摘要:

Russian Chemical Reviews 70 (8) 627 ± 639 (2001) Scanning tunnelling vibrational spectroscopy of single surface complexes and detection of single electron spins F I Dalidchik, S A Kovalevskii, B R Shub Contents I. Introduction II. Single molecule chemical physics of surfaces III. Threshold and resonance features of currents flowing through nanoscale tunnel junctions containing adsorbed species IV. Inelastic electron tunnelling spectroscopy with STM V. Vibrational scanning tunnelling spectroscopy using resonance features of STM currents VI. Kinetics of vibrational and spin transitions in single surface complexes VII. Scanning tunnelling spectroscopy using fluctuations of STM currents VIII. Time-resolved scanning tunnelling spectroscopy IX. Conclusion Abstract. scanning the employing techniques spectroscopic New New spectroscopic techniques employing the scanning tunnelling methods new The considered.are microscope tunnelling microscope are considered. The new methods allow allow measurements surface single of spectra vibrational the of measurements of the vibrational spectra of single surface com- com- plexes, of distributions nonequilibrium the of determination plexes, determination of the nonequilibrium distributions of such such complexes of kinetics the on studies levels, vibrational over complexes over vibrational levels, studies on the kinetics of vibra- vibra- tional relaxation vibrational of determination transitions, tional transitions, determination of vibrational relaxation param- param- eters, on studies and spins electron surface single of detection eters, detection of single surface electron spins and studies on the the dynamics The species.of migration surface fast of dynamics of fast surface migration of species. The physical physical grounds in methods the of applications possible and grounds and possible applications of the methods in chemical chemical research 80 includes bibliography The discussed. also are research are also discussed. The bibliography includes 80 refer- refer- ences. I. Introduction Determination of the structure and properties of surface complex- es belongs to the key problems of modern chemical physics of surfaces including heterogeneous catalysis. The number of differ- ently organised groups of adsorbed species can be rather large even in the simplest systems. For instance, the interaction of oxygen with metals can be accompanied by the formation of more than ten types of complexes, depending on the metal crystal face involved in the process, the metal oxidation state and temperature.These complexes differ not only in their adsorption sites, but also in atomic and electronic structure. Usually, such complexes coexist and interact with one another at sufficiently high coverages of the surface. In heterogeneous catalysis, the most reactive complexes play the role of active surface sites.1, 2 Different surface complexes can play the role of active surface sites in different stages of a catalytic reaction, i.e., in the course of adsorption and surface migration and in various chemical trans- formations (dissociation, desorption, as well as substitution, recombination or exchange reactions).The internal structure F I Dalidchik, S A Kovalevskii, B R Shub N N Semenov Institute of Chemical Physics, Russian Academy of Sciences, ul. Kosygina 4, 119991 Moscow, Russian Federation. Fax (7-095) 137 83 18. Tel. (7-095) 939 72 59 (F I Dalidchik), (7-095) 939 73 52 (S A Kovalevskii), (7-095) 137 82 73 (B R Shub) Received 27 April 2001 Uspekhi Khimii 70 (8) 715 ± 729 (2001); translated by AMRaevsky #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n08ABEH000678 627 628 628 630 631 634 637 637 637 and properties of the surface complexes have long been intensively studied by many experimental methods. However, the exact nature of the active surface sites remains a moot question as yet for the majority of systems including those studied in most detail.Determination of the exact nature faces great difficulties which are mainly associated with a large number of types of surface com- plexes and with low steady-state concentrations of the active sites due to their high reactivity. Experiments with structurally and chemically homogeneous surfaces (the so-called `ideal' surfaces) are free from these draw- backs. Carrying out high-vacuum experiments allows one to assemble macroscopic ensembles of regularly arranged surface complexes of a particular type by controlled low-temperature adsorption on microfacets of perfect single crystals.3 The structure and properties of such systems can be studied in detail by various spectroscopic methods including optical and corpuscular ones, beam and field emission techniques, as well as steady-state and kinetic methods.4 It should be noted that most of the widely used methods have initially been developed to study the dynamics of elementary processes in the gas phase.Experiments with ideal surfaces have significantly extended the ideas of both the internal structure of surface structures and the dynamics of elementary acts in heterogeneous processes. In such experiments, many complexes have been found for the first time. Beam experiments provided direct evidence for the depend- ence of the reactivity of ideal surfaces on their atomic structure.5 Femtosecond laser experiments allowed the characteristic times of electronic and vibrational relaxation of many surface complexes to be measured for the first time.6 Currently, heterogeneous processes on ideal surfaces are studied with a time resolution of *10713 ± 10714 s, which is sufficient for the real-time observation of the motion of individual species (molecules, ions, atoms) in elementary acts of chemical transformations.Since 1960s, intensive studies of ideal surfaces as model systems have been carried out in many countries. The results of such studies serve as one of the main sources of information necessary for devising physical models of the interactions of atomic species with the surface and at the solid surfaces. However, the results of high-vacuum measurements bear no direct relation to the chemistry of real surfaces. Typically, the time taken to form a real surface is of the order of 1077 s (P&1 atm, T&300 K).Such surfaces are characterised by disordered atomic structures. In real systems, the variety of types of ensembles of surface628 complexes is much greater than in ideal systems. Often, real surfaces are covered by complexes that cannot be produced in desired amounts in high-vacuum experiments to be studied then by conventional spectroscopic methods such as IR, Auger and ESR spectroscopy, etc. Additionally, the dynamics of elementary acts of various heterogeneous processes in ordered and disordered ensembles of the same surface complexes can be essentially differ- ent. For chemisorbed species this is due to changes in the potential energy surfaces upon the formation of new chemical bonds, whereas in the case of physisorbed particles the distinctions can be due to multiple scattering of both products and reagents by the species surrounding the reacting complex.Compared to modelling of gas-phase processes, the problem of devising physical models of heterogeneous surface reactions is much more complicated. The dynamics of all essential elementary gas-phase processes can be studied in detail using high-vacuum beam and optical experiments. However, the results of such experiments with ideal surfaces are insufficient to devise physical models of heterogeneous chemical reactions, especially catalytic ones, which are of prime interest in practice. Studies on the dynamics of elementary acts of gas-phase reactions can be successfully performed with femtosecond time resolution, which allows real-time monitoring of the motion of atomic species.In the case of heterogeneous chemical reactions, solving a similar prob- lem requires not only real-time, but also real-space monitoring of the motion of atomic species and, hence, atomic-scale spatial resolution. The present state-of-the-art in chemical physics of surfaces is characterised by great demand for novel methods which would allow assembling of single complexes of adsorbed species at specified points of the surface, studies on their atomic and electronic structure, measurements of physical parameters, determination of chemical properties and studies on the dynamics of elementary acts of chemical transformations at the single-event level. Currently, the development of such methods requires the use of scanning tunnelling microscopy (STM). Hence, the new meth- ods should be basically different from those used in studies of gas- phase processes.7, 8 II.Single molecule chemical physics of surfaces In experiments with STM, the atomic and electronic structure of conducting surfaces is probed with a thin metallic tip (the radius of curvature of well-fabricated tips is comparable with the character- istic atomic size) separated from the surface by a distance d of the order of 5 ¡¾ 10 A.8 In this case, the overlap of the atomic orbitals of the tip and the surface is very weak and the surface ¡¾ tip system represents a nanoscale tunnel junction whose conductance s a qJ qV , (J is the current and V is the voltage) at low voltages (V55j, j is the tip work function) is determined by the probability of electron tunnelling through the potential barrier (the barrier penetrability) (1) D(d )!exp ¢§ 2d pAAAAAA 2j and by the surface local density of electron states [r(e,r)] at the position of the tip 9 (2) s(V)!D(d )r[e(V),R], e(V)=eF7V.Here, e and r are the energy and coordinate of an electron, respectively, R is the tip coordinate and eF is the Fermi level. (In the text below, we will use the system of atomic units, except otherwise specified; the tip polarity is assumed to be negative.) According to relationship (2), displacements of the tip across the surface (at specified V and d) produce changes in the current flowing through the tunnel junction, which are proportional to the changes in the electron density r[e(V),R], which are determined by F I Dalidchik, S A Kovalevskii, B R Shub the relief of the surface.For `single-atom' tips, where the tunnel- ling current is determined by the overlap of the surface orbital with the orbital of the atom nearest to the surface, one gets dJ/dR&0.1 nA A71. This is sufficient for `current' imaging of a surface area with A E ngstroE m spatial resolution by simply scanning it. Spectroscopic measurements, i.e., measurements of the s ¡¾V dependences allow reconstruction of the energy distributions of electrons at specified points of the surface. [Note that relation- ships (1) and (2) include only the contribution of elastic tunnelling characterised by conservation of the energies of the tunnelling electrons. Usually, this is the most probable case.] The invention of the STM7 opened a new, amazing world of single-molecule phenomena.The STM is capable of imaging surfaces with A E ngstroE m spatial resolution and provides the possibility of seeing individual adsorbed atoms, molecules and adsorbate clusters in the real space, as well as of directly monitor- ing reconstruction { of ideal surfaces,10, 11 elementary acts of slow surface migration,12 dissociation 13 and desorption.14, 15 Numer- ous examples of manipulating individual adsorbed species with the STM tip by their targeted desorption, adsorption, dissociation and transfer between the surface and the tip have been reported. In modern experiments with STM, the atomic and electronic struc- ture of surfaces covered by adsorbed species are studied at the single complex level while the dynamics of heterogeneous proc- esses is in increasing frequency studied at the single-event level.Chemical physics of surface becomes a `single molecule' science.16 The opportunities of `single molecule' chemical physics of surface seem to be almost boundless, especially taking into account continuous evolution of spectroscopic methods which make it possible to obtain information on the structure of single surface complexes and the dynamics of individual acts of elemen- tary chemical transformations. Experiments with STM allow one not only to see individual adsorbed species and complexes and to reconstruct the corresponding electron energy distributions, but also to measure their vibrational spectra,17, 18 create and measure different types of nonequilibrium vibrational distributions 19 and reconstruct parameters of heterogeneous vibrational 20, 21 and electronic 22, 23 relaxation. It is also possible to study the kinetics of spontaneous and current-induced vibrational transitions in single surface complexes.(It is this kinetics that often determines the probabilities of elementary acts of chemical transformations of the complexes located under the tip of an STM.21) Recently, methods for detection of single surface paramagnetic centres have been proposed and evaluated.24 Some new experimental schemes have been considered, which would initiate studies on the kinetics of spin transitions in single paramagnetic centres, measurements of spin ¡¾ lattice relaxation times and relaxation times of individual electronically excited physisorbed molecules 22, 23 and research in the field of detection of single molecule magnetic resonance effects.25 ¡¾ 27 New methods for STM studies on the dynamics of fast migration of those adsorbed atomic species whose stable images cannot be obtained have been proposed and theoretically substantiated.28, 29 The main goal of this review is to describe and analyse recent advances in single molecule heterogeneous chemistry. III.Threshold and resonance features of currents flowing through nanoscale tunnel junctions containing adsorbed species Most of new spectroscopic methods exploiting STMs also employ the effects of spin-dependent and inelastic electron tunnelling. The former effect is associated with the dependence of tunnelling probability on the electron spin orientation while the latter is due { Before the invention of the STM, reconstruction of ideal surfaces was studied only by diffraction methods which allow one to obtain raw experimental information about the surface structure in the reciprocal lattice space rather than conventional coordinate space.Scanning tunnelling vibrational spectroscopy of single surface complexes and detection of single electron spins to processes in which energy exchange occurs between the tunnel- ling electrons and electronic and vibrational degrees of freedom of the adsorbed species.In experiments with STM, inelastic electron tunnelling including spin-dependent electron tunnelling can man- ifest themselves as two kinds of characteristic features on the J¡¾V curves, viz., threshold 17 and resonance features.18 Threshold features are observed at voltages corresponding to the opening of inelastic electron tunnelling channels.(Below the threshold voltage inelastic tunnelling of an electron is impossible since in this case the electron energy after excitation of a species located under the tip of an STM should be lower than that of the Fermi level corresponding to the highest occupied electron state.) An energy level diagram illustrating both elastic and inelastic electron tunnelling is presented in Fig. 1. j Je eF Ji eF7V Figure 1. An energy level diagram illustrating electron tunnelling through a nanoscale tunnel junction at voltages V55j; Je and Ji are the elastic and inelastic electron tunnelling currents, respectively.(3) At threshold voltages Vo=o (o is the excitation energy of a species located under the STM tip) the conductance of a tunnel junction changes jumpwise s(V)!Z(V7Vo), where Z(x) is the Heaviside function Z(x)=

ISSN:0036-021X    

出版商:RSC    

年代:2001

数据来源: RSC

摘要:

Russian Chemical Reviews 70 (8) 641 ± 653 (2001) 1,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues A I Kotyatkina, V N Zhabinsky, V A Khripach Contents I. Introduction II. Methods for the generation of nitrile oxides III. Methods for the transformations of isoxazoles and 4,5-dihydroisoxazoles IV. Intermolecular 1,3-dipolar cycloaddition reactions of nitrile oxides V. Intramolecular 1,3-dipolar cycloaddition reactions of nitrile oxides VI. Syntheses based on enantiocontrolled 1,3-dipolar cycloaddition reactions of nitrile oxides Abstract. cyclo- 1,3-dipolar of use the on data published The The published data on the use of 1,3-dipolar cyclo- addition reactions of nitrile oxides in the synthesis of natural addition reactions of nitrile oxides in the synthesis of natural compounds and systematised are analogues their and compounds and their analogues are systematised and reviewed.reviewed. The references 145 includes bibliography The bibliography includes 145 references. I. Introduction The cycloaddition of nitrile oxides to alkynes and alkenes is the most popular approach to the synthesis of isoxazoles and 4,5- dihydroisoxazoles.1±7 Isoxazoles and 4,5-dihydroisoxazoles are used as intermediates in total syntheses of natural compounds. The fact that these compounds represent equivalents of definite functional groups can be exploited in different steps of the synthesis. On the other hand, isoxazoles and 4,5-dihydroisoxa- zoles are relatively stable compounds and remain intact in the course of multistep transformations. The present review is devoted to the synthesis of natural compounds based on reactions of nitrile oxides with dipolaro- philes with subsequent transformations of the adducts formed.II. Methods for the generation of nitrile oxides Nitrile oxides are usually unstable and prone to dimerisation resulting in the corresponding furoxans.8 Therefore, they are usually generated in situ by dehydration of primary nitro com- pounds by phenyl isocyanate 9 or by dehydrohalogenation of hydroximoyl chlorides or bromides by triethylamine.10 Hydrox- imoyl chlorides are generated from oximes by chlorination with chlorine, N-chlorosuccinimide (NCS),11 nitrosyl chloride, sodium hypochlorite 12 or tert-butyl hypochlorite.13 A procedure for the synthesis of functionalised and non-functionalised hydroximoyl chlorides, which involves treatment of nitroalkanes or conjugated nitroalkenes with titanium(IV) chloride, has been developed.14 Several modified procedures for the generation of nitrile oxides, e.g., dehydration of nitroalkanes by toluene-p-sulfonic A I Kotyatkina, V N Zhabinsky, V A Khripach Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, ul.Acad. Kuprevicha 5/2, 220141 Minsk, Belarus. Fax (37-517) 264 86 47. Tel. (37-517) 263 76 13. E-mail: vz@ns.iboch.ac.by (A I Kotyatkina, V N Zhabinsky) Tel. (37-517) 264 86 47. E-mail: khripach@ns.iboch.ac.by (V A Khripach) Received 19 October 2000 Uspekhi Khimii 70 (8) 730 ± 743 (2001); translated by R L Birnova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n08ABEH000630 641 641 641 643 647 649 acid,15 benzenesulfonyl chloride or ethyl chloroformate in the presence of triethylamine 16 were developed in the 1980's. All these reactions are carried out at elevated temperatures.The use of di- tert-butyl pyrocarbonate and catalytic amounts of N,N-dimethyl- aminopyridine (DMAP) allows the dehydration of nitroalkanes under much milder conditions.17 Chloramine T is effective for the generation of nitrile oxides from oximes.18 This reaction is usually carried out by heating an aldoxime and an alkene in ethanol in the presence of chloramine T.Its role consists in the chlorination of aldoxime to hydroximoyl chloride. Subsequent elimination of HCl by treatment with a base results in nitrile oxide. Nitrosyl chloride or aqueous sodium hypochlorite can be used instead of chloramine T.12 Thermolysis of furoxans, which represent cyclic dimers of nitrile oxides, occurs under drastic conditions and is therefore seldom used;19 thermal generation of nitrile oxides from hydroxi- moyl chlorides by boiling in toluene is used far more often.20 This method was used, in particular, for the synthesis of fullereno-4,5- dihydroisoxazoles.21 A new method for the generation of nitrile oxides by micro- wave irradiation of hydroximoyl chlorides in the presence of dipolarophiles has recently been proposed.This procedure includes cycloaddition of nitrile oxides to weak dipolarophiles, such as nitriles 22 and polycyclic aromatic compounds (e.g., phenanthrene, anthracene, pyrene, etc.) in the absence of sol- vents.23 The yields of cycloaddition products exceed severalfold those obtained under standard conditions, whereas the reaction time is reduced to 3 ± 10 minutes against *24 h under standard conditions. Nitrile oxides are generated from O-trimethylsilylhydroxi- moyl chlorides by treatment with potassium fluoride in acetoni- trile at*20 8C (see Ref. 24) or from hydroximoyl chlorides using molecular sieves (3 ± 5 A) in CH2Cl2.25 In the latter case, the cycloadducts are formed in high yields, while no furoxans are formed at all.III. Methods for the transformations of isoxazoles and 4,5-dihydroisoxazoles Methods for the transformations of isoxazoles (1) and 4,5- dihydroisoxazoles are based on the lability of the N7O bond and are extremely diverse. In this section, we shall consider the main classes of compounds generated from the 1,3-dipolar cyclo- addition adducts of nitrile oxides and the methods for their transformation with special emphasis on novel approaches.642 The most common procedure is the reductive scission of isoxazoles by hydrogenation over Raney nickel or platinum dioxide to afford enamino ketones 2.26 ± 28 R2 a R1 R3 NH2 O 2R2 b, c R1 R3 O 3R2 a, d, e, f R1 R3 N O O 4 R3 R1 R2 a, d, e, g R1 R2 R2 1 OH O h R1 R3 O O b, i R1 R3 5R2 6R2 NH2 OH 7 (a) H2, Ni/Ra (Pt2O), EtOH; (b) Na/NH3, 3 equiv.ButOH, THF; (c) p-TsOH, PhMe, D; (d) PhCOCl, Py; (e) NaBH4; ( f) H+; (g) 90% AcOH; (h) Ni/Ra, BCl3, MeOH±H2O; (i ) Ni ± Al, MeOH, KOH. Enamino ketones 2 can also be prepared by reduction of isoxazoles with sodium in liquid ammonia in the presence of 1 equiv. of ButOH.29 With 3 equiv. of ButOH, this reaction yields intermediate b-amino ketones; their acid hydrolysis results in enones 3.29 The regioisomeric enones of the type 4 are obtained by benzoylation of enamino ketones 2 followed by reduction of the amido ketones formed and hydrolysis of the intermediate hydroxy enamides.30 Hydrolysis of hydroxy enamides by 90% AcOH yields b-hydroxy ketones 5.27, 31 b-Diketones 6 are pre- pared by catalytic hydrogenation of isoxazoles in the presence of Lewis acids.32 Isoxazoles are reduced to amino alcohols 7 using nickel ± aluminium alloys in the presence of an alkali.33 However, reductive scission of isoxazoles cannot be used if the substrates contain double bonds or protective groups susceptible to hydrogenolysis.In this case, cleavage of the N7O bonds is achieved by using other methods. Thus molybdenum or iron carbonyls were recommended for use in the synthesis of enamino ketones 2a ± f.34 O O R3 R3 Mo(CO)6 Mo(CO)6 N N R1 R2 R1 R2 1a ± f 8a ± f R1 O O NH2 H2O Mo(CO)6 N R1 R3 R3 R2 R2 9a ± f 2a ± f R1=R3=Ph, R2 = H (a); R1=Me, R2=H,R3=Ph (b); R1=R3=Me, R2= H (c); R1=Ph, R2=R3= H (d); R1=Ph, R2 ±R3 =(CH2)4 (e); R1=Ph, R2±R3=(CH2)3 (f).A I Kotyatkina, V N Zhabinsky, V A Khripach The mechanism of this reaction includes the formation of the molybdenumhexacarbonyl complexes 8a ± f involving the nitro- gen atom of the isoxazole with subsequent cleavage of the N7O bond and hydrolysis of the nitrene complexes 9a ± f to the enamino ketones 2a ± f. The reductive opening of isoxazoles leading to enamino ketones is achieved with samarium iodide in tetrahydrofuran containing methanol as the proton source in 57% to 80% yields.35 Dihydrolipoamide (10) was used for reductive cleavage of 4,5- dihydroisoxazoles 36 [lipoamide (11) is a coenzyme in redox reactions occurring in living organisms]. The reductive cleavage of N7O bonds in 3,5-disubstituted isoxazoles 1b,c,g ± i under the action of compound 10 in the presence of iron(II) salts also proceeds with high yields.R2 R1 R3 H2NCO(H2C)4 (CH2)4CONH2 S N O 1b,c,g ± i Fe2+ FeII 72H+ SH SH 10 12 S H2NCO(H2C)4 O 7R3 S H+ FeIII N 7Fe2+ R2 S R1 13b,c,g ± i NH2 O + (CH2)4CONH2 R3 R1 S S 11 R2 2b,c,g ± i R1=Me, R2=H: R3=Ph (b), Me (c); R1=R2=H, R3=Me (g); R1=Ph: R2=CO2Me, R3=Me (h); R2=CO2H, R3=Me (i). It is suggested that isoxazoles 1b,c,g ± i react with the complex (12) to give the intermediates 13b,c,g ± i which are further hydro- lysed to enamino ketones 2b,c,g ± i. Compound 10 is converted into lipoamide 11 under these conditions. N-Methylated b-oxo amides 14a ± c are formed in high yields upon fragmentation of N-methylated isoxazoles 15a ± c catalysed by Et3N.37 R R R O7 Et3N H2O C O + O 7OSO3Me 7H+ NHMe O Me N N+ Me16a ± c 14a ± c 15a ± c R=Me (a), CH=CHPh (b), CH2PO(OEt)2 (c).The isoxazolium salts 15a ± c are deprotonated with subse- quent cleavage of the N7O bond and generation of the nitrilium ions 16a ± c which are further converted into b-oxo amides 14a ± c in the presence of water. The reductive scission of 4,5-dihydroisoxazoles 17 has long been poorly understood.Amethod for their reduction over Raney nickel in the presence of trifluoroacetic or hydrochloric acid, which yielded a mixture of b-hydroxy ketones 5 and their dehydration products (a,b-unsaturated ketones 4), was developed in 1979.38 Later,39 it was suggested to carry out this reaction in the presence of boric acid, which afforded b-hydroxy ketones 5 in high yields. The latter can further be dehydrated into enones 4.40 This method for the opening of 4,5-dihydroisoxazoles is widely used in the synthesis of natural compounds.4 The use of rhodium on Al2O3 and platinum dioxide as catalysts in the hydrogenation of dihydroisoxazoles 17 has been described.41 Amino alcohols 7 are prepared by reduction of 4,5- dihydroisoxazoles by LiAlH4,42 ± 44 the BH3 .Me2S complex (see Ref.45) and zinc (or sodium) borohydride in the presence of nickel chloride in methanol.461,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues OH O a R3 R1 5 R2 O N O a, b R3 R1 R3 R1 4 R2 R2 NH2 OH 17 c R3 R1 7 R2 (a) H2, Ni/Ra, H3BO3, EtOH; (b) p-TsOH; (c) LiAlH4, Et2O.Hydroxy nitriles 18 are prepared from carboxydihydroisox- azoles.47 R1 O N D NCCHCHR2 R2 HO2C OH 18 R1 Similar to isoxazoles, 4,5-dihydroisoxazoles 17a ± e are opened under the action of molybdenum hexacarbonyl.48 This reaction occurs via the complexes 19a ± e and 20a ± e which are further converted into b-hydroxy ketones 5a ± e. The complexes 19a ± e undergo retrodegradation in the absence of water. O O Mo(CO)6 Mo(CO)6 R2 R2 N N R1 R1 19a ± e 17a ± e R1 R2 R1 R2 O7 N+ OH O5a ± e Mo(CO)6 20a ± e R1=Me2C(OH): R2=n-C8H17 (a), Bn (b); R1=MeO2C(CH2)2, R2=n-C10H21 (c); R1=HO2C(CH2)2, R2=n-C10H21 (d); R1=CH3(CH2)5, R2 = (Z)-MeCH=CH (e).The possibility of opening of dihydroisoxazoles 17f ± i by ozonolysis resulting in b-hydroxy ketones 5f ± i has been studied.49 It is suggested that similar to oxime ozonolysis 50 this involves the electrophilic attack of ozone at the C(3) atoms of dihydroisox- azoles resulting in the formation of the intermediates 21f ± i with subsequent cleavage of C7N bonds. + N O O N 7 O ON O3 O3 O3 R3 R3 R1 R1 R3 R1 R2 R2 21f ± i R2 17f ± i O O2NO O OH Me2S R1 R3 R1 R3 R2 22f ± i R2 5f ± i R1=Me, R2=R3=cyclo-C5H11, (f); R1=Ph, R2=H, R3=Bun (g); R1=CH2OH, R2=H, R3=Bun (h); R1=R2=R3=Me (i). Further oxidation leads to hydroxy ketone nitrates 22f ± i; their reduction by dimethyl sulfide yield b-hydroxy ketones 5f ± i.Although the yields of the final products are lower (61% ± 74%) than those obtained by hydrogenolysis, the ozonolysis of 4,5- dihydroisoxazoles is effective if the substrates 17 contain func- tional groups susceptible to hydrogenolysis. 643 IV. Intermolecular 1,3-dipolar cycloaddition reactions of nitrile oxides 1,3-Dipolar cycloaddition of nitrile oxides used in the synthesis of natural compounds can be effected in two ways, viz., as intermo- lecular and as intramolecular reactions. The first approach entails convergent syntheses of complex molecules from two simpler blocks. The latter approach can be used for the generation of new C7C bonds in preformed molecules and/or for the intro- duction of additional functional groups.1. Synthesis of talaromycin The structures containing spiroketal groups were discovered in insects, microorganisms, plants and fungi in the mid-1970's.51, 52 One of the representatives of this class, viz., talaromycin B (23), was isolated from the toxic fungus Talaromyces stipitatus.53 The synthesis of talaromycin involved intermolecular 1,3-dipolar cycloaddition of a nitrile oxide to the alkene.54 N O (CH2)2CH NOH (H2C)2 a b O O O O O O + O O 25 24 26 OH O (H2C)2 OH O c O O d O O O OH OH 27 OH O Et O O e, f, g, h O O O 23 OH OH (a) NaOCl, Et3N, H2O, CH2Cl2 (67%); (b) H2, Ni/Ra (72%); (c) MeOH, Amberlyst-15 (93%); (d ) Amberlyst-15, 1-methoxycyclohexene, THF (80%); (e) MsCl, Et3N, Et2O; ( f ) NaI, Me2CO; (g) Me2CuLi, THF; (h) HCl, MeOH, H2O.The nitrile oxide generated from the oxime 24 reacted with the alkene 25 to give 4,5-dihydroisoxazole 26. Cleavage of the N7O bond was achieved by hydrogenation over Raney nickel. Spiroke- talisation of the hydroxy ketone 27 proceeded in a weakly acidic medium in the presence of Amberlyst-15 in methanol. The resulting trihydroxy derivative 28 contained the main fragments of the talaromycin (23) backbone. After protection of cis-diol groups, racemic talaromycin (23) was formed in a total yield of 12%. 