Total synthesis of a dibromotyrosine alkaloid inhibitor of mycothiol S-conjugate amidase

Article abstract of DOI:10.1016/j.tetlet.2003.10.117

Two complementary synthetic sequences are described for the first total synthesis of a dibromotyrosine alkaloid (1) reported to inhibit a critical mycobacterial enzyme, mycothiol S-conjugate amidase. The O-benzyloxime of 4-hydroxyphenylpyruvic acid was dibrominated and successively linked to a 3-aminopropyl chain, then to a 4-aminobutylguanidine unit, followed by selective deprotections to yield alkaloid 1. In an improved variant, the O-tetrahydropyranyloxime 12 was condensed with 4-aminobutylguanidine then dibrominated to phenol 14, which upon Mitsunobu coupling to a 3-aminopropyl segment and deprotection produced the target 1.

Full text of DOI:10.1016/j.tetlet.2003.10.117

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 133–135
Total synthesis of a dibromotyrosine alkaloid inhibitor of
mycothiol S-conjugate amidase
*
Andrew S. Kende, Jiong Lan and Junfa Fan
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA
Received 5 September 2003;accepted 20 October 2003
Abstract—Two complementary synthetic sequences are described for the first total synthesis of a dibromotyrosine alkaloid (1)
reported to inhibit a critical mycobacterial enzyme, mycothiol S-conjugate amidase. The O-benzyloxime of 4-hydroxyphenylpyruvic
acid was dibrominated and successively linked to a 3-aminopropyl chain, then to a 4-aminobutylguanidine unit, followed by
selective deprotections to yield alkaloid 1. In an improved variant, the O-tetrahydropyranyloxime 12 was condensed with 4-amino-
butylguanidine then dibrominated to phenol 14, which upon Mitsunobu coupling to a 3-aminopropyl segment and deprotection
produced the target 1.
ꢀ
2003 Elsevier Ltd. All rights reserved.
In 2001 Bewley et al. reported the isolation of two novel
dibromotyrosine alkaloids from an Australian non-
verongid sponge of the Oceanapia species. These com-
To confirm the NMR-based structure assignment for 1,
and to scale up the synthesis of 1 and its analogs, we
have explored the total synthesis of this molecule using
two complementary synthetic sequences. Retrosynthetic
analysis reveals that the target 1 may be dissected into
three units: the ÔWesternÕ propylamine tail (3), the cen-
tral dibromo oxime acid unit (4), and the ÔEasternÕ
4-aminobutylguanidine chain (5).
1
pounds, represented by structures 1 and 2, showed
significant inhibitory activity against the mycobacterial
enzyme mycothiol S-conjugate amidase. Since this
enzyme appears to play a critical role in protecting
2
mycobacteria against alkylating agents and antibiotics,
alkaloids of this type are potentially useful therapeutic
agents against Mycobacterium tuberculosis and related
pathogens.
Our first synthetic route (Scheme 1) proceeded from 4-
hydroxyphenylpyruvic acid, which was converted to the
O-benzyloxime, then methylated with diazomethane to
OMe
Br
Br
HO
Br
H N
HO
NH
NH2
N
2
O
N
H
N
HN
O
N
N
H
NH2
Br
H
N
OH O
OH
O
O
N
1
H
2
OH
give the oxime methyl ester 6. Dibromination of 6 with
.0 equiv of NBS in THF at room temperature gave the
2
dibromo derivative 7. Careful hydrogenolysis of the O-
3
4
benzyl group in 1:1 dioxane–acetic acid produced the
crystalline dibromoester oxime 8, shown by X-ray
crystallography to possess the E-configuration as
Keywords: mycothiol S-conjugate amidase;dibromotyrosine alkaloid;
4
*
-hydroxyphenylpyruvamide oximes.
Corresponding author. Tel.: +1-716-275-4236;fax: +1-716-473-6889;
e-mail: kende@chem.rochester.edu
5
shown.
0
040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.117

134
A. S. Kende et al. / Tetrahedron Letters 45 (2004) 133–135
Br
HO
HO
Br
NH
N
H N
2
X
OH H N
2
N
H
NH2
O
3
5
4
1
2
)BnONH2
)CH N2
BnO
N
HO
O
HO
2
NBS
7%
OH
OCH3
91%
8
O
6
O
Br
Br
HO
BnO
HO
Br
Pd/C, H2
dioxane-HOAc(1:1)
9%
HO
Br
N
N
OCH3
OCH3
6
O
O
7
8
Scheme 1.
Br
Br
K CO BocHN
BnO
BnO
2
3
O
N
1)LiOH, CH OH/THF
3
HO
Br
N
BocNHC H Br
3
6
OCH3
OCH3
7
8%
Br
2)EDC/HOBT
NBoc
N
NHBoc
O
O
O
9
H N
2
7
H
8
6%
Br
RO
BocHN
N
NBoc
NHBoc
H
N
3
0% TFA/DCM
1
Br
N
H
82%
O
1
0, R=OBn
Pd/C, H2,
dioxane-HOAc(1:1)
11, R=OH
5
6%
Scheme 2.
THPO
HO
HO
N
EDC/HOBT
O
THPONH2
OH
OH
O
90%
H N
O
2
O
NHBoc
N
1
2
THPO
H
87%
HO
N
NBoc
H
N
NBS
89%
N
H
NHBoc
O
O
Br THPO
N
1
3
HO
Br
NBoc
NHBoc BocNHC H OH
DEAD/Ph3P
H
N
N
H
3
6
82%
1
4
THPO
N
Br
BocHN
O
NBoc
30% TFA/DCM
H
N
1
Br
N
NHBoc 82%
H
O
15
Scheme 3.

