Diastereoselective reduction of dimethyl γ-[(N-p-toluenesulfonyl) amino]-β-ketophosphonates derived from amino acids

Article abstract of DOI:10.1016/j.tetasy.2004.08.012

The reduction of dimethyl γ-[(N-p-toluenesulfonyl)amino]-β- ketophosphonates 7a-e with different hydrides gave dimethyl γ-[(N-p- toluenesulfonyl)amino]-β-hydroxyphosphonates 9a-e and 10a-e with good chemical yield and moderated diastereoselectivity. The c

Full text of DOI:10.1016/j.tetasy.2004.08.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3035–3043
Diastereoselective reduction of dimethyl
c-[(N-p-toluenesulfonyl)amino]-b-ketophosphonates
derived from amino acids
a,
Mario Ordon˜ez, Ricardo De la Cruz-Cordero, Mario Fernandez-Zertuche,
a
a
*
´
Miguel Angel Mun˜oz-Hernandez and Oscar Garcıa-Barradas
´
a
b
´
´
a
´
´
Centro de Investigaciones Quımicas, Universidad Autonoma del Estado de Morelos,
Av. Universidad No. 1001, 62210 Cuernavaca, Mor., Mexico
b
´
´
Unidad de Servicios de Apoyo en Resolucion Analıtica, Universidad Veracruzana,
Av. Dr. Luis Castelazo Ayala s/n. 91190 Xalapa, Ver., Mexico
Received 3 June 2004; revised 22 July 2004; accepted 9 August 2004
Abstract—The reduction of dimethyl c-[(N-p-toluenesulfonyl)amino]-b-ketophosphonates 7a–e with different hydrides gave
dimethyl c-[(N-p-toluenesulfonyl)amino]-b-hydroxyphosphonates 9a–e and 10a–e with good chemical yield and moderated diaster-
eoselectivity. The configuration of all new stereogenic centers were assigned by X-ray analysis and chemical correlation.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
a new synthetic methodology that affords 2 with much
better yields and moderate diastereoselectivities from
readily available starting materials.
Phosphonates and phosphinates functionalized with
amino and hydroxy groups have attracted considerable
attention in recent years for their role in biologically rele-
vant processes such as the inhibition of rennin and HIV
protease, human calpain I and their use as haptens in
the development of catalytic antibodies.1 In particular,
c-amino-b-hydroxyphosphonates 1 and 2 have resulted
in unique phosphate mimics with resistance to phospha-
tase hydrolysis.2 Additionally, phosphonates 1 and 2
served as excellent Leu10-Val11 replacements (LVRs)
in angiotensinII, providingamore potentinhibitoryactiv-
ity for rennin over porcine pepsin, and bovine cathepsin
D.3 However, to the best of our knowledge, only a few
synthetic approaches have been used to obtain optically
active c-amino-b-hydroxyphosphonates 1 and 2, which
involve the reaction of the anion of methylphosphonate
with a-aminoaldehydes,3,4 or the catalytic asymmetric
aminohydroxylation of unsaturated phosphonates.5
Although both synthetic strategies afford the
c-amino-b-hydroxyphosphonates 1 and 2, both yields
and diastereoselectivities remain low. Herein we report
O
O
OH
OH
R
R
P(OR')2
P(OR')2
NHR''
NHR''
1
2
2. Results and discussion
Recently we described the reduction of dimethyl c-N,
N-dibenzylamino-b-ketophosphonates with cate-
cholborane, obtaining dimethyl c-N,N-dibenzylamino-b-
hydrophosphonates syn-4 with high diastereoselectivity
and good chemical yield (Scheme 1).6
3
In order to induce the formation of anti-c-amino-b-
hydroxyphosphonates and inspired with the elegant
work by Rapoport and co-workers,7 who have
demonstrated the highly stereoselective reduction of
a-N-(phenylsulfonyl)amino ketones derived from ser-
ine, we decided to replace the benzyl groups of 3
with p-toluenesulfonyl. Thus, the total synthesis of
*
Corresponding author. E-mail: palacios@buzon.uaem.mx
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.012

´
M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3036
step, a-amino amino methyl esters hydrochloride were
OH
O
O
O
CB/THF
treated with p-toluenesulfonyl chloride and triethylam-
ine in dichloromethane at room temperature, to give
the corresponding N-p-toluenesulfonyl methyl esters
6a–e in 82–89% yield. Then, methyl esters 6a–e were
treated with 3equiv of the lithium salt of dimethyl meth-
ylphosphonate at ꢀ78ꢁC in dry THF to afford enantio-
merically pure b-ketophosphonates 7a–e in 69–98%
yield. The c-[N-p-methanesulfonyl)amino]-b-ketophos-
phonate 8e (R = Ph and R0 = Me) was obtained in a
similar fashion in 60% yield.
R
R
P(OMe)2
P(OMe)2
+ anti-5
-20 oC
69-89%
NBn2
NBn2
syn-4; 98% d.e.
3; R = Me, iPr, Bn, Ph
Scheme 1.
O
O
R
TsCl/Et3N
CH2Cl2, r.t.
82-89%
R
OMe
OMe
Having efficiently prepared b-ketophosphonates
7a–e and 8e, we turned out our attention to their diaster-
eoselective reduction to obtain c-[(N-p-toluenesulfonyl)-
amino]-b-hydroxyphosphonates 9 and 10. Table 1
summarizes the conditions used in the reduction and
results obtained.
NHTs
6a-e
NH2.HCl
7a; R = Me
7b; R = i-Pr
7c; R = i-Bu
7d; R = Bn
7e; R = Ph
O
n-BuLi
69-98%
CH3P(OMe)2
THF, -78 oC
From the c-[(N-p-toluenesulfonyl)amino]-b-ketopho-
sphonates 7a–e and 8e, we initially selected the isopropyl
analogue 7b (R = i-Pr) to evaluate the diastereoselective
reduction using a variety of reducing agents and condi-
tions. Thus, the reduction of 7b with NaBH4 at 0ꢁC in
methanol afforded c-[(N-p-toluenesulfonyl)amino]-b-
hydroxyphosphonates anti-9b and syn-10b in excellent
yield and with good diastereoselectivity, in favor of dia-
stereomer anti-9 (entry 1). In a similar fashion excellent
yields and good diastereoselectivities were obtained
when the reduction of 7b was carried out with Zn(BH4)2
and BH3ÆSMe2 (entries 2 and 3). Reduction of 7b with
O
O
R
P(OMe)2
NHTs
7a-e
Scheme 2.
