Patricia Van Arnum was executive editor of Pharmaceutical Technology.

Patricia Van Arnum

The global pharmaceutical market shows a mixed bag. Although established markets in the United States, Western Europe, and Japan are certainly important players, growth is slowing as the pharmaceutical markets in emerging economies increases. An in-depth review of healthcare spending on pharmaceuticals in the US shows increased generic-drug incursion, lower per-capita spending on pharmaceuticals, and a concentration of patients using pharmaceuticals 

Changing fundamentals for US pharmaceuticals

Total spending on US medicines fell 3.5% on a real per-capita basis in 2012 and the use of healthcare services overall declined for the second consecutive year, according to a new study released by the IMS Institute for Healthcare Informatics. The report finds that total dollars spent on medications in the U. reached $325.8 billion in 2012, or real per-capita spending of $898, down $33 from 2011. Underlying drivers for the overall decline in healthcare service use included fewer patient visits to office-based physicians, fewer nonemergency admissions to hospitals and outpatient facilities, and a less severe flu season in the early part of 2012. Patent expiries in 2012 contributed $28.9 billion to the reduction in medicine spending, making it the largest-ever impact from generic drugs as millions of patients accessed lower-cost generic versions of medicines, according to IMS. 

 “The cost curve for medicines was clearly bent in 2012, for better or for worse,” said Murray Aitken, executive director, IMS Institute for Healthcare Informatics, in a May 9, 2013 press release. “To some extent, this is a harbinger of more efficient use of our healthcare resources, but it also reflects a decline in utilization that may be the result of undertreatment and an imbalance between prevention and care. On the eve of the most transformative period in US healthcare, understanding the drivers of this cost-curve reduction is critical to effectively addressing the long-term implications.”

The report showed that the number of patient visits to doctors’ offices fell 0.9% 2012, a lower level of decline compared with the prior two years. Outpatient treatment and nonemergency room admissions also were down slightly. Only emergency room admissions increased, by 5.8% in 2012. Use of medicines per person declined slightly by 0.1% partly due to a milder cough, cold, and flu season in the initial months of 2012. 

At the same time, the total cost of medicines declined by 3.5% on a real per-capita basis to $325.8 billion. In addition to lower utilization of branded drugs, the primary drivers, according to the IMS report, were: the increased availability of lower-cost generics, which now account for 84% of all prescriptions; the moderating impact of price increases; and lower spending on recently launched medicines. Healthcare costs remain heavily concentrated among relatively few patients suffering from multiple chronic conditions, cancer, or other specialty diseases. In the case of the commercially insured, under-the-age-of-65 population, 5% of the members incurred 51% of total healthcare costs by using more than $15,684 of healthcare services per person in 2012. 

Patients with insurance are paying higher deductibles and higher copays or co-insurance, with nearly 20% of the insured now in a consumer-driven health plan. Average out-of-pocket costs for commercially insured under-the-age-of-65 patients reached $1,146 in 2012, a 30% jump from 2011 and entirely the result of higher deductibles. The average pharmacy benefit copay declined by $2 to $121 in 2012; patients filled 72% of all retail prescriptions with a copay of $10 or less. 

Following several years of slowing growth, the global market for medicines is expected to rebound from a recent low of 3–4% growth in 2012 to 5–7% growth in 2016, according to a 2012 analysis by the IMS Institute for Healthcare Informatics. Growth will primarily be from emerging markets as growth in established markets in the United States, Western Europe, and Japan remains weak comparative to historical levels. Overall, annual global spending on medicines will rise from $956 billion in 2011 to $1 trillion by 2013, to nearly $1.2 trillion in 2016, representing a compound annual growth rate (CAGR) of 3–6%. For purposes of the IMS analysis, spending is reported as ex-manufacturer prices and does not reflect off-invoice discounts and rebates and is converted from local currencies to US dollars. Absolute growth in global pharmaceutical spending between 2012–2016 will be between $220 billion and $250 billion, compared with $298 billion in the prior five years. 

