Total synthesis of TMC-95A

Article abstract of DOI:10.1002/anie.200351130

A Suzuki-Miyaura coupling reaction to form C1-C20, macrolactamization at N9-C10, and a mild decarboxylative anti elimination to selectively introduce the (Z)-1-propenylamide are key steps in a highly convergent and completely stereo-selective synthesis of

Full text of DOI:10.1002/anie.200351130

Communications
Natural Product Synthesis
tryptophan moiety, the (Z)-1-propenylamide, the 3-methyl-2-
oxopentanoic acid side chain with the configurationally
unstable methyl-substituted C36 center, and the aryl–oxin-
Total Synthesis of TMC-95A**
ꢀ
dole ring junction (C1 C20) (Scheme 1). It was envisaged
that the macrolactam structure could be assembled by a
Masayuki Inoue,* Hayato Sakazaki,
Hidetomo Furuyama, and Masahiro Hirama*
ꢀ
Suzuki–Miyaura coupling reaction (C1 C20) and peptide
bond formation (N9 C10).[8–11] To avoid epimerization at the
ꢀ
C36 stereocenter, we planned to introduce 3-methyl-2-
oxopentanoic acid as the reduced form 3, and to generate
the C35 ketone in the final stage of the synthesis. We
previously reported a stereoselective synthesis of the north-
ern part of the molecule[6] (7, Scheme 2) with the following
A proteasome is a multicatalytic protease that is involved in a
variety of biologically important processes, including immune
responses, cell-cycle control, metabolic adaptation, stress
response, and cell differentiation.[1] The selective inhibition of
proteasomes may therefore be a means of controlling these
essential pathways.[2] TMC-95A (1, Scheme 1) and its C36
epimer TMC-95B are potent proteasome inhibitors that bind
O
Z olefin
8
5
Br
N
O
E olefin
8
Pd0
DMDO
N
5
6
6
Boc
1
O
O
Boc
Br
BocN
O
O
N
Boc
HO
OH
4
Br
8
N
27
5
27
29
29
O
O
HO
O
H2N
27
HO
HO
NH
O
6
NH
29
L-allothreonine
L-asparagine
O
8
O
O
9
O
9
NH
N
Boc
NH
8
8
8
6
1
N
O
N
Boc
7
7
Br
HO
O
BzO
O
10
O
N
H
O
1
BF3·Et2O
O
O
2
6
6
6
NH2
O
O
O
HO
O
NH
20
N
Boc
N
Boc
N
H
O
1
1
1
14
35
L-tyrosine
Br
Br
Br
36
O
N
H
6
2
7
35
36
O
HO
Scheme 2. Synthesis of the northern part of TMC-95A. DMDO=3,3-
dimethyldioxirane.[6]
1: TMC-95A
OH
3
Scheme 1. Synthetic approach to TMC-95A. Boc=tert-butoxycarbonyl
to enzymes noncovalently with IC50 values at low nanomolar
levels.[3] Thus, TMC-95 may provide unique insight into the
detailed biological functions of proteasomes. Recently, the X-
ray crystallographic structure of a complex of 1 with a
proteasome was reported,[4] which has allowed the design of
novel TMC-95 analogues with tailored biological activities.[5]
The intriguing biological profile and the structural com-
plexity of TMC-95 immediately generated considerable
interest within the synthetic community, and chemical syn-
theses have been pursued by several research groups.[6,7]
These efforts have culminated in a total synthesis of TMC-
95A/B by Lin and Danishefsky,[8] and a formal synthesis by
Albrecht and Williams.[9] This report details a new solution to
the stereoselective construction of TMC-95A.
key features: 1) a Z-selective Mizoroki–Heck reaction to
construct the oxindole structure (4!5), 2) diastereoselective
epoxidation (5!6), 3) a 6-endo epoxide ring opening reac-
tion to establish the stereochemistry of the C6 and C7
stereocenters (6!2), and 4) decarboxylative anti elimination
under Mitsunobu conditions[12] to create the (Z)-1-propenyl-
amide 7. However, removal of the carbamate in 7 to liberate
the N9 amine was unsuccessful despite extensive experimen-
tation, which revealed the chemical instability of the propen-
ylamide both in strongly acidic and in strongly basic media.
