Total Synthesis of (+)-Lactacystin
J. Am. Chem. Soc., Vol. 118, No. 15, 1996 3589
mL, 29.6 mmol) and heated at reflux for 3.5 h. The reaction mixture
was cooled to room temperature and quenched with H2O (10 mL), the
layers were separated, and the aqueous phase was extracted with CHCl3
(3 × 30 mL). The combined organic solutions were dried over Na2-
SO4, filtered, and concentrated. Flash chromatography (8:1 hexane/
EtOAc) afforded (-)-6 (2.01 g, 82% yield) as a yellow oil: [R]D23
(dd, J ) 10.6, 1.7 Hz, 1 H), 6.17 (m, 1 H), 7.33 (m, 3 H), 7.93 (m, 2
H); 13C NMR (67.5 MHz, CDCl3) δ 16.9, 18.1, 20.7, 29.7, 39.5, 52.3,
78.4, 83.6, 89.2, 116.2, 128.3, 128.6, 128.8, 131.7, 139.1, 165.5, 172.7;
high-resolution mass spectrum (EI, 70 eV) m/z 331.1785 (M+; calcd
for C19H25NO4: 331.1783). Anal. Calcd for C19H25NO4: C, 68.85;
H, 7.60; N, 4.23. Found: C, 68.99; H, 7.88; N, 4.40. Data for
(-)-4b less polar; mp 102-104 °C (EtOAc); [R]2D8 -84° (c 0.5,
-124° (c 1.0, CHCl3); IR (CCl4) 2880 (m), 1740 (s), 1640 (s) cm-1
;
1H NMR (270 MHz, CDCl3) δ 0.98 (d, J ) 6.6 Hz, 3 H), 1.02 (d, J )
6.6 Hz, 3 H), 1.96 (m, 1 H), 3.79 (s, 3 H), 4.56 (d, J ) 7.3 Hz, 1 H),
4.67 (apparent t, J ) 6.6 Hz, 1 H), 7.44 (m, 3 H), 7.99 (d, J ) 7.3 Hz,
2 H); 13C NMR (67.5 MHz, CDCl3) δ 17.2, 17.3, 29.5, 52.3, 66.8,
80.1, 89.2, 126.8, 128.3, 128.6, 131.9, 166.4, 171.5; high-resolution
mass spectrum (EI, 70 eV) m/z 247.1208 (M+; calcd for C14H17NO3:
247.1208). Anal. Calcd for C14H17NO3: C, 67.98; H, 6.93; N, 5.67.
Found: C, 67.70; H, 6.86; N, 5.55.
CHCl3); IR (KBr) 3500 (m), 1710 (s), 1650 (s) cm-1; H NMR (270
1
MHz, CDCl3) δ 0.79 (d, J ) 6.6 Hz, 3 H), 1.11 (d, J ) 7.3 Hz, 3 H),
1.13 (d, J ) 7.3 Hz, 3 H), 1.99 (m, 1 H), 2.82 (m, 1 H), 3.36 (d, J )
11.6 Hz, 1 H), 3.41 (dd, J ) 11.2, 2.0 Hz, 1 H), 3.73 (s, 3 H), 4.83 (d,
J ) 3.0 Hz, 1 H), 5.00 (dd, J ) 10.2, 1.7 Hz, 1 H), 5.11 (dd, J ) 17.3,
1.7 Hz, 1 H), 5.77 (m, 1 H), 7.33 (m, 3 H), 7.93 (m, 2 H); 13C NMR
(67.5 MHz, CDCl3) δ 15.3, 19.9, 21.2, 29.6, 39.6, 52.1, 77.5, 81.7,
90.1, 115.9, 127.2, 128.3, 128.7, 131.7, 138.2, 165.1, 173.1; high-
resolution mass spectrum (EI, 70 eV) m/z 331.1780 (M+; calcd for
C19H25NO4: 331.1783). Anal. Calcd for C19H25NO4: C, 68.85; H,
7.60; N, 4.23. Found: C, 68.90; H, 7.54; N, 4.39.
Primary Alcohol (-)-17. A solution of lithium bis(trimethylsilyl)-
amide (1.0 M in hexane, 6.6 mL, 6.6 mmol) in THF (55 mL) was
cooled to -78 °C and treated dropwise with a solution of oxazoline
(-)-6 (1.49 g, 6.03 mmol) in THF (5 mL). After 1 h at -78 °C, a
freshly prepared solution of monomeric formaldehyde in Et2O (24 mL,
ca. 32 mmol of HCHO, maintained at -78 °C) was added via cannula.
