What Is Midland Reduction?
The Midland reduction, named after M. Mark Midland, refers to the enantioselective reduction of prochiral ketones using the chiral trialkylborane reagent B-isopinocampheyl-9-borabicyclo[3.3.1]nonane, commonly known as Alpine borane. This transformation provides efficient access to optically active secondary alcohols with high enantiomeric excess (ee), typically favoring the (S)-enantiomer for a wide range of aryl alkyl and alkynyl alkyl ketones.
- Reagent: Alpine borane (B-isopinocampheyl-9-borabicyclo[3.3.1]nonane), prepared from α-pinene and 9-BBN (9-borabicyclo(3.3.1)nonane).
- Reactants: Prochiral ketones, especially aryl alkyl ketones and alkynyl alkyl ketones.
- Products: Optically active secondary alcohols with high enantiomeric excess (typically (S)-alcohols when using (+)-Alpine borane).
- Reaction Type: Enantioselective reduction (hydride transfer).
- Related Reactions: CBS (Corey–Bakshi–Shibata) reduction, Noyori asymmetric hydrogenation, Meerwein–Ponndorf–Verley reduction.
- Experimental Tips:
a) Preparation: Alpine borane is best prepared fresh by reacting 9-BBN with α-pinene in THF or ether under inert atmosphere. The solution is stable at room temperature for short periods but should be used promptly or stored cold to prevent decomposition.
b) Strongest Matches: propargylic (alkynyl) ketones, some allylic and aryl-alkyl ketones — these commonly give especially high ee's. Gram-scale examples with >90% ee are reported.
c) Temperature: Reductions are usually carried out at 25–80 °C. Elevated temperatures can improve rates but may reduce enantioselectivity for sensitive substrates.
d) Troubleshooting: Low ee → Ensure anhydrous conditions; check reagent quality; consider slower addition for exothermic reactions. Incomplete Reaction → Increase temperature or add molecular sieves to scavenge trace water.
e) Scale-up: The reaction is scalable, but efficient mixing and temperature control are critical.
Fig 1. Midland reduction reaction and its mechanism. [1]
Mechanism of Midland Reduction
The reduction proceeds via a concerted, six-membered cyclic transition state, which explains its stereochemical outcome:
- Transition State: The ketone coordinates to the electron-deficient boron, positioning the carbonyl oxygen adjacent to the boron-bound hydrogen. The hydride transfer occurs through a cyclic Zimmerman-Traxler-type model, where the largest substituent (L) of the ketone avoids steric repulsion with the pinene-derived scaffold. This leads to preferential attack from the less hindered face.
- Stereochemical Outcome: For most aryl alkyl ketones, the (S)-alcohol is obtained with high ee when using Alpine borane from (+)-α-pinene. The selectivity is reversed with the enantiomeric reagent.
- Product Release: After hydride transfer, the resulting alkoxyborane is hydrolyzed during workup to yield the chiral alcohol and recoverable pinene-derived byproducts.
Application Examples of Midland Reduction
The Midland reduction has been employed in numerous syntheses of natural products and pharmaceuticals, such as: 1) fragrance and flavor compounds: synthesis of (s)-1-phenylethanol and related chiral alcohols used in perfumery. 2) pharmaceutical intermediates: key step in producing chiral building blocks for β-blockers, antifungal agents, and antiviral drugs. 3) natural product synthesis: used in routes to steroids, terpenoids, and alkaloids where enantiopure alcohols are required. 4) asymmetric synthesis planning: often paired with substrate modification or downstream transformations to access complex targets.
- Example 1: JD. Ramesh et al. reported a stereoselective total synthesis strategy for the biologically active pectin lactone H. This involved applying the Midland asymmetric reduction and Sharpless dihydroxylation reactions to generate stereocenters at C-4', C-5, and C-1'. [2]
- Example 2: Kurt Kiewel et al. described the stereoselective synthesis of the DE fragment of the marine alkaloid upenamide. In this synthesis, intermediate compound 13 was reduced using (R)-Alpine-Borane to yield propargyl alcohol (30S)-14 with a yield of 74% and an ee value of 93%. [3]
Fig 2. Synthetic examples via Midland reduction reaction.
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| 7338-94-5 |  | Diphenylpropynone | Inquiry |
| 1679-36-3 |  | 3-Hexyn-2-one | Inquiry |
| 116428-94-5 |  | 5-Nonen-3-yn-2-one,(Z)-(9ci) | Inquiry |
| 18245-82-4 |  | 1-Chloro-4-trimethylsilanyl-but-3-yn-2-one | Inquiry |
| 122124-41-8 |  | 1-Phenyl-4-hexyn-3-one | Inquiry |
| 20442-65-3 |  | 3-phenyl-1-p-Tolyl-propynone | Inquiry |
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Fourth Edition, 2014, 401-402.
- Ramesh, D., et al. Tetrahedron Letters 53.10 (2012): 1258-1260.
- Kiewel, Kurt, et al. Organic Letters 7.23 (2005): 5163-5165.
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