COMMUNICATIONS
0
.33 mmol). After the mixture had been stirred for 30 min at room
hyde catalyzed by N,N-diethylnorephedrine resulted in phenyl trans-
fer with 20:1 selectivity to give 3-phenylpyridylmethanol in 70% ee,
while the addition of ZnPh only afforded the product alcohol in
2
temperature, ferrocene 3 (12mg, 0.025 mmol) was added, and the resulting
solution was then cooled to 108C. Stirring was continued for an additional
1
0 min at this temperature, and the aldehyde (0.25 mmol) was then added
73% ee; J. Blacker in Third International Conference on the Scale Up
of Chemical Processes (Conference Proceedings) (Ed.: T. Laird),
Scientific Update, UK, 1998, p. 74.
directly in one portion. The Schlenk flask was sealed, and the reaction
mixture was stirred at 108C overnight. Quenching with water followed by
extracting with dichloromethane, drying of the combined organic phase
[13] In this study only isolated diphenylzinc (purchased from Strem) was
used. For the preparation of other salt-free diarylzinc compounds and
their subsequent catalyzed asymmetric addition to aldehydes, see:
A. J. Blacker, J. M. Fielden (Zeneca), WO 98/28306, 1998.
[14] We presume that ethylphenylzinc is formed in an equilibrium with
diethylzinc and diphenylzinc. Apparently, the ethyl group then
behaves as a nontransferable moiety on zinc, while phenyl is trans-
ferred to the aldehyde with complete selectivity (no ethyl addition
4
over MgSO , and evaporating the solvent under reduced pressure gave the
crude product. Column chromatography (silica gel; eluents: hexanes/
diethyl ether) afforded the pure secondary alcohol (for ee analyses by
HPLC see Supporting Information).
Received: May 29, 2000 [Z15183]
[
1] For examples see: a) K. Meguro, M. Aizawa, T. Sohda, Y. Kawamatsu,
A. Nagaoka, Chem. Pharm. Bull. 1985, 33, 3787; b) F. Toda, K.
Tanaka, K. Koshiro, Tetrahedron: Asymmetry 1991, 2, 873; c) M.
Botta, V. Summa, F. Corelli, G. Di Pietro, P. Lombardi, Tetrahedron:
Asymmetry 1996, 7, 1263; d) S. Stanchev, R. Rakovska, N. Berova, G.
Snatzke, Tetrahedron: Asymmetry 1995, 6, 183.
product was found). In order to reveal the nature of the zinc species,
1
we used low-temperature H NMR techniques. In a mixture of ZnEt
2
and ZnPh
was observed at almost the same position as the ones of ZnEt
(Dd(CH
and phenyl group protons were detected belonging to a new, albeit not
yet identified species. Further studies are in progress to characterize
the most relevant intermediates in this catalysis.
2 8
(2:1 ratio) in [D ]toluene only one set of ethyl group signals
2
2
) 0.03 ppm). In [D ]THF at À808C additional sets of ethyl
8
[
2] a) E. J. Corey, C. J. Helal, Tetrahedron Lett. 1995, 36, 9153; b) E. J.
Corey, C. J. Helal, Tetrahedron Lett. 1996, 37, 4837; c) E. J. Corey, C. J.
Helal, Tetrahedron Lett. 1996, 37, 5675; d) general review: E. J. Corey,
C. J. Helal, Angew. Chem. 1998, 110, 2092; Angew. Chem. Int. Ed.
[15] a) C. van der Stelt, W. J. Heus, W. T. Nauta, Arzneim. Forsch. 1969, 19,
2010; b) R. F. Rekker, H. Timmerman, A. F. Harms, W. T. Nauta,
Arzneim. Forsch. 1971, 21, 688; c) A. F. Casy, A. F. Drake, C. R.
Ganellin, A. D. Mercer, C. Upton, Chirality 1992, 4, 356.
1
998, 37, 1986.
[
3] a) T. Ohkuma, M. Koizumi, H. Ikehira, T. Yokozawa, R. Noyori, Org.
Lett. 2000, 2, 659; b) general review: R. Noyori, T. Ohkuma, Pure
Appl. Chem. 1999, 71, 1493.
[
4] For catalyses of this type involving metals other than zinc, see: a) Ti:
B. Weber, D. Seebach, Tetrahedron 1994, 50, 7473; b) Rh/B: M. Sakai,
M. Ueda, N. Miyaura, Angew. Chem. 1998, 110, 3475; Angew. Chem.
Int. Ed. 1998, 37, 3475. For early studies of enantioselective versions
involving stoichiometric amounts or excess of organometallic re-
agents, see: c) D. Seebach, A. K. Beck, S. Roggo, A. Wonnacott,
Chem. Ber. 1985, 118, 3673; d) R. Noyori, S. Suga, K. Kawai, S. Okada,
M. Kitamura, Pure Appl. Chem. 1988, 60, 1597; e) K. Tomioka, M.
Nakajima, K. Koga, Chem. Lett. 1987, 65; f) M. Kaino, K. Ishihara, H.
