LIBRARY Michigan State University This is to certify that the thesis entitled Approaches to the Synthesis of Bicyclo(5.3.0)decane Containing Natural Products via Furan-Terminated Cationic Cyclizations presented by Gary Michael Johnson has been accepted towards fulfillment of the requirements for Masters degree in Chemistry Major professor Date July 1, 1987 0-7639 MS U is an Affirmative Action/Equal Opportunity Institution —._—_ -_ V. 77777 7 i V __ MSU LIBRARIES RETURNING MATERIALS: ._c_. Place in book drop to remove this checkout from your record. ‘FINES will be charged if book is returned after the date stamped below. APPROACHES TO THE SYNTHESIS OF BICYCLO(5.3.0)DECANE CONTAINING NATURAL PRODUCTS MIA FURAN TERMINATED CATIONIC CYCLIZATIONS By Gary Michael Johnson A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry July, 1987 ABSTRACT APPROACH ES TO THE SYNTHESIS OF BICYCLO(5.3.0)DECANE CONTAINING NATURAL PRODUCTS MIA FURAN TERMINATED CATIONIC CYCLIZATIONS by Gary Michael Johnson The guaianolides and pseudoguaianolides are members of a class of natural products which possess a bicyclo(5.3.0)decane skeleton. These functionally and stereochemically complex natural products have exhibited a broad and potent spectrum of biological activities; and as a result have been the targets of extensive synthetic studies. As part of a general program in furan chemistry, we have examined and demonstrated the utility of furans as dianions in annulation sequences. When coupled with the ability of the furan nucleus to serve as the operational equivalent of a variety of acyclic, carbocyclic, and heterocyclic systems, this methodology should serve well in the synthesis of complex systems such as those represented by the guaianolides and pseudoguaianolides. We will describe general and flexible approaches to guaianolide precursors utilizing furan terminated cationic cyclizations to form the crucial bicyclo(5.3.0)decane ring system. Pseudoguaianolides might also be obtainable through simple modification of these precursors. Para mi bella esposa Linda Te Amo iv ACKNOWLEDGEMENTS The author wishes to thank Dr. Steven Tanis for his support, guidance, patience, and friendship throughout this project. Financial support for this project from the NIH-GM is greatfully acknowledged. Assistance in the form of a teaching assistantship from September, 1984 to December, 1985 was provided by Michigan State University. The author also wishes to acknowledge certain members of the faculty, the staff, and all the secretaries, for their assistance and advice throughout this project, as well as his fellow students for their advice and friendship. Thanks to the Tanis munchkins for many fine hours of entertainment. Thanks to Dr. Tanis and Dr. Reusch for many a splendid Cabernet and Zinfandel tastings. Vlve Ie Vinl I give my Love to my family for their comfort and support throughout this endeavour. Thanks to Kevin and Lori, Bill and Melinda, Tonya, and Yousef for lending an ear on numerous occasions. Special thanks to my wife Linda for her Love, comfort, patience, and especially her driving ability, without which this work would not have been possible. Vi TABLE OF CONTENTS List of Figures ........................................................................................ vii List of Schemes ..................................................................................... viii Introduction... .......................................................................................... 1 Results and Discussion ......................................................................... 6 Conclusions ............................................................................................ 16 Experimental ........................................................................................... 18 Bibliography ............................................................................................ 4O VII LIST OF FIGURES Figure 1. ............................................................................................ 3 Figure 2. ............................................................................................ 6 Figure 3. ............................................................................................ 8 Figure 4. ........................................................................................... 11 Figure 5. ........................................................................................... 12 viii LIST OF SCHEMES Scheme 1. .............................................................................................. 4 Scheme 2. .............................................................................................. 5 Scheme 3. .............................................................................................. 7 Scheme 4. .............................................................................................. 9 Scheme 5. .............................................................................................. 1 0 Scheme 6. .............................................................................................. 12 Scheme 7. .............................................................................................. 13 Scheme 8. .............................................................................................. 14 INTRODUCTION An abundance of bioactive molecules that exist in nature, are found to contain within their framework, 5-membered, oxygenated, heterocyclic rings in various states of oxidation1 . These include guaianolides2a (1 -4), pseudoguaianolidesza'c (5-9), tiglanes3 (10, 11), daphnanes3, and 1 2 ingenanes3. A common feature of compounds 1-11, in addition to a butyrolactone moiety, is the bicyclo(5.3.0) decane skeleton. Because of the challenges associated with the synthesis of highly substituted and/or oxygenated bicyclo(5.3.0) decanes, and the diverse biological activities associated with compounds like 1-1 1, which include allergenic4, contraceptive5 (8), cocarcinogenic3aubs 5 (10, 11), cytotoxic7 (3, 5), antitumor3, antineoplastic8 (9), antihelmenthic9, antifeedantm, and antileukemic11 (7) properties, extensive efforts have been expended in the syntheses of 1-11 and related compounds.12 In keeping with our current program in furan terminated cationic cyclizations, which have resulted in the construction of fused-, bridged-, and spirocyclic- ring systems”, we have extended our efforts towards the synthesis of bicyclo(5.3.0)- FUSED BRIDGED SPIRO decane precursers of 1-11. Of particular initial interest is the demonstration that a suitable intermediate for the synthesis of the relatively simple bicyclo(5.3.0) decane containing compounds2 1, 2, 3, and 5, can be readily prepared. We envision the furyl-ketone 12, as a particularily attractive precursor to both the guaianolide (1 -3) and pseudoguaianolide (5) families of sesquiterpenes. 12 We have previously demonstrated the ability of the furyl moiety to successfully participate in annulation processes, culminating with a regio-controlled, furan terminated cyclization”. These considerations,along with the plethora of useful functionalities which can be derived from the product furans (figure 1) have led us to approach compounds 1-11 via such a pathway. of) , Q :l I) O O \ r: HGURE1 As illustrated in scheme 1, the coupling of a hypothetical cyclopentane di- cation equivelent, selectively at the 6- position with a furyl anion equivalent would lead to the substituted cyclopentane 15, which after, cyclization by a Friedel- Crafts type process would afford 12. For this sequence to succeed, the 13 14 15 12 SCHEME1 reactivities of the di-anion and di-cation equivelents must be adjusted such that only one regioisomer results from the initial C-C bond formation. With respect to the furyl moiety, selectivity can be guaranteed by relying on the vastly different levels of reactivity displayed by a side chain organometallic and the neutral furan with respect to an electrophilic center. In order to assure regiochemical integrity in the initial carbon—carbon bond forming sequence, we anticipate utilizing a cyclopentane di-cation equivalent in which the second site of electron deficiency is developed as a result of the chemistry employed in the first carbon-carbon bond formation. In such a fashion 12 could