Preparation of spiro[4.4]oxaphospholene and -azaphospholene systems from carbohydrate templates

Article abstract of DOI:10.1021/jo400954p

Introduction of a spiro-phosphorus cycle in position 3 of monosaccharidic derivatives was studied starting from cyanohydrin or aminonitrile A. A two-step procedure involving (i) phosphonylation and (ii) carbanion-mediated phosphonate intramolecular cyclization (denoted CPIC) was used. The necessity of having an electron-withdrawing group α to the phosphorus atom in order to avoid undesired reactions was demonstrated.

Full text of DOI:10.1021/jo400954p

Article
pubs.acs.org/joc
Preparation of Spiro[4.4]oxaphospholene and -azaphospholene
Systems from Carbohydrate Templates
Marina Moura, Solen Josse, and Denis Postel*
Laboratoire des Glucides, CNRS-FRE 3517, 10 rue Baudelocque, 80039 Amiens, France
Institut de Chimie de Picardie (FRE 3085), UFR des Sciences-UPJV, 33, rue Saint Leu, 80039 Amiens Cedex 1, France
S
* Supporting Information
ABSTRACT: Introduction of a spiro-phosphorus cycle in
position 3 of monosaccharidic derivatives was studied starting
from cyanohydrin or aminonitrile A. A two-step procedure
involving (i) phosphonylation and (ii) carbanion-mediated
phosphonate intramolecular cyclization (denoted CPIC) was
used. The necessity of having an electron-withdrawing group α
to the phosphorus atom in order to avoid undesired reactions
was demonstrated.
the binding pockets. As replacement of the sulfur atom by a
phosphorus atom has never been undertaken on TSAO-T
derivatives, we were interested in the synthesis of new families
of these nucleosidic inhibitors with an O−P or N−P bond in
the spiro ring at position 3″. Compounds such as P-(A)TSAO-
T would also be unusual analogues of nucleoside cyclic
phosphates.
1. INTRODUCTION
[2′,5′-Bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3′-
spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide)thymine
(TSAO-T)1,2 is a nucleoside analogue bearing a spiro
heterocycle in position 3′ (Figure 1). It is known to have
human immunodeficiency virus type-1 (HIV-1) reverse tran-
scriptase (RT) inhibitory activity and to act through a
noncompetitive mechanism.3−5
A few years ago we synthesized new TSAO-T analogues
where the oxygen of the oxathiol ring was replaced by a
nitrogen (Figure 1, ATSAO-T).6 We recently reported the
synthesis of a new N-3-acylated TSAO where modifications
were performed on the nucleoside base.7 This new family of
TSAO compounds has shown significant activities against RT-
HIV-1 and HCV. We thus focused our research on the
synthesis of new derivatives by modifying the nature of the
spiro ring in position 3′. Different modifications have been
described on the oxathiol spiro ring of TSAO-T: in position
3″8−10 or on the amine in position 4″.11,12 Starting from A-
TSAO-T derivatives, our group reported the synthesis of
compounds functionalized at position 5″.13
Despite the wide number of modifications described, either
on the nucleobase or on the spiro ring, it was not possible to
establish a clear structure−activity relationship which could
explain the binding of TSAO to RT. Only recently, the crystal
structure of TSAO-T with HIV-1-RT has been published by
Das and co-workers.14 It has been demonstrated that the spiro
ring was buried inside the non-nucleosidic RT inhibitor binding
pocket and that hydrogen bonds were formed between water
and the substituents NH2 and SO2.
Phosphorus-containing molecules are popular targets for the
development of new biologically active compounds. In addition,
the difference in electronegativity of the phosphorus atom
involved in the PO bond relative to the sulfur atom induces a
difference of polarization of this bond and modifies the hard
and soft nature of the atoms involved in the interactions with
Regarding the preparation of 1,2-oxaphosphol-3-ene hetero-
cycles, many examples can be found in the literature. They can
be obtained starting from allenylphosphonates using a CuCl2-
mediated chlorocyclization reaction,15 by a Heck cyclization
reaction,16 or a reaction with PhSeCl.17 1,2-Oxaphosphol-3-ene
heterocycles have also been obtained using RCM reactions.18,19
The synthesis of trifluoromethylated oxaphospholenes by
iodocyclization under mild conditions has been described.20
The 2,5-dihydro-1,2-oxaphosphole derivatives were described
from reactions with phenylsulfenyl bromides and phenyl-
selenenyl bromides.21 A handy one-step synthesis of
oxaphospholenes was developed by a simple treatment of
acylallyl phosphonates with m-CPBA in the presence of 1 equiv
of MgSO4.22 2′-Azidoallylphosphonates were used to access 4-
amino-1,2-oxaphosphol-3-ene by reaction with tetramethylgua-
nidine azide.23 Very recently a one-pot, three-component
approach was used for the synthesis of novel heterocyclic α-
aminophosphonates starting from either 2-hydroxyacetophe-
nones or 2-hydroxybenzaldehydes.24
However, there are only a few examples in the literature of
the synthesis of 1,2-azaphosphol-3-ene heterocycles. Vinyl-
phosphonamidic anhydrides were derivatized via RCM
reactions, leading to the formation of bicyclic phosphonamidic
anhydrides.25,26 After reaction of vinylphosphonochloridate
with N-allyl-N-benzylamine, unsymmetrical allyl vinylphospho-
nates were obtained and subjected to RCM reactions to give
Received: October 22, 2012
Published: August 19, 2013
© 2013 American Chemical Society
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Figure 1. Nucleoside analogues TSAO-T and ATSAO-T and phosphorus derivatives.
access to 1,2-azaphosphol-3-enes.19 Recently the reaction of 2-
Scheme 2. Synthesis of Cyanohydrins and Aminonitrile ribo
(diethoxyphosphorylmethyl)furyl-3-isocyanate with methanol
was described for the preparation of cyclic phosphamide
derivatives.27
Derivatives
Among all the examples found in the literature, the employed
strategies seemed not very applicable to saccharidic substrates
for the introduction of a phosphonate or phoshonamidate
heterocycle in position 3. For this reason, we decided to
investigate a phosphonate version of the CSIC reaction
(carbanion-mediated sulfonate intramolecular cyclization re-
action).28,29
With regard to the synthesis of the nucleoside analogues,
retrosynthetic analysis of the precursor glycon moiety A
suggests that the preparation of an oxa or (aza)phospholene
ring in position 3′ could be obtained from derivative B after a
carbanion-mediated phosphonate intramolecular cyclization
reaction (CPIC) (Scheme 1). This phosphorus derivative B
could result from phosphonylation of the ribo-aminonitrile or
ribo-cyanohydrin C obtained from the well-known ketose D.
The phosphonylation step was performed by the reaction of
cyanohydrins or aminonitriles with methyl methylphosphono-
chloridate, which was prepared from dimethyl methylphosph-
onate and phosphorus chloride.31 The reaction of ribo-
cyanohydrins 3 and 4 and ribo-aminonitrile 5 using the
conditions described by Raushel et al.32 were performed (Et3N
(4.2 equiv) and methyl methylphosphonochloridate (2 equiv)
at refux in dichloromethane).
