Convenient synthesis of bicyclic carbohydrate 1,2-lactones and their stereoselective opening to 1-functionalized glucose derivatives

Article abstract of DOI:10.1002/chem.200802178

The convenient synthesis of lactone compounds and their stereoselective transformations by reactions with nucleophiles was reported. The method is applicable for unsaturated hexoses, pentoses, and disaccharide's, and is characterized by high yields and stereoselectivities. The release of carbon dioxide and methanol provides the driving force of the reaction, which favors the lactonization entropically. A convenient and general entry to bicycle carbohydrate 1,2-lactones in only three steps from glycals was developed. The opening of the gluco-configured lactone was demonstrated with various nucleophiles, which enabled the introduction of hetero and carbon substituents at the anomeric position.

Full text of DOI:10.1002/chem.200802178

COMMUNICATION
DOI: 10.1002/chem.200802178
Convenient Synthesis of Bicyclic Carbohydrate 1,2-Lactones and Their
Stereoselective Opening to 1-Functionalized Glucose Derivatives
Jian Yin and Torsten Linker*[a]
Lactones represent an important class of organic com-
pounds, are industrial intermediates, and can be synthesized
by various methods.[1] g-Lactones, in particular, are wide-
spread in nature and possess promising pharmacological
properties as enzyme inhibitors,[2] due to their common ring-
opening by nucleophiles. Interestingly, linking of carbohy-
drates to the reactive heterocycle increases water solubility,
which is advantageous for the bioavailability. d-Glucono-
1,5-lactone (1) is easily synthesized on a large scale by oxi-
dation of the anomeric position of d-glucose and represents
one of the cheapest chiral building blocks for organic chem-
ists.[3] On the other hand, carbohydrate-fused lactones have
been less intensively studied, with some examples for 1,6-
lactones 2.[4] Such compounds are available from uronic
acids and allow stereoselective glycosylations by nucleophil-
ic opening at the anomeric position.[5]
access to C-2 branched saccharides by reaction with nucleo-
philes at the anomeric center. Interestingly, unsubstituted
carbohydrate 1,2-lactones 4a (R=H) were not described
until now. Herein we report on the convenient synthesis of
such compounds and their stereoselective transformations
by reactions with nucleophiles.
During the course of our studies on transition-metal-
mediated radical reactions,[9] we developed a one-step entry
to 2-C-branched carbohydrates 5 by addition of dimethyl
malonate to glycals.[10] The method is applicable for unsatu-
rated hexoses, pentoses, and disaccharides, and is character-
ized by high yields and stereoselectivities. More recently, we
became interested in transformations of the side chain and
succeeded in the cleavage to the ester gluco-6 under drastic
reaction conditions (Scheme 1).[11] For a milder decarboxyla-
In some cases, carbohydrate 2,3-lactones 3 were synthe-
sized over many steps,[6] but the corresponding 1,2-lactones
4 attracted less attention. Besides a few examples of higher
oxidized analogues 4,[7] two papers on substituted lactone
rings 4b (R=I; R=NHAr) were published very recently.[8]
This is surprising, since such bicycles 4 should give easy
Scheme 1. Transformations of the 2-C-branched carbohydrate gluco-5.
tion, we saponified to the malonic acid 7 and heated only to
1108C. Surprisingly, during thermolysis direct cyclization to
lactone gluco-4 occurred, which was isolated in high yield.
Obviously, release of carbon dioxide and methanol provides
the driving force of the reaction, which favors the lactoniza-
tion entropically.
[a] J. Yin, Prof. Dr. T. Linker
Department of Chemistry, University of Potsdam
Karl-Liebknecht-Strasse 24-25, 14476 Potsdam (Germany)
Fax : (+49)331-9775606
E-mail: linker@chem.uni-potsdam.de
To further optimize the synthesis and to develop a general
entry to carbohydrate 1,2-lactones 4, we investigated differ-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802178.
Chem. Eur. J. 2009, 15, 49 – 52
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
49

