Proteínas

In order to get closer to the structure of the natural product, functionalisation of the 1-position through bridgehead deprotonation on the 7,8-diketo-6-azabicyclo[3.2.1]octane structure 140 was investigated. Computational analysis of the bridgehead deprotonation reaction was first conducted. The geometry optimisations were performed by Professor Chris Hayes from the University of Nottingham using the B3LYP/6-31G*//B3LYP/6-31G* computational method. This calculation method had been previously used in predicting the bridgehead deprotonation of a variety of ketones, lactams, lactones and imides.²²⁰ The study showed that if a positive Erxn

was obtained, the deprotonation was unfavourable whereas if it was a negative value, the deprotonation would be thermodynamically feasible. There are also borderline situations with small positive Erxn values which indicated that the deprotonation was possible but poor

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control was obtained with condensation with the starting material occurring instead of alkylation. These theoretical results were reproduced experimentally.

Ketone 547 showed a positive Erxn (Erxn=4.65 kcal.mol^-1) indicating that the deprotonation was unfavourable (Scheme 239). Bridgehead lithiation and subsequent alkylation using either LDA or LTMP as a base in combination with TMSCl proved impossible experimentally. Self-condensation was not observed in the absence of TMSCl.

Scheme 239

Camphelinone 550 showed a small positive Erxn (Erxn=0.976 kcal.mol^-1) indicating that the deprotonation was unfavourable (Scheme 240). However, aldol adduct 552 was obtained in 90% yield experimentally, suggesting that deprotonation to form 551 was occurring and it was followed by condensation with 550.

Scheme 240

A relevant structure for comparison with 140 is ketoindole 553, synthesized by Simpkins and co-workers, as it possesses a ketone carbonyl carbon as the sole bridging atom.²²¹ Its deprotonation had been investigated towards the total synthesis of welwistatin²²⁰ and a

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negative Erxn was obtained using the calculation (Erxn=-12.4 kcal.mol^-1), suggesting that the metallation was possible (Scheme 241). This was confirmed experimentally as TMS-substituted 555 was obtained in 54% yield using LTMP and TMSCl in THF.

Scheme 241

The calculations conducted by Professor Chris Hayes showed negative Erxn (Erxn=-20.0 kcal.mol-1 for 557 and -29.1 kcal.mol^-1 for 559) for the deprotonation of phenyl- and methyl-substituted bicyclic ketones 556 and 558. Bridgehead deprotonation should therefore be thermodynamically favourable. However, it is not possible to say from this calculation if the deprotonation is kinetically feasible.

Figure 29

Following Simpkins’ procedure, bicyclic ketone 140 was treated with 2 eq of LTMP formed in situ from TMP and nBuLi and 10 eq of TMSCl at -78 °C (Scheme 242).^220,222 The starting material was only sparingly soluble in THF at this temperature. No conversion was observed by tlc

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analysis even when the reaction mixture was warmed to rt (Table 53, entry 1). Quenching the reaction with D2O did not show any deuterium incorporation and the starting material was recovered. The same result was observed using LHMDS, another non nucleophilic strong base, in CH2Cl2 (entry 2). Methylation of the bridgehead position in 140 was then investigated.

Treatment of 140 with LHMDS followed by addition of MeI afforded only starting material in CH2Cl2 and 25% of lactam 561 in DMF (entries 3 and 4).

It was then decided to use thermodynamic conditions for the deprotonation. When 140 was reacted with NaH in DMF, lactam 561 was obtained in 90% yield with MeI and 81% yield with Me3OBF4 (Table 53, entries 5 and 6). This product is likely to arise from deprotonation of the

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hydrated form of bicyclic ketone 140 (Scheme 243). The ring-opening probably releases the strain present in the bicyclic structure and is a possible driving force for this reaction.

Scheme 243

The same yields for the formation of lactam 561 were observed when MeI was distilled or DMF was dried over molecular sieves prior to use, in order to remove any traces of H2O. When the bicyclic ketone 140 was stirred for 30 min over 3 Å molecular sieves in DMF prior to the addition of the base, three unidentified products were formed in small yields (Table 53, entry 7). Increasing the stirring time over molecular sieves to 18 h, one compound was formed but the data collected did not correspond to lactam 561 or to the desired methylated bicyclic ketone (entry 8).