c-[N-p-toluenesulfonyl)amino]-b-ketophosphonates 7a–
e starting from readily available a-amino acid methyl
esters hydrochloride is depicted in Scheme 2. In the first
Table 1. Reduction of 7a–e and 8e with various reducing agents
O
O
O
O
OH
OH
H-
P(OMe)2
P(OMe)2
R
R
R
P(OMe)2
+
NHSO2R'
NHSO2R'
NHSO2R'
syn-10a-e
anti-9a-e
7a-e and 8e
Entry
Compound
R
R0
Hydride
Conditions
Yield (%)b
anti:sync
1
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7a
7c
7d
7e
7e
8e
8e
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Me
i-Bu
Bn
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
Me
NaBH4
MeOH, 0ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
THF, ꢀ78ꢁC
MeOH, 0ꢁC
MeOH, 0ꢁC
MeOH, 0ꢁC
MeOH, 0ꢁC
THF, 0ꢁC
99
91
95
98
80
83
81:19
77:23
76:24
53:47
72:28
70:30
2
Zn(BH4)2
BH3ÆSMe2
LiBH4
a
3
4
5
LiBH4/ZnCl2
LiBH4/BCl3
LiBH4/TiCl4
LiBH4/Et2AlCl
DIBAL-H
L-selectride
CB
6
7
98
d
74:26
d
8
d
d
d
d
d
d
9
10
11
12
13
14
15
16
17
18
NaBH4
NaBH4
96
98
97
97
97
98
98
29:71
29:71
64:36
63:37
62:38
61:39
62:38
NaBH4
NaBH4
Ph
Ph
NaBH4
NaBH4
NaBH4
Ph
Ph
MeOH, 0ꢁC
THF, 0ꢁC
Me
a In presence of LiClO4 (1equiv).
b Chemical yield after purification.
c Determined by 1H NMR at 400MHz and 31P NMR at 200MHz in the crude.
d No reaction.

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M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3037
LiBH4 at ꢀ78ꢁC in anhydrous THF (entry 4) afforded
b-hydroxyphosphonates anti-9b and syn-10b in excellent
yield but with low diastereoselectivity. On the other
hand, when the reduction of 7b was carried out with
LiBH4 at ꢀ78ꢁC in the presence of ZnCl2, BCl3, and
TiCl4 (entries 5–7), respectively, b-hydroxyphospho-
nates anti-9b and syn-10b were obtained in both good
yield and diastereoselectivity. However, the reduction
of 7b with LiBH4 at ꢀ78ꢁC in the presence of Et2AlCl,
or with other reducing agents such DIBAL-H, L-selec-
tride, and catecholborane (entries 8–11) failed to pro-
vide b-hydroxyphosphonates anti-9b and syn-10b,
despite the use of longer reaction time. In all these cases,
b-ketophosphonate 7b was recovered.
Finally, the reduction of 7e with NaBH4 at 0ꢁC in meth-
anol or anhydrous THF (entries 15 and 16), afforded
c-[(N-p-toluenesulfonyl)amino]-b-hydroxyphosphonates
anti-9e and syn-10e with similar yields and diastereose-
lectivities. In addition, the substitution of a p-toluene-
sulfonyl group in the b-ketophosphonate 7e by a
methanesulfonyl group in 8e did not improve the chem-
ical yields and diastereoselectivities during the reduction
reaction with NaBH4 (entries 17 and 18). These last re-
sults suggest that the reduction of c-[(N-p-toluenesulfonyl)-
amino]-b-ketophosphonates 7a–e with NaBH4 took place
through an intermediate in which there is no hydrogen
bonding between the NH proton and the carbonyl oxygen,
and that the reaction is independent of the solvent polarity
and of steric demands placed upon increasing the size of
the R0 group at the sulfonyl group.
In the light of these results, we decided to carry out the
reduction of the rest of b-ketophosphonates 7 with
NaBH4 at 0ꢁC in methanol (entries 12–15), where b-
hydroxyphosphonates anti-9 and syn-10 were obtained
in good chemical yields and moderate diastereoselecti-
vity. The diastereofacial preference observed is in agree-
ment with the results previously reported for the
reduction of a-N-(phenylsulfonyl)amino ketones derived
from serine.7
The diastereomeric excesses of the products obtained
from the reduction of 7a–e and 8e were determined by
1H and 31P NMR data of the crude reaction mixtures,
and the configuration of the new generated stereo-
genic center at C(3) was assigned by comparison
with X-ray crystal structures of diastereomeric pure
syn-10d and anti-9e (Fig. 1).8,9 In addition, the absolute
Figure 1. X-ray molecular structure for syn-10d and anti-9e.

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M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3038
configurations of the new stereogenic center at C(3) in
the b-hydroxyphosphonates anti-9 and syn-10 were also
determined by chemical correlation. Thus, mixtures of
dimethyl c-N,N-dibenzylamino-b-hydroxyphosphonates
syn-4 and anti-5 (R = Me, i-Pr, Bn), were treated with
palladium on carbon in methanol under a hydrogen
atmosphere at room temperature yielding the corre-
sponding mixtures of dimethyl c-amino-b-hydroxyphos-
phonates,10 that without any further purification were
treated with p-toluenesulfonyl chloride and triethyl-
amine in dichloromethane at room temperature, to give
the corresponding c-[(N-p-toluenesulfonyl)amino]-b-
hydroxyphosphonates anti-9 and syn-10.
In order to rationalize the observed stereoinduction in
the reduction of 7a–e and 8e, the minimum energy con-
formers of the starting b-ketophosphonates were deter-
mined by applying the systematic search tool available
in the PC Spartan Pro v.1.0.511 with a MMFF94 force
field for geometry minimization and energy assessment12
(Fig. 2).
Examination of the lowest energy conformations for b-
ketophosphonates 7a–e, show that for 7a and 7c, the
nucleophilic attack of the hydride may take place via
the less hindered si face, leading to the corresponding
syn-b-hydroxyphosphonate 10 as the major product.
On the other hand, the hydride addition to b-ketophos-
phonates 7b, 7d–e, and 8e, may take place by the less
hindered re face, leading to the anti-b-hydroxyphospho-
nate 9 as the major product. These theoretical calcula-
tions are in good agreement with the experimental
data, and that the observed stereoselectivities depends
on the size of the R group on the side chain, as has been
shown with the reduction of a-amino ketones.13 The
stereoselectivity observed can be rationalized with
the Felkin–Anh14 model for the addition of hydride to
the free carbonyl group.
