Lewis Acid Triggered Regioselective Magnesiation and Zincation of Uracils, Uridines, and Cytidines

Article abstract of DOI:10.1021/acs.orglett.6b00190

The Lewis acid MgCl₂ allows control of the metalation regioselectivity of uracils and uridines. In the absence of the Lewis acid, metalation of uracil and uridine derivatives with TMPMgCl·LiCl occurs at the position C(5). In the presence of MgCl₂, zincation using TMP₂Zn·2LiCl·2MgCl₂ occurs at the position C(6). This metalation method provides easy access to functionalized uracils and uridines. Using TMP₂Zn·2LiCl·2MgCl₂ also allows to functionalize cytidine derivatives at the position C(6).

Full text of DOI:10.1021/acs.orglett.6b00190

Letter
pubs.acs.org/OrgLett
Lewis Acid Triggered Regioselective Magnesiation and Zincation of
Uracils, Uridines, and Cytidines
Lydia Klier, Eider Aranzamendi, Dorothee
Thomas Carell, and Paul Knochel*
́
Ziegler, Johannes Nickel, Konstantin Karaghiosoff,
̈
̈
Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany
*
S Supporting Information
ABSTRACT: The Lewis acid MgCl allows control of the
2
metalation regioselectivity of uracils and uridines. In the
absence of the Lewis acid, metalation of uracil and uridine
derivatives with TMPMgCl·LiCl occurs at the position C(5).
In the presence of MgCl , zincation using TMP Zn·2LiCl·
2
2
2
MgCl occurs at the position C(6). This metalation method
2
provides easy access to functionalized uracils and uridines.
Using TMP Zn·2LiCl·2MgCl also allows to functionalize cytidine derivatives at the position C(6).
2
2
he selective functionalization of uridines is an important
with good regioselectivity (C(5)/C(6) = 6:94, Scheme 1).
Based on previous studies on the chromone system, we
T
synthetic goal because of the biological relevance of many
1
substituted uridines. They are known to display antibiotic,
antifungal, anticancer, and antiviral activity. Many antiviral
agents are based on modified nucleosides including mod2-
ifications of both the sugar moiety and the heterocyclic system.
Therefore, the direct lithiation of various uridines has been
studied, and the use of dilithiated uridine intermediates has
allowed a selective functionalization by tuning the nature of the
Scheme 1. MgCl -Triggered Regioselective Magnesiation
2
and Zincation of Uracil 3 Leading to Products of Type 6 and
7
3
a,b,f
substituent at the C′(5)-hydroxyl function.
Alternatively,
the use of halogenated uracils and uridines allows cross-
coupling reactions or the preparation of metalated inter-
4
mediates via a direct zinc insertion or via a halogen−metal
5
exchange. A direct Pd-catalyzed C−H arylation of uracils in
the presence or absence of CuI allows functionalization of the
6
7
positions C(5) and C(6). Although lithium bases are
powerful bases for the direct lithiation of various heterocycles,
magnesium or zinc bases are of special interest since they
tolerate various functional groups as well as sensitive
8
heterocyclic scaffolds. Recently, we have reported a selection
of mild magnesium and zinc TMP-(2,2,6,6-tetramethylpiper-
9
idyl) bases such as TMPMgCl·LiCl (1) and TMP Zn·2LiCl·
2
1
0
2
MgCl (2) which allow a regioselective functionalization of
2
11
polyfunctionalized aromatics and heterocycles. We have
demonstrated that a regioselective switch can be achieved by
the presence or absence of Lewis acids for a range of
1
2
metalations. Herein, we report that the bases 1 or 2 allow a
highly regioselective metalation at the C(5) or C(6) position of
uracils and uridines or at the C(5) position of cytidine. More
importantly, we show that these metalated nucleoside
derivatives can be quenched with a range of electrophiles.
Preliminary experiments show that TMPMgCl·LiCl (1, 1.2
equiv, THF, −40 °C, 4 h) reacts smoothly with N,N-
dimethyluracil (3) to afford the C(5)-magnesiated uracil (4),
whereas treatment of 3 with TMP Zn·2LiCl·2MgCl (2, 0.7
a
b
Isolated yields of regioisomerically pure product. Electrophile used
c
(1.2 equiv). Obtained after transmetalation with CuCN·2LiCl (1.2
d
equiv, −40 °C, 30 min). 2 mol % of Pd(dba) , 4 mol % of tfp (25 °C,
2
3
2
e
h). Obtained after transmetalation with ZnCl (1.2 equiv, −40 °C,
0 min), 2 mol % of Pd(OAc) , and 4 mol % of XPhos (50 °C, 72 h).
