Chapter 36 — Case Study 2: Sharpless Asymmetric Dihydroxylation — Asymmetric Catalysis Comes of Age
"Before Sharpless, asymmetric synthesis was a research curiosity. After his asymmetric epoxidation (1980) and asymmetric dihydroxylation (1988), it became the standard tool for making chiral pharmaceuticals. The Nobel Prize in 2001 was for showing that catalytic chiral chemistry could deliver any enantiomer of any chiral compound, in any quantity, with high ee." — paraphrase of organic synthesis history
K. Barry Sharpless (Nobel 2001 + 2022) developed two enantioselective oxidation methods that transformed asymmetric synthesis: the Sharpless asymmetric epoxidation (AE, 1980) and the asymmetric dihydroxylation (AD, 1988). Both use chiral metal-ligand catalysts to oxidize alkenes with control of enantiomer selectivity (typically 90%+ ee). This case study explores AD in particular and shows how it became an industrial workhorse.
The challenge: enantioselective oxidation of alkenes
OsO₄ converts an alkene into a syn-1,2-diol (Section 16.7, also Ch 36): $$\text{C=C} + OsO_4 + H_2O \to \text{cis-1,2-diol}$$
But the reaction is achiral: starting from a prochiral alkene, you get a racemic diol mixture. For a drug requiring one enantiomer, the racemic mixture is half-wasted (or worse, the wrong enantiomer is the toxic one).
The challenge: develop conditions that direct the OsO₄ attack to one face of the alkene preferentially, giving one enantiomer of the diol.
Sharpless's solution: chiral cinchona alkaloid ligands
In 1988, Sharpless (UC Berkeley → Scripps) reported that adding chiral cinchona alkaloid derivatives as ligands to OsO₄ + NMO gave enantioselective dihydroxylation:
$$\text{C=C} + OsO_4 \text{ (cat.)} + NMO + (DHQ)_2PHAL \to \text{(R,R)-diol or (S,S)-diol depending on ligand}$$
The two main ligand families: - (DHQ)₂-PHAL (dihydroquinine derivative, attached via phthalazine): gives one enantiomer. - (DHQD)₂-PHAL (dihydroquinidine derivative): gives the opposite enantiomer.
By choosing the ligand, you choose the enantiomer. By using a catalytic amount of OsO₄ + NMO + ligand, you can run the reaction with stoichiometric NMO (the recyclable oxidant) and only catalytic OsO₄.
How the AD reagent works
The chemistry: 1. OsO₄ + ligand forms a chiral OsO₄-ligand complex. 2. The complex binds the alkene's faces differently (one face is more accessible than the other due to the chiral ligand). 3. [3+2] cycloaddition forms an osmate ester at the preferred face. 4. NMO regenerates OsO₄ from the osmate (after hydrolysis to give the diol). 5. The diol is released; the cycle continues.
Net: catalytic OsO₄ + chiral ligand + stoichiometric NMO gives enantioselective syn-diol from a prochiral alkene.
The enantiomeric excess (ee) is typically 70-99% depending on substrate. Some substrates work better than others.
A worked example: the AD of styrene
Styrene (Ph-CH=CH₂) + AD-mix-α (with (DHQ)₂PHAL) → (R)-1-phenyl-1,2-ethanediol with ee ~70%.
Styrene + AD-mix-β (with (DHQD)₂PHAL) → (S)-1-phenyl-1,2-ethanediol with ee ~70%.
Note: (DHQ)₂PHAL gives (R)-diols; (DHQD)₂PHAL gives (S). The two ligands are pseudo-enantiomers (not exact enantiomers — they have a small structural difference that makes them give "almost equal but opposite" results).
Sharpless's other Nobel-winning work
Asymmetric epoxidation (1980)
Sharpless developed the Sharpless AE: $TBHP$ + $Ti(OiPr)_4$ + $L$-(+)-DET (chiral tartrate) → epoxide of allylic alcohols. This was the first general asymmetric oxidation.
