Regio- and enantioselective synthesis of chiral pyrimidine acyclic nucleosides via rhodium-catalyzed asymmetric allylation of pyrimidines

Article abstract of DOI:10.1021/acs.orglett.7b02482

A direct route to branched N-allylpyrimidine analogues is herein reported via the highly regio- and enantioselective asymmetric allylation of pyrimidines with racemic allylic carbonates. With [Rh(COD)Cl]₂/chiral diphosphine as the catalyst, a r

Full text of DOI:10.1021/acs.orglett.7b02482

Letter
pubs.acs.org/OrgLett
Regio- and Enantioselective Synthesis of Chiral Pyrimidine Acyclic
Nucleosides via Rhodium-Catalyzed Asymmetric Allylation of
Pyrimidines
Lei Liang,† Ming-Sheng Xie,*,‡ Tao Qin,‡ Man Zhu,‡ Gui-Rong Qu,‡ and Hai-Ming Guo*,†,‡
‡
†School of Environment and Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation, School of Chemistry
and Chemical Engineering, Henan Normal University, Xinxiang, Henan Province 453007, China
S
* Supporting Information
ABSTRACT: A direct route to branched N-allylpyrimidine analogues is herein reported via the highly regio- and
enantioselective asymmetric allylation of pyrimidines with racemic allylic carbonates. With [Rh(COD)Cl]2/chiral diphosphine
as the catalyst, a range of chiral pyrimidine acyclic nucleosides could be obtained under neutral conditions in good yields (up to
95% yield) with high levels of regio- and enantioselectivities (15:1 to >40:1 B/L and up to 99% ee). Furthermore, chiral
pyrimidine acyclic nucleoside bearing two adjacent chiral centers has been successfully synthesized by asymmetric
dihydroxylation.
while its antipode, R-enantiomer is devoid of effect.2e (2)
hiral acyclic nucleosides are currently used as antiviral
Cdrugs. (S)-Cidofovir, a broad-spectrum antiviral agent, is The S-enantiomer of FPMPA has an IC50 of 1.85 μM, whereas
the R-enantiomer is inactive2f (Figure 1). Therefore, the
currently used to treat AIDS-related human cytomegalovirus
synthesis of optical purity acyclic nucleosides seems more
valuable, and considerable efforts have been devoted to the
construction of chiral pyrimidine acyclic nucleosides.
(HCMV) retinitis and has recognized therapeutic potential for
orthopox virus infections.1 Some other nucleosides and
nucleotides with chiral carbons in the acyclic side chain, such
as (S)-FPMPT, (S)-willardiine, (S)-HPMPA, and (R)-tenofo-
vir, possess various medicinal activities (Figure 1).2a−d The
absolute configuration of acyclic nucleosides has a significant
influence on their biological potency. For example, (1)
cidofovir, the S-enantiomer, shows high antiviral activity,
Early synthetic approaches to pyrimidine acyclic nucleosides
were based mainly on aza-Michael addition, SN2 reaction,
Mitsunobu reaction, or ring opening of epoxides.3 However,
strategies to obtain chiral pyrimidine acyclic nucleosides are still
rare. In 2006, Evans and co-workers successfully demonstrated
the feasibility of the synthesis of acyclic pyrimidine nucleosides
via Rh-catalyzed allylation of thymine.4 Nevertheless, strong
base was required to enhance the nucleophilicity of thymine,
and the allylated products were racemic. Furthermore, in order
to obtain chiral pyrimidine acyclic nucleosides, a chiral allylic
carbonate was necessary as the chiral starting material. In
contrast, low-cost and easily accessed achiral allylic electrophiles
have never been successfully applied in the synthesis of chiral
acyclic pyrimidine nucleosides. The asymmetric synthesis of
chiral acyclic pyrimidine nucleosides is still under-developed. As
part of our ongoing endeavors on the chemical synthesis of
chiral nucleosides,5 we became interested in addressing this
challenge.
Recently, the asymmetric addition of pronucleophiles to
allenes,6 alkynes,7 and racemic allylic carbonates8 catalyzed by
Figure 1. Structures of representative chiral acyclic nucleosides with
different biological activities.
