IChO 2011 · Theory problem 7

Synthesis of a carbasugar

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Carbohydrates are essential components of living cells and a source of energy for animals. They include simple sugars with small molecules as well as macromolecular substances. When the ring oxygen (endocyclic oxygen) in sugars is replaced by a methylene group, the compounds formed are called as pseudosugars or carbasugars. Since carbasugars are hydrolytically stable towards acids and enzymes, several carbasugars have found application in the field of glycosidase inhibition.

The total syntheses of two isomeric carbasugars having skeleton 1 are described below.

Figure 1

The total synthesis of 1 starts with a reduction of benzene by sodium in liquid ammonia to give A. The C-13 NMR spectrum of A consists of two signals at 124.0 and 26.0 ppm.

Trichloroacetyl chloride in the presence of Zn gives a reactive species S (see the Scheme 7.1). One equivalent of S undergoes [2+2]cycloaddition with A to form a racemic product B. The reaction of B with Zn in acetic acid gives C. Compound C contains only carbon, hydrogen and oxygen. The C-13 NMR spectrum of C exhibits three \(\mathrm{sp^2}\) carbon signals at 210.0, 126.5 and 125.3 ppm.

The reaction of C with one equivalent \(m\)-chloroperbenzoic acid (\(m\)-CPBA) in methylene chloride gives D as a major product. The C-13 NMR spectrum of D exhibits also three signals in the \(\mathrm{sp^2}\) region at 177.0, 125.8, 124.0 ppm.

Figure 2

\({}^{13}\mathrm{C}\)-NMR chemical shift ranges of typical functional groups

Figure 3

Scheme 7.1:

7.1 Draw the structures of A, B, C, D, and the intermediate S.

Reduction of D with \(\ce{LiAlH4}\) yields E which reacts with an excess of acetyl chloride in pyridine to give F (Scheme 7.2).

Figure 4

Scheme 7.2:

7.2 Draw the structures (use one enantiomer) of E and F using dashed-wedged line notation. Assign the configurations (\(R\) or \(S\)) at the asymmetric carbon atoms in E.

The compound F (use the drawn enantiomer) reacts with bromine to give the stereoisomers G₁ and G₂.

7.3 Draw the structures of G₁and G₂ using dashed-wedged line notation.

A mixture of G₁ and G₂ reacts with two equivalents of 1,8-diazabicyclo- [5.4.0]undec-7-ene (DBU), which is a strong amine base, to afford H.

7.4 Draw the structure of H using dashed-wedged line notation.

Reaction of H with singlet oxygen (in situ generated) affords I. Although two isomers are theoretically possible, I is formed as the single isomer due to steric hindrance and electronic repulsion.

The reaction of I with excess of \(\ce{LiAlH4}\) results in the formation of J (see the Scheme 7.3). The C-13 NMR spectrum of J shows 8 signals, two in the \(\mathrm{sp^2}\) region.

Reaction of J with excess acetyl chloride in the presence of pyridine yields K. Subsequent reaction of K with \(\ce{OsO4}\) in the presence of 4-methylmorpholine 4-oxide (NMO) gives stereoisomers L and M. Upon reduction with excess \(\ce{LiAlH4}\), L and M give the stereoisomers 1a and 1b, respectively.

Figure 5

Scheme 7.3:

7.5 Draw the structures of I, J, K, L, M, 1a, and 1b using dashed-wedged line notation.

Official English text of the problem.

Answers

Drawing convention. Use a flat hexagon numbered clockwise: \(C_1\) at the lower right, \(C_2\) at the bottom, \(C_3\) at the lower left, \(C_4\) at the upper left, \(C_5\) at the top, and \(C_6\) at the upper right. These fixed labels track atoms throughout the synthesis; they are independent of systematic-name locants.

A + denotes a solid wedge toward the reader; a − denotes a dashed wedge away. Write \(\mathrm{OAc}\) for \(\ce{-O-C(=O)-CH3}\). From E onward, the bond from \(C_1\) to the hydroxyethyl or acetoxyethyl side chain is always +.

The SMILES for B–D show one member of each racemic pair. All subsequent structures follow that chosen enantiomer. The labels G₁/G₂, and L/M together with 1a/1b, may be interchanged consistently.

  • 7.1

A — cyclohexa-1,4-diene: C1=CCC=CC1

S — dichloroketene: O=C=C(Cl)Cl

B — racemic cis-8,8-dichlorobicyclo[4.2.0]oct-3-en-7-one:
O=C1C(Cl)(Cl)[C@H]2[C@@H]1CC=CC2

C — racemic cis-bicyclo[4.2.0]oct-3-en-7-one:
O=C1C[C@H]2[C@@H]1CC=CC2

D — racemic cis-7-oxabicyclo[4.3.0]non-3-en-8-one:
O=C1C[C@H]2[C@@H](O1)CC=CC2

In B and C, a cyclobutanone is cis-fused to the cyclohexene. In D, oxygen is inserted between the carbonyl carbon and the adjacent bridgehead, giving a cis-fused five-membered lactone.