be produced possessing a variety of R functions, eventually leading to Estafiatin 19- 13, Compressanolide 214, and Zaluzanin 315. The development of synthetic methodology which will allow facile construction of compound 12 will be the subject of this thesis. An additional consideration, which heightens our interest in the preparation of 12, is that the alkylation of the putative thermodynamic enolate of 12 (scheme 2) should place a methyl at the desired ring fusion carbon, perhaps affording eventually a pseudoguaianolide such as 5. Alteration of the nature of the di- anion and di-cation equivelents should also provide access to more highly oxygenated compounds and yield products of annulation sequences with 5 alternate furan placement; thus furnishing assorted ambrosanolides, helenanolides, and tiglanes. SCHEME 2 RESULTS 8: DISCUSSION We planned to construct the bicyclo(5.3.0)decane ring system, present in 1-11, utilizing a furan terminated cationic cyclization. As described previously, this synthetic approach will couple a furyl di-anionic equivalent with a cyclopentenoid di-cation equivelent. The chemistry of Marina”, and Wender16, and results from our own laboratories12 suggested employing epoxy-cyclopentene enol ether 1612s ‘5 (n=1), and vinyl spiroepoxide 1712 as bis-elecrophiles. To determine oms o R l 0 Z (+) 16 17 FIGURE 2 the utility of such a construction, we examined the model system outlined in scheme 3. The enol silyl ether 19, prepared from 7-oxo-bicyclo(4.1.0)heptane, was treated with the Grignard reagent derived from 3-(3-furyl)propyl bromide 1817 and CuCN, which after Sn2' addition, hydrolysis and dehydration, provided the enone 2012h (70%). NaBH4 reduction of enone 20 according to Luche18 (CeCl3), afforded the allylic alcohol 21 (70%). Exposure of 21 to our previously described cyclization conditions12 (HCOOH, 06H12), led to the corresponding formate; none of the desired cyclized material was obtained. However, cyclization to 22 (25% unoptimised) was observed when either i) the initially formed formate was treated with stOH in refluxing benzene; or ii) stOH was added catalytically to the HCOOH/C5H12 reaction mixture. The 7 bicyclo(4.4.0)decane system 2412“, corresponding to 22 with a methyl group in a ring fusion position can also be prepared from 20 (scheme 3). Addition of OTMS O 69"” MgBr NaBH4 ' s cm ’ / \ W l O 19 a n=1 20 n=1 b n=0 H «1% R / ”“000“: C6H12 > 9. OH O 2) PTSA, Bz, reflux R O / 21 n=1,n =11 22n=1,R=H 23n=1,R =Me 24n=1,R=Me SCHEMES MeLi to enone 20, affords the tertiary allylic alcohol 23. Treatment of 23 with HCOOH/05H12 followed by stOH as described above gave a fine yield (72%) of cyclized product 2412h (n=1). These results suggested that a variety of linearly fused carbocyclic adducts related to 22 and 24 might be routinely prepared by variation of the ring size of bis electrophile 19, or via the chain length of the furyl organometallic. To obtain the bicyclo(5.3.0)decane system present in the target (1-3,5) guaianolide and pseudoguaianolide natural products, we wished to employ the same technology; however with 19b (n=0) in place of the cyclohexanone derived epoxy enol silyl ether. Unfortunately, despite the numerous attempts utilizing a wide variety of reaction conditions, we were unable to prepare and isolate 19b. We also examined the preparation and utilization of 19b Milli; to no avail. Therefore, we reluctantly concluded that the epoxy enol silyl ether constructed from cyclopentenone was too labile to be of any utility in this synthetic endeavor. The projected construction of the guaianolide and pseudoguaianolide bicyclo(5.3.0) ring system might yet be realized if we could replace 19b (n=0) with an alternative cyclopentenoid 1,2-bis-electrophile. We have previously employed enone derived vinyl spiroepoxides in this context”, suggesting application of this class of bis-electrophile equivelents to the problem at hand. Thus, methyl- thio-methyllithium (figure 3) addition to cyclopentenone 25 gave the MTM alcohol 26 in 94% distilled yield. Exposure of 26 to 30 equivelents of Mel led to a quantitative crude yield of the sulfonium salt 27, which could be recrystallized from ethanol. Salt 27 could be conviently converted 10.51111 to spiroepoxide 28 as shown below (figure 3). With the requisite spiroepoxide 8M92 SM62+ I - 0 Ho Ho 0 d m <5 Mi .._, 8 25 26 27 28 FIGURE 3 prepared, if not in hand, we turned our attention to the synthesis of the cyclization substrate, and the crucial annulation sequence (scheme 4). Assisted (CuCN) SN2- addition of the Grignard reagent prepared from 3- (3-furyl)propyl bromide 1817 to 28 gave allylic alcohol 29 in 70-90% yield. Based upon earlier experience”, we expected the primary allylic alcohol initiated cyclization to fail; therefore we prepared the secondary allylic alcohol as outlined in scheme 4. Thus allylic alcohol 29 was oxidized (PCC, 80-95%), and the crude product aldehyde was treated with methyllithium to provide the secondary allylic alcohol o O W MgBr CuCN (45), é (-78) > O 29 O HCOOH. 15 ' . . I-D mm» Mel—I (31) cat. PTSA, heat Me H 31 32 SCHEME 4 31 in 90-95% yield. Alcohol 31 underwent smooth cyclization when reacted with HCOOH/C5H12, followed by stOH in refluxing benzene, leading to 32 as a mixture of olefin isomers (54%). A slight modification of the cyclization conditions to include a catalytic amount of stOH fifteen minutes after introduction of HCOOH was found to lead almost exclusively to 32 in yields of 85-95%. This method allowed the routine preparation of several grams of furan 32. Having successfully constructed the model (5.3.0)decane skeleton, we turned our efforts to the synthesis of a suitably functionalized guaianolide precursor as illustrated in scheme 5. Copper catalyzed addition of the vinyl anion of 34 to the 10 d‘ / I \ SHBU3 ref 12 W Br CuBrSMea O 3,, O CDC Ho 3‘ 35 H / \ /. P00 (36) ’ o HCOOH,15E]'ln. H M9“ (37) I'D cat. PTSA, heat 0 \ \4 37 38 SCHEME 5 spiroepoxide 28 provided allylic alcohol 35 in 69% yield. Utilization of CuBr-SMeg19 in the sequence was found to be crucial to its success; with CuCN leading to dimerization of the vinyl Grignard. Moreover, the use of the vinyl Grignard (MgBrz-Et20)23, rather than the initally produced vinyl lithium, was found to be important as the lithium derivatives afforded less than 20% of the desired alcohol 35. By analogy to the observation reported in scheme 2 , 35 was smoothly converted (PCC, 85% crude, MeLi, 81%) to the secondary allylic alcohol 37. Cyclization with HCOOH/C5H12, and a catalytic amount of stOH, afforded adduct 38 in 72% yield as a mixture of olefin isomers. The somewhat lower yield might to be due to the increased fragility of the system. This assumption is based upon a rather simplistic examination (1H-NMR) of the effects of extended reaction time, heat, and amount of stOH added. However, consistent yields are readily obtained with careful monitering via TLC. 11 With cyclized substrates now in hand (32, 38), we needed to remove the two carbons of the alkylidine moiety to arrive at our desired intermediate ketone 12. Quite a few methods have been reported in the literature25;:‘29 for the cleavage FIGURE 4 of 0-0 double bonds to afford the corresponding ketone. In selecting some of them for the parent substrate, we had to consider their compatability with the relatively acid, and oxygen, sensitive disubstituted furan present in 32. With these considerations in mind we elected to examine the ability of a) i) 050425, ii) Nalo426; b) KMno427; c) Ruo428;d) 0329; and e) i) MCPBA, ii) H3O+, iii) NalO4; to perform this transformation. Reaction conditions a-c were examined in detail; to no avail. We observed either no reaction, or fruitless consumption and destruction of the substrate 32. Similiarly, ozone failed to afford the desired ketone 12. However, epoxidation (e), did provide variable yields of a mixture of epoxides. Unfortunately, the conversion of these epoxides to ketone 12 (HCOOH, K2C03, NalO4) was inefficient; providing 12 in but 3% overall yield from 32. Given the difficulties encountered in the ”direct" C-C double bond cleavage, we elected to investigate a multi-step approach via the corrresponding ketone 39 (figure 5). Hydroboration of 32 followed by oxidation of the organoborane, and 12 PCC oxidation of the product alcohol gave ketone 39 in 42% yield from 32. The design concept from this point was ”simple", to effect the hydroxylation of the 1) Thexyl)zBH ‘i- 3) FCC 32 39 40 FIGURE 5 putative thermodynamic enolate, providing 40. This could then be followed by cleavage to 12. Unfortunately, despite a number of attempts, we were unable to secure 40. We were also unable to demonstrate the production of the desired enolate precursor to 40. Therefore we modified our route to remove this problem as described in scheme 6. 