Enantiomerically pure 4-amino-1,2,3-trihydroxybutylphosphonic acids

Article abstract of DOI:10.1016/j.tet.2005.09.057

(1S,2R,3S)-, (1R,2R,3S)- and (1S,2R,3R)-4-amino-1,2,3- trihydroxybutylphosphonic acids were synthesised. The synthetic strategy involved preparation of the respective 4-azido-2,3-O-isopropylidene-l-threose or -d-erythrose, addition of dialkyl phosphites, separation of C-1 epimeric O,O-dibenzyl phosphonates, the reduction of azides and the removal of the protecting groups. The (2R,3S) and (2R,3R) configurations in the final products were secured by employing diethyl l-tartrate and d-isoascorbic acid as starting materials. The stereochemical course of the addition to the carbonyl groups in 4-azido-2,3-O-isopropylidene-l-threose or -d-erythrose followed that established earlier for 2,3-O-isopropylidene-d-glyceraldehyde and similar (3:1-4:1) diastereoselectivities were achieved.

Full text of DOI:10.1016/j.tet.2005.09.057

Tetrahedron 61 (2005) 11930–11938
Enantiomerically pure
4-amino-1,2,3-trihydroxybutylphosphonic acids
*
´
Andrzej E. Wroblewski and Iwona E. Głowacka
´
´
´
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łodz, 90-151 Łodz, Muszynskiego 1, Poland
Received 30 June 2005; revised 1 September 2005; accepted 15 September 2005
Available online 3 October 2005
This paper is respectfully dedicated to Professor Jan Michalski on the occasion of his 85th birthday
Abstract—(1S,2R,3S)-, (1R,2R,3S)- and (1S,2R,3R)-4-amino-1,2,3-trihydroxybutylphosphonic acids were synthesised. The synthetic
strategy involved preparation of the respective 4-azido-2,3-O-isopropylidene-L-threose or -D-erythrose, addition of dialkyl phosphites,
separation of C-1 epimeric O,O-dibenzyl phosphonates, the reduction of azides and the removal of the protecting groups. The (2R,3S) and
(2R,3R) configurations in the final products were secured by employing diethyl L-tartrate and D-isoascorbic acid as starting materials. The
stereochemical course of the addition to the carbonyl groups in 4-azido-2,3-O-isopropylidene-L-threose or -D-erythrose followed that
established earlier for 2,3-O-isopropylidene-D-glyceraldehyde and similar (3:1–4:1) diastereoselectivities were achieved.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
triazole moiety, including compounds 12 and 13 showed
inhibition of glycerol phosphate dehydratase.17 The phospho-
nate 14 was found to be a competitive inhibitor of human
glycinamide ribonucleosidetransformylase.18 One ofthemost
active bisphosphonates,19 15 is marketed as Alendronate for
treatment of osteoporosis and related diseases.
In comparison to a-aminophosphonates, which are surro-
gates of aminoacids, d-aminophosphonates are less known
class of compounds.1 Several important examples of
phosphonates bearing an amino group at C-4 are shown
on Figure 1. (2S,3Z)-2-amino-5-phosphono-3-pentenoic
acid 1 is a constituent of rhizocticin A, an antifungal
peptide antibiotic.2 4-Aminobutylphosphonic acid 2 has
often been used in studies on characterisation of GABAB
receptors.3 (R)-2-amino-5-phosphonovaleric acid (R)-3 is a
selective NMDA antagonist4 and was used as a lead
structure in development of other competitive NMDA
antagonists.5 On the other hand, (S)-3 showed antagonist
activity at mGluR2 receptor,6 while (R)-3 was almost not
active in this case. The b-ketophosphonate 4 as well as its
5-fluoro- and 5,5-difluoro analogues mimic b-aspartyl
phosphate and were shown to be inhibitors of aspartate-
semialdehyde dehydrogenase.7 Further studies from this
group led to synthesis of conformationaly rigid analogues
having a cyclopropane framework.8 In attempts to pharma-
cologically characterise glutamate receptor subtypes the
following d-aminophosphonates: 5,9 6,10 7,11 8,12 9,13 10
(a racemic mixture14 and both enantiomers15) and 1114,16
have been used. Several phosphonates containing a terminal
Recently, we have elaborated an efficient synthesis of enantio-
merically pure dimethyl (1R,2S)- and (1S,2S)-3-azido-2-
benzyloxy-1-hydroxypropylphosphonates from (S)-3-azido-
2-benzyloxypropanal and showed their clean transformation
into the respective 3-acetamido-1,2-dihydroxypropylphos-
phonates.20 Herein, we describe an extension of this approach
to the synthesis of (1R,2R,3S)-, (1S,2R,3S)- and (1S,2R,3R)-
Keywords: Amino acids and derivatives; Aldehydes; Configuration;
Conformation; Phosphonic acids and derivatives.
*
Corresponding author. Tel.: C48 42 677 92 33; fax: C48 42 678 83 98;
e-mail: aewplld@ich.pharm.am.lodz.pl
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.057

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A. E. Wroblewski, I. E. Głowacka / Tetrahedron 61 (2005) 11930–11938
11931
4-amino-1,2,3-trihydroxybutylphosphonates 16 through the
intermediacy of two new (2R,3S)- and (2R,3R)-4-azido-2,3-
O-isopropylidene-2,3-dihydroxybutanals 17 (Schemes 1
and 2), which were obtained from diethyl L-tartrate 18 and
D-isoascorbic acid 20, respectively, as starting materials.
Scheme 4. Synthesis of 4-azido-4-deoxy-2,3-O-isopropylidene-D-erythrose,
(2R,3R)-17. Reagents and conditions: (a) Refs. 27 and 28; (b) Me2C
(OMe)2, acetone, TsOH, rt, 16 h; (c) NaN3, DMF, 110 8C, 48 h; (d) MeI,
DMF, rt, 2 days; (e) NaBH4–LiCl, THF–EtOH (1/2), 0 8C to rt, 16 h;
(f) DMSO, (COCl)2, K78 8C, 2 h, DIPEA, K78–0 8C, 0.5 h.
using methyl iodide in DMF.30 Reduction of 26 was
achieved in a similar way as described above22 to furnish the
stable alcohol (2S,3R)-23, which was obtained in 98% yield
after purification on a silica gel column. Again, the Swern
protocol26 was applied to prepare the unstable 4-azidoal-
dehyde (2R,3R)-17, which was immediately subjected to
phosphonylations as a crude product.
Scheme 1. Retrosynthesis of (1RS,2R,3S)-4-amino-1,2,3-trihydroxy-
butylphosphonates.
Detailed analyses of the 1H NMR spectra of crude aldehydes
(2R,3S)-17 and (2R,3R)-17 clearly showed, that some
epimerisation at C-2 occurred during oxidation. Thus, a
93:7 mixture of (2R,3S)-17 and (2S,3S)-17 was obtained
from the azidoalcohol (2S,3S)-23, while from (2S,3R)-23, a
7:93 mixture of (2S,3R)-17 and (2R,3R)-17 was produced
independent of the amine (triethyl- vs diisopropylethyl-
amine) used in the last step of the Swern reaction. Oxidation
of structurally related azidoalcohols also led to partial
epimerisation.31 Attempts at employing the Dess-Martin
periodinane32 led to the formation of the aldehydes in low
yield.
Scheme 2. Retrosynthesis of (1RS,2R,3R)-4-amino-1,2,3-trihydroxy-
butylphosphonates.
