Bispericyclic Diels–Alder Dimerization of ortho-Quinols in Natural Product (Bio)Synthesis: Bioinspired Chemical 6-Step Synthesis of (+)-Maytenone

Article abstract of DOI:10.1002/anie.202103410

Many natural products of plant or microbial origins are derived from enzymatic dearomative oxygenation of 2-alkylphenolic precursors into 6-alkyl-6-hydroxycyclohexa-2,4-dienones. These so-called ortho-quinols cyclodimerize via a remarkably selective bispericyclic Diels–Alder reaction. Whether or not the intervention of catalytic or dirigent proteins is involved during this final step of the biosynthesis of these natural products, this cyclodimerization of ortho-quinols can be chemically reproduced in the laboratory with the same strict level of site-specific regioselectivity and stereoselectivity. This unique yet unified process, which finds its rationale in the inherent chemical reactivity of those ortho-quinols, is illustrated herein by an efficient and bioinspired first chemical synthesis of one of the most structurally complex and synthetically challenging examples of such natural cyclodimers, the bisditerpenoid (+)-maytenone.

Full text of DOI:10.1002/anie.202103410

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Bispericyclic Diels–Alder Dimerization of ortho-Quinols in Natural
Product (Bio)Synthesis – Bioinspired Chemical 6-Step Synthesis
of (+)-Maytenone
Authors: Philippe A. Peixoto, Mourad El Assal, Isabelle Chataigner,
Frédéric Castet, Anaëlle Cornu, Romain Coffinier, Cyril
Bosset, Denis Deffieux, Laurent Pouységu, and Stéphane
Quideau
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202103410
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
Bispericyclic Diels–Alder Dimerization of ortho-Quinols in Natural
Product (Bio)Synthesis – Bioinspired Chemical 6-Step Synthesis
of (+)-Maytenone
Philippe A. Peixoto,[a] Mourad El Assal,[a] Isabelle Chataigner,[b]† Frédéric Castet,[a] Anaëlle Cornu,[a]
Romain Coffinier,[a] Cyril Bosset,[a] Denis Deffieux,[a] Laurent Pouységu,*[a] and Stéphane Quideau*[a,c]
[a]
[b]
[c]
Dr P. A. Peixoto, Dr M. El Assal, Prof. F. Castet, A. Cornu, Dr R. Coffinier, Dr C. Bosset, Dr D. Deffieux, Prof. L. Pouységu, Prof. S. Quideau
Univ. Bordeaux, ISM (CNRS-UMR 5255)
351 cours de la Libération, 33405 Talence Cedex, France
E-mail: laurent.pouysegu@u-bordeaux.fr, stephane.quideau@u-bordeaux.fr
Prof. I. Chataigner
Laboratoire COBRA (CNRS-UMR 6014)
Normandie Université, INSA Rouen, UNIROUEN
1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France
Prof. S. Quideau
Institut Universitaire de France
1 rue Descartes, 75231 Paris Cedex 05, France
†Present address: Sorbonne Université, LCT (CNRS-UMR 7616), 4 place Jussieu, 75052 Paris Cedex, France
Supporting information for this article is given via a link at the end of the document.
Abstract: Many natural products of plant or microbial origins are
derived from enzymatic dearomative oxygenation of 2-alkylphenolic
precursors into 6-alkyl-6-hydroxycyclohexa-2,4-dienones. These so-
p systems. It is commonly accepted that these systems usually
react with each other according to the principles of the frontier
molecular orbital theory in line with the Woodward–Hoffmann
rules of orbital symmetry conservation[4] in a thermally-allowed
and concerted cyclizing process through orbital interactions
between the same faces (i.e., suprafacial) of both 4p and 2p
components. The four connecting sp2-centers are converted into
sp3-centers, all possibly stereogenic, and the remaining 2p unit of
the cyclohexenic adducts can be exploited for further
transformations. It is therefore not surprising that such reactivity
characteristics, bond-forming events and selectivity performances
have promoted the Diels–Alder reaction among organic chemists’
all-time favorite chemical transformations.
called ortho-quinols cyclodimerize via
a remarkably selective
bispericyclic Diels–Alder reaction. Whether or not the intervention of
catalytic or dirigent proteins is involved during this final step of the
biosynthesis of these natural products, this cyclodimerization of ortho-
quinols can be chemically reproduced in the laboratory with the same
strict level of site-specific regioselectivity and stereoselectivity. This
unique yet unified process, which finds its rationale in the inherent
chemical reactivity of those ortho-quinols, is illustrated herein by an
efficient and bioinspired first chemical synthesis of one of the most
structurally complex and synthetically challenging examples of such
natural cyclodimers, the bisditerpenoid (+)-maytenone.
The chemical synthesis of numerous natural products,
analogues thereof, as well as pharmaceutical drugs and diverse
agrochemicals has been rendered possible thanks to the
utilization of one or another variant of the Diels–Alder reaction.[5]
The biosynthesis of many natural products also relies on [4+2]
cycloaddition processes. The intervention of specialized enzymes,
referred to as Diels-Alderases, has often been invoked,[6]
although there exist several cases for which the cycloaddition step
can be reproduced in the laboratory under mild conditions without
any enzyme or any other type of catalysts or controlling
additives.[7] In this regard, the [4+2] cyclodimerization of 6-alkyl-
6-hydroxycyclohexa-2,4-dienones (commonly referred to as
ortho-quinols) into bicyclo[2.2.2]octenone derivatives constitutes
a fascinating example of such processes that relates to the
biosynthesis of numerous plant and microbial metabolites. The
bismonoterpenoid (+)-biscarvacrol (1),[8a] bissesquiterpenoids
Introduction
The Diels–Alder [4+2] cycloaddition belongs to the category of
those venerable chemical transformations that continue to
provide organic chemists with key tactical solutions for the
synthesis of complex molecules. Since its discovery in 1928,[1] the
Diels–Alder reaction has been the subject of countless
applications, variations and investigations on its mechanism,
modes of activation and levels of selectivity.[2] This two-bond-
forming pericyclic combination of a planar conjugated diene (4p
component) with a dienophile (2p component), which is not
restricted to olefins as it can also involve heteroatomic reacting
centers (e.g., N, O, S),[2d,3] is strongly influenced by the
stereoelectronic nature of substituents directly or even remotely
connected to the reacting p systems. The facility with which the
(+)-aquaticol
(2)[8b]
and
(–)-bacchopetiolone
(3),[8c]
bisditerpenoids (+)-maytenone (4)[8d,e] and (–)-hugonone A (5),[8f]
the plant cyclohexene oxide anabolite (–)-grandifloracin (6),[8g,h]
the phytoquinonoid (+)-illihendione A (7),[8i] the fungal polyketide
(+)-bisorbicillinol (8),[8j] and the bacterial phenol degradation
metabolite (–)-bis-2,6-xylenol (9)[8k] are representative examples
of such natural Diels–Alder cyclodimers (Figure 1).
