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Abstract
The total synthesis of 27-hydroxybullatacin and its C-15 epimer has been achieved using rhenium(VII) oxides-mediated and Co(modp)2catalyzed oxidative cyclization (OC), diastereoselective alkynylation, Browns enantioselective allylboration, and Grubbs cross metathesis
as the key reactions. The inhibitory effect of these compounds on the complex I function, as determined by using bovine submitochondrial
particles, was in low nanomolar range.
2007 Elsevier Ltd. All rights reserved.
1. Introduction
27-Hydroxybullatacin, 1a,1 is an adjacent asimicin-type
bis-THF acetogenin, isolated from the leaves extract of
Annona glabra L., family Annonaceae.2,3 The absolute structure of 1a was determined on the basis of detailed NMR spectroscopy studies of the parent molecule and its Moshers
esters. Evident from its nomenclature, 27-hydroxy-bullatacin
shares a framework identical to bullatacin, 2,4 possessing the
threo-trans-threo-trans-erythro bis-THF system, though the
structure of the former remains to be confirmed. Both bullatacin and 27-hydroxybullatacin are extremely potent anticancer
compounds with reported activities of approximately 105
times higher than adriamycin against several cancer cell lines,
including human prostate adenocarcinoma (PC-3) and pancreatic carcinoma (PACA-2). 27-Hydroxybullatacin is also very
potent against the human kidney carcinoma (A-498) cell
line. Therefore, annonaceous acetogenins and an asimicintype bis-THF acetogenin (such as 1a and 2) in particular,
* Corresponding author. Tel.: 1 858 784 8512; fax: 1 858 784 8732.
E-mail address: subhash@scripps.edu (S.C. Sinha).
0040-4020/$ - see front matter 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.089
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HO
OH
HO 4
15
HO
C7H15
O
1a: 27-Hydroxybullatacin (15R)
1b: 15-epi-27-Hydroxybullatacin (15S)
erythro
threo
threo
trans
trans
HO
OH
O
C10H21
HO 4
O
2: Bullatacin
OH
O
HO
1a (15R)
1b (15S)
C7H15
RO
HO 4
15
O
O
OH
O
RO
15
RO 4
+
II
Ia (15R)
Ib (15S)
C7H15
RO
O
RO
O
RO
C7H15
O
III
IV
C7H15
OR
O
O
V
55%
HO
80%
OBz
67%
HO
90%
OBz
24
C7H15
TBSO
C7H15
C7H15
OH
O
PhS
O
TBSO
15
16
TBSO
OH
TBSO
12a (R)
12b (S)
13
84-92%
SPh
6
TBSO
17 (51%)
1a, 1b
15
67%
OH
10, 75%
O
TBSO
TBSO
73-83%
11
TBSO
C7H15
C7H15
24
TBSO
CHO
TBSO
OBz
TBSO
OBz
TBSO
O
7
9, 75%
OBz
TBSO
C7H15
O
5
TBSO
HO
Co(modp)2, TBHP,
iPrOH, RT
TBSO
1605
1. m-CPBA, CH2Cl2, 0 C
2. toluene, 90 C
90%
13
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m), 3.63 (1H, m), 3.45 (1H, m), 2.89 (2H, m), 2.85 (1H, m),
2.56 (1H, m), 2.27 (4H, m), 1.60 (2H, m).
Freshly cut pieces of Na metal (900 mg) were added in portions to liquid NH3 (30 ml) in a round bottom flask at low
temperature (78 C). After 10 min, a solution of the abovedescribed diol (1.1 g, 6.5 mmol) in dry THF (10 ml) was
added, and the mixture was stirred at this temperature for
4 h. The reaction mixture was quenched using solid NH4Cl
(2 g) and the cooling bath was removed. After ammonia has
evaporated, the mixture was diluted with water and extracted
using EtOAc. The organic layer was washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was purified over silica gel (using
CH2Cl2eCH3OH) to yield the corresponding trans olefin
product, (9R)-dec-1,5-diene-9,10-diol (1.1 g, 100% yield).
1
H NMR: d 5.83 (1H, m), 5.47 (2H, m), 4.98 (2H, m), 3.73
(1H, m), 3.64 (1H, m), 3.44 (1H, m), 2.21 (8H, m), 1.50
(2H, m); 13C NMR: d 138.32, 130.48, 129.84, 114.62, 71.80,
66.74, 33.68, 32.81, 31.89, 28.63.
Benzoyl chloride (0.37 ml, 3.1 mmol) was added dropwise
to a solution of the above-described diol product (450 mg,
2.6 mmol) and Et3N (0.56 ml, 4 mmol) in CH2Cl2 (20 ml).
The solution was stirred overnight at 0 C, then diluted with
CH2Cl2, washed sequentially with saturated NaHCO3 solution
and brine, and evaporated. The residue was purified by flash
chromatography (using hexaneeEtOAc) to afford the mono
protected compound 4 (600 mg, 82%). 1H NMR: d 8.06 (2H,
d, J8.0 Hz), 7.56 (1H, t, J7.0 Hz), 7.44 (2H, t, J7 Hz), 5.81
(1H, m), 5.47 (2H, m), 4.97 (2H, m), 4.37 (1H, m), 4.23 (1H,
m), 3.99 (1H, m), 2.19 (6H, m), 1.62 (2H, m); 13C NMR: d
166.70, 138.31, 133.12, 133.12, 130.61, 129.82, 129.61,
129.59, 128.37, 114.58, 69.49, 69.04, 33.64, 33.09, 31.87,
28.45.