2. Results and discussion
To synthesise the aldehyde (2R,3S)-17 (Scheme 3), diethyl
L-tartrate 18 was protected as the isopropylidene deriva-
tive,21 which was later reduced with a sodium borohydride–
lithium chloride mixture22 leading to the known23 diol 21 in
86% yield. Tosylation of 21 with 1.1 equiv of tosyl
chloride24 produced the monotosylate 22 without traces of
a disubstituted compound. The monotosylate 22 could not
be purified on a silica gel column and a crude material was
subjected to standard azidation to give the known azide
(2S,3S)-23.25 Oxidation under Swern conditions26 gave
unstable 4-azidoaldehyde (2R,3S)-17, which was immedi-
ately used in the next step as a crude product.
When the crude azidoaldehyde (2R,3S)-17 was subjected to
the base-catalysed phosphonylation with dialkyl phosphites
(Scheme 5), 3:1 mixtures of C-1 diasteoreoisomeric
phosphonates (1S,2R,3S)-27a–30a and (1R,2R,3S)-27b–
30b were produced, respectively. They were contaminated
with the phosphonates (1R,2S,3S)-31a–34a and (1S,2S,3S)-
31b–34b, which were formed in 4:1 ratios. The 31P NMR
spectra also allowed to calculate the ratio of the
phosphonates (1SR,2R,3S)-27–30 to (1SR,2S,3S)-31–34 as
ca. 85:15. This observation results from further epimerisa-
tion of the 4-azidoaldehyde (2R,3S)-17 in the presence of a
basic catalyst used in the Abramov reaction. Previously, we
noticed similar process for the phosphonylation of Garner
aldehyde.33 Chromatographic purification on silica gel gave
pure phosphonates (1S,2R,3S)-27a and (1S,2R,3S)-28a as
colourless oils in 12 and 13% yields, respectively. From the
Scheme 3. Synthesis of 4-azido-4-deoxy-2,3-O-isopropylidene-L-threose,
(2R,3S)-17. Reagents and conditions: (a) H(OEt)3, acetone, 3.7 M HCl–
AcOEt, 4 days; (b) NaBH4–LiCl, THF–EtOH (1/2), 0 8C to rt, 16 h; (c)
TsCl, KI, Ag2O, CH2Cl2, rt, 2 h; (d) NaN3, DMF, 70 8C, 24 h; (e) DMSO,
(COCl)2, K78 8C, 2 h, TEA or DIPEA, K78 8C, 0.5 h.
In order to synthesise (2R,3R)-17 (Scheme 4), D-isoascorbic
acid was converted into D-erythronolactone,27,28 which was
subjected to isopropylidenation to give the protected lactone
24 in 75% yield.28 To open the lactone ring in 24 with
sodium azide the literature procedure was followed.29
Transformation of the crude sodium salt 25 into the
respective methyl ester 26 was accomplished in one step
Scheme 5. Phosphonylation of (2R,3S)-17. Reagents and conditions:
(a) (RO)2P(O)H, NEt3, rt, overnight.

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11932
crude mixtures of diastereoisomeric diisopropyl phosphon-
ates, (1S,2R,3S)-29a and (1R,2R,3S)-29b were isolated in 54
and 14% yields, respectively. We were also successful in
separating the dibenzyl phosphonates (1S,2R,3S)-30a (59%)
and (1R,2R,3S)-30b (24%).
Figure 2. A preferred conformation of (1S,2R,3S)-36a.
Base-catalysed phosphonylation of the 4-azidoaldehyde
(2R,3R)-17 with dialkyl phosphites (Scheme 6) gave 4:1
mixtures of diastereoisomeric phosphonates (1S,2R,3R)-
31a–34a and (1R,2R,3R)-31b–34b. All mixtures of esters
were contaminated with ca. 15% of the phosphonates
(1R,2S,3R)-31a–34a and (1S,2S,3R)-31b–34b, which were
formed in a 3:1 ratio. We were unable to purify the mixtures
of dimethyl, diethyl and diisopropyl esters, mostly because
of the presence of the phosphonates obtained from partially
epimerised aldehydes. However, dibenzyl esters (1S,2R,3R)-
34a and (1R,2R,3R)-34b were cleanly separated on a silica
gel column in 59 and 15% yield, respectively.
and thus, the major phosphonates (1S,2R,3S)-27a–30a
(Scheme 5) have 1S configuration at C-1.
The same approach to the assignment of the absolute
configuration at C-1 in the phosphonate (1S,2R,3R)-34a
1
failed, because the H NMR spectrum of the respective
azidotriacetate at 300 MHz was not amenable to the first-
order analysis. However, when the trihydroxyphosphonate
(1S,2R,3R)-34a was treated with an excess of benzaldehyde
dimethyl acetal in the presence of p-toluenesulfonic acid, a
clean transformation to a single product was observed by
31P NMR spectroscopy after 36 h at room temperature.
Purification on a silica gel column followed by crystal-
lisation gave fluffy needles, which were identified by 1H and
13C NMR as (4R,5R,6S)-4-azidomethyl-6-(O,O-dibenzyl-
phosphoryl)-5-hydroxy-2-phenyl-1,3-dioxane 37 (Scheme 8).
Scheme 6. Phosphonylation of (2R,3R)-17. Reagents and conditions:
(a) (RO)2P(O)H, NEt3, rt, overnight.
Scheme 8. Reagents and conditions: (a) MeOH, water, Dowex-50W!8
(HC), 75 8C, 4 h; (b) PhCH(OMe)2, TsOH, CDCl3, 48 h.
Configurational assignments at C-1 in the diastereoisomeric
pairs of phosphonates from the a and b series are based on
the well-established stereochemistry of the addition of
dialkyl phosphites to 2,3-O-isopropylidene(cyclohexyli-
dene)-D-glyceraldehyde.34–36 From the protected (2R)-
aldehydes, (1S,2R)-dihydroxyphosphonates were formed
as the major diastereoisomers in approximately 3:1 ratios.
To gather additional support, the isopropylidene acetal
(1S,2R,3S)-30a was hydrolysed to the azidotriol (1S,2R,3S)-
35a, which was acetylated to give the triacetate (1S,2R,3S)-
36a (Scheme 7).
1
A list of structurally important data extracted from H and
3
13C NMR spectra of (4R,5R,6S)-37 includes: J(H5–H6)Z
9.8 Hz, d(C2)Z102.0 ppm, 3J(P–C2)Z14.6 Hz, 3J(P–
C4)Z14.0 Hz and 4J(P–CH2N3)Z2.9 Hz.40–45 On these
basis we learned about diaxial disposition of H5 and H6
protons and, in consequence, the equatorial position of
the O,O-dibenzylphosphoryl group, which was further
supported by observation of large vicinal P–C couplings
to C2 and C4. Furthermore, the appearance of a four-bond
P-CH2N3 coupling (W-coupling) clearly shows that the
formation of conformationally rigid 1,3-dioxane ring forced
the acyclic azidotriol (1S,2R,3R)-35 to adapt fully extended
zig-zag conformation.
