Steroid Dimers E-Book

Professor Satyajit D. Sarker

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 881

Veröffentlichungsjahr: 2012

Beschreibung

Steroid dimers are an important group of compounds produced by various marine organisms, and also synthesized in the laboratories. This group of compounds possesses various pharmacological and biological properties, and can also be used to create  “molecular umbrellas” for drug delivery.

Steroid Dimers: Chemistry and Applications in Drug Design and Delivery provides an up-to-date overview on the chemistry and applications of steroid dimers of natural and synthetic origins. The book includes easy-to-follow synthetic protocols for various classes of important dimeric steroids, source details, valuable spectroscopic data and depiction of unique structural features of natural steroidal dimers, and the Structure-Activity-Relationships (SARs) of some pharmacologically active dimeric steroids. Topics covered include:

• introduction to steroid dimers
• synthesis and chemistry of noncyclic and cyclic steroid dimers
• naturally occurring steroid dimers – cephalostatins, ritterazines and crellastatins
• biological and pharmacological functions of steroid dimers and their application in drug design and discovery
• steroid dimers as “molecular umbrellas” for drug delivery

Steroid Dimers: Chemistry and Applications in Drug Design and Delivery is an essential guide to this important class of natural and synthetic compounds for researchers and students of natural products chemistry and biochemistry, synthetic organic and  medicinal chemistry, and drug design, discovery and delivery.

Leseprobe

Contents

Cover

Title Page

Copyright

Dedication

Preface

List of Abbreviations

Chapter 1: Introduction

1.1 Steroids and Steroid Dimers

1.2 General Physical and Spectroscopic Properties of Steroid Dimers

1.3 Chromatographic Behaviour of Steroid Dimers

1.4 Applications of Steroid Dimers

References

Chapter 2: Synthesis of Acyclic Steroid Dimers

2.1 Dimers via Ring A–Ring A Connection

2.2 Dimers via Ring B–Ring B Connection

2.3 Dimers via Ring C–Ring C Connection

2.4 Dimers via Ring D–Ring D Connection

2.5 Dimers via Ring A–Ring D Connection

2.6 Dimers via Connection of C-19

2.7 Molecular Umbrellas

2.8 Miscellaneous

References

Chapter 3: Synthesis of Cyclic Steroid Dimers

3.1 With Spacer Groups: Cholaphanes

3.2 Without Spacer Groups: Cyclocholates

References

Chapter 4: Naturally Occurring Steroid Dimers

4.1 Cephalostatins

4.2 Crellastatins

4.3 Ritterazines

4.4 Others

References

Chapter 5: Synthesis of Cephalostatin and Ritterazine Analogues

5.1 Introduction

5.2 Synthesis of Cephalostatin and Ritterazine Analogues

5.3 Total Synthesis of Naturally Occurring Cephalostatin 1

References

Chapter 6: Applications of Steroid Dimers

6.1 Application of Steroid Dimers as ‘Molecular Umbrellas’: Drug Delivery

6.2 Biological and Pharmacological Functions of Steroid Dimers: Drug Discovery and Design

References

Index

This edition first published 2012

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Library of Congress Cataloging-in-Publication Data

Nahar, Lutfun, Ph. D.

Steroid dimers [electronic resource] : chemistry and applications in drug

design and delivery / Lutfun Nahar, Satyajit D. Sarker.

1 online resource.

Includes bibliographical references and index.

Description based on print version record and CIP data provided by

publisher; resource not viewed.

ISBN 978-1-119-97285-3 (MobiPocket) – ISBN 978-1-119-97284-6 (ePub) – ISBN

978-1-119-97094-1 (Adobe PDF) – ISBN 978-0-470-74657-8 (cloth) (print)

I. Sarker, Satyajit D. II. Title.

[DNLM: 1. Steroids–chemistry. 2. Dimerization. 3. Drug Delivery Systems.

