Macrocycles are large ring structures found in myriad natural products, and over 100 of these molecules have been developed into approved drugs1,2
. Macrolactone and macrolactam structures are particularly prevalent (), often derived from polyketide or peptide biosynthetic pathways. The macrocyclic constraint is a key structural element that organizes the overall molecular scaffold to present functional groups to biological targets in appropriate pharmacophoric conformations3–5
. This conformational restriction can also provide increased binding affinity6
(although not necessarily entropic in origin7,8
) and bioavailability9
. Notably, a variety of macrocyclic natural products modulate challenging targets that are difficult to address with conventional drug-like molecules1
, which are often comprised of small heteroaromatic structures.
Macrocyclic natural products and overall strategy for the diversity-oriented synthesis of macrolactones and macrolactams
Accordingly, macrocycles are compelling targets in the diversity-oriented synthesis of natural product-based libraries for probe and drug discovery screening10,11
. However, macrocycles are severely underexploited in this regard due to challenges associated with their synthesis. Indeed, a recent substructure search of the >360,000-compound NIH Molecular Libraries Small Molecule Repository returned only 22 macrolactones and macrolactams with 10-, 11-, or 12-membered ring carbon scaffolds of the sort treated herein (Supplementary Fig. 1
). Thus, while individual macrocycles can commonly be synthesized by macrocyclization of an appropriate linear precursor, such reactions are highly sensitive to substrate effects that impact precursor conformation, such as ring size, substituent pattern, and stereochemical configuration12–15
. As a result, this class continues to pose major challenges in the context of diversity-oriented synthesis, in which efficient, flexible, and ideally systematic access to a range of macrocyclic scaffolds is required. Indeed, previous efforts to synthesize macrocycle libraries by macrocyclization of diverse linear precursors have been hampered by the highly variable and unpredictable efficiency of these reactions16–19
. The high-dilution conditions typically required for macrocyclizations are also poorly suited for use in library synthesis. Thus, macrocycles remain underrepresented in current diversity libraries and new approaches to macrocycle synthesis must be developed to capitalize fully upon the biological potential of these molecules1
To address this chemical challenge, we posited that ring expansion reactions that are insensitive to substrate conformational effects would provide an attractive alternative to conventional macrocyclization-based strategies for systematic macrocycle library synthesis20–22
. Such approaches have received very limited attention in diversity-oriented synthesis, restricted to the synthesis of individual core scaffolds23–25
. We envisioned the general synthetic strategy outlined in , which features rapid, modular substrate synthesis, leading to an oxidative ring expansion approach to macrolactones pioneered in the 1960s26–28
that builds upon the classic oxidative cleavage of Δ9,10
-octalin to 1,6-cyclodecanedione29
. Cyclic 1,3-diketone starting materials 1
, which are readily available with a variety of backbone functionalities and ring sizes, would first be converted to the corresponding 1,3-disiloxydienes 2
. Diels–Alder cyclocondensation reactions with various dienophiles (e.g.
, aldehydes, imines) would then provide the bicyclic enones 3
. Enantioselective versions of this transformation can be readily envisioned, and the resulting ketone functionality could undergo stereoselective transformations, leveraging cyclic stereocontrol, with introduction of additional diversity elements as desired. This would provide the key bicyclic precursors 4
having a bridging double bond for the pivotal oxidative ring expansion in only 4–5 synthetic steps. The ring expansion reaction would then ideally proceed to macrocycles 5
efficiently and independent of substrate conformational effects that would impact conventional macrocyclizations of the corresponding linear precursors (e.g.
-acids). Subsequent transformations could be used for additional downstream functionalization of these macrocyclic scaffolds.
We report herein the development of a concise, modular approach to the systematic synthesis of functionalized macrolactone and macrolactam scaffolds related to those found in numerous natural products, using oxidative ring expansion of polycyclic substrates having a bridging double bond. We further demonstrate that this ring expansion approach provides superior reaction efficiency and independence from substrate conformational effects compared to conventional macrocyclizations of related seco-acid substrates. We have successfully applied this strategy to the synthesis of a first-generation library of macrocycles having diverse ring sizes and substituent patterns. Cheminformatic analyses of structural and physicochemical parameters using PCA and of three-dimensional molecular shapes using principal moment of inertia (PMI) analysis indicate that this library accesses regions of chemical space that overlap with natural products, including known macrolactones and macrolactams, and are complementary to those addressed by high-profile synthetic drugs currently targeted by the pharmaceutical industry and related drug-like libraries.