New approach to the enantiomerically pure 1,2,3- trihydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2010.06.031

The replacement of 2,3-O-cyclohexylidene-d-glyceraldehyde with (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde (Ley's aldehyde) has led to significant improvements in the isolation of both diastereoisomers of the respective 2,3-O-BDA 1,2,3-trihydroxypropylphosphonates. The triethylamine-catalysed addition of dialkyl phosphites and lithium diethyl phosphonate gave the products in moderate (ca. 1:2) diastereoselectivity while the application of diethyl trimethylsilyl phosphite afforded a 1:9 mixture of diethyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan- 2-yl]methylphosphonates.

Full text of DOI:10.1016/j.tetasy.2010.06.031

Tetrahedron: Asymmetry 21 (2010) 2218–2222
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New approach to the enantiomerically pure 1,2,3-trihydroxypropyl-
phosphonates
*
Dorota G. Piotrowska , Iwona E. Głowacka, Andrzej E. Wróblewski
´
´
´
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 16 June 2010
Accepted 24 June 2010
The replacement of 2,3-O-cyclohexylidene-D-glyceraldehyde with (2R,5R,6R)-5,6-dimethoxy-5,6-
dimethyl-1,4-dioxane-2-carbaldehyde (Ley’s aldehyde) has led to significant improvements in the
isolation of both diastereoisomers of the respective 2,3-O-BDA 1,2,3-trihydroxypropylphosphonates.
The triethylamine-catalysed addition of dialkyl phosphites and lithium diethyl phosphonate gave the
products in moderate (ca. 1:2) diastereoselectivity while the application of diethyl trimethylsilyl phos-
phite afforded a 1:9 mixture of diethyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxan-2-yl]methylphosphonates.
Dedicated respectfully to Professor Jan
Michalski on the occasion of his 90th
birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
significantly different ratios of diastereoisomeric hydroxyphospho-
nates 4a and 4b, compared to those produced from D-glyceralde-
Over the decades, numerous applications of phosphonates in
medicinal chemistry have been recognised.1–3 Despite serving as
analogues of biologically important phosphates, they also mimic
hydroxy- and amino acids in studies on their mode of action in bio-
chemical transformations. For this reason it is necessary for various
hydroxy- and aminophosphonates to be synthetically available in
an enantiomerically pure form. Recent reviews on the asymmetric
syntheses of 1-hydroxyphosphonates4 and aminophosphonates5,6
confirmed that this is still an active field of research.
hyde protected as five-membered acetals, that is, 5a and 5b
(Scheme 1).
The N-Boc-aminodiols 8 could be easily transformed into (R)-
and (S)-6 via oxidative cleavage of the terminal diol moiety
followed by immediate NaBH4 reduction of the aldehyde and
hydrolysis of the resulting 1-amino-3-hydroxyphosphonates.
Herein, we report the synthesis and separation of diastereoiso-
meric phosphonates 6a–9a and 6b–9b prepared from the aldehyde
3 and dialkyl phosphites (R = Me, Et, Bn, i-Pr), (Scheme 2).
Several years ago, we showed that the enantiomerically pure
protected (1R,2R)- and (1S,2R)-1,2,3-trihydroxypropylphospho-
nates could be prepared in good yields when 2,3-O-isopropyli-
2. Results and discussion
dene-D
-glyceraldehyde 17–10 was replaced with the respective
The triethylamine-catalysed addition of dialkyl phosphites
(R = Me, Et, Bn, i-Pr) to the aldehyde 3 at room temperature was
complete in less than 24 h and gave mixtures of phosphonates
6–9 (Scheme 1). It was noticed that the diastereoselectivities of
the additions were only moderate (Me—30:70; Et—27:73; Bn—
35:65; i-Pr—25:75) and seem to be only slightly dependent on
the size of the alkoxy groups attached to the phosphorus atom.
The oily crude products were subjected to chromatographic purifi-
cation on silica gel columns. From the two diastereoisomeric
methyl esters, the minor phosphonate 6a was separated chromato-
graphically in 7% yield, while the major diastereoisomer was finally
purified by crystallisation to give phosphonate 6b in 59% yield. We
succeeded in the isolation of both diastereoisomeric ethyl esters 7a
and 7b. Compounds 7a (minor) and 7b (major) were obtained in 7%
and 58% yields, both as crystalline materials. On the other hand,
only the major phosphonate 8b was isolated in 60% yield as colour-
less oil. Similarly, the major phosphonate 9b was separated in 55%
yield, again, as colourless oil.
cyclohexylidene acetal 2.11,12
However, in order to achieve the described yields of the enanti-
omerically pure phosphonates several tedious chromatographic
purifications were necessary. For this reason, we looked for the
alternative protected glyceraldehydes in order to study the diaste-
reoselectivity of the addition of dialkyl phosphites and, hopefully,
to facilitate the chromatographic separation of the respective
hydroxyphosphonates. Recently, Ley et al. introduced (2R,5R,6R)-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde 3 easily
prepared from D
-mannitol in two steps (Fig. 1).13–15
Since the aldehyde (2R,5R,6R)-3 contains two additional stereo-
genic centres when compared to aldehydes (R)-1 and (R)-2, and the
aldehyde functionality is equatorially positioned in a conformation-
ally rigid six-membered ring, one could expect the formation of
* Corresponding author. Tel.: +48 42 677 92 35; fax: +48 42 678 83 98.
