Formal Synthesis of Optically Active Ingenol via Ring-Closing Olefin

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Formal Synthesis of Optically Active Ingenol via Ring-Closing Olefin Metathesis Kazushi Watanabe, Yuto Suzuki, Kenta Aoki, Akira Sakakura, Kiyotake Suenaga, and Hideo Kigoshi* Department of Chemistry, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki 305-8571, Japan [email protected] Received July 10, 2004

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk’s keto ester 6, the key intermediate aldehyde 9 in Winkler’s total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol. Introduction Ingenol (1) is a diterpenoid isolated from Euphorbia ingens, possessing a bicyclo[4.4.1]undecane skeleton with a highly strained inside-outside intrabridgehead stereochemistry (Figure 1), and many derivatives have also been isolated.1 Ingenol and its derivatives interest organic chemists not only because of their unique framework, but also due to their biological activities such as protein kinase C (PKC)-activating and anti-HIV activities.2,3 Several strategies4-8 for construction of the unique in,out-bicyclo[4.4.1]undecane skeleton have been reported, involving the de Mayo reaction and subsequent (1) (a) Zeichmeister, K.; Brandl, F.; Hoffe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 4075-4078. (b) Uemura D.; Hirata, Y. Tetrahedron Lett. 1971, 3673-3676. (c) Opferkuch H.; Hecker, E. Tetrahedron Lett. 1974, 261-264. (d) Uemura, D.; Ohwaki, H.; Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 25272528. (e) Uemura, D.; Hirata, Y.; Chen Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 2529-2532. (f) Uemura, D.; Hirata, Y. Tetrahedron Lett. 1975, 1701-1702. (g) Upadhyay, R. R.; Mohaddes, G. Curr. Sci. 1987, 56, 1058-1059. (h) Matsumoto, T.; Cyoun, J. C.; Yamada, H. Planta Med. 1992, 58, 255-258. (i) Wang, L.-Y.; Wang, N.-L.; Yao, X.-S.; Miyata, S.; Kitanaka, S. J. Nat. Prod. 2002, 65, 1246-1251. (2) Hasler, C. M.; Acs, G.; Blumberg, M. Cancer Res. 1992, 52, 202208. (3) (a) Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Shigeta, S.; Konno, K.; Wang, G.-Y.-S.; Uemura, D.; Yokota, T.; Baba, M. Antimicro. Agents Chemother. 1996, 40, 271-273. (b) Fujiwara, M.; Ijichi, K.; Tokuhisa, K.; Katsuura, K.; Wang, G.-Y.-S.; Uemura, D.; Shigeta, S.; Konno, K.; Yokota, T.; Baba, M. Antiviral Chem. Chemother. 1996, 7, 230-236. (4) Review: Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387399. (5) (a) Winkler, J. D.; Hey, J. P.; Williard, P. G. J. Am. Chem. Soc. 1986, 108, 6425-6427. (b) Winkler, J. D.; Henegar, K. E.; Williard, P. G. J. Am. Chem. Soc. 1987, 109, 2850-2851. (c) Winkler, J. D.; Henegar, K. E.; Hong, B.-C.; Williard, P. G. J. Am. Chem. Soc. 1994, 116, 4183-4188. (d) Winkler, J. D.; Hong, B.-C.; Bahador, A.; Kazanietz, M. G.; Blumberg, P. M. J. Org. Chem. 1995, 60, 1381-1390. (e) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg, P. M. J. Am. Chem. Soc. 1999, 121, 296-300. (f) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728.

fragmentation,5 the Ireland-Claisen rearrangement for ring contraction,6 1,5-H sigmatropy to change the intrabridgehead stereochemistry from out-out to in-out,7 and the tandem cyclization-rearrangement reaction;8 direct cyclization to the in,out-bicyclo[4.4.1]undecane system has not been reported. Recently, two total syntheses in a racemic form using the aforementioned strategies were reported by Winkler5f and Tanino-Kuwajima.8b Results and Discussion We have previously9 developed a direct cyclization method for the highly strained tricyclic skeleton of ingenol via ring-closing olefin metathesis to synthesize tricyclic compound 5, thus indicating the efficiency of olefin metathesis in the construction of highly strained carboskeletons (Scheme 1). Wood et al.10 also have reported a similar strategy for synthesizing the tetracyclic skeleton of ingenol. We describe herein the details of the synthesis of inside-outside tricyclic compound 5 and easy access to the Winkler’s aldehyde 9, an important intermediate of the total synthesis, utilizing ring-closing olefin metathesis to achieve a formal total synthesis of optically active ingenol (Scheme 2). (6) (a) Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298-3300. (b) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Org. Chem. 1993, 58, 5873-5875. (7) (a) Rigby, J. H.; de Sainte Claire, V.; Cuisiat, S. V.; Heeg, M. J. J. Org. Chem. 1996, 61, 7992-7993. (b) Rigby, J. H.; Hu, J.; Heeg, M. J. Tetrahedron Lett. 1998, 39, 2265-2268. (c) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Hohammadi, F. Org. Lett. 2002, 5, 799-801. (8) (a) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032-3033. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. (9) Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 3927-3930. (10) Tang, H.; Yusulff, N.; Wood, J. L. Org. Lett. 2001, 3, 15631566. 10.1021/jo048833l CCC: $27.50 © 2004 American Chemical Society

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Published on Web 10/13/2004

Synthesis of Optically Active Ingenol

FIGURE 2. Grubbs catalysts. FIGURE 1. Ingenol and the strained inside-outside bicyclic

SCHEME 3. Synthesis of Iodide 14a

skeleton.