Table 2. Opening of the lactone gluco-4 with nucleophiles 8a–k.[a]
Entry Nucleophile 8
Product 9 (%)[b]
ent 2-C-branched saccharides 5,[11b] where the free dicarbox-
ylic acids 7 were not isolated, but directly cyclized at 1108C
after acidification with acetic acid (Table 1, Experimental
Section). The method is suitable for hexoses (Table 1, en-
9a
(92)
1
2
3
MeOH
iPrOH
tBuOH
8a
8b
8c
Table 1. Synthesis of carbohydrate 1,2-lactones 4.[a]
9b
(78)
Entry
Malonate[11b]
Product
Yield [%][b]
1
2
3
4
5
6
gluco-5
galacto-5
xylo-5
arabino-5
malto-5
lacto-5
gluco-4
galacto-4
xylo-4
arabino-4
malto-4
lacto-4
92
91
88
88
87
84
9c
(65)
9d
(78)
4
5
8d
8e
[a] Procedure and conditions see Experimental Section. [b] Yields of ana-
lytically pure products, isolated by column chromatography.
9e
(60)
OctOH
tries 1 and 2), pentoses (Table 1, entries 3 and 4) and disac-
charides (entries 5 and 6), and provides the desired products
in high yields. Thus, the hitherto unknown carbohydrate 1,2-
lactones 4 become available in only three steps from glycals.
Next, we investigated the lactone opening with various
nucleophiles 8 and selected gluco-4 as substrate, since this
configuration is widespread in nature, and we expected in-
teresting products would arise. Lewis acids have proven to
be suitable catalysts for such openings,[12] and the functional-
ization of 1,6-lactones 2 at the anomeric center was accom-
plished with silylated nucleophiles in the presence of trime-
thylsilyl triflate[5a,b] or tin tetrachloride.[5c,e] However, lactone
gluco-4 afforded no conversion (TMSOTf) or cleavage of
the O-benzyl protecting groups (SnCl4). Evidently, the reac-
tivity of the Lewis acid had to be carefully tuned. Finally,
9 f
(53)
6
8 f
9g
(30)
7
8
8g
8h
9h
(95)
25% NH3/H2O
9
Me3SiN3
EtSH
8i
9i (75)
9j (82)
the best conditions were found with ScACTHNUTRGNEUNG
(OTf)3,[12] which was
10
11
8j
8k
previously applied for the opening of substituted lactones
4b.[8a] Thus, a broad variety of nucleophiles 8 afforded the
ring-opening products 9 in good yields (Table 2).
9k
(78)
Et3SiH
Initially, we investigated the addition of alcohols 8a–e
(Table 2, entries 1–5), where the free carboxylic acid was di-
rectly esterified under the reaction conditions after opening
at the anomeric center. Interestingly, a/b selectivities strong-
ly depend on the nucleophile and the reaction times. Thus,
methanol (8a) afforded the b-methyl glucoside 9a after
30 min in excellent yield, whereas an epimerization to the a-
anomer occurred after 4 h. 2-Propanol (8b) furnished an
anomeric mixture (Table 2, entry 2), however with alcohols
8c–e a-glucosides 9c–e were isolated selectively after longer
reaction times. Such an anomerization is in accordance with
the recently published opening of 1,6-lactones 2[5e] and is
very important for further transformations of the products
(vide infra). Even tert-butyl alcohol (8c) reacted as a nucle-
ophile with this method (Table 2, entry 3). Due to the two
long alkyl chains, octyl glucoside 9e was an interesting prod-
uct (Table 2, entry 5), which resembles a carbohydrate ana-
logue of phospholipids.[13] Finally, carbohydrates with a free
OH group were suitable nucleophiles 8 f,g, although disac-
charides 9 f,g were isolated in only moderate yields (Table 2,
entries 6 and 7). The lability of the glycosidic bond in the
[a] Procedure and conditions see Experimental Section. [b] Yields of ana-
lytically pure products (see the Supporting Information).
presence of scandium triflate required short reaction times,
which explains the selective formation of b-anomers and the
absence of esterification of the carboxylic acid.
We were able to introduce heteroatoms at the anomeric
center of lactone gluco-4 as well (Table 2, entries 8–10). The
reaction with aqueous ammonia is especially attractive,
since it opens simple access to bicyclic lactam 9h in excel-
lent yield. Glucosyl azide 9i was formed with trimethylsilyl
azide (8i) as nucleophile, which can be applied in click
chemistry[14] or as a precursor for dendrimers,[15] whereas
ethanethiol (8j) afforded ethyl thioglucoside 9j as a poten-
tial glycosyl donor[16] in good yield. Both reactions gave se-
lectively b-anomers, but with 9i the intermediary silyl ester
was hydrolyzed during workup (Table 2, entry 9), whereas
9j was isolated as stable thioester (Table 2, entry 10). Final-
50
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Chem. Eur. J. 2009, 15, 49 – 52