Alkylation was also attempted on freshly prepared N-C8H17 bicyclic ketone 181 which was more soluble in organic solvents. Addition of 3 eq of NaH and 10 eq of MeI to a mixture of 181 in THF did not afford bridgehead methylated 565 but lactam 566 in 88% yield.

Scheme 244

The formation of the hydrate of 140 being an issue for the bridgehead methylation, it was decided to form alkene 567 prior to alkylation. Treatment of 140 with 1.6 eq of

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methyltriphenylphosphonium bromide and nBuLi in THF afforded alkene 567 in 40% yield after an aqueous work-up (Scheme 245 and Table 54, entry 1).⁷⁰ Using the same procedure, alkene 567 was obtained in 24% yield after a work-up with hexane and a filtration to remove the triphenylphosphine oxide by-product (entry 2). Direct purification of the concentrated reaction mixture gave 567 in an improved 60% yield (entry 3). Finally, the use of 2.1 eq of reagents afforded alkene 567 in 93% yield (entry 4).

Low-temperature methylation of the bridgehead position on alkene 567 was then attempted using 2.5 eq of LDA prepared in situ and 5 eq of MeI (Scheme 245). Only starting material was obtained, even after the reaction mixture was warmed to rt. Bridgehead alkylation was then carried out using 2 eq of NaH and an excess of MeI in DMF. No conversion was observed and the starting material 567 was recovered after 18 h at rt.

Scheme 245

Entry Reagents in THF work-up T / time Result

1 Ph3P⁺CH3,Br^-, nBuLi (1.6 eq) NH4Cl, CH2Cl2 reflux / 18 h 567 40%

2 Ph3P⁺CH3,Br^-, nBuLi (1.6 eq) hexane

filtration reflux / 18 h 567 24%

3 Ph3P⁺CH3,Br^-, nBuLi (1.6 eq) concentration reflux / 18 h 567 60%

4 Ph3P⁺CH3,Br^-, nBuLi (2.1 eq) concentration reflux / 18 h 567 93%

Table 54: Synthesis of alkene 567

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Another option to incorporate a methyl at the bridgehead position of the 7,8-diketo-6-azabicyclo[3.2.1]octane structure would be to introduce it prior to the semipinacol rearrangement (Scheme 246). Oxidation of diol 569 would give -hydroxyketone 570 which could then be reacted with MeLi or MeMgBr to give 571 and/or 572. Semipinacol rearrangement of the cis diol 571 would then give the desired alkylated bicyclic ketone 573.

Scheme 246

Oxidation of diol 145 was first attempted with 1.2 eq of PCC at rt and degradation of the reaction mixture was observed (Scheme 247 and Table 55, entry 1).²²³ Using DMP in combination with pyridine or NaHCO3 provided trace amounts of -hydroxyketone 574 among products of degradation (entries 2 and 3).²²⁴ Swern oxidation of diol 145 afforded protected ketone 575 in 35% yield (entry 4).^225-226 To avoid the formation of 575, iPrOH was added in the same time as Et3N. Unfortunately, tlc analysis showed that 575 was the main component after the work-up (entry 5). Finally, diol 145 was reacted with RuO4 formed in situ from a mixture of RuCl3, NaHCO3 and Oxone^ as described by Plietker in 2004 (entry 6).²²⁷ -Hydroxyketone 574 was formed in a moderate 38% yield and was contaminated with some degradation products even after an attempted purification by column chromatography.

[182] mixture of H2O:toluene (Scheme 248).²²⁸ No reaction occurred and the starting material was recovered.

Scheme 248

Plietker described the formation of -hydroxyketones from oxidation of alkenes. Treatment of alkene 130 with 10 mol% RuO4 gave 576 in 23% yield. Even if low-yielding, the product was obtained pure. Full conversion was observed by tlc analysis. Increasing the catalyst loading to 20 mol% did not improve the yield for this oxidation. Insufficient quantities of -hydroxyketone 576 were formed and addition of a nucleophile could not be attempted.

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Scheme 249

5.7 Towards the synthesis of 546: nucleophilic addition to lactams and