Appendix G — Retrosynthesis Disconnections

A working reference for retrosynthetic analysis. Use alongside Appendix F (named reactions) and Appendix C (reactions by mechanism family). The Corey conventions: target on the left, disconnection arrow (⇒), synthons on the right, then synthetic equivalents below.

1. The disconnection mindset

Three things to do, in this order (Ch 14, 31, 38):

1. Recognize functional groups. What bonds carry distinguishable polarity? Each polarized bond is a possible disconnection.
2. Disconnect strategic bonds. Prefer bonds adjacent to FGs (where polarity is real, not contrived) and bonds whose disconnection halves the molecule (convergent over linear).
3. Match synthons to real reagents. A synthon is a charged intermediate (R-CO⁺, R⁻, H⁻); a synthetic equivalent is the actual reagent (RCOCl, RMgX, NaBH₄).

A useful prompt while staring at a target: "Where is the polarity? Where is the symmetry? What disconnection makes the precursors more available?"

2. Target FG → disconnection table

Alcohols

Aldehydes and ketones

Carboxylic acids

Esters

Amides

Amines

Alkenes

Alkynes

Aromatic compounds

3. Classic disconnections with worked examples

The skeleton patterns every chemist memorizes.

1,3-difunctional → aldol disconnection

β-hydroxy carbonyl, β-amino carbonyl, β-ketoester (Claisen variant).

   OH  O                O              O
   |   ||               ||             ||
R-CH-CH₂-C-R'    ⇒    R-CHO   +    CH₃-C-R'  (enolate of methyl ketone)
                       (acceptor)    (donor)

Choose disconnection so the donor (the enolate side) is the smaller and most easily enolized partner. Crossed aldol needs LDA + low T or one partner non-enolizable.

1,5-difunctional → Michael disconnection

Set up by α,β-unsat acceptor + enolate donor.

       O         O                       O           O
       ||        ||                      ||          ||
R'-C-CH₂-CH₂-CH₂-C-R'   ⇒   R'-C-CH=CH₂  +  R-CH₂-C-R'
                              (acceptor)    (donor)

If a six-membered ring with an enone is the target → Robinson annulation (Michael + intramol aldol/dehydration).

1,2-difunctional → Grignard or alkene transform

  OH                   O
  |                    ||
R-CH-CH₂-OH   ⇒   R-C-CH₂  (epoxide)  +  H⁻

or  R-CHO + HCHO (cross aldol → diol after reduction)

1,2-diol ⇒ alkene + OsO₄ (syn) or epoxide + H₂O (anti).

1,4-difunctional → umpolung

1,4-dicarbonyls reverse the natural polarity pattern. Solve with dithianes (Corey-Seebach) or Stetter reaction (NHC catalysis).

   O           O           O
   ||          ||          ||
R-C-CH₂-CH₂-C-R'   ⇒   R-CHO  +  [⁻C(=O)R']  (Stetter acyl anion)
                                  via NHC + R'CHO + enone

1,6-difunctional → oxidative cleavage

Cleave a cyclohexene with O₃ or RuO₄/NaIO₄ to give a six-carbon chain with carbonyls at C1 and C6.

  cyclohexene with FG    ⇒   R-CO-(CH₂)ₙ-CO-R'   (chain with two FGs at ends, n=4)

This is how chain dicarbonyls and dicarboxylic acids of defined length are made.

4. Synthon vocabulary

Umpolung = polarity inversion. The classic move: convert R-CHO (acyl is δ⁺) into a dithiane (acyl C now δ⁻). Enables 1,4-, 1,6-dicarbonyl synthesis that ordinary enolate chemistry can't reach.

5. Strategy: protecting groups

Pick the smallest set that lets you carry an FG through reactions it can't tolerate. Always plan install + carry + remove as a triple.

Order of operations: - Protect the more reactive FG first (1° OH usually before 2°). - Carry orthogonally: a Bn + TBS pair on different OHs can be removed independently. - For amines: Boc + Fmoc are orthogonal (acid vs base).

Convergent vs linear. A 10-step linear synthesis at 80% per step gives 11% overall. A 5+5 convergent at the same yields gives 27%. Halve, don't extend.

