Development of O-H insertion for the attachment of phosphonates to nucleosides; Synthesis of α-carboxy phosphononucleosides

Article abstract of DOI:10.1016/j.tet.2011.12.077

Development of rhodium catalysed O-H insertion reactions employing α-diazophosphonates with appropriately protected adenosine, uridine and thymidine derivatives is described. This synthetic methodology leads, following deprotection, to novel phosphononucl

Full text of DOI:10.1016/j.tet.2011.12.077

Tetrahedron 68 (2012) 1894e1909
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of OeH insertion for the attachment of phosphonates
to nucleosides; synthesis of a-carboxy phosphononucleosides
Isabelle Hladezuk a, Veronique Chastagner a, Stuart G. Collins a, Stephen J. Plunkett a, Alan Ford a,
,
Sebastien Debarge a, Anita R. Maguire b
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2011
Received in revised form 12 December 2011
Accepted 29 December 2011
Available online 3 January 2012
Development of rhodium catalysed OeH insertion reactions employing a-diazophosphonates with ap-
propriately protected adenosine, uridine and thymidine derivatives is described. This synthetic meth-
odology leads, following deprotection, to novel phosphononucleoside derivatives bearing a carboxylic
acid moiety adjacent to the phosphonate. Protection strategies are critical to the success of the key OeH
insertion. There are two important aspects: avoiding competing insertion pathways or catalyst poisoning,
and being able to achieve deprotection without degradation of the phosphononucleosides.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phosphononucleosides
Nucleosides
Phosphonates
HIV
Antiviral
Rhodium catalysed OeH insertion
Diazophosphonates
1. Introduction
the synthesis of phosphononucleoside analogues bearing an
carboxylic acid substituent (Fig. 1).5
a-
The search for novel antiviral agents has attracted enormous
attention over the past 25 years, especially in the drive for novel
compounds active against HIV and other viruses.1 Among the
strategies explored is the use of non-natural nucleoside analogues
envisaged to act as mimics of the natural nucleosides. To exert their
antiviral activities through inhibition of HIV reverse transcriptase,
these nucleosides analogues must be triphosphorylated by cellular
kinases. The first phosphorylation can be rate limiting with the
non-natural nucleosides as the substrate.2 Use of phosphate ana-
logues of the nucleosides as antiviral agents is not feasible in part
due to their potential for hydrolysis of the OeP link. To circumvent
the problematic first phosphorylation with non-natural nucleo-
sides, one strategy, which has proven successful is the use of isos-
teric phosphonate analogues as phosphate mimics providing
pronucleotides or nucleotide analogues.3,4 In the phosphonate
analogues, the key PeC bond cannot be cleaved by phosphatases or
by hydrolysis, and therefore the phosphononucleosides offer a dis-
tinct advantage over use of monophosphates as drugs. As part of
our ongoing drug discovery program, we have been investigating
O
HO
P
O
Base
HO
O
X
CO2H
Fig. 1.
It was envisaged that the novel phosphononucleosides illus-
trated in Fig.1 bearing a carboxylic acid moiety could potentially act
as analogues of a nucleoside diphosphate. Previously Gilbert and
co-workers explored the citrate derivatives of nucleosides as po-
tential triphosphate isosteres, but found that they were inactive.6 In
2007, Vederas reported the synthesis of nucleoside dicarboxylates
as potential mimics of nucleoside diphosphates, which were also
found to be inactive.7
Considering both phosphonoacetic and phosphonoformic acids
* Corresponding author. E-mail address: a.maguire@ucc.ie (A.R. Maguire).
have antiviral activity,8 our strategy combines these simple
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.077

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1895
antiviral agents with the phosphononucleoside approach leading to
potentially interesting compounds for evaluation, which can be
envisaged as nucleoside diphosphate mimics.
deoxyribose systems on the OeH insertion reaction and sub-
sequent deprotection.
The most commonly employed method for the attachment of
phosphonate moieties to nucleoside derivatives involves nucleo-
philic displacement of precursors such as (RO)2OPCH2OTs with an
alkoxide anion under strongly basic conditions.9 However, the
harsh conditions associated with this method are limiting in terms
of the substrate range, which can tolerate the high pH. In the
context of our ongoing program of research in rhodium and copper
2.1. Synthesis of
a-diazophosphonate precursors
Use of the -diazophosphonate precursors 5e8 was explored
a
(Scheme 1). The trimethyl and triethyl derivatives 523 and 624 are
known and were prepared by diazo transfer to the commercially
available trimethyl phosphonoacetate 1 and triethyl phosphonoa-
cetate 2. The conditions chosen in this case are those reported by
Koskinen for the synthesis of a range of diazophosphonate de-
rivatives,25 using tosyl azide and potassium carbonate in
acetonitrile.
catalysed transformation of
vised an alternative attractive synthetic strategy. We envisaged
that OeH insertion reactions with -diazophosphonate derivatives
a
-diazocarbonyl derivatives,10 we de-
a
could be employed to attach phosphonate moieties to nucleoside
derivatives under mild conditions, at neutral pH. The OeH in-
sertion reactions can occur thermally, photochemically, by acid
catalysis or most commonly by transition metal catalysis.11,12 In
1984, Paquet and Sinai reported the functionalisation of the pri-
mary alcohol group of a protected glucose derivative by an OeH
insertion reaction catalysed by rhodium acetate using trimethyl
diazophosphonoacetate.13 Related functionalisations were carried
out independently by Berchtold and co-workers in 1987,14 and by
Ganem and co-workers in 1992 on the synthesis of chorismic
acid.15
In 1986, Moody and co-workers began an extensive program
focused on the applications of the OeH insertion reaction catalysed
by rhodium carbenoids, particularly for the synthesis of seven- and
eight-membered ring ethers obtained in an intramolecular fash-
Scheme 1. Conversion of phosophonoacetates to diazophosphonoacetates.
ion.16 In 1991, they carried out the cyclisation with
a-diazo-b-
Use of benzyl derivatives 7 and 8 was of interest due to the
potential to deprotect later in the reaction sequence under neutral
conditions via hydrogenolysis, if hydrolysis of the carboxylic and
phosphonate esters under acidic or basic conditions proved prob-
lematic once attached to the nucleoside units.
ketophosphonates.17 This reaction was later applied to the syn-
thesis of the pyranooxepane and oxepanooxepane subunits of
marine polyether toxins.18
Moody and co-workers also investigated intermolecular OeH
a
-diazophosphonate derivatives,11,19,20 and
A number of approaches to prepare tribenzyl phosphonoacetate
4 were explored including esterification of phosphonoacetic acid,
transesterification of triethyl phosphonoacetate, MichaeliseBecker
type reactions or treatment of dibenzyl phosphite 9 with bases
followed by bromoacetate esters. However, the most successful
approach involved PeH insertion into dibenzyl phosphite. The re-
action of phosphites with diazo compounds under the influence of
copper catalysts has appeared a number of times in the literature.26
The most efficient catalyst is reported to be copper acetylacetonate,
and the reactions were generally conducted in benzene at reflux.
While Cu(acac)2 proved to be ineffective in our hands as a catalyst
for the reaction between dibenzyl phosphite and ethyl diazo-
acetate, better results were observed with copper(II) triflate, and
the desired PeH insertion product 3 was obtained (Scheme 2).
insertion reactions of
some examples of OeH insertion reactions with more highly
functionalised alcohols have been reported.21 In 2000, Kim and co-
workers demonstrated that insertion reactions of a-diazocarbonyl
compounds are possible in presence of heterocyclic bases.22 How-
ever, to the best of our knowledge, previous to our recent work,5 we
are not aware of any reports of transition metal catalysed OeH
insertion reactions of
carbocyclic analogues.
a-diazophosphonates with nucleosides, or
At the outset of the project, catalyst inhibition through co-
ordination with the heterocyclic bases was envisaged as a poten-
tial complication; however, this did not prove to be a significant
problem in practice, as judicious protecting group selection can be
used to avoid catalyst poisoning. Selecting rhodium(II) as the cat-
alyst system we focused on optimising conditions for the OeH in-
sertion reactions using
a-diazophosphonates with a range of
unprotected and protected nucleosides. In the screening process for
the OeH insertion, solvents, catalyst loading, reaction temperature
and other parameters were explored. Herein, we report the pro-
tection strategies investigated for the nucleosides, and the de-
velopment of the OeH insertion reaction for the synthesis of
a series of phosphononucleosides bearing an
a-carboxylic acid
moiety, envisaged as potential diphosphate mimics. The strategies
for deprotection and purification of the fully deprotected phos-
phononucleosides, following the key OeH insertion step leading to
the phosphonate attachment, are also discussed.
2. Results and discussion
Commercially available uridine, thymidine, adenosine and 20,30-
O-isopropylidene adenosine were employed as starting materials
for the development of the methodology, allowing exploration of
the impact of purine and pyrimidine bases and both ribose and 20-
Scheme 2. Synthesis of tribenzyl phosphonoacetate 4.

1896
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
The optimum conditions for this process were found to be ad-
protection, complexation of the nucleoside base to the rhodium
catalyst was resulting in catalyst poisoning.
dition over 30 min of a fivefold excess of neat ethyl diazoacetate to
dibenzyl phosphite in CH2Cl2 in the presence of 5 mol % Cu(OTf)2 at
room temperature followed by stirring overnight, which affords the
desired compound 3 as the predominant product in good yield (up
to 84%). A critical part of the optimisation was the identification of
a suitable method of purification; chromatography over silica gel
leads to poor recovery, but use of alumina (activity III) gives good,
reproducible results.
While extension of the PeH insertion process to the synthesis
of the tribenzyl phosphono ester 4 through reaction with benzyl
diazoacetate in place of ethyl diazoacetate can be envisaged, use
of a large excess of benzyl diazoacetate, which is not commer-
cially available, is not an attractive strategy. Instead conversion of
the ethyl dibenzyl phosphono ester 3 prepared above to the
tribenzyl derivative 4 proceeds efficiently as summarised in
Scheme 2.
Hydrolysis of the ethyl ester 3 with excess lithium hydroxide in
50% aqueous THF affords the acid 11 in good yield and purity
(Scheme 2); the acid 11 has been previously prepared by the car-
bonation of the anion derived from dibenzyl methylphosphonate
by treatment with methyllithium.27 The present method compares
favourably in terms of efficiency and overall cost with this pre-
viously reported method.
Scheme 3. Investigation of the OeH insertion reaction with adenosine derivatives.
Reaction conditions: (i) 5 or 6, Rh2(OAc)4 or Rh2(NHCOCF3)4, CH2Cl2, THF or C6H6,
reflux.
Table 1
OeH insertion of trimethyl and triethyl diazophosphonoacetate 5 and 6 with
adenosine derivatives 14e16
The esterification reaction of the acid 11 with benzyl bromide in
the presence of potassium carbonate in DMF proves to be highly
satisfactory (Scheme 2). This is significant since it means that tri-
benzyl phosphonoacetate 4 can be prepared in three steps from
dibenzyl phosphite in 45% typical overall yield following the re-
action sequence outlined in Scheme 2 with only one chromato-
graphic purification.
Entry Substrate Diazo
compound
Solvent Catalyst
(1 mol %)
Time Product
(h)
(% yield)a
(mol equiv)
1
12
6 (2)
C6H6 or Rh2(OAc)4
CH2Cl2
12
d
2
3
4
5
6
7
8
9
13
14
14
14
14
14
15
16
6 (2)
6 (2)
6 (2)
6 (2)
6 (2)
6 (2)
6 (2)
5 (1.2)
C6H6
CH2Cl2
C6H6
THF
C6H6
C6H6
C6H6
C6H6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(NHCOCF3)4 12
Rh2(NHCOCF3)4 12
Rh2(NHCOCF3)4 24
Rh2(NHCOCF3)4 24
12
12
12
d
d
17 (11)
17 (10)
17 (39)
17 (45)
18 (55)
19 (66)
Diazo transfer to the two benzyl phosphono esters 3 and 4 was
achieved using the conditions described by McKenna,28 leading to
the novel a-diazophosphonates 7 and 8 in 66 and 68% yields, re-
spectively. These diazo precursors were readily handled, stored and
characterised.
Rh2(OAc)4
12
a
After chromatography.
2.2. OeH insertion reactions
Further protection of 12 as N6,N6-dibenzoyl-20,30-O-iso-
propylidene adenosine 14, following a literature procedure,30 was
then undertaken to reduce the reactivity of the adenine moiety. As
summarised in Table 1, OeH insertion reaction with the diben-
zoylated precursor 14 bearing a free 50-hydroxyl group with triethyl
diazophosphonoacetate 6 was achieved using either rhodium(II)
acetate or rhodium(II) trifluoroacetamide as catalyst in a range of
solvents to form the desired product 17, which was readily purified
by chromatography on silica gel. Notably use of the lower boiling
dichloromethane as solvent (entry 3) does not result in any OeH
A range of unprotected and selectively protected nucleosides
were evaluated as substrates for OeH insertion reactions cata-
lysed by rhodium carboxylate and carboxamide catalysts. The key
objectives were to establish firstly if the OeH insertion could be
effected in the presence of purine and pyrimidine bases without
protection, and secondly, if base protection is required, which
protecting groups are compatible with the OeH insertion
process.
insertion indicating the increased stability of
a
-diazophosphonates
2.2.1. Investigation of OeH insertion reactions with adenosine de-
rivatives. The first substrate explored for the OeH insertion was
20,30-O-isopropylidene adenosine 12. As summarised in Scheme 3
and Table 1, initial investigation of the OeH insertion reaction
with 12 and triethyl diazophosphonoacetate 6 was carried out in
presence of rhodium(II) acetate as catalyst in refluxing benzene or
dichloromethane and in all cases no insertion was found in the
presence of the unprotected purine base; only the unreacted
starting material 12 was recovered after 12 h. Accordingly, suitable
protecting groups for the adenine base were sought. The N-mon-
obenzoyl adenosine derivative 1329 was then prepared as the
electron-withdrawing benzoyl group would be expected to de-
activate the adenine base towards interaction with the rhodium
complex. When the OeH insertion reaction was attempted with
this N-monoprotected derivative 13 in the presence of rhodium(II)
acetate in refluxing benzene for 12 h, again there was no evidence
of the insertion product. This suggested that even with partial
compared to
a-diazocarbonyl derivatives, in agreement with
Moody’s work.11,16e20 With the triethyl diazophosphonate pre-
cursor 6, optimum yields were obtained using rhodium tri-
fluoroacetamide as catalyst; in agreement with the observations
made by Moody (entries 6, and 7).20b
Investigation of other protecting groups was also carried out.
The N,N-dibenzyl formamidine protecting group described by
Mioskowski,31 which can be cleaved by hydrogenolysis, was ex-
plored to enable subsequent deprotection under neutral condi-
tions. Thus, 20,30-O-isopropylidene adenosine 12 was treated in
refluxing acetonitrile with N,N-dibenzylformamide dimethyl ace-
tal, formed in situ by transamidation between dibenzylamine and
N,N-dimethylformamide dimethyl acetal, to give the novel pro-
tected adenosine derivative 15 in 94% yield. Employing the most
efficient conditions for the OeH insertion observed with 14, i.e.,
rhodium(II) trifluoroacetamide in refluxing benzene for 24 h,
compound 15 afforded the phosphonate derivative 18 in 55% yield.

