Entry into the bi-aryl moiety of the TMC-95 proteasome inhibitors via the Stille protocol

Article abstract of DOI:10.1016/S0040-4039(01)00299-4

The synthesis of the bi-aryl moiety of the TMC-95 natural products has been achieved via a palladium-catalyzed Stille cross-coupling reaction of an aryl stannane tyrosine derivative and 7-iodoisatin.

Full text of DOI:10.1016/S0040-4039(01)00299-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2755–2757
Entry into the bi-aryl moiety of the TMC-95 proteasome
inhibitors via the Stille protocol
Brian K. Albrecht and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 30 January 2001; revised 15 February 2001; accepted 20 February 2001
Abstract—The synthesis of the bi-aryl moiety of the TMC-95 natural products has been achieved via a palladium-catalyzed Stille
cross-coupling reaction of an aryl stannane tyrosine derivative and 7-iodoisatin. © 2001 Elsevier Science Ltd. All rights reserved.
TMC-95 A–D are potent proteasome inhibitors isolated
from the fermentation broth of Apiosopora montagnei
Sacc. TC 1093 by Kohno and co-workers.1 These natu-
such as cell progression, antigen presentation, and cyto-
kine-stimulated signal transduction.2 The great interest
emerging in the field of proteasome inhibition, the con-
siderable biological activity, and the distinctive struc-
tures of the TMC-95s have provided motivation to
contemplate a total synthesis of these compounds that
would be readily adaptable to preparing analogs.
ral products are unique cyclic peptides containing
tyrosine, -asparagine, a highly oxidized -trypto-
L-
L
L
phan-derived oxindole, (Z)-1-propenylamine, and 3-
methyl-2-oxopentanoic acid units. It has been shown
that these compounds are biologically active against
chymotrypsin-like, trypsin-like, and peptidylglutamyl-
peptide hydrolysing proteases.1 Recently, proteasome
inhibitors have received considerable attention due to
the critical role they play in intracellular processes
When contemplating the synthesis of the TMC-95s, it
was envisioned that the biaryl moiety could best be
constructed via a palladium-catalyzed cross-coupling
reaction.3 When considering coupling partners, we envi-
Figure 1.
* Corresponding author. E-mail: rmw@chem.colostate.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00299-4

2756
B. K. Albrecht, R. M. Williams / Tetrahedron Letters 42 (2001) 2755–2757
sioned coupling two readily available, chemically
manipulative fragments such as 7-iodoisatin 3 (X=I)
and a 3-stannyltyrosine derivative 4 (Y=SnR3, Fig. 1).
It is conceivable that any type of biaryl coupling4
method could lead to the biaryl portion, but in our
hands the Stille coupling protocol proved to be both
compatible with other functionality and high yielding.
Herein we report the entrance into the biaryl moiety of
the TMC-95 natural products via a palladium-catalyzed
Stille cross-coupling reaction.5
treated with 2.2 equiv. of MeI and 1.5 equiv. of K2CO3
in refluxing acetone to give the O-methyl ether of
3-iodotyrosine-O-Me ester 8 (Scheme 1).
The aryl iodides were converted to the corresponding
aryl stannane by treatment with either hexamethylditin
or hexabutylditin and Pd(PPh3)4 in refluxing toluene
(Scheme 2).7
With both coupling partners in hand, we focused our
attention on optimising the Stille coupling conditions.
Stille coupling of 7-iodoisatin and aryl stannane
(Scheme 3) was attempted under several conditions, as
summarized in Table 1.
7-Iodoisatin was prepared from 2-iodoaniline via the
Sandmeyer procedure.6 In order to obtain the appropri-
ate aryl stannane necessary for the Stille coupling,
manipulations were made to commercially available
3-iodotyrosine 5. The free amino acid was first pro-
tected to give the N-Boc amino acid 6. Next, we
decided to explore several protecting group alternatives
to determine the effect of the blocking groups on the
coupling yields. First, compound 6 was subjected to
TMSCHN2, followed by bromomethyl methyl ether
and i-Pr2NEt to furnish fully protected MOM-ether-3-
iodotyrosine-O-Me ester 7. Secondly, compound 6 was
We had initially envisioned using the aryl trimethylstan-
nane derivatives due to the fact that access to these
compounds was accompanied by very high yields. In
the event, coupling experiments demonstrated that
there was competitive methyl group transfer to 7-
iodoisatin, especially in polar solvents such as DMF
(Table 1, entries 1, 2, 5, and 6). It has been shown that
aryl stannanes with ortho-substituents have significant
I
I
I
1. TMSCHN2, PhH
MeOH (92%)
HO
MOMO
O
OH
O
OMe
HO
O
OH
Boc2O, H2O
NHBoc
NHBoc
dioxane, 10% NaOH
95%
2. MOMBr, i-Pr2NEt
CH2Cl2 (96%)
NH2
H
H
H
5
7
6
I
MeO
MeI, K2CO3, ∆
acetone (96%)
O
OMe
NHBoc
H
8
Scheme 1.
I
SnR'3
RO
O
OMe
RO
O
OMe
(R3Sn)2, Pd(PPh3)4
NHBoc
PhMe, ∆
NHBoc
H
H
9, R = MOM, R' = Me (92%)
10, R = MOM, R' = Bu (50%)
11, R = R' = Me (90%)
7, R = MOM
8, R = Me
12, R = Me, R' = Bu (60%)
Scheme 2.
O
O
SnR'3
O
O
RO
O
OMe
see Table 1
+
O
N
O
+
H
N
H
N
H
RO
O
OMe
NHBoc
H
Me
I
9, R = MOM, R' = Me
10, R = MOM, R' = Bu
11, R = R' = Me
3
NHBoc
H
13, R = MOM
14, R = Me
15
12, R = Me, R' = Bu
Scheme 3.

