Synthesis of diethyl (1R,2R)- and (1S,2R)-3-acetamido-1,2-dihydroxypropylphosphonates

Article abstract of DOI:10.1016/S0957-4166(02)00199-4

Diastereomeric diethyl (1R,2R)- and (1S,2R)-2,3-epoxy-1-benzyloxypropylphosphonates were obtained from the respective 2,3-O-cyclohexylidene-1-hydroxypropylphosphonates via the following sequence of reactions: benzylation, acetal hydrolysis and transformation of the terminal diol into the epoxide using the Sharpless protocol. These epoxides were regioselectively opened with dibenzylamine to afford the title compounds after acetylation and hydrogenolysis.

Full text of DOI:10.1016/S0957-4166(02)00199-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 845–850
Synthesis of diethyl (1R,2R)- and
(1S,2R)-3-acetamido-1,2-dihydroxypropylphosphonates
Andrzej E. Wro´blewski* and Katarzyna B. Balcerzak
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszynskiego 1, Poland
Received 13 March 2002; accepted 22 April 2002
Abstract—Diastereomeric diethyl (1R,2R)- and (1S,2R)-2,3-epoxy-1-benzyloxypropylphosphonates were obtained from the
respective 2,3-O-cyclohexylidene-1-hydroxypropylphosphonates via the following sequence of reactions: benzylation, acetal
hydrolysis and transformation of the terminal diol into the epoxide using the Sharpless protocol. These epoxides were
regioselectively opened with dibenzylamine to afford the title compounds after acetylation and hydrogenolysis. © 2002 Published
by Elsevier Science Ltd.
1. Introduction
we present the efficient transformation of diethyl
(1R,2R)- and (1S,2R)-2,3-O-cyclohexylidene-1-hydroxy-
The biological activity of several phosphonate and
phosphinate derivatives containing amino and hydroxy
groups has been well documented.1–4 Synthetic
approaches to these compounds rely mostly on con-
necting H-phosphonates or phosphinates with appro-
priate carbon chirons. For the synthesis of a-amino-
alkylphosphonates various modifications of the Fields–
Kabachnik reaction have been applied5 including the
most recent examples.6,7 When b-amino-a-hydroxy-
alkylphosphonates are required, addition to protected
b-amino aldehydes is the method of choice.1–4,8–12 The
same strategy seems to be appropriate for the synthesis
of g-amino-a,b-dihydroxyalkylphosphonates.
propylphosphonates
oxypropylphosphonates 2 and 3-amino-1,2-dihydroxy-
propylphosphonates 1.
3
into
2,3-epoxy-1-benzyl-
2. Results and discussion
The reaction sequence leading to diethyl (1R,2R)- and
(1S,2R)-2,3-epoxy-1-benzyloxypropylphosphonates 2 is
outlined in Scheme 2.
Enantiomerically pure (1R,2R)-3a and (1S,2R)-3b14
were subjected to benzylation with benzyl bromide in
the presence of silver oxide and powdered molecular
sieves. Under these slightly alkaline conditions the
retro-Abramov reaction15 was suppressed, and the cor-
responding 1-O-benzylated phosphonates (1R,2R)-4a
and (1S,2R)-4b were separated as pure diastereoisomers
in 93 and 86% yield, respectively. However, in the 31P
NMR spectra of the crude products, small resonances
Terminal epoxides are extremely useful precursors to
vicinal v-amino alcohols. We have recently shown that
highly enantiomerically enriched 3-amino-2-hydroxy-
propylphosphonates can be prepared by regioselective
opening of diethyl 2,3-epoxypropylphosphonate
obtained via HKR of the racemic epoxide in the pres-
ence of the Jacobsen catalyst.13 In order to synthesise
substituted 3-amino-1,2-dihydroxypropylphosphonates
1 (Scheme 1) a similar strategy was applied. Our
approach takes advantage of the mild conditions and
full regiochemistry of the epoxide ring opening while
preserving the phosphonate ester functionality. Herein,
Scheme 1. Retrosynthesis of 3-amino-1,2-hydroxypropylphos-
phonates.
* Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@
ich.pharm.am.lodz.pl
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00199-4

846
A. E. Wro´blewski, K. B. Balcerzak / Tetrahedron: Asymmetry 13 (2002) 845–850
Scheme 2. Reagents and conditions: (a) BnBr, Ag2O, A4, 24 h; (b) HCl, H2O, dioxane, 24 h; (c) MeC(OMe)3, PPTS; (d) AcBr;
(e) K2CO3, MeOH, 2 h.
order to accelerate hydrogenolysis of the dibenzylamino
group and to prevent future nucleophilic attack of the
H2N–C(3) group at the phosphorus atom,22 the inter-
mediates 8 were first acetylated and the fully protected
phosphonates 9 were subjected to hydrogenolysis over
Pearlman’s catalyst to give the title compounds 10.