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1897
Use of the tetrabenzoyl adenosine derivative 16,32 which offers
Table 2
Rhodium catalysed reaction with 6 and 20,30-O-isopropylidene uridine 20a
practical advantages in terms of subsequent deprotection, together
with just a small excess of trimethyl diazophosphonate 5 led to
effective transformation using rhodium acetate as catalyst (entry 9)
in refluxing benzene for 12 h.5
Entry
Catalyst
6 (eq.)
21 (%)
22 (%)
23 (%)
1
2
3
Rh2(NHCOCF3)4
Rh2(OAc)4
Rh2(OAc)4
1.2
1.0
4.0
9
d
26
27
d
d
d
39
d
Throughout this work the products of OeH insertion were iso-
lated as an essentially equimolar mixture of diastereoisomers
readily identified spectroscopically from the characteristic signals
in the 1H and 13C NMR spectra for the CH adjacent to the phos-
phonate, for instance, for compound 17: dC 76.8 (d, JPC 156.6 Hz) and
dP 15.09 (54%), 15.00 (46%) or for compound 19: dC 76.4, 76.1 (d, JPC
156.6, 156.7 Hz, PCH) and dP 16.08 (two epimers).5 On occasion
a slight excess of one diastereoisomer can be observed but the ratio
was never greater than 60:40, indicating very low diaster-
eoselection in the insertion as described in Moody’s OeH insertion
with other systems.11,19e23 Interestingly, the NMR signals for the
bases adenine, thymine and uracil were frequently quite well dis-
tinguished in the two diastereomers, possibly due to different
conformations. Phosphorus NMR spectra proved to be very useful
in identifying and quantifying diastereoisomeric mixtures.
Thus the OeH insertion process cannot be carried out in the
presence of unprotected or monoprotected adenine, presumably
due to complexation of the catalyst to the base, but the reaction is
compatible with both N,N-dibenzoyl and N,N-dibenzyl for-
mamidine protection. Protection of the secondary 20,30-OH groups
either as isopropylidene acetals 14 and 15 or as benzoate esters 16,
to ensure selective insertion at the primary 50-OH, is equally ef-
fective in terms of OeH insertion efficiency. The OeH insertion
proceeds equally efficiently with both the trimethyl and triethyl
diazophosphonoacetates 5 and 6.
a
Reaction conditions: (entry 1) 1.2 equiv 6, Rh2(NHCOCF3)4 cat, benzene, reflux,
36 h; (entry 2) 1.0 equiv 6, Rh2(OAc)4 cat, benzene, reflux, overnight; (entry 3)
4.0 equiv 6, Rh2(OAc)4 cat, benzene, reflux, overnight.
The selectivity for NeH insertion is increased when rhodium(II)
acetate is employed as catalystdthe product of insertion at N-3 22
was isolated exclusively in 27% yield when an equimolar amount of
the triethyl diazophosphonoacetate 6 was employed (Scheme 4).
Use of 4 equiv of 6 resulted in exclusive isolation of the double
insertion product 23 in 39% yield as an essentially equimolar
mixture of four diastereoisomers.
2.2.2.2. Use of protection to achieve selective 50-OH insertion. In
order to obtain 21 in significant amounts, protection of the N-3
position on the uracil base in compound 20 is necessary. Single-
step N3-benzoylation of compound 20 can be effected using ben-
zoyl chloride and triethylamine in dichloromethane as shown in
Scheme 5.35 Treatment of N3-benzoyl-20,30-O-isopropylidene uri-
dine 25 with the triethyl diazophosphonoacetate 6 in the presence
of rhodium(II) acetate afforded the phosphononucleoside 29 in 60%
yield. The use of the benzoyl protecting group is again very effec-
tive, resulting in a relatively high yield of the OeH insertion
product.
Use of the methoxyethoxymethyl (MEM) group as a protecting
group for the uracil moiety was also explored as illustrated in
Scheme 5, as Takaku and co-workers showed that this group can be
removed under mild conditions using triphenylmethyl fluo-
roborate.36 We describe here the synthesis of the novel MEM
protected uridine derivative 26 under phase transfer conditions.
Conversion of 20,30-O-isopropylidene uridine 20 into the 50-ben-
zoylated derivative using standard conditions,37 then treatment
with MEMCl under phase transfer catalysis using benzyl-
triethylammonium chloride (BTEAC)38 (KOH/BTEAC/CH2Cl2) gave
2.2.2. Exploration of OeH insertion with uridine derivatives.
2.2.2.1. Without protection of the pyrimidine base. Uridine was first
converted to the 20,30-O-isopropylidene derivative 20 as described
in the literature,33 to block insertion at the 20 and 30 hydroxy
functions, and also to determine whether catalyst poisoning occurs
in the presence of the unprotected pyrimidine base. In this case,
reaction with the triethyl diazophosphonoacetate 6 in the presence
of rhodium(II) trifluoroacetamide in refluxing benzene gave two
phosphononucleoside derivatives (Scheme 4 and Table 2), which
indicates that catalyst poisoning is not a problem with the uracil
base. Unsurprisingly, products derived from both OeH and NeH
insertion are formed. The major product 22 (26%) was clearly
formed through NeH insertion at the N-3 position of the uracil
base, while a small amount of the 50-OH insertion product 21 (9%)
was also isolated from the reaction. Evidently the NeH insertion is
favoured over the OeH insertion.34 The two OeH and NeH in-
sertion products are readily characterised spectroscopically. The
characteristic pair of doublets in the 13C NMR spectra for the carbon
adjacent to the phosphonate was particularly useful in identifying
50-benzoyl-3-methoxyethoxymethyl-20,30-O-isopropylidene
uri-
dine. This compound was treated with aqueous methanolic
ammonia to give the novel N-protected derivative, 3-
methoxyethoxymethyl-20,30-O-isopropylidene uridine 26 in 51%
yield. The use of phase transfer catalysis was found to be preferable
to the more usual method for protection using MEMCl and diiso-
propylethylamine,39 which did not afford the desired MEM ether
derivative 26 in this case. On treatment with triethyl diazo-
phosphonoacetate 6 in the presence of rhodium(II) acetate, the
uridine derivative 26 was transformed to the desired phosphono-
nucleoside derivative 30 in 32% yield (Scheme 5, Table 3). The MEM
group does not result in any significant complication in the key
the products:
dc 76.6, 74.5 (JPC 158.0 Hz) for 21 and dC 71.1, 69.1 (JPC
160.0 Hz) for 22.
Scheme 4. Rhodium catalysed reaction with triethyl diazophosphonoacetate 6 and 20,30-O-isopropylidene uridine 20.

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I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
OeH insertion step, despite the possibility of side reactions such as
compounds 37a (34%), 37b (7%) and 37c (21%). Clearly insertion at
oxonium ylide formation.
the primary hydroxyl group is preferred. Notably the overall yields
Scheme 5. Strategy for the exclusive 50-OH insertion reaction. Reaction conditions: (i) selective protection, see Experimental section for details; (ii) 5 or 6, rhodium catalyst, C6H6,
reflux.
Table 3
of the insertion products were again quite respectable in the
presence of the benzoyl protecting group, as had been observed
with the uridine derivatives 25 and 28.
OeH insertion of trimethyl and triethyl diazophosphonoacetate 5 and 6 with uridine
derivatives 25e28
Entry Substrate Diazo
compound
Solvent Catalyst
(1 mol %)
Time Product
(% yield)a
Use of the MEM protecting group in the thymidine series was
also investigated (Scheme 6). The MEM protection of N-3 of the
thymine base was accomplished in a similar manner to that used
to protect the uracil base. Both hydroxy groups of thymidine
were protected by benzoylation,36 and the MEM group was
then introduced at N-3 under phase transfer conditions as de-
scribed above. Removal of the benzoyl groups using aqueous
methanolic ammonia gave the novel N-protected derivative, 3-
methoxyethoxymethyl thymidine 34 in 56% yield. Again while
OeH insertion at the 30- and 50-OH groups can be envisaged it was
expected that insertion at the primary hydroxyl group would be
preferred. Investigation of the OeH insertion reactions of 34 with
the diazophosphonate 6 in the presence of rhodium(II) acetate is
summarised in Scheme 6. The reaction employing 2.0 equiv of 6
yielded the products derived from insertion at the 50- and 30-hy-
droxyl groups 36a and 36b, respectively, and the bis-insertion
product 36c, which was isolated as the major product. From the
product ratios recovered it appears that there is a slight preference
for reaction at the primary 50-hydroxyl group as expected. Chro-
matographic separation of the three products 36a, 36b and 36c was
carried out for characterisation.
(mol equiv)
1
2
3
4
25
26
27
28
6 (2)
6 (2)
6 (2)
5 (1.2)
C6H6
C6H6
C6H6
C6H6
Rh2(OAc)4
Rh2(OAc)4
Rh2(NHCOCF3)4 12 h 31 (42)
Rh2(OAc)4 12 h 32 (72)
12 h 29 (60)
12 h 30 (32)
a
After chromatography.
The benzyl protected uridine derivative 2740 was also subjected
to the OeH insertion reaction affording 31 in 42% yield, highlight-
ing the fact that the insertion reaction proceeds well in the pres-
ence of the less electron-withdrawing benzyl protecting group on
the pyrimidine base.
As observed in the adenosine series the isopropylidene pro-
tecting group can be replaced with benzoyl protection for the 20-
and 30-OH groups without detrimental effect on the key OeH in-
sertion step. In fact the most efficient OeH insertion in the uridine
series was obtained using the tribenzoyl uridine derivative 28 with
rhodium acetate (1 mol %) and just 1.2 equiv of the trimethyl
diazophosphonate 5 in benzene at reflux overnight.5
Thus in the uridine series, the unprotected base does not lead to
catalyst poisoning and OeH insertion can be effected without base
protection, but with competing NeH insertion at the base. Use of N-
benzoyl, MEM or benzyl protection on the uracil base leads effi-
ciently to 50-OH insertion with either the triethyl or trimethyl
diazophosphonate 6 or 5.
Thus OeH insertion at the 50-OH is readily achieved in the
thymidine series but blocking of the 30-OH is necessary as the se-
lectivity for insertion at the 50-position is not particularly high.
Accordingly the dibenzoyl thymidine derivative 38 where both the
NeH and 30-OH groups are blocked was synthesised as a key sub-
strate for the OeH insertion process (Scheme 7).5
It is well known that 20-deoxy nucleoside derivatives are more
easily hydrolysed under acidic conditions than the other nucleosi-
des4j and therefore the potential to effect deprotection under
neutral conditions could be very significant. Thus, investigation of
OeH insertion using dibenzyl ethyl diazophosphonate 7 and tri-
benzyl diazophosphonate 8 with the 30-O,3-N-dibenzoylated thy-
midine 38 was carried out (Scheme 7, Table 4).
The reaction of 38 with dibenzyl ethyl diazophosphonate 7
proceeds with modest efficiency in benzene at reflux in the pres-
ence of 1 mol % rhodium acetate to afford compound 39 in ap-
proximately 60% yield. The reaction with the tribenzyl diazo
compound 8 was very sluggish under the same conditions, proba-
bly due to the bulky nature of 8. Even using a large excess of 8
added in portions, the reaction was not driven to completion. Fur-
thermore, OeH insertion with the tribenzyl diazo precursor 8 was
not very reproducible and yields of 40 varied from 30 to 40%.
2.2.3. Exploration of OeH insertion with thymidine de-
rivatives. Investigation of insertion reactions with thymidine was
also undertaken (Scheme 6); in this case we decided to focus on
OeH insertion with N-protection to enable investigation of com-
petition between the 50 and 30 OeH insertion. Thus, N3-ben-
zoylthymidine 33 was prepared from thymidine in two steps
following the procedure we have previously described.35 Rhodiu-
m(II) acetate catalysed reaction of the diazophosphonate
6
(2.0 equiv) with 33 gave three products: the products of insertion at
the 50-OH, 30-OH and bis-insertion at both sites 35a, 35b and 35c
were each recovered. These were purified as a mixture but not
separated. Instead, the mixture was directly heated in benzyl al-
cohol to give the analogous deprotected derivatives 37a, 37b and
37c. Separation was achieved by careful chromatography, affording

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1899
Scheme 6. OeH insertion reaction with N3-protected thymidine derivatives 33 and 34b. Reaction conditions: (i) 6 (2.0 equiv), Rh2(OAc)4, benzene, reflux, overnight; (ii) when R¼Bz,
BnOH, 90 ꢀC, 24 h.
Scheme 7. Synthesis of compounds 39e41. Reaction conditions: (i) selective protection, see Experimental section for details; (ii) dibenzyl ethyl diazophosphonoacetate 7 (2 equiv),
Rh2(OAc)4 (0.01 equiv), molecular sieves, benzene, reflux, 12 h; (iii) tribenzyl diazophosphonoacetate 8 (2 equiv), Rh2(OAc)4 (0.01 equiv), molecular sieves, benzene, reflux, 12 h; (iv)
trimethyl diazophosphonoacetate 5 (1.2 equiv), Rh2(OAc)4 (0.01 equiv), molecular sieves, benzene, reflux, 12 h.
Table 4
OeH Insertion of
2.3. Investigation of complete deprotection of the
phosphononucleosides subsequent to OeH insertion
a-diazophosphonoacetates 5, 7 and 8 with thymidine derivative 38
Entry Substrate Diazo
Solvent Catalyst
(1 mol %)
Time Product
(% yield)a
compound
2.3.1. Exploration
of
deprotection
with
adenosine
de-
(mol equiv)
rivatives. Deprotection of N6,N6-dibenzoylated adenosine de-
rivatives is generally accomplished with aqueous methanolic
ammonia.41 Treatment of 17 under these conditions afforded the
1
2
3
38
38
38
7 (2)
8 (2)
5 (1.2)
C6H6
C6H6
C6H6
Rh2(OAc)4 12 h
Rh2(OAc)4 12 h
Rh2(OAc)4 12 h
39 (w60%)
40 (30e40%)
41 (86%)
partially deprotected
a-amide phosphono adenosine 42 in 37%
a
After chromatography.
yield, resulting from debenzoylation accompanied by conversion of
the carboxylic ester to the primary amide (Scheme 8, Table 5).
Formation of the primary amide adjacent to the phosphonate was
of interest, as this substituent can also be envisaged as a potential
diphosphate mimic once the phosphonate is deprotected. Depro-
tection was also attempted using NaOH in MeOH at room tem-
perature;42 while the ester was efficiently hydrolysed, only one of
the benzoyl groups on the adenine was cleaved under these con-
ditions to afford compound 43. By conducting the base hydrolysis at
reflux overnight, efficient cleavage of the two benzoyl groups from
the adenine base in 19 was achieved.5
Reaction of 38 with 7 and 8 was attempted in toluene at 90 ꢀC and
using Rh2(NHCOCF3)4 as catalyst; while the OeH insertion products
39 and 40 were isolated, the yields were lower than those obtained
using Rh2(OAc)4 and benzene.
In contrast, treatment of 38 with trimethyl diazo-
phosphonoacetate 5 led very efficiently to the OeH insertion
product 41 (Scheme 7, Table 4). This process was employed as the
synthetic route to the fully deprotected phosphononucleoside.5
Thus, OeH insertion with the di- and tribenzyl diazophosphonate
precursors 7 and 8, while possible, is less favourable than with the
analogous methyl and ethyl derivatives 5 and 6.
Having prepared the phosphonate derivative 42, complete
deprotection was attempted using the McKenna procedure.43 It was

