Synthesis of new molecular scaffolds: 3-aza-7,9-dioxa-bicyclo[4.2.1]nonane (8-exo BTKa) and 3-aza-8,10-dioxa-bicyclo[5.2.1]decane (9-exo BTKa) carboxylic acids

Article abstract of DOI:10.1016/j.tet.2004.01.039

Two classes of enantiopure molecular scaffolds were prepared, whose lactam structure formally derives from the coupling between tartaric acid and β- or γ-ketoamines. We labelled these compounds as 8-exo and 9-exo BTKa, indicating the lactam size (8- and 9

Full text of DOI:10.1016/j.tet.2004.01.039

Tetrahedron 60 (2004) 2583–2591
Synthesis of new molecular scaffolds:
3-aza-7,9-dioxa-bicyclo[4.2.1]nonane (8-exo BTKa) and
3-aza-8,10-dioxa-bicyclo[5.2.1]decane (9-exo BTKa) carboxylic acids
*
Dina Scarpi, Daniela Stranges, Luca Cecchi and Antonio Guarna
`
Dipartimento di Chimica Organica ‘U. Schiff’, Universita di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
Received 10 September 2003; revised 10 December 2003; accepted 15 January 2004
Abstract—Two classes of enantiopure molecular scaffolds were prepared, whose lactam structure formally derives from the coupling
between tartaric acid and b- or g-ketoamines. We labelled these compounds as 8-exo and 9-exo BTKa, indicating the lactam size (8- and
9-membered ring, respectively). Starting from b- and g-nitroketones, the synthesis involves the ketal formation by (R,R)-dimethyl tartrate.
The subsequent amide bond formation occurs during the hydrogenation of the nitro group over Raney-Ni and no expected open chain amine
was observed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ketones.1b,2 For the sake of simplicity, we named these
compounds BTAa3 (1a–b) and BTKa4 (2a–b), respec-
tively. Their general structure is reported in Figure 1.
We recently reported on the synthesis of two new classes of
conformationally restricted dipeptide isosteres, whose
synthesis is based on the combination of a tartaric acid
derivative and either a-amino aldehydes1 or a-amino-
Both classes of compounds have some interesting features,
commonly required in designing new peptide isosteres: the
synthesis starts from commercially available enantiopure
precursors; the stereochemistry can be controlled by
choosing the suitable a-amino acid or tartaric acid
derivative; they are compatible with solid phase synthesis
techniques.5 The 7-endo BTAa isosteres (1b) proved to be
efficient reverse turn inducers in a peptide chain.1b,5,6
Furthermore, these compounds found an application as
monomers for the generation of oligomers7 and as chiral
auxiliares.8
Figure 1. General structure of peptide isosteres BTAa and BTKa.
Scheme 1. Retrosynthetic analysis of 8-exo and 9-exo BTKa.
Keywords: Ketal; Nitroketone; Peptidomimetic; Tartaric acid.
*
Corresponding author. Tel.: þ39-55-4573481; fax: þ39-55-4573569; e-mail address: antonio.guarna@unifi.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.039

2584
D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
With the aim to extend the methodology to new structures of
the BTKa family by ring enlargement from 7-membered
one (2a–b) up to the size of 8 and 9, we envisaged a
retrosynthetic approach (Scheme 1), where the formation of
the ketal (B) between the tartaric moiety and an amino-
ketone precedes the ring closure through the amide bond
(A).
encountered a few problems that did not occur to Levine
et al. These will be reported in details in the next section.
2. Results and discussion
With respect to the previously published methodology,1a,2
we inverted the order of the two key steps of the synthesis,
i.e. the formation first of the ketal with the tartaric moiety
and then of the amide bond to close the ring.
To avoid the formation of Schiff bases and facilitate the
ketalisation process, the amino group needs to be protected.
Therefore, b- and g-nitroketones (D) were used as starting
materials, where the nitro group masks the amine function
needed for the amide bond formation.
Although the preparation of ketals with tartaric acid is
extensively reported, the ketalisation of b- or g-nitroketones
is not as straightforward as one would expect it to be.
Furthermore, we were encouraged on the possible success
of the envisaged strategy by an analogue example reported
by Levine et al.9 In their paper, the authors used o-nitro-
benzaldehyde as starting material to be coupled with (R,R)-
diethyl tartrate to obtain the cyclic compound 3 (Fig. 2).
The reaction, reported in Scheme 2, has been performed
under many conditions, summarised in Table 1.
The classical ketalisation reaction, employing 4a as a diol
and 5b as a substrate,9 was performed under acidic catalysis
and Dean–Stark azeotropic distillation, affording the
unreacted starting material (entry 1). Because of this
unexpected result, we experimented alternative methods,
employing trimethyl orthoformate as dehydrating agent
(entry 2).10 Starting from 4a and 5b in a 2:1 ratio, in the
presence of 2 equiv. of HC(OMe)3 under MsOH catalysis at
100 8C for 3 h, unreacted 5b was recovered, whereas the
dimethyl tartrate 4a was transformed into 4b. This activated
form of tartaric acid has been used in trans-ketalisation
reactions, as exemplified by the synthesis reported by
Giordano et al.,11 where, in order to obtain a cyclic ketals
with dimethyl tartrate, 4a was first converted into 4b and
then added to the substrate. Performing the reaction under
Figure 2. Structure of the compound synthesised by Levine and
co-workers.9
However, there is an important difference with our case:
we used ketones instead of aldehydes and the nitro group
was bound to an aliphatic chain. Probably due to
these differences in substrates, during the synthesis we
Scheme 2. Ketalisation with (R,R)-dimethyl tartrate or its derivative. The reaction conditions are reported in Table 1.
Table 1. Ketal formation with (R,R)-dimethyl tartrate or its derivative under acidic catalysis
Entry
Substrate
(R,R)-4 (eq)
Eq HC(OMe)3
Solvent
Temp. (8C)
Time (h)
Hþ or L.A. (%)
Products (%)
1
2
3
4
5
6
7
8
5b
4a (1)
4a (2)
4b (1)
4b (1.2)
4b (1.3)
4b (1)
None
2
None
2
4
2
None
None
None
None
1.2
Benzene
None
DCM
DCM
DCM
DCM
DCM
DM
DCM
DCM
ACN
ACN
DCM
Reflux
100
25
25
25
25
25
25
25
25
25
25
25
30
3
p-TsOH (5)
MsOH (7)
H2SO4 (30)
H2SO4 (23)
H2SO4 (23)
MsOH (10)
Amberlyst15 (25 w/w)
H2SO4 (23)
H2SO4 (23)
nra
4b
48
88
136
60
60
36
24
48
19
48
48
6b (35)
6b (25)
6b (35)
4a
4b (1)
nra
5a
5e
4b (1.3)
4b (1.5)
4b (1.3)
4a (1.2)
4a (1.2)
4a (1.1)
6a (36)
6e (44)
6e (74)
6a (60)
6b (22)
nra
9
10
11
12
13
H2SO4 (23)
5a
5b
Sc(OTf)3 (10)
Sc(OTf)3 (10)
In(Otf)3 (10)
1.2
None
a
No reaction.