In the case of the ribo-cyanohydrin 4, a mixture of both
kinetic and thermodynamic products was obtained in 45% yield
(Scheme 3).
Scheme 1. Retrosynthetic Analysis of 4-Amino-1,2-
oxa(aza)phosphol-3-ene
When starting from the ribo-aminonitrile 5, only kinetic
products were observed in 30% yield. Because of the chirality of
the phosphorus atom, NMR analyses (1H, 13C, and 31P) exhibit
a doubling of signals that is typical for a pair of diastereomers.
In most cases, it was not possible to separate each
diastereomer; thus it was not possible to identify each
diastereomer. Nevertheless, a determination of the ratio was
1
performed by H NMR, by integration of the H-1 signals.
After modification of the conditions, the use of DMAP (2
equiv) in the presence of 2.4 equiv of methyl methylphospho-
nochloridate in pyridine allowed the exclusive formation of the
kinetic products in 56−90% yields as a mixture of two
diastereomers which could not be separated by chromatog-
raphy (Scheme 4).
In order to access the heterocycle in position 3, cyclization
was considered by a CPIC reaction. Unfortunately, under basic
conditions compound 9 was not obtained (Table 1).
Developing a successful strategy for the synthesis of A should
allow us to prepare the corresponding nucleoside analogues [P-
(A)TSAO-T].
Herein we report our studies affording the targeted 4-amino-
1,2-oxa(aza)phosphol-3-ene (A) starting from D-xylose.
In the presence of t-BuOK, DBU, NaH, or HMDS, only
starting material was recovered despite several variations of
experimental parameters (temperature, number of equivalents,
solvent; entries a−f). In the presence of Cs2CO3 or BuLi, a
mixture of several derivatives was obtained (TLC analysis). The
major product was isolated and characterized as a mixture of
xylo- and ribo-cyanohydrin resulting from isomerization at C3
(entries h and i). The formation of these two isomers could be
explained by the mechanism outlined in Scheme 5. In the
presence of NaHMDS, only xylo-cyanohydrin was isolated.
Moreover the ulose derivative formed is unstable, and under
the strongly basic conditions, degradation is not surprising.
In the case of the methylphosphonamidate derivative 8, the
reaction with LDA (4 equiv) in THF at −78 °C (the base used
2. RESULTS AND DISCUSSION
2.1. Chemical Synthesis. Classical Strecker conditions
applied to the protected erythro-pentofuranose-3-ulose deriva-
tives 1 and 2 obtained from protected D-xylose using PDC
oxidation afforded the corresponding ribo-cyanohydrins 3 and 4
in 87 and 76% yields, respectively (Scheme 2).30 The 3-(R)-
ribo-aminonitrile 5 was obtained stereoselectively using NH3-
MeOH, Ti(OiPr)4, and TMSCN in 85% yield.6
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Scheme 3. Kinetic and Thermodynamic Products
Scheme 4. Synthesis of Phosphonate Derivatives
Scheme 5. Proposed Mechanism of Phosphonate
Degradation under Basic Conditions
Table 1. Tested Conditions for CPIC Reaction on
Phosphonate Derivatives
Entry
Conditions
Results
starting
Compound 10 was obtained in the form of two inseparable
diastereomers in a 55/45 ratio.
a
t-BuOK (2 equiv), CH3CN, room temp
material
starting
material
starting
material
starting
material
starting
material
starting
material
b
c
d
e
f
t-BuOK (2 equiv), CH3CN, reflux
DBU (2 equiv), CH3CN, room temp
DBU (2 equiv), CH3CN, reflux
Scheme 6. Synthesis of Azaphospholene Derivative
NaH (1.2 equiv), THF, −78 °C to room temp
NaH (1.2 equiv), DMSO, room temp
Cs2CO3 (1 equiv), CH3CN, 0 °C
Cs2CO3 (1 equiv), CH3CN, room temp
BuLi (1.5 equiv), THF, −35 °C
g
h
i
starting
material
This difference in reactivity between the oxa and aza
analogues was not observed in the case of TSAO and A-
TSAO, as in both cases the CSIC was performed in good yield
using Cs2CO3 for TSAO and LDA for A-TSAO.6,30
It was considered that this difference in reactivity might be
due to the presence of the hydrogen atom on the nitrogen
atom. To this end, alkylation of nitrogen with a methyl group
has been performed to give compound 11 in 63% yield. This
alkylated derivative gives the azaphospholene ring after
cyclization with LDA in 72% yield, demonstrating that the
N−H is not necessary for cyclization (Scheme 7).
Presumably the reason for the different behaviors of 6 and 8
is that β-fragmentation in 6 gives rise to a carbonyl group (high
bond energy, ΔH = 719 kJ mol−1), whereas β-fragmentation in
8 gives an imine (lower bond energy, ΔH = 615 kJ mol−1). This
difference in behavior was not observed in the case of TSAO
and A-TSAO, as sulfur with two doubly bonded oxygens is
more stabilizing than a phosphoryl group with one oxygen and
xylo- and ribo-
cyanohydrin
xylo- and ribo-
cyanohydrin
j
LDA (4 equiv), THF, −78 °C
LDA (4 equiv), DMSO, room temp
degradation
degradation
degradation
k
l
LDA (4 equiv), THF-HMPA (2 equiv), −78 °C
LDA (4 equiv), THF/HMPA (4/1), −78 °C
m
xylo-
cyanohydrin
n
o
p
LDA (1.2 equiv), THF/HMPA (4/1), −78 °C
HMDS (1 equiv, 2 equiv, 4 equiv), THF, 0 °C
NaHMDS (1 equiv), THF, 0 °C
starting
material
starting
material
xylo-
cyanohydrin
for the carbonate-mediated sulfonate intramolecular cyclization
(CSIC) reaction)6 led to the desired cyclized derivative 4-
amino-1,2-(aza)phosphol-3-ene in 60% yield (Scheme 6).
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Using NaH, it was possible to carry out the synthesis of the
oxaphospholene compounds in a one-pot procedure. This
protocol gave us good results, oxaphospholenes being obtained
with yields ranging from 41% to 70% as mixtures of separable
(26a,b and 27a,b) or inseparable diastereomers (28) or as a
pure compound (29) (Table 3). For this last case, hydrolysis of
the CN group was observed during the reaction and amide 29
was the only product obtained.
Scheme 7. Synthesis of N-Methylazaphospholene Derivative
When using the phosphonochloridate bearing a phenyl group
α to the phosphorus (19) it was not possible to have a one-pot
reaction, as the cyclization step with NaH did not occur. The
cyclized compound 30 was obtained only with LDA (78%
yield) as a mixture of two diastereomers (Scheme 10).
Scheme 10. CPIC Reaction with LDA
therefore promotes the nucleophilic attack on the nitrile rather
than the β-fragmentation.
With these results in hand, we envisaged that introduction of
an electron-withdrawing group α to the phosphorus atom
should facilitate cyclization.
A series of phosphonyl chloride derivatives with electron-
withdrawing groups (COOEt, CN, Ph, and COOMe) was
prepared by reaction of POCl3 with the corresponding
phosphonate according to the procedure described by
Rewcastle et al. (Scheme 8).33 The phosphonochloridates
were obtained as liquids and used without any purification.
