Enantioselective synthesis of 2,6-diaminopimelic acid derivatives. Part 3

Article abstract of DOI:10.1016/S0957-4166(02)00126-X

Enantiomerically pure 2,6-diaminopimelic acid derivatives 9a-c and 10a-c have been synthesized starting from the glycine-derived chiral synthon (1′S,1″S)-1. The absolute configuration of stereocenters introduced on 2 and 3 were assigned on the basis of ¹H NMR data and conformational analysis.

Full text of DOI:10.1016/S0957-4166(02)00126-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 497–502
Enantioselective synthesis of 2,6-diaminopimelic acid derivatives.
Part 3†
Francesca Paradisi, Fabio Piccinelli, Gianni Porzi* and Sergio Sandri*
Dipartimento di Chimica ‘G. Ciamician’ Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 12 February 2002; accepted 8 March 2002
Abstract—Enantiomerically pure 2,6-diaminopimelic acid derivatives 9a–c and 10a–c have been synthesized starting from the
glycine-derived chiral synthon (1%S,1¦S)-1. The absolute configuration of stereocenters introduced on 2 and 3 were assigned on the
1
basis of H NMR data and conformational analysis. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(1S,4S)-3, obtained in good yields and diastereomeric
ratio of 7:3, respectively.1
In previous papers1,2 we have described a new stereo-
selective approach to both enantiomers of 2,6-
diaminopimelic (2,6-DAP) and 2,7-diaminosuberic
acids and (S,S)-ortho-phenylene-bis-alanine starting
from the homochiral heterocyclic synthon (1%S,1¦S)-1
already employed by us in the past.
The carbanions of 2 and 3 have been obtained by
employing CH3Li, n-C4H9Li and tert-C4H9Li, metalla-
tion with LHMDS and tert-C4H9OK does not occur.
The alkylation of (1R,4R)-2 occurs almost exclusively
at the bridgehead position giving diastereomers 4a–c in
good yields (entries 1–5 in Table 1), which can be easily
converted into the a-alkyl derivatives of 2,6-DAP 9a–c
(Scheme 1). The intermediates 4d and 8d cannot be
converted into the corresponding bis(a-amino acid)
derivatives because the double bond is not resistant to
the acidic conditions required for hydrolysis.
We aim to synthesize enantiomerically pure structural
analogues of 2,6-DAP because these derivatives have
potential antibacterial and herbicide activity,3 2,6-DAP
being the penultimate intermediate in the biosynthesis
of L-lysine necessary for the growth of Gram positive
and many Gram negative bacteria. Structural analogues
of 2,6-DAP can inhibit the formation or metabolism of
this compound, which lies on the metabolic route to
While the reaction yield is sensitive to the type of base
employed (compare entries 1 and 5), the electrophile
used has no effect on the regioselectivity of the alkyla-
tion (see entries 1–4). In fact, by treating the substrate
(1R,4R)-2 with 1.3 equivalents of base, followed by
addition of methyl iodide, alkylation at the bridgehead
position is accomplished with both CH3Li and n-
C4H9Li in 80 and 65% yield, respectively.
