Stereoselective synthesis of bis(α-amino acid) derivatives isosteric of cysteine. Part 4

Article abstract of DOI:10.1016/S0957-4166(02)00262-8

Enantiomerically pure α-alkyl derivatives of α,α′-diaminodicarboxylic acids isosteric of cysteine 8a,b,e, 9a,b,e and 10a,b,e have been synthesized starting from the glycine-derived chiral synthon (1′S,1″S)-1.

Full text of DOI:10.1016/S0957-4166(02)00262-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1181–1187
Stereoselective synthesis of bis(a-amino acid) derivatives isosteric
with cysteine. Part 4†,‡
Federico Ferioli, Fabio Piccinelli, Gianni Porzi* and Sergio Sandri*
Dipartimento di Chimica ‘G. Ciamician’, Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 12 April 2002; accepted 30 May 2002
Abstract—Enantiomerically pure a-alkyl derivatives with a,a%-diaminodicarboxylic acids isosteric with cysteine 8a,b,e, 9a,b,e and
10a,b,e have been synthesized starting from the glycine-derived chiral synthon (1%S,1¦S)-1. © 2002 Elsevier Science Ltd. All rights
reserved.
included in small peptides, are of potential medicinal
importance.
1. Introduction
Recently, we have directed our efforts towards the
synthesis of enantiomerically pure a,a%-diaminodicar-
boxylic acids1–3 and corresponding tripeptides,4 as use-
ful structural variants of 2,6-diaminopimelic acid
(2,6-DAP) which is involved in the biosynthetic conver-
2. Results and discussion
The a,a%-diamino diacids derivatives 8a,b,e, 9a,b,e and
10a,b,e have been synthesized starting from the glycine-
derived chiral synthon 1, already employed by us in the
past.1,2 The methodology followed is based on the
conversion of chiral synthon 1 into the bicyclic deriva-
tives (3S)-22 and (3R)-3,2 in a 35:65 diastereomeric
mixture easily separable by silica gel chromatography,
or (3S)-62 which are alkylated and then submitted to
acid-induced cleavage to bis(a-amino acid) derivatives,
as summarized in Scheme 1.
sion of pyruvate and
L-aspartate to L-lysine both in
bacteria and higher plants. Thus, structural analogues
of 2,6-DAP, which can function as inhibitors in the
biosynthetic diaminopimelate pathway of
L-lysine
(DAP/lysine pathway), could display potential biologi-
cal activity both as antibacterial5 and herbicidal
agents.6 In fact, meso-2,6-DAP and
L-lysine are con-
stituents of the cell wall peptidoglycan of Gram(−) and
many Gram(+) bacteria, respectively.7,8
The alkylation of bicyclic intermediates 2, 3 and 6 to 4,
5 and 7, respectively (see Table 1), is complicated by the
competitive acidity of the bridgehead hydrogens and
the benzylic hydrogens of the (S)-phenylethyl group, as
has been observed previously for analogous bicyclic
compounds containing a C3 bridge.3 In fact, on forming
the anion of diastereomer 3 by treatment with 1.2
equiv. of LHMDS and alkylating, using PhCH2Br as
the electrophile, in addition to 5b, a complex mixture
containing the product alkylated at the benzylic posi-
tion is recovered. The use of n-C4H9Li as the base
allows 5b to be obtained in good yield and no by-
product is formed. In contrast, the same alkylation
reaction of diastereomer 2 gives better results when
CH3Li is used as the base. Analogously, for the conver-
sion of bicyclic derivative 6 into the corresponding
monoalkyl derivative 7 the best results are achieved by
using CH3Li as the base. The moderate yield registered
Herein, we report a stereoselective synthesis of alkyl
derivatives of 2,7-diaminosuberic acid and (S,S)-ortho-
phenylene-bis-alanine which are cysteine isosteres, the
disulfide bridge being substituted by an ethylene unit.
Therefore, these bis(a-amino acid) derivatives with all-
carbon C4 bridges can act as substitutes for cysteine. As
known, the disulfide unit in bioactive peptides confers
conformational constraint to the structure which may
be a very important factor in determining interactions
between a biologically active substrate (a peptide or
protein) and its receptor.9 Thus, such structures, when
* Corresponding authors. E-mail: porzi@ciam.unibo.it
† Dedicated to Professor Gianfranco Cainelli on the occasion of his
70th birthday.
