Scalable Three-Dimensional Building Blocks: Synthesis, Derivatization, and Physicochemical Evaluation of Heteroatom-Proximal Oxa/Azaspiro[2.n]alkanes

Introduction

Not every new scaffold can become a practical building block in medicinal chemistry. For a new structure to be truly noteworthy, it should answer at least three questions at the same time: Can it introduce a clear three-dimensional structural change? Can it be prepared reliably on a sufficient scale? Can it be converted into functionalized building blocks that are usable in drug design?

The study by Galavskyy et al., published in Organic Chemistry Frontiers under the title “Multigram synthesis and physicochemical evaluation of (oxa)azaspiro[2.n]alkane building blocks,” was developed around these three questions. Starting from commercially available N-Boc-protected lactams and lactone-type substrates, the authors constructed oxa/azaspiro[2.n]alkanes containing five- to seven-membered heterocycles through Tebbe olefination and cyclopropanation. The synthesis was scaled up to as much as 62 g, and further derivatives, including carboxylic acids, amines, and gem-difluoro analogues, were obtained.

This work is not simply about “synthesizing a new class of spirocyclic molecules.” Rather, it advances a class of structures that were previously limited by synthetic efficiency and underutilized in drug design into a stage where they are scalable, modifiable, and applicable to fragment replacement.

1. Why Does Drug Design Need More Three-Dimensional Building Blocks?

1.1 From Flat Fragments to Three-Dimensional Scaffolds

Common structural motifs in drug molecules, such as aromatic rings, piperidines, pyrrolidines, and cyclohexanes, offer clear advantages: readily available starting materials, mature synthetic chemistry, and well-understood structure–activity relationships. However, during lead optimization, excessive reliance on flat structures or conventional saturated rings may limit the space available for property modulation. Common issues include:

Structural issue	Potential impact in medicinal chemistry
High proportion of aromatic rings	Reduced solubility, increased hydrophobicity, and potentially elevated risks of oxidative metabolism or hERG liability
Excessive conformational freedom	Unstable binding conformations, making activity or selectivity harder to optimize
Limited exit vectors	Restricted spatial extension of substituents
Repeated use of conventional ring systems	Limited structural novelty and reduced ability to further differentiate SAR

1.2 Spirocyclic Scaffolds Provide “Spatial Replacement Capability”

In spirocyclic compounds, two rings share a single atom. Such structures are compact, relatively rigid, and allow substituents to project in different directions. Compared with ordinary monocyclic structures, spirocyclic scaffolds can simultaneously alter:

① the distance between substituents;

② the angle between two points of attachment;

③ the conformational freedom of the molecule;

④ the three-dimensional shape of the saturated scaffold;

⑤ the distribution of local polarity, lipophilicity, and three-dimensional surface features.

1.3 The Special Value of Oxa/Azaspirocycles

Compared with all-carbon spirocycles, oxa/azaspirocycles can further introduce property modulation through heteroatoms. In azaspirocycles, after deprotection, the nitrogen atom can provide a basic center, salt-forming capability, and an entry point for further functionalization. Oxygen atoms, meanwhile, can modulate polarity, hydrogen-bond acceptor capacity, and lipophilicity. The spirocyclic framework controls three-dimensional shape, while the heteroatom controls physicochemical properties. Together, they form medicinal chemistry building blocks that combine conformational control with functional-group operability.

2. Why Have N-Proximal Spirocyclic Amines Long Been Underutilized?

2.1 Clear Structural Potential but Limited Synthetic Accessibility

Heteroatom-proximal oxa/azaspiro[2.n]alkanes refer to a class of spirocyclic structures in which the heteroatom is located very close to the spirocyclic junction. Their characteristic feature is:

 

 

This type of structure concentrates three design elements within a small scaffold:

Design element	Significance for drug design
Small spirocyclic ring	Increases rigidity and restricts conformation
N/O heteroatom	Modulates polarity, basicity, and solubility
Proximal connectivity	Alters substituent exit vectors and local three-dimensional shape

In theory, such scaffolds are suitable replacements for common fragments such as piperidine, pyrrolidine, azetidine, and cyclohexane. In practice, however, they have long been less common than classic spirocyclic amines, spiro[3.3]heptanes, spiro[3.4]octanes, and related scaffolds. The main reason is that existing synthetic routes have not been efficient enough and have struggled to provide functionalized derivatives in sufficient quantity and diversity.

