Chapter 31 — Exercises

Fifty problems on retrosynthetic analysis and multi-step synthesis design. ∗ marks problems with full worked solutions in Appendix Answers to Selected Exercises.

Section A — Functional-group disconnections

31.1∗ (routine) For each target, propose a single retrosynthetic disconnection and identify the precursors: (a) Methyl benzoate (an ester) (b) N-Methylacetamide (an amide) (c) 4-Phenyl-3-buten-2-one (an enone) (d) 3-Hydroxypentan-2-one (a β-hydroxy ketone) (e) Diethyl 2,4-dioxopentanoate (a β-keto ester from a Claisen)

31.2 (routine) For each target, identify the most strategic bond to disconnect: (a) cyclohexyl methyl ketone (from cyclohexanone + ?) (b) 4-methyl-3-penten-2-one (mesityl oxide; from acetone + ?) (c) 1,5-diphenyl-1,5-pentanedione (a 1,5-diketone)

31.3∗ (routine) Disconnect each amine to its precursor by reductive amination: (a) N-methyl-2-aminoheptane (b) N-benzylpiperidine (c) cyclohexylamine

31.4 (moderate) Disconnect a complex molecule to multiple fragments. For example: ibuprofen — what are the strategic bonds and the precursors?

Section B — Specific drug retrosyntheses

31.5∗ (routine) Perform a retrosynthesis of acetaminophen (paracetamol) from 4-aminophenol + acetic anhydride. Identify all steps.

31.6 (routine) Perform a retrosynthesis of aspirin from salicylic acid + acetic anhydride. (Already covered in Ch 26, but redo with retrosynthetic vocabulary.)

31.7∗ (routine) Perform a retrosynthesis of lidocaine (local anesthetic) showing the two strategic disconnections (amide + Cl-amine).

31.8 (moderate) Perform a retrosynthesis of ibuprofen using the BHC (Boots-Hoechst-Celanese) industrial process. Show the Friedel-Crafts step, the Pd-catalyzed carbonylation, and identify each strategic bond.

31.9 (moderate) Perform a retrosynthesis of atenolol (β-blocker) showing the epoxide + amine strategy.

31.10 (challenge) Perform a retrosynthesis of fluoxetine (Prozac, an SSRI). Identify the strategic bonds (one C-O ether and one C-N amine).

31.11 (challenge) Perform a retrosynthesis of morphine (the natural product). This is hard — get as far as you can with the rules of Ch 31.

Section C — Convergent synthesis

31.12∗ (routine) Compare the overall yield of: (a) a 10-step linear synthesis at 80% per step. (b) a 10-step convergent synthesis with two 5-step branches at 80% per step + 1 coupling at 80%.

31.13 (routine) Plan a convergent synthesis: target = a complex natural product with two distinct halves. Propose how to make each half separately + the coupling step.

31.14 (moderate) Why is convergent synthesis preferred for industrial production? Identify the economic and practical advantages.

31.15 (moderate) Design a convergent synthesis of a tertiary amine target. The amine has substituents from three different "halves" — design the convergent synthesis with the right disconnection.

Section D — Protecting groups

31.16∗ (routine) A target has both an aldehyde and a primary alcohol. The next step is a strong-base reaction. Propose a protecting-group strategy.

31.17 (routine) Match each protecting group to the functional group it protects: (a) acetal — ? (b) TBS silyl ether — ? (c) Boc — ? (d) Cbz — ? (e) Bn (benzyl) — ?

31.18 (moderate) Suggest the conditions to remove each protecting group from 31.17. (e.g., aqueous H⁺ for acetal; F⁻ for TBS; etc.)

31.19 (moderate) A peptide synthesis uses the Boc strategy: Boc-protected amino acid + free C-terminus reacts. After coupling, the Boc is removed (TFA), and the next amino acid is added. Why does the Boc strategy give "orthogonal" protection vs. the Fmoc (piperidine) and Cbz (Pd/C+H₂) groups?

31.20 (challenge) Design a synthesis of a target with both an alcohol and an amine, where the alcohol must be alkylated first. Propose a protecting-group strategy: protect the amine as Boc, do the alkylation, then deprotect.

Section E — Mechanism and reagent justification

31.21∗ (routine) For a Friedel-Crafts acylation step, justify the choice of: (a) acid chloride over anhydride; (b) AlCl₃ over BF₃ as catalyst.

31.22 (routine) For an aldol condensation step, justify the choice of: (a) NaOEt vs. LDA; (b) reflux vs. low temperature.

31.23 (moderate) For a reductive amination step, justify the choice of: (a) NaBH₃CN over NaBH₄; (b) pH 5–6 over pH 9; (c) acetic acid over HCl.

31.24 (moderate) For a Claisen condensation step, justify the choice of NaOEt over NaOMe. What goes wrong if you mismatch?

31.25 (challenge) For a Mukaiyama aldol step, justify the choice of TiCl₄ over BF₃. When would you choose each?

