Stereocontrolled synthesis of enantiomerically pure unsaturated analogues of 2,6-DAP. Part 5

Article abstract of DOI:10.1016/S0957-4166(02)00834-0

An efficient new stereocontrolled synthesis of (2R,6R)-(+)- and (2S,6S)-(-)-2,6-diamino-4-methylene-1,7-heptanedioic acid 8a and 9a, respectively, has been accomplished starting from the glycine-derived chiral synthon 1. The enantiomerically pure α-alkyl

Full text of DOI:10.1016/S0957-4166(02)00834-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 393–398
Stereocontrolled synthesis of enantiomerically pure unsaturated
analogues of 2,6-DAP. Part 5ꢀ
Fabio Piccinelli, Gianni Porzi,* Monica Sandri and Sergio Sandri*
Dipartimento di Chimica ‘G. Ciamician’ Universita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 13 November 2002; accepted 9 December 2002
Abstract—An efficient new stereocontrolled synthesis of (2R,6R)-(+)- and (2S,6S)-(−)-2,6-diamino-4-methylene-1,7-heptanedioic
acid 8a and 9a, respectively, has been accomplished starting from the glycine-derived chiral synthon 1. The enantiomerically pure
a-alkyl derivatives 8b–d and 9b–d have also been synthesized. The absolute configuration of the new stereocenters was assigned
1
on the basis of H NMR spectra. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
ertheless, the absolute configuration of the enantiomers
was not assigned.5 On the basis of the bacteriological
and enzymatic tests, performed on both isomers,
Girodeau et al.5 suggested that the target enzyme in the
In continuation of our program aimed at the stereospe-
cific synthesis of novel analogues of 2,6-diaminopimelic
acid (2,6-DAP),1–4 we have recently focused our atten-
tion on both the enantiomers of the 2,6-diamino-4-
methylene-1,7-heptanedioic acid (8a,9a). Our interest in
this g-methylene derivative of 2,6-DAP arises from a
preliminary study by Girodeau et al.,5 who found that
it displays potent bacterial growth inhibition (E. coli
ATCC9637), although it is a weak inhibitor of the
inhibition of
L-lysine biosynthetic pathway could be
L,L-DAP epimerase. However, this hypothesis was suc-
cessively questioned by Vederas et al.7 who synthesized
and tested some analogues of 2,6-DAP for inhibition
of meso-diaminopimelate
D
-dehydrogenase (from B.
sphaericus) and
E. coli ).
L,L-diaminopimelate epimerase (from
meso-2,6-DAP decarboxylase which produces L-lysine.
In fact, the 2,6-diamino-4-methylene-1,7-heptanedioic
acid can be considered a structural variant i.e. an
analog of 2,6-DAP, which is a building block of the
peptidoglycan synthesized by Gram(+) and many
Gram(−) bacteria. Nevertheless, it is known that the
Herein, we describe an efficient enantioselective synthe-
sis of (2R,6R)-8a and (2S,6S)-9a in addition to some
alkyl derivatives of g-methylene-2,6-DAP (8b–d, 9b–d)
which could exhibit biological activity. The synthesis of
these compounds has been accomplished starting from
the useful glycine derived chiral synthon 1, already
employed by us in the past in several stereocontrolled
synthesis of DAP derivatives.1–4
meso-2,6-DAP is generally
a component of the
peptidoglycan6 and
L
-lysine is also introduced as part
of the cross-linking moiety in this network, which gives
rigidity to the cell wall in many bacteria. Therefore,
compounds able to inhibit meso-2,6-DAP formation or
metabolism by bacteria will possess antibiotic
properties.7
2. Results and discussion
Both enantiomers of g-methylene-2,6-DAP 8a and 9a
have been synthesized following the efficient strategy
reported in Scheme 1 and already employed by us for
similar compounds, such as 2,6-diaminopimelic and
2,7-diaminosuberic acids.1–4 The chiral synthon (S,S)-
1,8 submitted to alkylation with 2-chloromethyl-3-
chloropropene employing 2 equiv. of base, furnished
(3R,6R,1%S)-2 and (3S,6S,1%S)-3 in very good chemical
yield with a diastereomeric ratio of 30:70 respectively.
The g-methylene analogue of 2,6-DAP was synthesized
in racemic form by means of a laborious procedure, the
two enantiomers (2S,6S and 2R,6R) were then sepa-
rated and the specific rotation values determined. Nev-
ꢀ Refs. 1, 2, 3 and 4 are considered to be Parts 1, 2, 3 and 4,
respectively.