SCHEME 1. Ring-Closing Olefin Metathesis in the Synthesis of Ingenol Derivativesa

a Reagents and conditions: (a) DIBAL, toluene, -78 °C, 5 h; (b) Ph3PdCHCOOMe, benzene, 60 °C, 4 h, 59% (2 steps); (c) I2, PPh3, imidazole, toluene, rt, 1.5 h, 81%; (d) DIBAL, toluene, -78 °C, 1 h; (e) 3,4-dihydro-2H-pyran, TsOH, CH2Cl2, rt, 40 min, 94% (2 steps).

a Reagents and conditions: (a) First generation Grubbs catalyst I, benzene, reflux, 18 h, 45%; (b) same conditions as a.

SCHEME 2. Synthetic Plan for Optically Active Ingenol (1) via Ring-Closing Olefin Metathesis

The key reaction of this synthesis is the ring-closing olefin metathesis with Grubbs’ ruthenium catalysts, RuCl2(dCHPh)(PCy3)2 and RuCl2(dCHPh)(PCy3)(bismesitylimidazolidinylidene) (Figure 2), which provides a new strategy for the synthesis of cyclic natural products.11 In the ring-closing olefin metathesis, it is important that the two olefins being attached to one another be located (11) Review: Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 44134450.

relatively close to one another. We therefore investigated ring-closing olefin metathesis for bicyclic skeletons and found that metathesis of trans-2,7-diallylcycloheptanone (2b) affords dimeric compounds rather than in,outbicyclo[4.4.1]undecene (3b) under conditions where cis2,7-diallylcycloheptanone (2a) is converted into out,outbicyclo[4.4.1]undecene (3a) (Scheme 1). We therefore chose spiro compound 4 as a key intermediate, in which the distance between the two terminal olefins is closer, approximately 3.6 Å based on a molecular mechanics calculation,12 than that of trans-2,7-diallylcycloheptanone (2b, 3.8 Å). The synthesis of 4 began with γ-butyrolactone as a starting material (Scheme 3). γ-Butyrolactone was reduced with DIBAL to give hemiacetal 10, the Wittig reaction of which afforded the unsaturated ester 11 (59%, 2 steps). Iodination of the hydroxy group in 11 and subsequent reduction with DIBAL afforded the allylic alcohol 13. The hydroxy group in 13 was protected to provide the THP ether 14 (76%, 3 steps). The alkylation reaction of cycloheptanone with 14 (LDA) afforded the alkylated ketone 16 in a 43% yield (Scheme 4). This step was improved by using the alkylation reaction13 of cycloheptanone N,N-dimethylhydrazone with 14 (n-BuLi) and subsequent hydrolysis with silica gel14 to give 16 in a 92% yield. Deprotection of the THP group in 16 and subsequent chlorination provided the allylic chloride 17 (90%), which was then treated with t-BuOK in t-BuOH to give the spiroketones 18a (28%) and 18b (43%). The stereochemistry of 18a and 18b was determined as follows (Scheme 5). The spiroketone 18b was reduced with NaBH4 in EtOH to give alcohol 19a (50%) and its diastereomeric alcohol 19b (21%). The stereostructures of 19a and 19b were determined by the coupling constant (12) The global minima were calculated in a Multiconformer conformational search with MacroModel (Version 6.0, MM2* force field). (13) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 3-6. (14) Kotsuki, H.; Miyazaki, A.; Kadota, I.; Ochi, M. J. Chem. Soc., Perkin 1 1990, 429-430.

J. Org. Chem, Vol. 69, No. 23, 2004 7803

Watanabe et al. SCHEME 4. Synthesis of Spiroketones 18a and 18ba

FIGURE 3. Plausible transition states of spirocyclization of 18a.

SCHEME 6. Synthesis of Tricyclic Ketone 5 and Its Isomer 21a

a Reagents and conditions: (a) BuLi, THF, -5 °C, 1 h, 14, rt, 1 h; (b) SiO2, CH2Cl2, 19 h, 92% (after rehydration of the recovered sm); (c) PPTS, EtOH, 55 °C, 12 h, 97%; (d) PPh3, CCl4, reflux, 5 h, PPh3, reflux, 4 h, 93%; (e) NaH, Et3COH, xylene, reflux, 30 min, 79% (18a), 7% (18b).

SCHEME 5. Stereochemistry of 18ba a Reagents and conditions: (a) KHMDS, THF, -78 °C, 1 h; allyl iodide, 0 °C, 3 h, 81% (4:20 ) 10:1); (b) first-generation Grubbs catalyst I, toluene, reflux, 5.5 h, 27%; (c) first-generation Grubbs catalyst I, toluene, reflux, 1.5 h, 62%; (d) H2, 10% Pd/C, EtOH, rt, 22 h, 55%; (e) H2, 10% Pd/C, EtOH, rt, 22 h, 69%.

a Reagents and conditions: (a) NaBH , EtOH, rt, 32 h, 50% 4 (19a), 21% (19b).

