Development of a stereoselective Ugi reaction starting from an oxanorbornene β-amino acid derivative

Article abstract of DOI:10.1039/c2ob25060h

We have synthesised a novel oxanorbornene β-aminoacid derivative and employed it in a stereoselective Ugi reaction. Hypothesis regarding the mechanism taking place during the reaction have been made and validated through the determination of the relative and absolute configuration of the Ugi adducts. Use of the correct choice of solvents can increase stereoselection. The resulting bicyclic peptidomimetics can be used as a novel class of pluripotent substrates to be elaborated according to the synthetic strategies previously elaborated in our laboratories.

Full text of DOI:10.1039/c2ob25060h

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PAPER
Development of a stereoselective Ugi reaction starting from an oxanorbornene
β-amino acid derivative†
Luca Banfi,a Andrea Basso,*a Cinzia Chiappe,*b Fabio De Moliner,c Renata Rivaa and Lorenzo Sonagliaa
Received 10th January 2012, Accepted 2nd March 2012
DOI: 10.1039/c2ob25060h
We have synthesised a novel oxanorbornene β-aminoacid derivative and employed it in a stereoselective
Ugi reaction. Hypothesis regarding the mechanism taking place during the reaction have been made and
validated through the determination of the relative and absolute configuration of the Ugi adducts. Use of
the correct choice of solvents can increase stereoselection. The resulting bicyclic peptidomimetics can be
used as a novel class of pluripotent substrates to be elaborated according to the synthetic strategies
previously elaborated in our laboratories.
scaffold in order to obtain the desired endo amine substituent:
we speculated that a Diels–Alder reaction between furan and
Introduction
Diversity oriented synthesis1 has emerged as a very powerful
trans-nitroacrylate 4 could be exploited to obtain an adduct
having the correct spatial orientation of the two groups.10
tool for the discovery of biologically relevant, natural product
like2 molecular entities, especially in challenging fields such as
Indeed, by performing the cycloaddition reaction at low tempera-
protein–protein interactions.3 We have recently applied this
ture, the desired endo-nitro adduct 5 could be obtained as the
major isomer.11 Various procedures are available to prepare
approach to the synthesis of norbornene derivative 1 and its elab-
oration to pluripotent substrate 2 (Scheme 1).4 First of all we
nitroacrylate 4: we first applied the Henry reaction with nitro-
methane and glyoxalate12,13 and the CAN mediated nitrosation
have elaborated a multicomponent approach to functionalise the
core structure of 1 in a combinatorial fashion,5 then we have
devised an organocatalytic approach to prepare the adducts in an
enantioselective manner.6 Subsequently, exploiting the peculiar
reactivity of the oxabicyclic system, we have elaborated products
2 from the multicomponent step via a number of transform-
ations7,8 leading to distinct classes of compounds, some of them
showing activity towards proteins of the Bcl-2 family.9
We have now identified compound 3 (Fig. 1) as a new pluripo-
tent substrate that, having opposite configurations of the carbons
bearing the amine and carboxyl functionalities, could lead to
novel classes of compounds similar to those obtained with 1 but
with different spatial orientations. We wish to report in this paper
the first results related to this novel derivative.
of ethyl acrylate14 giving, however, variable results and yields of
2-hydroxy-3-nitropropanoate (always lower than 60%). In
addition, the subsequent mesylation/elimination step was found
to be troublesome due to the instability and low boiling point of
the resulting nitroacrylate. On the other hand, the iodo nitrosa-
tion employed by Steel15 was considered unsafe due to the use
of highly toxic N2O4 gas. We eventually found that the pro-
cedure reported by Yuen,16 starting from acrylate 7 and involving
a nitromercuration, a bromination/demercuration and a final
sodium acetate-mediated elimination, although not very eco-
friendly and atom economical, allowed us to prepare up to 10 g
of the desired nitroacrylate in 75% overall yield starting from
cheap ethyl acrylate. Upon filtration of NaBr and excess sodium
acetate, crude nitroacrylate was purified by flash chromatography
(extractive work-up, as described in the original procedure, was
avoided because partial decomposition was observed) and was
immediately employed in the Diels–Alder cycloaddition.
Results and discussion
With respect to compound 1,6 a completely different synthetic
For this purpose equal volumes of furan and chloroform were
added to the reaction vessel; this was sealed and left standing
(with occasional manual stirring) for two weeks in a refrigerator
at −24 °C (Scheme 2). The two stereoisomers 5 and 6 were
obtained in an overall 71% yield with a 3.6 : 1 ratio in favour of
the desired isomer 5; the two isomers could be separated by
flash chromatography. Due to the high tendency of these adducts
to give the retro Diels–Alder reaction, however, the desired
endo-NO2 adduct 5 was immediately reduced, soon after chrom-
atography, with Zn/HCl to obtain the corresponding amine 8.
approach had to be planned for the elaboration of the bicyclic
aUniversità degli Studi di Genova, Dipartimento di Chimica e Chimica
Industriale, Genova, Italy. E-mail: andrea.basso@unige.it
bUniversità degli Studi di Pisa, Dipartimento di Chimica e Chimica
Industriale, Pisa, Italy. E-mail: cinziac@farm.unipi.it
cUniversity of Arizona, Department of Pharmacology and Toxicology,
Tucson, Arizona, USA
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR of all new compounds and output files for intermediates
10 and 15. See DOI: 10.1039/c2ob25060h
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Scheme 1 A diversity-oriented approach employing an oxanorbornene pluripotent substrate.
crude materials showed in most cases the desired Ugi adducts as
the main products present in the mixture. To our disappointment,
however, the final compounds were in most cases mixtures of
diastereoisomers (whereas with 1 complete diastereoselection
was typically observed) with one prevailing in a d.r. > 3 : 1
(Table 1).
Fig. 1 General structure of a novel pluripotent substrate.
In addition, different levels of stereoselectivity were observed
for the same reaction depending on the method employed for the
isolation of the amino acid 3 after ester hydrolysis of 9. In fact,
three different methods were employed: (a) neutralisation of the
reaction medium with HCl and collection of the precipitated
product by filtration, (b) catching of the product on an acidic ion
exchange resin and releasing in solution with aqueous ammonia
and (c) neutralisation of the reaction medium with HCl and evap-
oration of the solvents. Out of these three methods the latter
allowed for complete recovery of the amino acid, although it suf-
fered from contamination by NaCl, whereas the first two,
although affording pure product, allowed only its partial recovery
(55–76%).
