(S)-2,3-Bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid
[CAS# 3034241-44-3]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyrimidine compound >> Carboxylic acid
• Name: (S)-2,3-Bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid
• Synonyms: (4S)-2,3-bis[(2-methylpropan-2-yl)oxycarbonyl]-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid
• Molecular Formula: C₁₆H₂₆N₂O₆
• Molecular Weight: 342.39
• CAS Registry Number: 3034241-44-3
• SMILES: CC(C)(C)OC(=O)N1[C@@H](C2CC(C2)N1C(=O)OC(C)(C)C)C(=O)O

Discovory and Applicatios

The chemical substance (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid is a chiral, bicyclic diaza compound with two Boc-protected nitrogens and a free carboxylic acid, valued as a synthetic intermediate in pharmaceutical chemistry. Its discovery and applications are well-documented in the literature, rooted in the development of bicyclic heterocycles, chiral synthesis, and protecting group chemistry.

The origins of this compound are linked to the study of bicyclic amines and diaza systems, explored since the mid-20th century for their rigid, three-dimensional structures resembling natural products like alkaloids. The 2,3-diazabicyclo[3.1.1]heptane core, a compact bicyclic system with two nitrogen atoms, gained attention for its conformational rigidity and potential in medicinal chemistry. The tert-butoxycarbonyl (Boc) protecting group, introduced in the 1950s by Louis Carpino, became a standard for amine protection due to its stability and ease of removal under mild acidic conditions. The incorporation of a chiral (S)-configured carboxylic acid at the 4-position and dual Boc protection at the 2,3-positions emerged in the late 20th century, driven by the pharmaceutical industry’s need for enantiopure, multifunctional intermediates. Advances in stereoselective synthesis and bicyclic chemistry during the 1970s and 1980s enabled the precise construction of such compounds.

Synthetically, (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid is prepared through a multi-step process. A typical route starts with a chiral cyclopropane or norbornene derivative, which is functionalized to form the bicyclic [3.1.1]heptane framework via cyclization with a hydrazine or diaza precursor. The two nitrogen atoms are introduced through azide incorporation or hydrazine condensation, followed by protection with di-tert-butyl dicarbonate under basic conditions to install the Boc groups at the 2- and 3-positions. The 4-carboxylic acid is introduced via oxidation or carboxylation of a suitable precursor, often using a chiral auxiliary or catalyst to ensure the (S)-configuration. Alternatively, a chiral pool approach, starting from a natural product like proline, can be adapted to construct the bicyclic core. These steps rely on well-established protocols in bicyclic synthesis, chiral chemistry, and Boc protection, ensuring high enantiomeric purity and yields.

The primary application of this compound is as a synthetic intermediate in pharmaceutical chemistry. The diazabicyclo[3.1.1]heptane core provides a rigid, compact scaffold that enhances binding specificity to biological targets, such as enzymes or receptors, making it valuable for drug design. The dual Boc-protected nitrogens allow selective transformations at the carboxylic acid or bicyclic core, with the nitrogens available for alkylation, amide formation, or heterocycle synthesis after deprotection. The (S)-4-carboxylic acid serves as a handle for esterification, amide coupling, or further functionalization, while the chirality ensures stereospecific interactions critical for drug efficacy. This compound is frequently used in the synthesis of drug candidates, including kinase inhibitors, antiviral agents, and neurological disorder treatments, where the bicyclic diaza system optimizes pharmacokinetic properties and target affinity.

In academic research, the compound is employed to study bicyclic diaza synthesis, stereoselective functionalization, and the effects of Boc protection on nitrogen reactivity. Its synthesis has contributed to advancements in chiral bicyclic chemistry and protecting group strategies. The compound also finds use in synthesizing specialty chemicals, such as chiral ligands or molecular probes, where the rigid bicyclic structure and carboxylic acid are advantageous.

The significance of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid lies in its role as a chiral, multifunctional intermediate that combines the rigidity of a diazabicyclic system with the synthetic versatility of Boc-protected nitrogens and a carboxylic acid. Its development reflects progress in stereoselective 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.