α-Acylaminophosphonates possessing epoxyisoindolone moiety

Article abstract of DOI:10.1016/j.tet.2007.10.022

α-Acylaminophosphonates possessing an epoxyisoindolone moiety were prepared with good stereoselectivity (de≥80%) by?a tandem acylation/[4+2]-cycloaddition reaction between maleic anhydride and α-aminophosphonates derived from a furfurylamine. The cycloaddition products have an opposite orientation of epoxy and phosphonate groups, which was confirmed by NMR spectroscopy and X-ray crystal structure analysis.

Full text of DOI:10.1016/j.tet.2007.10.022

Tetrahedron 63 (2007) 12576–12582
a-Acylaminophosphonates possessing epoxyisoindolone moiety
*
Georgiy O. Kachkovskyi and Oleg I. Kolodiazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanska Street 1, Kyiv 02094, Ukraine
Received 24 July 2007; revised 19 September 2007; accepted 4 October 2007
Available online 6 October 2007
Abstract—a-Acylaminophosphonates possessing an epoxyisoindolone moiety were prepared with good stereoselectivity (deꢀ80%) by a
tandem acylation/[4+2]-cycloaddition reaction between maleic anhydride and a-aminophosphonates derived from a furfurylamine. The
cycloaddition products have an opposite orientation of epoxy and phosphonate groups, which was confirmed by NMR spectroscopy and
X-ray crystal structure analysis.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
These products are used as starting compounds for the
synthesis of [1,2]-isoindolo condensed heterocycles, and
7
Amino- and hydroxyphosphonates are important biologi-
cally active compounds and useful intermediates in organic
especially for the synthesis of such important biologically
active compounds as isoindolobenzazepine alkaloids.
8
1
,2
synthesis. Many of these compounds have attracted
attention because of their antibacterial, antiviral, antibiotic,
pesticidal, anticancer and enzyme inhibitory properties.
Continuing with our interest in the chemistry of phosphonic
acid derivatives, we report here the synthesis of epoxyisoin-
3
,4
9
dolyl phosphonates employing the cycloaddition reaction of
maleic anhydride with a-aminophosphonates derived from
a furfurylamine. These compounds can be used as interme-
diates for the synthesis of biomedical compounds. Moreover
cyclic a-aminophosphonates possessing the epoxyisoindo-
lone moiety are interesting from a viewpoint of biological
activity because the analogous tricyclic nitrogen heterocy-
Several amino- and hydroxyphosphonates are used in clinics
for treating different diseases (alaphospholine, phosphomy-
cin, bis-phosphonate derivatives of AZT and others),
1
,2b,c
while some functionalized phosphonates are used as inter-
mediates in the synthesis of penicillin. Therefore the syn-
5
thesis of new types of functionalized phosphonic acids and
their derivatives is an interesting problem.
6
a
cles possess high antipsychotic and antidyskinetic activity.
The interest in both natural and synthetic phosphonic acids
led us to reconsider the preparation of heterocyclic amino-
phoshonates through cycloaddition reactions. It is known
that N-substituted furfurylamines easily react with acylating
dienophiles, such as maleic anhydride, through a tandem
acylation/[4+2]-cycloaddition reaction. The tricyclic epoxy-
isoindolone system is formed via an initial N-acylation fol-
2. Results and discussion
The initial a-aminophosphonates bearing a furfurylamine
fragment could be easily prepared by the Kabachnik–Fields
reaction. Addition of dimethyl phosphite to Schiff bases 1
and 2 led to the formation of isomeric a-aminophosphonates
3 and 4, which were isolated and purified as oxalate salts
1
0
6
lowed by intramolecular Diels–Alder reaction (Scheme 1).
1
1
(
Table 1).
O
R
NR'
Next, these a-aminophosphonates 3 and 4 (in the form of
free base) underwent tandem acylation/[4+2]-cycloaddition
with maleic anhydride. Reaction was carried out by stirring
the reaction mixture in toluene at ambient temperature for
R
O
O
O
+
O
NHR'
O
COOH
3
9
5
days. Products 5 and 6 were isolated in good yields (70–
0%) as colourless solids (Scheme 2). Data for compounds
and 6 are shown in Table 2.
Scheme 1. Tandem acylation/[4+2]-cycloaddition reaction.
Keywords: a-Aminophosphonates; Epoxyisoindolones; Tandem acylation/
[4+2]-cycloaddition reaction.
Tandem acylation/[4+2]-cycloaddition reaction proceeded
with exclusive formation of the Diels–Alder exo-adducts 5
*
Corresponding author. Tel.: +38(044) 573 2555; fax: +38(044) 573 2552;
e-mail: oikol123@rambler.ru
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.022

G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
12577
and 6 that was confirmed by evaluation of spin–spin cou-
pling constants of hydrogen atoms of oxabicycloheptene
moiety. The H NMR spectra showed a doublet at d 2.49–
1
ba
2
.61 ppm, J ¼9.0–9.3 Hz for the endo-H proton (exo-H
H
b
b
ba
H
proton would disclose a double doublet, J ¼8.5–10 Hz
bc
H
and J ¼1.5–2 Hz). Such stereoselectivity was described
for tetrahydroepoxyisoindolones not containing phospho-
nate group.
6
c
exo-Epoxyisoindolyl phosphonates 5 were isolated as a
mixture of two diastereomers derived from the two chiral
elements: the bridged system and carbon atom a to the phos-
phonate (Scheme 3). The diastereomeric ratio varied
depending on the reaction conditions, though in general,
was w40:60. Attempts to separate them by crystallization
were unsuccessful.
Contrary to our expectations, isomeric compounds 6 were
formed with the major diastereomer having the opposite
orientation of epoxy and phosphonate groups (Fig. 1). The
biggest content (11%) of minor diastereomer, in which these
groups are unidirectional, was found for compound 6e. Prob-
ably such stereoselectivity is a consequence of a steric effect
of the phosphonate group in the transition state geometry of
the cycloaddition reaction. The major diastereomer of
compounds 6 was isolated in a pure state by crystallization
from appropriate solvent.