Additionally, patent expiries, which peaked in 2012, as well as increased cost-containment actions by payers, will constrain branded-medicine spending growth through 2016, at 0–3%. Developed markets experienced their lowest annual growth in 2012 at less than 1% or $3 billion, but will rebound to $18–20 billion in annual growth in the 2014–2016 period. Spending on medicines in developed nations will increase by a total of $60–70 billion from 2011 to 2016, following an increase of $104 billion between 2006 and 2011, according to IMS 

Growth in annual global spending is forecast to more than double by 2016 to as much as $70 billion, up from a $30-billion pace in 2012, driven by volume increases in what IMS terms the “pharmerging” markets and some uptick in spending in developed nations. The “pharmerging” markets are defined by IMS as counties with greater than $1 billion absolute spending growth of more than 2012–2016 and which have gross domestic product per capita of less than $25,000 at purchasing power parity. Using that criteria, China is classified as a Tier-1 country, and Brazil, Russia, and India as Tier-2 countries. Tier 3-countries are Mexico, Turkey, Poland, Venezuela, Argentina, Indonesia, South Africa, Thailand, Romania, Egypt, Ukraine, Pakistan, and Vietnam. Health systems in pharmerging markets will nearly double their medicine spending in five years, according to IMS. Annual spending on medicines in the pharmerging markets will increase from $194 billion in 2011 to between $345 billion and $375 billion by 2016, or $91 in drug spending per capita, according to IMS. The increase will be driven by rising incomes, continued low cost for drugs, and government-sponsored programs designed to increase access to treatments. Generic drugs and other products, including over-the-counter medicines, diagnostics, and nontherapeutics, will account for approximately 83% of the increase. China’s pharmaceutical market is expected to reach $161 billion by 2016, Brazil’s $47 billion, India’s $29 billion, and Russia’s $27 billion. The Tier-3 pharmerging countries are expected to collectively reach $95 billion in pharmaceutical spending by 2016, according to IMS. 

Articles

Emerging markets remain strong as established markets fare less well.

A Pharma Industry Mid-Year Review and Outlook

As pharmaceutical and biopharmaceutical companies face an increasingly competitive environment marked by greater globalization, more complex supply chains, and changing regulatory and technological requirements, they are tasked with finding ways to meet those demands. Sourcing and procurement activities play a crucial role in pharmaceutical/biopharmaceutical companies’ strategies and provide opportunities for value-creation as well as cost-savings. These issues will be addressed by an upcoming educational program, DCAT’s 

 on July 11, 2013 in New York City. Developed and organized by the Drug, Chemical and Associated Technologies Association (DCAT), the program brings together sourcing, procurement, and supply-chain professionals from the pharmaceutical and biopharmaceutical industries to discuss the megatrends affecting the industry, their impact on procurement organizations, and strategies to optimize sourcing and procurement activities. 

Speaking at the conference will be William L. Michels, CPM, CPSM, and president of ADR North America, who will examine the key megatrends (economic, industrial, regulatory, and social) affecting business strategy and operations. His interactive discussion will examine issues, such as talent management, sustainability, innovation capture, cost and value improvements, and social network’s impact on procurement and supply chains as a means to provide business teams a framework to facilitate their decision-making on strategy and operations. 

Several industry executives will offer their particular experience in procurement, sourcing, and supply-management activities.  Hans Melotte, vice-president and chief procurement officer at Johnson & Johnson, will share his knowledge and experience on how procurement organizations can be used to deliver value and implement company strategy. He will discuss how procurement leaders can be engaged in strategy development, influence corporate financial goals, and deliver results aligned with corporate strategy.  He will also examine the importance of partner/supplier relationships in facilitating those objectives. 