2.2 Medicinal Chemistry Needs Not a Single Molecule but a Set of Comparable Building Blocks

Drug optimization does not usually test only one scaffold. For a structure to genuinely support structure–activity relationship studies, it typically needs to form a set of comparable derivatives, for example:

Same spirocyclic core

├─ Carboxylic acid derivatives: for amide coupling

├─ Amine derivatives: for salt formation or further modification

├─ Diamine derivatives: for bifunctional connection

├─ Gem-difluoro analogues: for lipophilicity and conformational modulation

└─ Scaffolds with different ring sizes: for exit-vector comparison

If a scaffold can only be prepared in small amounts, or if it only leads to a single final compound, it is difficult for it to enter real medicinal chemistry programs. The fundamental reason heteroatom-proximal oxa/azaspiro[2.n]alkanes were previously underestimated is the lack of efficient, scalable, and derivatizable synthetic methods.

3. What Core Problem Is Solved by the Tebbe/Petasis-Type Olefination–Cyclopropanation Route?

3.1 Core Route: Converting Commercial Starting Materials into Spirocyclic Building Blocks

Galavskyy et al. used commercially available N-Boc-protected lactams and lactones as starting materials and constructed the spirocyclic core through olefination and cyclopropanation. The core scheme is shown below:

 

3.2 Role of Tebbe Olefination: Establishing Cyclopropanation-Ready Intermediates

The role of Tebbe/Petasis-type olefination is to convert the carbonyl groups of lactams or lactone-type substrates into exocyclic double bonds, affording exocyclic enamines or vinyl ether intermediates. The significance of this step is that the starting materials themselves are not directly suitable for constructing the small spirocyclic ring, whereas the exocyclic double bond provides a reaction site for subsequent cyclopropanation.

Lactam/lactone-type carbonyl substrate → N-Boc–C=CH2 exocyclic enamine or vinyl ether intermediate

Readily available starting materials are first converted into a unified reactive intermediate, and the spirocyclic scaffold is then rapidly generated through cyclopropanation.

3.3 Role of Cyclopropanation: Introducing a Rigid Small Ring and a Functionalization Handle in One Step

Cyclopropanation is the key step that forms the spirocyclic scaffold in this route. Depending on the cyclopropanation reagent used, the products can be directed toward different types of medicinal chemistry building blocks:

Cyclopropanation direction	Structure formed	Subsequent value
Cyclopropanation with diazoacetate	Spirocyclic carboxylate ester	Can be hydrolyzed to the carboxylic acid for amidation
Gem-difluorocyclopropanation	Gem-difluoro spirocyclopropane	Modulates LogP and three-dimensional rigidity
Diastereomer separation	cis/trans isomers	Enables comparison of different exit vectors

4. From “Synthesizable” to “Usable”: Three Criteria for Building-Block Value

4.1 Criterion 1: Can It Be Prepared on a Multigram Scale?

If a medicinal chemistry building-block scaffold is only available on the milligram scale, it is difficult to support subsequent coupling, derivatization, property testing, and SAR studies. The oxa/azaspiro[2.n]alkane scaffolds reported in this study could be prepared on a scale of up to 62 g, indicating that they have the foundation needed to move from literature structures into experimental applications.

4.2 Criterion 2: Can It Be Separated and Stored Stably?

Small spirocyclic rings and highly strained structures are often associated with purification, separation, and storage challenges. If the product is unstable, or if the cis/trans isomers cannot be separated, the scaffold’s value in drug design is significantly reduced. In this study, some exocyclic enamine intermediates could be stored for a period of time at −10 ℃, although stability varied among different ring systems. The cis/trans derivatives could also be obtained through separation. This is very important because different diastereomers may correspond to different three-dimensional exit vectors and cannot simply be treated as the same type of structure.

4.3 Criterion 3: Can It Be Converted into Common Functionalized Building Blocks?

A truly valuable building block should have clear entry points for downstream reactions. The derivatives obtained in this study include carboxylic acids, amines, amine salts, mono-protected diamines, and gem-difluoro analogues. These functional groups correspond to different medicinal chemistry uses:

Derivative type	Common use
Carboxylic acid	Couples with amines to form amides
Amine / amine salt	Modulates basicity, enables salt formation, and participates in nucleophilic substitution or acylation
Mono-protected diamine	Builds bifunctional linker fragments
Amino acid-type derivative	Used in peptidomimetics or polar fragment design
Gem-difluoro analogue	Used for lipophilicity and conformational modulation

5. Property Modulation by Gem-Difluoro Spirocyclic Scaffolds: Lipophilicity, Rigidity, and Isostere Design

5.1 Structural Features of Gem-Difluorocyclopropane

Gem-difluorocyclopropane refers to a structure in which two fluorine atoms are attached to the same carbon atom of a cyclopropane ring. In gem-difluoro oxa/azaspiro[2.n]alkanes, the gem-difluorocyclopropane shares a spiro carbon atom with the N/O-containing heterocycle. This spiro carbon belongs simultaneously to both the cyclopropane and the heterocycle, serving as the central connection point between the two rings.