4. Drug Design. QU 85]

5720.579—dc23

2011052550

Dedicated to our parents

Mariam Sattar   Sadhan SarkerAbdus Sattar   Madhuri Sarker

Preface

Steroid dimers form an important group of pharmacologically active compounds that are predominantly biosynthesized by various marine organisms, and also synthesized in laboratories. These dimers can also be used to create ‘molecular umbrella’ for drug delivery. While there are hundreds of such compounds and numerous research papers on these compounds available to date, there is no book documenting the chemistry and applications of these compounds. However, there are two reviews, one by Li and Dias, and the other one by us (Nahar, Sarker and Turner) published, respectively, in 1997 and 2007. We believe that this is the right time to publish a book on steroid dimers covering their chemistry and applications. This book will be a handy reference for the organic synthetic, medicinal and natural-products chemists working in the area of steroids, and drug design, discovery and development in general.

The primary readership of this book is expected to be the postgraduate synthetic organic, medicinal and natural-product chemists working either in academia or industries, especially in the area of drug design, discovery and delivery. This book will also be suitable for the postgraduate students (and undergraduate students to some extent) within the subject areas of Chemistry, Pharmacy, Biochemistry, Food Sciences, Health Sciences, Environmental Sciences and Life Sciences.

This book comprises six chapters. Chapter 1 introduces the topic, ‘steroid dimers’, and builds the foundation of the subsequent chapters. Chapters 2 and 3 deal with the synthesis and the chemistry of various classes of steroid dimers, including cyclic and acyclic dimers, placing particular emphasis on the types of connectivities. Chapter 4 presents an overview on the naturally occurring steroidal dimers, e.g., cephalostatins, crellastatins and ritterazines. Chapter 5 discusses the synthesis of cephalostatin and ritterazine analogues, as well as the total synthesis of the naturally occurring extremely cytotoxic steroidal dimer cephalostatin 1. Chapter 6 looks into the applications of both synthetic and natural steroid dimers, and evaluates the importance of these dimeric compounds in drug design, discovery and delivery. It also elaborates the concept of ‘molecular umbrella’ in the context of steroid dimers.

The major features of this book include easy-to-follow synthetic protocols for various classes of important dimeric steroids, source details, valuable spectroscopic data and depiction of unique structural features of natural steroidal dimers, applications of steroidal dimers, especially in relation to drug design, development and delivery, and the Structure-Activity-Relationships (SARs) of some pharmacologically active dimeric steroids.

Dr Lutfun NaharDe Montfort University, Leicester

Professor Satyajit D. SarkerUniversity of Wolverhampton, WolverhamptonOctober 2011

