Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2009.08.032

Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,1′S)-, (1S,2S,1′R)-, (1R,2R,1′S)- and (1R,2S,1′R)-[N-(1-phenylethyl)]-2,3-epimino-1-hy

Full text of DOI:10.1016/j.tetasy.2009.08.032

Tetrahedron: Asymmetry 20 (2009) 2240–2246
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Tetrahedron: Asymmetry
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Synthesis of four enantiomers of 2,3-di(N-Boc-amino)-1-
hydroxypropylphosphonates
*
Andrzej E. Wróblewski , Joanna Drozd
´
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódz, 90-151 Łódz, Muszynskiego 1, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2009
Accepted 27 August 2009
Available online 26 September 2009
Enantiomerically pure diethyl (1S,2R)-, (1S,2S)-, (1R,2R)- and (1R,2S)-2,3-di(tert-butoxycarbonyl)amino-
1-hydroxypropylphosphonates were synthesised from diethyl (1S,2R,10S)-, (1S,2S,10R)-, (1R,2R,10S)- and
(1R,2S,10R)-[N-(1-phenylethyl)]-2,3-epimino-1-hydroxypropylphosphonates, respectively, via aziridine
ring opening with neat TMSN3 followed by hydrogenolysis in the presence of Boc2O. A plausible mecha-
nism for the aziridine ring opening in 2,3-epimino-1-hydroxypropylphosphonates involving the interme-
diate aziridinium ions was proposed. Significant differences in the rates of the aziridine ring opening
between diastereoisomeric phosphonates (1S,2R,10S) and (1S,2S,10R) were rationalised taking into account
different conformations of the 1-phenylethyl group in both diastereoisomers.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The aim of this paper is the synthesis of all four enantiomeri-
cally pure diethyl 2,3-[di(tert-butoxycarbonyl)amino]-1-hydrox-
Several diaminoalkylphosphonates are known to exhibit biolog-
ical activity. 2-N-Substituted 1,2-diaminoethylphosphonates were
found to inhibit cytosolic and microsomal aminopeptidases.1 Pep-
tidomimetics containing substituted 1,2-diaminoethyl- and 1,3-
diaminopropylphosphonate fragments appeared to be potent
inhibitors of human fibroblast collagenase activity.2 Analogues of
phosphoramidone in which a phosphate residue was replaced by
1,3-diaminopropylphosphonate moiety inhibited endothelin-con-
verting enzyme (ECE).3 Tripeptides having the diphenyl 1-amino-
3-guaninylpropylphosphonate residue at the C-terminus inhibited
trypsin-like serine proteases.4 Analogues of glutathione modified
at the C-terminus with 2,3-diaminopropylphosphonate showed
modest activity as glutathionylspermidine synthethase inhibitors.5
Although a plethora of synthetic methods leading to 1,2-diam-
inoalkylphosphonates are known,2,4–16 1,3- and 2,3-diaminoalkyl
phosphonates are much less accessible. Recently, four of the eight
possible enantiomers of diethyl hydroxy-1-{[(R)- or (S)-1-phenyl-
ethyl]aziridin-2-yl}methylphosphonate 1 became readily available17
from the respective aldehydes employing the Abramov reaction.18
Since aziridines are known to react with various nucleophiles19
including ammonia,20 amines21–33 and azides24,26,27,34–45 we rea-
soned that the successful opening of the aziridine ring in 1 with nitro-
gennucleophileswouldprovideavicinaldiaminesystemandthusthe
protected 2,3-diamino-1-hydroxypropylphosphonates 2 could be
synthesised (Scheme 1). To achieve this goal trimethylsilyl azide
was selected as a source of highly nucleophilic azide possibly func-
tioning also as an aziridine nitrogen activator.45
ypropylphosphonates 3 (2 R = Boc) employing the appropriate
phosphonates 1 as the starting materials.
*
R
NHR
N
RHN
P(O)(OEt)2
P(O)(OEt)2
OH
OH
2
1
Scheme 1. Retrosynthesis of 2,3-diaminophosphonates.
2. Results and discussion
When a dichloromethane solution of aziridinephosphonate
(1S,2R,10S)-1a was treated with trimethylsilyl azide at room temper-
ature for 14 days, a 56:44 mixture of 1-trimethylsilyloxyphospho-
nate (1S,2R,10S)-4a and 1-hydroxyphosphonate (1S,2R,10S)-5a was
produced (Scheme 2). Both phosphonates were cleanly separated
on a silica gel column to give pure (1S,2R,10S)-4a and (1S,2R,10S)-5a
in 31% and 47% yield, respectively. After standard desilylation of
(1S,2R,10S)-4a with tetrabutylammonium fluoride, the total yield
of (1S,2R,10S)-5a reached 62%. We found that aziridine ring opening
in (1S,2R,10S)-1a could be also achieved without solvent to directly
give (1S,2R,10S)-5a which was isolated in 85% yield after column
chromatography. Catalytic [Pd(OH)2–C] reduction of the azide and
hydrogenolysis of the (S)-1-phenylethylamino group was
performed in the presence of Boc2O and led to the formation of
diethyl (1S,2R)-2,3-di(tert-butoxycarbonylamino)-1-hydroxypropyl
phosphonate (1S,2R)-3 in 87% yield (Scheme 2).
