Phosphorylation of 2-azabicyclo[2.2.1]hept-5-ene and 2-hydroxy-2- azabicyclo[2.2.1]hept-5-ene systems: Synthesis and mechanistic study

Article abstract of DOI:10.1039/c0nj00239a

The endo and exo isomers of (±)-methyl 2-hydroxy-2-azabicyclo[2.2.1] hept-5-ene-3-carboxylates and the in situ-prepared endo and exo isomers of (±)-methyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate were treated with diphenylphosphinic chloride (OPClPh₂) and chlorodiphenylphosphine (ClPPh₂) to afford the corresponding phosphorylated bicycles. The structure of all these compounds was unequivocally determined by NMR spectroscopy and mass spectrometry, and, based on the results obtained, a mechanistic scheme for the phosphorylation reaction of these adducts to afford the corresponding phosphorylbicycles is proposed.

Full text of DOI:10.1039/c0nj00239a

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PAPER
www.rsc.org/njc | New Journal of Chemistry
Phosphorylation of 2-azabicyclo[2.2.1]hept-5-ene and 2-hydroxy-2-
azabicyclo[2.2.1]hept-5-ene systems: synthesis and mechanistic studyw
a
a
Carlos A. D. Sousa,a M. Luı
Xerardo Garcı
´
´
´
´
sa C. Vale, Jose E. Rodrıguez-Borges* and
a-Merab
Received (in Montpellier, France) 31st March 2010, Accepted 17th May 2010
DOI: 10.1039/c0nj00239a
The endo and exo isomers of (Æ)-methyl 2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates
and the in situ-prepared endo and exo isomers of (Æ)-methyl 2-azabicyclo[2.2.1]hept-5-ene-3-
carboxylate were treated with diphenylphosphinic chloride (OPClPh2) and
chlorodiphenylphosphine (ClPPh2) to afford the corresponding phosphorylated bicycles.
The structure of all these compounds was unequivocally determined by NMR spectroscopy
and mass spectrometry, and, based on the results obtained, a mechanistic scheme for the
phosphorylation reaction of these adducts to afford the corresponding phosphorylbicycles
is proposed.
synthesis. Nucleoside monophosphate kinases are also
Introduction
required for the pharmacological activation of therapeutic
nucleoside and nucleotide analogues. On the other hand,
phosphorylated analogues may behave as mimetics of nucleo-
side monophosphates and be able to bypass the initial selective
enzymatic monophosphorylation step.8 Therefore, a full
understanding of non-natural phosphorylation processes
allowing for the construction of N–P bonds is a challenge of
major importance.
Azabicyclic compounds are important intermediates in the
preparation of a large variety of compounds of chemical,
biological and pharmaceutical interest.1 Within the diverse
transformations comprising cycloadditions, reactions of imine
derivatives and dienes leading to monocyclic and bicyclic
molecules have attracted much interest, especially those
employing cyclopentadiene (CPD) as a starting material.2
3-Functionalized 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates
and 2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates,
obtained by aza-Diels–Alder reactions between imines and
oximes of glyoxylates, respectively, and cyclopentadiene and
its derivatives are considered as synthetic intermediates in the
preparation of polyhydroxylated pyrrolidines (iminosugars),3
therefore being useful as precursors in the preparation
of nucleoside analogues.4 In particular, N-functionalized
azanucleoside and oxa-azanucleoside derivatives are com-
pounds that often present biological activity.5–8 Antiviral
nucleoside analogues inhibit replication of the viral genome,
whereas anticancer nucleoside analogues inhibit cellular DNA
replication and repair. As stated by Chiacchio et al.,6 the
action of most of the nucleoside analogues possessing antiviral
activities depends on phosphorylation by specific kinases in a
three step phosphorylation process, the first of which is
rate-limiting. These enzymes play an important role in the
synthesis of nucleotides that are required for a variety of
cellular metabolic processes, as well as for RNA and DNA
To the best of our knowledge, there are only a couple of
examples of N-functionalized azabicycles with phosphoryl
radicals, obtained from aza-Diels–Alder reactions of aryl
phosphorylimines.9 The non existence of a general method
for the preparation of non-aryl phosphorylimines suggests the
synthesis of N-phosphorylbicycles is a quite complex task.
In fact, N-phosphorylated azanucleosides have hardly been
studied, most probably due to the difficulty of their prepara-
tion. This difficulty can be rationalized by considering the
chemical behaviour of phosphorus, which may adopt several
coordination and oxidation states during a reaction, thus
making its outcome unpredictable.
