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Axially Chiral Amidinium Ions with a Biaryl Skeleton A New Class of Structure in HostЦGuest Chemistry.

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Axially Chiral Amidinium Ions with a
Biaryl Skeleton: A New Class of Structure
in Host- Guest Chemistry**
Stefan Lehr, K a r i n Schutz, Markus Bauch,
and Michael W. Gobel*
As part of our search for synthetic phosphodiesterases. we
reported some time ago['] on the cationic alcohol 1. This compound can reversibly coordinate deprotonated phosphoric acid
diesters to the amidinium group and react with them in a nucleophilic substituOH
tion reaction. On account of its constitutional symmetry, 1 is achiral. We now
describe a new stereochemical concept
1, H+:H;
which provides access to novel, axialiy
chirat['' arnidiniurn ions"' (2. 14, 15)
starting from the structural type 1
(Fig. 1). These ions are of interest as receptors and catalysts in host-guest
chemistry: potential applications include their use as phase transfer catalysts[41or-in the deprotonated form as chiral bases.['I
8 : R=Boc
9: R = H
l l a : R=Boc
12a: R = H
l l b : R=Boc
12b: R = H
Fig. 1. Structural formula and molecular model of the axially chiral amidinium
IOU 2.
The first step in the synthesis of 2 (Scheme 1 ) was the conversion of lactam 3 into nitrile 4. Construction of the biaryl carbon
skeleton of 2 was achieved in a palladium-catalyzed coupling of
4 with a copper reagent obtained from the ortlzo-lithiation of
rac-5 followed by reaction with copper(r) bromide. The two
diastereomeric products formed, rac-6a ((S*,R*) configuration) and rac-6 b ((S*,S*) configuration), could be hydrolyzed
to give the phenol rac-7 (63% from 4). The Mitsunobu reaction[61with N-Boc-aminoethanol provided rac-8 (79 "h).Removal of the protective group gave the aminonitrile rac-9. Subsequent base-induced cyclization (and protonation) yielded the
amidinium ion rac-10 (isolated as the picrate). This ten-membered ring formation was achieved without any problems
(78 %), even in relatively concentrated solutions. We attribute
the surprisingly smooth course of reaction to the fact that seven
of the ten atoms in the ring were already fixed in the starting
material in a conformation resembling that found in the
[*] Dr. M. W. Gobel, Dipl.-Chein. S. Lehr. Dip[.-Cheni. K. Schutr. Dr. M. Bauch
Institut fur Organische Cliemie der Universitiit
Marie-Curie-Strasse 11. D-60439 Frankfurt am Main (FRG)
Telefdx: Int. code + (69)5800-9250
This work was supported by the Fonds der Chemischen lndustrie. the Deutsche
Forschungsgemeinschaft (Go 545/1-1), and the Gradinrrtenkolleg "Cheniische und Biologische Synthese von Wirkstoffen". We thank Prof. Dr. G .
Quinkert for his generous support.
VCH ~,.i.,.lu~.\,~esPllsrhufrfr
m b H , 0-69451 Wemheim, 1994
3 a b c 4;
- 5th
rac-7 f +rac-8 9
rac-6a + racdb
- -
rac-5 d
rac-7 I
rac-9 h
I,12a+ 12b k
Scheme I . Synthesis of 2[picrate]. a) I . NaOH, H,O, A , 2. NaNO,, H,SO,; 3. K I
( S 5 - 6 0 % ) : b j 1 PC1,;2. NH,(91%).c)POCI,,pyridine(9la~);d)1.4equivruc-5.
1.4 equiv mbutyllithium. N.N,N'.W-tetramethylethylenediamine. T H E 0 C.
50min: then 1.4equivCuBr. -30 C ; then 1 equiv4and 0.1 equiv[(Ph,P),PdCIJ,
-30°C 'room temperature. 15 h (68%): e) HCI. MeOH, H,O (93%): f) N-Bocaminoethanol. diethyl azodicarboxylate. Ph,P. CH,CI,. room temperature, 20 h
(79%); g) HCI. MeOH. H,O (97%); h ) 5 equiv (Me,Si),NLi. 1.4-dioxane. A , 1 h
(ruc.-lO[picrate]: 78%): i) N-Boc-(S)-alaninol. diethyl azodicarboxylate, Ph,P,
THF, room temperature, 20 h (56%. 32% r o e 7 recovered); j j trifluoroacetic acid.