* Corresponding author. Tel.: +48 42 677 92 33; fax: +48 42 678 83 98.
E-mail address: andrzej.wroblewski@umed.lodz.pl (A.E. Wróblewski).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.08.032

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 20 (2009) 2240–2246
2241
Ph
H
Ph
NHBoc
P(O)(OEt)2
NH
1'
Me
N3
H
Me
H
a.
d.
BocHN
P(O)(OEt)2
N
P(O)(OEt)2
1
2
or c.
OH
OR
OH
(1S,2R,1'S)-1a
(1S,2R)-3
(1S,2R,1'S)-4a R = TMS
(1S,2R,1'S)-5a R = H
b.
Scheme 2. Reagents and conditions: (a) TMSN3, CH2Cl2, rt, 14 d; (b) Bu4NF, THF, 2 h, 59%; (c) TMSN3, rt, 14 d, 85% and (d) H2, 20% Pd(OH)2–C, Boc2O, ethanol, 3 d, 87%.
To synthesise diaminophosphonate (1S,2S)-3 aziridine
(1S,2S,10R)-1b was used as a starting material (Scheme 3). Aziridine
ringopening of phosphonate(1S,2S,10R)-1b with trimethylsilyl azide
in dichloromethane was complete at room temperature after four
days providing a 47:53 mixture of O-TMS derivative (1S,2S,10R)-4b
and 1-hydroxyphosphonate (1S,2S,10R)-5b. Again this mixture was
separated on a silica gel column to afford pure (1S,2S,10R)-4b and
(1S,2S,10R)-5b in 37% and 46% yield, respectively. Removal of the silyl
group from (1S,2S,10R)-4b gave the required 1-hydroxyphosphonate
(1S,2S,10R)-5b improving the total yield of (1S,2S,10R)-5b to 80%.
When phosphonate (1S,2S,10R)-1b was treated with neat trimethyl-
silyl azide, (1S,2S,10R)-5b was obtained in one step in 85% yield.
Standard transformation of the azide and 1-phenylethylamino
groups into N-tert-butoxycarbonylamino moieties gave di(N-Boc-
amino)phosphonate (1S,2S)-3 in 91% yield.
The synthesis of phosphonate (1R,2R)-3 could be accomplished
using aziridinephosphonate (1R,2R,10S)-1c (ent-1b) as a starting
material. Treatment of (1R,2R,10S)-1c with trimethylsilyl azide
without solvent at room temperature for four days cleanly pro-
vided 1-hydroxyphosphonate (1R,2R,10S)-5c (ent-5b) in 85% yield
after chromatographic purification (Scheme 4). Catalytic reduction
of this product with simultaneous N-Boc protection gave diam-
inophosphonate (1R,2R)-3 in 92% yield.
(1R,2S,10R)-5d (ent-5a) was obtained in 85% yield after column chro-
matography. Its transformation into phosphonate (1R,2S)-3 was
accomplished in 87% in a standard manner (Scheme 5).
Although the mechanism of the aziridine ring opening in phos-
phonates (1S,2R,10S)-1a and (1S,2S,10R)-1b was not studied in de-
tail, some comments can be made based on the literature data. It
is known that trimethylsilyl azide reacts with alcohols46–48 (with
ethanol even exothermically49) to give O-TMS ethers and hydrogen
azide (pKa 4.75). Since hydrogen azide readily reacts with aliphatic
amines to form stable ammonium salts49,50 one may envisage it is
also able to protonate the less basic nitrogen atom in aziridines 1
(pKa of the aziridinium ion 7.98) to produce the respective azirid-
inium ions 7 and thus to activate the three-membered ring for
the nucleophilic attack with the azide anion (Scheme 6). On the
other hand, in the presence of a residual water trimethylsilyl azide
is immediately hydrolysed and phosphonates 1 are transformed
into the respective aziridinium ions 8.
To verify our assumptions reactions of phosphonates (1S,2R,10S)-
1a and (1S,2S,10R)-1b with 2 equiv of trimethylsilyl azide were mon-
itored by the 31P NMR spectroscopy. The results of our observations
are collected in Tables 1 and 2.
