Chapter 31 — Further Reading

The two essential textbooks

• Corey, E. J., and Cheng, X.-M. (1989). The Logic of Chemical Synthesis. Wiley. The foundational text on retrosynthetic analysis. Corey's Nobel Prize (1990) was for "his development of the theory and methodology of organic synthesis." This book defines the field. Read it cover to cover if you can.

• Warren, S., and Wyatt, P. (2008). Organic Synthesis: The Disconnection Approach, 2nd ed. (Wiley). The student-friendly companion to Corey. Worked examples and a step-by-step approach. Excellent for learning retrosynthesis through practice.

Total synthesis classics

• Nicolaou, K. C., and Sorensen, E. J. (1996). Classics in Total Synthesis. Wiley. Detailed walkthroughs of landmark total syntheses (cortisone, colchicine, taxol, vitamin B12, etc.). Each synthesis is a master class in retrosynthesis applied to complex natural products.

• Nicolaou, K. C., and Snyder, S. A. (2003). Classics in Total Synthesis II. Wiley. Sequel covering more modern syntheses.

• Carreira, E. M., and Kvaerno, L. (2009). Classics in Stereoselective Synthesis. Wiley. Focused on stereocontrolled methods.

• Hudlicky, T., and Reed, J. W. (2008). The Way of Synthesis: Evolution of Design and Methods for Natural Products. Wiley-VCH. Synthesis from a process-chemistry perspective; emphasizes practical considerations (yield, cost, environmental impact).

Industrial synthesis references

• Anastas, P. T., and Warner, J. C. (1998). Green Chemistry: Theory and Practice. Oxford University Press. Defines the principles of green chemistry; relevant to synthesis design.

• Sheldon, R. A. (2017). "The E factor 25 years on: the rise of green chemistry and sustainability." Green Chemistry 19(1), 18–43. Quantitative analysis of waste in chemical synthesis.

• Zhang, T., and others. (2007). The BHC ibuprofen synthesis. Green Chemistry — describes the modern industrial synthesis of ibuprofen.

• Rouhi, A. M. (2003). "Atorvastatin: a complex drug, a complex synthesis." Chemical & Engineering News — describes the Pfizer Lipitor synthesis.

Computer-aided synthesis planning

• Coley, C. W., et al. (2017). "Prediction of organic reaction outcomes using machine learning." ACS Central Science 3(5), 434–443. One of the first major papers showing machine learning's effectiveness for reaction prediction.

• Segler, M. H. S., and Waller, M. P. (2017). "Neural-symbolic machine learning for retrosynthesis and reaction prediction." Chemistry — A European Journal 23(25), 5966–5971. Method paper for AI retrosynthesis.

• Kayala, M. A., et al. (2011). "Learning to predict chemical reactions." Journal of Chemical Information and Modeling 51(9), 2209–2222. Earlier ML approach.

• Bartlett, P. A., et al. (1980). "Computer-assisted analysis in organic synthesis." Topics in Current Chemistry. Historical context.

• Bartók, A., et al. (2018). "On representations in machine learning of chemical reactions." Chemistry — A European Journal 24(60), 16043–16058. Modern review.

• Coley, C. W., et al. (2023). "A robotic platform for flow synthesis of organic compounds informed by AI planning." Science 380(6644). The 2023 paper showing AI-proposed novel synthesis of natural products.

Stereochemistry in synthesis

• Eliel, E. L., and Wilen, S. H. (1994). Stereochemistry of Organic Compounds. Wiley. The classic reference for stereochemistry.

• Nógrádi, M. (1995). Stereoselective Synthesis. VCH. Methods for installing stereocenters.

• Reetz, M. T. (2008). "Directed evolution of enzymes for organic synthesis." Wiley-VCH. Modern enzyme-mediated stereoselective synthesis.

Pharmaceutical references

• Wermuth, C. G. (ed.) (2008). The Practice of Medicinal Chemistry, 3rd ed. Academic Press. Drug design and discovery; includes synthesis considerations.

• Patrick, G. L. (2017). An Introduction to Medicinal Chemistry, 6th ed. Oxford. Excellent intro; includes case studies.

• Lipinski, C. A., et al. (2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings." Advanced Drug Delivery Reviews 46(1-3), 3–26. Lipinski's rule of 5; relevant for drug design strategy.

Online resources

• Reaxys (https://www.reaxys.com/, often accessible via university library): the largest reaction database. Search by substructure, by reaction type, by author, etc. Indispensable for retrosynthesis research.

• PubChem (https://pubchem.ncbi.nlm.nih.gov/): structure/property/reaction database. Free.

• Synthia (https://www.synthia-online.com/): commercial AI retrosynthesis tool from Allchemy/Merck.

• IBM RXN (https://rxn.res.ibm.com/): free online AI retrosynthesis tool.

• AiZynthFinder (https://github.com/MolecularAI/aizynthfinder): open-source AI retrosynthesis from AstraZeneca.

• USPTO Reaction Database (https://uspto.gov/): public patent reaction database.

Data and chemometrics

• Lowe, D. M. (2017). "Extraction of chemical structures and reactions from the literature." Open-source patent text-mining for reactions. Used as training data for many AI tools.

• Schwaller, P., et al. (2018). "Found in translation: predicting outcomes of chemical reactions using transformer-style neural networks." ACS Central Science 4(11), 1–10. Modern deep learning for reaction prediction.

For practice problems

• Smith, M. B., and March, J. March's Advanced Organic Chemistry, 7th ed. (Wiley, 2013). Comprehensive treatment of organic chemistry; includes synthesis strategy.

• Klein, David. Organic Chemistry as a Second Language, 4th ed. (Wiley). Covers synthesis design.

• Karty, Joel. Organic Chemistry: Principles and Mechanisms, 2nd ed. (W. W. Norton, 2018). Modern textbook with retrosynthesis chapter.

Notes on this chapter's pedagogy

Chapter 31 is the synthesis capstone of Part VI. It pulls together everything from Chapters 10–30 and applies them to complex, real-world targets. The chapter is intentionally short on new chemistry (which is in the prior chapters) and long on methodology — how to use the chemistry you already know to design syntheses.

The chapter's structure: 1. Conceptual framework (retrosynthesis, strategic bonds, synthons). 2. Cookbook of disconnections. 3. Worked examples. 4. Modern tools (AI-assisted retrosynthesis). 5. Forward connections (Part VII bioorganic, Part VIII advanced syntheses).

This is a chapter to practice, not memorize. Students who internalize the disconnection patterns and try them on a variety of targets will find synthesis design becoming second nature. Those who only read the chapter will not master it.

The chapter ends Part VI of the textbook. Looking forward, Part VII will apply this synthesis chemistry to biological molecules (carbohydrates, nucleic acids, lipids, proteins). Part VIII will explore advanced topics including pericyclic reactions, total synthesis of natural products, green chemistry, and future directions.

Carbonyl chemistry is the workhorse of organic chemistry. Master Part VI and you have mastered the center of the field.