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. 2019 Feb 20;141(7):3083-3099.
doi: 10.1021/jacs.8b12247. Epub 2019 Feb 11.

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

Kevin Hung  1 , Matthew L Condakes  1 , Luiz F T Novaes  1 , Stephen J Harwood  1 , Takahiro Morikawa  1 , Zhi Yang  1 , Thomas J Maimone  1
Affiliations

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes

Kevin Hung et al. J Am Chem Soc. .

Abstract

The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs but failed in delivering a crucial hydroxy group in the final step. Insight gathered during these studies, however, ultimately led to a synthesis of the pseudoanisatinoids along with the allo-cedrane natural product 11- O-debenzoyltashironin. A second-generation strategy was then developed to access the more highly oxidized majucinoid compounds including jiadifenolide and majucin itself. Overall, one dozen natural products can be accessed from an abundant and inexpensive terpene feedstock. A multitude of general observations regarding site-selective C(sp3)-H bond functionalization reactions in complex polycyclic architectures are reported.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
(A) Illicium sesquiterpene family member subtypes characterized by lactonization pattern. Inset: shared skeleton, with an oxidation “heat map” showing the most commonly observed sites of oxidation. (B) Representative bioactive Illicium sesquiterpenes that have been studied by synthetic chemists.
Figure 2.
Figure 2.
Fukuyama’s proposed biosynthesis of the Illicium sesquiterpenes wherein farnesyl pyrophosphate undergoes various cyclizations and rearrangements to reach the core skeletons of the Illicium sesquiterpenes, which are then extensively oxidized to arrive at the natural products themselves.
Figure 3.
Figure 3.
(A) Overarching synthetic strategy to convert cedrol (15) to the Illicium sesquiterpenes. (B) Known enzymatic (left) and chemical (right) methods for the oxidation of 15. (C) Precedented ring shift to convert the cedrane skeleton to the allo-cedrane one.
Figure 4.
Figure 4.
(A) Successful preparation of the seco-prezizaane skeletone from 15 featuring C7 oxidation and an α-ketol rearrangement. (B) Extension of the oxidative lactionization reaction to other keto-acid substrates. (C) and (D) Attempted oxidations of terpene-derived substrates leading to rearranged products.
Figure 5.
Figure 5.
(A) Synthetic studies towards a successful C4 oxidation (B) Optimization of the iron(oxo)-catalyzed C4 oxidation by examination of ligand and terminal oxidant effects
Figure 6.
Figure 6.
Current list of Illicium sesquiterpene natural products accessible from (+)-cedrol.
Scheme 1.
Scheme 1.
