New Synthesis of 1â-Alkylcarbapenems
J . Org. Chem., Vol. 61, No. 22, 1996 7893
(1H, dd, J ) 5.3, 3.4 Hz), 5.90 (2H, s); MS (EI) m/z 618 (M+
-
3-ca r boxyla te (19): [R]30D ) +24.0° (c 1.01, CHCl3); IR (neat)
1
57); HRMS (FAB) m/z calcd for C30H49NO12SSi + Na 698.2642
1770, 1751, 1709, 1655, 1540 cm-1; H NMR (CDCl3) δ 0.08
(M+ + Na), found 698.2634.
(6H, s), 0.89 (9H, s), 1.22 (9H, s), 1.12-1.27 (6H, m), 1.80-
2.05 (1H, m), 2.54-2.79 (1H, m), 2.97, 2.99 (3H, each s), 3.06,
3.11 (3H, each s), 3.19-4.26 (7H, m), 4.50-4.60 (2H, m), 4.67-
4.78 (1H, m), 5.12-5.35 (2H, m), 5.73-6.05 (1H, m), 5.84 (1H,
d, J ) 5.5 Hz), 5.93 (1H, d, J ) 5.5 Hz); 13C NMR (CDCl3)
-4.89, -4.26, 17.10, 17.99, 22.49, 25.76, 26.92, 27.33, 29.33,
35.41, 36.12, 37.00, 38.77, 40.37, 41.20, 44.10, 46.63, 51.67,
54.17, 54.73, 55.79, 60.82, 66.10, 66.33, 76.44, 77.07, 77.70,
79.91, 117.9, 128.4, 128.4, 128.6, 132.0, 132.2, 132.8, 148.4,
154.0, 159.3, 170.9, 172.8, 176.8; MS (SI) m/z 696 (M+ + 1),
680 (M+ - 15), 638 (M+ - 57); HRMS (FAB) m/z calcd for
C33H53N3O9SSi + Na 718.3169 (M+ + Na), found 718.3208.
(3S,4R)-3-[(1R)-1-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-
4-[(1R)-3-[(ter t-bu tyld im eth ylsilyl)oxy]-1-[(4,4-d im eth yl-
2-t h i o x o o x a z o li d i n -3-y l)c a r b o n y l]p r o p y l]-2-a z e t i -
d in on e (21). To a stirred suspension of Sn(OTf)2 (3.70 g, 9.05
mmol) in dry THF (5 mL) with ice cooling under N2 was added
1-ethylpiperidine (1.30 mL, 9.40 mmol), and then a solution
of 3-[3-[(tert-butyldimethylsilyl)oxy]butyroyl]-4,4-dimethyl-2-
thioxooxazolidine (2.30 g, 6.96 mmol) in dry THF (5 mL) was
added dropwise. After the reaction mixture was stirred for 3
h, a solution of acetoxyazetidinone 20 (1.00 g, 3.48 mmol) in
dry THF (5 mL) was added dropwise. After being stirred for
an additional 2 h, the mixture was poured into saturated
aqueous NH4Cl, diluted with AcOEt, and stirred vigorously
for 10 min. The resultant slurry was passed through a cerite
pad to remove the precipitate and washed with AcOEt. The
combined organic layer was washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, and evaporated. The
residue was purified by silica gel column chromatography
(elution with n-hexane:AcOEt ) 4:1) to give acyloxazolidine-
2-thione 21 (1.28 g, 66%) as a greenish gum: [R]26D ) +32.56°
(3S,4S)-4-[(1R)-2-[[2,2-Bis(eth oxyca r bon yl)eth yl]th io]-
1-m eth yl-2-oxoeth yl]-3-[(1R)-1-[(ter t-bu tyld im eth ylsilyl)-
o x y ]e t h y l]-1-[h y d r o x y [[[(p iv a lo y lo x y )m e t h y l]o x y ]-
ca r bon yl]m eth yl]-2-a zetid in on e (15). To a solution of
R-keto ester 14 (1.70 g, 2.53 mmol) in AcOH (10 mL) and
CH2Cl2 (10 mL) with ice cooling was added Zn powder (5.0 g),
and the mixture was stirred vigorously for 30 min. After being
passed through a cerite pad, the mixture was poured into ice-
water and extracted with CH2Cl2. The organic layer was
washed successively with saturated aqueous NaHCO3, water,
and brine and dried over MgSO4. The solvent was evaporated
to give a residue, which was purified by silica gel column
chromatography (elution with n-hexane:AcOEt ) 3:1) to give
an epimeric mixture of alcohols 15 (1.52 g, 88%) as a colorless
1
syrup: IR (KBr) 3460, 1754, 1692 cm-1; H NMR (CDCl3) δ
0.07 (6H, m), 0.87 (9H, s), 1.22 (9H, s), 1.22-1.32 (12H, m),
2.90-3.12 (2H, m), 3.38 (2H, dd, J ) 7.1, 2.1 Hz), 3.61 (1H, t,
J ) 7.1 Hz), 4.04-4.28 (7H, m), 4.42 (1H, d, J ) 8.8 Hz), 5.30,
5.52 (1H, d, J )8.8 Hz), 5.77-5.91 (2H, m); MS (EI) m/z 620
(M+ - 57); HRMS (FAB) m/z calcd for C30H51NO12SSi + Na
700.2798 (M+ + Na), found 700.2765.
