An expeditious convergent synthesis of a dibromotyrosine alkaloid inhibitor of mycothiol-S-conjugate amidase

Article abstract of DOI:10.1016/j.tetlet.2005.07.109

A quick, economic synthesis of the alkaloid 1, an inhibitor of mycothiol-S-conjugate amidase (MCA) is reported. Starting from low-cost, commercially available 4-hydroxybenzaldehyde, the nine-step synthesis involved dibromination and coupling with N-acetylglycine to give a stable methyloxazole intermediate 5 which was hydrolyzed, oximated and coupled to agmatine to yield the oxime in ～30% overall yield. It was not necessary to protect the oxime in the synthetic sequence thereby circumventing a deprotection step.

Full text of DOI:10.1016/j.tetlet.2005.07.109

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6461–6463
An expeditious convergent synthesis of a dibromotyrosine
alkaloid inhibitor of mycothiol-S-conjugate amidase
Bhanu M. Chanda* and Rohidas S. Sulake
Division of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
Received 30 March 2005; revised 11 July 2005; accepted 22 July 2005
Abstract—A quick, economic synthesis of the alkaloid 1, an inhibitor of mycothiol-S-conjugate amidase (MCA) is reported. Start-
ing from low-cost, commercially available 4-hydroxybenzaldehyde, the nine-step synthesis involved dibromination and coupling
with N-acetylglycine to give a stable methyloxazole intermediate 5 which was hydrolyzed, oximated and coupled to agmatine to yield
the oxime in ꢀ30% overall yield. It was not necessary to protect the oxime in the synthetic sequence thereby circumventing a depro-
tection step.
Ó 2005 Elsevier Ltd. All rights reserved.
Two novel alkaloids 1 and 2 isolated1 from an Austra-
lian non-verongid sponge of the Oceanapia species exhi-
bit significant inhibitory activity against mycothiol-S-
conjugated amidase (MCA). Due to the crucial role
played by MCA, such alkaloids are marked as poten-
tially useful therapeutic agents against Mycobacterium
tuberculosis and related pathogens. As part of our ongo-
ing programme on the total synthesis of biologically
active natural products, we undertook the synthesis of
1 and the same is reported2 in this letter.
Retrosynthetic analysis of 1 revealed that the synthesis
of the alkaloid may be realized starting from inexpensive
and commercially available 4-hydroxybenzaldehyde 3.
Thus dibromination of 3 with 2 equiv of NBS in DMF
at room temperature gave the dibromo derivative in
93% yield. The latter was O-alkylated with 1,3-dibromo-
propane in K2CO3 and DMF at 80 °C for 4 h to furnish
the tribromoaldehyde 4 in excellent yield. The stable,
crystalline methyloxazolone intermediate3 5 was gener-
ated by condensation of 4 with N-acetylglycine in reflux-
ing acetic anhydride and sodium acetate for 3 h in about
79% yield. Hydrolysis of the oxazole with 2 M HCl in
THF at 70 °C for 12 h provided the pyruvic acid deriv-
ative 6 as a solid in 78% yield. Oximation of this tri-
bromoketo acid with hydroxylamine in dioxane
followed by conversion of the bromoether 7 to the azido
ether4 8 proceeded smoothly in near quantitative yield.
The crucial coupling reaction of 8 with N-Boc protected
agmatine5,6 9 to give the intermediate 10 was effected
with N-hydroxyphthalimide in DCC and dioxane at
ambient temperature in 78% yield. Other reagents7 were
also tried for this coupling reaction but the yields
obtained were not satisfactory and ranged between
50% and 55% (Scheme 1).
Br
H2N
O
HO
N
NH
H
N
Br
N
H
NH2
O
1
H2N
HN
Br
O
N
OH
H3CO
Br
O
H
OH
N
N
H
HO
N
O
HO
2
Further steps in the synthetic sequence involved reduc-
tion of the azidopropyl ether 10 to the corresponding
aminopropyl ether 11. This was achieved in 84% yield
with Ph3P in aqueous THF8 and the oil obtained was
fully characterized (see References and notes). Removal
of the two Boc groups in 11 was achieved with 30%
Keywords: Mycothiol-S-conjugate amidase; Marine alkaloid; 4-
Hydroxybenzaldehyde.