L
-lysine, offering promising biological activity. To this
end, we recently reported a new stereocontrolled syn-
thesis of uncommon tripeptides, which can be regarded
as structural variants of 2,6-DAP, starting from a
mono-lactim ether derived from L
-valine.4
2. Results and discussion
Conversely, with diastereomer (1S,4S)-3, the reaction
exclusively occurs at the competitive benzylic position
of the (S)-N-phenethyl group when 1.3 equivalents of
base is employed. In fact, treatment of the substrate 3
with CH3Li, n-C4H9Li or tert-C4H9Li (entries 6, 10 and
12) provides the alkyl derivatives at the benzylic posi-
tion 6 and 7 in about 40 and 25–30% yields, respec-
tively, the alkylation at the bridgehead not being
observed. Thus, it is reasonable to deduce that for the
diastereomer (1S,4S)-3 the benzylic protons are more
acidic than the bridgehead proton. By employing 2.3 or
Herein, we wish to report an efficient synthesis of
enantiomerically pure bis(a-amino acids) 9 and 10
which can be considered mimics of 2,6-DAP. The syn-
thetic route shown in Scheme 1 is based on the alkyla-
tion of the bicyclic intermediates (1R,4R)-2 and
* Corresponding authors. E-mail: porzi@ciam.unibo.it
† References 1 and 2 are considered to be Parts 1 and 2, respectively.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00126-X

498
F. Paradisi et al. / Tetrahedron: Asymmetry 13 (2002) 497–502
O
CH3
Ph
O
O
CH3
Ph
N
N
Ph
N
Ph
N
H
R
O
CH3
Ph
CH3
O
2
CH3
4a-d
N
Ph
N
O
CH3
O
CH3
Ph
CH3
O
N
Ph
N
N
1
Ph
N
Ph
CH3
H
CH3
O
CH3
O
3
5
O
O
O
CH3
Ph
H3C
N
H3C
N
CH3
Ph
CH3
Ph
C
H
C
N
Ph
N
N
N
Ph
Ph
R
H
C
C
C
H3C
H3C
CH3
CH3
CH3
H3C
O
O
O
8a-c
6
7
NH2
COOH
H2N
R
i
ii,iii
ii,iii
4a,b
4c
HOOC
9a-c
R
NH2
NH2
COOH
i
8a,b
8c
HOOC
10a-c
Scheme 1. R=(a) CH3; (b) CH2Ph; (c) CH2OCH3; (d) CH2CHCH2. Reagents and conditions: (i) 57% HI at reflux; (ii) Na/NH3;
(iii) 6N HCl at reflux.
Table 1. Alkylation of substrates (1R,4R)-2 and (1S,4S)-3 under various conditions
Entry
Substrate
Base (equiv.)
R–X (equiv.)
4 (%)
5 (%)
6 (%)
7 (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
3
3
3
3
3
3
3
CH3Li (1.3)
CH3Li (1.3)
CH3Li (1.3)
CH3Li (1.3)
n-C4H9Li (1.3)
CH3Li (1.3)
CH3Li (2.3)
CH3Li (3.3)
CH3Li (3.3)
n-C4H9Li (1.3)
n-C4H9Li (2.3)
tert-C4H9Li (1.3)
CH3I (1.3)a
80
80
80
75
65
CH2CHCH2Br (1.3)
PhCH2Br (1.3)a
CH3OCH2Br (1.3)a
CH3I (1.3)
CH3I (1.3)
40
30
70
55
35
30
90
25
CH3I (2.3)
30
15
45
CH3I (3.3)b
CH3I (1.3)
9
20
40
10
11
12
CH3I (1.3)
CH3I (2.3)
CH3I (1.3)
10
40
a,b The product from alkylation at both the bridgehead and one benzylic position is recovered in about 10% yielda and 25% yieldb.
3.3 equivalents of CH3Li followed by an equimolar
amount of CH3I (entries 7 and 8), the derivative alkyl-
ated at the bridgehead position 5 is obtained in 30 or
15% yield, respectively; however, in both the cases the
predominant reaction product was 7 in 70 and 55%
yields, respectively. If 3.3 equivalents of CH3Li and 1.3
equivalent of CH3I are used (entry 9), the methyl
derivative 5 is obtained in 45% yield together with both
6 (20% yield) and 7 (35% yield), which are alkylated at
the benzylic position.

F. Paradisi et al. / Tetrahedron: Asymmetry 13 (2002) 497–502
499
The product from alkylation at both the bridgehead
and one benzylic position is recovered in about 10% (a)
and 25% yield (b). It is interesting to emphasize that by
employing 2.3 equivalents of n-C4H9Li, followed by an
equimolar amount of CH3I (entry 11), a strong increase
of derivative 7 is registered (90% yield, along with a
10% yield of 5).
mental evidence, in that CH3Li is the only base which
allows formation of the alkyl derivative at the bridge-
head carbon of diastereomer 3 (entries 7–9 in Table 1).
As a consequence of this reduced stereoaccessibility to
the bridgehead carbon, preferential attack at the ben-
zylic position of the (S)-phenethyl group takes place in
the diastereomer 3.
