Stereoselective total synthesis of (-)-galantinic acid

Article abstract of DOI:10.1055/s-2006-941602

A concise, practical and stereoselective total synthesis of galantinic acid, constituent of the peptide antibiotic galantin, is reported. The title compound is obtained in six steps via Heathcock-Claisen condensation, Evans reduction and deprotection in 1

Full text of DOI:10.1055/s-2006-941602

1580
LETTER
Stereoselective Total Synthesis of (–)-Galantinic Acid
S
tereoselective To
a
tal Synthesi
n
s
of
G
alantin
n
ic
A
cid Bethuel, Karl Gademann*
Laboratorium für Organische Chemie, ETH Zürich, 8093 Zürich, Switzerland
Fax +41(44)6321328; E-mail: gademann@org.chem.ethz.ch
Received 2 March 2006
peptide synthetase and polyketide synthase enzymes.
Therefore, several syntheses of 1 were reported so far.2,5
All these routes, however, display limitations such as
length (12–18 steps),6 impracticability or use of expensive
Abstract: A concise, practical and stereoselective total synthesis of
galantinic acid, constituent of the peptide antibiotic galantin, is re-
ported. The title compound is obtained in six steps via Heathcock–
Claisen condensation, Evans reduction and deprotection in 10%
overall yield from protected serine. The route described herein thus reagents. We report in this letter a simple, short and effi-
constitutes the shortest and most efficient procedure for the prepa-
ration of the title compound disclosed so far.
cient route to (–)–galantinic acid (1), which favorably
compares to earlier approaches.
Key words: amino acids, antibiotics, natural products, peptides,
The synthesis started from the b-hydroxy-g-amino acid 5,
polyketides
which is readily prepared on a 20 g scale starting from
protected serine 4, which is commercially available
(Scheme 1).7 A Claisen condensation using the procedure
Galantinic acid (1) was first isolated as a degradation
of Heathcock8 employing six equivalents of lithiated tert-
product of the peptide antibiotic galantin I (3), obtained
butyl acetate gave the hydroxyketoester 6 in 75% yield.9
from fermentation of Bacillus pulvifaciens.1 The original-
This transformation is remarkable, as the dianion resulting
from deprotonation of the acidic NH and OH protons is
soluble and reactive towards the enolate. In situ trapping
of the resulting keto ester allowed for a high yielding ac-
ly proposed structure 2 of galantinic acid1 was later shown
to be incorrect by total synthesis and was revised to 1
(Figure 1).2 It is interesting to note that although many b-
hydroxy-g-amino acids are constituents of natural prod-
cess to this intermediate 6 in only three steps starting from
ucts with potent biological activity such as didemnin3a or
protected serine 4. As noted earlier by Heathcock,8 we
found that the use of an excess of the enolate lead to sig-
nificantly higher yields. The keto ester 6 is then reduced
dolastatin 10,3b the corresponding e-amino acids resulting
from an additional insertion of an acetate unit are much
less frequently observed.4 Galantinic acid (1) is consid-
by directed hydride delivery following the method of
ered an interesting target for synthesis, due to its biologi-
Evans and coworkers10 to give the anti 3,5-diol 7 in high
cal activity and the highly functionalized C7 framework.
stereoselectivity (>95:5).11 The carbamate-protected
Moreover, 1 can be considered of interesting biosynthetic
amine adjacent to the directing OH group is fully com-
patible with the reaction conditions and deterred neither
origin, as its bioproduction likely involves non-ribosomal
H
OH OH
O
H2N
HO
O
H
O
HO
OH
OH
NH2
galantinic acid (1)
revised structure
originally proposed structure 2
H2N
OH OH
O
Me
O
OH
OH
H
H
N
H2N
N
N
N
O
H
H
NH2
OH
O
O
HO
NH2
NH
O
galantin I (3)
HN
NH
O
Me
H
H2N
N
N
H
Figure 1
SYNLETT 2006, No. 10, pp 1580–1582
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-941602; Art ID: G08206ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Total Synthesis of Galantinic Acid
1581
OLi
1. i. carbonyldiimidazole
ii. KO2CCH2CO2Me,
MgCl2, 74%
O
O
OH
O
6 equiv
BnO
BnO
OH
BnO
OMe
2. NaBH4, Et2O, (90%,
dr 1.2:1), 42% after
recryst.
