Unexpected Observation of the Dimroth Rearrangement in the Ribosylation of 4-Aminopyrimidines

Article abstract of DOI:10.1021/acs.joc.7b00780

A method for the preparation of 1-(N-ribofuranosyl)-6-imino-1,6-dihydropyrimidin-4-amines 3 or 4-(N-ribofuranosyl)-6-aminopyrimidines 4 via glycosylation of 4-aminopyrimidines 2 or 5 is described. Silylated 4-aminopyrimidines 2 or 5 upon ribosylation with 1 provide products 3. When intermediates 3 contain a strongly electron-withdrawing group, such as C(4)-Cl or C(5)-NO₂, they rearrange to products 4 in the presence of aqueous ammonia. A mechanism is proposed that involves a ring-opening/ring-closing (Dimroth) rearrangement.

Full text of DOI:10.1021/acs.joc.7b00780

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Article
Unexpected Observation of the Dimroth Rearrangement
in the Ribosylation of 4-Aminopyrimidines
Ramil Y. Baiazitov, Nadiya Sydorenko, Hongyu Ren, and Young-Choon Moon
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 May 2017
Downloaded from http://pubs.acs.org on May 12, 2017
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Unexpected Observation of the Dimroth Rearrangement in the Ribosylation of 4-
Aminopyrimidines
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Ramil Y. Baiazitov,* Nadiya Sydorenko, Hongyu Ren, and Young-Choon Moon.
PTC Therapeutics, Inc., 100 Corporate Ct., South Plainfield, NJ 07080.
rbaiazitov@ptcbio.com
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Abstract: A method for the preparation of 1ꢀ(Nꢀribofuranosyl)ꢀ6ꢀiminoꢀ1,6ꢀdihydropyrimidinꢀ4ꢀ
amines 3 or 4ꢀ(Nꢀribofuranosyl)ꢀ6ꢀaminopyrimidines 4 via glycosylation of 4ꢀaminopyrimidines
2 or 5 is described. Silylated 4ꢀaminopyrimidines 2 or 5 upon ribosylation with 1 provide
products 3. When intermediates 3 contain a strongly electronꢀwithdrawing group, such as C(4)ꢀ
Cl or C(5)ꢀNO2, they rearrange to products 4 in the presence of aqueous ammonia. A mechanism
is proposed that involves a ringꢀopening/ringꢀclosing (Dimroth) rearrangement.
Graphical abstract
:
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Introduction
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Clitocine (Figure 1) was first isolated from the mushroom Clitocybe inversa in 1986.1 The
structure of this adenosine analog has been confirmed by the synthesis of the molecule and Xꢀray
crystal structure spectroscopy.2 Clitocine attracted significant attention from the scientific
community because in addition to strong insecticidal activity1, this compound also exhibits
antitumor3 and readꢀthrough4 activities. These pharmacological properties prompted several
research groups to optimize the synthesis of clitocine and its analogs3ꢀ5.
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Figure 1. Structure of clitocine.
Clitocine and its analogs have been prepared following two major routes (Scheme 1). In the
first route, the ribofuranosylamine i can react as the nucleophile with a 4ꢀchloropyrimidine ii as
the electrophile by an SNAr mechanism with formation of the nucleoside core.5 Unfortunately,
nucleophile i is not thermally stable and is known to decompose via extrusion of ammonia and
formation of the bisglycosylamine.6 This instability severely limits the reaction scope such that
only highly activated electrophiles such as 5ꢀnitroꢀ, 5ꢀsulfonyl, or 5ꢀalkoxycarbonylꢀ4ꢀ
chloropyrimidines, are suitable substrates. An additional drawback of this approach is that i
consists of a mixture of anomers at C(1) resulting in the formation of mixtures of αꢀ and βꢀ
anomeric products iii.
In the second route, condensation of a ribofuranosyl electrophile (such as iv) with a 4ꢀ
aminopyrimidine nucleophile, v, can produce the desired analog by a Vorbrüggen reaction7 in the
presence of a Lewis acid (Scheme 1). In this route, aminopyrimidine v is usually silylated prior
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to reaction to increase both solubility and reactivity. Surprisingly, this method has been used to
prepare only a limited number of 4ꢀ(Nꢀribofuranosyl)ꢀ6ꢀaminoꢀ (or 6ꢀhydroxyꢀ) pyrimidines.8
Moreover, it has been demonstrated that the 4ꢀ(Nꢀribofuranosyl)ꢀ6ꢀaminopyrimidine vii is not the
kinetic product of this reaction but rather the dearomatized 1ꢀ(Nꢀribofuranosyl)ꢀ6ꢀiminoꢀ1,6ꢀ
dihydropyrimidinꢀ4ꢀamine (vi, Y = NH, or the tautomer), which isomerizes to product vii upon
exposure to silica gel or in acetic acid.8b No mechanism for this rearrangement has been
proposed.
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Scheme 1
Isomerization such as from vi to vii is not common. There are numerous examples of the
Vorbrüggen reaction with 4ꢀaminopyrimidines where the endocyclic nitrogen atom, usually
opposite to the exocyclic amino group, formed the glycosylic bond with the sugar residue and no
isomerization followed.9 Apparently, the endocyclic nitrogen atom is the most nucleophilic one.
Products in which the exocyclic amino group forms the glycosylic bond are rare and only a few
such products could be found in literature. Moreover, it is not clear if these products were formed
directly or as a result of a similar isomerization.8a,d The phenomenon of a secondary
isomerization requires an explanation.
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In this report, we demonstrate that silylated 4,6ꢀdiaminopyrimidines during Vorbrüggen
reaction attack the ribofuranoside donor by the endocyclic nitrogen atom opposite to the
exocyclic amino group to form 1ꢀ(Nꢀribofuranosyl)ꢀ6ꢀiminoꢀ1,6ꢀdihydropyrimidinꢀ4ꢀamines vi.
Depending on the nucleophile substitution, a rearrangement of vi can take place via the
pyrimidine ring opening/closure (i. e., Dimroth rearrangement10) catalized by a nucleophile, such
as ammonia. This rearrangement is facile only when the intermediate is activated by an electronꢀ
withdrawing substituent on the pyrimidine, such as a nitroꢀgroup at C(5). This limitation helps to
explain the scarcity of the literature examples of such reactions. However, we found that even
the intermediates without C(5) activation can isomerize when one of the NH2ꢀgroups in the
nucleophile is replaced by an electronꢀwithdrawing Clꢀgroup, which provides the required
activation. This electronꢀwithdrawing Clꢀgroup overcomes this limitation and enables
preparation of 4ꢀ(Nꢀribofuranosyl)ꢀ6ꢀaminopyrimidines via Vorbrüggen reaction using 4ꢀchloroꢀ
6ꢀaminopyrimidines as the nucleophiles, followed by reaction with ammonia and in situ
Dimrothꢀlike rearrangement to provide products vii.
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Results and Discussion
1. Reactions between Silylated 4,6-Diaminopyrimidines 2 and Ribofuranoside 1. Only a
very limited number of clitocine analogs were prepared by Vorbrüggen reaction. The analogs of
clitocine in which the C(5)ꢀnitro group is replaced by hydrogen or chlorine atoms (4a, X = H;
4b, X = Cl; Table 1) were targeted first. It was expected that using conditions similar to the
previously published clitocine preparation procedure (Table 1, entry 4), 4,6ꢀdiaminopyrimidine
2a and 2b will be converted to 4a (X = H) and 4b (X = Cl). The procedure8c involved silylation
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of the 4,6ꢀdiaminopyrimidine 2c (Table 1, X = NO2) with HMDS, followed by Vorbrüggen
reaction and optional isomerization on silica gel.8b
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Table 1. Reactions between 4,6-Diaminopyrimidines 2 and Ribofuranoside 1
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Entry
X
Conditions
Temp, timea
Product
Yield, % b
1
H
BSA/TMSOTf
BSA/TMSOTf
TEA/TMSOTf
HMDS/TMSOTf
TEA/TMSOTf
rt, 8 h
39
85
86
72
92
3a
3a
3b
4c
4c
2
H
60 °C, 50 min
rt, 1.5 h
rt, 18 h
3
Cl
4c
NO2
NO2
5
rt, 16 h
aTemperature and time in the presence of TMSOTf. bIsolated yield. cTaken from Ref 8c.
