Computational and Synthetic Investigation of Cationic Rearrangement in the Putative Biosynthesis of Justicane Triterpenoids

Article abstract of DOI:10.1002/anie.201810566

A biomimetic cationic structural rearrangement of the oleanolic acid framework is reported for the gram-scale synthesis and structural reassignment of justicioside E aglycone. The mechanism of the putative biosynthetic rearrangement is investigated with kinetic, computational, and synthetic approaches. The precursor to rearrangement was accessed through two strategic advancements: (1) synthesis of a 1,3-diketone via oxidation of a β-silyl enone, and (2) diastereoselective 1,3-diketone reduction to form a syn-1,3-diol using SmI₂ with PhSH as a key additive.

Full text of DOI:10.1002/anie.201810566

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201810566
German Edition: DOI: 10.1002/ange.201810566
Biomimetic Synthesis
Computational and Synthetic Investigation of Cationic Rearrangement
in the Putative Biosynthesis of Justicane Triterpenoids
Masha Elkin+, Anthony C. Scruse+, Aneta Turlik, and Timothy R. Newhouse*
Dedicated to Larry E. Overman on the occasion of his 75th birthday
Abstract: A biomimetic cationic structural rearrangement of
the oleanolic acid framework is reported for the gram-scale
synthesis and structural reassignment of justicioside E agly-
cone. The mechanism of the putative biosynthetic rearrange-
ment is investigated with kinetic, computational, and synthetic
approaches. The precursor to rearrangement was accessed
through two strategic advancements: (1) synthesis of a 1,3-
diketone via oxidation of a b-silyl enone, and (2) diastereose-
lective 1,3-diketone reduction to form a syn-1,3-diol using SmI2
with PhSH as a key additive.
T
he pentacyclic triterpenoids are an ancient, populous, and
structurally diverse class of natural products with important
and wide-ranging biological activities.[1] Oleanane triterpe-
noids are actively being developed for pharmaceutical
purposes:[2] oleanolic acid is used in China to treat liver
disorders,[3] and synthetic oleananes have advanced to clinical
trials for chronic kidney disease.[2b] Decades of research have
established that the biosyntheses of these pentacyclic triter-
penoids occur via polyolefin cyclization of 2,3-oxidosqualene
and subsequent cationic rearrangements of the D and E
rings.[4–6] In contrast, the pathways that reorganize the A and
B rings of pentacyclic triterpenoids, as represented by the
justicanes (Figure 1),[7] are not clearly understood. Herein we
report a synthetic, kinetic, and computational evaluation of
the interconversion of the oleane skeleton to that of the
justicane class (i.e. 1–3). This work results in a structural
reassignment and gram-scale laboratory chemical synthesis of
1.
Figure 1. A) Potential structural reorganizations of justicioside A agly-
cone (3) towards 1 and 2. B) NMR predictions support structural
reassignment of 1. MAD=mean average deviation (ppm). Max=max-
imum deviation (ppm). Statistical analysis was performed using the
DP4 method.
A possible biosynthetic pathway of 1 involves reorganiza-
tion of the A,B-ring system of justicioside A aglycone (3)
from a 6,6- to the 5,7-ring system (Figure 1A).[7] Similar
decalin rearrangements by activation of the C1 position have
been employed in small molecule synthesis,[8] and the bicyclo-
[5.3.0]decane motif is widely observed in natural products.[9]
However, these decalin rearrangements have been reported
to undergo competitive alkyl migrations,[10,11] which prompted
us to consider whether the formation of 2 might compete with
the formation of 1. A detailed understanding of the reaction
mechanism would aid in rationally employing this and other
cationic rearrangement tactics in organic synthesis. The use of
kinetic isotope effects and computational modelling[12] in
studying decalin rearrangements may contribute to ration-
alizing chemo- and stereoselective migrations, in addition to
the analysis of product distribution that has been the main
tool for mechanistic investigations on related systems.[10,11]
An additional complication in the justicane case is that
a stereospecific 1,2-alkyl migration of 3 would result in a cis-
fused A,B-ring system (1), as opposed to the trans-A,B-ring
fusion reported for justicioside E aglycone (C1-epi-1).[7] To
resolve this ambiguity, we conducted NMR prediction
calculations (Figure 1B).[13,14] Deviations from experimental
data (in ppm) are shown for both assignments. The mean
[*] M. Elkin,[+] A. C. Scruse,[+] A. Turlik, T. R. Newhouse
Department of Chemistry, Yale University
225 Prospect Street, PO Box 20817, New Haven, CT 06511 (USA)
E-mail: timothy.newhouse@yale.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201810566.
