L
I. Strassnig et al.
Paper
Synthesis
added. The mixture was stirred under argon at r.t. for 22 h, and then
the suspension was filtered through Hyflo® and the solvent was
evaporated in vacuo. The syrupy crude product 10S was directly used
for the subsequent reaction.
(2S)-2-[(R)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)-2,3-dihydropyridine-4(1H)-one (12) and (2R)-2-[(R)-2-
{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)butyl]ami-
no}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl)-2,3-di-
hydropyridine-4(1H)-one (13)
(2S)-2-[(S)-2-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsil-
oxy)butyl]amino}heptyl]-1-(2,3,4-tri-O-pivaloyl-α-D-arabinopyra-
nosyl)-2,3-dihydropyridine-4(1H)-one (11); Typical Procedure
Following the typical procedure for 11 using imine 10R (5.3 mmol),
Danishefsky diene 2 (1.14 g, 6.4 mmol), 1 M ZnCl2 in THF (11.6 mL,
11.6 mmol), and anhyd THF (27 mL) gave a pale yellow, viscous oil;
yield: 3.23 g (58%, 2 steps); dr 67:33:0:0 [HPLC (gradient: 95% MeCN,
5% H2O to 100% MeCN, 15 min, then 30 min 100% MeCN): tR = 31.37
(minor diastereomer), 33.22 min (major diastereomer)]; Rf = 0.37 (cy-
clohexane–EtOAc, 2:1).
To the crude imine 10S (5.2 mmol) dissolved in anhyd THF (26 mL)
was added, under stirring at –78 °C, 1 M ZnCl2 in THF (11.4 mL, 11.4
mmol) and the mixture was stirred for 10 min. Danishefsky diene16
2
(1.1 g, 6.4 mmol) was added dropwise and the mixture was stirred for
a further 30 min at –78 °C and then 48 h at –20 °C. The reaction was
stopped by addition of 1 M aq HCl (5.2 mL). The mixture was concen-
trated in vacuo and the remainder taken up in Et2O (100 mL). The or-
ganic layer was separated and then washed with sat. NaHCO3 solution
(3 × 30 mL) and 10% Titriplex® solution (2 × 30 mL) to eliminate zinc
compounds. After additional washing with brine (50 mL), the solu-
tion was dried (MgSO4) and the solvent was evaporated in vacuo to
give an orange syrupy crude product (6.4 g) that was purified by flash
chromatography (cyclohexane–EtOAc, 4:1) to give a yellow amor-
phous solid; yield: 3.18 g (3.06 mmol, 59%, 2 steps); dr 98:1:1:0
[HPLC (gradient: 95% MeCN, 5% H2O to 100% MeCN (15 min), then 30
min 100% MeCN): tR = 30.52 (major diastereomer), 34.48 and 37.67
min (minor diastereomers)]; Rf = 0.35 cyclohexane–EtOAc, (2:1);
[α]D23 +80.6 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3, COSY): δ = 7.68–7.59 (m, 4 H, HAr, SiPh2),
7.46–7.26 (m, 11 H, HAr, SiPh2 and Bn), 6.89R, 6.78 (d, JH6,H5 = 7.9 Hz, 1
H, H6), 5.44R, 5.39 (t, JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H, H2′), 5.31–5.24 (m, 1
H, H4′), 5.21–5.02 (m, 3 H, PhCH2, H3′), 4.97R, 4.93 (d, JH5,H6 = 7.5 Hz, 1
H, H5), 4.40R, 4.28 (d, JH1′,H2′ = 9.0 Hz, 1 H, H1′), 4.16–4.03, 4.03–3.92R
(m, 1 H, H2′′), 3.85 (dd, JH5′a,H5′b = 13.3 Hz, 1 H, H5′a), 3.71–3.50 (m, 4
H, H5′b, H2, CH2OSi), 3.26–3.08 (m, 1 H, N′CHaCHb), 3.06–2.89 (m, 1 H,
N′CHaCHb), 2.69R, 2.58 (dd, JH3a,H3b = 16.8 Hz, JH3a,H2 = 5.9 Hz, 1 H, H3a),
