Stereoselective synthesis of Rp- and Sp-dithymidine phosphorothioates via chiral indolooxazaphosphorine intermediates derived from tryptophan

Article abstract of DOI:10.1002/1521-3773(20001215)39:24<4521::AID-ANIE4521>3.0.CO;2-M

A chiral auxilliary 1 and its enantiomer, which are easily prepared from L- and D-tryptophan, facilitate diastereoselective syntheses of phosphorothioate oligonucleotides. Phosphorothioate 2 was obtained from 1 in five steps with over 95% de, and the enan

Full text of DOI:10.1002/1521-3773(20001215)39:24<4521::AID-ANIE4521>3.0.CO;2-M

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imine 3d :5.00 g, 12.9 mmol) in CH2Cl2 :10 mL) was added by syringe to
the catalyst solution at 08C. Stirring the mixture for 10 min gave an orange
solution to which was rapidly added ethyl diazoacetate :1.484 mL,
14.2 mmol) by syringe. Some bubbling was noted after the addition. The
reaction was allowed to proceed for 6 hat 0 8C and then for 14 h at room
temperature :228C). The reaction mixture was transferred to a 500-mL
flask, diluted with hexanes :250 mL), and then the volatiles were removed
under vacuum to give the crude aziridine 3d as an off-white solid. The
1H NMR spectrum of this material revealed 3d with cis:trans ꢀ 50:1 and
indicated that <1% of 4d and 5d were formed. Purification of 3d by
column chromatography on silica gel with a mixture of ethyl acetate:hex-
anes :3:7) gave aziridine 3d :5.20 g, 11 mmol) as a white solid in 85% yield.
The optical purity of this material was determined to be 96% ee by HPLC
analysis :OD-H column). Crystallization from hexanes:CH2Cl2 :10:1,
300 mL) gave 3d :4.43 g) with99% ee. A second crop was taken but
found to be only 90% ee. Spectral data for 3d: m.p. 141 ± 1438C :hex-
anes:CH2Cl2); 1H NMR :400 MHz, CDCl3): d ˆ 0.99 :t, J ˆ 7 Hz, 3H), 2.24
:s, 3H), 2.25 :s, 3H), 2.68 :d, J ˆ 7 Hz, 1H), 3.18 :d, J ˆ 7 Hz, 1H), 3.95 :s,
1H), 3.95 :m, 2H), 7.07 :d, J ˆ 9 Hz, 1H), 7.19 :m, 1H), 7.28 :m, 7H), 7.45
:d, J ˆ 7 Hz, 2H), 7.81 :d, J ˆ 7 Hz, 2H). 13C NMR :100.6 MHz, CDCl3):
d ˆ 13.84, 20.64, 46.57, 47.03, 60.89, 77.49, 122.75, 122.78, 126.05, 127.18,
127.30, 127.45, 127.61, 128.55, 128.65, 133.97, 141.35, 141.57, 142.21, 167.45
168.07, 168.24; IR :thin film) 3030 :w), 2980 :w), 1770 :s), 1731 :s),
1600 cmÀ1 :m); MS :EI): m/z :relative intensity): 474 :21) [M‡1], 306 :12),
195 :10), 167 :100); m/z calcd for C28H27NO6: 474.1903, found 474.1903.
Elemental analysis calcd for C28H27NO6: C 71.02, H 5.75, N 2.96; found: C
71.23, H 5.88, N 2.94. [a]2D3 ˆ À17.38, :C ˆ 1 from CH2Cl2) taken on 99% ee
material :HPLC). Further experimental details can be found in the
Supporting Information.
[3] J. C. Antilla, W. D. Wulff, J. Am. Chem. Soc. 1999, 121, 5099.
[4] For other applications of the VAPOL ligand, see a) J. Bao, W. D. Wulff,
A. L. Rheingold, J. Am. Chem. Soc. 1993, 115, 3814; b) J. Bao, W. D.
Wulff, Tetrahedron Lett. 1995, 36, 3321; c) J. Bao, W. D. Wulff, J. B.