As outlined in Table 1, depending on the method employed
(methods a and b gave the same results), the diastereomeric ratio
varied, but a rationale could not be easily extrapolated, since in
some cases the presence of NaCl seemed beneficial, in others
not. It is worth noting that addition of NaCl to the amino acid 3
isolated with method a, resulted in an outcome similar to the one
obtained with method c. We therefore speculated that NaCl
could have a double effect, by increasing the polarity of the
solvent (in our hypothesis this could facilitate direct formation of
For our purposes a secondary amine was required and a reductive
amination step was devised to introduce a benzyl substituent
onto the amine functionality. Final hydrolysis of 9 afforded the
amino acid derivative 3, suitable for functionalisation via a mul-
ticomponent reaction.
In analogy with compound 1, we thought that an intramolecu-
lar Ugi reaction could be employed to introduce the peptidomi-
metic chain onto the nitrogen atom, following the same Ugi 5
centre 4 component reaction (U-5C-4CR) mechanism17 success-
fully employed before. Being interested to find whether this reac-
tion outcome occurred, we reacted amino acid 3 with various
aldehydes and isocyanides under classic Ugi conditions (in
MeOH at room temperature). Such a reaction probably involves
formation of a norbornene-fused 7-membered ring intermediate
10 as a consequence of interaction of 3 with one molecule of
aldehyde and one of isocyanide, and subsequent displacement of
the activated carboxy group by the alcohol employed as the
solvent, to afford the final product 11 (Scheme 3).
We were delighted to find that compounds 11a–j could be all
isolated in yields ranging from moderate to good. Moreover,
3820 | Org. Biomol. Chem., 2012, 10, 3819–3829
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Table 1 Outcome of the U-5C-4CR
Method c
Method a or b
Entry
R1
R2
Yielda (%)
d.r.
Yieldb
d.r.
a
b
c
d
e
f
g
h
i
Et
t-Bu
t-Bu
Bn
cHex
4-BnOPh
n-Bu
n-Bu
4-BnOPh
Bn
75
76
79
97
66
67
53
74
68
60
>95 : 5
>95 : 5
75 : 25
88 : 12
83 : 17
79 : 21
80 : 20
82 : 18
74 : 26
79 : 21
—
—
45%
—
55%
—
53%
—
—
—
93 : 7
—
82 : 18
—
75 : 25
—
i-Bu
i-Pr
Bn
i-Bu
Ph
Et
i-Pr
Bn
Ph
65%
53%
86 : 14
84 : 16
j
cHex
a Yield is referred to 9. b Yield is referred to 3.
the 7-membered ring intermediate 10, responsible for the stereo-
selection as it will be discussed below) but also by becoming an
active part of the reaction, possibly with Cl− acting as a nucleo-
phile transiently competing with the carboxylate or the isocya-
nide, thus affecting the configuration of the newly generating
stereogenic carbon. The fact that previous experiments showed
that the stereoselectivity of the U-5C-4CR for amino acid 1 did
not depend on the isolation method (and therefore on the pres-
ence or absence of NaCl) prompted us to investigate this effect
more in detail. We therefore moved to use different salts, such as
KCl or NaBr, and other alcohols as solvents. However, we could
not find a general trend, although interesting results were
obtained when trifluoroethanol (TFE) was employed with and
without the presence of NaCl. In both cases the reaction was
very sluggish, but in the absence of NaCl the stereoselectivity
was complete and only one trifluoroethyl ester was isolated. On
the other hand the presence of NaCl caused a marked decrease
in stereoselection. It seemed reasonable that the poor nucleophi-
licity of TFE could render more difficult the displacement of the
7-member ring intermediate 10 and increase, when NaCl was
employed, the extent of the Cl− mediated side reactions. At the
same time its higher polarity could favour the formation of the
more stable diastereoisomer. A good compromise between the
diminished reactivity and the increased polarity seemed to be the
use of a mixture of methanol and trifluoroethanol, the first being
the nucleophile becoming part of the U-5C-4CR and the latter
modulating polarity. Indeed, by employing a 1 : 1 mixture of the
two alcohols, the final compounds were obtained solely as the
corresponding methyl esters and with very good diastereomeric
ratios (Table 2); only in the case of benzaldehyde was more than
5% of the minor diastereoisomer isolated.
Scheme 2 Reagents and conditions: (a) CHCl3, −24 °C, 71%; (b)
HgCl2, NaNO2, water; (c) bromine, water, Et2O; (d) AcONa (an.), Et2O,
75%; (e) Zn dust, HCl, EtOH, 78%; (f) benzaldehyde, NaBH3CN,
AcOH, MeOH, quant.; (g) NaOH, dioxane, see text.
Having these results in hand we decided, in the case of entry
j, to investigate further reaction conditions, including various
solvent mixtures (i.e. ionic liquids (ILs)) and temperatures. As
summarised in Tables 3 and 4, best results in terms of stereo-
selectivity were obtained with a 9 : 1 mixture of TFE–MeOH,
although in this case also a certain amount of TFE ester was iso-
lated. On the other hand, no reaction was observed when DMSO
or water were used as co-solvent or solvent (when water was
employed we were indeed expecting to isolate the corresponding
carboxylic derivative). Also addition of benzaldehyde and cyclo-
hexylisocyanide at different times was investigated, but no
Scheme 3 Mechanism for the Ugi 5 centre 4 component reaction.
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Table 2 Outcome of the U-5C-4CR (3→11) performed in MeOH–TFE
1 : 1
Table 4 Outcome of the U-5C-4CR with benzaldehyde and
cyclohexyl isocyanide (3j→11j) with ionic liquidsa
Entry
R1
R2
d.r.
Yield (%)
IL
d.r.
Yield (%)
79
a
b
c
d
e
f
g
h
i
Et
t-Bu
t-Bu
Bn
cHex
4-BnOPh
n-Bu
n-Bu
4-BnOPh
Bn
>95 : 5
>95 : 5
95 : 5
>95 : 5
95 : 5
83 : 17
>95 : 5
>95 : 5
>95 : 5
83 : 17
50
75
73
74
77
97
80
74
93
98
61 : 39
i-Bu
i-Pr
Bn
i-Bu
Ph
74 : 26
45
Et
i-Pr
Bn
Ph
j
cHex
73 : 27
80 : 20
56
89
Table 3 Outcome of the U-5C-4CR with benzaldehyde and
cyclohexyl isocyanide (3j→11j) under various conditions
Conditions
d.r.
