Facile synthesis of C-aryl glycals from sugar-derived lactones

Article abstract of DOI:10.1016/j.tetlet.2006.02.150

A general entry to C(1) aryl-substituted glycals from the corresponding sugar lactones is described. This approach features one-pot access to aryl glycals. A variety of aryllithium reagents can be used and the method is compatible with various 2-deoxysuga

Full text of DOI:10.1016/j.tetlet.2006.02.150

Tetrahedron Letters 47 (2006) 3485–3488
Facile synthesis of C-aryl glycals from sugar-derived lactones
Hui Li, Kristen Procko and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Received 9 February 2006; accepted 24 February 2006
Available online 4 April 2006
Abstract—A general entry to C(1) aryl-substituted glycals from the corresponding sugar lactones is described. This approach
features one-pot access to aryl glycals. A variety of aryllithium reagents can be used and the method is compatible with various
2-deoxysugar lactones.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
high catalyst loadings to obtain products in useful yields.
The route to C-aryl glycals comprising the addition of
aryl Grignard reagents to 2-deoxysugar lactones, fol-
lowed by dehydration of the intermediate hemiketals
requires the use of large excesses of Martin’s sulfurane.
Because of the cost of this reagent, this approach is
impractical when larger quantities of material are
required. In view of the limitations of the aforemen-
tioned methods, we set to the task of developing a more
general procedure for the synthesis of C-aryl glycals from
readily available materials, and we now wish to report
these findings.
C-Alkyl and aryl glycosides are important synthetic
targets owing to their significant biological activities as
antibiotic and anticancer agents.1 In order to address
problems associated with the synthesis of these natural
products,2 we developed a general entry to the major
classes of C-aryl glycosides.3 The strategy features the
ring opening of cycloadducts that are obtained by the
Diels–Alder reaction of substituted benzynes with glyco-
syl furans. Having established the basic elements of the
approach, we then became interested in applying it to
the synthesis of natural and non-natural C-aryl glyco-
sides. In this context, we encountered a need for a facile
and efficient route to C-aryl glycals, especially those
derived from furans.
Of the existing methods for preparing C-aryl glycals, we
found the method of Sulikowski to be particularly
appealing,7 because it employed readily available sugar
lactones as the starting materials. We thus used this pro-
cedure as a starting point for our investigations. For
example, addition of 2-furyllithium to sugar lactone 1
proceeded smoothly, but we found that the hemiacetal
addition product 3 existed primarily in the open form
4 at room temperature in CDCl3 (Scheme 1). Although
this equilibrium is well known, it did not appear to inter-
fere in previously reported reductive processes to form
C-aryl glycosides.3,7 However, when we treated this mix-
ture with Martin’s sulfurane according to the two-pot
procedure of Sulikowski and co-workers,7 the desired
glycal 5 was obtained in only 32% yield. We were unable
to optimize the procedure further.
Owing to their obvious importance, a number of proce-
dures for preparing C-aryl glycals have been recorded,
including cross-coupling reactions of glycal derivatives,4
ring closing metatheses of dienes,5,6 and addition–elimi-
nations of sugar lactones.7 However, all of these methods
are subject to one or more limitations. For example,
approaches to C-aryl glycals based on palladium-cata-
lyzed cross-couplings of 1-iodoglycals or 1-metallated
glycals are restricted because routes to the requisite gly-
cal precursors are not general. Techniques involving
ring closing metathesis suffer from the requirement of
It then occurred to us that difficulties with the afore-
mentioned ring-chain tautomerism might be avoided
if the intermediate lithium alkoxide of the hemiketal
3 could be trapped in situ to give a derivative that
would undergo facile elimination to give the desired
Keywords: C-Aryl glycosides; Glycals; Sugar lactones; Addition–
dehydration.
*
Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471
4180; e-mail: sfmartin@mail.utexas.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.150