Received: August 10, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02482
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Letter
b
rhodium or iridium has provided a powerful tool to construct a
new chiral center (Scheme 1a). Inspired by these previous
Table 1. Optimization of the Reaction Conditions
Scheme 1. Synthetic Approaches to N-Allylated Products
works, we envisioned that the synthesis of chiral acyclic
pyrimidine nucleosides might be enabled by asymmetric allylic
substitution of less nucleophilic and more complex pyrimidines
with achiral allylic electrophiles. Herein, we report a rhodium-
catalyzed asymmetric allylation of pyrimidines with achiral
allylic electrophiles (easily prepared) for the synthesis of α-
chiral acyclic pyrimidine nucleosides (Scheme 1b). Notably, the
allylation of pyrimidines proceeded in a highly regio- and
enantioselective manner under neutral conditions.
c
d
e
entry
ligand
2
B/L
yield (%)
ee (%)
a
1
L1
L1
2b
2b′
2b
2b′
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
>50:1
15:1
92
NR
51
13
a
2
3
rac-BINAP-L2
4
rac-BINAP-L2
NR
73
5
L3
18:1
6
DPPP-L4
DPPB-L5
L6
trace
15
7
Initially, the reaction between N3-Bz-protected thymine 1a
and allylic carbonate 2b or 2b′ was chosen as the model
reaction (Table 1). N1-Allylated product 3ab was obtained with
highly branched regioselectivity in low ee (Table 1, entry 1)
when [Ir(COD)Cl]2-L1 was employed as the catalyst in THF
at 50 °C for 12 h. The enantioselectivity of N1-allylated
thymine was hardly controlled by the Ir-catalyst system (see the
Supporting Information for details). After that, [Rh(COD)-
Cl]2/diphosphine catalysts were examined, rac-BINAP was first
tested for the model reaction, and N-allylated 3ab was isolated
in moderate yield and a ratio of 15:1 B/L (Table 1, entry 3).
Interestingly, the allylic carbonate 2b′ was not suitable for the
allylation reaction, no matter whether an Ir catalyst or Rh
catalyst system was selected (Table 1, entries 1−4). Meanwhile,
carbonate 2b was the appropriate reaction partner. A series of
achiral ligands were next examined, including [Rh(COD)Cl]2
(3.0 mol %) and DPEPhos (6.0 mol %), and the reaction
proceeded smoothly and provided the desired branched
product 3ab with good branched/linear selectivity (Table 1,
entries 3−8). With an effective method for the racemic
allylation reaction in hand, different types of chiral bidentate
phosphine ligands were subsequently screened. Josiphos and
(R,R)-DIOP ligands resulted in moderate to high yields and
poor enantioselectivities (Table 1, entries 9 and 10). Biaryl-type
bisphosphine ligands were next examined. (R)-BINAP-L9 was
not effective at promoting this coupling reaction (Table 1, entry
11). Meanwhile (R)-Synphos-L10 led to moderate yield and ee
value. The use of (R)-Segphos-L11 and (R)-MeOBIPHEP-L13
further increased the enantioselectivity of the desired product
(Table 1, entries 13 and 15). To our delight, (R)-DTBM-
8
19
9
L7
13:1
>30:1
17:1
52
39
53
13
51
65
98
61
96
10
11
12
13
14
15
16
L8
88
L9
45
L10
20:1
75
L11
25:1
83
L12
>30:1
>30:1
>30:1
85
L13
79
L14
83
a
Entries 1−2, conditions A: 1a (0.2 mmol), 2b or 2b′ (0.4 mmol),
K3PO4 (0.2 mmol), [Ir(COD)Cl]2 (2 mol %) and L1 (4 mol %) in
b
THF (1.0 mL), 50 °C, N2, 12 h. Entries 3−16, conditions B: 1a (0.2
mmol), 2b or 2b′ (0.4 mmol), [Rh(COD)Cl]2 (3 mol %) and L (6
c
mol %), in DCE (1.0 mL), 80 °C, N2, 12 h. The ratio was determined
d
e
from the crude 1H NMR. Yields of isolated product. Determined by
chiral HPLC analysis. DPPP = 1,3-bis(diphenylphosphino) propane.
DPPB = 1,4-bis(diphenylphosphino)butane.
Segphos-L12 and (R)-DTBM-MeOBIPHEP-L14 (the ligands
bearing more bulkier substituent group) led to the desired
product in good yield, high regioselectivity, and high
enantioselectivity (Table 1, entries 14 and 16). On the basis
of these results, we believed that L12 was the best choice.
Under the optimized reaction conditions, N-allylation of
thymine with a series of allylic carbonates was evaluated as
summarized in Scheme 2. A variety of electron-neutral,
electron-rich, or electron-deficient phenyl-substituted allylic
carbonates containing ortho, meta, or para substituents gave the
corresponding chiral N-allylated thymine products in moderate
to good yields with good branched regioselectivities and good
B
DOI: 10.1021/acs.orglett.7b02482
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a
a
Scheme 2. Substrate Scope of Allylic Carbonates
Scheme 3. Substrate Scope of Pyrimidine Derivatives
a
1
The B/L ratio was determined from crude H NMR, and the ee
values were determined by chiral HPLC analysis. Yield of isolated
branched yield.
strong electron-withdrawing group such as −F and −CF3 were
also tolerated well in this reaction, delivering the corresponding
products in good ee values (3fb, 3gb). After that, N3-Boc-
protected pyrimidine derivatives were examined. When Boc-
protected uracil (1h) and Boc-protected thymine (1i) were
used, the intermolecular asymmetric allylic reaction smoothly
afforded the branched products in good results (3hb, 3ib).