Identification of the particular components of the reaction mix-
tures was accomplished as follows. Phosphonates (1S,2R,10S)-1a
and (1S,2S,10R)-1b are known,17 the reaction products (1S,2R,10S)-
4a and (1S,2R,10S)-5a as well as (1S,2S,10R)-4b and (1S,2S,10R)-5b,
respectively, are described in this paper and the formation of
O-TMS derivatives of the starting materials (1S,2R,10S)-6a and
(1S,2S,10R)-6b was proved by the 31P NMR spectroscopy (vide
Finally, for the synthesis of diaminophosphonate (1R,2S)-3 azi-
ridinephosphonate (1R,2S,10R)-1d (ent-1a) was selected. Based on
our previous experience it was necessary to keep (1R,2S,10R)-1d
(ent-1a) with neat trimethylsilyl azide at room temperature for
14 days to complete the aziridine ring opening. The respective azide
Ph
Me
H
N3
NH
NHBoc
H
a.
or c.
d.
P(O)(OEt)2
BocHN
P(O)(OEt)2
OH
(1S,2S)-3
H
N
P(O)(OEt)2
Me
OR
OH
Ph
(1S,2S,1'R)-1b
(1S,2S,1'R)-4b R = TMS
(1S,2S,1'R)-5b R = H
b.
Scheme 3. Reagents and conditions: (a) TMSN3, CH2Cl2, rt, 4 d; (b) Bu4NF, THF, 2 h, 88%; (c) TMSN3, rt, 4 d, 85% and (d) H2, 20% Pd(OH)2–C, Boc2O, ethanol, 3 d, 91%.
Ph
H
NH
NHBoc
P(O)(OEt)2
Me
N3
H
b.
a.
N
P(O)(OEt)2
OH
(1R,2R,1'S)-1c (ent-1b)
P(O)(OEt)2
OH
(1R,2R,1'S)-5c (ent-5b)
BocHN
Me
H
OH
Ph
(1R,2R)-3
Scheme 4. Reagents and conditions: (a) TMSN3, rt, 4 d; 85% and (b) H2, 20% Pd(OH)2–C, Boc2O, ethanol, 3 d, 92%.

2242
A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 20 (2009) 2240–2246
Ph
Me
H
N3
Ph
NH
NHBoc
P(O)(OEt)2
Me
H
a.
b.
N
P(O)(OEt)2
OH
(1R,2S,1'R)-1d (ent-1a)
P(O)(OEt)2
OH
(1R,2S,1'R)-5d (ent-5a)
BocHN
H
OH
(1R,2S)-3
Scheme 5. Reagents and conditions: (a) TMSN3, rt, 14 d; 85% and (b) H2, 20% Pd(OH)2–C, Boc2O, ethanol, 3 d, 87%.
*
*
R
R
N
N
P(O)(OEt)2
OH
P(O)(OEt)2
OTMS
+
Me3SiN3
+
HN3
1
6
*
R
N
*
NHR
H
P(O)(OEt)2
N3
P(O)(OEt)2
OR
R = TMS
R = H
OR
R = TMS
N3
7
8
4
5
R = H
Scheme 6. A plausible mechanism of the aziridine ring opening in phosphonates 1.
Table 1
Monitoring of the reaction of phosphonate (1S,2R,10S)-1a with 2 equiv of trimethyl-
azide occurred but amounts of the respective O-TMS phosphonates
(1S,2R,10S)-6a and (1S,2S,10R)-6b in both cases reached roughly 10%
in early stages of the reaction and the respective 31P NMR signals
soon collapsed. This observation supports our predictions that be-
sides O-TMS phosphonates (1S,2R,10S)-6a and (1S,2S,10R)-6b parent
phosphonates (1S,2R,10S)-1a and (1S,2S,10R)-1b can also be trans-
formed into the respective aziridinium ions before they react with
azide. The ratios of both products of the azidolysis of phosphonate
(1S,2R,10S)-1a, namely 3-azidophosphonate (1S,2R,10S)-4a and its
O-TMS derivative (1S,2R,10S)-5a, can be readily followed by the
31P NMR spectroscopy and are influenced by several factors includ-
ing possible hydrolysis of trimethylsilyl ethers during a long-term
monitoring. On the other hand, 3-azidophosphonates (1S,2S,10R)-
4b and (1S,2S,10R)-5b did not give well separated signals in the
31P NMR spectra at 121.5 MHz but the formation of these com-
pounds was evident from the 1H NMR spectra taken simulta-
neously. Finally, both monitorings support our observations from
the preparative scale experiments proving that phosphonate
(1S,2R,10S)-1a reacts with trimethylsilyl azide significantly slower
than diastereoisomer (1S,2S,10R)-1b.
silyl azide
Time (h)
Compound/d31P NMR
(1S,2R,10S)-5a (1S,2R,10S)-1a
(1S,2R,10S)-4a
(1S,2R,10S)-6a
23.85
23.75
23.03
22.77
6
24
48
72
96
168
264
360
720
3%
19%
25%
25%
26%
27%
28%
51%
32%
5%
14%
24%
33%
35%
43%
40%
29%
52%
81%
56%
46%
39%
35%
31%
30%
18%
14%
11%
11%
5%
2%
1%
n.d.
n.d.
n.d.
n.d.
n.d.—not detected.