B. K. Albrecht, R. M. Williams / Tetrahedron Letters 42 (2001) 2755–2757
Table 1. Reaction conditions for the Stille coupling outlined in Scheme 3
2757
Entry
R
R%
Conditions
Product, ratio
Yield (%)
1
2
3
4
5
6
7
8
MOM
MOM
MOM
MOM
MOM
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Pd(PPh3)2Cl2,a DMF, LiCl, 100°, 20 h
Pd(dppf)Cl2,a DMF, LiCl, 100°, 5.5 h
Pd(PPh3)2Cl2,a THF, CuI, reflux, 24 h
Pd(dppf)Cl2,a dioxane, CuI, reflux, 6 h
Pd(PhCN)2Cl2,b DMF, AsPh3, CuI, 100°, 1 h
Pd(dppf)Cl2,b DMF, CuI, dppf, 100°, 10 h
Pd(dppf)Cl2,b DMF, CuI, 100°, 2.5 h
Pd(PhCN)2Cl2,b DMF, AsPh3, CuI, 3 h
Pd(dppf)Cl2,a MeCN, CuBr, reflux, 7.5 h
Pd(dppf)Cl2,a PhMe, CuI, reflux, 24 h
Pd(dppf)Cl2,c MeCN, CuBr, reflux, 24 h
Pd(PPh3)2Cl2,c MeCN, CuBr, reflux, 48 h
13:15, 1:1
13:15, 1:1
No reaction
13
13:15, 1:1
14:15, 1:1
14
14
B5
B5
–
B2
18
6
15
20
80d
–
68
57
9
14
10
11
12
No reaction
13
13
MOM
MOM
a 5 mol% catalyst.
b 10 mol% catalyst.
c 7 mol% catalyst.
d Based on recovered starting material, 60% otherwise.
methyl group transfer, with phenyl transfer being only
five times faster than methyl transfer.8 These results
made us turn our attention to preparing the tributyl-
stannanes as potential coupling partners. We observed
that, although the yields for incorporation of the tri-
butylstannane are lower, the coupling reactions proceed
much more smoothly, with no butyl transfer observed.
It was also seen that solvents played an important role
in the coupling with, MeCN being better than DMF,
whereas THF, dioxane, and toluene displayed virtually
no reaction at all. As expected, we were unable to
observe any significant difference between the two phe-
nolic protecting groups used.
References
1. (a) Khono, J.; Koguchi, Y.; Nishio, M.; Najao, K.;
Juroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J.
Org. Chem. 2000, 65, 990; (b) Koguchi, Y.; Khono, J.;
Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.;
Komatsubara, S. J. Antibiot. 2000, 53, 105. For recent
work on TMC-95, see: Ma, D.; Wu, Q. Tetrahedron Lett.
2000, 41, 9089.
2. (a) Groll, M.; Kim, K. B.; Kairies, N.; Huber, R.; Crews,
C. M. J. Am. Chem. Soc. 2000, 122, 1237; (b) Peters, J. M.
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3. For a recent review, see: Hegedus, L. S. Transition Metals
in the Synthesis of Complex Organic Molecules; University
Science Books: Sausalito, CA, 1999.
4. For a review on biaryl couplings, see: Stanforth, S. P.
Tetrahedron 1998, 54, 263.
5. For a review of the Stille reaction, see: (a) Farina, V.;
Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1–652; (b) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986,
25, 508.
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Marvel, C. S.; Hiers, G. S. Org. Syn. Coll. 1943, coll. vol.
I, 327.
In summary, we have found that a palladium-catalyzed
Stille cross-coupling reaction between a tri-n-butylstan-
nane derivative of tyrosine and 7-iodoisatin is an
efficient method for the synthesis of the biaryl moiety
of the TMC-95 class of natural products. Studies to
apply this method for the construction of the TMC-95
proteasome inhibitors and select analogs is currently in
progress in these laboratories.
Acknowledgements
7. (a) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet.
Chem. 1981, 215, 49; (b) review: Marshall, J. A. Chem.
Rev. 2000, 100, 3163.
This work was supported by the National Science
Foundation (Grant CHE 9731947).
8. Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J.
Org. Chem. 1993, 58, 5434.
.