1900
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
Scheme 8. Partial deprotections of 17 and 18 and partial and full deprotection of 19. aSee Table 5 for conditions and yields.
aqueous methanol for 8 h to provide the deprotected derivative 44
in 58% yield (Scheme 8, Table 5). However, all attempts to deprotect
the ester derivative 44 using the McKenna procedure proved un-
successful leading only to complex mixtures of unidentifiable
products, as had been previously observed with the analogous
amide 42.
Given the challenges in effecting deprotection of the OeH in-
sertion products derived from isopropylidene adenosine, it was
decided to focus attention instead on the tetrabenzoyl derivative 19
with the expectation that all four benzoyl groups and the carbox-
ylate ester could be cleaved in a single-step. As mentioned earlier,
OeH insertion proceeded efficiently with the trimethyl diazo-
phosphonoacetate 5 and the selectively protected nucleoside 16 to
form 19. Complete deprotection of 19 to reveal 46 in a remarkable
61% overall yield can be conveniently effected in a one-pot reaction
using first excess TMSBr in dichloromethane at reflux for 2 h, to
cleave the phosphonate esters, followed by basic hydrolysis of the
remaining carboxylate methyl ester and benzoyl groups by addition
of a solution of NaOH (1 M, excess) and heating the biphasic mix-
ture at reflux overnight (Scheme 8, Table 5).5 When the TMSBr
deprotection was conducted at room temperature in CH2Cl2 or in
CH3CN the reaction was much less efficient. Interestingly when the
Scheme 9. Deprotection reaction of compounds 22 and 23. Reaction conditions: (i) (1)
TMSBr (10 equiv), CH3CN, rt, overnight, (2) H2O, rt, 1 h; (ii) (1) TMSBr (10 equiv),
CH3CN, rt, overnight, (2) H2O, rt, 1 h, (3) H2O, 90 ꢀC, overnight.
Table 5
Deprotection reactions of compounds 17e19
Entry
Substrate
Deprotection step 1
Partial deprotection (% yield)
Deprotection step 2
Full deprotection (% yield)a
1
2
17
17
18
19
19
NH4OH/MeOH
NaOH/MeOH
Pd(OH)2/C
42 (37)
43
44 (58)
Not isolated
Not isolated
TMSBrb then H2O
d
TMSBrb then H2O
NaOH (1 M) room temperature
NaOH (1 M) reflux
d
d
3
d
4c
5c
TMSBrd then H2O
TMSBrd then
H2O
45 (53)
46 (61)
a
After charcoal chromatography.
TMSBr, CH3CN, rt, 12 h.
Data from Ref. 5.
b
c
d
TMSBr, CH2Cl2, reflux, 2 h.
envisaged that in the case of the OeH insertion products such as 17,
once the acidic phosphonic acid was revealed following the addi-
tion of water, then under the aqueous acidic conditions hydrolysis
of both the ester and acetonide moieties would ensue. Accordingly
deprotection of 42 was investigated using TMSBr in acetonitrile at
room temperature overnight, followed by addition of water; while
the starting material was completely consumed in these conditions,
no identifiable products could be identified in the complex mixture
formed, presumably indicating decomposition of the nucleoside
derivative under the acidic conditions.
basic hydrolysis of the adenosine derivative 19 is conducted at
room temperature, one benzoyl group remains attached to the 6-
amino group of the adenine base to afford the partially depro-
tected compound 45 (Scheme 8, Table 5).
Purification of the highly polar phosphononucleosides 45 and
46 was readily effected by chromatography on a charcoal column by
elution with a solution of 20% NH4OH,44 affording the desired
compounds as ammonium salts, which were characterised by NMR
(1H, 13C, 31P) and MS. Thus, use of OeH insertion is feasible as
a method of attachment of the phosphonoacetic acid moiety in the
presence of adenine provided suitable protection/deprotection
strategies are employed.
As anticipated the formamidine was cleanly removed from 18 by
hydrogenolysis in the presence of the Pearlman catalyst in 50%

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1901
2.3.2. Deprotection reactions with uridine derivatives. Deprotection
of each of the insertion products 22 and 23 was achieved using
a large excess of trimethylsilyl bromide in acetonitrile at room
temperature overnight followed by hydrolysis of the resulting silyl
ester by addition of water (Scheme 9). Efficient deprotection of the
phosphonic acid and the acetonide groups occurs readily under
these conditions affording compound 47b; for complete hydrolysis
to 48 it was necessary to heat the reaction mixture with water at
90 ꢀC overnight. Interestingly in some of the deprotected phos-
phonic acid derivatives the signals for the CHP carbon were not
detected in the 13C NMR; it is believed that this is due to deuterium
exchange in either D2O or CD3OD.
The product 29 was deprotected in two sequences (Scheme 10).
In the first instance N-debenzoylation was effected by treatment in
benzyl alcohol at 90 ꢀC to give 49 in 77% yield,35,45 which was
subsequently treated with TMSBr in acetonitrile at room temper-
ature overnight followed by reaction with water at room temper-
ature for 1 h to reveal the phosphonic acid. The NMR spectra of the
product indicated that while the phosphonate esters and the iso-
propylidene group were efficiently hydrolysed, only partial cleav-
age of the carboxylic ester had taken place. Purification by charcoal
chromatography gave the phosphonate derivatives as the corre-
sponding ammonium salts 50a/50b (Scheme 10). To effect com-
plete deprotection, the mixture was re-exposed to TMSBr followed
by heating with water at 90 ꢀC, which afforded 50b in 23% overall
yield from 29. When TMSBr deprotection was applied to isolated
49, followed by heating in water at 90 ꢀC for 17 h, 50b was isolated
in 77% yield (59% overall from 29).
ammonia, the N-benzoyl group was removed and in addition the
ester was transformed to the corresponding primary amide 51
(Scheme 10). Then, the phosphonate esters were deprotected by
using TMSBr in acetonitrile at room temperature overnight to form
the phosphonate 52 bearing an amide group adjacent to the
phosphonate substituent. This amide derivative can be considered
as a potential diphosphate mimic and therefore is of interest for
biological evaluation for comparison to the analogous carboxylic
acid phosphonate 50b.
Attempted deprotection of the MEM protecting group in
compound 30 using the conditions described by Takaku and co-
workers36 proved particularly intractable. We therefore in-
vestigated other agents such as titanium(IV) chloride46 or iodo-
trimethylsilane47 and an alternative method described by Takaku
and co-workers (concd ammonia/pyridine 9:1 at 50 ꢀC).48 None
of these deprotection conditions proved effective. The NMR
spectra of the products revealed that the MEM group was still
present in each case. While the MEM protecting group is readily
introduced and proved compatible with the OeH insertion con-
ditions, its resistance to cleavage makes it unsuitable for this
sequence.
The benzyl protecting group in compound 31 also proved im-
possible to remove; literature precedent suggests that conventional
deprotection does not work,49 while attempted transfer hydro-
genolysis with excess HCO2NH4, Pd/C, aqueous MeOH for 6 days at
65 ꢀC failed to afford the desired product.
As observed with the adenosine series, the best conditions for
the full deprotection of 32 were found to be using the McKenna
Scheme 10. Deprotection of compounds 29 and 32. aSee Table 6 for conditions and yields.
Table 6
Deprotection reactions of compounds 29 and 32
Entry
Substrate
Deprotection step 1
Partial deprotection (% yield)
Deprotection step 2
Full deprotection (% yield)a
1
2
3
4
29
29
29
30
31
32
BnOH
BnOH
49 (77)
49 (77)
51
d
TMSBrb then H2O
50a/50b
50b (59)
52
TMSBrb then H2O at reflux
TMSBrb then H2O
NH4OH/MeOH
Triphenylmethylfluoroborate
HCO2NH4, Pd/C
TMSBrd then H2O
d
5
d
d
6c
Not isolated
NaOH (1 M)
50b (56)
a
After charcoal chromatography.
TMSBr, CH3CN, rt, 12 h.
Data from Ref. 5.
b
c
d
TMSBr CH2Cl2, reflux, 2 h.
Use of benzyl alcohol as described above to deprotect the N-
procedure with TMSBr in dichloromethane at reflux for 2 h to
cleave the phosphonate esters, followed by basic hydrolysis of the
remaining carboxylate methyl ester and benzoyl groups using
a solution of NaOH (1 M, excess) at room temperature (Scheme 10)
to afford compound 50b.5
benzoyl group is significant as these neutral conditions are com-
patible with the presence of the ester group.35 Alternatively, when
standard conditions for removal of a benzoyl group were employed
involving treatment of the insertion product 29 with methanolic

1902
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
2.3.3. Deprotection
reactions
with
thymidine
derivatives.
4. Experimental
4.1. General
Deprotection of compound 37a using excess of TMSBr in acetoni-
trile at room temperature overnight followed by hydrolysis gave
extensive decomposition of the compound and none of the desired
product was observed. This result is to be compared with the
deprotection of uridine derivative 49 highlighting the lability of 20-
deoxynucleosides compared to nucleosides. As described above for
the uridine derivative all attempts to remove the MEM group in
compounds 36aec proved unsuccessful.
Under atmospheric pressure of hydrogen, both the dibenzyl
and tribenzyl esters 39 and 40 are cleaved in the presence of 10%
w/w of 5% Pd/C. In the case of 39 the carboxylic ester is obviously
unaffected (Scheme 11, Table 7). Due to the easier synthesis of
compound 41 followed by its full deprotection in a one-pot re-
action using first the McKenna procedure, followed by basic hy-
drolysis at room temperature (Scheme 11, Table 7) to afford
compound 55,5 the deprotection of compounds 53 and 54 was not
pursued further.
Proton and 13C NMR were recorded on a Jeol GSX FT (270 MHz)
or a Bruker Avance DPX (300 MHz) spectrometer. Chemical shifts
are expressed in parts per million relative to tetramethylsilane, J
values are reported in hertz. Infrared spectra were recorded on
a Perkin Elmer Paragon 1000 FT-IR spectrometer as thin films or
KBr discs as appropriate. Elemental analyses were performed on
a PerkineElmer 240 elemental analyser. Mass spectra were recor-
ded on a Kratos Profile HV-4 double focussing high resolution mass
spectrometer (E.I.). Thin layer chromatography was performed on
DC-Alufoilen Kieselgel 60F254 0.2 mm plates (Merck) and visualised
under UV light and stained with phosphomolybdic acid/aqueous
sulfuric acid solution. Flash chromatography was performed on
Kieselgel 60 (Merck) 60e200 mesh. All solvents were distilled be-
fore use: hexane from calcium chloride, dichloromethane and ethyl
Scheme 11. Deprotection of compounds 39e41. aSee Table 7 for conditions and yields.
acetate from phosphorous pentoxide. Dry solvents were prepared
by refluxing over a drying agent under an inert atmosphere: THF
was dried over sodium/benzophenone while ether, benzene and
toluene were dried over LiAlH4, and DMF was distilled from calcium
hydride under reduced pressure (ca. 15 mmHg) then stored over
Table 7
Deprotection reactions of compounds 39e41
Entry Substrate Deprotection Partial
Deprotection Full
step 1
deprotection
(% yield)
step 2
deprotection
(% yield)a
ꢀ
1
2
3
30
40
41
H2, Pd/C,
1 bar
H2, Pd/C,
1 bar
53 (quantitative)
d
d
d
4 A molecular sieves.
Rhodium(II) acetate was obtained from Johnson Matthey. Rho-
dium(II) trifluoroacetamide,50 diazophosphonoacetates 6 and 8,25
N3-benzyl-20,30-O-isopropylidene uridine 2940 were synthesised
using the procedures described in the literature. The synthesis and
characterisation of compounds 32, 41, 45, 46 and 55 are described
elsewhere.5
54 (quantitative)
d
TMSBrb then Not isolated
H2O
NaOH (1 M) 55 (57)
a
After charcoal chromatography.
TMSBr, CH2Cl2, reflux, 2 h.
b
4.2. Ethyl dibenzylphosphonoacetate 3
3. Conclusions
Copper(II) triflate (0.34 g, 0.94 mmol) was added to a solution of
dibenzyl phosphite (5.0 g, 19.0 mmol) in CH2Cl2 (100 mL) and the
mixture was stirred for 15 min to give a slightly pinkish solution.
This was degassed by several cycles of evacuate/backfill and im-
mersed in a large water bath at 19 ꢀC, then neat ethyl diazoacetate
(10 mL, 10.85 g, 95.0 mmol) was added dropwise for 30 min by
means of a syringe pump. After the addition, the mixture was
allowed to stir for a further 30 min at room temperature then
concentrated and purified by flash chromatography over alumina
(150 mL activity II/III Al2O3, hexane/EtOAc 4:1 then hexane/EtOAc
1:1). Yield typically 3.30e5.60 g (50e86%). dH (CDCl3) 7.45e7.25 (m,
10H, ArH), 5.15e5.00 (m, 4H, PhCH2), 4.15 (q, J 7, 2H, CH2CH3), 2.99
(d, JPH 21, 2H, PCH2), 1.22 (t, J 7, 3H, CH2CH3); dC 165.6 (JPC 6.3), 135.9
(JPC 6.3), 128.6, 128.5, 128.0, 68.0 (JPC 6.3), 61.7, 34.7 (JPC 135.6), 14.0;
dP 22.1; nmax/cmꢁ1 (thin film) 3065 w, 2980 w (CeH), 1735 s (C]O),
In conclusion, rhodium(II) acetate or rhodium(II) tri-
fluoroacetamide catalysed reactions of the -diazophosphonates
5e8 can be employed to attach the phosphonate moiety bearing
an -carboxylic ester substituent to nucleosides, via an OeH in-
a
a
sertion process. In the case of adenosine, protection of the
base was required to enable the OeH insertion process; however,
with the pyrimidine derivatives, reaction is possible in the pres-
ence of the unprotected uracil base, albeit with competing NeH
insertion at the base. Protection at this site results in exclusive
OeH insertion. When both 30- and 50-hydroxyl groups are avail-
able in thymidine, insertion at each group occurs although in-
sertion at the 50-position is favoured. Deprotection of the
phosphonates using TMSBr was successfully achieved to provide
phosphononucleosides.