Table 2
Monitoring of the reaction of phosphonate (1S,2S,10R)-1b with 2 equiv of trimethyl-
silyl azide
Time (h)
Compound/d31P NMR
To gather NMR spectral data for O-TMS phosphonates (1S,2R,10S)-
6a and (1S,2S,10R)-6b silylation of phosphonates (1S,2R,10S)-1a and
(1S,2S,10R)-1b with 2 equiv of BSA in chloroform-d was monitored
by the 1H and 31P NMR spectroscopy. Silylation of phosphonate
(1S,2S,10R)-1b was almost complete in 26 h giving a 96:4 mixture
of phosphonates (1S,2S,10R)-6b and (1S,2S,10R)-1b, respectively. On
the other hand, from phosphonate (1S,2R,10S)-1a a 63:37 mixture
of phosphonates (1S,2R,10S)-6a and (1S,2R,10S)-1a, respectively,
was obtained after 26 h.
(1S,2S,10R)-4b and
(1S,2S,10R)-5b
23.40
(1S,2S,10R)-6b
22.57
(1S,2S,10R)-1b
22.42
2.5
7.5
23
48
72
13%
28%
59%
86%
94%
5%
8%
9%
2%
n.d.
82%
62%
29%
7%
2%
n.d.—not detected.
In attempts to rationalise different rates of azidolysis of phos-
phonates (1S,2R,10S)-1a and (1S,2S,10R)-1b structural features of
the respective aziridinium ions 9 (R = OH) and 10 (R = TMS) were
compared. Since the aziridine ring opening occurs by the SN2
mechanism, the azide anion approaches the CH2 carbon atom from
the side opposite to the ring nitrogen. Analysis of molecular mod-
els of (1S,2R,10S)-9a and (1S,2S,10R)-9b as well as their N-invertom-
ers 11 clearly shows that freely rotating 1-phenylethyl group does
infra). It should be noted that some unidentified phosphonates
were also formed in both cases and their quantities account for
the balance to 100%.
It appeared that silylation of the secondary hydroxy groups in
phosphonates (1S,2R,10S)-1a and (1S,2S,10R)-1b with trimethylsilyl

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 20 (2009) 2240–2246
2243
not shield the approach of the nucleophile to the reaction centre.
Although phosphonate (1S,2R,10S)-1a exists in a stable antiperipla-
nar conformation due to a strong intramolecular H-bond (Nꢀ ꢀ ꢀH–
O), in the respective aziridinium ion (1S,2R,10S)-9a, free rotation
of the (O,O-diethoxyphosphoryl)hydroxymethyl group around
C1–C2 is possible and the bulky O,O-diethoxyphosphoryl group is
responsible for the hindrance of the nucleophilic substitution with
azide. Furthermore, the approach of the nucleophile in the aziridi-
nium ion (1S,2R,10S)-10a is additionally restricted because of the
steric bulkiness of the trimethylsilyl group (Fig. 1).
Reaction with azide was regiospecific and less substituted carbon
in the aziridine ring was attacked. An application of neat trimeth-
ylsilyl azide cleanly gave 3-azido-1-hydroxyphosphonates, while
reactions performed in dichloromethane led to ca. 1:1 mixtures
of 3-azido-1-hydroxyphosphonates and their O-TMS derivatives.
A mechanism of the aziridine ring opening with trimethylsilyl
azide in 2,3-aziridine-1-hydroxyphosphonates was proposed based
on the monitoring of reactions by the 1H and 31P NMR spectroscopy
and the literature data. Silylation of the hydroxy group in phospho-
nates or hydrolysis of trimethylsilyl azide with a residual water pro-
duce hydrogen azide which transforms the aziridine ring nitrogen
into the intermediate aziridinium ion. Under these conditions regio-
specific ring opening with azide takes place at room temperature.
Attempts at rationalising reasons why phosphonate (1S,2S,10R)-
1b reacts with trimethylsilyl azide faster than phosphonate
(1S,2R,10S)-1a were undertaken based on the comparison of the
structural features of the starting phosphonates. Phosphonate
(1S,2R,10S)-1a is less reactive because the approach of the nucleo-
phile is shielded due to free rotation of the bulky (O,O-diethoxy-
phosphoryl)hydroxymethyl group in the respective aziridinium
ions (1S,2R,10S)-9a. Since phosphonate (1S,2S,10R)-1b exists as N-
invertomer having the 1-phenylethyl and the (O,O-diethoxyphos-
phoryl)hydroxymethyl groups in the cis-configuration, in the
respective aziridinium ions (1S,2S,10R)-11b and (1S,2S,10R)-12b
rotation of the substituent around the C1–C2 bond is restricted
and thus trajectory of the incoming azide anion is less hindered.
