Asymmetrie synthesis of α,β-Diaminophosphonic acid derivatives with a catalytic enantioselective mannich reaction

Article abstract of DOI:10.1002/adsc.200900208

Optically active α,β-diaminophosphonic acid derivatives were obtained from the catalytic enantioselective Mannich reaction of phosphoglycine Schiff bases with N-Boc-imines, generated in situ from a-amido sulfones.

Full text of DOI:10.1002/adsc.200900208

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DOI: 10.1002/adsc.200900208
Asymmetric Synthesis of a,b-Diaminophosphonic Acid
Derivatives with a Catalytic Enantioselective Mannich Reaction
Robert Djiokeng Momo,a Francesco Fini,a Luca Bernardi,a,* and Alfredo Riccia
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, V. Risorgimento, 4, I-40136 Bologna, Italy
Fax : (+39)-051-209-3564; e-mail: nacca@ms.fci.unibo.it
Received: March 31, 2009; Revised: August 5, 2009; Published online: September 23, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900208.
Abstract: Optically active a,b-diaminophosphonic
acid derivatives were obtained from the catalytic
enantioselective Mannich reaction of phosphogly-
cine Schiff bases with N-Boc-imines, generated in
situ from a-amido sulfones.
so far.[5] However, considering their similarity with
benzophenone imines derived from glycine,[6] un-
doubtedly one of the most successful substrates for
the preparation of optically active a-amino acid deriv-
atives,[7] we envisioned the possibility of using phase-
transfer catalysis (PTC)[8] for the productive activa-
tion of phosphoglycines 1 in enantioselective reac-
tions.
We present herein the development of a catalytic
asymmetric Mannich reaction of a phosphoglycine
Schiff base 1 with N-Boc-imines generated in situ
from a-amido sulfones 2,[9] giving access to precursors
of enantioenriched a,b-diaminophosphonic acids 4
Keywords: a-amido sulfones; asymmetric catalysis;
a,b-diaminophosphonic acids; Mannich reaction;
phase-transfer catalysis
a-Aminophosphonic acids are structural analogues of (Scheme 1).[10] Although these particular phosphonic
a-amino acids, and have been found to possess a acids bear considerable interest, being a,b-diamino
broad range of biological activities.[1] This activity, acid analogues,[11] and their activity as efficient amino-
often due to the inhibition of protease or synthetase peptidase inhibitors has been already demonstrat-
enzymes, is usually rationalized considering the mim- ed,[12] their enantioselective synthesis has not been
icking of the transition state of enzymatic peptide thoroughly studied. To the best of our knowledge,
bond hydrolysis (or formation) by the bulky and tet- only a handful of examples based on chiral auxiliary
rahedral phosphonic acid moiety.[2] As the absolute methodologies,[13] and a single catalytic asymmetric
configuration at the a-carbon influences dramatically reaction, limited to a-methyl-a,b-diaminophospho-
their biological response, several methods have been nates,[14] have been reported so far.
developed for the obtainment of these compounds in
enantioenriched form, especially based on catalytic
At the outset of our studies, diethyl (diphenyl-
AHCTUNGTRENNUNG
asymmetric methodologies.[3] In this context, a variety ed with a-amido sulfone 2a (Table 1), using commer-
of strategies has been reported relying on the catalytic
asymmetric hydrophosphonylation of imines,[3c,e]
which is however intrinsically limited to simple a-
alkyl- and a-aryl-substituted a-aminophosphonates.
To overcome this restriction, we set our focus on a
different approach, that is the use of the benzophe-
none imines 1 derived from phosphoglycine[4] as phos-
phoglycine anion equivalents, envisioning that this
strategy could open new possibilities for the obtain-
ment of other classes of a-aminophosphonic acids in
optically active form. The potential uses of Schiff
bases 1 in catalytic asymmetric transformations has
been rather overlooked, as only one example, a palla-
Scheme 1. Synthesis of optically active a,b-diaminophos-
phonic acids with a catalytic enantioselective Mannich reac-
dium-catalyzed allylic substitution, has been reported tion.
