A simple asymmetric synthesis of (+)- and (-)-2,6-diaminopimelic acids

Article abstract of DOI:10.1016/S0957-4166(00)00050-1

The asymmetric synthesis of both the enantiomers of 2,6-diaminopimelic acid (2,6-DAP) has been accomplished starting from the chiral synthon 1. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00050-1

Tetrahedron: Asymmetry 11 (2000) 1259±1262
A simple asymmetric synthesis of (+)- and
(^)-2,6-diaminopimelic acids
Francesca Paradisi, Gianni Porzi,* Samuele Rinaldi and Sergio Sandri*
Á
Dipartimento di Chimica `G.Ciamician', Universita degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 27 January 2000; accepted 2 February 2000
Abstract
The asymmetric synthesis of both the enantiomers of 2,6-diaminopimelic acid (2,6-DAP) has been
accomplished starting from the chiral synthon 1. # 2000 Elsevier Science Ltd. All rights reserved.
(2S,6S)-2,6-Diaminopimelic acid 6, biosynthesized in bacteria from pyruvate and aspartate, is
the penultimate precursor of l-lysine in the metabolic process necessary for the growth of Gram
positive and many Gram negative bacteria. In addition, meso-2,6-diaminopimelic acid [(R,S)-
DAP] functions as a cross-linking constituent of the peptidoglycan cell wall layer in bacteria.
Because mammals lack this biosynthetic pathway, speci®c inhibitors of the enzymes along this
metabolic route should potentially display antibacterial activity.1 Hence, in recent years the ste-
reoselective synthesis of several DAP analogues with potential therapeutic e€ects has received
considerable attention.2
Owing to our interest directed at the asymmetric synthesis of common and uncommon a-amino
acids,3 we have recently focused our attention on a new stereoselective process to both the
enantiomers 5 and 6 of 2,6-DAP. Our simple synthetic approach involves the use of the glycine
derived chiral synthon 1 (Scheme 1) which we have already used and can be achieved in good
yield starting from (S)-a-phenylethylamine.4 The intermediate 25 was obtained in about 90%
yield by alkylating the lithium enolate of 1 with an equimolar amount of 1,3-diiodopropane,
according to the previously reported procedure.4 The diastereomeric mixture of 2 was converted
in good yield into the corresponding lithium enolates then cyclized to a 7:3 diastereomeric
mixture of bicyclic derivatives6 (1R,4R)-3 and (1S,4S)-4. These intermediates, easily separated by
chromatography on silica gel, were then submitted to cleavage with 57% HI (Scheme 1) and the
enantiomerically pure 2,6-DAPs,7 (2R,6R)-5 and (2S,6S)-6, were recovered pure after adsorption
on Amberlist H-15 ion exchange resin following the protocol already described.8
* Corresponding authors. E-mail: porzi@ciam.unibo.it
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00050-1

1260
F. Paradisi et al. / Tetrahedron: Asymmetry 11 (2000) 1259±1262
Scheme 1. (i) LHDMS at ^10ꢀC, then I(CH2)3I at ^78ꢀC; (ii) LHDMS at ^10ꢀC; (iii) re¯uxing 57% HI, then adsorp-
tion on Amberlist H-15 ion exchange resin and elution with 5 M NH4OH7
The absolute con®gurations of the introduced stereocenters of 3 and 4 were determined
following the approach often employed for similar molecules.8 Actually, as has been previously
observed for analogous compounds, the 1H NMR spectra can be explained on the basis of phenyl
shielding e€ects which take place exclusively in those conformers where the benzylic hydrogen of
the (S)-phenethyl group is synperiplanar with respect to the carbonyl group with the heterocyclic
ring being in a boat conformation.8 The conformational analysis9 performed on both (1R,4R)-3
and (1S,4S)-4 showed that doubly synperiplanar conformers are more stable than those which are
doubly antiperiplanar by 1.6 kcal/mol and 1.1 kcal/mol, respectively (Fig. 1). In addition, in
both isomers 3 and 4 the conformation with one phenethyl group synperiplanar and the other
antiperiplanar is 0.8 and 0.5 kcal/mol, respectively, less stable than the doubly synperiplanar
conformer. In the present case the R con®guration of the new stereocenters introduced in 3 was
established on the basis of the remarkable up®eld shift su€ered by the six protons of the C3
Figure 1. Preferred conformations9 of isomers 3 and 4: in the former the shielding exerted by the phenyl ring on the six
protons of the C3 bridged chain is shown