reaction takes place, the manner through which both
p
components approach each other, the selection of transition
states, and hence the regio- and stereochemical outcomes all
critically depend on the substitution patterns of the starting
1
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
inherent chemical reactivity preferences and structural
particularities of those ortho-quinols. This enigmatic search has
kept organic chemists busy for decades since Wessely’s
pioneering work on ortho-quinol acetates sixty years ago.[12] Over
the years, several chemical methods relying on the use of, inter
alia, lead(IV)-, Se(IV)-, iodine(III)-, iodine(V)-, iodine(VII)-, and
copper(I)-based reagents have been developed to prepare ortho-
quinols in either racemic or stereocontrolled formats,[13] and their
self-cyclodimerizing variants were successfully utilized in the
chemical synthesis of a number of natural products, including
biscarvacrol (1),[11a,14] aquaticol (2),[14b,15] bacchopetiolone (3),[16]
grandifloracin (6),[8h,11a,17] illihendione A (7)[18] and bisorbicillinol
(8)[19] (Figure 1). Our own work on (chiral) iodine(V)-mediated
hydroxylative phenol dearomatization (HPD) reactions drove us
to accomplish several of these “biomimetic” syntheses,[11a,14c,15,16]
and hence to investigate what makes the behavior of those ortho-
quinols so special in their [4+2] cyclodimerization.
endo-
approach
5’
HO
5
R
diene
HO
R
HO
R
O
5’
4
O
HO
R
R
6
[4+2]
5
2’
2’
OH
4
2
O
cyclo-
dimerization
O
O
4
ortho-quinols
dienophile
bicyclo[2.2.2]octenones
HO
O
O
(–)-bacchopetiolone (3)
OH
OH
O
OH
(+)-biscarvacrol (1)
O
HO
O
HO
BzO
HO
O
(+)-aquaticol (2)
O
OH
BzO
O
HO
O
OH
O
HO
(–)-grandifloracin (6)
OH
O
(–)-hugonone A (5)
OH
OH
O
(+)-maytenone (4)
OH
O
OH
2
O
2
HO
HO
O
O
HO
O
OH
OH
[O]
O
6
OH
HO
O
HO
(–)-bis(2,6-xylenol) (9)
O
enzymatic
dearomative
6
O
S
OH
hydroxylation
SorbC
O
sorbicillin (11)
sorbicillinol (10)
an ortho-quinol
OH
(+)-bisorbicillinol (8)
O
O
HO
O
non-enzymatic
cyclodimerization !?
[4+2]
OH
(+)-illihendione A (7)
keto-enol
endo-
approach
OH
2’
HO
O
Figure 1. Examples of natural Diels–Alder cyclodimers of ortho-quinols. All of
these natural products of plant or microbial origins are elaborated by a [4+2]
cyclodimerization of ortho-quinols that strictly follows the same rules of site-
specific regioselectivity and stereoselectivity. R = alkyl groups.
OH
diene
O
O
5’
O
OH
OH
dienophile
O
O
4
OH
O
HO
5
12
O
OH
The requisite ortho-quinol intermediates would be biosynthetically
generated by enzymatic dearomative oxygenation of 2-
alkylphenolic precursors. Thorough investigations into this
hypothesis were conducted for the biosynthesis of sorbicillinoids
and led to the identification of the ortho-quinol sorbicillinol (10)
(Scheme 1).[9a] The dearomatization origin of this fungal quinol
was initially questioned,[9b] but was recently and firmly established
by the Cox group with the cloning of a polyketide synthase gene
keto-enol
tautomerism
(+)-bisorbicillinol (8)
Scheme 1. Final steps of the biosynthesis of (+)-bisorbicillinol (8). This
polyketide metabolite derives from the [4+2] cyclodimerization of the (S)-
enantiomer of sorbicillinol (10), the access to which being stereocontrolled by
the enzyme SorbC that mediates the enantioselective dearomative
hydroxylation of sorbicillin (11).
encoding
a
flavin
(SorbC)
adenine
capable
dinucleotide-dependent
of dearomatizing
monooxygenase
enantioselectively the 2,6-dimethylphenolic precursor sorbicillin
(11) into (S)-10,[10a] which can thereafter spontaneously
cyclodimerize into 12 to furnish (+)-bisorbicillinol (8) via a keto-
enol tautomerism (Scheme 1).[10b,c]
An ortho-quinol with a single stereogenic center at its C6-alcoholic
position gives rise to only one diastereomer, even if the ortho-
quinol is racemic, as exemplified in Scheme 2 by the conversion
of 6-hydroxy-3-iso-propyl-6-methylcyclohexa-2,4-dienone (13)
into biscarvacrol (1).[11a,14] There is no cross-reaction between the
two enantiomers, each cyclodimerizing only with itself. Only upon
heating at high temperatures (i.e., 165 °C), which enables retro-
Diels–Alder events, have cyclodimers resulting from such cross-
reactions been observed.[20] This exclusive and stereospecific
formation of cyclodimers is initially set by the dienophilic behavior
of the ortho-quinol, which solely engages its D-4,5 bond in an
endo-selective back-to-back approach with its dienic counterpart.
This regio- and facioselective combination of two ortho-quinols is
further fine-tuned to restrict connections specifically between their
C5 atoms (and hence between the dienophilic C4 atom and the
dienic C2 atom) according to a double diastereofacial control
through which the two faces bearing the C6-hydroxy groups
approach each other. Thus, out of 16 isomeric dimers that could
conceivably result from a racemic ortho-quinol, a single pair of
If biocatalysis is compulsory for mediating the biosynthetic
dearomative hydroxylation of natural 2-alkylphenols and for
controlling its stereoselectivity, the subsequent cyclodimerization
of the resulting chiral ortho-quinols does not require any enzyme
intervention for stereoselective control. Most ortho-quinols are
highly prone to participation in [4+2] cycloaddition events, and the
duality of reactivity of their cyclohexa-2,4-dienone core as both
diene and dienophile means that their self-cyclodimerization often
occurs spontaneously, unless their substitution pattern sterically
retards or prevents it. In fact, many ortho-quinols self-
cyclodimerize so rapidly even at ambient temperature that their
isolation is hardly possible.[10b,11]
What is enthralling is that their cyclodimerization follows the
exact same strict rules of regio- and stereocontrol, whose
underlying rationale had therefore to be searched only in the
2
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
enantiomeric dimers is formed (Scheme 2). No other cyclodimer
that could result from an exo-process, from alternative
connections between reacting carbon sites, from another mutual
approach of the two ortho-quinol faces, or from a dienophilic
participation of the D-2,3 bond has yet been either isolated or
chemically observed under standard conditions.