2
2
Received: January 20, 2016
2
2
equiv, THF, −30 °C, 48 h) affords the C(6)-zincated uracil (5)
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
rationalized the observed regioselectivity by the presence of
Table 1. Functionalization of Uridine 8 at C(5) Using
TMP Zn·LiCl·2MgCl (2) Leading to Products of Type 11
12b
MgCl (2.0 equiv) in the zinc TMP-base 2. This Lewis acid
2
2
2
complexes the C(4) carbonyl group and therefore directs the
13
metalation to position C(6) (Scheme 1). After the resulting
metalated nucleosides 4 and 5 were quenched with various
electrophiles such as aldehydes, aryl bromides, or iodides
1
4
(
Negishi cross-coupling), allylic halides and acid chlorides (in
15
the presence of CuCN·2LiCl), functionalized uracils (6a−c)
and (7a−c) were obtained in 69−84% yield.
These reaction conditions were readily applied to protected
1
6
uridine 8. Its treatment with TMPMgCl·LiCl (1, 1.2−1.8
equiv, THF, 40 °C, 24 h) affords the C(5)-magnesiated uridine
1
9
(C(5):C(6) = 98:2) in >95% yield as determined by H
NMR analysis of iodolyzed product 11a (Scheme 2). The
Scheme 2. Reactions and Conditions for C(5) and C(6)
Metalation of Uridine 8
presence of MgCl2 inverses the regioselectivity, and the
zincation of 8 with TMP Zn·2LiCl·2MgCl (2, 1.2 equiv,
2
2
THF, −30 °C, 72 h) produces the bis-zincated uridine (10) in
>
95% yield (C(5)/C(6) = 3:97, Scheme 2). With these
optimized metalation conditions in hand, a number of C(5)-
and C(6)-functionalized uridines were prepared. Reactions of
the C(5)-magnesiated uridine 9 with various electrophiles
(
iodine, alkenyl-, aryl-, and heteroaryl iodides, allylic bromides,
acid chlorides, morpholine-4-carbaldehyde, aldehydes, NC−
CO Et, Me S ) produced the expected regioisomerically pure
2
2 2
C(5)-substituted uridines (11a−k) in 42−86% yield (entries
1
−11, Table 1). Iodolysis of the magnesium reagent 9 provided
C(5)-iodinated uridine (11a) in 70% yield (entry 1). Thus,
after transmetalation of 9 to zinc, Pd-catalyzed Negishi cross-
coupling (8 mol % Pd(dba) (dba = trans,trans-dibenzylide-
2
16
neacetone) and 12 mol % of P(2-furyl)3) with 4-iodoanisole,
ethyl 4-iodobenzoate, or 3-iodopyridine provided the products
1
1b−d (66−81%, entries 2−4). Similarly, copper-mediated
allylation with ethyl 2-(bromomethyl)acrylate or bromocyclo-
hexene afforded the C(5)-functionalized uridine derivatives
(11e,f) in 73−86% yield (entries 5 and 6). Upon treatment of 9
with ethyl cyanoformate, the functionalized ester (11g) was
obtained in 44% yield (entry 7). The ketone (11h) was
obtained in 71% yield when 9 was transmetalated to the
corresponding copper derivative and acylated with cyclo-
propanecarbonyl chloride (entry 8). Aldehyde 11i was obtained
in 32% yield when 9 was formylated with morpholine-4-
carbaldehyde (entry 9). Furthermore, 9 added readily to 4-
cyanobenzaldehyde giving the corresponding alcohol 11j (47%,
a
b
Yield of isolated, analytically pure product. Obtained after
transmetalation with ZnCl (1.2−1.5 equiv, −40 °C, 30 min), 8 mol
% of Pd(dba) , and 12 mol % of P(2-furyl) . Obtained after
transmetalation with CuCN·2LiCl (1.2 equiv, −40 °C, 30 min).
2
c
2
3
B
DOI: 10.1021/acs.orglett.6b00190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entry 10). The thioether (11k) was obtained in 42% yield when
Scheme 3. Reactions and Conditions for the Preparation of
C(6)-Substituted Cytidines 14a−d
9
was treated with MeSSMe (entry 11). We also examined the
scope of the reaction of C(6) metalated uridine 10 with
representative electrophiles (Table 2). Iodolysis of the zinc
Table 2. Functionalization of the Uridine 8 at C(6) Using
TMP Zn·2LiCl·2MgCl (2) Leading to Products of Type 12
2
2
a
b
Yield of isolated, analytically pure product. 8 mol % Pd(dba) , 15
2
c
mol % tfp (25 °C, 2 h). Obtained after transmetalation with CuCN·
2
LiCl (1.5 equiv, −40 °C, 30 min).
deprotection of the arylated cytidine 15b with aqueous
CF CO H resulted in the formation of the cytidine 17 in
3
2
8
5% yield (Scheme 4).
