Third synthetic approach towards canataxpropellane

We decided to took advantage of isobenzofuran 221,⁸⁰ as an highly reactive diene for the Diels-Alder reaction which could be easily synthetized using a procedure developed by Warrener.⁸¹ The compound 221 was assembled from relatively simple building blocks. Tetrazine 223 was synthetized in two steps by refluxing 2-cyanopyridine 222 in aqueous hydrazine followed by oxidation with sodium nitrite (Scheme 36).⁸²

Scheme 36. Synthesis of tetrazine 223.⁸²

Arene 225 was accessed in one step from commercially available 1-bromo-2,5-dimethoxybenzene 224. Addition of LDA led to in situ formation of aryne, which was trapped by the excess of furan thus giving 225 in 72% yield (Scheme 37).⁸³

Scheme 37. Synthesis of oxabyciclo-arene 225.⁸³

Next the oxabyciclo-arene 225, enone 171 and tetrazine 223 were refluxed in toluene for 24h (Scheme 38). First, the Diels-Alder reaction with inverse electron demand between tetrazine 223 and arene 225 occurs already at room temperature. The following retro Diels-Alder reaction driven by the nitrogen elimination requires slightly elevated temperature (40-50 °C) thus giving pyrazine 227 and desired highly reactive unsubstituted isobenzofuran 221, which reacted further with dienone 171. Gratifyingly,

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we could obtain a separable mixture of endo and exo Diels-Alder products 220 and 228 in excellent yield.

Scheme 38. Synthesis of Diels-Alder adduct 220.

Next, we tried to oxidize endo-dimethoxyhydroquinone 220 to the corresponding quinone 229 using CAN (Scheme 39). Surprisingly, after multiple tries we were not able to obtain the desired product 229, instead, the decomposition of was observed, although, the exo isomer 228 smoothly undergoes this transformation.

Scheme 39. Oxidation of Diels-Alde adducts with CAN.

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As it was not possible to obtain quinone 229, direct ortho- photocycloaddition with endo 220 was attempted (Schem 40, Table 9). After testing several conditions and solvents, which failed to deliver product 231 (entries 1-6) benzene was used as solvent, since it was reported to be successful on the very similar system (entry 7).⁵⁵ To our great delight, the solvent occurred to be the crucial issue for this reaction, therefore the desired cycloadduct 231 was isolated by flash column chromatography in 32% yield along with recovered starting material. Interestingly, this transformation proved to be a reversible process, which resulted in almost same yields after prolonged irradiation times.

Scheme 40. Synthesis of intermediate 231 by [2+2]-cycloaddition.

Table 9. Conditions screened for the synthesis of 231.

Entry Solvent Additive Result

1 EtOAc - No reaction

5 MeCN Benzophenone No reaction

6 MeCN H2SO4 (cat.) Decomposition

7 Benzene - 32%, 80% brsm

To prove the structure of the pivotal cycloaddition intermediate 231 unambiguously, a series of 2D-NMR experiments was conducted. Based on to the HMBC spectrum, we could assign all quaternary carbon atoms of the cyclobutane ring in 231. The cross-peaks with the corresponding hydrogen atoms can be seen in Figure 7.

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Figure 7. HMBC spectrum of pivotal cage-like intermediate 231.

Additionally, we were lucky to obtain single crystals of 231 by slow crystallization from EtOAc which were further analyzed by X-ray diffraction. Indeed, as can be seen in Figure 8, we have the desired four-membered ring embedded in a cage-like backbone, whereas the isobenzofuran originating six-membered ring of the previous has lost the aromaticity thus forming the dimethoxy enol ether moiety.

Figure 8. X-ray structure of photocycloaddition product 231.

231

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As can be seen from the structure of 231, we were able to set up five of six quaternary carbon centers and build up the first [4.4.2]propellane fragment in only two particular steps starting from easily accessible isobenzofuran 221 and dienone 171. Although several stereogenic centers need to be installed, this should not be the main issue, since the obtained scaffold can be effectively used as a source of substrate-controlled stereoselectivity. The crucial issues which should be solved are the introduction of the last missing quaternary carbon center, which is neopentylic, as well as conversion of the oxygen-bridge, into a corresponding diol (Figure 9).

Figure 9. Comparison of the key structural elements of intermediate 231 and canataxpropellane 13.

After careful experimentation, we found out that both methyl ether moieties in 231 can be hydrolyzed using a 3:1 mixture of THF and 3M aqueous hydrochloric acid, thus providing triketone 232 in 87% yield (Scheme 41). Application of bulky L-selectride allowed regioselective reduction of less sterically hindered ketone moiety to alcohol 232 with the desired stereochemistry. This could be proven by the NOE experiments (Figure 10). The saturation of protons 1 and 2 results in the mutual response, whereas proton 3 does not cause any response to proton 1.

