Convenient synthesis of (3S,5S)-5-hydroxy- and (3R,5S)-5-chloropiperazic acids of a peptide antibiotic, monamycin G3

Article abstract of DOI:10.1246/cl.2001.1172

Convenient synthesis of (3S,5S)-5-hydroxy- and (3R,5S)-5-chloropiperazic acids, which are the important constituting moieties of an antibiotic monamycin G₃, and their possible stereoisomers constructing of similar antibiotics was achieved from

Full text of DOI:10.1246/cl.2001.1172

1172
Chemistry Letters 2001
Convenient Synthesis of (3S,5S)-5-Hydroxy- and
(3R,5S)-5-Chloropiperazic Acids of a Peptide Antibiotic, Monamycin G3
Reiko Ushiyama, Yasuchika Yonezawa, and Chung-gi Shin*
Laboratory of Organic Chemistry, Faculty of Technology, Kanagawa University, Kanagawa-ku, Yokohama 221-8686
(Received August 27, 2001; CL-010832)
Convenient synthesis of (3S,5S)-5-hydroxy- and (3R,5S)-5-
(LDA) in THF was followed by substitution with DBAD in
CH2Cl2 at –78 °C. As a result, the expected (2S)-[1,2- bis(N-
Boc)hydrazino]-(4R)-(O-TPS)methyl-γ-butyrolactone
[(2S,4R)-7a]7 and a small amount of 7d were obtained in 77%
yield in a 93:7 ratio. The obtained (2S,4R)-7a could be com-
pletely purified on a silica-gel column using a mixture of hexa-
ne and EtOAc (4:1 v/v). On the other hand, in the case of
smaller O-t-butyldimethylsiloxy(TBS) hydroxymethyl deriv-
ative 6, the difference in the formation ratio between the
obtained (2S,4R)-8a and (2R,4R)-8d appreciably decreased to
66:34. Accordingly, the diastereoselective substitution could be
conformed to take place apparently by the effect of the steric
hindrance of the bulky protecting group of the (S)-4-hydroxy-
methyl group, as shown in Scheme 1.
chloropiperazic acids, which are the important constituting moi-
eties of an antibiotic monamycin G3, and their possible
stereoisomers constructing of similar antibiotics was achieved
from D- and L-glutamic acids in short steps.
An antibiotic monamycin G3 (1),1 isolated from the culture
of Streptomyces jamaicensis, has a unique cyclic depsihexa-
peptide structure containing two kinds of (3S,5S)-5-hydroxy
(2b)- and (3R,5S)-5-chloropiperazic acid (3c) residues, as
shown in Figure 1.
So far, various synthetic methods for the protected 5-
hydroxypiperazic acid [protected Fragment A: (P)-2b], except
for the 5-chloro derivative [protected Fragment B: (P)-3c],
have been already reported. However, the methods have
required not only many steps but also the Evans chiral auxiliary
group in the diastereoselective substitution of an appropriate
substrate, derived from D-mannitol, D-glutamic acid (Glu) or 5-
bromovaleryl chloride, with di-tert-butyl azodicarboxylate
(DBAD).2–4 Similarly to the above case, we (C. S.) have also
reported the synthesis of (3S)- and (3R)-tetrahydropyridazic
acid derivative by the reaction of dimethoxybutanoic acid with
DBAD by the Evans method.5
In connection with the total synthesis of 1, an efficient syn-
thetic method for the important two constructing moeties, 2b
and 3c, was investigated. Herein, we would like to report a
convenient synthesis of the protected 2b [(P)-2b], 3c [(P)-3c],
and their possible stereoisomers, (3S,5R)-2a, (3R,5S)-2c,
(3R,5R)-2d, and (3R,5R)-3d derivatives from D- and L-Glu in
short steps without using the Evans auxiliary group.
Furthermore, deprotection of the TPS group of (2S,4R)-7a
(R = TPS) with t-butylammonium fluoride (TBAF), followed
by successive mesylation with methanesulfonyl chloride
(MsCl), treatment with NaH and then hydrolysis with 1 M
LiOH gave 1,2-bis(N-Boc)-(3S,5R)-5-hydroxypiperazic acid
(9a). Subsequent esterification of 9a with MeI in the presence
of KHCO3 gave the corresponding methyl ester (10a), the
hydroxy group of which was then acetylated with acetic anhy-
dride to give the corresponding (3S,5R)-5-O-acetyl derivative
(P)-2a.8 On the other hand, the inversion and acetylation of the
5-hydroxy group of 10a with trifluoromethanesulfonic anhy-
dride (Tf2O) and 4-(dimethylamino)pyridine (DMAP) and then
with CH3COOCs in the presence of 18-crown-6-ether was per-
formed to give the expected (3S,5S)-5-acetoxy derivative (P)-
2b,9 as shown in Scheme 2.