Formation of the Allo-Cedrane Skeletona aReagents and conditions: (a) CuSO4•5H2O (10 mol%), PhH, 80 °C, 4 h; (b) PhI(OAc)2 (3.0 equiv), tert-butyl hydroperoxide (70 wt% in H2O, 4.0 equiv), EtOAc, –20 °C, 12 h, 43% (two steps); (c) SeO2 (2.2 equiv), 1,4-dioxane, 120 °C, 14 h; (d) NaClO2 (10.0 equiv), NaH2PO4•H2O (8.0 equiv), 2-methyl-2-butene (25 equiv), t-BuOH:H2O (1:1), 19 h, 73% (two steps); (e) H2O2 (50 wt% in H2O, 10.0 equiv), NaOH (3.0 M, 4.0 equiv), MeOH, 0 → 23 °C, 7 h, 16% (81% BRSM); (f) TiCl4 (1.2 equiv), DCE, 50 °C, 4 h, 14%.
Scheme 2.
Scheme 2.
Synthesis of 14-Deoxydebenzoyldunnianina aReagents and conditions: (a) Et3OPF6 (3.0 equiv), proton-sponge (3.0 equiv), DCM, 50 °C, 12 h; (b) TBAF (3.0 equiv), AcOH (3.0 equiv), THF, 12 h, 50% (two steps); (c) VO(acac)2 (10 mol%), TBHP (ca. 5 M in decane, 2.5 equiv), PhH, 45 °C, 15 h, 99%; (d) KOH (10 wt% in H2O, 10.0 equiv), EtOH, 3 h; (e) Me4NBH(OAc)3 (3.0 equiv), MeCN/THF/AcOH (4:1:1), –40 °C, 12 h, 38% (two steps); (f) Me4NBH(OAc)3, MeCN/AcOH (3:1), –40 °C, 12 h; (g) NaH (60 wt% in mineral oil, 3.0 equiv), THF, 1 h, 95% (two steps from 52) or 71% (two steps from 51); (h) LDA (3.0 equiv), THF, –78 °C, 1 h, 71%; (i) OsO4 (1.2 equiv), pyridine, 12 h, then add NaHSO3 (10.0 equiv), MeOH/H2O (3:1), 60 °C, 4 h, 63%; (j) OsO4 (1.2 equiv), pyridine, 12 h, then add NaHSO3 (10.0 equiv), MeOH/H2O (3:1), 60 °C, 4 h, 94%; (k) TPAP (10 mol%), NMO (2.1 equiv), DCM/MeCN (9:1), 18 h; (l) LiAlH4 (2.0 M in THF, 3.1 equiv), THF, –78 °C, 2 h, 75% (two steps). Proton-sponge = 1,8-bis(dimethylamino)naphthalene, TBAF = tetra-n-butylammonium fluoride, TBHP = tert-butyl hydroperoxide, LDA = lithium diisopropylamide, TPAP = tetrapropylammonium perruthenate, NMO = N-methylmorpholine N-oxide.
Scheme 3.
Scheme 3.
Successful Oxidation of C14a aReagents and conditions: (a) PhI(OAc)2 (3.0 equiv), I2 (1.0 equiv), cyclohexane, hν (visible), 1.5 h, 73%; (b) Me3OBF4 (1.5 equiv), proton sponge (1.5 equiv), DCM, 55 °C, 12 h, 97%; (c) NaIO4 (5.0 equiv), RuCl3•xH2O (0.1 equiv), CCl4:MeCN:H2O (3:3:4), 1 h, 72%; d) CuBr2 (3.0 equiv), t-BuOH (3.0 equiv), diglyme, 150 °C, 12 h; (e) KOH (1.0 equiv), KOt-Bu (3.0 equiv), DMSO, 14 h, 45% (two steps), d.r. = 4:1; (f) NaH (5.0 equiv), TBSCl (4.0 equiv), THF, 65 °C, 8 h then add 3.0 M HCl (16 equiv), 65 °C, 16 h, 88%.
Scheme 4.
Scheme 4.
Formal Synthesis of 11-O-Debenzoyltashironin (4) and 3,6-Dideoxy-10-Hydroxypseudoanisatin (72)a aReagents and conditions: (a) TsOH•H2O (1.5 equiv), DCE, 60 °C, 10 h, 1:1.4 d.r.; (b) lithium naphthalenide (3.0 equiv), THF, –78 °C, 10 min, 74% (two steps), >20:1 d.r.; (c) [Fe(mep)(MeCN)2][(SbF6)2] (50 mol%), TBHP (3.0 equiv), MeCN, 1 h, 56% 69, 20% 70; (d) TMSCl (10.0 equiv), NaI (5.0 equiv), MeCN, 80 °C, 45 min, 46%.
Scheme 5.
Scheme 5.
Synthesis of Pseudoanisatin (5), 3-Oxopseudo-anisatin (79), and 3-Deoxypseudoanisatin (78) aReagents and conditions: (a) TBHP (5.0 equiv), [Fe] (0.5 equiv), Tl(OTf) (0.5 equiv), MeCN, 1 h, 20% 74, 11% 75, 6% 76; (b) Et3OPF6 (3.0 equiv), proton sponge (3.0 equiv), DCE, 85 °C, 12 h then add TFA/H2O (1:1), rt, 45 min, 66%; (c) TMSCl (10.0 equiv), NaI (5.0 equiv), MeCN, 80 °C, 12 h; (d) TBAF (5.0 equiv), AcOH (1.0 equiv), THF, 1 h, 64% (two steps); (e) [Co] (0.1 equiv), PhSiH3 (4.0 equiv), O2 (1 atm), THF, 0 °C, 24 h; (f) OsO4•TMEDA (1.5 equiv), DCM, −78 °C to rt, 2 h; (g) MsCl (10.0 equiv), pyr. (10.0 equiv), DCM, 12 h, then add aq. NaOH (2.0 M), 2 h, 80% (two steps).
