Synthesis of acinetobactin

Article abstract of DOI:10.1248/cpb.58.1552

A structure involving the absolute configuration of acinetobactin (1b) was clarified. It was reconfirmed that preacinetobactin (1a) produced 1b by a rearrangement reaction.

Full text of DOI:10.1248/cpb.58.1552

1552
Communication to the Editor
Chem. Pharm. Bull. 58(11) 1552—1553 (2010)
Vol. 58, No. 11
chloroethyl)imidazole hydrochloride (7) in 70% yield.4,5) The
synthesis of intermediate 5 was achieved by the coupling re-
action of 7 with N-tert-butoxycarbonyl(Boc)-O-benyloxy-
amine6) and a deprotection reaction.7)
Synthesis of Acinetobactin
Yasuo TAKEUCHI, ,a Satoru OZAKI,a Masahiro SATOH,a
*
Ken-ichiro MIMURA,a Sei-ichi HARA,a Hitoshi ABE,b
Compound 9, in which the hydroxy group of 1b was pro-
tected with a benzyl group, was successfully derived from
2,3-dihydroxybenzaldehyde (10) (Chart 3). Oxazolidine 13
was afforded by the reaction of a L-threonine derivative with
12,8—10) which was derived from 10. Carboxylic acid 1411)
was afforded in 80% yield by the hydrogenolysis of 13. The
desired compound 9 could be obtained by the coupling with
carboxylic acid 14 and 5.
Hiromi NISHIOKA,a and Takashi HARAYAMA
a
a Faculty of Pharmaceutical Sciences, Okayama University; 1–1–1
Tsushima-naka, Okayama 700–8530, Japan: and b Faculty of
Engineering, Toyama University; 3190 Gofuku, Toyama 930–8555,
Japan.
Received August 6, 2010; accepted August 20, 2010; published
online August 27, 2010
The hydrogenolysis of 9 afforded 1a,12) and the heat of 1a
successively yielded 1b,13) which was identified with a natu-
rally occurring antibacterial agent1,2) by comparison with 1H-
NMR and specific rotation (Chart 4). Thus, we could clarify
the structure of acinetobactin that was produced from 1a by
the intramolecular SN2 reaction.
A structure involving the absolute configuration of acineto-
bactin (1b) was clarified. It was reconfirmed that preacineto-
bactin (1a) produced 1b by a rearrangement reaction.
Key words total synthesis; acinetobactin; structure determination;
rearrangement
In order to confirm the structures of 1a, b, we continued
In 1994, acinetobactin was isolated from low-iron cultures the study on the design and synthesis of the related com-
of Acinetobacter baumannii ATCC1960, and the chemical pounds that correspond to the isomer. Compound 19,14)
structure (1a) of acinetobactin was proposed by using chemi- which corresponds to the diastereomer of 14, was success-
1
cal degradation, FAB-MS spectrometry, and H- and 13C- fully derived in three steps from 2,3-dihydroxybenzoic acid
NMR spectroscopy (Fig. 1).1,2) In 2009, it was suggested that (16)15) (Chart 5). However, the coupling reaction of 19 with 5
this reported structure is an unstable intermediate (1a: afforded not the desired compound cis-form 15 but the trans-
preacinetobactin) and the correct structure (1b) should be its form ent-9 corresponding to an enantiomer of 9.16) We think
rearrangement product obtained by using the high-resolution that the activated acyl derivative of 19 can be used for the
(HR)-MS technique.3) However, in this report, there is no de-
tailed positive proof about the relative and/or absolute con-
figuration of 1a, b because 1a is not isolated and the specific
rotation of 1b is not described. We thought that two evi-
dences, the isolation of the intermediate and the decision of
the absolute configuration of acinetobactin, are necessary
with a more certainly corrected structure.
We thought that 2,3-dihydroxybenzoic acid (2), L-threo-
nine (3), and N-hydoxyhistamine (4) can be used as the start-
ing material for the synthesis of 1a (Chart 1).
The intermediate corresponding to 4, O-benzyloxyhista-
Reagents and conditions: a i) NaNO2, HCl, 60 °C, 1 h; ii) SOCl2, reflux, 0.5 h,
70%; b O-Benzyl-N-tert-butoxycarbonylhydroxylamine, NaH, DMF, 50 °C, 3 h,
47%; c TFA, rt, 96%.
Chart 2
mine (5) was derived in three steps from histamine dihy-
drochloride (6) (Chart 2). The substitution reaction with
SOCl2 following the reaction of 6 with NaNO2 yielded 4-(2-
Fig. 1. Preacinetobactin (1a) and Acinetobactin (1b)
Reagents and conditions: a NH2OH·HCl, HCOONa, HCOOH, 68%; b i) AcCl,
dry. MeOH, ii) sat. NaHCO3 aq., 40% (2 steps);
c L-Thr-OBn·(COOH)2,
(CH2Cl)2, 64%; d H2, 10% Pd/C, MeOH, 84%; e 5, EDC·HCl, HOBt·H2O, DMF,
63%.
Chart 3
Reagents and conditions: a H2, 10% Pd/C, MeOH, rt, 64%; b MeOH, reflux,
86%.
Chart 4
Chart 1
∗ To whom correspondence should be addressed. e-mail: take@pharm.okayama-u.ac.jp
© 2010 Pharmaceutical Society of Japan