Figure 2. MMFF94 conformations of minimum energy for b-keto-
phosphonates 7a–e and 8e.
3. Conclusion
In summary, easy access to c-[(N-p-toluenesulfonyl)-
amino]-b-ketophosphonates 7 in conjunction with the
reduction of the carbonyl group using NaBH4 with
excellent yields and with good levels of diastereoselecti-
vity has been obtained. We consider this experimental
work an efficient and simple method to obtain diastereo-
merically enriched anti-c-N-p-toluenesulfonylamino-b-
hydroxyphosphonates.
TMS as internal reference. Microanalyses were obtained
from an Elemental VARIO EL III instrument.
Flasks, stirrings bars and hypodermic needles used for
the generation of organometallic compounds were dried
for ca. 12h at 120ꢁC and allowed to cool in a desiccator
over anhydrous calcium sulfate. Anhydrous solvents
(ethers) were obtained by distillation from benzophe-
none ketyl.
4. Experimental
4.1. General procedure for the preparation of (S)-N-p-
toluenesulfonyl methyl esters 6a–e
Optical rotations were measured on a Perkin–Elmer 241
polarimeter in a 1dm tube; concentrations are given in
g/100mL. Melting points were determined in a Buchi
¨
B-540 apparatus in open capillary tubes and are uncor-
rected. For flash chromatography, silica gel 60 (230–400
mesh ASTM, Merck) was used. The NMR spectra were
recorded on a Varian INOVA 400, 400MHz for 1H and
100MHz for 13C, and on a Varian Mercury 200 for 31P.
The spectra were recorded in CDCl3 solutions, using
To a stirred solution of 1.0equiv of a-amino acid methyl
ester hydrochloride and 2.2equiv of triethylamine in dry
dichloromethane (30mL) at 0ꢁC, was added slowly
1.1equiv of p-toluenesulfonyl chloride. The reaction
was stirred at room temperature for 12h. After this per-
iod of time, the solvent was removed in vacuo, the resi-
due was dissolved in ethyl acetate (25mL) and washed

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M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3039
with water (20mL). The organic phase was dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified by column
chromatography.
Harom). 13C NMR (100MHz, CDCl3)
d
21.6
((CH3)2CH), 21.7 (CH3Ar), 22.9 ((CH3)2CH), 24.5
(CH2), 42.5 (CH(CH3)2), 52.5 (OCH3), 54.5 (CHNH),
127.5, 129.8, 136.9, 143.8, 172.9 (C@O). Anal. Calcd
for C14H21NO4S: C, 56.16; H, 7.07; N, 4.68%. Found
C, 56.50; H, 7.26; N, 4.56%.
4.1.1. (S)-N-p-Toluenesulfonyl-alanine methyl ester
6a. The reaction was carried out starting from (S)-ala-
nine methyl ester hydrochloride (3.0g, 21.5mmol),
triethylamine (4.78g, 6.6mL, 47.3mmol), p-toluene-
sulfonyl chloride (4.5g, 23.6mmol), and dichlorometh-
ane (30mL) following the general procedure. The crude
product was purified by column chromatography using
hexane/ethyl acetate (80:20) to give 6a as a white solid,
4.86g, 88% yield. Mp 94–95ꢁC. [a]D = +0.4 (c = 1.2,
CHCl3). 1H NMR (400MHz, CDCl3) d 1.38 (d,
J = 7.6Hz, 3H, CH3), 2.42 (s, 3H, CH3Ar), 3.54 (s, 3H,
OCH3), 3.99 (m, 1H, CHN), 5.32 (d, J = 7.2Hz, 1H,
NH), 7.30 (AA0BB0 system, J = 8.0Hz, 2H, Harom),
7.73 (AA0BB0 system, J = 8.0Hz, 2H, Harom). 13C
NMR (100MHz, CDCl3) d 19.9 (CH3CH), 21.7
(CH3Ar), 51.6 (CHN), 52.8 (OCH3) 127.4, 129.8, 136.9,
143.9, 172.8 C@O. Anal. Calcd for C11H15NO4S: C,
51.35; H, 5.88; N, 5.44%. Found C, 51.26; H, 5.89; N,
5.42%.
4.1.4. (S)-N-p-Toluenesulfonyl-phenylalanine methyl ester
6d. The reaction was carried out starting from (S)-
phenylalanine methyl ester hydrochloride (3.0g,
13.9mmol), triethylamine (3.1g, 4.3mL, 20.6mmol), p-
toluenesulfonyl chloride (2.92g, 15.3mmol), and dichlo-
romethane (30mL) following the general procedure. The
crude product was purified by column chromatography
using hexane/ethyl acetate (80:20) to give 6d as a white
solid, 3.81g, 82% yield. Mp 97–98ꢁC. [a]D = +10.5
1
(c = 1.14, CHCl3). H NMR (400MHz, CDCl3) d 2.40
(s, 3H, CH3Ar), 3.03 (d, 6.0Hz, 1H, CH2Ph), 3.48 (s,
3H, OCH3), 4.20 (dt, J = 9.2, 6.0Hz, 1H, CHN),
5.10 (d, J = 9.2Hz, 1H, NH), 7.05–7.08 (m, 2H,
Harom), 7.22–7.26 (m, 5H, Harom), 7.63 (AA0BB0 system,
J = 8.0Hz, 2H, Harom). 13C NMR (100MHz, CDCl3) d
21.7 (CH3Ar) 39.5 (CH2Ph), 52.6 (OCH3), 56.8
(CHNH), 127.3, 127.4, 128.7, 129.6, 129.8, 135.1,
136.7, 143.8, 171.4 C@O. Anal. Calcd for C17H19NO4S:
C, 61.24; H, 5.74; N, 4.20%. Found C, 61.29; H, 5.81; N,
4.23%.
