A novel, highly enantioselective ketone alkynylation reaction mediated by chiral zinc aminoalkoxides

Article abstract of DOI:10.1002/(SICI)1521-3773(19990301)38:5<711::AID-ANIE711>3.0.CO;2-W

Kilogram-scale synthesis of the HIV reverse transcriptase inhibitor efavirenz was achieved by means of a highly enantioselective alkynylation of prochiral ketones 1 with alkynyllithium or alkynylmagnesium reagents in the presence of chiral zinc aminoalkoxides as mediators. With the achiral auxiliary 2,2,2-trifluoroethanol (R³=CF₃CH₂), the efavirenz precursor 2 (R¹ =H, R²=cyclopropyl) was obtained with an ee of 99.2%.

Full text of DOI:10.1002/(SICI)1521-3773(19990301)38:5<711::AID-ANIE711>3.0.CO;2-W

COMMUNICATIONS
Walsh, J. Biol. Chem. 1989, 264, 13880 ± 13887; d) the DNA sequence
slightly effects the binding (K ) of photolyases to a DNA ± DNA
double strand: D. L. Svoboda, C. A. Smith, J.-S. Taylor, A. Sancar, J.
Biol. Chem. 1993, 258, 10694 ± 10700.
selective, and practical alkynylation (up to 99.2% ee) of a
prochiral ketone by alkynyllithium and alkynylmagnesium
reagents with mediation by chiral zinc aminoalkoxides.
Efavirenz is a potent nonnucleosidal HIV reverse tran-
scriptase inhibitor which has just been approved by the US
d
[
13] a) K. B. Hall, L. W. McLaughlin, Biochemistry 1991, 30, 10606 ±
10613; b) L. Ratmeyer, R. Vinayak, Y. Y. Zhong, G. Zon, W. D.
Wilson, Biochemistry 1994, 33, 5298 ± 5304; c) J. I. Gyi, G. L. Conn,
A. N. Lane, T. Brown, Biochemistry 1996, 35, 12538 ± 12548.
[4]
FDA for treatment of AIDS. The importance of this
compound prompted us to seek an efficient and scaleable
synthesis that would allow the installation of the quaternary
carbon atom with absolute stereocontrol. A recently reported
asymmetric synthesis of this compound is based on a highly
enantioselective addition of lithium cyclopropylacetylide to
the PMB-protected ketoaniline 2 (Scheme 1).[ The reactive
[
[
14] L. A. Marky, K. J. Breslauer, Biopolymers 1987, 26, 1601 ± 1620.
15] a) F. N. Hayes, D. L. Williams, R. L. Ratliff, A. J. Varghese, C. S.
Rupert, J. Am. Chem. Soc. 1971, 93, 4940 ± 4942; b) F. Barone, A.
Bonincontro, F. Mazzei, A. Minoprio, F. Pedone, Photochem. Photo-
biol. 1995, 61, 61 ± 67; c) J.-S. Taylor, D. S. Garrett, I. R. Brockie, D. L.
Svoboda, J. Telser, Biochemistry 1990, 29, 8858 ± 8866.
16] a) J. Kemmink, R. Boelens, T. Koning, G. A. van der Marel, J. H.
van Boom, R. Kaptein, Nucleic Acids Res. 1987, 15, 4645 ± 4653; b) J.
Kemmink, R. Boehlens, T. M. G. Koning, R. Kaptein, G. A. van der
Marel, J. H. van Boom, Eur. J. Biochemistry 1987, 162, 37 ± 43; c) J.-K.
Kim, D. Patel, B.-S. Choi, Photochem. Photobiol. 1995, 62, 44 ± 50.
17] a) T. I. Spector, T. E. Cheatham III, P. A. Kollman, J. Am. Chem. Soc.
5]
[
O
Cl
F3C
CF3
NHR
1 R = H
R = PMB
Li
Cl
OH
NHR
[
LiO
Ph
1997, 119, 7095 ± 7104; b) M. G. Cooney, J. H. Miller, Nucleic Acids
N
Res. 1997, 25, 1432 ± 1436; c) H. Yamaguchi, D. M. F. van Aalten, M.
Pinak, A. Furukawa, R. Osman, Nucleic Acids Res. 1998, 26, 1939 ±
3 R = PMB
Me
2
4 R = H
1946; d) K. Miaskiewicz, J. Miller, M. Cooney, R. Osman, J. Am.
