RuO4-catalyzed oxidation reactions of isoxazolino-2- azanorbornane derivatives: A short-cut synthesis of tricyclic lactams and peptidomimetic γ-amino acids

Article abstract of DOI:10.1016/j.tet.2011.01.014

A rapid access to peptidomimetic conformationally constrained γ-amino acids has been developed through the efficient RuO₄-mediated oxidation of regioisomeric isoxazolino-2-azanorbornane derivatives. The key intermediates are tricyclic lactams,

Full text of DOI:10.1016/j.tet.2011.01.014

Tetrahedron 67 (2011) 1907e1914
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RuO4-catalyzed oxidation reactions of isoxazolino-2-azanorbornane derivatives:
a short-cut synthesis of tricyclic lactams and peptidomimetic g-amino acids
,
Misal Giuseppe Memeo a, Bruna Bovio b, Paolo Quadrelli a
*
a
ꢀ
Dipartimento di Chimica Organica, Universita degli Studi di Pavia, Viale Taramelli 10, 27100 Pavia, Italy
Dipartimento di Chimica Generale, Universita degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid access to peptidomimetic conformationallyconstrained g-amino acids has been developed through
the efficient RuO4-mediated oxidation of regioisomeric isoxazolino-2-azanorbornane derivatives. The key
intermediates are tricyclic lactams, which are quantitatively hydrolyzed into the desired amino acids. The
Received 19 October 2010
Received in revised form 9 December 2010
Accepted 6 January 2011
conformational analysis, conducted by means of DFT calculations, supports the use of these
as -turn inducers in peptide synthesis.
g-amino acids
Available online 18 January 2011
b
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ruthenium tetraoxide
Amino acid
Lactam
1,3-Dipolar cycloadditions
Azanorbornene
1. Introduction
best residue to generate a turn-inducer, also easy to prepare because
of the stereoselective DielseAlder (DA) approach.7
Agreatdealofattentionisconstantlyaddressedtomethods forthe
modulation or disruption of proteineprotein interactions in order to
increase the knowledge of cellular processes. These current interests
involve both the drug discovery industry and chemical biology and
generate an intensive search for peptidomimetics.1 Small organic
molecules are privileged structures2 of choice, and in particular un-
natural amino acids,3 to mimic the secondary structure of a specific
protein. These small-sized molecules are extremely useful as tradi-
tional drug substances, while medium- and large-sized molecules
(e.g., antibodies) utilize interactions involving a-helical regions of the
On the other hand, g-amino acids are known as biologically active
compounds in the central nervous system (CNS) of mammals and the
interacting partners to disrupt proteineprotein interaction.4
The incorporation of unnatural conformationally constrained
amino acids into peptides is often used to induce precise secondary
structure in adjacent regions of the peptide, the amide backbone is
often maintained and then unnatural amino acids are included in the
~
seminal ponderous review by Ordonez and Cativiela constitutes the
obligatory reference and canon for their stereoselective synthesis.8
Amongst the huge number of compounds reported, those including
either cyclopentane or cyclopentene spacers between the amino and
the carboxylic groups of type 3 are easily referred as the products of
the hydrolysis of the 2-azabicyclo[2.2.1]hept-5-en-3-one 4, a cyclic
lactam obtained from the a DA cycloaddition reaction of cyclo-
pentadiene and tosyl or mesyl cyanide.9 Lactam 4 has found wide
applications in carbocyclic nucleoside synthesis10 because of the easy
access tothe required aminols. However, tosyl or mesyl cyanides used
to prepare it require a potentially hazardous starting material (cy-
anogens chloride).9 Although available from various chemical sup-
pliers, the cost of both racemic and enantiopure forms is too high for
large scale preparations.11
sequence.5 Amongst the forces that induce protein folding,
b-turns
comprise about 25% of all residues in proteins and are determinant in
the biological activity. Various types of amino acids have been pro-
posed by different research groups as turn-inducers. Cage
acids of type 1 incorporate a bulky hydrophobic disubstituted cage6
while -amino acids of type 2 find in the norbornene skeleton the
a-amino
b
* Corresponding author. Tel.: þ39 0382 987 315; fax: þ39 0382 987 323.; e-mail
address: paolo.quadrelli@unipv.it (P. Quadrelli).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.014

1908
M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
Recently, we have proposed a novel approach to useful aminols for
reaction according to the well-known procedure.12a The 1,3-dipolar
cycloaddition of BNO with 5 was performed by generating the
1,3-dipole with the in situ procedure,18 affording the two regio-
isomeric cycloadducts 6a and 6b in 49% and 43% yields, respectively
(Scheme 2).13
the synthesis of carbocyclic nucleosides starting from a convenient
source, the 2-azanorborn-5-ene 5 (Scheme 1). Structurally similar to
lactam 4, Grieco’s 2-azanorborn-5-ene 5 is derived from the cyclo-
addition of cyclopentadiene with iminium salts generated in situ
under Mannich-like conditions, in a mild and convenient aqueous
aza-DielseAlder (ADA) reaction.12 Despite their easy availability, no
attempts have been made for their use in nucleosidic syntheses or in
order to prepare conveniently the lactam derivative. To this purpose
the aza-methylene bridge has to be modified, precisely the carbon C3
must be oxidized by appropriate unmasking procedures.13 The 2-
azanorbornene of type 5 (Scheme 1, R¼CH2ePh) displays a moderate
dipolarophilic activity towards benzonitrile oxide (BNO) and the 1,3-
dipolar cycloaddition reaction affords the regioisomeric cycloadducts
of type 6. Compared with norbornene, N-benzyl-2-azanorbornene
still remains a highly reactive dipolarophile but less than the classical
BNOtrapping agent, thatis, twicemorereactiveinapolarsolvents and
three times in polar or polarizable solvents.13
Ph
O
N
N
O
Ph
BNO
+
N
N
5
6a
(49%)
6b
(43%)
N
CH2Ph
CH2Ph
CH2Ph
Scheme 2.
