Midlands reagent

Alpine borane (the Midland reagent, 3) has found broad use in the synthesis of complex natural products. As early as 1980, only one year after Midland s seminal publication, Johnson and co-workers used 3 for the reduction of ketone 18 to afford alcohol 19 in 75% yield and 97% ee.12 This material was used to complete the synthesis of 20, a cyclization precursor in Johnson s total synthesis of hydrocortisone acetate. 

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. 

Conversion ofpropargyl esters to dihydrofurans1 (11,469-470). The reaction can be used for an enantioselective synthesis of dihydrofurans. Thus reduction of 3-hydroxy-l-alkynyl ketones (2) with Midland s reagent, (+)-l, provides (4S)-2-bu-tyne-l,4-diols (3) in 84-91% ee. Monoacylation (4) followed by treatment with... 

M. M. Midland, Asymmetric Reductions with Chganoborane Reagents, Chem. Rev. 1989, 89,1553-1561. 

E. Block, Olefin synthesis via deoxygenation of vicinal diols, Org. React. (N.Y.) 1984, 30, 457. M. M. Midland, Asymmetric reduction with organoborane reagents, Chem. Rev. 1989,89, 1553. H. C. Brown and P. V. Ramachandran, Asymmetric reduction with chiral organoboranes based... 

Midland and others reported that B-isopinocampheyl-9-borabicyclo[3.3.l]no-nane [Alpine-Borane (7 )-79] is an effective reagent for the highly asymmetric reduction of alkynyl ketones to afford the propargylic alcohol 8030 (Scheme 4.3z). The reagent (R)-19 is prepared from (+)-a-pinene and 9-borabicyclo[3.3.1]no-nane (9-BBN) and often represented as 19banana. The levels of asymmetric... 

Midland and co-workers demonstrated that certain p-alkyl-9-borabicyclo [3.3.1] nonanes can reduce benzaldehyde to benzyl alcohols under mild conditions. Several optically active terpenes such as (+)-a-pinene (6.54), (—)-P-pinene (6.55), (—) camphene (6.56) and (+)-3-carene (6.57) have been used to prepare asymmetric (3-alkyl-9-BBN reagents. 

Agent, was provided by W. Curtis White (Dow Coming Corp., Midland, Mich.). It is a methanolic solution containing 42 wt% of this active ingredient. Beta-lactamase was obtained from Sigma Chemical Co. (St. Louis, Mo.). Other chemicals were of reagent grade and were purchased from various commercial sources. 

An early success4 was Midland s Alpine-Borane , derived from 9-BBN 28 and a-pinene 22. Hydroboration takes place from the less hindered side of the double bond, away from the gem dimethyl groups, to give alpine borane 29. The reagent works well for acetylenic alcohols and the transition state 30 puts the acetylene in the outside position. 

Midland MM (1983) Reductions with chiral boron reagents. In Morrison JD (ed) Asymmetric synthesis. Academic, New York, vol 2, chap 2, p 45 Itsuno S (1996) The Alembic, Morton Performance Chemicals 53 1 Fiaud JC, Kagan HB (1969) Bull Soc Chim Fr 2742 Borch RF, Levitan SR (1972) J Org Chem 37 2347 Grundon MF, McCleery DG, WUson JW (1976) Tetrahedron Lett 295 Grundon MF, McCleery DG, WUson JW (1981) J Chem Soc Perkin Trans 1 231 Johnson CR, Stark CJ (1979) Tetrahedron Lett 4713... 

Two other purely chemical routes to chiral acetic acid have been pursued in our laboratory. In one of these, outlined in Scheme 4, stereospecifically o-deuterated or -tritiated 3,5-dimethoxybenzyl alcohol is prepared by reduction of the aldehyde with Midland s reagent (B-3-pinanyl-9-borabicyclo [3.3.1 ] -nonane, cr-pinanyl-9-BBN) (35), followed by conversion to the tosylate and reductive displacement with lithium aluminum hydride or superhydride (lithium... 

