A straightforward stereoselective synthesis of meso-, (S,S)- and (R,R)-2,6-diaminopimelic acids from cis-1,4-diacetoxycyclohept-2-ene

Article abstract of DOI:10.1016/j.bmcl.2007.07.106

A straightforward synthesis of meso-2,6-diaminopimelic acid (DAP) meso-1 was developed from 1,4-diacetoxycyclohept-2-ene (2) via an oxidative ring cleavage. Subsequently, an enantio-divergent synthesis of (S,S)- and (R,R)-1 was performed using a homochiral monoacetate 7 available from2 by enzymatic desymmetrization.

Full text of DOI:10.1016/j.bmcl.2007.07.106

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5894–5896
A straightforward stereoselective synthesis of meso-, (S,S)-
and (R,R)-2,6-diaminopimelic acids from
cis-1,4-diacetoxycyclohept-2-ene
Yukako Saito, Takumi Shinkai, Yuichi Yoshimura and Hiroki Takahata*
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai 981-8558, Japan
Received 4 July 2007; revised 24 July 2007; accepted 26 July 2007
Available online 26 August 2007
Abstract—A straightforward synthesis of meso-2,6-diaminopimelic acid (DAP) meso-1 was developed from 1,4-diacetoxycyclohept-
2-ene (2) via an oxidative ring cleavage. Subsequently, an enantio-divergent synthesis of (S,S)- and (R,R)-1 was performed using a
homochiral monoacetate 7 available from2 by enzymatic desymmetrization.
Ó 2007 Elsevier Ltd. All rights reserved.
2,6-Diaminopimelic acid (DAP) is a naturally occur-
ring amino acid found in both bacteria and higher
plants. It is a symmetrical a,a0-diaminodicarboxylic
acid and can therefore exist in three stereoisomeric
forms (Fig. 1). meso-DAP and (S,S)-DAP serve as
the precursors in the biosynthesis of L-lysine in both
bacteria and higher plants and meso-DAP is also an
essential component of the peptidoglycan of most
pathogenic bacteria (Fig. 2). Since DAP is not a con-
stituent of animal tissue and the DAP biosynthetic
pathway is absent in mammals, inhibitors of the dia-
minopimelate pathway have a good chance of display-
ing low toxicity toward the mammalian host.
Inhibition of either DAP biosynthesis or its utiliza-
tion, therefore, affords an attractive target for antibac-
a common substrate has not been reported. Herein,
we describe a convenient synthesis of meso-DAP
meso-1 and an enantio-divergent synthesis of (R,R)-,
and (S,S)-DAP as hydrochlorides using 1,4-diacetoxy-
cyclohept-2-ene (2) as a common starting material.
Our simple synthetic approach began with the
RuCl3-catalyzed oxidative cleavage of 1,4-diacetoxy-
cyclohept-2-ene (2),4 which is readily available from
cyclohepta-1,3-diene. Treatment of 2 with catalytic
RuCl3 in the presence of NaIO4 in a solution of
CH3CN, CCl4, and H2O gave the dicarboxylic acid,
which was subjected without isolation to dimethyla-
tion with TMSCHN2 to afford the dimethyl ester 3
in 85% yield. Chemoselective hydrolysis of 3 with
0.1 M sodium methoxide in CH3OH provided the
dihydoxide 4 in 71% yield. The diols of 4 were trans-
formed into diazides in a two-step sequence (i, mesy-
lation; ii, azidation) in 72% yield. The azide 5 was
reduced with Pd(OH)2-catalyzed hydrogenation in the
presence of di-tert-butyl dicarbonate (Boc2O) to give
N-Boc-DAP dimethylester 65 in 83% yield. Finally,
deprotection of 6 with 6 N HCl quantitatively fur-
nished the desired meso-DAP as a hydrochloride,
which displayed spectroscopic properties consistent
with the reported data (Scheme 1).3g,6
terial chemotherapy.1 In addition,
a number of
peptidoglycan fragments featuring the DAP residue
exhibit antitumor, immunostimulant, and sleep-induc-
ing biological activity.2 The development of efficient
routes to the synthesis of DAP stereoisomers and their
analogues has recently been the focus of considerable
attention.3 In general, most of the methodologies de-
scribed for the synthesis of DAP start from either a-
amino acids or chiral glycine templates. In addition,
the synthesis of all three stereoisomers of DAP from
With the process for synthesis of meso-DAP in hand,
we turned our attention to an enantio-divergent syn-
thesis of (R,R)- and (S,S)-DAP from 2. An enzymatic
asymmetrization of meso-diacetate 2 with Novozyme
Keywords: Amino acid; Enzymatic desymmetriztion; Antibacterial
chemotherapy; Peptidoglycan.
*
Corresponding author. Tel./fax: +81 22 727 0144; e-mail:
takahata@tohoku-pharm.ac.jp
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.106

