Asymmetric Transfer Hydrogenation of rac-α-(Purin-9-yl)cyclopentones via Dynamic Kinetic Resolution for the Construction of Carbocyclic Nucleosides

Article abstract of DOI:10.1021/acs.orglett.9b00451

An asymmetric transfer hydrogenation via dynamic kinetic resolution of a broad range of rac-α-(purin-9-yl)cyclopentones was first developed. A series of cis-β-(purin-9-yl)cyclopentanols were obtained with up to 97% yield, >20/1 dr, and >99% ee. This also provides an efficient synthetic route to a variety of chiral carbocyclic nucleosides.

Full text of DOI:10.1021/acs.orglett.9b00451

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Transfer Hydrogenation of rac-α-(Purin-9-
yl)cyclopentones via Dynamic Kinetic Resolution for the
Construction of Carbocyclic Nucleosides
Yi-Ming Zhang, Qi-Ying Zhang,* Dong-Chao Wang, Ming-Sheng Xie, Gui-Rong Qu,
and Hai-Ming Guo*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of Henan Province
for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, China
S
* Supporting Information
ABSTRACT: An asymmetric transfer hydrogenation via
dynamic kinetic resolution of a broad range of rac-α-(purin-9-
yl)cyclopentones was first developed. A series of cis-β-(purin-9-
yl)cyclopentanols were obtained with up to 97% yield, >20/1 dr,
and >99% ee. This also provides an efficient synthetic route to a
variety of chiral carbocyclic nucleosides.
Scheme 1. DKR-AH/ATH of rac-α-Aminocycloalkanones
hiral aminocycloalkanols have attracted considerable
interest because of their important pharmaceutical drug
C
frameworks and their roles as ligands in asymmetric synthesis.1
Various methods for enantio- and diastereoselective prepara-
tions of these compounds, including ring opening of meso-
epoxides or aziridines via asymmetric desymmetrization and
acylation of rac-β-aminocycloalkanols via kinetic resolution,
have been reported.1b Recently, dynamic kinetic resolution
(DKR) through asymmetric hydrogenation (AH)2 and
asymmetric transfer hydrogenation (ATH)3 of rac-α-amino-
cycloalkanones provided one of the most efficient approaches
to obtain chiral β-aminocycloalkanols. DKR coupled with Ru-
catalyzed hydrogenation processes has been demonstrated to
effectively convert rac-α-aminocyclohexanones to chiral β-
aminocyclohexanols (Scheme 1A).2a,b,3e,k However, to the best
of our knowledge, successful AH/ATH of rac-α-amino-
cyclopentones has been rare (only two examples with >90%
ee), and this may be attributed to the relatively rigid
cyclopentone skeletons which decrease the rate of racemiza-
tion.4 Hence, the AH/ATH of such substrates to furnish chiral
β-aminocyclopentanols is desirable but remains elusive.
More recently, we developed the AH of α-purine
nucleobase-substituted α,β-unsaturated esters using a chiral
Rh-(R)-Synphos catalyst,5 and it was found that purine base
possibly coordinated to the Rh center to facilitate stereo-
induction. This induction mode was distinct from the
conventional edge/face CH (sp3)/π attraction between the
η6-arene ligand and the carbonyl aryl substituent in ketone
ATH6 or the conventional nonbonded repulsion to control
steroselectivities. Inspired by this work, we envisioned that rac-
α-(purin-9-yl)cyclopentones could be ideal substrates for ATH
to synthesize chiral β-(purin-9-yl)cyclopentanols. Moreover,
these compounds have been reported to exhibit outstanding
biological activities7 (Figure 1). For example, abacavir and
entecavir have been approved by the FDA for the treatment of
HIV and HBV infections, respectively.8 Therefore, the
development of efficient synthetic routes to construct various
chiral carbocyclic nucleoside analogs is desirable. Continuing
from our previous works on nucleosides,9 herein we report the
Received: February 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00451
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Organic Letters
Letter
studies. With varying ratios of FA/TEA, results were not
further improved (entries 11 and 12). Finally, the catalyst
loading was examined (entries 13 and 14). To our delight, a
catalyst loading of 1 mol % was sufficient to produce high yield
of up to 96% without loss of ee (entry 13). Decreasing the
catalyst loading to 0.5 mol % resulted in a lower yield without
affecting ee value (81% yield, 97% ee, entry 14).
Figure 1. Representative biologically active chiral carbocyclic
nucleosides.
