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Recent advances in the synthesis of ent-kaurane

Cite this: DOI: 10.1039/d1np00028d
diterpenoids
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Xiangbo Zhao,† Bastien Cacherat,† Qifei Hu and Dawei Ma *

Covering: 2015 to 2020

Received 28th April 2021
DOI: 10.1039/d1np00028d
rsc.li/npr
The ent-kaurane diterpenoids are integral parts of tetracyclic natural products that are widely distributed in
terrestrial plants. These compounds have been found to possess interesting bioactivities, ranging from
antitumor, antifungal and antibacterial to anti-inflammatory activities. Structurally, the different
tetracyclic moieties of ent-kauranes can be seen as the results of intramolecular cyclizations, oxidations,
C–C bond cleavages, degradation, or rearrangements, starting from their parent skeleton. During the
past decade, great efforts have been made to develop novel strategies for synthesizing these natural
products. The purpose of this review is to describe the recent advances in the total synthesis of ent-
kaurane diterpenoids covering the period from 2015 to date.

1 Introduction 4.2 Asymmetric total syntheses of (
)-enmein, (
)-iso-

2 Total syntheses of C-20 non-oxygenated ent-kauranoids docarpin and (
)-sculponin R (Dong)
2.1 Asymmetric total syntheses of (+)-lungshengenin D and 4.3 Asymmetric total syntheses of (+)-longirabdiol, (
)-long-
(+)-1a,6a-diacetoxy-ent-kaura-9(11),16-dien-12,15-dione irabdolactone and (
)-effusin (Li)
(Ma) 5 Total syntheses of nor- or rearranged-ent-kauranoids
2.2 Asymmetric total syntheses of (
)-pharicin A, (+)-phar- 5.1 Total syntheses of ()-jungermannenone B and ()-jun-
icinin B, (+)-7-O-acetylpseurata C and (+)-pseurata C germannenone C (Lei)
(Ding) 5.2 Asymmetric total synthesis of (
)-maoecrystal V (Baran)
2.3 Total syntheses of ()-11b-hydroxy-16-kaurene, ()-11a- 5.3 Asymmetric total syntheses of (+)-jungermatrobrunin A,
hydroxy-16-kaurene, ()-liangshanin G and ()-gesner- (
)-1a,6a-diacetoxyjungermannenone C and (+)-12-
oidin B (Ma) hydroxy-1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one
2.4 Total synthesis of (
)-glaucocalyxin A (Jia) (Lei)
2.5 Total synthesis of (
)-euphoranginol C and (
)-euphor- 5.4 Asymmetric total syntheses of (+)-ent-kauradienone and
anginone D (Lou) (
)-jungermannenone C (Lei)
2.6 Total synthesis of ()-1a-hydroxykauran-12-one, ()-12- 5.5 Total synthesis of (+)-farnesin (Gao)
oxo-9,11-dehydrokaurene and ()-12a-hydroxy-9,11- 6 Total syntheses of grayananes
dehydrokaurene (Lei) 6.1 Total synthesis of (+)-principinol D (Newhouse)
3 Total syntheses of C-20 oxygenated ent-kauranoids 6.2 Total syntheses of ()-rhodomolleins XX and XXII (Ding)
3.1 Total synthesis of ()-maoecrystal P (Luo) 6.3 Total synthesis of (
)-rhodomollanol A (Ding)
3.2 Total syntheses of ()-eriocalyxin B, ()-neolaxiorin L 7 Conclusion and outlook
and ()-xerophilusin I (Lee) 8 Conicts of interest
3.3 Total synthesis of (
)-oridonin (Luo) 9 Acknowledgements
4 Total syntheses of seco-ent-kauranoids 10 References
4.1 Total synthesis of ()-trichorabdal A and ()-maoecrystal
Z (Liang)

State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China. E-mail: madw@sioc.ac.cn
† Both authors contributed equally to this article.
1 Introduction
In 1961, the simplest ent-kaurane diterpenoid, ent-kaurene (1),
was detected for the rst time in New Zealand in the leaf
essential oil in Agathis, a member of Araucariaceae, a conifer
family (Fig. 1).1 The plant being locally called kauri pine, this