synthesizing one of the most structurally complex natural
cyclodimers known as of today, (+)-maytenone (4) (Figure 1). This
bisditerpenoid was first isolated in 1961 from the outer root bark
of the tree Maytenus dispermus (Celastraceae) by Johnson and
co-workers,[8d] who had already suspected that the biogenesis of
4 could involve the [4+2] self-cyclodimerization of an ortho-quinol
derived from the diterpene ferruginol (17) (Figure 2a). They had
even attempted to generate 4 by treating 17 with Pb(OAc)4 in
glacial acetic acid, which gave rise to the ortho-quinol acetate 18a
in about 3% yield (115 mg from 3.2 g of 17).[24] The failure of
attempts to cyclodimerize this substance or its deacetylated
version 18b (Figure 2b) was blamed on the high steric demand of
HO
HO
S
R
O
O
6
1
and/or
3
(R)-13
(S)-13
homochiral
cyclodimerization
the tricyclic ferruginol system.[24] The structure of
4 was
[4+2]
unambiguously established only 20 years later by Falshaw and
King on the basis of the X-ray crystal structure of its mono-
reduction product.[8e] In 2000, Jankowski and co-workers reported
the isolation of a bisditerpenoid cyclodimer, which they named
celastroidine B, from the roots of Hippocratea celastroides.[25a]
Later on, a comparison of the available atomic coordinates led
Jaroszewski and co-workers to conclude that Jankowski’s
celastroidine B was in fact identical to Johnson’s maytenone
(4).[25b]
diene
5’
diene
back-to-back endo-
approaches of pairs
of identical ortho-
quinol enantiomers
5’
R
OH
HO
HO
S
5
5
OH
2’
2’
O
S
R
O
O
O
4
4
dienophile
dienophile
and/or
no cross-reaction between
two different ortho-quinol
enantiomers !
Thus, our contribution to yet another, perhaps ultimate,
episode to this several decade-long serial on (+)-maytenone (4)
commenced with the synthesis of (+)-ferruginol (17) (Figure 2a).
This short and efficient synthesis is inspired from the work
previously reported by González and Pérez-Guaita, who obtained
(+)-17 in 24% yield over 6 steps.[26a] Our synthesis also starts from
commercially available (+)-dehydroabietylamine (14), and the
Rapoport’s oxygenative deamination[26b] was carried out first.
Thus, 14 was treated with 4-formyl-1-methylpyridinium
benzenesulfonate (15) in a CH2Cl2/DMF mixture, in the presence
of 4Å molecular sieves, at ambient temperature for 12 hours, after
which time DBU was added dropwise and the reaction mixture
was further stirred for 2 hours. A hydrolytic workup procedure
using 1 M aqueous HCl converted the resulting Schiff base into
the aldehyde 16 in 59% yield (Figure 2a). This aldehyde was then
subjected to a Wolff–Kishner reductive deoxygenation,[26a] and
HO
OH
O
O
and/or
HO
OH
O
O
(+)-biscarvacrol (1)
(–)-1
natural
Scheme 2. Homochiral Diels–Alder cyclodimerization of ortho-quinols. An
ortho-quinol enantiomer, such as (R)-13 or (S)-13, gives rise to the formation of
a single diastereomer, such as (+)-biscarvacrol (1) from (R)-13. The same
diastereomer and its enantiomer are the only cyclodimers formed in equal
amounts from a racemic mixture of the ortho-quinol.
The ensemble of our experimental observations and
computational inquiries, combined with the examination of
numerous literature precedents reported since the end of the
1950s[12,20,21] led us to propose a first comprehensive rationale of
the factors controlling this extraordinary level of site-specific
regioselectivity
Independently of their substitution pattern, ortho-quinols thus
approach each other in back-to-back manner to reach
the resulting dehydroabietane was transformed through
regioselective Friedel–Crafts acetylation and a Baeyer–Villiger
oxygenation, according to slightly modified version of
a
and
diastereofacial
discrimination.[15,21d]
a
Gademann’s procedure.[26c] A methanolysis of the resulting O-
acetyl-ferruginol furnished the desired (+)-ferruginol (17), which
was thus advantageously obtained in 32% yield over only 4 steps
from (+)-14 (Figure 2a, see the Supporting Information, Figure S1).
With several hundreds of milligrams of (+)-17 in hand, we
initiated our attempts to convert it into maytenone (4) by relying
on the use of hypervalent iodine(V) reagents such as 2-
iodylbenzoic acid (IBX, 19a) or its stabilized variant SIBX, since
these oxygenating l5-iodanes had amply proven their worth in
analogous HPD/[4+2] cascade reactions.[11a,15,16] Unfortunately,
these attempts were fruitless, as well as those performed using
our chiral C2-symmetrical Salen-type bisiodyl reagents 19b and
19c (Figure 2c).[16,27] The desired ortho-quinol 18b was not
generated, and the known ortho-quinonoid 8,12-abietadiene-
11,12-dione 18c[28] was instead produced (Figure 2c, see the
Supporting Information, Figure S2). Notwithstanding this
deviation of regioselectivity toward oxygenation at the
unsubstituted instead of the iso-propylated ortho-position of the
starting phenol 17, we searched for more appropriate oxygen-
atom transfer l5-iodanes and opted for the axially chiral biphenylic
a
energetically favored endo-transition states leading to the
observed products (see Figure 1, and Schemes 1 and 2). These
transition states are (i) C2-symmetric, and hence (ii) bispericyclic,
both [4+2] and [2+4] cycloaddition pathways being fully
equivalent,[22] (iii) sealed by
a combination of classical
Woodward–Hoffmann (C3nC3’ p-orbitals) and additional Salem–
Houk (C2nC4’ p-orbitals) secondary orbital interactions
(SOIs).[21d,22] The privileged connection between the C5 and C5’
atoms would be due to stabilizing Cieplak–Fallis hyperconjugative
effects[23] between both electron-donating C6–Calkyl s-bonds and
the vacant s*-orbital of the incipient C5–C5’ bond with which they
are both mutually antiperiplanar[21d] (vide infra).
Results and Discussion
Here, we have put these theoretical elements to the test to further
underpin basic knowledge on these bispericyclic dimerizations of
ortho-quinols. To this aim, we took up the challenge of
3
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
O
H
(b)
(a)
OH
O
O
OAc
OH
N
2
6
PhSO3
1.