CH,CI,. room temperature (90"/;,):
k) 5 equiv (Me,Si),NLi, 1.4-dioxane, A, 3 h ;
separation of isomers by fractional crystallization of the picrate from MeOH/H,O
(2[picrate]. 61 YO.13[picrate]:6 % ) .
0S70-0833!94!0909-0984B 10.00+ 25.0
Angeii. Cliem. Int. Ed. Engl. 1994, 33, No. 9
In order to control the absolute configuration at the biaryl
axis, the phenol rac-7 was linked with a chiral building block, a
side chain synthesized from (S)-alanine.['I Again, two
diastereomers were formed, the non-racernic products 11 a
( ( S , R )isomer) and I1 b ( ( S , S )isomer; total yield of 5 6 % ; unreacted phenol r(iC-7 can be recovered). It was possible to separate
11a and 11b, which are interconvertible by rotation about the
biaryl axis, by HPLC. A barrier to rotation of 98.3 kJmol-'
(30 " C ; ethyl acetate/hexane; ratio of isomers at equilibrium
1 . 2 : l ) was calculated from the rate of isomerization. The
aminonitriles 12a and 12b, obtained by cleavage of the Boc
groups. can for steric reasons only undergo the base-induced
cyclization when the methyl group of the side chain becomes
equatorial and the adjacent methine proton axial (see Fig. 1).
This arrangement can only be achieved from the isomer 12a
with the ( X R ) configuration. By raising the reaction temperature we were able to increase the rate of isomerization of 12 b to
1 2 a to such an extent that both compounds cyclized stereoconvergc,nt/>,to give the same amidinium picrate 2[picrate] with the
( S , R , S ) configuration (61 %).['I
The coupling constants observed in the ' H N M R spectrum and the fact that the axial
methylene proton shows a strong nuclear Overhauser effect to
the phenyl ring provide evidence for the chair-type conformation in the ten-membered ring of 2. The (formal) C-N double
bond in the amidinium ion 2 has an ( E ) configuration. Compound 2 shows similar binding affinities towards dimethylphosphate ions''' like cation I. From the mother liquor of Z[picrate]
the ( Z )isomer 13[picrate] could also be isolated. Conversion of
13[picrate] to 2[picrate] was observed on application of heat.
Selected physical data for 2, rac-7, and rac-10 are given in
Table 1 .
Table 1. Selected physical data for Z[picrate], rue-7, and ruc-lO[pIcrate]
2 [picrate]: M.p. 266-268 "C (ethyl acetatein-hexane) - [a]:o = - 10.0 (c = 0.14 in
methanol). - ' H NMR (270MHz. [DJDMSO, locants see 7 ) : 6 =1.10 (d.
J = 6.7 Hz, 3 H. methyl-H). 3.58 (m, 1 H, methine-Hi,,), 3.98 (dd, Jgcm= 12.4 Hz,
J,,, = 3.7 Hr. 1 H. methylene-H,,). 4.30 (dd, JSem=12.3 Hz, A,, =10.7 Hz. 1 H.
methylene-H,,).7.12(dt.J, =7.4Hz,Jd =O.Y Hz,lH,4-H).7.28(m.2H,3'-Hand
6 - H ) . 7.40 (dd. J =7.1 and 1.3 Hz. 1 H. 7-H), 7.48 (ddd, 7-line signal, J = 8.6, 7.3
and1.8Hz. l H , 5 ' - H ) . 7 . 5 8 ( d d , J = 7 . 1 a n d 1 . 4 H z , l H , 2 - H ) . 7 . 7 2 ( t , J = 7 . 6 H z .