1)PCC 2) RPhM ”0 4x-Ph 4X'Ph 29 41a X.-.I-I 42a X: H b X=0Me b X: OMe SCHEME 6 The addition of phenyl-lithium or (4-methoxy)phenylMgBr to the aldehyde prepared from 29 gave 418 and 41b in 71% and 70% yield, respectively. 1:»; Exposure of 41a and 41b to HCOOH-05H12 furnished the desired cyclized compounds 42a (87%) and 42b (74%) as single olefin isomers. With 42a and 42b in hand, we next examined the conversion of these compounds to ketone 12. Hydroboration of 42a and 42b (scheme 7) provided alcohols 43a (55%, with 35% recd. SM.) and 43b (60%, with 8% recd. S.M.) as a mixture of stereoisomers. Oxidation with PCC afforded ketones 44a, 45a (55%) and 44b, 45b (59%) as 5:1, and (6-8):1 mixtures, respectively. These epimeric mixtures could be separated into major and minor components, which were initially assigned as Q- and B-benzoyl isomers respectively. At this point, the assignment 42a X: H 438 X= H D X: OMe b X: OMe 453 X: H D X: OMe SCHEME7 was based only on the mode of synthesis; the presumed conformation of the precursor olefins, and the previously demonstrated difficulty to effect proton removal at the tertiary position. Should this analysis be correct, we then have in hand, a preponderance of an epimer which is less stable than the alternative one 14 having benzoyl placement on the convex face of the molecule. To examine this possibility, ketones 44b, and 45b were separately exposed to NaOMe (6 equiv.) in refluxing methanol. In each of these cases, only the minor isomer 45b was isolated; this was previously presumed to be the more stable B-benzoyl compound, thus providing support for the assumption listed above. In one additional experiment, we observed that separate treatment of the major 01- ketone 44b, and the B-ketone 45b, with NaOMe in CH3OD afforded mono- deuterated 45b from 44!) at room temperature and mono-deuterated 45b from 45b only after prolonged reflux. This result suggested that the ketones did not enolize with equal facility and that the next stage of this study, namely the enolate hydroxylation, should be performed with purified ketones 44a, and 44b. Therefore, treatment of 44b with LDA (1.1 eq., -78°C, -45°C) followed by MoOPH-HMPA-Pyr30 (78°C to RT) yielded a single o-hydroxy ketone 46 (72%, with 24% recd. S.M.) as seen in scheme 8. The stereochemistry depicted O 4X'Ph’\° 4X-Ph/‘O 44D R: OMe 46 R: OMe 12 SCHEME 8 is based on the assumption that hydroxylation will occur from the more accessible convex face of the molecule. Reduction of 46 with LAH gave a single diol 47 (83%) which was immediately cleaved with NalO4 (aq. t- BuOH) to give 49% of a mixture of 12 and anisaldehyde, and 51% of an unknown compound with 15 molecular weight 310. Removal of anisaldehyde as a bisulfite complex provided pure 12 in 35% yield from the diol. Although 12 was only isolated in 35% yield, the conditions have not yet been optimised in terms of the solvent choice, amount of NalO4, or reaction time employed. Initial attempts at cleavage in aq. ether, or aq. acetone, resulted in no reaction over a twenty four hour period with up to three equivelents of NalO4. Optimium quantities of peroldate, reaction time, and solvent may very well raise the yield of 12, and these endeavours are in progress. The unknown material (MW. 310, Cl/MS) presently obtained was thought possibly to be a dehydration product based on the 250 NMR spectrum. Structural studies are continuing with the hope that the structure of the unknown compound will provide insight for the choice of the proper reaction conditions. CONCLUSIONS The approach described for the syntheses of the bicyclo(5.3.0) decane ring systems, which utilizes a furan terminated cationic cyclization sequence has proved to be useful and flexible; affording the desired guaianolide precursor 12. With this information in hand, we will examine the conversion of the more judiciously functionalized 38, or an equivelent, to an analog of 12. Additional studies will be directed toward the production of methyl and oxygen functionalized congeners of 38. Although there were some difficulties in the C-C bond cleavage steps, the matter did not prove to be impossible; only tedious. The adducts in question can be manipulated albeit with difficulty. Optimization of the final sequence, especially the NalO4 cleavage should raise the overall yield to a more palatable level. An interesting point noted during the course of this work was the cyclization of adduct 21 in the model (4.4.0) decane ring system to provide 22. In general, we have found that secondary allylic alcohols were not inclined to directly provide high yields of cyclized products. The fact that this system did cyclize is worthy of note. The modified cyclization procedure (cat. PTSA, heat) developed in this work should lead to a general increase in the product bicyclo(5.3.0)decane yield regardless of the nature of the secondary allylic alcohol. The bicyclo(4.4.0)decane system produced in this study is also of interest as the precursor of a variety of terpenoids. Time permitting, this avenue of research will also be examined. In order to prepare a guaianolide with the chemistry described above, we anticipate preparing analogs of 12 (R=H) in which R: (=CH2), (:0), (OR'). 16 17 Manipulation of these functionalities should afford the methylene moiety present in a number of target guaianolides. Furan manipulation to target butenolides is well precedented in the literature31 and has been examined in our laboratories. Manipulation of the ketone functionality should readily provide the desired structural features on the second pendant 5 membered ring. Additionally, the placement of a methyl moiety in the ring junction of 12 on related compounds should lead to the synthesis of the pseudoguaianolide family of natural products. In the current study, we believe that the 5-7 ring system is cis fused. However, molecular mechanics (MM2) calculations on both cis and trans epimers of 12 have indicated that trans is favored by 2.0 Kcal. Should this be the case, then trans fused pseudoguaianolides could be readily constructed. In summary, this work has demonstrated that systems such as 12 can be readily prepared; and that the chemistry is sufficiently flexible to allow incorporation of modifications that lead to the desired products. Therefore, we plan to utulize this methodology for the synthesis of a number of biologically significant guaianolides. EXPERIMENTAL General: Tetrahydrofuran, ethyl ether, benzene, and hexane were dried by distillation under argon from sodium benzophenone ketyl. Di-isopropyl amine, collidine, and methylene chloride were dried by distillation from calcium hydride. N,N dimethyl formamide was dried by distillation from phosphorous pentoxide. N-butyl-, sec-butyl-, and t-butyl lithium in hexane were purchased from Aldrich Chemical 00., Milwaukee, Wis., and were titrated by the method of Watson and Eastham.21 Magnesium metal was activated by successive washings with 0.1N aq. HCI, distilled water, acetone, and anhydrous ether respectively, and then dried in a dessicator over phosphorous pentoxide at reduced pressure. Chromatography was performed using the flash technique of Still et. al.22, using the silica gel and solvents mentioned. The column outer diameter (o.d.) is listed in millimeters. Thin layer chromatography used Merck SIL G/UV precoated glass plates. Spots were visualized by dipping into one of the following: 1) a solution of vanillin (1.5 g) in absolute ethanol100. ml) and cone. sulfuric acid (0.5 ml), or 2) a solution of phosphomolybdic acid (5.0 g) in absolute ethanol (100. ml); and then heating the plate. Proton magnetic resonance spectra were recorded at 60 MHz (Varian T-60), 80 MHz (Varian FT-80), and 250 MHz (Bruker WM-250) as solutions in deuteriochloroform unless otherwise indicated. Chemical shifts are reported in parts per million on the 5 scale relative to a tetramethylsilane internal standard. Data are reported as follows: chemical shift(multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, brs=broad singlet), coupling constant (Hz), integration). 