‡ For Parts 1, 2 and 3, see Refs. 1, 2 and 3, respectively.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00262-8

1182
F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
Scheme 1. R=(a) CH3; (b) CH2Ph; (c) CH2OCH3; (d) CH2CHCH2; (e) CH2OH.
when benzyl bromide is employed as electrophile
(entry 10 in Table 1) is due to competitive alkylation
at the benzylic position. The results collated in Table
1 clearly show that alkylation at the bridgehead posi-
tion is preferred in the bicyclic derivatives with a C4
bridge (described in this paper) compared to those
with a C3 bridge as previously reported.3 In fact,
alkylation at the bridgehead position of the (1S,4S)-
diastereomer occurs in moderate yields3 (not greater
than 45%) for the bicyclic derivatives with a C3
bridge, while good to very good yields can be
obtained in the case of the corresponding bicyclic
compounds carrying a C4 bridge (Table 1). At the
moment, such a difference in behaviour is not easy
to explain, the factors involved probably being more
than one.

F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
Table 1. Alkylation of (1S,4S)-2, (1R,4R)-3 and (1S,4S)-6
1183
Entry
Substrate
Base (equiv.)
RꢀX (equiv.)
Yield (%)
4
5
7
1
2
3
4
5
6
7
8
(1S,4S)-2
(1S,4S)-2
(1S,4S)-2
(1S,4S)-2
(1R,4R)-3
(1R,4R)-3
(1R,4R)-3
(1R,4R)-3
(1S,4S)-6
(1S,4S)-6
(1S,4S)-6
(1S,4S)-6
CH3Li (1.2)
CH3Li (1.2)
CH3Li (1.2)
CH3Li (1.2)
n-C4H9Li (1.2)
n-C4H9Li (1.2)
n-C4H9Li (1.2)
n-C4H9Li (1.2)
CH3Li (1.3)
CH3Li (1.3)
CH3Li (1.4)
CH3Li (1.3)
CH3I (1.2)
93
85
92
78
PhCH2Br (1.2)
CH3OCH2Br (1.2)
CH2ꢁCHCH2Br (1.2)
CH3I (1.2)
PhCH2Br (1.2)
CH3OCH2Br (1.2)
CH2ꢁCHCH2Br (1.2)
CH3I (1.3)
70
70
95
72
9
94
60a
87
72
10
11
12
PhCH2Br (1.3)
CH3OCH2Br (1.2)
CH2ꢁCHCH2Br (1.3)
a A by-product derived from alkylation at the benzylic position has been observed.
The bicyclic intermediates 4a–c, 5a–c and 7a–c were
then submitted to cleavage with 57% aqueous HI3,10
and, after adsorption on Amberlyst H-15 ion-exchange
resin, the pure optically active monoalkyl derivatives of
2,7-diaminosuberic acid 8a,b,e, 9a,b,e and (S,S)-ortho-
phenylene-bis-alanine 10a,b,e can be recovered, in zwit-
terionic form, by eluting with 5 M aqueous ammonia.
Due to the fact that hydrolysis in refluxing aqueous
57% HI is markedly slower (requiring at least 24 h)
than that previously observed for analogous bicyclic
compounds with a C3 bridge,3 the methoxymethyl
group undergoes cleavage and is converted into a
hydroxymethyl group. Thus, 8e, 9e, and 10e are
obtained from 4c, 5c and 7c, respectively. Under such
harsh hydrolytic conditions the double bond of the allyl
group in 4d, 5d and 7d also reacts and the correspond-
ing bis(a-amino acid) derivatives cannot be isolated. To
circumvent this problem, we tried a two step pathway
consisting of removal of the phenylethyl group (the
chiral inductor) by Birch reduction and subsequent acid
hydrolysis of intermediates 11c,d and 12c,d (Scheme 2).
Nevertheless, even using this alternative pathway, the
hydrolytic conditions required (refluxing aqueous 37%
HCl for at least 60 h) are drastic enough to effect
cleavage of the methoxymethyl ether to a hydroxy-
methyl group and additionally, the allyl double bond is
also reactive, giving a number of products. On the
other hand, in aqueous 3N HCl hydrolysis does not
occur, while in 6N HCl the reaction is very slow and
after 100 h only 20% of the substrate is reacted.
Most probably, the marked decrease in the rate of acid
hydrolysis observed for the bicyclic compounds 4 and 5
compared to the C3 bridged analogues,3 is due to the
size of the intermediate lactam derived from the cleav-
age of one amide function. In fact, the hydrolysis of a
bicyclic derivative bearing a C3 bridge furnishes a 2-
azacycleptanoic system, which is less flexible than the
2-azacyclooctanoic one derived from 4 or 5. The greater
flexibility of the eight-membered ring with respect to
the seven-membered one causes a decrease in the reac-
tivity of the lactam. The bicyclic derivatives 7, with an
ortho-substituted phenyl ring, showed intermediate
hydrolysis rates between 4, 5 and the bicyclic deriva-
tives bearing a C3 bridge.3 In actual fact, with the same
lactam ring size, the presence of the phenyl ring causes
a decrease in the flexibility of the cyclic system and
consequently a greater reactivity.