However, in our hands, the control reaction between 1 and 2c was irreproducible and the
product of ribosylation often could not be isolated in pure form after chromatography on silica
gel as judged by HPLC and NMR analyses. Moreover, the reaction was difficult to monitor by
TLC or HPLC, perhaps, because of the relatively fast conversion of 3c into 4c during the
analysis. Serendipitously, it was found that when the sample for the HPLCꢀMS analysis was
dissolved in acetonitrile containing ammonium hydroxide, the HPLCꢀpeak corresponding to the
product 4c could be clearly seen and no peak corresponding to 3c could be observed, suggesting
very fast isomerization from 3c to 4c. This fast isomerization was further confirmed when
ammonium hydroxide was used for the reaction quench and upon isolation of 4c.
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In the optimized procedure, 4,6ꢀdiaminopyrimidine 2c (Table 1, X = NO2) was combined
with ribofuranoside 1 in the presence of TMSOTf (2 equiv.) and triethylamine (1 equiv) to form
4c in 92% yield upon quench with iceꢀcold acetonitrileꢀammonium hydroxide mixture and
column chromatography (Table 1, entry 5). This improved procedure for the synthesis of 4c was
very reproducible in our hands.
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Next, similar reactions with other 4,6ꢀdiaminopyrimidines were attempted. Unexpectedly,
silylated 4,6ꢀdiaminopyrimidine 2a (Table 1, X = H) combined with ribofuranoside 1 in the
presence of TMSOTf to form 3a as a single βꢀisomer (Table 1, entries 1 and 2) instead of the
anticipated 4a. Heating to 60 °C accelerated the reaction and improved the isolated yield of 3a to
85%.
The structure of 3a was established using 1D and 2DꢀNMR spectroscopy (Figure 2). For
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example, the Hꢀ13CꢀHMBC spectrum (see Supporting Information, page S11) clearly shows
coupling (the crossꢀpeaks) that is comparable in magnitude between H(1’) of the furanose (δ =
6.43, d, J = 5.0 Hz, 1H) and both C(2) and C(4) of pyrimidine (δ = 154.0 (C(4)), 148.7 (C(2))).
Additionally, 2DꢀNOESY experiment (see Supporting Information, page S13) demonstrated
throughꢀspace correlation between H(2) of the pyrimidine ring with both H(1’) and H(2’) of the
furanose. The signal of H(1’) in 3a is a doublet, as opposed to the broad singlet (doublet of
doublets in several other analogs) observed in 4a (c.f. Figure 3).
Figure 2. Structural assignment of 3a
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Reaction of the 5ꢀchloropyrimidine 2b proceeded in an analogous fashion to provide 3b in
86% yield (Table 1, entry 3).11 In neither case could the product of isomerization 4 be observed
by HPLC or NMR analysis. Longer treatment of 3a with ammonium hydroxide led to removal of
the benzoate group at C(2’) and C(3’) without causing isomerization of the pyrimidine ring.12
2. Dimroth Rearrangement from 3 to 4. The described above failure to prepare 4a and 4b
was unexpected. It was demonstrated previously 8b that a similar analog 3c could be isolated and
isomerized to 4c in the presence of silica gel or acetic acid, Scheme 2. The reaction mechanism
was not proposed, although the acidic conditions suggest that it may involve breaking of the
C(1’)ꢀNb bond in the intermediate 3c and making of the C(1’)ꢀNa bond instead in Na-4c. This
may proceed, for example, via ionization at C(1’). The lability of C(1’)ꢀNb in an aminal, such as
3c, especially under acidic conditions (such as in the presence of acetic acid or silica gel as in
Ref 8b) supports this mechanism.
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Scheme 2
On the other hand, it is possible, that isomerization of 3c to 4c (Scheme 3) is initiated by a
nucleophilic attack onto the pyrimidine ring (NuH may be HOH or H2NH, etc.) with a
concominant ring opening to form a shortꢀlived intermediate xii. Rotation of the bond in xii
indicated on the scheme and extrusion of the nucleophilic catalyst regenerates the pyrimidine
ring in Nb-4c. The difference between Na-4c and Nb-4c is in the position of the nitrogen atoms:
atoms Na and Nb exchange positions within the pyrimidine ring.
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Scheme 3
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To establish which mechanism is operative, ribosylation with Nꢀlabelled pyrimidine 8 was
conducted (Scheme 4). This intermediate was prepared by treatment of 4,6ꢀdichloroꢀ5ꢀ
15
nitropyrimidine 7 with Nꢀlabelled ammonium hydroxide. The pyrimidine 8 was silylated and
glycosylated with 1 in the presence of tin (IV) chloride. After quenching with NH4OH, product
10 was isolated in 47 % yield.
Scheme 4
The structure of 10 was established by inspection of the magnitude of the Hꢀ15N coupling
1
constants from HꢀNMR spectroscopy.13 Thus, the absolute values for the J (1Hꢀ15N) couplings
in arylamines (Arylꢀ15NH) are expected to be around 90 Hz. Typical values for the endocyclic 2J
(1Hꢀ15N) couplings are between 0 and 20 Hz; and in pyridines it is close to 17 Hz.13 By
1
1
comparison, for the J (1Hꢀ15N) couplings the absolute values are typically between 0 and 5
3
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Hz.14,15 1HꢀNMR analysis of 10 revealed that each of the NH2 protons is a doublet with the
3
4
5
6
1
characteristically large J (1Hꢀ15N) coupling constants of 90 and 95 Hz. However, the other NH
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signal shows a characteristically smaller J (1Hꢀ15N) coupling constant value of 3.9 Hz. This
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suggests that the Nꢀatom attached to the anomeric center is no longer Nꢀlabelled. Instead, the
ring N(1)ꢀatom is labeled, which is further supported by the characteristic J (1H(2)ꢀ15N(1))
2
coupling constant value of 16 Hz. By comparison, in 8 this H(2) is a singlet (4J (1Hꢀ15N) ~ 0
Hz).
The position of the labelled 15Nꢀatoms in structure of 10 supports the mechanism presented in
Scheme 3. This result proves that the isomerization of a kinetic product 9 (or 3c) into the final
product 10 (or 4c) is possible through the pyrimidine ring opening when the ring is activated
enough. This attack by a nucleophilic catalyst onto 3c is faster than onto 3a and 3b, which
contain the less electrophilic pyrimidine rings. As a consequence, 3a and 3b do not isomerize
under these conditions. This result does not preclude the possibility of an alternative mechanism
that may be operative when the rearrangement is conducted in the presence of silica gel or acetic
acid.
3. Reactions between Silylated 4-Chloro-6-Aminopyrimidines and Ribofuranoside 1.
Another serendipitous discovery, which also involves Dimroth rearrangement, enabled the
preparation of the desired 4a as well as several other analogs. Silylation (BSA/TMSOTf) of 4ꢀ
chloroꢀ6ꢀaminopyrimidine (5a, X= H, Table 2, entry 1) followed by treatment with 1 afforded
exocyclic product 4a (X = H) as a single βꢀisomer after quenching the mixture with ammonium
hydroxide. This ribosylation is much faster than the formation of the endocyclic product 3a
during the reaction with 2a. Complete conversion is observed after only 1 h at room temperature
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in the presence of TMSOTf (2 equiv). Upon quenching into an iceꢀcold mixture of
5
6
acetonitrile/ammonium hydroxide (approx. 10/1) 4a was isolated in 89% yield.
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Table 2. Preparation of 4 by Ribosylation of 4-Chloro-6-Aminopyrimidines 5.