Ph
Ph
H
Me
Me
H
H
N
P(O)(OEt)2
N
P(O)(OEt)2
H
H
H
OR
OR
(1S,2R,1'S)-9a R = H
(1S,2S,1'R)-9b R = H
(1S,2R,1'S )-10a R = TMS
(1S,2S,1'R)-10b R = TMS
Hβ
H
H
β
H
H
H
N
P(O)(OEt)2
OR
N
P(O)(OEt)2
Me
H
H
Me
H
α
OR
H
α
H
H
Ph
(1S,2R,1'S)-11a R = H
(1S,2S,1'R)-11b R = H
(1S,2R,1'S)-12a R = TMS
(1S,2S,1'R)-12b R = TMS
4. Experimental
Figure 1. Possible N-invertomers of aziridinium ions formed from phosphonates
(1S,2R,10S)-1a and 1(S,2S,10R)-1b.
1H NMR spectra were recorded with a Varian Mercury-300
spectrometer; chemical shifts d in ppm with respect to TMS; cou-
pling constants J in hertz. 13C and 31P NMR spectra were recorded
on a Varian Mercury-300 machine at 75.5 and 121.5 MHz, respec-
tively. IR spectral data were measured on an Infinity MI-60 FT-IR
spectrometer. Melting points were determined on a Boetius appara-
tus and are uncorrected. Elemental analyses were performed by the
Microanalytical Laboratory of this Faculty on a Perkin Elmer PE 2400
CHNS analyser. Polarimetric measurements were conducted on a
Optical Activity PolAAr 3001 apparatus. The following absorbents
were used: column chromatography, Merck Silica Gel 60 (70–230
To investigate why phosphonate (1S,2S,10R)-1b reacts with azide
faster than the diastereoisomer (1S,2R,10S)-1a we turned attention
to possible structural differences between these phosphonates. It
appeared that H–CP and H –CHb in (1S,2S,10R)-1b are significantly
a
shifted upfield in comparison to those in (1S,2R,10S)-1a (by 0.49
and 0.20 ppm, respectively). Similar differences in chemical shifts
were observed earlier for structurally close aziridine alcohols and
together with vicinal coupling constants were employed in configu-
rational assignments.51 These upfield shifts are obviously a result of
shielding by the phenyl ring52,53 and can only be observed in
N-invertomers in which the 1-phenylethyl group is positioned cis
to the other substituent in the aziridine ring. If one assumes that this
configurational relationship is retained in the intermediate aziridi-
nium ions (1S,2S,10R)-11b and (1S,2S,10R)-12b the 1-phenylethyl
group again has no influence on the incoming nucleophile. However,
the trajectory of the approaching azide is now significantly less hin-
dered by the O,O-diethoxyphosphoryl group when compared to that
of the aziridinium ions (1S,2R,10S)-9a and (1S,2R,10S)-10a. This is
because the (O,O-diethoxyphosphoryl)hydroxymethyl group in
mesh); analytical TLC, Merck TLC plastic sheets Silica Gel 60 F254
.
4.1. Reaction of phosphonates 1 with trimethylsilyl azide in
CH2Cl2 (general procedure)
To a solution of phosphonates 1 (0.313 g, 1.00 mmol) in methy-
lene chloride (2 mL) TMSN3 (0.265 mL, 2.00 mmol) was added at
room temperature. The mixture was stirred at ambient tempera-
ture for 14 days (for 1a) or four days (for 1b) and then was chro-
matographed on a silica gel column with hexanes/ethyl acetate
(2:1, v/v) to give O-TMS derivatives 4 (first eluted) and 1-hydrox-
yphosphonates 5.
(1S,2S,10R)-11b
and
(O,O-diethoxyphosphoryl)(trimethylsilyl-
oxy)methyl group in (1S,2S,10R)-12b are no longer able to freely
rotate around the C1–C2 bond due to cis-configuration of substitu-
ents in the three-membered ring.
4.1.1. Reaction of phosphonate (1S,2R,10S)-1a with trimethylsilyl
azide
3. Conclusions
From aziridinephosphonate (1S,2R,10S)-1a (0.356 g, 1.14 mmol),
O-TMS derivative (1S,2R,10S)-4a (0.170 g, 31%) was obtained fol-
lowed by 1-hydroxyphosphonate (1S,2R,10S)-5a (0.168 g, 47%),
both as colourless oils.
An efficient synthetic strategy to all four enantiomers of diethyl
2,3-di(N-Boc-amino)-1-hydroxypropylphosphonates has been
elaborated. Readily available aziridinephosphonates (1S,2R,10S)-
1a and (1S,2S,10R)-1b and their enantiomers (1R,2S,10R)-1d and
(1R,2R,10S)-1c, respectively were selected as starting materials. A
two-step procedure included the aziridine ring opening with neat
trimethylsilyl azide followed by the reduction of the azido group
and hydrogenolytic removal of the 1-phenylethyl residue with
simultaneous protection of the amino groups as Boc derivatives.