These findings clearly show that alkylation at the
bridgehead carbon can be easily accomplished on the
substrate (1R,4R)-2, while its diastereomer (1S,4S)-3 is
alkylated preferentially at the benzylic position,5 partic-
ularly when a bulky base is employed.6
Finally, it is interesting to note that the intermediate 7,
in addition to 5, can also be used to obtain the enan-
tiomerically pure a-alkyl derivatives of 2,6-DAP 10a–c.
In fact, the derivative 7 can be further alkylated at the
bridgehead position to provide 8, by employing 1.3
equivalents of CH3Li and an equimolar amount of
electrophile. Analogously to 5, the intermediates 8a–c
can subsequently be converted into 10a–c (Scheme 1)
following the procedure already reported.10
These results can be explained in part by the reasoning
suggested by Eastwood7 for the factors affecting the
ability to lithiate the bridgehead position in analogous
compounds. Stabilization of a negative charge at the
bridgehead position would occur through the following
effects.
(a) Dipole stabilization by the partial positive charge
on the adjacent amide nitrogen.
(b) Inductive or field effects due to the adjacent
carbonyl group.
The absolute configuration of the introduced stereocen-
ters of 2 and 3 have been assigned through the 1H
NMR chemical shifts following the methodology
already employed.1,2 The approach is based on the
shielding induced by the aromatic ring of the (S)-
phenethyl group on the bridged chain protons of
diastereomer (1R,4R)-2 owing to the preferred doubly
synperiplanar conformation.
(c) Orbital overlap with the p-orbital of the carbonyl
group.
The last factor depends on the geometry of the
molecule because the conjugation of the lone pair at the
bridgehead carbon (in an ion pair) is stronger the more
coplanar the lone pair is with the p-orbital of the
adjacent carbonyl group. Thus, the enolate ion charac-
ter will be greater the closer the dihedral angle
LiꢀCꢀCꢁO is to 90°. Also a little orbital overlap implies
a molecular distortion which is very strong in bicyclic
systems where the bridge is small and it decreases when
the bridge length increases. The competitive acidity of
the benzylic protons with respect to that of the bridge-
head protons is due to both stabilization of the result-
ing benzylic anion (electrons of the CꢀLi bond) by a
resonance contribution with the aromatic ring and the
opportunity to give rise to a pentatomic cyclic system
by means of chelation between the adjacent carbonyl
oxygen and the lithium cation.8
3. Conclusion
In conclusion, we have carried out a new and
stereoselective approach to the synthesis of enan-
tiomerically pure analogues of 2,6-DAP with potential
biological activity3 (antibacterial and/or herbicide)
starting from the chiral heterocyclic synthon 1,
employed previously by us. The synthetic strategy is
based on the alkylation of diastereomeric bicyclic
intermediates (1R,4R)-2 and (1S,4S)-3, easily obtained
from 1, followed by simple cleavage to afford enan-
tiomerically pure a-alkyl derivatives of 2,6-DAP. This
strategy is a versatile approach because it allows the
preparation of various derivatives of 2,6-DAP mimics,
with promising possibilities as specific inhibitors of
enzymes along the biosynthetic ‘diaminopimelate
As already observed for analogous derivatives,1,2 the
conformation where both the benzylic protons of the
(S)-phenethyl groups are synperiplanar to the adjacent
carbonyl groups (the heterocyclic ring being in the boat
conformation) is energetically preferred.9 Since the
energy calculations show that, as predicted, the dihe-
dral angles LiꢀCꢀCꢁO of (1R,4R)-2 and (1S,4S)-3 are
very similar (about 14 and 10°, respectively), the acidity
of the bridgehead proton in 2 and 3 can reasonably be
considered the same. Thus, we believe that the better
chemical yields of 4 over those of 5 are probably
because the bridgehead proton in 2 is less sterically
encumbered than in 3 (as can be deduced from an
examination of the previously calculated geometries1).
