Photochemical Access to Tetra-and Pentacyclic Terpene-like Products

Photochemical Access to Tetra- and Pentacyclic Terpene-like Products from R-(+)-Sclareolide Marı´a C. de la Torre* and Isabel Garcı´a Instituto de Quı´mica Orga´ nica, Consejo Superior de Investigaciones Cientı´ficas (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain

Miguel A. Sierra Departamento de Quı´mica Orga´ nica, Facultad de Quı´mica, Universidad Complutense, 28040-Madrid, Spain [email protected] Received February 7, 2003

Fused tetracyclic oxetanes 4, highly substituted cyclobutenes 6, and the pentacyclic derivatives 7 and 8 were obtained by irradiation of derivatives 3 that were prepared from commercial R-(+)sclareolide (1) in three steps. Compounds 4 are formed through a Paterno-Bu¨chi reaction, while tricyclic derivatives 6 are the fragmentation products of the first formed oxetanes. In clear contrast, cyclopentenyl and 3-furyl derivatives, 3e and 3f, gave the [2+2] adducts, namely pentacyclic derivatives 7 and 8. All the reported reactions are totally regio- and stereoselective, with the exception of the cyclization of furyl derivative 3f, which gave the mixture of both the crossed (7b) and the right (8) isomers. Introduction The [2+2] photochemical cycloaddition reactions (including the Paterno-Bu¨chi reaction) are powerful technologies for accessing complex, strained structures, incorporating four-membered rings, that are difficult to obtain by other means.1 While the intermolecular processes generally lack both regiocontrol and syn/anti stereocontrol, the intramolecular reactions usually proceed with high regio- and stereoselectivities. In this regard, [2+2] cycloadditions carried out in appropriate modified terpenes may open the way to new structures, considerably more complex than the starting material.2 It is noteworthy that the first example of a [2+2] photocycloaddition was reported when the formation of carvone camphor was observed upon exposure of carvone * To whom correspondence should be addressed. Fax: +34915644853. Phone: +34-915622900. (1) Both, the [2+2] photochemical cycloaddition reaction of alkenes and the Paterno-Bu¨chi reaction have been profusely reviewed. See for exemple: (a) Crimmins, M. T.; Reinhold, T. C. In Organic Reactions; Paquette, L. A., Ed.; John Wiley: New York, 1993; Vol. 44, pp 296588. (b) Winkler, J. D.; Mazur-Bowen, C.; Liotta, F. Chem. Rev. 1995, 95, 2003-2020. (c) Bach, T. Synthesis 1998, 683-703. (d) Crimmins, M. T. Chem. Rev. 1988, 88, 1453-1473. (e) Mattay, J. In Organic Photochemistry and Photobiology; Horspool, W. M., Song, P. S., Eds.; CRC Press: Boca Raton, FL, 1995; pp 618-633. (f) Mattay, J.; Conrads, R.; Hoffman, R. In Houbn-Weyl, 4th ed.; Helmchem, G., Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, Germany, 1995; Vol. E21c, pp 3085-3178. (g) Porco, J. A.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 5, pp 151-192. (h) Carless, H. A. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984; pp 425-487. (i) Jones, G., II In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1981; Vol. 5, pp 1-123. (2) Synthesis of small natural product-like molecules is an area of increasing interest. For an excellent discussion of this field see: Toogood, P. L. J. Med. Chem. 2001, 45, 2145-2149.

to sunlight.3 Since the cyclobutane ring is part of many natural products, [2+2] photocycloaddition reactions have been repeatedly and successfully employed in their synthesis. Pioneering applications are the preparation of caryophyllene by Corey,4 or the syntheses of bourbonenes by Heathcock,5 Yoshihara,6 or White.7 Approaches to the monoterpene grandisol rest on the photochemical construction of the cyclobutane ring,8 and the same is true for spatol and other related diterpenes.9 In addition, the variety of ring-opening products that can be derived from cyclobutanes make them very attractive as strained synthetic intermediates.10 Analogously, the PaternoBu¨chi reaction has been used in the synthesis of oxetane(3) Ciamician, G.; Silber, P. Chem. Ber. 1908, 41, 1928. (4) Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem Soc. 1964, 86, 485-492. (5) Heathcock, C. H.; Badger, R. A. J. Chem. Soc., Chem. Commun. 1968, 1510-1511. (6) Yoshihara, K.; Ohta, Y.; Sakai, T.; Hirose, Y. Tetrahedron Lett. 1969, 2263-2264. (7) (a) White, J. D.; Gupta, D. N. J. Am. Chem. Soc. 1966, 88, 53645365. (b) White, J. D.; Gupta, D. N. J. Am. Chem. Soc. 1968, 90, 61716177. (8) The syhthesis of grandisol has been accomplished by numerous groups, some of them are: (a) Meyers, A. I.; Fleming, S. A. J. Am. Chem. Soc. 1986, 108, 306-307. (b) Demuth, M.; Palomer, A.; Sluma, H.-D.; Dey, A. K.; Kru¨ger, C.; Tsay, Y.-H. Angew. Chem., Int. Ed. Engl. 1986, 25, 1117-1119. (c) Hoffman, N.; Scharf, H.-D. Liebigs Ann. Chem. 1991, 1273-1277. (9) (a) Salomon, R. G.; Sachinvala, N. D.; Raychaudhuri, S. R.; Miller, D. B. J. Am. Chem. Soc. 1984, 106, 2211-2213. (b) Salomon, R. G.; Sachinvala, N. D.; Roy, S.; Basu, B.; Raychaudhuri, S. R.; Miller, D. B.; Sharma, R. B. J. Am. Chem. Soc. 1991, 113, 3085-3095. (c) Salomon, R. G.; Basu, B.; Roy, S.; Sachinvala, N. D. J. Am. Chem. Soc. 1991, 113, 3096-3106. (10) (a) Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. Top. Curr. Chem. 1986, 133, 85-157. (b) Wong, H. N. C.; Fitjer, L.; Heushmann, M.; Mann, G.; Muchall, H. M. In Houben-Weyl, 4th ed.; de Mejiere, A. D., Ed.; Thieme: Stuttgart, Germany, 1997; Vol. E17e, pp 435-610.

10.1021/jo034177y CCC: $25.00 © 2003 American Chemical Society

Published on Web 07/22/2003

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containing natural products such as the nucleoside oxetanocin,11 thromboxane A2 analogues,12 or the D-ring of taxol.13 In our ongoing project devoted to the preparation of elaborated terpene-based compounds,14 we devised the use of the intramolecular [2+2] photocycloaddition to increase the complexity of readily available terpene substrates. Herein, we report the preparation of type A oxetanes, type B cyclobutenes, and fused polycyclic terpene-like natural products types C and D, in a regioand stereoselective fashion, by irradiation of derivatives E and F (Scheme 1).

