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Chiral Dendrimers from Tris(hydroxymethyl)methane Derivatives.

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Nothing can be said about the diastereoselectivities of the three
steps (enolate formation, alkylation, and decarboxylation), since
all reactions have so far been carried out only with 1 : 1 mixtures
of diastereoisoiners (to obtain both separable epimers may be
an advantage rather than a disadvantage for medicinal chemists!).
It appears certain that this way of modifying peptidesC7]is more
suitable for larger oligopeptides than is polylithiation. Corresponding experiments are in progress, and these might lead to an
attractive general method of preparing entire series of peptides
from a single precursor, a process of much current interest in
connection with establishing peptide libraries.I8I
Received: July 26. 1993 [Z 6235 IE]
German version: A t f X m . Chcm. 1994. 106. 455
[ I ] Revicw: D. Seehach, A/dvic/rimicu Acio 1992. 25. 59: most recent papers: S.A.
Miller. S . L. Griftiths. D. Seebach. H d v . Clrim. Ariu 1993. 76. 563: D. Seebach,
A. K. Beck. H. G . Bossler. C Gerber, S.Y KO.
C . W. Murtiashafi. R. Naef. S.-I.
Shoda. A. Thaler, M . Krieger, R. Wenger. ihid. 1993. 76. 1564
[2] H. ci. Bossler. D. Sccbach, H c h . Chin?. A < i r r . 1994. 77. in press.
[3] Another strategy i b to tisc poly-Li derivates of the type B hith N-CH2Ph instead
of N-Me [?I.
[4] Another method for the preparation of this half ester has been described- U .
Schmidt. V. Leitenherger. H. Griesser. J. Schmidt, R. Meyer. .Yv?thesi.\ 1992,
1248.
[ 5 ] a ) H . E. Zaugg, M. Freifelder. H. J. Glenn, B W. Horrom. G. R. Stone. M. R.
Vernsten, J. A m . Clroti. Sor 1956, 78. 2626: b) P. Wheelan. W. M Kirsch. T. H.
Koch. J Or$ C/wii. 1989. 54. 1364: c) J. T. Repine. R. J. Himmelsbach. J. C
Hodges. J. S Kaltenbronn. 1. Sircar. R. W. Skccan. S.T. Brennan. T. R . Hurley.
Humblet. R. E Weishaar. S. Rapundalo. M. J. Ryan, D. G
Olson. B. M. Michnicuiu. B. E. Kornherg. D. T. Belmont.
M. D. Taylor. J ,Mrd. C h > t .1991. 34. 1935.
[6] S . Abdalla, E. Bayer. C / ? r ~ f ~ i f r / ~ ~ ~1987.
t , ~ ~23.
p / i 83.
ia
[7] As far a s we know. on14 the diketopiperazine from glycine and aminomalonic
acid half eFlcr (cited in [5a]). has been alkylated in such a way. On the other
hand. rir<-tryptoph;in is prepared by alkylation of acetainidomalonate with
ri~
Acrd.~,Wiley, New
gamine. \ee J. P. Greenstein. M. Winitz, C l i ~ i i i i s ~o/AiiiOio
York. 1961. p. 2330. and references therein.
[ 8 ] Recent reviefi article uith a discussion of peptide libraries: G . Jung. A. G.
Beck-Sickinger. A t r , y w . C'/ir,m. 1992. 104. 375- 391; Angew. Cliem. bif. Ed. En.r/.
1992. 31.
that this work will provide information about questions such as
a) Will a chiral core in a dendrimer with otherwise achiral building blocks cause the dendrimer to have a chird shape or to be
optically active? b) Will there be enantloselective clathrdtion or
host-guest interaction near the core of such a dendrimer? c)
Will a dendrimer contdining chirdl, unsymmetrical branching
units really have the predicted surface with fractal
and thus a pronounced cdpdblhty for chiral recognition'?