15,
CH2Cl2/DMF
Pb(OAc)4,
AcOH
2. NH2NH2•H2O, KOH, DGME
3. AcCl, AlCl3, CH2Cl2
4
[4+2] X
hydrolysis
4Å MS, 20 °C, 12 h
17
4
then DBU, 2 h, workup
with 1M HCl, 3 h
(59% yield)
4. m-CPBA, TFA, CH2Cl2,
then K2CO3, MeOH
(54% yield over 3 steps)
H
(ref. 24)
(ca 3%)
H
H
H
H
NH2
H
18b
18a
O
(+)-ferruginol (17)
(32% overall yield from 14)
(+)-dehydroabietylamine (14)
16
HO
O
O
IO2
O2I
O
λ5-iodanes:
(c)
CO2Me
CO2Me
I
R
R
O
O
O
O
O
NH HN
IO2
O2I
IO2
IO2
IO2
IO2
HN
S
R
R
O
NH
19b
19a (IBX)
R
CO2Me
CO2Me
18c
19c
(R)-19d
(S)-19d
O
chiral λ5-iodane
(R)-19d
(d)
OH
R
[4+2]
2
6
(+)-17
CH2Cl2, 25 °C, 2 d (0% yield)
neat, 25 °C, 3 d (13% yield)
TFA (1 equiv), CH2Cl2,
–50 °C, 30 min,
then Et3N (30 equiv)
4
HO
O
using
(S)-19d
R
R
H
CH2Cl2, 14 kbar, 25 °C, 16 h (60% yield)
OH
O
(6R)-18b
single diastereomer
O
(+)-maytenone (4)
ORTEP (+)-4
OH
S
6
OH
O
S
S
[4+2]
CH2Cl2, 14 kbar, 25 °C,16 h (29% yield)
H
HO
O
(6S)-18b
single diastereomer
H
(–)-20
ORTEP (–)-20
Figure 2. Chemical synthesis of (+)-maytenone (4) and its diastereomer (–)-20: (a) Preparation of (+)-ferruginol (17) from (+)-dehydroabietylamine (14).[26] (b)
Johnson’s early attempts to generate 4 from 17 through a dearomative oxygenation/[4+2] cycloaddition sequence.[24] (c) Structures of l5-iodanes 19a-d used as
oxygen-atom transfer reagents for the dearomative oxygenation of 17, and structure of 8,12-abietadiene-11,12-dione (18c), the undesired ortho-quinone resulting
from the use of the l5-iodanes 19a-c. (d) The completion of our 6-step asymmetric synthesis of (+)-4 and its diastereomer (–)-20 through the regio- and
diastereoselective dearomative oxygenation of (+)-17 by using the biphenylic l5-iodanes (R)-19d or (S)-19d, respectively, followed by the site-specific regio- and
diastereoselective [4+2] cyclodimerization of the ortho-quinols (6R)-18b or (6R)-18b under high pressure conditions.
bisiodyl reagent 19d[14c] available in atropopure forms in our
laboratory iodanes toolbox (Figure 2c). Gratifyingly, full
diterpenoid system,[24] which could nevertheless be overcome
herein, at least in part, under solventless conditions.
a
conversion of (+)-17 into a single dearomatized species different
from the ortho-quinone 18c was observed when using (R)-19d (1
equiv.) in the presence of TFA (1 equiv.) in CH2Cl2 at –50 °C. The
1H NMR analysis of the crude reaction product indicated that the
desired ortho-quinol 18b had been generated as a single
diastereomer. Therefore, a solution of this crude reaction product
in CH2Cl2 was stirred at ambient temperature for enabling 18b to
cyclodimerize into 4. After 2 days, no [4+2] cycloadduct was
formed and only degradation of 18b was observed. To our
To better thwart the steric barrier in the mutual approach of
two molecules of 18b, we decided to rely on high pressure to force
them into closer proximity for accelerating the [4+2]
cyclodimerization
event,
while
preventing
retro-
cyclodimerization.[2b,29] Fully aware of the risk of perturbing the
fine stereoelectronic factors of the required double diastereofacial
control under such conditions, we were delighted to isolate (+)-4
in 60% yield as the sole cyclodimer [m.p. = 189 °C, lit.[25a] m.p. =
189-190 °C; [ꢀ]ꢀꢁꢂ = + 116 (c = 0.16, CHCl3), lit.[8d] [ꢁ]ꢄꢃꢅ = + 115
(CHCl3)] after performing the reaction on a solution of 18b in
CH2Cl2 under 14 kbar for 16 h (Figure 2d, see the Supporting
Information). This successful outcome permitted us to conclude
that the use of the bisiodyl oxygen-atom transfer reagent (R)-19d
exclusively gives rise to the R configuration at the C6-alcoholic
center of the ortho-quinol 18b. The same HPD/high-pressure
[4+2] reaction sequence carried out using instead the bisiodyl
reagent (S)-19d furnished the expected diastereomeric endo-
surprise,
a neat sample of 18b left standing at ambient
temperature for 3 days gave rise to the formation of a single
cyclodimer, which was isolated in 13% yield as a white solid. This
solid was crystallized from a solution in ethyl acetate and its
analysis by X-ray crystallography unambiguously confirmed that
its structure was that of (+)-4. This glimpse of success reminded
us of Johnson and co-workers who, 56 years ago, had judiciously
imputed their failure to generate 4 to the bulkiness of the tricyclic
cyclodimer derived from the ortho-quinol 18b with the
S
4
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
configuration at its C6 center (Figure 2d). The NMR analysis of
this cyclodimer 20 [m.p. = 196 °C; [ꢀ]ꢁꢀꢂ = – 15 (c = 1.05, CHCl3)],
the yoke of theoretical calculations. We were of course particularly
eager to verify if the Cieplak–Fallis hyperconjugation that was put
which could also be analyzed by X-ray crystallography (Figure 2d), forward to explain the dimerization of a sesquiterpenoid ortho-
indicated that it was similar to a compound isolated from the roots
of Harpagophytum procumbens (Devil’s claw) by Jaroszewski
and co-workers.[25b] We then accordingly performed the extraction
of a sample of Devil’s claw roots from which we could also purify
a compound eluting in a major peak at a very similar retention
time. Its structure was confirmed by NMR analysis to be that of
the endo-cyclodimer 20 (see the Supporting Information, Figures
S6-S8), which was herein chemically produced in 29% yield from
(6S)-18b (Figure 2d). This lower yield relative to that obtained for
4 might be attributed to a stereochemical mismatched pairing
between (+)-17 and the bisiodyl reagent (S)-19d. This possibility
was conclusively assessed by running a test reaction on (+)-17
using the racemate 19d, which gave rise to a ca 2:1 mixture of 4
(matched case) and 20 (mismatched case). In both cases, each
atropoisomer of the racemic biphenylic reagent 19d manages to
transfer its oxygen atom with full stereocontrol at C6, and no
cross-reaction between the resulting two ortho-quinols (6R)- and
(6S)-18b was observed (see the Supporting Information, Table
S1 and Figure S3).
quinol into aquaticol (2)[15] could again be relied upon to
rationalize the (bio)synthesis of maytenone (4) and its
diastereomer 20. A search of the transition states (TS) of the
different possible endo-combinations of ortho-quinols (6R)- and
(6S)-18b was first performed and optimized at the B3LYP/6-
31G(d) level (Figure 3, see the Supporting Information, Tables
S2-S4).