2.2. Stereochemical Hypothesis. Examination of the 13C
NMR signals of diastereomer 26a shows two different chemical
shifts for the two isopropylidene CH3 groups (26.6 and 26.2
ppm), whereas for diastereomer 26b there is only one chemical
shift at 26.3 ppm for the two CH3 (Figure 2).
Scheme 8. Synthesis of Phosphonochloridate Derivatives
Reaction of these phosphonochloridates with cyanohydrins
was thus performed using NaH in DCM at 0 °C (Table 2). The
corresponding phosphonate diesters were obtained with high
conversion (NMR of the crude mixture) and were isolated in
moderate yields. Apparently, some compounds were lost on
silica during the purification procedure. Nevertheless, they were
all isolated and characterized as mixture of P* diastereomers
(all in the ribo configuration) with yields ranging from 22% to
65%.
Figure 2. 13C NMR of isopropylidene methyl groups of 26a,b.
In 26a,b, the two isopropylidene methyl groups are
diastereotopic.
In a modeling study (semiempirical PM3) we can observe
that in 26b (where the P has the S configuration), one of the
two methyls of the isopropylidene is located much closer to the
polar PO group than the other (Figure 3). This is consistent
with the quite different NMR chemical shifts. With 26a (where
the P has the R configuration), both CH3 groups are well away
from the PO group. Thus, we can assume that 26a
corresponds to the R diastereomer and 26b to the S
diastereomer.
Upon treatment of derivative 21 under basic conditions
(LDA or NaH) the desired oxaphospholene derivatives were
obtained in 56% or 70% yield, respectively (Scheme 9).
Scheme 9. CPIC Reaction
A similar analysis carried out for compound 27 enabled a
proposition of identification of the two isolated diastereomers
as 27a,b (Figure 4).
3. CONCLUSION
In conclusion, the synthesis of seven new saccharidic oxa- and
azaphospholene derivatives (Figure 5) has been reported. The
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Table 2. Synthesis of Phosphonate Saccharidic Derivatives with Electron-Withdrawing Groups
s/scan in the profile mode at a resolution of 10000 (FWMH). Column
chromatography was effected on Silica Gel 60 (230 mesh).
strategy for the introduction of these phosphorus heterocyles in
position 3 of xylose will be used to synthesize P-TSAO
analogues. The synthesis of these nucleosidic derivatives will be
reported in due course.
4.2. General Procedure for Phosphonylation with Methyl
Methylphosphonochloridate. To a solution of cyanohydrin 3 or
4
30 or aminonitrile 56 (1 equiv) and DMAP (2 equiv) in dry pyridine
at 0 °C was added methyl methylphosphonochloridate (2.4 equiv).
After 1 h at room temperature, water and Et2O were added; the
organic phase was separated, dried (Na2SO4), and concentrated. The
crude product was purified by flash chromatography.
4. EXPERIMENTAL SECTION
4.1. General Considerations: Materials and Methods. Melting
points are uncorrected. Optical rotations were recorded in CH2Cl2
1
solution. H NMR (300.13 MHz), 13C NMR (75.47 MHz), and 31P
5-O-Benzoyl-3-C-cyano-1,2-O-isopropylidene-3-O-methoxyme-
thylphosphonyl-α-D-ribofuranose (6). According to the general
procedure, compound 3 (103 mg, 0.32 mmol) and DMAP (79 mg,
0.64 mmol) in pyridine (2 mL) were treated with methyl
methylphosphonochloridate (76.3 μL, 0.77 mmol). The crude product
was purified by flash chromatography (EtOAc/cyclohexane, 5/5) to
give 6 as a white solid (118 mg, 90%) as a mixture of two
diastereomers (55/45). Rf = 0.22 (EtOAc/cyclohexane, 5/5). 1H
NMR (CDCl3; 300 MHz): δ 8.11 (m, 4H), 7.59 (m, 2H), 7.50−7.45
(m, 4H), 6.03 (d, J = 3.8 Hz, 1H), 6.01 (d, J = 3.7 Hz, 1H), 5.28 (d,
1H), 5.19 (d, 1H), 4.77−4.67 (m, 4H), 4.51−4.47 (m, 2H), 3.84 (d,
JH−P = 11.7 Hz, 3H), 3.81 (d, JH−P = 11.7 Hz, 3H), 1.63 (d, JH−P = 17.8
Hz, 3H), 1.54 (s, 6H), 1.55 (d, JH−P = 17.1 Hz, 3H), 1.28 (s, 3H), 1.25
(s, 3H). 13C NMR (CDCl3; 75 MHz): δ 165.9, 133.4, 129.8, 129.5,
128.4, 115.7, 114.9, 114.3, 104.1, 104.0, 81.9, 81.5, 77.4 (d, JC−P = 9.0
Hz), 77.0 (d, JC−P = 9.0 Hz), 76.7, 62.1, 62.0, 52.7 (d, JC−P = 7.5 Hz),
52.1 (d, JC−P = 7.5 Hz), 26.3, 26.2, 12.2 (d, JC−P = 145.8 Hz). 31P
NMR (CDCl3; 121 MHz): δ 36.2−35.8 (m), 34.2−33.7 (m). HRMS:
C18H22NO8NaP calcd 434.0981, found 434.1001.
NMR (121 MHz) (1H and 13C nondecoupled) spectra were recorded
in CDCl3. TLC measurements were performed on Silica F254 and
detection by UV light at 254 nm or by charring with cerium molybdate
reagent. High-resolution electrospray mass spectra in the positive ion
mode were obtained on a Q-TOF Ultima Global hybrid quadrupole/
time-of-flight instrument, equipped with a pneumatically assisted
electrospray (Z-spray) ion source and an additional sprayer (Lock
Spray) for the reference compound. The source and desolvation
temperatures were kept at 80 and 150 °C, respectively. Nitrogen was
used as the drying and nebulizing gas at flow rates of 350 and 50 L/h,
respectively. The capillary voltage was 3.5 kV, the cone voltage was
100 V, and the RF lens1 energy was optimized for each sample (40 V).
For collision-induced dissociation (CID) experiments, argon was used
as the collision gas at an indicated analyzer pressure of 5.10−5 Torr
and the collision energy was optimized for each parent ion (50−110
V). Lock mass correction, using appropriate cluster ions of sodium
iodide (NaI)nNa+, was applied for accurate mass measurements. The
mass range was typically 50−2050 Da, and spectra were recorded at 2
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Table 3. “One Pot−Two Step” Reactions
Figure 3. Modeling study of 26a,b.