Our trtfunctional chiral building blocks were prepared. as described previously.[61from the dioxanone 1, which 1s accessible
from poly (R)-3-hydroxybutanoate (PHB) "I The aldol adducts
of the dioxanone 1 to aldehydes can be reduced to the chiral tris(hydroxymethy1)methme derivatives 2-4 a By using the Frechet
OR'
1
2
= is@Pr
3 R=terf-Bu
4a R' = H, R' = OSiterl-BuPh,
4b R' = Me, R2 = OSiterl-BuPh,
4c R' = Me, R' = OH
4d R' = Me, R' = Br
method,[*' the triol 3, either prior to o r after attachment[6c]of
spacer groups, was converted into the products 5 and 6, 7, respectively. In these formulae, the 3-hydroxybutanoic acid skeleton IS marked in red, and the aldehyde part (from 3) in blue For
367-3x3
Chiral Dendrimers from Tris(hydroxymethy1)methane Derivatives **
Dieter Seebach,* Jean-Marc Lapierre,
Konstantinos Skobridis, and Guy Greiveldinger
Dendrimers are molecules in the no-man's land between the
conventional target molecules of organic synthesis and those of
polymer- chemistry.['] which may have interesting properties and
applications.[" 21 As far as we know, there is only one reportf3]on
chiral starburst[' -41 dendrimers which were obtained by attaching tryptophan units to the end groups of a second generation
dendrimer with a four-branch center piece or core. We report
here on the first synthesis of starburst dendrimers with chiral
core units and, in one case, also chiral branch units. We hope
[*I
["I
440
Prof. Dr. D. Seebach, Dr. J:M. Lapierre. Dr. K. Skobridis,
Dip1:Chem. G. Greiveldinger
Laboratorium fur Organische Chemie der
Eidgenossischen Technischen Hochschule
ETH-Zentrum. UniversitHtstrasse 16, CH-8092 Zurich (Switzerland)
Telefax: Int. code + (1)262-0529
J.-M. L. was recipient of a fellowship from the Natural Sciences and Engineering Research Council of Canada (1991 -1993). K. s. from the Deutsche
Forschungsgemeinschaft (1992/1993); part ofthe Diplomarbeit of(;. G., ETH
Zurich, 1993.
c) VCH Yerlug~gi~sL~lfsihufi
mbH, 0-69451 Wrmlrerni.1994
one branch, the spacer is marked in green, and the dendron,
introduced by etherification of the triol 3 with the corresponding benzylic bromide, is marked in gray. The compounds 5-7
with twelve terminal phenyl groups may be classified as third
generation dendrimers."] The second generation dendrimer 8
with twelve peripheral nitro groups was synthesized from the
triol 2 by esterification with 3,5-dinitrobenzoyl chloride in pyri-
0570-0833/94,/0404-0440 $10 OO+ 2510
Angrn C h m Ini Ed Engi 1994, 33, No 4
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'
FAB mass spectrometry. and elemental analysis. In the H N M R
spectra of the dendrimers 5-7 we noticed that nonequivalent
benzylic and aromatic protons gave rise to complex signals
when they are found near the core and to singlets when they are
found near the periphery of the dendrimer molecule. In the
formulae shown the molecular weights and the specific rotations[''] of the compounds 5-9 are also given. It turns out that
The six nitro groups of the product were reduced
dine ( > 95 YO).
to amino groups ( > 9 5 %), which were acylated with the same
acid cloride (83%). The dendrimer 9 (generation I), in which
both the core and the branches are chiral, was prepared from the
trials 3 and 4a.[91After the trio1 4 a was 0-methylated (+ 4b),
the tert-butyldiphenylsilyl (OTBDPS) group was cleaved (+ 4c),
and the benzylic alcohol was converted into a benzyl bromide
(+ 4d. Overall yield Of 70 yo). This in turn was used for etherification of the trio1 3. Compound 9 is one out of 4096 possible
stereoisomers !
After the etherification step with the corresponding benzylic
bromides, the dendrimers 5,6,7, and 9 were isolated in yields of
between 55 and 75 YOfrom reactions carried out on a 0.5 - 1.O g
scale. The dendrimers were purified by flash chromatography
and fully characterized by IR, 'H, and I3C N M R spectroscopy,
Angew. Chem. h r . Ed. Engl. 1994, 33. No. 4
0 VCH
the optical activity decreases as the dendrimers of type 5,6 and
7 increase in
1 1 in contrast, for the -fully
dendrimer 9, the rotation is approxilnatively the Same as that ofthe
building block ([a], o f 4 c and 4 d : + 88 and + 78).The transition
from the first to the second generation of the nitro-substituted
dendrimers leads to a change of sign for the optical activity
(dendrimer of first generation with six NO, groups: [a],, = - 17;
Dendrimer 8 with twelve NO, groups: [a], = +9).
With several of the starburst dendrimers we observed the
formation of very stable clathrates. Thus, compound 5 could be
freed from CCI, only by heating at 100°C/0.5 Torr for several
hours. Moreover, the dodecanitro derivative 8 was isolated and
characterized as a complex of composition [(Z . 8 ) . EtOAc .
