Pd-Catalyzed Regioselective Asymmetric Addition Reaction of Unprotected Pyrimidines to Alkoxyallene

Article abstract of DOI:10.1021/acs.orglett.7b02332

Catalytic asymmetric synthesis of N-heterocyclic glycosides free of protecting and directing groups is reported. The key reaction is highlighted by the atom-efficient and regioselective addition of unprotected pyrimidines to highly functionalized alkoxyal

Full text of DOI:10.1021/acs.orglett.7b02332

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Regioselective Asymmetric Addition Reaction of
Unprotected Pyrimidines to Alkoxyallene
Soyeong Kang, Seok Hyeon Jang, Juyeol Lee, Dong-gil Kim, Mijin Kim, Wook Jeong,
and Young Ho Rhee*
Department of Chemistry, Pohang University of Science and Technology, 77 Cheongam-Ro, Pohang, Kyungbuk 37673, Republic of
Korea
S
* Supporting Information
ABSTRACT: Catalytic asymmetric synthesis of N-heterocyclic
glycosides free of protecting and directing groups is reported. The
key reaction is highlighted by the atom-efficient and regioselective
addition of unprotected pyrimidines to highly functionalized
alkoxyallene. Numerous acyclic and cyclic N-heterocyclic glyco-
sides are accessed with minimal formation of organic byproducts.
The synthetic utility of the reaction is demonstrated by the first
catalytic asymmetric synthesis of anticancer pharmaceutical
(−)-Tegafur and stereoselective synthesis of an oxepane nucleoside
derivative.
nucleophiles and the delicate regiocontrol between the nitrogen
atoms make this task extremely challenging. Conventional
N-Heterocyclic glycosides, particularly pyrimidine nucleosides
and their analogs, represent a highly important class of chemical
compounds because of their significant biological activities and
essential roles in physiological processes (Scheme 1).1,2 Thus,
developing highly efficient and stereoselective synthesis of these
compounds has attracted significant attention over the past
decades.3,4 However, ill-defined properties of pyrimidine
chemical N-glycosylations (such as the Vorbruggen reaction)
̈
require extensive use of protecting groups on N-heterocycles
and activating groups on the glycosyl moiety. In addition,
conventional approaches rely heavily on the substrate-based
stereocontrol that needs directing groups. Thus, the ideal atom-
efficient N-glycosylation reaction free of protecting, activating,
and directing groups still remains to be determined. Here, we
report de novo N-glycosidic bond formation of pyrimidine
nucleophiles employing Pd-catalyzed atom-efficient asymmetric
addition of unprotected pyrimidines to alkoxyallene as the key
stereocontrol event. The reaction establishes a general synthetic
protocol for the acyclic N-glycosides, which cannot be readily
prepared by conventional methods. In addition, various cyclic
derivatives can also be accessed by combining the key reaction
with metal-catalyzed ring-closing-metathesis (RCM).5,6 This
sequential metal catalysis accomplishes a systematic and
versatile synthetic protocol for highly valuable pyrimidine
glycosides with minimal generation of organic waste. The value
of this method is demonstrated by the first catalytic asymmetric
synthesis of anticancer pharmaceutical Tegafur and stereo-
selective synthesis of an oxepane nucleoside derivative.
Scheme 1. De Novo Synthesis of Biologically Significant
Pyrimidine N-Glycosides
Rutjes reported a highly efficient Pd-catalyzed addition
reaction of amide nucleophiles and alcohols to alkoxyallene.7
We recently reported an asymmetric version of this reaction,
which led to the development of conceptually new azacycle8
and carbohydrate synthesis9 upon combination with the RCM
Received: July 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02332
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Letter
reaction.10,11 Compared with these precedents, the current
reaction is fundamentally more challenging because the
reaction requires an ene-alkoxyallene substrate that can induce
undesired reactions12 (such as cycloisomerization of enallenes).