F. Paradisi et al. / Tetrahedron: Asymmetry 11 (2000) 1259±1262
1261
bridged chain. Actually, these protons in isomer 4 absorb in the range 1.65±2.05 ppm, while in 3
they resonate at higher ®elds, i.e. 0.6±1.4 ppm. This up®eld shift registered in isomer 3 is ascribable
to the phenyl ring of the (S)-phenethyl moiety which, in the preferred synperiplanar conformation,
can exert a strong shield only on the six protons of the C3 bridged chain, as shown in Fig. 1.
Nevertheless, the assigned con®guration of the introduced stereocenters was unequivocally
con®rmed by converting stereoisomers 3 and 4 into the corresponding (R,R)-(5) and (S,S)-(6)
diaminopimelic acids, as reported in Scheme 1. The speci®c rotation values measured,
[ꢀ]D=^42.5 (c 1, 1N HCl) for 5 and [ꢀ]D=+42.1 (c 0.96, 1N HCl) for 6, are in good agreement
with those reported in the literature.10
Further investigations are in progress in order to develop a general methodology applicable to
the 2,6-diaminopimelic acid family of amino acids with potential antimicrobial activity.
Acknowledgements
Thanks are due to MURST (COFIN 1998±2000) and to the University of Bologna (Fondi
Ricerca Istituzionale, ex 60%) for ®nancial support.
References
1. Williams, R. M.; Fegley, G. J.; Gallegos, R.; Schaefer, F.; Pruess, D. L. Tetrahedron 1996, 52, 1149 and references
cited therein.
2. Gelb, M. H.; Lcin, Y.; Pickard, M. A.; Song, Y.; Vederas, J. C. J. Am. Chem. Soc. 1990, 112, 4932; Williams,
R. M.; Im, M.-N.; Cao, J. J. Am. Chem. Soc. 1991, 113, 6976; Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57,
6519; Abbott, S. D.; Lane-Bell, P.; Sidhu, K. P. S.; Vederas, J. C. J. Am. Chem. Soc. 1994, 116, 6513; Song, Y.;
Niederer, D.; Lane-Bell, P. M.; Lan, L. K. P.; Crawley, S.; Palcic, M. M.; Pickard, M. A.; Pruess, D. L.; Vederas,
J. C. J. Org. Chem. 1994, 59, 5784; Bull, S. D.; Chernega, A. N.; Davies, S. G.; Moss, W. O.; Parkin, R. M.
Tetrahedron 1998, 54, 10379 and references cited therein.
3. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996, 7, 189; Favero, V.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 1997, 8, 599; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1998, 9, 3411; Carloni, A.; Porzi, G.;
Sandri, S. Tetrahedron: Asymmetry 1998, 9, 2987; Di Felice, P.; Maestri, M.; Paradisi, F.; Porzi, G.; Sandri, S.
Tetrahedron: Asymmetry 1999, 10, 4709.
4. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1994, 5, 453.
5. After chromatography of the crude reaction (eluting with hexane/ethyl acetate) in addition to the 1,3-diiodo-
propane the byproduct 7 was isolated in about 10% yield, while the separation of diastereomers of 2 was unsuccessful.
However, the subsequent cyclization reaction6 leads to easily separable diastereomers 3 and 4. The structure of 7
was determined by 1H NMR spectroscopic data and further corroborated by smooth conversion into 6 with
re¯uxing 57% HI. (10S,2S)-1,3-Bis-[1,4-N,N-(10-phenethyl)-3,6-diketopiperazin-2-yl]-propane 7: 1H NMR ꢁ
(CDCl3) 1.5 (d, 6H, J=7.2 Hz), 1.6 (d, 6H, J=7.2 Hz), 1.6 (m, 2H), 1.85 (m, 4H), 3.56 (d, 2H, J=17.4 Hz), 3.68
(dd, 2H, J=4.5, 8.4 Hz), 3.94 (d, 2H, J=17.4 Hz), 5.78 (q, 2H, J=7.2 Hz), 5.8 (q, 2H, J=7.2 Hz), 7.3 (m, 20ArH);
13C NMR ꢁ (CDCl3) 15.2, 17.3, 21, 33.1, 44.4, 49.7, 51.8, 56.8, 126.8, 127.8, 127.9, 128.6, 128.7, 138.5, 138.9, 165,
165.9; [ꢀ]D ^176.1 (c 1.01, CHCl3).