Clive R. Heal, team leader and value-creation agent of the Supplier Relationship Center at Roche/Genentech Pharmaceuticals, will discuss Roche’s new global Supplier Relationship Center (SRC). Roche launched the SRC in June 2012 at its Genentech site in South San Francisco with the target to drive value-creation andinnovation through collaboration with five external suppliers. Heal will provide a progress report on the SRC, including the expectations of the SRC and the experiences and learnings thus far from the program. Dietmar Engels, PhD and vice-president of West Pharmaceutical Services, which is one of the initial partners in the SRC, will offer the supplier perspective on the SRC. 

The educational program, which runs from 1:15 to 5:15 PM on July 11, will be proceeded and followed by two important networking events. From 9:00 to 11:15 AM on July 11, DCAT will offer The Exchange, a newly created forum for biopharmaceutical, pharmaceutical, and chemical industry procurement and supply-management professionals to meet and interact with their peers. Facilitated by DCAT’s Supply Management Committee and experts from the Institute of Supply Management (ISM), participants will be able to interact in several small discussion groups to examine a variety of topics. These topics include the design of sourcing and procurement organizations, talent management, leadership competencies, risk management, decision-making, global trade, business challenges, and transformational challenges. Participants will be able to submit topic ideas to DCAT’s Supply Management Committee in advance to put a topic for discussion on the agenda. 

The Exchange is targeted for mid-career procurement and supply-management directors and senior directors, who are responsible for designing, organizing, and leading teams to ensure reliable, quality supply of goods and services at optimized costs. The Exchange is limited to DCAT member companies’ procurement and supply-management professionals. Information on the program and how to register can be found  

program will also include a luncheon beginning at 12:00 PM on July 11 and will feature keynote speaker Bill Rancic, an entrepreneur, businessman and 

best-selling author, who will discuss the challenges individuals face in the corporate arena and other issues, such as developing successful working relationships and meeting ethical challenges in business. Rancic came into prominence almost a decade ago as the first winner of the television show, 

 and subsequently worked in a management position in the construction of the Trump Tower in Chicago, He later became a prominent real-estate developer and restaurateur in Chicago. 

program, a networking reception and light dinner will follow from 5:00 to 7:00 PM on July 11. Also, a networking reception will be held on Wednesday July 10 from 8:30 PM to 10:30 PM prior to the 

 program and additional information may be found 

The upcoming DCAT Sharp Sourcing 2013 conference addresses the challenges and opportunities in pharmaceutical sourcing and procurement.

Innovation in Sourcing and Procurement

Decisions on how to build and sustain growth are at the heart of any company’s strategy. The CMO Aesica, based in Newcastle-Upon-Tyne in the United Kingdom, has used a combination of organic growth and acquisitions to grow the company from its founding in 2004 with an initial focus on contract API manufacturing to a company of approximately 1300 employees offering formulation development, API manufacturing, and finished product manufacturing and packaging. 

Aesica was founded in 2004 through a management buyout of the former BASF API manufacturing facility in Cramlington, UK. In 2006, Aesica acquired a chemical manufacturing facility from Merck & Co. in Ponders End, Enfield in the UK. In 2007, it opened a new API pilot plant at the Cramlington site and acquired a secondary manufacturing facility from Abbott (now AbbVie) in Queenborough, Kent, UK, its first foray into finished-product manufacturing. It later acquired in 2010, the formulation-development and clinical-trial manufacturing company, R5 Pharmaceuticals, in Nottingham, UK. 

These acquisitions were followed by internal investment to expand its manufacturing capabilities. In November 2011, the company opened a new $4.6-million high-potency manufacturing facility in Queenborough for formulated products. The facility, which includes suites for blending, compression, and blistering, is capable of producing SafeBridge Category 3 and Schedule II controlled drugs. The company later upgraded its API manufacturing facilities in Cramlington and Queenborough to manufacture high-potency APIs at a commercial scale in Cramlington and on small-scale in Queenborough. The new facilities can produce high-potency APIs in quantities of 1– 200 kg. Further investment in 2013 will equip Aesica to produce batch sizes up to 600 kg. The company also is completing an expansion of the capacity of its Queenborough facility by 1 billion tablets per year. It is expected to be commissioned at the end of 2013. 