Scheme 2. R=(c) CH2OCH3; (d) CH2CHCH2; (e) CH2OH.

1184
F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
3. Conclusion
4.5.1. (1S,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-1-
methyl-2,5-diazabicyclo[4.2.2]decane 4a. Obtained by
alkylating 2 with iodomethane and isolated in 93%
In conclusion, starting from the easily prepared chiral
heterocyclic synthon 1, we have accomplished an enan-
tioselective synthesis of 2,7-diaminodicarboxylic acid
derivatives, which can be considered interesting surro-
gates for cysteine in biologically active small peptides.
This methodology is of potential pharmacological
importance due to enhanced interaction with the recep-
tor. The approach, consisting of three steps, is simple
and suitable for preparing various derivatives isosteric
with cysteine.
1
yield. H NMR: l 0.9–2.2 (m, 8H), 1.4 (bs, 3H), 1.62
(d, 3H, J=7.4), 1.76 (d, 3H, J=7.4), 3.95 (d, 1H, J=6),
5.88 (q, 1H, J=7.4), 5.8–6.4 (broad, 1H), 7.2–7.5 (m,
10ArH). 1H NMR (DMSO, 80°C): l 0.88–2.24 (m, 8H),
1.37 (s, 3H), 1.58 (d, 3H, J=7.4), 1.7 (d, 3H, J=7.4),
3.82 (dd, 1H, J=1.5, 6), 5.69 (q, 1H, J=7.4), 5.71 (m,
1H), 7.15–7.35 (m, 10ArH). 13C NMR: l 16.6, 17.3,
22.7, 23.8, 25.8, 36.6, 44.9, 51 (broad), 52.2, 55.8, 65,
126.7, 126.9, 127.8, 128, 128.6, 139.2, 142.1, 171.4,
171.6. [h]D=−49.7 (c 0.84, CHCl3). Anal. calcd for
C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C,
76.66; H, 7.77; N, 7.15%.
4. Experimental
4.5.2.
(1R,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-benzyl-
4.1. General information
3,6-dioxo-2,5-diazabicyclo[4.2.2]decane 4b. Obtained by
alkylating 2 with benzyl bromide and isolated in 85%
yield. 1H NMR: l 0.44–2.27 (m, 8H), 1.27 (d, 3H,
J=7), 1.66 (d, 3H, J=7.3), 3.21 (d, 1H, J=16.8), 3.93
(dd, 1H, J=1.4, 6.6), 4.43 (q, 1H, J=7), 4.48 (d, 1H,
J=16.8), 5.79 (q, 1H, J=7.3), 7–7.8 (m, 15ArH). 13C
NMR: l 17.1, 20.8, 22, 23.1, 37.3, 43.8, 44.1, 53.9, 56.7,
58.2, 69.7, 126.4, 127.6, 128.1, 128.3, 128.6, 128.9,
129.4, 136.5, 139.1, 141.9, 170.7, 170.8. [h]D=+94.8 (c
0.22, CHCl3). Anal. calcd for C31H34N2O2: C, 79.79; H,
7.34; N, 6. Found: C, 80.02; H, 7.36; N, 5.98%.
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.
The coupling constants (J) are in Hz. Optical rotation
values were measured on a Perkin–Elmer 343 polarime-
ter. Dry THF was distilled from sodium benzophenone
ketyl. Chromatographic separations were performed
with silica gel 60 (230–400 mesh).
4.5.3. (1R,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-1-
4.2. (1S,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-2,5-
methoxymethyl-2,5-diazabicyclo[4.2.2]
decane
4c.
diazabicyclo[4.2.2]decane 2
Obtained by alkylating 2 with bromomethyl methyl
1
ether and isolated in 92% yield. H NMR: l 0.65–2.13
The procedure, NMR spectra and [h]D value are
reported in Ref. 2.
(m, 8H), 1.61 (d, 3H, J=7.2), 1.89 (d, 3H, J=6.9), 3.38
(s, 3H), 3.69 (dd, 1H, J=1.8, 6.6), 3.83 (d, 1H, J=
10.2), 4.33 (d, 1H, J=10.2), 4.78 (q, 1H, J=7.2), 5.81
(q, 1H, J=6.9), 7.15–7.7 (m, 10ArH). 13C NMR: l
16.4, 19.5, 22.1, 22.4, 36.4, 37.7, 52.4, 56, 56.1, 58.6,
69.1, 74.3, 126.8, 126.9, 127.3, 128.3, 138.8, 141.2,
169.5, 170.3. [h]D 133.7 (c 1.04, CHCl3). Anal. calcd for
C26H32N2O3: C, 74.26; H, 7.67; N, 6.66. Found: C,
74.17; H, 7.7; N, 6.67%.