SCHEME 2

SCHEME 1

SCHEME 3

Results and Discussion R-(+)-Sclareolide 1 was transformed into Weinreb’s amide 2 by sequential reaction with the dimethylaluminum amide derived from N-methoxy-N-methylamine followed by dehydration (Cl2SO/Py), according to our reported procedure (Scheme 2).14b The starting materials 3a-g, used to effect the intramolecular [2+2] photochemical cycloadditions, were prepared by reaction of amide 2 with the corresponding organolithium (3a-f)15 or organomagnesium reagents (3g). Yields were good to excellent in all cases tested (Scheme 2). Dry degassed acetonitrile solutions of compounds 3 were irradiated (quartz vessel, 450 W, medium-pressure Hg lamp) until the starting material was consumed (TLC). Irradiation of compounds 3a, 3b, and 3g was completed within less than 1 h. In these cases, a Paterno-Bu¨chi reaction involving the exocyclic double bond has occurred, leading to tetracyclic oxetanes 4a-c in excellent yields (Scheme 3).16 Compounds 4a-c show signals in their 1H NMR spectrum for an AB system (11) (a) Hambelek, R.; Just, G. Tetrahedron Lett. 1990, 31, 54455448. (b) Schreiber, S. L.; Desmaele, D.; Porco, J. A. TetrahedronLett. 1988, 29, 6689-6692. (c) Carless, H. A. J.; Halfhide, A. F. E. J. Chem. Soc., Perkin Trans. 1 1992, 1081-1082. (12) (a) Carless; H. A. J.; Fekarurhobo, G. K. J. Chem. Soc., Chem. Commun. 1984, 667-668. (b) Carless; H. A. J.; Fekarurhobo, G. K. Tetrahedron Lett. 1985, 26, 4407-4410. (13) Vasudevan, S.; Brock, C. P.; Watt, D. S.; Morita, H. J. Org. Chem. 1994, 59, 4677-4679. (14) (a) de la Torre, M. C.; Maggio, A.; Rodrı´guez, B. Tetrahedron 2000, 56, 8007-8017. (b) de la Torre, M. C.; Garcı´a, I.; Sierra, M. A. J. Nat. Prod. 2002, 65, 661-668. (c) de la Torre, M. C.; Garcı´a, I.; Sierra, M. A. Tetrahedron Lett. 2002, 43, 6351-6353. (15) (a) Kropp, P. I.; McNeely, S. A.; Davis, R. D. J. Am. Chem. Soc. 1983, 105, 6907-6915. (b) Barton, D. H.; O’Brien, R. E.; Sternhell, S. J. Chem. Soc. 1962, 470-475. (c) Pross, A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989-1003.

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attributable to the C-17 methylene protons in an oxetane ring.14a,17 Thus H-17 protons for compound 4c appear at (16) Although sensu estricto labdanes are those diterpenes isolated from natural sources, we have adopted for clarity and commodity the system numbering of the labdane diterpenoid backbone for the decaline framework of the compounds synthesized in this paper. See: Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids; Chapman and Hall: London, UK, 1991; Vol. 1.

Terpene-like Products from R-(+)-Sclareolide TABLE 1.

13C

NMR Data for Compounds 4a-c, 6a, 7a,

7b, and 8a carbon

4ab

TABLE 2. Relevant gHMBC Crossed Peaks for Compounds 4b, 4c, 6a, and 7aa

4bb

4cb

6ab t*

7ac

7bb,d

8b,d

t*

C-1 37.9 t 42.9 t 37.9 42.8 39.2 t 39.2 t 39.1 t C-2 18.0 t 18.4 t 18.0 t 19.5 t 18.0 t 17.9 t 18.0 t# C-3 42.6 t 42.3 t 42.6 t 43.0 t* 41.9 t 41.7 t 42.1 t C-4 33.3 s 33.1 s 33.3 s 33.6 s 34.9 s 32.9 s 33.2 s C-5 57.0 d 49.8 d 57.0 d 47.0 d 54.9 d 54.9 d 56.7 d* C-6 19.6 t 19.0 t 19.5 t 18.7 t 19.1 t 18.5 t 18.2 t# C-7 35.1 t* 27.1 t 34.7 t 25.2 t 35.3 t 35.6 t 36.4 t C-8 53.7 s 49.6 s 53.9 s 50.3 s 39.3 s 45.9 s 51.0 s C-9 49.4 d 51.6 d 49.3 d 56.7 d 54.3 d 50.6 d 56.6 d* C-10 37.6 s 34.2 s 37.6 s 36.2 s 38.5 s 38.4 s 37.5 s C-11 35.9 t* 37.2 t 35.5 t 126.8 d 35.4 t 32.4 t 36.4 t C-12 95.2 s 84.4 s 93.8 s 150.2 s 212.9 s 208.4 s 216.1 s C-1′ 32.4 t 76.2 s 37.8 t* 126.7 s 60.2 s 62.3 s 68.3 s C-2′ 28.1 t 88.2 s 132.6 d 126.6 d 56.0 d 102.9 d 96.8 d C-3′ 138.6 d 4.1 q 117.6 t 113.9 d 28.3 t 153.6 d 153.9 d C-4′ 114.3 t 159.2 s 26.8 t 92.5 d 81.3 d C-5′ 25.3 t OMe 55.3 q C-17 77.9 t 83.3 t 78.0 q 66.6 t 34.6 t 40.0 t 37.0 t C-18 33.4 q 33.6 q 33.4 q 32.9 q 33.6 q 33.6 q 33.4 q C-19 21.0 q 22.3 q 20.9 q 21.2 q 21.9 q 21.8 q 21.2 q C-20 15.8 q 17.9 q 15.8 q 19.1 q 13.7 q 13.7 q 14.6 q a Multiplicities were determined by DEPT experiments. Assignments were based on gHMQC and gHMBC experiments. Assignments with the same symbol, within the same column, may be interchanged. b Recorded at 50.3 MHz. c Recorded at 75.0 MHz. d Data taken from the mixture. Carbons C-1′ to C-4′ are C-13 to C-16.

5.42 and 4.27 ppm, coupled with a J value of 6.7 Hz, and the corresponding carbon C-17 resonates at 78.0 ppm, as expected for a carbon atom adjacent to oxygen (Table 1). These data exclude the formation of the crossed adducts such as 5 (Scheme 6, vide infra) in the photocycloaddition reactions, because structures such as 5 possess two quaternary centers instead of a methylene carbon vicinal to oxygen. Extensive 2D NMR experiments carried out on compounds 4b and 4c (Table 2) corroborate the tetracyclic oxetane structures of compounds 4. The stereochemistry of oxetanes 4a-c at carbon C-8 was established on the basis of nOe experiments. Selective irradiation of HB-17 for 4a and 4c produced a positive nOe increment on the signal corresponding to the axial C-20 methyl group at carbon C-10, and into the signal for HB-11. Accordingly, the C-17 methylene substituent has, in compounds 4a and 4c, a β configuration. Surprisingly, irradiation of HB-17 for compound 4b resulted in a positive nOe increment of the signal corresponding to proton H-9R. Thus, the C-17 methylene of 4b should be R oriented. Moreover, due to the high strain of the polycyclic system, the oxa-bicyclo[2.2.0]hexane can only adopt a cis arrangement.18 Therefore, the configuration of C-12 is related to the configuration of C-8. Thus for 4a and 4c the oxetane ring and Me-20 must be placed at the same side of the decaline plane, while for compound 4b the oxetane ring must have the opposite stereochemistry (Figure 1). (17) (a) Maltin, A. R.; Turk, B. E.; McGarvey, D. J.; Manevich, A. A. J. Org. Chem. 1992, 57, 4632-4638. (b) Srinivasan, R. J. Am. Chem. Soc. 1960, 82, 775-778. (c) Searless, S. In Comprehensive Hetrocyclic Chemistry; Lwowski, Ed.; Pergamon Press: New York, 1984; Vol. 7, Part 5, pp 363-402 and 366-367. (18) (a) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994; pp 771-794. (b) Wiberg, K. B.; Wendoloski, J. J. J. Am. Chem. Soc. 1982, 104, 56795686.