Aesica most recent move, made in 2011, expanded its finished-product manufacturing capacity. It acquired the former manufacturing facilities of UCB in Monheim and Zwickau, Germany, and Pianezza, Italy to enhance its injectables and oral liquid dosage capability and to add hard-encapsulation technology. The acquisition also added to the company’s packaging capabilities and enabled it to operate a dedicated line purely for the Japanese market. With the acquisition, Aesica also secured a long-term supply agreement with UCB. 

Building its manufacturing capacity has been a focus of the company as has advancing its scientific partnerships.  In 2012, the company formed the Aesica Innovation Board, comprised of experts from within Aesica, technology-based firms, and academia, to help stimulate pharmaceutical innovation in API manufacturing, formulation development/drug delivery, and finished-product manufacturing. The goal of the partnerships is to facilitate ways in which pharmaceutical companies can operate more competitively and efficiently, overcome technical and processing barriers, establish more sustainable manufacturing methods, and innovate drug-delivery systems and/or formulations. “The Innovation Board is part of strategy to develop technology as well as create a culture for scientific and manufacturing innovation,” explains Alan Raymond, sales and marketing director at Aesica. 

To that end, Aesica formed a partnership with EmulTech to access EmulTech’s sterile emulsion technology for microencapsulation (ET4ME). EmulTech, a spinout of Eindhoven University of Technology in the Netherlands, uses microfluidic processes to create microparticulate suspensions. The technology is used for injectables, including depot injections for sustained release, to achieve uniform droplet size, loading, and morphology. Aesica contributed an aseptic protocol in applying the technology, which was used to develop a dosage form for an acid-resistant nonsterile suspension for a particular client although the technology also can be applied to sterile products. 

In 2012, Aesica formed a pact with the Center for Pharmaceutical Engineering Science at the University of Bradford in the UK. Under the partnership, the center offers processing technologies, including hot-melt extrusion, and Aesica supplies formulation expertise and manufacturing capacity and expertise for GMP clinical-trial supplies. The company is also partnered with the University of Durham and the University of Leeds in the UK for developing new or improved routes for API manufacturing. To that end, the partners developed a detailed kinetic study and based on the study, a new flow process is being developed before being scaled up at Aesica’s Cramlington plant. Also, earlier this year, Aesica partnered with the University of Nottingham in the UK for the commercial development of routes for amide-bond synthesis.

Looking ahead, Raymond notes that the company is seeking to build its global footprint. “We are evaluating expansion in the United States to build our assets in both API and finished product manufacturing,” he says. Outside the US, the company is looking to expand into one of the BRIC (i.e., Brazil, Russia, India, China) regions, with primary emphasis on India, China, or Latin America.

The CMO Aesica has used a combination of organic growth and acquisitions to build its business and is seeking to expand its geographic footprint.

Aesica in an Expansion Mode

The 66th World Health Assembly (WHA), the decision-making body of the World Health Organization (WHO), was held last month in Geneva, Switzerland and concluded with agreement on a range of new public health measures. In all, 24 resolutions and five decisions were adopted by the nearly 2000 delegates representing WHO member states. The pharmaceutical industry was part of the discussions. The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), which represents research-based pharmaceutical companies and associations, weighed in on the discussions and provided input on various topics, including noncommunicable diseases (NCDs), mental and neurological disorders (MNDs), R&D for diseases of the developing world, counterfeit medicines, the global vaccine action plan, and neglected tropical diseases (NTDs). 