(J ) 10.0 Hz for 19b) and the half-height widths15 (W1/2 ) 10.8 Hz for 19a, 18.9 Hz for 19b) of oxymethine proton in their 1H NMR spectra. Both alcohols 19a and 19b exhibited an NOE between the oxymethine proton and the allylic proton, suggesting that the oxymethine group and the vinyl group in 19a and 19b are on opposite sides of the cyclopentane ring. This finding indicates that the carbonyl and vinyl groups in 18b are on opposite sides of the cyclopentane ring, and thus 18a possesses the desired stereochemistry for the synthesis of 4 and 5, which was confirmed later by the fact that compound 18a is converted into the known 22a5c through compounds 4 and 5. The stereoselectivity of this spirocyclization was investigated (Table 1). The addition of 18-crown-6, KI, or LiCl decreased the predominance of the desired 18a. The use of a bulky base, Et3COK in Et3COH/xylene, reversed the stereoselectivity to give 18a predominantly. Furthermore, Et3CONa in Et3COH/xylene afforded the desired 18a stereoselectively. Under the less polar conditions (15) Hassner, A.; Heathcock, C. H. J. Org. Chem. 1964, 29, 13501355.

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with Et3CONa in Et3COH/xylene, coordination of the chlorine atom to the sodium ion in the enolate possibly stabilized the transition state A to 18a (Figure 3). The addition of 18-crown-6, KI, or LiCl would interrupt the coordination to give 18b predominantly. Allylation of 18a with KHMDS and allyl iodide provided a 10:1 mixture of the allyl ketones 4 and 20 in an 81% yield, which were separated by silica gel column chromatography (Scheme 6). We could not determine the stereochemistry of 4 and 20 by spectroscopic analysis; however, we predicted that the allylation of 18a would occur from the less hindered side of the corresponding enolate, and that the allyl ketone 4 would be predominantly obtained. The ring-closing olefin metathesis of the allyl ketones 4 and 20 was investigated, respectively, and it was proved that this reaction requires a relatively higher temperature. The allyl ketone 4 reacted with the firstgeneration Grubbs’ ruthenium catalyst I in boiling toluene to give the tricycloketone 5 in 27% yield, whereas the ring-closing olefin metathesis of 20 gave the tricycloketone 21 in 62% yield. The use of a secondgeneration catalyst II improved the formation of 5 to a 31% yield. The tricycloketones 5 and 21 were catalytically hydrogenated to afford the previously reported compound 22a5c,16 (55%) and compound 22b16 (68%), respectively. Thus, the structures of 5 and 21 were confirmed. After determining the applicability of ring-closing olefin metathesis for synthesis of the highly strained (16) Yields are not optimized.

Synthesis of Optically Active Ingenol TABLE 1. Spirocyclization of Allylic Chloride 17

entry

base

solvent

1 2 3 4 5 6

t-BuOK t-BuOK t-BuOK t-BuOK Et3COKa Et3CONab

t-BuOH t-BuOH t-BuOH t-BuOH Et3COH/xylene Et3COH/xylene

a

conditions additive 18-crown-6 KI LiCl

temp/°C reflux 50 50 70 reflux reflux

time/h

product yield/%

18a:18b

12 1.5 5 5 0.5 0.5

88 86 74 86 58 86

1:1.8 1:4.8 1:3.2 1:4.8 2.4:1 12:1

Prepared from the alcohol and KH. b Prepared from the alcohol and NaH.

SCHEME 7. Synthesis of Winkler’s Aldehyde 9a

a Reagents and conditions: (a) NaH, DMF, rt, 1 h, 14, 100 °C, 6 h, 75%; (b) LiI, DMF, reflux, 4 h, 78%; (c) PPTS, EtOH, 55 °C, 3 h, 97%; (d) CCl4, PPh3, reflux, 7 h, 93%; (e) NaH, Et3COH, xylene, reflux, 30 min, 53%; (f) LDA, HMPA, THF, 0 °C, 40 min; allyl iodide, 0 °C, 6 h, 83%; (g) LDA, HMPA, THF, 0 °C, 40 min; methallyl iodide, -10 °C, 2 h, 59%; (h) second-generation Grubbs catalyst II, toluene, reflux, 30 min, 53%; (i) second-generation Grubbs catalyst II, toluene, reflux, 30 min, 87%; (j) SeO2, dioxane, reflux, 1 h, 85%.