2 H . 3-H and 6-H). 7.99(s, 1 H, NH,,). 8 . 1 3 ( d d , J = 8.3 and 1.2 Hz, 1H. 5-H), 8.31
(dd. J = 8.3 and 1.3 Hz. 1 H. 4-H). 8.59 (s. 2 H , picrate-H), 8.93 (s, 1 H, NH,,), 9.13
(d, J = 9.7 Hz. 1 H. RNH,,)
ruc-7: M.p. 202 -204 'C (ethyl acetateln-hexane). - ' H NMR (250 MHz,
[DJDMSO): d = 6.88 (m. 2H. 4'-H and 6'-H), 7.16 (dd, J =7.9 and 1.5 Hz. I H,
3'-H),7.27(dt.J, =7.0 Hz, Jd =1.2 Hz, 1 H.S'-H),7.45(dd, J = 7 . 1 and 1.3 Hz, 1 H .
7-H). 7.64 (dd. J = 8.2 and 7.2 Hz, I H) and 7.69 (dd, J = 8.2 and 7.1 Hz, 1 H. 3-H
and 6-H). 8.01 (dd. J =7.2 and 1.3 Hz, 1 H. 2-H). 8.09 (dd. J = 8.3 and 1.3 Hz, 1 H,
5-H). 8.33 (dd. J = 8.3 and 3.3 Hz, 1 H, 4-H), 9.37 (s, 1 H , OH)
Fig. 2 Structural formulae and molecular models of the amidinium ions 14 and 15.
above. The synthesis of derivatives of 2 tailor-made for the areas
of molecular recognition and catalysis thus appears to be feasible.
The CD spectrum of the picrate salt of 2 (Fig. 3) provides a
first impression of how coordination to the amidinium ion influ-
ruc-I0 [picrate]: M.p. 283-286 'C (methanol; decomp. beginning at 275'C). ' H NMR (770 MHr, [DJDMSO): 6 = 3.35 (m, superimposed by H,O, 2H,
NCH,), 4.01 ($d. J about 12 Hz, 1 H. OCH,,), 4.53 (ddd, 7-line signal, J a h o u t 13,
9.5 and 4.5 Hz. 1 H, OCH,,), 7.12 (t, J =7.4 Hz, 1 H. 4'-H), 7.27 (m, 2H. 3'-H and
1 H. 5'-H). 7.53 ( d d , J =7.1 and 1.1 Hz, 1 H.2-H), 7.72($t, Jabout7.6 Ha, 2H, 3-H
and6-Hl.8 I 4 ( d d . J = 8.4and 1.3 Hr, 1 H,5-H).8.31 (dd, J = 8.3and 1.2Hz, I H ,
4-H), 8.44 (s. I H. NH,,). 8.60 (s. 2H, picrate-H). 8.97 (s and d, superimposed, 2 H ,
NH,, and RNH,,,)
h [nrn]
Fig. 3. C D spectrum ofZ[picrate] (SO ~ L in
M CH2CI,, room temperature):
out addition, - - - with addition of 20 equiv 16.
The structural principle underlying the stereoconvergent ring
closure to 2 is as clear as it is general: It should apply to many
types of amino alcohol side chains and should be unaffected by
the presence of further substituents, aromatic o r heteroaromatic
moieties attached to the phenyl ring. Indeed, the synthesis of
amidinium ions 14 and 15 (isolated as their picrate salts) (Fig. 2)
was achieved following an analogous procedure to that outlined
AngeIl, Clwm In/. Ed. Enpl. 1994, 33, N o . 9
ences achiral guest molecules. Whereas no signals are recorded
beyond 350 nm in the spectrum of the tetraphenylborate salt
2[BPh,], a pronounced band is observed at longer wavelengths
in the spectrum of 2[picrate]. The origin of this effect is a chiral
disturbance of the picrate chromophore in the host-guest complex. On addition of the salt 16, whose anion binds to the ami-
; VC'H Verlugsge.sel1.s~
hu/i mbH, D-6Y451 Weinhebn, 1994
0571)-0833lY4!0Y0Y-0985 $ 10.00f .25/0
98 5
dinium ion, the long-wavelength band disappears. Our longterm goal with these investigations is to be able to enantioselectively control not only the spectroscopic behavior but also the
reactivity of prochiral guest molecules.
Rewved: November 29, 19Y3 [Z6521 IE]
German version: Angm. Ciiein. 1994. 106. 1041
[ l ] M. W. Gobel, J. W. Bats, G. Diirner. Angew. Chiw7. 1992. 1114, 217- 218: Angrit..
