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An effective oxidative protocol for the liberation of ketones from SAMP hydrazones employing peroxyselenous acid under aqueous buffered conditions (pH 7) has been developed. The procedure proceeds without epimerization of adjacent stereocenters or dehydration, respectively, in representative SAMP alkylation and aldol reaction adducts.
(S)- and (R)- Amino-2-methoxypyrrolidines (SAMP and RAMP), effective chiral auxiliaries introduced by the Enders group,1 have found wide use in asymmetric alkylation and aldol reactions.2 Consequently, a large number of methods have been developed to liberate the resultant aldehydes and ketones from the SAMP/RAMP hydrazone products.3 In conjunction with an ongoing synthetic program directed towards the total synthesis of (+)-nodulisporic acid A (1, Figure 1), a wide variety of known oxidative, hydrolytic, or reductive methods were explored to liberate ketone 3 from advanced SAMP intermediate 2, albeit with limited success (Table 1 entries 1–12). We eventually discovered that peroxyselenous acid, generated in situ from SeO2 and 30% H2O2 (1:4 equiv) was a superior oxidant for the removal of the chiral auxiliary in 2 accompanied by a small amount of epimerization at the α-position of ketone 3 (entry 13).
Pleasingly, the epimerization problem could be alleviated simply by the introduction of a pH buffer 7 (entry 14). Importantly, no epimerization or retro aldol fragmentation, which was observed with several of the alternative protocols, occurred under these optimized conditions. To the best of our knowledge, this report presents the first examples exploiting SeO2 and H2O2 under buffered conditions for the oxidative deprotection of ketone-derived hydrazones.
Previous reports have, however, recorded the oxidative cleavage of aldehyde SAMP hydrazones to furnish the corresponding nitriles, via an oxy-Cope-like elimination (Scheme 1),4 with oxidants such as m-CPBA,5 MMPP (magnesium monoperoxyphthalate), SeO2, or 2-nitrobezeneselenic acid with H2O2,6 and H2O2.7 A similar oxidative fragmentation is of course not an option with SAMP ketone hydrazones.
To explore the scope and viability of the pH 7 buffered peroxyselenous acid conditions, a series of ketone SAMP hydrazones were readily prepared from simple ketones 7–16 (Figure 2)8 using SAMP hydrazine and a catalytic amount of TsOH in cyclohexane at reflux; yields ranged from 70–98%. Application of the pH 7 buffered SeO2/H2O2 protocol, optimized during the (+)-nodulisporic acid A synthetic program, regenerated the corresponding ketones 7–15 in 68–96% yields.9 Liberation of cyclohexenone 16 from SAMP hydrazone 17 however was not successful. Instead, an epimeric mixture of 2-hydroxy-3-methoxyclohexanone 18 was isolated in 85% yield (Scheme 2).
We next turned our attention toward to SAMP hydrazones possessing an α-stereogenic center. The requisite substrates were readily prepared by alkylation of a series of ketone SAMP hydrazones with (S)-(+)-1-iodo-2-methylbutane (Scheme 3);10 yields for the alkylated-SAMP hydrazones (19–21) were again excellent (90–96%). Stereochemical assignments at the α-center were based on the Enders precedent.11 Treatment of the hydrazones with SeO2 and H2O2, again employing an aqueous buffer (pH 7), led to clean removal of the SAMP moiety to furnish ketones (22–24) in 88–90% yield. Importantly, no epimerization (>20:1, 500 MHz NMR) at the α-center was observed.
In addition to the SAMP alkylation products, a third series of hydrazones was examined involving the products derived from an aldol reaction with benzaldehyde (cf. 25–27).12 As these aldol products are generally sensitive to acid, we were not surprised initially to observe significant elimination (i.e., dehydration) and/or retro-aldol fragmentation. Pleasingly, such side reactions could be suppressed by increasing the amount of pH 7 buffer (i.e., from 1:18 to 1:3 v/v; buffer: methanol) to afford β-hydroxy ketones 28–30 in 65–81% yield (Scheme 4).13
A mechanistic picture of the pH 7 buffered oxidative hydrolysis using SeO2 and H2O2 is proposed in Scheme 5. After initial formation of peroxyselenous acid, oxidation of the pyrrolidine nitrogen in 31 is envisioned to generate intermediate 32, thereby activating the hydrazone toward hydrolysis. Addition of water followed by fragmentation would then deliver the ketone 34 and diazene 35 as a byproduct.
In summary, an efficient method to regenerate ketones from SAMP ketone hydrazones employing SeO2 and H2O2 under buffered conditions has been developed. Aldol hydrazone adducts derived from the SAMP hydrazone require additional buffer to suppress side reactions. Given the scope of this protocol, this method holds promise as an effective and mild alternative to the more conventional methods to regenerate ketones from SAMP hydrazones.
Support was provided by the National Institutes of Health (Institute of General Medical Sciences) through grant GM-29028 and the University of Pennsylvania. We thank Drs. G. Furst, J. Gu, and R. Kohli (University of Pennsylvania) for assistance in obtaining NMR spectra and high-resolution mass spectra, respectively.