  • 7.2

E — (1S,6S)-6-(2-hydroxyethyl)cyclohex-3-en-1-ol:
OCC[C@H]1[C@@H](O)CC=CC1

F — 2-[(1S,6S)-6-acetoxycyclohex-3-en-1-yl]ethyl acetate:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)CC=CC1

Both have \(C_4=C_5\). In E, the \(C_1\)-hydroxyethyl group and \(C_2\)-OH are +, hence cis. Both asymmetric carbons are \(S\). In F, replace both alcohol hydrogens by acetyl groups without changing either configuration.

  • 7.3

Both products are stereoisomers of 2-(2-acetoxy-4,5-dibromocyclohexyl)ethyl acetate.

G₁:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)C[C@@H](Br)[C@H](Br)C1
Draw \(C_4\)-Br + and \(C_5\)-Br −.

G₂:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)C[C@H](Br)[C@@H](Br)C1
Draw \(C_4\)-Br − and \(C_5\)-Br +.

The original \(C_1\) side chain and \(C_2\)-OAc remain + in both products.

  • 7.4

H — 2-(6-acetoxycyclohexa-2,4-dien-1-yl)ethyl acetate:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)C=CC=C1

Draw the conjugated diene \(C_3=C_4-C_5=C_6\), retaining + bonds to the \(C_1\) side chain and \(C_2\)-OAc.

  • 7.5

I — 2-(8-acetoxy-2,3-dioxabicyclo[2.2.2]oct-5-en-7-yl)ethyl acetate, the endoperoxide:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)[C@H]2C=C[C@@H]1OO2

Draw an \(\ce{-O-O-}\) bridge between \(C_3\) and \(C_6\), with both carbon–oxygen bonds −. The remaining double bond is \(C_4=C_5\).

J — 3-(2-hydroxyethyl)cyclohex-5-ene-1,2,4-triol:
OCC[C@H]1[C@@H](O)[C@H](O)C=C[C@@H]1O

Draw \(C_2\)-OH +, \(C_3\)-OH −, and \(C_6\)-OH −, with \(C_4=C_5\).

K — 2-(2,5,6-triacetoxycyclohex-3-en-1-yl)ethyl acetate:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C=C[C@@H]1OC(C)=O

This is the tetraacetate of J, retaining every configuration.

L — 2-(2,3,6-triacetoxy-4,5-dihydroxycyclohexyl)ethyl acetate, diastereomer L:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O

M — 2-(2,3,6-triacetoxy-4,5-dihydroxycyclohexyl)ethyl acetate, diastereomer M:
CC(=O)OCC[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](O)[C@H](O)[C@@H]1OC(C)=O

1a — 6-(2-hydroxyethyl)cyclohexane-1,2,3,4,5-pentol, stereoisomer 1a:
OCC[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O

1b — 6-(2-hydroxyethyl)cyclohexane-1,2,3,4,5-pentol, stereoisomer 1b:
OCC[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]1O

Their precise wedge–dash drawings are:

Compound \(C_2\) substituent \(C_3\) substituent \(C_4\) substituent \(C_5\) substituent \(C_6\) substituent
L OAc + OAc − OH + OH + OAc −
M OAc + OAc − OH − OH − OAc −
1a OH + OH − OH + OH + OH −
1b OH + OH − OH − OH − OH −

Solution

For reductions, the equations below use formal reducing-hydrogen equivalents: \(\ce{2[H]}\) represents \(\ce{2H+ + 2e-}\) in a balanced organic reduction half-equation. The stated reductant and work-up supply these equivalents.

7.1 — Identification of A, S, B, C, and D

Benzene, c1ccccc1, undergoes reduction to the nonconjugated diene A:

\[ \ce{C6H6 + 2[H] -> C6H8}. \]

Cyclohexa-1,4-diene has four equivalent alkene carbons and two equivalent methylene carbons. It therefore gives precisely the two observed carbon environments:

\[ \delta_{\text{alkene}}=124.0\ \mathrm{ppm}, \qquad \delta_{\text{methylene}}=26.0\ \mathrm{ppm}. \]

Trichloroacetyl chloride, O=C(Cl)C(Cl)(Cl)Cl, undergoes zinc-mediated dechlorination to dichloroketene S:

\[ \ce{Cl3CCOCl + Zn -> Cl2C=C=O + ZnCl2}. \]

The ketene’s central carbon is approximately linear. Its carbon–carbon double bond undergoes [2+2] cycloaddition with one double bond of A, producing the four-membered ketone ring of B:

\[ \underbrace{\ce{C6H8}}_{\mathbf A} + \underbrace{\ce{C2Cl2O}}_{\mathbf S} \longrightarrow \underbrace{\ce{C8H8Cl2O}}_{\mathbf B}. \]

The alkene’s relative configuration is retained, giving a cis-fused product. Attack on either face of the achiral diene produces the two enantiomers in equal amounts.

