A Novel Synthesis of Functionalized Tetrahydrofurans by an Oxa

Ben W. Greatrex,† Marc C. Kimber,† Dennis K. Taylor,*,† and Edward R. T. Tiekink‡. Department of Chemistry, The University of Adelaide, South ...
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A Novel Synthesis of Functionalized Tetrahydrofurans by an Oxa-Michael/Michael Cyclization of γ-Hydroxyenones Ben W. Greatrex,† Marc C. Kimber,† Dennis K. Taylor,*,† and Edward R. T. Tiekink‡ Department of Chemistry, The University of Adelaide, South Australia 5004, Australia, and Department of Chemistry, National University of Singapore, Singapore 117543 [email protected] Received November 18, 2002

An approach to highly functionalized tetrahydrofuran derivatives based upon a novel Oxa-Michael/ Michael dimerization of cis-γ-hydroxyenones is presented. The reaction begins with either 1,2dioxines or trans-γ-hydroxyenones and proceeds by addition of one molecule of trans-γ-hydroxyenone to another molecule of cis- or trans-γ-hydroxyenone catalyzed by an alkoxide or hydroxide base. Subsequent intramolecular Michael addition of the keto-enolate gives the observed tetrahydrofurans. Substitution at both the 2- and 4-positions of the γ-hydroxyenone is tolerated; however, for 4-substituted γ-hydroxyenones, selectivity issues arise due to the possibility of heterochiral or homochiral dimerizations. The major products were those with all contiguous groups trans. Introduction

SCHEME 1

The tetrahydrofuran (THF) ring is a core constituent of many bioactive molecules,1 and numerous methods for its synthesis have been developed.2 One particular approach that has been used in the synthesis of several natural products is the 1,4-addition of oxygen nucleophiles to conjugate acceptors. The reaction is normally intramolecular and proceeds under base catalysis. Compatible conjugate acceptors include R,β-unsaturated esters,3 ketones,4 and sulfonates.5 While R,β-unsaturated ketones are better conjugate acceptors than R,β-unsaturated esters, comparatively few examples of the 1,4addition of oxygen nucleophiles to R,β-unsaturated ketones exist. * To whom correspondence should be addressed. Phone: (+61) 8 8303 5495. Fax: (+61) 8 8303 4358. † The University of Adelaide. ‡ National University of Singapore. (1) For recent examples of THF-containing natural products, see: (a) Araya, H.; Hara, N.; Fujimoto, Y.; Srivastava, A.; Sahai, M. Chem. Pharm. Bull. 1994, 42 (2), 388. (b) Kim, E.; Tian, F.; Woo, M. J. Nat. Prod. 2000, 63 (11), 1503. (c) Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Kobayashi, J. J. Nat. Prod. 2002, 65 (3), 375. (2) For examples of THF syntheses, see: (a) Maioli, A. T.; Civiello, R. T.; Foxman, B. M.; Gordon, D. M. J. Org. Chem. 1997, 62 (21), 7413. (b) Jung, M. E.; Fahr, B. T.; D’Amico, D. C. J. Org. Chem. 1998, 63, 2982. (c) Shim, J.-G.; Yamamoto, Y. J. Org. Chem. 1998, 63, 3067. (d) Marshall, J.; Jiang, H. J. Org. Chem. 1999, 64, 971.(e) Guindon, Y.; Soucy, F.; Christiane, Y.; Ogilvie, W.; Plamondon, L. J. Org. Chem. 2001, 66, 8992. (f) Makasza, M.;, Przyborowski, J.; Klajn, R.; Kwast, A. Synlett 2000, 1773. (g) Makasza, M.; Judka, M. Chem.sEur. J. 2002, 4234. (3) (a) Ko, S.; Klein, L.; Pfaff, K.-P.; Kishi, Y. Tetrahedron Lett. 1982, 23, 4415. (b) Honda, T.; Ishikawa, F. J. Org. Chem. 1999, 64, 5542. (c) Jin, C.; Jacobs, H. K.; Gopalan, A. S. Tetrahedron Lett. 2000, 41, 9753. (d) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363. (e) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am. Chem. Soc. 2000, 122, 2742. (4) (a) Ireland, R. E.; Wardle, R. B. J. Org. Chem. 1987, 52, 1780. (b) Grigg, R.; Rasparini, M.; MacLachlan, W. Chem. Commun. 2000, 2241. (5) (a) Marot, C.; Rollin, P. Tetrahedron Lett. 1994, 35, 8377. (b) Craig, D. C.; Edwards, G. L.; Muldoon, C. A. Synlett 1997, 1318. (c) Ko, C.; Chou, T. J. Org. Chem. 1998, 63, 4645.

We have recently reported that cis-γ-hydroxyenones 1 undergo 1,4-addition exceedingly well with a variety of nucleophiles including stabilized phosphorus ylides,6 stabilized phosphonates,7 and malonates.8 The γ-hydroxyl group R to the site of “attack” within the cis-γ-hydroxyenone allows for interaction between the incoming nucleophile and hydroxyl group to occur after initial attack of the nucleophile. Furthermore, substitution at the γ-position effectively blocks one face of the molecule, leading to very high facial selectivity for 1,4-addition.6a As the γ-hydroxy group may also act as a nucleophile itself, cis-γ-hydroxyenones are unique electrophiles that give highly selective addition products. cis-γ-Hydroxyenones 1 may be conveniently generated from 1,2-dioxines 2 by base catalysis or by employing a (6) (a) Avery, T. A.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2000, 65, 5531. (b) Avery, T. D.; Greatrex, B. W.; Taylor, D. K.; Tiekink, E. R. T. J. Chem. Soc., Perkin Trans. 1 2000, 1319. (c) Avery, T. D.; Fallon, G.; Greatrex, B. W.; Pyke, S. M.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2001, 66, 7955. (d) Palmer, F. N., Taylor, D. K. J. Chem. Soc., Perkin Trans. 1 2000, 9, 1323. (7) Kimber, M. C.; Taylor, D. K. J. Org. Chem. 2002, 67, 3142. (8) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Fallon, G.; Tiekink, E. R. T. J. Org. Chem. 2002, 67, 5307.

10.1021/jo020700h CCC: $25.00 © 2003 American Chemical Society

Published on Web 05/01/2003

J. Org. Chem. 2003, 68, 4239-4246

4239

Greatrex et al. TABLE 1. Oxa-Michael/Michael Reactions of Enones Generated from 1,2-Dioxines yieldb (%) entrya

dioxine

time

base

solvent, temp (°C)

6

7

1 2d 3 4e 5 6 7e 8e 9f 10f

2a 2a 2a 2a 2b 2c 2c 2c 2d 2e

16 h 31 d 3h 1h 72 h 72 h 1h 1h 72 h 16 h

LiOH LiOH LiOH NaOEt LiOH LiOH NaOEt NaOEt LiOH LiOH

THF, rt THF, -15 THF, 65 CH3CN/EtOH, rt THF, rt THF, rt THF/EtOH, rt THF/EtOH, -10 THF, rt or 65 THF, rt or 65

50 (47) (62) 57 (78) 46 67 (87) 57 (63)

29c (53) (38) (22) 7 (8) 6 (16)

8

9

11 (5) 18 (21)

22

a Reactions were performed on a 1 mmol scale with 1 equiv of base in 5 mL of solvent. b Isolated yield; the numbers in parentheses indicate the ratio determined by 1H NMR. c An 11% yield of an additional unassignable THF also isolated. Assignment of stereochemistry was not possible due to ambiguous NOE data. d 79% complete by 1H NMR. e A 5:1 ratio of THF/ethanol was used. f Resulted in complete decomposition of starting material.