4.3. (1R,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-
2,5-diazabicyclo[4.2.2]decane 3
The procedure, NMR spectra and [h]D value are
reported in Ref. 2.
4.4. (1S,10S,1%S)-11,13-Bis-[N-(1%-phenethyl)]-11,13-
4.5.4. (1R,4S,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-allyl-3,6-
dioxo-2,5-diazabicyclo[4.2.2]decane 4d. Obtained by
alkylating 2 with allyl bromide and isolated in 78%
yield. 1H NMR: l 0.4–2.2 (m, 8H), 1.62 (d, 3H, J=7.4),
1.86 (d, 3H, J=7.1), 2.77 (dd, 1H, J=7.6, 15.6), 3.55
(m, 1H), 3.75 (dd, 1H, J=1.4, 6.4), 4.66 (q, 1H, J=
7.1), 5.3 (m, 2H), 5.64–5.84 (m, 2H), 7.2–7.77 (m,
10ArH). 13C NMR: l 16.7, 21.3, 21.9, 22.7, 36.9, 41.9,
42.8, 53, 56.2, 56.7, 69.3, 118.3, 126.9, 127.4, 127.6,
127.9, 128.5, 129.1, 132.7, 139, 141.6, 170.2, 171.3.
[h]D=+207.1 (c 1.26, CHCl3). Anal. calcd for
C27H32N2O2: C, 77.85; H, 7.74; N, 6.73. Found: C,
77.59; H, 7.76; N, 6.7%.
diazatricyclo[8.2.2.03,8]tetradeca-3,5,7-triene-12,14-dione
6
The procedure, NMR spectra and [h]D value are
reported in Ref. 2.
4.5. Alkylation of 2, 3 and 6: general procedure
To a stirred solution of 2, 3 or 6 (2 mmol) in dry THF
(60 mL) cooled at −78°C, was added the base (see
Table 1). After about 5 min the appropriate alkylating
reagent was added and the reaction was then monitored
by TLC. When the reaction was practically complete,
the mixture was allowed to warm to room temperature
with stirring. Diluted 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.
4.5.5. (1R,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-
1-methyl-2,5-diazabicyclo[4.2.2]decane 5a. Obtained by
alkylating 3 with iodomethane and isolated in 70%
yield. 1H NMR: l 0.75–2.13 (m, 8H), 1.57 (d, 3H,
J=7.4), 1.71 (s, 3H), 1.84 (d, 3H, J=6.9), 4.02 (dd, 1H,
J=1.4, 6.8), 4.63–4.95 (broad, 1H), 5.96 (q, 1H, J=

F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
1185
7.4), 7.15–7.5 (m, 10ArH). 13C NMR: l 16.7, 18.8, 22.5,
24.6, 26.5, 35.5, 43.5, 52.1, 54.4, 56.4, 65.9, 126.4, 126.9,
128.3, 128.4, 139.7, 142.4, 170.4, 171. [h]D=−168.2 (c
1.41, CHCl3). Anal. calcd for C25H30N2O2: C, 76.89; H,
7.74; N, 7.17. Found: C, 77.1; H, 7.75; N, 7.15%.
4.5.10. (1S,10S,1%S)-11,13-Bis-[N-(1%-phenethyl)]-1-ben-
zyl-11,13-diazatricyclo[8.2.2.03,8]tetradeca-3,5,7-triene-
12,14-dione 7b. Obtained by alkylating 6 with benzyl
1
bromide and isolated in 60% yield. H NMR: l 1.36 (d,
3H, J=7), 1.38 (d, 3H, J=7.4), 2.91 (d, 1H, J=15),
3.21 (d, 1H, J=15), 3.31 (d, 2H, J=6.4), 3.43 (d, 1H,
J=16.8), 4.4 (t, 1H, J=6.4), 4.46 (d, 1H, J=16.8), 4.59
(q, 1H, J=7), 5.37 (q, 1H, J=7.4), 6.78–7.71 (m,
19ArH). 13C NMR: l 17.6, 20.5, 40.1, 44.2, 51.1, 52.4,
54.6, 57.7, 68.4, 126.3, 126.6, 127.3, 127.5, 127.6, 128.2,
128.5, 128.6, 128.7, 128.8, 131, 131.4, 134.9, 136.6,
137.2, 141.3, 142.7, 168.3, 171.7. [h]D=+30.7 (c 0.91,
CHCl3). Anal. calcd for C35H34N2O2: C, 81.68; H, 6.66;
N, 5.44. Found: C, 81.91; H, 6.68; N, 5.42%.