Section F — Multistep synthesis design

31.26∗ (routine) Design a synthesis of (S)-2-aminobutane in 3 steps from butanal. (Hint: use Strecker synthesis.)

31.27 (routine) Design a synthesis of 3-hydroxy-3-phenyl-2-butanone in 3 steps from benzaldehyde + acetone.

31.28 (moderate) Design a synthesis of an α,β-unsaturated nitrile from a starting aldehyde. Hint: use a stabilized Wittig ylide.

31.29 (moderate) Design a synthesis of an α-bromo ester from an ester. (Hint: enolate + Br₂.)

31.30 (moderate) Design a synthesis of a β-amino ester from an α,β-unsaturated ester + amine (aza-Michael addition).

31.31 (challenge) Design a synthesis of a 6-membered ring with one ketone and one alcohol substituent — a target like 4-hydroxycyclohex-2-enone (a synthetic intermediate). Use either a Diels-Alder or a Robinson annulation approach.

31.32 (challenge) Design a synthesis of a 1,3-diol with two stereocenters using an aldol reaction + reduction.

Section G — Stereochemistry

31.33∗ (routine) A target has one stereocenter. Propose a synthesis using either a chiral starting material (chiral pool) or a chiral catalyst.

31.34 (routine) A target has two stereocenters in a syn relationship. Propose a synthesis using a Z-enolate aldol (Zimmerman-Traxler chair-like TS).

31.35 (moderate) A target has two stereocenters in an anti relationship. Propose a synthesis using an E-enolate aldol.

31.36 (challenge) Use a chiral oxazolidinone (Evans auxiliary) to direct an aldol reaction with high diastereoselectivity. Show the auxiliary, the aldol partner, and the product.

31.37 (challenge) Use proline as an organocatalyst for an asymmetric Michael addition. Sketch the mechanism (proline forms an iminium with the substrate; delivers the donor face-selectively).

Section H — Spectroscopy in synthesis planning

31.38∗ (routine) A target's IR spectrum shows: 3400 (broad), 1715, 2950. ¹H NMR: aldehyde signal at 9.7. Predict the synthesis: aldehyde + reduction (NaBH₄) → primary alcohol.

31.39 (routine) A target's ¹³C NMR shows two carbonyl peaks at 200 and 175 ppm. Identify the target as a β-keto ester or 1,3-dicarbonyl. Propose a Claisen-based synthesis.

31.40 (moderate) A target's mass spectrum shows M⁺ at 234. Major fragments at 119 (loss of 115) and 86. Hypothesize the structure and propose a synthesis.

Section I — Industrial vs. academic synthesis

31.41 (routine) What are the differences between an academic synthesis and an industrial synthesis? Consider: yield per step, total steps, atom economy, environmental impact, cost, scale.

31.42 (moderate) Why does an industrial synthesis prefer 4 steps with 80% yield to 8 steps with 95% yield each? (Despite the latter giving higher overall yield 0.95^8 = 66% vs. 0.80^4 = 41%.)

31.43 (challenge) Industrial atom economy: a synthesis with high atom economy uses most of the starting material atoms in the product. Compare the atom economy of: (a) Friedel-Crafts acylation, (b) Wittig reaction (which gives Ph₃P=O byproduct, large MW), (c) reductive amination. Rank by atom economy.

Section J — Computer-aided synthesis

31.44 (routine) AI-driven retrosynthesis tools (Synthia, IBM RXN, AiZynthFinder) propose retrosyntheses. How do these tools learn? What is their key advantage and disadvantage?

31.45 (moderate) A computer-proposed retrosynthesis suggests a "novel" disconnection that no one has tried. How do you evaluate whether to pursue it? What experiments would you do?

31.46 (challenge) A target molecule has been published before. The known synthesis uses 8 steps. A new AI tool proposes a 4-step route. Why might the AI route be wrong? What are the failure modes?

Section K — Final synthesis design

31.47∗ (challenge) Design a complete synthesis of a "complex" target: a natural product with one ring, one stereocenter, and two functional groups (e.g., an α-amino ester or a β-hydroxy ester). Show all steps with mechanism and yield estimates.

31.48 (challenge) Design a synthesis of a peptide bond (between glycine and alanine) using DCC coupling. Identify the protecting-group strategy.

31.49 (challenge) Design a synthesis of a complex amine drug with three different ring systems. Use convergent strategy.

31.50 (challenge) Open-ended: choose any commercially-available drug from the FDA list. Perform a retrosynthesis. Compare your route to the published industrial route.

Notes for instructors: This chapter is the synthesis capstone of Part VI. Common stumbling blocks: (1) jumping to specific reagents before identifying the strategic bond. (2) Forgetting protecting groups when the synthesis would have functional-group conflicts. (3) Making linear syntheses when convergent ones would give higher yield. (4) Overlooking commercial availability — disconnect to materials you can buy, not to esoteric intermediates. Computational exercises: use Synthia or IBM RXN to propose a retrosynthesis; compare to a hand-derived one.