Novel stereoselective synthesis of (R)-3-Aminotetradecanoic acid (Iturinic Acid)

Article abstract of DOI:10.2174/157017809787003089

(R)-3-Aminotetradecanoic acid (iturinic acid) has been synthesized starting from dodecanoyl chloride. This new synthetic approach involved the enantioselective reduction of an ynone to the corresponding propargylic alcohol and then into a protected propar

Full text of DOI:10.2174/157017809787003089

22
Letters in Organic Chemistry, 2009, 6, 22-24
Novel Stereoselective Synthesis of (R)-3-Aminotetradecanoic Acid (Iturinic
Acid)
Andrea Temperini*, Marcello Tiecco, Lorenzo Testaferri and Raffaella Terlizzi
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Perugia, I-06123 -
Perugia, Italy
Received May 28, 2008: Revised October 06, 2008: Accepted October 08, 2008
Abstract: (R)-3-Aminotetradecanoic acid (iturinic acid) has been synthesized starting from dodecanoyl chloride. This
new synthetic approach involved the enantioselective reduction of an ynone to the corresponding propargylic alcohol and
then into a protected propargylic amine. The iturinic acid was obtained by the transformation of a (phenylseleno)acetylene
intermediate into a carboxylic group followed by N-deprotection.
Keywords: ꢀ-amino acids, stereoselective synthesis, natural products, selenium, copper catalysis.
INTRODUCTION
of an ꢁ-amino acid or on the regio- and stereoselective func-
tionalization of linear dicarboxylic acid derivatives. The di-
astereoselective Michael addition of chiral nitrogen nucleo-
philes to enoates has been applied by Ohta [8] who obtained
the pure enantiomer (R)-2 as the methyl ester in low yield
after chromatographic separation and N-debenzylation of the
desired isomer. In a similar way, Enders [9] reported the
synthesis of (S)-2 (93% ee) by conjugate addition of lithiated
TMS-SAMP to an ꢁ,ꢀ-unsaturated ester. In a different ap-
proach, Bland [10] transformed the carboxylic group at C-1
of L-aspartic acid into the desired alkyl substituent to obtain,
after several steps, (R)-2 as Boc derivative and in 99% ee.
Moreover Sibi [11] prepared the same compound in 97% ee
through a regio- and stereoselective alkylation of a succinate
unit attached to a chiral auxiliary (oxazolidinone) and further
selective conversion of one of the carboxy groups into an
amino group by Curtius rearrangement. We report here a
simple and enantioselective procedure to prepare (R)-3-
aminotetradecanoic acid (2) hydrochloride starting from do-
decanoyl chloride.
Bioactive cyclic lipopeptides, such as the cytotoxic mix-
irins A-C [1], epichlicin [2], mycosubtilin [3], iturins A-E [4]
and bacillomycins D, E and L [5], have been isolated from
terrestrial or marine microorganisms. All members are cyclic
octapeptides with seven ꢁ-amino acids and one ꢀ3-amino
acid. Iturins are produced by Bacillus subtilis and in iturin-A
(1, Fig. 1) the nature of side chain (R in Fig. 1) in the ꢀ3-
amino acid (named iturinic acid) is the essential requisite for
the antifungal activity of the lypopeptide [6]. Iturin-A is
naturally produced as a mixture of up to eight isomers which
differ from each other in the length and isomerism of the ꢀ3-
amino acid side chain R. Thus the iturinic acids in iturin A
have been determined to have from 13 to 17 carbon atoms
and the (R)-configuration at the ꢀ-carbon [7]. The predomi-
nant iturin-A isomer (iturin-A2), contains the n-C14 isomer
2 of iturinic acid Fig. (1) [6]. Because of the pharmaceutical
importance of the long-chain ꢀ3-amino fatty acids, their syn-
thesis has attracted increasing interest.
R
CHCH2CO
NH
D-Asn
D-Tyr
Asn
RESULTS AND DISCUSSION
Ser
D-Asn
Pro
Gln
The application of our recent studies [12] on the trans-
formation of terminal alkynes into Se-phenyl selenocarboxy-
lates led us to develop a simple and stereospecific synthesis
of (R)-3-aminooctanoic acid starting from commercial (S)-1-
octyn-3-ol by conversion into the corresponding (R)-N-
phthalimido propargylic amine [13]. The availability of the
optically active propargylic alcohols is the limiting factor for
a wide application of our methodology to the synthesis of
other naturally occurring ꢀ3-amino acids as, for instance,
iturinic acids. However, optically active propargylic alcohols
can become available by asymmetric reduction of ynones.
