Enantioselective Total Synthesis of Berkeleyone A and Preaustinoids

Article abstract of DOI:10.1002/anie.202104014

Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (?)-berkeleyone A and its five congeners ((?)-preaustinoids A, A1, B, B1, and B2) in 12–15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)₃-mediated sequential Krapcho dealkoxycarbonylation/carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α-ketol, α-hydroxyl-β-diketone, etc.) responsible for the biomimetic diversification of (?)-berkeleyone A into its five preaustinoid congeners.

Full text of DOI:10.1002/anie.202104014

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Enantioselective Total Synthesis of Berkeleyone A and
Preaustinoids
Authors: Houhua Li, Yang Zhang, Yunpeng Ji, Ivan Franzoni, Chuning
Guo, Hongli Jia, and Benke Hong
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.202104014
Link to VoR: https://doi.org/10.1002/anie.202104014

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Total Synthesis of Berkeleyone A and
Preaustinoids
Yang Zhang,[a] Yunpeng Ji,[a] Ivan Franzoni,[b] Chuning Guo,[a] Hongli Jia,[a] Benke Hong,[a] and Houhua
Li*[a]
This paper is dedicated to Prof. Herbert Waldmann and Prof. Xiaoguang Lei
[a]
Dr. Y. Zhang,† Y. Ji,† C. Guo, Dr. H. Jia, Dr. B. Hong, Prof. Dr. H. Li
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences
Peking University
Xue Yuan Road No. 38, Beijing 100191, China
E-mail: lihouhua@pku.edu.cn
[b]
Dr. I. Franzoni
NuChem Sciences
2350 rue Cohen Suite 201, Saint-Laurent, Quebec, Canada H4R 2N6
These authors contributed equally to this work
[†]
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we report the first enantioselective total synthesis of
3,5-dimethylorsellinic acid-derived meroterpenoids (−)-berkeleyone A
and its five congeners ((−)-preaustinoids A, A1, B, B1 and B2) in 12-
15 steps, respectively, starting from commercially available 2,4,6-
trihydroxybenzoic acid hydrate. Based upon the recognition of latent
symmetry within D-ring, our convergent synthesis features two critical
reactions: (1) a symmetry-breaking, diastereoselective dearomative
alkylation to assemble the entire carbon core, and (2) a Sc(OTf)3-
mediated sequential Krapcho dealkoxycarbonylation/carbonyl -tert-
alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We
also conducted our preliminary biomimetic investigations and
uncovered a series of rearrangements (-ketol, -hydroxyl--diketone,
etc) responsible for the biomimetic diversification of (−)-berkeleyone
A into its five preaustinoid congeners.
racemic total synthesis of 1 and select andrastin/terretonin
congeners have been reported by Maimone and Newhouse
groups,
where
oxidative
ring
expansion
and
an
isomerization−cyclization cascade have been independently
applied for the installation of bicyclo[3.3.1]nonane core.[5] En route
to polycyclic terpenoids and terpenoid hybrids,[6] we also initiated
our investigations into DMOA-derived meroterpenoids. Herein we
report our synthetic endeavors, which ultimately accumulate into
the first enantioselective total synthesis of 1-6 in 12-15 steps,
respectively.
Fungal meroterpenoids derived from a simple aromatic polyketide
3,5-dimethylorsellinic acid (DMOA) are a large series of hybrid
natural products with huge structural diversity and impressive
bioactivities.[1] Since the isolation of their first congener in 1976,
over 100 compounds have been described. From a biosynthetic
point of view, (−)-berkeleyone A (1) stands as a potential gateway
compound through the union of a polyketide fragment DMOA with
farnesyl pyrophosphate (Figure 1).[2,3] Thereon, diversification at
A-ring generates (−)-preaustinoid A (2) and (−)-preaustinoid A1
(3), where contraction of D-ring produces (−)-preaustinoid B (4),
(−)-preaustinoid B1 (5), and (+)-preaustinoid B2 (6).[2]
Interestingly, 1-3 also possess anti-inflammatory properties by
inhibiting the signaling enzyme caspase-1.[2d] To further unveil the
biological function and therapeutic potential of DOMA-derived
meroterpenoids, both biological and chemical synthetic studies
have been done extensively in the past decade.[3-5]
Figure 1. Representative structures of 3,5-dimethylorsellinic acid (DMOA)-
derived meroterpenoids.