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
average deviation (MAD) and maximum difference (Max)
from the reported 1H- and 13C- NMR spectra are more
consistent with the revised structure 1. Furthermore, statis-
thermodynamic ketone reductions. After initial proton-cou-
pled electron transfer,[19] it is possible that the polarizability of
ꢀ
the S H bond facilitates H-atom abstraction by the sama-
tical evaluation of the H, 13C, and H & 13C data sets using
Goodmanꢀs DP4 method provides a 100% probability that
the reassignment is more accurate than the originally
proposed structure.[15] The structural reassignment may have
implications for the biosynthetic mechanism of rearrange-
ment, as a stereospecific concerted migration, among other
possibilities, would be consistent with the formation of cis-
fused 1.
rium-complexed ketyl radical, as opposed to proton transfer
to the samarium alkoxide from other proton donors. To our
delight, we found that the conditions of our diketone
formation and subsequent reduction were amendable to
a one-pot transformation, resulting in the requisite syn-diol in
77% yield.
1
1
The syn-diol was selectively protected with benzoyl
chloride in the presence of pyridine to yield migration
precursor 7. Treatment of 7 with acid under mild conditions
did not lead to the formation of 8. However, exposure to
trifluoromethanesulfonic anhydride and pyridine spontane-
ously elicited the key rearrangement to the 5,7-ring system of
justicioside E, forming 8 as a 10:1 mixture of olefin isomers in
86% yield. The structure of 8 was unambiguously assigned as
the cis isomer by X-ray crystallography. This is consistent with
the predicted structural reassignment and supports a stereo-
specific migration for ring rearrangement.
In exploring conditions for the alkyl migration, it was not
observed that 1,2-methyl shift to form 9 was competitive
under any conditions. This prompted us to prepare[20] and
investigate the reactivity of C1-epi-7. Treatment of C1-epi-7
with trifluoromethanesulfonic anhydride and pyridine
induced a 1,2-methyl shift to form 9 as a mixture of olefin
isomers in 93% yield with no detection of rearrangement
product 8. Under all conditions explored, the activated
derivatives of secondary alcohols 7 and C1-epi-7 migrated
with complete stereochemical control to form 8 and 9,
respectively. This selective migration of the bond antiper-
We planned to elucidate the mechanism of this rearrange-
ment by synthetic, computational,[16] and kinetic investiga-
tions. It was thus necessary to access a justicioside A-type
rearrangement precursor and examine the migration to
justicioside E aglycone (1). The synthesis of justicioside E
aglycone (1) began with the known enone 4, prepared from
oleanolic acid in two steps (Scheme 1). It was envisioned that
enone 4 could be converted to the 1,3-diketone via a two-step
approach involving palladium-catalyzed b-silylation and sub-
sequent oxidation. Our previously reported b-silylation pro-
tocol was modified and smoothly furnished 5 in 82% yield on
10.0-gram scale (see Supporting Information for details).[17] b-
Silyl enone 5 was then oxidized to the 1,3-diketone 6 with
basic tert-butyl hydroperoxide.
At this stage, it was necessary to perform a diastereose-
lective reduction of the diketone moiety to the syn-1,3-diol.
