Angewandte

A Journal of the Gesellschaft Deutscher Chemiker

International Edition Chemie www.angewandte.org

Accepted Article

Title: Computational Studies on Biosynthetic Carbocation

Rearrangements leading to Quiannulatene: Initial Conformation
Regulates Biosynthetic Route, Stereochemistry, and Type of
Skeleton

Authors: Hajime SATO, Takaaki Mitsuhashi, mami yamazaki, Ikuro

Abe, and Masanobu Uchiyama

This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.

To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807139

Angew. Chem. 10.1002/ange.201807139

Link to VoR: http://dx.doi.org/10.1002/anie.201807139

http://dx.doi.org/10.1002/ange.201807139
Angewandte Chemie International Edition
COMMUNICATION
Computational Studies on Biosynthetic Carbocation
Rearrangements leading to Quiannulatene: Initial Conformation
Regulates Biosynthetic Route, Stereochemistry, and Type of
Skeleton
Hajime Sato,* Takaaki Mitsuhashi, Mami Yamazaki, Ikuro Abe,* and Masanobu Uchiyama*
Abstract: The results of quantum chemical calculations on the
mechanism of the carbocation cascade of reactions in the
biosynthetic pathways leading to the pentacyclic sesterterpenes
quiannulatene and sesterfisherol provide reasonable answers to
several persistent mechanistic questions in sesterterpene
biosynthesis, including (1) the reaction pathways of the multi-cyclic
ring system construction and skeletal rearrangements, (2) the
mechanism of triquinane skeleton formation, which requires more
complicated rearrangements than previously proposed, (3) the
stereochemistry of the final carbocation intermediate, and (4) the
determining factor of biosynthetic selection of 5/6/4/6/5 or 5/6/5/5/5
pentacyclic skeleton formation. This in-depth mechanistic study on
sesterterpene biosynthesis revealed that the shape of the final
product and the type of triquinane skeleton formed are regulated by
the stereochemistry and conformation of the common starting
material, geranylfarnesyl diphosphate (GFPP).
Terpenes/terpenoids are a large and highly diverse group of
natural products; over 80,000 terpenoids with a wide range of
chemical structures and various biological activities have been
reported to date.1 The structural diversity and complexity are
generated in the course of the cyclization reactions catalyzed by
terpene cyclases (TCs), which provide remarkable examples of
exquisite enzymatic control of the course of a chemical reaction
cascade. Many terpene cyclases have been discovered and
characterized to date.1 Nevertheless, sesterterpenoids remain
the least common group of terpenoids, and only a very limited
number of sesterterpene synthases have been identified.2 We
have reported the sesterterpene quiannulatene,2e which was
originally isolated from Emericella variecolor and recently also
from Arabidopsis thaliana,2h characterized its synthase EvQS,
and proposed a biosynthetic mechanism based on labeling
experiments. Quiannulatene has a unique 5/6/5/5/5 pentacyclic
structure with eight chiral centers. Thus, it is of considerable
[*] Dr. H. Sato, Prof. M. Yamazaki
Graduate School of Pharmaceutical Sciences, Chiba University
1-8-1 Inohana, Chuoku, Chiba 260-8675 (Japan)
E-mail: hajime.sato@chiba-u.jp
T. Mitsuhashi, Prof. I, Abe, Prof. M. Uchiyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: abei@mol.f.u-tokyo.ac.jp, uchiyama@mol.f.u-tokyo.ac.jp
Dr. H. Sato, Prof. M. Uchiyama
Cluster of Pioneering Research (CPR), Advanced Elements
Chemistry Laboratory, RIKEN,
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.
10.1002/anie.201807139
Accepted Manuscript
interest to unveil the biosynthetic pathway/mechanism leading to
this chiral, congested, polycyclic and structurally complex
molecule.3
Terpene cyclization has been proposed to proceed via a
sophisticated multi-step carbocation cascade. In the early stage
of the ring construction, sesterterpene cyclization cascades can
be classified into two groups (Scheme 1).2b Initial dissociation of
