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Synthesis of Limonoid and Steroidal intermediates Richardson, Scott Rowand 1993

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Synthesis ofLimonoid and Steroidal IntermediatesByScott Rowand RichardsonB.Sc., The University of Alberta, 1990A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE STUDIES(Department of Chemistry)We accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIAOctober 1993© Scott R. RichardsonIn presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)Department of C- /74'71(57 -/QThe University of British ColumbiaVancouver, CanadaDate (2.4 /5 1/ /93DE-6 (2/88)AbstractThe cyclopentyl intermediate 4 is an easily obtained, highly enantiopure startingmaterial for the synthesis of numerous triterpenoids. Prepared from (+) -endo-3 -bromocamphor (2) in a four-step sequence, 4 has been converted into two advancedtriterpenoid intermediates.In an eleven-step sequence 4 was transformed into the bicyclic intermediate (42) thatcould be used in an enantiospecific approach to the limonoids. The enone 42 wassubsequently dialkylated in a regio- and stereoselective manner to produce the intermediate45. Removal of the silyl protecting group followed by oxidation and acid-catalysedannulation produced the tricyclic enone 53. Structure 53 represents a highly advanced ent-limonoid intermediate with correct relative and absolute stereochemistry with obvioussimilarities to limonoids such as ent-azadirone (6).Further investigations illustrated 4's utility in the synthesis of the steroidal hydrindanesystem. Using an analogous pathway 4 was again converted to a bicyclic enone 104 in eightsteps. Regiospecific alkylation followed by medium pressure hydrogenation andepimerization yielded the hydrindane 110. Extensive NMR analysis of this compound wasused to provide conclusive evidence of 110's absolute stereochemistry. This route istherefore potentially useful in an approach to natural products such as la, 25-dihydroxyvitamin D3 (58).ii6HOCO211Br2 4OMeOTBDPS 45104OTBDPS 1105853Table of ContentsAbstract ^iiTable of Contents ^ivList of Abbreviations ^vAcknowledgements ^viiiDedication ^ixGeneral Introduction ^1Chapter 11.1^Limonoid Introduction ^51.2^The Biosynthesis of the Limonoid System ^81.3^Previous Synthesis of the Limonoid System  ^101.4^Discussion ^16Chapter 22.1^Stereoselective Synthesis of the Steroid B,C,D RingSystem ^322.2^Discussion ^44Experimental ^53References ^87Appendix A ^92Appendix B ^93ivList of AbbreviationsAcOH^acetic acidAnal. microanalytically determined mass %APT^Attached Proton Test ( 13C NMR)aq aqueous solutionb^broad absorption (IR)nBu normal butyltBu^tertiary butylCalc. Calculated mass %Calc. Mass^Calculated exact Masscat.^catalytic amountconc. concentratedCSA^camphorsulfonic acidd doublet (NMR); daysdAB^AB doublet, i.e. one branch of an AB quartet (NMR)DEAD diethyl azodicarboxylateDHP^dihydropyranDIBAL diisobutylaluminum hydrideDIPA^diisopropylamineDMF dimethylformamideDMSO^dimethyl sulphoxideent-^ enantiomer (of)eq. equivalent (s)Et^ethylEt20 diethyl etherEt3N^triethylaminevviEtOAc^ethyl acetateEtOH ethanolGC^gas liquid chromatographyh hoursH^proton(s) (NMR)HetCor^heteronuclear correlation ( 13C, 1 H NMR experiment)He cis protons (NMR)Ht^trans protons (NMR)IR infrared spectrumJ^coupling constant (Hz) (NMR)J-resloved^resolved coupling constant (NMR experiment)m^multiplet (NMR)m/z mass to charge ratio (Mass Spec.)M+^molecular ion (MS)Me methylMeas. Mass^exact mass determined by high resolution MSMe0H methanolmin^minutesmm millimeters of mercury (distillation pressure)MMC^magnesium methyl carbonateMS mass spectrumn-^normal (primary)NaHS 03^sodium bisulfiteNMR nuclear magnetic resonance (spectrum)NOE^nuclear Overhauser effectNuc-^nucleophileviip^pentetPDC pyridinium dichromateppm^parts per million (NMR)q quartet (NMR)rt^room temperatures singlet (NMR); strong absorption (IR)sat.^saturated solution (aqueous)Si02 silica gelt^triplet (NMR)t- tertiaryTBAF^tetra-n-butylammonium fluorideTBDPS t-butyldiphenylsilylTFAA^trifluoroacetic anhydrideTHE tetrahydrofuranTig-^tigloyl ((E)-2-methyl-2-betenoyl-)TLC thin layer chromatographyp-TsOH^p -toluenesulphonic acidX-ray X-ray crystallograph[a]r^specific rotation at 589nm at T 0C8 chemical shift (ppm) (NMR).1)^absorption wave number (cm -1 ) (IR)AcknowledgmentsI would like to thank Mike Wong for his excellent advice in many areas of this thesis.His advice on experimental procedure and his editorial skills have been greatly appreciated.Monica Palme also deserves acknowledgement as she has been the source of insightful andvaluable comment with respect to the writing of this thesis.I would also like to thank S. Rak (glass blowing) and the mechanical and electricalworkshops for their prompt and talented repair of laboratory equipment. I would also like tothank, collectively the spectral services of the U.B.C. chemistry department for theirassistance in the analysis of the products reported in this thesis.Finally, I would like to thank Professor Thomas Money for making my graduateschool experience as enjoyable as it has been. From the discussion of current research to thehistory of organic chemistry, Dr. Money has made the past several years as entertaining asthey have been educational.viiiDedicationI dedicate this thesis to my parents,Patricia and Ronald Richardson,for their answering of my first questions and later fortheir encouragementand support in seeking answers to others.ix5 4 3(-)-camphor (ent-1)General IntroductionCamphor (1) is a naturally occurring monoterpenoid that is commercially available inboth enantiomeric forms. An important feature of camphor is the availability of procedures 1for the regiospecific functionalisation of the molecule at C(3), C(5), C(6), C(8), C(9) orC(10) position. (Scheme 1)1The mechanisms of some of these transformations have been fully investigated and describedin recent publications.la.b In general they are often the result of multiple Wagner - Meerweinrearrangements.Br;S. Br 0. 5.,..Br/'Br013r0^Br0^0 /^ 0BrScheme 1/v.' HO----v."HO(+)-9-bromocamphor (-)-dilrodysinin4, 0i‘%.^-------(+)-9,10-dibromocamphor CO2HBr0(-)-8-bromocamphor.----------"Ir'-----------A...(+)-8-bromocamphorCN'' \CH0—."" -1.1- `%•* 0/--)H^0,./vitamin B12 intermediate3R'0 H OR HMe02C^ ...'"CO2MeIllih. NOH(-)-9-bromocamphor-11111.- --MP-Br--ill.- -DI.-The potential utility of camphor as a chiral starting material is not immediatelyobvious. In fact, retrosynthetic analysis of only a few natural products would lead to(+)-longifolene7Scheme 22-310.- -ill■-3 4 5.-'.Br 2.-'7camphor as an obvious starting material. To illustrate this point a selection of synthetictransformations is given in scheme 2.The investigations reported in this thesis explore the utility of camphor as anenantiopure starting material in a synthetic route to the ent-limonoid (6) and steroid (7)Scheme 3systems. Beginning with the commercially available (+)-endo-3-bromocamphor (2), (+)-9,10-dibromocamphor (3) is easily prepared in multi-gram quantities using a three stepreaction sequence. The key reaction in both of the investigations reported is the Grob-typefragmentation of 3 1 e yielding the hydroxy-acid (4). 1 f It should be noted that this compoundpossesses absolute stereochemistry [at C(13) and C(17) position] that is appropriate for itssubsequent use in triterpenoid and steroid synthesis. (Scheme 3)For convenience, commercially available (+)-endo-3-bromocamphor (2) was used asa starting material in both investigations as both syntheses share a common intermediate, theenone ester (5) . Although (+)-endo-3-bromocamphor (2) yields the ent-series of thelimonoids (6), the work presented is valid as a synthetic route to the natural series of3compounds because (—)-endo-3-bromocamphor (ent-2) can be easily synthesised from (—)-camphor (ent-1).The ent-limonoid (6) and steroid (7) systems are structurally similar and during thisdiscussion particular carbon centres will be referred to by the steroidal numbering systemshown in structures 6 and 7. The convention of ring nomenclature (A through D) will alsobe used throughout this thesis.4256^ 7The first chapter of this thesis describes efforts to develop a simple synthetic route toa potentially useful intermediate in ent-limonoid synthesis. The second chapter discussesrecent approaches to a key intermediate for steroid synthesis.1.1 Limonoid Introduction: The limonoids are a large complex family of natural products that exist in relativelylarge concentrations in many citrus plants. Limonin (8), which lends its name to this familyof compounds is the bitter principle of citrus fruits and was the first of the limonoids8to be isolated. 9 Though limonin (8) was isolated some 150 years ago, its structural andstereochemical complexity was not fully elucidated until 1960. 10 Barton, Robertson, andtheir respective co-workers independently, over a three year period, determined the correctconstitution of limonin. Barton and co-workerslOa approached the problem through classicalspectroscopic analysis (IR, UV, NMR and mass spectrometry) of limonin and productsproduced by the systematic degradation of limonin. Their structural assignment was inagreement with the result obtained by Robertson and co-workers, 10b who used X-raycrystallography to determine both the relative and absolute stereochemistry of limonin.These results stimulated a great deal of interest in this family of compounds. Therelative abundance and obvious complexity of the limonoids were ideal challenges forchemists interested in structure elucidation. 11 a-c A recent review, for example, lists justunder 300 fully characterized limonoids found in the Meliaceae family of plants. 11aThe limonoids are defined by several common characteristics: i) they aretetranortriterpenoids [ i.e. they are formed by the loss of a four-carbon unit from the normal5apo-eupholof the triterpenoid side chain and iii) they often contain lactone rings formed by thebiological equivalent of the Baeyer-Villiger oxidation reaction on ring A and ring D ketones.Some representative examples of limonoids are shown above. These examples have beenchosen to illustrate some of the structural complexity and diversity found within this group ofnatural products.Structure-activity relationships in the limonoids are not well understood. It is knownthat many, if not most, limonoids are powerful insect anti-feedants 12 but the specifics of theinsect-limonoid interactions are not known. The large number of limonoids present in theseplants (albeit in small concentrations) appears to offer a very good chemical defense systemagainst insect predators. Feeding studies have shown that although indigenous insects areable to adapt to specific anti-feedants, the sheer number of different limonoids present inthese plants ensure adequate protection. Early investigations on the biological activity of thelimonoids attracted interest with respect to their possible use in chemotherapy. However6limonoids attracted interest with respect to their possible use in chemotherapy. HoweverJolad and co-workers have reported limited success in the use of these compounds aschemotherapeutic agents. 