15-Aza Epothilones
J . Org. Chem., Vol. 66, No. 12, 2001 4377
Hz, 1H), 2.70 (s, 3H), 2.32 (m, 1H), 2.24-2.21 (m, 1H), 2.04
(s, 3H), 1.96-1.94 (m, 2H), 1.55-1.43 (m, 3H), 1.66 (s, 3H),
1.48 (s, 9H), 1.42 (s, 9H), 1.37-1.20 (m, 2H), 1.31 (s, 3H), 1.25
1.78-1.71 (m, 1H), 1.67 (s, 3H), 1.59-1.17 (m, 5H), 1.24 (s,
3H), 1.14 (s, 3H), 1.09 (d, J ) 6.7 Hz, 3H), 0.98 (d, J ) 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 217.9, 171.6, 161.0, 161.3,
154.8, 143.9, 143.0, 142.9, 118.2, 116.7, 94.8, 83.9, 73.2, 58.8,
53.6, 52.2, 42.3, 36.5, 34.8, 32.2, 30.4, 27.8, 25.2, 23.8, 23.6,
22.5, 18.7, 16.4, 16.1, 14.1; LRMS (+electrospray): 705.1 [M
+ Na]+, 683.1 [M + H]+. HRMS cald for C30H45Cl3N2NaO7S,
705.1910, found 705.1936.
P r ep a r a tion of 26. The crude mixture, obtained from
above, was dissolved in DMF (10 mL) and further diluted with
CH2Cl2 (500 mL). Then HOAt (0.359 g, 2.64 mmol) was added
followed by diisopropylethylamine (1.02 g, 7.92 mmol) and
finally HATU (0.359 g, 2.64 mmol). The resultant mixture was
stirred at 25 °C for 16 h. The reaction mixture was then
washed with H2O (1 × 100 mL). The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The crude
mixture was then dissolved in HOAc/THF/H2O (3:1:1, 30 mL)
for 30 min. The reaction mixture was concentrated in vacuo,
neutralized with sat. aq NaHCO3, and extracted using EtOAc
(3 × 100 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. Chromatography
on silica gel (45% EtOAc/Hexanes) afforded Troc-protected aza-
dEpoB (26) (0.479 g, 79%) and Troc-protected C-15-epi-aza-
dEpoB, from 88% ee asymmetric dihydroxylation, (0.065 g,
11%) as a white foam.
(s, 3H), 1.10 (d, J ) 6.9 Hz, 3H), 0.92 (d, J ) 6.8 Hz, 3H); 13
C
NMR (125 MHz, CDCl3) δ 211.6, 172.2, 165.1, 164.5, 154.4,
153.3, 120.5, 118.9, 115.5, 97.9, 95.0, 82.9, 80.4, 76.9, 62.5, 56.3,
41.6, 35.0, 32.2, 31.8, 28.6, 28.4, 25.3, 23.8, 23.5, 23.1, 19.4,
16.2, 12.6; LRMS (+electrospray): 873.2 [M + Na]+, 851.2 [M
+ H]+. HRMS cald for C40H62Cl3N2O9S, 851.3241, found
851.3250.
P r ep a r a tion of 18. To a solution of enol ether 23 (0.309 g,
0.363 mmol) dissolved in acetone (9 mL) was added p-
toluenesulfonic acid (0.083 g, 0.436 mmol). The solution was
stirred at RT for 22 h. The reaction was neutralized by the
addition of sat. NaHCO3 and extracted with EtOAc (3 × 30
mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Chromatography on silica
gel (15% EtOAc/Hexanes) afforded â-keto-ester 18 as a white
foam (0.250 g, 82%): [R]D -36.8 (c 1.0, CHCl3); Rf ) 0.28 in
10% EtOAc/toluene; IR (neat) 2968, 2948, 1758, 1710, 1367,
1250, 1164, 1060, 927, 816, 733 cm-1 1H NMR (400 MHz,
;
CDCl3) δ *12.61 (s, 1H), 6.91 (s, 1H), 6.43 (s, 1H), 5.14-5.07
(m, 1H), 4.88-4.66 (m, 4H), 4.11 (m, 1H), 3.49 (d, J ) 16.2
Hz, 1H), 3.42 (d, J ) 16.0 Hz, 1H), 3.31-3.29 (m, 1H), 2.69 (s,
3H), 2.33-2.17 (m, 2H), 2.04 (s, 3H), 2.04-1.96 (m, 2H), 1.72-
1.61 (m, 2H), *1.65 and 1.63 (s, 3H), 1.45 (s, 9H), 1.42 (s, 9H),
1.24 (s, 9H), *1.10 and 1.08 (d, J ) 8.5 Hz, 3H), 0.92 and *0.88
(d, J ) 8.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.8, 203.4,
178.7, 166.5, 164.5, 154.4, 153.2, 140.2, 138.3, 120.6, 118.9,
115.5, 94.9, 82.2, 77.3, 76.9, 63.8, 60.6, 46.8, 41.8, 34.9, 32.3,
32.2, 31.5, 28.6, 28.2, 23.7, 22.4, 21.8, 21.1, 19.4, 15.9, 14.4,
11.6; LRMS (+electrospray): 837.5 [M + H]+, 859.6 [M + Na]+.
