New Catalytic Asymmetric Formation of Oxygen Heterocycles Bearing Nucleoside Bases at the Anomeric Carbon

Article abstract of DOI:10.1021/jacs.9b06050

Pyrimidine nucleosides are an important class of compounds with versatile applications across many fields, including biology and medicinal chemistry. Synthesis of nucleoside analogs in optically pure form via traditional glycosylation has always been a ch

Full text of DOI:10.1021/jacs.9b06050

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Communication
New Catalytic Asymmetric Formation of Oxygen Heterocycles
Bearing Nucleoside Bases at the Anomeric Carbon
Barry M. Trost, Shiyan Xu, and Ehesan U. Sharif
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06050 • Publication Date (Web): 13 Jun 2019
Downloaded from http://pubs.acs.org on June 13, 2019
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New Catalytic Asymmetric Formation of Oxygen Heterocycles Bear-
ing Nucleoside Bases at the Anomeric Carbon
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Barry M. Trost,* Shiyan Xu and Ehesan U. Sharif
Department of Chemistry, Stanford University, 333 Campus Dr. Stanford, CA 94305, USA
Supporting Information Placeholder
often requires the use of additional protecting groups and unde-
sired redox and functional group manipulations to arrive at a suit-
able glycosylation donor.14 Common in these methods are poor
yields and diastereoselectivities15 in the glycosylation steps, espe-
cially with substrates (Scheme 1) that do not have 2’ assisting gr-
oups to direct the stereochemistry of the amido-ether bond for-
mation.16
ABSTRACT: Pyrimidine nucleosides are an important class of
compounds with versatile applications across many fields, includ-
ing biology and medicinal chemistry. Synthesis of nucleoside
analogs in optically pure form via traditional glycosylation has
always been a challenge, especially for unnatural carbohydrate
motifs which do not have C2 substitution to dictate the stereo-
chemical outcome of the newly formed glyosidic bond. Herein,
we report an asymmetric Pd-catalyzed synthesis of nucleoside
analogs enabled by the development of a series of chiral ligands.
A variety of 5-substituted pyrimidine nucleobases, ranging from
5- to 12-membered ring nucleoside analogs are generated in good
yield (68% to 96%), diastereo- (> 20:1), and enantioselectivity
(85% ee to 99.5% ee). These nucleoside analogs bearing an iodide
functional group handle allow for rapid transformation to a variety
of other interesting pyrimidine nucleoside structures.
O
H
H
F
O
O
N
O
NH
N
(RO)2OPO
O
HO
O
N
O
N
N
O
Me
O
HO
F
N3
Tegafur5
AZT4
(Antiviral activity)
Sovaldi6
(Anticancer activity)
(Antiviral activity)
H
O
OR
N
O
O
Base
F
N
O
O
N
NHR
N
P
N
Me
The ubiquity of biological processes that rely on DNA or RNA
for cellular function has made the regulation of interference with
pathways related to the replication and translation of DNA and
RNA exceptionally useful targets for drug discovery.1 Almost half
of antiviral and anticancer drugs currently on the market are nu-
cleosides.2 Among them, most contain a tetrahydrofuran ring with
a 1’ amido-ether linkage to a natural or slightly modified nucleo-
side base. The most common structural variations are removal or
derivatization of either or both of the 2’ and/or 3’ hydroxyl groups
on the tetrahydrofuran ring. While appearing minor, these changes
produce compounds with significantly differential biological
properties, and more importantly, enhanced selectivity among
homologous proteins.3 Selected examples of nucleoside analogs
that represent the broad structural diversity of drugs which are
approved by the FDA or currently under various developmental
stages are listed in Figure 1. While most nucleoside derivatives
contain a tetrahydrofuran core, utilization of alternative tetrahy-
dropyran and oxepane moieties has become increasingly im-
portant, as represented by the approved drugs and synthetic nu-
cleoside analogs in Figure 1. Additionally, unnatural nucleosides,
such as those containing hexose9 or oxepane,10 have been studied
as interesting monomer backbones for unnatural oligonucleosides,
which are important for gene knockdown and antisense technolo-
gies.