ingenol skeleton, we attempted to synthesize the optically active ingenol itself (Scheme 2). Although our compound 5 lacks the D-ring, this strategy would be applicable to total synthesis of ingenol by starting from Funk’s keto ester 6. Cyclization of methallyl compound 7 gives trisubstituted olefin 8, which would be converted into the corresponding aldehyde 9, a key intermediate in Winkler’s total synthesis. 3-Carene was converted into the keto ester 6 in five steps following the procedure of Funk6a (Scheme 7). The keto ester 6 was alkylated with iodide 14 to give

compound 23 (75%), which was transformed into compound 24 by demethoxycarbonylation (78%). The THP group of 24 was removed to give alcohol 25 (97%), which was chlorinated to furnish allylic chloride 26 (95%). The spirocyclization of 26 was investigated (Table 2). The procedure applied to 17, t-BuOK in t-BuOH, did not afford the desired compound 28 but tert-butyl ether 27 (14%). To increase the steric hindrance of the base, we used Et3COK in the corresponding alcohol and found that the desired compound 28 was obtained as a sole product in 23% yield (entry 2). The stereochemistry of 28 was determined by the NOESY correlation between the allylic methine proton and the methine proton with a secondary methyl group (Figure 4). The corresponding lithium alkoxide and sodium tert-amyloxide were found to be less effective. DBU was inappropriate as a base. Although the addition of LiI or 18-crown-6 somehow enhanced the reaction rate, it did not increase the yield. As in the cyclization of 17, the use of xylene as a cosolvent improved the yield to some extent (entry 8). The conditions with Et3CONa in Et3COH/xylene afforded the best results as in the case of cyclization of 17 (entry 9, 53% yield). Replacement of the alcohol with tert-amyl alcohol decreased the yield (entry 10). Allylation of spiroketone 28 was effected by a standard procedure (allyl iodide and LDA) to give ketone 29 as a sole product in 83% yield. The bulky dimethylcyclopropane ring would interfere with the alkylation from the β-face. Ring-closing olefin metathesis of 29 was then investigated (Table 3). The reaction was effected with a 0.2 molar equiv of Grubbs catalyst in a boiling solvent (1.5 mM). The first-generation Grubbs catalyst in toluene gave tetracyclicketone 30 in only 14% yield (entry 1). The second-generation catalyst in toluene worked better (entry 2). The shorter reaction times provided the desired compound 30 in the best yield (entry 3). Use of the other hydrocarbon solvents, benzene and xylene, decreased the yield (entries 4 and 5), probably because of insufficient activation energy and decomposition of the catalyst or the product. No cyclization was observed in CH2Cl2 (entry 6). The methallyl compound 7 was prepared from ketone 28 as above (59%). Ring-closing olefin metathesis of methallyl compound 7 was achieved under the same conditions described in entry 3 of Table 3 to give tetracyclic compound 8 in 87% yield. The success of ringJ. Org. Chem, Vol. 69, No. 23, 2004 7805

Watanabe et al. TABLE 2. Spirocyclization of Allylic Chloride 26

entry

base

solvent

additive

1 2 3 4 5 6 7 8 9 10

t-BuOK Et3COKa Et3COLib t-AmONa DBU Et3COKa Et3COKa Et3COKa Et3CONac t-AmOKa

t-BuOH Et3COH Et3COH t-AmOH toluene Et3COH Et3COH Et3COH/xylene Et3COH/xylene t-AmOH/xylene

LiI 18-crown-6

temp

time/h

yield/%d

reflux reflux reflux reflux reflux reflux rt reflux reflux reflux

8 12 24 13 10 0.5 1.5 0.5 0.5 15

0e 23 0 13 0 12 5 46 53 11

a Prepared from the alcohol and KH. b Prepared from the alcohol and n-BuLi. c Prepared from the alcohol and NaH. d Isolated yield. Besides 28, an inseparable mixture of byproducts was obtained. e An allylic tert-butyl ether 27 was obtained in 14% yield.

Winkler’s aldehyde. This synthesis provides the first synthetic access to optically active ingenol. Application of this strategy to the synthesis of natural ingenol derivatives is now in progress in our laboratory.

Experimental Section

FIGURE 4. NOE in 28. TABLE 3. Ring-Closing Olefin Metathesis of Diene 29

entry

catalyst

conditions solvent

time

product yield/%

1 2 3 4 5 6

Ia IIb IIb IIb IIb IIb

toluene toluene toluene benzene xylene CH2Cl2

3h 6h 30 min 2h 10 min 3h

14 44 53 32 39 0

a RuCl (dCHPh)(PCy ) . 2 3 2 imidazolidinylidene).

b

RuCl2(dCHPh)(PCy3)(bismesityl-

closing olefin metathesis of the methallyl compound might be due to (1) stability of the trisubstituted double bond in the product under the reaction conditions and (2) a high-frequency factor in encountering the two olefins. Allylic oxidation of compound 8 with SeO2 afforded the desired aldehyde 9 (85%), which was a key intermediate of Winkler’s total synthesis. Conclusions We found the ring-closing olefin metathesis to be effective in the synthesis of highly strained ring systems, and to be a key step in synthesizing optically active 7806 J. Org. Chem., Vol. 69, No. 23, 2004