Accordingly, we decided to construct the propenylamide after
macrolactam formation, although the applicability of our
method in a more complex structure remained uncertain.[13]
Our modified route started with the previously reported
compound 2 (Scheme 3). The Boc group of 2 was selectively
removed with Mg(ClO4)2 in acetonitrile,[14] and the C7
secondary alcohol was protected as its ethoxyethyl (EE)
ether to afford 8 in 94% yield for the two steps. For effective
biaryl coupling, the bromide 8 was converted into the
corresponding iodide 9 in 86% yield through metalation
with nBuLi and subsequent addition of diiodoethane without
affecting the potentially reactive carbamate. The carbamate
group of 9 was in fact extremely resistant to removal under a
variety of conditions in the next step. Finally, it was found that
the “anhydrous hydroxide” method of Gassman et al.[15] with
tBuOK (15 equiv) and H2O (10 equiv) transformed 9 into the
aniline 10 (74% yield), in which both the carbamate and the
acetonide had been hydrolyzed.
The most notable features of TMC-95A from the per-
spective of the synthetic chemist are the highly oxidized
[*] Dr. M. Inoue, Prof. Dr. M. Hirama, H. Sakazaki, H. Furuyama
Department of Chemistry
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Fax: (+81)22-217-6566
E-mail: inoue@ykbsc.chem.tohoku.ac.jp
hirama@ykbsc.chem.tohoku.ac.jp
[**] Dr. Jun Kohno, Tanabe Seiyaku Co. (Japan), is gratefully acknowl-
edged for providing natural TMC-95A for comparative analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2654
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351130
Angew. Chem. Int. Ed. 2003, 42, 2654 – 2657

Angewandte
Chemie
with p-toluenesulfonic acid to give 12 as a salt. The formation
O
O
of 12 over 11 in acidic media is attributable to the preferential
protonation of the more basic N9 amine of 12.[16] The
transformation from 9 to 12 was performed more practically
in one pot by treating 9 under the Gassman conditions before
sequentially introducing water, methanol, and TsOH. The
liberated amine of 12 was then protected as its benzyl
carbamate (55% yield from 9), and the 1,3-diol was masked as
its p-methoxybenzylidene acetal to produce the tryptophan
fragment 13 (84% yield), suitably protected for the next
reaction sequence.
8
8
N
N
R1O
Br
O
EEO
O
7
7
c
O
O
O
O
23
NR2
N
H
1
9
I
2: R1=H, R2=Boc
8: R1=EE, R2=H
tBuO–, OH–
a,b
d or e
OH
OH
NH
8
8
HO
EEO
HO
7
7
H+
NH
HO
We then turned our attention to the synthesis of the
coupling partner of 13 (20, Scheme 5). The iodotyrosine
derivative 17[17] and the a-hydroxycarboxylic acid 3[18] were
prepared from l-tyrosine and l-isoleucine, respectively. After
23
23
O
O
NH+3 TsO–
NH2
I
11
I
10
PMP
O
O
I
HO
HO
OH
O
8
8
20
HO
HO
O
OMe
f,g
7
9
7
35
NH+3 TsO–
36
NHZ
O
HO
14
23 O
NH+3Cl–
OH
17
3
N
H
N
H
I
I
12
13
a
Scheme 3. Reagents andconditions: a) Mg(ClO 4)2, MeCN, 508C;
b) ethyl vinyl ether, PPTS, THF, 358C, 94% from 2; c) nBuLi,
ICH2CH2I, THF, ꢀ608C!room temperature, 86%; d) tBuOK
(15 equiv), H2O (10 equiv), Et2O, room temperature, 74%; e) tBuOK
(15 equiv), H2O (10 equiv), Et2O, room temperature; then H2O, TsOH,
MeOH, room temperature; f) ZCl, Et3N, DMF, 08C!room tempera-
ture, 55% from 9; g) p-MeOC6H4CH(OMe)2, TsOH, THF, 84%.
DMF=dimethylformamide, PMP=p-methoxyphenyl, PPTS=pyridi-
nium p-toluenesulfonate, TsOH=p-toluenesulfonic acid, Z=benzyloxy-
carbonyl.
I
20
R1O
O
OMe
18: R1=H, R2=H
19: R1=MOM, R2=TBS
O
b,c
14
35
N
H
OR2
d
O
O
B
20
MOMO
O
OMe
O
N
H
OTBS 20
The most plausible mechanism for this interesting out-
come is depicted in Scheme 4: Compound 14, generated upon
loss of the carbamate group in 9 by decarboxylation, is in
equilibrium with the imine 15, which can undergo attack by a
hydroxy anion to give 16. Expulsion of acetone from 16 and
transacylation from N22 to the more nucleophilic N9 then
results in the formation of 10.