O
O
OR
RO
N
NTs
Synthetic analog11 ()
Eteplirsen8
(Muscular dystrophy
activity)
Amicetin7
(Antiproliferative activity)
H
(antibiotic activity)
O
N
O
HO
HO
HO
O
N
OH
O
OR
Base
O
RO
HO
Base
Synthetic analog12 ()
Hexose9
Oxepane10
(Antiviral activity)
Figure 1. Biologically Important Pyrimidine Nucleoside De-
rivatives.
Given these limitations, the development of new methods that
allow for the high yielding and stereoselective synthesis of nucle-
oside amido-ether linkages could dramatically improve overall
synthetic efficiencies towards such structures. To the best of our
knowledge, the first report of an asymmetric synthesis17 of the N-
O amido-ether linkage was reported in 2017 by Rhee et. al
(Scheme 1). In this report, acyclic N-heterocyclic amide ethers
were synthesized by the Pd-catalyzed asymmetric addition of
pyrimidines to alkoxyallenes. In spite of this progress, the direct
asymmetric synthesis of cyclic pyrimidine nucleosides remains a
significant challenge.
Most unnatural nucleosides are synthesized by the derivatiza-
tion of natural nucleosides or by the coupling of activated bases
with anomerically activated sugars using traditional glycosyla-
tions.13 While the former is applicable only if a minor change to
the natural nucleoside is required and is limited by the scope of
derivatizations, the later reliance on traditional glycosylations
As a part of our ongoing investigations on ruthenium chemistry,
we have established an efficient synthesis of biologically im-
portant and versatile cyclic amido-ether building blocks.18 While
the reported method was a significant development, it lacked en-
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antioselectivity and suffered from a lack of generality. Herein, we
Scheme 2. Development of Chiral Ligands.
1
2
3
4
report the development of a new catalyst system that enables the
enantioselective synthesis of pyrimidine nucleoside analogs bear-
ing an iodide functional group handle for further functionalization,
with a broad substrate scope via iodoetherification (Scheme 1).
Scheme 1. Summary of Prior and Current Work.
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Table 1. Reaction Optimization. a
To initiate our studies, we used diene 1a, which is conveniently
prepared in 1 step from commercial materials using a Ru-
catalyzed alkene-alkyne coupling,19 as a standard substrate to
evaluate chiral ligands. In the absence of the Pd-catalyst, exclu-
sive iodination of the vinyl silane occurs with the vinyl pyrimi-
dine remaining untouched. While most of the ligands evaluated
gave unsatisfactory reactivity and/or enantioselectivity (see SI),
the N,P-bidentate PHOX ligand20 L1 and QUIPHOS ligand21 L2
(Scheme 2) gave good yields and moderate selectivities, 48% ee
and 63% ee respectively. Given these results, we focused on lig-
ands L3 to L6, which were synthesized from (1S,2S)-1,2-
diphenylethane-1,2-diamine 3. Buchwald-Hartwig amination22 of
the diamine with the corresponding aromatic bromide followed by
installation of the quinoline or pyridine using PCl3 gave rapid
access to this new class of diamidophosphite ligands. Within these
new ligands, changing the chiral backbone of L2 to L3 resulted in
an inproved ee of 76%. Changing the quinoline ring of L3 to a
pyridine (L4) was not productive; however, the more sterically
crowded pyridine in L5 was better tolerated. Having optimized
the backbone and the quinoline as the secondary metal coordina-
tion site, we turned to optimizing the N-aryl group. Pleasingly,
placing a p-CF3 group on the N-phenyl rings as shown in L6
further enhances the ee to 80% with a 91% yield.
entry
solvent
THF
T
yield (%)
0b
dr
ee
1
2
3
4
5
6
7
8
9
4 °C
4 °C
4 °C
−
−
THF
91
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
> 20:1
80%
84%
54%
74%
22%
90%
76%
89%
DME
91
Toluene 4 °C
32
EtOAc
Et2O
4 °C
4 °C
4 °C
rt
89
15
DCM
DCM
DCM
93c
89
-10 °C
88
a All reactions were performed on 0.10 mmol scale at 0.1 M for 12 hours.