4.1.1.1. Diethyl (1S,2R)-3-azido-2-[(S)-1-phenylethyl]amino-1-tri-
methylsilyloxypropylphosphonate
(1S,2R,10S)-4a. 1H
NMR
(300 MHz, CDCl3): d = 7.35–7.18 (m, 5H), 4.16–3.97 (m, 5H, CH2OP,
HCP), 3.90 (q, J = 6.6 Hz, 1H, HCCH3), 3.63 (ddd, J = 12.6, 3.9, 1.2 Hz,

2244
A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 20 (2009) 2240–2246
1H, HaCHb), 3.32 (dd, J = 12.6, 3.9 Hz, 1H, HaCHb), 2.90 (dddd, J = 12.3,
6.0, 3.9, 3.9 Hz, 1H, HC-2), 1.37 (d, J = 6.6 Hz, 3H, HCCH3), 1.30 and
1.26 (2 ꢁ t, J = 7.1 Hz, 6H, CH3CH2OP), 0.13 (s, 9H). 13C NMR
(75.5 MHz, CDCl3): d = 144.7, 128.4, 127.0, 126.8, 69.6 (d,
J = 165.0 Hz, CP), 62.7 and 62.4 (2 ꢁ d, J = 7.2 Hz, CH3CH2OP), 56.4
(d, J = 5.7 Hz, CCP), 55.4, 49.7 (d, J = 6.6 Hz, CCCP), 24.5, 16.6 (d,
J = 5.7 Hz, CH3CH2OP), 0.25. 31P NMR (121.5 MHz, CDCl3): d = 23.22.
4.2.1. Reaction of phosphonate (1S,2R,10S)-1a with neat
trimethylsilyl azide
From aziridinephosphonate (1S,2R,10S)-1a (0.200 g, 0.638 mmol),
1-hydroxyphosphonate(1S,2R,10S)-5a(0.193 g, 85%)wasobtainedas
a colourless oil in all respects identical with a sample described in
Section 4.1.1.2.
4.2.2. Reaction of phosphonate (1S,2S,10R)-1b with neat
trimethylsilyl azide
4.1.1.2. Diethyl (1S,2R)-3-azido-2-[(S)-1-phenylethyl]amino-1-
hydroxypropylphosphonate (1S,2R,10S)-5a. IR (film):
m
= 3307,
From aziridinephosphonate (1S,2S,10R)-1b (0.203 g, 0.648 mmol),
1-hydroxyphosphonate (1S,2S,10R)-5b (0.196 g, 85%) was obtained
as a colourless oil in all respects identical with a sample described
in Section 4.1.2.2.
2980, 2930, 2101, 1451, 1219, 1027, 763, 703 cmꢂ1. ½a D20
ꢃ
¼ ꢂ65:1
(c 3.07, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.34–7.22 (m, 5H),
4.22–4.07 (m, 4H, CH2OP), 3.98 (q, J = 6.6 Hz, 1H, HCCH3), 3.86 (dd,
J = 6.6, 5.7 Hz, 1H, HCP), 3.68 (dd, J = 12.9, 5.7 Hz, 1H, HaCHb), 3.61
(dd, J = 12.9, 5.4 Hz, 1H, HaCHb), 2.93 (dddd, J = 18.0, 5.7, 5.7, 5.4 Hz,
1H, HCN), 1.41 (d, J = 6.6 Hz, 3H, HCCH3), 1.32 and 1.30 (2 ꢁ t,
J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 144.1,
128.8, 127.6, 127.0, 67.5 (d, J = 159.8 Hz, CP), 63.4 and 62.7 (2 ꢁ d,
J = 7.2 Hz, CH3CH2OP), 56.0 (d, J = 4.0 Hz, CCP), 55.8, 50.8 (d,
J = 4.0 Hz, CCCP), 24.7, 16.8 and 16.7 (2 ꢁ d, J = 5.2 Hz, CH3CH2OP).
31P NMR (121.5 MHz, CDCl3): d = 23.01. Anal. Calcd for C15H25N4O4P:
C, 50.56; H, 7.07; N, 15.72. Found: C, 50.42; H, 7.18; N, 15.78.
4.2.3. Diethyl (1R,2R)-3-azido-2-[(S)-1-phenylethyl]amino-1-
hydroxypropylphosphonate (1R,2R,10S)-5c
From aziridinephosphonate (1R,2R,10S)-1c (0.207 g, 0.661 mmol),
1-hydroxyphosphonate (1R,2R,10S)-5c—ent-5b (0.199 g, 85%) was
obtained as a colourless oil. ½a D20
¼ ꢂ92:2 (c 1.00, CHCl3). Anal. Calcd
ꢃ
for C15H25N4O4P: C, 50.56; H, 7.07; N, 15.72. Found: C, 50.61; H, 7.29;
N, 15.71.