Chem. Soc. 1996, 118, 9156 ± 9163.
[
[
18] All thermodynamic experiments were performed in Tris/HCl buffer.
DG is reported at 158C. This allows the thermodynamic data to be
compared more directly with the enzymatic repair kinetics, which
were performed in a phosphate buffer (pH 7.0) at 158C.
19] For X-ray structures see: a) H.-W. Park, S.-T. Kim, A. Sancar, J.
Deisenhofer, Science 1995, 268, 1866 ± 1872; b) T. Tamada, K.
Kitadokoro, Y. Higuchi, K. Inaka, A. Yasui, P. E. de Ruiter, A. P. M.
Eker, K. Miki, Nature Struct. Biol. 1997, 11, 887 ± 891.
F3C
Cl
O
N
O
H
Efavirenz
Scheme 1. Synthesis of efavirenz. PMB ˆ p-methoxybenzyl.
species responsible for the strong chiral induction in this
6
reaction was well characterized on the basis of Li NMR
data.[ The chiral addition step, which proceeds with greater
than 98% ee, requires the use of 2.2 equivalents of lithium
cyclopropylacetylide, 2.2 equivalents of (1R,2S)-N-pyrrolidi-
nylnorephedrine alkoxide as chiral controller, and low
temperatures (� 608C). In addition, the success of the
reaction relies on the protection of the aniline moiety, and
this makes a protection/deprotection step necessary. The most
straightforward and efficient asymmetric synthesis of efavir-
enz would involve the direct enantioselective alkynylation of
the unprotected ketoaniline 1[ to afford amino alcohol 4.
Addition of lithium cyclopropylacetylide to 1 by the reported
method,[ however, suffered from low conversion and low
enantioselectivity. Furthermore, the strongly basic conditions
eventually led to decomposition of the product.
6]
A Novel, Highly Enantioselective Ketone
Alkynylation Reaction Mediated by Chiral
Zinc Aminoalkoxides
Lushi Tan,* Cheng-yi Chen, Richard D. Tillyer,
Edward J. J. Grabowski, and Paul J. Reider
Stereocontrolled nucleophilic addition to carbonyl com-
pounds is an important synthetic method. While the enantio-
selective alkylation of carbonyl compounds has been widely
5]
[
1]
studied, nucleophilic alkynylation has enjoyed only very
limited success. A few examples of enantioselective alkyny-
lation of aldehydes by organometallic compounds in combi-
nation with chiral modifiers have been reported.[2, 3] For
example, Soai and Niwa showed that the addition of
dialkynylzinc and alkylalkynylzinc reagents to benzaldehyde
in the presence of amino alcohols provides propargyl alcohols
5]
We reasoned that the inefficiency of the reaction between
lithium cyclopropylacetylide and 1 is due to the strong basicity
of the lithium reagent, which deprotonates the aniline group.
It was proposed that complexation of a zinc alkoxide
[
2c]
with an ee of less than 50%. Recently, Corey and Cimprich
reported the addition of alkynylboranes to aldehydes with
promotion by substoichiometric quantities of proline-derived
oxazaborolidines to give propargyl alcohols with up to 97% ee
Zn(OR) with the lithium acetylide would lower the basicity
2
while maintaining the nucleophilicity of the acetylide. In
addition, a chiral alkoxide could serve as a mediator for
asymmetric induction. This conceptually simple approach
proved to be highly effective for the asymmetric alkynylation
of the unprotected ketoaniline 1. The reaction of dimethylzinc
[
3]
at low temperature. We report here a novel, highly enantio-
[
*] Dr. L. Tan, C. Chen, R. D. Tillyer, E. J. J. Grabowski, P. J. Reider
Department of Process Research
Merck Research Laboratories
with one equivalent of (1R,2S)-N-pyrrolidinylnorephedrine
[7]
(
5) followed by one equivalent of methanol generated the
P.O. Box 2000, RY80E-108
[8a]
chiral zinc alkoxide 6 (Scheme 2).
