Total Syntheses of (-)-Macrolactin A
J. Am. Chem. Soc., Vol. 120, No. 16, 1998 3947
H), 2.60-2.00 (complex series of m, 6 H), 1.70-1.20 (complex series
of m, 6 H), 1.25 (d, J ) 6.2 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 3 H), 0.02
6.7 Hz, 1 H), 5.66-5.62 (m, 1 H), 5.58-5.47 (m, 3 H), 4.31-4.25
(m, 1 H), 4.22-4.15 (m, 1 H), 3.87-3.81 (m, 1 H), 3.69-3.63 (m, 1
H), 2.42-2.37 (m, 2 H), 2.34-2.30 (m, 2 H), 2.09-2.02 (m, 2 H),
1.58-1.19 (m, 6 H), 1.11 (d, J ) 6.3 Hz, 3 H); 13C NMR (125 MHz,
1
3
(
s, 3 H); C NMR (125 MHz, CDCl
3
) δ 166.4, 143.0, 140.5, 137.0,
34.9, 132.7, 130.7, 130.6, 130.0, 129.3, 126.6, 124.0, 117.6, 72.1,
0.9, 70.6, 69.7, 42.8, 40.9, 35.6, 35.1, 32.1, 25.9, 24.4, 20.0, 18.2,
1
7
CDCl ) δ 169.8, 146.1, 137.0, 135.4, 135.36, 131.4, 131.1, 130.9, 130.4,
3
-
4.3, -4.7; high-resolution mass spectrum (FAB, NBA) m/z 539.3176
129.1, 126.9, 117.5, 72.7, 69.9, 39.1, 68.4, 45.0, 42.1, 39.7, 37.2, 33.6,
26.6, 23.5.
+
[
(M + Na) ; calcd for C30
H
48
O
5
SiNa: 539.3169].
Macrolactin A [(-)-1] via (-)-55. A solution of monoprotected
(E)-Vinyl Iodide (+)-57. A solution of (+)-9 (7.3 mg, 0.013 mmol)
in dichloromethane (0.25 mL) was treated with a solution of iodine
(3.2 mg, 0.013 mmol) in dichloromethane (0.25 mL). Concentration
followed by flash chromatography (hexanes/ethyl acetate, 3:1) furnished
macrocycle (-)-55 (1.6 mg, 0.003 mmol) in anhydrous THF (0.25 mL)
was treated with a mixture of TBAF/AcOH (1:1, ca. 1 M in THF, 0.06
mL, 0.0.06 mmol). The flask was wrapped in aluminum foil and the
reaction mixture stirred at room temperature for 5 d. Concentration
(+)-57 (4.0 mg, 77% yield) as a yellow oil: [R]23
IR (CHCl
(500 MHz, CDCl
+5 (c 0.61, CH
Cl
) 3500 (w), 3150 (m), 2950 (s), 1690 (s) cm ; H NMR
) δ 7.34 (dd, J ) 15.3, 11.5 Hz, 1 H), 6.61 (t, J )
D
2
2
);
-
1
1
and flash chromatography (CHCl
3
/MeOH, 9:1) furnished (-)-1 (0.6
3
mg, 50% yield) as a white amorphous solid (mp 60-65 °C). All
attempts to crystallize synthetic (-)-macrolactin A proved unsuccessful.