Thus (R)-5 was synthesized according to the reaction se-
quence depicted in Scheme 1. The ynone (4), easily obtained
from the dodecanoyl chloride (3) by reaction with bis-
trimethylsilylacetylene in the presence of AlCl3 [14] was
enantioselectively reduced with S-Alpine-Borane, as re-
ported in the literature for the (R) isomer [15], to the (S)
propargylic alcohol (5) [16].
Iturin-A 1
NH2
O
nC11H23
OH
(R)-2
Iturinic acid
Fig. (1). Structure of iturin-A (R= C13-C17 alkyl chain) and iturinic
acid.
Few methods have been reported for the asymmetric syn-
thesis of iturinic acid. Some are based on the stereoselective
formation of the C-N bond and other on the transformation
*Address correspondence to this author at the Dipartimento di Chimica e
Tecnologia del Farmaco, Sezione di Chimica Organica, Università di Peru-
gia, I-06123 – Perugia, Italy; E-mail: tempa@unipg.it
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Novel Stereoselective Synthesis of (R)-3-Aminotetradecanoic Acid
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
23
O
O
that which uses hydrogen peroxide [13]. Moreover, by the
use of cupric chloride the selenium was recovered as
diphenyl diselenide. Finally, the phthalimido group was re-
moved by treating 10 with hydrazine hydrate in refluxing
ethanol. Compound (R)-2 was isolated as the hydrochloride
in 68% yield [20]. Because under these reaction conditions
the stereogenic carbon atom is not involved, it is suggested
that the enantiomeric ratio of (R)-2 hydrochloride was 92:8
as in the case of compound (6). This was established by
treating the (R)-2 hydrochloride with N-ethoxycarbonyl-
phthalimide in tetrahydrofuran [21] to obtain the acid (R)-10
which was esterified with methyl iodide in DMF and in the
presence of potassium carbonate [22] to afford (R)-9 which
showed the same enantiomeric ratio of the compound pre-
pared from 8, as described above.
i
ii
nC11H23
Cl
nC11H23
4
3
PhthN
OH
iii
nC11H23
nC11H23
6
5
Scheme 1. i) Me3Si-CꢀCSiMe3 (1.1 equiv.), AlCl3(1 equiv.),
CH2Cl2, 0 °C, 4 h then K2CO3, 81%; ii) (S)-Alpine-Borane (1.4
equiv.), 0 °C to rt, neat, 16 h then MeCHO (1.4 equiv.), H2O2 (3
equiv.), NaOH, 79%; iii) DIAD (1.8 equiv.), PhthNH (1.4 equiv.),
Ph3P (1.4 equiv.), THF, 0 °C to rt, 9 h, 70%.
In order to confidently determine the enantiomeric ex-
cesses by HPLC it was necessary to dispose of the enanti-
omers ent-6 and ent-9. These two compounds were obtained
following the same procedure and using the R-Alpine-
Borane as reducing agent of the ynone (4). The HPLC analy-
sis on chiral stationary phase of ent-6 and ent-9 was effected
By reaction with phthalimide under Mitsunobu condi-
tions, compound (5) was easily converted into (R)-N-
phthalimido propargylic amine (6) [17] with the expected
complete inversion of configuration at the stereogenic car-
PhthN
nC11H23
PhthN
nC11H23
PhthN
nC11H23
O
PhthN
nC11H23
O
i
ii
iii
SePh
OMe
SePh
6
8
8
9
7
PhthN
nC11H23
O
iv
v
(R)-2.HCl
OH
10
Scheme 2. i) PhSeBr (1.1 equiv.), CuI (2 equiv.), DMF, rt, 36 h; ii) p-TsOH (2 equiv.), CH2Cl2, reflux, 6 h; iii) CuCl2 dry (1.1 equiv.),
MeOH/ MeCN, rt, 6 h, 40% (three steps); iv) CuCl2·H2O (1.1 equiv.), MeCN, rt, 14 h, 68% (three steps); v) H2N-NH2 (2.2 equiv.), EtOH,
100 °C, 5 h then HCl, 68%.
bon atom (Scheme 1). The enantiomeric purity of (R)-6 was
estimated by HPLC analysis on chiral stationary phase.