2. Synthesis of milbemycin b3 Intermolecular 1,3-dipolar cycloaddition of a nitrile oxide to the alkene 28 was used in the first total synthesis of yet another compound containing a spiroketal system, viz., milbemycin b3 (29).55 Milbemycin b3 was isolated in 1974 56 and is one of more than twenty compounds of the milbemycin series.The interest in these compounds is due to their high antileukemic 57 and insecti- cidal 58, 59 activities and low toxicities for mammals. The synthesis644 of milbemycin (29) faced several complicated problems including stereo-controlled formation of six asymmetric centres of the molecule, viz., C(12), C(17), C(19), C(21), C(22) and C(23). The first step of this synthesis included cycloaddition of the optically active 1,3-dipolarophile 28 and the nitrile oxide prepared by treatment of protected nitropropanal with methyl isocyanate.The resulting mixture of isomeric dihydroisoxazoles 30 was reduced by lithium aluminium hydride with subsequent protec- tion of hydroxy and amino groups. The diastereomeric mixture of the ammonium salts 31 was treated with an aqueous solution of p-toluenesulfonic acid resulting in spiroketalisation and simulta- neous deprotection of the aldehyde group. The addition of isopropenyllithium cuprate to aldehyde 32, which was controlled by the chelate complex formed, yielded a mixture of allylic alcohols (7 : 1 in favour of the desired isomer). Compound 33 prepared by the reaction with propionyl chloride was selected for the Ireland ± Claisen rearrangement. An attempt to use lithium diisopropylamide (LDA) in the synthesis of enolate was unsuc- cessful; the ester 33 could be deprotonated by potassium bis(tri- methylsilyl)amide.Further treatment of the (Z)-enolate formed with trimethylchlorosilane and heating afforded the acid 34 with the required configuration of the C(12) centre. Total synthesis of the macrolide 29 required four additional steps. O OMe 28 O O H O 12CO2H (a) MeNCO, Et3N, PhH (68%); (b) LiAlH4, Et2O; (c) KH, BnI; (d ) MeI; (e) TsOH, H2O (24% ± 30%); ( f ) CH2=CH(Me)CuLi; (g) EtCOCl, CH2Cl2, Py (63%); (h) (Me3Si)2NK, THF,778 8C; (i) Me3SiCl (TMSCl), 55 8C (57%). 3. Synthesis of lingbiatoxin A The synthesis of indole 35, the intermediate product in the synthesis of the alkaloid lingbiatoxin A (36), has been described.60 O O2N a + O b, c, d O O OMe O N30 O O f, g O Et O O 32 OBn O O34 OBn 16 14 O 23 22 17 21 12 O 19 O O 29 OH e O OMe OBn +NMe3I731 O h, i O OBn 33 ...A I Kotyatkina, V N Zhabinsky, V A Khripach It is assumed that compound 36 is a potential carcinogen and plays a key role in cell responses to some hormones and drugs. Structurally, lingbiatoxin A (36) represents a tricyclic compound the indole fragment in which is fused to a nine-membered ring. MOMO MOMO CNO c N OH a, b (CH2)3OTBS 37 (CH2)3OTBS 38 Pri OTBS MeN d, e, f, g (CH2)3OTBS O N N OMOM CO2Et 40 Pri OTBS h MeN (CH2)3OTBS OH O OH NH41 Pri Pri OTBS MeN HN OH MeN O ... NH OH NH 35 36 OH Pri MOM�MeOCH2, TBS�SiMe2But; OTBS N (a) ButOCl,778 8C; (b) Et3N, 20 8C; (c) ( EtO2CN 39), Me N, PhH, 80 8C, 20 h (78%); (d ) HCl, MeOH (80 8C); (e) TBSCl, HN DMAP, THF; ( f ) 5%KOH, MeOH; (g) H2, Ra/Ni, MeOH, H2O, AcOH; (h) TBSOTf, CH2Cl2 (68%).The strategy of this synthesis was based on the reaction of the nitrile oxide 37, generated from the chiral oxime 38, with the pyrrole derivative 39 as the dipolarophile. The attempts to synthesise hydroximoyl chloride (bromide) from the oxime 38 using conventional halogenating reagents (e.g., N-chloro- or N-bromosuccinimide) were without success. Positive results were attained with tert-butyl hypochlorite in dichloromethane at 778 8C. Dehydrochlorination of hydroximoyl chloride by trie- thylamine at 20 8C afforded a highly stable nitrile oxide 37, which was isolated in a pure state and characterised.The cycloaddition of the nitrile oxide 37 to the alkene 39 in benzene with heating gave 4,5-dihydroisoxazole 40, which represented a mixture of diaster- eomers (2.5 : 1). The synthesis of hydroxy ketone 41 included manipulations with protective groups, elimination of the N-ethoxycarbonyl group and hydrogenolysis of 4,5-dihydroisox- azole under standard conditions. tert-Butyldimethylsilyl triflate proved to be the best catalyst in the formation of the annelated phenyl ring 61 of the indole 35, a convenient intermediate for lingbiatoxin A (36). 4. Synthesis of (+)-phyllanthocin Phyllanthocin (42) (Scheme 1) is an aglycone of the glycoside phyllanthoside isolated from the roots of the South American tree Phyllanthus acuminatus in 1977.62 This glycoside manifests high activity against mouse leukemia P 388 and mouse melanoma B16; therefore, it was decided to carry out its clinical trials as an1,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues Ac O O NOH H a b, c, d O Me O + Cl N O O 45 43 44 H O Ac OTBS e OH N H N H O O MeO2C 48a 46 MeO2C O OH+ OMe N OMe OH N H H O O MeO2C MeO2C 49aO O + OH H H O 50a MeO2C MeO2C (a) PhMe, D (45%); (b) K2CO3, MeOH; (c) Cl(S)COPh, DMAP, CH2Cl2 (83%); (d) Bu3SnH, azoisobutyronitrile (AIBN); (e) OHC LDA, THF (75%); ( f ) 5%HF, MeOH, 20 8C (70%); (g) H2, Ni/Ra, H3BO3, MeOH±H2O (89%); (h) CF3SO3H, CH2Cl2; (i ) MeS(O)=CH2, DMSO, THF, 1 h (89%); ( j ) trans-PhCH=CHCOCl, DMAP, CH2Cl2 (40%).anticancer drug for humans.63 Several structurally related com- pounds were isolated and given a common name `phyllanthosta- tins'.64 Total syntheses of (+)-phyllanthocin (42) have been described in a number of papers.65 ± 68 One of them involves 1,3- dipolar cycloaddition of a nitrile oxide to the cyclohexene deriv- ative 43. A detailed analysis of regio- and stereochemistry of the cycloadducts has been carried out (see Scheme 1).69 Lactone 43 was used as a starting compound for an increase in the stereo- and regioselectivity of the subsequent 1,3-dipolar cycloaddition reaction. The cycloadduct 44 of the required stereo- and regiochemistry was prepared by slow thermal generation of highly reactive nitrile oxide from the hydroximoyl chloride 45 in boiling toluene in the presence of the lactone 43 (yield 45%).4,5-Dihydroisoxazole 46 was synthesised from compound 44 in three steps. Aldol condensation of the optically active aldehyde 47 with the ketone 46 gave a mixture of adducts 48a,b in a 1 : 1.2 ratio. It is of note that several attempts to open the heterocycle in compounds 48a,b failed. Increased robustness of the 4,5-dihy- droisoxazole ring is presumably due to its conjugation with the keto group. A mixture of isomers 48a,b was converted into a mixture of methylglycosides 49a,b followed by hydrogenolysis of theN7O bond in 4,5-dihydroisoxazole fragments and cyclisation of the intermediates which gave a mixture of spiroketals 50a,b (1 : 18).The main isomer 50b was converted to the target product, viz., (+)-phyllanthocin (42). 5. Synthesis of vitamin A Vitamin A and its analogues remain in the focus of attention of synthetic chemists due to their prominent biological and pharma- cological activities.70, 71 The Grignard reaction between com- pounds incorporating C6- and C14-fragments of vitamin A is one of the most general approaches to the synthesis of the vitamin A backbone.72, 73 An alternative strategy for the construction of the basic backbone 74 consists in the simultaneous formation of the C7C bond and the introduction of functional groups in the interaction of the nitrile oxide 51 (the C14-fragment) with the alkene 52 (the O OTBS f + OH N H O 48b MeO2C O O g H OH O OH MeO2C 49b O O i, j O H O O OH 50b MeO2C 42 C6-fragment) resulting in 3,5-disubstituted 4,5-dihydroisoxazole 53.The cleavage of the N7O bond was achieved through the previously developed procedure using Mo(CO)6.48 The resulting b-hydroxy ketone 54 was dehydrated and enone 55 was reduced by NaBH4 to the intermediate 56, which is common in the synthesis of vitamin A. This scheme allows one to obtain large amounts of vitamin A and easy introduction of new functional groups in the synthesis of its analogues. OAc CNO+ 51 52 N O 53 OH O 54 O 55 OH (a) Mo(CO)6, MeCN (60%); (b) MsCl, Et3N, 0 8C; (c) NaBH4 (70%).645 Scheme 1 h OH O Ph O OOTBS (47), OAc a b OAc c OAcOAc 56646 6.Synthesis of burseran and brassilignan Preparations based on aloe have long been known in folk medicine.75, 76 Some aloe components are related to lignans, while certain representatives of this family possess antitumour activities and prevent metastasis.77, 78 Several approaches to the synthesis of natural lignans and their analogues manifesting biological activities have been developed.79 ± 82 In the majority of these syntheses, chiral compounds were used as starting materials. Achiral starting compounds were recommended for the synthesis of optically active natural lignans, viz., burserans 57e and 58e and brassilignans 57c and 58c, and some of their analogues.83 R1 R1 a b c O N O O O O HO 59a ± e 60a ± e R1 R1 R1 d O + O O AcO HO HO 62a ± e 61a ± e 63a ± e R1 R1 R1 g e f 4 62a ± e O O O 3 2 R2 R2 TsO 57a ± e 64a ± e 65a ± e SPh R1 R1 e, f, b h 63a ± e O O R2 HO 58a ± e 66a ± e OMe R1=R2= (a); R1=R2= (b); R1=R2= (c); OMe OMe OMe O R1=R2= (d); R1= ,R2= ( OMe e); O OMe O O (a) R1CCl=NOH, Et3N, Et2O,*20 8C (58% ± 84%); (b) H2, Ni/Ra, EtOH, H3BO3; (c) H2, Pd/C, MeOH±H2O; (d) CH2=CHOAc, lipase PS; (e) MeLi, THF,778 8C, TsCl; ( f) R2CH2SPh, BuLi, THF, 0 8C; (g) Ni/Ra, EtOH, D, 20 h; (h) K2CO3, MeOH.1,3-Dipolar cycloaddition of aromatic nitrile oxides to 2,5- dihydrofuran yielded furoisoxazoles 59a ± e.Hydrogenolysis of the cycloadducts 59a ± e over Raney nickel in the presence of a large excess of boric acid gave b-hydroxy ketones 60a ± e the keto group in which was reduced by hydrogen on palladium. Lipase PS was used to separate the optical antipodes of the resulting alcohols 61a ± e. The absolute stereochemistry of alco- hols 62a ± e and acetates 63a ± e was established later, following completion of the synthesis of the natural compounds 57e, 58e, 57c and 58c. Tosylation of compounds 62a ± e and 63a ± e (after preliminary hydrolysis) and subsequent nucleophilic substitution of the secondary tosyloxy group pursued two goals, viz., tntroduction of the second aromatic substituent and the inversion of the C(3) centre so that the configurations of the substituents corresponded to those of the natural compounds.p-Toluenesul- fonates 64a ± e gave a mixture of diastereomeric sulfides 65a ± e; their desulfurisation with Raney nickel in EtOH gave the target products 57a ± e in a total yield of 6%± 16%. The same reaction sequence was applied to the isomers 66a ± e resulting in the preparation of optically active products 58a ± e (yield A I Kotyatkina, V N Zhabinsky, V A Khripach 6%± 14%). Thus, a series of natural compounds, viz., burserans 57e and 58e, brassilignans 57c and 58c and artificial analogues viz., dehydroxycubebins 57d and 58d, 3,4-bis(3-methoxybenzyl)- tetrahydrofurans 57b and 58b, 3,4-dibenzyltetrahydrofurans 57a and 58a, were prepared. This method 83 gives an access to a vast variety of natural and non-natural lignans including their aza analogues owing to the high accessibility of 2,5-dihydrofuran, aromatic nitrile oxides and diverse phenyl sulfides.7. Synthesis of higher monosaccharides The role of monosaccharides in vital activities of animals, plants and human beings is generally acknowledged. The discovery of antibiotics 84, 85 containing higher monosaccharides gave strong impetus to investigations into their synthesis.86, 87 An approach described by Poton and Young 88 is based on cycloaddition of accessible unsaturated monosaccharides to nitrile oxides with subsequent reduction of the dihydroisoxazoles formed. Thus the reaction of the alkene 67 derived from D-glucose with the nitrile oxide 68 gave a mixture of diastereomeric 4,5-dihydro- isoxazoles 69a,b in a 14 : 86 ratio.Compound 69b gave the dihydroxy ketone 70 in two steps; its reduction with sodium borohydride yielded a mixture of 6-deoxy-D- and 6-deoxy-L- glycero-D-gluco-octofuranoses 71 and 72. a R +EtO2CCNO 68 67 O N N O b, c + H R EtO2C EtO2C R H 69b 69a OH OH OH OH OH O d HO HO 7 5 +HO R R R 70 71 (27%) 72 (43%) O O ; R= O BnO (a) Et2O, Et3N, 14 h (75%); (b) NaBH4, THF, EtOH; (c) H2, Pd/C, H3BO3, MeOH±H2O, 18 h (78% 69b); (d ) NaBH4, EtOH, H2O. The alkene 67 and D-glyceronitrile oxide 73 were used in the synthesis of (7R)- and (7S)-nonofuranoses 74 by the same reaction scheme. OH OH O 7 5 O O O O ... O 67 + BnO O CNO 73 (7R)-74, (7S)-74 (8S)- And (8R)-7-deoxydecopyranoses 75 were prepared from the nitrile oxide 73 and the alkene 76 derived from D-galactose. O O ...+ 73 O O O 76 OH OH O O 8 6 O O O O O (8S)-75, (8R)-751,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues 85 The configurations of the C(5) and C(7) centres in compounds 71, 72 and 74 and of the C(6) and C(8) centres in compounds 75 were established on the basis of 1H NMR spectroscopic data and stereochemistry of their precursors, viz., 4,5-dihydroisoxazoles, and confirmed by X-ray diffraction analysis. This approach enables the synthesis of diverse higher monosaccharides. 8. Synthesis of a heterocyclic analogue of daunomycin O HO Daunomycin is a typical representative of anthracycline anti- biotics used in the chemotherapy of malignant tumours.89, 90 However, its application is restricted due to side effects including high cardiotoxicity.An attempt was made to synthesise modified anthracycline derivatives in which the benzene rings (D) is replaced by a heteroaromatic rings. The daunomycin analogues thus synthesised contained thiophene 91 or indole fragments 92 as rings D and manifested high activities comparable to that of daunomycin, but lower toxicities. The synthesis of compound 77, an intermediate in the synthesis of the daunomycin analogue containing an isoxazole fragment as ring D, has been developed.93 O Ph O Ph O a b N O O N O O EtO2S SO2Et SO2Et SO2Et 78 80 i, f OH O O 90 O EtO2S81 Ph c, d, e A B A N B 78+ D C O MeO OH OH OH O OMe 79 77 (a) 2 equiv. BuLi, THF, 0 ± 20 8C, 6 h (90%); (b) NaOCl, CH2Cl2, 710 to720 8C, 5 h (80%); (c) SOCl2 ± Py,710 8C, 40 min; (d) H2, Ni/Ra, H3BO3, MeOH±H2O (60%); (e) H2, Pd/C (95%); ( f ) TsOH, PhH, 40 8C, 30 min; (g) (H2N)2C=NH, PhH, D, 36 h (35%); (h) HNO3; (i) Li ±EtNH2,770 8C, 30 min (85%).(a) PhCCl=NOH, molecular sieves, 20 8C, 10 h; (b) SiO2 (85%); (c) LDA, THF,778 8C; (d)72 8C, 120 h (40%); (e) BCl3,778 8C, 45 min (50%). The key stage in this synthesis is the annelation of furoisox- azole 78 and the bicyclic derivative 79 (the DC+BA strategy) under the action of lithium diisopropylamide.Compound 78 was synthesised by cycloaddition of benzonitrile oxide to 4,5-di(eth- ylsulfonyl)-2,5-dihydrofuran-2-one 80. Numerous experiments showed 94 that this dipolarophile far exceeds other dipolarophiles as concerns reactivity. Moreover, the presence of the ethylsulfonyl group at the C(5) atom significantly affects the regio- and stereo- chemistry of the cycloaddition reaction, whereas the ethylsulfonyl group in position 4 enables subsequent aromatisation of com- pound 81 into isoxazole 78. V. Intramolecular 1,3-dipolar cycloaddition reactions of nitrile oxides 1. Stereoselective synthesis of ptilocaulin and its epimer Aldol condensation of the ketone 85 with the hexenal oxime (86) dianion yields the b-hydroxy oxime 84. Its treatment with sodium hypochlorite gives tricyclic 4,5-dihydroisoxazole 87 as a mixture of four diastereomers. Compound 87 is dehydrated into a 1 : 1 mixture of unsaturated 4,5-dihydroisoxazoles 88 and 89 which are further subjected to reductive scission over Raney nickel.The unsaturated ketol 90 is the key intermediate in the synthesis of ptilocaulin (83) and its C(7) epimer (82).97, 98 The enone 91 prepared from the ketol 90 by hydrogenation of the double bond over palladium and subsequent dehydration reacted with guanidine to give isoptilocaulin 82. The epimer of enone 91 with the b-configuration of the methyl group at C(7) (compound 92) was prepared by reduction of the double bond in ketol 90 with lithium in diethylamine (in this case, the carbanion undergoes axial protonation) with subsequent dehydration.The use of lithium in liquid ammonia made it possible to achieve simulta- neous reduction of the double bond and the keto group. Ptilocau- lin (83) was prepared by heating of the enone 92 with guanidine. Compounds 82 and 83 were isolated as nitrates. 2. Synthesis of (7)-specionin Ptilocaulin (82) and its epimer at the C(7) atom, viz., isoptilocaulin (83), isolated from the sea sponge Ptilocaulis spiculfer in 1982 95 manifest antileukemic and antibacterial activities. These com- pounds have relatively simple but unusual structures in which guanidine is annelated with the hydrindan system. A seven-step stereoselective synthesis of compounds 82 and 83 has been developed,96 which includes the formation of a six-membered carbocycle by intramolecular cycloaddition of a nitrile oxide to the double bond in the cyclopentene derivative 84.(7)-Specionin (93) was isolated from leaf extracts of the tree Catalpa speciosa.99 This compound manifests insecticidal activity against various pests of coniferous plants which inflict severe damages to the wood-processing industry. The first synthesis of racemic specionin was carried out in 1985.100 Synthesis of the optically active compound based on the nitrile oxide-based approach was developed by Curran et al.41 The 4,5-dihydroisox- azole intermediate 94 was synthesised from the acetal 95 in eight steps. O +BunCH2CH NOH Me 86 O ONC Bun Me OH 87 N N O Bun + Me 88 89O O Bun e, f Me 90 91 O HN Bun g, h 3 1 Me 92 83 647 HC HON Bun b a Me OH 84 N Bun c Me OH d Bun Me NH.HNO3 NH HN Bun Bun 3 g, h 67 45 1 Me Me 82 NH.HNO3 NH Bun 67 45 Me648OAc f a, b, c d, e O2N(H2C)2 O O O PhS OEt OEt OEt MeO2C MeO2C 95 97 96 (75%) O N O N O N H H H g, h i, j, k l O O O PhS O H H H MeO2C MeO2C OEt TBSOCH2 OEt OEt 98 94 99 OH O OC(O)C6H4OH-4 H H 6 ...3 5 8 1 9 O O O O H H HOCH2 TBSOCH2 OEt OEt 100 93 (b) 110 8C; (c) MeI, KF±K2CO3; (d ) LDA, MeN (a) LDA, TBSCl, O Me N PhSSPh; (e) LDA, CH2=CHNO2 (85%); ( f ) p-ClC6H4NCO, Et3N, 110 8C (89%); (g) m-chloroperbenzoic acid (m-CPBA); (h) PhH, 80 8C; (i) Bui2BunAlHLi (42%); ( j ) TBSCl, DMAP, Et3N (72%); (k) 3,5-dinitroperbenzoic acid, Na2HPO4, CH2Cl2 (77%); (l) H2, Rh/Al2O3 (57%).The Ireland ± Claisen rearrangement yielded compound 96; its sulfenylation and the addition of the a-sulfite formed to nitro- ethylene led to the derivative 97, which was further involved in the intramolecular cycloaddition of the nitrile oxide fragment to the double bond. The sulfide group in the tricyclic 4,5-dihydroisox- azole 98 was oxidised and the sulfoxide formed was boiled in benzene, which resulted in elimination of PhSO2H and the formation of a double bond. Selective reduction of the ester group in the derivative 94 was carried out using a complex prepared from butyllithium and diisobutylaluminium hydride; the resulting alcohol was converted into the silyl ether.Its epoxidation by 3,5-dinitroperbenzoic acid could be performed due to the resistance of the dihydroisoxazole ring to oxidants; this reaction was stereoselective and yielded a single isomer (99). The dihy- droisoxazole ring in compound 99 was opened smoothly by hydrogenolysis in the presence of 5% rhodium on Al2O3 in aqueous methanol resulting in b-hydroxy ketone 100. The use of other catalysts (e.g., Ni-Ra, Pd/C, Pt2O) in this step resulted in the destruction of the molecule. (7)-Specionin (93) was obtained from its precursor 100 in eight steps; the total yield was 0.5% with respect to compound 95. 3. Synthesis of testosterone Total synthesis of steroids, which play an extremely important role in the human organism as well as in animal and plant organisms, has been the subject of numerous investigations.101, 102 The use of 4,5-dihydroisoxazoles in the formation of steroid backbones was described back in the 1960-70's.In some studies, 4,5-dihydroisoxazoles were used as parts of alkylating agents bearing a masked b-diketone function 103, 104 in the synthesis of D-homotestosterone, progesterone, testosterone and 13-ethyltes- tosterone. The synthesis of testosterone (101) made use of a new approach based on intramolecular 1,3-dipolar cycloaddition.105 This procedure enabled the construction of the ring B with the b-configuration of the C(19) methyl group and simultaneous introduction of functional groups for further synthesis of ring A.Starting from the optically active indanone 102, the oxime 103 was A I Kotyatkina, V N Zhabinsky, V A Khripach prepared in eight steps (total yield 37%). The intramolecular 1,3- dipolar cycloaddition of the nitrile oxide prepared from this oxime occurred stereospecifically and resulted in the cycloadduct 104. Although the stereochemistry of the angular methyl group of 4,5- dihydroisoxazole formed cannot be inferred from the spectro- scopic data, the structure 104 was assigned to this compound 105 on the assumption 106, 107 that the chair-like conformation is more preferable in the transition state than the boat-like conformation leading to the C(10) isomer. OBut OBut H a ... H H O HON 103 102 OBut OBut H H H d b, c O H H H O H N O 105 104 OBut OH H H e, f, g H H H H MeCO O O 101 107 (a) NaClO, CH2Cl2 (87%); (b) H2, Ni/Ra, B(OMe)3, MeOH (97%); (c) SO3 ± Py, DMSO (97%); (d ) MeCOCH=PPh3 (106), Me2C6H3 (89%); (e) H2, 10% Pd/C; ( f ) KOH, MeOH; (g) CF3CO2H (76%). The reductive opening of 4,5-dihydroisoxazole 104 over Raney nickel in the presence of trimethyl borate in aqueous methanol gave a hydroxy ketone; its oxidation yielded the aldehyde 105.A three-carbon fragment was introduced by the Wittig reaction with 1-triphenylphosphoranylidenepropan-2-one (106). The resulting enone 107 was converted into testosterone tert-butyl ether as a result of catalytic hydrogenation and treat- ment with potassium hydroxide in methanol, eventually resulting in the closure of the ring A.Removal of the protective group from the C(17) hydroxy group completed the synthesis of testosterone 101 in a total yield of 17%. Thus, the use of intramolecular 1,3-dipolar cycloaddition of nitrile oxide enabled effective con- struction of testosterone rings A and B. 4. Synthesis of calicheamicin gI1 Compounds related to antitumour antibiotics of the enedyine series, e.g., calicheamicin gI1, esperamycin A1, dinemycin A, were isolated from cultured bacterial cells of Micromonospora echino- spora.108, 109 These compounds produce strong therapeutic effects by cleaving double-stranded DNA at specific sequences.110, 111 A number of papers published soon after their discovery 112 ± 116 were devoted to the synthesis of their main backbones, e.g., to the racemic calicheamicin aglycone, calicheamicinone (108).The syntheses of oligosaccharide fragments attached to the hydroxy group at C(8) of calicheamicinone (108) have also been described.117, 118 The first enantioselective synthesis of (7)-calicheamicinone (108) and a total synthesis of calicheamicin gI1 were carried out by Nicolaou and coworkers.119, 120 This synthesis is based on the use of the intramolecular 1,3-cycloaddition reaction of alkenyl nitrile oxide prepared from the aldoxime 109. This aldoxime was treated with aqueous sodium hypochlorite under standard conditions, which resulted in intramolecular cyclisation and the formation of a 4 : 1 mixture of 4,5-dihydro-1,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues OMEM HON O O OBz 109 O O N d, e O O Me3SiC H OMEM 111O O NO AcOC O Me3SiC 113 O O NO Et3SiOC C CO2Me C C SiMe3 116 O NHCO2Me C C C 8 C HO HO 108 SSSMe MEM is MeO(CH2)2; (a) NaOCl, CH2Cl2, 25 8C, 2 h (65%); (b) NaOMe MeOH, 0 8C (100%); (c) CrO3, H2SO4, Me2O, 0 8C (95%); (d ) 1.5 equiv.Me3SiC:CLi, THF, 778 8C (67%); (e) Ac2O, 25 8C, 3 h; ( f ) 10 equiv. ZnBr2, CH2Cl2, 25 8C, 2 h; (g) COCl2, DMSO (54%); (h) Ph3P=CHCO2Me, PhMe, 90 8C, 16 h (84 %); (i) K2CO3, MeOH±CH2Cl2, 0 8C, 6 h (90%); ( j) Et3SiOTf, 2,6-lutidine, CH2Cl2, 0 8C, 30 min (96%); (k) (Z)-Me3SiC:CCH=CHCl (115), Pd(PPh3)4, CuI, BuNH2, PhH, 0 8C, 2 h (91%); (l) Mo(CO)6, MeCN±H2O, 80 8C, 1.5 h (82%).isoxazole diastereomers; the main isomer 110 was isolated in 51% yield. After removal of benzoyl protection, the secondary alcohol O O O O O HO 120 O HO MeO2C 123 (a) NaOCl, CH2Cl2, Et3N (61%); (b) Ra/Ni, H2, MeOH±H2O; (c) MeSO2Cl, CH2Cl2, Et3N. 649 O O NO b, c a BzO H OMEM 110 O O N f, g formed was oxidised by the Jones reagent to the ketone 111. The nucleophilic addition of lithium (trimethylsilyl)acetylenide to the ketone 111 was fully stereoselective; the hydroxy group in the resulting acetylenic alcohol was protected by acetylation. Removal of the methoxyethoxymethyl group in compound 112 and subsequent Swern oxidation of the alcohol formed yielded unexpectedly isoxazole 113 instead of 4,5-dihydroisoxazole. The use of other oxidants gave the same results.Therefore, the strategy of the synthesis had to be changed in favour of the Wittig reaction of the ketone 113 with methyl triphenylphosphoranylideneace- tate, which resulted in selective synthesis of compound 114 having the E-configuration of the double bond in the enediyne fragment. O AcOC H OMEM 112 O O After removal of the protective trimethylsilyl group, the enyne group was introduced by high-yielding palladium-catalysed addi- tion of (Z)-chloroenyne (115), which gave the enediyne 116. The opening of the isoxazole ring in this molecule under the action of molybdenum hexacarbonyl in aqueous acetonitrile resulted in the enamino aldehyde 117.N i, j, k The final product of this synthesis, i.e., (7)-calicheamicinone h O AcOC (108), was prepared from the aldehyde 117 in 16 steps. The total yield of compound 108 was 2.6% with respect to the starting aldoxime 109. Me3SiC CO2Me 114 5. Synthesis of zoapatanol O O NH2 l ... Et3SiO CHO C C CO2Me C C SiMe3 117 The intramolecular cycloaddition reaction was used to prepare compound 118, the optically active intermediate in the synthesis of zoapatanol (119), one of novel diterpenoids containing an oxe- pane ring.121 This is endowed with contraceptive activity 122, 123 and was isolated from the leaves of the Mexican plant Montanoa tomentosa.124 Syntheses of racemic zoapatanol 125, 126 and the optically active product (Scheme 2) have been described.127 D-Glucose diacetonide (120) was used as the starting com- pound in the 13-step synthesis of the oxime 121.The intra- molecular nitrile oxide cycloaddition reaction was carried out under standard conditions. The resulting dihydroisoxazole 122 (a mixture of diastereomers) was reduced over Raney nickel to the hydroxy ketone 123. Its dehydration gave a,b-unsaturated oxo ester 118 which is considered 121 to be a convenient intermediate in the synthesis of zoapatanol 119. VI. Syntheses based on enantiocontrolled 1,3-dipolar cycloaddition reactions of nitrile oxides The optical purity of natural compounds is of crucial importance where they are used as medicinal drugs or plant protectors. In contrast to non-symmetrical Diels ± Alder reactions, studies on enantiocontrolled cycloaddition reactions of nitrile oxides have a relatively short history.The feasibility of stereocontrolled cycloaddition using opti- cally active nitrile oxides or alkenes has been studied.128, 129 Dipolarophiles containing bulky chiral auxiliaries have become especially popular. As a result, the nitrile oxide attack occurs in a strictly stereoselective manner; the chiral substituents are then removed. Chiral (7)-menthyl acrylates,130 bornyl crotonates,131 alkenes containing tricarboxylic Kemp's acid 132 or the Oppolzer Scheme 2 O O O N ... O O a b HON O O O O MeO2C MeO2C 122 121 O OH O O O O O c (CH2)3 ...O O O O O MeO2C HOCH2 119 118650 sultam 133, 134 as substituents as well as alkenes coordinated to iron 135 or cobalt 136 complexes belong to such dipolarophiles. 