2411
C. G. Neochoritis et al.
Special Topic
Synthesis
concentrated in vacuo. Flash chromatography (silica gel, CH2Cl2) af-
forded 8 as a yellow solid; yield: 696 mg (65%); Rf = 0.72 (EtOAc–PE,
1:1).
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{5-[(phenethylamino)(p-
tolyl)methyl]-1H-tetrazol-1-yl}tetrahydro-2H-pyran-3,4,5-triyl
Triacetate (11)
1H NMR (500 MHz, CDCl3): δ (β-anomer) = 5.20–5.10 (m, 3 H), 4.83 (d,
J = 5 Hz, 1 H), 4.26 (dd, J = 10, 5 Hz, 1 H), 4.15 (dd, J = 10, 5 Hz, 1 H),
3.74 (ddd, J = 10, 5, 2 Hz, 1 H), 2.12 (s, 3 H), 2.12 (s, 3 H), 2.04 (s, 3 H),
2.02 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 170.5, 170.0, 169.1, 168.9, 164.8 (br s,
NC), 100.0, 79.4, 74.7, 72.1, 71.1, 67.3, 61.3, 20.7, 20.5, 20.4.
To a solution of phenylethylamine (0.5 mmol) in MeOH (1 mL), 4-
methylbenzaldehyde (0.5 mmol), isocyanide 8 (0.5 mmol), and
TMSN3 (0.5 mmol) were added. The mixture was stirred at r.t. for 24
h. Alternatively (with no significant effect on the yield), a solution of
phenylethylamine (0.5 mmol), 4-methylbenzaldehyde (0.5 mmol),
isocyanide 6 (0.5 mmol), and TMSN3 (0.5 mmol) in MeOH (1 mL) was
irradiated in a microwave oven at 100 °C for 30 min. The solvent was
evaporated and the residue was purified by flash chromatography
(silica gel, PE–EtOAc, 1:2) to afford 11 as a yellow oil; yield: 193 mg
(62%); Rf = 0.25 (EtOAc–PE, 1:1); mixture of diastereomers (dr 1:0.8).
1H NMR (500 MHz, CDCl3): δ = 7.34–7.31 (m, 3 H), 7.25–7.17 (m, 9 H),
7.16 (br s, 4 H), 6.08 (d, J = 10 Hz, 1 H), 6.03 (d, J = 10 Hz, 1 H), 5.90 (t,
J = 10 Hz, 1 H), 5.43 (s, 1 H), 5.36 (s, 1 H), 5.29–5.16 (m, 4 H), 4.17–
4.10 (m, 3 H), 3.96 (dd, J = 15, 0.5 Hz, 1 H), 3.79 (dd, J = 10, 0.5 Hz, 1
H), 3.58 (dt, J = 10, 10 Hz, 1 H), 3.57–3.56 (m, 1 H), 2.91–2.82 (m, 7 H),
2.34 (s, 3 H), 2.33 (s, 3 H), 2.11 (s, 3 H), 2.10 (s, 3 H), 2.03 (s, 3 H), 2.02
(s, 3 H), 2.00 (s, 3 H).
(2S,3S,4R,5R)-2-Isocyanotetrahydro-2H-pyran-3,4,5-triyl Triace-
tate (9a) and (2R,3S,4R,5R)-2-Isocyanotetrahydro-2H-pyran-3,4,5-
triyl Triacetate (9b)
Following the typical procedure for 8 using 7 gave 9 as a yellow solid;
yield: 616 mg (72%); Rf = 0.75 (EtOAc–PE, 1:1); mixture of anomers
(α/β, 1:2). Purification by column chromatography afforded anomers
9a and 9b.
α-Anomer 9a
Yellow solid; yield: 205 mg (24%); Rf = 0.75.
13C NMR (126 MHz, CDCl3): δ = 170.52, 170.5, 169.2, 168.3, 156.9,
139.4, 138.8, 134.6, 129.9 (2 CHPh), 128.8 (4 CHAr), 127.0 (2 CHPh),
126.7, 83.0, 74.8, 73.4, 69.6, 67.5, 61.2, 57.9, 48.8, 36.2, 21.2, 20.8,
20.7, 20.3, 20.1.
1H NMR (500 MHz, CDCl3): δ = 5.58 (d, J = 5 Hz, 1 H), 5.41 (br s, 1 H),
5.30 (dd, J = 10, 5 Hz, 1 H), 5.19 (dd, J = 5, 0.5 Hz, 1 H), 4.11 (d, J = 15
Hz, 1 H), 3.96 (dd, J = 10, 5 Hz, 1 H), 2.16 (s, 3 H), 2.15 (s, 3 H), 2.04 (s,
3 H).
MS (ESI): m/z [M + H]+ calcd for C31H37N5O9: 624.26; found: 624.17.
13C NMR (126 MHz, CDCl3): δ = 170.1, 170.0, 169.7, 164.6 (br s, NC),
79.8, 67.2, 66.7, 66.0, 63.4, 20.8, 20.6, 20.6.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[2-(4-bromophenyl)-2-(2-
oxoazetidin-1-yl)acetamido]tetrahydro-2H-pyran-3,4,5-triyl Tri-
acetate (12)
β-Anomer 9b
Yellow solid; yield: 410 mg (48%); Rf = 0.75.