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Robert Djiokeng Momo et al.
Table 1. Representative results from the screening of different catalysts, bases, solvents and temperatures.[a]
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Entry
Catalyst 5
Solvent
Base
T [8C]
Conversion[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5f
5f
5f
5f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
À30
À30
À30
À30
À30
À30
À30
À55
À55
À55
À55
>90
>90
>90
89
>90
>90
>90
>90
<10
70
0
55[d]
12
40
7
53
7
70
-
45
80
9
10
11
toluene/CH2Cl2 9:1
toluene/i-Pr2O 9:1
toluene/TBME 9:1
>90
[a]
Reactions were carried out with 2a (0.10 mmol), 1 (0.12 mmol), catalyst 5 (0.010 mmol), the inorganic base (0.50 mmol)
in the solvent (1 mL), at the stated temperature for 48 h. In all experiments, a single syn diastereoisomer was observed in
the crude mixture by 1H NMR spectroscopy.
Determined by H NMR spectroscopy.
Determined by chiral stationary phase HPLC.
0.20 mmol NaOH were used.
[b]
[c]
[d]
1
cially available catalyst 5a derived from quinine, in Allylation of the hydroxy group of 5f resulted in the
toluene as the solvent. Among the different bases very inefficient catalyst 5g, which furnished the prod-
tested, only hydroxides such as NaOH could promote uct in nearly racemic form (entry 7). The requirement
the reaction to a considerable extent at À308C, al- of a free alcoholic moiety in the catalyst structure is
though no appreciable enantioselectivity was ob- in line with the results observed in related transfor-
served with catalyst 5a (entry 1). Remarkably, in this mations,[9b,c,20] and has been recently rationalized con-
and in the following experiments, the product 3a was sidering its capability in coordinating and stabilizing
always obtained as a single syn-diastereoisomer.[16] the anionic nucleophile through a hydrogen bond in-
This excellent syn-diastereoselectivity is in line with teraction.[21] Using catalyst 5f, further experiments re-
literature precedents concerning base or phase-trans- vealed that with CsOH as the base it was possible to
fer catalyzed Mannich additions of glycine and phos- decrease the reaction temperature to À558C, increas-
phoglycine Schiff bases to N-Boc-imines,[9d,10a] where ing the enantioselectivity of the product 3a
it was explained considering an acyclic transition state (entry 8).[22] Given the non-feasibility of a further de-
model for the Mannich addition (i.e., kinetic con- crease in the temperature, we decided to test different
trol).[17,18]
solvent mixtures in the reaction. The use of mixtures
A series of ammonium salts derived from quinine of toluene and a small amount of a chlorinated or
featuring an ortho-substituted benzyl group was then ethereal co-solvent gave contrasting results (entries 9–
prepared and tested (entries 2–7), considering the 11). In particular, only TBME showed a positive
proven efficiency of this class of catalysts both in effect on the enantioselectivity observed (entry 11),
enantioselective alkylations of benzophenone glycine allowing the obtainment of the Mannich adduct 3a
imines,[19] and in asymmetric Mannich additions to N- with a reasonable 80% ee.
Boc-imines.[20] A strong influence of the nature of this
Under these conditions, the generality of the reac-
substituent on the reaction outcome could be in fact tion was inspected using different a-amido sulfones 2
observed, with the 2-picolyl N-oxide catalyst 5f giving derived from aromatic aldehydes (Table 2).[23]
the best results in terms of enantioinduction (entry 6). range of a,b-diaminophosphonic derivatives 3a–i
A
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Asymmetric Synthesis of a,b-Diaminophosphonic Acid Derivatives
Table 2. Generality of the Mannich reaction.[a]
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Entry Sulfone Ar1
Adduct Yield[b] ee[c]
2
3
[%]
[%]
Scheme 2. Synthetic elaborations of the Mannich adducts 3.
Cbz=benzyloxycarbonyl.