Results and discussion
(Æ)-Methyl 2-hydroxy-2-azabicyclo[2.2.1]hept-5-ene-3-endo-
carboxylate (1) and (Æ)-methyl 2-hydroxy-2-azabicyclo[2.2.1]-
hept-5-ene-3-exo-carboxylate (2) were prepared according to
our recently described methodology.10 Treatment of each of
these adducts with an equimolar amount of OPClPh2 in the
presence of triethylamine (Et3N) and a catalytic amount of
4-dimethylaminopyridine (DMAP) afforded the corresponding
O-phosphorylated adducts, (Æ)-methyl 2-diphenylphosphoryloxy-
2-azabicyclo[2.2.1]hept-5-ene-3-endo-carboxylate (3) and (Æ)-methyl
2-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-exo-
a
´
Centro de Investigac¸a˜o em Quımica, Department of Chemistry and
Biochemistry, Faculty of Science, University of Porto,
Rua do Campo Alegre 687 4169-007 PortoPortugal.
E-mail: jrborges@fc.up.pt; Fax: +351 220402659;
Tel: +351 220402564
b Department of Organic Chemistry, Faculty of Pharmacy,
University of Santiago de Compostela, E-15782 Santiago de
Compostela, Spain
carboxylate (4) (Scheme 1). The phosphorylation of
1
(endo isomer) has been revealed to be less effective than
that of the corresponding exo isomer 2 (yields of 43
and 80%, respectively), even though in both cases a single
compound was identified (3 endo and 4 exo, respectively). Such
w Electronic Supplementary Information (ESI) available: special care
with solvents and reagents used, spectra of mass spectrometry, NMR
spectra of adducts 3, 4, 5, 6, 7, 8 and 11, and spectra of HPLC-MS
analyses. See DOI: 10.1039/c0nj00239a
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Scheme 1 Phosphorylation of adducts 1/2 and 5/6 (endo : exo ratio =
77 : 23) via OPClPh2. (i): Et3N, DMAP, À15 1C to room temp., 6 h
under a stream of argon.
a difference may be related to the higher steric hindrance
caused by the phosphoryloxy group in the bicyclic endo
isomer.
Similarly, phosphorylation of the in situ-prepared mixture
of endo and exo isomers of (Æ)-methyl 2-azabicyclo[2.2.1]hept-
5-ene-3-carboxylate (5/6, ratio E 4 : 1)11 with OPClPh2 in
the presence of Et3N and a catalytic amount of DMAP
afforded the endo and exo isomers of the expected methyl
2-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate
(7/8; Scheme 1) in 50% yield, the ratio of the isomers being nearly
the same as in the starting materials.
Scheme 3 A proposed mechanism for the reaction of adducts 1/2
with PClPh2, affording phosphorylbicycles 3/4 and 7/8.
of 1/2 and 5/6 with PClPh2 is not so straightforward. The
full/partial identification of some of the trace by-products was
crucial for the establishment of a plausible mechanism that
fully explained the results obtained. In Scheme 3, such a
mechanism for the phosphorylation of adducts 1 and 2 with
PClPh2 affording phosphorylbicycles 3/7 and 4/8, respectively,
is proposed.
On the contrary to the results obtained by Hudson et al.12 in
the phosphorylation of phosphinylated oximes, adducts 7/8
did not result from a homolytic thermal PIII - PV rearrange-
ment of non-stable and non-isolable intermediate 9 (diphenyl-
phosphinyloxiamine). If it were so, a concentration of PClPh2
higher than that of the adduct (1 or 2) should lead to an
increase in the percentage of 7 or 8 in the reaction mixture. To
verify this assumption, a reaction was performed by slowly
(4 h) adding a highly dilute solution of the adduct (1 or 2) in
CH2Cl2 (0.009 M) to a more concentrated solution of PClPh2
in CH2Cl2 (0.2 M, thus ensuring an excess of PPh2Cl at any
given time during the reaction) using the reaction conditions
described in Scheme 2.
Adducts 1 and 2 were also treated with equimolar amounts
of PClPh2 in the presence of Et3N. In analogy with the results
obtained by Hudson et al.12 with phosphinylated oximes, the
formation of adducts 7 and 8 was observed, but the major
products of this reaction were 3 and 4, respectively (Scheme 2).
In order to gain some insight into the reaction mechanism,
phosphorylation of the mixture of isomers 5/6 with PClPh2
was also performed. All the starting material was consumed,
but the expected straightforward diphenylphosphinyl derivative
could not be detected in the reaction mixture. A significant
amount of by-products (methoxydiphenylphosphine oxide
and diphenylphosphinic acid), as well as a small amount of
7 (endo), were isolated. As the reaction took place in an
anhydrous environment and no extractions were made, we
may conclude that the oxygen atom bonded to phosphorus in
compound 7 must come from the ester group of the starting
material 5/6, thus explaining the formation of the by-products
and the low yield of 7 obtained (E4%, not isolated).