The zinc reagent 6 was
Rahway, New Jersey 07065 (USA)
Fax: (‡1)732-594-8360
then treated with lithium cyclopropylacetylide, which pre-
sumably generates the zincate 7.[ Reaction of 7 with 1
8]
E-mail: lushi_tan@merck.com
Angew. Chem. Int. Ed. 1999, 38, No. 5
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Table 2. Effect of the achiral auxiliary (HX) on the selectivity.[a]
O
F3C
Cl
Cl
MgCl
Zn(OR)X
CF3
NH2
OH
NH2
1
4
Entry
Auxiliary
ee of 4 [%]
1
2
3
4
5
6
7
8
9
CH
CH
(CH
CH
3
OH
CH
CCH
ˆCHCH
PhCH OH
87.0
55.0
95.6
90.0
89.0
95.7
89.4
71.6
89.0
3
2
OH
3
)
3
2
OH
OH
Scheme 2. Preparation of the zinc complex and its reaction with ketone 1.
2
2
2
CF
CF
3
CH
CO
2
OH
H
(
8
toluene/THF,258C, 7 h) afforded the amino alcohol 4 with
3
2
3% yield of isolated product and 83% ee.[9] This result
(CH ) CCO H
4-NO PhOH
2
3
3
2
prompted a systematic study of the reaction to improve the
enantioselectivity and yield.
[a] All reactions were carried out at 258C in THF/toluene with 1 equivalent
each of chiral auxiliary, methanol, dimethylzinc, and cyclopropylacetylide,
and 0.83 equivalents of 1.
As anticipated, the chiral auxiliary has a dramatic influence
on the enantioselectivity. Other chiral auxiliaries such as
cinchona alkaloids, binaphthol, and tartaric acid derivatives
gave very poor selectivity. The initial success with (1R,2S)-N-
pyrrolidinylnorephedrine as chiral auxiliary led us to focus
our attention on norephedrine derivatives for improving the
selectivity (Table 1). (1R,2S)-Ephedrine and (1R,2S)-nor-
ephedrine gave only moderate selectivities (entries 1 and 2),
might exert a steric effect on the stereoselectivity. However,
the increase in enantioselectivity from 55% to about 96%
when 2,2,2-trifluoroethanol was used instead of ethanol
indicates a possible significant inductive effect. Good enan-
tioselectivities were also obtained with carboxylic acids and
phenols as auxiliaries.
Further optimization of this reaction was carried out with
neopentyl alcohol or 2,2,2-trifluoroethanol as achiral auxil-
iary. We found that dimethyl- and diethylzinc were equally
effective, and the chiral zinc reagent could be prepared by
mixing the chiral auxiliary, the achiral auxiliary and the
dialkylzinc reagent in any order without affecting the
conversion and selectivity of the reaction. However, the ratio
of chiral to achiral additive does affect the efficiency of the
reaction. The enantioselectivity increased to 97.5% when
Table 1. Effect of the chiral auxiliary and the countercation on the
selectivity.[
a]
O
F3C
Cl
M
Cl
CF3
NH2
OH
NH2
Zn(OR)OCH3
1
4
Entry M
Ephedrine auxiliary (OR)
ee of 4 [%]
1
2
3
4
5
6
7
Li
Li
Li
Li
MgCl
MgBr
MgI
(1R,2S)-ephedrine
(1R,2S)-norephedrine
(1R,2S)-N-methylephedrine
(1R,2S)-N-pyrrolidinylnorephedrine
(1R,2S)-N-pyrrolidinylnorephedrine
(1R,2S)-N-pyrrolidinylnorephedrine
(1R,2S)-N-pyrrolidinylnorephedrine
28.2
41.6
81.0
83.0
87.0
53.6
50.6
1.2 equivalents of (1R,2S)-N-pyrrolidinylnorephedrine and
0
.8 equivalents of neopentyl alcohol were used to prepare
the zinc alkoxide (Table 3). Further increase in the ratio of
chiral to achiral auxiliary did not lead to significant improve-
ment in stereoselectivity. For instance, the zinc alkoxide
derived from two equivalents of (1R,2S)-N-pyrrolidinylnor-
ephedrine gave 4 with 95.8% ee but only 50% conversion.
Similar results were obtained with 2,2,2-trifluoroethanol. The
enantioselectivity was only slightly dependent on the reaction
temperature. Reactions with the zinc alkoxide derived from
(1R,2S)-N-pyrrolidinylnorephedrine and 2,2,2-trifluoroetha-
nol gave 4 with 99.2% ee at 08C and 94.0% ee at 408C.
