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DOI: 10.1055/s-0028-1088209
Expeditious Stereoselective Synthesis of l-Iminosugar Precursors via a Mitsunobu Reaction
Publikationsverlauf
Publikationsdatum:
16. März 2009 (online)
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Abstract
An efficient stereoselective synthesis of l-imino-C-gulosides is disclosed. Starting from the 2,3:4,6-di-O-isopropylidene-d-mannopyranose the synthetic pathway involves first a Wittig reaction with CMPP to introduce the carbon at the pseudo-anomeric position, followed by a Michael reaction under ultrasound activation to introduce the nitrogen center, and finally a Mitsunobu reaction for the ring closure leading to the C-iminosugar from the l-series.
Key words
carbohydrates - azasugars - stereoselective - Mitsunobu reaction - glycosidase
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References and Notes
Synthesis of Compound
2
To a solution of 2,3:4,6-Di-O-isopropylidene-d-manno-pyranose (1 equiv, 23 mmol, 6 g)
in anhyd benzene was added(cyanomethylene) triphenylphosphorane
(3 equiv, 69 mmol, 21 g). The mixture was stirred and refluxed under argon
atmosphere for 3 h. The reaction mixture was diluted with CH2Cl2 (200
mL) and washed twice with brine (50 mL). The organic layer was dried
over anhyd Na2SO4 for 30 min and concentrated
under vacuum to give pale yellowish oil. The crude was chromatographed
on SiO2 (PE-Et2O, 5:5) to afford
the two isomers (6.5 g, 70% for Z-isomer)
as colorless oils. R
f
= 0.16
(Z-isomer, major), 0.08 (E-isomer, minor; PE-Et2O,
5:5). ¹H NMR (400 MHz, acetone-d
6):
δ (Z-isomer) = 6.81 (dd, J
1-7 = 11.26
Hz, J
1-2 = 8.00
Hz, H1), 5.77 (dd, J
7-1 = 11.27
Hz, J
7-2 = 1.30
Hz, H7), 5.16 (dt,
J
2-1 = 7.85
Hz, J
2-3 = 7.80
Hz, J
2-7 = 1.27
Hz, H2), 4.72 (dd, J
3-2 = 7.48
Hz, J
3-4 = 1.45
Hz, H3), 4.29 (d, J
OH-5 = 6.01
Hz, -OH), 3.81-3.70 (m, H5, H6a),
3.58 (dd, J = 10.16,
9.07 Hz, H6a), 3.48 (dd, J
4-5 = 9.17
Hz, J
4-3 = 1.43
Hz, H4), 1.48, 1.41, 1.37, 1.31 (4 s, 12 H, H10,
H11, H13, H14). ¹³C
NMR (100 MHz, acetone-d
6): δ (Z-isomer) = 153.45 (C1),
117.16 (C8), 111.70 (C9), 102.34 (C7),
99.90 (C12), 77.87 (C2), 77.64 (C3), 74.44
(C4), 66.48 (C6), 63.94 (C5), 30.09,
27.90, 26.89, 19.96 (C10, C11, C13,
C14). MS (ESI+): m/z = 306.22 [M + Na]+.
Typical Procedure
for the Synthesis of Compounds 3-5
Compound 2 (1 equiv) was dissolved in dry amine
in excess. The mixture was placed in an ultrasound bath under an
argon atmosphere for 10 h. The unreacted amine was removed under
reduced pressure and the byproducts removed by flash chromatography
on SiO2 (PE-Et2O, 8:2) to afford compounds 3, 4, or 5 as colorless oils in 80% yield.