Dominy, M. J. Fumo, E. B. Grant, A. C. Rob, M. C. Whitcomb, S.-M.
Yeung, R. L. Ostrander, A. L. Rheingold, J. Am. Chem. Soc. 1996, 118,
3392; d) D. P. Heller, D. R. Goldberg, W. D. Wulff, J. Am. Chem. Soc.
1997, 119, 10551.
[5] The VANOL ligand was prepared according to the same procedure that
has been reported for the VAPOL ligand.[4c]
[6] A second crop was taken but had only approximately 90% ee.
[7] The optical rotation of an authentic sample of l-DOPAwas found to be
[a]D ˆ À8.28.
Stereoselective Synthesis of RP- and
SP-Dithymidine Phosphorothioates via Chiral
Indolooxazaphosphorine Intermediates
Derived from Tryptophan**
Yixin Lu and George Just*
The use of phosphorothioates as DNA analogues useful in
antisense-based therapy is well established[1] and led to the
development of Vitravene as the first antisense drug.[2]
Several other phosphorothioate oligonucleotides :PS-Oligos)
are in clinical trials. Although Stec et al. described an elegant
oxathiaphospholane-based approach[3]for preparing diaster-
eomerically pure phosphorothioates, it has not been used for
large-scale production of PS-Oligos, which are still used as a
mixture of about 106 diastereomers. The use of cyclic N-
acylphosphoramidites as promising monomers for the stereo-
controlled synthesis of phosphorothioates was recently re-
ported by Beaucage et al.[4]
Previously, we developed cyclic phosphoramidites[5]suchas
sugar-derived oxazaphosphorinanes,[5b,c] indolooxazaphos-
phorines :a),[5e, f] and indoleimidazoles[5i] for the stereoselec-
tive synthesis of PS-Oligos. Here we report on the use of
promising indolooxazaphosphorine precursors derived from
tryptophan which do not require a difficult chromatographic
separation and may form the basis of a practical process.
As demonstrated in the indolooxazaphosphorine ap-
proach,[5f] chiral auxiliary a led to the stereoselective synthesis
of phosphorothioate in solution. When it was applied to solid-
phase synthesis, a b-elimination caused rearrangement to give
Received: August 9, 2000 [Z15611]
[1] a) D. Tanner, Angew. Chem. 1994, 106, 625; Angew. Chem. Int. Ed.
Engl. 1994, 33, 599; b) W. H. Pearson, B. W. Lian, S. C. Bergmeier in
Comprehensive Heterocyclic Chemistry II, Vol. 1A :Ed.: A. Padwa),
Pergamon, Oxford, 1996, p. 1; c) K. M. L. Rai, A. Hassner in Compre-
hensive Heterocyclic Chemistry II, Vol. 1A :Ed.: A. Padwa), Pergamon,
Oxford, 1996, p. 61; d) J. Sweeney, H. M. I. Osborn, Tetrahedron:
Asymmetry 1997, 8, 1693; e) R. S. Atkinson, Tetrahedron 1999, 55, 1519.
[2] For previous work on catalytic asymmetric aziridinations, see a) D. A.
Evans, K. A. Woerpel, M. M. Hinman, M. M. Faul, J. Am. Chem. Soc.
1991, 113, 726; b) R. E. Lowenthal, S. Masamune, Tetrahedron Lett.
1991, 32, 7373; c) Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem. Soc.
1993, 115, 5326; d) D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A.
Anderson, D. M. Barnes, J. Am. Chem. Soc. 1993, 115, 5328; e) K.
Noda, N. Hosoya, R. Irie, Y. Ito, T. Katsuki, Synlett 1993, 469; f) D. A.
Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742;
g) D. Tanner, P. G. Andersson, A. Harden, P. Somfai, Tetrahedron Lett.
1994, 35, 4631; h) Z. Li, R. W. Quan, E. N. Jacobsen, J. Am. Chem. Soc.
1995, 117, 5889; i) H. Nishikori, T. Katsuki, Tetrahedron Lett. 1996, 37,
9245; j) A. M. Harm, J. G. Knight, G. Stemp, Synlett 1996, 677; k) P.