4.1.2. (S)-N-p-Toluenesulfonyl-valine methyl ester
6b. The reaction was carried out starting from (S)-va-
line methyl ester hydrochloride (3.0g, 17.8mmol), trieth-
ylamine (3.98g, 5.5mL, 39.4mmol), p-toluenesulfonyl
chloride (3.75g, 19.7mmol), and dichloromethane
(30mL) following the general procedure. The crude
product was purified by column chromatography using
hexane/ethyl acetate (80:20) to give 6b as a white solid,
4.33g, 85% yield. Mp 77–78ꢁC. [a]D = +15.6 (c = 0.89,
CHCl3). 1H NMR (400MHz, CDCl3) d 0.87 (d,
J = 6.8Hz, 3H, CH3), 0.95 (d, J = 6.8Hz, 3H, CH3),
1.97–2.08 (m, 1H, CH(CH3)2), 2.42 (s, 3H, CH3Ar),
3.44 (s, 3H, OCH3), 3.73 (dd, J = 10.0, 5.2Hz, 1H,
CHN), 5.12 (d, J = 10.0Hz, 1H, NH), 7.29 (AA0BB0 sys-
tem, J = 8.0Hz, 2H, Harom), 7.71 (AA0BB0 system,
J = 8.0Hz, 2H, Harom). 13C NMR (100MHz, CDCl3) d
17.8 ((CH3)2CH), 19.2 ((CH3)2CH), 21.8 (CH3Ar),
31.9 (CH(CH3)2), 52.4 (OCH3), 61.3 (CHN), 127.5,
129.7, 136.7, 143.8, 171.9 C@O. Anal. Calcd for
C13H19NO4S: C, 54.72; H, 6.71; N, 4.91%. Found C,
54.65; H, 6.84; N, 4.88%.
4.1.5. (S)-N-p-Toluenesulfonyl-phenylglycine methyl ester
6e. The reaction was carried out starting from (S)-
phenylglycine methyl ester hydrochloride (3.0g,
14.9mmol), triethylamine (3.31g, 4.6mL, 32.7mmol),
p-toluenesulfonyl chloride (3.12g, 16.4mmol), and
dichloromethane (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using hexane/ethyl acetate (80:20) to give
6e as a white solid, 4.21g, 89% yield. Mp 131–133ꢁC.
1
[a]D = +102.0 (c = 1.12, CHCl3). H NMR (400MHz,
CDCl3) d 2.38 (s, 3H, CH3Ar), 3.57 (s, 3H, OCH3),
5.06 (d, J = 7.6Hz, 1H, CHNH), 5.69 (d, J =
7.6Hz, 1H, NH), 7.19–7.27 (m, 7H, Harom),
7.62 (AA0BB0 system, J = 8.0Hz, 2H, Harom). 13C NMR
(100MHz, CDCl3) d 21.8 (CH3Ar), 53.2 (OCH3), 59.5
(CHNH), 127.3, 127.4, 128.8, 129.0, 129.7, 135.4,
137.1, 143.7, 170.8 C@O. Anal. Calcd for C16H17NO4S:
C, 60.17; H, 5.37; N, 4.39%. Found C, 60.16; H, 5.48; N,
4.34%.
4.1.3. (S)-N-p-Toluenesulfonyl-leucine methyl ester
6c. The reaction was carried out starting from (S)-leu-
cine methyl ester hydrochloride (3.0g, 16.5mmol),
triethylamine (3.76g, 5.1mL, 36.3mmol), p-tolu-
enesulfonyl chloride (3.46g, 18.2mmol), and dichloro-
methane (30mL) following the general procedure. The
crude product was purified by column chromatography
using hexane/ethyl acetate (80:20) to give 6c as a color-
less liquid, 4.83g, 98% yield. [a]D = +8.0 (c = 1.59,
CHCl3). 1H NMR (400MHz, CDCl3) d 0.88 (d,
J = 6.8Hz, 3H, CH3), 0.90 (d, J = 6.8Hz, 3H, CH3),
1.46 (ddd, 16.8, 8.8, 6.0Hz, 1H, CH2), 1.49 (ddd, 16.8,
8.4, 5.6Hz, 1H, CH2), 1.74–184 (m, 1H, CH(CH3)2,
2.42 (s, 3H, CH3Ar), 3.43 (s, 3H, OCH3), 3.93 (ddd,
J = 10.0, 8.4, 6.0Hz, 1H, CHN), 5.06 (d, J = 10.0Hz,
1H, NH), 7.25–7.29 (m, 2H, Harom), 7.67–7.72 (m, 2H,
4.2. General procedure for the preparation of (S)-c-N-p-
toluenesulfonyl-b-ketophosphonates 7a–e and 8e
A solution of dimethyl methylphosphonate (3.0equiv) in
anhydrous THF (40mL) was cooled at ꢀ78ꢁC before
the slow addition of 3.1equiv of n-BuLi in hexanes.
The resulting solution was stirred at ꢀ50ꢁC for 1.5h,
and then the solution cooled at ꢀ78ꢁC and slowly added
to a solution of methyl ester 6 (1.0equiv) in anhydrous
THF (30mL). The reaction mixture was stirred at
ꢀ78ꢁC for 4h and quenched with aqueous NH4Cl solu-
tion. The solvent was evaporated in vacuo, and the res-
idue was dissolved in water (30mL) and extracted with
ethyl acetate (3 · 40mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered,

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M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3040
and concentrated in vacuo. The crude b-ketophospho-
nates were purified by flash chromatography.
hexanes 2.5M, (10.8mL, 25.9mmol), (S)-N-p-toluene-
sulfonyl-leucine methyl ester 6c (2.5g, 8.4mmol) in
anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using hexane/ethyl acetate (1:2) to give 7c
as a colorless liquid, 2.82g, 86% yield. [a]D = +0.3
4.2.1. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-2-oxobu-
tylphosphonate 7a. The reaction was carried out start-
ing from dimethyl methylphosphonate (3.61g,
29.1mmol) in anhydrous THF (40mL), n-BuLi in hex-
anes 2.5M, (12.5mL, 30.1mmol), (S)-N-p-toluenesulfo-
nyl-alanine methyl ester 6a (2.5g, 9.7mmol) in
anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chroma-
tography using hexane/ethyl acetate (1:2) to give 7a as a
white solid, 3.1g, 90% yield. Mp 78–81ꢁC. [a]D = +0.15
1
(c = 5.02, CHCl3). H NMR (400MHz, CDCl3) d 0.69
(d, J = 6.4Hz, 3H, (CH3)2CH), 0.81 (d, J = 6.4Hz,
3H, (CH3)2CH), 1.37 (ddd, J = 13.6, 10.0, 4.4Hz, 1H,
CH2CH), 1.51 (ddd, J = 13.6, 10.0, 4.4Hz, 1H,
CH2CH), 1.53–1.64 (m, 1H, CH(CH3)2), 2.42 (s, 3H,
CH3Ar), 3.03 (dd, J = 22.0, 14.0Hz, 1H, CH2P), 3.47
(dd, J = 22.0, 14.0Hz, 1H, CH2P), 3.74 (d, J = 11.2Hz,
3H, (CH3O)2P), 3.77 (d, J = 11.2Hz, 3H, (CH3O)2P),
3.96 (ddd, J = 9.6, 8.8, 4.0Hz, 1H, CHN), 5.97 (d,
J = 8.8Hz, 1H, NH), 7.30 (AA0BB0 system, J = 8.0Hz,
2H, Harom), 7.75 (AA0BB0 system, J = 8.0Hz, 2H, Harom).