A solution of 4-bromobenzaldehyde (0.5 mmol), β-alanine (0.5
mmol), and the isocyanide 8 (0.5 mmol) in MeOH (1 mL) was irradiat-
ed in a microwave oven at 100 °C for 30 min. The solvent was evapo-
rated and the residue was purified by flash chromatography (silica
gel, PE–EtOAc, 1:2) to afford 12 as a yellow oil; yield: 202 mg (66%);
Rf = 0.10 (EtOAc–PE, 1:1); mixture of diastereomers (dr 1:1).
1H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 10 Hz, 2 H), 7.18 (d, J = 10
Hz, 2 H), 5.35–5.23 (m, 3 H), 5.06–5.03 (m, 2 H), 4.92–4.83 (m, 1 H),
4.35–4.27 (m, 2 H), 4.11–4.07 (m, 2 H), 3.83–3.79 (m, 2 H), 3.59–3.57
(m, 1 H), 3.49–3.48 (m, 1 H), 3.13–3.01 (m, 2 H), 2.90–2.88 (m, 1 H),
2.04 (m, 3 H), 2.03 (m, 3 H), 2.01 (m, 3 H), 2.00 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 170.9, 170.4, 169.3, 168.0, 153.2,
132.7, 132.6, 130.4, 130.2, 100.3, 78.9, 74.0, 72.8, 72.6, 70.4, 68.3,
61.7, 59.0, 39.3, 38.9, 36.7, 36.6, 20.9, 20.8, 20.7.
MS (ESI): m/z [M + Na]+ calcd for C25H29BrN2O11: 635.10; found:
635.01.
1H NMR (500 MHz, CDCl3): δ = 5.27–5.24 (m, 1 H), 5.23–5.22 (m, 1 H),
5.16 (dd, J = 10, 5 Hz, 1 H), 4.94 (d, J = 5 Hz, 1 H), 4.12 (dd, J = 10, 5 Hz,
1 H), 3.78 (dd, J = 5, 0.5 Hz, 1 H), 2.15 (s, 3 H), 2.13 (s, 3 H), 2.12 (s, 3
H).
13C NMR (126 MHz, CDCl3): δ = 170.1, 169.9, 169.2, 164.2 (br s, NC),
78.7, 69.0, 38.1, 65.6, 62.3, 21.0, 20.9, 20.8.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{[2-(N-(4-methoxyben-
zyl)formamido]-2-(p-tolyl)acetamido}tetrahydro-2H-pyran-3,4,5-
triyl Triacetate (10)
To a solution of 4-methoxybenzylamine (0.2 mmol) in MeOH (1 mL),
4-methylbenzaldehyde (0.2 mmol), isocyanide 8 (0.2 mmol), and for-
mic acid (0.2 mmol) were added. The mixture was stirred at r.t. for 24
h. The solvent was evaporated and the residue was purified by flash
chromatography (silica gel, PE–EtOAc, 1:2) to afford 10 as a yellow oil;
yield: 58 mg (45%); Rf = 0.20 (EtOAc–PE, 1:1); mixture of rotamers
and mixture of diastereomers (dr 2:1).
1H NMR (500 MHz, CDCl3): δ = 8.29 (s, 1 H), 8.26 (s, 1 H), 7.13–7.09
(m, 5 H), 7.03 (d, J = 10 Hz, 1 H), 6.96 (d, J = 10 Hz, 1 H), 6.86–6.85 (m,
1 H), 6.79 (t, J = 10 Hz, 1 H), 6.41–6.36 (m, 1 H), 5.33–5.22 (m, 3 H),
5.04–4.99 (m, 1 H), 4.88–4.76 (m, 1 H), 4.50–4.43 (m, 1 H), 4.36–4.27
(m, 1 H), 4.21–4.05 (m, 2 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 2.35 (s, 3 H),
2.33 (s, 3 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H).
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[1-(benzoyloxy)cyclohex-
anecarboxamido]tetrahydro-2H-pyran-3,4,5-triyl Triacetate (13)
To a solution of cyclohexanone (0.5 mmol) in CH2Cl2 (1 mL), benzoic
acid (0.5 mmol), and isocyanide 8 (0.5 mmol) were added. The mix-
ture was stirred at r.t. for 24 h. The solvent was evaporated and the
residue was purified by flash chromatography (silica gel, PE–EtOAc,
1:2) to afford 13 as a white solid; yield: 136 mg (47%); Rf = 0.39
(EtOAc–PE, 1:1).
13C NMR (126 MHz, CDCl3): δ = 171.7, 170.9, 170.1, 169.7, 163.7,
163.5, 130.2, 130.0, 129.7, 129.4, 129.4, 128.7, 114.4, 114.3, 78.9, 78.5,
73.7, 72.9, 70.4, 72.9, 70.4, 70.1, 68.5, 68.4, 61.9, 61.8, 61.1, 55.5, 49.9,
21.4, 20.9, 20.8.
1H NMR (500 MHz, CDCl3): δ = 8.04 (d, J = 5 Hz, 1 H), 7.64–7.59 (m, 1
H), 7.51–7.46 (m, 2 H), 6.66 (d, J = 10 Hz, 1 H), 5.32–5.27 (m, 1 H),
5.06–4.98 (m, 1 H), 4.89–4.85 (t, J = 10 Hz, 1 H), 4.33 (dd, J = 10, 0.5
MS (ESI): m/z [M + Na]+ calcd for C32H38N2O12: 665.24; found: 665.14.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2407–2413