Highly selective O-phosphitylation of amino alcohols using P IIIreagents containing 4-nitro and 2,4-dinitro aryloxy leaving groups

Article abstract of DOI:10.1039/b509150k

A method for direct highly O-selective phosphitylation of amino alcohols by reagents containing a 4-nitrophenoxy or 2,4 dinitrophenoxy leaving group has been developed. This method provides mild reaction conditions to access O-phosphitylated amino alcohol

Full text of DOI:10.1039/b509150k

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L E T T E R
Highly selective O-phosphitylation of amino alcohols using
PIIIreagents containing 4-nitro and 2,4-dinitro aryloxy leaving
groupsw
Wojciech Dabkowski,* Alfred Ozarek and Izabela Tworowskaz
´ ´
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90–363 %odz,
112 Sienkiewicza, Poland. E-mail: wdabkow@bilbo.cbmm.lodz.pl; Fax: 0-48-426847126;
Tel: 0-48-42-6843120
Received (in Montpellier, France) 29th June 2005, Accepted 12th September 2005
First published as an Advance Article on the web 23rd September 2005
A method for direct highly O-selective phosphitylation of amino
alcohols by reagents containing a 4-nitrophenoxy or 2,4 dini-
trophenoxy leaving group has been developed. This method pro-
vides mild reaction conditions to access O-phosphitylated
amino alcohols. The flexibility of the synthesis is exemplified
by the models of simple amino alcohols and of nucleosides
containing unprotected NH2 groups.
midite 3 was prepared in over 95% yield by the phosphitylation
of the 50-O-(tert-butyldimethylsilyl)deoxyadenosine 2 using
reagent 1 in the presence of equimolar amount of DBU
(Scheme 1, reaction a).
The phosphoramidite 3 was obtained as a 1 : 1 mixture of
diastereoisomers as estimated from 31P NMR spectroscopy
(dP: 147.6 ppm, 146.9 ppm) but no signals due to N-phosphi-
tylated products (dP: 123–127 ppm)4 were detected. Addition-
ally the structure of 3 was confirmed by its transformation into
fluorophosphoramidite 4 [dP: 156.0 ppm (d, JPF 1114.9 Hz) and
Trivalent phosphorus compounds PIII are not found in
nature. However they play a dominant role in the synthesis
of other classes of phosphorus compounds due to their high
reactivity.1 Phosphoramidites are at present the most popular
phosphitylating reagents. They are easily handled because of
their relative stability and, once suitably activated, the amino
group attached to the phosphorus center becomes a good
155.8 ppm (d, JPF 1114.5 Hz), (1 : 1); dF: ꢀ76.4 ppm (d, JPF
:
1116.9 Hz) and ꢀ77.0 ppm (d, JPF 1115.6 Hz.)] by tetra-n-butyl
ammonium fluoride (TBAF) in almost quantitative yield
(Scheme 1, reaction b). The replacement of the 4-nitrophenoxy
group by fluorine, as demonstrated in our previous studies,
proceeds very efficiently giving a convenient access to PIII–F
systems.2d The lack of affinity of the reagent 1 for the amino
group of the fully O-protected nucleoside 30,50-O,O-di(tert-
butyldimethylsilyl)-20-deoxyadenosine 5 was demonstrated in
the blank experiment. Compounds 1 and 5 were allowed to
interact for 16 h in acetonitrile solution at ambient temperature
and no sign of N-phosphitylation pathway leading to the
compound 6 was observed (Scheme 2).
leaving group. Over the past years we have employed PIII
OAryl compounds as a novel class of phosphitylating reagents
in the synthesis of biophosphates and their analogues.2 The PIII
–
–
OAr compounds are stable, and often crystalline phosphitylat-
ing reagents. P(III) compounds containing 2,4-dinitrophenoxy
living groups react with alcohols without additional activation.
In contrast, coupling of phosphite esters containing 4-nitro-
phenoxy living groups with alcohols requires intervention of
strong bases such as DBU or sodium hydride.
In this paper we report that both types of reagents are
O-selective toward systems containing free HO and NH2
groups. Significant pieces of information about selective O-
phosphitylation and O-phosphorylation are included in several
excellent papers. Most of them deal with tetracoordinate
phosphorus compounds and nucleotide chemistry.3 The bis
(O-4-nitrophenyl)-N,N-diisopropylphosphoramidite 1 is a ty-
pical reagent of this class in which the 4-nitrophenoxy group
can be replaced by O-nucleophiles without affecting the amido
function. The base of choice, to ensure its O-selectivity, is 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU). In the presence of other
bases like sodium hydride a considerable proportion of N-
phosphitylation products was observed.
