2-Oxaspiro[3.3]heptan-6-one: A High-Value Oxaspiro Building Block for Modern Drug Discovery

2-Oxaspiro[3.3]heptan-6-one (CAS 1339892-66-8) is an oxygen-containing spirocyclic compound that uniquely combines an oxetane ring with a cyclobutanone framework within a single, rigid scaffold. This distinctive architecture has established the molecule as a valuable building block in modern medicinal chemistry, giving chemists a versatile platform for introducing three-dimensionality, polarity, and reactive derivatization handles into candidate molecules. A 2025 review published in Chemical Communications (Royal Society of Chemistry) highlighted this compound among emerging spirocyclic motifs of growing interest to the drug discovery community.

1. Product Information

Property	Value
Product Name	2-Oxaspiro[3.3]heptan-6-one
CAS Number	1339892-66-8
EC Number	840-774-4
Molecular Formula	C₆H₈O₂
Molecular Weight	112.13 g/mol
Appearance	Colorless to pale yellow liquid
SMILES	O=C1CC2(COC2)C1
InChIKey	JWNCVDJOXJTJPB-UHFFFAOYSA-N
Hydrogen Bond Acceptors	2
Hydrogen Bond Donors	0
Rotatable Bonds	0
Topological Polar Surface Area (TPSA)	26.3 Ų
XLogP3-AA	−0.6 (calculated)

Structural identifiers, molecular descriptors, and base information are sourced from PubChem and Shenglan Chemical product data. Predicted or calculated values (boiling point, density, partition coefficient) should not replace measured quality specifications.

2. Why Oxaspiro Structures Matter in Drug Discovery

The growing emphasis on "escaping flatland" in medicinal chemistry has driven strong interest in saturated, three-dimensional scaffolds. 2-Oxaspiro[3.3]heptan-6-one exemplifies several key advantages:

(a) From Flat to Three-Dimensional Molecular Space

Traditional drug molecules rely heavily on benzene rings and other planar structures. Oxaspiro compounds provide more defined three-dimensional orientation within a smaller molecular volume, deploying substituents in relatively independent spatial directions. This structural characteristic helps medicinal chemists explore new binding conformations, adjust substituent orientations, and expand into chemical space that traditional flat scaffolds cannot easily cover.

(b) Introducing Rigidity and Polarity Simultaneously

The oxetane oxygen in the 2-oxaspiro[3.3]heptane scaffold can act as a hydrogen bond acceptor, adding defined polarity to the molecule. The spiro framework, composed of two four-membered rings, restricts free rotation and maintains a relatively defined conformation.

It should be emphasized that introducing an oxetane does not necessarily improve every candidate molecule's drug-likeness — the actual impact depends on the overall molecular structure and substitution position. However, numerous medicinal chemistry studies have shown that the rational introduction of oxetane structures can be used to modulate aqueous solubility, lipophilicity, metabolic stability, pKa, and metabolic clearance.

(c) Carbonyl as an Efficient Derivatization Handle

Compared to ordinary spiro hydrocarbons lacking active functional groups, 2-oxaspiro[3.3]heptan-6-one bears a cyclobutanone carbonyl at position 6. This carbonyl can participate in a variety of classical reactions, providing a direct entry point for downstream molecular design:

• Reductive amination with primary or secondary amines;
• Addition with organolithium and Grignard reagents as carbon nucleophiles;
• Reaction with alkynyl metal reagents to construct alkynyl-substituted spiro alcohols;
• Reduction to 2-oxaspiro[3.3]heptan-6-ol;
• Olefination and condensation to form further functionalizable derivatives;
• Conversion to amines, nitriles, olefins, and other 6-substituted spiro building blocks.

Therefore, this product represents not only a specific structure but also the common upstream starting material for an entire series of 2-oxaspiro[3.3]heptane derivatives.

3. Representative Patent Applications

Public patent literature demonstrates that 2-oxaspiro[3.3]heptan-6-one has been used in the synthesis of candidate compounds for multiple drug targets, proving its cross-project reusability as a platform-type pharmaceutical building block.