The WHA addressed NCDs through a global action plan for the prevention and control of NCDs (including heart disease, stroke, diabetes, cancer, and chronic lung diseases) by seeking to achieve nine globally agreed targets for NCDs, including a reduction in premature mortality from NCDs by 25% in 2025. The action plan also contains a monitoring framework, including 25 indicators to track mortality and morbidity, as well as ways to assess progress in addressing risk factors and evaluate the implementation of national strategies and plans. WHO was requested to develop draft terms of reference for a global coordination mechanism through a consultative process culminating in a formal meeting of WHO member states in November 2013. WHO also was tasked with providing technical support to member states and developing a limited set of action plan indicators to chart progress made with the implementation of the action plan in 2016, 2018, and 2021. 

IFPMA supports these efforts. “The Global Action Plan is a focused and pragmatic document, which recognizes the size of the challenge, identifies barriers that must be overcome, and proposes sounds approaches,” said IFPMA in a May 28, 2013 press release. “To achieve significant impact on NCDs, multistakeholder strategies are required at the global, regional, and national levels. These should be fully integrated into healthcare systems and extend beyond the traditional health sector.” 

A resolution on WHO’s mental health action plan 2013–2020 set four major objectives: strengthen effective leadership and governance for mental health; provide comprehensive, integrated, and responsive mental-health and social-care services in community-based settings; implement strategies for promotion and prevention in mental health; and strengthen information systems, evidence, and research for mental health. According to WHO, the plan sets important new directions for mental health, including a central role for provision of community-based care and a greater emphasis on human rights. It also emphasizes the empowerment of people with mental disabilities and the need to develop strong civil society and health promotion and prevention activities. The document proposes indicators and targets, such as a 20% increase in service coverage for severe mental disorders and a 10% reduction of the suicide rate in countries by 2020, which can be used to evaluate levels of implementation, progress, and impact. 

IFPMA supports the Mental Health Global Action Plan discussed at the WHA. “With annual mental and neurological disorders cases estimated at 700 million and accounting for 30% of the global NCD burden, MNDs are more than just a health issue; they should be a societal priority involving decision makers from education, employment, science, government, and other spheres,” said IFPMA in its release. To facilitate those efforts, IFPMA launched 

 an interactive website where people can explore how different stakeholders—policymakers,  researchers, patients, or relatives of someone with an MND—can play a part in addressing these disorders. 

At the WHA, WHO member states reiterated their support to the Global Vaccine Action Plan (GVAP) to prevent millions of deaths by 2020 through more equitable access to vaccines and for the proposed Framework for Monitoring, Evaluation and Accountability, which is linked to the Commission on Information and Accountability for Women’s and Children’s Health, according to WHO. Delegates also supported the independent review process to assess and report progress. Speakers highlighted the following: the need to mobilize greater resources to support low- and middle-income countries to implement the GVAP and monitor impact; ensure that support to countries to implement the GVAP includes a strong focus on strengthening routine immunization; and to facilitate vaccine technology transfer. 

 IFPMA emphasized the need to develop a holistic approach. “Looking ahead, the success of the GVAP requires a holistic approach to vaccine access that balances considerations of availability and continuity of supply, efficient management of the total cost of immunization in countries, development of adapted and safe products, and maintenance of R&D incentives to foster innovation of new vaccines that satisfy unmet medical needs from developing countries,” said IFPMA. “Greater recognition by policymakers and communities of the broader socioeconomic value of vaccination, beyond vaccine affordability and individual antigen disease burden, would be also an important step towards investing in immunization.” 

WHA delegates supported the decision to establish an open-ended working group to identify the actions, activities and behaviors that result substandard/spurious / falsely labeled/ falsified/counterfeit medical products (SSFFC) medical products. Participants highlighted the need for increased cooperation and collaboration among national and regional regulatory authorities, including the exchange of best practices and knowledge. IFPMA acknowledged its support for the working group of member states on SSFFC medical products 

At the WHA, a resolution on NTDs urged member states to ensure country ownership of prevention, control, elimination, and eradication program and calls on international partners to provide sufficient and predictable funding. It encourages greater harmonization of support to countries and the development of new technologies to support vector control and infection prevention. The resolution also calls on WHO to do the following: sustain its leadership in the fight against NTDs; to develop and update evidence-based norms, standards, policies, guidelines and strategies; monitor progress; and support member states in strengthening human resource capacity for the prevention, diagnosis, including vector control and veterinary public health. Many member states highlighted the particular importance of intensifying efforts to tackle dengue, according to WHO.