D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
2585
the reported conditions11 on 5b in DCM at room
temperature and under H2SO4 catalysis, 6b was eventually
obtained in 35% yield after 48 h, together with unreacted
5b (entry 3). Based on this result, we tried to increase
the reaction conversion by increasing the 4b:5b ratio, the
reaction time and the amount of HC(OMe)3 in the reaction
mixture (entries 4 and 5). In both cases the conversion never
exceeded 35%.
afford 7-exo BTKa, 2a), since in all cases the unreacted
starting material is recovered (data not shown). Further-
more, in the case of g-nitroketones, the presence of an
additional methylene unity between the carbonyl and the
nitro group (from 5b to 5e) breaks the extended conjugation
of the substrate, resulting in much higher conversion (from
35 to 74%).
Therefore, considering that in all cases the carbonyl group
must be activated in some way towards the attack by the
hydroxyls belonging to the tartaric acid derivative, we
decided to synthesise and isolate first the dimethyl ketal of
each substrate on which to perform a trans-ketalisation
reaction.
The change of acid catalyst from H2SO4 to MsOH (entry 6)
or to the sulphonic resin Amberlyst15 (entry 7) proved to be
inefficient towards the trans-ketalisation and resulted in the
hydrolysis of 4b or no reaction at all, respectively.
The reaction performed under the best conditions found so
far (entry 3) on the aliphatic substrate 5a, afforded 6a in
36% yield (entry 8). This unreactivity cannot be attributed
only to the reluctance of the substrate 5b to break the
conjugation of its enone moiety, since the same behaviour
was found in the case of the aliphatic nitroketone 5a.
Furthermore, the reaction proved much more efficient on the
aromatic substrate 5e, affording 6e in 44% yield (entry 9).
Conversion increased up to 74% (entry 10), simply by
extending the reaction time from 24 to 48 h.
This proved to be the successful method to afford the target
compounds and the final synthesis is reported in Scheme 3.
Ketones 5a–d and 5f were converted into their correspond-
ing dimethyl ketals by treatment with an excess of trimethyl
ortoformate in methanol under p-TsOH catalysis.14 Depend-
ing on the substrate, the reaction was left 72 h at room
temperature (5a and 5f) or refluxed for 5 h (5b–d) affording
7a–d and 7f in very good yields (75% to quantitative).
Apart from ketones 5b and 5c, conversions were always
quantitative and the product recovered after the usual work-
up could be used without further purification in the next
step. Trans-ketalisations using dimethyl (R,R)-tartrate (4a)
was performed under the conditions reported by Seebach
et al.15 for aromatic aldehydes. The use of 2 equiv. of
BF3·Et2O in anhydrous ethyl acetate at 0 8C allowed the
trans-ketalisation of 7a–d and 7f into 6a–d and 6f, yields
ranging from 42 to 71% after purification. In all cases,
starting b- or g-nitroketones (20–30%) are re-formed
during the reaction and they can be recovered by
chromatographic purification, allowing material recycling
when repeating the first step of the synthesis. Tartaric ketal
6e was synthesised starting from g-nitroketone 5e under the
conditions reported in Table 1 (entry 10).
Since the use of protic acids as catalysts afforded
unsatisfying results, at least in the case of b-nitroketones
5a and 5b, we decided to explore the use of Lewis acids
instead.
Scandium triflate and scandium triflimide promote ketalisa-
tion and trans-ketalisation reactions, under very mild
conditions and in very good yields.12
In their paper, Ishihara et al.12 report that Sc(OTf)3 gives
better results in the reaction of ketones with diethyl tartrate.
In our case, we had to increase the amount of catalyst up to
10% (using the advised 1% quantity gave no result; data not
shown) and the conversion, if fairly good in the case of
aliphatic ketone 5a (60%, Entry 11), was disappointing in
the case of aromatic 5b (22%, entry 12). The last attempt
using In(OTf)3 as catalyst resulted in the recovery of the
starting material 5b (entry 13), as actually expected since
this method has in fact been reported for thio- and trans-
thioketalisations.13
Reduction of the nitro group to amino was obtained by
hydrogenation on Raney-Ni of 7a–f in methanol at room
temperature in 16 h.16 Surprisingly, in the case of substrates
7a–f, we did not recover the corresponding amines 8a–f, as
we expected in analogy with the synthesis of 3.9 In our
case, the amide formation that allows the ring closure is
spontaneous during the reduction, so that cyclic 8-mem-
bered amides 9a–c were obtained in good yields (76–99%)
and high purity after filtration from the catalyst. On the other
hand, in the case of substrates 7d–f, cyclic 9-membered
amides 9d–f was obtained as main products, together with
unidentified by-products. After chromatographic purifi-
cation, pure 9d–f were obtained in 19–24% yields and in
the MeOH fraction we recovered a complex mixture of
by-products, where amines 8d–f were probably also present
but could not be isolated.
Unfortunately, when we repeated the reaction under the best
conditions found for each substrate, we always got different
results. Since the reaction represented in Scheme 1 is an
equilibrium and we did not find a way to shift it towards the
products, we must, therefore, assume that minimal varia-
tions of the reaction conditions, normally unperceptable by
the operator, have great influence on the outcome of the
reaction.
Thus, the real obstacle to the formation of the ketal could be
the proximity of the nitro group to the carbonyl. This is
probably due to the keto–enol and nitro–isonitro tautomer-
isms contemporarily present in the substrates (i.e., b-nitro-
ketones) that form an extended conjugate species that does
not easily undergo the ketalisation. The effect is increased in
aromatic substrates. This hypothesis seems to be confirmed
when a-nitroacetophenone is used as substrate (this would
Since compounds 9a–c are more readily accessible, we
decided to prepare their N-tert-butoxycarbonyl derivatives,
as an example of amide protection that could be useful in the
subsequent functional group transformation.
Amides 9a–c were protected as N-Boc derivatives by

2586
D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
Scheme 3. (a) HC(OMe)3, p-TsOH cat., MeOH, reflux or rt, 5 or 48 h; (b) 4a, BF3:Et2O, EtOAc, 0 8C, 4 h; (c) 4b, DCM, H2SO4 cat., rt, 48 h; (d) Raney-Ni, H2,
MeOH, rt, 16 h; (e) Boc2O, Et3N, DMAP cat., DCM, reflux, 18 h.
˚
˚
treatment in refluxing CH2Cl2 with Boc2O and Et3N in the
presence of a catalytic amount of DMAP.17 After 18 h,
10a–c were recovered in fair yields (60–76%).
