Enantioselective synthesis of (-)-galantinic acid

Article abstract of DOI:10.1016/j.tetlet.2004.05.151

An efficient enantioselective synthesis of (-)-galantinic acid 1, a non-proteogenic amino acid is described using Sharpless asymmetric epoxidation, dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfite as the key steps.

Full text of DOI:10.1016/j.tetlet.2004.05.151

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5877–5879
Enantioselective synthesis of ())-galantinic acid
Satyendra Kumar Pandey, SubbaRao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 30 March 2004; revised 20 May 2004; accepted 28 May 2004
Available online 19 June 2004
Abstract—An efficient enantioselective synthesis of ())-galantinic acid 1, a non-proteogenic amino acid is described using Sharpless
asymmetric epoxidation, dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfite as the key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
())-Galantinic acid 1 is a component of the peptide
antibiotic galantin I, isolated from a culture broth of
Bacillus pulvifaciens.1 The original structure of galantin I
was assigned after the synthesis of its unusual constitu-
ent amino acids, galantinic acid 1 and galantinamic acid
3. The originally proposed structure of ())-galantinic
acid 2 was later revised to 1 by Sakai and Ohfune2 who
also reported its first total synthesis.3 (Fig. 1) Galantinic
acid has been a synthetic target of considerable interest
due to its potent biological activity and unique structure
with an array of functionalities. Various methods for its
synthesis have been documented in the literature.4 Most
of these approaches employ chiral pool starting mate-
rials. Very recently, Raghavan and Ramakrishna
Reddy5 reported the stereoselective synthesis of ())-
galantinic acid using a sulfinyl moiety as an internal
nucleophile through 1,3-asymmetric induction. As part
of our research programme aimed at developing ena-
tioselective synthesis of naturally occurring amino
alcohols6 and lactones,7 the Sharpless asymmetric di-
hydroxylation and subsequent transformation of the
diols formed via cyclic sulfites/sulfates were envisioned
as powerful tools offering considerable opportunities for
synthetic manipulations. Herein we report a new and
highly enantioselective syntheses of ())-galantinic acid
employing the Sharpless asymmetric epoxidation and
dihydroxylation procedures as the source of chirality.
p-methoxybenzyl chloride in the presence of NaH gave 5
in 86% yield. Compound 5 was oxidized to the aldehyde
and subsequently treated with (ethoxycarbonylmethyl-
ene)triphenylphosphorane in THF at room temperature
to furnish the Wittig product 6 in 81% yield. The
reduction of olefinic ester 6 to the corresponding allylic
alcohol 7 was achieved with DIBAL-H at 0 °C–rt in
excellent yield. Compound 7 was then treated with
titanium tetraisopropoxide and t-butyl hydroperoxide in
the presence of ())-DIPT under the Sharpless asym-
metric epoxidation reaction conditions8 to give the
epoxide 89 in good yield. The trans-selective opening of
the epoxide 810 was accomplished using perchloric acid
and 60% DMSO to afford the triol, which was subse-
quently protected with benzaldehyde dimethyl acetal in
the presence of a catalytic amount of DMAP to afford a
mixture of 1,3- and 1,2-benzylidene derivatives in a 9:1
ratio. The desired major 1,3-benzylidene compound 9
was separated by silica gel column chromatography,
which was found to be enantiomerically pure as deter-
mined by converting its free hydroxy group into the
Mosher salt and analyzing the 1H NMR spectrum.
H2N
OH OH
O
O
O
OH
HO
HO
OH
NH2
2
1
The synthesis of ())-galantinic acid 1 started from
commercially available 1,3-propanediol 4 as illustrated
in Scheme 1. The mono hydroxyl protection of 4 with
Revised structure of galantinic acid
Originally proposed structure of
galantinic acid
OH OH
NH2
OH
galantinamic acid
O
H2N
OH
3
* Corresponding author. Tel.: +91-20-25893300x2050; fax: +91-20-
25893614; e-mail: tripathi@dalton.ncl.res.in
Figure 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.151