diphosphate of geranylfarnesyl diphosphate (GFPP) followed by
cation-mediated double-annulation gives a 5/15 bicyclic
intermediate (Type A) or a 5/11 bicyclic intermediate (Type B).
Quiannulatene belongs Type A sesterterpenoids. In Type A, two
cyclization paths are possible from the 5/15 bicyclic intermediate
to give tricyclic sesterterpenoids: for example, nitiol4 and
variculanol5 have a 5/12/5 tricyclic skeleton (Scheme 2, path a),
while thalianatriene6 and aspterpenacids7 have a 5/6/11 tricyclic
structure (Scheme 2, path b). Further, Osbourn & Tantillo
reported the 5/6/11 tricyclic skeleton as a common intermediate
in the biosynthesis of two sesterterpenoids, astellatene2h and
arathanadiene.2i On the other hand, our computational and
experimental studies have revealed that sesterfisherol
biosynthesis involves formation of a 5/12/5 tricyclic
intermediate.8 Thus, the multi-ring construction
processes/mechanisms in sesterterpenoid biosynthesis remain
controversial, mainly because TCs catalyze domino-type
sequential reactions in their active sites and isolation of
intermediates is extremely challenging.
Scheme 1. Classification of cyclization modes. After the dissociation of
pyrophosphate, the carbocation on C1 reacts with the IV and V double bonds
in Type A, but the III and IV double bonds in Type B.
A 5/6/8/5 tetracyclic intermediate is considered to be involved
in both quiannulatene and sesterfisherol biosynthesis. However,
four-membered ring formation from the intermediate proceeds in
quiannulatene biosynthesis, leading to the triquinane skeleton,
whereas five-membered ring formation occurs in sesterfisherol
biosynthesis to give another type of triquinane intermediate
(Scheme 2). Interestingly, terpene cyclization mechanisms were
suggested to be correlated with phylogenetic tree classification,
and EvQS is classified into a different clade from sesterfisherol
synthase (NfSS).2e Thus, there must be a determinant factor for
the selection of skeleton types and cyclization modes.
Angewandte Chemie International Edition
COMMUNICATION
We are also interested in the triquinane structure. Although
the triquinane skeleton is often seen in C15 sesquiterpenes,9
only a few C25 sesterterpenoids, such as retigeranic acid10 and
retigeranol11, contain this skeleton, as sesterterpenoids are still
relatively unexplored as a natural product group in comparison
to sesquiterpenes. A triquinane structure was identified as an
intermediate in our previous theoretical analysis of sesterfisherol
biosynthesis,2j but it was distinct from that in the case of
quiannulatene. The mechanism of triquinane formation is
complicated, involving multiple alkyl and hydrogen shifts.
In the present paper, we report the results of density
functional theory (DFT) calculations on the quiannulatene
biosynthetic pathway, as compared with sesterfisherol
biosynthesis. The aims of the study are as follows: (i) to uncover
the whole reaction pathway of the exquisitely controlled multi-
step biosynthetic carbocation-cascade reactions leading to
quiannulatene; (ii) to investigate the reaction mechanism of the
skeletal rearrangements that afford the complicated, chiral,
congested, polycyclic structure; and (iii) to analyze the
stereochemistry of each intermediate and to identify the
determinant of entry into the biosynthetic pathways leading to
5/6/5/5/5 (quiannulatene) and 5/6/4/6/5 (sesterfisherol) penta-
cyclic skeletons.
Scheme 2. Comparison of the proposed biosynthetic pathways of
quiannulatene and sesterfisherol via a 5/6/8/5 tetracyclic intermediate.
The full reaction pathway for the conversion of GFPP to IM11
and the relative energies to IM1 are shown in Scheme 3 and
Figure 1, respectively. The energy diagram (Figure 1)
immediately suggests that this is a thermodynamically and
kinetically favorable biosynthetic reaction cascade: 1) activation
barriers are all low enough for the reactions to proceed smoothly
at ambient temperature (no steps with individual barriers greater