E-mail address: dorota.piotrowska@umed.lodz.pl (D.G. Piotrowska).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.031

D. G. Piotrowska et al. / Tetrahedron: Asymmetry 21 (2010) 2218–2222
2219
OMe
Me
Me
Me
O
O
Me
O
CHO
CHO
O
CHO
O
O
OMe
H
H
H
(R)-1
(R)-2
(2R,5R,6R)-3
Figure 1. Protected D-glyceraldehydes.
To further study the diastereoselectivity of the addition to the
aldehyde 3, the lithium salt of diethyl phosphite was used. It ap-
peared that a 36:64 mixture of phosphonates 7a and 7b was
formed. However, due to lack of impurities this mixture was easier
to separate and phosphonates 7a and 7b were obtained in 18% and
45% yields, respectively, both after column chromatography and
crystallisations. We were also interested in the diastereoselectivity
of the addition of diethyl trimethylsilyl phosphite. The 1-O-silylat-
ed phosphonates were deprotected in the presence of fluorides to
give a 10:90 mixture of phosphonates 7a and 7b. Under these cir-
cumstances the major phosphonate 7b was isolated in 69% yield
after crystallisation.
The absolute configurations at C-1 in the diastereoisomeric
phosphonates in series a and b were established in the following
way. A 20:80 mixture of phosphonates 7a and 7b was subjected
to benzylation16 and then hydrolysed with trifluoroacetic acid17
to give a 20:80 mixture of the known (1R,2R)- and (1S,2R)-1-ben-
zyloxy-2,3-dihydroxypropylphosphonates,16
(1S,2R)-10b, respectively (Scheme 3).
(1R,2R)-10a
and
Thus, 1-O-benzyl phosphonate (1R,2R)-10a was obtained from
minor phosphonates (2R,5R,6R,10R)-7a and (1R,2R)-2,3-O-cyclo-
hexylidene-1-hydroxypropylphosphonate (1R,2R)-11a,11 while
both major phosphonates (2R,5R,6R,10S)-7b and (1S,2R)-2,3-O-cyclo
hexylidene-1-hydroxypropylphosphonate (1S,2R)-11b11 could be
transformed into 1-O-benzyl phosphonate (1S,2R)-10b.16 Based
on these observations one may conclude that the stereochemistry
of the triethylamine-catalysed addition of diethyl phosphite
to the carbonyl group in aldehydes (R)-2 and (2R,5R,6R)-3 follows
the same pattern. Furthermore, since no significant differences in
the diastereoselectivities of the addition were observed for the dial-
kyl phosphites used, we are confident that minor 2,3-BDA-pro-
tected phosphonates 6a, 8a and 9a and major 2,3-BDA-protected
phosphonates 6b, 8b and 9b have the (2R,5R,6R,10R)- and
(2R,5R,6R,10S)-configurations, respectively. Further evidence for
our configurational assignments comes from the comparison of
the 1H and 13C NMR spectroscopic patterns associated with the
substituted propylphosphonate fragment which are almost identi-
cal for the minor (series a) and major (series b) stereoisomers. Fi-
nally, all 31P NMR chemical shifts of the minor phosphonates
(2R,5R,6R,10R)-6–9a were observed in a higher field in comparison
to those of major phosphonates (2R,5R,6R,10S)-6–9b. The same
relationship was previously noticed for the minor and major
phosphonates obtained from 2,3-O-isopropylidene-9,10 and 2,3-O-
P(O)(OR)2
P(O)(OR)2
HO
OH
O
*
*
R
Me
Me
R
R
R
O
R
OMe
OMe
Me
OMe
OMe
Me
O
O
R
4a
4b
cyclohexylidene-D
-glyceraldehyde.11
Having established the absolute configurations of the diastereo-
isomeric 2,3-O-BDA-protected phosphonates 6–9 conformational
studies were performed on the minor 6a–8a and major 6b–9b
phosphonates. Based on the vicinal couplings (JCCCP = 12.6–14.3,
P(O)(OR)2
P(O)(OR)2
OH
(S)
HO
*
*
O
O
R'
R"
O
R'
R
R
0
JH2–H3eq = 3.3–3.4, JH1 –H2 = 3.0–3.9 and JH2–P = 4.7–5.1 Hz) observed
in the 1H and 13C NMR spectra18–23 of the minor isomers 6a–8a,
one can conclude that in a chloroform solution they exist almost
exclusively as single rotamers 12a (Fig. 2). This conclusion receives
additional evidence from the observation of a NOE signal between
H10 and H3eq resonances in the 2D NOESY spectrum of 7a due to a
spatial proximity of these protons in this isomer. Furthermore, the
1H NMR chemical shifts of H10 and H3eq in the minor isomers: 6a
(3.85 and 3.50 ppm), 7a (3.77 and 3.55 ppm) and 8a (3.81 and
O
R"
5a
5b
R'=R" =Me and R'=R" = -(CH2)5-
Scheme 1. Stereochemistry of 1-hydroxypropylphosphonates obtained from pro-
tected -glyceraldehydes.
