Reaction of Boranephosphonate Diesters with Amines in the Presence of Iodine: The Case for the Intermediacy of H-Phosphonate Derivatives

Article abstract of DOI:10.1021/acs.joc.8b00419

Mechanistic and stereochemical aspects of the reaction of boranephosphonate diesters with amines promoted by iodine were investigated. This is a complex, multistep reaction that ultimately produces the corresponding phosphoramidate diesters via a formal replacement of the borane group by an amine moiety. We found by a stereochemical correlation analysis that, contrary to a literature report, the whole transformation proceeded with total inversion of the configuration at the phosphorus center. Our study also showed that instead of the postulated nucleophilic substitution by iodide at the phosphorus center of the initially formed intermediate, the corresponding iodoboranephosphonate, the crucial step of the reaction involved intermediacy of H-phosphonate derivatives that reacted with iodine to afford ultimately phosphoramidate diesters. The reaction of the iodoboranephosphonate with the amine to produce an aminoboranephosphonate diester that rapidly dissociated into the corresponding H-phosphonate and the borane parts was apparently instrumental to the formation of an H-phosphonate diester intermediate.

Full text of DOI:10.1021/acs.joc.8b00419

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Reaction of boranephosphonate diesters with amines in the presence
of iodine: the case for the intermediacy of H-phosphonate derivatives
Justyna Go##biewska, Marta Rachwalak, Tomasz Jakubowski, Joanna Romanowska, and Jacek Stawinski
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00419 • Publication Date (Web): 23 Apr 2018
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Reaction of boranephosphonate diesters with amines in the presence of iodine:
the case for the intermediacy of H-phosphonate derivatives
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Justyna Gołębiewska, Marta Rachwalak, Tomasz Jakubowski,
Joanna Romanowska,* and Jacek Stawinski*
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14,
61ꢀ704 Poznań, Poland
Corresponding authors:
Jacek Stawinski: tel. (+) 48 61 852 85 02 ext. 181, fax (+) 48 61 852 05 32, eꢀmail
js@organ.su.se and jstaw@ibch.poznan.pl
Joanna Romanowska: tel. (+) 48 61 852 85 02 ext. 191, fax (+) 48 61 852 05 32, eꢀ
mail joarom@ibch.poznan.pl
Key words: boranephosphonates; boranophosphates; oxidation with iodine;
mechanism; stereochemistry; phosphoramidates; nucleotide analogues
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Abstract: Mechanistic and stereochemical aspects of the reaction of
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boranephosphonate diesters with amines promoted by iodine were investigated. This
is a complex, multistep reaction that ultimately produces the corresponding
phosphoramidate diesters via a formal replacement of the borane group by an amine
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moiety. We found by a stereochemical correlation analysis that contrary to a literature
report, the whole transformation proceeded with total inversion of configuration at the
phosphorus center. Our study also showed that instead of the postulated nucleophilic
substitution by iodide at the phosphorus centre of the initially formed intermediate,
the corresponding iodoboranephosphonate, the crucial step of the reaction involved
intermediacy of Hꢀphosphonate derivatives that reacted with iodine to afford
ultimately phosphoramidate diesters. The reaction of the iodoboranephosphonate with
the amine to produce an aminoboranephosphonate diester that rapidly dissociated into
the corresponding Hꢀphosphonate and the borane parts was apparently instrumental to
the formation of an Hꢀphosphonate diester intermediate.
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INTRODUCTION
Boranephosphonates1 are analogues of natural phosphate esters in which the ꢀBH3
group replaces one of the nonꢀbridging oxygen atoms.2 The borane group (ꢀBH3) is
isoelectronic with oxygen in phosphate esters, and also with sulfur and the methyl
group present in other phosphate analogues, e.g., phosphorothioates and
methylphosphonates, respectively.3 Despite high similarities (e.g., a tetrahedral
structure, the presence of a negative charge), there are significant differences between
boranephosphonates compared to phosphate diesters.4 The phosphorusꢀboron bond in
boranephosphonate diesters is a dative bond5 formed via transfer of a lone electron
pair from a phosphite diester to an electron deficient borane. This is reflected in
formula A in Fig. 1 with a formal negative charge placed on the boron atom. However,
since boron is less electronegative than oxygen, the negative charge resides mainly on
the phosphoryl oxygen atom as shown in a mesomeric form B. Moreover, in A and B
the formal negative charge on the boron atom is assumed to be spread on the
hydrogens as partial charges. Such charge distribution was supported by Xꢀray
analysis, and this bonding pattern is somewhat similar to that of phosphonium salts.4,6
Alternatively, boranephosphonates can be presented as complex anions, analogously
to [BH4]ꢀ, without assignment of a negative charge to the specific ligands (formula C).
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Fig. 1. Various structural formulas for boranephosphonate diesters.
The above makes clear that due to significant bonding differences compared to
phosphodiesters, incorporation of boranephosphonates into DNA or RNA can impart
new properties to these biomolecules, e.g., chirality at the phosphorus centers,
different bonds length, and disparate charge distribution in internucleotidic bonds.
Indeed, it was found that the presence of the PꢀBH3 group in oligonucleotides
modulates their nuclease resistance, interaction with proteins, lipophilicity, hydrolytic
stability, and secures generally low toxicity of the boron analogues.3,7 These features
constituted the basis for the development in the last two decades of
boranephosphonateꢀmodified nucleic acids as potential antisense/antigene and siRNA
gene silencing agents.2ꢀ3,8 Nucleoside boranephosphonates as phosphate analogues
were introduced by Shaw, Spielvogel and Sood in the early 1990s,9 and then further
developed by Shaw,10 Wada,6a,11 Caruthers,12 and others.4,7f,13
Recently, Caruthers et al.14 expanded the scope of possible applications of
boranephosphonates by developing the PꢀBH3 group as a potential postꢀsynthetic
modification for nucleic acids. In this concept, the borane group serves as a stable
chemical marker that can be targeted and labilized by a selective reagent to replace
the ꢀBH3 group with another functionality,14a or to introduce a modification at the
boron atom itself.14b The added value of such an approach is that due to chirality at
the phosphorus center of boranephosphonates, one can in principle obtain nucleic acid
mimics with stereochemically defined chiral internucleotide linkages.