Quite similarly to the above case, the protected methyl
(3R,5S)-5-hydroxypiperazinoate (10c) and its 5-acetoxy deriva-
tives of two stereoisomers (P)-2c and (P)-2d were also readily
synthesized from L-Glu.
To examine and determine the configurational structure of
the synthesized (P)-2b, comparison was made with the (3S,5S)-
2-acetyl-1-(2,4-dinitrophenyl)-5-hydroxypiperazic acid lactone
12,4 derived by reaction of the naturally occurring 2b with 2,4-
First of all, (S)-(–)-γ-hydroxymethyl-γ-butyrolactone (4)6
as the starting material was prepared from D-Glu. Subsequent
protection of the hydroxy group of 4 with t-butyldiphenylsilyl
chloride (TPS–Cl) in the presence of imidazole gave the corre-
sponding 5-(O-TPS)methyl derivative 5. To introduce a 1,2-
bis(N-Boc)hydrazino group (Boc = t-butoxycarbonyl) to the 2-
position of 5, usual lithiation with lithium diisopropylamide
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
1173
In conclusion, it is noteworthy that a convenient synthesis
of the possible stereoisomers of 5-hydroxy- and 5-chloropiper-
azic acids was achieved in short steps by the new method and
this synthetic method is applicable to the synthesis of various
similar 5-substituted derivatives.
This work was partly supported by “High-Tech Research
Project” from the Ministry of Education, Culture, Sports,
Science and Technology.
References and Notes
1
a) K. Bevan, J. Davies, C. Hassall, R. Morton, and D. Phillips, J.
Chem. Soc. C, 1971, 514; b) C. Hassall, Y. Ogihara, and W.
Thomas, J. Chem. Soc. C, 1971, 522; c) C. Hassall, R. Morton, Y.
Ogihara, and D. Phillips, J. Chem. Soc. C, 1971, 526; d) C.
Hassall, W. Thomas, and M. Moschidis, J. Chem. Soc., Perkin 1,
1977, 2369.
2
3
4
K. Hale, N. Jogiya, and S. Manaviazar, Tetrahedron Lett., 39,
1763 (1998).
T. Kamenecka and S. Danishefsky, Angew. Chem. Int. Ed., 37,
2995 (1998).
K. Depew, T. Kamenecka, and S. Danishefsky, Tetrahedron Lett.,
41, 289 (2000).
Y. Nakamura and C. Shin, Chem. Lett., 1991, 1953.
M. Taniguchi, K. Koga, and S. Yamada, Tetrahedron, 30, 3547
(1974).
dinitrophenyl fluoride (DNP-F). That is, deprotection of the
Boc group of (P)-2b with trifluoroacetic acid (TFA) and then N-
arylation with DNP-F in the presence of Et3N gave the corre-
sponding 1-(N-DNP) piperazine derivative 11. Subsequent lac-
tone ring formation by the hydrolyses of both the methyl ester
and acetoxy group of 11 with 1 M LiOH and then again acetyla-
tion with Ac2O gave the expected 12,10 as shown in Scheme 3.
5
6
7
(3S,5R)-7a: Colorless crystals. Mp 58.0–59.5 °C. [α]D26 –25.6° (c
1.00, MeOH). IR(KBr) 3403, 2976, 2933, 2361, 1785, 1716 cm–1.
1H NMR (CDCl3) δ = 1.07(s, 9H, TPS’s t-Bu), 1.46 and 1.47(each
s, 18H, Boc × 2), 2.45–2.62 (m, 2H, H-4), 3.65 and 3.87 (each dd,
2H, H-6, J = 3.0, 11.5 Hz), 4.58 (d, 1H, H-5, J = 8.5 Hz), 5.14 (br
s, 1H, H-3), 6.50 (br s, 1H, NH), 7.34–7.44 and 7.59–7.70 (each
m, 10H, TPS’s Ph × 2).
26
8
9
(P)-2a: Colorless needles. Mp 100.0–103.0 °C. [α]D +11.4° (c
1
1.06, MeOH). IR(KBr) 3445, 2977, 2930, 1692 cm–1. H NMR
(DMSO-d6) δ = 1.52 (s, 18H, Boc × 2), 1.99 (s, 3H, Ac) , 2.03–2.14
(m, 1H, H-4 ax), 2.40 (dd, 1H, H-4 eq, J = 1.4, 14.6 Hz), 3.08–3.10
(m, 1H, H-6 ax), 3.76 (s, 3H, Me), 4.19 (br d, 1H, H-6 eq, J = 13.8
Hz), 4.89 (br s, 1H, H-5), 4.96 (d, 1H, H-3, J = 6.8 Hz).
