An efficient synthesis of δ-glyconolactams by intramolecular Schmidt-Boyer reaction under microwave radiation

Article abstract of DOI:10.1016/j.tetlet.2012.10.098

δ-Glyconolactams were first synthesized by the intramolecular Schmidt-Boyer reaction using corresponding δ-azidosugars as starting material. The reaction could be efficiently performed in good yields of 61-69% under microwave radiation in acid condition,

Full text of DOI:10.1016/j.tetlet.2012.10.098

Tetrahedron Letters 53 (2012) 7147–7149
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of d-glyconolactams by intramolecular Schmidt–Boyer
reaction under microwave radiation
⇑
Hua Chen, Rui Li, Fang Gao, Xiaoliu Li
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China
a r t i c l e i n f o
a b s t r a c t
Article history:
d-Glyconolactams were first synthesized by the intramolecular Schmidt–Boyer reaction using corre-
sponding d-azidosugars as starting material. The reaction could be efficiently performed in good yields
of 61–69% under microwave radiation in acid condition, providing an alternative protocol to iminosugar
d-lactam.
Received 29 August 2012
Revised 16 October 2012
Accepted 23 October 2012
Available online 30 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Glyconolactam
Schmidt–Boyer reaction
Iminosugar
Microwave radiation
Iminosugars, which exhibit effective inhibition against carbohy-
drate-processing enzymes, have aroused great interest for their po-
tential clinical applications as anti-HIV, anti-diabetic, and anti-
cancer agents in past decades.1 d-Glyconolactams, a special kind
of iminosugar analogs, have also brought attention due to their
prominence as glycosidase inhibitor and their potential application
in the preparation of nojirimycin derivatives.2 The d-glycono lac-
either from d- or e-azido aldehyde, although the reason was un-
clear. Very interestingly, we occasionally obtained the d-glycono-
lactam as a predominant product from d-azidosugar in acid
conditions during our approach to new iminosugar,7 which in-
spired us to explore the potential application of the intramolecular
Schmidt–Boyer reaction in preparing d-glyconolactam directly
from the corresponding d-azidosugar rather than the
c-lactone.
tams were commonly synthesized by the condensation of a
c-ami-
The requisite azidosugars (1a–d) were readily prepared accord-
ing to the literatures starting from D-ribose and D-mannose. The
8
no carboxylic acid generated from the reduction of the azido
3
glyconic
c
-lactone. However, the alternative approach to synthe-
intramolecular Schmidt–Boyer reaction (Scheme 2) was first inves-
tigated using azidosugar 1a as the starting material at room tem-
perature catalyzed by a variety of protic (Table 1, entries 1–4, 12,
and 13) or Lewis acids (entries 5–11). The intramolecular reaction
was carried out successfully, accompanied with the removal of the
protecting groups of TBDMS and isopropylidene, and directly affor-
ded the corresponding product of d-glyconolactam 2a as the pre-
dominant product. As shown in Table 1, under the conditions of
sizing d-glyconolactams is of continuing interest.
The Schmidt–Boyer reaction of aldehydes or ketones with
hydrazoic acid or alkyl azide under acid conditions provided a very
convenient method to construct an amide bond.4 It has been suc-
cessfully applied to prepare amide by the intermolecular reaction,
and lactam and formyl cyclo amine derivatives by the intramolec-
5
ular reaction, respectively. However, the intramolecular Schmidt–
Boyer reaction of the d-azidoalkyl aldehyde was rarely reported to
form the d-lactam. To the best of our knowledge, only one exam-
ple has been demonstrated that the d-lactam was obtained from
d-azidoalkyl aldehyde as a minor product (8–22% yields), possibly
via hydride migration or E2 elimination through the hydroxyimine
tautomer (Scheme 1, unfavored routes b and c). Preferentially the
3
protic acid 80% TFA (entry 3) and Lewis acid BF (entry 9) the reac-
tion proceeded efficiently with the good yields of 68% and 74%,
respectively. Subsequently, the exploratory study of the intramo-
6
a
lecular reaction was further carried out under microwave radia-
9
tion using 80% TFA and BF
3
as acid catalyst, respectively. As
expected, the reaction could be dramatically accelerated under
microwave radiation within 5–10 min at the tolerable temperature
of 40–50 °C (entries 10–13), and especially, in 80% TFA the reaction
afforded d-glyconolactam 2a in a yield of 69% within 5 min at 50 °C
(entry 13). Furthermore, the reaction in 80% TFA (entries 12 and
major formamide product was formed through the migration of a
+
C–C bond antiperiplanar to a favorably disposed N
Scheme 1, favored route a: CH
periplanar alkyl migration only afforded the formamide products
2
moiety
(
migration). Especially,6b the anti-
2
1
3
3) gave higher yields than in BF (entries 10 and 11), indicating
⇑
Corresponding author. Tel./fax: +86 312 5971116.
E-mail address: lixl@hbu.cn (X. Li).
that the microwave-assisted reaction was more effective in protic
acid and polar solvent than in Lewis acid and nonpolar solvent.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.098

