Angewandte
Chemie
Scheme 2. Synthesis of the AB-ring fragment 9. Unless otherwise
noted, the reactions were performed at ambient temperature. a) Br2,
MeOH, 1 h (94%). b) 1,3-propanediol, 1 mol% Bu4N+Br3ꢀ, HC(OEt)3,
25 min. c) MOMCl, NaH, DMF, 15 min (2 steps, 94%). d) nBuLi
(1.1 mol equiv), Et2O, ꢀ788C, 35 min. 10 (1.2 mol equiv), BF3·OEt2
(1.3 mol equiv), ꢀ788C, 80 min, then 268C, 30 min (68%). e) 1,3-
propanediol, 1408C, 7 min (91%). f) PhNTf2 (1.2 mol equiv), K2CO3
(1.1 mol equiv), DMF, 15 h (82%). g) CO (1 atm), Pd(OAc)2
(10 mol%), dppp (10 mol%), Et3N (2 mol equiv), DMF, 1008C, 4 h
(91%). h) BCl3, CH2Cl2, 08C, 15 min. i) 0.5m H2SO4, 1,4-dioxane,
1008C, 5.5 h (2 steps, 99%). j) NaBH4, THF/MeOH (10:1), ꢀ788C,
1.5 h (99%). k) BnMe3N+ICl2ꢀ, NaHCO3, CH2Cl2, MeOH, ꢀ108C, 57 h
(85%). l) TIPSCl, imidazole, DMF, 4 h (quant.). MOM=methoxy-
methyl, DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl,
dppp=1,3-bis(diphenylphosphino)propane, Bn=benzyl, TIPS=triiso-
propylsilyl.
Scheme 3. Synthesis of the DEF-ring fragment 17. Unless otherwise
noted, reactions were performed at ambient temperature. a) NCS
(1.0 mol equiv), AcOH, 808C, 1 h (89%). b) NaBH4, THF/H2O (9:1),
1 h. c) 2,2-dimethoxypropane, TsOH, acetone, 1 h. d) PyHBr3, pyridine,
1 h. e) (MeO)2SO2, K2CO3, DMF, 31 h. f) 10% H2SO4 aq., 1,4-dioxane,
508C, 2.5 h. g) MnO2, EtOAc, 30 min (6 steps, 66%). h) BnBr, K2CO3,
DMF, 1.5 h (99%). i) 18 (1.1 mol equiv), nBuLi (1.1 mol equiv), tolu-
ene, 08C, 1.5 h; 13, THF, ꢀ78!ꢀ508C, 30 min (85%). j) IBX, DMSO,
3 h (quant.). k) 0.7m H2SO4 aq., 1,4-dioxane, 908C, 1 h (97%).
l) Cs2CO3, cyclohexane, reflux, 81 h (84%). m) LiOH, H2O, 1,4-dioxane,
2 h (99%). NCS=N-chlorosuccinimide, Ts=p-toluenesulfonyl, IBX=
o-iodoxybenzoic acid, DMSO=dimethyl sulfoxide.
the lactone moieties. This conversion was achieved by N-
methylation and subsequent treatment with NaBH(OMe)3.
The resulting N,O-acetal was hydrolyzed with acid to give
aldehyde 24.[17] The desilylation of 24 and oxidation of the
resulting alcohol gave dialdehyde 25 in high yield, ready for
the key pinacol cyclization.[18]
However, we were disappointed by the poor results for
this key step; SmI2 in THF at 08C gave the desired product
only in low yield (ca. 20%) and poor stereoselectivity (trans/
cis = 3:1). After many unproductive trials, we became con-
vinced that the difficulties mainly originated from the
presence of the xanthone moiety, and decided to convert
the xanthone into the corresponding xanthene temporarily.
Thus, xanthone 24 was reduced by a two-step process [l-
Selectride and NaBH3(CN)] to give xanthene 26, and removal
of the silyl group and subsequent oxidation of the resulting
diol gave dialdehyde 27.
Pleasingly, xanthene 27 behaved nicely in the pinacol
cyclization (Scheme 5); upon treatment with SmI2, the
reaction proceeded far more smoothly than the case of
xanthone 25, albeit the trans/cis selectivity remained low
(Table 1, entry 1). Additional screening revealed that addi-
tives could improve this situation.[19] Whereas the addition of
tetraglyme did not affect the stereoselectivity (Table 1,
entry 2), various crown ethers gave much improved stereose-
lectivities (Table 1, entries 3–6). Furthermore, pybox ligands
were effective for improving the yield and the stereoselectiv-
ity (Table 1, entries 7 and 8).
slightly improved the selectivity (16/19 = 3:1). Additional
screening showed that cyclohexane was the solvent of choice,
giving the desired xanthone 16 in high selectively (16/19 =
23:1), which was easily isolated by re-precipitation (CHCl3/
petroleum ether= 1:3). The saponification of methyl ester 16
gave the DEF-fragment 17.
Two fragments, 9 and 17, were combined via the acid
chloride, giving the corresponding ester quantitatively
(Scheme 4). After the removal of the benzyl group to give
20, the palladium-catalyzed cyclization gave hexacycle 21 in
high yield.[15] For inducing the axial chirality, biaryl lactone 21
was subjected to the asymmetric ring-opening using (S)-
valinol as a chiral nucleophile.[5] The stereoselectivity proved
to be highly dependent on the solvent, and THF gave the best
result, affording diastereomeric amides 22 and 22ꢀ in a 93%
combined yield with excellent selectivity (14:1);[16] the
diastereomers were easily separated by using silica gel
column chromatography (n-hexane/EtOAc = 2:1). After sep-
aration, the major isomer (22) was converted into dialdehyde
25: treatment of 22 with PPh3 and I2 afforded a mixture of the
corresponding iodide and oxazoline, which, without separa-
tion, was treated with BnBr and Cs2CO3 in DMF, wherein the
two phenols were benzylated and the cyclization to the
oxazoline was complete, giving oxazoline 23. The next stage
was the selective conversion of the oxazoline into the
corresponding aldehyde without altering the xanthone and
Angew. Chem. Int. Ed. 2009, 48, 3462 –3465
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3463