Transformation of pure dibenzyl esters (1S,2R,3S)-30a,
(1R,2R,3S)-30b and (1S,2R,3R)-34a into the respective
4-amino-1,2,3-trihydroxybutylphosphonic acids (1S,2R,3S)-
16, (1R,2R,3S)-16 and (1S,2R,3R)-16 was accomplished in
two steps involving acetal hydrolysis and catalytic hydro-
genation of azides with simultaneous hydrogenolysis of the
benzyl esters (Scheme 9). The intermediate dibenzyl
4-azido-1,2,3-trihydroxybutylphosphonates 35 were iso-
lated in 74–86% yields as white amorphous solids. The
final acids 16 appeared as creamy powders, which
decomposed before melting. They were insoluble in all
solvents including DMSO and only sparingly soluble in
Scheme 7. Reagents and conditions: (a) MeOH, water, Dowex-50W!8
(HC), 75 8C, 4 h; (b) Ac2O, NEt3, DMAP, rt, overnight.
Detailed analyses of the 1H and 1H{31P} NMR spectra of the
azidotriol [3J(H1–H2)Z9.3 Hz; 3J(H2–H3)Z1.5 Hz;
3
3J(H2–P)Z9.0 Hz; J(C3–P)Z11.3 Hz] and the respective
triacetate [3J(H1–H2)Z9.3 Hz; 3J(H2–H3)Z2.4 Hz;
3J(H2–P)Z11.4 Hz] led to the conclusion that they both
exist in a preferred conformation37,38 depicted in Figure 2
water to afford concentrations suitable for taking 1H and 31
P

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A. E. Wroblewski, I. E. Głowacka / Tetrahedron 61 (2005) 11930–11938
11933
To a solution of 18 (3.67 g, 14.9 mmol) in a THF–ethanol
mixture (1/2, v/v, 105 mL) containing lithium chloride
(3.80 g, 89.6 mmol), sodiumborohydride (3.39 g, 89.6 mmol)
was added portionwise below 5 8C. After stirring for 20 h at
room temperature, acetone (24 mL) was added to quench an
excess of borohydride and all precipitates were removed by
filtration through a layer of Celite. The solution was
concentrated in vacuo and the crude product was chromato-
graphed on a silica gel column with methylene chloride–
methanol (50/1, v/v) to give (2S,3S)-2123 (2.08 g, 86%) as
Scheme 9. Reagents and conditions: (a) MeOH–water, Dowex-50W!8
(HC), 75 8C, 4 h; (b) H2, Pd/C, MeOH–water, 24–48 h.
1
a colourless oil. H NMR (CDCl3): dZ4.03–4.00 (m, 2H,
H–C-2, H–C-3), 3.85–3.66 (m, 4H, CH2OH), 2.5–2.3 (br s),
1.44 (s, 6H, CH3).
NMR spectra only, but preventing 13C NMR and optical
activity measurements. However, optical activity of the
acids 16 was measured for solutions in 5% ammonia.
4.1.2. (2S,3S)-4-Azido-2,3-O-isopropylidene-1,2,3-butane-
triol, (2S,3S)-23. A suspension of the diol (2S,3S)-21
(1.13 g, 6.97 mmol), silver(I) oxide (2.42 g, 10.5 mmol),
tosyl chloride (1.46 g, 7.67 mmol) and potassium iodide
(0.231 g, 1.39 mmol) in methylene chloride (40 mL) was
stirred at room temperature for 2 h. Solids were filtered off
on a short layer of silica gel using ethyl acetate. Evaporation
of solvents in vacuo afforded a crude monotosylate (2S,3S)-
22 (2.20 g, 100%) as a colourless oil. 1H NMR (CDCl3): dZ
7.82–7.78 (m, 2H), 7.37–7.34 (m, 2H), 4.16–4.07 (m, 3H),
3. Conclusions
Two new four-carbon chirons, 4-azido-4-deoxy-2,3-O-
isopropylidene-L-threose, (2R,3S)-17 and 4-azido-4-deoxy-
2,3-O-isopropylidene-D-erythrose, (2R,3R)-17, were syn-
thesised from L-tartrate and D-isoascorbic acid, respectively.
They were partially (up to 7%) epimerised during oxidation
under Swern conditions. Diastereoselectivities of the
additions of dimethyl, diethyl, diisopropyl and dibenzyl
phosphites to (2R,3S)-17 were 3:1, while to (2R,3R)-17 -
4:1. Only mixtures of dibenzyl (1S,2R,3S)-, (1R,2R,3S)-,
(1S,2R,3R)- and (1R,2R,3R)-4-azido-2,3-O-isopropylidene-
1-hydroxybutylphosphonates 30 and 34 were easily separ-
able into pure C-1 epimeric 1-hydroxyphosphonates. The
absolute configurations at C-1 were unequivocally estab-
lished by detailed analysis of NMR spectra of dibenzyl
(1S,2R,3S)-4-azido-1,2,3-triacetyloxybutylphosphonate and
(4R,5R,6S)-4-azidomethyl-6-(O,O-dibenzylphosphoryl)-5-
hydroxy-2-phenyl-1,3-dioxane. The dibenzyl esters were
transformed in two steps into the respective (1S,2R,3S)-,
(1R,2R,3S)- and (1S,2R,3R)-4-amino-1,2,3-trihydroxybutyl-
phosphonic acids by hydrolysis of the isopropylidene
acetals followed by the reduction of the azide and hydro-
genolysis of the benzyl residues.
3.98 (ddd, JZ7.5, 4.2, 3.6 Hz, 1H), 3.81 (ddd, JAB
Z
11.9 Hz, JZ5.0, 3.6 Hz, 1H), 3.63 (ddd, JABZ11.9 Hz, JZ
7.7, 4.2 Hz, 1H), 2.48 (s, 3H), 1.96 (br s, 1H), 1.92 (s, 3H),
1.35 (s, 3H).
A solution of the crude monotosylate (2S,3S)-22 (2.20 g,
6.97 mmol) in DMF (15 mL) was stirred with sodium azide
(0.680 g, 10.5 mmol) at 80 8C for 24 h. The reaction mixture
was washed with water (20 mL) and aqueous phase was
extracted with methylene chloride (4!30 mL). The com-
bined organic phases were dried over MgSO4, solvents were
removed in vacuo, and the crude azide was purified on a
silica gel column with ethyl acetate–hexanes to furnish
1
(2S,3S)-2325 (1.26 g, 94%) as a colourless oil. H NMR
(CDCl3): dZ4.15–3.96 (m, 2H), 3.83 (dd, JZ11.9, 3.6 Hz,
1H, CHaHbO), 3.65 (dd, JZ11.9, 3.8 Hz, 1H, CHaHbO),
3.57 (dd, JZ13.1, 3.8 Hz, 1H, CHaHbN), 3.34 (dd, JZ13.1,
4.8 Hz, 1H, CHaHbN), 2.17 (br s, 1H), 1.47 (s, 3H), 1.44 (s,
3H).
