IChO 2022 · Theory problem 9

Total Synthesis of Capitulactone

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The plant of Curculigo capitulata grows in the Southern China and has long been used in traditional Chinese herbal medicine for the treatment of many diseases. Capitulactone (1) was isolated from the roots of Curculigo capitulata. Its structure with absolute configuration was unambiguously established by a combination of spectroscopic data and total synthesis.

Figure 1

Curculigo capitulata

Figure 2

Capitulactone (1)

The total synthesis of 1 began with the iodination of commercially available 4-bromoveratrole 2 through a key intermediate 12 as shown in the following scheme.

Figure 3

Note:

cat = catalyst

eq = equivalent

9.1 Draw the structures of compounds 3-5, 8, 9 and 11 and show the stereochemistry of any stereocenters.

(R)-Epichlorohydrin (7) was prepared from (+)-mannitol (13) through a route as shown below.

Figure 4

Note:

eq = equivalent

conc = concentrated

9.2 From the following conditions, choose the best for A.

(a) Pyridine

(b) 5% \(\ce{KOH/H2O}\)

(c) 1% \(\ce{HCl/H2O}\)

(d) Anhydrous \(\ce{ZnCl2}\)

9.3 Draw the structures of intermediate products 15, 16, 18 and 19 and show the stereochemistry of any stereocenters.

The diketal 14 can also be prepared by treating (+)-mannitol (13) with 2-methoxypropene (23) in the presence of catalytic amount of tolunesulfonic acid (TsOH) in anhydrous toluene. The model reaction is shown below.

Figure 5
Figure 6

9.4 The proposed mechanism for this reaction involves key intermediates (I-V) as shown above, choose the correct order of the formation of the key intermediates during the reaction process.

(a) I, II, III, IV, V

(b) III, II, I, V, IV

(c) III, I, II, IV, V

(d) III, I, II, V, IV

Official English text of the problem.

Answers

  • 9.1. The structures are:
Compound Name and absolute configuration SMILES
3 4-Bromo-5-iodo-1,2-dimethoxybenzene COc1cc(I)c(Br)cc1OC
4 4-Bromo-5-iodobenzene-1,2-diol Oc1cc(I)c(Br)cc1O
5 1-Bromo-2-iodo-4,5-bis[(tert-butyldimethylsilyl)oxy]benzene CC(C)(C)[Si](C)(C)Oc1cc(I)c(Br)cc1O[Si](C)(C)C(C)(C)C
8 (2R)-1-Chloro-3-{2-bromo-4,5-bis[(tert-butyldimethylsilyl)oxy]phenyl}propan-2-ol CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H](O)CCl)c(Br)cc1O[Si](C)(C)C(C)(C)C
9 (2R)-2-[(2-Bromo-4,5-bis[(tert-butyldimethylsilyl)oxy]phenyl)methyl]oxirane CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H]2CO2)c(Br)cc1O[Si](C)(C)C(C)(C)C
11 (2S)-1-{2-Bromo-4,5-bis[(tert-butyldimethylsilyl)oxy]phenyl}-5-(4-methoxyphenyl)pent-4-yn-2-ol CC(C)(C)[Si](C)(C)Oc1cc(C[C@@H](O)CC#Cc2ccc(OC)cc2)c(Br)cc1O[Si](C)(C)C(C)(C)C

Compounds 3–5 have no stereocenters. Compounds 8, 9, and 11 each have one.

  • 9.2. (d) Anhydrous zinc chloride, \(\ce{ZnCl2}\), [Zn+2].[Cl-].[Cl-].

  • 9.3. The structures are:

Compound Name and absolute configuration SMILES
15 (4R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde CC1(C)OC[C@H](C=O)O1
16 [(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol, also called (S)-solketal CC1(C)OC[C@H](CO)O1
18 (2R)-2,3-Dihydroxypropyl 4-methylbenzenesulfonate OC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
19 [(2R)-Oxiran-2-yl]methanol, also called (R)-glycidol OC[C@@H]1CO1
  • 9.4. (b): III → II → I → V → IV.

Solution

9.1 — Identification of compounds 3–5, 8, 9, and 11

For the explanations below, let:

  • \(\mathrm{Ar}\) denote the 2-bromo-4,5-bis[(tert-butyldimethylsilyl)oxy]phenyl group.
  • \(\mathrm{An}\) denote the 4-methoxyphenyl group.