The underlying chemistry for targeting and the replacement of the borane group by
nucleophiles developed by Caruthers et al.14 is shown in Scheme 1 and consists of an
oxidative conversion of boranephosphonates to stereochemically defined phosphate
diester derivatives, e.g., phosphoramidates, phosphotriesters, phosphorothiolates and
Cꢀphosphonates. This transformation, which bears high potential for postꢀsynthetic
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modification of oligonucleotides, was claimed to proceed with an overall retention of
configuration at the phosphorus center and to involve as a crucial step a nucleophilic
attack of iodide on the activated boranephosphonate intermediate 2 (Scheme 1).
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I
Nu
O
O
O
R1O P OR2
B
O
inversion
inversion
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R1O P OR2
R1O P OR2
R1O P OR2
B
I
Nu
H
I
H
H
H
H
total: retention of
configuration at P
I
I
3
1
2
Reaction conditions for amines:
Conclusions:
An overall retention of configuration at the phosphorus
center. The key stereochemical step: oxidative
nucleophilic substitution in 2.
3 equiv. of iodine, 10 equiv. of an
amine, acetonitrile, RT, overnight.
R1 and R2 = nucleoside moieties; Nu = nucleophile, e.g. amine, alkoxide, carbanion, etc.
Scheme 1. A mechanism for the formal replacement of the ꢀBH3 group by a
nucleophile in boranephosphonate diesters promoted by iodine postulated
by Caruthers et al.14a
Our interest in the development of synthetic methods based on Hꢀphosphonate
chemistry for the preparation of biologically important phosphorus compounds and
their analogues,15 and some unusual features of the above reaction prompted us to
take a closer look at the proposed mechanism. By analysing the reaction steps we
found a possibly fundamental flaw in the mechanism that might affect the predicted
stereochemistry of the reaction and also has a bearing for a general type of reactivity
postulated for boranephosphonate derivatives. Taking into account the potential
importance of this type of reaction in oligonucleotide chemistry and the claimed
significance of the proposed oxidative nucleophilic substitution step at the
boranephosphorus center to boron chemistry, we undertook these studies to clarify
some chemical and stereochemical aspects of the above reaction. As model
compounds for our studies we chose boranephosphonate diesters 1a and 1b, and nꢀ
butylamine as a nucleophile.
RESULTS AND DISCUSSION
Oxidation of a hydride in boranephosphonates 1 by iodine to produce
monoiodoboranephosphonates 2 (and possibly diꢀ or triiodo derivatives) that
subsequently may undergo nucleophilic substitution at the phosphorus centre by
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iodide are the initial steps in the mechanism postulated by Caruthers et al.14a (Scheme
1). While the first step, the oxidation of a borane hydride by iodine, is quite likely,16
the second step, a nucleophilic substitution of the iodoborane group by iodide seemed
very implausible on at least three counts. Firstly, iodide is not a particularly good
nucleophile for the phosphorus.17 As a soft base, it is unlikely that iodide would
efficiently attack hard phosphonate diesters in accordance with the principle of hard
and soft acids and bases.18 Secondly, the boranephosphonate group in
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boranephosphonate diesters, similarly to phosphate diesters, is negatively charged and
thus can hinder the approaching nucleophile. Thirdly, assuming a nucleophilic attack
by iodide on the phosphorus center in 2 would necessitate the departure of the
iodoborane group with an electron pair in the form of boryl dianion [:BH2I]2– with
two formal negative charges. This would be thermodynamically unfavorable given the
high basicity and nucleophilicity of boryl dianions.19 These are rather elusive species
that are formed under highly reducing conditions as evidenced by 11B NMR
spectroscopy (for generic [:BH3]2ꢀ)20 and their stability become manageable only
upon extensive delocalization of the lone electron pair (casus [B(CN)3]2ꢀ).21
The authors predicted retention of configuration at the phosphorus center for the
whole process and this claim was substantiated by the NOESYꢀexperiments. In the
later, the authors compared the NOE effects between protons of the BH3 group and
the ribose protons in the starting boranephosphonates of type 1 vs methyl and the
ribose protons in the corresponding methyl phosphotriesters.14a However, since spatial
arrangements of the BH3 vs OCH3 protons in these compounds may differ
significantly, we considered that this NMR spectroscopy evidence warrants additional
studies to firmly establish a stereochemical relationship between the substrates and
the products in this reaction.
Stereochemical correlation analysis.
To establish a stereochemical outcome of the investigated reaction, we carried out a
stereochemical correlation analysis. To this end dinucleoside Hꢀphosphonate 5a,
enriched in one of the diastereomer (31P NMR analysis; 2:1 mixture of the low field:
the high field diastereomers; δP = 9.38 and 8.31 ppm), was synthesized and subjected
to oxidative coupling with nꢀbutylamine (Scheme 2, lower reaction path).22 This
reference reaction that is known to be stereospecific and to occur with inversion of
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configuration at the phosphorus center, 22ꢀ23 produced two diastereomers of
dinucleoside phosphoramidate 4a in the expected ratio of 1:2 (the high field: the low
field diastereomers, 31P NMR analysis). In the second experiment, we converted the
same diastereomeric mixture of Hꢀphosphonate diesters 5a into boranephosphonate
diesters 1a (see the Experimental Section), and subjected these to a reaction with
iodine in the presence of nꢀbutylamine, as described by Caruthers et al.14a We found
that patterns of the signals in the 31P NMR spectra of diastereomeric
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phosphoramidates 4a obtained from Hꢀphosphonate 5a via boranephosphonate 1a as
an intermediate and that from a direct oxidative coupling of Hꢀphosphonate 5a with nꢀ
butylamine (the reference reaction), were identical (two signals between δP = 9ꢀ10
ppm, ratio 1:2; see Fig. 2), and thus both reactions had to proceed with the same
overall stereochemistry, namely, with total inversion of configuration at the
phosphorus center.
Fig. 2. Excerpts of 31P NMR spectra of crude reaction mixtures of: (a)
boranephosphonate 1a + nꢀbutylamine + iodine, and (b) Hꢀphosphonate 5a +
nꢀbutylamine + iodine (the reference reaction). For experimental details, see in
the text.
Since transformation of Hꢀphosphonate diesters into the corresponding
boranephosphonates is known to occur with retention of configuration,13d,24 it implied
that a reaction of boranephosphonate 1a with iodine to produce iodophosphate 3a also
has to occur with retention of the configuration at the phosphorus centre. This
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contradicted the finding by Caruthers et al.14a who claimed for the latter step inversion
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of the configuration for this process.