5878
S. K. Pandey et al. / Tetrahedron Letters 45 (2004) 5877–5879
O
c
b
a
OEt
O
PMBO
OH
PMBO
d
OH
HO
OH
6
5
4
Ph
O
O
e
f
PMBO
OH
PMBO
PMBO
8
7
9
OH
Ph
Ph
Ph
O
O
O
O
O
O
O
i
h
g
HO
EtO
PMBO
12
11
N3
10
N3
N3
O
Ph
N3
Ph
O
OH
OH
OH
O
O
O
O
k
O
OH
O
j
HO
EtO
EtO
S
N3
15
O
OH 13
N3
O
14
O
OH
OH
OH
l
HO
1
NH2
Scheme 1. Reagents and conditions: (a) p-CH3OC6H5CH2Cl, NaH, dry DMF, rt, 6 h, 86%; (b) (i) PCC, anhyd CH3COONa, dry CH2Cl2, 0 °C– rt,
6 h; (ii) Ph3P@CHCOOEt, dry THF, rt, 24 h, 81%; (c) DIBAL–H, dry CH2Cl2, 0 °C–rt, 2 h, 92%; (d) Ti(OPr-i)4, ())-DIPT, t-BuOOH, dry CH2Cl2,
)25 °C, 36 h, 72%; (e) (i) 60% DMSO, HClO4, 0 °C, 3 h, 89%; (ii) C6H5CH(OMe)2, DMAP (cat), dry CH2Cl2, rt, overnight, 65%; (f) (i) MsCl, Et3N,
dry CH2Cl2, 5 h, 83%; (ii) NaN3, dry DMF, 78%; (g) DDQ, dry CH2Cl2, rt, 3 h, 91%; (h) (i) PCC, anhyd CH3COONa, dry CH2Cl2, rt, 6 h; (ii)
Ph3P@CHCOOEt, dry THF, rt, 24 h, 83%; (i) (DHQ)2PHAL, OsO4, CH3SO2NH2, K3FeCN6, K2CO3, t-BuOH/H2O (1:1), 24 h, 0 °C, 87%; (j) SOCl2,
Et3N, 30 min, 89%; (k) (i) NaBH4, dry THF, MeOH; (ii) 4 N H2SO4, 2 h, rt, 77%; (l) 10% Pd/C, H2, MeOH, rt, 88%.
25
25
D
At this stage an attempt to convert the free hydroxyl
group of 9 to azide under Mitsunobu conditions was not
very satisfactory. Accordingly the free hydroxyl group
of 9 was converted into O-mesylate, which on nucleo-
philic displacement with sodium azide in dry DMF
afforded compound 1011 in 78% yield. The p-methoxy
benzyl-protecting group was cleaved by treating 10 with
DDQ to furnish the alcohol 11 in excellent yield.
[aꢀ )29.7 (lit.3 [aꢀ )29.4). The physical and spectro-
D
scopic data of 1 are in full agreement with the literature
data.3
In conclusion, a practical and enantioselective synthesis
of ())-galantinic acid has been achieved using Sharpless
asymmetric epoxidation and dihydroxylation and
through regioselective nucleophilic opening of a cyclic
sulfite. The synthetic strategy described has significant
potential for further extension to other isomers and
related analogues including galantinamic acid 3, the
other component of galantin I. Currently, studies are
in progress in this direction.
The PCC oxidation of 11 to the aldehyde and sub-
sequent reaction with (ethoxycarbonylmethylene)tri-
phenylphosphorane gave the olefin 12 in 83% yield. The
dihydroxylation of olefin 12 with osmium tetroxide
and K3Fe(CN)6 as co-oxidant in the presence of
(DHQ)2PHAL as the chiral ligand under the Sharpless
asymmetric dihydroxylation conditions12 furnished the
diol 1313 in excellent yield. The diol 13 was then treated
with thionyl chloride and Et3N to give the cyclic sulfite
1414 in 89% yield. The essential feature of the synthetic
strategy shown in Scheme 1 was based on the pre-
sumption that the nucleophilic opening of the cyclic
sulfite 14 would occur in a regiospecific manner at the a-
carbon atom. Indeed, the cyclic sulfite 14 reacted with
one equivalent of NaBH4 with apparent complete
selectivity for attack at C-2, the a-position, to furnish
the intermediate sulfite ester which, without further
isolation was subjected to acidic hydrolysis using 4 N
H2SO4 to give 15 in good yield. Reduction of the azide
under hydrogenation conditions using 10% Pd/C in
methanol furnished ())-galantinic acid 1 in 88% yield,
Acknowledgements
S.K.P. and S.V.K. thank CSIR New Delhi for financial
support. We are grateful to Dr. M. K. Gurjar for his
support and encouragement. This is NCL Communi-
cation No. 6664.
References and notes
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5879
25
D
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11. Spectral data of compound 10: ½aꢀ )4.39 (c 0.22, CHCl3);
IR (neat): 2104, 1612, 1513, 1465, 1362, 1248, 1216; 1H
NMR (500 MHz, CDCl3): d ¼ 7:37–7:42 (m, 5H), 7.29 (d,
J ¼ 10 Hz, 2H), 6.87 (d, J ¼ 10 Hz, 2H), 5.50 (s, 1H), 4.54
(s, 2H), 4.40–4.52 (m, 2H), 4.32–4.34 (m, 1H), 3.88 (td,
J ¼ 8:71, 3.21, 1H), 3.73 (t, J ¼ 3:67 Hz, 2H), 3.70 (s, 3H),
1.76–1.83 (m, 2H); 13C NMR (125 MHz, CDCl3):
d ¼ 29:67, 31.58, 38.26, 55.22, 64.62, 69.00, 72.25, 72.74,
75.63, 101.13, 113.77, 126.04, 128.24, 129.19, 129.49,
159.22; GC–MS: 369 (M+), 357.05, 331.05, 279.05,
261.05, 241.05, 200.05, 172.04. Anal. Calcd for
C20H23N3O4 (369.42) C, 65.03%, H, 6.28%, N, 11.37%.
Found C, 64.90%, H, 6.21%, N, 11.26%.
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13. The diastereomeric excess was found to be 91% using 13C
25
D
NMR analysis. Spectral data of compound 13: ½aꢀ )3.28
(c 0.80, CHCl3) IR (neat): 3561, 2112, 1716, 1522, 1343,
1218, 1210; 1H NMR (200 MHz, CDCl3): d ¼ 7.25–7.32
(m, 5H), 5.51 (s, 1H), 4.21–4.25 (m, 1H), 4.13 (d, J ¼ 8 Hz,
1H), 4.06 (q, J ¼ 6 Hz, 2H), 4.22 (q, J ¼ 8 Hz, 1H), 3.62–
3.74 (m, 2H), 3.06 (t, J ¼ 4 Hz, 2H), 3.54–3.56 (m, 1H),
2.06 (br, 2H), 0.93 (t, J ¼ 9 Hz, 3H); 13C NMR (50 MHz,
CDCl3) d ¼ 13.75, 22.02, 25.26, 29.23, 32.94, 54.85, 60.91,
69.40, 72.20, 78.67, 113.37, 128.84, 158.73, 170.56. Anal.
Calcd for C16H21N3O6 (351.38) C, 54.70%, H, 6.03%,
N, 11.96%. Found C, 54.62%, H, 5.98%, N, 11.99%.
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