In addition, the poor solubility and metal-coordinating ability of
unprotected pyrimidines may potentially affect the stereo- and
regioselectivity of the reaction. In fact, the use of unprotected
pyrimidines and other related N-heterocycles is very limited in
metal catalysis13,14 including the metal-catalyzed asymmetric
hydrofunctionalization15 and asymmetric allylic substitution
reactions.16−18
a
Scheme 2. Scope of Acyclic Pyrimidine Glycoside
Our concern was justified when we initially tested thymine
with alkoxyallene 1a (Table 1). Performing the reaction in
Table 1. Preliminary Test of Thymine with Alkoxyallene 1a
a
The reaction was conducted at 0 °C.
considerably improved the yield of the reaction without
deteriorating the enantioselectivity. In terms of the chiral
ligand, L1 showed high ee in most cases, even though some
reactions needed L2 or L3 for further improvement. Uracil
showed a comparable result to thymine to give 2-U. Notably, 5-
hydroxymethyluracil was also accommodated to produce the
corresponding N-glycosides 2-HmU with no competing O,O-
acetal formation.8 This chemoselectivity addresses a unique
feature of the current reaction because conventional N-
glycosylations usually require protection of hydroxyl groups.19
Unprotected cytosine also worked efficiently to give compound
2-C in high yield and ee.
Our next task was to expand the reaction to the synthesis of
cyclic N-glycosides by combining the key reaction with Ru-
catalyzed RCM. As described in Scheme 3, furanosylated N-
glycoside products 4 and 5 were prepared in high yield and ee
from achiral ene-alkoxyallene 3 by using the Pd-catalyzed
asymmetric addition of pyrimidine nucleobases and the
subsequent RCM reaction with a second-generation Hovey-
da−Grubbs catalyst. In addition to the above achiral
a
b
entry
solvent
additive
time yield (2a-T, 2a′)
ee (2a-T)
1
2
3
4
5
CH2Cl2
CH2Cl2
acetone
DMF
none
Et3N
Et3N
Et3N
K3PO4
1
<10
36
41
58
85
97
99
96
1
trace
33
24
5
21
80
15
pyridine
1
94
trace
a
b
Isolated yield. Determined by HPLC analysis.
CH2Cl2 gave the desired monoadduct 2a-T only in a small
amount with moderate ee (entry 1). In this case, bis-adduct 2a′
was obtained as the major product. Addition of an external base
such as Et3N gave the desired monoadduct 2a-T in low 36%
yield even under forced conditions, albeit with significant 85%
ee and high regioselectivity (entry 2). Using more polar solvents
such as acetone or DMF showed formation of bis-adduct 2a′ in
considerable amount, even though 2a was obtained again with
high ee (entries 3 and 4). After extensive studies, the optimal
balance between the solubility and regioselectivity was achieved
with the use of uncommon solvent pyridine (entry 5). For
example, the reaction of thymine with 1a in pyridine solvent
gave the product 2a-T in 94% yield and 96% ee, in the presence
of 2.5 mol % of Pd2(dba)3 and the ligand (R,R)-L1 along with
K3PO4 (0.25 equiv). In this case, the bis-adduct 2a′ was
obtained only in a trace amount. (For the optimization process
and the confirmation of regiochemistry of 2a-T, please see the
Supporting Information.)
Scheme 3. Synthesis of Cyclic Compounds
Having established the optimized conditions for the key
transformation, we explored the scope of this reaction (Scheme
2). Using smaller allene 1b as well as larger allene 1c with
thymine had little particular effect on the reaction, generating
the corresponding N-glycosides 2-T in high yield and ee. Then,
we tested the other pyrimidine N-heterocycles depicted in
Scheme 2. The reaction generally showed high yield (70−99%)
and enantioselectivity (88−99%) when 1.0−1.5 equiv of
nucleophile was reacted with the alkoxyallene compounds at
rt in the presence of a Pd precatalyst (5 mol %). In cases where
the addition reaction was slow, increasing the catalyst loading
B
DOI: 10.1021/acs.orglett.7b02332
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Letter
alkoxyallenes, chiral allene 6 also showed a high level of
stereoselectivity driven by the chiral ligand. Thus, N-glycosides
of thymine (7), uracil (8), and even 5-hydroxymethyluracil (9)
possessing a β-configuration were easily synthesized by the
sequential metal catalysis. Notably, diastereomeric α-N-glyco-
side of thymine (10) was also prepared in high yield and
stereoselectivity simply by changing the chiral information on
the ligand. Also, a nucleoside having a non-natural (L)-
configuration (ent-7) was synthesized from enantiomeric
alkoxyallene ent-6 with a comparable step and atom efficiency
to the D-form 7. This result illustrates another advantage of the
proposed method.20 In cyclic N-glycosides containing cytosine
(11), protection of the exocyclic amine was necessary before
the Ru-catalyzed metathesis reaction. Nevertheless, these
results verify that sp2-nitrogens in these compounds are
compatible with the metathesis reaction.21
Because unprotected pyrimidines were inactive in the Pd-
catalyzed asymmetric allylic substitution reaction,16 the result
described in this work strongly suggests a mechanistically
distinct pathway in the π-allyl chemistry (Scheme 5).
