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Bis(2 2 2-trichloro-1 1-dimethylethyl) Monochlorophosphate a Selective Reagent for the Phosphorylation and Protection of the 5-OH Group of Nucleoside Derivatives.

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compound (5) (m. p. = 135 C), which could be converted
into the 8-keto ester (6) (m.p.= 130°C; 97%) by treatment
with ethyl 2-oxovalerate (EtONa, 50 "C, 1 h). Saponification to the acid and decarboxylation (16OoC, 15 min) produced the ketone (7)(m.p.= 155-156"C, 94%) as the main
intermediate. To ensure that the planned reaction with Nbromosuccinimide selectively functionalized only the C-3
methyl group, the a-position to the keto group was protected by formation of the ethylene acetal (m. p. = 154155"C, 96%). The competing benzyl site on the side chain
at C-2 was sterically shielded by formation of the pivolate
(8) (m. p. = 143 "C, 94%). In the subsequent light-induced
bromination of (8) with N-bromosuccinimide, the monobromo-product (9) (m. p. = 141-142 "C, 70%) was the major
product formed. The ring-closure to the anthracyclinone
(10) (m. p. = 185- 186"C) proceeded in 63% yield by treatment of (9) with magnesium, which had previously been
activated with 1,2-dibromoethane. As in previous instancesish', the cyclization of (10) could be easily recognized from the coupling constants of the C-8 protons in the
'H-NMR spectrumr6].
Introduction of a hydroxy group at the C-7 position of
(10) was carried out via photolytic bromination; the labile
products were dissolved in 0 . 5 ~NaOH. Apart from aromatization products, only the racemic 7,9-cis-diol (11)
(m. p. = 216 "C), formed in a stereoselective reaction, could
be isolated in 62% yield. It's chromatographic and spectroscopic properties are in accord with the naturally occurring
Starting from (9). it should also be possible to synthesize the pharmacologically important class
of akalavinones'*].
O
~
Received: November 13, 1980 [ Z 765 IE]
German version: Angew. Chem. 93,575 (1981)
blocking the 5'-trityl- or 5'-dimethoxytrityl-derivatives followed by enzymatic or conventional preparative 5'-phosphorylation"].
In a preliminary investigation, we found that of the
many reagents studied, bis(2,2,2-trichloro-l,l-dimethylethyl) monochlorophosphate (l)[*][bis(trichloro-tert-butyl)
monochlorophosphate = bis-2-TCB monochlorophosphate] was the only one able to simultaneously selectively
phosphorylate and protect the terminal 5'-OH group in the
synthesis of 5'-phosphorylated oligonucleotides. This reagent attacks the 5'-OH group, in the presence of a free 3'OH group, just as selectively as trityl chloride and its analogues. The TCB-phosphate group survives all the necessary steps in the oligonucleotide synthesis, but can readily
be removed by the cobalt(1)-phthalocyanine anion
[Co Pc]Q[31.
'
RO\F:
P-O-CHz
I\;."d [CO*PC]O
Ro'
H
Hb
CAS Registry numbers:
(3). 3300-25-2; (4). 77825-00-4; (5). 77825-01-5; (t)-(6), 77825-02-6; (7).
77825-03-7; (8).77825-04-8; (9). 77825-05-9; (?)-(lo),77825-06-0: ( + ) - ( I I ) .
77880-65-0; ethyl 3-oxovalerate, 4949-44-4.
[ I ] F. Arcamone, G. Cassinelli, F. DiMatteo, S . Forenza. M. C. Ripamonti, G.
Rivola, A . Vigevani, J . Clardy, T. McCabe. J. Am. Chem. SOC. 102, 1462
(1980).
[2] Review: T. R. Kelly, Annu. Rep. Med. Chem. 14,288 (1979).
131 K . Krohn, M . Radeloff. Chem. Ber. I l l , 3823 (1978).
[4] K . Krohn, Tetrahedron Lett. 1980, 3557.
151 a) C. Marschalk, F. Koenig, N. Ouroussof, Bull. SOC.Chim. Fr. 3, 1545
(1936); b) K . Krohn, B. Behnke. Chem. Ber. 113, 2994 (1980).