After work-up (elimination of the solvent, addition of
AcOEt, filtration to remove Et3NHCl and evaporation of
the solvent), a 31P NMR analysis of the mixture showed no
significant difference between the ratios of the products
obtained, 3/7 or 4/8, respectively, when compared to the
results of the same reactions under normal conditions.
Furthermore, when the reaction was performed using
2.0 equiv. of 2, 1.0 equiv. of PClPh2 and 1.0 equiv. of Et3N,
no traces of compound 8 were detected by 31P NMR in
a sample of the reaction mixture, while compound 4 was
obtained in 73% yield (see the ESI, Fig. 23w).
Scheme 2 Phosphorylation of adducts 1/2 and 5/6 (ratio = 77 : 23)
via PClPh2. (i): Et3N, DMAP, À15 1C to room temp., 6 h under a
stream of argon.
The results obtained in these experiences are listed in Table 1.
The calculated yields refer to the amount of phosphorylated
bicycles formed (7 + 3 and 8 + 4) from the starting materials
1/2 or 5/6. Experiments realized at À60 1C or at room tempera-
ture lead to similar results.
As already referred to, the presence of the additional oxygen
bonded to phosphorus (OQP) in adducts 3 and 4 can be
explained if we assume that two molecules of starting
adduct (1 or 2) react with one molecule of PClPh2, probably
through the formation of intermediate 9, to give the corres-
ponding intermediate 10 (endo or exo), detected by ESI-MS
[peaks (M + 1) = 523.20 and (M + 23) = 545.20, see
the ESIw].
Whilst the formation of adducts 3/4 from 1/2, and 7/8 from
5/6, using OPClPh2 may easily be explained by a nucleophilic
displacement at phosphorus, the outcome of the reactions
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Table 1 Yields (Z) and ratios of phosphorylated adducts from the reactions between adducts 1/2 or 5/6 and the phosphorus reagents (according to
Scheme 3 and Scheme 4)
Product (%)c
Starting compound
Phosphorous reagent
Z (%)a
30b–35c
7/3
(15/85)
43
7/3
(0/100)
25b–30c
8/4
(15/85)
80
8/4
(0/100)
4e
7/3
(100/0)
50
7/8 / —
(80/20) / —
a
b
c
Combined yield of the two adducts. Yield after chromatographic purification. Values determined by 31P NMR from the crude of the reaction
d
by using an internal standard for quantification (diethylphosphoramidate—see supporting information). Values determined by H NMR from
the crude of the reaction (see supporting information). Value estimated by 1H NMR (not isolated, 8 was not detected probably due to its very low
concentration).
1
e
Intermediate 10 may rearrange (to a small extent), as
and PClPh2 (4%, see Table 1), thus justifying the low yield of
the overall reaction.
shown in Scheme 3, giving rise to diphenylphosphine oxide
1
(11; identified by H NMR) and to a few unidentified bicyclic
Taking into consideration the consistency of the reaction
outcome when some of the parameters were changed (reaction
temperature, order of addition of the reagents, reaction time
and time of addition of the reagents) and the small quantity of
by-products formed, the overall reaction may be described by
the chemical equation represented in Scheme 4.
compounds. Even though only traces of these compounds
were obtained, their detection (particularly of 11) is important
because it confirms the formation of intermediate 10
and, consequently, corroborates the proposed mechanism.
However, rearrangement of intermediate 10 (endo or exo) will
give essentially compounds 3 (or 4) and 5 (or 6). The latter
one reacts with another molecule of PClPh2, yielding 7 or 8
according to Scheme 3.
In order to identify as many species as possible and confirm
the proposed mechanism, a HPLC-MS analysis of a 30 min
reaction mixture (after the Et3NHCl had been filtered off and
the solvent evaporated) was performed. High intensity mass
peaks corresponding to compounds 1/2, 3/4, 5/6 and 7/8
were observed. Peaks corresponding to by-products, such as
diphenylphosphinic acid, diphenylphosphine oxide and methoxy-
diphenylphosphine oxide, were also detected (see the ESIw).
The minor percentage of adducts 7/8 relative to adducts 3/4 is
in accordance with the low yield of the reaction between 5/6
Scheme 4 A chemical equation that represents the overall reaction of
the phosphorylation of adducts 1/2 via PClPh2 through the mechanism
presented in Scheme 3.
The yields of this reaction, reported in Table 1, refer to the
sum of phosphorylated products obtained in each reaction,
considering the stoichiometry as represented in Scheme 4.
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Scheme 5 A chemical equation representing the overall reaction
of the phosphorylation of adducts 1/2 via PClPh2 considering a
2 : 1 stoichiometry.
However, if we consider that compounds 7 or 8 result from a
side reaction, which is reasonable in view of their low yields,
then we can rewrite the chemical equation of the phosphoryl-
ation reaction as represented in Scheme 5.