Scheme 5. Mechanism of the N-Glycoside Synthesis
As demonstrated by the benzylated form of the antiviral
pharmaceutical d4T (7),22 the cyclic N-glycosides prepared in
Scheme 3 represent a highly useful structure that can be found
in numerous bioactive compounds. In addition, they can
provide a versatile platform for further atom-efficient
functionalization. To further address the synthetic utility of
the reaction, we pursued the first catalytic asymmetric synthesis
of (−)-Tegafur, whose racemic form has been used as an
anticancer pharmaceutical.23 Pd-catalyzed asymmetric addition
of unprotected 5-fluorouracil to alkoxyallene 3 proceeded in
78% yield under the optimized conditions on 4 mmol scale.
RCM reaction of the resulting acyclic N-glycoside gave the
cyclic product 12 in 80% yield with 91% ee. Pd-catalyzed
hydrogenation reaction of this compound gave (−)-Tegafur in
78% yield with no deterioration of ee. Comparison of the
optical rotation with the literature value24 rigorously confirms
the absolute configuration of the Tegafur as depicted in Scheme
4 as well as that of other pyrimidine N-glycosides by analogy.
Unlike the classical substitution reaction, formation of the π-
allyl complex is promoted by the net addition reaction of Pd
metal and the neutral nucleophile to allene. In this case, the
counteranion nucleophile could form a tighter complex with
the Pd-allyl moiety, which should expedite the addition of a
relatively weak nucleophile such as the conjugate base of
pyrimidine. This hypothesis is supported by the small solvent
effect on the enantioselectivity observed during the optimiza-
tion process (Table 1). The competition experiment shown in
Scheme 5 gives further insight into the mechanism. When an
equimolar mixture of 5-fluorouracil and thymine was reacted
with alkoxyallene 3, the corresponding N-glycoside adducts
were obtained in a 2:1 ratio. Because 5-fluorouracil is more
acidic than thymine27 (accordingly the conjugate base of 5-
fluorouracil should be less nucleophilic), this result strongly
suggests formation of the π-allyl intermediate as the turnover-
limiting (and presumably enantio-determining) event.28 Based
upon these mechanistic aspects, the observed absolute
stereochemistry of the product could be reasonably explained
by the fast (outer-sphere) addition of the nucleophile to
kinetically formed anti π-allyl complex A.29 The excellent
regioselectivity of substituted uracils is also noteworthy because
the relative acidity of N1 vs N3 is very close and highly depends
upon the polarity of the medium.30 In fact, it was predicted that
the N1 position becomes more acidic in less polar solvents.31
This is consistent with the increase of N1 selectivity in pyridine
(ε = 12.7) compared with in DMF (ε = 36.4) observed in the
optimization study.32 Thus, the low dielectric constant yet high
solvolyzing power of pyridine is crucial in solving problems
associated with the use of unprotected pyrimidine derivatives.
In summary, we developed a de novo synthesis of N-
heterocyclic glycosides employing the catalytic asymmetric
addition of unprotected pyrimidines to alkoxyallene as the key
event. Remarkably, unprotected pyrimidines were established as
a superior nucleophile in a metal-catalyzed asymmetric reaction
without the need for protecting groups. This unique reactivity
led to the development of a conceptually new N-glycosylation
reaction that minimizes formation of organic waste. Various
natural and non-natural N-heterocyclic glycosides with
Scheme 4. Application of Pyrimidine N-Glycoside Synthesis
Notably, potentially competing reactions such as enallene
cycloisomerization (Scheme 1) was successfully minimized as
indicated by the high yield of the desired addition product.