List of Abbreviations

ÅAngstromAcClAcetyl chlorideAc2OAcetic anhydrideAcOHAcetic acidAgBF4Silver tetrafluoroborateAgNO3Silver nitrateAg2OSilver oxideAIBNAzobisisobutyronitrileAl(O-t-Bu)3Aluminum tert-butoxideArArgonBaCO3Barium carbonateBF3Boron trifluorideBF3.Et2OBoron trifluoride etherateBH3BoraneBH3·SMe2Borane-dimethyl sulphideBnBrBenzylbromideBnOHBenzyl alcohol(Boc)2ODi-tert-butyl dicarbonateBrCH2COBrBromoacetyl bromiden-BuLiButyllithiumBu4NOAcTetrabutylammonium acetate2-BuOH2-Butanolt-BuOHtert-Butanol or tert-butyl alcoholt-BuOKPotassium tert-butoxideBu3SbTributylstibineBu2SnCl2Dibutyltin dichloride or dichlorodibutylstannaneBu3SnHTributyltin hydride or tributylstannane13C NMRCarbon Nuclear Magnetic ResonanceCaCO3Calcium carbonateCaH2Calcium hydrideCaSO4Calcium sulphatem-CBPAmeta-Chloroperoxybenzoic acidCCColumn chromatographyCCl4Carbon tetrachlorideC5D5NDeuterated pyridineCeCl3Cerium trichlorideCeCl3.7H2OCerium trichloride heptahydrate(CF3CO)2OTrifluorocacetic anhydrideC6F5OHPentafluorophenolC6F5SHPentafluorothiophenolC6H6BenzeneC6H12CyclohexaneCHCl3ChloroformCH2I2DiiodomethaneCH2N2DiazomethaneC5H5NPyridineCH3NO2NitromethaneC2H6O2Ethane-1,2-diol or ethylene glycolCH(OMe)3Trimethoxymethane or trimethyl orthoformate(C3H5O)2OPropionic anhydrideCH3ReO3MethyltrioxorheniumCIMSChemical Ionization Mass SpectroscopyClCH2CO2HChloroethanoic acid(Cl3CO)2COTriphosgeneCl2P(O)OEtDichloroethylphosphateCMEChloromethyl ethyl etherCO2Carbon dioxide(COCl)2Oxalyl chlorideCOSYCorrelation SpectroscopyCrO3Chromium trioxideCSACamphorsulfonic acidCu(AcO)2Copper acetateCuCNCopper cyanideCuICopper IodideCu(OTf)2Copperbistrifluoromethanesulfonate or copper triflatedDay (s)DABCO1,4-diazabicyclo[2.2.2]octaneDBEDi-n-butyl etherDBU1,8-Diazabicyclo[5.4.0]undec-7-eneDCBC2,6-Dichlorobenzoyl chlorideDCCDicyclohexyl carbodiimideDCCCDroplet counter current chromatographyDCEDichloroethene or dichloroethyleneDCMDichloromethaneDEADDiethyl azodicarboxylateDEGDiethylene glycolDEPCDiethylphosphoryl cyanideDEPTDistortionless Enhancement by Polarisation TransferDHEADehydro-epi-androsteroneDHP2,3-DihydropyranDHTDihydrotestosterone(DHQ)2PHALHydroquinine 1,4-phthalazinediyl dietherDIADDiisopropyl azodicarboxylateDIBDiacetoxyiodobenzeneDibromo-PEGDibromo-polyethyleneglycolDIEAN,N-diisopropylethylamineDIPADiisopropylamineDIPEADiisopropylethylamineDMAP4-DimethylaminopyridineDMDODimethyldioxiraneDMEDimethyl etherDMFDimethylformamideDMSODimethyl sulphoxide2,4-DNP2,4-DinitrophenylhydrazineD2ODeuterated water or heavy waterDTBB4,4′-Di-tert-butylbiphenylEDC1-Ethyl-3-(3-dimethyl aminopropyl)-carbodiimide hydrochlorideEDTAEthylenediaminetetraacetic acidEEDQN-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinolineEIMSElectron Ionisation Mass SpectroscopyESIMSElectron Spray Ionisation Mass SpectroscopyEtCO2ClEthyl chloroformateEt3NTriethyl amineEtNO2NitroethaneEt2OEtherEtOAcEthyl acetateEtO2CC(N2)PO(OEt)2Ethyldiazophosphonate(EtO)3CHTriethyl orthoformateEtOHEthanolEtPPh3BrEthyltriphenylphosphonium bromideFABMSFast Atom Bombardment Mass SpectroscopyFCCFlash column chromatographyFeCl3.Et2OFerric chloride etherateFe(ClO4)3Ferric perchlorateFTIRFourier-Transfer Infrared SpectroscopyhHour (s)H2HydrogenH3BO3Boric acidHBrHydrobromic acid or hydrogen bromideHClHydrochloric acid or hydrogen chlorideHClO4Perchloric acidHCO2HFormic acidH2CrO4Chromic AcidHDTCEthylene glycolHFHydrofluoric acid or Hydrogen fluorideHgOMercury oxideHIO4Periodic acidHMBCHeteronuclear Multiple Bond Correlation(HMe2Si)2OTris(dimethylsilyl)methaneH2N(CH2)2NH2EthylenediamineHN3Hydrogen azide or hydrazoic acid1H NMRProton Nuclear Magnetic ResonanceH2OWaterH2O2Hydrogen peroxideHPLCHigh Performance Liquid ChromatographyHREIMSHigh Resolution Electron Impact Mass SpectroscopyHRFABMSHigh Resolution Fast Atom Bombardment Mass SpectroscopyH2SO4Sulphuric acidHSQCHeteronuclear Single Quantum CoherenceHzHertzI2IodineIRInfrared SpectroscopyKBrPotassium bromideK2CO3Potassium carbonateK2CrO4Potassium chromateK3Fe(CN)6Potassium ferricyanideKHPotassium hydrideKHCO3Potassium bicarbonate or potassium hydrogen carbonateKHMDSPotassium hexamethyldisilazaneKIPotassium iodideKMnO4Potassium permanganateKOAcPotassium acetateK2OsO4Potassium osmateK2S2O5Potassium metabisulphiteLDALithium