According to this equation, the stoichiometry of the reagents
is 2 : 1, and a recalculation of the yields of the phosphoryl-
ation reaction leads to values in the order of 51%. These
values are relatively close to those obtained when the reaction
was performed with 2 equiv. of 2 and 1 equiv. of PClPh2
(73%), the difference probably arising from the scale on
which the experiments were performed (Table 1—large scale
experiments).
Fig. 1 1H NMR spectra of the aromatic region of phosphorylbicycles
3, 4, 7 and 8, respectively.
Conclusions
(Æ)-Methyl 2-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-
5-ene-3-carboxylates (3/4) are easily obtained by nucleophilic
substitution between (Æ)-2-hydroxy-2-azabicyclo[2.2.1]hept-5-
ene-3-carboxylates (1/2) and diphenylphosphinic chloride
(OPClPh2).
Concerning the identification of the phosphorylated
compounds formed, bicycles 7/8 and 3/4 were not easy to
distinguish by NMR analysis. In order to find characteristic
patterns that would help in their discrimination, 15N and
31P NMR analyses were performed. Table
2 presents
15N NMR and 31P NMR data for the four synthesized
The same diphenylphosphoryloxy adducts (3/4) can also be
obtained from 1/2 via phosphinoylation (with PClPh2),
although in moderate yields. In addition to these adducts,
(Æ)-methyl 2-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-
ene-3-carboxylates (7/8) are formed as by-products (low yield)
if PClPh2 and 1/2 are used in equimolar amounts.
phosphorylbicycles.
As can be seen from Table 2, the 31P chemical shifts of
compounds 3 and 4 (N–O–P bonds) are slightly higher than
those of 7 and 8 (N–P). In the case of the 15N NMR chemical
shifts, the difference between these values for compounds 3/4
and 7/8 is much more pronounced, reflecting the greater
deprotection caused by the directly bonded oxygen atom in
compounds 3/4. The discrepancy observed for the 15N NMR
chemical shifts of 3 and 4 (endo and exo isomers) may
be related to steric effects, which may affect the N–O
bond stability. Further studies are being performed in our
laboratories in order to clarify this issue. Concerning the N–P
coupling constants, they are smaller in 3 and 4 (N–O–P bonds)
due to the longer distance between the P and N atoms in these
adducts. The different compounds also exhibit characteristic
splitting patterns in the region of the aromatic protons of their
1H NMR spectra, as illustrated in Fig. 1.
On the other hand, (Æ)-methyl 2-diphenylphosphoryl-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylates (7/8) can be obtained
by the phosphorylation of a mixture of (Æ)-2-azabicyclo-
[2.2.1]hept-5-ene-3-carboxylates (5/6). However, these bicyclic
amines are unstable and must be synthesized in situ or
immediately before the phosphorylation and used without
purification. Separation of the final products yields the endo
and exo isomers of the phosphorylated bicyclic amines, the
endo isomer (7) being the major product.
Experimental section
These features easily allow the distinction between N–O–P
and N–P bonds in the adducts. In fact, the ortho-hydrogens of
both phenyl rings are sufficiently different to give rise to two
distinct signals. The chemical shift difference between these
two signals is more significant in the diphenylphosphoryl-
azabicycles (7 and 8, N–P bond) than in the diphenyl-
phosphoryloxyazabicycles (3 and 4, N–O–P bond).
This experimental section contains the procedures for the
synthesis of adducts 5/6 and procedures for the phosphoryl-
ation of adducts 1/2 and 5/6, as well as analytical data for the
phosphorylated adducts 3, 4, 7 and 8. NMR analyses were
performed using a Bruker Avance III 400, with TMS as the
internal standard for 1H and 13C, H3PO4 85% for 31P and
NH3 for 15N nuclei. ESI-MS analyses were performed on a
liquid chromatography Finnigan Surveyor equipment coupled
to a mass detector Finnigan LQC DECA XP MX with an
API and an ESI interface. LC-MS analyses were performed
on an Applied Biosystems Q TRAP LC/MS/MS System (ESI)
coupled to an Agilent Technologies HPLC 1200 instrument.
The samples were analyzed with a C18 reverse phase Agilent
column (ZORBAX Eclipse XDB-C18 4.6 Â 150 mm 5-micron)
and an ACE 5 C18 3 mm pre-column.
Table 2 31P NMR and 15N NMR chemical shifts and coupling
constants of the phosphorylbicycles.
