Diastereoselective reduction of β-ketophosphonates derived from amino acids. A new entry to enantiopure β-hydroxy-γ-aminophosphonate derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00159-3

The reduction of γ-N,N-dibenzylamino-β-ketophosphonates 4 derived from readily available (S)-tribenzylated amino acids was achieved with catecholborane at -20°C affording γ-amino-β-hydroxyphosphonates 5 in high diastereoselectivity and good chemical yield. These reactions provide a new entry to enantiomerically pure γ-amino-β-hydroxyphosphonates.

Full text of DOI:10.1016/S0957-4166(02)00159-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 559–562
Diastereoselective reduction of b-ketophosphonates derived from
amino acids. A new entry to enantiopure
b-hydroxy-g-aminophosphonate derivatives
Mario Ordo´n˜ez,* Ricardo de la Cruz, Mario Ferna´ndez-Zertuche and
´
Miguel-Angel Mun˜oz-Herna´ndez
Centro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Morelos Av. Universidad No. 1001, 62210 Cuernavaca,
Mor, Mexico
Received 16 November 2001; accepted 18 March 2002
Abstract—The reduction of g-N,N-dibenzylamino-b-ketophosphonates 4 derived from readily available (S)-tribenzylated amino
acids was achieved with catecholborane at –20°C affording g-amino-b-hydroxyphosphonates 5 in high diastereoselectivity and
good chemical yield. These reactions provide a new entry to enantiomerically pure g-amino-b-hydroxyphosphonates. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
phosphonates.3d Both approaches afford the g-amino-
b-hydroxyphosphonates with low enantioselectivity.
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 rennin and HIV
protease and human calpain I, and as a result of their
use as haptens in the development of catalytic antibod-
ies.1 In particular, b-amino-a-hydroxyphosphonates of
the type 1 and g-amino-b-hydroxyphosphonates of the
type 2 have resulted in unique phosphate mimics with
resistance to phosphatase hydrolysis.2
As part of our ongoing program directed towards the
design of chiral g-amino-b-hydroxyphosphonates we
report herein a simple entry to these compounds that
takes advantage of the diastereoselective reduction of
the ketone group of g-N,N-dibenzylamino-b-ketophos-
phonates 4a–d,5 derived from readily available tribenzyl-
ated amino acids6 and catecholborane as the reducing
agent.
2. Results and discussion
The starting protected amino acids 3 were prepared in
74–80% yield by treatment of the corresponding amino
acids with K2CO3 and benzyl bromide under reflux.7
The reaction of benzyl esters 3 with 4 equiv. of the
lithiated dimethyl methylphosphonate at –78°C in THF
gave the corresponding b-ketophosphonates 4 in excel-
lent yield (Scheme 1).8
As a result, numerous synthetic methods for b-amino-
a-hydroxyphosphonates have been developed.1,3 How-
ever, to the best of our knowledge, only a few synthetic
approaches to obtain optically active g-amino-b-
hydroxyphosphonates 2 have been reported in the liter-
ature. These involve the reaction of the anion of
methylphosphonate with a-aminopropanal,4 or the cat-
alytic asymmetric aminohydroxylation of unsaturated
From the g-N,N-dibenzylamino-b-ketophosphonates
4a–d we selected the isopropyl analog 4b (R=i-Pr) to
evaluate diastereoselective reduction using several
hydrides (Table 1). As shown in Table 1, the yields and
stereoselectivities (entries 1–4) were higher when cate-
cholborane was used and,9 therefore, catecholborane
* Corresponding authors. E-mail: palacios@buzon.uaem.mx
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00159-3

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M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 13 (2002) 559–562
Figure 1. X-Ray crystal structure of syn-5c and syn-5d.

