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DOI: 10.1055/s-0029-1219189
A Practical Synthesis of Sugar-Derived Cyclic Nitrones: Powerful Synthons for the Synthesis of Iminosugars
Publikationsverlauf
Publikationsdatum:
11. Januar 2010 (online)
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Abstract
Sugar-derived cyclic nitrones were synthesized from the corresponding aldoses through an efficient and practical procedure involving a seven-step reaction sequence in good to excellent overall yield (10-42%). This synthetic strategy, requiring only inexpensive reagents, is easy to perform and hence suitable for large-scale preparations.
Key words
sugar-derived cyclic nitrones - synthesis - iminosugars - nitrones
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- Supporting Information
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References and Notes
General methods
for the synthesis of 5 and 10:
Method
A: Compounds 1 and 6 were
prepared from the corresponding aldoses (90 g 0.6 mol) in three
steps according to the literature²0 and were
used directly in the next step without further purification. NH2OMe˙HCl
(55.12 g, 0.66 mol, 1.1 equiv) and Et3N (91.9 mL, 0.66
mol, 1.1 equiv) were added to a solution of crude compound 1 or 6 (crude
product prepared from 0.6 mol aldose) in anhydrous CH2Cl2 (300
mL). The reaction reached completion after vigorous stirring for
about 12 h. The reaction mixture was then concentrated
in vacuo and the resulting mixture was dissolved in EtOAc-H2O.
The organic phase was separated and the aqueous phase was extracted
with EtOAc (3 × 150 mL). The combined
organic phases were dried with anhydrous Na2SO4 and
filtered, the filtrate was concentrated in vacuo to give the crude
product 2 or 7,
which was used directly in the next step of reaction without further purification.
To an ice-cooled solution of 2 or 7 in Et3N (91.9 mL, 0.66 mol,
1.1 equiv) and CH2Cl2 (300 mL), was
added methanesulfonyl chloride (51.08 mL, 0.66 mol, 1.1 equiv) slowly,
and the mixture was allowed to warm gradually to r.t. After 1 h,
the reaction mixture was quenched by addition of H2O
(200 mL). The organic phase was separated and the aqueous phase
was extracted with EtOAc (3 × 150 mL).
The combined organic phases were dried over anhydrous MgSO4.
After filtration, the solvent was removed in vacuo to give crude
product 3 or 8 as
a yellow oil, which was used directly in the next step without further
purification. To a well-stirred solution of 3 or 8 in THF (400 mL), p-TsOH (114
g, 0.6 mol) and aq HCHO (37%, 150 mL) were added subsequently.
After stirring for 36 h, the reaction was neutralized with
sat. aq NaHCO3. EtOAc (600 mL) was added to the reaction
mixture, the organic phase was separated and the aqueous phase was
extracted with EtOAc (3 × 150 mL). The
combined organic phases were dried with anhydrous Na2SO4.
After filtration, the filtrate was concentrated in vacuo, the resulting
crude product 4 or 9 was used
directly in the next step of reaction without further purification.
A solution of NH2OH˙HCl (93.15 g, 1.35 mol) and
NaHCO3 (113.4 g, 1.35 mol) in H2O (150 mL)
was added to the solution of crude 4 or 9 in EtOH (600 mL) dropwise. The reaction
mixture was stirred at r.t. for 12 h and then stirred at
about 60 ˚C until TLC showed the reaction to have
reached completion. The solvents were removed in vacuo and the residue
was dissolved in EtOAc (300 mL) and H2O (200 mL). The
organic phase was separated and the aqueous phase was extracted
with EtOAc (3 × 150 mL). The
combined organic phases were dried with anhydrous Na2SO4.
After filtration and concentration in vacuo, the resulting crude
product was either recrystallized or purified by flash column chromatography
(petroleum ether-EtOAc, 2:1→1:2). Method
B: The same procedure as method A was used with purified compounds 1 and 6 as starting
material. Compound 5a: 129.0 g
(23% from 200 g d-arabinose);
79.4 g from 210.3 g 1a (38%).
Yellow oil; [α]
d
²0 -78
(c 1.08, CH2Cl2) {Lit¹8d [α]
d
²³ -75.9
(c 0.54, CH2Cl2)}.
IR (thin film): 3030 (w), 2866 (m), 1582 (s), 1496 (w), 1454 (s),
1363 (m), 1095 (s), 737 (s), 697 (s) cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 7.27-7.14
(m, 15 H, Ph), 6.73 (s, 1 H, H-2), 4.67 (t, J = 2.1 Hz,
1 H, H-3), 4.58-4.38 (m, 6 H, PhCH
2), 4.28 (dd, J = 7.6, 4.5
Hz, 1 H, H-4), 4.08-4.03 (m, 1 H, H-5),
3.90 (dd, J = 10.1,
4.3 Hz, 1 H, H-6), 3.73 (dd, J = 10.1,
1.6 Hz, 1 H, H-6). ¹³C NMR
(75 MHz, CDCl3): δ = 138.0,
137.4, 137.3, 133.4 (C-2), 128.7, 128.6, 128.4, 128.2, 128.1, 128.0,
127.9, 127.6 (Ph), 83.2 (C-3), 80.6 (C-4), 74.2 (C-5), 73.6, 73.2,
72.5, 64.5 (C-6). Compound 10a: 88.2 g
(42% from 75 g d-arabinose);
94 g from 181.6 g 6a (52%).
Light-yellow oil; [α]
d
²0 -44
(c 1.17, CHCl3). IR (thin
film): 2960 (s), 2925 (s), 2855 (s), 1597 (w), 1454 (m), 1260 (s),
1023 (s), 800 (s), 739 (m), 698 (m) cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 7.33-7.25
(m, 15 H, Ph), 7.01 (d, J = 2.9
Hz, 1 H, H-2), 4.94-4.58 (m, 6 H, PhCH2),
4.31 (d, J = 3.6
Hz, 1 H, H-3), 4.06-3.82 (m, 4 H, H-6,
H-4, H-5). ¹³C NMR (75 MHz,
CDCl3): δ = 137.6, 137.3, 128.6, 133.4
(C-2), 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8 (Ph), 74.6,
73.5, 72.9, 72.8, 72.1, 71.4 (C-3, C-4, C-5), 60.0 (C-6). TOF-HRMS
(ESI+): m/z [M + H]+ calcd for
C26H28NO4: 418.2013; found: 418.2001.