Alkylation of Funk’s Keto Ester 6. To a suspension of NaH (60% in mineral oil, 238 mg, 6.0 mmol) in DMF (10 mL) was added a solution of keto ester 6 (1.07 g, 4.8 mmol) in DMF (2 + 1 mL), and the mixture was stirred at room temperature for 1 h. A solution of iodide 14 (1.72 g, 5.6 mmol) in DMF (3 × 1 mL) was added, and the reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The residual oil was chromatographed on silica gel (100 g, hexane-ether 10:1 to 5:1) to give alkylated ketone 23 (1.46 g, 75%) as a colorless oil. [R]D21 +95.4 (c 1.0, CHCl3); IR (neat) 2942, 1739, 1703, 1642, 1202, 1118, 1023 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.66 (dt, J ) 15.4, 5.6 Hz, 1 H), 5.57 (dt, J ) 15.4, 5.4 Hz, 1 H), 4.62 (dd, J ) 4.1, 2.7 Hz, 1 H), 4.17 (dd, J ) 11.3, 5.6 Hz, 1 H), 3.90 (dd, J ) 11.3, 5.6 Hz, 1 H), 3.86 (m, 1 H), 3.71 (s, 3 H), 3.50 (m, 1 H), 2.66 (dd, J ) 14.7, 8.3 Hz, 1 H), 2.27 (dd, J ) 14.7, 8.9 Hz, 1 H), 2.10-1.99 (m, 3 H), 1.88-1.35 (m, 11 H), 1.22 (m, 1 H), 1.12 (d, J ) 6.8 Hz, 3 H), 1.06 (s, 3 H), 1.02 (s, 3 H), 0.78 (ddd, J ) 8.5, 8.5, 6.8 Hz,1 H), 0.64 (ddd, J ) 8.9, 8.5, 8.3 Hz, 1 H); MS (FAB) m/z 407 (M + H)+; HRMS (ESI) m/z calcd for C24H38NaO5 (M + Na)+ 429.2617, found 429.2599 (∆ -1.8 mmu). Demethoxycarbonylation of Alkylated Ketone 23. A solution of alkylated ketone 23 (130.6 mg, 0.32 mmol) and LiI (650 mg, 4.9 mmol) in DMF (6 mL) was refluxed for 4 h. After being cooled to room temperature, the reaction mixture was diluted with triethylamine (0.1 mL) and water (10 mL) and extracted with hexane (3 × 10 mL). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The residual oil was chromatographed on silica gel (30 g, hexane-ether 8:1 to 5:1) to give ketone 24 (87.3 mg, 78%) as a colorless oil. [R]D21 +74.7 (c 0.96, CHCl3); IR (neat) 2939, 1704, 1454, 1381, 1200, 1118, 1076, 1023, 969 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.69 (br dt, J ) 15.5, 6.2 Hz, 1 H), 5.56 (ddd, J ) 15.6, 6.2, 5.8 Hz, 1 H), 4.63 (br t, J ) 4.0 Hz, 1 H), 4.17 (dd, J ) 11.9, 5.8 Hz, 1 H), 3.91 (dd, J ) 11.9, 6.2 Hz, 1 H), 3.85 (m, 1 H), 3.49 (m, 1 H), 2.50 (dd, J ) 11.5, 7.2 Hz, 1 H), 2.41 (m, 1 H), 2.10-2.02 (m, 4 H), 1.86-1.52 (m, 8 H),

