Fully Functionalized seco-Pancratistatin Analogues
Journal of Natural Products, 2008, Vol. 71, No. 3 361
5.90–5.92 (2H, s, OCH2O), 6.69 (1H, d, J ) 8.4 Hz, H-6′), 6.83 (1H,
dd, J ) 1.2, 8.4 Hz, H-5′), 6.86 (1H, d, J ) 1.2 Hz, H-2′); 13C NMR
(150 MHz, CDCl3) δ -5.00 (3q, Si(CH3)3), 0.77 (2q, Si(CH3)2), 14.3
(q, C-7′′), 18.2 (q, C-8′′), 18.7 (s, SiC(CH3)3), 26.1 (3q, SiC(CH3)3),
26.7 (q, O-C(CH3)2-O), 27.2 (q, O-C(CH3)2-O), 28.2 (d, C-6′′), 51.3
(d, C-2), 59.2 (d, C-4′′), 62.4 (t, C-5′′), 63.4 (t, C-6), 73.6 (d, C-3),
76.7 (d, C-5), 78.0 (d, C-4), 101.2 (t, OCH2O), 107.9 (s, O-C(CH3)2-
O), 108.5 (d, C-6′), 110.2 (d, C-2′), 123.6 (d, C-5′), 128.5 (s, C-1′),
147.5 (s, C-4′), 147.9 (s, C-3′), 153.7 (s, C-2′′), 172.2 (s, C-1); HRMS
(CI) calcd 638.3181 for C31H52NO9Si2, found 638.3170.
(s, O-C(CH3)2-O), 122.0 (d, C-5′), 126.3 (2d, C-3′′′, C-5′′′), 128.3 (2d,
C-2′′′, C-6′′′), 129.1 (d, C-4′′′), 131.2 (s, C-1′), 138.6 (s, C-1′′′), 146.9
(s, C-4′), 148.0 (s, C-3′); HRMS (CI) calcd 529.2622 for C29H41O7Si,
found 529.2625.
Preparation of [(2R,3R,4S,5S)-1-Bromo-2-(3′,4′-methylenedioxy)
phenyl-3-(O)-benzoyl-4,5-isopropylidenedioxy-6-tert-butyldimethyl-
silyloxy]hexane (22). Benzylidene 21 (0.100 g, 0.189 mmol) was
dissolved at room temperature in 1.9 mL of dry benzene (10 mL/mmol)
under argon, and N-bromosuccinimide (NBS) (0.034 g, 0.189 mmol)
and azoisobutyronitrile (AIBN) (3.1 mg, 0.0189 mmol) were added to
the stirred solution, which was then heated to 60 °C. Within 1 h the
reaction was complete, as indicated by TLC (10:90, EtOAc/hexane),
whereupon the mixture was diluted with saturated NaHCO3 solution
(5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic
fractions were dried over anhydrous Na2SO4 and filtered, and solvent
was removed under vacuum to give an amorphous residue, which was
columned on silica gel with 10:90 EtOAc/hexane, affording bromide
Preparation of [(2R,3R,4S,5S)-2-(3′,4′-Methylenedioxy)phenyl-
4,5-isopropylidenedioxy-6-tert-butyldimethylsilyloxy]hexan-1,3-
diol (20). A 98.1 mM solution of aldol adduct 19 (0.175 g, 0.275
mmol) in THF/MeOH (95:5) was cooled to 0 °C, and LiBH4 (0.024 g,
1.099 mmol) was slowly added to the stirred mixture under positive
argon pressure. After TLC (50:50, EtOAc/hexane) indicated consump-
tion of all starting material (∼3 h), the reaction mixture was diluted
with saturated NH4Cl solution (3 mL) and extracted with EtOAc (3 ×
3 mL). The pooled organic fractions were dried over anhydrous Na2SO4
and filtered to give an amorphous gum, which was subjected to column
chromatography on silica gel with 50:50 EtOAc/hexane, affording diol
20 as a colorless oil in 88% yield. Compound 20: [R]25D -80.0 (CHCl3,
c 0.2); IR νmax cm-1 (NaCl) 3405 (OH), 2936, 2865, 1670 (Ph), 1492,