(P iva loyloxy)m eth yl (2S,5R,6S,7S)-7-[(1R)-1-[(ter t-Bu -
t yld im et h ylsilyl)oxy]et h yl]-4,8-d ioxo-5-m et h yl-1-a za -3-
th ia bicyclo[4.2.0]octa n e-2-ca r boxyla te (16). The reaction
of alcohols 15 (967 mg, 1.43 mmol) was performed in a similar
way to that of alcohols 6 to give thiazinone 16 (557 mg, 80%)
as a colorless syrup: [R]26 ) -97.8° (c 1.0, CHCl3); IR (KBr)
D
1
1775, 1765, 1691 cm-1; H NMR (CDCl3) δ 0.06 (3H, s), 0.08
(3H, s), 0.87 (9H, s), 1.21 (9H, s), 1.19-1.25 (6H, m), 2.93 (1H,
dd, J ) 4.6, 3.0 Hz), 3.51 (1H, quintet, J ) 6.8 Hz), 4.10-4.30
(1H, m), 4.56 (1H, dd, J ) 7.2, 2.9 Hz), 5.82 (1H, d, J ) 5.4
Hz), 5.83 (1H, s), 5.91 (1H, d, J ) 5.4 Hz); 13C NMR (CDCl3)
-4.92, -4.33, 11.70, 17.91, 22.70, 25.70, 26.81, 38.77, 45.00,
53.52, 56.39, 62.53, 64.78, 80.30, 166.1, 169.5, 176.7, 196.9;
MS (EI) m/z 472 (M+ - 15), 430 (M+ - 57); HRMS (FAB) m/z
calcd for C22H37NO7SSi + Na 510.1958 (M+ + Na), found
510.1923.
(c 0.82, CHCl3); IR (neat) 3260, 1762, 1699 cm-1 1H NMR
;
(CDCl3) δ 0.04 (6H, s), 0.07 (3H, s), 0.08 (3H, s), 0.88 (9H, s),
0.89 (9H, s), 1.22 (3H, d, J ) 6.3 Hz), 1.56 (3H, s), 1.57 (3H,
s), 1.59 (9H, s), 1.65-1.83 (1H, m), 1.93-2.17 (1H, m), 3.19-
3.27 (1H, m), 3.52-3.75 (2H, m), 3.99 (1H, dd, J ) 5.2, 2.0
Hz), 4.11 (1H, d, J ) 8.7 Hz), 4.15 (1H, d, J ) 8.7 Hz), 4.09-
4.27 (1H, m), 5.28-5.37 (1H, m), 6.16 (1H, br s); MS (SI) m/z
559 (M+ + 1); HRMS (FAB) m/z calcd for C26H50N2O5SSi2 + H
559.3057 (M+ + H), found 559.3039.
Su lfid e Con tr a ction of Th ia zin on e 16 Lea d in g to
Ca r ba p en em 19. To a solution of thiazinone 16 (60 mg, 0.123
mmol) and Ph3P (32 mg, 0.123 mmol) in toluene (2 mL) at -40
°C under N2 was added KO-t-Bu (15 mg, 0.135 mmol), and
(3S,4R)-4-[(1R)-2-[[2,2-Bis(eth oxyca r bon yl)eth yl]th io]-
1-[2-[(ter t-b u t yld im et h ylsilyl)oxy]et h yl]-2-oxoet h yl]-3-
[(1R )-1-[(t er t -b u t y ld im e t h y ls ily l)o x y ]e t h y l]-2-a ze t i-
d in on e (22). To a solution of acyloxazolidine-2-thione 21 (4.53
g, 8.12 mmol) in dry CH3CN (30 mL) at rt under N2 was added
imidazole (2.76 g, 40.6 mmol), and the mixture was stirred
overnight. A solution of mercaptan 4 (1.88 g, 8.93 mmol) in
dry CH3CN (1 mL) was added to the mixture and stirring was
further continued for 3 days. The mixture was poured into 1
N HCl and extracted with AcOEt. The organic layer was
washed with water, saturated aqueous NaHCO3, and brine,
dried over MgSO4, and evaporated. The residue was purified
by silica gel column chromatography (elution with n-hexane:
AcOEt ) 4:1) to give thioester 22 (3.46 g, 67%) as a colorless
waxy solid: [R]25D ) -11.0° (c 1.0, CHCl3); IR (KBr) 3140, 3080,
the reaction mixture was stirred vigorously for 1.5 h.
