IChO 2017 · Theory problem 10

Total Synthesis of Alkaloids

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Alkaloids are a class of nitrogen-containing natural products. Their tructural complexity and potent biological activities has drawn attentions. Two representative examples of alkaloids – sauristolactam and pancratistatin are highlighted in following questions.

Part A

Sauristolactam possesses excellent cytotoxicity against various cancer cell lines. It could be prepared by following synthetic sequence on the page. (\(\ce{^1H}\)-NMR spectra were recorded in \(\ce{CDCl3}\) at 300 MHz.)

10.1 Draw the structures of A-G in the sequence.

Part B

Pancratistatin, isolated from a Hawaiian native plant, spider lily, exhibits potent in vitro and in vivo inhibitory activity of cancer cell growth in addition to its excellent antiviral activity.

Figure 1

Pancratistatin

Pancratistatin could be successfully synthesized via intermediates X1 and X2. The synthesis of these intermediates are shown in the attached scheme.

10.2 Draw the structures of A and B.

10.3 Intermediate X1 (a single enantiomer with the stereochemistry shown) is labeled with deuterium with configuration as indicated below, propose the 3-D chair structure of compound E and the structure of compound F, with stereochemistry. Is Y a proton (\(\ce{^1H}\)) or a deuterium (\(\ce{^2H}\))?

Syntetic sequence:

Figure 2

Scheme of the synthesis of Pancratistatin and structures of compound A and B:

Figure 3
Figure 4

Intermediate X1

Official English text of the problem.

Answers

  • 10.1. The structures are:
Compound Name SMILES
A 5-(Benzyloxy)-4-methoxy-2-methylbenzaldehyde COc1cc(C)c(C=O)cc1OCc1ccccc1
B 5-(Benzyloxy)-4-methoxy-2-methylbenzoic acid COc1cc(C)c(C(=O)O)cc1OCc1ccccc1
C Methyl 5-(benzyloxy)-4-methoxy-2-methylbenzoate COc1cc(C)c(C(=O)OC)cc1OCc1ccccc1
D Methyl 5-acetoxy-4-methoxy-2-methylbenzoate COc1cc(C)c(C(=O)OC)cc1OC(C)=O
E Methyl 5-acetoxy-3-bromo-4-methoxy-2-methylbenzoate COc1c(Br)c(C)c(C(=O)OC)cc1OC(C)=O
F Methyl 5-acetoxy-3-bromo-2-(bromomethyl)-4-methoxybenzoate COc1c(Br)c(CBr)c(C(=O)OC)cc1OC(C)=O
G 4-Bromo-6-hydroxy-5-methoxy-2-methylisoindolin-1-one CN1Cc2c(Br)c(OC)c(O)cc2C1=O
  • 10.2. The two visible operations give the following products. Their assignment to A and B, respectively, is inferred: the labeled product boxes are outside the supplied crop.
Inferred label Name SMILES
A, product of the Wittig reaction 2-[2-(7-Methoxy-1,3-benzodioxol-5-yl)ethenyl]-3,4-dihydro-2H-pyran COc1cc(C=CC2CCC=CO2)cc2OCOc12
B, product after aqueous acid and PCC 6-[2-(7-Methoxy-1,3-benzodioxol-5-yl)ethenyl]oxan-2-one, a six-membered lactone COc1cc(C=CC2CCCC(=O)O2)cc2OCOc12

These SMILES specify connectivity. The cropped scheme does not establish an \(E/Z\) designation or an absolute configuration for these products.

  • 10.3. E, F, and the identity of Y cannot be determined uniquely from the problem as printed. The deuterium-labeled structure and the reaction sequence defining these compounds are absent. The visible X1 has cis aryl and carboxyl substituents and is explicitly shown as a racemate.

Solution

10.1. Identification of A–G

For A–F, number the aromatic ring so that the carbon bearing the aldehyde or carboxyl-derived group is C1. The original ring methyl group is then at C2, the methoxy group at C4, and the protected phenolic oxygen at C5.

Formation of A: protection and regioselective formylation

The starting material is 2-methoxy-4-methylphenol, COc1cc(C)ccc1O.

Benzyl bromide and potassium carbonate protect its phenolic hydroxyl group as a benzyl ether, giving 1-(benzyloxy)-2-methoxy-4-methylbenzene, COc1cc(C)ccc1OCc1ccccc1. A balanced representation is

\[ \ce{ArOH + PhCH2Br + K2CO3 -> ArOCH2Ph + KBr + KHCO3}. \]

The \(\ce{POCl3}\)/DMF treatment is a Vilsmeier–Haack formylation. Formylation occurs para to methoxy and ortho to methyl.