diisopropylamideLiLithiumLiAlH4Lithium aluminium hydrideLiBH4Lithium borohydrideLiBrLithium bromideLiClO4Lithium perchlorateLi2CO3Lithium carbonateLiOHLithium hydroxideLSIMSLiquid secondary ion mass spectrometryMALDI-TOFMatrix-assisted laser desorption ionisation-time of flightMeCNAcetonitrileMeCOAcetyl or AcMe2COAcetoneMeIMethyl iodideMeLiMethyllithiumMeMgBrMethyl magnesium bromideMe2NEtN,N-DimethylethylamineMeOHMethanolMeONH2.HClO-Methylhydroxylamine hydrochlorideMsClMethanesulfonyl chlorideMe3SITrimethylsulfonium iodideMeSO2NH2Methane sulfonamideMgMagnesiumMgSO4Magnesium sulphateMHzMegahertzMpMelting pointMSMass SpectroscopyMsClMethanesulfonyl chloride or mesyl chlorideMTBEMethyl tertiary butyl etherMTOMethyltrioxorheniumMWAMMicrowave assisted metathesism/zMass to charge ratioN2NitrogenNaBH4Sodium borohydrideNaBH(OAc)3Sodium triacetoxyborohydrideNaClO2Sodium chloriteNaClO4Sodium perchlorateNaCNBH3Sodium cyanoborohydrideNa2CO3Sodium carbonateNa2Cr2O7Sodium dichromateNaHSodium hydrideNaHCO3Sodium bicarbonate or sodium hydrogen carbonateNa-HgSodium-mercury or sodium amalgamNaISodium iodideNaIO4Sodium periodate or sodium metaperiodateNaN3Sodium azideNaOAcSodium acetateNaOAc.3H2OSodium acetate trihydrateNaOHSodium hydroxideNaOMeSodium methoxideNa2SO4Sodium sulphateNa2S2O3Sodium thiosulphateNa2S2O5Sodium metabisulphiteNaTeHSodium hydrogen tellurideNBSN-BromosuccinimideNH3AmmoniaN2H4HydrazineNH4ClAmmonium chlorideN2H4.H2OHydrazine hydrateNH4OAcAmmonium acetateNH4OHAmmonium hydroxideNH2OH.HClHydroxylamine hydrochlorideNH2OMe·HClMethoxyamine hydrochloride(NH4)2SO4Ammonium SulphateNH2SO3HSulfamic acidNMON-Methylmorpholine-N-oxideNMRNuclear Magnetic ResonancenOeNuclear Overhauser EffectNOESYNuclear Overhauser Effect SpectroscopyO3OzoneOsO4Osmium tetroxideOTsTosylatePb(OAc)4Lead tetraacetatePCCPyridinium chlorochromatePd-CPalladium on carbonPDCPyridinium dichromatePd(MeCN)2Cl2Bis(acetonitrile)dichloropalladiumPetroleum etherPetroleum ether (40–60 °C)PFPOHPentafluorophenolPhPhenylPhI(OAc)2DiacetoxyiodobenzenePhLiPhenyllithiumPhMe3NBr3Phenyltrimethylammonium tribromidePh3PTriphenylphosphinePh3PAuClChloro(triphenylphosphine)goldPh3P=CH2BrTriphenyl(methyl)phosphonium bromidePPh3ClDichlorotriphenylphosphanePh3POTriphenylphosphine oxidePPh3ClDichlorotriphenylphosphane(Ph3P)4PdTetrakis(triphenylphosphine)palladiumPhSeBrPhenylselenyl bromide(PhSeO)2OPhenylseleninic anhydridePhSO2ClPhenylsulphonyl chloridePMPp-MethoxyphenolPPTSPyridinium p-toluenesulfonatePTABPhenyltrimethylammoniumbromide tribromidePTAPPhenyltrimethylammonium perbromidePTLCPreparative Thin Layer ChromatographyPtO2Platinum dioxide or Adams' catalystP2O5Phosphorus pentoxidePOPC1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholinei-Pr2NEtN,N-Diisopropylethylaminen-PrNH2n-propylaminei-Pr2ODiisopropyl etheri-PrOHiso-Propanol or propan-2-olPVPPolyvinylpyridineRCMRing-closing metathesisRh2(OAc)4Rhodium acetateROSEYRotating-frame Overhauser Effect SpectroscopYr.t.Room temperatureRuCl3Ruthenium trichlorideRuCl3.H2ORuthenium trichloride hydrateL-SelectrideLithium tris(sec-butyl)hydroborateSiO2Silica or silicon dioxideSO2Sulphur dioxideSO3Sulphur trioxideSOCl2Thionyl chlorideSPHRSIMSSuper Probe High Resolution Secondary Ion Mass SpectrometryTBAFTetrabutylammonium fluorideTBAHSTetrabutylammonium hydrogen sulphateTBDMSCltert-butyldimethylsilyl chlorideTBDPStert-ButyldiphenylsilylTBDPSCltert-ButylchlorodiphenylsilaneTBMStert-ButyldimethylsilylTBDMSOTftert-Butyldimethylsilyl trifluoromethanesulfonateTBSOTftert-Butyldimethylsilyl triflateTEATriethanolamineTEGTriethylene glycolTFATTrifluoroacetyl trifluoromethanesulfonateTHFTetrahydrofuranTHPTetrahydropyranTiCl3Titanium trichlorideTiCl4Titanium tetrachlorideTIPSTriisopropylsilylTIPSClTriisopropylsilyl chlorideTLCThin Layer ChromatographyTMGATetramethylguanidinium azideTMSTrimethylsilylTMSCNTrimethylsilyl cyanide(TMS)2O2Bis(trimethylsilyl) peroxideTMSOTfTrimethylsilyl trifluoromethanesulfonateTPAPTetrapropylammonium perruthenateTPSCltert-Butylchloro diphenylsilaneTrClTriphenylmethylchloridep-TsClp-Toluenesulfonyl chloride or tosyl chloridep-TsOHp-Toluenesulfonic acidp-TsOH.H2Op-Toluenesulfonic acid hydrateUVUltra violetVLCVacuum Liquid ChromatographyZnZincZnCl2Zinc chloride