6.53 mmol) in pyridine (20 mL) were treated with methyl
methylphosphonochloridate (800 μL, 8.16 mmol). The crude product
was purified by flash chromatography (EtOAc/cyclohexane, 5/5) to
give 7 as a white solid (710 mg, 55%) as a mixture of two
diastereomers (40/60). Rf = 0.35 (EtOAc/cyclohexane, 4/6). 1H
NMR (CDCl3; 300 MHz): δ 7.39−7.29 (m, 10H), 5.99 (d, J = 4.0 Hz,
1H), 5.97 (d, J = 3.8 Hz, 1H), 5.20 (d, 1H), 5.12 (d, 1H), 4.72 (d, J =
15.6 Hz, 1H), 4.70 (d, J = 15.7 Hz, 1H), 4.62 (d, 1H), 4.57 (d, 1H),
4.40−4.35 (m, 2H), 3.92−3.87 (m, 4H), 3.84 (d, JH−P = 11.6 Hz, 3H),
3.76 (d, JH−P = 11.6 Hz, 3H), 1.65 (d, JH−P = 21.0 Hz, 3H), 1.59 (s,
6H), 1.58 (d, JH−P = 18.0 Hz, 3H), 1.34 (s, 6H). 13C NMR (CDCl3;
75 MHz): δ 137.2, 137.1, 128.5, 127.9, 115.1, 114.1, 104.1, 81.8, 81.5,
78.8 (d, JC−P = 9.5 Hz), 78.4 (d, JC−P = 8.8 Hz), 73.9, 68.5, 68.4, 52.7
Figure 4. Identification of the two diastereomers 27a,b.
5-O-Benzyl-3-C-cyano-1,2-O-isopropylidene-3-O-methoxyme-
thylphosphonyl-α-D-ribofuranose (7). According to the general
procedure, compound 4 (996 mg, 3.2 mmol) and DMAP (798 mg,
(d, JC−P = 7.5 Hz), 52.0 (d, JC−P = 7.4 Hz), 27.0, 26.4, 12.2 (d, JC−P
=
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Figure 5. New saccharidic oxa- and azaphospholene derivatives.
146.3 Hz). 31P NMR (CDCl3; 121 MHz): δ 36.2−35.5 (m), 34.2−
33.5 (m). HRMS: C18H24NO7NaP calcd 420.1190, found 420.1188.
5-O-Benzyl-3-C-cyano-3-desoxy-1,2-O-isopropylidene-3-methox-
ymethylphosphoramidyl-α-D-ribofuranose (8). According to the
general procedure, compound 5 (4 g, 13.1 mmol) and DMAP (3.2
g, 26.2 mmol) in pyridine (20 mL) were treated with methyl
methylphosphonochloridate (3.1 mL, 31.6 mmol). The crude product
was purified by flash chromatography (EtOAc/cyclohexane, 5/5) to
give 8 as a white solid (4.5 g, 86%) as a mixture of two diastereomers
mixture of two diastereomers (50/50). Rf = 0.6 (CH2Cl2/MeOH, 9.5/
0.5); 1H NMR (CDCl3; 300 MHz): δ 7.42−7.24 (m, 10H), 5.95 (d, J
= 3.9 Hz, 1H), 5.93 (d, J = 3.9 Hz, 1H), 5.21 (dd, J = 2.4 Hz, J = 6.8
Hz, 1H), 5.13 (d, 1H,), 4.93−4.90 (m, 2H), 4.71−4.59 (m, 4H), 3.95
(dd, J = 10.9 Hz, 1H), 3.94−3.88 (m, 3H), 3.63 (d, JH−P = 11.5 Hz,
3H), 3.50 (d, JH−P = 11.6 Hz, 3H), 2.77 (d, JH−P = 8.3 Hz, 3H), 2.73
(d, JH−P = 8.7 Hz, 3H), 1.61 (s, 3H), 1.57 (s, 3H), 1.54 (d, JH−P = 20.2
Hz, 3H), 1.46 (d, JH−P = 16.8 Hz, 3H), 1.37 (s, 6H). 13C NMR
(CDCl3; 75 MHz): δ 138.0, 137.9, 128.4−127.6, 117.3, 116.6, 113.3,
112.9, 103.2, 102.9, 83.6, 82.2, 77.1, 76.7, 76.9, 76.5, 73.4, 73.3, 69.9,
1
(55/45). Rf = 0.5 (CH2Cl2/MeOH, 9.5/0.5). H NMR (CDCl3; 300
MHz): δ 7.37−7.32 (m, 10H), 5.94 (d, J = 3.7 Hz, 1H), 5.92 (d, J =
3.4 Hz, 1H), 5.15 (d, 1H), 5.03 (d, 1H), 4.60 (m, 4H), 4.15 (m, 2H),
3.90 (m, 4H), 3.70 (d, JH−P = 11.3 Hz, 3H), 3.62 (d, JH−P = 11.4 Hz,
3H), 1.55 (d, JH−P = 14.9 Hz, 3H), 1.54 (s, 6H), 1.52 (d, JH−P = 16.9
Hz, 3H), 1.37 (s, 6H). 13C NMR (CDCl3; 75 MHz): δ 137.2, 137.1,
128.5, 128.1, 127.9, 118.1, 117.3, 113.3, 104.4, 104.3, 83.0, 82.7, 78.9
(d, JC−P = 9.8 Hz), 78.6 (d, JC−P = 8.4 Hz), 74.1, 74.0, 69.2, 62.5, 61.8,
51.1 (d, JC−P = 6.8 Hz), 50.4 (d, JC−P = 6.8 Hz), 26.7, 26.3, 14.7 (d,
JC−P = 135.1 Hz), 14.4 (d, JC−P = 133.6 Hz). 31P NMR (CDCl3; 121
MHz): δ 34.5−34.1 (m), 32.9−32.5 (m). HRMS: C18H25N2O6PNa
calcd 419.1348, found 419.1349.
69.5, 50.3 (d, JC−P = 7.0 Hz), 50.0 (d, JC−P = 7.1 Hz), 33.3 (d, JC−P
=
33.2 Hz), 32.9 (d, JC−P = 28.7 Hz), 26.9, 26.8, 26.4, 26.2, 12.0 (d, JC−P
= 135.7 Hz), 11.8 (d, JC−P = 134.7 Hz). 31P NMR (CDCl3; 121 MHz):
δ 36.0−35.8 (m). HRMS: C19H27N2O6PNa calcd 433.1504, found
433.1497.
