Nitro-polyols via pyridine promoted C=C cleavage of 2-nitroglycals. Application to the synthesis of (-)-hyacinthacine A1

Article abstract of DOI:10.1021/acs.orglett.5b03607

A mild and convenient transformation for the synthesis of nitro-polyols is described. The nitro-polyol derivatives were prepared either from 2-nitroglycals via a pyridine-promoted scission of the carbon-carbon double bond or from glycals via a sequential

Full text of DOI:10.1021/acs.orglett.5b03607

Letter
pubs.acs.org/OrgLett
Nitro-polyols via Pyridine Promoted CC Cleavage of 2‑Nitroglycals.
Application to the Synthesis of (−)-Hyacinthacine A1
Shengbiao Tang,†,‡ De-Cai Xiong,‡ Shende Jiang,*,† and Xin-Shan Ye*,‡
†School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China
‡State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No.
38, Beijing, 100191, China
S
* Supporting Information
ABSTRACT: A mild and convenient transformation for the
synthesis of nitro-polyols is described. The nitro-polyol
derivatives were prepared either from 2-nitroglycals via a
pyridine-promoted scission of the carbon−carbon double
bond or from glycals via a sequential nitration−scission
procedure. The generated nitro-polyols could undergo a
stereoselective Michael addition reaction. The utility of the
addition products was exemplified by the concise synthesis of
(−)-hyacinthacine A1 and 7a-epi-(−)-hyacinthacine A1.
carbohydrates as “chiral pool” starting materials has drawn
considerable attention from organic chemists.2 Among them,
nitro-sugars and their derivatives are versatile intermediates in
organic synthesis, especially for carbon−carbon bond formation
by means of the Henry, Michael and various cycloaddition
reactions, as well as for the transformation of the nitro group to
the amino group.3 In addition, nitro-sugars decorate many
natural products including aromatic and reduced polyketides as
well as oligosaccharides.4 These nitro-sugar-related compounds
show many important biological activities such as antibiotic and
antitumor activity.5 However, only a handful of methods for the
preparation of nitro-sugars and their derivatives are known.3d,6
New transformations for the synthesis of nitro-sugar derivatives
are still needed.
he abundance of carbohydrates in Nature makes them an
1
Tideal chemical feedstock. Especially, the employment of
Table 1. Optimization of the Transformation of 2-
a
Nitroglucal 2a to Nitro-polyol 3a
b
entry
solvent
base
yield (%)
1
THF
KOtBu
NaOH
K2CO3
Et3N
0
2
THF
0
3
THF
0
4
THF
0
As part of our continuing studies on the synthesis and
biological evaluation of iminosugar derivatives,7 we have been
attempting to develop new transformations for the synthesis of
nitro-sugar derivatives and further explore their applications in
the synthesis of iminosugars. Glycals are a class of readily
available building blocks in synthetic carbohydrate chemistry.3g
Many “chiral synthons” have been obtained via the scission of
the carbon−carbon double bond in glycals.8 Nevertheless,
harsh reaction conditions are always employed for the
conversion. Therefore, we imagined that the introduction of a
nitro group at the C-2 position of glycals could make the
cleavage of the double bond easier and lead to nitro-sugar
derivatives being formed. Herein, we report a novel, mild, and
efficient transformation for the synthesis of nitro-polyols via a
Michael-type water addition- retro-Henry-type breakage of the
double bond in 2-nitroglycals, and we show some applications
5
THF
DMAP
pyridine
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
−
16
14
28
19
27
74
99
99
6
THF
7
THF
8
CH3CN
acetone
DMF
9
10
11
12
pyridine
pyridine
a
All reactions were carried out with 2a (0.24 mmol), base (3 equiv),
H2O (0.4 mL), and solvent (2 mL) at room temperature for 24 h.
Isolated yield. DMAP = 4-dimethylaminopyridine. dtbpy = 4,4′-di-
tert-butyl-2,2′-bipyridine.
b
Scheme 1. Sequential Protocol for the Cleavage Reaction of
D-Glucal 1a
Received: December 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of Glycals and 2-Nitroglycals
a
b
Condition A: nitroglycal (0.24 mmol), pyridine (2 mL), H2O (0.4 mL), room temperature for 24 h. Condition B: glycal (0.24 mmol), concd.
c
HNO3 (1.2 mmol), Ac2O (4.8 mmol); then pyridine (2 mL), H2O (0.4 mL), room temperature for 24 h. Isolated yield.
of this reaction in the synthesis of bicyclic polyhydroxylated
pyrrolidine compounds.