13 The limonoids remain a novel yet synthetically unexploredfamily of compounds.71.2 The Biosynthesis of the Limonoid System: As the number of known limonoids increased, speculation on their biosynthesis wasinevitable. The limonoids are believed to be biosynthesised by structural modification ofeuphol (11) or tirucallol (12). As shown in scheme 4, euphol (11) and tirucallol (12) areformed by cyclisation of squalene epoxide (9) in the chair-chair-chair-boat conformation.This conformation ensures the relative orientation of the methyl groups and hydrogen atomsat the various ring junctions, which then are able to undergo a series of 1,2-shifts to attain alimonoid-like structure. There is some evidence to support the specific proposal that thelimonoid biosynthesis involves rearrangement of an epoxide (13 or 14) derived from euphol(11) or tirucallol (12) 14 to provide apo-euphol (15) or apo-tirucallol (16) derivatives withstructure and stereochemistry appropriate for its subsequent conversion to the limonoids.Although the biosynthetic route from the parent triterpenoid(s) (15 and/or 16) toindividual limonoids has not been determined, it seems obvious that the overalltransformation involves a series of recognisable reactions. For example, a commonbiosynthetic process is the partial oxidative degradation of the C(17) side-chain in thetriterpenoid precursor to produce the characteristic C(17) furan ring that is common to alllimonoids. Other biosynthetic transformations likely to occur are epoxidations, allylicoxidations and the biological equivalent of the Baeyer-Villiger reaction. The latter processproduces A-ring and D-ring lactones that are a common structural feature to thesecompounds. Protolimonoids [e.g. grandifoliolenone] are intact triterpenoids with highlyfunctionalised side-chains that are likely biological precursors of the limonoids. They exhibitthe basic tetracyclic ABCD ring structure of the limonoids along with the properstereochemistry at the various ring junctions.811 ; euphol [20R]12 ; tirucallol [20S]H HPROTOLIMONOIDS(cf. grandifoliolenone)15 7a-hydroxy-apo-euphol [20R]16 , 7a-hydroxy-apo-tirucallol [20S]ftOHOHVLIMONOIDSScheme 491.3 Previous Synthesis of the Limonoid System: Possessing structural and stereochemical complexity, triterpenoids in general havebeen popular target molecules to showcase synthetic organic methodologies ever since thesynthesis of (±)-lanosterol was reported by Woodward, Barton and co-workers in 1957. 15Yet despite the numerous reviews outlining the isolation and structural elucidation of manylimonoids since 1960 there has only been one reported synthetic approach to the limonoidsystem. 16*Examination of the tetracyclic structure of the non-lactonic limonoids (e.g. ent-azadirone, 6, scheme 3) leads to the conclusion that synthesis of the basic framework couldbe accomplished by methods similar to those previously used in steroidal and triterpenoidsynthesis. (scheme 5) The three examples given below illustrate disconnections that havebeen used in the complete synthesis of various tetracyclic triterpenoids. The specifics ofthese approaches will not be discussed further, yet they do illustrate retrosynthetically severalplausible routes to a complete limonoid synthesis.10* After the completion of this thesis a communication was published which outlined another approach to thelimonoid system. It has been presented in Appendix B without commentref. 17a>^6s5ref. 17b >^rsssPssf) ^ref. 17c c11>Scheme 5In the only reported synthetic approach to the limonoid system, Corey and co-workers, however, used a biomimetic-type route (scheme 6) in which the key step was thestereoselective cyclisation of enol phosphate 18. This compound was prepared by thereaction of farnesyl bromide (17) with the dianion derivative of methyl acetoacetate 18,followed by the capture of the intermediate enolate with diethyl chlorophosphate. Cyclisationof 18 was promoted by mercuric trifluoroacetate and produced the tricyclic 0---keto-ester (19)in an isolated yield of 27-30 % over three steps. This cyclisation process therefore producedthe correct stereochemistry at the AB and BC ring junction. [Note: the stereochemistry isonly correct in a relative sense as the cyclisation produces a racemic product.] OP0(0E0212CO2Me iiiCIHg17 18 19i) LiCH2COCH(M)CO2Me, THE ii) C1P0(0Et)2, CH2Cl2 iii) Hg(02CCF3)2, CH3NO2Scheme 6The chloromercurio functionality in compound 19 was photolytically replaced with aphenylselenenyl group which was then oxidatively eliminated with MCPBA to provide olefin20. (Scheme 7) The (3-keto ester (20) was then converted to an enol phosphate and themethyl ester group was reduced with DIBAL to yield phosphoenolate 21.OPO(0C2H5)2CH2OHCIHg19^20^21i) PhSeSePh, CH2C12 ii) hu iii) NaH, CIP(0)(OEt)2 iv) DIBALScheme 7In a typical Michael reaction a nucleophile is added in a conjugate manner to an enonesystem. In Corey's synthetic route, the phosphoenolate (21) is converted in situ to enone21b under basic conditions. A reasonable description of bond rearrangements involve an21bScheme 922ii13^0.,f1.,60-Et^ 0PZ-OEt 0,II^0,ZH^*---1 P^---0Et..,, a)Base'21^ 21aScheme 8intermediate cyclic enol phosphate (21a). The formation of enone 21b in the presence of thesodium salt of 3-(2-nitroethyl)-furan resulted in a Michael reaction to provide the nitroketone(21c). A Nef reaction then converted nitroketone (21c) to the diketone (22) and base-catalysed aldol condensation provided the pentacyclic enone (23). (Scheme 9)(i) 12 N HCI, ethanol (1:3.3), 10°C(ii) 1M NaOEt, EtOH, 56°CAt this point the basic carbon skeleton was complete except for the angular methyl atthe C(13) position. Steric hindrance precluded the use of conjugate methylation of the enone(23); numerous organocopper reagents with and without electrophilic promoters failed to addin the desired conjugate manner. Cyclopropanation of the A 13,17 double bond andsubsequent cleavage would introduce this methyl group; however without a directinghydroxyl group (Simmons-Smith reaction) limited control of stereochemistry is likely. L-Selectride reduction of the enone resulted in formation of an allylic alcohol (24) with a (3—oriented hydroxyl group. (Scheme 10) This, however, is the opposite stereochemistryrequired for a hydroxyl-directed Simmons-Smith 13-cyclopropanation. Therefore 24 wasconverted to the a-hydroxy compound (25) by the Mitsunobu DEAD inversion technique(50% yield). Hydroxyl-directed stereoselective cyclopropanation of (25) then occurred toproduce (26) in 89% yield. Oxidation of the tetracyclic alcohol (26) followed by dissolvingmetal reduction (Li, NI-13) resulted in cleavage of the cyclopropyl group and production of theadvanced limonoid intermediate (28). (13% yield overall)14i) L-Selectride, THE (ii) a) benzoic acid, triphenylphosphine, DEAD b) KOH, EtOH(iii) Melt, Zn-Ag, 0°C, Et20 (iv) PDC, 3A mol. sieves CH2C12 (v) Li, NH3, -78 °CScheme 10This synthetic approach to the limonoids remains unfinished, although futurepublications from Corey's group can be anticipated. Nonetheless, this synthesis illustratesthe advantage of using biosynthetic ideas to devise synthetic strategies for complex carbonskeletons.15azadirone eupholHOent-3161.4 Discussion: The particular research reported in this chapter stems naturally from previousinvestigations in our laboratory. It was previously established that the Grob-typefragmentation of 9,10-dibromocamphor (ent-3 or 3) 1 e gave the hydroxy acids (ent-4 or 4). 1 fThey were immediately recognized as a potentially useful synthetic intermediates for thesynthesis of steroids and tetracyclic triterpenoids. (Scheme 11)Scheme 11Since hydroxy-acid 4 is more conveniently accessible than its enantiomer (ent-4) theformer compound was used as a common enantiopure intermediate in the limonoid projectand the steroid project (to be discussed in the following chapter). Specifically, 4 was seen asan enantiopure starting material from which an enantiospecific synthesis of the ent-limonoidC,D ring system could be based. With two stereocentres exhibiting the correct absolutestereochemistry, it was envisioned that the subsequent alkylations and annulations could beBr2 29 30achieved stereoselectively resulting in the highly stereoselective synthesis of an advancedlimonoid intermediate.(+)-9,10-Dibromocamphor (3) 1 e is readily available from (+)-3-bromocamphor (2)through a series of bromination and debromination reactions. (Scheme 12) The mechanismsproposed for the individual steps involve a combination of Wagner-Meerwein rearrangementsand 3,2-exo-methyl shifts. The particulars of these reactions will not be addressed here asthey have been dealt with extensively in previous theses and their resultant publications.'The debromination of (+)-3,9,10-tribromocamphor (30) can be explained by Zn acting as aLewis base, complexing with the carbonyl's oxygen and causing a displacement of bromineat C(3). Protonation of the zinc enolate and tautomerization of the resultant enol readilyyields (3).17Zn, HOAcEt20.13rB0^ r3Scheme 12Ring cleavagelf of (+)-9,10 dibromocamphor (3), however, is central to the researchthat will be described in this thesis and is conveniently accomplished in the following way.(Scheme 13) Treatment of (+)-9,10-dibromocamphor (3) with KOH in DMSO:H20 (5:1) atroom temperature for one hour produces bromo-acid (3a). When this reaction is carried outat 65°C for 24 hours the product is hydroxy-acid (4). TLC evidence indicates that during31H2 , heatHO-3 3aHO70%CO2HKOH, DMSOthis conversion a stable intermediate does exist. If the fragmentation is carried out underanhydrous conditions the 'stable intermediate' described above is the only product which isisolable. Analysis of the intermediate and structural confirmation by X-ray crystallography 19indicates that it is the lactone 31. The proposed mechanism illustrated in scheme 13 alsohelps to explain the unusual observation of hydroxide substitution of a neopentyl bromide.184Scheme 13Indications by TLC suggest that the conversion (+)-9,10-dibromocamphor to hydroxy-acid(4) is quantitative; however, the isolation of this compound is complicated by its solubility inwater. Optimum yields were obtained when numerous (>5) solvent-solvent extractions wereincorporated into the work-up procedure.Subsequent reaction of acid 4 with methyl iodide in the presence of K2CO3 yields thehydroxy-ester (32) as an easily purified oil. (Scheme 14) Swem oxidation 20 of thehydroxy-ester readily provided the aldehyde (33), and reaction of this compound with thestabilized trimethyl phosphonoacetate anion led to the trans-a,(3-unsaturated ester (34). 21This elaboration of the hydroxy-acid (4) has achieved several objectives. The esterification atC(21) allows for a future enolate alkylation in the preparation of the furan ring, and theWadsworth-Emmons (33 ->34) reaction has introduced the precursor to ring C.CO2Me19CO2Me333435i)^HO32Me02Ci) K2CO3, Mel, DMF ii) (C0C1)2, DMSO; Et3Niii) NaH, (Me0)2P(0)CH2CO2Me, THEiv) Mg, Me0H v) KOH, Me0H, H2Ovi) TFAA, CH2C12HOCO2H CO2Meii)Me02Cv)5Scheme 14Prior to cyclisation of ring C, reduction of the 0(43-unsaturated ester (34) wasrequired. This reduction could have been achieved through several methods, but obviouslythe other functionalisations of the molecule limited the possible choices. Dissolving metalreductions would have likely caused the reduction of the C(21) ester to the alcohol, whereascatalytic hydrogenation would have destroyed the exocyclic double bond. a,13-Unsaturatedesters, however, can be selectively reduced when treated with magnesium in dry methanoland this methodology was used to convert 34 to 35. 22 Work-up of the reaction mixtureentailed acidification, followed by immediate extraction of the diester into an organic mediumto avoid isomerization of the exocyclic double bond.Hydrolysis of the isolated diester (35) was readily achieved through treatment withKOH, Me0H and H2O. However in repetition of this work it was found convenient not toisolate the diester (35). Instead, 35 was directly hydrolysed by quenching the reactionmixture from Mg/MeOH reduction with 5 equivalents of KOH dissolved in a sufficientamount of water so as to allow efficient mixing of the resultant slurry.Cyclisation of diacid (36) to produce ring C was now possible. 