4.5. 1-Aza-7-oxa-2-phospha-spiro[4.4]-(1S,3R,4R,5R)-6-ben-
zyloxymethyl-8,9-isopropylidendioxy-2-methoxy-1-methyl-2-
oxonon-3-en-4-amine (12). To a solution of diisopropylamine (509
μL, 3.52 mmol) and BuLi (1.40 mL, 3.52 mmol) in dry THF (12 mL)
at −78 °C under argon was added a solution of compound 11 (361
mg, 0.88 mmol) in dry THF (12 mL). After 1 h, water was added and
the reaction mixture was neutralized with HCl and then extracted with
EtOAc. The organic phase was separated, dried (Na2SO4), and
concentrated. The crude product was purified by reverse phase flash
chromatography (C18) (acetonitrile/H2O) to give 12 as a white solid
(260 mg, 72%) as a mixture of two diastereomers (55/45). Rf = 0.45
4.3. 1-Aza-7-oxa-2-phosphaspiro[4.4]-(1S,3R,4R,5R)-6-ben-
zyloxymethyl-8,9-isopropylidendioxy-2-methoxy-2-oxonon-3-
en-4-amine (10). To a solution of diisopropylamine (542 μL, 3.86
mmol) and BuLi (1.45 mL, 3.76 mmol) in dry THF (12 mL) at −78
°C under argon was added compound 8 (373 mg, 0.94 mmol). After 1
h, water was added and the reaction mixture was neutralized with HCl
and then extracted with EtOAc. The organic phase was separated,
dried (Na2SO4), and concentrated. The crude product was purified by
flash chromatography (CH2Cl2/MeOH) to give 10 as a white solid
(225 mg, 60%) as a mixture of two diastereomers (55/45). Rf = 0.31
1
(CH2Cl2/MeOH, 9.5/0.5). H NMR (CDCl3; 300 MHz): δ 7.37−
7.29 (m, 10H), 5.89 (d, J = 3.9 Hz, 1H), 5.85 (d, J = 3.9 Hz, 1H),
4.87−4.71 (m, 2H), 4.70−4.49 (m, 8H), 3.72−3.66 (m, 4H), 3.58 (d,
JH−P = 11.7 Hz, 3H), 3.54 (d, JH−P = 11.6 Hz, 3H), 2.85 (d, JH−P = 7.9
Hz, 3H), 2.79 (d, JH−P = 8.0 Hz, 3H), 1.63 (s, 3H), 1.62 (s, 3H), 1.35
1
(s, 3H), 1.33 (s, 3H). 13C NMR (CDCl3; 75 MHz): δ 160.6 (d, JC−P
=
(CH2Cl2/MeOH, 9.8/0.2); H NMR (CDCl3; 300 MHz): δ 7.37−
7.20 (m, 10H), 5.90 (d, J = 3.0 Hz, 1H), 5.88 (d, J = 3.6 Hz, 1H),
4.66−4.50 (m, 4H), 4.47−4.45 (m, 2H), 4.39 (dd, J = 1.5 Hz, J = 4.5
Hz, 1H), 4.35 (d, J = 3.6 Hz, 1H), 4.18−4.15 (m, 2H), 3.80 (dd, J =
2.1 Hz, J = 11.4 Hz, 1H), 3.72−3.66 (m, 3H), 3.59 (d, JH−P = 12.3 Hz,
3H), 3.50 (d, JH−P = 12.3 Hz, 3H), 1.56 (s, 3H), 1.54 (s, 3H), 1.34 (s,
28.8 Hz), 159.9 (d, JC−P = 28.5 Hz), 137.7, 137.5, 129.0−127.8, 113.0,
112.9, 104.0,103.9, 85.9, 85.5, 81.5 (d, JC−P = 19.8 Hz), 80.2 (d, JC−P
19.2 Hz), 75.0, 74.8, 73.5, 69.7, 67.4, 67.2, 53.5 (d, JC−P = 6.6 Hz), 52.8
(d, JC−P = 6.2 Hz), 27.1−25.9. 31P NMR (CDCl3; 121 MHz): δ 43.2−
42.9 (m), 42.5−42.2 (m). HRMS: C19H27N2O6PNa calcd 433.1504,
found 433.1493.
=
3H), 1.32 (s, 3H). 13C NMR (CDCl3; 75 MHz): δ 159.8 (d, JC−P
=
30.6 Hz), 159.3 (d, JC−P = 29.4 Hz), 137.7, 137.5, 128.3, 127.7, 112.9,
103.9, 103.8, 82.8, 82.5, 81.9 (d, JC−P = 19.9 Hz), 80.3 (d, JC−P = 8.4
Hz), 80.1 (d, JC−P = 6.2 Hz), 79.5 (d, JC−P = 19.1 Hz), 73.5, 73.4, 68.6
4.6. General Procedure for Phosphonylation with Electron-
Withdrawing Phosphonochloridates. To a solution of furanose
derivative (1 equiv) in dry CH2Cl2 at 0 °C were added
phosphonochloridates (1 equiv) and NaH (1 or 4 equiv). After 1 h
at room temperature, the reaction mixture was neutralized with 1 N
HCl and then extracted with EtOAc. The organic phase was separated,
dried (Na2SO4), and concentrated. The crude product was purified by
flash chromatography.
5-O-Benzoyl-3-C-cyano-O-[ethyl-2-(ethoxyphosphonyl)acetate]-
1,2-O-isopropylidene-α-D-ribofuranose (21). According to the
general procedure, compound 1 (230 mg, 0.72 mmol) was treated
with ethyl (ethoxycarbonylmethyl)phosphonochloridate (ClOP(OEt)-
(CH2COOEt); 155 mg, 0.72 mmol) and NaH (29 mg, 0.72 mmol) in
CH2Cl2 (10 mL). The crude product was purified by flash
chromatography (cyclohexane/EtOAc, 6/4) to give 21 as a colorless
(d, JC−P = 4.6 Hz), 68.4 (d, JC−P = 5.4 Hz), 67.0, 66.7, 52.8 (d, JC−P
=
5.8 Hz), 52.5 (d, JC−P = 6.3 Hz), 26.3, 26.2. 31P NMR (CDCl3; 121
MHz): δ 43.0 (m), 45.9 (m). HRMS: C18H25N2O6PNa calcd
419.1348, found 419.1342.
4.4. 5-O-Benzyl-3-C-cyano-3-desoxy-1,2-O-isopropylidene-
3-methoxymethylphosphoramidyl-N-methyl-α-D-ribofuranose
(11). To a solution of 8 (417 mg, 1.03 mmol) in dry DMF (35 mL)
were added NaH (84 mg, 2.10 mmol) and then MeI (131 μL, 2.10
mmol). After 1 h at room temperature, 1 N HCl and CH2Cl2 were
added. The organic phase was separated, dried (Na2SO4), and
concentrated. The crude product was purified by flash chromatography
(cyclohexane/EtOAc) to give 11 as a white solid (270 mg, 63%) as a
9000
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Article
oil (150 mg, 40%) as a mixture of two diastereomers (30/70). Rf =
0.33 (EtOAc/cyclohexane, 5/5). 1H NMR (CDCl3; 300 MHz): δ
8.10−7.95 (m, 4H), 7.62−7.58 (m, 2H), 7.49−7.43 (m, 4H), 6.15 (d, J
= 4.4 Hz, 1H), 6.02 (d, J = 3.8 Hz, 1H), 5.28 (d, 1H), 5.16 (d, 1H),
4.88 (dd, J = 12.2 Hz, J = 3.4 Hz, 1H), 4,73−4.63 (m, 3H), 4.51−4.45
(m, 2H), 4.35−4.27 (m, 2H), 4.24−4.13 (m, 6H), 3.20−3.07 (m, 4H),
1.63 (s, 3H), 1.60 (s, 3H), 1.41 (s, 3H), 1.43−1.24 (m, 15H). 13C
NMR (CDCl3; 75 MHz): δ 167.3 (d, JC−P = 33.6 Hz), 165.9, 133.5,
129.9, 129.6, 128.5, 115.2, 114.6, 114.4, 104.1, 103.1, 81.8, 81.6, 77.3
(d, JC−P = 9.5 Hz), 77.2 (d, JC−P = 9.8 Hz), 65.6, 63.0, 63.5, 63.4, 61.9,
61.7, 35.1 (d, JC−P = 137.2 Hz), 27.4, 27.0, 26.9, 26.3, 16.1, 14.0. 31P
NMR (CDCl3; 121 MHz): δ 22.2−21.7 (m), 20.3−19.9 (m). HRMS:
C22H28NO10PNa calcd 520.1349, found 520.1349.
