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Bis(N N-diisopropylamino)trimethylsiloxy-phosphane A Novel Flexible Phosphitylating Reagent in Nucleoside Chemistry and Its Application in the Synthesis of P-Modified Nucleotides.

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161 B. M. Trost, E. Edstroni, M. B. Carter-Petillo, J Org Chem. 54 (1989)
4489.
171 B. M. Trost, T. R. Verhoeven, J Am. Chem. SOC.102 (1989) 4730.
[8] a) M. Kato, M. Kogeyama, R. Tanaka, K . Kumahara, A. Yoshikoshi, J
Org. Chem. 40 (1975) 1932; b) B. M. Trost, J. Timko, J. Stanton, .
I
Chem.
Soc. Chem. Commun. 1989,436.
[9] 0. Mitsunobu, M. Eguchi, Bull. Chem. Soc. Jpn. 44 (1971) 3427, G.
Grynkiewicz, H. Burzynska, Tetruhedron 32 (1976) 2109.
[lo] C. H. Heathcock, S. Kiyooka, T. A. Blumenkopf, J Org. Chem. 49 (1984)
4214.
[ l l ] E. J. Corey, H. Cho, C. Riicker, D. H. Hua, Tetruhedron Lett. 22 (1981)
3455; R. F.Cunico, L. Bedell, J. Org. Chem. 45 (1980) 4797.
[12] D. G. Lee, V S. Chang, J Org Chrm. 43 (1978) 1532.
[13] R. V. Lemieux. E. von Rudloff. Cun. J Chem 33 (19551 1701: J. W. A & mon, A. S. Y. Chau, W. G. Craig, ibid. 45 (1967) 1439.
A complete spectroscopic analysis has been carried out and the elemental
composition has been established by combustion analysis and/or high
resolution mass spectroscopy.
For brief reviews on the use of clays in synthesis, see A. M. McKillop,
0. W. Young, Synthesis 1975, 481; P. Laszlo, Science 2 f 0 (1987) 1473.
The enantiomerically pure precursor of 2 is known [3f, g, 8 b] as is also that
for 3, see H. C. Brown, K. S. Bhat, R. S. Randad, J Org. Chem. 54 (1989)
1570; A. I. Meyers, K . A. Babiak. A. L. Campbell, D. L. Comins, M. P.
Fleming, R. Henning, M. Heuschmann, J. P. Hudspeth, J. M. Kane, P. J.
Reider, D. M. Roland, K. Shimizu, K. Tomioka. R. D. Walkup, J Am.
Chem. SOC.103 (1983) 5015.
Mar/in et al. [3g]report a tentative assignment of structure 10b for a minor
product of his spiroketalization However, our data for 11b corresponds
to the compound described by Martin et al.
,
I
,
Bis( N,N-diisopropy1amino)trimeth ylsilox yphosphane: A Novel Flexible Phosphitylating
Reagent in Nucleoside Chemistry and Its Application
in the Synthesis of P-Modified Nucleotides **
other N,N-dialkylamino analogues exhibit phosphitylating
properties in the presence of 1H-tetrazole. Due to its ready
availability, stability, and relatively high phosphitylating
power, the phosphane 1 seems to be the current reagent of
choice.
The title phosphane 1 was prepared from readily available
chlorobis(N,N-diisopropylamino)phosphane~71in almost
quantitative yield (Scheme 1). This new phosphityiating reagent, which can be distilled without decomposition in vacuo, solidifies to a low-melting solid. It can be stored at room
temperature and used in phosphitylating procedures without
special precautions.
(iPr,N),PCI
H2
0
-
(iPr,N),POH
Me,SiCI (iPr,N),POSiMe,
1
Scheme 1. One-pot synthesis of 1. H,O/Et,N ( l / l ) in ether, 2h. 20"C,
Me,SiCl/Et,N (l/l), 2 h, 20°C; yield 90%. 1, b.p. 100-102°C/0.01 tom; ' H
NMR (CDCI,, TMS int.): b = 0.3 (s, 9H). 0.9 (d, 24H), 3.0-3.7 (m, 4H); "P
NMR (CDCI,, 85% H,PO, ext.): b = 108.23. DMTr = 4,4'-dimethoxytrityl.