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1903
1500 m, 1455 m, 1370 m (CeC), 1270 s (P]O), 998 s (PeO), 737 s,
700 s (CeH); HRMS (ESI) [MþH]þ: calculated for C18H22O5P:
349.1205, found: 349.1190.
product 8 as a viscous yellow oil (1.80 g, 68%). dH (CDCl3) 7.40e723
(m, 15H, ArH), 5.15e5.00 (m, 6H, CH2Ph); dC 162.0, 134.2, 134.1,
127.62, 127.56, 127.4, 127.2, 127.0, 68.1, 66.2; dP 11.8; nmax (thin film)
3034 w, 2957 w (CeH), 2132 m (C]N), 1704 s (C]O), 1498, 1456,
1379 (CeC), 1282 s (P]O), 998 s (PeO), 740 m, 697 m (CeH); HRMS
(ESI) [MþH]þ: calculated for C23H22N2O5P: 437.1266, found:
437.1251,.
4.3. Dibenzylphosphonoacetic acid 11
A solution of LiOH (1.65 g, 68.9 mmol) in water (80 mL) was
added to the ethyl ester 3 (20.0 g, 57.4 mmol) in THF (80 mL). The
resulting mixture was stirred overnight at room temperature then
diluted with ether and 1 M NaOH. The aqueous phase was sepa-
rated, washed with ether and made acidic by dropwise addition of
concd HCl. The acidic solution was extracted with ether, the com-
bined organic phases were dried over MgSO4 and concentrated to
afford the acid 11 as a pale, viscous oil (15.0 g, 82%) with spectro-
scopic characteristics in accordance with the literature.27 dH (CDCl3)
9.88 (1H, br s, CO2H), 7.40e7.25 (10H, m, ArH), 3.02 (2H, d, JPH 22,
PCH2); dC 168.3 (d, J 5.2), 136.0 (d, J 6.3), 129.02, 129.0, 128.5, 69.0 (d,
J 6.3), 34.9 (d, J 136.2); dP 23.5; nmax (thin film) 3035 w, 2945 w
(CeH), 1730 s (C]O), 1498, 1456, 1381 (CeC), 1217 s (P]O), 998 s
(PeO), 737 s, 697 s (CeH).
4.7. N6,N6-Dibenzylformamidine-20,30-O-isopropylidene
adenosine 15
A mixture of freshly distilled dibenzylamine (9.62 g, 48.7 mmol)
and N,N-dimethylformamide dimethyl acetal (1.95 g, 16.2 mmol) in
acetonitrile (15 mL) was heated at reflux temperature for 24 h.
Anhydrous toluene (15 mL) was added and the solution was con-
centrated in vacuo. The crude residue was dissolved in acetonitrile
(15 mL) and added dropwise to a stirring solution of 20,30-O-iso-
propylidene adenosine 12 (2.0 g, 6.5 mmol) in acetonitrile (10 mL).
The reaction mixture was stirred for 24 h at 45 ꢀC then concen-
trated in vacuo. Flash chromatography (hexane/EtOAc 1:1) afforded
15 as a white solid (3.19 g, 94%) with spectroscopic characteristics
in accordance with the literature.31 dH (270 MHz, CDCl3) 9.4 (1H, s,
CH]N), 8.57 (1H, s, H-2), 8.00 (1H, s, H-8), 7.42e7.18 (10H, m, 2Ph),
4.4. Tribenzyl phosphonoacetate 4
The acid 11 (15.0 g, 46.8 mmol) was dissolved in undistilled DMF
(ca. 100 mL) and K2CO3 (7.10 g, 51.40 mmol) was added. Benzyl
bromide (5.40 mL, 7.76 g, 45.40 mmol) was added and the resulting
mixture was stirred at room temperature overnight. The mixture
was diluted with water, acidified by dropwise addition of concd HCl
and extracted three times with Et2O. The combined organic layers
were washed three times with 2 M HCl, once with brine, dried over
MgSO4 and concentrated to afford the product 4 as a viscous oil
(15.4 g, 83.%), which could be used without purification. Spectro-
scopic data were in agreement with the literature.51 dH (CDCl3)
7.45e7.25 (15H, m, ArH), 5.13 (2H, s, CH2Ph), 5.10e4.97 (4H, m,
PhCH2), 3.04 (2H, d, JPH 21, PCH2); dC 165.4 (d, J 6.3), 135.9 (d, J 6.3),
135.1, 128.58, 128.56, 128.50, 128.4, 128.0, 68.0 (d, J 6.3), 67.4, 34.7
(d, J 135.6); dP 21.8;nmax (thin film) 3034 w, 2954 w (CeH), 1738 s
(C]O), 1498, 1456, 1378 (CeC), 1271 s (P]O), 998 s (PeO), 737 s,
697 s (CeH).
5.93 (1H, d, J1 ,2 4.6, H-10), 5.30e5.21 (1H, m, H-20), 5.15e5.08 (1H,
m, H-30), 4.88 (2H, s, CH2Ph), 4.60e4.53 (1H, m, H-40), 4.45 (2H, s,
CH2Ph), 4.05e3.77 (2H, m, 2H-50), 1.64, 1.37 (6H, 2s, 2CH3); dC
(67.8 MHz, CDCl3) 160.4 (C-6), 159.0 (CH]N), 152.0 (C-2), 150.4 (C-
4, C-5), 141.5 (C-8),135.5,135.1,129.1, 128.8, 128.6, 128.4, 127.9,127.6
(CeAr), 113.8 [C(CH3)2], 93.9 (C-10), 86.1 (C-20), 83.1 (C-30), 81.6 (C-
40), 63.2 (C-50), 54.6, 47.8 (2CH2), 27.5, 25.1 (2CH3).
0
0
4.8. N6,N6-Dibenzoyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene adenosine 17
A mixture of N6,N6-dibenzoyl-20,30-O-isopropylidene adeno-
sine30 14 (1.0 g, 19.4 mmol), triethyl diazophosphonoacetate 6
(0.97 g, 38.8 mmol) and rhodium(II) trifluoroacetamide (w1 mol %)
in benzene (15 mL) was heated at 80 ꢀC for 12 h under nitrogen
atmosphere. The solution was concentrated in vacuo and the crude
mixture purified by flash chromatography (EtOAc/hexane 1:1)
affording compound 17 as a clear yellow oil (0.56 g, 39%), which
was an essentially equimolar mixture of diastereoisomers. Found:
C, 56.59; H, 6.13; N, 9.55. C35H40N5O11P requires C, 56.99; H, 5.47; N,
9.49. dH (270 MHz, CDCl3) 8.67, 8.66, 8.64, 8.60 (2H, 4s, H-2, H-8, 2
isomers), 7.86e7.29 (10H, m, 2Ph), 6.30e6.21 (1H, m, H-10),
5.35e5.05 (2H, m, H-20, H-30), 4.55e4.41 (1H, m, H-40), 4.40e3.80
(9H, m, 2CH2OP, CH2ester, CHP, 2H-50), 1.65, 1.39 (6H, 2s, 2CH3),
1.30e1.20 (9H, m, 3CH3); dC (67.8 MHz, CDCl3) 172.1 (2COPh), 166.8,
166.4 (COester), 152.9, 152.7, 152.1 and 151.7 (C-6, C-2, C-4 and C-5),
143.9 (C-8), 134.2, 132.7, 129.4, 128.7 (CeAr), 114.5, 114.3 (C(CH3)2),
91.5, 90.3 (C-10), 84.9, 84.8, 84.7, 84.4 (C-20, C-30), 81.4, 81.2 (C-40),
76.8 (d, JPC 156.6, CHP), 72.2, 72.1 (2d, JPC 11.2, 11.2, C-50), 63.7e63.5
(m, 2CH2OP), 61.9 (CH2ester), 27.2, 25.3 (2CH3), 16.2, 16.3
(2CH3phosphonate), 14.0 (CH3ester); dP (121.5 MHz, CDCl3) þ15.09
(54%), 15.00 (46%); nmax (film)/cmꢁ1: 1750 (C]Oester), 1715 [C]
O(Bz)], 1600, 1238 and 1026 [PO(OEt)2]; m/z (%): 77 (100), 198 (50),
371 (21), 472 (2). When this reaction was repeated with a reaction
time of 24 h an increased yield (45%) was obtained.
4.5. Ethyl dibenzylphosphonodiazoacetate 7
A
solution of ethyl dibenzylphosphonoacetate 3 (1.21 g,
3.47 mmol) in toluene (10 mL) was added dropwise to a cooled
(0 ꢀC) suspension of t-BuOK (0.47 g, 4.17 mmol) in toluene (10 mL).
After 25 min stirring at 0 ꢀC, a solution of 2-naphthalenesulfonyl
azide (0.81 g, 3.47 mmol) in toluene (5 mL) was added, and the
mixture was stirred and allowed to warm to room temperature
overnight. The mixture was filtered and concentrated to afford
a yellow oil, which was further purified by flash chromatography
(hexanes/EtOAc 4:1) to afford the title product 7 as a pale, viscous
oil (0.85 g, 66%). dH (CDCl3) 7.43e7.25 (m, 10H, ArH), 5.22e5.08 (m,
4H, CH2Ph), 4.15 (q, J 7.1, 2H, CH2CH3), 1.22 (t, J 7.1, 3H, CH2CH3); dC
163.2, 135.5, 128.7, 128.6, 128.0, 69.1, 61.7; dP 12.2; nmax (thin film)
3035 w, 2955 w (CeH), 2130 m (C]N), 1704 s (C]O), 1499, 1457,
1381 (CeC), 1280 s (P]O), 998 s (PeO), 740 m, 700 m (CeH); HRMS
(ESI) [MþH]þ: calculated for C18H20N2O5P: 357.1110, found:
357.1095.
4.6. Tribenzyl phosphonodiazoacetate 8
4.9. N6,N6-Dibenzylformamidine-50-O-
[diethyl(ethoxycarbonyl)phosphonomethyl]-20,30-O-
isopropylidene adenosine 18
This was prepared using the same procedure as described above
for ethyl dibenzylphosphonodiazoacetate 7 starting from the tri-
benzyl ester 4 (2.50 g, 6.09 mmol), t-BuOK (0.82 g, 7.31 mmol) and
2-naphthalenesulfonyl azide (1.42 g, 6.09 mmol). Purification by
flash chromatography (hexanes/EtOAc 2:1) afforded the title
A
solution
propylidene adenosine 15 (0.5 g, 0.97 mmol), triethyl diazo-
phosphonoacetate (0.48 g, 1.94 mmol) and rhodium(II)
of
N6,N6-dibenzylformamidine-20,30-O-iso-
6