130 magnetic resonance spectra were recorded on a Bruker WM- 18 19 250 spectrometer (68.9 MHz) and are reported in parts per million from tetramethylsilane on the 6 scale. High resolution mass spectra were performed by the M. S. U. Regional Mass Spectroscopy Facility; Dept. of Biochemistry, East Lansing, Michigan 48824. Electron impact (El/MS) and chemical ionization (Cl/MS) mass spectra were recorded on a Finnigan 4000 utilizing an INCOS 4021 data system. A Pye- Unicam SP-1000 infrared spectrophotometer was used to record infrared spectra using polystyrene as a standard. Melting points were obtained on a Thomas- Hoover capillary melting point apparatus and are uncorrected. All reactions, unless otherwise stated, were carried out under a blanket of argon in flame dried glassware, with the rigid exclusion of moisture from all reagents. Base washed glassware was prepared as follows: washing in an KOH/EtOH base bath, followed by distilled water, ammonium hydroxide, distilled water, absolute ethanol, and flame drying. Syringes, cannulas, needles, and spin bars employed with base washed glassware were also prepared in the same manner. WWI-11181 - To a solution of triphenyl-phosphine (25.99 g, 99.2 mmol) in CH2CI2 (600. ml), cooled in an ice water bath, was added 3-(2- iuryl)-propan-1-ol12h (10.0 g, 79.4 mmol), followed by addition of NBS (17.66 g, 99.2 mmol) in 4 portions over ten minutes. After stirring at 0°C for four hours, the solution was warmed to RT and stirred one hour further. The solution was concentrated jam; cast into hexane (350. ml), and stored overnight in a freezer. The precipitated Ph3PO was removed by filtration through a pad of celite, the filter cake washed with hexane, and the combined filtrates were washed with NaH003, and brine (250. ml 9a.), dried (M9804), and concentrated lama to provide the crude product as a pleasant smelling pale yellow liquid. 20 Distillation (BP24 93-97°C) provided 11.0 g, (73.3%) of 18. Rf=0.68 in hex/ether (1/1). W - To a solution of the onono (20)12 (0.42 g, 2.10 mmol) in anhydrous MeOH (20. ml), cooled to 0°C in an ice water bath, was added CeCI3-7H20 (0.786 g, 2.10 mmol) in one portion. After five minutes, NaBH4 (0.159 g, 4.20 mmol) was added in two portions, and the reaction stirred for one half hour. The solution was quenched with sat. aq. NH 4Cl (20. ml), cast into hexane lether (150 ml, 1/2), and then washed with sat. aq. NH4CI, sat. aq. NaHCO3, and brine (150 ml ea.), followed by drying (MgSO4) and concentration We. Purification by chromatography on a column of silica gel (50 mm o.d., 100. 9, 230-400 mesh, hexane/ether (4/1), 25 ml fractions) using the flash technique provided 0.30 g (69%) of the alcohol 21 from fractions 24-49. Rf=0.24 in (1/1) hexane/ether. 7 : 206(M+,3.6), 188(1.5), 170(1.5), 159(5.4), 143(7.7), 124(6.7),108(31.9), 95(292), 81 (66.1), 70(59.1) 53(59.5), 41 (base) 1mm: 8 :7.30(brs,1),7.18(brs,1),6.24(brs,1),5.84(d, j=2.1Hz, 1), 5.70(m, 1), 4.00(brs, 1), 2.41 (m, 2), 2.01 (m,2),1 .80-1 .00(m, 8) IBM 3600-3100, 2980-2820, 1570, 1500, 1250, 1015, 780 cm‘1 ansmmmnenmumumwn - To a solution of the allylic alcohol (0.20 g, 0.97 mmol) in cyclohexane (4. ml) at RT was added in one portion formic acid (1. ml). The mixture stirred for ten minutes, and then was cast into ether/ water (40 ml, 1/1) and the organic phase separated. The aqueous phase was extracted with ether (3 x 25ml), and the combined organic layers washed with NaHCO3, and brine (100 ml ea.), dried (M9804). and concentrated W. The crude product was purified by chromatography on a column of silica gel (30 21 mm o.d., 40.0 9, 230-400 mesh, hexane/ether (4/1), 15 ml fractions) using the flash technique. Fractions 9-15 provided 0.110 g, (49%) of the formate esters of allylic alcohol 21. Rf=0.6 in (10/1) hexane/ether. v : 234(M+, 1.9), 188(12.8), 171 (2.0), 159(24), 147(8.8), 131 (6.9), 1 17(4.6), 104(25.1), 94(734), 81 (base), 67(26.5) 1W1): 5 :,7.87(s 1),7.84(s,1),7.,33(d J=1 Hz, 1),7.18(brs,1), 6.,25(brs 1) 60 -.,512(m 4), 2.,24(m 2), 2.,05(m 2), 1.95-1.10(m, 5) Mean: 3015, 2980-2860, 1720, 1500, 1450-1430, 1220-1130(w),1020, 870, 780 cm-1 W - To a solution of the formate esters, (0.036 g, 0.152 mmol) in benzene (10. ml) was added stOH (0.066 g, 0.69 mmol), and the mixture was refluxed gently for one half hour. The clear solution which had turned blue in color, was diluted with ether (40 ml), and carefully quenched with sat. aq. NaHCO3 (40 ml). This was followed by solid NaHCO3 until one obtained a pH of 9.0. The organic phase was separated, and the aqueous phase extracted with ether (3 x 40 ml). The combined organic layers were washed with brine (100 ml), dried (M9804), and concentrated Mm. Purification by chromatography on a column of silica gel (20 mm o.d., 20. 9, 230-400 mesh, packed in (300/1) hexane/ether run in (100/1) hexane/ether, 10.0 ml fractions) using the flash technique, provided 0.00719, (25%) of the cyclized product 22, from fractions 7- 16. Rf=0.36 in (99/1) hexane/ether. w: 188(M+, 47.0), 173(3.5), 160(base), 145(229), 131 (34.9),1 1 7(20.6), 105(10.6), 91 (28.7), 77(133), 65(5.85), 53(3.31) 1 W: 6 : 7.22(d, J=1.5 Hz, 1), 6.18(d, J=2.5 Hz, 1), 5.82(d of t, J=14, 4 Hz, 1), 5.5(d of t, J=13, 1 Hz, 1), 2.42(t, J=8.4 Hz,2), 2.20-1.55(m, 1) M931): 3010-2840, 1510, 1450, 1210, 1170-1030, 970, 895, 800,730 cm' 22 Hl°°.llll ---- -- H1131! - (A)Toa solution of 1-((dimethylsulfonio)methyl)cyclopent-2-en-1-ol12h (27), (3.78 g, 13.23 mmol) in THF (150 ml) in a 250 ml base washed round bottom flask, was added NaH (0.480 g, 15.87 mmol) in one portion. The mixture stirred for five and one half hours and was then cooled in a dry ice-isopropanol bath (-78°C). (B) To activated Mg metal (0.50 g, 20.6 mmol), in a 500 ml base washed round bottom flask with condenser, is added 10% of a solution of 3-(3 furyl)-propyl bromide17 18 (3.00 g, 15.87 mmol) in THF (10. ml). After reaction began, the remaining 90% of the bromide solution was diluted with THF (85. ml) and added over one half hour, followed by gentle refluxing for two hours. The mixture was cooled in a dry ice-isopropanol bath, and CuCN (1.42 g, 15.87 mmol) was added in one portion. After stirring at -78°C for one hour, the mixture was warmed to - 45°C (dry ice-acetonitrile) for one half hour, then cooled to -78°C for one quarter hour. The spiroepoxide (A) at -78°C, was then added 116128001113 over one half hour. After stirring at -78°C for three hours, the mixture was warmed to RT over one and one half hours. The solution was then quenched with sat. aq. NH4Cl (100 ml) and NH4OH/H20 (220 ml, 1:1). The mixture was saturated with NaCl, separated, and the aqueous phase was extracted with ether (3 x 100. ml). The combined organic layers were washed with NaHCO3, and brine (200 ml 98.), dried (M9804). and concentrated W. The crude product was purified by chromatography on a column of silica gel (50 mm o.d., 200. 9, 230-400 mesh, packed hexane/ether (4/1), run hexane/ether (2/1), 100 ml fractions) using the flash technique. Fractions 11-23 provided 2.089 g (76.6%) of 29. Rf=.28 in (1/1) hexane/ether) as a pale yellow viscous liquid. 23 : 206(M+, 8.8), 188(14.9), 175(193), 159(5.5), 147(3.5),131(6.6), 123(8.6), 106(14.8), 95(47.3), 79(base), 67(83.3),53(56.3), 41 (86.7) 1mm: 6 :7.31(t, J=1 Hz, 1), 7.18(brs, 1), 6.26(brs, 1), 5.06(m, 1), 4.16(s, 2), 2.67(m, 1), 2.40(t, J=7.5 Hz, 2),2.30(m, 2), 2.10(m, 1), 1.65-1.20(m, 5) 13mm): 3640-3100, 2980-2880, 2860, 1500, 1450, 1430, 1380, 1160, 1020(w), 875, 775, 720 om-1 - -_t -... - our-at: -:..-o.:.-_-t 0.‘ -Toasolutionof alcohol 29 (1.00 g, 4.854 mmol) in CH2CI2 (400. ml), in a 1L base washed round bottom flask, was added celite (25. 9), followed by PCC (1.57 g, 7.28 mmol). After stirring two hours at room temperature, ice cold hexane (200 ml) was added and the mixture was filtered through a plug of celite/silica gel. The filtrate was dried (MgSO4), and concentrated 11118910.. to give the crude aldehyde as a viscous yellow liquid. The crude product was purified by chromatography on a column of silica gel (50 mm o.d., 100. 