SCHEME 2a

a

Key: (a) AcCl/pyridine/CH2Cl2.

transition metal such as Co(II), Ru(II), or Fe(II); however, as they undergo ready dehydration to furans 3 under acidic and neutral conditions they must be used immediately.6a,9 When amine bases are employed, cis-γ-hydroxyenones are also susceptible to further rearrangement to their isomeric 1,4-diketones, Scheme 1.6a,10 We have found that hydroxide and alkoxide bases do not favor the rearrangement to 1,4-diketone but alternately promote the 1,4-addition of oxygen nucleophiles. This leads to the possibility of interesting tandem reactions of γ-hydroxyenones initiated by an oxa-Michael addition. In this paper we describe the base-promoted self-condensation of γhydroxyenones affording substituted THFs 5 by an oxaMichael/Michael ring-closing reaction as depicted in Scheme 1. Results and Discussion THF Synthesis from 1,2-Dioxines. 1,2-Dioxines 2a-e were initially employed as a source of cis-γhydroxyenones and were prepared from their corresponding 1,3-butadienes by the Rose Bengal sensitized addition (9) (a) Boyd, J. D.; Foote, C. S.; Imagawa, D. K. J. Am. Chem. Soc. 1980, 102, 3641. (b) O’Shea, K. E. J. Org. Chem. 1989, 54, 3475. (c) Avery, T. A.; Jenkins, N. F.; Kimber, M. C.; Lupton, D. W.; Taylor, D. K. J. Chem Soc., Chem. Commun. 2002, 28. (10) (a) Kornblum, N.; De La Mare, H. J. Am. Chem. Soc. 1951, 73, 881. (b) Clennan, E. L. Tetrahedron 1991, 47, 1343.

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of singlet oxygen.6a,8,10b The 1,2-dioxines 2a-e were allowed to react with alkoxide and hydroxide bases under various conditions, the results of which are summarized in Table 1 and Scheme 2. 1,2-Dioxines 2a-c afforded the substituted THFs 6a-c, 7a-c, 8b-c, and 9b as the sole isolable products in good combined yields. The initial discovery was made from 1,2-dioxine 2a, so the effects of varying reaction conditions versus outcome were examined for this example. Although not tabulated, the reaction proceeded in the presence of both stoichiometric and catalytic quantities of base with only the rate of reaction being affected. Allowing these reactions to stand under basic conditions for prolonged periods of time failed to result in altered ratios. Additionally, reexposure of either 6f or 8f to the basic reaction conditions over 16 h resulted only in reisolation of starting material. These observations indicate that these THFs are not undergoing further isomerization once formed. When ethoxide in ethanol/THF was employed to catalyze the reaction, the outcome was not dramatically affected although reaction times were reduced, entries 4, 7, and 8. Varying the reaction temperature was found to mildly affect the reaction outcome. Lower temperatures led to an increase in the percentage of the minor isomer 7 with the reaction times significantly increased, entries 2, 3, 7, and 8. Substitution on the double bond at the site of nucleophilic attack (2e, entry 10) prevented the reaction from occurring at both ambient temperature and reflux. With the

Synthesis of Functionalized Tetrahydrofurans SCHEME 3

SCHEME 4

TABLE 2. Synthesis of trans-Hydroxyenones entrya

ylide

1 2 3

13c 13f 13g

yieldb of 14 (%) 95 86 c

entrya

ylide

4 5 6

13h 13i 13j

yieldb of 14 (%) c

TABLE 3. Reaction of trans-Hydroxyenones with LiOH yieldb (%)

61 93

entrya

enone

6

7

1 2 3 4c

14a 14c 14f 14g

62 (82) 54 (90) 58 65

(18) 6 (10) 3

a

Reactions were performed by refluxing in THF for 4 h with 1.2 equiv of ylide. b Isolated yield. c trans-γ-Hydroxyenones 14g and 14h were not separable from TPPO but instead were allowed to react with LiOH after filtering through Florisil.

possibility of so many stereoisomeric products, the moderate diastereoselectivity observed for the major isomer 6 in all cases was an encouraging result and gave us incentive to further investigate this reaction. THF Synthesis from trans-γ-Hydroxyenones. The isomerization of cis-γ-hydroxyenones 1 to trans-γhydroxyenones 14 may be promoted by nucleophiles such as triethylamine and triphenylphosphine.6a The isomerization of the trans-enone back to the cis-enone has been promoted by light and heat.6a,d It has been shown that the cis-enone and not the trans-enone acts as the conjugate acceptor in the conjugate addition of nucleophiles to this type of system. However, additions to cisγ-hydroxyenones afford R,S relative stereochemistry between the initial site of addition and the R-chiral center within the conjugate acceptor. As R,R relative stereochemistry was found in the products from the reaction of the 1,2-dioxine (vide infra), there exists the possibility that the reaction was proceeding through the isomeric trans-enone. To examine whether this was the case, trans-enones 14a,c,f-j were prepared. The majority of the enones 14c,f-j were prepared by allowing glycoaldehyde to react with the appropriate stabilized keto ylide in refluxing CHCl3, Scheme 3 and Table 2.6d,11 Both the alkyl-substituted enones 14g and 14h could not be readily separated from TPPO by chromatography and so were used without rigorous purification. Finally, treatment of 1,2-dioxine 2a with Co(II) Salen and then exposure to triphenylphosphine gave 14a according to a published literature procedure.6a With a range of trans-enones in hand, their isomerization and subsequent reactions could now be examined. Treatment of trans-enones 14a,c,f,g with lithium hydroxide gave the THFs 6a,c,f,g, 7a,c,f,g, and 8a,c,f,g in good yield, Scheme 4 and Table 3. Reaction times were (11) Ylides not commercially available were synthesized by reacting the appropriate haloalkanone with triphenylphosphine in refluxing toluene, collecting the precipitate, and deprotonating with Na2CO3 in MeOH/H2O. (a) Bestmann, H. J.; Attygalle, A. B.; Glasbrenner, J.; Riemar, R.; Vostrowsky, O.; Constantino, M. G.; Melikyan, G.; Morgan, E. D. Liebigs Ann. Chem. 1988, No. 1, 55-60.

8

15 9

a Reactions were performed on a 1 mmol scale in THF (5 mL). Isolated yield; the numbers in parentheses indicate the ratio determined by 1H NMR. c A 15% yield of 1,4-dioxane 15 was also isolated.

b

SCHEME 5a

a

Key: (a) LiOH.

significantly shorter than if starting from the appropriate 1,2-dioxine 2 due to the absence of the rate-limiting ringopening step. The major isomer was again 6 with all contiguous groups trans, the same as that found when starting from 1,2-dioxine 2. All isomers were readily separable by flash chromatography on silica gel. When starting with trans-enone 14g, in addition to the expected THFs a 1,4-dioxane 15 was also isolated. The formation of the 1,4-dioxane is a result of a sequential oxa-Michael-enolate quenching/proton-transfer oxaMichael addition sequence. In the case of methyl ketone 14h further intramolecular Aldol condensation resulted in the formation of the fused bicycle 16,12 which under the experimental conditions underwent slow decomposition, Scheme 5. The stereochemistry of 16 was determined by 2D 1H NMR; the two rings were found to be cis-fused, which indicated stereochemistry about the THF ring different from that found for all other major isomers. 2-Methyl-substituted trans-enones 14i and 14j were expected to afford THFs with further substitution about the ring. trans-γ-Hydroxyenone 14i gave two diastereomeric products, both with identical stereochemistry about the THF ring but isomeric at the tertiary center R to the ring, Scheme 6. (12) Brown, P. M., Ka¨ppel, N., Murphy, P. J. Tetrahedron Lett. 2002, 43, 8707.