The relative stereochemistry of the major diastereomer of
compounds 6 was confirmed by a single-crystal X-ray anal-
ysis of a representative compound 6e (Fig. 1).
Both epoxyisoindolyl phosphonates 5d and 6d were prepared
from the same aminophosphonate 3d (or 4d) as the initial
compound. Compound 3d (or 4d) reacted with maleic anhy-
dride to afford the compounds 5d+6d in a ratio of 55:45.
These isomeric epoxyisoindolyl phosphonates appeared as
a mixture of minor and major diastereomers (Table 2).
1
Some interesting features have been found in H NMR spec-
tra of phosphonates 5 and 6. The doublet signal of the hydro-
gen geminal to the phosphonate group in compounds 5
2
(except 5e) arrived at 5.60–5.70 ppm with J 21–22 Hz. In
contrast, the signal of the same H-atom of compounds 6 is
shifted to 3.95–4.70 ppm with the coupling constant value
J 5.3–8.7 Hz, which is unusual for a-aminophosphonates
2
1
2
(
Fig. 2, Table 2).
These data probably are the consequence of the rigid fixation
of the phosphonate group to the bridged tricyclic moiety of
compound 6.
A PHCOSYexperimentshowedremote(throughfivebounds)
spin–spin interaction between H and phosphorus in the minor
a
diastereomer of compounds 5 with the coupling constant
value of J 2.5–2.7 Hz that is unusual for the l s -phosphorus
atom (Fig. 3).
5
5 4
1
3
It should be noted that the interaction of a-amino-a-(2-
furyl)phosphonates with maleic anhydride was previously
1
4
described by Borisov et al. However, they characterized
isolated products only as Diels–Alder adducts, without
aminogroup acylation.

12578
G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
MeO
MeO
O
P
N
R
O
1
. (MeO) P(O)H
H
N
2
maleic anhydride,
toluene, 3 days, rt
R
OMe
N
R
2. H C O 2H O
O
2
2
4
2
Ha
O
O
O
P
H
H C O
b
2
2
4
OMe
COOH
Hc
1
3
5
MeO
O
H
N
OMe
P
R
1
. (MeO) P(O)H
maleic anhydride,
toluene, 3 days, rt
2
R
N
MeO
2
. H C O 2H O
O
2
2
4
2
N
R
O
O
P
O
H C O
H
H
2
2
4
a
b
OMe
O
COOH
2
4
Hc
R = (a) Ph, (b) 4-FC H , (c) piperonyl, (d) 2-furyl, (e) H (3e was not isolated)
6
6
4
Scheme 2. Synthesis of epoxyisoindolyl phosphonates 5 and 6.
Table 2. Isomeric epoxyisoindolyl phosphonates 5 and 6 (Scheme 2)
a
2
Compound
R
Yield (%)
dr
d
CHP (ppm)
J
HP (Hz)
d
P
(ppm)
Minor
Major
Minor
Major
Minor
Major
5
5
5
5
5
6
6
6
6
6
a
b
c
d
e
a
b
c
d
e
Ph
4-FC H
6 4
Piperonyl
2-Furyl
H
Ph
6 4
4-FC H
Piperonyl
2-Furyl
H
85
75
82
60:40
60:40
60:40
66:33
—
97:3
98:2
98:2
91:9
89:11
5.60
5.62
5.52
5.67
5.66
5.66
5.56
5.69
21.0
21.4
21.5
22.2
22.3
22.0
22.2
22.2
26.16
25.94
26.09
23.67
26.92
26.70
26.87
24.44
b
b
c
80
29
d
3.71; 3.83
16.6
28.37
e
e
e
e
e
e
e
e
e
e
81
89
91
3.98
4.03
3.95
4.15
4.44
4.65
4.65
4.64
4.66
4.69
5.7
5.7
5.7
5.3
5.7
8.1
8.1
7.8
8.7
8.1
25.59
25.58
25.60
25.55
26.10
25.16
25.14
25.26
25.12
25.59
c
80
68
a
b
c
d
e
1 31
dr Values were obtained by integration of H and P NMR spectra.
3,4-(Methylenedioxy)phenyl.
Yield of mixture 5d:6d.
Yield within two steps.
Data obtained from H NMR spectrum of crude (not crystallized) product.
1
MeO
O
MeO
MeO
O
MeO
MeO
MeO
O
N
O
P
N
P
N
R
O
R
O
P
P
MeO
R
O
R
N
MeO
O
O
O
O
O
COOH
COOH
COOH
COOH
major
minor
5a-d
6a-e
Scheme 3. Diastereomer pairs of isomeric epoxyisoindolyl phosphonates 5 and 6.
3. Conclusion
4. Experimental
In conclusion, new a-acylaminophosphonates, possessing
an epoxyisoindolyl moiety, 5 and 6 have been synthesized
by a tandem acylation/[4+2]-cycloaddition reaction. Phos-
phonates 5 were obtained as a mixture of two diastereomers
in a typical 40:60 ratio. Isomeric phosphonates a-acylami-
nophosphonates 6 possessing an epoxyisoindolone moiety
were prepared with good stereoselectivity (deꢀ80%). The
epoxy and phosphonate groups in these compounds are
4.1. General
All commercially available reagents were used without fur-
ther purification, with the exception of 2-furaldehyde, which
was distilled prior to use. Melting points are uncorrected. IR
spectra were obtained in KBr pellets and recorded on a
1
13
Specord M80 Carl Zeiss Jena spectrometer. H, C and
P NMR spectra were measured at 300, 100 and 80 MHz
3
1
1
13
oppositely oriented. This was confirmed by H, C and
P NMR spectroscopies as well as X-ray crystal structure
(for 3 and 4) or 200 (for 5 and 6) MHz, respectively, for
DMSO-d solution with TMS as internal or H PO as exter-
3
1
6
3
4
analysis. Phosphonates 5 and 6 are interesting as intermedi-
ates for the synthesis of [1,2]-isoindolo condensed hetero-
cyclic systems.
nal standard on Varian VXR-300, Bruker Avance 500 and
Gemini 2000 (400 MHz) spectrometers. 2D NMR spectra
(PH COSY) were measured using standard Bruker software.