D
OMe
Me
OMe
Me
OMe
Me
OH
H
Me
Me
Me
O
O
O
a
+
O
CHO
O
O
P(O)(OR)2
H
P(O)(OR)2
OH
OMe
OMe
OMe
H
H
H
(2R,5R,6R)-3
(2R,5R,6R,1'R)-6a
(2R,5R,6R,1'R)-7a
(2R,5R,6R,1'R)-8a
(2R,5R,6R,1'R)-9a
(2R,5R,6R,1'S)-6b
(2R,5R,6R,1'S)-7b
(2R,5R,6R,1'S)-8b
(2R,5R,6R,1'S)-9b
R = Me
R = Et
R = Bn
R = i-Pr
Scheme 2. Addition of dialkyl phosphites to the aldehyde (2R,5R,6R)-3. Reagents and conditions: (a) (RO)2P(O)H, 10 mol % NEt3, rt, 24 h or (EtO)2P(O)Li, ꢀ70 °C, 3 h or
(EtO)2POSiMe3, rt, 24 h; Bu4NF in THF, rt, 1 h.

2220
D. G. Piotrowska et al. / Tetrahedron: Asymmetry 21 (2010) 2218–2222
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
OBn
HO
OH
O
BnO
Me
OMe
Me
OMe
a, b
O
O
+
OH
OH
+
OH
OH
O
OMe
Me
(2R,5R,6R,1'R)-7a
OMe
Me
(2R,5R,6R,1'S)-7b
(1R,2R)-10a
(1S,2R)-10b
Scheme 3. Correlation of the absolute configurations of the phosphonates (2R,5R,6R,10R)-7a and (2R,5R,6R,10S)-7b with (1R,2R)-10a and (1S,2R)-10b. Reagents and
conditions: (a) BnBr, Ag2O, 4 Å MS, CH2Cl2, rt, 24 h, 83%; (b) 70% CF3COOH, rt, 2 h, 92%.
diethyl trimethylsilyl phosphate, a 1:9 mixture of diethyl (R)-
and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-di-
oxan-2-yl]methylphosphonates was obtained.
H
O
OMe
Me
H
H
O
O
P
H
O
Me
O
3
OR
OR
H
O
O
2
The absolute configurations of the diastereoisomeric 1-hydrox-
yphosphonates obtained from Ley0s aldehyde were established by
chemical correlation with the known diethyl (1R,2R)- and
(1S,2R)-1-benzyloxy-2,3-dihydoxypropylphosphonates.16
The minor 1-hydroxyphosphonates, for example, diethyl (R)-
hydroxy-[(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxan-2-yl]
methylphosphonate 7a, exist as single conformers due to hydrogen
bonding, which places the dialkoxyphosphoryl groups in an
energetically favoured position, while the (dialkoxyphosphoryl)
hydroxymethyl group in the major phosphonates 6b–9b freely
rotates around C2–C10(P) bond.
1'
OMe
OR
H
H
H
P
H
H
P
OR
(2R,5R,6R,1'R)-12a
R
O
O
O
OMe
Me
H
ax
R
O
H
O
3
Me
H
eq
H
O
P(O)(OR)2
OH
1'
H
O
OMe
H
H
4. Experimental
(2R,5R,6R,1'S)-12b
The 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. 2D NMR (COSY and NOE) measurements were performed on
a Bruker Avance III (600 MHz) spectrometer. IR spectral data were
measured on an Infinity MI-60 FT-IR spectrometer. Melting points
were determined on a Boetius apparatus and are uncorrected. Ele-
mental analyses were performed by the Microanalytical Laboratory
of this Faculty on a Perkin–Elmer PE 2400 CHNS analyzer. Polari-
metric measurements were conducted on an Optical Activity PolA-
Ar 3001 apparatus. The following absorbents were used: column
chromatography, Merck Silica Gel 60 (70–230 mesh); analytical
Figure 2. Conformations 12a and 12b of the minor and major isomers of
phosphonates 7a/8a and 7b/8b.