A
solution of (PhO)2POCl (36 mg, 0.135 mmol) in dry CH3CN (3
mL) was added, and the reaction mixture was gradually
warmed to 0 °C and stirred for an additional 3 h to form
enolphosphate 18. The mixture was poured into 0.2 M
phosphate buffer (pH 7.0) and extracted with AcOEt. The
organic layer was washed with water and brine, dried over
MgSO4, and evaporated. The residue was dissolved in dry
DMF (3 mL), and mercaptan 8b (35 mg, 0.135 mmol) and
i-Pr2EtN (26 µL, 0.148 mmol) was added to the mixture with
ice cooling under N2. After standing at 0 °C in the refrigerator
for 3 days, the mixture was poured into water and extracted
with AcOEt. The organic layer was washed with water and
brine, dried over MgSO4, and evaporated. The residue was
purified by silica gel column chromatography (elution with
n-hexane:AcOEt ) 1:3) to afford carbapenem 19 (33 mg, 39%)
as a yellowish gum. Enolphosphate 18 was isolatable (48%)
as a yellowish syrup by silica gel column chromatography
(elution with n-hexane:AcOEt ) 6:1).
(P iva loyloxy)m eth yl (1R,5R,6S)-6-[(1R)-1-[(ter t-bu tyl-
d im eth ylsilyl)oxy]eth yl]-2-[(d ip h en ylp h osp h or yl)oxy]-1-
m eth ylca r ba p en -2-em -3-ca r boxyla te (18): [R]28D ) +31.1°
(c 0.51, CHCl3); IR (neat) 1787, 1746, 1635, 1590 cm-1; 1H NMR
(CDCl3) δ 0.06 (3H, s), 0.06 (3H, s), 0.87 (9H, s), 1.18 (3H, d,
J ) 7.2 Hz), 1.19 (9H, s), 1.22 (3H, d, J ) 7.1 Hz), 3.23 (1H,
dd, J ) 6.3, 3.0 Hz), 3.32-3.53 (1H, m), 4.13 (1H, dd, J ) 10.4,
3.0 Hz), 4.09-4.25 (1H, m), 5.78 (1H, d, J ) 5.5 Hz), 5.81 (1H,
d, J ) 5.5 Hz), 7.15-7.43 (10H, m); MS (EI) m/z 687 (M+),
630 (M+ - 57).
1
1766, 1728, 1681 cm-1; H NMR (CDCl3) δ 0.04 (6H, s), 0.06
(6H, s), 0.86 (9H, s), 0.88 (9H, s), 1.13 (3H, d, J ) 6.3 Hz),
1.28 (6H, t, J ) 7.0 Hz), 1.60-1.74 (1H, m), 1.84-1.95 (1H,
m), 2.86-3.00 (2H, m), 3.28 (1H, d, J ) 1.1 Hz), 3.37 (1H, s),
3.45-3.70 (3H, m), 3.83 (1H, dd, J ) 6.4, 2.0 Hz), 4.09-4.21
(5H, m), 5.96 (1H, br s); MS (SI) m/z 634 (M+ + 1), 618 (M+
-
15), 576 (M+ - 57); HRMS (FAB) m/z calcd for C29H55NO8SSi2
+ Na 656.3084 (M+ + Na), found 656.3083.
(3S,4R)-1-[(Allyloxy)oxa lyl]-4-[(1R)-2-[[2,2-bis(eth oxy-
ca r bon yl)eth yl]th io]-1-[2-[(ter t-bu tyld im eth ylsilyl)oxy]-
et h yl]-2-oxoet h yl]-3-[(1R)-1-[(ter t-b u t yld im et h ylsilyl)-
oxy]eth yl]-2-a zetid in on e (23). To a solution of thioester 22
(1.00 g, 1.50 mmol) and (allyloxy)oxalyl chloride (0.67 g, 4.50
mmol) in dry CH2Cl2 (30 mL) with ice cooling was added
dropwise a solution of Et3N (2.76 g, 40.6 mmol) in dry CH2Cl2
(15 mL), and the mixture was stirred overnight. The mixture
was poured into water and extracted with CH2Cl2. The organic
layer was washed with water and brine, dried over MgSO4,
(P iva loyloxy)m eth yl (1R,5S,6S)-6-[(1R)-1-[(ter t-bu tyl-
d im eth ylsilyl)oxy]eth yl]-2-[[(3S,5S)-5-[(d im eth yla m in o)-
ca r bon yl]p yr r olid in -3-yl]th io]-1-m eth ylca r ba p en -2-em -