Compound (6) presented an enantiomeric ratio of 92:8 which
is identical to that of the alkynol (R)-5 reported in the litera-
ture [15]. The N-protected propargylic amine (6) (Scheme 2)
was then converted, in nearly quantitative yield, into the cor-
responding alkynyl phenyl selenide (7) which was directly
employed in the reaction with p-toluenesulfonic acid mono-
hydrate [12] to give the Se-phenyl selenocarboxylate (8). No
racemization occurred during this conversion as demon-
strated by HPLC analysis of the corresponding methyl ester
derivative (9) [18] prepared by reaction of 8 with methanol in
acetonitrile and in the presence of anhydrous cupric chloride
[12].
as described above for the (R) enantiomers and the measured
ratio was 93:7. Compound ent-10 could then be transformed
into the (S) enantiomeric form of 2.
In summary, the present paper describes a new enantiose-
lective synthesis of iturinic acid (2) hydrochloride and we
can envision that the present procedure with the use of the
appropriate acid chloride will allow the synthesis of the dif-
ferent iturinic acid side chains to be easily effected.
ACKNOWLEDGEMENTS
Financial support from MIUR, National Projects
PRIN2003, PRIN2005 and FIRB2001, Consorzio CINMPIS,
Bari and University of Perugia is gratefully acknowledged.
When the crude 8 was treated with cupric chloride hy-
drate in acetonitrile at room temperature the corresponding
(R)-N-phthalimido-3-aminotetradecanoic acid (10) [19] was
obtained in good yield (Scheme 2). The use of cupric chlo-
ride hydrate described here represents a new and very simple
procedure to obtain carboxylic acids from the Se-phenyl se-
lenocarboxylates. This procedure is more convenient than
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GC-MS (EI, 70 eV): m/z (%) = 387 (61) [M]+, 314 (53), 232 (52),
200 (100), 160 (54), 130 (35); FT-IR (diffuse reflectance): 2915,
1733, 1702, 1370, 976 cm-1; Anal. Calcd for C23H33NO4 (387.5): C,
71.29; H, 8.58; N, 3.61; Found: C, 71.66; H, 8.21; N, 3.19.
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[19]
Conversion of selenocarboxylic acid Se-phenyl esters (8) into acid
(10): A mixture of selenocarboxylic acid Se-phenyl ester (8) (1
mmol) and copper (II) chloride hydrated (1.1 mmol) in acetonitrile
(8 mL) was stirred at room temperature. The progress of the reac-
tion was monitored by TLC. After 14 h the selenolester was com-
pletely consumed. Tartaric acid (1.2 mmol) was then added. The
reaction mixture was stirred for few minutes, then filtered through
a celite path and the filtrate concentrated. The crude product was
purified by column chromatography on silica gel using a 98:2 mix-
ture of dichloromethane and methanol as eluant. Compound (10)
was obtained as colorless oil in 68% global yield. Selected data for
[6]
[7]
[8]
[9]
[10]
[11]
compound (10): [ꢀ]D31 = -29.57 (c= 0.45 in DMSO); 1H NMR (200
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MHz, CDCl3, TMS): ꢁ = 0.85 (t, J = 6.5 Hz, 3H, CH3), 1.10-1.31
(m, 18H, CH2), 1.58-1.81 (m, 1H, CH2), 1.96-2.21 (m, 1H, CH2),
2.82 (dd, J= 16.6, 5.4 Hz, 1H, CH2), 3.21 (dd, J= 16.6, 9.5 Hz, 1H,
CH2), 4.65 (m, 1H, CHN), 7.76-7.90 (m, 4H, CH), 8.56 (brs, 1H,
[14]
[15]
[16]
OH); 13C NMR (50 MHz, CDCl3, TMS): ꢁ = 13.9, 22.5, 26.1, 28.9,
29.1, 29.2, 29.3, 29.4 (2C), 31.7, 32.2, 36.6, 47.6, 123.1 (2C), 129.2
(2C), 135.3 (2C), 168.2 (2C), 176.7; FT-IR (diffuse reflectance):
2921, 2853, 1704.7, 1712.5, 1375.4 cm-1; Anal. Calcd for
C22H31NO4 (373.4): C, 70.75; H, 8.37; N, 3.75: Found: C, 70.30; H,
8.99; N, 4.08.