The mixture was stirred for 10 min further and then rapidly quenched
with water (50 mL) at -78 °C. The cooling bath was removed and
the mixture allowed to warm to room temperature. The aqueous layer
was extracted with Et2O (3 × 50 mL), and the combined organic phases
were dried over Na2SO4, filtered, and concentrated. Flash chromatog-
raphy (2:1 hexane/EtOAc) furnished (-)-17 (1.42 g, 85% yield) as a
white powder: mp 76-77 °C (EtOAc); [R]2D3 -1.8° (c 1.0, CHCl3);
IR (KBr) 3500-3100 (w), 1730 (s), 1640 (s) cm-1; 1H NMR (270 MHz,
CDCl3) δ 1.12 (d, J ) 6.6 Hz, 3 H), 1.13 (d, J ) 6.6 Hz, 3 H), 2.13
(m, 1 H), 2.30 (t, J ) 7.3 Hz, 1 H), 3.88 (s, 3 H), 3.95 (dd, J ) 11.5,
7.3 Hz, 1 H), 4.11 (dd, J ) 11.5, 7.3 Hz, 1 H), 4.56 (d, J ) 7.3 Hz, 1
H), 7.55 (m, 3 H), 8.07 (m, 2 H); 13C NMR (67.5 MHz, CDCl3) δ
18.6, 19.4, 29.5, 52.3, 66.8, 80.1, 89.2, 126.8, 128.3, 128.6, 131.9, 166.4,
171.5; high-resolution mass spectrum (EI, 70 eV) m/z 278.1392 (M+;
calcd for C15H19NO4: 278.1392). Anal. Calcd for C15H19NO4: C,
64.72; H, 7.25; N, 5.03. Found: C, 65.00; H, 6.99; N, 5.16.
Carboxylic Acid (-)-18. A solution of olefin (-)-4a (717 mg, 2.16
mmol) in absolute MeOH (20 mL) and CH2Cl2 (10 mL) was cooled to
-78 °C and treated with a stream of O3 in O2 until TLC analysis
indicated the complete consumption of starting material. The solution
was purged with O2 to remove excess O3, Me2S (0.43 mL, 5.88 mmol)
was added, and the mixture was stirred for 1 h at -78 °C and 1 h at
room temperature. Concentration followed by exposure to high vacuum
for 2 h afforded the aldehyde as a yellow oil. Without purification, a
portion of aldehyde (12.2 mmol maximum) was dissolved in a mixture
of t-BuOH (21.6 mL), and 2-methyl-2-butene (4.8 mL, 45.4 mmol)
and treated with a solution of NaClO2 (1.96 g, 21.6 mmol) and NaH2PO4
(4.49 g, 28.9 mmol) in H2O (10.8 mL). The mixture was stirred
vigorously at room temperature for 45 min, and then an adequate
amount of Na2SO3 was added to consume the excess NaClO2. After
10 min, the reaction mixture was concentrated and extracted with CHCl3
(3 × 30 mL), and the combined organic phases were dried over Na2SO4,
filtered, and concentrated. Flash chromatography (10:1 CHCl3/MeOH)
gave (-)-18 (423 mg, 56% yield) as a white powder: mp 116-118
°C (MeOH); [R]2D5 -20° (c 0.1, MeOH); IR (KBr) 3300 (m), 1720 (s),
1
1630 (s) cm-1; H NMR (270 MHz, CD3OD) δ 0.83 (d, J ) 6.6 Hz,
Aldehyde 5. A solution of alcohol (-)-17 (1.23 g, 4.44 mmol) in
benzene (24.2 mL) and DMSO (6.67 mL) was treated with DCC (2.75
g, 13.3 mmol), pyridine (0.36 mL, 4.4 mmol), and trifluoroacetic acid
(0.17 mL, 2.2 mmol). The mixture was stirred overnight at room
temperature and then concentrated, and the residue was dissolved in
n-pentane (20 mL). Following suction filtration through a fritted glass
funnel, under N2 into an oven-dried flask, concentration and exposure
to high vacuum for 15 h furnished 5, a yellow oil which was not
purified: 1H NMR (270 MHz, CDCl3) δ 0.88 (d, J ) 6.6 Hz, 3 H),
1.03 (d, J ) 6.6 Hz, 3 H), 2.00 (m, 1 H), 3.77 (s, 3 H), 4.85 (d, J )
8.2 Hz, 1 H), 7.42 (m, 3 H), 7.92 (d, J ) 9.9 Hz, 2 H), 9.73 (s, 1 H).
Homoallylic Alcohols (-)-4a and (+)-4b. A mixture of trans-2-
butene (2.00 mL, 22.2 mmol), 90% potassium tert-butoxide (1.32 g,
10.6 mmol), and THF (6.35 mL) was cooled to -78 °C, and
n-butyllithium (2.5 M in THF, 4.22 mL, 10.6 mmol) was added
dropwise. The resultant bright yellow solution was stirred at -50 °C
for 10 min and recooled to -78 °C. A solution of (-)-B-methoxy-
(diisopinocampheyl)borane (4.00 g, 12.7 mmol) in Et2O (12.7 mL) was
then introduced dropwise, and the mixture was stirred for 30 min further.