In addition, ring-expanded homologues of 7 (compounds 14
and 16) were uneventfully prepared from the corresponding
allene precursors (compounds 13 and 15) in an analogous
manner.25 Notably, stereo- and regioselective synthesis of these
ring-expanded derivatives is still very challenging despite their
promising biological functions. These examples highlight a
unique feature of the current approach based upon ligand
control in the synthesis of various natural and unnatural deoxy-
N-glycosides that cannot be easily accessed by conventional
methods.26
C
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Letter
Z.; Dong, V. M. J. Am. Chem. Soc. 2015, 137, 8392. (c) Li, C.; Kahny,
K.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 13780.
potentially new biological activities/functions can be evolved
from this method. Extrapolation of this method to other N-
heterocyclic glycosides as well as synthetic application is in
progress.
(16) For unsuccessful examples using Pd-catalyzed reactions where
the unprotected pyrimines showed poor reactivity, see: (a) Trost, B.
M.; Madsen, R.; Guile, S. D.; Brown, B. J. Am. Chem. Soc. 2000, 122,
5947. (b) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037.
(17) For Ir-catalyzed asymmetric allylic substitution reaction using
unprotected purines, see: Stanley, L. M.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 8971.
(18) For selected recent examples of metal-catalyzed asymmetric
allylic amination reaction, see: (a) Yang, Z.-P.; Wu, Q.-F.; You, S.-L.
Angew. Chem., Int. Ed. 2014, 53, 6986. (b) Wang, X.; Meng, F.; Wang,
Y.; Han, Z.; Chen, Y.; Liu, L.; Wang, Z.; Ding, K. Angew. Chem., Int.
Ed. 2012, 51, 9276.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02332.
1
Experimental details and spectral data; H and 13C scan
of all new compounds (PDF)
(19) Zhang, Y.; Knapp, S. J. Org. Chem. 2016, 81, 2228.
(20) For a review on the synthesis of L-nucleosides, see: Romeo, G.;
Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010, 110, 3337.
(21) For selected examples on the RCM reaction of Lewis basic
amines, see: (a) Amblard, F.; Nolan, S. P.; Agrofoglio, L. A.
Tetrahedron 2005, 61, 7067. (b) Compain, P. Adv. Synth. Catal.
2007, 349, 1829.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yhrhee@postech.ac.kr.
ORCID
(22) Luzzio, F. A.; Menes, M. E. J. Org. Chem. 1994, 59, 7267.
(23) Nomura, H.; Yoshioka, Y.; Minami, I. Chem. Pharm. Bull. 1979,
27, 899.
Young Ho Rhee: 0000-0002-2094-4426
Notes
(24) Yasumoto, M.; Moriyama, A.; Unemi, N.; Hashimoto, S.; Suzue,
T. J. Med. Chem. 1977, 20, 1592.
The authors declare no competing financial interest.
(25) Sabatino, D.; Damha, M. J. Am. Chem. Soc. 2007, 129, 8259.
(26) Unprotected adenine also showed high yield and selectivity in
the reaction with alkoxyallenes 1a and 6. For the detailed information
and experimental procedure, see the Supporting Information
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Research Foundation of Korea, which is funded by the Korean
Government (NRF-2015R1A2A1A15056116).
̆
(27) Jang, Y. H.; Sowers, L. C.; Çagin, T.; Goddard, W. A. J. Phys.
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see: Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006,
39, 747.
(29) An inner-sphere addition reaction of the nucleophile to the
isomeric palladium syn complex cannot be excluded. For a related
study, see: Keith, J. A.; Behenna, D. C.; Sherden, N.; Mohr, J. T.; Ma,
S.; Marinescu, S. C.; Nielsen, R. J.; Oxgaard, J.; Stoltz, B. M.; Goddard,
W. A. J. Am. Chem. Soc. 2012, 134, 19050.
(30) The regioselectivity of pyrimidine (particularly substituted
uracils) addition may be explained by the higher reactivity of the N3
nitrogen atom. For a related discussion, see: Boncel, S.; Gondela, C.;
Walczak, K. Synthesis 2010, 2010, 1573.
(31) According to calculation studies, the N3 position is predicted to
be more acidic in water while the N1 position is predicted be more
acidic in a nonpolar environment. For reference, see: Kurinovich, M.
A.; Lee, J. K. J. Am. Chem. Soc. 2000, 122, 6258. Also see ref 27.
(32) Smallwood, I. M. Handbook of organic solvent properties; Halsted
Press: Arnold, 1996; p 301.
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DOI: 10.1021/acs.orglett.7b02332
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