3.4 and 3.0 A, respectively, and it averages 3.8 A in the
7-exo BTKa. This observation is confirmed by the
experimental 1H NMR data: the shielding effect of
the aromatic ring increases and the OCH3 group resonates
at 3.75 (7-exo BTKa,2 2a), 3.70 (8-exo BTKa, 9b) and
3.37 ppm (9-exo BTKa, 9e).
In this way we realised the synthesis of two new classes
of BTKa, where the cyclic amide consists in a 8- or
9-membered ring and the substituent on the bridgehead
carbon that derives from the ketone moiety is an aliphatic
chain (9a, 9d) or a phenyl group (9b, 9e) or a p-substituted
aromatic ring (9c, 9e).
3. Conclusions
In this work, we prepared two classes of modified BTKa,
where the ring size was increased from 7- up to 8- and
9-members.
There are a few advantages in this approach: first, since the
formation of the amide bond spontaneously occurs after
the reduction of the nitro group, there is no need to use
expensive peptide coupling reagents nor, in most cases, to
purify the product; then, the isostere is obtained as the free
amide that can be suitably protected, depending on the
subsequent use of the substrate.
As starting materials we used b- and g-nitroketones. The
synthesis presents the two key steps in reversed order with
respect to the previously reported methodology: first the
carbonyl is protected as ketal, and then the amide bond is
formed. The presence of the nitro group seems to influence
the reactivity of the carbonyl and the ketalisation using
(R,R)-dimethyl tartaric ester as a partner diol was thus
extensively studied, since the well known reaction con-
ditions failed on these substrates. When tartaric ketals were
obtained, the subsequent hydrogenation on Raney-Ni of the
nitro group surprisingly afforded directly the 8-membered
cyclic compounds, whereas in the case of 9-membered
cyclic amides the reaction afforded a complex mixture of
compounds, including the target lactames.
The aim of the present work was to obtain the ring
enlargement of the rigid exo BTKa scaffolds and it also
seemed interesting to evaluate how this modification would
affect the conformational freedom of these compounds that
represent a new class of dipeptide isosteres.
We, therefore, performed a complete conformational
analysis on amides 9a, 9b, 9d and 9e.
As expected, these compounds are less rigid than their
7-membered counterparts and the 8-exo and 9-exo BTKa are
more prone to take different conformations. Molecular
modeling calculations revealed that the most interesting
feature lies in the distance between the aromatic ring and the
carbomethoxy group. This is found to decrease as the ring
enlarges: in compounds 9b and 9e, the average distance is
As expected by considering the ring dimensions, confor-
mational analysis performed on these molecules revealed an
increased flexibility with respect to 7-exo BTKa. However,
an interesting feature of these compounds consists in the
distance between the carbomethoxy group and the aromatic
ring on the bridgehead carbon that decreases as the ring

D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
2587
enlarges. This explains the experimental upfield shift of the
1
added. The solution was left under magnetic stirring at room
temperature. After 72 h, satd NaHCO3 was added (10 mL),
the product extracted with CH2Cl2 (3£10 mL) and the
organic layer dried over Na2SO4. After filtration and
evaporation of the solvent, crude 7a was obtained in
quantitative yield and used in the next step without further
purification.
OCH3 group observed in the H NMR when passing from
the 7-exo BTKa to the 8- and 9-exo ones. This structural
characteristic could be useful in further applications.
4. Experimental
4.1. General
1
Compound 7a. H NMR d (ppm): 4.34 (m, 2H, CH2NO2),
3.15 (s, 6H, OCH3), 2.33 (m, 2H, CH2CH2NO2), 1.56 (q,
J¼7.7 Hz, 2H, CH2CH3), 0.86 (t, J¼7.7 Hz, 3H, CH3). 13
C
Melting points are uncorrected. Chromatographic separa-
tions were performed under pressure on silica gel by flash-
column techniques; Rf values refer to TLC carried out on
25-mm silica gel plates (Merck F254), with the same eluent
as indicated for the column chromatography. IR spectra
were recorded with a Perkin–Elmer 881 spectrophotometer
in CHCl3 solution. 1H NMR (200 MHz) and 13C NMR
(50.33 MHz) spectra were recorded with a Varian XL 200
instrument in CDCl3 solution. Mass spectra were carried out
by EI at 70 eV, unless otherwise stated, on 5790A–5970A
Hewlett–Packard and QMD 1000 Carlo Erba instruments.
Microanalyses were carried out with a Perkin–Elmer
2400/2 elemental analyser. Optical rotations were deter-
mined with a JASCO DIP-370 instrument. Molecular
modeling was carried out by using the MM2* force field
implemented in MacroModel v6.5 using the default values
of the software for all calculations. (4R,5R)-2-Methoxy-
[1,3]dioxolane-4,5-dicarboxylic acid dimethyl ester 4b,18
b-nitroketone 5a,19 and g-nitroketones 5d–f16 were synthe-
sised as reported.
NMR d (ppm): 101.6 (s), 71.5 (t), 48.0 (q, 2C), 29.8 (t), 25.9
(t), 7.9 (q). MS m/z (%): 178 (Mþþ1, 1.2), 113
(Mþ2(CH2)2NO2, 10), 103 (53), 71 (57), 57 (100).
4.1.4. (1,1-Dimethoxy-3-nitro-propyl)-benzene (7b). Pre-
pared as described for 7a, starting from 5b (506 mg,
2.83 mmol) but refluxing the solution for 5 h. Crude 7b,
isolated after the work up in 80% yield, was used in the next
step without further purification.
1
Compound 7b. H NMR d (ppm): 7.39–7.22 (m, 5H, Ph),
4.00 (m, 2H, CH2NO2), 3.12 (s, 6H, OCH3), 2.57 (m, 2H,
CH2CH2NO2). 13C NMR d (ppm): 138.8 (s), 128.8 (d),
128.4 (d, 2C), 126.5 (d, 2C), 101.4 (s), 71.3 (t), 48.9 (q, 2C),
34.6 (t). MS m/z (%): 225 (Mþ, 1), 178 (8), 151 (21), 105
(100), 77 (54).
4.1.5. 1-Chloro-4-(1,1-dimethoxy-3-nitro-propyl)-ben-
zene (7c). Prepared as described for 7a, starting from 5c
(285 mg, 1.33 mmol) but refluxing the solution for 5 h.
Crude 7c, isolated after the work up in 75% yield, was used
in the next step without further purification.
4.1.1. 1-Phenyl-3-nitro-1-propanone (5b). Synthesised as
reported for 5a,19 starting from 1-phenylpropenone (2.10 g,
15.9 mmol). After chromatografic purification (eluent:
CH2Cl2–petroleum ether, 1:1, Rf¼0.13), pure 5b (1.37 g,
48%) was obtained as white solid.