The complete molecular structures, including all protecting groups, are specified by the SMILES in the Answers section.

Formation of 3: electrophilic aromatic iodination.

The starting material, 4-bromoveratrole (2), is 4-bromo-1,2-dimethoxybenzene, COc1ccc(Br)cc1OC.

The methoxy groups activate the ring toward electrophilic aromatic substitution. N-Iodosuccinimide supplies electrophilic iodine. Iodination occurs at the position adjacent to bromine and para to one methoxy group. This position is also fixed unambiguously by the carbon bearing lithium in the supplied structure of 6.

Thus 3 is 4-bromo-5-iodo-1,2-dimethoxybenzene.

N-Iodosuccinimide, O=C1CCC(=O)N1I, becomes succinimide, O=C1CCC(=O)N1. The balanced net equation is

\[ \ce{C8H9BrO2 + C4H4INO2 -> C8H8BrIO2 + C4H5NO2}. \]

Formation of 4: cleavage of both methyl ethers.

Boron tribromide coordinates to the ether oxygens and promotes cleavage of the oxygen–methyl bonds. Hydrolytic work-up gives the two phenolic groups. The aryl–oxygen bonds and both aryl–halogen bonds remain intact.

Therefore 4 is 4-bromo-5-iodobenzene-1,2-diol.

One balanced representation including hydrolytic work-up is

\[ \ce{C8H8BrIO2 + 2 BBr3 + 6 H2O -> C6H4BrIO2 + 2 CH3Br + 2 B(OH)3 + 4 HBr}. \]

Formation of 5: protection of both phenolic groups.

The two equivalents of tert-butyldimethylsilyl chloride convert both phenolic groups into TBS ethers. DMAP assists silylation and accepts the released protons.

Consequently, 5 has the same substituted aromatic ring as 4, with each \(\ce{OH}\) replaced by \(\ce{O-Si(CH3)2-C(CH3)3}\).

Using the molecular formulas of TBSCl and DMAP, the balanced net equation is

\[ \ce{C6H4BrIO2 + 2 C6H15ClSi + 2 C7H10N2 -> C18H32BrIO2Si2 + 2 C7H11N2+ + 2 Cl-}. \]

Formation of 8: opening of (R)-epichlorohydrin.

Iodine–lithium exchange converts 5 into the drawn aryllithium 6, while retaining the aryl bromide.

The electrophile 7 is (R)-epichlorohydrin, or (2R)-2-(chloromethyl)oxirane, ClC[C@H]1CO1.

The aryl nucleophile attacks the less substituted epoxide carbon, the terminal ring \(\ce{CH2}\). The carbon–oxygen bond at the stereogenic carbon is not broken. Protonation of the resulting alkoxide gives

\[ \mathrm{Ar{-}CH_2{-}CH(OH){-}CH_2Cl}. \]

This is 8, with R configuration. Its priorities at the stereocenter are

\[ \ce{OH}>\ce{CH2Cl}>\ce{CH2Ar}>\ce{H}. \]

A balanced net equation combining lithium–iodine exchange, epoxide opening, and aqueous work-up is

\[ \ce{C18H32BrIO2Si2 + C4H9Li + C3H5ClO + H2O -> C21H38BrClO3Si2 + C4H9I + LiOH}. \]

The product formula matches the supplied \(\ce{C21H38BrClO3Si2}\).

Formation of 9: intramolecular epoxide formation.

Hydroxide converts the alcohol into an alkoxide. The alkoxide attacks the neighboring primary carbon bearing chlorine by an intramolecular \(S_\mathrm{N}2\) reaction.

The new epoxide therefore contains the original alcohol-bearing carbon and the carbon that previously belonged to \(\ce{CH2Cl}\). Its substituent is \(\mathrm{Ar{-}CH_2{-}}\).

The attacked carbon is not the stereocenter, so the existing spatial arrangement is retained. The configuration of 9 is R:

\[ \text{epoxide O}>\text{epoxide }\ce{CH2}> \ce{CH2Ar}>\ce{H}. \]

The balanced equation is

\[ \ce{C21H38BrClO3Si2 + NaOH -> C21H37BrO3Si2 + NaCl + H2O}. \]

Thus the formula changes by loss of \(\ce{HCl}\), exactly as shown in the problem.

Formation of 11: acetylide opening of epoxide 9.

Compound 10 is 1-ethynyl-4-methoxybenzene, COc1ccc(C#C)cc1.