7
148
H. Chen et al. / Tetrahedron Letters 53 (2012) 7147–7149
OH
H
O
OH
O
H
N
N
N
OH
N
3
N3
HO
H
H
N
OH
N2
2
HN
Unfavored
Route b:
HO
N
HO
H
O
OH
N
N
N
OH
OH
Favored
Route a:
migration
OH
OH
H migration
N
2
lactam product
Unfavored
Route c:
CH
2
H elimination
O
HO
OH
N
H
formamide product
Scheme 1. The proposed mechanisms of the intramolecular Schmidt–Boyer reaction.
O
acid
NH
withdrawing substituent) on the C-2 position led to diminish the
C–C migration.
OH
O
11
N
3
M.W.
PO
HO
In conclusion, d-glyconolactams were conveniently synthesized
from the corresponding d-azido sugars by the microwave-assisted
intramolecular Schmidt–Boyer reaction in good yields, providing
an alternative protocol to construct the iminosugar like d-lactam.
Although it was unclear why the results of the intra-molecular
1
2
TBDMSO
O
TBDMSO
O
O
O
OH
OH
OH
OH
O
N
3
N3
N
3
N
3
1:
O
O
O
O
O
O
O
O
6
reaction were different from those reported, our findings would
a
b
c
d
be an important supplement for the potential application of the
Schmidt–Boyer reaction.
HO
HO
HO
HO
HO
HO
NH
NH
NH
NH
O
O
HO
HO
O
HO
HO
2:
OH
OH
OH
OH
Acknowledgments
a
b
c
d
The financial supports from the National Natural Science
Foundation of China (NSFC) (20972039, 21172051), the Medicinal
Joint Funds of the Natural Science Foundation of Hebei Province
and Shijiazhuang Pharmaceutical Group (CSPC) Foundation
Scheme 2. Synthesis of d-glyconolactams by the intramolecular Schmidt–Boyer
reaction. Reagents and conditions: 80% CF COOH, 50 °C, M.W., 5 min, 61–69%.
3
(
B2011201169, B2012201113), and the Natural Science Founda-
Table 1
The exploratory study of the intramolecular reaction using 1a
tions of Education Department of Hebei (ZH2011110, Y2011119)
are acknowledged.
Entry Acid
Solvent
Dioxane rt
Temp (°C) Reaction timea Yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1N-HCl
CF COOH
9 h
54
64
68
56
61
50
20
43
74
32
30
60
69
c
Supplementary data
3
—
—
—
rt
rt
rt
15 h
26 h
48 h
c
c
80% CF
50% CF
3
COOH
COOH
3
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
AlCl
FeCl
ZnCl
TiCl
3
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
2
2
2
rt
rt
rt
rt
12 h
12 h
12 h
15 h
3
1
0.098.
2
4
BF
3
BF
3
BF
3
rt
10 h
References and notes
0
1
2
3
M.W. 40
M.W. 50
M.W. 40
M.W. 50
10 min
5 min
10 min
5 min
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c
80% CF
80% CF
3
COOH
COOH
—
c
3
—
1
911; (c) Afarinkia, K.; Bahar, A. Tetrahedron: Asymmetry 2005, 16, 1239–1287;
a
b
c
Compound 1a disappeared on TLC.
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10277–10302.
CF
3
COOH as solvent.
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5
Under the same conditions as described in entry 13, the d-glycon-
olactams 2b–d were conveniently synthesized in good yields of
6
Tetrahedron 2006, 62, 7455–7458; (c) Chaveriat, L.; Stasik, I.; Demailly, G.;
Beaupère, D. Tetrahedron 2004, 60, 2079–2081; (d) Fleet, G. W. J.; Carpenter, N.
M.; Petursson, S.; Ramsden, N. G. Tetrahedron Lett. 1990, 31, 409–412.
1–69% from the corresponding azidosugars 1b–d.10 It should be
mentioned that, although we could not absolutely rule out small
4. (a) Smith, P. A. S. J. Am. Chem. Soc. 1948, 70, 320–323; (b) Boyer, J. H.; Hamer, J. J.
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Murphy, J. A. Chem. Soc. Rev. 2006, 2, 146–156.
1
(
<5%, determined by H NMR) amounts of the formamide products
from these reactions, their presence was not evident from exami-
nation of the crude reaction mixtures. The results indicated that
the intramolecular Schmidt–Boyer reaction would take place pref-