The lowest-energy transition state thus calculated (TS-A) was
identified to be the one leading to (+)-maytenone (4) from two
molecules of (6R)-18b with the faces bearing the C6-hydroxyl
groups in pseudo-equatorial orientations (possibly fostered by
intramolecular H-bonding with the adjacent C1-carbonyl
functions) approaching each other. The two electron-richer C6–
Ciso-propyl bonds are both quasi antiperiplanar to the first forming
C5–C5’ bond (both dihedral angles = 162°, Table S4). As
expected, this transition state is C2-symmetric and hence
bispericyclic.[22] The [4+2] and [2+4] cyclodimerization modes are
fully equivalent with the C4–C2’ and C2–C4’ distances being
identical (see TS-A’, and Table S3). Imposing two molecules of
(6R)-18b to approach each other with their faces flipped, while
maintaining the same site connectivities, gives rise to a transition
state higher in energy by 27.7 kcal/mol (TS-B)
To further enlighten the rules of control in these [4+2]
cyclodimerizations, the different available options open to the
diterpenoid ortho-quinols 18b for dimerizing were passed under
TS-A
TS-A’
C5–C5’ = 2.052 Å
diene
C4–C2’ = 3.546 Å
C2–C4’ = 3.546 Å
5’
H
4’
6’
R
3’
5’
6’
HO
R
dihedral angles between
each C6–Ciso-propyl bond
and the first forming C5–C5’ bond = 162 °
=> dual hyperconjugative effects !
OH
2’
2’
O
5
R
1
5
6
2
2’
R
6
1
dienophile
O
3
3’
4’
4
4
4
2
3
(+)-4
H
2×(6R)-18b
5
5’
6’
6
R
R
C2
C5–C5’ = 2.044 Å
C4–C2’ = 3.535 Å
C2–C4’ = 3.535 Å
TS-B
TS-C
TS-D
6’
S
5’
5’
6’
dihedral angles between
5’
6
R
6’
2’
S
each C6–Ciso-propyl bond and the
first forming C5–C5’ bond = 163 °
=> dual hyperconjugative effects !
2’
2’
6
5
6
5
4
S
5
R
S
4
4
+27.7 kcal/mol
rel. TS-A
+24.4 kcal/mol
rel. TS-D
+1.2 kcal/mol
rel. TS-A
(–)-20
TS-G
TS-E
TS-F
S
5’
4’
R
5’
4’
5’
6’
6’
2’
4
6’
S
R
5
R
6
R
5
2
5
2
6
6
+13.0 kcal/mol
rel. TS-A
+21.2 kcal/mol
rel. TS-A
+27.0 kcal/mol
rel. TS-A
Figure 3. Calculated endo-transition states (TS) of the Diels–Alder cyclodimerization of the ferruginol-derived ortho-quinol 18b. TS-A: Transition state derived from
2 × (6R)-18b with the faces bearing the C6-hydroxyl groups approaching each other to furnish (+)-maytenone (4); TS-A’: C2-symmetric view of the same transition
state; TS-B: Transition state derived from 2 × (6R)-18b with the faces bearing the C6-iso-propyl groups approaching each other; TS-C: Transition state derived from
2 × (6S)-18b with the faces bearing the C6-iso-propyl groups approaching each other; TS-D: Transition state derived from 2 × (6S)-18b with the faces bearing the
5
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
C6-hydroxyl groups approaching each other to furnish the cyclodimer (–)-20; TS-E: Transition state derived from (6R)-18b + (6S)-18b with the same site
connectivities as TS-A; TS-F: Transition state derived from (6R)-18b + (6S)-18b connecting C5 to C4’ and C5’ to C2; TS-G: Transition state derived from 2 × (6R)-
18b connecting C5 to C4’ and C5’ to C2.
Similarly, the transition state calculated from two molecules of
(6S)-18b with the faces bearing the pseudo-equatorial C6-iso-
propyl groups approaching each other (TS-C) is also a higher-
energy state with a difference of + 24.4 kcal/mol relatively to the
energy of the transition state for which the faces bearing the C6-
hydroxyl groups are approaching each other (TS-D) and for which
the C6-iso-propyl groups are again mutually oriented in a quasi
antiperiplanar fashion with the first forming C5–C5’ bond (Figure
3, and Tables S2-S4). In fact, TS-D is the appropriate C2-
symmetric transition state leading to the diastereomeric
cyclodimer (–)-20, and its calculated energy differs from that of
TS-A by only 1.2 kcal/mol. According to Maxwell–Boltzmann
statistics, this difference of energy would correspond to a ratio of
analyses of the four C2-symmetric transition states (i.e., TS-A, -
B, -C and -D). These calculations first reveal that the two lower-
energy TS-A and TS-D would be in part stabilized by a
delocalization from the bonding orbital (s#) of the incipient C5–C5’
bond into the antiperiplanar antibonding orbitals (s*) of the two
C6–Ciso-propyl bonds, which amounts to ca 3.6 kcal/mol per
orbital interaction (Table S5). Felkin–Ahn interactions between
this same s# orbital and the vacant s* orbital of the two electron-
poorer C6–OH bonds are also present, although they are of much
smaller magnitudes (ca 1.0 kcal/mol, Table S5), since the C6–OH
bonds are not properly oriented for hyperconjugation (Table S4).
NBO analyses further indicate that Cieplak–Fallis effects, which
are reversely associated to electron density transfers from the s
88:12 between TS-A and TS-D, which is also, at least qualitatively, orbitals of the electron-rich C6–Ciso-propyl bonds into the s#*
in agreement with the higher chemical yield observed for the
formation of (+)-4 relatively to that observed for (–)-20 under the
same reaction conditions (see Figure 2d and Figure S3).