23 (Scheme 15)Treatment of 36 with TFAA in methylene chloride followed by removal of solvent andaddition of anhydrous methanol and a catalytic amount of p-TsOH provided the hydrindenone5. It is likely that in this reaction the initial cyclisation product is the mixed anhydride (36b),and is subsequently converted to the methyl ester.Scheme 15Hydrindenone (5) has considerable potential as an intermediate for the synthesis oflimonoids and steroids. Its evaluation as an intermediate in limonoid synthesis is describedbelow.The limonoids' characteristic furan ring, like furan rings in general, are known to beacid sensitive. As a result we decided to elaborate this structural sub-unit at a later stage in20CO2Meii)—0—CO2Mei) 5i) PPTS, ethylene glycol, C6H6, 90°Cii) LDA, methyl bromoacetate, THE[38-95%, 39 —5%]the synthesis. It was convenient at this point, however, to establish the basic carbonframework of the furan ring. This was accomplished by the conversion of the enone ester(5) into the ketal ester (37), and the alkylation of 37 with methyl bromoacetate.28 (Scheme16) This provided the diastereoisomers 38 and 39.21Scheme 16As expected (see below) this alkylation occurred stereoselectively. Although the stereo-centre created in this reaction will be removed later by the formation of the furan ring thisreaction provides a useful way of introducing stereochemistry at the C(20) centre for otherrelated structures, such as steroidal side chains. NMR analysis of the resultant diestersuggests that the stereoselectively of the reaction produces a — 19:1 mixture of 38:39 asindicated by integration of the appropriate peaks (A slight twinning of the angular methylsignal (1.05 ppm) was noted and expanded to measure the relative proportion of 38 to 39).Similar alkylations reported by our research group are consistent with theseobservations. 24,28The stereoselective alkylations of ketal ester (37) can be explained in the followingway.26 As shown below the ester enolate (37a) can adopt a conformation in which thedouble bond eclipses or nearly eclipses the a hydrogen at C(17). The electrophile (E+) thenapproaches the enolate preferentially from the least hindered face (as illustrated). Clearly theleast sterically congested face of the molecule is that on which the C(16) methylene groupresides (re-face), as the si-face attack would require the electrophile to accommodate aquaternary carbon at C(13).22OMe• re-face37aWith the ketal diester (38) in hand, reduction with LiAIH4 provided ketal diol 40.27(Scheme 17) Infrared spectroscopy showed the expected emergence of a strong hydroxylpeak centered at approximately 3340 cm -1 and the disappearance of the carbonyl peak at1733 cm-1 . The hydroxyl groups were then protected as the corresponding methyl ethers(41). Spectral proof of structure 41 was most apparent in the NMR spectrum as there was adisappearance of a very broad singlet at 2.85 ppm, which integrated to two hydrogens (2 xOH) and the emergence of two 3H singlets at 3.27 and 3.30 ppm (2 x OMe). Subsequenthydrolysis of the ketal yielded enone 42. NMR analysis showed the disappearance of theketal hydrogens (4H, m, 3.36 - 3.45 ppm), and a strong carbonyl peak at 1665 cm -1 in theIR spectrum consistent with what is expected for an a,13-unsaturated carbonyl.23OHOHii)3 8 40i) LiA1H4 , THF ii) KH, MeI, THFiii) IN HC1, acetone42Scheme 17Retrosynthetically it was observed that ring B of the limonoids could be synthesizedthrough an intramolecular aldol condensation (scheme 18) involving compound 52.Therefore the dialkylation of enone 42, suitable for this elaboration, was our next majorobjective.Scheme 1842OROR'It was reasoned that the methyl and the n-pentyl groups at C(8) of compound 52could be added by successive alkylations of the thermodynamic dienolate of 42. Thestereochemistry would be dictated by the 1,3-interactions of the angular methyl group [C(18),steroidal numbering] with the second of the two alkylating agents added. The first alkylatingagent would add producing a planar a-substituted a,13-unsaturated carbonyl. The secondalkylation would produce a spa center a to the carbonyl at the C(8) position moving thedouble bond out of conjugation. The stereochemistry at the C(8) center would depend onwhich face of the dienolate would be attacked by the second alkylating agent. In the dienolate43a, the C(18) methyl group was seen to present significant steric hindrance along the (3-faceof the molecule.(Scheme 19) Therefore it was assumed that the second alkylation(methylation) would occur preferentially from the a-face producing the requiredstereochemistry.Scheme 19The obvious choice for the n-pentyl alkylating agent, in view of the retrosyntheticanalysis presented in scheme 18, was an appropriately protected 1-iodo-3-pentanol (50).24The choice of iodo-alkane (50) was determined by consideration of the alkylating tendencies(to be discussed later) of the various alkyl halides and the stability of the ten-butyldiphenylsily129 ether. The procedure used to synthesize 50 is outlined in scheme 20.The spectral detail of the compounds shown below agree favourably with a similar compound(TBDMS ether) reported by Mander and co-workers. 30,./.....,...„,....,C1^ii)OH CIOTBDPS 4 947^ 48i) LiAIH4, THE ii) TBDPSCI, NEt3 iii) NaI, acetone, reflux 72 h........--..„.......„,"...........„, I^50OTBDPSScheme 20Based on literature precedence we expected that a-alkylation of enone 42 with theelectrophilic iodo-alkane (50) may not occur in high yields. 30 (Scheme 21) A review of theliterature shows that alkylations of this type (1,2-additions of dienolates) rarely produceyields greater than 70 %. 31 Specifically, to achieve the intended alkylation (42 -> 43,scheme 16) the thermodynamic enolate must be formed, C-alkylation must predominate over0-alkylation and dialkylation must be avoided.2542 OTBDPS44OTBDPS43IOTBDPS5042a 42bOMeOMe\^ OMeOMe(0Scheme 21It is known that, in the presence of NaH/DMSO, conjugated enones are converted tothermodynamic dienolates. As DMSO has a pK of —35 and the enone a-protons have a pKof —25 any proton abstraction by the dimsyl sodium base is essentially irreversible.However, the reaction with DMSO to form the dimsyl sodium is slow 34 and as a result, theeffective concentration of the dimsyl sodium in solution is low relative to that of the substrateenone. Thus the initially formed, kinetic dienolate (42a) can equilibrate with the more stable,thermodynamic dienolate (42b) via the unreacted enone (42).Under these reaction conditions it was found that a reaction time of — 2 hours was sufficientto form the thermodynamic enolate exclusively as the reaction of the dienolate 42 with iodo-alkane 50 produced no C(11) alkylation product.26The use of dimsyl sodium/DMSO served another purpose as DMSO has excellentsolvation characteristics. DMSO is a polar aprotic solvent and is able to solvate the sodiumcation extremely well, yet is unable to effectively solvate the enolate anion due to its inabilityto form hydrogen bonds through the 'donation' of its methyl hydrogens. 32 Consequentlythis leaves the enolate unencumbered with solvent molecules and is very reactive towardselectrophiles.Controlling C- versus 0-alkylation is another concern in achieving efficientconversion of 42 to 43. Enolate (42a or 42b) is an ambident nucleophile and thepreference for C-alkylation or 0-alkylation is best understood through the concept of hardand soft acids and bases. 33Hard and soft refer to an atom's ability to attract its valence electrons. Those atomswhich are moderately electronegative hold onto their valence electrons in a relatively tightmanner and are considered hard. Conversely those atoms which are weakly electronegativeare considered soft as their valence electrons are less tightly bound by the nucleus. [Acid andbase terminology is in the Lewis sense, where bases (nucleophiles) donate electrons andacids (electrophiles) accept electron pairs.]As enolates are ambident one must consider both the carbon and oxygen as possiblenucleophiles. The oxygen anion is considered to be hard and the carbon anion is soft due totheir respective electronegativities. With respect to electrophiles, a highly polarised carbon-halide bond decreases electron density about the carbon and its electrons become more closelyassociated with the nucleus, hence there is an increases in its hardness. A weaker or lesspolar carbon-halide bond allows for greater electron density about the carbon atom and thecarbon is regarded as soft. In a comprehensive investigation it was shown that of all leavinggroups iodide promotes C-alkylation best. 33 As the alkylating agent (50) is an iodoalkane,theory suggests C-alkylation will predominate. In our alkylation reaction of thethermodynamic enolate (42a), in fact no 0-alkylated product was isolated.27The major difficulty encountered in the alkylation of 42 was that of dialkylation. Thereaction produces a mixture of unreacted starting material as well as monoalkylated (43) anddialkylated product (44). The fact that alkylated enone (43) underwent further alkylationwas unexpected.Two possible explanations would account for this observation. The first is that thealkylating agent (50) was being added too slowly. This would allow for the alkylated enone(43) to become deprotonated by contact with unreacted enolate (42b). If the addition ofiodo-alkane (50) was slow enough an equilibrium could form between the enolate (42b) andalkylated enone (43), allowing for a substantial amount of dialkylation.The second explanation for substantial dialkylation occurring can be understood by acloser examination of the reaction mechanism (below). Upon alkylation of thethermodynamic dienolate (42b) the unconjugated enone (42c) is formed. Subsequentisomerization of the 6,y-unsaturaton may produce the more stable a,13-unsaturated enone(43, path A). However, as the initial step of this isomerization is a deprotonation of 42c'sa-proton a second alkylation is possible resulting in compound 44 (path B). Thisexplanation, though extrermely similar to the first explanation, is not the result of poorexperimental technique but rather a natural consequence of the reaction mechanism.28294 2 b R4 3 bR—I (50)(PATH B)R 4 2 c7-protonation(PATH A)base•■•••■••••41..OMe^ OMeOMe OMeR R44R43R—I^=---:^..„..--......r.".........