Muller, C. Baud, Y. Jacquier, M. Moran, I. Nageri, J. Phys. Org. Chem.
1996, 9, 341; l) T.-S. Lai, H.-L. Kwong, C.-M. Che, S.-M. Peng, Chem.
Commun. 1997, 2373; m) M. J. Sodergren, D. A. Alonso, P. G. Ander-
sson, Tetrahedron: Asymmetry 1997, 8, 3563; n) K. B. Hansen, N. S.
Finney, E. N. Jacobsen, Angew. Chem. 1995, 107, 750; Angew. Chem.
Int. Ed. Engl. 1995, 34, 676; o) K. G. Rasmussen, K. A. Jorgensen, J.
Chem. Soc. Chem. Commun. 1995, 1401; p) V. K. Aggarwal, A.
Thompson, R. V. H. Jones, M. C. H. Standen, J. Org. Chem. 1996, 61,
8368; q) L. Casarrubios, J. A. Perez, M. Brookhart, J. L. Templeton, J.
Org. Chem. 1996, 61, 8358; r) H.-J. Ha, K.-H. Kang, J.-M. Suh, Y.-G.
Ahn, Tetrahedron Lett. 1996, 37, 7069; s) K. G. Rasmussen, K. A.
Jorgensen, J. Chem. Soc. Perkin Trans. 1 1997, 1287; t) C. Langham, P.
Piaggio, D. Bethell, D. F. Lee, P. McMorn, P. C. Bulman Page, D. J.
Willock, C. Sly, F. E. Hancock, F. King, G. J. Hutchings, J. Chem. Soc.
Chem. Commun. 1998, 1601; u) S. Minakata, T. Andl, M. Nishimura, I.
Ryu, M. Komatsu, Angew. Chem. 1998, 110, 3596; Angew. Chem. Int.
Ed. 1998, 37, 3392; v) P. Müller, C. Baud, Y. Jacquier, Can. J. Chem.
1998, 76, 738; w) S. K. Bertilsson, L. Tedenborg, D. A. Alonso, P. G.
Andersson, Organometallics 1999, 18, 1281; x) K. Juhl, R. G. Hazell,
K. A. Jorgensen, J. Chem. Soc. Perkin Trans. 1 1999, 2293.
[*] Prof. Dr. G. Just, Dr. Y. Lu
Department of Chemistry
McGill University
Montreal, PQ, H3A 2K6 :Canada)
Fax : :‡1)514-398-3797
E-mail: just@chemistry.mcgill.ca
[**] This work was financially supported by Natural Science and Engineer-
ing ResearchCouncil of Canada :NSERC). We thank Nadim Saadeh
and Dr. Orval Mamer, McGill University biomedical mass spectro-
scopy unit, for recording mass spectra.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
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a cyanoethyl phosphonate.[5g] We therefore
decided to synthesize a chiral auxiliary of type
b, which can be derived from tryptophan.
Removal of the chiral auxiliary could then be
H
O
4
COOCH3
Bn
O
C
3
O
O
b
a
N
O2N
NBn
N
O
2
1
N
H
H
RO
1
2 R = p-nitrobenzoyl
3 R = H (64%)
4 (80%)
c
N
Scheme 1. a) Nb-Benzyl tryptophan methyl ester, toluene, reflux, Dean ± Stark trap;
b) NaOMe, MeOH; c) iPrNH2, 808C.
