Parallel to the pursuit of the route depicted in Section 3.4.3, a different pathway that branches off from ester 157 was explored (Scheme 3.15) in an effort to

facilitate the synthetic program. So, instead of cleaving the acetonide functionality

associated with this compound and "reshaping" the latter into a photolysis

substrate, the ester side chain was first transformed into a vinyl group thus paving

the way for the introduction of a diol as required in the original synthetic plan. This

procedure stands in contrast to the original route, wherein modifications to the side

chain were to be made after the photochemical step had been carried out (see

Chapter 4). It emerged that manipulations on the side chain are easier to carry out

within the bicyclo[2.2.2]octene framework rather than on the photochemically-

derived diquinanes. In particular, the outcome of an individual reaction was easier

to interpret in the former case, as the signals in the

1H NMR spectra are more

widely dispersed over the spectral range and thus easier to assign. In addition, the

diquinanes were often less stable than the precursor bicyclo[2.2.2]octenes which

could routinely be stored at room temperature.

Scheme 3.15 shows the synthesis of photochemical product

from the

bicyclo[2.2.2]octene precursor

The latter compound was prepared according to

the method described in Section 3.4.3. The reaction time for the previously

mentioned reduction of substrate

with NaBH4 in THF/MeOH was increased from

4.5

h to 16 h (to ensure the complete consumption of the starting material).

Reduction of olefin

gave ester

as a 1:1 mixture of epimers.

Disappointingly, the epimerisation of undesired isomer

into the desired one

(1 5 7 a )

was not very efficient. Under the most favourable conditions found so far -

heating with NaOMe/MeOH - a 1:2.5 mixture of esters

and

was

Second key-step: the oxa-di-n-methane rearrangement 65

observed in the crude product An alternative was to reduce the undesired epimer

157 b with DIBAL - a rather useful reaction that gave a 1:13 mixture of epimeric aldehydes 1 7 1 a and 171b in 70% yield - and then effect epimerisation of aldehyde 171b . Regrettably, the epimerisation of this aldehyde was even less efficient than the equivalent process involving the corresponding ester 157 b . Thus, heating this material with DBU/benzene - the most "favourable" conditions found - gave a ca. 1:4.8 mixture of aldehydes 1 7 1 a and 171 b .

Schem e 3 .1 5 . Alternative procedure for the synthesis o f a photoprecursor

0 0 o 157b 157a 171b 171a OH 174 OBz 175 176

Reagents and conditions: (a) NaBH4, THF, MeOH, 0°C->18°C, 16 h; (b) MeONa, MeOH, 0°C->70°C,

24 h; (c) DIBAL, CH2CI2, hexane, -78°C, 0.03-1.25 h; (d) DBU, benzene, 70°C, 16 h; (e) S 0 3-pyridine,

EtsN, DMSO, CH2CI2, 0°c, 1 h; (f) MePPh3Br, NaHMDS, THF, 0°C, 4.5 h; (g) DOWEX-50, MeOH, H20 ,

110°C, 6 days; (h) p-Ts0H*H20 , 4-AcNH-TEMPO, CH2CI2/ 0°C^21°C, 17 h; (i) BzCI, Et3N, DMAP, CH2CI2/ 0°C->18°C, 16 h; (j) acetophenone, acetone, hv, 15°C, 4.5 h.

66 C hapter 3

After extensive purification to separate it from its epimer, ester 157a was reduced with DIBAL and varying amounts of alcohol 170 and aldehyde 171a were obtained. Gratifyingly, these two reduction products were easy to separate. Initial attempts to oxidise alcohol 170 with reagents such as TPAP/NMO and PDC/Celite failed. However, treatment of the latter with S03-pyridine gave aldehyde 171a in reasonable yield. Methylenation of the latter was achieved by way of a Wittig reaction that proceeded uneventfully, producing olefin 172 in 60% yield. This last conversion concluded the modification of the side chain for the time being. Even though the required side-chain diol unit could have been established before the oxa-di-7i-methane rearrangement, there was a risk that dihydroxylation conditions could affect the double bond within the bicyclo[2.2.2]octene moiety that is needed to induce the photoreaction. It was, therefore, decided at this point to delay the introduction of the diol functionality until after the photochemical step.

With the vinyl group in place, attention was shifted towards cleavage of the acetonide group within compound 172. Once again, this was achieved with activated DOWEX-50 in refluxing aqueous methanol and the more accessible hydroxy group of the diol so formed was then oxidised using the oxoammonium salt

162 (Figure 3.4, page 58) derived from 4-AcNH-TEMPO. The product acyloin was then converted into the corresponding benzoate, 175, under standard conditions. Photolysis of compound 175 using set-up (b) shown in Figure 3.5 (page 62) afforded compound 176 as a mixture of epimers in excruciatingly low yield (32%). This could be due to interference/decomposition of the terminal double bond during the photoreaction. A solution to this problem might have been the conversion of the double bond to a protected diol before the photochemistry step. However, too little material was left at this point, so this approach could not be evaluated. Instead, the small quantities of photoproduct 176 that had been obtained by the means detailed here were carried forward as described in the next Chapter.

3.5 Conclusion

This Chapter has described the elaboration of the intermolecular Diels-Alder products first encountered in Chapter 2 into substrates suitable for the proposed oxa-di-7c-methane rearrangement reactions. The first sequence starting from Diels- Alder adducts 124a and 124b had to be abandoned, as decarbonylation of the aldehyde group caused difficulties as described in Section 3.3. However, Diels-Alder adducts 126a and 126b could be successfully converted into substrates for the photochemical reaction. As a result, two sets of diastomeric diquinanes 169a-d and

Second key-step: the oxa-di-7r-methane rearrangement 67

Compounds 1 6 9 a , 169 b , 1 76 a and 176 b possess the correct stereochemistry for the third key-step, an intramolecular alkylation reaction as detailed in the original synthetic plan, to take place. Diquinanes 16 9 c -d have the wrong configuration at C2 for such purposes but were taken further on the basis that epimerisation of the ester group could be effected at some point. The following Chapter details efforts to use the photochemical products 1 69 a, 169 b , 1 7 6 a and 17 6 b in the construction of the tricyclic framework of 2-isocyanoallopupukeanane.

1 69b

169d

176b

68 C h a pte r 3