Asymmetric synthesis of differentially protected meso-2,6-diaminopimelic acid

Article abstract of DOI:10.1016/S0040-4039(02)01844-0

meso-2,6-Diaminopimelic acid, an important linking component of bacterial cell walls and a biosynthetic precursor of L-lysine has been prepared differentially protected in a stereospecific manner from both L-aspartic and L-glutamic acid. The key step to establish the second chiral center involves the asymmetric reduction of a pyruvate moiety with Alpine-Borane. S-2-Amino-6-oxopimelic acid, the hydrolyzed open chain form of tetrahydrodipicolinic acid, a biosynthetic precursor of meso-2,6-diaminopimelic acid, was also prepared via deprotection of the key pyruvate intermediate.

Full text of DOI:10.1016/S0040-4039(02)01844-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7679–7682
Asymmetric synthesis of differentially protected
meso-2,6-diaminopimelic acid
John L. Roberts* and Cecil Chan
Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Nutley, NJ 07110, USA
Received 6 August 2002; accepted 30 August 2002
Abstract—meso-2,6-Diaminopimelic acid, an important linking component of bacterial cell walls and a biosynthetic precursor of
L
-lysine has been prepared differentially protected in a stereospecific manner from both L-aspartic and L-glutamic acid. The key
step to establish the second chiral center involves the asymmetric reduction of a pyruvate moiety with Alpine-Borane®.
S-2-Amino-6-oxopimelic acid, the hydrolyzed open chain form of tetrahydrodipicolinic acid, a biosynthetic precursor of
meso-2,6-diaminopimelic acid, was also prepared via deprotection of the key pyruvate intermediate. © 2002 Elsevier Science Ltd.
All rights reserved.
2,6-Diaminopimelic acid (DAP) is a naturally occurring
amino acid found in both bacteria and higher plants. It
is a symmetrical a,a%-diaminodicarboxylic acid and can
therefore exist in three stereoisomeric forms. meso-DAP
serves as the final precursor in the biosynthesis of
the DAP biosynthetic pathway. Since DAP is not a
constituent of animal tissue and the DAP biosynthetic
pathway is absent in mammals, then inhibitors of the
diaminopimelate pathway have a good chance of dis-
playing low toxicity toward the mammalian host.
Therefore inhibition of either DAP biosynthesis or its
utilization affords an attractive target for antibacterial
chemotherapy.
L
-lysine in both bacteria and higher plants1 and is also
an essential component of the peptidoglycan of most
pathogenic bacteria (nearly all Gram-negative and most
Gram-positive bacteria with the notable exception of
Staphylococcus aureus where it is replaced by lysine).2 It
is involved as the nucleophilic component in the key
peptide cross-linking step between two adjacent glycan
strains. This is one of the final steps in peptidoglycan
biosynthesis and not only defines the two- and three-
dimensional structural array of the cell wall but also
imparts structural rigidity and strength to it. In Gram-
negative bacteria DAP serves the additional function of
anchoring the outer membrane to the cell wall via the
Braun lipoprotein.2 Both LL-DAP and meso-DAP are
also components of a number of immunostimulants
derived from bacterial cell wall substructures.3
The development of inhibitors of the DAP pathway
requires the stereoselective synthesis of analogs and
derivatives of DAP. In spite of the apparent simplicity
of this amino acid, it is only in recent years that
stereochemically unambiguous syntheses of meso-DAP
or L,L-DAP and their analogs have been reported in the
published literature.5–11 The establishment of the requi-
site chiral centers in these syntheses fall into three
general categories; the use of chiral auxiliaries, the
coupling of two fragments derived from the chiral pool,
or the asymmetric reduction of an intermediate with
one chiral center already established. The latter is exem-
plified by a number of stereoselective syntheses7b,8,9 of
differentially protected meso-DAP, involving the cata-
lytic asymmetric reduction of an amino-acrylate inter-
The DAP biosynthetic pathway has been well eluci-
dated in Escherichia coli.4 In this aspartate-derived
biosynthetic pathway, L,L-DAP is converted to meso-
mediate derived from L-glutamic acid. In this paper we
DAP by the action of diaminopimelate epimerase.
Because of its pivotal role in bacterial cell wall biosyn-
thesis and function and the fact that meso-DAP is the
precursor to the essential amino acid lysine, much
interest has been generated in regulating or inhibiting
describe our complementary approach to the asymmet-
ric synthesis of differentiated meso-DAP and related
compounds.
Conceptually, the approach we describe utilizes one
chiral center from the ‘chiral pool’ in the form of either
aspartic acid (Scheme 1) or glutamic acid (Scheme 2),
and introduces the other chiral center via Alpine-
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01844-0