Cheni. I n f . Ed. Enyl. 1992, 31, 207-209.
[2] Chiral biaryl structures: a) D. J. Cram, Angeii. Chem. 1988. 100. 1041-1052:
Arigeii'. Chen?. I n f . Ed. Eiigl. 1988. 27, 1009-1020: b) R . Noyori. Chem. Soc.
R w . 1989. 18, 187-208; c) R. Noyori. H. Takaya. Acc. Cheni.RPS.1990, 23,
345-350; d) T. Hayashi. K. Haydshizaki, T. Kioyi. Y. Ito. J Arn. Chrm. Soc.
1988. 110. 8153-8156: e) G. Bringmann. R. Walter. R. Weirich. A n p i ' . Chetn.
1990. 102. 1006- 1019; Angeii.. Chei??.In[. Ed. Engl. 1990. 29. 977; f ) G. Bringmann, T. Hartung. Trt~r~ilierlron
1993. 49. 7891 -7902.
[3] For ureoaration and use of non-racemic chirdl eudnidines in host-west chemistry. see: a) A. Gleich, F. P. Schmidtchen. P. Mikulcik, G. Muller. J. Chem. Soc.
Chem. Conimun 1990, 55-57; b) A. Gleich. F P. Schmidtchen, Chew. Ber.
1990. 123.907-915: c j F. P. Schmidtchen, Liebig3 Ann. Cheni. 1991. 539-543;
d ) H. Kurrmeier. F. P. Schmidtchen. J. Org. Chetn. 1990,55. 3749-3755; ej P.
Schiessl. F. P. Schmidtchen. Tetruherlron Let[. 1993, 34. 2449-2452; f) A.
Echavarren, A. Galin, J. de Mendoza. A. Salmeron, J.-M. Lehn. H e h . Chin?.
Acru 1988. 71, 685-693; g ) A . Echavarren. A. Galan. L M . Lehn. J. de Mendozd. J. Am. Chem. Sot.. 1989, 111, 4994-4995; h ) A . Galin. E. Pueyo. A.
Salmeron. J. de Mendozd, Tefrahetlron Lett. 1991. 32, 1827-1830: I) A. Galin.
J. de Mendoza. C. Toiron, M . Bruix. G. Deslongchamps. J. Rebek. J. An?. Clieni.
SO(. 1991, 113. 9424-9425: j) A. Galin. D. Andreu, A. M . Echavarren. P.
Prados. J. de Mendoza, ibirl. 1992, 114. 1511-1512: k) G. Deslongchamps. A.
Galin, J. de Mendom. J. Rebek. Jr.. Angew. Chew. 1992. 104, 58-60; Angeii
C/ic*n?.In[. Ed. Engl. 1992, 31, 61-63; 1) E. J. Corey. M. Ohtani. 7errahcdmn
Let,. 1989. 31). 5227-5230: ni) P. Molina. M. Alajarin. A. Vidal. J. O q . Chen?.
1993.58. 1687-1695.
For a n early example of extraction of anions from water using a nonpolar phase
and a lipophilic amidinium ion, see: F. Heinzer. M. Soukup, A . Eschenmoser,
H d i . Chirn. Acru 1978, 61, 2851 -2874.
For formation and structural characterization of ion pair complexes between
nitroalkanes and bicyclic amidines and gudnidines. see: a) P. H. Boyle. M. A.
Convery. A. P. Davis, G. D. Hosken. B. A. Murray, J. Chem So<,.Cheni. Commun. 1992. 239-242; b) E. van Aken, H. Wynberg. F. van Bolhuis. hid. 1992.
629 -630.
0 . Mitsunobu. .Yim[hrsi.\ 1981. 1 -28.
T. Moriwake. S. Hamano. S. Saito, S. T0rii.J Org. Chen7. l989,54,4114-4120.
For an example of a diastereoselective ring closure reaction of a biaryl derivative
leading to kinetic separation of isomers. see: G. Bringmann. J. R. Jansen. H.
Busse. Liehigs Ann. Cheni. 1991, 803-812: see also [2e.f].