Compound 3: R
f
= 0.11
(PE-Et2O, 8:2). ¹H NMR (400
MHz, acetone-d
6): δ = 7.46-7.19
(m, 5 H, Hc, Hd, He), 4.48 (dd,
J
3-2 = 6.29
Hz, J
3-4 = 1.55
Hz, H3), 4.28 (dd, J
2-1 = 8.85
Hz, J
2-3 = 6.29
Hz, H2), 4.22 (d, J
OH-5 = 5.88
Hz, OH), ν0 = 3.82 (ABq,
2 H, νA = 4.03, νB = 3.87, Δν = 64.2
Hz, J
AB = 14.0 Hz,
Ha), 3.79-3.68 (m, H5, H6a),
3.63-3.50 (m, H6b), 3.61 (dd, J
4-5 = 8.93
Hz, J
4-3 = 1.57
Hz, H4), 3.33 (ddd, J
1-2 = 8.92 Hz, J
1-7b = 5.18
Hz, J
1-7a = 4.49
Hz, H1), 2.81 (dd, J
7a-7b = 17.39
Hz, J
7a-1 = 4.44
Hz, H7a) 2.58 (dd, J
7b-7a = 17.40 Hz, J
7b-1 = 5.29
Hz, H7b), 1.48, 1.33, 1.23, 1.20 (4 s, 12 H, H10, H11,
H13, H14). ¹³C
NMR (100 MHz, acetone-d
6): δ = 142.55 (Cb),
130.07 and 129.87 (2 C, Cc, Cd), 128.55 (Ce),
119.67 (C8), 110.31 (C9), 99.82 (C12),
80.65 (C2), 75.79 (C3), 74.44 (C4),
66.48 (C6), 63.92 (C5), 53.73 (C1),
52.16 (Ca), 29.98, 27.75, 27.20, 20.03 (4C, C10,
C11, C13, C14), 22.03 (C7).
MS (ESI+): m/z = 391.13 [M + H]+,
413.13 [M + Na]+.
MS (ESI-): m/z = 425.46 [M + Cl]-.
Compound 4: R
f
= 0.28
(Et2O). ¹H NMR (400 MHz, acetone-d
6): δ = 4.48
(dd, J
3-2 = 6.26
Hz, J
3-4 = 1.56
Hz, H3), 4.20 (dd, J
2-1 = 8.53
Hz, J
2-3 = 6.26
Hz, H2), 3.84-3.67 (m, H4, H5,
H6a), 3.64-3.56 (m, H6b), 3.28 (ddd, J
1-2 = 8.52
Hz, J
1-7b = 5.54
Hz, J
1-7a = 4.52
Hz, H1), 2.73 (dd, J
7a-7b = 17.31 Hz, J
7a-1 = 4.53
Hz, H7a), 2.55 (dd, J
7b-7a = 17.32
Hz, J
7b-1 = 5.54
Hz, H7b), 2.78-2.70 (m, H9a), 2.68-2.61
(m, H9b), 1.49-1.32 (m, H10, H11),
1.50, 1.48, 1.33, 1,32 (4 s, 12 H, H14, H15, H17,
H18), 0.91 (t, J
12-11a = 7.20, J
12-11b = 7.20
Hz, H12). ¹³C NMR (100 MHz,
acetone-d
6): δ = 119.83
(C8), 110.15 (C13), 99.91 (C16),
80.26 (C2), 75.83 (C3), 74.45 (C4),
66.57 (C6), 64.07 (C5), 55.36 (C1),
48.30 (C9), 34.09 (C10), 30.15, 27.75, 27.13,
20.45 (4 C, C14, C15, C17, C18),
21.95 (C11), 15.25 (C12). MS (ESI+): m/z = 357.31 [M + H]+,
379.33 [M + Na]+. MS
(ESI-): m/z = 355.36 [M - H]-,
391.28
[M + Cl]-.
Compound 5: R
f
= 0.08
(PE-Et2O, 9:1). ¹H NMR (400
MHz, acetone-d
6): δ = 5.90
(dddd, J
10-11
trans
= 17.29
Hz, J
10-11
cis
= 10.33 Hz, J = 6.15 Hz, J = 5.19 Hz,
H10), 5.25 (qd, J
11
trans
-10 = 17.29
Hz, J = 1.80,
1.80, 1.79 Hz, H11
trans
),
5.08 (ddd, J
11
cis
-10 = 10.34
Hz, J = 3.42
Hz, J = 1.48
Hz, H11
cis
), 4.48
(dd,
J
3-2 = 6.28
Hz, J = 1.57
Hz, H3), 4.24 (dd, J = 8.68
Hz, J
2-3 = 6.27
Hz, H2), 3.82-3.55 (m, 4 H, H4, H5,
H6a, H6b), 3.47-3.29 (m, 3 H, H1,
H9a, H9b), 2.75 (dd, J
7a-7b = 17.35
Hz, J = 4.49 Hz,
H7a), 2.55 (dd, J
7b-7a = 17.35
Hz, J = 5.41
Hz, H7b), 1.48, 1.32 (2 d, 12 H, H13, H14,
H16, H17). ¹³C
NMR (100 MHz, acetone-d
6): δ = 139.48
(C10), 119.76 (C8), 116.70 (C11), 110.26
(C12), 99.90 (C15), 80.52 (C2),
75.85 (C3), 74.52 (C4), 66.54 (C6),
63.96 (C5), 53.15 (C1), 51 (C9),
30.16, 27.74, 27.74, 20.34 (C13, C14, C15,
C17), 22.26 (C7). MS (ESI+):
m/z = 341.27 [M + H]+,
363.29 [M + Na]+.