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J. L. Roberts, C. Chan / Tetrahedron Letters 43 (2002) 7679–7682
Scheme 1. (a) BOC2O, CH2Cl2, cat. DMAP, 95%; (b) BOC2O, 1 equiv. DMAP, CH3CN, 24 h, 90%; (c) 10% PdꢀC, H2, CH3OH,
100%; (d) BH3·(CH3)2S, THF, 100%; (e) CrO3·(Py)2, CH2Cl2, 85%; (f) 4, K2CO3, DMF, 92%; (g) 10% PdꢀC, H2O–HOAc (1:9),
45%; (h) CrO3·(Py)2, CH2Cl2, 65%.
Scheme 2. (a) BOC2O, Et3N, CH2Cl2, 93%; (b) BOC2O, 1 equiv. DMAP, CH3CN, 24 h, 94%; (c) 10% PdꢀC, H2, THF, 100%;
(d) BH3·(CH3)2S, THF, 100%; (e) PCC, CH2Cl2, Celite, 85%; (f) 11, LiHMDS, THF, −78°C, 86%; (g) Zn, HOAc, Et2O, +10°C,
90%.
Borane®12 reduction on the keto-moiety of a pyruvate
ester11b (Scheme 3).
groups was adopted to permit the use of the more
convenient diborane reduction sequence (rather than a
borohydride reduction of the mixed anhydride that is
used when only mono-BOC protection is used). In
addition the mono-BOC protected aldehydes corre-
sponding to aldehydes 3 and 10, are relatively unstable,
with the C5 series rapidly cyclizing to the aminal which
is then often reluctant to undergo further reactions.
Aldehydes 3 and 10 on the other hand are relatively
stable and can be stored in the freezer for months
without any loss of reactivity.
As shown in Scheme 1, the readily available aspartate
diester, 1, was treated with di-t-butyldicarbonate to
form the mono-t-BOC protected derivative and a sec-
ond t-BOC protecting group was then introduced
under more forcing conditions (t-BOC2O, 1 equiv.
DMAP, CH3CN, rt, 24 h, 90%). Removal of the C-4
benzyl-protecting group by catalytic hydrogenation
afforded the acid 2 in an overall yield of 86% from 1.
The acid, 2 was then converted to the aldehyde, 3, via
the corresponding alcohol, in a routine two step reduc-
tion–oxidation sequence. Application of this same
chemistry to the glutamic acid series (Scheme 2)
afforded the corresponding C5-aldehyde, 10, in an over-
all yield of 74% from 8. Protection with two BOC
Condensation of the aldehyde 3, with the stabilized
phosphorane three carbon synthon, 4,13 afforded the
corresponding unsaturated oxime ester, 5, in a 92%
yield. This compound served as a versatile intermediate
to a variety of DAP analogs, since one can selectively

J. L. Roberts, C. Chan / Tetrahedron Letters 43 (2002) 7679–7682
7681
Scheme 3. (a) R-(+)-Alpine-Borane® (14), made in situ from R-(+)-a-pinene and 9-BBN, CH2Cl2, 86%, S:R=94:6; (b) MsCl, Py,
1 equiv. DMAP, CH2Cl2, 100%; (c) NaN3, DMF, 100%; (d) 10% PdꢀC, H2, 100%, R:S=93:7; (e) 2.5N HCl, D, 100%.
reduce the oxime and the olefinic moieties.13 Hydro-
genation of 5 in aqueous acetic acid, afforded the
corresponding hydroxy ester, 6, in 45% yield which was
then oxidized to the pyruval ester, 7 in 60% yield
(conditions for these two steps were not optimized). In
a complimentary approach depicted in Scheme 2, the
Another useful application of this chemistry has been
its application to the synthesis of a number of sub-
strates for the enzymes of the DAP biosynthetic path-
way. Tetrahydrodipicolinic acid, 20, the natural
substrate for the succinyl-transferase in the DAP path-
way has not been available optically active and is rather
unstable in aqueous solution.16 A form of tetra-
hydrodipicolinic acid that can be isolated and charac-
terized was required to help set up an assay for the
reductase and succinylase enzymes. Hydrolysis of 7
with 1N NaOH in THF afforded the corresponding
pyruvic acid analog, 21, which was deprotected under
anhydrous conditions to afford the stable amino pyru-
vate 22 as the TFA salt (Scheme 4). On dissolution in
assay buffer, 22 establishes an equilibrium mixture con-
taining the open form (22) and the ring closed tetra-
hydrodipicolinic acid, 20 (via 23).
C5 aldehyde, 10 underwent
a
facile Horner–
Wadsworth–Emmons reaction with the trichlorobutyl-
oxycarbonyl(TCBOC)-protected oxygenated phos-
phonate, 11,14 to afford the enol ester 12, in an 86%
yield with an E:Z ratio of 8:1. Reductive elimination of
the TCBOC protecting group with zinc dust in a dilute
solution of acetic acid in ether, unmasked the pyruval
ester function to give 13, the corresponding t-butyl
ester analog of 7.
Treatment of the pyruval ester 7 with R-(+)-Alpine-
Borane®, 14,12 afforded the desired S-hydroxy ester, 15
[S:R=94:6]. The stereochemical outcome of this reduc-
tion was determined by 19F NMR analysis of the
Mosher esters15 of 15 in comparison to the correspond-
ing diastereomeric mixture of Mosher esters from 6.
The alcohol was converted to the corresponding R-
azido ester, 17 (via the mesylate, 16), and then con-
verted to the corresponding R-amino ester, 18
[R:S=93:7] by catalytic hydrogenation. The stereo-
chemical outcome of the sequence was determined by
19F NMR analysis of the corresponding Mosher
amides.15 Protection of the free amino group in 18 as
the Cbz followed by selective removal of the two BOC
groups from the amine at the other end of the pimelic
acid chain afforded 19. This compound was utilized for
Mosher amide determination of the stereochemical
integrity of the other chiral center in the molecule. 19F
NMR analysis showed that no racemization had
occurred at this center for any step during the entire
synthetic sequence.
In summary, this synthesis provides a flexible, stereo-
selective route for the preparation of differentially
protected meso-DAP and analogs. The approach, in
principle also allows for the preparation of the corre-
sponding
D,D- or L,L-DAP isomers and analogs
depending on the choice of starting amino acid [L or D]
and the Alpine-Borane® [R or S] used. Furthermore,
the procedure provides a variety of versatile intermedi-
ates amenable for further elaboration.

7682
J. L. Roberts, C. Chan / Tetrahedron Letters 43 (2002) 7679–7682
Scheme 4. (a) 1N NaOH, aqueous THF, 100%; (b) TFA, CH2Cl2, 100%.
Holcomb, R. C.; Schow, S.; Ayral-Kaloustian, S.; Powell,
D. Tetrahedron Lett. 1994, 35, 7005.
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