161 (10). 'H-NMR (270 MHz, CDCI,): 6=1.75 (dt, .lac,,,=
13.3, J7,"=7.8,
J7."=8.0 Hz; I H , 8a-H), 1.94 (dt, J,,,=13.3,
J7.!,=5.6, J7.!,=5.5,
1.0 Hz; I H, 8e-H).
Jx,
171 Prof. F. Arcamone (Farmitalia, Milan) is thanked for providing a sample
of ( I I).
[S] Review: H. Brockmann, Fortschr. Chem. Org. Naturst. 21, 121 (1963); T.
Oki. J. Antibiot. 30, S-70 (1977).
Bis(2,2,2-trichloro-l,l-dimethylethyl) Monochlorophosphate, a Selective Reagent
for the Phosphorylation and Protection
of the 5'-OH Group of Nucleoside Derivatives'**'
By Herbert A . Kellner, Ruth G . K . Schneiderwind,
Heiner Eckert. and lvar K . Ugi"
Dedicated to Professor Helmut Zahn on the occasion
of his 65th birthday
5'-Phosphorylated oligonucleotides, required for enzymatic nucleotide syntheses, are normally obtained by de[*I Prof. Dr. 1. K. Ugi, Dr. H. A. Kellner,
[**I
DipLChem. R. G. K. Schneiderwind, Dr. H. Eckert
Institut fur Organische Chemie der Technischen Universitat Miinchen
Lichtenbergstrasse 4, D-8046 Garching (Germany)
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie.
Angew. Chem.
Int.
Ed. Engl. 20 (1981) No. 6 / 7
H
141
The synthetic principles are illustrated in the following
example:
Thymidine (2) reacts with (1) in pyridine, in the presence
of 10 mol% 4-dimethylaminopyridine (DMAP)[41,to give
(3) in 72% yield. The latter product when treated with
[Co'Pc]' releases thymidine 5'-phosphate (4). The DMAPcatalysis of the reaction ( I ) + (2)- (3) depends o n the intermediate formation of (5) from (1) and DMAPrS1.
Deblocking with [ C O ' P C ] ~ in
, which the first TCBmoiety is cleaved considerably more rapidly that the second, proceeds almost quantitatively at sufficiently long
reaction times. For example, from a molar solution, 84%
(4) and 16% of the mono-TCB derivative were obtained
after 2 d at 20"C,while after 4 d the ratio was 90: 10.
Procedure
Improved synthesis of ( 1 ) (cf.I2"'): A solution of dry 2trichloromethyl-2-propanol (177.5 g, 1 mol) and pyridine
(80.5 cm3, 1 mol) in 300 cm3 pentane is treated with PC13
(43.5 cm', 0.5 mol) in 150 cm3 pentane at 0°C under an
N,-atmosphere; the mixture is stirred for 1 d at room temperature and finally stirred and refluxed for 2 h. The
precipitate of pyridine hydrochloride is filtered off, the
0 Verlag Chemie GmbH. 6940 Weinheim, 1981
0570-0833/81/0707-0577 $ 02.50/0
577
solvent removed and the residue fractionally distilled in
uacuo. 150 g (71%) of bis(2,2,2-trichloro-l,l-dimethylethyl)
monochlorophosphite (m. p. =46"C, b. p. = 134"/0.015
torr) is obtained. A cooled solution of the phosphite (109 g,
259 mmol) in 200 cm3 chloroform is added in the dark under an N2-atmosphere to a suspension of (diacetoxyiodo)benzene[61 (91 g, 294 mmol) in 500 cm3 chloroform
cooled to - 15°C. The mixture is allowed to warm u p
slowly to room temperature and is stirred for 2 d. After
evaporation of the solution and covering the residue with
pentane, 74 g (65%, relative to the phosphite) of crystalline
( I ) is obtained (m. p. = 8 1 C).
(3): A mixture of ( , ? ) "(0.24
I
g, 1 mmol), ( I ) (0.87 g, 2
mmol) and DMAP (0.02 g, 0.2 mmol) is stirred for 24 h at
50 "C. The solvent is then removed, the residue taken u p in
a little chloroform and precipated with 100 cm3 pentane.