Yield
71 : 29
83 : 17
18
40
MeOH–CF3CH2OH 1 : 3 (0.2 M)
MeOH–CF3CH2OH 1 : 3 (0.2 M) at 0 °C
MeOH–CF3CH2OH 1 : 9 (0.2 M)
H2O (0.2 M)
88 : 12
83 : 17
93 : 7
—
96%
84%
63%
—
MeOH–H2O 1 : 1 (0.2 M)
MeOH–DMSO 1 : 1 (0.2 M)
MeOH–NMP 1 : 1 (0.2 M)
MeOH–phenol 1 : 1 (0.2 M)
MeOH (0.2 M) with tetrazole (2 eq)
—
—
85 : 15
85 : 15
79 : 21
—
—
18%
69%
81%
80 : 20
85 : 15
42
45
differences were observed. We also investigated if the lower
stereoselectivities observed in the case of benzaldehyde were
common to other aromatic aldehydes, and indeed aryl aldehydes
with EW and ED groups behaved similarly, as outlined in
Scheme 4.
Particularly interesting, is the use of ILs; in this investigation
conventional ILs (differently substituted imidazolium, pyridi-
nium and pyrrolidinium salts combined with anions such as
chloride, hexafluorophosphate, bistriflimide and dicyanamide)
and task-specific ILs, characterized by one or more functional
groups on the cation, have been used in 1 : 1 (w/v) mixtures with
methanol.18 As evidenced in Table 4, depending on the IL
employed the diastereoisomer ratio and reaction yield varied;
although only in a few cases were selectivities higher than those
obtained with pure methanol. This result is not completely sur-
prising since IL polarities, at least as expressed by solvatochro-
mic parameters, not only present some peculiarities,19 but they
are strongly affected by the presence of a molecular solvent,
such as methanol, which is able to destroy the three-dimensional
structure of the IL and modify significantly these parameters.
Depending on concentration, polarity parameters can become
practically identical to those of molecular solvents.20 Conse-
quently, under the employed conditions the polarity of the inves-
tigated media is probably not very different from that of
methanol.
73 : 27
75 : 25
68
96
77 : 23
72 : 28
77
74
a Reactions were performed with IL–MeOH 1 : 1 at
a 0.2 M
concentration.
On the other hand, the specific interactions of methanol with
the components of IL (in the case of protic solvents the inter-
action should be preferentially with the anion) can modify as
observed the diastereoisomeric ratios and yields affecting the
ability of the IL to interact with the species which should favor
formation of intermediate 10. For example, the high
diastereoselectivity associated with a low yield observed in
dicyanamide based ILs can be considered a consequence of the
higher ability of this anion to interact with methanol. The anion–
methanol interaction can reduce the amount of “free” and faster
reacting methanol molecules. A similar explanation can be
given for the moderate yields of the reaction in [bm2im]Cl and
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[mim1,e]Cl, whereas the positive results obtained in the hydroxyl
difunctionalized [mim1,g]Cl can be attributed to the capability of
this cation to compete efficiently with methanol in chloride
coordination. On the other hand, in the case of [omim]Cl the
presence on the cation of a long alkyl chain can favor the for-
mation of polar and apolar domains which are able to determine
a different methanol distribution and binding mode. Finally, it is
necessary to consider that depending on the IL, cosolvent and
substrate, the preferential solvation phenomena can also occur20
in these media. Independent of the complexity of these systems,
which can affect selectivity and reactivity through several differ-
ent mechanisms, since in all the investigated ILs the diastereo-
isomer ratios are comparable or lower than those obtained in the
1 : 1 mixture methanol–TFE we can state that, although some
combinations are more favorable than pure methanol, probably
the specific interactions of IL cations and/or anions with the
species which should favor the formation of intermediate 10 are
never so efficient to give complete diastereospecificity.
Although poor stereoselectivity is quite typical in isocyanide-
based multicomponent reactions, we were surprised at such an
outcome, on the basis of the results obtained with bicyclic amino
acid 1, where the Ugi reactions were found to be completely
stereoselective, independently from the aldehyde and isocyanide
employed. In the case of this bicyclic amino acid, it was postu-
lated that the reaction proceeded through formation of a transient
6-member ring intermediate 12, generated by intramolecular
attack of the carboxylate onto the iminium ion. This hypothesis
was taken into account to rationalise the unusually high diaster-
eoselection observed in the multicomponent reaction.4,6 Indeed,
the small energy difference of the two diastereomeric 7-member
ring intermediates 13 could not be sufficient to justify such an
outcome. The more stable diastereoisomer 12a would be then
nucleophilically attacked by the isocyanide onto the Cα carbon
with subsequent inversion of the configuration and formation of
13a through the attack of the carboxylate onto the sp carbon
derived from the isocyanide. Final methanolysis affords com-
pound 2 with the correct configuration at the Cα carbon
(Scheme 5). If a similar mechanism could be applied also in the
case of 3, intermediate 15 would be generated from iminium ion
14 prior to attack of the isocyanide (Scheme 6). We were there-
fore intrigued to find out if the same hypothesis could be applied
also in this case.
Having established a method to generate the Ugi adducts in a
stereoselective manner, it became evident that the relative
configuration of the final products had to be determined, also to
confirm that the major diastereoisomer was originating from the
more stable 7-member ring intermediate. Being the final com-
pounds foams rather than giving crystalline solids, methods
other than crystallography had to be employed. It was therefore
decided to exploit the bicyclic system as a chiral auxiliary and to
remove it at the end of the Ugi condensation in order to deter-
mine the absolute configuration of the resulting α-aminoamide
17,21 as outlined in Scheme 7.
Removal of the bicyclic system had already been performed
on compounds 2 and did not seem to be problematic at this
Scheme 4 Reagents and conditions: (a) cyclohexylisocyanide,
MeOH–CF3CH2OH 1 : 1 (0.2 M).
Scheme 5 Postulated mechanism occurring when amino acid 1 is employed in the U-5C-4CR.
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Scheme 6 Postulated mechanism occurring when amino acid 3 is employed in the U-5C-4CR.
Scheme 7 Synthetic scheme for the determination of the configuration of 11.
stage, while more concern regarded the preparation of the bi-
cyclic aminoacid in an optically pure form.
toluene and by treating the resulting enamine with HCl in
dioxane. Comparison of the sign of the optical rotatory power of
products 17 with that of authentic samples derived from L- and
D-phenylalanine confirmed that (−)-19 afforded (R)-17 and
(+)-18 afforded (S)-17 (Scheme 8). Going backwards, we could
therefore assign the relative configuration of the newly generated
stereocenter of the major diastereoisomer of 11 during the Ugi
reaction, as depicted in Fig. 2.
