Chapter 38 — Quiz

Twenty-five questions on the art of synthesis. ∗ marks questions answered in the answer key.

Multiple choice

1.∗ Total synthesis aims to: (a) build a specific target molecule from simple, commercial starting materials (b) improve an existing drug's potency (c) modify an existing natural product (d) discover a new drug from scratch

2.∗ Artemisinin is used as: (a) an antibiotic (b) an antimalarial (the gold standard for severe malaria) (c) an anti-inflammatory (d) a pain reliever

3.∗ Artemisinin's key functional group for biological activity is: (a) amide (b) endoperoxide (O-O bond) (c) phenol (d) ester only

4.∗ Tu Youyou received the Nobel Prize for artemisinin in: (a) 2010 (b) 2015 (Physiology or Medicine, the first Chinese woman Nobelist) (c) 2001 (d) 2020

5.∗ Retrosynthesis is performed: (a) forward (starting material to product) (b) backward (target to precursors via strategic disconnections) (c) randomly (d) only by computer

6.∗ Convergent synthesis is preferred over linear because: (a) higher overall yield (multiplicative effect of yield is reduced) (b) easier to publish (c) cheaper materials (d) all of the above

7.∗ A "strategic bond" is: (a) reliable to form (known reaction) and simplifying (precursor is structurally simpler) (b) hard to break (c) random (d) only at quaternary carbons

8.∗ Robert Woodward is famous for the total synthesis of: (a) morphine, chlorophyll, strychnine, vitamin B12, and many others (b) only DNA (c) only steroids (d) gene editing

9.∗ K. C. Nicolaou is famous for: (a) Taxol, brevetoxin, vancomycin, and many natural products (b) DNA sequencing (c) only sterols (d) only oxidations

10.∗ "Elegance" in total synthesis means: (a) fewer steps, convergent strategy, high yield, minimal protecting groups (b) most steps possible (c) only enantiopure (d) hardest possible route

11.∗ Which is a characteristic of a good retrosynthesis? (a) breaks down complex target to commercially-available starting materials (b) uses strategic bond disconnections (c) accounts for stereochemistry (d) all of the above

12.∗ The chiral pool approach uses: (a) a chiral starting material (amino acid, sugar, terpene) to set initial stereochemistry (b) racemic starting materials with subsequent resolution (c) only synthetic chiral compounds (d) all of the above

13.∗ Asymmetric methods (Sharpless, Noyori, etc.) provide: (a) enantioselective transformations using chiral catalysts (b) only racemic products (c) only natural products (d) only photochemistry

14.∗ Modern total synthesis uses: (a) Pd cross-coupling, RCM, asymmetric methods, biocatalysis, photoredox (b) only NaOH and HCl (c) only Sn₂ chemistry (d) only photochemistry

15.∗ Industrial-scale synthesis prefers: (a) shorter syntheses with higher yield per step (atom economy + cost) (b) longer syntheses with more steps (c) academic-style elegance over efficiency (d) only racemic mixtures

16.∗ AI-guided synthesis planning (Synthia, IBM RXN, AiZynthFinder): (a) proposes retrosyntheses based on training on millions of published reactions (b) replaces human chemists (c) only works for simple targets (d) cannot work on novel scaffolds

17.∗ Why is the artemisinin synthesis difficult? (a) the endoperoxide is rare and challenging to install (b) multiple stereocenters (c) fused ring system (d) all of the above

18.∗ Industrial production of artemisinin uses: (a) plant extraction + semi-synthesis from yeast-engineered artemisinic acid (b) total synthesis at scale (c) only chemical synthesis (d) only enzymatic synthesis

19.∗ A famous quote about total synthesis: "If you can synthesize it, you have proved its structure." This reflects: (a) the ultimate proof of a natural product's structure (b) total synthesis as a hobby (c) only chemistry, not biology (d) only academic relevance

20.∗ Looking forward, total synthesis will increasingly use: (a) AI for retrosynthesis, automation for execution, biocatalysis for stereocontrol, photoredox for new disconnections (b) only traditional batch chemistry (c) only Pd cross-coupling (d) primarily classical methods

Short answer

21. Sketch the structure of artemisinin. Identify the endoperoxide, lactone, and at least 4 of the 7 stereocenters.

22. Outline 3 strategic disconnections for artemisinin retrosynthesis. Explain each.

23. Compare the synthesis strategies of Woodward (e.g., morphine 1954) and a modern chemist (e.g., Phil Baran, 2010s). What's changed?