Its terminal alkyne is deprotonated by \(n\)-butyllithium. The resulting acetylide attacks the less substituted carbon of epoxide 9, giving, after protonation,

\[ \mathrm{Ar{-}CH_2{-}CH(OH){-}CH_2{-}C{\equiv}C{-}An}. \]

This identifies 11.

Again, the carbon–oxygen bond at the existing stereocenter is retained. Nevertheless, its descriptor becomes S, because the priorities now are

\[ \ce{OH}> \mathrm{CH_2Ar}> \mathrm{CH_2C{\equiv}CAn}> \ce{H}. \]

The two carbon chains initially tie in the CIP comparison; the path through the ortho-brominated aromatic ring eventually reaches bromine and takes priority over the alkynyl chain.

The balanced net equation, including deprotonation and aqueous work-up, is

\[ \ce{C21H37BrO3Si2 + C9H8O + C4H9Li + H2O -> C30H45BrO4Si2 + C4H10 + LiOH}. \]

This gives the stated formula \(\ce{C30H45BrO4Si2}\).

As a structural check, the alcohol of 11 can undergo the supplied NaH/CuCl-mediated intramolecular aryl ether formation at the adjacent aryl bromide. This produces the five-membered ring of 12:

(2S)-5,6-bis[(tert-butyldimethylsilyl)oxy]-2-[3-(4-methoxyphenyl)prop-2-yn-1-yl]-2,3-dihydrobenzofuran,
CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)O[C@@H](CC#Cc1ccc(OC)cc1)C2.

The net cyclization is

\[ \ce{C30H45BrO4Si2 + NaH ->[CuCl] C30H44O4Si2 + NaBr + H2}. \]

9.2 — Selection of condition A

The starting material 13 is D-(+)-mannitol,
OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.

Reaction with acetone, CC(=O)C, protects the terminal 1,2- and 5,6-diol pairs as cyclic ketals. The product 14 is 1,2:5,6-di-O-isopropylidene-D-mannitol,
CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1.

The balanced equilibrium is

\[ \ce{C6H14O6 + 2 C3H6O <=>[ZnCl2] C12H22O6 + 2 H2O}. \]

Anhydrous \(\ce{ZnCl2}\), option (d), is the best condition. It acts as a Lewis acid to activate acetone, and anhydrous conditions favor ketal formation.

Pyridine and aqueous KOH do not provide the required acid activation. Aqueous HCl supplies acid, but the large amount of water opposes ketal formation and favors ketal hydrolysis.

9.3 — Identification of 15, 16, 18, and 19

Formation of 15: periodate cleavage of the central diol.

In 14, the two terminal diols are protected, leaving only the hydroxyl groups at the original mannitol carbons 3 and 4 available for periodate oxidation.

Periodate forms a cyclic intermediate with this vicinal diol and cleaves the bond between those two carbons. Each becomes an aldehyde carbon. The two halves are identical and give two molecules of (R)-glyceraldehyde acetonide, 15.

The balanced equation is

\[ \ce{C12H22O6 + NaIO4 -> 2 C6H10O3 + NaIO3 + H2O}. \]

To draw 15, retain the acetonide ring and stereochemical arrangement shown in 17, but replace its \(\ce{CH2OTs}\) substituent by \(\ce{CHO}\). The ring stereocenter is R.

Formation of 16: aldehyde reduction.

Sodium borohydride reduces the aldehyde group of 15 to a primary alcohol. It does not alter the existing stereocenter or the acetonide.

Thus 16 is (S)-solketal. To draw it, replace the \(\ce{CH2OTs}\) group of 17 by \(\ce{CH2OH}\), keeping the depicted geometry.

A balanced formal reduction equation including aqueous work-up is

\[ \ce{4 C6H10O3 + NaBH4 + 4 H2O -> 4 C6H12O3 + Na[B(OH)4]}. \]

The change from R in 15 to S in 16 is a priority change, not an inversion:

Compound CIP priority order at the existing stereocenter
15 Ring O \(>\) \(\ce{CHO}\) \(>\) ring \(\ce{CH2O}\) \(>\) H
16 Ring O \(>\) ring \(\ce{CH2O}\) \(>\) \(\ce{CH2OH}\) \(>\) H

In 15, the aldehyde carbon is compared as \((\mathrm{O,O,H})\), which outranks the ring methylene carbon’s \((\mathrm{O,H,H})\). After reduction, the two methylene branches initially tie, but the ring oxygen is attached to carbon whereas the hydroxyl oxygen is attached to hydrogen.