JC−P = 6.7 Hz). 31P NMR (CDCl3; 121 MHz): δ 16.4−15.9 (m),
14.5−14.0 (m). HRMS: C20H23N2O8PNa calcd 473.1090, found
473.1086.
5-O-Benzoyl-3-O-benzylethoxyphosphonyl-3-C-cyano-1,2-O-iso-
propylidene-α-D-ribofuranose (25). According to the general
procedure, compound 1 (194 mg, 0.61 mmol) was treated with
ethyl (benzyl)phosphonochloridate (ClOP(OEt)(CH2Ph); 133 mg,
0.61 mmol) and NaH (48.6 mg, 1.21 mmol) in CH2Cl2 (30 mL). The
crude product was purified by flash chromatography (cyclohexane/
EtOAc, 6/4) to give 25 as a colorless oil (200 mg, 65%) as a mixture of
1
two diastereomers (70/30). Rf = 0.5 (EtOAc/cyclohexane: 5/5). H
NMR (CDCl3; 300 MHz): δ 8.13 (d, J = 7.9 Hz, 2H), 7.98 (d, J = 8.5
Hz, 2H), 7.59−7.32 (m, 6H), 7.30−7.25 (m, 10H), 6.03 (d, J = 3.7
Hz, 1H), 6.00 (d, J = 3.7 Hz, 1H), 5.33 (d, 1H), 5.18 (d, 1H), 4.76−
4.65 (m, 4H), 4.55−4.39 (m, 2H), 4.26−4.10 (m, 2H), 4.03−3.98 (m,
2H), 3.38−3.29 (m, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.42 (s, 3H), 1.37
(s, 3H), 1.29−1.25 (m, 3H), 1.19−1.15 (m, 3H). 13C NMR (CDCl3;
75 MHz): δ 165.8, 133.5, 133.4, 129.9−127.1, 115.4, 114.9, 114.5,
5-O-Benzyl-3-C-cyano-O-[ethyl-2-(ethoxyphosphonyl)acetate]-
1,2-O-isopropylidene-α-D-ribofuranose (22). According to the
general procedure, compound 2 (216 mg, 0.71 mmol) was treated
with ethyl (ethoxycarbonylmethyl)phosphonochloridate (ClOP(OEt)-
(CH2COOEt); 456 mg, 2.12 mmol) and NaH (28.3 mg, 0.71 mmol)
in CH2Cl2 (10 mL). The crude product was purified by reverse flash
chromatography (C18, acetonitrile/H2O) to give 22 as a white solid
(212 mg, 62%) as a mixture of two diastereomers (50/50). Rf = 0.36
114.2, 104.0, 81.9, 81.7, 77.6, 77.4 (d, JC−P = 7.5 Hz), 77.0 (d, JC−P
=
9.7 Hz), 63.3 (d, JC−P = 7.7 Hz), 62.9 (d, JC−P = 7.6 Hz), 62.0, 61.9,
34.5 (d, JC−P = 138.7 Hz), 34.3 (d, JC−P = 138.4 Hz), 26.9, 26.5, 26.3,
26.2, 16.1 (d, JC−P = 6.5 Hz), 15.8 (d, JC−P = 6.8 Hz). 31P NMR
(CDCl3; 121 MHz): δ 28.0−27.4 (m), 26.8−26.5 (m). HRMS:
C25H28NO8PNa calcd 524.1450, found 524.1437.
1
(EtOAc/cyclohexane, 8/2). H NMR (CDCl3; 300 MHz): δ 7.39−
7.29 (m, 10H), 5.99 (d, J = 3.8 Hz, 2H), 5.20 (d, 1H), 4.68 (d, 1H),
4.65−4.40 (m, 6H), 4.32−4.22 (m, 4H), 4.22−4.16 (m, 4H), 3.92−
3.87 (m, 4H), 3.16 (d, JH−P = 22.7 Hz, 2H), 2.93 (d, JH−P = 21.7 Hz,
2H), 2.03 (s, 6H), 1.38 (s, 6H), 1.48−1.17 (m, 12H). 13C NMR
(CDCl3; 75 MHz): δ 165.2−164.8, 137.3, 128.6−127.5, 115.5, 114.7,
114.4, 104.5, 104.1, 82.0, 81.6, 81.5, 79.9, 79.6 (d, JC−P = 9.8 Hz), 74.1,
73.9, 68.9, 68.3, 63.4 (d, JC−P = 7.1 Hz), 61.7, 35.2 (d, JC−P = 138.8
Hz), 27.0, 26.9, 26.4, 26.3, 16.0 (d, JC−P = 6.7 Hz), 14.1. 31P NMR
(CDCl3; MHz): δ 21.9−21.6 (m), 20.0−19.8 (m). HRMS:
C22H30NO9PNa calcd 506.1556, found 506.1543.
Ethyl 1,7-Dioxa-2-phosphaspiro[4.4]-(1S,3R,4R,5R)-4-amino-6-
benzoyloxymethyl-2-ethoxy-8,9-isopropylidenedioxy-2-oxonon-3-
en-3-carboxylate (26). According to the general procedure,
compound 1 (626 mg, 1.96 mmol) was treated with ethyl
(ethoxycarbonylmethyl)phosphonochloridate (ClOP(OEt)-
(CH2COOEt); 421 mg, 1.96 mmol) and NaH (157 mg, 3.92
mmol) in CH2Cl2 (50 mL). The crude product was purified by flash
chromatography (cyclohexane/EtOAc, 6/4) to give 26a (370 mg) and
26b (310 mg) as white solids (70%). Data for 26a are as follows. Rf =
0.18 (EtOAc/cyclohexane, 5/5). Mp: 235−236 °C. [α]20D = −5 (c 0.1,
5-O-Benzoyl-3-C-cyano-1,2-O-isopropylidene-3-O-[methyl-2-
(methoxyphosphonyl)acetate]-α-D-ribofuranose (23). According to
the general procedure, compound 1 (72 mg, 0.22 mmol) was treated
with methyl (methoxycarbonylmethyl)phosphonochloridate (ClOP-
(OMe)(CH2COOMe); 42.1 mg, 0.22 mmol) and NaH (18 mg, 0.40
mmol) in CH2Cl2 (10 mL). The crude product was purified by flash
chromatography (cyclohexane/EtOAc, 5/5) to give 23 as a colorless
oil (23 mg, 22%) as a mixture of two diastereomers (60/40). Rf = 0.21
1
CH2Cl2). H NMR (CDCl3; 300 MHz): δ 7.97 (d, J = 7.2 Hz, 2H),
7.83 (s, 1H), 7.49 (m, 1H), 7.38−7.30 (m, 2H), 6.55 (s, 1H), 6.06 (d,
J = 3.9 Hz, 1H), 4.71 (dd, J = 2.8 Hz, J = 7.2 Hz, 1H), 4,62−4.45 (m,
2H), 4.52 (d, 1H), 4.22−4.02 (m, 4H), 1.57 (s, 3H), 1.31 (s, 3H),
1.27−1.17 (m, 6H). 13C NMR (CDCl3; 75 MHz): δ 167.3 (d, JC−P
=
33.6 Hz), 165.9, 164.3 (d, JC−P = 14.3 Hz), 133.5, 129.8, 129.4, 128.3,
114.2, 104.0, 84.8, 82.7 (d, JC−P = 196.2 Hz), 81.4, 77.3 (d, JC−P = 7.0
Hz), 63.7 (d, JC−P = 6.5 Hz), 61.0, 60.4, 26.6, 26.2, 16.3 (d, JC−P = 6.3
Hz), 14.2. 31P NMR (CDCl3; 121 MHz): δ 33.7 (t, JP−H = 3.0 Hz).