13C NMR (100MHz, CDCl3) d 21.2 ((CH3)2CH), 21.7
(CH3Ar), 23.2 (CH3)2CH), 24.5 (CH(CH3)2), 38.1 (d,
J = 129.1Hz, CH2P), 40.7 (CH2CH), 53.3 (d,
J = 6.1Hz, (CH3O)2P), 53.4 (d, J = 6.1Hz, (CH3O)2P),
61.1 (CHN), 127.4, 129.8, 137.4, 143.8, (201.9 (C@O).
31P NMR (200MHz, CDCl3): d 23.45. Anal. Calcd for
C16H26NO6PS: C, 49.10; H, 6.70; N, 3.58%. Found: C,
48.88; H, 6.82; N, 3.54%.
1
(c = 6.36, CHCl3). H NMR (400MHz, CDCl3) d 1.23
(d, J = 7.2Hz, 3H, CH3CH), 2.43 (s, 3H, CH3Ar), 3.08
(dd, J = 22.4, 14.0,Hz, 1H, CH2P), 3.54 (dd, J = 22.4,
14.0Hz, 1H, CH2P), 3.73 (d, J = 11.2Hz, 3H,
(CH3O)2P), 3.78 (d, J = 11.2Hz, 3H, (CH3O)2P), 4.03
(q, J = 7.6Hz, 1H, CHN), 6.19 (d, J = 7.6Hz, 1H,
NH), 7.31 (AA0BB0 system, J = 8.0Hz, 2H, Harom),
7.75 (AA0BB0 system, J = 8.0Hz, 2H, Harom). 13C
NMR (100MHz, CDCl3) d 18.0 (CH3CH), 21.7
(CH3Ar), 37.9 (d, J = 127.5Hz, CH2P), 53.4
(d, J = 6.1Hz, (CH3O)2P), 53.5 (d, J = 6.1Hz,
(CH3O)2P), 58.3 (CHN), 127.2, 129.9, 137.4, 143.8,
201.3 (d, J = 4.5Hz, C@O). 31P NMR (200MHz,
CDCl3): d 23.29. Anal. Calcd for C13H20NO6PS: C,
44.70; H, 5.77; N, 4.01%. Found: C, 44.60; H, 5.77; N,
4.01%.
4.2.4. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-2-oxo-4-
phenylbutylphosphonate 7d. The reaction was carried
out starting from dimethyl methylphosphonate (2.79g,
22.5mmol) in anhydrous THF (40mL), n-BuLi in
hexanes 2.5M, (9.7mL, 23.2mmol), (S)-N-p-toluene-
sulfonyl-phenylalanine methyl ester 6d (2.5g, 7.5mmol)
in anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using hexane/ethyl acetate (1:2) to give 7d
as a white solid, 2.99g, 94% yield. Mp 110–112ꢁC.
[a]D = +0.2 (c = 4.73, CHCl3). 1H NMR (400MHz,
CDCl3) d 2.39 (s, 3H, CH3Ar), 2.87 (dd, J = 14.0,
8.4Hz, 1H, CH2Ph), 3.06 (dd, J = 22.8, 14.0Hz, 1H,
CH2P), 3.08 (dd, J = 14.0, 5.2Hz, 1H, CH2Ph), 3.66
(dd, J = 22.8, 14.0Hz, 1H, CH2P), 3.71 (d, J = 11.4Hz,
3H, (CH3O)2P), 3.77 (d, J = 11.4Hz, 3H, (CH3O)2P),
4.17 (ddd, J = 8.0, 8.0, 5.2Hz, 1H, CHN), 5.90 (d,
J = 8.0Hz, 1H, NH), 6.98 (AA0BB0 system, J = 8.0Hz,
2H, Harom), 7.12–7.17 (m, 5H, Harom), 7.44 (AA0BB0 sys-
tem, J = 8.0Hz, 2H, Harom). 13C NMR (100MHz,
CDCl3) d 21.7 (CH3Ar), 37.8 (CH2Ph), 38.7 (d,
J = 127.5Hz, CH2P), 53.4 (d, J = 6.1Hz, (CH3O)2P),
53.5 (d, J = 6.1Hz, (CH3O)2P), 63.8 (CHN), 127.0,
127.1, 128.8, 129.5, 129.8, 135.8, 136.9, 143.6, 201.2
(C@O). 31P NMR (200MHz, CDCl3): d 23.34. Anal.
Calcd for C19H24NO6PS: C, 53.64; H, 5.69; N, 3.29%.
Found: C, 53.38; H, 5.52; N, 3.43%.
4.2.2. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-4-methyl-
2-oxopentylphosphonate 7b. The reaction was carried
out starting from dimethyl methylphosphonate
(3.26g, 26.3mmol) in anhydrous THF (40mL), n-BuLi
in hexanes 2.5M, (11.3mL, 27.2mmol), (S)-N-p-tolu-
enesulfonyl-valine methyl ester 6b (2.5g, 8.8mmol) in
anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using hexane/ethyl acetate (1:2) to give 7b
as a white solid, 3.25g, 98% yield. Mp 108–110ꢁC.