The use of hexamethylphosphoramide (HMPA) and thiophe-
nol[18] in the presence of SmI2 uniquely effected the reduction
to the desired product. Thiophenol may act as a hydrogen
atom transfer agent to enhance the diastereoselectivity of
Scheme 1. Synthesis of justicioside E aglycone (1). Reagents and conditions: (3) PhMe2SiLi (1.2 equiv), HMPA (2.9 equiv), THF (0.4m), ꢀ788C,
5 m; [Pd(allyl)Cl]2 (2.5 mol%), diethyl allyl phosphate (1.0 equiv), 708C, 40 m, 82%; (4) NaH (3.0 equiv), t-BuO2H (6.0 equiv), NMP-THF (3:1,
0.08m), 0 ! 238C, 1 h; HMPA (36.0 equiv), PhSH (18.0 equiv), SmI2 (13.1 equiv), 238C, 30 m, 77%; (5) BzCl (1.6 equiv), pyridine (0.25m), 238C,
12 h, 76%; (6) Tf2O (1.8 equiv), pyridine (3.7 equiv), CH2Cl2 (0.02m), ꢀ78 ! 238C, 3 h, 86%, 10:1 exo:endo olefin from 7; 93% from C1-epi-7; (7)
CrO3 (20.4 equiv), pyridine (40.6 equiv), CH2Cl2 (0.01m), 238C, 12 h, 56%; (8) LiAlH4 (5.0 equiv), THF (0.02m), 0 ! 238C, 13 h, 71%, 10:1 dr.
2
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Figure 2. A) Kinetic isotope effect experiment indicates a concerted ionization and rearrangement. B) Reaction coordinate for carbocationic
rearrangement indicates kinetic preference for the 1,2-alkyl shift product 14 via transition state 13 and thermodynamic preference for the 1,2-
methyl shift product 12 via transition state 11 (mPW1PW91/6–311+G(2d,p)//B3LYP/6–31+G(d,p) (gas phase)).[24] Values listed are relative free
energies (DG).
iplanar to the leaving group suggests a concerted or tight ion
pairing mechanism with complete stereoelectronic control is
operative, as the formation of an intermediate carbocation
would result in common products from both starting materi-
als.
Completion of the synthesis of 1 from 8 required enone
formation with Collins reagent and global carbonyl reduction
with lithium aluminum hydride. The spectral data for the
material thus obtained are in excellent agreement with those
reported for justicioside E aglycone (1).[7]
With synthetic access to 1, we investigated the mechanism
of the key bond rearrangement with kinetic and computa-
tional studies (Figure 2). A kinetic isotope effect (KIE)
experiment was designed which required a C1-deuterated
decalin precursor.[21] Substrate 7-D was prepared, with
deuterium incorporation at C1 and C3, and mixtures of 7
and 7-D were subjected to rearrangement reaction conditions
in a one-pot competition experiment (Figure 2A). The
dideuterated substrate was used to simplify spectroscopic
analysis (see Supporting Information), and it is not expected
that deuteration at C3 would significantly impact the value of
the KIE.[22] The 28 aD KIE was calculated using the Singleton
method to be 1.00 ꢁ 0.01.[23] This value reflects a lack of
rehybridization at C1 and is indicative of a concerted 1,2-alkyl
shift. This is consistent with the stereospecific migration of the
group antiperiplanar to the C1 leaving group observed in 7 !
8 and C1-epi-7 ! 9 (Scheme 1). A KIE of 1.00 does not
support stepwise leaving group ionization and subsequent
bond reorganization, for which a normal or inverse 28 KIE
should be observed. The concerted nature of the synthetic
transformation suggests the possibility that the biosynthetic
transformation also proceeds via a concerted pathway.
While benzoate 7 undergoes concerted bond rearrange-
ment under abiotic conditions, the enzymatic machinery
responsible for the biosynthetic transformation might medi-
ate the stepwise rearrangement mechanism. This mechanistic
possibility was investigated computationally. When the C1
carbocation of 7 was subjected to gas phase optimization,[24]
only energy-minimized structures corresponding to the 5,7-
ring system or methyl-shift product were obtained, and all
efforts to identify the initial C1 carbocation were unsuccess-
ful. This suggests that the C1 carbocation of 7 is not a local
minimum on the energetic landscape for the computational
methods used. In contrast, the C1 carbocation 10 was
observed as an energy-minimized structure when subjected
to gas-phase optimization (Figure 2B).