HRMS: C22H28NO10PNa calcd 520.1349, found 520.1340. Data for
26b are as follows: Rf = 0.07 (EtOAct/cyclohexane, 5/5). Mp: 153−
154 °C. [α]20D = +16 (c 0.1, CH2Cl2). 1H NMR (CDCl3; 300 MHz):
δ 8.01 (d, J = 7.3 Hz, 2H), 7.83 (s, 1H), 7.49 (m, 1H), 7.45−7.40 (m,
2H), 6.23 (s, 1H), 6.06 (d, J = 3.8 Hz, 1H), 4.68 (m, 2H), 4,35−4.24
(m, 2H), 4.21−4.06 (m, 4H), 1.64 (s, 3H), 1.30 (s, 3H), 1.35−1.21
(m, 6H). 13C NMR (CDCl3; 75 MHz): δ 166.7 (d, JC−P = 33.8 Hz),
166.0, 165.3 (d, JC−P = 14.3 Hz), 133.3, 129.8, 129.3, 128.4, 114.4,
103.8, 84.9, 83.9 (d, JC−P = 197.1 Hz), 81.8, 77.1 (d, JC−P = 8.5 Hz),
64.1 (d, JC−P = 6.2 Hz), 61.2, 60.4, 26.3, 16.4 (d, JC−P = 5.6 Hz), 14.2.
31P NMR (CDCl3; 121 MHz): δ 34.1 (t, JP−H = 3.0 Hz). HRMS:
1
(EtOAc/cyclohexane, 5/5). H NMR (CDCl3; 300 MHz): δ 8.14−
8.09 (m, 4H), 7.63−7.59 (m, 2H), 7.48−7.45 (m, 4H), 6.04 (d, J = 3.7
Hz, 2H), 5.28 (d, 1H), 5.16 (d, 1H), 4.90 (dd, J = 12.2 Hz, J = 3.4 Hz,
1H), 4,73−4.62 (m, 3H), 4.51 (m), 3.94 (d, JH−P = 11.8 Hz, 3H), 3.83
(d, JH−P = 11.8 Hz, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 3.18 (d, JH−P
=
23.2 Hz, 2H), 3.13 (d, JH−P = 22.3 Hz, 2H), 1.64 (s, 3H), 1.62 (s, 3H),
1.45 (s, 3H), 1.43 (s, 3H). 13C NMR (CDCl3; 75 MHz): δ 165.9,
165.0 (d, JC−P = 15.2 Hz), 133.5, 133.4, 129.9, 129.8, 128.5, 115.2,
114.6, 114.4, 104.2, 104.1, 81.8, 81.6, 77.5, 77.3, 61.9, 53.9 (d, JC−P
=
7.6 Hz), 53.9 (d, JC−P = 7.3 Hz), 53.0, 52.7, 34.6 (d, JC−P = 139.7 Hz),
34.5 (d, JC−P = 139.7 Hz), 27.0, 26.9, 26.4, 26.3. 31P NMR (CDCl3;
121 MHz):
C20H24NO10PNa calcd 492.1036, found 492.1031.
δ 23.5−22.8 (m), 21.6−20.9 (m). HRMS:
5-O-Benzoyl-3-C-cyano-3-O-cyanomethylethoxyphosphonyl-1,2-
O-isopropylidene-α-D-ribofuranose (24). According to the general
procedure, compound 1 (64 mg, 0.20 mmol) was treated with ethyl
(cyanomethyl)phosphonochloridate (ClOP(OEt)(CH2CN); 33.6 mg,
0.20 mmol) and NaH (16 mg, 0.40 mmol) in CH2Cl2 (12 mL). The
crude product was purified by flash chromatography (cyclohexane/
EtOAc, 3/7) to give 24 as a colorless oil (40 mg, 44%) as a mixture of
C22H28NO10PNa calcd 520.1349, found 520.1340.
Ethyl 1,7-Dioxa-2-phosphaspiro[4.4]-(1S,3R,4R,5R)-4-amino-6-
benzyloxymethyl-2-ethoxy-8,9-isopropylidenedioxy-2-oxonon-3-
en-3-carboxylate (27). According to the general procedure,
compound 2 (203 mg, 0.66 mmol) was treated with ethyl
(ethoxycarbonylmethyl)phosphonochloridate (ClOP(OEt)-
(CH2COOEt); 143 mg, 0.66 mmol) and NaH (80 mg, 1.99 mmol)
in CH2Cl2 (50 mL). The crude product was purified by flash
chromatography (cyclohexane/EtOAc) to give 27a (95 mg) and 27b
(40 mg) as white solids (42%). Data for 27a are as follows. Rf = 0.43
(EtOAc/cyclohexane, 8/2). Mp: 180−184 °C. 1H NMR (CDCl3; 300
MHz): δ 7.35−7.27 (m, 5H), 5.96 (d, J = 3.9 Hz, 1H), 4.56−4.52 (m,
2H), 4.49 (d, 1H), 4.38−4.16 (m, 5H), 3.81 (dd, J = 2.5 Hz, J = 11.3
Hz, 1H), 3.70 (dd, J = 6.5 Hz, 1H), 1.62 (s, 3H), 1.37 (s, 3H), 1.39−
1.26 (m, 6H). 13C NMR (CDCl3; 75 MHz): δ 168.3 (d, JC−P = 33.4
Hz), 165.4 (d, JC−P = 14.2 Hz), 137.4, 129.9, 128.4, 127.8, 114.5,
1
two diastereomers (58/42). Rf = 0.36 (EtOAc/cyclohexane, 5/5). H
NMR (CDCl3; 300 MHz): δ 8.14−8.11 (m, 4H), 7.66−7.63 (m, 2H),
7.52−7.47 (m, 4H), 6.06 (d, J = 3.8 Hz, 1H), 6.04 (d, J = 3.8 Hz, 1H),
5.28 (d, 1H), 5.16 (d, 1H), 4.78 (dd, J = 12.9 Hz, J = 5.7 Hz, 1H),
4,73−4.56 (m, 3H), 4.44−4.35 (m, 2H), 4.34−4.25 (m, 2H), 4.25−
4.16 (m, 2H), 3.24−2.93 (m, 4H), 1.66 (s, 3H), 1.61 (s, 3H), 1.47−
1.41 (m, 9H), 1.38−1.33 (m, 3H). 13C NMR (CDCl3; 75 MHz): δ
165.9, 133.5, 129.9, 129.1, 128.5, 114.8, 114.6, 114.4, 104.1, 103.9,
81.8, 81.4, 77.2, 77.1, 65.6, 64.6 (d, JC−P = 7.4 Hz), 61.7, 61.5, 26.9,
26.8, 26.2, 17.6 (d, JC−P = 148.7 Hz), 16.1 (d, JC−P = 5.9 Hz), 15.9 (d,
9001
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Article
103.9, 83.3 (d, JC−P = 220.9 Hz), 82.1, 78.8 (d, JC−P = 5.8 Hz), 77.5,
73.6, 66.6, 63.7 (d, JC−P = 6.4 Hz), 60.5, 26.7, 26.3, 16.3 (d, JC−P = 6.1
Hz), 14.3. 31P NMR (CDCl3; 121 MHz): δ 33.7 (t, JP−H = 9.7 Hz).
