Synthesis and applications of a chiral-oxygenated 3-chloro-3,6-dihydro-2H-pyran obtained under Overman rearrangement conditions

Article abstract of DOI:10.1016/j.tetlet.2009.10.136

A chlorinated side product was formed under Overman rearrangement conditions from a trichloroacetimidate along with the expected allylic amide. The chlorinated product derived from a hex-2-enopyranoside was obtained in a totally stereoselective manner, and it can be a useful synthetic intermediate for chlorinated sugars. In order to improve the isolated yields of either the expected Overman rearrangement product or the chlorinated compound, we carried out a thorough study on the experimental conditions. The application of the latter for the synthesis of potential calpain inhibitors is also reported.

Full text of DOI:10.1016/j.tetlet.2009.10.136

Tetrahedron Letters 51 (2010) 277–280
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and applications of a chiral-oxygenated 3-chloro-3,6-dihydro-2H-
pyran obtained under Overman rearrangement conditions
Ana Montero a,b, Esperanza Benito a, Bernardo Herradón a,
*
a Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
b The Scripps Research Institute, Department of Chemistry, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A chlorinated side product was formed under Overman rearrangement conditions from a trichloroace-
timidate along with the expected allylic amide. The chlorinated product derived from a hex-2-enopyr-
anoside was obtained in a totally stereoselective manner, and it can be a useful synthetic intermediate
for chlorinated sugars. In order to improve the isolated yields of either the expected Overman rearrange-
ment product or the chlorinated compound, we carried out a thorough study on the experimental con-
ditions. The application of the latter for the synthesis of potential calpain inhibitors is also reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 October 2009
Revised 25 October 2009
Accepted 28 October 2009
Available online 3 November 2009
Keywords:
Chlorinated carbohydrate
3,6-Dihydro-2H-pyran
Experimental modulation of the selectivity
Overman rearrangement
Peptide–carbohydrate hybrid
Unsaturated sugar
Functionalized chiral heterocycles are useful intermediates as
well as target compounds for a variety of technological1 and
biological applications.2 In connection with our longstanding inter-
est on carbohydrates3 and their synthetic applications to natural
products as well as peptide–carbohydrate hybrids,4 we surmised
that sigmatropic rearrangements5,6 from derivatives of hexenopyr-
anosides A would provide suitable building blocks for the synthesis
of peptide–carbohydrate hybrids B.7
Table 1). These results show that certain experimental parameters
can be modulated to influence the selectivity of the reaction.14
Whereas the Claisen rearrangement from 1 gave the branched
chain product 2 in high yield, which in turn was used in the
synthesis of peptide derivatives B (Y = CH2CO);8 the Overman rear-
rangement from 1 required considerable experimentation, since
the yield of the expected 3 was lowered by the presence of a chlori-
nated side product. Finally, we could obtain the desired amide 3 in
good yield that was used for the synthesis of the target molecules.9
On studying the reaction in-depth, we found that the chlori-
nated side product was 5.9,10 Remarkably, this side reaction took
place in a totally stereoselective way, affording exclusively the
3b-chloro diastereoisomer, which is an unreported kind of chiral
allylic chloride. These facts, along with the known synthetic appli-
cations of allylic chlorides11 and their utility for the preparation of
halogenated sugars (with potential applications in glycobiology12
and in the field of nonmetabolizing sugars13) prompted us to
perform an in-depth study of this reaction sequence (Scheme 1,
* Corresponding author. Tel.: +34 91 5615086; fax: +34 91 5644853.
E-mail address: herradon@iqog.csic.es (B. Herradón).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.136