N
N
H
H
CN
HO
HO
a
b
O
O
COX
N
e
d
N
H2
Bn
HN
effected by direct displacement of
N
(95%)
N
R
(81%)
N
H1
N
H
Bn
H
N
the primary alcohol group or by
neighboring-group participation of
an appropriately positioned func-
tionality. When benzyl serves as a
H
5 X = OH, R = Cbz
6 X = Pyr, R = Cbz
7 X = Pyr, R = H
a (96%)
O
HO
10
b
c
O
8 X = Pyr, R = Bn (76%)
9
NO2
protecting group for Nb of trypto-
Scheme 2. a) Pyrrolidine, Et3N, HBTU, CH3CN, RT; b) H2, Pd/C, ethyl acetate/H2O/AcOH; c) PhCHO,
NaCNBH3, MeOH, pH 6; d) 1, toluene, reflux, Dean ± Stark trap; e) NaOH, H2O/THF, 558C. Cbz ˆ car-
boxybenzyl, HBTU ˆ O-:benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Pyrˆ 1-
pyrrolidyl.
phan, a Pictet ± Spengler reaction
tends to yield a single diastereo-
mer.[6] This could well solve the
chirality problem of the new chiral
auxiliary. Furthermore, the chiral
between the H1 and H2 protons in the NOESY spectra of 10
means the expected trans configuration is very likely.[6a]
The application of chiral auxiliary 10 to the stereoselective
synthesis of phosphorothioates is outlined in Scheme 3. A
solution of 10 and triethylamine in dichloromethane was
added slowly to phosphorus trichloride at 08C. Initially,
several 31P NMR signals were observed. After heating at 508C
for one day to equilibrate, a single peak at around d ˆ 145 was
observed, corresponding to 11. When intermediate 11 was
further treated with 5'-O-TBDMS-thymidine :T3'OH) in the
auxiliary can be derived from natural chiral tryptophan,
making the method very attractive and inexpensive.
The synthesis of the chiral auxiliary is illustrated in
Scheme 1. Dimethylallyl alcohol was transformed into its p-
nitrobenzoate, ozonolysis of which then gave aldehyde 1.
Pictet ± Spengler reaction between 1 and Nb-benzyl trypto-
phan methyl ester[6] in toluene without acid catalyst afforded
the desired condensed product 2. Ester 2 was then methano-
lyzed by reaction withsodium methoxide in methanol. To our
surprise, lactone 4 or its enantiomer was obtained as the
product.
Cook et al. showed that Pictet ± Spengler
reactions between Nb-benzyl tryptophan meth-
yl ester and bulky aldehydes led to stereo-
O
O
N
N
c
N
a
specific formation of the trans diastereomer.[6a]
N
H
Bn
N
10
N
P
Bn
Since our product was a single isomer, it follows
that epimerization occurs readily at C1 or C3.
These facile epimerizations are precedented.[6b]
Participation of the neighboring amide group
has been reported.[5d, 7] We therefore consid-
ered synthesizing a chiral auxiliary with an
T5'O
O
P
X
O
OT3'
11 X = Cl (δ (31P) = 145.3)
12 X = OT3' (δ (31P) = 118.2)
(51% for two steps)
b
13 (δ (31P) = 140.2)
d
O
amide group. Removal of the chiral auxiliary by
N
T
HO
neighboring-group participation can be expect-
ed at the end of the synthesis should facile
epimerization occur during removal.
O
O
N
N
H
Bn
N
+
O
P
O
P
f
N
N
H
H2N
Bn
Chiral auxiliary 10 witha neighboring pyrro-
lidine amide :Pyr) group was easily prepared
:Scheme 2). Commercially available Nb-Cbz-l-
tryptophan :5) was coupled withpyrrolidine to
yield amide 6. The Cbz protecting group was
then removed to give 7, which upon reductive
amination withbenzaldehyde was transformed
into 8. Pictet ± Spengler condensation of 8 with
aldehyde 1 afforded 9 as a single diastereomer,
which was then hydrolyzed to furnish 10 as a
single isomer. The absence of cross-peaks
O
T
S
T
O
O
(89%)
O
O
S
O
NH4
OR
OR
17
OH
(δ (31P) = 56.0)
O
T
(RP)-16
14 R = TBDMS
15 R = H (61%)
(δ (31P) = 68.6)
e
Scheme 3. a) PCl3, Et3N, CH2Cl2; b) T3'OH, Et3N, CH2Cl2; c) T5'OH, DBU, THF; d) Beau-
cageꢁs reagent; e) TBAF; f) conc. ammonia/EtOH, 558C. DBU ˆ 1,8-diazabicyclo[5.4.0]un-
dec-7-ene, Tˆ thymine residue, TBAF ˆ tetrabutylammonium fluoride, TBDMS ˆ tert-butyl-
dimethylsilyl, T3'OH ˆ 5'-O-TBDMS-thymidine, T5'OH ˆ 3'-O-TBDMS-thymidine.