The regioisomeric cycloadducts 6a and 6b were oxidized by
using the catalytic system RuO2/NaIO4 with the H2O/AcOEt biphasic
conditions (Scheme 3).19 The protocol needs only a catalytic
amount of the expensive RuO2$H2O (20 mol %) in the presence of
2.5 equiv (with respect to the substrate to be oxidized) of sodium
periodate as oxidant in order to regenerate the oxidizing species
RuO4 at the highest oxidation state after the end of the catalytic
cycle.20 Typically, RuO2$H2O is added to a solution of NaIO4 in water
in inert atmosphere and left under stirring for 30 min. The for-
mation of the RuO4 species at the highest oxidation state becomes
clear because of the bright yellow colour solution.
Scheme 1.
We then transformed the cycloadducts 6 into more convenient
derivatives, through the oxidation to the corresponding N-oxides
and their conversion into N-acetyl derivatives via the mild Polo-
novski rearrangement. Insertion of an acetyl as a protecting group
(PG) on the 1,3-dipolar cycloadducts allowed for the oxidation at
the carbon atom C3 by means of NBS/AIBN bromination reaction,
which afforded a complex mixture of products whose elaboration
allowed for the isolation of the protected aldehyde 8 through ring
opening. Reduction of the aldehyde group and deprotection affor-
ded the target aminols 9. The overall protocol required from the
beginning eight steps to prepare the aminols 9, which were further
converted into the desired adenine nucleosides.14
In the search for a fast and convenient oxidation protocol we
took advantage of the oxidative ability of RuO4, a strong oxidizing
agent. Since its introduction into organic chemistry more than fifty
years ago,15 RuO4-catalyzed reactions in a biphasic system were
often considered to be sluggish or unselective.16 Two recent papers
by Petride and co-workers17 dealing with the RuO4-mediated oxi-
dation of N-benzylated tertiary amines (cyclic and acyclic)
prompted us to test the RuO4 on our tricyclic isoxazolino-2-aza-
norbornane derivatives of type 6 probing the regioselectivity of the
oxidation process with the aim to get straightly the carbonyl
functionality in the position C3 of the azanorbornane moiety to
Scheme 3.
At this point, the substrates dissolved in ethyl acetate are added
in one portion. The reaction mixture instantly turns an opaque-
black colour. The cycloadducts 6a,b disappear almost completely in
the reaction time (TLC) and the formation of three new products is
observed. N-benzoyl derivatives 12a,b are the major products (35%
and 33%, respectively) obtained upon the oxidation of the more
reactive benzylic methylene group. Oxidation of the C3 of the
azanorbornene moiety afforded the N-benzyl-lactams 13a,b in 17%
and 15% yields, respectively. Finally, lactams 10a,b were also found
and isolated in 13% and 12% yields, respectively. The isolation of the
oxidized products displayed some difficulties, which is reflected in
the yields of the pure compounds. The mixtures were in fact diluted
with ethyl acetate before a first filtration through a Celite pad. The
organic layer was washed with a saturated NaHSO3 solution en-
suring precipitation of Ru-black. This required a second filtration
through a Celite pad and a final washing with brine of the organic
phase. Presumably, this long and tedious work-up procedure does
not permit the complete recovery of the polar oxidized products,
which could in principle also act as ligands in ruthenium com-
plexes. A simplified work-up was then applied to the oxidation
reactions by diluting the reaction mixture with ethyl acetate and
washing immediately with a saturated NaHSO3 solution. Ru-black
and other impurities were filtered off through a Celite pad and the
organic phase dried and submitted to chromatographic separation
to isolate the products.
prepare the lactams 10 and from these latters the g-amino acids 11
under hydrolytic conditions.
2. Results
2.1. The oxidation of the regioisomeric N-benzyl isoxazolino-
2-azanorbornane cycloadducts
N-Benzyl-2-azanorborn-5-ene 5 was prepared by addition of
freshly distilled cyclopentadiene to an aqueous solution of ben-
zylamine hydrochloride and 37% aqueous formaldehyde in an ADA

M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
1909
This resulted in an increase of the reaction yields of about 10%
with respect to the yields of the products reported in Scheme 3. The
structures of all the products rely upon their analytical and spec-
troscopic data. Lactams 10a,b derive from the RuO4-mediated oxi-
dation on the C3 of the azanorbornane moiety and de-benzylation
reaction. The presence of the carbonyl groups is testified in the IR
spectra by the stretching bands in the expected regions and in the
and syn refer to the relative position of the phenyl groups. We have
identified the major rotamer as 12a(anti), in the ratio 1.7:1 with the
minor 12a(syn), on the base of sizeable anisotropic effects of the
amide group,21 which cause deshielding of the hydrogen atoms
proximal to the carbonylic oxygen atom and shielding of the hy-
drogen atoms proximal to the aromatic ring. Thus, the two
rotamers exhibit similar energies but the presence of the aromatic
rings on the same side or the tricyclic structure shifts the equilib-
rium towards the rotamer 12a(anti). The assignments were estab-
lished with the aid of 13C NMR and corroborated by the appropriate
13Ce1H COSY (HSQC) experiment, which show the C1eN signal at
13C NMR spectra by the signals at
d 177.2 and 178.5, respectively, for
the two regioisomers. The IR spectra also showed the NH bands
around 3250 cmꢀ1. The 1H NMR spectra clearly showed the pres-
ence of the NH groups giving broad singlets at
10a and 10b, respectively, while the presence of the isoxazoline
4.2 and 5.3
d 6.76 and 5.88, for
d
60.5 in the major rotamer 12a(anti) while in the minor rotamer
protons H4 and H5 as doublets (J¼8 Hz) between
d
12a(syn) the same signal is shielded and found at 57.5. A similar
d
indicated that the oxidation had no effects on the heterocyclic
rings. The structural assignments were confirmed through X-ray
analyses of single crystals. Fig. 1 reports the ORTEP views of lactam
10a and 10b.
