IChO 2009 · Theory problem 4

Synthesis of Amprenavir

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One class of anti-HIV drugs, known as protease inhibitors, works by blocking the active site of one of the enzymes used in assembly of the viruses within the host cell. Two successful drugs, saquinavir and amprenavir, contain the structural unit shown below which mimics the transition state within the enzyme. In the structure, \(R^1\), \(R^2\) and \(R^3\) may represent any atom or group other than hydrogen.

Figure 1

Amprenavir may be synthesised as shown in the convergent scheme below.

Figure 2

The reagent \(\ce{R2B-H}\) used in the first step is chiral.

Product A is formed as the \((S)\)-enantiomer.

Three of the signals in the \({}^{1}\mathrm{H}\) NMR spectrum of Amprenavir disappear on shaking with \(\ce{D2O}\): \(\delta\) 4.2 (2H), \(\delta\) 4.9 (1H) and \(\delta\) 5.1 (1H).

4.1 Suggest structures for:

a) the intermediates A, B, C, W, X, Y and Z,

b) Amprenavir.

Your answers should clearly show the stereochemistry at each centre.

Official English text of the problem.

Answers

  • 4.1(a), A — \((3S)\)-Tetrahydrofuran-3-ol.
    O[C@@H]1COCC1

  • 4.1(a), B — \((3S)\)-Tetrahydrofuran-3-yl chloroformate.
    O=C(Cl)O[C@@H]1COCC1

  • 4.1(a), C — N-Succinimidyl \((3S)\)-tetrahydrofuran-3-yl carbonate, the activated carbonate of A.
    O=C(ON1C(=O)CCC1=O)O[C@@H]1COCC1

  • 4.1(a), W — tert-Butyl [(2S,3R)-3-hydroxy-4-[(2-methylpropyl)amino]-1-phenylbutan-2-yl]carbamate.
    CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCC(C)C

  • 4.1(a), X — tert-Butyl [(2S,3R)-3-hydroxy-4-[(2-methylpropyl)(4-nitrobenzenesulfonyl)amino]-1-phenylbutan-2-yl]carbamate.
    CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

  • 4.1(a), Y — N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-4-nitrobenzenesulfonamide, shown as the free base.
    N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

  • 4.1(a), Z — \((3S)\)-Tetrahydrofuran-3-yl [(2S,3R)-3-hydroxy-4-[(2-methylpropyl)(4-nitrobenzenesulfonyl)amino]-1-phenylbutan-2-yl]carbamate.
    O=C(O[C@@H]1COCC1)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

  • 4.1(b), Amprenavir — the 4-amino analogue of Z. Its tetrahydrofuran centre is \((3S)\), and its amino-alcohol chain has configuration \((2S,3R)\), numbering from the phenyl-bearing methylene.
    O=C(O[C@@H]1COCC1)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Solution

4.1(a): Identification of the intermediates

A: asymmetric hydroboration–oxidation.

The starting alkene is 2,3-dihydrofuran, C1COC=C1. Hydroboration places boron on the alkene carbon farther from the ring oxygen and hydrogen on the carbon adjacent to that oxygen. Oxidation replaces the carbon–boron bond by a carbon–oxygen bond with retention of configuration.

The product is therefore tetrahydrofuran-3-ol. The problem specifies formation of the \((S)\)-enantiomer, establishing A as \((3S)\)-tetrahydrofuran-3-ol.

B and C: formation of an activated carbonate.

The alcohol oxygen of A attacks phosgene, O=C(Cl)Cl, displacing chloride and giving chloroformate B:

\[ \ce{C4H8O2 + COCl2 -> C5H7ClO3 + HCl}. \]

Here hydrogen chloride has SMILES Cl. The stereogenic carbon is unaffected, so B retains the \((3S)\) configuration.

The next reagent is N-hydroxysuccinimide, ON1C(=O)CCC1=O. Its hydroxyl oxygen replaces the remaining chloride of B, giving activated carbonate C:

\[ \ce{C5H7ClO3 + C4H5NO3 -> C9H11NO6 + HCl}. \]

Thus C contains the linkage

\[ \ce{(tetrahydrofuran-3-yl)-O-C(=O)-O-N(succinimide)}. \]

Its molecular formula is exactly the supplied \(\ce{C9H11NO6}\). Again, reaction occurs at the carbonyl carbon, so the tetrahydrofuran stereocentre remains \((3S)\).

W: regioselective epoxide opening.