The most important property of the siloxyphosphane 1 is
its ability to undergo highly selective nucleophilic substitution at the tricoordinate phosphorus atom without affecting
the silicon center under conditions which are commonly used
in the phosphite triester approach. In the phosphitylation of
alcohols the reactivity of the phosphane 1 is similar to that
of the corresponding alkoxy derivatives. A number of 3 ' 3 dinucleoside trimethylsilylphosphites 3 have been prepared
in this way in very high yield without isolation of the intermediate 2 (Scheme 2).
By Wojciech Dqbkowski, Jan Michalski,* and Wang Qing
In 1976, Letsinger et al.['I developed a method for the
linking of nucleosides via phosphite groups with phosphorochloridites which was more convenient than earlier routes.
This method was further improved by the phosphoroamidite
approach of Caruthers et al.['] Since then a variety of modified Letsinger reagents have been pr0posed.1~1However,
only those containing simple alkoxy groups attached to the
tricoordinate phosphorus are suitable for constructing intermediates for the synthesis of P-modified nucleotides via the
Michaelis-Arbuzov reaction.[41Prior to our present studies
phosphitylating reagents containing siloxy groups were almost unknown.[5]
Bis(N,N-diethy1amino)trimethylsiloxyphosphane had already been characterized by Alfonsov et al. in 1976 and was
used for the silylation of ethyl alcohol.r61
(Et,N),POSiMe,
+ EtOH
+
(Et,N),P(O)H
+ EtOSiMe,
In contrast we were able to demonstrate that bis(N,N-diisopropylamino)trimethylsiloxyphosphane (1) as well as
[*I
['I
Prof. Dr. J. Michalski, Dr. W. Dgbkowski, Wang Qing ['I
Centre of Molecular and Macromolecular Studies,
Polish Academy of Sciences
Sienkiewicza 112, 90-363 t o d i (Poland) and
Max-Planck Institut fur experimentelle Medizin Abteilung Chemie
Hermdnn-Rein-Strdsse 3, D-3400 Gottingen (FRG)
Permanent address: Chemical Research Institute, Beijing (Peoples Republic of China)
[**I The authors thank Prof. Friedrich Cramer, the Polish Academy of Sciences
and the Max-Planck-Gesellschaft for support of this work. We are grateful
to Dr. Dieter Cuuss for help in preparing the manuscript.
522
0 VCH
Verlagsgesellschufi mhH, 0-6940 Wemheim, 1990
B
DMTr0-Q
Dedicated to Professor Giinther Wilke on the occasion of his
65th birthday
N
OH
Me,SiO-P(
DMTrO
yB
P
>
Me,SiO/'\N<
L
n
OAc
1
P
L
P-OSiMe,
I
3a, B = B' = Thy[8a]; 3b. B = B'
3d, B = Ade(bz), B' = Thy
=
OAc
Ade(bz); k,B = Thy, B' = Ade(bz);
Scheme 2. One-pot synthesis of 3 (via 2). Nucleoside with a free 3'-hydroxygroup/diisopropylarnmoniumtetrazolide(l/l), 15 min, ZOT, CH,CN; nucleoside with a free 5'-hydroxy group/diisopropylammonium tetrazolide, 5 min,
2 0 ° C CH,CN. Yield (determined by 3 i P N M R spectroscopy) 95-97%
31PNMR(CDCI,.85% H,PO,ext.): 6 = 117.6, 116.8(3a); 117.6, 116.0(3b);
118.1, 117.5 ( 3 c ) ; 118.5, 118.0 (3d). The mononucleoside 2 can be isolated
quantitatively.
The trimethylsilylphosphites of type 3 can also be obtained by silylation[81of phosphonates with P-H bonding.[g1
The esters 3 exhibit remarkable chemical properties characteristic of trimethylsilylphosphites.~'olThe value of the esters 3 in nucleotide chemistry is clearly evident from their
selective and efficient participation in Michaelis-Arbuzov-
I~S70-0833190j05OS-0522
$O2.50/0
Anxew. Chem. Int. Ed. Engl. 29 (1990) No. 5
type reactions and from reactions which are unique for this
reagent, for example the one-pot synthesis of the biologically
interesting methylphosphonates of type 41"l (Scheme 3) and
phosphorofluoridates."21 The chemical and enzymatic properties of 4 compare with those of other dinucleoside
methylph~sphonates.[~*
mediates in nucleotide chemistry, can be readily obtained by
hydrolysis from 2 and 3 in a one-pot procedure.