A. S. Kende et al. / Tetrahedron Letters 45 (2004) 133–135
135
6
Direct O-alkylation of the phenolic hydroxyl in 7 with
BocNH(CH Br introduced the protected propylamine
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC218527.
6. Zistler, A.;Koch, S.;Schluter, A. D. J. Chem. Soc., Perkin
Trans. 1 1999, 501–508;Schoenfeld, R. C.;Conova, S.;
Rittschof, D.;Ganem, B. Bioorg. Med. Chem. Lett. 2002,
2 3
)
7
tail to give 9. Saponification of the ester followed by
coupling of the resulting acid with a protected 4-amino-
8
butylguanidine established the Eastern chain to yield
9
1
2, 823–825.
the amide 10. The delicate chemoselective catalytic
debenzylation of 10 required use of the 1:1 dioxane–
acetic acid solvent system described earlier, and led to
7
. Spectroscopic data for compound 9: mp 110–112 ꢁC
1
(
3
hexane/dichloromethane). H NMR (CDCl , 400 MHz):
d 1.47 (s, 9H), 2.04 (m, 2H), 3.46 (m, 2H), 3.85 (s, 2H),
3.89 (s, 3H), 4.03 (t, J ¼ 5:8 Hz, 2H), 4.98 (br s, 1H),
10
the free oxime 11 in only 56% yield. Removal of all
Boc groups in 11 was achieved in 30% CF CO H in
dichloromethane to produce the target 1 as its bis tri-
1
3
3
2
5.35 (s, 2H), 7.35–7.44 (m, 5H), 7.41 (s, 2H).
C
NMR (CDCl
1
7
3
, 100 MHz): d 163.5, 156.0, 151.6, 149.4,
35.8, 134.4, 133.3, 128.7, 128.5 (2 · C), 117.9, 79.0, 78.3,
1.2, 53.0, 38.0, 30.1, 30.0, 28.4 (3 · C). MS (API-ES,
: C,
fluoroacetate salt in good yield (Scheme 2).
2 2 6
pos.): 635(M+Na). Anal. Calcd for C25H30Br N O
To enhance the chemoselectivity of the oxime depro-
tection step, the protecting group was switched from
4
4
8.87;H, 4.92;N, 4.56. Found: C, 48.76;H, 4.89;N,
.46%.
11
O-benzyl to O-tetrahydropyranyl. In this second syn-
thetic sequence, 4-hydroxyphenylpyruvic acid was con-
verted to the THP-oxime acid 12, which was coupled
with the protected 4-aminobutylguanidine shown to
install the Eastern chain as in 13. Then 13 was dibrom-
8
. Wagner, J.;Kallen, J.;Ehrhardt, C.;Evenou, J. P.;
Wagner, D. J. Med. Chem. 1998, 41, 3664–3674;Bailey,
K. L.;Molinski, T. F. Tetrahedron Lett. 2002, 43, 9657–
9660.
1
9. Spectroscopic data for compound 10: colorless oil.
NMR (CDCl
H
12
inated to the dibromophenol amide 14 (Scheme 3). At
this point, Mitsunobu coupling
3
, 400 MHz): d 1.46 (s, 9H), 1.51 (s, 18H),
.61 (m, 4H), 2.03 (m, 2H), 3.35 (m, 2H), 3.45 (m, 4H),
13
1
3
of the phenolic
hydroxyl with 3-(t-butoxycarbonylamino)propanol
produced the fully elaborated system 15. Removal of
.83 (s, 2H), 4.02 (t, J ¼ 5:8 Hz, 2H), 5.01 (br s, 1H), 5.23
(
(
s, 2H), 6.80 (t, J ¼ 6:0 Hz, 1H), 7.31–7.45 (m, 5H), 7.44
1
3
s, 2H), 8.35 (br s, 1H), 11.52 (s, 1H). C NMR (CDCl ,
3
3 2
both the THP and all Boc groups by 30% CF CO H in
dichloromethane led smoothly to the target aminogua-
nidine 1 as its bis trifluoroacetate salt.
1
1
7
00 MHz): d 163.4, 162.0, 156.1, 156.0, 153.3, 151.4,
51.2, 136.2, 134.8, 133.5, 128.6, 128.4, 128.2, 117.8, 83.1,
9.3, 79.0, 77.5, 71.2, 40.4, 39.1, 38.0, 29.9, 28.6, 28.4
(
pos.): 911(M+H). HRMS calcd for C H N O Br :