Entry
X
Conditions
BSA/TMSOTf
BSA/TMSOTf
BSA/TMSOTf
HMDS/SnCl4
HMDS/SnCl4
BSA/TMSOTf
Time, temp
rt, 1 h
Product
Yield, %
1
2
3
4
5
6
H
89
4a
Cl
Me
OMe
F
0 °C, 1 h
0 °C, 1 h
0 °C, 1h
0 °C, 2.5 h
rt, 1 h
4ba
65
100
4d
4e
73
26
4fꢀβb
F
34 (+ 45 % of 3f)
4fꢀβ/ 4fꢀα ∼ 2.7
aEndo-product 3b was observed by reversedꢀphase LCꢀMS16 but not isolated (~ 10 % relative to the exoꢀ
product, UVꢀ254 nm). Exoꢀproduct 4b: M+H+ = 589, 1.41 min; endoꢀproduct 3b: M+H+ = 589, 1.17 min.
bEndo-product 3f was observed by LCꢀMS but not isolated (~ 30 % peak area relative to the exoꢀproduct,
UVꢀ254 nm). Exoꢀproduct 4f: M+H+ = 573, 1.34 min; endoꢀproduct 3f: M+H+ = 573, 1.16 min.
The structure of 4a was established via 1D and 2DꢀNMR spectroscopy. For example, the
COSY spectrum (see Supporting Information, pages S32, S33) shows a coupling between the
N(H) linking the two rings and H(1’) of the furanose. A similar crossꢀpeak in the COSY
spectrum of 3a is absent (see Supporting Information, page S10). Unlike the HMBCꢀspectrum of
3a, there is no coupling in HMBC spectrum of 4a between H(1’) and any of the aromatic carbon
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atoms (see Supporting Information, page S34). The N(H) signal is a doublet in DMSOꢀd6 and the
H(1’) signal is a doublet of doublets in some analogs (a broad signal in others).
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The reaction scope is quite broad as illustrated by the examples in Table 2. Substrates bearing
electron donating methylꢀ and methoxyꢀgroups at C(5) of the pyrimidine are viable (2d, entry 3
and 2e, entry 4). As entry 4 in Table 2 demonstrates, HMDS can be used for silylation instead of
BSA, and SnCl4 can replace TMSOTf as the Lewis acid.17,18
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Substrates bearing electronꢀwithdrawing groups at C(5) are less viable. For example, while
the 5ꢀchloropyrimidine (entry 2) provided product 4b in 65% yield, a trace amount of,
presumably, product 3b could be observed by LCꢀMS analysis of the crude reaction mixture.
Reaction of the 5ꢀfluoropyrimidine was even more complex (Table 2, entries 5 and 6). Thus
silylation of pyrimidine 5f with BSA followed by ribosylation using TMSOTf as the Lewis acid
(entry 6) afforded 4f in 34% yield as a mixture of two epimers at C(1’) together with a 45% of
3f. Use of the HMDS/SnCl4 combination (Table 2, entry 5) afforded the pure βꢀisomer of 4f
albeit in only 26% yield. The αꢀisomer was not observed in this case; 3f was also formed, but
could not be isolated in pure form.
4. Proposed Mechanism of the Reaction between the Silylated Aminopyrimidines with
Ribofuranoside 1. Formation of the different products upon a small change (3 from 2 vs. 4 from
5) of the nucleophile structures requires an explanation. It may seem that in silylated 6ꢀchloroꢀ4ꢀ
aminopyrimidines 5 the most nucleophilic nitrogen atom is the exocyclic one, while in the 4,6ꢀ
diaminopyrimidine 2 the most nucleophilic nitrogen atom is the endocyclic one. However,
another explanation is possible, which involves the initial formation of the same product of the
endocyclic attack in both cases, followed by isomerization, which is possible only when the
chlorinated nucleophile is used.
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For example, the reaction can start with the attack of the N(3) atom of the silylated
pyrimidine ix (Scheme 5), onto the cationic intermediate viii from the convex face with
formation of intermediate x. If the intermediate x contains the electronꢀwithdrawing chloroꢀ
group at C(4) (Z = Cl), then the pyrimidine ring in x may be electronically activated enough to
be opened with ammonia during the subsequent reaction quench providing intermediate xi by the
attack at C(2). Upon Clꢀatom displacement in xi with ammonia and C=C bond isomerization,
intermediate xii forms, which cyclizes with extrusion of ammonia and regeneration of the
aromatic pyrimidine 4. This process is very similar to the isomerization from 3c to 4c, Scheme 3.
In each case the dearomatized intermediate is electronically activated towards attack by ammonia
followed by Dimroth rearrangement and aromatization. The difference is in the nature and
position of the activating group: C(4)ꢀCl in x vs. C(5)ꢀNO2 in 3c. Formation of 3f (Table 2,
entries 5 and 6) may be explained by the alternative attack with ammonia at C(4) of the
chlorinated intermediate x (Z = Cl). Similar to 3a or 3b (but unlike 3c), pyrimidine 3f cannot be
opened with ammonia at the conditions studied because it is not activated enough.
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Scheme 5
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If the mechanism described in Scheme 5 is operative, then the bold nitrogen atom in 4, was
not originaly there but comes from the ammonia used in the quench. To confirm the proposed
mechanism, 15Nꢀlabelled ammonia was used for the reaction quench, Scheme 6. As would be
expected from the mechanistic proposal, the product 4a-15N (which was isolated in 48% yield)
incorporated the label at the endocyclic N(2) position.
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Scheme 6
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5. The Structure Elucidation of 4a-15N. The position of the 15Nꢀatom in 4a-15N was
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determined by HꢀNMR analysis (Figure 3). 15NꢀNMR spectra of several pyrimidines 4 in
CD3CN also were recorded. The analysis of the 15NꢀNMR spectra is complicated because we
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were unable to reference them according to IUPAC recommendations. The HꢀNMR spectrum
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(DMSOꢀd6) of 4a-15N features a doublet for H(C(2)) due to the J (1Hꢀ15N) coupling to the
neighboring 15Nꢀatom. The magnitude of this coupling (15.1 Hz) is within the range for the
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absolute values typical for the endocyclic J (1Hꢀ15N) couplings (between 0 and 20 Hz; and in
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pyridines it is close to 17 Hz).13 In contrast, in the Nꢀanalog 4a this signal is a barely resolved
doublet (J = 0.6 Hz) at 500 MHz. The magnitude (15.1 Hz) of this 1Hꢀ15N coupling in 4a-15N is
15
consistent with the structure 4a-15N. This value (15.1 Hz) is matched by the NꢀNMR data19 of
4a-15N, which exhibits a doublet at 223 ppm (J = 15.6 Hz). Additionally, the signal for HꢀN
connected to C(4) is a doublet of doublets (J = 2.2, 9.5 Hz, in the unlabeled analog 4a this signal
is a doublet, J=9.1 Hz). The magnitude of the smaller coupling constant (2.2 Hz) is consistent
with 3J (1Hꢀ15N), further confirming the structure. Unfortunately, the signal for H(C(5)) could not
be analyzed due to an overlap; H2N(C(6)) is a broad singlet.
Figure 3. 1HꢀNMR spectra of 4a and 4a-15N confirming the position of the 15Nꢀatom.
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A method of preparation of 1ꢀ(Nꢀribofuranosyl)ꢀ6ꢀiminoꢀ1,6ꢀdihydropyrimidinꢀ4ꢀamines 3
and 4ꢀ(Nꢀribofuranosyl)ꢀ6ꢀaminopyrimidines 4 via glycosylation of 4ꢀaminopyrimidines is
presented. Upon Vorbrüggen reaction with a ribofuranosyl donor 1 silylated 4ꢀaminopyrimidines
attack by the endocyclic nitrogen atom, opposite to the exocyclic amino group. When
sufficiently activated and in the presence of ammonium hydroxide, the kinetic product 3 can
isomerize to 4. The activation can be provided by C(4)ꢀCl or C(5)ꢀNO2 groups. The formation of
4 from 3 involves ringꢀopening of the intermediate. Extension to other substrates is possible.20
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Experimental Section
1H and 13C NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer (500 MHz
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1H, 126 MHz C) in methanolꢀd4, acetoneꢀd6, or DMSOꢀd6. Data are reported in the following
order: chemical shift in ppm (δ); multiplicities are indicated (br (broadened), s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet)); coupling constants, J, are reported in hertz (Hz);
integration is provided and assignment when possible. 1H and 13C NMR assignments are
corroborated by 2D experiments (COSY, HMQC, HMBC, and NOESY) when relevant. Spectra
are available in the SI. HRMS analysis (ESI Positive) was performed on an LTQ Orbitrap
Discovery mass spectrometer. UPLCꢀMS analysis was conducted using a column Acquity
UPLC HSS C18 1.8 ꢀM; Solvent A: 0.1 % aqueous formic acid, Solvent B: acetonitrile; gradient
from A:B=95:5 to A:B=5:95 over 2 min or similar. Analytical thinꢀlayer chromatography was
performed on silica gel plates with Fꢀ254 indicator. Visualization was accomplished by UV
light. Column chromatography was performed with silica gel. Anhydrous solvents were
purchased from Acros. All commercially available reagents were purchased and used without
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further purification. All temperatures refer to the external aluminum heat block temperature
unless otherwise noted, all reactions were conducted in test tubes equipped with a stir bar, a
septum, and a nitrogen inlet through a needle.