 

5.2 Relationship Between Gem-Difluoro Spirocyclic Scaffolds and the CF3 Group

CF3, or the trifluoromethyl group, is commonly used to increase lipophilicity, alter electronic effects, and influence metabolic stability. However, CF3 itself is mainly a local substituent and has limited control over the overall molecular conformation. Gem-difluoro spirocyclopropanes are different. While modulating lipophilicity, they also increase rigidity through the cyclopropane structure and alter the spatial direction of the attachment point. The differences can be summarized as follows:

Structure	Main contribution	Limitation
CF3	Increases lipophilicity and enhances electron-withdrawing effects	Limited effect on the overall three-dimensional shape
Gem-difluoro spirocyclopropane	Modulates LogP, increases rigidity, and changes spatial exit vectors	More synthetically challenging than ordinary CF3 substitution

This study shows that, in the tested model compound series, spiro-fused gem-difluorocyclopropanes can significantly increase LogP, with an effect comparable in magnitude to that of a CF3 group. Oxygen-containing scaffolds can serve as comparative structures for modulating local polarity and lipophilicity.

5.3 Specific Significance for Drug Design

In drug optimization, gem-difluoro spirocyclopropanes are suitable for the following situations:

Project need	Possible contribution
Need to moderately increase hydrophobicity or passive membrane permeability	Improves hydrophobic matching by increasing LogP, while solubility and nonspecific binding must be monitored in parallel
Avoidance of flexible hydrophobic chains	Small-ring structure maintains rigidity
Replacement of CF3 while changing spatial shape	Modulates both properties and conformation
Need to reduce molecular planarity	Spirocyclic structure increases three-dimensional character

It should be noted that an increase in LogP does not necessarily mean an improvement in drug-like properties. If the parent molecule already has high lipophilicity, further introduction of a gem-difluoro spirocyclic unit may lead to reduced aqueous solubility and increased nonspecific binding. Therefore, this type of structure is better suited to optimization scenarios requiring a moderate increase in lipophilicity, maintenance of scaffold rigidity, and adjustment of spatial exit vectors. It should not be regarded as a universal fluorination strategy.

6. From Three-Dimensional Configuration to Exit Vectors: Can Spirocyclic Scaffolds Replace Common Saturated Rings?

6.1 X-ray and EVP Provide Structural Basis for Isosteric Replacement

X-ray crystallography can be used to determine the three-dimensional configuration and key geometric parameters of a molecule. EVP, or exit vector plot, is used to compare the spatial relationships of substituent attachment directions across different scaffolds.

For heteroatom-proximal oxa/azaspiro[2.n]alkanes, EVP analysis focuses on whether they can mimic the substituent exit vectors of common saturated rings such as piperidine, pyrrolidine, or cyclohexane. If the exit vectors are similar, these spirocyclic scaffolds may preserve key spatial arrangements while introducing higher rigidity, stronger three-dimensionality, or different physicochemical properties, thereby becoming candidate bioisosteres or scaffold isosteres.

6.2 Exit-Vector Analysis Provides Structural Basis for Scaffold Replacement

In drug molecules, many saturated rings do not merely provide volume or a hydrophobic surface. More importantly, they fix the spatial positions of two or more pharmacophoric groups. Therefore, when performing scaffold replacement, it is not sufficient to compare only functional-group types; one must also compare the distance, angle, and dihedral angle between points of attachment.

In traditional 1,3-disubstituted piperidines, 1,3-disubstituted pyrrolidines, or 1,4-disubstituted cyclohexanes, the two substituents have relatively defined spatial orientations. If heteroatom-proximal oxa/azaspiro[2.n]alkanes are used to replace these ring systems, it is necessary to determine whether the new scaffold can present similar substituent exit directions in three-dimensional space.