Phosphorylated adduct
15N/ppm
JN–P/Hz
31P/ppm
3
4
7
8
99.1
177.5
72.1
74.5
3.1
5.7
8.6
10.3
31.8
33.8
27.4
26.0
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Syntheses
CPD (0.60 mL, 7.5 mmol) was added and the reaction left to
react for a further 18 h. The reaction mixture was extracted
once with hexane to remove excess CPD and the organic layer
discarded. The aqueous phase was adjusted to pH 9 with an
aqueous saturated solution of NaHCO3 and/or NaOH 1 M,
and extracted with AcOEt until no compound remained in the
aqueous phase (TLC). The organic extract was dried and the
solvent evaporated, affording an orange-coloured oil, identi-
fied as methyl 2-azabicyclo[2.2.1]hept-5-ene-3-carboxylates
(5/6) (60% yield, not purified). The oil was dissolved in dry
CH2Cl2 (15 mL), and Et3N (2.00 mL, 14.3 mmol) and a
catalytic amount of DMAP (10 mg, 0.08 mmol) were added.
The mixture was stirred at À15 1C under an argon atmosphere
for 5 min before the dropwise addition of OPClPh2 (1.40 mL,
7.35 mmol). The mixture was stirred for 2 h at À15 1C and
then allowed to reach room temperature, reacting during a
further 4 h. The solvent was evaporated under low pressure
and the residue filtered through a funnel with cotton using
AcOEt. After removal of the solvent, the residue was purified
by flash chromatography (SiO2, AcOEt). (Rf: [0.27–0.30]).
(Æ)-Methyl 2-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-
5-ene-3-carboxylates (3/4). A solution of 2-hydroxy-2-azabi-
cyclo[2.2.1]hept-5-ene-3-carboxylate10 (0.56 g, 3.3 mmol),
Et3N (0.98 mL, 7.0 mmol) and a catalytic amount of DMAP
(5.0 mg, 0.04 mmol) in dry CH2Cl2 (5 mL) was stirred under
an argon atmosphere at À5 1C for 5 min, before the dropwise
addition of OPClPh2 (0.63 mL, 3.31 mmol). The mixture was
left to react for 2 h at À5 1C and then allowed to reach room
temperature, reacting during a further 2 h. The solvent was
evaporated under low pressure and the residue filtered through
a funnel with cotton using ethyl acetate. After removal of the
solvent, the residue was purified by flash chromatography
(SiO2, CH2Cl2–Et2O 1 : 1). (Rf: 3, 0.23; 4, 0.50).
Analytical data for 3. 1H NMR (400 MHz, CDCl3): d =
7.96–7.89 (m, 2H, ArHortho), 7.86–7.79 (m, 2H, ArHortho),
7.55–7.41 (m, 6H, ArH), 6.25 (t, 1H, J = 3.3 Hz, 6-H), 6.18
(d, 1H, J = 3.7 Hz, 5-H), 4.96 (ddd, 1H, J = 12.9, 5.8, 2.5 Hz,
1-H), 3.92 (s, 1 H, 3-H), 3.69 (s, 3H, OCH3), 3.32 (t, 1 H,
À
J = 2.9 Hz, 2-H), 1.99 (dt, 1 H, J = 12.5, 2.8 Hz, 7syn-H), 1.91
(dd, 1H, J = 12.5, 5.8 Hz, 7anti-H); 13C NMR (100 MHz,
Analytical data for 5. 1H NMR (400 MHz, CDCl3): d =
6.33–6.28 (m, 1 H, 6-H), 5.90–5.85 (m, 1 H, 5-H), 4.01 (s, 1 H,
CDCl3): d = 169.97 (CO2CH3), 140.31 (C-6), 134.51 (C-5),
132.27 (d, JC–P = 2.9 Hz, Cpara), 132.22 (d, JC–P = 2.9 Hz,
À
1-H), 3.94 (d, 1 H, J = 3.0 Hz, 3-H), 3.68 (s, OCH3), 3.44
À
(brs, 1 H, 4-H), 2.05 (brs, 1 H, NH), 1.64 (d, 1 H, J = 8.3 Hz,
syn-H), 1.44 (d, 1 H, J = 8.3 Hz, 7anti-H); 13C NMR
À
C
para), 132.06 (d, JC–P = 94.1 Hz, Cipso), 132.05 (d, JC–P =
7
10.5 Hz, 2 Â Cortho), 131.38 (d, JC–P = 10.3 Hz, 2 Â Cortho),
130.70 (d, JC–P = 87.7 Hz, Cipso), 128.51 (d, JC–P = 13.3, 2
(100 MHz, CDCl3): d = 175.08 (CO2CH3), 137.38 (C-6),
À
130.82 (C-5), 61.79 (OCH3), 57.91 (C-3), 52.80 (C-1), 50.35
À
C
meta), 128.48 (d, JC–P = 13.3, 2 Cmeta), 89.54 (d, JC–P =
(C-7 = CH2), 48.80 (C-4); 15N NMR (40 MHz, CDCl3): d =
43.5; ESI-MS: calculated for [C8H11NO2+H]+ (M + H+)
154.08, found 154.53.