behaviour is observed in the case of the AB system for the methy-
lene in the C3; the signals are splitted apart one each other when
the carbonyl group is directed towards the methylene in the minor
rotamer 12a(syn). A NOESY experiment showed a selective cross-
peak correlating the ortho-aromatic protons of the benzoylic ring
with hydrogen atom exo of the C3 methylene group belonging to
the major rotamer 12a(anti).
When the oxidationof theazanorbornenemoietyoccursontheC3
carbon atom N-benzyl-lactams 13a,b are obtained. The exocyclic
benzylic methylene group survives oxidation and gives, in the 1H
NMR spectra, the typical AB system array between
newly formed carbonyl groups give in the 13C NMR spectra signals at
173.5 and 175.2 for 13a and 13b, respectively, while the IR spectra
show thestretchingbandsoftheC]Ogroupsintheexpectedregions.
The transformation of the lactams 10a,b into the desired
amino acids 11a,b was secured by the easy and quantitative hy-
drolysis in the presence of 3 equiv of methanesulfonic acid (MSA)
and 4 equiv of water in THF at reflux for 24 h.22 Insoluble meth-
anesulfonic acid salts of the regioisomeric amino acids 11a,b sep-
arate from the organic solution and the products are easily isolated
in quantitative yields by simple filtration (Scheme 4).
d 4.2 and 4.6. The
Fig. 1. ORTEP plots of lactams 10a and 10b with atom labelling (ellipsoid at 20%
probability). Hydrogen atoms are omitted for clarity, except for the isoxazoline ring
protons, bridgehead protons and NH.
d
g-
N-benzoylated compounds 12a,b derive from the starting
cycloadducts through the oxidation of the highly reactive methy-
lene of the exocyclic benzylic moiety. This is not an unexpected
result since Petride and co-workers had already demonstrated the
facile oxidation of the benzyl group in the RuO4-mediated oxida-
tion of N-benzylated tertiary amines.17 The absence of the benzylic
methylene is clearly shown in the 1H NMR spectra and the presence
of the benzoyl carbonyl group is indicated by stretching IR bands in
the expected regions and by the signals in the 13C NMR spectra at
O
N
O
N
MSA (3 eq.)
H2O (4 eq.)
THF, Δ, 24h
between
presence of the signals referred to the methylene in C3 between
3.1 and 3.7 and the H4 and H5 protons of the isoxazoline ring in
d 168.0 and 170.0. The structures are confirmed by the
Ph
O
Ph
COOH
-
NH3+ CH3SO3
d
N
10a
11a
the typical range.
(100%)
H
While the NMR spectra of the regioisomer 12b exhibits resolved
signals in all the regions, the regioisomer 12a, where the two
phenyl groups are on the same side with respect to the norbornane
moiety, showed only a couple of distinguishable signals both in 1H
and 13C spectra. For a better understanding of the nature of these
features, the NMR spectra were recorded in DMSO at room tem-
perature and 80 ꢁC, allowing for the detection of the presence at
room temperature of two rotamers in slow equilibrium. Upon
heating, the two sets of signals in the proton spectra coalesce. The
two rotamers are indicated as 12a(anti) and 12a(syn), where anti
Ph
Ph
N
N
MSA (3 eq.)
H2O (4 eq.)
THF,Δ, 24h
O
O
O
COOH
NH3+ CH3SO3
-
N
10b
11b
(100%)
H
Scheme 4.

1910
M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
The structures of the
g
-amino acids 11a,b rely upon their ana-
2.3. Peptidomimetic ability
lytical and spectroscopic data. In the IR spectra two intense and
broad bands in the region 3210e2500 cmꢀ1 are found indicative of
the presence of the carboxylic groups, while the carbonyl groups
gave two bands at 1729 and 1716 cmꢀ1, respectively. In the 1H NMR
The facile hydrolysis of these lactams 10 afforded the desired
amino acids 11 whose structure are well designed to induce
in peptides. To analyze the type of turns exhibited by a peptido-
mimetic derivative, a brief summary of the -turn conventions and
definitions is required.1 The definition of
-turn refers to a tetra-
b-turn
spectra the carboxylic acid protons are found at
singlets for 11a and 11b, respectively, while the NHþ3 protons are
found at 8.11and 8.23. The presence of the heterocyclic rings fused
to the cyclopentane moieties are clearly indicated by the isoxazo-
line protons at
5.46 (H5, d, J¼9 Hz) and 4.44 (H4, d, J¼9 Hz) for
compound 11a and at
d
13.10 and 13.06 as
b
b
d
peptide in a turned conformation where the amino group of the
fourth amino acid forms a hydrogen-bond with the C]O group of
d
the first amino acid as represented in the Fig. 2. A critical distance is
ꢁ
d
5.20 (H5, dd, J¼11, 5 Hz) and 4.67 (H4, dd,
defined between the C
a
carbon atoms, which must be <7 A. A
J¼11, 6 Hz) for compound 11b.