3 · C), 28.2 (3 · C), 28.0 (3 · C), 26.8, 26.5. MS (API-ES,
1
3
The proton and C NMR of our synthetic alkaloid 1 as
the bis trifluoroacetate salt and free base were in
agreement with the corresponding spectra provided by
3
9
57
6
9
2
911.2554;found: 911.2535.
10. Spectroscopic data for compound 11: colorless oil.
NMR (CDCl
1
H
14
, 400 MHz): d 1.45 (s, 9H), 1.48 (s, 9H), 1.49
s, 9H), 1.55 (m, 4H), 2.01 (m, 2H), 3.30 (m, 2H), 3.42 (m,
Dr. Bewley. This comprises the first total synthesis of
the Bewley compound 1, and provides reliable meth-
odology for the synthesis of related structures which
may act as inhibitors of mycothiol S-conjugate amidase.
3
(
4
6
H), 3.86 (s, 2H), 3.99 (t, J ¼ 5:6 Hz, 2H), 4.93 (br s, 1H),
.83 (t, J ¼ 6:0 Hz, 1H), 7.49 (s, 2H), 8.42 (br s, 1H), 10.42
1
3
(
3
br s, 1H), 11.49 (br s, 1H). C NMR (CDCl , 100 MHz):
d 163.1, 162.9, 156.2, 156.1, 153.2, 151.20, 151.17, 135.4,
33.4, 117.7, 83.3, 79.6, 79.2, 71.1, 40.5, 38.9, 38.1, 31.5,
29.9, 28.4 (3 · C), 28.2 (3 · C), 28.0 (3 · C), 26.7, 26.4. MS
API-ES, pos.): 821(M+H).
1
References and Notes
(
1
. Nicholas, G. M.;Newton, G. L.;Fahey, R. C.;Bewley, C.
A. Org. Lett. 2001, 3, 1543–1545;For a full paper see:
Nicholas, G. M.;Eckman, L. L.;Newton, G. L.;Fahey,
R. C.;Ray, S.;Bewley, C. A. Bioorg. Med. Chem. 2003,
11. Showalter, H. D. H.;Haskell, T. H. J. Heterocyclic Chem.
1981, 18, 367–370.
1
12. Spectroscopic data for compound 14: white foam.
NMR (CDCl
H
3
, 400 MHz): d 1.50 (s, 9H), 1.51 (s, 9H), 1.61
1
1, 601–608.
. Newton, G. L.;Av-Gray, Y.;Fahey, R. C. Biochemistry
000, 35, 10739–10746.
(m, 5H), 1.71–1.73 (m, 2H), 1.86 (m, 3H), 3.25–3.45 (m,
4H), 3.61–3.63 (m, 2H), 3.86 (AB, J ¼ 9:7 Hz, 2H), 5.41
(s, 1H), 5.80 (br, 1H), 6.93 (br, 1H), 7.48 (s, 2H), 8.35 (br,
1H), 11.50 (br, 1H). MS (API-ES, pos.): 750(M+H).
13. Heinonen, P.;Virta, P.;Lonnberg, H. Tetrahedron 1999,
55, 7613–7624.
2
3
2
. For a related dibromination, see: Boehlow, T. R.;
Harburn, J. J.;Spilling, C. D. J. Org. Chem. 2001, 66,
3111–3118;See also: Forrester, A. R.;Thomson, R. T.;
Woo, S. J. Chem. Soc., Perkin. Trans. 1 1975, 2340–2353.
. Murakata, M.;Tamura, M.;Hoshino, O. J. Org. Chem.
14. Spectroscopic data for synthetic 1 as the bis trifluoro-
1
4
5
acetate salt (white foam): H NMR (d
4
-MeOH, 400 MHz):
1997, 62, 4428–4433.
d 7.50 (s, 2H), 4.08 (t, J ¼ 5:6 Hz, 1H), 3.84 (s, 2H), 3.27
. The X-ray structure of a related compound, ethyl 3-(3-
bromo-4-hydroxyphenyl)-2-(E)-(hydroxyimino)propano-
ate, has been reported: Rath, N. P.;Boehlow, T. D.;
Spilling, C. D. Acta Cryst. Section C 1995, 51, 2654–2656.
Crystallographic data (excluding structure factors) for the
structure 8 in this paper have been deposited with the
(m, 2H), 3.25 (m, 2H), 3.17 (m, 2H), 2.18 (m, 2H), 1.57
1
3
6
(m, 4H). C NMR (100 MHz): d (in d -DMSO): 163.1,
156.7, 151.1, 150.5, 136.5, 132.9, 117.2, 70.4, 40.4, 38.3,
36.5, 28.0, 27.7, 26.3, 26.0. MS (API-ES, pos.):
521(M+H). We thank Dr. Bewley for providing original
spectra of the natural alkaloid.