A simple synthesis of (R)-3-aminooctanoic acid (D-BAOA) from (S)-1-octyn-3-ol

Article abstract of DOI:10.1016/j.tetlet.2007.04.115

A simple substrate-controlled asymmetric synthesis of (R)-3-aminooctanoic acid (D-BAOA) is described. The present method involves the conversion of commercially available (S)-1-octyn-3-ol into the protected propargylic amine, with complete inversion of co

Full text of DOI:10.1016/j.tetlet.2007.04.115

Tetrahedron Letters 48 (2007) 4343–4345
A simple synthesis of (R)-3-aminooctanoic acid (D-BAOA)
from (S)-1-octyn-3-ol
Marcello Tiecco,* Lorenzo Testaferri, Andrea Temperini,* Raffaella Terlizzi,
Luana Bagnoli, Francesca Marini and Claudio Santi
`
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Universita di Perugia, I-06123 Perugia, Italy
Received 19 March 2007; revised 18 April 2007; accepted 23 April 2007
Available online 27 April 2007
Abstract—A simple substrate-controlled asymmetric synthesis of (R)-3-aminooctanoic acid (D-BAOA) is described. The present
method involves the conversion of commercially available (S)-1-octyn-3-ol into the protected propargylic amine, with complete
inversion of configuration, and the successive transformation of the (phenylseleno)acetylene intermediate into the Se-phenyl seleno-
carboxylate, which is then easily converted into the carboxylic group. The phthalimido group was eventually removed by treatment
with hydrazine hydrate.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Several bioactive cyclic peptides of lipophilic nature
have been isolated from different types of microorgan-
isms1 such as the antifungal cyclic peptides iturines,2
bacillomycins and mycosubtilin.3 An unusual structural
motif common to all of these peptides is the occurrence
of one b-amino acid4 with lipophilic and structurally
unique side chain. Thus hormothamnin A,5 a cytotoxic
cyclic peptide, was isolated from the tropical marine
cyanobacterium Hormothamnion enteromorphoides and
(R)-3-aminooctanoic acid 1 (D-BAOA) (Fig. 1) was
characterized as the lipid-like b-amino acidic structural
component. Because of the importance of this lipophilic
b-amino acid its synthesis has attracted increasing inter-
est and this letter reports a simple and enantiospecific
route to (R)-3-aminooctanoic acid 1 starting from read-
ily available (S)-1-octyn-3-ol.
NH2
O
nC5H11
OH
(R
)-1
D-BAOA
Figure 1. Structure of D-BAOA.
mediate. In a similar way, Enders7 reported an
enantioselective synthesis (ee P95%) of (S)-1 by conju-
gate addition of lithiated TMS-SAMP to an a,b-unsatu-
rated ester. Moreover, in a different approach, Gmeiner8
and Jefford9 transformed the carboxylic group at C-1 of
L-asparagine or L-aspartic acid into the desired alkyl
substituent to obtain (R)-1 in 99% ee by several steps
without altering the integrity of the initial stereogenic
center.
Some reported methods for the synthesis of 1 are mainly
based on the stereospecific formation of the C–N bond
or the transformation of an a-amino acid. The Michael
addition of ‘chiral ammonia’ equivalent as lithium (R)-
N-benzyl-N-a-methylbenzyl amide to achiral a,b-unsat-
urated ester has been studied by Davies6 who obtained
(R)-1 in good yield and in high ee (>95%) after N-de-
benzylation and hydrolysis of the b-amino ester inter-
Following our recent studies10 on the transformation of
terminal alkynes into Se-phenyl selenocarboxylates, we
show here an alternative and very convenient method
to synthesize (R)-1 starting from commercially available
(S)-1-octyn-3-ol 2 (99% ee). By reaction with phthal-
imide under Mitsunobu conditions, compound 2 was
easily converted into N-phthalimido propargylic amine
311 (Scheme 1) with the expected complete inversion of
the configuration at the stereogenic carbon atom. As
indicated by HPLC analysis on chiral stationary phase11
compound 3 presented the same enantiomeric ratio as
the starting alkynol 2. The N-protected propargylic
Keywords: Alkynols; Alkynyl selenides; Se-Phenyl selenocarboxylates;
b-Aminoacids; Stereoselective reactions.