Scheme 5. Reagents andconditions: a) 3 (2 equiv), EDC·HCl, HOBt, 4-
methylmorpholine, DMF, 08C, 56%; b) MOMCl, K2CO3, acetone, 85%;
c) TBSOTf, 2,6-lutidine, CH2Cl2, 08C, 88%; d) bis(pinacolato)diboron,
[Pd(dppf)Cl2], KOAc, DMSO, 808C, 71%. DMSO=dimethylsulfoxide,
dppf=1,1’-bis(diphenylphosphany)ferrocene, EDC=ethylcarbodiimide
chloride, HOBt=1-hydroxy-1H-benzotriazole, MOM=methoxymethyl,
TBSOTf=tert-butyldimethylsilyl trifluoromethanesulfonate.
As shown in Scheme 3, regeneration of the oxindole
structure from the aniline 10, accompanied by loss of the
ethoxyethyl group, was realized by lowering the pH value
condensation of these two structural units in the presence of
EDCand HOBt (56% yield), selective protection of the
phenolic hydroxy group of 18 as its methoxymethyl ether,
followed by protection of the remaining C35 alcohol with
TBS, produced 19 in 75% yield over the two steps. The
protected iodide 19 was converted into the aryl boronate 20 in
71% yield by palladium-mediated borylation.[19]
O
OH
8
EEO
8
9
N
7
9
NH
O
HO
7
tBuOK (15 equiv), H O (10 equiv)
EEO
I
O
2
23
O
ꢀ
The C1 C20 biaryl bond was formed by treating the two
O
22
N
H
Et2O, RT, 74%
23
NH2
advanced intermediates 13 and 20 with a catalytic amount of
[Pd(PPh3)4] and Na2CO3 in aqueous DME at 958Cto give the
adduct 21 in 84% yield (Scheme 6).[11,20] Basic hydrolysis of
the methyl ester 21, followed by amidation with l-asparagine
benzyl ester, afforded 22 in 75% yield. Hydrogenolysis of
both the benzyloxycarbonyl (Z) and benzyl groups gave a
seco acid, which was subjected to cyclization in the presence
of EDCand HOAt to afford the macrolactam 23 in 78%
yield. In this way, the macrocyclic structure was constructed
effectively through the assembly of three key fragments.
22
I
10
9
– Me2CO
transacylation (N22→N9)
– CO2
EEO
HO
EEO
HO
EEO
7 8
7
8
7
8
O
O–
O–
HO
N
– N9
– N
14
OH
15
– OH
16
Scheme 4. Possible reaction mechanism for 9!10.
Angew. Chem. Int. Ed. 2003, 42, 2654 – 2657
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2655

Communications
a
PMP
PMP
PMP
O
13 + 20
O
O
O
25
O
HO
HO
R2
NH
O
HO
NHZ
O
HO
9
7
7
HO
9
NHZ
O
NH
b,c
d,e
O
O
h
OBn
O
O
O
O
10
10
O
O
N
H
N
H
N
N
H
O
1
H
NH2
20
NH2
NH2
MOMO
O
OMe
O
MOMO
NH
MOMO
O
NH
O
MOMO
O
NH
O
13
13
O
35
N
H
N
H
N
H
N
H
OTBS
OTBS
OR1
OTES
23: R1=TBS
24: R1=TES
25: R2=CH2OH
26: R2=COOH
21
22
f,g
i,j
k
OH
O
R3O
O
27
27
28
O
O
O
27
28
O
R5O
HO
NH
HO
HO
NH
HO
HO
25 NH
–O
O
OP+Ph3
m
7
7
27
NH 28
NH
NH
NH
o
O
O
O
O
O
O
O
O
N
H
N
H
N
H
29
NH2
NH2
NH2
R6O
O
NH
MOMO
O
NH
MOMO
O
NH
O
anti elimination
19
O
O
35
35
N
H
N
H
N
H
O
OR4
OTES
30: R4=TES
32: R4=H
27: R3=Bn
28: R3=H
33: R5=H, R6=MOM
34: R5=COCH2Cl, R6=MOM
1: R5=H, R6=H (TMC-95A)
n
p
q
l
31: R4=TBS
Scheme 6. Reagents andconditions: a) 20 (1.5 equiv), [Pd(PPh3)4], Na2CO3, DME/H2O (4:1), 958C, 84%; b) LiOH, THF/H2O (1:1), 08C; c) H-
Asn-OBn·TFA, EDC·HCl, HOBt, DMF, 08C, 75% from 21; d ) H, Pd(OH)2/C, THF/H2O (1:1); e) EDC·HCl, HOAt, DMF, 08C, 78% from 22;