1. Syntheses using the chiral Oppolzer reagent The chiral Oppolzer reagent, viz., L-camphor sultam (124), was used 137 in the synthesis of several natural compounds, e.g., the sex pheromone of the butterfly Hepialis californicus [(+)-hepialone 125)138], (7)-(1R,3R,5S)-1,3-dimethyl-2,9-dioxabicyclo[3.3.1]no- nane (126),139 the constituent of the Norwegian spruce bark, and (7)-(1S)-7,7-dimethyl-6,8-dioxabicyclo[3.2.1]octane (127)140 iso- lated from hop oil and confering characteristic odour to beer. O O O O Et O HN O 127 125 126 124 SO2 Syntheses of compounds 125 ± 127 were performed according to non-sophisticated and efficient schemes the key step in which included the addition of readily accessible nitrile oxides to the amide 128 prepared by treatment of the chiral sultam 124 with acryloyl chloride in the presence of sodium hydride and CuCl.Subsequent reduction of the adducts 129 resulted in 4,5-dihydroi- soxazoles 130 and regeneration of L-camphor sultam 124. O a RCNO N HN 128 SO2 124 SO2 OH O Bus3BHLi R R N 7124 N O O N SO2 129 130 (a) COCl , NaH, CuCl. (+)-Hepialone (125) was synthesised from the nitro ketal 131.137 The cycloaddition performed under standard conditions 9 yielded a mixture of epimeric 4,5-dihydroisoxazoles (88 : 12); the main diastereomer 132 was isolated by chromatography.Its reduction by L-selectride (Bus3BHLi) gave the alcohol 133 with recovery of the chiral reagent 124. Tosylation of the alcohol 133 and subsequent treatment of the p-toluenesulfonate with lithium a b N O O O O O N NO2 131 SO2 132 O c, d, e f N O H O HO 125 H O O O O OH Et 133 134 (a) 128, PhNCO, Et3N; (b) Bus3BHLi, THF, 25 8C, 30 min (85%); (c) TsCl, Et3N, DMAP, 25 8C, 26 h (100%); (d) Me2CuLi, Et2O,75 8C, 18 h (57%); (e) Ni/Ra, H2O, MeOH, H3BO3 (75%); ( f ) 3 M HCl, Et2O, 25 8C, 20 h (88%). dimethylcuprate led to the replacement of the hydroxymethyl group by the ethyl group. Reduction of 4,5-dihydroisoxazole by A I Kotyatkina, V N Zhabinsky, V A Khripach hydrogen over Raney nickel occurred with the retention of the original configuration of the chiral centre and yielded the b-ketol 134 .Subsequent ring closure under conditions of acid catalysis afforded the pheromone 125. (7)-(1R,3R,5S)-1,3-Dimethyl-2,9-dioxabicyclo[3.3.1]nonane (126) was synthesised from the oxime 135 and the amide 128.137 Cycloaddition gave epimeric 4,5-dihydroisoxazoles (92 : 8); the main isomer was isolated in 89% yield by column chromatogra- phy. Deoxygenation of the hydroxy group had to be carried out following removal of the chiral reagent by L-selectride. c, d, e, f a, b N O H O O O O CH2I (CH2)3 (CH2)3CH NOH 135 136 g O HO H O O (CH2)3 137 O h H HO H HO O O O (CH2)3 126 138 a) 128, NCS, DMF; (b) Et3N, Et2O; (c) Bus3BHLi, THF, 25 8C, 45 min (86%); (d ) TsCl, CH2Cl2, Et3N, DMAP, 9 h (83%); (e) NaI, NaHCO3, MeCOEt, D (98%); ( f ) Ni/Ra, H2, H3BO3, MeOH±H2O (15 : 1), 16 h (74%); (g) Et2BOMe,770 8C, NaBH4, THF±MeOH (86%); (h) Et2O, 3MHCl, 20 8C, 16 h (57%).Initially, this was attempted by radical reduction of the iodide 136 prepared from the corresponding p-toluenesulfonate, which however resulted in racemisation. Numerous experiments allowed finally elaboration of the optimum conditions for such reduction [viz., Bu3SnH, diazabicycloundecene (DBU), AIBN, 50 8C]. Hydrogenation of the 4,5-dihydroisoxazole 136 over Raney nickel, which was accompanied by reductive deiodination, appeared to be the shortest way to the optically pure ketol 137. The target product 126 was obtained by treatment of the optically active 1,3-diol 138 with HCl.(7)-(1S)-7,7-Dimethyl-6,8-dioxabicyclo[3.2.1]octane (127) was synthesised from the oxime 139.137 The optically pure cyclo- adduct 132 was isolated in 70% yield from a mixture of epimers (85 : 15). The Grignard reaction of the 4,5-dihydroisoxazole 132 with MeMgBr gave compound 140, the chiral reagent 124 was recovered simultaneously. Reduction of the dihydroisoxazole 140 with lithium aluminium hydride occurred stereoselectively to give the optically active amino alcohol in 97% yield. The latter was deaminated with sulfamic acid and the diol 141 obtained was treated with an acid, which resulted in the target bicyclic product 127. a, b c N O O O O O N NOH 139 SO2 132 O f d, e N O HO H H O O O O OH OH 140 1411,3-Dipolar cycloaddition reactions of nitrile oxides in the synthesis of natural compounds and their analogues O O 127 (a) 128, NCS, CH2Cl2; (b) Et3N, CH2Cl2 (70%); (c) MeMgBr, THF, 778 8C (72%); (d ) LiAlH4, Et2O, 778 8C (97%); (e) NH2OSO3H, NaOH, CH2Cl2, 1 h, 60 8C (54%); ( f ) PhH, TsOH, 48 h, 60 8C (61%).2. Synthesis of (+)-(S)-gingerol A group of French chemists 141 studied the enantiocontrolled synthesis of dihydroisoxazoles using the chiral acyclic irontricar- bonyl complex 142 as a dipolarophile. The complex 142 was prepared by olefination of optically active aldehydes coordinated to ironpentacarbonyl.135 The method proved to be efficient in the synthesis of (+)-(S)-gingerol (143), a biologically active com- pound 144, 145 isolated from plants.142 ± 145 a BnO (CH2)2NO2+ Me MeO 145 Fe(CO)3 142 O N b Me BnO (CH2)2 Fe(CO)3 MeO 146 O N c, d BnO (CH2)2 Me MeO 144 OH O (CH2)4Me HO (CH2)2 143 MeO (a) PhNCO, Et3N,*20 8C, 48 h (75%); (b) (NH4)2Ce(NO3)6, MeOH, 720 8C, 25 min (62%); (c) H2, Ni/Ra, H3BO3, MeOH±H2O, 3.5 h (80%); (d) H2, 10% Pd/C, MeOH, 20 8C, 40 min (66%).Synthesis of compound 143 has been the subject of numerous studies; two of those employ the 1,3-dipolar cycloaddition of nitrile oxides with subsequent reductive scission of the cyclo- adducts formed.31, 46 The formation of the b-hydroxycarbonyl fragment in gingerol 143 was achieved by enantioselective reduc- tion of chiral enamido ketones 31 and transformation of chiral 3-sulfenyldihydroisoxazoles.46 The 4,5-dihydroisoxazole 144 was synthesised by the 1,3- dipolar cycloaddition of a nitrile oxide to the chiral acyclic irontricarbonyl complex 142.141 The nitrile oxide precursor, viz., the nitrocompound 145, was synthesised in five steps from the readily accessible 4-benzyloxy-3-methoxybenzaldehyde (total yield 33%). The cycloaddition of triene 142 to the nitrile oxide generated from the nitro compound 145 yielded a mixture of diastereomeric 4,5-dihydroisoxazoles in a 89 : 11 ratio; the main isomer 146 was isolated in 75% yield.The irontricarbonyl com- plex was decomposed by oxidation with cerium ammonium nitrate in methanol. The final product, viz., (+)-(S)-gingerol (143), was prepared from the 4,5-dihydroisoxazole 144 in two steps.First, 4,5-dihydroisoxazole was reduced into the corre- sponding b-hydroxy ketone over Raney nickel under standard conditions. In this step, the diene group was partly reduced. 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年代:2001

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Russian Chemical Reviews 70 (8) 655 ± 672 (2001) Sulfur ylides in the synthesis of heterocyclic and carbocyclic compounds S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov Contents I. Introduction II. Rearrangements of cyclic sulfur ylides III. Intramolecular cyclisation of sulfur ylides IV. Reactions of thiocarbonyl ylides V. Cycloaddition of ylides to alkenes Abstract. of synthesis the in ylides sulfonium of use the on Data Data on the use of sulfonium ylides in the synthesis of carbocyclic the over published compounds heterocyclic and carbocyclic and heterocyclic compounds published over the last last 15 years are analysed, systematised and generalised. The bibliog- 15 years are analysed, systematised and generalised. The bibliog- raphy includes 139 references raphy includes 139 references.I. Introduction The chemistry of ylides attracted considerable interest in the early 1950s after Wittig has discovered the reaction of phosphonium ylides with carbonyl compounds giving rise to alkenes.1 Inves- tigations carried out by Corey 2 and Franzen 3, 4 extended the Wittig reaction to sulfur ylides and initiated extensive studies of sulfonium ylides. The further development of the chemistry of these compounds demonstrated that they could be widely used in organic synthesis. Sulfur ylides contain a negatively charged carbon atom directly bound to a positively charged sulfur atom. In the general form, these compounds can be represented by two resonance structures, viz., ylide 1 and ylene 2.5 + 7 S C S C 2 1 Sulfonium (1) and sulfoxonium (3) ylides containing two organic substituents at the sulfur atoms are most often used in organic synthesis.6± 9 Sulfinyl ylides (4), sulfonyl ylides (5), thiocarbonyl ylides (6) and iminosulfuranes (7) are also known.8 S N Lakeev, I O Maydanova Institute of Biology, Ufa Scientific Centre of the Russian Academy of Sciences, prosp.Oktyabrya 69, 450054 Ufa, Russian Federation. Fax (7-347) 235 26 41. Tel. (7-347) 235 53 41. E-mail: bmch@anrb.ru (S N Lakeev) F Z Galin Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, prosp. Oktyabrya 71, 450054 Ufa, Russian Federation. Fax (7-347) 235 60 66. Tel. (7-347) 235 52 88. E-mail: galin@anrb.ru G A Tolstikov N N Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, prosp.Akad. Lavrent'eva 9, 630090 Novosibirsk, Russian Federation. Fax (7-383) 234 47 52. Tel. (7-383) 234 38 50. E-mail: kim@nioch.nsc.ru Received 21 December 2000 Uspekhi Khimii 70 (8) 744 ± 762 (2001); translated by T N Safonova #2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n08ABEH000645 655 656 665 667 669 O O O + 7 7 7 + + 7 + + 7 S C S C S C S C S N O 4 5 7 6 3 Sulfur ylides act as nucleophilic reagents, their reactivities being inversely proportional to their stability. Ylides are stabilised through the electron density delocalisation under the action of electron-withdrawing substituents at the carbanionic centre.The properties of stabilised sulfur ylides are summarised and com- pared with the properties of non-stabilised ylides in reviews.6, 10, 11 The reactions of sulfur ylides with compounds containing C=X bonds (X=O, C or N) gained wide acceptance in organic synthesis. These reactions proceed as the nucleophilic addition followed by 1,3-elimination of a sulfur-containing group to form epoxide, cyclopropane or aziridine, respectively.6 R3 R3 R4 R3 X C 7X C + 7 C R4 R12 S CHR2 R4 X 7R12 S C C R2 R2 1S + R2 H H X=O, C, N. The data on these reactions were surveyed in detail in the monograph 6 and in a series of studies.7, 12 ± 16 Due to their zwitterionic character, sulfonium ylides are also widely used in rearrangements generating new C7C bonds (often with high stereo- and regioselectivity).16 ± 20 In the last decade, interest in sulfur ylides was quickened owing to their successful use in asymmetric synthesis.16 A one-stage procedure, which has been developed recently for the synthesis of optically active epoxides and aziridines,21, 22 represents a considerable achievement in this field.Optically pure sulfur ylides, which are generated in situ in reactions of catalytic amounts of chiral sulfides with diazo compounds in the presence of dirhodium tetraacetate or copper acetylacetonate, react with aldehydes or imines to give epoxides or aziridines, respectively, and the sulfide is recovered and recycled to the catalytic cycle.This procedure was used for the syntheses of various substituted epoxides and aziridines in good yields and with high enantioselectivity.16, 23 ± 25656 X 7 + ML R3 R22 S CHR3 N2 R1 R3 X LM R22 S N2 R1 H R2 X=Me3Si(CH2)2SO2N, O; ML=Rh2(OAc)4 , Cu(acac)2 . Sulfur ylides also find wide application in the synthesis of other cyclic compounds as well as of hetero-, macro- and polycyclic structures, including natural compounds and their analogues. Special-purpose reviews devoted to this aspect are lacking. The only study dealing with this problem 13 has covered the results published up to 1986 inclusive. The present review surveys the data on the use of sulfur ylides in syntheses of complex cyclic, heterocyclic and natural compounds published over the last 15 years.Systematisation and analysis of the available data will help in evaluating the possibilities of the use of sulfur ylides in the synthesis of complex structures and give a deeper insight into prospects of the further development of this line of investigation. Reactions of ylides giving rise to three-membered carbo- and heterocycles are beyond the scope of the present review. II. Rearrangements of cyclic sulfur ylides Sigmatropic rearrangements of cyclic sulfur ylides were inves- tigated in most detail. In these studies, sulfur ylides were used in the synthesis of various carbo- and heterocyclic compounds. The reactions are carried out with the use of either ylides generated in situ or individual compounds prepared in advance.The 1,2- Stevens rearrangements 18, 20 and 2,3-sigmatropic rearrangements of sulfur ylides find most extensive synthetic applications.16 ± 20, 26 1. 1,2-Stevens rearrangements The 1,2-Stevens rearrangements of sulfur and nitrogen ylides were discovered in 1928.27 According to orbital symmetry rules, the concerted mechanism of this thermal rearrangement is forbid- den.28 Hence, the most probable mechanism involves the dissoci- ation ± recombination process. It was demonstrated 29, 30 that the rearrangements proceed through the formation of a radical pair, the rate of radical recombination being higher than the rate of their diffusion into a solvent. R2 7 + *1,2 R2 S R2 R1 SR3 R1 R1 SR3 R3 The employment of rearrangements of sulfur ylides in the synthesis of cyclic compounds appeared to be particularly prom- ising in connection with the development of the carbene method for the generation of cyclic sulfur ylides.20, 31 ± 34 Ylides are formed through the electrophilic addition of a carbenoid species, which is generated from the diazo group under the action of transition metal (predominantly, Rh or Cu) compounds, to the sulfur atom.34 These reactions are most often performed with stable diazoesters or diazoketones.Recently,35, 36 it was demonstrated that trimethylsilyldiazomethane can also be successfully used for the generation of sulfur ylides. S ML + 7 C ML C N2 S C 7N2 Sometimes the process is complicated by a side reaction of insertion of the carbene formed into the C7H bond.Thus intramolecular cyclisation of diazosulfide 8 afforded not only the major reaction product 9, generated through the 1,2-rearrange- ment of intermediate unstable tricyclic thiophenium ylide 10, but also a product of insertion into the C7H bond (11).37 S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov S MeO2CCC O8 N2 *1,2 O S+7 O S CO2Me CO2Me Rh2(OAc)4 10 9 OH MeO2C S 11 New stable four-to-seven-membered cyclic ylides were syn- thesised by intramolecular cyclisation of diazosulfides and their thermal rearrangements giving rise to heterocyclic compounds were carried out virtually simultaneously by two independent research groups.38 ± 40 It was demonstrated 38, 39 that six- and seven-membered cyclic ylides 12a,b underwent the 1,2-Stevens rearrangement on heating to give the corresponding substituted cyclic thioesters 13a,b in 40%± 60% yields.Decomposition of the diazoallyl sulfide 12b catalysed by Rh2(OAc)4 afforded directly the rearranged thiepane 13b (the yield was 59%); intermediate cyclic sulfonium ylide was not detected. The fact that the thiepane 13b was formed through the 2,3-rearrangement rather than through the [1,2]-shift was exem- plified by the reactions of diazosulfides 12c ± e containing the prenyl, cinnamyl or crotyl substituent at the sulfur atom, which were accompanied by the allylic inversion. O O Rh2(OAc)4 D (H2C)n (H2C)n 7 + PhH, D CO2Et RS CO2Et N2 R S 12a,b O (H2C)n CO2Et R S 13a,b R=Bn, n=1 (a); R=H2C=CHCH2 , n = 2 (b).O O Rh2(OAc)4 D (H2C)n (H2C)n 7 + S CO2Et CO2Et S N2 R2 12c ± e R1 R2 R1 O (H2C)n CO2Et S R1 R2 13c ± e R1=R2=Me, n=1 (c); R1=Ph, R2=H, n=2 (d); R1=Me, R2=H, n=2 (e). On heating, four- (14) and six-membered S-phenyl-substi- tuted (15) sulfur ylides underwent the 1,4-rearrangement to form derivatives of dihydro- (16) and tetrahydrofuran (17), respec-Sulfur ylides in the synthesis of heterocyclic and carbocyclic compounds tively.40 Seven-membered and some six-membered cyclic ylides decompose giving rise to unsaturated sulfur-free compounds.40 OEt CO2Et O O 7 O CO2Et Rh2(OAc)4 808C SPh + N2 S PhSH2C Ph O 16 (50%) 14 O CO2Et PhS 7 O CO2Et Rh2(OAc)4 CO2Et 1608C + O S N2 PhS(H2C)3 Ph 15 17 The 1,2-rearrangement of cyclic ylide 18 stabilised by two ethoxycarbonyl groups, which was formed in the reaction of 2,3- dihydroisothiazol-3-one with diazomalonic ester, was accompa- nied by insertion of carbene into the S7N bond to form 3,4- dihydro-1,3-thiazin-4(2H)-one 19.41 O O O N2C(CO2Me)2 *1,2 NEt + NEt S NEt Rh2(OAc)4 S S CO2Et 7 EtO2C CO2Et EtO2C 18 19 (70%) Substituted 1,3-dithianes 20 were synthesised by the 1,2- rearrangement proceeding with the cleavage of the S7S bond of intermediate 1,2-dithiolane ylides 21.42 The ylides 21 were gen- erated by the reactions of cyclic disulfides with carbenes, which were prepared from diazo compounds under conditions of cata- lytic or photochemical reactions.If cyclic disulfides contain more than four substituents, the C7S bond in the ylides 21 can be cleaved. Subsequent desulfation of intermediates 22 afforded thietanes 23. R3 R3 R4 R1 CR62 R4 R1 R5 R2 + R5 R2 S S S S R6 7 2C 21 R3 R4 R1 R5 R2 S S R6 R6 20 R3 R3 R4 R1 R1 R4 + + R5 R2 R2 R5 S S S S 7 R6 R62 C 27C 22 7R62 C=S R3 R4 R1 R5 R2 S 23 657 The generation of cyclic ylides by intramolecular reactions of sulfur-containing compounds with carbenes followed by their thermal rearrangements was successfully used in the synthesis of carbocyclic natural compounds. Thus the 1,2-rearrangement of ylide 24 proceeded with ring contraction to give substituted cyclopentane 25.The latter served as the key compound in the synthesis of sesquiterpenes ()-cuparene (26) and ()-laurene (27).43, 44 N2 Rh2(OAc)4 SPh Me CO2Et 4-MeC6H4 Me Ph 4-MeC6H4 Me CO2Et 7 S+ PhS 4-MeC6H4 25 24 EtO2C ... 4-MeC6H4 Me Me Me 26 ... 4-MeC6H4 Me Me 27 An analogous strategy was applied to the synthesis of pyrro- lizidine alkaloids, viz., ()-trachelanthamidine (28a), ()-isore- tronecanol (28b) and ()-supinidine (29).45, 46 Diazoketone 30 was converted under the action of a rhodium catalyst into bicyclic sulfonium ylide 31 whose subsequent rearrangement afforded a compound of the pyrrolizidine series (32). The latter was used for the synthesis of the alkaloids 28a,b and 29. Ph SPh S+7 CO2Et Rh2(OAc)4 N (CH2)2CCO2Et N N2 O 30 O 31 R1 H R2 ...N PhS CO2Et 28a,b R1=CH2OH, R2 = H (a); R1=H,R2=CH2OH (b). N CH2OH H O 32 ... N29 1,2-Rearrangements proceed with high stereoselectivity, par- ticularly, at low temperature and in viscous solvents. These reactions involving chiral sulfides can be employed in asymmetric synthesis.18 In particular, the Stevens rearrangement allows one to solve the key problem in the synthesis of natural nitrogen- containing compounds consisting in the stereoselective formation of new C7C bonds at the a position with respect to the nitrogen atom. Thus a new approach to 6-amidocarbopenicillan antibiotics was exemplified by the synthesis of bicyclic b-lactam 33.47 Photolysis of diazoketone 34 afforded ylide 35, which was rearranged to give the compound 33, the new C7C bond being formed stereoselectively.658 N2 O H Bn N hn CO2C6H4NO2-4 Me N O SMe H 34 R Me O O H Bn N 7 Me N +SCO2C6H4NO2-4 Me H 35 R Me O H Bn N O Me N H CO2C6H4NO2-4 SMe R Me 33 (72%) This synthetic approach was further developed in the stereo- selective synthesis of alkaloids (+)-heliotridine (36a) and (+)-ret- ronecine (36b).48 Ph TBSO CO2Bn TBSO 7 SPh S+ N2C(CO2Bn)2 CO2Bn Rh2(OAc)4 NR1 NR1 O 37 O 38 PhS TBSO TBSO CO2Bn H 7 CO2Bn CO2Bn SPh CO2Bn + NR1 NR1 O 39 O 40 (82.6%) R3 CH2OH R2 H ...N 36a,b TBS is ButMe2Si; 36a: R1=(CH2)2OC(O)But, R2=H, R3=OH; 36b: R1=(CH2)2OC(O)But, R2=OH, R3=H.The catalytic reaction of optically active sulfide 37, which can be readily derived from (S)-malic acid, with dibenzyl diazomalonate afforded ylide 38 whose 1,2-rearrangement proceeded with high stereoselectivity. It is believed that the first stage of this reaction involved the cleavage of the C7S bond to produce salt 39. The attack of the carbanion on the C=N bond proceeded predom- inantly from the less shielded side to form 2,3-trans-pyrrolidone derivative 40, which was used as the starting compound in the synthesis of the alkaloids 36a,b. The application of the intramolecular rearrangement of cyclic sulfonium ylides allowed the development of a new method for the preparation of lactones,49 which were used in the synthesis of C-nucleosides.Diazoacetyl thioglycoside 41 was prepared from precursor 42 according to the modified Corey method.50 When refluxed in benzene with a catalytic amount of rhodium acetate, the compound 41 was converted into lactone 45 through sulfur ylide 43 and oxonium intermediate 44. The lactone 45 served as the key compound in the synthesis of nucleoside antibiotic (+)-showdomycin. S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov SPh HC CO SPh HO NNHTs O O N2 O HCCOCl Rh2(OAc)4 PhH O O O O 42 41 (91%) O O O SPh 7 SPh O O O 7 +SPh O O+ O O O O O O O 45 (56%) 44 43 2. 2,3-Sigmatropic rearrangements In the last two decades, the synthesis of cyclic compounds made wide use of 2,3-sigmatropic rearrangements of allylic and benzyl sulfur ylides. Baldwin was the first to carry out these studies 51 ± 53 as early as 1968. Since then the 2,3-sigmatropic rearrangements of ylides have found many applications. The rearrangement of allylic ylides into homoallylic sulfides can be represented in general form as follows: H2C CH CH2CH2 CH2CH RS RS RS+ CH2 H2C CH2 CH2 H2C H2C7 According to the orbital symmetry rules, 2,3-sigmatropic rearrangements are allowed 28 and they proceed either on heating or photolysis of ylides with complete inversion of the allylic substituent.54, 55 Since these reactions proceed by a concerted mechanism, high regio-, diastereo- and enantioselectivity are achieved, which is of particular interest from the standpoint of their application in asymmetric synthesis. A gentle and efficient procedure for the synthesis of 3-allyl- isothiochroman-4-one (46) 56 involves the 2,3-sigmatropic rear- rangement of cyclic sulfur ylide 47 formed by intramolecular cyclisation of diazosulfide 48 under the action of a rhodium catalyst.O O 7 [Rh] *2,3 + S CHN2 S 48 47 O S 46 The use of chiral allylic sulfides in 2,3-sigmatropic rearrange- ments offers considerable possibilities for enantioselective synthe- ses of cyclic compounds, including analogues of natural compounds. Thus the synthesis of optically active thioxanones 49a ± d was based on the 2,3-sigmatropic rearrangement of optically pure cyclic sulfur ylide 51, which proceeded with high asymmetric induction.57, 58 Crotyl thiodiazoester 50 derived from L-valine was converted into the corresponding cyclic allylic sulfur ylide by either rhodium-catalysed intramolecular cyclisation or depro- tonation of sulfonium salt 52 derived from the compound 50.The rearrangement of the ylide 51 afforded four isomeric thioxanones 49a ± d. The best yield and diastereoselectivity were achieved on deprotonation of the sulfonium salt 52.Sulfur ylides in the synthesis of heterocyclic and carbocyclic compounds O Pri [Rh] O RO2C Rh2(OAc)4 O S O N2 (CH2)n Me N2 Pri O 50 + SPh S O HBF4 . Et2O 7 RO2C O Me PhS 51 Pri DBU O O + 778 8C S (CH2)n O BF¡454a,b Me 52 R=Me, Et; n=1, 2. Pri Pri Pri Pri O O O O H H H H S + + + S S S O O O O Lactone 57 was prepared according to an analogous proce- dure and was used in the stereoselective synthesis of perhy- dro[2,3-b]furanone derivative 58.62 Me Me Me Me Me O O 49d 49c 49b 49a PhS ...DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene. EtO2C Isomer ratio 57 Reagent Total yield (%) Starting compound 49d 49c 49b 49a 15traces 2 7221 883 493 84 10 94 4 35 28 66 64 [Rh] [Rh] DBU DBU (Z)-50 (E)-50 (Z)-52 (E)-52 The rearrangement of sulfur ylides, which were prepared by treatment of sulfur-containing diazoketones 59 and 60 with dirhodium tetraacetate in boiling benzene, was used in a new approach to the synthesis of bridging d-lactones 61 64 as well as of spiro-fused five- and six-membered lactones 62a,b 65 and spiro- carbocyclic compounds 62c,d.66 O CO2Et O Rh2(OAc)4 N2 PhH, D SPh The reactions involving the Z-isomers of the compounds 50 and 52 yielded the thioxanone 49a as the major product, whereas the reactions with the participation of the E-isomers gave rise to the thioxanone 49b.This stereoselectivity was attributed 59 to the endo conformation of the allyl-containing five-membered ring in the prevailing transition states A or B. (H2C)n Me R Me 59 O O O O O O 7 49a (H2C)n S S SPh CO2Et + R A Pri Pri 61 R=H, Me; n=1, 2. MeO MeO CH2SPh O O O (H2C)n 7 49b CO2R2 X S + S R1 60 N2 B Pri Pri Ph+ S O 7 R1O2C Substituted five-to-eight-membered lactones 53a,b and 54a,b were prepared by the 2,3-sigmatropic rearrangements of allylic sulfonium ylides 55a,b and 56a,b generated from the correspond- ing diazoesters under the action of dirhodium tetraacetate.60 ± 63 O RO2C O RO2C (H2C)n R1 7 PhS A CO2R + Rh2(OAc)4 PhS O O N2 O R1=Pri, R2=Et (CH2)n (CH2)n ...(H2C)n 62c PhS O 53a,b 55a,b Pri 63 R1, R2=Alk; X=O, n = 1 (a), 2 (b); X=CH2, n = 1 (c), 2 (d). 659 O *2,3 RO2C 7 O Ph +S (CH2)n 56a,b H O O H O Me H 58 O O + Ph S (H2C)n 7 R CO2Et Rh2(OAc)4 PhH, D SPhCO2R2 O (H2C)n X X R1 62a ± d O660 Spiroannelation using the [2,3]-sigmatropic rearrangement via cyclic allylic sulfonium ylide was applied in the enantioselective synthesis of sesquiterpene (+)-acorenone B (63).66 High stereo- selectivity of the sigmatropic rearrangement is attributed to the fact that the less sterically hindered side opposite to the isopropyl group is favourable for the attack of the carbanion on the sulfonium reaction centre (transition state A).Rhodium-catalysed stereoselective cyclisation of diazosulfide 64 followed by the 2,3-rearrangement of the resulting ylide afforded cis-2-oxa-9-vinyldecalin derivative 65, which served as the starting compound in the synthesis of vernolepin (66).67 O MeO CO2Me Rh2(OAc)4 O N2 SPh 64H OH MeO O ... O O H O CO2Me O PhS O 66 65 (77%) The rhodium-, copper- and palladium-catalysed stereoselec- tive reactions of diazosulfides 67a and 67b were studied.68 Depending on conditions, these reactions can afford either sulfonium ylides, which undergo the 2,3-sigmatropic rearrange- ment to form bicyclic compounds 68a and 68b, or tricyclic cyclo- propane derivatives 69a and 69b.The latter are products of intramolecular cyclopropanation. Decomposition of the diazo- amides 67a,b in the presence of the rhodium complex with caprolactam gave rise predominantly to the azabicyclooctanes 68a,b, whereas cyclopropane derivatives were selectively formed as the major products in the presence of catalysts containing electron-withdrawing ligands [Rh2(OAc)4 , Cu(acac)2 , Cu(OTf)2 or Pd(OAc)2].SPh H H CH2SPh H cat, PhH + SPh N N N N2 O O 67a O 69a 68a PhS H H H cat, PhH + SPh N N N CH2SPh N2 O O 67b O 69b 68b The rearrangements of diaminosulfoxonium salts of type 70 to form dihydro-2,1-benzoisothiazole derivatives 71 were described.69 Treatment of the salts 70, which were prepared by alkylation of sulfonimidoamides, with ButOK resulted in the 2,3- sigmatropic rearrangement of intermediate ylides 72 to produce cyclohexadieneimine derivatives 73 in the first stage.The transfer of the hydrogen atom in the latter compounds was accompanied by rearomatisation. Cyclisation of intermediates 74 afforded the final products 71. 