*
Corresponding authors. Tel.: +39 0755855100; fax: +39 0755855116
(M.T.); e-mail: tiecco@unipg.it
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.115

4344
M. Tiecco et al. / Tetrahedron Letters 48 (2007) 4343–4345
OH
PhthN
nC5H11
PhthN
nC5H11
a
b
nC5H11
SePh
3
4
2
PhthN
nC5H11
O
PhthN
O
e
c
d
(R)-1.HCl
SePh
nC5H11
OH
6
5
Scheme 1. Reagents and conditions: (a) DIAD, PhthNH, Ph3P, THF, 0 ꢁC to rt, 86%; (b) PhSeBr, CuI, DMF, rt, 85%; (c) p-TsOH, CH2Cl2, reflux,
86%; (d) H2O2, THF, rt, 93%; (e) H2N–NH2, EtOH, reflux, 97%.
amine 3 was then converted, according to the general
procedure reported in the literature,12 into the
corresponding alkynyl phenyl selenide 4, which, in the
presence of an excess of p-toluenesulfonic acid mono-
hydrate,10 gave the Se-phenyl selenocarboxylate 513 in
excellent yield. No racemization occurred during this
conversion as demonstrated by the enantiomeric ratio
of 5 measured by HPLC.13 The Se-phenyl selenocarb-
oxylate 5 was then treated with a 30% solution of hydro-
gen peroxide in tetrahydrofuran at room temperature14
and the corresponding (R)-N-phthalimido-3-aminoocta-
noic acid 615 was obtained in good yield. Finally, the
phthalimido group was removed by treating 6 with
hydrazine hydrate in refluxing ethanol. Compound
(R)-1 was isolated as the hydrochloride in 97% yield.
Since under these reaction conditions the stereogenic
carbon atom is not involved, it is suggested that the ena-
tiomeric ratio of 1 is >99:1. Comparison of the spectro-
scopic data and of the sign of the specific rotation16 of
the (R)-1 hydrochloride synthesized by this protocol
with those reported in the literature6 allowed the unam-
biguous assignment of its structure and of its absolute
configuration to be made. These results also confirm
that all the steps described above proceed without loss
of enantiomeric purity.
Acknowledgements
Financial support from MIUR, National Projects
PRIN2003, PRIN2005 and FIRB2001, Consorzio
CINMPIS, Bari, and University of Perugia is gratefully
acknowledged.
Supplementary data
HPLC data for compounds 3 and 5 are reported in the
Supplementary data. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.04.115.
References and notes
1. (a) Helms, G. L.; Moore, R. E.; Niemczura, W. P.;
Patterson, G. L. M.; Tomer, K. B.; Gross, M. L. J. Org.
Chem. 1988, 53, 1298–1307; (b) Moore, R. E.; Bornemann,
V.; Niemczura, W. P.; Gregson, J. M.; Chen, J. L.;
Norton, T. R.; Patterson, M. L.; Helms, G. L. J. Am.
Chem. Soc. 1989, 111, 6128–6132; (c) Carter, D. C.;
Moore, R. E.; Mynderse, J. S.; Niemczura, W. P.; Todd, J.
S. J. Org. Chem. 1984, 49, 241–263; (d) Munro, M. H. G.;
Luibrand, R. T.; Blunt, J. W. In Bioorganic Marine
Chemistry; Scheuer, P. J., Ed.; Springer: Berlin, 1987; pp
94–176.
2. Isogai, A.; Takayama, S.; Murakoshi, S.; Suzuki, A.
Tetrahedron Lett. 1982, 23, 3065–3068.
3. Volpon, L.; Besson, F.; Lancelin, J. M. Eur. J. Biochem.
1999, 264, 200–210.
4. Juaristi, E. In Enantioselective Synthesis of b-Amino Acids;
Juaristi, E., Soloshonok, V. A., Eds.; Wiley-Interscience:
New York, 2005; pp 1–17.