At the outset of our investigations, the recognition of a hidden
symmetry within the D-ring of (−)-berkeleyone A (1) proved to be
essential to our synthetic plan. As has already been constantly
recognized in many landmark total syntheses, the recognition of
latent symmetry in a target molecule would drastically simplify the
task at hand.[7] Depicted in Figure 2A, upon replacement of CH2
with O at C23 position, the highly oxidized D-ring can therefore be
From a chemical synthesis perspective,[4,5] DMOA-derived
meroterpenoids present an exceedingly challenge, as exemplified
by (−)-berkeleyone A (1), which possess a dense tetracyclic
framework with a hallmark bicyclo[3.3.1]nonane core, three
quaternary carbon centers within C-ring, and a highly oxidized D-
ring without any hydrogen atom substituents. Hitherto two elegant
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
extracted to
a
symmetrical methyl 4-methoxy-3,5-dimethyl
diastereoselectivity (>20:1). To the best of our knowledge, this is
the first diastereoselective dearomative alkylation of
acylphloroglucinols with cyclic electrophiles.
phloroglucinol carboxylate (7). Thus, (−)-berkeleyone A (1), a
common precursor to preaustinoids 2-6 through biomimetic
diversification, were retrosynthetically reduced to the tetracyclic
intermediate 8 (Figure 2B). The challenging C11-C12 linkage of 8
can be forged through an intramolecular carbonyl -tert-alkylation
of keto-ester 9,[8-11] which also simultaneously installs two
adjacent quaternary carbon centers C11 and C12.[12] To achieve
a convergent synthesis, intermediate 9 was assembled through a
symmetry-breaking dearomative alkylation of 7 with bicyclic
fragment 10.[13] Finally, carboxylate 7 would be easily obtained
through a successive ortho-methylation sequence, starting from
commercially available 2,4,6-trihydroxybenzoic acid hydrate
(11).[14]
Figure 3. Diastereoselectivity rationale based on DFT calculations.
Diastereoselective determined transition state calculation at the M06-2X/6-
31+G(d,p)//B3LYP-D3BJ/6-31G(d) level in THF (SMD solvation model).
Figure 2. Retrosynthetic analysis of 1-6 based on hidden symmetry recognition.
To rationalize the unprecedented high level of
diastereoselectivity observed in the crucial triflate nucleophilic
displacement step, we carried out DFT calculations at the
SMD(THF)/M06-2X/6-31+G(d,p)//B3LYP-D3BJ/6-31G(d) level of
theory (Figure 3 and see Supporting Information (SI) for details).
The inclusion of the dispersion correction term was found to be
pivotal in computationally rationalizing our experimental results.
Detailedly, among the diverse, plausible forms of the nucleophilic
partner 7 (i.e. bisdeprotonated, lithium ion adducts), mono anion
13 was firstly identified as computed active species.[16] This
intermediate is characterized by a stable intramolecular H-bond
interaction between the hydroxyl and carbonyl groups. In the
computed transition states, mono anion 13 approaches 10c from
the most accessible face while maximizing the contact between
the aromatic π-system of 13 and the lipophilic surface of the 6,6-
fused bicyclic framework of 10c. The computed relative energy
difference between two transition states TS-major 14 and TS-
minor 15 is 2.1 kcal/mol, corresponding to a predicted
As shown in Scheme 1, we commenced our studies by
synthesizing aldehyde 12 following a known 4-step protocol (see
Scheme S1).[14] Subsequent reduction afforded carboxylate 7. In
addition, using a modified Sharpless asymmetric dihydroxylation
of commercially available farnesyl acetate followed by a reductive
cyclization, enantioenriched bicyclic fragment 10 could also be
easily prepared through a modified 5-step protocol (see Scheme
S2).[15] With 7 and 10 in hand, we embarked on our investigation
into symmetry-breaking dearomative alkylation.[13] Whereas
dearomative alkylation of acylphloroglucinols have previously
been well explored by Porco and George groups,[13] currently this
annulative method is limited to acyclic electrophiles, with always
poor diastereoselectivity in all cases owing to the lack of remote
stereocontrol. In our case, we initially observed decomposition
with iodide 10a or bromide 10b derived from 10 due to their inner
instability. Later on, upon treatment of 7 with in-situ formed 10c
under basic conditions (LHMDS), two inseparable tautomers 9a
and 9b were isolated in 69% yield on a gram scale, with excellent
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Enantioselective total synthesis of 1-6. THF = tetrahydrofuran, DIPEA = N,N-diisopropylethylamine, MMPP = magnesium monoperoxyphthalate, TMSOTf
= trimethylsilyl trifluoromethanesulfonate, LDA = lithium diisopropylamide, m-CPBA = 3-chloroperbenzoic acid.