second requirement is the distance between the carbonyl oxygen of
The N-benzoyl cycloadducts 12a,b cannot be further oxidized at
the carbon C3 through the RuO2 protocol presumably because of
the complexation of ruthenium at the carbonyl group. Control ex-
periments performed with cycloadducts 12a,b in the presence of
different amounts of RuO2/NaIO4 allowed for the recover of un-
altered starting materials. Every attempt to submit the N-benzyl
lactams 13a,b to hydrogenolysis failed because of the amide group,
which does not allow for the detachment of the benzyl group from
the amidic nitrogen.
the first amino acid and the amide hydrogen of the fourth one,
ꢁ
which must be <4 A. In general the use of cage amino acids allows
for the induction of a b-turn by the complete replacement of the
three amino acids required normally.
R4
O
α
N
R3
2.2. More efficient and expedite route to lactams
H
The direct oxidation of the 1,3-dipolar cycloadducts of BNO to
N-benzyl 2-azanorbornene 6a,b afforded a pool of oxidized com-
pounds, only 20% of which is useful for the preparation of the
target amino acids. The remaining 80% is represented by the
products derived from the oxidation of either the C3 or the ben-
zylic methylene. This prolific composition of the reaction mixtures
is undoubtably due to the presence of the benzyl group in the
starting cycloadducts. In order to remove of the benzyl substituent,
we took advantage of the already applied protocol of replacement
through the oxidation of the regioisomeric cycloadducts 6a,b to
the corresponding N-oxides, followed by the Polonovski rear-
rangement to prepare the N-acetyl derivatives 14a,b in quantita-
tive yields.13 A facile hydrolysis with boiling HCl 6 N for 12 h
afforded quantitatively the deprotected cycloadducts 15a,b
(Scheme 5) whose structures were easily attributed through their
spectroscopic data.
NH
<4Å
dcrit = <7Å
O
O
α
N
H
R2
R1
Fig. 2. Criteria for the identification of b-turns.
The conformational analysis of the 2,3-oxaza[3.3.0]bicyclooct-3-
ene derivatives discloses their potential use as peptidomimetic
compounds. When fused to an isoxazoline ring or similar rings23
the cyclopentane moiety usually adopts an envelope conforma-
tion with the flap directed towards the isoxazoline ring thus giving
a boat-like appearance to the structure. When the flap is directed
away from the isoxazoline ring, the resulting chair-like conforma-
24
*
tion is usually higher in energy. Fig. 3 shows the B3LYP/6-31G
optimized structure of the boat-like and chair-like conformations
of the parent 2,3-oxaza[3.3.0]bicyclooct-3-ene as a model where
the phenyl group has been replaced with a methyl for sake of
simplicity in calculations.
The boat-like conformation allows for the relief of non-bonded
interactions between the heterocyclic ring and the substituents on
the adjacent cyclopentane carbons and cause the dihedral angles
between the isoxazoline protons and the adjacent trans cyclo-
pentane protons to be near 90ꢁ. The chair-like conformation is
higher in energy by 1.6 kcal/mol and the dihedral angles range
about 140ꢁ. When introducing formyl and amino substituents in
the trans cyclopentane positions to mimic the C]O/HeN in-
teractions, the differences between the boat and chair conforma-
tions remain essentially the same as in the parent systems, i.e.,
supporting a preferential faced location of the two groups. When
the formyl and amino groups are replaced by amide groups as in
peptide models (E) and (F) the gap between boat and chair con-
formation increases favouring the boat ones while the hydrogen-
bonding distances are maintained in the required range.
Scheme 5.
In the IR spectra the NH bands are found at 3318 and 3320 cmꢀ1
and the NH proton is clearly visible in the 1H NMR spectra at
d 1.91
and 1.59 for 15a and 15b, respectively. In the aromatic region of the
proton spectra, a single phenyl group belonging to the isoxazoline
ring is shown. By applying the oxidation protocol with RuO2/NaIO4,
the cycloadducts 15a,b were converted in good yields into the de-
sired lactams 10a,b. The same protocol can be successfully applied
to the N-benzoyl derivatives 12a,b, which can be quantitatively
transformed into the amines 15a,b allowing for the recover of the
major components of the oxidation reaction mixtures directly
obtained from the oxidation of the cycloadducts 6a,b. Subsequent
hydrolysis of the lactam prepared through the new route afforded
the amino acids 10a,b in high yields (>80%).
The boat conformations are then preferred to be involved in
a peptide skeleton. The distances involved in the intramolecular

M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
1911
O
H
O
Ru
OH
Ru
H
C
O
O
+
O
C
Ru
X
HO
O
X
O
O
O
OH
H
X
A
B
C
Scheme 6.