5.5 Hz, C-3), 75.64 (C-1), 52.10 (OCH3), 43.46 (C-4), 35.77
(d, JC–P = 3.3 Hz, C-7 = CH2); 31P NMR (162 MHz,
CDCl3): d = 31.78; 15N NMR (40 MHz, CDCl3): d = 99.09
(d, JP–N = 3.1 Hz); ESI-MS: calculated for [C20H20NO4P + H]+
(M + H+) 370.11, found 370.13.
À
À
Analytical data for 6. 1H NMR (400 MHz, CDCl3): d =
6.33–6.28 (m, 2 H, 6-H, 5-H), 4.09 (brs, 1 H, 1-H), 3.78 (s, 3 H,
OCH3), 3.29 (brs, 1 H, 3-H), 2.97 (brs, 1 H, 4-H), 2.05
À
Analytical data for 4. 1H NMR (300 MHz, CDCl3): d =
7.86–7.79 (m, 2 H, ArHortho), 7.78–7.71 (m, 2 H, ArHortho),
7.53–7.37 (m, 6 H, ArH), 6.62 (ddd, 1 H, J = 5.5, 3.2, 1.1 Hz,
6-H), 6.32 (dd, 1 H, J = 5.6, 2.1 Hz, 5-H), 4.59 (m, 1 H, 1-H),
(brs, 1 H, NH), 1.66–1.61 (m, 1 H, 7syn-H), 1.38 (d, 1 H,
J = 8.5 Hz, 7anti-H); 13C NMR (100 MHz, CDCl3): d =
175.79 (CO2CH3), 137.53 (C-6), 136.58 (C-7), 61.18 (OCH3),
À
À
À
58.36 (C-3), 52.99 (C-1), 48.98 (C-4), 46.54 (C-7 = CH2);
15N NMR (40 MHz, CDCl3): d = 45.8.
3.39 (s, 3 H, OCH3), 3.07 (d, 1 H, J = 2.1 Hz, 3-H), 3.06 (brs,
À
1 H, 4-H), 1.95 (d, 1 H, J = 9.5, 7syn-H), 1.91 (ddd, 1H, J =
9.5, 3.5, 2.0 Hz, 7anti-H); 13C NMR (100 MHz, CDCl3): d =
171.37 (CO2CH3), 138.51 (C-6), 133.28 (C-5), 132.44 (d, JC–P =
Analytical data for 7. 1H NMR (400 MHz, CDCl3): d =
8.10–8.04 (m, 2 H, ArHortho), 7.80–7.74 (m, 2 H, ArHortho),
7.58–7.48 (m, 3 H, ArH), 7.44–7.31 (m, 3 H, ArH), 6.52
(dd, 1 H, J = 5.5, 2.6 Hz, 6-H), 6.11 (dd, 1 H, J = 5.5,
2.7 Hz, 5-H), 4.37 (brs, 1 H, 1-H), 4.22 (dd, 1 H, J = 11.9,
À
10.0 Hz, 2 Â Cortho), 132.09 (d, JC–P = 2.6 Hz, Cpara), 131.95
(d, JC–P = 2.8 Hz, Cpara), 131.57 (d, JC–P = 9.7 Hz, 2 Â Cortho),
131.50 (d, JC–P = 39.8 Hz, Cipso), 130.16 (d, JC–P = 39.0 Hz,
3.4 Hz, 3-H), 3.50 (brs, 1 H, 4-H), 3.35 (s, OCH3), 1.96 (d, 1 H,
C
ipso), 128.32 (d, JC–P = 10.7, 2 Â Cmeta), 128.19 (d, JC–P
=
=
=
À
J = 8.3 Hz, 7syn-H), 1.63 (d, 1 H, J = 8.3 Hz, 7anti-H);
13C NMR (100 MHz, CDCl3): d = 172.16 (d, JC–P = 2.5 Hz,
CO2CH3), 137.37 (d, JC–P = 7.6 Hz, C-6), 135.26 (C-5), 133.09
11.0, 2 Â Cmeta), 70.31 (d, JC–P = 2.3 Hz, C-3), 69.22 (d, JC–P
4.5 Hz, C-1), 51.90 (OCH3), 47.96 (C-4), 44.39 (d, JC–P
À
3.3 Hz, C-7 = CH2); 31P NMR (162 MHz, CDCl3): d = 33.84;
À
À
15N NMR (40 MHz, CDCl3): d = 177.48 (d, JP–N = 5.7 Hz);
ESI-MS: calculated for [C20H20NO4P + H]+ (M + H+)
370.11, found 370.20.
