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Book Review Anthracycline- and Anthracenedione-Based Anticancer Agents. Edited by J. W. Lown

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All the imines used (aside from 3) consist of a mixture of
syn- and anti-isomers; in the case of the imine 1a the antilsyn
ratio is 5: 1 (‘H-NMR measurements). Since both the equilibrium syn-isomer + anti-isomer as well as the equilibrium
imine F? enamine proceed more rapidly than the hydrogenation (‘H-NMR measurements, H/D exchange with [DJmethanol) we conclude that the antilsyn ratio is not selectivity-determining. More detailed investigations on the elucidation of the reaction mechanism are currently under way.
All operations were carried out under argon. A solution of [Ir(cod)C1I1
(134.4 mg, 0.2 mmol) in 10 mL of a 1:1 solvent mixture of benzene and methanol was treated with 219.7 mg (0.44 mmol) of (2s. 3S)-DIOP and. after 15 min,
with 295.8 mg (0.8 mmol) oftetrabutylammonium iodide; the mixture was then
stirred for a further 15min. A separate solution of the imine l a (7.65g,
40 mmol) in methanol ( 5 mL)/benzene ( 5 mL) was now prepared. The imine
solution and catalyst solution were successivelytransferred via a steel capillary
into a 50 mL steel autoclave under an inert atmosphere. The inert gas was
replaced in the autoclave by hydrogen in three cycles (20 barinorma1 pressure).
Finally 20 bar of hydrogen were compressed into the autoclave. After completion of reaction the conversion was determined gas chromatographically and
the product distilled under high vacuum. After flash chromatographic purification of the crude product 2 a (silica gel, hexane/ethyl acetate 1 :I), the optical
yield was determined by polarimetry[l4] and ‘H-NMR spectroscopy(l51.
Received: October 14. 1989;
revised: February 14, 1990 [Z 3581 IE]
German version: Angew. Chem. 102 (1990) 561
CAS Registry numbers.
la , 85385-06-4; 1 b. 118604-68-5; (R)-Za, 118604-66-3; (.S-Za, 11860467-4;
(S)-Zb, 118604-70-9; [Ir(COD)Cl],. 12112-67-3; [Ir(COD),]BF,. 35138-23-9;
(2S.3.S-chiraphos. 64896-28-2; (2R, 3R)-norphos, 71042-54-1 ; (2S, 3S)-diop,
37002-48-5; ( S ,4S)-bppm, 61478-28-2; (2s. 4S)-bdpp. 77876-39-2.
[I] Review article: a) R. Noyori, M. Kitamura in R. Scheffold (Ed.): Modern
$rnthetic Methods, Vol. 5, Springer, Berlin 1989, pp. 115-198; b) K.
Koenig in J. Morrison (Ed.): AsymmefricSynthesis, Yo/ 5. Academic Press,
New York 1985. pp. 71 - 101; c) L. H. Pignolet (Ed.): Homogeneous Curufpsis with Metul Phosphine Compfexes, Plenum Press, New York 1983;
d) J. M. Brown. P. A. Chaloner in [l c], pp. 137-165; e) B. Heil, L. Marko.
S. Toros in [I c], pp. 317-341.
[2] a) M. Kitamura, T. Ohkuma, S . Inoue. N. Sayo, H. Kumobayashi, S.
Akutagawa, T. Ohta, H. Takaya, R. Noyori, J Am. Chem. Soc. f 10 (1988)
629-631; b) T Hayashi, N. Kawamura, Y Ito. Tetrahedron Lett. 29(1988)
5969-5972; c)A. Chan, C. Landis. J. Mol. Curul. 49 (1989) 165-173.
[3] a) K. Harada in S. Patai (Ed.): The Chemistry of Ihe Curhon-Nitrogen
Double Bond, Intersience, London 1970. pp. 276-293; b) P. Rylander:
CafulyrkHydrogenation over Platinum Meruls, Academic Press, New York
1967, pp. 123-138; c)K. Yamada, M. Takeda, T lwakuma. Trtruhrdron
Lett. 22 (1981) 3869-3872.
[4] a) J. Bakos, I. Toth, B. Heil, L. Marko, J. Orgunometul. Chem. 279 (1985)
23-29; b) S. Vastag, J. Bakos, S. Toros, N. E. Takach, R. B. King. B. Heil.
L. Marko, J. Mol. Curd 22 (1983) 283-287; c)S. Vastag. B. Heil, S.
Toros, L. Marko, Transition M e t . Chem. (Weinheim, Ger.) 2 (1977) 5859; d) J. Bakos, 1. Toth, B. Heil, G. Szalaontai, L. ParkPnyi. V. Fiilop, J
Orgunometul. Chem. 370 (1989) 263-76.
[5] G. Kang. W. R. Cullen, M. D. Fryzuk. B. R. James, J. P. Kutney, J Chem.
Soc. Chem. Commun. 1988. 1466- 1467.
[6] H. Moser. G. Rihs, H. Sauter, 2. Nuturforsch. B 37 (1982) 451 -462.