state (TS) yielding the metal alcoholate with a reduced Ru(VI) (B);
(2) fragmentation of the metal alcoholate affording the carbonyl
compound while Ru(VI) is reduced at Ru(IV) (C), which must be re-
oxidized to Ru(VIII) by the sodium periodate to re-start the catalytic
cycle.16,19,28
The regioselectivity of the oxidation of heterocyclic compounds
and in particular of N-benzylated tertiary amines (morpholine, pi-
peridine, pyrrolidine) has already been discussed by Petride and co-
workers;17 they showed that in these systems where two different
methylenes (exocyclic and endocyclic) are activated by the same
nitrogen atom, the oxidation reaction proceeds with poor regio-
selection and both the methylene are involved affording two dif-
ferent amides.29 These findings correspond well to our results with
the tricyclic compounds at hand. Cycloadducts 6 undergo oxidation
by RuO4 on both the endocyclic (path a) and exocyclic (path b)
methylenes affording the amides 12 and 13 in the ratio 2:1 with
a preference for the benzylic methylene (Scheme 7). In the case of
path b, the Ru(VI) complex of type 16 can undergo to oxidation of
the benzylic methylene to afford the benzoyl derivative 12 (path b0)
or alternatively undergo the elimination (path bi00) of stable benz-
aldehyde through the iminium ion of type 17 affording the 2-aza-
norbornane derivative 15, which undergoes a further oxidation
occurring exclusively on the endocyclic C3 carbon atom to give the
final lactam 10.
Fig. 3. Boat- and chair-like conformations of 2,3-oxaza[3.3.0]bicyclooct-3-ene (A) and
(B). Relative energies are given near the conformational labels. Curved arrows specify
the dihedral angles in degrees between the bridgehead protons and the protons of the
adjacent methylenes. Dotted lines indicate hydrogen-bonds along with C]O/N dis-
tances in A. syn ( ) and anti ( ) labels refer to the relative positions of the substituent on
the nitrile oxide moiety and the NH2 group. Models of boat- and chair-like confor-
mations of 2,3-oxaza[3.3.0]bicyclooct-3-ene derivatives (C) and (D) with a formyl and
an amino substituents in the trans cyclopentane positions are also reported along with
peptide models (E) and (F).
0
00
ꢁ
hydrogen-bonding are given in the figure and correspond well to
cases of strong hydrogen-bonding in the case of boat conformers.25
If we consider the more stable boat conformations the distance
between the amino nitrogen atom and the carbonyl group ranges
ꢁ
around 3.3 A while the hydrogen-bond between the amino hy-
ꢁ
ꢁ
drogen and the carbonyl oxygen is about 2.5 A, i.e., less than the 4 A
required to induce a -turn.
b
3. Discussion and conclusion
The RuO4-catalyzed oxidation protocol has been applied to the
isoxazolino-2-azanorbornane derivatives in the search of an expe-
dite and selective oxidation towards lactam derivatives as pre-
cursors of peptidomimetic g-amino acids. The results obtained with
Scheme 7.
the RuO4-mediated oxidation of tricyclic heterocyclic systems con-
stitute a newprobe of the oxidation mechanism and regioselectivity.
Ruthenium tetroxide was firstly employed by Djerassi in 1953 in
diol synthesis and conversion of sulfides into sulfones or sulfox-
ides.15 Due to its high reactivity, it was mainly used in diol synthesis
from alkenes or oxidative fragmentation of aromatic compounds.
RuO4 was considered for a long time too reactive and unselective.
The reactions required a biphasic system of organic solvent and
water to be performed, determining a few problems in isolation of
the polar oxidized products. Four decades later, Piccialli and Shing
reported an efficient and selective dihydroxylation of olefins, the
first successful application of this metal oxide.26 RuO4 is a tetrahe-
dral 16-electron d0 species, isoelectronic to OsO4 but a much more
powerful oxidizing agent.16 Oxidation of CeH bonds represent the
most intriguing property of the ruthenium tetroxide as oxidant in
1,2-dehydrogenation of alcohols and amines as well as in 1,1-de-
hydrogenation of saturated hydrocarbons, a quite uncommon
process but extremely useful from the synthetic point of view,
allowing for the introduction of oxidated functionalities on acti-
vated methylenes.19 The mechanism proposed by Bakke27 and
widely recognised in its validity is shown in Scheme 6. The oxida-
tion process takes place in two separate steps: (1) oxidative addi-
tion of RuO4 to the CeH bond (A) through a concerted transition
The strong directing effect produced by the presence of a ben-
zylic group in the oxidation can be only avoided by eliminating the
group itself.
The transformation from the 1,3-dipolar cycloadducts 6 to the
N-acetyl derivatives 14 is the method to prepare the 2-azanorbo-
nane derivative 15 and allows for an efficient high yielding route to
the lactam 10. In principle, the simple 2-azanorborn-5-ene are
available from the ADA cycloaddition between cyclopentadiene,
ammonium chloride and formaldehyde, but the low reaction yields
and the high instability of the product towards cycloreversion12
limit somewhat this approach.30
In conclusion, we have developed a short synthetic procedure for
the synthesis of peptidomimetic g-amino acids conformationally
constrained because of the fused heterocyclic ring to the cyclo-
pentane moiety and able to act as turn-inducers. The key in-
termediates are the lactams 10a,b whose preparation can be either
performed starting from the regioisomeric cycloadducts to the N-
benzyl 2-azanorbornene 6a,b or the corresponding derivatives
14a,b taking advantage of the efficient oxidation by RuO4 whose
selectivityon activemethyleneshas been discussed. The preferences

1912
M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
of the 2,3-oxaza[3.3.0]bicyclooct-3-ene derivatives for a boat con-
formation support the possible use of the amino acids 11a,b as
C
13H12N2O2 (MW¼228.25): C, 68.41; H, 5.30; N, 12.27. Found: C,
b
-
68.38; H, 5.29; N, 12.30.
turninducers inpeptidesynthesis. Inclusionof thistype ofunnatural
amino acids in a peptide sequence will also benefit of the additional
features, which characterize the synthesized compounds, where the
presence of an isoxazoline ring allows for the establishment of hy-
drogen-bonds from polar residues of peptide side chains as well as
the phenyl substituent is able to be inserted in a hydrophobic pocket
generated by other amino acid residues. Samples of compounds
10a,b will be soon submitted to a short peptide synthesis to confirm
these expectations.
