M. Gensini et al.
MED
Final compounds 37a–o were synthesized according to GP 1 (see
above).
[Methoxy-(2H-pyran-4(4H,5H,6H)-ylidene)methoxy]trimethylsi-
lane (43): Methyl ester 42 (10.00 g, 69.44 mmol) was added to a
freshly prepared LDA solution (75.87 mmol, 28.1 mL of 2.7m solu-
tion of nBuLi in heptane and 76.27 mmol, 10.69 mL of iPr2NH) in
THF (65 mL) at 08C. The yellow mixture was stirred at 08C for
30 min, then TMSCl (22 mL, 0.17 mol) was added and the mixture
warmed to RT. After 30 min stirring, Et2O (150 mL) was added and
the solid was removed by filtration. The filtrate was concentrated
in vacuo and the residue treated with Et2O in order to precipitate
more lithium salts, which were again removed by filtration. Silyl
ketene acetal 43 was obtained as a yellow liquid (13.55 g, 90%):
1H NMR (200 MHz, CDCl3): d=3.61–3.55 (m, 4H), 3.49 (s, 3H), 2.23–
2.09 (m, 4H), 0.19 ppm (s, 9H).
Benzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-(tetrahy-
dropyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl}ethylcarba-
moyl)cyclopentyl]amide (37a): HPLC (B): tR =11.9 min, 97% purity;
1H NMR (600 MHz, [D6]DMSO): d=8.80 (s, 1H), 7.84 (d, J=8.6 Hz,
1H), 7.80 (d, J=7.7 Hz, 1H), 7.67 (dd, J=8.4, 0.8 Hz, 1H), 7.62 (d,
J=0.9 Hz, 1H), 7.51–7.47 (m, 2H), 7.38–7.34 (m, 1H), 7.20–7.11 (m,
5H), 4.45 (ddd, J=10.5, 8.6, 4.3 Hz, 1H), 3.82–3.78 (m, 2H), 3.28–
3.22 (m, 2H), 3.15 (dd, J=13.8, 4.3 Hz, 1H), 3.00–2.95 (m, 1H),
2.92–2.87 (m, 1H), 2.83 (dd, J=13.9, 10.5 Hz, 1H), 2.69–2.66 (m,
2H), 2.25 (dt, J=13.4, 8.1 Hz, 1H), 2.02–2.00 (m, 2H), 1.97–1.92 (m,
1H), 1.81–1.76 (m, 1H), 1.72–1.51 (m, 12H), 1.38–1.32 (m, 1H),
1.10–1.01 ppm (m, 4H); MS (ESI+): m/z: 615.3 [M+H]+.
4-Formyltetrahydro-2H-pyran-4-carboxylic acid methyl ester
(44): A solution of dry DMF (0.31 mol) in dry CH2Cl2 (40 mL) was
added to a solution of PCl5 (11.98 g, 77.80 mmol) in dry CH2Cl2
(22 mL) at 08C. The colorless solution was stirred for 30 min, then
43 (8.40 g, 38.89 mmol) was added. The reaction mixture was
stirred at RT for 20 h, then diluted with CH2Cl2 (100 mL). The organ-
ic phase was washed with saturated aq NaHCO3 (2ꢂ100 mL), H2O
(2ꢂ100 mL), brine (100 mL) and dried (Na2SO4). After removal of
the solvent, ester 44 was obtained as an orange oil (5.64 g, 84%):
7-Methylbenzo[b]furan-2-carboxylic acid [1-(2-phenyl-1(R)-{[1-
(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl}e-
thylcarbamoyl)cyclopentyl]amide (37b): Compound 37b was
synthesized from carboxylic acid 36i and purified by column chro-