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(2R,3R,4R,5R)-2-((6-Amino-5-nitropyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl
Dibenzoate
(4c).
To
5ꢀnitroꢀ2,6ꢀ
diaminopyrimidine (2c, 465 mg, 3 mmol) in a test tube cooled in a room temperature water bath
was added acetonitrile (6 mL) and triethylamine (0.42 mL, 3 mmol), followed by dropwise
addition of TMSOTf (1.08 mL, 6 mmol). The mixture was stirred at room temperature for 1 h,
then cooled in ice bath and 1 (1.51 g, 3 mmol) was added in one portion. The reaction mixture
was stirred at room temperature for 16 h, then was quenched with an iceꢀcold mixture of
acetonitrile and ammonium hydroxide (10/1, 20 mL), partitioned between water and ethyl
acetate, washed with brine, dried with MgSO4, concentrated and purified by chromatography on
silica gel (gradient hexanes/ethyl acetate from 1/0 to 60/40 to provide the title compound 4c as a
1
white solid material (1.65 g, 92 %). The HꢀNMR spectrum of this material matched previously
reported data.8c
(2R,3R,4R,5R)-2-(4-Amino-6-iminopyrimidin-1(6H)-yl)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (3a). To 4,6ꢀdiaminopyrimidine (2a,
110 mg, 1 mmol) was added (3R,4R,5R)ꢀ2ꢀacetoxyꢀ5ꢀ((benzoyloxy)methyl)tetrahydrofuranꢀ3,4ꢀ
diyl dibenzoate 1 (504 mg, 1 mmol, 1 equiv), the tube was flushed with nitrogen, and acetonitrile
(3 mL) was added, followed by bis(trimethylsilyl)acetamide (BSA, 0.5 mL, 2 mmol). The
reaction mixture was heated to 90 °C under nitrogen for 10 min, then cooled in an ice bath.
TMSOTf (0.36 mL, 2 mmol) was added and the contents were heated to 60 °C for 1 hour, when
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the UPLC/MS analysis showed complete consumption of 1. The reaction mixture was quenched
into an iceꢀcold mixture of acetonitrile (20 mL) and ammonium hydroxide (2 mL), extracted
with toluene, washed with water, brine, dried with MgSO4, concentrated and purified by
chromatography on silica gel (gradient dichloromethane/ethyl acetate from 1/0 to 0/1, then ethyl
acetate/trimethylamine (50/1, then 20/1), then ethyl acetate/methanol ~ 10/1 to provide an oily
residue. The material was triturated with ether while cooling in an ice bath, diluted with equal
volume of pentane, filtered, and washed with pentane, then dried under vacuum to provide the
title compound 3a as a white solid material (473 mg, 85 %): TLC (streaking in EtOAc/MeOH ~
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10/1) Rf ~ 0.44ꢀ0.72; H NMR (500 MHz, methanolꢀd4) δ = 8.58 (s, 1H, H(2)), 8.09 (dd, J=1.3,
8.2 Hz, 2H), 8.04 (dd, J=1.1, 8.4 Hz, 2H), 7.97 (dd, J=1.3, 8.5 Hz, 2H), 7.68 ꢀ 7.60 (m, 3H), 7.52
(t, J=7.9 Hz, 2H), 7.48 ꢀ 7.40 (m, 4H), 6.36 (d, J=5.0 Hz, 1H, H(1’)), 6.05 (t, J=6.0 Hz, 1H,
H(2’)), 5.94 (t, J=5.8 Hz, 1H, H(3’)), 5.78 (s, 1H, H(5)), 4.97 (td, J=3.6, 5.4 Hz, 1H, H(4’)), 4.86
1
(t, J=4.4 Hz, 2H, H(5’)); H NMR (500 MHz, DMSOꢀd6) 21 δ = 8.72 (s, 1H, H(2)), 8.22 ꢀ 8.04
(m, 6H, includes NH and NH2), 7.99 (dd, J=7.6, 15.4 Hz, 4H), 7.79 ꢀ 7.64 (m, 3H), 7.58 (t, J=7.6
Hz, 2H), 7.52 (q, J=7.8 Hz, 4H), 6.47 (d, J=5.0 Hz, 1H, H(1’)), 6.08 (t, J=5.7 Hz, 1H, H(2’)),
5.98 (t, J=6.0 Hz, 1H, H(3’)), 5.73 (s, 1H, H(5)), 4.97 ꢀ 4.76 (m, 3H) 13C NMR (126 MHz,
DMSOꢀd6) δ = 165.5, 164.56, 164.54, 162.2 (C(6)), 154.0 (C(4)), 148.7 (C(2)), 134.1, 134.00,
133.7, 129.49, 129.45, 129.3, 129.1, 128.84, 128.7, 128.5, 128.3, 87.7, 80.9 (C(5)), 80.1 (C(4’)),
73.4 (C(2’)), 69.9 (C(3’)), 63.5 (C(5’)). One signal is missing, probably, due to overlap. UPLC:
+
1.05 min, 555 [M+H]+, also 445, 341, 201; HRMS (ESI) [M+H]+ calcd for C30H27N4O7
555.1874, found 555.1857.
(2R,3R,4R,5R)-2-(4-(l4-Azanyl)-5-chloro-6-iminopyrimidin-1(6H)-yl)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (3b). 5ꢀchloropyrimidineꢀ4,6ꢀdiamine
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2b (144 mg, 1.0 mmol) and trimethylamine (0.14 mL, 1.0 mmol) were mixed in dry acetonitrile
(2 mL) under N2. The mixture was cooled to 0 °C in an iceꢀwater bath and trimethylsilyl
trifluoromethanesulfonate (0.4 mL, 2.2 mmol) was added slowly. The reaction was warmed up to
room temperature and allowed to stir for 1 hour at room temperature. It was then cooled to 0 °C
in an iceꢀwater bath and 1 (504 mg, 1.0 mmol) was added after which the reaction mixture was
stirred at room temperature for 1.5 hours until UPLC showed complete consumption of 1. It was
then quenched with 20 mL 10% NH4OH/acetonitrile solution at 0 °C, concentrated and purified
using silica gel column chromatography (eluent 20% ethyl acetate/hexane to 100% ethyl acetate)
to yield the title compound 3b as a white solid material (505 mg, 86 %). 1H NMR (500 MHz,
methanolꢀd4) δ = 8.64 (s, 1H, H(2)), 8.11 ꢀ 8.07 (m, 2H), 8.05 ꢀ 7.98 (m, 4H), 7.68 ꢀ 7.62 (m,
3H), 7.54 ꢀ 7.49 (m, 2H), 7.48 ꢀ 7.42 (m, 4H), 6.46 (d, J=4.1 Hz, 1H, H(1’)), 6.07 (dd, J=3.8, 5.7
Hz, 1H, H(2’)), 5.95 (t, J=6.0 Hz, 1H, H(3’)), 5.01 (td, J=3.8, 6.0 Hz, 1H, H(4’)), 4.87 (dd,
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J=1.7, 3.8 Hz, 2H, H(5’)); H NMR (500 MHz, acetone) δ = 8.95 (s, 1H, H(2)), 8.24 ꢀ 8.06 (m,
6H, includes NH2), 8.06 ꢀ 7.99 (m, 2H), 7.87 (br. s, 1H), 7.72 ꢀ 7.67 (m, 2H), 7.65 (tt, J=1.3, 7.6
Hz, 1H), 7.60 ꢀ 7.37 (m, 6H), 6.81 (d, J=3.8 Hz, 1H, H(1’)), 6.27 (dd, J=3.8, 5.4 Hz, 1H, H(2’)),
6.13 (dd, J=5.7, 6.6 Hz, 1H, H(3’)), 5.24 (ddd, J=2.8, 4.0, 6.7 Hz, 1H, H(4’)), 5.03 (dd, J=4.1,
12.9 Hz, 1H, HH(5’)), 4.94 (dd, J=2.8, 12.9 Hz, 1H, HH(5’)); 13C NMR (126 MHz, Acetone) δ =
166.69, 166.65, 165.8, 160.1 C(6), 152.4 C(4), 146.9 (C(2)), 135.2, 134.8, 134.5, 130.9, 130.7,
130.6, 129.8, 129.72, 129.71, 129.6, 123.4, 120.9, 91.29 (C5), 91.25 (C(1’)), 82.5 (C(4’)), 75.5
(C(2’)), 70.6 (C(3’)), 63.9 (C5’)); UPLC: 1.39 min, 589 [M+H]+, also 297, 282; HRMS (ESI)
+
[M+H]+ calcd for C30H26ClN4O7 589.1485, found 589.1461.