[
a] All reactions were carried out at 258C in THF/toluene with 1 equivalent
each of chiral auxiliary, methanol, dimethylzinc, and cyclopropylacetylide,
and 0.83 equivalents of 1.
and the best results were obtained with (1R,2S)-N-pyrrolidi-
nylnorephedrine and (1R,2S)-N-methylephedrine (entries 3
and 4). The countercation also had a significant effect on the
enantioselectivity. For example, with the chloromagnesium
acetylide, 4 was obtained with 87% ee (entry 5), but only
about 50% ee was obtained with the bromo- and iodomagne-
sium acetylides.
Interestingly, variation of the achiral additive has a
profound influence on the enantioselectivity of the alkynyla-
tion reaction (Table 2). At 258C with complexes derived from
Table 3. Effect of the amount of chiral auxiliary on the selectivity.[a]
Entry
Equiv of chiral auxiliary[b]
ee of 4 [%]
1
2
3
4
5
6
0.8
1
1.1
1.2
1.5
2
58.8
95.6
95.8
97.5
97.7
95.8
(1R,2S)-N-pyrrolidinylnorephedrine and chloromagnesium
cyclopropylacetylide, the use of ethanol as achiral auxiliary
gave 4 with 55% ee (entry 2), while neopentyl alcohol
[
a] All reactions were carried out at 258C in THF/toluene with neopentyl
alcohol as the achiral auxiliary, (1R,2S)-N-pyrrolidinylnorephedrine as the
chiral auxiliary, and (CH
ZnMe
(entry 3) and methanol (entry 1) gave 96 and 87% ee,
ꢀ
2
)
2
CHC CMgCl as the nucleophile. [b] Relative to
respectively. These results suggested that the achiral alcohol
2
.
7
12
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COMMUNICATIONS
The scope of this new alkynylation reaction was briefly
examined. The reaction is applicable to other acetylenes such
as 5-chloropentyne and 2-methyl-1-buten-3-yne, which gave
Keywords: alkynylations
nucleophilic additions ´ zinc
´ amino alcohols ´ ketones ´
[
11]
[12]
8
and 9 in high yield and enantioselectivity. The presence
of the unprotected amino group in the ketoaniline seems to be
important for the efficiency of the reaction. Under similar
conditions only 45% ee was obtained with the PMB-protected
ketoaniline 2, and essentially no reaction was observed when
the nitrogen center was protected with a bulky group such as
trityl. Interestingly, alkynylation of 1-{1-amino-4-(2,2,2-tri-
fluoroacetyl)naphth-2-yl}-2,2,2-trifluoroethan-1-one under the
same conditions resulted in exclusive addition at the carbonyl
group flanking the aniline moiety and provided 10 in 91%
yield with 97% ee. This result clearly demonstrates that the
presence of an unprotected aniline group ajacent to the
carbonyl group in the substrate is important for the reactivity
[1] a) R. Noyori, M. Kitamura, Angew. Chem. 1991, 103, 34 ± 55; Angew.
Chem. Int. Ed. Engl. 1991, 30, 49 ± 69; b) K. Soai, S. Niwa, Chem. Rev.
1
8
992, 92, 833 ± 856; c) R. O. Duthaler, A. Hafner, Chem. Rev. 1992, 92,
07 ± 832; d) D. A. Evans, Science 1989, 240, 420; e) T. Shibata, H.
Morioka, T. Hayase, K. Choji, K. Soai, J. Am. Chem. Soc. 1996, 118,
471 ± 472, and references therein.
[2] a) T. Mukaiyama, K. Suzuki, K. Soai, T. Sato, Chem. Lett. 1979,
4
47 ± 448; b) T. Mukaiyama, K. Suzuki, Chem. Lett. 1980, 255 ± 256;
c) S. Niwa, K. Soai, J. Chem. Soc. Perkin Trans. 1 1990, 937 ± 943;
d) G. M. R. Tombo, E. Didier, B. Loubinoux, Synlett 1990, 547 ± 548;
e) M. Ishizaki, O. Hoshino, Tetrahedron: Asymmetry 1994, 5, 1901 ±
1904.
[
13]
[
[
3] E. J. Corey, K. A. Cimprich, J. Am. Chem. Soc. 1994, 116, 3151 ± 3152.