Moreover, switching the configuration at C6 of just one molecule,
orbital of the incipient C5–C5’ bond, might also contribute to the
stabilization of these two TSs with energies of ca 4.0 kcal/mol
(Table S5). As a result of these hyperconjugative effects, the
length of the C6–Ciso-propyl bonds is systematically and
while maintaining the same endo-approach and site connectivities, expectedly longer (e.g., 1.593 Å in TS-A versus 1.554 Å in TS-B,
prevents the adequate orientation of the corresponding C6–Ciso-
propyl bond antiperiplanar to the forming C5–C5’ bond. The
resulting non-C2-symmetric transition state TS-E is 13.0 kcal/mol
higher in energy than the most stable C2-symmetric TS-A.
Attempting to reorient the C6–Ciso-propyl bond in order to have
both iso-propyl groups pointing away from the connecting faces,
like in the case of TS-A or TS-D, implies a facial reversal of the
corresponding reacting partner. However, this operation imposes
a switch of site connectivities (i.e., C5 to C4’ and C5’ to C2) in
order to maintain an approach of the two molecules in an endo-
mode. Each C6–Ciso-propyl bond ends up being antiperiplanar to
either the forming C5–C4’ or the C5’–C2 bond instead of being
both antiperiplanar to the C5–C5’ bond. The corresponding
transition state TS-F is higher in energy than TS-A by 21.2
kcal/mol, which is in agreement with the lack of observation of any
cross-reaction between the two enantiomers of the ortho-quinol
18b. A similar situation is found when two identical enantiomers
are forced to connect via C5 to C4’ and C5’ to C2, hence imposing
a facial reversal of one enantiomer with an in-plane reorientation
of the molecule to enable its endo-approach toward its reacting
partner. The corresponding transition state TS-G has also an
energy that is much higher than that of TS-A by 27.0 kcal/mol.
The two most stable calculated transition states TS-A and TS-
D are thus those experimentally leading to (+)-maytenone (4) and
its diastereomer (–)-20, respectively. These C2-symmetric
transition states fulfill all the criteria for bispericyclic Diels–Alder
cyclodimerization, as illustrated in Figure 4 for TS-A. Secondary
orbital interactions (SOI) between the p-orbitals at C3 and C3’ (i.e.,
Woodward–Hoffmann SOI, C3nC3’ = ca 3.8 Å, Table S3) can
stabilize the endo-approach of the two reacting partners, which is
further stabilized by Salem–Houk SOI between p-orbitals at C2
and C4’ or at C4 and C2’, since the [4+2] and the [2+4]
cycloaddition modes are equivalent. The alignment of the two C6–
Ciso-propyl bonds antiperiplanar to the C5–C5’ connection could
then also enable the privileged initial formation of this bond
through dual Cieplak–Fallis effects.
see Table S3).[30] In TS-B and TS-C, Cieplak–Fallis effects cancel
out due to the unfavorable orientation of the C6–Ciso-propyl
bonds with respect to the incipient C5–C5’ bond, while the
antiperiplanar alignment of the C6-OH bonds reinforces Felkin–
Ahn s#C5–C5’®s*C6–OH interactions up to ca 5.5 kcal/mol (Tables
S4 and S5). However, the much higher energies of TS-B and TS-
C compared to those of TS-A and TS-D indicate that Cieplak–
Fallis interactions constitute a better descriptor than Felkin–Ahn
interactions for rationalizing the relative stabilities of these late
transition states (Figure S9).
stabilizing
Cieplak–Fallis
hyperconjugation
H
O
H
O
2 x (6R)-18b
[4+2] [2+4]
σ
σ
H
H
=
O
O
O
O
σ#*
R
σ#*
R
5
4
5
σ
5’
5’
σ
2
2
Salem–Houk
4π
2π
R
4’
R
4’
4π
2π
4
secondary orbital
interactions
2’
2’
O
O
3
3
3’
3’
Woodward–Hoffmann
Figure 4. Cyclodimerization of the ferruginol-derived ortho-quinol into (+)-
maytenone (4). This simplified drawing of the C2-symmetric Diels–Alder TS-A
(the terpenoid decalin motif connected at C3 and C4 of the ortho-quinol
monomer (6R)-18b is omitted for clarity) shows the positioning of the
Woodward–Hoffmann and Salem–Houk secondary orbital interactions, and the
dual Cieplak–Fallis hyperconjugation that sealed this bispericyclic ([4+2] =
[2+4]) transition state leading to (+)-4. NB: the same stabilizing effects are at
play in the making of its diastereomer (–)-20 from the ortho-quinol (6S)-18b via
TS-D (Figure 3).
Conclusion
The first chemical synthesis of the bisditerpenoid (+)-maytenone
(4) described here required only 6 steps (19% overall yield) from
commercially available (+)-dehydroabietylamine (14). This
synthesis of such a complex natural product follows the manner
by which this Diels–Alder cyclodimer of an ortho-quinol derived
from the diterpenoid (+)-ferruginol (17) is plausibly biosynthesized
and showcases (i) the performance of chiral iodyl reagents in
To further inform us on those possible hyperconjugative
effects and others, we performed natural bond orbital (NBO)
6
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
Chem. Rev. 2008, 108, 5359-5406; e) G. Deslongchamps, P.
Deslongchamps, Tetrahedron 2013, 69, 6022-6033; f) P. Vermeeren, T.
A. Hamlin, I. Fernández, F. M. Bickelhaupt, Angew. Chem. Int. Ed. 2020,
59, 6201-6206.
regioselective asymmetric dearomative oxygenation reactions
and (ii) the utility of high pressure conditions to force Diels–Alder
processes with recalcitrant materials without any loss of expected
selectivities. The computational calculations underlined the
significant role played by Cieplak–Fallis hyperconjugative effects
in controlling the connecting site-specific regioselectivity and the
stereoselectivity in such a natural case of bispericylic Diels–Alder
reactions.
[3]
[4]
[5]
a) D. L. Boger, Chem. Rev. 1986, 86, 781-793; b) H. Waldmann,
Synthesis 1994, 535-551.
a) R. B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 1969, 81, 781-
853; b) K. N. Houk, Acc. Chem. Res. 1975, 8, 361-369.
a) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogiannakis,
Angew. Chem. Int. Ed. 2002, 41, 1668-1698; b) K.-i. Takao, R. Munakata,
K.-i. Tadano, Chem. Rev. 2005, 105, 4779-4807; c) J.-A. Funel, S. Abele,
Angew. Chem. Int. Ed. 2013, 52, 3822-3863.