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
3a
3b
3c
3d
3e
3f
89
89
79
96
60
78
88
83
85
80[d]
92
78
72
94
66
50
74
90
o-MeC6H4
m-MeC6H4
p-MeC6H4
o-BrC6H4
p-ClC6H4
phosphonic esters are also susceptible to acidic hy-
drolysis, we envisioned the direct obtainment of opti-
cally active a,b-diaminophosphonic acids in a single
step from the Mannich adducts. To this purpose, 3a
and 3i were treated with 10M HCl overnight, giving
in quantitative yield the expected a,b-diaminophos-
phonic acid dihydrochlorides 4a·2HCl and 4i·2HCl
(Scheme 2). On the other hand, due to its lability to
aqueous acidic conditions, the benzophenone imine
can be chemoselectively hydrolyzed with diluted
aqueous acid even in the presence of the Boc protect-
ing group, giving thus the possibility of accessing or-
thogonally protected a,b-diaminophosphonic acid de-
rivatives, as exemplified for the N1-Cbz, N2-Boc pro-
tected 7a (Scheme 2).
p-MeOC6H4 3g
2-naphthyl
1-naphthyl
3h
3i
[a]
Reactions were carried out with
2 (0.20 mmol), 1
(0.24 mmol), catalyst 5f (0.020 mmol), CsOH·H2O
(1.0 mmol) in a toluene/TBME mixture (2.0 mL, 9:1), at
À558C for 60 h.
[b]
[c]
Isolated yield after chromatography on silica gel. A
single syn diastereoisomer was observed in all cases by
means of H,13C and 31P NMR spectroscopy.
1
Determined by chiral stationary phase HPLC.[d] Absolute
configuration determined by chemical derivatization (see
Supporting Information).
In conclusion, we have developed a catalytic asym-
metric Mannich reaction using the phosphoglycine
could be obtained using this procedure in good yields benzophenone imine 1 and a-amido sulfones 2 as
(60–96%), and as single syn diastereoisomers in all imine precursors. This new transformation represents
cases.[16] The enantioselectivities observed varied with one of the very few options for the preparation of
the structure of the a-amido sulfones 2 employed. In a,b-diaminophosphonic acids in optically active form
particular, substituents at the para-position of the aro- with a catalytic method, and presents several attrac-
matic ring in 2d, f, g gave a slight decrease in the tive features such as the user-friendly operative condi-
enantioselection (entries 4, 6, 7), compared to their tions, the employment of cheap and easily obtained
unsubstituted counterpart 2a (entry 1), whereas a sub- chiral catalysts and materials, and the straightforward
stituent at the meta-position had nearly no influence conversion of the Mannich adducts to the unprotected
(entry 3). In contrast, an electron-withdrawing or re- a,b-diaminophosphonic acids. Furthermore, the dem-
leasing ortho-substituent in 2b and 2e had a striking onstration of the productive activation of Schiff bases
positive effect, as the corresponding Mannich adducts 1 using asymmetric phase-transfer catalysis might
3b and 3e were obtained with excellent enantioselec- open new opportunities for the employment of these
tivities (entries 2 and 5). The beneficial influence of convenient phosphoglycine anion equivalents in asym-
sterical hindrance at the ortho-position was further metric catalysis.[24]
confirmed by the results obtained in the reactions
with the isomeric naphthyl derivatives 2h and 2i (en-
tries 8 and 9).
Experimental Section
A good asset of the present method is the possibili-
ty of obtaining directly a,b-diaminophosphonic acid
derivatives bearing a Boc protecting group and a ben-
General Procedure
zophenone imine at the two nitrogen atoms, both
easily removable under mild acidic conditions. As (0.20 mmol), diethyl phosphonate 1 (78 mg, 0.24 mmol),
Catalyst 5f (9.5 mg, 0.020 mmol), a-amido sulfone
2
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Robert Djiokeng Momo et al.