at −0.25 ppm were found, i.e. ca. 1% and up to 8%
during benzylation of 3a and 3b, respectively. This is
probably (2,3-O-cyclohexylidene-2,3-dihydroxypropyl)-
diethyl phosphate, which is formed by the a-hydroxy-
phosphonate–phosphate rearrangement.16 Deprotection
of the cyclohexylidene group was accomplished under
standard conditions17 to give the terminal diols
(1R,2R)-5a and (1S,2R)-5b almost quantitatively. Sev-
eral attempts to achieve a clean transformation of 5
into terminal epoxides 2 have been reported in the
literature.18–20 The best results were obtained when the
Sharpless three-step (5“6“7“2) one-pot procedure21
was applied. Under these conditions the epoxides
(1R,2R)-2a and (1S,2R)-2b were formed from the cor-
responding diols in 77 and 53% yield, respectively. In
preliminary experiments intermediate bromides 7 were
Diastereoisomeric
3-acetamido-1,2-dihydroxypropyl-
phosphonates 10a and 10b exist preferentially as anti-
conformers (Scheme 4). They are stabilised by the
antiperiplanar disposition of the largest substituents
about the C(1)ꢀC(2) bond and by the formation of the
hydrogen bond between the HOꢀC(2) and P=O
groups, possibly within six-membered rings, which
adopt a chair conformation. These conclusions are
3
based on the large JCCCP coupling constant values
(12.9 Hz for 10a and 13.5 Hz for 10b) together with
vicinal C(1)H–C(2)H couplings (3.0 Hz for 10a and
10.0 Hz for 10b).23–26
1
separated and characterized by H, 13C and 31P NMR
spectroscopy.
O-Benzylated phosphonates 2 were used as starting
materials in the synthesis of 3-amino-1,2-dihydroxy-
propylphosphonates 1 (Scheme 3).
3. Conclusions
Following our previous experience with the regioselec-
tive opening of the epoxide ring in structurally related
systems13 dibenzylamine was selected. In the presence
of 1.1 equiv. of this amine the phosphonates 2 were
cleanly and completely reacted at 50°C after 3 days. In
Diastereoisomerically pure diethyl (1R,2R)- and
(1S,2R)-2,3-O-cyclohexylidene-1-hydroxypropylphos-
phonates were efficiently transformed into the respec-
tive diethyl 1-benzyloxy-2,3-epoxypropylphosphonates,
Scheme 3. Reagents and conditions: (a) HNBn2, 3 days; (b) Ac2O, TEA, cat. DMAP, 1.5 h; (c) H2−Pd(OH)2/C, 6 days.

A. E. Wro´blewski, K. B. Balcerzak / Tetrahedron: Asymmetry 13 (2002) 845–850
847
Scheme 4. Preferred conformations of 10a and 10b.
which are useful starting materials for the synthesis of
3-substituted 1,2-dihydroxypropylphosphonates. Fully
C(3)-regioselective oxirane ring opening in these 2,3-
epoxyphosphonates was achieved with dibenzylamine
leading after acetylation and hydrogenolysis to diethyl
(1R,2R)- and (1S,2R)-3-acetamido-1,2-dihydroxypro-
pylphosphonates.
w=2981, 2935, 2862, 1255, 1101, 1027, 740 and 699
1
cm−1; H NMR (300 MHz, CDCl3): l=7.40–7.27 (m,
5H), 4.86 and 4.80 (AB, J=11.3 Hz, 2H), 4.43 (dddd,
J=7.0 Hz, J=7.0 Hz, J=3.2 Hz, J=1.9 Hz, 1H, H-2),
4.20–4.03 (m, 7H), 1.66–1.60 (m, 8H), 1.40–1.35 (m,
2H), 1.32 and 1.30 (2t, J=7.0 Hz, 6H); 13C NMR (75.5
MHz, CDCl3): l=137.41, 128.22, 128.11, 127.80,
109.47, 75.64 (d, J=5.3 Hz, C-2), 75.09 (d, J=12.7 Hz,
OCH2Ph), 74.57 (d, J=163.6 Hz, C-1), 64.35 (d, J=2.6
Hz, C-3), 62.69 (d, J=6.8 Hz), 62.53 (d, J=7.2 Hz),
35.74, 34.91, 25.08, 23.92, 23.78, 16.41 (d, J=5.8 Hz);
31P NMR (121.5 MHz, CDCl3): l=20.60. Anal. calcd
for C20H31O6P: C, 60.28; H, 7.84. Found: C, 59.99; H,
8.02%.
4. Experimental
General procedures and instrumentation were described
earlier.14 In addition, some 1H, 13C and 31P NMR
spectra were obtained on a Varian-Mercury spectrome-
ter at 300, 75.5 and 121.5 MHz, respectively.
