WHEFSlS This is to certify that the dissertation entitled Furans as Terminators in Cationic Cyclizations presented by Paul Matthew Herrinton has been accepted towards fulfillment of the requirements for Ph.D. degree in Chemistry Major pm I' Date ill—3M— Ilflli-n- A&_ o' ‘ ‘ I- 'm . I - . 0-‘2771 MSU LIBRARIES —:III—- RETURNING MATERIALS: Place in book drop to remove this checkout from your record. FINES will be charged if book is returned after the date stamped below. FURANS AS TERMINATORS IN CATIONIC CYCLIZATIONS By Paul Matthew Herrinton A DISSERTATION Submitted to Michigan State University in partial fulfillments of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1984 To my lovely Joan. Thank you for making this possible. ii ACKNOWLEDGMENTS The author wishes to thank Dr. Steven P. Tanis for his patience, support, guidance and friendship throughout this project. Financial support from Michigan State University and the Walter R. Yates Scholarship Fund is gratefully acknowledged. The author also wishes to acknowledge the members of the faculty and staff, in particular Dr. William Reusch, for their assistance and advice throughout this work. The author wishes to thank his fellow students for their advice and companionship. In particular, Red Shoes Olsen for running the mass spectra herein, and Wheels McMills for providing an ample supply of 2-methyl— cyclopentenone. Special thanks to my parents and family for their love and support without which this work would not have been possible. iii ABSTRACT FURANS AS TERMINATORS IN CATIONIC CYCLIZATION By Paul Matthew Herrinton Several 3-substituted furans with latent electrophiles in the side chain were prepared as cyclization substrates. 3-Furylmethyl magnesium chloride is readily coupled with a variety of u-haloalkenes to afford the corresponding 3-substituted furan in good to excellent yields. Epoxidation of the product furyl olefins was found to be effective in producing the desired cyclization substrates only when the olefin was trisubstituted. Less highly substituted epoxy furans were prepared via the coupling of (3-furylmethyl) lithium with u-iodo epoxides or protected w-iodo diols followed by closure. The cyclizations of these epoxy furans were examined with a number of Lewis acids. Treatment with Ti(OiPr)3C1 and Zn12 led to the isolation of cyclized products in moderate to excellent yields. Cyclization of 7,8-epoxydendrolasin with Ti(OiPr)3Cl and Zn12 provided 3 p—hydroxypallescensin A in 62% and 65% yields respectively. Additionally, allylic alcohols and enones derived from the CuCN moderated SNZ' addition of Grignard reagents prepared from 2-(3-furyl)-l-bromoethane and 3—(3-furyl)—l-bromopropane to vinyl epoxides and epoxy-enolethers were employed as cyclization substrates. Treatment of substrate allylic alcohols with a two phase mixture of formic acid and cyclohexane resulted in facile cyclization when the forming ring was 6-, or 7-membered. Enone closures proceeded only when a 6-membered ring was produced or in the case of a bridged system which leads to nakafuran-Q. TABLE OF CONTENTS LIST OF TABLES LIST OF FIGURES INTRODUCTION EPOXIDE INITIATED CYCLIZATIONS ALLYLIC ALCOHOL AND ENONE CYCLIZATIONS SUMMARY AND CONCLUSIONS EXPERIMENTAL BIBLIOGRAPHY iv Page vi 22 36 38 85 LIST OF TABLES Page Table 1 Cyclization Substrates and Possible Results 9 Table 2 Synthesis and Oxidation of (3-furyl)—olefins 12 Table 3 Cyclization Results 17 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure ‘DQOthNH NHHHHHHHHHH O‘DQQQWDWNHO N H “NNNNNNNN OQQQQMBWN “w NH 09090000 05010:» LIST OF FIGURES Natural Products Oxidation States Substitution Patterns Furan Equivalencies Cationic Cyclizations Bond Forming Polarities Furyl Anion Equivalents Furyl Epoxide Synthesis Furan Oxidations Oxidation of 37 Coupling of lodoepoxides Preparation of 32 Preparation of 14b Preparation of Pallascensin A (52) Dianion Couplings Additions to Vinyl Epoxides Preparation of 66-68 Oxidation of 66-68 Preparation of 73-74 Oxidation of 73-74 Preparation of 79 Preparation of 62-83 Prepration of 66-87 Preparation of 86-95 Cyclization of 66-68 Cyclization of 73-74 Cyclization of 62-83 Cyclization of 86-67 Cyclization of 94-95 Attempted Cyclization of 69-71 Attempted Cyclization of 75-76 Preparation of 110 Restrosynthesis of Nakafuran-9 Preparation of Nakafuran-9 vi INTRODUCTION Five-membered oxygen-containing heterocyclic rings are ubiquitous subunits that are observed in diverse classes of biologically active natural products.1 This ring system is an integral part of molecules such as the 2 6 F icon I Natural Products 2 insect anti-feedant fl-neoclerodane ajugarin I 12, the antileukemic pseudo- guaianolide rudmollin 23, the witchweed germination promoter strigol 3,4 the cytotoxic vernolepin 45:6, and the fish anti-feedants nakafuran-8 5 and nakafuran-9 6.7 Compounds 1-6 represent two of the four common oxidation states of the five-membered oxygen-containing heterocyclic system, ranging from fully aromatic furan 7 to tetrahydrofuran lo. Terpenoids 1-6 also exhibit two of p (21.5100 2, s 2, :9 Figure 2 Oxidation States the three A-C substitution patterns commonly observed about this ring system in natural products. Ajugarin-l 1 illustrates the 3-substituted substructure A and nakafuran-8 5 possesses a ring fused to the 2,3-positions of the five- membered heterocycle (substructure B). . .0 Ci (39d N V Figure 3 Substitution Patterns 3 The synthesis of molecules such as 1-6 has generally been approached by a careful stereocontrolled construction of a parent carbocycle upon which the five-membered heterocycle is appended. These routes have generally not acknowledged the basic five—membered ring nucleus as an integral part of the molecule. A truly general approach to the synthesis of molecules 1-6 should provide access to the various states of oxidation 7-10 as well as the different patterns of substitution (A-C) about the heterocyclic nucleus. Central to such an approach is the use of common intermediates which will impart regio- and stereochemical control in bond forming reactions about the periphery of the heterocycle, as well as afford the desired oxidation state. In principle, the oxidation states 7-10 found in representative natural products might be prepared by the reduction8 or oxidation9 of a furanoid precursor 7. Tetrahydrofuran 10 might result from the reduction of 7; butenolide 6 should be available by the oxidation of 7 and in turn butyrolactone (35 Hflonh— fl “(Lo / Q0 (1 O O 0 Figure 4 Furon Equivalencles 4 9 would result from the reduction of 8. However, butenolides 8, prepared from precursor furans, must be generated without regiochemical ambiguity. A more suitable solution to this problem is the unraveling of an appropriate 2- or 5-substituted-3-alkylfuran.9 Therefore, the fully aromatic furan should serve as a precursor to the plethora of functional groupings illustrated in Figure 4. The synthesis of the type A substitution pattern in oxidation states 8-10 can then be simplified to the preparation of an appropriate 3-substituted furan. Although numerous syntheses of 3-substituted furans have been reported,” they generally require many steps, relatively inaccessible starting materials or proceed in low overall yield. However, l‘anis11 has reported a general method for the preparation of 3-substituted furans which allows for the direct introduction of a wide variety of functionality as part of the side chain (R) introduced in the cOUpling process. The type 8 structure, present in compounds 2-6, should be accessible if the propensity of furans to undergo electrophillic attack at an a-position is exploited. As illustrated in equation 1, the generation of an electron deficient center (R) in the side chain of a 3-substituted furan, should lead to 12 after an electrophilic attack and rearomitzation. Therefore, an efficient synthesis of the more complex type B substructure would be realized from the much simpler type A furan ll possessing a latent electrophilic center in its side chain. Farm ——~ p2. :2 N A, 5 The eXploitation of this type of cationic w-cyclization in the construction of carbocyclic ring systems has been the object of intense study since 1950.12 These investigations have served to verify, in YEP—0: the Stork--Eschemoserl3 hypothesis that the stereochemical course of the biological cyclization of squalene could be rationalized on stereoelectronic grounds. Applications of this methodology have resulted in the biomimetic synthesis of a variety of naturally occurring steroids and natural products.14v15 For successful polyene cyclization, a suitable electrophilic initiator functionality and nucleophilic terminator functionality are necessary. A wide variety of groups have been used to "trigger" cyclization reactions. The most common initiators are simple olefins (which require strongly acidic reaction conditions), epoxides (5a,16a b1“), allylic alcohols (5c,12a d”) and their oxidation products, a - p unsaturated carbonyls (5e,18 f19). Additionally, Johnson20 has demonstrated that acetals may initiate cyclization and that chiral acetals will result in the transfer of chirality to the cyclization products (5g, h). Finally, recent attention has been directed to N-acyliminium ions, which are readily generated, very reactive, and serve as precursors to alkaloid products (5i,21 j“). The scope of nucleophilic terminators examined has been somewhat more limited than that of initiators. Only simple olefins (5e,18 f,19 gzo), aromatic rings (5316a), acetylenes (5d17), and allenes (5c12a) are used with regularity. Comparatively few examples of more complex terminators such as vinyl ethers (5b15f) or heteroaromatics, such as thiophene and pyrrole, (5j22) have been reported. This is particularly true of furan terminated cyclizations. The paucity of pertinent literature precedent is likely the result of the inaccessibility of suitable substrates“):11 the poor nucleophilic character of the furyl residue relative to standard terminator functions, 16'22, and the 32.2.65 25:5 0 2:9... 3 x. :95 o o \ E 3 \\ s 0. r4 1. \fi . :0 IO 2. F _/ E . f'. I _ H “.\\ :3 _ no «ma. _ a: E .3 7 increased acid lability of the derived disubstituted furan compared with starting material. The use of standard terminator functions presents two major problems. The first is the apparent need for strongly acidic reaction conditions, which are not compatible with many synthetically useful functional groups. The second is the limited functionality which remains after the cyclization is completed, frequently leaving the resultant molecule without sufficient "handles" to readily complete the synthesis. Furthermore, while methods for the preparation of fused-ring systems are well-developed and extensively utilized, relatively few general strategies for the construction of Spiro-23 and bridged—24 ring systems exist. Therefore, methods must be developed to facilitate the preparation of spiro-, bridged-, and fused-ring systems, especially those within complex molecular environments. These methods should proceed in high chemical yield with excellent regio- and stereochemical control; and in addition, the conditions employed must be sufficiently mild to ensure the survival of synthetically useful functional groups. It was the goal of this study to demonstrate the utility of the furyl moiety as a terminator in cationic cyclizations, and to develop a general methodology for the synthesis of bioactive natural products containing five- membered oxygen-containing heterocycles. EPOXIDE INITIATED CYCLIZA'I‘IONS The elegant studies of Goldsmith,15a:b vanTamelen,1‘5¢‘e Boeckman,15f, and Sharpless,168 among others, have shown that the epoxide function can be employed as the trigger for cationic cyclizations. These workers have employed a variety of Lewis acids to initiate the cyclization sequence. These relatively mild conditions coupled with the ease of epoxide introduction, either via epoxidation of a precursor olefin or direct incorporation, make the epoxide the initiator of choice. The cyclization substrates which were examined were designed to permit entry into five-, six-, or seven-membered ring systems. In order to avoid ambiguity in the ring size expected from a given oxirane, the epoxide function will be biased where necessary to favor one mode of. C-0 bond polarization over the alternative. This design concept is in accord with the proposed polarized nature of the intermediate.16 We have also examined the effect of placing the initiating function within the ring being formed (endocyclic) or outside the forming cycle (exocyclic).26 According to Baldwin,26 the exocyclic closures which generate five-, six-, or seven-membered rings should be favorable, whereas for the endocyclic closures only the formation of a six- membered ring is favorable. The required epoxyfurans and possible reaction products are illustrated in Table I. The most obvious, and at the outset simplest, path to the desired epoxy- furans involved preparation of 3-furyl olefins followed by oxidation with peracid. The necessary olefins could be prepared by coupling the appropriate haloalkene with a judiciously functionalized isoprenoid furyl synthon. Standard bond forming reactions to furans customarily are polarized so that the furan serves as an electrophilc and the alkyl group as a nucleophile (path a, Figure 6). In this approach, we have examined the "reverse polarity" bond formation, in Deflqmflhn S-Endo 5' End G-Endo 6°Exo T-Endo T'Exo Towel CychzaNon Egoflde /I o 0 l3 M o O L.