Diastereoselective synthesis of novel 5-substituted morpholine-3-phosphonic acids: Further exploitation of N-acyliminium intermediates

Article abstract of DOI:10.1016/j.tetasy.2014.02.014

The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported. The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substituted morpholin-3-ones. The procedure is based

Full text of DOI:10.1016/j.tetasy.2014.02.014

Tetrahedron: Asymmetry 25 (2014) 485–487
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of novel 5-substituted
morpholine-3-phosphonic acids: further exploitation
of N-acyliminium intermediates
⇑
Israel Bonilla-Landa, José Luis Viveros-Ceballos, Mario Ordóñez
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Accepted 27 February 2014
The first diastereoselective total synthesis of 5-substituted morpholine-3-phosphonic acids is reported.
The principal feature of the synthesis is the introduction of a dimethyl phosphonate group into 5-substi-
tuted morpholin-3-ones. The procedure is based on the preparation of N-Boc-(S)-5-phenyl- and N-Boc-
(S)-5-benzylmorpholin-3-one from L-phenylglycine and L-phenylalanine methyl esters, followed by the
formation of the 3-methoxylated compounds and subsequent reaction with trimethyl phosphite in the
presence of BF3ꢀOEt2. Diastereoselectivity in the formation of cis-disubstituted products is in agreement
with the nucleophilic addition to other methoxylated derivatives.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
described in the literature,18 despite the great importance that
these compounds could have in medicinal and organic synthesis,
Over the last few years, the synthesis and the incorporation of
cyclic amino acids, where the nitrogen atom of the amino func-
tional group is part of a ring, has led to a better understanding of
the bioactive conformation of peptidomimetic molecules, due to
the inability of the nitrogen atom to act as a hydrogen bond donor,
unless it is located at the N-terminal position of the molecule, and
to the conformational strain imparted by the cyclic structure.1 Also,
the cis/trans isomerism of the tertiary amide bond formed by cyclic
amino acids is responsible for the modulation of conformational
preferences.2 In particular, morpholine-3-carboxylic acid (Mor) 1,
as a proline surrogate, that has been used as a key intermediate
in the synthesis of several compounds with medical purposes, such
as Alzheimer’s disease,3 neurotrophic agents,4 modulators of cell
growth,5 TORC1/2 inhibitors,6 as imaging probes for diagnostic in
melanoma growth,7 b-lactamase inhibitors,8 T-type Ca2+ channel
blockers,9 TACE inhibitors,10 potent VLA-4 antagonists,11 as ligands
such as that shown by the a-aminophosphonic acids and their
derivatives,19,20 hence there is great importance in the develop-
ment of new methods for the preparation of these compounds.21
O
O
OH
N
H
N
H
P(OH)2
O
O
2
1
O
N
R
P(OH)2
O
H
3a
; R = Ph
3b; R = Bn
for avb3/a
vb5 integrins,12 ICE inhibitors,13 and MMP and TNF inhib-
Considering the high value of these non-coded compounds in
connection with our current research interest in the synthesis of
itors.14 Furthermore, Mor 1 has also been used in organic synthesis
as a precursor in the preparation of more complex compounds15
and as catalysts.16 Due to the relevant utility exhibited by 1 and
its derivatives, much effort has been dedicated to the preparation
of these compounds.17 However, to the best of our knowledge,
the synthesis of its analogue morpholine-3-phosphonic acid (MorP)
2 in enantio- or diastereoisomerically pure form has not yet been
novel conformationally restricted
a
-aminophosphonic acids,22 we
herein report the first stereoselective synthesis of (3R,5S)-5-phenyl-
and (3R,5S)-5-benzylmorpholine-3-phosphonic acids 3a and 3b.
2. Results and discussion
The synthesis of the target chiral 5-substituted morpholine-3-
phosphonic acids 3a,b began with the preparation of Boc-protected
morpholin-3-ones 7a,b from readily available a-amino acid methyl
⇑
Corresponding author. Tel./fax: +52 7773297997.
E-mail address: palacios@uaem.mx (M. Ordóñez).
