of 1 emanated from the enantiomerically pure epoxyquinone
(+)-5, which had two strategically placed and chemo-
differentiated sidearms on the epoxyquinone core.
Scheme 1 a
Dibal-H reduction in (+)-5 was both regio- and stereo-
selective to furnish (-)-9 through a chelation-controlled
process involving the intermediacy of an aluminum chelate5
8 and hydride delivery from the same face as the epoxide
ring (Scheme 1).6 TEMPO-mediated oxidation7 in (-)-9 was
chemoselective and exclusively furnished the aldehyde (-)-
106 through the oxidation of the allylic primary hydroxyl
group. The secondary hydroxy group in (-)-10 was protected
at this stage to give diacetate (-)-11 (Scheme 1). Four-carbon
Wittig olefination in (-)-11 was chemoselective and engaged
only the allylic aldehyde group but the stereoselectivity in
this reaction was unsatisfactory and led to a cis:trans mixture
of diastereomers 12a,b (2.6:1) (Scheme 1). Since only the
(5) Kiyooka, S.-I.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986,
27, 3009.
(6) All new compounds were fully characterized on the basis of spectral
1
data (IR, H and 13C NMR, mass). Selected spectral data: (-)-9: [R]23
D
1
(-)176 (c 4.5, CHCl3); H NMR (300 MHz, CDCl3) δ 4.99 (1H, s), 4.88
(1H, d, J ) 12.3 Hz), 4.77 (1H, d, J ) 12.0 Hz), 4.55 (2H, br s), 4.04 (1H,
s), 3.84 (1H, s), 3.56 (1H, s), 3.46 (1H, s), 2.02 (3H, s); 13C NMR (75
MHz, CDCl3) 193.2, 171.6, 154.5, 127.5, 64.3, 61.2, 56.6, 56.1, 52.6, 20.8;
HRMS (ES) m/z calcd for C10H12NaO6 [M + Na]+ 251.0532, found
251.0536. (-)-10: [R]24 (-)305 (c 2.36, CHCl3); 1H NMR (300 MHz,
D
a Reagents and conditions: (a) DIBALH (2 equiv), THF, -78
°C, 74%; (b) TEMPO, O2, CuCl, DMF, rt, 77%; (c) Ac2O, pyridine,
DMAP, DCM, 0 °C, 71%; (d) n-C4H9PPh3Br, t-BuOK, THF, 0
°C, 54%; (e) hυ, 450 W (Hanovia), I2, CDCl3, 2 h, quant.
CDCl3) δ 10.33 (1H, s), 5.21 (1H, d, J ) 12.6 Hz), 5.20 (1H, s), 5.14 (1H,
d, J ) 12.6 Hz), 3.88 (1H, d, J ) 3.9 Hz), 3.66 (1H, d, J ) 3.6 Hz), 2.05
(3H, s); 13C NMR (75 MHz, CDCl3) 194.5, 192.7, 170.4, 144.0, 134.7,
60.8, 55.7, 54.8, 52.8, 20.6; HRMS (ES) m/z calcd for C10H10NaO6 [M +
Na]+ 249.0375, found 249.0369. (-)-12b: [R]24D (-)194 (c 1.09, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.44 (1H, d, J ) 15.9 Hz), 6.35 (1H, s),
6.29-6.21 (1H, m), 5.02 (1H, d, J ) 11.7 Hz), 4.85 (1H, d, J ) 11.7 Hz),
3.75 (1H, m), 3.57 (1H, d, J ) 3.9 Hz), 2.21 (2H, q, J ) 7.2 Hz), 2.13
(3H, s), 2.05 (3H, s), 1.47 (2H, sextate, J ) 7.2 Hz), 0.92 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) 193.1, 170.7, 169.9, 145.7, 142.5, 128.2,
125.0, 63.2, 56.4, 53.0, 52.0, 35.9, 21.9, 20.8, 20.7, 13.5; HRMS (ES) m/z
trans-isomer 12b was considered serviceable for further
elaboration to the natural product 1, considerable effort was
expended toward improving the stereoselectivity of the Wittig
reaction but without much success. However, a solution to
this problem was devised by exploiting the possibility of
photochemical cis-trans isomerization of the disubstituted
double bond in the dienone chromophore present in 12a,b.
