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. 2024 Aug 23;15(9):1575-1583.
doi: 10.1021/acsmedchemlett.4c00297. eCollection 2024 Sep 12.

Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment

William F Tracy  1 , Geraint H M Davies  2 , Lei Jia  3 , Ethan D Evans  4 , Zhenghang Sun  3 , Jennifer Buenviaje  3 , Gody Khambatta  3 , Shan Yu  3 , Lihong Shi  3 , Veerabahu Shanmugasundaram  2 , Jesus Moreno  3 , Emily C Cherney  5 , Huw M L Davies  1
Affiliations

Asymmetric Dirhodium-Catalyzed Modification of Immunomodulatory Imide Drugs and Their Biological Assessment

William F Tracy et al. ACS Med Chem Lett. .

Abstract

Cereblon (CRBN) has been successfully co-opted to affect the targeted degradation of "undruggable" proteins with immunomodulatory imide drugs (IMiDs). IMiDs act as molecule glues that facilitate ternary complex formation between CRBN and a target protein, leading to ubiquitination and proteasomal degradation. Subtle structural modifications often cause profound and sometimes unpredictable changes in the degradation selectivity. Herein, we successfully utilize enantioselective cyclopropanation and cyclopropenation on intact glutarimides to enable the preparation of stereochemically and regiochemically matched molecular pairs for structure-activity relationship (SAR) analysis across several classical CRBN neosubstrates. The resulting glutarimide analogs were found to reside in unique chemical space when compared to other IMiDs in the public domain. SAR studies revealed that, in addition to the more precedented impacts of regiochemistry, stereochemical modifications far from the glutarimide can lead to divergent neosubstrate selectivity. These findings emphasize the importance of enabling enantioselective methods for glutarimide-containing compounds to tune the degradation selectivity.

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Conflict of interest statement

The authors declare the following competing financial interest(s): HMLD is a named inventor on a patent entitled, Dirhodium Catalyst Compositions and Synthetic Processes Related Thereto (US 8,974,428, issued March 10, 2015).

Figures

Figure 1
Figure 1
Navigating the synthetic challenges of introducing glutarimides and functionalizing glutarimide-containing compounds via enantioselective cyclopropanation/cyclopropenation.
Scheme 1
Scheme 1. Cyclopropanation and Cyclopropenation of Vinyl and Ethynyl IMiD Derivatives
Product arising from reaction with Rh2(S-p-Ph-TPCP)4. Product arising from reaction with Rh2(R-p-Ph-TPCP)4. Diastereomeric ratio for the relative configuration of the two new stereogenic centers, determined by 1H NMR analysis. Asymmetric induction arising from formation of the major relative diastereomer, determined by SFC analysis. All reactions were performed on racemic glutarimide intermediates. Yields are reported as isolated yields of purified product.
Scheme 2
Scheme 2. Stereoretentive Cyclopropanation of (S)- and (R)-3-(1-oxo-5-vinylisoindolin-2-yl)piperidine-2,6-dione
Product arising from reaction with Rh2(S-p-Ph-TPCP)4. Product arising from reaction with Rh2(R-p-Ph-TPCP)4. Diastereomeric ratio for the relative configuration of the two new stereogenic centers, determined by 1H NMR analysis. Asymmetric induction arising from formation of the major relative diastereomer, determined by SFC analysis. Stereochemical information from the starting material was retained in all cases, as determined by 1H NMR and SFC. Yields are reported as isolated yields of purified product.
Scheme 3
Scheme 3. Introduction of Further Complexity
Product arising from reaction with Rh2(S-p-Ph-TPCP)4 Product arising from reaction with Rh2(R-p-Ph-TPCP)4 Diastereomeric ratio for the relative configuration of the two new stereogenic centers, determined by 1H NMR analysis d Asymmetric induction arising from formation of the major relative diastereomer, determined by SFC analysis Stereochemical information from the starting material was retained, as determined by 1H NMR and SFC analysis. 1.2 M acetate buffer: calcd pH = 3.7. All reactions were performed on racemic glutarimide intermediates. Yields are reported as isolated yields of purified product.
Figure 2
Figure 2
Representation of chemical and structural space accessed by the novel IMiDs relative to literature precedence (18,175 compounds). (a) Two-dimensional UMAP projection from 2048 bit ECFP4 fingerprints. (b) Principal moments of inertia analysis. Both plots depict the new IMiDs shown in orange relative to existing compounds shown in blue.
Figure 3
Figure 3
Biological activity and trends. (a) Correlation of CRBN binding (HTRF IC50) to neosubstrate degradation (Ymin). (b) Trends in neosubstrate activity with EC50 (concentration required to achieve 50% of total degradation effect) reported in μM and boxes colored by Ymin (with red showing weak depth of degradation and green showing strong depth of degradation); data reported as an average of N ≥ 3 test occasions.
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