° R-Nh b R-H /| O O 13 /I 0 0 ”E /l 0 L7. /1 0 L9 Substrates and Possible Products Products /' OH '3 2.9 /I /' z /’ OH H 23 as gyIR-Me bRsH /I /l o °”° OH 2: z; / / OH OH as 21 / of}; OH ' 0” as re 10 which the furyl moiety serves as a nucleophile and the alkyl group as an electrophilc (path b, Figure 6). [DESK Re-q-b Cf;- qug Re Figure 6 Bond Forming Polarities This approach would involve the reaction of furyl organolithium 32 or Grignard reagent 33 with an appropriate electrophilc. To the best of our knowledge, 32 has been reported only once in the literature.27 Tanis11 has demonstrated the usefulness of 33 in the preparation of 3-substituted furans by effecting its reaction with a variety of primary, secondary, and allylic halides in the presence of Kochi's catalyst Li2CuCl4.11 3128i CHzMgCI ,3 :s Figure 7 Furyl Anion Equivalents A general approach to epoxyfurans is outlined in Figure 8. The cOUpIing of Grignard reagent 33 with a haloalkene provides the correSponding (3-furyl) olefin 34. Treatment of 34 with m-chlorobenzoic acid (MCPBA) should afford epoxide 35. Although the furyl nucleus is known to be susceptible to oxidation 11 CHZMOC' (CH2)n\/R (CH ) R / \ halo- __,C°'- / \ I 'mam \ z" ' ° alkene /l\ / O O Fl2 R3 0 R2 R3 29 as as Figure 8 Furyl Epoxide Synthesis (fig. 8938,29), relative rates of furan vs. olefin reaction with peracids as a function of the degree of substitution have not been reported. emsmfw rel—(3&0 (28°) Br _ HQ _ Rfla Meon' “QR ——’ I; (28b) 0 NaOAc M00 0 OMe R o R m asLbL. (280‘) o o *ng Figure 9 Furan Oxidation: As shown in Table II the coupling reactions proceeded smoothly and in high yield when 33 was reacted with alkyl and allylic haides (runs 2-5, LiZCuCl4 12 Table 2 Synthesis and Oxidation of (3-turyl)-olefine Olefin Catalyst Producflxield) Oxidation Producflyimdl Br I Feet, /0 I g9 (82%) gee-x) :3 km LizCuCL4 /O I B 0 3(82%) 13g (25%) I Cl. Li Cu Cl / I \ W 2 ‘ o o §§(85%) @857.) .o \E l f L izCuCl4 /o ] 3‘83 °/e) L6} 0%) I LiZCuClq o\ o\ grew mat-x.) 13 as catalyst).11 However the synthesis of 36 (n = 1, Figure 8) required a vinyl halide as a coupling partner. In this case anhydrous FeC1330 (run 1, Table II) was employed as the catalyst providing an excellent yield of 36 (68%). Furyl olefins 36-40 were then each submitted to standard epoxidation conditions, 1.05 equiv of MCPBA in CH2C12 at 0°C. As can be seen in Table II the yield of the derived epoxide was dependent upon the olefin substitution. Trisubstituted furyl alkenes 36, 36 and 40 gave oxiranes 13, 15, and 17 in 81- 66% yields. Furyl alkene 37 afforded epoxide Me in a greatly reduced yield (25%), and 39 failed to give even trace quantities of 16. A closer examination of the oxidation of 37 (Figure 10) showed that epoxide Me was accompanied by anhydride 41 (37%), with 23% of alkene 37 recovered. However, olefin 39, a homologue of 37, afforded only the corresponding anhydride and unreacted 39. Replacing MCPBA with other oxidants31 did not lead to increased selectivity. Clearly, the degree of olefin substitution has a profound effect on the product distribution. In general, the protocol outlined in Figure 6 is not viable if the olefin is mono- or disubstituted. 0’ o 000 g [$1(25%) $3770) Figure IO Oxidation of :15] We then examined alternate routes to epoxides 14b, 16, and 16. Our observation11 that the reaction of 33 with an allylic halide possessing a potentially reactive distal epoxide function afforded only 7,8-epoxydendrolasin 14 42 (79%, eq 2) suggested this sequence be applied to the preparation of 14b, 16 and 16. Epoxy iodides 43, 44a, and 45a and tosylates 44b and 45b were each separately treated with 33 (Figure 11) to provide only the products of attack at the epoxide residue. Although Boeckman has demonstrated that organolithium reagents may be coupled with epoxy iodides in good yields,16f we initially avoided employing of 3-furylmethyllithium (32) in this context. Our major concern was the possibility that the precedented allylic-type rearrangement of anion 32 would intervene, resulting in electrophilc capture at the adjacent a-position.32 CHzMgCI \ 0 Q . Mei _..._. We) 3 43317970) 0 M 2 CHz’n (/ \S . mesa)" a —’ [/ \S o o )3 WW! 3; x=I,n-I,R=H |4b n=l, R=H ;.2,M-Li 4 a sin-2,R-Me "' N bX'UTstfiWe 16 n82.R=Me La X=I,n-3,R-Me N bx-Gfe,n=3,R:Ma. L9, n=3,R=Me Figure II Coupling of lodoepoxides Organolithium 32 was readily prepared as described in (Figure 12). Treatment of 3--(chloromethyl)furan11 46, with n-Bu3SnLi33 provided stannylfuran 47 in 69% distilled yield. Tin-lithium exchange proceeded smoothly, affording a virtually quantitative yield of 32 as determined by 15 titration. To our delight, 32 reacted with iodo epoxides 44a and 45a in the presence of HMPA (-25°C)16f to give epoxy-furans 16 and 16 in 73% and 68% mm w. w3n(n8u)3&_’ flu 45 47 32 N N Figure l2 Preparation of 12 yields, respectively. Products resulting from the rearranged anion or from attack at the epoxide could not be detected. However, oxirane 14b could not be prepared by this technique. As a result, we were forced to take the rather circuitous route to 14b described in (Figure 13). Coupling of 33 with the protected iodo diol 46 afforded furan 49 in 73% yield. This, after hydrolysis, conversion of 50 to the monotosylate 51, and closure of the epoxide ring with Nail gave 14b (94%). MgCl 0 / \ Irv W’I’ 0 0 _—_. o\ —» °>< .33 4x8, gnaw.) 0H . OR o H —+ UV“ 0 o 59 R=H(64%) 0 ~51! R=Ts (34%) Igb(54 x.) Figure 13 Preparation of lgb 16 Cyclization Studies. With the desired cyclization substrates in hand, the ring closing sequence was then examined. Of the many Lewis acids which are available, powerfully acidic substances such as boron trifluoride etherate are often selected to catalyze epoxy olefin cyclizations. Given the relatively poor nucleophilic character of the furyl residue and the acid lability of the starting materials and desired products, the choice of Lewis acid should have a profound effect in the partitioning of this reaction between a fruitful cyclization pathway and undesired products. Six Lewis acids were selected to determine their ability to promote epoxy furan cyclization (Table III). Other than the standard BF3'OEt2168'f the choice of these Lewis acids was dictated by two factors: (i) the ability to modify the potency of a group of Lewis acids with a common metal center and (ii) the possibility of moderating the Bronsted acidity of the medium through the choice of Lewis acid. Thus, adventitious protic acid might be scavenged by Lewis acids possessing a carbon-metal bond. Alternatively, with proper choice of metal, the product metal-alcohol complex should be a much weaker protic acid compared to a BF3-alcohol complex. Snider has reported the successful application of alkyl aluminum halides as Lewis acids in acid-sensitive cyclizations. The alkyl aluminum halides cover a wide range of Lewis acidity35 from EtAlClg, which is only slightly less potent than AlCl3, to the very mild Me3Al. Both the range of Lewis acidity presented by the alkyl aluminum halides and their ability to scavenge protic acids make them likely candidates for initiating epoxy furan cyclizations. Further modification of aluminum centered Lewis acids is possible, as demonstrated by Boeckman.16f Basic alumina in hexane (24 h, room temperature) was also found to cyclize various epoxy vinyl ethers (Figure 5b) in good yields .1 6f 17 3333 $23... $83 game: 3253 Afigvva 33:." gig: SEEN" “flutes 368 «.55 3:33 .3383. £83 $33" § 33 Aamhvvu .cxm oz GmNSNN Aficmvau :59 «ESE. $2.5. .383... $33" .Aficvau 3:8: .983 $33... 5:83 338:" ”of. $838 .38...» 3 85 .3253 333: .3253 53..." £25 3352 3:83 3383 308 625m 5:3: Seflaosfi a man’s 33.83 .333" 3:53 .333" $2.5 £83 §$§ .53: ems £23m 3.2:... .3352. § 53 .333“ gay: 325;" $3.3m § mvvnu Afimmvaa Afiwwvca 33.8 Numommm au um o~ an a: a: nu 33 Row :35 £33 izxoam 16 Titanium tetrachloride is a powerful Lewis acid which has-been observed to react with epoxides to provide {B-chlorotitanates.36 The affinity of titanium for an epoxide oxygen, and the acidity of the alcohol-Ti complex, can be tempered by replacing chloride by alkoxy groups, such as isopropoxy. The mildly acidic titanium tetraalkoxides have been shown to be effective in the catalysis of aldol condensations.35 Stork37 and Sharplesslfig have successfully applied Ti(O-i-Pr)4 to intramolecular Michael addition and p-OH-epoxide- initiated olefin cyclizations, respectively. Zinc iodide,38 the final Lewis acid examined in this study, was selected based on an assumption that the product zinc-alcohol complex, generated during the course of the cyclization, would be a weak protic acid. The correctness of this supposition is illustrated by Marshall's successful closure of an acid-labile diene-aldehyde during his synthesis of occidentalol.38a The substrate epoxy furans were then submitted to cyclization conditions as follows. Oxirane 13 was initially treated by "standard" conditions for polyene cyclizations, 0.33 equiv of BF3'OEt213 in 032012 at -25°c. As anticipated, 13 failed to yield the cyclized product 19. Instead, 62% of allylic alcohol 20 was obtained. Epoxy furans 14a, 14b, 15, 16, 17, and 16 were then treated with BF3-0Et2, in a similar fashion (Table III). Only the six- membered endocyclic precursor 15 and the 6-exo-epoxy furan 16 provided appreciable quantities of cyclized products, leading to 24 and 26 in 47% and 30% yields, respectively. The majority of the materials recovered from the attempted cyclizations of 14a, 14b, 17, and 16 were the corresponding allylic alcohols. In all of these cases the material balance was poor, with only about 60% of the starting mass recovered. The general lack of cyclization, coupled with the poor mass balance, clearly demonstrates that the standard cyclization conditions are not generally applicable. 19 Our study of aluminum based Lewis acids in the cyclization of epoxy furans began with EtAlClg, and EtgAlCl. Treatment of epoxy furans 13-16 with two equiv of either EtAIClz or EtzAlCl, in CHZCIZ at -25°C, provided little cyclized materials (Table 111). As with BF3°OEt2 only the 6-endo-epoxide 15 yielded appreciable quantities of cyclized products, 16% and 22%, respectively. Smaller quantities of 26 (10%) and 26 (10%) were isolated after treatment of 16 and 17 with EtgAlCl. However, as is obvious. from an inspection of Table [11, this modification of the Lewis acid resulted in a marked improvement in the mass balance. The results from these cyclization studies demonstrated that the majority of the substrate was being diverted to undesired elimination products. Therefore, further moderation of the Lewis acid was required. Stirring epoxy furans l3 and 15-17 with alumina resulted in very high yields (60-90%) of elimination products. Only substrate 15 afforded cyclized product, and 24 was obtained in 32% yield. Again elimination was preferred over cyclization in all of the cases examined. In the titanium series, 'I'i(O-i-Pr)4 was initially examined as a Lewis acid for cyclization of epoxides 13-16. EXposure of these substances to 3 equiv. of Ti(O-i-Pr)4 in CHZCIZ for extended periods at room temperature resulted in quantitative starting material recovery. The next acid in this series Ti(O-i-Pr)3Cl, prepared by the disproportionation of 3 equiv. of Ti(O-i-Pr)4 with 1 equiv. TiCl436 (1.5 M in CH2C12), proved to be an efficient and useful promoter of epoxy furan cyclization. As before, oxiranes 13 and 14a provided only products of elimination, allylic alcohols 20 (80%) and 22 (72%), respectively. Epoxide 14b could not be induced to react, even after treatment with 3 equiv. of 20 Ti(O-i-Pr)3Cl (CHZClg) at room temperature for 24 h. Similar treatment of epoxy furan 15 led to the formation of the desired cyclized adduct 24 in 78% yield, virtually uncontaminated by elimination products. 6-exo—Epoxide 16 and 7-endo—epoxide 17 afforded excellent yields of cyclized products 26 (89%) and 26 (87%), respectively, the latter being accompanied by a modest amount of allylic alcohol 29 (8%). Even epoxide 18, designated as 7-exo, gave a respectable yield of cyclic prodinct 30 (36%) when exposed to Ti(O—i-Pr)3Cl. Cyclizations of furyl epoxides 13-16 with anz, the final Lewis acid in this study, were performed in CH2C12 at room temperature. Treatment of furyl epoxides 11 and 12a with 3 equiv. of freshly prepared Zn12 led to the isolation of high yields of the derived allylic alcohols (Table III). However furyl epoxide 14b afforded the elusive five-membered cyclic product 21b, albeit in only 25% yield under similar conditions. Epoxy furans 15-16 provided good to excellent yields of the corresponding cyclic products accompanied by small quantities of allylic alcohols. A more rigorous test of the epoxy furan cyclization as a route to naturally occurring terpenoids might require the formation of two or more rings during the sequence. Pallescensin-A (52)39 provided an appropriate test. In the event, epoxydendrolasin (42)11 (eq 2) gave 3 - p-OH pallascensin-A (53)“ in 47% yield upon treatment with 353-059 (Figure 14). Zinc iodide O\ Q\ \ \ I —. —. O HO H 9.2, 5 Figure i4 Heparation at Pallascensin A (2) 21 and triisopropoxytitanium chloride gave even higher yields of 53, 62% and 65%, respectively, as well as a cleaner reaction mixture. Compound 53 was then smoothly converted to pallescensin—A (52) as described by Nasipurifl0 These results (Table III) clearly demonstrate the potential of the epoxy furan cyclization for the formation of six- and seven-membered rings. Good to excellent yields of cyclic products can be realized with a judicious choice of Lewis acid. However, closure to form five-membered rings remains problematic. As anticipated, the 5-endo type of closure, represented by epoxide 13, afforded only elimination products. In this case the overlap necessary for cyclization is precluded by the presence of but a single sp3 carbon in the forming cycle. The low yield of product 21b from 5-exo-epoxide 14b was initially disappointing, since there is ample literature precendent for cyclizations to form five-membered rings with similar steric constraints.151335bi41 However, each of these cases the terminator function is considerably more nucleophilic than a furan. A solution, in principle, to this problem is to increase the nucleophilicity of the furyl terminator by introduction of an electron donating substituent onto the furan ring. Unfortunately few examples of stable, appropriately substituted furans related to organometallics 33 and 32 are known.9 ALLYIJC ALCOHOL AND ENONE INITIATED CYCLIZA‘I'IONS Our previous work demonstrated the utility of epoxide initiated furan terminated cationic cyclizations. However, these substrates provided access only to rather simple and relatively unfunctionalized fused-ring systems; and in addition, the difficulties encountered in the preparation of the requisite epoxy-furans reduced the generality of this approach. In an attempt to eXpand the usefulness of furan terminated cationic cyclizations, we have examined the reaction of furyl dianion equivalent 54 (Figure 15) with a variety of bis- electrophillic synthons 55-57. Theinteraction of the active furan side chain nucleophilic center with the bis-electrophilc will provide a coupling product; subsequent activation of the second electrophilic center followed by aromatic substitution could provide fused—58, spirocyclic-59 and bridged-60 ring systems. Manipulation of the furan nucleus (see Figure 4) and other residual functional groups would provide complex intermediates for the preparation of diverse classes of bioactive natural products. Figure I5 Dianion Couplings 23 Design and Synthesis of Cyclization Substrates Of paramount importance to this study was the selection of the bis- electrophilic moieties illustrated in Figure 15. The relative level of reactivity must be arranged so that the active furan side-chain nucleOphilic center reacts selectively at one of the electrophilic sites so as to furnish the desired regioisomer upon cyclization. In order to minimize potential selectivity problems in the initial addition, we sought equivalents of bis-electrophiles 55 and 56 (Figure 15, paths A and B) which would reveal a second electrophilic center on the adjacent carbon as a result of the initial addition. Recent reports by Marino423-c‘f, Wender428, and Ziegler42b have demonstrated the usefulness of vinyl epoxides42‘i‘f and enol ethers of a, p-epoxy ketones in SNz' type addition of cuprates (Figure 16). In these processes, an allylic alcohol. and enone, are created respectively, providing a potential second electrophilic center on the carbon adjacent to the position of initial attack. These results suggest the applicability of 0, p-epoxy ketone enol ethers 60 and vinyl Spiro-epoxides 61 (Figure 17) as equivalents of the hypothetical 55 in the formation of fused ring compounds (Figure 15, path A). An exo- methylene vinyl epoxide 62 (Figure 18) would provide access to spirocyclic substances as the operational equivalent of 56 (Figure 15, path B). The syntheses of bridged species (Figure 15, path C) in which the distance between the electrophilic centers can be variable is best dealt with on a case-to-case basis. This analysis pinpoints allylic alcoholslza‘h’23vt43, prepared directly from 61 and 62 (Figures 16-18) or by reduction of the enone product of 60, and/or enones and ena1823V»44 prepared from allylic alcohols, as the initiators in cyclization step. 24 R-M . N —. RWOH TMS TMS R-Mo 0-—- —» Figure I6 Additions to Vinyl Epoxides 99 ‘21 . 