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Tr-O
Thy
O
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O
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H
H B P O
H
O
Thy
O
(iii)
(i)
Tr-O
(ii)
1a
Tr-O
Thy
Tr-O
Thy
O
O
O
O
BuNH P O
O
H P O
O
Thy
Thy
O
O
Tr-O
(iv)
(v)
Tr-O
5a
4a
Tr = trityl
Thy = thymin-1-yl
Tr-O
Thy
O
O
I P O
O
Thy
O
Tr-O
3a
Scheme 2. Conversion of Hꢀphosphonate diester 5a into phosphoramidate 4a via
oxidative coupling with an amine (lower path) and via boranephosphonate
intermediate 1a (upper path), both promoted by iodine. Reaction
conditions: (i) 5 equiv. TMSꢀCl, 5 equiv. TEA in CH2Cl2; (ii) 10 equiv.
.
BH3 SMe2 in THF, followed by 25% aq. ammonia treatment; (iii) 3 equiv.
I2, 10 equiv. nꢀBuNH2 in acetonitrile;14a (iv) 2 equiv. I2, 4 equiv. TEA in
acetonitrile;22a (v) 5 equiv. nꢀBuNH2 in acetonitrile.22b Abbreviations:
TMSꢀCl – trimethylsilyl chloride; TEA – triethylamine; THF –
tetrahydrofuran.
To clarify this point, all steps important for the stereochemical correlation analysis
from Schemes 2 and 1 were summarized in Scheme 3. The correlation hinges on the
common intermediacy of phosphoroiodidate 3. This on one hand, can be
stereospecifically converted in the presence of an amine to the corresponding
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phosphoramidate 4 through inversion of configuration at the phosphorus,22b and on
the other one, can be generated on two independent routes, bifurcated from Hꢀ
phosphonate 5. In the reference reaction, a tricoordinated form of Hꢀphosphonate 5
reacted directly with iodine to afford with retention of configuration iodophosphate
3,22a while for the investigated reaction, the same starting material 5 (after silylation)
was used for the preparation of boranephosphonate 1. Since transformation of Hꢀ
phosphonate diesters into the corresponding boranephosphonates (5 into 1) proceeds
with retention of configuration13d,24 and the subsequent reaction with iodine (1 into 2)
does not involve the phosphorus center (boron hydride oxidation), sense of chirality
of iodoboranephosphonate 2 must be the same as that of Hꢀphosphonate 5. Thus, in
Scheme 3 the stereochemistry of all the reaction steps but one, namely that from 2 to
3, is known. To obtain agreement with the experimental data we had to assume that
the conversion of iodoboranephosphonate 2 into the corresponding iodophosphate 3
occurred with retention of the configuration as indicated in Scheme 3. This, on
stereochemical ground, in principle ruled out a nucleophilic substitution by iodide at
the phosphorus centre suggested by Caruthers et al.14a Having said that, there could be
a remote possibility for this step to be anyway a nucleophilic substitution, provided it
would involve a pseudorotation of the initially formed trigonal bipyramid
intermediate (tbp). However, in acyclic phosphorus compounds nucleophilic
substitution occurs with inversion of configuration without intermediacy of tbp and a
pseudorotation step is usually invoked to explain the stereochemical outcome of
reactions when phosphorus is part of a ring system.25 This adds another argument to
those in the text above against an SN2(P) process and thus called for another
mechanism for this step for this reaction.
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O
R1O P OR2
retention
retention
B
H
2
H
I
O
O
O
inversion
R1O P OR2
R1O P OR2
R1O P OR2
NHR3
B
I
H
H
4
H
3
O
total: inversion
1
R1O P OR2
retention
retention
H
5
1a - 5a, R1 and R2 = nucleoside moieties as in Scheme 2: R3 = n-butyl
1b - 5b, R1 = R2 = ethyl: R3 = n-butyl
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Scheme 3. A stereochemical correlation scheme for the conversion of Hꢀphosphonate
diester 5 into phosphoramidate 4 via a direct oxidative coupling (the lower
path) and via intermediacy of boranephosphonate 1 (the upper path).
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To provide a mechanistic explanation for this crucial step of the transformation (step
2 to 3) we propose that iodoboranephosphonate 2, formed by a borane hydride
oxidation of the boranephosphonate 1, could undergo dissociation to a phosphite
anion and iodoborane, followed by oxidation of the former by iodine to afford
phosphoroiodidate 3 (Scheme 4).
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O
R1O P OR2
O
O
R1O P OR2
B
retention
retention
R1O P OR2
I
I
+
I
H
I
B
H
H
2
H
I
3
2a, 3a, R1 and R2 = nucleoside moieties as in Scheme 2.
2b, 3b, R1 = R2 = ethyl
Scheme 4. A possible mechanism for transformation of iodoboranephosphonate 2
into phosphoroiodidate 3 with retention of configuration.
Since both reactions in Scheme 4, i.e. the dissociation of iodoboranephosphonate
213d,24 and the oxidation of the phosphite anion,22 do not involve any change in
stereochemistry at the phosphorus atom, a total retention of configuration is expected
for this step, as depicted in the stereochemical correlation diagram (Schemes 4 and 5).
One should note that in contradistinction to a mechanism proposed by Caruthers et
al.14a where iodine acted only as an activator for the borane group of
boranephosphonates of type 1 (via oxidation of a borane hydride), in our mechanism
iodine plays a dual role, being also a stoichiometric oxidant for the in situ generated
P(III) species (phosphite anion of an Hꢀphosphonate diester; Scheme 4). Thus, the
two mechanisms could in principle be also distinguished by the amount of iodine
consumed during the reaction. For the oxidative nucleophilic substitution mechanism,
only 1 molar equivalent of iodine was claimed to be necessary14a however, to get
reproducible results, the authors routinely used 3 equivalents of iodine (see Scheme 1).
In our hands, the reaction consistently required at least 2ꢀ3 equiv. of iodine to go to
completion. Apparently, due to some subsequent reactions of iodine with an amine
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present and with borane derivatives formed, its consumption varied, depending on the
reaction conditions.
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Formation of an H-phosphonate diester as a key intermediate.
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The dissociation step that generates an Hꢀphosphonate species (as a phosphite anion
or its protonated form; Scheme 4) is critical for the discussed mechanism to be
operative during the reaction of boranephosphonates with amines. Boranephosphonate
diesters are stable compounds that can be stored and handled at ambient temperature
without any particular precautions. In chemical terms this means that the PꢀB bond in
these compounds is rather strong and does not undergo a spontaneous scission. Since
boranephosphonates are Lewis acid–base complexes, their stability is controlled by
acidity and basicity of the parent borane and the phosphonate parts.