This is in accordance with the results obtained by preliminary
molecular modelling calculations. Molecular modelling
calculations on the postulated intermediates originating from
the reaction of 3 with benzyl isocyanide and phenylacetal-
dehyde were carried out (conformational analysis was
performed with CONFLEX22 software using GB/SA calculation,
while SCF energy of more stable conformers was calculated
in methanol using GAUSSIAN (RB3LYP/6-31G SCRF =
PCM).23 Such preliminary calculations showed that dia-
stereomeric 6-membered ring intermediates 15i_a and 15i_b had
an energy difference of less than 0.06 kcal mol−1, favouring
15i_a.
Desymmetrisation of a meso compound according to the
method developed by Bolm24 could not be applied in this case.
It seemed more feasible to employ kinetic resolution through
enzymatic hydrolysis of ester 18, following the approach devel-
oped by Steel.15 Compound rac-18 was prepared from 8 via pro-
tection of the primary amine with Boc2O, while hydrolysis was
performed with horse liver acetone powder in TRIS buffer. At
this stage the enzymatic reaction was not optimised, since the
main aim was to be able to determine the configuration of ami-
noamide 17. The unoptimised methodology afforded (−)-acid 19
in approximately 86% ee and (+)-ester 18 in 85% ee, as deter-
mined by absolute optical rotatory power. Both enriched enantio-
meric mixtures were transformed into the corresponding N-
benzyl aminoacid derivative 3 and reacted under the optimised
Ugi conditions with phenylacetaldehyde and benzyl isocyanide,
affording, as expected, only one diastereoisomer. Conversion of
the Ugi adducts 11i into the α-aminoamide was performed as
previously described,6 by heating the compound in refluxing
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Scheme 8 Reagents and conditions: (a) enzymatic hydrolysis, see text; (b) toluene, reflux, quant.; (c) HCl, dioxane, 87%.
Fig. 2 The major diastereoisomer originating from the U-5C-4CR with
amino acid 3.
In contrast, diastereomeric 7-membered ring compounds
10i_a and 10i_b, have an energy difference of about 4.5 kcal
mol−1, favouring 10i_b, (→ major diastereoisomer of 11i;
Fig. 3).
We had therefore to conclude that, in the case of compound 3,
differently from what observed in the case of 1, the observed
stereoselection was probably determined at the level of the
7-membered ring intermediate.
It is worth noting that, according to our postulated mechanism,
the more stable 6-membered ring intermediate 15i_a would lead
to the minor diastereoisomer of 11 via formation of 10i_a (the
attack of the isocyanide proceeds with inversion of the configur-
ation). One possible explanation of the different stereoselectivity
observed in MeOH and trifluoroethanol could therefore be that
in the former solvent the reaction proceeds to some extent via
the formation of intermediate 15, thus lowering diastereoselectiv-
ity as a consequence of the formation of a certain amount of
10i_a, while the employment of the more polar trifluoroethanol
could stabilise the iminium ion 14, which could directly react
Fig. 3 SCF energies of diastereomeric 6- and 7-member ring
intermediates.
with the isocyanide to afford solely 10i_b (Scheme 6). Accord-
ing to this hypothesis, the detrimental effect of NaCl on stereose-
lection observed for 3 and not for 1 could be rationalised with a
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higher tendency of chloride anions to interact (and thus giving
transient nucleophilic addition to the iminium group) with the
open intermediate 14 rather than with cyclic adduct 12.
7.20–7.35 (m, 5H). 13C NMR: δ 14.4 (CH3), 52.36 (CH), 53.1
(CH2), 61.1 (CH2), 62.1 (CH), 79.6 (CH), 82.0 (CH), 127.3
(CHAr), 128.2 (CHAr), 128.6 (CHAr), 134.5 (CH), 137.4 (CH),
140.0 (C), 173.0 (C). HRMS calculated for C16H19NO3
273.1365, found 273.1358.
Experimental
3-endo-(Benzylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2-exo-
carboxylic acid 3. 1H NMR (d6-DMSO): δ 1.90 (d, J = 3.4 Hz,
1H), 3.40–3.44 (m, 1H), 3.66 (d, J = 13.6 Hz, 1H), 3.74 (d, J =
13.6 Hz, 1H), 4.73 (d, broad, J = 4.3 Hz, 1H), 4.95 (m, 1H),
6.35 (dd, J = 5.8, 1.5 Hz, 1H), 6.53 (dd, J = 5.8, 1.7 Hz, 1H),
7.17–7.38 (m, 5H). 13C NMR (d6-DMSO): δ 51.6 (CH), 51.9
(CH2), 61.2 (CH), 78.8 (CH), 81.8 (CH), 126.6 (CHAr), 128.0
(CHAr), 128.1 (CHAr), 134.0 (CH), 136.9 (CH), 140.8 (C),
174.6 (C). HRMS calculated for C14H15NO3 245.1052, found
245.1050.
General remarks
The reagents and solvents of the highest purity available were
used as purchased or purified/dried by standard procedures when
necessary. All ionic liquids, namely, 1-octyl-3-methylimidazo-
lium chloride ([omim]Cl), 1-butyl-2,3-dimethylimidazolium
chloride ([bm2im]Cl), 1-hydroxyethyl-3-methylimidazolium
chloride ([mim1,e]Cl), 1-glyceryl-3-methylimidazolium chloride
([mim1,g]Cl), 1-butyl-3-methylimidazolium hexafluorophosphate
([bmim][PF6]),
([bmim][Tf2N]),
1-butyl-3-methylimidazolium
1-(1-cyanobutyl)pyridinium
bistriflimide
bistriflimide
([CNC4py][Tf2N]), 1-butylpyridinium dicyanamide ([BPy]-
[N(CN)2]), 1-butyl-4-aza-1-azaniabicyclo[2.2.2]octane dicyana-
mide ([C4dabco][N(CN)2]), 1-octyl-4-aza-1-azaniabicyclo[2.2.2]
octane dicyanamide ([C8dabco][N(CN)2]), N-butyl-N-methyl-
morpholinium dicyanamide ([Mor1,4][N(CN)2]) and N-methyl-
N-butylmorpholinium triflate ([bmpy][TfO]) were prepared
according to well-established synthetic procedures18 and
confirmed by NMR analysis and electrospray ionization mass
spectrometry (ESI-MS). All ILs were dried under vacuum
(pressure 10−2 – 10−3 mbar) at 80 °C for 24 h prior spectral
analysis.
General procedure for the Ugi reaction
Amino acid 3 (0.20 mmol, 50 mg) was dissolved in the appropri-
ate solvent (2 mL), then the aldehyde (1.5 eq) and the isocyanide
(1.2 eq) were added in this order. The reaction mixture was
stirred at room temperature for 48 h. Brine (10 mL) and dichloro-
methane (10 mL) were added and the phases separated. The
organic phase was dried with Na2SO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by silica
gel flash column chromatography.