3
11.4 Hz, 1 H), 6.51 (dd, J ) 14.4, 5.9 Hz, 1 H), 6.25 (d, J ) 14.4 Hz,
1 H), 6.03 (apparent td, J ) 15.0, 7.3 Hz, 1 H), 5.61 (d, J ) 11.3 Hz,
1 H), 4.18-4.15 (m, 1 H), 2.39 (apparent t, J ) 6.5 Hz, 2 H), 0.87 (s,
2
3
[
(
7
1
R]
D
-8.9 (c 0.09, MeOH); IR (CHCl
3
) 3300 (br w), 2950 (s), 1730
) δ
.58 (m, 1 H), 7.00 (dd, J ) 15.6, 11.5 Hz, 1 H), 6.63 (t, J ) 11.2 Hz,
H), 6.56 (dd, J ) 15.6, 11.2 Hz, 1 H), 6.36 (dt, J ) 15.2, 6.3 Hz, 1
-
1
1
s), 1640 (m), 1605 (m) cm ; H NMR (500 MHz, pyridine-d
5
9 H), 0.02 (s, 3 H), 0.01 (s, 3 H); 13C NMR (125 MHz, CDCl
) 170.9,
3
148.2, 146.8, 141.0, 129.6, 125.0, 115.5, 76.3, 41.1, 25.8, 18.2, -4.6,
H), 6.22 (dd, J ) 17.4, 11.5 Hz, 1 H), 6.18 (dd, J ) 14.5, 10.4 Hz, 1
H), 6.00 (dd, J ) 14.9, 5.6 Hz, 1 H), 5.96 (dd, J ) 15.3, 6.3 Hz, 1 H),
-4.9; high-resolution mass spectrum (FAB, NBA) m/z 431.0509 [(M
+
+ Na) ; calcd for C15
H25IO
3
SiNa: 431.0516].
5
(
1
2
1
.82 (dd, J ) 17.5, 8.6 Hz, 1 H), 5.75 (d, J ) 11.2 Hz, 1 H), 5.69
Trimethylvinyl Stannane (+)-58. A solution of (+)-30 (25.5 mg,
0.042 mmol) in N-methyl-2-pyrrolidinone (NMP) (0.4 mL) was
degassed with argon for 5 min, treated with tris(dibenzylideneacetone)-
dipalladium (Pd dba ) (3.7 mg, 0.004 mmol), and degassed with argon
ddd, J ) 14.1, 6.7, 6.7 Hz, 1 H), 5.17-5.09 (m, 1 H), 4.95-4.90 (m,
H), 4.57-4.52 (m, 1 H), 4.49-4.45 (m, 1 H), 2.88-2.80 (m, 2 H),
.71-2.56 (m, 4 H), 2.15-2.09 (m, 1 H), 2.04-1.97 (m, 2 H), 1.70-
2
3
.40 (m, 3 H), 1.20 (d, J ) 6.0 Hz, 3 H); 1 C NMR (125 MHz, CDCl
3
3
)
5 min further. The reaction mixture was treated with hexamethylditin
(12 µL, 0.055 mmol), stirred for 30 min, diluted with ether (20 mL),
washed with water (10 mL) and brine (10 mL), dried over MgSO4,
filtered, and concentrated. Flash chromatography (gradient elution,
hexanes f hexanes/ethyl acetate, 9:1) provided (+)-58 (17.5 mg, 64%
δ 166.2, 142.7, 139.3, 136.0, 135.0, 132.8, 130.7, 130.4, 129.9, 128.3,
1
2
1
6
27.6, 125.0, 118.8, 71.3, 70.9, 70.4, 69.6, 41.5, 41.0, 35.5, 35.1, 32.0,
4.1, 19.9; (125 MHz, acetone-d ) δ 166.4, 144.0, 142.0, 137.9, 135.9,
6
34.2, 131.4, 130.7, 130.0, 129.6, 128.3, 125.0, 117.9, 71.4, 71.0, 69.5,
2
3
9.1, 43.2, 42.9, 36.3, 35.7, 32.5, 25.4, 20.1; high-resolution mass
yield) as a colorless oil: [R] +13 (c 0.49, CHCl ); IR (CHCl ) 1730
D
3
3
+
-1 1
spectrum (FAB, NBA) m/z 425.2318 [(M + Na) ; calcd for C24
H
34
O
5
-
(m) cm ; H NMR (500 MHz, CDCl ) δ 6.43 (apparent dt, J ) 12.6,
3
Na: 425.2304].