Under the optimal reaction conditions, the scope of reaction
was investigated, and the results are presented in Scheme 2. In
first highly enantioselective ATH of a broad range of rac-α-
(purin-9-yl)cyclopentones, which could provide an easy access
to a variety of chiral carbocyclic nucleosides in excellent yields
and stereoselectivities (Scheme 1B).
Scheme 2. Substrate Scope of rac-α-(Purin-9-
yl)cycloalkanones
a−d
In our studies, we utilized 2-(6-methoxy-9H-purin-9-yl)-
cyclopentan-1-one 1a as a model substrate to optimize the
reaction conditions (Table 1). Among the typically efficient
a b
,
Table 1. Screening of Reaction Conditions
c
d
entry
cat. (mol %)
solvent
temp (°C) yield (%) ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(R,R)-A (2)
(R,R)-B (2)
(R,R)-C (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (2)
(R,R)-D (1)
(R,R)-D (0.5)
dioxane
dioxane
dioxane
dioxane
CHCl3
EtOAc
DCM
27
27
27
27
27
27
27
27
27
27
27
27
27
27
93
95
35
98
90
91
93
32
92
95
96
90
96
81
52
38
79
96
94
94
82
89
36
65
82
90
97
97
THF
a
Unless otherwise noted, the reaction was performed with 1a−t (0.1
mmol), (R,R)-D (1 mol %), and 70 μL of FA/TEA (1:1) in dioxane
CH3OH
CH3CN
dioxane
dioxane
dioxane
dioxane
b
c
d
(1.0 mL) at 27 °C for 24 h. >20:1 dr. Isolated yields. The ee values
e
were determined by HPLC using chiral columns.
f
general, the reactions worked considerably well, generating
chiral β-(purin-9-yl)cyclopentanols with excellent yields and
enantioselectivities. The absolute configuration of product 2l
was determined to be (1R,2S) by single-crystal X-ray
diffraction analysis. Substrates with an increasingly bulky
group at the C6 of purine, such as OMe, OEt, S(CH2)2CH3,
and Ph, were evaluated and their reductions proceeded in
excellent yields and good ee’s (2a-d, 88−96% yields, 85−97%
ee). Notably, ee values decreased with increasing steric
hindrance at the C6 of purine. Substrates 1e−i bearing
different amine groups, such as dimethylamino, diethylamino,
pyrrolidino, piperidino, and morpholino groups, at the C6
position of the purine skeleton were also examined.
Interestingly, the introduction of different amine substituents
to the purine skeleton appeared to have little effect on the
reaction (2e−i, 93−97% yields, 94 → 99% ee). This may be
because the electron-donating effects of the substituents are
stronger than their steric hindrance. Subsequently, subtrates
1j,k bearing a Br atom or a Cl atom at C6 of the purine
skeleton were studied. Although the reactions proceeded with
excellent yields (2j,k, 92−93% yields), the ee values obviously
a
Unless otherwise noted, reaction conditions: rac-α-(purin-9-yl)-
cyclopentone 1a (0.1 mmol), respective mol % of catalyst and 70 μL
b
c
of FA/TEA (1:1) in solvent (1.0 mL) for 24 h. >20:1 dr. Isolated
yields. Determined by chiral HPLC analysis. FA/TEA (2.5:1) was
used. FA/TEA (0.2:1) was used. FA = formic acid. TEA =
triethylamine.
d
e
f
catalysts for ATH, several chiral 1,2-diamine-based Ru(II)
catalysts were first examined at 27 °C using formic acid (FA)/
triethylamine (1:1) as the hydrogen source in dioxane (entries
1−4). When (R,R)-A and (R,R)-B were used as catalysts, high
reduction yields were achieved, albeit with low ee (93−95%
yields, 38−52% ee, entries 1 and 2). A low yield was obtained
from reduction with Noyori’s catalyst (R,R)-C (35% yield,
entry 3). When Ru-(R,R) FsDPEN ((R,R)-D) was used as
catalyst, the corresponding product 2a was obtained with a
high yield of up to 98% and 96% ee (entry 4). Thus, the best
catalyst (R,R)-D was selected to further optimize solvents.
However, dioxane turned out to already be the best solvent
(entries 5−10). Therefore, dioxane was used in subsequent
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DOI: 10.1021/acs.orglett.9b00451
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Scheme 3. Experimental Mechanistic Studies
decreased (70−75% ee). On the other hand, the reductions of
α-(purin-9-yl)cyclopentones 1l−o bearing different amine
groups at the C2 position and Cl at the C6 of purine
proceeded very well (2l−o, 93−97% yields, 94 → 99% ee).