diastereoisomeric ratio of 34:1 in favor of 9a/9b over 16a/16b.
This result fully matches with the experimental ratio (>20:1). The
relative energy difference between transition states 14 and 15
presumably stems from a balance between attractive dispersion
forces and steric repulsion between 13 and 10c.[17] Overall, the
rigidity of 6,6-fused bicyclic scaffold defines better the interaction
between electrophile and aryl nucleophile, thereby inducing high
diastereoselectivity, while in the case of an acyclic electrophile, its
conformational flexibility is expected to significantly reduce the
diastereo-outcome of the reaction. Of note, the computed energy
difference for two tautomers 9a and 9b is 0.4 kcal/mol,
responsible for a predicted ratio of 2:1 in favor of 9a, which also
fully matched with the ratio observed (2:1).
Mn(OAc)3-mediated oxidative cyclization.[11] Disappointedly,
numerous studies with 9a/9b proved unfruitful and mainly led to
decomposition into unidentified side products (entries 1-4). With
a hope that the removal of methyl ester at C11 position might
drastically reduce steric crowding during carbonyl C11--tert-
alkylation, we conducted Krapcho dealkoxycarbonylation of 9a/9b
using 10 mol% of Sc(OTf)3 and 17 was generated smoothly.[18]
Diketone 17 was then engaged into different intramolecular
carbonyl -tert-alkylation conditions. Initial treatment of 17 with
various Brønsted acids again resulted in decomposition (entry 5).
Pleasingly, the desired carbonyl -tert-alkylation product 18 was
firstly obtained by using SnCl4 (entry 6), albeit contaminated with
O-tert-alkylation product 19 as the main product (27% yield).
Further screening of various Lewis acids identified Sc(OTf)3 as an
optimal catalyst which promoted 17 to preferentially undergo
carbonyl C11--tert-alkylation and delivered 18 in 50% yield
(entry 7).[9c] Of interesting note, Et2AlCl promoted a novel Prins
cyclization to afford 20 (entry 8).[19] Finally, starting from
With access to 9a/9b secured, we proceeded to the
intramolecular carbonyl -tert-alkylation (Table 1). At this stage,
we considered three distinct tactics to achieve this challenging
transformation: (i) Brønsted or Lewis acid-mediated cationic
cyclization;[8,9] (ii) photocatalyzed radical cyclization;[10] (iii)
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
inseparable 9a/9b, we maneuvered to operate a Sc(OTf)3-
mediated sequential Krapcho dealkoxycarbonylation/carbonyl -
tert-alkylation and 18 was isolated in 41% yields (entry 9). The
structures of three cyclization products 18, 19, and 20 described
above were determined based on 2D-NMR spectroscopy or
confirmed by X-ray crystallographic analysis.[20]
Meanwhile, we resorted to -ketol rearrangement for D-ring
contraction.[24] Whereas the reaction did not take place under
various acidic, basic and thermal conditions, pleasingly, upon
treatment with BF3●Et2O, -ketol rearrangement of 2 occurred
smoothly to afford (−)-preaustinoid B (4) as a sole ring contraction
product. Later on, treating 4 with 2.0 equivalent of aqueous NaOH
in EtOH afforded (−)-preaustinoid B2 (6) in 95% yield.