* Corresponding authors. E-mail: porzi@ciam.unibo.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00834-0

394
F. Piccinelli et al. / Tetrahedron: Asymmetry 14 (2003) 393–398
Scheme 1.
The bicyclic diastereomers, easily separable by silica gel
chromatography, were submitted to the Birch reduction
(Na/NH3) to remove the chiral inductor (S)-phenethyl
group. The intermediate enantiomers (3R,6R)-4a and
(3S,6S)-5a were then obtained and subsequently fur-
nished the optically active g-methylene derivatives of
2,6-DAP 8a and 9a after hydrolysis in 2N aqueous HCl
at 60°C (Scheme 1). The specific rotations determined
(+20.1 (c 0.73, H2O) for (2R,6R)-8a and −20 (c 0.65,
H2O) for (2S,6S)-9a) are higher than the values
reported in the literature,5 i.e. −18 (c 0.2, H2O) and +14
(c 0.17, H2O), respectively.
tory to good yields and unreacted starting material
(Scheme 1). In the case of diastereomer 3, by using
CH3Li as base, the alkylation generally occurred in
good yields at the bridgehead position, giving 7. If the
alkylation with CH3I is accomplished using the bulkier
n-C4H9Li as base, the bicyclic diastereomer 7 was
formed in lower yield owing to competitive reaction at
the benzylic position, which furnishes the by-products
10 and 11 (Fig. 1 and entry 8 in Table 1). Therefore,
while the formation of 6 appears to be accomplished
irrespective of the bulkiness of the base used, CH3Li,
which is less bulky than n-C4H9Li, seems to allow
better yields of 7.
According to observations with a similar substrate,3 the
alkylation of 2 occurred exclusively at the bridgehead
position giving the bicyclic diastereomer 6 in satisfac-
It is interesting to note that it is possible to achieve
good regioselectivity for the alkylation at the bridge-

F. Piccinelli et al. / Tetrahedron: Asymmetry 14 (2003) 393–398
395
bicyclic compounds investigated,3,4 such an effect is
more evident for the bicyclic derivative with a saturated
C3 bridge.
Figure 1.
head in the bicyclic derivatives with a C4 bridge4 or a
C3 bridge with an exocyclic double bond, while in the
case of the bicyclic derivative with a saturated C3
bridge3 the regioselectivity at the bridgehead position
can be accomplished only with the (3R,6R) stereoiso-
mer. In fact, the alkylation at the bridgehead position
on (3S,6S,1%S)-3 and on the configurationally identical
bicyclic compound with a C4 bridge4 occurs in better
yield (i.e. is more selective) in comparison with the
analogous isomer with a saturated C3 bridge previously
investigated.3
Figure 2. Optimized geometries9 of 2 and 3: the green ball
indicates the benzylic hydrogen and the yellow ball indicates
the bridgehead hydrogen.
The configuration of the new stereocenters introduced
on diastereomers (3R,6R,1%S)-2 and (3S,6S,1%S)-3 rela-
tive to the phenethyl moiety bound to the nitrogen, has
1
been assigned through the H NMR chemical shifts on
the basis of the methodology already employed,1,2 the
absolute configuration following on from the note (S)-
configuration of the phenethyl group. The approach is
It is our opinion that the different regioselectivity gen-
erally observed between diastereomeric (3S,6S,1%S) and
(3R,6R,1%S) bicyclic derivatives can be ascribed to steric
factors, the competitive alkylation at the bridgehead or
at the benzylic position appearing sensible to the bulki-
ness of the base used.3,4 In fact, from molecular model-
ing studies it is possible to observe that the hydrogen at
the bridgehead position is sterically more accessible in
the (3R,6R,1%S)-isomers than in the (3S,6S,1%S)-iso-
mers. Such a condition is demonstrated by the opti-
mized geometries9 of (3R,6R,1%S)-2 and (3S,6S,1%S)-3
reported in Fig. 2. Very similar geometries have also
been obtained for the other bicyclic compounds previ-
ously investigated.3,4 Therefore, the reaction at benzylic
position is most probably favored for the (3S,6S,1%S)-
isomers, especially when a bulky base is employed,
because of the poorer accessibility of the bridgehead
hydrogen than the benzylic one. Really, in the
(3S,6S,1%S)-isomers the bridgehead position appears
buried more deeply inside the molecule than the ben-
zylic one (regardless of the bridge length). Among the
1
based on the comparison between the H NMR spectra
of diastereomers 2 and 3. In fact, owing to the thermo-
dynamically
preferred
doubly
synperiplanar
conformation2 (see Fig. 2), the bridge chain protons of
(3R,6R,1%S)-2 are more shielded by the phenyl ring of
the (S)-phenethyl moiety with respect to the same
protons in (3S,6S,1%S)-3. In contrast the bridgehead
proton is more heavily shielded in 3 compared to 2 (see
Fig. 2). The (R)-configuration of the two new stere-
ocenters in 2 was established on the basis of the marked
upfield shift of the CH2 protons of the bridge chain
(which resonate at 1.39 and 2.17 ppm) with respect to 3
(where they resonate at 2.5 and 2.75 ppm), according to
that previously observed for analogous intermediates.1,2
In all cases, as a consequence of the thermodynamically
preferred doubly synperiplanar conformation, the
bridgehead proton in the diastereomer 3 is less shielded
(3.86 ppm) than the same proton in 2 (3.92 ppm) (Fig.