1904
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
trifluoroacetamide (w1 mol %) in benzene (15 mL) was heated at
reflux temperature for 24 h under nitrogen atmosphere. The solu-
tion was concentrated in vacuo and the crude mixture purified by
flash chromatography (EtOAc/hexane 7:3) affording the insertion
product 18 as a yellow oil (0.39 g, 55%) and an essentially equimolar
mixture of diastereoisomers. Found: 56.95; H, 6.28; N, 11.04.
C36H45N6O9P.H2O requires C, 57.29; H, 6.28; N, 11.13. dH (270 MHz,
CDCl3) 9.43, 9.42 (1H, 2s, CH]N), 8.64, 8.63 (1H, 2s, H-2), 8.34, 8.29
4.11. N3-[Diethyl(ethoxycarbonyl)phosphonomethyl]-20,30-O-
isopropylidene uridine 22
A
solution of 20,30-O-isopropylidene uridine 20 (0.50 g,
1.75 mmol), triethyl diazophosphonoacetate 6 (0.44 g, 1.75 mmol)
and rhodium(II) acetate (w1 mol %) in benzene (10 mL) was heated
at 80 ꢀC overnight under nitrogen atmosphere. The solution was
concentrated in vacuo and flash chromatography (EtOAc) afforded
22 as a colourless oil, which was an essentially equimolar mixture
of diastereoisomers (0.250 g, 27%). Spectroscopic data were iden-
tical to that described above.
(1H, 2s, H-8), 7.46e7.21 (10H, m, 2Ph), 6.25 (1H, d, J1 ,2 3.0, H-10),
5.44e5.34 (1H, m, H-20), 5.24e5.13 (1H, m, H-30), 4.99e4.81 (2H, m,
CH2Ph), 4.60e4.10 (10H, m, H-40, 2CH2OP, CH2ester, CH2Ph, CHP),
4.08e3.77 (2H, m, 2H-50), 1.60, 1.41 (6H, 2s, 2CH3), 1.40e1.18 (9H, m,
3CH3); dC (67.8 MHz, CDCl3) 166.7, 166.5 (COester), 159.6 (C-6),
158.9 (CH]N), 152.6 (C-2), 151.4, 151.2 (C-4, C-5), 140.8 (C-8), 135.6,
135.2, 128.7, 128.5, 128.0, 127.9, 127.8, 127.6 (CeAr), 114.2, 114.0
[C(CH3)2], 90.9, 90.0 (C-10), 85.2, 84.7 (C-20), 84.3, 84.0 (C-30), 81.7,
81.2 (C-40), 76.8, 76.7 (2d, JPC 156.2, 156.2, CHP), 72.0, 71.9 (2d, JPC
11.2, 11.2, C-50), 63.8e63.1 (m, 2CH2OP), 61.7, 61.6 (CH2ester), 54.4,
47.5 (2CH2Ph), 27.1, 25.2 (2CH3), 16.2, 16.1 (2CH3phosphonate), 13.8
(CH3ester); dP (121.5 MHz, CDCl3) þ15.06; nmax (film)/cmꢁ1: 1744
(C]Oester), 1556 (C]N), 1265 (P]O); m/z (%): 43 (100), 91 (69),
197 (41), 285 (4).
0
0
4.12. N3,50-O-[Bis-diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene uridine 23
A
solution of 20,30-O-isopropylidene uridine 20 (0.50 g,
1.80 mmol), triethyl diazophosphonoacetate 6 (1.75 g, 7.5 mmol)
and rhodium(II) acetate (w1 mol %) in benzene (25 mL) was heated
at reflux temperature overnight under nitrogen atmosphere. The
solution was concentrated in vacuo and purification by flash
chromatography (EtOAc) then (EtOAc/MeOH 95:5) afforded 23 as
a yellow oil (0.528 g, 39%), which was an essentially equimolar
mixture of diastereoisomers. Found: C, 46.38; H, 6.31; N, 3.83.
C28H46N2O16P2 requires C, 46.16; H, 6.36; N, 3.83. dH (270 MHz,
CDCl3) 8.29, 8.19, 8.18, 8.13 (1H, 4d, J5,6 7.4, 7.4, 7.4, 7.4, H-6),
6.20e6.11 (1H, m, H-5), 6.10e6.00 (1H, m, H-10), 5.99e5.86 (1H, m,
H-20), 5.00e4.90, 4.89e4.78 (1H, 2m, H-30), 4.77e4.60 (1H, m, H-
40), 4.40e3.70 (16H, m, PCHO, PCHN, 4CH2OP, 2CH2ester, 2H-50),
1.50 (3H, s, CH3), 1.32e1.10 (21H, m, 7CH3); dC (67.8 MHz, CDCl3)
170.5, 170.4 (COester), 167.1, 166.9 (COester), 165.2, 165.1 (C-4),
155.2, 155.1 (C-2), 146.5, 146.3, 146.1 (C-6), 114.6, 114.4 (C(CH3)2),
96.1, 95.7, 95.6, 95.5 (C-5), 94.4, 93.9, 93.3, 92.8 (C-10), 86.4, 86.2,
86.1, 85.9, 85.8, 85.7 (C-20, C-30), 80.9, 80.8, 80.7, 80.6 (C-40), 77.7,
76.4, 75.6, 74.2 (4d, JPC 159.5, JPC 157.6, 157.6, 158.1, 158.1, PCHO),
71.4, 71.3, 70.7, 69.1, 69.0, 68.6 (6d, JPC 159.5, 159.5, 160.2, 160.2, 9.1,
9.1, 12.1, 12.1, PCHN, C-50), 64.3e63.8 (m, 4CH2OP), 63.0, 61.2
(2CH2ester), 27.6, 27.5, 25.8, 25.7 (2CH3), 16.8, 16.6, 16.5
(2CH3phosphonate), 14.6, 14.5, 14.4 (CH3ester); dP (121.5 MHz,
CDCl3) þ15.23 (11%), 15.16 (10%), 15.05 (10%), 15.02 (14%), 14.00
(16%), 13.97 (17%), 13.95 (10%), 13.91 (11%); nmax (film)/cmꢁ1: 1750
(C]Oester), 1670, 1265 (P]O); m/z (%): 228 (100), 286 (83), 514
(60), 571 (8).
4.10. 50-O-[Diethyl(ethoxycarbonyl)phosphonomethyl]-20,30-
O-isopropylidene uridine 21 and N3-[diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene uridine 22
A
solution of 20,30-O-isopropylidene uridine 20 (0.66 g,
2.3 mmol), triethyl diazophosphonoacetate 6 (0.7 g, 2.7 mmol) and
a catalytic amount of rhodium(II) trifluoroacetamide (w1 mol %) in
benzene (10 mL) was heated at 80 ꢀC for 36 h under nitrogen at-
mosphere. The solution was concentrated in vacuo and the crude
mixture purified by flash chromatography (EtOAc/hexane 2:8) to
afford a mixture of 21 and 22 each as a pair of diastereoisomers.
Separation was achieved on preparative TLC plates (ether/EtOAc
4:6) and gave the less polar product 21 (0.106 g, 9%) and the more
polar product 22 (0.305 g, 26%) each as a colourless oil, which was
an essentially equimolar mixture of diastereoisomers. Compound
21: Found: C, 47.61; H, 5.99; N, 5.27. C20H31N2O11P requires C, 47.43;
H, 6.17; N, 5.53. dH (300 MHz, CDCl3) 7.99, 7.89 (1H, 2d, J5,6 8.1, 8.1,
0
0
0
H-6), 6.08, 6.14 (1H, 2d, J1 ,2 3.6, 3.6, H-1 ), 5.82, 5.76 (1H, 2d, J5,6 8.1,
8.1, H-5), 5.08e5.00, 4.95e4.88 (1H, 2m, H-20), 4.79e4.69 (1H, m,
H-30), 4.43e4.09 (7H, m, 2CH2OP, CH2ester, PCHO), 4.01e3.78 (2H,
m, 2H-50), 1.50 (3H, s, CH3), 1.35e1.20 (12H, m, 4CH3); dC (75.4 MHz,
CDCl3) 165.8, 165.1 (COester), 162.4, 162.3 (C-4), 149.2 (C-2), 140.7,
140.5 (C-6), 113.9, 113.8 (C(CH3)2), 102.1, 101.5 (C-5), 90.9, 89.8 (C-
10), 83.6, 83.4, 83.2, 83.1 (C-20, C-30), 79.8, 79.3 (C-40), 76.6, 74.5 (2d,
JPC 158.0, PCHO), 71.3, 71.1 (2d, JPC 9.2, 12.0, C-50), 63.2e62.3 (m,
2CH2OP), 61.1 (CH2ester), 26.3, 24.4 (2CH3), 15.4, 15.3
(2CH3phosphonate), 13.1 (CH3ester); dP (121.5 MHz, CDCl3) þ15.37
(55%), þ15.10 (45%); nmax (film)/cmꢁ1: 3020 (CH), 1716 (C]Oester),
1695, 1265 (P]O); m/z (%): 43 (100), 224 (18).
4.13. N3-Methoxyethoxymethyl-20,30-O-isopropylidene
uridine 26
A
mixture of methoxyethoxymethyl chloride (0.16 mL,
1.4 mmol), KOH (0.08 g, 1.4 mmol), benzyltriethylammonium
chloride (20 mg, 0.09 mmol) and 50-O-benzoyl-20,30-O-iso-
propylidene uridine37 (0.46 g, 1.2 mmol) in CH2Cl2 (20 mL) was
stirred at room temperature for 8 h, then washed with water
(20 mL). The organic layer was dried, concentrated, redissolved in
MeOH (10 mL) and treated with concd ammonia (10 mL). The so-
lution was stirred at room temperature for 8 h, concentrated and
purified by flash chromatography (CH2Cl2/EtOH 95:5) to afford 26
as a colourless oil (0.23 g, 51%). Found: C, 50.87; H, 6.48; N, 7.42.
C16H24N2O8þ0.3H2O requires C, 50.87; H, 6.56; N, 7.42. dH
(300 MHz, CDCl3) 7.55 (1H, d, J5,6 8.1, H-6), 5.75 (1H, d, J5,6 8.1, H-5),
5.74e5.65 (1H, m, H-10), 5.50e5.38 (2H, m, CH2 of MEM), 5.00e4.88
(2H, m, H-20, H-30), 4.35e4.25 (1H, m, H-40), 3.98e3.88, 3.87e3.75
(4H, 2m, 2H-50, CH2 of MEM), 3.58e3.51 (2H, m, CH2 of MEM), 3.35
(3H, s, CH3 of MEM), 1.60, 1.38 (6H, 2s, 2CH3); dC (75.4 MHz, CDCl3)
162.7 (C-4), 151.1 (C-2), 141.1 (C-6), 114.2 (C(CH3)2), 101.9 (C-5), 95.6
(C-10), 86.9 (C-20), 84.3 (C-30), 80.4 (C-40), 71.7, 71.0, 69.9 (3CH2 of
MEM), 62.5 (C-50), 58.9 (CH3 of MEM), 27.2, 25.2 (2CH3); nmax (film)/
Compound 22: Found: C, 47.09; H, 6.31; N, 5.43. C20H31N2O11
P
requires C, 47.43; H, 6.17; N, 5.53. dH (270 MHz, CDCl3) 7.95, 7.87
(1H, 2d, J5,6 8.1, 8.1, H-6), 6.17e6.15, 6.14e6.12, 6.02e5.95 (2H, 3m,
0
H-5, H-10), 5.67, 5.62 (1H, 2d, J2 ,3 2.4, H-20), 5.11e5.07, 5.06e4.96
(2H, 2m, H-30, H-40), 4.38e4.12 (7H, m, 2CH2OP, CH2ester, PCHN),
3.96e3.74 (2H, m, 2H-50), 1.60 (3H, s, CH3), 1.42e1.18 (12H, m,
4CH3); dC (67.8 MHz, CDCl3) 170.4, 170.1 (COester), 164.8, 164.7 (C-
4), 154.9 (C-2), 147.3, 147.0 (C-6), 114.0 [C(CH3)2], 97.7, 97.2 (C-5),
95.5, 95.4 (C-10), 88.0, 87.8 (C-20), 84.2, 84.0 (C-30), 80.4, 80.3 (C-40),
71.1, 69.1 (2d, JPC 160.0, 160.0, PCHN), 64.2e64.1 (m, 2CH2OP), 62.6,
62.5 (CH2ester, C-50), 27.2, 25.2 (2CH3), 16.3 (2CH3phosphonate),
14.0 (CH3ester); dP (121.5 MHz, CDCl3) þ13.82 (56%), þ13.79 (44%);
nmax (film)/cmꢁ1: 3091 (CH), 1751 (C]Oester), 1671, 1265 (P]O),
1218; m/z (%): 43 (95), 224 (100), 464 (20).
0