Typical Procedure
for the Synthesis of Compounds 6-8
Compounds 3, 4, or 5 (1 equiv) and Ph3P (2 equiv)
were dissolved in a minimum amount of dry toluene. The mixture was
stirred under argon at r.t. DEAD (2 equiv, 2.56 mmol, 1.2 mL) was
added dropwise, and the mixture was stirred further 3 h. The crude
product was purified by chromatog-raphy on SiO2 (PE-Et2O,
7:3) to afford compounds 6, 7,
or 8 in 70% yield.
Compound 6: R
f
= 0.2
(PE-Et2O, 7:3); [α]D +5.86
(c 1, HCCl3, 25 ˚C). ¹H
NMR (400 MHz, acetone d
6
): δ = 7.42 (m,
2 H, Hc), 7.30 (m, 2 H, Hd), 7.23 (m, 1 H,
He), 4.43 (dd, J
3-4 = 2.5
Hz, J
3-2 = 8.0
Hz, H3), 4.25 (dd, J
4-3 = 2.7
Hz,
J
4-5 = 5.6
Hz, H4), 4.23 (dd, J
2-1 = 2.1
Hz, J
2-3 = 8.1
Hz, H2), ν0 = 3.99
(ABq, 2 H, νA = 4.13, νB = 3.85, Δν = 112.3
Hz, J
AB = 14.3
Hz, Ha), 3.85 (ddd, J
1-2 = 2.2
Hz, J
1-7b = 7.3
Hz, J
1-7a = 7.4
Hz, H1), 3.38 (dd, J
6a-5 = 6.1
Hz, J
6a-6b = 11.7
Hz, H6a), 3.33 (dd, J
6b-5 = 6.4
Hz, J
6b-5 = 11.8
Hz, H6b), 2.99 (dd, J
7a-1 = 7.7
Hz, J
7a-7b = 17.0
Hz, H7a), 3.00 (ddd, J
5-6a = 6.3 Hz, J
5-6b = 6.4
Hz, J
5-4 = 5.7
Hz, H5), 2.91 (dd, J
7b-1 = 7.2 Hz, J
7b-7a = 17.0
Hz, H7b), 1.61 (s, CH3), 1.38 (d, J = 0.4 Hz, CH3),
1.30 (s, CH3), 1.30 (s, CH3). ¹³C
NMR (100 MHz, acetone-d
6): δ = 143.17
(Cb), 130.49, 129.94 (C
ortho
/
meta
), 128.71 (C
para
), 120.32 (C8),
110.60 (C9), 101.23 (C12), 75.99 (C3),
73.64 (C4), 65.87 (C2), 63.77 (C6),
56.87 (Ca), 56.15 (C5), 53.49 (C1),
27.67, 27.25, 24.44, 22.68 (C10, C11, C13, C14),
19.81 (C7). MS (ESI+): m/z = 373.32 [M + H]+,
395.28 [M + Na]+,
411.18 [M + K]+,
767.57 [2 M + Na]+.