Compound 7c. 1H NMR d (ppm): 7.34–7.26 (m, 4H, C6H4),
3.97 (m, 2H, CH2NO2), 3.08 (s, 6H, OCH3), 2.54 (m, 2H,
CH2CH2NO2). 13C NMR d (ppm): 144.8 (s), 137.5 (s),
128.6 (d, 2C), 128.1 (d, 2C), 101.1 (s), 71.1 (t), 48.9 (q, 2C),
34.5 (t). MS (30 eV) m/z (%): 185 (Mþ2(CH2)2NO2, 19),
139 (100).
Compound 5b. Mp 77–78 8C. 1H NMR d (ppm): 7.99–7.95
(m, 2H), 7.65–7.45 (m, 3H), 4.82 (t, J¼6.2 Hz, 2H), 3.65
(t, J¼6.2 Hz, 2H). 13C NMR d (ppm): 195.4 (s), 138.6 (s),
129.4 (d), 129.3 (d, 2C), 128.7 (d, 2C), 69.8 (t), 35.4 (t). MS
m/z (%): 105 (Mþ2(CH2)2NO2, 100), 77 (65). IR (CDCl3):
1708, 1689, 1555 and 1364 cm21. Anal. Calcd for
C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.52; H,
5.05; N, 7.58.
4.1.6. 4,4-Dimethoxy-1-nitro-pentane (7d). Prepared as
described for 7a, starting from 5d (651 mg, 4.96 mmol) but
refluxing the solution for 5 h. Crude 7d, isolated after the
work up in quantitative yield, was used in the next step
without further purification.
4.1.2. 1-(4-Chlorophenyl)-3-nitro-1-propanone (5c). Syn-
thesised as reported,20 starting from 3-chloro-1-(4-chloro-
Compound 7d. 1H NMR d (ppm): 4.38 (t, J¼7.0 Hz,
2H, CH2NO2), 3.15 (s, 6H, OCH3), 2.14–1.96 (m, 2H,
CH2CH2CH2NO2), 1.70–1.61 (m, 2H, CH2CH2CH2NO2),
1.27 (s, 3H, CH3). 13C NMR d (ppm): 100.6 (s), 75.2 (d),
47.7 (q, 2C), 32.8 (t), 22.2 (t), 20.5 (q). MS m/z (%) 177
(Mþ, 1), 89 (Mþ2(CH2)3NO2, 100).
phenyl)-1-propanone
(2.00 g,
9.85 mmol).
crystallisation from hexane, pure 5c (1.68 g, 80%) was
After
obtained as pale yellow solid.
Compound 5c. Mp 71–72 8C (lit.20b 79–80 8C). 1H NMR d
(ppm): 7.91 (d, J¼8.4 Hz, 2H), 7.47 (d, J¼8.4 Hz, 2H), 4.82
(t, J¼5.8 Hz, 2H), 3.62 (t, J¼5.8 Hz, 2H). 13C NMR d
(ppm): 193.8 (s), 140.3 (s), 133.8 (s), 129.4 (d, 2C), 129.0
(d, 2C), 69.0 (t), 34.7 (t). MS m/z (%): 213 (Mþ, 1), 167
(Mþ2NO2, 18), 139 (Mþ2(CH2)2NO2, 100). IR (CDCl3):
4.1.7. 1-(1,1-Dimethoxy-3-nitro-butyl)-4-methoxy-ben-
zene (7f). Prepared as described for 7a, starting from 5f
(1.01 g, 4.53 mmol). Crude 7f, isolated after the work up in
quantitative yield, was used in the next step without further
purification.
1691, 1560, 1374 cm21
.
1
Compound 7f. H NMR d (ppm): 7.34 (d, J¼8.8 Hz, 2H,
4.1.3. 3,3-Dimethoxy-1-nitro-pentane (7a). To a solution
of 5a (686 mg, 5.23 mmol) in MeOH (8 mL), trimethyl
ortoformate (8 mL) and a catalytic amount of p-TsOH were
Ph), 6.86 (d, J¼8.8 Hz, 2H, Ph), 4.17 (t, J¼7.0 Hz, 2H,
CH2NO2), 3.80 (s, 3H, C6H4OCH3), 3.12 (s, 6H, OCH3),

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D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
1.96–1.90 (m, 2H, CH2CH2CH2NO2), 1.89–1.63 (m, 2H,
CH2CH2CH2NO2). 13C NMR d (ppm): 159.2 (s), 131.9 (s),
127.9 (d, 2C), 113.4 (d, 2C), 102.7 (s), 75.1 (t), 55.2 (q),
48.6 (q, 2C), 33.7 (t), 21.8 (t). MS m/z (%) 181
(Mþ2(CH2)3NO2, 73), 135 (100).
CO2CH3), 3.45 (s, 3H, CO2CH3), 2.75–2.47 (m, 2H,
CH2CH2NO2). 13C NMR d (ppm): 168.5 (s), 168.4 (s),
137.8 (s), 135.1 (s), 128.4 (d, 2C), 127.1 (d, 2C), 112.0 (s),
77.6 (d), 76.2 (d), 70.0 (t), 53.0 (q), 52.5 (q), 37.2 (t). MS
m/z (%): 299 (Mþ2(CH2)2NO2, 95), 139 (100), 111 (40). IR
(CDCl3): 3151, 1601, 1560 and 1381 cm21. Anal. Calcd for
C15H16ClNO8: C, 48.20; H, 4.32; N, 3.75. Found: C, 48.60;
H, 4.49; N, 3.69.
4.1.8. (4R,5R)-2-Ethyl-2-(2-nitro-ethyl)-[1,3]dioxolane-
4,5-dicarboxylic acid dimethyl ester (6a). To a solution
of 7a (927 mg, 5.23 mmol) and (R,R)-dimethyl tartrate 4a
(1.86 g, 10.46 mmol) in anhydrous EtOAc (10 mL), cooled
at 0 8C, BF3:Et2O (2 equiv., 1.23 mL) was added. After 4 h,
the solution was diluted with EtOAc (10 mL) and NaHCO3
satd (10 mL) added; the resulting mixture was left under
vigorous stirring for 10 min. After separation of the phases,
the organic layer was dried over Na2SO4. After filtration and
evaporation of the solvent, crude 6a was obtained and
purification by chromatography (eluent: EtOAc–petroleum
ether, 1:3, Rf¼0.20) afforded pure 6a (637 mg, 42%) as
colourless oil.
4.1.11. (4R,5R)-2-Methyl-2-(3-nitro-propyl)-[1,3]dioxo-
lane-4,5-dicarboxylic acid dimethyl ester (6d). Prepared
as described for 6a, starting from 7d (400 mg, 2.25 mmol)
and obtaining 6d (467 mg, 71%) after chromatographic
purification (eluent: EtOAc–petroleum ether, 1:3, Rf¼0.26)
as colourless oil.