than 10 kcal mol-1), 2) the entire energy profile descends as the
reactions proceed, and 3) the overall exothermicity is very large
(nearly 50 kcal mol-1). The E-ring formation (C6–C10 bond
formation) process (TS_3b-4) or the conformational change
This article is protected by copyright. All rights reserved.
10.1002/anie.201807139
(TS_6a-6b) for B-ring formation is the rate-determining step with
the highest energy barrier in this cyclization cascade. Our
calculation results provide several new insights into the
complicated ring formation/skeletal reaction processes and the
conformational changes (the cartesian coordinates of the 3D
structures of all species are shown in the supporting information).
Details of the Biosynthetic Pathway to Quianulatene.
Dissociation of diphosphate from GFPP yields an allylic
carbocation (IM1) partially stabilized by a cation–p interaction
with a distal C14–C15 double bond. Cation-mediated double-
annulation proceeds smoothly to form a bicyclic tertiary cation
intermediate (IM2), which undergoes 1,5-hydrogen transfer
reaction to give a more stable internal allyl cation intermediate
Accepted Manuscript
(IM3a) with a very small activation energy. After the
conformational change of IM3a to IM3b with an activation barrier
of 6.2 kcal mol-1, the E-ring (C6–C10) cyclization proceeds to
give a 5/12/5 tricyclic intermediate (IM4) with a stabilization
energy of 9.0 kcal mol-1. This is an important branching point in
sesterterpene biosynthesis: 1) in astellatene2h and
2i
arathanadiene biosynthesis, C2–C12 bond (B-ring) formation
proceeds preferentially to give 5/6/11 tricyclic intermediates at
this stage, whereas 2) C6–C10 bond (E-ring) formation
proceeds selectively to give the 5/12/5 tricyclic intermediate
(IM4) in sesterfisherol biosynthesis. Our calculation clearly
shows that E-ring (5/12/5 tricyclic skeleton) formation proceeds
preferentially by 3.0 kcal mol-1 in activation energy compared to
B-ring (5/6/11 tricyclic skeleton) formation in quiannulatene
biosynthesis (Figure S2). It would be interesting to discover the
determining factor that regulates this pathway branching, and
the information would also be helpful for engineering
sesterterpene TCs (vide infra).
Subsequently, two successive 1,2-hydrogen shifts occur to
generate allylic cation intermediate (IM6). IM6 has five
conformers within ca. 4 kcal mol-1, since the 12-membered ring
is quite flexible. After multiple conformational changes of IM6b
into IM6e with small activation barriers, the C2–C3 p bond in
IM6e approaches the cation center to undergo B-ring formation
to give the tertiary cation intermediate (IM7). Cyclobutane ring
formation next takes place to yield a 5/6/4/6/5-pentacyclic
intermediate (IM8) with a very small activation energy barrier. At
this cyclization step, we could also locate another type of
annulation pathway affording a 5/6/5/5/5-pentacyclic
intermediate, as seen in sesterfisherol bio-synthesis. The details
of this regioselectivity will be discussed later. From IM8, skeletal
rearrangement takes place via a non-classical carbocation
transition state (TS_8-9a) with very low activation energy (4.6
kcal mol-1) to give another bridgehead tertiary cation (IM9). After
a conformational change from IM9a to IM9b, two sequential
skeletal rearrangements via non-classical carbocation transition
states give a triquinane intermediate (IM11). IM11 is at least 10
kcal mol-1 more stable than IM8, owing to the different strain
magnitudes of the multi-cyclic ring systems. Finally,
deprotonation affords the product, quiannulatene.
This work also revealed the full stereochemistry of IM11. Unlike
the terpene-forming reactions we have previously reported,8,12,13
in which the termination step is hydroxylation, quiannulatene
biosynthesis ends with deprotonation to afford an olefin.
Consequently, the stereochemistry of the C2 position is
experimentally inaccessible. Thus, both possibilities were
Angewandte Chemie International Edition 10.1002/anie.201807139