G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
12579
Chemical shifts (d) are reported in parts per million. Cou-
pling constants (J) are reported in Hertz. Elemental analyses
were performed in the analytical laboratory of our institute.
All solvents were distilled and purified by standard proce-
dures.
4.2. X-ray crystallography
Crystallographic data for the structure of major diastereomer
of 6e have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no.
CCDC-650983 and can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336 033,
or e-mail: deposit@ccdc.cam.ac.uk.
Figure 1. Major diastereomer of compound 6e: molecular structure showing
the numbering used in the crystallographic work.
*
O
O
COOH
O
COOH
O
H
2
N
N
(
MeO) P
Me
2
(
MeO) P
O
H
Me
O
75 : 25
1
Figure 2. H NMR spectrum of diastreomeric mixture of epoxyisoindolyl phosphonate 6e (enriched with minor diastereomer (*) mixture was obtained by evap-
oration of mother liquid after recrystallization of major diastereomer).
OMe
P
OMe
N
O
O
J = 2.6 Hz
O
Ha
COOH
Minor
Figure 3. PH COSY spectrum of epoxyisoindolyl phosphonate 5a.

12580
G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
Table 3. CHP analyses of aminophosphonates 3a–d, 4a–e
Compound Calculated (%) Formula Found (%)
diastereomer: dH (300 MHz, DMSO-d ) 2.53 (1H, d, J
6
9
J 11.7 Hz, CH N), 3.64 (3H, d, J 10.7 Hz, OCH ), 3.73
.1 Hz, H ), 2.95 (1H, dd, J 9.1, 2.6 Hz, H ), 3.52 (1H, d,
b a
2
3
C
H
P
C
H
P
(3H, d, J 10.7 Hz, OCH ), 4.18 (1H, d, J 11.7 Hz, CH N),
3 2
3
3
3
3
4
4
4
4
a
b
c
49.88 5.23 8.04
47.65 4.75 7.68
47.56 4.70 7.21
44.81 4.83 8.25
49.88 5.23 8.04
47.65 4.75 7.68
47.56 4.70 7.21
38.84 5.22 10.02
C
16
C
16
C
17
C
14
C
16
C
16
C
17
C
10
H
H
H
H
H
H
H
H
20NO
19FNO
20NO10
8
P
49.68 5.35 7.95
47.70 4.73 7.65
47.48 4.55 7.09
44.59 4.70 8.15
49.71 5.29 8.05
47.50 4.63 7.90
47.60 4.80 7.10
39.01 5.35 9.95
4.98 (1H, d, J 1.5 Hz, H ), 5.66 (1H, d, J 22.3 Hz, PCHN),
c
8
P
6
5
7
.43 (1H, dd, J 5.8, 1.5 Hz, CH]CH), 6.65 (1H, d, J
.8 Hz, CH]CH), 7.30–7.43 (3H, m, Ph), 7.47 (2H, d, J
.5 Hz, Ph), 12.18 (1H, br s, COOH); dC (100.6 MHz,
P
ad ¼4d
b
c
e
18NO
20NO
9
P
P
8
19FNO
20NO10
16NO
8
P
DMSO-d ) 44.74, 46.06, 49.61, 50.28 (d, J 155 Hz), 52.92
6
P
P
(d, J 6.8 Hz), 53.25 (d, J 6.8 Hz), 81.00, 88.06, 127.98,
8
1
1
28.27 (d, J 7.5 Hz), 128.58, 132.54 (d, J 4.0 Hz), 135.29,
36.67, 170.59 (d, J 5.5 Hz), 172.40; dP (202 MHz,
4.3. General procedure for the preparation of the ami-
nophosphonate precursors 3a–d, 4a–e
DMSO-d ) 26.92.
6
4
.4.2. Dimethyl 1-[3-aza-6-carboxy-10-oxa-exo-tricyclo-
1
,5
A solution of aldehyde (50 mmol) and amine (50 mmol) in
toluene (100 ml) over anhydrous Na SO was stirred at am-
[5.2.1.0 ]-4-oxodec-8-en-3-yl]-1-(4-fluorophenyl)-
methylphosphonate (5b). Yield 75%; pale solid; dr¼40:60.
Found C, 55.67; H, 4.70; P, 7.50. C H FNO P requires C,
2
4
bient temperature overnight. The mixture was filtered and
evaporated to give aldimines 1, 2 as an oil. Then dimethyl
phosphite was added to the prepared aldimine and the reac-
tion mixture was left for 24 h at room temperature. Upon
standing the neat reaction mixture was dissolved in 25 ml
acetone and a solution of oxalic acid dihydrate (12.6 g,
1
8
19
7
52.56; H, 4.66; P, 7.53%. nmax (KBr): 1740 (COO), 1700
(NCO), 1221 (P]O). Major diastereomer: dH (300 MHz,
DMSO-d ) 2.50 (1H, d, J 9.1 Hz, H ), 2.81 (1H, d, J
6
b
9.1 Hz, H ), 3.52 (3H, d, J 10.7 Hz, OCH ), 3.73 (3H, d, J
a
3
10.7 Hz, OCH ), 3.74 (1H, d, J 11.5 Hz, CH N), 4.15 (1H,
3
2
1
00 mmol) in acetone (50 ml) was added. The solution
d, J 11.5 Hz, CH N), 5.01 (1H, d, J 1.6 Hz, H ), 5.62 (1H,
2 c
was refrigerated and precipitated oxalate of the amino-
phosphonate was filtered off, washed with acetone and dried.
The product appears as colourless or pale solid.
d, J 21.4 Hz, PCHN), 6.41 (1H, dd, J 5.8, 1.6 Hz,
CH]CH), 6.51 (1H, d, J 5.8 Hz, CH]CH), 7.28 (2H, t, J
8.9 Hz, Ar), 7.59 (2H, dd, J 8.9, 5.7 Hz, Ar), 12.23 (1H, br
s, COOH); dC (100.6 MHz, DMSO-d ) 45.10, 46.31,
6
Yields, melting points, NMR spectra and CHP analyses are
reported in Tables 1 and 3.