27
[17]
Selected data for compound (6): colorless wax mp 30-32 °C; [ꢀ]D
= + 3.51 (c = 1.69 in Et2O); HPLC analysis: Chiracel OD-H col-
umn (250x4 mm, Daicel), eluent: i-PrOH/hexane (0.4:99.6) flow
rate: 0.5 mL/min, UV detection at 230 nm; tR 27.3 min: er = 92:8;
1H NMR (200 MHz, CDCl3, TMS): ꢁ= 0.94 (t, J = 6.9 Hz, 3H,
CH3), 1.27-1.49 (m, 18H, CH2), 2.09-2.30 (m, 2H, CH2), 2.43 (d, J
= 2.5 Hz, 1H, CH), 5.11 (td, J = 8.0, 2.5 Hz, 1 H; CHN), 7.73-7.95
(m, 4H, CH); 13C NMR (50 MHz, CDCl3, TMS): ꢁ = 14.0, 22.6,
26.1, 28.7, 29.2, 29.3, 29.4, 29.5 (2C), 31.8, 33.3, 41.4, 71.7, 80.3,
123.3 (2C), 131.7 (2C), 134.0 (2C), 167.0 (2C); GC-MS (EI, 70
eV): m/z (%) = 296 (17)[M-41]+, 212 (10), 199 (16), 184 (100), 130
(21), 94 (12); FT-IR (diffuse reflectance): 2922, 2115, 1766, 1713,
1385, 1077 cm-1; Anal. Calcd for C22H29NO2 (339.4):C, 77.84; H,
8.61; N, 4.13. Found: C, 77.41; H, 8.90; N, 3.85.
[20]
Formation of (R)-2 hydrochloride by deprotection of 10: Hydrazine
hydrate (0.11 mL, 2.2 mmol) was added to a stirred solution of 10
(0.37 g, 1 mmol) in EtOH (3 mL). After stirring for 5 h at 100 °C,
the reaction mixture was allowed to slowly reach room temperature
and concentrated. The residue was treated with 6 mL of 2N hydro-
chloric acid, the solid was allowed to settle down and then filtered.
Evaporation of the filtrate gave a residue which was dried under
reduced pressure to afford (R)-2 hydrochloride in 68% yield. Selec-
25
ted data for compound 2: White solid mp 131-135 °C; [ꢀ]D
=
-17.80 (c= 0.59 in H2O). 1H NMR (200 MHz, D2O): ꢁ = 0.65-0.81
(m, 3H, CH3), 0.97-1.35 (m, 18H, CH2), 1.42-1.78 (m, 2H, CH2),
2.62 (d, J= 6.3 Hz, 2H, CH2), 3.38-3.57 (m, 1H, CHN); 13C NMR
[18]
Selected data for compound (9): pale yellow oil; [ꢀ]D29 = 2.48 (c=
1.43 in CHCl3); HPLC analysis: Chiracel OD-H column (250x4
mm, Daicel), eluent: i-PrOH/hexane (1:99) flow rate: 0.5 mL/min,
(50 MHz, D2O): ꢁ = 14.4, 23.3, 26.0, 28.9, 29.9, 30.2, 30.3, 30.5
(2C), 32.6, 32.8, 48.9, 67.2, 174.2; FT-IR (diffuse reflectance):
2923, 1946.7, 1711.5, 1482.9 cm-1; Anal. Calcd for C14H30ClNO2
(279.8): C, 60.09; H, 10.81; N, 5.01. Found: C, 59.80; H, 11.27; N,
4.78.
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1
UV detection at 230 nm; tR 33.6 min: er = 92:8; H NMR (200
MHz, CDCl3, TMS): ꢁ = 0.68-0.92 (m, 3H, CH3), 1.05-1.31 (m,
18H, CH2), 1.55-1.76 (m, 2H, CH2), 2.61 (dd, J= 16.1 , 5.3 Hz, 1H,
CH2), 3.11 (dd, J= 16.1, 9.5 Hz, 1H, CH2), 3.55 (s, 3H, CH3) 4.58
(m, 1H, CHN), 7.65-7.90 (m, 4H, CH); 13C NMR (50 MHz, CDCl3,
TMS): ꢁ = 14.0, 22.5, 26.2, 28.7, 29.4 (4C), 31.0, 31.7, 32.2, 36.6,
47.9, 51.6, 123.1 (2C), 131.6 (2C), 133.8 (2C), 168.2 (2C), 171.3;
[21]
[22]