7 OS+ N OS+ N O O Me CH2 NMe NMe ButOK BF¡4 608C 72 X X 70 S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov O O O S N O S N ButOK NHMe NMe X X 73 O O S N 7 Me N NMe S O O 7HN X X 71 74 X=Me, Cl.Yet another promising synthetic application of sulfur ylides is based on the 2,3-sigmatropic rearrangements of cyclic allylic sulfonium ylides proceeding with ring expansion.17, 70 7 R R + S S S *2,3 (H2C)n (H2C)n (H2C)n Z Z Z Z is the carbon atom or a heteroatom. Ylides can be generated by reactions of cyclic a-vinyl sulfides with diazo compounds in the presence of copper 17, 70 or rhodium catalysts 71 or by reactions of bases 17, 70 with sulfonium salts. These procedures were used for the preparation of various macro- cyclic compounds. For example, the synthesis of thiacycloundeca- 4,7-diene derivative 75, which is a precursor of aglycon of macro- lide antibiotic methymycin, viz., methyneolide 76, was carried out starting from tetrasubstituted thiolane 77.72 ± 74 The rearrange- ment of ylide 78 derived from salt 79 afforded thiacyclooctene 80 from which ylide 81 was synthesised in several steps.The subse- quent stereoselective 2,3-sigmatropic rearrangement of the ylide 81 gave rise to thiacycloundecadiene 75 (Scheme 1). The 2,3-sigmatropic rearrangements of bicyclic allylic sulfo- nium ylides, which gave rise to compound 82 containing the thiabicyclo[6.3.1]undec-3-ene fragment, was used in the total synthesis of cytochalasines.75, 76 In this synthesis, vinyl iodide 83 served as the starting compound. The key stage of this synthesis involved the rearrangement of ylide 84 generated from sulfonium salt 85 under the action of potassium carbonate.CH2TMS I MeCN K2CO3 OAc I7 Ph 70 8C S+ OAcS N O Ac 83 85 O O CH2TMS OAcS+ 7 Ph OAcS N O Ac 84 O O 82 (65%) Difficultly accessible bicyclic unsaturated disulfides 86 (the so- called betweenanene structures) and 87 were synthesised.77, 78 Heating of dithioketal 88 with diazoacetate in the presence of CuSO4 afforded ylide 89, which underwent the 2,3-sigmatropicSulfur ylides in the synthesis of heterocyclic and carbocyclic compounds RO RO RO OR a b + S +SS OTf7 EtO2C S 7 S 80 (36%) CO2Et 79 77 CO2Et 78 O ... OR OH 7 S+ OR S O HO Et O O Et Et O 75 (89%) 81 76 Tf=F3CSO2; (a) TfOCH2CO2Et; (b) K2CO3; (c) TfOCHMeCOEt, K2CO3. rearrangement to give two geometric isomers 86 and 87 in a ratio of 4 : 1.CO2R1 S+ 7 SiMe3 CsF, DBU R2 + S S DMSO, 20 8C OTf7 S S *2,3 N2C(R1)CO2R2, CuSO4, D R 96 (CH2)8 88 (CH2)8 89 R=H, Me, Cl, CF3 . R1 CO2R2 OTf7 R1 R1 SiMe3 CsF, DBU S + CO2R2 S S + (H2C)8 DMSO, 20 8C R2 S (CH2)8 S O 97 87 86 R1 S O R2 99 R1, R2=H, Me, OMe, CF3. The structures of the 2,3-sigmatropic rearrangement products of acetylenic ylides 90a ± c derived from the corresponding sulfo- nium salts 91a ± c depend on the nature of the substituent at the triple bond. Thus the ylides containing alkyl substituents were converted into allenic sulfides 92a,b, whereas the phenyl substitu- ent promoted isomerisation into 1,3-diene 93c.79 S+ S+ OTf7 DBU 7 OEt OEt O CC O CC 90a ± c 91a ± c R R S R=Me, Bu Analogous thermal 2,3-sigmatropic rearrangements accom- panied by ring expansion proceeded in the case of a-vinyl iminosulfurane ylides 100a ± c, which were prepared by treatment of sulfides 101a ± c with chloramine T in methanol at *20 8C.82 The rearrangements of the ylides 100a ± c afforded azathiacy- clenes 102a ± c.It should be noted that treatment of 2-vinyl- thiepane 101c with chloramine T gave rise to the final product 102c even at room temperature. Attempts to isolate the inter- mediate ylide 100c failed. CO2Et C (CH2)n chloramine T R 92a,b MeOH, 20 8C S 7 S R=Ph 101a ± c NTs 100a ± c CO2Et Ph n 93c Yield of 100 (%) Compound 101 R=Me (a), Bu (b), Ph (c).70 61 abc 140 140 7 *20 123 Aryl-substituted ylides 94 and 95, which were formed on desilylation of salts 96 and 97, underwent the Sommelet ± Hauser rearrangement giving rise predominantly to substituted 2,5,8,9- tetrahydrodibenzo[c, f ]thionines 98 80 and 3,4,6,7-tetrahdydro- 1H-5,2-benzooxathionines 99, respectively.81 661 Scheme 1 OR cS+ 7 S CH2 R R 98 94 7 R1 CH2 + S R2 O 95 (CH2)n (CH2)n *2,3 +S N S Ts 102a ± c Yield of 102 (%) Temperature of the rearrangement /8C 55 54 61662 Under the same conditions, benzoiminosulfuranes 103 and 104 produced 1,2- (105) and 3,4-benzothiazonines (106), respec- tively.82 chloramine T 140 8C +S S S 7 NTs 105 (55%) NTs 103 (70%) S chloramine T 140 8C NTs S S+7NTs 106 (57%) 104 (83%) The reactions of 3,4-disubstituted 2,5-dichlorothiophenes 107 with diazoketones in the presence of rhodium catalysts afforded derivatives of a new heterocyclic system, viz., of 1,4-oxathiocine 108.83, 84 The reaction scheme involves the formation of sulfur ylides 109 and their subsequent thermal 2,3-sigmatropic rear- rangement proceeding through intermediates 110.Heating of oxathiocine 111 at 110 8C gave rise to benzene derivative 112 due to elimination of the sulfur atom and 1,2-shift of the chlorine atom. It should be noted that the reactions of diazoketones with thiophenes, which do not contain chlorine atoms at positions 3 and 5, do not yield oxathiocine derivatives.R1 R1 R1 R1 [Rh], R2CN2COR3 60 ± 100 8C + Cl Cl S Cl Cl O S 7 R2 107 R3 109 R1 R1 R1 R1 Cl Cl Cl Cl O S O SR2 R3 R3 R2 110 108 R1=H, Cl; R2=CO2Et, CO2But, Ts; R3=Me; R2±R3=COCH2CMe2CH2. Cl Cl Cl Cl Cl 110 8C Cl OH O S O S Me EtO2C Me Me EtO2C EtO2C 112 111 The 2,3-sigmatropic rearrangements of bi- and tricyclic sulfur ylides derived from substituted thiaphenanthrenes and isothio- chromans, respectively, afforded both ring expansion products and spirane compounds.85 ± 88 The direction of the reaction and the structures of the final products depend essentially on the nature of the substituents at the sulfur atom and at position 1 of the initial ylide. For example, the reaction of stabilised ylide 113 with succinimide gave rise to the ring expansion product, viz., 2-phenyl-4,5-dihydro-3,5-benzooxathionine 114, in high yield.The reaction mechanism involves deprotonation of intermediate 115 with the imide anion to form exocyclic methylide 116 whose 2,3-sigmatropic rearrangement yielded the target product 114.85 The reaction of the ylide 113 with phthalimide proceeded analo- gously. S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov ONH, PhH, D O 7 S+Me COPh 113 S+7CH2 COPh 116 SO Ph 114 The reaction of 1-cyanoisothiochroman ylide 117a proceeded by the same mechanism; however, due to the presence of the cyano group, the 2,3-sigmatropic rearrangement of intermediate exome- thylide 118a proceeded differently to form spirocyclic compound 119.86 On thermolysis, the compound 119 was isomerised to tetrahydrothiepin 120, whereas its reactions with acetylenedicar- boxylic esters afforded cycloadducts 121a,b.The course of the reaction is substantially affected by the substituent at the sulfur atom. Thus the bulkier ethyl substituent in the ylide 117b hinders the 2,3-rearrangement and the reaction gave rise to a mixture of benzothiopyran 122 and dimer 123. a or b 7 S+Me CN 117ac S NC 120 CO2Et EtO2C d 121a NC e S+ 7 Et CN 122 117b O (a) EtOH or MeOH, D; (b) O (d) EtO2CC:CCO2Et; (e) EtOH, D. Due to the presence of one more substituent (Cl, Br or Me) at position 1 in ylides 124, their reactions proceeded through the 2,3-sigmatropic rearrangement involving the S7N bond.The reactions of the ylides 124 with succinimide afforded ketenimines 125, which gave amides 126 or enol acetates 127 upon acid hydrolysis.86 O 7N 7 S+ O O O Me NH COPh 115 S CH2 O Ph S S+7 H CH2 CN CN 119 (85%) 118a CO2Et S EtO2C S + H H NC 121b(CH2)2SEt CN + S CN NC EtS(CH2)2 123 NH, PhH; (c) 205 8C;Sulfur ylides in the synthesis of heterocyclic and carbocyclic compounds 124 R=Me, Cl, Br; a) The reactions of the 1-cyano ylides 117a,b with activated acetylenes (dimethyl acetylenedicarboxylate or methyl propiolate) afforded fused compounds 128 and 129a,b.86 The methyl deriva- tive 117a gave a mixture of the compounds 128 and 129a (*1 : 1) in 75% total yield.The reaction mechanism involves the inter- mediate formation of zwitterions 130a,b whose isomerisation can take two different pathways (path a and path b). Intramolecular deprotonation of the S-methyl group (path a) gave rise to ylide 131 whose 2,3-sigmatropic rearrangement afforded the compound 128. The nucleophilic attack of the vinyl anion on the positively charged sulfur atom produced unstable s-sulfurane intermediate 132a, which was converted into the ylide 129a. The ethyl deriva- tive 117b gave only the doubly stabilised ylide 129b in 31% yield. 117a 117b R1 132b R1=H,R2=CO2Me (129a); R1=R2=CO2Me (129b). S a S+7CH2 C N 125 R CN R ONH, PhH; b) HCl; c) AcOH. O R1C CR2 S+Me 7 NC R2 R1 130a path a S+7CH2 NC R2 R1 131 S path b MeR2 NC R1 132a R1C CR2 S+Et 7 NC R2 R1 130b S Et R2 NC 663 S b NH R O 126 S c NH The reactions of stabilised isothiochromene sulfonium ylides 133a,b with acetylenic dienophiles proceeded differently.87 These compounds reacted as heterodiene systems and the reactions proceeded as [4+2]-cycloaddition to yield intermediates 134a,b.Depending on the solvent, subsequent conversions of these intermediates afforded either dihydrocyclopropa[a]naphthalene derivatives 135a,b (in aprotic solvents) or naphthalene derivative 136a (in protic solvents). It should be noted that only [2+1]- adduct 137 was formed in high yield in the reaction of the compound 133a with methyl propiolate in sulfolane. This adduct was generated by the interaction of intermediate 138 with the starting ylide 133a.R OAc R3 127 R2 R2C CR3 + 7 SMe 7 +SMe R1 133a,b R1 134a,b SMe R3 PhH R2 R1 135a,bR3 R2 R3 R1=CN 7 EtOH + R2 SMe NC CN 136a (19%) R1=CN(a), COPh (b); R2=H, R3=CO2Me; R2=R3=CO2Me, CO2Et. + S SMe HC CCO2Me 133a 7 NC SO2 CO2Me R2 NC R1 H MeS H MeS 128 MeS 133a CN + CO2Me SMe CO2Me 7 R2 137 138 NC NC R1 NC129a Ph The reaction of 2-cyano-a-thiochromene ylide 139 with dimethyl acethylenedicarboxylate afforded the ring expansion product 140 in low yield. Ph CN path b MeO2CC CCO2Me CO2Me 7 + CN S Me S CO2Me 139 140 (12%) +SEt 7 R2 R1 NC129b The reactions of tricyclic sulfur ylide 141a stabilised by the adjacent cyano group (the thiaphenathrene derivative) with acti- vated acetylenes produced spirocyclic compounds 142 (the yields were up to 31%), which underwent the 1,5-rearrangement upon heating to give dibenzothionine derivatives 143 in yields of up to 95%.88 It is assumed that the reaction mechanism involves the formation of zwitterionic intermediates 144, which are rearranged to exocyclic sulfonium ylides 145.The ylides 145 can undergo the664 Sommelet ± Hauser rearrangement to produce the compounds 142. In the case of the ethyl-substituted ylide 141b, spirocyclic compounds were not formed; instead, the reaction afforded dibenzothiepin derivatives 146 as the major products (the yields were up to 38%).Since the ethyl substituent at the sulfur atom in the compound 141b causes steric hindrances to the Somme- let ± Hauser, this compound underwent the 1,2-Stevens rearrange- ment to form the ring expansion product 146. The rearrangements of the zwitterions 144 afforded dibenzothiocine derivatives (in the yields of up to 22%) along with the compounds 146 (see the scheme for the formation of the compound 129a).86 R2C CR2 PhH 7 S+CH2R1 CN 141a,b S+CH2R1 7 NC R2 R2 144 R1=CH2R2, MeO2CC CCO2Me 7+SR1 N 147a ± f MeO2CC CCO2Me 147a ± f H2O R1=CH2R2 (R2 = H (a), Me (b), Et (c), C5H11 (d)); R1=Ph (e), CH=CPh2 (f). + 7 S CHR1 R2 NC R2145 +SR1 N 7 MeO2C MeO2C CO2Me 153a ± f R1 S N CO2Me 155a ± f MeO2C R1S N MeO2C 2 152a ± f S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov R1=Me SMe R2 NC R2 146 S S R1=H 200 8C CN R2 NC R2 R2 143 R2 142 R1=H(a), Me (b); R2=CO2Me, CO2Et.The reactions of sulfur ylides 147a ± f, viz., 9-alkyl-9-thia-10- azaphenanthrenes, with dimethyl acetylenedicarboxylate gave rise to dibenzothiazonium derivatives (compounds 148 and 149), dibenzothiazocine derivatives (compounds 150), 2-alkylsulfinyl- 20-vinylamionbiphenyls 151 and bis(biphenylylimino)ethane derivatives 152 (Scheme 2).89 The composition of the reaction products depends substan- tially on the substituent at the sulfur atom. Thus the compound 147a produced predominantly dibenzothiazonine derivatives 149a and 148a, whereas the ylides 147b,c,d gave predominantly diben- zothiazocine derivatives 150 and biphenyls 151.The ylides 147e,f Scheme 2 + 7 S S SCHR2 N R2 R2 HN N MeO2C MeO2C CO2Me 149a ± d CO2Me 148a ± d CO2Me 154a ± d R1 S H2O + NH R1 O S SiOx N 7 CO2Me CO2Me 151a ± f 150a ± f MeO2C MeO2CSulfur ylides in the synthesis of heterocyclic and carbocyclic compounds containing the phenyl or vinyl substituent at the sulfur atom produced only dibenzothiazocine derivatives 150e,f. The reaction mechanism involves the formation of zwitterions 153 and 154. The exocyclic ylide 154 was isomerised to form the compounds 148 and 149. The zwitterion 153 can produce intermediate 155 from which the derivatives 150 and 151 are generated or can react with water giving rise to the dimers 152.The reactions of 9-alkylthiaazaphe- nanthrenes 147a ± c with methyl propiolate afforded 1 : 2 adducts, which are dibenzothiazocine derivatives 156a ± c.89 + 147a ± c HC CCO2Me N +SR1 N 7 CO2Me CO2Me The rearrangements of tricyclic sulfonium salts 157 under the action of various bases have been studied thoroughly.90 Thus treatment with strong bases [lithium diisopropylamide(LDA), NaH or K2CO3] afforded ylides 158 and 159, which underwent the 2,3- and 1,4-sigmatropic rearrangements to form spirovinyl- cyclopropane derivatives 160 or tricyclic compounds 161. The ratio of the reaction products depends on both the base used and the nature of the substituents.R1 + BF¡ S 4 R2 157 R3 R1 + S 7 R2 158 R3 R1 + S 7R2 159 R3 R3 R2 R1 Me Me Me Me Me Me Me Me Me Me HMe HBz HBz HMe 35 57 28 75 44 46 H Me Me K2 CO3 21 64 Me Me Bz 665 In the reactions with the salts 157, weak bases, such as Et3N, Et2NH, BuNH2 or AcOK, act as nucleophilic reagents and attack the CH2 group adjacent to an electron-deficient centre to yield ring expansion products 162 in high yields. R1 X S 157 R2 162 R3 X=NEt3BF4, NEt2, OAc, NHBu. HC CCO2Me SR1 7 CO2Me Interesting results were obtained in studies of the rearrange- ments of dibenzothiocine salts 163a,b, which took place under the action of a KOH solution in methanol.91 Thus the sulfoxide 163a was converted into a mixture of enantiomers of dibenzothiepin derivative 164a,b (in a ratio of*2 : 1).Under the same conditions, the sulfide 163b unexpectedly gave compound 165. The assumed reaction mechanism involves the tandem of the 2,3- and 1,3- sigmatropic rearrangements with the intermediate formation of spirocyclic intermediates 166 and 167. R1 +S CO2Me N (O)n (O)n 7 S S *2,3 CO2Me 156a ± c + + Y7 S S 7 163a,b Me Me O S R2 (O)n S R1 164a,b R1=H, R2=SMe (a); R1=SMe, R2 = H (b). MeS 166 S *1,3 R1 S *2,3 MeS167 *1,3 R3 R2 160 R1 SMe S 165 *1,4 R3R2 n=1, Y=SbCl6 (a); n=0, Y=BF4 (b). S 161 III. Intramolecular cyclisation of sulfur ylides Base 161 Yield (%) 160 LDA LDA NaH NaH NaH NaH 52 770 045 46 22 0 K2CO3 A promising approach to the synthesis of nitrogen-containing heterocycles, including analogues of alkaloids, is based on intra- molecular cyclisation of phthalimido-substituted sulfur ylides stabilised by the carbonyl group.92 ± 98 Under the conditions of the Arndt ± Eistert reaction,99 N-phthaloyl-a- (168) and -b-amino acids (169) generated bromo ketones, which were converted into the corresponding sulfonium salts.Deprotonation of these salts afforded stabilised ylides 170 and 171, respectively, which under- went intramolecular cyclisation on heating in toluene with an equimolar amount of benzoic acid 96 to give methylthio-substi- tuted pyrrolizidine- (172) and indolizidinediones 173 and 174.It is significant that racemisation does not take place in the reactions666 involving optically active ylides. Longer-chain sulfur ylides derived from g- and d-amino acids did not undergo cyclisation; instead, alkyl thioketones and oxobenzoates were formed as the major products.96 The effect of the substituents in the phthalimide fragment on the regioselectivity of the reaction and the yields of the products was also studied.97 O R a, b, c, d, e NCHCO2H O 168a ± d O R + 7 NCHC(O)CHSMe2 7PhCO2Me O 170a ± dYield (%) R Compound 172 H 8685 84 83 Me Pri Bn abcd R1 O R2 a, b, c, d, e N(CH2)2CO2H O 169a ± d R1 O R2 + 7 N(CH2)2C(O)CHSMe2 O 171 O R1 N R2 +R2 O MeS 173a ± d R2 Compound 169 R1 174 Yield (%) 173 NO2 Cl H H H 86 H 5275 H NO2 38 abcd 35 (a) SOCl2; (b) CH2N2; (c) HBr; (d) Me2S; (e) NaOH±K2CO3; ( f ) PhCO2H, 110 8C.Ylides 175 and 176 containing the tetrahydrophthalimide or succinimide fragment, respectively, instead of the phthalimide fragment did not undergo cyclisation.97 O O 7 + N(CH2)nC(O)CHSMe2 N(CH2)nC(O)CHSMe2 O O 175 n=1, 2. Under the conditions of cyclisation, ylide 177, which was synthesised from b-alanine and pyridine-2,3-dicarboxylic anhy- dride, selectively formed a tricyclic compound, viz., 5-methylthio- 7,8-dihydro-4,8a-diazafluorene-6,9-dione (178).98 O R N O SMe 172a ± d f O N O SMe R1 174a ± d + 7 176 S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov O O + N 7 N(CH2)2C(O)CHSMe2 N N O O 177 MeS 178 (58%) The assumed mechanism of a new type of intramolecular cyclisation, which is not quite typical of sulfonium ylides, involves, apparently, the attack of the anionic centre on one of the carbonyl groups of the phthalimide fragment followed by migration of the methyl group.100, 101 The reaction ends in elimination of the methanol fragments from intermediate 179 under the action of benzoic acid to form rearrangement product 180, methyl benzoate and water. O O N + N O 7 7 HC O O O Me2S+ +SMe2 O O PhCO2H N N 7PhCO2Me,7H2O O O MeOMeS MeS 180 179 Intramolecular cyclisation of ylides 181 containing the sulfur atom in the ring gave rise to benzoates 182. O O + PhCO2H 7 N N(CH2)nC(O)CHS (CH2)n O 181 O PhOCO(CH2)4S 182 n=1, 2.Diazosulfides (R)- or (S )-183 generated from D- or L-methio- nine, respectively, underwent cyclisation under the action of HBr to form optically active sulfonium salts (R)- or (S )-185 (the yields were 54 and 62%, respectively). Subsequent treatment of these salts with potassium carbonate afforded cyclic ylides (R)- or (S )-184 stabilised by the carbonyl group (the yields were 75% and 90%, respectively).102 O O O O K2CO3 HBr + CH2N2 SMe N SMe N Br7 O 183 O 185 O O 7+SMe N O 184 Anew approach to the stereoselective synthesis of amino acids from chiral lactams through intermediate formation of b-ketosul- foxonium ylides was developed.103, 104 Previously,105, 106 it was found that these ylides were converted into intermediates of the carbene type on photolysis or under the action of transition metals.The reactions of activated chiral lactams 186a,b with dimethylsulfoxonium methylide were demonstrated to produce ylides 187a,b in high yields.103, 104 Under the action of rhodiumSulfur ylides in the synthesis of heterocyclic and carbocyclic compounds catalysts, the reactions of the ylides 187a,b proceeded stereo- selectively giving rise to derivatives of 4-oxopyrrolidine 188a or 5- oxopiperidine 188b formed as a result of cyclisation of intermedi- ate carbenes 189a,b.The compounds 188a,b were used in the synthesis of optically active a-amino acids.107 CO2Bn O7 O7 CO2Bn a (H2C)n b 2+ S N NHBoc Me (CH2)n Me O Boc 187a,b 186a,b O O CO2Bn (CH2)n NHBoc (CH2)n CO2Bn 189a,b NBoc 188a,b Boc=ButOCO; n = 1 (a), 2 (b); + (a) Me2S(O)CH¡2 , DMSO, 20 8C; (b) [Rh2+]. IV. Reactions of thiocarbonyl ylides Considerable recent attention has been given to thiocarbonyl ylides, which are readily accessible and highly reactive intermedi- ates. Several procedures were developed for the preparation of thiocarbonyl ylides among which are the 1,3-dipolar cycloaddi- tion of diazo compounds to thioketones to form 1,3,4-thiadiazo- lines followed by nitrogen elimination,108 the addition of thioketones to oxiranes 109 or photoisomerisation of aryl vinyl sulfides.110 Thiocarbonyl ylides readily undergo rearrangements.These compounds are involved in cycloaddition with dipolaro- philes and in 1,3- and 1,5-electrocyclisations, which often proceed with high regio- and stereoselectivity. The reactions of thiocar- bonyl ylides with compounds of the RXH type (X=N, O or S) giving rise to 1 : 1 adducts were also studied.111 ± 113 Recently, cyclisation of carbenes generated by catalytic decomposition of diazothioamides has gained wide acceptance for the preparation of thiocarbonyl ylides.114 Thus diazothioamide 190 gave cyclic thiocarbonyl ylide 191 under the action of a rhodium catalyst. The ylide 191 was converted into enaminoketone 193 due to elimina- tion of sulfur from intermediate episulfide 192.115 S N(Me)Ph [Rh2+] N(Me)Ph S+ 7 N2 O O CO2Et 191 CO2Et 190 N(Me)Ph N(Me)Ph CO2Et S O CO2Et O 193 (90%) 192 Intramolecular cyclisation of diazothioamide 194 catalysed by dirhodium tetraacetate afforded thiocarbonyl ylide 195 stabilised through the aromatic mesoionic structure.The ylide 195 reacted with N-phenylmaleimide according to the scheme of the diene synthesis to give adduct 196.115 O O O S N N NPh Rh2(OAc)4 S S+ N NPh N2 7 O O O O CO2Me CO2Me CO2Me 194 195 196 (75%) 667 Thiocarbonyl ylides were successfully used in the synthesis of natural alkaloids.116 ± 120 Thus non-stabilised ylide 198 was gen- erated from diazothioamide 197 under the action of rhodium acetate followed by the rearrangement of the latter into episulfide 199.Isomerisation of the compound 199 afforded thioketone 200, which underwent desulfurisation under the action of Raney nickel to yield dihydropyridone 201.116 This procedure was used for the synthesis of dihydropyridone 202, which was the key intermediate in the total synthesis of antibiotic indolisomycin 203.117, 118 Diazothioamide 204 was used as the starting compound. N2 7 O O S+ S Rh2(OAc)4 N N H H 204 SH O OH ... N NH H 203 202 Alkaloids helenine (205) 119 and cephalotaxine (206) 120 were synthesised using compounds 207 and 208, respectively. The latter were prepared by cyclisation of hydrazones 209 and 210, which were synthesised from substituted benzaldehydes and N-amino- 1,2-diphenylaziridine, in the presence of dirhodium tetraacetate.The reactions proceeded through the corresponding carbenoids and cyclic thiocarbonyl ylides (Scheme 3). Thiocarbonyl ylide 211, which was generated in situ on heating of a suspension of iodonium compound 212 in carbon disulfide in the presence of copper acetylacetonate, underwent cyclisation to yield oxathiol heterocycle 213.121 O O Me Me CS2 7 C S +SIPh Cu(acac)2 Me Me O O 211 212 O Me S Me S O 213 (85%) The reaction of di-tert-butylthioketene (214) with diazomalo- nate afforded thioketene ylide 215, which underwent cyclisation to give 2-alkylidene-1,3-oxathiol 216.1227C(CO2Me)2 +S S N2C(CO2Me)2 C C Rh2(OAc)4 But But But But 215 214 CO2MeOMe +S MeO2C S But O7 C But O MeO2C But But 216668 O N (CH2)2 O H S O Ph N N Ph O N (CH2)2 O H S O Ph N N Ph 210 R1 C C R3 C S+R4 R2 S R1 C R2 R1=R2=R3=R4=But; R1±R2=CMe2(CH2)3CMe2, R3=R4=But; B is a base.Various cumulenes and cumulene episulfides were prepared by the addition of alkenylidene dicarbenes to thioketenes.123 Episulfides 217 were isolated as stable crystal compounds, which underwent predominantly desulfurisation on heating or photol- ysis to give tetraenes 218 in yields from 50% to 69% and were also partially isomerised to episulfides 219. Substituted thietane- thiones 221 were obtained as by-products (9% ± 20%) due to the intermolecular transfer of the sulfur atom through biradical intermediate 220 (Scheme 4).Vinylthiocarbonyl ylides generated from vinyldiazoalkanes 222 and thiochromones 223 or 224 gave 1,3- (225) or 1,5-electro- cyclisation (226 or 227) products depending on the nature of substituents in the ylide.124 Unstable thiirane 225 (R=H) was immediately converted into diene derivative 228 with elimination of sulfur. The reactions of diazo compounds 222a,b with thio- chromone 224 proceeded through the formation of analogous dienes. Diazo compound 222c containing the bulkier phenyl substituent was involved in 1,5-electrocyclisation with the thio- chromones 223 and 224 to give dihydrothiophene derivatives 226 and 227, respectively. R C6H4Cl-4 + CN N2 222 OMe OMe O Rh2(OAc)4 O 209 O Rh2(OAc)4 O 208 Cl R1 + 7 B C S C 7HCl R2 H S D or hn R1 R2 R3 S R1 R4 R2 S R1 R2 220 S Rh2(OAc)4 O 223 N 207O NR3 R1 C R4 R3 C C R4 217 R3 C R1 R4 R2 R3 C R4 R=H, Me R=Ph R=H(a), Me (b), Ph (c). R1=CN, R2=C6H4Cl-4 (55%); R1 =C6H4Cl-4, R2=CN (28%).S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov O O ... O OMe OMeO ... N H O HO OMe 206 S D or hn R3 C R2 R4 219 S R1 R3 + C R2 R4 S 221 NC C6H4Cl-4 R S R=H 7S O 225 (74%) R C6H4Cl-4 S CN O 226 (66%) Ph S 222 Rh2(OAc)4 O 224 227 Scheme 3 O N OMe O HO OMe 205 Scheme 4 R3 C C C R4 218 NC C6H4Cl-4 R O 228 (82%) R1R2 S OSulfur ylides in the synthesis of heterocyclic and carbocyclic compounds Amino-substituted thiocarbonyl ylide 229 underwent intra- molecular condensation of a new type providing an approach to 1,6-dithia-3,9-diazaspiro[4.4]non-2-enes 230.125 Me MeMe N N PhMe, D + Me S CO2Me CO2Me S 7 S S C PhN CO2Me CO2Me PhHN 230 229 The reactions of thiocarbonyl ylide 231 with thioamides 232 were accompanied by unusual intramolecular cyclisation.108 Adduct 233 generated initially underwent cyclisation to give 2-thia-4-azabicyclo[3.1.1]hept-2-ene derivative 234.This is the first example of the nucleophilic addition of a cyclobutanone derivative to the carbonyl group proceeding without opening of the four-membered ring.SMe O S +SO + S 7 R CH2 NH2 231 232 R HN233 S MeS R N OH 234 (64%) R=Me, Ph. V. Cycloaddition of ylides to alkenes The reactions of stabilised sulfonium ylides with electron-deficient alkenes of the C=C7X=Y type generally afford cyclopropanes (the AdN±E1,3 mechanism);6 however, five-membered hetero- cycles can also be formed due to the involvement of the activating X=Y group, where X=Y=NO2 , N=O or N=NAr (the AdN±E1,5 mechanism).10, 13 + + R12 S R12 S C +7 7 C C R12 SCHCOR2 C HC C HC C R2C R2C 7 X X X Y Y Y O O 7R12 S 7R12 S H H X X Y C(O)R2 Y R2CO These reactions were considered in sufficient detail in the review,13 which surveyed the data available up to 1986.Hence, we dwell only on the recent most interesting results published in the literature. The reactions of nitroalkenes with stabilised sulfonium ylides were demonstrated 126, 127 to proceed stereoselectively to give both trans-4,5-dihydroisoxazole N-oxides 235 and substituted cyclo- propanes, the ratio of the reaction products being essentially dependent on the a-alkyl substituent in nitroalkenes. In the case 669 of bulkier substituents R, heterocyclic adducts are formed in substantially higher yields.+ Et3N, MeOH ArCH C(R)NO2+Me2SCH2COPh Br7 Ar R + Ph N O7 O O 235 Ar=3-NO2C6H4,R=CO2Et (85%); Ar=Ph, R=Me (41%). The reactions of arylmethylenecyanothioacetamides with stabilised sulfur ylides 236 proceeded stereoselectively to give mixtures of 2-amino-4,5-dihydrothiophenes 237 and cyclopro- panethiocarboxamides 238.128 In most cases, the dihydrothio- phenes 237 were obtained as the major reaction products.For R=cyclo-C3H5, cyclopropane derivatives did not form at all. + Et3N, MeOH ArCH C(CN)CSNH2+Me2SCH2COR Br7 236 Ar Ar CN + CN RC(O) RC(O) NH2 C(S)NH2 S 238 237 Ar=2-MeC6H4, 2-NO2C6H4, 4-MeOC6H4, 3-pyridyl, 2-thienyl; R=Ph, 2-thienyl, cyclo-C3H5 . A simple and efficient procedure for the preparation of 2,5- dihydrofurans 239 containing the N-tosylamino substituent is based on the reaction of N-sulfonylimines with sulfur ylides generated from cis-4-hydroxybut-2-enyldimethylsulfonium salts 240.129 The assumed mechanism involves the formation of azir- idine derivative 241, ring opening through the attack of the internal nucleophile and subsequent cyclisation to form 2,5- dihydrofuran.The reaction involving the trans-isomer of the sulfonium salt 240 afforded only the aziridine derivative. BPh¡4KOH, MeCN + CH2OH PhCH NTs+Me2SCH2 20 8C, 7 min 240 TsHN Ph Ph O HO O 7 Ts N NTs 241 Ph 239 (52%, anti : syn=2:1) As mentioned above, thiocarbonyl ylides are readily involved in 1,3-dipolar cycloaddition to give the corresponding cyclo- adducts in high yields and with high regioselectively. Thus when heated, dihydrothiadiazoles 242, which were formed in the reac- tions of diazomethane with derivatives of oxodithiocarboxylic acids 243, gave intermediate 244, which reacted with dienophiles to yield substituted thiolanes 246 ± 248.130 In the absence of dienophile, the ylide 244 produced intramolecular cyclisation product 245.670 O O CH2N2 S 7 COR SMe D SMe R R 770 8C + SMe 7N2 N N S S 242 244 243 O R S SMe 245 S COR CO2Me SMe CO2Me 246 CO2Et NC S CN EtO2C COR SMe CN CO2Et NC EtO2C 247 MeS COR O O O O S O 248 O 1,3-Dipolar cycloaddition of thiocarbonyl ylide 249 to sulfur dioxide gave rise to 1,2,4-oxadithiolane 2-oxide 250.131 Pri Pri S Pri S SO2 + 7 D S CH2 Pri Pri 7N2 O S Pri N N 249 O 250 (95%) The reaction of thiocarbonyl ylide 251, which was generated in situ from oxospiro[cyclobutanedihydrothiadiazole] 252, with trans-1,2-bis(trifluoromethyl)-1,2-dicyanoethylene afforded thio- lane 253 and stable strained cyclic ketenimine 254 in a ratio of *1 : 4.132 CN Me F3C Me Me Me S 7 + NC CF3 40 8C O O S CH2 Me Me Me N N Me 252 251 Me CF3 Me Me MeS S CN CF3 O + O CN CF3 C N CF3 Me Me Me Me CN 254 253 Adamantanethione-S-methylide (255) reacted with methyl acrylate to form substituted thiolane 257, whereas its reactions with thioketones 256 gave rise to 1,3-dithiolanes 258a ± c and 259a ± e.The reactions involving thiobenzophenone (256a), thio- fluorenone (256b) or thioxanthione (256c) produced two regioisomers.133 1,3-Dipolar cycloaddition of thiocarbonyl ylides 260 to thia- zole-5(4H)-thiones 261 134 or azodimethyl carboxylate 262 135 proceeded with high regioselectivity to give the corresponding spirocyclic adducts 263 ± 266 in high yields.S N Lakeev, I O Maydanova, F Z Galin, G A Tolstikov 7CH2 + S 255 R2C=Ph2C (a), C (d), O R42 C S CH2 R2R3 N R1 S S 261 MeO2CN NCO2Me 262 R42 C=Ph2C (a), O Cycloaddition of the thiocarbonyl ylides 251 and 260a to N-sulfinylaniline and N-sulfinyltosylamide gave rise to both substituted 1,3,4-dithiazolidine 3-oxides (adducts at the N=S bond) and 1,2,4-oxadithiolane-2-tosylimides (adducts at the S=O bond).136 The reactions of thioketones with diazoacetates performed on heating in THF137, 138 afforded acyl-substituted thiocarbonyl ylides as the initial reaction products, which either underwent 1,3- or 1,5-dipolar electrocyclisation or reacted with the second thioketone molecule to give a 1,3-dipolar cycloaddition product.The first example of 1,3-dipolar cycloaddition of thio- carbonyl ylide CH2=S7CH2 to fullerene C60 giving rise to a tetrahydrothiophene derivative was reported.139 This product is a convenient starting compound for subsequent functionalisation. MeO2C CO2Me S 257 R S S S R2C S 256a ± e R S R + R 259a ± e 258a ± c C C (c), (b), S C (e). R2 N R3 S R1 S SPh Ph 263 + R2 7 N 260a ± c R1 R3 S S O S 264 R2 N R1 R3 S S S 265 R4 S 260a ± d R4 N N CO2Me MeO2C 266 C C (d). (c), (b), CSulfur ylides in the synthesis of heterocyclic and carbocyclic compounds * * * As evident form the published data, the recent investigations dealt with more and more complex conversions involving sulfur ylides.We believe that the synthesis of heterocyclic compounds with unique structures and the total synthesis of natural products and biologically active synthetic analogues will be the major field of application of ylides in the coming years. The reactions of ylides producing alkaloids and alkaloid-like compounds are worthy of particular attention because they have an increasingly important place among drugs used in oncology and cardiology. 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出版商:RSC    

年代:2001

数据来源: RSC

