Conclusions and future work

During the course of this research project, a novel one-pot multi-reaction process has been developed which comprises of an Overman rearrangement, a RCEYM reaction and a Diels-Alder reaction (Scheme 120). The product was isolated as a single diastereomer due to a hydrogen bond directed Diels-Alder reaction, which led to the formation of product

198 in 72% yield from allylic alcohol 194. The structure of polycycle 198 was elucidated

using NOE studies with the Diels-Alder reaction creating four contiguous stereogenic centres due to the hydrogen bond directing effect.

Scheme 120- One-pot process for the synthesis of polycycle 198

The scope of this process was expanded by changing the dienophile. Diels-Alder products such as 206 and 209 were again isolated again as a single diastereomers in good yield (Figure 21). An X-ray crystal structure of product 206 proved the relative stereochemistry of the C-1 and C-12b hydrogen atoms. The one-pot process was then further expanded using allylic alcohol 215 to generate amino-substituted bicyclo[4.3.0]nonanes. Using hetero-Diels-Alder and Diels-Alder reactions generated polycycles 219 and 228 in moderate to good yields and as single diastereomers. Bicyclo[4.3.0]nonane 228 was also isolated as a single regioisomer giving further evidence of the hydrogen bond directing effect observed in the Diels-Alder reaction.

Figure 21- Structures of isolated bicyclo[4.4.0]decanes 206 and 209 and [4.3.0]nonanes 219 and 228

In an attempt to carry out the one-pot process asymmetrically, work was then carried out to instigate a Pd(II)-catalysed Overman rearrangement. Through the use of a phenyl substituted alkyne, a Pd(II)-catalysed Overman rearrangement was achieved forming 1,6- and 1,7-enynes in excellent yields. Overall, a one-pot multi-reaction process was developed to form 5-aryl aminobicyclo[4.3.0]nonane 253 in a 49% yield and isolated as a single diastereomer (Scheme 121). Work is currently underway to examine the scope of disubstituted alkyne derived allylic alcohols and the use of chiral Pd(II)-catalysts in these one-pot multi-reaction processes for the asymmetric synthesis of medicinally important compounds and natural products.

Scheme 121- One-pot process involving a Pd(II)-catalysed Overman rearrangement

Alternatively, the substituent on the alkyne could be changed to a labile protecting group that could be cleaved after the rearrangement. For example, a silyl protecting group could easily be cleaved after the Overman rearrangement forming enyne 222 which can then participate in the developed one-pot procedure (Scheme 122).

Scheme 122- Proposed one-pot process using silyl protected alkynes

The next stage of the research programme was to apply the developed one-pot process for the first total synthesis of the natural product netamine A, which has an amino-substituted bicyclo[4.3.0]nonane core. Unlike the previously synthesised compounds from this work, netamine A has further functionality in the C-7 position. It was proposed that this functionality could be introduced by utilising a tandem catalytic process involving RCEYM/cross metathesis. A one-pot multi-step process was then developed and by using a variety of cross metathesis partners and dienophiles, highly functionalised amino- substituted bicyclo[4.3.0]nonanes and [4.4.0]decanes were synthesised in good yields as single diastereomers (Scheme 123).

Scheme 123- One-pot multi-reaction process involving a tandem catalytic process

Significant progress has been made towards the total synthesis of netamine A. By exploiting a tandem catalytic process and a hydrogen bond directed Diels-Alder reaction, the bicyclo[4.3.0]nonane 257 was successfully formed with the desired relative stereochemistry for the synthesis of netamine A (Scheme 124). The deprotection of polycycle 257 generated bicyclo[4.3.0]nonane 288, however a subsequent hydrogenation reaction was only able to reduce the nitro group, not the olefin. It is proposed that future work will be to complete the synthesis of netamine A by repeating the hydrogenation step using a combination of both Raney-Ni™ and Pd/C catalysts. Once diamine 256 has been generated, cyanogen bromide would then be added to the reaction mixture to complete the first total synthesis of netamine A.130-133

Scheme 124- Attempted route towards the synthesis of netamine A

Further work on this project could be done to exploit the usefulness of the cross metathesis and the Diels-Alder step to produce netamine B. This would involve changing the alkyl chain length on the cross coupling partner and employing a different dienophile in the Diels-Alder reaction. To form netamine B, 1-butene, which is a highly flammable gas, would be required to perform the ring-closing-enyne-metathesis cross metathesis reaction. By using the homodimerisation product of 1-butene, as used by Grubbs and co-workers as an alternative way of performing cross metathesis, the olefin 3-hexene 344 could be used as an alternative to form substituted 1,3-diene 345 (Scheme 125).122 Using nitroalkene 346, a Diels-Alder reaction could be used to form polycycle 347 which would then be transformed to netamine B. A total synthesis of this compound would allow the elucidation of its structure.

Scheme 125- Proposed synthesis of netamine B

Finally, a novel approach for the synthesis of a diverse library of compounds containing partially saturated amino-substituted indanes and tetralins was developed (Scheme 126). These privileged structures are found within a range of pharmaceutically important agents. Utilising both carbo- and heterocyclic 1,3-dienes in a Diels-Alder reaction with quinone and alkyne dienophiles, resulted in the formation of 1,4-diene products. These 1,4-dienes were then aromatised using DDQ or manganese dioxide resulting in the formation of aromatic products such as 309, 312, 321 and 323 in a one-pot process. All aromatic products were generated in moderate to good yields with the products from the reaction with 2-tert-butyl-1,4-benzoquinone and methyl propiolate being isolated as single regioisomers. Tricycle 312 formed as a single regioisomer due to a sterically controlled Diels-Alder reaction with the tert-butyl group being in the C-8 position which was confirmed by X-ray crystallography. In the case of methyl propiolate, the Diels-Alder reaction was highly regioselective due to a hydrogen bond directing effect, yielding compound 323 as a single regioisomer.

Scheme 126- One-pot process for the synthesis of partially saturated indenes and tetralins

This one-pot process involving a Diels-Alder reaction followed by aromatisation was extended for the synthesis of pyridine and pyridazine ring systems (Scheme 127). Reacting the cyclic-1,3-dienes with nitrile dienophiles at temperatures of 160 °C, facilitated the Diels-Alder reaction and at the same time aromatising the resulting 1,4-dihydropyridines. The pyridazine scaffold 343 was also formed in good yields. Compound 343 was produced via a Diels-Alder reaction followed by treatment of the resulting Diels-Alder adduct with bromine. This led to a tandem sequence of bromination, N-Boc deprotection followed by aromatisation.

Scheme 127- One-pot process for the synthesis of pyridine and pyridazine scaffolds

A range of drug-like derivatives could be prepared by employing the developed one-pot process. One example would be to synthesise derivatives of rasagiline (Scheme 128). This could be achieved by deprotecting indene 335 and the resulting product 348 could then be

treated with propargyl bromide and methylsulfonic acid to form the rasagiline derivative

349.

Scheme 128- Proposed synthesis of rasagiline derivatives

4.0 Experimental