2).
Table 1. Alkylation of substrates (3R,6R,1%S)-2 and (3S,6S,1%S)-3
Entry
Substrate
Base (1.3 equiv.)
R-X (1.3 equiv.)
% yield 6
% yield 7
1
2
3
4
5
6
7
8
2
2
2
2
3
3
3
3
n-C4H9Li
n-C4H9Li
n-C4H9Li
CH3Li
CH3Li
CH3Li
CH3I
82
70
70
85
CH2CHCH2Br
CH3OCH2Br
CH3I
CH3I
90 (a)
76 (b)
86 (c)
77 (d)
CH2CHCH2Br
CH3OCH2Br
CH3I
CH3Li
n-C4H9Li
(a) The methyl derivative 10 was obtained in 10% yield. Monoalkylation at the benzylic position was observed in 14% yield (b) and 10% yield
(c); (d) the products 10 and 11 were isolated in 4 and 17% yield, respectively.

396
F. Piccinelli et al. / Tetrahedron: Asymmetry 14 (2003) 393–398
3. Experimental
methanol. Since traces of LiCl were always present, the
enantiomers 4a and 5a were not isolated in sufficiently
pure form for elemental analysis and to measure the
specific rotation.
3.1. 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.
The coupling constants (J) are in Hz. Optical rotation
values were measured at 25°C on a Perkin–Elmer 343
polarimeter. Dry THF was distilled from sodium ben-
zophenone ketyl. Chromatographic separations were
performed with silica gel 60 (230–400 mesh).
3.3.1.
(3R,6R)-2,5-Dioxo-8-methylene-1,4-diazabicy-
clo[3.2.2]nonane, 4a. The product was isolated in about
1
90% yield. H NMR (D2O) l: 2.5–2.8 (m, 4H); 3.88
(dd, 2H, J=3.8, 4.4); 5.03 (m, 2H). 13C NMR
(CD3OD) l: 38.3, 55.4, 119.5, 141.2, 174.2.
3.4. Conversion of 4a and 5a into 8a and 9a,
respectively
3.2. Conversion of 1 into 2 and 3
A mixture of 4a or 5a (0.133 g, 0.8 mmol) in aqueous
2N aqueous HCl (4 mL) was stirred at 60°C and after
about 40 h the solution was evaporated to dryness in
vacuo. The crude reaction product was purified by
adsorption on Amberlist H-15 ion exchange resin and
recovered pure 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 then evaporated under vacuum
to dryness and the diaminodiacid 8a or 9a was recov-
ered, as the hydrochloride salt, in practically quantita-
tive yield. The enantiomeric purity of 8a and 9a was
ascertained on the corresponding amino acids in zwitte-
rionic form by TLC on cellulose plates, as reported in
Ref. 5.
Under an inert atmosphere, to a stirred solution of 1
(9.45 g, 29.35 mmol) in dry THF (100 mL) cooled at
−10°C, was added 1 M solution of LHMDS in dry
THF (29.35 mL). After 30 min the reaction mixture was
cooled to −78°C and then 2-chloromethyl-3-chloro-
propene (3.67 g, 29.35 mmol) was dropped. After about
4 h, LHMDS (1 M, 29.35 mL) was added and the
mixture was then allowed to warm up to rt under
stirring. Diluted aqueous HCl and ethyl acetate were
added and after separation the organic solution was
evaporated in vacuo. The residue was submitted to
silica gel chromatography eluting with hexane/ethyl
acetate and the diastereomers (2 and 3) were separated.
3.2.1.
(3R,6R,1%S)-1,4-Bis-(1%-phenethyl)-2,5-dioxo-8-
3.4.1.
