Face-selective hydride

This observation has led to the preparation of more effective bicyclic oxaza-borolidines such as 1, prepared from (S)-(-)-2-(diphenylhydroxymethyl)pyrrolidine and BH3 (la) or methylboronic acid (lb). Both reagents catalyze borane reduction of alkyl aryl ketones to furnish (R)-alcohols in > 95% ee, by face-selective hydride transfer within a complex such as B. Catalyst lb is somewhat more effective than... 

The first step of the mechanism is the coordination of BFI3 (Lewis acid) to the tertiary nitrogen atom (Lewis base) of the CBS catalyst from the -face. This coordination enhances the Lewis acidity of the endocyclic boron atom and activates the BH3 to become a strong hydride donor. The CBS catalyst-borane complex then binds to the ketone at the sterically more accessible lone pair (the lone pair closer to the smaller substituent) via the endocyclic boron atom. At this point the ketone and the coordinated borane in the vicinal position are cis to each other and the unfavorable steric interactions between the ketone and the CBS catalyst are minimal. The face-selective hydride transfer takes... 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

Some further examples of the reduction of adamantanones have highlighted that increasing the positive dipole on the C=0 using Lewis acids, or placing charged substituents at C(5) within the adamantyl framework, enhances face selectivities in borohydride and aluminium hydride reductions due to Cieplak effects. 

The face-selectivity of hydride reductions of the conformationally-rigid ketone series (100) has been examined for pure axial and equatorial isomers with four different R groups, viz. Me, Cl, OMe, and SMe.162 The reactivities show Taft correlations with the inductive effects of the substituents. Only through-bond and -space electrostatic interactions are used to explain the results neither Cieplak nor Anh antiperiplanar effects are invoked. 

The use of baker s yeast for selective reductions has a long history, while the use of isolated enzymes is more recent. Dehydrogenases and reductases require a nicotinamide cofactor (NADH or NADPH), from which a hydride is transferred to the substrate carbonyl. Enzymes from different species have been classified according to their selectivity (hydride transfer to si- or re-face of the carbonyl) [14]. The cofactors to be used together with isolated enzymes are commercially available (e.g. from Sigma-Aldrich), but are for most applications too costly to use in stoichiometric amounts. However, cofactor in situ regeneration can be... 

Addition of -butylmagnesium bromide to 624 followed by Swem oxidation affords the ketone 642. Zinc borohydride addition occurs with almost exclusive anri-selectivity (>99 1), leading to 646 in accordance with an a-coordinated transition-state model in which the r -face of the carbonyl is exposed to the reagent. Presumably the MOM-ethers display a crown ether effect to facilitate a-chelation. In marked contrast, L-Selectride shows excellent 5y -selectivity to provide 645 (92 8), consistent with a j5-chelation and/or Felkin— Anh model. The a ri-adduct 646 is converted in five steps to ketone 647, which undergoes a similar highly selective hydride reduction with zinc borohydride to yield the anti,syn,syn-alcohol 648 (96 4). This product is converted in six steps to the r n5-(2i ,57 )-pyrroline 649, which undergoes a Wacker oxidation followed by catalytic reduction to (— )-indolizidine 195B (650) and its C-5 epimer (86 14) (Scheme 142). 

The face selectivity in stericaUy unbiased systems, exhibited in 2-adamantyl cation addition and elimination reactions, among others, has been reviewed, " and so have the elecuonic factors governing the diastereofacial selectivity of many reactions, including the nucleophilic capture of 5-substituted adamantyl cations. The standard enthalpy of formation of the 1-adamantyl cation (99) in the gas phase has been determined experimentally to be 162.0 2.0 kcalmoP, and the ab initio calculations on this species have been re-assessed. It has been found that the inuamolecular hydride transfer occurring in the cation derived from (198) is competitive with intermolec-ular processes, and that the rates of the hydride transfers and the reaction products observed were dependent upon R. The direct synthesis of stable adamantylide-neadamantane bromonium salts is reported the anions used contained or Mo, and the resulting salts proved to be more stable than the Brs salts. The synthesis, reactions, and properties of some 2,8-didehydronoradamantane derivatives are reported. " ... 

The face selectivity in hydride reductions of ketone 287 serves as an encouraging example in this field. The electronic nature of the substituents obviously influences the Dunitz-trajectory of the approaching hydride equivalent. 

Another way to incorporate an enantiomerically-pure oxygenated stereogenic center into a molecule is the enantio face-selective addition of hydride to a ketone such as 6. Alain Burgos and his team at PPG-SIPSY in France have described Tetrahedron Lett. 2007, 48, 2123) a NaBH -based protocol for taking the Itstmo-Corey reduction to industrial scale. 

As noted in Chapter 18, the enzymes that require nicotinamide coenzymes are stereospecific and transfer hydride to either the pro-i or the pro-S positions selectively. The table (facing page) lists the preferences of several dehydrogenases. 

Mehta et al. also studied the facial selectivities of 5,6-exo,eji o-disubstituted bicyclo[2.2.2]octan-2-ones 18 [75, 78]. These systems are related to the 2,3-exo,ex( -disubstituted 7-norbomanones 14, but differ in the direction of the carbonyl n face. Hydride reduction of 5,6-exo,ex( -disubstituted bicyclo[2.2.2] octan-2-ones (18) with NaBH and DIBAL-H and methylation with MeLi were smdied [75, 78],... 

The sterically unbiased dienes, 5,5-diarylcyclopentadienes 90, wherein one of the aryl groups is substituted with NO, Cl and NCCHj), were designed and synthesized by Halterman et al. [163] Diels-Alder cycloaddition with dimethyl acetylenedicarbo-xylate at reflux (81 °C) was studied syn addition (with respect to the substituted benzene) was favored in the case of the nitro group (90a, X = NO ) (syrr.anti = 68 32), whereas anti addition (with respect to the substituted benzene) is favored in the case of dimethylamino group (90b, X = N(CH3)2) (syn anti = 38 62). The facial preference is consistent with those observed in the hydride reduction of the relevant 2,2-diaryl-cyclopentanones 8 with sodium borohydride, and in dihydroxylation of 3,3-diarylcy-clopentenes 43 with osmium trioxide. In the present system, the interaction of the diene n orbital with the o bonds at the (3 positions (at the 5 position) is symmetry-forbidden. Thus, the major product results from approach of the dienophile from the face opposite the better n electron donor at the (3 positions, in a similar manner to spiro conjugation. Unsymmetrization of the diene % orbitals is inherent in 90, and this is consistent with the observed facial selectivities (91 for 90a 92 for 90b). 

With an efficient synthesis of allylic alcohol 46 in our hands, our attention turned to the selective reduction of the double bond. As stated above, we intended to use the hydroxy group in 46 to deliver hydride from the same face as the hydroxy group. Mainly there were two methods available (i) transition metal-mediated hydrogenation and (ii) metal hydride reduction. 

If the catalyst is chiral, it can transfer hydride selectively to one prochiral face of an acceptor to provide an optically active product (Fig. 35.1). 

Another interesting approach was developed by Ikegami and coworkers, who used an anomeric orthoester as the key intermediate (Scheme 7.14).59 Formation of orthoester 16 from lactone was effected by TMSOTf and TMSOMe. Subsequent Lewis acid mediated reduction afforded p-mannoside in high selectivity, presumably because of the stereoelectronically controlled hydride delivery from the a face. 

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