Chapter Three The Intramolecular Oxa-Michael Addition – Total Synthesis of Gonytolide C
Total Synthesis of Gonytolide C
Revised Intramolecular Oxa-Michael Addition Strategy
The difficulties encountered with installation of a chiral butenolide precursor 138a or furan chromanone 290 via the intermolecular conjugate addition of furan-based nucleophiles to a chromone substrate led us to consider an alternative synthetic strategy towards gonytolide C (30a) (Scheme 3.1). Our revised synthesis involved the key change whereby the conjugate addition step and construction of the required carbon framework for gonytolide C (30a) were separated into two independent disconnections.
As gonytolide C (30a) would be available from its furan chromanone precursor 290, an alternative approach to establish this chromanone core 290 could be achieved by disconnection of the carbon-oxygen bond through a base-catalysed intramolecular oxa-Michael addition of enone 291. Recent developments in the organocatalytic cyclisation of enones to synthesise enantioenriched flavanones77,78 also revealed the possibility that the organocatalytic version of this intramolecular oxa-Michael cyclisation could be employed to access our required chromanone core 290 in enantioenriched form. Enone 291 would in turn be constructed via an Horner-Wadsworth-Emmons (HWE) olefination between β-ketophosphonate 292 and furan ketone 293, which could be synthesised from commercially available orcinol (165) and furan (268), respectively.
Model Studies of the oxa-Michael Addition Reaction
To examine the viability of the proposed intramolecular oxa-Michael addition strategy, simplified enones 294 and 295 were synthesised to enable investigation of the base-catalysed cyclisation to construct chromanone 296 as a model system (Scheme 3.2).
Accordingly, trisubstituted acetophenone 182 was used to synthesise the second model enone 295, which possesses the same substitution pattern on the aromatic ring as natural gonytolide C (30a). One of the free hydroxyl groups in acetophenone 182 was first protected as an ethoxymethyl (EOM) ether since the direct condensation of trisubstituted acetophenone 182 with furfural (197) could not be achieved. Protected acetophenone 297 was then subjected to the same condensation conditions as acetophenone 223, to provide enone 298 in good yield. Subsequent EOM deprotection of enone 298 with concentrated hydrochloric acid in isopropanol afforded the required enone 295 in an excellent 97% yield.
Attention now turned to the cyclisation of model enones 294 and 295 to generate the corresponding furan-substituted chromanone core. Although cyclisations of hydroxychalcones to flavanones are generally achieved in good yields under basic conditions,137,138 successful conversion of enone 294 to furan chromanone (±)-285 was only reported using polyethylene glycol,139 microwave irradiation140 or using a Lewis acid catalyst in an ionic liquid.141 A brief screen of basic conditions was therefore conducted initially in an attempt to cyclise the enone substrate 294 to chromanone (±)-285 (Table 3.1).
When sodium hydroxide was employed as the base, no cyclised product (±)-285 was formed and enone 294 could be recovered from the crude reaction mixture (Table 3.1, entries 1 and 2). Treatment of enone 294 with potassium tert-butoxide or potassium carbonate only resulted in trace formation of chromanone (±)-285 after an extended reaction time of more than 72 hours (entries 3 and 4). Use of piperidine as an organic base additive with potassium hydroxide (entry 5), which was reported to exhibit excellent catalytic performance to generate cyclised flavanones,138 did not lead to any improved formation of chromanone (±)-285. Surprisingly, this cyclisation was achieved by using sodium acetate as a base to afford the furan-substituted chromanone (±)-285 in 20% yield (entry 6). The structure of chromanone (±)-285 was confirmed by the agreement of the 1H and 13C NMR data with those reported in the literature.140
As model enone 295 was expected to be more reactive than the monohydroxy enone 294, due to the enhanced electrophilicity afforded by a hydrogen bond of the additional phenol proton to the carbonyl group, the catalytic conditions using sodium acetate were employed to effect its cyclisation to form chromanone (±)-299 (Scheme 3.4). Satisfyingly, cyclisation of the substituted enone 295, the structure of which was based on the substitution pattern present in gonytolide C (30a), was achieved efficiently affording chromanone (±)-299 in an excellent 95% yield.
An asymmetric version of the oxa-Michael cyclisation of enone 295 was also attempted using the commercially available alkaloid cinchonidine (300). The C-2 furan-substituted chromanone 299 was produced in 57% yield by stirring a mixture of enone 295 and cinchonidine (300) in dichloromethane at room temperature for 50 hours. The structure of chromanone 299 was identified by a combination of NMR and HRMS analysis and the enantiomeric excess (e.e.) of the the cyclised product 299 wasestablished to be 10% by chiral HPLC analysis (Fugire 3.1), suggesting that the reaction occurred with slight asymmetric induction.
1.1 Chromanone Natural Products – an Overview
1.2 Methods for the Asymmetric Synthesis of 2-Substituted Chromanones
1.3 Previous Syntheses of 2-γ-Butyrolactone-substituted Chromanones
1.4 Aim of Current Research
2.1 Overview – the Intermolecular Conjugate Addition Strategy
2.2 Synthesis of Chromone Conjugate Acceptors
2.3 Copper-catalysed Conjugate Additions to Chromones
2.4 Rhodium-catalysed Conjugate Additions to Chromones
3.1 Revised Intramolecular Oxa-Michael Addition Strategy
3.2 Model Studies of the oxa-Michael Addition Reaction
3.3 Development of a Suitable Enone Substrate to Construct the Chromanone Core
3.4 Final Elabloration to Gonytolide C (30a)
3.5 Summary of the Total Synthesis of Gonytolide C (30a)
3.6 Conclusions and Future Work
4.1 General Details
4.2 The Intermolecular Conjugate Addition Approach
4.3 The Intramolecular Oxa-Michael Addition Approach
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Total Synthesis of Gonytolide C