„. IOTBDPS50The fact that some starting material (42) was recovered may be a result of hydrolysisof some 0-alkylated product during work-up. Future studies in this area will investigate thepossibility of controlling these reaction difficulties.The introduction of the a-oriented methyl group at C(8) was then addressed. Using aset of reaction conditions similar to those described in the previous alkylation, dimsyl sodiumwas used to produce the conjugated enolate (43b) and after several hours of equilibration,iodomethane was added and alkylation of the thermodynamic enolate (43b) was achieved aspredicted. (Scheme 22) The stereochemistry of this alkylation was from the a-face. AnNOE experiment was performed on compound 45. Irradiation of the C(18) signal providedno positive enhancement of the new methyl substituent introduced at C(8), and thussuggesting the stereochemistry shown for 45 is correct. The NMR spectra of this compoundis extremely complex through the 1.00 to 2.50 ppm region and identification of specifichydrogens was not possible. Therefore other irradiations were not possible in an attempt todetermine the stereochemistry of the C(8) centre.OTBDPS 45OTBDPS 43TBAF, THFOH1N He',-NI Me0H, reflux OTBDPS43 aOTBDPS43 bLittle difficulty had been expected in the deprotection of the TBDPS-protectedhydroxyl group of 45 since numerous examples of the removal of TBDPS groups have beenreported.25 In general treatment with 5 equivalents of TBAF or mildly acidic conditionsusually result in the complete removal of the TBDPS group in a few hours. However it wasfound that conversion of 45 to 51 (scheme 22) required 25 equivalents of TBAF in THEstirring at room temperature for 5 days to achieve a 70 % conversion. The amount of 45that was available at this time precluded optimization of this deprotection reaction. [ It wasScheme 2230later found that in similar systems 2 hours of reflux in 35 - 50 excess of TBAF achievedquantitative deprotection35] The availability of 51 then allowed us to attempt an oxidationfollowed by cyclisation of the resulting diketone (52) in an acid-catalysed intramolecularaldol reaction. (Scheme 22)Several attempts to obtain 52 by Swern oxidation of 51 were unsuccessful. Thesmall scale of the reaction undoubtedly had some effect on the outcome of the experiment.When a chromic acid oxidation [Jones reagent] of 51 was attempted, diketone (52) wasisolated in excellent yield. Finally the diketone (52) was refluxed in an acidic methanolsolution overnight to produce the tricyclic enone (53) in an isolated yield of >90%.Tricyclic enone 53 represents a potentially useful intermediate in the projectedsynthesis of limonoids. For example, it is hoped that dissolving metal reaction 31a followedby the Stork-Boeckman annulation procedure 31/06,37 will provide a tetracyclic enone whichcan be gem-dimethylated to yield the tetracyclic ketone (57). Elaboration of the furan sidechain unit and allylic oxidation could then provide a typical limonoid structure such as ent-azadirone (ent-4). (Scheme 23)ent-azadirone^ 57^ 56(ent - 4)Scheme 2331592.1 $tereoselective Synthesis of Steroid B.C.D Ring System:The widespread occurrence and biological importance of the steroids has stimulatedconsiderable interest in their total synthesis. Much of the recent synthetic work in the steroidarea has been concerned with the development of synthetic routes to the biologicallyimportant* seco -steroid, calcitriol (58) [syn. 1a,25 -dihydroxycholecalciferol, 1,25-dihydroxyvitamin D3]. Thus it is not surprising that a large proportion of recently publishedwork involves the development of synthetic routes to appropriate hydrindane derivatives (cf.59 and 60) that represent the C,D ring system and side chain unit of this and relatedsteroids.38-41 It is also clear that considerable importance has been given to routes thatprovide these intermediates with the correct absolute stereochemistry at C(13), C(14), C(17),and C(20).OHHO's^OH58A selection of synthetic routes to hydrindane derivatives that can serve as keyintermediates in steroid synthesis is presented in Schemes 24-27 to provide an overview ofwork done in this area. In the first of these (scheme 24), Lythgoe and co-workers reported asynthetic route to the previously known bicyclic diol (61). 38* The use of calcitriol and analogues for the treatment of osteoporosis, psoriasis and leukemiais currently being investigated by a number of research groups.3260Diol 61 was first described by Inhoffen and co-workers 39 in 1958, as a degradation productof vitamin D2 and is now commonly referred to as the Inhoffen-Lythgoe diol.33OHKey reactions in the synthetic route (scheme 24) developed by Lythgoe and co-workers are the ortho-ester Claisen rearrangement that leads to the formation of (64) and thesubsequent Claisen rearrangement of the hydroxy-lactone (65) to the dimethyl amide (66) viaa Meerwein-Eschenmoser reaction.H72 73 R . OBri_41--1xii61R=H ^70 R = H^..^viii71 R = OBnvCH2COX1 iv66 X = NMe267 X = OMe  .4----1OR68OH63Et0 OEt6264 R = C(0):: ..65 R = H^n'flitii) CH3CH2CO2H, xylene, reflux, 44h ii) Me0H, NaOMe,18 h iii) 1-dimethylamino-1-methoxyethylene,xylene, reflux, 21h iv) KOH, Et0H:H20 (1:3), reflux, 19h ; 6N HC1 2h @ 20 °C; CH2N2 , Et20v) KOtBu, C6H6, reflux, 4h; 20 °C, 16h; p-TsOH,4:1 AcOH:H20, reflux 2h; dil KOH, 16h, 20°Cvi) p-TsOH, DHP; LAH, Et20 vii) NaH, THF, imidazole, reflux, 1.5h, CS2 0.5h,MeI, 0.5h; nBu3SnH, C7H8,reflux, 21h viii) KOH, C6H6, PhCH2C1, reflux 13.5h ix) AcOBr, CC14 ; ; KOH, EtOH, 2h; 55°C x) LAH, Et20xi) H2, Pd/CScheme 24The stereochemistry of the alcohol functionality of compound 63 (a readily availableenantiopure starting material) directs the ortho-ester Claisen rearrangement that produces theproper stereochemistry at C(13) and C(17) in 64 via the mechanism illustrated in scheme 25.34RO6264 R = C(0)Ph ---165 R = H OH6335Scheme 25The Claisen rearrangement, being a concerted [3,3] sigmatropic rearrangement, proceedswith retention of configuration, transferring the stereochemistry of the a-oriented hydroxylgroup of 63 to the a-oriented substituent at C(13) (64).The f3-orientation of the benzoate group of compound 64 was used in a similarmanner to produce the trans cyclohexane derivative 66. Hydrolysis of 64 to allylic alcohol(65) followed by treatment with dimethylamino-l-methoxyethylene caused a Meerwein -Eschenmoser type reaction producing the intermediate (65a, scheme 26). Heating (65a)caused a spontaneous [3,3] sigmatropic rearrangement to the advanced intermediate 66. 65 66Scheme 26The resultant amide (66) was readily hydrolysed, esterified as the methyl ester (67) andcyclised through a base-catalysed Claisen condensation to produce the requiredstereochemistry at C(13), C(14), C(17) and C(20) [steroidal numbering] as illustrated inBir-Ti.........74i xCI^ I 171.AcO 7 9 AcO7 8x-xii.,, SiEt3I ivvi - viii...,,, SiEt377OH87% trans : 13% cisIIcstructure 68 in scheme 24. Subsequent functional group transformations as shown inscheme 24 converted 68 to Inhoffen-Lythgoe diol (61).Other approaches to the Inhoffen-Lythgoe diol (61) have also been described40a-d.As a result of its stereochemistry and functional utility, it is considered a central intermediatein vitamin D3 synthesis. One of the more interesting approaches to 61 is the biomimetic-typesynthesis reported by Johnson and co-workers in 1984.40a This involves the cyclisation ofthe enyne acetal (76) to provide a trans-hydrindane derivative (79) that can be elaborated byan ene reaction and subsequent stereoselective reduction to the Inhoffen-Lythgoe diol (61)(61).i) BuLi, THF ; Et 3SiCH2OTf ii) NaCH(CO2Me)2, EtOH ; LiC1, DMSO, H2Oiii) DIBA1, THF^iv) 2S,4S-pentanediol, THF, oxalic acid, Linde 4A sievesv) TiC14 , CH2C12, 2,4,6-trimethylpyridine, -78° vi) PCC, CH2C 1 2vii) KOH, THF, Me0H viii) Ac 20, pyridine, DMAP, 70° ix) H2, Lindlar catalyst,Me0H x) CH2O, BF3.Et20 xi) H2, Pt02, EtOH xii) KOH, Me0H, THFHO61 Scheme 273676aThe stereochemistry achieved by the cyclisation of enyne 76 is directly related to thestereochemistry of the acetal group. The stereochemistry of the dimethyl ligand is believed toaffect the conformation of 76 prior to cyclisation. In this particular synthesis the (2S, 4S)-pentanediol was used to produce 77. [Johnson and co-workers report that ent-77 isproduced, predictably, when (2R,4R)-pentanediol is used.] Scheme 28 illustrates thepossible influence of the acetal's methyl substituents on the enyne's conformation prior tocyclisation.Et3 Si\Scheme 28The cyclic acetal assumes a chair conformation in which the enyne chain is in the equatorialorientation, minimizing 1,3-diaxial interactions.(cf. 76a & 76b) As drawn in (76b), theaxial methyl group (denoted with an asterisk) is in relative proximity to what is to becomeC(15). The conformation (76a) in which C(15) moves away from the 'offending' methylgroup (*), is the more stable and it is this conformation that defines the stereochemistry of theproduct (77).37CH2O Ac079OH61OHHAc0H2 ,cat.OHHaving established the stereochemistry of C(8), C(13) and C(14) by this cyclisationreaction, Johnson and co-workers used a stereoselective ene reaction to introduce the correctstereochemistry at C(20). (shown below)38Partial hydrogenation of the allene 77 produced the Z-isomer 78 which was then reacted withparaformaldehyde in an ene reaction giving 79. Catalytic hydrogenation and hydrolysis ofthe acetate group finally gave the Inhoffen-Lythgoe diol (61).Along with the Inhoffen-Lythgoe diol, the enedione 84 is one of the most widelyusedzlia-f enantiopure intermediates in steroid synthesis. The stereoselective synthesis ofenedione 84 was independently reported by research groups at Hoffmann-La Roche, Inc. 41aand Schering Corp. 41 b and involves the use of (S)-(—)-proline (82) as a chiral auxiliary in theintramolecular aldol condensation of monocyclic diketone 81. Hajos and Parrish 's synthesisand elaboration of 84 to an advanced steroidal intermediate is given in scheme 29.41a8439838 0S-(-)- proline 82,^MVK , H20, 5 days , 200^DMF, 20 h.^VD- ^ to-87%81S-(-)-proline, MeCN ,HC104 , 22 h.^TsOH , C6H6refluxi NaBH4 , MOH 84ii Me2C=CH2 ,BFA .Et20,H3ro4^—87-97% e.e.013u'Of16171HO2C^87crude90° ( in vacuo) , 30 min.37% CH20 (aq) , DMSO , piperidine89880ButH , Pd - BaSO4 ,Me0H , 0°0ButScheme 29By using S-(—) proline (82), the initial cyclisation is mediated by a chiral ligand present in thetransition state. It is reasoned that proline (82) reacts with the methyl ketone of 81 to form achiral enamine (81a, scheme 30), which in turn causes stereoselective annulation, giving thechiral products 83 or 84 in 87-97 % e.e.83 or 84HNc ) .„‘CO2H81aScheme 30KA cHO2C81One of the main problems associated with the elaboration of hydrindenone 84 to moreadvanced steroidal intermediates is the stereoselective reduction of the enone group toproduce the required trans-hydrindane ring system. Simple hydrogenation of the enedione(84) will produce a cis-hydrindanone.42c This is due to the fact that formation of thehydrindane involves addition of hydrogen to the less hindered convex side of the enedione(84). Hajos and Parrish were able to obtain the trans-hydrindane (87, scheme 31),however, by incorporating an acid functionality at C(8). The carboxylic acid group isthought to form a 'pseudo C ring' by hydrogen bonding with the C(9) carbonyl group andthis effectively obstructs the upper face of the molecule (86, scheme 29). Using a platinumcatalyst Hajos and Parrish hydrogenated compound 86 and obtained a P-keto acid (87) thatcould be decarboxylated to provide the trans-hydrindanone (88). In addition they alsoreported the synthesis of enone 89 from the crude (3-keto acid 87.40In more recent investigations Haynes and co-workers43a have determined that thepresence of large substituents at C(17) and C(8) [steroidal numbering] in hydrindenones (90)promote a-face hydrogenation and the formation of trans-hydrindanes.R90Haynes and co-workers have reported the synthesis of hydrindenones by using the reactionsequence outlined in scheme 31,43b which when followed by reasonably high pressurecatalytic hydrogenation produced trans-hydrindanes almost exclusively.41420HPI ' ButPhUI91:P` „ ButPhS-(+)-919^ 0IIPt But PButPh 0^ Ph94 96011P■''---- 1" But-PhO"..- P s PhButR-(-)-910I I%4V4.4*■".... F":"" But-Phsimilarly...