After dropwise treatment with neat boron trifluoride etherate (1.74 mL,
14.2 mmol), aldehyde 5 (1.22 g, 4.44 mmol maximum) in THF (11
mL) was immediately added dropwise, and the mixture was allowed
to stir overnight at -78 °C. The reaction mixture was warmed to 0
°C, and 10% NaOH (7.80 mL, 19.5 mmol) followed by 35% H2O2
(2.72 mL, 28.0 mmol) was added very slowly. The solution was heated
at reflux for 1 h and cooled to room temperature. The aqueous layer
was extracted with Et2O (3 × 20 mL), and the combined organic phases
were dried over Na2SO4, filtered, and concentrated. Flash chromatog-
raphy (50:1 hexane/EtOAc) afforded (-)-4a (1.03 g, 70% yield) and
(-)-4b (275 mg, 17%) as white powders. Data for (-)-4a: more polar;
mp 98-99 °C (EtOAc); [R]2D5 -4° (c 0.5, CHCl3); IR (KBr) 3550 (w),
3 H), 0.99 (d, J ) 6.9 Hz, 3 H), 1.19 (d, J ) 7.3 Hz, 3 H), 1.89 (m,
1 H), 2.60 (m, 1 H), 3.68 (s, 3 H), 4.05 (d, J ) 3.6 Hz, 1 H), 4.71 (d,
J ) 5.3 Hz, 1 H), 7.40 (m, 3 H), 7.90 (d, J ) 7.3 Hz, 2 H); 13C NMR
(67.5 MHz, CD3OD) δ 17.9, 18.3, 21.7, 31.8, 43.9, 53.5, 79.2, 85.6,
91.3, 108.7, 129.1, 130.3, 130.6, 134.0, 168.6, 173.7; high-resolution
mass spectrum (FAB, glycerol matrix) m/z 350.1607 [(M + H)+; calcd
for C18H24NO6: 350.1603]. Anal. Calcd for C18H23NO6: C, 61.86;
H, 6.64; N, 4.01. Found: C, 61.62; H, 6.89; N, 3.85.
γ-Lactam (+)-19. A mixture of carboxyoxazoline (-)-18 (61.0 mg,
0.175 mmol), ammonium formate (55 mg, 0.88 mmol), palladium black
(175 mg), and acetic acid (5.4 mL) was heated at reflux until TLC
analysis showed complete consumption of the starting material (ca. 4
h). The catalyst was filtered off and washed with CHCl3 (10 mL).
The filtrate was partially concentrated to remove CHCl3 and the
remaining solution neutralized with 2 N NaOH. The resultant mixture
was extracted with CHCl3 (3 × 10 mL), and the combined organic
phases were dried over Na2SO4, filtered, and concentrated. Flash
chromatography (15:1 CHCl3/MeOH) gave (+)-19 (38.9 mg, 91% yield)
as a colorless powder: [R]2D4 +65° (c ) 0.3, MeOH); H NMR (270
1
MHz, CD3OD) δ 0.84 (d, J ) 6.6 Hz, 3 H), 0.88 (d, J ) 6.6 Hz, 3 H),
1.06 (d, J ) 7.3 Hz, 3 H), 1.65 (m, 1 H), 2.94 (m, 1 H), 3.72 (s, 3 H),
3.90 (d, J ) 7.3 Hz, 1 H), 4.43 (d, J ) 5.9 Hz, 1 H); mass spectrum
(FAB, glycol matrix) m/z 246 [(M + H+); calcd for C11H20NO5: 246].
Carboxylic Acid (+)-3. A solution of lactam methyl ester (+)-19
(14 mg, 0.06 mmol) in EtOH (0.57 mL) was treated with 0.1 N NaOH
(1.14 mL), and the resultant mixture was stirred for 9 h at room
temperature and then neutralized with 2 N HCl. Following partial
concentration to remove EtOH, the solution was subjected to column
chromatography on activated carbon (80% acetone), affording (+)-3
(11.9 mg, 90% yield) as a colorless powder: mp 244 °C dec (acetone/
1720 (s), 1640 (s) cm-1; H NMR (270 MHz, CDCl3) δ 0.82 (d, J )
H2O); [R]23 +42° (c 0.5, MeOH); IR (KBr) 3600-3100 (s), 1660 (s),
1
D
1
6.6 Hz, 3 H), 1.01 (d, J ) 6.9 Hz, 3 H), 1.09 (d, J ) 6.9 Hz, 3 H),
1.88 (m, 1 H), 2.56 (m, 1 H), 3.71 (s, 3 H), 3.87 (dd, J ) 9.1, 2.8 Hz,
1 H), 4.70 (d, J ) 5.0 Hz, 1 H), 4.95 (dd, J ) 15.8, 1.7 Hz, 1 H), 5.07
1600 (s) cm-1; H NMR (270 MHz, CD3OD) δ 0.85 (d, J ) 6.6 Hz,
3 H), 0.86 (d, J ) 6.6 Hz, 3 H), 0.98 (d, J ) 7.6 Hz, 3 H), 1.69 (m,
1 H), 2.86 (m, 1 H), 3.83 (d, J ) 5.3 Hz, 1 H), 4.30 (d, J ) 5.9 Hz,