4290 J. Am. Chem. Soc., Vol. 119, No. 18, 1997
Conroy et al.
Reactions were conducted under an atmosphere of dry nitrogen in
oven-dried glassware. Anhydrous procedures were conducted using
standard syringe and cannula transfer techniques. THF and toluene
were distilled from sodium and benzophenone. Methylene chloride
was distilled from CaH2. Other solvents were of reagent grade and
were stored over 4 Å molecular sieves. All other reagents were used
as received. Organic solutions were dried with MgSO4 unless otherwise
noted. Solvent removal was performed by rotary evaporation at water
aspirator pressure.
(dd, J ) 3.4, 12.2 Hz, 1H), 4.12 (dd, J ) 3.4, 11.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 38.5, 39.2, 40.3, 54.2, 65.5, 67.8, 69.2; HRMS-
EI (M+) calcd for C8H12O3S2 220.0228, found 220.0224.
Tetrahydropyranone Carbamate 18. A solution of 14 (0.22 g,
1.0 mmol), N,N-diisopropylethylamine (DIEA, 1.9 g, 1.50 mmol), and
diphenylphosphoryl azide (DPPA, 0.28 g, 1.0 mmol) in benzene (10
mL) was refluxed overnight. Aliquots of the reaction mixture were
monitored for disappearance of the acyl azide peak at 2168 cm-1 and
appearance of the isocyanate peak at 2245 cm-1 by FT-IR. After the
Curtius rearrangement was judged complete by IR, the solution was
cooled in an ice bath and slowly added to an ice-cold solution of
potassium tert-butoxide (0.34 g, 3.0 mmol) in THF (10 mL). The
reaction was stirred for 15 min and then partitioned between 15 mL of
1 N HCl and 15 mL of EtOAc. The organic layer was separated and
washed with 1 N NaOH and brine (15 mL). The solution was dried,
filtered, and concentrated, and the crude material was purified by flash
chromatography (1:4 EtOAc/hexanes) to yield 18 (0.19 g, 65%) as a
white solid: 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 2.21 (t, J )
4.5 Hz, 2H), 3.26-3.35 (m, 4H), 3.61-3.64 (m, 1H), 3.79-3.82 (m,
1H), 3.89-3.99 (m, 2H), 5.04 (brd, J ) 7.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 27.5, 37.7, 37.9, 40.9, 54.2, 66.1, 70.0, 78.1, 154.4;
HRMS-EI (M+) calcd for C12H21NO3S2 291.0963, found 291.0959.
Experimental details of the synthesis of inhibitors 30, 31, and 34
are available in the Supporting Information.
Di-n-propyl 4-Oxa-1,7-heptanedioate 2. A solution of 3,3′-
oxydipropionitrile (18.9 g, 152 mmol) and p-toluenesulfonic acid (p-
TsOH) monohydrate (115.8 g, 608 mmol) in n-propanol (200 mL) was
refluxed for 24 h. The solution was cooled and concentrated to
approximately 150 mL. The resulting solution was partitioned between
350 mL of water and 350 mL of hexanes. The organic layer was
separated and washed with saturated NaHCO3 (200 mL), water (300
mL), and brine (150 mL). The solution was dried, filtered, and
concentrated, and the crude material was purified by flash chromatog-
raphy (1:3 EtOAc/hexanes) to yield 2 (21.2 g, 57%) as a colorless liquid.
The product can also be purified by vacuum distillation (bp 158 °C, 6
mm) in somewhat lower yields (45%): Rf 0.66 (1:1 EtOAc/hexanes);
1H NMR (400 MHz, CDCl3) δ 0.94 (t, J ) 7.4 Hz, 3H), 1.66 (dt, J )
7.0, 7.1 Hz, 2H), 2.57 (t, J ) 6.1 Hz, 2H), 3.73 (t, J ) 6.4 Hz, 2H),
4.04 (t, J ) 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 10.3, 21.9,
35.0, 66.1, 66.4, 171.5; HRMS-FAB calcd for C12H22O5 246.1467,
found 246.1467.
