Zhu and Mootoo
SCHEME 5a
Diisopropylethylamine (40 mL, 0.35 mmol) was added to a
solution of 10 (163 mg, 0.23 mmol) and triphenylphosphine
(240 mg, 0.92 mmol) in anhydrous toluene (4 mL) and
acetonitrile (2 mL). The reaction mixture was heated at reflux
under an atmosphere of argon for 24 h. Most of the solvent
was then removed under reduced pressure. The resulting
syrup was triturated with cold hexane. Drying of the residue
under high vacuum for 12 h afforded 3 as a white solid (220
mg, 90%): Rf ) 0.42 (80% EtOAc/20% MeOH); [R]22 +12 (c
D
1
1.6, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.6-7.9 (m, 15H),
4.5-4.9 (m, 6H), 3.80-4.00 (m, 3H), 3.60-3.80 (m, 1H), 3.40-
3.50 (m, 3H), 3.36 (s, 3H), 3.35 (s, 3H), 3.34 (s, 3H), 1.30-2.00
(m, 20H), 1.20 (s, br, 18H), 0.85 (t, 3H, J ) 6.5 Hz); 13C NMR
(CDCl3, 75 MHz) δ 135.7, 135.7, 134.4, 134.3, 131.3, 131.1,
97.4, 82.3, 81.7, 80.9, 80.7, 80.4, 79.5, 56.5, 35.7, 32.8, 32.6,
32.1, 30.6, 30.3, 30.1, 29.2, 29.2, 28.0, 27.7, 26.3, 23.4, 14.8;
HRMS (ESI) calcd for C51H78O8P (M -I -) 849.5434, found
849.5440.
a
Reaction conditions: (a) BuLi, THF, -78 °C, 44%; (b)
Rh(PPh3)3Cl, H2, 89%; (c) AcCl, MeOH-CH2Cl2, 71%.
sequence used by Keinan and Sinha. The 1H and 13C
NMR spectra for compound 2 and the material obtained
by this group were essentially identical. Unfortunately,
the unavailability of optical rotation data for the original
sample of 2 did not allow for a direct comparison of optical
purity.
Bis-THF -bu ten olid e 16. BuLi (2.5 M solution in hexane,
12.3 mL, 0.029 mmol) was added dropwise to a solution of 3
(28 mg, 0.028 mmol) in dry THF (1 mL) at 0 °C, under an
atmosphere of argon. The mixture was stirred for 30 min, and
a solution of 2 (25 mg, 0.057 mmol) in dry THF (1 mL) was
added dropwise at -78 °C. The reaction was warmed to rt,
quenched with saturated aqueous NH4Cl, and extracted with
ether. The combined organic phase was dried (Na2SO4),
filtered, and concentrated under reduced pressure. FCC of the
crude product provided 16 (12.6 mg, 44%): Rf ) 0.30 (20%
Treatment of the ylide generated by treatment of
phosphonium salt 3 with butyllithium, with 2 equivalents
of aldehyde 2, following the reported protocol,6 afforded
alkene 16 in 44% yield as an undetermined mixture of
E/Z isomers (Scheme 5). Selective hydrogention of 16 and
exposure of the product to methanolic HCl provided 1.
EtOAc/petroleum ether); [R]22 +7.4 (c 0.60, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 7.65-7.67 (m, 4H), 7.35-7.43 (m, 6H),
6.91 (s, 1H), 5.08-5.12 (m, 1H), 5.22-5.25 (m, 1H), 4.82-4.89
(m, 4H), 4.65-4.68 (m, 3H), 4.03 (t, 1H, J ) 5.5 Hz), 3.96-
3.97 (m, 3H), 3.85 (m, 1H), 3.44 (m, 3H), 3.39 (s, 9H), 2.45 (t,
2H, J ) 5.5 Hz), 1.91-1.99 (m, 8H), 1.38-1.74 (m, 16H), 1.31
(d, 3H, J ) 7 Hz), 1.2 (s, br, 16H), 1.0 (s, 9H), 0.85 (t, 3H, J )
5.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 173.9, 151.3, 136.0, 134.2,
130.8, 130.2, 129.9, 129.2, 127.8, 97.0, 81.8, 81.2, 80.3, 80.0,
79.4, 71.8, 56.0, 36.7, 35.8, 32.5, 32.2, 32.1, 31.6, 30.1, 30.0,
29.9, 29.6, 28.9, 28.8, 28.8, 27.6, 27.5, 27.4, 26.7, 25.9, 23.2,
23.0, 19.7, 19.3, 14.4; HRMS (ESI) calcd for C59H94O11Si (M +
Na+) 1029.6463, found 1029.6437.
The H and 13C NMR were essentially identical to those
1
for bullatanocin (squamostatin C, Supporting Informa-
tion). The [R]D’s of 1 in CHCl3 and MeOH were found to
be 16.5 and 18.7 compared with corresponding values of
14.4 (bullatanocin) and 12.0 (squamostatin C), respec-
tively.