29 Figure I? In the event, Grignard reagents prepared from 3-chloromethyl furan 46453, 2-(3-furyl)-1-bromoethane 6345b, and 3(3-furyl)—1-brom0propane45c 64 were treated with CuCri73:°"f and allowed to react with the readily available vinyl epoxide 65 (Figure 19) to provide allylic alcohols 66-66, precursors to Wait" um dew)“ (50% fi fl 0 2)CuCN o - am 0 . Yield 2366 GIN-l3 WQQIX 1313):; aim—I: 5% Figurel9 Preparation of §§'§§ 25 Spiro-[4.51decane, [5.5lundecane and [5.63dodecane systems, respectively, in good to excellent yields. The corresponding enones 69-71 were readily prepared (Figure 20) gig oxidation (PCC)46 of alcohols 66-66. Additionally, the Grignard H PCC ——. aim 09"“ )o o n _n_ Ytdd 55 l 5,3. l 57* 67 2 2.9 2 33* £6 3 21, 3 34% Figure 20 Oxidation of §§'§§ reagents prepared from 63 and 64 were treated with CuCN and coupled with vinyl epoxide 72 (Figure 21) to provide the acid labile allylic alcohols 73 and 74, precursors to the spiro-[4.5]decane, and [4.6]undecane systems in good yield. The corresponding enones 75 and 76 were prepared by oxidation of the alcohols (Figure 22). on tcu,),er W (CH,i,M (55 1’3 .. (I9) safer (oi —"' “MG .n_ _n_ Yigid ft} 2 u a. 59% 93 3 :9, 3 63% Figure 2| Reparatian of L313 0H 0 (0+6th (0+,th a ma. .0. 2 2 73% 3 g? 3 74% N (3‘61 Figure 22 Oxidation of 235-13 26 The synthesis of fused-ring compounds requires 60 and 61 as annulation partners. For this study, cyclohexenone and cyclopentenone were selected as the precursors to 60 and 61 which, when treated with the Grignard reagents derived from 63 and 64, might lead to fused bicyclo-[4.4.0]—decane and bicyclo- [5 .4.0]-undecane ring systems, respectively. Enol ether 77 was easily prepared by the methods of Marino42f and Wender428 from cyclohexenone; however, enol ether 76 had to be prepared and used in situ. To the best of our knowledge, 79 has not been reported in the literature. A direct approach to 79 using Corey's dimethylsulfonium methylide47 provided 79 in variable (0-35%) OTMS was». s «_.,«~s zgiav.) Figure 23 Preparation of 1% yields. We then examined the alternative procedure outlined in Figure 23. The addition of methylthiomethyl lithium48 to cycthexenone provided the 3°- allylic alcohol in 88% yield. Methylation at sulfur (CH3I, 100%) and treatment of the resulting sulfonium salt with KOtBu (THF) provides 79 in 80% overall yield from cyclohexenone.49 With 71-79 available, the fused-ring cyclization substrates were prepared as described in Figures 24 and 25. 27 {.609} ling CH HeLi 01 H 0 \ 2 —' 2 Yield 3i}; .0... .5. .0. Lied. .9. ._'__ s3, 2 Br 99 2 75% 93 2 90% pg 3 Br 9; 3 72% as, 3 90% Figure 24 Preparation of 82-9; a “(crater M (Cl-I, on I. mu 0 276.957" ’ l ——-t “Wu-é— 3) 19 3.. L Yield LL M 63 2 as 2 32% g 2 83% 55 3 93 3 54% ,1, 3 78% Figure 25 Reparation at fig-y Treatment of the Grignard reagents derived from 63 aqnd 64 with CuCN7 followed by 79 provided enones 60 and 61 in 75% and 72% yields, respectively. The addition of MeLi afforded 3°-allylic alcohol cyclization substrates 62 and 63 (90%). Similarly, addition to 76 provided the enones 64 (52%) and 85 (55%), which on treatment with methyl lithium afforded the very unstable tertiary allylic alcohols 86 and 67 in 83% and 78% yields respectively. SNZ' addition to spiroepoxide 79 (Figure 25) provided allylic alcohols 66 (78%), 69 (56%), and 90 (58%). Oxidation (PCC) of 66-90 gave enals 91 (79%), 92 (83%), and 93 (76%); the addition of CH3Li to 92 and 93 afforded 2°-allylic alcohols 94 (90%) and 95 (85%). 28 (”Six I) Ha I) PCC / \ \ (ZS 2.)ch gel”. 2mm ggwb 3);; 1 1 _ Yidd n L Yield 45, l Cl as i 78% 2L i CHO 79% 9:3 2 Br as, 2 56% ea 2 CH0 83% s9 3 a: 99 3 58% 93 3 CHO 78% $5 2 CH,CHG—l 90% a; 3 CHp-lOi-l 85% Figure 26 Preparation of QB‘?.§ Cyclization Studies With the desired cyclization substrates available, the ring closing sequence was examined. Given the relatively poor nucleophilic character of the furyl residue relative to standard terminator function523v50 and the increased acid lability of the derived product disubstituted furans compared with the starting materials“, the choice of reaction conditions should have a profound effect in the partitioning of the reaction between a fruitful cyclization pathway and undesired products. During our study of epoxide initiated cyclizations , we observed that the mild Lewis acids Ti(OiPr)3Cl and ZnIZ-OEtZ provided the best balance between Lewis and Bronsted acidity of the medium, resulting in high yields of cyclized products. Such Lewis acids, as well as the alkyl aluminum halides examined by Snider9k might cause enones 69-71 and 75-76, and enals 94 and 95 to undergo cyclization. Enones and enals have also been cyclized with acid“, ACZO-H+44, and (CF3CO)20, CF3C02H44, however, the fragility of the products and the facility of furan acylation may render these reaction conditions useless. Allylic alcohol 29 initiators for cationic cyclizations have been extensively examined by Johnson and others 12341243 and the reaction conditions which have been employed generally involve a protic acid of reasonable strength in a solvent in which it is soluble. Of the many conditions reported in the literature, the two-phase mixture of cyclohexane and anhydrous formic acid“3 appeared to be the mildest method for initiating the cyclization of allylic alcohols. (3“ H000“ ’ 3 emu/C) can. \ 00.. O \ .9. 3.de §§ I as l Miami. 84%) a} 2 2;! 2 72% 6,3 3 g 3 55% Figure 27 Cyclization at 55‘§§ EXposure of allylic alcohols 66-68 (Figure 27) to anhydrous formic acid- cyclohexane for 5-15 minutes at room temperature resulted in the smooth closure of 67 and 68 to provide the correSponding spiro[5.5]undecane 97 (72%) and spiro[5.6]dodecane 96 (58%) ring systems. Allylic alcohol 66, precursor to a spiro[5.4]decane, failed to provide 96, yielding instead the formate (84%). The inability of allylic alcohol 96 to form a five-membered ring was expected based upon our earlier experience with epoxy-furans. As we have previously noted with cyclization substrates related to 96, the overlap required for ring closure to occur is difficult to achieve, as the cation derived from 96, possesses but two sp3-hybridized carbon atoms in the forming cyclefi"1 Alcohols 73 and 74 were smoothly converted, in good yield, to the spiro[4.5]decene 99 and the spiro[4.6]undecene 100 respectively in good yield (Figure 28). 30 OH HO Sx°x7 €310“ C (012)" '2 \ \ CH2), :1 __n_ Yield 3 g 93 2 53% ~ '29 3 53% Figure 28 Cyclizaion of lg-zg / 0 o HCOOH / (1L ——~ (C cc,H,, “3H9" A A 11$ 93 2 Lo; 2 73% a; 3 Log 3 56% Figure 29 Cyclization of gg-g; Alcohols 82 and 83, when treated with formic acid and cyclohexane (Figure 29), provide good yields of the fused furan containing bicyclo- [4.4.0]decane 101 (73%) and bicyclo[5.6.0hndecane 102 (56%). The assignment of the cis-ring fusion in 101 and 102 is based upon precedent12 and is expected from the method of synthesis. Similar exposure of alcohols 86 and 87 (Figure 30) provided the bicyclo[3.4.0]nonene 103 and the bicyclo[3.5.0]decene 104 in good yields. Additionally, treatment of primary allylic alcohols 88, 89 and 90, also precursors to fused ring systems, with formic acid/cyclohexane, led to the isolation of the corresponding formate esters in excellent (80-90%) yields. However, the related secondary allylic alcohols 94 and 95 cyclized smoothly as is illustrated in Figure 31, affording 103 (68%) and 104 (61%) as a mixture of exo-ethylidene double bond isomers. 31 \ (map “:6le (CH2. / ' 1 _n_ Yield 93? 2 L9; 2 64% 93 3 I93 3 57% Figure 30 Cyclization d 9&1} aM £915 _l'l_ l Yield 93 2 pm; 2 66% 955 3 '29 3 6l‘/. Figure 3| Cyclization of 93-95 With allylic alcohols firmly established as effective initiators for furan terminated cationic cyclization, we next examined the cyclization of enones 69-71, 75, 76 and enals 91-93. Compounds 69-71 and 91-93 were exposed to various Lewis acids52 under numerous sets of reaction conditions to no avail. The more potent Lewis acids AlCl3, TiCl4, BF3 extensively decomposed substrates 69-71 and 91-93, however, when milder Lewis acids such as MgBrz, Zn12 and Ti(0iPr)3Cl were employed, the starting materials were recovered in nearly quantitative yields. Acylative-type enone and enal cyclizations similar to those reported by Andersen44ih, Marshall44 and Harding“:i were then attempted. Treatment of enones 69-71 and enals 91-93 with either Ac20,HClO4,EtOAc or (CF3CO)20,CF3C02H resulted in a facile and high 32 yield acylation of the furyl nucleus at the 2-position. Having failed to cyclize 69-71 and 91-93 under the relatively mild Lewis acid or acylation reaction conditions, we turned to a protic acid mediated closure. Enones 69-71 were each dissolved or suspended in cyclohexane, and formic acid was added to generate a red color. Quenching of the reaction after 5-15 minutes (Figure 32) and analysis of the product mixtures demonstrated that, of the three substrates 69-71, only 70 had suffered cyclization, providing the furan- containing spiro[5.5]undecane 105 in 60% yield, enones 69 and 70 were recovered quantitatively. Additionally, acid treatment of enones 75 and 76 provided 106 in 61% yield and unreacted 76 respectively. More vigorous reaction conditions led to the complete destruction of 69, 70 and 76. Similar treatment of enals 91-93 resulted in starting material recovery; or in cases of harsher treatment, polymerization. 0 I o HCOOH o (C n / (Conn \| CH). _n_ A Yigld Q l NR 29 2 m 2 66% ll, 3 . NR Figure 32 Attempted Cyclization of 63-21“ 0 H:LOH ' ° l2 S\ /7 0‘ (6142),, \ (042)" n. n. mm. 2.5 2 LQQ 2 72% lg 3 3 NR Figure 33 Attempted Cyclizdllon of 2316; 33 In order to investigate the possibility that enone cyclization is reversable and, in the case of seven-membered ring formation, thermo-dynamically unfavorable, the ketone 111, which would result from cyclization of enone 71, was prepared from alkene 98 and submitted to the reaction conditions used in the attempted cyclization of 71. Hydroboration of 98 provided a 10:1 mixture of regioisomers with 109 being the major isomer, produced in 73% yield. Oxidation of 109 with PCC provided an excellent yield of ketone 110, which, when submitted to the two phase mixture of formic acid-cyclohexane for 1 hour, was recovered unchanged. ‘6 66w 9 937%) #8236) Figure 34 Preparation of ”9 The Synthesis of a Edged System. The Preparation of lineman-9 6. The construction of bridged-ring systems was demonstrated as part of a synthesis of nakafuran-9 6. Nakafuran-9 6 was recently isolated by Scheuer7 from the marine sponge 218312 Maud from the nudibranchs Hypselodoris godeffroyana and Chromodoris maridadilus which graze upon D. fragili . Nakafuran-9 6 and the closely related nakafuran-8 5 possess fish antifeedant properties, having been observed to repel predacious reef fishes which feed upon the soft bodied nudibranchs. A retrosynthesis of nakafuran-9 6, presented 34 in Figure 35, suggests that the bicyclo[4.3.1]decane skeleton of 6 ultimately would be available from 3-furyl-methyl dianion and a highly substituted dication. Figure 35 Relrosyrlhesis of Nakafuron-Q The dication equivalent selected was the vinyl expoxide 111 (Figure 35). The coupling of the Grignard reagent prepared from 3-chloromethyl furan 46 with 11 (CuCN) provided allylic alcohol 112 (62%), thus establishing the C-4, C- 5 bond of 6. Oxidation (PCC, 89%) and treatment of the derived enone with MeCu-BF353 introduces the C-6-CH3 group giving ketone 113 (70%) as a 60:40 mixture at pro-C-7 in 62% overall yield from 102. The second electrophilic center needed for closure at C-10 was introduced smoothly as the enone 1i_a selenylation54 of the kinetic enolate followed by oxidation (H202, Eth) and elimination of the selenoxide, giving enone 114 (72%). We found it necessary to perform the oxidation-elimination in the presence of a base (Et3N) because the phenylseleninic acid produced in the elimination promoted cyclization of 114 providing a mixture of 114 and 115 in greatly reduced yield. Cyclization of 114 was effected with HCOZH-cCGHIZ affording the crucial bicyclo[4.3.1]decanone 115 in excellent (79%) yield as a 60:40 mixture at C- 7. All that remained to complete the synthesis of nakafuran-9 6 was the introduction of a methyl at C-8 and the placement of a double bond at C-7-C- 8. A methyl equivalent and double bond were simultaneously introduced _yi_a a Wittig olefination of 115 using the conditions of Conia55 35 \0 46 gg(62%) :12. I3 _"_.. 3‘ ugi'rzv.) J... 3‘ _i_.. 3‘ 3‘ ugieosu 9_ 60941965) LLZ 0) "9.6000; mmfi '. 6) PCCMHIOCUJfi'NO, ; 6)LDA 30‘5“? 59)H,O, ,EQN; n) chn .c6,H,-. i) 4,901,: ,KOtMIylcte ; n 9101.46.23 Figure 36 Preparation of Nokoturon-S (o3P-CH31, K-t—amylate) to give 116 in 80% yield as a 60:40 mixture at C-7. Olefin migration was attempted with (¢CN)2PdClz563, RhCl3(H20)356b, and (¢3P)3RhH0122°; in each case, starting material 116 was recovered unchanged. Acid catalyzed olefin migration was investigated and after extensive experimentation, we found that exposure of 116 to a solution of stOH in refluxing benzene for 15 minutes provided a 95:5 mixture of nakafuran—9 9 and 8,9-isonakafuran-9 117 in 80% yield. The identity of the extremely acid labile 6 was confirmed by a comparision of spectral data with those of authentic 6.57 SUMMARY AND CONCLUSIONS Several 3-substituted furans with latent electrophiles in the side chain were prepared as cyclization substrates. 