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presence of triethylamine in dichloromethane, the
reaction went to completion in 10 min to yield a
single isomer of phosphoramidite 12 witha 31P
NMR signal at d ˆ 118.2. Cyclic phosphoramidite
12 was stable enoughto be easily purified by
column chromatography on silica gel. When puri-
fied 12 was treated with3 '-O-TBDMS-thymidine
:T5'OH) in the presence of five equivalents of DBU,
the displacement was completed within 20 min at
room temperature, as established by the formation
of a characteristic major 31P NMR peak at d ˆ 140
corresponding to phosphite triester 13. The DBU
was removed by filtration through a short column,
and sulfurization withBeaucageꢁs reagent [8] afford-
ed phosphorothioate 14 witha major 31P NMR
signal at around d ˆ 68. Removal of silyl protecting
groups gave dithymidine phosphorothioate 15.
We next attempted to remove the chiral auxiliary.
The solution of 15 in water/THF was first heated at
558C. No reaction had occurred after one day. We
then treated 15 withconcentrated ammonia/etha-
nol :3/1) at 558C for 16 h. To our delight, phos-
phorothioates 16 were obtained, as indicated by the
presence of two peaks at d ˆ 56.1 and 56.0 in a ratio
O
N
T
RO
O
N
N
P
Bn
O
H
+
CPG
O
O
N
O
N
O
O
O
DMTrO
T
19 R = DMTr
20 R = H
a
18
b,c,d
O
N
T
HO
O
N
N
H
Bn
e
O
P
O
P
T
S
O
T
O
O
O
O
S
O
O
H
NH4
CPG
O
N
OH
N
O
OH
21
T
(RP)-16
O
O
Scheme 4. a) Cl3CCOOH; b) DBU, then 18; c) Beaucageꢁs reagent; d) Cl3CCOOH;
e) conc. ammonia/EtOH, 558C. DMTrˆ 4,4'-dimethoxytrityl.
of 1 to 40 in the 31P NMR spectrum. The configurations of
minor and major isomers were assigned as SP and RP,
respectively, on the basis of their 31P NMR chemical shifts.[5h]
The chiral auxiliary we recovered had structure 17, and this
means direct attack by ammonia was responsible for its
removal. Should the chiral auxiliary epimerize to give a cis
configuration, neighboring-group participation would be ex-
pected to yield lactone 4 or its hydrolyzed product after
deprotection.
dithymidine phosphorothioate anion. Similarly, the monomer
derived from d-tryptophan led to the formation of the SP
dimer, which was also confirmed by HPLC comparison and
HPLC-MS analysis.
In summary, chiral indolooxazaphosphorine auxiliaries can
be easily prepared from l- and d-tryptophans. When applied
in solution and solid-phase syntheses of dithymidine phos-
phorothioates, the l-tryptophan-derived chiral auxiliary led
to the formation of the RP isomer, and the d-tryptophan-
derived precursor to the SP isomer. The adaptation of the
methodology to routine solid-phase synthesis of oligonucleo-
tides is underway.
The methyl ester chiral auxiliary 3 was used for the
stereoselective synthesis of phosphorothioates in a similar
manner, and the same results were obtained.
To demonstrate that our methodology is compatible with
solid-phase synthesis of oligonucleotides, we synthesized RP-
and SP-dithymidine phosphorothioates on a solid phase. The
solid-phase syntheses of dithymidine phosphorothioates were
performed manually :Scheme 4). 5'-O-DMTr-thymidine :19),
obtained by immobilizing thymidine on controlled pore glass
Experimental Section
10: Amide 8 :0.35 g, 1 mmol) and aldehyde 1 :0.23 g, 1.1 mmol) in toluene
were heated to reflux with removal of water. After 4 h, evaporation to a
small volume provided a light yellow crystalline product 9 :0.32 g, 60%).