Chapter 1

Introduction

1.1 Steroids and Steroid Dimers

Steroids are a family of biologically active lipophilic molecules that include cholesterol, steroidal hormones, bile acids and plant sterols (also known as phytosterols). These metabolic derivatives of terpenes are biosynthesized by plants as well as animals including humans, and play an important role in biological systems (Li and Dias, 1997; Nahar et al., 2007a). Structurally, a steroid is a lipid molecule having a carbon skeleton with four fused rings; three fused cyclohexane rings, known as phenanthrene, are fused with a cyclopentane ring (Sarker and Nahar, 2007). The basic tetracyclic seventeen carbon steroidal ring system is known as 1,2-cyclopentano-perhydrophenanthrene or simply cyclopentaphenanthrene (Figure 1.1.1). All steroids are derived from the acetyl CoA biosynthetic pathway. The four rings are lettered A, B, C, and D, and the carbon atoms are numbered beginning in the A ring. In steroids, the B, C, and D rings always are trans-fused, and in most natural steroids, rings A and B also are trans-fused. Each member of the steroid family has a structure that differs from the basic cyclopentaphenanthrene skeleton in the degrees of unsaturation within the rings and the identities of the hydrocarbon side chain substituents, e.g., alkyl, alcohol, aldehyde, ketone or carboxylic acid functional groups, attached to the rings.