3-Furylmethyl magnesium chloride is readily coupled with a variety of w-haloalkenes to afford the corresponding 3-substituted furan in good to excellent yields. Epoxidation of the product furyl olefins was found to be effective in producing the desired cyclization substrates only when the olefin was trisubstituted. Less highly substituted epoxy furans were prepared via the coupling of (3-furylmethyl) lithium with w-iodo epoxides or protected w-iodo diols followed by closure. The cyclizations of these epoxy furans were examined with a number of Lewis acids. Treatment with Ti(OiPr)3Cl and Zn12 led to the isolation of cyclized products in moderate to excellent yields. Cyclization of 7,8-epoxydendrolasin with Ti(OiPr)3Cl and Zniz provided 3 p-hydroxypallescensin A in 62% and 65% yields respectively. Additionally, allylic alcohols and enones derived from the CuCN moderated SN2' addition of Grignard reagents prepared from 2-(3-furyl)—1-bromoethane and 3-(3-furyl)—l-bromopropane to vinyl epoxides and epoxy-enolethers were employed as cyclization substrates. Treatment of substrate allylic alcohols with a two phase mixture of formic acid and cyclohexane resulted in facile cyclization when the forming ring was 6-, or 7-membered. Enone closures proceeded only when a 6—membered ring was produced or in the case of a bridged system which leads to nakafuran-Q. These results clearly demonstrate the potential of furans as terminators in cationic cyclization. Cyclization of epoxyfurans provides good to excellent yields of simple cyclized products and allylic alcohol initiated cyclizations form fused-, Spiro-cyclic, and bridged systems providing reasonably well functionali zed products. 36 37 The closure to form five membered rings remains problematic. This is analogous to the constraints encountered by Stork513 and van Tamelen51b in similar work. This result is probably due to the fact that the orbital overlap necessary for closure to occur is difficult to achieve and, therefore, cyclization is slow in comparison to other available pathways. EXPERIMENTAL SECTION General. Tetrahydrofuran (THF) was dried by distillation, under nitrogen from sodium benzophenone ketyl; methylene chloride was dried by distillation under nitrogen from calcium hydride; N,N-dimethy1formamide (DMF) was dried by distillation at reduced pressure from phOSpOl‘OUS pentoxide; hexamethyl— phOSphoramide (HMPA) was dried by distillation at reduced pressure from calcium hydride; pyridine was dried by distillation, under nitrogen, from calcium hydride; diisopropylamine was dried by distillation, under nitrogen, from calcium hydride; formic acid was dried by distillation under argon from phthalic anhydride. Petroleum ether refers to 30-60°C boiling point fraction of petroleum benzin. Diethyl ether was purchased from Mallinkrodt, St. Louis, MO, and used as received. n—Butyllithium and methyllithium in hexane were purchased from Aldrich, Milwaukkee, WI, and titrated by the method of Watson and Eastham.34 Ethylaluminum dichloride and diethylaluminum chloride were purchased as hexane solutions from Alfa Products, Danvers, MA, and used as received. Magnesium metal turnings were activated by successive washings with 1 N aqueous hydrochloric acid, water, acetone, and ether and dried in a dessicator over phOSphorous pentoxide at reduced pressure. All other reagents were used as received unless otherwise stated; all reactions were carried out under a blanket of argon with the rigid exclusions of moisture from all reagents and glassware unless otherwise mentioned. Melting points were determined on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Pye—Unicam SP—1000 infrared Spectrophotometer with polystyrene as standard. Proton magnetic resonance spectra were recorded on a Varian T-60 at 60 MHz or a Bruker WWI-250 spectrometer at 250 MHz as indicated, as solutions 38 39 in deuteriochloroform unless otherwise indicated. Chemical shifts are reported in parts per million of the 6 scale relative'to a tetramethylsilane internal standard. Data are reported as follows: chemical shift (multiplicity (s = broad), single, d = doublet, t = triplet, q = quartet, m - multiplet, br coupling constant (Hz), integration). 13C magnetic resonance spectra were recorded on a Bruker WM-250 spectrometer (68.9 MHz) and are reported in parts per million from tetramethylsilane on the 6 scale. Electron impact (El/MS) and chemical ionization (CI/MS) mass spectra were recorded on a Finnigan 4000 with an INCOS 4021 data system. Elemental analyses were performed by Spang Microanalytical Laboratory, Eagle Harbor, MI. High resolution mass spectra were performed by the MSU Department of Biochemistry, Mass Spectroscopy Facility, East Lansing, MI. Flash chromatography was performed according to the procedure of Still, et al53 by using the Whatman silica gel mentioned and eluted with the solvents mentioned. The column outer diameter (od) is listed in millimeters. (3-furyD-chloromethane (46)“. To a mechanically stirred solution of LiCl (2.12 g, 0.05 mmol) in anhydrous DMF (40 mL) was added a mixture of (3-fury1)—methanol (4.9 g, 0.05 mmol) and 2,4,6—trimethylpyridine (6.66 g, 0.055 mol). The resulting solution was cooled to 0°C in an ice-water bath and methanesulfonyl chloride (6.3 g, 0.055 mol, distilled from calcium hydride) was added over a period of 20 minutes. The mixture became bright yellow and a thick suSpension. After stirring at 0°C for 2 hours the mixture was cast into ice-water (150 mL) and ether-pentane (1:1, 150 mL). The organic phase was separated and washed with saturated aqueous cupric nitrate (3 x 150 mL), dried (NaZSO4) and concentrated it; 19539 to give a light yellow liquid. Distillation provided 4.8 g 75%, of product as a colorless liquid B.P. (25mm) 40 = 40°C. (lit. B.P.32u7mm) = 42-43°C). Ell/MS (70 eV): 118 (w, 34.5), 81 (base). 1H NMR (60 MHz)6:7.32 (t, J=2Hz, 2H), 6.28 (d, J=2Hz, 1H), 4.56 (s, 2H). 2-Methyl-4-(2-furyD-but-2-ene (36). To activated magnesium metal turnings (0.243g, 10 mmol) covered by THE (15mL) was added (3-furyl)- chloromethane (1.16 g, 10 mmol) in one portion. The mixture was allowed to stir at room temperature until all the magnesium had been consumed (about 1 h). The resulting golden solution was cooled to 0° and l-bromo-Z- methylprOpene54 (1.35 g, 10 mmol) was added in one portion followed immediately by anhydrous FeCl3 (16 mg, 0.01 mmol). The resulting deep red reaction mixture was stirred at 0°C for 1 h and then was cast into saturated aqueous NH4C1 (100 mL) and ether (100 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried (NaZSO4), and concentrated i_n M9 to yield a golden liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 100 g, 50 mm od, ether-petroleum ether 1:99, 30-mL fractions) using the flash technique. Fractions 6-9 provided 1.12 g, 82%, of 36 as a colorless liquid: 1H NMR (250MHz)- 6 7.22 (t, J=2 Hz, 1H), 7.04 (m, 1H), 6.13 (br s, 1H), 4.54 (t, J=10 Hz, 1H), 3.10 (d, J=10 Hz, 2H), 2.62 (s, 3H), 2.50 (s, 38); IR (neat) 2900, 1500, 1450, 1375, 1155, 1070, 1010, 870, 780 cm-1; EI/MS (70 eV) 136 (NH, base), 121 (42), 93 (41), 91 (37), 77 (36). GENERAL PROCEDURE FOR PREPARATION OF 3-FURYL OLEPINS 2-Methyl-4-(3-furyD-but-1-ene (37). To activated magesium metal turnings (0.243g, 10 mmol) covered by THF (15 mL) was added (3- furyl)chloromethanell (1.16g, 10 mmol) in one portion. The mixture was stirred at room temperature. until all the magnesium had been consumed (about 1 h). The resulting golden solution was cooled to 0°C in an ice-water bath and 41 3--chloro-2-methyl-propene55 (0.90g, 10 mmol) was added followed immediately by LiZCuCl4 (0.12 mL, 0.1M in THF). The reaction mixture immediately warmed and turned black. After the solution had stirred at 0°C for 30 min., it was cast into saturated aqueous NH4C1 (100 mL) and ether (100 mL). The organic phase was separated and washed with water (100 mL), brine (100 mL), dried (NaZSO4) and concentrated in w to yield a colorless liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 100g, 50mm o.d., ether-pet. ether 1:99, 30mL fractions) using the flash technique. Fractions 611 provided 1.10g, 81% of 37 as a colorless liquid: 1H NMR (250 MHz):6=7.28 (t,J=1.8Hz, 16), 7.13 (m, 1H), 6.19 (brs, 111), 4.62 (hrs, 28), 2.27 (m, 4H), 1.76 (s, 311); IR (neat) 2950, 2870, 1500, 1150, 1080, 1025, 900, 890, 780 cm'l; EI/MS (70 eV) 136 (M+, 15), 121 (11.7), 94 (46.7) 81 (base). 2-methyl-5-(3-furyD-pent-1-ene (39). 10 mmol of Grignard reagent 32 was reacted with 196g (10 mmol) of 4--iodo-2-methyl--l--butene56 according to the general procedure for the preparation of (3-furyl) olefins to provide 1.24g, 83%, of 38 as a colorless liquid: 1H NMR (250 MHz):.6= 7.25 (t, J=1.8Hz, 18) 7.08 (m, 1H), 6.15 (br s, 1H), 4.72 (br s, 28), 2.39 (m, 4H), 1.98 (m, 2H) 1.68 (s, 311); IR (neat) 2930, 2865, 1500, 1150, 1070, 1025, 900 cm-1; ELI/MS (70 eV) 150 (M+, 19.2), 122 (10.0), 107 (9.8), 95 (15.6), 94 (97), 82 (76.4), 81 (base). 2-Iethyl-6-(3-furyD-hex-2-ene (40). 10mmol of Grignard reagent 33 was reacted with (2.10g, 10 mmol) 5-iodo--2-methyl-Z-pentene57 according to the general procedure outlined above to provide 1.19g, 73%, of 40 as a colorless liquid: 1:1 NMR (250 MHz):6 = 7.29 (t, J=2Hz, 1H), 7.16 (m, 1H), 6.20 (s, 111), 5.18 (t, J=6Hz, 1H), 2.38 (t, J=6Hz, 2H), 2.36-1.03 (m, 4H), 1.64 (8, 3H), 1.58 (s, 38); IR (neat) 2950, 2880, 1500, 1160, 1070, 1025, 905, 865, 780 cm‘l; EI/MS (70 eV) 164 (M+, 2) 149 (3), 121 (9.1), 108 (8), 94 (14), 82 (base). 42 GENERAL PROCEDURE FOR EPOXIDATION OF (3-FURYL)-OLEFINS Preparation 2-methyl-4-(3-furyD-2-epoxy-butene (13). To a magnetically stirred solution of 36 (1.36 g, 10 mmol) in methylene chloride (30 mL), cooled to 0°C in an ice-water bath, was added a solution of m-chloroperoxybenzoic acid (2.32 g, 11 mmol, 85%) in methylene chloride (50 mL) over a period of 30 min. The resulting mixture was stirred at 0°C for 30 min, the suspension was then filtered, and the filtrate cast into 10% aqueous sodium bisulfite (150 mL) and ether (200 mL). The organic phase was separated, washed with saturated aqueous NaHC03 (100 mL), water (100 mL) and brine (100 mL), dried (NagsO4), and concentrated in gm to yield a light yellow liquid. The crude product was purified by chromatography on a column of silica gel (60-230 mesh, 75g, 60 mm od, ether-petroleum ether 1:4, 40 mL fractions) by using the flash technique. Fractions 6-11 provided 1.33 g, 88%, of 13 as a colorless liquid: 10 NMR (250 MHz):6=7.42 (t, J=2.8 Hz, 1H), 7.27 (s, 1H), 6.30 (s, 1H), 2.89 (t, J=6 Hz, 1H), 2.70 (dq, J=6, 12 Hz, 2H), 1.42 (s, 3H), 1.40 (s, 3H); 13C NMR (CDC13):6= 144.4, 140.7, 122.0, 112.35, 69.49, 59.77, 26.24, 26.06; IR (neat) 2965, 2925, 1500, 1445, 1375, .1155, 1125, 1020, 870, 780, 760 cm’l; EI/MS (70 eV) 152 (M+, 4.5), 137 (base), 123 (6.8), 108 (29). 2-MethyH-(3-furyl)-l,2epoxybutane (14a). 37 (1.3 g, 10 mmol) was treated with m-chloroperoxybenzoic acid (MCPBA) (2.02 g, 10 mmol, 85%) according to the general procedure for epoxidation of 3-furyl olefins to provide 0.38 g, 25%, of 14a as a clear colorless liquid: 1H NMR (250 MHz)i6=-7.21 (t, J=2 Hz, 1H), 7.09 (m, 1H), 6.23 (br s, 1H), 2.53 (m, 4H), 1.83 (m, 2H), 1.38 (s, 3H); IR (neat) 2930, 2860, 1500, 1450, 1430, 1390, 1175, 1030, 890 cm’l; EI/MS (70 eV) 156 (M+, 54.6), 139 (84.3), 121 (43.13), 112 (63.10), 96 (48.7), 81 (67.0), 55 (base). 43 2-Methyl-5-(3-furyD-2,3epoxybutane (15). 3811 (1.50 g, 10 mmol) was treated with MCPBA (2.02 g, 10 mmol, 85%) according to the general procedure for epoxidation of 3-furyl olefins to provide 1.40 g, 85%, of 15 as a clear colorless liquid: 1H NMR (250 MHz)35‘7.39 (t, J=2 Hz, 1H), 7.22 (s, IH), 6.29 (s, 1H), 2.78 (t, J=6 Hz, 1H), 2.56 (M, 2H), 1.78 (dd, J=6, 6 Hz, 2H), 1.32 (s, 3H), 1.21 (s, 3H); 130 NMR (CDC13)'.6=155.8, 141.4, 114.16, 110.00, 76.59, 37.81, 28.64, 24.10, 21.20, 18.99; IR (neat) 2980, 2940, 2880, 1500, 1,440, 1380, 1160, 1115, 1025, 925, 875, 790 cm'l; EI/lVlS (70 eV) 166 (M+, 7.1), 151 (12), 133 (10), 123 (13.4), 108 (42.8), 95 (39.4), 85 (75.0), 81 (83.4), 72 (38.5), 59 (base). Anal. Calcd for C10H1502: C, 72.29; H, 8.43. Found: C, 72.25; H, 8.51. 2—lethyI-6-(3-ftlryD-2-3epoxybutane (17). 40 (1.64 g, 10 mmol) was reacted with MCPBA (2.02g, 10 mmol, 85%) according to the general procedure for the epoxidation of 3—furyl olefins to epoxides to provide 1.45 g, 81%, of 17 as a clear colorless liquid: 1H NMR (250 MHz)'-6=7.28 (t, J=2 Hz, 1H), 7.18 (t, J=2 Hz, 1H), 6.21 (br S, 18), 2.67 (t, J=6 Hz, 111), 2.45 (M, 211), 1.58 (m, 4H), 1.22 (s, 3H), 1.13 (s, 3H); 130 NMR (CDC13)26:157.6, 140.2, 114.4, 109.6, 75.81, 38.62, 29.43, 23.21, 24.1, 20.65, 19.34; IR (neat) 2980, 2950, 2880, 1500, 1440, 1390, 1150, 1115, 1020, 915, 875, 790, 720 cm‘l; El/MS (70 eV) 180 (M+, 1.7), 151 (7.4), 135 (5.6), 121 (14), 107 (11.3), 98 (2), 94 (base). Anal. Calcd for 011H1602: C, 73.33; H, 8.89. Found: C, 73.40; H, 8.95. ((Tri-n-butylstannyDIIethnyuran (47). To a solution of diisopropylamine (4.44 g, 44 mmol) in anhydrous THF (50 mL) cooled to 0°C in an ice-water bath was added n-butyllithium (1.7 M, 25.8 mL, 44 mmol) over a period of 10 min, and the mixture was allowed to stir for an additional 10 min. after the addition was complete. To the resulting solution was added tri-n-butyltin hydride (11.6 g, 40 mmol) over a period of 10 min and the mixture allowed to stir for an additional 15 min. and then cooled to -25°C in a dry ice-carbon 44 tetrachloride bath. To the resulting yellow solution was added (3-furyl)- chloromethane (4.55 g, 40 mmol) over a period of 10 min. The cooling bath was removed and the reaction allowed to stir and warm to room temperature over 1 h. The mixture was then cast into ether (300 mL) and saturated aqueous NH4C1 (200 mL). The organic phase was separated, washed with water (200 mL) and brine (200 mL), dried (Na2504), and concentrated it} w to yield a yellow liquid. Distillation provided 13.15 g, 89% of 47 as a colorless liquid: bp (0.05 mm) 125°C (111.27 bp 116-119 °c (0.55 mm)); 19 NMR (60 MHz)6 7.23 (t, J=2 Hz, 111), 7.18 (m, 1H), 6.21 (8, 1H), 2.0-0.7 (M, 29H); EI/MS (70 eV) 372 (1.3), 355 (6), 315 (10), 291 (28), 235 (32), 201 (19), 179 (base). 3-nethyl-but-3-en-1-ol p—toleunesulfonate. To a solution of 3-methyl- but-3-en—1-ol (2.6 g, 30 mmol) in pyridine (20 mL), cooled to 0°C in an ice- water bath, was added freshly crushed p-toluenesulfonyl chloride (7.63 g, 40 mmol) in one portion. The mixture was stirred at 0°C for 1 hour and then placed in a freezer (-20°C) overnight. The resulting suspension was cast into a mixture of ice-water and concentrated hydrochloric acid (50 g - 50 mL) and extracted with ether (150 mL). The organic phase was separated and washed with 1N aqueous hydrochloric acid (100 mL), saturated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (Na2804), and concentrated i_n va_cu_o to yield 6.0 g, 83%, of a viscous yellow liquid which was used without further purification. 3-methy1-3-epoxy-buten—1-ol p-toluenesulfonate (44b). To a solution of 3-methyl—but-3-en—1-ol p-toluenesulfonate (7.62 g, 30 mmol) in methylene chloride (50 mL), cooled to 0°C in an ice-water bath, was added a solution of m-chloroperbezoic acid (8.08 g, 30 mmol, 85%) in methylene chloride (50 mL) over a period of 30 minutes. The mixture was allowed to stir for 3 hours at 45 0°C and the resulting suspension was then suction filtered and the filtrate was taken up in ether (150 mL) and washed with 10% aqueous sodium bisulfite (2 x 100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried (N82S04), and concentrated _ifl 39302 to yield a viscous liquid. The crude product was purified by chromatography on a column of silica gel (60-230 mesh, 50 g, 40 mm o.d:, ether-pet. ether 1:1, 30 mL fractions) using the flash technique. Fractions 8-13 provided 5.52 g, 68%, of 44b as a colorless liquid. EI/MS (70 eV): 256 (M+, 2.1), 155 (11), 101 (11.6), 91 (38.5), 84 (24.4), 68 (23.7), 43 (base). 