The mother liquid was purified by chromatography to give more 9 :0.11 g,
21%; HRMS :FAB): calcd for C31H31N4O5: 539.2294; found: 539.2293). A
solution of 9 :110 mg, 0.2 mmol) in 2n aqueous NaOH :3 mL) and THF
:3 mL) was warmed to 558C for 1 h. Extraction with ethyl acetate provided
13 as a white solid :74 mg, 95%). 1H NMR :500 MHz, CDCl3): d ˆ 8.05 :br,
1H), 7.56 :d, 1H, J ˆ 7.5 Hz), 7.10 ± 7.30 :m, 8H), 4.10 :m, 2H), 4.01 ± 4.03
:m, 2H), 3.90 ± 3.96 :m, 1H), 3.72 ± 3.80 :m, 2H), 3.40 ± 3.58 :m, 4H), 2.72 ±
2.76 :dd, 1H, J ˆ 4.0, 16.5 Hz), 1.87 ± 2.03 :m, 4H); 13C NMR :125.7 MHz,
CD3COCD3): d ˆ 169.79, 139.32, 136.17, 130.35, 128.58, 128.42, 127.12,
126.83, 121.83, 119.40, 118.27, 110.73, 108.66, 63.71, 57.75, 56.86, 52.75, 46.17,
26.30, 23.99, 19.04, 14.02; HRMS :EI) calcd for C24H27N3O2: 389.2103;
found: 389.2099.
[9]
:CPG) witha DBU-resistant sarcosinyl-succinoyl linker,
was detritylated and treated withexcess DBU followed by
the addition of l-tryptophan-derived monomer 18. After
20 min at room temperature, the solid support was washed
withacetonitrile and sulfurized withBeaucageꢁs reagent,
followed by detritylation to furnish phosphorothioate 21. Th e
solid support was heated in concentrated ammonia at 558C
for 16 h to cleave the dimer and remove the chiral auxiliary to
furnish: RP)-dithymidine phosphorothioate 16.
The configuration at the phosphorus center of 16 was
established by comparison of reverse-phase HPLC :RP-
HPLC) chromatograms of 16 and thymidine dimers synthe-
sized by a nonstereoselective method. It is documented in the
literature[10] that the RP isomer of the dinucleotide eluted
faster than SP isomer in RP-HPLC. The configuration of 16
was accordingly assigned as RP. The identity of 16 was also
proved by HPLC-MS, which showed the peak of the
12: A solution of 10 :39 mg, 0.1 mmol) in CH2Cl2 containing Et3N :30.7 mL,
0.22 mmol) was added slowly to a solution of PCl3 :8.7 mL, 0.1 mmol) in
CH2Cl2 :0.25 mL) at 08C. The NMR tube was then sealed. After heating at
508C for 24 h, a solution of 5'-O-TBDMS-thymidine :39 mg, 0.11 mmol)
and Et3N :15.4 mL, 0.11 mmol) was added to the solution of 11, and the
NMR tube was resealed. When 31P NMR spectroscopy showed the
disappearance of the signal at d ˆ 144 and the formation of new signal at
around d ˆ 118, the solvent was removed in vacuo. Purification by flash
chromatography afforded 12 as a white solid :39 mg, 51%). 31P NMR
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:202.3 MHz, CDCl3): d ˆ 116.96; 1H NMR :500 MHz, CDCl3): d ˆ 8.48 :br,
1H), 7.54 :d, 1H, J4,5 ˆ 7.5 Hz), 7.51 :d, 1H, J6,7 ˆ 7.5 Hz), 7.45 :s, 1H), 7.19 ±
7.35 :m, 7H), 6.12 :m, 1H), 4.90 :m, 1H), 4.36 :m, 1H), 3.45 ± 4.00 :m, 8H),
3.50 :m, 3H), 3.26 :m, 1H), 3.13 :m, 1H), 2.96 :m, 1H), 2.23 :m, 1H), 2.01 ±
2.06 :m, 1H), 1.82 ± 1.95 :m, 7H), 0.91 :s, 9H), 0.08 :2s); HRMS :FAB):
calcd for C40H53N5O7PSi: 774.3452; found: 774.3455.