4.5.6.
(1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-benzyl-
3,6-dioxo-2,5-diazabicyclo[4.2.2]decane 5b. Obtained by
alkylating 3 with benzyl bromide and isolated in 70%
yield. 1H NMR: l 0.94–2.3 (m, 8H), 1.67 (d, 3H,
J=7.4), 1.8 (d, 3H, J=7), 3 (d, 1H, J=16), 4.07 (dd,
1H, J=1, 6.2), 4.29 (d, 1H, J=16), 4.69 (q, 1H, J=7),
5.87 (q, 1H, J=7.4), 6.56–7.53 (m, 15ArH). 13C NMR:
l 16.1, 17.6, 21.8, 23.7, 35.7, 43.5, 43.8, 52.7, 54.4, 56.7,
69.2, 125.2, 125.7, 125.9, 126.9, 127.7, 127.8, 128.1,
129.1, 135.6, 139.1, 140.9, 170.5, 170.7. [h]D=−187.5 (c
1.03, CHCl3). Anal. calcd for C31H34N2O2: C, 79.79; H,
7.34; N, 6. Found: C, 80.08; H, 7.37; N, 6.01%.
4.5.11.
(1R,10S,1%S)-11,13-Bis-[N-(1%-phenethyl)]-1-
methoxymethyl - 11,13 - diazatricyclo[8.2.2.03,8]tetradeca-
3,5,7-triene-12,14-dione 7c. Obtained by alkylating 6
with bromomethyl methyl ether and the product was
1
isolated in 87% yield. H NMR: l 1.29 (d, 3H, J=7.4),
4.5.7. (1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-3,6-dioxo-1-
1.82 (d, 3H, J=7), 2.68–3.12 (broad, 2H), 3.15–3.36 (m,
2H), 3.5 (s, 3H), 3.86–4.47 (broad, 3H), 4.7–5.2 (broad,
1H), 5.54 (q, 1H, J=7.4), 6.82–7.63 (m, 14ArH). 13C
NMR: l 16.6, 19.4 (broad), 39.5, 45.6, 51.2, 54.4, 56.3
(broad), 59, 67.4 (broad), 73.5, 126.4, 126.9, 127.3,
127.4, 127.5, 127.9, 128.3, 128.5, 130.7, 131.3, 135.7,
136.4, 140, 142, 167.9, 171.1. [h]D=+82.4 (c 2.08,
CHCl3). Anal. calcd for C30H32N2O3: C, 76.9; H, 6.88;
N, 5.98. Found: C, 76.8; H, 6.85; N, 6.0%.
methoxymethyl-2,5-diazabicyclo[4.2.2]
decane
5c.
Obtained by alkylating 3 with bromomethyl methyl
1
ether and isolated in 95% yield. H NMR: l 0.74–2.05
(m, 8H), 1.59 (d, 3H, J=7.4), 1.82 (d, 3H, J=7), 3.25
(s, 3H), 3.68 (d, 1H, J=10.2), 3.96 (dd, 1H, J=1.6,
6.6), 4.31 (d, 1H, J=10.2), 4.74 (q, 1H, J=7), 6.02 (q,
1H, J=7.4), 7.15–7.56 (m, 10ArH). 13C NMR: l 16,
16.6, 22, 22.6, 34.7, 37.8, 51.3, 53.3, 55.5, 58.2, 68.1,
74.1, 125.5, 125.8, 127.1, 127.4, 127.5, 127.9, 139, 141.9,
168.8, 170.1. [h]D=−224.9 (c 0.53, CHCl3). Anal. calcd
for C26H32N2O3: C, 74.26; H, 7.67; N, 6.66. Found: C,
74.51; H, 7.7; N, 6.64%.
4.5.12. (1S,10S,1%S)-11,13-Bis-[N-(1%-phenethyl)]-1-allyl-
11,13 - diazatricyclo[8.2.2.03,8]tetradeca - 3,5,7 - triene-
12,14-dione 7d. Obtained by alkylating 6 with allyl
1
4.5.8. (1S,4R,1%S)-2,5-Bis-[N-(1%-phenethyl)]-1-allyl-3,6-
dioxo-2,5-diazabicyclo[4.2.2]decane 5d. Obtained by
alkylating 3 with allyl bromide and isolated in 72%
yield. 1H NMR: l 0.75–2.18 (m, 8H), 1.62 (d, 3H,
J=7.4), 1.85 (d, 3H, J=6.6), 2.58 (dd, 1H, J=7.4,
15.4), 3.35 (m, 1H), 4.04 (dd, 1H, J=1.4, 7), 4.72 (q,
1H, J=6.6), 4.86–5 (m, 2H), 5.47 (m, 1H), 5.96 (q, 1H,
J=7.4), 7.15–7.54 (m, 10ArH). 13C NMR: l 16.8, 18.3,
22, 23.7, 35.5, 42.1, 42.6, 51.8, 54.4, 56, 68.7, 118.7, 126,
126.2, 127.6, 127.8, 127.9, 128.3, 132.3, 139.1, 142.2,
170, 171.2. [h]D=−185.4 (c 0.58, CHCl3). Anal. calcd
for C27H32N2O2: C, 77.85; H, 7.74; N, 6.73. Found: C,
78.11; H, 7.77; N, 6.7.
