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Biosynthesis of Endiandric Acid B

Biosynthesis of Endiandric Acid B

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Interactive 3D molecular animation of the biosynthesis of endiandric acid B [1-11]

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Fig.1

Endiandric acid B belongs to the class of endiandric acids (A-G), which was first isolated in the early 1980s by D.St.C. Black et al. from a tall rainforest tree, the Australian dorrigo plum (Endiandra introrsa) [1-6]. The biosyntheses of all endiandric acids contain two subsequent nonenzymatic electrocyclic reactions. In the case of endiandric acids A, B, and C, an intramolecular Diels-Alder reaction follows. As a result of the whole reaction sequence, an open-chain compound is converted into a tetracyclic compound.

In the meantime, biomimetic total syntheses of endiandric acids were developed by K.C. Nicolaou's group, for instance [7-11]. These syntheses utilize the same pericyclic reactions for constructing the bi- and tetracyclic skeletons as are found in biosynthesis.

In the following, the pericyclic reactions in the biosynthesis of endiandric acid B are explained in detail.

The starting product contains a conjugated tetraene system, as well as a conjugated diene system. Thus, it already displays the π electron systems required for the three pericyclic reactions - that is, the two electrocyclizations and the Diels-Alder reaction.

The reaction sequence begins with an electrocyclic ring closure of the 8 π electron tetraene system, which yields a cyclooctatriene. According to the Woodward-Hoffmann rules, this reaction can be explained in detail by studying the highest-occupied molecular orbitals (HOMO).

Fig.2
π molecular orbitals of a conjugated 8 π electron system.

1.    First, take a look at the HOMO (Ψ4) of the conjugated 8 π electron system of the starting product (17-phenyl-heptadecane-2E,5E,7Z,9Z,11E,14E,16E-heptaenoic acid), which belongs to the first electrocyclization in the biosynthesis of endiandric acid B.

Fig.3

2.    Now, the molecular model is rotated into a view which makes the following electrocyclization easier to understand. In addition, the lobes of the terminal p orbitals of the HOMO (Ψ4) at the carbon atoms 5 and 12 are emphasized by colouring green (previously blue) and yellow (previously red), respectively, as these orbitals are overlapping in the course of ring closure.

3.    The 8 π electron electrocyclization, which yields the cyclooctatriene system, is a concerted reaction. Under thermal reaction conditions, it is the result of the following processes:

  • Conrotatory (same sense of rotation) rotation of the two terminal p orbitals of the HOMO (Ψ4), which results in the overlapping of lobes that have the same sign. Thus, according to the Woodward-Hoffmann rules, this process is allowed under thermal conditions.
  • Change of these two p orbitals into sp3 hybrid orbitals.
  • Formation of a new σ bond between carbons C5 and C12.
  • The alteration of hybridization of the remaining 8 π electron system's orbitals into the new 6 π electron system's molecular orbitals (shown here by the change of the sequence of the wave function's signs of the orbital lobes of the HOMOs).
Fig.4

Now, click here for a look at the whole process of the first electrocyclization. In this process, the conrotatory rotation and the trans configuration of the double bonds in the positions 5 and 11 of the starting product lead to the trans orientation of the alkyl substituents at the carbon atoms 5 and 12 in the product of the electrocyclization.

Principally speaking, four diastereomers of the product are possible. Nevertheless, the conrotatory 8 π electron electrocyclization depicted above stereoselectively yields only the two trans diastereomers. However, only the formation of one of the trans diastereomers is shown. The other trans diastereomer would arise from the conrotatory ring closure with opposite sense of rotation that is also allowed, according to the Woodward-Hoffmann rules. In the biosynthesis of endiandric acid B, both trans diastereomers are actually formed and are both equally suitable as starting product for the second electrocyclization. The two diastereomers with cis orientation of the alkyl substituents cannot be formed because their formation would require a disrotatory 8 π electron electrocyclization that is not allowed under thermal conditions, according to the Woodward-Hoffmann rules.

4.    Take a look again at the change of hybridization that results in the HOMO (Ψ3) of the conjugated 6 π electron system, whose distribution of signs of the wave function among the orbital lobes differs from that of the 8 π electron system's HOMO (Ψ4) (first, the distribution of the signs of the wave function is put back to that of the 8 π electron system).

