One of the endgame steps in the synthesis would have included a diastereoselective 1,3-anti- reduction of a E-hydroxy ketone (Scheme 57). While there are established and well-tested methods for 1,3-anti-reductions, such as the Evans-Carreira-Chapman modification of Saksena reduction,125 and Evans-Tishchenko reduction,126 at the time of our studies there were no reports on the diastereoselectivity in the reduction of E-hydroxy ketones with immobilized borohydrides. Formally, the resin bound borohydride would correspond to a quaternary ammonium borohydride compound (Scheme 64). Further modification to a triacetoxyborohydride would then give an immobilized version of the Evans-Saksena reagent that might be applicable to continuous flow conditions. Hence, we set out to briefly investigate the matter.
Scheme 64. Reduction of E-hydroxyketone with immobilized borohydrides and the corresponding transition state leading to 1,3-anti-enriched product via complexation and intramolecular hydride attack.
For model compounds we synthesized 265-267 by standard aldol reactions between corresponding ketones and aldehydes (Figure 19). A commercial polymer supported borohydride was purchased from SigmaAldrich, but after it showed rather poor activity in the model reaction, we carried out the immobilization ourselves.130 The borohydride ion was
91 immobilized on Amberlite IRA-400 (Cl– form) by washing the resin first with 1 M HCl and distilled H2O, and then stirring it in a 1 M aqueous solution of NaBH4 and then drying the resin cautiously in vacuum.
Figure 19. Model substrates for reduction studies
Reactions with solid supported borohydride were carried out by dissolving 1 mmol of E- hydroxyketone into an alcoholic solvent, adjusting to desired temperature and then adding 1 gram of borohydride resin (2-3 equivalents based on theoretical loading). The Rychnovsky cyclic acetonide method was used for determining the diastereoselectivity, and the 1H NMR signals of CHOH protons at 3.37 (anti) and 3.45 (syn) were used for integration according to Cohen.131,132 The products were isolated by filtering the reaction mixture and evaporating solvents to dryness. An example of the reaction is shown in Scheme 65.
Scheme 65. Reduction of 265 with solid supported borohydride
The model reaction gave a syn-selective product, as usually does a standard reduction with NaBH4 (a control experiment characterized with crude 1H NMR spectroscopy). Pretreating the resin with glacial AcOH should give the triacetoxyborohydride species.134 The borohydride resin was stirred in THF at 0°C with 3 equivalents of AcOH for 45 minutes, then filtered and washed. However, the activity of the treated resin was lower, and still gave a syn- enriched product with practically same selectivity as the untreated resin (Scheme 66). We also attempted to perform the reaction in a mixture of AcOH and MeOH, but observed no reaction
92
taking place after strong initial bubbling during which the acid reacted with the borohydride ions.
Scheme 66. Reduction of 265 with resin pretreated with glacial AcOH
To see how the selectivity could be tuned, we briefly investigated the effect of temperature and solvents. Scheme 67 highlights the effect of temperature in the model reaction. By heating the reaction we were able to boost the reaction speed significantly, with no great effect to diastereoselectivity. This indicates also that the polymer supported borohydride could theoretically be used in a continuous flow fashion as a packed column reactor, although resin based borohydrides have been previously reported to be unreliable in flow conditions.76 However, this problem has been solved recently by using a monolithic quaternary ammonium polymer loaded with borohydride ions.134
Scheme 67. The effect of temperature on reaction speed and selectivity
The effect of solvents is depicted in Table 9. For borohydride reductions, MeOH is usually the best solvent with respect to reaction speed, since a precomplexation between the solvent and the borohydride ion apparently results in a more active reagent. When the reaction was run in i-PrOH, we observed an anti-enriched product although the reaction was very slow and not as clean as in MeOH (entry 1). A non-alcoholic solvent gave no reaction (entry 2).
Mixtures of MeOH and other solvents gave slower reaction times and varying selectivities
93 (entries 3-6). Mixing i-PrOH with MeOH reversed the selectivity once more towards the syn- isomer. Heating the reaction in i-PrOH gave a faster conversion (not shown in table), but after filtration no product was isolated, which may be due to the instability of the resin in higher temperatures. In entry 6 we carried out a hydrolytic and oxidative work-up with NaOH/H2O2, which gave a further 50% yield of recovered product after extraction. The product thus recovered consisted only of the syn-isomer, bringing the total yield to about 80% and selectivity to 3:1 syn:anti. Keeping in mind the original goal of achieving an anti-selective diastereoselective reduction in continuous flow conditions, these results were less than promising, due to the slow kinetics and synthetically unusable selectivities even in the case of i-PrOH.
Table 9. Effect of solvents on the reduction of 265
Entry Solvent Time Conversion syn:antia Yield
1 i-PrOH 6 d Full 1:~2.5b n.d
2 THF 6 d – – n.d
3 1:1 MeOH:THF 21 h Full 3:1 95%
4 4:1 i-PrOH:MeOH 16 h Full 1-1.5:1 n.d 5 1:1 i-PrOH:MeOH 16 h Full 2.5:1 n.d 6 4:1 s-BuOH:MeOH 5 d Full 1:1.5 30%
a) The diastereoselectivity was determined via Rychnovski acetonide method. b) Approximated from crude product 1H NMR spectrum.
Finally, we attempted a simple substrate experiment to determine the effect of substitution.
Whereas compound 267 gave a diastereoselectivity of 2:1 syn:anti, reversing the position of the ketone and hydroxyl groups gave a completely nonselective reaction (Scheme 68). In the case of 267 we also treated the remaining resin with NaOH/H2O2 and recovered further 27%
of pure syn-product.
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Scheme 68. Substrate experiments