Early Transition Metal a-Diazoalkane
Complexes**
Victorio Cadierno, Maria Zablocka, Bruno Donnadieu,
Alain Igau, and Jean-Pierre Majoral*
15: DBU :37 mL, 0.25 mmol) was added to a stirred solution of 12 :38.6 mg,
0.05 mmol) and 3'-O-TBDMS-thymidine :35.6 mg, 0.1 mmol) in dry THF
:2 mL) at room temperature. After 20 min, the 31P NMR spectrum of the
reaction mixture showed a single signal at around d ˆ 140. The mixture was
then loaded onto a short column to filter off DBU. After evaporation of the
solvent, the residue was dissolved in dry CH2Cl2, and Beaucageꢁs reagent
:10 mg, 0.05 mmol) was added at room temperature. After stirring for
5 min, 31P NMR spectroscopy revealed a single peak at around d ˆ 68. The
solvent was removed, the residue was dissolved in THF, and TBAF was
added. After 2 h, the solvent was removed in vacuo. CH2Cl2 was added to
the residue, and the extract was washed with water and brine and dried over
magnesium sulfate. Purification by column chromatography afforded 15 as
a white solid :28 mg, 61%).
The reaction of diazoalkanes with transition metals results
either in coordination through the nitrogen atoms or in
formation of a carbon ± metal bond. Many N-bonded sub-
stituted transition metal diazoalkanes have been studied,[1]
but only four series of C-bonded late transition metal
compounds have been isolated.[2] a-Metalated diazoalkanes
À
LnM C:N2)R containing an early transition metal have not
yet been reported. Treatment of zirconocene ZrIV complexes
[3]
[3c]
À
À
withdiazoalkanes results in insertion into Zr C, Zr H,
Zr P, [4] and zirconium ± metal bonds[5] to give the correspond-
À
ing hydrazonato ligands I [Eq. :1)].
16 and 17: Phosphorothioate 15 :28 mg, 0.026 mmol) was dissolved in
concentrated ammonia/ethanol :3/1, 5 mL). The mixture was heated at
558C for 16 h. The 31P NMR signal shifted quantitatively from d ˆ 68 to 56.
The reaction mixture was extracted with chloroform several times. The
combined organic extracts were washed with brine and dried over
magnesium sulfate. The solvent was removed to provide 17 :9.2 mg,
91%) as a light yellow solid. The aqueous crude product was purified by
flash chromatography to give 16 :15 mg, 89%).
17: 1H NMR :500 MHz, CDCl3): d ˆ 7.41 :d, 1H, J ˆ 8.0 Hz), 7.23 ± 7.35 :m,
6H), 7.13 :m, 1H), 7.02 :m, 1H), 4.71 :br, 1H), 4.04 ± 4.14 :m, 2H), 3.94 :m,
2H), 3.68 ± 3.86 :m, 2H), 3.11 ± 3.23 :m, 4H), 2.97 :m, 1H), 2.82 :m, 1H),
1.55 ± 1.82 :m, 5H); HRMS :FAB): calcd for C24H29N4O: 389.2341
We have shown that 1-aza-zirconacyclopentene complexes
1a and 1b[6] :see Scheme 1) contain a strongly electrophilic
metal center :mostly because of the inductive electron-
withdrawing properties of the s-bonded nitrogen atom) and
a rather nucleophilic imido group that does not share its lone-
pair electron density withthe adjacent metal center because
of the strain in the metallacycle.[7] Indeed phosphanes 1a and
‡
[:M‡1)] ; found: 389.2343.
Received: July 17, 2000 [Z15468]
[1] E. Uhlmann, A. Peyman, Chem. Rev. 1990, 90, 543.
[2] See webpage at http://www.isip.com.
[3] W. J. Stec, A. Grajkowski, A. Kobylanska, B. Karwowski, M.