To the best of our knowledge, all other reported cases of
cyclodimerization of natural[31] or unnatural chiral ortho-quinols
strictly follow the exact same selectivities, as well as those of
related ortho-quinone (spirolactonic) monoketals[13,20,21,32] and
even those of dimerizing cyclohexa-2,4-dienones bearing non-
oxygenated substituents at C6.[21a,33] The question as to whether
or not natural cases of such bispericyclic [4+2] cycloadditions
benefit from the intervention of particular enzymes (i.e., Diels-
Alderases) remains open, but the spontaneity with which most of
these cyclizations experimentally occurred casts doubt on this
possibility. Other biosynthetically relevant examples of Diels-
Alderase-free [4+2] dimerizations have been demonstrated,
notably with alkenylbutenolides for which the process is also
bispericyclic.[7] Nevertheless, the fact that we had to rely on high
pressure conditions to drive the construction of (+)-maytenone
and its diastereomer ex vivo might indicate that some kind of a
[4+2] cyclase accelerates the process in vivo.[5c] However, the role
of such a protein would be essentially to chaperone two ortho-
quinol monomers toward operational proximity, as all the
elements of controls and transition state stabilization are
inherently embedded in the structure of those monomers
[6]
[7]
[8]
a) E. M. Stocking, R. M. Williams, Angew. Chem. Int. Ed. 2003, 42, 3078-
3115; b) K. Cottet, M. Kolympadi, D. Marković, M.-C. Lallemand, Curr.
Org. Chem. 2016, 20, 2421-2442; c) B. R. Lichman, S. E. O’Connor, H.
Kries, Chem. Eur. J. 2019, 25, 6864-6877.
a) T. Wang, T. R. Hoye, Nat. Chem. 2015, 7, 641-645, and references
cited therein; b) A. Minami, H. Oikawa in Biomimetic Organic Synthesis,
Vol. 2 (Eds.: E. Poupon, B. Nay), Wiley-VCH, Weinheim, 2011, pp. 753-
-786.
a) R. M. Carman, L. K. Lambert, W. T. Robinson, J. M. A. M. Van Dongen,
Aust. J. Chem. 1986, 39, 1843-1850; b) B.-N. Su, Q.-X. Zhu, Z.-J. Jia,
Tetrahedron Lett. 1999, 40, 357-358; c) C. Zdero, F. Bohlmann, H. M.
Niemeyer, Phytochemistry 1991, 30, 1597-1601; d) A. W. Johnson, T. J.
King, R. J. Martin, J. Chem. Soc. 1961, 4420-4425; e) C. P. Falshaw, T.
J. King, J. Chem. Soc. Perkin Trans. I 1983, 1749-1752; f) L. K. Mdee,
R. Waibel, M. H. H. Nkunya, S. A. Jonker, H. Achenbach, Phytochemistry
1998, 49, 1107-1113; g) Y.-H. Liao, L.-Z. Xu, S.-L. Yang, J. Dai, Y.-S.
Zhen, M. Zhu, N.-J. Sun, Phytochemistry 1997, 45, 729-732; h) M. J.
Palframan, G. Kociok-Köhn, S. E. Lewis, Org. Lett. 2011, 13, 3150-3153;
i) P.-Y. Zhuang, S.-G. Ma, G.-J. Zhang, X.-J. Wang, Y. Zhang, S.-S. Yu,
Y.-B. Liu, J. Qu, Y. Li, Phytochem. Lett. 2013, 6, 444-448; j) N. Abe, T.
Murata, A. Hirota, Biosci. Biotechnol. Biochem. 1998, 62, 661-666; k) H.
Kneifel, C. Poszich-Buscher, S. Rittich, E. Breitmaier, Angew. Chem. Int.
Ed. Engl. 1991, 30, 202-203.
[9]
a) N. Abe, O. Sugimoto, K.-i. Tanji, A. Hirota, J. Am. Chem. Soc. 2000,
122, 12606-12607; b) N. Abe, T. Arakawa, K. Yamamoto, A. Hirota,
Biosci. Biotechnol. Biochem. 2002, 66, 2090-2099.
Acknowledgements
Financial support from the Agence Nationale de la Recherche
(ANR-10-BLAN-0721, IODINNOV), the CNRS, the Conseil
Régional d’Aquitaine, and the Ministère de l’Enseignement
Supérieur, de la Recherche et de l’Innovation, including doctoral
research assistantships for M.E.A, R.C. and C.B. is gratefully
acknowledged. This work has benefited from the analytical
facilities of the CESAMO platform at the University of Bordeaux.
We thank B. Kauffman and S. Massip (CNRS-UMS 3033) for
conducting X-ray diffraction experiments and solving the
structures of compounds 4 and 20, Prof. C. K. Jankowski for
kindly providing us with the NMR spectra of natural 4, and Dr A.
Fedotova for her kind help in the use of the high pressure
equipment.
[10] a) A. al Fahad, A. Abood, K. M. Fisch, A. Osipow, J. Davison, M.
Avramović, C. P. Butts, J. Piel, T. J. Simpson, R. J. Cox, Chem. Sci. 2014,
5, 523-527; b) A. Sib, T. A. M. Gulder, Angew. Chem. Int. Ed. 2017, 56,
12888-12891; c) L. Kahlert, E. F. Bassiony, R. J. Cox, E. J. Skellam,
Angew. Chem. Int. Ed. 2020, 59, 5816-5822.
[11] a) N. Lebrasseur, J. Gagnepain, A. Ozanne-Beaudenon, J.-M. Léger, S.
Quideau, J. Org. Chem. 2007, 72, 6280-6283; b) S. A. Baker Dockrey, A.
L. Lukowski, M. R. Becker, A. R. H. Narayan, Nat. Chem. 2017, 10, 119-
125.
[12] W. Metlesics, F. Wessely, Monatsh. Chem. 1957, 88, 108-117.
[13] S. Quideau, L. Pouységu, Org. Prep. Proced. Int. 1999, 31, 617-680.
[14] a) R. M. Carman, S. Owsia, J. M. A. M. Van Dongen, Aust. J. Chem.
1987, 40, 333-340; b) S. Dong, J. Zhu, J. A. Porco, Jr., J. Am. Chem.
Soc. 2008, 130, 2738-2739; c) C. Bosset, R. Coffinier, P. A. Peixoto, M.
El Assal, K. Miqueu, J.-M. Sotiropoulos, L. Pouységu, S. Quideau,
Angew. Chem. Int. Ed. 2014, 53, 9860-9864.