Unlike the C1 carbocation of 7, that of 10 benefits from
increased stability: the pC1 orbital is situated in a pseudoe-
quatorial orientation and is therefore stabilized by the
nonbonding orbitals of the allylic hydroxyl group (nO
!
pC1).[25] This intermediate was modelled undergoing 1,2-
methyl shift to 12 and 1,2-alkyl shift to 14. The 1,2-methyl
shift pathway is kinetically accessible (DG° =+ 8.6 kcal
molꢀ1) and exergonic (DG = ꢀ13.5 kcalmolꢀ1). The 1,2-alkyl
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
2006, 23, 394; b) R. A. Hill, J. D. Connolly, Nat. Prod. Rep. 2018,
35, 1294.
shift pathway leading to 14 is also thermodynamically
favorable (DG = ꢀ9.5 kcalmolꢀ1), and the transformation is
nearly barrierless (DG° =+ 0.2 kcalmolꢀ1). The kinetic favor-
ability of the alkyl migration can be explained by the chair-
like A-ring conformation of 10, which situates the pC1 orbital
antiperiplanar to the migrating C5-C10 bond, facilitating ring
rearrangement.[25] The close energetic and geometrical
homology between 10 and transition state 13 results in
a low kinetic barrier to migration. In contrast, the transition
state for the 1,2-methyl shift pathway (11) shows that
a distortion to an A-ring half-chair conformer is necessary
to allow migration via the axial pC1 hyperconjomer.[25] Taken
together, the results of the calculations and KIE measurement
indicate that both the concerted and stepwise mechanisms
would favor formation of the 5,7-ring system from a suitable
decalin precursor without competitive methyl migration.
A gram-scale synthesis of justicioside E aglycone (1) is
reported, featuring a substrate-controlled cationic rearrange-
ment. This work has resulted in several synthetic advances
and the structural reassignment of 1 by synthetic and
computational methods. These results, along with a kinetic
isotope effect study and a computational investigation into
gas phase carbocation reactivity suggest two orthogonal
means to control structural reorganization of neopentyl
carbocations common to terpenoid frameworks, and offer
insight into the 6,6- to 5,7-ring system rearrangement. This
report further highlights the synergistic relationships between
organic synthesis, mechanistic analysis, and computational
chemistry, with similar investigations ongoing in our labora-
tory.[26]
[2] a) J. Liu, J. Ethnopharmacol. 1995, 49, 57; b) K. T. Liby, M. B.
Sport, Pharmacol. Rev. 2012, 64, 972; c) N. R. Parikh, A.
Mandal, D. Bhatia, K. S. Siveen, G. Sethi, A. Bishayee,
Phytochem. Rev. 2014, 13, 793; d) T. B. Ayeleso, M. G. Matumba,
E. Mukwevho, Molecules 2017, 22, 1915; e) M. Masullo, C. Pizza,
S. Piacente, Expert Opin. Ther. Pat. 2017, 27, 237.
[3] X. Wang, X.-l. Ye, R. Liu, H.-L. Chen, H. Bai, X. Liang, X.-D.
Zhang, Z. Wang, W.-l. Li, C.-X. Hai, Chem.-Biol. Interact. 2010,
184, 328.
[4] For seminal experimental studies on triterpene biosynthesis, see:
a) R. G. Landgon, K. Bloch, J. Am. Chem. Soc. 1952, 74, 1869;
b) R. B. Woodward, K. Bloch, J. Am. Chem. Soc. 1953, 75, 2023;
c) G. Stork, A. W. Burgstahler, J. Am. Chem. Soc. 1955, 77, 5068;
d) A. Eschenmoser, L. Ruzicka, O. Jeger, D. Arigoni, Helv.
Chim. Acta 1955, 38, 1890.
[5] For reviews of triterpene biosynthesis, see: a) W. S. Johnson,
Acc. Chem. Res. 1968, 1, 1; b) E. E. van Tamelen, Acc. Chem.
Res. 1968, 1, 111; c) D. E. Cane, Chem. Rev. 1990, 90, 1089; d) I.