Additionally, the approach of the electrophile, which
occurs from the opposite side of the C3 bridge, appears
more hindered sterically in the carbanion of 3 than in
that of 2. This explanation is supported by the experi-
pathway’ leading to
plants.
L-lysine in bacteria and higher
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded on a Gemini
spectrometer at 300 MHz using CDCl3 as solvent,
unless otherwise stated. Chemical shifts are reported in
ppm relative to CDCl3 or to 1,4-dioxane if D2O is used
as solvent. The coupling constants (J) are in Hz. Dry
THF was distilled from sodium benzophenone ketyl.
Chromatographic separations were performed with sil-
ica gel 60 (230–400 mesh). Optical rotation values were
measured on a Perkin–Elmer 343 polarimeter.

500
F. Paradisi et al. / Tetrahedron: Asymmetry 13 (2002) 497–502
4.2. (1%S)-1,4-Bis-[N-1%-phenethyl)]-piperazine-2,5-dione
4.5.3. (1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-1-
methoxymethyl-bicyclo[3,2,2]nonane 4c. The product
was obtained by alkylating 2 with bromomethyl methyl
1
1
The product was prepared following the procedure
reported in Ref. 10.
ether (see entry 4 in Table 1). H NMR l: 0.6 (m, 1H);
1.46 (d, 3H, J=7); 1.6 (m, 5H); 1.8 (d, 3H, J=7); 3.38
(s, 3H); 3.69 (dd, 1H, J=3, 4.8); 3.86 (d, 1H, J=11.4);
4.02 (d, 1H, J=11.4); 4.86 (q, 1H, J=7.0); 5.95 (q, 1H,
J=7); 7.3 (m, 10ArH). 13C NMR l: 16, 16.9, 20.3,
24.8, 30.1, 50.5, 53.7, 54.9, 58.8, 66, 73.2, 125.6, 125.9,
127.6, 127.8, 128.3, 138.7, 142.3, 168.2, 169.7. [h]D
−191.3 (c 1.15, CHCl3). Anal. calcd for C25H30N2O3: C,
73.86; H, 7.44; N, 6.89. Found: C, 73.88; H, 7.46; N,
6.92%.
4.3. (1R,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-2,5-diaza-
3,6-dioxo-bicyclo[3,2,2]nonane 2
The product was prepared following the procedure
reported in Ref. 2. For NMR spectra and [h]D value see
Ref. 1.
4.5.4. (1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-allyl-3,6-
dioxo-bicyclo[3,2,2]nonane 4d. The product was
obtained by alkylating 2 with allyl bromide (see entry 2
in Table 1). 1H NMR l: 0.7 (m, 1H); 1.53 (d, 3H,
J=7); 1.4–2 (m, 5H); 1.83 (d, 3H, J=7); 2.89 (dd, 1H,
J=7.8, 16); 3.08 (dd, 1H, J=5.6, 16); 3.76 (dd, 1H,
J=3.4, 4.8 Hz); 4.96 (q, 1H, J=7); 5.05–5.2 (m, 2H);
5.9–6.15 (m, 2H); 7.2–7.45 (m, 10ArH). 13C NMR l:
16.3, 17.4, 20.8, 24.9, 34.5, 40.7, 50.9, 53, 55, 65.6,
118.7, 125.5, 126.1, 127.8, 128, 128.5, 133.5, 138.9,
141.8, 169.2, 170.6. [h]D −182.7 (c 0.79, CHCl3). Anal.
calcd for C26H30N2O2: C, 77.58; H, 7.51; N, 6.96.
Found: C, 77.45; H, 7.48; N, 6.97%.
4.4. (1S,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-2,5-diaza-3,6-
dioxo-bicyclo[3,2,2]nonane 3
The product was prepared following the procedure
reported in Ref. 2. For NMR spectra and [h]D value see
Ref. 1.
4.5. Alkylation of 2 and 3: general procedure
A stirred solution of 2 or 3 (0.8 g, 2.1 mmol) in dry
THF (30 mL) cooled to −78°C was treated with base
(see Table 1). After about 5 min, the appropriate
alkylating reagent (see Table 1) was added and the
reaction was then monitored by TLC. When the reac-
tion was practically complete, the mixture was allowed
to warm to room temperature with stirring. Dilute
aqueous HCl and ethyl acetate were added and after
separation, the organic solution was evaporated in
vacuo. The residue was purified by silica gel chro-
matography eluting with hexane/ethyl acetate.
