in 79% yield The total synthesis of pimpinellin was thus completed over 10 steps in an overall yield of 14.7%.

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Scheme 3.9 Synthesis of Pimpinellin(3.4) [Reagents and Conditions: i) a) AgNO3 (aq), EtOH, 18 °C, 0.75 h; b) KCN (aq) (excess), 18 °C, 1.5 h; ii) a) n-BuLi (1.05 equiv.), THF, −78 °C; b) CH3OCOCl (4.3 equiv.); iii) CAN (2.2 equiv.), MeCN, 18 °C, 0.25 h; iv) H2, Pd on CaCO3 (5 mol%); v) K2CO3 (4.0 equiv.), CH3I (excess), 18- crown-6, toluene, 18 °C, 3 h].

The synthesis of pimpinellin (3.4) carried out by the author and reported here started with vanillin (3.26) (Scheme 3.10). Bromination of this compound, using molecular bromine in acetic acid, afforded the previously reported 5-bromovanillin (3.27) in 69% yield221. Replacement of the newly installed bromine by a hydroxyl group was attempted using the procedure of Ellis and Lenger.176 However, only traces amount of the desired product could be isolated on attempting to repeat this protocol. Various control experiments eventually established the source of the hydroxyl group oxygen in this reaction. Notably, bubbling a stream of oxygen through the reaction mixture stopped the process entirely. Eventually, sodium hydroxide was identified as the source of this atom and so the reaction solvent had to be deoxygenated by bubbling nitrogen through it for an extended period of time. By such means the desired product, 3.28, was obtained in 93% yield. Selective methylation of catechol 3.28

then afforded the dimethoxylated compound 3.29 (87% yield) and bromination of this using freshly recrystallised NBS afforded the desired halide 3.30 in 84% yield. The structure of this last compound was confirmed by single-crystal X-ray analysis (Figure 3.9).

Scheme 3.10 Synthesis of Sonogashira Coupling Precursor 3.30 [Reagents and Conditions: i) Br2 (1.1 equiv.), AcOH, 18 °C, 1 h; ii) Cu(0) (5 mol%), NaOH (10.0 equiv.), H2O, 100 °C, 24 h; iii) Na2CO3 (1.0 equiv.), (MeO)2SO2 (1.1 equiv.), acetone, 60 °C, 5 h; iv) NBS (1.02 equiv.), THF, 0 to 18 °C, 16 h].

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As a prelude to establishing the furan ring of target 3.4, the pentasubstituted arene 3.30

was subjected to a Sonogashira cross-coupling reaction with triisopropylsilylacetylene. This produced a 1:8 mixture of acetylene 3.31 (5%) and the isomeric benzofuran 3.32 (39%). These were chromatographically separable (Scheme 3.11) and thereby allowing each to be subjected to comprehensive characterization. The benzofuran 3.31 arises from 5-endo-dig cyclisation of the phenolate anion onto the proximal alkyne moiety of 3.32, which is a favoured process according to Baldwin’s rules. The rather modest yields associated with the conversion

3.30 → 3.31 + 3.32 may be attributed to competitive oxidative coupling of the triisopropylsilylacetylene, although the (likely volatile) product of such a process was not detected in the crude reaction mixture.

Scheme 3.11 Sonogashira Coupling of Precursor 3.30 [Reagents and Conditions: i) tri-iso-propylsilylacetylene (2.95 equiv.), Et3N, Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), MeCN, μW, 120 °C, 1.5 h].

Gratifyingly, the structure of the uncyclised product could be confirmed by single-crystal X-ray analysis (Figure 3.10).

The 1_{H NMR spectrum of compound 3.31 (Figure 3.11) shows a one-proton aromatic} resonance at δ = 7.07 ppm while its aldehyde counterpart resonates at δ = 10.41 ppm. The two sets of methoxy group protons appear at δ = 3.95 and 3.90 ppm as two three protons singlets while the signal due to the hydroxyl group appeared at δ = 6.17 ppm. The 13C NMR spectrum of compound 3.31 (Figure 3.12) shows a diagnostic resonance for an aldehyde carbon at δ = 190.6 ppm while the aromatic carbon appeared at δ = 102.4 ppm. The remaining non-protonated sp2-hybridised carbons appear as low intensity signals in the range δ = 153.3 to δ = 96.9 ppm. The two methoxy group carbons appear at δ = 61.2 and 56.4 ppm while the carbons of the three equivalent isopropyl groups give rise to signals at δ = 18.7 and 11.2 ppm.

The 1H NMR and 13C NMR spectra of compound 3.32 (Figure 3.13 and 3.14, respectively) reveal analogous characteristics all of which are in keeping with the assigned structure. The most important peaks that are diagnostic of the furan formation appear as two aromatic signals at 7.72 and 7.43 ppm and corresponding to the phenyl and furan ring respectively.

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Figure 3.11 1_{H NMR Spectrum of Compound 3.31 Recorded in CDCl} 3.

Figure 3.12 13_{C NMR Spectrum of Compound 3.31 Recorded in CDCl} 3.

Figure 3.13 1_{H NMR Spectrum of Compound 3.32 Recorded in CDCl} 3.

Figure 3.14 13_{C NMR Spectrum of Compound 3.32 Recorded in CDCl} 3.