Compound 7: R
f
= 0.6
(PE-Et2O, 8:2); [α]D +6.52
(c 1, HCCl3, 25 ˚C). ¹H
NMR (400 MHz, acetone-d
6): δ = 4.38 (dd, J
3-4 = 26.0
Hz, J
3-2 = 8.0
Hz, H3), 4.26 (dd, J
4-3 = 2.6 Hz, J
4-5 = 5.6
Hz, H4), 4.15 (dd, J
2-1 = 2.2
Hz, J
2-3 = 8.0
Hz, H2), 3.78 (dd, J
6a-5 = 6.2
Hz, J
6a-6b = 11.7
Hz, H6a), 3.69 (ddd, J
1-2 = 2.2
Hz, J
1-7a = 7.7
Hz, J
1-7b = 8.4
Hz, H1), 3.56 (dd, J
6b-5 = 6.6
Hz, J
6b-6a = 11.7
Hz, H6b), 3.05 (q, J
5-4 =
J
5-6a = J
5-6b = 6.1
Hz, H5), 2.86-2.64 (m, 4 H, H7a,
H7b, H9a, H9b), (s, 3 H, CH3),
1.41-1.20 (m, 4 H, H10a, H10b, H11a,
H11b), 1.47, 1.36, 1.33, 1.30 (4 s, 12 H, H14,
H15, H17, H18). ¹³C NMR
(100 MHz, acetone-d
6): δ = 120.20
(C8), 110.46 (C13), 101.13 (C16),
75.97 (C3), 73.47 (C2), 65.69 (C4),
64.57 (C6), 57.07 (C5), 53.58 (C1),
52.66 (C9), 35.35 (C10), 27.60, 27.08, 24.47,
22.85 (C14, C15, C17, C18),
21.60 (C11), 19.81 (C7), 15.38 (C12).
MS (ESI+): m/z = 339.36 [M + H+],
361.26
[M + Na]+,
699.47 [2 M + Na]+.
Compound 8: R
f
= 0.28
(PE-Et2O, 8:2); [α]D +8.34
(c 1, HCCl3, 25 ˚C). ¹H
NMR (400 MHz, acetone-d
6): δ = 5.76 (dddd, J
10-11
trans
= 17.19
Hz, J
10-11
cis
= 10.07
Hz, J
10-9b = 7.99
Hz, J
10-9a = 4.40
Hz, H10), 5.15 (dtd, J
11
trans
-10 = 17.21 Hz, J = 2.03 Hz, J
11
trans
-11
cis
= 1.11
Hz, H11
trans
),
5.00 (dtd, J
10-11
cis
= 10.07
Hz, J = 1.88
Hz, J
11
cis
-9a = 1.87
Hz, J
11
cis
-11
trans
= 0.92
Hz, H11
cis
), 4.37
(dd, J
3-2 = 7.94
Hz, J
3-4 = 2.60 Hz,
H3), 4.25 (dd, J
4-5 = 5.27
Hz, J
4-3 = 2.60
Hz, H4), 4.17 (dd, J
2-3 = 7.95
Hz, J
2-1 = 2.12
Hz, H2), 3.78 (td, J = 8.17 Hz, J
1-2 = 1.94
Hz, J = 1.94
Hz, H1), 3.74 (dd, J
6a-6b = 11.82 Hz, J = 5.63 Hz,
H6a-6b), 3.60 (tdd, J
9a-9b = 14.88
Hz, J
9a-10 = 4.12
Hz, J
9a-11
cis
= 1.87
Hz, J = 1.87
Hz, H9a), 3.57 (dd,
J
6b-6a = 11.76
Hz, J = 5.85
Hz, H6a-6b), 3.26 (tdd, J
9b-9a = 14.88
Hz, J
9b-10 = 7.99
Hz, J = 1.04,
1.04 Hz, H9b), 2.99 (q, J
5-4 = 5.59
Hz, J
5-6a = 5.59
Hz, J
5-6b = 5.59
Hz, H5), 2.84 (d, J = 0.65
Hz, H7a), 2.82 (s, H7b), 1.50, 1.37, 1.34,
1.30 (4 d, 12 H, J = 0.58
Hz, H13, H14, H16, H17). ¹³C
NMR (100 MHz, acetone-d
6): δ = 140.93
(C10), 120.04 (C8), 116.88 (C11), 110.53
(C12), 101.04 (C15), 75.88 (C3),
73.75 (C2), 66.04 (C4), 64.51 (C6),
55.81 (C9), 55.67 (C5), 53.38 (C1),
28.07, 27.20, 24.50, 22.38 (C14, C13, C16,
C17), 19.77 (C7). MS (ESI+): m/z = 323.27 [M + H]+,
345.21 [M + Na]+,
361.20
[M + K]+.