► "...N. ••■••►0ent-94 ent-9693 95011PV ButPh0HPI 4s ButPhi) BuLi, THF, -50 ° ; propylene oxide ; BF3.Et20 ii) CSA, xylene, reflux iii) BuLi, THF, -70° ,2-methylcyclopent-2-enone ; 4-chlorobut-3-en-2-one,THF, -30° iv) H2, Pd-C, EtOAc, C5H5Nv) Ph2SiH2 , ZnC12, CuC12, (Ph3P)4Pd vi) 2% KOH, Me0H, refluxScheme 31The key step in this synthesis is the stereoselective conjugate addition of the allylic anion of achiral phosphonate ( 9 1 ) to 2-methylcyclopent-2-en-l-one to produce enone 92 as a pureenantiomer. The rationale proposed for the stereoselectivity of this reaction is the formationof the "chair-chair" ten-membered cyclic conformation of the transition state.Facial selectivity arises from the preferred axial orientation of the phenyl over that of thelarger t-butyl group. (below)43 C 0Ph I I IE+Scheme 32In this research both the natural (94 and 96) and 'unnatural' (ent -94 and ent 96)hydrindenone intermediates were synthesized by using S-(+)-91 or R-(—)-91 as startingmaterials, respectively.2,2 Discussion: Our interest in the hydrindane system is due in the part to the common structural andstereochemical features it shares with the hydroxy-acid (2) formed by the ring cleavage of(+)-9,10-dibromocamphor (4, below).44 ..,Br0^Br4Br2 4 5In the previous section several representative examples were given to illustrateapproaches that have been taken towards the synthesis of the hydrindane system. They aresimilar in that chiral ligands are used to introduce stereochemistry to otherwise achiralsystems. In our approach chiral induction is not required as our enantiopure starting material,(+)-endo-3--bromocamphor (2), is transformed into the hydroxy-acid (4) with retention ofconfiguration at the C(4) and C(7) positions [camphor numbering] (above). Thus theenantiomeric purity of our product is directly related to the enantiomeric purity of the startingmateria1.44Previous investigations in our laboratory have resulted in the development of anenantiospecific approach to enone (101; scheme 33) with the correct absolute configurationat C(13), C(17) and C(20) [steroidal numbering].24 In addition, the nature of the side-chainunit at C(20) can be pre-determined by the choice of electrophilic agent used in the alkylationof ketal ester (37).**** The biological activity of steroids is often related directly to the nature of the side chainused.i) Br2, CISO3H, 3h ii) Br2, CISO3H, 5-7 d iii) Zn, AcOH iv) KOH, DMSO, H2O, heatv)K2CO3, MeI vi) DMS0,(C0C1)2; Et3N vii) KH, (MeO)2P(0)CH2CO2Me viii) Me0H,Mg;KOH, H2O, Me0H ix) TFAA,CH2C12; Me0H x) (CH2OH)2, PPTS, C6H6, refluxxi) LDA,THF, ICH2CH2C(H)=C(CH3)2 xii) LiAlai, THF xiii) MsCI, DMAP, Et3N,CH2Cl2 xvi) LiEt3BH, THF xv) IN HCI, acetoneScheme 3345The objective of further studies in this area was the development of an amendedprocedure to provide a steroidal intermediate with the correct absolute configuration at C(8),C(13), C(14), C(17) and C(20) and with the capability of being converted to specific steroidswith structurally different C(20) side chain units. To achieve this objective ketal ester (37)(cf Scheme 33, p 45) was reduced and the resulting alcohol (102) converted to enone 104by 0-methylation and hydrolysis of the ketal protecting group.37^102^103^104i) LiAIH4, THE ii) KH, MeI, THE iii) IN HCI, acetone / H2OScheme 34Reaction of (104) with sodium hydride in DMSO followed by alkylation with 1-iodo-34-butyldiphenylsilyloxy)pentane (50) provided enone (105) in a —55% yield. The dialkylatedproduct (106) was a co-product in this reaction.46OMeNall, DMSOIOTBDPS50104105^ 106Scheme 35By analogy with the work of Haynes and co-workers 43a it seemed likely that 105would undergo stereoselective reduction to some degree. Previous studies by Haynes and107 1080/co-workers 43a showed that reduction of enone 107 could be accomplished with excellentstereoselectivity when the hydrogenation was carried out at 820 psi.(scheme 36).Subsequent epimerization of the C(8) centre was achieved by reaction with KOH / Me0H andthe saturated product (108) was obtained in good yield..„.^POPh2^ .„...^POPh2Scheme 36It was suggested by Haynes and co-workers that the stereochemical bulk of substituents atC(8) and C(17) would effectively promote a-face hydrogenation. They found that underseveral atmospheres of pressure (conditions used successfully on similar systems) substantialamounts of product with I3-face hydrogenation was formed. Since the formation of a trans-hydrindane compound seemed to require the presence of groups at the C(8) and C(17)position we considered the reduction of 105 could be expected to undergo hydrogenation atthe a-face of the enone system.47OTBDPS110OTBDPS109OTBDPS10548i) H2 (820 psi) Pd, ethanolii) KOMe, Me0HScheme 37Hydrogenation of 105 under the same conditions (820 psi, EtOH, Pd•C) used byHaynes and co-workers, followed by epimerization with sodium methoxide resulted in theformation of ketone 110. The stereoselectivity of these reactions, however, was notimmediately obvious and detailed NMR analysis and an extensive comparison of chemicalshift values reported in the literature (appendix A) eventually convinced us that thestereochemistry of 110 is indeed as indicated in scheme 37.A priori it seemed that the stereochemistry of compound 110 could be readily verifiedby a series of decoupling experiments to identify specific protons, followed by NOEmeasurements to determine the orientation of the C(8) and C(14) hydrogens relative to theangular methyl at C(13). [•3 = 0.79 ppm, s] Several factors however made thesedeterminations difficult. For example, the methylene and methine region of the NMR spectraappears as complex multiplets ranging from 1.3 to 1.9 ppm, effectively obscuring the C(14)proton signal. Also, the C(8) and C(11) protons (a to the carbonyl), at 2.0 to 2.4 ppm,exhibit complex splitting patterns due to the number of neighbouring diastereotopichydrogens, making the analysis of coupling interactions very difficult.(Spectrum 1).52.5^2.0^1 . 5^1 . 0Ju? ^3 . 5OMe4. 0PPMOTBDPS1103.049,^i^,^ ,^ 7^1^7^7^•^I^7^ -7---a .0 3 . 5^3.0^2. 5^2 . 0 1 . 5 t.0^5PP MSpectrum 1Though the C(8) proton of compound 110 appears as a well-resolved multiplet (2.03 to 2.16ppm) its orientation relative to the C(14) proton is not immediately apparent. As the C(14)proton signal is completely obscured, the C(14) and C(8) coupling interactions must beobtained solely through the analysis of the C(8) proton signal.The complete stereochemical analysis of 110 begins with the comparison of the H(8)signal before and after epimerization of 109. The splitting pattern of the signal representingH(8) is shown in spectrum 2 for both 109 and 110. As one can see they are both complexbut sufficiently different as to suggest epimerization has occurred.H8 multiplet of 109^ H8 multiplet of 11050frlwit4kSpectrum 2A NOE experiment showed that after epimerization of (109) the C(8)-H was in the f3-orientation, as a positive enhancement was observed when the angular methyl group at C(13)was irradiated. This is good evidence that after catalytic hydrogenation but prior toepimerization, the C(8)-H was oriented on the a-face of the molecule along with C(14)-H,suggesting a trans ring junction in (109) or (110). Further NMR experiments were carriedout to provide further evidence to support this conclusion.Numerous NMR experiments were carried out (including J-resolved, HETCOR, APTand a series of 1H homonuclear decoupling experiments) yet little additional information wasgained with respect to the stereochemistry of the ring junction. It was only through closeexamination of C(8)-H's splitting pattern that the stereochemistry of the ring junction couldbe inferred. One would expect that C(8)-H signal would appear as a doublet of doublets ofdoublets due to coupling with C(7)-H', C(7)-H" and C(14)-H.110^110a^110bExperimentally it was found that C(8)-H appears as a multiplet of 13 distinguishablepeaks in the 400 MHz spectrum. This is substantially more that the eight expected and maybe due to the presence of diastereoisomers (110a and 110b). The presence ofdiastereoisomers was investigated by running a simple 500 1H MHz NMR. The H(8) signalin the 500 1 H MHz NMR spectrum was then compared with the H(8) signal in the 1H 400MHz spectrum. As seen in spectrum 3 the overall symmetry of the signal in the 1H 400 MHzspectrum is different from that in the 500 1 H MHz spectrum.H8 multiplet of 110 400 MHz500 MHzSpectrum 3If the complexity of the multiplets was simply due to coupling interactions no change wouldhave been noted between the two when observed at different field strengths. Couplinginteractions and their respective magnitudes are independent of the applied magnetic field;51signal frequencies, however, are not and the frequency difference between signals willchange according to magnetic field strength. That is what spectrum 3 illustrates: an increasedseparation of the overlapping C(8)-H signals in the two diastereoisomers 110a and 110b.Careful examination of the C(8)-H multiplet in the 500 MHz spectrum indicates thatthe two diastereoisomers have signals at 2.12 ppm and 2.07 ppm. Each signal is composedof a doublet of doublets of doublets with the approximate coupling of 3.3 Hz, 9.2 Hz and13.2 Hz. All three couplings are consistent with those reported by Haynes for compound(108) [ 2.8 Hz, 9.7 Hz and 12.7 Hz] (scheme 36). The unequal coupling of C(8)-H withC(7)-H' and C(7)-H" indicates an unequal dihedral angle in the most stable conformation of(110). The larger coupling of 13.3 Hz coupling is consistent with an axial-axial relationshipbetween C(8)-H and C(14)-H. This in turn is consistent with our original assumption thatC(14)-H is in the a-orientation and is trans to the angular C(13) methyl group.At this point the NMR evidence had strongly suggested that the stereochemistry of(110) at the CD ring junction was trans. Examination of the chemical shifts of angularmethyl groups at C(13) in other steroidal systems increased our confidence. It was observedthat the chemical shift of the angular methyl group at C(13) was correlated to its relativeorientation to the hydrogen at C(14). The C(13) methyl hydrogens typically resonate at achemical shift of approximately 0.70 to 0.95 ppm when in a trans ring junction, whereas a cisring junction often showed the C(13) methyl group hydrogens resonate between 0.90 to 1.25ppM.45-52 ( Appendix A) As compound 110 exhibits a methyl resonance at 0.79 ppm it isreasonable to suggest a trans ring junction.Though this research is not complete, the results observed illustrate a simple, effectiveway of synthesising advanced intermediates for steroid synthesis.52.Experimental General ExperimentalUnless otherwise stated the following statements are implied.All reagents were of commercial grade and were used as received unless otherwisespecified. The solvents that were used were spectral grade and were purified as follows:THE and Et20 were distilled from Na/benzophenone; ata2, i-Pr2NH and Me0H weredistilled from CaH2; and DMSO and Et3N were distilled from KOH.Thin layer chromatography (TLC) was carried out under specified solventconditions using Merck 5735 Precoated Silica Gel 60 F254 on plastic backing (0.2 mm inthickness). Development of TLC plates were carried out using one or several of thefollowing methods: 12 vapour, UV light or ammonium molybdate/H2SO4. Flashchromatography was carried out using Merck Silica Gel 60 (230 - 400 mesh) and varioussolvents as noted. Radial chromatography was accomplished using SiO2 coated plates(Silica Gel 60 F254 with gypsum) at thickness of 1 or 2 mm. The chromatotron used was aHarrison Research Chromatotron® 7924T. Gas chromatography was performed using aHewlett-Packard HP5830A instrument, which was equipped with a 0.2 mm x 11 m OV-101 column. Helium was used as the carrier gas.Infrared spectra were carried out using a Bomem Michelson 100 Fourier TransformInfrared spectrophotometer, equipped with an internal standard. Samples were prepared asneat films between NaCI plates or as solutions in a NaC1 cell (0.1 mm path length). ProtonNMR was carried out on a Bruker WH-400 spectrometer (field strength 400 MHz) orBruker AMX-500 (field strength 500 MHz). Signals are reported on the 8 scale and arepositioned relative to the chloroform singlet (7.24 ppm). Low resolution mass spectrawere recorded on a Kratos MS-80 spectrometer and high resolution mass spectra wererecorded on a Kratos MS-50 spectrometer.53Elemental analyses were performed by Mr. P. Borda, Microanalytical Laboratory,Department of Chemistry, U.B.C.