tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate
[CAS# 1801766-82-4]

Identification

• Name: tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate
• Molecular Formula: C₁₄H₂₅NO₄
• Molecular Weight: 271.35
• CAS Registry Number: 1801766-82-4
• SMILES: C[C@H]1C(C2(CCN(CC2)C(=O)OC(C)(C)C)CO1)O

Properties

• Density: 1.1±0.1 g/cm³ Calc.^*
• Boiling point: 396.7±42.0 ºC 760 mmHg (Calc.)^*
• Flash point: 193.7±27.9 ºC (Calc.)^*
• Index of refraction: 1.516 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H315-H319
• Precautionary Statements: P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313

Discovory and Applicatios

The chemical substance tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate is a chiral spirocyclic compound featuring a Boc-protected piperidine, a hydroxyl group, and an oxazolidine ring, recognized as a valuable synthetic intermediate in pharmaceutical chemistry. Its discovery and applications are well-documented in the literature, rooted in the development of spirocyclic compounds, chiral synthesis, and protecting group chemistry.

The origins of this compound are tied to the study of spirocycles, which have been investigated since the early 20th century for their rigid, three-dimensional structures that enhance binding specificity in drug design. The spiro[4.5]decane framework, combining a five-membered oxazolidine ring with a six-membered piperidine, gained prominence in the mid-20th century for its conformational stability and versatility. The tert-butoxycarbonyl (Boc) protecting group, introduced in the 1950s by Louis Carpino, became a standard for amine protection due to its stability under basic conditions and ease of removal under mild acidic conditions. The incorporation of a chiral (3S)-3-methyl-4-hydroxy oxazolidine ring emerged in the late 20th century, driven by the pharmaceutical industry’s demand for enantiopure intermediates with polar functionalities to optimize pharmacokinetic properties. Advances in stereoselective synthesis during the 1970s and 1980s enabled the precise construction of such compounds.

Synthetically, tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate is prepared through a multi-step process. A typical route starts with a spirocyclic precursor, such as 2-oxa-8-azaspiro[4.5]decan-4-one, synthesized by cyclizing a piperidine derivative with an oxygenated five-membered ring precursor under acidic or basic conditions. The piperidine nitrogen is protected by reaction with di-tert-butyl dicarbonate to introduce the Boc group. The chiral (3S)-3-methyl-4-hydroxy functionality is introduced through stereoselective transformations, often involving a chiral auxiliary or catalyst. For example, a ketone precursor is subjected to asymmetric reduction using a chiral reducing agent, such as a borane complex with a chiral ligand, followed by methylation to achieve the (3S) configuration. These steps rely on well-established spirocycle synthesis, chiral chemistry, and Boc protection protocols, ensuring high stereochemical purity and yields.

The primary application of this compound is as a synthetic intermediate in pharmaceutical chemistry. The spirocyclic core provides a rigid, three-dimensional scaffold that enhances selectivity in binding to biological targets, such as enzymes or receptors. The Boc-protected piperidine allows selective transformations, with the nitrogen available for alkylation, amide formation, or heterocycle synthesis after deprotection. The chiral (3S)-3-methyl-4-hydroxy group offers a polar, stereospecific handle for further functionalization, such as etherification or esterification, and contributes to hydrogen-bonding interactions in drug molecules. This compound is frequently used in the synthesis of drug candidates, including kinase inhibitors, G-protein-coupled receptor modulators, and analgesics, where the combination of chiral and polar groups optimizes pharmacokinetic properties and target affinity.

In academic research, the compound is employed to study spirocyclic synthesis, stereoselective reductions, and the effects of Boc protection on piperidine derivatives. Its synthesis has contributed to the development of new chiral catalysts and oxazolidine chemistry. The compound also finds use in the synthesis of specialty chemicals, such as chiral ligands or molecular probes, where the spirocyclic framework and hydroxyl functionality are advantageous.

The significance of tert-butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate lies in its role as a chiral, multifunctional intermediate that combines the rigidity of spirocycles with the stereospecificity of a hydroxylated oxazolidine and Boc protection. Its development reflects progress in asymmetric synthesis and heterocyclic chemistry. By enabling the efficient synthesis of enantiopure, biologically active molecules, it has become a critical tool in advancing pharmaceutical and chemical research.