J. Org. Chem, Vol. 68, No. 11, 2003 4241

Greatrex et al. SCHEME 6a

SCHEME 7

The relative stereochemistry between C3 and C7 in 17a was found to be R,S as determined by X-ray crystallographic structure analysis.13 The minor isomer 17b when converted to its O-benzoyl derivative 18 also afforded crystals suitable for X-ray analysis and again allowed for confirmation of assignment.14 The reaction of 14j afforded only a single isolable product, 19, with undefined stereochemistry at the methyl R to the ring. Small singlets at δ 5.8 in the crude spectra indicated the presence of compounds of structure similar to that of 16; however, these could not be isolated. Thus, 2-methyl substitution in the trans-enone did not significantly affect the reaction outcome as enones still afforded THFs with contiguous large groups trans. Tetrahydrofurans 6a-c,f-g were assigned on the basis of COSY, ROESY, HMBC, and HMQC 2D NMR spectra. A typical ROESY spectra for 6b (C6D6) showed crosspeaks between the protons attached to C6 (δ 3.61) and C7 (δ 2.72) and the proton at C4 (δ 4.15) as well as between protons on C7 (δ 2.72) and that on C2 (δ 3.98), confirming the trans relationship of contiguous groups about the ring. THF 6a has previously been reported in the reduction of trans-1,2-dibenzoylethylene with aluminum isopropoxide; however, in this study the stereochemistry of the side chain was not determined.15 The stereochemistry of the C6 hydroxyl center for THF 6 was found by conversion of 6b to its corresponding acetate 10b and X-ray crystallographic structure determination, Figure 2 in the Supporting Information. Tetrahydrofurans 7a-c,f also showed characteristic splitting patterns and cross-peaks in their 2D NMR spectra. Specifically, the ROESY spectra for 7a showed cross-peaks between the proton attached to C6 (δ 4.88) and those at C4 (δ 4.48) and C3 (δ 3.14) as well as between the protons on C7 (δ 2.84, 3.24) and that on C2 (δ 5.12). Further support for the structural assignment came by conversion of 7a to the corresponding acetate 11a and X-ray crystallographic structure determination, Figure 3 in the Supporting Information. When both the hydroxyl and adjacent ketone moieties were on the same face of the THF as in the case of 8, the

molecule existed in its isomeric furanol form 20 as evidenced by a hemiketal signal in the 13C NMR spectra, δ 100-110 ppm, Scheme 7. Only a single cyclic furanol isomer was visible in the NMR spectra for all THFs 8 synthesized. The relative stereochemistry between the hemiketal carbon and adjacent tertiary center was found to be S,S on the basis of 2D 1H NMR. The alternative R,S isomer does not form, presumably due to steric crowding between the large Ph or tert-butyl groups and the THF ring. The cyclization of THF 8b to its furanol allowed for the determination of the relative stereochemistry of C6-C6a, the only furanol isolated which contained a stereogenic center at C6. THF 8b was assigned as having R,S relative stereochemistry at C6-C6a, which is different from that found for all other THFs. These furanol compounds were found to be very acid sensitive and although stable in the solid state decomposed quickly when dissolved in CDCl3 due to trace acid. Their spectra were therefore more readily obtained in either d6-acetone or d6-benzene. Mechanism for the Formation of THFs. With a broad range of THFs produced under a range of experimental conditions from a range of isomeric starting materials, it was now possible to propose a mechanism for their formation, Scheme 8. Thus, when starting from 1,2-dioxines of type 2, initial ring opening by the base affords the cis-γ-hydroxyenones 1. 1,4-Addition of the hydroxide to the cis-enone followed by rotation about the C2-C3 axis followed by elimination establishes an equilibrium between the cis- and trans-enones. Once the equilibrium has been established, there exist two possible reaction pathways. Pathway 1 involves the cis-enone as the initial conjugate acceptor. Pathway 2, represented in Scheme 8, involves the trans-enone as the initial conjugate acceptor. The relative stereochemistry between C5 and C6 is established in the initial hetero-Michael addition, and this is governed by the conformation of the conjugate acceptor. As R,R relative stereochemistry is found in the major product, pathway 2 is the more dominant pathway in operation on the basis of previous observations of the selectivity of nucleophilic additions to cis-enones.6 Consideration must also be given to whether it is the cis- or trans-enone that acts as the initial nucleophile.16 To determine this, the intramolecular ring closure must be examined. The intramolecular cyclization of enolates onto conjugate acceptors, giving rise to cyclopentanoid or tetrahydrofuranoid products, has been rationalized by invoking secondary orbital interactions.17 It is easiest to consider the unsubstituted case of 14c, for which all possible cyclic transition states leading to the observed

(13) Greatrex, B W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. Z. Krystallogr., in press. (14) Greatrex, B W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. Z. Krystallogr., in press. (15) Inamura, Y. Nippon Kagaku Kaishi 1974, 2011.

(16) For examples of hetero-Michael addition to enones, see: (a) Betancort, J. M.; Martı´n. V. S.; Padro´n, J. M.; Palazo´n, J. M.; Ramı´rez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570. (b) Ramı´rez, M. A.; V. S.; Padro´n, J. M.; Palazo´n, J. M.; Martı´n. V. S. J. Org. Chem. 1997, 62, 4584.

a

Key: (a) LiOH; (b) BzCl, pyridine/CH2Cl2.

4242 J. Org. Chem., Vol. 68, No. 11, 2003

Synthesis of Functionalized Tetrahydrofurans SCHEME 8

products are drawn, Figure 1. Thus, if the nucleophile were the trans-enone, then the dominant interaction for cyclization proceeding through chair transition state 22a to give 6 would involve the HOMO of the enolate and the LUMO of the unsaturated ketone carbonyl.18 If the nucleophile were the cis-enone, then a cyclic transition state giving rise to the donor and acceptor being trans would not be obtainable. Furthermore, the only possible cyclic transition state involving the cis-enone as the nucleophile 22d appears highly congested. Thus, if the reaction does indeed involve cyclic transition states, then the initial nucleophile must be the trans-γ-hydroxyenone. Thus, the trans-enone appears to be the key intermediate in this reaction sequence.19 When 1 contains a stereogenic center and is racemic, as is the case when starting from 2a,b and 14a, there exist two possibilities for the initial heteroconjugate addition; these are the homochiral and heterochiral combinations yielding the two intermediates 21a and 21b, respectively, Scheme 8. The heterochiral combination of enones affords only the observed major isomers 6a,b with all contiguous groups trans. For the homochiral combination, the Michael ring closure yields 7 or 8 with poor selectivity. Conclusions In summary, a novel synthesis of highly substituted tetrahydrofuran building blocks has been described starting either from trans-γ-hydroxyenones derived from stabilized phosphorus ylides and R-hydroxy aldehydes or from 1,2-dioxines. The discovery that the trans-enone and not the cis-enone is the key intermediate in this reaction is significant as it may be conveniently generated from

FIGURE 1. Cyclic transition states leading to THFs for transenone 14c.

a variety of starting materials and is appreciably more stable than the isomeric cis-enone. Further reactions involving the addition of oxygen nucleophiles to cis- and trans-γ-hydroxyenones are under development.