*
Corresponding author. Tel./fax: +91 020 25893614; e-mail addresses:
bhanu@dalton.ncl.res.in; bhanuchanda@yahoo.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.109

6462
B. M. Chanda, R. S. Sulake / Tetrahedron Letters 46 (2005) 6461–6463
Br
Br
Br
O
HO
Br
O
N
a, b
c
Br
7
O
CHO
Br
Br
CHO
O
5
4
3
Br
Br
O
Br
O
HO
f
e
d
O
N
OH
OH
Br
Br
O
6
O
Br
Br
N3
O
HO
N3
O
HO
g
N
NBoc
NHBoc
N
H
N
OH
Br
N
H
Br
O
O
10
8
Br
H2N
O
HO
N
NBoc
NHBoc
i
h
H
1
N
Br
N
H
O
11
Scheme 1. Reagents and conditions: (a) NBS, DMF, 0–25 °C, 2 h, 93%; (b) K2CO3, DMF, Br(CH2)3Br, 70–80 °C, 4 h, 79%; (c) N-acetylglycine,
Ac2O, CH3COONa, 150 °C, 3 h, 79%; (d) HCl–THF (1:3), 70 °C, 12 h, 78%; (e) NH2OHÆHCl, NaHCO3, dioxane, 25–30 °C, 4 h, 76%; (f) NaN3,
DMSO, 50 °C, 8 h, 89%; (g) N-hydroxyphthalimide, DCC, dioxane, N-Boc protected agmatine 9, 25–30 °C, 6 h, 78%; (h) Ph3P, THF–H2O, 40 °C,
24 h, 84%, (i) 30% TFA–CH2Cl2, 25 °C, 1 h, quantitative.
CF3COOH in dichloromethane to produce the target 1
as its bis-trifluoroacetate salt in quantitative yield
(Scheme 1). The spectral data of synthetic 1 as the bis-
trifluoroacetate salt was in full conformity with its struc-
ture (see References and notes).
no function with Boc functionality. Activation of the
carboxylic group and coupling of 8 with N-Boc pro-
tected agmatine 9 could thus be achieved with the
unprotected oxime. Our sequence thus avoided protec-
tion–deprotection of the hydroxyl group of the oxime
as well as the amino group of the O-alkyl ether. All
the intermediates in our synthetic sequence, except the
azido 10 and the amino 11 compounds were stable crys-
talline solids with definite mps.11–16
While our synthesis was in progress, two reports
appeared on the synthesis of 1. The first total synthesis
of 1 by Kende et al.9 utilized 4-hydroxyphenylpyruvic
acid as the starting material and involved O-benzylated
hydroxylamine and O-THP protected hydroxylamine
for oximation. In the former case, a careful chemoselec-
tive catalytic debenzylation was achieved in only 56%
yield. In the second synthetic approach, Fetterolf and
Bewley10 utilized the expensive dibromotyrosine as the
starting material and, via an unstable trifluoromethyl
oxazolone intermediate, completed the synthesis. De-
benzylation was not smooth and gave rise to the amine
(instead of the oxime) as the major product. Finally, pal-
ladium black was used for this purpose, which also gave
the amine as a minor product in addition to the required
oxime as the major product.
Our ultimate goal in this project is to develop a solid
phase combinatorial strategy so that a number of new
entities can be synthesized. Therefore, all the reactions
in our synthesis were carried out under homogenous
and mild reaction conditions in high yields. We would
like to use the hydroxyl group in the starting material
for anchoring to a solid phase such as the bromo Wang
polystyrene resin or the chlorosulfamyl resin by install-
ing a suitable spacer.