Compound 6d. [a]2D5¼223.5 (c 1.0, CHCl3). H NMR d
1
(ppm): 4.80 (d, J¼5.9 Hz, 1H, CHCO2Me), 4.69 (d, J¼
5.9 Hz, 1H, CHCO2Me), 4.43 (t, J¼7.3 Hz, 2H, CH2NO2),
3.80 (s, 6H, CO2CH3), 2.23–2.12 (m, 2H, CH2CH2CH2-
NO2), 1.87–1.79 (m, 2H, CH2CH2CH2NO2), 1.42 (s, 3H,
CH3). 13C NMR d (ppm): 169.8 (s), 169.4 (s), 114.5 (s), 77.4
(d), 76.9 (d), 75.3 (t), 52.9 (q, 2C), 35.6 (t), 24.5 (q), 21.8 (t).
MS m/z (%): 276 (Mþ2CH3, 20), 232 (Mþ2CO2Me, 6),
203 (Mþ2(CH2)3NO2, 100). IR (CDCl3): 1755, 1554 and
1383 cm21. Anal. Calcd for C11H17NO8: C, 45.36; H, 5.88;
N, 4.81. Found: C, 45.40; H, 5.89; N, 4.44.
1
Compound 6a. [a]2D5¼212.1 (c 0.3, CHCl3). H NMR d
(ppm): 4.78 (d, J¼6.2 Hz, 1H, CHCO2Me), 4.64 (d, J¼
6.2 Hz, 1H, CHCO2Me), 4.57–4.48 (m, 2H, CH2NO2), 3.83
(s, 3H, CO2CH3), 3.80 (s, 3H, CO2CH3), 2.54–2.45 (m, 2H,
CH2CH2NO2), 1.70 (q, J¼7.4 Hz, 2H, CH2CH3), 0.96 (t,
J¼7.4 Hz, 3H, CH2CH3). 13C NMR d (ppm): 169.5 (s),
169.2 (s), 115.2 (s), 77.5 (d), 76.9 (d), 70.3 (t), 52.9 (q, 2C),
33.1 (t), 30.6 (t), 7.9 (q). MS m/z (%) 291 (Mþ, 0.12), 244
(1), 217 (48), 215 (84), 55 (100). IR (CHCl3) 1751, 1557 and
1383, 1439 cm21. Anal. Calcd for C11H17NO8: C, 45.36; H,
5.88; N, 4.81. Found: C, 45.81; H, 6.05; N, 4.25.
4.1.12. (4R,5R)-2-(2-Nitro-propyl)-2-phenyl-[1,3]dioxo-
lane-4,5-dicarboxylic acid dimethyl ester (6e). To a
solution of 5e (100 mg, 0.52 mmol) and 4b (150 mg,
0.68 mmol) in CH2Cl2 (2 mL), H2SO4 (50 mL) is added.
After 48 h solvent is removed and 10% NaHCO3 solution
(5 mL) is added and the product extracted with CH2Cl2
(3£5 mL). The combined organic layers were dried on
Na2SO4 and filtration and evaporation of the solvent
afforded crude 6e. This was purified by flash chroma-
tography (eluent: EtOAc–petroleum ether, 1:3, Rf¼0.24),
obtaining pure 6e (135 mg, 74%) as yellow oil.
4.1.9. (4R,5R)-2-(2-Nitro-ethyl)-2-phenyl-[1,3]dioxolane-
4,5-dicarboxylic acid dimethyl ester (6b). Prepared as
described for 6a, starting from 7b (630 mg, 2.83 mmol) and
obtaining 6b (600 mg, 63%) after chromatographic purifi-
cation (eluent: EtOAc–petroleum ether, 1:4, Rf¼0.19) as
yellow oil.
1
Compound 6b. [a]2D5¼þ7.91 (c 0.6, CHCl3). H NMR d
1
(ppm): 7.48–7.42 (m, 2H, Ph), 7.36–7.28 (m, 3H, Ph), 4.87
(d, J¼5.1 Hz, 1H, CHCO2Me), 4.73 (d, J¼5.1 Hz, 1H,
CHCO2Me), 4.69–4.47 (m, 2H, CH2NO2), 3.84 (s, 3H,
CO2CH3), 3.47 (s, 3H, CO2CH3), 2.86–2.57 (m, 2H,
CH2CH2NO2). 13C NMR d (ppm): 168.9 (s), 168.7 (s),
139.1 (s), 129.2 (d), 128.2 (d, 2C), 125.6 (d, 2C), 112.4 (s),
77.5 (d), 76.1 (d), 70.1 (t), 52.9 (q), 52.4 (q), 37.2 (t). MS
m/z (%) 292 (Mþ2HNO2, 0.6), 265 (100), 232 (6), 155 (1),
105 (27), 77 (14). IR (CHCl3) 1752, 1557 and 1383,
1439 cm21. Anal. Calcd for C15H17NO8: C, 53.10; H, 5.05;
N, 4.13. Found: C, 53.24; H, 5.08; N, 4.30.
Compound 6e. [a]2D5¼þ13.6 (c 1.0, CHCl3). H NMR d
(ppm): 7.46–7.41 (m, 2H, Ph), 7.34–7.29 (m, 3H, Ph), 4.87
(d, J¼5.4 Hz, 1H, CHCO2Me), 4.76 (d, J¼5.4 Hz, 1H,
CHCO2Me), 4.48–4.41 (m, 2H, CH2NO2), 3.83 (s, 3H,
CO2CH3), 3.49 (s, 3H, CO2CH3), 2.21–2.00 (m, 4H,
CH2CH2CH2NO2). 13C NMR d (ppm): 162.9 (s), 169.0
(s), 139.8 (s), 128.8 (d), 128.1 (d, 2C), 125.7 (d, 2C), 113.9
(s), 77.4 (d), 76.1 (d), 75.1 (t), 52.9 (q), 52.4 (q), 36.8 (t),
21.4 (t). MS m/z (%): 265 (Mþ2(CH2)3NO2, 100), 105 (25),
77 (11). IR (CHCl3): 1751, 1554 and 1371, 1438 cm21
.
Anal. Calcd for C16H19NO8: C, 54.39; H, 5.42; N, 3.96.
Found: C, 54.34; H, 5.56; N, 4.27.
4.1.10. (4R,5R)-2-(4-Chloro-phenyl)-2-(2-nitro-ethyl)-
[1,3]dioxolane-4,5-dicarboxylic acid dimethyl ester (6c).
Prepared as described for 6a, starting from 7c (276 mg,
1.06 mmol) and obtaining 6c (175 mg, 44%) after chro-
matographic purification (eluent: CH2Cl2, Rf¼0.38) as dark
yellow oil.