9, 230-400 mesh, hexane/ether (5/1), 30 ml fractions) using the flash technique. Fractions 10-16 afforded 0.667 g. (67.4%) of 30. Rf=0.48 in (1/1) hexane/ether. :204(M+, 30.2), 186(3.2), 175(7.7), 147(131), 133(50), 122(base), 109(13.2), 95(340), 81 (74.1 ), 67(55.5), 53(45.6) 1m: 6 :9.73(s,1), 7.31 (m, 1), 7.20(brs,1), 6.75(m,1),6.26(brs, 1 ), 2.89(m, 1 ), 2.55(m, 2), 2.45(t, J=6.3 Hz, 2),2.18(m, 1), 2.00-1.35(m, 5) 13mm: 2980-2880, 2860, 2710, 1675,1610,1500.1430,1350, 1255,1160, 1020, 870, 770, 720 cm-1 I °°.\‘I -.l. 1-... - Hz-i'i: - To a solution of the aldehyde 30 (1.151 g, 5.642 mmol) in ether (500. ml), in a 1L base washed round bottom flask cooled in a dry ice-isopropanol bath to -78°C, is added MeLi(1.4M, 7.6 ml, 10.64 mmol), and the mixture stirred for one hour. 24 Additional MeLi (0.33 equiv.) was then added and the mixture stirred for one additional half hour until no starting material was observed by TLC. The solution was warmed to room temperature over one half hour, and was quenched with sat. aq. NH4Cl (200 ml). After separation, the aqueous phase was extracted with ether (3 x 150 ml). The combined organic layers were dried (M9804), and concentrated Mug. The crude product was purified by chromatography on a column of silica gel (50 mm o.d., 125. 9, 230-400 mesh, hexane/ether (2.5/1), 40 ml fractions) using the flash technique. Fractions 14-35 afforded 1.161 g (94%) of 31. Rf=0.20 in (1/1) hexane/ether. : 220(M+, 3.0), 2020.4), 187(1.1), 175(30), 159(25), 147(24), 133(24), 120(9.9), 111(4.4), 95(15.4), 81(18.5), 67(15.3) 53(12.8), 43(base) 1mm: 5 :7.34(t, J=1.5 Hz, 1), 7.19(brs, 1), 6.23(brs, 1), 5.51 (brs, 1), 4.39(q, J=6.3 Hz, 1), 2.64(m, 1), 2.40(t, J=8.4 Hz,2), 2.28(m, 2), 2.09(m, 1), 1.66-1.30(m, 6), 1.27(d of d, J=5.4, 1 Hz, 3) 18.03260: 3700-3100, 3000-2820, 1500, 1450-1430, 1370, 1160, 1060, 1020, 870, 840, 770 cm-1 W - To a solution of the alcohol 31 (0.100 9, 0.4545 mmol) in cyclohexane (40. ml), in a 100 ml base washed round bottom, was added formic acid (10. ml) in one portion. After stirring twenty minutes, stOH (two crystals) was added and the mixture was heated gently (50°) for five minutes. After stirring twenty five minutes, the mixture was diluted with cyclohexane (25 ml) and carefully quenched with sat. aq. NaHCO3 (60 ml). This was followed by solid NaHCO3 until pH 9.0 was obtained. The aqueous phase was extracted with ether (3 x 50 ml), and the combined organic layers were washed with brine (75 ml), dried (M9804), and concentrated lama. The crude product was purified by chromatography on a column of silica gel (40 mm o.d., 30. 9, 230-400 mesh, hexane/ether (15/1), 10 ml fractions) using the flash 25 technique. Fractions, 5-10 afforded 0.089 g (96.7%) of 32. Rf=0.64 in (10/1) hexane/ether. w: 202(M+, base), 187(47.3), 173(62.8) 159(19.4), 145(16.3),131 (23.8), 117(16.8), 105(14.9), 91(37.5), 77(28.8), 65(24.9) 1W: 6 : 7.20(d, J=1.5 Hz, 1), 7.17(d, J=1.5 Hz, .33), 6.19(d, J=1.5 Hz, .33), 6.15(d, J: 1.5 Hz, 1), 5.26(t, J=1 Hz, .33), 4.88 (d of q, J=6, 4 Hz, 1), 3.78(m, 1), 2.8-1.2(m, 13) IBM: 3000-2800, 1505, 1460-1420,1 150, 890, 830, 790, 725, 690 cm‘1 W- To a solution of 3312 (12.0 g, 32.42 mmol) in THF (75. ml), in a 250 ml base washed round bottom flask, cooled in a dry ice- isopropanol bath, was added n-BuLi (2.4M, 17.6 ml, 1.3 eq.) over fifteen minutes. After stirring for one hour at -78°C, CuCN (3.78 g, 42.2 mmol, 1.3 eq.) was added in one portion and the reaction stirred one hour further. The mixture was warmed (45°) in a dry ice-acetonitrile bath for one half hour, and then cooled again to - 78°C. To the cuprate was added a solution of 2,3-dibromopropene24 (8.43 g, 42.2 mmol) in THF (15. ml) by cannula over one half hour. After stirring at -78°C for three hours, the reaction was quenched with sat. aq. NH4Cl (100 ml) and the organic phase separated. The aqueous phase was extracted with ether (3 x 250 ml), and the combined organic layers were then dried (M9804) and concentrated Lump, (NO HEAT). The crude product was purified by chromatography on a column of silica gel (60 mm o.d., 500. g.,230-400 mesh, (99/1) hex./ether, 250 ml fractions) using the flash technique. Fractions 23-40 gave 5.15 g. (79%) of the pure product 34. Rf=0.19 in hexane. . : 202(M++1, 4.9), 200(5.11), 121(66.9), 103(5.59), 91(15.2), 81 (base), 53(57.6), 39(42.7) 1W: 5 27.28 (m, 2), 6.28 (m,2), 5.58 (m, 1), 5.42 (m, 1), 2.70(s, 4) 26 IBJNeatl: 3000-2860, 1630, 1570, 1500. 1450, 1430, 1385, 1190, 1160, 1115, 1070, 1035, 890, 875, 780, 725 crn‘1 - 10.0..11‘ --- - t --_-t---- «om-t: - (A)Toa solution of 1-((dimethylsulfonio)methyl)-cyclopent-2-en-1-o|12 (0.10 g, 0.350 mmol) in THF (4.0 ml), in a 25 ml base washed round bottom flask, was added NaH (0.01 g, 0.420 mmol, 85%) in one portion. After stirring at room temperature for three hours, the mixture was cooled to -78°C, in a dry ice-isopropanol bath. (B) To a solution of 2-bromo-4-(3-furyl)-butene (0.211 g, 1.05 mmol) in other (4.0 ml) in a 25 ml base washed round bottom flask cooled in a dry ice-isopropanol bath was added n-BuLi (1.3M, 1.05 mmol, 0.81 ml). After stirring for one hour at -78°C, the mixture was warmed to -45°C (dry ice-acetonitrile bath) and the reaction stirred for one hour. The solution was then cooled to -78°C once more, and was added W to 1.10 mmol of MgBrg at -78°C; prepared mm from 1.10 mmol of ethylene dibromide and 1.25 mmol of magnesium metal in 5.0 ml of ether. After addition was complete, the mixture was warmed to -45°C for one half hour, and then cooled back to -78°C, and copper bromide dimethyl sulfide (0.108 g, 0.525 mmol) was added in one portion. After stirring one half hour at - 78°C, the imam.) generated spiroepoxide (A), at -78°C, was added W over fifteen minutes. The reaction stirred at -78°C for three hours and was then allowed to warm to room temperature and quenched with NaHCO3 (10 ml). This solution was diluted with other (200 ml), and cast into NaHCO3/sat. aq. NH4Cl/H20 (90/60/40 ml). After separation, the aqueous phase was extracted with ether (3 x 100 ml), and the combined etheral layers were washed with NaHCO3, brine, (200 ml 9a.), dried (M9804), and concentrated 10.169.052- The crude product was purified by chromotography on a column of silica gel (30. mm o.d., 30. 9., 230-400 mesh, packed in hexane/ether (6/1), run in hexane/ether 27 (3/1),10 ml fractions) using the flash technique. Fractions 20-72, gave 0.0525 g (68.9%) of pure 35. Rf=0.25 in (1/1) hexane/ether. : 218(M+, 3.7), 200(2.4), 187(2.6), 171(1.5), 162(2.8), 149(5.5), 137(base), 119(19.9), 105(222), 96(41.9), 81(88.6), 67(84.9) 1W: 5 .7330, J=2 Hz, 1), 7.,21(m 1),6.28(m,1),5.,,56(m1) 4.81(m,1),4.,73(m 1), 4.,21(brs 2), 3.35(m, 1), 259 (t 74 Hz 2), 2.27(m, 5), 1.761.35(m 2) 13mm): 3640- 3100, 3000- 2800, 1630, 1500, 1450, 1430, 1380, 1150 ,1020(w), 890, 870, 780, 720 cm-1 --. - 111 ~- . - 1- .. 1 - ::1 .=. .010.- -:1 0.: -Toasolutlonof the alcohol 35 (0.375 g, 1. 72 mmol) in CHZCIZ (150. ml), in a 500 ml base washed round bottom flask, is added celite (10. 9) followed by PCC (0.593 g, 2.75 mmol) in one portion. After stirring for one and one half hours, ice cold hexane (75 ml) was added and the mixture filtered through a plug of celite/silica gel. The solution was dried (M9804), and concentrated W to provide the aldehyde as a viscous yellow liquid. The crude product was purified by chromatography on a column of silica gel (30 mm o.d., 30. 9, 230-400 mesh, hexane/ether (5/1), 10 ml fractions) using the flash technique. Fractions12-27 afforded 0.240 g (65%) of 36. Rf=0.51 in (1/1) hexane/ether. : 217(M++1, 2.3), 216(M'i', 15.6), 201(2.1), 187(12.7), 172(1.94), 1:113:23, 135(24.9), 122(12.9), 107(16.1), 95(11.8), 81(base), 67(21.6), 53(36.6), 1W: 5 :.,971(s 1), 7.34(t, J: 2.1 Hz, 1), 7.21(m, 1), 6.,73(m 1), 6.,28(brs1),4.85(brs,1),4.,81(brs1),3.53(m,1),2.