IFPMA noted the pharmaceutical industry’s efforts in addressing NTDs. In 2012, the industry announced a major commitment to donate 14 billion treatments this decade to control or eliminate nine major NTDs responsible for the 90% of the global burden and currently leads 132 R&D projects for NTDs, 85% of which are carried out in product development partnerships. IFPMA also said it welcomed a a systematic and standardized global review of both unmet needs for Type II (HIV, malaria, tuberculosis) and III (NTDs) diseases and supports identifying how current efforts can be leveraged to achieve progress on diseases disproportionately affecting the developing world, R&D flows, and research capacity. “This task will help develop a clear picture of needs, gaps and priorities and should be performed by talking, among others, to those with experience in planning and conducting R&D and those who provide significant funding,” said IFPMA.”In a time of scarce financial resources and high fragmentation, we believe that understanding key research gaps is a precondition to addressing them.”

Highlights from the 66th World Health Assembly and the pharmaceutical industry?s role in addressing noncommunicable diseases, mental and neurological disorders, R&D for diseases of the developing world, counterfeit medicines, the global vaccine action plan, and neglected tropical diseases.

Pharma Industry Participates in Global Health Initiatives

 International markets play an important role in pharmaceutical and biopharmaceutical companies’ growth strategies, and it is crucial that companies meet the challenge of global regulatory compliance. Optimizing a quality management system to ensure regulatory and corporate compliance for product registrations for new and existing drugs in new geographic markets is essential for commercial success. 

 will examine the operational, organizational, and technological-based requirements on how to reduce risk and achieve operational efficiency for global product registrations in a live 

 on Tuesday June 11 from 2:00 to 3:00 PM EST.

		Managing product registrations with numerous regulatory agencies, each with its own requirements, can be a challenge. The webcast will feature industry experts, who will share their insight on how to create a robust quality management system for complying with country-based and regional-based regulatory requirements for new product registrations, product changes, and labeling changes. The webcast will further examine how to use automation for effectively tracking product registration and related correspondence to ensure global regulatory compliance.

		Speaking at the webcast will be Jake Doran, IT Director, Global Regulatory Affairs, Janssen R&D; KR Karu, Industry Solution Director, Pharmaceutical Sciences, Sparta Systems; and Ashley Watkins,Industry Solution Manager, Pharmaceutical Sciences,Sparta Systems. The panelists will provide insight on how to optimize the regulatory affairs workflow, improve cycle times of approvals through better management of registration data and correspondence activities, and how to integrate other processes, such as change control, document management, pharmacovigilance reporting, and Annual Product Reviews

		Audience members will be able to ask the panelists questions. The live webcast will be on June 11, 2:00 to 3:00 PM EST with on-demand viewing available thereafter. Information on how to register for the webcast may be found 

International markets play an important role in pharmaceutical and biopharmaceutical companies’ growth strategies, and it is crucial that companies meet the challenge of global regulatory compliance.

Key Ways for Ensuring Global Regulatory Compliance

Heterocyclic compounds play an important role in medicinal chemistry and drug synthesis. Like any important functional class of compounds, developments that facilitate their production or elucidate their reaction mechanisms are significant for process chemists in the pharmaceutical industry. In two separate developments, researchers at The Scripps Research Institute (TSRI) in La Jolla, California recently reported on the use of zinc sulfinates as reagents for the direct chemical functionalization of nitrogen-based heterocycles and on reaction-tracking tools to better elucidate copper-catalyzed reactions in making triazoles.  