The following scheme illustrates O-selective phosphitylation
procedures of O-(50-O-(tert-butyldimethylsilyl)deoxyadenosine
by the bis (O-4-nitrophenyl)-N,N-diisopropylphosphoramidite
1. In this way O-(4-nitrophenyl)-N,N-diisopropylphosphora-
w Electronic Supplementary Information (ESI) available. Experimental
conditions and characterisation of all presented compounds. See DOI:
10.1039/b509150k
z Permanent address: Department of Biochemistry and Cell Biology,
Rice University, MS-140, 6100 Main Street, Houston, Texas 77251–
1892, USA.
Scheme 1 Synthesis of O-[50-O-(tert-butyldimethylsilyl)deoxyadeno-
sidin-30-yl] N,N-diisopropylfluorophosphoramidite.4 Reagents and con-
ditions: (a) 1 eq DBU CH3CN, 16 h; (b) 1 eq TBAF, THF, 10 min, rt.
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
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Scheme 4 Synthesis of O-(50-O-(tert-butyldimethylsilyl)deoxyadeno-
sidin-30-yl) O-(30-O-acetylthymidin-50-yl)-N,N-diisopropylphosphora-
midite. Reagents and conditions: 1 eq DBU, CH3CN, 10 h, rt.
Scheme 2 Reagents and conditions: 1 eq DBU, CH3CN, 16 h, rt.
The phosphitylating reagent 1 allowed selective O-phosphi-
tylation of 9-(2-hydroxyethoxymethyl)guanine (acyclovir, Zo-
virax s) 7 in excellent yield without any formation of N- or O-
phosphitylated product on the guanine moiety (Scheme 3).
The 31P NMR spectra data for O-(9-[(2-hydroxyethyloxy)-
methyl]guanin-40-yl) O-(4-nitrophenyl) N,N-diisopropylpho-
sphoramidite 8 [dP: 145.0 ppm] are consistent with those
observed by us for the O-{N2-(4-methoxytrityl-9-[(2-hydro-
xyethoxy)methyl]guanin-40-yl}O-(4-nitrophenyl) N,N-diisopro-
pylphosphoramidite5 and the nucleotide analogues containing
the protected NH2 group.
The aryloxyphosphoramidite 8 obtained in excellent yield is
an example of a useful ambident phosphitylating reagent which
can react with a variety of nucleophiles in a chemoselective
manner by the replacement of either the 4-nitrophenoxy group
or the diisopropylamino group to give compounds of potential
interest as antivirus agents.6
amount of DBU was monitored at room temperature by 31P
NMR spectroscopy. Generation of the cationic P(III) species 11
is observed in the region expected for the tricoordinate
phosphorus compounds values: d: 127.39 ppm 128.11 ppm
(Scheme 5).
Involvement of DBU in the phosphitylation procedure is
supported by the fact that when 30-O-acetylthymidine 9 is
added the complex 11 disappears forming the corresponding
dinucleotide 10. The ability of the tricoordinate phosphorus
species to form complexes with DBU has recently been de-
scribed by Bertrand et al.7 and also recently observed by us in
the case of tricoordinate systems containing an aryl ligand.8
Having defined the methodology of O-phosphitylation via
reagents containing the 4-nitrophenoxy group we turned our
attention to their analogues bearing the 2,4-dinitrophenoxy
group. Recently it was demonstrated in this laboratory that the
latter class of compounds phosphitylates alcohols without any
need for activation.9 This approach has been successfully
applied to the preparation of cyclic phosphate triesters.10 The
phosphite 12 is readily formed in almost quantitative yield
from the phosphoramidite 3 by the reaction with one equiva-
lent of 2,4-dinitrophenol.11 Because of its low stability the
phosphite 12 was used in situ to phosphitylate the nucleoside 9
to give the final phosphate 13 in over 95% yield with-
out attacking the NH2 group attached to the adenine ring
(Scheme 6).
Another example of O-phosphitylation not interfering with
the NH2 group attached to the adenine ring is the highly
efficient synthesis of O-(50-O-(tert-butyldimethylsilyl)deoxy-
adenosidin-30-yl) O-(30-O-acetylthymidin-50-yl)-N,N-diisopro-
pylphosphoramidite 10 (Scheme 4). The latter dinucleotide 10
was prepared in 98% yield by coupling of compound 3 with 30-
O-acetylthymidine 9 in acetonitrile solution in the presence of
an equimolar amount of DBU (Scheme 4). The structure of 10
and the purity of the crude material were confirmed by the 31
P
NMR spectrum, which shows two prominent signals at 149.2
ppm and 148.8 ppm supporting the presence of the diaster-
eomeric phosphotriester functions, but no detectable signals
due to N-phosphitylated products (dP: 123–127 ppm)3f.