-71-2.,0(m 7), 1.79(m, 1) 134N920: 3000-2880, 2850, 2700, 1720,1670, 1620,1500, 1450, 1430,1380, 1350, 1300-1250(w), 1160-1100(w), 1015, 890, 780 cm-1 28 - -1 9'11l -‘ -1 .. -1-- 0°3I1I3 -Toasolutionof the aldehyde, 36, (0.0438 g, 0.203 mmol) in ether (25. ml) in a 50 ml base washed round bottom cooled in a dry ice-isopropanol bath, was added MeLi (1.1M, 0.304 mmol, 0.19 ml), and the mixture stirred for one half hour. Additional MeLi (0.5 equiv.) was added, and the mixture stirred one half hour further until no starting material was seen by TLC. The solution was slowly warmed to 0°C, quenched with sat. aq. NH4Cl (35 ml), and extracted with ether (3 x 50 ml). The other layers were combined, washed with brine (75 ml), dried (MgSO4), , and concentrated We. The crude product was purified by chromatography on a column of silica gel (10 mm o.d., 10.0 9, 230-400 mesh, packed hexane/ether (4/1), run hexane/ether (2/1), 6 ml fractions) using the flash technique. Fractions 8-18 provided 0.042 g (89%) of 37. Rf=0.18 in (1/1) hexane/ether. : 232(M+, 2.8), 214(1.6), 189(2.7), 171(1.2), 162(3.0) 151 (23.6), 133(4.14), 121(4.9), 107(242), 93(18.3), 81(51.1), 67(12.5), 43(BASE) 1W: §: 7.,12(t J=2 Hz, 1), 7.,06(brs 1),6.09(brs,1),545(m,1), 4.90(brs,1),4.,77(brs 1),4.15(m,1),3.,25(m1),2.,49(t J=8.5 Hz, 2), 2.2,0(m 2), 2.02(m,1),1.,57(m 1),1..4-115(m,3),1.,13(dofd J=6.3Hz, 1 Hz, 3) 111mm: 3660-3100, 3000-2840, 1630, 1500, 1450, 1430, 1370, 1160, 1065, 1020, 890, 870, 780 cm-1 W - To a solution of the alcohol 37 (0.058 g, 0.250 mmol) in cyclohexane(10. ml) in a 25 ml base washed round bottom was added formic acid (2.5 ml, 98%) in one portion . After one half hour the mixture was cast into cyclohexane (50.0 ml), and carefully quenched with sat. aq. NaH003 (50 ml). After separation, the aqueous phase was extracted with ether (3 x 40 ml), and the combined organic layers were washed with brine (75 ml), dried (M9804), and concentrated mm. The crude product was purified by chromatography on a column of silica gel (30 mm o.d., 30. 9, 230-400 mesh, packed hexane/ether (15/1), run in hexane/ether (10/1), 8-10 ml fractions) using the flash technique. 29 Fractions 5-9 and 11-22, respectively, resulted in 0.0271 g (51%) of the cyclized product 38, and 0.0355 g (49%) of the formate ester 37. Rf=0.7 (38),and 0.21 (37) in (10/1) hexane/ether. 111114542061): (cyclized): 214(M+, base), 199(43.7), 185(48.0), 171(19.2), 157(24.7), 143(130), 129(17.7), 115(15.1), 105(9.1), 91(24.1), 77(14.9), 65(10.5), 55(8.3) 1mm: 5 : (cyclized): 7.23 (d, J=1 Hz, 1 ), 6.14(d, J=2 Hz, 1 ), 5.01(d of q, J=6.4, 2.1 Hz, 1), 4.86(brs, 1), 4.78(m, 1), 3.83(m, 1), 2.98(q. J=6 Hz, 1), 2.52(t, 2), 2.54-2.16(m, 5), 1.92(m, 1), 1.58(d of d, J=8.3, 1 Hz, 3) 13mm: (cyclized): 3000-2820, 1630, 1505, 1460-1420, 1260, 1180-1000(w), 890, 830-790(w), 725 cm-1 w: (formate): 260(M+, 12.8), 214(37.4), 199(10.8), 185(14.9), 172(35.7), 157(13.6), 145(8.81), 133(base), 119(23.4), 105(223), 91(39.8), 81 (55.6), 65(10.3), 53(192) 1mm: 5 :(formate): 7.76(brs, 1), 7.70(s, .57), 7.22(m, 1), 7.18 (m, 1), 6.2(m, 1), 5.65(m, 1), 5.58(m, 1), 4.98(s, .58), 4.95(s,1), 4.85(t, J=1 Hz, 1), 4.55(brs, .57), 3.25(m, 1), 2.49(m, 2), 2.20(m, 2), 2.02(m, 1), 1.57(m, 1), 1.14s, 3), 1.15(d of d, J=6.3, 2.4 Hz, 1.57) 134mm): (formate): 3000-2820, 1720, 1630, 1500, 1450,1380,1200- 1150(w), 1050(w), 890, 870, 830, 780, 730 cm-1 W: The combined reagents were allowed to stir at RT for twenty minutes. PTSA (2 crystals) was then added and the solution heated gently (50°) for two minutes, and after stirring for twenty minutes further, the reaction was diluted with cyclohexane (20 ml). The aqueous phase was separated, diluted with cyclohexane (20 ml), quenched with NaHCO3 (20 ml sat. aq. and then solid), saturated with NaCl, and extracted with ether (3 x 50 ml). The combined organic layers were washed with NaH003 and brine (50 ml 9a.), dried (M9304), and concentrated lawn. The cyclized product 38 was obtained in 72% yield after purification by flash chromatography. 30 - -1 ._ o.1.o.:11 - - 1 -- :1- 0013-1‘13‘2'ToaSOIUIIOR of the aldehyde, (36), (0.460 g, 2.256 mmol) in other (150. ml) cooled in a dry-ice isopropanol bath (-78°) was added phenyI-lithium (2M, 1.73 ml, 1.5 eq.) dropwise, and the mixture stirred for three hours. Additional phenyl-lithium (0.75 ml) was added and the mixture stirred for three hours further. The mixture was allowed to warm to RT and stirred overnight. The mixture was quenched with NH4Cl (50 ml), separated, and the aqueous phase was extracted with ether (3 x 50 ml). The combined organic layers were dried M9804, and concentrated in yam. The crude product was purified by chromatography on a column of silica gel (50 mm o.d.,100 9., 230-400 mesh, 300 ml forerun, hexane/ether(2.5/1), 30 ml fractions) using the flash technique. Fractions 8-25 provided 0.4469 g. (70.3%) of 41a. Rf=0.35 in (1/1) hexane/ether. : 282(M+, 0.51), 264(8.4), 182(19.5), 175(4.31), 145(4.82), 128(7.87), 115(939), 105(BASE), 91 (28.9), 77(500), 67(18.8) -:5 7.,30(m 6), 7.,18(s 1),6.,23(s1),5.,65(m 1),5.28(brs,1), 2.66(brs,1),2.,40(tJ=13.,2Hz 2),2.15(m,3),1.901 J=8.,5H21),1.,4(m 5) IBM): 3640-3140, 3030, 2930, 2860, 1600, 1495, 1455, 1380, 1300, 1200, 1160, 1070, 1025, 875, 775, 705 cm"1 W - To a solution of the alcohol 418 (0.4118 g, 1.460 mmol) in cyclohexane (175. ml) was added formic acid (35. ml, 98%) in one portion. After stirring one half hour, the mixture was separated and the organic phase washed twice with sat. aq. NaHCO3 (50 ml). The solution was dried (M9804), and concentrated 10.239110. The crude product was purified by chromatography on a column of silica gel (40 mm o.d., 50. 9., 230-400 mesh, (20/1) hexane/ether, 25 ml fractions) using the flash technique. Fractions 5-15 gave 0.3343 g. 87% of 42a. Rf=0.66 in (1/1) hexane/ether. 31 : 264(M+ BASE), 235(22), 207(22), 191(22), 173(97.8), 165 (14.4), 147(200), 128(22.2), 115(40.0), 91 (63.3), 77(17.7) ' 6 :.,725(m 6),6.22(d,J=2Hz,1), 5.84(Q.J —78 Hz 1) 4.0(brs,1),2.8,5(m 2), 2.62-1.,44(m 9) W): 3020, 2920, 2840, 1650, 1600, 1560, 1540, 1440, 1150, 1060, 910, 900, 860, 790, 760, 730, 690 cm"1 "I °°.' “110.9314 "" II 9 ' ll ' '013I1I- ‘ ' To Mg metal (0.233 g, 9.59 mmol) was added ten percent of a solution of p- bromoanisole (1.570 g, 8.400 mmol) in THF (10. ml). After the reaction began the remaining bromide was diluted with THF (90. ml) and then added over one quarter hour. After two hour of gentle reflux, the solution was cooled in a dry-ice is0propanol bath (~78°), and a solution of the aldehyde 36, (0.979 g, 4.799 mmol) in THF (25. ml) was added over one half hour. After stirring for three hours at - 78°, the mixture was warmed to RT and stirred overnight until no further starting material could be seen by TLC. The mixture was quenched with sat. aq. NH 4Cl (25 ml), separated, and the aqueous phase was extracted with ether (3 x 50 ml). The combined organic layers were dried (MgSO4). and concentrated W. The crude product was purified by chromatography on a column of silica gel (50. mm o.d., 100. 9, 230-400 mesh, 200. ml forerun, hexane/ether(2.5/1), 50 ml fractions) using the flash technique. Fractions 8-18 provided 1.305 g. (87%) of 41 b. Rf=0.21 in (1 /1) hexane/ether. :312(M+, 1.1), 241(1.1), 171(122), 161(1.1), 147(22), 129(BASE), 1 1 1 (18.9), 101 (8.9), 83(20.0), 71 (34.4), 55(94.4) Wzfl 7.,34(brs 1), 7.,24(d J: 8.4 Hz, 2), 7.,18(brs 1), 6.8,5(d J=8.4Hz, 2), 6.,75(d J=1 Hz, 1),6.24(brs,1),5.,63(m 1), 5.22(brs,1), 3.8(s, 3), 3.75(s,1),2.6,6(brs 1), 2.4(t, J=10.5Hz, 2), 2.,1(m 3),1.,83(brs 1), 1.64-1.22 (m,5 32 MAI): 3640-3080, 2930, 2850, 1610. 1585,1510, 1460, 1440, 1305,1250, 1175, 1105, 1025, 875, 830, 780, 735 cm-1 W: calculated for C20H24O3: 312.1725; observed: 312.1724 W - To a solution of the alcohol 41b (1.300 g, 4.17 mmol) in cyclohexane (500. ml) was added formic acid (35. ml, 98%) in one portion. After stirring ten minutes, the mixture was separated and the organic phase washed twice with sat. aq. NaHCO3 (150 ml). The solution was dried (M9804). and concentrated jaw. The crude product was purified by chromatography on a column of silica gel (50 mm o.d., 50. 