Synthetic Studies of Polycyclic Polyprenylated Acylphloroglucinols: Asymmetric Construction of a Cyclohexanone Moiety

Abstract

As a common intermediate for polycyclic polyprenylated acylphloroglucinols (PPAPs), we successfully synthesized a cyclohexanone moiety that contains two adjacent stereocenters, one of which is a quaternary carbon. Our synthetic strategy relied on an asymmetric Claisen rearrangement using Oppolzer’s camphorsultam and a regioselective Dieckmann condensation.

Key words

polycyclic polyprenylated acylphloroglucinols - cyclohexanone - Claisen rearrangement - Oppolzer’s camphorsultam - Dieckmann condensation

• References and Notes

• 1 Current address: Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
• 2a Ciochina R, Grossman RB. Chem. Rev. 2006; 106: 3963
• 2b Yang X.-W, Grossman RB, Xu G. Chem. Rev. 2018; 118: 3508
• 2c Database for naturally occurring PPAPs: https://organicchemistrydata.org/grossman/ppap/welcome.html (accessed Feb. 20, 2025)
• 3 Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN. Tetrahedron Lett. 1975; 16: 2791
• 4 Xu W.-J, Zhu M.-D, Wang X.-B, Yang M.-H, Luo J, Kong L.-Y. J. Nat. Prod. 2015; 78: 1093
• 5 Gustafson KR, Blunt JW, Munro MH. G, Fuller RW, McKee TC, Cardellina JH. II, McMahon JB, Cragg GM, Boyd MR. Tetrahedron 1992; 48: 10093
• 6 Yan X.-T, An Z, Huangfu Y, Zhang Y.-T, Li C.-H, Chen X, Liu P.-L, Gao J.-M. Phytochemistry 2019; 159: 65

For reviews on synthetic studies of PPAPs, see:
• 7a Njardarson JT. Tetrahedron 2011; 67: 7631
• 7b Richard J.-A, Pouwer RH, Chen DY.-K. Angew. Chem. Int. Ed. 2012; 51: 4536
• 7c Simpkins NS. Chem. Commun. 2013; 49: 1042
• 7d See also Ref. 2b.
• 8a Shimizu Y, Shi S.-L, Usuda H, Kanai M, Shibasaki M. Angew. Chem. Int. Ed. 2010; 49: 1103
• 8b Shimizu Y, Shi S.-L, Usuda H, Kanai M, Shibasaki M. Tetrahedron 2010; 66: 6569
• 9 Sparling BA, Moebius DC, Shair MD. J. Am. Chem. Soc. 2013; 135: 644
• 10 Uwamori M, Nakada M. Tetrahedron Lett. 2013; 54: 2022
• 11a Bellavance G, Barriault L. Angew. Chem. Int. Ed. 2014; 53: 6701
• 11b Bellavance G, Barriault L. J. Org. Chem. 2018; 83: 7215
• 12a Ting CP, Maimone TJ. J. Am. Chem. Soc. 2015; 137: 10516
• 12b Ting CP, Maimone TJ. Synlett 2016; 27: 1443
• 13 Ji Y, Hong B, Franzoni I, Wang M, Guan W, Jia H, Li H. Angew. Chem. Int. Ed. 2022; 61: e202116136
• 14 Horeischi F, Biber N, Plietker B. J. Am. Chem. Soc. 2014; 136: 4026
• 15 Takao K, Sakamoto S, Touati MA, Kusakawa Y, Tadano K. Molecules 2012; 17: 13330
• 16 Kanai, Shibasaki and co-workers constructed a cyclohexanone moiety of 1 using an asymmetric Diels–Alder reaction (see Ref. 8). We set keto-ester 5 with a methoxycarbonyl group at the C-5 position as an intermediate that is different from that of the Kanai–Shibasaki group.
• 17a For the synthesis of exo-PPAPs, see: Ahmad NM, Rodeschini V, Simpkins NS, Ward SE, Blake AJ. J. Org. Chem. 2007; 72: 4803
• 17b For the synthesis of endo-PPAPs, see: Biber N, Möws K, Plietker B. Nat. Chem. 2011; 3: 938
• 18a Takao K, Hayakawa N, Yamada R, Yamaguchi T, Morita U, Kawasaki S, Tadano K. Angew. Chem. Int. Ed. 2008; 47: 3426
• 18b Takao K, Hayakawa N, Yamada R, Yamaguchi T, Saegusa H, Uchida M, Samejima S, Tadano K. J. Org. Chem. 2009; 74: 6452
• 19 Patwardhan SA, Gupta AS, Dev S. Agric. Biol. Chem. 1976; 40: 697
• 20 Inanaga J, Baba Y, Hanamoto T. Chem. Lett. 1993; 22: 241
• 21a The configuration of the two adjacent stereocenters in 7 was determined by converting 7 into known compound 11:¹⁵
• 21b (i) NaBH₄, EtOH; (ii) Amberlyst 15, CH₂Cl₂; (iii) Dess–Martin periodinane, CH₂Cl₂.
• 22 Recently, we also reported the asymmetric synthesis of cyclopentene compounds containing all-carbon quaternary stereocenters via (3+2) cycloaddition using Oppolzer’s camphorsultam, see: Oga M, Takamatsu Y, Ogura A, Takao K. J. Org. Chem. 2022; 87: 8788