(+)-3,9-Dibromocamphor (29):2^29(+)-endo-3-Bromocamphor (2, 100 g, 0.43 mol) was cooled to 00C in a largeround-bottom flask and a solution of Br2 (35 mL, 110 g, 1.5 eq.) in chlorosulfonic acid(80 mL) was slowly added over 5 min. After 20 min, the ice bath was removed and thereaction mixture was allowed to warm to room temperature (1.5 h) before being quenchedby careful addition to NaHSO3 (50 g) and ice (0.5 L). The resultant yellow solid wascollected by filtration, dissolved in CH2C12 (600 mL) and the organic layer washed withsat. NaHCO3 solution (2 x 100 mL), H2O ( 2 x 100 mL) and brine (200 mL). The organicextract was dried over MgSO4, filtered and the solvent removed to provide (29) as a crudeyellow solid (230 g). Recrystallization from Me0H produced (+)-3,9-dibromocamphor(29) as a white solid (105.5 g) that was shown by GC analysis to be 85% pure. A smallsample was recrystallised from Me0H to yield a pure sample for 1H NMR analysis.1H NMR (CDC13): 8 = 1.04 (3H, s, C(10)H3); 1.12 (3H, s, C(8)H3); 1.43 - 1.58 (1H, m,C(6) endo H); 1.73 (1H, ddd, J = 16, 12, 4 Hz, C(5) endo H); 1.84 - 1.94 (1H,m, C(5) exo H); 2.19 (1H, m, C(6) exo H); 2.70 ( 1H, t, J = 4 Hz, C(4) exo H);2.29, 3.65 (2H, qAB, J = 11Hz, C(9)H2Br ); 4.57 (1H, dd, J = 4,1 Hz, C(3)H).54(+)-3,9,10-Tribromocamphor (30):55Br^ B29 30A solution of Br2 (155 g, 0.98 mol, 1.5 eq.) in chlorosulfonic acid (200 mL) wasslowly added to (+)-3,9-dibromocamphor (29)( 201.2 g, 92% purity by GC, 0.60 mol) at00C. The reaction mixture was allowed to warm to room temperature and after 4 days anadditional amount of Br2 (15 mL) and C1S03H (15 mL) were added. This was repeated onthe llth day and after a further 16 h the reaction mixture was added to a mixture of ice (600g) and NaHSO3 (150 g). The reaction mixture was extracted with CH2C12 (1 x 500 mL, 2x 250 mL) and the organic layer washed with saturated NaHCO3 solution (3 x 200 mL).The organic extracts were then washed with brine, dried over MgSO4, filtered, and thesolvent removed to provide crude (+)-3,9,10-tribromocamphor (30) as a dark brown oil(208 g; 48% pure by GC) that was used without further purification.(+)-9,10-Dibromocamphor (3):Br30^3Crude (+)-3,9,10-tribromocamphor (30, 190 g, 50% purity) was dissolved in a 1:1solution of diethyl ether and acetic acid (700 mL) and cooled to 0 °C. Zinc dust (84 g,1.28 mol) was slowly added over 1 h and after warming to room temperature the reactionmixture was filtered through Celite. The filtrate was washed successively with water (3 x200 mL), saturated NaHCO3 (2 x 100 mL) and brine (2 x 200 mL), and then dried overMgSO4. Removal of solvent provided a brown solid that was crystallised from Me0H toyield (+)-9,10-dibromocamphor (3) as a white solid (49.45 g, 0.128 mol; yield 64% ).C10H14Br20^Calc. Mass: 311.9371Meas. Mass: 311.9377IR (CHC13): u = 2975, 2900 (C—H); 1740 cm -1 (C=0).MS (70 eV) : m/z (%) = 312, 310, 308 (M+, 0.5, 0.9, 0.4)1H NMR (CDC13): 8 = 1.10 (3H, s, C(8)H3); 1.43 - 1.58 (2H, m, C(5) and C(6) endo H);1.98 (1H, dAB, J = 18 Hz, C(3) endo H); 2.05 (1H, dddAB, JAB=18 Hz, J= 5, 4Hz, C(3) exo H); 2.25 - 2.35 (1H, m, C(6) exo H); 2.41 ( 1H, dt, J= 19, 4 Hz,C(5) exo); 2.66 (1H, t, J=5Hz, C(4) ); 3.48 and 3.59 (1 H each); 3.70 (2H) 3 dAB,J = 12 Hz, C(9)H2Br and C(10)H2Br).56Hydroxy-acid (4):57Br0^Br 3^4A solution of (+)-9,10-dibromocamphor (3, 45.35 g, 0.146 mol) in DMSO (1 L),150 mL H2O and 33.6 g of KOH (0.730 mol, 5 eq.) were stirred at 90 0C for 21 h. Thesolution was then allowed to cool to room temperature at which point it was acidified to pH1 by the addition of 6 M HC1. The product was then extracted with EtOAc (4 x 150 mL)and the organic extracts dried over MgSO4. Removal of solvent produced hydroxy-acid(4) as a yellow crystalline solid (18.77 g, 0.10 mol; yield 70%).C10H1603^Calc. Mass: 184.1099Meas. Mass: 184.1103IR (CHC13) v = 3400 - 2600 ( COOH, OH); 2975, 2895 (C-H); 1705 (C=0); 1650C=CH2); 900 cm -1 (=C-H).MS (70 eV) : m/z(%) = 184 (M+, 0.3); 166 (4.9); 154 (7.7) 94 (100).1H NMR (CDC13): 8 = 0.88 (3H, s, CH3); 1.33 - 1.44 (1H, m); 1.95-2.03 (1H, m); 2.23(1H, dd, J = 15, 9Hz); 2.28 - 2.40 (1H, m); 2.43 - 2.55 (4H, m) 3.43, 3.54 (2H,dAB, J = 11.5 Hz, CH2-O-); 4.83, 5.03 (1 each, 2t, J = 2.5 Hz, (=CH2).4 32HO HOHydroxy-ester (32):Anhydrous K2CO3 (7.51 g, 54.3 mmol) was added to a solution of hydroxy-acid(4, 5.00 g, 27.0 mmol) in DMF (200 mL). The reaction mixture was stirred for 2 h underargon and then iodomethane (3.4 mL, 7.7 g, 53.6 mmol) was added by syringe. After 3 hthe reaction mixture was quenched with water (250 mL) and extracted with Et20 (5 x 50mL). The ethereal layer was washed and dried and removal of solvent produced crudehydroxy-ester (32) as an orange oil (5.69 g). Flash chromatography (230 - 400 meshSi02, 7 x 15 cm) using 35% EtOAc / 65% hexane as eluant, afforded pure hydroxy-ester (32) as a colorless oil (5.28 g; yield 98%).IR (neat): u = 3450 (OH); 3090 (vinyl C-H); 2950, 2880 (C-H); 1730 (C=0); 1665(C=CH2); 885 cm- 1 ( vinyl C-H).MS (70 eV): m/z(%) = 169 (M+— OCH3, 1.8); 168 (M+— CH3OH, 23.0); 167 (17.9);135 (7.7); 107 (100).1H NMR (CDC13): 8 = 0.87 (3H, s, CH3); 1.31 - 1.43 (1H, m); 1.90 - 1.99 (1H, m);2.21 (1H, dd, J = 17, 11 Hz); 2.28 - 2.40 (1 H, m); 2.42 - 2.55 (3H, m); 3.41,3.54 ( 2H, dAB 12 Hz); 3.70 (3H, s, CO2CH3); 4.83, 5.02 (1H each, 2t, J = 2 Hz,=CH2).58CO2Me^ CO2meHO32^ 33Aldehyde-ester (33):A solution of oxalyl chloride (4.12 g; 32.4 mmol, 1.2 eq.) in dry CH2C12 (30 mL)was cooled to -78°C. DMSO (2.3 mL) and dry CH2C12 (50 mL) were added and after 35min a solution of hydroxy-ester (32)( 5.28 g, 26.6 mmol) dry CH2C12 (75 mL) was addedover a 1 h period. Stirring was continued for 1.5 h at -78°C and Et3N (11.3 mL, 8.2 g,81 mmol) was added. The reaction mixture was allowed to warm to room temperature (18h) and washed with water (100 mL), 1 M HO (2 x 100 mL), saturated NaHCO3 (100 mL)and brine (100 mL). Removal of solvent yielded aldehyde (33) as a colorless viscous oil(4.43 g; yield 82%) that required no further purification.IR (neat): 1) = 2960, 2920, 2840 (C-H); 1740 (C=O, ester); 1710 (C=0); 1650 (C=CH2);895 cm -1 (=C-H).MS (70 eV): m/z (%): 182 (M+, 10.5); 168 (12.6); 167 (24.5); 166 (11.8); 107 (100).1H NMR (CDC13): 8 = 1.05 (3H, s, CH3); 1.98 - 2.06 (1H, m); 2.34 (2H, dd, (J = 7, 1.5Hz); 2.38 - 2.51 (3H, m) 2.77 (1H, dq, J = 12, 7 Hz); 3.67 (3H, s, -OCH3); 4.78and 5.12 (1H each J = 2 Hz, =CH2); 9.30 (1H, s, CHO).59CO2Me^ CO2Me meo2e3 3^ 3 4Ester (34):A solution of trimethyl phosphonoacetate (5.28 g, 29.0 mmol) in dry THF (50 mL)was added dropwise over a 30 min period to a slurry of KH (0.70 g, 29.0 mmol) and dryTHF (50 mL). After 1 h a solution (50 mL) of ester-aldehyde (33, 4.43 g, 24.3 mmol) inTHF (50 mL) was added dropwise over 30 min and the reaction mixture allowed to standfor 18 h. Addition of water (100 mL), extraction with Et20 (4 x 100 mL), and removal ofsolvent provided colorless diester (34) that was purified by flash chromatography (230 -400 mesh Si02, 5.5 x 17 cm; 40% EtOAc / 60% hexane as eluant ) to provide pure (Rester(34, 4.99 g; yield 80%).IR (neat); v = 2970 - 2850 (C-H); 1735 (C=O, saturated ester); 1720 (C=O, a,(3-unsaturated ester); 1650 (C=C); 890 cm-1 (=CH2).MS (70 eV): m/z (%): 252 (M+, 10.6); 232 (1.7); 221 (23.6); 222 (72.6); 205 (8.4); 192(26.8); 119 (100).1H NMR (CDC13): 6 = 1.05 (3H, s, CH3), 1.43-1.53 (1H, m) 1.97-2.05 (1H, m) 2.11-2.20 (1H, m) 2.28-2.39 (2H, m); 2.40-2.48 (1H, m); 2.50-2.58 (1H, m); 3.65and 3.75 (3H each, 2 s, 2x(-OCH3); 4.70 and 4.93 (1 each, 2 t , J = 2.5 Hz,=CH2); 5.85 (1H, d, J = 16 Hz, -C(0)Cli=CHR); 6.88 (1H, d, J = 16 Hz, —C(0)CH=CUR).6034 35me02c Me02CDiester (35):A solution of diester (34, 5.95 g, 23.6 mmol) in dry Me0H (150 mL) was addedto flame-dried Mg turnings (1.43 g). After stirring for 4.5 h under argon at roomtemperature the reaction mixture was quenched with water (100 mL) and the Mg(OH)2suspension dissolved by addition of 6 M HCI. The aqueous reaction mixture was extractedwith ether (3 x 100 mL) and the combined extracts washed with saturated NaHCO3 (100mL), water (100 mL) and brine (100 mL). Removal of the solvent provided diester (35) asa pale yellow oil (5.513 g, 21.7 mmol; yield 92%).IR (neat): v = 3090 (=C-H); 2955, 2880, 2850 (C-H); 1740 ( C=0); 1650 (C=C); 885cm -1 (=CH2).MS (70 eV): m/z (%) = 254 (M+, 3.2); 224 (11.4); 223 (51.3); 222 (56.3); 220 (10.8);207 (15.5); 180 (65.2); 107 (100).1 H NMR (CDC13): 8 = 0.89 (3H, s, CH3); 1.27 - 1.37 ( 1H, m); 1.70 - 1.85 (2H, m);1.86 - 1.94 (1H, m); 2.10 - 2.18 (2H, m); 2.22 - 2.34 (3H, m); 2.36 - 2.47 (2H,m); 3.66 and 3.68 (3H each, 2s, 2 x -OCH3); 4.73 and 4.93 (1 H each, 2 t, J = 2Hz, 2 Hz, =CH2).61Preparation of Diacid (36) from Diester (35):CO2Me^ .CO2HMe02C^ HO2C35^36The diester (35, 5.024 g, 22.2 mmol) was dissolved in a 1:1 solution of methanoland water (300 mL). KOH (6.3 g, 0.11 mmol) was added to the vigorously stirredsolution at room temperature and after 8.5 h the reaction was quenched by acidifying to pH1 with 6 M HCI. Extraction with Et20 (6 x 75 mL) followed by removal of solventprovided crude diester (36) as a yellow oil (5.2 g) that was further purified by redissolvingin Et20, extraction with 1 M KOH, acidification, and extraction with ether. Removal ofsolvent provided diacid (36) as a pale yellow oil (4.56 g, 20.1 mmol; yield 91%).IR (CHC13): D = 3450 - 2300 ( broad, -COOH); 2960, 2945 (C-H); 1710 (C=0); 1655(C=C); 885 cm -1 (=CH2).MS (70 eV): m/z (%) = 208 (MI-- H2O, 23.0); 190 (6.7); 180 (5.7); 166 (50.7); 153 (100).1H NMR (CDC13): 8 = 0.89 (3H, s, CH3); 1.30 - 1.42 (1H, m); 1.85 and 1.91 (2H, qABt,J = 14 Hz, 7.5 Hz, -CEI2CH2CO2H); 2.00 - 2.10 (2H, m); 2.13 - 2.20 (1H, m);2.24 - 2.38 (3H, m); 2.43 - 2.55 (2H, m); 4.72 and 4.93 (1H each, 2 t, J = 2.5Hz, 2 Hz, =CH2); 11.20 - 12.50 (2H, broad singlet, 2 x -COOH).62Preparation of Diacid (36) from Diester (34):CO2Me^ CO2HHO2C3 4^ 36A solution of diester (34, 5.28 g, 20.9 mmol) in dry Me0H (75 mL) was added toflame -dried magnesium turnings (1.53 g, 62.7 mmol) under argon at room temperature.After 15 h a solution of KOH (5.9 g, 0.10 mol) in water (150 mL) was added to thevigorously stirred reaction mixture and after 7.5 h the reaction mixture was acidified with 6N HC1. Extraction with EtOAc (4 x 125 mL) followed by washing with brine (125 mL)and removal of solvent produced diacid (36) as a crude yellow oil (5.1 g). Although thisrepresents slightly more than 100% weight recovery the crude product was used withoutfurther purification. Spectral data for the crude diacid (36) is consistent with thatpreviously reported.Enone-ester (5):63me02cHO2CCO2Me36^5Trifluoroacetic anhydride (2.54 g, 12.1 mmol) was added via syringe to the crudediacid (36, 1.09 g, —5.0 mmol) dissolved in dry CH2C12 (100 mL). After 2 h at roomtemperature the solvent was removed by rotary evaporation, with care been taken tominimize exposure to atmospheric moisture. Dry Me0H (35 mL) and a catalytic amount ofp-toluenesulfonic acid was added and the reaction mixture was stirred for 15 h at roomtemperature under an argon atmosphere. The Me0H was then removed and replaced byEtOAc (50 mL) which was partitioned with water (100 mL). The product was extractedwith Et20 (3 x 25 mL), washed with brine, dried over MgSO4, filtered and the