Scheme 6.
Scheme 6.
Studies on the Intramolecular C–H Abstraction of the C4 Methine Positiona aReagents and conditions: (a) BH3•THF (1.3 equiv), THF, 1.5 h then NaOH (3.6 equiv), H2O2 (5.0 equiv), 0 °C to rt, 10 min; (b) DMP (1.5 equiv), t-BuOH (3.0 equiv), DCM, rt, 30 min; (c) NaBH4 (2.0 equiv), MeOH, rt, 30 min, 67% (3 steps); Inset: (a) PhI(OAc)2 (1.1 equiv), I2 (0.4 equiv), cyclohexane, hν (visible), 1.5 h then Ac2O (10.0 equiv), H3PO4 (2.0 equiv), 67%; (b) BH3•THF (1.3 equiv), THF, 1.5 h then CrO3•2pyr (25.0 equiv), DCM, 30 min; (c) NaBH4 (1.5 equiv), MeOH, 30 min, 72% over two steps. (d) PhI(OAc)2 (3.0 equiv), I2 (1.0 equiv), DCM, hν (visible), 0 °C, 1.5 h, 93%
Scheme 7.
Scheme 7.
Ruthenium- and Selenium-Based Methods for the Near-Exhaustive Oxidation of 87a aReagents and conditions: (a) RuCl3•xH2O (3 × 3 mol%), KBrO3 (2 × 5.0 equiv), CCl4/MeCN/H2O (2:2:3), 75 °C, 72 h, 72% 89, 7% 90; (b) SeO2 (3.5 equiv), diglyme, 110 °C, 3 h, then K2CO3 (3.0 equiv), Me2SO4 (1.0 equiv), with 4 Å MS (1.0 mass equiv): 55% 91, without 4 Å MS, 43% 91, 15% 92.
Scheme 8.
Scheme 8.
Synthesis of the Majucinoidsa aReagents and conditions: (a) L-selectride (1.2 equiv), THF, −78 °C, 30 min then KOH (10.0 equiv), MeOH, 0 °C, 30 min, 50% (two steps from 89); (b) DMDO (1.5 equiv), 12 h; (c) PhCF3, 170 °C, 2 h; (d) Me4NBH(OAc)3 (7.0 equiv), MeCN/AcOH (3:1), −40 °C, 16 h, 64% (three steps); (e) TsOH•H2O (2.2 equiv), n-BuOH, 150 °C, 26 h, 71%; (f) LHMDS (3.0 equiv), MoOPH (5.0 equiv), THF, −78 → 0 °C, 2.5 h, 65%; (g) [Ru2(PEt3)6(OTf)3](OTf) (0.1 equiv), NMM (0.2 equiv), TFE/dioxane (1:1), 120 °C, 18 h then i-PrOH (3.0 equiv), 120 °C, 5 h, 75%; (h) Mn(dpm)3 (0.2 equiv), TBHP (1.5 equiv), PhSiH3 (2.0 equiv), O2 (1 atm), DCM/i-PrOH (4:1), 0 °C, 20 h, 50%; (i) OsO4•TMEDA (1.0 equiv), DCM, −78 → 0 °C, 2 h then NaHSO3 (10.0 equiv), H2O, 16 h, 61%; (j) MsCl (5.0 equiv), pyr. (10.0 equiv), DCE, rt →80 °C, 15 h, 92%. DMDO = dimethyldioxirane, LHMDS = lithium bis(trimethylsilyl)amide, MoOPH = oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide), dpm = dipivaloylmethane.
Scheme 9.
Scheme 9.
C–H Activation Studies of the Unactivated C13 Methyl Groupa aReagents and conditions: (a) KOH (3.0 equiv), MeOH, 48 h, 91%; (b) [Ir(COD)(OMe)]2 (0.5 mol %), Et2SiH2 (1.5 equiv), THF, 12 h; (c) [Rh(COE)2Cl]2 (2 mol %), (S)-DTBM-SegPhos (4 mol%), norbornene (1.2 equiv), THF, 100 °C, 12 h, 25% (two steps); (d) H2O2 (50 wt% in H2O, 10.0 equiv), KHCO3 (5.0 equiv), 50 °C, 36 h, 76%; (e) NaH (1.1 equiv), ClSO2NH2 (1.5 equiv), 0 → 23 °C, 4 h, 72%; (f) Rh2(esp)2 (3 mol%), PhI(OPiv)2 (1.5 equiv), PhH, 16 h, 63%. esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid.
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References

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