An alternative procedure for (2R,3R,4R,5R)-2-(4-(l4-Azanyl)-5-chloro-6-iminopyrimidin-
1(6H)-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (3b). To 1 (504 mg, 1.0
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mmol), 5ꢀchloropyrimidineꢀ4,6ꢀdiamine 2b (144 mg, 1.0 mmol, 1 equiv.) and N,Oꢀ
bis(trimethylsilyl)acetamide (0.5 mL, 2.0 mmol, 2 equiv.) in dry acetonitrile (3mL) were heated
to 90 °C under N2 for 10 minutes after which clear solution was formed. The reaction mixture
was then cooled in an iceꢀwater bath and trimethylsilyl trifluoromethanesulfonate (0.36 mL, 2.0
mmol) was added slowly. The reaction mixture was stirred for 1.5 hours at room temperature and
then heated to 60 °C for 2.5 hours until UPLC analysis showed complete consumption of 1. The
reaction was then quenched with 20 mL 10% NH4OH/acetonitrile solution at 0 °C, concentrated
and purified using silica gel column chromatography (eluent 20% ethyl acetate/hexane to 100%
ethyl acetate) to yield the title compound 3b as an offꢀwhite solid material (124 mg, 21%). The
1HꢀNMR and 13CꢀNMR spectra of this material match the one obtained via a different procedure
(see above).
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(2R,3R,4R,5R)-2-((6-Aminopyrimidin-4-yl)amino)-5-((benzoyloxy)methyl)tetrahydrofuran-
3,4-diyl Dibenzoate (4a). To 4ꢀchloroꢀ6ꢀaminopyrimidine (5a, 130 mg, 1 mmol) was added 1
(504 mg, 1 mmol, 1 equiv.), the tube was flushed with nitrogen, and acetonitrile (3 mL) was
added, followed by bis(trimethylsilyl)acetamide (BSA, 0.25 mL, 1 mmol, 1 equiv.). The reaction
mixture was heated to 90 °C under nitrogen for 10 min, then cooled in an ice bath. TMSOTf
(0.36 mL, 2 mmol, 2 equiv.) was added and the contents were stirred at room temperature for 1
hour, when the UPLC/MS analysis showed almost complete consumption of both starting
materials. The reaction mixture was quenched into an iceꢀcold mixture of acetonitrile (20 mL)
and ammonium hydroxide (2 mL), extracted with toluene/ethyl acetate ~ 1/1, washed with water,
brine, dried with MgSO4, concentrated and purified by chromatography on silica gel (gradient
dichloromethane/ethyl acetate from 1/0 to 0/1, then ethyl acetate/methanol ~ 20/1 to 10/1 to
provide the title compound 4a as a white solid material (495 mg, 89 %): 1H NMR (500 MHz,
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DMSOꢀd6) δ = 8.05 ꢀ 8.02 (m, 2H), 7.96 (d, J=0.6 Hz, 1H, H(2)), 7.91 ꢀ 7.88 (m, 2H), 7.87 ꢀ 7.84
(m, 2H), 7.83 (d, J=9.1 Hz, 1H, NH), 7.70 ꢀ 7.60 (m, 3H), 7.54 ꢀ 7.50 (m, 2H), 7.49 ꢀ 7.41 (m,
4H), 6.33 (s, 2H, NH2), 6.04 (br. s., 1H, H(1’)), 5.80 (dd, J=4.4, 5.7 Hz, 1H, H(3’)), 5.62 ꢀ 5.56
(m, 2H, H(2’) and H(5)), 4.59 ꢀ 4.49 (m, 3H, H(4’ and 5’)); 13C NMR (126 MHz, DMSOꢀd6) δ =
165.5, 164.8, 164.7, 163.9 (C(4) or C(6)), 161.5 (C(4) or C(6)), 157.7 (C(2)), 133.8, 133.7,
133.5, 129.34, 129.28, 129.23, 129.20, 128.78, 128.71, 128.67, 128.65, 128.58, 83.9 (C(5)), 83.4
(C(1’)), 77.3 (C(4’)), 73.7 (C(2’)), 71.1 (C(3’)), 64.3 (C(5’)); UPLC/MS: 1.16 min, 555 [M+H]+;
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HRMS (ESI) [M+H]+ calcd for C30H27N4O7 555.1874, found 555.1849.
(2R,3R,4R,5R)-2-((6-Amino-5-methylpyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4d) was prepared following the same
1
procedure as for 4a. Yield: 574 mg (100 %) of white solid material. TLC Rf ~ 0.39 (EtOAc); H
NMR (500 MHz, DMSOꢀd6) δ = 8.11 (s, 1H, H(2)), 8.03 ꢀ 7.99 (m, 2H), 7.93 ꢀ 7.89 (m, 2H),
7.85 ꢀ 7.82 (m, 2H), 7.79 (d, J=8.8 Hz, 1H, NH), 7.69 ꢀ 7.59 (m, 3H), 7.53 ꢀ 7.45 (m, 4H), 7.44 ꢀ
7.39 (m, 2H), 6.88 (br. s., 2H, NH2), 6.26 (dd, J=5.0, 9.1 Hz, 1H, H(1’)), 5.88 (t, J=5.7 Hz, 1H,
H(3’)), 5.84 (dd, J=4.7, 6.0 Hz, 1H, H(2’)), 4.63 ꢀ 4.55 (m, 2H, H(4’+5a’)), 4.51 (dd, J=4.3, 11.2
Hz, 1H, H(5b’)), 1.89 (s, 3H, Me); 13C NMR (126 MHz, DMSOꢀd6) δ = 165.5, 164.8, 164.7,
158.7, 157.7, 150.9 (C(2)), 133.9, 133.8, 133.5, 129.32, 129.30, 129.28, 129.22, 128.8, 128.71,
128.68, 128.63, 128.59, 91.3 (C(5)), 84.0 (C(1’)), 77.3 (C(4’)), 73.8 (C(2’)), 70.8 (C(3’)), 63.9
+
(C(5’)), 8.9 (Me). UPLC: 1.18 min, 569 [M+H]+; HRMS (ESI) [M+H]+ calcd for C31H29N4O7
569.2031, found 569.2005.
(2R,3R,4R,5R)-2-((6-Amino-5-methoxypyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4e).