Synthesis of Optically Active Ingenol 1.43-1.16 (m, 4 H), 1.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 6.5 Hz, 3 H), 0.68 (m, 1 H), 0.55 (m, 1 H); MS (FAB) m/z 349 (M + H)+; HRMS (ESI) m/z calcd for C22H36NaO3 (M + Na)+ 371.2562, found 371.2569 (∆ +0.7 mmu). Allylic Alcohol 25. A solution of ketone 24 (1.03 g, 3.0 mmol) and pyridinium p-toluenesulfonate (55 mg, 0.22 mmol) in ethanol (50 mL) was stirred at 55 °C for 10 h. After the addition of pyridinium p-toluenesulfonate (20.8 mg, 0.083 mmol), the mixture was stirred at the same temperature for a further 10 h. The mixture was concentrated, and the residual oil was chromatographed on silica gel (30 g, hexane-ether 1:1) to give allylic alcohol 25 (761 mg, 97%) as a colorless oil. [R]D21 +104 (c 1.01, CHCl3); IR (neat) 3420, 2931, 1699, 1457, 969 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.73-5.57 (m, 2 H), 4.08 (m, 2 H), 2.51 (dd, J ) 11.3, 7.0 Hz, 1 H), 2.41 (dt, J ) 8.6, 4.3 Hz, 1 H), 2.11-1.99 (m, 4 H), 1.83 (m, 1 H), 1.64 (m, 1 H), 1.42-1.15 (m, 5 H), 1.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 6.8 Hz, 3 H), 0.69 (ddd, J ) 10.9, 10.6, 5.9 Hz, 1 H), 0.56 (ddd, J ) 10.6, 9.2, 7.0 Hz, 1 H); MS (FAB) m/z 287 (M + Na)+; HRMS (ESI) m/z calcd for C17H29O2 (M + H)+ 265.2167, found 265.2177 (∆ +1.0 mmu). Chloride 26. A solution of allylic alcohol 25 (46.5 mg, 0.176 mmol) and triphenylphosphine (96.3 mg, 0.37 mmol) in CCl4 (1 mL) was refluxed for 7 h. After being cooled to room temperature, the reaction mixture was filtered through a cotton plug to remove triphenylphosphine oxide. The filtrate was concentrated, and the residue was chromatographed on silica gel (4 g, hexane-ether 20:1) to give chloride 26 (47.1 mg, 95%) as a colorless oil. [R]D21 +95.9 (c 0.95, CHCl3); IR (neat) 2938, 2864, 1703, 1455, 1380, 1249, 966 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.73 (dt, J ) 15.3, 6.3 Hz, 1 H), 5.70 (dt, J ) 15.3, 6.9 Hz, 1 H), 4.02 (d, J ) 6.9 Hz, 2 H), 2.51 (dd, J ) 11.5, 6.8 Hz, 1 H), 2.41 (dt, J ) 8.8, 4.4 Hz, 1 H), 2.10-2.01 (m, 3 H), 1.85 (m, 1 H), 1.65 (m, 1 H), 1.42-1.10 (m, 5 H), 1.08 (s, 3 H), 1.07 (s, 3 H), 0.81 (d, J ) 7.0 Hz, 3 H), 0.69 (ddd, J ) 9.9, 9.4, 5.9 Hz, 1 H), 0.56 (ddd, J ) 10.7, 9.4, 6.8 Hz, 1 H); MS (FAB) m/z 283 (M + H)+; HRMS (ESI) m/z calcd for C17H28ClO (M + H)+ 283.1828, found 283.1801 (∆ -2.7 mmu). Spirocyclization of Chloride 26. To a solution of chloride 26 (24.2 mg, 0.086 mmol) in xylene (1.5 mL) and 3-ethyl-3pentanol (0.07 mL, 0.50 mmol) was added a mixture of NaH (60% in mineral oil, 9.3 mg, 0.23 mmol), and the mixture was quickly heated to reflux. After 30 min, the mixture was cooled to room temperature. diluted with saturated aqueous NH4Cl (1 mL), and extracted with hexane (3 × 5 mL). The extract was washed with brine, dried (Na2SO4), and concentrated. The residual xylene solution was chromatographed on silica gel (2 g, hexane-ether 200:1 to 100:1) to give spiro ketone 28 (11.1 mg, 53%) as a colorless oil. [R]D21 +135 (c 1.0, CHCl3); IR (neat) 2954, 1696, 1634, 1456, 1378, 1286, 1160, 993, 912 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.59 (ddd, J ) 16.9, 10.0, 8.7 Hz, 1 H), 5.00 (dd, J ) 16.9, 1.6 Hz, 1 H), 4.92 (dd, J ) 10.0, 1.6 Hz, 1 H), 2.69 (ddd, J ) 8.7, 7.5, 2.0 Hz, 1 H), 2.30 (dd, J ) 11.8, 6.8 Hz, 1 H), 2.21 (dd, J ) 11.8, 10.7 Hz, 1 H), 1.99 (m, 1 H), 1.97 (dd, J ) 9.9, 4.1 Hz, 1 H), 1.89 (m, 1 H), 1.85 (dt, J ) 14.7, 6.2 Hz, 1 H), 1.78 (td, J ) 6.7, 2.2 Hz, 1 H), 1.71 (m, 1 H), 1.65 (dd, J ) 14.7, 10.2 Hz, 1 H), 1.54 (dd, J ) 4.9, 3.0 Hz, 1 H), 1.51 (m, 1 H), 1.07 (s, 3 H), 1.05 (s, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H), 0.69 (ddd, J ) 10.2, 9.6, 6.2 Hz, 1 H), 0.55 (ddd, J ) 10.7, 9.6, 6.8 Hz, 1 H); 13C NMR (67.8 MHz, CDCl3) δ 211.1, 140.5, 114.9, 68.8, 50.1, 39.4, 34.8, 30.8, 28.8, 28.7, 26.3, 23.1, 21.2, 21.1, 20.7, 15.3, 14.8; MS (FAB) m/z 247 (M + H)+; HRMS (ESI) m/z calcd for C17H26NaO (M + Na)+ 269.1881, found 269.1861 (∆ -2.0 mmu). Allylation of Spiro Ketone 28. To a ice-cooled solution of spiro ketone 28 (45.1 mg, 0.18 mmol) in THF (0.2 mL) were added HMPA (0.04 mL, 0.23 mmol) and LDA (0.71 mmol) solution in THF-hexane (0.6 mL). After 40 min, allyl iodide (0.07 mL, 0.77 mmol) was added, and the mixture was stirred at 0 °C for 6 h. The mixture was diluted with saturated aqueous Na2S2O3 (2 mL) and saturated aqueous NH4Cl (2 mL) and extracted with ether (3 × 5 mL). The combined extracts