3.46 ppm) are observed at upper field when compared to the shifts
of the same protons in the major isomers: 6b (4.04 and 3.72 ppm),
7b (3.97 and 3.73 ppm) and 8b (4.05 and 3.73 ppm). We suggest
that the shielding effect of H10 and H3eq protons in the minor iso-
mers 6a, 7a and 8a originates from the repulsive interactions of the
electron densities similar to those in the 1,3-diaxial interactions in
six-membered rings.24
On the other hand, the 1-hydroxymethylphosphonate fragment
freely rotates around the C10–C2 bond in the major isomers 6b–9b,
0
since the values of diagnostic vicinal couplings JH1 –H2 and JCCCP are
TLC, Merck TLC plastic sheets Silica Gel 60 F254.
close to 6 Hz and below 10 Hz, respectively.18–23
While looking for the reasons for the conformational stability of
minor phosphonates (2R,5R,6R,10R)-6a–8a we suggest the forma-
tion of a strong hydrogen bond as depicted in 12a (Fig. 2). In this
conformation the bulky diethoxyphosphoryl group is located
gauche to both the ring oxygen and H–C2. On the other hand, in or-
der to observe similar H-bonding in major phosphonates
(2R,5R,6R,10S)-7b/8b one needs to position the diethoxyphosphoryl
group gauche to the ring oxygen and Hax–C3–Heq. However, in this
arrangement, serious repulsion of the diethoxyphosphoryl group
and hydrogen atoms connected to C3 are expected to make this
conformation energetically unfavourable.
4.1. Reaction of dialkyl phosphites 4 with (2R,5R,6R)-5,6-dime-
thoxy-5,6-dimethyl-1,4-dioxane-2-carboxaldehyde (2R,5R,6R)-3
(general procedure)
A mixture of the aldehyde (2R,5R,6R)-3 (1.10 mmol), dialkyl
phosphite (1.00 mmol) and triethylamine (0.10 mmol) was stirred
at room temperature for 24 h. After removal of all the volatiles in
vacuum (0.1 mm Hg) the oily residue was analysed by 1H and 31P
NMR spectroscopy and subjected to chromatographic purification.
4.1.1. Dimethyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimeth-
oxy-5,6-dimethyl-1,4-dioxan-2-yl]methylphosphonates, (2R,5R,
6R,10R)-6a and (2R,5R,6R,10S)-6b
3. Conclusions
After chromatography of the crude product [obtained from the
aldehyde (2R,5R,6R)-3 (0.350 g, 1.71 mmol) and dimethyl phos-
phite (0.150 mL, 1.62 mmol)] on a silica gel column with chloro-
form–methanol (gradient: 100:1–50:1, v/v), phosphonate 6a
(0.036 g, 7%) and phosphonate 6b (0.332 g, 65%) were isolated.
Ley0s aldehyde, (2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-
dioxane-2-carbaldehyde 3, was found to be more effective than
2,3-O-cyclohexylidene-D-glyceraldehyde 2 in the syntheses of the
respective 1-hydroxyphosphonates greatly facilitating the separa-
tion of diastereoisomers. No significant differences in the moderate
(ca. 1:2) diastereoselectivities of the triethylamine-catalysed addi-
tions of phosphites as well as of lithium diethyl phosphonate were
observed for both aldehydes. However, from the aldehyde 3 and
4.1.1.1. Dimethyl phosphonate (2R,5R,6R,10R)-6a. Colourless oil.
½
a 2D0
ꢁ
¼ ꢀ134:6 (c 0.95, CHCl3). IR (film):
m = 3500, 3223, 2933,
1458, 1374, 1214, 1124, 1034 cmꢀ1 1H NMR (300 MHz, CDCl3):
.

D. G. Piotrowska et al. / Tetrahedron: Asymmetry 21 (2010) 2218–2222
2221
d = 4.30 (dddd, J2–3ax = 11.5, J2–P = 4.7, J2–1 = 3.4, J2–3eq = 3.4 Hz, 1H,
HCCP), 3.91 (t, J3ax–3eq = J3ax–2 = 11.5 Hz, 1H, HaxCCCP), 3.85 (d,
J = 10.5 Hz, 3H, CH3OP), 3.84 (dd, J1–P = 11.6, J1–2 = 3.4 Hz, 1H,
HCP), 3.80 (d, J = 10.7 Hz, 3H, POCH3), 3.50 (dd, J3eq–3ax = 11.5,
J3eq–2 = 3.4 Hz, 1H, HeqCCCP), 3.36 (s, 3H, OCH3), 3.27 (s, 3H,
OCH3), 2.50 (br s, 1H, OH), 1.32 (s, 3H, CH3), 1.29 (s, 3H, CH3). 13C
NMR (75.5 MHz, CDCl3)—spectral data were extracted from the
spectrum of a 87:13 mixture of 6a and 6b: d = 99.66 (OCO), 97.98
(OCO), 67.88 (d, J = 161.8 Hz, CP), 66.79 (d, J = 4.5 Hz, CCP), 59.87
(d, J = 12.9 Hz, CCCP), 53.75 (d, J = 6.3 Hz), 52.97 (d, J = 6.3 Hz),
48.60 and 48.29 (2s, 2 ꢂ OCH3), 17.90 and 17.80 (2s, 2 ꢂ CH3).