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Mixture of 6ꢀchloroꢀ5ꢀmethoxypyrimidinꢀ4ꢀamine 5e (159 mg, 1.0 mmol), (NH4)2SO4 (159
mg, 1.2 mmol) and pyridine (0.6 mL) in hexamethyldisilazane (5 mL) under inert atmosphere
(N2) was heated to 140 °C in a sealed tube over a period of 1 h. The reaction mixture was cooled
and concentrated under reduced pressure. To the crude silylated pyrimidine was added 1 (504
mg, 1.0 mmol) and dry acetonitrile (3 mL). The resulting mixture was cooled in an iceꢀwater
bath and SnCl4 (1.0 M solution in CH2Cl2, 2 mL, 2 mmol) was added dropwise. After 1 h at 0 °C
the UPLC analysis showed complete consumption of 1. The mixture was then quenched with 20
mL of 10% NH4OH/acetonitrile solution at 0 ºC. The white precipitate was removed by
filtration, the filtrate was concentrated and purified using silicaꢀgel column chromatography
(eluent 10% ethyl acetate/hexane to 100% ethyl acetate) to yield the title compound 4e as a white
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solid material (428 mg, 73%). H NMR (500 MHz, Acetoneꢀd6) δ = 8.11 (d, J=7.88 Hz, 2 H),
7.99 (dd, J=14.03, 8.04 Hz, 4 H), 7.86 (s, 1 H, H(2)), 7.57 ꢀ 7.68 (m, 3 H), 7.50 (t, J=7.57 Hz, 2
H), 7.45 (q, J=7.88 Hz, 4 H), 6.99 (d, J=9.60 Hz, 1 H, NH), 6.43 (dd, J=9.60, 6.00 Hz, 1 H,
H(1’)), 5.96 (dd, J=5.99, 4.41 Hz, 1 H, H(3’)) 5.92 (dd, J=6.30, 6.00 Hz, 1 H, H(2’)), 5.75 (br.
s., 2 H, NH2), 4.71 (dd, J=11.03, 3.47 Hz, 1 H, H(5’a)), 4.65 (q, J=4.40 Hz, 1 H, H(4’)), 4.62
13
(dd, J=11.00, 4.40 Hz, 1 H, H(5’b)), 3.59 (s, 3 H, OMe) . C NMR (126 MHz, Acetone) δ =
166.6, 166.0, 165.9, 157.5 (C(4) or C(6)), 154.9 (C(4) or C(6)), 153.7 (C2)), 134.40, 134.35,
134.1, 130.9, 130.5, 130.42, 130.41, 130.35, 130.29, 129.5, 129.4 (may be two overlapping
signals), 123.6 (C(5)), 84.9 (C(1’)), 79.1 (C(4’)), 75.2 (C(2’)), 72.5 (C(3’)), 65.2 (C(5’)), 58.9
+
(OMe); UPLC/MS: 1.25 min, 585 [M+H]+; HRMS (ESI) [M+H]+ calcd for C31H29N4O8
585.1980, found 585.1984.
(2R,3R,4R,5R)-2-((6-Amino-5-chloropyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4b) was prepared following the same
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procedure as for 4a. Yield: 378 mg (65 %), a white solid material. TLC Rf ~ 0.38
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(EtOAc/hexanes ~ 1/1); H NMR (500 MHz, DMSOꢀd6) δ = 8.03 (dd, J=1.3, 8.2 Hz, 2H, H(2)),
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7.94 (s, 1H), 7.90 (dd, J=1.3, 8.2 Hz, 2H), 7.85 ꢀ 7.81 (m, 3H, contains NH), 7.69 ꢀ 7.59 (m, 3H),
7.51 (t, J=7.7 Hz, 2H), 7.47 (t, J=7.9 Hz, 2H), 7.41 (t, J=7.9 Hz, 2H), 6.82 (br. s., 2H, NH2), 6.25
(dd, J=4.7, 9.1 Hz, 1H, H(1’)), 5.91 ꢀ 5.86 (m, 2H, H(2’+3’)), 4.62 ꢀ 4.48 (m, 3H, H(4’+5’)); 13C
NMR (126 MHz, DMSOꢀd6) δ = 165.5, 164.8, 164.7, 159.4 (C(6) or C(4)), 156.4 (C(6) or C(4)),
154.8 (C(2)), 133.8, 133.7, 133.5, 129.4, 129.30, 129.27, 129.22, 128.8, 128.71, 128.68, 128.66,
128.62, 91.8 (C(5)), 83.7 (C(1’)), 77.3 (C(4’)), 73.7 (C(2’) or C(3’)), 70.8 (C(2’) or C(3’)), 64.0
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(C(5’)); UPLC/MS: 1.39 min, 589 [M+H]+; HRMS (ESI) [M+H]+ calcd for C30H26ClN4O7
+
589.1485, found 589.1457.
(3R,4R,5R)-2-((6-Amino-5-fluoropyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4f, mixture α/β) and (2R,3R,4R,5R)-
2-(4-Amino-5-fluoro-6-iminopyrimidin-1(6H)-yl)-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-
diyl Dibenzoate (3f) were prepared following the same procedure as for 4a. Purification by
chromatography (gradient ethyl acetate/hexanes ~ 1/4 to 1/0, then to ethyl acetate/methanol 5/1)
provided the less polar material, which was dissolved in ether and precipitated by adding slowly
the same volume of hexanes, then filtered, and washed with hexanes to provide a white solid
1
material containing 4f (mixture α/β ~ 1/2.7). Yield: 194 mg (34 %). H NMR (500 MHz,
Acetoneꢀd6, integration of the mixture is normalized, signals of the minor components are set as
1H, see the supporting information for the spectrum) δ = 8.13 ꢀ 8.06 (m, 7H), 8.04 ꢀ 7.92 (m,
15H), 7.85 (d, J=1.3 Hz, 2.7H), 7.81 (d, J=1.6 Hz, 1H), 7.68 ꢀ 7.56 (m, 11H), 7.54 ꢀ 7.39 (m,
23H), 7.24 (d, J=9.1 Hz, 2.7H), 6.74 (dd, J=5.0, 10.1 Hz, 1H), 6.41 (dd, J=6.0, 9.5 Hz, 2.7H),
6.28 (d, J=8.8 Hz, 1H), 6.01 (t, J=5.0 Hz, 1H),5.99 ꢀ 5.92 (m, 10H), 5.88 (t, J=5.7 Hz, 2.7H). The
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more polar material (3f, 370 mg, 64%) was dissolved in 2 mL of ethyl acetate, diluted with 20
mL of ether, cooled in an ice bath, diluted with 20 mL of hexanes, stirred, then filtered and dried
under vacuum to provide 3f as a white solid material. Yield 255 mg (45 %). 1H NMR (500 MHz,
DMSOꢀd6) δ = 8.61 (s, 1H), 8.48 ꢀ 8.15 (m, 4H, NH2+NH+extra H), 8.02 (dd, J=1.3, 8.5 Hz,
2H), 7.95 (dt, J=1.1, 8.1 Hz, 4H), 7.72 ꢀ 7.64 (m, 3H), 7.54 (t, J=7.7 Hz, 2H), 7.48 (q, J=7.6 Hz,
4H), 6.49 (d, J=4.7 Hz, 1H, H(1’)), 6.05 (dd, J=5.0, 6.0 Hz, 1H, H(2’)), 5.95 (t, J=5.8 Hz, 1H,
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H(3’)), 4.92 ꢀ 4.87 (m, 1H, H(4’)), 4.85 ꢀ 4.75 (m, 2H, CH2(5’)); C NMR (126 MHz, DMSOꢀ
d6) δ = 165.5, 164.51, 164.49, 150.7 (d, J=9.1 Hz), 144.9 (d, J=20.0 Hz), 144.2 (d, J=6.4 Hz,
C(2)), 134.1, 134.0, 133.7, 129.5, 129.42, 129.32, 129.0, 128.8, 128.7 (two overlapping signals),
128.42, 128.37, 126.4 (d, J=237.1 Hz, C(5)), 88.1 (C1’)), 80.4 (C(4’)), 73.9 (C(2’)), 69.8 (C(3’)),
63.4 (C(5’)), (four extra signals observed between 116 and 125 ppm. Cannot explain);
+
UPLC/MS: 1.14 min, 573 [M+H]+ also 445, 201; HRMS (ESI) [M+H]+ calcd for C30H26FN4O7
573.1780, found 573.1750.
