Coupling studies

Finally, attention was turned towards the copper-catalysed coupling of our complex fragments to form the desired precursor to (–)-lyngbyaloside B. The conditions developed by Dean Holt (Scheme 65, page 41) were first applied towards this key fragment union, but were observed to give decomposition of the iodonium salt with no apparent coupling to the desired product (Table 43, entry 1). Interestingly, diene 584 was recovered in 32% yield from the reaction mixture, presumably formed via the elimination of the carbamoyl group from substrate 470. The identity of this product was confirmed by a de novo synthesis (Scheme 129). Secondly, due to uncertainty over the reliability of the (CuOTf)2•PhH, the catalytic combination of copper(I) iodide and silver triflate was tested for the desired oxy-alkenylation (entry 2). In addition to the production of diene 584, this reaction gave a 47% crude yield of tricycle 552 but still produced no desired product. Sodium carbonate was then added to the reaction mixture in order to prevent the acid-mediated cyclisation. This reaction unfortunately led to the elimination of the iodonium salt and no starting material conversion (entry 3).

Cl

1.2 equiv. 1.5 equiv. 1,1-CDI

MeCN, 40 ºC, 3h 6.0 equiv. HNMe₂

THF, 55 ºC, 4 h

Entry Conditions

a yield determined by ¹H NMR with 1,3,5-trimethoxybenzenetricarboxylate as internal standard Table 43 – Initial attempts to couple fragments 470 and 558

Scheme 129 – Formation of diene 584 via Wittig coupling of ketone 586 and phosphonium salt 584

As both coupling partners were unstable in the tested copper-catalysed oxy-alkenylation reactions, little insight could be gained into how the coupling process should be optimised. As the carbamate substrate

O

was thought to be the more stable of the two fragments, it was questioned whether this carbamate would undergo the desired reaction with a simple iodonium salt, thereby allowing coupling conditions to be developed that would maximise the stability of the substrate. These conditions could then be applied to the key fragment union. Accordingly, Dominik Reich investigated the coupling of the southern fragment with propenyl iodonium salt 581. Following extensive studies, it was discovered that the oxy-alkenylation could be effected with 30 mol% copper(I) triflate, one equivalent di-tert-butylpyridine and one mass equivalent of 4 Å molecular sieves. These conditions gave the desired carbonate in 45% yield and in an intractable mixture of diastereoisomers (Scheme 130).²¹³

Scheme 130 – Coupling of southern fragment 470 with iodonium salt 581 (NMR) – Dominik Reich²¹³

The low diastereoselectivity of the oxy-alkenylation process (2:2:1, 589:590:other) was attributed to the tertiary alcohol-appended carbamate substrate. With the presence of a tertiary centre, it was considered that the putative transition states leading to the two suspected major isomers would differ only with respect to the steric demands of an axial methyl group compared with an axial methylene group (Scheme 131). Consistent with the similar A-values of a methyl and an ethyl group (1.70 vs. 1.75),²¹⁴ there appears to be little energetic preference for either transitions state structure and hence no appreciable diastereoselectivity.

Scheme 131 – Proposed origin of poor oxy-alkenylation diastereoselectivity

However, as the model reaction proceeded with no apparent decomposition of the carbamate substrate, the same conditions were applied to a fragment union reaction using our northern fragment iodonium salt 558 (Scheme 132). Pleasingly, evaluation of the crude reaction mixture by ¹H NMR and LCMS

O

indicated the presence of trace amounts of the desired product. Extensive chromatographic purification allowed the isolation of 1 mg (2%) of a species observed to bear ¹H signals and COSY cross-peaks consistent with coupled product 559 (Figure 13). The assignment was further supported by high resolution mass spectrometry with the observation of a diagnostic [M+Na]⁺ signal. However, consistent with the model reactions performed by Dominik Reich, the NMR data indicated the coupled polyketide backbone to be formed in a low d.r. of 5:5:2 (559:591:other).

Scheme 132 – Coupling of southern fragment 470 and northern fragment 558 to furnish linear polyketide backbone 559

Figure 13 – ¹H spectrum of linear polyketide backbone 559 (500 MHz)

O

Whilst the above reaction was low yielding and poorly diastereoselective, this study indicates that our oxy-alkenylation methodology may be used as a fragment union strategy in polyketide synthesis. It is hoped that our approach will be pursued further in the future to produce (–)-lyngbyaloside B or other natural products.

3.8 Summary

This project has described investigations into the application of Gaunt’s oxy-alkenylation strategy to the synthesis of the macrolide (–)-lyngbyaloside B. Efforts were directed toward the use of this reaction as a novel fragment union for polyketide synthesis. As such, this chapter has detailed studies into model fragment couplings, the synthesis of a highly complex polyoxygenated iodonium salt and the coupling of this fragment to an elaborate homoallylic carbamate substrate.

It has been demonstrated that protected, secondary, α-oxygenated alkenyl iodonium salts can be generated and isolated in moderate yields. Similarly, it was observed that model reactions for the desired fragment coupling proceed in synthetically useful yields. It was noted that the temperature of the reaction and steric parameters of the iodonium salt are important factors in controlling carbamate conversion and product stability. Furthermore, it was shown that an iodonium salt bearing a protected 1,3-diol with three contiguous stereocentres can be transferred to a simple homoallylic carbamate.

It was discovered that the choice of alcohol protecting group is very important in the synthesis of complex iodonium salts. Such elaborate iodanes were generally observed to be unstable to both acid and base, cyclising and eliminating under these conditions respectively. Finally, it was determined that acetonide protection was suitable for the generation and isolation of northern fragment iodonium salt 558.

Following extensive investigations, the desired oxy-alkenylative fragment coupling was achieved in 2%

yield and in 5:5:2 d.r.. Although the result of this reaction is not synthetically useful, it does evidence that the coupling of polyketide fragments using our methodology is possible.

4 Towards a Mechanistic Understanding of Copper-Catalysed