Zinc in acetic acid, CC(=O)O, replaces both chlorines by hydrogen:

\[ \ce{C8H8Cl2O + 2Zn + 2CH3COOH -> C8H10O + ZnCl2 + Zn(CH3COO)2}. \]

Thus C is the corresponding chlorine-free bicyclic cyclobutanone. Its three \(\mathrm{sp^2}\) signals are assigned as follows:

Chemical shift Assignment
\(210.0\ \mathrm{ppm}\) Ketone carbonyl carbon
\(126.5,\ 125.3\ \mathrm{ppm}\) The two inequivalent alkene carbons

The next reagent is 3-chloroperoxybenzoic acid, O=C(OO)c1cccc(Cl)c1. The shift from a ketone carbonyl at \(210.0\ \mathrm{ppm}\) to an ester carbonyl at \(177.0\ \mathrm{ppm}\), together with retention of two alkene signals, identifies a Baeyer–Villiger oxidation.

The more substituted bridgehead carbon migrates preferentially over the methylene carbon. Oxygen is therefore inserted between the bridgehead and the carbonyl carbon, expanding the cyclobutanone to the five-membered lactone D. Migration retains configuration.

The balanced oxidation is

\[ \ce{C8H10O + C7H5ClO3 -> C8H10O2 + C7H5ClO2}, \]

where the acid by-product is 3-chlorobenzoic acid, O=C(O)c1cccc(Cl)c1.

An alkene epoxidation would remove the two alkene-carbon signals and retain the ketone carbonyl; that does not match the observed spectrum.

7.2 — Reduction, acetylation, and configurations of E

Lithium aluminium hydride, [Li+].[AlH4-], reduces the lactone carbonyl and opens the lactone:

\[ \underbrace{\ce{C8H10O2}}_{\mathbf D} +\ce{4[H]} \longrightarrow \underbrace{\ce{C8H14O2}}_{\mathbf E}. \]

The acyl–oxygen bond is broken. The oxygen already attached to \(C_2\) becomes its hydroxyl group, while the former carbonyl carbon becomes the terminal carbon of the \(\ce{-CH2CH2OH}\) side chain at \(C_1\). Consequently, the two substituents remain cis.

For the chosen drawing, both substituent bonds are solid wedges and both stereocentre hydrogens point away. The CIP priorities are:

Centre Priority 1 Priority 2 Priority 3 Priority 4
\(C_1\) Ring path through \(C_2\) Hydroxyethyl side chain Ring path through \(C_6\) H
\(C_2\) OH Ring path through \(C_1\) Ring path through \(C_3\) H

At \(C_1\), the side chain outranks the path through \(C_6\) because its terminal carbon encounters oxygen before the competing ring path does. In the specified projection, \(1\rightarrow2\rightarrow3\) is counterclockwise at both centres with H away. Therefore,

\[ \boxed{C_1=S,\qquad C_2=S.} \]

These centres are positions 6 and 1, respectively, in the systematic name of E. The mirror-image choice would give \(R,R\).

Acetyl chloride, CC(=O)Cl, acetylates both alcohols. Pyridine, n1ccccc1, captures the hydrogen chloride as pyridinium chloride, [Cl-].[nH+]1ccccc1:

\[ \ce{C8H14O2 + 2CH3COCl + 2C5H5N -> C12H18O4 + 2C5H6NCl}. \]

Acetylation changes the oxygen substituents without breaking either stereogenic carbon–oxygen bond, giving F with unchanged configurations.

7.3 — Bromination to G₁ and G₂

Bromine, BrBr, adds across \(C_4=C_5\):

\[ \underbrace{\ce{C12H18O4}}_{\mathbf F} +\ce{Br2} \longrightarrow \underbrace{\ce{C12H18Br2O4}}_{\mathbf{G_1}\text{ or }\mathbf{G_2}}. \]

The alkene forms a bridged bromonium intermediate. Bromide opens it from the opposite face, so addition is anti and the two bromines are trans.