4. Experimental
4.1. General
4.1.3. Methyl (2R,3R)-4-azido-1,2-dihydroxy-2,3-O-iso-
propylidenebutanoate, (2R,3R)-26. A mixture of 2,3-O-
isopropylidene-D-erythronolactone27,28 (1.08 g, 6.81 mmol)
and sodium azide (1.77 g, 27.2 mmol) in DMF (7.5 mL) was
stirred at 110 8C for 24 h. After cooling to room tem-
perature, the solids were filtered off. The solution was
treated with methyl iodide (40 mL) and kept at room
temperature for 2 days. Ether (100 mL) was added and the
solution was washed with water (3!60 mL). The organic
phase was dried over MgSO4, concentrated in vacuo and the
crude product was purified on a silica gel column with
chloroform–methanol (100/1, v/v) to afford (2R,3R)-26
(0.764 g, 52%). IR (film): nZ2995, 2962, 2101, 1731, 1438,
1212 cmK1. [a]D20 C78.9 (c 1.42, CHCl3). 1H NMR
(CDCl3): dZ4.67 (d, JZ7.2 Hz, 1H, H–C-2), 4.52 (ddd,
General procedures and instrumentation have been
described earlier.39
4.1.1. (2S,3S)-2,3-O-Isopropylidene-1,2,3,4-butanetetrol,
(2S,3S)-21. To a solution of diethyl L-tartrate (4.71 g,
22.8 mmol) and ethyl orthoformate (5.0 mL, 30 mmol) in
anhydrous acetone (6.0 mL), 3.5 M HCl in ethyl acetate
(0.25 mL) was added and the reaction mixture was kept at
room temperature for 4 days. After neutralisation with
triethylamine, the mixture was concentrated, diluted with
ether (60 mL), the solution was washed with water (3!
20 mL) and finally dried over MgSO4. Evaporation of all
volatiles in vacuo gave crude diethyl 2,3-O-isopropylidene-
L-tartrate 18 (3.67 g, 84%) as a yellowish oil, which was
pure enough to be used in the next step.
JZ7.2 Hz, 6.0, 3.9 Hz, 1H, H–C-3), 3.49 (dd, JAB
13.2 Hz, JZ3.9 Hz, 1H, HaHbC-4), 3.32 (dd, JAB
Z
Z
13.2 Hz, JZ6.0 Hz, 1H, HaHbC-4), 1.40 (s, 3H), 1.63 (s,
3H). 13C NMR (CDCl3): dZ169.7, 111.3, 76.6, 75.4, 52.5,

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A. E. Wroblewski, I. E. Głowacka / Tetrahedron 61 (2005) 11930–11938
11934
50.5, 27.0, 25.5. Anal. Calcd for C8H13N3O4!1⁄4 H2O: C,
43.73; H, 5.96; N, 19.12. Found: C, 43.50; H, 5.72; N,
19.09%.
All volatiles were removed in vacuo, the crude 1-hydro-
xyphosphonates were analysed by 1H and 31P NMR
spectroscopy and later subjected to column chromatography
on silica gel.
4.1.4. (2S,3R)-4-Azido-2,3-O-isopropylidene-1,2,3-butane-
triol, (2S,3R)-23. To a solution of (2R,3R)-26 (0.565 g,
2.63 mmol) in a THF–ethanol mixture (1/2, v/v, 30 mL)
containing lithium chloride (0.334 g, 7.88 mmol), sodium
borohydride (0.298 g, 7.88 mmol) was added portionwise
below 5 8C. After stirring for 24 h at room temperature,
acetone (10 mL) was added to quench an excess of
borohydride and all precipitates were removed by filtration
through a layer of Celite. The solution was concentrated in
vacuo and the crude product was chromatographed on a
silica gel column with methylene chloride–methanol (100/1,
v/v) to give (2S,3R)-23 (0.483 g, 98%) as a colourless oil. IR
(film): nZ3315, 2991, 2972, 2110, 1425, 1217 cmK1. [a]D20
4.2.1. Dimethyl (1S,2R,3S)-4-azido-1,2,3-trihydroxy-2,3-
O-isopropylidenebutylphosphonate, (1S,2R,3S)-27a.
According to the general procedure, from the aldehyde
(2R,3S)-17 (1.09 g, 5.89 mmol) and dimethyl phosphite
(0.45 mL, 5.9 mmol), a 3:1 mixture of the phosphonates
(1S,2R,3S)-27a and (1R,2R,3S)-27b (1.14 g) was obtained.
After chromatography with ethyl acetate–hexanes (1/1, v/v),
(1S,2R,3S)-27a was separated (0.204 g, 12%) as a yellowish
oil. IR (film): nZ3304, 2103, 1224, 1051 cmK1. [a]D20
1
K67.7 (c 1.21, CHCl3). H NMR (CDCl3): dZ4.35 (ddd,
JZ7.3, 5.2, 2.8 Hz, 1H, H–C-3), 4.17 (ddd, JZ7.3, 6.0,
6.0 Hz, 1H, H–C-2), 4.10 (dd, JZ7.9, 6.0 Hz, 1H, H–C-1),
3.84 (d, JZ10.5 Hz, 6H), 3.70 (dd, JZ13.2, 2.8 Hz, 1H,
HaHbC-4), 3.42 (dd, JZ13.2, 5.2 Hz, 1H, HaHbC-4), 1.48 (s,
3H), 1.44 (s, 3H). 13C NMR (CDCl3): dZ110.3, 78.2 (d, JZ
9.4 Hz), 76.4 (d, JZ5.4 Hz), 68.6 (d, JZ160.9 Hz, C-1),
54.0 and 53.7 (2d, JZ7.0 Hz, COP), 52.7 (s, C-4), 27.3,
27.2. 31P NMR (CDCl3): dZ24.65. Anal. Calcd for
C9H18N3O6P: C, 36.62; H, 6.14; N, 14.23. Found: C,
36.82; H, 6.12; N, 14.45%.
1
C16.8 (c 0.92, CHCl3). H NMR (CDCl3): dZ4.30–4.18
(m, 2H), 3.69 (dd, JABZ11.7 Hz, JZ4.8 Hz, 1H, CHaHbO),
3.66 (dd, JABZ11.7 Hz, JZ5.1 Hz, 1H, CHaHbO), 3.46 (dd,
JZ12.6, 6.6 Hz, 1H, CHaHbN), 3.36 (dd, JZ12.6, 4.8 Hz,
1H, CHaHbN), 1.45 (s, 3H), 1.33 (s, 3H). 13C NMR
(CDCl3): dZ109.1, 77.0, 75.8, 60.8, 50.9, 27.0, 25.3. Anal.
Calcd for C7H13N3O3: C, 44.91; H, 7.00; N, 22.45. Found:
C, 44.62; H, 6.93; N, 22.57%.
4.1.5. (2R,3S)-4-Azido-2,3-O-isopropylidene-2,3-di-
hydroxybutanal (4-azido-4-deoxy-2,3-O-isopropylidene-
L-threose), (2R,3S)-17. To a solution of oxalyl chloride
(0.473 mL, 5.42 mmol) in methylene chloride (10 mL)
cooled to K70 8C a solution of DMSO (0.807 mL,
11.4 mmol) in methylene chloride (4.0 mL) was added
dropwise followed, after 15 min, by a solution of (2S,3S)-23
(0.819 g, 4.37 mmol) in methylene chloride (4.0 mL). After
stirring for 2 h at K70 8C, triethylamine (1.8 mL,
13.1 mmol) was injected at this temperature and the reaction
mixture was allowed to reach 0 8C, when it was treated with
a saturated solution of NH4Cl (10 mL). The reaction
mixture was extracted with methylene chloride (3!