2.46R, 2.30 (d, JH3b,H3a = 16.4 Hz, 1 H, H3b), 2.17–2.02, 2.01–1.87R (m, 2
H, H1′′a, H1′′b), 1.85–1.17 (m, 10 H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2,
5′′-CH2), 1.28–1.10 (m, 2 H, CH3CH2), 1.26R, 1.19, 1.13, 1.11 [s, each 9
H, Piv-C(CH3)3], 1.03 [s, 9 H, SiC(CH3)3], 0.90–0.76 (m, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, DEPT, HMQC): δ = 192.00 (C4), 177.39,
177.28, 177.00 (Piv-C=O), 156.35, 156.25R (Cbz-C=O), 148.60, 148.38R
(C6), 137.06, 136.85R (C1′Ar, Bn), 135.65, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 134.01, 133.95R (C1Ar, SiPh2), 129.75 (C4Ar, SiPh2), 128.69,
128.60R, 128.31R, 128.22 (C2′Αρ, C3′Ar, C5′Ar, C6′Ar, Bn), 128.00 (C4′Ar,
Bn), 100.01R, 99.73 (C5), 91.40, 90.86R (C1′), 71.41R, 71.22 (C3′),
67.88R, 67.67 (C4′), 67.21, 67.01R (PhCH2), 66.98, 66.84R (C5′), 66.73,
66.47R (C2′), 63.74, 63.63R (CH2OSi), 54.53, 54.41R (C2′′), 51.30R, 50.34
(C2), 42.31 (C1′′′), 39.58 (C3), 39.04, 38.99, 38.93 [Piv-C(CH3)3], 33.96R,
33.87 (C1′′), 34.40, 31.92R, 31.81, 30.69, 30.53R, 26.38, 25.82 (C3′′, C4′′,
C5′′, C2′′′, C3′′′), 27.32, 27.22 [Piv-C(CH3)3], 26.97 [SiC(CH3)3], 22.68
(CH3CH2), 19.31 [SiC(CH3)3], 14.15 (CH3CH2).
Major Diastereomer 12
1H NMR (400 MHz, CDCl3, COSY): δ = 7.69–7.59 (m, 4 H, HAr, SiPh2),
7.46–7.27 (m, 11 H, HAr, SiPh2 and Bn), 6.92R, 6.85 (d, JH6,H5 = 7.6 Hz, 1
H, H6), 5.53R, 5.49 (t, JH2′,H1′ = JH2′,H3′ = 9.6 Hz, 1 H, H2′), 5.28–5.06 (m, 3
H, H4′, PhCH2), 5.13 (dd, JH3′,H2′ = 9.9 Hz, JH3′,H4′ = 2.9 Hz, 1 H, H3′),
5.04R, 4.99 (d, JH5,H6 = 7.7 Hz, 1 H, H5), 4.69R, 4.39 (d, JH1′,H2′ = 9.2 Hz, 1
H, H1′), 3.83, 3.72R (d, JH5′a,H5′b = 13.1 Hz, 1 H, H5′a), 3.67–3.47 (m, 3 H,
H2, CH2OSi), 3.37–3.26 (m, 1 H, H2′′), 3.52, 3.16R (d, JH5′b,H5′a = 13.1 Hz,
1 H, H5′b), 3.10–2.91 (m, 2 H, N′CH2), 2.76R, 2.66 (dd, JH3a,H3b = 16.3 Hz,
JH3a,H2 = 6.4 Hz, 1 H, H3a), 2.34–1.84 (m, 3 H, H3b, 1′′-CH2), 1.76–1.39,
1.25–1.17 (m, 12 H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2),
1.27, 1.14, 1.12 [s, each 9 H, Piv-C(CH3)3], 1.03 [s, 9 H, SiC(CH3)3], 0.85
(t, J7′′-CH3,6′′-CH2 = 6.6 Hz, 3 H, CH3CH2).
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 191.76R, 191.40 (C4), 177.42,
177.29, 177.19 (Piv-C=O), 157.01R, 156.35 (Cbz-C=O), 149.11, 147.27R
(C6), 137.26R, 137.07 (C1′Ar, Bn), 135.67, 127.78 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 134.04, 133.95R (C1Ar, SiPh2), 129.76 (C4Ar, SiPh2), 128.76,
128.67R, 128.41, 128.06R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 127.96 (C4′Ar,
Bn), 100.48R, 100.29 (C5), 92.17, 90.84R (C1′), 71.74R, 71.19 (C3′),
68.30R, 67.85 (C4′), 67.35, 67.18R (PhCH2), 66.34R, 66.18 (C5′), 65.61
(C2′), 63.80, 63.72R (CH2OSi), 54.07 (C2′′), 52.72R, 51.63 (C2), 42.80
(C1′′′), 40.66 (C3), 39.09, 39.02, 38.93 [Piv-C(CH3)3], 35.08, 34.88R
(C1′′), 33.92, 33.84R, 32.80, 31.93R, 31.85, 30.52, 26.11 (C3′′, C4′′, C5′′,
C2′′′, C3′′′), 27.35, 27.23 [Piv-C(CH3)3], 26.99 [SiC(CH3)3], 22.72R, 22.64
(CH3CH2), 19.32 [SiC(CH3)3], 14.16 (CH3CH2).