1
Yields and dr were determined by crude H NMR spectroscopic analysis
using 1,3,5-trimethoxybenzene as an internal standard; ee determined by
chiral HPLC. b Without L6. c Isolated yield.
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Adopting L6 as the standard ligand, variations of the reaction
served with 5-fluorouracil (2m), 5-chlorouracil (2n), 5-
bromouracil (2o) and 5-iodouracil (2p). The nitrogen protecting
group could also be changed to PhSO2 (2q) while maintaining
good yield as well as high ee and dr.
1
2
3
4
5
6
7
8
conditions were examined to further enhance the ee (see Table 1).
No reactivity was observed without ligand L6 (entry 1). When the
solvent was changed from THF to DME (entry 3), the enantiose-
lectivity increased to 84%. With toluene, EtOAc or Et2O as sol-
vents, both the yield and enantioselectivity were lower than with
THF (entries 4-6). Fortunately, DCM gave significantly better
results, and 2a was obtained in a much-improved 93% isolated
yield, > 20:1 dr, and 90% ee (entry 7). Higher or lower tempera-
ture had no benefit on yields or selectivities (entries 8, 9).
We were pleased to find that our method was not limited to tet-
rahydrofuran, tetrahydropyran and oxepane ring systems. Notably,
this new catalyst system could effectively form medium and large
ring systems at concentration as high as 0.1 M, in contrast to
many macrocyclization processes. Along these lines, the 8-
membered medium ring 2r was obtained in 87% yield, 87% ee
and > 20:1 dr, and its structure was determined by X-ray crystal-
lography.24 The absolute stereochemistry at C5 and C6 were both
determined to have the S configuration, placing the uracil and the
iodide in a trans configuration. The 9-membered medium ring 2s
was obtained in 92% ee and > 20:1 dr. Excellent enantio- (95% ee
to 99.5% ee) and diastereoselectivities (> 20:1 dr) were also ob-
served with the 10-, 11-, and 12-membered large rings 2t, 2u, and
2v.
9
With optimized conditions (Table 1, entry 7) in hand, we set
out to evaluate the scope of pyrimidine nucleobases in this trans-
formation (Scheme 3). Use of thymine did not significantly im-
pact yield or selectivity, giving 2b in good yield and selectivity.
Halogen substituents on the nucleobase were well-tolerated, and
excellent results were observed with 5-fluorouracil (2c), 5-
chlorouracil (2d) and 5-bromouracil (2e). Varying the substitution
on the alcohol tether was also possible. Switching the TMS group
in 1a for a PhMe2Si group gave 2f, which bears a vinyl silane that
can be directly utilized for cross-coupling reaction.23 Furthermore,
vinyl substitution on the alcohol linker was not required for reac-
tivity, as cyclization of 1g proceeded cleanly to 2g. A sterically
bulky tertiary alcohol was also tolerated, and 1h cyclized to 2h
with a slightly reduced enantioselectivity of 85%, but with excel-
lent yield and dr. Interestingly, tetrahydrofuran (2i) and tetrahy-
dropyran (2j) products with dimethyl substitution on different
positions were both obtained remarkably efficiently with 99% ee
and 99.5% ee respectively.
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Scheme 4. Substrate Scope with Nitrogen on the Ring. a
Scheme 3. Substrate Scope without Nitrogen on the Ring. a
a All reactions performed on 0.10 mmol scale. Yields are isolated yields;
dr determined by crude 1H NMR, ee determined by chiral HPLC.
a All reactions performed on 0.10 mmol scale. Yields are isolated yields;
dr determined by crude 1H NMR, ee determined by chiral HPLC.