Bicyclic Carbohydrate 1,2-Lactones
COMMUNICATION
ly, we succeeded in synthesizing the 1-deoxy derivative 9k
in 78% yield by hydride opening (Table 2, entry 11).
The last topic of our studies was the reaction of lactone
gluco-4 with C-nucleophiles 8l–p in the presence of scandi-
um triflate (Table 3). This should give easy access to inter-
ates in total synthesis.[18] On the other hand, allyl ester 9d is
predestined for ring-closing metathesis,[19] since due to the
selective a-anomerization during the lactone opening, both
double bonds occupy the same side of the carbohydrate.
Indeed, we were able to synthesize macrolide 11, which,
flanked by the saccharide, might possess interesting biologi-
cal properties.[20]
Table 3. Opening of the lactone gluco-4 with C-nucleophiles 8l–p.[a]
In conclusion, we developed a convenient and general
entry to bicyclic carbohydrate 1,2-lactones in only three
steps from glycals. Opening of the gluco-configured lactone
was demonstrated with various nucleophiles, which enabled
the introduction of hetero and carbon substituents at the
anomeric position. The reactions proceed with good yields
and high stereoselectivities, and the products allow further
interesting transformations.
Entry
Nucleophile 8[b]
Product 9 (%)[c]
1
Me3SiCN
8l
9l (90)
2
3
8m
9m (83)
8n
8o
9n (85)
9o (67)
Experimental Section
General procedure for the synthesis of carbohydrate 1,2-lactones 4: A so-
lution of the 2-C-branched carbohydrate 5 (2.0 mmol) and LiOH·H2O
(210 mg, 5.0 mmol) in MeOH/H2O (4/1, 20 mL) was heated under reflux
for 1 h. After cooling to room temperature, the solvent was removed
under reduced pressure. The crude product was dissolved in toluene, and
the pH value was adjusted to 3 with acetic acid. The solution was heated
under reflux for 1 h. After the solvents were evaporated, the crude prod-
uct was purified by flash chromatography (cyclohexane/ethyl acetate 7:1).
4
5
8p
9p (77)
General procedure for the ring opening with nucleophiles: A solution of
lactone gluco-4 (475 mg, 1.0 mmol), ScACHTNUTRGNEUNG(OTf)3 (740 mg, 1.5 mmol), and
[a] Procedure and conditions see Experimental Section. [b] Yields of ana-
lytically pure products (see the Supporting Information).
Drierite (20–40 mesh) (680 mg, 5.0 mmol) in dry dichloromethane
(20 mL) was stirred at 08C under an argon atmosphere. After 30 min the
nucleophile 8 (5.0 mmol, 5.0 equiv) was added to the mixture. The solu-
tion was stirred at room temperature until TLC showed complete conver-
sion. The reaction was quenched with saturated NaHCO3 solution
(30 mL), and the mixture was extracted with dichloromethane (3ꢁ
20 mL). The combined organic extracts were dried (Na2SO4) and concen-
trated, and the products 9 were isolated by flash chromatography. All
products 4 and 9 were completely characterized (see Supporting Informa-
tion).
esting C-glycosides,[17] which was already demonstrated with
other Lewis acids and 1,6-lactones 2.[5a,b] Indeed, we were
able to isolate 1,2-bis-C-branched glucose derivatives 9l–n
with the silylated nucleophiles 8l–n in high yields (Table 2,
entries 1–3). Additionally, electron-rich arenes enabled the
simple synthesis of C-aryl glycosides 9o,p (Table 3, entries 4
and 5). The opening proceeds for all reactions stereoselec-
tively to b-anomers, since subsequent epimerization is not
possible.
Acknowledgements
Finally, we present interesting applications of the synthe-
sized ring-opening products with two examples (Scheme 2).
Nitrile 9l was smoothly converted into the diester 10 in
86% yield. Such 1,2-bis-C-branched glucose derivatives with
a methyl ester group at the 1-positon are suitable intermedi-
This work was generously supported by the Deutsche Forschungsgemein-
schaft (Li 556/7–3).
Keywords: carbohydrates · lactones · nucleophilic addition ·
ring-opening · synthetic methods
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Received: October 21, 2008
Published online: December 3, 2008
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