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Russian Chemical Reviews 70 (8) 673 ± 715 (2001) Marine polar steroids V A Stonik Contents I. Introduction II. Polyhydroxysteroids and related compounds III. Steroid sulfates IV. Steroid glycosides V. Steroidal alkaloids VI. Miscellaneous marine steroids VII. Problems of isolation and structural analysis of marine polar steroids VIII. Conclusion Abstract. activ- biological and distribution taxonomic Structures, Structures, taxonomic distribution and biological activ- ities of polar steroids isolated from various marine organisms over ities of polar steroids isolated from various marine organisms over the last 8 ± 10 steroid of peculiarities The considered. are the last 8 ± 10 years years are considered. The peculiarities of steroid biogenesis in the marine biota and their possible biological biogenesis in the marine biota and their possible biological functions are discussed.Syntheses of some highly active marine functions are discussed. Syntheses of some highly active marine polar steroids are described. The bibliography includes 254 polar steroids are described. The bibliography includes 254 references. I. Introduction Many representatives of this group are widely used in medicine as essentials of antiinflammatory, anabolic and contraceptive drugs. Steroids isolated from various marine organisms (marine steroids) manifest diverse biological activities. Some of them are extremely toxic against tumour cells and show antimicrobial and other effects. It is therefore not surprising that marine steroids arouse considerable interest in not only chemists, but also in pharmacol- ogists and physicians.Besides, these compounds fall under the scope of biology and biochemistry. Studies on taxonomic distri- bution of marine steroids make it possible to detect compounds which can be used as chemotaxonomic markers able to resolve many moot points in systematics of marine organisms and phylogenetic relationships in the marine biota. Since marine organisms comprise a large number of the so-called living fossils, comparison of their metabolisms with those of representatives of younger taxa sheds additional light on the evolution of secondary metabolic processes. Polar (often, water-soluble) steroids constitute an abundant group of marine steroids;{ many highly active and structurally unique compounds belong to this group.Studies of marine (including polar) steroids carried out before 1987 are reviewed in a monograph.1 Some problems related to marine polar steroids are also discussed in the reviews 2, 3 published in the early 1990's. This review is an attempt to generalise the experimental data on marine polar steroids published over the last 8 ± 10 years. II. Polyhydroxysteroids and related compounds The marine biota differs essentially from the terrestrial one in taxonomic composition and extreme diversity. This includes representatives of much more numerous large animal and plant taxa (i.e., animal phyla and plant divisions) in comparison with those dwelling on land.Many of these taxa contain exclusively marine organisms (e.g., echinoderms, bryozoans, ascidians, nearly all divisions of algae) or comprise very small groups of terrestrial species. For example, only one sponge family inhabits freshwater reservoirs, whereas all other sponges are exclusively sea and ocean dwellers. Taxonomic peculiarities of various producers and their unusual dwelling habitat provide the rationale for the non- coincidence of structures of the absolute majority of marine secondary metabolites and natural products found in terrestrial organisms. The uniqueness and structural diversity of natural compounds isolated from marine organisms draw the attention of chemists to this particular field. Published material devoted to this problem can now be found in virtually every issue of the majority of international chemical journals.Chemical investigations of marine organisms are making rapid strides. Of *12 000 newly discovered compounds, 1400 are marine steroids. It is well known that steroids play an important biological role. They represent constituents of biomembranes and hor- mones, fulfil protective functions, stimulate plant growth, etc. Marine organisms contain a great number of oxygenated sterol derivatives; the majority of these secondary metabolites are related to polyhydroxylated derivatives. These compounds were found in algae and marine invertebrates, particularly in sponges, echinoderms and octocorals (one of the orders of the Anthozoa class which in turn belongs to the phylum Coelenterata).In this section, we shall consider those oxygenated marine steroids and related compounds which have been discovered very recently, namely, after 1993 when Minale et al.2 published a review devoted to polyhydroxylated marine steroids. V A Stonik Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, prosp. 100-letiya Vladivostoka 159, 690022 Vladivostok, Russian Federation. Fax (7-423) 231 40 50. Tel. (7-423) 231 23 60, (7-423) 231 11 68. E-mail: piboc@stl.ru Received 14 May 2001 Uspekhi Khimii 70 (8) 763 ± 808 (2001); translated by R L Birnova { Steroid compounds which contain three or more oxygen atoms as well as steroid alkaloids, sulfates, phosphates and glycosides of steroid aglycons are usually referred to as polar steroids.#2001 Russian Academy of Sciences and Turpion Ltd DOI 10.1070/RC2001v070n08ABEH000679 673 673 684 692 703 708 710 711674 1. Polyhydroxysteroids from algae Com- pound 7 a A series of steroid hydroperoxides 1a,b and 2a,b were isolated from the red alga Galaxaura marginata collected near the coasts of Taiwan.4 These compounds manifest high cytotoxic activities against tumour cells P-388, KB, A-549, HT-29 (their semi- inhibiting concentrations, IC50, lie within the range 0.2 ± 1.0 mg ml71). b R 18 17 19 H 11 9 14 OOH 21 22 26 c 1 20 25 10 ; 1a: R = H H 27 4 6 O . 1b: R = d OOH OH 1a,b R e H OOH ; 2a: R = H H f O .2b: R = OOH O 2a,b ghij The oxygenated 3,4-dinorcholestane derivative 3 was isolated from extracts of the red alga Laurencia obtusa.5 The steroidal 3,6- diketone 4 oxygenated at C(16) was isolated from the alga Jania rubens, it exhibited high toxicity against some tumour cells (IC50&0.5 mg ml71) (see Ref. 6). The hydroperoxides 5a,b iso- lated from the brown alga Turbinaria conoides also possessed cytotoxic properties.7 H H OH H H H O H O O 3 OH 4 O H HOO It should be noted that the presence of unusual side chains in sponge polar steroids is due to the presence in the sponges of their precursors (sterols) having identical side chains. In contrast to higher plants where sterols represent minor components, some representatives of sponges and cnidarians (coelenterates) contain unusual sterols as predominant, and sometimes single compo- nents of steroid fractions.The side chain of the steroid ketone mycalone 8 from the Australian sponge Mycale sp. contains a lactone fragment formed upon oxidation of the ketone precursor at C(21) and C(24).13 H H H O 5a: R = O; 5b: R = b-OH. 5a,b R However, highly oxygenated sterols are not very common in algae. These metabolites are much more widely distributed in marine invertebrates. 2. Polyhydroxysteroids from sponges Among the compounds mentioned above, aragusterols man- ifesting strong cytotoxic and antitumour activities present special interest. The IC50 values of aragusterols 7c and 7d against tumour cells (KB) are 0.042 and 0.041 mg ml71, respectively. These steroids (1.6 mg kg71) increase the lifespan of mice with leukemia L-1210 in vivo by 220% and 257%, respectively.The 5,6-epoxide 6 isolated from the sponge Ircinia fasciculata collected near the coasts of India 8 and a series of steroids isolated from the Taiwanese sponge Xestospongia sp., viz., araguste- rols A±D (7c ± f),9 ±11 xestokerols A, B (7a,b) and araguste- rols E ±H (7g ± j), relate to sponge polyhydroxysteroids.12 Aragusterols and related compounds have unusual side chains, which contain cyclopropane fragments, while aragusterol C (7e) contains a chlorine atom in the side chain, which is a unique structural feature of natural steroids. OH R1 R3 H H H O HO OH H HR2 7a ± j 6 O 5-Epiaragusterol A synthesised from deoxycholic acid pos- sessed cytotoxic properties comparable to those of aragusterol A (7c).14 The synthesis of aragusterols from (+)-hekogenin15 included stereoselective formation of side chains, the addition of the corresponding fragment 9 to the 20-ketosteroid 10 prepared from hekogenin and preparation of aragusterol B (7d) via the intermediate 17 with subsequent transformation of 7d into 7c, 7e and 8f (Scheme 1).The triethylsilyl (TES) derivative 10 was synthesised in six steps from the readily available hekogenin. The fragment 9, which is structurally similar to the side chain of Name R1 HO OHOH xestokerol A OH xestokerol B OH O aragusterol A OH aragusterol B ClOHOH aragusterol C O aragusterol D OH aragusterol E aragusterol F aragusterol G (3a-OH) aragusterol H (3b-OH) 25 OAc 28 24 29 O 21 O H H H O 8 (mycalone) V A Stonik R3 R2 28 26 27 29 H H 25 OH HH H H H H H H H H H OH H H H H HMarine polar steroids OH H H HO H hekogenin b O O 11, 12 OR a 11: R =H 12: R=TBS TBDPSO OH H H H O O H (a) But3SiCl (TBSCl), imidazole,DMF(92%); (b)Me2CuLi, Et2O,778 8C (90%); (c) LiAlH4, THF; 80% AcOH (89%); (d) Pb(OAc)4, K2CO3, benzene; Ph3P=CHCO2Me, benzene (67%); ButPh2SiCl (TBDPSCl), imidazole, DMF; Bui2AlH (DIBAH), CH2Cl2, 778 8C (91%); (e) CH2 I2, Et2 Zn+ BuBO2(CH)2(CONMe2)2, CH2Cl2 (99%); (f) Ph3P, CBr4, CH2Cl2; LiAlH4, THF±Et2O; Bun4 NF, THF (88%); (g) Ph3P, N-bromosuccinimide (NBS), CH2Cl2 (75%); (h) lithium naphthalenide, THF, 0 8C; Bu4NF, THF (93%); (i) Al(OBut)3, cyclohexanone, toluene (66%); (j ) ethylene glycol, TsOH, boiling benzene (79%); (k) ButO2H, VO(acac)2, CH2Cl2 (78%); (l) Pri2NMgBr, THF (93%); 80% AcOH (98%); (m) m-CPBA, Na2HPO4, CH2Cl2, 0 8C (54%); (n) Li2CuCl4, THF (90%); (o ) pyridinium dichromate (PDC), molecular sieves (4 A), CH2Cl2 (100%).aragusterols, was synthesised from (5R)-hydroxymethyl-2(5H)- furanone (11) which in its turn was prepared from L-ascorbic acid. Protection of the hydroxy group (as the tris-tert-butylsilyl ether) and subsequent reaction of the derivative 12 with lithium dime- thylcuprate yielded the lactone 13 with high stereoselectivity.The latter was reduced, and the protective group was removed by treatment with acetic acid. The intermediate triol was converted into the allylic alcohol 14 in four steps, which included oxidation with lead tetraacetate, the Wittig reaction, protection of the hydroxy group as a silyl ether and subsequent reduction of the ester with diisobutylaluminium hydride. The key step in the synthesis of compound 9 was the conversion of the alcohol 14 into the cyclopropane derivative 15 by treatment with diiodo- methane in the presence of diethylzinc and N,N,N0,N0-tetra- methyl-(S,S)-tartarodiamide n-butylboronate. This reaction proceeded with high stereospecificity (yield 99%). Compound 15 was first converted into the alcohol 16 and then into the bromide 9.The stereoselective reaction of the 20-ketosteroid 10 with the alkyllithium derivative prepared from the bromide 9 and subse- quent removal of the protective group at C(3) with tetrabutylam- monium fluoride resulted in the alcohol 17 with high stereoselectivity. Its Oppenhauer oxidation gave aragusterol B (7d) which was further used for the synthesis of the other three aragusterols 7c,e,f by chemical modification of the side chain via the intermediates 18 ± 20. The oxidation of the steroid alkene 18 to the epoxide 19 was carried out stereoselectively with tert-butyl hydroperoxide in the presence of vanadyl bisacetylacetonate. The sponge Spongia officinalis represents the source of a series of novel 5,6-epoxysteroids 21a ± c and 22a ± c which were isolated as acetates and differed in the structures of side chains and the positions of double bonds in the steroid nuclei.16 Compound 21a was also isolated from Ircinia fasciculata.8 OO ... TESO c HO O O 13 OTBS f OH HO 15 k H O 18 O H OH H H H OH OH g 16 O OH H H 19 O H10 d TBDPSO Br 9 l H O H AcO O AcO O Steroids oxidised in positions 5 and 6 were repeatedly found in sponges where they were apparently formed from D5-sterols.17 The ketone 23 from Spirostrella inconstans is one of such newly discovered steroids.18 H HO HO O OH 14 OH H 10, h H H HO H OH OH H H 20 R 21a: R = 21b: R = H 21c: R = OAc 21a ± c R 22a: R = 22b: R = 22c: R = HOAc 22a ± c 23 675 Scheme 1 e OH j i 7d 17 n m 7e 7c o 7f ;;.;;.676 Incrustasterols A and B (24a,b) from the Mediterranean sponge Dysidea incrustans differ from other polar sponge steroids in the presence of D8(9)-7-hydroxy-9-keto- and D8(9)-7,9-diketo- fragments, which are uncommon for marine steroids.O H 24a: R = a-OH, H; 24b: R = O. HO R HO 24a,b OH Compounds 24a,b are toxic for tumour cells (lung and kidney carcinomata, melanoma).19 These compounds were synthesised from the readily available cholest-7-enol.20 The so-called agosterol 25 from Spongia sp. abrogates drug resistance of carcinoma cells, conditioned by enhanced expression of membrane glycoproteins.21 Xestobergsterols A±C (26a ± c), which contain five carbocycles with the cis-fused rings C and D, were found in Xestospongia bergquistia and Ircinia sp.22, 23 Pre- sumably, the presence of an additional ring in these steroids is due to intramolecular aldol condensation of the yet non-isolated 23-keto derivative.Compounds 26a and 26b manifest cytotoxic activities and inhibit the anti-IgE-induced release of histamine from mast cells when used in small doses. Thus these compounds present considerable interest as potential active substances of novel antihistamine drugs. Their activities are closely related to strong inhibition of phosphatidylinositol phospholipase C. OH HO H H AcO H OAc 25 (agosterol) AcO 21 H 25 E 23 17 HO R1 C H D R2 H OH A B H O HOH HO H 26a: R1=R2=H; 26b: R1=H, R2=OH; 26c: R1=R2=OH.26a ± c OH Yet another polar sponge steroid with the cis-fused rings C and D, viz., contignasterol (27) from Petrosia contignata, discov- ered simultaneously with xestobergsterols 24 produces strong antihistamine effect. Although contignasterol is inferior to com- pounds 26a and 26b in the activity, it is far more active than antihistamine drugs routinely used in clinical practice and is the subject of intense pharmacological studies as a promising candi- date for antiallergic and antiasthmatic drugs. OH 29 O 28 20 22 24 25 H H H O HO OH H 27 (contignasterol) OH V A Stonik Geodisterol (28), the first marine steroid containing an aro- matic ring A, was isolated from extracts of Geodia sp.25 OHOH H H H 28 (geodisterol) HO Previously, such compounds were referred to as hormones; however, in contrast to the latter, geodisterol (28) has a ten-carbon side chain characteristic of sterols.Bienmasterol (29 ) from Bienma sp.,26 which is toxic against tumour cells (L-1210 and KB), contains a 22,25-diene fragment in the side chain, which is uncommon for natural steroids. An analogous fragment has been detected by us previously in baicalosterol isolated from the sponge Baicalospongia bacilifera.27 H H HO HO 29 (bienmasterol) OH Cytotoxic kicheisteronesAand B (compounds 30 and 31) with the cis-fused rings A and B, which contain carboxy groups in position 21 and furan fragments in the side chains, were isolated from an unidentified Hawaiian sponge of the Poecilosclerida order.These compounds are rather stable in acidic media but are easily interconverted in alkaline media to form 1 : 1 mixtures.28 O 22 25 HO 23 21 28 O H 29 HO H H O H 30 (kicheisterone) O HO O H O H H HO 31 (kicheisterone B) H Steroids 30 and 31 were found in the sponge Strongylacidon sp. together with kicheisterones C± E (compounds 32a,b, 33). The latter contain chlorine atoms and belong to the group of extremely rare halogenated steroids.29 O HO R O (kicheisterone C) 32a: R= H H H (kicheisterone D) 32b: R= O Cl 32a,bMarine polar steroids O HO O H H H O H 33 (kicheisterone E) Cl It is of note that no bromine-containing steroids have been isolated so far despite the wide occurrence of brominated metab- olites in marine organisms. Three pregnane derivatives 34a ± c from Strongylophora sp.were found to contain unusual (19?2)-lactone rings; their structures were established by X-ray diffraction analysis.30 Hydroperoxides and related peroxides are more common for algal steroids; however, the novel biofouling inhibitor steroid 35 containing a peroxy group has recently been isolated from the sponge Lendenfeldia chondrodes.31 Peroxides similar to compound 35 are readily formed by oxidation of D5,7-sterols, which are abundant in fungi, but scarce in sponges. R O H O H H 34a: R= 34b: R= ;; HO O 34c: R = , D16.34a ± c OH HOO H HO HO 35 O The novel acetylated polyhydroxysteroids 36, 37, 38a,b32 and related steroids 33 were detected in some sponges of the Dysidea genus. The steroid 37 and, to a lesser degree, steroids 38a,b inhibit the binding of interleukin-8 to its specific receptor of the type A. O O H H HO HO O HO HO 37 36 OAc OAc AcO H RO HO 38a: R =H; 38b: R=Ac. 38a,b OAc Secosteroids occur widely in sponges. The most common of them are 9,11-secosteroids, such as blancasterol (39), a cytotoxic diacetate from the Northern Pacific sponge Pleraplysilla sp., which inhibits the growth of various tumour cells including drug-resistant cell cultures of human mammary carcinoma MCF-7.34 Stelletasterol (40a), the antifungal secosteroid from Stelletta sp.isolated simultaneously with stelletasterone (40b),35 differs from the previously known herbasterol (40c) from Dysidea herbacea only in the stereochemistry of the hydroxy group at the C(3) atom. AcO HO O H HO OH 39 (blancasterol) AcO HOO HO H HO H R H OH 40a ± c Like many other marine secosteroids, luffasterols A±C (41a ± c) from Luffariella sp.36 and the related secosteroid 41d from Spongia matamata 37 contain 5,6-epoxy rings. 3-Deacetyl- luffasterol B (41e) and the related compound 41f were isolated from Spongia agaricina. Both compounds manifest highly toxic activities against tumour cells.38 H O R2 O H R1 41a ± f O 41a: R1=OAc, R2= 41b: R1=OAc, R2= 41c: R1=OAc, R2= 41d: R1=OH, R2= 41f: R1=OH, R2= Secosteroids 42a,b and 43a,b along with biogenetically related oxygenated sterols 44 and 45 were found in the Mediterranean sponge Dysidea fragilis.39 HO R O H HO O 42a,b HO R O H HO HO 43a,b OH O H HO HO HO 44 OH 677 40a: R=b-OH, H (stelletasterol); 40b: R=O (stelletasterone); 40c: R=a-OH, H (herbasterol).(luffasterol A); (luffasterol B); (luffasterol C); ; ; 41e: R1=OH, R2= . ; 42a: R = . 42b: R = 43a: R = ; 43b: R = . H H HO OH 45678 A series of euryspongiols 46a ± e and the epimeric 3a-hydroxy analogues possessing antihistamine properties were isolated from the sponge Euryspongia sp.40 These compounds are the most strongly oxygenated sponge secosteroids known so far.The strong inhibiting effect of these and some other secosteroids on histamine release from mast cells during stimulation of the latter with anti- IgE suggests that marine secosteroids are promising candidates for antiallergic and antiasthmatic drugs. HO R HO O H HO H HO H OH 46a ± e HO HO O HO H HO H 47 (stelletasterenol) OH The unusual cyclic 9(11)-secosterenol, viz., stelletasterenol (47) from Euryspongia arenaria, contains an oxygen atom between the C(9) and C(11) atoms and manifests the properties of a PAF (platelet activation factor) agonist.41 In addition to 9,11-secosteroids common for marine inverte- brates, sponges contain less abundant groups of compounds, which comprise 8,14- and 8,9-secosteroids. The former include jereisterol B (48) from Jereicopsis graphidiophora 42 and swinhos- terols A and B (49a,b) from Theonella swinhoe.43 Sponge 8,9- secosteroids are represented by unique 8a,9a-epoxy compounds, e.g., jereisterol A (50a) from J.graphidiophora 42 and its homo- logue 50b isolated from the Senegalese sponge Microscleroderma spirophora together with the isomeric D8(14),9(11) steroid 51.44 These compounds contain O-methyl groups, which occur rarely in natural steroids. Their structural analogues, viz., tilopiols A (52) and B (53), have recently been found in the microscopic fungus Tilopilus plumbeoviolaceus.45 This finding suggests that microorganisms can be involved in the biosynthesis of sponge steroids 50a,b and 51.O H O MeO 48 (jereisterol B) H O O H HO H 49a,b ; 46a: R= ; 46b: R= 46c: R = ; 46d: R= ; 46e: R = . R (swinhosterol A); 49a: R= (swinhosterol B). 49b: R= R O 50a: R= MeO 50b: R= 50a,b H O O HO MeO 51 H H O O HO H 53 (tilopiol B) It is not excluded that the great diversity of polar sponge steroids and the unique structures of many of them are due to biochemical conversions of the original sterols of both the sponge cells and microbial endosymbionts which are present in some sponges in amounts comparable to the populations of host cells. However, this hypothesis needs further verification and experi- ment in each particular case.Although not a single sterol-oxidising enzyme has been isolated from sponges, symbiont bacteria, fungi or microalgae so far, such enzymes obviously differ from analogous enzymes of higher animals and terrestrial microorganisms in those sites in their sterol systems which oxidise the respective substrates. Thus some sponges were found to contain various secosteroids which are absent in terrestrial animals. 3. Polyhydroxysteroids from cnidarians Polyhydroxysteroids are even more abundant in cnidarians (Coe- lenterata), particularly octocorals (soft corals) and gorgonian corals than in sponges. A great number of polyhydroxysteroids and secosteroids were detected in these marine invertebrates as long ago as 1970 ± 1980.In the recent years, the list of these compounds was supplemented with many new names. Thus nephalsterol B (54a) found in Nephthea erecta,46 N. chabroli 47 and Litophyton arboreum 48 [the latter contains additionally the D8(9)-triol 55 and related compounds, e.g., litosterol (54b) and nephalsterol C (54c)] are characteristic components of soft corals of the Nephthea genus. Compounds 54b,c manifest strong anti- microbial activities, viz., they inhibit Mycobacterium tuberculosis by 90% and 96% when used in the doses of 3.13 and 12.5 mg ml71, respectively. The antituberculotic activity of neph- alsterol B (54a) is less pronounced.49 R2 H H H HO R1 54a: R1=R2=OH (nephalsterol B); 54b: R1=H, R2=OH (litosterol); 54c: R1=OAc, R2=OH (nephalsterol C).54a ± c V A Stonik (jereisterol A); . 52 (tilopiol A)Marine polar steroids OH HO H HO Some novel steroids of this series, viz., polyols 56a,b, the triol 57 and the tetrol 58 from Nephthea chabroli, have recently been described.47 Their structurally related analogues, viz., the triol 59 and the dihydroxy ketone 60, were isolated from Nephthea erecta collected near the coasts of Taiwan.46 R1 OHR3 H HR2 HO 56a,b HO HO H H H HO 57 HO H H H OH HO 59 Triols 61a,c and the tetrol 61b from Sinularia mayi contain several hydroxy groups in their side chains.50 The novel steroidal polyol 62 oxygenated at C(3), C(6), C(9) and C(11) was found in S. hirta.51 The triol 63 and the corresponding glycosides were isolated from extracts of S.gibbrosa,52 whereas the novel steroid pentol 64a and its acetate 64b were isolated from S. dissecta.53 The pentol 65a and the ketone 65b from Sinularia sp.54 and S. micro- clavulata,55 respectively, contain oxygen atoms in the same positions, viz., at C(1), C(3), C(5), C(6) and C(16). The steroidal peroxide 66 from Sinularia sp.56 proved to be highly toxic for tumour cells (IC50=0.4 ± 2.7 mg ml71). This compound was isolated together with pregnenolone earlier detected in the sponge Haliclona rubens.57 The stereochemistry of the C(22), C(23) and C(24) asymmetric centres of the peroxide 66 was established by comparison of its spectra with those of some synthetic model compounds. H H H HO 61a ± c 5556a: R1 =OH, R2=R3=H; 56b: R1 =H, R2=R3=OH.OH H OH HO HOH 58 OH H H HO HO 60 OH R 61a: R = ; OH OH 61b: R = ; OH OH OH 61c: R = . OH HO OH HO HO H 62 OH HO R H H H HO HO 64a,b OH HO H OH H H HO HO 65a,b RHO H H H H O HO 66 O Several novel polar steroids were discovered in soft corals of the Lobophyton genus. For example, the tetrol 67 was isolated from L. crassum,58 whereas two monoacetates 68a,b were isolated from L. cf. pauciflorum.59 These steroids contain 5a,6b-diol frag- ments similar to those present in oxygenated steroids isolated from soft corals of the Sarcophyton genus. For example, sarcoal- desterol B (69a) represents a deacetylated derivative of the steroid 68a.It was isolated from the Okinawian soft coral Sarcophyton sp. HOH H H HO HO 67 OH HO AcO H H H HO HO 68a,b OH HO R HO H H H HO HO 69a,b OH 679 H OH H H OH 63 64a: R=OH; 64b: R=OAc. 65a: R = b-OH, H; 65b: R = O. R 68a: R = (24S )-CH3; 68b: R=CH2=. ; 69a: R= H 69b: R= .680 together with sarcoaldesterol A (69b), which contains a side chain similar to that of gorgosterol, the well-known sterol of cnidar- ians.60 Steroids 70a ± d from the soft coral S. subviride collected near the coasts of the Andaman Islands are oxygenated to a greater degree. Some of them contain an acetate group at C(25) character- istic of polar steroids of Coelenterata.61 Two novel polar steroids 71a,b containing unique 17,20-epoxy fragments, two hippurin derivatives 72a,c differing in stereochemistry at C(22) (hippurin is a well-known polar steroid of Coelenterata) and their acetates 72b,d, were isolated from extracts of S.crassocaule.62 70a: R1= R2 R1 OH H 70b: R1= H H 70c: R1= HO HO OH 70a ± d 70d: R1= RO H H H 71a,b AcO O HO 24 22O H H H 72a ± d R Aseries of polar steroids including the hippurin analogue, viz., compound 73, as well as derivatives 74a,b, 75 and 76 were detected in the soft coral Alcyonium graccilum by Shin et al.63 Presumably, compound 76 is a biosynthetic precursor of all this group of secondary metabolites. OO H H H 73 O HOO H H H 74a,b O O H H H O O 75 H , R2=OH; OAc , R2=H; OH OAc , R2=H; OH , R2=H.H 71a: R=OH; 71b: R =OAc. 72a: R=OH(22S,24S); 72b: R =OAc (22S,24S); 72c: R=OH (22R,24S); 72d: R =OAc (22R,24S). 74a: 4,5-dihydro; 74b: D4. O H H H H 76 Yet another species of this genus, viz., Alcyonium graccilum (its mixture with Dendronephthea sp. has been studied), contains related steroids 77a,b,64 which are toxic for barnacle (Balanus amphitrite) larvae (LD100=100 mg ml71). R OH H 77a: R= H H OH O 77b: R= 77a,b The steroidal pentol 78 was found in the soft coral Sclerophy- tum sp. together with several previously known steroids.65 Anda- mansterol (79) 66 containing hydroxy groups in positions 9 and 11, which takes its name after the place where it was first collected (Andaman Islands), was detected in another unidentified species of the same genus.Such oxidation can precede the formation of 9,11-secosteroids widely distributed in marine invertebrates. An interesting feature of andamansterol (79) is the presence of a hydroxy group at C(21), which is uncommon for polar steroids of Coelenterata, but is common for steroids of some echinoderms, particularly, for ophiuroid metabolites. OH H OH H H HO HO 78 OH OH HO H OH H HO 79 (andamansterol) H Gorgonian corals are distinguished for a great diversity of oxygenated steroids containing from 2 ± 3 to 5 ± 6 oxygen atoms. Thus melithasterols A±D (80a ± d), each containing an 5,6-epoxy ring and an additional OH-group in position 7, were found in Melithaea ocracea.67 Melithasterol A (80a) has recently been synthesised.68 Steroids 81a,b from Acabaria undulata also contain epoxide rings, however, in positions 7 and 8.69 Anastomosacetals A±D (82a ± d) from Euplexaura anastomosans collected near the coasts of Korea contain oxygen atoms in positions 17, 21 and 24.70 80a: R= R 80b: R= H 80c: R = HO OH O 80a ± d 80d: R= R 81a: R= H H O HO HO 81b: R= OH 81a,b V A Stonik , 4,5-dihydro; CO2CH3 , D4.(melithasterol A); (melithasterol B); (melithasterol C); (melithasterol D). ; .Marine polar steroids H O 24 21 20 HO HO H17 OH H 1 82a: D1,4 (anastomosacetal A); 82b: D4 (anastomosacetal B); 82c: D1 (anastomosacetal C); 82d: 1,2,4,5-tetrahydro (anastomosacetal D).3 H H O 4 82a ± d The so-called black coral Anthiphates subpina related to the Antipatharia order contains steroid triols 83a,b and diketone 84, which are toxic for crustaceans.71 The tetrol monoacetate 85a and the corresponding tetrol 85b were isolated from Telesto viisei.72 R HO H ; 83a: R = H . 83b: R = OH HO 83a,b OH RO H H O H H H H O HO 84 85a: R=Ac; 85b: R = H. OH HO 85a,b The steroidal hemiacetal 86 possessing antimicrobial, antiviral and antitumour properties was isolated from the gorgonian coral Ctenocella sp.73 Punacine (87) from the gorgonian coral Lopho- gorgia punicea dwelling near the coasts of Brazil contains a hydroxy group at C(17), which is uncommon for cnidarian steroids.74 O OH HO H H O H H HO H H HO 87 86 O OH Polyhydroxylated steroids 88a,b from the octocoral Dendro- nephthea gigantea 75 manifested moderate cytotoxic activities against tumour cells (L-1210).AcOH H H R2 R1 HO HO 88a: R1=R2=H; 88b: R1=OH, R2=H. 88a,b OH A series of steroids oxygenated in positions 1, 5, 6 and 11 (compounds 89a,b, 90a,b, 91a ± d and 92) were isolated from the Okinawian coral Clavularia viridis.76 Compounds 89a,b manifest cytotoxic properties and are similar to vitanolides, the higher terrestrial plant metabolites, in the structures of their polycyclic fragments. R AcO O H H H 89a,b O R AcO O H H H AcO 90a,b O R AcO O H H H HO O 91a ± d AcO O H H H HO O 92 Secosteroids are common metabolic products of octocorals.The 9,10-secosteroids, viz., calicopherols A and B (93a,b), which are toxic for shrimps, were isolated from the gorgonian coral Caligorgia sp. collected near the coasts of Japan.77 A series of novel calicopherols differing structurally from compounds 93a,b have recently been isolated from the gorgonian coral Muricella sp. These compounds manifest high cytotoxic activities against tumour cells and inhibit phospholipase A2.78 22 H OH 9 HO H 19 10 93a: 22,23-dihydro (calicopherol A); 93b: D22 (calicopherol B). 