Fig.5
π molecular orbitals of a conjugated 6 π electron system.

5.    The molecular model is now rotated again in order to make the following 6 π electron electrocyclization more comprehensible. The subsequently overlapping lobes of the terminal p orbitals of the HOMO (Ψ3) at the carbon atoms 6 and 11 are again emphasized by green colouring (previously red) and yellow (previously blue), respectively.

6.    The cyclooctatriene ring induces the all-cisoid conformation of the 6 π electron system that is required for the electrocyclization. As a result, this electrocyclization proceeds easily. In contrast to the 8 π electron electrocyclization, under thermal conditions, the 6 π electron electrocyclization is merely allowed, according to the Woodward-Hoffmann rules, when it occurs by a disrotatory ring closure.

The 6 π electron electrocyclization is also a concerted reaction, in which several processes proceed parallel to each other. This results in the formation of a bicyclo[4.2.0]octane system (endiandric acid F):

  • Disrotatory (opposite sense of rotation) rotation of the two terminal p orbitals of the HOMO (Ψ3).
  • Change of these two p orbitals into sp3 hybrid orbitals.
  • Formation of a new σ bond between the carbons C6 and C11.
  • Change of hybridization of the remaining 6 π electron system's orbitals into the new 4 π electron system's molecular orbitals (shown here by the change of the sequence of the wave function's signs of the orbital lobes of the HOMOs).
Fig.6

Now, click here for a look at the whole process of the second electrocyclization. In this process, the disrotatory rotation and the cis configuration of the double bonds in the positions 6 and 10 of the starting product lead to the cis orientation of the alkyl substituents at the carbon atoms 6 and 11 in the product of the electrocyclization (endiandric acid F).

The side chain at carbon C12 contains an additional conjugated 4 π electron system that has, so far, been depicted in the thermodynamically more stable, transoid conformation. The transoid conformation can be converted into the cisoid conformation, which is required for the third pericyclic reaction in the biosynthesis of endiandric acid B, rather easily. In the molecular animation of the second electrocyclization above, this change of conformation is shown simultaneously with the electrocyclization (however, in reality, these two processes do not necessarily have to proceed simultaneously (!)).

Fig.7

In principle, four diastereomers of the product are again possible. However, due to the bicyclic construction of the product with a four-membered ring, the two diastereomers with trans orientation of the alkyl substituents at the carbons C6 and C11 cannot be formed. In addition, under thermal conditions, the formation of these trans diastereomers is prohibited, according to the Woodward-Hoffmann rules, as it requires a conrotatory ring closure, which would result in the overlapping of two orbital lobes with opposite signs. In the molecular animation, only the formation of one cis diastereomer (endiandric acid F) is shown, though both cis diastereomers are, in fact, formed, as the disrotatory ring closure with an opposite sense of rotation is also allowed under thermal conditions, according to the Woodward-Hoffmann rules. However, the second (not shown) cis diastereomer (endiandric acid G) is unsuitable for the subsequent Diels-Alder reaction in the biosynthesis of endiandric acid B, because the conjugated 4 π electron system cannot be positioned under the six-membered ring of the bicycle.

For the sake of completeness it should be mentioned that the two diastereomeric trans products of the first 8 π electron electrocyclization lead to the same result in the second 6 π electron electrocyclization - that is, a mixture of the endiandric acids F and G. In contrast to the products of the second electrocyclization, the products of the first electrocyclization are therefore both equally suitable as starting product for the subsequent steps in the biosynthesis of endiandric acid B.

7.    The side chain at carbon C12 of endiandric acid F can be positioned under the bicyclo[4.2.0]octane skeleton's six-membered ring in such a way that the HOMO of the conjugated diene of the side chain can approximate to an "ethene-like" part of the LUMO of the six-membered ring's diene. In contrast to the two previous electrocyclizations, the molecular orbitals of two different, separate π electron systems interact in this case. Therefore, HOMO - LUMO overlappings have to be examined in order to detect possible bonding interactions.

Fig.8
π molecular orbitals of a conjugated 4 π electron system.