M. M. Midland and A. Tramontano, /. Org. Chem., 1978, 43,1470. This reagent is probably most valuable for the preferred reduction of aldehydes in the presence of ketones. 

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). ... 

Extension of this methodology to an enantioselective variant soon followed. In 1979 Midland showed that by using the chiral reagent derived from hydroboration of a-pinene by 9-BBN (3), deuterium labeled benzaldehyde (6b) could be reduced to enantiomerically enriched alcohol 7b in 98% ee Subsequent studies found that 3 was also useful for the enantioselective reduction of acetylinic ketones (8) to propargylic alcohols (9).4... 

Asymmetric Reductions with Organoborane Reagents" Midland. M.M. Chem. Rev., 1989, 89, 1553. 

Prior to this work, Mosner and Yamaguchi" reported similar reduction with an LAH-quinine combination however, no example of acetylenic ketone was attempted. In a later study, Midland et al. developed a-pinene-9-Borabicyclo [3.3.1] nonane complex as an excellent reagent for the reduction of a,P-acetylenic ketones and observed high asymmetric induction in aliphatic systems (Table 21.1). 

In a totally different approach, Noyori et al. have used binaphthol-modifled aluminum hydride reagent for enatioselective reduction of alkynyl ketones. Suitably modified boranes can be used for stereoselective reduction of ketones. Along these same lines. Midland" has developed Alpine borane (1, Scheme 21.5), which is excellent for several acetylenic ketones but has been found inefficient for hindered ot,p-acetylenic ketones. To overcome this problem, Brown et al." have introduced P-chlorodiisopinocamphenyl borane 2(-)-DIP-Cl (2, (Scheme 21.5), which reacts well with hindered ketones to provide the corresponding propargyl alcohols in 96 to 99% e.e. 

Diisopinocampheylchloroborane has been demonstrated to reduce aromatic prochiral ketones, even those which prove to be less reactive towards Midland s reagent (Vol.2, p.115), in enantiomeric... 

The, B-3-pinanyl-9-borabicyclo[3.3.1]nonane or Midland s reagent or Alpine-Borane is commercially available [9]. 

Midland and coworkers [13,14] achieved the reduction of sterically less congested propargyl ketones with AIpine-Borane. The reduction is accomplished using 2 equiv of 0.5-M solutions of AIpine-Borane (Table 26.11) [14]. Terminal acetylenic ketones and acetylenic ketoesters are completely reduced after 8 h at room temperature. Internal acetylenic ketones require 1-4 days at room temperature for complete reductions. The optically active chromanyl substrates (entries 7, 8) yield diastereomeric alcohols with (R,R) R,S) ratios of 85 15 for internal and 91 9 for the terminal acetylenes with the AIpine-Borane derived from (-i-)-a-pinene of 100% ee. The reagent obtained from pure (-)-a-pinene affords 18 82 ratio of the two diastereomeric internal propargylic alcohols. 

Midland and coworkers [Ic] have reported that reduction of alkynyl ketones affords excellent chemical and optical yields that approached 100% in many cases. In general, under Midland s reaction condition, for example, 4-phenyl-3-butyn-2-one takes 48 h for complete reduction at 25 °C with 100% excess of Alpine-Borane. On the other hand Brown has reported [3] the reduction of ketones in 8-12 h, using a 40% excess of the neat reagent (Scheme 26.2 Table 26.12), and products show a substantially higher optical rotation as compared to reported by Midland [Ic]. 

Reagent A, B-Ipc-9-BBN, THF. This reagent is available from Aldrich Chemical Co. as Al-pine-Borane (a) Midland MM, Greer, S, Tramontane A, Zderic SA (1979) J Am Chem Soc 101 2352 (b) Midland MM, Tramontane A, Kazubski A, Graham RS, Tsai DJS, Cardin DB (1984) Tetrahedron 40 1371 (c) Tramontane A (1980) Ph.D. Thesis, University of California, Riverside... 

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