Compund 10b: (0.55 g, 12%), white powder, mp 176e179 ꢁC from
iPr2O. IR: nmax 3203, 1710 cmꢀ1. Rf (cyclohexane/ethyl acetate 1:1)
0.20. 1H NMR:
d (CDCl3) 1.81 (dd, 1H, J 11, 1 Hz, HeCH); 1.85 (dd, 1H,
J 11, 1 Hz, HCeH); 2.95 (s, 1H, CHeCO); 4.16 (s, 1H, CHeN); 4.20 (d,
1H, J 8 Hz, H4isox.); 5.11 (d, 1H, J 8 Hz, H5isox.); 5.88 (b, 1H, NH); 7.44
(m, 3H, arom.); 7.75 (m, 2H, arom.). 13C NMR:
d (CDCl3) 35.2, 47.2,
53.7, 59.3, 87.5,126.8,128.9,129.9,130.5,155.3,178.5. Anal. Calcd for
C13H12N2O2 (MW¼228.25): C, 68.41; H, 5.30; N, 12.27. Found: C,
68.39; H, 5.31; N, 12.29.
Compound 12a: (2.23 g, 35%), colourless crystals, mp 205e208 ꢁC
from Benzene/Ligroin. IR: nmax 1633 cmꢀ1. Rf (cyclohexane/ethyl
4. Experimental section
4.1. General
acetate 1:1) 0.37. Major rotamer 12a(anti): 1H NMR:
d (DMSO) 1.43
and 1.65 (d, 1Hþ1H, J 11 Hz, CH2); 2.95 (s, 1H, CHeCH2); 3.14 (d, 1H, J
11 Hz, HendoeCH); 3.42 (dd, 1H, J 11, 4 Hz, HCeHexo); 4.03 (s, 1H,
CHeN); 4.25 (d, 1H, J 8 Hz, H4isox.); 4.99 (d, 1H, J 8 Hz, H5isox.); 7.59
All melting points are uncorrected. Elemental analyses were
done on a C. Erba 1106 elemental analyzer available in our De-
partment. IR spectra (Nujol mulls) were recorded on an FT-IR Per-
kineElmer RX-1. 1H and 13C NMR spectra were recorded on a Bruker
AVANCE 300 in the specified deuterated solvents. Chemical shifts
(m, 8H, arom.); 7.80 (m, 2H, arom.). 13C NMR:
d
(DMSO) 31.8, 43.1,
45.7, 58.1, 60.5, 85.4, 126.3, 126.7, 128.0, 128.6, 128.8, 129.9, 130.2,
136.9, 154.8, 168.6. Minor rotamer 12a(syn): 1H NMR:
(DMSO) 1.55
d
and 1.75 (d, 1Hþ1H, J 11 Hz, CH2); 2.87 (s, 1H, CHeCH2); 2.99 (d, 1H, J
10 Hz, HendoeCH); 3.63 (dd, 1H, J 10, 4 Hz, HCeHexo); 4.16 (d, 1H, J
8 Hz, H4isox.); 4.67 (s, 1H, CHeN); 4.90 (d, 1H, J 8 Hz, H5isox.); 7.59 (m,
are expressed in ppm (d) from internal tetramethylsilane. Column
chromatography and TLC: silica gel 60 (0.063e0.200 mm) (Merck);
eluant cyclohexane/ethyl acetate from 9:1 to 5:5. MPLC: Biotage
FMP apparatus equipped with KP-SIL columns, eluant cyclohexane/
ethyl acetate from 9:1 to 7:3. The identification of samples from
different experiments was secured by mixed mps and superim-
posable IR spectra.
8H, arom.); 7.80 (m, 2H, arom.). 13C NMR:
d (DMSO) 30.1, 44.2, 49.5,
56.6, 57.5, 85.0, 126.4, 127.6, 128.3, 128.5, 129.1, 130.3, 130.6, 135.6,
155.1, 169.2. Anal. Calcd for C20H18N2O2 (MW¼318.37): C, 75.45; H,
5.70; N, 8.80. Found: C, 75.42; H, 5.69; N, 8.75.
Compound 12b: (2.10 g, 33%), colourless crystals, mp 156e157 ꢁC
from Benzene/Ligroin. IR: nmax 1711 cmꢀ1. Rf (cyclohexane/ethyl
4.2. Materials
acetate 1:1) 0.30. 1H NMR:
d (CDCl3) 1.77 (m, 2H, CH2); 2.86 (s, 1H,
CHeCH2); 3.40 (d, 1H, J 11 Hz, HeCH); 3.67 (dd, 1H, J 11, 3 Hz,
HCeH); 3.90 (d, 1H, J 8 Hz, H4isox.); 4.40 (s, 1H, CHeN); 4.99 (d, 1H, J
8 Hz, H5isox.); 7.48 (m, 6H, arom.); 7.55 (m, 2H, arom.); 7.77 (m, 2H,
Benzhydroximoyl chloride, prepared according to the reported
method,31 has been used to prepare BNO by treating with distilled
Et3N in a typical in situ cycloaddition reaction in the presence of
N-benzyl 2-azanorborn-5-ene 5. Cycloadducts 6a,b have been
isolated according to the previously published procedure.13 Ru-
thenium(IV) oxide hydrate (RuO2$H2O) and sodium periodate are
from SigmaeAldrich and were used without purification.
arom.). 13C NMR:
d (CDCl3) 30.8, 39.4, 50.3, 56.1, 62.7, 85.5, 126.8,
126.9, 128.1, 128.6, 130.1, 133.3, 135.7, 156.6, 169.8. Anal. Calcd for
C20H18N2O2 (MW¼318.37): C, 75.45; H, 5.70; N, 8.80. Found: C,
75.47; H, 5.71; N, 8.76.