4.5.5. (1S,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-1-
methyl-bicyclo[3,2,2]nonane 5. The product was
obtained by alkylating 3 with iodomethane (see entry 9
1
in Table 1). H NMR l 1.38 (bs, 3H); 1.57 (d, 3H,
J=7.2); 1.6–2 (m, 6H); 1.74 (d, 3H, J=7.2); 3.83 (bs,
1H); 5.6–6 (bs, 1H); 5.88 (q, 1H, J=7.2); 7.17–7.4 (m,
10ArH). 13C NMR l: 16.8, 18.1, 21.4, 23.3, 27, 36.3,
51.2 (broad), 55.4, 63.6, 126.8, 126.9, 128, 128.4, 128.8,
140.2, 142.2, 170.5, 170.9. [h]D −39 (c 0.51, CHCl3).
Anal. calcd for C24H28N2O2: C, 76.56; H, 7.5; N, 7.44.
Found: C, 76.79; H, 7.52; N, 7.42%.
4.5.1. (1R,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-
1-methyl-bicyclo[3,2,2]nonane 4a. The product was
obtained by alkylating 2 with iodomethane (see entry 1
1
in Table 1). H NMR l: 0.8–1.8 (m, 6H); 1.51 (d, 3H,
4.5.6. (1S,4S,1%S)-2-N-(1%-Phenethyl)-5-N-(1¦-phenyliso-
propyl)-3,6-dioxo-bicyclo[3,2,2]nonane 6. The product
was obtained by alkylating 3 with iodomethane (see
entry 6 or 10 in Table 1). After chromatographic sepa-
ration the product was not isolated in pure enough
form to measure the specific rotation and to obtain
satisfactory elemental analysis. 1H NMR l: 1.57 (d,
3H, J=7.2); 1.6–2.05 (m, 6H); 1.66 (s, 3H); 1.85 (s,
3H); 3.65 (t, 1H, J=4); 4.28 (t, 1H, J=4); 5.83 (q, 1H,
J=7.2); 7.3 (m, 10ArH); 13C NMR l: 17, 20, 26.6,
26.9, 27.1, 29.8, 50.4, 56.9, 57.8, 62, 124.6, 126.6, 126.8,
127.8, 128.3, 128.7, 139.9, 146.5, 169, 169.6.
J=6.9); 1.67 (s, 3H); 1.83 (d, 3H, J=7.2); 3.79 (bs,
1H); 5 (m, 1H); 5.96 (q, 1H, J=7.2); 7.3 (m, 10ArH).
13C NMR l: 16.1, 18, 20.9, 23.4, 24.7, 35.7, 51, 52.7,
55.2, 63.6, 125.7, 126.5, 127.7, 127.9, 128, 128.4, 138.8,
141.7, 169.8, 170.2. [h]D −154.5 (c 0.71, CHCl3). Anal.
calcd for C24H28N2O2: C, 76.56; H, 7.5; N, 7.44. Found:
C, 76.79; H, 7.52; N, 7.42%.
4.5.2.
(1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-benzyl-
3,6-dioxo-bicyclo[3,2,2]nonane 4b. The product was
obtained by alkylating 2 with benzyl bromide (see entry
3 in Table 1). 1H NMR l: 0.7 (m, 1H); 1.4–1.7 (m, 5H);
1.65 (d, 3H, J=7); 1.79 (d, 3H, J=7); 3.26 (d, 1H,
J=16); 3.91 (dd, 1H, J=3, 4.8); 4 (d, 1H, J=16); 5
(broad, 1H); 6.01 (q, 1H, J=7); 6.8–7.5 (m, 15ArH).
