A straightforward enantiospecific synthesis of N-(Z)-galantinic butyl ester

Article abstract of DOI:10.1016/S0040-4039(01)00753-5

A short and efficient access to the naturally occurring amino acid galantinic acid is reported using two highly diastereoselective reactions, namely a vinylogous Mukaiyama reaction and a 1,3-hydroxy directed Evans reduction.

Full text of DOI:10.1016/S0040-4039(01)00753-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4467–4469
A straightforward enantiospecific synthesis of N-(Z)-galantinic
butyl ester
Xavier Moreau and Jean-Marc Campagne*
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 9 April 2001; revised 2 May 2001; accepted 6 May 2001
Abstract—A short and efficient access to the naturally occurring amino acid galantinic acid is reported using two highly
diastereoselective reactions, namely a vinylogous Mukaiyama reaction and a 1,3-hydroxy directed Evans reduction. © 2001
Elsevier Science Ltd. All rights reserved.
The natural amino acid galantinic acid 1 is a key
component of Galantin I, a potent peptide antibiotic
isolated from Bacillus pulvifaciens.1 Due to its original
structure and biological activity, the synthesis of galan-
tinic acid has prompted several reports.2 In connection
withanongoingprojectdirectedtowardsthedevelopment
and applications of vinylogous Mukaiyama-aldol reac-
tions,3 we planned (Scheme 1) to construct the galantinic
acid carbon skeleton using a Lewis acid catalyzed aceto-
acetate aldol-type reaction4–6 on a protected serinal 2. The
C5(OH)ꢀC6(NH) syn relationship was expected to be
fixed during this step through chelation control.7
The reaction of known8 serinal aldehyde 2a (R1=
TBDMS, R2=Z) with dienolate 3,9 in the presence of 10%
of Eu(fod)3 led to the formation of the vinylogous aldol
product 4 with a good (9:1) diastereoselectivity.10 After
purification by flash chromatography, compound 411 was
isolated in 60% yield, and >98:2 diastereoselectivity
(Scheme 2).
O
R1O
H
NH
OH
O
O
R2
OH OH
O
7
HO
OH
2
HO
OH
1
NH2
NH2
OR3 OR4
OTMS
(-)-Galantinic Acid 1
Scheme 1.
Eu(fod)3 10%
DCM
O°C -> r. t. overnight
OH
O
O
O
O
O
TBDMSO
O
TBDMSO
H
OTMS
NHZ
NHZ
60%
2a
3
4
Scheme 2.
* Corresponding author. E-mail: jean-marc.campagne@icsn.cnrs-gif.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00753-5

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X. Moreau, J.-M. Campagne / Tetrahedron Letters 42 (2001) 4467–4469
1) nBuOH reflux
2) TBAF
3) 2,2 dimethoxypropane
OH
O
O
O
O
O
PPTS
COOnBu
TBDMSO
O
NHZ
NHZ
4
5
BuO2C
O
O
NHZ
H
Me
O
H
Me
H
H
Scheme 3.
n-butanol
reflux
OH
O
O
OH
O
O
6
TBDMSO
56%
OnBu
TBDMSO
O
NHZ
NHZ
4
NaHB(OAc)3
CH3CN/AcOH
(over 2 steps)
OH OH
O
TBDMSO
OnBu
NHZ
7
Scheme 4.
The expected C5(OH)ꢀC6(NH) syn relationship was
confirmed by conducting a 400 MHz NOESY NMR
experiment on compound 5 (Scheme 3), synthesized in
three steps (30% yield) from 4.
Acknowledgements
The authors are grateful to M.-T. Martin for the
NOESY experiment and to Dr. J. Poncet for the HPLC
determination of diastereoselectivity on compounds 4
and 7.
The C5(OH)ꢀC6(NH) syn relationship thus established,
the dioxinone ring was opened-up6c by refluxing 4 in
butanol at 120°C, to give the keto-alcohol 6. Com-
pound 6 was found to be quite unstable towards purifi-
cation by flash chromatography, and was directly used,
in the next reaction, without purification. Reduction of
the 3,5-keto-alcohol 6, under Evans conditions,2c,12 led
after purification to the galantinic butyl ester 713 in 56%
yield (over two steps) and 98:214 diastereoselectivity
(Scheme 4).
References
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In conclusion, we have developed, starting from pro-
tected serinal 2a, an efficient and short access (three
steps) to galantinic acid, based on two highly
diastereoselective reactions, namely
a
vinylogous
Mukaiyama-aldol reaction and an Evans hydroxy
directed ketone reduction.

X. Moreau, J.-M. Campagne / Tetrahedron Letters 42 (2001) 4467–4469
4469
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11. Compound 4: 1H NMR (CDCl3, 300 MHz): l 7.35 (m,
5H), 5.41 (bd, J=9 Hz, 1H), 5.32 (s, 1H), 5.11 (s, 2H),
4.27 (m, 1H), 3.85 (ꢀd, J=3 Hz, 2H), 3.64 (ꢀd, 1H),
3.34 (s, 1H), 2.4 (m, 2H), 1.67 (s, 6H), 0.88 (s, 9H), 0.055
and 0.048 (2s, 6H); 13C NMR (CDCl3, 300 MHz): l
168.35, 160.35, 156.32, 136.20, 128.52, 128.20, 128.05,
106.55, 95.26, 69.69, 66.96, 65.71, 54.11, 38.44, 25.70,
25.23, 24.66, 18.05, −5.50; IR (CHCl3): 3684, 3012, 1718,
1521, 1237, 793 cm−1; MS (ESI, %): 518 (M+K+) (68), 502
(M+Na+) (100), 485.5 (12), 443 (25), 242 (33); [h]2D5=1.64
(c 0.7, CHCl3). Anal. calcd for C24H37NO7Si: C, 60.10;
H, 7.78; N, 2.92. Found: C, 59.84; H, 7.76; N, 3.01.
12. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am.
Chem. Soc. 1988, 110, 3560–3578.
13. Compound 7: 1H NMR (CDCl3, 300 MHz): l 7.35 (m,
5H), 5.44 (bd, J=9.0 Hz, 1H), 5.1 (bs, 2H), 4.3 (m, 2H),
4.1 (t, J=6.6 Hz, 2H), 3.86 (bs, 2H), 3.6 (ꢀd, J=8.8 Hz,
1H), 2.48 (bd, J=6.0 Hz, 2H), 1.75–1.50 (m, 4H), 1.40
(m, 2H), 0.95 (t, J=7.3 Hz, 3H), 0.88 (s, 9H), 0.055 and
0.042 (2s, 6H); 13C NMR (CDCl3, 300 MHz): l 173.15,
156.74, 136.71, 128.77, 128.38, 128.30, 69.83, 67.07, 66.36,
65.39, 64.89, 55.14, 41.62, 40.16, 30.81, 26.00, 19.34,
18.36, 13.91, −5.40; IR (CHCl3): 3441, 1723 cm−1; MS
(ESI, %): 536 (30), 520 (M+Na+) (100), 498 (M+H+) (30),
236 (30); [h]2D5=+15.45 (c 1.1, CHCl3). Anal. calcd for
C25H43NO7Si: C, 60.33; H, 8.71; N, 2.81. Found: C,
60.56; H, 8.91; N, 2.66.
14. On the crude material, the diastereoselectivity was found
(HPLC: Ultrasphere 250×4.6 mm; iPrOH/cyclohexane
1.5/98.5; 1 ml/min) to be 88:12, by comparison with a
43:57 sample obtained by a non-diastereoselective reduc-
tion using NaBH4 in THF.
.