4.2. Diethyl (1R,2R)-1-benzyloxy-2,3-dihydroxypropyl-
phosphonate 5a
4.1. Diethyl (1R,2R)-1-benzyloxy-2,3-O-cyclohexylidene-
2,3-dihydroxypropylphosphonate 4a
A solution of (1R,2R)-4a (3.24 g, 8.13 mmol) in diox-
ane (42 mL) containing aqueous HCl (4.5%–82 mL)
was left at room temperature for 24 h. The volatiles
were evaporated at 20 mmHg (bath 40°C). The residue
was evaporated with dry dioxane (5×20 mL), dissolved
in CH2Cl2 (50 mL), neutralised with NEt3 and dried
over MgSO4. After removal of the solvent the crude
product (2.48 g) was purified on a silica gel column
with chloroform:methanol (50:1, v/v) to give (1R,2R)-
5a as a colorless syrup (2.22 g, 89%). [h]D=−14.1
(c=4.45, CHCl3); IR (film): w=3380, 2983, 2932, 1217,
1028, 970, 743 and 701 cm−1; 1H NMR (300 MHz,
CDCl3): l=7.40−7.26 (m, 5H), 4.90 (d, J=11.3 Hz,
1H), 4.62 (dd, J=11.3 Hz, J=1.2 Hz, 1H), 4.30–4.15
(m, 4H), 3.96 (dddd, J=9.9 Hz, J=5.2 Hz, J=5.1 Hz,
J=4.8 Hz, 1H, H-2), 3.83 (dd, J=7.1 Hz, J=4.8 Hz,
1H, H-1), 3.77 (dAB, JAB=11.7 Hz, J=5.2 Hz, 1H,
H-3a), 3.62 (dAB, J=11.7 Hz, J=5.1 Hz, 1H, H-3b),
2.9–1.9 (brs, 2H), 1.36 (t, J=6.9 Hz, 6H); 13C NMR
(62.9 MHz, CDCl3): l=136.89, 128.45, 128.41, 128.21,
74.97 (d, J=161.7 Hz, C-1), 74.67 (d, J=2.9 Hz,
OCH2Ph), 71.04 (d, J=4.1 Hz, C-2), 63.08 (d, J=7.0
Hz), 62.83 (d, J=9.0 Hz, C-3), 62.48 (d, J=7.0 Hz),
16.43 and 16.42 (2d, J=5.7 Hz); 31P NMR (101.3 MHz,
CDCl3): l=23.24. Anal. calcd for C14H23O6P: C, 52.82;
H, 7.29. Found: C, 52.63; H, 7.55%.
A solution of (1R,2R)-3a (4.50 g, 0.015 mol) in dry
CH2Cl2 (120 mL) was added to a mixture of ground
molecular sieves (1.5 g) and freshly prepared silver
oxide (5.35 g, 0.022 mol). After addition of benzyl
bromide (5.17 g, 0.0291 mol) the suspension was vigor-
ously stirred at room temperature for 24 h. The reac-
tion mixture was filtered through Celite, washed with
CH2Cl2, and the solution was concentrated in vacuo.
The residue was purified on a silica gel column with
chloroform–methanol (100:1, v/v) to give (1R,2R)-4a as
a colorless oil (5.42 g, 93%). [h]D=−6.5 (c=2.38,
CHCl3); IR (film): w=2982, 2936, 2863, 1252, 1028, 741
1
and 699 cm−1; H NMR (300 MHz, CDCl3): l=7.40–
7.26 (m, 5H), 4.88 and 4.83 (AB, J=11.6 Hz, 2H), 4.40
(dddd, J=7.8 Hz, J=7.2 Hz, J=6.2 Hz, J=3.4 Hz,
1H, H-2), 4.23–4.10 (m, 4H), 4.05 (dd, J=8.7 Hz,
J=6.2 Hz, 1H, H-3a), 3.82 (dd, J=8.7 Hz, J=7.2 Hz,
1H, H-3b), 3.69 (dd, J=9.1 Hz, J=7.8 Hz, 1H, H-1),
1.64–1.54 (m, 8H), 1.44–1.36 (m, 2H), 1.33 and 1.32 (2t,
J=7.1 Hz, 6H); 13C NMR (62.9 MHz, CDCl3): l=
137.32, 128.29, 128.16, 127.72, 109.86, 76.44 (d, J=
160.5 Hz, C-1), 75.60 (d, J=11.0 Hz, OCH2Ph), 74.67
(d, J=5.4 Hz, C-2), 65.75 (d, J=2.8 Hz, C-3), 62.67 (d,
J=7.6 Hz), 62.44 (d, J=6.8 Hz), 36.08, 34.97, 25.00,
23.84, 23.74, 16.31 (d, J=5.8 Hz); 31P NMR (121.5
MHz, CDCl3): l=20.16. Anal. calcd for C20H31O6P: C,
60.28; H, 7.84. Found: C, 60.05; H, 7.64%.
In a similar manner from (1S,2R)-4b (0.357 g, 0.896
mmol), (1S,2R)-5b (0.253 g, 89%) was obtained as a
colorless syrup. [h]D=+46.5 (c=1.10, CHCl3); IR
(film): w=3392, 2983, 2931, 1221, 1048, 1027, 743 and
In a similar manner, from (1S,2R)-3b (4.50 g, 0.015
mol), (1S,2R)-4b (5.02 g, 86%) was obtained as a
colorless oil. [h]D=+16.4 (c=1.78, CHCl3); IR (film):
1
700 cm−1; H NMR (300 MHz, CDCl3): l=7.40–7.30

848
A. E. Wro´blewski, K. B. Balcerzak / Tetrahedron: Asymmetry 13 (2002) 845–850
(m, 5H), 4.81 (d, J=10.9 Hz, 1H), 4.64 (d, J=10.9 Hz,
1H), 4.30–4.08 (m, 4H), 3.97 (dddd, J=9.7 Hz, J=7.7
Hz, J=3.8 Hz, J=3.4 Hz, 1H, H-2), 3.88 (dd, J=7.7
Hz, J=4.8 Hz, 1H, H-1), 3.82 (ddAB, J=11.9 Hz,
J=3.4 Hz, J=1.2 Hz, 1H, H-3a), 3.75 (dAB, J=11.9
Hz, J=3.8 Hz, 1H, H-3b), 2.9–41.5 (2brs, 2H), 1.36 (t,
J=7.0 Hz, 6H); 13C NMR (75.5 MHz, CDCl3): l=
137.12, 128.57, 128.38, 128.24, 75.52 (d, J=159.8 Hz,
C-1), 75.03 (d, J=3.2 Hz, OCH2Ph), 71.07 (d, J=4.3
Hz, C-2), 63.58 (d, J=7.2 Hz), 62.91 (d, J=10.0 Hz,
C-3), 62.80 (d, J=7.2 Hz), 16.81 and 16.77 (2d, J=5.5
Hz); 31P NMR (121.5 MHz, CDCl3): l=24.38. Anal.