49.94, 50.79 (d, J 159 Hz), 53.02 (d, J 7.0 Hz), 54.75 (d, J
7.0 Hz), 81.53, 88.39, 116.23 (d, J 21.5 Hz), 129.28 (t,
J 3.4 Hz), 132.14 (t, J 8.2 Hz), 135.85, 137.10, 162.46
4.4. General procedure for the tandem acylation/[4D2]-
cycloaddition reaction
(d, J 246 Hz), 170.91 (d, J 5.0 Hz), 173.27; d (202 MHz,
P
DMSO-d ) 25.94. Minor diastereomer: dH (300 MHz,
6
DMSO-d ) 2.53 (1H, d, J 9.1 Hz, H ), 2.94 (1H, dd, J 9.1,
6
b
To a stirred solution of the aminophosphonate oxalate
2.6 Hz, H ), 3.52 (1H, d, J 11.5 Hz, CH N), 3.65 (3H, d, J
a 2
(
(
10 mmol) in water (50 ml) was added anhydrous Na CO3
2
15 mmol). After evolution of CO had stopped, the reaction
2
10.7 Hz, OCH ), 3.74 (3H, d, J 10.7 Hz, OCH ), 4.18 (1H,
3 3
d, J 11.5 Hz, CH N), 4.98 (1H, d, J 1.6 Hz, H ), 5.66 (1H,
2 c
mixture was extracted with chloroform, dried over anhy-
drous Na SO and evaporated. The resulting colourless oil
was dissolved in toluene (20 ml) and maleic anhydride
d, J 22.0 Hz, PCHN), 6.43 (1H, dd, J 5.8, 1.5 Hz,
CH]CH), 6.65 (1H, d, J 5.8 Hz, CH]CH), 7.23 (2H, t, J
8.8 Hz, Ar), 7.50 (2H, dd, J 8.8, 5.5 Hz, Ar), 12.23 (1H, br
s, COOH); d (100.6 MHz, DMSO-d ) 45.13, 46.46, 49.95
(d, J 157 Hz), 50.00, 53.43 (d, J 7.0 Hz), 53.79 (d, J
7.0 Hz), 81.44, 88.54, 115.99 (d, J 21.5 Hz), 129.31 (t,
J 2.8 Hz), 130.89 (t, J 8.0 Hz), 135.77, 137.17, 162.17
2
4
(
3
10 mmol) was added. The reaction mixture was stirred for
ꢁ
C
6
days at 25 C. The crystalline product was collected by
filtration, washed with toluene and dried in air to give the
desired product as a colourless solid.
(d, J 246 Hz), 171.22 (d, J 5.5 Hz), 173.04; d (202 MHz,
DMSO-d ) 26.70.
P
4
[
.4.1. Dimethyl 1-[3-aza-6-carboxy-10-oxa-exo-tricyclo-
5.2.1.0 ]-4-oxodec-8-en-3-yl]-1-phenylmethylphospho-
6
1
,5
nate (5a). Yield 85%; white solid; dr¼40:60. Found C,
4.4.3. Dimethyl 1-[3-aza-6-carboxy-10-oxa-exo-tricyclo-
1
,5
5
5.02; H, 5.20; P, 7.68; C H NO P requires C, 54.97; H,
8
[5.2.1.0 ]-4-oxodec-8-en-3-yl]-1-piperonylmethyl-
phosphonate (5c). Yield 82%; pale solid; dr¼40:60. Found
C, 52.30; H, 4.71; P, 7.00. C H NO P requires C, 52.18; H,
1
20
7
5
.13; P, 7.87%. nmax (KBr) 1741 (COO), 1706, 1695
NCO), 1221 (P]O). Major diastereomer: dH (300 MHz,
(
DMSO-d ) 2.50 (1H, d, J 9.1 Hz, H ), 2.81 (1H, d, J
19
20
9
4.60; P, 7.08%. Major diastereomer: d (300 MHz, DMSO-
H
6
b
9
.1 Hz, H ), 3.50 (3H, d, J 10.5 Hz, OCH ), 3.73 (3H, d, J
a
d ) 2.49 (1H, d, J 9.2 Hz, H ), 2.80 (1H, d, J 9.2 Hz, H ), 3.52
6
3
b
a
1
d, J 11.7 Hz, CH N), 5.01 (1H, d, J 1.5 Hz, H ), 5.60 (1H,
0.5 Hz, OCH ), 3.74 (1H, d, J 11.7 Hz, CH N), 4.18 (1H,
(3H, d, J 10.7 Hz, OCH ), 3.71 (3H, d, J 10.7 Hz, OCH ),
3 3
3.76 (1H, d, J 11.4 Hz, CH N), 4.14 (1H, d, J 11.4 Hz,
2
3
2
2
c
d, J 21.0 Hz, PCHN), 6.41 (1H, dd, J 5.7, 1.5 Hz,
CH]CH), 6.51 (1H, d, J 5.7 Hz, CH]CH), 7.33–7.46
CH N), 5.01 (1H, d, J 1.5 Hz, H ), 5.52 (1H, d, J 21.5 Hz,
2
PCHN), 6.06 (2H, s, OCH O), 6.41 (1H, dd, J 5.6,
2
c
(
3H, m, Ph), 7.54 (2H, d, J 7.5 Hz, Ph), 12.18 (1H, br s,
COOH); d (100.6 MHz, DMSO-d ) 44.74, 46.01, 49.51,
1.5 Hz, CH]CH), 6.52 (1H, d, J 5.6 Hz, CH]CH), 6.89–
7.10 (3H, m, Ar), 12.25 (1H, br s, COOH); dC
(100.6 MHz, DMSO-d ) 45.09, 46.32, 49.99, 51.19 (d, J
160 Hz), 53.00 (d, J 6.8 Hz), 54.70 (d, J 6.8 Hz), 81.53,
88.37, 101.65, 108.68, 110.00 (d, J 8.5 Hz), 122.58 (d,
J 7.7 Hz), 126.37 (d, J 3.7 Hz), 135.88, 137.05, 147.85,
C
6
5
1.23 (d, J 158 Hz), 52.55 (d, J 6.8 Hz), 54.18 (d,
J 6.8 Hz), 81.09, 87.95, 128.44, 128.83, 129.37 (d, J
.0 Hz), 132.52 (d, J 3.5 Hz), 135.37, 136.57, 170.34 (d,
J 5.0 Hz), 172.63; d (202 MHz, DMSO-d ) 26.12. Minor
6
8
P
6

G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
12581
1
47.88, 170.83 (d, J 5.5 Hz), 173.30; d (202 MHz, DMSO-
P
89.03 (d, J 6.6 Hz), 107.92, 111.00, 134.32, 137.90,
142.92, 149.45 (d, J 1.2 Hz), 171.12 (d, J 1.8 Hz), 172.89;
d (202 MHz, DMSO-d ) 25.55. Minor diastereomer: d
P
d6) 26.09. Minor diastereomer: dH (300 MHz, DMSO-d6)
.52 (1H, d, J 9.2 Hz, H ), 2.93 (1H, dd, J 9.2, 2.5 Hz,
H ), 3.52 (1H, d, J 11.5 Hz, CH N), 3.64 (3H, d, J
2
b
P
6
(202 MHz, DMSO-d ) 25.12.
