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Nucleophilic Substitutions with Pyrimidine Nucleoside N3 Sodium Salts.

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,,
Br
CHBr-CHBr-@-CH3
H3CO
C H B r - C H B r - 2-(=&C
minated in chloroform solution: zero rotation. The other
half was directly exposed to bromine gas and gave optically
active dibromide. Bromination of a mixture made up of
crystals grown in separate vessels (to eliminate observed
inoculation effects) gave a product having zero rotation.
Because of the absence of well defined { h k l ] forms and our
inability to measure optical rotation of the crystals, correlation between the sign of rotation of the initial matrix and of
the reaction product could not be achieved.
We believe that experiments of the kind described are relevant,
apart from their synthetic implications, to the analysis of
solid-state and enzymatic reaction mechanisms.
Experimental:
Adequately homogeneous crystals of 4.4’-dimethylchalcone,
m.p. 132 “C, were grown from slowly cooled solutions (60 to
20 “Cin lodays) inethyl acetate. Crystallographicconstants [61:
a = 15.26, b = 5.91, c = 14.65 A. Space group P212121. D x
( Z = 4): 1.19 g/cm3.
The gas/solid reaction has been carried out in a flask containing a powdered single crystal of ( I ) ; bromine (10% excess) was admitted as vapor and the material agitated at
room temperature with a magnetic stirrer. After the reaction
had been completed (2-3 h) the product was chromatographed (hexane : benzene) over a Kieselgel column to remove
traces of ( I ) or ( 3 ) . Alternately, the crushed crystal in a
round-bottom flask was covered with cold liquid bromine
(excess) and the whole shaken for 5 min at 0°C. Excess
bromine was partially removed in a stream of nitrogen. The
remaining brown oil was dissolved in chloroform, and the
solvent, some bromine and HBr evaporated with nitrogen;
three such operations produced crystalline material which,
if still slightly yellow, was passed through a short Kieselgel
column.
Rotation of the colorless chloroform solutions of the so purified compounds (c = 1.2--12g/lOOml) was measured in a
polarimeter [Perkin-Elmer 141; 1 ml cuvette, I = 10cmI.
Rotation was constant over weeks, even after addition of
acid or of small amounts of bromine. An optically pure enantiomer of (2) ([a]g = 167) was obtained from the reaction
product after nine recrystallizations (constant specific rotation) from benzene : hexane (1 :1) in the temperature range
60-10 ‘C.
The structure of (2) (m.p. 175-179OC, decomp., from
benzene : hexane) is based on elemental analysis and its
NMR spectrum. (3) (m.p. 153-154 O C , from hexane : chloroform) has been prepared independently from 3-bromo-4,4’dimethylchalcone (m.p. 140 OC, from benzene) by bromine
addition; elemental analysis and its NMR spectrum afford
proof of structure.
Received: July 16, 1969
IZ 40 IEI
German version: Angew. Chem. 81. 628 (1969)
[‘I Dr. K. Penzien [**I and Prof. G. M. J. Schmidt
Department of Chemistry
Weizmann Institute of Science
Rehovot (Israel)
[**I K.P. acknowledges the award of a Stiftung Volkswdgenwerk Stipend.
Angew. Cheni. internat. Edit. J Vol. 8 (1969)/ No. 8
H3
[l] Cf. F. Wudl, D . A . Lightner, and D . J . Cram, I. Amer. chem.
SOC.89, 4099 (1967).
[2] G. M . J . Schmidt, Photochemistry of the Solid State, in
Reactivity of the Photoexcited Organic Molecule. J. Wiley, New
York 1961, p. 221.
[ 3 ] e.g. L . Leiserowitr and G. M . J . Schmidt, J. chem. SOC. (London) A, in press.
141 D . Rabinovich, G. M . J . Schmidt, and 2. Shaked, J. chern.
SOC.(London) B, in press.