Traditional saturated ring scaffold:

R1 — piperidine / pyrrolidine / cyclohexane — R2

Substituents have a defined distance and spatial angle

Heteroatom-proximal oxa/azaspiro[2.n]alkane:

R1 — spirocyclic scaffold — R2

The spirocyclic structure changes substituent distance, angle, and dihedral angle

Through X-ray crystallography and EVP analysis, Galavskyy et al. showed that some representative oxa/azaspiro[2.n]alkanes possess well-defined three-dimensional exit vectors and overlap with the spatial regions of several common saturated ring scaffolds. This suggests that they have a structural basis for serving as candidate replacement scaffolds for fragments such as piperidine, pyrrolidine, azetidine, or cyclohexane.

It should be emphasized that similar exit vectors do not guarantee retention of drug activity. They only indicate that the new scaffold has potential for replacement in terms of spatial orientation. Further validation is still required based on the target binding mode, physicochemical properties, conformational stability, and biological activity data.

7. Application Scenarios and Validation Strategies for Heteroatom-Proximal Oxa/Azaspiro[2.n]alkanes

7.1 Structural Optimization Problems That Can Be Prioritized

The application value of heteroatom-proximal oxa/azaspiro[2.n]alkanes is mainly reflected in situations where an existing molecule encounters optimization needs related to spatial configuration, conformational restriction, physicochemical properties, or scaffold replacement. In such cases, these scaffolds can be evaluated as candidate three-dimensional saturated building blocks.

Medicinal chemistry problem	Possible structural adjustment
Unsatisfactory properties of common saturated heterocycles such as piperidine or pyrrolidine	Introduce azaspiro[2.n]alkanes and compare changes in basicity, conformational restriction, and substituent spatial orientation
Mismatched exit vectors in cyclohexane or other saturated rings	Use cis/trans spirocyclic isomers to tune substituent distance, angle, and dihedral angle
Excessive molecular planarity	Replace part of the flat fragment with a three-dimensional saturated spirocyclic scaffold to increase local stereochemical character
SAR is difficult to further differentiate	Use scaffold replacement to alter substituent spatial arrangement and explore new SAR directions
Need to modulate lipophilicity or local polarity	Compare the effects of gem-difluoro spirocyclic, oxaspirocyclic, and azaspirocyclic derivatives on LogP/LogD
Need for bifunctional three-dimensional building blocks	Select carboxylic acids, amines, amine salts, or mono-protected diamine derivatives for coupling, linker design, or polar fragment introduction

The common feature of these application scenarios is that the spirocyclic scaffold is used to simultaneously modulate spatial orientation, conformational freedom, and physicochemical properties.

7.2 Situations Where Introduction Should Be Approached with Caution

Heteroatom-proximal oxa/azaspiro[2.n]alkanes are not universal replacement fragments. If the activity or properties of the original molecule are highly dependent on a specific planar structure, flexible conformation, or hydrophobic/polar balance, direct introduction of a spirocyclic scaffold may have unfavorable effects.

Situation requiring caution	Main reason
The parent molecule is already highly lipophilic	A gem-difluoro spirocyclic unit may further increase LogP, raising the risk of reduced aqueous solubility or increased nonspecific binding
Activity depends on π–π interactions involving an aromatic ring	Replacement with a saturated spirocycle may weaken or disrupt key aromatic interactions
The target binding pocket is narrow	The relatively rigid spirocyclic structure may cause local steric clashes
The original flexible chain participates in induced fit	Conformational restriction may reduce the molecule’s ability to adapt to the binding pocket
Only minor tuning of a terminal substituent is needed	Scaffold replacement changes conformation, volume, and physicochemical properties simultaneously, introducing too many variables and making single-factor interpretation difficult

Therefore, before introducing this type of scaffold, the optimization goal should be clearly defined: Is the aim to tune exit vectors, reduce planarity, restrict conformation, or alter LogP/LogD? If the optimization goal is unclear, spirocyclic replacement can introduce additional structural variables and weaken the clarity of SAR interpretation.