solventremoved. This extraction process was sufficient to yield a pure sample of the enone-ester(5, 1.04 g, 4.7 mmol; yield 97%).IR (neat): v = 2950 (C-H); 1740 (C=O, ester); 1660 cm -I (C=O, enone).MS (70 eV): m/z (%) = 222 (M+, 33.6); 207 ( 15.4); 194 (22.4); 191 (21.8); 180 (43.2);121 (100.0).1H NMR (CDC13): 8 = 1.05 (3H, s, CH3); 1.54 - 1.66 (1H, m); 1.80 (1H, dABdd, J = 15,14, 5Hz); 1.97 (1H, dmidd, J = 15, 6, 2 Hz); 2.05 - 2.14 (2H, m); 2.30 (1H,dABd, J = 15, 9 Hz); 2.39 (1H, dABdd, J = 18, 5, 2 Hz); 2.44 - 2.57 (3H, m);2.68 (1H, dABdt, J = 20, 11, 2 Hz); 3.71 (3H, s, -OCH3); 5.80 (1H, s, =CH2).Ketal-ester (37):64CO2Me CO2Me5^37A Dean-Stark apparatus was charged with a solution of benzene, ethylene glycol(1.70 mL, 1.88 g, 30.3 mmol), PPTS (0.115 g, 0.45 mmol) and the enone-ester (5, 670mg, 3.03 mmol) and the solution was refluxed overnight. The reaction mixture was cooledto room temperature, diluted with Et20 (100 mL) and the organic layer washed with H2O(3 x 100 mL), brine (50 mL) and finally dried over MgSO4. Filtration and solvent removalyielded a yellow mobile oil (1.26 g). The crude material was purified by radialchromatography, eluting with 15% EtOAc / 85% hexane. This provided ketal (37) as acolorless mobile oil (645 mg, 2.62 mmol; yield 80%).IR (neat): u = 3050 (=C-H); 2960, 2900, 2860 (C-H); 1740 cm -1 (C=0).MS (70 eV): m/z (%) = 266 (M+, 2.1); 235 (1.2); 99 (100.0).1H NMR (CDC13): 5 = 0.92 (3H, s, CH3); 1.51 - 1.59 (1H, m); 1.65 - 1.74 (2H, m);1.79 - 1.88 (1H, m); 1.99 - 2.07 (1H, m); 2.32 - 2.52 ( 6H, m); 3.67 (3H, s,-OCH3); 3.93 - 4.00 (4H, m, O(CH2)20-); 5.33 ( 1H, s, =CH2).Ketal-diester (38):65CO2Me 37^38A solution of diisopropylamine (1.40 mL, 1.26 g, 12.4 mmol) and dry THE (30mL) was cooled to 0°C under an argon atmosphere and n-BuLi (1.55 M, 7.1 mL, 11.3mmol) was added by syringe. The reaction mixture was stirred for 45 min and then cooledto -78°C. Ketal-ester (37, 3.02 g, 11.3 mmol) in dry THE (20 mL) was added via syringeand allowed to react for a further 1 h. Methyl bromoacetate (2.65 g, 17.3 mmol) was thenadded and the reaction mixture was kept at -78 0C for 1 h and was then allowed to warm toroom temperature overnight (14 h). The reaction mixture was quenched by addition ofsaturated NH4CI solution (100 mL). Extraction with Et20 (3 x 100 mL) followed byremoval of solvent yielded a red-brown oil (3.5 g). Flash chromatography using a 65 x180 mm column of silica gel (230 - 400 mesh) and elution with 40% Et20 / 60% petroleumether afforded unreacted starting material (1.66 g) and diester (38) (1.94 g).IR (CHC13): v = 2934 (C-H); 1733 (C=0); 1156 cm -1 (C-0).MS (70 eV) : m/z (%) = 338 (M+, 1.9), 307 (M+ - OMe, 2.5); 192 (2.0); 179 (2.0); 131(4.3); 99 (100.0).1H NMR (CDC13): 5 = 1.05 (3H, s, C-13-Me); 1.43(1H, ddd, J = 4, 11, 11 Hz); 1.50 -1.64 (2H, m); 1.75 (1H, ddd, J = 4, 14, 14 Hz); 1.94 - 2.03 (1H, m); 2.27 - 2.36(3H, m); 2.47 (1H, dd, J = 4, 16 Hz, C-22 H); 2.12 (1H, ddd, J = 4, 11, 11 Hz,C-17 H); 2.65 ( 1H, dd, J = 11, 16 Hz, C-22 H); 2.93 (1H, ddd, J = 4, 11, 11Hz); 3.63 (3H, s, CO2Me); 3.64 (3H, s, CO2Me); 3.86 - 3.94 (4H, m, -OCH2CH20-); 5.30 (1H, s, =CH).66Ketal-diol (39):38^39To a stirred suspension of LiA1H4 ( 0.83g,21.9 mmol) and dry THF (60 mL) at0°C was added a solution of ketal-diester (38, 1.24 g, 3.66 mmol) in dry THF (15 mL) viasyringe over 15 min. The reaction mixture was stirred at room temperature under argonfor 13.5 h and then carefully quenched by slow addition of NaSO4.10 H2O and H2O (100mL). Extraction with Et20 (4 x 100 mL) followed by removal of the solvent (dried overMgSO4) yielded ketal-diol (39, 0.73 g; yield 71%) which was used without furtherpurification.IR (neat): .0 = 3340 (s,b; OH); 2930 (C-H); 1620 (C=C); 1110 cm -1 (C-0).MS (DCI, NI-13) : m/z (%) = 283 ((M+H)+, 96.0); 282 ( M+, 5.2); 265 (M+-0H, 13.2);221 (23.5); 99 (100.0).1H NMR (CDC13): 8 = 0.97 (3H, s, C-13-Me); 1.52 - 1.68 (3H, m); 1.75 - 2.04 (6H, m);2.25 - 2.40 (3H, m); 2.60 - 3.10(2H, broad singlet, 2 x OH); 3.50 - 3.55 (1H, m,C-21-HHOH); 3.62 - 3.70 (1H, m, C-21-HHOH); 3.72 - 3.80 (2H, m, C -22-H2-OH); 3.87 - 3.97 (4H, m, -OCH2CH2O-); 5.29 (1H, s, =CH).67Dimethoxy-ketal (41):68 41Ketal-diol 40 (0.733 g, 26.0 mmol) in dry THE (50 mL) was treated with KH(2.92 g, 73 mmol) for 0.5 h. Methyl iodide (2.53 mL, 1.11 g, 78 mmol) was added andafter 1.5 h the reaction mixture was quenched by the careful addition of H2O (100 mL).Extraction with Et20 (4 x 100 mL) followed by removal solvent from the dried, combinedextracts provided dimethoxy-ketal as a pale yellow oil (> 95% pure by GC) that was usedwithout further purification.C i8H3004^Calc. mass^310.2144Meas. mass^310.2143IR (neat): I) = 2900 (C-H); 1455 (C-H); 1106 cm -1 (C-0).MS (70 eV) : miz (%) = 310 (M+, 9.1); 278 ((M+— Me0H), 1.1); 265 (12.0); 193 (5.0);147 (10.9); 99 (100.0).1H NMR (CDC13): 8 = 0.90 (3H, s, C-13-H3); 1.50 - 1.65 (3H, m); 1.70 - 1.90 (4H, m);1.90 - 2.05 (2H, m); 2.27 - 2.40 (3H, m); 3.27 (3H, m, OCH3); 3.30 (3H, s,OCH3); 3.36 - 3.45 (4H, m, -OCH2CH2O-); 5.28 (1H, s, =CH).Dimethoxy-enone (42):41^42A solution of dimethoxy-ketal (41, 37 mg, 0.11 mmol), 1 M HC1 (2 mL) andacetone (4 mL) was refluxed for 1.5 h. TLC and GC analysis showed completeconversion of starting material to a single product. The reaction mixture was cooled toroom temperature, diluted with H2O (10 mL) and extracted with Et20 (3 x 30 mL). Theether extracts were washed with sat. NaHCO3 and dried over MgSO4. Removal of solventafforded dimethoxy-enone (42) as a yellow oil (25.8 mg; yield 84%). Purification of thiscompound was accomplished by column chromatography (SiO2; 230-400 mesh) using60% EtOAc / 40% hexane.C16112603^Calc. Mass^266.1882Meas. Mass^266.1880IR (neat): .0 = 2900 (C-H); 1665 (C=0); 1456 (C-H); 1110 cm -1 (C-0).MS (70 eV) : m/z (%) = 266 (M+, 16.6); 251 (M+-CH3), 46.5); 234 (M+-Me0H);202(15.1); 121 (94.0).1H NMR (CDC13): 6 = 1.11 (3H, s, C-13-Me); 1.53 (2H, m); 1.74 - 1.84 (3H, m); 1.89(1H, dt, J = 5, 14 Hz); 2.34 (1H, ddd, J = 1, 4, 18 Hz); 2.38 - 2.59 (2H, m); 2.6569OH(1H, dddd(2, 2, 11, 20 Hz); 3.31 (3H, s, OCH3); 3.34 (3H, s, OCH3); 3.38 (2H,d, J = 4 Hz, -CHCI120); 3.40 (2H, t, J = 7 Hz); 5.75 (1H, s, =CH-).1-Chloro-3-hydroxypentane (48):CIO47^ 48Freshly distilled 1-chloropentan-3-one (47, 9.16 g, 76.0 mmol) was dissolved indry THE (30 mL) and cooled to 00C. LiA1H4 (1.10 g, 28.5 mmol) was added in threeequal portions over 15 min and after 1 h the reaction mixture was quenched by carefuladdition of Na2SO4.10H20 (— 5 g) and H2O (20 mL). The gelatinous precipitate wasdissolved in 1 M HC1 and the mixture extracted with Et20 (4 x 100 mL). Removal ofsolvent from the dried extract gave 3-hydroxy-l-chloropentane (48) as a mobile oil (7.86g). The IR spectrum of the crude product showed no carbonyl stretching bands, and thecrude product was used without further purification. For spectral analysis 300 mg of thecrude sample was purified by radial chromatography (2 mm plate, PF-254 Si02) elutingwith 1:1 hexane/CH2C12.IR (neat): u = 3332 (OH); 2966, 2931, 2879 (-C-H); 1459 cm -1 ( OH bend).1 H NMR (CDC13): 8 = 0.95 (3H, t, J = 8Hz, -CH2CH3); 1.46 - 1.58 ( 2H, m); 1.82 -1.96 (2H, m); 2.06 (1H, broad singlet, -OH); 3.65 - 3.80 (3H, m, -CH2I,CHOH)70 ^IN-ClOTBDPS1-Chloro-3-(t-butyldiphenylsilyloxy)pentane (49):71.,,,,,,■1„,..••■,...,,, CIOH48^ 4 9A solution of 1-chloro-3-hydroxypentane (48, 6.03 g, 49.2 mmol), imidazole(16.7 g, 0.246 mol, 5 eq.) and TBDPSC1 (13.2 mL, 13.9 g, 50.8 mmol) in DMF (150mL) was stirred for 11 h at room temperature. TLC analysis showed a substantial amountof product as well as starting material in the reaction mixture. After addition of H2O (200mL) the reaction mixture was extracted with Et20 (4 x 100 mL). The organic layer waswashed with saturated NaHCO3 solution (200 mL), brine (200 mL) and dried overMgSO4. Removal of solvent yielded crude product (18.1 g). Column chromatography ofa sample (3.3 g) of product provided (49) (1.56 g) and starting material (48) (0.4 g).IR (neat): v = 3070 (aromatic C-H); 2955, 2940, 2857 (-CH); 1427 (CH bend); 1109 cm-1(-C-0 stretch).1H NMR (CDC13): 5 = 0.73 (3H, t, J = 8Hz, -CH7CH3); 1.04 (9H, s, -C(CH3)3); 1.42 -1.48 (2H, m); 1.87 - 1.95 ( 2H, m); 3.53 (2H, t, J = 11.5 Hz, -CH2C1); 3.82 (1H,q, J = 9 Hz, R2CHOR); 7.25 - 7.40 (6H, m, phenyl); 7.60 - 7.70 (4H, m,phenyl).1-Iodo-3-(t-butyldiphenylsilyloxy)pentane (SO):IOTBDPS^ OTBDPS49 50A solution of 1-chloro-3-(t-butyldiphenylsilyloxy)pentane (49, 2.50 g, 6.70 mmol)and NaI (4.02 g, 26.8 mmol) in acetone (100 mL) was refluxed for 65 h and then cooled toroom temperature. The reaction mixture was diluted Et20 (200 mL) and washed withsaturated NaHS03 solution (100 mL). Solvent removal afforded SO as a colorless oil(2.50 g, 5.50 mmol; yield 80%).C211-130SiOI^Calc. mass^453.1115Meas. mass^453.1111IR (neat): u = 3070 (C-H, phenyl); 2947, 2857 (C-H); 1466 (C-H); 1100 cm -1 (C-0).MS (DCI, NI-I3) : m/z (%) = 453 ((M+H)+, 58); 412 (37); 395 (55); 196 (100).1 H NMR (CDC13): 8 = 0.67 (3H, t, J = 8 Hz, -CH2C1 -11); 0.99 (9H, s, -C(CH3)3); 1.30 -1.46 (2H, m); 1.80 - 2.00 (2H, m); 3.07 (1H, t, J = 8 Hz, -CHAHBI); 3.08 (1H, t,J = 8Hz, -CHAL113I); 3.63 (1H, t, J= 6Hz, -CH(OR)); 7.25 - 7.40 (6H, m,phenyl); 7.60 - 7.70 (4H, m, phenyl).72Dimethoxy-enone (43):42^43^44A slurry of freshly distilled DMSO (20 mL) and NaH (67 mg ; 60% oil dispersion ;40.2 mg, 1.68 mmol, 1.37 eq.) was stirred under argon for 1 h at room temperature andthen at 85 °C for 45 min. After cooling, a solution of dimethoxy-enone (42, 326 mg, 1.22mmol) in dry DMSO (10 mL) was added via syringe and the mixture allowed to react for2.5 h. The alkylating agent (50, 1.10 g, 2.44 mmol, 2 eq.) in DMSO (2 mL) was thenadded via syringe and the reaction mixture allowed to stir for 18 h at room temperature.Addition of saturated NH4C1 solution (50 mL) followed by extraction with Et20 (4 x 50mL) and subsequent removal of solvent followed by column chromatography (35 x 150mm Si02, 230 - 400 mesh; 10% EtOAc / 90% hexane) provided dimethoxy-enone (43)(500 mg), dialkylated product (44) (465 mg), and recovered starting material (42) (205mg). Radial chromatography of the alkylated product (43) using a 2 mm Si02 plate and thesame solvent system yielded pure dimethoxy-enone (43, 413 mg; yield 57% (based onrecovered starting material)).Dimethoxy-enone (43):IR (neat): .1) = 3100 (C-H, phenyl); 2907 (C-H); 1671 (C=0); 1428(C-H);1100 cm -1 (C-0).73MS (DCI, NH3) : m/z (%) = 592 ((M+H)+, 100.0); 591 (M+, 29.5); 514 (53.5).1H NMR (CDC13): 6 = 0.78(3H, t, J = 8Hz, -CH2CH3); 1.00(3H, s, C-13-H3); 1.04(9H, s, C(CH3)3); 1.28 - 1.38 (1H, m); 1.39 - 1.62 (5H, m); 1.84 - 1.94 (1H, m);1.97 - 2.10 (3H, m); 2.18 - 2.39 (3H, m); 2.42 - 2.54 (1H, m); 3.28 (3H, s,OCH3); 3.32 (3H, s, OCH3); 3.30 - 3.38 (2H, m, CHC1j20Me); 3.43 (2H, t,CH2CH20Me); 3.60 (1H, p, (CH-OTBDPS); 7.30 - 7.41 (6H, m, phenyl); 7.63 -7.70 (4H, m, phenyl).