2
f) TBAF, 4-Š MS, THF, 86%; g) TESCl, imidazole, DMF, 85%; h) Zn(OTf)2, EtSH, NaHCO3, CH2Cl2, 100%; i) SO3·pyr, Et3N, CH2Cl2/DMSO (3:1),
room temperature; j) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH/H2O (5:1), room temperature; k) l-allo-Thr-OBn·TFA, EDC·HCl, HOBt, DMF,
08C, 67% from 25; l) H2, Pd(OH)2/C, THF/H2O (1:2); m) DEAD, PPh3, 4-Š MS, 08C!room temperature, 59% from 27; n) HF·pyridine, THF,
79%; o) Dess–Martin periodinane, CH2Cl2, 80%; p) (ClCH2CO)O, pyridine, CH2Cl2, 08C; q) aqueous HCl (1n)/THF (3:1), room temperature;
then saturatedaqueous NaHCO 3, 64% from 33. Bn=benzyl; DEAD=diethyl azodicarboxylate, DME=1,2-dimethoxyethane, HOAt=1-hydroxy-7-
azabenzotriazole, MS=molecular sieves, pyr=pyridine, TBAF=tetrabutylammonium fluoride, TES=triethylsilyl, TFA=trifluoroacetic acid.
We had thus reached a critical stage of the total synthesis:
introduction of the (Z)-propenylamide, construction of the
dicarbonyl moiety, and the final deprotection. First, the TBS
group of the C35 alcohol was exchanged for TES (23!24) for
facile deprotection at a later stage. The PMP acetal was then
removed with zinc triflate and ethanethiol in the presence of
NaHCO3 as a buffer[21] to afford the triol 25 in 73% yield over
three steps. Selective oxidation of the C25 primary alcohol of
25 allowed differentiation of the oxidation levels of C7 and
C25 and led to the carboxylic acid 26 in two steps. Attachment
of l-allothreonine benzyl ester to 26 produced 27 (67% yield
from 25), which was then subjected to hydrogenolysis to
provide the b-hydroxycarboxylic acid 28. Subsequent treat-
ment of 28 with PPh3 and DEAD[12] in the presence of
molecular sieves induced dehydrative decarboxylation at
room temperature and led to the isomerically pure (Z)-
propenylamide 30 in 59% yield over the two steps.[6,22] The
geometry of the resultant olefin is thought to be defined
through the Grob-type anti elimination of 29.[23] Thus, the
applicability of this method in a complex setting was clearly
demonstrated. The neutral nature and high chemoselectivity
of the reaction should make it suitable for use in the synthesis
of a wide variety of TMC-95 analogues and other compounds
containing enamides.[8,24]
To adjust the oxidation level to that of the natural product,
the C35 alcohol in 30 had to be deprotected. ATBS-protected
compound 31 had been prepared by a similar route to 30, but
extensive investigations had failed to identify conditions that
would allow the selective removal of the TBS group while
leaving the rest of the molecule intact. However, the TES
group in 30 was readily removed and the alcohol 32 was
obtained in 79% yield upon treatment of 30 with HF·pyridine.
Selective oxidation of the C35 alcohol of 32 in the presence of
the C7 alcohol with Dess–Martin periodinane[25] then
afforded MOM-protected TMC-95A 33 in 80% yield.
