How Tandem Reactions Are Forging the Future of Drug Discovery
In the 1990s, pharmaceutical companies hit a wall. Despite screening millions of flat, carbon-rich compounds, drug discovery pipelines stagnated. The culprit? A chemical universe dominated by "flatland" molecules ill-suited to interact with complex biological targets.
Early combinatorial chemistry focused on planar, aromatic compounds that were easy to synthesize but biologically inept. Their limitations became starkly apparent:
Poor binding selectivity and off-target effects 1
Inability to interact with intricate protein surfaces 6
High lipophilicity hindered cellular uptake 3
Natural products offered a blueprint for success. Compounds like artemisinin (anti-malarial) and eribulin (anti-cancer) derive their efficacy from stereochemically complex, "sp³-rich" frameworks—characterized by high Fsp³ values (fraction of sp³-hybridized carbons). Studies show molecules with Fsp³ > 0.42 exhibit:
Creating sp³-rich scaffolds demands innovative synthesis. Tandem reactions—where multiple transformations occur in one pot—mimic nature's efficiency by:
The European Lead Factory's synthesis of 1,617 drug candidates started with a dialdehyde intermediate subjected to Petasis and Diels-Alder cascades. This generated polycyclic scaffolds with up to 6 stereocenters in 3 steps 2 7 . Key advantages:
Inspired by natural oxacycles like aculeatin A, researchers used iodoetherification to convert olefins into bioactive tetrahydropyrans. The process:
Olefin activation by I⺠(from I₂ or NIS)
Intramolecular O-nucleophile attack
Functionalization of iodide handles
This yielded sp³-rich libraries with Fsp³ > 0.80 and low cLogP—ideal for CNS drugs 3 .
Traditional metallocatalysts failed at intramolecular cyclopropanations. Engineered myoglobin variants (e.g., MbBTIC-C2) achieved it with:
enantioselectivity
TON (turnover number)
whole-cell compatibility
Experiment: Engineering myoglobin for intramolecular cyclopropanation of benzothiophenes 6
Wild-type myoglobin showed zero activity with diazoester substrate 1a.
Mb(F43I,F46L,H64F,V68G,I107A) dubbed MbBTIC-C2
| Variant | Yield of 2a | TON | ee (%) |
|---|---|---|---|
| Wild-type | 0% | 0 | – |
| Mb(H64F) | 2% | 10 | 61 |
| MbBTIC-C2 | 75% | 440 | >99 |
| MbBTIC-C3* | 60%→99%* | 440 | >99 |
Produced furo[2,3-f]isoindoles (Fsp³=0.36) and thieno[2,3-f]isoindoles
X-ray crystallography revealed mutations enlarged the active site, accommodating bulky cyclization transition states.
| Reagent/Technique | Function | Key Example |
|---|---|---|
| N-Iodosuccinimide (NIS) | Halogen source for iodoetherification | Synthesis of tetrahydropyrans 3 |
| Engineered Myoglobin | Biocatalyst for asymmetric cyclopropanation | MbBTIC-C2 for benzothiophenes 6 |
| Dialdehydes | Precursors for Petasis/DA cascades | European Lead Factory libraries 2 |
| Maleic Anhydride | Dienophile in Ugi/DA reactions | Furoisoindole synthesis |
| Vinylfuran Derivatives | Dienes for intramolecular cycloadditions | Tandem Ugi/DA sequences |
The field is accelerating through:
Predicting viable sp³-rich scaffolds (e.g., European Lead Factory's virtual libraries 3 )
Leveraging Rule-of-3 compliant scaffolds (MW<300, cLogP<3) 6
Expanding to carbene insertions and C–H functionalizations 6
"The fusion of tandem synthesis with biocatalysis will unlock chemical space we've only imagined"
From iodoetherification to evolved myoglobin, tandem reactions are dismantling barriers to 3D molecular complexity. As these strategies converge, they promise a new era of drugs targeting today's untreatable diseases—one stereocenter at a time.