calcd for C14H23O6P: C, 52.82; H, 7.29. Found: C,
52.64; H, 7.57%.
2.79 (ddAB, JAB=5.5 Hz, J=3.9 Hz, J=1.0 Hz, 1H,
H-3b), 1.34 and 1.33 (2t, J=7.1 Hz, 6H); 13C NMR
(62.9 MHz, CDCl3): l=137.19, 128.38, 128.22, 128.03,
75.11 (d, J=7.6 Hz, OCH2Ph), 72.51 (d, J=164.5 Hz,
C-1), 62.91 and 62.88 (2d, J=6.8 Hz), 50.46 (d, J=10.0
Hz, C-2), 44.04 (d, J=4.5 Hz, C-3), 16.54 and 16.52
(2d, J=5.7 Hz); 31P NMR (101.3 MHz, CDCl3): l=
19.74. Anal. calcd for C14H21O5P: C, 55.98; H, 7.06.
Found: C, 56.03; H, 7.05%.
4.3.1. Diethyl (1R,2S)-2-acetyloxy-1-benzyloxy-3-bromo-
propylphosphonate 7a. This compound was obtained as
follows: when the formation of 7a was complete, the
solution was concentrated and the residue was chro-
matographed to give a yellowish oil, which slowly
decomposed. [h]D=−55.8 (c=0.76, CHCl3); IR (film):
w=3032, 2983, 2934, 1746, 1227, 1026, 971, 764, 701
4.3. Diethyl (1R,2R)-1-benzyloxy-2,3-epoxypropylphos-
phonate 2a
1
and 598 cm−1; H NMR (300 MHz, CDCl3): l=7.40–
A solution of (1R,2R)-5a (0.647 g, 2.03 mmol) and
trimethyl orthoacetate (0.293 g, 2.44 mmol) in CH2Cl2
(6 mL) containing pyridinium p-toluenesulfonate (0.005
g) was stirred at room temperature for 30 min. After
evaporation of solvents (finally at 0.1 mmHg), the
residue was dissolved in CH2Cl2 (6 mL), treated with
NEt3 (5.7 mL) followed by acetyl bromide (0.303 g, 2.46
mmol), while maintaining temperature of the reaction
mixture below 40°C. When the formation of the bromo-
acetate intermediate 7a was complete (TLC, ca. 40
min), the solution was concentrated, the residue was
dissolved in methanol (5 mL) and K2CO3 (0.313 g, 2.26
mmol) was added. The suspension was vigorously
stirred at room temperature for 2 h. Saturated NH4Cl
(20 mL) was added and the solution was extracted with
CH2Cl2 (3×20 mL). The combined organic extracts
were dried (MgSO4), filtered and concentrated. The
crude product was chromatographed on a silica gel
column with chloroform:methanol (100:1, v/v) to give
(1R,2R)-2a as a colorless oil (0.393 g, 77%). [h]D=
+20.7 (c=1.23, CHCl3); IR (film): w=2985, 2932, 2872,
1257, 1049, 1027, 971, 743 and 700 cm−1; 1H NMR (300
MHz, CDCl3): l=7.41–7.27 (m, 5H), 4.88 and 4.77
(AB, J=11.9 Hz, 2H), 4.25–4.09 (m, 4H), 3.39 (dd,
J=13.0 Hz, J=7.2 Hz, 1H, H-1), 3.29 (ddd, J=7.2 Hz,
J=4.2 Hz, J=2.5 Hz, 1H, H-2), 2.88 (dd, J=4.7 Hz,
J=4.2 Hz, 1H, H-3a), 2.68 (dd, J=4.7 Hz, J=2.5 Hz,
1H, H-3b), 1.34 and 1.33 (2d, J=7.2 Hz, 6H); 13C
NMR (62.9 MHz, CDCl3): l=136.95, 128.27, 128.14,
127.83, 76.76 (d, J=164.6 Hz, C-1), 73.37 (d, J=10.8
Hz, OCH2Ph), 62.88 and 62.74 (2d, J=6.9 Hz), 51.47
(d, J=10.1 Hz, C-2), 43.63 (d, J=1.1 Hz, C-3), 16.39
and 16.37 (2d, J=5.8 Hz); 31P NMR (121.5 MHz,
CDCl3): l=18.68. Anal. calcd for C14H21O5P: C, 55.98;
H, 7.06. Found: C, 55.67; H, 7.04%.