Figure 1.1.1 Cyclopentaphenanthrene skeleton (left) and trans-fused rings (right)

Even minor changes in the functionalities attached to the steroid skeleton can lead to significant changes in their biological and pharmacological activities (Nahar et al., 2007a). That is why synthetic chemists have always been keen to carry out structural modifications of steroids to optimize their biological and pharmacological properties or to discover new properties. Steroid dimers are one of such group of modified steroids that are well known for their rigid, predictable and inherently asymmetric architecture.

Steroid dimer formation was first noticed during photochemical studies on steroids. During the investigation of the effect of sensitized light on the activation of ergosterol (1) in the absence of oxygen, it was discovered that in an alcoholic solution containing sensitizer, ergosterol on exposure to sunlight had undergone dehydrogenation to form a strongly levorotatory substance ([α]D: −209°, mp: 205 °C) having double the original molecular weight and two hydroxyl groups. This bimolecular product was named bisergostatrienol (2) (Scheme 1.1.1) (Windaus and Borgeaud, 1928). Since this discovery, several dimeric steroids have been found in nature, particularly from marine sponges, and also have been synthesized in the laboratory (Nahar et al., 2007a).

Scheme 1.1.1 Conversion of ergosterol (1) to bisergostatrienol (2)

Steroid dimers can be classified broadly into acyclic dimers (also known as ‘linear dimers’) and cyclic dimers (Figure 1.1.2). Acyclic dimers involving connections between A, B, C or D rings, or via C-19, direct or through spacers, form the major group of steroid dimers (see Chapter 2). In the cyclic steroid dimers, dimerization of steroids, direct or through spacers, leads to formation of new ring systems or macrocyclic structures, e.g., cyclocholates or cholaphanes, respectively (see Chapter 3). Steroid dimers can also be classified as symmetrical and unsymmetrical dimers; when a dimer is composed of two identical steroid monomeric units, it is called a symmetrical dimer, and when two different monomeric steroid units are involved or two identical monomeric steroid units are joined in a way that there is no symmetry in the resulting dimer, the dimer is known as an unsymmetrical dimer (Figure 1.1.2). One other way of classifying steroid dimers is to divide them into natural and synthetic dimers (Figure 1.1.2).

Figure 1.1.2 Classification of steroid dimers

1.2 General Physical and Spectroscopic Properties of Steroid Dimers

In general, like most monomeric steroids, steroid dimers are lipophilic in nature and are not water soluble. However, depending on the monomeric steroid, spacer group or other functionalities present on the dimeric steroid skeleton, the solubility of such molecules can be quite variable. For example, steroid dimers composed of two sterol (steroid alcohol) units where the hydroxyl groups are not altered, as in bisergostatrienol (2), will retain some degree of polar character due to the hydroxyl groups, while keeping its nonpolar or hydrophobic nature because of the ring systems and other alkyl substituents or aliphatic side chains, and thus, these dimers will have properties like amphipathic lipids.

Most dimeric steroids are solids and can be transformed into well-formed crystals from various solvents (see Chapters 2 and 3), e.g., bis[estra-1,3,5(10)-trien-17-on-3-yl]oxalate (3) was crystallized from CHCl3-EtOAc (2:1) (Nahar, 2003).

The melting points of steroid dimers are quite variable and depend on the monomer, the spacer groups and other functionalities. The UV absorption spectra of steroid dimers depend on the presence or absence of chromophores, e.g., conjugated double bonds. The IR spectra can be different from dimer to dimer based on the functional groups present. Details on these spectral data of various steroid dimers will be presented in Chapters 2–5. Like the monomeric steroids, the dimeric steroids have several chiral centres in the molecule that make these molecules optically active. Therefore, specific rotation [α]D data can provide additional characteristic information for any dimer.