9., 230-400 mesh, (8/1) hexane/ether, 25 ml fractions) using the flash technique. Fractions 58 gave 0.9063 g. 74% of 42b. Rf=0.77 in (1/1) hexane/ether. : 294(M+ BASE), 264(8.4), 251 (3.6), 235(50), 186(15.4), 173(591), 147(44.9), 121(349), 105(14.1), 91(30.6), 77(18.9) 1W2): 6 :7.26(d,J=1 Hz,1),7.2(d,J=8.4 Hz, 2), 6.81(d,J=8.4 Hz, 1), 6.19(d, J=1 Hz, 1), 5.73(m, 1), 3.94(m, 1), 3.78 (s, 3), 2.65(m, 2), 2.58- 1.18(m, 9) 13.111931): 2920, 2840, 1740(w), 1605, 1510, 1460, 1440, 1295, 1245, 1175,1150, 1125, 1060, 1035, 900, 860, 820, 735,690 cm-1 W: calculated for Con2203: 294.1620; observed: 294.1614 W: To a THF solution of borane-dimethyl sulfide23 (1.8 M, 1.36 ml, 2.44 mmol) cooled to -10°C in a ice-salt water bath, was added 2,3-dimethyl-2- butene (0.290 ml, 2.44 mmol) dropwise. The mixture was warmed to 0°C, stirred one hour, warmed to room temperature, and stirred two hours further. A solution of cyclized product 428 (0.258 g, 0.975 mmol) in THF (3. ml) was added dropwise and the mixture stirred 21 hours at room temperature. The mixture was cooled to 0°C, quenched carefully with water (2.0 ml), followed by 3N NaOH (3.0 33 ml), and 30% hydrogen peroxide (5.0 ml). The solution stirred at 0°C for one hour, warmed to room temperature over one hour, and was then cast into sat. aq. NH4Cl (30 ml) and ether (50 ml). The organic layer was separated and washed with 10% sodium bisulfite, and sat. aq. NaHCO3 (30 ml 9a.). The aqueous phases were combined, saturated with sodium chloride, and extracted with ether (3 x 50 ml). The combined organic phases were washed with brine (50 ml), dried (MgSO4), and concentrated W. The crude alcohols were purified by chromatagrophy on a column of silica gel (20 mm o.d., 15.0 9., 230-400 mesh, hexane/ether (15/1), 5-7 ml fractions) using the flash technique. Fractions 6-14 gave 88.8 mg. (34.5%) recovered starting material 428. Fractions 16-23 gave 0.1524 g. (55.4%) of 438. :282(M+,3.5), 264 (8.0), 173(8.8), 149(25.2), 134 (19.5),119(55.4), 105(BASE), 91 (62.8), 77(332), 71 (18.5), 55(309) 1W: 5 :7.,22(m 6H), 6.12(d, J=1.,2Hz 1), 6.04(d, J=1.2Hz, 0.2,) 4.,59(d J=8.,9Hz 0.,2)4.39(d,J=8.,9Hz1),3.,57(tJ=15.6Hz,1),2.-71-,1.09(m13) IBM”; 3580, 3500-3200, 3010(w), 2990-2800, 1820(w), 1600(w), 1510, 1490, 1450, 1370(w), 1270(w), 1150, 1070-1000, 895, 875, 760, 730, 695 cm-1 W6: To a THF solution of borane-dimethyl sulfid923 (2.0 M, 0.272 ml, 0.544 mmol) cooled to -10°C in a ice-salt water bath, was added 2,3-dimethyl-2- butene (64.7 ul, 0.544 mmol) dropwise. The mixture was warmed to 0°C, stirred one hour, warmed to room temperature, and stirred one hour further. A solution of cyclized product 42b (64.0 mg., 0.218 mmol) in THF (1.0 ml) was added dropwise and the mixture stirred 20 hours at room temperature. The mixture was cooled to 0°C, quenched with water (1.0 ml), followed by 3N NaOH (2.0 ml), and 30% hydrogen peroxide (3.0 ml). The solution stirred at 0°C for one hour, warmed to RT over one hour, and was cast into sat. aq. NH4Cl (30 ml) and ether (50 ml). The organic layer was separated and washed with 10% sodium bisulfite, 34 and sat. aq. NaHCOg (30 ml 68.). The aqueous phases were combined, saturated with sodium chloride, and extracted with ether (3 x 50 ml). The combined organic phases were washed with brine (50 ml), dried (M9804), and concentrated W. The crude alcohols were purified by chromotagrophy on a column of silica gel (10 mm o.d., 1.5 9., 230-400 mesh, hexane/ether (2/1), 2 ml fractions) using the flash technique. Fractions 2,3 gave 5.4 mg. (8.%) recovered starting material 42b. Fractions 8-14 gave 40.6 mg. (59.8%) of 43b. : 312(M+, 6.5), 294(24.4), 186(3.9), 176(17.0), 147(36.7),137(BASE), 121 (26.6), 109(127), 91 (22.3), 77(20.9), 55(10.0) :5 :7.28(d,J=1.,2Hz1),7.,21(d J= 89 Hz 1.,3) 6.83(d, J=1.,2Hz 1.,3) 6.,19(d .l-89 Hz 1), 4.,39(d J: 10.1 Hz, 1), 3.,78 3.,79(s s 3.,7) 3.58(t, J=15.,6Hz 1), 2.62(m, 4), 2.,30(m 2), 2..15-115(m, 7) 18.01931): 3600-3320, 3080-2800, 1730(w),1610, 1580, 1510, 1465, 1450, 1380, 1305, 1250, 1175, 1105, 1025, 895,830, 735,690 cm-1 W: calculated for Con24O3: 312.1725; observed: 312.1728 WM: To the alcohol 438 (0.1493 9, 0.5294 mmol) in CH2CI2 (50. ml) was added celite (3.0 9), followed by PCC (0.228 g, 1.06 mmol) in one portion. After stirring 2.5 hours another 50 mgs. (0.25 mmol) of FCC was added, and the mixture stirred one half hour further. The mixture was then diluted with ice cold hexane (50 ml), and filtered through a plug of celite/silica gel. The filter cake was rinsed with hexane/ether (400 ml, 95/5), and the combined organic phase was dried (M9804) and concentrated W. The crude product was purified by chromatography on a column of silica gel (20. mm o.d., 25. 9., 230-400 mesh, hexane/ether (8/1), 8 ml fractions) using the flash technique. Fractions 7- 16 gave 0.0798 g (54%) of the products 448, and 458 as a 5:1 mixture 35 (alpha/beta) which could be separated by flash chromatography. Fractions 18-23 gave 0.010 g (6.7%) recovered starting material 438. w: (44a, 45a): 280(M+, 33.3), 264(2.8), 152(1.89), 203(3.78), 175(6.8),160(31.9), 147(730), 133(48.6), 119(17.5), 105(BASE), 91(44.3), 77(81.0), 65(8.1) Wu 5. (44a 45a):7.,67(d .)=8.5 Hz, 0.2) 7.,60(d .)= 8.5 Hz, 2), 7.23(dJ = 8.5Hz, 0.,2) 7.,20(d .)_85 Hz 2),7.,12(s1.,2)6.,82(d .)= 1 Hz, 0.,2) 1Hz,1),5.91(d,J=1 Hz, 0.2), 5.60(d,J=1 Hz, 1), 4.19(m, 1.2), 3.6(m, 1), 227-1 08(1rn,11) 184N260: (44a, 45a): 3020(w), 2960-2800, 1665, 1585, 1570, 1500, 1438, 1360, 1205,1150, 990, 885, 860, 755, 720, 675 cm-1 W: To the alcohol 43b (0.038 9, 0.1218 mmol) in CH 20|2 (10. ml) was added celite (0.5 9), followed by PCC (0.066 g, 0.305 mmol) in one portion. After stirring 2.5 hours another 15 mg. (0.075 mmol) of FCC was added, and the mixture stirred one half hour further. The mixture was then diluted with ice cold hexane (30 ml), and filtered through a plug of celite/silica gel. The filter cake was rinsed with hexane/ether (200 ml, 95/5), and the combined organic phase was dried (MgSO4) and concentrated W. The crude product was purified by chromatography on a column of silica gel (10. mm o.d., 2. 9., 230-400 mesh, hexane/ether (2/1), 1 ml fractions) using the flash technique. Fractions 2-5 gave 0.0221 g (58.5%) of the products 44b, and 45b as a (6-8):1 mixture (alpha/beta) which could be further separated by flash chromatography. Mp (major isomer): 93-94°, Mp(mixture):78-81°, Minor isomer: oil. aw: (44b): 310(M+, 47.1), 174(133), 163(74.8), 149(43.2), 135(BASE), 119(16.3), 105(18.4), 91(37.7), 77(37.9), 55(60.4) 1W5 :(44b) :.,779(dd J=8.9, 1 Hz, 2), 6.,80(dd .)=8.9, 1 Hz, 2), 6.,34(d .)=1 Hz, 1) 5.74(d,J=1Hz,1),4.24(m, 1), 3.82(s,,1) 3.,71(m 1), 2.60- 1 1(m,11) 36 113.com: (44b): 3010-2860, 1760(w),1670, 1605,1580. 1515,1460, 1450, 1420, 1375, 1260, 1235, 1190-1170, 1118, 1070, 1030, 920, 850, 820,790, 750, 700, 690 cm-1 W: calculated for C20H2203: 310.1569; observed: 310.1566 :(45b): 310(M+, 24.0), 293(4.89), 202(501), 174(16.6), 163(46.7), 148(17.3), 135(BASE), 107(8.81), 91 (19.8), 77(25.2) - : 6 :(45b): 7.80(dd, .)=8.9, 1 Hz, 2), 6.96(d, 1 Hz, 1), 6.86(dd, J= 8.9, 1 Hz, 2), 6.03(d, J=1 Hz, 1), 3.92(m, 1), 3.84(s, 1), 3.80(m,1), 2.60- 1.40(m, 11) 134mm): (45b): 3010-2820, 1725(w), 1670, 1600, 1580, 1510, 1455, 1420, 1365, 1310, 1260, 1215, 1170, 1070, 1030, 900,840, 740,695 cm-1 W: To a solution of the major ketone 44b, (0.1467 9, 0.4732 mmol) in THF (6. ml) at -78°C was added LDA (1.5 M, 1.5 eq., 0.47 ml) dropwise. The mixture stirred for one half hour, was warmed to -45°C (dry- ice/acetonitrile) for one half hour, and then cooled back to -78°C . MoOPh-HMPA-PYR30 (0.410 g, 0.710 mmol, 2 eq.) was then added in one portion, and the mixture was allowed to warm from -78° to RT over 2.5 hours. The mixture was diluted with ether (50 ml), and washed with sodium sulfite (20 ml) and citric acid (30 ml). The aqueous layers were salted and extracted with ether (3 x 50 ml), and the combined organic layers were dried (MgSO4) and concentrated W. The crude was purified via chromatography on a column of silica gel (30 mmm o.d., 20. 9. 230-400 mesh, (10/1) hexane/ether for tract. 1- 36, (3/1) hexane/ether for tract. 37-72, 8 ml fractions, 30 ml forerun) using the flash technique. Fractions 2-15 gave 35.2 mgs (24%) recovered 44b, and fractions 30-68 gave 111. mgs (72%) of the product 46. Rf = 0.32 in (1/1) hexane/ether. : 308(M-18, BASE), 191(4.1), 179(53.4), 148(22.5), 135(71.2), 119(139), 105(11.5), 91 (8.4), 84(27.4) 37 : 367(M+41, .98), 355(M+29, 1.97), 327(M+1, 17.3), 309(797), 191 (22.4), 163(2.95), 147(22.4), 135(BASE), 121 (13.4) W: 5 :(0606): 8.24, 8.2,(d, J=8.9 Hz, 2), 6.79 (d, J=1 Hz, 1), 6.65, 6.61 (d, .)=8.9 Hz, 2), 5.80(d, J=1 Hz, 1), 3.65(d, J=8.9 Hz, 1), 3.25(d, .)