[a]D = +66.1 (c = 5.92, CHCl3). 1H NMR (400MHz,
CDCl3) d 0.70 (d, J = 6.8Hz, 3H, (CH3)2CH), 0.94 (d,
J = 6.8Hz, 3H, (CH3)2CH), 2.25 (m, 1H, CH(CH3)2),
2.41 (s, 3H, CH3Ar), 2.98 (dd, J = 22.4, 14.4Hz, 1H,
CH2P), 3.24 (dd, J = 22.4, 14.4,Hz, 1H, CH2P), 3.69
(d, J = 11.2Hz, 3H, (CH3O)2P), 3.73 (d, J = 11.2Hz,
3H, (CH3O)2P), 3.99 (dd, J = 9.0, 3.6Hz, 1H, CHN),
5.80 (d, J = 9.0Hz, 1H, NH), 7.28 (AA0BB0
system, J = 8.0Hz, 2H, Harom), 7.73 (AA0BB0 system,
J = 8.0Hz, 2H, Harom). 13C NMR (100MHz, CDCl3) d
16.4 (CH3)2CH), 20.1 (CH3)2CH), 21.7 (CH3Ar), 29.8
(CH(CH3)2), 38.5 (d, J = 129.1Hz, CH2P), 53.3 (d,
J = 6.1Hz, (CH3O)2P), 53.4 (d, J = 6.1Hz, (CH3O)2P),
67.6 (d, J = 2.3Hz, CHNH), 127.4, 129.8, 137.4, 143.7,
200.5 (d, J = 6.0Hz, C@O). 31P NMR (200MHz,
CDCl3): d 22.70. Anal. Calcd for C15H24NO6PS: C,
47.74; H, 6.41; N, 3.71%. Found: C, 47.50; H, 6.38; N,
3.69%.
4.2.5. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-2-oxo-4-
phenylpropylphosphonate 7e. The reaction was carried
out starting from dimethyl methylphosphonate (2.91g,
23.5mmol) in anhydrous THF (40mL), n-BuLi in hexa-
nes 2.5M, (10.1mL, 24.3mmol), (S)-N-p-toluenesulfonyl-
phenylglycine methyl ester 6e (2.5g, 7.8mmol) in
anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using hexane/ethyl acetate (1:2) to give 7e
4.2.3.
Dimethyl
(S)-3-[(p-toluenesulfonyl)amino]-5-
methyl-2-oxohexylphosphonate 7c. The reaction was
carried out starting from dimethyl methylphosphonate
(3.1g, 25mmol) in anhydrous THF (40mL), n-BuLi in

´
M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3041
as a white solid, 2.23g, 69% yield. Mp 129–130ꢁC.
[a]D = +0.5 (c = 5.71, CHCl3). 1H NMR (400MHz,
CDCl3) d 2.34 (s, 3H, CH3Ar), 2.82 (dd, J = 22.4,
14.0Hz, 1H, CH2P), 3.18 (dd, J = 22.4, 14.0Hz, 1H,
CH2P), 3.69 (d, J = 11.2Hz, 3H, (CH3O)2P), 3.70 (d,
J = 11.2Hz, 3H, (CH3O)2P), 5.29 (d, J = 6.0Hz, 1H,
CHN), 6.23 (d, J = 6.0Hz, 1H, NH), 7.11 (AA0BB0 sys-
tem, J = 8.0Hz, 2H, Harom), 7.12–7.14 (m, 2H, Harom),
7.21–7.26 (m, 3H, Harom), 7.51 (AA0BB0 system,
J = 8.0Hz, 2H, Harom). 13C NMR (100MHz, CDCl3) d
21.6 (CH3Ar), 37.9 (d, J = 129.1Hz, CH2P), 53.4 (d,
J = 7.6Hz, (CH3O)2P), 53.4 (d, J = 7.6Hz, (CH3O)2P),
66.5 (CHN), 127.2, 128.4, 129.1, 129.4, 129.5, 134.6,
137.4, 143.3, 196.5 (d, J = 6.1Hz, C@O). 31P NMR
b-hydroxyphosphonates anti-9a and syn-10a, in the ratio
29:71, respectively. 31P NMR (200MHz, CDCl3): d
34.62 for anti-9a and 34.18 for syn-10a. The diastereo-
meric mixture was not isolated in a sufficiently pure
form for elemental analysis and determining the specific
rotation.
4.3.2. Reduction of 7b. The reaction was carried out
starting from b-ketophosphonate 7b (1.0g, 2.65mmol)
in methanol (50mL), NaBH4 (401mg, 10.6mmol) fol-
lowing the general procedure, to afford 992mg, 99%
yield of b-hydroxyphosphonates anti-9b and syn-10b,
in the ratio 81:19, respectively. 31P NMR (200MHz,
CDCl3): d 34.69 for anti-9b and 34.46 for syn-10b. The
diastereomeric mixture was not isolated in a sufficiently
pure form for elemental analysis and determining the
specific rotation.
(200MHz, CDCl3):
d
21.97. Anal. Calcd for
C18H22NO6PS: C, 52.55; H, 5.39; N, 3.40. Found: C,
52.36; H, 5.37; N, 3.40%.
4.2.6. Dimethyl (S)-3-[(methanesulfonyl)amino]-2-oxo-4-
phenylpropylphosphonate 8e. The reaction was carried
out starting from dimethyl methylphosphonate (1.53g,
12.3mmol) in anhydrous THF (30mL), n-BuLi in hexa-
nes 1.8M, (7.1mL, 12.7mmol), (S)-N-p-methanesulfo-
nyl-phenylglycine methyl ester (1.0g, 4.1mmol) in
anhydrous THF (30mL) following the general proce-
dure. The crude product was purified by column chro-
matography using ethyl acetate/hexane (8:1) to give 8e
as a white solid, 1.1g, 60% yield. Mp 107–108ꢁC.
[a]D = ꢀ0.2 (c = 2.11, CHCl3). 1H NMR (200MHz,
CDCl3) d 2.64 (s, 3H, CH3SO2), 2.89 (dd, J = 22.4,
14.0,Hz, 1H, CH2P), 3.24 (dd, J = 22.4, 14.0Hz, 1H,
CH2P), 3.77 (d, J = 11.4Hz, 3H, (CH3O)2P), 3.79 (d,
J = 11.4Hz, 3H, (CH3O)2P), 5.44 (d, J = 6.0Hz, 1H,
CHN), 5.99 (d, J = 6.0Hz, 1H, NH), 7.25–7.47 (m,
5H, Harom). 13C NMR (50MHz, CDCl3) 38.3 (d,
J = 128.5Hz, CH2P), 42.1 CH3SO2, 53.6 (d, J = 6.4Hz,
(CH3O)2P), 53.7 (d, J = 6.4Hz, (CH3O)2P), 66.6
(CHN), 128.3, 128.4, 129.7, 134.6, 196.3 (d, J = 6.1Hz,
C@O). 31P NMR (200MHz, CDCl3): d 21.76. Anal.
Calcd for C12H18NO6PS: C, 42.98; H, 5.41; N, 4.18.
Found: C, 42.57; H, 5.32; N, 4.45%.
