Carbogallation of Alkynes
COMMUNICATION
(1 mL) at room temperature for 2 h, the successive addition
of Pd2ACHTUNGTRENNUNG(dba)3·CHCl3 (0.05 mmol), PhI (3 mmol), NaOtBu
ylphenylketene silyl acetals were also successful (Scheme 6,
7m and 7n).
(3 mmol), and DMF (3 mL) afforded a highly satisfactory
Finally, we demonstrated the utility of trisubstituted
alkene synthesis through carbogallation for the total synthe-
sis of Nodosol, which is antibacterial active-meroterpenoid
extracted from the seagrass Cymodocea nodosa.[13] The car-
bogallation using enyne 9 and ketene silyl acetal 2a fol-
lowed by Pd-catalyzed coupling between produced alkenyl-
gallium and 4-bromoiodobenzene gave ester 10, although
the yield was only 15%. Instead of direct coupling, the
cross-coupling of 4-bromophenylboronic acid with iodoal-
kene 11, which was produced by quenching with I2 after the
carbogallation, gave ester 10 effectively. Subsequent conver-
sion to aldehyde 12 followed by a Wittig reaction produced
triene 13. Finally, the transformation from the bromoarene
moiety to the phenol moiety of 13 by the treatment with
nBuLi and O2 provided Nodosol (14, Scheme 7).
90% yield of coupling product 7a as a single isomer under
heating at 1008C (Table 1, entry 1).[12] Pd
ACHTUNGTRENNUNG
catalytic effect than Pd2ACHTUNGTRENNUNG
cross-coupling without NaOtBu resulted in a product yield
of only 18% (Table 1, entry 3). The reaction of GaI3 gave a
lower yield than that of GaBr3 (Table 1, entry 4).[10] The use
of 0.5 equivalent of GaBr3 also produced a satisfactory yield
(Table 1, entry 5).
Carbogallations and successive Pd-catalyzed couplings
using various alkynes, ketene silyl acetals, and aryliodides
are summarized in Scheme 6. Both aromatic alkynes with
electron-donating and -withdrawing groups gave high yields
(compounds 7b, 7c, and 7d). 1-Octyne was also applicable
to give the desired product 7e in a 54% yield. Various func-
tional moieties, including methoxy, chloro, nitro, cyano,
ester, and ketone groups, survived the coupling reactions to
give moderate to excellent yields (Scheme 6, compounds 7 f,
7g, 7h, 7i, 7j, and 7k). 3-Iodopyridine was used as a facile
coupling partner (compound 7l). Use of diethyl- and meth-
Scheme 7. Total synthesis of meroterpenoid nodosol. Reagents and condi-
tions: a) GaBr3 (1 equiv), 8 (1 equiv), 2a (1.5 equiv), CH2Cl2, RT, 2 h;
Pd
(3 equiv), DMF, 1008C, 15%; b) GaBr3 (1 equiv),
(1.5 equiv), CH2Cl2, RT, 2 h, and then, I2 (1.5 equiv) and Et2O, 81%; c) 4-
bromophenylboronic acid (4 equiv), Pd(PPh3)4 (0.1 equiv), Na2CO3
(dba)3·CHCl3 (0.05 equiv), 4-bromoiodobenzene (1.5 equiv), NaOtBu
8
(1 equiv), 2a
AHCTUNGTRENNUNG
(4 equiv), toluene, MeOH, 59%. d) DIBAL (3 equiv), THF, 76%; e) Pyr-
idinium chlorochromate (2 equiv), CH2Cl2, 64%; f) Ph3PCH3I (1.6 equiv),
nBuLi (2.1 equiv), 40%; g) nBuLi, O2, 29%.
In summary, we have achieved a new type of carbogalla-
tion of alkynes. Quenching the produced alkenylgalliums
with I2 gave the corresponding iodoalkenes as a trisubstitut-
ed alkene. For the first time, alkenylgalliums produced by
carbogallation were directly used on sequential Pd-catalyzed
cross-coupling with a variety of aryl iodides to give the tri-
substituted alkenes stereo- and regioselectively. These meth-
ods for synthesizing a trisubstituted alkene were used as key
processes to accomplish the total synthesis of the meroterpe-
noid Nodosol. Results of the present study show that the
concept developed in the previous carboindation was appli-
cable to gallium salts, which indicates that this convenient
procedure has the potential for application to other metals.
Scheme 6. Application of various alkynes, aryliodides, and ketene silyl
acetals. Reaction conditions: 1) GaBr3 (1 mmol),
1 (1 mmol), 2
(1.5 mmol), and CH2Cl2 (1 mL), 2) Pd2A(dba)3·CHCl3 (0.05 mmol), ArI
CTHUNGTRENNUNG
Experimental Section
(1.5 mmol), NaOtBu (3 mmol), and DMF (3 mL). Yields of isolated prod-
ucts. [a] HMPA (3 mL) was used instead of DMF. [b] 2a (1.5 mmol), and
NaOMe instead of NaOtBu. [c] ArI (3 mmol). [d] Yields were deter-
General procedure: (Table 1, Entry 1): Phenylacetylene (1a, 1 mmol) was
added to a solution of GaBr3 (1 mmol) and dimethylketene methyl trime-
1
mined by H NMR analysis using internal standard in crude products.
Chem. Eur. J. 2011, 17, 11135 – 11138
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11137