= 6.5 Hz,1), 3.18(s, 3), 2.88(brs, 1), 2.72(d of t, 13.4, 8. Hz, 1), 2.6-1.2(m, 9) 13mm): 3620-3200, 3080-2800, 1710(w),1670, 1600, 1510, 1450, 1420, 1370, 1300, 1245, 1170, 1030, 860-780, 735, 685 cm-1. W: calculated for Con2204: 326.1518; observed: 326.1546 M: To a solution of LAH (12.4 mg., 0.326 mmol) in other (1.5 ml) at 0°C was added a solution of compound 46 (0.1061 g., 0.3255 mmol) in other (1.5 ml). The mixture was stirred for one half hour at 0°C, and then warmed to RT over 1.5 hours. LAH (6.2 mgs, 0.5 eq.) was added and the mixture stirred one hour further. The mixture was quenched with water (1 ml), diluted with ether (50 ml), and washed with 15% NaOH (25 ml). The aqueous layers were saturated with salt and extracted with ether (3 x 50.ml), and the combined organic layers were dried (MgSO4), and concentrated imam to give 88.6 mgs. (83%) of the crude diol 47, which was used without further purification. : 310(M-18, 2.65), 190(252), 163(35.9), 147(BASE), 137(521), 121(15.1), 109(8.13), 91(27.1), 77(26.7), 55(45.7) : 369(M+41, .50), 355(M+29, 3.65), 339(M+11, 4.92), 329(M+1, 11.7), 311(M-18, BASE), 293(11.3), 190(13.3), 175(21.2), 147(434), 137(29.3), 121(120), 85(25.6) W: 5 :(CeHa): 7.29, 7.26,(d, J=8.9 Hz, 2), 7.10 (d, .)=1 Hz, 1), 6.74, 6.70(d, .)=8.9 Hz, 2), 5.93(d, J=1 Hz, 1), 4.31 (d, .)=4.4 Hz, 1), 3.82(d, .)= 6.7 Hz,1), 3.31 (s, 3), 2.55-0.90(m, 13) m: 3700-3100, 3020-2810, 1735(w), 1620, 1520, 1460, 1300, 1250,1190, 1100-1000, 970, 910, 840, 810, 750 om-1 W: calculated for Con24O4: 328.1675; observed: 328.1671 38 W: To diol 47 (0.0886 9., 0.2701 mmol) in t-BuOH (3.5 ml) was added NalO4 (0.145 g., 0.675 mmol) in H20 (3.5 ml). The mixture was stirred for 1.5 hours, diluted with ether (50 ml), and separated. The aqueous layer was diluted with brine (6.5 ml), and extracted with ether (3 x 50 ml). The combined organic layers were dried (M9804), and concentrated W. The crude product was purified by chromatography (30 mm o.d., 40. 9 230-400 mesh, 50 ml fractions, tract. 1-20 (10/1) Hexane/ether, tract. 21-40 (8/1) hexane/ether, fract. 41-60 (5/1) hexane/ether, tract. 61-80 (2/1) hexane/ether, fract. 81-100 (ether), 200. ml forerun) using the flash technique. Fractions 7-40 gave 25.8 mg. (49%) of a 3/1 mixture of compound 12 and anisaldehyde. Fractions 41-70 gave 62.0 mg. of a compound MW. 310 (Cl/MS). The anisaldehyde/product mixture was taken up in ethanol (50 ml) and washed with cold sat. aq. NaHCO3. The aqueous was extracted with ether (3 x 10 ml), and the combined organic phases were dried (MgSO4) and concentrated in vacuo to provide 17.7 mg. (35%) of ketone 12. : 190(M+,13.6), 163(7.14), 149(37.1), 134(BASE), 119(18.6), 105(7.14), 96(10.0), 91 (20.0), 77(100), 69(7.14), 55(25.7) - : 5 :7.28(d,J=1 Hz, 1), 6.15(d, .)=1 Hz, 1), 3.66(d,J=6.6 Hz, 1), 2.6-1.0(m, 11) 1134mm): 3080-2800, 1730, 1600, 1515, 1460, 1385, 1340-1230,1125, 1075, 905, 880, 840, 740, 700 cm-1 W: calculated for C12H1402: 190.0999; observed: 190.0979 1) 2) 3) 4) 5) 6) 7) 3) 9) 1 0) BIBLIOGRAPHY See Devon, T. K., Scott, A. l. "Handbook of Naturally Occurring Compounds”, Academic Press, New Y0lk, 1972, Vol. II. a) Fischer, H. S., Olivier, E. J., Fischer, H. D. in "Forschritte der Chemie Organischer Naturstoffe", Springer Verlag, New York, 1979, Vol. 38. pp. 47-388. b) Romo, J., Romo de Vivas, A., "Forschritte der Chemie Organischer Naturstoffe", Springer Verlag, New York, 1963, Vol. 25, pp. 90-130. 0) Yoshioka, H., Mabry, T. J. ,Tlmmerman, B. N. 'Sesquiterpene Lactones", Univ. of Tokyo Press, Tokyo, 1973. a) For an excellent review see Evans, F. J., Soper, C. 1me 1978, 41, 193; b) Blumberg, P. M. W 1980, 153; 112151., idem. 1981, 199; c) Hecker, E., Schmidt, R. W. 1974, 31, 377; d) Evans, F. J., Taylor, S. E. idem. 1983, 43, 1. e) Wonder, P. A., Hilleman, C. L., Szymonitka mm. 1980, 21, 2205. 8) Mitchell, J. C. in "Recent Advances in Phytochemistry" Runeckles, V. C. Ed., Plenum Press: New York, 1975, Vol. 9, pp. 119-139; b) Blenmink, E., Mitchell, J. C., Geissman, T. A., Towers, G. H. N. 29.01291. 0663601151976. 2. 81; c) Amy, H. V. ,Lflam. 1890, 121; 1897, 169; d) Herz, W., Watanabe, H. LAW 1959, 81, 6088; e) Herz, W., Watanabe, H., Miyazaki, M., Kishida,Y., ibid., 1962, 84, 2605; f) Emerson, M. T., Caughlan, C. N., Herz, W. W. 1966, 6151; g) Rodriguez, E., Towers, G. H. M, Mitchell, J. C. W 1976, 15, 1573. Melsels, A., Weizmann, A. W 1953,15, 3865. Stuart, K. L., Barret, M. W. 1969 2399. Kupchan, S. M., Eakin, M. A., Thomas, A. M. Men]. 1971 , 14, 1 147. Pettit, G. R., Herald, C. L., Gust, D., Herald, D.L, Vanell, L. D., 1910420901. 1978. 4.3. 1092. Sanchez-Viesca, F., Romo, J. W 1963, 19, 1285. Cook, C. E., Wichard, L. R, Turner, B., Wall, M. E., Egley, G. H., 40 11) 12) 13) 41 Enigma, 1966.154. 1189. Herz, W., Kumar, M, Blount, J. F. m 1981, 46, 1356. a) Tanis, S. P. WW 1982, 26, 3115; b) Tanis, S. P., Head, D. B. W. 1982, 26, 5509; c) Tanis, S. P., Herrinton, P. M. W- 1983,46, 4572, d) Tanis, S. P., Herrinton, P. M. 16131.,198560, 3988; e) Tanis, S. P., Head, D. B.Ie_tLalleg_LQ_n_Le_n,1984,25, 4551; f) Tanis, S. P., Head, D. B., Raggon, J. W. unpublished results; 9) Tanis, S. P., Herrinton, P. M., Dixon, L. W. 1985,26, 5347; h) Tanis, S. P., Herrinton, P. M., McMills, M. W. 1985, 59. 5887: i) Tanis, S. P., Chang, Y., Head, D. B. W. 1985 26, 6147. 8) Homo. J. W. 1970.21. 123; b) Bohlmann, F., Borbowski, H., Amdt, C. W. 1966, 96, 2828; 0) Edgar, M. T., Greene, A. E., Crabbe, P. m. 1979, 44, 159; d) Rigby, J. H., Wilson, J. A. W 1984.166, 847. 14) a) Ogura, M.,Cordell, G., Fainsworth, N. R. W911]. 1978, 11, 957; b) Devreese, A. A., DeClerq, P. J., Vandewalle, M. W. 1980, 21. 4767. 15) a) Romo de Vivas, A., Cabrera, A., Ortega, A., Romo, J. 191311951320 16) 17) 18) 19) 20) 1967 23.3903; b) Bohlman, F., Brindophe, G., Rastogi, R. 0.311151126116111. 1978, 11, 475; c) Jolad, S. D., Wiedhopf, R. M., Cole, J. R. W. 1974, 66, 1321; d) Ando, M., Yamoaka, H., Takase, K. W. 1982, 501. a) Wender, P. A., Erhardt, J. M., Letendre, L. J. W 1981, 1113, 2114; b) Marino, J. P., Jaen, J. C. W1982, 194, 3165. 8) Anderson, A. 6., K80 L. G. WELLI- 1982,41, 3590; b) Keck, G. E., Webb, R.Ie_t[ang1mn_Lgn,1979, 1185; c) Keck, G. E., Webb, R., Yars, J. B. 1613116511611 1981, 61, 4007. Luche, J. L., Gemal, A. L. mm 1981, 166, 5454. a) Piers, E., Karunaratne V. W- 1984,62, 629. b) Ashley, E. C., Arnott, R. C. Wm. 1968,14, 1. Piers, E., Karunaratne V. W. 1984,62, 629. 21) Watson, S. L., Eastham, J. F. W. 1967, 2, 165. 22) Still, W. C., Mitra A., Khan, M. W— 1978,41, 2923. 42 23) Brown, H. C. , Helm P., Yoon, N. M., W 1970, 92, 1637. 24) Lespieau, R., Bourguel M., "Organic Synthesis", Wiley and Sons, New York, 1946, Vol. 1., 209. 25) a) Sharpless, K. B., Palermo, R. E.,Akashi K. W- 1978,46, 2063. 26) 27) 28) 29) 30) 31) b) Schroeder, M. 9.0901391. 1980,66, 187 c) Van Rheenen, V., Kelley, R. 0., Cha, D.Y.,Ie1rane_d_r_g_r1_Le_n,1976, 26, 1973. d) Piers, E., Abeysekera B. F., Herbert, D. J., Suckling, I. D. W 1985, 66, 3418. e) Pappo, R., Allen Jr., D. S., Lemieux, R. U., Johnson, W. S. 11.123111211901- 1956, 21, 478. f) Danishefsky, 8., Hirama, M., Gombatz, K., Harayama, T., Berman, E., Schuda, P. F. W 1979, 161, 7020. a) Fatiadi, A. J., W 1974, 229. b) Bunton ,C. A., Shiner V. J., 1.611611115661960, 1953. c) Dyhurst, G. "Periodate Oxidation of Diols and other Functional Groups", Pergammon Press, New York, 1970. a) Kishi ,Y., Smith-Palmer, T., Schmidt, G., Nakata, T., Okigawa, M., Vranesic, B. W 1978, 166, 2933. b) Lemieux, R. U., Rudloff, E. V., W 1955, 66, 1701 ; 1mg” idgm, 1955, 1710.,jmgqmm1955. 1714. a) Sharpless, K. B., Carlson, H. J., Martin, V. S., Tsutomu, K. WWW _§ 3936 b) Torii, S, Tsutomul. W- 1985, 96, 1822. c) Danishefsky,S., DeNinno, M. 1_Qrg,_Qh_e_m. 1986, 51, 2617. d) Mosher, H. S., Williams, T. M, Halaska, R. C., Tian-Pa, Y., Nachman, R. J., Talhouk, J. W., Weber, J. F. W. 1986, 61, 2702. a) Baily, P. S., "Ozonation in Organic Chemistry”, Academia Press, New York 1978. b) Bauld, N. L., Thompson, J. A., Hudson, C. E., Baily, B. S. W 1968. 99. 1822. c) Lattimer, R. P., Gillies, C. W., Kuczkowski R. L. W 1974, 96, 348. d) Pappas, J. J., Keaveney, E. O., Berger, M., Rush, R. V. W 1966, 4273. Vedej, E., Engler, D. A., Telchow, J. C. W. 1978,46, 188. a) Feringa, B. L., Dannenberg, W. W- 1983,16, 509. b) Kuwajima, l., Umbe, H.1911anegmn16n. 1981, 51,, 5191. c) Crabbe, P., Greene, A. 0., Edgar, M. T. mum 1979,44, 159. d) Tanis, S. P., Head, D. B.,I_e1Lah_e_dr_Q_n_Len. 1984, 26, 4451. e) Ando, M., Yamaoka, H., Takase, K. 61191111911. 1982, 501. 43 f) Kuwajima, l., Urube, H., Yasuda, A., Takano, Y. W. 1985, 26, 6225. 9) Marshall, J. A., DeWoff, B. S., Andrews, R. C. Mm. 1986,16, 1593. .A