24. Calculate the overall yield of: (a) 14-step linear synthesis at 80% per step; (b) 14-step convergent synthesis with two 7-step branches at 80% + coupling at 80%. Why is convergent preferred?

25. Explain why convergent synthesis is preferred for complex targets. Use the multiplicative yield argument.

Answer key

  1. a — Total synthesis builds from simple to complex.
  2. b — Artemisinin is antimalarial.
  3. b — Endoperoxide is the pharmacophore.
  4. b — Tu Youyou Nobel 2015.
  5. b — Retrosynthesis is target → precursors.
  6. a — Convergent gives higher yield.
  7. a — Strategic bond definition.
  8. a — Woodward's syntheses.
  9. a — Nicolaou's syntheses.
  10. a — Elegance characteristics.
  11. d — All listed.
  12. a — Chiral pool description.
  13. a — Asymmetric methods.
  14. a — Modern methods.
  15. a — Industrial preferences.
  16. a — AI synthesis planning.
  17. d — All challenges.
  18. a — Modern artemisinin production.
  19. a — Total synthesis as structural proof.
  20. a — Future of synthesis.

21. Artemisinin has: - A 6-6-6 fused ring system (3 fused 6-membered rings, A, B, C). - The endoperoxide bridge (O-O within ring B, between two specific carbons). - A lactone at one end (cyclic ester in ring C). - 7 stereocenters total: 4 on the ring system + 1 quaternary + 2 on the lactone-containing ring. - A methyl group at C5 (one of the quaternary stereocenters). - An angular methyl at the ring junction. The structure is C₁₅H₂₂O₅.

22. Three strategic disconnections:

  1. Endoperoxide → 1,3-diene + ¹O₂: install the endoperoxide late by singlet oxygen [4+2] cycloaddition with a diene. The diene must be set up correctly to give the endoperoxide regiochemistry.

  2. Lactone → hydroxy acid + Fischer esterification: cyclize the open-chain hydroxy acid to the lactone in late stage.

  3. Fused 6-6 ring → diene + dienophile (Diels-Alder) OR Robinson annulation (Michael + intramolecular aldol). The decalin-like skeleton is built by one of these strategies.

23. Woodward (1954, morphine, 30+ steps): used solution-phase peptide chemistry, classical reductions, multiple protecting groups. Each step had moderate yield; total yield ~5%. Used resolution rather than asymmetric methods.

Phil Baran (2010s, e.g., welwitindolinone, 12 steps): uses Pd cross-coupling, photoredox catalysis, biocatalysis, and modern asymmetric methods. Less reliance on protecting groups. Higher yield per step (often 80-95%); total yield ~30-50%.

What changed: development of catalysis (Pd, Ru, Rh), asymmetric methods (chiral catalysts), modern coupling reactions (Suzuki, Heck, RCM), green chemistry principles. The conceptual approach (retrosynthesis, strategic bonds) is the same.

24. Linear: 0.80^14 = 0.044 = 4.4% overall yield. Convergent: each branch is 0.80^7 = 0.21 = 21%. Coupling at 80% gives 0.21 × 0.80 = 16.8% overall. Convergent is ~4× higher yield. Reason: convergent reduces the multiplicative loss; each branch has only 7 steps to survive, then a single coupling. Industrial benefit: 4× higher yield = 4× more product per starting material; potentially 4× lower cost; 4× less waste.

25. Convergent synthesis is preferred because the overall yield is multiplicative for sequential steps, but only multiplied across one branch in convergent synthesis. With 80% yield per step: - Linear N steps: yield = 0.80^N. For N=10, yield = 10.7%. - Convergent (two branches of N/2 steps each + 1 coupling): yield = 0.80^(N/2) × 0.80^(N/2) × 0.80 = 0.80^N × 0.80 / 1 = ... wait, this isn't right. Let me redo.

For 10-step convergent with two 5-step branches: each branch's yield is 0.80^5 = 32.8%. The coupling step between the two branches has 80% yield. So if you start with X grams of each branch starting material, you end with 0.328X grams of each fragment, and 0.328 × 0.80 X = 0.26X grams of final product (per limiting branch). So overall yield = 26.2% per limiting branch.

Compared to linear's 10.7%, convergent gives ~2.5× higher yield. The point is that convergent reduces the depth of multiplicative loss.

This is why convergent synthesis is the gold standard for complex targets: it gives substantially higher yield, allowing more material to be made per unit of starting materials and per unit of effort.