7.30 (m, 5H), 5.34 (dddd, J=6.9 Hz, J=6.3 Hz, J=6.3
Hz, J=4.2 Hz, 1H, H-2), 4.95 (d, J=11.1 Hz, 1H), 4.69
(dd, J=11.1 Hz, J=1.1 Hz, 1H), 4.25–4.15 (m, 4H),
4.15 (dd, J=9.3 Hz, J=4.2 Hz, 1H, H-1), 3.55 (dAB,
JAB=10.5 Hz, J=6.3 Hz, 1H, H-3a), 3.51 (dAB, JAB=
10.5 Hz, J=6.3 Hz, 1H, H-3b), 2.08 (s, 3H), 1.35 (t,
J=7.0 Hz, 6H); 13C NMR (75.5 MHz, CDCl3): l=
169.71, 136.83, 128.63, 128.60, 128.37, 75.47 (d, J=2.3
Hz, OCH2Ph), 73.99 (d, J=166.9 Hz, C-1), 71.78 (d,
J=4.3 Hz, C-2), 63.26 (d, J=6.6 Hz), 63.00 (d, J=7.1
Hz), 29.66 (d, J=8.3 Hz, C-3), 21.13, 16.83 and 16.73
(2d, J=5.4 Hz); 31P NMR (101.3 MHz, CDCl3): l=
19.81. Anal. calcd for C16H24BrO6P: C, 45.40; H, 5.73.
Found: C, 45.34; H, 5.97%.
In a similar way (1S,2S)-7b was isolated as a yellowish
oil, which slowly became brownish. [h]D=+32.9 (c=
1.01, CHCl3); IR (film): w=3032, 2984, 2934, 1747,
1241, 1025, 973, 737 and 700 cm−1; 1H NMR (300
MHz, CDCl3): l=7.38–7.29 (m, 5H), 5.31 (dddd, J=
8.7 Hz, J=7.3 Hz, J=4.8 Hz, J=3.2 Hz, 1H, H-2),
4.88 (d, J=11.3 Hz, 1H), 4.69 (dd, J=11.3 Hz, J=1.1
Hz, 1H), 4.25–4.10 (m, 4H), 4.00 (dd, J=8.7 Hz, J=4.8
Hz, 1H, H-1), 3.83 (dd, J=11.3 Hz, J=3.2 Hz, 1H,
H-3a), 3.66 (dd, J=11.3 Hz, J=7.3 Hz, 1H, H-3b),
2.04 (s, 3H), 1.35 and 1.34 (2t, J=7.1 Hz, 6H); 13C
NMR (75.5 MHz, CDCl3): l=169.76, 136.75, 128.57,
128.53, 128.31, 75.09 (d, J=3.7 Hz, OCH2Ph), 74.83 (d,
J=164.9 Hz, C-1), 72.04 (d, J=8.9 Hz, C-2), 63.17 and
63.08 (2d, J=6.9 Hz), 31.42 (d, J=4.9 Hz, C-3), 21.06,
16.78 and 16.75 (2d, J=5.7 Hz); 31P NMR (121.5 MHz,
CDCl3): l=19.58. Anal. calcd for C16H24BrO6P: C,
45.40; H, 5.73. Found: C, 45.57; H, 5.90%.
4.4. Diethyl (1R,2R)-3-(N,N-dibenzylamino)-1-benzyl-
oxy-2-hydroxypropyl-phosphonate 8a
In a similar way, from (1S,2R)-5b (1.483 g, 4.661
mmol), the epoxide (1S,2R)-2b was obtained as a color-
less oil (0.741 g, 53%). [h]D=+22.1 (c=0.997, CHCl3);
IR (film): w=2986, 2932, 2872, 1254, 1026, 970, 744 and
A mixture of (1R,2R)-2a (100 mg, 0.333 mmol) and
dibenzylamine (66.7 mL, 0.347 mmol) was kept at 50°C
(bath) for 72 h. The crude product was chro-
matographed on a silica gel column using chloro-
form:methanol (100:1, v/v) to give (1R,2R)-8a as a
colorless oil (131 mg, 79%). Crystallisation from ethyl
acetate gave white needles. Mp 87.2–87.5°C; [h]D=−4.0
(c=0.73, CHCl3); IR (film): w=3467, 2988, 2924, 2838,
1
700 cm−1; H NMR (300 MHz, CDCl3): l=7.36–7.26
(m, 5H), 4.72 (s, 2H), 4.23–4.10 (m, 4H), 3.93 (dd,
J=11.9 Hz, J=3.2 Hz, 1H), 3.33 (dddd, J=3.9 Hz,
J=3.2 Hz, J=2.6 Hz, J=1.2 Hz, 1H, H-2), 2.88
(ddAB, JAB=5.5 Hz, J=2.6 Hz, J=0.4 Hz, 1H, H-3a),

A. E. Wro´blewski, K. B. Balcerzak / Tetrahedron: Asymmetry 13 (2002) 845–850
849
1
1230, 1026, 752 and 701 cm−1; H NMR (300 MHz,