Received: December 13, 1989;
revised: February 12, 1990 [Z 3684 IE]
German version: Angew. Chem. 102 (1990) 565
CAS Registry numbers:
1,114071-78-2; Za, 126256-30-2; 2b, 126256-31-3; 3 a pa isomer, 126256-32-4;
3a P, isomer, 126373-38-4; 3 b P, isomer, 126451-68-1; 3 b ps isomer, 12625640-4; 3c P, isomer, 126256-35-7; 3c P, isomer, 126373-40-8; 3d P, isomer,
126256-36-8; 3d P, isomer, 126373-41-9; 4 a P, isomer, 90865-75-1; 4 a P, isomer, 90865-76-2;5 a PRisomer, 126256-33-5; 5 a P, isomer, 126373-45-3; 5 b P,
isomer, 126256-31-9;5 b P,isomer, 126373-42-0;5 c P, isomer, 126256-39-1;5 c
P, isomer, 126373-442; 6 a P, isomer, 126256-34-6; 6a Ps isomer, 126373-39-5;
561836 b PRisomer, 126256-38-0; 6b P, isomer, 126373-43-1; [(IR)~N],PC~,
63-2; 3'-o-Ac-thymidine, 21090-30-2; 5'-0-DMT-thymidine. 40615-39-2;
3'-o-Ac-N6-benzoyl-2'-deoxyadenosine,
251 52-95-8; 5'-o-DMT-Nh-benzoyl-2'deoxyadenosine, 64325-78-6.
OAc
Scheme 3. Synthesis of 4 (2 h, 20°C) [Sb]. ,'P-NMR (CDCI,, 85% H,PO,
ext.): 6 = 32.7, 32.5.
Unique for reagents of type 3 is the reaction with oxalylazolides and anilides to form in excellent yields the dinucleotide azolides 5a, b and anilides 5 c (Scheme 4).
"MTrovThy
00
0
I
.N-C-C -NR.
7..
J
P
R L
' "=P-NR,
v-
5
~
-2 CO
-Me,SiNR,,
I
Thv
o
v
OAc
5a, R,NH
= imidazole;
5b, R,NH
=
triazole; 5c, R,NH
= aniline
Scheme 4. Synthesis of 5 from 3 a and (R,N-CO), (l/l); 3 h, 20°C. Yield.
NMR (CDCI,, 85%
(determined by ,'PNMR spectroscopy) 90-94%.
H,PO,ext.):&= -12.0, -11.5(5a); -10.6, -10.3(5b); f2.0, +1.6(5c).
In this way the anilides of type 5 c have become readily
accessible for the first time. Nucleotide anilides are of importance for the stereospecific synthesis of nucleoside phosphorothioates.1' 31
The reaction of 5 a leading to the anhydrides 6 a and 6 b
further illustrates the potential of this approach (Scheme 5).
DMTroYThy
0I
" " O Y T h Y
0
1
O=P-NJ
F N
y20
Jv
Thy
~
O=P-0-Y
J
OAc
6
5a
= CH,SO,;
Catalytic Hydration of Acrylonitrile to Acrylamide
under Mild Conditions **
By Jik Chin* and .
I
H . Kim
~-N^N
OAc
6a, Y
[l] R. L. Letsinger, W. B. Lunsford, 1 Am. Chem. Soc. 98(1976) 3655-3661.
[2] L. J. McBride, M. H. Caruthers, Tetrahedron Lect. 24 (1983) 245-248.
[3] S . A. Narang (Ed.): Synthesis and Applications of D N A and R N A , Academic Press, Orlando, FL 1987.
[4] a) M. J. Nemer, K. K. Ogilvie, Tetrahedron Lett. 21 (1980) 4149-4252;
b) S. A. Noble, E. F. Fisher, M. H. Caruthers, Nucleic Acids Res. 12(1984)
3387-3404; c) W J. Stec, G. Zon, W. Egan, R. A. Byrd, L. R. Philips.