Interestingly, by using 0.4 equivalent of aqueous NaOH, we
obtained a mixture of (−)-preaustinoid B1 (5) and (−)-preaustinoid
B2 (6). Thus, an -hydroxyl--diketone rearrangement through in-
situ generated epoxyalkoxide (23) intermediate followed by basic
hydrolysis was most likely responsible for this deacylation
process.[25] All physical and spectroscopic data of synthetic 1-6
were in good accordance with those reported.[2] Moreover, the
structures of 2, 3, 4 and 6 were elucidated unambiguously by X-
ray crystallographic analysis.[26] Of note, we also corrected the
optical rotation of 6 as −54.0, which was originally reported as
+90.0.[2c]
Now in possession of key intermediate 18, we focused our
next efforts on the elaboration of highly oxidized D-ring (Scheme
1). Wittig olefination of 18 delivered 21 in 75% yield. The absolute
configurations were also secured at this stage by X-ray
crystallographic analysis of 21.[21] Subsequent C11 acylation of
either 18 or 21 under various basic conditions (LDA, LTMP, etc)
turned out to be problematic, presumably due to the interference
of C21 allylic methyl group within 18 or 21. Therefore, we
performed
demethylation/stereoselective
a
sequential
oxidation
Krapcho-type
magnesium
with
monoperoxyphthalate (MMPP).[5c] Subsequent TMS protection
delivered diketone 22, which underwent C11 acylation smoothly
using Mander’s reagent.[22] Acidic removal of silyl groups (TBS,
TMS) afforded the natural product (−)-berkeleyone A (1).
To conclude, benefited from the recognition of a hidden
symmetry within the D-ring, we have accomplished the first
enantioselective total synthesis of 1-6 in 12-15 steps, respectively,
starting from commercially available 2,4,6-trihydroxybenzoic acid
hydrate. In the course of our synthetic studies, we devised a
Table
1.
Sc(OTf)3-mediated
sequential
Krapcho
dealkoxycarbonylation/carbonyl -tert-alkylation[a]
.
highly convergent route relied upon
dearomative alkylation. Meanwhile,
a
diastereoselective
Sc(OTf)3-mediated
a
sequential Krapcho dealkoxycarbonylation/carbonyl -tert-
alkylation have been developed to forge bicyclo[3.3.1]nonane
core. At last, we also disclosed our preliminary biomimetic
investigations, which generated five additional preaustinoid
congeners through
a
series of rearrangements (-ketol
rearrangement, -hydroxyl--diketone rearrangement, etc).
Overall, our convergent route is highly modular, thereby should
be amenable to access structurally diverse DMOA-derived
meroterpenoids, as well as other bicyclo[3.3.1]nonane-containing
meroterpenoids, which are currently underway and will be
reported in due course.
Acknowledgements
Entry
1
Conditions
18[b]
19[b]
20[b]
We thank Prof. Chao Li (NIBS) and Prof. Yu-Ming Zhao (SNNU)
for helpful discussion. The computational study presented in this
paper was carried out on facilities provided by WestGrid
9a/9b, Brønsted acids (formic
acid, TFA, p-TsOH, etc)
9a/9b, Lewis acids (SnCl4,
Et2AlCl, BF3•Et2O, etc)
100% cons.[c]
2
(https://www.westgrid.ca/)
and
Compute
Canada
unidentified decomposed
side products
(www.computecanada.ca). Financial support from National
Natural Science Foundation of China (Grant No. 22071006),
Clinical Medicine Plus X-Young Scholars Project (Grant No.
PKU2020LCXQ003), Peking University, and National 1000-Youth
Talents Program is gratefully acknowledged.
3
4
9a/9b, LED 390 nm, MeCN
9a/9b, Mn(OAc)3, Cu(OAc)2,
AcOH
17, Brønsted acids (formic
acid, TFA, etc)
5
0
-
-
6
7
8
19%
50%
5%
27%
13%
-
10%
23%
67%
17, SnCl4, CH2Cl2, 23C
17, Sc(OTf)3, CH2Cl2, 23C
17, Et2AlCl, CH2Cl2, 23C
Keywords: hidden symmetry • biomimetic rearrangements •
meroterpenoids • natural products • total synthesis
9a/9b, Sc(OTf)3, DMSO,
100C, then CH2Cl2, 23C
9
41%
6%
9%
[1]
[2]
a) R. Geris, T. Simpson, J. Nat. Prod. Rep. 2009, 26, 1063-1094; b) Y.