http://dx.doi.org/10.1016/j.tetasy.2014.02.014
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

486
I. Bonilla-Landa et al. / Tetrahedron: Asymmetry 25 (2014) 485–487
O
O
esters as shown in Scheme 1. In the first step, L-phenylgycine and
DIBAL-H, THF
-10 to -78 ºC
L-phenylalanine methyl esters hydrochlorides were reacted with
N
chloroacetyl chloride and K2CO3 in a dichloromethane/water mix-
ture at 0 °C, to give the corresponding chloroacetamides (S)-4a,b
in 74% and 81% yields.23 Next, the methyl esters 4a,b were reduced
with NaBH4 in a methanol/dichloromethane mixture at 0 °C to
afford the N-chloroacetamido alcohols 5a,b in 79% and 87% yields,24
which upon treatment with potassium tert-butoxide in isopropyl
alcohol at 0 °C,25 provided the (S)-5-phenylmorpholin-3-one 6a
and (S)-5-benzylmorpholin-3-one 6b in 76% and 78% yields, respec-
tively.26 The resulting morpholin-3-ones 6a,b were transformed
into tert-butylcarbamates 7a,b in excellent yield by reaction with
N
O
R
OR'
R
Boc
Boc
7a
7b
; R = Ph
; R = Bn
8
; R = H
MeOH
PPTS
9; R = Me
BF3·OEt2, CH2Cl2
-10 to -78 ºC
O
O
P(OMe)3
+
N
R
P(OMe)2
O
N
R
(Boc)2O and
a catalytic amount of 4-dimethylaminopyridine
(DMAP) in THF at room temperature (Scheme 1).27
Boc
Boc
11a
11b
10
; R = Ph, 56%, 76:24 dr
O
; R = Bn, 65%, >98:2 dr
MeO
R
MeO
R
O
O
N
Cl
O
Cl
Cl
HCO2H, r.t.
O
K2CO3, 0 o
C
NH2.HCl
CH2Cl2-H2O
H
O
4a
; R = Ph, 74%
+
4b; R = Bn, 81%
N
H
R
P(OMe)2
N
H
R
P(OMe)2
NaBH4, 0 o
C
O
O
MeOH-CH2Cl2
(3R,5S)-12a; R = Ph, 44%
12b
(3S,5S)-13a; R = Ph, 27%
(3R,5S)-
; R = Bn, 98%
HO
R
O
Cl
t-BuOK
Scheme 2.
i-PrOH, 0 °C
N
H
O
N
H
O
R
nucleophilic addition of diethyl phosphite to 2-methoxylated
proline29a and the allylation of a 3-methoxylated morpholine-3-
carboxylic acid derivative.32
6a
6b
5a
; R = Ph, 76%
; R = Ph, 79%
5b; R = Bn, 87%
; R = Bn, 78%
The stereochemistry assignment in the diastereoisomers
(3R,5S)-12a and (3R,5S)-12b was assigned based on the 2D NOESY
experiments. The key nOe signals are the cross-peaks between H-3
and H-5 and the axial correlation exhibited by H-2 and H-6. The
nOe effect was not observed for the diastereoisomer (3S,5S)-13a.
Additionally, H-3 for (3R,5S)-12a appears at 3.53 ppm as a ddd sig-
nal (JH/P = 10.8 Hz, Janti = 10.8 Hz, and Jgauche = 2.8 Hz), and the H-3
for (3R,5S)-12b appears in 3.27 also as a ddd signal (JH/P = 11.8,
Janti = 10.8, and Jgauche = 3.0 Hz), (Fig. 1).
(Boc)2O, DMAP
THF, r.t.
O
N
O
R
Boc
7a
; R = Ph, 100%
7b; R = Bn, 98%
nOe
nOe
H
H
Scheme 1.
H
H
2
2
6
6
O
O
To further expand upon the synthetic potential of N-acyliminium
ions 1028 obtained from methoxylated derivatives of type 9 in the
P
Bn
Ph
P
3
3
N
N
5
5
H
H
synthesis of cyclic a
-aminophosphonates,22,29 the tert-butylcarba-
H
H
H
H
mate 7a was reduced with diisobutylaluminium hydride (DIBAL-
H) at ꢁ10 to ꢁ78 °C to obtain the corresponding hemiaminal 8,
which was not isolated but treated immediately with methanol
and a catalytic amount of pyridinium p-toluenesulfonate (PPTS),
to obtain the methoxyaminal 9. Subsequent treatment of 9 with
trimethyl phosphite and boron trifluoride–diethyl ether at ꢁ78 °C,
nOe
(3R,5S)-12b
nOe
(3R,5S)-12a
Figure 1. Relative stereochemistry assignment of phosphonates 12a and 12b.
Finally, hydrolysis of (3R,5S)-12a and (3R,5S)-12b with hydro-
gen bromide (33% solution in acetic acid) followed by treatment
with propylene oxide in methanol afforded 5-phenyl morpho-
line-3-phosphonic acid (3R,5S)-3a in 98% yield and 5-benzyl mor-
pholine-3-phosphonic acid (3R,5S)-3b in 96% yield (Scheme 3).33
gave the (3R,5S)- and (3S,5S)-cyclic
a-aminophosphonates 11a
in 56% yield and a 76:24 diastereoisomeric ratio, through the
N-acyliminium ion intermediate 10. Selective N-Boc bond cleavage
in 11a with formic acid gave, after chromatographic separation the
cyclic a-aminophosphonates (3R,5S)-12a (more polar diastereoiso-
mer) and (3S,5S)-13a (less polar diastereoisomer) in 44% and
O
O
27% yields, respectively.30 In a similar manner, 7b gave the
1. HBr/AcOH, r.t.
2.