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For synthetic purposes, it was more convenient to treat the mixture of compounds 3.31

and 3.32 (Scheme 3.12) with tetra-n-butylammonium fluoride (TBAF) and thereby generating the desilylated benzofuran 3.33. This was obtained as a colorless, crystalline solid in 80% yield. The completion of the synthesis of pimpinellin from compound 3.33 required installation of the unsaturated lactone ring, and this proved to be a straightforward matter. Thus, aldehyde 3.33

was subjected to a Dakin oxidation using m-chloroperoxybenzoic acid (m-CPBA), and the ensuing formate ester was cleaved with ammonia saturated methanol to give phenol 3.34 in 68% yield.

Scheme 3.12 Synthesis of Phenol Precursor 3.34 [Reagents and Conditions: i) TBAF (6.0 equiv.), THF, 0 to 18 °C, 1 h; ii) a) m-CPBA (1.2 equiv.), KHCO3 (3.4 equiv.), 18 °C, 1 h; b) ammonia saturated methanol (excess), 18 °C, 1 h].

Treatment of the phenol 3.34 (Scheme 3.13) with 3-(trimethylsilyl)propiolic acid in the presence N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl)

afforded ester 3.35 (79% yield at 48% conversion) with accompanying loss of the TMS group associated with the alkyne (an event that probably took place during chromatographic purification). Upon treatment with a 5 mol% Echavarren’s gold(I) catalyst in dichloromethane at 25 °C, compound 3.35 cyclised to give pimpinellin (3.4) which was obtained as a colorless, crystalline solid in 72% yield.

Scheme 3.13 Synthesis of Pimpinellin (3.4) [Reagents and Conditions: i) 3-(trimethylsilyl)-propynoic acid (1.2 equiv.), EDC (1.2 equiv.), DCM, 18 °C, 24 h; ii) Echavarren's gold catalyst (5 mol%), DCM, 18 °C, 0.5 h].

All of the spectral data recorded on pimpinellin (3.4), including the 1_{H and} 13_{C NMR} spectra (Figure 3.15 and 3.16) compared favourably with those reported by Moore (Table 3.4).175

Figure 3.15 1_{H NMR Spectrum of Pimpinellin (3.4) Recorded in CDCl} 3.

Figure 3.16 13_{C NMR Spectrum of Pimpinellin (3.4) Recorded in CDCl} 3.

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Table 3.4 Comparison of the 1_{H and} 13_{C NMR Data Recorded for Synthetically-Derived Pimpinellin}

(3.4) with those Reported for the Natural Product.

13_{C NMR Resonances (δC)*} 1_{H NMR Resonances (δH)*}

Synthetically- Derived Material

Natural Product Synthetically-

Derived Material Natural Product 161.1 160.4 8.06, d, J = 9.7 Hz, 1H 8.08, d, J = 9.7 Hz, 1H 150.0 149.7 7.64, d, J = 2.2 Hz, 1H 7.65, d, J = 2.2 Hz, 1H 145.6 145.4 7.07, d, J = 2.2 Hz, 1H 7.08, d, J = 2.2 Hz, 1H 144.7 144.4 6.35, d, J = 9.7 Hz, 1H 6.37, d, J = 9.7 Hz, 1H 143.4 143.1 4.13, s, 3H 4.15, s, 3H 140.1 139.8 4.02, s, 3H 4.06, s, 3H 135.4 134.9 114.4 115.5 114.0 113.8 109.7 109.3 104.6 104.1 62.6 62.2 61.5 61.1

* All spectra recorded in CDCl3.

The synthesis of pimpinellin had thus been completed using a late-stage IMHA reaction with 6% overall yield over 10 steps. It is noteworthy that this synthesis highlights the possibility to effect the desired transformation on an already pentasubstituted aryl ring.

4.1 SUMMARY

A gold(I)-catalysed, 6-endo-dig cyclisation of arylpropiolates has been developed that allows for the synthesis of a wide range of coumarins. In principle, heterocycles of this type that incorporate substituents at all possible positions on the framework are accessible by this means. That said, the nature of the cyclisation process is such that only aryl propiolates bearing electron-donating substituents on the aromatic ring participate especially well in such reactions. Furthermore, the reactive substrates cyclise rapidly under very mild conditions to give the desired coumarins in generally excellent yield. The various coumarins prepared using this approach are shown in Figure 4.1. It is noteworthy that meta-substituted propiolates are expected to afford the regio-isomer favouring para- SEAr reaction.

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Figure 4.1 The Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation of o, m and p-Substituted Propiolate Esters.

The extensions of the methodology just described to the synthesis of di-substituted coumarins as well as annulated variants are summarised in Figures 4.2 and 4.3.

Figure 4.2 Cyclisation of Disubstituted Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation.

Figure 4.3 The Polycyclic Coumarin Derivatives Synthesised Through the Gold(I)-Catalysed Cyclisation.

The same basic cyclisation process can be exploited in the preparation of certain gem- dimethylated chromene derivatives as shown in Figure 4.4.

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Two total syntheses of coumarin-containing natural products were completed so as to emphasise the utility of the methodology summarised in the preceeding section. The scalability of this method was also shown through the preparation of fraxetin (3.1) on a gram scale and thus allowing for the preparation of two biologically active derivatives, namely capensin (3.2) [as well as its regioisomer (3.14)] and purpurasol (3.3). The total synthesis of fraxetin (3.1) from 2,3-dihydroxy-4-methoxybenzaldehyde (3.20) was achieved in just 7 steps and an overall yield of 37% (Scheme 4.1).