Substrates 1p−q bearing a Cl atom or an H atom at the C6, or
a NH2 or a N(CH3)2 at the C2 of purine also underwent
reduction well, delivering the desired products 2p−q with 86−
90% yields and 90−91% ee. Varying the size of carbocyclic ring
had no effect on enantioselectivities (2r,s, 99% ee). In
addition, the benzo-fused cyclopentone 1t was also reduced
satisfactorily (2t, 89% yield, 98% ee).
To better understand the origins of enantioselectivity, a
series of control experiments were conducted (Scheme 3A).
When benzimidazole was used as the N-heteroaromatic
substituent, both a low yield and enantioselectivity were
observed, although an excellent diastereoselectivity was still
obtained (4a, 32% yield, > 20/1 dr, 9% ee). When
cyclopentones 3b−d with different N-heteroaromatic sub-
stituents such as N-benzotriazole, an N-heteroaromatic group
bearing an N atom at the 1-position, and an N-heteroaromatic
group bearing nitrogen atoms at the 2- and 6-positions were
reduced, low enantioselectivities were observed (4b−d, 25−
44% ee); however, a 91% yield was obtained in the case of α-
heteroaromatic-substituted cyclopentone 3c. Remarkably,
when cyclopentone 3e having an α-N-heteroaromatic group
bearing an N atom at the 3 position, was reduced, the
enantioselectivity was significantly increased. Moreover, the
ATH of rac-α-(purin-9-yl)cyclopentone 3f also proceeded well,
producing the desired product with excellent yield and
satisfactory enantioselectivity (4f, 91% yield, 82% ee). These
results (4a−d, 9−44% ee vs 4e−f, 82−90% ee) indicate that
the enantioselectivities of the ATH can be influenced by the N
atom at the 3 position of the heteroaromatic group.
Interestingly, the α-(xanthin-9-yl)-substituted cyclopentone
3g was also efficiently reduced to the desired product 4g
with 90% yield and 91% ee, which further corroborated that
the N atom at the 3 position of the heteroaromatic group
played an important role in the enantioselectivities of the
ATH. Presumably, the purine base may coordinate the
ruthenium (Ru) center of the catalyst (R,R)-D; thus the
enantioselectivities of the ATH was significantly influenced by
the interaction between the purine group and Ru atom. In
addition, when rac-α-(purin-9-yl)cyclopentone 3h containing a
quaternary stereocenter at the α position was employed as the
substrate, a classical kinetic resolution occurred. The
corresponding product 4h was produced in 43% yield and an
excellent ee of 99%, with the starting material (S)-3h being
recovered with 45% yield and 99% ee (S factor is 1057).10b
When enol acetate 3i was used as the substrate, the reaction
did not proceed. These results demonstrate that the CO
group is hydrogenated through the classic six-membered
transition state, rather than through an enol intermediate.
In light of the above results and literature precedents,11 we
propose the mechanism for Ru-FsDPEN-catalyzed DKR-ATH,
as shown in Scheme 3B. Based on Noyori’s metal−ligand
bifunctional mechanism, the catalyst (R,R)-D can be easily
converted to the amine hydrido Ru complex in the presence of
Et3N and HCOOH. The complex subsequently forms a 6-
membered pericyclic transition state (TSRS) with S-1a, which is
stabilized by hydrogen bonds formed between the NH unit
and the carbonyl oxygen atom. Meanwhile, the purine base
also coordinated to the Ru atom to facilitate reactivity and
stereoinduction. The hydridic Ru−H and protic N−H of Ru
complex are then simultaneously transferred to the CO
bond of S-1a to generate product 2a. As R-1a is not efficiently
reduced due to the unfavorable transition state (TSRR), it
́
tautomerizes to S-1a through enol intermediate 3i in the
presence of Et3N. When 3h bearing a quaternary stereocenter
is used, racemization of R-3h cannot take place; as a result, the
reaction follows a kinetic resolution process.
The introduction of fluorine, sulfur, N3, or amino groups
into the sugar moieties of nucleosides can modulate or
C
DOI: 10.1021/acs.orglett.9b00451
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improve biological activities.12 Consequently, a series of
transformations of compound 2a were carried out (Scheme
4). In the presence of NH3/CH3OH, adenine nucleoside 5a
Accession Codes
CCDC 1866376 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Product 2a Elaboration
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhangqiying@htu.edu.cn.
*E-mail: ghm@htu.edu.cn.
ORCID
Dong-Chao Wang: 0000-0002-5037-4727
Ming-Sheng Xie: 0000-0003-4113-2168
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. 21672055,
21602045, and U1604283) and the 111 Project (No.
D17007).
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Experimental procedures and compound characteriza-
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D
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