Enantioselective construction of the oxidized tryptophan fragment of proteasome inhibitors TMC-95A and TMC-95B

Article abstract of DOI:10.1016/S0040-4039(00)01657-9

The oxidized tryptophan analogue 5, a proposed intermediate for a synthesis of the proteasome inhibitors TMC-95A and TMC-95B, is prepared using the condensation of oxindole 7 with the (R)-Garner aldehyde and stereoselective dihydroxylation of olefin 6 as key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01657-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9089–9093
Enantioselective construction of the oxidized tryptophan
fragment of proteasome inhibitors TMC-95A and TMC-95B
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 12 July 2000; revised 13 September 2000; accepted 20 September 2000
Abstract
The oxidized tryptophan analogue 5, a proposed intermediate for a synthesis of the proteasome
inhibitors TMC-95A and TMC-95B, is prepared using the condensation of oxindole 7 with the (R)-
Garner aldehyde and stereoselective dihydroxylation of olefin 6 as key steps. © 2000 Elsevier Science Ltd.
All rights reserved.
TMC-95A-D are four cyclic peptides containing
L
-tyrosine,
L
-asparagine, highly oxidized
L
-tryptophan, (Z)-1-propenylamine, and 3-methyl-2-oxopentanoic acid units.1,2 These com-
pounds were recently isolated from the fermentation broth of Apiospora montagnei Sacc. TC
1093, isolated from a soil sample. Biological studies indicated that these natural products,
especially TMC-95A, exhibit potent inhibition activity towards proteasome (IC50=5.4 nM).
The important biological activities displayed by TMC-95 A and TMC-95B and their unique
structures stimulated us to embark on a program directed toward a total synthesis of these
two compounds.
Our retrosynthetic analysis is shown in Fig. 1. The target molecule could be obtained by
a Suzuki coupling3 of the bromide 5 with the intermediate E and subsequent conversions,
while the dihydroxy moiety in 5 could be introduced by a stereospecific dihydroxylation of
olefin 6. Further simplification gave oxindole 7 and the (R)-Garner aldehyde as two possible
precursors. In this report, we wish to present our efforts for the synthesis of 5 by this
strategy.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01657-9

9090
Figure 1.
As outlined in Scheme 1, we started our synthesis from 2-bromoaniline, which was reacted
with trichloroacetaldehyde to afford isatin 8. Upon treatment with hydrazine, isatin 8 was
reduced to oxindole 7 in 88% yield.4 Condensation of 7 with the (R)-Garner aldehyde (ꢀ90%
ee)5 was attempted under several conditions that are summarized in Table 1. Initially, we tried
to use piperidine as the catalyst and found that at high temperature the reaction gave coupling
products in good yield (entry 1).6 However, the rotation of the product 6 was zero, which meant
that racemisation had occurred during the coupling reaction. A lower reaction temperature was
still not satisfactory (entry 2). At this stage we studied stepwise coupling.7 Thus, treatment of 7
with LHMDS followed by trapping the lithium enolate with the (R)-Garner aldehyde afforded
the aldol condensation product. This product was converted into 6 and 9 in 54% yield upon
treatment with TEA/MsCl. The ee value of 6 at this time was about 90% as detected by HPLC
(entry 3). Further improvement of the reaction conditions provided 6 and 9 in 76% yield without
any racemization (entry 6). The olefin 6 was predicted to be E-isomer and this was confirmed
by further conversions discussed later. The Z-isomer 9 was converted into the E-isomer 6 with
I2/NaHCO3 in 89% yield based on 42% recovery of 9.
Scheme 1.

