by their high-field NMR spectra in comparison with those of
authentic samples.[16]
HO
HO
HO
OR
HO
OTIPS
O
In summary, the total syntheses of TMC-95A and TMC-95B
have been achieved. The program featured a sequential
assembly of oxindole 7, Garner×s aldehyde (8), aryl boronate
13, asparagine derivative 15, 3-methyl-2-oxopentanoic acid
(21), and a-silylallyl amine 6. Highlights of the synthesis
include a Suzuki biaryl construction ((E)-9 13 !14), a
diastereofacial dihydroxylation reaction that took advantage
of the Garner method (16 !17), and a macrolactamization
(formation of 20). We also note that new chemistry to
accomplish stereospecific cis-propenyl amide formation (26/
27 !28/29) was inspired by goal system 1. The application to
the delicate case at hand serves to build confidence in its
generality.
HN
O
O
Boc
O
O
c)
HN
a)
N
N
OtBu
17
H
H
BnO
b)
O
BnO
NH
N
H
NH2
O
NH2
O
Cbz
HN
HN
HN
18 R = H
Cbz
20
R2O
19 R = TIPS
R2O
R2O
R2O
O
OR1
O
R1
O
8
O
HN
O
f)
d) 21
R3O
N
N
O
H
O
H
R3O
O
O
NH
NH2
NH
NH2
O
14
O
N
N
Received: November 16, 2001 [Z18229]
H
H
O
O
22a,b R1 = TIPS, R2 = R3 = H
24a,b R1 = OH, R2 = R3 = TES
e)
23a,b R1 = R2 = R3 = TES
25a,b R1 = OH, R2 = TES, R3 = H
TES
g)
[1] a) A. Ciechanover, A. L. Schwartz, Proc. Natl. Acad. Sci. USA 1998,
95, 2727 2730; b) M. Bochtler, L. Ditzel, M. Groll, C. Hartmann, R.
Huber, Annu. Rev. Biophys. Biomol. Struct. 1999, 28, 295 317;
c) A. F. Kisselev, A. L. Goldberg, Chem. Biol. 2001, 8, 739 758.
[2] a) Y. Koguchi, J. Kohno, M. Nishio, K. Takahashi, T. Okuda, T.
Ohnuki, S. Komatsubara, J. Antibiot. 2000, 53, 105 109; b) J. Kohno,
Y. Koguchi, M. Nishio, K. Nakao, M. Kuroda, R. Shimizu, T. Ohnuki,
S. Komatsubara, J. Org. Chem. 2000, 65, 990 995.
, R2 = R3 = TES
26a,b R1
27a,b R1
=
=
N
H
TES
, R2 = TES, R3 = H
N
H
Scheme 5. Synthesis of a-silylallyl amides 26a,b and 27a,b. a) PPTS/
MeOH, reflux, 2 h; b) TIPSCl, imidazole/DMAP, CH2Cl2, RT, 5 h; 88%
(two steps); c) 1) TFA/CH2Cl2 (4:1), RT, 2 h; 2) EDC/HOAT/DIEA,
CH2Cl2/DMF(2 mm), RT, 24 h; 52% (two steps); d) 1) Pd/C, H2, EtOH,
RT, 19 h; 2) (Æ)-3-methyl-2-oxopentanoic acid (21), EDC/HOAT, CH2Cl2/
DMF, RT, 2 h; 85% (2 steps); e) 1) HF/Py; 2) TESOTf, 2,6-lutidine,
CH2Cl2, 08C !RT, 15 h; 3) NaHCO3; 4) citric acid, EtOAc/H2O; 73%
(from 22); f) Jones reagent, acetone, 08C, 2 h; g) 6, EDC/HOAT, CH2Cl2/
DMF, RT, 13 h; 45% (two steps). DMAP 4-dimethylaminopyridine,
TFA trifluoroacetic acid, DIEA N,N-diisopropylethyl amine.
[3] M. Groll, Y. Koguchi, R. Huber, J. Kohno, J. Mol. Biol. 2001, 311,
543 548.