November 2010
1553
(1963).
6) Grigg R., Rankocic Z., Thoroughgood M., Tetrahedoron, 56, 8025—
8032 (2000).
7) Sulsky R., Demers J., Tetrahedron Lett., 30, 31—34 (1989).
8) Es T. B., J. Chem. Soc., 1964, 1564 (1964).
9) Bergeron R. J., Wiegand J., McManis J. S., Weimar W. R., Park J., Mc-
Manis E., Bergeron J., Brittenham F. M., J. Med. Chem., 48, 821—831
(2005).
10) Veejendra K. Y., Ganesh B., Eur. J. Org. Chem., 70, 452—456 (2005).
11) 14: Yellow powder. mp 91.2—98.7 °C (decomp.). 1H-NMR (300 MHz,
CD3OD) d: 1.54 (3H, d, Jϭ6.3 Hz, CH3), 4.54 (1H, d, Jϭ7.2 Hz, 4-H),
4.98 (1H, m, 5-H), 6.74 (1H, t, Jϭ7.8 Hz, 5Ј-H), 6.95 (1H, dd, Jϭ7.8,
1.5 Hz, 4Ј-H), 7.16 (1H, dd, Jϭ7.8, 1.5 Hz, 6Ј-H).
1
12) 1a: Yellow amorphous, H-NMR (300 MHz, CD3OD) d: 1.51 (3H, m,
CH3), 2.97 (2H, t, Jϭ6.0 Hz, Imid. CH2CH2), 3.79—3.93 (2H, m,
Imid. CH2CH2), 4.89 (2H, s, PhCH2), 4.8—5.0 (1H, m, oxazoline 5Ј-
H), 5.09 (1H, d, Jϭ6.0 Hz, oxazoline 4Ј-H), 6.69—6.76 (1H, m, Ph 5Љ-
H), 6.92—6.96 (1H, m, Ph 4Љ-H), 7.12 (1H, s, Imid. 4Ј-H), 7.15 (1H,
dd, Jϭ7.8, 1.5 Hz, Ph 6Љ-H), 7.70 (1H, s, Imid. 2-H).
Reagents and conditions: a L-Thr-OBn·(COOH)2, EDC·HCl, DMAP, DMF,
88%; b SOCl2, 88%; d H2, 10% Pd/C, MeOH, 80%; c 5, EDC·HCl, HOBt·H2O,
DMF, 55%.
1
13) 1b: Yellow amorphous, H-NMR (500 MHz, CDOD3) d: 1.46 (3H, t,
Jϭ6.0 Hz, CH3), 3.01 (2H, m, Imid. CH2CH2), 3.89 (2H, m,
Imid. CH2CH2), 4.48 (1H, qd, Jϭ10.5, 6.0 Hz, 5H), 4.71 (1H,
Jϭ11.0 Hz, 4-H), 6.73 (1H, t, Jϭ8.0 Hz, 5ЉH), 6.96 (1H, dd, Jϭ7.5,
1.0 Hz, 4ЉH), 7.07 (1H, s, 5ЈH), 7.26 (1H, dd, Jϭ8.0, 1.5 Hz, 6Ј-H),
7.93 (1H, s, 2ЈH), [a]D16 Ϫ43.2 (cϭ0.5, MeOH) {lit. [a]D20 Ϫ37.4
(cϭ1.0, MeOH)}.1)
Chart 5
epimerization to produce the sterically stable trans form.
We clarified a structure involving the absolute configura-
tion of acinetobactin (1b) and reconfirmed that preacineto-
bactin (1a) produced 1b by a rearrangement reaction.
14) 19: Yellow powder. mp 116.3—124.5 °C (decomp.). 1H-NMR
(300 MHz, CD3OD) d: 1.46 (3H, d, Jϭ6.6 Hz, CH3), 5.02 (1H, d,
Jϭ11.1 Hz, 4-H), 5.11—5.21 (1H, m, 5-H), 6.74 (1H, t, Jϭ7.8 Hz, 5Ј-
H), 6.95 (1H, dd, Jϭ7.8, 1.5 Hz, 6Ј-H), 7.16 (1H, dd, Jϭ7.8, 1.5 Hz,
4Ј-H).
Acknowledgments We are grateful to the SC-NMR Laboratory of
Okayama University for the use of the facilities.
15) Gardner R. A., Kinkade R., Wang C., Phanstiel O., J. Org. Chem., 69,
3530—3537 (2004).
16) 9 and ent-9: Yellow amorphous. H-NMR (500 MHz CDCl3) d: 1.31
References and Notes
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1
(3H, d, Jϭ6.6 Hz, CH3), 3.01 (2H, m, Imid. CH2CH2), 3.95 (1H, m,
Imid. CH2CH2), 4.09 (1H, m, Imid. CH2CH2), 4.75 (1H, d, Jϭ5.7 Hz,
4-H), 4.93 (3H, m, 5-H, PhCH2), 6.76 (1H, t, J ϭ 7.8 Hz, 5Љ-H), 6.82
(1H, s, 4Ј-H), 7.02 (1H, d, Jϭ7.8 Hz, 4Љ-H), 7.17 (1H, d, Jϭ7.8 Hz, 6Љ-
H), 7.39 (5H, s, PhCH2), 7.54 (1H, s, 2Ј-H). 9: [a]D22 ϩ149 (cϭ1.0,
CHCl3). ent-9: [a]D27 Ϫ114 (cϭ1.0, CHCl3).
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