In the first development, scientists at TSRI developed a set of chemical tools to simplify the synthesis of nitrogen-based heterocycles through more time- and cost-efficient chemical modifications of these compounds. In their work, the researchers pointed out that although advances in transition-metal-mediated cross-coupling have simplified the synthesis of such heterocycles, the carbon–hydrogen functionalization of medicinally important heterocycles that does not rely on prefunctionalized starting materials was an area requiring further research (1). Although the properties of heterocycles, such as their aqueous solubility and their ability to act as ligands, are desirable for biological applications, these properties also make such heterocycles challenging as substrates for direct chemical functionalization (1). To address that problem, the researchers used zinc sulfinate salts to transfer alkyl radicals to heterocycles, thereby allowing for the mild (i.e., moderate temperature, 50 °C or less), direct, and simple formation of carbon–carbon bonds while reacting in a complementary fashion to other carbon–hydrogen functionalization methods (i.e., Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated carbon–hydrogen insertion, and carbon–hydrogen deprotonation) (1). The researchers prepared a toolkit of these reagents and studied their reactivity across a range of heterocycles (natural products, drugs, and building blocks) without recourse to protecting-group chemistry. The reagents could be used in tandem in a single pot in the presence of water and air (1).  			

"Feedback from companies that have started to use this toolkit indicates that it solves a real problem for them by boosting their chemists' productivity and by expanding the realm of compounds that they can feasibly generate," said Phil S. Baran, PhD, a professor in the Department of Chemistry and a member of the Skaggs Institute for Chemical Biology at TSRI who led the study, in a Nov. 28, 2012 TSRI press release. The resistance of nitrogen heterocycles to modification by traditional techniques has slowed drug discovery and has put potential modifications out of reach, notes TSRI.  

The genesis behind the toolkit began with the goal for a more a simplified approach. "The ideal for discovery chemists would be a method that works in water, in an open flask, [and] with procedures that are simple enough to be automated," said Baran. His group's previous work in synthesizing a natural product heterocycle, palau'amine, a toxin made by sea sponges in the Western Pacific that has shown anticancer, antibacterial and antifungal pharmaceutical promise, was a helpful beginning.  

"As we developed an understanding of how that compound reacts, we recognized that it might help us solve this larger problem that discovery chemists face," said Baran in the release. In that synthesis, palau'amine was made by a route featuring highly chemoselective transformations, cascade reactions, and a transannular cyclization to produce the 

-5,5 ring junction (2) and led the researchers to examine reagents that would modify heterocycles directly.  

Although direct methods exist, they often require extreme temperatures as well as expensive and hazardous reagents. During 2010 and 2011, Baran's laboratory experimented with several comparatively safe chemical reagents that work in mild conditions to make commonly desired heterocycle modifications, such as the addition of a difluoromethyl group, according to the TSRI 2012 release. One of these new reagents, a zinc dialkylsulfinate salt (DFMS), which was designed to transfer the difluoromethyl group, turned out to work particularly well. "We quickly realized that we might be able to make related zinc sulfinate salts that would attach other functional groups to heterocycles," Baran said. 

In their recent work, Baran and his team developed an initial toolkit consisting of 10 of these zinc-based salts, each of which attaches a different functional group to a heterocycle framework. "We selected these groups because they are commonly used by medicinal chemists," said Fionn O'Hara, PhD, a postdoctoral researcher in the Baran laboratory and a co-author of the recent study (1). In many cases, these reagents can be used to sequentially make more than one modification to a starting compound. The groups that can be attached with the new reagents include trifluoromethyl, difluoromethyl, trifluoroethyl, monofluoromethyl, isopropyl and triethylene glycol monomethyl ether. 

To show the ability of the reagents to work in biological media, Baran's team used the reagents to difluoromethylate or trifluoromethylate heterocycles in a solution of cell lysate as well as to serve as a buffer medium (i.e., tris), which is commonly used in laboratory-dish tests.  