When the mixture of diastereomers 12a,b was irradiated from
a 450-W Hg lamp through Pyrex in the presence of iodine,
it cleanly and quantitatively furnished the desired trans-
isomer (-)-12b (Scheme 1).6
Acetate hydrolysis in (-)-12b led to the diol (-)-13 and
the primary hydroxyl group was selectively protected as the
TBS derivative (-)-14 (Scheme 2).6 Epoxidation of the trans
double bond in the side chain with m-chloroperbenzoic acid
in aqueous buffer was stereoselective and occurred exclu-
sively from the face opposite to the neighboring secondary
hydroxyl group to deliver the γ,δ-epoxyenone (-)-15,6 an
outcome along the lines previously observed by Porco et al.2
When (-)-15 was exposed to 40% HF in acetonitrile to
remove the TBS protecting group, concomitant hydroxy-
mediated endo-epoxide opening was also encountered to
furnish (-)-cycloepoxydon 1 as the predominant product.6,8
Our synthetic (-)-1 had spectral data (1H and 13C NMR)
identical with that reported in the literature1c for the natural
product and had an [R]D value of -135° (CHCl3-CH3OH
90:10), lit. [R]D -145° (CHCl3-CH3OH 95:5).1c
calcd for C16H20NaO6 [M + Na]+ 331.1158, found 331.1161. (-)-13: [R]24
D
(-)231 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.56-6.48 (2H, m),
5.04 (1H, s), 4.37 (2H, s), 3.87 (1H, dd, J ) 1.2, 3.6 Hz), 3.5 (1H, dd, J )
0.6, 3.6 Hz), 2.29-2.21 (2H, m), 1.51 (2H, sextate, J ) 7.2 Hz), 0.95 (1H,
t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) 196.2, 148.9, 143.4, 129.5,
125.2, 63.1, 55.8, 55.5, 52.4, 36.0, 22.0, 13.7; HRMS (ES) m/z calcd for
C12H16NaO4 [M + Na]+ 247.0946, found 247.0950. (-)-15: [R]23 (-)-
D
140 (c 0.72, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.64 (1H, d, J ) 12.6
Hz), 4.43 (1H, d, J ) 12.3 Hz), 4.36 (1H, br s), 3.97 (1H, d, J ) 2.4 Hz),
3.78 (1H, dd, J ) 1.5, 3.6 Hz), 3.53 (1H, dd, J ) 0.6, 3.6 Hz), 3.19-3.15
(2H, m), 1.79-1.73 (1H, m), 1.68-1.46 (3H, m), 0.99 (3H, t, J ) 7.2 Hz),
0.86 (9H, s), 0.02 (3H, s); 13C NMR (75 MHz, CDCl3) 192.2, 150.4, 134.3,
61.5, 60.2, 56.4, 55.6, 55.5, 52.7, 33.9, 25.8 (3 C), 19.1, 18.2, 13.8, -5.2,
-5.4; HRMS (ES) m/z calcd for C18H30NaO5Si [M + Na]+ 377.1760, found
1
377.1743. (-)-1: [R]23 (-)135 (c 0.55, CHCl3:MeOH 90:10); H NMR
D
[300 MHz, CDCl3:MeOH-d4 90:10] δ 4.92 (1H, s), 4.51 (1H, dd, J ) 2.1,
17.1 Hz), 4.07-4.04 (2H, m), 3.77 (1H, dd, J ) 1.2, 3.6 Hz), 3.40 (1H,
dd, J ) 0.9, 3.6 Hz), 3.30 (1H, m), 1.72 (1H, m), 1.52 (1H, m), 1.44-1.32
(2H, m), 0.9 (3H, t, J ) 7.2 Hz); 13C NMR [75 MHz, CDCl3:MeOH-d4
90:10] 191.9, 150.5, 129.3, 77.7, 64.9, 62.0, 59.9, 57.0, 52.2, 33.9, 18.5,
13.9‚ (-)-19: [R]25D (-)159 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.61-6.51 (1H, m), 6.31 (1H, d, J ) 16.2 Hz), 4.57 (1H, dd, J ) 6.9,
12.9 Hz), 4.44 (1H, dd, J ) 5.1, 12.6 Hz), 3.89 (1H, d, J ) 4.2 Hz), 3.86
(1H, d, J ) 3.9 Hz), 2.40 (1H, t, J ) 6.3 Hz), 2.23 (2H, q, J ) 7.2 Hz),
1.88 (2H, sextate, J ) 7.2 Hz), 0.94 (3H, t, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) 193.8, 192.9, 147.4, 141.6, 137.0, 120.5, 57.3, 54.0, 53.7,
36.5, 21.8, 13.7; HRMS (ES) m/z calcd for C12H14NaO4 [M + Na]+
245.0790, found 245.0779. (+)-24: [R]23D (+)144 (c 0.90, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.89 (1H, s), 5.68 (1H, s), 4.37 (1H, q, J ) 4.8 Hz),
4.18 (1H, t, J ) 6.3 Hz), 3.88 (1H, d, J ) 3.6 Hz), 3.84 (1H, d, J ) 4.2
Hz), 3.82 (1H, d, J ) 3.6 Hz), 3.67 (1H, d, J ) 3.6 Hz), 3.28 (1H, s), 2.64
(1H, d, J ) 2.7 Hz), 1.35-1.17 (8H, m), 0.89-0.83 (6H, m); 13C NMR
(75 MHz, CDCl3) 199.9, 187.7, 187.6, 187.0, 159.3, 145.0, 143.5, 112.3,
81.4, 71.4, 69.5, 60.6, 55.7, 54.6, 54.2, 49.9, 38.8, 36.9, 36.4, 35.0, 18.9,
18.5, 13.8, 13.4; HRMS (ES) m/z calcd for C24H24NaO8 [M + Na]+
463.1369, found 463.1360.
It has been demonstrated recently that dimeric products
derived from epoxyquinones, both of natural as well as
synthetic origin, exhibit a notable and sometimes enhanced
(7) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou, C. S. J.
Am. Chem. Soc. 1984, 106, 3374.
808
Org. Lett., Vol. 6, No. 5, 2004