TYK2 Inhibitors

An international patent for TYK2 inhibitors employs 2-oxaspiro[3.3]heptan-6-one in reductive amination with a nitrogen-containing bicyclic intermediate, introducing the 2-oxaspiro[3.3]heptan-6-yl group into the target molecule. The patent example achieved a 67.4% yield. TYK2 belongs to the Janus kinase family and is an important target in autoimmune and inflammatory drug discovery — the value here lies not in the raw material having TYK2 inhibitory activity itself, but in its ability to rapidly introduce a rigid, oxygen-containing three-dimensional substituent into candidate molecules.

EBP Inhibitors

Patents for EBP (emopamil-binding protein) inhibitors similarly use 2-oxaspiro[3.3]heptan-6-one multiple times in reductive amination. Different examples connect the spiro unit to various nitrogen-containing heterocyclic scaffolds, with isolated yields reported at approximately 32–43%. This demonstrates that 2-oxaspiro[3.3]heptan-6-one can serve as a carbonyl-type module directly participating in the parallel compound synthesis and SAR studies commonly used in medicinal chemistry.

HDAC6 Inhibitors

In 1,3,4-oxadiazole-based HDAC6 inhibitor patents, the product is connected to piperidine-type nitrogen-containing intermediates via reductive amination, forming target compounds bearing 2-oxaspiro[3.3]heptanyl substitution. HDAC6 is a common target in oncology, inflammation, and neurological drug research, further demonstrating the spiro group's compatibility with complex nitrogen-containing pharmacophores.

RIP1 Inhibitors

In RIP1 inhibitor patents, lithium trimethylsilylacetylide undergoes carbonyl addition with 2-oxaspiro[3.3]heptan-6-one, generating a 6-alkynyl-2-oxaspiro[3.3]heptan-6-ol intermediate. This reaction demonstrates the product's value in constructing alkynyl and hydroxyl structures amenable to further transformation.

KAT6 Inhibitors

A KAT6 inhibitor patent uses an aryllithium reagent to attack the carbonyl of 2-oxaspiro[3.3]heptan-6-one, obtaining an aryl-substituted spiro alcohol with a reported yield of 72%. Subsequent methylation, bromination, and coupling steps build more complex drug candidate structures.

The above examples cover reductive amination, alkynyl addition, and aryl addition — different reaction types that demonstrate the product's excellent synthetic versatility.

4. Potential R&D Directions

According to public literature and patents, the 2-oxaspiro[3.3]heptane structure has appeared in or is being studied for the following directions:

• TYK2 and other kinase inhibitors
• EBP-related inhibitors
• RIP1 inhibitors
• HDAC6 and other epigenetic target inhibitors
• KAT6 inhibitors
• TDO2 inhibitors
• SGLT inhibitors
• Oxaspiro lead compound libraries
• High-Fsp³ small molecule 3D scaffold screening
• Novel saturated ring and carbonyl bioisostere research

The 2025 RSC review cited applications of the 2-oxaspiro[3.3]heptane structure in TDO2- and SGLT-related drug candidates and explicitly listed 2-oxaspiro[3.3]heptan-6-one as an important synthetic raw material for this scaffold.

The above information reflects R&D applications of the structure and synthesis route and does not represent that this product can be directly used as a drug or possesses corresponding therapeutic efficacy.