(8 H,O)], and for its hexaamine precursor we have identified
1 :1, 2 : 1 , and 6: 1 complexes with 1,4-dio~ane.[~"]
The preliminary results obtained so far lead us to believe that
the synthesis of higher generation chiral dendrimers1'21 will
provide answers to the questions posed in the introduction and
Verlagsgesellschaji mbH. 0-69451 Weinheim, 1994
0570-0833/94/0404-0441 $10.00+ ,2510
441
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thus deepen our understanding of organized complex molecules
and their interactions with small molecules.[' 31
Received: August 12. 1993 [Z 6276 IE]
' AiigriL
C/ii,ni. 1994. 106. 457
Crerman bersion
[I] a) D. A. Tomalia. A . M . Na>Ioi-.\4'. A. Goddiird 111. .Aii,zoi.. C ' / i e n i . 1990. 103.
119; An,znir Chrni. l i r / . G I . G i g / . 1990, 7Y. 138: h ) Gerieri/ogi~itl/i~
Dirccted
Iiirhiir ii ,C'ii \i.ndi9Di,iidririii,r\ ond H i.i'i~rIir.oiii.hri/Slrtii l i i i r ! (Ed?. :
D A. Toni:ili:i. H . D. Durst). lop C i t i ~Chivi7. 1993. lh5. 193: cj I+.-B. Mekelburgcr. W. J;iworek. I; Vhgtle. .4ngci1 C ' h n i . 1992. 104, 1609; A n g c i i . C/iivn.
lii/.
G / . h g l . 1992. 31. 1571.
[2] See the report on drndrimrr synthesis by the Dutch DSM company (Chein
Riiiiibdi 1993. 36 ( 1 5). 3) xnd the xrticle on Ru-containing deiidriincrs ( C / I P I I I .
D i : . ,Vcii v 1993. 71 (51, 2X) and o n possible applications of dendrimery (ihid
1992. 70 (51). 16).
131 G. R . Newkoiiie. X . Lin. C. D.Wac. Ii~frri/iciIrnri..4.51'ninii~lr~'
1991. 2, '957.
[4] For chiral one- and t\*o-directiomil cascade molecule5 starting froiii Igsine and
oligonucleotides. see [I a], there [73. 741: R. H. E Hudson. M. J. Dainha. J. A m .
C'h('Fi1. S O < . 1993.
?ll').
[S] See [I a]. there "-82.
841.
161 a ) W. Amberg. D. Seehach. C ' / i ~ n r .Bcr. 1990. 12.1. 2411; h) D. Seebach. J.-M.
Lapierre. W. Jaworck. P. Seiler. Ilidr. C ' h i i . Acru 1993. 76. 459; c) J.-M.
ILapierre. K . Skobridia. D . Sscbach. i/d.1993. 76. 2419 (includes experiment;il
dctails for the preparation of chiral cores with spacer of 6 iind 7).
[7] H - M Mtiller. D. Seebach. .Angm C/7eni. 1993, 105. 483-509: Angeii~.C ' / i m i .
/ i l l . Ed. Eiigl. 1993. 32. 477-501.
[XI C.-J. Hiiakcr. J. V . J . Frkchet. .I 4n1. ('hem. S o l . 1990. 112, 7 6 3 8 : K L.
Wooley. C J. Hawker. J. hl. J. FrCchrt, J. ( 7 i o n . S O . . Perkiir T,.irii.s. 1 1991,
105').
[Y] Compound 4 a was obtnincd as thc niiiior diastereomeric product from I and
~-(ri~r~-biityldiphenylsiloxymethyl)benraldehyde,
see [6c]. The epimer a t the
benrylic position of 4a was also u5ed for preparing the corresponding
diestereomer of 9.
[ I O ] 5 . 6 . 7 . 9 i n C H C 1 , (( = I Z g 1 0 0 m L j , 8 i i i d i o x a n e ( ~ ~ = 1 . 0 5 g : 1 O O m L ~
1111 The [.I,, valucs in generation 1 (three peripheral OBn). 2 (six OBn). and 3
(twelve O B n ) o r the dcndrimer without spacer (type 51, with aliphatic spacer
-1,-2:-0.2,
(type6). a n d with aromatic spacer (type7) are: +15:+8:+4,
and + 12' +7: f 4 . respcctivcly: for siinple presentation of the generations of
such Frkchet dendrimers, see [ I c].
[I?] Thei-c ale five principle methods of asacmbling chiral dendritic structures: I )
chiral corc Mith achirtil branch unit\, 2) achiral core w i t h chiral branch units.
3 ) both the core end the building blocks for the branches are chiral. 4) constitution;illy different branches attached to an achiral core (see discussion in: J.
Ehrlci-. D. Seebxh. tic,hi,a.\ Aiin. Ciirm. 1990. 379: G. Guaiiti, L. Banfi. E.