Compound 13a: (1.10 g, 17%), white plates, mp 142e144 ꢁC from
AcOEt. IR: nmax 1703 cmꢀ1. Rf (cyclohexane/ethyl acetate 1:1) 0.40.
4.3. Oxidation reactions of cycloadducts 6a,b
1H NMR:
d (CDCl3) 1.82 (d, 1H, J 10 Hz, HeCH); 1.97 (dd, 1H, J 10,
1 Hz, HCeH); 3.33 (s, 1H, CHeCO); 3.75 (d, 1H, J 8 Hz, H4isox.); 3.95
(s, 1H, CHeN); 4.38 and 4.55 (AB syst., 2H, J 15 Hz, CH2ePh); 5.15 (d,
RuO2$H2O (0.51 g, 3.9 mmol) was added to a solution of 10.6 g
(49 mmol) NaIO4 in 15 mL of water under inert atmosphere (N2) and
left stirring for 30 min. The formation of the RuO4 species at the
highest oxidation is indicated when the colour solution turns into
a bright yellow colour. At this point, 6 g (20 mmol) of cycloadducts
6a,b are dissolved in the minimum amount of ethyl acetate (75 mL)
and added to the ruthenium solution in two portions. The reaction
mixtures turn immediately an opaque-black colour and a further 4 g
(19 mmol) of sodium periodate are added to ensure the presence of
active RuO4. Monitoring of the reactions by TLC allows for the
identification of the disappearance of the starting material; typically
the reactions are completed afterone night. The mixtures are diluted
with ethyl acetate (150 mL) and treated with NaHSO3 saturated
solution (100 mL) for a couple of hours until metal ruthenium sep-
arates off. Filtration through a Celite pad provides a clear organic
phase, which is washed with water and dried over anhydrous
Na2SO4. After evaporation of the solvent, the crude mixtures are
submitted to chromatographic separation to isolate the products.
Compound 10a: (0.59 g, 13%), white powder, mp 166e169 ꢁC
from iPr2O. IR: nmax 3306, 1712 cmꢀ1. Rf (cyclohexane/ethyl acetate
1H, J 8 Hz, H5isox.); 7.42 (m, 10H, arom.). 13C NMR:
d (CDCl3) 26.8,
34.6, 45.7, 54.0, 58.4, 61.4, 85.1, 126.4, 127.9, 128.3, 128.7, 129.1,
130.3, 135.7, 154.9, 173.5. Anal. Calcd for C20H18N2O2 (MW¼318.37):
C, 75.45; H, 5.70; N, 8.80. Found: C, 75.43; H, 5.68; N, 8.77.
Compound 13b: (0.95 g, 15%), white plates, mp 162e165 ꢁC from
AcOEt. IR: nmax 1702 cmꢀ1. Rf (cyclohexane/ethyl acetate 1:1) 0.36. 1H
NMR: d (CDCl3) 1.74 (d,1H, J 11 Hz, HeCH); 1.97 (d,1H, J 10 Hz, HCeH);
3.10 (s, 1H, CHeCO); 3.98 (s, 1H, CHeN); 4.16 (d, 1H, J 8 Hz, H4isox.);
4.26 and 4.56 (AB syst., 2H, J 15 Hz, CH2ePh); 4.84 (d, 1H, J 8 Hz,
H5isox.); 7.46 (m, 8H, arom.); 7.77 (m, 2H, arom.). 13C NMR:
d (CDCl3)
34.3, 45.5, 48.3, 54.4, 63.0, 85.8,126.8,128.0,128.1,128.4,128.9,129.0,
133.5, 155.5, 175.2. Anal. Calcd for C20H18N2O2 (MW¼318.37): C,
75.45; H, 5.70; N, 8.80. Found: C, 75.46; H, 5.69; N, 8.79.
4.4. Hydrolysis of lactams 10a,b
In a round-bottom flask, 0.17 g (0.79 mmol) of lactams 10a,b
were dissolved in 25 mL of THF and 0.15 mL (2.36 mmol) of MSA are
added along with 0.06 mL (3.16 mmol) of water. The mixture was
heated at reflux for 2 days. The white solids of the amino acid 11a,b
quantitatively separate from the solution and are collected by fil-
tration in pure form as methanesulfonic salt.
1:1) 0.23. 1H NMR:
d
(CDCl3) 1.96 and 2.10 (d, 1Hþ1H, J 10.5 Hz,
CH2); 3.21 (s, 1H, CHeCO); 4.22 (d, 1H, J 8 Hz, H4isox.); 4.25 (s, 1H,
CHeN); 5.28 (d, 1H, J 8 Hz, H5isox.); 6.76 (b, 1H, NH); 7.45 (m, 3H,
arom.); 7.75 (m, 2H, arom.). 13C NMR:
d
(CDCl3) 35.5, 52.6, 57.7, 60.6,
Compound 11a: (0.27 g, 100%), white crystals, mp>200 ꢁC (dec)
from THF. IR: nmax 3050, 1729 cmꢀ1. Rf (ethyl acetate) 0.10. 1H NMR:
84.4, 126.2, 127.6, 128.8, 130.1, 154.6, 177.2. Anal. Calcd for

M.G. Memeo et al. / Tetrahedron 67 (2011) 1907e1914
1913
d
(DMSO) 2.15 (m, 2H, CH2); 2.30 (s, 3H, CH3SOꢀ3 ); 3.15 (m, 1H,
anhydrous Na2SO4. After evaporation of the solvent, the crude
products 10a,b are submitted to chromatographic purification.