31P NMR (121.5 MHz, CDCl3): d = 24.65 ppm. Anal. Calcd for
Mp 70–71 °C, ½a 2D0
ꢁ
¼ ꢀ142:7 (c 1.1 CHCl3). IR (KBr):
m
= 3437,
3254, 2993, 2926, 2836, 1448, 1376, 1212, 1124, 1034,
878 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 4.23 (dddd, J2–3ax
. =
11.4, J2–P = 7.8, J2–1 = 6.0, J2–3eq = 3.3 Hz, 1H, HCCP), 4.23–4.11
(m, 4H, 2 ꢂ CH2OP), 3.97 (dd, J1–P = 7.5, J1–2 = 6.0 Hz, 1H, HCP),
3.86 (t, J3ax–3eq = J3ax–2 = 11.4 Hz, 1H, HaxCCCP), 3.73 (dd,
J3ax–3eq = 11.4, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.30 (s, 3H, OCH3),
3.26 (s, 3H, OCH3), 2.0 (br s, 1H, OH), 1.33 (t, J = 7.2 Hz, 6H,
2 ꢂ CH3CH2OP), 1.28 (s, 6H, 2 ꢂ CH3). 13C NMR (75.5 MHz, CDCl3):
d = 99.56 (OCO), 98.07 (OCO), 68.78 (d, J = 162.0 Hz, CP), 67.09 (d,
J = 5.3 Hz, CCP), 63.16 (d, J = 6.8 Hz, CH2OP), 62.88 (d, J = 6.9 Hz,
CH2OP), 60.47 (d, J = 7.9 Hz, CCCP), 48.42 and 48.24 (2s, 2 ꢂ OCH3),
17.96 and 17.87 (2s, 2 ꢂ CH3), 16.79 (d, J = 5.9 Hz, CH3CH2OP),
16.76 (d, J = 6.2 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 22.63 ppm. Anal. Calcd for C13H27O8P: C, 45.61; H, 7.95. Found:
C, 45.83; H, 8.18.
C11H23O8P: C, 42.04; H, 7.38. Found: C, 42.10; H, 7.35.
4.1.1.2. Dimethyl phosphonate (2R,5R,6R,10S)-6b. The fractions
obtained after chromatography (0.332 g) were recrystallised from
ethyl acetate–hexanes to give colourless plates (0.301 g, 59%). Mp
135–137 °C, ½a 2D0
ꢁ
¼ ꢀ157:4 (c 1.37, CHCl3). IR (KBr):
m
= 3500,
4.1.3. Dibenzyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-
5,6-dimethyl-1,4-dioxan-2-yl]methylphosphonates,
3223, 2933, 1458, 1374, 1214, 1124, 1034 cmꢀ1.1H NMR
(300 MHz, CDCl3): d = 4.24 (dddd, J2–3ax = 11.4, J2–P = 7.5, J2–1 = 5.7,
J2–3eq = 3.3 Hz, 1H, HCCP), 4.04 (dd, J1–P = 8.4, J1–2 = 5.7 Hz, 1H,
HCP), 3.91 (t, J3ax–3eq = J3ax–2 = 11.4 Hz, 1H, HaxCCCP), 3.84 (d,
J = 10.8 Hz, 3H, CH3OP), 3.83 (d, J = 10.8 Hz, 3H, POCH3), 3.72 (dd,
J3eq–3ax = 11.4, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.32 (s, 3H, OCH3),
3.28 (s, 3H, OCH3), 1.65 (br s, 1H, OH), 1.31 (s, 3H, CH3), 1.30 (s,
3H, CH3). 13C NMR (75.5 MHz, CDCl3): d = 99.51 (OCO), 98.12
(OCO), 68.56 (d, J = 161.5 Hz, CP), 67.03 (d, J = 4.5 Hz, CCP), 60.71
(d, J = 9.8 Hz, CCCP), 53.69 (d, J = 6.9 Hz), 53.41 (d, J = 6.9 Hz),
48.38 and 48.20 (2s, 2 ꢂ OCH3), 17.91 and 17.84 (2s, 2 ꢂ CH3).
31P NMR (121.5 MHz, CDCl3): d = 25.03 ppm. Anal. Calcd for
(2R,5R,6R,10R)-8a and (2R,5R,6R,10S)-8b
After chromatography of the crude product [obtained from the
aldehyde (2R,5R,6R)-3 (0.386 g, 1.89 mmol) and dibenzyl phosphite
(0.418 mL, 1.89 mmol)] on a silica gel column with ethyl acetate–
hexane (2:1, v/v) phosphonate 8b (0.423 g, 60%) was obtained. The
remaining fractions were again chromatographed on a silica gel col-
umn with methylene chloride–methanol (100:1, v/v) to give a 9:1
mixture of phosphonates 8a and 8b (0.169 g, 24%).