(2R,3R,4R,5R)-2-((6-Amino-5-fluoropyrimidin-4-yl)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4f, β−isomer). To 2ꢀchloroꢀ3ꢀfluoroꢀ
4ꢀaminoꢀpyrimidine (2f, 148 mg, 1 mmol) was added ammonium sulfate (7 mg, 5 mol%),
HMDS (3 mL), and the mixture was heated under nitrogen at 135 °C (external temperature)
overnight (15 hours). A clear solution was not formed. Pyridine (1 mL) was added and a clear
solution was formed immediately. After 30 min the mixture was concentrated under vacuum. To
the crude silylated pyrimidine was added 1 (504 mg, 1 mmol), acetonitrile (3 mL), the reaction
mixture was cooled in an ice bath and treated with SnCl4 (1M solution in DCM, 2 mL), which
led to instantaneous dissolution. After 3 h at this temperature, the reaction mixture was quenched
into iceꢀcold mixture of acetonitrile (20 mL) and ammonium hydroxide (2 mL). The reaction
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mixture was diluted with toluene and filtered through Celite, concentrated and purified by
chromatography twice. First purification used a gradient ethyl acetate/hexanes ~ 1/4 to 1/0, then
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to ethyl acetate/methanol
~
5/1. Second purification used
a
gradient ethyl
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acetate/dichloromethane ~ 1/4 to 1/0, then to ethyl acetate/methanol ~ 5/1. The product (352 mg,
0.61 mmol) was dissolved in ether and precipitated with pentane, then washed with pentane to
provide the title compound as a white solid material (147 mg, 26 %, single betaꢀisomer). The
endoꢀisomer 3f was also present in the more polar fractions; however, it could not be isolated
1
clean. Data for 4f: H NMR (500 MHz, DMSOꢀd6) δ = 8.07 (d, J=9.1 Hz, 1H, NH), 8.05 ꢀ 8.01
(m, 2H), 7.93 ꢀ 7.88 (m, 2H), 7.87 ꢀ 7.82 (m, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.69 ꢀ 7.58 (m, 3H),
7.55 ꢀ 7.49 (m, 2H), 7.49 ꢀ 7.44 (m, 2H), 7.44 ꢀ 7.39 (m, 2H), 6.67 (br.s, 2H, NH2), 6.19 (dd,
J=5.4, 9.5 Hz, 1H, H(1’)), 5.89 ꢀ 5.84 (m, 1H, H(3’)), 5.78 (t, J=5.7 Hz, 1H, H(2’)), 4.62 ꢀ 4.48
(m, 3H, H(4’ and 5’)); 13C NMR (126 MHz, DMSOꢀd6) δ = 165.5, 164.8, 164.7, 152.2 (d, J=10.0
Hz, C(2)), 151.7 (d, J=8.2 Hz, C(4) or C(6)), 148.3 (d, J=7.3 Hz, C(4) or C(6)), 133.8, 133.7,
133.5, 129.4, 129.3, 129.24, 129.20, 130.1 (d, J=246.1 Hz, C(5)), 128.8, 128.7 (broad, three
signals may overlap here), 128.6, 83.1 (C(1’)), 77.3 (C(4’)), 73.7 (C(2’)), 70.9 (C(3’)), 64.1
+
(C(5’)); UPLC/MS: 1.36 min, 573 [M+H]+; HRMS (ESI) [M+H]+ calcd for C30H26FN4O7
573.1780, found 573.1750.
(2R,3R,4R,5R)-2-((6-Aminopyrimidin-4-yl-3-15N)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (4a-15N). To 2a (130 mg, 1 mmol) was
added 1 (504 mg, 1 mmol), acetonitrile (3 mL), BSA (0.25 mL), and the mixture was heated to
90 °C for 10 minutes, then cooled in an ice bath. TMSOTf was added (0.36 mL, 2 mmol) and the
reaction was continued at room temperature for 25 minutes, then quenched into stirred iceꢀcold
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mixture of acetonitrile (20 mL), water (5 mL), 15NH4Cl (98 % 15N, 550 mg, 10 mmol), and
K2CO3 (1,380 mg, 10 mmol). The mixture was diluted with toluene, washed with water, brine,
dried (MgSO4) concentrated and purified by chromatography (gradient ethyl
acetate/dichloromethane ~ 0/1 to 1/0). The isolated material was dissolved in ether, cooled in an
ice bath, and precipitated by addition of hexanes. The solid material was washed with pentane
and dried under vacuum to provide the title compound as a white solid material (159 mg, 0.29
mmol, 29 %). The mother liquor was partially concentrated in a flow of nitrogen at rt to provide
additional amount of the title compound (105 mg, 0.19 mmol). 1H NMR (500 MHz, DMSOꢀd6) δ
= 8.05 ꢀ 8.00 (m, 2H), 7.96 (d, J=15.1 Hz, 1H, H(2)), 7.92 ꢀ 7.88 (m, 2H), 7.87 ꢀ 7.84 (m, 2H),
7.83 (dd, J=2.2, 9.5 Hz, 1H, NH), 7.70 ꢀ 7.60 (m, 3H), 7.55 ꢀ 7.50 (m, 2H), 7.49 ꢀ 7.41 (m, 4H),
6.34 (s, 2H, NH2), 6.04 (br. s., 1H, H(1’)), 5.80 (dd, J=4.4, 5.7 Hz, 1H, H(3’)), 5.62 ꢀ 5.55 (m,
2H, H(2’) and H(5)), 4.59 ꢀ 4.47 (m, 3H, H(4’) and H(5’)); 13C NMR (126 MHz, DMSOꢀd6) δ =
165.5, 164.8, 164.7, 163.9 (d, J=1.8 Hz, C(4 or 6)), 161.5 (d, J=4.5 Hz, C(4 or 6)), 157.8,
133.83, 133.76, 133.5, 129.4, 129.28, 129.25, 129.23, 128.8, 128.73, 128.71, 128.66, 128.6, 83.9
(C(5)), 83.4 (C(1’)), 77.3 (C(4’)), 73.7 (C(2’)), 71.1 (C(3’)), 64.3 (C(5’)); UPLC/MS: 1.15 min,
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+
556 [M+H]+; HRMS (ESI) [M+H]+ calcd for C30H27N3 NO7 556.1845, found 556.1820.
5-Nitropyrimidine-4,6-diamine-15N2 (8). To 15NH4Cl (460 mg, 8.4 mmol) was added
acetonitrile and the mixture was cooled in an ice bath. Triethylamine (2.1 mL, 15 mmol) was
added, followed by 4,6ꢀdichloroꢀ5ꢀnitropyrimidine (7, 386 mg, 2.0 mmol) and the mixture was
stirred in a sealed tube at room temperature for 6 hours, then diluted with water and filtered,
washed the solid material with water and acetonitrile, then dried to provide 8 as a light brown
colored material (281 mg, 1.8 mmol, 90 %). 1H NMR (500 MHz, DMSOꢀd6) δ = 8.49 (d, J=92.4
13
Hz, 2H, 2 x NHaHb), 8.42 (d, J=91.4 Hz, 2H, 2 x NHaHb), 7.87 (s, 1H, H(2)). Satisfactory Cꢀ
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NMR spectrum could not be obtained due to poor solubility of the material. See HSQC spectrum
in the Supporting Information, page S102) for the approximate location of the C(2) signal (158.5
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+
ppm); HRMS (ESI) [M+H]+ calcd for C4H5N3 N2O2 158.0457, found 158.0448.