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1905
cmꢁ1: 1718, 1670; m/z (%): 59 (100), 69 (61), 89 (54), 113 (62), 173
atmosphere. The solution was concentrated in vacuo and purified
by flash chromatography (EtOAc/hexane 2:8) to afford 31 (0.32 g,
42%). Found: C, 50.58; H, 6.47; N, 4.50. C27H35N2O12Pþ2.5H2O re-
quires C, 50.54; H, 6.60; N, 4.37. dH 7.88e7.81 (m, 1H, H-6),
7.48e7.21 (m, 5H, Ph), 6.08e6.00 (dd, 1H, H-10), 5.87e5.82 (m, 1H,
H-5), 5.18e5.00 (m, 2H, CH2Ph), 4.91e4.81 (m, 1H, H-20), 4.78e4.69
(m, 1H, H-30), 4.35e4.10 (m, 8H, 2CH2OP, CH2ester, CHPO, H-40),
4.03e3.74 (m, 2H, 2H-50), 1.59 (s, 3H, CH3), 1.37e1.30 (m, 12H,
4CH3); dC 166.4, 166.2 (COester, two isomers), 162.3, 162.2 (C-4),
150.6, 150.4 (C-2), 139.2, 139.0 (C-6), 136.7, 129.1, 129.1, 128.4, 128.3,
127.6 (CeAr), 113.8, 113.5 (C(CH3)2, two isomers), 102.0, 101.4 (C-5),
93.3, 91.7 (C-10), 84.6e84.4 (C-20 and C-30), 80.8, 80.1 (C-40), 77.0,
72.1 (d, JPC 157.2, PeCH), 71.9e69.7 (m, C-50), 63.8e63.6 (m,
2CH2OP), 62.1 (CH2ester), 43.7 (CH2Ph), 27.8, 24.9 (2CH3), 15.9
(2CH3phosphonate), 13.8 (CH3ester); dP þ15.24 (45%), þ15.04
(55%); nmax (film)/cmꢁ1: 3054e2986, 1746 (COester), 1670, 1265
(PO); m/z (%): 43 (86), 99 (100), 167 (67), 596 (3) [Mþ].
(56), 372 (1, Mþ).
4.14. N3-Benzoyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene uridine 29
A solution of N3-benzoyl-20,30-O-isopropylidene uridine 2535
(0.31 g, 8 mmol), triethyl diazophosphonoacetate
6 (0.40 g,
16 mmol) and rhodium(II) acetate (w1 mol %) in benzene (10 mL)
was heated at reflux temperature overnight under nitrogen atmo-
sphere. The solution was concentrated in vacuo and purification by
flash chromatography (EtOAc) afforded the insertion product 29 as
a colourless oil (0.29 g, 60%), which was an essentially equimolar
mixture of diastereoisomers. Found: C, 52.13; H, 5.92; N, 4.33.
C27H35N2O12Pþ0.5H2O requires C, 52.34; H, 5.86; N, 4.52. dH
(300 MHz, CDCl3) 8.10, 8.00 (1H, 2d, J5,6 8.2, 8.2, H-6), 8.05e7.90,
7.75e7.40 (5H, 2m, HeAr), 6.07, 6.01 (1H, 2d, J5,6 3.6, 3.3, H-10), 5.94,
5.88 (1H, 2d, J5,6 8.2, 8.2, H-5), 5.10e5.00, 4.96e4.88 (1H, 2m, H-20),
4.86e4.75 (1H, m, H-30), 4.50e4.05 (8H, m, 2CH2OP, CH2ester, CHP,
H-40), 4.02e3.72 (2H, m, 2H-50), 1.55 (3H, s, CH3), 1.44e1.16 (12H, m,
4CH3); dC (75.4 MHz, CDCl3) 167.7 (COPh), 165.7, 165.4 (COester),
162.3, 162.2 (C-4), 149.4 (C-2), 141.5, 141.3 (C-6), 135.1, 131.5, 130.5,
129.1 (CeAr), 114.3, 114.0 [C(CH3)2], 103.0, 102.3 (C-5), 92.7, 91.4 (C-
10), 84.9, 84.6, 84.3, 84.2 (C-20, C-30), 81.1, 80.6 (C-40), 76.5, 76.4 (2d,
JPC 157.5,157.0, CHP), 72.3, 72.2 (2d, JPC 9.4,12.1, C-50), 63.8e63.5 (m,
2CH2OP), 62.2 (CH2ester), 27.3, 27.2, 25.4, 25.3 (2CH3), 16.5, 16.4
(2CH3phosphonate), 14.1 (CH3ester); dP (121.5 MHz, CDCl3) þ15.14
(42%), þ15.05 (58%); nmax (film)/cmꢁ1: 1749 (C]Oester), 1709,1673,
1269 (P]O); m/z (%): 77 (66), 105 (100, Phþ), 137 (80), 241 (35), 395
(66), 610 (1, Mþ).
4.17. N3-Methoxyethoxymethyl thymidine 34
A
mixture of methoxyethoxymethyl chloride (0.05 mL,
0.43 mmol), KOH (24 mg, 0.43 mmol), benzyltriethylammonium
chloride (10 mg, 0.05 mmol) and 30,50-O-dibenzoyl thymidine37
(0.16 g, 0.36 mmol) in CH2Cl2 (10 mL) was stirred at room tem-
perature for 8 h then washed with water (20 mL). The organic layer
was dried, concentrated, redissolved in MeOH (10 mL) and treated
with concd ammonia (10 mL). The solution was stirred at room
temperature for 8 h, concentrated in vacuo and purified by flash
chromatography (CH2Cl2/EtOH 20:1) to afford 34 as a colourless oil
(66 mg, 56%). Found: C, 50.12; H, 6.66; N, 8.17.
C14H22N2O7þ0.25H2O requires C, 50.22; H, 6.77; N, 8.37. dH
4.15. N3-Methoxyethoxymethyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene uridine 30
(300 MHz, CDCl3) 7.50 (1H, s, H-6), 6.18 (1H, t, J1 ,2 6.7, H-10),
5.41e5.32 (2H, m, CH2 of MEM), 4.51e4.40 (1H, m, H-30), 3.97e3.90
(1H, m, H-40), 3.82e3.75 (2H, m, 2H-50), 3.74e3.67 (2H, m, CH2 of
MEM), 3.51e3.40 (2H, m, CH2 of MEM), 3.28 (3H, s, CH3 of MEM),
2.40e2.15 (2H, m, 2H-20), 1.83 (3H, 1s, CH3); dC (75.4 MHz, CDCl3)
162.6 (C-4), 150.1 (C-2), 134.5 (C-6), 109.3 (C-5), 86.1 (C-40), 85.4 (C-
10), 70.6 (CH2 of MEM), 70.2 (C-30), 70.0, 68.5 (2CH2 of MEM), 61.0
0
0
A solution of N3-methoxyethoxymethyl-20,30-O-isopropylidene
uridine 26 (0.29 g, 1.09 mmol), triethyl diazophosphonoacetate 6
(0.54 g, 2.18 mmol) and rhodium(II) acetate (w1 mol %) in benzene
(10 mL) was heated at 80 ꢀC overnight under nitrogen atmosphere.
The solution was concentrated in vacuo and flash chromatography
(EtOAc) afforded the insertion product 30 as a yellow oil (0.15 g,
32%), which was an essentially equimolar mixture of di-
(C-50), 57.8 (CH3 of MEM), 39.1 (C-20), 12.2 (CH3) ; nmax (film)/cmꢁ1
:
1706, 1653, 1265, 1092; m/z (%): 73 (69), 99 (56), 117 (100), 139 (46),
214 (21), 330 (1).
astereoisomers. Found: C, 48.62; H, 6.87; N, 4.96. C24H39N2O13
P
requires C, 48.48; H, 6.61; N, 4.71. dH (300 MHz, CDCl3) 7.88, 7.78
(1H, 2d, J5,6 8.1, 8.1, H-6), 6.05e6.00, 5.99e5.92 (1H, 2m, H-10), 5.78,
5.73 (1H, 2d, J5,6 8.1, 8.1, H-5), 5.48e5.32 (2H, m, CH2 of MEM),
5.00e4.91, 4.86e4.77 (1H, 2m, H-20), 4.73e4.62 (1H, m, H-30),
4.40e4.02 (8H, m, 2CH2OP, CH2ester, CHP, H-40), 3.99e3.80,
3.79e3.60 (4H, 2m, 2H-50, CH2 of MEM), 3.50e3.45 (2H, m, CH2 of
MEM), 3.25 (3H, s, CH3 of MEM),1.48 (3H, s, CH3),1.35e1.10 (12H, m,
4CH3); dC (75.4 MHz, CDCl3) 165.7, 165.4 (COester), 161.8, 161.7 (C-
4), 150.2 (C-2), 139.2, 139.2 (C-6), 113.4, 113.1 [C(CH3)2], 101.6, 101.0
(C-5), 91.9, 90.7 (C-10), 83.9, 83.5, 83.4, 83.1 (C-20, C-30), 79.9, 79.4
(C-40), 75.5 (d, JPC 157.2, CHP), 71.3, 71.2 (2d, JPC 9.2, 12.3, C-50), 70.7,
70.0, 68.7 (3CH2 of MEM), 63.2e61.7 (m, 2CH2OP), 61.2 (CH2ester),
57.9 (CH3 of MEM), 26.3, 24.3 (2CH3), 15.5, 15.3 (2CH3phosphonate),
13.1 (CH3ester); dP (121.5 MHz, CDCl3) þ15.20 (45%), þ15.05 (55%);
nmax (film)/cmꢁ1: 1741 (C]Oester),1671,1265 (P]O),1217; m/z (%):
137 (100), 224 (29), 395 (26), 594 (1, Mþ).
4.18. N3-Methoxyethoxymethyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]thymidine 36a and N3-
methoxyethoxymethyl-30-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]thymidine 36b
A solution of N3-methoxyethoxymethyl thymidine 34 (0.263 g,
0.8 mmol), triethyl diazophosphonoacetate 6 (0.44 g, 1.6 mmol)
and rhodium(II) trifluoroacetamide (w1 mol %) in benzene (10 mL)
was heated at reflux temperature overnight under nitrogen atmo-
sphere. The solution was concentrated in vacuo and purified by
flash chromatography (EtOAc) to afford two compounds: the more
polar 50-OH insertion product 36a (98 mg, 22%), and the less polar
30-OH insertion product 36b (72 mg, 16%) each as a colourless oil,
which was an essentially equimolar mixture of diastereoisomers.
Compound 36a: Found: C, 47.70; H, 6.80; N, 4.50. C22H37NO12P re-
quires C, 47.83; H, 6.75; N, 5.07. dH (300 MHz, CDCl3) 7.70, 7.50 (1H,
0
0
0
2s, H-6), 6.35 (1H, t, J1 ,2 7.0, H-1 ), 5.50e5.35 (2H, m, CH2 of MEM),
4.65e4.50 (1H, m, H-30), 4.40e3.80 (10H, m, 2CH2PO, CH2ester,
CHP, H-40, 2H-50), 3.78e3.69 (2H, m, CH2 of MEM), 3.52e3.42 (2H,
m, CH2 of MEM), 3.30 (3H, s, CH3 of MEM), 2.38e2.05 (2H, m, 2H-
20), 2.00 (3H, s, CH3), 1.40e1.10 (9H, m, 3CH3); dC (75.4 MHz, CDCl3)
166.7, 166.5 (COester), 162.3 (C-4), 151.1 (C-2), 135.0, 134.8 (C-6),
110.5, 110.3 (C-5), 84.5, 84.1, 84.0, 83.9 (C-40, C-10), 75.3, 75.1 (2d, JPC
158.8, 158.6, CHP), 71.2, 71.1 (2d, JPC 9.8, 10.9, C-50), 70.7 (CH2O of
4.16. N3-Benzyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]-20,30-O-isopropylidene uridine 31
A
solution of N3-benzyl-20,30-O-isopropylidene uridine 27
(0.47 g, 1.2 mmol), triethyl diazophosphonoacetate (0.62 g,
6
2.4 mmol) and rhodium(II) trifluoroacetamide (w1 mol %) in ben-
zene (10 mL) was heated at 80 ꢀC for 36 h under nitrogen

1906
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
MEM), 70.5, 70.4 (C-30), 70.2, 70.1, 68.6, 68.7 (2CH2 of MEM),
62.9e62.5 (m, 2CH2PO), 61.1 (CH2ester), 57.9 (CH3 of MEM), 39.7,
39.6 (C-20), 15.5, 15.4 (2CH3phosphonate), 13.1 (CH3ester), 11.9, 11.8
(CH3); dP (121.5 MHz, CDCl3) þ15.68 (54%), þ15.29 (46%); nmax
(film)/cmꢁ1: 1747 (C]Oester), 1706, 1215 (P]O); m/z (%): 81 (100),
99 (58), 139 (70), 224 (73), 552 (1). Compound 36b: Found: C, 47.71;
H, 6.72; N, 5.17. C22H37N2O12P requires C, 47.83; H, 6.75; N, 5.07. dH
rhodium(II) acetate (w1 mol %) in benzene (10 mL) was heated at
80 ꢀC overnight under nitrogen atmosphere. The solution was
concentrated in vacuo and subjected to flash chromatography
(EtOAc/MeOH 95:5) to afford a mixture of the intermediate prod-
ucts 35aec, which was then heated at 90 ꢀC in benzyl alcohol
(4 mL) for 12 h. The solvent was evaporated in vacuo and the crude
products were separated by preparative TLC (MeOH/EtOAc 1:9) to
afford compounds 37a (154 mg, 34%, most polar), 37b (31 mg, 7%)
and 37c (140 mg, 21%, least polar) each as a colourless oil, which
was an essentially equimolar mixture of diastereoisomers. Com-
pound 47a: Found: C, 46.05; H, 6.22; N, 5.22. C18H29N2O10Pþ0.2H2O
requires C, 46.19; H, 6.22; N, 5.99. dH (300 MHz, CDCl3) 9.65e9.55
(1H, m, NH), 7.75, 7.55 (1H, s, H-6), 6.42e6.25 (1H, m, H-10),
4.62e4.48 (1H, m, H-30), 4.46e3.95 (9H, m, H-40, CHP, 2CH2OP,
CH2ester), 3.93e3.65 (2H, m, 2H-50), 2.45e2.08 (2H, m, 2H-20), 1.86,
1.85 (3H, 2s, CH3), 1.40e1.07 (9H, m, 3CH3); dC (75.4 MHz, CDCl3)
166.1, 165.6 (COester,), 163.3, 163.2 (C-4), 149.8 (C-2), 135.6, 135.4
(C-6), 110.5, 110.3 (C-5), 84.4, 84.2, 83.9, 83.4 (C-40, C-10), 75.8, 75.5
(2d, JPC 158.6, 157.6, CHP), 71.3, 71.1 (2d, JPC 9.2, 11.5, C-50), 70.7 (C-
30), 62.9e62.5 (m, 2CH2OP), 61.2, 61.1 (CH2ester), 39.3, 39.0 (C-20),
15.4, 15.3 (2CH3phosphonate), 13.1 (CH3ester), 11.2, 11.1 (CH3); dP
0
0
(300 MHz, CDCl3) 7.49, 7.40 (1H, 2s, H-6), 6.13, 6.10 (1H, 2t, J1 ,2 6.3,
6.3, H-10), 5.53e5.41 (2H, s, CH2 of MEM), 4.53e4.07 (9H, m,
2CH2PO, CH2ester, CHP, H-40, H-30), 4.00e3.82 (2H, m, 2H-50),
3.81e3.74 (2H, m, CH2 of MEM), 3.61e3.49 (2H, m, CH2 of MEM),
3.38 (3H, s, CH3 of MEM), 2.56e2.30 (2H, m, 2H-20), 1.95 (3H, s,
CH3), 1.47e1.22 (9H, m, 3CH3); dC (75.4 MHz, CDCl3) 167.2, 166.7
(COester), 163.5, 163.4 (C-4), 150.9 (C-2), 135.7, 135.4 (C-6), 110.4,
110.3 (C-5), 87.6, 87.0 (C-40), 84.9, 84.5 (C-10), 81.0e80.8 (m, C-30),
75.2, 74.6 (2d, JPC 158.0, 158.0, CHP), 71.7, 71.2, 71.1, 69.8, 69.7 (3CH2
of MEM), 64.3e63.7 (m, 2CH2PO), 62.3, 62.2 (CH2ester), 61.8 (C-50),
59.0 (CH3 of MEM), 37.5, 36.8 (C-20), 16.4, 16.3 (2CH3phosphonate),
14.2, 14.1 (CH3ester), 13.2 (CH3); dP (121.5 MHz, CDCl3) þ15.37
(44%), þ14.68 (56%); nmax (film)/cmꢁ1: 1747 (C]Oester), 1709, 1215
(P]O); m/z (%): 81 (100), 99 (71), 139 (82), 241 (86), 552 (1).
(121.5 MHz, CDCl3) þ15.67 (58%), þ15.30 (42%); nmax (film)/cmꢁ1
:
4.19. N3-Methoxyethoxymethyl-50-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]thymidine 36a, N3-methoxyethoxymethyl-
30-O-[diethyl(ethoxycarbonyl)-phosphonomethyl]thymidine
36b and N3-methoxyethoxymethyl-30,50-bis-O-
1749 (C]Oester), 1688, 1264 (PO); m/z (%): 49 (84), 81 (100), 111
(29), 321 (44), 464 (3, Mþ). Compound 37b: Found: C, 46.52; H, 5.92;
N, 6.58. C18H29N2O10P requires C, 46.55; H, 6.29; N, 6.03. dH
(300 MHz, CDCl3) 9.40, 9.35 (1H, 2s, NH), 7.43, 7.37 (1H, s, H-6),
6.15e6.00 (1H, m, H-10), 4.50e4.00 (9H, m, H-30, H-40, CHP, JPH 18.4,
2CH2OP, CH2ester), 3.90e3.72 (2H, m, 2H-50), 2.50e2.18 (2H, m, 2H-
20), 1.80 (3H, s, CH3), 1.35e1.04 (9H, m, 3CH3); dC (75.4 MHz, CDCl3)
166.2, 165.9 (COester), 163.1, 163.0 (C-4), 149.5 (C-2), 136.1, 135.9 (C-
6), 110.0, 109.8 (C-5), 85.9, 85.5 (C-40), 84.1, 83.7 (C-10), 80.4e80.2
(m, C-30), 74.6, 74.3 (2d, JPC 158.6, 159.2, CHP), 63.3e62.8 (m,
2CH2OP), 61.2 (CH2ester), 60.9 (C-50), 36.4, 35.8 (C-20), 15.4, 15.3
(2CH3phosphonate), 13.1 (CH3ester), 11.5, 11.4 (CH3); dP (121.5 MHz,
CDCl3) þ15.34 (47%), þ14.84 (53%); nmax (film)/cmꢁ1:1749 (C]
Oester), 1689, 1266 (PO); m/z (%): 49 (100), 71 (18), 84 (92), 99 (18),
149 (20), 256 (3), 430 (1). Compound 37c: Found: C, 45.61; H, 6.29;
N, 4.37. C26H44N2O15P2 requires C, 45.48; H, 6.46; N, 4.08. dH
(300 MHz, CDCl3) 9.35e9.14 (1H, m, NH), 7.80, 7.76, 7.60, 7.56 (1H, s,
H-6), 6.43e6.25 (1H, m, H-10), 4.52e4.00 (16H, m, H-30, H-40, 2CHP,
4CH2OP, 2CH2ester), 3.98e3.68 (2H, m, 2H-50), 2.48e2.00 (2H, m,
2H-20), 1.90, 1.88 (3H, s, CH3), 1.40e1.10 (18H, m, 6CH3); dC
(75.4 MHz, CDCl3) 166.1, 165.9, 165.6, 165.5 (COester), 163.2, 163.1
(C-4), 149.5 (C-2), 135.3, 134.9 (C-6), 110.6, 110.4 (C-5), 84.0, 83.8,
83.3, 83.1 (C-40), 82.4, 82.3, 82.1, 82.0 (C-10), 82.3, 81.6, 81.5, 80.9
(4d, JPC 9.9, 9.1, 12.6, 12.6, C-30), 76.8e72.9 (16 line m, 2CHP), 71.8,
70.9 (2t, JPC 12.6, 12.6, C-50), 63.1e62.4 (m, 2CH2PO), 61.2, 61.1, 60.9
(2CH2ester), 36.8, 36.5, 36.0, 35.8 (C-20), 15.4, 15.3 (2CH3phospho-
nate), 13.1 (CH3ester), 11.8, 11.7 (CH3); dP (121.5 MHz, CDCl3) þ15.45
(14%), þ15.43 (19%), þ15.28 (13%), þ15.16 (12%), þ15.04 (11%),
þ14.98 (20%), þ14.67 (17%); nmax (film)/cmꢁ1: 1747 (C]Oester),
1688, 1265 (P]O); m/z (%): 43 (100), 91 (98), 167 (45), 196 (84), 300
(66), 386 (13), 647 (4).
[diethyl(ethoxycarbonyl)phosphonomethyl]thymidine 36c
A solution of N3-methoxyethoxymethyl thymidine 34 (0.19 g,
0.58 mmol), triethyl diazophosphonoacetate 6 (0.29 g, 1.15 mmol)
and rhodium(II) acetate (w1 mol %) in benzene (10 mL) was heated
at reflux temperature overnight under nitrogen atmosphere. The
solution was concentrated in vacuo and flash chromatography
(EtOAc) afforded three compounds: the most polar 50-OH insertion
product 36a (68 mg, 21%), the 30-OH insertion product 36b (52 mg,
16%) and the least polar 30,50-bis-OH insertion product 36c (120 mg,
45%) each as a colourless oil and an essentially equimolar mixture
of diastereoisomers. The spectral data for 36a and 36b were iden-
tical to those described above. Compound 36c: Found: C, 46.51; H,
7.00; N, 3.69. C30H52N2O17P2 requires C, 46.51; H, 6.77; N, 3.62. dH
(300 MHz, CDCl3) 7.76, 7.75, 7.57, 7.56 (1H, 4s, H-6), 6.45e6.30 (1H,
m, H-10), 5.50e5.35 (2H, s, CH2 of MEM), 4.52e4.00 (16H, m,
4CH2PO, 2CH2ester, 2CHP, H-40, H-30), 3.95e3.82 (1H, m, 1H-50),
3.81e3.62 (3H, m, 1H-50, CH2 of MEM), 3.58e3.40 (2H, m, CH2 of
MEM), 3.20 (3H, s, CH3 of MEM), 2.50e2.00 (2H, m, 2H-20),1.92,1.88
(3H, 2s, CH3), 1.40e1.20 (18H, m, 6CH3); dC (75.4 MHz, CDCl3) 166.1,
166.0, 165.9, 165.8, 165.6, 165.5 (COester), 162.7, 162.6 (C-4), 150.2,
150.1 (C-2), 134.1, 133.7 (C-6), 109.9, 109.6 (C-5), 84.6, 84.4, 84.0,
83.8 (C-40), 82.6, 82.5, 82.1, 82.0 (C-10), 82.2, 81.5, 81.4, 80.8 (4d, JPC
9.8, 10.9, 12.6, 12.6, C-30), 76.8e72.9 (16 line m, 2CHP), 71.6, 70.9 (2t,
JPC 12.6, 12.6, C-50), 70.7, 70.2, 70.1, 68.6, 68.7 (3CH2 of MEM),
63.2e62.4 (m, 2CH2PO), 61.2, 61.1, 60.0 (2CH2ester), 57.9 (CH3 of
MEM), 36.8, 36.5, 36.0, 35.8 (C-20), 15.4, 15.3 (2CH3phosphonate),
13.1 (CH3ester), 11.8, 11.7 (CH3); dP (121.5 MHz, CDCl3) þ15.47 (13%),
þ15.38 (16%), þ15.26 (11%), þ15.12 (10%), þ14.96 (11%), þ14.89
(10%), þ14.63 (14%), þ14.61 (15%); nmax (film)/cmꢁ1: 1749 (C]
Oester),1709,1669,1266 (P]O); m/z (%): 45 (70), 81 (100),139 (56),
224 (50).
4.21. N3,30-O-Dibenzoyl-50-O-[dibenzyl(ethoxycarbonyl)
phosphonomethyl]thymidine 39
Rhodium acetate (4.9 mg, 11 mmol) was added to a degassed
solution of 38 (250 mg, 0.55 mmol) and the diazo compound 7
(415 mg, 1.1 mmol) in PhMe (20 mL) and the mixture was placed in
a pre-equilibrated bath at 90 ꢀC for 18 h. The volatiles were re-
moved after which flash chromatography (EtOAc/hexane 1:1)
afforded 207 mg (53%) of 39 as a mixture of diastereomers. dH
(CDCl3) 8.03e7.97 (m, 2H, ArH), 7.96e7.85 (m, 2H, ArH), 7.93 (s with
unresolved splitting, 1H, H-6), 7.67e7.53 (m, 2H, ArH), 7.52e7.39
(m, 4H, ArH), 7.37e7.28 (m, 10H, ArH), 6.66e6.48 (m, 1H, H-10),
4.20. 50-O-[Diethyl(ethoxycarbonyl)phosphonomethyl]
thymidine 37a, 30-O-[diethyl(ethoxycarbonyl)
phosphonomethyl]thymidine 37b and 30,50-O-bis
[diethyl(ethoxycarbonyl)phosphonomethyl]thymidine 37c
A solution of N3-benzoylthymidine 3335 (0.338 g, 0.98 mmol),
triethyl diazophosphonoacetate
6
(0.49 g, 1.95 mmol) and