The final deprotection step proved to be nontrivial
because of the intrinsic instability of the enamide. Various
attempts to remove the MOM group of 33 under acidic
conditions led to a complex mixture of products, and TMC-
95A (1) was obtained in only minute amounts. The free C7
alcohol may be responsible for these difficulties as it may
react in an intramolecular fashion with the propenylamide to
form a six-membered ring.[26] Therefore, the alcohol at C7 was
temporarily protected as its chloroacetyl ester (33!34),
which indeed suppressed the side reactions. Exposure of 34 to
HCl (1n)/THF and then saturated aqueous NaHCO3 in one
pot effectively afforded fully synthetic TMC-95A (1) in 64%
yield from 33 without destruction of the enamide or the
2656
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angew. Chem. Int. Ed. 2003, 42, 2654 – 2657

Angewandte
Chemie
[15] a) P. G. Gassman, W. N. Schenk, J. Org. Chem. 1977, 42, 918;
stereochemistry of epimerizable C36 center. The physical
data (1H NMR, IR, MS) for the synthetic material were
identical to those for the natural product.[3,8]
b) P. G. Gassman, P. K. G. Hodgson, R. J. Balchunis, J. Am.
Chem. Soc. 1976, 98, 1275.
[16] a) P. A. Thio, M. J. Kornet, J. Heterocycl. Chem. 1971, 8, 479;
b) M. Nakagawa, S. Kato, H. Fukazawa, Y. Hasegawa, J.
Miyazawa, T. Hino, Tetrahedron Lett. 1985, 26, 5871.
[17] J. Chiarello, M. M. Joullie, Synth. Commun. 1988, 18, 2211.
[18] M. Winitz, L. Bloch-Frankenthal, N. Izumiya, S. M. Birnbaum,
C. G. Baker, J. P. Greenstein, J. Am. Chem. Soc. 1956, 78, 2423.
[19] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60,
7508.
[20] S. Boisnard, A.-C. Carbonnelle, J. Zhu, Org. Lett. 2001, 3, 2061.
[21] K. C. Nicolaou, C. A. Veale, C.-K. Hwang, J. Hutchinson,
C. V. C. Prasad, W. W. Ogilvie, Angew. Chem. 1991, 103, 304;
Angew. Chem. Int. Ed. Engl. 1991, 30, 299.
In summary, an efficient, highly convergent total synthesis
of TMC-95A has been achieved. The key transformations in
this synthesis are 1) a new deprotection protocol for the
removal of the hindered carbamate and the acetonide of 9,
2) conversion of the aniline 10 into the oxindole 12 by
lowering the pH value, 3) a Suzuki–Miyaura coupling reac-
tion and macrolactamization to efficiently create the macro-
cyclic framework 23, and 4) a mild decarboxylative anti
elimination to selectively produce the (Z)-1-propenylamide
as part of a complex structure. The chemistry and biology of
TMC-95A are being investigated further in our laboratory.
[22] S. V. Pansare, J. C. Vederas, J. Org. Chem. 1989, 54, 2311.
[23] a) J. Mulzer, A. Pointner, A. Chucholowski, G. Brüntrup, J.
Chem. Soc. Chem. Commun. 1979, 52; b) J. Mulzer, O. Lammer,
Angew. Chem. Suppl. 1983, 887.
Received: February 7, 2003 [Z51130]
[24] For selected examples of the preparation of enamides, see: a) S.
Sergeyev, M. Hesse, Synlett 2002, 1313; b) P. RibØreau, M.
Delamare, S. CØlanire, G. QuØguiner, Tetrahedron Lett. 2001, 42,
3571; c) R. Shen, J. A. Porco, Jr., Org. Lett. 2000, 2, 1333; d) B. B.
Snider, F. Song, Org. Lett. 2000, 2, 407; e) K. Kuramochi, H.
Watanabe, T. Kitahara, Synlett 2000, 397; f) T. Mecozzi, M.
Petrini, Synlett 2000, 73; g) N. M. Laso, B. Quiclet-Sire, S. Z.
Zard, Tetrahedron Lett. 1996, 37, 1605; h) U. Schmidt, A.
Lieberknecht, Angew. Chem. 1983, 95, 575; Angew. Chem. Int.
Ed. Engl. 1983, 22, 550; i) U. Redeker, N. Engel, W. Steglich,
Tetrahedron Lett. 1981, 22, 4263; j) J. K. Stille, Y. Becker, J. Org.
Chem. 1980, 45, 2139.
Keywords: biaryls · macrocycles · natural products · olefination ·
total synthesis
.
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[26] The attempted isolation of 35 was unsuccessful, presumably
because of its instability under the reaction conditions.
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H+
27
O
O
NH
HO
HO
NH
O
O
HO
?
7
7
NH
NH
O
O
O
N
H
N
H
35
33
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www.angewandte.org
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