CDCl3): l=7.35–7.14 (m, 15H), 4.70 (d, J=11.1 Hz,
1H); 4.25–4.10 (m, 5H), 4.11 (d, J=11.1 Hz, 1H), 3.78
(dd, J=7.1 Hz, J=2.4 Hz, 1H, H-1), 3.60 and 3.55 (AB,
In a similar fashion, from (1S,2R)-8b (250 mg, 0.502
mmol), the acetate (1S,2R)-9b was obtained as a colorless
oil (219 mg, 80%). [h]D=+37.5 (c=0.841, CHCl3); IR
(film): w=3086, 2982, 2931, 2910, 2799, 1738, 1240, 1039,
1
J
AB=13.5 Hz, 4H), 2.66 (ddAB, JAB=12.8 Hz, J=7.2
968, 747 and 699 cm−1; H NMR (300 MHz, CDCl3):
Hz, J=1.2 Hz, 1H, H-3a), 2.58 (dAB, JAB=12.8Hz,
J=6.4 Hz, 1H, H-3b), 1.32 and 1.30 (2t, J=6.9 Hz, 6H):
13C NMR (75.5 MHz, CDCl3): l=138.74, 137.41,
129.30, 128.45, 128.38, 128.33, 127.94, 127.30, 75.29 (d,
J=164.0 Hz, C-1), 74.67 (d, J=2.0 Hz), 67.92 (d, J=2.0
Hz, C-2), 62.80 and 62.60 (2d, J=6.9 Hz), 58.65, 56.04
(d, J=12.0 Hz, C-3), 16.83 (d, J=5.7 Hz); 31P NMR
(121.5 MHz, CDCl3): l=23.18. Anal. calcd for
C28H36NO5P: C, 67.58; H, 7.31; N, 2.81. Found: C, 67.58;
H, 7.36; N, 2.95%.
l=7.35–7.19 (m, 15H), 5.42 (dddd, J=10.7 Hz, J=7.7
Hz, J=4.8 Hz, J=2.7 Hz, 1H, H-2), 4.66 and 4.54 (AB,
J=11.7 Hz, 2H), 4.15–4.00 (m, 4H), 3.85 (dd, J=12.8
Hz, J=2.7 Hz, 1H, H-1), 3.75 and 3.43 (AB, J=13.7 Hz,
4H), 2.92 (dAB, J=14.4 Hz, J=4.8 Hz, 1H, H-3a), 2.88
(dAB, J=14.4 Hz, J=7.7 Hz, 1H, H-3b), 1.98 (s, 3H),
1.29 and 1.27 (2t, J=7.0 Hz, 6H); 13C NMR (75.5 MHz,
CDCl3): l=170.13, 139.40, 137.12, 129.08, 128.41,
128.37, 128.19, 128.02, 126.94, 76.05 (d, J=164.0 Hz,
C-1), 74.47 (d, J=6.3 Hz, OCH2Ph), 71.40 (d, J=9.4 Hz,
C-2), 62.91 and 62.75 (2d, J=7.0 Hz), 58.88, 53.44 (s,
C-3), 21.46, 16.81 and 16.73 (2d, J=5.6 Hz); 31P NMR
(121.5 MHz, CDCl3): l=19.73. Anal. calcd for
C30H38NO6P: C, 66.77; H, 7.11; N, 2.59. Found: C, 66.98;
H, 7.15; N, 2.89%.
In a similar fashion, from (1S,2R)-2b (299 mg, 0.996
mmol) and dibenzylamine (0.201 mL, 1.045 mmol),
(1S,2R)-8b (360 mg, 73%) was obtained as a white solid
after crystallisation from heptane–ether. Mp 56–57°C;
[h]D=+45.4 (c=0.82, CHCl3); IR (KBr): w=3314, 3030,
2977, 2926, 2866, 1226, 1059, 750 and 700 cm−1; 1H NMR
(300 MHz, CDCl3): l=7.40–7.20 (m, 13H), 7.18–7.10
(m, 2H), 4.59 and 4.52 (AB, JAB=11.3 Hz, 2H), 4.16–
4.02 (m, 5H), 3.90 (dd, J=12.0 Hz, J=3.4 Hz, 1H, H-1),
3.85 (d, J=13.5 Hz, 2H), 3.75 (brs, 1H), 3.44 (d, J=13.5
Hz, 2H), 2.88 (dAB, JAB=13.0 Hz, J=10.0 Hz, 1H,
H-3a), 2.77 (dAB, J=13.0 Hz, J=3.8 Hz, 1H, H-3b),
1.28 (t, J=7.0 Hz, 6H); 13C NMR (75.5 MHz, CDCl3);
l=138.53, 137.56, 129.26, 128.67, 128.49, 128.26, 127.79,
127.33, 77.06 (d, J=163.2 Hz, C-1), 75.40 (d, J=7.2 Hz),
67.92 (d, J=10.6 Hz, C-2), 63.07 and 62.45 (2d, J=6.9
Hz), 58.67, 54.36 (d, J=3.7 Hz, C-3), 16.82 and 16.77 (2d,
J=5.4 Hz); 31P NMR (121.5 MHz, CDCl3): l=21.60.
Anal. calcd for C28H36NO5P: C, 67.58; H, 7.31; N, 2.81.