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Fig. 1 ent-Kaurene skeleton.
type of diterpene with negative optical rotation was conse-
quently called ent-kaurene, “ent” meaning enantiomeric.
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As a family composed of structurally diverse and biologically
active natural products of terrestrial plants, ent-kaurane diter-
penoids, with their 20 C-atoms, account to date for more than
Xiangbo Zhao was born and
raised in Xuzhou, China and
obtained his BSc degree at
Northwest University (Xi'an,
China) in 2012. Then, he went to
Shanghai Institute of Organic
Chemistry (SIOC) to pursue his
PhD degree in Professor Dawei
Ma's group, working on the total
synthesis of ent-kaurane diter-
penoids and napelline alkaloids.
Aer graduation in 2017, he
continued his work in the same
group for one year and then joined the Macmillan group as a post-
doc at Princeton University in 2019, where he mainly focused on
the development of new cross-coupling methods using metal-
laphotoredox catalysis. He is currently research associate in SIOC
and his research interest includes total synthesis of natural prod-
ucts and photo-induced methodologies.
Bastien Cacherat studied at the
École Nationale Supérieure de
Chimie de Mulhouse from 2011
to 2014, earning a M.Sc. in
sciences, technologies, health
and research, together with
a Diplôme d’Ingénieur in chem-
istry. As a doctoral student sup-
ported by a Max-Planck-
Gesellscha fellow-ship in the
laboratory of Prof. Bill Morandi
at the Max-Planck-Institut für
Kohlenforschung, he then devel-
oped new strategies in organic synthesis, using either transition
metals or Brønsted acids. Subsequently, he moved to Shanghai,
China to undertake a postdoctoral fellowship with Prof. Dawei Ma
at the Shanghai Institute of Organic Chemistry, where he mainly
focused on the total synthesis of a marine alkaloid. He is currently
research chemist at Spirochem AG, a CRO based in Basel,
Switzerland.
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1000 varieties of natural enantiomers that have been either
identied or isolated, or both. Most of them were isolated from
the plants of the Isodon genus,2 which have long been known in
Asian traditional medicine for their curative properties, espe-
cially because of the bioactive diterpenoids that they contain.
Moreover, not only do Isodon, as a group of owering plants in
the Labiatae (or Lamiaceae) family, feature numerous ent-
kauranoids, but other families, for example Asteraceae (or
Compositae), Annonaceae, Pteridaceae, Euphorbiaceae, as well
as liverworts and microbial metabolites, are also a source of
a plethora of ent-kauranoids.2c Sun and co-workers notably
achieved the separation, the identication as well as biological
activity testing of more than 300 diterpenoids from the Isodon
species.2a,b In recent years, more and more studies have shown
Qifei Hu was born in Xi'an,
China and graduated from
Nankai University (Tianjin,
China) in 2015. Then, he
continued his education under
the supervision of Prof. Dawei
Ma at Shanghai Institute of
Organic Chemistry (Shanghai,
China), working on the total
synthesis of rearranged ent-
kaurane diterpenoids. In 2020,
he received his PhD and joined
Pharmaron Inc. as a R&D Senior
Scientist in the same year. His research interest includes total
synthesis of natural products with signicant bioactivities and
efficient methodologies in drug research and development.
Dawei Ma received his PhD in
1989 from Shanghai Institute of
Organic Chemistry and did his
postdoctoral studies at the
University of Pittsburgh and
Mayo Clinic. He returned to
SIOC in 1994 and was appoin-
ted as research professor in
1995. His research interests
currently focus on the develop-
ment of new synthetic method-
ologies, the total synthesis of
complex natural products, and
their SAR and action mode studies, as well as the discovery of
small modulators for target proteins and special biological
processes.
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that most of these natural products showcase excellent prop-
erties, including but not limited to antibacterial, anticancer,
antifungal, antitumor and antiviral biological activities. Con-
cerning biosynthesis, it appears that the biosynthesis of ent-
kaurene is well known.3a,b Indeed, geranylgeranyl pyrophos-
phate (GGPP, 2), the universal precursor of all plant diterpenes,
is rst converted to copalyl diphosphate (CPP) under the action
of the enzyme named CPP synthase or CPS or sometimes known
as kaurene synthase A. It is important to mention that two
products, either ent-CPP or syn-CPP, can result from this
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transformation. It depends whether the enzyme is ent-CPP