Nxisario. ./. Orz. ( % w i . 1992. 57. 1540). and 5 ) con~titutionally different
br'inches iittiiched to (I c h i d core
[I31 Sir/irui,ioli,6iilair C'licnii? ( E d . : F. Vdgtle). Teubner. Stuttgart. 1992; M ~ U C J iviiii C ' / i i v m / i ! (Eds B. Dietrich. P. Viout. I - M . Lehn). VCH. Weinheim.
1993.
The structure of cyclosporin in organic solvents,141in the solid
state,[51and in a complex with its cytoplasmatic
binding- .Drotein
. cyclophilin['. 71 is weil known from NMR s p e c t r o ~ c o p y [ ~and
.'~
X-ray structure determination^,[^. 'I but its structure in an
aaueous environment is still uncertain. Interactions of cvclosporin with metal ions are known;["."] it was shown by thermoanalytical methods that surprisingly high enthalpies result when
Li salts are added to cyclosporin solutions in tetrahydrofuran
(up to 125 kJmol- ').I9]
Similar conformational changes[''] as in
the complexation with cyclophilin [('. 'I (e.g. the isomerization of
a 9.10-ci.5 to a 9.10-rmtzs peptide bond) occur when cyclosporin
complexes metal ions. Inspired by the pronounced interaction of
cyclosporin with metal ions we set out to look for possible
ionophoric activity of cyclosporin.
We investigated the migration of alkali and alkaline-earth
metal ions across an organic solvent phase under the influence
of cyclosporin A (1). C (2). and H ( 3 )as well as of ascomycin (4)
and the Ca-ionophore ETH 129 ( 5 ) , by using the U-tube technique we recently employed for studying ion transport by
derivatives of 3-hydroxybutanoic acid." '. l1
,
R2
0
R3
0
1 Cyclosporin A (CS), R' = Et, R3 = (34Pr
2 Cyclosporin C ([Thr'ICS), R2 = CH(OH)CH3, R3 = ( 3 - i P r
3 Cyclosporin H ([D-MeVal"]CS), R2 = Et, R3 = (R)-iPr
'
4 Ascornycin
(21-Dihydro-nor-FK506)
Cyclosporin: A Li- and Ca-Specific Ionophore!**
H. Michael Burger and Dieter Seebach*
The cyclic undecapeptide cyclosporin A (1) is an immunosuppressive agent that has revolutionized the field of organ transplantation.['] Although its biological activity is subject to intensive research, the detailed mode of interaction in the complex
immune reaction of mammals is far from being completely understood.". 31 It has been established that an initial step of the
immunosuppressive action of cyclosporin and F K 506 (another.
although nonpeptidic immunosuppressive agent) is the inhibition of Ca2 ' -dependent signaling pathways in T and mast cells.
[*I
[**I
Prof Dr D. Seehach. Dr H . M . Burger
Laboriitorium f u r Organische Cheinie der
Eidgendsiischen Technischen Hochscliule
ETH -Zentrum. U niversitststrasse 16. CH-8092 Zurich (Switzerland)
lelcfax. I n t . code + {1)26?-0529
Part ofthe Ph.D. Thesis ofH. M. Burger.dissertation no. 10436, ETH. Zurich,
1993.
5 ETH 129
To determine the ionophoric properties of compounds 1-5
we overlayered their dichloromethane solutions in a U tube with
two buffered (pH 8.1) aqueous phases, one containing the metal
chloride and its picrate. The extent of migration was monitored
by UV spectrometry (356 nm; see Experimental Procedure). The
transport rates for the alkali and alkaline-earth metal salts
shown in Figures 1 a and b were measured with a 0.005 M solution of cyclosporin A (1). The rates follow the Hofmeister or
lyotropic sequence (increasing ionic radius decreasing heat of
hydration increasing transport rate)['3i in both series- with
two remarkable exceptions: first Li migrates faster than Na',
K + , and R b + and second Ca2' migrates Faster than the other
alkaline-earth metal ions, even significantly faster than Ba" !
The C a 2 + transport is strongly dependent on the cyclosporin A
c ~ n c e n t r a t i o n , ~as' ~evident
]
from the data collected in Table 1 .
Like the physiological activity," 51 the C a z + migration through
the organic phase depends upon the substituents on the cyclosporin skeleton: ;i comparison of compounds 1-5 shows
(Fig. 1 c) that cyclosporin H ( 3 ) is slightly more and cyclosporin C (2) distinctly less efficientr16' than cyclosporin A (I)
-
-
+
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chiral, trish, dendrimer, hydroxymethyl, derivatives, methane
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