COMMUNICATION

Accepted Manuscript
-1
Scheme 3. Whole biosynthetic pathway of quianulatene. Potential energies (kcal mol , Gibbs free energies calculated at the mPW1PW91/6-31+G(d,p) level
based on B3LYP/6-31+G(d,p) geometries) relative to IM1 are shown in parenthesis. IM stands for intermediate. TS stands for transition state.

-1
Figure 1. Energy diagram of the quiannulatene biosynthetic pathway. Potential energies (kcal mol , Gibbs free energies calculated at the mPW1PW91/6-
31+G(d,p) level based on B3LYP/6-31+G(d,p) geometries) relative to IM1 are shown in parenthesis.

This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
COMMUNICATION
examined computationally. The results clearly show that IM11
has a hydrogen at the C2 position; this is the opposite
stereochemistry to that previously proposed (Figure S1). If
IM11 had b hydrogen at the C2 position, the GFPP would
need to have had a (Z) C2–C3 double bond. As we used
GFPP with a (E) C2-C3 double bond, IM11 should have a
hydrogen at the C2 position.
(a) (b)
H H H H
H H
H H
Quiannulatene
cis-fused B/C ring
Sesterfisherol
trans-fused B/C ring
(c) (d)
Conformation A Conformation B
Figure 2. The 5/6/8/5 tetracyclic skeletons of quiannulatene and
sesterfisherol. (a) 2D structure of quiannulatene (b) 2D structure of
sester-terfisherol (c) 3D structure of quiannulatene (d) 3D structure of
sesterfisherol.
Rearrangement Mechanism Leading to Triquinane
Skeleton. In our previous study, we proposed that skeletal
rearrangement from IM8 to IM11 occurs as a single event via
only two alkyl shifts (scheme 4, path b). However, the present
calculations revealed that the triquinane structure formation
requires two more skeletal rearrangements and one more
conformational change (scheme 4, path a). This mechanism
appears to be very complicated, but it is energetically viable,
since all the steps require less than 6 kcal mol-1 activation
Scheme 4. Rearrangement reaction mechanisms. Path a: newly discovered pathway in this study, including four alkyl shifts and one conformational change.
path b: previously proposed pathway, including two alkyl shifts.
This article is protected by copyright. All rights reserved.
10.1002/anie.201807139
energy. This detour pathway appears to be necessary to set
up the molecule in an appropriate conformation for further
skeletal rearrangement. Tantillo has reported seminal
theoretical studies on the formation of several kinds of
triquinane skeleton, such as a-isocomene,14 modhephene,14
a-terrecyclene14 and pentalenene,15 which are all C15
sesquiterpenes. The 5/5/6-type tricyclic skeleton in
IM9a/IM9b is also seen in a-isocomene and a-terrecyclene
biosynthesis, but the reaction mechanism is slightly different
from that of quiannulatene.
Stereochemical Analysis. We next studied in detail the
conformation of the intermediary diastereomeric 8-membered
ring (Figure 2, quiannulatene: conformation A, sesterfisherol:
Accepted Manuscript
conformation B). Interestingly, when IM6 in quiannulatene
biosynthesis is artificially fixed in conformation B (albeit this is
thermodynamically unfavorable by ca. 2.3 kcal mol-1 over
conformation A), 5/5-membered ring formation proceeds
smoothly to give a sesterfisherol-type 5/5/5-triquinane
structure (Scheme 5b). Likewise, when the corresponding
intermediate in sesterfisherol biosynthesis is changed to
conformation A, 4/6-membered ring formation proceeds to
form a quiannulatene-type 5/5/6-type tricyclic skeleton
(Scheme 5c); however, this pathway needs an activation
energy of 26.6 kcal mol-1 and appears not to be viable under
ambient conditions. This simulation computation implies that
skeleton formation is influenced by the conformation of the
intermediary 12-membered ring resulting from the
stereochemistry of the 5/12/5 tricyclic intermediate. It appears
that the stereochemistry of the right part of the molecule
regulates the structure of the left part in the sesterterpene
biosynthesis. However, these results raised a new question
as to what determines the stereochemistry.
Angewandte Chemie International Edition 10.1002/anie.201807139

COMMUNICATION

H
(a) conformation A H H H H H
7 6
H H
H
5 3 barrierless
4 H H

H 2.3 kcal/mol 5/5/6 type Quiannulatene

7
favorable
6
H
5

4 3
H H H H
ΔG‡ = 6.3 Not isolated
6 4 H
7 3 H
(b) conformation B 5 H H

5/5/5 type triquinane

(c) conformation A

Accepted Manuscript
H H H H
7 ΔG‡ = 26.6 Not isolated
H
6 H
5
3 H H
4
H
7 5/5/6 type
6
H 2.3 kcal/mol
5
favorable
4 3
7 H H OH H

6 H
(d) 5 H
barrierless
conformation B 4
3
H H

5/5/5 type triquinane Sesterfisherol

Scheme 5. The effect of conformation on triquinane skeleton formation. (a) Quiannulatene original pathway (conformation A) (b) Quiannulatene swapped
pathway (conformation B) (c) Sesterfisherol original pathway (conformation A) (d) Sesterfisherol swapped pathway (conformation B).