1H NMR (60 lvlllzlcbs7.76 (d, J=8Hz, 2H), 7.31 (d, J=8Hz, 2H) 4.14 (t, J=6.5Hz, 2H), 2.61 (s, 1H), 1.96 (t, J=6.5Hz, 2H), 1.31 (s, 3H). 4-iodo-2-methyI-1-epoxy-butene (446). To a solution of 3-methyI-3-epoxy- buten-l-ol p-toluenesulfonate, 44b, (2.02 g, 7.89 mmol) in acetone (25 mL, dried over CaClz) was added sodium iodide (1.50 g, 10 mmol) in one portion and the solution heated under reflux for 4 hours. The resulting suspension was cooled to room temperature and suction filtered. The filtrate was diluted with ether (150 mL) and washed with water (100 mL), 10% aqueous sodium bisulfite (100 mL), water (100 mL), brine (100 mL), dried (NaZSO4) and concentrated it; w to yield a colorless liquid. Distillation of the crude product provided 1.47 g, 88%, of 44a as a clear, colorless liquid. B.P. (25mm)=58°C. El/MS (70 eV) 212 (M*, 4.3), 194 (1.13), 110 (14.2), 85 (25.4), 55 (66.1), 43 (base). 1H NMR (60 MHZ)36:3.11 (t, J=8Hz, 2H), 2.60 (AB,J=4Hz, 2H), 2.12 (m, 28), 1.28 (S, 3H). IR(neat): 3000, 2920, 1430, 1375, 1215, 1150, 10650, 895, 790, 720 em-l. 4-methyl—pent-4-en-1—ol p-toluenesulfonate. To a solution of 4-methyl— pent-4--en-1--ol58 (3.0 g, 30 mmol) in pyridine (161 mL) cooled to 0°C in an ice-water bath was added freshly crushed p-toluenesulfonyl chloride (7.63 g, 46 40 mmol) in one portion. The mixture was allowed to stir at 0°C for 1 hour and then placed in the freezer (-20°C) overnight. The mixture was cast into ice-concentrated hydrochloric acid (50 g - 50 mL) and extracted with ether (150 mL). The organic phase was washed with 1N aqueous hydrochloric acid (100 mL), brine (100 mL), dried (N82504), and concentrated i_n mug to yield 7.62 g, 100% of a viscous yellow liquid. This product was used without further purification. Hethyl—4-epoxy-penten-1-ol p-toluenesulfonate (45b). To a solution of 4-methyl-pent—4-en-1-ol p—toluenesulfonate (7.62 g, 30 mmol) in methylene chloride (40 mL) cooled to 0°C in an ice-water bath was added a solution of m-chloroperbenzoic acid (6.08 g, 30 mmol, 85%) in methylene chloride (50 mL) and the resulting suspension was stirred at 0°C for 1 hour and then overnight at room temperature. The mixture was suction filtered and the filtrate was diluted with ether (200 mL) and washed with 10% aqueous sodium bisulfite (150 mL), saturated aqueous sodium bicarbonate (150 mL), water (150 mL), brine (150 mL), dried (NaZSO4) and concentrated in La_cu_o to yield a cloudy colorless liquid. The crude product was purified by chromatography on a column of silica gel (60-230, 50 g, 40 mm o.d., ether-pet. ether 1:1, 25 mL fractions) using the flash technique. Fractions 10—14 yielded 5.52 g, 68% of 45b as a colorless liquid. 1H NMR (60 MHz)i6=7.73 (d, J=7.5Hz, 2H), 7.30 (d, J=7.5Hz, 2H), 4.03 (t, J=6Hz, 2H), 2.44 (s, 3H), 1.63 (m, 4H), 1.23 (s, 3H). 5-iodo-4Pmethyl-1-epoxy-pentene 45a. To a solution of 4-methyl—4-epoxy— penten-l-ol p-toluenesulfonate, 45b, (5.6 g, 20 mmol) in acetone (50 mL, dried over CaC12) was added sodium iodide (3.3 g, 22 mmol) in one portion and the solution was heated under reflux for 6 hours. The resulting suspension was cooled to room temperature and suction filtered. The filtrate was cast into water (200 mL) and ether (200 mL). The organic phase was separated and 47 washed with 10% aqueous sodium bisulfite (100 mL), saturated aqueous sodium bicarbonate (100 mL), water (100 mL), brine (100 mL), dried (Na2804), and concentrated y! w to yield a water white liquid. Distillation of the crude product provided 3.79 g, 84.5%, of 45a as a colorless liquid. B.P. (20mm)=62°C. 1H NMR (60MHz):6=3.20 (m, 2H), 2.58 (s, 2H), 2.10-1.53 (m, 4H), 1.29 (s, 3H). EI/MS (70 eV) 227 (M+, 1.22), 226 (M+, 8), 199 (26), 141 (14), 100 (82), 43 (base). IR (neat): 3000, 2930, 1460, 1800, 1385, 1225, 1180, 915, 840, 750 cm‘l. 2-MethyP5-(3-furyD-1,2epoxybutane (16). To a solution of 47 (1.85 g, 5 mmol) in THF (5 mL) cooled to -78°C in a dry ice-2-propanol bath was added n-butyllithium (3.3 mL, 5 mmol, 1.51 M in hexane) over a period of 5 min. The solution was stirred at -78°C for an additional 10 min. and then HMPA (0.90 g, 5 mmol) was added in one portion. The resulting red solution was transferred via cannula into a solution of 44a (1.06 g, 5 mmol) in THF (10 mL) which was cooled to -25°C in a dry ice-carbon tetrachloride bath. The cooling bath was removed and the mixture stirred at room temperature overnight. The solution was cast into saturated aqueous NH4C1 (100 mL) and ether (100 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried (Nast4), and concentrated _ig M9 to yield a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 75 g, 40 mm od, ether-petroleum ether 1:4, 25-mL fractions) by using the flash technique. Fractions 12-17 provided 0.60 g, 73%, of 16 as a clear colorless liquid: 1H NMR (250 .Vle)'-6:7.32 (t, J=2 Hz, 1H), 7.20 (m, 1H), 6.22 (m, 1H), 3.18 (m, 2H), 2.76-2.50 (m, 2H), 1.77- 1.51 (m, 2H), 1.32 (s, 3H); IR (neat) 2925, 2860, 1500, 1450, 1390, 1160, 1070, 1025, 975, 905, 890 cm-1; EI/MS (70 eV) 166 (01+, 2.3), 149 (8.1), 141 (19), 135 (8.6), 129 (7.8), 121 (12.0), 109 (17.6), 94 (base). Anal. Calcd for CHM-11602: C, 72.29; H, 8.43. Found: C, 72.25; H, 8.51. 48 2-flethyl-6-(3-furyD-1,2epoxybutane (18). To a solution. of 47 (1.85 g, 5 mmol) in THF (5 mL) cooled to -78°C in a dry ice-2-propanol bath was added n-butyllithium (3.3 mL, 5 mmol, 1.51 M in hexane) over a period of 5 min. The solution was stirred at -78°C for an additional 10 min. and then HMPA (0.896 g, 5 mmol) was added in one portion, and the mixture was stirred at -78°C for an additional 10 min. The resulting solution was transferred via cannula into a solution of 45a (1.12 g, 5 mmol) in THF (10 mL) cooled to -25°C in a dry ice-carbon tetrachloride bath. The cooling bath was removed and the mixture stirred at room temperature overnight. The solution was cast into saturated aqueous NH4C1 (100 mL) and ether (150 mL). The organic phase was separated, washed with water (100 mL) and brine (100 mL), dried (NaZSO4), and concentrated jg m to yield a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 75 g, 40 mm od, ether-petroleum ether 1:4, 25-mL fractions) by using the flash technique. Fractions 8-13 afforded 0.612 g (68%) of 18 as a colorless liquid: 1H NMR (250 MHz)6 7.36 (t, J=2 Hz, 1H), 7.21 (t, J=2 Hz 1H), 6.24 (br s, 1H), 3.90 (t, J=9 Hz, 1H), 3.38 (m 1H), 2.58 (m, 28), 2.42 (t, J=9 Hz, 2H), 1.66-1.38 (m, 4H), 1.31 (s, 311); IR (neat) 3010, 2990, 2925, 1540, 1500, 1445, 1380, 1150, 1110, 1070, 900, 805, 780 cm‘l; El/MS (70 eV) 180 (M+, 12), 163 (11), 149 (14.4), 135 (28), 121 (18.7), 108 (60, 82 (base). Anal. Calcd for C11H1302; C, 73.33; H, 8.89. Found: C, 73.21; H, 8.96. 1,2-Di-0-isopropylidene-4-(3—fury0butene-1,2-diol (49). To an activated magnesium metal turnings (0.73g, 30 mmol) covered by THF (40 mL) was added (3-furyl)chloromethane (3.5g, 30 mmol) and the mixture stirred at room temperature until the magnesium was consumed (about 2 h). The resulting golden solution was cooled to 0°C in an ice-water bath and 4859 (6.05 g, 25 mmol) was added in one portion followed immediately by Li2CuCl4 (0.2 mL, 49 0.1 M in THF). The mixture was stirred at room temperature for 6 h and then was cast into saturated aqueous NH4C1 (150 mL) and ether (150 mL). The organic phase was separated, washed with 10% aqueous sodium bisulfite (100 mL), water (100 mL), and brine (100 mL), dried (NaZSO4), and concentrated _ifl w to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 110 g, 50 mm od, ether-petroleium ether 5:95, 40-mL fractions) by using the flash technique. Fractions 18-29 provided 3.57 g, 73%, of 49 as a clear colorless liquid: 1H NMR (60 MHz)6 7.28 (t, J=2 Hz, 1H), 7.19 (m, 1H), 6.22 (br s, 1H), 4.06 (t, J=6.5 Hz, 1H), 3.98 (t, J=6.5 Hz, 1H), 3.40 (m, 1H), 2.52 (m, 2H), 1.87 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H); IR (neat) 2990, 2950, 2880, 1500, 1365, 1240, 1165, 1080, 1025, 890, 700 cm‘l; EI/MS (70 eV) 196 (M+, 4.43), 181 (4.33), 138 (5.28), 121 (25.48), 94 (21.56), 82 (53.72), 81 (45.28), 72 (19.0), 53 (18.46) 43 (base). H3-FuryD-butane-1,2-diol (50). A solution of 49 (1.00 g, 5.10 mmol) in THF-1 N HCl (1:1, 5 mL) was stirred at room temperature for 12 h. The mixture was neutralized by the addition of solid NaHCO3 (0.5 g) and saturated with NaCl. The mixture was extracted with ether (3 X 50 mL), and the combined organic layers were washed with brine (100 mL), dried (Na2804), and concentrated in mug to provide 0.51 g, 64%, of a yellow liquid which was used without further purification: 1H NMR (60 MHz)6 7.21 (t, J=2 Hz, 1H), 7.12 (m, 1H), 6.12 (br s, 1H), 3.50 (m, 5H), 2.55 (t, J=8 Hz, 2H), 1.83 (br t, J=8 Hz, 211); IR (neat) 3400 br, 2930, 1500, 1450, 1155, 1060 Dr, 915, 880 790 cm'l; EI/MS (70 eV) 156 (M+, 9.37), 107 (5.50), 95 (11.22), 82 (70.1), 81 (base). H3-FuryD-butane-1,2-diol 1-p—toluenesulfonate (51). To a solution of 50 (0.51 g, 3.2 mmol) in pyridine (5 mL) cooled to 0°C an ice-water bath was added p-toluenesulfonyl chloride (0.61 g, 3.2 mmol) and the resulting mixture 50 was stirred at 0°C for 6 h. The mixture was then cast into ice-1 N aqueous HCl (30 g, 30 mL) and the solution extracted with ether (100 mL). The organic layer was washed with 1 N HCl (100 mL), water (100 mL), and brine (100 mL), dried (NaZSO4), and concentrated i_n (m to provide 0.84 g, 84% of a viscous orange liquid which was used without further purification: 1H NMR (60 MHz)6 7.68 (m, 4H), 7.21 (m, 2H), 6.18 (br s, 1H), 3.93 (br s, 1H), 3.74 (m, 3H), 2.68 (m, 2H), 2.35 (s, 3H), 1.85 (m, 2H); IR (neat) 3500 br, 2980, 2875, 1595, 1500, 1440, 1370, 1185, 1100, 990, 875, 820 cm'l; ELI/MS (70 eV) 310 (M+, 4.91), 155 (12.78), 138 (33.87), 120 (21.06), 107 (10.71), 94 (50.85), 81 (base). 4-(3-FuryD-l,2-epoxybutane (14b). To a suspension of NaH (0.13 g, 2.7 mmol, 50% in oil washed with 5 X 1 mL of dry hexane) in THF (5 mL) was added a solution of 51, (0.84 g, 2.7 mmol) in THF (5 mL) over a period of 5 min. The resulting mixture was heated under reflux for 2 h. The mixture was allowed to cool to room temperature and was cast into water (50 mL) and ether (50 mL). The organic phase was separated, washed with brine (100 mL), dried (NaZSO4), and concentrated 111 m to yield a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 30 g, 20 mm od, ether-petroleum ether 1:4, 20—mL fractions) by using the flash technique. Fractions 11-15 provided 0.350 g, 94%, of 14b as a clear colorless liquid: 1H NMR (250 MHz)6 7.39 (t, J=1.8 Hz, 1):), 7.22 (m, 1H), 6.23 (br s, 111), 2.98 (M, 1H), 2.78 (t, J=4.8 Hz, 1H), 2.57 (m, 1H), 2.48 (dd, J=4.8 Hz, 1H), 1.77 (m, 2H); IR (neat) 2990, 2910, 2860, 2150, 1500, 1450, 1160, 1065, 1025, 910, 870, 780, 720 cm‘l; EI/MS (70 eV) 138 (ll/1+, 18.87). 107 (35.28), 94 (21.23), 81 (base). Anal. Calcd for C3H1002: C, 69.56; H, 7.24. Found: C, 69.49; H, 7.33. General Procedure for Cyclization with BF3-OEt2 Preparation of 7 ,7- Di-ethyI-6-hydroxy-4,5,6,7-tetrahydrobenzofuran (24). To a solution of 15 51 (0.1 g, 0.60 mmol) in CH2C12 (10 mL) cooled to -25°C in a dry ice-carbon tetrachloride bath was added freshly distilled boron trifluoride etherate (0.28 g, 0.20 mmol). After the mixture had stirred for 5 min at -25°C it was quenched with saturated aqueous NH4Cl (10 mL). The mixture was cast into ether (50 mL) and the organic phase was separated, washed with water (50 mL) and brine (50 mL), dried (Na2804), and concentrated _i_r_) w to yield a dark red liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether-petroleum ether 1:1, 10 mL fractions) by using the flash technique. Fractions 14-17 provided 47 mg, 47%, of 24 as a viscous colorless liquid which affords a white solid on cooling: 1H NMR (250 MHz):6= 7.26 (d, J=1.8 Hz, 1H), 6.14 (d, J=1.8 Hz, 1H), 3.83 (br s, 1H), 3.40 (td, J=8, 6 Hz, 2H), 1.92 (m, 211), 1.38 (8, 3H), 1.22 (s, 3H); 130 NMR (CDCI3)=6=155.8, 141.4, 114.4, 109.9, 76.3, 37.7, 28.0, 25.5, 21.1, 18.9; IR (neat) 3435 (br), 2900, 1620, 1500, 1470, 1385, 1360, 1280, 1150, 1120, 1085, 1045, 890, 780 cm'l; Ell/MS (70 eV) 166 (M+, 40.4), 151 (9.4), 133 (4.80), 122 (base). Anal. Calcd for C10H1602: C, 72.29; H, 8.43. Found: C, 72.18; H, 8.54 ' General Procedure for Cyclization with EtAlClg. Preparation of 22 and 2-Methyl-6-(3-IuryD-3-hydroxyhex-l-ene (25). To a solution of 15 (0 .1 g, 0.60 mmol) in CH2C12 (10 mL) cooled to -78°C in a dry ice-2-propanol bath was added EtAlClz (0.82 mL, 1.2 mmol, 1.47 M in hexane). The mixture was then warmed slowly to -25°C for 30 min and then quenched by the addition of saturated aqueous NH4C1 (10 mL). The mixture warmed to room temperature and cast into ether (50 mL). The organic phase was separated, washed with 1N aqueous HCl (50 mL), water (50 mL), and brine (50 mL), dried (Na2S04), and concentrated g; m to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 52 mm od, ether-petroleum ether 1:1, 10-mL fractions) by using the flash technique. Fractions 9-12 provided 0.057 g, 57%, of 25 as a clear colorless liquid: 1H NMR (250 MHz)i6-‘-7.23 (t, J=2 Hz, 1H), 7.16 (M, 111), 6.19 (br s, 1H), 4.88 (br s, 1H), 4.76 (br s, 1H), 4.0 (br s, 1H), 3.38 (M, 1H), 2.36 (M, 2H), 1.98 (m, 2H), 1.98 (m, 2H), 1.78 (s, 3H); IR (neat) 3450 (br), 2990, 2900, 1500, 1470, 1385, 1290, 1160, 1085, 890, 780 cm‘l; EI/MS (70 eV) 166 (M+, 9.7), 135 (base), 82 (47). Fractions 15-18 gave 0.022 g, 22%, of 22. General Procedure for Cyclization with EtgAlCl. Preparation of 24 and 25. To a solution of 15 (0.10 g, 0.60 mmol) in CH2C12 (10 mL) cooled to 0°C in an ice-water bath was added EtzAlCl (0.82 mL, 1.2 mmol, 1.48 M in hexane) and the mixture immediately turned yellow. The solution was stirred at 0°C for 1 h and then was cast into saturated aqueous NH4C1 (60 mL) and ether (50 mL). The organic phase was separated, washed with 1 N aqueous HCl (50 mL), water (50 mL), and brine (50 mL), dried (Na2S04), and concentrated i_n 399.49. to yield a yellow liquid. Flash chromatography of the crude product provided 0.049 g, 49%, of 25 and 0.022 g, 22%, of 24. General Procedure for Cyclization with Alumina. Preparation of 24 and 25. To a solution of 15 (0.1 g, 0.60 mmol) in dry hexane (15 mL) was added basic alumina (2.0 g, activity I) and the suspension was stirred at room temperature for 24 h. Methanol (10 mL) was added, the mixture was filtered, and the alumina rinsed with methanol (25 mL). The solvent was removed jg gaggle to yield a colorless liquid. Flash chromatography of the crude product provided 0.032 g, 32%, of 24 and 0.051 g, 51%, of 23. General Procedure for Cyclization with Ti(O-i-Pr)3Cl. Preparation of 22. To a solution of 15 (0.10 g, 0.60 mmol) in CH2C12 (10 mL) was added Ti(0- i-Pr)3Cl35:5° (2.40 mL, 1.8 mmol, 0.75 M in CH2C12). The solution was allowed to stir at room temperature for 2 h. The reaction was quenched by 53 the addition of saturated aqueous NH4C1 (10 mL) and the resulting two phase mixture was cast into saturated aqueous NH4C1 (50 mL) and ether (50 mL). The organic phase was separated, washed with 1 N aqueous HCl (50 mL), water (50 mL), and brine (50 mL), dried (NaZSO4), and concentrated i_n m to yield a light yellow liquid. Flash chromatography of the crude product provided 0.078 g, 78%, of 24. General Procedure for Cyclization with ang. Preparation of 24. To a solution of 15 (0.1 g, 0.50 mmol) in 062012 (10 mL) was added anhydrous sodium acetate (50 mg, 0.60 mmol) followed immediately by Z.n12-OEt2"51 (0.70 g, 1.8 mmol). The resulting mixture was stirred in the dark for 3 h. The mixture was then cast into saturated aqueous NH4CI (50 mL) and ether (50 mL). The organic phase was separated, washed with 10% aqueous sodium bisulfite (50 mL), water (50 mL), and brine (50 mL), dried (50 mL), and concentrated i_n w to provide a yellow liquid. Flash chromatography of the crude product provided 0.071 g, 71%, of 24. Attempted Cyclization of Epoxy Furan 13 with BF3-0Et2. A solution of 13 (0.10 g, 0.66 mmol) in CH2C12 (10 mL) was reacted with BF3-OEt2 (0.031 g, 0.22 mmol) according to the general procedure for cyclization with BF3.OEt2. The crude product was purified by chromatogrophy on a column of silica gel (230—400 mesh, 40 g, 30 mm od, ether-petroleum ether, 1:1, 10-mL fractions) by using the flash technique. Fractions 10-14 provided 0.062 g, 62%, of 20 as a clear colorless liquid: 1H NMR (250 MHz)6 7.34 (t, J=2 Hz, 18), 7.24 (m, 1H), 6.28 (br s, 1H), 4.90 (br s, 1H), 4.79 (br s, 1H), 3.60 (m, 1H), 2.48 (d, J=7.2 Hz, 2H), 1.53 (s, 311); IR (neat) 3500 (br), 3000, 2980, 1500, 1495, 1170, 1080, 1025, 915, 870, 780 cm'li El/MS (70 eV) 152 (M+, 3.7), 137 (23.4), 117 (8.3), 81 (base). 