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 13 (2002) 559–562
561
References
1. Aminophosphonic and Aminophosphinic Acids: Chemistry
and Biological Activity; Kukhar, V. P.; Hudson, H. R.,
Eds.; John Wiley: New York, 2000 and references cited
therein.
2. (a) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard,
J. A. K. Tetrahedron 1996, 52, 165; (b) Burke, T. R., Jr.;
Smyth, M. S.; Nomizu, M.; Otaka, A.; Roller, P. P. J.
Org. Chem. 1993, 58, 1336.
Scheme 1.
3. (a) Yamagishi, T.; Suemune, K.; Yokomatsu, T.;
Shibuya, S. Tetrahedron Lett. 2001, 42, 5033; (b) Ham-
merschmidt, F.; Lindner, W.; Wuggenig, F.; Zarbl, E.
Tetrahedron: Asymmetry 2000, 11, 2955; (c) Barco, A.;
Benetti, S.; Bergamini, P.; De Risi, C.; Marchetti, P.;
Pollini, G. P.; Zanirato, V. Tetrahedron Lett. 1999, 40,
7705; (d) Thomas, A. A.; Sharpless, K. B. J. Org. Chem.
1999, 64, 8379; (e) Wro´blewski, A. E.; Piotrowska, D. G.
Tetrahedron 1998, 54, 8123; (f) Gravotto, G.; Gioven-
zana, G. B.; Pagliarin, R.; Palmisano, G.; Sisti, M.
Tetrahedron: Asymmetry 1998, 9, 745.
4. (a) O’Brien, P.; Powell, H. R.; Raithby, P. R.; Warren, S.
J. Chem. Soc., Perkin Trans. 1 1997, 1031; (b) O’Brien,
P.; Warren, S. Tetrahedron Lett. 1996, 37, 4271; (c)
Froestl, W.; Mickel, S. J.; Hall, R. G.; Sprecher, G. V.;
Strub, D.; Baumann, P. A.; Brugger, F.; Gentsch, C.;
Jaekel, J.; Olpe, H.-R.; Rihhs, G.; Vassout, A.; Vald-
meier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38, 3297;
(d) Dellaria, J. F., Jr.; Maki, R. G.; Stein, H. H.; Cohen,
J.; Whittern, D.; Marsh, K.; Hoffman, D. J.; Plattner, J.
J.; Perum, T. J. J. Med. Chem. 1990, 33, 534; (e)
Chakravarty, P. K.; Greenlee, W. J.; Parsons, W. H.;
Patchett, A. A.; Combs, P.; Roth, A.; Busch, R. D.;
Mellin, T. N. J. Med. Chem. 1986, 32, 1886.
was the reducing agent used for the other b-ketophospho-
nates 4a–d.10
From the results summarized in Table 1, it should be
pointed out that the diastereoselectivity of the reduction
of g-N,N-dibenzylamino-b-ketophosphonates 4a–d is
independent of the steric demands placed upon increasing
size of the R group at C(3). The diastereomeric excesses
for syn-5 and anti-5 were determined by 1H NMR at 400
MHz. The configuration at the carbinol center was
assigned by analogy of other phosphonates reported in
the literature3d and confirmed by the X-ray crystal
structures of diastereomeric pure 5c and 5d (Fig. 1).13
In summary, ready access to g-N,N-dibenzylamino-b-
ketophosphonates 4 in conjunction with the reduction of
a ketone group using catecholborane with very high
diastereoselectivity and good chemical yield as described
in this paper make this experimental operation a good,
simple and general method to obtain enantiomerically
pure g-N,N-dibenzylamino-b-hydroxy-phosphonates 5.
5. Chung, S.-K.; Kang, D.-H. Tetrahedron: Asymmetry
1997, 8, 3027.
Acknowledgements
6. (a) Hungerhoff, B.; Samanta, S. S.; Roels, J.; Metz, P.
Synlett 2000, 77; (b) Lagu, B. R.; Crane, H. M.; Liotta,
D. C. J. Org. Chem. 1993, 58, 4191.
We wish to thank CONACYT (Project 28762-E) and to
Emanuel Herna´ndez for financial and technical support.
Table 1. Diastereoselective reduction of g-N,N-dibenzylamino-b-ketophosphonates 4a–d
Entry
R
H:−
Temp. (°C)
Yield (%), 5a
syn:antib
c
c
1
2
3
4
5
6
7
i-Pr, 5b
i-Pr, 5b
i-Pr, 5b
i-Pr, 5b
Me, 5a
Bn, 5c
BH3·SMe2
DIBAL-H
NaBH4
CBd
−20
−78
−20
−20
−20
−20
−20
50
44
69
85
89
82
82:18
85:1512
\98:2
\98:2
\98:2
90:10
CBd
CBd
Ph, 5de
CBd
a Chemical yield after purification by column chromatography.11
b Determined by 1H NMR at 400 MHz.
c The reaction did not proceed.
d Catecholborane.
e The configuration of the amino acid used was (R).

