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Addition of Metal-H bonds to Carbonyl Groups

Addition of Metal-H bonds to Carbonyl Groups. Group 13 Hydride-Donor Reagents. Chemoselectivity. reactivity towards nucleophiles. = reacivity towards metal-hydride. LiAlH(O- t -Bu) 3. LiAlH(OMe) 3. LiAlH(O- t -Bu) 3. LiBH(CH 2 CH 3 ) 3 Rt , 2 min. (LiAlH 4 ).

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Addition of Metal-H bonds to Carbonyl Groups

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  1. Addition of Metal-H bonds to Carbonyl Groups Group 13 Hydride-Donor Reagents

  2. Chemoselectivity reactivity towards nucleophiles = reacivity towards metal-hydride LiAlH(O-t-Bu)3 LiAlH(OMe)3 LiAlH(O-t-Bu)3

  3. LiBH(CH2CH3)3 Rt,2 min (LiAlH4)

  4. How to reduce esters to alcohols tetrahedral intermediate How to reduce amides to amines tetrahedral intermediate does not happen: -NR2 is not eliminated in this step

  5. Borane can also reduce amides to amines tetrahedral intermediate collapses to iminium ion only reactive towards protonated imines at pH 6~7, essentially unreactive towards carbonyl groups

  6. How to reduce esters and amides to aldehydes tetrahedral intermediate stable at －78℃ stable cyclic tetrahedral intermediate

  7. Making ketones from Weinreb amides (esters) DIBALH tetrahedral intermediate stabilized by cooordination of the second oxygen atom to the magnesium atom H

  8. How to reduce carboxylic acids to alcohols

  9. Other synthetically important reduction protocols Narasaka 1984 Evans 1988

  10. Reductions in an industrial scale are crucial transformations Glaxo anti-asthma Drugs H2, Pd-C sulbutamol

  11. Glaxo anti-asthma Drugs

  12. Selective Reduction — Hypothesis NaBH4 NaBH4

  13. Combination of BH3 with catalytic NaBH4 (Brown, Yoon; 1968) Route “a” Route “b”

  14. Selective Reduction — Results chemoenzymatic process

  15. Mechanism (1) ?

  16. Mechanism (2) — catalytic cycle

  17. Mechanism (3) — catalytic cycle

  18. Mechanism (4) — catalytic cycle

  19. Synthetic Applications K. Mori, T. Takigawa, T. Matsuo, Tetrahedron, 1979

  20. Commercial Production of Grams-to-Tons of Chiral HGB — Synthon Corporation — +

  21. has been playing an important role in

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