HRMS cald for C39H60Cl3N2O9S, 837.3084, found 837.3108
(*corresponds to enol tautomer).
Characterization for Troc-protected aza-dEpoB 26: [R]D
-16.3 (c 1.0, CHCl3); Rf ) 0.35 in 70% EtOAc/Hexanes; IR
(neat) 3318, 2932, 1758, 1620, 1370, 1248, 1143, 1069, 926
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.04 (s, 1H), 6.92 (d, J )
7.80 Hz, 1H), 6.51 (s, 1H), 5.18 (t, J ) 7.8 Hz, 1H), 5.08 (d, J
) 7.7 Hz, 1H), 4.79 (s, 2H), 4.64-4.63 (m, 1H), 4.34 (dd, J )
10.9, 7.0 Hz, 1H), 4.05 (d, J ) 9.0 Hz, 1H), 2.68 (s, 3H), 2.52-
2.46 (m, 2H), 2.31-2.21 (m, 3H), 2.09 (s, 3H), 1.98-1.92 (m,
1H), 1.69 (s, 3H), 1.65-1.51 (m, 4H), 1.35 (s, 3H), 1.37-1.20
(m, 2H), 1.17 (d, J ) 6.8 Hz, 3H), 1.09 (s, 3H), 0.99 (d, J ) 6.8
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 216.3, 170.7, 165.9,
154.5, 140.0, 139.6, 120.7, 118.4, 115.6, 94.9, 84.9, 76.8, 73.0,
56.4, 52.9, 43.8, 39.6, 38.7, 32.0, 31.8, 30.8, 27.2, 24.1, 22.0,
21.3, 19.2, 17.6, 16.9, 16.0; LRMS (+electrospray): 687.0 [M
+ Na]+, 665.1 [M + H]+. HRMS cald for C30H44Cl3N2O6S,
665.1985, found 665.2002.
P r ep a r a tion of 24. Diketone 18 (1.234 g, 1.48 mmol) was
dissolved in 0.12 N HCl in MeOH (24.6 mL, 2.95 mmol) at 25
°C. The solution was then sparged with argon gas for 30 min.
The ruthenium catalyst (0.150 g, 0.089 mmol) was then added
and the mixture was transferred to a Parr apparatus. The
vessel was purged with H2 for 10 min and then pressurized to
1200 psi. After 18 h at 25 °C, the reaction was returned to
atmospheric pressure and poured into sat. aq NaHCO3 (60
mL). After extraction with EtOAc (3 × 100 mL), the combined
organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. Chromatography on silica gel (20% EtOAc/
Hexane) afforded the hydroxy ester 24 (0.955 g, 78%) as a
white foam: [R]D -33.5 (c 1.0, CHCl3); Rf ) 0.20 in 20% EtOAc/
hexanes; IR (neat) 3385, 2974, 2936, 1758, 1703, 1504, 1471,
Characterization for Troc-protected C-15-epi-aza-dEpoB:
[R]22 -1.50 (c 1.0, CHCl3; Rf ) 0.61 in 70% EtOAc/Hexanes;
D
IR (neat) 3315, 2966, 1759, 1696, 1646, 1526, 1466, 1382, 1248,
1183, 925, 733 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H),
6.40 (s, 1H), 6.34 (d, J ) 5.8 Hz, 1H), 5.15 (t, J ) 7.0 Hz, 1H),
4.92 (d, J ) 12.0 Hz, 1H), 4.84-4.77 (m, 1H), 4.74 (d, J ) 12.0
Hz, 1H), 4.69-4.60 (m, 1H), 4.57-4.52 (m, 1H), 3.40-3.35 (m,
1H), 2.71 (s, 3H), 2.34-2.09 (m, 3H), 2.07 (s, 3H), 1.97-1.91
(m, 3H), 1.70 (s, 3H), 1.43-1.20 (m, 6H), 1.33 (s, 3H), 1.17 (d,
J ) 6.9 Hz, 3H), 1.04 (s, 3H), 0.98 (d, J ) 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 215.9, 172.5, 164.9, 154.8, 152.6,
139.7, 139.0, 120.8, 118.4, 115.8, 94.8, 77.1, 71.8, 55.9, 54.3,
53.6, 52.9, 45.9, 38.8, 34.7, 32.1, 31.8, 30.8, 24.7, 22.5, 19.3,
16.6, 15.7; LRMS (+electrospray) 687.0 [M + Na]+, 665.2 [M
+ H]+. HRMS cald for C30H44Cl3N2O6S, 665.1985, found
665.1988.