Having verified the feasibility of cleavage of the double bond
in 2-nitroglucal 2a, and with the optimized conditions in hand,
we further imagined the nitration of glucal and scission of the
carbon−carbon double bond could be realized in a sequential
manner. Thus, glucal 1a was treated under the standard
nitration conditions. The nitration product was generated
within 30 min. Indeed, after the addition of pyridine−water (5/
1, v/v) to the reaction mixture, compound 3a was obtained in
67% yield (Scheme 1; see Supporting Information for the
detailed procedure). Therefore, compound 3a was prepared
either from 2-nitroglucal 2a or from glucal 1a via the sequential
protocol with high efficiency.
To test the reaction, 2-nitro-glucal 2a was employed as the
starting material in the initial experiments and variations were
made to either the solvent or the base (Table 1). The
quantitative conversion to 3a was achieved at room temper-
ature within 24 h using pyridine as both the solvent and base
(entry 12). Other bases such as KOtBu, NaOH, K2CO3, and
Et3N were found to be ineffective (entries 1−7, Table S1 in
Supporting Information). It was found that 4,4′-di-tert-butyl-
2,2′-bipyridine (dtbpy) was also effective when using DMF or
pyridine as the solvent (entries 10−11, Table 1). Water was
essential for the transformation to be efficient (Table S1). So,
the optimized reaction conditions are 2-nitroglycal (0.24
mmol), H2O (0.4 mL), and pyridine (2.0 mL), at room
temperature for 24 h.
Next, the scope of glycals and 2-nitroglycals in this reaction
was examined. As shown in Table 2, benzylated/tbutyldimethyl-
silylated/methylated/benzylidenated 2-nitroglucals, or 2-nitro-
glucals with tosyl, bromo, or azido substituents, could be used
B
DOI: 10.1021/acs.orglett.5b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
rhamnal/2-nitroarabinal/5-nitro-3,4-dideoxy-glucal proceeded
smoothly as well under the same conditions (entries 4−6, 10,
and 15−18), leading to the desired products in high yields.
Although the cleavage reaction of the nitroglycal 2i with an
acetyl protective group took place in satisfactory yield, the
acetyl group was absent in the product due to deacetylation
that resulted from the influence of the neighboring nitro group
(entry 9). Furthermore, the nitrosugar derivatives 3a−3r were
also prepared directly from glycals 1a−1r via sequential
nitration and breakage of the carbon−carbon double bond in
a “one-pot” protocol. Except for glycals with acid-sensitive
functionalities such as silyl and benzylidene groups (entries 2,
7−9), most glycals underwent this reaction smoothly in
moderate to good yields.
To further demonstrate the utility of this transformation for
organic synthesis, the Michael addition reaction of the nitro-
sugar derivative 3d with methyl acrylate (4) in pyridine−water
was performed (Table 3). To our delight, the reaction
proceeded smoothly in satisfactory yields. It was found that
water could accelerate the reaction and is essential for this
transformation. Notably, the ratio of the octanoate products
(7a, 7b, 8a, and 8b) and diastereoselectivity changed with
alteration in the ratio of pyridine/H2O (entries 2−6). A
decrease of the ratio of pyridine/H2O to 1/5 resulted in the
formation of products 8a and 8b along with a significant
improvement in diastereoselectivity (8a/8b = 13/1, entry 7). It
was noticed that the deformylated product 8 increased with the
decrease of pyridine. Thus, under the condition of pyridine/
H2O (1/5), a total deformylation of 3d may occur.
Table 3. Michael Addition Reaction of 3d with Methyl
Acrylate
a
b
entry solvent (vPyr/vH O
)
time (h) yield (%) 7a:8a:7b:8b
4R:4S
2
1
2
3
4
5
6
7
1:0
5:1
3:1
2:1
1:1
1:2
1:5
72
36
24
24
12
8
0
−
1:1
37:0:37:0
38:0:37:0
30:15:30:0
20:35:11:4
0:57:0:12
0:67:0:5.3
1:1
1.5:1
4:1
4.8:1
13:1
8
a
All reactions were carried out with 3d (0.24 mmol), methyl acrylate
(4) (1.20 mmol), mixed solvent of pyridine−H2O (6 mL), room
b
temperature. Isolated yield.
