Highly diastereoselective synthesis of anti-γ-N-benzylamino-β- hydroxyphosphonates

Article abstract of DOI:10.1039/b316262a

The reduction of γ-N-benzylamino-β-ketophosphonates 7 derived from readily available amino acids can be carried out stereoselectively with Zn(BH₄)₂ at -78°C to produce the anti-γ-amino- β-hydroxyphosphonates 8.

Full text of DOI:10.1039/b316262a

Highly diastereoselective synthesis of
anti-g-N-benzylamino-b-hydroxyphosphonates
Mario Ordóñez,* Ricardo de la Cruz-Cordero, Citlali Quiñónes and Angelina González-Morales
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001,
62210 Cuernavaca, Mor, Mexico. E-mail: palacios@buzon.uaem.mx; Fax: 52(777)3297997;
Tel: 52(777)3297997
Received (in Corvallis, OR, USA) 12th December 2003, Accepted 14th January 2004
First published as an Advance Article on the web 10th February 2004
The reduction of g-N-benzylamino-b-ketophosphonates 7 de-
rived from readily available amino acids can be carried out
stereoselectively with Zn(BH4)2 at 278 °C to produce the anti-
g-amino-b-hydroxyphosphonates 8.
in acetonitrile at room temperature. Then, the methyl esters 6a–e
were treated with three equivalents of the lithium salt of dimethyl
methylphosphonate at 278 °C in THF to afford the corresponding
N-benzylamino-b-ketophosphonates 7a–e in excellent yield
(Scheme 2).
Phosphonates and phosphinates functionalized with amino and
hydroxy groups have attracted considerable attention in recent
years for their role in biologically relevant processes such as
inhibition of renin and HIV protease, human calpain I and for their
use as haptens in the development of catalytic antibodies.1 In
particular, b-amino-a-hydroxyphosphonates 1 and g-amino-b-
hydroxyphosphonates 2 have resulted in unique phosphate mimics
with resistance to phosphatase hydrolysis.2
Having efficiently prepared the b-ketophosphonates 7a–e, we
turned our attention to the diastereoselective reduction to obtain the
g-N-benzylamino-b-hydroxyphosphonates 8 and 9. The reduction
was carried out with a variety of reducing agents and conditions.
Yields and diastereomeric excess are summarized in Table 1.
Reduction of 7a–e was carried out using NaBH4, catecholborane,
LiBH4 and Zn(BH4)2. Our first trials sought to determine the most
suitable reducing agent. The reduction of 7a–e with NaBH4 at 0 °C
in methanol (entries 1–5) afforded the g-N-benzylamino-b-
hydroxyphosphonates anti-8 and syn-9 with good chemical yields
and moderate diastereoselectivity, in favour of diastereomer anti-8.
As a result, numerous synthetic methods for chiral non-racemic
b-amino-a-hydroxyphosphonates have been developed.3 However,
to the best of our knowledge, only a few synthetic approaches to
obtain optically active g-amino-b-hydroxyphosphonates 2 are