Yamamoto, Bull. Chem. Soc. Jpn. 1989, 62, 3736; g) J.-T. Wang, X. Fan,
X. Feng, Y.-M. Qian, Synthesis 1989, 291; h) M. Nakajima, K.
Tomioka, K. Koga, Tetrahedron 1993, 49, 9751.
A Synthetic Azinomycin Analogue with
Demonstrated DNA Cross-Linking Activity:
Insights into the Mechanism of Action of this
Class of Antitumor Agent**
John A. Hartley,* Ali Hazrati, Lloyd R. Kelland,*
Ruzwana Khanim, Michael Shipman,* Franck Suzenet,
and Louise F. Walker
[
5] Reviews on diorganozinc additions to aldehydes: a) R. Noyori, M.
Kitamura, Angew. Chem. 1991, 103, 34; Angew. Chem. Int. Ed. Engl.
1
991, 30, 49; b) K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833; c) K. Soai,
Chemical agents capable of inducing DNA interstrand
cross-links (ISCs) comprise an extremely important class of
clinical cancer chemotherapeutic agents.[ The azinomycins (1
T. Shibata in Comprehensive Asymmetric Catalysis, Vol. 2 (Eds.: E. N.
Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, p. 911.
6] a) K. Soai, Y. Kawase, A. Oshio, J. Chem. Soc. Perkin Trans. 1 1991,
2]
[
1
613; b) for a diastereoselective version, see: J. Hübscher, R. Barner,
Helv. Chim. Acta 1990, 73, 1068.
7] a) P. I. Dosa, J. C. Ruble, G. C. Fu, J. Org. Chem. 1997, 62, 444; b) for a
[
*] Prof. J. A. Hartley, A. Hazrati, R. Khanim
CRC Drug-DNA Interactions Research Group
Department of Oncology
Royal Free & University College Medical School
University College London
[
3
-exo-(dimethylamino)isoborneol (DAIB)-catalyzed asymmetric ad-
dition of ZnPh to ketones, see: P. I. Dosa, G. C. Fu, J. Am. Chem. Soc.
998, 120, 445.
2
1
[
[
8] a) W.-S. Huang, L. Pu, J. Org. Chem. 1999, 64, 4222; b) W.-S. Huang,
Q.-S. Hu, L. Pu, J. Org. Chem. 1999, 64, 7940; c) W.-S. Huang, L. Pu,
Tetrahedron Lett. 2000, 41, 145.
9
1 Riding House Street, London W1P 8BT (UK)
Fax : (44)20-7436-2956
E-mail: john.hartley@ucl.ac.uk
9] C. Bolm, K. Mu nÄ iz, Chem. Commun. 1999, 1295.
Dr. L. R. Kelland
[
10] For the use of ferrocene 3 in dialkylzinc additions, see: a) C. Bolm, K.
Mu nÄ iz-Fern a ndez, A. Seger, G. Raabe, Synlett 1997, 1051; b) C. Bolm,
K. Mu nÄ iz Fern a ndez, A. Seger, G. Raabe, K. Günther, J. Org. Chem.
CRC Centre for Cancer Therapeutics
Institute of Cancer Research
Sutton, Surrey, SM2 2N G (UK)
Fax : (44)181-7224101
1
998, 63, 7860; c) C. Bolm, K. Mu nÄ iz, J. P. Hildebrand, Org. Lett. 1999,
1, 491.
E-mail: lloyd@icr.ac.uk
[
11] For selected reports on other mixed zinc species, see: a) H. Nehl,
W. R. Scheidt, J. Organomet. Chem. 1985, 289, 1; b) W. Oppolzer,
R. N. Radinov, Helv. Chim. Acta 1992, 75, 170; c) S. Berger, F. Langer,
C. Lutz, P. Knochel, T. A. Mobley, C. K. Reddy, Angew. Chem. 1997,
Dr. M. Shipman, Dr. F. Suzenet, Dr. L. F. Walker
School of Chemistry
University of Exeter
Stocker Road, Exeter, EX4 4QD (UK)
Fax : (44)1392-263434
1
09, 1603; Angew. Chem. Int. Ed. Engl. 1997, 36, 1454; d) C. Lutz, P.
Knochel, J. Org. Chem. 1997, 62, 7895; e) P. Wipf, S. Ribe, J. Org.
Chem. 1998, 63, 6454; f) L. Tan, C. y. Chen, R. D. Tillyer, E. J. J.
Grabowski, P. J. Reider, Angew. Chem. 1999, 111, 72 4;Angew. Chem.
Int. Ed. 1999, 38, 711.
E-mail: m.shipman@exeter.ac.uk
[**] The authors gratefully acknowledge the financial support provided by
the CRC and the EPSRC. We are indebted to the EPSRC National
Mass Spectrometry Centre for performing mass spectral measure-
ments, and the EPSRC Chemical Database Service at Daresbury.[
[
12] An example of the use of a combination of ZnPh
2 2
and ZnMe in this
1]
reaction has been described before: Phenyl transfer to nicotinalde-
Angew. Chem. Int. Ed. 2000, 39, No. 19
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