To demonstrate the scalability of our method, nucleoside ana-
log 2k was prepared on gram-scale (Scheme 5). Notably, the reac-
tion could be performed at a reduced catalyst loading of 1 mol%
with no deterioration in yield or selectivity (cf. Scheme 4). Prod-
uct 2k was obtained in 88% yield, > 20:1 dr, and 96% ee. With
this material in hand, we set out to highlight the synthetic utility
of the nucleoside analogs bearing an iodide functional group han-
dle that are accessible using this methodology. A Ni-catalyzed
radical addition25 of 2k to methyl acrylate furnished ester 5 as a
single diastereoisomer, presumably due to steric control by the
Adding a nitrogen linker to the pyrimidine side chain allows
access to aza-hetero ring systems, a class of products which show
good anticancer activities11 (Scheme 4). Utilizing uracil with an
N-tosyl group in the side chain produces aza-oxepane product 2k
in 90% yield, 96% ee and > 20:1 dr. The thymine nucleoside ana-
log (2l) was also obtained in high yield and dr with 90% ee. Halo-
gen substituents were well-tolerated; excellent results were ob-
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adjacent nucleobase. Alternatively, nickel in the absence of me-
Scheme 6. Proposed Reaction Mechanism.
1
2
3
4
5
6
7
thyl acrylate reduced the iodide, furnishing compound 8. Upon
treatment with water, nucleoside analog 2k underwent hydroly-
sis26 to afford secondary alcohol 6 with clean inversion of config-
uration. The absolute stereochemistry at C6 of 5 and 6 were as-
signed by 2D NOE (see SI). Secondary alcohol 6 could also be
oxidized to deliver ketone 7. Interestingly, intramolecular cycliza-
tion of nucleoside analog 2k occurred upon treatment with K2CO3
to afford tricycle 9.
Nucleoside analog 2a could be converted to vinyl iodide 10 via
treatment with NIS in the dark. Palladium catalyzed carboxyla-
tion27 of vinyl iodide 10 occurred with concurrent intramolecular
cyclization to give tricyclic vinyl ester 11.
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Scheme 5. Gram-Scale Synthesis and Derivatizations.
In conclusion, we report the development of a new catalyst sys-
tem that enables the enantioselective synthesis of pyrimidine nu-
cleoside analogs with a broad substrate scope. The unusual reac-
tivity of this Pd-catalyzed process is highlighted by the reaction of
diene 1 in the absence of the Pd-catalyst, wherein exclusive io-
dination of the vinyl silane occurs and the vinyl pyrimidine is
untouched. Thus, the Pd catalyst completely inverts the inherent
chemoselectivity. This transformation occurs with good to excel-
lent enantio- and diastereoselectivity and yields are typically high.
A variety of 5-substituted pyrimidine nucleobases can be used,
and a variety of differently substituted rings are well tolerated. In
addition to providing access to the more common 5-, 6-, and 7-
membered rings, this process extends to more challenging 8- to
12-membered rings as well, which is rather unusual. The pyrimi-
dine nucleoside analogs bearing an iodide functional group handle
that are accessible using this methodology are versatile scaffolds
for further functionalization, and can be transformed into a variety
of new pyrimidine nucleoside analogs.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and spectral datas (PDF)
Crystallographic data for 2r (CIF).
AUTHOR INFORMATION
Corresponding Author
A proposed mechanism is depicted in Scheme 6. It should be
noted that a N-protected pyrimidine substrate without free N-H
did not work. This fact leads to our proposal shown. Presumably
this reaction proceeds via a Pd(II)/(IV) catalytic cycle.28 The ca-
talysis is initiated by oxidative addition of NIS to Pd(0), generat-
ing Pd(II) species A, which undergoes coordination to the adja-
cent olefin of nucleobase in substrate 1 providing Pd(II) species B.
Loss of succinimide and formation of a palladium-oxygen bond
generates intermediate C, which triggers a Wacker-type process to
form D. Proton transfer and oxidative addition of NIS to D pro-
vides Pd(IV) species E, which undergoes reductive elimination to
release the product 2 and regenerate Pd(II) species A. The effi-
ciency of the cyclization going from C to D accounts for the in-
sensitivity of this reaction to ring size.
*Email: bmtrost@stanford.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Funding provided by The Job and Gertrud Tamaki Foundation.
We thank Dr. Jana Maclaren for X-ray crystallographic analysis at
the Stanford Nano Shared Facilities (SNSF) sponsored by the
National Science Foundation under award ECCS-1542152.
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