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Highly Effective Hydrogen-Bonding Receptors for Guanine Derivatives.

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taken froin ref [ N ] .Full-matrix least-squares refinement based on IF1 using
tlie \beighttn:r 1 d t ; ,gave
) final values R = 0.043. il-R = 0.023. and S = 1 .78
(or 313 vari;ihlc.s m d 2091 contrihuting I-eflectiona. The maximum shiftwror
O I I t h c Iri\t cycle w a s 0.003. All coordinates of the hydrogen atoms were ohscrbcd .ind refined with a fixed \ a l u c of isotropic displacement parameters
(I! - 11.05 A'). and tlie 26 other atoms "ere relined with anisotropic displace-
The final difference electron density map showed a tniixiid a minimum of -0.50 e k ' . Further details o f t h e crystal
a t i ~ i may
i
he obtained from the Director of the Cambridge
Dat;i Centre. Univer5ity Chemicnl Laboratory. 11 Union
Roiid. (;B-<~:i~iihridpe
CB2 1 EZ ( U K ) . on quoting the rull journiil ctlation.
t Blanc. L). Schwnrreiibach. H. D. Flack. J. AppI. c'rj~scullo,qr.1991.24. 1035I04I
I' hliiiii. S.I . I:is!.e.
S. t. Hull. L. Lessinper. C;. German. J:P. Declercq.
M. M . ~ O ~ l ~ ~ S.+~. ~l Il: sll r. i l tOf ~ ~ l n f 1 p I d lPi~llgf'U~1l.S
~'r
for I i l c ,fiut~J/?wiicso/ilflon
( I / < r i \idS i r i r i iim\ 1rofir X - K q l , D i / f r u r i i o / i 1)afu. University of York. Engl ~ i i dand
.
I.~iii\,iiii-la-Nsu~e.
Belgium. 1991.
S I<Ilull, H 13 1.~1;icl~
J. M . Stewart. XTAL3.2 C;\c,r'\ Manual, Universities of
Wc\lcrii A i i \ i r ~ i I i ; i a n d Maryland, 1Y92.
C'. li. Johnwn. 0 R 7 ' t : P 11: Report O R N L - S I X ; Oak Ridge National Lahorator? 0 , i k Ridge. T N . 1976.
I i i i i ~ ir i u r i o i w l I i d / h f o r I - r u i . ('r~.\lrilliipr~i/)ln..
Val. IV. Blrmingh;im. Kynoch.
I974
Iiiicratiiiii1;ii tl-tr,iilsIer i\ frequent i n polyeiie -metal complexes. For il recent
I
e w n p l e i n fcrrocenr chemistry see A. Cunningham, Jr.. O r ~ ~ i ~ n o i ~ i e ~ i u l l i ~ . \ ,
1994. i.+.2JX(I 24x5. I n the reaction of[D,]-Za with iBuLi. the product [Di]-7i
4
~ O C In
\ o t display the ' H N M R signal associated with themdo H ;itoiii at C1 of
the bcii/oc~cloliexadienylligmd ( 6 = 3.89).
I'ri1)l c i i t ~ o ~ ihave
s
been used extensively to remo\e c.w hydride from
have varying degrees of
~~rgiiiii~iiiet~illic
complexes: F o r a n exninple in Fe chemistry see D. Mandon.
bonding sites, enabling
I.. 7oupct. I).Astruc. J A n . C'lrrtii. SOC. 1986, IO#. 1320-1322.
