Scripps Research chemists develop new method for making gamma chiral centers on simple carboxylic acids C-H activation-based method should speed drug molecule design and diversification.
May 17, 2024
LA JOLLA, CA Scripps Research chemists have accomplished a long elusive feat in synthetic chemistry: the invention of a broadly useful method for constructing gamma chiral centers on simple starting compounds called carboxylic acids. The method, published on May 16, 2024 in Science, significantly extends the ability of chemists to build and modify complex pharmaceutical molecules and other valuable chemical products.
The term chiral refers to a type of asymmetry that allows some chemical compounds to exist in left-handed and right-handed forms. Often, only one of these forms has the desired biochemical activity, but for synthetic chemists, stereoselective reactions those that yield just the desired form are almost always challenging.
The new method enables what had been impossible except in narrow cases: creating a center of chiral asymmetry at a hard-to-reach position called the gamma position on a cyclic carboxylic acid.
This approach offers unprecedented and relatively easy access to a broad set of chiral carbocycles that are privileged structures for pharma industry drug discovery programs, says study senior author Jin-Quan Yu, PhD, Frank and Bertha Hupp Professor of Chemistry and Bristol Myers Squibb Endowed Chair in Chemistry at Scripps Research.
The co-first authors were Tao Zhang, PhD, and Zi-Yu Zhang, PhD, both postdoctoral research associates in the Yu lab.
A potentially valuable but elusive method
The development of small molecule pharmaceuticals or other chemical products typically involves the construction of many hundreds or thousands of compounds, each representing a variation on a central structural theme. Once these libraries of compounds are constructed, they are methodically tested for the desired biological or chemical activity; in this way, developers can zero in on the best compound for further refinement. Naturally, in constructing these libraries and in making more refined variants, chemists would like to have easy and versatile techniques for building and modifying molecules. But while their tools have greatly improved over the years, some types of molecular transformation have remained essentially undoable, despite the obvious value they would have. Gamma chiral center construction using readily available carboxylic acids has been one of these, defying the efforts of prominent synthetic chemistry labs.
The Yu lab's success hinged on the development of special ligand molecules containing both oxazoline and pyridone structural elements. Ligand molecules help bring the reaction catalyst to the right spot on the initial compound. In this case, they fasten to one point on the starting carboxylic acid which contains a ring of mostly carbon atoms and direct a bond-breaking palladium atom to the distant gamma position on the other side of the ring. The effect is to remove a hydrogen atom from the backbone carbon atom at the targeted spot, allowing a new cluster of atoms to bond to the carbon thus adding complexity to the molecule in a precise way.
This type of reaction is called a C-H activation, and over the past decade, Yu and his team have reported similar C-H activation methods for constructing chiral centers at alpha and beta positions on carboxylic acids.
The chemists demonstrated the power and versatility of their new method by using it to make gamma chiral centers on a wide variety of relatively simple carboxylic acid starting compounds containing rings of from five to eight carbon atoms. In one case, they achieved a single-step synthesis of a chiral version of a cancer drug molecule called an HDAC inhibitor whose standard, patented synthesis method requires 10 steps and a costly separation to obtain pure samples of the left-handed or right-handed form.
The team also used the new technique to add complexity to existing drug molecules, including the steroid hormone pregnenolone.
Finally, the chemists showed they could use their new approach sequentially on a starting molecule to construct three chiral centers including a very challenging delta chiral center.
The Yu lab is now working to extend the new approach so it can be used for making other types of chiral molecules.
Enantioselective Remote Methylene C H (Hetero)Arylation of Cycloalkane Carboxylic Acids was co-authored by Tao Zhang, Zi-Yu Zhang, Guowei Kang, Tao Sheng, Jie-Lun Yan, Yuan-Bin Yang, Yuxin Ouyang and Jin-Quan Yu, all of Scripps Research.
Support for the research was provided by the National Institutes of Health (2R01GM084019).
Chemistry Yu, Jin-Quan
Most recent headlines
05/01/2027
Worlds first 802.15.4ab-UWB chip verified by Calterah and Rohde & Schwarz to be ...
06/09/2026
June 9 2026, 23:00 (PDT) Dolby and MagentaTV Bring Fans Closer to the FIFA Worl...
04/08/2026
Dalet, a leading technology and service provider for media-rich organizations, t...
04/07/2026
April 7 2026, 19:00 (PDT) Detective Conan: Fallen Angel of the Highway Opens in...
02/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
02/07/2026
Standalone processors acknowledged for the innovation and value they bring to Pro AV
Cobalt Digital, a leading designer and manufacturer of signal processing ...
02/07/2026
Synamedia announced today the appointment of Dr Tzvi Gerstl as Chief Executive Officer. Paul Segre, who has served as CEO for the past six years, will transitio...