reported in the literature, which involve the reaction of the anion of
methylphosphonate with a-amino-aldehydes,4 or the catalytic
asymmetric aminohydroxylation of unsaturated phosphonates,4 but
both synthetic approaches yield the g-amino-b-hydroxyphospho-
nates with low enantioselectivity.
Recently we described the reduction of dimethyl g-N,N-
dibenzylamino-b-ketophosphonates 3 with catecholborane, obtain-
ing the dimethyl g-N,N-dibenzylamino-b-hydroxyphosphonates
syn-4 with high diastereoselectivity and good chemical yield
(Scheme 1).5
Scheme 2
Table 1 The reduction of 7a–e with various reducing agents10
The absolute configuration of the new stereogenic centre in 4c
and 4d (R = Bn and Ph, respectively) was established by single-
crystal X-ray crystal analysis. The absolute configuration of the
other g-N,N-dibenzylamino-b-hydroxyphosphonates syn-4 was
assigned by analogy. Therefore, the reduction of 3 took place under
nonchelation control or the Felkin–Anh model,6 based on steric
constraints imparted by the bulky N,N-dibenzyl protecting group,
and is independent of the steric demand placed upon the increasing
size of the R group at C-3. This diastereofacial preference is in
agreement with that reported previously for the reduction of
1-aminoalkylchloromethyl ketones,7 for the reductive amination of
a-amino ketones,8 and reduction of 1-aminoalkyl-chloromethyl
ketimines.9
Yielda 31P NMR
(%)
banti : syn
anti :
Entry
R
Hydride
Conditions
synb
1
2
3
4
5
6
7
8
9
10
11
12
13
Me NaBH4
i-Pr NaBH4
i-Bu NaBH4
Bn NaBH4
Ph
i-Pr CB
MeOH, 0 °C 86
MeOH, 0 °C 70
MeOH, 0 °C 88
MeOH, 0 °C 65
MeOH, 0 °C 75
THF, 278 °C 70
THF, 278 °C 78
THF, 278 °C 50
34.94 : 34.68 46 : 54
35.65 : 33.44 85 : 15
34.84 : 34.71 46 : 54
34.56 : 34.80 55 : 45
35.22 : 34.16 63 : 37
35.65 : 33.44 79 : 21
35.65 : 33.44 79 : 21
35.65 : 33.44 91 : 9
34.94 : 34.68 67 : 33
35.65 : 33.44 96 : 4
34.84 : 34.71 94 : 6
34.56 : 34.80 96 : 4
35.22 : 34.16 88 : 12
In order to induce the formation of anti-g-amino-b-hydroxy-
phosphonates, we choose now only one benzyl as protecting group.
Thus, the starting N-benzyl methyl esters 6a–e (R = Me a, iPr b,
iBu c, Bn d, Ph e) were prepared by treatment of corresponding
amino methyl ester hydrochloride with K2CO3 and benzyl bromide
NaBH4
i-Pr LiBH4
i-Pr LiBH4
c
Me Zn(BH4)2 THF, 278 °C 88
i-Pr Zn(BH4)2 THF, 278 °C 85
i-Bu Zn(BH4)2 THF, 278 °C 95
Bn Zn(BH4)2 THF, 278 °C 70
Ph
Zn(BH4)2 THF, 278 °C 80
a Chemical yield after purification by column chromatography. b De-
termined by 1H NMR at 400 MHz and 31P NMR at 200 MHz in the crude
reaction. c In presence of ZnCl2 (1 equiv.).
Scheme 1
672
C h e m . C o m m u n . , 2 0 0 4 , 6 7 2 – 6 7 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

