Asymmetric Corey-Chaykovsky epoxidation with activated alkyl halides

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Table 18. Epoxidation of 6-bromopiperonal using cinnamyl bromide - catalyst screening.

Entry Thioether Time (h) 6-bromopiperonal (%) ^a) 240 (%) ^a) trans:cis

1 ITC 5 80 14 7:1

96 2 97 6.3:1

336 3 90 7.5:1

2 241 5 88 2.5 1:1

96 86 14 1.2:1

336 70 14 1.1:1

3 242 5 85 5 4:1

96 25 74 4.5:1

336 3 90 3:1

4 243 5 75 1.5 -

96 60 36 2.5:1

336 15 86 2.4:1

5 244 5 94 0 -

96 93 6 1:1

336 90 9 1:1

a) Relative concentration by ¹H NMR based on internal quant. standard (p-xylene).

As the results in table 18 shows, none of the newly tested catalysts performed better than ITC, which gave 97% conversion to 240 after 96 h (entry 1). After purification, only 50% yield was obtained due to the instability of 240. The cis isomer decomposed significantly faster on silica so that essentially pure trans isomer was obtained (dr 40:1). This allowed easier separation of enantiomers of trans-240 by chiral HPLC as there was now no peak overlap with cis-240, giving 14% ee. Catalysts 241 (entry 2) and 244 (entry 5) were less active and more importantly, produced almost equimolar mixtures if cis-240 and trans-240. Catalysts 242 (entry 3) and 243 (entry 4), bearing smaller Me and Et groups on sulfur, were reasonably competent at promoting the reaction, reaching almost full conversion after 336 h. The low final dr did not unfortunately allow separation of enantiomers by chiral HPLC even after attempted purification of trans-240. The absolute configuration of 247 was not assigned.

In search for a more selective catalyst, we were inspired by a report on tertiary amine- promoted epoxidation of benzaldehydes ²⁰⁴ Stoichiometric amount of alkaloid brucine (245) was tested under otherwise identical conditions as in previous experiments (scheme 77). The reaction proceeded to high conversion but afforded only 15% of trans-240 (dr 17:1, 40% ee) after purification due to stability issues. Unfortunately, unlike the previous thioether-catalysed reactions, the crude product from this reaction cannot be directly used in the conjugate addition/cyclisation step, because 245 would interfere with lithiation.

89 Scheme 77. Asymmetric Darzens-type epoxidation using brucine (250).

Even though the reactivity of cinnamyl bromide was much higher than allyl bromide, the reaction times were still impractically long, hampering optimization and screening of catalysts. The strategy was once again re-evaluated based on the following reasoning. 1) The choice of base and solvent are mostly dictated by the requirement for stabilisation of the epoxide, making K2CO3 in t- BuOH mandatory. 2) The rate limiting step of the organocatalytic epoxidation is likely either the initial alkylation of sulfur or more likely the ylide formation by deprotonation. 3) Changing the alkylating agent to be even stronger electrophile would accelerate the first step, while adding substituents that stabilise a negative charge would shift the unfavourable protonation equilibrium (scheme 78, A).

Therefore, we proposed 3,3-diphenylallyl bromide (246) as an ideal reagent that would satisfy both requirements. 246 can be prepared easily from benzophenone by addition of vinylmagnesium bromide, followed by SN2’ bromination of the resulting diphenylvinylcarbinol. This peculiar reagent is a stable solid but must be protected from light as it photolyzes even under common laboratory lighting.

A) B)

Scheme 78. A) Protonation equilibrium between sulfonium ion and ylide. B) Preparation of 246.

Table 19 summarizes the screening of amine, thioether and selenoether catalysts in epoxidation of 6-bromopiperonal using 246. Tertiary amines brucine (245) and L17 were not catalytically active (entries 1, 2). Tetrahydrothiophene-catalysed reaction (entry 3) reached 42%

conversion after 34 h, when 246 was depleted due to competing solvolysis. 242-catalysed reaction reached nearly full conversion after 168 h giving 3.7:1 mixture of trans-247 and cis-247 (entry 4), while 243-catalysed reaction was slower and les selective (entry 5). Finally, ITC proved very active, reaching nearly full conversion after 17 h using 3 equivalents of 246 (entry 6) or after 72 h using just 1 equiv. of 246 (entry 7). Reducing the loading of the catalyst ITC to just 5% still led to 83%

conversion after 140 h. These results were very promising, because the short reaction time and the reduced loading of the alkylating reagent and catalyst, combined with good diastereoselectivity (~5.4:1) would make the product epoxide pure enough for direct lithiation and cyclisation.

Table 19. Asymmetric epoxidation of 6-bromopiperonal using 246 – catalyst screening.