1445, 1362, 1255 (SiCH3), 1130, 1074 (C-O), 934 (OCH2O); CIMS
70 eV, m/z (rel int) 441 [M + 1]+ (20), 383 (10), 307 (15), 255 (15),
22 as a pale yellow oil in 70% yield. Compound 22: [R]25 +22.5
D
(CHCl3, c 0.2); IR νmax cm-1 (NaCl) 2858, 2338, 1719 (CdO), 1653
(Ph), 1559, 1507, 1490, 1456, 1376, 1248 (SiCH3), 1041 (C-O), 936
(OCH2O); CIMS 70 eV, m/z (rel int) 607 [M + 1]+ (15), 551 (10),
529 (25), 471 (13), 407 (5), 349 (17), 291 (18), 279 (23), 201 (15),
1
149 (45), 105 (100), 77 (34); H NMR (600 MHz, CDCl3), δ -0.05
(6H, s, Si(CH3)2), 0.80 (9H, s, SiC(CH3)3), 1.30 (3H, s, O-C(CH3)2-
O), 1.43 (3H, s, O-C(CH3)2-O), 3.56 (1H, ddd, J ) 5.0, 7.0, 9.6 Hz,
H-2), 3.61 (1H, dd, J ) 7.0, 10.0 Hz, H-1a), 3.65 (1H, dd, J ) 5.0,
10.0 Hz, H-1b), 3.67 (1H, dd, J ) 4.8, 10.5 Hz, H-6a), 3.69 (1H, dd,
J ) 6.5, 10.5 Hz, H-6b), 3.71 (1H, ddd, J ) 4.8, 6.5, 8.4 Hz, H-5),
3.90 (1H, d, J ) 8.4 Hz, H-4), 5.38 (1H, d, J ) 9.6 Hz, H-3), 5.97
(2H, s, OCH2O), 6.80 (1H, d, J ) 8.4 Hz, H-6′), 6.82 (1H, dd, J )
1.2, 8.4 Hz, H-5′), 6.84 (1H, d, J ) 1.2 Hz, H-2′), 7.50 (2H, dd, J )
7.8, 7.8 Hz, H-3′′, H-5′′), 7.62 (1H, dd, J ) 7.2, 1.2 Hz, H-4′′), 8.13
(2H, dd, J ) 1.2, 7.2 Hz, H-2′′,H-6′′); 13C NMR (150 MHz, CDCl3) δ
0.01 (2q, Si(CH3)2), 18.3 (s, SiC(CH3)3), 26.4 (3q, SiC(CH3)3), 27.0
(q, O-C(CH3)2-O), 27.2 (q, O-C(CH3)2-O), 34.9 (d, C-2), 49.7 (t, C-1),
61.9 (t, C-6), 73.8 (d, C-3), 76.6 (d, C-5), 76.8 (d, C-4), 101.3 (t,
OCH2O), 108.6 (d, C-6′), 108.7 (d, C-2′), 109.1 (s, O-C(CH3)2-O), 122.1
(d, C-5′), 128.8 (2d, C-3′′, C-5′′), 129.5 (s, C-1′), 130.1 (2d, C-2′′,
C-6′′), 132.4 (s, C-1′′), 133.7 (d, C-4′′), 147.3 (s, C-4′), 148.1 (s, C-3′),
166.4 (s, CdO); HRMS (CI) calcd 607.1727 for C29H39SiBrO7, found
607.1737.
1
219 (25), 155 (30), 135 (100). H NMR (700 MHz, CDCl3), δ 0.00
(6H, s, Si(CH3)2), 0.81 (9H, s, SiC(CH3)3), 1.31 (3H, s, O-C(CH3)2-
O), 1.44 (3H, s, O-C(CH3)2-O), 2.96 (1H, ddd, J ) 5.6, 7.0, 9.8 Hz,
H-2), 3.56 (1H, dd, J ) 3.5, 10.5 Hz, H-6a), 3.63 (1H, dd, J ) 5.6,
10.5 Hz, H-6b), 3.78 (1H, d, J ) 9.8 Hz, H-4), 3.84 (1H, dd, J ) 9.8,
9.8 Hz, H-3), 3.87 (1H, dd, J ) 7.0, 10.8 Hz, H-1a), 4.00 (1H, ddd, J
) 3.5, 5.6, 9.8 Hz, H-5), 4.07 (1H, dd, J ) 5.6, 10.8 Hz, H-1b), 5.92
(2H, s, OCH2O), 6.67 (1H, dd, J ) 1.4, 8.0 Hz, H-5′), 6.71 (1H, d, J
) 1.4 Hz, H-2′), 6.74 (1H, d, J ) 8.0 Hz, H-6′); 13C NMR (176 MHz,
CDCl3) δ -5.51 (2q, Si(CH3)2), 18.3 (s, SiC(CH3)3), 26.0 (3q,
SiC(CH3)3), 26.8 (q, O-C(CH3)2-O), 27.1 (q, O-C(CH3)2-O), 49.8 (d,
C-2), 63.8 (t, C-6), 63.9 (t, C-1), 75.8 (d, C-3), 76.9 (d, C-5), 79.8 (d,
C-4), 101.0 (t, OCH2O), 108.4 (d, C-2′), 108.8 (d, C-6′), 109.2 (s,
O-C(CH3)2-O), 122.0 (d, C-5′), 134.9 (s, C-1′), 146.5 (s, C-4′), 147.8
(s, C-3′); HRMS (CI) calcd 441.2309 for C22H37O7Si, found 441.2301.