Matsuda, I. Abe, Nat. Prod. Rep. 2016, 33, 26-53; c) Y. Matsuda, T.
Awakawa, T. Mori, I. Abe, Curr. Opin. Chem. Biol. 2016, 31, 1-7.
a) R. M. Geris dos Santos, E. Rodrigues-Fo, Phytochemistry 2002, 61,
907-912; b) R. M. Geris dos Santos, E. Rodrigues-Fo, Z. Naturforsch.
2003, 58c, 663-669; c) T. P. Fill, G. K. Pereira, R. M. Geris dos Santos,
E. Rodrigues-Fo, Z. Naturforsch. 2007, 62b, 1035-1044; d) D. B. Stierle,
[a] See Table S19 for details. [b] Isolated yield. [c] cons. = consumption.
Finally, we turned our attention to biomimetic diversification of
1. Therefrom, oxidation with Dess−Martin periodinane delivered
(−)-preaustinoid A (2) in 88% yield. Further Baeyer−Villiger
oxidation of 2 generated (−)-preaustinoid A1 (3) in 43% yield.[23]
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
A. A. Stierle, B. Patacini, K. McIntyre, T. Girtsman, E. Bolstad, J. Nat.
Prod. 2011, 74, 2273-2277.
Zhang, B. Mitasev, J. Qi, J. A. Porco, Jr., J. Am. Chem. Soc. 2010, 132,
14212-14215; c) A. J. Grenning, J. H. Boyce, J. A. Porco, Jr., J. Am.
Chem. Soc. 2014, 136, 11799-11804; d) M. Hayashi, L. E. Brown, J. A.
Porco, Jr., Eur. J. Org. Chem. 2016, 4800-4804. and Ref.s [3f], [4g], [8],
[10], [11b-d].
[3]
For
selected
biosynthetic
studies
towards
DMOA-derived
meroterpenoids, see: a) H.-C. Lo, R. Entwistle, C.-J. Guo, M. Ahuja, E.
Szewczyk, J.-H. Hung, Y.-M. Chiang, B. R. Oakley, C. C. C. Wang, J.
Am. Chem. Soc. 2012, 134, 4709-4720; b) C.-J. Guo, B. P. Knox, Y.-M.
Chiang, H.-C. Lo, J. F. Sanchez, K.-H. Lee, B. R. Oakley, K. S. Bruno, C.
C. C. Wang, Org. Lett. 2012, 14, 5684-5687; c) T. Itoh, K. Tokunaga, E.
K. Radhakrishnan, I. Fujii, I. Abe, Y. Ebizuka, T. Kushiro, ChemBioChem
2012, 13, 1132-1135; d) Y. Matsuda, T. Awakawa, T. Itoh, T. Wakimoto,
T. Kushiro, I. Fujii, Y. Ebizuka, I. Abe, ChemBioChem 2012, 13, 1738-
1741; e) Y. Matsuda, T. Awakawa, I. Abe, Tetrahedron 2013, 69, 8199-
8204; f) T. Mitsuhashi, L. Barra, Z. Powers, V. Kojasoy, A. Cheng, F.
Yang, Y. Taniguchi, T. Kikuchi, M. Fujita, D. J. Tantillo, J. A. Porco, Jr., I.
Abe, Angew. Chem. 2020, 132, 23980-23989; Angew. Chem. Int. Ed.
2020, 59, 23772-23781.
[14] M. Schmid, D. Trauner, Angew. Chem. 2017, 129, 12500-12504; Angew.
Chem. Int. Ed. 2017, 56, 12332-12335.
[15] a) A. F. Barrero, M. Mar Herrador, J. F. Quílez del Moral, P. Arteaga, J.
F. Arteaga, M. Piedra, E. M. Sánchez, Org. Lett. 2005, 7, 2301-2304; b)
V. Domingo, L. Silva, H. R. Diéguez, J. F. Arteaga, J. F. Quílez del Moral,
A. F. Barrero, J. Org. Chem. 2009, 74, 6151-6156.
[16] Attempts to experimentally identify active species mono anion 13 was
unsuccessful due to the formation of a heterogeneous reaction mixture
during the deprotonation step.