4.1.3.1. Dibenzyl phosphonate (2R,5R,6R,10R)-8a. Colourless oil.
(All spectroscopic data of phosphonate 8a were extracted from spec-
tra of a 9:1 mixture of phosphonates 8a and 8b). 1H NMR (300 MHz,
CDCl3): d = 7.30–7.25 (m, 10H), 5.12 (d, J = 7.8 Hz, 2H, CH2Ph), 5.08
(dAB, JAB = 11.7, J = 8.7 Hz, 1H, HaCHbPh), 5.02 (dAB, JAB = 11.7,
J = 7.8 Hz, 1H, HaCHbPh), 4.34 (dddd, J2–3ax = 11.4, J2–P = 5.1,
C11H23O8P: C, 42.04; H, 7.38. Found: C, 42.00; H, 7.23.
4.1.2. Diethyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dimethoxy-
5,6-dimethyl-1,4-dioxan-2-yl]methylphosphonates, (2R,5R,6R,
10R)-7a and (2R,5R,6R,10S)-7b
J2–3eq = 3.3, J2–1 = 3.0 Hz, 1H, HCCP), 3.91 (t, J3ax–3eq = J3ax–2
=
After chromatography of the crude product [obtained from the
aldehyde (2R,5R,6R)-3 (0.268 g, 1.31 mmol) and diethyl phosphite
(0.152 mL, 1.18 mmol)] on a silica gel column with chloroform–
methanol (gradient: 100:1–20:1, v/v), phosphonate 7a (0.055 g,
14%) was obtained. The remaining fractions were chromato-
graphed again on a silica gel column with ethyl acetate–hexane
(2:1, v/v) to give phosphonate 7b (0.280 g, 69%).
11.4 Hz, 1H, HaxCCCP), 3.81 (dd, J1–P = 11.4, J1–2 = 3.0 Hz, 1H, HCP),
3.46 (dd, J3ax–3eq = 11.4, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.29 (s, 3H,
OCH3), 3.25 (s, 3H, OCH3), 2.60 (br s, 1H, OH), 1.28 (s, 3H, CH3),
1.27 (s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3): d = 136.22 (d,
J = 6.0 Hz, POCH2Cipso), 136.06 (d, J = 6.1 Hz, POCH2Cipso), 128.67,
128.64, 128.56, 128.54, 128.14, 128.07, 99.64 (OCO), 97.95 (OCO),
68.43 (d, J = 6.7 Hz, POCH2), 68.34 (d, J = 162.8 Hz, CP), 68.01 (d,
J = 6.7 Hz, POCH2), 66.63 (d, J = 2.0 Hz, CCP), 59.93 (d, J = 14.3 Hz,
CCCP), 48.61 and 48.29 (2s, 2 ꢂ OCH3), 17.88 and 17.81 (2s,
2 ꢂ CH3). 31P NMR (121.5 MHz, CDCl3): d = 22.95 ppm. Anal. Calcd
for C23H31O8P: C, 59.22; H, 6.70. Found: C, 59.00; H, 6.78.
4.1.2.1. Diethyl phosphonate (2R,5R,6R,10R)-7a. The fractions ob-
tained after chromatography (0.055 g) were recrystallised from
diethyl ether to give colourless plates (0.029 g, 7%). Mp 130–
131 °C, ½a 2D0
ꢁ
¼ ꢀ143:4 (c 0.90, CHCl3). IR (KBr):
m
= 3393, 3273,
2934, 2840, 1234, 1203, 1132, 1025, 968, 879 cmꢀ1
.
1H NMR
4.1.3.2. Dibenzyl phosphonate (2R,5R,6R,10S)-8b. Colourless oil.
(300 MHz, CDCl3): d = 4.30 (dddd, J2–3ax = 11.4, J2–P = 4.8, J2–1 = 3.9,
J2–3eq = 3.3 Hz, 1H, HCCP), 4.26–4.12 (m, 4H, 2 ꢂ CH2OP), 3.93 (t,
J3ax–3eq = J3ax–2 = 11.4 Hz, 1H, HaxCCCP), 3.77 (dd, J1–P = 11.4,
J1–2 = 3.9 Hz, 1H, HCP), 3.51 (dd, J3ax–3eq = 11.4, J3eq–2 = 3.3 Hz, 1H,
HeqCCCP), 3.36 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.0 (br s, 1H,
OH), 1.35 (t, J = 7.2 Hz, 6H, 2 ꢂ CH3CH2OP), 1.31 (s, 3H, CH3), 1.29
(s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3): d = 99.63 (OCO), 97.97
(OCO), 68.15 (d, J = 161.4 Hz, CP), 66.79 (s, CCP), 63.09 (d,
J = 5.6 Hz), 62.61 (d, J = 6.3 Hz), 60.09 (d, J = 12.6 Hz, CCCP), 48.65
and 48.35 (2s, 2 ꢂ OCH3), 17.94 and 17.84 (2s, 2 ꢂ CH3), 16.89 (d,
J = 4.5 Hz, CH3CH2OP), 16.76 (d, J = 5.1 Hz, CH3CH2OP). 31P NMR
(121.5 MHz, CDCl3): d = 22.06 ppm. Anal. Calcd for C13H27O8P: C,
45.61; H, 7.95. Found: C, 45.90; H, 8.24.