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were weighed in a test tube, and suspended in a toluene/
TBME mixture (9:1, 2.0 mL). The mixture was stirred at
room temperature for 5 min, then cooled to À558C. Finely
ground CsOH·H2O (170 mg, 1.0 mmol), weighed in an oven-
dried vial, was then added in one portion. The mixture was
stirred at the same temperature for 60 h, then charged di-
rectly on a silica gel column. The Mannich adduct 3 was
then obtained by eluting with a n-hexane/EtOAc 6:4 mix-
Int. Ed. 2005, 44, 4564; e) T. Ooi, M. Kameda, J.-i.
Fujii, K. Maruoka, Org. Lett. 2004, 6, 2397.
[10] Catalytic, non-asymmetric Mannich reaction of phos-
phoglycine Schiff bases: a) S. Kobayashi, R. Yazaki, K.
Seki, Y. Yamashita, Angew. Chem. 2008, 120, 5695;
Angew. Chem. Int. Ed. 2008, 47, 5613; synthesis of race-
mic a,b-diaminophosphonic acids from isothiocyanato-
methyl phosphonates and a-amido sulfones: b) R.
Błaszczyk, T. Gajda, Tetrahedron Lett. 2007, 48, 5859.
[11] A. Viso, R. Fernandez de La Pradilla, A. Garcꢆa, A.
Flores, Chem. Rev. 2005, 105, 3167.
1
ture. H, 13C, and 31P NMR spectra of the purified products
showed the presence of a single diastereoisomer in all cases.
The ee of the products 3 was determined by chiral stationary
phase HPLC.
[12] B. Lejczak, P. Kafarski, J. Zygmunt, Biochemistry 1989,
28, 3549.
[13] See for example: a) A. Studer, D. Seebach, Heterocy-
cles 1995, 40, 357; b) B.-F. Li, M.-J. Zhang, X.-L. Hou,
L.-X. Dai, J. Org. Chem. 2002, 67, 2902; c) E. K. Do-
lence, J. B. Roylance, Tetrahedron: Asymmetry 2004,
15, 3307; d) C. De Risi, D. Perrone, A. Dondoni, G. P.
Pollini, V. Bertolasi, Eur. J. Org. Chem. 2003, 1904.
[14] J. C. Wilt, M. Pink, J. N. Johnston, Chem. Commun.
2008, 4177.
[15] Diethyl phosphonate 1 was prepared in three steps fol-
lowing a literature procedure requiring a single purifi-
cation: J. A. Steere, P. B. Sampson, J. F. Honek, Bioorg.
Med. Chem. Lett. 2002, 12, 457.
[16] The syn notation refers to the nitrogen substituents,
considering the phosphonate moiety lying in the plane
being part of the chain. For the assignment of the syn
relative configuration, see the Supporting Information.
[17] T. Shibuguchi, H. Mihara, A. Kuramochi, T. Ohshima,
M. Shibasaki, Chem. Asian J. 2007, 2, 794.
[18] A thermodynamic equilibration at the phosphonate
substituted chiral centre under the basic reaction condi-
tions is less likely considering the expected much lower
acidity of the a-phosphonate proton of 3a, compared to
1. In glycine benzophenone imines, a-substitution de-
creases the pKa of about 4 units, due to the sterically
forced rotation of the two phenyl rings of the ketimine
in the a-substituted compound, which prevents enolate
delocalization. See: M. J. OꢅDonnell, W. D. Bennett,
W. A. Bruder, W. N. Jacobsen, K. Knuth, B. LeClef,
R. L. Polt, F. G. Bordwell, S. R. Mrozack, T. A. Cripe,
J. Am. Chem. Soc. 1988, 110, 8520.
Acknowledgements
We acknowledge financial support from “Stereoselezione in
Sintesi Oranica Metodologie e Applicazioni” 2007. The fi-
nancial support by the Merck-ADP grant 2007 is also grate-
fully recognized. We thank Claudio Gioia for preparing com-
pound 7a.
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Asymmetric Synthesis of a,b-Diaminophosphonic Acid Derivatives
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