Following the same procedure the commercially
available (R)-1-octyn-3-ol ent-2 (99% ee) was easily
transformed in four steps into the (S)-N-phthalimido-
3-aminooctanoic acid ent-6 with practically the same
global yield (54%). The HPLC analysis on the chiral
stationary phase of ent-3 and ent-5 was effected as de-
scribed above for the (R) enantiomers. The measured
enantiomeric ratios were >99:1. Compound ent-6 can
then be transformed into the (S) enantiomeric form of 1.
5. Gerwick, W. H.; Jiang, Z. D.; Agarwal, S. K.; Farmer, B.
T. Tetrahedron 1992, 48, 2313–2324.
6. Davies, S. G.; Garrido, N. M.; Kruchinin, D.; Ichihara,
O.; Kotchie, L. J.; Price, P. D.; Price Mortimer, A. J.;
Russell, A. J.; Smith, A. D. Tetrahedron: Asymmetry 2006,
17, 1793–1811.
7. Enders, D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed.
Engl. 1995, 34, 455–457.
8. Gmeiner, P. Tetrahedron Lett. 1990, 31, 5717–5720.
9. Jefford, C. W.; Wang, J. Tetrahedron Lett. 1993, 34, 1111–
1114.
In conclusion, starting from a commercially available
chiral building block, enantiomerically pure (R)-3-
aminooctanoic acid 1 (D-BAOA) was synthesized
through very simple chemical reactions involving the
versatile organoselenium intermediates. The reaction is
based on our previously described conversion of a termi-
nal alkyne into a carboxylic group.10 Because of the ste-
reospecific transformation of a C–O bond of the starting
alkynol into a C–N bond, this procedure could be easily
applied to the synthesis of other optically active b-amino
acids. Further applications of our method are presently
under investigation.
10. Tiecco, M.; Testaferri, L.; Temperini, A.; Bagnoli, L.;
Marini, F.; Santi, C.; Terlizzi, R. Eur. J. Org. Chem. 2004,
3447–3458.

M. Tiecco et al. / Tetrahedron Letters 48 (2007) 4343–4345
4345
18
11. Selected data for compound 3: mp 59 ꢁC; ½aꢀD ꢁ3.57 (c
1.97 in CHCl3); HPLC analysis: Chiralcel OD-H column
(250 · 4 mm, Daicel), eluent: i-PrOH/hexane (0.5:99.5)
flow rate: 0.5 mL/min, UV detection at 220 nm; tR
29.6 min: er >99:1; 1H NMR (200 MHz, CDCl3, TMS):
14. Derkach, N. Y.; Tishchenko, N. P. Zh. Organ. Khim.
1977, 13, 100–103; Derkach, N. Y.; Tishchenko, N. P.
Chem. Abstr. 1977, 86, 155314.
19
15. Selected data for compound 6: mp 80–82 ꢁC; ½aꢀD ꢁ5.01 (c
1.95 in CHCl3); 1H NMR (200 MHz, CDCl3, TMS):
3
3
d = 0.8 (t, JH,H = 6.8 Hz, 3H; CH3) 1.1–1.5 (m, 6H;
d = 0.85 (t, JH,H = 6.5 Hz, 3H; CH3), 1.10–1.31 (m, 6H;
CH2), 1.86–2.2 (m, 2H; CH2), 2.36 (d, 4JH,H = 2.1 Hz, 1H;
CH), 4.90–5.08 (m, 1H; CH), 7.63–7.90 (m, 4H; CH); 13C
NMR (50 MHz, CDCl3, TMS): d = 13.8, 22.4, 25.7, 30.8,
33.1, 41.2, 71.9, 80.2, 123.2 (2C), 131.5 (2C), 134.0 (2C),
166.6 (2C); GC–MS m/z (%): 226 (13) [M+], 212 (13), 199
(8), 184 (100), 130 (16); FT-IR (diffuse reflectance): 2924,
2118, 1773, 1708, 1387, 1087 cmꢁ1. Elemental Anal. Calcd
(%) for C16H17NO2 (255.3): C, 75.27; H, 6.71; N, 12.53.
Found: C, 74.69; H, 6.55; N, 12.39.
