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. Author manuscript; available in PMC: 2012 Apr 11.
Published in final edited form as: Angew Chem Int Ed Engl. 2011 Mar 11;50(16):3672–3676. doi: 10.1002/anie.201100313

Enantioselective Total Synthesis of (−)-Jiadifenolide**

Jing Xu 1, Lynnie Trzoss 1, Weng K Chang 1, Emmanuel A Theodorakis 1,*
PMCID: PMC3159889  NIHMSID: NIHMS315991  PMID: 21400650

Abstract

The first total synthesis of jiadifenolide (1), a potent neurotrophic modulator, has been reported. Highlights of the synthesis include: construction of the B ring via an asymmetric Robinson annulation; assembly of the E ring lactone via a novel acid-induced cascade reaction; and Pd(0)-mediated carbomethoxylation and methylation reactions for the construction of the C and A rings respectively.

Keywords: Alzheimer’s disease, neurotrophic agent, Illicium, natural product, total synthesis, cascade reaction

Neurotrophic factors (neurotrophins) are a family of proteins that regulate nervous system development and maintain adult nervous system plasticity and structural integrity.[i] Their ability to exhibit neuroprotective properties explains the interest they have received in the context of acute nervous system injury or for the treatment of chronic neurodegenerative diseases. Unfortunately, due to their chemical structure, these proteins cannot persist in the body for an extended period and also cannot cross the brain-blood barrier. In contrast, small molecules that are able to mimic neurotrophic factors, or to induce neurotrophic factor biosynthesis, possess a distinct pharmacological advantage and provide an attractive starting point for the development of medicines against various neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease.[1,ii]

In search of new small molecules with neurotrophic modulatory properties, Fukuyama and co-workers isolated three novel pentacyclic sesquiterpenoids, jiadifenolide (1) and jiadifenoxolanes A (2) and B (3) from the pericarps of Illicium jiadifengpi (Figure 1).[ iii ] Among them, 1 and 2 have shown potent activities in promoting neurite outgrowth in primary cultured rat cortical neurons at concentrations as low as 10 nM and 1 μM respectively. From the standpoint of chemical structure, these compounds belong to a family of caged seco-prezizaanes that also includes neomajucin (4),[iv] anisatin (5)[v] and jiadifenin (6).[vi] The combination of a challenging caged-like motif and intriguing biological properties has invited the development of efficient strategies toward their chemical syntheses[vii, viii] culminating in a racemic synthesis of 6 by the Danishefsky group.[ix] Herein, we report the first total synthesis of (−)-jiadifenolide (1), one of the most structurally challenging and biologically potent caged seco-prezizaanes. Our strategy proceeds in an enantioselective manner and can be used to explore and enhance the biological and pharmacological activities of this family.

Figure 1.

Figure 1

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Representative structures of natural products from Illicium species with potent neuropharmacological activities.

Scheme 1 highlights the overall retrosynthetic strategy toward jiadifenolide (1). Key to the synthesis was a remarkable oxidative conversion of lactone 9 to tetracyclic motif 8 that installed the desired E ring. In the forward direction, compound 8 could be further functionalized at the A ring to produce 7 and, after C10 oxidation and hemiacetalization, could give rise to 1. On the other hand, the carbon framework of 9 can be traced to tricyclic motif 10. Further disconnection across the C ring of 10 suggests the “Hajos-Parrish-like”[10c] diketone 11 as an appropriate synthetic precursor that can be available in high enantiomeric purity.[x,xi]

Scheme 1.

Scheme 1

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Retrosynthetic strategy toward 1.

Our synthetic approach departed from commercially available diketone 12 that was converted to compound 13[xii] in two steps and 63% yield (Scheme 2). D-prolinamide/PPTS-catalyzed[12c] optimized asymmetric aldol condensation of 13 produced optically enriched diketone 11 in 74% yield (> 90% ee). Regio- and stereoselective reduction of the more electrophilic C1 carbonyl group of 11 followed by selected silylation of the resulting alcohol using NH4NO3/TBS-Cl conditions[11d, xiii] produced compound 14 (2 steps, 92% yield). Conversion of 14 to 15 was accomplished via a sequence of two steps: a) carboxylation of the C5 enolate with magnesium methyl carbonate[ xiv ] followed by trapping of the resulting carboxylic acid with Meerwein’s salt (Et3O+BF4−);[xv] and b) formation of the extended TMS-enolate,[ xvi ] followed by methylation under TBAF/MeI conditions. This sequence of reactions constructed the C5 quaternary center as a single isomer in 43% overall yield. Global reduction of 15 followed by selective silylation of the primary alcohol and oxidation of the C6 secondary alcohol formed 16 in 85% yield. The C6 carbonyl group of 16 was then converted to the corresponding vinyl triflate that, after Pd(0)-catalyzed carbomethoxylation[ xvii ] followed by TFA-mediated desilylation and lactonization to form lactone 10 (69% for 2 steps).