THF, 75%
NH
NH
Z
Z
Z
4
5
OH OH
O
O
OH
O
O
Me4NB(OAc)3H
BnO
O
MeCN, AcOH
81%
NH
NH
6
Z
7
OH OH
O
1. H2, Pd/C, MeOH, AcOH
HO
OH
2. CH2Cl2, CF3CO2H
50 %
NH2
galantinic acid (1)
Scheme 1 Synthesis of galantinic acid (1)
rate nor selectivity. The diol 7 was then deprotected first
by hydrogenolysis, where the addition of acetic acid was
found to be crucial. Without this additive, the OBn group
was found to be unreactive. The conditions for the
cleavage of the tert-butyl ester also needed to be carefully
evaluated, as exposure to mineral acids such as HCl or
prolonged reaction times resulted in significant amounts
of the galantinic acid d-lactone. Short treatment with
trifluoroacetic acid gave, after purification on Dowex®
ion-exchange resin, a sample of (–)-galantinic acid (1), of
which the physical data was found in full agreement with
the published values.2b
References and Notes
(1) Shoji, J.; Sakajaki, R.; Wakisaka, Y.; Koizumi, K.; Mayama,
M.; Matsurra, S. J. J. Antibiot. 1975, 28, 122.
(2) (a) Sakai, N.; Ohfune, Y. Tetrahedron Lett. 1990, 29, 4151.
(b) Sakai, N.; Ohfune, Y. J. Am. Chem. Soc. 1992, 114, 998.
(3) For didemnins, see for example: (a) Rinehart, K. L.; Gloer,
J. B.; Hughes, R. G.; Renis, H. E.; McGovern, J. P.;
Swynenberg, E. B.; Stringfellow, D. A.; Kuentzel, S. L.; Li,
L. H. Science 1981, 211, 933. (b) Dolastatin 10: Pettit, G.
R.; Kamano, Y.; Herald, C. L.; Tuinman, A. A.; Boettner, F.
E.; Kizu, H.; Schmidt, J. M.; Baczynskyj, L.; Tomer, K. B.;
Bontems, R. J. J. Am. Chem. Soc. 1987, 109, 6883.
(4) See, for example: Kondo, S. I.; Akita, E.; Sezaki, M. J.
Antibiot. 1966, 19, 137.
In conclusion, we report a short, stereoselective total syn-
thesis of (–)-galantinic acid (1), constituent of the peptide
antibiotic galantin (3). Key features of our synthesis in-
clude (1) a Claisen condensation according to Heathcock,
(2) directed hydride delivery and (3) a short access to a
complex aminohydroxy acid in just six steps starting from
commercially available, protected serine 4. The route dis-
closed in this letter thus favorably associates both the
number of steps (i.e., 6 vs. 12–18) and overall yield to
previously published procedures for the synthesis of
galantinic acid.6,12 This procedure exemplifies that the
homologation–reduction strategy provides a rapid access
to certain polyacetate structures. Moreover, the prepara-
tion of galantin analogues allowing for structure–activity
relationships as well as the use of this interesting building
block (e.g., for protease inhibitors) can now be envi-
sioned.
(5) (a) Ikota, N. Heterocycles 1991, 31, 521. (b) Kumar, J. S.
R.; Datta, A. Tetrahedron Lett. 1999, 40, 1381.