4] a) S. D. Young, S. F. Britcher, L. O. Tran, L. S. Payne, W. C. Lumma,
T. A. Lyle, J. R. Huff, P. S. Anderson, D. B. Olsen, S. S. Carrol, D. J.
Pettibone, J. A. OꢁBrien, R. G. Ball, S. K. Balani, J. H. Lin, I.-W. Chen,
W. A. Schleif, V. V. Sardana, W. J. Long, V. W. Byrnes, E. A. Emini,
Antimicrob. Agents Chemother. 1995, 39, 2602; b) D. Mayers, S.
Riddler, M. Bach, D. Stein, M. D. Havlir, J. Kahn, N. Ruiz, D. F.
Labriola, and the DMP-266 clinical development team, Clinical data
presented at the ICAAC meeting (Toronto) 1997, I-175, Durable
Clinical Anti-HIV-1 Activity and Tolerability for DMP-266 in
Combination with Indinavir (IDV) at 24 Weeks.
(and probably selectivity).
H2N F C
3
3Cl
F3C
F3C
OH
Cl
Cl
OH
NH2
(93%, 95.2% ee)
OH
NH2
9 (94%, 97.0% ee)
O
CF3
[
[
5] A. S. Thompson, E. G. Corley, M. F. Huntington, E. J. J. Grabowski,
Tetrahedron Lett. 1995, 36, 8937 ± 8940.
6] a) A. S. Thompson, E. G. Corley, M. F. Huntington, E. J. J. Grabowski,
J. F. Remenar, D. B. Collum, J. Am. Chem. Soc. 1998, 120, 2028 ± 2038;
b) Feng Xu (Merck), personal communication.
8
10 (91%, 97.0% ee)
We have developed a novel, highly efficient, and practical
asymmetric alkynylation of the ketoaniline 1. The reaction has
been carried out successfully and reliably on a multi-kilogram
scale and is now the cornerstone of the most efficient synthesis
[7] D. Zhao, C.-Y. Chen, F. Xu, L. Tan, R. D. Tillyer, M. E. Pierce, J. R.
Moore, Org. Synth., submitted.
[
5]
[8] a) A similar species has been reported: D. Enders, J. Zhu, G. Raabe,
Angew. Chem. 1996, 108, 1827; Angew. Chem. Int. Ed. Engl. 1996, 35,
of efavirenz to date. The degreee of stereocontrol with a
chiral zinc aminoalkoxide is remarkable. The reaction mech-
anism and extension of the method to other carbonyl
compounds are currently under investigation.
1
13
1
725Ð1728; b) Preliminary H and C NMR studies of the solution
showed a very complicated system. The observed chiral amplification
supported the formation of dimer or higher order aggregates: the
enantiomeric excess of the product was 97.5, 94.4, and 79.6%,
respectively, when (1R,2S)-N-pyrrolidinylnorephedrine with 100, 80,
and 50% ee was used for the reaction at room temperature.
Experimental Section
[9] The enantiomeric excess was determined by HPLC assay on a
chiralcel-AD column (hexane/isopropyl alcohol, 3/1)
[10] Trifluoroethanol is preferred to neopentyl alcohol because it gives a
faster reaction.
In a typical experiment, THF (240 mL, dried over molecular sieves), 2,2,2-
trifluoroethanol[10] (19.2 g, 0.19 mol), and (1R,2S)-N-pyrrolidinylnorephe-
drine (59.1 g, 0.29 mol) were mixed under nitrogen. The mixture was
cooled to 08C, and diethylzinc (1.1m in toluene, 218 mL, 0.24 mol) was
added slowly enough to keep the temperature below 308C. A solution of
chloromagnesium cyclopropylacetylide was prepared by reaction of cyclo-
propylacetylene (15.9 g, 0.24 mol) and n-butylmagnesium chloride (2.0m in
THF, 120 mL, 0.24 mol) at 08C for 1 h. The solution was then transferred to
the zinc reagent by cannula with THF (100 mL) as a wash. The mixture was
cooled to 08C, and 1 (44.7 g, 0.20 mol) was added. The reaction mixture was
quenched with 1m citric acid (400 mL) after 15 h. The two layers were
separated. The aqueous layer was saved for recovery of (1R,2S)-N-
pyrrolidinylnorephedrine. The organic layer (assay of this solution
[
11] 1H NMR (CDCl
3
, 300 MHz): d ˆ 7.53 (d, J ˆ 2.4 Hz, 1H), 7.12 (dd, J ˆ
.4, 8.7 Hz, 1H), 6.62 (d, J ˆ8.7 Hz, 1H), 4.68 (brs, 3H), 3.69 (m, 2H),
.57 (m, 2H), and 2.06 (m, 2H); 13C NMR (CDCl
, 75.5 MHz): d ˆ
43.18, 130.37, 130.28, 130.21, 125.60(q), 122.16, 121.09, 88.49, 76.65
2
2
1
3
(
q), 74.74, 43.42, 30.62, 16.18; elemental analysis calcd for
C
13
H
12NOCl
N 4.15.