17) F. Spindler. B. Pugin, EP-A-0256982 (1988), Ciba-Geigy AG.
[8] 2.2-Dimethyl-4,5-bis(diphenylphosphinomethyl)-l.3-dioxolane:
H B. Kagan, T. Dang, J Am. Chem. Soc. 94 (1972) 6429-6433.
[9] (2S, 4S)-N-(tert-Butyloxycarbonyl)-4-(diphenylphosphino)-2-(diphenylphosphinomethy1)pyrrolidine: K. Achiwd, J. Am. Chem. Soc. 98 (1976)
[lo] (2s. 3S)-Bis(diphenylphosphino)butane: M. D. Fryzuk, B. Bosnich, J.
Am. Chem. Sor. 99 (1977) 6262-6267.
[ I l l H. Brunner, W. Pieronczyk, Angew. Chem. 91 (1979) 656-656; Angew.
Chem. In!. Ed. Engl. 18 (1979) 620.
[12] H. Wang, L. H. Pignolet, Inorg. Chem. 19 (1980) 1470-1480.
1131 D. Chadosh, R. Crabtree, H. Felkin, S. Morebouse, G. Morris, inorg.
Chem. 21 (1982) 1307-1311.
[14] Prof. K. Bernuuer. Universitit Neuchatel (Switzerland) kindly supplied us
with an enantiomerically pure sample of 2a [[d]:&: - 130.5” ( c = 3, hexane) for (s)-Za]. 2 b was converted with chloroacetyl chloride into the corresponding chloracetamide. The optical rotation of the diastereomeric
mixture of the atropisomers (1‘s. RS) i s known [[a]:”: -9 (c = 2.073,
[15] ‘H-NMR spectroscopic determination of the enantiomeric purity with the
chiral shift reagent (9-(
Anthracycline- and Anthracenedione-Based Anticancer
Agents. Edited by .
W: Lown. Elsevier, Amsterdam 1988.
738 pp., hard cover, HFl440.00.--ISBN 0-444-87275-2
“Anthracyclines represent one of the most useful and
widely prescribed classes of anticancer agents” writes J. W
Lown, the editor of this book in the series with the general
title “Bioactive Molecules”. In accordance with the great
clinical importance of this class of compounds, a wealth of
new original papers has appeared since the last interdisciAngeu’. Clwni. Inr. Ed. Engl. 29 (1990) No. 5
plinary multi-author volumes were published in the years
1980 to 1982. This has brought added urgency to the task of
editing an up-to-date review of the field of anthracyclines,
including all aspects from synthesis to clinical application.
It must be acknowledged that the editor, who has himself
contributed to the field through synthetic and biophysical
studies on anthracyclines, has made an excellent choice of
topics to be covered. The total of 20 articles are divided into
three sections as follows: Section 1 : Isolation, Synthesis and
Properties; Section 2: Biophysical and Biochemical Studies
Related to Mechanisms of Action; Section 3 : Pharmacology,
Toxicity and Clinical Aspects.
Only two articles are actually devoted to synthesis, that by
E: Arcamone and S. Penco on doxorubicin analogues, and
that by E. M . Acton et al. on the very promising new class of
compounds, the morpholinyl-anthracyclines. This limited
choice of topics is justified, since recent comprehensive review articles on anthracycline syntheses already exist. Next
comes a contribution by I: Oki on anthracyclines of microbial origin, including very recent results on the biogenesis of
these compounds. The last three reports in Section 1 deal
with topics that have scarcely been reviewed before, namely
anthracycline-metal complexes ( A . Garnier-Suillerot), and
the pharmacological aspects of mitoxanthrones and ametanthrones ( E E. Durr), and of anthrapyrazoles ( H . D. Hollis
Showalter et a].).
Yerlugsgesellschufi mhH, 0.6940 Weinheim, 1990
S 02.5010
Section 2 on biophysical and biochemical studies is the
longest in the book, with eight articles. The interaction with
DNA, which is important in relation to the effectiveness of
the compounds, is treated first, in articles dealing with quantitative aspects (E. Stutter et al.), X-ray diffraction studies
(G. Ughetto), computer modeling (.
R.IBrown and S. Neidle), and sequence selectivity (B. Pullman). However, there is
still no consensus among experts on the basic mechanism of
action, as is shown by the general articles on anthracyclines
by C. E. Myers et al. and on anthracenediones by K. Reszka.
Thus, in addition to the interaction with DNA, there are
discussions of the effects on DNA-topoisomerase I1 ( M . Potmesil) and on lipid oxidation and prostaglandin formation
(R. E Novak et al.).