5. From Single Product to Spiro Building Block Series

An important value of 2-oxaspiro[3.3]heptan-6-one lies in its ability to form a series of downstream derivatives, for example:

• 2-Oxaspiro[3.3]heptan-6-ol
• 2-Oxaspiro[3.3]heptan-6-amine and its salts
• 6-Aryl-2-oxaspiro[3.3]heptane derivatives
• 6-Alkynyl-2-oxaspiro[3.3]heptane derivatives
• 6-Alkyl or heteroaryl substituted derivatives
• 6-Nitrogen-linked medicinal chemistry intermediates
• Polysubstituted 2-oxaspiro[3.3]heptane building blocks

A 2021 study published in the Journal of the American Chemical Society used 2-oxaspiro[3.3]heptan-6-one in an aldol condensation, combined with visible-light-promoted cross-[2+2] photocycloaddition, to obtain polysubstituted 2-oxaspiro[3.3]heptanes. The authors viewed this structural class as a pharmaceutically valuable bioisostere for gem-dimethyl and carbonyl groups. For companies engaged in innovative drug discovery, building block development, and custom synthesis, this product can serve as the core starting point for constructing an oxaspiro product matrix.

6. Supply Market and Customer Needs

From public reagent catalogs, this product is still primarily supplied at gram scale and in small R&D packages — common specifications are 1 g, 5 g, and 10 g, with some Japanese catalogs listing delivery times of several weeks. This indicates several typical market characteristics:

• Demand drivers — primarily drug discovery, lead compound optimization, patent compound verification, and custom synthesis projects, rather than bulk chemical consumption.
• Project phasing — customer purchase quantities may scale from gram-level screening to hundred-gram or kilogram-level process validation.
• Comprehensive evaluation — customers focus not only on price but also on batch consistency, impurity control, analytical methods, packaging, delivery stability, and technical responsiveness.

Therefore, the competitive focus is not simple catalog listing, but whether one can provide stable, traceable, and scalable products and delivery solutions aligned with the customer's R&D timeline.

7. Quality and Safety

Supplier SDS data classifies this product as a flammable liquid and warns of possible skin irritation, serious eye damage, and respiratory irritation. Common hazard statements include H227, H315, H318, and H335. Storage temperature recommendations vary by supplier; in practice, the SDS and COA of the corresponding batch and local regulations should always be authoritative.

During R&D and production use, observe the following:

• Keep containers tightly closed, away from heat sources, sparks, and open flame;
• Work under proper ventilation or local exhaust;
• Use appropriate protective gloves, goggles, and protective clothing;
• Avoid strong acids, strong oxidants, and harsh conditions that may cause oxetane ring opening;
• Monitor purity, moisture, residual solvents, color, and related substances per project requirements;
• Complete thermal safety, reaction calorimetry, and process risk assessment before scale-up production.

This product is intended solely for industrial production, research and development, and chemical synthesis, and must not be used directly on humans or as an unapproved drug.

8. Shenglan Chemical — Products and Services

Shandong Shenglan Chemical Technology Co., Ltd. lists 2-oxaspiro[3.3]heptan-6-one as a key product, serving innovative pharmaceutical companies, pharmaceutical intermediate manufacturers, CRO/CDMO organizations, research institutions, and fine chemicals customers with product supply and project docking services. Across different R&D stages, Shenglan Chemical can communicate specifically with customers on product specifications, packaging, batch documentation, delivery plans, and related spirocyclic derivative requirements.

Item	Information
Product Name	2-Oxaspiro[3.3]heptan-6-one
CAS Number	1339892-66-8
Product Code	SL1112012
Molecular Formula	C₆H₈O₂
Molecular Weight	112.13
Appearance	Colorless to pale yellow liquid
Purity	≥97%

Conclusion

The value of 2-oxaspiro[3.3]heptan-6-one lies not merely in structural novelty, but in its simultaneous satisfaction of multiple demands of modern medicinal chemistry: three-dimensional scaffolds, conformational rigidity, polarity modulation, and rapid derivatization. From TYK2, EBP, RIP1, HDAC6 to KAT6 patent routes, this product has become a reusable tool for introducing oxygen-containing spiro character in innovative drug research. As drug discovery continues to expand its exploration of high-Fsp³, non-planar, and oxygen-containing small-ring scaffolds, 2-oxaspiro[3.3]heptan-6-one and its downstream derivatives are poised to find broader application in lead compound design, molecular library construction, and innovative drug intermediate development.