4.1.13. (4R,5R)-2-(4-Methoxy-phenyl)-2-(2-nitro-pro-
pyl)-[1,3]dioxolane-4,5-dicarboxylic acid dimethyl ester
(6f). Prepared as described for 6a, starting from 7f (500 mg,
1.85 mmol) and obtaining 6f (285 mg, 45%) after chro-
matographic purification (eluent: EtOAc–petroleum ether,
1:3, Rf¼0.25) as colourless oil.
1
Compound 6c. [a]2D5¼þ12.4 (c 0.1, CHCl3). H NMR d
1
(ppm): 7.35 (d, J¼8.6 Hz, 2H, Ph), 7.24 (d, J¼8.6 Hz, 2H,
Ph), 4.76 (d, J¼5.5 Hz, 1H, CHCO2Me), 4.67 (d, J¼5.5 Hz,
1H, CHCO2Me), 4.64–4.39 (m, 2H, CH2NO2), 3.77 (s, 3H,
Compound 6f. [a]2D5¼þ12.1 (c 0.3, CHCl3). H NMR d
(ppm): 7.35 (d, J¼8.8 Hz, 2H, Ph), 6.82 (d, J¼8.8 Hz, 2H,
Ph), 4.85 (d, J¼5.5 Hz, 1H, CHCO2Me), 4.73 (d, J¼5.5 Hz,

D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
2589
1H, CHCO2Me), 4.44–4.40 (m, 2H, CH2NO2), 3.82 (s, 3H,
CO2CH3), 3.77 (s, 3H, OCH3), 3.52 (s, 3H, CO2CH3), 2.17–
2.02 (m, 4H, CH2CH2CH2NO2). 13C NMR d (ppm): 169.0
(s), 168.8 (s), 159.6 (s), 131.7 (s), 126.9 (d, 2C), 113.7
(s), 113.2 (d, 2C), 77.2 (d), 75.9 (d), 75.0 (t), 55.0 (q), 52.6
(q), 52.2 (q), 36.8 (t), 21.4 (t). MS m/z (%) 295
(Mþ2(CH2)3NO2, 100), 135 (79), 107 (6). IR (CDCl3):
1751, 1553 and 1372 cm21. Anal. Calcd for C17H21NO9: C,
53.26; H, 5.52; N, 3.65. Found: C, 53.38; H, 5.49; N, 3.58.
NHCvO). 13C NMR d (ppm): 174.4 (s), 169.3 (s), 139.2
(s), 134.6 (s), 128.3 (d, 2C), 126.3 (d, 2C), 113.2 (s), 82.0
(d), 77.4 (d), 52.7 (q), 41.1 (t), 37.6 (t). MS m/z (%) 252
(Mþ2CO2Me, 19), 139 (100), 111 (46). IR (CDCl3): 1763,
1674 cm21. Anal. Calcd for C14H14ClNO5·H2O: C, 50.10;
H, 4.89; N, 4.25. Found: C: 50.00; H, 4.69; N, 4.19.
4.1.17. (1R,7S,9R)-7-Methyl-2-oxo-8,10-dioxa-3-aza-bi-
cyclo[5.2.1]decane-9-carboxylic acid methyl ester (9d).
Prepared as described for 9a, starting from 7d (445 mg,
1.53 mmol) and obtaining crude 9d. After chromatografic
purification (eluent: EtOAc–petroleum ether, 3:1, Rf¼0.36)
pure 9d (68 mg, 19%) as white solid.
4.1.14. (1R,6S,8R)-6-Ethyl-2-oxo-7,9-dioxa-3-aza-bicyclo-
[4.2.1]nonane-8-carboxylic acid methyl ester (9a). A
solution of 7a (637 mg, 2.19 mmol) in MeOH (20 mL) was
added under stirring to a prehydrogenated suspension of wet
Raney-Ni (924 mg, washed three times with 5 mL of MeOH
before the addition of the solution of 7a) in the same solvent
(10 mL). The mixture was left under hydrogen atmosphere
for 16 h at room temperature and then filtered twice on a
Celite layer and finally evaporated to give pure 9a (491 mg,
99%) as pale yellow solid.
Compound 9d. Mp 149–150 8C. [a]2D5¼269.8 (c 0.2,
1
CHCl3). H NMR d (ppm): 6.53 (br s, 1H, NH), 5.00 (d,
J¼2.6 Hz, 1H, CHCHCO2CH3), 4.86 (d, J¼2.6 Hz, 1H,
CHCO2CH3), 4.12–3.95 (m, 1H, CHaHbNHCvO), 3.79 (s,
3H, CO2CH3), 3.20–3.04 (m, 1H, CHaHbNHCvO), 1.89–
1.67 (m, 4H, CH2CH2CH2NHCvO), 1.51 (s, 3H, CH3). 13
C
NMR d (ppm): 174.2 (s), 170.5 (s), 115.1 (s), 79.3 (d), 78.9
(d), 52.8 (q), 41.1 (t), 33.6 (t), 25.1 (t), 24.8 (q). IR (CDCl3):
1751, 1653 cm21. MS (30 eV) m/z (%): 230 (Mþþ1, 11),
214 (Mþ2CH3, 3), 187 (51), 84 (100). Anal. Calcd for
C10H15NO5: C, 52.40; H, 6.60; N, 6.11. Found: C: 52.23; H,
6.43; N, 5.95.
Compound 9a. Mp 66–67 8C. [a]2D5¼275.6 (c 0.8, CHCl3).
1H NMR d (ppm): 6.26 (s br, 1H, NH), 4.90 (br s, 1H,
CHCHCO2CH3), 4.76 (d, J¼1.8 Hz, 1H, CHCO2CH3), 3.78
(s, 3H, CO2CH3), 3.33–3.25 (m, 2H, CH2NHCvO), 2.08–
2.02 (m, 2H, CH2CH2NHCvO), 1.88 (q, J¼7.4 Hz, 2H,
CH2CH3), 0.99 (t, J¼7.2 Hz, 3H, CH2CH3). 13C NMR d
(ppm): 174.9 (s), 169.8 (s), 115.2 (s), 81.6 (d), 77.1 (d), 52.6
(q), 38.6 (t), 37.5 (t), 32.0 (t), 7.4 (q). MS m/z (%) 229 (Mþ,
17), 170 (40), 113 (79), 97 (80), 56 (100). IR (CHCl3) 3405,
1760, 1671, 1357 cm21. Anal. Calcd for C10H15NO5: C,
52.40; H, 6.60; N, 6.11. Found: C, 52.63; H, 6.46; N, 5.99.
4.1.18. (1R,7R,9R)-2-Oxo-7-phenyl-8,10-dioxa-3-aza-
bicyclo[5.2.1]decane-9-carboxylic acid methyl ester
(9e). Prepared as described for 9a, starting from 7e
(90 mg, 0.26 mmol) and obtaining crude 9e. After chroma-
tografic purification (eluent: EtOAc–petroleum ether, 1:3,
1% Et3N, Rf¼0.16) pure 9e (17 mg, 24%) as yellow oil.