To determine the molecular weight and molecular formula of steroid dimers, it is often essential to employ soft ionization techniques like fast-atom bombardment (FAB), electrospray ionization (ESI) or chemical ionization (CI) mass spectroscopy. The use of the MALDI–TOF technique has also been observed for some dimers very recently. MS information is particularly important for the symmetrical dimers composed of two identical steroid momoners without any spacer groups, where the information obtained from the nuclear magnetic resonance (NMR) spectroscopy may not be adequate to confirm the structure.

A range of 2D NMR techniques, particularly, correlation spectroscopy (COSY), nuclear Overhauser spectroscopy (NOESY), heteronuclear multiple bond coherence (HMBC) and heteronuclear single quantum coherence (HSQC), could be useful to confirm the structures of a number of dimeric steroids (Nahar, 2003; Nahar and Turner, 2003; Nahar et al., 2006, 2007b). Sometimes, the use of the rotating frame Overhauser effect spectroscopy (ROESY) could be useful in establishing the relative stereochemistry, as in the case of crellastatins (D'Auria et al., 1998; see Chapter 4). Fuzukawa et al. (1996) used -HMBC NMR technique to determine the orientation of the steroidal units about the pyrazine ring in ritterazine A (4). However, the use of the -HMBC NMR technique is rather limited.

1.3 Chromatographic Behaviour of Steroid Dimers

Most steroid dimers are nonpolar in nature and can be separated by normal-phase column, flash or thin layer chromatography (FCC or TLC) on silica gel (SiO2) as the stationary phase and using various solvent mixtures, e.g., n-hexane-EtOAc or CHCl3-MeOH, as the mobile phase or eluent (Nahar, 2003). However, alumina or celite as the stationary phase has also been utilized for the separation of several steroid dimers.

On the TLC plates, steroid dimers can be detected by I2 vapour, or using various sprays reagents, e.g., vanillin-H2SO4 and Liebermann–Burchard reagents. For the detection of steroidal alkaloid dimers, e.g., cephalostatin 1 (5), any alkaloid-detecting reagents, e.g., Dragendorff's reagent, may be used.

The use of the reversed-phase high-performance liquid chromatography (HPLC) can equally be useful, and generally, MeOH-H2O or MeCN-H2O as the mobile phase, and a C18 reversed-phase column as the stationary phase can be used (Nahar, 2003). However, for the purification of some cephalostatins and ritterazines, a C8 reversed-phase column was reported to be used (see Chapter 4).

In some cases, for the initial separation of naturally occurring cytotoxic steroid dimers, e.g., cephalostatins or ritterazines, solvent partitioning methods and droplet countercurrent chromatography (DCCC) have been regularly employed (see Chapter 4).

1.4 Applications of Steroid Dimers

Dimerization of steroid skeleton renders some unique characteristics that are applicable to different areas. Dimeric steroids have miceller, detergent, and liquid-crystal properties, and have been used as catalysts for different types of organic reactions. A number of dimeric steroids, e.g., cephalostatins [e.g., cephalostatin 1 (5)], are among the most potent natural cytotoxins. It has been suggested that a polyamine dimeric steroid binds to DNA due to the presence of two parts, one hydrophilic (positively charged nitrogen) and the other is hydrophobic steroid skeleton. Steroid dimers have also found their applications as ‘molecular umbrella’ for drug delivery. Applications of steroid dimers are discussed further in Chapter 6.

References

D'Auria, M. V., Giannini, C., Zampella, A., Minale, L., Debitus, C. and Roussakis, C. (1998). Crellastatin A: a cytotoxic bis-steroid sulfate from the Vanuatu marine sponge Crella sp. Journal of Organic Chemistry63, 7382–7388.

Fukuzawa, S., Matsunaga, S. and Fusetani, N. (1996). Use of 15N-HMBC techniques to determine the orientation of the steroidal units in ritterazine A. Tetrahedron Letters37, 1447–1448.

Li, Y. X. and Dias, J. R. (1997). Dimeric and oligomeric steroids. Chemical Review97, 283–304.