13C NMR l: 16.7, 18.7, 20.6, 25, 34.4, 41.5, 51.4, 54.2,
55.1, 67.7, 125.8, 126, 126.3, 127.4, 128, 128.1, 128.2,
128.6, 130.2, 135.8, 138.9, 141.3, 169.6, 171.2. [h]D
−194.7 (c 0.59, CHCl3). Anal. calcd for C30H32N2O2: C,
79.61; H, 7.13; N, 6.19. Found: C, 79.35; H, 7.15; N,
6.18%.
4.5.7. (1S,4S)-2,5-Bis-[N-(1%-phenylisopropyl)]-3,6-dioxo-
bicyclo[3,2,2]nonane 7. The product was obtained by
alkylating 3 with iodomethane (see entry 11 in Table 1).
1H NMR l: 1.64 (s, 6H); 1.6–2.1 (m, 6H); 1.91 (s, 6H);
4.1 (t, 2H, J=6); 7.3 (m, 10ArH). 13C NMR l: 19.8,
26.7, 29.8, 59.1, 61.5, 124.4, 126.6, 128.1, 146.5, 169.2.
[h]D 166.7 (c 0.66, CHCl3). Anal. calcd for C25H30N2O2:
C, 76.89; H, 7.74; N, 7.17. Found: C, 76.09; H, 7.75; N,
7.2%.

F. Paradisi et al. / Tetrahedron: Asymmetry 13 (2002) 497–502
501
4.6. Alkylation of 7: general procedure
The resin was washed with methanol then distilled
water and eluted with 5 M NH4OH to recover the
enantiomerically pure 2,6-DAP derivatives 9a,b or
10a,b.
To a stirred solution of 7 (0.4 g, 1.02 mmol) in dry
THF (15 mL) cooled to −55°C was added a solution of
CH3Li in diethyl ether (1.4 M, 0.9 mL). After about 5
min the appropriate alkylating reagent (2 mmol) was
added and the reaction was then monitored by TLC.
When the reaction was practically complete, the mix-
ture was allowed to warm to room temperature with
stirring. Dilute aqueous HCl and ethyl acetate were
added and after separation the organic solution was
evaporated in vacuo. The residue was purified by silica
gel chromatography eluting with hexane/ethyl acetate.
4.7.1. (2R,6R)-2-Methyl-2,6-diaminopimelic acid 9a. The
1
product was obtained from 4a in 88% yield. H NMR
(D2O) l: 1.3–1.5 (m, 2H); 1.49 (s, 3H); 1.7–2 (m, 4H);
3.95 (t, 1H, J=6). 13C NMR (D2O) l: 19.7, 20.2, 30.1,
36.7, 53.1, 60.5, 171.2, 174.2. [h]D −28.2 (c 0.75, 1N
HCl). Anal. calcd for C8H16N2O4: C, 47.05; H, 7.9; N,
13.72. Found: C, 47.15; H, 7.95; N, 13.7%.
4.7.2. (2S,6S)-2-Methyl-2,6-diaminopimelic acid 10a.
The product was obtained from 8a in 90% yield. [h]D 28
(c 0.534, 1N HCl).
4.6.1. (1S,4S)-2,5-Bis-[N-(1%-phenylisopropyl)]-3,6-dioxo-
1-methyl-bicyclo[3,2,2]nonane 8a. Iodomethane was
used as alkylating reagent. The product was isolated in
70% yield, the remaining 30% being starting material.
1H NMR l: 0.86 (s, 3H); 1.66 (s, 3H); 1.6–2.2 (m, 6H);
1.9 (s, 3H); 1.92 (s, 3H); 1.99 (s, 3H); 4.44 (t, 1H,
J=5.4); 7.1–7.45 (m, 10ArH). 13C NMR l: 21.4, 25.7,
26.5, 27.6, 27.9, 30, 35.5, 39, 59.2, 61.2, 65.1, 65.8,
123.8, 124.3, 126.3, 126.4, 128.1, 128.4, 147.4, 149.7,
169.7, 173.7. [h]D 132.2 (c 0.5, CHCl3). Anal. calcd for
C26H32N2O2: C, 77.19; H, 7.97; N, 6.92. Found: C,
76.95; H, 7.95; N, 6.9%.