6
a
2
1
d, J 11.5 Hz, CH N), 4.97 (1H, d, J 1.5 Hz, H ), 5.56 (1H,
d, J 22.2 Hz, PCHN), 6.03 (2H, d, J 1.8 Hz, OCH O), 6.43
2
0.7 Hz, OCH ), 3.73 (3H, d, J 10.7 Hz, OCH ), 4.16 (1H,
3 3
4.4.5. Dimethyl N-benzyl-3-aza-6-carboxy-10-oxa-exo-
2
c
1
,5
tricyclo[5.2.1.0 ]-4-oxodec-8-en-2-yl-endo-phosphonate
(6a). Yield 81%; dr¼97:3. Found C, 54.56; H, 5.20; P, 7.84.
C H NO P requires C, 54.97; H, 5.13; P, 7.87%. n
max
(
1H, dd, J 5.6, 1.5 Hz, CH]CH), 6.64 (1H, d, J 5.6 Hz,
CH]CH), 6.89–7.10 (3H, m, Ar), 12.25 (1H, br s,
COOH); d (100.6 MHz, DMSO-d ) 45.09, 46.32, 50.08,
1
8
20
7
(KBr): 1725 (COO), 1700 (NCO), 1224 (P]O). Major dia-
stereomer: white solid; mp 206–207 C (MeOH); dH
C
6
ꢁ
5
6
1
1
0.26 (d, J 158 Hz), 53.38 (d, J 6.8 Hz), 53.70 (d, J
.8 Hz), 81.42, 88.51, 101.78, 108.98, 109.21 (d, J 8.5 Hz),
23.83 (d, J 9.0 Hz), 126.33 (d, J 3.7 Hz), 135.77, 137.17,
(300 MHz, DMSO-d ) 2.61 (1H, d, J 9.1 Hz, H ), 2.94
6
b
(1H, d, J 9.1 Hz, H ), 3.77 (3H, d, J 10.6 Hz, OCH ), 3.78
a
3
47.52, 147.90, 171.06 (d, J 5.5 Hz), 173.07; d (202 MHz,
P
(3H, d, J 10.6 Hz, OCH ), 3.98 (1H, d, J 5.7 Hz, PCHN),
3
DMSO-d ) 26.87.
6
4.21 (1H, d, J 16.2 Hz, CH N), 5.02 (1H, d, J 16.2 Hz,
2
CH N), 5.07 (1H, br s, H ), 6.51 (1H, dd, J 5.7, 1.6 Hz,
2
c
4
.4.4. Dimethyl 1-[3-aza-6-carboxy-10-oxa-exo-tricyclo-
5.2.1.0 ]-4-oxodec-8-en-3-yl]-1-(2-furyl)methyl-
CH]CH), 6.58 (1H, d, J 5.7 Hz, CH]CH), 7.21–7.35
(5H, m, Ph), 12.28 (1H, br s, COOH); dC (100.6 MHz,
DMSO-d ) 45.21, 45.64, 50.24, 53.90 (d, J 7.0 Hz), 54.11
1
,5
[
phosphonate (5d) and dimethyl N-((2-furyl)methyl)-3-
aza-6-carboxy-10-oxa-exo-tricyclo[5.2.1.0 ]-4-oxodec-
8
8
C, 50.29; H, 4.83; P, 8.03. C H NO P requires C, 50.14;
H, 4.73; P, 8.08%.
6
1
,5
(d, J 7.0 Hz), 54.73 (d, J 147 Hz), 81.26, 89.30 (d, J
6.0 Hz), 127.85, 127.98, 129.07, 134.87, 136.21, 137.99,
171.74, 173.30; d (202 MHz, DMSO-d ) 25.59. Minor dia-
-en-2-yl-endo-phosphonate (6d). Yellow solid; yield
0%—mixture of four diastereomers; 5d/6d¼55:45. Found
P
6
stereomer: d (202 MHz, DMSO-d ) 25.16.