Koziolkiewicz, K. Misiura, A. Okruszek, A. Wilk, P. Guga, M.
Boczkowska, J. Am. Chem. Soc. 1995, 117, 12019.
À
1b activate C H bonds in relatively acidic carbonic acids, such
as acetylenes and methylene compounds.[8] Although electro-
À
philic, metal-mediated, aliphatic C H bond cleavage is
[4] A. Wilk, A. Grajkowski, L. R. Phillips, S. L. Beaucage, J. Am. Chem.
Soc. 2000, 122, 2149.
precedented,[9] its application to the functionalization of
complex substrates is very rare. The present report deals with
[5] a) Z. Xin, G. Just, Tetrahedron Lett. 1996, 37, 969; b) Y. Jin, G.
Biancotto, G. Just, Tetrahedron Lett. 1996, 37, 973; c) E. Marsault, G.
Just, Tetrahedron Lett. 1996, 37, 977; d) E. Marsault, G. Just,
Tetrahedron 1997, 53, 16945; e) J. Wang, G. Just, Tetrahedron Lett.
1997, 38, 705; f) J. Wang, G. Just, Tetrahedron Lett. 1997, 38, 3797; g) J.
Wang, G. Just, A. P. Guzaev, M. Manoharan, J. Org. Chem. 1999, 24,
2595; h) Y. Jin, G. Just, J. Org. Chem. 1998, 63, 3647; i) Y. Lu, G. Just,
Tetrahedron 2000, 56, 4355.
[6] a) F. Ungemach, M. DiPierro, R. Weber, J. M. Cook, J. Org. Chem.
1981, 46, 164; b) E. D. Cox, L. K. Hamaker, J. Li, P. Yu, K. M.
Czerwinski, L. Deng, D. W. Bennett, J. M. Cook, J. Org. Chem. 1997,
62, 44.
2
À
a novel electrophilic sp -C H bond activation and its appli-
cation for the preparation of a-diazomethylzirconium com-
plexes, which are the first C-metalated diazoalkanes
LnMC:N2)R withan early transition metal.
Treatment of 1a and 1b withethyl diazoacetate : 2) in THF
at room temperature gave the light yellow, thermally stable
solids 4a and 4b :Scheme 1) in excellent yields :>88%). The
31P NMR spectra of 4a and 4b display a singlet at d ˆ 49.4 and
58.5, respectively. The total disappearance of the sp2-CH
[7] a) R. P. Iyer, D. Yu, T. Devlin, N.-H. Ho, S. Agrawal, J. Org. Chem.
1995, 60, 5388; b) R. P. Iyer, D. Yu, N.-H. Ho, W. Tan, S. Agrawal,
Tetrahedron: Asymmetry 1995, 6, 1051.
[8] R. P. Iyer, W. Egan, J. B. Regan, S. L. Beaucage, J. Am. Chem. Soc.
1990, 112, 1253.
[9] M. J. Damha, P. A. Giannaris, S. U. Zabarylo, Nucleic Acids Res. 1990,
18, 3813.
[10] a) W. J. Stec, G. Zon, B. Uznanski, J. Chromtogr. 1985, 326, 263; b) H.
Kanehara, T. Wada, M. Mizugachi, K. Makino, Nucleosides Nucleo-
tides 1996, 15, 1169.
[*] Dr. J.-P. Majoral, Dr. V. Cadierno,
Dr. B. Donnadieu, Dr. A. Igau
Laboratoire de Chimie de Coordination, CNRS
205 route de Narbonne, 31077 Toulouse Cedex :France)
Fax : :‡33)05-61-55-30-03
E-mail: majoral@lcctoul.lcc-toulouse.fr
Dr. M. Zablocka
PolishAcademy of Sciences
Sienkiewicza 112, 90-363 Lodz :Poland)
[**] This work was supported by the CNRS, France and KBN :Poland,
Grant No 3T09A03619). V.C. thanks the Spanish Ministerio de
Educacion y Cultura for postdoctoral fellowship.
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/angewandte/ or from the author.
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