The precipate is dissolved in 50 cm3 chloroform, filtered,
washed twice with citrate buffer (pH 6) and twice with water, and then dried over Na2S04. Chromatography on silica gel (Merck 60F2,,) using chloroform/methanol (9 : l)
as eluent gives (3) (0.46 g, 72%) (m.p.= 186°C).
(4): A solution of Li'[Co'Pc] .4.5 tetrahydrofuran (2.51 g,
2.8 mmol) and (3) (0.39 g, 0.6 mmol) in 20 cm3 acetonitrile
is stirred in the absence of oxygen at room temperature for
48 h. The green mixture is treated, at O'C, with 40 cm3
H,O and C 0 2and air immediately passed in for 5 min. The
violet precipate is centrifuged off (5 min, 3000 r.p.m.) and
washed three times with water. The combined centrifugates are treated with 1 N hydrochloric acid until decomposition of the LiHCO, at pH 6.5 occurs, concentrated and
the product converted to the Na salt on a Lewatit SlOO GI
ion exchanger: 300 mg (41, which contains 16% of the
mono-TCB-derivative as impurity, is obtained.
O
Received: October 17, 1980 [Z 770 IE]
German version: Angew. Chem. 93, 581 (1981)
CAS Registry numbers:
(1). 17677-92-8; (2). 50-89-5; (3), 77825-23-1; (4). disodium salt, 33430-62-5.
[ I ] A . Kossel, H. Seliger. Fortschr. Chem. Org. Naturst. 32, 297 (1975); H.
Koster, H. Blocker. R . Frank. S. Geussenhainer. W . Kaiser. Hoppe Seyler's 2. Physiol. Chem. 356, 1585 (1975); P. I. Zdhanou. S. M . Zhenodar o w , Synthesis 1975, 222; L. A. Slotm, Synthesis 1977, 737; F. Eckstein.
Kontakte 3, 3 (1978); H. Koster, H. Blocker, R . Frank, S Geussenhainer,
W . Kaiser. Justus Liebigs Ann. Chem. 1978, 839; H. Koster. Nachr.
Chem. Tech. Lab. 27, 694 (1979).
[21 a) H. A . Kellner, I . Ugi.2. Naturforsch. B 34, 1159 (1979); b) W. Gerrard,
J. Chem. SOC.1944, 85: W. Gerrard. P. L. Wyuill, Research (London) 2,
536 (1949); W. Gerrard, M. J . D . Isaacs. G . Machell, K. B. Smifh. P. L.
Wyuill,J. Chem. SOC.1953, 1920; J. B. Honeycuit, C. A. 49, 157 (1955); V.
S. Abramou. V. K . Khairullin. J. Gen. Chem. USSR 27, 501 (1957); K .
Sasse in E. Miiller: Methoden der organischen Chemie (Houben-Weyl),
Vol. X11/2, p. 45f.. Thieme, Stuttgan 1964.
[31 H . Eckert. I. Ugi. Angew. Chem. 87, 847 (1975): Angew. Chem. Int. Ed.
Engl. 14, 825 (1975); see also R. Taube, M . Zach. K . A . Stanske, S.Heidrich. Z . Chem. 3,392 (1963); H . Eckert, Dissertation, Technische Universitat Miinchen 1976; H . Eckert, I. Ugi, W . Breuer. J . Geller, I . Lagerlund.
M . Listl. D . Marquarding, S.Stiiber, S.Zahr. H. u. Zychhnski, Pure Appl.
Chem. 51, 1219 (1979); H. Eckeri, I. Ugi, Liebigs Ann. Chem. 1979,
278.
141 G . Hope. W . Steglich, H. Vorbrijggen, Angew. Chem. 90,602 (1978): Angew. Chem. Int. Ed. Engl. 17, 569 (1978).
I51 H. A. Kellner, Dissertation, Technische Universitat Miinchen 1980.