carbon

δH

4b C-2′ 88.2 s C-12 84.4 s C-1′ 76.2 s C-9 51.6 d 4c C-12 93.8 s

1.93 s (Me-3′) 4.64 d (HB-17), 2.66 dd (HB-11) 1.93 s (Me-3′) 4.64 and 4.34 d (2H-17), 0.98 s (Me-20)

5.82 ddt (H-2′), 5.42 d (HB-17), 4.27 d (HA-17), 2.56 t (HB-11), 2.40 dd (2H-1′) 57.0 d 1.03 s (Me-20), 0.80 s (Me-18), 0.75 s (Me-19) 132.6 d 5.09 ddd and 5.07 d (2H-3′), 2.40 dd (2H-1′)

C-5 C-2′ 6a C-12

150.2 s 3.77 overlapped (2H-17), 2.30 d (H-9R), 7.20 d (2H-2′) 126.8 d 2.30 d (H-9R) 66.6 t 2.30 d (H-9R) 56.7 d 6.25 d (H-11), 3.77 (2H-17), 0.93 s (Me-20)

C-11 C-17 C-9 7a C-12 C-1′ C-5 C-9 C-3 a

212.9 s 56.0 d 54.9 d 54.3 d 41.9 t

2.46 dd and 2.39 dd (2H-11), 2.12 dd (HB-17) 2.12 dd (HB-17) 0.90 s (Me-20), 0.85 s (Me-18), 0.81 s (Me-19) 2.46 dd and 2.39 dd (2H-11), 0.90 s (Me-20) 0.85 s (Me-18), 0.81 s (Me-19)

Spectra recorded at 400 MHz.

FIGURE 1. Main nOe increments for compounds 4 and 7.

A rather different behavior is observed in the irradiation of the p-anisyl and 2-furyl derivatives 3c and 3d, respectively. In both cases, a single compound was obtained in quantitative yield (Scheme 4). The 1H NMR and 13C NMR spectra (Table 1) of the products confirmed the disappearance of the keto group of the starting material as well as of the exocyclic double bond. However, in contrast with compounds 4a-c, the products arising from the irradiation of 3c and 3d lack the signals attributable to an oxetane ring. SCHEME 4

Extensive 2D-NMR experiments allowed us to propose structure 6a for the product resulting from the irradiation of the p-anisyl derivative 3c. Especially useful are the cross-peaks shown by the fully substituted carbon at J. Org. Chem, Vol. 68, No. 17, 2003 6613

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δC 150.2, assigned to C-12. This carbon correlates, in the gHMBC spectrum, with the protons for an isolated methylene group (δH 3.77, δC 66.6), attributed to C-17, with a methine proton on a sp3 carbon (δH 2.30, δC 47.9) assigned to C-9, and with the aromatic protons at δH 7.20 (Table 2). In addition, the COSY experiment revealed a coupling between H-9 (δH 2.30, J ) 1.1 Hz) and the signal at δH 6.25 (δC 126.8), assigned to H-11. The NMR, as well as the IR and the EIMS data are in complete agreement with structure 6a. The single product, derived from 2-furyl derivative 3d, was unstable but its 1H NMR was almost identical to 6a except for the signals corresponding to the R-substituted furan ring. Therefore we assigned structure 6b to the irradiation product of 3d.19 Irradiation of enone 3e produced a single cycloadduct to which structure 7a was assigned (Scheme 5). The presence of a signal for a ketone group and the lack of signals attributable to olefinic carbons in the 13C NMR spectra unequivocally establish that a [2+2] cycloaddition has taken place between the ∆8(17) and the conjugated endocyclic double bond. The regiochemistry of this single cyclobutane was established by spectroscopic means. Thus, the 13C NMR spectrum (Table 1) showed the presence of three methine carbons at δC 56.0, 54.9, and 54.3, and on the basis of extensive 2D-NMR analyses (Table 2), the above signals were assigned to carbons C-2′, C-5, and C-9, respectively. In addition, the 1H NMR spectrum showed one signal (δH 2.12) for one proton as a doublet of doublets (J ) 10.5 and 5.2 Hz) that was assigned to one of the protons of the methylene C-17. This proton showed a cross-peak in the gHMBC espectrum with carbon C-9 (δC 54.3). This correlation is only compatible with structure 7a. Thus, the irradiation of 3e yields exclusively the crossed regioisomer (type C in Scheme 1).

TABLE 3. Relevant gHMBC Crossed Peaks for Compounds 7b and 8a,b proton

δC

7b H-15 6.54 d H-14 5.39 d H-16 4.07 d H-9R 1.60 overlapped 8 H-15 6.66 d H-14 4.69 d H-16 4.54 dd H-B-17 2.99 dd H-9R a

92.5 d (C-16), 62.3 s (C-13) 153.6 d (C-15), 92.5 d (C-16), 62.3 (C-13) 208.4 s (C-12), 50.6 d (C-9), 40.0 t (C-17) 92.5 d (C-16)

96.8 d (C-14), 81.3 d (C-16), 68.3 s (C-13) 153.9 d (C-15), 81.3 d (C-16), 68.3 d (C-13) 216.1 s (C-12), 51.0 s (C-8) 81.3 d (C-16), 68.3 s (C-13), 56.6 d (C-9), 51.0 s (C-8), 36.4 t (C-7) 1.50 over- 68.3 s (C-13) lapped

Spectra recorded at 400 MHz. b Data taken from the mixture.

The stereochemistry of the new chiral centers of 7a, formed in the photocycloaddition, was established on the basis of nOe experiments. Selective irradiation of proton HB-17 (δH 2.12) caused a positive nOe enhancement in the intensity of the signal corresponding to the β-axial C-20 methyl group. Accordingly, the cyclobutane methano carbon C-17 must be β-oriented and HB-17 have an endo