1455, 1367, 1249, 1161, 1051, 926, 817, 733 cm-1 1H NMR
;
(500 MHz, CDCl3) δ 6.90 (s, 1H), 6.42 (s, 1H), 5.08 (t, J ) 6.7
Hz, 1H), 4.85 (t, J ) 5.7 Hz, 1H), 4.82 (d, J ) 12.0 Hz, 1H),
4.71 (d, J ) 12.0 Hz, 1H), 4.66 (br s, 1H), 4.15-4.09 (m, 2H),
3.46-3.39 (m, 2H), 2.70 (s, 3H), 2.39-2.21 (m, 4H), 2.03 (s,
3H), 1.98-1.94 (m, 2H), 1.73-1.71 (m, 1H), 1.65 (s, 3H), 1.44
(s, 9H), 1.42 (s, 9H), 1.37-1.20 (m, 2H), 1.18 (s, 3H), 1.16 (s,
3H), 1.09 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 216.2, 172.7, 164.4, 154.5, 153.2,
140.2, 138.3, 120.6, 120.5, 118.9, 115.5, 95.0, 83.3, 81.6, 77.3,
76.9, 73.2, 52.1, 41.7, 37.6, 35.0, 32.5, 32.3, 31.5, 28.6, 28.3,
25.4, 25.3, 23.7, 22.2, 19.3, 16.4, 12.4; LRMS (+electrospray):
P r ep a r a t ion of 4a . To a solution of Troc-protected aza-
dEpoB (0.038 g, 0.057 mmol) dissolved in THF/HOAc (1:3, 6
mL) was added a spatula tip of activated nanosized zinc. The
reaction mixture was then sonicated at 25 °C for 2 h. The
solution was filtered to remove the zinc metal followed by
concentration in vacuo. The residue was then dissolved in
EtOAc (20 mL) and neutralized with sat. aq NaHCO3 (10 mL).
The aqueous layer was extracted using EtOAc (3 × 20 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. Chromatography on silica gel (60%
EtOAc/Hexanes) afforded aza-dEpoB (0.025 g, 88%) as a white
foam.
861.2 [M + Na]+, 832.2 [M + H]+. HRMS cald for C39H62
Cl3N2O9S, 839.3241, found 839.3278.
-
P r ep a r a tion of 25. To a solution of the bis-Boc protected
amino acid (0.738 g, 0.880 mmol) dissolved in CH2Cl2 (20 mL)
was added trifluoroacetic acid (10 mL). The solution was
stirred at RT for 2 h followed by concentration in vacuo. The
crude material was used without further purification: [R]D
t
+3.4 (c ) 1.0, CHCl3); Rf ) 0.5 in 75:15:10 BuOH: HCOOH:
H2O; IR (neat) 3076, 2971, 1757, 1668, 1378, 1255, 1187, 926,
1
818 cm-1; H NMR (400 MHz, DMFd7) δ 8.61 (br s, 3H), 7.48
Characterization for aza-dEpoB (4a ) [R]D -61.9 (c 0.5,
(s, 1H), 6.67 (s, 1H), 5.14 (t, J ) 6.8 Hz, 1H), 5.03 (d, J ) 12.4
Hz, 1H), 4.98 (d, J ) 12.3 Hz, 1H), 4.88 (t, J ) 6.6 Hz, 1H),
4.28 (dd, J ) 9.8, 1.1 Hz, 1H), 4.00 (m, 1H), 3.63-3.60 (m,
1H), 2.70 (s, 3H), 2.68-2.66 (m, 2H), 2.49 (dd, J ) 15.4, 2.0
Hz, 1H), 2.26 (s, 3H), 2.25-2.21 (m, 1H), 2.12-2.04 (m, 2H),
CHCl3); Rf ) 0.55 in 100% EtOAc; IR (neat) 3330, 2929, 1690,
1
1634, 1510, 1456, 1381, 1147, 732 cm-1; H NMR (500 MHz,
CDCl3) δ 6.92 (s, 1H), 6.46 (s, 1H), 5.99 (d, J ) 6.5 Hz, 1H),
5.13 (t, J ) 7.6 Hz, 1H), 4.31 (dd, J ) 11.6, 6.8 Hz, 1H), 4.06
(d, J ) 8.9 Hz, 1H), 3.82-3.74 (m, 2H), 3.14 (q, J ) 6.9 Hz,