1262
F. Paradisi et al. / Tetrahedron: Asymmetry 11 (2000) 1259±1262
6. Procedure for the preparation of diastereomers 3 and 4. To 1.34 g (2.73 mmol) of the diastereomeric mixture of 2
(puri®ed by chromatographic separation of the 1,3-diiodopropane and the byproduct 7), dissolved in dry THF
(100 mL) at ^10ꢀC, 2.8 mL (1 M solution in THF) of LHMDS (2.8 mmol), in 10 mL of dry THF, were slowly
added. After a few minutes the cooling bath was removed allowing the reaction mixture to warm up to room
temperature. Then, diluted HCl was added, the mixture extracted with ethyl acetate and the organic solution
evaporated in vacuo. The residue was submitted to silica gel chromatographic separation eluting with hexane/ethyl
acetate. The diastereomers 3 and 4 were isolated pure in 70% yield. (10S,100S,1R,4R)-2,5-Bis-[2,5-N,N-(10-phenethyl)]-
3,6-dioxo-2,5-diazabicyclo[3,2,2]nonane 3: 1H NMR ꢁ (CDCl3) 0.6 (m, 2H), 1.22 (m, 2H), 1.4 (m, 2H), 1.52 (d, 6H,
J=6.9 Hz), 3.89 (t, 2H, J=4 Hz), 5.82 (q, 2H, J=6.9 Hz), 7.3 (m, 10ArH); 13C NMR ꢁ (CDCl3) 16.2, 19.8, 24.8,
50.4, 55.1, 127.8, 128.1, 128.6, 138.8, 169.1; mp 213±215ꢀC; [ꢀ]D ^300.9 (c 1.016, CHCl3). (10S,100S,1S,4S)-2,5-bis-
[2,5-N,N-(10-phenethyl)]-3,6-dioxo-2,5-diazabicyclo[3,2,2]nonane 4: H NMR ꢁ (CDCl3) 1.53 (d, 6H, J=7.2 Hz),
1
1.75 (m, 6H), 1.95 (m, 2H), 3.81 (t, 2H, J=3.9 Hz), 5.73 (q, 2H, J=7.2 Hz), 7.15 (m, 4ArH), 7.3 (m, 6ArH); 13C
NMR ꢁ (CDCl3) 16.5, 20.1, 26.6, 50.1, 55.2, 126.5, 127.7, 128.5, 139.6, 168.8; mp 143±145ꢀC; [ꢀ]D ^167.6 (c 1.004,
CHCl3).
7. 1H NMR ꢁ (D2O vs DSS) 1.4 (m, 2H), 1.8 (m, 4H), 3.7 (m, 2H).
8. Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992, 57, 6532; Orena, M.; Porzi, G.; Sandri, S. J. Chem. Res. (S)
1993, 318, 2125.
9. Energy calculations were performed by the AM1 method (HyperChem Program, 1994) using the `Polak-Ribiere
algorithm' (RMS gradient 0.01 kcal).
10. Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57, 6519: [ꢀ]D=44.5 (c 0.95, 1N HCl).