1H and 13C NMR spectra were recorded at 300 and 75 MHz
respectively in CDCl3 if not specifically indicated, and calibrated
to internal standard (TMS) or the residual peak of the solvent.
Methyl 3-endo-(benzyl(1-(tert-butylamino)-1-oxobutan-2-yl)
amino)-7-oxabicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
11a.
Pale yellow oil, Rf = 0.48 (PE–EtOAc 7 : 3). 1H NMR: δ 1.02 (t,
J = 7.4 Hz, 3H), 1.32 (s, 9H), 1.45–1.72 (m, 1H), 1.74–1.96 (m,
1H), 2.26 (d, J = 4.2 Hz, 1H), 2.76–3.05 (m, 1H), 3.60 (d, J =
14.7 Hz, 1H), 3.74 (s, 3H), 3.86 (d, J = 14.7 Hz, 1H), 3.86 (d, J
= 4.1 Hz, 1H), 4.95 (d, J = 3.9 Hz, 1H), 5.05 (d, J = 0.8 Hz,
1H), 5.98 (dd, J = 5.8, 1.2 Hz, 1H), 6.45 (dd, J = 5.8, 1.7 Hz,
1H), 6.81 (s, 1H), 7.27 (m, 5H). 13C NMR: δ 12.9 (CH3), 21.3
(CH2), 28.9 (3CH3), 49.1 (CH), 51.0 (C), 52.6 (CH3), 54.5
(CH2), 65.7 (CH), 66.1 (CH), 81.0 (CH), 82.3 (CH), 127.4
(CHAr), 128.5 (CHAr), 128.8 (CHAr), 135.4 (CH), 135.5 (CH),
140.2 (CAr), 171.4 (C), 174.3 (C). HRMS calculated for
C23H32N2O4 400.2362, found 400.2375.
Synthesis of amino acid 3
Amino ester 8 has been prepared following the literature pro-
cedure.15 Benzaldehyde (1.08 mmol, 110 μL) and acetic acid
(1.5 mL) were added to a solution of 8 (0.72 mmol, 132 mg) in
dry methanol and the reaction was stirred at room temperature
over night. Sodium cyanoborohydride (1.3 mmol, 81 mg) was
then added and the reaction stirred at room temperature for 4 h.
Saturated aqueous NaHCO3 and dichloromethane were added,
the phases separated and the organic one was dried with
Na2SO4, filtered and concentrated under reduced pressure. The
crude mixture was purified by silica gel flash column chromato-
graphy (gradient: petroleum ether–ethyl acetate 70 : 30 up to
50 : 50) to afford 9 (0.53 mmol, 145 mg). Ester 9 (0.53 mmol)
was then treated with aqueous NaOH 1.0 M (0.58 mmol) in
dioxane (3.5 mL) at room temperature overnight. The reaction
was quenched with aqueous HCl 1.0 M (0.58 mmol) and a pre-
cipitate was formed. The solid was filtered after cooling the flask
with an ice bath and washed with cold water to give acid 3
(0.29 mmol, 71 mg) in 55% yield.
Methyl 3-endo-(benzyl(1-(tert-butylamino)-4-methyl-1-oxopen-
tan-2-yl)amino)-7-oxabicyclo [2.2.1]hept-5-ene-2-exo-carboxylate
1
11b. Colourless oil, Rf = 0.30 (PE–EtOAc 8 : 2). H NMR: δ
0.90 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 1.30 (s, 9H),
1.36 (dd, J = 8.8, 4.0 Hz, 1H), 1.71–1.83 (m, 2H), 2.28 (d, J =
4.1 Hz, 1H), 3.04 (dd, J = 7.9, 4.7 Hz, 1H), 3.62 (d, J = 14.7
Hz, 1H), 3.75 (d, J = 14.7 Hz, 1H), 3.76 (s, 3H), 3.85 (t, J = 4.1
Hz, 1H), 4.98 (d, J = 3.9 Hz, 1H), 5.05 (d, J = 1.3 Hz, 1H), 6.09
(dd, J = 5.8, 1.5 Hz, 1H), 6.47 (dd, J = 5.8, 1.8 Hz, 1H), 6.75 (s,
1H), 7.19–7.35 (m, 5 H). 13C NMR: δ 22.5 (CH3), 23.5 (CH3),
26.0 (CH), 28.8 (3CH3), 37.0 (CH2), 48.8 (CH2), 51.0 (C), 52.6
(CH3), 54.4 (CH2), 62.3 (CH), 65.6 (CH), 81.2 (CH), 82.3 (CH),
127.5 (CHAr), 128.6 (CHAr), 128.6 (CHAr), 135.4 (CH), 135.5
(CH), 140.2 (CAr), 171.6 (C), 174.2 (C). HRMS calculated for
C25H36N2O4 428.2675, found 428.2679.
Ethyl 3-endo-(benzylamino)-7-oxabicyclo[2.2.1]hept-5-ene-2-
carboxylate 9. 1H NMR: δ 1.28 (t, J = 7.1 Hz, 3H), 2.05 (d, J =
3.4 Hz, 1H), 3.69 (dd, J = 4.3, 3.5 Hz, 1H), 3.79 (d, J = 13.2
Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 1H),
4.87–4.92 (m, 1H), 5.14 (dd, broad, J = 1.7, 0.7 Hz, 1H), 6.44
(d, J = 5.8, 1.6 Hz, 1H), 6.55 (dd, J = 5.8, 1.8 Hz, 1H),
3826 | Org. Biomol. Chem., 2012, 10, 3819–3829
This journal is © The Royal Society of Chemistry 2012

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Methyl 3-endo-(benzyl(1-(benzylamino)-3-methyl-1-oxobutan-
2-yl)amino)-7-oxabicyclo[2.2.1] hept-5-ene-2-exo-carboxylate
52.6 (CH3), 52.8 (CH2), 64.1 (CH), 67.5 (CH), 79.4 (CH), 80.3
(CH), 127.6 (CHAr), 128.2 (CHAr), 128.5 (CHAr), 128.7
(CHAr), 128.8 (CHAr), 129.8 (CHAr), 134.9 (CH), 135.1 (CH),
137.3 (CAr), 138.9 (CAr), 170.5 (C), 174.5 (C). HRMS calcu-
lated for C27H32N2O4 448.2362, found 448.2363.