7.3 Systematic Validation as SAR Control Scaffolds

In practical medicinal chemistry research, heteroatom-proximal oxa/azaspiro[2.n]alkanes are well suited to enter SAR studies as a set of control scaffolds. A recommended comparison strategy is as follows:

Parent structure

├─ Original piperidine / pyrrolidine / cyclohexane fragment

├─ Corresponding heteroatom-proximal azaspiro[2.n]alkane

├─ Corresponding heteroatom-proximal oxaspiro[2.n]alkane

├─ Gem-difluoro spirocyclic analogue

└─ Separate comparison of cis/trans isomers

Key evaluation indicators include:

Evaluation indicator	Evaluation purpose
Activity	Determines whether the spatial arrangement of key pharmacophores can still support target binding
Selectivity	Evaluates the effect of three-dimensional scaffold replacement on the target and potential off-target interactions
LogP / LogD	Compares the effects of azaspirocyclic, oxaspirocyclic, and gem-difluoro spirocyclic structures on lipophilicity
Solubility	Determines whether changes in polarity, basicity, and hydrophobicity affect drug-like properties
Metabolic stability	Examines the effect of conformational restriction and scaffold changes on exposure of metabolic sites
Conformation and exit vectors	Determines whether the new scaffold preserves or changes the spatial direction of key substituents
Permeability	Evaluates the effect of lipophilicity changes and three-dimensional scaffolds on membrane permeability

The rational use of heteroatom-proximal oxa/azaspiro[2.n]alkanes is to build a set of control compounds around a clearly defined structural optimization problem, and then evaluate their real value through activity, selectivity, physicochemical properties, and conformational analysis.

8. Representative Classification Tables of Chemicals Related to Heteroatom-Proximal Oxa/Azaspiro[2.n]alkanes

Table 1. Key Reaction Reagents, Catalysts, and Derivatization Reagents

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Difluorocarbene source / gem-difluorocyclopropanation precursor	81290-20-2	T434250	Trimethyl(trifluoromethyl)silane solution	2 M in THF	Can serve as a difluorocarbene source for gem-difluorocyclopropanation studies of substrates such as exocyclic enamines and vinyl ethers. It can be used to construct gem-difluoro-substituted oxa/azaspiro[2.n]alkanes for the development of rigid fluorinated spirocyclic building blocks and lipophilicity modulation studies.
Carboxylate-forming cyclopropanation reagent	623-73-4	E433136	Ethyl diazoacetate	15% in toluene	Used in olefin cyclopropanation reactions. It can introduce an ethyl ester functional group into the small spirocyclic ring, which can subsequently be hydrolyzed to obtain spirocyclic carboxylic acid building blocks.
Olefination reagent	67719-69-1	T466030	Tebbe reagent solution	0.5 M in toluene	Used for methylenation of lactam and lactone carbonyl groups to generate exocyclic enamine or vinyl ether intermediates. It is a representative olefination reagent relevant to the construction of exocyclic olefin precursors for oxa/azaspiro[2.n]alkanes.
Protecting reagent	24424-99-5	D106159	Di-tert-butyl dicarbonate	≥99%	Used for tert-butoxycarbonyl protection of amine-containing substrates. It can be used to prepare or modify N-Boc lactams, N-Boc spirocyclic amines, and mono-protected diamine building blocks.
Cyclopropanation catalyst	34946-82-2	C100681	Copper(II) trifluoromethanesulfonate	≥98%	Can be used in studies of copper-catalyzed cyclopropanation reactions involving diazo esters, and is suitable for constructing ester-containing spirocyclopropane frameworks.
Curtius rearrangement reagent	26386-88-9	D106412	Diphenyl phosphoryl azide (DPPA)	≥97%	Used for the conversion of carboxylic acids into isocyanates, amines, or carbamate derivatives. It can further convert spirocyclic carboxylic acids into spirocyclic amines, amine salts, and diamine-type building blocks.

Table 2. Oxaspirocyclic Precursors and Oxaspirocyclic Building Blocks

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Oxaspirocyclic precursor	96-48-0	H1506297	γ-Butyrolactone (controlled precursor chemical)	≥99%	Five-membered lactone precursor. It can generate vinyl ether intermediates through olefination and be used in studies on the construction of oxaspiro[2.4]heptane scaffolds.
Oxaspirocyclic precursor	502-44-3	C109521	ε-Caprolactone	≥99%	Seven-membered lactone precursor. It can be used in the design of oxaspiro[2.6]nonane-related scaffolds and is suitable for studies on the synthesis of larger-ring oxaspirocyclic building blocks.
Oxaspirocyclic precursor	542-28-9	V100560	δ-Valerolactone (DVL)	≥98%	Six-membered lactone precursor. It can be used for constructing oxaspiro[2.5]octane scaffolds and is suitable for studies on saturated oxacyclic isosteres.
Oxaspirocyclic core	185-60-4	O1345788	1-Oxaspiro[2.4]heptane	≥97%	A related oxaspirocyclic core that can be used in small-ring oxaspirocyclic structure studies, three-dimensional saturated scaffold screening, and fragment replacement studies.
Oxaspirocyclic carboxylate ester	909406-74-2	E178146	Ethyl 6-oxaspiro[2.5]octane-1-carboxylate	≥97%	An oxaspiro[2.5]octane carboxylate building block that can be derivatized through hydrolysis or amidation, and used for constructing oxaspirocyclic carboxylic acid derivatives.
Oxaspirocyclic carboxylic acid	909406-73-1	O178145	6-Oxaspiro[2.5]octane-1-carboxylic acid	≥97%	An oxaspiro[2.5]octane carboxylic acid building block that can be used for amide coupling, saturated oxacycle replacement, and three-dimensional carboxylic acid fragment design.