Baran's laboratory collaborated with scientists from Pfizer. "They provided insight into the types of compounds that would be valuable, assistance with optimization, and, most importantly, testing of the chemistry in their drug-discovery laboratories, where it is meant to be used," Baran said. 

The first of the zinc sulfinate salts, DFMS, also known as Baran difluoromethylation reagent, is being manufactured in bulk and marketed by chemical suppliers, according to the TSRI release. Baran is working to expand his initial toolkit to provide more heterocycle-modifying choices.  

Other researchers at TSRI recently reported on reaction-tracking techniques used to elucidate the mechanism behind the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. This reaction involves the use of copper compounds to catalyze the linkage of two functional groups, a nitrogen-containing azide and a hydrocarbon alkyne, to make a stable five-membered heterocycle, 1,2,3-triazole. The CuAAC process is an example of click chemistry, a term coined in 2001 by Nobel Laureate K. Barry Sharpless to describe a set of bond-forming reactions useful for the rapid assembly of molecules with desired function (3). Click transformations are easy to perform, give rise to their intended products in high yields with little or no byproducts, and work well under many conditions (3). Organic azides, as highly energetic and selective functional groups, were used in organic dipolar cycloadditions with olefins and alkynes among the reactions fulfilling the click criteria, but the low reaction rate of the azide–alkyne cycloaddition did not make them useful in the click context until the copper-catalyzed reaction (3). The copper-catalyzed reaction was reported separately by Sharpless et al. in the United States and Melda et al. in Denmark (3). It transforms organic azides and terminal alkynes into the corresponding 1,4-disubstituted 1,2,3-triazoles, in contrast to the uncatalyzed reaction, which requires higher temperatures and provides mixtures of 1,4- and 1,5-triazole regioisomers (3).  

The simplicity and reliable performance of CuAAC under diverse conditions, including in water and in the presence of oxygen, has made it a useful method whenever covalent stitching of small molecules or large biopolymers is needed, exemplified by protein and nucleic-acid labeling, 

imaging, and drug synthesis, according to an Apr. 4, 2013 TSRI press release.  

"Despite its many uses, the nature of the copper-containing reactive intermediates that are involved in the catalysis had not been well understood, in large part due to the promiscuous nature of copper, which rapidly engages in dynamic interactions with other molecules," said Valery Fokin, an associate professor at TSRI, who was principal investigator for the new study examining the reaction-tracking techniques of CuAAC, in the TSRI April 2013 release.  

The researchers explained that despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes was difficult to establish due to multiple equilibria between several reactive intermediates (4). They reported that real-time monitoring of a representative cycloaddition process by means of heat-flow reaction calorimetry showed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst was added. Additional experiments with an isotopically enriched exogenous copper source showed the stepwise nature of the carbon–nitrogen bond-forming sequence and the equivalence of the two copper atoms within the cycloaddition steps (4). 

The research revealed that in the CuAAC reaction, two copper-containing catalytic units—copper centers—are needed to help build the new triazole structure. "By monitoring the reaction in real time, we showed that both copper atoms are needed and established the involvement of copper-containing intermediates that could not be isolated or directly observed," said Brady Worrell, a co-author in the study in the TSRI April 2013 release. The researchers used isotopic copper as one of the copper centers to track the reaction. "We hypothesized that the two copper centers would have distinct roles, but found unexpectedly that their functions during key steps in the reaction are effectively interchangeable," said Jamil Malik, also a co-author, in the TSRI 2013 release. 

The research not only provides insight into the CuAAC reaction, but also enables development of new reactions that exploit weak interactions of copper catalysts with carbon–carbon triple bonds. Fokin and his team have begun to devise new reactions in which one copper center can be replaced with a different element, to pursue complementary biocompatible and efficient techniques, notes TSRI.  

 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,  

 4. B. T. Worrell, J. A. Malik, and V.V. Fokin, 

Researchers at the Scripps Research Institute advance heteorcylic chemistry trhough new reagents and reaction-tracking techniques.