K. A. Gallo, J. Org. Chem. 50 (1985) 3908-3913; d) A. Wilk, W. J. Stec,
Nucleic Acids Res. Symp. Ser. 18 (1987) 289-292.
[5] a) K. Imai, T. Ito, S. Kondo, T. Takaku, Nucleosides& Nucleatides 4 (1985)
669-679; b) W. Dgbkowski, F. Cramer, J. Michalski, Tetrahedron Lett. 28
(1987) 3559-3560.
[6] E. S. Batyeva, V. A. Alfonsov, A. N. Pudovik, Izv. Akad. Nauk SSSR. Ser.
Khim. 1976,463-466.
[7] a) R. B. King, P. M. Sundaram, 1 Org. Chem. 49 (1984) 1784- 1789; b) S .
Hamamoto, H. Takaku, Chem. Lett. 1986, 1401-1404.
[S] a ) A . Kurne, M. Fujii, M. SekinqT. Hata, J. Org. Chem. 49(1984) 21392143; b) E. de Vroom, M. L. Spierenburg, C. E. Dreef, G. A. van der
Marel, J. H. van Boom, Red. Eav. Chim. Pays-Bas 106 (1987) 65-66.
[9] a ) R . H. Hall, A. Todd, R. F. Webb, J. Chem. Sac. 1957. 3291-3296;
b) P. J. Garegg, T. Regberg, J. Stawinski, R. Stromberg, Chem. Srr. 25
(1985) 280-282; c) B. C. Froehler, M. D. Matteucci, Tetrahedron Lelt. 27
(1986) 469-472; d) J. E. Marugg, M. Tromp, E. Kuyl-Yeheskiely, G. A.
van der Marel, J. H. van Boom, ibid. 27 (1986) 2661 -2664; e) M. Fujii, K.
Ozaki, M. Sekine, T. Hata, Tetrahedron 43 (1987) 3395-3407. and references cited therein.
[lo] a) A. Lopusinski, J. Michalski, M. Potrzebowski, Phosphorus Suljiur 28
(1986) 299-305; b) W. Dgbkowski, J. Michalski, 1 Chem. Sac. Chem.
Commun. 1987, 755-756; c) W. Dqbkowski, F. Cramer, J. Michalski, Tecrahedron Lett. 28 (1987) 3559-3560; d) A. Skowronska, R. Dembinski,
R. Kaminski, J. Michalski, 1 Chem. Sac., Perkin Trans. 1 1988, 21972201.
[Ill P. S . Miller, P. 0. P. Ts'o, Annu. Rep. Med. Chem. 23(1988)295-304, and
references cited therein.
[12] W. Dgbkowski, F. Cramer, J. Michalski, Tetrahedron Left.29 (1988) 3301 3302.
[13] Z. J. Lesnikowski, M! Niewiarowski, W. S . Zielinski, W J. Stec, Tetrahedren
40 (1984) 15-32.
6b, Y
= CF,CO
Scheme 5. Synthesis of 6 (15min, 2 0 T , CH,CN). Yield (determined by
"PNMR spectroscopy) 95-97%. " P NMR (CDCl,, 85% H,PO, ext.):
6 = -15.6, -15.3 (6a); -9.8, -9.5 (6b).
All compounds 3-6 are mixtures of diastereoisomers.
Phosphonates with P-H bonding, which are versatile interAngew. Chem. Int. Ed. Engl. 29 (1990) No. 5
Numerous articles have been written on the development
of catalysts that hydrolyze amides, esters and nitnles. Due to
the stability of these substrates, most studies have been focused on model systems involving activated substrates"] or
intramolecular catalysis.r21Perhaps it is now time to exploit
[*] Prof. J. Chin, J. H. Kim
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, Quebec H3A 2K6 (Canada)
[**I Support by the National Science and Engineering Research Council of
Canada is gratefully acknowledged.
0 VCH Verlagsgesellschajt mbH, 0-6940 Weinheim. !990
0570-0833190j0505-0523$02.50/0
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flexible, reagents, nucleotide, application, chemistry, trimethylsilyl, synthesis, phosphane, modified, diisopropylamino, phosphitylating, bis, novem, nucleoside
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