Computational studies on biosynthetic carbocation rearrangements leading to sativene, cyclosativene, α-ylangene, and β-ylangene

Journal of Organic Chemistry

Volumn 73, Issue 17, 2008, Pages 6570-6579

  Lodewyk, Michael W ^a   Gutta, Pradeep ^a   Tantillo, Dean J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL REACTIONS; IONIZATION POTENTIAL; QUANTUM CHEMISTRY; RAW MATERIALS;

CHEMICAL EQUATIONS; REARRANGEMENT PATHWAYS; SESQUITERPENES;

OLEFINS;

ALPHA YLANGENE; BETA YLANGENE; CYCLOSATIVENE; FARNESYL DIPHOSPHATE; NATURAL PRODUCT; SATIVENE; SESQUITERPENE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BIOSYNTHESIS; QUANTUM CHEMISTRY; REACTION ANALYSIS; STEREOCHEMISTRY;

ALGORITHMS; BIOLOGICAL PRODUCTS; CARBON; CATIONS; CYCLIZATION; MODELS, THEORETICAL; POLYISOPRENYL PHOSPHATES; QUANTUM THEORY; SESQUITERPENES; STEREOISOMERISM; THERMODYNAMICS;

EID: 51549118248     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo800868r     Document Type: Article

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42. Schemes found in ref 19 also include β-cubebene (found as a minor product of γ-humulene synthase and proposed to arise from a 1,2-hydride shift in intermediate 3, Scheme 1) and α-copaene (a diastereomer of α-ylangene found as a minor product of both γ-humulene synthase and δ-selinene synthase). However, we find that the relative stereochemistry in structure 3 that leads to sativene, cyclosativene, and the ylangenes is not consistent with the relative stereochemistry of β-cubebene and α-copaene. Therefore, we believe that β-cubebene and α-copaene do not arise directly from intermediate 3, but rather may arise via an earlier branch point. See the Supporting Information for a scheme which illustrates this relationship. Additionally, according to ref 19, there are several other sesquiterpenes which may arise from deprotonation-reprotonation sequences along the way to sativene, etc. (e.g. germacrenes, amorphenes, sibirene, and gurjunene); these are not discussed further in this manuscript.
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66. (a) Although rotation of the isopropyl group at this point is not essential for the ultimate formation of sativene, cyclosativene, and the ylangenes, it does result in an overall lower energy pathway. See the Supporting Information for structures and energies corresponding to the pathway leading to sativene without this early conformational change.
67. (b) The conformation of the isopropyl group also appears to perturb the potential energy surface in the region of the 3c→5 and 3c→6 reaction steps. Specifically, whereas the IRC results pictured in Figure 4 smoothly connect TS3c→5 to intermediate 3c in the reverse direction, the corresponding IRC result for TS3c′→ 5′ (where the isopropyl group is in its 2a conformation) appears to lead directly to TS3c′→6′, a transition-state structure leading to the ylangene cation; this feature is most likely indicative of a bifurcation along this pathway. See the Supporting Information for diagrams and additional details.
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77. Structures 3b and 3c can be considered to be hyperconjomers: Rauk, A.; Sorensen, T. S.; Schleyer, P. v. R. J. Chem. Soc. Perkin Trans. 2 2001, 6, 869-874. In 3b, the cation is hyperconjugated to two neighboring C-C sigma bonds, while in 3c, the cation is hyperconjugated to two neighboring C-H σ bonds.
78. If the C15 methyl group were to be absent, then the alkyl shift would result in an alternative secondary carbocation. Interestingly, an IRC calculation on such a structure also shows the alkyl shift to occur in a concerted fashion along with the ring closure. Optimization of the resulting minimum results in a bridged, nonclassical carbonium ion species. See the Supporting Information for the IRC and associated minimum.
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80. These attempts included the use of constrained optimizations (in order to prevent the alkyl shift from occurring) both on structures similar to the transition state structure (Figure 4) and on structures with ammonia complexed to several nearby hydrogen atoms. In all cases, when the constraint was removed, the structure relaxed to one corresponding to structure 5 (Figure 2).
81. The exo and endo deprotonation transition state structures for sativene differ by less than 0.2 kcal/mol (B3LYP/6-31+G(d,p)).
82. 3) to form cyclosativene is approximately 9.9 kcal/mol and the barrier for deprotonation to form sativene is approximately 2.6 kcal/mol (B3LYP/6-31+G(d,p), including unscaled ZPE corrections).
83. Formation of the ylangenes is related to the formation of the pinenes, camphenes, tricyclene, bergamotenes, and santalene, but we hesitate to draw conclusions about these other terpenes based on our ylangene results due to their structural differences. We will, however, describe calculations on all of these systems in due course.
84. It is tempting to correlate the relative barriers for the production of sativene/cyclosativene and the ylangenes to the observed product distribution described in ref 19 (a total of 5.3% and 3.2% respectively). However, these gas-phase barriers do not take into account any effect the enzyme might have on the conformation of the substrate. Additionally, one cannot rule out the possibility that other products arise from diversions after this branch point. Note also that although the barrier to formation of the ylangene cation is smaller than that for the sativene/cyclosativene cation, the overall exothermicity is much less (see Figure 8).
85. This is a result of the ZPE correction. When the non-ZPE corrected B3LYP energies are considered, the minimum (6) is actually lower in energy than the transition structure by 0.07 kcal/mol.
86. These attempts included constrained calculations where the C2-C7 and C3-C7 distances were constrained at 2.05 Å each and also where the C2-C7 and C3-C7 distances were constrained to 1.85 Å and 2.00 Å, respectively.
87. Structure 13 shows significant perturbation from cation 6; the perturbation is such that the C2-C7 bond is no longer aligned with the empty p-orbital of the carbocationic center. Thus there is essentially no hyperconjugative interaction between the two, and the C2-C7 bond distance is decreased to 1.58 Å. This distance is slightly elongated in going to the corresponding transition-state structure, 14.
88. Note also here that 14 is 2.15 kcal/mol higher in energy (B3LYP/6-31+G(d,p)) than 12.