P 6
1
6
18
8
4
.4.6. Dimethyl N-(4-fluorophenylmethyl)-3-aza-6-carb-
1
,5
Compound 5d: dr¼33:66. Major diastereomer: dH
oxy-10-oxa-exo-tricyclo[5.2.1.0 ]-4-oxodec-8-en-2-yl-
endo-phosphonate (6b). Yield 89%; dr¼98:2. Found C,
52.58; H, 4.63; P, 7.45. C H FNO P requires C, 52.56;
(
300 MHz, DMSO-d ) 2.51 (1H, d, J 9.3 Hz, H ), 2.86
6 b
(
1H, d, J 9.3 Hz, H ), 3.57 (3H, d, J 10.8 Hz, OCH ), 3.66
a 3
18 19
7
(
1H, d, J 11.5 Hz, CH N), 3.72 (3H, d, J 10.8 Hz, OCH ),
2
H, 4.66; P, 7.53%. Major diastereomer: white solid; mp
ꢁ
3
4
5
1
5
.10 (1H, d, J 11.5 Hz, CH N), 5.01 (1H, d, J 1.5 Hz, H ),
2
169–170 C (i-PrOH); d (300 MHz, DMSO-d ) 2.61 (1H,
H
c
6
.67 (1H, d, J 22.2 Hz, PCHN), 6.43 (1H, dd, J 5.6,
.6 Hz, CH]CH), 6.53 (2H, br s, Furyl), 6.54 (1H, d, J
.6 Hz, CH]CH), 7.75 (1H, d, J 1.1 Hz, Furyl), 12.27
d, J 9.1 Hz, H ), 2.93 (1H, d, J 9.1 Hz, H ), 3.77 (3H, d, J
b a
10.7 Hz, OCH ), 3.78 (3H, d, J 10.7 Hz, OCH ), 4.03 (1H,
3
3
d, J 5.7 Hz, PCHN), 4.22 (1H, d, J 16.0 Hz, CH N), 4.97
2
(
1H, br s, COOH); dC (100.6 MHz, DMSO-d ) 45.10,
6
(1H, d, J 16.0 Hz, CH N), 5.06 (1H, br s, H ), 6.51 (1H,
2
c
4
5
2
1
5.77 (d, J 160 Hz), 46.55, 49.95, 53.43 (d, J 6.8 Hz),
4.78 (d, J 6.8 Hz), 81.52, 88.38, 111.30 (d,
.0 Hz), 111.47 (d, J 4.2 Hz), 135.83, 137.14, 144.29 (d, J
.5 Hz), 146.07 (d, J 8.0 Hz), 170.78 (d, J 4.2 Hz), 173.23;
dd, J 5.7, 1.5 Hz, CH]CH), 6.59 (1H, d, J 5.7 Hz,
CH]CH), 7.12 (2H, t, J 8.8 Hz, Ar), 7.30 (2H, dd, J 8.8,
5.7 Hz, Ar), 12.30 (1H, br s, COOH); dC (100.6 MHz,
J
DMSO-d ) 44.33, 45.32, 49.97, 53.69 (d, J 6.3 Hz), 53.82
6
d (202 MHz, DMSO-d ) 23.67. Minor diastereomer: d
H
(d, J 6.3 Hz), 54.40 (d, J 159 Hz), 80.99, 89.04 (d, J
7.1 Hz), 115.49 (d, J 21.2 Hz), 129.66 (d, J 8.2 Hz),
132.15 (d, J 2.1 Hz), 134.58, 137.68, 161.81 (d, J 241 Hz),
171.52 (d, J 1.0 Hz), 173.09; dP (202 MHz, DMSO-d6)
25.58. Minor diastereomer: d (202 MHz, DMSO-d ) 25.14.
P
6
(
300 MHz, DMSO-d ) 2.52 (1H, d, J 9.2 Hz, H ), 2.91
6 b
(
1H, dd, J 9.2, 2.6 Hz, H ), 3.59 (1H, d, J 11.5 Hz, CH N),
a 2
3
OCH ), 4.21 (1H, d, J 11.5 Hz, CH N), 4.95 (1H, d, J
.64 (3H, d, J 10.8 Hz, OCH ), 3.74 (3H, d, J 10.8 Hz,
3
3
2
P
6
1
.5 Hz, H ), 5.69 (1H, d, J 22.2 Hz, PCHN), 6.44 (1H, dd,
c
J 5.6, 1.6 Hz, CH]CH), 6.64 (1H, d, J 5.6 Hz, CH]CH),
.67 (2H, m, Furyl), 7.72 (1H, br s, Furyl), 12.27 (1H, br
s, COOH); d (100.6 MHz, DMSO-d ) 45.17, 45.68 (d, J
4.4.7. Dimethyl N-(piperonylmethyl)-3-aza-6-carboxy-
1
,5
6
10-oxa-exo-tricyclo[5.2.1.0 ]-4-oxodec-8-en-2-yl-endo-
phosphonate (6c). Yield 91%; dr¼98:2. Found C, 52.20; H,
4.57; P, 7.11. C H NO P requires C, 52.18; H, 4.60; P,
C
6
1
60 Hz), 46.57, 49.92, 53.70 (d, J 6.8 Hz), 53.88 (d,
J 6.8 Hz), 81.42, 88.45, 111.23 (d, J 5.1 Hz), 111.27 (d, J
.0 Hz), 135.61, 137.36, 144.24 (d, J 1.5 Hz), 145.97 (d,
1
9
20
9
ꢁ
7.08%. Major diastereomer: white solid; mp 189–190 C
(CH CN); d (300 MHz, DMSO-d ) 2.60 (1H, d, J 9.3 Hz,
2
3
H
6
J 5.3 Hz), 170.65 (d, J 4.2 Hz), 172.96; dP (202 MHz,
DMSO-d ) 24.44.
H ), 2.92 (1H, d, J 9.3 Hz, H ), 3.78 (6H, d, J 10.7 Hz,
b a
OCH ), 3.95 (1H, d, J 5.7 Hz, PCHN), 4.08 (1H, d, J
3
6
15.7 Hz, CH N), 4.95 (1H, d, J 15.7 Hz, CH N), 5.06 (1H,
2 2
Compound 6d: dr¼91:9. Major diastereomer: d (300 MHz,
br s, H ), 5.98 (2H, d, J 2.6 Hz, OCH O), 6.51 (1H, dd, J
c 2
H
DMSO-d ) 2.59 (d, J 9.1 Hz, 1H, H ), 2.91 (1H, d, J 9.1 Hz,
6
5.7, 1.5 Hz, CH]CH), 6.59 (1H, d, J 5.7 Hz, CH]CH),
6.72 (1H, d, J 8.0 Hz, Ar), 6.77 (1H, s, Ar), 6.84 (1H, d, J
8.0 Hz, Ar), 12.31 (1H, br s, COOH); dC (100.6 MHz,
b
H ), 3.80 (6H, d, J 10.8 Hz, OCH ), 4.16 (1H, d, J 5.3 Hz,
a
3
PCHN), 4.26 (1H, d, J 16.1 Hz, CH N), 4.90 (1H, d, J
2
1
Furyl), 6.40 (1H, dd, J 3.0, 1.4 Hz, Furyl), 6.51 (1H, dd, J
6.1 Hz, CH N), 5.03 (1H, br s, H ), 6.30 (1H, d, J 3.0 Hz,
DMSO-d ) 44.60, 45.28, 50.06, 53.69 (d, J 6.7 Hz), 53.83
6
2
c
(d, J 6.7 Hz), 54.03 (d, J 160 Hz), 80.97, 88.95 (d, J
6.6 Hz), 101.25, 108.14, 108.38, 121.25, 129.52, 134.58,
137.68, 146.85, 147.92, 171.41 (d, J 1.3 Hz), 173.11; dP
(202 MHz, DMSO-d ) 25.60. Minor diastereomer: d
5
7
.7, 1.6 Hz, CH]CH), 6.58 (1H, d, J 5.7 Hz, CH]CH),
.58 (1H, d, J 1.4 Hz, Furyl), 12.27 (1H, br s, COOH); dC
(
100.6 MHz, DMSO-d ) 45.44, 46.53, 49.61, 53.75 (d, J
6
6
P
6
.8 Hz), 53.83 (d, J 6.8 Hz), 54.74 (d, J 161 Hz), 80.90,
(202 MHz, DMSO-d ) 25.26.
