Mousanes: Convergent Synthesis and Diversification of Serially Spiro-Fused Cyclobutanes
5 affiliations
- 1Department of Chemical Synthesis, Biocon Bristol Myers Squibb R&D Centre, Biocon Park, Plot No. 2 & 3, Jigani Link Road, Bommasandra IV, Bangalore, India, 560100
- 2Analytical Research & Development, Biocon Bristol Myers Squibb R&D Centre, Biocon Park, Plot No. 2 & 3, Jigani Link Road, Bommasandra IV, Bangalore, India, 560100
- 3Bristol Myers Squibb Therapeutic Discovery Sciences, P.O. Box 4000, Princeton, New Jersey, 08543
- 4Bristol Myers Squibb Therapeutic Discovery Sciences, 250 Water Street, Cambridge, Massachusetts, 02141
- 5Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts, 02138
Abstract
Connecting cyclobutanes through successive spiro junctions offers a way to restrict the relative positions and orientations of functional groups along a saturated framework. Here we describe a convergent synthesis of mousanes, dispirodecane scaffolds comprising three cyclobutanes. A functionalized methylenecyclobutene is prepared on decagram scale by elimination of an iodo-bicyclo[1.1.1]pentanederived precursor. This 1,3-diene undergoes regioselective, triplet-sensitized [2+2] homodimerization to construct the central cyclobutane and both spiro junctions. Hydrolysis and stereoconvergent hydrogenation provide a bifunctional mousane on multigram scale, from which amino acid, diamine, diol and differentially functionalized derivatives are prepared. Calculations suggest that regioselectivity is established during the initial C–C bond-forming step and show that mousane stereochemistry controls terminal geometry. The exo,exo framework has dimensions comparable to short hydrocarbon linkers but displays a narrower calculated range of terminal-vector orientations. We illustrate the use of these building blocks through incorporation into drug analogues and a BRD4-targeting heterobifunctional ligand directed degrader.
Related
- A convergent total synthesis of the ivermectin aglycon through transition metal-mediated and anionic transformations
- Convergent Approach for the Asymmetric Synthesis of Vinyl Sulfoximines via Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides with (Diazomethyl)phosphonates
- Synthesis and diversification of SuFEx-active 2H-indazoles from azobenzenes and ethenesulfonyl fluoride.
- Recent advances in the synthesis, structural diversification, and biological evaluation of sulfamethoxazole derivatives.
- Convergent synthesis of azabicyclo[4.1.1]octanes through the formal cycloaddition of bicyclobutanes with 2-azadienes.
BibTeX
@misc{pitchai2026mousanes,
title = {{Mousanes: Convergent Synthesis and Diversification of Serially Spiro-Fused Cyclobutanes}},
author = {Manivel Pitchai and Sankar Ulaganathan and Nanjundaswamy K.C. and Mohammad Javeed and Pavan Srinivas and Sourav Roy and Shabana Ansar and Lokesh Babu Jarugu and Iulia Teleuca and Renyu Guo and Martins S. Oderinde and Trevor C. Sherwood and Emily C. Cherney and Helen Pham and Lindsay Collier and Gerry Everlof and James Mignone and Elizabeth A. Jurica and Susan Pieniazek and Steven H. Spergel and Ellen K. Kick and Sarah C. Traeger and Christine Jorge and Kumar B. Pabbisetty and Muthalagu Vetrichelvan and Anuradha Gupta and Richard Y. Liu and Michael D. Mandler},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15009866/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009866/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Mousanes: Convergent Synthesis and Diversification of Serially Spiro-Fused Cyclobutanes
AU - Manivel Pitchai
AU - Sankar Ulaganathan
AU - Nanjundaswamy K.C.
AU - Mohammad Javeed
AU - Pavan Srinivas
AU - Sourav Roy
AU - Shabana Ansar
AU - Lokesh Babu Jarugu
AU - Iulia Teleuca
AU - Renyu Guo
AU - Martins S. Oderinde
AU - Trevor C. Sherwood
AU - Emily C. Cherney
AU - Helen Pham
AU - Lindsay Collier
AU - Gerry Everlof
AU - James Mignone
AU - Elizabeth A. Jurica
AU - Susan Pieniazek
AU - Steven H. Spergel
AU - Ellen K. Kick
AU - Sarah C. Traeger
AU - Christine Jorge
AU - Kumar B. Pabbisetty
AU - Muthalagu Vetrichelvan
AU - Anuradha Gupta
AU - Richard Y. Liu
AU - Michael D. Mandler
PY - 2026
DA - 2026/10/05
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009866/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009866/v1
AB - Connecting cyclobutanes through successive spiro junctions offers a way to restrict the relative positions and orientations of functional groups along a saturated framework. Here we describe a convergent synthesis of mousanes, dispirodecane scaffolds comprising three cyclobutanes. A functionalized methylenecyclobutene is prepared on decagram scale by elimination of an iodo-bicyclo[1.1.1]pentanederived precursor. This 1,3-diene undergoes regioselective, triplet-sensitized [2+2] homodimerization to construct the central cyclobutane and both spiro junctions. Hydrolysis and stereoconvergent hydrogenation provide a bifunctional mousane on multigram scale, from which amino acid, diamine, diol and differentially functionalized derivatives are prepared. Calculations suggest that regioselectivity is established during the initial C–C bond-forming step and show that mousane stereochemistry controls terminal geometry. The exo,exo framework has dimensions comparable to short hydrocarbon linkers but displays a narrower calculated range of terminal-vector orientations. We illustrate the use of these building blocks through incorporation into drug analogues and a BRD4-targeting heterobifunctional ligand directed degrader.
ER -