Synthesis of the biaryl moiety of the proteasome inhibitors TMC-95 via a ligandless Pd(OAc)2-catalyzed Suzuki-coupling reaction

Article abstract of DOI:10.1016/S0040-4039(01)00966-2

The biaryl moiety of proteasome inhibitors TMC-95 was synthesized via a Pd(OAc)₂-catalyzed Suzuki-coupling reaction of 7-iodoisatin and a tyrosine-derived arylboronic acid in the absence of phosphine ligands using potassium fluoride as a base.

Full text of DOI:10.1016/S0040-4039(01)00966-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5279–5281
Synthesis of the biaryl moiety of the proteasome inhibitors
TMC-95 via a ligandless Pd(OAc)2-catalyzed
Suzuki-coupling reaction
Dawei Ma* and Qingquan Wu
State Key Laboratory of Bio-organic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 15 May 2001; accepted 1 June 2001
Abstract—The biaryl moiety of proteasome inhibitors TMC-95 was synthesized via a Pd(OAc)2-catalyzed Suzuki-coupling
reaction of 7-iodoisatin and a tyrosine-derived arylboronic acid in the absence of phosphine ligands using potassium fluoride as
a base. © 2001 Elsevier Science Ltd. All rights reserved.
Recently, we reported our efforts1 on the construction
of an oxidized tryptophan analogue 5, a proposed
intermediate for synthesizing the proteasome inhibitors
TMC-95A and TMC-95B.2 When we attempted to cou-
ple 5 with arylboronic acid 6 derived from (S)-tyrosine
under various Suzuki-coupling reaction conditions,3 we
found that no desired coupling product was isolated.
The best result we observed was that the biaryl com-
pound 7 was obtained in 19% yield by refluxing a
mixture of 5 and 6, palladium acetate and sodium
carbonate in ethanol (Scheme 1).
The formation of 7 implied that the highly oxidized
tryptophan moiety could not survive under typical
Suzuki-coupling reaction conditions, which promoted
us to study the coupling reaction of 7-iodoisatin with a
suitable arylboronic acid derived from (S)-tyrosine.
Once we obtained this coupling product, we could do
further conversions to TMC-95A and TMC-95B using
the same reaction sequence reported earlier.1 The inves-
tigation thus undertaken is described here.4
We first synthesized 7-iodoisatin 8 from 2-iodoaniline
Me
O
O
NH
NH
O
NH
R
HO R'
N
O
O
NHBoc
O
O
O
O
N
H
CONH2
H
HO
O
NH
Pd(OAc)2
O
Br
R'''
O
R''
O
5
Na2CO3
19%
N
Me
+
N
H
H
MeO
O
OMe
NHCbz
B(OH)2
O
TMC-95
R
A (1) OH
B (2) OH
R' R" R'''
H
H
OH Me
OH
MeO
OMe
NHCbz
Me
H
H
7
Me
H
Me
C (3)
D (4)
H
H
6
H
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00966-2