Spectroscopic analyses confirmed that the compounds are identical
to authentic specimens previously prepared.
CHeCOOH); 3.77 (b, 1H, CHeN); 4.44 (d, 1H, J 9 Hz, H4isox.); 5.46
(dd, 1H, J 9, 3 Hz, H5isox.); 7.49 (m, 3H, arom.); 7.78 (m, 2H, arom.);
8.11 (s, 3H, NHþ3 ); 13.06 (b, 1H, COOH). 13C NMR:
d (DMSO) 32.3,
40.7, 52.1, 54.7, 57.7, 89.2,127.5,128.2,129.4,130.7,156.2,174.6. Anal.
Calcd for C14H18N2O6S (MW¼342.37): C, 49.11; H, 5.30; N, 8.18.
Found: C, 49.09; H, 5.29; N, 8.20.
Acknowledgements
Compound 11b: (0.27 g, 100%), white crystals, mp>210 ꢁC (dec)
Financial support by the University of Pavia (Fondo d’Ateneo per
la Ricerca, FAR), MIUR (PRIN 2008) and EUTICALS S.p.a.dV.le
Milano, 86/88d26900 Lodi, Italy is gratefully acknowledged. The
authors wish to thank the Fondazione Banca del Monte di Lom-
bardia for a research grant. Thanks are due to Dr. Massimo Boiocchi
(CGS) for X-ray data collection. The authors wish to thank warmly
Prof. P. Caramella for fruitful suggestions and helpful discussion.
from THF. IR: nmax 2950, 1719 cmꢀ1. Rf (ethyl acetate) 0.10. 1H NMR:
d
(DMSO) 1.98 (m, 1H, HeCH); 2.28 (m, 1H, HCeH); 2.31 (s, 3H,
CH3SOꢀ3 ); 3.01 (q, 1H, J 8 Hz, CHeCOOH); 3.70 (m, 1H, CHeN); 4.67
(dd,1H, J 11, 6 Hz, H4isox.); 5.20 (dd,1H, J 11, 5 Hz, H5isox.); 7.48 (m, 3H,
arom.); 7.70 (m, 2H, arom.); 8.23 (s, 3H, NHþ3 ); 13.10 (b, 1H, COOH).
13C NMR:
d (DMSO) 33.2, 40.1, 46.5, 54.4, 57.5, 88.2, 126.9, 127.9,
129.0,130.4,158.1,174.4. Anal. Calcd for C14H18N2O6S (MW¼342.37):
C, 49.11; H, 5.30; N, 8.18. Found: C, 49.12; H, 5.28; N, 8.20.
Supplementary data
4.5. Hydrolysis of N-acetyl derivatives 14a,b and N-benzoyl
derivatives 12a,b
Crystal structure analyses of lactams 10a and 10b, CCDCs
796635 (a¼9.813), 796636 (a¼9.303), respectively. Cartesian Co-
ordinates of calculated boat- and chair-like conformations. Sup-
plementary data associated with this article can be found in the
online version at doi:10.1016/j.tet.2011.01.014.
In a round-bottom flask, 2.68 g (10 mmol) of N-acetyl de-
rivatives 14a,b or N-benzoyl derivatives 12a,b were suspended in
HCl 6 N and the mixtures were heated at reflux for 24 h until dis-
appearance of the starting material. The resulting solutions are
neutralized with NaHCO3 and the products extracted with
dichloromethane (DCM, 2 ꢂ 100 mL). The organic phases are dried
over anhydrous Na2SO4 and the solvent removed under reduced
pressure to leave the crude 2-azanorbornane derivatives in quan-
titative yields.
References and notes
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Compound 15a: (2.14 g, 100%), white powder, mp 116e119 ꢁC
from iPr2O. IR: nmax 3318, 1559 cmꢀ1. Rf (Chloroform/Methanol 9:1)
0.20. 1H NMR:
d
(CDCl3) 1.46 and 1.74 (d, 1Hþ1H, J 11 Hz, CH2); 1.91
(s, 1H, NH); 2.57 (d, 1H, J 10 Hz, CH2eN); 2.84 (s, 1H, CHeCH2); 2.92
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from iPr2O. IR: nmax 3320, 1560 cmꢀ1. Rf (Chloroform/Methanol 9:1)
0.20. 1H NMR:
d
(CDCl3) 1.51 and 1.66 (d, 1Hþ1H, J 11 Hz, CH2); 1.59
(s, 1H, NH); 2.71 (s, 1H, CHeCH2); 2.72 (d, 1H, J 9 Hz, CH2eN); 2.96
(dd, 1H, J 9, 3 Hz, CH2eN); 3.70 (s, 1H, CHeN); 3.71 (d, 1H, J 8 Hz,
H4isox.); 4.71 (d, 1H, J 8 Hz, H5isox.); 7.43 (m, 3H, arom.); 7.74 (m, 2H,
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d (CDCl3) 31.8, 39.3, 48.7, 55.9, 59.4, 87.1, 126.7,
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~
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