3 1 OH 93a,b 9,11-Secosteroids are much more abundant in soft and gorgo- nian corals.Among the most recent findings, we should make reference to dioxoaldehyde 94 from Subergorgia suberosa col- lected near the coasts of India;79 steroids 95a ± c from the same species collected near the coasts of the Comores Islands;80 the epoxide 96 from the Indonesian coral Lobophytum sp.81 and 4a-methylsecosteroids 97 and 98 from Pseudopterogorgia sp.82 manifest moderate inhibitory activities with respect to protein kinase C and possess antiinflammatory and cytotoxic properties. O HO H 94 O 681 ; 89a: R= . 89b: R= ; 90a: R= . 90b: R= 91a: R= 91b: R= 91c: R = O 91d: R= ;;;.682 HO R O H HO H OH 95a ± cHOO H H HO OH O 96 HOO H H HO 98 The unusual hemiacetal 99 (nicobarsterol) from Sclerophytum sp.was named after the place where it was first collected (the Nicobar Islands in the Indian Ocean).66 O HOO H HO H OH A search for novel compounds able to prevent biofouling of ship bottoms and submerged structures undertaken by the Fuse- tani group 93 resulted in the isolation of four novel unprecedented 13,17-secosteroids 100a,b and 101a,b (isogosterols A± D) from Dendronephthea sp. They manifested much higher antifouling activities in comparison with steroids 77a,b and inhibited the settlement of barnacle (Balanus amphitrite) larvae when used in concentrations of*2 mg ml71 (see Ref. 83). AcO OO H H 100a,b O AcOH OH O H O 101a,b Oxygenated steroids with the pregnane skeleton were often found in various representatives of Coelenterata; in particular, acetylated pregnanes 102a ± d and 103 have recently been found in the South African population of Pieterfaura inilobata.84 95a: R = ; 95b: R = ; 95c: R = .HOO H H HO H 97 OH 99 (nicobarsterol) R 100a: R=H (isogosterol A); 100b: R=OAc (isogosterol D). OH R 101a: R=O (isogosterol B); 101b: R=OAc, H (isogosterol C). V A Stonik R4 R1 H H H 102a: R1=R3=H, R2=Ac, R4=OH; 102b: R1=H, R2=R3=Ac, R4=OH; 102c: R1=OAc, R2=Ac, R3=R4=H; 102d: R1=OAc, R2=R3=Ac, R4=OH. OR3 R2O 102a ± d AcO H H HOAc AcO 103 The detection of polar steroids in the sea pens of the Penna- tulaceae order is the most uncommon case. Thus the triol 104, the simplest oxygenated steroid formed upon oxidation of cholesterol at the 5(6)-double bond, was isolated from Pteroides esperi.85 H H H HO HO 104 OH It should be said in conclusion that hydroxylation in Coelen- terata predominantly occurs in positions 3, 5, 6, 22 and 25 and less frequently in positions 1, 2, 11, 16, etc.Steroids containing angular hydroxymethyl groups are widespread in these invertebrates; the oxygenation of the 19-methyl group occurs most often. In these animals, sterols can be oxidised to pregnane derivatives. 9,11-Seco compounds are as widely occurring in cnidarians as in sponges. It is noteworthy that polar steroids are seldom found in other taxa of Coelenterata, with the exception of octocorals. 4.Polyhydroxylated steroids from molluscs Polar steroids are seldom found in molluscs, usually these are of exogenous origin, viz., they are consumed with food and accumu- lated in either an unchanged or a modified form. In most cases, the steroids accumulated in molluscs play the protective role. For example, unusual 2a,3a-dihydroxy cross-conjugated ketones, such as diaulusterols A and B (105a,b), one of which containing a hydroxybutyrate substituent in the side chain, were detected in the nudibranch mollusc Diaula sandiegensis.86 Recent in vitro studies of 1,2-13C-acetate as a biosynthetic precursor showed that the steroid 105a is not biosynthesised by these molluscs but is modified by addition of a substituent to the hydroxy group at C(25); this substituent is biosynthesised from acetate.87 It is of note that nudibranch molluscs are devoid of shells and other mechanical protective means, they readily absorb toxic and deterrent metabolites from the sponges they feed on.OR HO H H HO 105a: R =COCH2CH(OH)CH3 (diaulusterol A); 105b: R=H (diaulusterol B). O 105a,b The triol 106a and its 6-O-methyl derivative 106b widely occurring in sponges were isolated from fertilised eggs of the mollusc Aplysia juliana.88Marine polar steroids HO HO Table 1. The structures of polyhydroxysteroids isolated from starfishes. Com- pound Unsaturation R1 type 107 7 108 D8(14) 109 D8(14) 110 7 111 7 112 7 113 7 114 7 115 7 116 7 117 7 118 7 119 7 120 7 121 7 122 7 b-OH H 123 7 b-OH H 124 7 b-OH H 125 7 b-OH H 126 7 H H 106a,b OR 106a: R =H; 106b: R = CH3 .R5 R4 R3 R2 H b-OH H H a-OH H b-OH H H a-OH H b-OH H H a-OH OH a-OH H H a-OH H a-OH H H b-OH H a-OH H H b-OH H a-OH H H b-OH H a-OH H H b-OH H a-OH H H b-OH OH a-OH H H b-OH OH a-OH H H b-OH OH a-OH H H b-OH OH a-OH H H b-OH OH a-OH H H b-OH OH a-OH H H b-OH OH b-OH a-OH OH b-OH a-OH OH b-OH a-OH OH b-OH b-OH H H a-OH a-OH b-OH 5.Polyhydroxysteroids of echinoderms Echinoderms, particularly starfishes, are the source of the most oxygenated steroids. A great number of polyhydroxy derivatives have been discovered in these organisms since 1974. More than 20 novel compounds, (compounds 107 ± 128) 89 ± 95 have been iso- lated recently (Table 1).The hydroxy groups in positions 3b, 6a or 6b, 8b, 15a or 15b, 16b and 26 are especially abundant in starfish steroids, while polyhydroxysteroids containing hydroxy groups in positions 4a or 4b, 7a, 14a, 24, 28 and 29 are isolated less often. Some starfish polar steroids contain eight or nine hydroxy groups, The side chain (R7) R6 OH b-OH H OH OH H OH H OH b-OH OH b-OH OH b-OH b-OH OH OH OH b-OH OH OH b-OH OH b-OH OH b-OH b-OH OH b-OH OH OH OH H OH H OH Hb-OH OH OH H OH b-OH 683 Ref. The biological source Ceramaster patagonicus 89 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Ceramaster patagonicus 89 91 Echinasteridae gen.sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. 91 Echinasteridae gen. sp. Acodontaster conspicuus 90 Acodontaster conspicuus 90 Henricia derjugini 93 Ctenodiscus crispatus 94684 Table 1 (continued). Com- pound Unsaturation R1 type 127 7 128 7 although the corresponding pentols and hexols are more common for these animals. R4 HO R1 R2 R3 Sometimes starfish metabolites contain other functional groups or manifest other structural features. For example, the pentol 129 from Luidia clathrata 92 is a 5b-cholestane derivative in contrast to other polar steroids of this series.One of the hydroxy groups in compound 130 from Echinasteridae gen sp. is oxidised to the keto group,91 whereas steroids 131 and 132 from Myx- oderma platyacanthus contain carboxy groups in their side chains.96 H HO H OHH H HO O H H H HO HO OHH H HO HO OH Recent studies on the distribution of polyhydroxy compounds in various body components and organs and structures of star- fishes 97 prompted several conclusions concerning their biological roles. Since polyhydroxysteroids and related mono- and biosides were found only in digestive organs and solubilise lipid suspen- R3 R2 H a-OH b-OH H a-OH b-OH R7 R6 H R5 107 ± 128 OH OH H OH 129 OH OH H OH 130 CO2H H131 CO2H H132 V A Stonik Ref.The side chain (R7) R6 R5 R4 The biological source Ctenodiscus crispatus 94 H b-OH a-OH OH OH Luidiaster dawsoni 95 H b-OH a-OH OH sions like bile acids, their role in starfishes can be similar to that of bile acids and bile alcohols in vertebrates. Some starfish polyhydroxysteroids manifested antimicrobial activities against the gram-positive bacterium Staphylococcus aureus but did not inhibit the gram-negative bacterium Escher- ichia coli.Aseries of octols and nonols containing hydroxy groups in positions 4, 7, and 8 manifested high cytotoxic activities against human lymphoma cells JURCAT.98 It is interesting to note that polyhydroxysteroids are not common in other classes of echinoderms.Related sulfated polyols were found only in ophiuroids, whereas in holothurians and sea urchins polar steroids have not been identified yet. Recently, steroidal 3b,5a,6b-triols of the D7-series were found in one representative of sea lilies (Crinoidea).99 Not all groups of marine invertebrates are rich in polyhydr- oxysteroids. The latter are not common for bryazoans and ascidians, but occur predominantly as ecdysteroids in crustaceans; however this group of polar steroids fall beyond the scope of the present review. In sponges, cnidarians and echinoderms, they are represented by only very few orders or classes. Notwithstanding, the immense diversity of marine polyhydroxysteroids is amazing and seems to reflect the intense evolutional search characteristic of taxa located in the basements of phylogenetic trees.Obviously, cnidarians and sponges are the most ancient animal organisms that have come down to us. The biological roles of oxygenated sterol derivatives and related pregnane and other steroids are different in vertebrates and marine invertebrates. Whereas in the former they predom- inantly act as hormones and take part in digestion as bile acids, in sponges and cnidarians they usually perform protective functions, e.g., they frighten away predators, inhibit the growth of patho- genic microorganisms, protect producers from fouling with algae, barnacles, molluscs, etc. It is interesting to note that there are such biochemical trans- formations of sterols in some primitive marine invertebrates, which as happy findings of the Nature are repeated many time in other types of organisms and become to be of considerable importance in more advanced animal taxa and in higher plants. For example, as it was mentioned above, sponges and cnidarians contain pregnenolone, a biosynthetic precursor of steroid hor- mones of higher animals. Compounds of the spirostane series, which are analogous to aglycons of steroid saponins of higher plants, were repeatedly found in cnidarians and some other marine invertebrates.C28-Steroid lactones, which are structurally similar to some witanolides (metabolites of terrestrial higher plants of the Solanaceae family), were found in the soft coral Minabea sp.100 These biochemical parallelisms presumably testify to some degree of determinism in evolution of secondary meta- bolic processes occurring in living organisms.III. Steroid sulfates Sulfated compounds are extensively distributed in marine organ- isms. They were found in micro- and macroalgae, marine inverte- brates (e.g., sponges, echinoderms, molluscs), hemichordates and fishes. Sulfation is an essential mechanism of biosynthetic con- versions occurring in the marine biota. This is not surprising, since sulfur (in the form of a sulfate ion) is the fourth most abundantMarine polar steroids element in sea water after chlorine, sodium and magnesium. The introduction of a sulfate group increases the solubility of marine natural products and makes them biphilic, which is especially important for manifestation of their detergent and toxic activities and signal functions in various inter- and intraspecies interactions. The presence of sulfate groups ensures efficient transport of the corresponding compounds in water, while the presence of hydro- phobic fragments in their molecules facilitates their binding to hydrophobic receptors of recipient organisms.In macroalgae and some microalgae, sulfated compounds are largely represented by polysaccharides, while those in marine animals are represented by low-molecular-weight bioregulators. Over 500 sulfated secondary metabolites of different chemical groups (e.g., terpenoids, carotenoids, steroids, alkaloids, aromatic metabolites, etc.) have been identified.101 Sulfated steroids constitute one of the most numerous groups of these compounds.They were mostly isolated from animals related to two large phyla of marine invertebrates, viz., echino- derms (Echinodermata) and sponges (Porifera), although sulfated steroids were also found in other marine organisms. The bio- logical functions of compounds related to this group are still poorly understood, although the facts that the least polar of them are essential components of biomembranes, while other represen- tatives of this group are used for chemical protection against predators and pathogenic or fouling microorganisms leave no doubts. 1. Sterol sulfates Structurally, sterol sulfates are the simplest sulfated steroids.In echinoderms, they occur as common metabolites; their concen- H 7O3SO 133a ±mH 7O3SO H H 7O3SO H 7O3SO H R136a,b 133a: R = R 17 H H 133c: R = (cholesterol sulfate); 133b: R = ;; 133d: R = ; R ; 134a: R = 134d: R = H 134e: R= ; 134b: R = H ; 134c: R = 134a ± i 135d: R = 135a: R = ; R 135e: R= 135b: R = ; H 135c: R= ; 135f: R = 135a ± k H 7O3SO H 136a: R =H; 136b: R = CH3 . trations in starfishes (Asteroidea), holothurians (Holothurioidea), ophiuroids (Ophiuroidea) and sea lilies (Crinoidea) amount to 4 ± 5 mg per gram of dry tissue, those in sea urchins (Echinoidea) are somewhat lower.1 The predominant component in the respec- tive fractions is cholesterol sulfate 133a.In addition, these fractions always contain sulfates of other D5-sterols. Toxic repre- sentatives of holothurians and starfishes contain small amounts of sulfated stanols and sulfates of D7-sterols along with sulfates of the D5 series. For example, the Far Eastern holothurian Eupentacta (=Cucumaria) fraudatrix was found to contain polar steroids 133a ± i, 134a ± k and 135a ± l. Moreover, the same holothurian species contain trace amounts of sulfates of 14a-methyl-D9(11)- sterols 136a,b and of triterpenoids 137 and 138.102 Practically all free sterols from E. fraudatrix are subject to sulfation, however, in different degrees. D5-Sterols (in the first place, cholesterol), which are consumed with food, are sulfated in the greatest degree.In contrast with sulfates, free sterols of the D5 series are present in toxic holothurians in small amounts; they can be transformed into sulfates, stanols and D7-sterols. Stanols and D7-sterols, contra- riwise, predominate in fractions of free sterols, but are sulfated in a very low degree. These peculiarities of steroid metabolism in holothurians and starfishes are explained by the presence of toxic glycosides, which react with the membrane cholesterol and other D5-sterols resulting in the formation of membrane pores. This is why cholesterol and its homologues are highly toxic for holothurian cells; their substitution by D9(11)- and D7-sterols, stanols and sulfates of the type 133, which are less capable to form membrane complexes with holothurian toxins, protects these animal cells from deleterious effects of their intrinsic glyco- sides.103 133e: R= ; 133h: R = 133f: R = ; 133i: R = 133g: R = ; 133j: R = 134f: R = ;; 134g: R = 135g: R = ;; 135h: R = ; 135i: R = H H 7O3SO 137 685 133k: R = ; (hymenosulfate);; ; 133l: R = .; 133m: R = ; 134h: R = ; . 134i: R = ;; 135j: R = ;. 135k: R = ; ; H H 138686 These data suggest that sulfation of free cholesterol in echinoderms is a result of their adaptation to the effects of intrinsic membranolytic toxins and that sterol sulfates fulfil a membrane- protective function by preventing the effects of these toxins on cell membranes. 7O3SO Recently, Indian and Italian scientists have isolated two novel sulfated sterols 133l,m from the tropical sea cucumber Holothuria sp.104 7O3SO Sterol sulfates were detected not only in echinoderms but also in some other marine organisms.For example, 24-methylidene- cholesterol sulfate 133g was detected in the diatomic microalga Nitzchia alba as long as 35 years ago,105 whereas the so-called hymenosulfate 133k, which contains an unusual side chain similar to those of some free microalgal (dynoflagellate) sterols, was found in the haptophytic microalga Hymenomonas sp.106 2. Polyhydroxysteroid monosulfates 7O3SO Polyhydroxysteroid monosulfates from sponges and echinoderms contain sulfate groups in 3b- or other positions. Thus compounds 139a ± c containing additional hydroxy groups at C(19) were isolated from the sponge Toxadocia zumi.107 A new b-1,3-gluca- nase inhibitor, viz., annasterol sulfate 140, was isolated in our laboratory from the Pacific deep-water sponge Poecilastra lami- naris.108 R 139a: R= ; HO H H2C 139b: R= ; H H 7O3SO 139c: R= 139a ± c .H 7O3SO H The steroid 146 from the sponge Stilopus australis 111 is unrelated to sterol derivatives, this rather resembles steroid hormones because of the presence of the pregnane skeleton. H 7O3SO HOAc 140 (annasterol sulfate) 7O3SO One of a few steroid monosulfates 147 with the sulfate group in position 2b was isolated from Echinoclathria suhispida collected near the coasts of Japan.Echinoclasterol sulfate 147 is a salt in which protonated tyramine is the counter-ion.112 C6H5(CH2)2NH3 The unusual steroid polymastiamide A (141a) was isolated from the sponge Polymastia boletiformis collected near the coasts of Norway.109 This is the amide of a rarely occurring amino acid, viz., p-methoxyphenylglycine, and its steroidal fragment is a D8(14)-derivative methylated in position 4. Earlier, 4a-methyl- D8(14)-sterols were detected in some archaebacteria of the Methyl- ococcus genus. This points to participation of symbiont bacteria in biosynthesis of compound 141a, since archaebacteria have recently been identified as symbionts in some sponges. Polymas- tiamides B ±F (141b, 142a,b, 143a,b) isolated from the same sponge are structurally close to polymastiamide A (141a).Their treatment withCH3OH/HCl is accompanied by both migration of the double bond and aromatisation of the ring C resulting in the artificial products 144 and 145.110 O NH HOCO H 7O3SO H 141a: R=CH3; 141b: R=H. R 141a,b OCH3 The unique cytotoxic steroid 148 containing a sulfate group in position 6a was found in the sponge Dysidea fragilis collected from the lagoon of Venice.39 Haliclostanone sulfate (149) from the Malaysian sponge Haliclona still remains the only sulfated sponge steroid with an uncommon cis-fusion of rings C andD.113 Sulfates of acanthosterols A± J (150a ± j) from the sponge Acanthoden- drilla sp. contain sulfate groups in position 6.114 Thus, sponges contain various steroid metabolites, mostly those sulfated in positions 3, 2 or 6.O HOCO H H 142a,b R O HOCO H H 143a,b R O H H CH3OCO H 144 O CH3OCO H 145 O H H H H 146 HO HO + OH H 7O3SO H H OH HO 147 (echinoclasterol sulfate) H V A Stonik NH 142a: R =CH3; 142b: R =H. C6H4OCH3-p NH 143a: R =CH3; 143b: R =H. C6H5 NHC6H5 NHC6H5 OHMarine polar steroids H HO HO HO OSO¡3 H 7O3SO H H HO H OH 149 (haliclostanol sulfate) HO R1 R2O H H R3O H 150a ± j OSO¡3 Compound 150 R1 O a O b O c O d O e OOOO fghi O j Non-glycosylated polyhydroxysteroid sulfates are abundant in starfishes and usually contain sulfate groups in the side chains.If sulfation takes place in the steroid nucleus, the sulfate group is bound to C(3), C(6), C(15) or C(16). Thus different starfish species contained steroids of the general formula 151. Steroids 151a,c are genuine algycons of many asterosaponins.3, 115 Presumably, these compounds are biosynthetic precursors of asterosaponins, which are converted into them after the attachment of the carbohydrate chain. The related compound apheloketotriol (151b) was isolated from Aphelasterias japonica.116 The novel steroid 152 sulfated at C(6) was detected in the starfish Oreaster reticulatus together with 16 steroid glycosides and several polyhydroxysteroids.117 148 OH O R3 R2H H H Ac H H Ac H H Ac H H Ac H H Ac H HH Ac 7O3SO H 151a ± c HO H The monosulfates 153a,b and 154 containing sulfate groups in position 15 or 16 were isolated from Luidia clathrata,92 whereas the 3-monosulfate 155 was isolated from L.quinaria.118 R HO HO HO HO 7O3SO Alarge series of compounds 156b ± e containing sulfate groups in different positions of their side chains were found in L. cla- thrata.92 The structurally related monosulfate 156a was isolated from extracts of Luidia ludwigi.119 The related sulfates 156f ± i from the starfish Styracaster caroli 120 collected at 2-km depth near the coasts of New Caledonia have highly oxygenated side chains. Sulfates 156j and 156k were isolated from the starfish Ctenodiscus crispatus.94 Steroids 157a ± c sulfated in side chains and hydroxylated at C(16) of the side chains were found in L.clathrata 92 and Styracaster caroli (157c).120 The unusual steroidal ketones, viz., asterosterols B and C (158a,b) containing saturated ketone fragments in rings B charac- teristic of ecdysteroids, were isolated from antarctic starfishes belonging to the Asteriidae family.121 These animals also con- tained a unique sulfate 159 with a seven-membered unsaturated lactone ring. Regioisomeric lactone rings are present in brassino- steroids, the higher-plant growth stimulants. 687 HO 151a: R= O R (tornasterol A sulfate); H OH H 151b: R= O (apheloketotriol); OH O(asterone sulfate). 151c: R= OH OH H H OH 152 OSO¡3 OH OSO¡3 H H ; 153a: R = OH OH. 153b: R = 153a,b OH OH H H H OSO¡3 154 OH OH H OH H H OH HO 155 OH688 R H H H OH HO HO 156a ± k OH R H H H OH HO HO 157a ± c OH 7 H H HO H 158a,b OH H HO H O O Finally, a group of steroid sulfates containing sulfate groups in the taurine fragments or in other sulfated amino alcohol fragments, which represent the corresponding amides, have been isolated recently from Myxoderma platyacanthum (compounds 160a,b) 96 and Styracaster caroli (compounds 161a ± c).122 In contrast to other starfish steroids, the latter are cholanic acid derivatives. H H H H HO HO 160a,b OHH H H OH HO R1 161a ± c R2 In ophiuroids (brittle stars) belonging to yet another class of echinoderms, polyhydroxysteroid sulfates are represented pre- dominantly by 3a-derivatives.Monosulfates are less widely dis- tributed in these animals in comparison with di- and trisulfates, although several compounds of this type have been isolated from 156a: R = 7O3SO 156b: R = 156c: R =7O3SO 156d: R = OH 157a: R = 157b: R = O3SO 158: 22,23-dihydro; 158b: D22. OSO¡ 159 7O3SOR NHO 160a: R = H; 160b: (24R)-CH3 , D22. ONH OH OH7O3SO 161a: R1=OH; R2=b-OH, H; 161b: R1=OH; R2=O; 161c: R1=H; R2=a-OH, H. 7O3SO OSO¡ ; 156e: R = 3 156f: R = ; OSO¡3 ; 156g: R = HO OH 156h: R = ; 3 OSO¡ ; 157c: R = 3 OSO¡ ; different representatives of the class Ophiuroidea. Thus com- pounds 162a,b were found in Far Eastern brittle stars Ophiura leptoctenia and O.sarsi.123, 124 The monosulfated steroid 163 was isolated from Ophiarachna incrassata collected near the coasts of New Caledonia.125 Later, it was found that this compound inhibits protein kinase pp 60v-src responsible for regulation of cell growth and intercellular signalling.126 3 7O3SO 7O3SO Sulfated bile alcohols from fishes (for an early review, see Ref. 1) are also related to polyhydroxysteroid monosulfates. Among those, scymnol sulfate 164a isolated from the shark Scymnus borealis as long ago as in 1898 is the most widely known one. Recently, both C(24) epimers of this compound have been isolated from the shark Lamna ditropis.127 The related bile alcohol, chymaerol sulfate 164b, was found in the bile of two shark species, viz., Lamna ditropis and Rhizoprionodon acutis.128 Three novel steroid sulfates 165a,b and 166 were found in the bile of the sunfish Mola mola.129 Compounds 165a,b represent 25R- and 25S-isomers, whereas compound 166 represents a taurine conjugate of an acid, which differs from cholic acid in that one of its hydroxy groups occupies position 11 rather than 12.The novel sulfated pregnane derivative 167 was isolated from the urine of HO 164a: R=OH, 3b-OH, 24S and 24R (scymnol sulfate); 164b: R =H, 3a-OH, 24R and 25S (chymaerol sulfate). V A Stonik OH 7O3SO ; ; 156i: R = 3 OSO¡ ; OH 156j: R = 3 OSO¡ ; OH OSO¡3; OH OH 7O3SO . 156k: R = 3 OSO¡; OH OSO¡3 . OH HO H H H 162a: R =H; 162b: R=OH. 162a,b R HO HO H H H 163 HO H OH OH CH2OSO¡3 H CH2R H HOH 164a,b HMarine polar steroids R2 R1 H H HOH HO H HO H H HOH HO H H H H 167 O female salmon Salmo solar.130 The most recent findings and the data obtained previously testify to the fact that sulfated steroids are extensively distributed in fishes.3. Steroid disulfates Some sponge steroids contain sulfate groups in positions 3a and 2b. This series of compounds includes compound 168, a possible biogenetic precursor of halistanol sulfate,131 which is the most widely occurring trisulfate of sponges, and weinbersterolsAand B (169a,b) from the sponge Petrosia weinbergi. The latter have unique side chains containing cyclopropane fragments, which makes them different from other polysulfated sponge steroids.Steroids 169a,b manifest antiviral activities against cat leukemia and mouse influenza viruses.132 The absolute configurations (24S,28S) of weinbersterols A and B were established by compar- ing them with those of the free sterols, which represent biogenetic precursors of steroids 169a,b isolated from the same sponge.133 H 7O3SO H H 7 168 O3SO R1 H 7O3SO H H OH 7O3SO 169a,b H Yet another group of antiviral disulfates, the so-called orthoestrols A±C from the Caribbean sponge P. weinbergi,134 comprises derivatives of orthobutyric acids. The stereochemistry of orthoestrol B (170b) appears as 24R,28S; that of orthoestrol C (170c) is 24R.Halistanol B disulfate (171) from the South African sponge Pachastrella sp.135 presents interest with regard to both its structure (its side chain contains no methyl group in position 27, which makes this compound different from cholesterol) and biological activity. It inhibits the activity of the enzyme catalysing the conversion of the protein precursor of endothelin into endo- thelin-1 (IC50=1.3 mg ml71). Endothelin induces vascular OSO¡3 165a: R1=OH, R2=H; 165b: R1=H,R2=OH. 165a,b O OSO¡3HN 166 3 OSO¡ OH R2OHOH 169a: R1=H,R2=OH (weinbersterol A); 169b: R1=OH, R2=H (weinbersterol B). 689 R 170a: R = (orthoestrol A); O O 170b: R = H O 7O3SO (orthoestrol B); H H OH 7O3SO 170a ± c H 170c: R = (orthoestrol C).spasms and is abundant in patients with hypertension and renal insufficiency. Compound 171 as an inhibitor of endothelin syn- thesis is a promising model substance for development of new antihypertensive drugs.H 7O3SO H H 7O3SO 171 H A series of steroid disulfates were found in starfishes and ophiuroids. Thus compounds 172a ± d were isolated from the starfish Tremaster novaecaledonia 136 and compound 172e, from Aphelasterias japonica.137 OH 172a: R = , D0; OAc R 172b: R = , D0; OH H 172c: R= , D9(11); H OAc 7O3SO 172d: R = OSO¡ , D9(11); 3 H 172a ± e 172e: R = , D9(11). OH In contrast to their starfish counterparts, steroid disulfates isolated from ophiuroids have a number of specific structural features.In nearly all of them, one sulfate group is in position 3a and the second one is in the side chain at C(21). These steroids comprise stanol derivatives as well as 5(6)-unsaturated deriva- tives. For example, sulfated stanols of the general formulas 173 and 174 are widely distributed in various representatives of this class, e.g., in more than 30 species of Ophiuroidea.3, 99 Disulfate 173a, which was first discovered together with compound 173b,c in Ophioderma longicaudum138 and later in different species of Ophiuridae, Gorgonocephalidae and Asteronychnidae families,99 is the most widespread disulfate of the general formula 173. The steroid 173d was isolated from the antarctic brittle star Astrotoma agassizii.139 OSO¡3 ; 173a: R = R OSO¡3 ; 173b: R = H OSO¡ H H 3 7 173c: R= ; O3SO 173a ± d H OSO¡3 173d: R = , 2b-OH.690 Steroid disulfates of many ophiuroids are characterised by cis- fusion of rings A and B.For example, compound 174a first described by Italian scientists in 1985140 was later discovered in various representatives of the Ophiocoma, Ophioarthrum, Ophio- lepis, Ophionereis and Ophiozona genera.3, 99 The steroid 174b was found in Ophiocoma dentata, Ophioarthrum elegans, Ophiorachna incrassata, Ophiolepis superba and Ophiomastix annulosa.3 The steroid 174c, which differs from the latter in the structure of its side chain, was first discovered in Ophiocoma dentata,3 whereas com- pounds 174d ± f were found in Ophiolepis superba, which also contains additionally oxygenated derivatives 174g,h,i.141 The steroid 174j containing an additional hydroxy group at C(12) was isolated from Ophioderma longicaudum,138 whereas steroids 174k,l were isolated from Ophiomastix annulosa 142 and Ophioph- olis superba.141 The steroid 174m containing an unusual 5,9-epoxy fragment was found in Ophiomastix annulosa 142 and compound 174n was detected in the antarctic ophiura Astrotoma agassizi.139 R5 R4 H R1 H 7O3SO R3 174a ± n R2 R3 R2 Compo- R1 und 174 a H H a-OH b H H a-OH c H H a-OH d H H a-OH e H H a-OH f H H a-OH g H b-OH H a-OH h H b-OH a-OH i H b-OH a-OH j H H a-OH k H H a-OH [D9(11)] l H a-OH H a-OH m H 4a,9a- H H H epoxy n H b-OH H R6 H R5 R4 b-OH HH H H H H H H H H H HH H H Hb-OH b-OH H H HH H R6 7O3SO 7O3SO 7O3SO 7O3SO HO 7 OH O3SO 7 OH O3SO 7O3SO 7O3SO HO 7O3SO 7O3SO 7O3SO 7O3SO 7O3SO 7O3SO 5(6)-Unsaturated steroids of the general formula 175 are often present in ophiuroids. Thus compounds 175a and 175b were isolated from the Far Eastern brittle star Ophiura sarsi 124 and steroids 175c-f were isolated from Ophiopholis aculeata.143 The steroid 175a was also isolated from Ophiura texturata,144 Gorgo- nocephalus caryi,145 Ophiotrix fragilis 2 and some other species.The steroid 175g was found in O. texturata,144 the steroid 175h was detected in Ophiarachna incrassata.140 The disulfate 175i containing three functional groups in the ring A was isolated from the antarctic brittle star Ophiosparte gigas146 as well as from Astroclades exiguus and Amphiophiura ponderosa.147 R2 7O3SO Compound 175 abcdef(24S and 24R) ghij The unusual steroid disulfate 176a was detected in the brittle star Ophiosparte gigas.146 It contains a sulfate group in position 2b but not in position 3a, like other sulfates of this series.Later, this disulfate was isolated from several other representatives of this class.99 Its 24(25)-unsaturated derivative 176b and related ophiu- roid disulfates 175j and 174n from Astrotoma agassizii 139 and their acetates manifested strong antiviral activities against the pathogenic virus HSV-2, which evokes meningitis and other severe infections in humans.147 7O3SO HO R4 R1 H H H175a ± j R3 R4 R3 R2 R1 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H H b-OH 7O3SO H b-OH H 7O3SO H b-OH b-OH 7O3SO H H b-OH R 7O3SO X H H H 176a: R=H, X=H; 176b: R=H, X=H, D24; 176c: R=H, X=OH.176a ± c V A Stonik OHMarine polar steroids Compound 178 defgh The typical ophiuroid steroids 175a,b and 176a were unex- pectedly found in the starfishes of the Pteraster genus.148 These compounds differ from steroids of the majority of other starfish species in the stereochemistry of substituents at C(3) (3a instead of more common 3b) and oxygenation at C(21).A detailed analysis of steroids isolated from this group of starfishes led to the discovery of a compound earlier identified in ophiuroids (com- pound 175g) and novel compounds 176c and 177a,b which combine structural features of steroids from brittle stars (e.g., oxygenation in positions 3a and 21) and starfish (e.g., oxygenation in position 26).149 The presence of the same or structurally related secondary metabolites in brittle stars and starfishes corroborates the viewpoint of some taxonomists that these two classes of echinoderms are phylogenetically more closely related in compar- ison with other classes of Echinodermata. i R j OH H HO k H H 7 177a: R = CH2 ; 177b: R =H2 . 