bromide and isolated in 72% yield. H NMR: l 1.29 (d,
3H, J=7.4), 1.79 (d, 3H, J=7), 2.8–3.2 (bm, 3H),
3.2–3.5 (bm, 3H), 4.18 (dd, 1H, J=4.8, 8.8), 5–5.2
(broad, 1H), 5.2–5.4 (m, 2H), 5.5 (q, 1H, J=7.4),
5.8–6.1 (m, 1H), 6.9–7.6 (m, 14ArH). 13C NMR: l 16.6,
20.1, 39.4, 42.8, 49.7, 51.1, 54.2, 55 (broad), 67, 118.4,
126.1, 127, 127.2, 127.4, 128, 128.2, 128.4, 130.4, 131.2,
134.6, 135.3, 136.8, 140.3, 142.1, 168.3, 172.1. [h]D 77.2
(c 1.94, CHCl3). Anal. calcd for C31H32N2O2: C, 80.14;
H, 6.94; N, 6.03. Found: C, 80.32; H, 6.97; N, 6.01%.
4.6. Acid hydrolysis of bicyclic intermediates 4a–c, 5a–
c and 7a–c: general procedure
4.5.9. (1S,10S,1%S)-11,13-Bis-[N-(1%-phenethyl)]-1-methyl-
The procedure used is described in Ref. 10. The crude
reaction product was purified by adsorption on
Amberlyst H-15 ion-exchange resin and recovered in
pure form after elution with aqueous 5 M NH4OH. The
aqueous solution was evaporated in vacuo and the
residue dissolved in aqueous 2N HCl. The acid solution
was evaporated under vacuum to dryness and the
diamino diacid, as its hydrochloride, was then recov-
ered in practically quantitative yield.
11,13 - diazatricyclo[8.2.2.03,8]tetradeca - 3,5,7 - triene-
12,14-dione 7a. Obtained by alkylating
6
with
1
iodomethane and isolated in 94% yield. H NMR: l 1.4
(d, 3H, J=7.2), 1.48 (s, 3H), 1.68 (d, 3H, J=7.8), 3.19
(qAB, 2H, J=15.3), 3.27 (dd, 1H, J=7.8, 15.5), 3.46
(dd, 1H, J=5, 15.5), 4.31 (dd, 1H, J=5, 7.8), 5.63 (q,
1H, J=7.2), 5.8 (m, 1H), 6.96–7.42 (m, 14ArH). 13C
NMR: l 16.4, 17.5, 25.7, 39.8, 50.8 (broad), 51.7, 54,
63.4, 126.1, 126.3, 126.4, 127.1, 127.2, 127.4, 128, 128.3,
130.6, 135.7, 136.4, 140.1, 141.8, 169.8, 171.1. [h]D=
−31.4 (c 1.57, CHCl3). Anal. calcd for C29H30N2O2: C,
79.42; H, 6.9; N, 6.39. Found: C, 79.21; H, 6.88; N,
6.36%.
4.6.1. (2S,7S)-2-Methyl-2,7-diaminosuberic acid dihy-
drochloride 8a. The product was obtained by refluxing
1
4a for about 24 h. H NMR (D2O): l 1.09–1.4 (m, 2H),

1186
F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
1.4–1.62 (m, 1H), 1.42 (s, 3H), 1.63–2.08 (m, 5H), 3.88
(t, 1H, J=6.3). 13C NMR: l 22.4, 23.2, 24.7, 30, 36.9,
53.4, 60.7, 172.5, 174.5. [h]D 31.1 (c 0.49, 1N HCl).
Anal. calcd for C9H20Cl2N2O4: C, 37.13; H, 6.92; N,
9.62. Found: C, 37.05; H, 6.95; N, 9.6.
4.6.9.