12] 1H NMR (CD
2
F
3
(%): C 47.88, H 3.71, N 4.29; found: C 48.14, H 3.39,
[
[
3
CN, 300 MHz): d ˆ 7.47 (d, J ˆ 2.4 Hz, 1H), 7.11 (dd,
J ˆ 2.4, 8.7 Hz, 1H), 6.66 (d, J ˆ8.7 Hz, 1H), 5.48 (m, 2H), 5.00 (brs,
3
H), 1.95 (m, 3H); 13C NMR (CD
130.39, 126.32, 125.54, 125.40(q), 121.27, 120.04, 119.06, 90.75, 84.02,
3
CN, 75.5 MHz): d ˆ 147.19, 131.09,
indicated 99.2% ee[9]) was washed with water (200 mL) and concentrated
7
5
5.08 (q), 22.94; elemental analysis calcd for C13 11NOClF (%): C
H
3
to about 180 mL. Toluene (100 mL) was added and the solution was again
concentrated to about 180 mL to remove all THF. Heptane (240 mL) was
added slowly. The mixture was cooled to 08C, and the solid was collected by
filtration, washed with heptane (ca. 50 mL), and dried to give 55.2 g (95.3%
3.80, H 3.77, N 4.72; found: C 53.67, H 3.80, N 4.67.
CN, 400 MHz): d ˆ 9.29 (d, J ˆ 9.2 Hz, 1H), 8.60 (brs,
13] 1H NMR (CD
3
1
H), 7.85 (d, J ˆ 8.7 Hz, 1H), 7.69 (dd, J ˆ 9.0, 9.2 Hz, 1H), 7.59 (dd,
J ˆ 8.7, 9.0 Hz, 1H), 6.35 (brs, 2H), 3.40 (brs, 1H), 1.41 (m, 1H), 0.90
yield, 99.2% ee) of analytically pure 4 as a white solid. M.p. 139 ± 1418C;
(m, 4H); 13C NMR (CDCl , 100.6 MHz): d ˆ 179.0 (q), 150.4, 138.9,
1
H NMR (CDCl
3
, 300 MHz): d ˆ 7.52 (d, J ˆ 2.4 Hz, 1H), 7.12 (dd, J ˆ 2.4,
3
1
33.5, 130.5, 126.5, 126.4, 125.3 (q), 123.2, 122.5 (q), 120.8, 113.5, 108.3,
8
1
1
.7 Hz, 1H), 6.61 (d, J ˆ8.7 Hz, 1H), 4.70 (s, 1H), 4.39 (s, 2H), 1.39 (m,
13
95.4, 76.5 (q), 70.1, 8.5, 8.4, � 0.8; elemental analysis calcd for
H), 0.85 (m, 4H); C NMR (CDCl
3
, 75.5 MHz): d ˆ 143.21, 130.44,
C
19
H
13
F
6
NO (%): C 56.87, H 3.27, N 3.49; found: C 56.99, H 2.98, N
2
30.04, 123.94, 123.93 (q), 121.11, 120.81, 93.51, 74.80 (q), 70.58, 8.59, � 0.85;
3
.42.
elemental analysis calcd for C13
3
H11NOClF (%): C 53.80, H 3.77, N 4.72;
found: C 53.71, H 3.75, N 4.64.
Received: September 28, 1998 [Z12462IE]
German version: Angew. Chem. 1999, 111, 724 ± 727
Angew. Chem. Int. Ed. 1999, 38, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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713