Scheme 4. Deprotection of Substituted Uridines and a
Cytidine Leading to the Nucleosides 16a−d and 17
a
b
Yield of isolated, analytically pure product. Obtained using 8 mol %
c
Pd(dba)2 and 15 mol % P(2-furyl) . Obtained using 4 mol %
Pd(PPh ) . Obtained after transmetalation with CuCN·2LiCl (1.2
3
d
3
4
equiv, −40 °C, 30 min).
reagent 10 provided the C(6)-iodinated uridine (12a) in 95%
yield (entry 1). Pd-catalyzed Negishi cross-coupling (8 mol %
1
7
of Pd(dba)2 and 15 mol % of P(2-furyl)3) with 4-
chloroiodobenzene, 4-iodobenzonitrile, 2-iodothiophene, or
(E)-1-iodooctene furnished the expected C(6)-arylated and
alkenylated uracils 12b−e (67−97%, entries 2−5). Similarly,
copper-mediated acylation with pivaloyl chloride afforded the
C(6) functionalized uridine 12f (97%, entry 6).
The substitution of the cytidine scaffold is of biological
interest, and its lithiation in C(6) is only briefly described in the
In summary, we have shown that the presence or absence of
1
8
19
literature. The bis-Boc-protected cytidine 13 was readily
zincated using TMP Zn·2LiCl·2MgCl (2, 1.1−1.2 equiv, THF,
MgCl , which is acting as a Lewis acid, allows the efficient and
2
2
2
regioselective preparation of metalated uracils, uridines, and
cytidine derivatives. The resulting highly functionalized Mg− or
Zn−organometallics thereafter react readily with a broad range
of electrophiles leading to diversely functionalized uridines at
position C(5) or C(6). Applications to the synthesis of
biologically active uridines and cytidines are currently underway
in our laboratories.
−
30 °C, 4 h); it gave rise to the C(6)-metalated zinc reagent 14
in 68% yield. This bis-heteroarylzinc was iodolyzed, allylated,
acylated, and cross-coupled leading to the expected products
20
1
5a−d (43−61% yield, Scheme 3).
The selective deprotection of the uridines 11a,h and 12b,c
could be readily performed using concd HCl to afford the
2
0
MOM-protected uridines 16a−d in 72−82%. A full
C
DOI: 10.1021/acs.orglett.6b00190
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
004, 116, 2256−2276; Angew. Chem., Int. Ed. 2004, 43, 2206−2225.
ASSOCIATED CONTENT
Supporting Information
■
(f) L’Helgoual’c, J. M.; Seggio, A.; Chevallier, F.; Yonehara, M.;
*
S
Jeanneau, E.; Uchiyama, M.; Mongin, F. J. Org. Chem. 2008, 73, 177−
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(8) (a) Wunderlich, S.; Knochel, P. Chem. Commun. 2008, 6387−
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00190.
6
3
1
389. (b) Mosrin, M.; Petrera, M.; Knochel, P. Synthesis 2008, 2008,
697−3702. (c) Mosrin, M.; Bresser, T.; Knochel, P. Org. Lett. 2009,
1, 3406−3409. (d) Mosrin, M.; Knochel, P. Chem. - Eur. J. 2009, 15,
Full experimental details and NMR data (PDF)
AUTHOR INFORMATION
Corresponding Author
1468−1477. (e) Zimdars, S.; Mollat du Jourdin, X.; Crestey, F.; Carell,
■
*
̈
T.; Knochel, P. Org. Lett. 2011, 13, 792−795. (f) Samann, C.; Coya,
E.; Knochel, P. Angew. Chem. 2014, 126, 1454−1458; Angew. Chem.,
Int. Ed. 2014, 53, 1430−1434. (g) Nafe, J.; Knochel, P. Synthesis 2015,
48, 103−114.
E-mail: paul.knochel@cup.uni-muenchen.de.
Notes
(
9) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. 2006,
The authors declare no competing financial interest.
1
(
18, 3024−3027; Angew. Chem., Int. Ed. 2006, 45, 2958−2961.
10) Wunderlich, S.; Knochel, P. Angew. Chem. 2007, 119, 7829−
ACKNOWLEDGMENTS
This research has received funding from the Deutsche
Forschungsgesellschaft (SFB 749). We also thank BASF AG
Ludwigshafen) and Rockwood Lithium GmbH (Frankfurt) for
the generous gift of chemicals.
■
7832; Angew. Chem., Int. Ed. 2007, 46, 7685−7688.
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