54 Attempted Cyclization of Epoxy Furan 13 with EtzAlCl. A solution of 13 (0.1 g, 0.66 mmol) in CHZCIZ (10 mL) was treated with Et2AlCl (0.90 mL, 1.32 mmol, 1.47 M in hexane) according to the general procedure for cyclization with Et2AlCl to provide 0.085 g, 85%, of 20. Attempted Cyclization of Epoxy Furan 13 with Alumina. A solution of 13 (0.1 g, 0.66 mmol) in dry hexane (10 mL) was treated with 2.0 g of alumina according to the general procedure for cyclization with alumina to provide 0.083 g, 83%, of 20. Attempted Cyclization of Epoxy Furan 148 with BPyOEtz. A solution of 14a (0.10 g, 0.66 mmol) in CH2C12 (10 mL) was treated with BF3~OEt2 (0.031 g, 0.22 mmol) according to the general procedure for cyclization with BF3-OEt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether-petroleum ether 1:1, 10- mL fractions) by using the flash technique. Fractions 9-12 provided 0.053 g, 53%, of 22 as a mixture of isomers: 1H NMR (60 MHz)6 7.26 (t, J=2 Hz, 10), 7.18 (m, 1H), 6.21 (br s, 1H), 5.48 (m, 0.5 H), 4.94 (s, 0.5 H), 4.83 (s, 0.5 H), 4.0 (br s, 1H), 3.49 (br s, 1H), 3.12 (d, J=6 Hz, 2H), 2.40 (m, 4H), 1.86 (s, 1.5 H); IR (neat 3450 (br), 2990, 2980, 2780, 1500, 1380, 1165, 1070, 1030, 925, 880, 790 cm’l; El/MS (70 eV) 152 (M+, 5.3), 137 (17.6), 121 (41.3), 106 (10.9), 82 (base). Attempted Cyclization of Epoxy Furan 14b with BF3-0Et2. A solution of 14b (0.10 g, 0.73 mmol) in CH2C12 (10 mL) was treated with BF3-OEt2 (0.034 g, 0.24 mmol) according to the general procedure for cyclization with BE3-OFt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether-petroleum ether 1:1, 10- mL fractions) by using the flash technique. Fractions 10-12 provided 0.49 g, 49%, of 23 as a mixture of isomers: 1H NMR (250 MHz) 7.35 (t, J=2 Hz, 55 1H), 7.22 (m, 1H), 6.22 (br s, 1H), 4.58 (m, 2H), 3.30 (m, 2H), 2.54 (m, 2H); IR (neat) 3450 (br), 2995, 2890, 1500, 1410, 1150, 1090, 1015, 890, 780 cm'l; EI/MS (70 eV) 138 (M+, 28.8), 121 (14.4), 95 (21.7), 81 (base). Cyclization of Epoxy Furan 14b with ZnIrOEtz. Preparation of 23 and HflymoxylethyMMydrHE-cyclopentalblfuran (21b). A solution of 14b (0.10 g, 0.73 mmol) in CH2C12 (10 mL) was reacted with anz-OEtg (0.86 g, 2.19 mmol) and sodium acetate (60 mg, 0.73 mmol) according to the general procedure for cyclization with ZnI2.OEt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether-petroleum ether, 1:1, 10 mL fractions) by using the flash technique. Fraction 8-11 provided 0.044 g, 44%, of 23 and fractions 13-14 provided 0.025 g, 25%, of 21b as a clear colorless liquid: 1H NMR (250 MHz)=6=7.22 (d, J=1.8 Hz, 1H), 6.41 (d, J=1.8 Hz, 1H), 3.19 (m, 2H), 2.78 (m, 5H); IR (neat) 3480 (br), 2900, 1500, 1425, 1120, 1080, 1050, 1010, 890, 780 cm‘l; El/MS (70 eV) 138 (04”, 23.4), 121 (8.3), 109 (8.51), 94 (base), Anal. Calcd for C3H1002: C, 69.56; H, 7.24. Found: C, 69.54; H, 7.27. Cyclization of Epoxy Furan 16 with BF3-0Et3. Preparation of 7-Methyl- 7-(hydroxymethyD-4,5,6,7-tetrahydrobenzofuran 26 and Alcohols 27. A solution of 16 (0.10 g, 0.60 mmol) in CH2C12 (10 mL) was reacted with BF3-0Et2 (0.28 g, 0.20 mmol) according to the general procedure for cyclization with BF3°OEt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether petroleum-ether, 1:1, 10 mL fractions) by using the flash technique. Fractions 10-12 provided 0.01 g, 10%, of 27 as a mixture of isomers: 1H NMR (250 MHz)=6=7.26 (t, J=2.0Hz, 1H), 7.16 (m, 1H), 6.19 (br s, 1H), 5.52 (t, J=8 Hz, 0.5H), 4.90 (br s, 0.5 H), 4.82 (br s, 0.5 H), 3.56 (br s, 1H), 2.36 (m, 5H), 1.78 (s, 1.5 H): EI/MS (70 eV) 166 (Mt, 12.3), 151 (8.3), 135 (43.1), 120 (10.3), 94 (14.9), 82 (base). Fractions 13-17 provided 56 0.03 g, 30%, of 26 as a pale yellow liquid: IH NMR (250 MHz)6 7.21 (d, J=1.8 Hz, 1H), 6.15 (d, J=1.8 Hz, 1H), 3.52 (s, 2H), 2.38 (m, 2H), 1.96 (m, 28), 1.24 (s, 3H); IR (neat) 3440 (br), 2940, 1500, 1380, 1205, 1160, 1040, 890, 740 cm-1; EI/MS (70 eV) 166 (W, 8.8), 149 (4.4), 135 (base). Anal. calcd for C10H502: C, 72.29; H, 8.43. Found: C, 71.96; H, 8.51. Attempted Cyclization of Epoxy Furan 17 with BF3-OEt2. Preparation of 2-Methyl-6-(3-furyD-3-hydroxyhex-l-end29). A solution of 17 (0.10 g, 0.55 mmol) in CHzClg (10 mL) was reacted with BF3-0Et2 (0.25 g, 0.18 mmol) according to the general procedure for cyclization with BF3-OEt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 70 g, 40 mm od, ether-petroleum ether, 1:1, 25-mL fractions) by using flash technique. Fractions 11-13 provided 0.041 g, 41% of 29: 1H NMR (60 MHz)6 7.39 (t, J=2 Hz, 1H), 7.21 (m, 1H), 6.24 (br s, 1H), 4.85 (s, 1H), 4.80 (s, 1H), 4.10 (m, 1H), 3.62 (br s, 1H), 2.60 (M, 2H), 2.44 (m, 4H), 1.61 (s, 3H); IR (neat) 3450 (br), 2990, 1500, 1450, 1390, 1290, 1150, 1090, 890, 780 cm‘l; EI/MS (70 eV) 180 (M+, 10.6), 162 (8.3), 139 (28.3), 94 (43.2), 82 (base). Cyclization of Epoxy Furan 17 with EtzAlCl. Preparation of 8,8- Dimethyl-7-hydroxy-4,5,6,7-tetrahydro-6E—cyclohepta[b1furan 28 and 29. A solution of 17 (0.10 g, 0.55 mmol) in CH2012 (10 mL) was treated with EtZAICl (0.75 mL, 1.10 mmol, 1.47 M in hexane) according to the general procedure for cyclization with EtzAlCl. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 45 g, 30 mm od, ether-petroleum ether, 1:1, 10-mL fractions) by using the flash technique. Fractions 9-12 provided 0.069 g, 69%, of 29 and fractions 15-17 provided 0.01 g, 10%, of 28 as a pale yellow liquid: 1H NMR (250 MHz)6 7.24 (d, J=1.8 Hz, 1H), 6.13 (d, J=1.8 Hz, 1H), 3.73 (t, J=4.2 Hz, 1H), 2.47 (m, 2H, 1.91 (m, 6H), 1.30 (8, 3H), 1.22 (8, 3H); IR (neat) 3430 (br), 2980, 1620, 1500, 1470, 1380, 57 1360, 1285, 1160, 1115, 1090, 1030, 890, 730 cm-1; El/MS (70 eV) 180 (10*, 5.28), 166 (32.2), 151 (12.6), 149 (17.9), 122 (base). Anal. Calcd for 011111602: C, 73.33; H, 8.80. Found: C, 73.32; H, 8.83. Cyclization of Epoxy Furan 18 with BF3-OEt2. Preparation of 8-Methyl- 8-(hydroxylethyD-4,5,7 ,8-tetrahydro-GE-cycloheptaibluran 30 and Alcohol 31 . A solution of 18 (0.10 g, 0.55 mmol) in CHZCIZ (10 mL) was reacted with BF3°OEt2 (0.25 g, 0.18 mmol) according to the general procedure for cyclization with BF3-OEt2. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 40 g, 30 mm od, ether petroleum-ether, 1:1, 10 mL fractions) by using the flash technique. Fractions 9-12 provided 0.012 g, 12%, of 31 as a mixture of isomers: 1H NMR (250 MHz)6 7.28 (t, J=2 Hz, 1H), 7.16 (br s, 1H), 6.18 (br s, 1H), 4.96 (S, 0.5 H), 4.80 (S, 0.5 H), 4.10 (m, 0.5 H). 3.10 (br s, 1H), 3.28 (m, 2H), 2.86 (m, 2H), 2.23 (m, 5H), 1.83 (s, 1.5 H); IR (neat) 3450 (br), 2900, 1500, 1460, 1320, 1290, 1160, 1075, 780 cm'l; EI/MS (70 eV) 180 (M+, 9.2), 165 (10.5), 149 (23.6), 139 (10.3), 94 (32.6) 82 (base). Fractions 14-16 provided 0.010 g, 10%, of 30 as a clear liquid: 1H NMR (250 MHz)6 7.17 (d, J=1.8 Hz, 1H), 6.12 (d, J=1.8 Hz, 1H), 3.79 (d, J=11.1 Hz, 1H), 3.58 (d, J=11.1 Hz, 1H), 2.47 (m, 2H), 1.96-1.31 (br 0), 6H), 1.22 (s, 3H); 130 NMR (CDCI3)6 155.6, 141.1, 113.9, 109.8, 76.6, 37.7, 28.0, 25.7, 21.3, 19.0; IR (neat) 3470 (br), 2920, 1500, 1460, 1385, 1290, 1210, 1165, 1090, 890, 780 cm‘l; EI/MS (70 eV) 180 (M+, 10.0), 150 (11.7), 149 (base). Anal. Calcd for 01181602: 0, 73.33; H, 8.89. Found: C, 73.40; H, 8.99. Cyclization of Epoxydendrolasin (42) with Ti(O-i-Pr)3Cl. Preparation 3 B-Hydroxypallescensin A (53). A solution of epoxydendrolasin (42)10 (0.20 g, 0.85 mmol) in. CH2012 (10 mL) was treated with Ti(O-i-Pr)3Cl (3.4) mL, 2.55 mmol, 0.75 M in CH2C12) according to the general procedure for cyclization with Ti(o-i-p,)3Cl. The crude product was purified by chromatography on a 58 column of silica gel (230-400 mesh, 70 g, 50 mm od, ether-petroleum ether 1:3, 25-mL fractions) by using flash technique. Fractions 16-19 provided 0.124 g, 62%, of'53 as a white solid: mp 120-122 °C (lit.40 mp 122-122.5 °C); 1H NMR (250 MHz).6=7.13 (d, J=1.8 Hz, 1H), 6.02 (d, J=1.8 Hz, 1H), 3.31 (m, 3H), 3.43 (m, 4H), 2.22 (m, 1H), 1.5-2.1 (m, 4H), 1.18 (s, 3H), 1.07 (8, 3H), 0.89 (m, 3H); EI/MS (70 eV) 234 (MI; 46.4), 219 (82), 201 (base). Preparation of 2-(3-furyl)-1-bromoethane (63). A solution of 2-(3-furyl) ethanol“5b (3.35 g, 30 mmol) in pyridine (25 mL) was cooled to 0°C (ice- water) and p-toluenesulfonyl chloride (6.29 g, 33 mmol) was added all in one portion. The resulting yellow mixture was stirred at 0°C for four hours. The suspension was cast into ice-conc. HCl (50 g - 50 mL) and ether (250 mL). The organic phase was separated and washed with 1N aq. H01 (200 mL), water (200 mL), brine (200 mL), and dried (MgSO4). The solvent was removed _in w to provide a viscous yellow liquid which was immediately taken up in dry acetone (150 mL) and LiBr (3.5 g, 40 mmol) was added. The mixture was heated under reflux for 12 hours; after cooling to room temperature, the solvent was removed i_n w and the residue dissolved in water (200 mL) and ether (200 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (200 mL), brine (200 mL), dried (MgSO4) to provide 4.64 g, 88%, of a light red liquid which was used without further purification. 1H NMR (60 MHz):6= 7.24 (m, 2H); 6.21 (d, J=1.7 Hz, 1H); 3.42 (t, J=5.1 Hz, 2H); 2.93 (t, J=5.1 Hz, 2H). EI/MS (70 eV): 176 (22.9), 174 (25.1), 95 (49.7), 81 (base). IR (neat): 2995, 2980, 1505, 1435, 1385, 1280, 1170, 1075, 1030, 880, 790 cm'l. Preparation of 3-(3-furyD-1-bromopropane (64). To a solution of triphenyl-phoSphine (7.41 g, 30 mmol) in ether (50 mL) cooled to 0°C in an ice bath was added carbon tetrabromide (10.05 g, 30 mmol)62 all in one portion 59 and the resulting suspension stirred at 0°C for 30 minutes. A solution 3-(3- furyl)propan-1-ol45c (1.89 g, 15 mmol) in ether (10 mL) was added all in one portion and the mixture heated under reflux for 4 hours. The resulting suspension was cooled to room temperature and cast into hexane (150 mL) and was cooled (0°C) for 30 minutes. The mixture was filtered through celite and the solvent removed i_n w to provide a yellow liquid. The product was purified by chromatography on a column of silica gel (60-230 mesh, 50 g, 40 mm. od, pet. ether, 25 mL fractions) using the flash technique. Fractions 4- 9 provided 2.04 g, 72%, of the bromide 64 as a clear, colorless, sweet-smelling liquid. 1H NMR (60 MHz): 6:7.18 (t, J=1.7 Hz, 1H); 7.07 (m, 1H); 6.17 (m, 1H); 3.36 (t, J=6.2 Hz, 2H); 2.68 (t, J=6.6 Hz, 2H); 2.08 (m, 2H). EI/MS (70 eV): 190 (21.9), 188 (23.9), 109 (6.1). 95 (4.5), 82 (base). IR (neat): 2990, 2890, 1500, 1430, 1380, 1280, 1170, 1030, 880, 780 cm-1. Preparation of 2-methylene-7-oxabicycIo-[4J.01-heptane (65). To a solution of methyltriphenylphosphonium bromide (35.7 g, 0.1 mmol) in anhydrous THF (150 mL), cooled to -23°C (dry ice - CC14) was added diisopropylamine (10.1 g, 0.1 mol) followed immediately by the addition n-butyllithium over a period of 15 minutes. The resulting red solution was stirred at -22°C for 1 hour and then warmed to 0°C for 1 hour. A solution of 7-oxabicyclo [4.1.0] heptan-2-one63 (7.8 g, 0.07 mol) in THF (50 mL) was added to the red solution over a period of 5 minutes and the resulting suspension stirred at 0°C for 1 hour and then at room temperature for 2 hours. The suspension was cast into hexane (500 mL) and cooled to 0°C for 3 hours. The 4390 was removed by filtration through a pad of celite and the hexane was removed by distillation. The residue was distilled under reduced pressure to provide 5.4 g, 70%, of 65 as a clear, colorless oil. B.P.ggmm = 62-63°C. 1H NMR (250MHz): 6:5.23 (d, J=1.4 Hz, 1H); 5.10 (m, 1H); 3.42 (d, J=3.9 Hz, 1H); 3.38 (m, 1H); 2.26 (m, 60 1H); 2.02 (m, 2H); 1.83 (m, 1H); 1.57 (m, 1H); 1.42 (m, 1H). El/MS (70 eV): 110 (M+, 12.1), 95 (17), 81 (25.4), 67 (31), 55 (55), 40 (base). IR (neat): 3050, 2900, 3895, 1645, 1440, 1400, 940, 910, 835, 755 cm-1. MS: 04*“ calc. 110.073160, obs. 110.07323. 1-methyl-2-methylene—6-oxabicyclo-[3.1.0}-hexane (7 2). To a liquid ammonia (30 mL), cooled to -78°C (dry ice-isopropanol), was added sodium metal (0 .5 g, 22 mmol) and the mixture stirred until all the sodium had dissolved (about 30 minutes). Several crystals of ferric nitrate were added and the solution stirred until the color became a light grey. Methyltriphenyl- phosphonium bromide (8.08 g, 20 mmol) was added and the ammonia allowed to evaporate as the mixture was slowly warmed to room temperature. Anhydrous ether was added and the resulting orange suspension heated under reflux for 30 minutes. The ether was decanted into a clean dry 50 mL round bottom flask and a solution of 1-methyl-6-oxabicyclo [3.1.0J-hexan-2-on653 (1.6 g, 15 mmol) in ether (10 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The mixture was cast into pentane (50 mL), cooled to 0°C and filtered through a pad of celite. The filtrate was washed with saturated aqueous NH4CI (50 mL), brine (50 mL), dried (MgSO4) and the solvent removed by distillation. The residue was purified by chromatography on a column of silica gel (60-230 mesh, 40 g, 30 mm o.d., 10% ether-pet. ether 15 mL fractions) using the flash technique. Fractions 9-12 provided 0.52 g, 32% of 72 as a clear, colorless, sweet smelling liquid. 