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Both our model compounds, dinucleoside boranephosphonate 1a and diethyl
boranephosphonate 1b, afforded the corresponding phosphoramidates 4a and 4b
when treated separately in dichloromethane or acetonitrile with nꢀbutylamine (10
equiv.) and iodine (3 equiv.).14a The 31P NMR experiments showed that the starting
materials, boranephosphonates 1a and 1b, were stable in pyridine, acetonitrile, and
dichloromethane in the presence of nꢀbutylamine (50 equiv., 24 h, room temperature).
Since upon addition of elemental sulfur (10 equiv.) or sulfur and trimethylsilyl
chloride, (10 equiv. of each) to such solutions, no sulfurization products (formation of
the corresponding phosphorothioate diesters) could be detected, we inferred that
under these experimental conditions boranephosphonates 1 did not dissociate
spontaneously to afford detectable equilibrium mixtures of the parent Hꢀphosphonate
derivatives and borane. Thus, it seemed that the generation of appreciable amounts of
Hꢀphosphonate diesters from boranephosphonates must apparently involve an initial
activation of 1 by iodine26 as was suggested by Caruthers et al.14a To unravel this
point, first we wanted to know if we could observe, by 31Pꢀ or 11B NMR spectroscopy,
the formation of the postulated initial intermediates of the reaction, namely, the
corresponding iodoboranephosphonate derivatives 2. This would permit further
studies on susceptibility of intermediates 2 to dissociation into the Lewis acid ꢀ Lewis
base components, a critical step in our mechanistic proposition. We considered two
scenarios: (i) a direct fragmentation of iodoboranephosphonates 2 into the
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corresponding Hꢀphosphonate diesters 5, and (ii) a possible formation of Hꢀ
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5
phosphonates 5 from 2 via other, unidentified yet boranephosphonate intermediates.
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Scheme 5 depicts some possible pathways for generation of Hꢀphosphonate diesters 5
during the course of the reaction of boranephosphonates 1 with amines promoted by
iodine. Oxidation of a borane hydride in 1 by iodine might initially form a trigonal,
electronꢀdeficient borane intermediate [X] that coordinated iodide to afford
iodoboranephosphonate 2. In the presence of amine nucleophile during the hydride
oxidation by iodine, it could intercept the incipient intermediate [X] to form
aminoboranephosphonate 6. Alternatively, both species 2 and 6 could also be formed
directly from boranephosphonate 1 without the intermediacy of [X] via fourꢀcenter
transition states involving iodine (for iodoboranephosphonate 2) or amineꢀiodine
complexes27 (for aminoboranephosphonate 6). Irrespective how they were formed, 2
and 6 might afford Hꢀphosphonate 5, but their propensity to spontaneous dissociation
should depend on the Lewis acid strength of the borane moieties in these compounds.
By comparing the inductive vs the πꢀelectron donating effects of iodo and amino
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substituents in trigonal borane derivatives, we expected that the latter should
significantly prevail in aminoboranes, making them weaker Lewis acids.
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O
R1O P OR2
B
H
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1
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O
R1O P OR2
B
H
H
NH2R3
I
[X]
O
R1O P OR2
B
O
NH2R3
R1O P OR2
B
H
NHR3
H
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H
H
2
6
O
R1O P OR2
+
or
BH2I
BH2NH2R3
TEAH+
O
R1O P OR2
H
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O
R1O P OR2
NHR3
4
2a, 5a, 6a, R1 and R2 = nucleoside moieties as in Scheme 2; R3 = n-butyl
2b, 5b, 6b, R1 = R2 = ethyl; R3 = n-butyl
Scheme 5. Various possible pathways for the formation of Hꢀphosphonate diester 5
intermediates.
By this token we anticipated that aminoboranephosphonates 6 would be more
susceptible to dissociation into the parent Lewis acid – Lewis base components than
iodoborane 2 derivatives, and thus a pathway to Hꢀphosphonate 5 via aminoborane 6
intermediates (Scheme 5) should be thermodynamically favoured.
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To find support for this hypothesis we carried out a reaction of boranephosphonates 1
with iodine under various experimental conditions by varying solvents, ratio, and
kinds of reactants. When iodine (3 equiv.) was added to a solution of
boranephosphonates 1 and nꢀbutylamine (5ꢀ10 equiv.) in dichloromethane or
acetonitrile, the reaction proceeded to completion within a few minutes to afford the
expected phosphoramidates 4 without the formation of any detectable intermediates.
This indicated that the first step of the reaction in Scheme 5, i.e. the oxidation of a
borane hydride in 1 by iodine appeared to be the rate limiting step of the whole
transformation.
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To get some insight into the possible intermediates involved in this reaction, we first
attempted to react diethyl boranephosphonate 1b in dichloromethane with iodine
alone (an activation process). Since amine is apparently involved in the very last step
of the reaction, its absence should possibly cause accumulation, and thus detection by
31P NMR spectroscopy, some of the postulated upstream intermediates. Indeed, after
the addition of 1 equiv. of iodine to a dichloromethane solution of 1b, the first 31P
NMR spectrum recorded revealed, besides the starting material 1b (ca 29%, δP =
99.80 ppm) and diethyl phosphoroiodidate 3b (ca 7%, δP = ꢀ41.88 ppm), also the
presence of an intermediate we searched for, namely, diethyl Hꢀphosphonate 5b (ca
22%, δP = 8.21 ppm), and a signal from an unknown species, resonating at δP = 67.42
ppm (ca 35%). Significant broadening of this resonance indicated the presence of a
boron atom and thus the signal was tentatively assigned to the postulated, initial
intermediate of the reaction, diethyl iodoboranephosphonate 2b (Scheme 5). The
reaction with 2 equiv. of iodine proceeded analogously, except the starting material
1b completely disappeared and the intermediate 2b amounted to 68%. In both
instances, addition of nꢀbutylamine (10 equiv.) and more iodine (another 1ꢀ2 equiv)
resulted in the immediate, complete disappearance of all the intermediates, and the
formation of diethyl nꢀbutylphosphoramidate 4b (δP = 8.45 ppm) as the sole
phosphorusꢀcontaining product (31P NMR analysis). A similar course of the reaction
was also observed in acetonitrile,29 but since the activation of boranephosphonates 1
was more efficient in dichloromethane than in acetonitrile, the former solvent was
used in further studies.
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These results were consistent with the proposed reaction pathway of
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boranephosphonate diesters with amines promoted by iodine, depicted in Scheme 5.