However, it is in clinical application that biochemical
models undergo their ultimate test. This aspect, together
with pharmacology and toxicity, is treated in Section 3. The
introductory article by M . Grandi et al. on screening methods, which is fairly basic in content, is followed by newer
aspects of anthracycline resistance ( D . H. Kessel), of the
pharmacology of Menogaril, which has been developed from
nogalamycin (J. P. McGovern et al.), and that of anthracenedione ( M . D. Green et al.), together with tumor cell differentiation by anthracyclines ( A . M . Casazza). The short closing
contribution by the editor again emphasizes the fact that,
despite the wealth of experimental results, a firm understanding of antitumor activity is still a long way off. However, he urges continued research “... in order to understand
the mode of action of these valuable agents and to improve
their performance”.
This volume is extremely useful for everyone working on
synthetic, pharmacological or clinical aspects of anthracyclines or on antitumor therapy in general. Nowadays it is
hardly possible for an individual to read every original paper
which has an interdisciplinary connection with this topic.
This collective volume makes it easier to see beyond the
confines of one’s own special field. Thus, it enables the synthetic chemist and the natural products chemist, for example, to learn which compounds have progressed from
promising animal trials to clinical trials or use. However,
sentences such as “Aclacinomycine A is therefore essentially
ineffective in the major solid tumors” (p. 672), or “The side
effects were in general similar to those seen with doxorubicin” have a sobering effect.
As in the parallel series “Studies in Natural Products
Chemistry”, also published by Elsevier, the authors’ contributions are reproduced in “camera ready” form. Consequently the visual appearance is that of a wide variation in
type styles and in the presentation of formulas. The incidence
of typographical errors varies considerably from author to
author, and in this respect the standard falls far short of that
usually found in books that are typeset. These superficial
shortcomings would, of course, be acceptable if they were
offset by the contributions being more up-to-date and by an
advantage in price. Unfortunately, however, in most of the
articles the references extend only up to the end of 1986, or
occasionally to the beginning of 1987. Even with this method
of production it appears that at least a year has elapsed
between the submission of the manuscripts and the publication of the book, a delay which this reviewer has also experienced as an author in the parallel series. The subject index
consists of 8 1/2 pages. There is no index of cited authors; in
the computer age it should have been easily possible to
provide such an index, which would have been very useful.
Despite the fact that much of the work of publication has
been off-loaded onto the authors, the price of the book is
very high. Nevertheless, this should not deter libraries and
Verlagsgeselischaft mbH, 0-6940 Weinheim. I990
scientists working in the field from buying it, as this is offset
by the wealth of information that is compressed into it.
Kursten Krohn “€3 1031 IE]
Institut fur Organische Chemie
der Technischen Universitat Braunschweig (FRG)
Die Technik der organischen Trennungsanalyse. Eine Einfiihrung. By H. Laatsch. Thieme, Stuttgart 1988. xii, 223 pp.,
paperback, DM 36.00. - ISBN 3-12-722801-8
Owing to the considerable advances that have occurred in
chromatography (thin layer chromatography, column chromatography and gas chromatography), and the relatively
little new progress that has been made in the classical organic
techniques of separation and analysis (“wet chemical methods”), many chemists will take the view that it was not really
necessary to add another survey to the already large number
of review articles on the latter topic. However, the author of
this book intends it to be used by students of experimental
chemistry, who would find a readable and lucid introduction
to the subject very helpful. In meeting this aim he has been
very successful. However, the book should also serve as a
useful introduction for advanced and post-graduate students
engaged in isolating and analyzing natural products, a line of
research which unfortunately tends to be neglected in the
organic chemistry departments of German universities in
comparison with preparative studies.
The first part of the book includes (in Section C, pp. 925) a very detailed description of the “ether separation process”, which is successful for the majority of analytical problems. If the sample contains substances which tend to decompose easily, it is recommended that the separation should be
carried out using derivatives, or by column chromatography.
Attention is also drawn to the possibilities offered by the
color changes exhibited by certain substances at different
pH-values, which make it easier to recognize their presence.
Section D (pp. 26-40) deals with methods for purifying the
crude products of separation and measuring their physical
constants. It is commendable that this section even includes
a detailed account of the purification of solids by crystallization. Crystallization experiments are nowadays often neglected because of the availability of chromatographic separation methods, but they are in fact indispensable for isolating new natural products. The author emphasizes that one
cannot claim to have a pure substance until crystals with a
well-defined melting point have been obtained. A mixture of
two compounds with identical or similar R,-values can
sometimes be mistaken for a pure compound.
The second part of the book (pp. 53- 104) describes the
reactions that can be used to demonstrate the presence of
particular functional groups. Although not all such reactions
are included, the most important ones undoubtedly are, and
attention is drawn to compounds which can interfere with
the analysis. The author describes how the substances isolated are first assigned to particular compound classes, followed by the preparation of the derivatives that are needed
to arrive at an identification. Here again, only the most important derivatives, preferably those which crystallize well,
are described. The preparation of crystalline derivatives
from oily or amorphous compounds is of considerable interest in natural products chemistry, since in many cases the
structures of complex natural products can only be determined by X-ray crystallography. The specimen analytical
reports (Section H, pp. 174-195) are probably unnecessary,
8 02.50jO
Angew. Ckem. hi.Ed. EngI. 29 (1990) No. 5
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