20 mL), organic phases were combined, dried over
MgSO4 and concentrated in vacuo to give a crude aldehyde
(2R,3S)-17 as a yellowish oil (1.12 g), which was
4.2.2. Diethyl (1S,2R,3S)-4-azido-1,2,3-trihydroxy-2,3-O-
isopropylidenebutylphosphonate, (1S,2R,3S)-28a. From
the aldehyde (2R,3S)-17 (1.02 g, 5.55 mmol) and diethyl
phosphite (0.71 mL, 5.55 mmol), a 3:1 mixture of the
phosphonates (1S,2R,3S)-28a and (1R,2R,3S)-28b (1.59 g)
was obtained. After chromatography with ethyl acetate–
hexanes (1/1, v/v), (1S,2R,3S)-28a was separated (0.228 g,
13%) as colourless plates. Mp 58–59 8C. IR (film): nZ3229,
2991, 2935, 2117, 1223, 1031 cmK1. [a]D20 K59.4 (c 1.37,
CHCl3). 1H NMR (CDCl3): dZ4.36 (ddd, JZ7.5, 5.2,
2.6 Hz, 1H, H–C-3), 4.25–4.15 (m, 5H, CH2OP, H–C-2),
4.08 (dd, JZ8.5, 5.6 Hz, 1H, H–C-1), 3.71 (dd, JZ13.3,
2.7 Hz, 1H, HaHbC-4), 3.44 (dd, JZ13.3, 5.3 Hz, 1H,
HaHbC-4), 1.48 (s, 3H), 1.44 (s, 3H), 1.36 (t, JZ7.0 Hz, 6H,
CH3CH2). 13C NMR (CDCl3): dZ110.1, 77.7 (d, JZ
6.8 Hz), 76.7 (d, JZ6.0 Hz), 68.5 (d, JZ161.5 Hz, C-1),
63.6 and 63.3 (2d, JZ7.0 Hz, COP), 52.7 (s, C-4), 27.3,
27.2, 16.8 and 16.7 (2d, JZ2.3 Hz, CCOP). 31P NMR
(CDCl3): dZ21.30. Anal. Calcd for C11H22N3O6P: C,
40.86; H, 6.86; N, 13.00. Found: C, 41.03; H, 7.05; N,
13.13%.
1
immediately used in the next step. H NMR (CDCl3): dZ
9.81 (d, JZ0.6 Hz, 1H, CHO), 4.26–4.24 (m, 2H), 3.69–
3.64 (m, 1H), 3.36–3.30 (m, 1H), 1.55 (s, 3H), 1.43 (s, 3H).
4.1.6. (2R,3R)-4-Azido-2,3-O-isopropylidene-2,3-di-
hydroxybutanal(4-azido-4-deoxy-2,3-O-isopropylidene-
D-erythrose), (2R,3R)-17. In a similar way as described for
(2R,3S)-17 (Section 4.1.5), from (2S,3R)-23 (0.955 g,
5.10 mmol), the crude aldehyde (2R,3R)-17 (1.10 g) was
4.2.3. Diisopropyl (1S,2R,3S)- and (1R,2R,3S)-4-azido-1,
2,3-trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3S)-29a and (1R,2R,3S)-29b. These compounds
were obtained according to the general procedure using the
aldehyde (2R,3S)-17 (0.96 g, 5.2 mmol) and diisopropyl-
phosphite (0.77 g, 4.7 mmol). A 3:1 mixture of the
phosphonates (1S,2R,3S)-29a and (1R,2R,3S)-29b was
subjected to chromatography on a silica gel column with
chloroform–methanol (150/1, v/v) to give (1S,2R,3S)-29a
(0.987 g, 54%) and (1R,2R,3S)-29b (0.266 g, 14%), both as
colourless needles.
1
obtained as a yellowish oil. H NMR (CDCl3): dZ9.76 (d,
JZ2.1 Hz, 1H, CHO), 4.59 (ddd, JZ8.1, 4.2, 3.3 Hz, 1H,
H–C-3), 4.42 (dd, JZ8.1, 2.1 Hz, 1H, H–C-2), 3.59 (dd, JZ
13.5, 3.3 Hz, 1H, HaHbC-4), 3.22 (dd, JZ13.5, 4.2 Hz, 1H,
HaHbC-4), 1.64 (s, 3H), 1.42 (s, 3H).
4.2. Phosphonylation of the aldehydes 17 (general
procedure)
To the crude aldehyde 17 (1.0 mmol), dialkyl phosphite was
added followed by triethylamine (0.1 mmol) and the
reaction mixture was left at room temperature for 24 h.
The phosphonate (1S,2R,3S)-29a. Mp 91–92 8C, from
hexanes. IR (KBr): nZ3180, 2982, 2933, 2101, 1216,
1016 cmK1. [a]D20 K57.6 (c 1.21, CHCl3). 1H NMR

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A. E. Wroblewski, I. E. Głowacka / Tetrahedron 61 (2005) 11930–11938
11935
(CDCl3): dZ4.86–4.69 (m, 2H), 4.38 (ddd, JZ7.5, 5.1,
2.7 Hz, 1H, H–C-3), 4.18 (ddd, JZ7.5, 5.1, 3.6 Hz, 1H, H–
C-2), 4.04 (dd, JZ9.6, 5.1 Hz, 1H, H–C-1), 3.73 (dd, JZ
13.2, 2.7 Hz, 1H, HaHbC-4), 3.45 (dd, JZ13.2, 5.1 Hz, 1H,
HaHbC-4), 1.48 (s, 3H), 1.44 (s, 3H), 1.36 (d, JZ6.3 Hz,
3H), 1.35 (d, JZ6.3 Hz, 9H). 13C NMR (CDCl3): dZ109.9,
77.1 (d, JZ6.8 Hz), 76.8 (d, JZ6.0 Hz), 72.4 and 72.1 (2d,
JZ7.2 Hz, COP), 68.4 (d, JZ163.8 Hz, C-1), 52.6 (s, C-4),
27.3, 27.2, 24.5 (d, JZ3.0 Hz, CCOP), 24.4 (d, JZ3.0 Hz,
CCOP), 24.2 (d, JZ4.5 Hz, CCOP) and 24.1 (d, JZ5.3 Hz,
CCOP). 31P NMR (CDCl3): dZ20.12. Anal. Calcd for
C13H26N3O6P: C, 44.44; H, 7.46; N, 11.96. Found: C, 44.75;
H, 7.71; N, 11.91%.
13.2, 3.6 Hz, 1H, HaHbC-4), 3.35 (dd, JZ13.2, 4.5 Hz, 1H,
HaHbC-4), 1.45 (s, 3H), 1.39 (s, 3H). 13C NMR (CDCl3):
dZ136.2 and 136.0 (2d, JZ6.0 Hz, Cipso), 128.7, 128.7,
128.6, 128.1, 128.1, 110.6, 77.0 (s, C-2), 75.6 (d, JZ
11.3 Hz, C-3), 68.7 and 68.5 (2d, JZ6.9 Hz, COP), 67.3 (d,
JZ161.2 Hz, C-1), 51.6 (s, C-4), 27.3, 27.1. 31P NMR
(CDCl3): dZ22.79. Anal. Calcd for C21H26N3O6P: C,
56.37; H, 5.86; N, 9.39. Found: C, 56.23; H, 5.81; N, 9.61%.
4.2.5. Dimethyl (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,
3-trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3R)-31a and (1R,2R,3R)-31b. According to the
general procedure, from the aldehyde (2R,3R)-17 (0.263 g,
1.42 mmol) and dimethyl phosphite (0.117 mL, 1.28 mmol),
a 4:1 mixture of the phosphonates (1S,2R,3R)-31a and
(1R,2R,3R)-31b (0.419 g) was obtained. After chromato-
graphy with chloroform–methanol (150/1–100/1, v/v) only
minute quantities of impure (1S,2R,3R)-31a (purity ca.
90%) and (1R,2R,3R)-31b (purity ca. 90%) were separated
as yellowish oils.