a
-aminophosphonate (3R,5S)-11b in 65% yield and with >98:2
diastereoisomeric ratio, which upon treatment with formic acid
afforded the -aminophosphonate (3R,5S)-12b in quantitative yield
(Scheme 2).31
N
H
N
R
P(OH)2
O
R
P(OMe)2
O
, MeOH
O
Boc
a
12a
12b
(3R,5S)-3a; R = Ph, 98 %
(3R,5S)-3b; R = Bn, 96%
(3R,5S)-
(3R,5S)-
; R = Ph
; R = Bn
The diastereoselectivity in the nucleophilic addition of dimethyl
phosphite to N-acylaminium cation 10 is in agreement with the
Scheme 3.

I. Bonilla-Landa et al. / Tetrahedron: Asymmetry 25 (2014) 485–487
487
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3. Conclusion
In conclusion, we have demonstrated the utility of this method-
ology in the diastereoselective nucleophilic addition of trimethyl
phosphite to 3-methoxylated (5S)-5-phenyl- and (5S)-5-ben-
zylmorpholine via the intermediacy of N-acyliminium cation 10,
which allows the construction of cyclic
a-aminophosphonates
from -amino acids. The N-Boc cleavage and hydrolysis of the
L
dimethyl phosphonate moiety produced, for the first time, the syn-
thesis of (3R,5S)-5-phenyl- and (3R,5S)-5-benzylmorpholine-3-
phosphonic acids 3a,b. Additionally, we anticipate that the use of
N-acyliminium cations as templates could be extremely important
in the synthesis of large libraries of cyclic
acids with significant potential in pharmacology and organic syn-
a-aminophosphonic
thesis areas.
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Acknowledgments
The authors thank CONACYT of México for financial support via
project 181816. We also thank V. Labastida-Galván for the deter-
mination of mass spectra. I.B.L. and J.L.V.C. also thank the CONACYT
for Graduate Scholarships.
ˇ
ˇ
27. Hlavácek, J.; Marík, J.; Konvalinka, J.; Bennettová, B.; Tykva, R. Amino Acids
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30. (3R,5S)-12a. ½a D
ꢂ
¼ þ60:0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d 2.30 (br s,
1H, NH), 3.32 (dd, J = 10.7, 10.7 Hz, 1H, H-6), 3.53 (ddd, J = 10.7, 10.7, 2.8 Hz,
1H, H-3), 3.63 (ddd, J = 10.8, 10.7, 3.1 Hz, 1H, H-2), 3.79–3.83 (m, 1H, H-6), 3.81
(d, J = 10.7 Hz, 3H, OCH3), 3.89 (d, J = 10.5 Hz, 3H, OCH3), 3.89–3.93 (m, 1H,
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J = 6.4 Hz, OCH3), 60.4 (d, J = 14.9 Hz, C-5), 66.6 (C-2), 73.3 (C-6), 127.3, 128.1,
128.6, 139.6. 31P NMR (81 MHz, CDCl3)
d
24.8. HRMS (FAB+): calcd for
12H19NO4P [M+H]+, m/z 272.1052; found for [M+H]+, m/z 272.1057. (3S,5S)-
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13a. ½a D
ꢂ
¼ þ53:3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d 2.97 (ddd, J = 12.0,
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8.5, 3.7 Hz, 1H, H-3), 3.20 (dd, J = 10.6, 3.6 Hz, 1H, H-5), 3.36 (dd, J = 11.1,
11.1 Hz, 1H, H-6), 3.70–3.75 (m, 1H, H-6), 3.77–3.81 (m, 1H, H-2), 3.80 (d,
J = 10.8 Hz, 3H, OCH3), 3.90 (d, J = 10.6 Hz, 3H, OCH3), 4.16–4.21 (m, 1H, H-2),
7.24–7.43 (m, 5H, Harom). 13C NMR (100 MHz, CDCl3) d 52.5 (d, J = 7.0 Hz,
OCH3), 53.7 (d, J = 6.6 Hz, OCH3), 61.1 (d, J = 156.3 Hz, C-3), 67.8 (C-2), 69.1 (d,
J = 15.2 Hz, C-5), 73.4 (C-6), 127.9, 128.0, 128.7, 139.2. 31P NMR (81 MHz,
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for [M+H]+, m/z 272.1088.