Highly Effective Hydrogen-Bonding Receptors
for Guanine Derivatives**
2
1,
'0
H
I
.
o
-..-
6
5
I
flexibility and numbers of hydrogenestimation of enthalpic and entropic
contributions to the binding free energy.['] The design of 4 and
5 combines the fused pyridine framework of hexagonal lattice
receptors for urea,"".
guanidinium,[6d,el and benzamidiniurnrsc1with o-aminonitrile hydrogen bond donors''"] that are
complementary to acceptor sites on guanine. Preorganized receptors 4 and 5 were synthesized from benzylidene ketone W",'I
by the methods shown in Scheme 1, and flexible analogue 6 was
Thomas W. Bell,* Zheng Hou, Steven C. Zimmerman,*
and Paul A. Thiessen
Many artificial receptors have been designed and synthesized
lor thc purpose of recognizing nucleobases.[' -41 Hydrogenbonding receptors can bind nucleobase derivatives tightly in
nonpolar organic solvents.['. 2l but ionic or solvophobic interactions are usu~illyneeded for strong complexation of nucleosides
and nucleotides in polar solvents."". ', 3,41 Hydrogen bonds are
critical to biomolecular recognition of guanosine phosphates[51
and other nucleotides, but they are greatly weakened in polar
solvents. Herein we show that receptors having hydrogen bonding sites positioned on a hexagonal lattice (hexagonal lattice
rcceptors)'"l can bind guanine derivatives tightly through hydrogen bonds alone. even in ii highly competitive solvent such as
DMSO. Decreasing the preorganiration or number of hydrogen
bond donor or acceptor sites in the receptor weakens the complex.
Guanine dcrivatives 1-3"l were chosen as guests for the current study, and hosts 4-7 were designed to form hydrogen
bonded complexes, as shown for 4 in structure 1. Receptors 4--7
[*I
I' ]
10
'
N o r iid d rc % I)ep,irtment of Chenii\try:216, University 06 Nevada
i<cn{1.NV x ~ ~ i ~ 7 - 0(USA)
0~0
+ l702)784-6804
Ikil.. S C' /iinindrnman. P. A Thiessen
Lklxirliiieiii
01 Chemistry. University o f Illinois at Urbana-Champaign
hOO South M a l h e w Avenue. Urbana. I L 61x01 (USA]
c-iiiiiil
[**I
Q
9
I'rcir. T. W Hell.' ' %. Hou
Depai-lmcnr of Chemistry. Stiite Uiiivercit) of New York
Slciny B i - o i ~ k N
, Y 11794-3400 (USA)
Iiil.code
["I
8
Thi\
'
Z i i n i n c r i i i : ~ ~aries.scs.iiiiie.edu
~r
iborh
% a \ funded by the National Institutes of Health (GM 32937 and
GM 3NHtl\.
Scheme I . Synthcis of preorganized receptors 4 and 5 . a) I')rrolid~ne, benzene.
reflux. 24 h (64%): b) CH,CH,OCH=C(CN),, THF. -20 C . 0.5 h , c . conc. aq.
NH,. THF. reflux, 4 h (61 % from 9) [9]: d) CH,CI,:CH,OH. 0 , . - ~ 7 8C (76%):
e) 2-aminonicotinaldehyde [ lo] , CH,OH:toluene ( 5 : 3 . v , v ) . 1.X-diazabicyclo[5 4.0]undec-7-ene (DBU). reflux, 24 h (73%); f ) 4-amino-I.D-pyrimidine-5-carboxaldehyde [ I l l . CH,OH:toluene ( 3 . 2 . v/v). 15% KOH ('H,OH, reflux, 30 h
(36%); g) 0.2 N HCI. reflux. I 2 h (100%). ti) CH,(C")?, CH ,OH:toluene (3:2, viv).
piperidine. retlux. 24 h (79%) (121.
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Br
r
Table I . Stability constants [ M - ' 1 and free energies ofassociation ([kcalmol~'1, in
parentheses) for 1 : 1 complexes of receptors 4-7 with guanine derivatives 1-3
(298 K ) [a]. as calculated from changes in 'H NMR chemical shifts (AS) on coniplexation.
16
15
Complex
Ari,,,, fbl
Solvents
([D,]DMSO:CDCI,. v!v)
1:0
1:l
1.4
4.2
140 & 20
0.14 [c]
5.2
0 47 [K]
5-3
0.47 [el
6.1
0.19. -0.2s.