As a result, the spectral data (IR and 1H NMR) and the spe-
cific rotation of the synthesized 12 {[α]D +380° (c 0.09, diox-
ane)} were completely identical with those {[α]D +380° (c 0.06,
dioxane)} derived from the natural product 2b.1c
(P)-2b: Colorless needles. Mp 96.0–98.5 °C. [α]D26 –5.9° (c 1.08,
MeOH). IR(KBr) 3444, 2981, 2360, 1739, 1713, 1648, 1539 cm–1.
1H NMR (DMSO-d6) δ = 1.32 and 1.39 (each s, 18H, Boc × 2),
1.81 (s, 3H, Ac), 1.99 (ddd, 1H, H-4 eq, J = 3.0, 6.5, 14.8 Hz),
2.26 (br d,1H, H-4 ax, J = 14.5 Hz), 2.91 and 3.05 (each d, 1H, H-
6 ax, J = each 14.5 Hz), 3.60 (s, 3H, OMe), 3.97–4.05 (m, 1H, H-6
eq), 4.67–4.85 (m, 2H, H-3 and H-5).
Furthermore, another important constructing component,
(3R,5S)-5-chloropiperazic acid (P)-3c,11 was also readily syn-
thesized by substitution of the hydroxy group of 13, which was
derived from 10c, with N-chlorosuccinimide (NCS) and Ph3P in
CH2Cl2.12 On the other hand, (3R,5R)-5-chloro derivative (P)-
3d13 was also obtained by SN2 reaction of 13 with Ph3P in a
mixture of CCl4 and MeCN, by the method reported by Hale,2
as shown in Scheme 4.
10 12: Yellow syrup. [α]D20 +380° (c 0.09, dioxane). 1H NMR δ = 2.14
(s, 3H, Ac), 2.26 (d, 1H, H-4 ax, J = 12.4 Hz), 2.46–2.54 (m, 1H, H-
4 eq), 3.16 (dd, 1H, H-6 eq, J = 3.2, 13.5 Hz), 3.83 (d, 1H, H-6 eq, J
= 13.2 Hz), 5.00 (t, 1H, H-5, J = 4.3 Hz), 5.20 (d, 1H, H-3, J = 3.5
Hz), 7.55 (d, 1H, DNP’s Ph-6, J = 9.7 Hz), 8.34 (dd, 1H, DNP’s Ph-
5, J = 2.7, 9.7 Hz), 8.77 (d, 1H, DNP’s Ph-4, J = 2.7 Hz).
11 (P)-3c: Colorless syrup. [α]D26–29.3° (c 0.14, MeOH). IR(KBr)
2979, 2932, 2361, 1738, 1709 cm–1 1H NMR (DMSO-d6) δ =
.
1.40 and 1.45 (each s, 18H, Boc × 2), 1.89 (ddd, 1H, H-4 ax, J =
5.9, 10.7, 13.8 Hz), 2.44 (br s, 1H, H-4 eq), 2.88 (dd, 1H, H-6 ax,
J = 9.9, 12.6 Hz), 3.68 (s, 3H, OMe), 4.31 (ddd, 1H, H-6 eq, J =
3.5, 5.7, 10.3 Hz), 4.41 (dt, 1H, H-5, J = 5.7, 10.3 Hz), 5.00 (dd,
1H, H-3, J = 2.7, 5.9 Hz).
12 A. Kozikowski and J. Lee, Tetrahedron. Lett., 29, 3053 (1988).
26
13 (P)-3d: Colorless syrup. [α]D –47.0° (c 0.99, MeOH). IR(KBr)
2979, 2932, 2361, 1738, 1709 cm–1 1H NMR (DMSO-d6) δ =
.
1.39 and 1.44 (each s, 18H, Boc × 2), 1.88 (ddd, 1H, H-4 ax, J =
6.0, 11.0, 13.5 Hz), 2.44 (br d, 1H, H-4 eq, J = 13. 5Hz), 2.87 (t,
1H, H-6 ax, J = 11.0 Hz), 3.67 (s, 3H, OMe), 4.30 (dd, 1H, H-6
eq, J = 4.5, 12.8 Hz), 4.40 (ddd, 1H, H-5, J = 4.5, 11.0, 15.4 Hz),
4.99 (d, 1H, H-3, J = 3.5 Hz).