[5] E. HaGoudis, E . Kariv, and G . M . J . Schmidt, unpublished.
[6] D . Rabinovich, unpublished.
Nucleophilic Substitutions with Pyrimidine
Nucleoside N3 Sodium Salts
By H . Seliger and F. Crarner[*l
As can be deduced from the pH dependence of the ultraviolet
spectrum of pyrimidine nucleosides [I], the nucleobases are
deprotonated at N3 in alkaline media. The resulting pyrimidine nucleoside N3-anions can act as nucleophiles in addition
and in substitution reactionsrzl. We have prepared the N3
sodium salts of derivatives of uridine and thymidine in nonaqueous medium and studied their reactions with aralkyl
halides.
2’,3’-0,0-(2,4-Dimethoxybenzylidene)uridine ( l a ) 131, dissolved in 1,2-dichloroethane, is treated with the stoichiometric amount of sodium ethoxide in ethanol. After removal
of the solvent, the sodium salt ( I b ) is precipitated by addition
of light petroleum. 3’,5’-0,O-Ditritylthymidine( I c ) is converted into the sodium salt ( I d ) in a similar manner. The
uridine N3 sodium salt ( I e ) precipitates from an ethanolic
solution of uridine on addition of sodium ethoxide. The UV
spectra of the sodium salts, recorded in absolute CH2C12 or
CzH4C12. agree with the spectra of the corresponding nucleosides and nucleoside derivatives in aqueous-alcoholic KOH
= 261 nm, Amin = 246nm; ( I d ) ,
CpH > 12): ( I b J , A,,
Amax = 264nm. A,,
= 250nm; ( l e ) . Amax
= 261 nm,
A,in = 242 nm.
The reaction of pyrimidine nucleoside sodium salts with aralkyl halides (2) in inert, anhydrous solvents yields N3aralkylated derivatives ( 3 ) , whose UV spectra no longer
change on going from neutral to alkaline media. Substitution
of the sugar alcohol group or removal of the protective
groups does not occur under the above conditions. The reaction conditions and yields are given in the Table. As expected,
the reaction is facilitated by electron-attracting p-substituents
on the benzyl halide; the reactivity, and also the tendency to
undergo side reactions, increases on going-from chloride to
iodide.
The sugar protective group is removed by treatment with 80 %
acetic acid. After 60-100 min at room temperature, (3ba),
(3bb). (3bc), and (3bd) give quantitative yields of the N3aralkylated uridines. Removal of the trityl groups from (3dc)
and (3dd) (two hours at 100 “C) gave 93 % of p-nitrobenzylthymidine and 80 % of p-bromobenzylthymidine respectively.
In contrast to techniques used previously for the aralkylation
of pyrimidine nucleosides 14351, in which predominantly or ex-
609
The Absolute Co&guration
of Bacteriochlorop h y l l - a C l l [**I
By H . Brockmann j r . and Ingrid Kleber [*I
(I)
Y
J
R2
We recently derived the absolute configuration (3 R , 4R, 7s.
8 5') for bacteriochlorophyll-a and thus also for bacteriomethylpheophorbide-a ( I ) [lbl. In order to confirm unequivocally this configurational assignment two experiments remained to be carried out:
R3
1. Direct comparison of the bis(p-bromophenacyl) 3-ethyl-2'
methylsuccinate (4) obtained by oxidative degradation of
bacteriochlorophyll-a derivatives with an authentic sample [lbl
of known absolute configuration 131.
II
RS
H
oxybenzylidene)
H
Product
Ial
XI/
Yield
( %MI
___
CI
Br
I
CI
Br
Br
CH2Cl2
acetonitrile
CHzCI2
CHzClz
acetonitrile
acetonitrile
acetonitrile
then
52
80
73
15
58
78
91
60
Br
Br
-
40
_____
~
-___
dichloroethanc
dichloroethane
20
8
reRux
reflux
-___
90
89
-
H
[a] R'-R6 as for (I) and ( 2 ) .