Firstly, they indicated that iodoboranephosphonate intermediate 2b can, to some
extent, spontaneously dissociate to afford some amounts of Hꢀphosphonate 5b, a
stereochemically important type of intermediate for this reaction, and secondly, that
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all the intermediates observed, i.e. iodoboranephosphonate 2b, Hꢀphosphonate diester
5b, and phosphoroiodidate 3b, are possible or factual intermediates in the above
reaction.
As mentioned above, addition of iodine as the last reagent (i.e. when
boranephosphonate diester and amine were both present in the reaction mixture),
could trigger a new reaction pathway. This concerns a putative
aminoboranephosphonate 6 intermediate, which could be formed both via a direct
coordination of an amine to an electronꢀdeficient borane intermediate [X] (or directly
from 1 via a fourꢀcenter transition state), and a nucleophilic attack of an amine at the
boron center of iodoboranephosphonate 2b (Scheme 5) under these conditions.
Since these pathways are cryptic during the course of a regular reaction (i.e. when all
reactants are present in sufficient amounts), we addressed this issue by (i) reacting 1a
with a limited amount of iodine in the presence of nꢀbutylamine, and (ii) treating a
generated iodoboranephosphonate 2b with nꢀbutylamine. To this end we added to a
solution of boranephosphonate 1b in dichloromethane containing nꢀbutylamine (1
equiv.), 1 equiv. of iodine. In the 31P NMR spectrum obtained the pattern of the
signals was qualitatively similar to that of the reaction of 1b with iodine alone
(presence of signals from the starting material 1b, the putative
iodoboranephosphonate intermediate 2b, Hꢀphosphonate 5b, and iodophosphate 3b;
vide supra), except for a new resonance from an unknown intermediate at δP = 42.63
ppm (ca 10%).30 Quenching this reaction mixture with nꢀbutylamine (10 equiv.)
caused the signals from iodoboranephosphonate 2b (at ca 69 ppm) and the unknown
intermediate (at ca 42 ppm) to immediately disappear, and only the unreacted starting
material 1b, Hꢀphosphonate 5b, and a small amount of phosphoramidate 4b (from
iodophosphate 3b), remained (31P NMR analysis).
These experiments indicated that the signal at ca 42 ppm was not due to a side
product formation but corresponded to a legitimate intermediate of the reaction, and
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thus it was tempting to assign it to the postulated aminoboranephosphonate 6b.
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5
Although the signal at ca 42 ppm was clearly observed when the activation of
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boranephosphonate 1b was carried out in the presence of nꢀbutylamine, we exercised
some caution as it was rather broad and could be overlooked in noisy 31P NMR
spectra, especially at low concentration of the intermediate. Indeed, scrutiny of all our
previous 31P NMR spectra from the reaction of 1b with iodine in the absence of nꢀ
butylamine showed that in a few instances we could discern a slight bump in the
spectra at ca 42 ppm that might correspond to the sought intermediate. This was a
compelling argument that an intermediate resonating at ca 42 ppm did not contain nꢀ
butylamine moiety as a structural fragment, and thus could not be assigned to
aminoboranephosphonate 6b.
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In the light of the above we hypothesized that when the activation of
boranephosphonate 1b with iodine is carried out in the presence of a base (nꢀ
butylamine), the initially formed activation product, iodoboranephosphonate 2b, can
be prone to further borane hydride oxidation and form diiodoboranephosphonate 2′b
(Scheme 6). We assigned this structure to an intermediate that resonated at ca 42 ppm
in the 31P NMR spectra.
H
O
R1O P OR2
B
O
R1O P OR2
B
O
R1O P OR2
B
R3NH2
H
O
R1O P OR2
B
I
H
I
H
H
H
I
H
H
I
I
I
I
I
less susceptible
[Y]
2'
2
to oxidation than 2
2a, 2'a, R1 and R2 = nucleoside moieties as in Scheme 2.
2b, 2'b, R1 = R2 = ethyl.
Scheme 6. Formation of a putative diiodoboranephosphonate intermediate under
basic conditions.
To substantiate this hypothesis we reacted boranephosphonate 1b in dichloromethane
with iodine (2 equiv.) in the presence of 2,6ꢀlutidine (5 equiv.). The 31P NMR
spectrum (after 5 min.) revealed, apart from a resonance due to iodophosphate 3b (δP
= ꢀ 41.32 ppm, ca 13%), two, broad signals at 62.56 ppm (ca 60%) and 40.75 ppm (ca
27%). These were assigned to the two putative intermediates, namely,
iodoboranephosphonate 2b and diiodoboranephosphonate 2′b, respectively. Since
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both of them were converted into phosphoramidate 4a upon the addition of nꢀ
butylamine, they were assumed to be potential intermediates involved in the
investigated reaction.
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We also probed the reactivity of iodoboranephosphonate 2b towards nꢀbutylamine as
a possible step in the investigated reaction (step 2 to 6, Scheme 5). The most revealing
experiment consisted of an incremental addition of nꢀbutylamine to the reaction
mixture resulted from activation of boranephosphonate 1b with a limited amount of
iodine (Fig. 3). We tried to minimize the amount of iodine used so that in the reaction
mixture after generation of iodoboranephosphonate intermediate 2b, no iodine was
left. 31
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5b
1b
4b
(d)
(c)
2b
(b)
(a)
Fig. 3. 31P NMR spectra of the reaction of iodoboranephosphonate 2b with nꢀ
butylamine in dichloromethane: (a) the reaction of 1a with nꢀbutylamine (1
equiv) and iodine (0.8 equiv.), (b) after the addition of 1 equiv. of nꢀ
butylamine, (c) after the addition of another equiv. of nꢀbutylamine (total 2
equiv.), (d) after the addition of total 10 equiv. of nꢀbutylamine.
This would permit us to observe what species are formed upon reaction of 2b with the
added nꢀbutylamine. Under such conditions (Fig. 3) no new intermediates could be
detected, and only a gradual disappearance of 2b and accumulation of Hꢀphosphonate
5b was observed (Fig. 3). This strongly suggested that in the presence of nꢀ
butylamine iodoboranephosphonate 2b underwent a rapid nucleophilic substitution at
the boron center to form aminoboranephosphonate 6b that immediately collapsed to
the corresponding Hꢀphosphonate 5b and the aminoborane. Apparently, due to
inherent instability of aminoboranephosphonates 6, the postulated intermediate 6b did
not accumulate and thus could not be detected under the reaction conditions.