(2%R,2¦S)-1[(2%-Amino-2%-carboxy-2%-hydroxy-
methyl)ethyl] - 2 - [(2¦ - amino - 2¦ - carboxy)ethyl]benzene
dihydrochloride 10e. The product was obtained by
refluxing 7c for about 30 h. H NMR (D2O): l 3.02–
1
3.32 (m, 4H), 3.7 (d, 1H, J=12.1), 3.98 (d, 1H, J=
12.1), 4.06 (q, 1H, J=6.6, 8.4), 7.1–7.4 (m, 4ArH). 13C
NMR: l 33.2, 34.4, 54.7, 63.7, 66.2, 129.2, 129.6, 131.5,
132.1, 134.5, 171.7, 172.1. [h]D=+10.6 (c 0.44, 1H
HCl). Anal. calcd for C13H20Cl2N2O5: C, 43.96; H,
5.68; N, 7.89. Found: C, 43.8; H, 5.7; N, 7.86%.
4.6.2. (2R,7S)-2-Benzyl-2,7-diaminosuberic acid dihy-
drochloride 8b. The product was obtained by refluxing
1
4b for about 24 h. H NMR (D2O): l 1.05–2.04 (m,
8H), 2.86 (d, 1H, J=14.3), 3.18 (d, 1H, J=14.3), 3.58
(t, 1H, J=6.2), 7.04–7.33 (m, 5ArH). 13C NMR: l 23.5,
25.1, 30.7, 36.3, 42.5, 55.3, 66.3, 128.4, 129.6, 130.7,
134.5, 175.3, 175.7. [h]D=+18.2 (c 0.18, 1N HCl). Anal.
calcd for C14H24Cl2N2O4: C, 47.33; H, 6.81; N, 7.89.
Found: C, 47.19; H, 6.83; N, 7.91%.
4.7. Conversion of 4c,d and 5c,d into 11c,d and 12c,d:
general procedure
Under an inert atmosphere, a solution of 4c,d or 5c,d
(1.5 mmol) in dry THF (10 mL) and t-butanol (1 mL)
was added to a stirred solution of Na (0.46 g, 20 mmol)
in liquid ammonia (about 60 mL) cooled to −60°C.
After 5 min the reaction was quenched with NH4Cl (1
g) and the cooling bath was removed to allow the
complete evaporation of NH3. Water was added, the
crude product was extracted with ethyl acetate and the
organic solvent evaporated in vacuo The product was
recovered pure after silica gel chromatography eluting
with hexane/ethyl acetate in very good yield.
4.6.3. (2R,7S)-2-Hydroxymethyl-2,7-diaminosuberic acid
dihydrochloride 8e. The product was obtained by reflux-
ing 4c for about 30 h. It can be also obtained in very
good yield by refluxing 11c for at least 60 h in 37%
1
HCl. H NMR (D2O): l 0.98–1.5 (m, 4H), 1.52–2 (m,
4H), 3.59 (d, 1H, J=12.1), 3.87 (d, 1H, J=12.1), 3.89
(m, 1H). 13C NMR: l 22.8, 24.7, 29.9, 31.9, 53.3, 64.2,
65.7, 172.4, 172.6. [h]D=+20.9 (c 0.96, 1N HCl). Anal.
calcd for C9H20Cl2N2O5: C, 35.19; H, 6.56; N, 9.12.
Found: C, 35.3; H, 6.54; N, 9.1%.
4.6.4. (2R,7R)-2-Methyl-2,7-diaminosuberic acid dihy-
drochloride 9a. The product was obtained from 5a.
[h]D=−31.5 (c 0.53, 1N HCl).
4.7.1. (1R,4S)-3,6-Dioxo-1-methoxymethyl-2,5-diazabi-
cyclo[4.2.2]decane 11c. The product was obtained from
compound 4c. 1H NMR (CH3OD): l 1.38–1.66 (m,
2H), 167–1.92 (m, 4H), 1.95–2.2 (m, 2H), 3.37 (s, 3H),
3.39 (d, 1H, J=9.6), 3.73 (d, 1H, J=9.6), 3.94 (dd, 1H,
J=3, 4.8). 13C NMR: l 23.9, 24.2, 37.2, 40.1, 56.1,
59.5, 62.8, 76.2, 173.7, 173.9. [h]D=+164.6 (c 1.15,
CH3OH). Anal. calcd for C18H24N2O3: C, 68.33; H,
7.65; N, 8.85. Found: C, 68.08; H, 7.68; N, 8.88%.
4.6.5. (2S,7R)-2-Benzyl-2,7-diaminosuberic acid dihy-
drochloride 9b. The product was obtained from 5b.
[h]D=−18.8 (c 0.15, 1N HCl).
4.6.6. (2S,7R)-2-Hydroxymethyl-2,7-diaminosuberic acid
dihydrochloride 9e. The product was obtained from 5c.