4.3.3. Reduction of 7c. The reaction was carried out
starting from b-ketophosphonate 7c (1.0g, 2.55mmol)
in methanol (50mL), NaBH4 (387mg, 10.2mmol) fol-
lowing the general procedure, to afford 981mg, 98%,
yield of b-hydroxyphosphonates anti-9c and syn-10c,
in the ratio 29:71, respectively. 31P NMR (200MHz,
CDCl3): d 34.75 for anti-9c and 33.80 for syn-10c. The
diastereomeric mixture was not isolated in a sufficiently
pure form for elemental analysis and determining the
specific rotation.
4.3.4. Reduction of 7d. The reaction was carried out
starting from b-ketophosphonate 7d (1.0g, 2.35mmol)
in methanol (50mL), NaBH4 (355mg, 9.4mmol) follow-
ing the general procedure. The diastereomeric mixture
was purified by flash chromatography hexane/AcOEt
(1:3) to afford 978mg, 97% yield.
4.3.5. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-(S)-2-
hydroxy-4-phenylbutylphosphonate anti-9d. The dia-
stereomer anti-9d was not isolated in a sufficiently pure
form for elemental analysis and determining the specific
rotation.
4.3. General procedure for the reduction of (S)-c-N-p-
toluenesulfonyl-b-ketophosphonates 7a–e and 8e with
NaBH4
4.3.6. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-(R)-2-
hydroxy-4-phenylbutylphosphonate
syn-10d.
White
1
solid, mp 131–132ꢁC. [a]D = ꢀ79.4 (c = 1.89, CHCl3). H
NMR (400MHz, CDCl3) d 1.73 (ddd, J = 17.6, 15.2,
2.0Hz, 1H, CH2P), 2.16–2.26 (m, 1H, CH2P), 2.40 (s,
3H, CH3Ar), 2.50 (dd, J = 13.4, 5.8Hz, 1H, CH2Ph),
2.87 (dd, J = 13.4, 9.4Hz, 1H, CH2Ph), 3.35–3.41 (m,
1H, CHOH), 3.68 (d, J = 11.2Hz, 3H, (CH3O)2P),
3.73 (d, J = 11.2Hz, 3H, (CH3O)2P), 3.91–3.98 (m, 1H,
CHN), 5.56 (d, J = 9.2Hz, 1H, NH), 7.03 (AA0BB0 sys-
tem, J = 8.0Hz, 2H, Harom), 7.14–7.25 (m, 5H, Harom),
7.66 (AA0BB0 system, J = 8.0Hz, 2H, Harom). 13C
NMR (100MHz, CDCl3) d 21.7 (CH3Ar), 29.8 (d,
J = 139.6Hz, CH2P), 38.4 (CH2Ph), 52.8 (d,
J = 6.1Hz, (CH3O)2P), 52.9 (d, J = 6.1Hz, (CH3O)2P),
60.3 (d, J = 18.2Hz, CHOH), 65.4 (d, J = 4.5Hz,
CHNH), 126.7, 127.0, 128.7, 129.5, 129.9, 137.6, 138.5,
143.4. 31P NMR (200MHz, CDCl3): d 34.56. Anal.
Calcd for C19H26NO6PS: C, 53.39 H, 6.13; N, 3.22%.
Found: C, 53.07; H, 6.06; N, 3.22%.
A solution of (S)-c-N-p-toluenesulfonyl-b-ketophospho-
nates 7 or 8 (1.0equiv) in methanol or dry THF (50mL)
was cooled at 0ꢁC, and then NaBH4 (4.0equiv) added.
The reaction mixture was stirred at room temperature
for 4h. The solvent was then evaporated in vacuo and
the residue dissolved in water (30mL) and extracted
with ethyl acetate (3 · 50mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The crude b-hydroxyphos-
phonates were analyzed by 1H NMR at 400MHz
and 31P NMR at 200MHz, and purified by flash
chromatography.
4.3.1. Reduction of 7a. The reaction was carried out
starting from b-ketophosphonate 7a (1.0g, 2.9mmol)
in methanol (50mL), NaBH4 (433 g, 11.5mmol) follow-
ing the general procedure, to afford 962mg, 96% yield of

´
M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3042
4.3.7. Reduction of 7e. The reaction was carried out
starting from b-ketophosphonate 7e (1.0g, 2.43mmol)
in methanol (50mL), NaBH4 (368mg, 9.7mmol) follow-
ing the general procedure. The diastereomeric mixture
was purified by flash chromatography hexane/AcOEt
(1:3) to afford 973mg, 97% yield.
Acknowledgements
We wish to thank CONACYT of Mexico, for financial
support via grant 41657-Q for this work. One of us,
R.C.C., also wishes to thank CONACYT for a Gradu-
ate Scholarship. We also thank Citlali Quin˜ones for
technical support.
4.3.8. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-(S)-2-
hydroxy-4-phenylpropylphosphonate
anti-9e. White
References
1
solid, mp 169–170ꢁC. [a]D = +0.5 (c = 1.19, CHCl3). H
NMR (400MHz, CDCl3) d 1.67 (ddd, J = 16.2, 15.6,
10.0Hz, 1H, CH2P), 1.96 (ddd, J = 19.6, 15.6, 2.4Hz,
1H, CH2P), 2.31 (s, 3H, CH3Ar), 3.69 (d, J = 10.8Hz,
3H, (CH3O)2P), 3.73 (d, J = 10.8Hz, 3H, (CH3O)2P),
3.97 (d, J = 3.2, 1H, OH), 4.29 (dd, J = 7.6, 4.4Hz,
1H, CHNH), 4.31–4.38 (m, 1H, CHOH), 6.26 (d,
J = 7.6Hz, 1H, NH), 7.03–7.18 (m, 7H, Harom), 7.46
(AA0BB0 system, J = 8.4Hz, 2H, Harom). 13C NMR
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.; O0Hagan, 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.
3. 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.
4. (a) Dellaria, J. F., Jr.; Maki, R. G. Tetrahedron Lett. 1986,
27, 2337; (b) 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. 1989, 32, 1886.
5. Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64,
8379.
(100MHz, CDCl3)
d
21.6 (CH3Ar), 29.4 (d,
J = 139.7Hz, CH2P), 52.8 (d, J = 7.6Hz, (CH3O)2P),
53.0 (d, J = 6.1Hz, (CH3O)2P), 62.5 (d, J = 19.7Hz,
CHOH), 69.1 (d, J = 4.5Hz, CHNH), 127.2, 127.9,
128.3, 128.4, 129.4, 136.4, 137.7, 143.1. 31P NMR
(200MHz, CDCl3):
d
33.73. Anal. Calcd for
C18H24NO6PS: C, 52.29; H, 5.85; N, 3.39. Found: C,
52.11; H, 5.89; N, 3.42%.