stereochemical relationship with respect to the decaline system. Since HB-17 showed a long-range W-coupling (J4 ) 5.2 Hz) with proton H-2′, methano carbon C-17 and the proton H-2′ must be trans oriented (Figure 1). All these data, as well as IR and MS spectra, are in agreement with structure 7a for the adduct obtained in the irradiation of 3e. Finally, we studied the photochemical behavior of 3f, having a furane ring conjugated with the ketone group. It should be noted that the synthetic derivative 3f has all of the structural features of a labdane diterpenoid, although it remains to be isolated from a natural source.20 Irradiation of the furolabdane 3f yielded an inseparable mixture of two compounds. According to the 13C NMR spectrum of the mixture (Table 1), both reaction products retain the ketone moiety (δC 216.1 and 208.4). The 1H NMR and the 13C NMR spectra lack the signals corresponding to the exocyclic double bond ∆8(17), and the pattern attributable to the furan moiety was upfield shifted. Therefore, we assumed that a [2+2] photocycloaddition between the ∆8(17) double bond and the furan ring has occurred. We assigned structures 7b and 8 (Scheme 5) to the reaction products of the irradiation of 3f. This assignment was based on the following grounds. First, proton H-16 (δH 4.54) for the major isomer 8 showed coupling constant values (J ) 5.9 and 1.8 Hz) attributable to vicinal couplings with 2H-17 protons. A careful analysis of the gHMBC spectrum revealed a crosspeak between carbon C-13 (δC 68.3) and one proton at δH 1.50 that was assigned to H-9R (Table 3) . This crosspeak was only compatible with structure 8. With respect to the minor isomer 7b, the H-16 proton appears at δH 4.07 as a doublet, with a coupling constant value of 5.7 Hz. The analysis of the cross-peaks of proton H-16 established that 7b is the crossed cycloadduct. Thus, proton H-16 showed gHMBC correlations with the carbonyl carbon (δC 208.4) and with a methylene at δC 40.0, assigned to C-17. Additionally, H-16 showed a cross-peak with carbon C-9 (δC 50.6) that was only compatible with structure 7b. According to these data, it can be concluded that in the irradiation of 3f the two possible regioisomers 7b and 8 were obtained, each one as a single diastereoisomer.

(19) Compound 6b was unstable and it could not be fully characterized. Therefore, the stereochemistry at carbon C-8 remains undetermined.

(20) Compound 3f has been prepared previously during the synthesis of (-)-acuminolide. Furuichi, N.; Hata, T.; Soetjipto, H.; Kato, M.; Katsumura, S. Tetrahedron 2001, 57, 8425-8444.

SCHEME 5

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Terpene-like Products from R-(+)-Sclareolide

The formation of compounds 4, 6, 7, and 8 deserves some comments. First, the reactions were highly efficient. In fact, no other photoadducts were obtained during the irradiation of compounds 3a-g. Second, the reaction is totally chemo-, stereo-, and, except for the formation of compounds 7b and 8, regioselective. The regiochemistry of the photoreactions to form oxetanes 4 can be explained by accepting that the Paterno-Bu¨chi cycloaddition goes through a stepwise mechanism.1f The observed products are those derived from biradical 9, which should be more stable that primary biradical 10 (Scheme 6). SCHEME 6

evolve to the final cyclobutene products by 1,5-intramolecular hydrogen transfer.23 The results obtained in the intramolecular [2+2] photocycloaddition of enones 3e and 3f can be explained by considering the competitive formation of 1,4-biradicals 12 and 13 in the photoprocess.24 Formation of the regioisomer 7 occurs through biradical 12, generated by approach of the endocyclic double bond from the less hindred R-face of the ∆8(17) unsaturation (Scheme 7), while formation of biradicals 13 leads to regioisomer 8. Radical 12a derived from 3e should be considerably more stable than 13a by the effect of the adjacent carbonyl group in 12a.25,26 Therefore, in this case pentacycle 7 is obtained as the single product. The presence of the oxygen adjacent to the radical center in 13b should considerably stabilize this intermediate.26 Therefore, in this case there is a competition between intermediates 12b and 13b, which would explain the formation of the mixture of regioisomers 7b and 8, respectively. SCHEME 7

The sense of the ring closure of biradical 9 should be defined by the interaction between the angular C-20 methyl group and the R group in the emerging oxabicyclohexane. The intermediate biradical derived from 3b having the linear alkynyl moiety collapses by an inward disrotatory ring closure to yield compound 4b. The intermediates derived from 3a and 3g have sterically more demanding substituents and collapse through an outward disrotatory ring closure forming products 4a and 4c.21 Cyclobutenes 6 may in turn derive from an alternate reaction pathway of biradical 9. In fact, in this case biradical 11 may be formed at the expense of oxetanes 4 due to a combination of the steric demand of the aryl and 2-furyl groups, which should render the tetracyclic systems of 4 unstable due to steric crowding in the tetracyclic oxetanes,22 and the increased stabilization of 11 provided by the aromatic rings. Biradicals 11 would (21) This is an example of asymmetric torquoselectivity in the sense defined by Houk. See: Houk, K. N.; Li, Y.; Evansek, J. D. Angew. Chem., Int. Ed. Engl. 1992, 32, 682.

In conclusion, the preparation of diverse products having polycyclic terpene-like structures has been photochemically achieved starting from easily available R-(+)-sclareolide derivatives. Four different structural types of compounds have been accessed until now following this approach in highly selective and efficient reactions. Efforts to extend this methodology to other (22) For examples of the oxetane ring opening, see, among others: (a) Bach. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 884-886. (b) Bach, T.; Jo¨dicke, K.; Kather, K.; Hecht, J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2271-2273. (c) Bach, T.; Jo¨dicke, K.; Kather, K.; Fro¨hlichh, R. J. Am. Chem. Soc. 1997, 119, 2437-2445. (23) Wagner, P. J. Acc. Chem. Res. 1989, 22, 83-91. (24) For discussions of the mechanism of [2+2] enone-olefin photocycloadditions see: (a) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93, 3-22 and references therein. (b) Andrew, D.; Hastings, D. J.; Weedon, A. C. J. Am. Chem. Soc. 1994, 116, 10870-10882. (c) Maradyn, D. J.; Weedon, A. C. Tetrahedron Lett. 1994, 35, 8107-8110. (d) Maradyn, D. J.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 53595360. (25) The regiochemistry of the triplet state addition of benzophenone to isobutene is derived from the formation of the most stable 1,4biradical (Markovnikov-type addition). Gilbert, A.; Baggot, J. Essentials of Molecular Photochemistry; Blackwell Science Ltd: Oxford, UK, 1995. (26) For an excellent discussion of the influence of the relative stabilities of radicals on the regiochemistry of their cyclizations, see: Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim, Germany, 1996.

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de la Torre et al.

natural-product-like derivatives are actively underway in our laboratories.