6

12582
G. O. Kachkovskyi, O. I. Kolodiazhnyi / Tetrahedron 63 (2007) 12576–12582
4
.4.8. Dimethyl N-methyl-3-aza-6-carboxy-10-oxa-exo-
and Aminophosphinic Acids. Chemistry and Biological Activity;
Kukhar, V. P., Hudson, H. R., Eds.; John Wiley: New York, NY,
2000; pp 1–32; (b) Pratt, R. F. Science 1989, 246, 917–919; (c)
Mikolajczyk, M.; Drabowicz, J.; Lyzwa, P. Asymmetric Synthe-
sis of Phosphonic Analogs of b-Amino Acids. In Enantioselec-
tive Synthesis of Beta-Amino Acids; Juaristi, E., Soloshonok,
V. A., Eds.; John Wiley: New York, NY, 2005; pp 261–277.
2. (a) Kolodiazhnyi, O. I. Tetrahedron: Asymmetry 2005, 16,
3295–3340; (b) Kolodiazhnyi, O. I. Russ. Chem. Rev. 2006,
75, 227–253; (c) Migianu, E.; Even, P.; Monteil, P.; Lecouvey,
M. The 16th International Conference on Phosphorus
Chemistry (Abstract of Reports), Birmingham, 2004; p 173.
3. (a) Beers, S. A.; Schwender, C. F.; Loughney, D. A.; Malloy, E.;
Demarest, K.; Jordan, J. Bioorg. Med. Chem. 1996, 4, 1693–
1701; (b) Kaplan, A. P.; Barlett, P. A. Biochemistry 1991, 30,
8165–8170; (c) Kafarski, P.; Lejczak, B. Curr. Med. Chem.
Anti-Cancer Agents 2001, 1, 301–312.
1
,5
tricyclo[5.2.1.0 ]-4-oxodec-8-en-2-yl-endo-phosphonate
6e). Yield 68%; dr¼89:11. Found C, 45.40; H, 5.11; P, 9.81.
C H NO P requires C, 45.43; H, 5.08; P, 9.76%. Major dia-
(
1
2
16
7
ꢁ
stereomer: white solid; mp 189–190 C (i-PrOH); dH
300 MHz, DMSO-d ) 2.52 (1H, d, J 9.5 Hz, H ), 2.78 (1H,
d, J 9.5 Hz, H ), 2.85 (3H, s, NCH ), 3.78 (3H, d, J
(
6
b
a
3
1
d, J 5.7 Hz, PCHN), 4.99 (1H, br s, H ), 6.50 (1H, dd, J 5.8,
0.7 Hz, OCH ), 3.79 (3H, d, J 10.7 Hz, OCH ), 4.44 (1H,
3 3
c
1
(
.7 Hz, CH]CH), 6.58 (1H, d, J 5.8 Hz, CH]CH), 12.20
1H, br s, COOH); dC (100.6 MHz, DMSO-d ) 29.69,
6
4
(
4.85, 49.06, 53.07 (d, J 7.0 Hz), 53.18 (d, J 7.0 Hz), 56.67
d, J 159 Hz), 80.48, 88.71 (d, J 6.8 Hz), 133.97, 137.17,
1
2
70.48 (d, J 1.6 Hz), 172.40; dP (202 MHz, DMSO-d6)
6.09. Minor diastereomer: d (300 MHz, DMSO-d ) 2.50
H
6
(1H, d, J 9.0 Hz, H ), 2.75 (1H, d, J 9.0 Hz, H ), 2.80 (3H,
b a
s, NCH ), 3.67 (3H, d, J 10.9 Hz, OCH ), 3.69 (3H, d, J
3
3
1
d, J 1.6 Hz, H ), 6.42 (1H, dd, J 5.7, 1.6 Hz, CH]CH),
0.9 Hz, OCH ), 4.69 (1H, d, J 8.1 Hz, PCHN), 5.05 (1H,
4. (a) Mikolajczyk, M. J. Organomet. Chem. 2005, 690, 2488–
2496; (b) Meyer, F.; Laaziri, A.; Papini, A. M.; Uziel, J.;
Juge, S. Tetrahedron 2004, 60, 3593–3597.
5. (a) Firestone, R. A.; Maciejewicz, N. S.; Ratcliffe, R. W.;
Christensen, B. G. J. Org. Chem. 1974, 39, 437; (b) Cama,
L. D.; Christensen, B. G. J. Am. Chem. Soc. 1974, 96, 7582–7584.
6. (a) Paulvannan, K.; Jacobs, J. W. Tetrahedron 1999, 55, 7433–
3
c
6
dC (100.6 MHz, DMSO-d ) 28.96, 44.47, 49.92 (d, J
.56 (1H, d, J 5.7 Hz, CH]CH), 12.20 (1H, br s, COOH);
6
6
1
.5 Hz), 52.59 (d, J 6.5 Hz), 52.89 (d, J 6.5 Hz), 55.67 (d, J
60 Hz), 81.45, 88.35 (d, J 8.1 Hz), 135.15, 135.64, 170.91
(
d, J 8.3 Hz), 172.35; d (202 MHz, DMSO-d ) 25.59.