Experimental Section General Procedure for the Synthesis of trans-γHydroxyenones 14. To a solution of the appropriate stabilized ylide (3.6 mmol) in THF (15 mL) was added glycoaldehyde dimer (180 mg, 3 mmol), and the resulting solution was heated under reflux for 3 h. The solution was cooled and the solvent evaporated in vacuo. The product was purified by chromatography (Florisil, 1:1 hexane/ethyl acetate) and was used immediately. Decomposition of the trans-γ-hydroxyenones to the corresponding furan was especially rapid in CDCl3 due to trace acid. (E)-1-(4-Bromophenyl)-4-hydroxy-2-buten-1-one (14f): white solid; mp 77-79 °C; Rf 0.58 (40:60 hexane/ethyl acetate); IR (Nujol) 3427, 1665, 1614, 1586, 1302, 1012, 794 cm-1; 1H NMR (200 MHz, d6-acetone) δ 2.96 (br s, 1H), 4.37-4.39 (m, 2H), 7.13 (ddd, J ) 15.4, 3.2, 1.4 Hz, 1H), 7.25 (ddd, J ) 15.4, 1.6, 1.6 Hz, 1H), 7.69-7.75 (m, 2H), 7.88-7.94 (m, 2H); 13C NMR (d6-acetone, 50 MHz) δ 61.4, 122.7, 127.2, 130.3, 131.9, 137.0, 149.4, 188.6; MS (EI) m/z (rel intens) 242 (M+, 81Br, 20), 240 (M+, 79Br, 20), 213 (81Br, 40), 211 (79Br, 40), 185 (81Br, 100), 183 (79Br, 100). (E)-4-Hydroxy-2-methyl-1-phenyl-2-buten-1-one (14i): colorless oil; Rf 0.17 (1:1 hexane/ethyl acetate); IR (neat) 3429, 3058, 2925, 1644, 1597, 1446, 1332, 1267, 1014 cm-1; 1H NMR (d6-acetone, 200 MHz) δ 1.88 (dt, J ) 1.2, 1.2 Hz, 3H), 4.14 (t, J ) 5.5 Hz, D2O exch, 1H), 4.39 (ddq, J ) 5.5, 5.5, 1.2 Hz, 2H), 6.33 (tq, J ) 5.5, 1.2 Hz, 1H), 7.42-7.69 (m, 5H); 13C NMR (50 MHz, d6-acetone) δ 12.5, 59.8, 128.9, 129.9, 132.2, 135.9, 139.3, 146.3, 198.3. (E)-5-Hydroxy-3-methyl-3-penten-2-one (14j): colorless oil; Rf 0.42 (40:60 hexane/ethyl acetate); IR (neat) 3420, 2929, 1670, 1652, 1436, 1362, 1026 cm-1; 1H NMR (d6-acetone, 200 MHz) δ 1.66 (dt, J ) 1.0, 1.0 Hz, 3H), 2.62 (s, 3H), 4.14 (br s, 1H), 4.30-4.40 (br m, 2H), 6.71 (tq, J ) 5.6, 1.4 Hz, 1H); 13C NMR (50 MHz, d6-acetone) δ 11.6, 25.3, 59.9, 136.6, 144.0, 199.0. General Procedure for the Synthesis of THFs from 1,2-Dioxine Precursors. To 3,6-diphenyl-3,6-dihydro-1,2(17) (a) Sevin, A.; Tortaja, J.; Pfau, M. J. Org. Chem. 1985, 51, 2671. (b) Bunce, R. A.; Dowdy, E. D.; Jones, P. B.; Holt, E. M. J. Org. Chem. 1993, 58, 7143. (c) Bunce, R. A.; Dowdy, E. D.; Childress, S.; Jones, P. B. J. Org. Chem. 1998, 63, 144. (18) (a) See ref 17. (b) d’Angelo, J.; Guinant, A. Tetrahedron Lett. 1988, 29, 2667. (c) Dumas, F.; d’Angelo, J. Tetrahedron: Asymmetry 1990, 1, 167. (19) (a) See ref 6a. (b) Friedrich, L. E.; Cormier, R. A. J. Org. Chem. 1971, 36, 3011. (c) Coxon, J. M.; Hii. G. S. C. Aust. J. Chem. 1977, 30, 161.

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Greatrex et al. dioxine (2a) (238 mg, 1 mmol) in THF (5 mL) was added lithium hydroxide (23 mg, 1 mmol), and the resulting suspension was stirred for 16 h. The mixture was evaporated, and the products were separated by flash chromatography (60:40 hexane/ethyl acetate) to afford the following compounds. (()-2-{(2S,3S,4S,5S)-4-Benzoyl-5-[(S)-1-hydroxy-1phenylmethyl]-2-phenyltetrahydro-3-furanyl}-1-phenyl1-ethanone (6a): white solid; mp 150-152 °C; Rf 0.38 (60:40 hexane/ethyl acetate); IR (Nujol) 3411, 1683, 1667, 1043 cm-1; 1 H NMR (600 MHz) δ 2.89 (d, J ) 3.0 Hz, 1H), 3.00-3.07 (m, 2H), 3.15-3.19 (m, 1H), 4.11 (dd, J ) 8.4, 6.6 Hz, 1H), 4.69 (dd, J ) 7.2, 6.6 Hz, 1H), 4.78 (dd, J ) 7.2, 3.0 Hz, 1H), 4.96 (d, J ) 3.6 Hz, 1H), 7.12-7.37 (m, 13H), 7.44-7.48 (m, 5H), 7.59-7.61 (m, 2H); 13C NMR (150 MHz) δ 38.1, 50.1, 53.1, 75.6, 85.6, 87.4, 127.2, 127.5, 127.8, 128.1, 128.2, 128.4, 128.5, 128.5, 128.6, 132.7, 133.2, 136.5, 136.9, 138.9, 139.5, 197.9, 199.7 (1 masked aromatic); MS (EI) m/z (rel intens) 477 (M+, 5), 459 (25), 369 (80), 221 (100). 6a was converted to its acetate 10a for comparison with literature data. 6a (36 mg, 0.075 mmol) was dissolved in dichloromethane (1 mL), and acetyl chloride (12 mg, 0.15 mmol) was added. Pyridine (1 drop) was added and the reaction left to stir overnight. Evaporation of the volatiles in vacuo, purification by flash chromatography, and then recrystallization from hot hexane afforded a white solid (14 mg, 36%): mp 190-192 °C (lit.14 mp 193-194 °C). The spectral data were consistent with those reported. (()-2-{(2S,3S,4R,5R)-4-Benzoyl-5-[(R)-1-hydroxy-1phenylmethyl]-2-phenyltetrahydro-3-furanyl}-1-phenyl1-ethanone (7a): white solid; mp 140-142 °C; Rf 0.56 (60:40 hexane/ethyl acetate); IR (Nujol) 1681, 1672, 1237, 1047, 1023 cm-1; 1H NMR (600 MHz) δ 2.84 (dd, J ) 18.0, 4.2 Hz, 1H), 3.06 (br s, 1H), 3.10-3.16 (m, 1H), 3.24 (dd, J ) 18.0, 10.2 Hz, 1H), 4.48 (dd, J ) 7.8, 4.8 Hz, 1H), 4.51 (dd, J ) 7.8, 4.8 Hz, 1H), 4.88 (d, J ) 7.8 Hz, 1H), 5.12 (d, J ) 9.6 Hz, 1H), 7.12-7.58 (m, 18H), 7.58-7.60 (m, 2H); 13C NMR (75 MHz) δ 35.8, 46.7, 49.0, 77.2, 77.3, 86.4, 126.9, 127.5, 127.6, 128.2, 128.2, 128.3, 128.4, 128.6, 128.7, 133.0, 136.4, 136.6, 139.5, 139.7, 198.3, 201.2 (2 masked aromatic); MS (EI) m/z (rel intens) 477 (M+, 10), 459 (40), 440 (30), 369 (95), 105 (100). Anal. Calcd for C32H28O4: C, 80.65; H, 5.92. Found: C, 80.21; H, 5.98. 7a (81 mg, 0.17 mmol) was converted to its corresponding acetate for X-ray diffraction studies as per 6a to give 11a as colorless crystals (46 mg, 52%): mp 184-186 °C; Rf 0.30 (80:20 hexane/ethyl acetate); IR (Nujol) 1743, 1670, 1591, 1576, 1232, 1207 cm-1; 1H NMR (300 MHz) δ 2.08 (s, 3H), 2.81 (dd, J ) 17.7, 7.2 Hz, 1H), 3.03 (dddd, J ) 10.2, 7.2, 8.7, 4.5 Hz, 1H), 3.12 (dd, J ) 17.7, 10.2 Hz, 1H), 4.44 (dd, J ) 8.4, 5.4 Hz, 1H), 4.78 (dd, J ) 6.0, 6.0 Hz, 1H), 5.02 (d, J ) 8.7 Hz, 1H), 6.09 (d, J ) 6.9 Hz, 1H), 7.16-7.57 (m, 20H); 13C NMR (75 MHz) δ 21.1, 35.8, 47.1, 49.1, 77.3, 83.7, 86.1, 126.9, 127.5, 127.8, 128.2, 128.3, 128.5, 133.0, 133.1, 136.4, 136.8, 136.8, 139.8, 170.1, 198.2, 201.4; MS (EI) m/z (rel intens) 518 (M+, 5), 517 (10), 501 (30), 440 (50), 369 (100). Anal. Calcd for C34H30O5: C, 78.74; H, 5.83. Found: C, 78.72; H, 5.85. (()-2-{(2S,3R,4R,5R)-4-Benzoyl-5-[(1R)-1-hydroxyethyl]2-methyltetrahydro-3-furanyl}-1-phenyl-1-ethanone (6b): colorless oil; Rf 0.21 (60:40 hexane/ethyl acetate); IR (neat) 3468, 2973, 1681, 1596, 1448, 1366, 1265, 1214, 1074 cm-1; 1 H NMR (600 MHz, C6D6) δ 1.07 (d, J ) 6.0 Hz, 3H), 1.35 (d, J ) 6.6 Hz, 3H), 1.80-2.20 (br s, 1H), 2.72-2.73 (m, 2H), 3.16 (dddd, J ) 8.4, 7.6, 6.8, 6.8 Hz, 1H), 3.61 (dq, J ) 6.6, 3.3 Hz, 1H), 3.98 (dq, J ) 7.6, 6.0 Hz, 1H), 4.15 (dd, J ) 8.2, 8.4 Hz, 1H), 4.23 (dd, J ) 8.2, 3.3 Hz, 1H), 7.01-7.13 (m, 6H), 7.677.69 (m, 2H), 8.12-8.14 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 19.8, 19.9, 40.5, 48.2, 54.1, 68.1, 80.8, 85.7, 127.9, 128.4, 128.5, 128.6, 133.2, 133.3, 136.5, 137.4, 198.1, 200.0; MS (EI) m/z (rel intens) 353 (M+, 8), 335 (10), 307 (20),159 (100). 6b was converted to its acetate 10b for X-ray diffraction studies. 6b (83 mg, 0.23 mmol) was treated as per 6a to give colorless crystals of 10b (69 mg, 74%): mp 99-101 °C (CH3CN/H2O); Rf 0.38 (60:40 hexane/ethyl acetate); IR (Nujol) 1741, 1683, 1667, 1596, 1246, 1216 cm-1; 1H NMR (300 MHz, C6D6) δ 1.21