Scheme 2. Control Experiments
To account for the high diastereoselectivity of the Michael
addition reaction, we propose an intermediate 6d where there is
an eight-membered-ring intramolecular hydrogen bond, in
which the si-face of the carbon−nitrogen double bond is
effectively shielded, as depicted in Scheme 2A. To verify this
assumption, the deformylated compound 5d was subjected to
the mixed solvent (pyridine/H2O, 1/5). Indeed, compound 8a
was obtained with high diastereoselectivity (8a/8b = 15/1, 63%
yield). In addition, it was found that 7a and 7b can transform
into each other and an equilibrium can be reached eventually in
the solvent of pyridine/H2O (Scheme 2B and Table S3). The
equilibrium between 8a and 8b was observed as well (Scheme
2C and Table S3). Next, we conducted the scission-Michael
addition reaction in a one-pot manner, and similar diaster-
eoselectivity was obtained (Scheme 3).
Scheme 3. One-Pot Scission-Michael Addition Reaction
Scheme 4. Synthesis of 7a-epi-(−)-Hyacinthacine A1 and
(−)-Hyacinthacine A1
Iminosugars have many important biological activities.
Hyacinthacine A1 was isolated from the bulbs of Muscari
armeniacum in about 0.0005% yield and was confirmed to be an
effective inhibitor of rat intestinal lactase (IC50 value of 4.4
μM).9 Thus, the synthesis of these pyrrolidine alkaloids and
their analogues from simple and readily accessible chemicals is
of importance.10 Therefore, with compounds 7b and 8a in
hand, the synthesis of (−)-hyacinthacine A1 and 7a-epi-
(−)-hyacinthacine A1 was attempted. As shown in Scheme 4,
the reduction of compound 8a gave alcohol 9a in 89% yield.
Then the alcohol 9a was mesylated to produce compound 10a
in 93% yield. Compound 10a was treated with H2 (4 atm), Pd/
C, and Et3N to smoothly generate the bicyclic compound 11a
in 85% yield. The debenzylation of 11a via hydrogenolysis
afforded the target compound 7a-epi-(−)-hyacinthacine A1
(12a) (69% overall yield, four steps from 8a) (Scheme 4A).
In the same way, (−)-hyacinthacine A1 (12b) was successfully
prepared from 7b in 73% overall yield (Scheme 4B).
for the reaction and gave the ring-opening nitrosugar
derivatives in good to excellent yields (entries 1−3, 7−9, and
11−14). The cleavage reaction of 2-nitrogalactal/2-nitro-
C
DOI: 10.1021/acs.orglett.5b03607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, a new and convenient transformation for the
synthesis of nitro-polyols via either a pyridine-promoted
scission of the carbon−carbon double bond in 2-nitroglycals
or a successive nitration-scission reaction of glycals in a “one-
pot” protocol has been disclosed. One of the formed 4-O-
formyl-nitro-polyol derivatives underwent a unique and stereo-
selective Michael addition reaction. Moreover, a concise and
asymmetric total synthesis of (−)-hyacinthacine A1 and 7a-epi-
(−)-hyacinthacine A1 was achieved in four steps from the
Michael addition products in high overall yield. Thus, the
disclosed protocol may find wide application in the preparation
of nitro-sugar intermediates and hold the potential to allow the
synthesis of iminosugars and other bioactive natural or non-
natural products.
ASSOCIATED CONTENT
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03607.
Detailed experimental procedures and spectral data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Torii, S.; Inokuchi, T.; Kondo, K. J. Org. Chem. 1985, 50,
4980−4982. (b) Yang, D.; Zhang, C. J. Org. Chem. 2001, 66, 4814−
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340, 753−758. (d) Daw, P.; Petakamsetty, R.; Sarbajna, A.; Laha, S.;
Ramapanicker, R.; Bera, J. K. J. Am. Chem. Soc. 2014, 136, 13987−
13990.
*E-mail: sjiang@tju.edu.cn.
*E-mail: xinshan@bjmu.edu.cn.
Notes
The authors declare no competing financial interest.
(9) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.;
Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1−8.
ACKNOWLEDGMENTS
■
This work was financially supported by grants (2012CB822100,
2013CB910700) from the Ministry of Science and Technology
of China, the National Natural Science Foundation of China
(Grant No. 21232002), and Beijing Higher Education Young
Elite Teacher Project (YETP0063).
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(e) Si, C. M.; Mao, Z. Y.; Ren, R. G.; Du, Z. T.; Wei, B. G. Tetrahedron
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