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7. General procedure for the preparation of benzyl g-N,N-
mL) was cooled at –78°C before the slow addition of a
solution of chatecolborane in THF (1 M, 0.28 mL, 28
mmol) The reaction mixture was stirred at −20°C for 4 h
and at room temperature for 3 h then quenched by the
addition of a saturated aqueous solution of NH4Cl. The
organic phase was separated and the aqueous layer was
extracted with ethyl acetate (3×25 mL). The combined
organic extracts were dried over Na2SO4 and evaporated
under reduced pressure. The crude b-hydroxyphospho-
dibenzylamino acids 3a–d. A solution of benzyl bromide
(170.7 mmol) in ethanol (40 mL) was slowly added to
solution of the amino acid (42.68 mmol) and K2CO3
(170.7 mmol) in a 5:1 mixture of ethanol–water (250 mL).
The reaction mixture was heated under reflux for 14 h.
The solvent was removed under reduced pressure. Water
was added to the residue and the resulting slurry
extracted with ethyl acetate (3×150 mL). The combined
organic layers were dried over Na2SO4 and evaporated
under reduced pressure. The crude products were purified
by flash chromatography.
1
nate was analyzed by H NMR at 400 MHz and purified
by flash chromatography.
11. All compounds were fully characterized by 13C, 1H and
31P NMR at 400 MHz.
8. General procedure for the preparation of g-N,N-dibenzyl-
amino-b-ketophosphonates g-substituted 4a–d. A solution
of dimethylmethylphosphonate (18.97 mmol) in anhy-
drous THF (45 mL) was cooled at –78°C before the slow
addition of a solution of n-BuLi in hexanes (1.5 M, 12.4
mL, 19.45 mmol). The resulting solution was stirred at
–50°C for 1 h. The solution was cooled to –78°C and
slowly added to a solution of the benzyl ester (18.97
mmol) in THF (45 mL). The reaction mixture was stirred
at –78°C for 3 h before the addition of a saturated
solution of NH4Cl. The organic phase was separated and
the aqueous layer was extracted with ethyl acetate (3×40
mL). The combined organic extracts were dried over
Na2SO4 and evaporated under reduced pressure. The
crude ketophosphonates were purified by flash
chromatography.
12. Similar relations have been reported by related com-
pounds, see Refs. 4a,b.
13. X-Ray crystal data of syn-5c and syn-5d were collected at
293 K using a Bruker APEX instrument (Mo Ka radia-
,
tion, u=0.71073 A). The SHELXTL v. 6.1 program
package was used for structures solution and refinement.
An absorption correction was applied using SADABS in
both cases. The structures were solved by direct methods
and refined by full-matrix least square procedures. All
non-hydrogen atoms were refined anisotropically. syn-5c:
C24H32NO4P, M=453.49, monoclinic space group P21/c,
o
,
a=10.144(1), b=17.122(1), c=14.425(1) A, i=90.77(1) ,
V=2505.3 (2) A , Z=4, Dc=1.202 g cm−1, 12013 reflec-
3
,
tions measured, 4213 unique (Rint=0.0205) wich were
used in all calculations, final R values were 0.0616 [F>
4|(F)] and 0.0647 (all data). syn-5d: C25H30NO4P, M=
9. High diastereoselectivity was also found in the reduction
of b-amino-a-ketophosphonates with catecholborane in
the presence of a catalytic amount of oxazaborolidine, see
Ref. 3c.
439.47, monoclinic space group C2/c, a=16.533(1),
o
,
b=15.774(1), c=19.369(2) A, i=108.01(1) , V=4803.72
(6) A , Z=8, Dc=1.215 g cm−1, 29233 reflections mea-
3
,
sured, 7869 unique (Rint=0.0269) which were used in all
calculations, final R values were 0.0574 [F>4|(F)] and
0.0679 (all data).
10. General procedure for the diastereoselective reduction of
b-ketophosphonates g-substituted 4a–d. A solution of b-
ketophosphonate 4 (0.57 mmol) in anhydrous THF (7