Experimental Procedures General Methods. All manipulations with air-sensitive reagents were carried out under dry argon atmosphere, using standard Schlenk techniques. All reagents were used as obtained from commercial sources. THF, Et2O, and CH2Cl2 were distilled under positive pressure of argon from Nabenzoquinone (THF, Et2O) or CaH2 (CH2Cl2). Other solvents were HPLC grade and were used without purification. Na2SO4 was used to remove water from the organic layer in reaction workups. Silica gel 60 F254 plates were used for TLC. Flash column chromatography was performed with silica gel (Merk, no. 9385, 230-400 mesh) and mixtures of AcOEt: hexanes or hexanes:CH2Cl2 as eluents. Melting points were determined on a Koffler block. Chemical shifts for 1H NMR are reported with respect to residual CHCl3 (δ 7.25) and with respect to CDCl3 (δ 77.0) for 13C NMR spectra. MS were recorded in the positive EI mode (70 eV). Preparation of 3a from Amide 2. To a solution of 4-bromo-1-butene (4.0 mmol, 0.4 mL) in Et2O (40 mL) at -78 °C was added a solution of t-BuLi (1.7 M in hexanes, 8.0 mmol, 4.7 mL). The mixture was stirred for 10 min, and a solution of amide 2 (0.4 g, 1.4 mmol) in 20 mL of THF at 0 °C was added via cannula. After 20 min the substrate was consumed, and the reaction was quenched with NH4Cl (saturated solution). When the reaction mixture reached room temperature, most of the organic solvents were removed under reduced pressure. The residue was diluted with water (30 mL) and extracted with AcOEt (3 × 40 mL). The combined organic phases were dried and the residue obtained after removal of the solvents was chromatographed with hexanes:CH2Cl2 (4:1) to yield 0.305 g (83%) of pure 3a. Colorless oil, [R]23D - 15.1 (c 0.106, CHCl3); IR (film) νmax 2929, 2862, 2840, 1717, 1643, 1459, 1365, 1201, 910 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.78 (1H, ddt, J ) 17.1, 10.3, 6.5 Hz), 5.17 (1H, ddd, J ) 17.1, 3.3, 1.6 Hz), 4.96 (1H, ddd, J ) 10.3, 2.7, 1.3 Hz), 4.71 (1H, br s), 4.30 (1H, br s), 2.64-2.24 (6H, m), 2.09 (1H, td, J ) 12.8, 5.2 Hz), 1.73 (1H, ddd, J ) 12.6, 5.4, 2.4 Hz), 1.6-1.0 (8H, m), 0.87 (3H, s), 0.79 (3H, s), 0.68 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 209.6, 149.2, 137.2, 115.0, 106.3, 55.1, 51.2, 42.0, 41.8, 39.2, 39.1, 38.8, 37.5, 33.5, 33.4, 27.7, 23.9, 21.7, 19.0, 14.5; EIMS m/z (rel intensity) 288 [M]+ (4), 273 (9), 255 (4), 217 (3), 203 (3), 190 (74), 175 (22), 163 (11), 149 (10), 137 (57), 121 (25), 123 (26), 109 (30), 107 (19), 105 (18), 95 (43), 93 (24), 91 (20), 83 (54), 81 (45), 79 (24), 69 (42), 55 (100), 41 (43). Anal. Calcd for C20H32O: C, 83.27; H, 11.18. Found: C, 82.89; H 10.93. Preparation of 3b from Amide 2. To a solution of 1-bromo-1-propene (0.17 mL, 2.0 mmol) in THF (10 mL) at -78 °C was added a solution of t-BuLi (2.4 mL, 4.0 mmol, 1.7 M in hexanes). The mixture was stirred for 1.5 h, and then it was added via cannula to a solution of 2 (0.2 g, 0.68 mmol) in THF (8 mL) at 0 °C. After 2.5 h the amide was consumed. NH4Cl-saturated solution (2.0 mL) was added and the mixture was allowed to reach room temperature. The organic solvents were removed under vacuum, 30 mL of water was added, and the mixture was extracted with AcOEt (3 × 30 mL). After the combined organic phases were dried and the solvents removed, the residue was chromatographed with AcOEt:hexanes (5:95) as eluent, yielding 0.130 g (70%) of pure 3b. White solid, mp 81-84 °C, [R]20D - 47.8 (c 0.09; CHCl3); IR (KBr) νmax 2900, 2200, 1670, 1653, 1450, 1300, 1205, 1195, 1150, 870 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.76 (1H, d, J ) 1.1 Hz), 4.44 (1H, d, J ) 1.1 Hz), 2.65 (1H, dd, J ) 16.3, 6.3 Hz), 2.63 (1H, dd, J ) 29.1, 16.3 Hz), 2.40-2.55 (2H, m), 2.10 (1H, m), 2.36 (1H, dd, J ) 4.1, 2.3 Hz), 2.00 (3H, s), 1.65-1.10 (8H, m), 0.89 (3H, s), 0.81 (3H, s), 0.70 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 188.2, 148.6, 107.1, 89.6, 80.3, 55.2, 52.0, 42.0, 41.9, 39.2, 38.9, 37.5, 33.5, 23.9, 21.7, 19.3, 14.6, 4.1; EIMS m/z (rel intensity)

6616 J. Org. Chem., Vol. 68, No. 17, 2003

272 [M]+ (1), 257 (8), 239 (5), 201 (6), 190 (51), 175 (27), 161 (11), 147 (17), 137 (89), 123 (38), 119 (27), 109 (35), 107 (28), 105 (29), 95 (52), 93 (33), 91 (32), 81 (55), 69 (47), 67 (100), 55 (44), 41 (68). Anal. Calcd for C19H28O: C, 83.77; H, 10.36. Found: C, 83.54; H, 10.12. Preparation of 3c from Amide 2. To a solution of p-bromoanysole (0.25 mL, 2.0 mmol) in THF (6.0 mL) at 0 °C was added n-BuLi (1.5 mL, 2.4 mmol, 1.6 M in hexanes). The mixture was stirred for 30 min at room temperature, and then it was added via cannula to a solution of amide 2 (300 mg, 1.0 mmol) in THF (20 mL) at 0 °C. The mixture was stirred for 30 min and then quenched with 4 mL of NH4Cl-saturated solution. The organic solvents were removed at reduced pressure, and water was added (40 mL). The aqueous phase was extracted with AcOEt (3 × 40 mL). The combined organic phases were dried, and the residue obtained after removing the solvents was chromatographed with AcOEt:hexanes (5:95) to obtain 270 mg (80%) of pure 3c. White amorphous solid, mp 61-63 °C; [R]23D -13.28 (c 0.128; CHCl3); IR (Nujol) νmax 2854, 1667, 1603, 1574, 1508, 1377, 1255, 896, 839 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.96 (2H, d, J ) 9.0 Hz), 6.91 (2H, d, J ) 9.0 Hz), 4.67 (1H, br s), 4.29 (1H, br s), 3.84 (3H, s, OMe), 3.19 (1H, dd, J ) 17.0, 9.7 Hz), 2.84 (1H, dd, J ) 17.0, 3.5 Hz), 2.68 (1H, br d, J ) 9.7 Hz), 2.37 (1H, dt, J ) 13.2, 2.2 Hz), 2.14 (1H, m), 1.80-1.00 (9H, m), 0.88 (3H, s), 0.81 (3H, s), 0.78 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 198.4, 163.1, 149.3, 130.5, 130.1, 113.6, 106.2, 55.0, 55.3, 51.4, 41.9, 39.2, 38.9, 37.5, 33.7, 33.5, 33.4, 23.9, 21.7, 19.2, 14.8; EIMS m/z (rel intensity) 340 [M]+ (13), 325 (6), 190 (9), 175 (5), 150 (8), 135 (100), 121 (7), 107 (10), 77 (13). Anal. Calcd for C23H32O2: C, 81.13; H, 9.47. Found: C, 80.92; H, 9.18. Preparation of Compound 3d from Amide 2. To a solution of furane (0.23 mL, 3.0 mmol) in THF (7 mL) at -30 °C was added n-BuLi (1.9 mL, 3.0 mmol, 1.6 M in hexanes), and the mixture was stirred for 1 h. The resulting yellow solution was added via cannula to a solution of amide 2 (300 mg, 1.0 mmol) in THF (20 mL) at 0 °C. After 30 min, the amide was completely consumed and the reaction was quenched with NH4Cl (4 mL, saturated solution). The organic solvents were removed under vacuum, water (40 mL) was added to the residue, and the residue was extracted with AcOEt (3 × 40 mL). The combined organic phases were dried and the solvents removed. The residue obtained yielded, after column chromatography with AcOEt:hexanes (5:95), 240 mg (78%) of pure 3d. White amorphous solid, mp 89-91 °C; [R]22D -28.74 (c 0.167; CHCl3); IR (KBr) νmax 2923, 2854, 1663, 1562, 1466, 1381, 1166, 896, 763 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.56 (1H, dd, J ) 1.7, 0.7 Hz), 7.19 (1H, dd, J ) 3.7, 0.7 Hz), 6.52 (1H, dd, J ) 3.5, 1.7 Hz), 3.11 (1H, dd, J ) 16.7, 9.9 Hz), 2.76 (1H, dd, J ) 16.7, 3.7 Hz), 2.66 (1H, br d, J ) 10.1 Hz), 2.37 (1H, ddd, J ) 13.6, 3.7, 2.0 Hz), 2.11 (1H, m), 1.70 (1H, m), 1.60-1.00 (7H, m), 0.88 (3H, s), 0.81 (3H, s), 0.77 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 189.3, 153.0, 149.1, 145.9, 116.4, 112.1, 106.4, 55.0, 51.2, 42.0, 39.2, 39.0, 37.4, 34.2, 33.6, 33.5, 23.9, 21.7, 19.2, 14.6; EIMS m/z (rel intensity) 300 [M]+ (9), 285 (13), 215 (4), 190 (89), 175 (40), 163 (11), 147 (12), 136 (30), 95 (100), 81 (35), 69 (25), 55 (29), 41 (23). Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.66; H, 9.15. Preparation of 3e from Amide 2. To a solution of 1-iodocyclopentene15 (0.12 g, 0.62 mmol) in THF (3 mL) cooled at -78 °C was added t-BuLi (0.82 mL, 1.4 mmol, 1.7 M in hexanes) dropwise and the mixture was stirred for 1 h. The resulting suspension was added via cannula to a solution of amide 2 (0.08 g, 0.28 mmol) in THF (12 mL) cooled at 0 °C. After 10 min amide 2 was consumed, then a NH4Cl-saturated solution (10 mL) was added and the reaction mixture was allowed to reach room temperature. THF was removed under vacuum and the aqueous residue was extracted with AcOEt (3 × 15 mL). The combined organic phases were dried and the solvents were removed to dryness. Chromatography of the residue with AcOEt:hexane (2:98) as eluent yielded 45 mg of pure 3e (74%). Amorphous white solid, mp 77-80 °C; [R]23D +