9091
Table 1
Reaction conditions for condensation of 7 with the (R)-Garner aldehyde
Entry Reaction conditions
Yield (%)a 9/6
ee% of 6
1
2
3
Piperidine, EtOH, reflux
Piperidine, EtOH, rt
LHMDS (2 equiv.)/THF, −78°C, then TEA (4 equiv.), MsCl (3
equiv.), CH2Cl2, −60°C
76
37
54
45/55
46/54
44/56
0
13
ꢀ90
4
5
6
LDA (2 equiv.)/THF, −78°C, then TEA (4 equiv.), MsCl (3 equiv.),
CH2Cl2, −60°C
n-BuLi (2 equiv.)/THF, −78°C, then TEA (4 equiv.), MsCl (3 equiv.), 71
CH2Cl2, −60°C
n-BuLi (1.5 equiv.)/THF, −78°C, then TEA (2 equiv.), MsCl (1
equiv.), CH2Cl2, −60°C
62
41/59
46/54
44/56
ꢀ90
ꢀ90
ꢀ93
76
a Isolated yield.
Dihydroxylation of 6 was found to be another challenging step of our synthesis. Several
oxidation systems were tried using our substrate 6 and most gave no products or provided the
by-product, isatin 8, in high yields (Table 2, entries 1–4). Fortunately, treatment of 6 with
OsO4/pyridine produced our desired product 10 in about 79% yield (entry 5). Protection of the
diol 10 as its cyclic carbonate gave 11 in 91% yield. The carbonate 11 was crystalline and
therefore we could determine its stereochemistry by X-ray analysis (Fig. 2). Thus we found that
the configuration of 11 is 3S,1%R,2%R, which is the one required for synthesizing TMC-95A and
TMC-95B. The stereochemistry in the dihydroxylation step is consistent with Fig. 3, the oxidant
attacking the CꢀC double bond from the outer, less hindered face, to give the diol 10. Next, the
selective cleavage of the acetonide to form the alcohol 12 was attempted. We found that TMSI
formed in situ13 was the most effective catalyst for this transformation while CSA, TsOH, or
Dowex-50W were not so good. Finally, Jones oxidation of 12 followed by amidation with
allylamine gave 5 in 65% yield (Scheme 2).
Table 2
Dihydroxylation of 6
Entry
Reaction conditions
Product
Yield (%)a
1
2
3
4
5
AD-mix-b, t-BuOH-H2O, 0°C to rt8
OsO4ꢀNMO, THF/H2O, rt9
8 (0)
10 (0)
10 (0)
10 (31)
10 (0)
10 (79)
8 (73)
8 (64)
8 (40)
8 (10)
NaIO4/RuCl3·xH2O, EtOAc/MeCN/H2O, −10°C10
KMnO4, EtOH/H2O, −40°C9,11
OsO4, pyridine, THF, 0°C12
a Isolated yield.

9092
Figure 2.
Figure 3.
In conclusion, we have developed a method to prepare the oxidized tryptophan fragment of
TMC-95A and TMC-95B. Further efforts for the total synthesis of these two natural products
as well as structure-activity relationship studies are underway in our laboratory.

9093
Scheme 2.
Aknowledgements
The authors are grateful to the Chinese Academy of Sciences, National Natural Science
Foundation of China (grant 29725205), and Qiu Shi Science & Technologies Foundation for
their financial support.
References
1. Kohno, J.; Koguchi, Y.; Nisshio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. J.
Org. Chem. 2000, 65, 990.
2. Koguchi, Y.; Kohno, J.; Nisshio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.; Komatsubara, S. J. Antibiot. 2000,
53, 105.
3. For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem.
1999, 576, 147.
4. Crestini, C.; Saladino, R. Syn. Commun. 1994, 24, 2835.
5. Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361.
6. Daisley, R. W.; Walker, J. J. Chem. Soc. (C) 1971, 3357.
7. McKillop, A.; Taylor, R. L. J.; Waston, R. J.; Lewis, N. Synthesis 1994, 31.
8. Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993, 34, 2079.
9. Cheikh, A. B.; Craine, L. E.; Recher, S. G.; Zemlicka, J. J. Org. Chem. 1988, 53, 929.
10. Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem. Int. Ed. Engl. 1994, 33, 2312.
11. Angermann, J.; Homann, K.; Reissig, H.-U.; Zimmer, R. Synlett. 1995, 1014.
12. Honda, T.; Takada, H.; Miki, S.; Tsubuki, M. Tetrahedron Lett. 1993, 34, 8275.
13. Williams, L.; Zhang, Z.-D.; Shao, F.; Carrol, P. L.; Joullie, M. M. Tetrahedron 1996, 52, 11674.
.
.