(c) Kiyooka, S.; Goh, K.; Nakamura, Y.; Takesue, H.; Hena,
M. A. Tetrahedron Lett. 2000, 41, 6599. (d) Moreau, X.;
Campagne, J.-M. Tetrahedron Lett. 2001, 42, 4467.
(e) Raghavan, S.; Reddy, S. R. J. Org. Chem. 2003, 68,
5754. (f) Kumar Pandey, S.; Kandula, S. V.; Kumar, P.
Tetrahedron Lett. 2004, 45, 5877.
(6) For example: ref. 2a, 13 steps from protected serine; ref. 5f,
12 steps from propanediol; ref. 5e, 18 steps from a
propargylic epoxide. Moreau and Campagne obtained a
semi-protected ester derivative of 1 in six steps overall (ref.
5d).
(7) (a) Gademann, K.; Bethuel, Y. Angew. Chem. Int. Ed. 2004,
43, 3327; Angew. Chem. 2004, 116, 3389; there are
numerous methods for the stereoselective preparation of
b-hydroxy-g-amino acids, so-called statins. Reviews:
(b) Javier Sardina, F.; Rapoport, H. Chem. Rev. 1996, 96,
1825. (c) Vera, M. D.; Joullié, M. M. Med. Res. Rev. 2002,
22, 102. (d) See also: Brenner, M.; Seebach, D. Helv. Chim.
Acta 2001, 84, 1181. (e) Jouin, P.; Castro, B.; Nisato, D. J.
Chem. Soc., Perkin Trans. 1 1987, 1177.
Acknowledgment
(8) (a) Hubbs, J. L.; Heathcock, C. H. J. Am. Chem. Soc. 2003,
125, 12836. (b) Earlier works used reduced amounts of
enolate, see, for example: Lynch, J. E.; Volante, R. P.;
Wattley, R. V.; Shinkai, I. Tetrahedron Lett. 1987, 28, 1385.
(9) Preparation and Selected Data for Compound 6:
n-BuLi (1.6 M solution in hexane, 2.90 mL, 4.60 mmol, 6.00
equiv) was added dropwise to a solution of i-Pr2NH (691 mL,
4.90 mmol, 6.40 equiv) in dry THF (2.00 mL) at 0 °C. The
reaction mixture was stirred at this temperature for 10 min
K.G. thanks Prof. Dr. Erick M. Carreira for generous financial sup-
port in the context of his habilitation, as well as the Schweizerischer
Nationalfonds zur Förderung der wissenschaftlichen Forschung
(Grant Nr. 200021-101601/1, PhD fellowship to Y.B.).
Synlett 2006, No. 10, 1580–1582 © Thieme Stuttgart · New York

1582
Y. Bethuel, K. Gademann
LETTER
(11) Preparation and Selected Data for Compound 7.
and then cooled to –78 °C. Then, t-BuOAc (623 mL, 4.60
mmol, 6.00 equiv) was added dropwise and the reaction
mixture was stirred at this temperature for 1 h. The resulting
enolate was cannulated into a solution of (3S,4S)-5-
A solution of 6 (135 mg, 0.290 mmol, 1.00 equiv) in MeCN
(1.50 mL) was cooled to –35 °C and Me4N(OAc)3BH (534
mg, 2.03 mmol, 7.00 equiv) dissolved in MeCN–AcOH
(1.00 mL/1.00 mL) was added. The reaction mixture was
stirred at this temperature for 62 h. It was then warmed to
0 °C and a sat. solution of Na-K tartrate was added. The
solution was stirred at this temperature for 4 h. The phases
were separated and the aqueous phase was extracted three
times with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, filtered and
evaporated under reduced pressure. Flash chromatography
(hexane–EtOAc, 6:4) gave 7 (111 mg, 0.235 mmol, 81%) as
a colorless oil. Rf = 0.38 (EtOAc–hexane, 1:1); [a]D25 +0.35
(c 0.86, CHCl3). 1H NMR (300 MHz, CDCl3): 1.46 (s, 9 H),
1.50–1.60 (m, 1 H), 1.64–1.78 (m, 1 H), 2.39 (d, 2 H, J = 5.6
Hz), 3.43 (m, 1 H), 3.58 (d, 1 H, J = 3.73 Hz), 3.67 (d, 2 H,
J = 4.1 Hz), 3.72 (m, 1 H), 4.18–4.30 (m, 2 H), 4.50 (s, 2 H),
5.10 (s, 2 H), 5.51 (d, 1 H, J = 9.3 Hz), 7.20–7.40 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 28.2, 39.7, 42.3, 54.2, 65.4,
66.8, 68.8, 72.2, 73.6, 81.3, 127.6, 127.8, 127.8, 127.9,
128.0, 128.4, 136.3, 137.3, 156.4, 172.2. IR: 3636–3117 (w),
2977 (w), 1715 (s) cm–1. MS: m/z (%) = 496.2 (41) [M +
Na]+, 440.2 (100) [M – 2H2O + H]+. HRMS (MALDI):
m/z calcd for C26H35NO7Na [M + Na]+: 496.2306; found:
496.2299.