Terpene-like Products from R-(+)-Sclareolide 5.0 (c 0.996, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.71 (1H, s), 5.62 (1H, br s), 4.25 (1H, br s), 2.87 (1H, dd, J ) 17.6, 10.7 Hz), 2.56-2.44 (4H, m), 2.30 (1H, ddd, J ) 17.6, 4.2, 2.5 Hz), 2.05 (1H, m), 1.84 (1H, q, J ) 7.6 Hz), 1.58-1.02 (12H, m), 0.81 (3H, s), 0.74 (3H, s), 0.60 (3H, s); 13C NMR (75 MHz, CDCl3) δ 198.5, 149.6, 146.1, 142.2, 106.2, 55.0, 51.2, 42.0, 39.1, 38.9, 37.5, 37.4, 33.8, 33.6, 33.5, 30.8, 23.9, 22.7, 21.7, 19.3, 14.7; EIMS m/z (rel intensity) 300 [M]+ (6), 285 (4), 267 (2), 190 (23), 175 (11), 163 (8), 137 (11), 121 (10), 95 (100), 81 (15), 67 (31), 55 (14), 41 (28). Anal. Calcd for C21H32O: C, 83.94; H, 10.73. Found: C, 83.35; H, 10.29. Preparation of 3f from Amide 2. To a solution of n-BuLi (1.6 M in hexanes, 3.2 mL, 5 mmol) in dry THF, at -78 °C, under argon, was added 0.5 mL of 3-bromofuran (4.8 mmol) dropwise. The mixture was stirred for 1 h and then it was added via cannula to a solution of amide 2 (0.74 g, 2.5 mmol) in THF (40 mL) cooled at -78 °C. After 1 h amide was consumed and the reaction was quenched with NH4Clsaturated solution (50 mL). The organic phase was removed and the aqueous phase was extracted with AcOEt (3 × 50 mL). The combined organic layers were dried and the solvents removed under vacuum. The residue was chromatographed with hexanes:CH2Cl2 (4:1) as eluent, yielding 0.72 g (95%) of pure 3c.White solid, spontaneous crystalization, mp 104-107 °C; [R]20D - 63.08 (c 0.130; CHCl3); IR (KBr) νmax 2870, 2780, 1650, 1550, 1500, 1310, 1155, 880, 860 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.06 (1H, dd, J ) 1.5, 0.9 Hz), 7.42 (1H, dd, J ) 2.0, 1.5), 6.76 (1H, dd, J ) 2.0, 0.9 Hz), 4.70 (1H, br s), 4.36 (1H, br s), 2.93 (1H, dd, J ) 16.6, 9.6 Hz), 2.74 (1H, dd, J ) 16.7, 3.7 Hz), 2.64 (1H, br d, J ) 9.5 Hz), 2.38 (1H, ddd, J ) 13.7, 4.1, 2.3 Hz), 2.13 (1H, td, J ) 12.2, 5.4 Hz), 1.801.10 (7H, m), 0.88 (3H, s), 0.81 (3H, s), 0.75 (3H, s); 13C NMR (75 MHz, CDCl3) δ 194.5, 149.2, 146.6, 144.0, 128.1, 108.8, 106.4, 55.1, 51.2, 42.0, 39.3, 39.0, 37.5, 36.4, 33.5, 33.6, 24.0, 21.8, 19.3, 14.7; EIMS m/z (rel intensity) 300 [M]+ (6), 285 (3), 190 (38), 175 (19), 137 (22), 121 (16), 109 (12), 95 (100), 81 (20), 41 (24). Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.78; H, 9.20. Preparation of 3g from Amide 2. To a solution of amide 2 (0.2 g, 0.68 mmol) in THF (15 mL) at 0 °C was added 0.68 mL of allylmagnesium chloride in THF (2 M solution), and the mixture was stirred for 30 min. A NH4Cl-saturated solution (1 mL) was added, and the reaction mixture was allowed to reach room temperature. After that, 20 mL of water was added. The organic phase was separated, and the aqueous phase was extracted with AcOEt (3 × 25 mL). The combined organic phases were dried, and the solvent was removed to obtain a residue that was chromatographed with AcOEt: hexanes (5:95) as eluent, yielding 0.176 g of pure 3g (95% yield). Colorless oil, [R]22D - 24.5 (c 1.09, CHCl3); IR (film) νmax 3078, 2929, 1718, 1643, 1459, 1387, 1323, 1202, 993, 882 cm-1; 1H NMR (200 MHz, CDCl ) δ 5.92 (1H, ddt, J ) 16.9, 10.4, 7.0 3 Hz), 5.15 (1H, ddd, J ) 10.4, 1.5, 2.9 Hz), 5.13 (1H, ddd, J ) 16.9, 3.1, 1.5 Hz), 4.72 (1H, d, J ) 1.3 Hz), 4.31 (1H, d, J ) 1.1 Hz), 3.18 (2H, dt, J ) 7.0, 1.2 Hz), 2.62 (1H, dd, J ) 10.3, 17.0 Hz), 2.50-2.30 (2H, m), 2.08 (1H, m), 1.80-0.90 (8H, m), 0.87 (3H, s), 0.79 (3H, s), 0.68 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 208.1, 149.1, 130.9, 118.5, 106.3, 55.2, 51.2, 47.7, 42.0, 39.2, 38.8, 38.7, 37.5, 33.5, 23.9, 21.7, 19.2, 14.5; EIMS m/z 274 [M]+ (8), 259 (12), 241 (7), 233 (13), 215 (13), 205 (12), 190 (90), 175 (26), 163 (13), 137 (63), 123 (28), 121 (27), 119 (16), 109 (40), 107 (24), 105 (21), 95 (50), 93 (34), 91 (28), 81 (54), 79 (39), 69 (82), 55 (36), 41 (100). Anal. Calcd for C19H30O: C, 83.15; H, 11.02. Found: C, 82.93; H, H, 10.83. General Procedure for Irradiation of Compounds 3af. Solutions of 3a-f (10-3 M) in dry, degassed MeCN were irradiated in a quartz vessel at room temperature, using a 450W, medium-pressure Hg lamp. Progress of the reaction was followed by TLC. Irradiation was interrupted when the substrate was consumed or when decomposition was observed.