(2R,6R)-2,6-Diamino-4-methylene-1,7-heptane-
1
methylene-1,4-diazabicyclo[3.2.2]nonane, 2. The product
dioic acid dihydrochloride, 8a. H NMR (D2O) l: 2.53
(dd, 2H, J=9.6, 15); 2.77 (dd, 2H, J=4.8, 15); 4.13 (dd,
2H, J=4.8, 9.6); 5.19 (s, 2H). 13C NMR (D2O) l: 36.0,
51.6, 122.8, 136.0, 171.7. [h]D +20.1 (c 0.73, H2O); mp
240–2°C, with decomposition. Anal. calcd for
C8H16Cl2N2O4: C, 34.92; H, 5.86; Cl, 25.77; N, 10.18.
Found: C, 35.05; H, 5.88; Cl, 25.85; N, 10.20%.
1
was isolated in pure form, as an oil, in 27% yield. H
NMR l: 1.39 (dd, 2H, J=4.5, 15); 1.52 (d, 6H, J=6.9);
2.17 (dd, 2H, J=3, 15); 3.92 (dd, 2H, J=3, 4.5); 4.45
(s, 2H); 5.79 (q, 2H, J=6.9); 7.2–7.45 (m, 10ArH). 13C
NMR l: 16.2, 35.6, 50.4, 54.7, 118.6, 128.0, 128.2,
128.4, 138.3, 138.4, 168.6. [h]D −243.0 (c 1.02, CHCl3).
Anal. calcd for C24H26N2O2: C, 76.98; H, 7.0; N, 7.48.
Found: C, 77.27; H, 7.02; N, 7.5%.
3.4.2. (2S,6S)-2,6-Diamino-4-methylene-1,7-heptanedioic
acid dihydrochloride, 9a. [h]D −20 (c 0.65, H2O). Anal.
calcd for C8H16Cl2N2O4: C, 34.92; H, 5.86; Cl, 25.77;
N, 10.18. Found: C, 35.0; H, 5.85; Cl, 25.82; N,
10.16%.
3.2.2.
(3S,6S,1%S)-1,4-Bis-(1%-phenethyl)-2,5-dioxo-8-
methylene-1,4-diazabicyclo[3.2.2]nonane, 3. The product
1
was isolated pure, as an oil, in 63% yield. H NMR l:
1.53 (d, 6H, J=7); 2.5 (dd, 2H, J=4.8, 15); 2.75 (dd,
2H, J=3.3, 15); 3.86 (dd, 2H, J=3.3, 4.8); 4.97 (s, 2H);
5.71 (q, 2H, J=7); 7.1–7.4 (m, 10ArH). 13C NMR l:
16.2, 37.3, 49.9, 54.6, 118.5, 126.3, 127.6, 128.4, 138.7,
139.3, 168.1. [h]D −165.9 (c 1, CHCl3). Anal. calcd for
C24H26N2O2: C, 76.98; H, 7.0; N, 7.48. Found: C,
77.15; H, 7.01; N, 7.51%.
3.5. Alkylation of 2 and 3
Under an inert atmosphere, to a stirred solution of 2 or
3 (0.8 g, 2.14 mmol) in dry THF (20 mL) cooled at
−78°C, was added n-C4H9Li or CH3Li (see Table 1).
After about 5 min the appropriate alkylating reagent,
reported in Table 1, was added and the reaction was
then monitored by TLC. When the reaction was practi-
cally complete, the mixture was allowed to warm to rt.
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 chro-
matography eluting with hexane/ethyl acetate.
3.3. Conversion of 2 and 3 into 4a and 5a respectively
Under an inert atmosphere, a solution of 2 or 3 (1
mmol) in dry THF (10 mL) and t-butanol (1 mL) was
added to a stirred solution of Li (0.1 g, 15 mmol) in
about 50 mL of liquid ammonia cooled to −60°C. After
5 min the reaction was quenched with NH4Cl (0.75 g)
and the cooling bath was removed allowing the com-
plete evaporation of NH3. The crude reaction product
was evaporated in vacuo and the residue submitted to
silica gel chromatographic elution with ethyl acetate/
3.5.1.
(3R,6R,1%S)-1,4-Bis-(1%-phenethyl)-2,5-dioxo-3-
methyl-8-methylene-1,4-diazabicyclo[3.2.2]nonane,
6b.
The product was obtained, as an oil, in 85% yield by
1
alkylating 2 with iodomethane. H NMR l: 1.45 (dd,

F. Piccinelli et al. / Tetrahedron: Asymmetry 14 (2003) 393–398
397
1H, J=4.8, 15); 1.5 (d, 3H, J=7); 1.68 (s, 3H); 1.78 (d,
3H, J=7); 2.26 (dd, 1H, J=3.4, 15); 2.48 (m, 2H); 3.85
(dd, 1H, J=3.4, 4.8); 4.60 (s, 1H); 4.8 (s, 1H); 4.9–5.3
(broad, 1H); 5.91 (q, 1H, J=7); 7.18–7.43 (m, 10ArH).