4244 J. Org. Chem., Vol. 68, No. 11, 2003

(d, J ) 6.6 Hz, 3H), 1.36 (d, J ) 6.0 Hz, 3H), 2.00 (s, 3H), 2.85 (dddd, J ) 8.5, 8.2, 7.4, 5.8 Hz,1H), 3.05 (dd, J ) 16.7, 7.4 Hz, 1H), 3.16 (dd, J ) 16.7, 5.8 Hz, 1H), 3.89 (dd, J ) 6.6, 8.5 Hz, 1H), 4.09 (dq, J ) 8.2, 6.0 Hz, 1H), 4.28 (dd, J ) 7.2, 4.7 Hz, 1H), 5.00 (dq, J ) 6.6, 4.7 Hz, 1H), 7.37-7.45 (m, 4H), 7.517.56 (m, 2H), 7.75-7.79 (m, 2H), 7.88-7.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 16.1, 19.3, 21.1, 39.9, 48.2, 53.8, 70.9, 80.7, 83.2, 127.9, 128.3, 128.6, 128.7, 131.1, 133.2, 136.6, 137.2, 170.3, 198.0, 199.8; MS (EI) m/z (rel intens) 395 (MH+, 10), 335 (10), 159 (95), 105 (100). Anal. Calcd for C24H26O5: C, 73.07; H, 6.64. Found: C, 72.93; H, 6.77. (()-2-[(2R,3S,3aS,4S,6S,6aR)-4-Hydroxy-2,6-dimethyl4-phenylperhydrofuro[3,4-b]furan-3-yl]-1-phenyl-1-ethanone (8b): white solid; mp 148-150 °C; Rf 0.50 (60:40 hexane/ ethyl acetate); IR (neat) 3368, 2924, 1673, 1595, 1320, 1267 cm-1; 1H NMR (600 MHz) δ 0.95 (d, J ) 6.0 Hz, 3H), 1.33 (d, J ) 6.6 Hz, 3H), 1.59 (dddd, J ) 9.6, 9.2, 8.2, 3.6 Hz, 1H), 2.43 (dd, J ) 15, 9.6 Hz, 1H), 2.71 (s, 1H), 2.74 (dd, J ) 15, 3.6 Hz, 1H), 2.89 (dd, J ) 8.2, 7.6 Hz, 1H), 3.64 (dq, J ) 9.2, 6.0 Hz, 1H), 4.36 (dq, J ) 6.6, 4.8 Hz, 1H), 4.58 (dd, J ) 7.6, 4.8 Hz, 1H), 7.01-7.13 (m, 6H), 7.67-7.69 (m, 2H), 8.12-8.14 (m, 2H); 13C NMR (150 MHz) δ 13.75, 18.6, 40.8, 46.3, 62.1, 75.3, 81.2, 83.2, 106.2, 126.8, 128.0, 128.3, 128.4, 128.5, 132.9, 136.3, 140.8, 198.7; MS (EI) m/z (rel intens) 335 (MH+ - H2O, 8), 316 (15), 290 (20), 105 (100). Anal. Calcd for C22H24O4: C, 74.97; H, 6.86. Found: C, 74.72; H, 6.70. (()-2-{(2R,3R,4R,5R)-4-Benzoyl-5-[1-hydroxyethyl]-2methyltetrahydro-3-furanyl}-1-phenyl-1-ethanone (9b): isolated as a 75:25 mixture together with an unidentified isomer not separable by chromatography; colorless oil; Rf 0.33 (60:40 hexane/ethyl acetate); 1H NMR (300 MHz, C6D6) δ 1.00 (d, J ) 6.6 Hz, 3H), 1.02 (d, J ) 6.6 Hz, 3H), 2.00 (br d, J ) 7.5 Hz, 1H), 2.74-2.90 (m, 2H), 3.44 (dq, J ) 6.6, 5.7 Hz, 1H), 3.56 (br m, 1H), 3.99-4.06 (m, 2H), 4.56 (dq, J ) 8.4, 6.6 Hz, 1H) 6.89-7.16 (m, 6H), 7.73-7.76 (m, 2H), 8.13-8.17 (m, 2H); 13 C NMR (150 MHz) δ 16.7, 20.3, 38.1, 43.6, 52.8, 67.7, 76.8, 85.9, 127.9, 128.5, 128.5, 128.7, 133.2, 133.4, 136.6, 137.2, 198.4, 200.7; MS (EI) m/z (rel intens) 334 (MH+ - H2O, 20), 307 (30), 159 (90), 105 (100). 9b (46 mg, 0.19 mmol) was converted to its corresponding acetate 12b as per 6a to give a colorless oil as a single isomer (38 mg, 75%): IR (neat) 2980, 1732, 1682, 1597, 1448, 1372, 1242 cm-1; 1H NMR (600 MHz, C6D6) δ 1.24 (d, J ) 6.0 Hz, 3H), 1.25 (d, J ) 6.0 Hz, 3H), 1.91 (s, 3H), 3.00 (dd, J ) 16.8, 8.4 Hz, 1H), 3.06-3.10 (m, 1H), 3.30 (dd, J ) 16.8, 6.0 Hz, 1H), 3.75 (dd, J ) 6.6, 4.2 Hz, 1H), 4.17 (dd, J ) 7.2, 4.2 Hz, 1H), 7.41-7.47 (m, 4H) 7.53-7.58 (m, 2H), 7.87-7.89 (m, 4H); LSIMS m/z (rel intens) 395 (MH+, 90), 393 (100), 377 (20), 215 (90); HRMS m/z calcd for 12b (+H) C24H27O5 395.1858, found 395.1864. (()-2-[(3S,4S,5S)-4-Benzoyl-5-(hydroxymethyl)tetrahydro-3-furanyl]-1-phenyl-1-ethanone (6c): colorless oil; Rf 0.30 (50:50 hexane/ethyl acetate); IR (neat) 3459, 2874, 1681, 1596, 1448, 1213 cm-1; 1H NMR (600 MHz) δ 2.21 (br s, 1H), 3.17 (dd, J ) 17.4, 8.4 Hz, 1H), 3.1 (dd, J ) 17.4, 6.0 Hz, 1H), 3.35 (m, 1H), 3.57 (br d, J ) 12.0 Hz, 1H), 3.78 (dd, J ) 9.0, 5.4 Hz, 1H), 3.86 (dd, J ) 12.0, 3.0 Hz, 1H), 3.96 (dd, J ) 7.8, 6.6 Hz, 1H), 4.14 (ddd, J ) 8.4, 3.0, 3.0 Hz, 1H), 4.30 (dd, 8.4, 7.2 Hz, 1H), 7.40-7.43 (m, 2H), 7.46-7.49 (m, 2H), 7.527.55 (m, 1H), 7.57-7.60 (m, 1H), 7.86-7.87 (m, 2H), 7.998.01 (m, 2H); 13C NMR (150 MHz) δ 40.7, 41.9, 52.1, 62.3, 73.6, 83.5, 127.9, 128.5, 128.6, 128.8, 133.2, 133.5, 136.4, 137.1, 198.2, 199.9; MS (EI) m/z (rel intens) 325 (MH+, 15), 305 (20), 145 (40), 105 (100); HRMS m/z calcd for 6c (+H) C20H21O4 325.1439, found 325.1434. (()-2-[(3S,4R,5R)-4-Benzoyl-5-(hydroxymethyl)tetrahydro-3-furanyl]-1-phenyl-1-ethanone (7c): colorless oil; Rf 0.29 (ethyl acetate); IR (neat) 3402, 2918, 1680, 1596, 1448, 1379, 1219 cm-1; 1H NMR (600 MHz) δ 1.90 (br s, 1H), 2.88 (dd, J ) 17.9, 5.1 Hz, 1H), 3.11 (dd, J ) 17.9, 9.7 Hz, 1H), 3.37 (m, 1H), 3.62 (dd, J ) 11.9, 4.0 Hz, 1H), 3.77 (dd, J ) 8.9, 5.5 Hz, 1H), 3.87 (dd, J ) 11.9, 3.6 Hz, 1H), 4,29 (dd, J ) 8.1, 8.1 Hz, 1H), 4.33 (dd, J ) 8.7, 6.2 Hz, 1H), 4.54 (ddd, J )