HRMS: C22H30NO9PNa calcd 506.1556, found 506.1559. Data for
27b are as follows. Rf = 0.15 (EtOAc/cyclohexane, 8/2). Mp: 127−
129 °C. 1H NMR (CDCl3; 300 MHz): δ 7.39−7.30 (m, 5H), 5.94 (d,
J = 3.8 Hz, 1H), 4.65−4.51 (m, 4H), 4.36−4.14 (m, 4H), 3.76 (dd, J =
3.0 Hz, J = 12.0 Hz, 1H), 3.66 (dd, J = 6.0 Hz, 1H), 1.66 (s, 3H), 1.38
(s, 3H), 1.39−1.28 (m, 6H). 13C NMR (CDCl3; 75 MHz): δ 167.8 (d,
JC−P = 33.2 Hz), 165.4 (d, JC−P = 14.3 Hz), 137.3, 129.8−127.7, 114.5,
103.7, 84.7 (d, JC−P = 219.1 Hz), 84.8 (d, JC−P = 3.6 Hz), 82.2 (d, JC−P
= 2.6 Hz), 76.6, 73.6, 66.2, 63.8 (d, JC−P = 6.3 Hz), 60.5, 26.4, 26.3,
16.5 (d, JC−P = 6.0 Hz), 14.3. 31P NMR (CDCl3; MHz): δ 33.8 (t, JP−H
= 7.2 Hz). HRMS: C22H30NO9PNa calcd 506.1556, found 506.1541.
Methyl 1,7-Dioxa-2-phosphaspiro[4.4]-(1S,3R,4R,5R)-4-amino-6-
benzoyloxymethyl-8,9-isopropylidenedioxy-2-methoxy-2-oxonon-
3-en-3-carboxylate (28). According to the general procedure,
compound 1 (380 mg, 1.19 mmol) was treated with methyl
(methoxycarbonylmethyl)phosphonochloridate (ClOP(OMe)-
(CH2COOMe); 222 mg, 1.19 mmol) and NaH (190 mg, 4.76
mmol) in CH2Cl2 (40 mL). The crude product was purified by reverse
flash chromatography (C18, acetonitrile/H2O) to give 28 as a
colorless oil (180 mg, 41%) as a mixture of two diastereomers (60/
79.9 (d, JC−P = 4.8 Hz), 79.4 (d, JC−P = 3.4 Hz), 64.7 (d, JC−P = 7.4
Hz), 64.5 (d, JC−P = 6.5 Hz), 57.8, 57.2, 26.6, 26.5, 26.3, 16.4−16.1.
31P NMR (CDCl3; 121 MHz): δ 34.1 (t, JP−H = 8.5 Hz), 33.7 (t, JP−H
= 9.5 Hz). HRMS: C25H28NO8PNa calcd 524.1450, found 524.1459.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of compounds 6−8,
10−12, and 21−30. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for D.P.: denis.postel@u-picardie.fr.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Conseil Reg
́
ional de Picardie for financial
support.
1
40). Rf = 0.13 (EtOAc/cyclohexane, 5/5). H NMR (MeOD; 300
REFERENCES
■
MHz): δ 8.05−8.02 (m, 4H), 7.68−7.62 (m, 2H), 7.54−7.48 (m, 4H),
6.16 (d, J = 3.8 Hz, 2H), 4.70 (d, 1H), 4.63 (d, 1H), 4.61−4.43 (m,
6H), 3.81 (d, JH−P = 11.7 Hz, 3H), 3.79 (s, 6H), 3.78 (d, JH−P = 11.7
Hz, 3H), 1.64 (s, 3H), 1.63 (s, 3H), 1.41 (s, 6H). 13C NMR (MeOD;
75 MHz): δ 168.1, 166.0 (d, JC−P = 3.8 Hz), 165.2 (d, JC−P = 15.0 Hz),
133.2, 133.1, 129.5, 129.4, 128.3, 113.9, 113.8, 104.2, 104.1, 85.6, 81.9,
77.2 (d, JC−P = 4.6 Hz), 77.0 (d, JC−P = 4.4 Hz), 61.1, 60.8, 53.7 (d,
JC−P = 6.2 Hz), 50.5, 50.4, 25.3, 25.2. 31P NMR (CDCl3; MHz): δ 38.7
(q, JP−H = 11.7 Hz). HRMS: C20H24NO10PNa calcd 492.1036, found
492.1031.
1,7-Dioxa-2-phosphaspiro[4.4]-(1S,3R,4R,5R)-4-amino-6-benzoy-
loxymethyl-2-ethoxy-8,9-isopropylidenedioxy-2-oxonon-3-en-3-
carboxamide (29). According to the general procedure, compound 1
(204 mg, 0.64 mmol) was treated with ethyl (cyanomethyl)-
phosphonochloridate (ClOP(OEt)(CH2CN); 107 mg, 0.64 mmol)
and NaH (102 mg, 2.55 mmol) in CH2Cl2 (20 mL). The crude
product was purified by reverse flash chromatography (C18,
acetonitrile/H2O) to give 29 as a white solid (160 mg, 53%) (only
one diastereomer). Rf = 0.1 (EtOAc). Mp: 209−211 °C. [α]20D = −40
(c 0.1, CH2Cl2). 1H NMR (MeOD; 300 MHz): δ 9.43 (d, J = 7.1 Hz,
2H), 9.04 (m, 1H), 8.95−8.90 (m, 2H), 7.62 (d, J = 3.8 Hz, 1H), 6.33
(d, 1H), 6.29 (m, 1H), 6.00 (dd, J = 5.4 Hz, J = 11.7 Hz, 1H), 5.75
(dd, J = 7.4 Hz, 1H), 5.11−5.05 (m, 2H), 3.05 (s, 3H), 2.83 (s, 3H),
2.52 (t, J = 7.1 Hz, 3H). 13C NMR (MeOD; 75 MHz): δ 178.6 (d,
JC−P = 17.3 Hz), 175.2 (d, JC−P = 6.9 Hz), 167.0, 134.8, 130.8, 129.8,
129.6, 115.9, 105.6, 97.9 (d, JC−P = 132.2 Hz), 95.0 (d, JC−P = 10.6
Hz), 83.0, 75.7, 62.1, 61.7 (d, JC−P = 5.3 Hz), 26.7, 26.6, 16.8 (d, JC−P
= 7.5 Hz). 31P NMR (CDCl3; 121 MHz): δ 2.65 (t, JP−H = 6.0 Hz).
HRMS: C20H26N2O9P calcd 469.1376, found 469.1380.
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