11c. Colourless oil, Rf = 0.22 (PE–Et2O–EtOAc 6 : 3 : 1). 1H
NMR: δ 0.87 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 7.1 Hz, 3H),
1.98–2.12 (m, 1H), 2.27 (d, J = 4.2 Hz, 1H), 2.64 (d, J = 10.5
Hz, 1H), 3.21 (d, J = 15.1 Hz, 1H), 3.67 (s, 3H), 3.83 (t, J = 4.1
Hz, 1H), 4.34 (d, J = 15.1 Hz, 1H), 4.46 (dd, J = 14.7, 5.6 Hz,
1H), 4.54 (dd, J = 14.7, 5.6 Hz, 1H), 4.79 (d, broad, J = 4.1 Hz,
1H), 5.07 (d, J = 1.1 Hz, 1H), 5.35 (dd, J = 5.8, 1.3 Hz, 1H),
6.28 (dd, J = 5.8, 1.8 Hz, 1H), 7.19–7.38 (m, 10H). 13C NMR: δ
19.9 (CH3), 20.6 (CH3), 28.4 (CH), 43.4 (CH2), 50.1 (CH), 52.9
(CH3), 54.8 (CH2), 67.3 (CH), 72.2 (CH), 81.5 (CH), 81.8 (CH),
127.2 (CHAr), 127.5 (CHAr), 128.1 (CHAr), 128.4 (CHAr),
128.8 (CHAr), 129.2 (CHAr), 134.6 (CH), 136.5 (CH), 139.0
(CAr), 140.9 (CAr), 170.4 (C), 175.7 (C). HRMS calculated for
C27H32N2O4 448.2362, found 448.2358.
Methyl
3-endo-(benzyl(1-(butylamino)-1-oxobutan-2-yl)
11g.
amino)-7-oxabicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
1
Colourless oil, Rf = 0.33 (PE–EtOAc 7 : 3). H NMR: δ 0.93 (t,
J = 7.2 Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H), 1.28–1.38 (m, 2H),
1.38–1.53 (m, 2H), 1.66 (m, H), 1.82–2.01 (m, 1H), 2.27 (d, J =
4.3 Hz, 1H), 2.99 (dd, J = 7.5, 6.0 Hz, 1H), 3.07–3.19 (m, 1H),
3.26 (td, J = 13.3, 7.0 Hz, 1H), 3.58 (d, J = 14.7 Hz, 1H), 3.76
(s, 3H), 3.85 (d, J = 14.7 Hz, 1H), 3.85 (d, J = 4.2 Hz, 1H),
4.87– 4.95 (m, 1H), 5.07 (dd, J = 1.8, 0.7 Hz, 1H), 5.95 (dd, J =
5.8, 1.5 Hz, 1H), 6.44 (dd, J = 5.8, 1.8 Hz, 1H), 6.94–7.07 (m,
1H), 7.17–7.40 (m, 5H). 13C NMR: δ 12.7 (CH3), 13.8 (CH3),
20.2 (CH2), 21.7 (CH2), 31.7 (CH2), 38.9 (CH2), 49.0 (CH),
52.6 (CH3), 54.1 (CH2), 65.6 (CH), 80.9 (CH), 81.8 (CH), 127.3
(CHAr), 128.4 (CHAr), 128.6 (CHAr), 135.2 (CH), 135.3 (CH),
139.9 (CAr), 171.8 (C), 174.4(C). HRMS calculated for
C23H32N2O4 400.2362, found 400.2368.
Methyl 3-endo-(benzyl(1-(cyclohexylamino)-1-oxo-3-phenyl-
propan-2-yl)amino)-7-oxabicyclo [2.2.1]hept-5-ene-2-exo-carbox-
ylate 11d. Pale yellow oil, Rf = 0.42 (PE–EtOAc 7 : 3).
1H-NMR: δ 0.98–1.76 (m, 10H), 1.84–1.94 (m, 1H), 2.28 (d, J
= 4.0 Hz, 1H), 2.87 (dd, J = 13.4, 5.8 Hz, 1H), 3.28–3.43 (m,
2H), 3.64 (d, J = 14.6 Hz, 1H), 3.76 (s, 3H), 3.81 (d, J = 14.6
Hz, 1 H), 3.98 (t, J = 4.0 Hz, 1H), 4.93–4.99 (m, 1 H), 5.06 (m,
1H), 6.06 (dd, J = 5.8, 1.5 Hz, 1H), 6.43 (dd, J = 5.8, 1.8 Hz,
1H), 6.69 (m, 1H), 7.12–7.51 (m, 10H). 13C NMR: δ 25.0, 25.7,
33.0, 33.4, 34.3 (CH2), 48.6 (CH), 48.8 (CH), 52.7 (CH3), 54.9
(CH2), 65.7 (CH), 66.3 (CH), 81.1 (CH), 82.5 (CH), 126.3
(CHAr), 127.5 (CHAr), 128.5 (CHAr), 128.6 (CHAr), 128.7
(CHAr), 129.6 (CHAr), 135.4 (CH), 135.5 (CH), 139.7 (CAr),
140.2 (CAr), 170.5 (C), 174.2 (C). HRMS calculated for
C30H36N2O4 488.2675, found 488.2661.
Methyl
3-endo-(benzyl(1-(4-(benzyloxy)phenylamino)-3-
methyl-1-oxobutan-2-yl)amino)-7-oxabicyclo[2.2.1]hept-5-ene-2-
exo-carboxylate 11h. Pale yellow oil, Rf = 0.53 (PE–EtOAc
1
7 : 3). H NMR: δ 0.92 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz,
3H), 1.99–2.15 (m, 1H), 2.33 (d, J = 4.1 Hz, 1H), 2.72 (d, J =
10.5 Hz, 1H), 3.31 (d, J = 15.1 Hz, 1H), 3.76 (s, 3H), 3.91 (t, J
= 4.1 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H), 4.80 (d, J = 4.1 Hz,
1H), 5.13 (s, 2H), 5.17 (d, J = 1.1 Hz, 1H), 5.23 (dd, J = 5.9,
1.4 Hz, 1H), 6.30 (dd, J = 5.9, 1.9 Hz, 1H), 6.92–6.99 (m, 2H),
7.23–7.48 (m, 10H), 7.59–7.68 (m, 2H), 9.30 (s, 1H). 13C
NMR: δ 20.0 (CH3), 20.5 (CH3), 28.4 (CH), 51.2 (CH), 53.3
(CH3), 54.9 (CH2), 67.8 (CH), 70.5 (CH2), 73.4 (CH3), 81.8
(CH), 115.4 (CHAr), 121.3 (CHAr), 127.3 (CHAr), 127.6
(CHAr), 128.1 (CHAr), 128.4 (CHAr), 128.8 (CHAr), 129.4
(CHAr), 132.1 (CAr), 134.3 (CH), 136.6 (CH), 137.3 (CAr),
140.9 (CAr), 155.4 (CAr), 168.4 (C), 176.2 (C). HRMS calcu-
lated for C33H36N2O5 540.2624, found 540.2636.