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
1907
5.73e5.68 (m, 0.5H, H-40 one diastereomer), 5.48e5.44 (m, 1H, H-40
one diastereomer), 5.19e5.08 (m, 4H, PhCH2O), 4.58 (d, 0.5H, J 15.6,
PCH one diastereomer), 4.41 (d, 0.5H, J 17.9, PCH one diastereomer),
4.28e4.22 (m, 3H, CH3CH2O, H-30), 4.01e3.77 (m, 2H, 2ꢂH-50),
2.44e2.21 (m, 2H, 2ꢂH-20), 1.98, 1.93 (2ꢂs, 3H, CH3 both di-
astereomers), 1.27 (t, 3H, CH3CH2O); dC 169.0, 169.1, 166.7, 166.4,
166.1, 163.0, 162.9, 149.8, 149.7, 135.6 (d, J 5.8), 135.4 (d, J 6.3), 135.3
(d, J 5.7), 134.9, 133.6, 131.8, 131.7, 130.5, 129.7, 129.3, 129.2, 129.14,
129.12, 128.9, 128.8, 128.78, 128.76, 128.6, 128.5, 128.17, 128.16,
112.2, 111.9, 85.0, 84.5, 83.8, 83.7, 77.0 (d, J 158), 76.6, 76.5 (d, J 158),
76,3, 72.7 (d, J 12.1), 72.3 (d, J 10.9), 69.1 (d, J 6.3), 69.0 (d, J 6.3), 68.9
(d, J 6.3), 68.7 (d, J 6.3), 62.5, 37.4, 37.0, 14.2, 14.1, 12.2, 12.0; dP 17.52,
16.06.
The mixture was stirred at room temperature for 12 h, then con-
centrated in vacuo to afford compound 43, which was characterised
only by NMR spectroscopy. Yield 63 mg, 77%. dH (270 MHz, CDCl3)
8.58, 8.47, 8.2 (3ꢂs, 3H, H-2, H-8, NH), 8.10e7.43 (m, 5H, ArH), 6.20
(m, 1H, H-10), 5.35 (m, 1H, H-20), 5.12 (m, 1H, H-30), 4.55 (m, 1H, H-
40), 4.30e4.00 (m, 5H, 2ꢂCH2PO, CHPO), 3.7 (m, 2H, 2ꢂH-50), 1.63,
1.40 (2ꢂs, 6H, 2ꢂCH3); dC (67.8 MHz, CDCl3) 173.1 (CO2H), 169.5
(COPh), 155.6e143.5 (C-6, C-2, C-4, C-5), 143.3 (C-8), 135.7e130.1
(CAr), 116.9 (C(CH3)2), 93.6e93.1, 88.4e88.1, 87.5 (C-10, C-20, C 40),
87.5e84.8 (d, JPC 158.3, CHP), 75.1e75.0 (m, C-50), 66.1e66.0 (m,
2ꢂCH2OP), 29.1, 27.3 (2ꢂCH3), 18.3, 18.2 (2ꢂCH3).
4.25. 50-O-[Diethyl(ethoxycarbonyl)phosphonomethyl]-20,30-
O-isopropylidene adenosine 44
4.22. N3,30-O-Dibenzoyl-50-O-[dibenzyl(benzyloxycarbonyl)
phosphonomethyl]thymidine 40
Compound 18 (0.17 g, 0.23 mmol) and Pd(OH)2/C (20% Pd, 50%
water, 0.3 g, ca. 1.8 equiv w/w) were placed in 50% aqueous
methanol (10 mL) and stirred under a hydrogen atmosphere
(50 psi) for 5 h. The mixture was filtered, concentrated and puri-
fied by flash chromatography (EtOAc/EtOH 9:1) to afford 44 as
a colourless oil (71 mg, 58%), which was an essentially equimolar
mixture of diastereoisomers. Found: C, 47.60; H, 6.06; N, 13.00.
C21H32N5O9P requires C, 47.64; H, 6.09; N, 13.23. dH (300 MHz,
CDCl3) 8.37, 8.35, 8.34, 8.30 (2H, 4s, H-2, H-8), 6.80e6.55 (2H, m,
NH2), 6.28e6.18 (1H, m, H-10), 5.28e5.16, 5.15e5.02 (2H, 2m, H-20,
H-30), 4.60e4.52, 4.51e4.47 (1H, 2m, H-40), 4.45e4.09 (7H, m, CHP,
2CH2OP, CH2ester), 4.07e3.72 (2H, m, 2H-50), 1.65, 1.40 (6H, 2s,
2CH3), 1.38e1.15 (9H, m, 3CH3); dC (75.4 MHz, CDCl3) 165.9, 165.7
(COester), 154.4 (C-6), 151.9 (C-2), 148.6, 148.4 (C-4, C-5), 136.8 (C-
8), 113.9, 113.2 (C(CH3)2), 90.0, 88.9 (C-10), 84.1, 83.9, 83.7, 83.6 (C-
20, C-30), 80.7, 80.2 (C-40), 75.9, 75.8 (d, JPC 188.0, CHP), 71.3, 71.2
(2d, JPC 10.9, 11.5, C-50), 62.8e61.5 (m, 2CH2OP), 61.1, 61.0
(CH2ester), 26.6, 24.4 (2CH3), 15.4, 15.3 (2CH3phosphonate), 13.1
(CH3ester); dP (121.5 MHz, CDCl3) þ15.15 (66%), þ15.05 (34%); nmax
(film)/cmꢁ1: 1713 (C]Oester), 1223 (P]O); m/z (%): 44 (100), 112
(45), 285 (40).
Rhodium acetate (6 mg, 12.5 mmol) was added to a degassed
mixture of 3-N,30-O-dibenzoyl thymidine 38 (0.40 g, 0.89 mmol),
tribenzyl phosphonodiazoacetate 8 (0.50 g, 1.15 mmol) and acti-
vated molecular sieve beads (a small spoonful, ca. 0.8 g undried
weight) in benzene (10 mL). The mixture was placed in a pre-
equilibrated bath at 85 ꢀC and stirred at this temperature for
48 h. After filtration the volatiles were removed in vacuo and the
residue was purified by flash chromatography (EtOAc/hexane 1:1)
to afford 0.35 g (45%) of colourless, slightly oily foam, shown by 1H
NMR to be a roughly 1.66:1 mixture of diastereomers. dH (CDCl3)
8.05e7.92 (m, 4H, ArH), 7.82 (d, 0.4H, J 1.0, H-6 minor di-
astereomer), 7.66e7.55 (m, 2.6H, H-6 major diastereomer, ArH),
7.52e7.40 (m, 4H, ArH), 7.37e7.20 (m, 15H, ArH), 6.53e4.46 (m, 1H,
H-10), 5.67e5.62 (m, 0.4H, H-40 minor diastereomer), 5.47e5.43 (m,
0.6H, H-40 major diastereomer), 5.32e5.15 (m, 2H, carboxyl
PhCH2O), 5.10e4.95 (m, 4H, phosphonate PhCH2O), 4.45 (d, 0.4H, J
18, PCH minor diastereomer), 4.31 (d, 0.6H, J 19, PCH major di-
astereomer), 4.26e4.22 (m, 1H, H-30), 4.00e3.78 (m, 2H, H-50),
2.39e2.16 (m, 2H, H-20), 1.95 (d, 1.2H, J 1.0, CH3 minor di-
astereomer), 1.85 (d, 1.8H, J 0.9, CH3 major diastereomer).
4.23. 50-O-[Diethyl(amido)phosphonomethyl]-20,30-O-
4.26. N3-[(Carboxyl)phosphonomethyl]uridine 47a
isopropylidene adenosine 42
Trimethylsilyl bromide (0.62 mL, 4.7 mmol) was added via sy-
ringe to a solution of compound 22 (0.250 g, 0.47 mmol) in aceto-
nitrile (10 mL) and the resulting mixture was stirred at room
temperature overnight under a nitrogen atmosphere. Water (1 mL)
was added and the mixture was stirred for a further 1 h then
concentrated in vacuo. The residue was redissolved in water (2 mL)
and the resulting mixture was heated at 90 ꢀC overnight. The vol-
atiles were evaporated to afford 55 mg (31%) of 47a. dH (300 MHz,
D2O) 7.70 (1H, d, J5,6 7.32, H-6), 5.7e5.58 (2H, m, H-10 and H-5),
4.50e3.80 (3H, m, H-20, H-30, H-40), 3.79e3.50 (2H, m, 2H-50); dC
(75.4 MHz, D2O) 173.3 (CO2H), 166.3 (C-4), 151.82 (C-2), 142.1 (C-6),
102.6 (C-5), 89.5 (C-10), 84.4 (C-20), 73.9 (C-30), 69.7 (C-40), 61.1 (C-
50); PCHO not seen in 1H and 13C NMR spectra presumably due to D
exchange; dP (121.5 MHz, D2O) þ14.86.
A solution of concd aqueous ammonia (4 mL) was added to
a stirring solution of compound 17 (0.1 g, 0.13 mmol) in methanol
(4 mL). The mixture was stirred at room temperature for 12 h then
concentrated in vacuo. Flash chromatography (EtOAc) afforded 42
as a yellow oil (22 mg, 37%), which was an essentially equimolar
mixture of diastereoisomers. Found: C, 45.76; H, 6.10; N, 14.98.
C19H29N6O8P requires C, 45.60; H, 5.84; N, 16.79. dH (270 MHz,
CDCl3) 8.25, 8.22, 8.14 and 8.10 (2H, 4 s, H-2, H-8), 7.40e6.60 (4H, m,
2NH2), 6.16e6.11, 6.07e6.01 (1H, 2m, H-10), 5.46e5.37 (1H, m, H-
20), 5.19e5.11, 5.09e5.02 (1H, 2m, H-30), 4.51e4.38 (1H, m, H-40),
4.29e3.81 (7H, m, 2CH2OP, CHP, 2H-50), 1.60, 1.37 (6H, 2s, 2CH3),
1.35e1.25 (6H, m, 2CH3); dC (67.8 MHz, CDCl3) 168.9, 168.8
(CONH2), 156.0, 153.2, 149.4, 149.2 (C-6, C-2, C-4, C-5), 140.0 (C-8),
114.6, 114.5 [C(CH3)2], 90.6 (C-10), 85.5, 84.7 (C-20), 84.0, 83.7 (C-30),
81.3, 81.0 (C-40), 78.0, 77.9 (2d, JPC 156.6, 156.4, CHP), 72.8, 72.7 (2d,
JPC 8.7, 7.4, C-50), 63.8e63.7 (m, 2CH2OP), 27.2, 25.3 (2CH3), 16.3,
16.2 (2CH3phosphonate); dP (121.5 MHz, CDCl3) þ17.3 (56%), þ16.8
(44%); nmax (film)/cmꢁ1: 3334e2936, 1693 (C]Oamide), 1644, 1265
and 1024 [PO(OEt)2]; m/z (%): 43 (100), 306 (4), 368 (2).
When the reaction was heated in water at 90 ꢀC for only 1 h
then a mixture of compounds 47a and N3-[(ethoxycarbonyl)-
phosphonomethyl]uridine 47b (3:1) was obtained as a brown oil.
Signals due to compound 47b: dH (300 MHz, MeOH-d4) 7.45 (1H,
d, J5,6 7.9, H-6), 4.61e4.50 (1H, m, H-20), 4.34e4.12 (3H, m, H-30,
CH2), 1.38e1.25 (CH3); dC (75.4 MHz, MeOH-d4) CO2Et not seen,
166.3 (C-4), 101.7 (C-5), 62.8 (CH2), 14.4 (CH3); PCHO not seen in
1H and 13C NMR spectra presumably due to D exchange; dP
(121.5 MHz, MeOH-d4) þ16.3. HRMS (ESIþ): exact mass calculated
for C11H16N2O11P [MþH]þ 383.0492, found 383.0486; m/z (%): 383
(Mþ1, 56%), 377 (5), 245 (25), 242 (100), 180 (6), 139 (16), 74 (17),
46 (9).
4.24. N6-Benzoyl-50-O-[diethyl(carboxyl)phosphonomethyl]-
20,30-O-isopropylidene adenosine 43
A solution of NaOH (0.2 M, 14 mL, 2.8 mmol) was added to
a solution of compound 17 (0.1 g, 0.13 mmol) in methanol (10 mL).