n-Propyl Tetrahydropyran-4-one-3-carboxylate 5. To a solution
of diispropylamine (4.65 g, 45.9 mmol) in THF (50 mL) at -78 °C
was added n-butyllithium (4.38 mL of 10.0 M in hexanes). This
solution was added via cannula to a solution of 2 (5.14 g, 20.9 mmol)
in THF (300 mL) at -78 °C. The solution was stirred at -78 °C for
15 min, and then the reaction was quenched by the addition of 25 mL
of H2O. The solution was partitioned between 200 mL of 1 N HCl
and 200 mL of hexanes. The resulting aqueous layer was extracted
with EtOAc (150 mL), and the combined organic layers were washed
with brine (300 mL). The solution was dried, filtered, and concentrated,
and the crude material purified by flash chromatography (1:4 Et2O/
hexanes) to yield 5 (1.19 g, 31%) as a mixture of keto and enol
tautomers: Rf ) 0.54 (1:1 Et2O/hexanes); 1H NMR (400 MHz, CDCl3)
δ 0.95 (t, J ) 6.3 Hz, 3H), 1.27-1.31 (m), 1.61-1.75 (m, 2H), 2.37-
2.41 (m, 3H), 2.52-2.59 (m), 2.66-2.73 (m), 3.46-3.50 (m), 3.71-
3.75 (m), 3.85 (t, J ) 5.7 Hz, 2H), 3.98-4.10 (m), 4.12 (t, J ) 6.6 Hz,
2H), 4.16-4.25 (m), 4.28 (t, J ) 1.7 Hz, 2H), 11.85 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 10.2, 21.9, 28.6, 41.8, 57.8, 63.9, 65.8, 66.3,
67.0, 68.1, 69.6, 97.4, 127.8, 129.7, 168.7, 170.1, 201.4; HRMS-EI
(M+) calcd for C9H14O4 186.0892, found 186.0894.
Tetrahydropyranone Thioketal 10. To a solution of 5 (1.26 g,
6.8 mmol) and 1,2-ethanedithiol (1.28 g, 13.6 mmol) in CH2Cl2 (20
mL) cooled in an ice bath was added BF3‚Et2O (1.04 mL, 8.5 mmol).
The solution was stirred at 0 °C for 4 h, and then it was washed with
10% aqueous NaOH solution, water, and brine (20 mL). The organic
layer was dried, and concentrated, and the crude material was purified
by flash chromatography (2:3 EtOAc/hexanes) to yield 10 (0.77 g, 43%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J ) 7.4 Hz,
3H), 1.63-1.73 (m, 2H), 1.93 (dm, J ) 13.7 Hz, 1H), 2.84-2.88 (m,
1H), 2.91-2.92 (m, 1H), 3.24-3.32 (m, 4H), 3.64-3.69 (m, 1H), 3.90-
3.93 (m, 2H), 4.08-4.14 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
10.4, 21.9, 38.3, 39.1, 40.0, 54.8, 65.7, 66.5, 67.8, 69.5, 171.0; HRMS-
EI (M+) calcd for C11H18O3S2 262.0697, found 262.0707.
Tetrahydropyranone Carboxylic Acid 14. To a solution of 10
(0.41 g, 1.58 mmol) in MeOH (10 mL) was added 1 N NaOH (10
mL). The solution was stirred at 30 °C for 50 h. The solution was
then cooled and diluted with 0.2 N NaOH (10 mL). The solution was
washed with 1:1 EtOAc/hexanes (10 mL), and the aqueous layer was
separated and acidified with 1 N HCl. The acidic aqueous solution
was extracted with EtOAc (2 × 40 mL). These organic extracts were
washed with brine (50 mL), dried, and concentrated. The resulting
solid was recrystallized from EtOAc/hexanes to yield 14 (0.22 g, 68%)
as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.98 (d, J ) 13.8 Hz,
1H), 2.76 (m, 1H), 2.99 (t, J ) 3.3 Hz, 1H), 3.29-3.35 (m, 4H), 3.68-
3.74 (m, 1H), 3.88 (t, J ) 4.3 Hz, 1H), 3.93 (t, J ) 4.2 Hz, 1H), 3.99
Aminotetrahydropyranone‚Trifluoroacetic Acid Salt 21. Tri-
fluoroacetic acid (TFA, 3.0 mL) was added to a solution of 18 (0.18 g,
0.62 mmol) in CH2Cl2 (10 mL) that was cooled in an ice bath. The
reaction was stirred at 0 °C for 1 h, concentrated, redissolved in CH2-
Cl2, and then concentrated again to remove excess TFA. The crude
oil was then triturated with ether to yield 21 (0.18 g, 95%) as a white
solid: 1H NMR (400 MHz, CDCl3) δ 2.14 (dt, J ) 14.3, 5.6 Hz, 1H),
2.44 (dt, J ) 14.1, 5.0 Hz, 1H), 3.32-3.47 (m, 5H), 3.70-3.76 (m,
3H), 4.04 (dd, J ) 12.2, 3.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
39.9, 40.1, 41.1, 56.7, 68.1, 68.5, 68.6, 118.2 (q), 162.9 (q); HRMS-EI
(M+) calcd for C7H13NOS2 191.0439, found 191.0437.