Methyl
3-endo-(benzyl(1-(4-(benzyloxy)phenylamino)-4-
methyl-1-oxopentan-2-yl)amino)-7-oxabicyclo[2.2.1]hept-5-ene-
2-exo-carboxylate 11e. Colourless oil, Rf = 0.50 (PE–EtOAc
1
75 : 25). H NMR: δ 0.92 (d, J = 6.5 Hz, 3H), 0.97 (d, J = 6.5
Hz, 3H), 1.35–1.47 (m, 1H), 1.77–1. 95 (m, 2H), 2.34 (d, J =
4.3 Hz, 1H), 3.27 (dd, J = 8.0, 4.6 Hz, 1H), 3.65 (s, 3H), 3.73
(s, 2H), 3.88 (t, J = 4.1 Hz, 1H), 4.97 (d, J = 3.9 Hz, 1H), 5.04
(s, 2H), 5.08 (d, J = 1.3 Hz, 1H), 6.11 (dd, J = 5.8, 1.3 Hz, 1H),
6.46 (dd, J = 5.8, 1.8 Hz, 1H), 6.88–6.98 (m, 2H), 7.21–7.50
(m, 12H), 8.85 (s, 1H). 13C NMR: δ 22.5 (CH3), 23.6 (CH3),
26.1 (CH), 37.3 (CH2), 48.8 (CH), 52.9 (CH3), 54.2 (CH2), 62.2
(CH), 65.7 (CH), 70.5 (CH2), 81.2 (CH), 82.0 (CH), 115.4
(CHAr), 120.9 (CHAr), 127.7 (CHAr), 127.8 (CHAr), 128.1
(CHAr), 128.75 (CHAr), 128.81 (CHAr), 128.84 (CHAr), 131.7
(CAr), 135.4 (CH), 135.7 (CH), 137.2 (CAr), 139.7 (CAr),
155.4 (CAr), 170.5 (C), 174.5 (C). HRMS calculated for
C34H38N2O5 554.2781, found 554.2781.
Methyl
3-endo-(benzyl(1-(benzylamino)-1-oxo-3-phenylpro-
pan-2-yl)amino)-7-oxabicyclo [2.2.1]hept-5-ene-2-exo-carboxy-
late 11i. Colourless oil, Rf = 0.36 (PE–EtOAc 7 : 3). 1H NMR: δ
2.26 (d, J = 4.0 Hz, 1H), 2.90 (dd, J = 13.8, 6.2 Hz, 1H),
3.36–3.46 (m, 1H), 3.48–4.54 (m, 1H), 3.66 (m, 5H), 3.98 (t, J
= 4.0 Hz, 1H), 4.28 (dd, J = 14.7, 5.5 Hz, 1H), 4.37 (dd, J =
14.7, 6.1 Hz, 1H), 4.93–4.96 (m, 1H), 4.97–4.99 (m, 1H), 6.06
(dd, J = 5.8, 1.5 Hz, 1H), 6.17 (dd, J = 5.8, 1.8 Hz, 1H),
7.05–7.36 (m, 16H). 13C NMR: δ 34.1 (CH2), 43.5 (CH2), 48.4
(CH), 52.7 (CH3), 54.9 (CH2), 65.4 (CH), 65.8 (CH), 81.0 (CH),
82.4 (CH), 126.5 (CHAr), 127.6 (CHAr), 127.6 (CHAr), 128.0
(CHAr), 128.6 (CHAr), 128.7 (CHAr), 128.8 (CHAr), 129.6
(CHAr), 135.3 (CH), 135.5 (CH), 138.5 (CAr), 139.2 (CAr),
140.0 (CAr), 171.7 (C), 174.1 (C). HRMS calculated for
C31H32N2O4 496.2362, found 496.2363.
Methyl 3-endo-(benzyl(2-(butylamino)-2-oxo-1-phenylethyl)
amino)-7-oxabicyclo[2.2.1]hept-5-ene-2-exo-carboxylate
11f.
1
Pale yellow oil, Rf = 0.28 (PE–Et2O–EtOAc 7 : 2 : 1). H NMR:
δ 0.93 (t, J = 7.3 Hz, 3H),1.28–1.38 (m, 2H), 1.43–1.56 (m,
2H), 2.43 (m, 1H), 3.10–3.22 (m, 1H), 3.38–3.46 (m, 1H), 3.46
(d, J = 14.5 Hz, 1H), 3.64 (m, 1H), 3.79–3.89 (m, 5H), 4.46 (s,
1H), 5.02 (d, J = 1.4 Hz, 1H), 6.05 (dd, J = 5.8, 1.6 Hz, 1H),
6.39 (dd, J = 5.8, 1.8 Hz, 1H), 7.20–7.49 (m, 11H). 13C NMR: δ
14.3 (CH3), 20.1 (CH2), 31.7 (CH2), 39.0 (CH2), 46.8 (CH),
Methyl 3-endo-(benzyl(2-(cyclohexylamino)-2-oxo-1-phenyl-
ethyl)amino)-7-oxabicyclo[2.2.1] hept-5-ene-2-exo-carboxylate
1
11j. Pale yellow oil, Rf = 0.20 (PE–Et2O–EtOAc 4 : 5 : 1). H
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 3819–3829 | 3827

View Article Online
NMR: δ 1.10–1. 45 (m, 5H), 1.61–1.97 (m, 5H), 2.44 (d, J = 4.9
Hz, 1H), 3.52 (d, J = 14.9 Hz, 1H), 3.71–3.75 (d, broad, 1H),
3.79–3.84 (m, 4H), 3.86 (m, 1H), 4.44 (s, 1H), 4.98–5.00 (m,
1H), 6.08 (dd, J = 5.8, 1.6 Hz, 1H), 6.40 (dd, J = 5.8, 1.8 Hz,
1H), 7.16 (d, J = 8.4 Hz, 1H), 7.21–7.42 (m, 10H). 13C NMR: δ
25.4 (CH2), 25.8 (CH2), 32.8 (CH2), 33.5(CH2), 47.1 (CH), 48.5
(CH), 52.7 (CH3), 53.5 (CH2), 64.3 (CH), 67.9 (CH), 79.8 (CH),
80.9 (CH), 127.7 (CHAr), 128.3 (CHAr), 128.7 (CHAr), 128.8
(CHAr), 129.0 (CHAr), 130.0 (CHAr), 135.1 (CH), 135.3 (CH),
137.7 (CAr), 139.3 (CAr), 169.8 (C), 174.5 (C). HRMS calcu-
lated for C29H34N2O4 474.2519, found 474.2532.
