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Crosslinked Polymers Having Activated Ester GroupsЧA Versatile Support Material.

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Bulky substituents in the endo-3-position of tropanes ( 1 )
can lead to adoption of the boat form (2) or to flattening15J
of the chair. The endo-3-methyl compound ( 1 d) can be prepared by reaction of tropinone with methyllithium, dehydration of the resulting tertiary alcohol, and subsequent hydrogenation. Its existence in the boat form (2) can be ruled
out in the same way as for tropine ( I b ) on the basis of
the I3C-NMR shifts, which in particular for C3 should appear
some -7 ppm upfield for (2). In fact the signals of C3
and (C3)-CH3 recorded above 230K display a broadening
of 1-2 Hz which must be attributed to some slight participation of the boat form (2). The flattening of the piperidine
chair reduces hindrance by the axial hydrogen atoms on C2
and C4 and thus shifts the N-invertomer equilibrium in favor
of a-(I) (see Table 1).
Preliminary measurements confirm the shift of the invertomer equilibrium by protic solvents which is frequently discussed for piperidine. It appears that the conformer having
the axial electron pair e-(I d) will profit more from hydrogen
bonding with methanol than will a-(1 d). In the case of the
piperidine analog nortropane. (1 e ) inversion is so fast in
the presence of methanol that not even line broadening can
be observed at - 100°C. Line shape analyses with 10, 6, and
2 mol % of nortropane in CFCI, and with admixture of dimethylformamide indicate an almost constant inversion barrier
to within f0.15 kcal/mol, so that the unexpectedly small
activation energy (see Table 1 ) relative to the N-methyl compound cannot be explained by participation of an intermolecular proton exchange but rather in terms of an additional
tunneling mechanism[', 'I.
The significantly negative AS* value for nortropane ( I e)
can likewise be regarded as the result of a tunneling contribution decreasing with rising temperature. The increase in activation energy on going from CFClj to C H 3 0 H m the case
of ( I b ) is attributable to the desolvation necessary in the
inversion transition state in a protic
Received: May 10, 1976;
revised: May 25, 1976 [Z 483 IE]
German version: Angen. Chem. ex, 574 (1976)
CAS Registry numbers:
( l u ) , 529-17-9; i l h ) , 120-29-6: ( l c ) , 135-97-7: ( I d ) , 6011X-06-1;
( l e ) . 280-05-7
[I]
"C-NMR Spectroscopic and Stereochemical Investigations, Part 13.Part 12: H . 4 . Schnetdrr and F . Thomas, Tetrahedron, in press.
[Z] I . D . Blackhuriie, A. R. K a / r i t z k y , and Y E/rhwcbi. Acc. Chem. Res.
K. 300 (1975); J . B. Lunihrrt and S . I . Frathermuti, Chem. Rev. 75,
[3]
611 (1975).
D . K . Dolling and D . M . Grail/, J. Am. Chem. Soc. 96, 1527 (1974),
references cited therein.
[4] Cf. E . L. Eiiel and F. W Vierhupprr, J. Am. Chem. SOC. 97, 2424 (1975):
E. L. € / i d , V S. Ruu, F . W Vierhupprr.. and G . Z. Juorisri, Tetrahedron
Lett. 1975. 4339.
[5] Cf. R . J . B i h o p . G . Fodor. A . R. K u t r i f z h j , F . Sotfi, L. E . S t , / / i n i . and
F . J . Swinhourne. J. Chem. Soc. C 1966, 74; A F . Cu!) and J. €. Court%
Org. Mag. Reson. 6, 441 (1974).
[6] J. M . L e h , Fortschr. Chem. Forsch. 15, 31 1 (1970).
[7] R. E. Curter, 7: Drukeiiberg, and N.-A. Bergmun, J. Am. Chem. Soc.
97, 6990 (1975).
Crosslinked Polymers Having Activated
Groups-A Versatile Support Material[**]
Ester
by Merrifield['], variously functionalized polymers have found
application in the synthesis of oligomeric natural products,
as polymeric reagents, for immobilization of enzymes, and
in affinity chromatography. The first two applications mainly
utilize inert hydrophobic polymers having a defined functional
group, while the last two require hydrophilic polymers.
It appeared of interest to develop a single insoluble swellable
polymer from which products having different properties can
be generated and therefore can be utilized for all four kinds
of application. With this aim in mind we have synthesized
the acrylic esters ( l a ) , (2a), and (3a), as well as the methacrylic esters ( I b), ( Z b ) , and ( 3 b)12]and polymerized them in
::
["I
546
Institut fur Organische Chemie und Biochemie der Universitat
Martin-Luther-King-PIatz 6, 2000 Hamburg 13 (Germany)
This work was supported by the Deutsche Forschungsgemeinschaft.