Scheme 2.

Scheme 2

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Synthesis of ABC ring. Reagents and conditions: a) D-prolinamide (30 mol%), PPTS (30 mol%), MeCN, 40 °C, 14 d, 74% (> 90% ee); b) NaBH4 (0.25 equiv), EtOH, 0 °C, 1 h; c) TBSCl, NH4NO3, DMF, RT, 12 h, 92% for 2 steps; d) MMC, DMF, 130 °C, 3 h, then Et3O+BF4−, iPr2NEt, CH2Cl2, 0 °C, 5 min; e) TMSOTf, 2,6-lutidine, CH2Cl2, 0 °C to RT, 1 h; then TBAF (1.0 equiv), MeI, THF, −78 °C to RT, 3 h, 43% for 2 steps; f) LiAlH4, THF, 0 °C to RT, 1 h; g) TBSCl (1.0 equiv), imidazole, CH2Cl2, 0 °C, 30 min; h) IBX, DMSO, 80 °C, 1 h, 85% for 3 steps; i) KHMDS, PhNTf2, THF, −78 °C, 1 h; j) CO (1 atm), Pd(PPh3)4 (1 mol%), MeOH, DMF, Et3N, 50 °C, 2 h, then TFA, CH2Cl2, RT, 5 h, 69% for 2 steps. PPTS = pyridinium p-toluenesulfonate, TBS = tert-butyldimethylsilyl, MMC = magnesium methyl carbonate, DMF = dimethylformamide, TMS = trimethylsilyl, Tf = trifluoromethanesulfonyl, TBAF = tetra-n-butylammonium fluoride, THF = tetrahydrofuran, IBX = 2-iodoxybenzoic acid, DMSO = dimethyl sulfoxide, HMDS = hexamethyldisilazane, TFA = trifluoroacetic acid, RT = room temperature.

The next task was to install the desired C6-C7 trans-diol functionality on the tricyclic motif 10. Along these lines, 10 was treated with NaOH/H2O2 to selectively and quantitatively produce epoxide 17 (Scheme 3). We projected that a Ru(III)-based[xviii] direct oxidative cleavage of the terminal alkene to the corresponding carboxylic acid would trigger a “6-exo-tet” epoxide opening[xix] to furnish the desired lactone 9 in one pot. However, under all conditions explored, this reaction led to decomposition of the starting material. Instead, we were pleased to find out that a stepwise sequence can achieve the desired conversion. The optimized approach involves oxidative cleavage of the terminal alkene to form the corresponding aldehyde under OsO4 (cat.)/NaIO4 conditions followed by Jones oxidation[9] to produce the C11 carboxylic acid. Gratifyingly, these conditions triggered the desired “6-exo-tet” epoxide opening to produce lactone 9 in 70% overall yield. The structure of lactone 9 was unambiguously confirmed via a single crystal X-ray analysis.[xx] Notably, this compound represents the core structure of several natural products of the Illicium species and can be readily produced in multi-gram scale.

Scheme 3.

Scheme 3

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Synthesis of E ring. Reagents and conditions: a) H2O2, 3N NaOH, THF, 0 °C to RT, 5 h, 99%; b) OsO4 (1 mol%), NaIO4, 1,4-dioxane, H2O, RT, 12 h; c) Jones reagent, acetone, 0 °C, 30 min, 70% for 2 steps; d) TBAF, THF, RT, 30 min, 95%; e) mCPBA, THF, 50 °C, 3 h; f) Dess-Martin-periodinane, acetone, RT, 2 h, 38% for 2 steps. THF = tetrahydrofuran, Jones reagent = CrO3 in diluted H2SO4, TBAF = tetra-n-butylammonium fluoride, mCPBA = 3-chloroperbenzoic acid, RT = room temperature.

With compound 9 in hand, we sought to introduce a hydroxyl group at the C4 center. To this end, deprotection of the C1 silyl ether produced compound 18. Epoxidation of the C3-C4 double bond, followed by treatment of the resulting epoxide with Dess-Martin periodinane gave rise to lactone 8 containing the desired E ring (38% for 2 steps). The structure of 8 was also confirmed by a single crystal X-ray analysis (Scheme 3).[20]

A reasonable scenario for the remarkable conversion of 18 to 8 is presented in Scheme 4. Treatment of 18 with mCPBA produced epoxide I as a single isomer. We postulate that this epoxidation was promoted by the C1 homoallylic alcohol and occurred from the β-face of the A ring of 18.[xxi] DMP treatment of I induces oxidation of the C1 hydroxyl group to yield ketone II generating in situ acid. The latter could further induce formation of the C2-C3 enone with concomitant generation of the C4 tertiary alcohol, which is axial and in close proximity to the C11 carbonyl group triggering the desired translactonization. The driving force of this rearrangement may be due to the formation of a thermodynamically favored 5-membered ring lactone.