The phosphonate (1R,2R,3S)-29b. Mp 54–56 8C, from
hexanes. IR (film): nZ3284, 2985, 2935, 2103, 1219,
997 cmK1. [a]2D0 K47.5 (c 2.53, CHCl3). 1H NMR (CDCl3):
dZ4.85–4.73 (m, 2H), 4.28–4.20 (m, 2H, H–C-3, H–C-2),
3.75 (dd, JZ11.4, 2.7 Hz, 1H, H–C-1), 3.59 (dd, JZ13.2,
3.3 Hz, 1H, HaHbC-4), 3.39 (dd, JZ13.2, 4.5 Hz, 1H,
HaHbC-4), 1.48 (s, 3H), 1.45 (s, 3H), 1.37 (d, JZ6.3 Hz,
3H), 1.36 (d, JZ6.0 Hz, 6H), 1.34 (d, JZ6.3 Hz, 3H). 13C
NMR (CDCl3): dZ110.5, 77.3 (C-2), 76.0 (d, JZ11.3 Hz,
C-3), 72.3 and 72.0 (2d, JZ6.8 Hz, COP), 67.4 (d, JZ
163.1 Hz, C-1), 51.8 (s, C-4), 27.3, 27.3, 24.6 (d, JZ3.0 Hz,
CCOP), 24.4 (d, JZ3.8 Hz, CCOP), 24.3 (d, JZ5.3 Hz,
CCOP) and 24.1 (d, JZ5.3 Hz, CCOP). 31P NMR (CDCl3):
dZ19.88. Anal. Calcd for C13H26N3O6P: C, 44.44; H, 7.46;
N, 11.96. Found: C, 44.71; H, 7.72; N, 11.78%.
1
The phosphonate (1S,2R,3R)-31a. H NMR (CDCl3): dZ
4.44–4.32 (m, 2H, H–C-2, H–C-3), 4.04 (dd, JZ9.0, 5.4 Hz,
1H, H–C-1), 3.84 and 3.83 (2d, JZ10.5 Hz, 6H), 3.67 (dd,
JZ13.2, 3.3 Hz, 1H, HaHbC-4), 3.53 (dd, JZ13.2, 7.5 Hz,
1H, HaHbC-4), 1.50 (s, 3H), 1.40 (s, 3H). 31P NMR
(CDCl3): dZ26.67.
1
The phosphonate (1R,2R,3R)-31b. H NMR (CDCl3): dZ
4.54 (ddd, JZ7.2, 5.1, 1.8 Hz, 1H, H–C-2), 4.38 (dddd, JZ
7.5, 7.2, 5.1, 1.8 Hz, 1H, H–C-3), 4.04 (dd, JZ12.6, 1.8 Hz,
1H, H–C-1), 3.85 and 3.83 (2d, JZ10.5 Hz, 6H), 3.71 (dd,
JZ12.6, 7.5 Hz, 1H, HaHbC-4), 3.50 (dd, JZ12.6, 5.1 Hz,
1H, HaHbC-4), 1.55 (s, 3H), 1.41 (s, 3H). 31P NMR
(CDCl3): dZ24.31.
4.2.4. Dibenzyl (1S,2R,3S)- and (1R,2R,3S)-4-azido-1,2,3-
trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3S)-30a and (1R,2R,3S)-30b. According to the
general procedure employing the aldehyde (2R,3S)-17
(0.476 g, 2.57 mmol) and dibenzylphosphite (0.606 g,
2.31 mmol), a 3:1 mixture of the phosphonates (1S,2R,3S)-
30a and (1R,2R,3S)-30b was obtained. After purification on
a silica gel column with chloroform–ethyl acetate–methanol
(200/1/0.5, v/v), (1S,2R,3S)-30a (0.683 g, 59%) as a white
powder and (1R,2R,3S)-30b (0.274 g, 24%) as a colourless
oil were obtained.
4.2.6. Diethyl (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,3-
trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3R)-32a and (1R,2R,3R)-32b. From the aldehyde
(2R,3R)-17 (208 mg, 1.12 mmol) and diethyl phosphite
(0.13 mL, 1.0 mmol), a 4:1 mixture of the phosphonates
(1S,2R,3R)-32a and (1R,2R,3R)-32b (0.463 g) was obtained.
Attempts to purify the crude product by the silica gel
chromatography with chloroform–methanol (200/1, v/v)
failed.
The phosphonate (1S,2R,3S)-30a. Mp 105–106 8C, from
ethyl acetate–hexanes. IR (KBr): nZ3222, 2995, 2923,
2102, 1271, 1222, 997, 744, 698 cmK1. [a]D20 K47.8 (c 1.28,
1
CHCl3). H NMR (CDCl3): dZ7.37–7.26 (m, 10H), 5.14–
4.2.7. Diisopropyl (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,
2,3-trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3R)-33a and (1R,2R,3R)-33b. From the aldehyde
(2R,3R)-17 (0.337 mg, 1.82 mmol) and diisopropyl phos-
phite (0.27 mL, 1.63 mmol), a 4:1 mixture of the phosphon-
ates (1S,2R,3R)-32a and (1R,2R,3R)-32b was obtained
(0.543 g). An attempt at purifying the crude product by
the silica gel chromatography with chloroform–methanol
(100/1, v/v) failed.
5.02 (m, 4H, CH2OP), 4.31 (ddd, JZ7.5, 5.0, 3.0 Hz, 1H,
H–C-3), 4.17 (ddd, JZ7.5, 6.0, 4.5 Hz, 1H, H–C-2), 4.09
(dd, JZ7.5, 6.0 Hz, 1H, H–C-1), 3.62 (dd, JZ13.2, 3.0 Hz,
1H, HaHbC-4), 3.35 (dd, JZ13.2, 5.1 Hz, 1H, HaHbC-4),
1.44 (s, 3H), 1.38 (s, 3H). 13C NMR (CDCl3): dZ135.8 and
135.8 (2d, JZ6.0 Hz, Cipso), 128.7, 128.7, 128.6, 128.1,
128.0, 110.3, 78.1 (d, JZ9.4 Hz), 76.5 (d, JZ5.4 Hz), 69.1
(d, JZ160.6 Hz, C-1), 68.8 and 68.6 (2d, JZ7.2 Hz, COP),
52.6 (s, C-4), 27.3, 27.2. 31P NMR (CDCl3): dZ22.96.
Anal. Calcd for C21H26N3O6P: C, 56.37; H, 5.86; N, 9.39.
Found: C, 56.41; H, 5.92; N, 9.41%.
4.2.8. Dibenzyl (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,
3-trihydroxy-2,3-O-isopropylidenebutylphosphonates,
(1S,2R,3R)-34a and (1R,2R,3R)-34b. According to the
general procedure employing the aldehyde (2R,3R)-17
(0.945 g, 5.10 mmol) and dibenzylphosphite (1.34 g,
5.10 mmol), a 4:1 mixture of the phosphonates (1S,2R,3R)-
34a and (1R,2R,3R)-34b was obtained. Purification on a
The phosphonate (1R,2R,3S)-30b. IR (film): nZ3259, 2988,
2934, 2103, 1242, 1217, 1018, 737, 698 cmK1. [a]D20 K46.2
(c 2.50, CHCl3). 1H NMR (CDCl3): dZ7.38–7.26 (m, 10H),
5.18–5.03 (m, 4H, CH2OP), 4.26–4.18 (m, 2H, H–C-2, H–
C-3), 3.85 (dd, JZ11.6, 2.1 Hz, 1H, H–C-1), 3.49 (dd, JZ

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11936
silica gel column with chloroform–ethyl acetate–methanol
(200/1/0.5, v/v) gave (1S,2R,3R)-34a (1.34 g, 59%) and
(1R,2R,3R)-34b (0.353 g, 15%) as white powders.