Initial Conformation Analysis. We then focused on the initial
conformation of GFPP, especially the orientation of the methyl
groups on the double bonds (Figure 3b). Comparing the
stereochemistry of the five double bonds of GFPP between
quiannulatene and sesterfisherol, two of them are facing in the
same direction, whereas other three are facing in the opposite
side (Figure 3a). GFPP does not have any polar functional
groups except for the pyrophosphate moiety, so it is of interest
to know
Figure 3. Initial conformation of GFPP in each biosynthetic pathway. (a)
Comparison of the 3D structure of IM1 for quiannulatene (left) and
sesterfisherol (right). (b) I, II, III, IV represent the direction of the methyl groups.
V represents the direction of the isopentenyl moiety.
how TCs fix the initial conformation of GFPP. TCs have several
roles and functions, such as dissociation of diphosphate from
GFPP, protection of reactive cation intermediates, deprotonative
olefination to afford quiannulatene16 and so on. In addition,
based on our study, it appears that EvQS controls the regio- and
stereochemistry by fixing the initial conformation of GFPP, which
determines the fate of the carbocation-stitching cascade,
including multiple ring formations and skeletal rearrangements
that in turn elegantly determine the regio- and stereoselectivity.
Further studies on how TCs fix GFPP by means of theoretical
calculations and X-ray crystal structural technique are in
progress. We believe the present work provides a theoretical
basis for designing new synthetic methods and strategies to
construct medium- to large-sized rings in a controllable and
diversified manner.
The current computational study has clarified the whole
biosynthetic route to quiannulatene. DFT calculations reveal that
the core framework of quiannulatene is constructed via a
tandem carbocation cascade, involving construction of several
rings, hydrogen-shifts, and skeletal rearrangements. Such a
reaction cascade provides high efficiency and selectivity, and is
well supported by the experimental results. There are several
branching points in sesterterpene biosynthesis, in which the
stereochemistry and conformation regulate the successive
tandem carbocation cascade. Furthermore, we elucidated the
complicated rearrangement pathway/mechanism (IM8-IM11)
leading to the triquinane skeleton, which involves four alkyl shifts
and two conformational changes. An in-depth mechanistic study
on quiannulatene and sesterfisherol biosynthesis indicated that
the initial conformation of GFPP controls the fate of the
carbocation-stitching cascade, including ring formations and
skeletal rearrangements that in turn determine the regio- and
stereoselectivity. We believe this work provides a theoretical

