Organic Letters
Letter
1
1
Scheme 2. Synthesis of Building Block 6
Scheme 4. Friedel−Crafts Acylation of Acid 16
1
1
(
a) N,N,N′-Trimethylethylendiamine (1.1 equiv), n-BuLi (1.05
(a) ZnCl (0.10 equiv), AcOH, Ac O, 120 °C, 30 min; (b) Ghosez’s
2 2
equiv), toluene, 0 °C to rt, 1 h; (b) PhLi (3.0 equiv) toluene, rt, 8
Reagent (5.0 equiv), ZnCl (2.0 equiv), DMAP (cat.), Ac O, pyridine,
CH Cl , 0 °C to rt, 16 h; (c) TFAA (2.0 equiv), CH Cl , 0 °C, 15
2 2 2 2
min; (d) DMAP (0.10 equiv), pyridine, Ac O, 0 °C to rt, 16 h.
2
2
h; (c) MeI (6.0 equiv), THF, −78 °C to rt 16 h; (d) NaClO (2.0
2
equiv), NaH PO (5.0 equiv), 2-methyl-2-butene (8.0 equiv), H O, t-
2
4
2
2
BuOH, rt, 1 h; (e) oxalyl chloride (1.2 equiv), DMF (cat.), CH Cl , 0
2
2
°
C to rt, 1 h; (f) Et N (3.0 equiv), MeOH (20 equiv), 0 °C to rt, 15
9
3
ZnCl or in a two-step procedure via the corresponding acid
2
h; (g) NBS (1.01 equiv), AIBN (0.02 equiv), cyclohexane, 90 °C, 4 h.
chloride gave complex reaction mixtures and were unsatisfying.
Therefore, a two-step reaction sequence was applied. In the
first step, the mixed anhydride was formed using TFAA, which
undergoes Friedel−Crafts acylation to anthracenol 17. Because
of its oxidative instability, the latter was directly acetylated to
produce the desired tetracyclic product 18 in 72% overall yield.
Deprotection of silyl ether 18 using HF led to allylic alcohol
Starting point for the synthesis of the type-5 intermediate
was the tetralone 12, which was converted into the allylic
alcohol 13 in a known three-step procedure using a Shapiro
6
reaction (Scheme 3). Protection of the alcohol using TIPSCl
1
Scheme 3. Synthesis of Carboxylic Acid 16
1
9 in good yield (Scheme 5). Asymmetric Sharpless-
epoxidation of 19 provided the epoxide 20.
10
1
Scheme 5. Asymmetric Synthesis of Epoxide 20
1
(a) TIPSCl (1.5 equiv), imidazole (2.0 equiv), DMF, rt, 20 h; (b) t-
BuLi (1.3 equiv), TMEDA (1.1 equiv), pentane 0 °C, 1 h; (c) CuI
(
1.0 equiv), nBu P (2.2 equiv), THF, 0 °C, 30 min; (d) benzylic
3
bromide 6 (1.0 equiv), THF, −78 °C to rt, 3 h; (e) KOH (20 equiv),
1
EtOH/H O 9:1, 90 °C, 4 h.
(a) HF (48%, 10 equiv), MeCN, rt, 1 h; (b) (−)-DET (1.5 equiv),
Ti(Oi-Pr) (1.0 equiv), t-BuOOH (2.0 equiv), 4 Å MS, CH Cl , −20
2
4
2
2
°
C to −40 °C, 22 h.
and imidazole gave silyl ether 15 in excellent yield. With
protected building block 14 in hand, its ortho-metalation and
subsequent alkylation with benzyl bromide 6 to obtain the
diarylmethane 15 was investigated. Using t-butyl lithium,
ortho-lithiation was achieved at 0 °C, and after transmetalation
to Cu(I) at −78 °C using bis(tri-n-butylphosphine)copper(I)
The next synthetic task consisted of the conversion of the
epoxy alcohol into the trans-β-hydroxy ester of the C9 and 10
substructure. The structurally simpler epoxy alcohol rac-21 was
used first as a model system to investigate this case (Scheme
6). Kende reported a trans-selective epoxide opening using a
palladium catalyzed hydrogenolysis for a related example. In
contrast, the hydrogenolysis of our epoxy alcohol rac-21 gave
the cis product rac-22 only, whose structure was confirmed by
X-ray. We were able to synthesize the trans-alcohol using
boron trifluoride and triethyl silane as hydrogen source but
only in 20% yield. Fortunately, we observed that epoxide rac-
21 rearranges with Lewis acids such as boron trifluoride or
TMSOTf to the trans-aldehyde rac-23 via a 1,2-hydride shift
(24 → 25). The relative configuration of rac-23 was
confirmed after DIBAH-reduction to the corresponding
7
iodide, the reaction with bromide 6 led to the diarylmethane
6
1
5. The subsequent saponification of the ortho,ortho′-
disubstituted methyl ester 15 to the carboxylic acid 16
required higher reaction temperatures, which caused side
reaction (e.g., silyl ether cleavage). Screening of different bases
such as NaOH, LiOH, KOH as well as temperatures, solvents,
and reaction times showed that the best results were obtained
with KOH at 90 °C for 4 h.
11
A Friedel−Crafts acylation of the carboxylic acid 16 was
12
hampered by oxidative side reactions of the electron rich
trimethoxyanthracenol 17 (Scheme 4). Attempts to obtain the
8
13
more stable acylated anthracenol 18 directly using Ac O/
literature known trans-diol (not shown).
2
B
Org. Lett. XXXX, XXX, XXX−XXX