Stereoselective synthesis of α,α′-diamino-dicarboxylic acids. Part 2

Article abstract of DOI:10.1016/S0957-4166(00)00450-X

Enantiomerically pure ,′-diamino-dicarboxylic acids (R,R)-4, (S,S,)-5 and (S,S)-7 have been synthesized starting from the glycine-derived chiral synthon (S,S)-1.

Full text of DOI:10.1016/S0957-4166(00)00450-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4617–4622
Stereoselective synthesis of a,a%-diamino-dicarboxylic acids.
Part 2†
Francesca Paradisi, Gianni Porzi,* Samuele Rinaldi and Sergio Sandri*
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 30 October 2000; accepted 13 November 2000
Abstract
Enantiomerically pure a,a%-diamino-dicarboxylic acids (R,R)-4, (S,S)-5 and (S,S)-7 have been synthe-
sized starting from the glycine-derived chiral synthon (S,S)-1. © 2000 Elsevier Science Ltd. All rights
reserved.
1. Introduction
In a continuation of our program aimed at the stereoselective synthesis of naturally and
non-naturally occurring amino acids,1 we have recently focused our attention on a new synthetic
approach to a,a%-diamino-dicarboxylic acids, which could be useful structural variants of
2,6-diaminopimelic acid (penultimate intermediate in the metabolic process to peptidoglycan and
L
-lysine for the growth of Gram(+) and many Gram(−) bacteria). In fact, because mammals lack
this biosynthetic pathway, aromatic and non-aromatic a,a%-diamino-dicarboxylic acids have
received much attention in recent years for their potential antibacterial activity.2 The interest in
such compounds is also motivated by the possibility of incorporating them into biologically
active peptides: for instance, the disulfide linkage of cystine in peptoid bioorganics, where it
mainly exerts a structural skeletal function, can be replaced by a C2 unit.3
Recently, we reported a new and simple asymmetric synthesis of (+)- and (−)-2,6-
diaminopimelic acids4 accomplished by using the glycine-derived heterocyclic synthon (S,S)-1.
* Corresponding authors. E-mail: porzi@ciam.unibo.it
†
For Part 1 see Ref. 4.
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00450-X

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2. Results and discussion
In the present study our efforts have been directed towards producing enantiomerically pure
a,a%-diamino-dicarboxylic acids, 2,7-diaminosuberic acid (2R,7R)-4 and (2S,7S)-5 and (S,S)-
ortho-phenylene-bis-alanine 7, which can be considered structural analogs of 2,6-diaminopimelic
acid. The methodology followed is based on the alkylation of the enolate of homochiral synthon
1 with an equimolar amount of the appropriate dihalo-derivative and subsequent base-induced
cyclization to the bicyclic intermediates 2, 3 and 6, which are easily purified by chromatography
on silica gel and smoothly cleaved with 57% HI. The enantiomerically pure a,a%-diamino-diacids
(2R,7R)-4, (2S,7S)-5 and (S,S)-7, respectively, were then recovered pure in quantitative yield
after adsorption on Amberlist H-15 ion-exchange resin following the protocol already used4 by
us (Scheme 1).
Scheme 1. (i) 1.1 equiv. of base at −10°C, then 1 equiv. of the appropriate dihalo-derivative followed by 1.1 equiv.
of base at −78°C and chromatographic separation; (ii) refluxing 57% HI, then adsorption on Amberlist H-15
ion-exchange resin and elution with 5 M NH4OH4
While the bicyclic intermediates (1R,4R)-2 and (1S,4S)-3 were obtained in a 65:35
diastereomeric mixture (de=30%), respectively, the derivative (1S,10S)-6 was recovered as a
single stereoisomer in
diastereoselective.
a practically quantitative yield, i.e. the reaction is totally
In order to obtain the best results, different bases, such as Li-, Na- and K-bis(trimethyl-
silyl)amide, were tested by using 1,4-diiodobutane as the electrophile. While the sodium-enolate of
1 gave a mixture of (R,S)- and (S,S)-monoiodobutyl-derivatives of 1 (precursors of 2 and 3) in