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The above experiment was also pertinent to the mechanism proposed by Caruthers et
al.14a If iodoboranephosphonates 2 would be susceptible to nucleophilic substitution
by iodide,14a they should even more readily react with nꢀbutylamine to afford
phosphoramidates 4. Since this was not the case, the reaction of 2b with nꢀbutylamine
lent support for the mechanism depicted in Scheme 5 that involves the intermediacy
of Hꢀphosphonate diester 5. Additionally, in a separate experiment
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iodoboranephosphonate 2b, generated from 1b and iodine (1 equiv.) in
dichloromethane, was subjected to a reaction with 10 equiv. of the added
tetrabutylammonium iodide to probe its susceptibility to nucleophilic substitution.
Since no measurable increase in the amount of phosphoroiodidate 3b could be
detected this, again, argued against a mechanism involving a nucleophilic attack of
iodide on the phosphorus center. It seems that a mechanism in Scheme 5 is rather
general for amine nucleophiles as analogous types of intermediates were observed in
the reactions with aromatic amines (e.g., aniline) and 2° amines (e.g., diethylamine).
To sum up this part, all the above experiments indicate that various pathways are
possible for the investigated reaction (Scheme 5 and 6). The reaction of
boranephosphonate diesters 1 with nꢀbutylamine promoted by iodine most likely
commences with a borane hydride oxidation to produce a putative trivalent borane
intermediate [X]. Under the reaction conditions, this may coordinate iodide and nꢀ
butylamine to produce two putative intermediates: iodoboranephosphonate 2 and
aminoboranephosphonate 6, respectively. The latter, due to its inherent instability,
immediately collapsed to afford the corresponding Hꢀphosphonate diester 5, while the
former, most likely reacted with the amine present to be converted into 5, with the
intermediacy of the corresponding aminoboranephosphonate 6. Alternatively, 2 and 6
could be formed from boranephosphonate 1 directly via reactions involving fourꢀ
center transition states. Under basic conditions, monoiodoborane intermediate 2 can
partially be converted into diiodoboranephosphonate 2′ that is apparently also
susceptible to the reaction with amine. HꢀPhosphonate 5 can probably be also formed
directly from iodoboranephosphonate 2, but this process is expected to be much
slower than the reaction with the amine. All the above reaction steps occur with a
retention of configuration and thus the sense of chirality of boranephosphonate 1 is
preserved in the Hꢀphosphonate diester 5 formed. There are two more reaction steps
that follow this key intermediate formation, namely, the oxidation of 5 by iodine to
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the corresponding phosphoroiodidate 3 (with retention of configuration) and its
reaction with nꢀbutylamine (with inversion of configuration). These furnished the
final product, the corresponding phosphoramidate 4, with a total inversion of
configuration at the phosphorus center.
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Finally, due to probably similar kinetics of the formation of 2 and 6 (directly from 1
or via intermediate [X]), and formation of 2′ from 2, as well as conversion of 2 and 2’
into 6, all these pathways can most likely be operative during the course of the
reaction. Although changes in the reaction conditions can modulate their contributions
this, however, should not affect the final stereochemical outcome of the whole
transformation that is governed by stereochemistry of the key intermediate formed,
namely the corresponding Hꢀphosphonate diester.
CONCLUSIONS
We designed and carried out a stereochemical correlation analysis for the formation
of phosphoramidate diesters from the corresponding boranephosphonate derivatives.
Contrary to previous studies14a we found that the reaction of boranephosphonate
diesters 1 with amines promoted by iodine proceeded with total inversion of
configuration at the phosphorus center and involved the formation of the
corresponding Hꢀphosphonate as a stereochemically important intermediate. On this
basis we could dismiss an oxidative nucleophilic attack on the phosphorus as a crucial
step in this reaction. The role of iodine in the whole transformation was found to be
twofold: (i) activation of the borane group via oxidation of the hydride anion to
produce an iodoborane function (ꢀBH2I; intermediate 2 and possibly 2′) and (ii)
oxidation of the key intermediate, Hꢀphosphonate diester 5, to the corresponding
phosphoroiodidate diester. The reaction of iodoboranephosphonates 2 with an amine
to produce a putative aminoboranephosphonate 6 that apparently rapidly dissociated
into the Hꢀphosphonate 5 and the borane parts is most likely instrumental to the
formation of the Hꢀphosphonate intermediate. Since all the reaction steps leading to
Hꢀphosphonate diesters 5 occur with retention of configuration, the sense of chirality
of boranephosphonates 1 is preserved in this intermediate. The two final steps,
oxidation of Hꢀphosphonate 5 by iodine, followed by the reaction with the amine
present, furnished the final phosphoramidates 4 with total inversion of configuration.
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EXPERIMENTAL SECTION
All reagents were of analytical grade, obtained from commercial suppliers and used
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without further purification. Anhydrous solvents used for reactions were stored over
molecular sieves 4 Å. TLC analyses were carried out on Merck silica gel 60 F 254
precoated plates using CH2Cl2–MeOH 9:1 (v/v) solvent system. All evaporations
were carried out on rotatory evaporators under reduced pressure at 40 °C.
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HꢀPhosphonate diester 5a was synthesized from the appropriate Hꢀphosphonate
monoesters32 and alcohols according to standard coupling procedures.33 The Pꢀ
diastereomers of 5a were separated using silica gel chromatography with ethyl
acetate : toluene 99:1 (v/v) as a solvent system. These diastereomers are referred to as
“slow” and “fast” (chromatographic mobility) or “low field” and “high field” (signals
in the 31P NMR spectra). For these studies 5a was used as a 2:1 or 1:2 mixture of the
diastereomers.
The NMR spectra were recorded using Bruker Avance II 400 MHz instrument. The
chemical shifts are reported in ppm, relative to solvent peaks (1H, 13C NMR), 2%
H3PO4 solution in D2O (31P NMR), and BF3 diethyl etherate (11B NMR). Assignment
of the NMR signals was accomplished on the basis of the expected chemical shift
values, splitting pattern of the signals, and 2D correlation experiments. High
resolution mass spectra (HRMS) were recorded on Thermo Fisher Scientific Qꢀ
Exactive Orbitrap mass spectrometer. Identification of intermediates observed in the
31Pꢀ and 11B NMR spectra of the reaction mixtures was done on the basis of the
expected chemical shifts, coupling constants, shapes of the multiples, and spiking of
the reaction samples with compounds of known structures.
For compounds 1a and 4a, due to the presence of two Pꢀdiastereomers and similar
chemical shifts of the protons in the 3′ꢀ and 5′ꢀnucleoside units, multiplicity and
overlapping of the resonances were observed in the 1H NMR spectra. For this reason
only selected diagnostic signals are listed. Purity of the isolated compounds was
>97% (1H NMR spectroscopy).