278
A. Montero et al. / Tetrahedron Letters 51 (2010) 277–280
Reasoning that the formation of the chloride 5 might be due to a
side product in the first step of the synthetic sequence that was not
removed by filtration, we purified acetimidate 4 by chromatogra-
phy. Purified 4 was submitted to Overman rearrangement condi-
tions to give the amide 3 in 82% yield (entry 11) that was used
in the previously reported synthetic applications.9 To confirm that
the formation of chloride 5 was promoted by a side product in the
preparation of the acetimidate 4, we mixed Cl3CCN and DBU in the
absence of alcohol 1 to give a brown tar 6 (with Rf = 0 in a variety of
chromatographic mobile phases and whose structure is being stud-
ied). When the Overman reaction of purified 4 was conducted in
the presence of 6, a quantitative yield of an equimolecular mixture
of 3 and 5 was obtained in a slow reaction (entry 12).
This last result undoubtedly illustrates that the side product in
the formation of the trichloroacetimidate can hamper the yield and
selectivity of the Overman rearrangement product. However, as
commented above, the allylic chloride 5 can be a useful synthetic
intermediate, and, for further synthetic applications, the experi-
mental conditions reported in entry 2 (50% isolated yield from
alcohol 1 and high scale) can be considered suitable for the synthe-
sis of this kind of chiral allylic chloride, which is unprecedented in
the literature. It is also remarkable that 5 is obtained in a totally
stereoselective manner, whose relative configuration was deter-
mined by NOESY experiments and secured by X-ray diffraction
analysis of a derivative.10,16
Scheme 1. Synthesis of either amide 3 or chloride 5.
Literature precedent guided our initial experimental set-up,15
With a ready supply of 5 in hand, we performed several syn-
thetic applications. In connection with current projects in our
group, we are singularly interested on heterocycles having either
peptide or aromatic substitution due to their potential applications
as calpain inhibitors.17–19 Compound 5 would be a good starting
material to test the influence of chlorine substitution on biological
activity. To this end, the TBDPS-protecting group of 5 was removed
under standard conditions (Bu4NFꢀ3H2O/THF/rt) to give alcohol 7
(74% yield) that was transformed to the aromatic esters 8–10,
the sulfonate 11, and the amino acid derivative 12 by acylation
with the corresponding acyl chloride or sulfonyl chloride in
51–99% yields as indicated in Scheme 2. On the other hand, the
amino acid derivative 13 and the peptide derivative 14 were pre-
pared by Mitsunobu reaction20 from the corresponding sulfon-
amide in 97% and 76% yields, respectively (Scheme 2).
To conclude, an ‘anomalous’ variant of the Overman rearrange-
ment has been uncovered resulting from impurities present
following trichloroacetimidate formation. The selectivity of this
process can be controlled by proper choice of experimental condi-
tions, providing practical access to either the amide 5 or the chlo-
ride 6, which have proven to be useful synthetic intermediates for
the synthesis of functionalized chiral heterocycles as potential
calpain inhibitors. Work is in progress in order to establish the
which involves the reaction of 1 with trichloroacetonitrile in the
presence of DBU, filtration through a short path of CeliteÒ and
heating in xylene solution in the presence of K2CO3. However,
the expected amide 3 was obtained in low yield with chloride 5
as the main product (entry 1). Since we reasoned that the chlorina-
tion reaction was radical based, we tried the reaction in the
presence of hydroquinone as radical scavenger under argon
atmosphere. Unexpectedly, we did not obtain amide 3 but rather
obtained chloride 5 as the single product in a moderate yield
(entry 2). Therefore, we followed the opposite trend using AIBN
as radical initiator and obtaining a roughly 3:2 mixture of 3 and
5 in 74% overall yield (entry 3). Entries 1, 4, and 5 demonstrate
the influence of the concentration on the selectivity. Under
relatively dilute conditions, the selectivity was improved (up to
3:1) and the overall yield was higher; but still a considerable
amount of 5 was obtained. Entries 6–9 show the effect of temper-
ature, preheating (i.e., compound 4 was added when xylene is at
the indicated temperature) and the reaction time. It was observed
that a higher temperature (140 °C) and a longer reaction time were
required to achieve an appropriate conversion, although the
chloride was still obtained. As shown in entry 10, the reaction
was sluggish when run in the absence of a solvent.
Table 1
Experimental results obtained in the thermal treatment of the acetimidate 4a
Entry Intermediate (4) Additive
T (°C)
140–150 No
Hydroquinone/Ar 140–150 No
Preheating Time (h) Concentration (M) Reaction scale Yield (4) (%) Yield (3) (%) Yield (5) (%)
1
2
3
4
5
6
7
8
9
Filtration
Filtration
Filtration
Filtration
Filtration
Filtration
Filtration
Filtration
Filtration
Filtration
No
65
28
31
68
68
22
22
22
46
48
74
99
0.2
0.36
0.1
11.1 g
6.0 g
0
0
0
0
23
0
44
75
70
0
37
50
30
25
30
0
AIBN
No
No
No
No
No
No
No
140–150 No
140–150 No
140–150 No
100 mg
100 mg
100 mg
20 mg
20 mg
20 mg
3.6 g
20 mg
4.1 g
12 mg
0.1
0.02
0.02
0.02
0.02
0.02
Neat
0.02
0.02
0
80
110
Yes
Yes
100
95
68
0
31
0
5
0
0
140–150 Yes
140–150 Yes
140–150 Yes
140–150 Yes
140–150 Yes
32
57
69
82
50
29
Trace
0
10
11
12
Chromatography No
Chromatography
6
0
50
a
All the reactions (except that indicated in entry 10) were carried out in xylene in the presence of a catalytic amount of K2CO3. When crude 4 was used, the isolated yield
refers to overall yield from alcohol 1 (two steps).