Abe, M. Rohmer, G. D. Prestwich, Chem. Rev. 1993, 93, 2189;
e) G. D. Brown, Nat. Prod. Rep. 1998, 15, 653; f) K. U. Wendt,
G. E. Schulz, E. J. Corey, D. R. Liu, Angew. Chem. Int. Ed. 2000,
39, 2812; Angew. Chem. 2000, 112, 2930; g) I. Abe, Nat. Prod.
Rep. 2007, 24, 1311.
[6] For computational studies on triterpene biosynthesis, see: a) C.
Jenson, W. L. Jorgensen, J. Am. Chem. Soc. 1997, 119, 10846;
b) R. Rajamani, J. Gao, J. Am. Chem. Soc. 2003, 125, 12768; c) L.
Kꢁrti, R.-J. Chein, E. J. Corey, J. Am. Chem. Soc. 2008, 130, 9031;
d) L. Smentek, B. A. Hess, Jr., J. Am. Chem. Soc. 2010, 132,
17111; e) D. J. Tantillo, Nat. Prod. Rep. 2011, 28, 1035; f) B. A.
Hess, Jr., Org. Biomol. Chem. 2017, 15, 2133.
[7] a) T. Kanchanapoom, P. Noiarsa, S. Ruchirawat, R. Kasai, H.
Otsuka, Phytochemistry 2004, 65, 2613; b) T. Kanchanapoom, P.
Noiarsa, R. Kasai, H. Otsuka, S. Ruchirawat, Tetrahedron 2005,
61, 2583.
[8] a) M. Kato, H. Kosugi, A. Yoshikoshi, J. Chem. Soc. D 1970, 185;
b) C. H. Heathcock, R. Ratcliffe, J. Am. Chem. Soc. 1971, 93,
1746; c) M. Ando, K. Ibayashi, N. Minami, T. Nakamura, K.
Isogai, J. Nat. Prod. 1994, 57, 433.
[9] a) B. M. Fraga, Nat. Prod. Rep. 2013, 30, 1226; b) F. Le Bideau,
M. Kousara, L. Chen, L. Wei, F. Dumas, Chem. Rev. 2017, 117,
6110.
[10] For stereospecific migrations, see: a) D. H. R. Barton, O. C.
Bçckman, P. de Mayo, J. Chem. Soc. 1960, 2263; b) S. Huneck,
Tetrahedron Lett. 1963, 4, 1977; c) L. L. Smith, T. J. Foell, D. M.
Teller, J. Org. Chem. 1965, 30, 3781; d) R. E. Corbett, R. A. J.
Smith, H. Young, J. Chem. Soc. C 1968, 1823; e) C. H. Heath-
cock, R. Ratcliffe, Chem. Commun. 1968, 994; f) H. W. Whit-
lock, Jr., P. B. Reichardt, F. M. Silver, J. Am. Chem. Soc. 1971,
93, 485.
Acknowledgements
Dr. Brandon Mercado is acknowledged for X-ray crystallog-
raphy of compound 8. This work was supported by the HPC
facilities operated by, and the staff of, the Yale Center for
Research Computing. Financial support was provided by Yale
University and the Sloan Foundation. Graduate student
support was provided through National Science Foundation
Graduate Research Fellowships (A.C.S. and A.T.), a Ford
Foundation Fellowship (A.C.S.), and a Dox Fellowship
(M.E.).
[11] For nonselective migrations, see: a) R. E. Corbett, R. A. J.
Smith, J. Chem. Soc. C 1969, 44; b) H. W. Whitlock, Jr., L. E.
Overman, J. Am. Chem. Soc. 1971, 93, 2247; c) R. C. Ebersole,
F. C. Chang, J. Org. Chem. 1973, 38, 2579.
Conflict of interest
The authors declare no conflict of interest.
[12] For reviews of the use of computational chemistry in natural
product synthesis, see: a) D. J. Tantillo, Chem. Soc. Rev. 2018, 47,
7845; b) M. Elkin, T. R. Newhouse, Chem. Soc. Rev. 2018, 47,
7830.