The NMR description fixes this position. In the starting phenol’s numbering, introduction of the formyl group at C5 leaves hydrogens at C3 and C6. These are para to one another and appear as two aromatic singlets. The benzyl protecting group supplies the monosubstituted phenyl ring.

A formal balanced equation including aqueous workup is

\[ \ce{Ar-H + HCON(CH3)2 + POCl3 + 3H2O -> Ar-CHO + HN(CH3)2 + H3PO4 + 3HCl}. \]

Thus A is 5-(benzyloxy)-4-methoxy-2-methylbenzaldehyde, with formula \(\ce{C16H16O3}\), as required.

A → B: aldehyde oxidation

Buffered sodium chlorite oxidizes the aldehyde to a carboxylic acid:

\[ \ce{ArCHO + ClO2^- + H+ -> ArCO2H + HOCl}. \]

The strong carbonyl absorption at \(1725\text{–}1700\ \mathrm{cm^{-1}}\), together with the broad \(3300\text{–}2500\ \mathrm{cm^{-1}}\) absorption, identifies a carboxylic acid.

Therefore B is 5-(benzyloxy)-4-methoxy-2-methylbenzoic acid.

B → C: esterification

Methanol and catalytic sulfuric acid give the methyl ester by Fischer esterification:

\[ \ce{ArCO2H + CH3OH <=> ArCO2CH3 + H2O}. \]

The reported \(1750\text{–}1735\ \mathrm{cm^{-1}}\) carbonyl absorption supports the ester assignment.

Thus C is methyl 5-(benzyloxy)-4-methoxy-2-methylbenzoate.

C → D: hydrogenolysis and acetylation

Hydrogen over palladium removes the benzyl protecting group:

\[ \ce{ArOCH2Ph + H2 -> ArOH + PhCH3}. \]

The resulting phenol is acetylated:

\[ \ce{ArOH + (CH3CO)2O -> ArOCOCH3 + CH3CO2H}. \]

Consequently, D is methyl 5-acetoxy-4-methoxy-2-methylbenzoate.

Its four three-proton singlets are consistent with:

Signals, \(\delta/\mathrm{ppm}\) Assignment
3.87 and 3.84 Aromatic methoxy and methyl ester
2.63 Ring methyl
2.31 Acetate methyl

The two methoxy resonances need not be individually distinguished to identify the structure.

D → E: aromatic bromination

Bromination replaces the hydrogen at C3:

\[ \ce{D + Br2 -> E + HBr}. \]

C3 is activated by the neighboring methoxy group. The remaining aromatic hydrogen is H6, adjacent to the ester, consistent with its relatively downfield singlet at \(\delta 7.59\ \mathrm{ppm}\).

Thus E is methyl 5-acetoxy-3-bromo-4-methoxy-2-methylbenzoate.

Its spectrum accounts for one aromatic hydrogen and four methyl groups, matching \(\ce{C12H13BrO5}\).

E → F: benzylic bromination

N-Bromosuccinimide under irradiation brominates the benzylic methyl group:

\[ \ce{ArCH3 + NBS ->[h\nu] ArCH2Br + succinimide}. \]

Here NBS is N-bromosuccinimide, O=C1CCC(=O)N1Br; succinimide is O=C1CCC(=O)N1.

The aryl bromine remains in place. Conversion of \(\ce{CH3}\) to \(\ce{CH2Br}\) explains:

  • disappearance of the benzylic three-proton signal;
  • appearance of a two-proton singlet at \(\delta 5.19\ \mathrm{ppm}\);
  • the formula \(\ce{C12H12Br2O5}\).

Therefore F is methyl 5-acetoxy-3-bromo-2-(bromomethyl)-4-methoxybenzoate.

F → G: substitution, lactam formation, and deprotection

Methylamine first displaces the benzylic bromide, producing a tethered secondary amine. That amine attacks the adjacent methyl ester intramolecularly, eliminating methanol and forming a five-membered lactam.

Excess methylamine also removes the phenolic acetate by aminolysis; aqueous workup furnishes the phenol.

A balanced net equation for this pathway is

\[ \ce{F + 3CH3NH2 -> G + CH3OH + CH3CONHCH3 + CH3NH3Br}. \]

The organic by-products are methanol, CO, and N-methylacetamide, CNC(C)=O; the salt is methylammonium bromide, C[NH3+].[Br-].

The product is 4-bromo-6-hydroxy-5-methoxy-2-methylisoindolin-1-one, G.