5280
D. Ma, Q. Wu / Tetrahedron Letters 42 (2001) 5279–5281
through the known procedure.5 Recently, many groups
have disclosed their efforts on the development of new
and more efficient catalytic systems for the Suzuki-cou-
pling reaction.6 However, few reports were concerned
with 7-iodoisatin or even o-iodoaniline as coupling
reagents.6 In order to find suitable reaction conditions
for our case, we did a model coupling reaction between
8 and arylboronic acid 9. The results are summarized in
Table 1.
thesized from (S)-tyrosine as outlined in Scheme 2.
Protection of the amino group of (S)-tyrosine with
N-ethoxycarbonylphthalimide followed by esterification
provided 11 in 76% yield. Treatment of 11 with benzyl
bromide/potassium carbonate in DMF afforded the
benzyl ether, which was subjected to iodination medi-
ated by silver trifluoroacetate to give iodide 12. As
compound 12 contains functional groups sensitive to
strong bases, we employed Masuda’s method8 to con-
vert 12 to the arylboronic acid 14. Accordingly,
PdCl2(dppf)-catalyzed coupling reaction of 12 with
pinacolborane produced boronate 13, which was
treated with diethanolamine followed by acidification
to afford 14 in 67% yield. The coupling reaction of 14
with 8 was attempted under several conditions and the
results are summarized in Table 2. Heating a mixture of
8, 14, 3 mol% Pd(OAc)2 and KF in methanol for 8 h
gave 15 in 55% yield (entry 1). Neither increasing the
amount of catalyst nor changing bases could improve
the reaction yield (entries 2–4). However, when the
reaction was carried out at 20°C and prolonging the
reaction time, a better yield was observed (entry 5).
This reaction was also performed in other solvents such
as acetonitrile, DME or a mixed solvent, but with lower
yields (entries 6–9).
Initially, we tried to carry out the reaction in DME/
H2O using Pd(PPh3)4 as the catalyst and NaHCO3 as a
base, because it was reported recently that under these
conditions 8 coupled with simple arylboronic acids to
give the corresponding coupled products with 55–70%
yield.6d However, only 18% yield was observed (entry
1), which might result from the steric hindrance of 9.
So, we attempted to employ Buchwald’s6a and Fu’s6b
catalytic systems that were reported to be effective for
highly sterically hindered substrates. Under their condi-
tions, little or no coupling product was delivered
(entries 2 and 4). Finally, we found that this reaction
worked in methanol using Pd(OAc)2 as a catalyst to
give the desired coupling product 10 in 45% yield
(entries 5 and 6).7 Changing the base from alkali metal
carbonates to potassium fluoride gave the best result
(entry 7). A ligandless Pd catalyst was necessary for this
reaction, because phosphine-containing palladium such
as PdCl2(dppf), Pd2(dba)2/P(t-Bu)3 were found inactive
for this coupling reaction even when potassium fluoride
was used as the base (entries 8–10).
In summary, we have obtained the biaryl fragment for
synthesizing TMC-95 via a ligandless Pd(OAc)2-cata-
lyzed Suzuki-coupling reaction of 7-iodoisatin 8 with
sterically hindered arylboronic acid 14 in reasonable
yield. The reaction conditions for Suzuki coupling dis-
cussed here should be of benefit for synthesizing biaryl
compounds with an o-amino moiety. Studies towards
the total synthesis of TMC-95 using 15 as the key
intermediate are underway in our laboratory.
After we had developed suitable reaction conditions for
a model reaction, we planned to run the coupling
reaction of 8 with arylboronic acid 14 which was syn-
Table 1. Pd-catalyzed cross coupling of 8 and 9 under various conditions
O
OBn
O
O
B(OH)2
see Table 1
N
H
O
+
BnO
N
H
I
CO2Me
CO2Me
8
9
10
Entrya
Catalyst
Base
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
NaHCO3
K3PO4
K3PO4
K3PO4
Na2CO3
K2CO3
KF
KF
KF
KF
DME/H2O
toluene
DMF
90
90
60
75
50
60
60
60
75
60
5
24
72
24
24
36
24
72
24
24
18
Trace
0
Pd(OAc)2-Lc,d
Pd(OAc)2-PPh3
d
d
d
Pd2(dba)2/P(t-Bu)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2-PPh3
DMF
0
MeOH
MeOH
MeOH
DMF
DMF
MeOH
45
52
75
0
0
0
d
Pd2(dba)2/P(t-Bu)3
PdCl2(dppf)
10
a The reactions were carried out utilizing 3 mol% of Pd catalyst, 1.0 equiv. of 8 and 1.5 equiv. of 9 in corresponding solvent under argon.
b Isolated yield.
c L=o-(dicyclohexylphosphino)biphenyl.
d The ratio for [Pd] and phosphine ligand was 1:2.

D. Ma, Q. Wu / Tetrahedron Letters 42 (2001) 5279–5281
5281
O
OH
OBn
OH
O
O
NCO2Et
I
BH
1.
1. BnBr, K2CO3
2. I2/CF3COOAg
85%
O
PdCl2(dppf)/TEA
CO2Me
2.HCl/MeOH
76%
CO2H
CO2Me
NPhth
NH2
NPhth
12
11
O
OBn
O
OBn
B
B(OH)2
O
O
8
1. (HOCH2CH2)2NH
N
H
see Table 2
2.1 N HCl
BnO
O
OMe
NPhth
CO2Me
CO2Me
67% from 12
NPhth
13
NPhth
14
15
Scheme 2.
Table 2. Pd(OAc)2-catalyzed coupling reaction of 8 with 14
Entrya
Solvent
Base
Temp. (°C)
Time (h)
Yield (%)b
1
2c
3
4
5
6
7
8
9
MeOH
MeOH
MeOH
MeOH
KF
KF
NaHCO3
Bu4NF
KF
KF
KF
KF
KF
60
60
60
60
20
60
60
60
60
8
8
20
20
72
8
8
8
8
55
51
41
45
64
25
35
40
45
MeOH
CH3CN
MeOH/CH3CN
DME
MeOH/DME
a The reactions were carried out utilizing 3 mol% of Pd(OAc)2, 1.0 equiv. of 8, 1.2 equiv. of 14 and 3 equiv. of base in the corresponding solvent
under argon.
b Isolated yield.
c 10 mol% Pd(OAc)2 was used.
Acknowledgements
Wiely-VCH: Weinheim, 1998; p. 49; (b) Stanforth, S. P.
Tetrahedron 1998, 54, 263.
4. During the preparation of this manuscript, a report
regarding the synthesis of the biaryl moiety of TMC-95 via
a Stille coupling reaction was published. See: Albrecht, B.
K.; Williams, R. M. Tetrahedron Lett. 2001, 42, 2755.
5. Newman, M. S.; Logue, M. W. J. Org. Chem. 1971, 36,
1798.
The authors are grateful to the Chinese Academy of
Sciences, National Natural Science Foundation of
China (Grant No. 29725205), and Qiu Shi Science &
Technologies Foundation for their financial support.
6. (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J. Am. Chem. Soc. 1999, 121, 9550; (b) Littke, A. F.;
Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020; (c)
Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830; (d)
Lisowaki, V.; Robba, M.; Rault, S. J. Org. Chem. 2000,
65, 4193.
7. For ligandless Pd(OAc)2-catalyzed Suzuki-coupling reac-
tions, see: Bumagin, N. A.; Bykov, V. V. Tetrahedron
1997, 53, 14437 and references cited therein.
References
1. Ma, D.; Wu, Q. Tetrahedron Lett. 2000, 41, 9089.
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