177a,b O3SO lm Disulfates from ophiuroids manifest the properties of activa- tors of some enzymes, particularly glucanases.150 Steroids of the D5-series isolated from Ophiopholis aculeata activate the transport of calcium ions into different cells without disturbing the integrity of biomembranes.151 n 4.Steroid trisulfates op The sulfated steroids of this series manifest a broad range of biological activities (e.g., antimicrobial, hemolytic, ichthyotoxic, etc.), inhibit HIV-1-induced infection,161 suppress the activities of some enzymes including that of b-1,3-glucanase 162 and interact with the thrombin receptor.155 Several related trisulfates have recently been identified in sponges. These include halistanol sulfate E (179) from Epipolasis sp.,155 which contains an additional hydroxy group at C(16), ibisterol sulfate 180a from the sponge Topsentia sp., which inhibits HIV-1 and, in contrast to related steroids, possesses a 9(11)- double bond and an unusual side chain with a cyclopropane fragment.163 Topsentiasterols 180b and 181a ± d from an uniden- tified sponge of the Topsentia genus carry hydroxy groups at C(4) and in the majority of cases contain oxygenated side chains.These compounds possess antimicrobial properties.164 Trisulfated polyhydroxysteroids are typical representatives of marine metabolites. They were found in sponges and echino- derms.1, 17, 99, 152 Halistanol sulfate (178a), the most widespread sponge steroid sulfate, was isolated from the sponge Halichondria moori in 1981 by Fusetani et al.153 It contains three sulfate groups in rings A and B of the steroid tetracyclic nucleus.The structure of socotrasterol sulfate (178b) isolated repeatedly from different sponges was established in our laboratory.154 Both compounds have unusual side chains, which are additionally alkylated (com- pared with those of terrestrial sterols). The side chain of soco- trasterol sulfate is unique in that it contains two `extra' methyl groups at C(26) and a 23(24) double bond uncommon for natural steroids.Alarge series of analogous natural compounds have been isolated from different sponges. These include halistanol sulfates A±D (178c ± f) from Epipolasis sp.,155 norsocotrasterol sulfate (178g) from sponges of the Halichondridae family,156 dihydroso- cotrasterol sulfate (ophirapstanol sulfate) 178h from Topsentia ophiraphidites,157 halistanol sulfates F ±H(178i ± k) from Pseudax- inyssa digitata,158 compound 178l from Trachiopsis halichon- droides 159 and steroids 178m ± p from T.halichondroides and Cymbastella coralliophila.160 R H 7O3SO H H 7O3SO OSO37 H 178a ± pName R Compound 178 25 a halistanol sulfate 26 b socotrasterol sulfate c halistanol sulfate A 691 R Name halistanol sulfate B halistanol sulfate C halistanol sulfate D 26-norsocotrasterol sulfate 26 ophirapstanol sulfate halistanol sulfate F halistanol sulfate G halistanol sulfate H 77777 H OH 7O3SO H 7O3SO H OSO¡ 179 (halistanol sulfate E) 3 H 7O3SO 7O3SO H 180a,b R 180a: R=H (ibisterol sulfate); 180b: R =OH (topsentiasterol E).OSO¡3692 R H 7O3SO 7O3SO H HO 181a ± d OSO¡3 O O OH O O 181c: R = O 181a: R = 181b: R = (topsentiasterol C); OH (topsentiasterol A); O (topsentiasterol B); O (topsentiasterol D). 181d: R = Several trisulfated steroids were found in echinoderms, partic- ularly in ophiuroids. Thus steroids 182a,b were isolated from Ophiorachna incrassata extracts3 and the steroid 183 was isolated from Ophiura sarsi.124 OSO¡3H 7O3SO H H 7 182a: 5(6)-dihydro, (25R,25S); 182b: D5, (25R,25S). O3SO 182a,b OSO¡3 H H H 7O3SO 183 OSO¡3 On the whole, sulfated steroids present substantial interest owing to their unusual chemical structures and biological activ- ities.Some of them are attractive objects for synthetic modelling aimed at the design of novel antimicrobial, antiviral and other drugs. It is of note that sulfated steroids seem to be absent in Coelenterata. In any case, none has been isolated from these invertebrates so far. IV. Steroid glycosides Over a long time, steroid glycosides were considered to be typical metabolites of higher plants; however, in the last 25 ± 30 years they were isolated from starfishes along with the corresponding polyols and sulfates.1, 3 Later, they were found in sponges, cnidarians and fishes of the Pardachiras genus. A small review devoted to marine steroid glycosides was published in 1996.165 Therefore, in this section we shall consider the results of the most recent studies published 4 ± 6 years ago and those data which have not been discussed in this review.Marine steroid glycosides, like any other marine polar ste- roids, have original structures, no one of them coincides with the structures of glycosides isolated from taxonomically remote bio- logical sources, such as terrestrial plants. Starfish glycosides are conventionally divided into several large groups,3 viz., (i) steroid glycosides, which are sulfated at C(3) [their carbohydrate chains are attached at O(6) (classical asterosaponins)]; (ii) mono- and biosides of polyhydroxylated steroid, containing as a rule carbohydrate residues in their side chains and (iii) glycosides containing carbohydrate fragments attached to C(3) and C(6) of the aglycons to form macrocycles.The structures of individual representatives of these groups are V A Stonik given below. Glycosides related to the first structural type, e.g., tornasteroside A (184) 166 from Acanthaster planci (a starfish commonly referred to as the `crown of thorns'), differ from each other in both the structures of their carbohydrate chains which usually contain from four to six monosaccharide residues and in the structures of the aglycon side chains. Glycosides related to yet another structural type, e.g., nodososide (185a) from Protoreaster nodosus 167 and asterosaponin P1 (185b) from Asterina (=Patiria) pectinifera 168), are structurally very diverse and may contain sulfate groups. OH O H H 7O3SO H O 1,3 1,4 1,2 Glc Fuc Gal Xyl 1,2 184 (tornasteroside A) Oui OX OHH H OH HO R1 185a,b R2 HOH2COH O (nodososide); O O 185a: R1=OH, R2=b-OH, X = HO HO OMe O OCH3 (asterosaponin P1).185b: R1=H, R2=a-OH, X=7O3SOH2C OH Glycosides containing carbohydrate chains involved in a macrocycle exemplified in sepositoside A (186) 169 were detected only in a few species of starfishes of the Echinaster genus. O H H O HO2C O H O O HO HO OH O O HO O OH OH 186 (sepotositoside A) OH HO Classical asterosaponins are usually present in starfishes as complex mixtures; they are toxic to fishes, manifest cytotoxic and hemolytic activities, are predominantly accumulated in animal body walls and probably fulfil protective functions.All these compounds contain aglycons of the same structural type with a 9(11) double bond and a sulfate group at C(3), the aglycon of tornasteroside A being the most common fragment. Tetraosides usually possess linear carbohydrate chains, whereas the carbohydrate chains of penta- and hexaosides have one or (more seldom) two branch points, predominantly at the second monosaccharide of the chain. Monosaccharides are repre- sented mostly by pyranose forms of D-fucose, D-quinovose, D-glucose, D-galactose, D-xylose and 6-deoxy-D-xylo-hexos-4-Marine polar steroids ulose (the latter contains the hydrated keto group in position 4). The glycosidic bonds have usually b-configurations. Quite a lot of novel asterosaponin oligoglycosides have recently been isolated from starfishes (Table 2).For example, the so-called nipoglycosides A±D (187 ± 190) were isolated from the starfish Distolasterias nipon 170 and brasiliensoside (191) was isolated from Echinaster brasiliensis.171 In contrast with the glyco- sides from the other two species of this genus, these glycosides are devoid of carbohydrate chains incorporated in a macrocycle. Cosmasterosides A±D (192 ± 195) containing two xylose residues each in their carbohydrate chains were isolated from the starfish Cosmasterias lurida.172 R H H 7O3SO H OX 187 ± 208 In contrast to most asterosaponins containing five to six sugar residues, compounds 194 and 195 have only four monosaccharide residues.Reticulatosides A and B (196, 197) and asterosaponin (198) containing a pregnane aglycon were found in Oreaster reticulatus.117 About 20 steroid glycosides including the novel asterosaponins 199 ± 203 were isolated from a non-identified star- fish species belonging to the Echinasteriidae family collected near Antarctic coasts by Italian scientists,173 whereas asteriidosides A±E (204 ± 208) were isolated from a non-identified Antarctic species belonging to the Asteriidae family.174 Asterosaponin-like glycosides with `shortened' carbohydrate chains were first isolated from Asterias forbesi 175, 176 and Lethas- terias nanimensis chelifera.115 Forbesides E, E1, E2 and E3 (209a ± d) and cheliferoside L1 (209e) represent pregnane mono- R3 H H R2O H CH3OO OH R1O 209a ± e OHName Compound 209 forbeside E forbeside E1 forbeside E2 forbeside E3 cheliferoside L1 abcde OH OH O H H COO7O H OSO¡3 O OH HO 213a,b OH 213a: R1=CH3, R2=H (downeyoside A); 213b: R1=H,R2=CH3 (downeyoside B).R3 R2 R1 SO3Na SO3Na H SO3Na OH H SO3 Na OH OH H SO3 Na OO SO3Na SO3Na R1 R2 COO7O O OH HO OH 693 quinovosides; most of them contain additional sulfate groups in their monosaccharide residues. Aphelasteroside C (210a) from Aphelasterias japonica differs from cheliferoside L1 (209e) in its relatedness to cholestane, rather than to pregnane derivatives; its side chain contains a 23-keto-24- hydroxy fragment uncommon for asterosaponins.116 Latespino- sides A±D (210b,c, 211, 212) from Asteropecten latespinus differ from aphelasteroside C (210a) exclusively in the structures of their side chains, compound 212 being the first androstane steroid isolated from starfishes.177 R H H OH NaO3SO (aphelasteroside C); 210a: R = O OH H CH3OO (latespinoside A); 210b: R = OH OH NaO3SO (latespinoside B).210c: R = OH 210a ± c O H O H H H NaO3SO NaO3SO H H CH3OO OH CH3OO OH NaO3SO NaO3SO OH 212 (latespinoside D) OH 211 (latespinoside C) Yet another recently discovered group of asterosaponins with shortened carbohydrate chains includes downeosides (213 ± 216) from Henricia downeyae.178, 179 These compounds contain one or two monosaccharide residues in their carbohydrate fragments; their high polarities are due to the presence of glucuronic acid residues, which are not common in `classical' asterosaponins, but are present in cyclic asterosaponins.In contrast to other astero- saponins, the carbohydrate fragments in these glycosides are bound to C(3) atoms, whereas their sulfate groups are bound to C(6). Downeyosides A and B (213a,b) possess additional tetrahy- drofuran rings and side chains containing three contiguous hydroxy groups at C(20), C(22) and C(23), which is uncommon for natural steroids. Downeyosides C±Gand J (214a ± f) resemble `classical' asterosaponins in the structures of their side chains, whereas downeyosides K and L (215a,b) contain additional hydroxy groups at C(16).And, finally, downeyosides H and I OH O R 214d: R = 214a: R = (downeyoside C); H O (downeyoside F); OH O H 214b: R = 214e: R = (downeyoside D); H OSO¡3 O (downeyoside G); OH OH O 214c: R= 214a ± f 214f: R = O (downeyoside E); 9(11)-dihydro, (downeyoside J) .Table 2. Asterosaponins isolated from starfishes. Name Com- pound nipoglycoside A 187 nipoglycoside B 188 nipoglycoside C 189 nipoglycoside D 190 brasiliensoside 191 cosmasteroside A 192 cosmasteroside B 193 cosmasteroside C 194 cosmasteroside D 195 reticulatoside A 196 reticulatoside B 197 a Sug is 6-deoxy-xylo-hexos-4-ulose. The structure of The structure of the carbohydrate chain (X) the side chain (R) OH Glc O H Fuc O Fuc O Fuc OH OH Fuc O OH Fuc OH Fuc O OH Xyl O OH Xyl O HO OH Fuc HO OH Fuc Ref.1,3 1,4 1,2 1,3 Qui Xyl Gal Fuc 170 1,2Qui 1,2 1,4 1,3 Qui Glc Glc 170 1,2Qui 1,2 1,4 1,3 Qui Glc Glc 170 1,2Qui 1,2 1,4 1,3 Qui Glc Glc 170 1,2Qui 1,4 1,2 Qui Sug a Gal 171 1,2Qui1,3 1,2 1,4 Qui Xyl Xyl 172 1,2Qui1,3 1,4 1,2 Glc Xyl Xyl 172 1,2Qui 1,3 1,4 Qui Xyl 172 1,2Qui1,3 1,4 Glc Xyl 172 1,2Qui 1,3 1,2 1,4 Qui Xyl Xyl 117 1,2Qui1,3 1,2 1,4 Qui Xyl Xyl 117 1,2Qui Name Com- pound 7 198 24-methylbrasilien- 199 soside antarcticoside A 200 antarcticoside B 201 antarcticoside C 202 24-methylpecteno- 203 side A asteriidoside A 204 asteriidoside B 205 asteriidoside C 206 asteriidoside D 207 asteriidoside E 208 The structure of the side chain (R) O OH O OH O OH O OHO H OH O OH O OH OH OH OH The structure of the carbohydrate chain (X) 1,3 1,4 1,2 Qui Xyl Xyl Fuc 1,2Qui 1,4 1,2 Qui Sug a Gal Fuc 1,2Qui1,3 1,4 1,2 Qui Qui Glc Fuc 1,4 1,2 Glc Qui1,3 1,4 1,2 Qui Qui Glc Fuc 1,4 1,2 Glc Qui1,3 1,4 1,2 Qui Qui Glc Fuc 1,4 1,2 Glc Qui1,3 1,4 1,2 Qui Qui Glc Fuc 1,2Qui Gal 1,3 1,4 1,2 Qui Gal Fuc 1,2Qui 1,2 1,4 1,3 Fuc Fuc Xyl Gal 1,2Qui 1,2 1,4 1,3 Fuc Fuc Xyl Gal 1,2Qui 1,2 1,4 1,3 Ara Fuc Xyl Gal 1,2Qui 1,2 1,4 1,3 Ara Fuc Xyl Gal 1,2Qui Ref.117 173 173 173 173 173 1,3 Qui 174 1,3 Qui 174 1,3 Qui 174 1,3 Qui 174 1,3 Qui 174Marine polar steroids R OH COO7O OH COO7O (downeyoside K); 215a: R = OSO¡3 O O OH O OH HO HOOH O OH HO 215a,b , 215b: R = OH 9(11)-dihydro (downeyoside L). OH (216a,b) are biosides, each containing an additional L-arabinose residue bound to glucuronic acid by a-glycosidic bond. In recent years, the list of newly discovered mono- and biosides of polyhydroxysteroids has been supplemented with more than 50 new names (Table 3). X R5 R7 H H R6 7O3SO HO R4 R2 217 ± 268 R3 R1 isolated from the Antarctic starfish belonging to Asteriidae gen. sp.174 and echinasterosides B1 (273) and F (274) from Echinaster sepositus 188 and E.brasiliensis,171 respectively. R As a rule, the carbohydrate fragments of these compounds are bound to C(24) or C(26) (cholestane series), to C(28) or C(26) (ergostane series) and to C(29) or C(26) (stigmastane series). Xylose, its various methylated derivatives (in a pyranose form), arabinose and 3-O-methylarabinose (in a furanose form) are the monosaccharide components. Glucopyranose, arabinopyranose, xylofuranose, galactofuranose and fucofuranose are found less often. The glycosides of this series contain sometimes one or several sulfate groups in the carbohydrate part and the aglycons. In biosides, the monosaccharides are linked by 1,2-bonds or, less frequently, by 1,5- and 1,6-bonds (the author's data), e.g., as in compounds 262, 264 ± 267.184 ± 186 O OH HO OH Novel structural series of glycosides recently discovered in starfishes include compounds containing two monosaccharide fragments, viz., one at C(3) and the other in the side chain.Some representatives of this class, viz., distolasterosides D1±D3 (269a ± c) were found in Distolasterias nipon.187 Reinvestigations of polar steroids from the same species collected near the coasts of Japan led to the isolation of yet another steroid bisglycoside, viz., distolasteroside D4 (269d) and distolasteroside D5 (270), which contains a sulfate group instead of a monosaccharide residue at C(3).170 In the most recent times, this group of compounds was further expanded owing to asteriidosides F± I (271a,b and 272a,b) R O OH HO OH O OH HO O OH OH H H OH O H OH O OH HO 3 269a: R =H (distolasteroside D1); 269b: R =H, D22 (distolasteroside D2); 269c: R=CH2OH (distolasteroside D3); 269d: R = CH2OSO¡ (distolasteroside D4).269a ± d OH O OH HO OCH3 R OH OSO¡3 216a: R = 216b: R = 216a,b O OH HO OH OH OH H H OH H OH 270 (distolasteroside D5) OH OH H H OH O H OH 271a: R=H (asteriidoside F); 271b: R = CH3 (asteriidoside G). 271a,b O OSO¡3 HO OH OHH H OH O R H OH 272a,b 272a: R=H (asteriidoside H); 272b: R=OH (asteriidoside I). O OH HOH2C OH OHH H OAc O H OH HO273 695 O (downeyoside H); O (downeyoside I).O O O OH HO OH OOTable 3. Some novel polyhydroxysteroid glycosides isolated from starfishes. Name Com- pound validoside A 217 validoside B 218 luridoside A 219 luridoside B 220 helianthoside 221 oreasteroside A 222 oreasteroside B 223 oreasteroside C 224 oreasteroside D 225 oreasteroside E 226 oreasteroside F 227 oreasteroside G 228 oreasteroside H 229 oreasteroside I 230 R3 R2 R1 6a-SO¡ H OH 3 a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H a-OH H H 6a-SO¡ H H 3 6a-SO¡ H H 3 6a-SO¡ H H 3 R7 R6 R5 R4H OH b-OH H b-OH H OH H b-OH H OH H b-OH H OH H a-OH H OH H a-OH H OH H a-OH H OH H a-OH H OH H a-OH H OH H b-OH H OH H a-OH b-OH OH HH OH a-OH b-OH H OH a-OH H H OH a-OH H The side chain (X) (the double bond) OY OY OY OY OY OY OY OY OY OY YO YO OY OY The carbohydrate fragment (Y) 2,4-(OCH3)2-Xylp-(1?2)-Araf 2-SO3-3-OCH3-Xylp 4-SO3-Xylp 4-SO3-Xylp 3-SO3-Xylp 3-OCH3-Araf Xylp-(1?2)-3-OCH3-Araf 2-OCH3-Xylp-(1?2)-Araf 2-OCH3-Xylp-(1?2)-3-OCH3-Araf Xylp-(1?2)-3-OCH3-Araf 5-OCH3-Galf 5-OCH3-Galf 3-OCH3-Araf Araf The source Odontaster validus Odontaster validus Cosmasterias lurida Cosmasterias lurida Heliaster helianthus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Oreaster reticulatus Ref.180 180 181 181 182 117 117 117 117 117 117 117 117 117Table 3 (continued). Name Com- pound oreasteroside J 231 oreasteroside K 232 antarcticoside D 233 antarcticoside E 234 antarcticoside F 235 antarcticoside G 236 antarcticoside H 237 antarcticoside I 238 antarcticoside J 239 antarcticoside K 240 antarcticoside L 241 antarcticosideM 242 antarcticoside N 243 antartcicoside O 244 antarcticoside P 245 ceramasteroside C1 246 R4 R3 R2 R1 a-OH OH H H a-OH OH H H a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH a-OH H H OH 6a-SO¡ H OH b-OH H H OH 3 6a-SO¡ H OH b-OH H H OH 3 a-OH H H OH R7 R6 R5 b-OH b-OH OH b-OH b-OH OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH H OH b-OH b-OH OH The side chain (X) (the double bond) OY YO OY OY OY OY OY OY OY OY OY OY YO OHOY OY YO The carbohydrate fragment (Y) 2-SO3-3-OCH3-Xylp 2-SO3-3-OCH3-Xylp 3-OCH3-Xylp 3-OCH3-Xylp 2,4-(OCH3)2-Xylp-(1?2)-Araf Xylp-(1?2)-Araf Araf Galf 4-SO3-3-OCH3-Xylp 3-OCH3-Xylp 4-OCH3-Xylp-(1?2)-Galf 4-OCH3-Xylp-(1?2)-Araf Araf 3-OCH3-Glcp 2,4-(OCH3)2-Xylp-(1?2)-Galf 2-OCH3-Xylp-(1?2)-Galf The source Oreaster reticulatus Oreaster reticulatus Echinasteridae gen.sp. Echinasteridae gen.sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Echinasteridae gen. sp. Ceramaster patagonicus Ref. 117 117 91 91 91 91 91 91 91 91 91 91 91 91 91 89Table 3 (continued). Name Com- pound ceramasteroside C2 247 ceramasteroside C3 248 ceramasteroside C4 249 ceramasteroside C5 250 leptasteroside L 251 acodontasteroside A 252 acodontasteroside B 253 acodontasteroside C 254 acodontasteroside D 255 acodontasteroside E 256 acodontasteroside F 257 acodontasteroside G 258 acodontasteroside H 259 R3 R2 R1H H a-OH H H a-OH a-OH H OHH H a-OH OH b-OH H 6a-SO¡ H OH 3 6a-SO¡ H OH 3 6a-SO¡ H OH 3 a-H H OH a-H H OH a-H H OH a-H H OH a-H H H R7 R6 R5 R4 b-OH b-OH OH H b-OH b-OH OH H b-OH H OH H b-OH H OH H a-OH H OH HH OH b-OH H H OH b-OH H H OH b-OH H b-OH H OH H b-OH H OH H b-OH H OH H b-OH H OH H b-OH H H H The side chain (X) (the double bond) YO YO OY OY YO OY YO YO YO OY YO OY OY (D8(14)) The carbohydrate fragment (Y) 2,4-(OCH3)2-Xylp-(1?2)-Galf 2-OCH3-Xylp-(1?2)-Galf 2-OCH3-Xylp-(1?2)-Galf 2-OCH3-Xylp-(1?2)-Xylp Glcp 2-OCH3-Xylp-(1?2)-Galf 2-OCH3-Xylp-(1?2)-Xylp 2-OCH3-Xylp-(1?2)-Xylp Xylp-(1?2)-Xylp 2-OCH3-Xylp-(1?2)-Xylp 2-OCH3-Xylp-(1?2)-Xylp 2-OCH3-Xylp-(1?2)-Xylp 2-OCH3-Xylp-(1?2)-Xylp Ref.The source 89 Ceramaster patagonicus 89 Ceramaster patagonicus 89 Ceramaster patagonicus 89 Ceramaster patagonicus 183 Leptasterias polaris acervata 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuus 90 Acodontaster conspicuusTable 3 (continued). Name Com- pound acodontasteroside I 260 crossasteroside P3 261 crossasteroside P4 262 solasteroside S1 263 solasteroside S2 264 mediasteroside M1 265 mediasteroside M2 266 mediasteroside M3 267 mediasteroside M4 268 R3 R2 R1 a-H H HH H a-H a-H H OHH H b-OH H H a-H H H a-H H H a-H H H a-H H H a-H R7 R6 R5 R4 b-OH H H H H H OH H b-OH H OH H a-H H H H b-OH b-OH OH H b-OH H OH H b-OH H OH H b-OH H OH H b-OH H OH H The side chain (X) (the double bond) YO (D8(14)) OY (D14(15)) OY OY OH YO OY OY OY OY The carbohydrate fragment (Y) Xylp 3-OCH3-Glcp 2,4-(OCH3)2-Xylp-(1?5)-Araf Xylp Galf -(1?6)-Galf 2-OCH3-Xylp-(1?5)-Araf Xylp-(1?5)-Araf 2,4-(OCH3)2-Xylp-(1?5)-Araf 2,3-(OCH3)2-Xylp-(1?2)-Araf The source Acodontaster conspicuus Crossaster papposus Crossaster papposus Solaster dawsoni Solaster dawsoni Mediaster murrayi Mediaster murrayi Mediaster murrayi Mediaster murrayi Ref.90 184 184 185 185 186 186 186 186V A Stonik 700 O Name R1 R3 R2 O Compo- und 276 OH HO OH f henricioside H2 H CH3OH g H CH3 henricioside H3 OH OH OH H H OSO¡3O OH In contrast to all other polyhydroxysteroid glycosides con- taining one or two monosaccharide residues, cytotoxic com- pounds 277a ± c from Fromia monilis 189 contain three monosaccharides.O OH HO 274 OCH3 O OH O O OR O O OH OH O OCH3 HO OH Yet another group of recently discovered glycosides contains only one carbohydrate fragment linked to the C(3) atom. These compounds include desulfated 26-norechinasteroside A (275a) R3 OH OH R1 OH H H H H OH OH 277a: R = CH3; 277b: R = CH3, D22; 277c: R =H. HO O H 277a ± c OH HO OH O OH HO 275a,b OR2 Name R3 R2 R1 Compo- und 275 a (D4) OHCH3OH OSO¡3 b H H asteriidoside L The impressive diversity of glycosides of polyhydroxysteroids and other polar steroids found in starfishes reflects the immense variety of oxidising and glycosylating enzymes present in these animals, which is comparable only to the wide occurrence of steroid-oxidising enzymes in microorganisms and glycosyl trans- ferases in terrestrial higher plants.Several newly discovered groups of glycosides not mentioned in previous reviews 2, 3 include monoquinovosides related to classical asterosaponins as well as mono- and biosides sulfated at C(6) and containing carbohydrate chains in position 3. from Henricia downeyae,179 compounds 276a ± e from Echinaster brasiliensis,171 henriciosides H2 and H3 (276f,g) from H.derju- gini 93 and asteriidoside L (275b) from Asteriidae gen sp.174 R3 It should be stressed that starfish enzymes differ from known enzymes of terrestrial origin in the specificities of hydroxylation and ability to transfer mono- or oligoside residues into definite positions of sterol substrates. Sulfation of metabolites in different positions is a distinguishing feature of biogenesis of steroid glyco- sides in starfishes. OH OH H H OR1 OH O O OR2 HO 276a ± g OCH3 Name R3 R2 R1 Compo- und 276 a H SO¡3OH b H H In other phyla of marine invertebrates, such as sponges, glycosides have been discovered much later than in starfishes. Sponge glycosides usually contain mono-, di- or trimethylsterol aglycons and carbohydrate chains linked to C(3).These metabo- lites were first isolated from Asteropus sarasinosum by Kitagawa et al.190, 191 Sarasinosides represent oligoglycosides of hitherto unknown dimethylsterol aglycons. They manifest high ichthyo- toxic activities and moderate cytostatic activities in tests with fertilised eggs of the starfish Asterina pectinifera. Compounds 278a ± c, 279a ± c and 280a ± c were found in the starfish A. sar- asinosum collected near the Palau Island in the Pacific Ocean,191 whereas compounds 281, 282a ± b and 283 were isolated from the same sponge species dwelling in the region of the Solomon Islands.192 The aglycons of sarasinoside D (281) contain a rarely occurring 4,4,8-trimethylsterane skeleton system similar to that of scalarane sesterterpenoids, but differing from that of dammarane triterpenoids in a 1,2-shift of the methyl group from C(14) to C(13).OH c H echinasteroside C SO¡3 d H echinasteroside D SO¡3OH HO e H H echinasteroside E The so-called pachastrelloside A (284), which inhibits cell division in fertilised sea urchin eggs without affecting cell nuclei resulting in the formation of multinuclear unicellular embryos, was isolated from Pachastrella sp. Unlike other steroid glycosides, pachastrelloside A (284) contains monosaccharide residues in unusual positions. Thus, one of them, viz., galactose, is linked to C(4), whereas the other one, viz., xylose, is bound to C(7) of the aglycon.193 Comparison of the aglycon structures of eryloside A (285) from Erylus lendenfeldi,194 erylosides C and D (286a,b) fromMarine polar steroids Erylus sp.,195 eryloside E (287 ) from E.goffrileri 196 and uloso- sides (288, 289) isolated by us from Ulosa sp.197, 198 showed that stepwise demethylation of the lanostane or the related terpene precursor in sponges resembles the conversion of lanosterol into cholesterol in higher animals. This process consists in oxidative removal of the methyl group from position 14 and subsequent elimination of the methyl groups linked to C(4) (Table 4). The hopaioside 290 isolated from the Micronesian sponge Cribrochalina olemda differs significantly from other sponge steroid glycosides.199 This compound is related to 19-norpregnane rather than to sterol or norlanostane derivatives.Interesting steroid glycosides were also detected in some octocorals. Most of them are monosides of the pregnane series and contain one or several acetate or propionate groups. Several novel glycosylated sterol derivatives and novel pregnane glyco- Table 4. Sponge glycosides. Structural formula O H XO H O H XO H O XO H HO O H H XO H R O H XO OH Compound 278a 278b 278c 279a 279b 279c 280a 280b 280c 281 282a (R=H) 282b (R=OCH3) sides have recently been isolated from these animals. Thus a-L- fucosides containing aglycons of the 24-methylcholesterol series 291a ± c were found in some soft corals (e.g., Alcyonium sp.) and some representatives of the Sinularia and Lobophytum genera.200 The related glycosides 292a,b and 293 were isolated from Sinularia gibberosa 52, 201 and S.grandilobata.202 H H H O a-L-Fucp Structure of the carbohydrate chain (X) b-1,2 b-1,6 Glcp Glcp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2Xylp b-1,2Xylp Glcp b-1,6NAcGlcp b-1,4 NAcGalp b-1,6 Xylp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2 b-1,6 Glcp Glcp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2Xylp b-1,2Xylp Glcp b-1,6NAcGlcp b-1,4 NAcGalp b-1,6 Xylp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2 b-1,6 Glcp Glcp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2Xylp b-1,2Xylp Glcp b-1,6NAcGlcp b-1,4 NAcGalp b-1,6 Xylp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,6 Xylp b-1,2 Glcp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,6 Xylp b-1,2 Glcp Xylp b-1,2 NAcGlcp b-1,4 NAcGalp b-1,2Xylp b-1,2Xylp Glcp b-1,6NAcGlcp b-1,4 NAcGalp 701 OH 291a ± c 291a: R =H; 291b: R = b-OH; 291c: R=a-OH.R Name sarasinoside A1 sarasinoside B1 sarasinoside C1 sarasinoside A2 sarasinoside B2 sarasinoside C2 sarasinoside A3 sarasinoside B3 sarasinoside C3 sarasinoside D sarasinoside E sarasinoside F702 Table 4 (continued). Structural formula O H H XO H H HO H H HO O O O OH O HOH2C HOOH AcO OH OH OH XO H H H CO2H XO H OH COO XO H O OH HO OH OH OH H XO H CO2H OH OH H XO H CO2HH H H XO OH O Compound 283 284 285 286a 286b 287 288 289 290 Structure of the carbohydrate chain (X) b-1,6 Xylp b-1,2 Glcp b-1,2 NAcGlcp b-1,4 NAcGalp 7 b-1,2Galp Galp 1,3 1,4 Galp Galp Galp 1,2Galp 1,3 Galp Galp 1,2Galp 1,2 NAcGlcp Galp b-1,6Glcp GlcpA NAcGlcp7 4-OAc-L-Fuc7 V A Stonik Name Xylp sarasinoside G pachastrelloside A eryloside A eryloside C eryloside D eryloside E ulososide A ulososide B chopaiosideMarine polar steroids R1 R2 H OH H R2 292a ± c O a-L-Fucp 292c: R1= ; 292a: R1= ; OH R2=H.R2=H; 292b: R1= ; R2=OH; OH H OH H H 293 O b-Arap The cytotoxic pregnane glycoside verrucoside (294) from Eunicella verrucosa 203 contains L-digitalose as a carbohydrate component, enantiomeric with the corresponding 6-deoxyhexose occurring in terrestrial plants.This compound inhibits tumour cells P-388, A-549 and HT-29 (IC50=5.9, 7.2 and 6.3 mg ml71, respectively). The glycoside 295 from the gorgonian coral Eunicea sp. is its structural analogue.204 Glycosides 296 and 297 from the soft corals Scleronephthya palida 205 and Alcyonium sp.64 collected near the coasts of Thailand represent 19-norpregnane derivatives. H H H H H H HO H O O O O CH3 HO CH3 X AcO HO 295 294 OH OCH3 X=OCOCH3 . H H H H O H H H3C AcO O OH O 296 b-Arap 297 OH Some fish species also contain steroid glycosides. This fact is surprising in that glycosides are not common for terrestrial vertebrates.Among other known secondary marine glycoside metabolites, special mention should be made of shark reppelant compounds isolated from the corresponding glands of the sole Pardachirus marmoratus and the peacock fish Pardachirus pav- oninus. Although these fishes swim extremely slowly, they success- fully withstand the attacks of predatory fishes in their vehement struggle for existence under conditions of coral reefs. Both fish species belong to the same genus and secrete toxic substances at the moment of danger. These substances contain the peptides pardaxins causing paralysis of shark's gnathic muscles and two groups of toxic glycosides endowed with hemolytic activities, viz., pavonins 298a,b and 299a ± d from P.pavoninus 206, 207 and mose- sines 300a ± d and 301 from P. marmoratus.208 H H H NAcGlc O O 298a,b H H H O NAcGlc R 299a ± d H H H HO O O 300a ± d RO H H H OH HO O O 301 HO These data suggest that steroid glycosides can be synthesised by taxonomically very distant and diverse groups of marine animals (from invertebrates to fishes). As regards the diversity of their constituent biologically active steroid glycosides, starfishes resemble other well-known sources of these compounds, viz., higher terrestrial plants. V. Steroidal alkaloids Bissteroidal pyrazines constitute a special group among other natural compounds, which are supertoxic for tumour cells. The structure of cephalostatin 1 (302a), the first compound of this series isolated from the marine tubular worm Cephalodiscus gilchristi by Pettit et al.