0
I1
R-C -0-CH-C
-0CII3
1-71
(1)
a
8
R-C-0-CIIz-C-OC
,IT,
the presence of N,N'-dimethyl-N,N'-ethylenebis(acry1amide)
(4)or N,N'-dimethyl-N,N'-hexamethylenebis(acry1amide)
(5)
as crosslinking reagents and of N,N-dimethylacrylamide to
improve the solubility of the crosslinking agent. A non-macroporous bead polymer is obtained. If inert components (e.g.
1 -heptanoI, n-butyl acetate, di-n-butyl ether) are present during
the polymerization step macroporous bead polymers can also
be obtained.
0 (21x3
II
I
HzC CII-C-N-(CHz),-N
141, n
= 2;
1.51, n
YH3
F:
-C-CH:CHz
= 6
Polymeric ester (6)
A mixture of ester (3a) (1 7.8 g), N,N-dimethylacrylamide
(1.8 g, 10 wt %), compound (4)(0.4 g, 2 wt %), and azoisobutyronitrile (100 mg) was added under N 2 to a stirred (720 rpm)
solution of polyvinyl alcohol (3g) in water (250ml). After
polymerization for 1 h at 6 0 T , 2 h at 70"C, and 2 h at 80°C
the product was washed with hot water, ethanol, acetone,
benzene, acetone, ethanol, and ether and dried in uacuo at
50°C. The sieve fraction of 0.1 to 0.31 5 mm particle diameter
was used. Yield of (6): 12.1 g (61 %).
The bead polymers of acrylic esters are soft, and those
of methacrylic esters hard and flowable. They have a degree
of swelling (volume after solvation relative to volume of dry
beads) of 6 in acetone and DMSO, 4 in dimethylformamide
and acetonitrile, and 2 in benzene and ethyl acetate.
The activated ester groups in polymer (6) provide a means
of incorporating other functional groups into the product.
Thus reaction of (6) with dimethylamine affords the polymeric
carboxamide ( 7 ) . As a result of the excellent miscibility of
8
By Hubert Koster and Walter Heidmann[*]
Since the use of a polystyrene crosslinked with 1 to 2 %
of divinylbenzene for solid phase synthesis of polypeptides
r] Priv.-Doz. Dr. H. Koster and Dr. W. Heidmann
0
R-C -0-C 112-C N
( 6~,
J
,
HN(CH3k
A
8
@-C-N,
@-
= (-CHz-CH-).
17)
a
,CH3 + HOCH2-C-OCzHs
CH3
I
crosslinked
Angrw. C h m . l i l t . Ed. Engl. f Vol. / 5 (1976) No. Y
N,N-dimethylacrylamide with most solvents (e.g..water, alcohols, benzene, light petroleum) a bead polymer (7) is only
accessible in this way.
Polymeric carboxumide (7)
To a suspension of polymer (6) (12.1 g) in acetone (350ml)
and glacial acetic acid (600mg) in a glass autoclave cooled
to 0°C is added anhydrous dimethylamine (l00ml). The mixture was shaken for 30min at room temperature and 24h
at 50°C; after washing with acetone, ether, acetone, pyridine,
ethanol, acetone, and ether the polymer was dried in uucuo
at 50°C. Elemental analysis (N 4.9%) shows the polymer
to contain 34.7 mol % of amide groups. (7) possesses excellent
solvation properties. The degree of swelling is 12 in pyridine,
15 in dimethyl sulfoxide, 10 in dimethylformamide, 5 in water,
5 in ethanol, and 12 in water/methanol (1 : 1, v/v).
It is also possible to react the activated ester groups in
(6) first with a limiting amount of a nucleophile (primary
reactant) and subsequently with another nucleophile (secondary reactant). In this way the amount of primary reactant
to be introduced and the solvation (swelling) properties of
its environment can be varied within wide limits. In (7) part
of the N,N-dimethylamide groups obtained on reaction with
an excess of dimethylamine can be hydrolyzed to carboxyl
groups. A polymer of this kind is used in the solid phase
synthesis of oligonucleotide^[^!
Received: May 20, 1976;
revised. June 16, 1976 [Z 484a IE]
German version: Angew. Chem. 88.576 (1976)
CAS Registry numbers:
(30),21045-68-1; ( 4 ) , 60134-80-7; (6). 60134-81-8; N,N-dimethylacrylamide.