Table 3. Azaspirocyclic Precursors and Azaspirocyclic Building Blocks

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Azaspirocyclic precursor	106412-36-6	N468560	N-Boc-ε-caprolactam	≥97%	Seven-membered N-Boc lactam precursor. It can be converted through olefination and cyclopropanation to construct azaspiro[2.6]nonane scaffolds, and is used in studies of larger-ring azaspirocyclic building blocks.
Azaspirocyclic precursor	85909-08-6	T139347	1-(tert-Butoxycarbonyl)-2-pyrrolidinone	≥95%	Five-membered N-Boc lactam precursor. It can be used for constructing azaspiro[2.4]heptane scaffolds and supports studies on saturated pyrrolidine replacement.
Azaspirocyclic precursor	85908-96-9	I135693	1-Boc-2-piperidone	≥95%	Six-membered N-Boc lactam precursor. It can be used for constructing azaspiro[2.5]octane scaffolds and is suitable for studies on piperidine-type structural isosteres.
Spirocyclic amino acid building block	1129634-44-1	S172097	(6S)-5-[(tert-Butoxy)carbonyl]-5-azaspiro[2.4]heptane-6-carboxylic acid	≥97%	Chiral N-Boc azaspirocyclic carboxylic acid building block. It can be used for amide coupling, peptidomimetic construction, and introduction of chiral three-dimensional fragments.
Bifunctional azaspirocyclic building block	150543-45-6	T174366	5-tert-Butyl 1-ethyl 5-azaspiro[2.4]heptane-1,5-dicarboxylate	≥97%	Contains both an N-Boc protecting group and an ethyl ester functional group. It can be used for selective deprotection, hydrolysis, coupling, and preparation of azaspirocyclic carboxylic acid derivatives.
N-Boc azaspirocyclic core	955028-67-8	A678207	tert-Butyl 6-azaspiro[2.5]octane-6-carboxylate	≥97%	N-Boc-protected azaspiro[2.5]octane core. It can be used for piperidine replacement, screening of three-dimensional saturated amine fragments, and subsequent N-position modification.
Aminomethyl azaspirocyclic building block	1823426-03-4	T630758	tert-Butyl 6-(aminomethyl)-5-azaspiro[2.4]heptane-5-carboxylate	≥97%	Contains an aminomethyl side chain and an N-Boc protecting group. It can be used for amidation, reductive amination, linker design, and construction of bifunctional spirocyclic amines.
Amino azaspirocyclic building block	1026609-83-5	T626570	tert-Butyl 7-amino-5-azaspiro[2.4]heptane-5-carboxylate	≥97%	Contains a free amino group and an N-Boc protecting group. It can be used for preparing diamine-type spirocyclic building blocks, introducing polar fragments, and conducting structure–activity relationship studies.

Note: The above products are representative research reagents and building-block products related to this article. Some products are not specific compounds directly prepared or evaluated in the original work by Galavskyy et al.; they are included only to illustrate the relevant reaction reagents, precursors, and medicinal chemistry building-block space. For specific catalog numbers, inventory status, specifications, purity, regulatory attributes, COA, and SDS information, please refer to the Aladdin website and the actual product documents.

References

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[2] Lovering F., Bikker J., Humblet C. Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. Journal of Medicinal Chemistry, 2009, 52(21): 6752–6756. DOI: 10.1021/jm901241e.

[3] Carreira E. M., Fessard T. C. Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities. Chemical Reviews, 2014, 114(16): 8257–8322. DOI: 10.1021/cr500127b.

[4] Adekenova K. S., Wyatt P. B., Adekenov S. M. The preparation and properties of 1,1-difluorocyclopropane derivatives. Beilstein Journal of Organic Chemistry, 2021, 17: 245–272. DOI: 10.3762/bjoc.17.25.

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