A. Montero et al. / Tetrahedron Letters 51 (2010) 277–280
279
NO2
O2N
Cl
O
O
O
O
O2N
O
O
Cl
or
or
O
O
O
O
F
O
O
10
9
Cl
Cl
Cl
8
HO
F
F
O
S
F
O
O
(b)
(a)
5
O
O
F
O
Cl
O
7
11
Cl
O
N
O
O
O
(d)
O
O
Cl
12
S
Tos
Tos
N
O
N
H3CO2C
N
H3CO2C
H
or
O
O
O
O
Tos O
14
Cl
Cl
13
Scheme 2. Reagents and conditions: (a) Bu4NFꢀ3H2O, THF, rt (74%); (b) Et3N, CH2Cl2, 0 °C to rt; for 8: (4-NO2)C6H4–COCl (99%); for 9: (2,6-Cl2)C6H3–COCl (51%); for 10: [(3,5-
(NO2)2]C6H3–COCl (93%); for 11: C6F5–SO2–Cl, Et3N, CH2Cl2, 0 °C to rt (75%). (c) Fmoc- -Pro-Cl, Et3N, CH2Cl2, 0 °C to rt (84%) (d) PPh3, DIAD, THF, rt; for 13: Ts- -Tyr-(Ts)-OMe
(97%); for 14: Ts- -Phe- -Met-OMe (76%).
L
L
L
L
2. (a) Eguchi, E. Bioactive Heterocycles II. In Topics in Heterocyclic Chemistry;
Gupta, R. R., Ed.; Springer: Berlin, 2007; Vol. 8, (b) Sugawara, K.; Hashiyama, T.
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Groom, C. R. J. Med. Chem. 2009, 52, 2952–2963.
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precise origin of the chlorine atom), synthetic applications, and
biological activity.21,22
3. For selected examples on the reactivity, synthesis, and applications of
carbohydrates, see: (a) Valverde, S.; Herradon, B.; Rabanal, R. M.; Martin-
Lomas, M. Can. J. Chem. 1987, 65, 339–342; (b) Valverde, S.; Martin-Lomas, M.;
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Acknowledgment
This work was financially supported by Spanish Ministry of
Science and Innovation (Grant CTQ2007-64891).
Supplementary data
4. Mann, E. Ph.D. Thesis, Universidad Autónoma de Madrid, 2002.
5. For
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analytical methods (see Supplementary data).