It can be also obtained in very good yield by refluxing
12c for at least 60 h in 37% HCl. [h]D=−21.4 (c 0.82,
1N HCl).
4.7.2. (1R,4S)-1-Allyl-3,6-dioxo-2,5-diazabicyclo[4.2.2]-
decane 11d. The product was obtained from compound
1
4d. H NMR (CH3OD): l 1.43–2.28 (m, 8H), 2.21 (m,
4.6.7. (2%S,2¦S)-1[(2%-Amino-2%-carboxy-2%-methyl)ethyl]-
1H), 2.75–2.86 (m, 1H), 3.91 (dd, 1H, J=3, 5.2), 5.05–
5.26 (m, 2H), 5.62–5.85 (m, 1H). 13C NMR: l 23.8,
24.7, 37.4, 43.1, 44.8, 56.2, 71.1, 119.7, 133.6, 174,
174.5. [h]D=+239 (c 0.79, CH3OH). Anal. calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C,
73.25; H, 7.76; N, 8.94%.
2-[(2¦-amino-2¦-carboxy)ethyl]benzene
dihydrochloride
10a. The product was obtained by refluxing 7a for
1
about 24 h. H NMR (D2O): l 1.44 (s, 3H), 3.02 (dd,
1H, J=8, 15), 3.13 (qAB, 2H, J=15.8), 3.26 (dd, 1H,
J=6.6, 15), 3.77 (dd, 1H, J=6.6, 8), 7.1–7.3 (m, 4ArH).
13C NMR: l 22.8, 34.2, 39.2, 56.3, 62.6, 128.6, 128.9,
131.3, 131.9, 133.8, 135.4, 174.1, 176.3. [h]D=+5.6 (c
1.26, 1N HCl). Anal. calcd for C13H20Cl2N2O4: C,
46.03; H, 5.94; N, 8.26. Found: C, 46.13; H, 5.92; N,
8.24%.
4.7.3. (1S,4R)-3,6-Dioxo-1-methoxymethyl-2,5-diazabi-
cyclo[4.2.2]decane 12c. The product was obtained from
5c. [h]D=−166 (c 0.73, CH3OH).
4.6.8. (2%R,2¦S)-1[(2%-Amino-2%-benzyl-2%-carboxy)ethyl]-
4.7.4. (1S,4R)-1-Allyl-3,6-dioxo-2,5-diazabicyclo[4.2.2]-
decane 12d. The product was obtained from 5d. [h]D=
−240.7 (c 0.32, CH3OH).
2-[(2¦-amino-2¦-carboxy)ethyl]benzene
dihydrochloride
10b. The product was obtained by refluxing 7b for
about 24 h. 1H NMR (D2O): l 3 (d, 1H, J=14.6),
3.07–3.37 (m, 2H), 3.2 (d, 1H, J=14.6), 3.45 (d, 2H,
J=14.6), 4.02 (t, 1H, J=7.2), 7.11–7.35 (m, 9ArH). 13C
NMR: l 33.7, 38.4, 42, 54.9, 66.1, 128.9, 129.2, 129.6,
129.8, 130.8, 131.6, 132.2, 132.6, 133.3, 134.8, 172,
173.3. [h]D=−10.7 (c 0.51, 1N HCl). Anal. calcd for
C19H24Cl2N2O4: C, 54.95; H, 5.82; N, 6.75. Found: C,
55.07; H, 5.8; N, 6.76%.
Acknowledgements
Thanks are due to MIUR (COFIN 2000) and to the
University of Bologna for financial support.

F. Ferioli et al. / Tetrahedron: Asymmetry 13 (2002) 1181–1187
1187
References
6519.
6. Dereppe, C.; Bold, G.; Ghisalba, O.; Erbert, E.; Schar,
H. P. Plant Physiol. 1992, 98, 813.
1. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetra-
hedron: Asymmetry 2000, 11, 1259.
2. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetra-
7. Vederas, J. C.; et al. J. Org. Chem. 1994, 59, 5784.
8. Bull, S. D.; Chernega, A.; Davies, S. G.; Moss, W. O.;
Parkin, R. M. Tetrahedron 1998, 54, 10379.
hedron: Asymmetry 2000, 11, 4617.
9. Kremminger, P.; Undheim, K. Tetrahedron 1997, 53,
6925 and references cited therein.
3. Paradisi, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetra-
hedron: Asymmetry 2002, 13, 497.
10. (a) Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992,
57, 6532; (b) Orena, M.; Porzi, G.; Sandri, S. J. Chem.
Res. (S) 1993, 318, 2125.
4. Paradisi, F.; Porzi, G.; Sandri, S. Tetrahedron: Asymme-
try 2001, 12, 3319.
5. Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57,