Crystallographic parameters for compounds 4 and 20 are
available free of charge from the Cambridge Crystallographic
Data Centre under CCDC-1148173[25a] and CCDC-1967527. The
coordinate files of the calculated transition states are available
from the authors on request as .pdb files (TS-A to TS-G) for 3D
molecular viewing.
[15] J. Gagnepain, F. Castet, S. Quideau, Angew. Chem. Int. Ed. 2007, 46,
1533-1535; Corrigendum 2008, 47, 628.
[16] R. Coffinier, M. El Assal, P. A. Peixoto, C. Bosset, K. Miqueu, J.-M.
Sotiropoulos, L. Pouységu, S. Quideau, Org. Lett. 2016, 18, 1120-1123.
[17] M. Bergner, D. C. Duquette, L. Chio, B. M. Stoltz, Org. Lett. 2015, 17,
3008-3010.
[18] X.-D. Ren, N. Zhao, S. Xu, H.-N. Lü, S.-G. Ma, Y.-B. Liu, Y. Li, J. Qu, S.-
S. Yu, Tetrahedron 2015, 71, 4821-4829.
Keywords: total synthesis • cycloaddition • asymmetric
[19] K. C. Nicolaou, K. S. Simonsen, G. Vassilikogiannakis, P. S. Baran, V. P.
Vidali, E. N. Pitsinos, E. A. Couladouros, Angew. Chem. Int. Ed. 1999,
38, 3555-3559.
synthesis • hypervalent compounds • transition states
[20] K. Holmberg, Acta Chem. Scand. 1974, B 28, 857-865.
[21] a) A. S. Kende, P. MacGregor, J. Am. Chem. Soc. 1961, 83, 4197-4204;
b) E. Adler, K. Holmberg, Acta Chem. Scand. 1974, B 28, 549-554; c) A.
Bérubé, I. Drutu, J. L. Wood, Org. Lett. 2006, 8, 5421-5424; d) J.
[1]
[2]
O. Diels, K. Alder, Justus Liebigs Ann. Chem. 1928, 460, 98-122.
a) J. Sauer, R. Sustmann, Angew. Chem. Int. Ed. 1980, 19, 779-807; b)
U. Pindur, G. Lutz, C. Otto, Chem. Rev. 1993, 93, 741-761; c) E. J. Corey,
Angew. Chem. Int. Ed. 2002, 41, 1650-1667; d) S. Reymond, J. Cossy,
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
Gagnepain, R. Méreau, D. Dejugnac, J.-M. Léger, F. Castet, D. Deffieux,
L. Pouységu, S. Quideau, Tetrahedron 2007, 63, 6493-6505.
[22] P. Caramella, P. Quadrelli, L. Toma, J. Am. Chem. Soc. 2002, 124, 1130-
1131.
[23] a) A. S. Cieplak, B. T. Tait, C. R. Johnson, J. Am. Chem. Soc. 1989, 111,
8447-8462; b) J. B. Macaulay, A. G. Fallis, J. Am. Chem. Soc. 1990, 112,
1136-1144; c) K. Ohkata, Y. Tamura, B. B. Shetuni, R. Takagi, W.
Miyanaga, S. Kojima, L. A. Paquette, J. Am. Chem. Soc. 2004, 126,
16783-16792.
[24] C. P. Falshaw, A. W. Johnson, T. J. King. J. Chem. Soc. 1963, 2422-
2428.
[25] a) M. Jiménez-Estrada, R. Reyes-Chilpa, S. Hernández-Ortega, E.
Cristobal-Telésforo, L. Torres-Colin, C. K. Jankowski, A. Aumeals, M. R.
van Calsteren, Can. J. Chem. 2000, 78, 248-254; b) C. Clarkson, D.
Stærk, S. H. Hansen, P. J. Smith, J. W. Jaroszewski, J. Nat. Prod. 2006,
69, 1280-1288.
[26] a) M. A. González, D. Pérez-Guaita, Tetrahedron 2012, 68, 9612-9615;
b) T. F. Buckley, H. Rapoport, J. Am. Chem. Soc. 1982, 104, 4446-4450;
c) C. Thommen, C. K. Jana, M. Neuburger, K. Gademann, Org. Lett.
2013, 15, 1390-1393.
[27] M. El Assal, P. A. Peixoto, R. Coffinier, T. Garnier, D. Deffieux, K. Miqueu,
J.-M. Sotiropoulos, L. Pouységu, S. Quideau, J. Org. Chem. 2017, 82,
11816-11828.
[28] M. Tada, J. Kurabe, T. Yoshida, T. Ohkanda, Y. Matsumoto, Chem.
Pharm. Bull. 2010, 58, 818-824.
[29] a) C. L. Hugelshofer, T. Magauer, Synthesis 2014, 46, 1279-1296; b) K.
Matsumoto, H. Hamana, H. Iida, Helv. Chim. Acta 2005, 88, 2033-2234;
c) M. Uroos, P. Pitt, L. M. Harwood, W. Lewis, A. J. Blake, C. J. Hayes,
Org. Biomol. Chem. 2017, 15, 8523-8528.
[30] J. M. Coxon, D. Q. McDonald, Tetrahedron Lett. 1992, 33, 651-654.
[31] For another example of a recently isolated natural cyclodimer to add to
the list, see: J. L. Ward, Y. Wu, C. Harflett, H. Onafuye, D. Corol, C.
Lomax, W. J. Macalpine, J. Cinatl Jr., M. N. Wass, M. Michaelis, M. H.
Beale, Sci. Rep. 2020, 10, 6477.
[32] T. B. Milzarek, M. Einsiedler, H. Aldemir, P. M. D’Agostino, J. K. Evers,
G. Hertrampf, K. Lamm, M. Malay, A. Matura, J. I. Müller, T. A. M. Gulder,
Org. Lett. 2019, 21, 4520-4524.
[33] R. J. Phipps, F. D. Toste, J. Am. Chem. Soc. 2013, 135, 1268-1271.
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10.1002/anie.202103410
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
O
single ortho-quinol
diastereomer
OH
chiral
R
bis-iodyl
reagent
H
OH
HO
O
R
bispericyclic
endo-[4+2]
R
14 kbar
OH
O
H
(+)-Ferruginol
(+)-Maytenone (60%)
The biosynthesis of many natural bicyclo[2.2.2]octenone products involves the Diels–Alder cyclodimerization of ortho-quinols, which
always occurs according to the same rules of selectivity. This phenomenon is herein illustrated by the first and enzyme-free synthesis
of the bisditerpenoid (+)-maytenone, which was achieved via a chiral iodane-mediated dearomative hydroxylation of (+)-ferruginol and
a high pressure-promoted Diels–Alder reaction.
9
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