3.3. ((2R,5R)-5-((R)-1-Hydroxypent-4-enyl)tetrahydrofuran-2-yl)methyl benzoate 5
TFAOReO3 was prepared in situ as described in literature.18
In a general process, Re2O7 (484 mg, 1 mmol) was transferred
into a flask, and THF (10 ml) and TFAA (170 ml, 1.2 mmol)
were added sequentially. The mixture was stirred at room temperature for 1 h. The flask was cooled using an ice cold bath
and solvents were removed in vacuo. The residue was washed
twice using cold pentane and used directly for the OC reaction. Cold CH2Cl2 (10 ml) was added to the above prepared
TFAOReO3 and the mixture was cooled to 0 C. A cold solution of TFAA (170 ml, 1.2 mmol) and compound 4 (140 mg,
0.5 mmol) in CH2Cl2 (5 ml) was added dropwise sequentially.
After the reaction was stirred at 0 C to room temperature for
4 h, the reaction mixture was worked up using a saturated
solution of NaHCO3 (5 ml) and 30% H2O2 (0.5 ml), then
extraction with EtOAc. The organic layer was washed with
saturated NaHSO3 solution followed by brine, dried over
Na2SO4, and solvents were removed. The resulting residue
was purified over silica gel using hexaneseEtOAc as the eluting solvents affording the corresponding trans-mono OC product, 5. 1H NMR: d 7.98 (2H, d, J7.0 Hz), 7.54 (1H, t,
J7.5 Hz), 7.41 (2H, t, J7.0 Hz), 5.78 (1H, m), 5.04 (1H, dd,
J17.0, 1.0 Hz), 4.98 (1H, d, J10.0 Hz), 4.56 (1H, m), 4.35
(2H, m), 4.26 (1H, m), 4.10 (1H, m), 3.04 (3H, s), 2.28e2.06
(4H, m), 1.78 (1H, m), 1.66 (3H, m); 13C NMR d 166.08,
136.81, 133.01, 129.75, 129.37, 128.29, 115.63, 85.38,
80.19, 76.71, 66.36, 38.71, 30.41, 28.90, 28.59, 28.33.
3.4. ((2R,20 R,5R,50 R)-50 -(Hydroxymethyl)octahydro-2,20 bifuran-5-yl)methyl benzoate 6
TBHP (0.1 ml, 0.5e0.6 mmol, 5e6 M in decane) was
added dropwise to a well-stirred solution of 5 (150 mg,
0.5 mmol) and Co(modp)2 (41 mg, 0.076 mmol) in 10 ml isopropanol and 0.05 ml water under 1 atm oxygen. The solution
was warmed up to 50 C and stirred for 24 h. Solvents were
evaporated and the residue was purified by flash chromatography to give 6 (72 mg, 46%) and recovered starting material
1
(36 mg). [a]20
D 8.3 (c 2.25, CHCl3); H NMR: d 8.04 (2H,
d, J7.5 Hz), 7.55 (1H, t, J7.5 Hz), 7.42 (2H, t, J
7.5 Hz), 4.40 (1H, m), 4.36 (2H, m), 4.16 (1H, m), 4.01
(1H, dd, J14.0, 6.5 Hz), 3.94 (1H, dd, J14.0, 7.0 Hz),
3.71 (1H, dd, J11.5, 2.5 Hz), 3.51 (1H, dd, J11.5,
3.5 Hz), 2.13 (1H, m), 2.07e1.95 (3H, m), 1.82e1.66 (4H,
m); 13C NMR: d 166.51, 132.94, 130.06, 129.65, 128.29,
82.37, 82.14, 80.03, 77.25, 66.78, 64.53, 28.77,
28.53, 28.41, 27.38. MS (ESI): m/z: 307 [MH], 329
[MNa].
3.5. ((2R,20 R,5R,50 R)-50 -Formyloctahydro-2,20 -bifuran5-yl)methyl benzoate 7
DMSO (0.4 ml, 5 mmol) in 2 ml dichloromethane was
added to a pre-cooled solution of oxalyl chloride (2 ml,
4 mmol, 2 M in dichloromethane) in 10 ml dichloromethane
at 78 C. After 20 min, the bis-THF 6 (600 mg, 2 mmol)
in 2 ml dichloromethane was added dropwise, and the reaction
was stirred for 30 min at this temperature. Diisopropylethylamine (1.74 ml, 10 mmol) was added into the above solution,
the reaction was warmed to room temperature slowly,
quenched by saturated ammonium chloride solution, and extracted with dichloromethane. The organic layers were combined and washed with brine, dried over sodium sulfate, and
concentrated under reduced pressure. The residue was purified
by flash chromatography to yield aldehyde 7 (500 mg, 85%).
1
H NMR: d 9.69 (1H, d, J1.5 Hz), 8.03 (2H, d, J7.5 Hz),
7.54 (1H, t, J7.5 Hz), 7.42 (2H, t, J7.5 Hz), 4.34 (3H,
m), 4.04 (2H, m), 2.23e1.92 (5H, m), 1.82e1.70 (3H,
m); 13C NMR: d 202.67, 166.43, 132.92, 129.59, 128.32,
128.27, 83.28, 83.17, 81.67, 77.32, 66.70, 28.47, 28.38,
27.90, 27.29.
3.6. ((2R,20 R,5R,50 R)-50 -((1S,4S)-1,4-di(tert-Butyldimethylsilyloxy)undec-2-ynyloctahydro-2,20 -bifuran-5-yl)methyl
benzoate 9
BuLi (2.5 M in hexanes, 1.1 ml, 2.75 mmol) was added
dropwise to a solution of 8 (730 mg, 2.72 mmol) in 40 ml
1607
1608
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