Formation of 18: tosylation followed by acetonide hydrolysis.

Tosylation of the only free alcohol in 16 gives the supplied 17, [(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate,
CC1(C)OC[C@H](COS(=O)(=O)c2ccc(C)cc2)O1.

Acidic hydrolysis removes the acetonide, regenerating the primary and secondary hydroxyl groups while retaining the terminal tosylate. Hence 18 has the connectivity

\[ \ce{HOCH2-CH(OH)-CH2OTs} \]

and R configuration.

The balanced hydrolysis is

\[ \ce{C13H18O5S + H2O ->[H+] C10H14O5S + C3H6O}. \]

Its formula is therefore \(\ce{C10H14O5S}\), as required.

Formation of 19: intramolecular displacement of tosylate.

Methoxide deprotonates the secondary alcohol of 18. The resulting alkoxide attacks the adjacent primary \(\ce{CH2OTs}\) carbon, expelling tosylate and forming an epoxide.

The product is (R)-glycidol, 19: an epoxide bearing a hydroxymethyl substituent. The substitution occurs at a primary carbon, so the existing stereocenter retains its spatial arrangement.

The balanced net equation is

\[ \ce{C10H14O5S + CH3ONa -> C3H6O2 + C7H7NaO3S + CH3OH}. \]

To draw 19, use the epoxide geometry shown for 20, replacing \(\ce{MsO}\) by \(\ce{HO}\). This gives the required formula \(\ce{C3H6O2}\).

The subsequent supplied transformations provide a consistency check:

  • 20, [(2S)-oxiran-2-yl]methyl methanesulfonate, CS(=O)(=O)OC[C@@H]1CO1, results from mesylating the primary alcohol.
  • Terminal epoxide opening gives 21, (2R)-3-chloro-2-hydroxypropyl methanesulfonate, CS(=O)(=O)OC[C@@H](O)CCl.
  • Intramolecular displacement of mesylate then gives the supplied (R)-epichlorohydrin, 7.

These steps preserve the stereogenic carbon’s geometry; changes in descriptors arise from changes in substituent priorities.

9.4 — Ordering the ketalization intermediates

The reactants are ethylene glycol (22), OCCO, and 2-methoxyprop-1-ene (23), C=C(C)OC.

The correct sequence is III → II → I → V → IV, for the following reasons.

  1. III: methoxy-stabilized isopropyl oxocarbenium ion, C[O+]=C(C)C.

The alkene is protonated at its terminal carbon, converting that carbon into a methyl group. Donation from the methoxy oxygen stabilizes the resulting cation. The drawing represents its oxygen-positive, carbon–oxygen double-bond resonance contributor.

  1. II: the mixed ketal protonated on the incoming ethylene-glycol oxygen, COC(C)(C)[OH+]CCO.

One hydroxyl oxygen of ethylene glycol attacks the electrophilic carbon of III. The carbon–oxygen \(\pi\) electrons move onto the methoxy oxygen. The attacking oxygen now has three bonds and bears the positive charge.

  1. I: the mixed ketal protonated on the methoxy oxygen, C[OH+]C(C)(C)OCCO.

Proton transfer, which may be mediated by other molecules in the reaction mixture, moves the proton from the incoming glycol oxygen to the methoxy oxygen. This converts the methoxy group into a suitable neutral leaving group upon bond cleavage.

  1. V: 2-hydroxyethoxy-stabilized isopropyl oxocarbenium ion, CC(C)=[O+]CCO.

Methanol, CO, leaves. Donation from the remaining ether oxygen produces the oxocarbenium resonance form shown as V.

  1. IV: O-protonated 2,2-dimethyl-1,3-dioxolane, CC1(C)OCC[OH+]1.

The remaining hydroxyl group attacks the electrophilic carbon intramolecularly. This closes the five-membered ring, while the carbon–oxygen \(\pi\) electrons move onto the other oxygen.

Finally, deprotonation of IV regenerates the acid catalyst and gives 2,2-dimethyl-1,3-dioxolane (24), CC1(C)OCCO1.

The balanced overall reaction is

\[ \ce{C2H6O2 + C4H8O ->[H+] C5H10O2 + CH3OH}. \]

The SMILES for III and V encode the resonance contributors drawn in the question; the actual positive charge is delocalized over the oxygen–carbon unit.

The answers were checked against the official answers published by the organisers.