The 2D and 3D illustrations show the LUMO (Ψ3) in the six-membered ring and the HOMO (Ψ2) in the side chain at C12.

Fig.9
HOMO - LUMO interactions in endiandric acid F.

When the diene system approximates to the monoene system, a suprafacial, bonding interaction between the now overlapping p orbitals of the HOMO in the side chain and the LUMO in the six-membered ring occurs. In this Diels-Alder reaction, it is not the endo , but the exo transition state that appears. This is because the endo transition state is prevented due to large steric interactions between the side chain at C12 and the bicyclic skeleton. Therefore, the reaction yields the exo product.

8.    First, take a look at the Diels-Alder reaction, which is illustrated by the familiar Lewis formulae:

Fig.10

The overlapping of the LUMO'S and HOMO's p orbitals leads to the alteration of all p and sp2 orbitals of the carbon atoms C9, C10, C14, and C17 into sp3 hybrid orbitals. In addition, two new σ bonds between C9 and C17, as well as C10 and C14, are formed. The unequivocal stereochemistry at the four new asymmetric carbon atoms within the product (C9, C10, C14, C17) is the result of the configuration of the double bonds in the starting product (trans, trans in the side chain and cis in the six-membered ring), the stereospecificity of the Diels-Alder reaction regarding these configurations, as well as the highly selective formation of the exo product. In addition, the stereochemistry of the reaction is considerably influenced by the intramolecular course of the reaction that determines the direction of the diene's attack on the dienophile by the bicyclic skeleton.

Now, take a look at the three-dimensional animation of the concluding Diels-Alder reaction resulting in endiandric acid B.

Fig.11

As a result of the Diels-Alder reaction, two conjugated 4 π electron systems in the six-membered ring and the side chain were transformed into two isolated 2 π electron systems.

9.    To sum it up, in the biosynthesis of endiandric acid B, the open-chain starting product, 17-phenyl-heptadecane-2E,5E,7Z,9Z,11E,14E,16E-heptaenoic acid, is converted into a complex tetracyclic compound by the following consecutive processes: a conrotatory 8 π electron electrocyclization, a disrotatory 6 π electron electrocyclization, and an intramolecular [4 π + 2 π] cycloaddition (Diels-Alder reaction).

Fig.12

Have a look at the product endiandric acid B !

1. - 9.    Finally, here is a nonstop animation of the whole process of all cyclizations in the endiandric acid B biosynthesis (about 60 seconds, in Chime no interruption possible).

Literature

  1. Bandaranayake, W.M., Banfield, J.E., Black, D.St.C., Fallon, G.D., Gatehouse, B.M., J. Chem. Soc., Chem. Commun. 1980, 162.
  2. Bandaranayake, W.M., Banfield, J.E., Black, D.St.C., ibid 1980, 902.
  3. Bandaranayake, W.M., Banfield, J.E., Black, D.St.C., Fallon, G.D., Gatehouse, B.M., Aust. J. Chem. 1981, 34, 1655.
  4. Bandaranayake, W.M., Banfield, J.E., Black, D.St.C., ibid 1982, 35, 557.
  5. Bandaranayake, W.M., Banfield, J.E., Black, D.St.C., Fallon, G.D., Gatehouse, B.M., ibid 1982, 35, 567.
  6. Banfield, J.E., Black, D.St.C., Johns, S.R., Willing, R.I., ibid 1982, 35, 2247.
  7. Nicolaou, K.C., Petasis, N.A., Zipkin, R.E., Uenishi, J., J. Am. Chem. Soc. 1982, 104, 5555.
  8. Nicolaou, K.C., Petasis, N.A., Uenishi, J., Zipkin, R.E., J. Am. Chem. Soc. 1982, 104, 5557.
  9. Nicolaou, K.C., Zipkin, R.E., Petasis, N.A., J. Am. Chem. Soc. 1982, 104, 5558.
  10. Nicolaou, K.C., Petasis, N.A., Zipkin, R.E., J. Am. Chem. Soc. 1982, 104, 5560.
  11. Nicolaou, K.C., Petasis, N.A., In Strategies and Tactics In Organic Synthesis, Lindberg, T., Ed., Academic Press: San Diego 1984, Vol. 1, 155.
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