6.5 Hz, 1 H), 6.05-5.95 (m, 2 H), 5.87 (dd, J ) 12.6, 1.0 Hz, 1 H),
5.62 (dt, J ) 14.5, 7.0 Hz, 1 H), 5.48 (dd, J ) 14.5, 7.5 Hz, 1 H),
4.23-4.17 (m, 1 H), 3.89-3.84 (m, 1 H), 3.80-3.77 (m, 1 H), 2.25-
2.21 (m, 2 H), 2.11-2.07 (m, 2 H), 1.70-1.40 (m, 6 H), 1.17 (d, J )
6.2 Hz, 3 H), 0.87-0.86 (m, 18 H), 0.14 (s, 9 H), 0.05 (s, 3 H), 0.03
Macrolactin A [(-)-1] via (-)-40. A solution of protected
macrocycle (-)-40 (18.2 mg, 0.024 mmol) in anhydrous THF (0.5 mL)
was treated with a mixture of TBAF/AcOH (1:1, ca. 1 M in THF, 0.37
mL, 0.37 mmol). The flask was wrapped in aluminum foil and the
reaction mixture stirred at room temperature for 5 d. Concentration
(s, 3 H), 0.025 (s, 3 H), -0.01 (s, 3 H); 13C NMR (125 MHz, CDCl
)
3
and flash chromatography (CHCl
mg, 49% yield) that was equivalent in all respects to synthetic (-)-1
prepared via (-)-55.
3
/MeOH, 9:1) furnished (-)-1 (4.9
δ 145.3, 134.8, 134.2, 130.9, 130.01, 129.97, 71.0, 69.2, 68.0, 46.7,
44.7, 38.8, 32.5, 25.97, 25.96, 25.4, 23.5, 18.2, 18.1, -3.5, -3.8, -4.2,
-4.5, -8.6; high-resolution mass spectrum (FAB, NBA) m/z 669.3134
+
Macrolactin A Triacetate (+)-56. Synthetic macrolactin A (-)-1
2.6 mg, 0.006 mmol) was treated with pyridine (0.1 mL), acetic
[(M + Na) ; calcd for C30
H
62
3
O Si
2
SnNa: 669.3157].
(
Trimethylvinyl Stannane (+)-59. A solution of acid (+)-57 (59.2
mg, 0.145 mmol) and alcohol (+)-58 (85.1 mg, 0.132 mmol) in
anhydrous benzene (3 mL) was cooled to 10 °C, treated with
triphenylphosphine (208 mg, 0.792 mmol), and stirred for 5 min at 10
°C. Diethyl azodicarboxylate (DEAD) (0.125 mL, 0.792 mmol) was
added dropwise via syringe, and the reaction mixture was stirred 20
min further and then diluted with hexanes (20 mL), washed with water
anhydride (0.015 mL, 0.159 mmol), and a single crystal of N,N-
dimethylamino)pyridine (DMAP). The reaction mixture was stirred
for 2 h, diluted with ethyl acetate (20 mL), washed with brine (5 mL),
dried over MgSO , filtered, and concentrated. Flash chromatography
(
4
2
3
(
(
6
6
5
hexanes/acetone, 3:2) gave (+)-56 (1.8 mg, 54% yield). [R]
D
+5.3
1
c 0.15, CHCl ); H NMR (500 MHz, CDCl ) δ 7.24-7.22 (m, 1 H),
3
3
.49 (t, J ) 11.5 Hz, 1 H), 6.46 (dd, J ) 15.2, 11.1 Hz, 1 H), 6.17-
.08 (m, 2 H), 6.00-5.91 (m, 2 H), 5.58 (d, J ) 11.5 Hz, 1 H), 5.55-
.44 (m, 2 H), 5.42-5.35 (m, 1 H), 5.33-5.28 (m, 1 H), 5.04-5.01
4
(15 mL) and brine (15 mL), dried over MgSO , filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 9:1) af-
2
3
forded (+)-59 (112.2 mg, 83% yield) as a colorless oil: [R]
D
+25 (c
-
1 1
(