were washed with brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel (4 g, hexanebenzene 100:1) to give allyl spiro ketone 29 (42.8 mg, 83%) as a colorless oil. [R]D21 +93.4 (c 0.79, CHCl3); IR (neat) 2955, 1695, 1638, 1458, 1378, 995, 909 cm-1; 1H NMR (500 MHz, CDCl3) δ 5.67 (m, 1 H), 5.60 (dt, J ) 17.0, 9.9 Hz, 1 H), 5.01 (m, 1 H), 4.98 (m, 1 H), 4.97 (m, 1 H), 4.94 (m, 1 H), 2.73 (m, 1 H), 2.31 (m, 2 H), 2.15 (m, 1 H), 2.03-1.80 (m, 5 H), 1.71 (m, 1 H), 1.63 (m, 1 H), 1.56-1.49 (m, 2 H), 1.02 (s, 3 H), 1.0 (s, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H), 0.70 (ddd, J ) 10.2, 9.3, 6.3 Hz, 1 H), 0.14 (dd, J ) 9.5, 9.5 Hz, 1 H); 13C NMR (67.8 MHz, CDCl3) δ 212.0, 140.6, 136.5, 115.4, 114.7, 68.4, 49.8, 47.5, 35.7, 34.6, 30.8, 28.9, 28.7, 27.0, 26.4, 22.9, 21.0, 20.9, 16.0, 14.6; MS (FAB) m/z 287 (M + H)+; HRMS (ESI) m/z calcd for C20H31O (M + H)+ 287.2375, found 287.2379 (∆ +0.4 mmu). Ring-Closing Olefin Metathesis of 29. A solution of allyl spiro ketone 29 (21.9 mg, 0.077 mmol) and the secondgeneration Grubbs catalyst, RuCl2(dCHPh)(PCy3)(bismesitylimidazolidinylidene) (13.6 mg, 0.016 mmol), in toluene (45 mL) was refluxed for 30 min. The mixture was filtered through a pad of silica gel (3 g), and the pad was washed with benzene. The filtrate and washings were combined and concentrated to give an oil, which was chromatographed on silica gel (4 g, benzene) to give tetracyclic ketone 30 (10.6 mg, 53%) as a colorless oil. [R]D21 +74.0 (c 0.128, CHCl3); IR (neat) 3006, 2956, 2873, 1716, 1459, 1434, 1380, 1366, 1337, 1210, 1192, 1138, 944 cm-1; 1H NMR (600 MHz, CDCl3) δ 5.56 (ddd, J ) 12.0, 5.8, 3.3 Hz, 1 H), 5.14 (ddd, J ) 12.0, 4.4, 2.1 Hz, 1 H), 3.17 (ddd, J ) 12.5, 11.8, 3.1 Hz, 1 H), 3.13 (m, 1 H), 2.40 (m, 1 H), 2.36 (m, 1 H), 2.09 (dddd, J ) 16.8, 5.8, 3.1, 3.1 Hz, 1 H), 1.91 (m, 1 H), 1.87 (m, 1 H), 1.81 (ddd J ) 15.3, 10.0, 1.9 Hz, 1 H), 1.68 (dddd, J ) 10.0, 10.0, 5.0, 5.0 Hz, 1 H), 1.58 (m, 1 H), 1.52 (ddd, J ) 10.0, 4.4, 1.0 Hz, 1 H), 1.43 (m, 1 H), 1.28 (ddd, J ) 13.4, 10.3, 7.6 Hz, 1 H), 1.12 (s, 3 H), 1.03 (s, 3 H), 0.94 (d, J ) 6.9 Hz, 3 H), 0.69 (ddd, J ) 10.0, 8.5, 6.1 Hz, 1 H), 0.62 (dd, J ) 11.8, 8.5 Hz, 1 H); 13C NMR (67.8 MHz, CDCl3) δ 211.2, 137.3, 132.3, 72.0, 46.0, 45.6, 39.6, 34.8, 31.9, 29.5, 28.7, 27.9, 25.3, 23.6, 23.2. 22.8, 15.5, 15.2; MS (FAB) m/z 281 (M + Na)+; HRMS (ESI) m/z calcd for C18H26NaO (M + Na)+ 281.1883, found 281.1882 (∆ -0.1 mmu). Methallylation of Spiro Ketone 28. Spiro ketone 28 (21.7 mg, 0.090 mmol) was methallylated with methallyl iodide (37 mg, 0.20 mmol) by the same procedure used in the preparation of 29 to give methallyl spiro ketone 7 (15.7 mg, 59%) as colorless crystals. Mp 87.0-91.0 °C (hexane-ether-MeOH); [R]21D +44.5 (c 0.26, CHCl3); IR (neat) 2954, 1685, 1454, 1377 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.61 (ddd, J ) 16.9, 9.9, 9.8 Hz, 1 H), 5.05 (dd, J ) 16.9, 1.9 Hz, 1 H), 4.97 (dd, J ) 9.9, 1.9 Hz, 1 H), 4.75 (br s, 1 H), 4.68 (br s, 1 H), 2.75 (br t, J ) 7.4 Hz, 1 H), 2.42 (ddd, J ) 10.9, 9.9, 3.0 Hz, 1 H), 2.29 (dd, J ) 12.1, 10.9 Hz, 1 H), 2.07 (dd, J ) 12.1, 3.0 Hz, 1 H), 2.01-1.43 (m, 9 H), 1.65 (s, 3 H), 0.98 (s, 3 H), 0.95 (s, 3 H), 0.91 (d, J ) 6.5 Hz, 3 H), 0.67 (ddd, J ) 9.5, 9.4, 6.1 Hz, 1 H), 0.10 (dd, J ) 9.9, 9.5 Hz, 1 H); 13C NMR (67.8 MHz, CDCl3) δ 212.1, 143.3, 140.7, 114.9, 112.1, 68.5, 49.8, 46.6, 39.4, 34.6, 31.1, 29.7, 28.9, 28.6, 27.8, 26.7, 23.1, 22.9, 20.9, 16.0, 14.7; HRMS (FAB) m/z calcd for C21H32NaO (M + Na)+ 323.2351, found 323.2372 (∆ +2.1 mmu). Ring-Closing Olefin Metathesis of 7. Methallyl spiro ketone 7 (6.3 mg, 0.021 mmol) was cyclized with secondgeneration Grubbs catalyst, RuCl2(dCHPh)(PCy3)(bismesitylimidazolidinylidene) (4.5 mg, 5.3 µmol), in boiling toluene (13 mL) for 0.5 h by the same procedure used in the preparation of 30 to give tetracyclic ketone 8 (5.0 mg, 87%) as a colorless oil. [R]D21 +24.4 (c 0.16, CHCl3); IR (neat) 2950, 1724, 1455, 1379 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.88 (br s, 1 H), 3.19 (ddd, J ) 12.5, 12.2, 3.2 Hz, 1 H), 3.13 (br s, 1 H), 2.33 (m, 1 H), 2.30 (m, 1 H), 2.06 (br d, J ) 16.7 Hz, 1 H), 1.89 (m, 1 H), 1.85 (m, 1 H), 1.80 (ddd, J ) 14.7, 9.4, 2.6 Hz, 1 H), 1.65 (m, 1 H), 1.64 (s, 3 H), 1.58 (m, 1 H), 1.47 (m, 1 H), 1.44 (m, 1 H), 1.26 (ddd, J ) 13.3, 10.1, 7.6 Hz, 1 H), 1.12 (s, 3 H), 1.03 (s, 3 H), 0.94 (d, J ) 6.8 Hz, 3 H), 0.69 (ddd, J ) 9.4, 8.8, 6.2 Hz,