(d, JC–P = 9.2 Hz, 2 Â Cortho), 132.71 (d, JC–P = 44.1 Hz,
C
ipso), 132.37 (d, JC–P = 9.9 Hz, 2 Â Cortho.), 132.06 (d, JC–P
=
2.7 Hz, Cpara), 131.67 (d, JC–P = 2.7 Hz, Cpara), 131.42
(d, JC–P = 35.1 Hz, Cipso), 128.63 (d, JC–P = 12.7, 2 Â Cmeta),
127.99 (d, JC–P = 12.7, 2 Â Cmeta), 63.91 (d, JC–P = 1.6 Hz,
(Æ)-Methyl 2-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-
ene-3-carboxylate (7/8). To a stirred solution of ammonium
chloride (NH4Cl) (1.50 g, 28.0 mmol) and methyl 2-hydroxy-2-
methoxyacetate (methyl hemiacetal of methyl glyoxylate)
(1.20 g, 9.99 mmol) in water (15 mL) at room temperature
was added CPD (0.60 mL, 7.5 mmol). After 2.5 h, additional
C-1), 57.48 (d, JC–P = 2.4 Hz, C-3), 51.51 (OCH3), 50.51
À
(d, JCÀP = 2.9 Hz, C-7 = CH2), 48.63 (C-4); 31P NMR
(162 MHz, CDCl3): d = 27.44; 15N NMR (40 MHz, CDCl3):
d = 72.06 (d, JP–N = 8.6 Hz); ESI-MS: calculated for
[C20H20NO3P+H]+ (M+H+) 354.12, found 354.67.
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Analytical data for 8. 1H NMR (400 MHz, CDCl3): d =
8.15–8.08 (m, 2 H, ArHortho), 7.69–7.77 (m, 2 H, ArHortho),
7.57–7.48 (m, 3 H, ArH), 7.44–7.31 (m, 3 H, ArH), 6.52
(dd, 1 H, J = 3.4, 2.2 Hz, 6-H), 6.33–6.28 (m, 1 H, 5-H),
1795–1798; (j) Z. Liu and J. D. Rainier, Org. Lett., 2006, 8,
459–462; (k) S. E. Ward, A. B. Holmes and R. McCague, Chem.
Commun., 1997, 2085–2086; (l) S. Alonso De Diego, P. Munoz,
R. Gonza
E. Cenarruzabeitia, D. Frechilla, J. Del Rio, M. L. Jimeno and
T. Garcıa-Lopez, Bioorg. Med. Chem. Lett., 2005, 15, 2279–2283;
lez-Muniz, R. Herranz, M. Martın-Martınez,
´ ´ ´
´
´
4.25 (brs, 1 H, 1-H), 3.39 (s, OCH3), 3.31 (d, 1 H, J = 10.1 Hz,
À
(m) P. W. R. Harris, M. A. Brimble, V. J. Muir, M. Y. H.
Lai, N. S. Trotter and D. J. Callis, Tetrahedron, 2005, 61,
10018–10035.
2 (a) D. L. Boger and S. M. Weinred, in Hetero-Diels–Alder
Methodology in Organic Synthesis, Organic Chemistry, ed.
H. H. Wasserman, Academic Press, New York, 1987;
(b) S. M. Weinreb, in Comprehensive Organic Synthesis, ed.
B. M. Trost, I. Fleming and L. A. Paquette, Pergamon Press,
Oxford, 1991, vol. 5, pp. 401–449; (c) G. B. Rowland,
E. B. Rowland, Q. Zhang and J. C. Antilla, Curr. Org. Chem.,
3-H), 3.22 (brs, 1 H, 4-H), 2.19 (d, 1 H, J = 8.4 Hz, 7syn-H),
1.40–1.34 (m, 1 H, 7anti-H); 13C NMR (100 MHz, CDCl3): d =
173.14 (d, JC–P = 1.7 Hz, CO2CH3), 138.05 (d, JC–P = 1.7 Hz,
À
C-6), 134.66 (C-5), 132.89 (d, JC–P = 9.3 Hz, 2 Â Cortho),
132.25 (d, JC–P = 26.0 Hz, Cipso), 132.05 (d, JC–P = 9.8 Hz,
2 Â Cortho), 131.92 (d, JC–P = 2.7 Hz, Cpara), 131.54 (d, JC–P
=
2.7 Hz, Cpara), 130.96 (d, JC–P = 17.5 Hz, Cipso), 128.55
(d, JC–P = 12.6, 2 Â Cmeta), 127.92 (d, JC–P = 12.6, 2 Â Cmeta),
´
2006, 10(9), 981–1005; (d) M. L. Cardoso do Vale, J. E. Rodrıguez-
Borges, O. Caamano, F. Fernandez and X. Garcıa-Mera,
62.74 (C-1), 58.94 (d, JC–P = 1.9 Hz, C-3), 51.68 (OCH3), 50.18
À
´
´
(d, JC–P = 5.3 Hz, C-4), 45.31 (d, JC–P = 8.7 Hz, C-7 = CH2);
31P NMR (162 MHz, CDCl3): d = 25.95; 15N NMR (40 MHz,
CDCl3): d = 74.51 (d, JP–N = 10.3 Hz); ESI-MS: calculated for
[C20H20NO3P+H]+ (M + H+) 354.12, found 354.63.