Phenylalanyltetrahydropyranone 24. To a solution of 21 (250
mg, 0.82 mmol) and DIEA (529 mg, 4.1 mmol) in CH2Cl2 (10 mL)
was added solid N-Boc-phenylalanyl fluoride28 (240 mg, 0.90 mmol).
The solution was stirred for 1 h and then washed with 1 N HCl,
saturated NaHCO3, and brine (10 mL). The solution was dried over
Na2CO3 and concentrated, and the crude material was purified by flash
chromatography (2:3 EtOAc/hexanes) to yield a mixture of diastere-
omers of 24 (218 mg, 61%) as a white solid: 1H NMR (400 MHz,
CDCl3) δ 1.31 (s, 9H), 1.34 (s, 9H), 2.03-2.15 (m, 4H), 2.82 (brs,
1H), 2.94-3.16 (m, 13H), 3.46-3.51 (m, 2H), 3.57 (brm, 1H), 3.67-
3.77 (m, 3H), 4.14 (brm, 1H), 4.19-4.27 (m, 2H), 4.37 (brm, 1H),
5.14 (brm, 1H), 5.31 (brm, 1H), 6.18 (brm, 1H), 6.58 (d, J ) 9.0 Hz,
1H), 7.11-7.24 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 27.8, 28.0,
37.7, 38.1, 38.77, 38.79, 38.84, 41.8, 52.8, 52.9, 53.0, 53.1, 55.4, 55.9,
66.79, 66.84, 69.4, 69.6, 69.7, 69.9, 79.8, 126.5, 126.6, 128.3, 128.4,
129.0, 129.2, 155.1, 170.6, 170.9; HRMS-FAB (M + Na+) calcd for
C21H30N2NaO4S2 461.1545, found 461.1544.
(Methoxysuccinyl)tetrahydropyranone 28. A solution of 24 (200
mg, 0.46 mmol) and TFA (3 mL) in CH2Cl2 (7 mL) was stirred at 25
°C for 1 h. This solution was concentrated, and the resulting material
was triturated with ether to precipitate the TFA salt as a white solid.
This solid was washed with ether, dried under vacuum, and then added
to a solution of methyl succinate (61 mg, 0.46 mmol), 1-hydroxyben-
zotriazole (HOBT, 72 mg, 0.46 mmol), 1-(3-(dimethylamino)propyl)-
3-ethylcarbodiimide hydrochloride (EDC, 114 mg, 0.60 mmol), and
N-methylmorpholine (0.10 mL) in CH2Cl2 (5 mL). The reaction was
stirred overnight at room temperature, and then it was washed with
water, 1 M KHSO4, saturated Na2CO3, and dried over Na2CO3. The
dried solution was concentrated, and the crude material was purified
by flash chromatography (7:3 EtOAc/hexanes) to yield a mixture of
diastereomers of 28 (144 mg, 70%) as a white solid: 1H NMR (400
MHz, CDCl3) δ 2.11-2.14 (m, 4H), 2.45-2.50 (m, 2H), 2.52-2.54
(m, 2H), 2.57-2.64 (m, 4H), 2.97-3.13 (m, 5H), 3.19-3.26 (m, 9H),
3.53-3.62 (m, 3H), 3.65 (s, 3H), 3.67 (s, 3H), 3.76-3.86 (m, 3H),
4.17-4.22 (m, 1H), 4.26-4.31 (m, 1H), 4.66-4.71 (m, 1H), 4.77-
4.82 (m, 2H), 6.25 (d, J ) 6.3 Hz, 1H), 6.68 (d, J ) 9.1 Hz, 1H), 6.77
(d, J ) 8.0 Hz, 1H), 6.96 (d, J ) 7.7 Hz, 1H), 7.21-7.30 (m, 10H);
13C NMR (100 MHz, CDCl3) δ 29.0, 29.1, 30.59, 30.61, 37.9, 38.2,
38.81, 38.88, 38.93, 41.9, 51.6, 53.0, 53.3, 54.3, 54.7, 66.9, 67.0, 69.48,
69.50, 69.7, 69.9, 126.6, 126.8, 128.4, 128.5, 129.1, 129.3, 136.5, 170.3,