J. Org. Chem, Vol. 69, No. 23, 2004 7807

Watanabe et al. 1 H), 0.60 (dd, J ) 12.2, 8.8 Hz, 1 H); 13C NMR (67.8 MHz, CDCl3) δ 211.3, 139.4, 132.3, 71.9, 45.7, 45.5, 39.6, 36.1, 35.0, 29.5, 28.7, 27.8, 26.2, 25.3, 23.6, 23.2. 22.8, 15.4, 15.3; HRMS (FAB) m/z calcd for C19H28NaO (M + Na)+ 295.2038, found 295.2023 (∆ -1.5 mmu). Allylic Oxidation of 8. A solution of tetracyclic ketone 8 (1.8 mg, 6.6 µmol) and SeO2 (11.8 mg, 0.11 mmol) in dioxane (0.5 mL) was refluxed for 1 h. The mixture was cooled to room temperature and filtered through a pad of Celite, and the residue was washed with dioxane. The filtrate and washings were concentrated, and the residue was diluted with ether (5 mL), washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and concentrated. The residue was chromatographed on silica gel (0.5 g, ether 5:1) to give aldehyde 9 (1.6 mg, 85%) as colorless prisms. Mp 145.5-147.5 °C (hexane); [R]D21 +29.5 (c 0.078, CHCl3); IR (neat) 2940, 1722, 1687, 1594, 1458 cm-1; 1 H NMR (500 MHz, CDCl3) δ 9.28 (s, 1 H), 6.23 (d, J ) 1.9 Hz, 1 H), 3.36 (br s, 1 H), 3.09 (ddd, J ) 14.0, 10.9, 3.1 Hz, 1 H), 2.58 (dddd, J ) 17.1, 13.4, 3.7, 1.7 Hz, 1 H), 2.38 (m, 1 H), 2.30 (m, 1 H), 2.02 (m, 1 H), 1.94 (ddd, J ) 15.6, 5.3, 5.3 Hz, 1 H), 1.85 (m, 1 H), 1.79 (m, 1 H), 1.70 (m, 1 H), 1.45-1.25 (m, 3 H), 1.10 (s, 3 H), 1.05 (s, 3 H), 0.98 (d, J ) 6.9 Hz, 3 H), 0.72 (m, 2 H); 13C NMR (100 MHz, C6D6) δ 208.1, 193.8, 159.3, 146.5, 72.0, 46.9, 45.0, 39.8, 34.6, 29.6, 29.0, 28.4, 28.1, 25.8, 23.7, 23.3, 22.8, 15.4, 15.0; HRMS (FAB) m/z calcd for C19H26NaO2 (M + Na)+ 309.1831, found 309.1853 (∆ +2.2 mmu).

7808 J. Org. Chem., Vol. 69, No. 23, 2004

Acknowledgment. We would like to thank Prof. Daisuke Uemura (Nagoya University) for his helpful discussion and Ms. Satomi Omura for her technical assistance. We appreciate Prof. J. D. Winkler (The University of Pennsylvania) for providing the spectral data for racemic aldehyde 9. This work has been supported in part by the 21st Century COE program and a Grant-in-Aid for Scientific Research (Ministry of Education, Culture, Sports, Science and Technology, Japan). Financial support from the Suntory Institute for Bioorganic Research, Shorai Foundation for Science and Technology, Yamada Science Foundation, the Fujisawa Foundation, the Naito Foundation, University of Tsukuba Research Projects, and Wako Pure Chemical Industries, Ltd. is also acknowledged. The IR and NMR spectra were recorded at the Chemical Analysis Center, University of Tsukuba. Supporting Information Available: General experimental procedures, experimental procedures, and spectral data for the synthesis of tricyclic ketone 5, as well as 1H and/or 13C NMR charts for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. JO048833L