To draw it, fuse a five-membered lactam to the benzene ring. Its nonaromatic sequence is

\[ \text{aryl–}\ce{CH2-N(CH3)-C(=O)}\text{–aryl}. \]

The aryl carbon adjacent to the methylene-bearing fusion carbon carries bromine; the next two aromatic carbons carry methoxy and hydroxyl groups, respectively.

Every reported NMR feature is accounted for:

Observation Assignment in G
\(\delta 7.40\), singlet, 1 H Sole aromatic hydrogen
\(\delta 4.22\), singlet, 2 H Lactam-ring methylene
\(\delta 3.98\), singlet, 3 H Methoxy
\(\delta 3.19\), singlet, 3 H N-methyl
One exchangeable proton Phenolic OH

The total is ten hydrogens, consistent with \(\ce{C10H10BrNO3}\).

The final reaction provides a further connectivity check: Suzuki coupling replaces the aryl bromine with the ortho-formylphenyl group. Subsequent intramolecular condensation involving the lactam methylene closes the additional ring, giving sauristolactam, COc1c(O)cc2c3c(cc4ccccc4c13)N(C)C2=O.

10.2. Products of the visible Part B reactions

The aromatic starting material is 6-(bromomethyl)-4-methoxy-1,3-benzodioxole, COc1cc(CBr)cc2OCOc12.

For the following discussion, \(\mathrm{Ar}\) denotes 7-methoxy-1,3-benzodioxol-5-yl, represented as an attachment-point fragment by *c1cc(OC)c2OCOc2c1.

First visible operation: Wittig olefination

Triphenylphosphine converts the benzyl bromide into a phosphonium salt. Deprotonation with \(n\)-butyllithium gives the corresponding benzyl Wittig ylide.

Its charged-resonance representation is COc1cc([CH-][P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc2OCOc12.

The aldehyde partner is 3,4-dihydro-2H-pyran-2-carbaldehyde, O=CC1CCC=CO1.

The balanced olefination is

\[ \ce{ArCH=PPh3 + RCHO -> ArCH=CHR + OPPh3}, \]

where \(R\) is the 3,4-dihydro-2H-pyran-2-yl group. The by-product is triphenylphosphine oxide, O=P(c1ccccc1)(c1ccccc1)c1ccccc1.

The aldehyde carbon becomes one carbon of the new alkene; the original benzylic carbon becomes the other. The existing enol-ether double bond remains unchanged.

The resulting structure, provisionally assigned as A, is therefore

COc1cc(C=CC2CCC=CO2)cc2OCOc12.

Second visible operation: hydration followed by lactone formation

Aqueous acid hydrates the cyclic enol ether, giving a cyclic hemiacetal, or lactol:

6-[2-(7-methoxy-1,3-benzodioxol-5-yl)ethenyl]oxan-2-ol,
COc1cc(C=CC2CCCC(O)O2)cc2OCOc12.

The formula change is

\[ \ce{C15H16O4 + H2O -> C15H18O5}. \]

PCC oxidizes the hemiacetal carbon to an ester carbonyl, producing the six-membered lactone. The oxidation half-equation is

\[ \ce{C15H18O5 -> C15H16O5 + 2H+ + 2e^-}. \]

Thus the product, provisionally assigned as B, is

6-[2-(7-methoxy-1,3-benzodioxol-5-yl)ethenyl]oxan-2-one,
COc1cc(C=CC2CCCC(=O)O2)cc2OCOc12.

For the drawing, use a six-membered ring with the sequence

\[ \ce{O-C(=O)-CH2-CH2-CH2-CH(-CH=CHAr)}, \]

closed back to the ring oxygen. The aryl–alkene unit remains intact.

10.3. What the visible X1 establishes

The structure of X1 shown in the statement is (±)-cis-2-(7-methoxy-1,3-benzodioxol-5-yl)cyclohex-3-ene-1-carboxylic acid.

Its two enantiomers can be represented by:

  • O=C(O)[C@H]1[C@@H](c2cc(OC)c3OCOc3c2)C=CCC1
  • O=C(O)[C@@H]1[C@H](c2cc(OC)c3OCOc3c2)C=CCC1

Both the aryl and carboxyl bonds are drawn as solid wedges, establishing their cis relationship. The \((\pm)\) label specifies the racemate.

However, question 10.3 refers to a separate drawing containing:

  1. a specified single enantiomer of X1;
  2. a deuterium atom at a specified position and configuration;
  3. the transformations defining E, F, and Y.

None of those details appears in the supplied fragments. Consequently, a unique chair conformation for E, stereochemical structure for F, or assignment of Y as \(\ce{^1H}\) or \(\ce{^2H}\) does not follow from the available information.

The answers were checked against the official answers published by the organisers. Where this solution differs from the official solution, the official solution contains an error or a misprint.