13C NMR l: 16.0, 18.0, 22.7, 29.5, 35.5, 46.0, 51.0,
52.6, 54.6, 63.2, 118.2, 125.8, 126.5, 127.9, 128.3, 138.3,
139.5, 141.4, 169.4, 169.6. [h]D −89.7 (c 1.46, CHCl3).
Anal. calcd for C25H28N2O2: C, 77.29; H, 7.26; N, 7.21.
Found: C, 77.55; H, 7.28; N, 7.23%.
J=6.9); 5.95–6.1 (m, 1H); 7.2–7.5 (m, 10ArH). 13C
NMR l: 16.2, 19.4, 37, 39.9, 44.1, 50.7, 53.3 (broad),
54.4, 65.5, 117.9, 118.1, 126.1, 126.7, 127.3, 127.7,
128.3, 133.8, 138.7, 139.4, 141.6, 168.6, 170.1. [h]D
+50.9 (c 2.52, CHCl3). Anal. calcd for C27H30N2O2: C,
78.23; H, 7.29; N, 6.76. Found: C, 78.5; H, 7.32; N,
6.75%.
3.5.6. (3R,6S,1%S)-1, 4-Bis-(1%-phenethyl)-2,5-dioxo-8-
methylene-3-methoxymethyl-1,4-diazabicy-
clo[3.2.2]nonane, 7d. The product was obtained, as an
oil, in 86% yield by alkylating 3 with methoxymethyl-
3.5.2.
(3S,6R,1%S)-1,4-Bis-(1%-phenethyl)-3-allyl-2,5-
dioxo-8-methylene-1,4-diazabicyclo[3.2.2]nonane, 6c. The
product was obtained, as an oil, in 70% yield by
alkylating 2 with allylbromide. 1H NMR l: 1.54 (d, 3H,
J=7); 1.79 (d, 3H, J=6.8); 2.25 (dd, 1H, J=3.2, 15);
2.58 (m, 3H); 2.95 (dd, 1H, J=7, 15.4); 3.11 (dd, 1H,
J=6, 15.8); 3.82 (dd, 1H, J=3.6, 4.4); 4.61 (s, 1H); 4.88
(s, 1H); 5 (m, 1H); 5.15 (m, 1H); 5.6 (m, 1H); 5.98 (q,
1H, J=7); 6.0 (m, 1H); 7.3 (m, 10ArH).13C NMR l:
16.1, 17.5, 35.7, 40.2, 44.8, 50.9, 52.9, 54.4, 65.2, 118.5,
119, 125.4, 126.1, 127.5, 127.7, 127.9, 128.3, 133.1,
138.3, 139.2, 141.6, 168.7, 169.9. [h]D −117.1 (c 1.1,
CHCl3). Anal. calcd for C27H30N2O2: C, 78.23; H, 7.29;
N, 6.76. Found: C, 78.45; H, 7.3; N, 6.78%.
1
bromide. H NMR l: 1.57 (d, 3H, J=6.8); 1.83 (d, 3H,
J=6.8); 2.3–2.7 (m, 4H); 3.48 (s, 3H); 3.70 (dd, 1H,
J=4, 4.6); 3.98 (broad, 2H); 4.84 (s, 2H); 5.10 (broad,
1H); 5.85 (q, 1H, J=6.8); 7.2–7.6 (m, 10ArH). 13C
NMR l: 16.6, 18.5, 37.1, 41.1, 51.0, 55.3 (broad), 59.0,
66.3, 72.9, 118.4, 126.6, 126.7, 127.7, 127.8, 128.6,
139.0, 139.6, 141.7, 168.3, 169.6. [h]D +20.8 (c=0.83,
CHCl3). Anal. calcd for C26H30N2O3: C, 74.61; H, 7.23;
N, 6.69. Found: C, 74.5; H, 7.22; N, 6.66%.
3.6. Conversion of 6b–d and 7b–d into 4b–d and 5b-d,
respectively
The procedure followed was that previously described
to prepare 4a and 5a from 2 and 3, respectively. The
reaction products, recovered in practically quantitative
yield, were submitted to silica gel chromatography elut-
ing with hexane/ethyl acetate. However, the enan-
tiomers 4b–d and 5b–d were not obtained in sufficiently
pure form for elemental analysis and to measure the
specific rotation because of the presence of LiCl traces.
3.5.3.