Click chemistry (2001 → Nobel 2022)
Decades later, Sharpless developed click chemistry — Cu-catalyzed azide-alkyne cycloaddition (CuAAC) that joins two molecules with high yield, mild conditions, and biocompatibility. This gave him a second Nobel Prize in 2022, for chemistry that revolutionized bioconjugation.
Industrial applications
The AD reaction is widely used industrially for:
Crixivan (HIV protease inhibitor)
A key step in the synthesis of indinavir (Crixivan), an HIV protease inhibitor approved 1996, is an AD step. The AD installs the chiral diol that becomes the central hydroxyl of the drug, enabling stereoselective synthesis at multi-tonne scale.
Many natural products
Various terpenes, alkaloids, and other natural products use AD in their synthesis when chiral diols are needed.
Industrial blockbuster: the Pfizer L-687-414 synthesis
A 1990s Pfizer process used AD on a key intermediate. The single-enantiomer requirement of pharmaceuticals + the scalability of catalytic AD made this commercially viable.
The broader impact
Before the 1980s, asymmetric synthesis was hard. Most chiral drugs were made racemic and resolved (via diastereomeric salt formation, chromatography, or enzymatic separation) — a wasteful approach.
After Sharpless (and Knowles, Noyori — also 2001 Nobel), asymmetric catalysis became routine: - Knowles: asymmetric hydrogenation of α,β-unsaturated acids → L-DOPA. - Noyori: asymmetric hydrogenation of ketones with chiral Ru/BINAP. - Sharpless: AE + AD.
These three methods cover most asymmetric oxidations and reductions. Combined, they can deliver any enantiomer of any chiral target.
The 2001 Nobel Prize (Knowles, Noyori, Sharpless) recognized that asymmetric catalysis had become the central tool of pharmaceutical chemistry. By 2025, ~70% of approved drugs are sold as single enantiomers (vs ~10% in 1990). The chemistry of Chapter 36 + chiral catalysts has transformed the industry.
Other modern asymmetric oxidations
Beyond AD and AE, modern asymmetric oxidation includes:
Jacobsen epoxidation
Eric Jacobsen developed Mn-salen catalysts for asymmetric epoxidation of unfunctionalized alkenes (e.g., simple cis-alkenes). Used in the synthesis of HIV drugs, antifungals, and other chiral molecules.
Shi epoxidation
Yian Shi developed a chiral fructose-derived ketone catalyst that converts alkenes to chiral epoxides via a dioxirane intermediate. Used in many natural product syntheses.
Asymmetric C-H oxidation
Modern C-H activation methods (Pd-, Rh-, Cu-catalyzed) can introduce O at specific C-H bonds with stereocontrol. An active research area.
Photocatalytic asymmetric oxidation
Light-driven catalysts (Ir, Ru photocatalysts) enable asymmetric oxidations under mild conditions. The 2010s saw rapid progress.
Take-home
- The Sharpless asymmetric dihydroxylation (AD, 1988) converts prochiral alkenes to chiral syn-diols using chiral cinchona ligands with OsO₄ + NMO.
- Two ligand families ((DHQ)₂PHAL and (DHQD)₂PHAL) give opposite enantiomers.
- The chemistry: OsO₄ + ligand → chiral [3+2] cycloaddition → osmate → diol after hydrolysis.
- Sharpless was awarded two Nobel Prizes: 2001 (asymmetric oxidations) and 2022 (click chemistry).
- AD is used industrially for HIV protease inhibitors, natural products, and many chiral pharmaceuticals.
- Modern asymmetric synthesis (Sharpless + Knowles + Noyori, all Nobel 2001) transformed the pharmaceutical industry from racemic mixtures to single-enantiomer drugs.
- The chemistry of Chapter 36 + chiral catalysis = the pharmaceutical industry's tool for making any enantiomer of any chiral drug at industrial scale.
- Mastery of Chapter 36 + Chapter 7 stereochemistry is the foundation for asymmetric synthesis.