½
a 2D0
ꢁ
¼ ꢀ84:5 (c 1.40, CHCl3). IR (film):
m = 3270, 2950, 2834, 1456,
1374, 1214, 1144, 1037, 995, 878 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d = 7.45–7.25 (m, 10H), 5.10 (dAB, JAB = 12.0, J = 8.7 Hz, 1H,
HaCHbPh), 5.09 (d, J = 7.8 Hz, 2H, CH2Ph), 5.05 (dAB, JAB = 12.0,
J = 8.7 Hz, 1H, HaCHbPh), 4.27 (dddd, J2–3ax = 11.7, J2–P = 7.8,
J2–1 = 5.7, J2–3eq = 3.3 Hz, 1H, HCCP), 4.05 (dd, J1–P = 7.8, J1–2
=
5.7 Hz, 1H, HCP), 3.88 (t, J3ax–3eq = J3ax–2 = 11.7 Hz, 1H, HaxCCCP),
3.73 (dd, J3ax–3eq = 11.7, J3eq–2 = 3.3 Hz, 1H, HeqCCCP), 3.26 (s, 3H,
OCH3), 3.21 (s, 3H, OCH3), 2.5 (br s, 1H, OH), 1.27 (s, 3H, CH3), 1.25
(s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3): d = 136.19 (d, J = 6.3 Hz,
POCH2Cipso), 136.15 (d, J = 6.3 Hz, POCH2Cipso), 129.56, 128.54,
128.43, 128.39, 128.10, 127.98, 99.47 (OCO), 98.10 (OCO), 69. 03
(d, J = 161.6 Hz, CP), 68.46 (d, J = 6.8 Hz, POCH2), 68.26 (d,
J = 7.5 Hz, POCH2), 67.02 (d, J = 3.9 Hz, CCP), 60.34 (d, J = 10.2 Hz,
CCCP), 48.36 and 48.20 (2s, 2 ꢂ OCH3), 17.88 and 17.84 (2s,
2 ꢂ CH3). 31P NMR (121.5 MHz, CDCl3): d = 23.65 ppm. Anal. Calcd
for C23H31O8P: C, 59.22; H, 6.70. Found: C, 58.98; H, 6.78.
4.1.2.2. Diethyl phosphonate (2R,5R,6R,10S)-7b. The fractions ob-
tained after chromatography (0.280 g) were recrystallised from
diethyl ether–hexanes to give colourless plates (0.234 g, 58%).

2222
D. G. Piotrowska et al. / Tetrahedron: Asymmetry 21 (2010) 2218–2222
4.1.4. Diisopropyl (R)- and (S)-hydroxy-[(2R,5R,6R)-5,6-dime-
thoxy-5,6-dimethyl-1,4-dioxan-2-yl]methylphosphonates,
(2R,5R,6R,10R)-9a and (2R,5R,6R,10S)-9b
After chromatography of the crude product [obtained from the
aldehyde (2R,5R,6R)-3 (0.285 g, 1.40 mmol) and diisopropyl phos-
phite (0.209 mL, 1.26 mmol)] on a silica gel column with ethyl ace-
tate–hexane (2:1, v/v), phosphonate 9b (0.256 g, 55%) was
obtained as a colourless oil.
concentrated and treated with tetrabutylammonium fluoride
(1 M, 2.0 mL, 2.0 mmol) for 1 h. After removal of all volatiles the
residue was filtered through a pad of silica gel as a chloroform
solution. The crude product was subjected to silica gel chromatog-
raphy with ethyl acetate–hexane (2:1, v/v) to give phosphonate 7b
(0.350 g, 68%), which was identical to the material described
earlier.
4.4. Benzylation and hydrolysis of a mixture of diethyl
4.1.4.1. Diisopropyl phosphonate (2R,5R,6R,10S)-9b. ½a D20
ꢁ
¼
phosphonates (2R,5R,6R,10R)-7a and (2R,5R,6R,10S)-7b
ꢀ113:2 (c 1.0, CHCl3). IR (film):
m = 3266, 2981, 2948, 1384, 1227,
1144, 1123, 1039, 999, 879 cmꢀ1
.