Preparation of [(2R,4R,1′′R,2′′S,5R)-2-Phenyl-4-(1′′,2′′-isopropy-
lidenedioxy-3′′-tert-butyldimethylsilyloxypropyl)-5-(3′,4′-methylene-
dioxy)phenyl]-1,3-dioxane (21). Benzaldehyde dimethyl acetal (BDMA)
(0.041 mL, 0.273 mmol) was added slowly under an atmosphere of
argon to a solution of diol 20 (0.120 g, 0.273 mmol) and p-
toluenesulfonic acid monohydrate (5.00 mg, 0.0273 mmol) in dry
dichloromethane (2.7 mL). After 15 min stirring at room temperature,
TLC (15% EtOAc in hexane) indicated the reaction to be complete.
The mixture was then diluted with 3 mL of saturated NaHCO3 solution
and extracted with dichloromethane (3 × 3 mL), and the combined
organic fractions were dried over anhydrous Na2SO4 and filtered. The
residue obtained after vacuum removal of solvent was loaded on a silica
gel column and eluted with 15% EtOAc in hexane, giving benzylidene
21 (95%) as white crystals, which were recrystallized from EtOAc/
Preparation of [(2R,3R,4S,5S)-1-Azido-2-(3′,4′-methylenedioxy)
phenyl-3-(O)-benzoyl-4,5-isopropylidenedioxy-6-tert-butyldimethyl-
silyloxy]hexane (23). Sodium azide (10.71 mg, 0.165 mmol) was added
at room temperature under argon to a stirred solution of bromide 22
(0.100 g, 0.165 mmol) in dry DMF (1.7 mL, 10 mL/mmol), and the
temperature was raised to 60 °C. TLC (10:90 EtOAc/hexane) indicated
the reaction to be complete after ∼5 h. The reaction mixture was then
diluted with saturated NaCl solution (3 mL) and extracted with EtOAc
(3 × 3 mL). The pooled organic fractions were dried over anhydrous
Na2SO4 and filtered, and the solvent was removed under vacuum to
give a crude gum, which was eluted with 10:90 EtOAc/hexane on silica
gel, affording azide 23 as a colorless oil in 85% yield. Compound 23:
[R]25 +25.3 (CHCl3, c 0.2); IR νmax cm-1 (NaCl) 2858, 2337, 2101
D
hexane. Compound 21: mp 73–75 °C. [R]25 -44.0 (CHCl3, c 0.15);
(N3), 1719 (CdO), 1653 (Ph), 1559, 1507, 1490, 1457, 1376, 1250
(SiCH3), 1064 (C-O), 938 (OCH2O); CIMS 70 eV, m/z (rel int) 570
[M + 1]+ (5), 526 (15), 420 (17), 344 (10), 286 (10), 232 (12), 213
(15), 135 (20), 122 (50), 105 (100), 77 (37); 1H NMR (700 MHz,
CDCl3) δ -0.039 (6H, s, Si(CH3)2), 0.79 (9H, s, SiC(CH3)3), 1.30 (3H,
s, O-C(CH3)2-O), 1.44 (3H, s, O-C(CH3)2-O), 3.52 (1H, ddd, J ) 5.0,