This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
COMMUNICATION
basis and a new strategy for designing and engineering ses-
terterpenoid synthases.
Acknowledgements
This work was supported by JSPS KAKENHI (S) (No. 17H06173
(M.U.)), JSPS Grant-in-Aid for Scientific Research on Innovative
Areas (No. 17H05430 (M.U.), JP16H06454 (M.Y.), and
JP16H06443 (I.A.)). Allotment of computational resource
(Project G18008) from RICC (RIKEN Integrated Cluster of
Clusters) and HOKUSAI GreatWave (RIKEN) is gratefully
acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Keywords: DFT calculation, Sesterterpene, Triquinane,
Conformation, Rearrangement
[1] a) M. B. Quin, C. M. Flynn, C. Schmidt-Dannert, Nat. Prod. Rep. 2014,
31, 1449. b) J. S. Dickschat, Nat. Prod. Rep. 2016, 33, 87. c) D. W.
Christianson, Chem. Rev. 2017, 117, 11570.
[2] a) R. Chiba, A. Minami, K. Gomi, H. Oikawa, Org. Lett. 2013, 15, 594.
b) Y. Ye, A. Minami, A. Mandi, C. Liu, T. Taniguchi, T. Kuzuyama, K.
Monde, K. Gomi, H. Oikawa, J. Am. Chem. Soc. 2015, 137, 11846. c) Y.
Matsuda, T. Mitsuhashi, S. Lee, M. Hoshino, T. Mori, M. Okada, H.
Zhang, F. Hayashi, M. Fujita, I. Abe, Angew. Chem. Int. Ed. 2016, 55,
5785. d) Y. Matsuda, T. Mitsuhashi, Z. Quan, I. Abe, Org. Lett. 2015, 17,
4644. e) M. Okada, Y. Matsuda, T. Mitsuhashi, S. Hoshino, T. Mori, K.
Nakagawa, Z. Quan, B. Qin, H. Zhang, F. Hayashi, H. Kawaide, I. Abe,
J. Am. Chem. Soc. 2016, 138, 10011. f) Qin, B.; Matsuda, Y.; Mori, T.;
Okada, M.; Quan, Z.; Mitsuhashi, T.; Wakimoto, T.; Abe, I. Angew.
Chem. Int. Ed. 2016, 55, 1658-1661. g) Bian, G.; Han, Y.; Hou, A.;
Yuan, Y.; Liu, X.; Deng, Z.; Liu, T. Metab. Eng. 2017, 42, 1-8. h) A. C.
Huang, S. A. Kautsar, Y. J. Hong, M. H. Medema, A. D. Bond, D. J.
Tantillo, A. Osbourn, Proc. Natl. Acad. Sci. USA. 2017, 114, E6005. i) A.
C. Huang, Y. J. Hong, A. D. Bond, D. J. Tantillo, A. Osbourn, Angew.
Chem. Int. Ed. 2018, 57, 1291. j) J. Rinkel, L. Lauterbach, J. S.
Dickschat, Angew. Chem. Int. Ed. 2017, 56, 16385. k) T. Mitsuhashi, J.
Rinkel, M. Okada, I. Abe, J. S. Dickschat, Chem. Eur. J. 2017, 23,
10053. l) H. Chai, R. Yin, Y. Liu, H. Meng, X. Zhou, G. Zhou, X. Bi, X.
Yang, T. Zhu, W. Zhu, Z. Deng, K. Hong, Sci. Rep, 2015, 6, 27181. m)
J. Shao, Q.-W. Chen, H.-J. Lv, J. He, Z.-F. Liu, Y.-N. Lu, H.-L. Liu, G.-D.
This article is protected by copyright. All rights reserved.
10.1002/anie.201807139
Wang, Y. Wang, Org. Lett. 2017, 19, 1816. n) A. Minami, T. Ozaki, C.
Liu, H. Oikawa, Nat. Prod. Rep. 2018, in press. o) T. Mitsuhashi, I. Abe,
ChemBioChem 2018, 19, 1106.
[3] a) H. Seto, H. Yonehara, J. Antibiot. 1980, 33, 92. b) D. E. Cane, A. M.
Tillman, J. Am. Chem. Soc. 1983, 105, 122. c) D. E. Cane, C. Abell, A.
M. Tillman, Bioorg. Chem. 1984, 12, 312. d) M. Seemann, G. Zhai, J-W.
Kraker, C. M. Paschall, D. W. Christianson, D. E. Cane. J. Am. Chem.
Soc. 2002, 124, 7681. e) G. F. Santos, J. Moraga, J. A. Takahashi, M.
Viaud, J. R. Hanson, R. H. Galán, I. G. Collado, Org. Biomol. Chem.,