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(2R,3R,4R,5R)-2-((4-(Amino-15N)-5-nitropyrimidin-6-yl-1-15N)amino)-5-
((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl Dibenzoate (10). To 8 (159 mg, 1 mmol) was
added ammonium sulfate (7 mg, 0.05 equiv), HMDS (3 mL), pyridine (1 mL), and the mixture
was heated under nitrogen in a 130 °C heat block. After 5 hours a clear solution was formed and
the reaction mixture was concentrated under vacuum using rotovap, then under high vacuum. To
this crude silylated aminopyrimidine was added 1 (454 mg, 0.9 mmol), acetonitrile (3 mL),
TMSOTf (0.36 mL, 2 mmol) and the mixture was left at room temperature overnight (18 hours)
and then quenched with ammonium hydroxide (0.5 mL), partitioned between EtOAc and brine,
the organic layer was dried with MgSO4, concentrated and purified by chromatography (gradient
ethyl acetate/dichloromethane ~ 0/1 to 1/3). The isolated material was recrystallized from
isopropanol to provide the title product 10 (281 mg, 47 %). Additional recrystallization from
1
methanol provided analytically pure 10 (147 mg) as a lightly colored yellow solid material. H
NMR (500 MHz, DMSOꢀd6) δ = 9.63 (dd, J=3.9, 8.4 Hz, 1H, HN), 8.63 (d, J=91.1 Hz, 1H,
NHaHb), 8.56 (d, J=93.6 Hz, 1H, NHaHb), 8.04 (d, J=15.8 Hz, 1H, H(2)), 8.02 ꢀ 8.00 (m, 2H),
7.92 ꢀ 7.88 (m, 2H), 7.87 ꢀ 7.83 (m, 2H), 7.69 ꢀ 7.60 (m, 3H), 7.53 ꢀ 7.40 (m, 7H), 6.37 (dd,
J=4.9, 8.4 Hz, 1H, H(1’)), 6.00 (dd, J=5.0, 6.0 Hz, 1H, H(2’)), 5.91 (t, J=5.4 Hz, 1H, H(3’)),
4.67 ꢀ 4.61 (m, 2H, H(4’+5’a)), 4.60 ꢀ 4.54 (m, 1H, H(5’b)). 13C NMR (126 MHz, DMSOꢀd6) δ =
165.5, 164.7, 164.6, 159.1 (d, J=2.7 Hz, (C(2))), 158.5 (dd, J=1.8, 21.8 Hz, (C(6))), 156.5 (d,
J=3.6 Hz, (C(4))), 133.8, 133.7, 133.5, 129.29, 129.27, 129.22, 128.8, 128.68, 128.67, 128.63,
128.5, 112.5 (C(5)), 83.9 (C(1’)), 78.0, 74.0 (C(2’)), 71.0 (C(3’)), 63.8 (C(5’)). One Bz signal is
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missing, probably due to overlap. UPLC: 1.43 min, 602 [M+H]+, also 445, 201; HRMS (ESI)
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+
[M+H]+ calcd for C30H25N3 N2O9 602.1666, found 602.1637.
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Acknowledgment. The authors are thankful to Mrs. Jane Yang for analytical support and to
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Prof. Scott E. Denmark from the University of Illinois, UrbanaꢀChampaign for discussions.
Supporting Information Available. Spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org or from rbaiazitov@ptcbio.com.
References
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(2)
Kubo, I.; Kim, M.; Wood, W. F.; Naoki, H. Tetrahedron Lett. 1986, 27, 4277.
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(a) Fortin, H.; Tomasi, S.; Delcros, J.; Bansard, J.; Boustie, J. ChemMedChem 2006, 1,
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CN 101333236, 2008; Chem. Abstr. 2008, 150, 106103. (e) Liu, F. Y.; Guo, T. D.; Wu,
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(5)
(a) Lee, C.ꢀH.; Daanen, J. F.; Jiang, M.; Yu, H.; Kohlhaas, K. L.; Alexander, K.; Jarvis,
M. F.; Kowaluk, E. L.; Bhagwaty, S. S. Bioorg. Med. Chem. Lett. 2001, 11, 2419–2422;
(b) Kamikawa, T.; Fujie, S.; Yamagiwa, Y.; Kim, M.; Kawaguchi H. Chem. Commun.
1988, 195ꢀ196.
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(6)
(7)
(8)
(a) Linek, K.; Alföldi, J. Carb. Res., 1987, 164, 195ꢀ205; (b) Linek, K.; Alföldi, J.;
Defaye, J. Carb. Res., 1993, 247, 329ꢀ335.
Vorbbrüggen, H.; RuhꢀPohlenz, C. Synthesis of Nucleosides in Organic Reactions 2000,
55, DOI: 10.1002/0471264180.or055.01.
(a) Kusano, S.; Hattori, K.; Imoto, S.; Nagatsugi, F. Nucleic Acids Symposium Series,
2009, 53, 169ꢀ170; (b) Choi, H.; Choi, B. S.; Chang, J. H.; Lee, K. W.; Nam, D. H.; Kim,
Y. K.; Lee, J. H.; Heo, T.; Shin, H.; Kim, N.ꢀS. Synlett, 2005, 1942ꢀ1944; (c) Moss, R. J.;
Petrie, C. R.; Meyer Jr., R. B.; Nord, L. D.; Willis, R. C.; Smith, R. A. Larson, S. B.;
Kini, G. D.; Robins, R. K. J. Med. Chem. 1988, 31, 786ꢀ790; (d) Rokos, H.; Pfleiderer,
W. Chem. Ber. 1971, 104, 748ꢀ769.
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For example: (a) Rajeev, K. G.; Broom, A. D. Org. Lett., 2000, 2, 3595ꢀ3598; (b)
Gosselin, G.; Bergogne, M.ꢀC.; Rudder, J. D.; Clercqm E. D.; Imbach, J.ꢀL. J. Med.
Chem., 1987, 30, 982ꢀ991; (c) Ciceri, S.; Ciuffreda, P.; Grisenti, P.; Ferraboschi, P.
Tetrahedron Lett., 2015, 56, 5909ꢀ5913; (d) Chien, T.ꢀC.; Chen, C.ꢀS.; Yu, F.ꢀH.; Chern,
J.ꢀW. Chem. Pharm. Bull, 2004, 52, 1422—1426; (e) Kovaliov, M.; Segal, M.; Fischer,
B. Tetrahedron, 2013, 69, 3698ꢀ3705.
(10) For example, reviews: (a) El Ashry, E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H. Adv.
Het. Chem. 1999, 75, 79ꢀ165; (b) Fujii, T.; Itaya, T. Heterocycles 1998, 48, 359ꢀ390.
Relevant applications in chemistry: (c) Macon, J. B.; Wolfenden, R. Biochem. 1968, 7,
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The Journal of Organic Chemistry
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3453ꢀ3458; (d) Brown, D. J; Harper, J. S. J. Chem. Soc. 1965, 5542ꢀ5551; (e) Brown, D.
J; Harper, J. S. J. Chem. Soc. 1963, 1276ꢀ1284.
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(11) BSA/TMSOTf combination also worked; however, the yield was lower (21 %)
(12) The product could not be isolated sufficiently pure.
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(13) Witanowski, M.; Stefaniak, L.; Webb, G. A. Nitrogen NMR spectroscopy in Annual
reports on NMR spectroscopy, G. A. Webb, Ed., Volume 11b, 1981
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(14) Although there may be a trend that the absolute value of J (1Hꢀ15N) is lower in
2
heterocycles than that of J (1Hꢀ15N), this is not always true and cautious analysis is
required.
(15) Unfortunately, there is no clear trend for the 13Cꢀ15N couplings. For example, the
3
2
magnitude of J (13Cꢀ15N) in pyridine is larger (ꢀ3.85 Hz) than J (13Cꢀ15N) coupling
(+2.53 Hz) or 1J (13Cꢀ15N) coupling constant (+0.62 Hz). As a consequence, the 13CꢀNMR
coupling constants could not be used for the structure confirmation.
(16) See the Experimental Section for details.
(17)
Various
combinations
of
silylating
agents
(HMDS,
BSA,
BSTFA,
TMSOTf/triethylamine) and Lewis acids (TMSOTf or SnCl4) in dichloromethane,
acetonitrile or 1,2ꢀdichloroethane can often be used. Moreover, 2,3,5ꢀtriacetate analog of
1 can be used (86 % yield, not shown).
(18) Attempted debenzoylation of several analogs 4 with ammonia or NaOMe in methanol led
to formation of a material that was a complex mixture of products according to NMR
analysis. The mass spectrometry analysis suggested that a compound with the expected
mass is present. TLC analysis shows a single spot with the retention different from either
animopyrimidine or ribose. We believe that upon deprotection the product undergoes
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