Compound 9e. [a]D25¼232.8 (c0.5, CHCl3). 1H NMR d
(ppm): 7.51–7.46 (m, 2H, Ph), 7.40–7.27 (m, 3H, Ph), 6.35
(br s, 1H, NH), 5.31 (d, J¼1.8 Hz, 1H, CHCHCO2CH3),
4.93 (d, J¼1.8 Hz, 1H, CHCO2CH3), 4.15–4.07 (m, 1H,
CHaHbNHCvO), 3.37 (s, 3H, CO2CH3), 3.25–3.16 (m, 1H,
CHaHbNHCvO), 2.24–1.82 (m, 4H, CH2CH2CH2-
NHCvO). 13C NMR d (ppm): 173.8 (s), 169.3 (s), 141.5
(s), 128.3 (d), 127.8 (d, 2C), 125.3 (d, 2C), 114.7 (s), 79.6
(d), 78.8 (d), 52.3 (q), 42.2 (t), 36.7 (t), 25.8 (t). MS m/z (%):
291 (Mþ, 2), 105 (24), 104 (100). IR (CDCl3): 3400, 1745,
1655 cm21. Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88;
N, 4.81. Found: C, 60.62; H, 5.92; N, 4.76.
4.1.15. (1R,6R,8R)-2-Oxo-6-phenyl-7,9-dioxa-3-aza-bi-
cyclo[4.2.1]nonane-8-carboxylic acid methyl ester (9b).
Prepared as described for 9a, starting from 7b (400 mg,
1.18 mmol) and obtaining pure 9b (279 mg, 85%) as pale
yellow solid.
Compound 9b. Mp 95–96 8C. [a]2D5¼232.8 (c 0.5, CHCl3).
1H NMR d (ppm): 7.63–7.58 (m, 2H, Ph), 7.43–7.29 (m,
3H, Ph), 6.30 (br s, 1H, NH), 5.05 (s, 1H, CHCHCO2CH3),
4.95 (d, J¼2.2 Hz, 1H, CHCO2CH3), 3.70 (s, 3H, CO2CH3),
3.51–3.42 (m, 2H, CH2NHCvO), 2.42–2.33 (m, 2H,
CH2CH2NHCvO). 13C NMR d (ppm): 174.8 (s), 169.5 (s),
140.6 (s), 128.6 (d), 128.2 (d, 2C), 124.8 (d, 2C), 113.7 (s),
82.0 (d), 77.3 (d), 52.6 (q), 40.9 (t), 37.5 (t). MS m/z (%) 277
(Mþ, 2), 218 (22), 147 (26), 104 (100), 77 (92). IR (CHCl3)
3405, 1761, 1710, 1673 cm21. Anal. Calcd for C14H15NO5:
C, 60.64; H, 5.45; N, 5.05. Found: C: 60.21; H, 5.56; N,
4.61.
4.1.19. (1R,7R,9R)-7-(4-Methoxy-phenyl)-2-oxo-8,10-
dioxa-3-aza-bicyclo[5.2.1]decane-9-carboxylic acid
methyl ester (9f). Prepared as described for 9a, starting
from 7f (150 mg, 0.39 mmol) and obtaining crude 9f. After
chromatografic purification (eluent: EtOAc, Rf¼0.52) pure
9f (29 mg, 23%) as yellowish solid.
4.1.16. (1R,6R,8R)-6-(4-Chloro-phenyl)-2-oxo-7,9-dioxa-
3-aza-bicyclo[4.2.1]nonane-8-carboxylic acid methyl
ester (9c). Prepared as described for 9a, starting from 7c
(150 mg, 0.40 mmol) and obtaining pure 9c (95 mg, 76%)
as yellow oil.
Compound 9f. Mp 124–125 8C. [a]2D5¼225.7 (c0.3,
1
CHCl3). H NMR d (ppm): 7.41 (d, J¼8.8 Hz, 2H, Ph),
6.83 (d, J¼8.8 Hz, 2H, Ph), 6.58 (br s, 1H, NH), 5.28 (d,
J¼1.5 Hz, 1H, CHCHCO2CH3), 4.91 (d, J¼1.5 Hz, 1H,
CHCO2CH3), 4.13–4.03 (m, 1H, CHaHbNHCvO), 3.78
(s, 3H, OCH3), 3.43 (s, 3H, CO2CH3), 3.27–3.13 (m, 1H,
CHaHbNHCvO), 2.22–1.86 (m, 4H, CH2CH2CH2-
NHCvO). 13C NMR d (ppm): 173.9 (s), 169.3 (s), 159.5
(s), 133.5 (s), 126.7 (d, 2C), 114.7 (s), 113.1 (d, 2C), 79.5
1
Compound 9c. [a]2D5¼223.6 (c 0.3, CHCl3). H NMR d
(ppm): 7.54 (d, J¼8.4 Hz, 2H, Ph), 7.33 (d, J¼8.4 Hz, 2H,
Ph), 6.75 (br s, 1H, NH), 5.01 (s, 1H, CHCHCO2CH3), 4.94
(br s, 1H, CHCO2CH3), 3.69 (s, 3H, CO2CH3), 3.52–3.34
(m, 2H, CH2NHCvO), 2.40–2.22 (m, 2H, CH2CH2-

2590
D. Scarpi et al. / Tetrahedron 60 (2004) 2583–2591
(d), 78.7 (d), 55.2 (q), 52.4 (q), 42.1 (t), 36.3 (t), 25.8 (t).
MS m/z (%): 321 (Mþ, 3), 262 (13), 177 (19), 135 (100).
(t), 28.0 (q, 3C). MS m/z (%): 320 (Mþ2tBu, 1), 279
(Mþ2Boc, 4), 105 (100). IR (CDCl3): 1763, 1718 cm21
Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71.
Found: C: 60.28; H, 6.00; N, 3.53.
.
IR (CDCl3): 1747, 1653 cm21
.
Anal. Calcd for
C16H19NO6·H2O: C, 56.63; H, 6.24; N, 4.13. Found: C,
57.09; H, 6.08; N, 3.93.
4.1.22. (1R,6R,8R)-6-(4-Chloro-phenyl)-2-oxo-7,9-dioxa-
3-aza-bicyclo[4.2.1]nonane-3,8-dicarboxylic acid 3-tert-
butyl ester 8-methyl ester (10c). Prepared as described for
10a, starting from 9c (90 mg, 0.29 mmol) and obtaining,
after chromatographic purification (eluent: petroleum
ether–EtOAc, 7:1, Rf¼0.23) pure 10c (88 mg, 74%) as
yellow oil.
