unit.7 DeUG was designed as a synthetically versatile, robust
analogue of UG, a guanosine-derived urea, which formed
highly stable quadruply hydrogen-bonded complexes with
2,7-diamido-1,8-naphthyridine (DAN).8 Although the re-
ported synthesis of DeUG served our needs at the time, it
suffered from low overall yields (ca. 15% over 4 steps) and
required the use of capricious hydrolysis conditions. More-
over, the structure did not easily accommodate further
synthetic elaboration.
yield.10 Although both 4 and 5 are commercially available,
they are easily and less expensively prepared as described.
Beginning from advanced intermediate 5 offers only a small
improvement in overall yield (ca. 5%) at significant cost.
Displacement of the chloride by cyclohexanemethylamine
proceeds smoothly in refluxing 1-butanol with triethylamine.
Cyclocondensation via slow addition of ethyl 4-chloroac-
etoacetate in DMF/H2O with sodium acetate afforded dea-
zaguanine analogue 7.11
Formation of the urea of 7-deazaguanine using 1-butyl
isocyanate in pyridine gave 1 in moderate yield. Lithium
hydroxide mediated hydrolysis of the ethyl ester in 1:1
ethanol/H2O affords analytically pure carboxylic acid func-
tionalized DeUG 8 in excellent yield.
As a demonstration of the ease with which 8 can be
functionalized with “clickable” groups, both alkyl azide and
terminal alkyne variants were prepared using standard
carbodiimide coupling protocols. Additionally, 1 can readily
be transesterified using ethylene glycol with potassium
cyanide12 to provide the 2-hydroxyethyl ester variant, thus
expanding the reactivity profile of DeUG (Scheme 2).
Herein, we report a convenient and scalable synthesis of
DeUG bearing a synthetic handle for further elaboration,
including clickable functionality. Detailed complexation
studies are reported including an X-ray analysis revealing
the solid-state structure of DeUG and a DeUG·DAN hetero-
complex, the latter the first reported structure of a quadruply
hydrogen-bonded heterocomplex.
Relatively minor changes to the previously reported
synthesis resulted in an approximately 3-fold improvement
in overall yield at reduced cost. As shown in Scheme 1,
Scheme 1. DeUG Synthesis
Scheme 2. DeUG Functionalization
analytically pure carboxylic acid functionalized DeUG 8 was
readily prepared on multigram scale (>10 g) in an overall
yield of approximately 35% over six steps without the need
to employ column chromatography for purification.
1H NMR dilution studies of DeUG 1 in deuterated
chloroform were performed as previously reported.7 Both
the N1-H and the aromatic C7-H resonances gave adequate
signal-to-noise ratios. However, the N2-H and N3-H
resonances showed substantial broadening at low concentra-
tions and could not be used to determine a dimerization
constant (Kdimer). Kdimer values of 520 M-1 and 700 M-1
Commercially available pyrimidine 3 was treated with
phosphorus oxychloride with slow addition of N,N-dimethy-
laniline to afford dichloropyrimidine 4 in excellent yield.
Other more environmentally benign bases, such as triethy-
lamine, can also be used for this transformation, albeit with
minor reductions in yield.9 Hydrolysis of 4 in refluxing
aqueous NaOH gave chloropyrimidinone 5, also in excellent
(10) Burgdorf, L. T.; Carell, T. Chem. Eur. J. 2002, 8, 293–301.
(11) The major side product during the cyclocondensation step was found
to be diethyl 2,5-dioxo-1,4-cyclohexanedicarboxylate (DESS), which is
presumably formed via self-condensation of ethyl 4-chloroacetoacetate. Slow
addition of the ꢀ-keto ester modestly decreases the amount of DESS formed;
however, attempts at further reducing this side reaction proved unsuccessful
and had minor impact on the yield of 7.
(7) Ong, H. C.; Zimmerman, S. C. Org. Lett. 2006, 8, 1589–1592.
(8) (a) Park, T.; Mayer, M. F.; Nakashima, S.; Zimmerman, S. C. Synlett
2005, 1435–1436. (b) Park, T.; Zimmerman, S. C.; Nakashima, S. J. Am.
Chem. Soc. 2005, 127, 6520–6521. (c) Park, T.; Zimmerman, S. C. J. Am.
Chem. Soc. 2006, 128, 11582–11590. (d) For an initial report of a DAN
derivative in molecular recognition, see: Lu¨ning, U.; Ku¨hl, C. Tetrahedron
Lett. 1998, 39, 5735–5738.
(12) Mori, K.; Tominaga, M.; Takigawa, T.; Matsui, M. Synthesis 1973,
790–791.
(9) Appleton, W. C.; Parziale, P. A. Eur. Pat. WO9507265, 1995.
62
Org. Lett., Vol. 11, No. 1, 2009