The two faces of the alkene are diastereotopic because F already contains stereocentres. Addition from the alternative faces therefore gives the two diastereomers listed in the Answers:

\[ \mathbf{G_1}:\ (C_4\text{-Br},C_5\text{-Br})=(+,-), \] \[ \mathbf{G_2}:\ (C_4\text{-Br},C_5\text{-Br})=(-,+). \]

7.4 — Double elimination to H

DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene, has SMILES C1CCC2=NCCCN2CC1.

In a reactive chair conformation of either dibromide, the vicinal trans bromines can occupy axial positions. Each then has an antiperiplanar axial hydrogen on an adjacent methylene carbon. Two E2 eliminations remove:

  • the bromine at \(C_4\) and a hydrogen at \(C_3\);
  • the bromine at \(C_5\) and a hydrogen at \(C_6\).

This gives the conjugated diene

\[ \boxed{C_3=C_4-C_5=C_6}. \]

Both dibromides converge to H, since the stereocentres created during bromination become trigonal alkene carbons.

The balanced reaction is

\[ \ce{C12H18Br2O4 + 2C9H16N2 -> C12H16O4 + 2C9H17BrN2}. \]

The salt is DBU hydrobromide, [Br-].C1CCC2=[NH+]CCCN2CC1. The original configurations at \(C_1\) and \(C_2\) are retained.

7.5 — Endoperoxide formation and completion of the carbasugars

Formation of I. Singlet dioxygen has connectivity SMILES O=O; its \({}^{1}\Delta_g\) electronic state must be specified separately because ordinary SMILES does not encode that state.

It undergoes [4+2] cycloaddition with the conjugated diene:

\[ \underbrace{\ce{C12H16O4}}_{\mathbf H} +\ce{O2} \longrightarrow \underbrace{\ce{C12H16O6}}_{\mathbf I}. \]

The two new carbon–oxygen bonds form at \(C_3\) and \(C_6\), and the remaining double bond is \(C_4=C_5\). The cis \(C_1\) and \(C_2\) substituents occupy the + face. Approach from the opposite face minimizes the stated steric and electronic repulsions. Thus the peroxide bridge has both carbon–oxygen bonds −.

Formation of J. Excess lithium aluminium hydride reduces the peroxide bond and both acetate groups. The carbon–oxygen bonds at \(C_3\) and \(C_6\) remain intact, so both resulting hydroxyl groups retain the − configuration.

Reduction of each acetate requires four formal hydrogen equivalents and releases ethanol, CCO. Peroxide cleavage requires two more:

\[ \ce{C12H16O6 + 10[H] -> C8H14O4 + 2C2H5OH}. \]

The product therefore has:

  • a hydroxyethyl side chain at \(C_1\), +;
  • OH at \(C_2\), +;
  • OH at \(C_3\) and \(C_6\), both −;
  • one double bond, \(C_4=C_5\).

This gives the stated formula \(\ce{C8H14O4}\). Its eight carbons are inequivalent, and precisely two are \(\mathrm{sp^2}\), as required by the NMR data.

Formation of K. All four hydroxyl groups are acetylated:

\[ \ce{C8H14O4 + 4CH3COCl + 4C5H5N -> C16H22O8 + 4C5H6NCl}. \]

Thus K is the tetraacetate of J, with unchanged stereochemistry and the same \(C_4=C_5\) double bond.

Formation of L and M. Osmium tetroxide, O=[Os](=O)(=O)=O, adds to the alkene through a cyclic osmate ester. Hydrolysis produces a syn vicinal diol.

The co-oxidant is 4-methylmorpholine 4-oxide, C[N+]1([O-])CCOCC1; its reduced product is 4-methylmorpholine, CN1CCOCC1. The balanced net transformation, including hydrolytic work-up, is

\[ \ce{C16H22O8 + C5H11NO2 + H2O -> [OsO4] C16H24O10 + C5H11NO}. \]

Addition from either face gives:

\[ \mathbf L:\quad C_4\text{-OH }+,\quad C_5\text{-OH }+; \] \[ \mathbf M:\quad C_4\text{-OH }-,\quad C_5\text{-OH }-. \]

All previously established configurations remain unchanged.

Formation of 1a and 1b. Finally, excess lithium aluminium hydride removes the four acetate protecting groups. For either diastereomer,

\[ \ce{C16H24O10 + 16[H] -> C8H16O6 + 4C2H5OH}. \]

The transformations are therefore

\[ \boxed{\mathbf L\longrightarrow\mathbf{1a}, \qquad \mathbf M\longrightarrow\mathbf{1b}.} \]

Each final product contains five ring hydroxyl groups and one terminal side-chain hydroxyl group. The two carbasugars differ at \(C_4\) and \(C_5\), the centres introduced during osmium-mediated syn dihydroxylation.

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