( - 2.9)
3800 ? 300
(-4.8)
3x0 I 50
( < -7.1)
(-
-0.71 [f]
2.52. 1.33 [i]
20
21
Scheme 2. Synthesis of flexible receptor 6. a) HCO,Et. NaH, ethanol!henzene.
hydrochloride 1131. ethanol (50%
reflux. 22 h ; b) ethyl 3.3-diamino-2-propeno~~te
from IS): c) 2-methyl-3-butyn-2-ol. [(PPh,),PdClJ. Cul, PPh,, Et,N. reflux. 2 h
(92%) 1141: d) NaH. toluene. distillation (80%) 1151; e) conc. HCOOH, sealed tube,
150 C. 10 h (92%) [16]; f ) 2,6-diamino-3-pyridiiiecarboxaldehyde1171. 20%
Na0H;MeOH. toluene, reflux. 1 h: g) n-pentaiiol. H,SO,, reflux. 15 h (67% from
19); h ) (CH,CO)J). CH,Cl2. room temperature. 1 5 min (67%).
5.7)
5.3)
1x0
( - 3.0)
170~10
( - 3.0)
190
( - 3.1)
ca. 14
(-1.5)
7.1
1 b-Na+
19000 F 3000
((-
1.57 [g]
6.3
2.21 [h]
~
> 190000 [d]
YO00 & 1000
6.2
-
3.5)
1.19
~~
4600
( - 4.9)
5000
( - 5.0)
360
( - 3.4)
~
[a1 Errors given are CJ values for the averages of K., values calculated for each data
point. duplicate measurements by nonlinear regression were within 20% of the K,
values. for which no errors are given. [b] Unless stated otherwise, chemical shifts on
complexation for the species at a fixed concentration were calculated from analysis
o r the results of titrations in [D,]DMSO:CDCI, ( I :4): positive
value for
downfield shift [c] H4 in 4. [D,]DMSO/CDCI, ( I : I ) . [d] Estimated by assuming
that the difference between the binding energies of 4 - 2 and 5 . 2 should he larger in
1 : 4 [D,]DMSO!CDCI, than In the 1 : 1 solvent mixture. [el HI3 in 5 . [f] HI'. H2'.
and H3'. respectively, in 1. [g] HZ in 6. [h] NH in 3. [i] N H and WH2. respectively.
iii I .
Stony Brook. These results indicate both that the minor structural difference between guests 1 and 2 is irrelevent to binding
strength and that experimental variations between the different
laboratories negligibly affect the binding analyses.
The most striking result shown in Table I is that receptor 4
prepared as shown in Scheme 2. Receptor 7 was prepared from
acetophenone and 2,6-diarnino-3-pyridine~arboxaldehyde"~~ binds triacylated guanosine 2 in 1 : 1 [D,]DMSO/CDCI, with a
K , value of greater than 3000 M-' by means of hydrogen bondby analogy with the synthesis of 6."''
ing alone. Even in pure DMSO the complex 4 . 2 is moderately
Binary mixtures of CDCI, and [DJDMSO served as convestable. Flexible receptor 6 can form the same number of primary
nient solvents for ' H N M R studies of complexation for the folhydrogen bonds with guanosine 2, but in 1 . 4 [D,]DMSO/
lowing reasons: 1) guests 1-3 and hosts 4-7 are soluble over
CDCI, the complex 6 . 2 is a t least 4.1 kcalmol-' weaker than
wide concentration ranges; 2) the [D,]DMSO/CDCI, ratio can
4 . 2 . The source of the difference in the stabilities of these two
be decreased to observe host and guest aggregation.[' 91 then
complexes cannot be elucidated completely because receptors 4
increased to conduct binding studies without competing aggregation; and 3) the (D,]DMSO/CDCI, ratio can be increased to
and 6 have several structural differences. Nevertheless, it is instructive to consider the factors that may be responsible.Is1 Two
weaken 1 : 1 complexes, enabling measurement of stability condegrees of rotational freedom must be lost in 6 upon complexaThe stability
stants (K,) by titration and dilution
tion. In a related host-guest study the energy cost of freezing an
constants of complexes listed in Table 1 were determined by
aryl-aryl bond was determined to be 0.9 kcal mol-1,[211in line
addition of the guanine guests to solutions of the hosts or by
with Jencks's estimate of 0.5-1.4 kcalmol- per restricted rotaaddition of the hosts to solutions of the guests. The chemical
tion.'8d1This loss in entropy accounts for less than half of the
shifts of the compound with the fixed concentration were used
difference between the stabilities of complexes 4 . 2 and 6.2. The
to model complexation equilibria. The stability constants were
remainder can be attributed to enthalpic factors, including secchecked by dilution of the 1 :I complexes or by multiple titraondary electrostatic interactions["] that stabilize 4 . 2 (structions. A 1 : 4 mixture of [DJDMSO and CDCI, was found to be
ture I) and conformational strain in 6 . 2 caused by steric interacthe best solvent for comparing the binding abilities of all four
tions involving the aromatic hydrogens (structure 11).