Synthesis of Functionalized Tetrahydrofurans 8.1, 4.0, 3.6 Hz, 1H), 7.36-7.58 (m, 6H), 7.76-7.77 (m, 2H), 7.98-8.00 (m, 2H); 13C NMR (150 MHz) δ 37.6, 39.1, 49.3, 63.3, 74.2, 81.1, 127.8, 128.3, 128.5, 128.8, 133.2, 133.7, 136.5, 137.0, 198.2, 199.6; MS (EI) m/z (rel intens) 325 (MH+, 15), 305 (20), 145 (40),105 (100); HRMS m/z calcd for 7c (+H) C20H21O4 325.1439, found 325.1449. (()-2-[(3R,3aR,4R,6aS)-4-Hydroxy-4-phenylperhydrofuro[3,4-b]furan-3-yl]-1-phenyl-1-ethanone (8c). Although stable as a solid, 8c slowly decomposed in CDCl3 solution: white solid; mp 134-135 °C; Rf 0.50 (ethyl acetate); IR (Nujol) 3384, 1678, 1596, 1265, 1228 cm-1; 1H NMR (600 MHz) δ 2.08 (ddddd, 1H), 2.53 (s, 1H), 2.59 (dd, J ) 16.2, 10.2 Hz, 1H), 2.80 (dd, J ) 16.2, 5.1 Hz, 1H), 2.80 (dd, J ) 6.6, 6.6 Hz, 1H), 3.36 (dd, J ) 9.0, 6.6 Hz, 1H), 3.62 (dd, J ) 9.0, 6.0 Hz, 1H), 4.12 (d, J ) 10.2 Hz, 1H), 4.27 (dd, J ) 10.2, 4.5 Hz, 1H), 4.88 (dd, J ) 6.6, 4.5 Hz, 1H), 7.32-7.54 (m, 8H), 7.65-7.68 (m, 2H); 13C NMR (150 MHz) δ 39.5, 41.2, 59.9, 72.4, 73.5, 83.5, 107.8, 126.5, 127.9, 128.3, 128.5, 128.6, 128.9, 133.0, 140.6, 189.5; MS (EI) m/z (rel intens) 306 (M+ - H2O, 5), 288 (20), 168 (10), 105 (100). Anal. Calcd for C20H20O4: C, 74.05; H, 6.21. Found: C, 73.80; H, 6.21. (()-2-[(3S,4S,5S)-4-(4-Bromobenzoyl)-5-(hydroxymethyl)tetrahydro-3-furanyl]-1-(4-bromophenyl)-1-ethanone (6f): white solid; mp 63-65 °C; Rf 0.57 (40:60 hexane/ ethyl acetate); IR (Nujol) 3445, 2955, 2871, 1681, 1674, 1584, 1397, 1070, 1007 cm-1; 1H NMR (600 MHz) δ 3.13 (dd, J ) 17.0, 7.6 Hz, 1H), 3.18 (dd, J ) 17.0, 6.8 Hz, 1H), 3.31 (m, 1H), 3.52 (dd, J ) 3.1, 12.5 Hz, 1H), 3.77 (dd, J ) 9.0, 5.4 Hz, 1H), 3.87 (dd, J ) 12.5, 2.7 Hz, 1H), 3.89 (dd, J ) 8.0, 6.8 Hz, 1H), 4.08 (ddd, J ) 7.8, 3.2, 3.2 Hz, 1H), 4.29 (dd, J ) 8.8, 7.3 Hz, 1H), 7.56-7.63 (m, 4H), 7.71-7.73 (m, 2H), 7.84-7.87 (m, 2H); 13C NMR (75 MHz) δ 40.7, 41.9, 52.1, 62.1, 73.6, 83.7, 128.6, 128.9, 129.4, 130.0, 132.0, 132.1, 135.1, 135.8, 197.2, 198.9; MS (EI) m/z (rel intens) 465 (MH+ - H2O - H2, 2 × 81Br, 5), 463 (MH+ - H2O - H2,79Br, 81Br, 10), 461 (MH+ - H2O - H2, 2 × 79Br, 5), 225 (81Br, 20), 223 (79Br, 20), 185 (81Br, 100), 183 (79Br, 100). (()-2-[(3S,4R,5R)-4-(4-Bromobenzoyl)-5-(hydroxymethyl)tetrahydro-3-furanyl]-1-(4-bromophenyl)-1-ethanone (7f): colorless solid; mp 130-132 °C; Rf 0.55 (40:60 hexane/ethyl acetate); IR (neat) 3442, 2931, 1681, 1584, 1567, 1484, 1398, 1071, 732 cm-1; 1H NMR (600 MHz) δ 1.80-2.00 (br s, 1H), 2.95 (dd, J ) 18.0, 6.6 Hz, 1H), 3.03 (dd, J ) 18.0, 8.4 Hz, 1H), 3.30-3.36 (m, 1H), 3.59 (dd, J ) 12.0, 3.6 Hz, 1H), 3.76 (dd, J ) 8.4, 6.0 Hz, 1H), 3.85 (dd, J ) 12.0, 3.6 Hz, 1H), 4.27 (dd, J ) 8.4, 8.4 Hz, 1H), 4.30 (dd, J ) 8.4, 6.0 Hz, 1H), 4.46 (ddd, J ) 8.4, 3.6, 3.6 Hz, 1H); 13C NMR (150 MHz) δ 37.5, 39.1, 49.0, 63.2, 74.2, 81.5, 128.5, 129.1, 129.3, 129.8, 131.8, 132.1, 135.1, 135.7; MS (EI) m/z (rel intens) 464 (M+ H2O - H2, 2 × 81Br, 5), 462 (M+ - H2O - H2, 79Br, 81Br, 10), 460 (M+ - H2O - H2, 2 × 79Br, 5), 453 (2 × 81Br, 5), 451 (79Br, 81 Br, 10), 449 (2 × 79Br, 8), 225 (81Br, 25), 223 (79Br, 25), 185 (81Br, 100), 183 (79Br, 100); HRMS m/z calcd for 7f (-H2O H2) C20H14O3Br2 459.9310, found 459.9278. (()-2-[(3S,3aS,4S,6aR)-4-Hydroxy-4-(4-bromophenyl)perhydrofuro[3,4-b]furan-3-yl]-1-(4-bromophenyl)-1-ethanone (8f): white solid; mp 149.5-155 °C; Rf 0.69 (40:60 hexane/ethyl acetate); IR (Nujol) 3353, 1683, 1584, 1068, 1008, 975 cm-1; 1H NMR (300 MHz, d6-acetone) δ 1.90-2.00 (m, 1H), 2.75-2.90 (m, 2H), 3.28 (dd, J ) 8.4, 6.3 Hz, H), 3.83 (dd, J ) 8.7, 6.3 Hz, 1H), 3.95 (d, J ) 9.9 Hz, 1H), 4.18 (dd, J ) 9.9, 4.5 Hz, 1H), 4.81 (dd, J ) 6.9, 4.5 Hz, 1H), 7.49-7.65 (m, 8H); MS (EI) m/z (rel intens) 465 (MH+ - H2O - H2, 2 × 81Br, 15), 463 (MH+ - H2O - H2, 79Br, 81Br, 20), 461 (MH+ - H2O - H2, 2 × 79Br, 10), 225 (81Br, 20), 223 (79Br, 20), 185 (81Br, 100), 183 (79Br, 100). Anal. Calcd for C20H18O4Br2: C, 49.82; H, 3.76. Found: C, 49.76; H, 3.62. (()-1-[(3S,4S,5S)-4-(2,2-dimethylpropanoyl)-5(hydroxymethyl)tetrahydro-3-furanyl]-3,3-dimethyl-2butanone (6g): colorless oil; Rf 0.25 (60:40 hexane/ethyl acetate); IR (neat) 3454, 2968, 1702, 1479, 1367, 1067 cm-1; 1 H NMR (600 MHz) δ 1.12 (s, 9H), 1.15 (s, 9H), 2.19 (br s,