161 K . H. Pausacker. J. Chem. SOC.1953, 107.
171 Before the reaction, thymidine (Fa. Merck) was treated several times with
pyridine (10 cm'/mmol), which was then removed (azeotropic drying)
151.
578
0 Verlag Chemie GmbH. 6940 Weinheim. 1981
Redox Reltionship between
Carbeneiron and a-Alkyliron Porphyrins'**'
By Doris Lexa, Jean-Michel Saueant, Jean-Paul Battioni,
Marc Lange, and Daniel Mansuy"'
Porphyrin complexes with Fe-C bonds are likely to be
involved in the enzymatic reactions of cytochrome P450
hemoproteins of the monooxygenase systems responsible
for the detoxification of exogenous compounds by living
organisms. In this connection, evidence has been given for
the formation of iron-carbene bonds during the oxidation
of 1,3-benzodioxole derivatives by the active oxygen cytochrome P450 complex[']. Involvement of o-alkyliron
complexes as intermediates in this reaction has also been
proposed"']. On the other hand, carbeneiron complexes
are formed upon reduction of various polyhalogenated
compounds by cytochrome P450-Fe"[21o r by reacting the
polyhalogenated substrates with iron(r1)-porphyrins under
reducing condition^^^]. These reactions may involve the intermediacy of o-halogenated alkyliron porphyrins of the
same type as those recently observed in a pulse radiolysis
study of the reaction of halogenated alkyl radicals with
Fe"-p~rphyrins'~].
It is noteworthy that only one o-alkyl[5"1
and very few o-aryliron p ~ r p h y r i n s [have
~ ~ been reported
so far: they have all been obtained as Fe"' o-derivatives,
prepared by reaction of a Grignard reagent with Fell'-porph yrins.
We report here the preliminary results of a study based
on an electrochemical investigation of the reduction of carbeneiron(1r)-porphyrin complexes in aprotic medial6],
which establishes a redox relationship between carbeneiron and o-alkyliron porphyrins and opens a new route to
o-alkyliron porphyrins both at the Fe" and Fe"' oxidation
levels.
The three rneso-tetraphenylporphyrin complexes (TPP"])
(TPP)FeC = X
(Za): X = C@C,H,CI),
( 2 ~ )X
: = C(C6H5),
(3a): x = s
were prepared according to previously described procedures[*'; the reaction medium was a 0.1 M solution of
Bu,NBF4 in DMF[91. Typical cyclic voltammograms obtained under these conditions are shown in Figure 1.
The Fe"-carbene complex is reduced in two successive
one-elgctron steps. While the first one-electron reduction
gives rise to products [(lb),(2b) o r (3bn which are stable for
ca. 1 s, the second reduction product undergoes irreversible decomposition leading to new types of complexes
[(ld), (2d) o r (3dJ which can be electrochemically reoxidized between -0.4 and -0.6 V. This process is reversible
for complexes (Id) and (2d) and irreversible for (3d) at low
sweep rates. In the latter case, reversibility can, however,
be restored by raising the sweep rate. The standard potentials for this new redox couple are: ( l d d ) -0.62 V , (2c/d)
- 0.64 V and ( W d ) - 0.44 V (us. SCE). The second wave
can also be rendered reversible by drastically raising the
sweep rate to ca. 100-1000 vs-I. Addition of water de-
[*I
Prof. J.-M. Saveant [+I, Dr. D. Lexa
Laboratoire d'Electrochimie de I'Universite Pans 7
2, place Jussieu, F-75221 Pans Cedex 05 (France)
Dr. D. Mansuy [ '1, Dr. J.-P. Battioni, Dr. M. Lange
Laboratoire de Chimie de 1-Ecole Normale Superieure
24, rue Lhomond, F-75005 Paris (France)
I +] Author to whom correspondence should be addressed.
[**I This work was supported in part by the CNRS (ATP "Composks de
coordination, Catalyse homogene").
OS70-0833/81/0707-0S78 !3 02.50/0
Angew. Chem. Int. Ed. Engl. 20 (1981) No. 6/7
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monochlorophosphate, trichloro, phosphorylation, reagents, group, protection, selective, bis, nucleoside, derivatives, dimethylethyl
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