Examples of the O-phosphitylating ability of simple
PIII-compound 14 containing a 2,4-dinitrophenoxy leaving
group is given in Scheme 7.
The question is: what is the origin of the observed O-selective
phosphitylation in the presence of DBU? The same reaction
carried out in the presence of sodium hydride or triethylamine
led to a mixture of O- and N-phosphitylated products. This
could indicate that DBU acts in this case not only as base but
also as nucleophilic activator by formation of the intermediate
species 11. The reaction of compound 3 with an equimolar
Both reactions b and c (Scheme 7) proceeded very fast at
room temperature in THF or acetonitrile solution yielding the
O-phosphitylated product: 3-[(5,5-dimethyl-1,3,2-dioxaphos-
phorinan-2-yl)oxy]-propylamine 15 (dP: 122.0 ppm) or
Scheme 3 Preparation of O-{9-[(2-hydroxyethyloxy)methyl]guanin-
40-yl} O-(4-nitrophenyl) N,N-diisopropylphosphoramidite. Reagents
and conditions: 1 eq. DBU, CH3CN, 2 h, rt.
Scheme 5 Formation of the intermediate species 11 between O-[50-O-
(tert-butyldimethylsilyl)deoxyadenosidin-30-yl] O-(4-nitrophenyl)-N,N-
diisopropylphosphoramidite 3 and DBU.
N e w J . C h e m . , 2 0 0 5 , 2 9 , 1 3 9 6 – 1 3 9 9
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tylated derivative. Some N-phosphitylated product (dP: 137.5
ppm, 1% yield as determined by 31P NMR) was observed in the
synthesis of 16.13
Smooth formation of PIII-O-2,4-dinitrophenoxy structures
from the corresponding phosphoramidites is a principal ele-
ment of the catalytic action of 2,4-dinitrophenol described by
us in earlier study.9 Most recently this catalyst was used in the
O-selective phosphitylations leading to oligonucleotides.14
In summary we have uncovered a mild and efficient method
for selective O-phosphitylation of amino alcohols. This method
is applicable for a wide range of amino alcohols. The full scope
and reaction mechanism will be reported in due course.
Experimental
General
The solvents were reagent grade and were distilled and dried by
conventional methods before use. The products were purified
by flash chromatography on silica gel 60 (Merck 0.063 mm, 230
–400 mesh ASTM). NMR spectra were obtained on a Bruker
AC 200 and MSL 300 MHz spectrometers. d-Values are
1
reported in ppm relative to Me4Si as standard for H NMR
(200.13 and 300.13 MHz), relative to H3PO4 as external
standard for 31P NMR (80.96 and 121.49 MHz), and relative
to CFCl3 as external standard for 19F NMR (188.15 MHz).
The signals are expressed as s (singlet), d (doublet), t (triplet) or
m (multiplet). Coupling constants (J) are in Hz.
General syntheses
A solution of the appropriate amino alcohol (10 mmol) and
DBU (10 mmol) in dry CH3CN was added at room tempera-
ture under N2 atmosphere to a solution of corresponding
O-arylphosphite (10 mmol) in dry CH3CN. The progress of
the reaction was monitored by 31P NMR and TLC. When the
reaction was complete the reaction mixture was evaporated in
vacuo. The residue was purified by flash chromatography
or distillation.
Scheme 6 Synthesis of O-(50-O-(tert-butyldimethylsilyl)deoxyadeno-
sidin-30-yl) O-(30-O-acetylthymidin-50-yl) O-(4-nitrophenyl)phosphite
13 using 2,4-dinitrophenyl as the activator. Reagents and conditions: (a)
2,4-dinitrophenol, CH3CN, (b) CH3CN, 1 h, rt.
Acknowledgements
We are indebted to Professor J. Michalski for his interest in
this work. The authors’ work was supported by the Polish
State Committee of Scientific Research.
2-[(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)oxy]propylamine
16 (dP: 122.6 ppm) in very good yield. A similar chemical shift
was observed for O-phosphitylated derivatives of 5,5-dimethyl-
1,3,2-dioxaphosphorinane.12 The reactions b and c (Scheme 7)
were monitored by 31P NMR. In the case of the reaction b, the
spectrum showed a signal at 122.0 ppm supporting the presence
of the O-phosphitylated product, but no detectable signal
around dP: 140 ppm, which could be assigned to an N-phosphi-
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6
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