4.7.3. (2S,6R)-2-Benzyl-2,6-diaminopimelic acid 9b. The
1
product was obtained from 4b in 90% yield. H NMR
(D2O) l: 1.2–1.6 (m, 2H); 1.7–2.1 (m, 4H); 2.96 (d, 1H,
J=14.6); 3.25 (d, 1H, J=14.6); 3.94 (t, 1H, J=6.2); 7.3
(m, 5ArH). 13C NMR (D2O) l: 19.7, 30.2, 35.5, 41.8,
53.1, 64.7, 128.9, 129.8, 130.8, 133.2, 172, 173. [h]D
−11.7 (c 0.6, 1N HCl). Anal. calcd for C14H20N2O4: C,
59.99; H, 7.19; N, 9.99. Found: C, 60.13; H, 7.2; N,
10.02%.
4.6.2. (1R,4S)-2,5-Bis-[N-(1%-phenylisopropyl)]-1-benzyl-
3,6-dioxo-bicyclo[3,2,2]nonane 8b. Benzyl bromide was
used as alkylating reagent. The product was isolated in
55% yield along with 25% of starting material and an
4.7.4. (2R,6S)-2-Benzyl-2,6-diaminopimelic acid 10b.
The product was obtained from 8b in 92% yield. [h]D
11.5 (c 0.71, 1N HCl).
1
unidentified by-product. H NMR l: 1.6–2.2 (m, 6H);
4.8. Conversion of 4c into 9c and 8c into 10c: general
procedure
1.74 (s, 3H); 1.85 (s, 3H); 1.94 (s, 6H); 3.05 (qAB, 2H,
J=15); 4.42 (t, 1H, J=4); 6.95–7.5 (m, 15ArH). 13C
NMR l: 21.2, 26.8, 27.6, 29, 34.7, 35.1, 41.5, 59.2, 61.5,
65.7, 69.1, 124, 124.5, 125.9, 126.2, 126.5, 127.7, 128.2,
128.3, 130.8, 138, 147.1, 149.8, 169.1, 172.8. [h]D 69 (c
1.37, CHCl3). Anal. calcd for C32H36N2O2: C, 79.96; H,
7.55; N, 5.83. Found: C, 80.15; H, 7.57; N, 5.85%.
Under an inert atmosphere, a solution of 4c or 8c (1.2
mmol) in dry THF (10 mL) and ethanol (1 mL) was
added to a stirred solution of Na (0.2 g, 8.7 mmol) in
liquid ammonia (about 30 mL) cooled to −60°C. After
5 min the reaction was quenched with 0.5 g of NH4Cl
and the cooling bath was removed allowing complete
removal of NH3. Water was added and the solution was
extracted with ethyl acetate. The product was recovered
in good yield after purification by silica gel chromatog-
raphy eluting with hexane/ethyl acetate.
4.6.3.
(1R,4S)-2,5-Bis-[N-(1%-phenylisopropyl)]-3,6-
dioxo-1-methoxymethyl-bicyclo[3,2,2]nonane 8c. Bro-
momethyl methyl ether was used as alkylating reagent.
The product was isolated in 80% yield, the remaining
20% being starting material. 1H NMR (CD3OD, at
50°C) l: 1.62 (s, 3H); 1.9 (s, 6H); 1.93 (s, 3H); 1.6–2 (m,
6H); 3.04 (s, 3H); 3.3 (broad, 2H); 4.2 (broad, 1H);
7.1–7.6 (m, 10ArH). 13C NMR l: 20.8, 24.1 (broad),
26.3, 26.8 (broad), 29.6, 34.6 (broad), 57.7, 58.5
(broad), 61.3 (broad), 65.4 (broad), 67 (broad), 73.2
(broad), 124.1, 124.3, 125.8, 126.4, 127.5, 128, 146.9,
148.8 (broad), 168. [h]D 165.7 (c 2.47, CHCl3). Anal.
calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45.
Found: C, 74.6; H, 7.92; N, 6.48%.
