Hydride delivery

The NaBH4-CeCl3 reagent has been observed to give hydride delivery from the more hindered face of certain bicyclic ketones.121... 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

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. 

Estradiol is formed by lithium aluminium hydride reduction of the ketone. We can formulate this simply as hydride acting as the nucleophile, though hydride delivery by LAH is strictly more complex than this. Unless you are specifically asked for details, treat LAH as a source of hydride ion. 

Reduction of C(5)-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane RsSiH reductants and 2,4-frans-chromans using the smaller silane PhSiH3. The stereochemical outcome has been rationalized on the basis of a Curtin-Hammett kinetic situation arising from hydride delivery to two different conformations of an intermediate oxocarbenium ion.363... 

Piperidine synthesis.3 The important glycohydrolase inhibitor 1-deoxynojiri-mycin (3) can be prepared in two steps from 5-keto-D-glucose (1). Thus 1 on treatment with benzhydrylamine and sodium cyanoborohydride in CH3OH at 0° undergoes double reductive amination to form essentially only one product (2), which on deprotection provides the piperidine 3. The high stereoselectivity is attributed to hydroxyl-directed hydride delivery. 

As mentioned elsewhere, the development of transition metal catalysts that allowed for high enantioselectivity in reduction reactions showed that chemists could achieve comparable yields and ee s to enzymes. A large number of transition metal catalysts and ligands are now available. A number of reactions have been scaled up for commercial production that use an asymmetric hydrogenation (Chapters 12-18) or a hydride delivery (Chapters 12, 16, and 17) for the key step that forms the new stereogenic center. 

R. M. Kellogg, Reduction of C=X to CHXH by Hydride Delivery from Carbon, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 8, 79, Pergamon Press, Oxford, 1991. 

The diastereoselectivity of this reaction reflects competition between two chairlike transition states A and B, each of which involves intramolecular hydride delivery as well as activation by acid catalysis. The 1,3-diaxial interaction between R2 and acetoxy groups would destabilize transition state B to a greater extent than the analogous interaction between hydroxy and acetoxy groups in the favored transition state, A1 (Scheme 4.2b). 

This suggests that the two protons are on the same side of the molecule and that reduction has occurred by hydride delivery to the face of the ketone opposite the two methyl groups on the three-membered ring. 

Several reactions in organometaUic chemistry also appear to contravene the rule, but which can be explained in a somewhat similar way. Hydrometallation [5.45, see (Section 5.1.3.4) page 162], carbometallation, metallo-metallation, and olefin metathesis reactions are all stereospecifically suprafacial [2 + 2] additions to an alkene or alkyne, for which the all-suprafacial pathway is forbidden. Hydroboration, for example, begins with electrophilic attack by the boron atom, but it is not fully stepwise, because electron-donating substituents on the alkene do not speed up the reaction as much as they do when alkenes are attacked by electrophiles. Nevertheless, the reaction is stereospecifically syn—there must be some hydride delivery more or less concerted with the electrophilic attack. The empty p orbital on the boron is the electrophilic site and the s orbital of the hydrogen atom is the nucleophilic site. These orbitals are orthogonal, and so the addition 6.126 is not pericyclic. 

On the basis of Kiyooka s working hypothesis for the aldol reaction mechanism, the reduction proceeds via by an intramolecular hydride transfer this is accelerated by matching between the chirality of the promoter and that of the newly formed aldol (Eq. 50). An alternative mechanism without chelation is also possible, and involves hydride delivery to the preferred O-silyl oxocarbenium ion conformer (Eq. 51). 

Zinc borohydride was effective for the reduction of a,P-epoxy ketones (49) to the corresponding anti-a,3-epoxy alcohols (50) in ether at 0 °C irrespective of the substituents on the epoxide (equation 14). The selectivity was rationalized by intramolecular hydride delivery from a five-membered zinc chelate avoiding the epoxide ring. In a limited study of the stereoselective reduction of y,8-epoxy ketones (51), LAH and di-2-(o-toluidinomethyl)pyrrolidine in ether at -78 C gave the desired c/j-epoxy alcohols (52) required for ionophore synthesis with good selectivity (>10 1) (equation 15). ... 

The stereocontrolled reduction of optically pure P-keto sulfoxides (60) with DIBAL-H anti selective, >93 7) or DlBAL-H in the presence of zinc chloride (syn selective, >95 5) provided an entry to enantio-merically pure alcohols after desulfurization (Scheme 9). The stereoselectivity may be rationalized by consideration of transition states analogous to those described for P-hydroxy ketone reduction (31 and 32), cyclic chelation by zinc chloride and external hydride delivery giving the syn isomer, and coordination of the DIBAL-H to the sulfoxide and internal hydride delivery giving the anti product. 

Reduction of C=X to CHXH by Hydride Delivery from Carbon... 

---