Communication
acid-catalyzed reaction with prenal provided the 8-oxygenated
pyrano[3,2-a]carbazole 27. Oxidation with 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) afforded 28 which on removal
of the silyl group gave clauszoline-G (8), isolated by Ito et al.
from the stem bark of Clausena excavata.[18] Catalytic hydroge-
nation of 8 led to heptazolicine (9), isolated by Chowdhury
et al. from the roots of Clausena heptaphylla.[19,20]
The synthesis of the pyrano[2,3-a]carbazole alkaloids 10 and
11 required a protecting group reversal, as removal of the
benzyl group by hydrogenolysis should be done prior to annu-
lation of the pyran ring. Coupling of the bromoarene 29 and
the arylamine 30 by the sequence of Buchwald–Hartwig reac-
tion and palladium(II)-catalyzed cyclization was followed by hy-
drogenolysis to afford the 8-hydroxycarbazole 31 (Scheme 6).
Boronic acid-catalyzed reaction of 31 with prenal led to the
pyrano[2,3-a]carbazole 32. Oxidation of 32 with DDQ and sub-
sequent removal of the silyl group provided clauszoline-B (10),
isolated by Ito et al. from the stem bark of Clausena excava-
ta.[18] Fluoride-promoted desilylation of 32 to compound 33
followed by O-methylation provided clauszoline-H (11), ob-
tained by Ito et al. from the roots of Clausena excavata.[21]
Next, we have developed a total synthesis of the 8-methoxy-
substituted pyrano[3,2-a]carbazole alkaloids 2, 5, and
7
(Scheme 7). Buchwald–Hartwig coupling of o-bromoanisole
(34) and arylamine 13 followed by palladium(II)-catalyzed cycli-
zation and benzyl hydrogenolysis afforded carbalexin-B (35).
Greger et al. described the stress-induced formation of this
phytoalexin in Glycosmis parviflora and isolated it from the
leaves of that plant.[22,23] Carbalexin-B (35) exhibits a strong an-
tifungal activity. Boronic acid-catalyzed reaction of 35 with
prenal led to mupamine (2), isolated by Mester and Reisch
from the root bark of Clausena anisata.[23,24] The structural as-
signment for our synthetic mupamine (2) has been additionally
confirmed by an X-ray crystal structure determination
(Figure 1).[25] The boronic acid-catalyzed annulation of 35 and
citral provided murrayamine-B (5), isolated by Wu from the
leaves of Murraya euchrestifolia.[11] Finally, cyclization of 5 in the
presence of trifluoroacetic acid led to murrayamine-H (7). Mur-
Scheme 5. Synthesis of clauszoline-G (8) and heptazolicine (9): a) 6 mol%
Pd2(dba)3, 12 mol% DavePhos, 1.2 equiv NaOtBu, toluene, reflux, 24 h (98%);
b) 20 mol% Pd(OAc)2, 20 mol% K2CO3, HOPiv, air, 858C, 20 h (85%); c) 10%
Pd/C, H2 (1 atm), MeOH/CH2Cl2 (4:1), RT, 3 d (100%); d) 1.5 equiv prenal,
20 mol% PhB(OH)2, 110 equiv EtCOOH, toluene, reflux, 21 h (76%);
e) 2.2 equiv DDQ, MeOH/THF/H2O (4:1.5:1), 458C, 3 h (64%); f) 1.6 equiv
TBAF, DMF, 08C, 5 min (93%); g) 10% Pd/C, H2 (1 atm), MeOH/CH2Cl2 (3:1),
RT, 3 d (68%).
Scheme 6. Synthesis of clauszoline-B (10) and clauszoline-H (11): a) 10 mol%
Pd(OAc)2, 10 mol% rac-BINAP, 1.4 equiv Cs2CO3, toluene, reflux, 21 h (82%);
b) 20 mol% Pd(OAc)2, 20 mol% K2CO3, HOPiv, air, 858C, 26 h (70%); c) 10%
Pd/C, H2 (1 atm), MeOH/CH2Cl2 (4:1), RT, 3 d (95%); d) 1.5 equiv prenal,
20 mol% PhB(OH)2, 110 equiv EtCOOH, toluene, reflux, 3 d (78%);
e) 1.5 equiv DDQ, MeOH/THF/H2O (4:1:1), RT, 30 min (32%); f) 1.6 equiv
TBAF, DMF, 08C, 10 min (75%); g) 1.6 equiv TBAF, DMF, 08C, 10 min;
h) 1.3 equiv NaH, 1.0 equiv MeI, THF, 08C to RT, 24 h (80% over 2 steps).
Scheme 7. Synthesis of mupamine (2), murrayamine-B (5), and murraya-
mine-H (7): a) 10 mol% Pd(OAc)2, 20 mol% XPhos, 1.4 equiv Cs2CO3, toluene,
reflux, 24 h (98%); b) 10 mol% Pd(OAc)2, 10 mol% K2CO3, HOPiv, air, 858C,
24 h (60%); c) 10% Pd/C, H2 (1 atm), MeOH/CH2Cl2 (2:1), RT, 5 d (64%);
d) 1.5 equiv prenal, 20 mol% PhB(OH)2, 110 equiv EtCOOH, toluene, reflux,
48 h (82%); e) 1.5 equiv citral, 20 mol% PhB(OH)2, toluene, reflux, 48 h
(81%); f) 1.5 equiv TFA, toluene, RT, 24 h (60%).
Chem. Eur. J. 2014, 20, 1 – 6
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