3486
H. Li et al. / Tetrahedron Letters 47 (2006) 3485–3488
OBn
groups were then globally protected as benzyl (or
methyl) ethers.
OBn
OH
O
O
O
O
O
Li
+
THF, –78 ºC
Use of pyridinium chlorochromate (PCC)10,12 to oxi-
dize these glycals to lactones was somewhat capricious
in our hands, and we found a two-step procedure to be
more efficient. In the event, hydration of the glycals in
the presence of PPh3ÆHBr13 and subsequent oxidation
of the intermediate lactols with TPAP14 gave the de-
sired sugar lactones. The amino lactone 11 was synthe-
sized from the known azide 20,15 in good overall yield
according to the sequence of reactions depicted in
Scheme 3.
BnO
BnO
71%
OBn
OBn
1
2
3
OBn
OBn
O
O
OH
O
Martin's
O
sulfurane
32%
BnO
BnO
OBn
OBn
4
5
BnOH, K-10
O
OAc
O
OBn
Montmorillonite
Scheme 1.
AcO
AcO
PhH
50%
N3
N3
20
21
glycal 5. Thus, following addition of 2 to 1, the alkox-
ide 6 was treated at À78 °C with a mixture of pyridine,
4-N,N-dimethylaminopyridine (DMAP), and trifluoro-
acetic anhydride (TFAA) to furnish the furylglucal 5
in very good yield (Scheme 2). If a large excess of
TFAA was present, acylation of the glycal enol ether
ensued,8 affording the a-furyl-b-trifluroacetoxyglucal 7
as a significant by-product (22% yield). Indeed, when
5 was treated with an excess of TFAA in the presence
of pyridine and DMAP, 7 was isolated in 63% yield.
Several experiments were conducted to see whether
other electrophilic trapping agents might prove supe-
rior to TFAA. However, use of acetic anhydride
(Ac2O), methanesulfonyl chloride (MsCl), and triflic
anhydride (Tf2O) furnished 5 in significantly reduced
yields (12–32%).
O
OBn
1) LiAlH4, Et2O
1) K2CO3, MeOH
2) Boc2O, CH2Cl2
88%
MeO
N3
2) MeI, NaH, DMF
92%
22
O
OBn
O
OBn
NaH, MeI, DMF
97%
MeO
MeO
NMeBoc
NHBoc
24
23
O
O
1) H2, Pd/C, EtOAc
2) NMO, TPAP, CH2Cl2
93%
MeO
NMeBoc
11
OBn
O
Scheme 3.
O
Py, DMAP
TFAA
O
1 + 2
Generally good to excellent yields of aryl glycals were
obtained using a variety of aryllithiums and sugar lac-
tones (Table 1). The yield of the aryl glycal seems to
be directly related to the nature of the starting sugar.
For example, C-aryl rhamnals were invariably formed
in the best yields (Table 1, entries 4–7). The 6-deoxy
aminoglycal was also formed in excellent yield (entry
9). On the other hand, the formation of C-aryl galac-
tals proved to be somewhat problematic (Table 1, en-
try 8), and significant quantities of the corresponding
acyclic d-hydroxy ketone were consistently isolated. It
thus appears that trapping of the alkoxide generated
by addition of an aryllithium reagent to 2-deoxy galac-
tose lactone 10 is slow relative to collapse of the hemi-
acetal alkoxide to give the open chain d-hydroxy
ketone. All attempts to improve the yield by varying
the temperature, time, and equivalents of TFAA were
unsuccessful.
THF, –78ºC
–78 ºC
75%
BnO
OBn
6
O
OBn
O
O
O
BnO
BnO
COCF3
BnO
OBn
OBn
5
7
Scheme 2.
Having optimized the procedure for the preparation of
5,9 we explored the generality of the method using a
variety of aryllithium reagents and the known sugar lac-
tones 1,10 811, 9,12 and 10.11 Lactones 1, 8, 9, and 10
were prepared from the corresponding commercially
available peracetoxy glycals. The acetoxy groups were
first removed by saponification, and the hydroxyl
In summary, we have developed a general and efficient
method for the synthesis of C-aryl glycals from the corre-
sponding 2-deoxysugar lactones in a one-pot operation.

H. Li et al. / Tetrahedron Letters 47 (2006) 3485–3488
Table 1. Preparation of C-aryl glycals from sugar lactones9
3487
O
Ar
O
O
Ar–Li,THF, –78 ºC
then Py, DMAP, TFAA
RO
RO
Entry
1
Lactone
Ar–Li
Producta
Yieldb
BnO
BnO
O
1
75%c
76%
75%
Li
Li
O
O
BnO
5
BnO
BnO
O
2
3
1
BnO
12
MeO
MeO
MeO
MeO
MeO
O
O
O
O
O
Li
O
O
O
O
MeO
13
8
O
BnO
BnO
BnO
BnO
4
5
92%
91%
Li
Li
14
9
O
BnO
BnO
9
9
9
15
O
BnO
BnO
OMe
6
7
86%
95%
Li
Li
OMe
16
O
BnO
BnO
17
BnO
BnO
BnO
BnO
O
O
O
8
9
31%
92%
Li
Li
O
O
O
BnO
BnO
10
18
O
O
MeO
O
MeO
O
BocMeN
BocMeN
11
19
a Products obtained were >95% pure by 1H NMR.
b Reported yield for 0.2 mmol scale reaction, except for entry 9 (0.8 mmol scale).
c Reaction also performed on 8.3 mmol scale in 71% yield.
A number of aryllithium reagents and sugar-derived
lactones have been shown to be compatible with the
Acknowledgements
procedure, so it should be of general utility in the carbo-
hydrate field.
We thank the Robert A. Welch Foundation, the
National Institutes of Health (GM 31077), Pfizer Inc.,

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H. Li et al. / Tetrahedron Letters 47 (2006) 3485–3488
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and Merck Research Laboratories, for their generous
support of this research.
Supplementary data
5. Calimente, D.; Postema, M. H. D. J. Org. Chem. 1999, 64,
1770.
6. For a review of RCM to prepare oxygen heterocycles, see:
Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
7. Boyd, V. A.; Drake, B. E.; Sulikowski, G. A. J. Org.
Chem. 1993, 58, 3191.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.02.150.
References and notes
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9. General procedure for the formation of C-aryl glycals from
sugar-derived lactones: A solution (0.25 M) of aryllithium
(1.1 equiv) was added to a solution of the sugar lactone at
À78 °C in THF (0.1 M solution). The solution was stirred
for 1–4 h at À78 °C, whereupon pyridine (3.0 equiv),
DMAP (1.15 equiv), and TFAA (2.5 equiv) were added
sequentially at À78 °C. The reaction mixture was then
warmed to room temperature over a 2–3 h period, and
then stirring was continued for 12 h. Aqueous workup
followed by column chromatography afforded the aryl
glycal. This method was used to prepare 5 on a 2.5 g scale.
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