The diastereomeric excess of the reduction of 7a–e was determined
by means of 1H and 31P NMR. In fact, the signals in 31P NMR for
the diastereomers syn-9 were more shielded than for the diaster-
eomers anti-8 (Table 1). Assignment of the absolute configuration
of the new stereogenic centre in the diastereomer anti-8 was by
chemical correlation. Thus, the mixture of the diastereomers anti-8
and syn-9 was treated with benzyl bromide in acetonitrile at room
temperature to afford a mixture of the known g-N,N-dibenzyla-
mino-b-hydroxyphosphonates. The 31P NMR signals for these b-
hydroxyphosphonates were identical to those obtained for anti-5
and syn-4.5
method to obtain the anti-g-N-benzylamino-b-hydroxyphospho-
nates with high diastereoselectivity, which could be used for the
preparation of phosphostatine analogues.
We gratefully acknowledge CONACYT, Mexico, for financial
support via grant 41657-Q and graduate fellowships for R.C.C.,
C.Q. and A.G.M.
Notes and references
1 V. P. Kukhar and H. R. Hudson, Eds., Aminophosphonic and
Aminophosphinic Acids: Chemistry and Biological Activity; John
Wiley: New York, 2000 and references therein.
When the reduction of 7b was carried out with catecholborane
and LiBH4 (entries 6–7), the diastereomers anti-8b and syn-9b
were obtained in a ratio of 79 : 21; these last results were better than
those obtained when the reduction was carried out with NaBH4.
The syn/anti relations obtained with NaBH4, catecholborane and
LiBH4 in the reduction of 7 (entries 1–7) took place under chelation
control, but the chelating atom is not the metal counterion, rather
hydrogen bonding between the NH proton and the carbonyl oxygen
significantly influences the diastereoselection. When LiBH4/ZnCl2
was used at 278 °C (entry 8) the corresponding b-hydrox-
yphosphonates were obtained with high diastereoselectivity and
with a predominance of the desired anti product. However, under
these conditions the reaction was not completed, in spite of using
excess of LiBH4 and a long reaction time.
Finally, with the reduction of 7a–e with Zn(BH4)2 at 278 °C in
THF (entries 9–13), the corresponding g-N-benzylamino-b-hy-
droxyphosphonates were obtained in high diastereoselectivity and
good chemical yield, with a predominance of the desired anti
product. Therefore, the reduction of 7 takes place under chelation
control predominantly, where an acid–base reaction between the
NH proton and Zn(BH4)2 takes place, with molecular hydrogen
evolution, while the zinc ion coordinates with the oxygen of the
carbonyl group (Fig. 1). The reducing agent is more tightly bound
to the substrate, so hydrogen transfer takes place intramolecularly
in a more rigid structure, and is dependent on the steric demand
placed upon the increasing size of the R group at C-3.
2 J. Nieschalk, A. S. Batsanov, D. O’Hagan and J. A. K. Howard,
Tetrahedron, 1996, 52, 165; T. R. Burke, Jr., M. S. Smyth, M. Nomizu,
A. Otaka and P. P. Roller, J. Org. Chem., 1993, 58, 1336.
3 M. Drag, R. Latjka, E. Gumienna-Kontecka, H. Kozlowski and P.
Kafarski, Tetrahedron: Asymmetry, 2003, 14, 1837; A. E. Wróblewski
and D. G. Piotrowska, Tetrahedron: Asymmetry, 2002, 13, 2509 and
references therein; F. Hammerschmidt, W. Wolfgang, F. Wuggenig and
E. Zarbl, Tetrahedron: Asymmetry, 2000, 11, 2955; A. Barco, S. Benetti,
P. Bergamini, C. De Risi, P. Marchetti, G. P. Pollini and V. Zanirato,
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6 M. Cherest and H. Felkin, Tetrahedron Lett., 1968, 18, 2199; M. Cherest
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In summary, ready access to g-N-benzylamino-b-ketophospho-
nates 7 in conjunction with the reduction of the carbonyl group
using Zn(BH4)2 with very high diastereoselectivity and good
chemical yield under chelation control as described in this paper,
make this experimental operation a good, simple and general
8 R. V. Hoffman, N. Maslouh and F. Cervantes-Lee, J. Org. Chem., 2002,
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10 General procedure for the reduction of 7: A solution of b-ketophospho-
nate 7 (1 equiv.) in anhydrous THF was cooled at 278 °C before the
slow addition of a solution of Zn(BH4)2 in THF (0.2 M, 4 equiv.) which
had been recently prepared.11 The reaction mixture was stirred at 278
°C for 6 h and quenched at room temperature by the addition of a
saturated aqueous solution of NH4Cl. The organic phase was separated
and the aqueous layer was extracted with ethyl acetate. The combined
organic extracts were dried over Na2SO4 and evaporated under reduced
pressure. The crude mixture of the b-hydroxyphosphonates anti-8 and
syn-9 was analyzed by 1H and 31P NMR and purified by flash
chromatography.
Fig. 1 Transition state for the intramolecular hydride transfer on the re
face.
11 A. Pelter, K. Smith and H. Brown, Borane Reagents, Academic Press,
London, 1988, p. 414.
C h e m . C o m m u n . , 2 0 0 4 , 6 7 2 – 6 7 3
673