Scheme 41. Synthesis of alcohol 233 and attempted TIPS-protection.

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Unexpectedly, during the attempt to protect alcohol 233 with TIPSOTf, intermediate 234 was obtained instead, revealing a strong structural rigidity of this system. The attempts to protect the alcohol 233 with a benzyl group using either standard basic conditions or acidic conditions with Bundles reagent failed, therefore we subjected substrate 233 to the relatively neutral protection with Dudley salt (Scheme 42).⁸⁴ A complex mixture of benzylated products was obtained (233, 236, 237 and 238), which was directly hydrolyzed to alcohol 233 and protected alcohol 236. These two compounds could be easily separated by the column chromatography.

Figure 10. NOE experiments with alcohol 233. Mutual response by the saturation of protons 1 and 2 proves their spatial proximity.

233

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Scheme 42. Synthesis of α, β-unsaturated ester 240.

The initial olefination attempts of the upper ketone moiety failed, probably due to the bulkyness of the neopentylic position. In contrast, the vinyl triflate was smoothly formed after some work-up optimization using Comins´ reagent.⁸⁵ The crude triflate was further subjected to palladium-catalyzed carbonylation⁸⁶, furnishing the desired ester 240 in 90% yield over (Figure 42). Treatment of intermediate 240 with magnesium powder in methanol resulted in 1,4-reduction giving exclusively single stereoisomer of 241 in a high yield. The stereochemistry of 241 was clearly assigned by performing a NOESY experiment. The cross peaks corresponding to the couplings of α-proton 1 with the spatially proximate bridged proton 2 and proton 3 of the secondary benzyl-protected alcohol could be clearly observed (see Figure 11).

Scheme 43. Synthesis of derivative 242.

46 Figure 11. NOESY spectrum of ester 241.

Figure 12. NOESY spectrum of methylated ester 242.

241

242

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To our delight, following stereoselective methylation was achieved by deprotonation of 241 with LDA and treatment of the generated enolate with an excess of methyl iodide, resulting in the smooth formation of α-methylated compound 242. Again, single stereoisomer was isolated (Figure 12), which clearly indicates that the back side of the six-membered ring is completely shielded.

Subsequent reduction of the ester moiety of 242 with lithium aluminium hydride was performed at room temperature, therefore the accompanied reduction of the ketone could not be avoided. Since partial TBS-deprotection was observed during this process, the crude mixture was treated with TBAF providing triol 243 in 88% yield over two steps. After that, a triple Swern oxidation was performed and the obtained crude tricarbonyl compound was subjected to a titanium-catalyzed pinacol coupling.

To the best of our knowledge, the only reagent which has been reported to provide trans-diols on small rings is the Cp²TiPh reagent, in contrast to exclusive cis-selectivity provided by all the other organometallic reagents (Scheme 45).⁸⁷ The five-membered ring was indeed formed, but unfortunately it was accompanied by the alcohol elimination and opening of the cyclobutane ring, giving olefin 244 (Scheme 44). After several attempts with slightly different conditions the same results were obtained, which could probably indicate that this reagent is not suitable for our substrate.

Scheme 44. Synthesis of triol 243 and attempted pinacol coupling.

Scheme 45. Trans-selective pinacol coupling.⁸⁷

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Therefore, we switched to a samarium(II) iodide catalyzed pinacol coupling which provided a mixture of diols 247 and 248 in approximately 40% yield (Scheme 46). The diols 247 and 248 could be separated by flash column chromatography, along with already observed decomposition product 244. The stereochemistry of the obtained diols was carefully secured by NOESY experiments (Figure 13 and 14).

Scheme 46. Synthesis of advanced intermediates 247 and 248.

The NOESY spectrum of cis-pinacol product 247 shows characteristic cross peaks between methyl group 1 and protons 2 and 3, but only proton 3 possesses cross peak between methyl group 4 (Figure 13). In product 248 protons 2 and 3 do not couple with each other, presumably because of the trans orientation where dihedral angel is about 90°. Similar to 247 proton 3 in trans-248 has cross peak between methyl group 4 (Figure 14). In contrast, proton 2 shows interaction with methyl groups 7 and 8, which confirm the proposed relative stereochemistry (Figure 14).

In this manner, we have successfully established the route towards advanced intermediate 248, starting from simple building blocks 171, 223 and 225. The last task, which should be solved, is a functionalization of the oxygen-ether-bridge, which will be discussed in the next chapter.

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Figure 13. NOESY spectrum of cis-pinacol product 247.

Figure 14. NOESY spectrum of trans-pinacol product 248.

247

248

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