02/07/2026
Screen Australia backs audience-led filmmaking with new insight-driven initiativ...
02/07/2026
Screen Australia refines guidelines for Narrative Content Development and Docume...
02/07/2026
Maxon Autograph: Introduction to working with Tables
Simon Ubsdell July 1, 2026
0 Comments
An overview of Autograph's ridiculously powerful tables...
02/07/2026
Boston Conservatory's Soir e Breaks Records to Fund Student Scholarships The event achieved 127 percent of its fundraising goal in an evening celebrating ...
02/07/2026
How Adam Rosenwach Pivoted from Music to Med Tech Without Missing a Beat What do the rehearsal room and the boardroom have in common? More than you might thin...
01/07/2026
Broadcast Management Group (BMG) has announced the appointment of Kathy Samuels ...
01/07/2026
Shade has announced Custom Objects and Automations, a platform expansion releasing June 29, 2026, that adds database and workflow automation capabilities direct...
01/07/2026
FOR-A America has announced the addition of Jaz Wray and Fernando Cruz to its U.S. sales team. Both report to Ernie Leon, Senior VP and Head of Sales and Strate...
01/07/2026
NBC Sports will air all 15 MLB games nationally on Sunday, July 5, across NBC, P...
01/07/2026
Clear-Com has announced a wireless communications upgrade for Jeopardy! and Wheel of Fortune, deploying FreeSpeak II and FreeSpeak Icon systems across both prod...
01/07/2026
England's performance team will use Sony's STATSports APEX GPS tracking system to monitor player physical data in real time during FIFA World Cup 2026 m...
01/07/2026
Adder Technology has announced the appointment of Neil Hillier as Chief Executive Officer, effective July 1, 2026. Hillier succeeds Adrian Dickens, who transiti...
01/07/2026
Bitcentral, Inc. has announced a strategic transaction creating two separate companies. The Production and Playout business will continue as Bitcentral, now own...
01/07/2026
DAZN has announced results from DAZN48, its creator initiative for the FIFA World Cup 2026. Launched in April 2026, the program received thousands of applicatio...
01/07/2026
Sarah Rose, VP, global services, Daktronics (NASDAQ: DAKT), will be inducted into the Information Display and Entertainment Association (IDEA) Hall of Fame at t...
01/07/2026
Gravity Media and the World Economic Forum's production team provided broadc...
01/07/2026
Insight Productions has announced the launch of Insight Storm, a 53-foot mobile broadcast unit built for esports production. The truck is built around a Ross Vi...
01/07/2026
ESPN has announced several content initiatives marking America's 250th anniversary, as part of The Walt Disney Company's Disney Celebrates America pro...
01/07/2026
Eleven production kits, REMI workflows, and cloud distribution bring 40 World Cu...
01/07/2026
The conference also discussed the opportunities offered an industry that is endu...
01/07/2026
The Mountain West Conference has announced the launch of MW , a direct-to-consumer streaming platform powered by Kiswe. The platform will carry live Mountain We...
01/07/2026
New AI Assistant, Multi-channel Audio, ARA2 improvements & more
Tracktion's DAW software has just received its latest major update, gaining a selection ...
01/07/2026
Stammering, stuttering, strangulated tones
The Crow Hill Company's latest creation promises to be the most original sound set they've produced to d...
01/07/2026
Exclusive run of limited-edition modelling pedals
Sweetwater and Andertons M...
01/07/2026
The National Film and Video Foundation (NFVF) is pleased to announce that the ca...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Manfrotto Introduces UNCOVER, the new premium camera bag collection for modern h...
01/07/2026
Blackmagic Design Powers Houston Tamil Sangam Literacy Competition
Brie Clayton July 1, 2026
0 Comments
Volunteers use ATEM Mini Pro, Blackmagic Desig...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
PlayBox Technology has published State of Broadcast Infrastructure 2026, an in-depth industry research report examining the technologies, operational challenges...
01/07/2026
LONDON, UK, 1 JULY Jigsaw24 has appointed Alan Henry as Head of Sales for Media and Entertainment, reinforcing its continued investment in helping broadcaster...
01/07/2026
Content Vault, the patent-pending secure content distribution platform protecting high-value media from disclosures, theft and unauthorised access, today announ...
01/07/2026
Bitcentral, Inc. a leading provider of enterprise software and digital media solutions for news, sports and entertainment broadcasters, as well as streaming pla...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Share
Copy link
Facebook
X
Linkedin
Bluesky
Email...
01/07/2026
Groundbreaking First Nations Screen Business Accelerator launched through nation...
Scripps Research chemists develop new method for making gamma chiral centers on simple carboxylic acids C-H activation-based method should speed drug molecule design and diversification.