´
´
6. Ordon˜ez, M.; De la Cruz-Cordero, R.; Fernandez-Zertu-
che, M.; Mun˜oz-Hernandez, M. A. Tetrahedron: Asym-
´
4.3.9. Dimethyl (S)-3-[(p-toluenesulfonyl)amino]-(R)-2-
syn-10e. White
metry 2002, 13, 559.
hydroxy-4-phenylpropylphosphonate
7. (a) Maurer, P. J.; Takahata, H.; Rapoport, H. J. Am.
Chem. Soc. 1984, 106, 1095; (b) Roemmele, R. C.;
Rapoport, H. J. Org. Chem. 1989, 54, 1866.
1
solid, mp 150–153ꢁC. [a]D = +0.6 (c = 1.23, CHCl3). H
NMR (400MHz, CDCl3) d 1.80 (ddd, J = 19.6, 15.6,
2.4Hz, 1H, CH2P), 2.08 (ddd, J = 16.8, 15.6, 10.8Hz,
1H, CH2P), 2.32 (s, 3H, CH3Ar), 3.69 (d, J = 11.2Hz,
3H, (CH3O)2P), 3.73 (d, J = 11.2Hz, 3H, (CH3O)2P),
4.09–4.16 (m, 1H, CHOH), 4.20 (dd, J = 7.2, 5.6Hz,
1H, CHNH), 4.28 (d, J = 4.0, 1H, OH), 6.19
(d, J = 6.4Hz, 1H, NH), 7.04–7.16 (m, 7H, Harom),
7.46 (AA0BB0 system, J = 8.4Hz, 2H, Harom).
13C NMR (100MHz, CDCl3) d 21.6 (CH3Ar), 29.8 (d,
J = 139.7Hz, CH2P), 52.7 (d, J = 6.1Hz, (CH3O)2P),
53.1 (J = 6.1Hz, (CH3O)2P), 63.4 (d, J = 19.8Hz,
CHOH), 69.9 (d, J = 4.6Hz, CHNH), 127.5, 127.2,
127.9, 128.5, 129.4, 137.7, 138.1, 143.1. 31P NMR
8. X-ray crystal data of syn-10d (CCDC 249670) were
collected at 273(2)K using a Bruker APEX instrument
˚
(Mo Ka radiation, k = 0.71073A). The SHELXTL v. 6.1
program package was used for structure solution and
refinement. The structure was solved by direct methods
and refined by full-matrix least squares procedures. All
nonhydrogen atoms were refined anisotropically. syn-10d:
C19H26NO6PS, M = 427.45, monoclinic space group P21,
˚
a = 9.2038(10), b = 10.7658(12), c = 10.9662(12)A,
˚
Dc = 1.308gcmꢀ1
3
a = 90ꢁ, b = 93.145(2)ꢁ, c = 90ꢁ, V = 1085(2)A , Z = 2,
, 11,608 reflections measured, 4662
unique (Rint = 0.0182), which were used in all calculations,
final R values were 0.0379 [I > 2r(I)] and 0.0390 (all data).
9. X-ray crystal data of anti-9e (CCDC 249669) were
collected at 273(2)K using a Bruker APEX instrument
(200MHz, CDCl3):
d
33.66. Anal. Calcd for
C18H24NO6PS: C, 52.29; H, 5.85; N, 3.39. Found: C,
52.31; H, 5.93; N, 3.39%.
˚
(Mo Ka radiation, k = 0.71073A). The SHELXTL v. 6.1
program package was used for structure solution and
refinement. The structure was solved by direct methods
and refined by full-matrix least squares procedures. All
nonhydrogen atoms were refined anisotropically. anti-9e:
C18H24NO6PS, M = 413.43, triclinic space group P-1,
4.4. General procedure for the reduction of (S)-c-N-p-
toluenesulfonyl-b-ketophosphonates 7a–e with the rest of
hydrides
˚
a = 6.9930(14), b = 8.6008(18), c = 17.012(4)A, a =
A solution of (S)-c-N-p-toluenesulfonyl-b-ketophospho-
nates 7 (1.0equiv) dry THF (50mL) was cooled at
ꢀ78ꢁC, and then the corresponding hydride (4.0equiv)
added. The reaction mixture was stirred at ꢀ78ꢁC for
4h, and then quenched with aqueous NH4Cl solution.
The solvent was evaporated in vacuo, the residue dis-
solved in water (30mL) and extracted with ethyl acetate
(3 · 30mL). The combined organic extracts and dried
over anhydrous Na2SO4, filtered, and concentrated
in vacuo. The crude b-hydroxyphosphonates were ana-
lyzed by 1H NMR at 400MHz and 31P NMR at
200MHz, and purified by flash chromatography.
92.665(3)ꢁ,
b = 98.064(4)ꢁ,
c = 104.679(4)ꢁ,
V =
3
976.4(3)A , Z = 2, Dc = 1.403gcmꢀ1, 4875 reflections
measured, 3376 unique (Rint = 0.0345), which were used
in all calculations, final R values were 0.0496 [I > 2r(I)]
and 0.0549 (all data).
˚
10. Full paper on the preparation of c-amino-b-hydroxypro-
pylphosphonic acids from dimethyl c-N,N-dibenzylamino-
b-hydroxyphosphonates syn-4 and anti-5 is in process.
11. Deppmeier, B. J.; Driessen, A. J.; Hehre, W. J.; Johnson,
J. A.; Klunzinger, P. E.; Watanabe, M.; Yu, J. PC Spartan
Pro v.1.0.5: Wavefunction; 18401 Von Karman Ave., Suite
370, Irvine, CA 92612.
12. Halgren, T. A. J. Comput. Chem. 1996, 17, 490.

´
M. Ordon˜ez et al. / Tetrahedron: Asymmetry 15 (2004) 3035–3043
3043
13. Benedetti, F.; Miertus, S.; Norbedo, S.; Tossi, A.;
Zlatoidzky, P. J. Org. Chem. 1997, 62, 9348, and
references cited therein.
14. (a) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968, 18,
2199; (b) Cherest, M.; Felkin, H. Tetrahedron Lett. 1968,
18, 2205; (c) Anh, N. T.; Eisenstein, O. Nouv. J. Chem.
1977, 1, 61; For an excellent summary, see: (d) Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; John Wiley and Sons: New York, 1984;
p 876.