The starting epoxide is tert-butyl [(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethyl]carbamate:

CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1

The nucleophile is 2-methylpropan-1-amine (isobutylamine), CC(C)CN. Its nitrogen attacks the less hindered, terminal epoxide carbon. The carbon–oxygen bond at that carbon breaks; subsequent proton transfer gives the alcohol and secondary amine in W:

\[ \ce{C15H21NO3 + C4H11N -> C19H32N2O3}. \]

For the common four-carbon chain, number from the phenyl-bearing methylene: C2 bears the protected amino group, and C3 bears the newly formed hydroxyl group.

Neither existing stereocentre undergoes geometric inversion. Nevertheless, the substituted epoxide carbon changes its descriptor from \(S\) to \(R\), because its CIP priorities change:

At the substituted epoxide carbon After opening, at the alcohol carbon
\(1:\) oxygen \(1:\) hydroxyl oxygen
\(2:\) terminal epoxide carbon, whose next atoms are \(\ce{O,H,H}\) \(2:\) adjacent amino-bearing carbon, whose next atoms are \(\ce{N,C,H}\)
\(3:\) adjacent amino-bearing carbon, whose next atoms are \(\ce{N,C,H}\) \(3:\) terminal aminomethyl carbon, whose next atoms are \(\ce{N,H,H}\)
\(4:\) hydrogen \(4:\) hydrogen

The interchange of priorities 2 and 3 changes the descriptor without changing the geometry. Consequently, W has the required \((2S,3R)\) configuration.

X: sulfonamide formation.

The reagent is 4-nitrobenzenesulfonyl chloride:

O=S(=O)(Cl)c1ccc([N+](=O)[O-])cc1

The secondary aliphatic amine of W attacks sulfur and displaces chloride. This nitrogen is more nucleophilic than the carbamate nitrogen or alcohol oxygen. Its N–H hydrogen is replaced by the 4-nitrobenzenesulfonyl group, producing tertiary sulfonamide X:

\[ \ce{C19H32N2O3 + C6H4ClNO4S -> C25H35N3O7S + HCl}. \]

The hydroxyl group and both carbon configurations are retained.

Y: removal of the Boc protecting group.

Hydrogen chloride removes the tert-butoxycarbonyl (Boc) group, exposing the primary amine. The specified coproducts are carbon dioxide, O=C=O, and 2-chloro-2-methylpropane (tert-butyl chloride), CC(C)(C)Cl.

Writing Y as its neutral free base gives the balanced equation:

\[ \ce{C25H35N3O7S + HCl -> C20H27N3O5S + CO2 + (CH3)3CCl}. \]

With excess hydrogen chloride, the primary amino group is protonated. The corresponding Y hydrochloride is:

[NH3+][C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1.[Cl-]

The base in the following step makes the amine available for coupling. Neither stereocentre changes. The \((2R,3S)\) descriptors in Y’s sulfonamide name arise solely from numbering its side chain from the opposite end.

Z: coupling the two synthetic fragments.

The primary amine of Y attacks the carbonate carbonyl of C. Collapse of the tetrahedral intermediate expels the N-hydroxysuccinimide-derived leaving group, forming the carbamate Z:

\[ \ce{C20H27N3O5S + C9H11NO6 -> C25H33N3O8S + C4H5NO3}. \]

The amino group is acylated preferentially to the alcohol. The product therefore retains a free hydroxyl group and gains the linkage connecting the amino-alcohol chain to the \((3S)\)-tetrahydrofuran fragment.

All three stereocentres retain their configurations: \((2S,3R)\) in the amino-alcohol chain and \((3S)\) in the tetrahydrofuran ring.

4.1(b): Formation and identification of Amprenavir

Catalytic hydrogenation reduces the para-nitro group of Z to an amino group:

\[ \ce{C25H33N3O8S + 3H2 ->[Pd/C] C25H35N3O6S + 2H2O}. \]

Hydrogen has SMILES [H][H], and water has SMILES O. No stereogenic carbon is altered, giving the Amprenavir structure listed above.

The product contains exactly four exchangeable hydrogens:

  • The aromatic \(\ce{NH2}\) group accounts for the 2H signal at \(\delta 4.2\).
  • The alcohol \(\ce{OH}\) and carbamate \(\ce{NH}\) account for the two 1H signals at \(\delta 4.9\) and \(\delta 5.1\).
  • The sulfonamide nitrogen has no hydrogen.

The two one-proton signals need not be assigned individually to establish the structure; the stated exchange experiment identifies them collectively as OH and NH. Their disappearance on treatment with \(\ce{D2O}\) agrees with the proposed product.

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