P 6
7
440; (b) Zubkov, F. I.; Nikitina, E. V.; Varlamov, A. V. Russ.
4
4
.5. Synthesis of epoxyisoindolyl phosphonate 5e
Chem. Rev. 2005, 74, 639–669; (c) Bolotukhina, E. V.;
Zubkov, F. I.; Nikitina, E. V.; Varlamov, A. V. Synthesis
2005, 1859–1875; (d) Kouznetsov, V. V.; Cruz, U. M.;
Zubkov, F. I.; Nikitina, E. V. Synthesis 2007, 375–384; (e)
Zylber, J.; Tubul, A.; Brun, P. Tetrahedron: Asymmetry 1995,
6, 377–380.
.5.1. Dimethyl 3-aza-6-carboxy-10-oxa-exo-tricyclo-
1
,5
[
5.2.1.0 ]-4-oxodec-8-en-3-yl-methylphosphonate (5e).
Mixture of furfurylamine (1.94 g, 20 mmol), dimethyl phos-
phite (2.20 g, 20 mmol) and paraformaldehyde (0.90 g,
3
0 mmol) in benzene (25 ml) was refluxed in Dean–Stark
7. (a) Bolotukhina, E. V.; Zubkov, F. I.; Varlamov, A. V. Chem.
Heterocycl. Comp. 2006, 963–994; (b) Bolotukhina, E. V.;
Zubkov, F. I.; Varlamov, A. V. Chem. Heterocycl. Comp.
2006, 1123–1157.
apparatus for 5 h. The reaction mixture was filtered off and
maleic anhydride (1.96 g, 20 mmol) was added to the filtrate.
The resulting solution was stirred at 25 C for 3 days. The
ꢁ
layer of dark oil was collected and dissolved in methanol.
The product was crystallized from the refrigerated solution
to give 1.83 g (29%) of pale solid; mp 175–176 C. Found
8. (a) Valencia, E.; Weiss, I.; Firdous, S.; Freyer, A. J.; Shamma,
M. Tetrahedron 1984, 40, 3957–3962; (b) Sarang, P. S.; Yavad,
A. A.; Patil, P. S.; Krishna, U. M.; Trivedi, G. K.; Salunkhe,
M. M. Synthesis 2007, 1091–1095.
ꢁ
C, 45.38; H, 5.01; P, 9.67. C H NO P requires C, 45.43;
1
2
16
7
H, 5.08; P, 9.76%. d (300 MHz, DMSO-d ) 2.48 (1H, d, J
H
9. Kachkovskiy, G. A.; Andrushko, N. V.; Sheiko, S. Yu.;
Kolodiazhnyi, O. I. Russ. J. Gen. Chem. 2005, 75, 1735–1743.
10. (a) Kabachnik, M. I.; Medved’, T. Ya. Dokl. Akad. Nauk SSSR
1952, 689; Chem. Abstr. 1953, 47, 2724b; (b) Cherkasov, R. A.;
Galkin, V. I. Russ. Chem. Rev. 1998, 67, 857–882.
11. Boduszek, B. Phosphorus, Sulfur Silicon Relat. Elem. 1995,
104, 63–70.
6
9
J 10.8 Hz, OCH ), 3.66 (3H, d, J 10.8 Hz, OCH ), 3.71
.3 Hz, H ), 2.81 (1H, dd, J 9.3, 2.7 Hz, H ), 3.660 (3H, d,
b a
3
3
(
CCH N), 3.83 (1H, dd, J 16.6, 11.1 Hz, NCH P), 4.11
1H, dd, J 16.6, 11.1 Hz, NCH P), 3.77 (1H, d, J 11.8 Hz,
2
2
2
(
1H, d, J 11.8 Hz, CCH N), 4.98 (1H, d, J 1.6 Hz, H ),
2 c
6
.43 (1H, dd, J 5.8, 1.6 Hz, CH]CH), 6.61 (1H, d,
J 5.8 Hz, CH]CH), 12.20 (1H, br s, COOH); dC
100.6 MHz, DMSO-d ) 36.99 (d, J 152 Hz), 44.53, 48.80,
12. H €a gele, G. Physical Properties and NMR-Spectroscopic Charac-
terization of Aminophosphonates and Aminophosphinates. In
Aminophosphonic and Aminophosphinic Acids. Chemistry and
Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; John
Wiley: New York, NY, 2000; pp 217–285.
(
6
4
8
9.42, 52.57 (d, J 6.2 Hz), 52.74 (d, J 6.2 Hz), 81.04,
8.25, 135.31, 136.68, 170.24 (d, J 3.2 Hz), 172.57; dP
(
202 MHz, DMSO-d ) 28.37.
6
1
3. (a) Nelson, J. H. Coord. Chem. Rev. 1995, 139, 245–280; (b)
Griffiths, D. V.; Griffiths, P. A. NMR Data of Four
Coordinated Phosphorus Compounds. In CRC Handbook of
Phosphorus-31 Nuclear Magnetic Resonance Data; Tebby,
J. C., Ed.; CRC: Boston, MA, 1991; pp 477–495; (c)
Phosphorus-31 NMR Spectroscopy in Stereochemical
Analysis (Methods in Stereochemical Analysis); Verkade,
J. G., Quin, L. D., Eds.; John Wiley: New York, NY, 1994.
Acknowledgements
We thank Dr. A. N. Chernega for performing X-ray analysis
and O. B. Ryabitskiy for PH COSY measurement.
References and notes
14. (a) Kraicheva, I.; Liogonkii, B. I.; Stefanova, R.; Borisov, G.
Phosphorus Sulfur Relat. Elem. 1988, 40, 145–148; (b)
Kraicheva, I.; Stefanova, R.; Borisov, G. Phosphorus, Sulfur
Silicon Relat. Elem. 1993, 79, 107–111.
1
. (a) Mastalerz, P.; Kafarski, P. Naturally Occurring Amino-
phosphonic and Aminophosphinic Acids. In Aminophosphonic