Reduction Midland

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

The reduction is considered to proceed through a six-membered transition state30 (Scheme 4.3aa). In the hydride-bridged six-membered transition state A, the acetylenic unit positions itself away from the isopinocampheyl skeleton. The hydrogen P to the boron is then transferred to the carbonyl group from the bottom face of the ketone. Computational analysis on the proposed transition state of the Midland reduction has not, however, been reported.32... 

Mulzer and Berger used the Midland reduction en route to the total synthesis of the boron-containing macrodiolide antibiotic tartrolon B (90), which acts... 

MIDLAND ALPINE-BORANE REDUCTION (MIDLAND REDUCTION)... 

Kinetic studies of the Midland reduction confirmed that the reduction of aldehydes is a bimolecular process and the changes in ketone structure have a marked influence on the rate of the reaction (e.g., the presence of an EWG in the para position of aryl ketones increases the rate compared to an EDG in the same position). However, when the carbonyl compound is sterically hindered, the rate becomes independent of the ketone concentration and the structure of the substrate. The mechanism with sterically unhindered substrates involves a cyclic boatlike transition structure (similar to what occurs in the Meerwein-Ponndorf-Verley reduction). The favored transition structure has the larger substituent (Rl) in the equatorial position, and this model correctly predicts the absolute stereochemistry of the product. 

The first total synthesis of the neuritogenic spongean polyacetylene lembehyne A was accomplished by M. Kobayashi and co-workers. The single stereocenter of the molecule was introduced via the Midland reduction of a propargylic ketone using an Alpine-Borane , which was prepared from (+)-a-pinene and 9-BBN. 

The cyclic peroxide natural product (+)-chondrillin was prepared by P.H. Dussault and co-workers using a singlet oxygenation/radicai rearrangement sequence as the key step. The first stereocenter was introduced via the Midland reduction of an ynone substrate. 

The Midland reduction is the enantioselective reduction of a ketone (It to an optically active alcohol (2) using the commercially available reagent alpine borane (3). ... 

Initial debate over the mechanism of the Midland reduction centered around the idea that this reduction could reasonably proceed via either a one-step (Path A) or two-step (Path B) mechanism as shown below. However, mechanistic investigations by Midland showed that the rate of the reaction was dependent on the concentration of the aldehyde, thus lending support to the reaction proceeding via Path A5. The subsequent development of the enantioselective variant of this reaction using 3 essentially eliminated Path B as a possible mechanism because it is not consistent with the optically active alcohols produced in the reaction. Thus, Path A is widely accepted as the mechanism for this reaction. 

The Midland reduction has also been used in the large-scale synthesis of chiral glycines. Deuterium labeled anisaldehyde was reduced with 3 to provide deuteriated arylmethyl alcohol 21 in 82% ee.13 This alcohol was then converted in 4 steps to JV-Boc-glycine (22). 

The synthesis of the DE ring system of upenamide (28) utilized a Midland reduction to set the initial stereocenter in the synthesis. Conversion of 25 to 26 proceeded in 74% yield and 93% ee.15 This material was carried on through a series of transformations to achieve a synthesis of the DE ring system (27). 

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