16 NMR (60 MHz): 6 =5.0 (br m, 2H); 3.32 (brs, 1H); 2.14 (m, 2H); 1.96 (m, 2H); 1.43 (s, 36). EI/MS (70 eV): 110 (00*, 12.7), 95 (134, 69 (17.7), 55 (33.8), 43 (base). l-methyl-2-methylene—7-oxabicycloI4.1.0]-heptane (111). According to the above procedure for the preparation of vinyl epoxides 1-methyl—7- 61 oxabicyclo[4.1.Olhepan-Z-one53 (9.0 g, 70 mmol) provided 4.6 g,. 53%, Of 111; BP25mm = 65-70°C. 16 NMR (60 MHz): 6: 5.19 (d, J=1.3 Hz, 1H); 5.07 (m, 1H); 3.11 (t, J=2.1 HZ, 1H); 1.92 (m, SH); 1.42 (S, 311). EI/MS (70 eV): 124 (M+, 1.5), 97 (13.7), 81 (30.6), 67 (19.7), 57 (22.1), 43 (base). IR (neat); 3070, 2980, 2790, 1650, 1440, 940, 910, 835, 760 cm-1- GENERAL PROCEDURE FOR THE PREPARATION OF ALLYLIC ALCOHOLS 3-(2-(furyD-ethyD-cyclohex-2-en-l-ol (66). To magnesium turnings (0.36 g, 15 mmol) covered by THF (15 mL) was added (3-furyD-chloromethane 103 (1.74 g, 15 mmol) and the mixture stirred at room temperature until all the magnesium had been consumed (about 2 hours). The resulting golden solution was cooled to ~78°C (dry ice - isopropanol) and copper (I) cyanide (1.34 g, 15 mmol) was added all in one portion. The mixture became a yellow-green suspension which was stirred at -78°C for 30 minutes. To this suspension was added a solution of vinyl epoxide 65 (1.20 g, 10 mmol) in THF (10 mL) over 5 minutes and the resulting yellow suspension was allowed to slowly warm to room temperature over 4 hours. The mixture was cast into saturated aqueous NH4CI (100 mL) and ether (150 mL). The organic phase was separated and washed with 1N HC1 (100 mL), saturated aqueous NaHCO3 (100 mL), dried MgSO4) and concentrated H} w to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 50 g, 40 mm o.d., 2:5 ether-pet. ether, 25 mL fractions) using the flash technique. Fractions 9-15 provided 1.57 g, 82.3%, of the product as a viscous, colorless oil. 16 NMR (250 MHz): 5: 7.34 (dd, J=1.6, 1.4 Hz, 1H); 7.21 (m, 1H); 6.26 (brs, 1H); 5.52 (t, J=1.5 Hz, 1H); 4.19 (brs, 1H); 2.55 (dd, J=8.3, 7.3 Hz, 2H); 2.22 (dd, J=8.3, 7.3 Hz, 2H); 1.95 (m, 2H); 1.5-1.7 (m, 4H). EI/MS (70 eV): 192 (04*, 10.4), 174 (33.4), 110 (62.1), 97 (45), 91 (19), 81 (base). IR 62 (neat): 3400, 2970, 2900, 1675, 1510, 1460, 1170, 1080, 1035, 975, 885, 790, 740 cm'l. 3-(3-(3-furyD-propyD-cyclohex-2en-l-ol (67). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 2-(3-furyl)-1-bromethane (2.6 g, 15 mmol) was reacted (CuCN) with vinyl epoxide 65 (1.1 g, 10 mmol) to provide 1.19 g, 58%, of 67 as a colorless oil. 16 NMR (250 MHz): 6= 7.22 (dd, J=1.7, 1.4 Hz, 1H); 7.06 (m, 1H); 6.18 (m, 1H); 5.36 (brs, 1H); 4.20 (br, 1H); 4.09 (m, 1H); 2.41 (t, J=6.8 Hz, 2H); 1.42 (m, 10H). EI/MS (70 eV): 206 (M+, 6.6), 123 (45.1), 110 (14.2), 97 (base). IR (neat): 3400 (br), 3050, 2970, 2900, 1675, 1500, 1460, 1170, 1055, 975, 850, 790 cm'l. Anal. Calcd. for C13H1302: c, 75.72: H, 8.73. Found: c, 75.56; H, 8.62. 3-(4-(3-furyD-butyD-cyclohex-2en-l-ol (68). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 3-(3-fury1)-1-bromethane (2.8 g, 15 mmol) was reacted (CuCN) with vinyl epoxide 65 (1.10 g, 10 mmol) to provide 1.36 g, 62%, of 68 as a colorless oil. 16 NMR (250 MHz): 6 7.38 (dd, J=1.7, 1.4 Hz, 1H); 7.22 (m, 1H); 6.25 (m, 1H); 5.49 (d, J=1.4 Hz, 1H); 4.18 (m, 1H); 2.23 (t, J=6.3 Hz, 2H); 2.1-1.35 (m, 12H). EI/MS (70 eV): 220 (M+, 6.33), 218 (22.2), 202 (29.3), 136 (85), 123 (55), 110 (44), 97 (48), 81 (base). IR (neat): 3500 (br), 3010, 2980, 2900, 1670, 1500, 1430, 1170, 975, 850, 780 cm-1. 3-(3-(3-furyD-propyD-2-methylcyclopent-2-en—1-ol (7 3). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 2-(3-furyl)-1-bromoethane (0.53 g, 3 mmol) was reacted (CuCN) with vinyl epoxide 72 (0.11 g, 1 mmol) to provide 120 mg, 59% of 73 as a clear, colorless oil. 16 NMR (250 MHz)6=7.17 (dd J=1.4, 1.2 Hz, 16), 7.09 (m, 1H), 6.00 (m, 1H), 4.42 (t, J=8.5 Hz, 1H), 2.26 (t, J=6.6 Hz, 2H), 1.89 (m, 63 26), 1.75 (m, 26). EI/MS (70 eV): 206 (M+, 4.53); (188, 32.4); 120 (14.3); 94 (base). IR (neat): 3450 (br, 3040, 2980, 1500, 1460, 1170, 1080, 890 cm-1. 3-(4-(3-furyD-butyD-2-methylcyclopent-z-en-l-ol (74). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 3-(3-furyl)-l-bromopropane (0.26 g, 1.4 mmol) was reacted (CuCN) with vinyl epoxide 72 (0.75 g, 0.68 mmol) to provide 95 mg, 63% of 74 888 clear, colorless oil. 16 NMR (250 MHz): 6:7.18 (dd, J=1.4, 1.2 Hz, 16), 7.07 (m, 1H), 6.04 (m, 1H), 4.42 ( t, J=8.2 Hz, 1.H), 2.26 (t, J=6.6 Hz, 2H), 1.98 (m, 4H), 1.77 (m, 2H), 1.60 (brs, 311), 146 (m, 4H). EI/MS (70 eV): 220 (M+, 5.68), 202 (18.4), 120 (base). IR (neat): 3440 (br), 3045, 2980, 1500, 1465, 1170, 1080, 780 cm'l. GENERAL PROCEDURE FOR THE PREPARATION OF 2-EN-l-ONES AND 2-EN-1-ALS 3-(2-(3-furyD-ethyl)-cyclohex-2-en-l-one (69). To a solution of allylic alcohol 66 (1.92 g, 10 mmol) in CH2C12 (10 mL) was added NagCOg (0.1 g, 1 mmol) and the mixture cooled in an ice water bath. Pyridinium chlorochromate (3.23 g, 15 mmol) was added in small portions over 10 minutes. The resulting red-brown suspension was stirred at 0°C for 30 minutes and cast into 1N HCI (50 mL) and ether (100 mL). The organic phase was separated and washed with 1N HC1 (50 mL), saturated aqueous NaHCOg (50 mL), water (50 mL), dried (MgSO4) and concentrated i_n Egg; to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 55 g, 40 mm o.d., 1:1 ether-pet. ether, 25 mL fractions) using the flash technique. Fractions 8-11 provided 1.65 g, 87%, of the 69 as a colorless, sweet-smelling oil. 1H NMR (250 MHz): 6:7.37 (dd, J=1.7, 1.4 Hz, 1H); 7.21 (brs, 1H); 6.24 (brs, 1H); 5.88 (s, 1H); 2.63 (t, J=6.3Hz, 2H), 2.43 (t, J=6.4 Hz, 64 2H); 2.28 (m, 4H); 2.01 (m, 2H). EI/MS (70 eV): 190 (M+, 19.6), 172 (15.1), 134 (12), 81 (base). IR (neat): 2990, 2790, 1680 (s), 1500, 1230, 1180, 1040, 880, 800 cm-1. 34H3-fwyD-propyD—cyclohex-2-en-1-me (70). According to the general procedure for the preparation of 2-en-1-ones, allylic alcohol 67 (2.06 g, 10 mmol) was treated with PCC (3.23 g, 15 mmol) to provide 1.7 g, 83%, of 70 as a light yellow oil. 16 NMR (250 MHz): 6:7.28 (dd, J=1.7, 1.5 Hz, 1H); 7.18 (m, 1H); 6.19 (brs, 1H); 5.76 (s, 1H); 2.58 (t, J=6.8 Hz, 2H); 2.36 (m, 4H); 2.28 (m, 2H); 1.98 (m, 4H). EI/MS (70 eV): 204 (M+, 22.8), 188 (66), 147 (73), 123 (20.2), 110 (32.8), 94 (65.7), 82 (base). IR (neat): 2980, 2790, 1685 (br), 1500, 1245, 1170, 1030, 880, 800 cm‘l. Anal. Calcd. for 01361602: c, 76.47; H, 7.84. Found: C, 76.44; H, 7.81. 3-(4-(3-furyl)-butyl)-cyclohex-2-en-l-one (71). According to the general procedure for the preparation of 2-en-1-ones, allylic alcohol 68 (2.20 g, 10 mmol) was treated with PCC (3.23 g, 15 mmol) to provide 1.83 g, 85%, of 71 as a light yellow oil. 16 NMR (250 MHz): =7.38 (dd, J=1.2, 1.5 Hz, 1H); 7.20 (m, 1H): 6.23 (brs, 1H); 5.83 (s, 1H); 2.46 (t, J=6.4 Hz, 28); 2.38 (t, J=7.2 Hz, 2H); 2.21 (m, 2H); 1.98 (m, 4H); 1.68 (m, 4H). EI/MS (70 eV): 218 (16*, 37), 175 (7.17), 126 (17.8), 94 (28.7), 82 (base). IR (neat): 2980, 2795, 1680 (br), 1630, 1260, 1195, 1030, 875, 880 cm-1. 2-methyI-5-[2-(3-furyDethyIJ-cyclopent-2-en-l-one (75). To a solution of oxalyl chloride (175 mg, 1.38 mmol) in dichloromethane (2 mL) cooled to -60°C in a dry ice-chloroform bath was added dimethylsulfoxide (215 mg, 2.75 mmol) and the solution stirred at -60°C. After 30 minutes, a solution of alcohol 73 (100 mg, 0.5 mmol) in dichloromethane (2 mL) was added and the solution stirred at -60°C for 1 hour. Triethylamine (0.5 g, 5 mmol) was added and the mixture warmed to room temperature for 30 minutes. The solution was 65 cast into dichloromethane (25 mL) and water (25 mL). The organic phase was separated and washed with 1N HC1 (25 mL), saturated aqueous NaCO3 (10 mL), dried (MgSO4) and concentrated i_n M to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 15 g, 20 mm o.d., 1:1 EtZO/pet. ether, 10 mL fractions) using the flash technique. Fractions provided 72 mg, 7 3% of 75 as a clear colorless oil. 1H NMR (250 MHz):6=7.21 (m, 1H); 7.08 (m, 1H); 6.09 (m, 1H); 2.23 (m, 2H); 2.05 (m, 4H); 1.95 (m, 4H); 1.80 (m, 4H); 1.76 (brS, 3H). EI/MS (70 eV): 204 (04*, 15.5); 161 (600); 149 (47.5); 123 (72.9); 110 (45.6); 95 (86.01); 82 (base). IR (neat): 2990, 2980, 1685(s), 1500, 1450, 1230, 1040, 980, 780 cm'l. 2-methyl-5-[3-(3-furprropyIJ-cyclopent-2-en-l-one (76). According to the general procedure for the preparation of 2-en-l-ones allylic alcohol 74 (100 mg, 0.45 mmol) was treated with PCC (0.29 g, 1.36 mmol) to provide 73 mg, 74% of 76 as a light yellow oil. 1H NMR (250 MHz): 6:7.24 (m, 1H); 7.08 (m, 1H); 6.04 (m, 1H); 2.18 (t, J=8.2 Hz, 2H); 2.01 (m, 2H); 1.92 (m, 4H); 1.80 (m, 4H); 1.66 (brs, 3H). EI/MS (70 eV): 218 (M+, 11.7); 204 (3.5); 159 (6.7); 136 (56.9); 123 (44.5); 110 (49.0); 95 (70.8); 81 (base). IR (neat): 2995, 2980, 1690, 1500, 1245, 1040, 980, 780 cm-1. 6-(4-(3-furyD-ethyD-cyclohex-2-en-1-one (80). To magnesium metal (0.24 g, 10 mmol) covered by THF (10 mL) was added 2-(3-furyl)—l-bromethane 63 (1.75 g, 10 mmol) and the mxiture stirred at room temperature until all the magnesium had been consumed (about 2% hours). The resulting golden yellow solution was cooled to -78°C (dry ice - isopropanol) and copper (I) cyanide (0.89 g, 10 mmol) was added in one portion. The resulting green suspension was stirred at -78°C for 30 minutes and a solution of 7742f (1.47 g, 8 mmol) in THF (5 mL) was added over a period of 5 minutes. The resulting yellow- brown suspension was stirred at -78°C for 2 hours. The mixture was cast 66 into saturated aqueous NH4CI (50 mL) and ether (75 mL). The organic phase was separated, washed with 1N HC1 (50 mL), saturated aqueous NaHC03 (50 mL), brine (50 mL), dried (MgSO4), and concentrated _in w to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 50 g, 40 mm o.d., 1:1 ether:hexane) using the flash technique. Fractions 7-9 provided 1.14 g, 75%, of 80 as a light yellow liquid. 16 NMR (250 MHz): 5:7.37 (dd, J=1.6, 1.4 Hz, 16); 6.25 (m, 1H); 6.92 (dt, J=8.l, 3.5 Hz, 1h); 6.32 (brs, 1H); 6.00 (dt, J=8.1, 2.1 Hz, 1H); 2.49 (m, 2H); 2.37 (m, 2H); 1.79 (m, 28); 1.58 (m, 2H). EI/MS (70 eV): 190 (M+, 7.37), 167 (2.56), 96 (base), 81 (24.6). IR (neat): 2940, 2880, 1685, 1500, 1450, 1390, 1030, 880, 800 cm-1. 6-(3-(3-furyD-propyD-cyclohex-2-en-l-one (81). To magnesium metal (0 .12 g, 5 mmol) covered by THF (3 mL) was added 3-(3-furyl)-1-brom0propane10° (0.94 g, 5 mmol) and the mixture stirred at room temperature until all the magnesium had been consumed (about 2 hours). The resulting golden yellow solution was cooled to -78°C (dry ice - isopropanol) and copper (I) cyanide (0.45 g, 5 mmol) was added in one portion. The resulting green suspension was stirred at -78"C for 30 minutes and a solution of 77 (0.73 g, 4 mmol) in THF (3 mL) was added over a period of five minutes and the resulting brown suspension stirred at ~78°C for 2 hours. The mixture was cast into saturated aqueous NH4C1 (25 mL) and ether (50 mL). The organic phase was separated, washed with 1N HC1 (50 mL), saturated aqueous NaHCO3 (50 mL), brine (50mL), dried (MgSO4), and concentrated in M2 to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 50 g, 40 mm o.d., 1:1 ether:hexane) using the flash technique. Fractions 10-14 provided 0.72 g, 72%, of 81 as a clear, colorless liquid. 1H NMR (250 MHz): 6:7.18 (dd, J=1.6, 1.4 Hz, 1H); 6.99 (m, 1H); 6.68 (dt, J=9.8, 67 3.92 Hz, 1H); 6.03 (brs, 1H); 5.73 (dt, J=9.8, 2.4 Hz, 1H); 2.22 (t, J=8.2 Hz, 26); 2.14 (m, 3H); 1.90 (m, 2H); 1.75-1.2 (m, 46). El/MS (70 eV): 204 (6+, 6.5), 159 (11.7), 122 (17.7), 108 (base), 96 (54), 81 (48). IR (neat): 2950, 2880, 1685, 1500, 1445, 1380, 1140, 1030, 880, 800 cm'l. Anal. Calcd. for C13H1602: C, 76.47; H, 7.84. Found: C, 76.45; H, 7.84. l—methyl-6-(2-(3-furyD-ethyD-cyclohex-2-en-l-ol (82). To a solution of 80 (0.38 g, 2 mmol) in THF (3 mL) cooled to -78°C (dry ice -isopropanol) was added methyl lithium (3.07 mL), 1.3M, 4 mmol) in one portion and the mixture stirred at -78°C for 30 minutes. The resulting solution was cast into saturated aqueous NH4C1 (20 mL) and ether (20 mL). The organic phase was separated, washed with brine (20 mL), dried (MgSO4) and concentrated g) M to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230-400 mesh, 30 g, 30 mm o.d., 1:4 ether-hexane, 10 mL fractions) using the flash technique. Fractions 14-18 provided 0.37 g, 90%, of 82 as a clear, colorless liquid which is a 3:2 mixture of isomers by capillary GLC. 16 NMR (250 MHz): 8:7.36 (dd, J=1.6, 1.4 Hz, 16); 7.22 (m, 1H); 6.28 (m, 1H); 5.72-5.53 (m, 2H); 2.47 (m, 2H); 2.06 (m, 2H); 1.76 (m, 2H); 1.29 (s, 1.2H): 1.18 (s, 1.8H). El/MS (70 eV): 206 (IVI+, 4.2), 188 (3.4), 108 (10.3), 94 (20.7), 82 (base). IR (neat): 3500 (br), 3010, 2980, 2900, 1665, 1500, 1430, 1165, 975, 780 curl. l-methyPH3-(3-furyD-propyD-cyclohex-2-en-l-ol (83). To a solution of 81 (0.15 g, 0.75 mmol) in THF (2 mL) cooled to —78°C (dry ice -isopropanol) was added methyl lithium (2.85 mL, 1.3M, 3.7 mmol) in one portion and the mixture stirred at -78°C for 30 minutes. The resulting solution was cast into saturated aqueous NH4C1 (10 mL) and ether (10 mL). The organic phase was separated, washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to provide a yellow liquid. The crude product was purified by 68 chromatography on a column of silica gel (230-400 mesh, 30 g, 40 mm o.d., 1:1 ether-hexane, 25 mL fractions) using the flash technique. Fractions 7—10 provided 146 mg, 90%, of 83 as a 3:2 mixture of isomers by GLC. 1H NMR (250 MHz): 6:7.35 (dd, J=1.6, 1.4 Hz, 1H); 7.21 (m, 1H); 6.29 (brs, 1H); 5.79- 5.50 (m, 2H); 2.47 (m, 2H); 2.03 (m, 2H); 1.81-1.38 (m, 4H); 1.29 (8, L811); 1.17 (s, 1.2H). El/MS (70 eV): 220 (M+, 3.16), 202 (2.75), 167 (39.2), 157 (22.9), 120 (11.2), 108 (14.8), 93 (39.0), 84 (base). IR (neat): 3500 (br), 3010, 2990, 2890, 1670, 1500, 1430, 1170, 975, 880, 780 cm-1. 2-methy1-5-[2-(3-IuryDethyDcycIopent-2-en-I-one (84). To magnesium metal (0.05 g, 2 mmol) covered by THF (1 mL) was added 2-(3-furyl)-1- bromoethane (0.35 g, 2 mmol) and the mixture stirred at room temperature until all the magnesium had reacted (about 1 hour). The resulting golden solution was cooled to -78°C (dry ice-isopropanol) and copper (I) cyanide (0.18 g, 2 mmol) was added and the green suspension stirred at -78°C for 30 minutes. To a solution of diisopropyl amine (0.1 g, 1 mmol) in THF (1 mL) cooled to -78°C (dry ice-isopropanol) was added n-BuLi (0.4 mL), 2.5 m, 1.0 mmol) and the mixture stirred at -78°C for 15 minutes. To this solution was added 1-methyl-6-oxabicyclo [3.1.0]lexane-2-one (0.11 g, 1mmol) and the mixture stirred for 30 minutes at -78°C. To this solution was added trimethyl chlorosilane (0.13 g, 1.25 mmol) and the mixture warmed to 0°C. After 30 minutes, this mixture was slowly added via syringe to the cuprate prepared above and the suspension stirred at -78°C for 2 hours. The resulting suspension was cast into 1N HC1 (10 mL) and ether (10 mL). The organic phase was separated and washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried (MgSO4) and concentrated in M to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 15 8: 20 mm o.d., 1‘1 E"20: hexane, 10 mL fractions) using the flash 69 technique. Fractions 9-14 provided 105 mg, 55% of 84 as a light yellow oil. 1H NMR (250 MHz): 6:7.28 (dd, J=1.4, 1.2 Hz); 7.15 (m, 1H); 7.10 (m, 1H); 6.21 (m, 1H): 2.78 (m, 1H), 2.73 (m, 1H); 2.57 (m, 2H), 2.24 (m, 3H); 1.88 (m, 3H). EI/MS (70 eV): 190 (MI) 17.7); 169 (5.18); 109 (5.08); 96 (base). 