Synthesis of Curvulone B Using the 2-Chlorobenzyl Protecting Group

Abstract

A total synthesis of curvulone B has been completed using a Friedel–Crafts reaction and a highly cis-selective intramolecular oxa-Michael addition. The 2-chlorobenzyl protecting group was employed and found to have much greater Lewis acid stability compared to the simple benzyl group.

Key words

tetrahydropyran - metathesis - Friedel–Crafts - protecting groups - cyclization

• References and Notes

• 1a Dai J, Krohn K, Flörke U, Pescitelli G, Kerti G, Papp T, Kövér KE, Bényei AC, Draeger S, Schulz B, Kurtán T. Eur. J. Org. Chem. 2010; 6928

Dothiolerone A, also known as phomopsin B, is related to this group of compounds:
• 1b Izuchi Y, Koshino H, Hongo Y, Kanomata N, Takahashi S. Org. Lett. 2011; 13: 3360
• 2a Bates RW. Song P. Tetrahedron 2007; 63: 4497
• 2b Bates RW, Song P. Synthesis 2010; 2935
• 2c Bates RW, Lek TG. Synthesis 2014; 46: 1731

For reviews of intramolecular oxa-Michael addition, see:
• 3a Fuwa H. Heterocycles 2012; 86: 1255
• 3b Nising CF, Bräse S. Chem. Soc. Rev. 2012; 41: 988
• 3c Larossa I, Romea P, Urpí F. Tetrahedron 2008; 64: 2683
• 3d Clarke PA, Santos S. Eur. J. Org. Chem. 2006; 2045
• 4 Takahashi S, Akita Y, Nakamura T, Koshino H. Tetrahedron: Asymmetry 2012; 23: 952
• 5 Denmark SE, Regens CS, Kobayashi T. J. Am. Chem. Soc. 2007; 129: 2774
• 6 Comber MF, Sargent MV, Skelton BW, White AH. J. Chem. Soc., Perkin Trans. 1 1989; 441
• 7 Schoenberg A, Bartoletti I, Heck RF. J. Org. Chem. 1974; 39: 3318
• 8 The alternative would be three steps: substitution with cyanide, hydrolysis, and esterification; see ref. 6.
• 9 Chincilla R, Nájera C. Chem. Rev. 2007; 107: 874
• 10 Goure WF, Wright ME, Davis PD, Labadie SS, Stille JK. J. Am. Chem. Soc. 1984; 106: 6417
• 11 Hori H, Nishida Y, Ohrui H, Meguro H. J. Org. Chem. 1989; 54: 1346

4-Bromo- and 4-chlorobenzyl ethers have been found to be more stable to TFA than simple benzyl ethers:
• 12a Yamashiro D. J. Org. Chem. 1977; 42: 523

4-Chloro, 4-iodo, and 2-bromobenzyl ethers have been employed in carbohydrate chemistry. The groups were cleaved by amination, and considered to be of ‘comparable chemical inertness’ to simple benzyl ethers:
• 12b Plante OJ, Buchwald SL, Seeburger PH. J. Am. Chem. Soc. 2000; 122: 7148
• 13 The yield obtained using the 4-fluorobenzyl group was similar.

2-Halobenzyl ethers, cleaved by hydrogenolysis, have been reported in the patent literature:
• 14a Cao SX, Feng J, Imaeda Y, Gwaltney SL, Hosfield DJ, Takakura N, Tang M. US 2007197532 A1, 2007
• 14b Alihodzic S, Bosnar M, Culic O, Erakovic Haber V, Hutinec A, Jelic D, Kragol G, Marjanovic N, Marusic-Istuk Z, Ribic M, Vela V. US 2008221046 A1, 2008

Such ethers are still labile to strong Lewis acids, such as tin tetrachloride:
• 15a Li N.-S, Lu J, Piccirilli JA. Org. Lett. 2007; 9: 3009

Or zinc chloride:
• 15b Huston RC, Gyorgy HH. J. Am. Chem. Soc. 1950; 72: 4171
• 16 Connon SJ, Blechert S. Angew. Chem. Int. Ed. 2003; 42: 1900
• 17 Takahashi et al. reported that cross-metathesis does not proceed with the unprotected alcohol 3a (ref. 4). We also found this to be the case. We propose that an unreactive chelate forms.
• 18a Samojłowicz C, Bieniek M, Pazio A, Makal A, Woźniak K, Poater A, Cavallo L, Wójcik J, Zdanowski K, Grela K. Chem. Eur. J. 2011; 17: 12981

For a helpful discussion of metathesis conditions, see:
• 18b Bieniek M, Michrowska A, Usanov DL, Grela K. Chem. Eur. J. 2008; 14: 806

For the specific production of trans-THPs in this way, see:
• 19a Banwell MG, Bui CT, Pham HT. T, Simpson GW. J. Chem. Soc., Perkin Trans. 1 1996; 967
• 19b Banwell MG, Bissett BD, Bui CT, Pham HT. T, Simpson GW. Aust. J. Chem. 1998; 51: 9
• 20 2-Chlorotoluene was detected in the crude reaction mixture.
• 21 A solution of compound 14c (69 mg, 0.128 mmol) in EtOAc (5 mL) containing 20% Pd(OH)₂ on carbon (30 mg) was stirred overnight under hydrogen (balloon). The mixture was filtered through Celite and concentrated. Purification by flash chromatography on silica eluting with 50% EtOAc–hexane gave 1 as a colorless oil (42 mg, 81%). [α]_D ²¹ –19 (c 0.28, EtOH) {lit.:^1a,⁴ [a]_D ²⁵ –22 (c 0.27, EtOH), –15.1 (c 0.52, EtOH)]. ¹H NMR (400 MHz, CDCl₃): δ = 9.77 (s, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 6.21 (d, J = 2.3 Hz, 1 H), 4.13 (m, 1 H), 3.94 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.5 Hz, 1 H), 3.30 (dd, J = 14.2, 10.3 Hz, 1 H), 2.57 (dd, J = 14.3, 3.2 Hz, 1 H), 1.84 (m, 1 H), 1.67 (m, 1 H), 1.63 (m, 1 H), 1.57 (m, 1 H), 1.44 (m, 1 H), 1.27 (m, 1 H), 1.17 (d, J = 5.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): J = 204.24, 172.44, 159.51, 159.41, 135.77, 120.88, 111.73, 104.05, 77.90, 74.87, 52.10, 49.04, 39.74, 32.68, 30.73, 23.11, 21.50.