Keywords: biomimetic synthesis · biosynthesis ·
density functional calculations · natural products synthesis ·
structural reassignment
[13] Gaussian09, revisionD.01, M. J. Frisch et al., Gaussian, Inc.,
Wallingford, CT, 2013.
[14] a) M. W. Lodewyk, M. R. Siebert, D. J. Tantillo, Chem. Rev.
2012, 112, 1839; b) P. H. Willoughby, M. J. Jansma, T. R. Hoye,
Nat. Protoc. 2014, 9, 643.
[15] S. G. Smith, J. M. Goodman, J. Am. Chem. Soc. 2010, 132, 12946.
[16] G.-J. Cheng, X. Zhang, L. W. Chung, L. Xu, Y.-D. Wu, J. Am.
Chem. Soc. 2015, 137, 1706.
[1] a) P. Dzubak, M. Hajduch, D. Vydra, A. Hustova, M. Kvasnica,
D. Biedermann, L. Markova, M. Urban, J. Sarek, Nat. Prod. Rep.
4
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
[17] A. W. Schuppe, D. Huang, Y. Chen, T. R. Newhouse, J. Am.
[22] a) K. Humski, H. L. Goering, J. Am. Chem. Soc. 1969, 91, 4594;
Chem. Soc. 2018, 140, 2062.
[18] M. G. Banwell, D. C. R. Hockless, M. D. McLeod, New J. Chem.
2003, 27, 50.
b) M. A. Imhoff, R. M. Ragain, K. Moore, V. J. Shiner, Jr., J.
Org. Chem. 1991, 56, 3542.
[23] D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117,
9357.
[24] S. P. T. Matsuda, W. K. Wilson, Q. Xiong, Org. Biomol. Chem.
2006, 4, 530.
[25] a) A. Rauk, T. S. Sorensen, C. Maerker, K. W. de M. Carneiro,
S. Sieber, P. v. R. Schleyer, J. Am. Chem. Soc. 1996, 118, 3761;
b) A. Rauk, T. S. Sorensen, P. v. R. Schleyer, J. Chem. Soc.
Perkin Trans. 2 2001, 869.
[19] a) J. M. Mayer, Annu. Rev. Phys. Chem. 2004, 55, 363; b) T. V.
Chciuk, W. R. Anderson, Jr., R. A. Flowers, J. Am. Chem. Soc.
2016, 138, 8738; c) S. S. Kolmar, J. M. Mayer, J. Am. Chem. Soc.
2017, 139, 10687; d) T. V. Chciuk, W. R. Anderson, R. A.
Flowers, J. Am. Chem. Soc. 2018, 140, 15342.
[20] C1-epi-7 was prepared from enone 4 via the following sequence:
nucleophilic epoxidation, reductive opening, and diastereose-
lective reduction (see Supporting Information for details).
[21] a) K. C. Westaway, Advances in Physical Organic Chemistry,
Vol. 41, Elsevier, London, 2006, p. 217; b) K. C. Westaway, J.
Labelled Compd. Radiopharm. 2007, 50, 989; c) M. P. Meyer,
Advances in Physical Organic Chemistry, Vol. 46, Elsevier,
London, 2012, p. 57; d) J. S. Dickschat, Eur. J. Org. Chem.
2017, 4872.
[26] G. Xu, M. Elkin, D. Tantillo, T. R. Newhouse, T. Maimone,
Angew. Chem. Int. Ed. 2017, 56, 12498; Angew. Chem. 2017, 129,
12672.
Manuscript received: September 13, 2018
Revised manuscript received: October 30, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Biomimetic Synthesis
Rearrangement process: A biomimetic
cationic structural rearrangement of the
oleanolic acid framework is reported for
the gram-scale synthesis of justicioside E
aglycone. The mechanism of the putative
biosynthetic rearrangement is investi-
gated with kinetic, computational, and
synthetic approaches.
M. Elkin, A. C. Scruse, A. Turlik,
T. R. Newhouse*
&&&& — &&&&
Computational and Synthetic
Investigation of Cationic Rearrangement
in the Putative Biosynthesis of Justicane
Triterpenoids
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!