
BnO
O
34a and 34b was then converted into b-(1→4)-linked C-
disaccharide mimic 37 in a three-step procedure. At first,
treatment of compounds 34a and 34b with TFA followed
by decarboxylation in toluene afforded 35 in 53% yield.
Subsequently, Pd-catalyzed deallylation of 35 provided
acetal 36 in 82% yield that was reduced to C-disacharide
mimic 37 in 85% yield. The observed coupling constant
between H-1 and H-2 (3JH1,H2 = 9.4 Hz) confirms the b-C-
glycosidic linkage in 37. Compound 37 can be converted
into disaccharide mimic 38 as previously reported13
(Scheme 5).
29a,b
OBn
BnO
BnO
PdCl2, NaOAc
AcOH, H2O
O
O
88%
BnO
OH
30, 31
OBn
H2
BnO
BF3⋅OEt2, Et3SiH
DCE, 0 °C
O
O
BnO
In summary, we have developed synthetic access to an
acyclic galactose-derived b-keto ester enolate that serves
as a C-nucleophile in alkylation reactions using reactive
alkyl halides. Choice of the proper reaction conditions
permit control of the mono- and dialkylated products and
limit O-alkylation. The C-alkylated products can be con-
verted into b-C-galactosides with high diastereoselectivi-
ty. Mono- and dialkylation of the b-keto ester opens up the
possibility to prepare novel and unusual b-C-galactosides.
Moreover, conjugate addition of the galactose-derived b-
keto ester enolate to Michael acceptors provide C-disac-
charide analogues that may find utility as glycomimetics
to study carbohydrate-mediated recognition in biology.
Due to the well-established ubiquitous importance of b-
keto esters in organic chemistry14 our study suggests that
carbohydrate-based b-keto ester will find use in carbon–
carbon bond-forming reactions involving carbohydrate
moieties.
32: 91%
33: 93%
BnO
H1
32, 33
Scheme 4 Synthesis of a b-C-galactoside via Michael 1,4-addition
Encouraged by these results we then focused on the con-
jugate addition of galactose-derived b-keto ester enolates
to Michael donor levoglucosenone (Scheme 5).
Previous studies have shown that conjugate additions of
C- and S-nucleophiles to levoglucosenone proceed with
high exo-face selectivity.12,13 In addition, biological stud-
ies have shown that Michael adducts of this type serve as
glycomimetics to probe carbohydrate–protein interac-
tions.13 We were pleased to observe that base-catalyzed
exposure of 315 to levoglucosenone in DMF–acetonitrile
cosolvent produced a 1:1 mixture of two diastereomers
34a and 34b in 90% yield. The diastereomeric mixture
Synlett 2008, No. 16, 2475–2478 © Thieme Stuttgart · New York

2478
D. Mondal, F. Schweizer
LETTER
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Acknowledgment
The authors thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the University of Manitoba for fi-
nancial support.
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In an inert atmosphere a solution of ketose 2 (150 mg, 0.23
mmol) in dry DMF (5 mL) was cooled to 0 °C and a
suspension of NaH (60 wt% in oil, 137 mg, 15 equiv) was
added slowly over 5 min. After 30 min at 0 °C, allyl chloride
(562 mL, 30 equiv) was added. The reaction was stirred at r.t.
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Synlett 2008, No. 16, 2475–2478 © Thieme Stuttgart · New York