erentially via the unfavored route of b or c as shown in Scheme 1. It
was likely that the presence of the hydroxyl group (an electron-
5. (a) Puppala, M.; Murali, A.; Baskaran, S. Chem. Commun. 2012, 48, 5778–5780;
(
6
1
b) Liu, R. Z.; Gutierrez, O.; Tantillo, D. J.; Aubé, J. J. Am. Chem. Soc. 2012, 134,
528–6531; (c) Chen, Z. H.; Tu, Y. Q.; Zhang, S. Y.; Zhang, F. M. Org. Lett. 2011,
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Z.; Wei, S.-N.; Li, C.-X.; Chen, H.; Meng, M. Bioorg. Med. Chem. Lett. 2012, 22,
168 °C2b), 1H NMR (600 MHz, MeOD) d
(t, J = 3.6 Hz, 1H, CH), 3.80 (t, J = 4.8 Hz, 1H, CH), 3.77 (dd, J = 10.8 Hz, 4.2 Hz,
H
(ppm): 4.26 (d, J = 3.6 Hz, 1H, CH), 3.96
1
13
7
1H, CH), 3.62 (dd, J = 10.8 Hz, 7.2 Hz, 1H, CH
NMR (150 MHz, MeOD) d (ppm): 174.2, 74.3, 69.8, 69.6, 64.0, 60.5; HRESIMS:
calcd for C 11NO Na ([M+Na] ) 200.0535, found: 200.0541. (3S,4S,5R,6S)-
3,4,5-Trihydroxy-6-(hydroxymethyl) piperidin-2-one (2b): White solid, yield 67%,
2
), 3.31–3.33 (m, 1H, CH
2
);
C
C
+
6
H
5
2
712–2716.
3
2
+27.1 (c 1.0, MeOH); 1H NMR (600 MHz, MeOD) d
H
8
.
(a) Suhara, Y.; Kittaka, A.; Ono, K.; Kurihara, M.; Fujishima, T.; Yoshida, A.;
Takayama, H. Bioorg. Med. Chem. Lett. 2002, 12, 3533–3536; (b) Isabel García-
Moreno, M.; Mellet, C. O.; García-Fernández, J. M. Eur. J. Org. Chem. 2004, 1803–
mp 172–173 °C; ½
aꢀ
D
(ppm): 4.30 (d, J = 3.0 Hz, 1H, CH), 4.14 (t, J = 3.6 Hz, 1H, CH), 4.07–4.08 (m, 1H,
13
CH), 3.73–3.77 (m, 2H, CH, CH
NMR (150 MHz, MeOD) d (ppm): 173.9, 70.9, 67.5, 67.1, 61.4, 54.3; HRESIMS:
calcd for C 11NO Na ([M+Na] ) 200.0535, found: 200.0523. (3S,4S,5R)-3,4,5-
Trihydroxy piperidin-2-one (2c): White solid, yield 61%, mp 196–198 °C; ½
2
), 3.69 (dd, J = 10.2 Hz, 4.2 Hz, 1H, CH
2
);
C
1
819; (c) Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov, D. V.;
C
+
Plaisier, J. R.; van der Marel, G. A.; Overkleeft, H. S.; van Boom, J. H. Tetrahedron:
Asymmetry 2005, 16, 177–185; (d) Cosme, G. F.; Raimundo, F.; Concepcion, C.
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(a) Xu, J.-X. Chemistry 2007, 19, 700–712 (in Chinese); (b) Kappe, C. O. Angew.
Chem., Int. Ed. 2004, 43, 6250–6284.
6
H
5
3
2
a
ꢀ
D
1
ꢁ18.6 (c 1.0, MeOH); H NMR (600 MHz, MeOD) d
H
(ppm): 4.32 (d, J = 3.0 Hz,
9
.
1H, CH), 4.09 (t, J = 4.2 Hz, 1H, CH), 4.03 (t, J = 4.2 Hz, 1H, CH), 3.66 (dd,
13
2 2
J = 13.2 Hz, 3.6 Hz, 1H, CH ), 3.16 (dd, J = 13.2 Hz, 2.4 Hz, 1H, CH ); C NMR
1
0. General procedure for the synthesis of d-glyconolactams 2: Azidosugar
1.0 mmol) was dissolved in 3 mL 80% CF COOH and was stirred in sealed
tube at 50 °C under microwave irradiation in CEM Discover S-Class
1
(150 MHz, MeOD) d (ppm): 173.6, 74.9, 71.0, 67.3, 44.8; HRESIMS: calcd for
C
+
(
3
C
5
H
9
NO
piperidin-2-one (2d): White solid, yield 63%, mp 147–148 °C; ½
MeOH); 1H NMR (600 MHz, D
O) d (ppm): 4.11–4.16 (m, 3H, 3CH), 3.34 (dd,
J = 12 Hz, 6.6 Hz, 1H, CH ), 3.22 (t, J = 10.2 Hz, 1H, CH
O) d (ppm): 173.3, 70.9, 68.2, 64.7, 42.5; HRESIMS: calcd for C
4
Na ([M+Na] ) 170.0429, found: 170.0433. (3R,4R,5R)-3,4,5-trihydroxy
32
a
aꢀ
+35.3 (c 1.0,
D
Synthesizer for 5 min. After the reaction complete, the solvent was
evaporated under reduced pressure to get a crude product that was purified
using flash column chromatography (ethyl acetate–methanol V/V = 7:1–3:1) to
get d-glyconolactams 2. (3S,4S,5R,6R)-3,4,5-Trihydroxy-6-(hydroxymethyl)
piperidin-2-one (2a): White solid, yield 69%; mp 164–165 °C (lit. mp 163–
2
H
13
2
2
); C NMR (150 MHz,
NO Na
D
2
C
5
H
9
4
+
([M+Na] )170.0429, found:170.0421.
11. Szostak, M.; Yao, L.; Aube, J. Org. Lett. 2009, 11, 4386–4389.