(3S,6R,1%S)-1,4-Bis-(1%-phenethyl)-2,5-dioxo-8-
methylene-3-methoxymethyl-1,4-diazabicy-
clo[3.2.2]nonane, 6d. The product was obtained as an oil
in 70% yield by alkylating 2 with methoxymethylbro-
mide. 1H NMR l: 1.4–1.55 (m, 1H), 1.49 (d, 3H, J=7);
1.8 (d, 3H, J=7); 2.23 (dd, 1H, J=3, 14.6); 2.6 (qAB
,
2H, J=15); 3.40 (s, 3H); 3.75 (dd, 1H, J=3, 5.1);
3.9–4.18 (broad, 2H); 4.57 (s, 1H); 4.9 (m, 2H); 5.9 (q,
1H, J=7); 7.18–7.5 (m, 10ArH). 13C NMR l: 16.2,
17.2, 35.8, 41, 50.8, 54.1, 54.7, 59.1, 65.8, 73.3, 118.7,
125.7, 126.3, 127.9, 128.1, 128.4, 138.4, 139.0, 142.4,
168.0, 169.4. [h]D −95.4 (c 0.75, CHCl3). Anal. calcd for
C26H30N2O3: C, 74.61; H, 7.23; N, 6.69. Found: C,
74.55; H, 7.2; N, 6.7%.
3.6.1. (3R,6R)-2,5-Dioxo-3-methyl-8-methylene-1,4-diaz-
abicyclo[3.2.2]nonane, 4b. The product was obtained as
1
a wax in 92% yield. H NMR (CD3OD) l: 1.38 (s, 3H);
2.4–2.7 (m, 4H); 3.82 (dd, 1H, J=3.2, 4.4); 4.96 (m,
2H). 13C NMR (CD3OD) l: 20.5, 36.0, 44.7, 53.7, 57.0,
117.4, 139.9, 168.4, 169.5. [h]D −86.0 (c 0.4, CH3OH).
Anal. calcd for C9H12N2O2: C, 59.99; H, 6.71; N, 15.55.
Found: C, 60.2; H, 6.7; N, 15.5%.
3.5.4. (3S,6S,1%S)-1, 4-Bis-(1%-phenethyl)-2,5-dioxo-3-
methyl-8-methylene-1,4-diazabicyclo[3.2.2]nonane,
7b.
The product was obtained, as an oil, in 90% yield by
3.6.2.
(3S,6R)-2,5-Dioxo-3-allyl-8-methylene-1,4-diaz-
1
alkylating 3 with iodomethane. H NMR l: 1.35 (s,
abicyclo[3.2.2]nonane, 4c. The product was obtained as
1
3H); 1.56 (d, 3H, J=7.2); 1.71 (d, 3H, J=7.2); 2.45
(dd, 1H, J=3.6, 14.7); 2.51 (s, 2H); 2.73 (dd, 1H,
J=3.6, 14.7); 3.92 (t, 1H, J=3.6); 4.86 (s, 1H); 4.91 (s,
1H); 5.7–6 (broad, 1H); 5.86 (q, 1H, J=7.2); 7.1–7.4
(m, 10ArH). 13C NMR l: 16.6, 17.8, 22.6, 37.6, 46.8,
51.0 (broad), 54.6, 63.1, 118.5, 126.3, 126.6, 126.8,
127.9, 128.3, 128.7, 139.7, 139.8, 142.0, 170.0, 170.2.
[h]D −76.6 (c 1.15, CHCl3). Anal. calcd for C25H28N2O2:
C, 77.29; H, 7.26; N, 7.21. Found: C, 77.5; H, 7.28; N,
7.2%.
a wax in 85% yield. H NMR (CD3OD) l: 2.3–2.8 (m,
6H); 3.81 (dd, 1H, J=3.4, 4.8); 4.97 (s, 2H); 5.1–5.3 (m,
2H); 5.7–6 (m, 1H). 13C NMR (CD3OD) l: 38, 40.4,
45.5, 55.3, 61, 119.3, 120.1, 133.4, 141.6, 174.2. [h]D
−117.2 (c 0.48, CH3OH). Anal. calcd for C11H14N2O2:
C, 64.06; H, 6.84; N, 13.58. Found: C, 63.92; H, 6.87;
N, 13.55%.
3.6.3. (3S,6R)-2,5-Dioxo-8-methylene-3-methoxymethyl-
1,4-diazabicyclo[3.2.2]nonane, 4d. The product was
1
obtained as a wax in 90% yield. H NMR (CD3 OD) l:
3.5.5.