31P NMR (CD3OD): dZ26.45. Anal. Calcd for
C18H22N3O6P: C, 53.07; H, 5.44; N, 10.32. Found: C,
53.25; H, 5.34; N, 10.23%.
The phosphonate (1S,2R,3R)-34a. Mp 110.1–110.6 8C, from
ethyl acetate–hexanes; IR (KBr): nZ3212, 2088, 1484,
1240, 1140, 1056, 936 cmK1. [a]D20 C25.8 (c 1.18, CHCl3).
1H NMR (CDCl3): dZ7.37–7.26 (m, 10H), 5.15–5.00 (m,
4H, CH2OP), 4.43–4.34 (m, 2H, H–C-2, H–C-3), 4.05 (dd,
JZ9.3, 4.8 Hz, 1H, H–C-1), 3.60 (dd, JZ13.2, 3.3 Hz, 1H,
HaHbC-4), 3.46 (dd, JZ13.2, 7.5 Hz, 1H, HaHbC-4), 1.42 (s,
3H), 1.34 (s, 3H). 13C NMR (CDCl3): dZ136.3 and 136.2
(2d, JZ5.7 Hz, Cipso), 128.7, 128.7, 128.6, 128.6, 128.1,
128.0, 109.9, 77.3 (d, JZ13.6 Hz, C-3), 75.5 (s, C-2), 68.8
and 68.6 (2d, JZ7.2 Hz, COP), 66.7 (d, JZ160.8 Hz, C-1),
51.0 (s, C-4), 28.1, 25.8. 31P NMR (CDCl3): dZ25.02.
Anal. Calcd for C21H26N3O6P: C, 56.37; H, 5.86; N, 9.39.
Found: C, 56.26; H, 5.55; N, 9.65%.
4.3.2. The phosphonate (1R,2R,3S)-35. From the phos-
phonate (1R,2R,3S)-30b (0.154 g, 0.342 mmol), the triol
(1R,2R,3S)-35 (0.120 g, 86%) was obtained. Mp 73.6–
74.2 8C. IR (KBr): nZ3361, 3276, 2101, 1481, 1247, 1231,
1150, 1037, 937 cmK1. [a]D20 K2.6 (c 1.03, CH3OH). H
1
NMR (CD3OD): dZ7.42–7.31 (m, 10H), 5.12 (d, JZ
8.0 Hz, 2H, CH2OP), 5.07 (dd, JZ8.1, 3.0 Hz, 2H, CH2OP),
4.40 (dd, JZ9.6, 3.9 Hz, 1H, H–C-1), 3.95–3.87 (m, 2H, H–
C-3, H–C-2), 3.38 (d, JZ5.4 Hz, 2H, HaHbC-4). 13C NMR
(CD3OD): dZ137.8 and 137.6 (2d, JZ5.7 Hz, Cipso), 129.6,
129.4, 129.4, 129.1, 129.0, 128.7, 72.8 (d, JZ10.6 Hz, C-3),
72.1 (d, JZ3.8 Hz, C-2), 69.9 and 69.2 (2d, JZ6.8 Hz,
COP), 69.4 (d, JZ162.3 Hz, C-1), 54.7 (s, C-4). 31P NMR
(CD3OD): dZ24.02. Anal. Calcd for C18H22N3O6P!H20:
C, 50.83; H, 5.69; N, 9.89. Found: C, 50.72; H, 5.89; N,
9.82%.
The phosphonate (1R,2R,3R)-34b. Mp 78.2–79.0 8C, from
diethyl ether–hexanes. IR (KBr): nZ3241, 2079, 1472,
1249, 1130, 1059, 940 cmK1. [a]D20 C36.0 (c 1.03, CHCl3).
1H NMR (CDCl3): dZ7.37–7.32 (m, 10H), 5.17–5.02 (m,
4H, CH2OP), 4.55 (ddd, JZ6.9, 5.1, 1.8 Hz, 1H, H–C-2),
4.31 (dddd, JZ7.8, 6.9, 5.1, 1.8 Hz, 1H, H–C-3), 4.00 (dd,
JZ12.3, 1.8 Hz, 1H, H–C-1), 3.64 (dd, JZ12.6, 7.8 Hz, 1H,
HaHbC-4), 3.40 (dd, JZ12.6, 5.1 Hz, 1H, HaHbC-4), 1.48 (s,
3H), 1.37 (s, 3H). 13C NMR (CDCl3): dZ136.2 and 136.0
(2d, JZ5.7 Hz, Cipso), 128.6, 128.6, 128.6, 128.5, 128.4,
128.3, 128.1, 128.0, 109.4, 76.3 (d, JZ13.7 Hz, C-3), 74.6
(d, JZ1.4 Hz, C-2), 68.8 and 68.4 (2d, JZ7.2 Hz, COP),
66.6 (d, JZ160.9 Hz, C-1), 51.5 (s, C-4), 27.1, 24.9. 31P
NMR (CDCl3): dZ22.69. Anal. Calcd for C21H26N3O6P: C,
56.37; H, 5.86; N, 9.39. Found: C, 56.29; H, 5.59; N, 9.37%.
4.3.3. The phosphonate (1S,2R,3R)-35. From the phos-
phonate (1S,2R,3R)-34a (0.173 g, 0.387 mmol), the triol
(1S,2R,3R)-35 (0.117 g, 74%) was obtained. Mp 113.1–
113.8 8C, from methanol–water; IR (KBr): nZ3352, 3269,
2090, 1474, 1251, 1242, 1139, 1042, 943 cmK1. [a]D20 C3.1
(c 1.8, CH3OH). 1H NMR (CD3OD): dZ7.39–7.28 (m,
10H), 5.16–4.99 (m, 4H, CH2OP), 4.25 (dd, JZ8.4, 6.0 Hz,
1H, H–C-1), 4.07 (ddd, JZ6.6, 6.6, 3.3 Hz, 1H, H–C-3),
3.91 (ddd, JZ17.1, 6.6, 6.0 Hz, 1H, H–C-2), 3.48 (dd, JZ
13.0, 3.3 Hz, 1H, HaHbC-4), 3.41 (dd, JZ13.0, 6.6 Hz, 1H,
HaHbC-4). 13C NMR (CD3OD): dZ138.0 and 137.9 (2d,
JZ5.7 Hz, Cipso), 129.5, 129.4, 129.3, 129.0, 74.8 (d, JZ
2.0 Hz, C-2), 73.0 (d, JZ6.9 Hz C-3), 70.8 (d, JZ161.6 Hz,
C-1), 69.8 and 69.1 (2d, JZ7.6 Hz, COP), 54.8 (s, C-4). 31P
NMR (CD3OD): dZ26.26. Anal. Calcd for C18H22N3O6P:
C, 53.07; H, 5.44; N, 10.32. Found: C, 52.85; H, 5.19; N,
10.23%.