Found: C, 67.48; H, 7.24; N, 3.08%.
4.6. Diethyl (1R,2R)-3-acetamido-1,2-dihydroxypropyl-
phosphonate 10a
A solution of (1R,2R)-9a (0.442 g, 0.819 mmol) in
anhydrous ethanol (5 mL) was hydrogenated over
Pd(OH)2/C (20%, 136 mg) at room temperature for 6
days. The catalyst was removed by filtration, the solu-
tion was concentrated, and the residue was chro-
matographed on
a
silica gel column with
chloroform:methanol (20:1, v/v) to give (1R,2R)-10a as
a colorless oil (0.170 g, 77%). [h]D=+19.0 (c=0.98,
CHCl3); IR (film): w=3285, 2984, 2921, 2852, 1648,
1559, 1218, 1045, 971 cm−1; 1H NMR (300 MHz,
CDCl3): l=6.40 (brt, J=5.5 Hz, 1H), 4.23 (qu, J=7.1
Hz, 2H), 4.19 (dq, J=7.3 Hz, J=7.1 Hz, 2H), 4.3–4.1
(brs, 2H), 4.01 (dddd, J=7.1 Hz, J=6.1 Hz, J=3.5 Hz,
J=3.0 Hz, 1H, H-2), 3.85 (dd, J=11.0 Hz, J=3.0 Hz,
1H, H-1), 3.65 (ddd, J=14.0 Hz, J=7.1 Hz, J=5.5 Hz,
1H, H-3b), 3.32 (ddd, J=14.0 Hz, J=6.1 Hz, J=5.5
Hz, 1H, H-3a), 2.02 (s, 3H), 1.36 (t, J=7.1 Hz, 6H);
13C NMR (75.5 MHz, CDCl3): l=171.92, 69.82 (d,
J=2.0 Hz, C-2), 68.99 (d, J=163.8 Hz, C-1), 63.64 and
62.99 (2d, J=7.2 Hz), 42.57 (d, J=12.9 Hz, C-3), 16.73
and 16.69 (2d, J=5.7 Hz); 31P NMR (121.5 MHz,
CDCl3): l=23.09. Anal. calcd for C9H20NO6P: C,
40.14; H, 7.50; N, 5.20. Found: C, 39.87; H, 7.19; N,
5.02%.
4.5. Diethyl (1R,2R)-2-acetyloxy-3-(N,N-dibenzyl-
amino)-1-benzyloxypropyl-phosphonate 9a
Standard acetylation of (1R,2R)-8a (88 mg, 0.18 mmol)
with acetic anhydride (20.0 mL, 0.22 mmol) in the
presence of NEt3 (38.0 mL, 0.27 mmol) and DMAP (one
crystal) in CH2Cl2 (1 mL) gave after chromatography on
a silica gel column (1R,2R)-9a as a colorless oil (70 mg,
73%). [h]D=−11.3 (c=1.42, CHCl3); IR (film): w=2982,
2915, 2836, 1738, 1239, 1045, 1026, 969, 739, 698 cm−1;
1H NMR (300 MHz, CDCl3): l=7.38–7.17 (m, 15H),
5.37 (dddd, J=7.3 Hz, J=6.8 Hz, J=5.7 Hz, J=2.5 Hz,
1H, H-2), 4.74 (d, J=11.5 Hz, 1H), 4.23–4.04 (m, 4H),
4.02 (d, J=11.5 Hz, 1H), 3.96 (dd, J=8.5 Hz, J=2.5 Hz,
1H, H-1), 3.64 and 3.49 (AB, J=13.1 Hz, 4H), 2.83 (dd,
J=13.1 Hz, J=7.3 Hz, 1H, H-3a), 2.58 (ddd, J=13.1 Hz,
J=5.7 Hz, J=3.2 Hz), (1H, H-3b), 2.05 (s, 3H), 1.28 (t,
J=7.0 Hz, 6H); 13C NMR (75.5 MHz, CDCl3): l=
170.13, 139.01, 137.50, 129.25, 128.36, 128.28, 128.27,
127.86, 127.19, 74.93 (d, J=1.7 Hz, OCH2Ph), 74.38 (d,
J=167.5 Hz, C-1), 70.12 (s, C-2), 63.16 and 62.39 (2d,
J=7.1 Hz), 58.76, 53.82 (d, J=9.7 Hz, C-3), 21.43, 16.85
and 16.77 (2d, J=5.5 Hz); 31P NMR (121.5 MHz,
CDCl3): l=20.77. Anal. calcd for C30H38NO6P: C,
66.77; H, 7.11; N, 2.59. Found: C, 67.01; H, 7.35; N,
2.32%.