benzyloxy-4-benzyloxycarbonylamino-3-(tert-butyl-
dimethylsilanyloxy)pentanoic acid methyl ester (5, 0.300 g,
775 mmol, 1.00 equiv) in dry THF (2.00 mL) at 0 °C. The
reaction mixture was stirred 1 h at 0 °C, 30 min at r.t. and
then quenched with sat. aq NH4Cl solution and the THF was
evaporated. A mixture of NH4Cl–H2O (1:1) was added and
the solution was extracted 3× with EtOAc. The combined
organic layers were washed with sat. aq NH4Cl solution,
dried over Na2SO4, filtered and evaporated under reduced
pressure. Purification by flash chromatography (EtOAc–
hexane, 1:7) gave 6 (274 mg, 581 mmol, 75% yield) as a
colorless oil. Rf = 0.34 (EtOAc–hexane, 4:6); [a]D25 +0.2 (c
5.22, CHCl3). 1H NMR (300 MHz CDCl3): d = 1.45 (s, 9 H),
2.65 (dd, 1 H, J1 = 4.0 Hz, J2 = 17.7 Hz), 2.79 (dd, 1 H,
J1 = 8.7 Hz, J2 = 17.4 Hz), 3.33 (dd, 1 H, J1 = 2.5 Hz,
J2 = 10.3 Hz), 3.35 (s, 2 H), 3.64 (m, 2 H), 3.76–3.86 (m, 1
H), 4.40–4.48 (m, 1 H), 4.51 (s, 2 H), 5.11 (s, 2 H), 5.39 (d,
1 H, J = 9.3 Hz), 7.28–7.36 (m, 10 H). 13C NMR (75 MHz,
CDCl3): d = 28.0, 28.1, 46.6, 51.1, 53.3, 66.9, 67.3, 67.4,
71.0, 82.2, 127.5, 127.8, 128.3, 128.6, 136.2, 137.4, 156.3,
165.9, 203.0. IR: 3606–3187 (w), 2977 (w), 1744 (m), 1712
(s) cm–1. MS: m/z (%) = 494.2 (17) [M + Na]+, 394.2 (81)
[M – CO2t-Bu + Na]+. HRMS (MALDI): m/z calcd for
C26H33NO7Na [M + Na]: 494.2149; found: 494.2141.
(12) Ref. 5d describes the synthesis of protected galantinic butyl
ester in eight steps from a commercially available serine
derivative. We found that the deprotection of this butyl ester
under basic conditions results in partial decomposition,
epimerization, lactone formation and dehydration. The use
of an acid-labile protecting group such as in the route
presented in this letter thus greatly facilitates deprotection
and thus the preparation of target galantinic acid.
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
Synlett 2006, No. 10, 1580–1582 © Thieme Stuttgart · New York