4.2.4. Diethyl (1R,2S)-3-azido-2-[(R)-1-phenylethyl]amino-1-
hydroxypropylphosphonate (1R,2S,10R)-5d
4.1.2. Reaction of phosphonate (1S,2S,10R)-1b with trimethyl-
silyl azide
From aziridinephosphonate (1R,2S,10R)-1d (0.198 g, 0.632 mmol),
1-hydroxyphosphonate (1R,2S,10R)-5d(0.192 g, 85%) wasobtainedas
From
aziridinephosphonate
(1S,2S,10R)-1b
(0.132 g,
0.408 mmol), O-TMS derivative (1S,2S,10R)-4b (0.063 g, 37%) and
1-hydroxyphosphonate (1S,2S,10R)-5b (0.074 g, 46%) were ob-
tained, both as colourless oils.
a colourless oil. ½a D20
¼ þ64:6 (c 1.98, CHCl3). Anal. Calcd for
ꢃ
C15H25N4O4P: C, 50.56; H, 7.07; N, 15.72. Found: C, 50.26; H, 7.31;
N, 15.75.
4.1.2.1. Diethyl (1S,2S)-3-azido-2-[(R)-1-phenylethyl]amino-1-
trimethylsilyloxypropylphosphonate (1S,2S,10R)-4b. 1H NMR
(300 MHz, CDCl3): d = 7.29–7.11 (m, 5H), 4.11–3.95 (m, 4H,
CH2OP), 3.88 (q, J = 6.6 Hz, 1H, HCCH3), 3.88 (dd, J = 7.8, 4.5 Hz,
1H, HCP), 3.39 (ddd, J = 12.3, 6.3, 1.2 Hz, 1H, HaCHb), 3.28 (dd,
J = 12.3, 6.0 Hz, 1H, HaCHb), 2.81 (dddd, J = 18.6, 6.3, 6.0, 4.5 Hz,
1H, HC-2), 1.26 (d, J = 6.6 Hz, 3H, HCCH3), 1.19 and 1.19 (2 ꢁ t,
J = 7.2 Hz, 6H, CH3CH2OP), 0.00 (s, 9H). 13C NMR (75.5 MHz, CDCl3):
d = 145.5, 128.8, 127.5, 126.9, 69.6 (d, J = 167.8 Hz, CP), 63.0 and
62.3 (2 ꢁ d, J = 7.2 Hz, CH3CH2OP), 57.1 (d, J = 3.1 Hz, CCP), 56.4,
51.7 (d, J = 8.0 Hz, CCCP), 25.0, 16.8 and 16.7 (2 ꢁ d, J = 6.0 Hz,
CH3CH2OP), 0.25. 31P NMR (121.5 MHz, CDCl3): d = 22.77.
4.3. Hydrogenolysis of 1-hydroxyphosphonates 5a, 5b, 5c and
5d (general procedure)
A solution of 1-hydroxyphosphonates 5a, 5b, 5c and 5d (0.426 g,
1.00 mmol) in ethanol(5 mL) containing Boc2O (0.546 g, 2.50 mmol)
was stirred under atmospheric pressure of hydrogen over 20%
Pd(OH)2–C (50 mg) at room temperature for three days. The suspen-
sion was filtered through a layer of Celite, the solution was concen-
trated and chromatographed on a silica gel column with chloroform/
methanol (100:1 and 50:1, v/v).
4.3.1. Diethyl (1S,2R)-2,3-di(tert-butoxycarbonylamino)-1-
hydroxypropylphosphonate (1S,2R)-3
4.1.2.2. Diethyl (1S,2S)-3-azido-2-[(R)-1-phenylethyl]amino-1-
From
1-hydroxyphosphonate
(1S,2R,10S)-5a
(0.143 g,
hydroxypropylphosphonate (1S,2S,10R)-5b. IR (film):
m
= 3274,
0.401 mmol), diaminophosphonate (1S,2R)-3 (0.149 g, 87%) was
obtained as a white amorphous solid. Mp 60–61 °C. IR (KBr):
2980, 2929, 2102, 1452, 1224, 1028, 764, 703 cmꢂ1. ½a D20
ꢃ
¼ þ92:8
(c 0.75, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.46–7.31 (m, 5H),
4.23–4.10 (m, 4H, CH2OP), 4.02 (q, J = 6.6 Hz, 1H, HCCH3), 3.85
(dd, J = 6.9, 5.1 Hz, 1H, HCP), 3.79 (dd, J = 12.9, 5.1 Hz, 1H, HaCHb),
3.74 (dd, J = 12.9, 3.9 Hz, 1H, HaCHb), 2.94 (dddd, J = 9.9, 6.9, 5.1,
3.9 Hz, 1H, HCN), 1.50 (d, J = 6.6 Hz, 3H, HCCH3), 1.35 and 1.29
(2 ꢁ t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz, CDCl3):
d = 143.8, 128.8, 127.5, 126.9, 66.3 (d, J = 166.2 Hz, CP), 63.5 and
62.6 (2 ꢁ d, J = 6.8 Hz, CH3CH2OP), 55.1, 54.1 (d, J = 3.4 Hz, CCP),
50.6, (d, J = 6.3 Hz, CCCP), 25.1, 16.6 (d, J = 5.7 Hz, CH3CH2OP). 31P
NMR (121.5 MHz, CDCl3): d = 22.73. Anal. Calcd for C15H25N4O4P:
C, 50.56; H, 7.07; N, 15.72. Found: C, 50.84; H, 7.24; N, 15.62.