2-IethyI-5-[3-(3-ftlrprropyDcyclopent-2-en-l-one (85). According to the procedure outlined for the preparation of 84, 3-(3-furyl)-1-bromopropane (0 .38 g, 2 mmol) was reacted with 1-methyl—6-oxabicycloI3.1.0]hexan-2-one (0.11 g, 1 mmol) to provide 110 mg, 54% of 85 as a clear oil. 1H NMR (250 llez):6=7.21 (dd, J=1.6, 1.2 Hz, 1H); 7.16 (m, 1H); 7.09 (m, 1H); 6.17 (m, 1H); 4.02 (m, 1H); 3.43 (m, 2H); 2.38 (m, 4H); 1.64 (brs, 3H); 1.49 (m, 2H). EI/MS (70 eV): 204 (M13 21.2); 185 (8.13), 122 (37.9), 108 (base). 1.2-dimethyl-5-[2-(3-furyDethylkyclopent-2-en-l-ol (86). To a solution of 84 (50 mg, 0.25 mmol) in THF (1 mL), cooled to -78°C (dry ice-isopropanol) was added methyl lithium (1.0 mL, 1.3 M, 1.3 mmol) in one portion and the mixtured was stirred at -78°C for 30 minutes. The resulting solution was cast into saturated aqueous NH4CI (10 mL) and ether (10 mL). The organic phase was separated and washed with brine (10 mL), dried (MgSO4) and concentrated i_n w to provide 41.3 mg, 78% of a yellow liquid which was used without further purification. 1H NMR (250 MHz): 527.21 (6), 1H); 7.09 (m, 1H); 6.10 (tn, 1H); 5.24 (m, 1H); 2.24 (m, 4H); 1.98 (m, 6H); 1.85 (brS, 3H); 123 (m, 3H). EI/MS (70 eV): 206 (M+, 14.2), 188 (61.5), 173 (43.0), 157 (12.4), 149 (25.5), 123 (37.0), 109 (73.9), 94 (97.0), 81 (base). 1,2-dimethy1-5-[3-(3-furprropyIJ-cyclopent-2-en-l-ol (87). To a solution of 85 (50 mg, 0.25 mmol) in THF (1 mL), cooled to -78°C (dry ice-isopropanol) was added methyl lithium (1.0 mL, 1.3 M, 1.3 mmol) in one portion and the mixture stirred at -78°C for 30 minutes. The resulting solution was cast into saturated aqueous NH4Cl (10 mL) and ether (10 mL). The organic phase was 70 separated and washed with brine (10 mL), dried MgSO4) and concentrated i_n mg to provide 46 mg, 83% of a yellow liquid which was used without further purification. 1H NMR (250 MHz): 6:7.19 (m, 1H); 7.06 (m, 1H); 6.09 (m, 1H); 5.22 (m, 1H); 2.24 (m, 6H); 1.95 (m, 4H); 1.80 (brs, 3H); 1.21 (m, 3H). El/MS (70 eV): 220 (M+, 4.5); 202 (13.1), 185 (16.9), 169 (13.6), 15.7 (151), 120 (53.5), 108 (58.3), 95 (48.9), 81 (61.6), 43 (base). 1-(methylthiomethy1ene)cyclohex-2-en-l-ol. To n-butyl lithium (28.6 mL, 1.75 M in hexane, 50 mmol) chilled in an ice-water bath was added tetra methylethylenediamine (TMEDA 5.8 g, 50 mmol). The mixture was warmed to room temperature and allowed to stir for 30 minutes. The mixture was cooled to 0°C and dimethyl sulfide13 (3 g, 48.4 mmol) was added. The resulting pale yellow solution was stirred for 3.5 hours at room temperature, cooled to -78°C (dry ice - isoprOpanol) and a solution of 2-cyclohexen-l-one (4.85 g, 50 mmol) in THF (30 mL) was added over 5 minutes. The mixture was warmed to room temperature, cast into ether (150 mL) and saturated aqueous (NH4SO4) and concentrated i_n _v_a__c_t_lg to provide a viscous yellow liquid. The crude product was purified by distillation. B-P-0.007mm = 65-68°C to provide 6.7 g, 88%, of 1-(methylthiomethylene)cyclohex-2-en-1-ol as a colorless, viscous liquid. 1H NMR (250 MHz): 6 = 5.85 (ddd, J=10, 4, 3.15 Hz, 1H); 5.66 (dddd, J=9.5, 2.4, 2.0, 0.77 Hz, 1H); 2.75 (d, J=13.4 Hz, 1H); 2.67 (d, J=13.4 Hz, 1H); 2.50 (brs, 1H); 2.20 (s, 3H); 1.95-2.09 (m, 2H); 1.57-1.85 (m, 4H). El/MS (70 eV): 158 (M+, 6.65), 141 (32.3), 97 (base). IR (neat): 3470 (br), 3050, 2950, 2855, 1645, 1435, 1220, 1185, 1055, 1000, 965 (br), 740 cm'l. 1-(dimethylsulfonium methyleneHyclohex-z-en-l-ol. To a solution of allylic alcohol (3.16 g, 20 mmol) in dry acetone (10 mL) was added methyl iodide (5.67 g, 40 mmol). The mixture was allowed to stir at room temperature overnight and then concentrated i_n vacuo to provide 6.0 g, 100%, of the 71 sulfonium salt as a white solid, lVl.P. = 155° (dec), which was used without further purification. 8-oxaspiro[5.2}-oct-2-ene (79). To a suspension of the sulfonium salt (6.0 g, 20 mmol) in 250 mL of THF was added 2.9 g (25.9 mmol) of freshly sublimed KOtBu. The mixture was allowed to stir at room temperature for 4 hours, quenched with saturated aq. NaHC03 (50 mL), and was cast into ether (250 mL). The aqueous phase was separated, extracted with ether (4 x 100 mL), and the combined organic extracts were washed with saturated aq. NaHC03 (0.5 L), brine (0.5 L), and dried (MgSO4, K2003). The solvent was removed by distillation at atmospheric pressure and the residue was purified by distillation, B.P.37mm = 70-72°C to provide 2.0 g, 91%, 79 as a colorless liquid. 16 NMR (250 MHz): 5= 6.12 (dd, J=10.07, 3.97, 3.66 Hz, 1H); 5.25 (brd, J=10.07 Hz, 1H); 2.84 (d, J=4.88 Hz, 1H); 2.79 (d, J=4.88 Hz, 1H); 1.5-2.3 (m, 6H). EI/MS (70 eV): 110 (M+, 83), 93 (51), 79 (base). IR (neat): 3080, 3020, 1460, 950, 810, 760 cm-1. MS: 16" calc. for C7H100; 110.073160; 16* found 110.07320. 1-hydroxymethyl-3-(3-furylmcthyD-1-cyclohexene (88). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from (3—furyl)-chloromethaneloa (1.7 g, 15 mmol) was reacted (CuCN) with vinyl epoxide 79 to provide 1.5 g, 78%, of 88 as a clear, colorless liquid. 1H NMR (250 MHz): 6: 7.35 (dd, J=1.7, 1.4 Hz, 1H); 7.22 (dd, J=1.7, 0.77 Hz, 1H); 6.27 (m, 1H); 5.58 (brs, 1H); 3.98 (brs, 2H); 2.38 (m, 2H); 2.30 (brs, 1H); 1.98 (brs, 2H); 1.77 (m, 1H); 1.58 (m, 1H); 1.52 (m, 1H); 1.20 (m, 1H). EI/MS (70 eV): 192 (M"’, 1.44), 174 (6.8), 161 (1.72), 128 (1.60), 111 (69), 93 (base). IR (neat): 3400 (br), 2965, 2895, 1515, 1460, 1175, 1080, 1040, 890, 800, 785, 745 cm‘l. 72 1-hydroxymethyl-3-(2-(3-furyD-ethyD-l-cyclohexene (89). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 2-(3-furyl)-1-bromoethane10b (2.6 g, 15 mmol) was reacted (CuCN) with vinyl epoxide 79 to provide 1.15 g, 56%, of 89 as a colorless oil. 16 NMR (250 MHz): 6= 7.35 (dd, J=1.7, 1.4 Hz, 1H); 7.24 (m, 16); 6.25 (m, 1H); 5.43 (brs, 1H); 3.83 (brs, 2H); 2.41 (t, J=6.3 Hz, 2H); 2.33 (m, 2H); 1.98- 1.23 (m, 7H). EI/MS (70 eV): 206 (M+, 1.34), 175 (36), 188 (19.0), 124 (10), 95 (16), 82 (base. IR (neat): 3400 (br), 2965, 2895, 1500, 1460, 1175, 1080, 1040, 890, 800, 780 cm’l. Anal. Calcd. for C13H1302: c, 75.72; H, 8.73. Found: C, 75.66; H, 8.74. 1-hydroxymethyl-3-(H3-furyD-propyD-l-cyclohexenc (90). According to the general procedure for the preparation of allylic alcohols, the Grignard reagent derived from 3-(3-furyD-l-bromoethane10c (2.8 g, 15 mmol) was reacted (CuCN) with vinyl epoxide 79 to provide 1.27 g, 58%, of 90 as a light yellow oil. 1H NMR (250 MHz): 6:7.38 (dd, J=1.7, 1.6 Hz, 1H); 7.21 (m, 1H); 6.29 (brs, 1H); 5.58 (brs, 1H); 3.98 (s, 2H); 2.40 (t, J=6.1 Hz, 2H); 2.18-2.00 (m, 4H); 1.8-1.3 (m, 7H). El/MS (70 eV): 220‘ 06*, 10.8), 202 (27.5), 189 (10.8), 120 (46.1), 111 (23.7), 95 (70.1), 81 (base). IR (neat): 3500 (br), 2980, 2895, 1500, 1450, 1190, 1060, 1045, 800, 750 cm‘l. 3-(3-furylmethyD-cyclohex-l-en-l-earboxaldehyde (91). According to the general procedure for the preparation of 2-en-1-als, allylic alcohol 88 (1.92 g, 10 mmol) was oxidized with PCC (3.23 g, 15 mmol) to provide 1.5 g, 78.9%, of 91 as a clear, colorless liquid. 1H NMR (250 MHz): 6: 9.41 (s, 1H), 7.31 (dd, J=1.6, 1.4 Hz, 1H), 7.22 (m, 1H), 6.64 (brs, 1H), 2.52 (m, 2H), 1.2-8.18 (m, 8H). EI/MS (70 eV): 190 (M+, 20), 172 (1.12), 161 (2.57), 108 (9), 81 (base). IR (neat): 2980, 2880, 2710, 1685, 1630, 1450, 1390, 1180, 1020, 880, 800 cm'l. 73 3-(2-(3-furyD-ethyD-cyclohex-l-ene-l-carboxaldehyde (92). According to the general procedure for the preparation of 2-en—1-als, allylic alcohol 89 (2.06 g, 10 mmol) was oxidized with PCC (3.23 g, 15 mmol) to provide 1.7 g, 83%, of 92 as a pale yellow oil. 16 NMR (250 MHz): 6: 9.23 (s, 1H); 7.21 (dd, J=1.6, 1.4 Hz, 1H); 7.10 (m, 1H); 6.52 (brs, 1H); 6.18 (m, 1H); 2.54 (t, J=5.8 Hz, 2H); 2.1 (t, J=5.7 Hz, 2H); 1.8-1.6 (m, 7H). EI/MS (70 eV): 204 (M+, 25.8), 186 (12.7), 173 (26.3), 123 (23.9), 95 (13.2), 82 (base). IR (neat): 3140 (w), 2980, 2880, 1690, 1630, 1500, 1450, 1190, 1070, 1030, 880, 780 cm‘l. Anal. Calcd. for 01361602: 0, 76.47; H, 7.84. Found: c, 76.34; H, 7.88. 3-(3-(3-furyl)-propyl)-cyclohex-l-ene-l-carboxaldehyde (93). According to the general procedure for the preparation of 2-en-l-als, allylic alcohol 90 (2.20 g, 10 mmol) was oxidized with PCC (3.23 g, 15 mmoD to provide 1.7 g, 78%, of 93 as a yellow oil. 16 NMR (250 MHz): 6: 9.26 (s, 1H); 7.34 (dd, J=1.6, 1.5 Hz, 1H); 7.21 (m, 1H); 6.23 (brs, 1H); 6.31 (m, 1H); 2.43 (t, J=7.3 Hz, 2H); 2.38 (m, 2H); 2.08 (m, 2H); 1.98-1.16 (m, 7H). 131/005 (70 eV): 218 (M+ 11.2), 189 (5.8), 147 (6.9), 136 (base), 107 (12.6), 95 (19.2), 81 (33.4). IR (neat): 2980, 2880, 2720, 1690, 1630, 1500, 1450, 1380, 1185, 1020, 880, 790 cm’l. 1-(1-hydroxyethyI)-3-(2-(3-furyl)-ethyl)-1-cyclohexene (9 4). To a solution of 92 (0.102 g, 0.5 mmol) in THF (3 mL) cooled to -78°C (dry ice—isopropanol) was added a solution of methyllithium in hexane (1.15 mL, 1.3 M, 1.5 mmol) in one portion and the mixture stirred at -78°C for 20 minutes. The mixture was cast into saturated aqueous NH4CI (10 mL) and ether (10 mL). The organic layer was separated and washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated i_n £9112 to provide a yellow liquid. The crude product was purified by chromatography on a column of silica gel (230- 400 mesh, 40 g. 40 mm o.d., 1:4 Et20/Hex, 25 mL fractions) using the flash 74 technique. Fractions 5-8 proviced 99 mg, 90%, of (94) as a clear, colorless liquid. 1H NMR (250 MHz): 6 = 7.20 (dd, J=1.6, 1.4 Hz, 1 H); 7.10 (m, 1H); 6.13 (m, 1H); 5.43 (brs, 1H); 3.98 (q, J=7.3 Hz, 1H); 2.42 (t, J=6.3 Hz, 2H); 2.0-1.3 (m, 5H); 1.14 (d, J=7.3 Hz, 3H). ELI/M‘s (70 eV): 220 (M+, 0.5), 202 (19.9), 138 (5.5), 123 (6.2), 95 (49.1), 82 (base). IR (neat): 3400 (br), 2995, 2890, 1500, 1460, 1185, 1060, 1045, 800, 760 cm-1. 1-(1-hy£. 1980, m, 5872. 36. Feld, R.; Cowe, D. L. "The Organic Chemistry of Titanium", Butterworth, Inc., Washington D.C., 1965; and references cited therein. 37. Stork, G.; Shiner, C. S.; Winkler, J. D. J. Amer. Chem. Soc. 1982, 104, 310. 38. (a) Marshall, J. A.; Wuts, P. G. M. J. Org. Chem. 1977, 12, 1794. (b) Reetz, M. T.; Huttenhain, S.; Hubner, F. Sm. Comm. 1981, l_1_, 217. 39. Cimino, G.; DeStefano, S.; Guerriero, A.; Minale, L. Tet. Lett. 1975, 1417; ldem., Ibid. 1975, 1425. 40. Nasipuri, D; Das, G. J. Chem. Soc. Perkin I 1979, 2776; Nasipuri has examined the cyclization of 39 with BF3-OEt2 and has reported obtaining 49 in 23% yield. 41. Sutherland, J. K.; Chem. Soc. Rev. 1980, g, 265; Hashimoto, S.; ltoh, A.; Kitagawa, Y.; Yamamoto, H.; Nosaki, H. J. Amer. Chem. Soc. 1977, Q, 4192. 42. For recent examples of the reaction of cuprates with vinyl epoxides, see: (a) Marino, J. P.; Abe, H. J. Am. Chem. Soc. 1981, 1_0_3, 2907. (b) Ziegler, F. E.; Cady, M. A. J. OrLChem. 1981, 46, 122. (c) Marino, J. P.; Abe, H. Synthesis 1980, 11, 872. (d) (e) 91 Marino, J. P.; Hatanaka, N. J. OrLChem. 1979, g, 4467. Marino, J. P.; Floyd, D. M. Tetrahedron Lett. 1979, 675. For reactions of cuprates with enol ethers of , -epoxy enones, see: (f) (g) Marino, J. P.; Jaen, J. C. J. Am. Chem. Soc. 1982, _1_04, 3165. Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am. Chem. Soc. 1981, _1_0_3, 2114. 43. For some other recent examples of allylic alcohol initiated cationic cyclizations, see: Brunke, 15.-J.; Hammerschmidt, J.-J.; Struwe, H. Tetrahedron 1981, _31, 1033; and references cited therein. 44. (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (l) (m) (n) (o) Stork, G.; Burgstahler, A. J. Am. Chem. Soc. 1951, 2.3.: 3544. Ziegler, F. E.; Kloek, J. A. Tetrahedron 1971, _3_3, 373. Andersen, H. H.; Uh, H. Tetrahedron Lett. 1973, 2079. Dastur, K. P. J. Am. Chem. Soc. 1974, 9_6, 2605. Marshall, J. A.; Wuts, P. G. M. J. Oggcmm. 1977, 42, 1794. Cooper, J. L; Harding, K. E. Tetrahedron Lett. 1977, 3321. Naegeli, P. lbod. 1978, 2127. Andersen, N. H.; Ladner, D. W.; Moore, A. L. Syn. Comm. 1978, _8_. 437. Harding, K. E.; Cooper, J. L.; Puckett, P. MK.; Ryan, J. D. J. Org Chem. 1978, 43, 4363. Matsumoto, T.; Ohmura, T.; Usui, S. Bull. Chem. Soc. JaLan 1979, 12, 1957. Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc. 1980, 1_0_2, 5872. Sutherland, J. K. J. Chem. Soc. Rev. 1980, _9_, 265. Amupitan, J. A.; Bug, E.; Mellor, M.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc. Perkin I 1983, 751. Amupitan, J. A.; Scovell, E. G.; Sutherland, J. K. lbod. 1983, 755. Amupitan, J. A.; Beddoes, R. L.; Mills, 0. S.; Sutherland, J. K. Ibid. 1983, 759. 45 . (a) (b) (c) 92 Tanis, S. P. Tetrahedron Lett. 1982, 26, 3115. Prepared from 2-(3-furyl)ethanol: Sherman, E.; Amstutz, E. D. J. Am. Chem. Soc. 1950, 32, 2195; Novitskii, K. Y.; Gresl, K.; Yur'ev, U. K. J. 013. Chem. U.S.S.R. 1965, 2, 531. Prepared from 3-(3-furyl)-1-propanol: Vig, O. P.; Chugh, O. P.; Handa, U. K.; Vig, A. K. J. Indian Chem. Soc. 1975, Q, 199. 46. Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647. 47. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 61, 1353. 48. Peterson, D. J. J. Org. Chem. 1967, 3_2_, 1717. 49. Several other examples have been examined: Tanis, S. P.; McMills, M. C.; Herrinton, P. M. Tetrahedron Lett. submitted. 50. See: (a) (b) (c) (d) Dunlop, A. P.; Peters, F. N. in "The Furans"; Reinhold, New York, 1953. Bosshard, P.; Eugster, C. H. Adv. Heterocycl. Chem. 1966, 2, 377-491. Sargent, M. V.; Crisp, T. M. in "Comprehensive Organic Chemistry"; Sammes, P. G., Ed.; Pergamon Press: Oxford, 1979; Vol. 4, PP 693-744. Dean, F. M. Adv. Heterocycl. Chem. 1982, 3_()_, 167-238. 51. Stork (a) and van Tamelen (b) have also noted similar constraints in five-membered ring formation. (a) (b) Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 66, 5270. van Tamelen, E. E.; Pedlar, A. D.; Li, E.; James, D. R. Ibid. 1977, 92, 6778; van Tamelen, E. E.; Leiden, l‘. M. Ibid. 19 2, 266, 2061. 52. BF3-OEt2, SnCl4, TiCl4, EtAlClz, EtzAlCl, MgBr2°OEt2, Zn12 and Ti(OiPr)3Cl were employed as Lewis Acids. 53. Still, W. C.; Mitra, A.; Khan, M. J. Org. Chem. 1978, 32, 2923. 54. Braude, E. A.; Evans, E. A. J. Chem. Soc. 1955, 3324. 55. Purchased from Aldrich Chemical Co. 93 56. Trost, B. M.; Konz, R. A. J. 03. Chem. 1974, Q, 2475. 57. McCormick, J. P.; Barton, D. L. J. Chem. Soc. Chem. Common. 1975, 303. 58. Mori, K.; Kobayashi, S.; Matsui, M. Agi. Biol. Chem. 1975, 22, 1889. 59. Fischer, E.; Pfahler, E. Ber. Dtsch. Chem. Ges. 1920, 62, 1606. 60. Reetz, M. T.; Peter, R. Tet. Lett. 1981, 22, 4691. 61. Brauer, G., Ed. "Hanbook of Preparative Inorganic Chemistry"; Academic Press: New York, 1965; p. 1017. 62. Hooz, J.; Gilani, S. S. H. Can. J. Chem. 1968, 26, 86. 63. House, H. 0.; Wasson, R. L. J. Amer. Chem. Soc. 1957, 72, 1488. 64. We wish to thank Prof. P. J. Scheuer for providing Spectra of authentic nakafuran-9. MIIWHISIIWWI “WWW IILHIIEIRWITIES 3 1293 03085 1889