4.1.20. (1R,6S,8R)-6-Ethyl-2-oxo-7,9-dioxa-3-aza-bicyclo-
[4.2.1]nonane-3,8-dicarboxylic acid 3-tert-butyl ester
8-methyl ester (10a). To a solution of 9a (350 mg,
1.55 mmol) in anhydrous CH2Cl2 (10 mL) Boc2O
(690 mg, 3.10 mmol), Et3N (325 mL, 2.32 mmol) and
catalytic DMAP (18 mg, 0.16 mmol) were added under
nitrogen atmosphere. The resulting solution was refluxed for
6 h; a second portion of Boc2O (690 mg, 3.10 mmol) was
added after this period and the mixture refluxed for further
16 h. After cooling to rt, H2O (10 mL) was added and the
phases separated. The organic layer was washed with 5%
KHSO4 (2£10 mL), satd NaHCO3 (2£10 mL), brine
(2£10 mL) and dried over Na2SO4. After filtration and
evaporation of the solvent, crude 10a was obtained.
Chromatographic purification (eluent: petroleum ether–
EtOAc, 6:1, Rf¼0.33) afforded pure 10a (388 mg, 76%) as
yellow oil.
1
Compound 10c. [a]2D5¼2102.5 (c0.8, CHCl3). H NMR d
(ppm): 7.44 (d, J¼8.6 Hz, 2H, Ph), 7.31 (d, J¼8.6 Hz, 2H,
Ph), 5.15 (d, J¼2.2 Hz, 1H, CHCHCO2CH3), 4.95 (d, J¼
2.2 Hz, 1H, CHCO2CH3), 4.43–4.27 (m, 1H, CHaHbN),
3.73 (s, 3H, CO2CH3), 3.55–3.38 (m, 1H, CHaHbN), 2.32–
2.18 (m, 2H, CH2CH2N), 1.51 (s, 9H, Boc). 13C NMR d
(ppm): 173.8 (s), 169.1 (s), 153.0 (s), 138.9 (s), 134.7 (s),
128.4 (d, 2C), 126.6 (d, 2C), 114.4 (s), 83.3 (s), 82.9 (d),
78.0 (d), 52.9 (q), 39.9 (t), 39.2 (t), 28.0 (q, 3C). MS (30 eV)
m/z (%): 358 (Mþ2tBu, 3), 314 (Mþ2Boc, 2), 254 (7), 139
(94), 57 (100). IR (CDCl3): 1744, 1718 cm21. Anal. Calcd
for C9H22ClNO7: C, 55.41; H, 5.38; N, 3.40. Found: C:
55.59; H, 5.22; N, 3.19.
Compound 10a. [a]D25¼247.8 (c1.0, CHCl3). 1H NMR
(1.6:1 mixture of rotamers) d (ppm): 4.92 (d, J¼2.2 Hz, 1H
major rotamer, CHCO2Me), 4.71 (d, J¼2.2 Hz, 1H minor
rotamer, CHCO2Me), 4.69 (bs s, 1H minor rotamer,
CHCHCO2Me), 4.48 (br s, 1H major rotamer, CHCHCO2-
Me), 4.12 (dt, J¼15.8, 4.0 Hz, 1H major rotamer, CHaHbN),
3.71 (s, 3H major rotamer, CO2CH3), 3.70 (s, 3H minor
rotamer, CO2CH3), 3.70–3.64 (m, 1H minor rotamer,
CHaHbN), 3.41–3.04 (m, 1H, CHaHbN), 2.05–1.82 (m,
2H, CH2CH2N), 1.77 (q, J¼7.3 Hz, 2H, major rotamer,
CH2CH3), 1.60 (q, J¼7.3 Hz, 2H minor rotamer, CH2CH3),
1.39 (s, 9H major rotamer, t-Bu), 1.38 (s, 9H minor rotamer,
t-Bu), 0.89 (t, J¼7.3 Hz, 3H major rotamer, CH2CH3), 0.83
(t, J¼7.3 Hz, 3H minor rotamer, CH2CH3). 13C NMR d
(ppm): 174.0 and 169.4 (s), 169.8 and 168.1 (s), 116.9 and
116.3 (s), 83.4 and 83.1 (s), 82.5 and 77.6 (d), 77.4 and 76.9
(d), 52.7 and 52.6 (q), 39.2 and 37.2 (t), 35.6 and 35.4 (t),
31.3 and 30.5 (t), 28.4 and 27.9 (q, 3C), 7.9 and 7.4 (q). MS
m/z (%): 228 (Mþ2Boc, 7), 203 (95), 201 (32). IR (CDCl3):
1753, 1711 cm21. Anal. Calcd for C15H23NO7: C, 54.70; H,
7.04; N, 4.25. Found: C: 54.57; H, 7.24; N, 4.18.
Acknowledgements
`
We thank MURST and Universita di Firenze, Cofin 2002–
2004 and FIRB project code RBNE01RZH4_004 for
financial support. Mr Maurizio Passaponti and Mrs Brunella
Innocenti are acknowledged for their technical support.
References and notes
1. (a) Guarna, A.; Guidi, A.; Machetti, F.; Menchi, G.; Occhiato,
E. G.; Scarpi, D.; Sisi, S.; Trabocchi, A. J. Org. Chem. 1999,
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4.1.21. (1R,6R,8R)-2-Oxo-6-phenyl-7,9-dioxa-3-aza-bi-
cyclo[4.2.1]nonane-3,8-dicarboxylic acid 3-tert-butyl
ester 8-methyl ester (10b). Prepared as described for 10a,
starting from 9b (200 mg, 0.72 mmol) and obtaining,
after chromatographic purification (eluent: petroleum
ether–EtOAc, 6:1, Rf¼0.38) pure 10b (163 mg, 60%) as
yellow oil.
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4. Byciclic compounds derived from tartaric acid and
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1
Compound 10b. [a]2D5¼2114.2 (c0.5, CHCl3). H NMR d
(ppm): 7.63–7.58 (m, 2H, Ph), 7.40–7.30 (m, 3H, Ph), 5.17
(d, J¼2.2 Hz, 1H, CHCHCO2CH3), 4.96 (d, J¼2.2 Hz, 1H,
CHCO2CH3), 4.36 (dt, J¼15.8, 4.0 Hz, 1H, CHaHbN), 3.72
(s, 3H, CO2CH3), 3.53–3.40 (m, 1H, CHaHbN), 2.49–2.32
(m, 1H, CHaHbCH2N), 2.26–2.12 (m, 1H, CHaHbCH2N),
1.51 (s, 9H, Boc). 13C NMR d (ppm): 174.0 (s), 169.1 (s),
153.0 (s), 139.6 (s), 128.8 (d), 128.2 (d, 2C), 124.9 (d, 2C),
114.8 (s), 83.6 (s), 82.8 (d), 77.9 (d), 52.8 (q), 39.9 (t), 39.3
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4227–4238.

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