m
= 3395, 2978, 2932, 1702, 1537, 1249, 1039 cmꢂ1. ½a D20
¼ ꢂ33:7
ꢃ
(c 1.07, CHCl3). 1H NMR (300 MHz, CDCl3): d = 5.41 (d, J = 6.0 Hz,
1H, HNC-2), 5.17 (br m, 1H, HNC-3), 4.73 (dd, J = 13.2, 7.2 Hz, 1H,
HOC-1), 4.26–4.14 (m, 4H, CH2OP), 4.04–3.87 (br m, 2H, HC-1,
HC-2), 3.65–3.52 (br m, 1H, HaCHb), 3.48–3.36 (br m, 1H, HaCHb),
1.44 [s, 18H, (CH3)3], 1.36 and 1.35 (2 ꢁ t, J = 7.1 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 157.3, 156.1, 80.0,
68.7 (d, J = 164.1 Hz, CP), 63.3 and 63.2 (2 ꢁ d, J = 6.9 Hz,
CH3CH2OP), 53.0, 41.1, 28.6, 16.8 (d, J = 4.3 Hz, CH3CH2OP). 31P
NMR (121.5 MHz, CDCl3): d = 22.77. Anal. Calcd for C17H35N2O8P:
C, 47.88; H, 8.27; N, 6.57. Found: C, 47.60; H, 7.98; N, 6.87.
4.2. Reaction of phosphonates 1 with neat trimethylsilyl azide
(general procedure)
4.3.2. Diethyl (1S,2S)-2,3-di(tert-butoxycarbonylamino)-1-
hydroxypropylphosphonate (1S,2S)-3
From
1-hydroxyphosphonate
(1S,2S,10R)-5b
(0.176 g,
A mixture of phosphonates 1 (0.313 g, 1.00 mmol) and TMSN3
(0.265 mL, 2.00 mmol) was stirred at room temperature for 14 days
(for 1a and 1d—ent-1a) or four days (for 1b and 1c—ent-1b). Crude
products were chromatographed on a silica gel column with hex-
anes/ethyl acetate (2:1, v/v) to give 1-hydroxyphosphonates 5.
0.494 mmol) diaminophosphonate (1S,2S)-3 (0.191 g, 91%) was ob-
tained as a colourless oil. IR (film):
m = 3346, 2979, 2933, 1711,
1515, 1248, 1027 cmꢂ1. ½a D20
ꢃ
¼ ꢂ13:9 (c 2.25, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 5.52 (d, J = 8.1 Hz, 1H, HNC-2), 5.35 (t,
J = 7.8 Hz 1H, HNC-3), 5.06 (dd, J = 17.4, 6.0 Hz, 1H, HOC-1),

A. E. Wróblewski, J. Drozd / Tetrahedron: Asymmetry 20 (2009) 2240–2246
2245
4.23–4.13 (m, 4H, CH2OP), 4.03 (ddd, J = 12.0, 6.0, 2.4 Hz, 1H, HC-1),
Acknowledgments
3.99–3.87 (m, 1H, HC-2), 3.45–3.21 (br m, 2H, HaCHb), 1.43 [s, 18H,
(CH3)3], 1.34 (t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR (75.5 MHz,
CDCl3): d = 157.6, 156.0, 80.3, 79.8, 67.2 (d, J = 169.3 Hz, CP), 63.1
and 63.0 (2 ꢁ d, J = 6.9 Hz, CH3CH2OP), 52.0, 41.4, (d, J = 12.6 Hz,
C-3), 28.6, 16.8 and 16.7 (2 ꢁ d, J = 5.7 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 22.74. Anal. Calcd for C17H35N2O8P: C,
47.88; H, 8.27; N, 6.57. Found: C, 47.85; H, 8.43; N, 6.38.
´
Financial support from the Medical University of Łódz (502-13-
772) is gratefully acknowledged. The authors wish to express their
gratitude to Mrs. Edyta Grzelewska and Mrs. Agata Lasota for
excellent technical assistance. A part of this project was conducted
by Mr. Paweł Szuberski.
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´
[Spectral data were calculated from a spectrum of a 63:37 mix-
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CH2OP), 3.83 (dd, J = 8.7, 3.3 Hz, 1H, HCP), 2.50 (q, J = 6.6 Hz, 1H,
HCCH3), 1.98 (d, J = 3.3 Hz, 1H, HaCHb), 1.87 (dddd, J = 6.3, 3.3,
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3.37 (dd, J = 8.1, 8.1 Hz, 1H, HCP), 2.48 (q, J = 6.6 Hz, 1H, HCCH3),
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