Question 11 of 13: Brevicomin — Structure and Synthesis

Question 11: Brevicomin — Structure and Synthesis (equal value)

Question text not reproduced: the examination questions are © Engineers and Geoscientists BC. Open the official past paper (linked at the top of this page) to read the question, then follow the worked solution below.

a) Structure of brevicomin. Acid protonates the ketone; the nearer diol oxygen (C6–OH, five atoms away around the chain) attacks intramolecularly to give a cyclic hemiketal, and then the second, adjacent diol oxygen (C7–OH) closes a second ring onto the very same (former ketone) carbon, expelling water and leaving that carbon bonded to two ring oxygens — a bridged bicyclic ketal, exactly the 6,8-dioxabicyclo[3.2.1]octane skeleton drawn for frontalin in the question, except that brevicomin's longer nonanone chain leaves an ethyl group (not a second methyl) on the far bridgehead.

Formula check: 6,7-dihydroxy-2-nonanone is C₉H₁₈O₃; forming the hemiketal is atom-neutral, and the second (hemiketal → full ketal) ring closure expels exactly one H₂O, so brevicomin is C₉H₁₆O₂.

b) Synthesis of 6,7-dihydroxy-2-nonanone from 6-bromo-2-hexanone. The C6–C7 bond is the new bond that must be formed. A Grignard reagent made directly from the bromide would attack any electrophile at C6 with C6 keeping its original two hydrogens — that can extend the chain, but it can never put an OH on C6 itself. To get a diol sitting right across the old C6/new C7 junction, the new bond has to be made at the future alkene (via a Wittig reaction on a C6 aldehyde), and the resulting C6=C7 double bond then dihydroxylated:

1. Protect the ketone. HOCH₂CH₂OH, TsOH (cat.), Δ (–H₂O) converts the C2 ketone to a 1,3-dioxolane acetal so it survives the organometallic/basic steps below; the C6–Br is untouched.
2. Kornblum oxidation. DMSO, NaHCO₃, Δ converts the primary C6–Br directly to the C6 aldehyde (no chain extension yet — still 6 carbons).
3. Wittig olefination with a 3-carbon ylide. The "three carbon alcohol" allowed by the question is 1-propanol; PBr₃ converts it to 1-bromopropane, which forms a phosphonium salt with PPh₃ and is deprotonated (BuLi or NaH) to the ylide Ph₃P=CH–CH₂CH₃. Wittig reaction with the C6 aldehyde installs the C6=C7 double bond together with the C8–C9 ethyl tail, in one step reaching the full 9-carbon nonanone skeleton.
Intermediate after the Wittig step: the ketone-protected C6=C7 alkene (9 carbons, ketal still on)
4. Dihydroxylate the new alkene. OsO₄, NMO installs the cis- (or via mCPBA/H₃O⁺, the trans-) vicinal diol exactly at C6/C7; the question does not specify which diastereomer brevicomin needs, so either dihydroxylation method is an acceptable answer here.
5. Deprotect. H₃O⁺ hydrolyses the acetal back to the ketone, revealing 6,7-dihydroxy-2-nonanone (which then cyclises to brevicomin under the same acidic conditions, part (a)).