Chapter 38 — Exercises

Forty-five problems on total synthesis design and the art of synthesis. Drawing required wherever a structure or mechanism is asked for. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Retrosynthesis of artemisinin

38.1∗ (routine) Sketch the structure of artemisinin. Identify: (a) the endoperoxide bridge. (b) the lactone. (c) the three fused rings. (d) the stereocenters.

38.2 (routine) Identify the strategic disconnections of artemisinin. List 3 main disconnections.

38.3∗ (moderate) The endoperoxide is installed by singlet oxygen [4+2] with a 1,3-diene. Sketch this disconnection. What is the dienophile? What is the diene?

38.4 (moderate) Why is the endoperoxide essential for artemisinin's antimalarial activity? Connect to the iron-mediated radical mechanism.

38.5 (challenge) Design a 5-step retrosynthesis of artemisinin from a chiral terpene starting material. Identify the strategic bonds and the methods.

Section B — Retrosynthesis of common drugs

38.6∗ (routine) Design a retrosynthesis of aspirin (acetylsalicylic acid) from commercial materials. (1-step from salicylic acid + acetic anhydride.)

38.7 (routine) Design a retrosynthesis of ibuprofen using the BHC industrial process (3 steps from isobutylbenzene).

38.8∗ (routine) Design a retrosynthesis of acetaminophen (paracetamol) from 4-aminophenol + acetic anhydride.

38.9 (moderate) Design a retrosynthesis of lidocaine (local anesthetic). Identify the 2 strategic disconnections.

38.10 (moderate) Design a retrosynthesis of fluoxetine (Prozac, an SSRI). Identify the strategic disconnections (one C-O ether, one C-N amine).

38.11 (challenge) Design a retrosynthesis of morphine. (This is hard — get as far as you can with the rules of Ch 31.)

38.12 (challenge) Choose a drug not discussed in this book (e.g., amoxicillin, diclofenac, sertraline, or any FDA-approved drug). Propose a retrosynthesis from commercial materials.

Section C — Strategic disconnections

38.13∗ (routine) What is a "strategic bond"? List three criteria.

38.14 (routine) For a target with a 6-membered ring containing one alkene, what disconnection do you reach for first? (Diels-Alder.)

38.15 (moderate) For a complex target with three stereocenters, what general approach to setting them?

38.16 (challenge) Compare two retrosynthetic strategies for a complex target: (a) start from a chiral pool material; (b) use asymmetric methods at key steps. What are the trade-offs?

Section D — Convergent vs linear

38.17∗ (routine) Calculate the overall yield of: (a) 12-step linear synthesis at 80% per step. (b) 12-step convergent synthesis with two 6-step branches at 80% per step + 1 coupling at 80%.

38.18 (routine) Why is convergent synthesis preferred for complex targets? Identify three benefits.

38.19 (moderate) Design a convergent synthesis of a complex target with two distinct halves. Identify the strategic disconnection that splits it.

38.20 (challenge) A complex natural product has 30 carbons. Compare a 25-step linear vs a 25-step convergent synthesis. Calculate the yield difference.

Section E — Stereocontrol

38.21∗ (routine) Identify the four main strategies for stereocontrol in synthesis: (a) chiral pool starting material. (b) chiral catalyst (asymmetric reaction). (c) chiral auxiliary. (d) substrate-directed stereocontrol.

38.22 (routine) A target has one chiral center. Choose a strategy: chiral pool, asymmetric, or chiral auxiliary?

38.23 (moderate) A target has multiple chiral centers (5+). Plan how to set each one. Which is the most challenging? In what order?

38.24 (moderate) Use Sharpless AD (Ch 36) for a stereocontrolled C=C oxidation in a synthesis. What product results?

38.25 (challenge) A natural product has a quaternary stereocenter. Discuss the challenges of installing it and the strategies (Heathcock aldol, alkylation of chiral enolate, etc.).

Section F — Famous total syntheses

38.26∗ (routine) Name three famous total syntheses by Woodward. Why are they considered classics?

38.27 (routine) Name three famous total syntheses by Corey. What did each contribute to the field?

38.28 (routine) Name three famous total syntheses by Nicolaou. What were the key innovations?

38.29 (moderate) Compare Woodward's morphine synthesis (1954, 30+ steps) with a modern morphine synthesis (e.g., Trost 2002, 14 steps). What changed in 50 years of synthesis methodology?

38.30 (challenge) Choose a Nobel-winning total synthesis (Woodward 1965, Corey 1990, or another). Read a review. What strategies were used? Could a modern chemist do it in fewer steps?

Section G — Practical synthesis design

38.31 (routine) Design a synthesis of a hypothetical β-amino alcohol with one stereocenter. Use asymmetric reductive amination.

38.32 (moderate) Design a synthesis of a 14-membered macrocyclic lactone using ring-closing metathesis. Identify the linear precursor.

38.33 (moderate) Design a synthesis of a complex amine drug using Buchwald-Hartwig + reductive amination + Suzuki coupling. Show the sequence.

38.34 (challenge) Combine multiple chapters: design a 6-step synthesis of a pharmaceutical that uses chemistry from Chapters 24-37. Identify each chapter's contribution.

38.35 (challenge) Design a synthesis of a peptide drug (e.g., a 10-mer with one non-natural amino acid). Use SPPS + click chemistry.

Section H — Modern methods

38.36 (routine) What is C-H activation? How does it transform total synthesis?

38.37 (routine) What is photoredox catalysis? Why is it gaining importance in synthesis?

38.38 (moderate) What is flow chemistry? Why is it preferred for some industrial syntheses over batch?

38.39 (challenge) AI-driven synthesis planning: how do tools like Synthia and IBM RXN work? Compare to human-designed retrosynthesis.

Section I — Industrial vs academic synthesis

38.40 (routine) What are the differences between an academic and industrial synthesis? Consider scale, cost, environmental impact, atom economy.

38.41 (moderate) Why might an industrial synthesis prefer 4 steps with 80% yield over 8 steps with 95% yield?

38.42 (challenge) Industrial atom economy: a synthesis with high atom economy uses most of the starting material atoms in the product. Compare: (a) Friedel-Crafts acylation, (b) Wittig reaction, (c) reductive amination. Which has the highest atom economy?

Section J — Final integration

38.43 (challenge) Design a complete synthesis of a complex natural product (e.g., a sesquiterpene like artemisinin) using everything from Chapters 1-37. Show all steps with mechanisms.

38.44 (challenge) Open-ended: choose any natural product you find interesting. Look up its known total syntheses. Compare 2-3 different routes. What are the trade-offs? Which would you use, and why?

38.45 (challenge) Imagine the future of synthesis (2030 and beyond). What chemistry will we have that we don't have now? AI? Automation? New reactions? Speculate based on current trends.

Notes for instructors: Common stumbling blocks for Chapter 38: (1) Choosing strategic bonds — students often choose easy disconnections rather than strategic ones. (2) Not setting stereochemistry early enough. (3) Forgetting protecting groups when needed. (4) Designing linear when convergent would be better. Computational exercises: use Synthia or IBM RXN to propose a retrosynthesis for a published natural product; compare to the actual published synthesis.