receptors, though only the lower limit of the stability constant
Additionally, the convergence of nonbonded electrons shown in
could be estimated for the strongest complex (4.2) in this solstructure 111 may weaken solvation of the host cleft per hydrovent.
gen bond acceptor, enhancing hydrogen bond strengths in comThe complexation shifts and relative stability constants in
plex 4.2. The large increase in binding energy observed upon
Table 1 are all consistent with the binding model shown in strucligand extension from 5 to 4 apparently reflects the "intrinsic
ture I. For example. extending receptor 5 to 4 o r receptor 7 to
energy" described by Jencks[8d1and shows that much of the
6 markedly increases the K, value, indicating that the aminopyentropy cost i n 4 . 2 is already paid upon formation of 5.2.
ridine units contribute to the binding. Furthermore. stability
constants are inversely related to the amount of [DJDMSO in
Although acetamido. n-arninoester. and o-aminonitrile
the solvent mixture, showing that desolvation of host and guest
groups are all expected to be good hydrogen bond donors, host
is a significant factor. Finally. the K, values for complexes beseries 4-7 does not allow comparison of relative donor abilities.
tween receptors 4-6 and 1 measured at Illinois were identical to
To determine i f 4 . 2 and 5 . 2 might be stabilized by an additional
those for the analogous complexes of 4-6 and 2 measured at
interaction between the 2'-ester group of 2 and the o-aminoni-
'
COMMUNICATIONS
I
Ill
H
vo
CN
[4] a) P. Schiessl. F. P. Schmidtchen. J. Org. Chon. 1994, 509 51 1: b) A . V. EIiseek. H.-J. Schneider. J h i . Chon. So(. 1994. 1 / 6 . 60x1 6088. c ) M. Dhaenens. JLM. Lehn. J:P. Vigneron. J. C/wn. Soi.. I ' c i L i i i /ruii.$. 2 1993. 137913x1: d) V. M. Rotello. E. A. Viani. G. Deslongch;iiiip\, B. A. Murray. J.
Rebek. Jr.. J. Ain. C/iei?i.Soc. 1993. 115. 797-798.
[S] a)T. S.McConnell, T. R Cech. Biocheniisrr~~
1995.34.4056 4067:h) E. F Pai,
W. Kabsch. U. Krcngel, K. C. Holmes. J. John. A. Willitighorw. Norirrp 1989.
141. 209-214.
[6] a ) D. Beckles. J. Maioriello, V. J. Santora. T. W. Bcll. L. Ch;ipote;iu, 8.P.
Czech. .A. Kumar. Terrrihcdriroii 1995, 51, 363 376. b) T. W. Bell. Y:M. Cho. A.
Firestone. K. Healy. J. Liu. R . Ludwig. S. D Rothenhel-$i'r in Orguiii( Srririicse,, Co//wriw Vd. L'///(Ed.: J P. Freeman). Wiley. Nc\\ York. 1993. 87L93:
c) T. M' Bell. V. J. Santora. J .4m Chon. So[. 1992. 114. X300-X301. d ) 'I-. W.