6. Worked retrosynthesis examples

Aspirin (acetylsalicylic acid) — recap from Ch 14

              O                            O
              ||                           ||
   AcO-Ar-COOH        ⇒        HO-Ar-COOH    +    Ac₂O
   (acetate ester)            (salicylic acid)   (anhydride)

   HO-Ar-COOH        ⇒        ArOH + CO₂     (Kolbe-Schmitt)

   ArOH (phenol)     ⇒        ArSO₃Na + NaOH/fusion  OR Ar-N₂⁺ + H₂O
                              (industrial alkali fusion)

Two steps from phenol: (1) Kolbe-Schmitt with NaOH then CO₂ at 125 °C, 100 atm → sodium salicylate → acidify → salicylic acid; (2) Ac₂O/H₂SO₄ → aspirin.

Ibuprofen (BHC route) — recap from Ch 31

   Ar-CH(CH₃)-COOH  ⇒  Ar-CH(CH₃)-OH + CO (Pd-cat. carbonylation)
   (1)                  (2)

   Ar-CH(CH₃)-OH   ⇒   Ar-CO-CH₃ + H₂/Raney Ni
   (2)                  (3)

   Ar-CO-CH₃       ⇒   isobutylbenzene + Ac₂O/AlCl₃   (Friedel-Crafts)
   (3)                  (4)

   Ar = p-isobutylphenyl

Three industrial steps (BHC won the 1997 EPA Green Chemistry award): FC acylation → catalytic H₂ → catalytic CO insertion. ~80% atom economy vs the 6-step Boots route (~40%).

Wieland-Miescher ketone — Robinson annulation case

   bicyclic enone (W-M ketone)  ⇒  2-methyl-1,3-cyclohexanedione  +  MVK
                                    (Michael donor)                 (Michael acceptor)

   Michael → triketone → intramol. aldol/dehydration → enone

The product, when made asymmetrically (L-proline cat. → Hajos-Parrish-Eder-Sauer-Wiechert), provides the optically active scaffold for ~30 steroid total syntheses. This is the Robinson annulation in its most famous setting.

Atorvastatin sidechain — recap from Ch 31

The chiral 3,5-dihydroxyhexanoate side chain of Lipitor.

   (3R,5R)-syn-diol-hexanoate ester   ⇒   β-hydroxy-δ-ketoester + diastereoselective reduction
                                            (Evans-Saksena or Narasaka-Prasad)
   β-hydroxy-δ-ketoester              ⇒   aldol of acetoacetate + chiral β-hydroxyaldehyde
   chiral β-hydroxyaldehyde           ⇒   epichlorohydrin + cyanide  (chiral pool, ECH)

The industrial synthesis (Pfizer/PD-129) uses an enzymatic resolution (HHDH halohydrin dehalogenase) on (S)-ECH-CN, then chemo-/diastereoselective syn-1,3-diol reduction. See Ch 31 for the full route.

Artemisinin — recap from Ch 38

Endoperoxide antimalarial.

   artemisinin (target)                   ⇒  dihydroartemisinic acid + ¹O₂ (photochemistry / Schenck ene)
   dihydroartemisinic acid                ⇒  artemisinic acid + H₂  (selective alkene reduction)
   artemisinic acid                       ⇒  amorpha-4,11-diene + Cyt-P450 oxidations  (microbial in Amyris route)
   amorphadiene                            ⇒  farnesyl pyrophosphate + amorphadiene synthase  (engineered yeast)
   FPP                                     ⇒  acetyl-CoA + isoprenoid pathway   (chiral pool / metabolic)

The semi-synthetic Amyris/Sanofi route bridges metabolic engineering and ¹O₂ photochemistry — a model for natural-product manufacturing where chemo-only synthesis is uneconomic. Ch 38 walks through the full mechanism of the singlet-oxygen step, including the [4+2] ene followed by Hock cleavage.

7. Strategic considerations checklist

• Bond polarity matches synthon? If not, consider umpolung.
• Symmetry / latent symmetry? Disconnecting a symmetric bond doubles your reagent simplicity.
• Chirality early or late? Early = compact, exposes chiral C to many steps (must protect it); late = flexibility, but stereochemistry must survive built-up framework.
• Convergence? Two 5-step branches > one 10-step linear. Always.
• Stable intermediates? Don't build a precursor that can't be purified.
• Reagent compatibility? Check FG compatibility for every step on every other FG in the molecule.
• Cost? $1 of LDA on a 100-g target is fine; $1000 of chiral ligand on the same scale needs alternatives.

Retrosynthesis is iterative. Draw the target, list disconnections, rate each on simplicity-of-precursor, then re-draw from the precursor and repeat. After a half-dozen targets, the patterns become reflexive.