F. Paradisi et al. / Tetrahedron: Asymmetry 11 (2000) 4617–4622
4619
a 65:35 ratio, respectively, 30% de with the lithium-enolate reaction was non diastereoselective
1
(de=0) (the diastereomeric ratios being ascertained by H NMR). The subsequent addition of
a second equivalent of base converted the monoiodobutyl-derivatives of 1 into a mixture of 2
and 3. In contrast, when K-bis(trimethylsilyl)amide was employed the bicyclic compounds 2 and
3 were obtained directly with no diastereoselectivity (de=0) and the addition of a second
equivalent of base converted the remaining starting material 1 into 2 and 3. Considering that the
chromatographic separation of diastereomeric monoiodobutyl-derivatives was unsuccessful, the
formation of 2 and 3 can be accomplished in only one step, i.e. without isolating the
monoiodobutyl intermediates.
However, independent of the base used, about 10% of the dialkyl byproduct (1%S,2S)-1,4-bis-
[1,4-N,N-(1%-phenethyl)-3,6-diketopiperazin-2-yl]butane was isolated, consistent with previous
observations with 13-diiodopropane.4
The best chemical yields (90%) of 6 were registered by employing a,a%-dibromo-o-xylene as the
electrophile and Li-bis(trimethylsilyl)amide as the base. However, it is interesting that when one
equivalent of the base was used the reaction did not give the intermediate monobromoalkyl-
derivative of 1 in appreciable amounts, but rather gave the bicyclic compound 6 along with the
starting material 1. Because the formation of 6 was noticed by TLC analysis from the beginning
of reaction, the one-step procedure was tried by adding one equivalent of base to 1, then the
a,a%-dibromo-o-xylene and again a second equivalent of base, as described for 2 and 3. By this
simple protocol very good chemical yields were achieved and similar results have also been
obtained by using a,a%-dichloro-o-xylene and K-bis(trimethylsilyl)amide.
In order to explain the stereochemical results observed, a conformational analysis of the
lithium-enolate of 1 was performed5 showing the conformation 8a to be slightly more stable
(about 2 kcal/mol) than 8b (the hydrogen atoms are omitted for clarity). Conformer 8a should
induce the approach of the electrophile to the re face of the lithium-enolate (which is shielded
by the phenyl rings of the (S)-phenethyl group) leading to the (R)-diastereomer. In contrast,
conformer 8b should bring the electrophile onto the si face, affording the (S)-diastereomer. The
total stereocontrol observed on the bicyclic product (1S,10S)-6 might be rationalized by
considering that the sterically demanding a,a%-dibromo-o-xylene is forced to attack on the si face
of 8b instead of the sterically encumbered re face of 8a. Besides, the stereochemical outcome
might also be explained by supposing that the ring closure to the bicyclic compound 6 occurs
with an entropic gain due to the conformationally rigid electrophile used: in fact, as reported
above, the formation of bicyclic intermediate 6 was revealed from the beginning of the reaction.
The moderate diastereoselection observed with 1,4-diiodobutane could be in agreement with the
smaller steric hindrance of this electrophile rendering it unable to strongly discriminate between
the diastereotopic faces of the lithium-enolate, i.e. the electrophile can approach both the re and
si faces of 8a and 8b, respectively.

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3. Stereochemical assignments
The configurations of the introduced stereocenters of 2 and 3 relative to the phenethyl
1
moieties were assigned through the H NMR chemical shifts following the methodology already
employed,1,4 the absolute configuration following on from the known (S)-configuration of the
phenethyl groups. This approach is based on the shielding induced by the phenyl ring of the
(S)-phenethyl group on the bridged chain protons. From a preliminary conformational analysis
conducted on the simple model compound (1S,4S)-2,5-N,N-dimethyl-3,6-dioxo-2,5-diazabi-
cyclo[2,2,4]decane 9, conformers 9a and 9b have been found, the former being 7 kcal/mol more
stable than the latter. Thus, on the basis of the preferred geometry 9a, a complete conforma-
tional search of both 2 and 3 was performed showing that, as observed for analogous
derivatives,4 the conformation where the benzylic hydrogen of the (S)-phenethyl group is
synperiplanar to the adjacent carbonyl group (the heterocyclic ring being in the boat conforma-
tion) is energetically preferred.
Since the preferred geometry for these compounds is also the doubly synperiplanar conforma-
tion,4 the (R)-configuration of the two introduced stereocenters in 2 was established on the basis
of the remarkable upfield shift shown by the protons of the bridged chain (which resonate at
0.6–1.65 ppm) with respect to 3 (which resonate at 1.2–2.2 ppm), according to that observed for
previously investigated4 analogous intermediates.
Nevertheless, the assigned configuration of the new stereocenters was unequivocally confirmed
by converting the bicyclic intermediates into the corresponding a,a%-2,7-diaminosuberic acids
(R,R)-4 and (S,S)-5 (Scheme 1). The values of [h]D measured for 4, −40.8 (c 0.3, 5N HCl) or
−24.5 (c 0.22, H2O), and for 5, +41 (c 0.29, 5N HCl) or +24.6 (c 0.2, H2O), are in agreement
with those reported in the literature.6a,b Because only the diastereomer (1S,10S)-6 was obtained,
its configuration was established on the basis of the good agreement of specific rotation value
[h]D=+22.9 (c 0.8, 5N HCl), measured for (S,S)-7, with that reported in the literature.7