Ciieiri. 1990, 102. 931 933: A q y i > ( ' h i i i . 1iit E d Eii'ql.
1990.2Y. 923L925: e) T. W. Bell. A . Firestone. J Liu. R 1 udwig. S. D. Rothenherger i n /nc/ir.siin Plrtviomwiu uiirl Mo/?i ulur Rcmgnirioii (Ed.: J. L. Alwuood),
Plenum New York. 1990, pp. 49 56; f ) T. W. Bell. J Liu. .I Ani C h t . S W
1988. 110. 3673- 3674.
[7] For the synthesis of I and 2. see A. Matauda. M Shiii<imki. M. Suauki. K .
Watanabe. T. Miynsaka. Sriit/ic,si.\ 1986. 385 4 8 6 . For i l i c synthesis of 3. sec
F. Seel'c. A. Kehne. t i . - 0 . Winkeler. Lichi~sA i i n . C'/i(,iii. 1983. 137 146: I .
Kjellbcrg. M. Liljcnberg. N. G. Johansson, ?I,rru/ivilriiri L.c.ri. 1986. 27. 877
~
8x0.
[S]
4046 4050.
V
IV
trile group (cf. structure IV), the complexation studies were repeated using 9-octylguanine ( 3 ) . Interestingly, 5 . 2 is
0.8 kcal mol- I more stable than 5 . 3 . whereas 6 binds 9-octylguanine ( 3 ) as strongly as it does 1 or 2. It is possible that
intramolecular hydrogen bonding in the o-aminoester group of
6 (see structure V) weakens this additional interaction, which
represents a final contribution to the remarkable stability of4.2.
This comparison of synthetic receptors for guanosine derivatives demonstrates that hydrogen-bonded complexes between
neutral organic molecules can be stable in highly competitive
solvents if some of the energy costs of binding are paid in advance during the synthesis of highly preorganized receptors. The
synthetic price of preorganized receptors is comparable to that
of flexible analogues explored in this study. Questions that remain are whether such hosts can select between different nucleosides and whether chromogenic or fluorogenic groups can
be incorporated into their structures to optically signal the binding event.[". 231
Received: March 20. 1995
Revised version. May 29. 1995 [27812IE]
German version: Angw. Ciirni. 1995. 107, 2321 -2324
Keywords: hydrogen bonds
cleosides
-
molecular recognition
*
w\:; I ) S C. Zimtnernian. Top. C'nrr. C ' h ~ n i .1993. 165, 71 102; b) A. D.
h i i 1991. 1. 1-64: c) J. Rebek. Jr.. Arc. C l i m .
-
M. Inou!c. K . Kim. T. Kitao. J. A i n C'heni. Sou. 1992. 114. 778 780; b) E
Vogtlc. A/I,~<,II. ( ' h i i i . 1991. 101, 433 436: A i i g ~ w Chun.
.
h r . E d h g l . 1991.
30, 441 444: i.) S. C'. Ziminerman, Z. Zcng. W. Wu. D. E. Reichert. J. A i i i .
( 7 w i i i . So,. 1991. 113. 196 201 ; d ) K. S. Jeong. T. Tjivikua. A. Muehldorf. G.
Deslonpchainp\. M. Famulok. J. Rebek. Jr.. ihid. 1991. 113. 201 209.
[3] ; I ) V. Kril. J. L. Sessler, Z,iruhe(lroii 1995. J1. 5iY 554; b) M. M. Conn. G .
L)c\loiigch~imp\..I. de Mendoza. J. Rebek. Jr.. J Aiii. C/i(vii. So<. 1993. 115.
3i4X 1557. c ) E B Schwiirti. C. B. Knoblci-. D. J. Cram. ihirl. 1992. 114,
10775 107x4: d) H. Fui-uta. D. Masda.1. L. Srssler. iiiid. 1991. 113. 978-985.
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[lo] T. G. Majewicr. P. J. Caluwe, .I Org. Chiw 1974. 3Y. 710 721
[ l l ] J Baddiley. B. Lythgoe. A . R. Todd, J. C h r i i i . So(.. 1943. .M- 387.