The solvent was removed under vacuum and the residues were submitted to column chromatography producing pure reaction products. Irradiation of 3a: Preparation of 4a. Irradiation of 3a (100 mg) in MeCN (60 mL) for 45 min yielded, after chromatography with AcOEt:hexanes (1:99), 84 mg (84%) of pure 4a. White amorphous solid, mp 32-36 °C, [R]23D -27.8 (c 0.108; CHCl3); IR (film) νmax 2994, 2968, 2923, 2864, 2850, 1640, 1462, 1442, 1387, 1371, 1178, 1001, 963, 921, 909 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.83 (1H, ddt, J ) 16.9, 10.1, 6.5 Hz), 5.42 (1H, d, J ) 7.0 Hz), 5.00 (1H, dd, J ) 18.7, 3.3, 2.0 Hz), 4.93 (1H, br d, J ) 10.0 Hz), 4.25 (1H, d, J ) 7.0 Hz), 2.56 (1H, t, J ) 11.5 Hz), 2.20-1.94 (2H, m), 1.90-1.26 (8H, m), 1.240.80 (4H, m), 1.03 (3H, s), 0.78 (3H, s), 0.75 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 138.6, 114.3, 95.2, 77.9, 57.0, 53.7, 49.4, 42.6, 37.9, 37.6, 35.9, 35.1, 33.4, 33.3, 32.4, 28.1, 21.0, 19.6, 18.0, 15.8; EIMS m/z (rel intensity) 288 [M]+ (2), 273 (5), 255 (3), 205 (5), 190 (42), 175 (22), 163 (11), 149 (26), 137 (58), 123 (32), 121 (20), 119 (18), 109 (42), 107 (27), 105 (23), 95 (56), 93 (32), 91 (26), 79 (29), 81 (55), 83 (53), 69 (42), 67 (30), 55 (100), 41 (40). Anal. Calcd for C20H32O: C, 83.27; H, 11.18. Found: C, 83.59; H, 10.94. Irradiation of 3b: Preparation of 4b. Irradiation of 3b (80 mg) in MeCN (50 mL) for 30 min yielded, after chromatography with AcOEt:hexanes (2:98), 64 mg (80%) of pure 4b. White amorphous solid, mp 56-59 °C, [R]23D +18.4 (c 0.204; CHCl3); IR (Nujol) νmax 2924, 2854, 2200, 1644, 1462, 1377, 1289, 1067, 1038, 964 cm-1; 1H NMR (200 MHz, CDCl3) δ 4.64 (1H, d, J ) 6.0 Hz), 4.34 (1H, d, J ) 6.0 Hz), 2.66 (1H, dd, J ) 14.0, 8.3 Hz), 2.50 (1H, dd, J ) 14.0, 4.6 Hz), 2.20 (1H, m), 2.11 (1H, dd, J ) 8.2, 4.6 Hz), 1.93 (3H, CH3), 1.66-1.04 (9H, m), 0.98 (3H, s), 0.87 (3H, s), 0.84 (3H, s), 0.68 (1H, dd, J ) 10.8, 3.7 Hz); 13C NMR (50.3 MHz, CDCl3) δ 88.2, 84.4, 83.3, 76.2, 51.6, 49.8, 49.6, 42.9, 42.3, 37.2, 34.2, 33.6, 33.1, 27.1, 22.3, 19.0, 18.4, 17.9, 4.1; EIMS m/z (rel intensity) 272 [M]+ (1), 257 (2), 239 (2), 201 (3), 190 (19), 175 (15), 159 (6), 147 (11), 137 (40), 123 (22), 121 (27), 119 (21), 109 (28), 107 (27), 105 (30), 95 (45), 93 (34), 91 (50), 81 (50), 79 (36), 77 (29), 69 (56), 67 (100), 55 (41), 41 (72). Anal. Calcd for C19H28O: C, 83.77; H, 10.36. Found: C, 83.64; H, 10.15. Irradiation of 3c: Preparation of 6a. Compound 3c (130 mg) was irradiated in MeCN (100 mL) for 30 min. The solvent was removed under vacuum and the residue was dissolved in AcOEt (10 mL) and filtered through a short pad of silica gel. Removal of the solvent yielded 123 mg (95%) of cyclobutene 6a. 1H NMR (200 MHz, CDCl3) δ 7.27 (2H, d, J ) 8.8 Hz), 6.83 (2H, d, J ) 8.8 Hz), 6.25 (1H, d J ) 1,1 Hz), 3.77 (5H, overlapped), 2.30 (1H, d J ) 1.1 Hz), 2.28-1.00 (12 H, m), 0.93 (3H, s), 0.90 (3H, s), 0.87 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 159.2, 150.2, 126.8, 126.7, 126.6, 113.9, 66.6, 56.7, 55.3, 50.3, 47.0, 43.0, 42.8, 36.2, 33.6, 32.9, 25.2, 21.2, 19.5, 19.1, 18.7; EIMS m/z (rel intensity) 340 [M]+ (2), 325 (2), 309 (1), 297(1), 223 (4), 187 (11), 166 (15), 148 (30), 135 (100), 121 (25), 95 (12), 91 (19), 77 (26), 69 (21), 55 (25). Anal. Calcd for C23H32O2: C, 81.13; H, 9.47. Found: C, 80.82; H, 9.22. Irradiation of 3d: Preparation of 6b. 3d (240 mg) was irradiated in MeCN (150 mL) for 2 h. The solvent was removed under vacuum and the residue was dissolved in AcOEt (20 mL) and filtered through a short pad of silica gel. Removal of the solvent yielded 228 mg (95%) of cyclobutene 6b. 1H NMR (200 MHz, CDCl3) δ 7.35 (1H, d, J ) 1.8 Hz), 6.36 (1H, dd, J ) 3.3, 1.8 Hz), 6.25 (1H, br d, J ) 3.3 Hz), 6.15 (1H, br s), 3.76 (1H, br d, J ) 11.2 Hz), 3.67 (1H, br d, J ) 11.2 Hz), 2.32 (1H, br s), 1.90-1.00 (11H, m), 0.95 (3H, s), 0.90 (3H, s), 0.82 (3H, s). The product was unstable and correct analytical data could not be obtained. Irradiation of 3e: Preparation of 7a. Irradiation of 3e (40 mg) in MeCN (60 mL) for 1 h yielded after chromatography with AcOEt:hexanes (5:95) 25 mg (63%) of pure 7a. White crystals, mp 135-137 °C; [R]23D +15.3 (c 0.085; CHCl3); 1H NMR (300 MHz, CDCl3) δ 2.46 (1H, dd, J ) 19.1, 9.0 Hz, HB11), 2.39 (1H, dd, J ) 19.1, 7.4 Hz), 2.12 (1H, dd, J ) 10.5, 5.2