To further evaluate the prospect of using the methodology in
synthesis, a gram-scale synthesis of N1-allylthymine 3ab was
performed. As shown in Scheme 4, 3ab was obtained in 80%
a
1
The B/L ratio was determined from crude H NMR, and the ee
values were determined by chiral HPLC analysis. Yield of isolated
b
c
branched yield. 18 h. [Rh(COD)Cl]2 (1.0 mol %), L12 (2.0 mol %).
enantioselectivities (Scheme 2, 3aa−ak). The reactions with
phenyl-substituted allylic carbonates containing diverse elec-
tronic properties at the para position furnished the products in
moderate to high yields, and the results were similar to the
phenyl allylic carbonate 2a (Scheme 2, 3ad, 3ag−aj). The
highest selectivities were observed with the o-I phenyl-
substituted allylic carbonate (Scheme 2, 3ak). Notably, the
yields of desired products were decreased when a chlorine atom
was present at the ortho or meta position of the phenyl (Scheme
2, 3ae, 3af). However, the reaction of the corresponding allylic
carbonate 2b gave the branched allylation product 3ab in good
yield (85%) and regioselectivity (>30:1) with high enantiose-
lectivity (98% ee). Both 3,4-dimethylphenyl and 2-naphthyl
allylic carbonates reacted selectively with thymine, and the
reaction time of 2m was prolonged to 18 h (Scheme 2, 3al,
3am). Alkyl-substituted allylic carbonates were also reacted to
provide allylated products 3an−ap. Methyl allylic carbonate 2n
furnished the corresponding product in high yield (95%) with a
relatively good enantioselectivity (92% ee), whereas α-branched
isopropyl 2o and α-branched cyclohexyl 2p allylic carbonates
afforded the desired substitution products in good yields with
excellent enantioselectivities (Scheme 2, 3ao, 3ap). Notably, in
all cases, the allylated products were obtained with >10:1
branched-to-linear selectivity. The absolute configuration of the
chiral allylic thymine analogue 3ak was determined to be S by
single-crystal X-ray diffraction analysis.
Scheme 4. Gram-Scale Synthesis of 3ab
yield (1.25 g), >30:1 B/L, and 98% ee by treatment of 4.35
mmol of Bz-protected thymine 1a with allylic carbonate 2b in
the presence of 3 mol % of [Rh(COD)Cl]2 and 6 mol % of
(R)-DTBM-Segphos-L12. When the reaction was performed
with 1 mol % of [Rh(COD)Cl]2, 2 mol % of L12, the allylate
ion product 3ab was obtained in 48% yield along with the
recovery of the starting material 1a in 44% yield.
In order to highlight its synthetic utility, the transformations
of N-allylated pyrimidine derivatives were next examined. The
acylic nucleoside analogue 4ab was successfully synthesized
with good selectivity (ds = 45:1) by the Sharpless asymmetric
dihydroxylation9 of 3ab. Hydrogenation of 3ab provided N-
alkylpyrimidine 5ab in 95% yield with 96% ee. A broader range
of products could be obtained through the modification of the
Subsequently, a series of pyrimidine derivatives with different
substituents at the C5 position were investigated (Scheme 3).
5-Ethyl- and 5-halo-substituted pyrimidines (1b−f) reacted
smoothly to provide the allylic pyrimidine derivatives 3bb−fb
in 73−93% yields, >15:1 B/L, and 90−96% ee. In addition,
C
DOI: 10.1021/acs.orglett.7b02482
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pyrimidine skeleton via Suzuki and Sonogashira coupling
reactions which performed well and delivered the correspond-
ing products 4cb and 5cb in good yields (Scheme 5, c and d).
21402041), the Plan for Scientific Innovation Talent of Henan
Province (164200510008), and Program for Innovative
Research Team in Science and Technology in University of
Henan Province (15IRTSTHN003).
Scheme 5. Synthesis of Acyclic Nucleoside Analogue and the
Transformations of N-Allylated Pyrimidine Derivatives
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
Experimental procedures, the synthesis method of the
starting materials, and compound characterization data
(PDF)
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X-ray data for compound 3ak (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xiemingsheng@htu.edu.cn.
*E-mail: ghm@htu.edu.cn.
ORCID
Hai-Ming Guo: 0000-0003-0629-4524
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. U1604283 and
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DOI: 10.1021/acs.orglett.7b02482
Org. Lett. XXXX, XXX, XXX−XXX