[I21 E. W. Hawcs, D. K. J. Gorccki. D. D. Johnson. J Mcd C h n . 1973, l 6 - X49
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[I31 S. M. McElvain. B. E. Tate, J. .4ni. C h i . So<.1951. i.t. 2760 -2764; H. Meyer.
t Bosaert. H. Horstmann, Lirhig.5 . 4 1 i i i . C/irni 1977. 1x95 190X.
[I41 E. 7 Sabourin. A. Onopchenko, J. Org. C h w . 1983. 4S. .Sl?S- 5137.
[IS] S.J. HaLen?. P. M Hergenrother. J. Org. Ch~mi.1985. ill. 1763 1765.
[I61 N . Menashe, Y Shvo. J. Orx. Ciimi. 1993, i X . 7434 7-119
[17j E. E. Fciilon, T. J. Murray. M . H Baloga. S. C. Ziiniiicrm;in, J. 01.q. C h i ? .
1993, S X . 6625 h62X.
[18] All new compounds gave elemental analyscs and spec~iiiin accord with assigned structures.
[19] Variilble-concentration ' H NMR experiments indicated lliili I :ind 2 aggregate
in [D,]DMSO:CDCI, mixtures containing less than 5 " L [DJDMSO by volume. Guanosine dimerizes weakly in pure DMSO: R A Newmark. C. R.
Cantor. J. Am. Chwii. Soc. 1968, YO. 5010-5017.
[20] a ) C:. S Wilcox in Frontiers (#! Siipruinolwiilur Orgunk (7ieini.sfrr and Photor / i ( w i i . w i s (Eds: H:J.
Schneider. H. Durr). VCH. Wcinlieim, 1990. pp. 123
143; b) T. Wang, J. S. Bradshaw,. R. M. Izatt. J. Heri,rwri/. C/iim. 1994. 31.
1097- 1 1 14.
[21] S. C. Znnmerman. M. Mrksich, M . Baloga. .I An!. ('lrcni Soc. 1989. / / / ,
8528-8530.
[22] a ) S. C. Zimmerman. T. J. Murry. in C'ompururrowul A p p r w d w , \ in .Siipraiiiii/eciilurC/ic,nii.trr~.(Ed.:W. Wipff).(NATOASIScr. 1994.426. 109 -115):h)W. L.
Jorgenaeii. J. Pranata. J Aiii. C/iein. Soi.. 1990. 112. 20OX--2010.
[23] T W. Bell. D. L Beckles. P. J. Cragg, J. Liu. J. Maioriello. A T. P a p o u h . V. J.
Santora in F(rrorcwwir ('ii[,r?in.sr.iisor.r of 1oii mid :Midi,( id(, Rmynrrtnn. (Ed.:
A . W. Czarnik), (AC'S L ' ~ i ~ i pSLW.
.
1993. 538. X5 10.11.
nu-
I l a i n i l t o n A h Snpruino/. C
l<c~\
1990. 23. 19')L404.
121
D. H Williams. M. S. Searle, P. Groves. J. P. Miicka). M S . Weiluell. D. A .
Bc;curegard. M. F. Cristohro. Pnrr .4pp/. C / i m i . 1994,GO. 1975- 19x2: b) D. H.
Williama. M. S. Searle. J. P. Mackay. U . Gerhiird. R. A . Maplestone. Pror
Nurl. A t u d S c i . USA 1993. YO. 1172 117X: c) A R. I-ci-sht. Twiidr Biochrni.
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ii)
Corrigendum
In the communication "1.5-Anhydrohexitol Nucleic Acids.
a New Promising Antisense Construct" by Arthur Van
Aerschot.* Ilse Verheggen, Chris Hendrix, and Piet Herdewijn
(Angew. Cliem. Int. Ed. Engl. 1995. 34, 1338-1339) the curves
of Figure 3 were inadvertently exchanged in the legend. The
dashed curve was determined a t 260 nm ( A and the solid curve
at 284 nm ( A , ) .
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