[bl Products obtained analytically pure by preparative thin-layer chromatography and crystallization
clusively the sugar component is substituted, the present
method permits the preparation, in high yield, of pyrimidine
nucleosides that are aralkylated at the base only.
Compound (16) also reacts with chloromethylated polystyrene and thus makes possible the linkage of nucleotides
and oligonucleotides with "Merrifield polymers" 161 via dimethoxybenzylideneuridine
as
phosphate-protecting
group 171. Studies on the use of this possible mode of linkage in
the synthesis of oligonucleotides on carriersrsl are in progress.
2. Confirmation of the (7S, 8s) configuration of bacteriochlorophyll-a.
The latter follows from the identity of 3.4-dehydrobacteriochlorophyll-a derivatives 14-61 with compounds that are
accessible from chlorophyll-a[7~*lwhose (7S,8 S) configuration has been proved 197 101. The proofs of identity used
Received: June 9, 1969
[Z 30 IE]
German version: Angew. Chem. 81, 576 (1969)
[*I Dr. H. Seliger [**I and Prof. Dr. F. Cramer
Max-Planck-Institut fur experimentelle Medizin,
Abteilung Chemie
34 Gottingen, Hermann-Rein-Strasse3 (Germany)
[**I Present address: Institut fur makromolekulare Chemie
der Universitat
78 Freiburg, Stefan-Meier-Strasse31 (Germany)
[l] See, e.g. J. Sugar and J . J. Fox, Biochim. biophysica Acta 9,
269 (1952).
[2] R . W. Chambers, Biochemistry 4, 219 (1965).
[3] F. Cramer, W. Saenger, K . H . Scheit, and J. Tennigkeit,
Liebigs Ann. Chem. 679, 159 (1964); see also ref. [7].
[4] A. M . Michelson and A . Todd, J. chem. SOC.(London) 1956,
3459.
[ 5 ] N. Zmura, T. Tsuruo, and T . Ukita, Chem. pharmac. Bull.
(Tokyo) 16, 1105 (1968); K. Kikugawa, F. Sam, T. Tsuruo, N.
Imura, and T. Ukita, ibid. 16, 1110 (1968).
[6] See, e.g. R . B. Merrifield, Science (Washington) 150, 178
(1965).
[7] F. Cramer and F. Kathawala, Liebigs Ann. Chem. 709, 185
(1967); 712, 195 (1968).
[8] Cf., inter alia, F. Cramer, R . Helbig, H . Hettler, K. H . Scheit,
and H. Seliger, Angew. Chem. 78, 640 (1966); Angew. Chem.
internat. Edit. 5, 601 (1966); F. Cramer and H . Koster, Angew.
Chem. 80,488 (1968); Angew. Chem. internat. Edit. 7,473 (1968).
610
~O~CH,
( I ) , R = C02CH3
(2), R = H
( 3 ) , R = H, double bond
between C-3 and C-4
hitherto were based mainly on agreement of melting points,
basicity, crystalline form. absorption spectra, and DebyeSchemer photographs, whereas the values obtained for optical rotation agreed only qualitatively [51. Moreover, the
acidic, levorotatory oil obtained on oxidative degradation of
bacteriochlorophyll-a could only be insufficiently characterized as (-)-threo-dihydrohematinimide (5) E53-51.
We have isolated bacteriochlorophyll-a from Rhodospirillum
rubrum and thence prepared bacteriomethylpheophorbide-a
( I ) [ l l l . Oxidative degradation of ( I ) with CrO3 in 25%
H 2 S 0 4 (3 h at -10 "C [lzl) and subsequent chromatography
on silica gel with light petroleum (4&60°C), ethyl acetate,
isopropanol (44:5:1) afforded threo-3-ethyI-2-methylsuccinAngew. Chem. internut. Edit. / Vol. 8 (1969) /No.8
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