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de la Torre et al. Hz, HB-17), 2.04 (1H, m), 1.88-1.92 (4H, m), 1.68-1.72 (3H, m), 1.50-1.60 (3H, m), 1.36 (3H, m), 1.20-1.34 (4H, m), 1.12 (H-3, m), 0.84 (2H, m), 0.90 (3H, s, Me-20), 0.85 (3H, s, Me18), 0.81 (3H, s, Me-19); 13C NMR (75 MHz, CDCl3) δ 212.9, 60.2, 56.0, 54.9, 54.3, 41.9, 39.3, 39.2, 38.5, 35.4, 35.3, 34.6, 33.6, 34.9, 28.3, 26.8, 25.0, 21.9, 19.1, 18.0, 13.7; EIMS m/z (rel intensity) 300 [M]+ (12), 285 (12), 257 (3), 243 (2), 215 (4), 190 (38), 175 (15), 147 (13), 109 (21), 105 (25), 95 (100), 81 (33), 79 (339, 77 (20), 67 (41), 41 (49). Anal. Calcd for C21H32O: C, 83.94; H, 10.73. Found: C, 83.52; H, 10.23. Irradiation of 3f: Preparation of 7b and 8. Irradiation of compound 3f (140 mg) in MeCN (60 mL) for 1 h and 30 min yielded, after chromatography with hexanes:CH2Cl2 (9:1), 65 mg (46%) of pure 7b and 8 as an inseparable mixture of regioisomers. Amorphous solid; IR (KBr) νmax 2928, 1728, 1725, 1590, 1133, 708 cm-1; 1H NMR (300 MHz, CDCl3) δ for 7b 6.54 (1H, J ) 2.7 Hz, H-15), 5.39 (1H, d, J ) 2.7 Hz, H-14), 4.07 (1H, d, J ) 5.7 Hz, H-16), 2.45 (2H, overlapped, 2H-17), 0.93 (3H, Me-20), 0.89 (3H, Me-18), 0.83 (3H, Me-19); δ for 8 6.66 (1H, d, J ) 2.7 Hz, H-15), 4.69 (1H, d, J ) 2.7 Hz, H-14), 4.54 (1H, dd, J ) 5.9, 1.8 Hz, H-16), 2.99 (1H, dd, J ) 14.7, 6.0 Hz, HB-17), 2.53 (1H, t, J ) 15.9 Hz, HB-11), 2.19 (2H, overlapped, HA-11 and HA-17), 0.91 (3H, s, Me-20), 0.85 (3H, s, Me-18), 0.81 (3H, s, Me-19), 13C NMR (50.3 MHz, CDCl3) δ for 7b 208.4, 153.6, 102.9, 92.5, 62.3, 54.9, 50.6, 45.9, 41.7, 40.0, 39.2, 38.4, 35.6, 33.6, 32.9, 32.4, 21.8, 18.5, 17.9, 13.7; δ for 8 216.1, 153.9, 96.8, 81.3, 68.3, 56.7, 56.6, 51.0, 42.1, 39.1, 37.5, 37.0, 36.4, 33.4, 33.2, 21.2, 18.2, 18.0, 14.6; EIMS m/z (rel intensity) 300 [M]+ (19), 285 (7), 257 (2), 215 (3), 190 (47), 175 (27), 162 (14), 147 (16), 137 (25), 121 (20), 105 (17), 95 (100, 81 (32), 69 (22), 55 (21). Anal. Calcd for C20H28O2: C, 79.96; H, 9.39. Found: C, 79.63; H, 9.15. Irradiation of 3g: Preparation of 4c. Irradiation of ketone 3g (100 mg) in MeCN (50 mL) for 45 min yielded, after

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chromatography with AcOEt:hexanes (2:98), 82 mg (82%) of pure 4c. Colorless oil, [R]23D -33.9 (c 0.221; CHCl3); IR (film) νmax 3076, 2923, 1641, 1463, 1443, 1370, 1181, 1037, 988, 965, 912 cm-1; 1H NMR (200 MHz, CDCl3) δ 5.82 (1H, ddt, J ) 17.0, 10.1, 7.0 Hz), 5.42 (1H, d, J ) 7.0 Hz), 5.07 (1H, br d, J ) 10.1, 2.9 Hz), 5.09 (1H, ddd, J ) 18.7, 2.9, 1.3 Hz), 4.27 (1H, d, J ) 7.0 Hz), 2.56 (1H, t, J ) 11.7 Hz), 2.40 (2H, dd, J ) 7.0, 1.3 Hz), 2.12 (1H, dd, J ) 11.6, 9.7 Hz), 1.90-1.10 (12 H, m), 1.03 (3H, s), 0.80 (3H, s), 0.75 (3H, s); 13C NMR (50.3 MHz, CDCl3) δ 132.6, 117.6, 93.8, 78.0, 57.0, 53.9, 49.3, 42.6, 37.9, 37.8, 37.6, 35.5, 34.7, 33.4, 33.3, 20.9, 19.5, 18.0, 15.8; EIMS m/z (rel intensity) 274 [M]+ (1), 259 (4), 233 (3), 190 (30), 175 (20), 149 (22), 137 (71), 123 (43), 121 (42), 109 (60), 107 (40), 105 (29), 95 (81), 93 (49), 81 (84), 79 (45), 69 (98), 55 (45), 41 (100). Anal. Calcd for C19H30O: C, 83.15; H, 11.02. Found: C, 83.10; H, 10.82.

Acknowledgment. Financial support by the Spanish Ministerio de Ciencia y Tecnologı´a (Grant No. BQU2001-1283) and by the Consejerı´a de Educacio´n (Comunidad de Madrid, Grant Nos. 07M/0044/2002 to M.C.T. and 07M/0043/2002 to M.A.S.) is gratefully acknowledged. I. Garcı´a thanks the MEC (Spain) for a predoctoral fellowship. Supporting Information Available: A full set of 2D spectra for compounds 4b,c, 6a, 7a, and the mixture of 7b + 8b, together with 1D spectra for compounds 6a,b and the mixture of 7b + 8b. This material is available free of charge via the Internet at http://pubs.acs.org. JO034177Y