matography (CH2Cl2/CH3OH, 10:1): HPLC (B): tR =13.2 min, 99%
1
purity; mp: 121–1248C; H NMR (600 MHz, [D6]DMSO): d=8.69 (s,
1H), 7.85 (d, J=8.6 Hz, 1H), 7.63 (s, 1H), 7.60 (d, J=7.7 Hz, 1H),
7.52 (brt, J=5.8 Hz, 1H), 7.30–7.22 (m, 2H), 7.20–7.11 (m, 5H), 4.46
(ddd, J=10.5, 8.7, 4.3 Hz, 1H), 3.81–3.78 (m, 2H), 3.27–3.21 (m,
2H), 3.17 (dd, J=13.9, 4.2 Hz, 1H), 3.01–2.97 (m, 1H), 2.92–2.87 (m,
1H), 2.84 (dd, J=13.9, 10.6 Hz, 1H), 2.69–2.61 (m, 2H), 2.55 (s, 3H),
2.27 (dt, J=13.3, 8.0 Hz, 1H), 2.00–1.98 (m, 2H), 1.96–1.90 (m, 1H),
1.80–1.75 (m, 1H), 1.70–1.43 (m, 12H), 1.38–1.31 (m, 1H), 1.09–
1.01 ppm (m, 4H); MS (ESI+): m/z: 629.4 [M+H]+; HRMS: m/z
[M+H]+ calcd for C37H49N4O5: 629.3703, found: 629.3719.
1
Rf =0.56 (EtOAc/hexane, 1:1); H NMR (200 MHz, CDCl3): d=9.50 (s,
1H), 3.73 (s, 3H), 3.64–3.59 (m, 4H), 2.15–1.89 ppm (m, 4H).
4-(Benzyloxymethyl)tetrahydro-2H-pyran-4-carboxylic acid (45):
NaBH4 (0.39 g, 9.21 mmol) was added portionwise to a solution of
44 (5.64 g, 32.79 mmol) in CH3OH (65 mL) and H2O (13 mL) at 08C.
After the addition was complete, the reaction mixture was stirred
at RT for 30 min. Then 1m aq HCl (4.8 mL) was added and CH3OH
removed in vacuo. The residue was diluted with CHCl3 (80 mL), the
phases were separated and the organic phase was washed with
H2O (20 mL), brine (20 mL) and dried (Na2SO4). Removal of the sol-
vent in vacuo gave a yellow oil (4.64 g, 81%): Rf =0.47 (EtOAc/
hexane 4:1). The residue was dissolved in THF (60 mL) and added
to a mixture of NaH (60% dispersion in silicone oil, 2.34 g,
58.50 mmol, pre-washed with pet ether) in THF (36 mL) at 08C. The
resulting mixture was stirred at RT for 30 min, then a solution of
benzyl bromide (4.48 g, 26.00 mmol) in THF (20 mL) was added
and the reaction mixture stirred at RT overnight. Et2O (100 mL) was
added and the solid filtered off. The filtrated was concentrated in
vacuo to give the correspondent benzyloxymethyl ester (7.10 g,
91%) as a yellow oil: Rf =0.78 (EtOAc/hexane 1:1). The latter was
treated with aq 1m NaOH and the resulting mixture was stirred at
RT for 1 d. The aqueous phase was extracted with EtOAc (55 mL),
then acidified to pH 1 using 37% aq HCl and extracted with EtOAc.
The combined organic fractions were dried (Na2SO4) and the sol-
vent was removed in vacuo to give carboxylic acid 45 (3.08 g,
46%) as a solid: HPLC (A): tR =3.1 min; Rf =0.64 (EtOAc/hexane
For characterization data of compounds 37c–o, see Supporting In-
formation.