concentrated under reduced pressure. The crude mixture was
purified by silica gel flash column chromatography, mobile
phase petroleum ether–diethyl ether 50 : 50 for the ester (+)-18
(0.85 mmol, 243 mg) and petroleum ether–diethyl ether 50 : 50
+ 1% acetic acid for the acid (−)-19 (0.73 mmol, 187 mg). NMR
data were in accordance with those reported in the literature.15
(+)-18 [α]D = +116.9 (CHCl3, C 0.78), lit. +136;15 (−)-19
[α]D = −50.9 (CHCl3, C 1.06), lit. −58.15
Conclusions
In conclusion we have demonstrated that a novel oxabicyclic
system can be efficiently prepared and employed in a stereo-
selective Ugi reaction to prepare collection of compounds with
very high value. Hypothesis regarding the mechanism taking
place during the reaction have been made and validated through
the determination of the relative and absolute configuration of
the Ugi adducts. Use of the correct choice of solvents can sensi-
bly increase stereoselection. ILs, analogously to polar solvents,
can stabilize the zwitterionic species through specific interactions
of cation and anion with opposite charged moieties of intermedi-
ate 14. Although no IL among the presently tested was able to
give a complete diastereoselection the variability of the data
suggests that it should be possible to design and synthesise a
more efficient IL.
Methyl 3-endo-(benzyl(2-(cyclohexylamino)-1-(4-methoxyphe-
nyl)-2-oxoethyl)amino)-7-oxabicyclo[2.2.1] hept-5-ene-2-exo-car-
boxylate 11k. Pale yellow oil, inseparable mixture of
1
diastereoisomers. Rf = 0.22 (PE–EtOAc 7 : 3). H NMR: major
diastereoisomer δ 1.10–1. 45 (m, 5H), 1.50–1.90 (m, 5H),
2.40–2.45 (m, 1H), 3.49 (d, J = 14.7 Hz, 1H), 3.61 (d, J = 5.1
Hz, 1H), 3.76–3.86 (m, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 4.39 (s,
1H), 4.99 (d, J = 1.8 Hz, 1H), 6.09 (d, J = 5.7 Hz, 1H), 6.40
(dd, J = 5.7, 1.8 Hz, 1H), 6.90 (d, broad, J = 8.7 Hz, 2H),
7.20–7.34 (m, 8H). 13C NMR: major diastereoisomer δ 25.3
(CH2), 25.7 (CH2), 32.8 (CH2), 33.5(CH2), 47.1 (CH), 48.4
(CH), 52.6 (CH3), 53.4 (CH2), 55.4 (CH3), 64.2 (CH), 67.3
(CH), 79.9 (CH), 81.0 (CH), 114.3 (CHAr), 127.6 (CHAr),
128.6 (CHAr), 128.7 (CHAr), 129.6 (CAr), 131.1 (CHAr),
135.1 (CH), 135.3 (CH), 139.4 (CAr), 159.5 (CAr), 170.0 (C),
174.4 (C). HRMS calculated for C30H36N2O5 504.2624, found
504.2622.
Studies are now carried out in our laboratories to increase the
selectivity of the enzymatic hydrolysis and to have access to
enantiomerically pure bicyclic aminoacids to be used as a novel
class of pluripotent substrates to be elaborated according to the
synthetic strategies previously employed for compounds 2.
Methyl 3-endo-(benzyl(2-(cyclohexylamino)-1-(4-nitrophenyl)-
2-oxoethyl)amino)-7-oxabicyclo[2.2.1] hept-5-ene-2-exo-carboxy-
late 11l. Pale yellow oil, inseparable mixture of diastereoi-
somers. Rf = 0.14 (PE–EtOAc 75 : 25). 1H NMR: major
diastereoisomer δ 1.10–1. 45 (m, 5H), 1.60–2.00 (m, 5H), 2.44
(d, J = 4.5 Hz, 1H), 3.60 (d, J = 14.7 Hz, 1H), 3.62–3.64 (m,
1H), 3.70–3.90 (m, 3H), 3.79 (s, 3H), 4.50 (s, 1H), 5.02–5.04
(m, 1H), 6.09 (dd, J = 5.7, 1.5 Hz, 1H), 6.47 (dd, J = 5.7, 1.8
Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.15–7.35 (m, 5H), 7.53 (d,
broad, J = 8.7, 2H), 8.22 (d, broad, J = 8.7, 2H). 13C NMR:
major diastereoisomer δ 25.2 (CH2), 25.7 (CH2), 32.8 (CH2),
33.4 (CH2), 47.7 (CH), 48.7 (CH), 52.8 (CH3), 53.9 (CH2), 64.6
(CH), 67.2 (CH), 79.8 (CH), 81.3 (CH), 123.8 (CHAr), 128.0
(CHAr), 128.6 (CHAr), 128.9 (CHAr), 130.9 (CHAr), 134.9
(CH), 135.9 (CH), 138.6 (CAr), 145.1 (CAr), 147.6 (CAr),
168.5 (C), 174.1 (C). HRMS calculated for C29H33N3O6
519.2369, found 519.2373.
Acknowledgements
The authors thank Fondazione San Paolo, Università di Genova
(progetto di Ateneo 2010 per giovani ricercatori) and Merck
Serono for financial support and Dr. Daniele Duce for helpful
discussion on the use of Gaussian.
Notes and references
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1925.
HLPA (880 mg) was added to a vigorously stirred suspension of
ester rac-19 (1.7 mmol, 500 mg) in TRIS buffer (43 mL) and
the reaction mixture stirred for 23 h at room temperature. To the
mixture were then added ethyl acetate (10 mL) and HCl 0.5 M
until pH was 3/4 and the suspension was saturated with solid
NaCl, then filtered. The solid filtrate was washed in sequence
with a mixture of ethyl acetate–methanol 9 : 1, brine and ethyl
acetate–methanol 9 : 1 again. The phases were separated and the
aqueous one was extracted with ethyl acetate. The combined
organic phases were dried with Na2SO4, filtered and
14 K. Jayakanthan, K. P. Madhusudanan and Y. D. Vankar, Tetrahedron,
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3828 | Org. Biomol. Chem., 2012, 10, 3819–3829
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