(3R,6S,1%S)-1,4-Bis-(1%-phenethyl)-3-allyl-2,5-
2.52 (qAB, 2H, J=14.6); 2.53–2.73 (m, 2H); 3.42 (s,
3H); 3.52 (d, 1H, J=9.6); 3.72 (d, 1H, J=9.6); 3.85
(dd, 1H, J=3.6, 4.8); 5 (m, 2H). 13C NMR (CD3OD) l:
38.1, 41.7, 55.3, 59.6, 61.3, 73.8, 119.5, 141.2, 173.5,
173.8. [h]D −77.4 (c 0.42, CH3OH). Anal. calcd for
C10H14N2O3: C, 57.13; H, 6.71; N, 13.33. Found: C,
57.1; H, 6.73; N, 13.35%.
dioxo-8-methylene-1,4-diazabicyclo[3.2.2]nonane, 7c. The
product was obtained, as an oil, in 76% yield by
alkylating 3 with allylbromide. 1H NMR l: 1.59 (d, 3H,
J=7.4); 1.79 (d, 3H, J=6.9); 2.43 (m, 3H); 2.55–2.85
(m, 2H); 2.95–3.2 (broad, 1H); 3.80 (t, 1H, J=3.9); 4.65
(s, 1H); 4.80 (s, 1H); 5.1–5.35 (m, 3H); 5.9 (q, 1H,

398
F. Piccinelli et al. / Tetrahedron: Asymmetry 14 (2003) 393–398
3.6.4. (3S,6S)-2,5-Dioxo-3-methyl-8-methylene-1,4-diaz-
abicyclo[3.2.2]nonane, 5b. The product was obtained as
a wax in 91% yield. [h]D +85.7 (c 0.38, CH3OH). Anal.
calcd for C9H12N2O2: C, 59.99; H, 6.71; N, 15.55.
Found: C, 60.1; H, 6.72; N, 15.6%.
6.27; Cl, 24.52; N, 9.69. Found: C, 37.48; H, 6.3; Cl,
24.6; N, 9.72%.
3.7.5. (2S,6S)-2,6-Diamino-2-allyl-4-methylene-1,7-hep-
tanedioic acid dihydrochloride, 9c. The product was not
isolated in sufficiently pure form for the elemental
analysis/specific rotation determination.
3.6.5.
(3R,6S)-2,5-Dioxo-3-allyl-8-methylene-1,4-diaz-
abicyclo[3.2.2]nonane, 5c. The product was obtained as
a wax in 86% yield. [h]D +116.1 (c 0.5, CH3OH). Anal.
calcd for C11H14N2O2: C, 64.06; H, 6.84; N, 13.58.
Found: C, 64.15; H, 6.82; N, 13.6%.
3.7.6.
(2R,6S)-2,6-Diamino-4-methylene-2-methoxy-
methyl-1,7-heptanedioic acid dihydrochloride, 9d. The
product was not isolated in sufficiently pure form for
the elemental analysis and to determine the specific
rotation.
3.6.6. (3R,6S)-2,5-Dioxo-3-methoxymethyl-8-methylene-
1,4-diazabicyclo[3.2.2]nonane, 5d. The product was
obtained as a wax in 90% yield. [h]D +76.6 (c 0.4,
CH3OH). Anal. calcd for C10H14N2O3: C, 57.13; H,
6.71; N, 13.33. Found: C, 57.23; H, 6.7; N, 13.38%.
3.7.7. (3S,6S,1%S)-1-(1%-Phenethyl)-4-(1%%-phenylisopro-
pyl)-2, 5-dioxo-8-methylene-1, 4-diazabicyclo[3.2.2]-
1
nonane, 10. H NMR l: 1.57 (d, 3H, J=7.4); 1.67 (s,
3H); 1.84 (s, 3H), 2.5 (m, 2H); 2.74 (bs, 1H); 2.81 (bs,
1H); 3.71 (t, 1H, J=4); 4.32 (dd, 1H, J=3.8, 4.8); 5 (s,
2H); 5.81 (q, 1H, J=7.4); 7.3 (m, 10ArH). 13C NMR l:
16.9, 27.2, 29.8, 37.5, 50.5, 56.6, 57.5, 59, 62.2, 118.5,
124.6, 126.5, 126.8, 127.8, 128.3, 128.6, 139.2, 139.7,
146.2, 168.4, 169. The product was not isolated in
sufficiently pure form for the elemental analysis and to
determine the specific rotation.
3.7. Conversion of 4b–d and 5b–d into 8b–d and 9b–d,
respectively
A mixture of 4b–d or 5b–d (0.8 mmol) in aqueous 2N
HCl (4 mL) was heated at 80°C under stirring. After 12
h, the solution was evaporated in vacuo to dryness and
the reaction product was worked up following the
procedure previously described to obtain 8a and 9a.