^Elemental Analysis: Calc. C^75.19 %^Measured^C^75.30 %H^9.23% H^9.10%Dialkylated Product (44):IR (neat): u = 3070, 3049 (C-H, phenyl); 2912 (C-H); 1705 (C=0); 1461(C-H);1075 cm-1 (C-0).MS (DCI, NH3) : m/z (%) = 934 (M++NH4+, 54); 918 (15.5); 860 (15.5); 660 (M+-OTBDPS, 100.0).1 H NMR (CDC13): 8 = 0.65 - 0.80 (6H, m, 2 x CH2CH,1); 0.94 - 1.09 (21 H, m, C-13-H3, 2 x -C(CH3)3); 1.13 - 1.28 (6H, m); 1.32 - 1.48(5H, m); 1.55 - 1.67 (3H, m);1.68 - 1.83 (4H, m); 1.84 - 2.01 (2H, m); 2.16 - 2.42 (2H, M); 3.28 (3H, s,OCH3); 3.32 (3H, s, OCH3); 3.30 - 3.38 (2H, m, CHCH20Me); 3.43 (2H, t,CH2CH20Me); 3.60 (1H, p, (CH-OTBDPS); 7.30 - 7.41 (12H, m, phenyl); 7.637.70 (8H, m, phenyl).74Dimethoxy-ketone (45):75OTBDPS43OTBDPS45A slurry of freshly distilled DMSO (20 mL) and NaH (34 mg; 60% oil dispersion;20.1 mg, 0.84 mmol) was stirred under argon for 1 h at room temperature and then at 85°Cfor 45 min. After cooling, a solution of enone (43, 413 mg, 0.70 mmol) in DMSO (5 mL)was added at room temperature and stirring was continued under argon for 3 h. Methyliodide (0.119 g, 0.84 mmol) was added and after 1 h the reaction mixture was quenchedwith saturated NH4C1 solution (150 mL) and extracted with Et20 (5 x 50 mL). The etherextracts were washed with brine and dried over MgSO4. Solvent removal followed byradial chromatography of the crude product using 30% EtOAc / 70% hexane and a 2 mmSi02 plate afforded dimethoxy-ketone (45, 301 mg; yield 83% (based on recoveredstarting material)) and starting material (43, 57 mg).C38115604Si^Calc. mass^604.3948Meas. mass^604.3904IR (neat): u = 2916 (C-H); 1708 (C=0); 1460 (C-H); 1108 cm -1 (C-0).MS (70 eV) : m/z (%) = 604 (M+, 0.6); 547 (M+-tBu, 44.7); 299 (11.3); 199 (100.0).45 51OMe^ OMeOMe OMeOHOTBDPS1H NMR (CDC13): 8 = 0.70 - 0.80 (3H, m, CH2CH,a); 0.90, 0.92 ( 3H, 2 s(diastereomers), C-11-H3); 1.00 (9H, s, C(CH3)3); 1.06 (3H, s, C-13-H3);1.22 - 1.48 (6H, m); 1.53 - 1.68 (2H, m); 1.69 - 2.08 (6H,m); 2.21 - 2.32 (3H,m); 2.44 - 2.59 (1H, m); 3.26 (3H, s, -OCH3); 3.29 - 3.38 (5H, m); 3.40 - 3.49(2H, m); 3.60 (1H, p, CH-OTBDPS); 5.23, 5.31 (1H, broad singlet (diastereo-mers), =CH); 7.30 - 7.68 (10H, m, phenyl).Hydroxy-ketone (51):A solution of dimethoxy-ketone (45, 251 mg, 0.415 mmol) and 1 M TBAF (2 eq.)in dry THE (10 mL) was stirred at room temperature under for 48 h. Addition of H2O (20mL) and Et20 extraction (4 x 20 mL) and removal of solvent yielded a crude product (246mg) that was purified by radial chromatography ( 2mm Si02 plate, 30% EtOAc / 70%hexane) to provide hydroxy-ketone (51, 113 mg; yield 99% (based on recovered startingmaterial)) and unreacted starting material (62 mg).76IR (CHC13):1) = 3456 (OH); 2906 (C-H); 1709 (C=0); 1457 (C-H); 1109 cm -1 (C-0).1H NMR (CDC13): 8 = 0.87 (3H, t, J = 4 Hz, CH2CH3 .); 1.05 (3H, s, C-13-H3); 1.16(3H, s, C-11-H3); 1.18 - 1.60 (10H, m); 1.63 - 2.03 (8H, m); 2.06 - 2.16 (1H,m); 2.28 - 2.40 (2H, m); 2.53 - 2.63 (1H, m); 3.28 (3H, s, OCH3); 3.31 (3H, s,OCH3); 3.31 - 3.37 (2H, m); 3.39 - 3.48 (3H, m); 5.43 (1H, s, =CH).Diketone (52):51^52Hydroxy-ketone (51, 23 mg, 0.062 mmol) was added to a solution of Cr03 (12mg), H2SO4 (0.2 mL) and H2O (3 mL) and the reaction mixture was stirred for 00C for 1 hand then 2.5 h at room temperature. Work-up in the usual way yielded pure diketone (52)(12 mg; yield 99%).C221-13604^Calc. mass^364.2643Meas. mass^364.2622IR (CHC13): v = 2927 (C-H); 1713 (C=0); 1460 (C-H); 1114 cm -1 (C-0).MS (70 eV) : m/z (%) = 364 (M+, 4.7); 349 (M+-CH3, 31.2); 332 (29.8); 314 (21.1); 57(100.0).771H NMR (CDC13): 8 = 1.00 (3H, t, J = 12 Hz, -CH2CHa); 1.03 (3H, s, C-13-H3); 1.15(3H, s, C-11-H3); 1.47 - 2.12 (9H, m); 2.12 - 2.45 (6H, m); 2.48 - 2.68 (1H, m);3.27 (3H, s, OCH3); 3.31 - 3.36 (2H, m, OCH2); 3.37 - 3.47 (2H, m, OCH2);5.47 ( 1H, broad singlet, =CH).Tricyclic enone (53):52^53A solution of diketone (52, 14 mg, 0.038 mmol) in Me0H (5 mL) containing 3 MHC1 (1 mL) was refluxed for 22 h. The reaction mixture was extracted with Et20 (75 mL)and the ether extracts washed with H2O and saturated NaHCO3 solution. Removal ofsolvent followed by radial chromatography (1 mm SiO2 plate, 20% EtOAc / 80% hexane)of the crude product yielded tricyclic enone (53, 8 mg; yield 77% (based on recoveredstarting material)) and starting material (52, 3 mg).C22113403^Calc. mass^346.2508Meas. mass^346.2510IR (neat): D = 2909 (C-H), 1661 (a,I3-unsaturated C=0), 1454 (C-H, bend), 1108 (C-0).78MS (70 eV) : rniz (%) = 346 (M+, 9.6); 331 (M+— CH3, 11.6); 314 (19.2); 299 (29.0);213 (100).1H NMR (CDC13): 5 = 0.81 (3H, s, C-13-H3); 1.32 (3H, s, C11-H3); 1.57 - 1.68 (1H,m); 1.75 - (3H, s, vinyl methyl); 1.76 - 1.87 (4H, m); 1.93 - 2.07 (5H, m); 2.25 -2.35 (2H, m); 2.40 (1H, dm, J = 16 Hz); 2.51 - 2.61 (2H, m); 3.29 (3H, s,OCH3); 3.32 (3H, s, OCH3); 3.34 - 3.40 (2H, m, OCH2); 3.41 - 3.46 (2H, dd, J= 7, 7 Hz,OCL12CH2).Hydroxy-ketal (37):79CO2Me OH37A solution of ketal ester (37, 248 mg, 0.93 mmol) in dry THF (10 mL) was addedvia syringe to a slurry of LiA11-i4 (45 mg, 1.22 mmol) and dry THF (20 mL) at 0°C. Afterstirring for 1 h the ice bath was removed and the mixture stirred at room temperatureovernight. The reaction mixture was quenched with Na2SO4.10 H2O (150 mg) and thegelatinous mass filtered and rinsed with Et20 (50 mL). The filtrate washed with H2O (50mL) and brine (50 mL). Evaporation of solvent afforded hydroxy-ketal (102) as acolorless oil (186 mg, 0.78 mmol; yield 84%). NMR and TLC analysis showed noimpurities and this product was used without further purification.IR (neat): v = 3388 (-OH); 2915 (C-H); 1691 (C=C).MS (70 eV): m/z (%) = 238 (M+, 2.3); 169 (1.0); 141 (1.2); 105 (4.6); 99 (100.0).1H NMR (CDC13): 8 = 0.82 (3H, s,-CH3); 1.40 (2H, m); 1.61 (4H, m); 1.80 (1H, m);2.15 (3H, m); 3.27 (1H, m); 3.38 - 3.60 (2H, m); 3.75 (4H, -OCH2CH2O-); 5.32(1H, =CH-).Methoxy-ketal (103):80OH OMe103KH (36 mg, 0.89 mmol) was added to a stirred solution of hydroxy-ketal (102,152 mg, 0.64 mmol) in dry THE (35 mL). After 1 h H2 evolution ceased and MeI (60 p.L,126 mg, 0.89 mmol) was added via micro-syringe. After 2.5 h an additional portion ofKH (15 mg) was added and then, after a further 2 h MeI (254.) was added and thereaction mixture left for 16 h. The reaction mixture of diluted with Et20, washed withbrine, and dried over anhydrous MgSO4. Evaporation of the solvent yielded a darkviscous oil that was purified by column chromatography (5% EtOAc / 95% hexane, 12 x170 mm of 230-400 p.m Si02) to produce methoxy-ketal (103, 57 mg; yield 35%(unoptimized)).IR (neat): v = 2916 (C-H); 1667 ( C=C); 1116 cm -1 (C-0).MS (70eV) : m/z (%) = 252 (M+, 3.9); 165 (1.0); 121 (1.9); 105 (2.9); 99 (100.0).1 1-1 NMR (CDC13): 0.91 (3H, s, -CH3); 1.45-2.0 ( 7H, complex overlapping multiplet);2.39 (4H, m, allylic H's); 3.35 ( 3H, OCH3); 3.39 (2H, m,-OMe); 3.95 (4H,m, -OCH2CH2O-); 5.32 (1H, s, =CH).Methoxy -enone (104):81OMe OMe104A solution of ketal ester (103, 350 mg, 1.38 mmol), acetone (20 mL) and 1 M HC1(10 mL) was refluxed for 1.5 h. The reaction mixture was cooled to room temperature,neutralized with a sat. NaHCO3 solution and extracted with Et20 (4 x 100 mL). Thecombined extracts were washed with brine (100 mL) and dried over MgSO4. Evaporationof the solvent followed by radial chromatography (2 mm plate; 30% EtOAc / 70% hexane)afforded methoxy-enone (104) as a colorless oil (285 mg) .C13H2002^Calc. mass^208.1463Meas. mass^208.1463IR (neat): 1) = 2933, 2870, 2830 (C-H); 1731 (C=0); 1679 cm -1 (C=C).MS (70 eV) m/z: 208 (M+, 28.2); 193 (M+-CH3, 35.6); 180 (10.0); 176 (15.4); 148(66.0); 121 (100.0).1H NMR (CDC13): 8 = 1.00 (3H, s, -CH3); 1.41 - 1.55 (2H, m); 1.60 - 1.80 (3H, m);1.92 - 2.03 (2H, m); 2.26 - 2.68 (4H, m, allylic and a protons to the carbonyl);3.32 (3H, s, -OCH3); 3.38 (4H, m, -OCH2CH2O-); 5.73 (1H, s, =CH2).Methoxy-enone (105):104^105^106A mixture of NaH (83 mg of 60% oil dispersion; 50 mg, 2.1 mmol) and freshlydistilled DMSO (15 mL) was stirred at room temperature under argon for 30 min, and at80 OC for a further 40 minutes. After cooling to room temperature, a solution of enone(104, 393 mg, 1.89 mmol) in DMSO (8 mL) was added and after an additional 5 h, theiodide (50, 1.03 g, 2.227 mmol), dissolved in dry DMSO (4 mL) was added. After 16 hthe reaction mixture was acidified with 1 N HC1 and extracted with Et20 (4 x 100 mL).Removal of solvent followed by radial chromatography (2 mm Si02 plate; 25% EtOAc /75% hexane) of the crude product provided methoxy-enone (105, 478 mg), dialkylatedketone (106, 526 mg), and starting material (77 mg).Methoxy-enone (105):82C341-14803Si^Calc. mass^532.337383Meas. mass^532.3372IR (neat): u = 3070 (aromatic C-H); 2914 (-C-H); 1656 cm -1 (C=O, C=C).MS (70 eV) : m/z (%) = 503 (1.3); 475 (M+ - C(CH3)3, 82.8); 285 (1.2); 277 (2.1); 199(100.0).1H NMR (CDC13) = 0.79 (3H, t, J = 7Hz, -CHS132); 0.92 (3H, s, CH3); 1.05 (9H, s,-C(CH3)3); 1.30 - 1.38 (1H, m); 1.41 -1.80 (9H, m); 1.90 - 1.98 (2H, m); 2.03 -2.13 (2H, m); 2.26 - 2.39 (2H, m); 2.43 - 2.53 (1H, m); 3.34 ( 3H, s, -OCH3);3.35 - 3.44 (2H, m); 3.71 (1H, q, J = 5.3Hz); 7.30 - 7.42 (6H, m, phenyl); 7.65 -7.72 (4H, m, phenyl).^Elemental Analysis: Calc. C^76.62 %^Meas C^76.55 %H^9.10 % H^9.14 %Ketone (106):IR (neat): .1) = 3070 (phenyl C-H); 2914 (C-H); 1704 (C=0); 1589 cm -1 (C=C).MS (70 eV): m/z (%): 857 (M+, 0.4); 800 (M+-C(CH3)3, 12.9); 544 (42.3); 543 ( M+-(OTBDPS + tBu), 73.8); 475 (23.7); 199 (100.0).1 H NMR (CDC13): 8 = 0.64 - 0.79 (9H, m, C-13 Me, 2 x RCH2-CII.a); 0.98- 1.08 (18 H,4 singlets - representative of diastereoisomers present, 2 x tBu); 1.12 - 1.28 ( 5H,m); 1.32- 1.57 (9 H, m); 1.64 - 1.76 ( 3H, m); 1.76 - 1.86 (1H, m); 3.32 -3.38( 3H, s, OCH3); 3.38 - 3.45 (2H, m); 3.51 - 3.62 (2H, m); 4.96 - 5.08 ( 1H, m,=CH); 7.28 - 7.43(12H, m, phenyl); 7.56 - 7.72 (8H, m, phenyl).Methoxy-ketone (109):OTBDPS^ OTBDPS105 109A solution of enone (105, 165 mg, 0.31 mmol) in EtOH (10 mL) and a catalyticamount of 10% Pd•C were placed in a high pressure hydrogenation bomb and pressurisedto 1000 psi H2. The reaction slurry was stirred at room temperature for 24.5 h and thenfiltered through Celite. Evaporation of solvent yielded (109) as a viscous oil (132 mg;crude yield 81 %) that was used without further purification.IR (CHC13): u = 3072 ( C-H, phenyl); 2918 (C-H); 1700 (C=0); 1100 cm-1 (C-0).1H NMR (CD03): 5 = 0.70 - 0.85 (6H, m, C-13-Me, RCH2C141); 1.03 (9H, s, tBu);1.27 - 1.51 (11H, m); 1.51 - 1.62 (2H, m); 1.64 - 1.78 (2H, m); 1.80 - 1.98 (2H,m); 2.05 - 2.29 (2H, m); 2.32 - 2.50 (1H, m); 3.27 - 3.32 (3H, 2 s representingdiastereoisomers, OCH3); 3.32 - 3.43 (2H, m, £1:12-0Me); 3.60 - 3.72 (1H, m,CH- OTBDPS); 7.29 - 7.42 (6H, m, phenyl); 7.60 - 7.70 (4H, m, phenyl).84Methoxy-ketone (110):109^110A aliquot (0.18 mL; 0.4 eq.) of 0.25 M NaOMe in Me0H was injected into asolution of ketone (109, 58 mg, 0.11 mmol) in dry Me0H (5 mL). The reaction mixturewas refluxed for 4 h and then quenched with saturated NH4C1 solution (50 mL).Extraction with Et20 (4 x 50 mL) followed by removal of solvent from the dried combinedextracts yielded a colorless oil (59 mg) that was purified by radial chromatography (1 mmplate (Si02); 5% EtOAc / 95% hexane) to provide pure methoxy-ketone (110, 55 mg; yield94%).IR (CHC13): v = 3073 (C-H, phenyl); 2939, 2859 ( C-H); 1705 (C=0); 1100 cm -1 (C-0).MS (DCI, NH3) : m/z (%) = 536 ((M+H)+, 5.6); 535 (M+, 5.6); 479 (15); 477 (67.0);279 (100.0).1H NMR (CDC13): 8 = 0.70(3H, t, J=3Hz, -CH2CF11) 0.75 (3H, s, C-13-Me); 1.06 (9H,s, tBu); 1.30 - 1.55 (11H, m); 1.62 - 1.96 (5H, m); 2.05 - 2.42 (3H, m); 3.31(3H, s, OCH3); 3.34 - 3.45 (2H, m, CH2-OMe); 3.60 - 3.73 (1H, m, CH-OTBDPS); 7.32 - 7.43 (6H, m, phenyl); 7.63 - 7.74 (4H, m, phenyl).85BIBLIOGRAPHY & APPENDICES861. (a) T. Money. Nat. Prod. Rep. 2, 253 (1985) (b) T.Money In Studies in NaturalProducts Chemistry. Vol. 4. 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Perkin Trans. 1.995 (1993).91Appendix ACorrelation of C(13) methyl chemical shifts (ppm)with respect to the relative stereochemistryof the CD ring junction in hydrindane systems.Href. 47 ref. 48Href. 50Href. 50ref. 450.950 .70 OTBDPS^1.04 OTBDPSHref. 51 ref. 51Href. 52Href. 53OH OH0OTHP483  CO2Et92i iiAppendix B53112 i^ii 1--.— 113; X = - S-CH2-CH2,S-1-1111■114; X = 0 ^111115enol -117116i) HS(CH2)2SH, BF3 'Et20, Me0H; ii) 3-furyl lithium, THF; iii) Tl(NO 3)31120, Me0H;iv) MsCI, NEt3 , CH2C12; v) MCPBA, CH2C12- phosphate buffer, vi) Si02iv93


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