Raj Rajagopalan (Singapore) & Bernhardt L. Trout (MIT) Program Co-Chairs

1. Chemical & Pharmaceutical Engineering (Begun on July 1, 2006)PSRC Review of Flagship ProgramJune 20, 2007 Raj Rajagopalan (Singapore) & Bernhardt L. Trout (MIT) Program Co-Chairs

2. Overview of the Flagship ProgramThree thrusts focusing on the Pharmaceutical Industry • Thrust A:Metabolic Engineering: Molecular Biotechnology for Engineering Targeted Biological Pathways • Thrust B:Chemical Catalysis: Engineering Catalysts at the Molecular and Nanometer Scales • Thrust C:Downstream Processing: Molecular Engineering for Separation Technology, Purification, and Formulation

3. Overview of the Flagship ProgramPrincipal Professors in Each Thrust • Thrust A: Metabolic Engineering: • Saif Khan (NUS) & Li Zhi (NUS) Greg Stephanopoulos, Too Heng-Phon (NUS) & Danny Wang (MIT) • Thrust B: Chemical Catalysis: • Steve Buchwald (MIT), Saif Khan (NUS), Loh Teck Peng (NTU) & Mark Saeys (NUS) • Thrust C: Downstream Processing: • T Alan Hatton (MIT), Raj Rajagopalan (NUS), Michael Tam (NTU), Bernhardt Trout (MIT), Miranda Yap (BTI, NUS)

4. Manpower • 5 Direct PhD students entering in 2006 • 6 Direct PhD students to enter in 2007 (Another is pending) • 1 Joint Post-Doc (started Feb., 2007) • 1 Post-Doc at NUS (started in March 2007) • 7 MIT PhD students started in 2006-2007 • 6 MIT post-docs started in 2006-2007

5. Key Accomplishments • Thrust A: Metabolic Engineering: • Initiated enzymatic synthesis on chiral chemical intermediate and co-factor regeneration using magnetic nanoclusters.  Preliminary results show excellent promise on this new and novel biocatalysis and co-factor regeneration systems • Demonstrated taxadiene biosynthesis in Escherichia coli at significant amounts. Taxadiene is the first, most difficult step in the synthesis of taxol from precursors of the isoprenoid pathway. (Planning to submit a patent application) • Thrust B: Chemical Catalysis: • Developed the state of the art catalyst system for the carbonylation of aryl sulfonates, including the first system for the carbonylation of aryl mesylates. These (aryl tosylates) are less reactive than aryl halides and are industrially very desirable precursors to aromatic amides and esters. • Set up a working microfluidics facility at NUS; Currently fabricating microreactors for chemical synthesis. • Thrust C: Downstream Processing: • Demonstrated control of protein mobility selectively using light responsive gels, that certain liquid crystal mixtures can show chiral selectivity in solubilization of derivatized amino  acids, and that magnetic nanoparticles can be fucntionalized with chiral selectors. • Developed initial molecular understanding of synthon growth of target crystals. • Developed a molecular thermodynamic model to follow aggregation in the presence of excipients.

6. Industrial Interactions and Anticipated Sponsorships • Pfizer – verbal commitment, finalizing contract • MerLion – verbal commitment, finalizing scope of work • A-Bio – project to be defined in 2007 • Other companies with prospective interest are: Novartis, Merck, Schering-Plough, andS*Bio

7. Other Efforts in Progress • “Industry Day” Workshop for Singapore’s pharmaceutical industries is planned to highlight CPE Program’s research and educational activities and their relation to Singapore’s needs (e.g., Glaxo) (This effort will also be used to develop closer interactions with local pharmaceutical and chemical companies and the CPE Team in order to continually refine the program needs and goals.) • Industrial tours are planned for both DM and DP students to local industries. One to Glaxo was conducted earlier this year. • Career Planning Workshops for the students (to emphasize the “soft” skills they need) are planned at NUS. • Critical Thinking Boot Camp: DP students will be asked to enroll in the “Critical Thinking Boot Camp”, to be run by ChBE @ NUS, to learn how to read technical papers, how to develop research projects and proposals, etc. • Presentation Skills Workshop: Students will enroll in Professional Presentation Skills Workshop run by Prof. Bill Krantz at ChBE @ NUS.

8. Personnel Changes • Prof. Michael Tam (Thrust C) has resigned from NTU (effective July 1, 2007) to accept a faculty position in Canada. • Prof. Neal Chung (Thrust C), who has strong expertise and industrial collaborations in the area of membrane separations for pharmaceuticals, will join the team in July 2007.

9. Goals for Next Year • Thrust A:Metabolic Engineering: • Enzymatic synthesis of chiral intermediate will be investigated along with the regeneration of co-factor analogs.  Once these are achieved, patent disclosure will be filed. • Optimization of the above pathway for maximum taxadiene production and initiate the construction of the additional ~10 steps to complete the full taxol pathway. Also, initiation of the engineering of the amporphadiene pathway for artemisinin synthesis (antimalaria drug). • Thrust B:Chemical Catalysis: • Development of a full understanding of the controlling features in our new carbonylation system as well as extension to the preparation of other important functional groups such as carboxylic acids. Also, initiation of work on the carbonylation of aliphatic substrates (much more challenging than for aromatic substrates). • Thrust C:Downstream Processing: • Application of functionalized magnetic nanoparticles to continuous chiral separations and continued development of responsive gels for pharmaceutical separations and purification. • Preliminary design and operation of ferrofluid-based microfluidic separation processes. • Development of rational understanding of selected crystallization processes and formulations.

10. Summary • Research flourishing: anticipated joint publications in 2007-2008, potentially patent disclosures. • Strong interest for industrial sponsorship. • Needs: more Direct PhD slots for industrially funded projects.