1908
I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
4.27. N3,50-O-[Bis(carboxyl)phosphonomethyl]uridine 48
4.30. 50-O-[(Carboxyl)phosphonomethyl]uridine 50b
The deprotected compound 48 (47 mg, w33% yield) was pre-
pared from 23 (0.2 g, 0.27 mmol) following the procedure de-
scribed for 47a with trimethylsilyl bromide (0.36 mL, 2.7 mmol)
and was obtained as a brown oil, which was an essentially equi-
molar mixture of diastereoisomers. dH (300 MHz, D2O) 8.12, 7.91
(1H, 2d, J5,6 8.1, 8.1, H-6), 5.88e5.60 (2H, m, H-10, H-50), 4.50e4.35,
4.32e4.18, 4.15e3.95 (5H, 3m, H-20, H-30, H-40, PCHO, PCHN),
3.90e3.40 (2H, m, 2H-50); dC (75.4 MHz, D2O) 173.14, 171.80 (CO2H),
166.6, 166.5 (C-4), 151.98 (C-2), 142.85, 142.47 (C-6), 102.80, 102.53
(C-5), 88.91 (C-10), 83.63, 83.42 (C-20), 77.5, 77.4 (2d, JPC 147.3, 147.3,
PCHO), 74.27, 73.99 (C-30), 71.37 (C-50), 70.31, 70.19 (C-40); dP
(121.5 MHz, D2O) þ15.36, þ12.21. HRMS (ESIþ): exact mass calcu-
lated for C13H19N2O16P2 [MþH]þ 521.0210; found 521.0203; m/z
(%): 521 (Mþ1, <5%), 459 (3), 405 (22), 383 (45), 286 (4), 242 (10),
171 (6), 127 (11), 115 (62), 74 (88), 64 (100), 59 (40).
Compound 49 (0.072 g, 0.15 mmol) was dissolved in anhydrous
acetonitrile (5 mL), cooled to 0 ꢀC and treated dropwise with tri-
methylsilyl bromide (0.07 mL, 0.58 mmol). The resulting mixture
was stirred at room temperature overnight after which water
(1 mL) was added and the mixture was stirred for a further 1 h then
evaporated under reduced pressure. The residue was redissolved in
water (10 mL) and the resulting mixture was heated at 90 ꢀC
overnight then concentrated in vacuo. Compound 50b was purified
using charcoal chromatography as described above to afford the
acid as its ammonium salt (0.044 g, 77%). dH (300 MHz, D2O) 8.15,
8.03 (1H, 2d, J5,6 8.1, 8.1, H-6), 5.91e5.69 (2H, m, H-5, H-10),
4.41e3.81 (3H, m, H-20, H-30, H-40, CHP), 3.80e3.50 (2H, m, 2H-50);
dC (75.4 MHz, D2O) 166.66 (C-4), 152.16 (C-2), 143.20, 142.86 (C-6),
103.02, 102.82 (C-5), 89.32, 89.00 (C-10), 83.74, 83.59 (C-20), 74.11,
74.04 (C-30), 71.13 (C-50), 70.50, 70.33 (C-40); dP (121.5 MHz, D2O)
þ12.89. HRMS (ESIþ): exact mass calculated for C11H16N2O11
P
4.28. 50-O-[Diethyl(ethoxycarbonyl)phosphonomethyl]-20,30-
O-isopropylidene uridine 49
[MþH]þ 383.0492, found 383.0488; m/z (%): 383 (Mþ1, 39%), 377
(5), 153 (5), 143 (38), 102 (41), 74 (42), 42 (100).
Compound 29 (0.29 g, 0.47 mmol) was dissolved in benzyl al-
cohol (1 mL) and heated at 90 ꢀC for 24 h. The solvent was removed
in vacuo and the residue was purified by flash chromatography
(EtOAc/MeOH 95:5) to afford 49 as a colourless oil (0.18 g, 77%),
which was an essentially equimolar mixture of diastereoisomers.
Found: C, 47.61; H, 5.99; N, 5.27. C20H31N2O11P requires C, 47.43; H,
6.17; N, 5.53. dH (300 MHz, CDCl3) 7.99, 7.89 (1H, 2d, J5,6 8.1, 8.1, H-
4.31. 50-[Diethyl(amido)phosphonomethoxy]-20,30-O-
isopropylidene uridine 51
A solution of concd aqueous ammonia (4 mL) was added to
a solution of compound 29 (0.14 g, 0.27 mmol) in methanol (4 mL).
The mixture was stirred at room temperature for 12 h, then con-
centrated in vacuo. Flash chromatography (EtOAc) afforded 51
(57 mg, 44%) as a yellow solid. Found: C, 44.55; H, 5.65; N, 8.21.
C18H28N3O10Pþ0.5H2O requires C, 44.44; H, 6.01; N, 8.64. dH
(300 MHz, CDCl3) 7.40e7.30 (m, 1H, H-6), 6.98, 6.64 (2s, 2H, NH2,
two isomers), 5.68e5.65 (m, 1H, H-5), 5.60e5.50 (m, 1H, H-10),
5.08e4.73 (m, 2H, H-20, H-30), 4.41e3.85 (m, 8H, 2CH2OP, CHPO,
2H-50, H-40), 1.50 (3H, s, CH3), 1.30e1.15 (9H, m, 3CH3); dC
(75.4 MHz, CDCl3) 169.5, 167.8 (CONH2), 162.8 (C-4), 149.9, 149.4 (C-
2), 142.5, 141.7 (C-6), 113.4, 113.2 [C(CH3)2], 102.3, 101.8 (C-5), 95.6,
93.3 (C-10), 86.1, 84.3, 83.3, 83.2 (C-20, C-30), 80.1, 79.4 (C-40), 76.6,
76.4 (2d, JPC 155.9, 157.0, PCH), 72.0, 71.8 (2d, JPC 12.0, 7.5, C-50),
62.8e62.7 (m, 2CH2OP), 26.2, 24.3 (2CH3), 15.4 (2CH3phospho-
nate); dP (121.5 MHz, CDCl3) þ17.45 (47%),þ16.66 (53%); nmax
(CHCl3)/cmꢁ1: 3054e2986 (NH), 1697 (C]Oamide), 1266 (P]O);
m/z (%): 121 (43), 155 (56), 229 (26), 275 (75), 289 (100), 303 (16),
426 (3).
6), 6.08, 6.14 (1H, 2d, J1 ,2 3.6, 3.6, H-10), 5.82, 5.76 (1H, 2d, J5,6 8.1,
8.1, H-5), 5.08e5.00, 4.95e4.88 (1H, 2m, H-20), 4.79e4.69 (1H, m,
H-30), 4.43e4.09 (7H, m, 2CH2OP, CH2ester, PCHO), 4.01e3.78 (2H,
m, 2H-50), 1.50 (3H, s, CH3), 1.35e1.20 (12H, m, 4CH3); dC (75.4 MHz,
CDCl3) 165.8, 165.1 (COester), 162.4, 162.3 (C-4), 149.2 (C-2), 140.7,
140.5 (C-6), 113.9, 113.8 (C(CH3)2), 102.1, 101.5 (C-5), 90.9, 89.8 (C-
10), 83.6, 83.4, 83.2, 83.1 (C-20, C-30), 79.8, 79.3 (C-40), 75.5 (d, JPC
158.0, PCHO), 71.3, 71.1 (2d, JPC 9.2, 12.0, C-50), 63.2e62.3 (m,
2CH2OP), 61.1 (CH2ester), 26.3, 24.4 (2CH3), 15.4, 15.3
(2CH3phosphonate), 13.1 (CH3ester); dP (121.5 MHz, CDCl3) þ15.37
(55%), þ15.10 (45%); nmax (film)/cmꢁ1: 3020 (CH), 1716 (C]Oester),
1695, 1265 (P]O); m/z (%): 43 (100), 224 (18).
0
0
4.29. 50-O-[(Ethoxycarbonyl)phosphonomethyl]uridine 50a
and 50-O-[(carboxyl)phosphonomethyl]uridine 50b
Trimethylsilyl bromide (0.39 mL, 2.96 mmol) was added via
syringe to a solution of compound 49 (0.15 g, 0.296 mmol) in ace-
tonitrile (10 mL) and the resulting mixture was stirred overnight at
room temperature under a nitrogen atmosphere. Water (1 mL) was
introduced and the mixture was stirred for 1 h then concentrated in
vacuo. The residue was purified by ‘dry flash’ charcoal chroma-
tography using activated carbon Darco G-60, 100 Mesh (charcoal:
sample w20:1, 3 g). The column was pre-eluted with ethanol
(30 mL) then water (30 mL) and the sample was applied to the
column using water (2 mL). The column was eluted with water
(30 mL) to remove inorganic impurities, with 10% aqueous am-
monia (30 mL) and then with 25% aqueous ammonia (20 mL) to
afford a mixture of 50a and 50b (4:1) (0.11 g, w87% yield). Com-
pound 50a: dH (300 MHz, D2O) 8.31, 8.08 (1H, 2d, J5,6 8.1, 8.1, H-6),
5.98e5.80 (2H, m, H-5, H-10), 4.45e4.10 (6H, m, H-20, H-30, H-40,
CH2ester, CHP), 3.90e3.62 (2H, m, 2H-50), 1.31e1.12 (3H, m, CH3); dC
(75.4 MHz, D2O) 170.7, 170.6 (COester), 165.5, 165.4 (C-4), 150.9 (C-
2), 142.8, 141.6 (C-6), 101.8, 101.5 (C-5), 87.8, 87.7 (C-10), 82.6, 82.5
(C-20), 78.1, 78.2 (2d, JPC 140.8, 140.2, CHP), 73.1, 72.7 (C-30), 70.2,
70.1 (2d, JPC 11.5, 11.5, C-50), 69.4, 69.3 (C-40), 61.5 (CH2ester), 12.5
(CH3ester); dP (121.5 MHz, D2O) þ9.08. Signals attributed to the acid
50b (w20%) were seen at dH 8.20, 8.10 and dC 72.9, 72.8.
4.32. 50-O-[(Amido)phosphonomethyl]uridine 52
Trimethylsilyl bromide (0.32 mL, 2.4 mmol) was added via sy-
ringe to a solution of compound 51 (0.153 g, 0.32 mmol) in aceto-
nitrile (10 mL). The reaction mixture was stirred at room
temperature overnight after which water (1 mL) was added and the
mixture was stirred for 1 h then concentrated in vacuo. The residue
was purified by charcoal chromatography as described above to
give 52 (91 mg, 72% yield) as a yellow solid, which was an essen-
tially equimolar mixture of diastereoisomers. dH (300 MHz, D2O)
7.75e7.30 (1H, m, H-6), 5.85e5.68 (2H, m, H-5, H-10), 4.35e4.00
(3H, m, H-20, H-30, H-40), 3.92e3.55 (3H, m, CHP, 2d, JPH 16.4, 16.7,
2H-50); dC (300 MHz, D2O) 175.4, 175.2 (COamide), 166.6, 166.5 (C-
4),152.0 (C-2), 142.8, 142.7 (C-6), 102.9, 102.8 (C-5), 89.7, 89.4 (C-10),
83.1 (C-20), 81.9, 81.7 (2d, JPC 136.7, 137.2, CHP), 73.8, 73.7 (C-30),
71.7, 71.3 (2d, JPC 10.9, 9.9, C-50), 70.1, 69.9 (C-40); dP (121.5 MHz,
D2O) þ10.18 (50%), þ9.94 (50%).
Acknowledgements
Financial support for this research from the EU Human Capital
and Mobility Programme (V.C.), University College Cork’s

I. Hladezuk et al. / Tetrahedron 68 (2012) 1894e1909
13. Paquet, F.; Sinay, P. Tetrahedron Lett. 1984, 25, 3071.
1909
President’s Research Fund (S.P.) Tanaud Ireland (I.H., S.G.C., A.F.),
and Science Foundation Ireland (Grant numbers 05/PICA/B802, 05/
PICA/B802 TIDA 09; A.R.M., S.D.) is gratefully acknowledged. A loan
of rhodium acetate from Johnson Matthey is gratefully
acknowledged.
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