Minor Diastereomer 13
1H NMR (400 MHz, CDCl3, COSY): δ = 7.71–7.58 (m, 4 H, HAr, SiPh2),
7.47–7.28 (m, 11 H, HAr, SiPh2 and Bn), 7.16R, 7.12 (d, JH6,H5 = 7.9 Hz, 1
H, H6), 5.33 (t, JH2′,H1′ = JH2′,H3′ = 9.7 Hz, 1 H, H2′), 5.24–5.07 (m, 4 H, H5,
H4′, PhCH2), 5.06–4.97 (m, 1 H, H3′), 4.00 (d, JH1′,H2′ = 9.2 Hz, 1 H, H1′),
3.86 (d, JH5′a,H5′b = 13.4 Hz, 1 H, H5′a), 3.70–3.59 (m, 2 H, CH2OSi), 3.59–
3.50 (m, 1 H, H2′′), 3.42 (d, JH5′b,H5′a = 13.3 Hz, 1 H, H5′b), 3.38–3.24 (m,
1 H, H2), 3.21–3.09 (m, 1 H, N′CHaCHb), 3.09–2.95 (m, 1 H, N′CHaCHb),
2.64R, 2.56 (dd, JH3a,H3b = 16.3 Hz, JH3a,H2 = 5.7 Hz, 1 H, H3a), 2.48–2.34
(m, 1 H, H3b), 2.10–1.98 (m, 2 H, 1′′-CH2), 1.76–1.36, 1.24–1.16 (m, 12
H, 2′′′-CH2, 3′′′-CH2, 3′′-CH2, 4′′-CH2, 5′′-CH2, 6′′-CH2), 1.27, 1.13, 1.12
[s, each 9 H, Piv-C(CH3)3], 1.04 [s, 9 H, SiC(CH3)3], 0.89–0.77 (m, 3 H,
CH3CH2).
MS (ESI): m/z = 1039.6 [M + H]+, 1061.6 [M + Na]+, 2079.3 [2 M + H]+,
2101.2 [2 M + Na]+.
HRMS: m/z [M + Na] calcd for C60H86N2O11SiNa: 1061.5899; found:
1061.5897.
13C NMR (100.6 MHz, CDCl3, HMQC): δ = 191.32 (C4), 177.31, 177.25,
176.60 (Piv-C=O), 156.20R, 156.13 (Cbz-C=O), 147.54R, 147.47 (C6),
137.22R, 137.17 (C1′Ar, Bn), 135.66, 127.82 (C2Ar, C3Ar, C5Ar, C6Ar,
SiPh2), 133.97, 133.87R (C1Ar, SiPh2), 129.81 (C4Ar, SiPh2), 128.77R,
128.66, 128.58, 128.49R (C2′Ar, C3′Ar, C5′Ar, C6′Ar, Bn), 128.41, 128.35R
(C4′Ar, Bn), 101.29, 101.20R (C5), 91.13, 90.87R (C1′), 71.28, 71.15R
(C3′), 67.97R, 67.92 (C4′), 67.41R, 67.33 (C2′), 67.04, 66.96R (PhCH2),
66.46R, 66.39 (C5′), 63.71, 63.62R (CH2OSi), 58.99R, 58.92 (C2), 55.77
2-N-[(R)-3-{(Benzyloxycarbonyl)[4-(tert-butyldiphenylsiloxy)but-
yl]amino}octylidene]-2,3,4-tri-O-pivaloyl-α-D-arabinopyranosyl-
amine (10R)
Following the typical procedure for 10S using 3 (2.13 g, 5.3 mmol), 9R
(3.74 g, 6.36 mmol), n-pentane (65 mL), and molecular sieves (4.5 g).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–R