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.

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 3and 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).

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.

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.

Solution:

2.1. Danishefsky’s diene (3):

Rawal–Kozmin diene (4):

Carbon atoms with higher electron density are indicated by the * symbol.

2.2. Compound 4 is a more reactive diene in a DA reaction with maleic anhydride due to the higher electron-donating ability of nitrogen compared to oxygen.

2.3.

2.4.

2.5.

2.6. The circled alkene reacts selectively with m-CPBA as it is the more electron-rich alkene.

All of the following structures are acceptable answers (E, E1, or E2).

2.7.