(USA),209 was established by X-ray diffraction analysis. This compound in extremely low concentra- tion was toxic for tumour cells P-388 (IC50= 1077 ± 1079 mg ml71). Later, about 20 cephalostatins of this series, e.g., compounds 302b ± g, 303, 304a,b, 305, 306a,b and 307, were isolated from this animal.210 ± 215 Structurally close dimeric steroid alkaloids were unexpectedly found in the sea squirt Ritterella tokioka by Fusetani et al.216 ± 219 Ritterasine A (308a), the first compound in this series, is highly toxic for P-388 cells (IC50=3.561073 mg ml71) (see Ref. 216). The origin of the unusual fragment containing four five-mem- bered rings in ritterazine A and related compounds was explained by the rearrangement of the 12-hydroxy-D14-steroid system of their precursor (Scheme 2).Later, this group of Japanese chemists isolated more than twenty ritterazines, e.g., compounds 308b, 309a,b, 310, 311, 312a,b and 313, differing in the structures of rings C, D, E and F in one or both steroid fragments.217 ± 219 The majority of ritter- azines appeared to be highly toxic for tumour cells; some of them manifested superhigh activities (Table 5).218 703 OR 298a: R=Ac; 298b: R =H. OAc 299a: D5, R=a-OH; 299b: D5, R=b-OH; 299c: 5(6)-dihydro, R=a-OH; 299d: 5(6)-dihydro, R=b-OH; OAc OH OHOH 300a: D4, R=Ac; 300b: 4(5)-dihydro, R=Ac; 300c: D4, R =H; 300d: 4(5)-dihydro, R=H.OAc OH OHOH704 O OH 22 17 12 13 HO H H H+ O OH7 H + O H O OH HH H R1 3 H 17 R3 12 O O O 20 25 22 R2 OH H OH O H O O O OH H H H OHO O OH OH 305 (cephalostatin 7) Scheme 2 HO H 17 12 13 + O [O] 22 O H O O O 260 OH 220 HO HO 170 R4 O H OH N H 30 Compo- und 302 N H302a ± g abcdefg OH HO HO O H OH N H N H HO 303 (cephalostatin 4) HO OH O OH OH OHO H N H N H The isolation of two closely related groups of compounds from phylogenetically distant taxa, such as sea worms and ascidians, prompted a suggestion that their biosynthesis is carried out by symbiont microorganisms rather than by the host organ- ism.Cephalostatin 7 (305) is the most active compound of this series. Studies carried out at the National Cancer Institute (USA) showed that its average IC50 for 60 strains of tumour cells was equal to 1079 mol litre71. Later, this and some other dimeric steroidal alkaloids were synthesised. According to Pettit,209 these compounds are formed by dimerisation and subsequent oxidation of steroidal a-amino ketones. Fuchs et al.220 described the biomimetic synthesis of cephalostatins 7 (305), 12 (307) and ritterazin K (311). The starting compound in this synthesis was steroid pentacyclic aldehyde 314 prepared from readily available hekogenin acetate. This was converted via the intermediate ketones 315, 316 and bromo ketones 317 and 318 into azido ketones 319 and 320 (Scheme 3).Treatment of the azido ketone mixture (1 : 1) with 6 equiv. of NaHTe in ethanol for 1 h and subsequent addition of silica gel as a mild catalyst yielded a mixture of 321 (14%), 322 (35%) and 323 (23%). Compounds Name cephalostatin 1 cephalostatin 2 cephalostatin 3 cephalostatin 10 cephalostatin 11 cephalostatin 18 (22 0epimer) cephalostatin 19 (22 0epimer) H R H OHO OH O 304a,b V A Stonik R4 R3 R2 R1 HH HHCH3 HHHH HOH OH OH OH HH a-OCH3 Ha-OCH3 HHH H H Ha-OCH3 Ha-OCH3 R OH OO N OH N H 304a: R=CH3 (cephalostatin 5); 304b: R=H (cephalostatin 6).Marine polar steroids H OH O H O O O 306a,b R OH H HO70 H 160 H120 OHO O 170 260 220 OH 210 OH 308a,b H HO H H OHO OH O 310 (ritterazine C) OH H H H H O H OH O 312a,b OH 321 ± 323 were purified by chromatography; their subsequent deprotection gave products identical with natural cephalostatins 7 (305) and 12 (307) and ritterazine K (311), respectively.Pyrazine steroidal dimeric alkaloids belong to the most toxic natural products for tumour cells presently known. The synthesis of some of them has opened new opportunities for their further pharmacological and clinical investigations. Squalamine (324a), an unusual sulfated derivative of spermi- dine, was isolated from the shark Squalus acanthis.221, 222 Its structure was determined by spectroscopic methods; the stereo- HO HO O H N H N H 306a: R=H (cephalostatin 15); 306b: R=CH3 (cephalostatin 16).18 O OHH 11 12 13 H 9 17 N 14 8 30 H 3 H N 10 H 308a: ritterazine A (22R); 308b: ritterazine D (22S). O OH O H N H H N H O OH O H N H H N H 312a: ritterazine R (22 0R); 312b: ritterazine S (22 0S). OH OH OHO O HO O 25 22 O OHO O OH HO OHO O OH O H O OH Table 5. The cytotoxic activities of ritterazines against tumour cells P-388.218 Compound ritterazine A 0.0035 ritterazine B 0.00015 ritterazine C 0.092 ritterazine D 0.016H N H N H HOH 307 (cephalostatin 12) H HO N H N HOH 309a: ritterazine B (22R); 309b: ritterazine F (22S).309a,b H N H H N H HOH 311 (ritterazine K) H N H N HOH 313 (ritterazine Y) Compound IC50 /mg ml71 ritterazine F ritterazine K ritterazine S ritterazine Y 705 OH O OH OH OHO O OH O H H H H OH OH O OHO H H O OH O H H H H IC50 /mg ml71 0.00073 0.0095 0.46 0.0035706 O H BrO H TMGA, CH3NO2 N3 O H TBDMS, tert-butyldimethylsilyl; PTAB, phenyltrimethylammonium tribromide; TMGA, tetramethylguanidinium azide. TBDPSO TBDMSOO TMSO O OH O TMSO O OH TBAF, tetrabutylammonium fluoride. OTBDMS O AcOH OTBDPS OOH H 315 PTAB 72% OTBDMS O AcOH OTBDPS OOH H 317 100% OTBDMS O AcOH OTBDPS OOH H 319 H N H N H OHO OAc O 321 H N H N H HOAc 322 H HO N H N H H 323 OAc AcO CHO H OOAc ...... H AcO 314 H OTBDMS O AcO OHO H OTBDPS TBAF, THF H H OTBDMS O AcO OHO H TBAF, THF OTBDPS 305 (80%) (cephalostatin 7) H OH AcO O OTMS O H TBAF, THF H 311 (80%) (ritterazine K) V A Stonik Scheme 3 H O H H TMSOO O OAc316 OCH2SCH3 PTAB 76% H O H Br H TMSOO O OAc318 OCH2SCH3 96% TMGA, CH3NO2 H O H N3 H TMSOO O OAc320 OCH2SCH3 307 (80%) (cephalostatin 12)Marine polar steroids chemistry of the asymmetric centre C(24), (24R), was established based on the synthesis of desulfosqualamine and its (24S) isomer starting from stigmasterol.223 In contrast to bile alcohols of fishes, squalamine (324a) is present not only in the liver and the gallbladder but also in other shark organs, e.g., in the spleen and ovaries.Squalamine (324a) manifests interesting properties, viz., its antibacterial activity is comparable to that of the broad- spectrum antibiotic ampicillin (see Table 6), but its antifungal and antiprotozoan effects are stronger. NH HN NH2 Compound 324 abcd Some novel alkaloids of this series, viz., compounds 324b ± d, 325a,b, 326 and 327, have been isolated recently. Noteworthy, the antimicrobial activity of compound 327 is comparable to that of squalamine.234 Compounds of this series suppress the appetite in NH HN NH2 NH HN NH2 NH HN NH2 NH 707 Table 6.Comparison of the antimicrobial activities of squalamine (mini- mum IC /mg ml71) and the antibiotic ampicillin. Ampicillin Squalamine Microorganism R3 R2 R1 E.coli Pseudomonas aeruginosa Staphylococcus aureus Streptococcus faecalis Proteus vulgaris Serratia marcescens Candida albicans Paramecium caudarum 2 ±4 62 ± 125 <1 <0.25 8 ±16 4 ± 62 >125 >65 1 ±2 4 ± 8 1 ±2 1 ± 2 4 ±8 >125 4 ± 8 4 ± 8 H R4 H HOH H mice and other animals, which prompted a conclusion about their role in sporadic alimentary behaviour of the shark S. acanthis, which eats only once in two weeks.324a ± d R4 R3 R2 R1 Two novel alkaloids 328a,b 225 related to the previously known antimicrobial metabolites, plakinamides A and B (329a,b) from the sponge Plakina sp.,226 were isolated from extracts of the sponge Corticum sp. collected near the coasts of Indonesia. Compounds 328a,b are highly toxic for tumour cells and manifest moderate immunomodulating and antimicrobial activities. OH OSO3H HH OSO3H H OSO3H CH2 OH HHOH H HOSO3H HH N H R1 N H 328a: R1=R2=CH3; 328b: R1=COCH3, R2=H. HO 328a,b R2 O H N R H H HOH RHN H H 329a: R =H; 329b: R=COCH3 . 329a,b 325a,b The unusual steroidal alkaloids 330 and 331 with expanded ring B have been found recently in the Pacific sponge Corticum sp.227 325a: R=SCH2CHNH2CO2H; 325b: R=OSO3H.O H N N H HOH H H H H 331 330 H2N H2N 326 OSO3H The steroidal oximes 332 and 333 from the sponge Cinachyr- ella sp. inhibit competitively human placental aromatase and are H H HOH H H H O O 333 332 NOH NOH 327708 potential inhibitors of hormone-dependent tumours.228 The syn- theses of these compounds have been described.229 Although marine steroid alkaloids known thus far are not numerous, they present substantial interest with regard to their chemical structures and physiological activities. VI. Miscellaneous marine steroids In this section, we shall consider those marine steroids which can hardly be related to any of the above-mentioned structural groups.Steroid phosphates were found in the starfish Tremaster novaecaledoniae. Tremasterols A±C (334a ± c) related to glyco- sides were the first to be described.230 The monosaccharide residues in these compounds are bound to aglycons by phospho- diester rather than glycosidic bonds. The signals for the protons at C(6) in the 1H NMR spectra of tremasterols represented doublets of doublets of doublets of doublets (J=9.5, 9.5, 7.5 and 4.5 Hz), i.e., they contained an additional spin coupling constant com- pared with the corresponding spectra of 6a-hydroxy cholestane derivatives due to the HC7O7P coupling. Their 31P NMR spectra contained triplet signals at d 3.54, which coalesced into doublets upon irradiation of CH(6) or CH(10), which suggests the presence of a phosphate group between C(6) and the monosac- charide residue.Chemical shifts of phosphorus atoms for phos- phate and other functional groups in the 31P NMR spectra are well established (see, e.g., Ref. 231). Later, the steroid 335 containing sulfate and phosphate groups in positions 3 and 6, respectively, was isolated from the same starfish species.136 7O3SO HO O HO HO HO H OAc H H H O O P 7O R2O O CH2O OR1 R1O OR1 334a ± c O H H H 337 (bisconicasterone) O H H O 3 OSO¡ 340 (crellastatin A) 7O3SO H 7O 334a: R1=R2=H; 334b: R1=R2=Ac; 334c: R1=H, R2=Ac. H O OH HO H O HO O HO OSO¡ 341 (crellastatin I) V A Stonik Some sponges were found to contain dimeric steroids.Thus bistheonellasterone (336) and bisconicasterone (337) were isolated from the Okinawian sponge Theonella swinhoei by Japanese scientists.232, 233 Compound 338 was prepared in nearly quantita- tive yield from theonellasterone 338 upon heating and evapora- tion of the latter in chloroform (50 8C, 2 h). The coupling occurred with excellent regio- and stereospecificity. It is assumed that the dimeric steroids 336 and 337 are formed as a result of the Diels ± Alder cycloaddition of theonellasterone 338 to its D4-iso- mer or, correspondingly, by cycloaddition of two molecules of conicasterone 339 to each other. Ketones 338 and 339, the possible precursors of compounds 336 and 337, and related compounds have been isolated from the same sponges where they occur as crystalline inclusion compounds.Crellastatin A (340) was the first sulfated steroid dimer isolated from the sponge Crella sp.234 The related compounds 341, 342, etc., were isolated later.235 Hymnosterone A (343), the unusual cytotoxic steroid deriva- tive of mixed biogenesis, was isolated from the microscopic fungus Gymnascella dankaliensis associated with the sponge Halichondria japonica.236 Hymnostatins containing a non-steroid fragment of compound 343, e.g., hymnostatin A (344), were detected in the same microorganism. They manifest high toxicities against tumour cells P-388.237 Polar steroids are seldom found in scleroactinian corals. However, steroidal acids 345a and 346, the carbon skeletons of which are identical with those of cholic acids, were discovered in deep-water Deltocyanthus magnificus by Pietra et al.238. Some of OAc H H H H O H O O H P O7 335 O 336 (bistheonellasterone) H H O H H 339 (conicasterone) 338 (theonellasterone) O OH H O O HO H H H O HO H O HO 3 3 OSO¡ 342 (crellastatin L)Marine polar steroids OH H HO O HN CHO H13C6 O 343 (hymnosterone A) H H H O 345a ± c H H H O 346 these compounds were isolated as methyl esters by treatment of the corresponding fractions with diazomethane. * * * Several interesting papers devoted to marine polar steroids were published after this review had been written.Thus Fujita et al.239 reported on the isolation of two novel unusual polar steroids, viz., haplosamate A (347) and the minor steroid 348 from the sponge Cribrochalina sp.dwelling near the Western coast of Japan. H H H OH NaO3SO H HO OH 347 (haplosamate A) H H NaO3SO H OH OH These compounds were discovered during the search for inhibitors of matrix metalloproteinases of the membrane type (MT-MMPs), the key enzymes in tumour metastasis. These enzymes activate progelatinase A, which causes the degradation of type IV collagen. The latter inhibits invasion of tumour cells in different body organs and tissues. It is suggested that MT-MMPs inhibitors hold considerable promise as antitumour agents. Com- pounds 347 and 348 inhibited MT-MMPs (IC50=150 and 160 mg ml71, respectively).Haplosamate A was found to be identical with the inhibitor of integrase, a specific enzyme of the human immunodeficiency virus, with a tentative formula 349, which has earlier been isolated from two Philippine sponges.240 O Cl Cl H O HN OH H13C6 O 344 (hymnostatin A) R CO2CH3 ; 345a: R = CO2CH3 ; 345b: R = CO2CH3 . 345c: R = CO2CH3 OH O O O P OCH3 ONaO O H O P OCH3 OH ONa 348 709 O H H H NHCH3 O SO2 NaO3SO OH H 349 OH HO It was suggested that this polyhydroxylated steroid contains one sulfate group and one N-methylsulfamate group. However, theNMRspectra of haplosamate A displayed additional splitting of signals for certain protons, which could not be inferred from the formula 349.Thus the proton signal corresponding to the methoxy group occurred as a doublet, which points to the presence of a phosphorus atom in this steroid. Further structural analysis corroborated the correctness of the structure 347 for haplosamate A and the compound isolated from Philippine sponges. Haplosamate A (347) and the related steroid 348 are the first sponge steroids containing both sulfate and methyl phosphate groups. The absolute stereochemistry of compounds 347 and 348 was established on the basis of their chemical conversions and using a modified Mosher's method. The structure of haplosamate B (350),239 which was errone- ously identified as compound 351,240 is even more surprising. Haplosamate B is the first polar steroid containing two phosphate and one sulfate groups; one of the phosphate groups in steroid 350 is methylated.O H O H H O P OCH3 NaO3SO OPO3Na2 H ONa HO OH 350 (haplosamate B) O H H H NHCH3 NaO3SO H O SO2 OSO3Na 351 OH HO The number of marine steroid glycosides is rapidly increasing. A recent report is devoted to the isolation of three novel antibacterial asterosaponins, viz., goniopectenosides A±C (352a ± c), from the starfish Goniopecten demonstrans.241 R O HO ; 352a: R = OH H O HO H ; 352b: R = NaO3SO H O 1,2 HO Qui 1,3Xyl 1,2 O Fuc Xyl 1,2 . 352c: R = 352a ± c 3-MeO Qui The carbohydrate chains of these compounds contain a rarely occurring monosaccharide, viz., 3-O-methylquinovose, whereas their aglycons contain a keto group in position 22 rather than in 23.The use of a new instrumental approach, viz., liquid chroma- tography combined with NMR and mass-spectroscopic detection (LC-NMR-MS), in the analysis of the well-studied asterosaponin fraction isolated from the starfish Asterias rubens revealed five novel steroid glycosides named ruberosides A± D.242710 Four novel glycosides of this series, viz., sarasinosides H1, H2, I1 and I2 (compounds 353a ± d), were isolated from the sponge Melophlus isis together with the previously identified sarasino- sides A1 and A3.243 In contrast to sarasinosides, the cytotoxic glycosides ectyoplasides A and B (354a,b) from the Caribbean sponge Ectyoplasia ferox,244 represent oxygenated derivatives of 4,14-dimethylsterols and contain two galactose and one arabinose residues in their carbohydrate chains.O OH R1R2 Glcp7Glcp7NAcGlcp7Xylp7O H 353a ± d NAcGalp 353a: R1=OH, R2=H (sarasinoside H1); 353b: R1=OCH3, R2=H (sarasinoside H2); 353c: R1=H, R2=OH (sarasinoside I1); 353d: R1=H, R2 = OCH3 (sarasinoside I2). OH CO¡2 O CH2OH HO O OH H HO R O O O CH2OH HOOH O OH 354a: R=H (ectyoplasides A); 354b: R=OH (ectyoplasides B). OH 354a,b OH Yet another series of steroid glycosides, viz., wondosterols A±C(355a ± c), were detected in a mixture of two different sponge species dwelling near the coasts of Korea.245 These compounds contain carbohydrate chains linked to C(4) of the aglycons. Wondosterols (355a ± c) belong to the same structural series as the known bioside pachastrelloside A (284), but differ from the majority of other sponge glycosides in that they derive from polyhydroxysterols rather than from methylsterols.R H HO H H HO OH O O OH (wondosterol A); 355a: R= (wondosterol B); 355b: R= O O (wondosterol C). 355c: R= HO HOH2C HOOHOH 355a ± c Among novel steroids isolated from Coelenterata, special mention should be made of a series of compounds similar to witanolides isolated recently from the Okinawian soft coral Clavularia viridis, viz., the so-called jonarasterols A±C (356a ± c) 246 and the steroidal pentol 357 from the soft coral Sarcophyton trocheliophorum,247 which was weakly toxic against normal human leucocytes, but inhibited leukemia cells HL-60, melanoma cells M-14 and mammary carcinoma cells MCF-7 (IC50=3±5 mg ml71).V A Stonik R HO O H (jonarasterol A); 356a: R= H H (jonarasterol B); 356b: R= HO OAc H 356c: R= (jonarasterol C). 356a ± c H OH HO H H H HO HO 357 OH VII. Problems of isolation and structural analysis of marine polar steroids Polar steroids are usually present in marine organisms as very complex mixtures of structurally related compounds, which sig- nificantly complicates their isolation and separation. These ste- roids may contain several functional groups or fragments. Thus trisulfated sterol derivatives are widespread in sponges, whereas steroids containing sulfate or phosphate groups in addition to monosaccharide fragments are more common for starfishes.Moreover, many highly active marine steroids are minor compo- nents of extracts where their concentrations do not exceed 0.001% of the dry weight of the corresponding organisms. Their isolation and purification present a difficult and not always solvable problem, although these procedures are usually carried out with the use of the most advanced separation techniques. In our laboratory, we use reversed-phase column chromatog- raphy on a PTFE powder (Polychrome-1) in the first step of isolation of polar steroids. This consists in application of aqueous extracts on columns with this sorbent, elution of salts by washing the columns with water and elution of polar steroids with aqueous alcohol.99, 160 Italian chemists perform this procedure on a column with Amberlite XAD-2.3, 165 Further separation usually requires the use of several separation techniques including gel-permeation chromatography on Sephadexes LH-20 and LH-60, adsorption chromatography on silica gel, reversed-phase HPLC as well as drop counter-current distribution.The isolation of 22 novel polar steroids from the starfish Oreaster raticulatus,117 about 20 ceph- alostatins from Cephalodiscus gilchristi 211 ± 217 and 20 ritterazines from Ritterella tokioka 216 ± 219 provide illustrative examples of progress achieved. NMR spectroscopy including the most updated techniques, e.g., HMBC and NOESY experiments, is the most popular structural physicochemical method.The absolute configurations of asymmetric carbon atoms of polyhydroxysteroids are often established by the Mosher's method,248 which consists in the conversion of the corresponding hydroxy groups into ester groups by treatment with chiral R-(+)- and S-(7)-a-methoxy-a-tri- fluoromethylphenylacetyl chlorides (MTPA) with subsequent determination of the chemical shifts of protons at the adjacent carbon atoms of the diastereomeric esters formed. In the case of the 24R-configuration of the corresponding asymmetric centres in (+)- and (7)-MTPA esters, the signals corresponding to the C(26)H3 and C(27)H3 groups are observed at d 0.89 ± 0.91, whereas those for the 24S-isomers are found in the higher field, viz., at d 0.83 ± 0.86.FAB-mass spectrometry is the most popular modern mass spectrometric technique for the determination of molecular masses of polar steroids and establishment of the sequences ofMarine polar steroids monosaccharide units in carbohydrate chains of steroid glyco- sides. Although the chemical properties of many marine polar steroids are still poorly investigated, the use of chemical proce- dures for the establishment of their chemical structures sometimes demonstrates their unusual or unpredicted chemical behaviour especially in acidic media, e.g., migration of the double bond in the steroid nucleus from position 8(9) to positions 8(14) and 14(15),110, 191, 197 aromatisation of a ring in the steroid skeleton,110 etc. VIII.Conclusion In marine organisms, steroid substrates can be oxygenated at any carbon atom without exceptions (Table 7). Even the products of steroid metabolism formed by oxidative cleavage of the bonds between the quaternary carbon atoms, e.g., C(10) or C(13), and the neighbouring carbon atoms, were found in these organisms. Compounds containing hydroxy groups in methine and methyl- ene groups instead of hydrogen atoms are even more numerous. Some representatives of starfishes, sponges and cnidarians con- tain steroids with three, four and even more (up to nine) hydroxy groups. Further modifications of polar steroids in marine organ- isms include sulfation (sponges, starfishes, ophiuroids and fishes), acylation (octocorals and some other cnidarian species and sponges), methylation (sponges), oxidation of hydroxy groups to keto and carboxy groups (sponges, cnidarians and echinoderms), phosphorylation (starfishes and sponges) and glycosylation (star- fishes, sponges, fishes, cnidarians, less frequently, ophiuroids).Sometimes, biochemical conversions of polar steroids lead to the formation of nitrogen-containing derivatives, viz., alkaloids. All this provides evidence for the wide structural diversity of marine polar steroids. The analysis of published data suggests that in-depth studies in this area are still in progress. In the last few years, the number of newly discovered marine steroids increases annually by 50 ± 100 compounds. Many novel unexpected findings still remain to be made.Table 7. Examples of marine organisms containing oxygenation polar steroids with oxiden-containing functional groups at different positions. Carbon Marine organisms atom 12 sponges (Xestospongia), corals (Sinularia), etc. many ophiuroids, sponges (Aplyinopsis, Echinoclathria, Halichondria, Topsentia, etc.) all marine organisms excluding bacteria many ophiuroids and starfishes, corals, sponges (Stilopus, Haliclona) many sponges, corals and starfishes, some sea lilies many sponges, corals and starfishes, some sea lilies some starfishes and octocorals, fishes, sponges (Poecilastra) many starfishes, sponges (Jereicopsis, Theonella), fungi (Tilopilus) many sponges and corals, fungi (Tilopilus) 3456789a In the side chains of ergostane derivatives.b In the side chains of ergostane and stigmastane derivatives. Carbon Marine organisms atom 10 11 12 13 14 15 16 17 18 gorgonian corals (Caligorgia), sponges (Corticum) many sponges and corals, some ophiuroids, fishes (Mola) some fishes, sea worm (Cephalodiscus gilchristi), ascidia (Ritterella tokioka) octocorals (Dendronephthea) some starfishes, sponges (Jereicopsis, Theonella) many starfishes Many starfishes, corals, sea worm (Cephalofiscus gilchristi) sponges (Echinoclathria, etc.), corals (Dendronephthea), sea worm (Cephalofiscus gilchristi) octocorals (Sinularia, etc.), sponges (Echinoclathria) Although the biological activities and functions of marine polar steroids have not been adequately investigated yet, many of them have attracted the attention of pharmacologists and physi- cians.This concerns supercytotoxic antitumour compounds, efficient antimicrobial agents, inflammation inhibitors, etc. In- depth studies of antiinflammatory activities of contignasterol, antitumour activities of cephalostatins and specific physiological activities of other marine polar steroids are currently under way. However, the array of activities tested employed in the isolation of novel polar steroids is still rather narrow. Thus the majority of investigators have concentrated on the search for novel antitu- mour compounds, whereas all other types of activities of marine steroids are neglected.The experimental data and the unusual structural peculiarities of some polar steroids attract keen attention of synthetic chemists. Recent developments in this field culminated in complete and partial syntheses of these natural compounds, their analogues and derivatives. Thus the syntheses of two novel sponge 9,10-secoste- roids,250 viz., calicopherol E and astrogorgiadiol (by the method of Barton 249); of cytotoxic stolonipherones earlier isolated from the soft coral Clavularia viridis;251 of incrustasterols possessing antitumour activities;252 of xestobergsterol A obtained in 24 steps from stigmasterol 253 and of 3-epi-6,7-dideoxysestobergsterol A254 have recently been carried out. Apparently, the synthetic trend in the study of marine polar steroids will be developed in the future.It is obvious that the vast pool of fundamental knowledge concerning the structure, taxonomic distribution and properties of marine polar steroids created owing to joint efforts of many research groups all over the world will serve as a basis for the development of novel biotechnological approaches to their prep- aration in sufficiently large amounts. Close cooperation of bio- organic chemistrs and specialists in aquatic, cell and tissue cultures and gene engineering will be a valuable contribution. In the next few years, significant progress can be anticipated in the study of biogenesis of marine steroids, particularly in isolation and investigation of enzymes responsible for their biosynthesis 711 Carbon Marine organisms atom 19 20 21 22 23 24 25 26 27 28 a corals (Nephthea, Antiphates, Litophyton), sponges (Toxadocia, Strongylophora, Crella) many starfishes, sponges (Petrosia, Geodia), corals (Sarcophyton, etc.) many ophiuroids, starfishes (Pteraster), some corals and sponges sponges (Haliclona, Petrosia, etc.), corals (Alcyonium, etc.) many starfishes, some corals, sponges (Xestospongia, Ircinia) many starfishes, fishes, sponges (Crella) some starfishes and octocorals many starfishes, some fishes, sponges (Polymastia) many starfishes, some fishes, sponges (Polymastia) many starfishes many starfishes, sponges (Petrosia) 29 b712 and the use of these enzymes or competent cells for targeted transformations of steroid substrates. 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年代:2001

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