Tetrahedron, 2006, 62, 9475–9482 and references therein;
(e) J. E. Rodriguez-Borges, X. G. Mera, F. Fernandez, V. H. C.
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Phys. Lett., 2009, 477, 60–64; (h) M. B. Hursthouse, K. M. A.
Malik, D. E. Hibbs, S. M. Roberts, A. J. H. Seago, V. Sik and
R. Storer, J. Chem. Soc., Perkin Trans. 1, 1995, 2419–2425.
Adducts 3, 4, 7 and 8 from (Æ)-2-hydroxy-2-azabicyclo[2.2.1]-
hept-5-ene-3-carboxylates. A solution of methyl 2-hydroxy-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1 or 2)12 (2.06 g,
12.2 mmol), Et3N (3.30 mL, 23.8 mmol) and a catalytic
amount of DMAP (20 mg, 0.16 mmol) in dry CH2Cl2
(25 mL) at À15 1C was stirred under an argon atmosphere
for 5 min. Then, PClPh2 (2.10 mL, 12.0 mmol) was added
dropwise and the mixture left to react for 4 h at À15 1C and for
an additional 2 h at room temperature. The solvent was
removed under low pressure, and the residue taken up in
AcOEt and filtered through a funnel with a cotton plug.
After removal of the solvent, the compounds formed were
isolated by column chromatography (SiO2, CH2Cl2–Et2O 1 : 1
and/or AcOEt).
3 (a) M. J. Alves, X. Garcıa-Mera, M. L. C. Vale, T. P. Santos,
´
F. R. Aguiar and J. E. Rodrıguez-Borges, Tetrahedron Lett., 2006,
´
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M. L. C. Vale, F. R. Aguiar, M. J. Alves and X. Garcia-Mera,
Synthesis, 2008, 971–977 and references therein; (c) W. Maison,
D. C. Grohs and A. H. G. P. Prenzel, Eur. J. Org. Chem., 2004,
1527–1543.
4 (a) Nucleoside Analogs in Cancer Therapy, ed. B. D. Cheson,
M. J. Keating and W. Plunkett, Marcel Dekker, New York,
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(c) J. T. Slama, N. Mehta and E. Skrzypezak-Jankun, J. Org.
Chem., 2006, 71, 7877–7880; (d) E. De Clerq, Curr. Med. Chem.,
2001, 8, 1543; (e) J. Ena and F. Pasquau, Clin. Infect. Dis., 2003,
36, 1186; (f) M. Louie, C. Hogan, M. Di Mascio, A. Hurley,
V. Simon, J. Rooney, N. Ruiz, S. Brun, E. Sun, A. S. Perelson,
D. D. Ho and M. Markowitz, J. Infect. Dis., 2003, 187, 896;
(g) P. Abeijon, J. M. Blanco, O. Caamano, F. Fernandez,
M. D. Garcia, X. Garcia-Mera, J. E. Rodriguez-Borges,
J. Balzarini and E. De Clercq, Synthesis, 2009, 16, 2766–2772
and references therein.
Acknowledgements
Thanks are due to Fundac¸ ao para a Ciencia e Tecnologia
(FCT) for financial support given to Faculdade de Ciencias
do Porto (project PTDC/QUI/67407/2006) and for financial
support through the re-equipment program REDE/1517/
RMN/2005 and CONC-REEQ/275/QUI. C. A. D. S. gives
thanks for grant SFRH/BD/31526/2006.
5 H. Yoda, H. Yamazaki, M. Kawauchi and K. Takabe, Tetrahedron:
Asymmetry, 1995, 6, 2669–2672.
6 U. Chiacchio, A. Rescifina, D. Iannazzo, A. Piperno, R. Romeo,
L. Borrello, M. T. Sciortino, E. Balestrieri, B. Macchi, A. Mastino
and G. Romeo, J. Med. Chem., 2007, 50, 3747–3750.
7 E. Balestrieri, C. Matteucci, A. Ascolani, A. Piperno, R. Romeo,
G. Romeo, U. Chiacchio, A. Mastino and B. Macchi, Antimicrob.
Agents Chemother., 2008, 52, 54–64.
8 A. R. Van Rompay, M. Johansson and A. Karlsson, Pharmacol.
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This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 2546–2551 | 2551