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Ligand-enabled distal desaturative lactonization of aliphatic acids

Transition metal catalysis serves as a fundamental strategy for transforming inert C−H bonds into valuable functional motifs.1,2 However, achieving regioselective activation of remote C−H bonds remains challenging, particularly in unbiased hydrocarbon frameworks.2,3 In this context, distal C(sp3)−H bonds are especially difficult to functionalize, as conformational flexibility favors proximal C−H activation.3,4 In this study, we demonstrate a ligand-enabled strategy using designed O-allyl amido ester (OAAE) ligands for palladium-catalyzed activation of γ-methylene and methine C−H sites in unbiased aliphatic carboxylic acids, derived from readily available fatty and cyclic acid feedstocks. This protocol enables direct transformation of aliphatic carboxylic acid substrates into distal desaturated γ-lactones and double dehydrogenated γ-spirolactones. Mechanistic studies are consistent with a pathway involving Pd(II)-mediated γ-C(sp3)−H activation, followed by dehydrogenation and intramolecular cyclization. These lactones with an unsaturated arm, serve as key intermediates for the formation of complex natural products and pharmaceuticals. For instance, muricatacin (from soursop/laxman phal) and its analogue were rapidly assembled in three steps from margaric acid using this strategy and evaluated for anticancer activity, thereby demonstrating the potential of our approach for providing a rapid access to biologically relevant frameworks for traditional medicine. The introduced distal desaturation further opens up new avenues for remote functionalization, streamlining access to diverse bioactive molecules with improved step and atom economy.

Nemotron 3 Ultra: Open, Efficient Mixture-of-Experts Hybrid Mamba-Transformer Model for Agentic Reasoning

We introduce Nemotron 3 Ultra, a 550 billion total and 55 billion active parameter Mixture-of-Experts Hybrid Mamba-Attention language model. We pre-trained Nemotron 3 Ultra on 20 trillion text tokens, then extended the context length to 1M tokens, and post-trained using Supervised Fine Tuning (SFT), Reinforcement Learning (RL), and Multi-teacher On-Policy Distillation (MOPD). Nemotron 3 Ultra is our most capable model yet, employing multiple key technologies - LatentMoE, Multi Token Prediction (MTP), NVFP4 pre-training, multi-environment RLVR, MOPD, and reasoning budget control. Nemotron 3 Ultra achieves up to ~6x higher inference throughput as compared to state-of-the-art publicly available LLMs while attaining on-par accuracy. The state-of-the-art accuracy, high inference throughput, and 1M token context length make Nemotron 3 Ultra ideal for long-running autonomous agentic tasks. We open-source the base, post-trained, and quantized checkpoints, along with the training data and recipe on HuggingFace.