Synthesis of 3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl boranephosphonate 1a,
triethylammonium salt
3′ꢀOꢀTritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl Hꢀphosphonate 5a (0.1 mmol) was
placed in a 100 mL pearꢀshaped flask and evaporated twice the added anhydrous
dichloromethane (2 x 20 mL). The residue was dissolved in anhydrous
dichloromethane (20 mL), and triethylamine (0.5 mmol), followed by trimethylsilyl
chloride (0.5 mmol), were added. After stirring for 10 min., borane dimethyl sulfide
complex in THF (1 mmol) was added to the generated silyl phosphite derivative. The
reaction mixture was stirred for another 10 min. and progress of the reaction was
monitored by 31P NMR spectroscopy. After quenching the reaction mixture by the
addition of an aqueous ammonia (25%, 2 mL) and the removal of the solvents, the
product was purified by a silica gel column chromatography using a gradient of
methanol in dichloromethane (0ꢀ5%, v/v) containing triethylamine (1%). Fractions
containing the desired product were collected and evaporated, to yield 1a as a white
solid (96 mg). Yield 85%. Rf = 0.13 and 0.28. HRMS m/z: [MꢀEt3NH+]ꢀ Calcd for
C58H57BN4O11P 1027.3860; Found 1027.3878.
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1H NMR (CDCl3, 400 MHz): (diagnostic signals) δ ꢀ0.20ꢀ0.80 (br m, 3H), 1.36 (s,
3H), 1.88 (s, 3H), 6.30ꢀ6.70 (m, 2H). 13C NMR (CDCl3, 100.6 MHz): δ 8.6, 11.6, 12.5,
39.1, 39.5, 45.6, 64.2, 74.9, 76.0, 84.9, 85.5, 85.9, 87.6, 87.8, 111.4, 127.4, 128.1,
31
128.7, 128.9, 135.79, 136.5, 143.3, 144.1, 144.3, 150.8, 164.2. P NMR (CDCl3, 162
Hz): δ 94.15 (br m). 11B NMR (CDCl3, 128.4 Hz): δ ꢀ38.47 (br).
Synthesis of diethyl boranephosphonate 1b, triethylammonium salt
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1b was obtained analogously to 1a using diethyl Hꢀphosphonate (0.1 mmol) as a
starting material. The product was purified by a silica gel column chromatography
using 0ꢀ10% gradient of methanol in dichloromethane containing triethylamine (1%).
The separation was controlled by TLC chromatography by evocating spots in a
chamber with iodine vapour. Compound 1b was obtained as a colorless oil (23 mg).
Yield 90%. HRMS m/z: [MꢀEt3NH+]ꢀ Calcd for C4H13BO3P 151.0701; Found
151.0689.
1H NMR (CDCl3, 400 MHz): δ ꢀ0.40ꢀ0.60 (br m, 3H), 0.15 (m, 3H), 1.06 (t, 6H, 3JHH
= 7.1 Hz), 1.13 (t, 6H, 3JHH = 7.3 Hz), 2.9 (q, 4H, 7.3 Hz), 3.73 (m, 4H, 3JHH = 7.3 Hz).
13C NMR (CDCl3, 100.6 MHz): δ 8.1, 16.4 (d, 3JPC = 5.8 Hz), 45.4, 59.1 (d, 2JPC = 4.1
Hz). 31P NMR (CDCl3, 162 Hz) : δ 95.31 (br q, 1JPB = 131.0 Hz). 11B NMR (CDCl3,
128.4 Hz): δ ꢀ41.25 (d, 1JPB = 134.7 Hz).
Transformation of 3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl Hꢀphosphonate
5a into 3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3’ꢀyl nꢀbutylphosphoramidate 4a
(the reference reaction)
3′ꢀOꢀTritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl Hꢀphosphonate 5a (0.1 mmol; a ca
2:1 mixture of the low and high field diastereomers; δP = 9.38 and 8.31 ppm) was
made anhydrous by evaporation of the added pyridine (2 x 20 mL), then acetonitrile
(2 x 20 mL), and left overnight on the vacuum line. The residue was dissolved in
anhydrous acetonitrile (20 mL), and nꢀbutylamine (0.5 mmol), followed by iodine
(0.3 mmol) dissolved in acetonitrile (0.5 mL), were added. After stirring for 5 min.
the 31P NMR spectrum was recorded. It showed two signals of intensities ca 1:2 at δP
= 9.91 and 9.51 ppm corresponding to the expected phosphoramidate 4a. The product
was isolated by a silica gel column chromatography using a gradient of methanol in
dichloromethane (0ꢀ5%). Compound 4a was obtained as a white solid (80 mg). Yield
74%. Rf = 0.66. HRMS m/z: [MꢀH]ꢀ Calcd for C62H63N5O11P 1084.4267; Found
1084.4277.
1H NMR (CDCl3, 400 MHz): (diagnostic signals) δ 1.42 (s, 3H), 1.84 (s, 3H), 6.27ꢀ
13
6.45 (br m, 2H). C NMR (CDCl3, 100.6 MHz): δ 14.1, 14.8, 16.1, 22.1, 36.0, 41.5,
43.4, 65.9, 68.5, 86.8, 87.3, 87.7, 90.1, 90.5, 113.5, 114.0, 130.0, 130.5, 131.1, 131.2,
137.7, 138.2, 145.4, 146.3, 152.9, 166.4. 31P NMR (CDCl3, 162 Hz): δ 9.51, 9.91
(integration ca 2:1).
Transformation of 3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl
boranephosphonate 1a into 3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl nꢀ
butylphosphoramidate 4a
3′ꢀOꢀtritylthymidinꢀ5′ꢀyl 5′ꢀOꢀtritylthymidinꢀ3′ꢀyl boranephosphonate 1a (0.1 mmol;
obtained from ca 1:2 diastereomeric mixture of 5a as described above) was dried by
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evaporation of the added anhydrous acetonitrile (2 x 20 mL) and dissolved in the
same solvent (20 mL). To this, nꢀbutylamine (1 mmol), followed by iodine (0.3 mmol,
dissolved in 0.5 mL of acetonitrile), were added. After stirring for 5 min. the 31P
NMR spectrum was recorded. It showed two signals of intensities 1:2 at δP = 9.66 and
9.30 ppm corresponding to the expected phosphoramidate 4a. The pattern of the
signals was the same as in the reference reaction, and after isolation of the product (74
mg) it was found to be identical to that from the direct oxidative coupling above.