4.8.1. (1S,4R)- or (1R,4S)-2,5-Diaza-3,6-dioxo-1-meth-
1
oxymethyl-bicyclo[3,2,2]nonane. H NMR (CD3OD) l:
1.6–1.95 (m, 6H), 3.4 (s, 3H), 3.43 (d, 1H, J=9.6), 3.7
(d, 1H, J=9.6), 3.77 (m, 1H); 13C NMR (CD3OD) l:
21.5, 27, 30.6, 55.6, 59.5, 61.4, 74.1, 174.3.
The pure intermediate (1 mmol) was then heated under
reflux for 12 h in 6N aqueous HCl (15 mL). The acid
solution was adsorbed on ion-exchange resin Amberlist
H 15 and then eluted with 5 M NH4OH to recover the
enantiomerically pure 2,6-DAP derivative 9c or 10c.
4.7. Conversion of 4a,b into 9a,b and 8a,b into 10a,b:
general procedure
4.8.2. (2S,6R)-2-Methoxymethyl-2,6-diaminopimelic acid
9c. The product was obtained from 4c in 82% overall
A solution of compound 4a,b or 8a,b (1 mmol) in 57%
HI (5 mL) was heated under reflux.10 After about 8 h,
the reaction mixture was evaporated in vacuo, the
residue was dissolved in water (5 mL) and the solution
was adsorbed on ion-exchange resin Amberlist H 15.
1
yield. H NMR (D2O) l: 1.2–1.6 (m, 2H); 1.7–2.0 (m,
4H); 3.25 (s, 3H); 3.51 (d, 1H, J=10.4); 3.78 (d, 1H,
J=10.4); 3.95 (t, 1H, J=6.2). 13C NMR (D2O) l: 19.3,
30.1, 32.1, 53, 59.8, 64.3, 73.9, 172.2, 172.3. [h]D −19.4

502
F. Paradisi et al. / Tetrahedron: Asymmetry 13 (2002) 497–502
(c 0.68, 1N HCl). Anal. calcd for C9H18N2O5: C, 46.15;
H, 7.75; N, 11.96. Found: C, 46.28; H, 7.77; N, 11.92%.
H.; et al. J. Am. Chem. Soc. 1990, 112, 4932; (e) Vederas,
J. C.; et al. J. Biol. Chem. 1986, 261, 13216; (f) Vederas,
J. C.; et al. J. Biol. Chem. 1988, 263, 11814; (g) Schar, H.
P.; et al. Plant Physiol. 1992, 98, 813.
4.8.3. (2R,6S)-2-Methoxymethyl-2,6-diaminopimelic acid
10c. The product was obtained from 8c in 80% overall
yield. [h]D 19.1 (c 0.7, 1N HCl).
4. Paradisi, F.; Porzi, G.; Sandri, S. Tetrahedron: Asymme-
try 2001, 12, 3319.
5. Faibish, N. C.; Park, Y. S.; Lee, S.; Beak, P. J. Am.
Chem. Soc. 1997, 119, 11561.
Acknowledgements
6. (a) Keresztes, I.; Williard, P. G. J. Am. Chem. Soc. 2000,
122, 10228; (b) McGarrity, J. F.; Ogle, C. A.; Brich, Z.;
Loosli, H. R. J. Am. Chem. Soc. 1985, 107, 1810; (c)
Al-Aseer, M. A.; Smith, S. G. J. Org. Chem. 1984, 49,
2608.
Thanks are due to MIUR (COFIN 2000) and to the
University of Bologna for financial support.
7. Eastowood, F. W.; Gunawardana, D.; Wernert, G. T.
Aust. J. Chem. 1982, 35, 2289.
8. (a) Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000, 65,
6196; (b) Gawley, R. E.; Low, E.; Zhang, Q.; Harris, R.
J. Am. Chem. Soc. 2000, 122, 3344.
9. Performed by the AM1 method (HyperChem program
1994) by using the ‘Polak-Ribiere algorithm’ (RMS gradi-
ent 0.01 Kcal).
10. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1994, 5,
453.
References
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hedron: Asymmetry 2000, 11, 4617.
3. (a) Cox, R. J. Nat. Prod. Rep. 1996, 13, 29; (b) Williams,
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