4.3. Dibenzyl 4-azido-1,2,3-trihydroxybutylphospho-
nates 35 (general procedure)
Enantiomerically pure dibenzyl 4-azido-1,2,3-trihydroxy-2,
3-O-isopropylidenebutylphosphonates, (1S,2R,3S)-30a or
(1R,2R,3S)-30b or (1S,2R,3R)-34a (0.40 mmol) were dis-
solved in aqueous methanol (20 mL) and Dowex 50W!4
(HC) (1.00 g) was added. The slurry was stirred at 70 8C for
4 h. Cooled solution was filtered, the resin was washed with
methanol and water. After concentration the solid residue
was crystallised from methanol–water to give pure dibenzyl
4-azido-1,2,3-trihydroxybutylphosphonates as white amor-
phous solids.
4.3.4. Dibenzyl 4-azido-1,2,3-triacetyloxybutylphospho-
nates, (1S,2R,3S)-36. Standard acetylation of the phosphon-
ate (1S,2R,3S)-35a (0.043 g, 0.11 mmol) with acetic
anhydride (0.035 mL, 0.37 mmol) in the presence of NEt3
(0.052 mL, 0.37 mmol) and one crystal of DMAP in
chloroform (1 mL) gave the crude triacetate (1S,2R,3S)-36
(0.040 g; purity O95%) as a colourless oil. 1H NMR
(CDCl3): dZ7.38–7.25 (m, 10H), 5.58 (ddd, JZ11.4, 9.3,
2.4 Hz, 1H, H–C-2), 5.42 (dd, JZ9.3, 7.5 Hz, 1H, H–C-1),
5.30 (ddd, JZ7.2, 4.8, 2.4, Hz, 1H, H–C-3), 5.11–4.92 (m,
4H, CH2OP), 3.39 (dd, JZ13.2, 4.8 Hz, 1H, HaHbC-4), 3.31
(dd, JZ13.2, 7.2 Hz, 1H, HaHbC-4), 2.08 (s, 3H), 2.02 (s,
3H), 1.98 (s, 3H). 31P NMR (CDCl3): dZ19.40.
4.3.1. The phosphonate (1S,2R,3S)-35. From the phos-
phonate (1S,2R,3S)-30a (0.196 g, 0.438 mmol), the triol
(1S,2R,3S)-35 (0.140 g, 78%) was obtained. Mp 138.0–
138.6 8C. IR (KBr): nZ3384, 3288, 2096, 1488, 1256, 1240,
1140, 1040, 940 cmK1. [a]D20 C17.4 (c 1.04, CH3OH). H
4.3.5. (4R,5R,6S)-4-azidomethyl-6-(O,O-dibenzylphos-
phoryl)-5-hydroxy-2-phenyl-1,3-dioxane, 37. To a solu-
tion of the phosphonate (1S,2R,3R)-35 (0.029 g, 0.071 mmol)
in chloroform-d (0.7 mL) and benzaldehyde dimethyl acetal
(0.021 mL, 0.14 mmol) a crystal of p-toluenesulfonic acid
was added. The progress of the reaction was monitored by
31P NMR spectroscopy at room temperature for 48 h. After
concentration the residue was chromatographed on a silica
gel column with chloroform–methanol (100/1, v/v) to give
(4R,5R,6S)-37 (0.030 g, 83%) as a white solid, which was
1
NMR (CD3OD): dZ7.37–7.28 (m, 10H), 5.10 and 5.08 (2d,
JZ8.1 Hz, 4H, CH2OP), 4.13 (dd, JZ9.3, 4.5 Hz, 1H, H–C-
1), 4.03 (dddd, JZ7.8, 5.1, 1.5, 1.2 Hz, 1H, H–C-3), 3.80
(ddd, JZ9.3, 9.0, 1.5 Hz, 1H, H–C-2), 3.47 (dd, JZ12.6,
7.8 Hz, 1H, HaHbC-4), 3.31 (dd, JZ12.6, 5.1 Hz, 1H,
HaHbC-4). 13C NMR (CD3OD): dZ136.2 and 136.0 (2d,
JZ5.7 Hz, Cipso), 129.5, 129.4, 129.1, 129.0, 72.2 (d, JZ
2.3 Hz, C-2), 70.4 (d, JZ11.3 Hz, C-3), 69.5 and 69.3 (2d,
JZ7.2 Hz, COP), 69.5 (d, JZ163.8 Hz, C-1), 55.0 (s, C-4).

´
A. E. Wroblewski, I. E. Głowacka / Tetrahedron 61 (2005) 11930–11938
11937
recrystallised from ethyl acetate–petroleum ether. Mp
106.9–107.2 8C. IR (KBr): nZ3384, 3184, 2096, 1488,
1256, 1208, 1052, 976 cmK1. [a]D20 C21.3 (c 0.96, CHCl3).
1H NMR (CDCl3): dZ7.45–7.25 (m, 15H), 5.47 (s, 1H,
H–C-2), 5.20–5.07 (m, 4H, CH2OP), 3.95 (dd, JZ9.8,
7.4 Hz, 1H, H–C-6), 3.87–3.74 (m, 2H, H–C-4, H–C-5),
3.62 (dd, JZ13.2, 1.3 Hz, 1H, HaHbC–N), 3.48 (s, 1H, HO)
3.47 (dd, JZ13.2, 4.6 Hz, 1H, HaHbC–N). 13C NMR
(CDCl3): dZ136.6, 135.7 and 135.5 (2d, JZ5.7 Hz,
Cipso), 129.4, 128.9, 128.8, 128.7, 128.4, 128.2, 128.1,
126.3, 102.0 (d, JZ14.6 Hz, C-2), 80.6 (d, JZ14.0 Hz, C-4),
76.8 (d, JZ166.6 Hz, C-6), 69.6 and 69.0 (2d, JZ7.2 Hz,
COP), 62.8 (d, JZ2.3 Hz, C-5), 51.4 (d, JZ2.9 Hz,
CH2N3). 31P NMR (CDCl3): dZ20.28. Anal. Calcd for
C26H26N3O6P!0.5H2O: C, 60.46; H, 5.27; N, 8.14. Found:
C, 60.22; H, 5.45; N, 8.15%.
17.54. Anal. Calcd for C4H12NO6P!H2O: C, 21.92; H,
6.44; N, 6.39. Found: C, 21.62; H, 6.58; N, 6.13%.
Acknowledgements
´
Financial support from the Medical University of Łodz
(503-314-1 and 502-13-853) is gratefully acknowledged.
The authors wish to express their gratitude to Mrs. Jolanta
Płocka for her excellent technical assistance and to
Mr. Rafał Janusz, MSc for his preliminary experiments in
the synthesis of 27a, 27b, 28a and 28b.
References and notes
4.4. 4-Amino-1,2,3-trihydroxybutylphosphonic acids 16
(general procedure)
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Enantiomerically pure dibenzyl 4-azido-1,2,3-trihydroxy-
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(1S,2R,3R)-35 (0.25 mmol) were dissolved in methanol
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phosphonic acid (1S,2R,3S)-16 (0.037 g, 72%) was
obtained. IR (KBr): nZ3500–2500 (broad), 1632, 1536,
1140, 1080, 1052, 920 cmK1. [a]D20 C16.1 (c 1.0, 5%
¨
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ammonia). H NMR (D2O): dZ4.24 (dd, JZ6.0, 6.0 Hz,
1H, H–C-3), 3.84–3.75 (m, 2H, H–C-1, H–C-2), 3.26–3.16
(m, 2H, HaHbC-4). 31P NMR (D2O): dZ18.28. Anal. Calcd
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(KBr): nZ3500–2500 (broad), 1641, 1529, 1145, 1076,
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