In our opinion, the amidoxime and the guanidine moie-
ties are the two prominent pharmacophores. It is there-
fore possible to synthesize new and small molecules
analogous to 1 having only one of the two pharmaco-
phores above so that the actual unit responsible for
the anti-mycobacterial activity can be identified. Our
results in this direction will be disclosed in due course.
In our approach to the synthesis of 1 we wished to retain
the oxime 8 without protection and to realize this, we
carried out the dibromination of 4-hydroxybenzalde-
hyde followed by O-alkylation with 1,3-dibromopro-
pane as the first two steps of the synthetic scheme.
Compared to 1-bromo-3-aminopropane, 1,3-dibromo-
propane is cheaper and hence, the latter was used. Also,
by converting the bromoether 7 to the azido ether 8,
which was later reduced to the amino compound 11,
we avoided the protection and deprotection of the ami-
In conclusion, our approach to the total synthesis of 1
gives a methodology amenable to scale up. The starting
material is cheap and easily accessible; all the reactions
lead to good to excellent yields of the products. This
synthetic approach also offers methodology for the

B. M. Chanda, R. S. Sulake / Tetrahedron Letters 46 (2005) 6461–6463
6463
C14H12Br3NO3: C, 34.89; H, 2.51; N, 2.91. Found: C,
35.05; H, 2.62; N, 2.98.
synthesis of related analogues with equal/better activity
as inhibitors of MCA.
12. Spectroscopic data for compound 6: white solid, mp 147–
1
149 °C. H NMR (CDCl3+DMSO-d6, 200 MHz): d 2.25
(m, 2H), 3.63–3.81 (m, 2H), 4.09 (m, 2H), 6.29 (s, 1H),
7.33 (br s, 1H), 7.85 (s, 2H). 13C NMR (CDCl3, 75 MHz):
d 28.7, 31.8, 68.6, 105.0, 116.3, 131.8, 133.0, 141.6, 149.8,
164.9. FT IR (Nujol) mmax 3200, 2925, 1698, 1456,
1377 cmÀ1. Anal. Calcd for C12H11Br3O4: C, 31.41; H,
2.42. Found: C, 31.59; H, 2.52.
Acknowledgements
One of us (R.S.S.) is thankful to the CSIR (India) for
the award of a junior research fellowship. We also thank
Dr. D. D. Sawaikar and Dr. Hotha Srinivas for useful
discussions.
13. Spectroscopic data for compound 7: white solid, mp 170–
172 °C. 1H NMR (CDCl3, 200 MHz): d 2.23 (m, 2H),
3.70–3.83 (m, 4H), 4.04 (t, J = 6 Hz, 2H), 7.43 (s, 2H). 13
C
NMR (CDCl3+DMSO-d6, 75 MHz): d 28.8, 29.5, 32.9,
69.4, 117.4, 133.1, 135.4, 150.9, 166.3. FT IR (chloroform)
mmax 3234, 3019, 1699, 1455 cmÀ1. Anal. Calcd for
C12H12Br3NO4: C, 30.41; H, 2.55; N, 2.96. Found: C,
30.54; H, 2.61; N, 3.14.
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, 601–608.
2. Preliminary results of this synthesis were submitted as an
oral presentation at the International Conference On
Chemistry Biology Interface: Synergistic New Frontiers
(CBISNF), New Delhi in November 2004.
3. Herbst, R. M.; Shemin, D. In Organic Synthesis; Blatt, A.
H., Ed.; John Wiley: New York, 1943; Coll. Vol. 2, p 1.
4. Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413–414.
5. Marakata, M.; Yamada, K.; Hoshino, O. Tetrahedron
1996, 52, 14713–14722.
6. N-Boc protected agmatine 9 was synthesized as described
by: Exposito, A.; Fernandez-Suarez, M.; Iglesias, T.;
Munoz, L.; Riguera, R. J. Org. Chem. 2001, 66, 4206.
7. Paul, R.; Anderson, G. W. J. Am. Chem. Soc. 1960, 82,
4596–4600.