F. Paradisi et al. / Tetrahedron: Asymmetry 11 (2000) 4617–4622
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4. Experimental
4.1. General information
1H and 13C NMR spectra were run on a Varian Gemini 300 spectrometer and coupling
constants (J) are in hertz. Optical rotation values were measured at 25°C using a Perkin–Elmer
343 polarimeter. The reactions involving organometallic reagents were carried out under an
argon atmosphere in dry solvent.
4.2. Conversion of 1 into 2 and 3
To 1.6 g (5 mmol) of 1, dissolved in dry THF (100 mL) at −10°C, 5.5 mmol of Na-
bis(trimethylsilyl)amide base were added and the solution was stirred for 1 hour. Then the
reaction mixture was cooled at −78°C and 5 mmol of 1,4-diiodobutane were added. After 1
hour, 5.5 mmol of base were added and the reaction was then slowly allowed to warm up to
room temperature under stirring. Diluted HCl was then added, the mixture extracted with ethyl
acetate and the organic solution evaporated in vacuo. The residue was submitted to silica gel
chromatography eluting with hexane/ethyl acetate and the diastereomers 2 and 3 were separated.
4.3. (1R,4R,1%S)-2,5-Bis-[N,N-(1%-phenethyl)]-3,6-dioxo-2,5-diazabicyclo[4,2,2]decane 2
1
Compound 2 was isolated pure in 52% yield. H NMR l (CDCl3): 0.6–0.95 (m, 4H), 1.1–1.3
(m, 2H), 1.45–1.65 (m, 2H), 1.56 (d, 6H, J=6.8), 4.15 (dd, 2H, J=1.6, 7), 5.93 (q, 2H, J=6.8),
7.2–7.5 (m, 10ArH). 13C NMR l (CDCl3): 16, 22.6, 34.4, 50.9, 56.2, 128, 128.2, 128.5, 139,
169.3; [h]D −347.3 (c 0.67, CHCl3). Anal. calcd for C24H28N2O2: C, 76.56; H, 7.5. Found: C,
76.85; H, 7.52.
4.4. (1S,4S,1%S)-2,5-Bis-[N,N-(1%-phenethyl)]-3,6-dioxo-2,5-diazabicyclo[4,2,2]decane 3
1
Compound 3 was isolated pure in 28% yield. H NMR l (CDCl3): 1.2–1.4 (m, 2H), 1.58 (d,
6H, J=7.2), 1.8–1.95 (m, 2H), 2–2.2 (m, 4H), 3.94 (dd, 2H, J=2, 6.5), 5.85 (q, 2H, J=7.2),
7.2–7.45 (m, 10ArH). 13C NMR l (CDCl3): 16.7, 22.9, 36.1, 51.2, 56.2, 126.9, 127.9, 128.7,
139.2, 169.7; [h]D −136.5 (c 0.66, CHCl3). Anal. calcd for C24H28N2O2: C, 76.56; H, 7.5. Found:
C, 76.36; H, 7.47.
4.5. (1S,10S,1%S)-11,13-Bis-[N,N-(1%-phenethyl)]-11,13-diazatricyclo[8.2.2.03,8]tetradeca-3,5,7-
triene-12,14-dione 6
Compound 6 was isolated pure in 90% yield by starting from a,a%-dibromo-o-xylene and
1
Li-bis(trimethylsilyl)amide and following the procedure described for 2 and 3. H NMR l
(CDCl3): 1.41 (d, 6H, J=7.2), 3.2 (dd, 2H, J=6.6, 15.3), 3.46 (dd, 2H, J=6.6, 15.3), 4.15 (t, 2H,
J=6.6), 5.6 (q, 2H, J=7.2), 7.1–7.4 (m, 14ArH). 13C NMR l (CDCl3): 16.8, 40.9, 50.4, 54.4,
126.7, 127.7, 127.9, 128.7, 131.5, 136.3, 139.9, 168.7; [h]D −119.5 (c 0.66, CHCl3). Anal. calcd for
C28H28N2O2: C, 79.22; H, 6.65. Found: C, 79.51; H, 6.68.

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Acknowledgements
Thanks are due to MURST (COFIN 1998–2000) and to the University of Bologna for
financial support.
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