Y. Saito et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5894–5896
5895
HOOC
COOH
NH2
HOOC
COOH
NH2
HOOC
COOH
NH2
S,S)-DAP
S,S)-1
NH2
NH2
NH2
(
(
R,R)-DAP
R,R)-1
(
(
meso-DAP
meso-1
Figure 1. Stereoisomers of diaminopimelic acid (DAP).
435 in phosphate buffer solution gave a single enantio-
mer of monoacetate (1S,4R)-77 in 81% yield (99% ee)
together with the diol 8 (10%). The Mitsunobu reac-
tion of 7 with acetic acid using diisopropyl azodicarb-
oxylate (DIPAD) and triphenylphosphine in THF
furnished C2-symmetric diacetate (1S,4S)-9 in 83%
yield, which was converted into dibenzoate 10 in a
two-step sequence (i, deacetylation; ii, benzoylation).
The ee of 10 was determined to be 99% with chiral
HPLC. Having a homochiral C2-symmetric diacetate
(1S,4S)-9 obtained, an enantio-controlled synthesis of
(R,R)-DAP was accomplished, as shown in Scheme 2
according to a similar procedure described for the syn-
thesis of meso-DAP from 2.8,9
HO
*
OH
O
O
O
O
O
n
NHAc
HO
NHAc
O
HN
O
NH
CO2H
O
HO2C
R
NH
NH
NH
O
O
R'
-ala-meso-DAP-
(MurNAc-GllcNAc)n, R' =
R =
D
D
-glu-
L-ala-
D
-ala
The ultimate goal was the synthesis of (S,S)-DAP.
Treatment of (1S,4R)-7 with pivaloyl chloride in the
presence of pyridine gave pivaloate 13, which was che-
moselectively hydrolyzed to provide the monoester 14
in a two-step 96% yield. The Mitsunobu inversion of
14 afforded trans-diacylate 15 (95%), which was quanti-
Figure 2. Peptidoglycan of a bacterial cell wall.
H3COOC
a,b
COOCH3
OAc
c
AcO
OAc
tatively transformed into
a homochiral diacetate
OAc
71%
85%
(1R,4R)-9 via a C2-symmetric diol in a two-step
sequence (i, reductive deprotection with LiAlH4; ii, acet-
ylation). Similarly, (S,S)-DAP10 was obtained from
(1R,4R)-9 as described in Scheme 3.
3
2
H3COOC
COOCH3
d,e
H3COOC
COOCH3
OH
OH
N3
N3
72%
5
4
In conclusion, a concise synthesis of meso-, (S,S)-, and
(R,R)-2,6-diaminopimelic acids 1 as hydrochlorides
was accomplished from an achiral cis-1,4-diacetoxy-
cyclohept-2-ene (2) as a common educt. This proce-
dure can apply to the synthesis of meso-DAP
homologues such as diaminoadipic acid11 and diami-
nosuberic acid.12 The homochiral monoacetate
(1S,4R)-7 can be used as a building block for prepara-
tion of differently protected DAP analogues13 for
g
f
83%
H3COOC
COOCH3
NHBoc NHBoc
1•HCl
99%
6
Scheme 1. Reagents and conditions: (a) cat. RuCl3, NaIO4,
CCl4AH2OACH3CN; (b) TMSCHN2, CH3OH; (c) 0.1 M NaOCH3,
CH3OH; (d) CH3SO2Cl, pyridine, CH2Cl2; (e) NaN3, DMF; (f) H2,
cat. Pd(OH)2, Boc2O, CH3OH; (g) 6 N HCl.
b
83%
c,d
a
82%
PhOCO
OCOPh
AcO
OAc
)-9
AcO
HO
OH
2
97%
(1S,4S
(1S
,4R)-7
(1S,4
S
)-10
OH
8
g-j
k
(
quant.
e,f
H3COOC
COOCH3
R,R)-1•HCl
H3COOC
COOCH3
(1S,4S)-9
NHBoc NHBoc
12
81%
69%
OAc
OAc
11
i
Scheme 2. Reagents and conditions: (a) Novozyme 435, phosphate buffer; (b) AcOH, PPh3, Pr2OOCN@NCOOiPr2, THF; (c) 0.1 M NaOCH3,
CH3OH; (d) PhCOOH, DCC, DMAP, toluene; (e) cat. RuCl3, NaIO4, CCl4AH2OACH3CN; (f) TMSCHN2, CH3OH; (g) 0.1 M NaOCH3, CH3OH;
(h) CH3SO2Cl, pyridine, CH2Cl2; (i) NaN3, DMF; (j) H2, cat. Pd(OH)2, Boc2O, CH3OH; (k) 6 N HCl.