A ' H N M R titration of 2[picrate] with sodium dimethylphosphate at 30 C in
[DJDMSO gave a K,, value of 250+30 L m o l - ' .
Rudi J. H. Hafkamp, Martinus C. Feiters,* and
Roeland J. M. Nolte"
In recent years, the interest in supramolecular structures has
grown steadily. Self-assembling systems have been prepared
from a variety of building blocks including surfactants,"] polymers,['] r ~ d l i k e ,and
~ ~ ]disklike mesogen~,[~I
etc.I5]As part of our
program aimed at the development of novel chiral matrices for
catalytic applications, we report here on the synthesis and selfassembling properties of the n-octyl-D-gluconamide derivative 3, which contains a metal-coordinating imidazole group.
Our interest in gluconamides and related carbohydrates was
Prof. Dr. R. J. M. Nolte, Dr. M. C . Feiters. R. J. H. Hafkamp
Nijmegen SON Research Center
University of Nijmegen
Toernooiveld, NL-6525 ED Nijmegen (The Netherlands)
Telefax: Int. code + (80)553450
Tunable Supramolecular Structures from a
Gluconamide Containing Imidazole
raised by the recent studies of Fuhrhop et al. and others,[']
which indicate that these compounds can form a great variety of
nanometer-sized structures in water.
Compound 3 was synthesized as shown in Scheme 1. 1 , 5 - ~ Gluconolactone was hydrolyzed and protected a t its secondary
hydroxyl functions in a one-step procedure.['] The resulting
product was esterified to give methyl-2,4;3,5-dimethylene-~gluconate which was aminolyzed with octylamine to give the
amide 2. The latter compound was tosylated and subsequently
converted into 3 by reaction with imidazole in an autoclave at
high pressure (15 Kbar).
VCH VerluyJ~ive/lc<huflnihH 0-69451 Weinhelm 1994
Scheme 1. a) Trioxane, H,OjH+ (74%); b) H'IMeOH (61 %); cj excess of octylamine (no additional solvent used, 77%). d) TsCl/pyridine. 0 - C (87%): e) imidarole, CHCI,, 15 kbar, 50°C (66%). R = w C 8 H , , .
Although the polarity of carbohydrate 2 is decreased due to
the methylene bridges, it appears that this compound is soluble
in water. However, unlike the unprotected derivative,[6a.f1 it
does not form well-defined aggregates, as judged by electron
microscopy (EM). Apparently, the amide bond and the primary
hydroxyl function in 2 cannot form hydrogen bonds leading to
stable suprastructures in water. The DSC studies (DSC =
differential scanning calorimetry) of an aqueous solution of 2
showed only one transition near 53 "C, which can be assigned to
the disappearance of amide hydrogen bonds. No transition was
observed upon cooling.[81 The thermogram of n-OCtyl-D-glUconamide shows two transitions upon heating,['] which are attributed to the breaking of a network of intermolecular hydrogen bonds between the hydroxyl groups (at 61 "C), and between
the amide hydrogen bonds (at 70 "C) .['I
Compound 3 is also soluble in water. From a titration experiment in methanol/water (95j5,v/v), it followed that the apparent pK, value (pK:) of the imidazole group is 6.28.['01 For comparison, methylimidazole and iinidazole were also titrated in this
medium and were found to have pK,* values of 7.03 and 6.96,
respectively, which are comparable to their values in water (6.95
for both compounds["]).
The copper complexation properties of 3 were investigated by
UVjVIS controlled titrations. Addition of Cu(CIO,), to a
solution of 3 in water led to the appearance of a broad band
at approximately /I = 620 nm. Unfortunately, the complex
[Cu(3)J2+ was not soluble enough in water to carry out an
accurate UVjVIS titration. In mixtures of organic solvents such
as chloroform/methanol (1/2, vjv), clear solutions were obtained and the complexation behavior of 3 could be determined.
During the titrations of 3 with Cu(ClO,),, the &,, gradually
shifted from 600 to 780 nm when the ratio [Cu]/[3] was increased
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class, chemistry, chiral, structure, hostцguest, skeleton, biaryl, axially, ions, amidinium, new
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