1,6-Dioxaspiro[2.5]octane (39): NaH (2.19 g, 57.00 mmol, 60% dis-
persion in mineral oil pre-washed with pet ether) was added to a
suspension of trimethylsulfonoxonium iodide (12.62 g, 57.00 mmol)
in THF (95 mL). The reaction mixture was heated at reflux for 3 h,
then ketone 38 (4.90 g, 49.00 mmol) was added, and the mixture
was held at reflux for a further 2 h. The mixture was filtered and
the filtrate was concentrated in vacuo. The residue was redissolved
in CH2Cl2 (90 mL) and any solid material removed by filtration. The
filtrate was concentrated in vacuo to give the epoxide 39 as a
liquid (4.11 g, 73%): 1H NMR (200 MHz, CDCl3): d=3.79–3.71 (m,
4H), 2.61 (s, 2H), 1.85–1.71 (m, 2H), 1.50–1.34 ppm (m, 2H).
6-Methylbenzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1(R)-
{[1-(4-hydroxytetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl]-
carbamoyl}ethylcarbamoyl)cyclopentyl]amide (41): A mixture of
epoxide 39 (9.92 mmol), amine 40 (1.00 g, 1.83 mmol) and LiN-
(SO2CF3)2 (525 mg, 1.83 mmol) in CH3CN (50 mL) was stirred at RT
for 7 d. The reaction mixture was concentrated in vacuo and the
residue diluted with CH2Cl2 (50 mL). The organic phase was
washed with 5% aq NaHCO3 (5 mL) and dried (Na2SO4). After re-
moval of the solvent in vacuo, the residue was triturated with Et2O
and filtered off to give compound 41 (1.18 g, 98%) as a yellow
1
1:1); H NMR (200 MHz, CDCl3): d=7.37–7.24 (m, 5H), 4.49 (s, 2H),
3.82–3.68 (m, 2H), 3.55–3.38 (m, 2H), 3.47 (s, 2H), 2.12–2.05 (m,
2H), 1.64–1.51 ppm (m, 2H).
4-Methyltetrahydro-2H-pyran-4-carboxylic acid (46): Prepared in
the same way as compound 47 (see below): 1H NMR (200 MHz,
CDCl3): d=3.81 (dt, J=4.2, 11.9 Hz, 2H), 3.60–3.47 (m, 2H), 2.14–
2.04 (m, 2H), 1.52 (ddd, J=14.1, 10.0, 4.1 Hz, 2H), 1.29 ppm (s, 3H).
1
solid: HPLC (A): tR =3.6 min, 97% purity; mp: 101–1058C; H NMR
(600 MHz, [D6]DMSO): d=8.80 (s, 1H), 8.22 (s, 1H), 7.86–7.80 (m,
3H), 7.49 (brt, J=5.7 Hz, 1H), 7.28 (dd, J=8.2, 0.9 Hz, 1H), 7.20–
7.11 (m, 5H), 4.47–4.42 (m, 1H), 4.03 (s, 1H), 3.62–3.52 (m, 4H),
3.17 (dd, J=13.9, 4.1 Hz, 1H), 2.98–2.78 (m, 5H), 2.45 (s, 3H), 2.22
(dt, J=13.7, 8.2 Hz, 1H), 2.16 (s, 2H), 2.05–1.98 (m, 2H), 1.92–1.88
(m, 1H), 1.80–1.75 (m, 1H), 1.70–1.44 (m, 9H), 1.39–1.27 (m, 3H),
1.14–1.07 ppm (m, 2H); MS (ESI+): m/z: 661.4 [M+H]+; HRMS: m/z
[M+H]+ calcd for C37H49N4O5S: 661.3424, found: 661.3423.
4-Methoxymethyltetrahydro-2H-pyran-4-carboxylic acid (47):
Methyl ester 42 (5.00 g, 34.72 mmol) was added to a freshly pre-
pared LDA solution (23.6 mL of 2.7m solution of nBuLi in heptane
and 5.35 mL of iPr2NH) in THF (35 mL) at 08C. The reaction mixture
was stirred at the same temperature for 30 min, then bromomethyl
methyl ether (7.72 g, 59.00 mmol) was added and the resulting
74
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ChemMedChem 2010, 5, 65 – 78