Initial optimization of organocatalytic Corey-Chaykovsky epoxidation

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decarboxylation via 236 should therefore focus on either a Barton-type reduction or oxidative decarboxylation using a variant of the Hunsdiecker reaction.^196,197

83 Table 13. Corey-Chaykovsky epoxidation of 6-bromopiperonal catalysed by ITC - initial solvent screening.

Entry Solvent Time 230 by ¹H NMR ^a) trans : cis

1 DMSO 30 h 0 % -

2 MeOH 30 h 0 % -

3 DMF 30 h 0 % -

4 DMF 7 h ^b) 0 % -

5 MeCN/H2O 9:1 30 h <1 % -

6 t-BuOH 96 h 8 % 5.5:1

7 t-BuOH 144 h 13 % 6:1

a) Conversion relative to 6-bromopiperonal, no significant side-products detected. ^b) Heated to 60 °C.

Finally in t-BuOH (entries 6, 7), a very slow reaction occurred, giving 13% conversion to 230 after 144 h at r.t. Importantly, little decomposition of the product was observed. The diastereomeric ratio improved to 6:1 compared to the 1.7:1 obtained previously with THT. Although the reaction was impractically slow under these conditions, this result had proven that ITS can in principle be used as the sole catalyst for the Corey-Chaykovsky epoxidation.

The next reaction parameter we decided to optimize was the base. A set of parallel experiments was run with increased loading of the different bases (5 equiv.) to accelerate the reaction.

The optical purity of the product was evaluated by chiral HPLC (table 14). Both K2CO3 and Cs2CO3

(entries 1, 2) promoted a slow reaction giving product 230 as a roughly 6:1 mixture of diastereomers, but only in 22% ee and 29% ee respectively. Addition of TBAI ¹⁹⁹ seemed to moderately accelerate the reaction with Cs2CO3 (entry 3), giving a 9% yield after only 13 h instead of the 72 h previously required to attain equivalent yield. NaOH promoted faster reaction, leading to 47% conversion after 144 h (entries 4, 5), but the dr of 230 was lower at 4:1 as well as giving lower ee of 24%. DIPEA failed to promote the reaction with or without the addition of TBAI (entries 6-7). Based on these results, K2CO3 was selected for further study because it was roughly equivalent in performance to Cs2CO3 but is significantly cheaper.

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Table 14. Corey-Chaykovsky epoxidation of 6-bromopiperonal catalysed by ITC - base screening.

Entry R Base Time (h) Conv. (%) ^a) 230 (%) trans:cis % ee (trans) ^b)

1 allyl K2CO3 168 31 26 6:1 <22

2 allyl Cs2CO2 72 10 10 6.5:1 <29

3 allyl Cs2CO2c) 13 9 9 5.2 <30

4 allyl NaOH ^c) 72 33 - 4:1 -

5 114 47 37 4.6:1 <24

6 allyl DIPEA 72 0 0 - -

7 alllyl DIPEA ^c) 72 0 0 - -

8 prenyl K2CO3 72 0 0 - -

9 cinn. K2CO3 72 58 - 13:1 -

10 120 100 23 20:1 17

Yields refer to isolated 230. Entries 4,5 and 9,10 each refer to the same experiment. ^a) Conversion to 230as measured by ¹H NMR. ^b) Upper estimate of ee due to peak overlap with inseparable cis-230 in chiral HPLC. ^c) TBAI (1.0 equiv.) added. ^d) Yield of 240.

In an attempt to increase the diastereoselectivity and enantioselectivity, the more sterically demanding prenyl bromide was also tested (entry 8), but no reaction occurred after 72 h. Cinnamyl bromide (entries 9, 10) on the other hand reacted much faster than allyl bromide, giving 58%

conversion after 72 h and reaching full conversion after 120 h. The diastereomeric ratio between trans- and cis-240 was also much higher at 13:1 in the crude mixture and 20:1 in the isolated compound.

The reason behind this observation is likely both the higher selectivity of the reaction itself and the faster decomposition rate of the cis isomer during purification as the yield after purification was only 23%. The increased reactivity of cinnamyl bromide likely stems from the faster rate of alkylation of ITC as well as higher stabilisation of the ylide form. Unfortunately, the enantiomeric excess was only 17%.

Increased diastereoselectivity of epoxidation using ITC bodes well for our synthetic strategy for the synthesis of neopodophyllotoxin, however the enantiomeric excess attained so far was too low.

We hypothesized that the low selectivity might stem from catalyst decomposition, which instead of shutting the reaction down might lead to formation of more kinetically competent but unselective thioethers like diallyl ether etc. These may be formed by dealkylation of the sulfonium ion formed by alkylation of ITC via E2 elimination (scheme 76).