1H), 2.65-2.69 (m, 2H), 2.72-2.77 (m, 1H), 3.24 (dd, J ) 7.2, 4.8 Hz, 1H), 3.54-3.57 (br d, 1H), 3.99 (ddd, J ) 6.6, 3.6, 3.0 Hz, 1H), 4.11 (dd, J ) 6.8, 6.0 Hz, 1H); 13C NMR (150 MHz) δ 25.8, 26.2, 40.2, 42.0, 43.9, 44.7, 51.1, 62.5, 73.8, 84.3, 214.2, 216.4; MS (EI) m/z (rel intens) 285 (MH+, 10), 267 (100), 253 (10), 209 (20). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found: C, 67.83; H, 9.63. (()-1-[(3S,3aS,4S,6aR)-4-(tert-Butyl)-4-hydroxyperhydrofuro[3,4-b]furan-3-yl]-3,3-dimethyl-2-butanone (8g): colorless solid; mp 92-94 °C; Rf 0.55 (ethyl acetate); IR (Nujol) 3346, 1698, 1137, 1083, 997 cm-1; 1H NMR (600 MHz) δ 1.12 (s, 9H), 1.23 (s, 9H), 2.43 (s, 1H), 2.53 (dd, J ) 7.5, 1.2 Hz, 1H), 2.63-2.70 (m, 2H), 3.23-3.26 (m, 1H), 3.76 (d, J ) 8.4, 3.0 Hz, 1H), 4.04 (dd, J ) 9.6, 6.0 Hz, 1H), 4.13 (dd, J ) 9.6, 4.2 Hz, 1H), 4.62 (dd, J ) 9.0, 6.0 Hz, 1H), 4.65 (ddd, J ) 6.6, 6.6, 4.2 Hz, 1H); 13C NMR (75 MHz) δ 25.0, 26.1, 37.5, 38.5, 40.7, 43.8, 53.6, 70.9, 75.7, 83.5, 109.7, 213.0; MS (EI) m/z (rel intens) 285 (MH+, 5), 267 (80), 227 (15), 125 (40), 83 (100). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found: C, 67.48; H, 9.79. 1-[(2R,5S)-5-(3,3-Dimethyl-2-oxobutyl)-1,4-dioxan-2-yl]3,3-dimethyl-2-butanone (15): colorless solid; mp 125 °C (sublimes); Rf 0.77 (60:40 hexane/ethyl acetate); IR (Nujol) 1708, 1127, 1083, 1054 cm-1; 1H NMR (300 MHz) δ 1.12 (s, 9H), 2.32 (dd, J ) 17.4, 5.7 Hz, 1H), 2.78 (dd, J ) 17.4, 5.4 Hz, 1H), 3.33 (dd, J ) 11.4, 10.5 Hz, 1H), 3.79 (dd, J ) 11.4, 2.4 Hz, 1H), 3.99 (dddd, J ) 10.5, 5.7, 5.4, 2.4 Hz, 1H); 13C NMR (75 MHz) δ 26.0, 38.4, 44.2, 70.8, 71.0, 212.6; MS (EI) m/z (rel intens) 285 (MH+, trace), 143 (20), 125 (100), 57 (80), 41 (40). Anal. Calcd for C16H28O4: C, 67.57; H, 9.92. Found: C, 67.60; H, 9.66. (()-(3S,3aR,7aR)-3-(Hydroxymethyl)-6-methyl1,3,3a,4,7,7a-hexahydro-4-isobenzofuranone (16): colorless oil; Rf 0.48 (ethyl acetate); IR (neat) 3435, 2935, 1651, 1435, 1381, 1054 cm-1; 1H NMR (600 MHz) δ 1.99 (s, 3H), 2.31 (dd, J ) 18.6, 6.6 Hz, 1H), 2.43 (br s, 1H), 2.49 dd, J ) 18.6, 6.6, 1H), 2.76 (dd, J ) 7.2, 7.2 Hz, 1H), 2.89 (ddddd, J ) 7.2, 6.6, 6.6, 6.6, 6.6 Hz, 1H), 3.63-3.68 (m, 2H), 3.81 (br d, J ) 11.4 Hz, 1H), 3.99 (dd, J ) 8.1, 5.4 Hz, 1H), 4.14 (ddd, J ) 6.6, 4.8, 4.8 Hz, 1H), 5.96 (d, J ) 0.6 Hz, 1H); 13C NMR (150 MHz) δ 24.5, 30.5, 38.2, 49.1, 64.7, 72.9, 81.2, 125.5, 160.7, 197.6; MS (EI) m/z (rel intens) 183 (MH+, 40), 152 (40),152 (40), 69 (100); HRMS m/z calcd for 16 (+H) C10H15O3 183.1021, found 183.1020. (()-(2R)-2-[(3S,4S,5S)-4-Benzoyl-5-(hydroxymethyl)-4methyltetrahydro-3-furany l]-1-phenylpropan-1-one (17a): colorless solid; mp 102-104 °C; Rf 0.42 (1:1 hexane/ethyl acetate); IR (neat) 3394, 1673, 1248, 1051, 964, 723 cm-1; 1H NMR (600 MHz) δ 1.05 (d, J ) 7.2 Hz, 3H), 1.39 (s, 3H), 1.80 (br s, 1H), 3.44 (dd, J ) 9.6, 9.0 Hz, 1H), 3.53 (dq, J ) 10.2, 7.2 Hz, 1H), 3.64 (dd, J ) 12.0, 5.4 Hz, 1H), 3.76 (dd, J ) 12.0, 7.2 Hz, 1H), 3.83 (ddd, J ) 9.6, 9.6, 9.6 Hz, 1H), 4.26 (dd, J ) 8.4, 8.4 Hz, 1H), 4.61 (dd, J ) 6.6, 4.8 Hz, 1H), 7.43-7.51 (m, 5H), 7.56-7.58 (m, 1H), 7.78-7.80 (m, 2H), 7.89-7.90 (m, 2H); 13 C NMR (150 MHz) δ 12.1, 17.6, 40.7, 50.9, 58.2, 61.8, 71.0, 86.1, 128.2, 128.3, 128.4, 128.8, 131.4, 133.4, 135.7, 138.1, 202.0, 205.8; MS (EI) m/z (rel intens) 353 (MH+, trace), 321 (10), 238 (20), 201 (40), 105 (100). Anal. Calcd for C22H24O4: C, 74.97; H, 6.86. Found: C, 74.68; H, 7.14. (()-(2S)-2-[(3S,4S,5S)-4-Benzoyl-5-(hydroxymethyl)-4methyltetrahydro-3-furanyl ]-1-phenylpropan-1-one (17b): colorless oil; Rf 0.20 (ethyl acetate); IR (neat) 3455, 2976, 2878, 1681, 1596, 1251, 974, 733 cm-1; 1H NMR (600 MHz) δ 1.05 (s, 3H), 1.15 (d, J ) 7.2 Hz, 3H), 2.28 (br s, 1H), 3.53 (dd, J ) 12.0, 4.2 Hz, 1H), 3.56 (dq, J ) 10.2, 7.6 Hz, 1H), 3.67 (dd, J ) 12.0, 7.8 Hz, 1H), 3.76 (ddd, J ) 10.2, 9.6, 8.4 Hz, 1H), 3.85 (dd, J ) 9.6, 8.4 Hz, 1H), 4.34 (dd, J ) 8.4, 8.4 Hz, 1H), 4.60 (dd, J ) 7.2, 4.2 Hz, 1H), 7.38-7.46 (m, 5H), 7.55-7.57 (m, 1H), 7.84-7.85 (m, 2H), 7.89-7.91 (m, 2H); 13C NMR (150 MHz) δ 13.5, 18.1, 40.5, 50.1, 57.8, 61.7, 70.6, 86.4, 128.0, 128.2, 128.3, 128.7, 130.7, 133.3, 135.2, 138.1, 201.8, 204.3; MS (EI) m/z (rel intens) 353 (MH+, 15), 345 (15), 321 (50), 238

