Reducing agents diastereoselectivity

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center to the carbonyl group, even an achiral reducing agent can give more of one diastereomer than of the other. Such diastereoselective reductions have been carried out with considerable success. In most such cases Cram s rule (p. 147) is followed, but exceptions are known. ... 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

Alternatively, silylalkynes underwent highly diastereoselective couplings with a-silyloxyaldehydes with (z-pr)3SiH as the reducing agent and IMes as... 

The enantioselective reduction of y-nitroketones and y-nitrodiketones by the chiral reducing agent (+)- or (-)-dusopinocamphenylchloroborane (DIP-C1 ) gives nitro alcohols having from 33 to 86% ee and nitrodiols with complete diastereoselectivity and > 95% ee.122... 

Common achiral reducing agents such as borohydrides produce the anri-isomer 18 as the major product of the reduction of the carbamate protected y-amino-p-oxo esters 31 (Table 4, entries a-e)J36 38 41 50l The syn-isomer is accessible with high diastereoselectivity by reduction of the corresponding AA-dibenzyl p-oxo esters using sodium borohydride stereoselective reduction under nonchelation control (Table 4, entry f).t45 52l... 

On the other hand, Takacs and coworkers added organometallic reducing agents to the reaction mixture and promoted the formation of low-valent iron(O) bipyridine complexes. The mechanism of the low-valent iron-catalyzed Alder-ene reaction involves coordination of the two starting materials within the ligand sphere of the iron, which makes the Woodward-Hoffmann rules for such reactions obsolete [11]. Thereby, the scope of the reactions was broadened so that alkenes and 1,3-dienes could also be used as educts in a formal [4 + 4]-cycloisomerization (Scheme 9.3) [12]. Intriguingly, the diastereoselectivity of the cydopentane products can be influenced by either the application of the 2Z-isomer 3 or the 2 E-isomer 4. Especially the E-isomers 4 gave almost exclusive cis selectivity [13]. 

The direct enantioselective a-hydroxylation of activated ketones [22], specifically cyclic / -dicarbonyl compounds, can be performed using dihydroquinine as the chiral catalyst and simple commercially available peroxides as the oxidant. The use of cumyl hydroperoxides led to the a-hydroxylation of / -ketoesters 21 in high yields and moderate to good enantioselectivities (66-80% ee) (Eq. 5). These optically active alcohols (22) undergo a diastereoselective reaction to anti-diols with excellent diastereoselectivity (99 1) using BH3-4-ethylmorpholine as the reducing agent. 

Ni(0) catalyst. A radical 5-exo cyclization to the potentially zinc or nickel-complexed ketone provides an alkoxyl radical that combines with the co-produced Ni(I) species. A transmetalation to a zinc alkoxide regenerates the catalyst and forms the zinc cyclopentoxide, from which products 79 are liberated on hydrolysis. A bimetallic Cu(I)-Mn(II) system provided similar results (see Sect. 8.4). Analogous samarium diiodide-mediated reactions require in contrast stoichiometric amounts of the reducing agent and are less diastereoselective [26, 27],... 

In the attack by sterically undemanding reducing agents, this stereoelectronic effect is fully effective (for a completely different but perfectly diastereoselective reduction of 4-fert-butylcyclohexanone to the equatorial alcohol, see Figure 14.46). However, in the attack of such a bulky hydride donor as L-Selectride the stereoelectronic effect is overcompensated by the opposing steric effect discussed above. 

Of course, the highest diastereoselectivities in the reduction of a-chiral a-oxygenated carbonyl compounds are expected when the reducing agent and the protecting group direct in one and the same direction that is, when both make possible or both prevent... 

Keck recently applied the diastereoselective reduction of ( S-hydroxy ketones in an approach to the anti-tumour natural products epothilone A and B. Sml2-mediated reduction of p-hydroxy ketone 15 in THF-MeOH gave anti- 1,3-diol 16 in 94% yield and as a 96 4 mixture of diastereoisomers.18 Attempts to carry out the reduction using common hydride reducing agents gave 16 with poor levels of diastereoselectivity (Scheme 4.10).18... 

In this case, the silylation of the metal alkoxide initially formed represents the key step of the overall process which releases the chromium salt from the organic product. The other crucial parameter is the use of the stoichiometric reducing agent for the regeneration of the active Cr" species. Commercial Mn turned out to be particularly well suited, as it is very cheap, its salts are essentially non-toxic and rather weak Lewis acids, and the electrochemical data suggest that it will form an efficient redox couple with Cr . Moreover, the very low propensity of commercial Mn to insert on its own into organic halides guarantees that the system does not deviate from the desired chemo- and diastereoselective chromium path. Thus, a mixture of CrX ( = 2, 3) cat., TMSCl and Mn accounts for the first Nozaki reactions catalytic in chromium [13]. 

However, the reducing agent may influence the conformation of ketone, and thereby the diastereoselectivity. If the small and medium substituents are close in size, then this model fails to predict the exact selectivity. This model also assumes less interaction between the large group and R group, which is not entirely correct. 

Two major mechanisms have to be taken into consideration for the alkylation of Co -corrins. The classical mechanism of a bimolecular nucleophilic substitution reaction at carbon (the Co -corrin acts as a nucleophile) leads to /3-aUcylated Co -corrins with high diastereoselectivity. Secondly, an electron transfer-induced radical process (where the Co -corrin acts as a one-electron reducing agent) may also lead to cobalt alkylation. The observed formation of incomplete a-aUcylated Co -corrins under kinetically controlled conditions has been proposed to occur via this path. The high nucleophilic reactivity of Co -corrins and their diastereoselective nucleophilic reaction on the ( upper ) /3-face are not increased by the nucleotide function on the ( lower ) a-face rather they appear to be an inherent reactivity of the corrin-bound tetracoordinate Co -center. Among the organometallic B12 derivatives prepared to date, neopentylcobalamin, benzylcobalamin, and... 

Subsequent reduction of the ketone produces either the syn or anft p-hydroxyamides with high diastereoselectivity (eqs 4 and 5). Pyrrolidine-derived a-ketoamides have also been shown to react stereospecifically with reducing agents, as well as with other organometallic reagents. ... 

This approach is also applicable to selective functionalization of carbonyl substrates with a trifluoromethyl group in an appropriate position, as exemplified by the diaster-eoselective reduction of 2-trifluoromethylcyclohexanone (62) with MesAl and BusSnH (Sch. 40) [68]. This selectivity can be interpreted in terms of the formation of the intermediate chelate-like pentacoordinate Mc3Al complex [I]. When DIB AH was employed as a reducing agent, total lack of selectivity was observed, and the opposite diastereoselectivity was observed for the reduction with NaBFLj in methanol at 0 °C. 

Examples of asymmetric induction from more remote hydroxy groups in the reduction of hydroxy ketones are rare. However the correct choice of reducing agent allowed complete diastereoselectivity to be achieved in the reduction of "y-hydroxy ketone (43) in a synthesis of ancistrofuran. 2 equiv. of LiEtsBH in THE, one presumably coordinating the "y-hydroxy ketone in a fixed conformation, gave the diol (44) as the sole product in 88% yield (equation II). 

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