Communication
Scheme 4. Synthesis of 2, 3, 10, and 11: a) 1.2–1.3 equiv 23, 1.0 equiv 22, 5–
6 mol% Pd(OAc)2, 11–14 mol% SPhos, 1.4–1.7 equiv Cs2CO3, toluene, 1008C,
21–31 h (96–100%); b) 20 mol% Pd(OAc)2, 2.5 equiv Cu(OAc)2, HOPiv, air,
1308C (MW), 2–3 h (51–76%); c) a: 10% Pd/C, H2, CH2Cl2/MeOH (1:1), RT,
25 h (86%); b: 4 equiv AlCl3, dioxane, reflux, 2 h (69%); d) a: 1. 1.25 equiv
25a (X=OH), 1.15 equiv TFAA, 2.8 equiv DBU, 0.5 mol% CuCl2, MeCN, À20
to +158C, 8 h, 2. xylene, reflux, 23 h (72%, two steps); b: 1. 1.6 equiv 25b
(X=OCOOMe), 1.3 equiv DBU, 1.1 mol% CuI, MeCN, RT, 22 h, 2. toluene,
reflux, 24 h (76%, two steps); e) Table 2.
Scheme 5. Synthesis of murrayacinine (4) and mukoenine-B (12): a) 1.
1.0 equiv 18, 1.5 equiv 27, 1.3 equiv DBU, 0.7 mol% CuI, MeCN, RT, 15 h, 2.
toluene, reflux, 24.5 h (82%); b) see Table 3.
hydroxycarbazoles. Therefore, reaction of the 2-hydroxycarba-
zole 18 with carbonate 27[25] was used to prepare the cor-
responding pyrano[3,2-a]carbazole 28 (Scheme 5 and Table 3).
Reduction of compound 28 using DIBAL-H at À788C provided
murrayacinine (4) in 87% yield (Table 3).[26] Addition of DIBAL-H
at À788C followed by an increase of the temperature to
À308C afforded a mixture of mukoenine-B (clausenatine-A)
(12)[27] and its corresponding Z-isomer Z-12 (ratio=1:2.4) in
71% yield. Both compounds could be separated by HPLC (see
the Supporting Information).
The synthesis of the 7-oxygenated carbazoles 2, 3, 10, and
11 started with a Buchwald–Hartwig coupling of the bromoar-
enes 22a and 22b with the arylamine 23 (Scheme 4). Subse-
quent palladium(II)-catalyzed oxidative cyclization and removal
of the benzyl group provided the 2-hydroxycarbazoles 24. An-
nulation of the pyran ring via Godfrey’s procedure[15] afforded
the pyrano[3,2-a]carbazoles 26. Reduction of 26a using DIBAL-
H at À788C followed by removal of the silyl group with TBAF
provided clauraila-E (2) in 86% yield (Table 2),[21] whereas addi-
tion of DIBAL-H at À788C followed by an increase of the tem-
perature to À208C and desilylation led primarily to reductive
pyran ring opening and afforded 7-hydroxyheptaphylline (10)
in 71% yield (Table 2).[22] Along the same lines, DIBAL-H reduc-
tion of 26b at À788C led to 7-methoxymurrayacine (3) in 68%
yield,[23] whereas addition of DIBAL-H to 26b at À788C and
subsequent temperature increase to À408C afforded 7-me-
thoxyheptaphylline (11) in 63% yield.[24]
Table 3. DIBAL-H promoted reductive ring opening of compound 28.
Yield [%]
Reaction conditions
4
12 (E/Z)
3.5 equiv DIBAL-H, CH2Cl2, À788C, 3.5 h
87
16
–
4.0 equiv DIBAL-H, CH2Cl2, À78 to À308C, 5.5 h
71 (1:2.4)
We next investigated whether our procedure of reductive
pyran ring opening could be applied to the conversion of ho-
moprenyl-substituted pyrano[3,2-a]carbazoles to 1-geranyl-2-
According to our proposed mechanism (Scheme 3), a coordi-
nation of the aluminum center to the imine nitrogen atom and
to the pyran oxygen atom is required to induce the pyran ring
opening at the stage of intermediate 20 prior to reduction by
the second equivalent of DIBAL-H. Thus, our DIBAL-H promot-
ed reductive pyran ring opening should not be applicable to
3-methyl-substituted pyrano[3,2-a]carbazoles. In fact, treat-
ment of girinimbine (5)[28] with four equivalents of DIBAL-H re-
sulted in complete recovery of the starting material. Therefore,
we envisaged to promote an opening of the pyran ring by the
presence of an additional Lewis acid along with DIBAL-H. Addi-
tion of weak Lewis acids (1 equiv of magnesium bromide or
tetrapropoxytitanium) along with an excess of DIBAL-H had no
Table 2. DIBAL-H promoted reductive ring opening of 26a and 26b.
DIBAL-H
Reaction conditions
Products, Yields [%]
a
a
b
b
2.5 equiv
3.0 equiv
3.0 equiv
3.0 equiv
CH2Cl2, À788C, 3 h;[a]
2 86; 10 14
2 20; 10 71
3 68; 11 9
3 13; 11 63
CH2Cl2, À78 to À208C, 4.5 h;[a]
CH2Cl2, À788C, 3.5 h
CH2Cl2, À78 to À408C, 3 h
[a] then, 1.5 equiv TBAF, DMF, À208C to RT, 5 min.
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