2680-03-7; dimethylamine, 124-40-3
R . B. Mrrr$eld, J. Am. Chem. Soc. X5, 2145 (1963)
[ 2 ] R . Schwyzer, M . Frurur, and B. Ise/iii, Helv. Chim. Acta 38, 83 (1955);
[I]
H. KBster and W Hridmnnn, to be published.
[ 3 ] W Heidinorin and H . Kiisrtv, Angew. Chem. 88, 577 (1976); Angew.
Chem. Int. Ed. Engl. 1 5 . 547 (1976).
OligonucleotideSynthesis on a Polymeric Support with
Avoidance of Failure Sequences“][**I
By Wulter Heidmann and Hubert Kiister“’
Using a non-macroporous polystyrene crosslinked with 1 %
of divinylbenzene, Merrijield and Gutte”] were able to synthesize polypeptide chains having a molecular weight of more
than 15000. Since the decanucleotides required for a DNA
synthesis have a molecular weight of only cu. 5000[31,a weakly
crosslinked, non-macroporous polymer should possess cavities
of adequate size to permit its functioning as a support for
an oligonucleotide synthesis. A disadvantage of this support
for synthesis of oligonucleotides using the diester concept
has so far consisted in the failure to find satisfactory swelling
conditions for the nonpolar polymer bearing polar oligonucleotide chains.
Our previous communication[41described the synthesis of
a support ( I ) devoid of these difficulties. The carboxylate
groups in (2), which arise by partial hydrolysis of the amide
groups in ( I ) , serve to anchor the first nucleoside (3). It
is protected by the acid-labile a-ethoxyethyl group at the
3’-OH group[51.Esterification is accomplished after activation
of the carboxylate groups of (2) with 2,4,6-triisopropylbenzenesulfonyl chloride (TIPS-CI).
~-
[‘I
Priv.-Dor. Dr. H. Koster and Dr. W. Heidmann
lnstitut fur Organische Chemie und Biochemie der Universitat
Martin-Luther-King-Plat2 6, 2000 Hamburg 13 (Germany)
[**I This work was supported by the Deutsche Forschungsgemeinschaft.
Angrw. Cheiii. 1111. Ed. Engl.
1 b/.I5 ( 1 9 7 6 ) Nu. 9
I
OR
14)
N
- ‘”-8-00
H.0
I
0-C
I
N
H3C’
OH
‘CH,
OR
R = N‘-Benzoyladenine,
Thymine,
H,OC ZH5
R = C,
C H3
c rossl t n k e d
Carrier-bound nucleoside ( 5 )
The support (2) (4g, 1.6mmol of carboxylate groups) was
shaken for 24 h at room temperature in pyridine (50ml) containing TiPS-Cl(8 mmol). The activated polymer was washed
with pyridine and ether in the absence of moisture and shaken
with the nucleoside ( 3 ) (7.2 mmol) in pyridine (20ml) at room
temperature. The unreacted activated carboxylate groups were
blocked by 6 hours’ shaking with an excess of methanol.
The product ( 4 ) was washed with pyridine and ether and
dried in uucuo. It contained 85 pmol (3)/g, which could be
released by treatment with conc. aqueous ammonia for t 6 h
at room temperature or with 1 N aqueous sodium hydroxide
at 0°C for 30 min. Removal of the a-ethoxyethyl group from
the carrier-bound nucleoside ( 4 ) could be accomplished quantitatively by 15 hours’ shaking in glacial acetic acid/water/
methanol ( 3 :4:3, v/v). After thorough washing with pyridine,
ethanol/water (1 : 1, v/v), and ether the product ( 5 ) is dried
in uucuo at 40°C.
Currier-bound dinucleotide ( 7 )
The support ( 5 ) (1 g, 85 pmol of bound nucleoside) is shaken
in pyridine (1 0 ml) with the nucleotide (6) (4 mmol) and TiPSC1 (8mmol) for 8h. Washing with pyridine is followed by
drying in uucuo. The product is shaken for 16h with acetic
anhydndejpyridine (1 : 1, vjv, 10ml) at room temperature,
washed with pyridine and ether, and the a-ethoxyethyl group
then removed. After washing and drying of (7) the nucleotide
chain can once again be elongated.
I . TIPS-Cl
Use of an alkali-labile anchoring and an acid-labile 3’-0
protecting group permits blocking of those 3’-OH groups
which have failed to react in a condensation reaction by
acylation, thus avoiding failure sequences. Furthermore using
547
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