1H NMR (300 MHz, CDCl3):
To a solution of a 20:80 mixture of diethyl phosphonates
(2R,5R,6R,10R)-7a and (2R,5R,6R,10S)-7b (0.050 g, 0.15 mmol) in
CH2Cl2 (4 mL) powdered molecular sieves (0.2 g) were added fol-
lowed by Ag2O (0.054 g, 0.23 mmol) and benzyl bromide
(0.036 mL, 0.29 mmol). The suspension was stirred at room tem-
perature for 24 h. After standard work-up16 a 20:80 mixture of
crude 1-O-benzyl derivatives was obtained (0.052 g, 83%). This
mixture was treated at room temperature with 70% CF3COOH
(2.5 mL) for 2 h, concentrated in vacuo and co-evaporated with
dioxane (5 ꢂ 3 mL). The residue was chromatographed on a silica
gel column with chloroform–methanol (50:1, v/v) to give a 20:80
mixture of phosphonates (2R,5R,6R,10R)-10a and (2R,5R,6R,10S)-
10b (0.034 g, 92%), which was identical in all respects to the com-
pounds described earlier.16
d = 4.90–4.65 (m, 2H, 2 ꢂ POCH), 4.21 (dddd, J2–3ax = 11.4,
J2–P = 6.3, J1–2 = 5.4, J2–3eq = 3.3 Hz, 1H, HCCP), 3.93 (dd, J1–P = 7.8,
J1–2 = 5.4 Hz, 1H, HCP), 3.88 (t, J3ax–3eq = J3ax–2 = 11.4 Hz, 1H,
HaxCCCP), 3.75 (dd, J3ax–3eq = 11.4, J3eq–2 = 3.3 Hz, 1H, HeqCCCP),
3.31 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.80 (br s, 1H, OH), 1.35
(d, J = 6.3 Hz, 3H, CH3CHOP), 1.34 (d, J = 6.0 Hz, 9H, CH3CHOP),
1.29 (s, 6H, 2 ꢂ CH3). 13C NMR (75.5 MHz, CDCl3): d = 99.55
(OCO), 97.95 (OCO), 71.85 (d, J = 7.0 Hz, POCH), 71.49 (d,
J = 7.3 Hz, POCH), 69.06 (d, J = 164.3 Hz, CP), 67.31 (d, J = 5.5 Hz,
CCP), 60.37 (d, J = 7.7 Hz, CCCP), 48.42 and 48.22 (2s, 2 ꢂ OCH3),
24.47 (d, J = 5.4 Hz), 24.42 (d, J = 5.7 Hz), 24.27 (d, J = 5.0 Hz),
24.24 (d, J = 5.4 Hz), 17.97 and 17.87 (2s, 2 ꢂ CH3). 31P NMR
(121.5 MHz, CDCl3): d = 21.08 ppm. Anal. Calcd for C15H31O8P: C,
48.64; H, 8.44. Found: C, 48.39; H, 8.72.
Acknowledgements
4.2. Reaction of the lithium salt of diethyl phosphite with
(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-
carboxaldehyde (2R,5R,6R)-3
The authors wish to express their gratitude to Mrs. Jolanta
Płocka and Mrs. Edyta Grzelewska for the excellent technical assis-
tance. A part of this project was conducted by Miss Magdalena
Włodarczyk. The financial support from the Medical University of
To a solution of lithium diethyl phosphonate [from diethyl
phosphite (0.258 mL, 2.00 mmol), diisopropylamine (0.28 mL,
2.0 mmol) and 1.6 M butyl lithium (1.25 mL, 2.0 mmol)] in THF
(5 mL) cooled to ꢀ70 °C, was added the aldehyde (2R,5R,6R)-3
(0.448 g, 2.20 mmol) in THF (2 mL). The reaction mixture was stir-
red at this temperature for 3 h and allowed to reach ꢀ10 °C. A sat-
urated aqueous ammonium chloride solution (3 mL) was added
followed by methylene chloride (20 mL). The layers were separated
and the aqueous phase was extracted with methylene chloride
(3 ꢂ 10 mL). The combined organic extracts were dried over
MgSO4, concentrated and subjected to column chromatography
on silica gel with chloroform–methanol (100:1, v/v) to give
phosphonate 7a, (0.180 g, 29%) which was recrystallised from
ether–hexane to provide crystalline 7a, (0.115 g, 18%) which was
in all respects identical to material described above. The remaining
fractions were combined and chromatographed on a silica gel
column with ethyl acetate–hexane (2:1, v/v) to give phosphonate
7b (0.350 g, 56%) which was recrystallised from diethyl ether–hex-
anes to give colourless plates (0.280 g, 45%), and was in all respects
identical with the material described earlier.
´
Łódz (503-3014-1) is gratefully acknowledged.
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4.3. Reaction of diethyl trimethylsilyl phosphite with
(2R,5R,6R)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-
carboxaldehyde (2R,5R,6R)-3
To a solution of the aldehyde (2R,5R,6R)-3 (0.355 g, 1.65 mmol)
in methylene chloride (2 mL), diethyl trimethylsilyl phosphite
(0.34 mL, 1.5 mmol) was added dropwise at room temperature.
The reaction mixture was left at this temperature overnight, then
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