The products were recovered as the hydrochloride salts
in practically quantitative yield.
3.7.8. (3S,6S)-1,4-Bis-(1%-phenylisopropyl)-2,5-dioxo-8-
methylene-1,4-diazabicyclo[3.2.2]nonane, 11. 1H NMR
l: 1.65 (s, 6H); 1.87 (s, 6H); 2.55 (m, 4H); 4.14 (t, 2H,
J=4); 5.02 (s, 2H); 7.3 (m, 10ArH). 13C NMR l: 22.7,
29.9, 37.5, 59, 61.8, 118.3, 124.7, 126.3, 126.6, 126.8,
128.3, 128.7, 146.4, 169.9. The product was not isolated
in sufficiently pure form for the elemental analysis and
to determine the specific rotation.
3.7.1. (2R,6R)-2,6-Diamino-2-methyl-4-methylene-1,7-
1
heptandioic acid dihydrochloride, 8b. H NMR (D2O) l:
1.47 (s, 3H); 1.75 (dd, 1H, J=8.4, 15); 1.81 (d, 1H,
J=14.7); 1.9 (dd, 1H, J=5.7, 15); 1.95 (d, 1H, J=
14.7); 2.46 (dd, 1H, J=8.1, 15.9); 2.51 (d, 1H, J=15);
2.62 (dd, 1H, J=6, 15.3); 2.70 (d, 1H, J=15). 13C
NMR (D2O) l: 22.9, 37.5, 42.1, 51.8, 59.9, 123.7, 135.8,
171.8, 174.2. [h]D +6.9 (c 0.79, 1N HCl). Anal. calcd for
C9H18Cl2N2O4: C, 37.38; H, 6.27; Cl, 24.52; N, 9.69.
Found: C, 37.48; H, 6.3; Cl, 24.6; N, 9.72%.
Acknowledgements
Thanks are due to MIUR (COFIN 2000) and to the
University of Bologna for financial support.
3.7.2. (2R,6R)-2,6-Diamino-2-allyl-4-methylene-1,7-hep-
1
tandioic acid dihydrochloride, 8c. H NMR (D2O) l: 2.5
(m, 6H); 4.1 (dd, 1H, J=6, 8.1); 5.17 (s, 1H), 5.23 (s,
2H); 5.26 (s, 1H), 5.7 (m, 1H). 13C NMR (D2O) l: 37.6,
41, 41.2, 51.9, 63.1, 123.4, 123.6, 129.5, 135.8, 171.9,
173.5. The product was not isolated in sufficiently pure
form for elemental analysis and specific rotation
determination.
References
1. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron:
Asymmetry 2000, 11, 1259.
2. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron:
Asymmetry 2000, 11, 4617.
3. Paradisi, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetra-
hedron: Asymmetry 2002, 13, 497.
3.7.3. (2S,6R)-2,6-Diamino-2-methoxymethyl-4-methyl-
1
ene-1,7-heptandioic acid dihydrochloride, 8d. H NMR
(D2O) l: 2.4–2.75 (m, 4H); 3.25 (s, 3H); 3.48 (d, 1H,
J=10.6); 3.76 (d, 1H, J=10.6); 4.05 (dd, 1H, J=6.2,
8), 5.15 (s, 1H); 5.19 (s, 1H). 13C NMR (D2O) l: 37.5,
37.7, 51.9, 59.8, 63.8, 74.3, 123.7, 135.3, 172.0, 172.5.
The product was not isolated in sufficiently pure form
for the elemental analysis and specific rotation
determination.
4. Ferioli, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 2002, 13, 1181.
5. Girodeau, J. M.; Agouridas, C.; Masson, M.; Pineaau, R.;
Le Goffic, F. J. Med. Chem. 1986, 29, 1023.
6. Satyanarayana, S.; Grossert, J. S.; Lee, S. F.; White, R. L.
Amino Acids 2001, 21, 221.
7. Vederas, J. C.; et al. J. Biol. Chem. 1988, 263, 11814.
8. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1994, 5, 453.
9. Energy calculations were performed with the semi-empiri-
cal AM1 method (HyperChem Program, 1994) by using
the ‘Polak-Ribiere algorithm’ (RMS gradient 0.01 Kcal).
3.7.4.
(2S,6S)-2,6-Diamino-2-methyl-4-methylene-1,7-
heptandioic acid dihydrochloride, 9b. [h]D −6.5 (c 0.92,
1N HCl). Anal. calcd for C9H18Cl2N2O4: C, 37.38; H,