In summary, the total synthesis of the acetogenin
bullatanocin (squamostatin C) has been described, thereby
supporting the structure originally assigned to the natu-
ral product. A feature of this synthesis is the three-
component modular design. In principle, this approach
should be applicable to stereoisomers and homologues of
building blocks 2, 4, and 5 and is well suited to split
synthesis of libraries of nonadjacently linked cyclic ether
containing acetogenins.13
Bu lla ta n ocin 1. Chlorotris(triphenylphosphine)rhodium-
(I) (1.7 mg, 1.8 mmol) was added to a degassed solution of 16
(12 mg, 12 µmol) in benzene-EtOH (1:1, 0.5 mL), and the
mixture was stirred under an atmosphere of hydrogen for 12
h. The solvent was removed under reduced pressure, and the
residue was purified by FCC to give the 7,8-dihydro derivative
of 16 (10.8 mg, 89%): Rf ) 0.56 (30% EtOAc/70% petroleum
ether); [R]22D +9.5 (c 0.42, CHCl3); 1H NMR (CDCl3, 500 MHz)
δ 7.63-7.70 (m, 4H), 7.36-7.42 (m, 6H), 6.91 (s, 1H), 4.84-
4.89 (m, 4H), 4.68 (m, 3H), 3.98 (m, 4H), 3.85 (m, 1H), 3.45
(m, 3H), 3.39 (s, 9H), 2.43 (s, 2H), 1.90-2.00 (m, 8H), 1.00-
1.70 (m, 23H), 1.6 (s, br, 16H), 1.0 (s, 9H), 0.88 (t, 3H, J ) 7.0
Hz); 13C NMR (CDCl3, 75 MHz) δ 151.2, 136.0, 134.4, 130.9,
129.8, 128.5, 127.7, 97.0, 81.8, 81.1, 80.3, 80.3, 80.0, 79.6, 72.1,
56.0, 36.8, 36.2, 32.6, 32.2, 31.7, 30.7, 30.2, 29.9, 29.7, 29.6,
28.9, 28.8, 28.8, 27.6, 27.5, 27.4, 26.6, 25.9, 25.2, 23.0, 22.7,
19.7, 19.3, 14.4; HRMS (ESI) calcd for C59H96O11Si (M + Na+)
1031.6620, found 1031.6587.
Exp er im en ta l Section
P h osp h on iu m Sa lt 3. A mixture of triphenylphosphine
(139 mg, 0.13 mmol), imidazole (72 mg, 0.26 mmol), iodine (135
mg, 0.13 mmol), and benzene (100 mL) was stirred at rt for
30 min, at which time alcohol 9 (160 mg, 0.26 mmol) was
introduced. The reaction mixture was stirred at reflux for 2
h, diluted with ethyl ether (100 mL), and filtered through a
column of Florisil. The filtrate was concentrated under reduced
pressure and the residue purified by FCC to afford iodide 10
(164 mg, 88%): Rf ) 0.77 (50% EtOAc/petroleum ether); [R]22
D
AcCl (5%) in MeOH (0.15 mL) was added at rt to a solution
of the material obtained in the previous step (3.8 mg, 3.8 µmol)
in CH2Cl2 (0.5 mL). The mixture was stirred at this temper-
ature for 2 h, diluted with CH2Cl2, and washed with a
saturated aqueous NaHCO3. The organic layer was dried (Na2-
SO4), filtered, and concentrated under reduced pressure. FCC
of the residue afforded 1 (1.7 mg, 71%) and a mixture of less
polar fractions (1.8 mg) that appeared to be partially depro-
tected products. For 1: Rf ) 0.36 (EtOAc); mp 97-99 °C
+18.5 (c 2.92, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.80-
4.82 (m, 3H), 4.63-4.67 (m, 3H), 3.95 (m, 3H), 3.85 (m, 1H),
3.38 (s, 3H), 3.37 (s, 6H), 3.1 (t, 2H, J ) 7 Hz), 1.6-2.0 (m,
12H), 1.3-1.5 (m, 8H), 1.20 (s, br, 16H), 0.85 (t, 3H, J ) 6.5
Hz); 13C NMR (CDCl3, 75 MHz) δ 96.9, 81.7, 81.1, 80.1, 79.8,
79.1, 56.0, 34.9, 33.8, 32.5, 32.15, 31.5, 30.1, 29.9, 29.6, 28.8,
28.7, 27.6, 27.4, 25.8, 22.9, 14.4, 7.1; HRMS (ESI) calcd for
C
33H63O8INa (M + Na) 737.3465, found 737.3478.
(EtOAc) [lit.5c mp 95-97 °C]; [R]22 +18.7 (c 0.23, MeOH),
D
+16.5 (c 0.23, CHCl3) [lit.5c [R]22 +12.0 (c 0.20, MeOH), lit.5a
D
(13) For a recent example in THF acetogenin synthesis, see: Zhang,
Q.; Lu, H.; Richard, C.; Curran, D. P. J . Am. Chem. Soc. 2004, 126,
36-37.
[R]22 +14.4 (c 0.55, CHCl3)]; 1H NMR (CDCl3, 500 MHz) δ
D
7.18 (s, 1H), 5.06 (dd, 1H, J ) 6.5 Hz), 3.78-3.88 (m, 5H),
3156 J . Org. Chem., Vol. 69, No. 9, 2004