In a similar manner, from (1S,2R)-9b (0.260 g, 0.491
mmol), the acetamide (1S,2R)-10b (0.098 g, 74%) was
obtained as an almost colorless oil. [h]D=−77.2 (c=
1.01, CHCl3); IR (film): w=3304, 2985, 2913, 1643,
1556, 1226, 1044, 970 cm−1; 1H NMR (300 MHz,
CDCl3): l=6.29 (brt, J=4.8 Hz, 1H), 5.33 (dd, J=27.0
Hz, J=5.3 Hz, 1H, HOC-1), 4.35–4.15 (m, 5H), 4.05–
3.90 (m, 2H, H-2, H-3b), 3.58 (dt, J=10.0 Hz, J=10.0
Hz, J=5.3 Hz, 1H, H-1), 3.19 (dddd, J=14.7 Hz,
J=4.8 Hz, J=3.0 Hz, J=3.0 Hz, 1H, H-3a), 2.08 (s,
3H), 1.38 and 1.37 (2t, J=7.0 Hz, 6H); 13C NMR (75.5
MHz, CDCl3): l=172.0, 69.25 (d, J=2.9 Hz, C-2),
66.25 (d, J=164.0 Hz, C-1), 62.40 and 62.08 (2d, J=7.0
Hz), 40.21 (d, J=13.5 Hz, C-3), 21.77, 15.45 and 15.37

850
A. E. Wro´blewski, K. B. Balcerzak / Tetrahedron: Asymmetry 13 (2002) 845–850
(2d, J=6.3 Hz); 31P NMR (121.5 MHz, CDCl3): l=
25.27. Anal. calcd for C9H20NO6P: C, 40.14; H, 7.50;
N, 5.20. Found: C, 40.15; H, 7.80; N, 4.93%.
10. Wro´blewski, A. E.; Piotrowska, D. G. Tetrahedron:
Asymmetry 2001, 11, 2524–2615.
11. Wro´blewski, A. E.; Piotrowska, D. G. Tetrahedron:
Asymmetry 2001, 12, 2977–2984.
12. Wro´blewski, A. E.; Balcerzak, K. B. Tetrahedron: Asym-
metry 2001, 12, 427–431.
Acknowledgements
13. Wro´blewski, A. E.; Halajewska-Wosik, A. Tetrahedron:
Asymmetry 2001, 11, 2053–2055.
14. Wro´blewski, A. E.; Balcerzak, K. B. Tetrahedron 1998,
54, 6833–6840.
15. Wro´blewski, A. E.; Konieczko, W. T. Monatsh. Chem.
1984, 115, 785–791.
We thank Mrs. Edyta Grzelewska for her skilled exper-
imental contributions. Financial support from the Med-
ical University of Ło´dz´ (502-13-379 and 503-302-4) is
gratefully acknowledged.
16. Hammerschmidt, F.; Schmidt, S. Phosphorus, Sulfur Sili-
con 2001, 174, 101–118 and references cited therein.
17. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; Wiley: New York, 1991; pp. 123–127.
18. Page, P.; Blonski, C.; Perie, J. Tetrahedron 1996, 52,
1557–1572.
References
1. Dellaria, J. F., Jr.; Maki, R. G.; Stein, H. H.; Cohen, J.;
Whittern, D.; Marsh, K.; Hoffman, D. J.; Plattner, J. J.;
Perun, T. J. J. Med. Chem. 1990, 33, 534–542.
2. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C.
A.; Rogers, W. L.; Smith, S. A.; DeForrest, J.; Oehl, R.
S.; Petrillo, E. W., Jr. J. Med. Chem. 1995, 38, 4557–
4569.
3. Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625–6628.
4. Tao, M.; Bihovsky, R.; Wells, G. J.; Mallamo, J. P. J.
Med. Chem. 1998, 41, 3912–3916.
5. Aminophosphonic and Aminophosphinic Acids. Chemistry
and Biological Activity; Kukhar, V. P.; Hudson, H. R.,
Eds.; Wiley: Chichester, UK, 2000.
6. De Risi, C.; Dondoni, A.; Perrone, D.; Pollini, G. P.
Tetrahedron Lett. 2001, 42, 3033–3036.
19. Cink, R. D.; Forsyth, C. I. J. Org. Chem. 1995, 60,
8122–8123.
20. Simpson, T. J.; Smith, R. W.; Westaway, S. M.; Willis, C.
L.; Buss, A. D.; Cannell, R. J. P.; Dawson, M. J.; Rudd,
B. A. M. Tetrahedron Lett. 1997, 38, 5367–5370.
21. Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
10515–10530.
22. Tong, G.; Perich, J. W.; Johns, R. B. Aust. J. Chem.
1992, 45, 1225–1240.
23. Genov, D. G.; Kresinski, R. A.; Tebby, J. C. J. Org.
Chem. 1998, 63, 2574–2585.
24. Genov, D. G.; Tebby, J. C. J. Org. Chem. 1996, 61,
2454–2459.
25. Gancarz, R.; Latajka, R.; Maluszek, B.; Zymanczyk-
Duda, E.; Kafarski, P. Magn. Reson. Chem. 2000, 38,
197–200.
7. Klepacz, A.; Zwierzak, A. Tetrahedron Lett. 2002, 43,
1079–1080.
8. Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1401–1404.
26. Bentrude, W. G.; Setzer, W. N. Phosphorus-31 NMR
Spectroscopy in Stereochemical Analysis, Verkade, J. G.;
Quin, L. D., Eds., VCH: Deerfield, 1987; Chapter 11.
9. Zygmunt, J.; Gancarz, R.; Lejczak, B.; Wieczorek, P.;
Kafarski, P. Bioorg. Med. Chem. Lett. 1996, 6, 2989–
2992.