[4] a) S. Lin, S. J. Danishefsky, Angew. Chem. 2001, 113, 2020 2024;
Angew. Chem. Int. Ed. 2001, 40, 1967 1970. For synthetic efforts
directed to the TMC-95 metabolites from other laboratories, see:
b) M. Inoue, H. Furyama, H. Sakazaki, M. Hirama, Org. Lett. 2001, 3,
2863 2865; c) D. Ma, Q. Wu,. Tetrahedron Lett. 2001, 42, 5279 5281;
d) B. K. Albrecht, R. M. Williams, Tetrahedron Lett. 2001, 42, 2755
2757; e) D. Ma, Q. Wu, Tetrahedron Lett. 2000, 41, 9089 9093.
[5] a) J. K. Stille, Y. Becker, J. Org. Chem. 1980, 45, 2139 2145; b) P.
Ribereau, M. Delamare, S. Celanire, G. Queguiner, Terahedron Lett.
2001, 42, 3571 73; c) K. Kuramochi, H. Watanabe, T. Kitahara,
Synlett 2000, 3, 397 399; d) R. Chen, J. A. Porco, Jr., Org. Lett. 2000,
2, 1333 1336.
Construction of the (Z)-1-propenylamide was now achiev-
ed by thermally driven rearrangement of the a-silylallyl
amides corresponding to 3 (Scheme 6). The rearrangement of
[6] Amine 6 (S.-F. Chen, E. Ho, P. S. Mariano, Tetrahedron 1988, 44,
7013 7026) was synthesized by using an improved procedure from
allyl alcohol through a one-pot TES ether formation, retro-Brook
TESO
TESO
R1O
R1O
O
TES
O
N
H
O
N
H
O
O
O
rearrangement, and mesylation, followed by
a displacement of
HN
HN
N
N
a)
mesylate with ammonia. Acylation in entries 1 4 (Table 1) was
accomplished by coupling of 6 with the acid chlorides, while in entry 5
an EDC-mediated coupling with protected amino acid with amine 6
was involved. Details will be forthcoming in a full disclosure.
[7] The formation of silyl imidates 4 was clearly observed by 1H NMR
spectroscopy when these reactions were carried out in deuterated
solvents.
[8] a) P. Garner, J. M. Park, J. Org. Chem. 1987, 52, 2361 2364; b) A.
McKillop, R. K. Taylor, R. J. Watson, N. Lewis, Synthesis 1994, 31 33.
Garner×s aldehyde was employed since it was found that an N,O-
acetonide was crucial for the stereoselective installation of diol
functionality at C6 C7position (see ref. [4a]).
O
O
H
H
O
O
RO
R2O
NH
NH
NH2
NH2
O
O
N
N
H
H
O
O
28a,b R1 = R2 = TES
26a,b R = TES
27a,b R = H
29a,b R1 = TES, R2 = H
1a,b R1 = R2 = H
b)
Scheme 6. Synthesis of TMC-95A (1a) and TMC-95B (1b). a) 1) o-xylene,
1408C, 3 d; 2) H2O; b) HF/Py, THF/Py; then Me3SiOMe; 49% (two steps).
[9] To address the issues raised by problematic deprotection of the
phenolic methyl group at
Scheme 1), a benzyl group, instead of a methyl group, was used for
the protection of the phenol (see ref. [4a]).
a later stage (that is, compound 2,
the complex mixture[15] in anhydrous o-xylene at 1408C
provided (Z)-1-propenylamides 28a,b and 29a,b. The crude
mixture of these compounds was globally deprotected with
pyridine-buffered HF/pyridine to afford a mixture of our total
synthesis goals–TMC-95A and TMC-95B (1a and 1b; 1:1).
This mixture was separated by RP-HPLC[16] to provide the
individual compounds 1a and 1b. These were characterized
[10] a) T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60, 7508
7510; b) A. M. Elder, D. H. Rich, Org. Lett. 1999, 1, 1443 1446.
[11] For a review of Suzuki coupling reactions, see: N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457 2483.
[12] The atropisomer shown for 20 follows from the C6 stereochemistry
(see ref. [2b]).
514
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
1433-7851/02/4103-0514 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2002, 41, No. 3