52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL

Problem 2. Istanbulins and Related Sesquiterpene Natural

Products

Some elements received their names from different places around the world. In this respect, the
record belongs to the Swedish village of Ytterby, after which four elements were named:
ytterbium (Yb), yttrium (Y), erbium (Er), and terbium (Tb). However, elements are not the only
chemical entities that owe their names to such places. Interestingly, a class of natural products,
istanbulins A–E, received their names from the city of Istanbul. The first two members of this
family, istanbulins A and B, were first isolated by Prof. Dr. Ayhan Ulubelen and co-workers
from the plant Smyrnium olusatrum in 1971. The isolation of the remaining members,
istanbulins C–E, was reported by Ulubelen and co-workers between 1979 and 1982.

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52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL

Istanbulins constitute a subclass of a much larger family of natural products called

sesquiterpenes. Two important sesquiterpene natural products with a similar 6-6-5 fused ring
system are vernolepin (1) and vernomenin (2). Danishefsky and co-workers reported an elegant
total synthesis of these two natural products in 1976 via the utilization of the Diels–Alder (DA)
chemistry of the so-called Danishefsky’s diene.

Please note that all formulae depicting chiral molecules in this question refer to racemic
mixtures.

In this context, Danishefsky’s diene (3) and the Rawal–Kozmin diene (4) are two electron-rich
dienes that found widespread use in organic synthesis, and their structures are shown below.

TMS: trimethylsilyl; TBS: tert-butyldimethylsilyl

2.1. Draw the major resonance structures of dienes 3 and 4. Indicate the carbon atoms with
higher electron density on each diene.

2.2. Compounds 3 and 4 have been extensively used as diene components in Diels–Alder
reactions. Draw the conformations of 3 and 4 required to be able to enter a DA reaction. Predict
which compound is a more reactive diene in a DA reaction with maleic anhydride (5).

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52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL

2.3. When a mixture of Danishefsky’s diene (3) and compound 6 was heated followed by
treatment with acid (TsOH, p-toluenesulfonic acid), compound A was obtained as the major
product.

Draw the structures of all possible Diels–Alder products with the molecular formula of
C12H14O3 that can be obtained from the reaction of 3 and 6. Drawing only one enantiomer of an
enantiomeric pair is sufficient.

2.4. Determine the structure of the major product A.

2.5. Diels–Alder adduct A was converted to compound 7 via a sequence of 4 steps as shown
below. Compound B is known to be acidic. Draw the structures of B–D.

2.6. When compound 7 is reacted with 1 equiv of m-CPBA, product E was obtained as a major
product. Circle the functional group that reacts selectively with m-CPBA, and draw the
structure of E.

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52nd International Chemistry Olympiad, Istanbul, TURKEY Preparatory problems: THEORETICAL

2.7. The syntheses of vernolepin (1) and vernomenin (2) were completed as shown in the scheme
below. Draw the structures of compounds F–J. In the final step, compound I is the precursor
of 1.

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