7.0, 10.5 Hz, H-2), 3.58 (1H, dd, J ) 7.0, 10.5 Hz, H-1a), 3.59 (1H,
dd, J ) 5.0, 10.5 Hz, H-1b), 3.61 (1H, dd, J ) 4.8, 10.5 Hz, H-6a),
3.62 (1H, dd, J ) 6.6, 10.5 Hz, H-6b), 3.67 (1H, ddd, J ) 4.8, 6.6, 8.4
Hz, H-5), 3.89 (1H, dd, J ) 1.4, 8.4 Hz, H-4), 5.40 (1H, d, J ) 10.5
Hz, H-3), 5.96 (2H, s, OCH2O), 6.80 (1H, d, J ) 8.4 Hz, H-6′), 6.84
(1H, dd, J ) 1.4, 8.4 Hz, H-5′), 6.86 (1H, d, J ) 1.4 Hz, H-2′), 7.50
(2H, dd, J ) 7.7, 8.4 Hz, H-3”, H-5′′), 7.62 (1H, t, J ) 7.7 Hz, H-4′′),
8.13 (2H, dd, J ) 1.4, 8.4 Hz, H-2”, H-6′′); 13C NMR (176 MHz,
CDCl3) δ -5.55 (q, Si(CH3)2), -5.47 (q, Si(CH3)2), 18.3 (s, SiC(CH3)3),
25.9 (3q, SiC(CH3)3), 27.0 (q, O-C(CH3)2-O), 27.2 (q, O-C(CH3)2-O),
47.2 (d, C-2), 53.6 (t, C-1), 61.9 (t, C-6), 72.7 (d, C-3), 76.2 (d, C-5),
76.7 (d, C-4), 101.3 (t, OCH2O), 108.8 (d, C-6′), 108.9 (d, C-2′), 109.1
(s, O-C(CH3)2-O), 122.1 (d, C-5′), 128.9 (2d, C-3”, C-5′′), 129.5 (s,
C-1′), 130.1 (2d, C-2′′, C-6′′), 131.9 (s, C-1”), 133.7 (d, C-4′′), 147.4
D
IR νmax cm-1 (NaCl) 2930, 2875, 1673 (Ph), 1490, 1452, 1360, 1253
(SiCH3), 1135, 1064 (C-O), 933 (OCH2O). 70 eV, m/z (rel int) 529
[M + 1]+ (15), 513 (30), 471 (35), 453 (25), 413 (20), 347 (30), 307
1
(65), 289 (35), 215 (35), 187 (40), 161 (90), 148 (100), 135 (40); H
NMR (600 MHz, CDCl3) δ 0.00 (6H, s, Si(CH3)2), 0.84 (9H, s,
SiC(CH3)3), 1.33 (3H, s, O-C(CH3)2-O), 1.42 (3H, s, O-C(CH3)2-O),
3.39 (1H, ddd, J ) 4.8, 11.4, 12.0 Hz, H-5), 3.54 (1H, dd, J ) 6.6,
10.2 Hz, H-3′′a), 3.74 (1H, dd, J ) 3.6, 10.2 Hz, H-3′′b), 3.76 (1H,
dd, J ) 4.8, 10.8 Hz, H-6a), 3.94 (1H, dd, J ) 10.8, 12.0 Hz, H-6b),
3.99 (1H, dd, J ) 4.8, 9.0 Hz, H-1′′), 4.26 (1H, dd, J ) 4.8, 11.4 Hz,
H-4), 4.29 (1H, ddd, J ) 3.6, 6.6, 9.0 Hz, H-2′′), 5.62 (1H, s, O-CH(Ph)-
O), 5.95 (2H, s, OCH2O), 6.74 (1H, dd, J ) 1.8, 8.0 Hz, H-5′), 6.77
(1H, d, J ) 1.8 Hz, H-2′), 6.78 (1H, d, J ) 8.0 Hz, H-6′), 7.35 (1H,
d, J ) 8.4 Hz, H-4′′′), 7.37 (2H, d, J ) 8.4 Hz, H-3′′′, H-5′′′), 7.54
(2H, d, J ) 8.4 Hz, H-2′′′, H-6′′′); 13C NMR (150 MHz, CDCl3) δ
1.05 (2q, Si(CH3)2), 18.3 (s, SiC(CH3)3), 26.0 (3q, SiC(CH3)3), 26.9
(q, O-C(CH3)2-O), 27.5 (q, O-C(CH3)2-O), 42.7 (d, C-5), 64.0 (t, C-3′′),
72.4 (d, C-4), 74.9 (d, C-2′′), 78.0 (t, C-6), 79.9 (d, C-1′′), 101.2 (t,
OCH2O), 101.9 (d, O-CH(Ph)-O), 108.7 (d, C-6′), 108.9 (d, C-2′), 109.5