[17] a) G. Lu, R. Y. Liu, Y. Yang, C. Fang, D. S. Lambrecht, S. L. Buchwald,
P. Liu, J. Am. Chem. Soc. 2017, 139, 16548-16555; b) A. A. Thomas, K.
Speck, I. Kevlishvili, Z. Lu, P. Liu, S. L. Buchwald, J. Am. Chem. Soc.
2018, 140, 13976-13984; c) U. Dhawa, R. Connon, J. C. A. Oliveira, R.
[4]
For previous synthetic studies towards DMOA-derived meroterpenoids,
see: a) J. E. Spangler, E. J. Sorensen, Tetrahedron 2009, 65, 6739-6745;
b) J. E. Spangler, Ph.D. Dissertation, Princeton University, 2011; c) J. W.
Lockner, Ph.D. Dissertation, The Scripps Research Institute, 2011; d) R.
Okamoto, K. Takeda, H. Tokuyama, Ihara, M.; Toyota, M. J. Org. Chem.
2013, 78, 93-103; e) K. Suzuki, H. Yamakoshi, S. Nakamura, Chem. Eur.
J. 2015, 21, 17605-17609; f) G. Zhu, C. Zhou, S. Chen, S. Fu, B. Liu,
Org. Lett. 2019, 21, 7809-7812; g) Z. Powers, A. Scharf, A. Cheng, F.
Yang, M. Himmelbauer, T. Mitsuhashi, L. Barra, Y. Taniguchi, T. Kikuchi,
M. Fujita, I. Abe, J. A. Porco, Jr., Angew. Chem. 2019, 131, 16287-
16292; Angew. Chem. Int. Ed. 2019, 58, 16141-16146.
Steinbock,
L.
Ackermann,
Org.
Lett.
2021,
DOI:
10.1021/acs.orglett.1c00615.
[18] For a review, see: A. P. Krapcho, E. Ciganek, Org. React. 2013, 81, 1-
535.
[19] For a review, see: X. Han, G. Peh, P. E. Floreancig, Eur. J. Org. Chem.
2013, 1193-1208.
[20] CCDC 2042296 (20) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[5]
a) C. P. Ting, G. Xu, X. Zeng, T. J. Maimone, J. Am. Chem. Soc. 2016,
138, 14868-14871; b) M. Elkin, S. M. Szewczyk, A. C. Scruse, T. R.
Newhouse, J. Am. Chem. Soc. 2017, 139, 1790-1793; c) G. Xu, M. Elkin,
D. J. Tantillo, T. R. Newhouse, T. J. Maimone, Angew. Chem. 2017, 129,
12672-12676; Angew. Chem. Int. Ed. 2017, 56, 12498-12502.
[21] CCDC 2042297 (21) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[22] L. N. Mander, S. P. Sethi, Tetrahedron Lett. 1983, 24, 5425-5428.
[23] T.-K. Ma, P. J. Parsons, A. G. M. Barrett, J. Org. Chem. 2019, 84, 4961-
4970.
[6]
[7]
a) B. Hong, C. Li, Z. Wang, J. Chen, H. Li, X. Lei, J. Am. Chem. Soc.
2015, 137, 11946-11949; b) B. Hong, W. Liu, J. Wang, J. Wu, Y.
Kadonaga, P.-J. Cai, H.-X. Lou, Z.-X. Yu, H. Li, X. Lei, Chem 2019, 5,
1671-1681.
[24] For a review, see: a) L. A. Paquette, J. E. Hofferberth, Org. React. 2003,
62, 477-567. For selected examples, see: b) L. A. M. Murray, S. M. K.
McKinnie, H. P. Pepper, R. Erni, Z. D. Miles, M. C. Cruickshank, B.
López-Pérez, B. S. Moore, J. H. George, Angew. Chem. 2018, 130,
11175-11180; Angew. Chem. Int. Ed. 2018, 57, 11009-11014. (c) H. Wu,
R. Andres, Q. Wang, J. Zhu, Angew. Chem. 2019, 131, 509-513; Angew.
Chem. Int. Ed. 2019, 58, 499-503.
For recent reviews, see: a) J. K. Kisunzu, R. Sarpong, Angew. Chem.