8. Vaultier, M.; Krouzi, N.; Carrie, R. Tetrahedron Lett.
1983, 24, 763–764.
9. Kende, A. S.; Lan, J.; Fan, J. Tetrahedron Lett. 2004, 45,
133–135.
10. Fetterolf, B.; Bewley, C. A. Bioorg. Med. Chem. Lett.
2004, 14, 3785–3788.
11. Spectroscopic data for compound 5: white solid, mp 125–
127 °C. 1H NMR (CDCl3, 200 MHz): d 2.43 (m, 5H), 3.72
(t, J = 6.4 Hz, 2H), 4.18 (t, J = 6.8 Hz, 2H), 6.89 (s, 1H),
8.49 (s, 2H). 13C NMR (CDCl3, 75 MHz): d 15.4, 29.4,
33.2, 80.0, 118.3, 126.6, 131.6, 133.6, 135.6, 154.4, 166.6,
167.2. FT IR (chloroform) mmax 3019, 1808, 1660,
1216 cmÀ1. FABMS (pos) 483.5 (M+H). Anal. Calcd for
14. Spectroscopic data for compound 10: colourless oil. 1H
NMR (CDCl3, 200 MHz): d 1.45 (s, 9H), 1.48 (s, 9H), 2.02
(t, J = 6.7 Hz, 2H), 3.40 (m, 4H), 3.79 (s, 2H), 4.00 (t,
J = 6.9 Hz, 2H), 4.66 (s, 1H), 6.78 (t, J = 4.3 Hz, 1H), 7.40
(s, 2H), 8.29 (s, 1H), 11.5 (s, 1H). 13C NMR (CDCl3,
75 MHz): d 26.5, 26.7, 28.0, 28.6, 29.5, 39.0, 40.4, 48.2,
69.7, 79.1, 83.0, 117.7, 133.5, 134.9, 151.4, 153.2, 156.0,
162.0. FT IR (chloroform) mmax 3419, 3330, 3017, 2099,
1719, 1671, 1637 cmÀ1. Anal. Calcd for C27H40Br2N8O7:
C, 43.33; H, 5.39; N, 14.97. Found: C, 43.55; H, 5.53; N,
15.08.
15. Spectroscopic data for compound 11: colourless oil. 1H
NMR (CDCl3, 200 MHz): d 1.48 (s, 18H), 1.58 (m, 4H),
2.00 (br s, 2H), 2.18 (m, 2H), 3.00–3.42 (m, 6H), 3.80 (s,
2H), 4.02 (t, J = 5.3 Hz, 2H), 6.78 (t, J = 3.9 Hz, 1H), 7.41
(s, 2H), 8.31 (s, 1H), 11.47 (s, 1H). 13C NMR (CDCl3,
50 MHz): d 26.1, 26.3, 27.5, 27.8, 28.2, 29.0, 29.1, 38.6,
39.9, 43.5, 69.3, 78.1, 82.6, 117.3, 133.0, 134.4, 150.8,
150.9, 152.8, 155.6, 161.6. FT IR (chloroform) mmax 3673,
3419, 3330, 3018, 1720, 1672, 1633 cmÀ1. Anal. Calcd for
C27H42Br2N6O7: C, 44.89; H, 5.86; N, 11.63. Found: C,
45.11; H, 5.69; N, 11.56.
16. Spectroscopic data for synthetic 1: as the bis-trifluoro-
acetate salt (white foam). 1H NMR (MeOH-d4, 300
MHz): d 1.59 (m, 4H), 2.17 (m, 2H), 3.20–3.33 (m, 6H),
3.84 (s, 2H), 4.1 (m, 2H), 7.46 (s, 2H). 13C NMR (DMSO-
d6, 75 MHz): d 25.8, 25.9, 27.5, 28.3, 36.5, 39.7, 40.4, 69.9,
117, 132.9, 136.5, 149.8, 151.5, 156.7, 162.6. FT IR (Nujol)
mmax 3363, 2930, 1670, 1674, 1122 cmÀ1. MS. 521.3
(M+H).