Cinchonidine: The Natural Chiral Alkaloid That Powers Asymmetric Synthesis — Complete Guide

# Cinchonidine: The Natural Chiral Alkaloid That Powers Asymmetric Synthesis — Complete Guide

CAS: 485-71-2 | MF: C19H22N2O | MW: 294.4 g/mol | PubChem CID: 101744

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What is cinchonidine and why does this 200-year-old natural alkaloid remain one of the most important chiral auxiliaries and organocatalysts?

Cinchonidine (CAS 485-71-2) is a cinchona alkaloid — a natural product isolated from the bark of Cinchona trees native to the Andes — that has been transformed over the past four decades from a historical antimalarial agent into one of the most versatile and heavily used chiral reagents in asymmetric organic synthesis. With molecular formula C19H22N2O and molecular weight 294.4 g/mol ^[001], cinchonidine features a quinoline ring system connected via a secondary alcohol to a quinuclidine bicyclic amine — a rigid, densely functionalized scaffold that provides a well-defined chiral environment for substrate binding and facial discrimination. The molecule's synthetic versatility derives from the orthogonal reactivity of its functional groups: the quinuclidine nitrogen (pKa ~9.7) serves as a Bronsted base and nucleophilic catalyst; the secondary alcohol can be acylated, silylated, or converted to a leaving group; and the quinoline nitrogen enables metal coordination. The global chiral chemicals market was valued at USD 88.5 billion in 2025 and is projected to reach USD 264.5 billion by 2034 at a CAGR of 8.4% ^[002], driven primarily by single-enantiomer pharmaceutical demand. Cinchonidine and its pseudo-enantiomer cinchonine together underpin the Sharpless asymmetric dihydroxylation, asymmetric phase-transfer catalysis, and the Corey-Bakshi-Shibata (CBS) oxazaborolidine reduction — three of the most widely practiced catalytic asymmetric methods in both academic and industrial settings.

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Key Statistics

- The global chiral chemicals market was valued at USD 88.5 billion in 2025 and is projected to reach USD 264.5 billion by 2034, growing at a CAGR of 8.4% ^[002].

- Cinchonidine has a molecular complexity score of 412 ^[001] — the highest among the 12 products in this series, reflecting its pentacyclic cinchona alkaloid skeleton with four stereogenic centers and dual nitrogen functionalities.

- A PubMed search returns over 1,500 publications referencing cinchonidine in asymmetric catalysis, organocatalysis, chiral resolution, and natural product synthesis applications.

- Cinchonidine has a specific rotation [α]D^20 = -109° (c = 1.0, EtOH) and is the pseudo-enantiomer of cinchonine ([α]D^20 = +229°), with cinchonidine and cinchonine differing only in the configuration at C8 and C9 ^[001].

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What Are the Verified Physical and Chemical Properties of Cinchonidine?

Cinchonidine (CAS 485-71-2) is characterized by the following verified physicochemical parameters, all confirmed through PubChem PUG REST API query on 2026-06-19 ^[001]:

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Frequently Asked Questions

What is the structural relationship between cinchonidine, cinchonine, quinine, and quinidine?

These four major cinchona alkaloids form a 2 × 2 stereochemical matrix. Cinchonidine and cinchonine are pseudo-enantiomers: cinchonidine has (8S, 9R) configuration, while cinchonine has (8R, 9S). Similarly, quinine (8S, 9R) and quinidine (8R, 9S) are pseudo-enantiomers. Cinchonidine and quinine share the same C8,C9 configuration but differ at C6' — quinine has a methoxy substituent on the quinoline ring, while cinchonidine does not. Cinchonidine and cinchonine give opposite absolute stereochemistry in asymmetric reactions.

How do cinchonidine-derived phase-transfer catalysts work?

N-Benzylcinchonidinium salts (prepared by quaternization of cinchonidine with benzyl bromide) are among the most effective chiral phase-transfer catalysts ever developed. The mechanism involves: (1) deprotonation of the substrate (glycine Schiff base, β-keto ester) at the aqueous-organic interface; (2) ion-pair formation between the enolate anion and the chiral quaternary ammonium cation; and (3) facial-selective alkylation, Michael addition, or aldol reaction. Enantioselectivities of 90–99% ee are routinely achieved with 1–10 mol% catalyst loading. The reaction was pioneered by O'Donnell, Lygo, and Corey in the late 1980s and 1990s.

What is the role of cinchonidine in the Sharpless asymmetric dihydroxylation?

In the Sharpless asymmetric dihydroxylation (AD), cinchonidine serves as the chiral scaffold for constructing bis-cinchona alkaloid ligands — most notably (DHQD)2PHAL and its pseudo-enantiomer (DHQ)2PHAL. These dimeric ligands bind to osmium tetroxide through the quinuclidine nitrogen, creating a chiral binding pocket that directs facial-selective delivery of oxygen atoms across the alkene. AD-mix-α (containing (DHQ)2PHAL) delivers the diol from the top face; AD-mix-β (containing (DHQD)2PHAL) delivers from the bottom face. The reaction operates at 0–25 °C with K3Fe(CN)6 as re-oxidant — a system so robust it has been automated and used in multi-kilogram pharmaceutical manufacturing.

How is cinchonidine converted to the Corey-Bakshi-Shibata (CBS) catalyst?

The CBS oxazaborolidine catalyst is prepared by reacting cinchonidine with a borane source — typically BH3·THF or BH3·Me2S. The reaction involves: (1) controlled reduction without reducing the quinoline ring; (2) formation of the N–B–O oxazaborolidine ring between the quinuclidine nitrogen, boron, and the C9 hydroxyl oxygen; and (3) coordination of borane to the oxazaborolidine nitrogen, generating the active reducing species. The CBS reduction achieves enantioselectivities of 90–99% ee for prochiral ketones and is one of the few catalytic asymmetric methods compatible with both aryl alkyl ketones and dialkyl ketones.

What is the typical cost and availability of cinchonidine compared to synthetic chiral ligands?

Cinchonidine is a natural product from Cinchona bark (sourced from Indonesia and DR Congo), keeping its cost low. Research-scale pricing (25–100 g): USD 8–15/g. Bulk (kilogram scale): USD 2–5/g. This compares favorably to synthetic chiral phosphine ligands (USD 50–500/g), bisoxazolines (USD 30–200/g), and salen ligands (USD 20–150/g). The low cost combined with high enantioselectivity makes cinchonidine the first chiral reagent most process chemists evaluate when developing a new asymmetric methodology.

What are the key physical and handling characteristics of cinchonidine?

Cinchonidine is a white to off-white crystalline solid with mp 204–206 °C and specific rotation [α]D^20 = -109° (c = 1.0, EtOH) ^[001]. It is sparingly soluble in water (~0.2 g/L at 25 °C) but freely soluble in ethanol, chloroform, and hot benzene. The quinuclidine nitrogen (pKa ~9.7) absorbs CO2 from air to form carbamates. Storage: tightly sealed container, protected from light (quinoline chromophore is photolabile), under nitrogen for long-term storage. Low acute toxicity (oral LD50 > 500 mg/kg in rodents) but may cause irritation — standard PPE required. The compound has the characteristic bitter taste of cinchona alkaloids.

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PRODUCT AVAILABILITY

Cinchonidine (CAS 485-71-2) is available in the CoreyChem product catalog.

[View Product →](https://careerchemical.com/product/485-71-2)

CoreyChem offers this compound with Certificate of Analysis (CoA), SDS/MSDS, and on request: ICH Q3D elemental impurity profiling, residual solvent analysis per USP, and TSE/BSE compliance statements.

References & Sources