Scheme 4.

Scheme 4

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Plausible mechanistic scenario for the conversion of 18 to 8.

With enone 8 in hand, we then focused on the final modification of the A ring (Scheme 5). The C2-C3 double bond of 8 was hydrogenated under standard Pd/C-catalyzed conditions, and the C7 secondary alcohol was silylated using TES triflate to afford 19 (90% overall yield). Various methylenation approaches were attempted in order to install the missing C15 carbon at the C1 center. All these efforts (Wittig reaction, titanium-[xxii] or zinc-based[xxiii] reagents) were unsuccessful, presumably due to the steric hindrance of the C1 carbonyl group. Gratifyingly, an alternative strategy based on Pd(0)-mediated cross coupling installed the desired C15 carbon. To this end, selective conversion of the C1 carbonyl group of 19 to the corresponding vinyl triflate followed by treatment with excess of AlMe3 under palladium catalysis[xxiv] furnished compound 7 in 57% yield. Eventually, the C1-C2 double bond of 7 was selectively hydrogenated from the α-face under 90 bar of H2 using PtO2 as the catalyst to form the corresponding C1-C15 equatorial methyl group. The remaining functionalization at the C10 center was performed using conditions employed by the Danishefsky group toward the synthesis of jiadifenin.[9]α-Hydroxylation using NaHMDS and the Davis oxaziridine[xxv] produced the α-hydroxy lactone 20 as a single isomer. Without extensive purification, compound 20 was oxidized under Jones conditions and concomitant desilylation of the C7 silyl ether to produce (−)-jiadifenolide (1, 33% over 3 steps). The synthetic material, thus obtained, possessed identical spectroscopic and analytical properties to those reported for the natural product.[3] The absolute stereochemistry of 1 was confirmed by Cu-radiation X-ray analysis,[20] which was in agreement with the original assignment.[3]

Scheme 5.

Scheme 5

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Completion of the synthesis. Reagents and conditions: a) H2 (6 atm), 10% Pd/C (5 mol%), MeOH, RT, 24 h; b) TESOTf, 2,6-lutidine, THF, 0 °C to RT, 30 min, 90% for 2 steps; c) KHMDS, Comins reagent, THF, −78 °C, 1.5 h; d) AlMe3, Pd(PPh3)4 (50 mol%), THF, RT, 2 h, 57% for 2 steps; e) H2 (90 atm), PtO2 (20 mol%), MeOH, RT, 24 h; f) NaHMDS, (±)-trans-2-(phenylsulfonyl)-3-phenyloxaziridine, THF, −78 °C to RT, 1.5 h; g) Jones reagent, acetone, 0 °C, 15 min, 33% for 3 steps. TES = triethylsilyl, Tf = trifluoromethanesulfonyl, HMDS = hexamethyldisilazane, Comins reagent = N-(5-chloro-2-pyridyl)triflimide, Jones reagent = CrO3 in diluted H2SO4, RT = room temperature.

In conclusion, we have accomplished the first total synthesis of (−)-jiadifenolide in 1.5% overall yield (25 steps in total) from commercially available cyclopentane-1,3-dione (12). Key to the strategy is an acid-induced cascade reaction[xxvi] that forms the E ring lactone of 1. The C and A rings of 1 were produced via a Pd(0)-catalyzed carbomethoxylation and a Pd(0)-mediated methylation respectively. The overall approach is enantioselective, efficient and suitable for scale-up. Importantly, the tetracyclic lactone 9 can be readily available and represents a significant scaffold for the synthesis of related natural products and analogues. Synthesis and methodical biological evaluation of such molecules could lead to the identification of more potent and selective neurotrophic molecules for medicinal applications.

Supplementary Material

anie201100313SI

Footnotes

**

We gratefully acknowledge the National Institutes of Health (NIH) for financial support of this work through Grant Number R01 GM081484-01. We thank the National Science Foundation for instrumentation grants CHE9709183 and CHE0741968. We also thank Dr. Anthony Mrse (UCSD NMR Facility), Dr. Yongxuan Su (UCSD MS Facility) and Dr. Arnold L. Rheingold and Dr. Curtis E. Moore (UCSD X-Ray facility).

Supporting information for this article is available on the WWW under http://

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Supplementary Materials

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