Nahar, L. (2003). PhD thesis: Synthesis and some reactions of steroid dimers, University of Aberdeen, UK.

Nahar, L. and Turner, A. B. (2003). Synthesis of ester-linked lithocholic acid dimers. Steroids68, 1157–1161.

Nahar, L., Sarker, S. D. and Turner, A. B. (2007a). A review on synthetic and natural steroid dimers: 1997–2006. Current Medicinal Chemistry14, 1349–1370.

Nahar, L., Sarker, S. D. and Turner, A. B. (2007b). Synthesis of 17β-hydroxy-steroidal oxalate dimers from naturally occurring steroids. Acta Chimica Slovenica54, 903–906.

Nahar, L., Sarker, S. D. and Turner, A. B. (2006). Facile synthesis of oxalate dimers of naturally occurring 3-hydroxysteroids. Chemistry of Natural Compounds42, 549–552.

Sarker, S. D. and Nahar, L. (2007). Chemistry for Pharmacy Students: General, Organic and Natural Product Chemistry, John Wiley & Sons, London.

Windaus, A. and Borgeaud, P. (1928). Liebig's Annuals460, 235–237.

Chapter 2

Synthesis of Acyclic Steroid Dimers

Several steroid dimers have been synthesized over the years (Li and Dias, 1997a; Nahar et al., 2007a), and acyclic dimers involving connections between A, B, C or D rings, direct or through spacers, form the major group of such molecules. These dimers are also referred to as ‘linear dimers’. In this chapter, dimers connected via ring A–ring A, ring B–ring B, ring C–ring C, ring D–ring D, ring A–ring D, dimers via C-19 and ‘molecular umbrellas’ are discussed.

2.1 Dimers via Ring A–Ring A Connection

2.1.1 Direct Connection

Direct ring A–ring A connection between two steroid units can be achieved by using an active metal reduction or a photochemical condensation. Several dimers were synthesized from steroidal 4-en-3-one by photochemical, electrolytic, and metal reduction (Squire, 1951; Lund, 1957; Bladon et al., 1958). Squire (1951) reported the synthesis of bicholestane (5) in three steps by chlorination of cholesterol (1, cholest-5-en-3β-ol), hydrogenation of cholesteryl chloride (2, 3β-chlorocholest-5-ene) and finally the coupling between cholestanyl chloride (3, 3β-chloro-5α-cholestane) and cholestenyl magnesium chloride (4, 3β-magnesium chloro-5α-cholestane) (prepared in situ) (Scheme 2.1.1).

Scheme 2.1.1 Synthesis of 3β-chlorocholest-5-ene (2), 3β-chloro-5α-cholestane (3) and bicholestane (5)

Cholesteryl chloride (2) was first obtained from cholesterol (1) using the method described in the literature (Daughenbaugh, 1929). To a stirred solution of 1 (5.0 g, 12.93 mmol) in dry C5H5N (1 mL), SOCl2 (10 mL) was added and the reaction mixture was refluxed for 60 min (Scheme 2.1.1). After complete liberation of SO2, the reaction mixture was cooled, H2O was added, and extracted with Et2O. The etheral solution was dried (Na2CO3) and evaporated under pressure to a semicrystalline residue, which was recrystallized from EtOH and identified as cholesteryl chloride (2, 3.3 g, 63%, mp: 95–96 °C) (Daughenbaugh, 1929). Compound 2 was then utilized for the synthesis of cholestanyl chloride (3) (Squire, 1951).

To a stirred solution of 2 (630 mg, 1.56 mmol) in Et2O (15 mL) and EtOH (15 mL), PtO2 (38 mg) was added (Scheme 2.1.1). The reaction mixture was kept under 2 atm of H2 for 60 min with stirring. On completion of the hydrogenation, the reaction mixture was filtered and rotary evaporated to yield cholestanyl chloride (, 510 mg, 80%, mp: 115–115.5 °C), which was employed for the synthesis of bicholestane () (Squire, 1951).