Scheme 76. Possible pathway of ITC decomposition via E2 elimination.

85 To test this hypothesis, we tested several simple off-the-shelf thioethers and sulfides for their ability to catalyse the epoxidation. Sodium methanethiolate, sodium sulfide, allyl phenyl thioether and dibutyl thioether (table 15, entries 1-4) failed to promote the reaction. This is strong evidence against the idea that diallyl sulfide or other simple thioethers kinetically overtake ITC during the organocatalytic epoxidation. In contrast to the previously mentioned sulfides, thioanisole (entry 5) did promote the reaction reaching 30% conversion after 168 h, although with poor

diastereoselectivity (1.4:1). To help guide the future selection or design of potential future catalyst, several selenides were tested as well (table entries 6-8). Of those, only selenoanisole (entry 6) was found to be active, albeit less than thioanisole, reaching 9% conversion after 168 h.

Table 15. Screening of other organosulfur and organoselenium compounds for catalytic activity.

Entry Catalyst Time (h) Conv. (%) ^a) Yield (%) trans:cis

1 MeSNa 168 0 - -

2 Na2S 168 0 - -

3 PhS(allyl) 168 0 - -

4 Bu2S 168 0 - -

5 thioanisole 24 2 - 1.8:1

72 9 - 1.4:1

168 30 29 1.4:1

6 selenoanisole 24 0 - -

72 6 - 1.3:1

168 9 9 1.3:1

7 Ph2Se2 168 0 - -

8 Ph2Se 168 0 - -

a) Conversion to 230 in crude as measured by ¹H NMR.

Since the initial solvent screening, all reaction ahd been done in t-BuOH. Even though it was found optimal for reactivity and product stabilisation, the starting 6-bromopiperonal has only limited solubility in t-BuOH. This puts a limit on maximum concentration, in turn limiting reaction rate.

Addition of DCM (20-35%) was found to increase solubility while maintaining good reactivity. This prompted us to re-evaluate the base/solvent choice at higher concentration with added DCM (table 16). Parallel experiments in t-BuOH//DCM 3:1 using Na2CO3, K2CO3, Cs2CO3 and NaOH (entries 1- 4) were run under otherwise identical conditions. Na2CO3 failed to promote the reaction completely, while NaOH caused excessive decomposition of the product even at low conversion. The reactions using K2CO3, Cs2CO3 were stopped after 23 days, when sufficient conversion for isolation of 230 was reached. Purification yielded 36% (dr 6:1) and 24% (dr 5.4:1) of 230 respectively. Importantly, the enantiomeric excess in both cases was around 41%, more than in the previous experiments (table 14).

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Table 16. Re-optimization of the Corey-Chaykovsky epoxidation with added DCM.

Entry Solvent Base 1 day ^a) 4 days ^a) 9 days ^a) 23 days ^a) trans:cis % ee ^b)

1 t-BuOH Na2CO2 0 0 - - - -

2 t-BuOH K2CO3 4 12 21 36 ^c) 6:1 <41

3 t-BuOH Cs2CO3 6 12 21 24 ^c) 5.4:1 <43

4 t-BuOH NaOH 6 11 ^d) - 6:1 -

5 MeCN Na2CO2 0 0 ^d) - - -

6 MeCN K2CO3 8 21 41 ^c) - 4.3:1 <12

7 MeCN Cs2CO2 12 24 ^d) - 6:1 -

8 MeCN NaOH 5 4 ^d) - 20:1 -

9 ^e) t-BuOH K2CO3 7 - 65 ^c) - 5:1 <28

a) Conversion to 230 in % by ¹H NMR (p-xylene as internal quant. standard). ^b) Upper estimate of ee due to peak overlap with inseparable cis-230 in chiral HPLC. ^c) Isolated yield of 230. ^d)

Decomposition. ^e) Allyl iodide used instead of allyl bromide.

From a similar set of experiments in MeCN/DCM 3:1 (entries 5-8) under otherwise identical conditions, only the reaction using K2CO3 was chemoselective enough to allow isolation of 230 in 41% yield. The reaction rate was generally higher in MeCN, but product decomposition and lower stereoselectivity make acetonitrile an inferior solvent for the epoxidation. Additionally, the concentration of the catalyst decreased more significantly over time in MeCN compared to t-BuOH.

To increase the reaction rate, allyl iodide was tested instead of allyl bromide using the optimal base K2CO3 in t-BuOH//DCM 3:1 (entry 9). Indeed, 65% yield of 230 (dr 5:1) was obtained only after 9 days. Together with the increased reactivity of cinnamyl bromide observed earlier (table 14, entry 10), this result suggested that more reactive allylic halides should be used for future optimisation.

87