J. Org. Chem, Vol. 68, No. 11, 2003 4245

Greatrex et al. (55), 201 (55), 105 (100). 17b (40 mg, 0.11 mmol) was dissolved in CH2Cl2 (1 mL), then benzoyl chloride (31 mg, 0.22 mmol) and triethylamine (2 drops) were added, and the reaction was stirred for 3 h. The solvent was removed under reduced pressure and the residue purified by flash chromatography (dichloromethane) to give 18 as colorless crystals suitable for X-ray structure analysis (28 mg, 56%): mp 132-135 °C; Rf 0.11 (CH2Cl2); IR (Nujol) 1723, 1673, 1664, 1595, 1280, 1114, 971, 716 cm-1; 1H NMR (300 MHz) δ 1.17 (s, 3H), 1.19 (d, J ) 6.9 Hz, 3H), 3.64 (dq, J ) 9.6, 6.9 Hz, 1H), 3.85-4.01 (m, 2H), 4.27 (dd, J ) 11.4, 5.1 Hz, 1H), 4.44-4.52 (m, 2H), 4.98 (dd, J ) 7.5, 5.1 Hz, 1H), 7.35-7.60 (m, 9H), 7.85-7.95 (m, 6H); 13C NMR (75 MHz) δ 13.5, 18.2, 40.6, 50.2, 58.3, 63.5, 71.1, 83.7, 128.1, 128.2, 128.3, 128.3, 128.8, 129.6, 129.7, 130.9, 133.0, 133.3, 135.3, 137.8, 166.2, 201.7, 203.3; MS (EI) m/z (rel intens) 439 (MH+ - H2O, 10), 397 (20), 351 (20), 105 (100). Anal. Calcd for C29H28O5: C, 76.12; H, 6.38. Found: C, 76.14; H, 6.33. (()-2-[(3S,4S,5S)-4-Acetyl-5-(hydroxymethyl)-4-methyltetrahydro-3-furanyl]butan-2-one (19): colorless oil; Rf 0.50 (ethyl acetate); IR (neat) 3436, 2979, 2881, 1697, 1657, 1358, 1047 cm-1; 1H NMR (600 MHz) δ 0.98 (d, J ) 6.6 Hz, 3H), 1.13 (s, 3H), 2.13 (s, 3H), 2.29 (s, 3H), 2.51 (dd, J ) 10.4, 6.6

4246 J. Org. Chem., Vol. 68, No. 11, 2003

Hz, 1H), 3.17 (ddd, J ) 10.4, 9.6, 8.4 Hz, 1H), 3.39 (dd, J ) 9.6, 8.4 Hz, 1H), 3.52 (dd, J ) 11.4, 6.0 Hz, 1H), 3.71 (dd, J ) 11.4, 6.0 Hz, 1H), 4.14 (dd, J ) 6.6, 6.0 Hz, 1H), 4.71 (dd, J ) 8.4, 8.4 Hz, 1H); 13C NMR (150 MHz) δ 10.1, 15.8, 26.4, 28.2, 47.2, 49.3, 57.9, 61.4, 70.8, 85.7, 210.2, 210.7; MS (EI) m/z (rel intens) 229 (MH+, 20), 211 (10), 197 (10), 157 (20), 97 (100); HRMS m/z calcd for 19 (+H) C12H21O4 229.1439, found 229.1441.

Acknowledgment. B.W.G. thanks the Faculty of Science, University of Adelaide, for support in the form of a scholarship. We also thank the Australian Research Council for financial support and Prof. J. Bowie for helpful discussion involving mass spectrometry. Supporting Information Available: General experimental information, ORTEP diagrams of THFs 10b (Figure 2) and 11a (Figure 3), and general X-ray crystallography data for 10b and 11a. This material is available free of charge via the Internet at http://pubs.acs.org. JO020700H