Yield 68%. Rf = 0.68. HRMS m/z: [MꢀH]ꢀ Calcd for C62H63N5O11P 1084.4267; Found
1084.4276.
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1H NMR (CDCl3, 400 MHz): (diagnostic signals) δ 1.43 (s, 3H), 1.85 (s, 3H), 6.30ꢀ
6.45 (br m, 2H). 13C NMR (CDCl3, 100.6 MHz): δ 11.7, 12.4, 13.6, 14.1, 19.6, 19.7,
22.7, 29.7, 30.0, 31.9, 33.7, 39.1, 41.0, 63.6, 66.01, 74.4, 84.3, 85.4, 87.7, 88.1, 111.1,
111.7, 127.6, 128.09, 128.14, 128.7, 128.8, 135.2, 135.5, 143.0, 144.0, 150.3, 163.7.
31P NMR (CDCl3, 162 Hz): δ 9.30, 9.66 (integration ca 2:1).
Synthesis of diethyl nꢀbutylphosphoramidate 4b
4b was obtained analogously to 4a using diethyl Hꢀphosphonate (0.1 mmol) as a
starting material. The product was purified by a silica gel column chromatography
using 0ꢀ10% gradient of methanol in dichloromethane containing triethylamine (1%).
The separation was controlled by TLC chromatography by evocating spots in a
chamber with iodine vapour. Compound 4b was obtained as a colorless oil (17.5 mg).
Yield 85%. HRMS m/z: [MꢀH]ꢀ Calcd for C8H19NO3P 208.1108; Found 208.1100.
3
1H NMR (CDCl3, 400 MHz): δ 0.84 (t, 3H, JHH = 7.3 Hz), 1.25 (m, 8H), 1.41 (m,
2H), 2.82 (m, 2H), 3.98 (m, 4H). 13C NMR (CDCl3, 100.6 MHz): δ 13.6, 16.1 (d, 2JPC
2
2
= 7.1 Hz), 19.6, 33.7 (d, JPC = 6.1 Hz), 41.0, 62.0 (d, JPC = 5.3 Hz). 31P NMR
(CDCl3, 162 Hz) : δ 9.33.
Supporting information
1H, 13C, 31P, and 11B NMR spectra.
ACKNOWLEDGEMENTS
We would like to thank Prof. Zofia Gdaniec and Dr. Witold Andrałojć for their help
with 11B NMR measurements, and Jakub Idkowiak for MS analysis. Financial support
from the National Centre for Research and Development (grant LIDER/041/711/Lꢀ
4/NCBR/2013 to JR) and the Polish Ministry of Science and Higher Education (the
KNOW program) is greatly acknowledged.
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References and Notes
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(1)
(2)
Since boron is less electronegative than carbon or hydrogen, for this class of
compounds we prefer a generic name “phosphonate” over “phosphate”,
analogously to Cꢀphosphonate and Hꢀphosphonate derivatives.
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electron pair to iodine. This would not affect stereochemistry of the formed
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Lewis AcidꢀBase Complexes of BH3, BF3, BCl3, AlCl3, and SO2; J. Am. Chem.
Soc 1994, 116, 8141ꢀ8753; (b) Niedenzu, K., Recent Developments in the
Chemistry of Aminoboranes; Angew. Chem. Int. Ed. Engl. 1964, 3, 86ꢀ92; (c)
Ishihara, K. In Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wileyꢀ
VCH: Weinheim, 2000, p 89ꢀ190.
(29) In acetonitrile, the analogous reactions were less efficient. With 1 equiv. of
iodine only formation of diethyl phosphoroiodidate (ca 14%) was observed.
When the amount of iodine was increased to 2 equiv., formation of diethyl
iodoboranephosphonate 2b intermediate could also be detected (ca 22%).
(30) In this reaction formation of a minute amount (ca 1%) of the corresponding
phosphoramidate 4b was also observed. When the reaction was carried out
with 2 equiv. of iodine and 4 equiv. of the amine, the resonance from the
phosphoramidate became the major signal. In this instance, no signals from
the starting material 1b and Hꢀphosphonate 5b could be detected.
(31) The reaction of boranephosphonate 1b with amines in the presence of iodine
was very sensitive to the ratio of the reagents used. With 0.5 ꢀ 0.8 equiv. of
iodine in the presence of 1 equiv. of nꢀbutylamine only
iodoboranephosphonate 2b and the unreacted starting material 1b could be
observed in the 31P NMR spectra, while with 1 equiv. of iodine, additional
signals due to diiodoboranephosphonate 2b’ and iodophosphate 3b, appeared.
When the amount of nꢀbutylamine was increased to 3 equiv., pattern of the
signals was similar to that of the reaction with 1 equiv. of the amine, but the
signal from 3b was replaced by that of the corresponding phosphoramidate 4b.
(32) Jankowska, J.; Sobkowski, M.; Stawinski, J.; Kraszewski, A., Studies on aryl
Hꢀphosphonates. I. Efficient method for the preparation of deoxyriboꢀ and
ribonucleoside 3'ꢀHꢀphosphonate monoesters by transesterification of diphenyl
Hꢀphosphonate; Tetrahedron Lett. 1994, 35, 3355ꢀ3358.
(33) (a) Garegg, P. J.; Regberg, T.; Stawinski, J.; Strömberg, R., Nucleosides Hꢀ
Phosphonates. V. The Mechanism of Hydrogenphosphonate Diester
Formation Using Acyl Chlorides as Coupling Agents in Oligonucleotide
Synthesis by the Hydrogenphosphonate Approach; Nucleosides Nucleotides
1987, 6, 655ꢀ662; (b) Johansson, T.; Stawinski, J., The case for
configurational stability of Hꢀphosphonate diesters in the presence of
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diazabicyclo[5.4.0]undecꢀ7ꢀene (DBU); Bioorg. Med. Chem. 2001, 9, 2315ꢀ
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2322; (c) Stawinski, J.; Strömberg, R. In Oligonucleotide Synthesis: Methods
and Applications; Herdewijn, P., Ed.; Humana Press: Totowa, NJ, 2004; Vol.
288, p 81ꢀ100.
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Graphical abstract
O
O
1
2
R3NH
*
R O P OR
1
2
*
Iodine,
R O P OR
B
2
NHR3
acetonitrile
H
H
H
total: inversion at phosphorus
R3NH2
iodine
iodine
R3NH2
O
O
O
R1O P OR2
R1O P OR2
R1O P OR2
B
B
H
H
I
H
NHR3
H
H
R1 and R2 = ethyl or a nucleoside; R3 = n-butyl
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