2013, 125, 10890-10892; Angew. Chem. Int. Ed. 2013, 52, 10694-10696;
b) W.-J. Bai, X. Wang, Nat. Prod. Rep. 2017, 34, 1345-1358. For
selected recent examples, see: c) S. Mahapatra, R. G. Carter, Angew.
Chem. 2012, 124, 8072-8075; Angew. Chem. Int. Ed. 2012, 51, 7948-
7951; d) S. Mahapatra, R. G. Carter, J. Am. Chem. Soc. 2013, 135,
10792-10803; e) J. T. Malinowski, R. J. Sharpe, J. S. Johnson, Science
2013, 340, 180-182; f) M. Nagatomo, M. Koshimizu, K. Masuda, T.
Tabuchi, D. Urabe, M. Inoue, J. Am. Chem. Soc. 2014, 136, 5916-5919;
g) M. Yang, J. Li, A. Li, Nat. Commun. 2015, 6, 6445.
[25] a) M. B. Rubin, S. Inbar, Tetrahedron Lett. 1979, 52, 5021-5024; b) M. B.
Rubin, S. Inbar, J. Org. Chem. 1988, 53, 3355-3358; c) M. Kawamura, S.
Kamo, S. Azuma, K. Kubo, T. Sasamori, N. Tokitoh, K. Kuramochi, K.
Tsubaki, Org. Lett. 2017, 19, 301-303.
[26] CCDC 2042298, 2042313, 2053783 and 2053785 [2, 3, 4, 6] contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre.
[8]
[9]
For Brønsted acid-mediated cationic carbonyl -tert-alkylation, see: a) J.
H. Boyce, J. A. Porco, Jr., Angew. Chem. 2014, 126, 7966-7971; Angew.
Chem. Int. Ed. 2014, 53, 7832-7837; b) J. H. Boyce, V. Eschenbrenner-
Lux, J. A. Porco, Jr., J. Am. Chem. Soc. 2016, 138, 14789-14797.
For Lewis acid-mediated cationic carbonyl -tert-alkylation, see: a) E. E.
van Tamelen, J. R. Hwu, T. M. Leiden, J. Chem. Soc. Chem. Commun.
1983, 62-63; b) E. Fillion, D. Fishlock, J. Am. Chem. Soc. 2005, 127,
13144-13145; c) C. C. McAtee, D. C. Ellinwood, R. C. McAtee, C. S.
Schindler, Tetrahedron 2018, 74, 3306-3313.
[10] For photocatalyzed radical carbonyl -tert-alkylation, see: S. Wen, J. H.
Boyce, S. K. Kandappa, J. Sivaguru, J. A. Porco, Jr., J. Am. Chem. Soc.
2019, 141, 11315-11321.
[11] For Mn(OAc)3-mediated oxidative carbonyl -tert-alkylation, see: a) B. B.
Snider, Chem. Rev. 1996, 96, 339-363; b) B. Mitasev, J. A. Porco, Jr.,
Org. Lett. 2009, 11, 2285-2288; c) H. P. Pepper, H. C. Lam, W. M. Bloch,
J. H. George, Org. Lett. 2012, 14, 5162-5164; d) H. P. Pepper, S. J. Tulip,
Y. Nakano, J. H. George, J. Org. Chem. 2014, 79, 2564-2573.
[12] For recent reviews, see: a) R. Long, J. Huang, J. Gong, Z. Yang, Nat.
Prod. Rep. 2015, 32, 1584-1601; b) M. Bꢀschleb, S. Dorich, S.
Hanessian, D. Tao, K. B. Schenthal, L. E. Overman, Angew. Chem. 2016,
128, 4226-4258; Angew. Chem. Int. Ed. 2016, 55, 4156-4186.
[13] For examples of dearomative alkylation of acylphloroglucinols, see: a) J.
Qi, J. A. Porco, Jr., J. Am. Chem. Soc. 2007, 129, 12682-12683; b) Q.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202104014
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Based upon the recognition of latent symmetry within D-ring, we accomplished the first enantioselective total synthesis of (−)-
berkeleyone A and its five preaustinoid congeners. Meanwhile, we also uncovered a series of biomimetic rearrangements that would
lend credence to the proposed biosynthetic sequence of DMOA-derived meroterpenoids.
6
This article is protected by copyright. All rights reserved.