31. (3R,5S)-12b. ½a D
ꢂ
¼ ꢁ65:3 (c 3.0, CH2Cl2). 1H NMR (400 MHz, CDCl3) d 2.16 (br s,
1H, NH), 2.53 (dd, J = 12.8, 7.2 Hz, 1H, CH2Ph), 2.58 (dd, J = 12.8, 5.6 Hz, 1H,
CH2Ph), 2.92–2.99 (m, 1H, H-5), 3.16 (dd, J = 10.4, 10.4 Hz, 1H, H-6), 3.27 (ddd,
J = 11.8, 10.8, 3.0 Hz, 1H, H-3), 3.47 (ddd, J = 11.0, 10.8, 3.4 Hz, 1H, H-2), 3.70–
3.76 (m, 1H, H-6), 3.72 (d, J = 10.4 Hz, 3H, OCH3), 3.76 (d, J = 10.4 Hz, 3H, OCH3),
3.93 (dd, J = 11.0, 3.0 Hz, 1H, H-2), 7.11–7.28 (m, 5H,
(100 MHz, CDCl3) 39.1 (CH2Ph), 53.2 (d, J = 7.3 Hz, OCH3), 53.4 (d,
H
arom). 13C NMR
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d
J = 155.2 Hz, C-3), 53.6 (d, J = 7.3 Hz, OCH3), 56.6 (d, J = 13.2 Hz, C-5), 66.9
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33. (3R,5S)-3a. Mp = 256–258 °C,
½
a D
ꢂ
¼ þ32:0 (c 1.0, 1 M NaOH). 1H NMR
(400 MHz, NaOD-D2O) d 2.91 (ddd, J = 14.4, 11.4, 2.9 Hz, 1H, H-3), 3.33 (dd,
J = 11.0, 11.0 Hz, 1H, H-6), 3.46 (ddd, J = 11.5, 11.4, 2.7 Hz, 1H, H-2), 3.72–3.80
(m, 2H, H-5, H-6), 3.93 (dd, J = 11.5, 2.9 Hz, 1H, H-2), 7.18–7.35 (m, 5H, Harom).
13C NMR (100 MHz, NaOD-D2O) d 56.2 (d, J = 136.1 Hz, C-3), 59.8 (d, J = 11.7 Hz,
C-5), 68.4 (C-2), 71.3 (C-6), 127.0, 128.1, 128.8, 139.4. 31P NMR (162 MHz,
NaOD-D2O) d 8.9. HRMS (FAB+): calcd for C10H15NO4P [M+H]+, m/z 244.0739;
16. Laars, M.; Raska, H.; Lopp, M.; Kanger, T. Tetrahedron: Asymmetry 2010, 21,
562–565.
found for [M+H]+, m/z 244.0726. (3R,5S)-3b. Mp = 280–281 °C, ½a D
ꢂ ¼ ꢁ42:7 (c
3.0, 1 M NaOH). 1H NMR (400 MHz, NaOD-D2O) d 2.39 (dd, J = 13.6, 7.6 Hz, 1H,
CH2Ph), 2.44 (dd, J = 13.6, 6.4 Hz, 1H, CH2Ph), 2.61 (ddd, J = 14.0, 11.2, 2.8 Hz,
1H, H-3), 2.77–2.84 (m, 1H, H-5), 3.03 (dd, J = 10.8, 10.8 Hz, 1H, H-6), 3.27 (ddd,
J = 11.2, 11.2, 3.0 Hz, 1H, H-2), 3.54 (d, J = 10.8 Hz, 1H, H-6), 3.77 (dd, J = 11.2,
2.8 Hz, 1H, H-2), 7.06–7.18 (m, 5H, Harom). 13C NMR (100 MHz, NaOD-D2O) d
37.7 (CH2Ph), 56.3 (d, J = 136.1 Hz, C-3), 56.6 (d, J = 11.7 Hz, C-5), 68.5 (C-2),
70.6 (C-6), 126.6, 128.7, 129.3, 137.9. 31P NMR (81 MHz, NaOD-D2O) d 15.2.
HRMS (FAB+): calcd for C11H17NO4P [M+H]+, m/z 258.0895; found for [M+H]+,
m/z 258.0922.
17. (a) Jagodzinski, J. J.; Aubele, D. L.; Quincy, D. A.; Dappen, M. S.; Latimer, L. H.;
Homa, R. K.; Galemmo, R. A., Jr.; Konradi, A. W.; Sham, H. L. Tetrahedron Lett.
2011, 52, 2471–2472; (b) Ciofi, C.; Morvillo, M.; Sladojevich, F.; Guarna, A.;
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M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257–260; (d) Sladojevich, F.; Trabocchi,
A.; Guarna, A. J. Org. Chem. 2007, 72, 4254–4257; (e) Dave, R.; Sasaki, N. A
Tetrahedron: Asymmetry 2006, 17, 388–401; (f) Brown, G. R.; Foubister, A. J.;
Wright, B. J. Chem. Soc., Perkin Trans. 1 1985, 2577–2580; (g) Kogami, Y.;
Okawa, K. Bull. Chem. Soc. Jpn. 1987, 60, 2963–2965.