5896
Y. Saito et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5894–5896
a
b
AcO
OCOC(CH3)3
AcO
OH
)-7
HO
OCOC(CH3)3
96%
from (1
(1S,4R
13
14
S
,4
R
)-7
c
f-l
d,e
AcO
OAc
(S,S)-1•HCl
AcO
OCOC(CH3)3
47%
95%
quant.
15
(1R,4R)-9
Scheme 3. Reagents and conditions: (a) (CH3)3CCOCl, pyridine; (b) 0.1 M NaOCH3, CH3OH; (c) AcOH, PPh3, iPr2OOCN@NCOOiPr2, THF; (d)
LiAlH4, THF; (e) Ac2O, pyridine; (f) cat. RuCl3, NaIO4, CCl4AH2OACH3CN; (g) TMSCHN2, CH3OH; (h) 0.1 M NaOCH3, CH3OH; (i)
CH3SO2Cl, pyridine, CH2Cl2; (j) NaN3, DMF; (k) H2, cat. Pd(OH)2, Boc2O, CH3OH; (l) 6 N HCl.
incorporation into peptides.14 To accomplish this, fur-
Allmendinger, T.; Herold, P.; Moesch, L.; Schaer, H. P.;
Duthaler, R. O. Helv. Chim. Acta 1992, 75, 865 ; (k)
Bouchaudon, J.; Dutruc-Rosset, G.; Farge, D.; James, C.
J. Chem. Soc. Perkin Trans. 1989, 1, 695; (l) Syntheses of
(R,R)-DAP 3c; (m) Williams, R. M.; Yuan, C. J. Org.
Chem. 1992, 57, 6519.
ther studies are in progress.
Acknowledgments
4. Ba¨ckvall, J. E.; Granberg, K. L.; Hopkins, R. B. Acta
Chem. Scand. 1990, 44, 492.
This work was supported, in part, by the High Tech-
nology Research Program from the Ministry of Edu-
cation, Culture, Sports, Sciences, and Technology of
Japan.
´
5. Hernandez, N.; Martın, V. S. J. Org. Chem. 2001, 66,
´
4934.
6. For meso-1. Mp 250–2 °C (dec.); 1H NMR (400 MHz,
D2O) d: 1.40 (1H, m), 1.54 (1H, m), 1.86 (4H, m), 3.95
(2H, t, J = 6.6 Hz). 13C NMR (150 MHz, D2O) d: 21.1,
30.2, 53.6, 173.0.
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23
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23
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23
23
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23
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