2017, 15, 5357.
[4] N. Kawahara, M. Nozawa, A. Kurata, T. Hakamatsuka, S. Sekita, M.
Satake, Chem. Pharm. Bull. 1999, 47, 1344.
[5] S. B. Singh, R. A. Reamer, D. Zink, D. Schmatz, A. Dombrowski, M. A.
Goetz, J. Org. Chem. 1991, 56, 5618.
[6] J. Shao, Q.-W. Chen, H.-J. Lv, J. He, Z.-F. Liu, Y.-N. Lu, H.-L. Liu, G.-D.
Accepted Manuscript
Wang, Y. Wang, Org. Lett. 2017, 19, 1816.
[7] Z. Liu, Y. Chen, S. Chen, Y. Liu, Y. Lu, D. Chen, Y. Lin, X. Huang, Z.
She, Org. Lett. 2016, 18, 1406.
[8] H. Sato, K. Narita, A. Minami, M. Yamazaki, C. Wang, H. Suemune, S.
Nagano, T. Tomita, H. Oikawa, M. Uchiyama, Sci. Rep, 2018, 8, 2473.
[9] a) L. H. Zalkow, R. N. Harris, D. Van Derveer, J. Chem. Soc. Chem.
Commun. 1978, 420. b) L. H. Zalkow, R. N. Harris III, D. Van Derveer, J.
A. Bertrand, J. Chem. Soc. Chem. Commun. 1977, 456. c) J. F. Cicció,
C. Chaverri, Rec. Nat. Prod. 2012, 6, 371. d) M. Klobus, L. Zhu, R. M.
Coates, J. Org. Chem. 1992, 57, 4327. e) P. Blagojevic, N. Radulovic,
R. Palic, G. J. Stojanovic, Agric. Food Chem. 2006, 54, 4780.
[10] a) M. Kaneda, R. Takahashi, Y. Iitaka, S. Shibata Tetrahedron Lett.
1972, 45, 4609. b) H. Sugawara, A. Kasuya, Y. Iitaka, S. Shibata, S.
Chem. Pharm. Bull. 1991, 39, 3051. c) M. Kaneda, Y. Iitaka, S. Shibata,
Acta Cryst. 1974, B30, 358.
[11] M. Millot, M. Martin-de-Lassalle, M. Chollet-Krugler, Y. Champavier, L.
Mambu, J.-A. Chulia, M.-A. Lacaille-Dubois, Helv. Chim. Acta 2016, 99,
169.
[12] a) H. Sato, K. Teramoto, Y. Masumoto, N. Tezuka, K. Sakai, S. Ueda,
Y. Totsuka, T. Shinada, M. Nishiyama, C. Wang, T. Kuzuyama, M.
Uchiyama, Sci. Rep. 2015, 18471. b) Y. J. Hong, D. J. Tantillo, Org.
Biomol. Chem. 2015, 13, 10273.
[13] K. Narita, H. Sato, A. Minami, K. Kudo, L. Gao, C. Liu, T. Ozaki, M.
Kodama, X. Lei, T. Taniguchi, K. Monde, M. Yamazaki, M. Uchiyama, H.
Oikawa, Org. Lett. 2017, 19, 6696.
[14] P. Gutta, D. J. Tantillo, J. Am. Chem. Soc. 2006, 128, 6172.
[15] a) Y. J. Hong, S. Irmisch, S. C. Wang, S. Garms, J. Gershenzon, L. Zu,
T. G. Kollner, D. J. Tantillo, Chem. Eur. J. 2013, 19, 13590. b) M. W.
Lodewyk, D. Willenbring, D. J. Tantillo, Org. Biomol. Chem. 2014, 12,
887. c) L. Zu, M. Xu, M. W. Lodewyk, D. E. Cane, R. J. Peters, D. J.
Tantillo, J. Am. Chem. Soc. 2012, 134, 11369.
[16] K. C. Potter, J. Zi, Y. J. Hong, S. Schulte, B. Malchow, D. J. Tantillo, R.
J. Peters, Angew. Chem. Int. Ed. 2016, 55, 634.
Angewandte Chemie International Edition 10.1002/anie.201807139

COMMUNICATION
Entry for the Table of Contents (Please choose one layout)

Layout 2:

COMMUNICATION
Hajime Sato*, Takaaki Mitsuhashi, Mami
Yamazaki, Ikuro Abe* and Masanobu
((Insert TO Graphic here)) Uchiyama*

Page No. – Page No.

Accepted Manuscript
Computational Studies on
Biosynthetic Carbocation
Text for Table of Contents
Rearrangements leading to
Quiannulatene: Initial Conformation
Regulates Biosynthetic Route,
Stereochemistry, and Type of
Skeleton

This article is protected by copyright. All rights reserved.