CH2), 1.60–1.81 (m, 1H; CH2), 1.95–2.11 (m, 1H; CH2),
2.82 (dd, 2JH,H = 16.5 Hz, 3JH,H = 5.5 Hz, 1H; CH2), 3.21
(dd, 2JH,H = 16.5 Hz, 3JH,H = 9.3 Hz, 1H; CH2), 4.65 (ddt,
3JH,H = 9.3, 5.5, 4.9 Hz, 1H; CH), 7.76–7.90 (m, 4H; CH),
8.3 (br s, 1H; OH); 13C NMR (50 MHz, CDCl3, TMS):
d = 13.9, 22.3, 25.8, 31.1, 32.2, 36.7, 47.7, 129.2 (2C),
131.6 (2C), 133.9 (2C), 168.3 (2C), 176.3; FT-IR: 3002,
2925, 1773.7, 1712.5, 1376.4 cmꢁ1. Elemental Anal. Calcd
(%) for C16H19NO4 (289.3): C, 62.42; H, 6.62; N, 4.84.
Found: C, 62.28; H, 6.81; N, 4.72.
12. Braga, A. L.; Silveira, C. C.; Reckziegel, A.; Menezes, P.
H. Tetrahedron Lett. 1993, 34, 8041–8042.
16. Formation of 1 by deprotection of 6. Hydrazine hydrate
(0.22 mL, 4.70 mmol) was added to a stirred solution of 6
(0.17 g, 0.58 mmol) in EtOH (10 mL). After stirring for
2 h at 110 ꢁC, the reaction mixture was allowed to slowly
reach room temperature and concentrated. The residue
was treated with 10 mL of 4 N hydrochloric acid and
then the solid was allowed to settle down. Evaporation of
the filtrate gave crude (R)-1 hydrochloride, which was
dissolved in distilled water (5 mL). Hydrogen peroxide
30% w/w (0.5 mL) was then added at rt to decompose the
residual hydrazine. The mixture was then concentrated in
vacuo and the residue dried under reduced pressure to
afford (R)-1 hydrochloride. Selected data for compound
18
13. Selected data for compound 5: oil; ½aꢀD ꢁ90.69 (c 2.48 in
CHCl3); HPLC analysis: Chiralcel OD-H column
(250 · 4 mm, Daicel), eluent: i-PrOH/hexane (2:98) flow
rate: 0.6 mL/min, UV detection at 220 nm; tR 25.8 min:
1
er >99:1; H NMR (200 MHz, CDCl3, TMS): d = 0.7–0.9
(m, 3H; CH3), 1.1–1.4 (m, 6H; CH2), 1.79–1.80 (m, 1H;
2
CH2), 1.95–2.25 (m, 1H; CH2), 3.18 (dd, JH,H = 15.9 Hz,
2
3JH,H = 5.2 Hz, 1H; CH2), 3.6 (dd, JH,H = 15.9 Hz,
3
3JH,H = 9.3 Hz, 1H; CH2), 4.71 (ddt, JH,H = 9.3, 5.2,
4.6 Hz, 1H; CH), 7.25–7.45 (m, 3H; CH), 7.50–7.60 (m,
2H; CH), 7.70–7.80 (m, 2H; CH), 7.80–7.90 (m, 2H; CH);
13C NMR (50 MHz, CDCl3, TMS): d = 13.8, 22.3, 25.8,
31.1, 32.2, 47.8, 49.1, 123.2 (2C), 125.9, 128.9, 129.3 (2C),
131.6 (2C), 133.9 (2C), 135.6 (2C), 168.1 (2C), 197.6; FT-
16
1: mp 110–112 ꢁC (lit,6 mp 103–104 ꢁC); ½aꢀD ꢁ11.16 (c
20
1.35 in H2O). The value reported in the literature6 is ½aꢀD
IR (diffuse reflectance): 2929, 1772, 1711, 1370, 976 cmꢁ1
.
ꢁ16.6 (c 1.10 in H2O). Anal. Calcd for C8H18ClNO2: C,
49.10; H, 9.27; N, 7.16. Found: C, 48.84; H, 9.43; N,
6.84.
Elemental Anal. Calcd (%) for C22H23NO3Se (428.4): C,
61.68; H, 5.41; N, 3.27. Found: C, 61.39; H, 5.77; N, 3.00.