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Entry Catalyst 246 (equiv.) Time (h) Conversion ^a) trans:cis Yield

1 245 2.0 15 0 - -

2 L17 2.0 15 0 - -

3 THT 2.0 34 42 3.0:1 28

4 242 1.4 168 95 3.7:1 -

5 243 1.4 192 45 2.6:1 -

6 ITC 3.0 17 95 5.4:1 10 ^b)

7 ITC 1.0 62 82 5.5:1 -

8 ITC ^c) 1.3 140 83 5.3:1 -

a) Conversion to 247 based on internal quant. standard (p-xylene). Reactions stopped when conversion asymptotically decayed due to depletion of RBr. ^c) Dr after purification 11:1. ^b) 5% of catalyst used.

As expected, 247 was even less stable to silica than previously studied epoxides, but isolation of reduced amounts was still possible (entries 3, 6). Unfortunately, the enantiomers could not be separated by chiral HPLC. Therefore, the only way to learn the enantiomeric excess was to carry the epoxide forward to the next step.

Further optimization for larger scale preparations led to reduction of the catalyst loading to 10% while using 1.4 equiv. of 246. The reaction was monitored by ¹H NMR, until reaching full conversion while the concentration of 246 decreased below 5% due to a combination of epoxidation and solvolysis. The (near-) complete consumption of 246 is crucial, because if left in the mixture, it would interfere with the following step. Its solvolysis product is the inert 3,3-diphenylallyl tert-butyl ether, which is easily tolerated during the lithiation. In order to prevent decomposition, crude epoxide 247 (dr 6:1) was obtained from the reaction mixture by filtering off the base and removal of t-BuOH by co-evaporation with benzene. After drying, 247 was used directly in the next step (scheme 79).

Scheme 79. Conjugate addition/cyclisation of epoxide 247.

Conjugate addition/cyclisation of 247 under standard conditions of Florio resulted in the expected double cyclisation giving 248 in 38% yield (dr 3.5:1) over 2 steps from 6-bromopiperonal.

Furoindane product 249 was formed in 16% yield and could be separated from 248 by chromatography. During attempted crystallization from benzene, it partially decarboxylated to 250.

The cyclisation selectivity (6-exo/5-exo) was approximately 2.3:1. Both 248a and 248b were formed from trans-247, while 248b originates from cis-247. The ratio of cyclisation products derived from the respective diastereomers of the epoxide is 5.4:1, which roughly corresponds to the original trans/cis ratio 6:1 of 247.

91 Most importantly, the enantiomeric purity of the cyclic products could be determined for the first time because 249 (and less reliably 248a) could be separated by chiral HPLC giving enantiomeric excess of 49%, which can be also assumed for trans-247 and its cyclisation product 248a. This result was surprising, because none of the previously measured samples during optimization had similar or higher excess. The 3,3-diphenylallyl group therefore not only increases reactivity during the Corey- Chaykovsky olefination, but also increases asymmetric induction compared to allyl and cinnamyl groups. The absolute configuration of products 248-250 was not assigned. The synthesis was continued by decarboxylation of 248a using LiOH in a refluxing mixture of EtOH and THF (scheme 80). After workup, insoluble 251 precipitated from benzene.

Scheme 80. Saponificaiton of 248a followed by acid-induced decarboxylation.

Pure 252 proved surprisingly stable to both decarboxylation and lactonization, requiring treatment with CSA in deuterated acetonitrile to recyclise to 248a without detectable decarboxylation.

This result was consistent with the previously observed behaviour of 235 (chapter 4.4.2, scheme 72).

The minor diastereomer 248b resisted saponification by excess LiOH, presumably due to increased steric hindrance in the vicinity of the carbonyl group compared to 248a. This allowed easy removal of this isomer and bodes well for the overall synthesis. Due to the lack of time, the synthetic effort was not continued. The planned final steps of the total synthesis of 8’-fluoropodophyllotoxin (25) via neopodophyllotoxin (222) are outlined in scheme 81.

Scheme 81. Plan for the final oxidative decarboxylation and unmasking of the C-9 hydroxy group.

The stability of the free carboxylic acid at C-8’ should allow oxidative generation of radical and may allow radical halogenation ¹⁹⁷ instead of simple decarboxylation.¹⁹⁶ This would enable direct and elegant synthesis of the medicinally relevant 8’-fluoropodophyllotoxin (25) without the need for late-stage fluorination. After decarboxylation, the latent hydroxy group at C-9 should be unmasked by oxidative cleavage of alkene 253, followed by reduction to 8’-fluoroneopodophyllotoxin (8’- fluoro-222), which should easily undergo neopodophyllotoxin-like translactonization to 25.

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