m, 1 H), 4.99-4.94 (m, 1 H), 2.59-2.39 (m, 4 H), 2.20-1.60 (complex
0.73, CHCl
3
); IR (CHCl
3
) 1705 (s) cm ; H NMR (500 MHz, CDCl )
3
series of m, 8 H), 2.06 (s, 3 H), 2.01 (s, 3 H), 1.98 (s, 3 H), 1.24 (d,
δ 7.38 (dd, J ) 15.3, 11.2 Hz, 1 H), 6.50 (dd, J ) 14.4, 5.7 Hz, 1 H),
6.50 (t, J ) 12.0 Hz, 1 H), 6.43 (dt, J ) 12.6, 6.8 Hz, 1 H), 6.24 (dd,
J ) 14.5, 1.1 Hz, 1 H), 6.05-5.94 (m, 3 H), 5.87 (d, J ) 12.6 Hz, 1
H), 5.61 (dt, J ) 12.3, 7.1 Hz, 1 H), 5.56 (d, J ) 11.3 Hz, 1 H), 5.48
(dd, J ) 14.6, 7.3 Hz, 1 H), 4.95-4.92 (m, 1 H), 4.22-4.14 (m, 1 H),
3.88-3.84 (m, 1 H) 2.37 (apparent t, J ) 9.4 Hz, 2 H), 2.22 (apparent
t, J ) 6.6 Hz, 2 H), 2.10-2.05 (m, 2 H), 1.71-1.3 (m, 6 H), 1.22 (d,
J ) 6.3 Hz, 3 H), 0.870 (s, 9 H), 0.869 (s, 9 H), 0.86 (s, 9 H), 0.14 (s,
9 H), 0.05 (s, 3 H), 0.030 (s, 3 H), 0.026 (s, 3 H), 0.023 (s, 3 H), 0.019
1
3
J ) 6.2 Hz, 1 H); C NMR (125 MHz, CDCl
3
) δ 170.4, 170.2, 170.1,
1
1
2
66.1, 142.9, 138.1, 135.9, 132.7, 131.7, 130.9, 129.8, 129.7, 128.3,
27.2, 127.1, 118.1, 73.3, 70.7, 70.6, 69.6, 38.8, 37.4, 34.9, 32.2, 31.8,
9.7, 24.4, 21.2, 21.1, 19.9.
Macrolactinic Acid (-)-7. A solution of synthetic macrolactin A
-)-1 (3.9 mg, 0.01 mmol) in methanol (0.8 mL) was treated with
(
KOH (1 N, 0.4 mL), stirred at 40 °C for 2 h, and then treated further
with KOH (1 N, 0.2 mL) and stirred for 0.5 h. The reaction mixture
was cooled to 0 °C, acidified with HCl (1 N, 0.6 mL), diluted with
water (2 mL), and extracted with ethyl acetate (2 × 10 mL). The
(s, 3 H), 0.00 (s, 3 H); 13C NMR (125 MHz, CDCl
) δ 166.0, 148.2,
3
145.3, 144.4, 139.5, 134.9, 134.0, 130.9, 130.1, 129.9, 129.5, 128.3,
117.0, 74.7, 71.0, 70.4, 69.1, 46.7, 44.7, 41.1, 35.6, 32.4, 25.9 (2C),
25.8, 25.1, 20.1, 18.2 (2C), 18.1, -3.5, -3.8, -4.2, -4.5, -4.6, -4.9,
4
combined ethyl acetate extracts were dried with MgSO , filtered, and
concentrated. Filtration (SiO
afforded (-)-7 (3.4 mg, 69% yield) as a yellow oil: [R]
.29, MeOH); IR (CHCl ) 3600 (br w), 2950 (s), 1725 (s) cm ; H
NMR (500 MHz, MeOD) δ 7.37 (dd, J ) 14.8, 11.6 Hz, 1 H), 6.57
2
plug, ethyl acetate) and concentration
2
3
-13.03 (c
-8.6 high-resolution mass spectrum (FAB, NBA) m/z 1059.3657 [(M
D
-
1
1
+
0
3
+ Na) ; calcd for C45
H85IO
5
Si
3
SnNa: 1059.3671].
7,13,15-Tris(O-TBS) Macrolacin A (-)-40 via (+)-59. A solution
(
(
dd, J ) 11.1, 11.0 Hz, 1 H), 6.52 (dd, J ) 14.9, 11.3 Hz, 1 H), 6.16
dd, J ) 15.2, 10.8 Hz, 1 H), 6.08-5.99 (m, 3 H), 5.69 (dd, J ) 14.9,
of (+)-59 (123.8 mg, 0.119 mmol), N,N-diisopropylethylamine (DIPEA)
11
(0.21 mL, 1.19 mmol), and tetrabutylammonium diphenylphosphonate