synthase or syn-CPP synthase, respectively. When using ent-CPP
synthase, the desired ent-CPP intermediate is obtained and then
transformed into ent-kaurene in a few steps under the action of
ent-kaurene synthase (KS) or kaurene synthase B. The classic
mechanism has also been described (Scheme 1).4d Starting from
ent-CPP (3), the cyclization cascade generates the tricyclic
intermediate PA (4) with a tertiary carbocation at C-8. The
double bond at C-14 then intramolecularly attacks the carbo-
cation at C-8, which results in the formation of the key tetra-
cyclic beyeranyl-13-cation intermediate PB (5), with a secondary
carbocation at C-13. A 1,2-alkyl migration then occurs, forming
the ent-kaurenyl-16-cation intermediate PE (6) with a more
stable tertiary carbocation. Alternatively, Tantillo's calculation
work on the ent-kaurene biosynthetic pathway indicates that
secondary carbocations can be avoided by combining two or
more mechanistic steps into concerted processes that lead to
tertiary carbocations.3c,d Therefore, the tertiary carbocation PE
(6) is also expected to be formed from PA (4) via a concerted
cyclization/alkyl shi process. Finally, ent-kaurene is generated
through proton removal which quenches the tertiary carboca-
tion, yielding the desired exocyclic olen.
For this parent ent-kaurene carboskeleton, oxidation, C–C
bond cleavage, fragmentation or rearrangement within these
diterpenoids are incredibly common and lead to a variety of
additional structures. Based on structural features, ent-kaurane
diterpenoids were classied into different sub-classes: the C-20
non-oxygenated ent-kauranoids (such as pharicin A, 7), the C-20
oxygenated ent-kauranoids (such as xerophilusin I, 8), the seco-
ent-kauranoids (such as sculponeatin N, 12), nor- or rearranged-
ent-kauranoids (such as maoecrystal V, 14), and grayananes
(such as principinol D, 15) (Fig. 2).2 ent-Kauranoids exhibit
numerous frameworks and oxidation patterns, as well as
a variety of bioactivities, and so these molecules have naturally
Scheme 1 Biosynthesis of ent-kaurene.
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Fig. 2 Structures of related ent-kauranes.
attracted extensive attention from synthetic chemists and
a tremendous amount of total syntheses were disclosed over the
past decade.4–6 To the best of our knowledge, there have been
several elegant reviews focusing on the total synthesis of these
diterpenoids between 1962 (the rst total synthesis of ent-
kaurane diterpenoids by Ireland and co-workers)5a and 2014,
published by the Thomson, Hong, Lei, and Schindler groups.4a–d
Many of the classic methods that were invented for total
synthesis of these natural products in this period, such as
Mori's fragmentation of unique cyclopropane intermediate,5f
Corey's cationic cyclization,5h,i and Yang's oxidative
dearomatization/intramolecular Diels–Alder reaction,6g remain
effective in this eld and continue as fruitful resources to
inspire total synthesis and method development to this day.4e
During the past seven years, rapid development of new
synthetic strategies and methodologies, particularly unprece-
dented C–C bond formation reactions, has offered numerous
new opportunities for the total synthesis of ent-kaurane and
related diterpenoids. Dozens of unique synthetic strategies have
been developed towards accessing the more recently isolated,
highly oxidized, and unusual members of this family.7–11 In this
review, we cover the recent total syntheses of the ent-kauranoids
from 2015 to date.
2 Total syntheses of C-20 non-
oxygenated ent-kauranoids
The C-20 non-oxygenated ent-kaurane diterpenoids are the most
widely distributed products among ent-kauranes, accounting
for about one third of the whole family. Their structural
particularity is the presence of a C-20 methyl at C-10, whereas an
H-atom is usually found at C-5 or C-9, two positions that are
rarely oxidized. Most of the natural products that were isolated
from fragrant plant genera contain several oxidized carbons,
including C-15 that is usually connected to an O-atom.2a During
past years, several elegant strategies have been developed to
assemble these natural products, which are summarized below.
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2.1 Asymmetric total syntheses of (+)-lungshengenin D and
(+)-1a,6a-diacetoxy-ent-kaura-9(11),16-dien-12,15-dione (Ma)
In 2017 the Ma group completed the rst asymmetric total
syntheses of two highly oxidized ent-kaurane diterpenoids,
lungshengenin D and 1a,6a-diacetoxy-ent-kaura-9,16-dien-
12,15-dione,7a in which a [3.2.1] bicyclic unit was designed as
a common intermediate. This unit was established by using
a Hoppe homoaldol reaction and a Lewis acid-mediated
Mukaiyama–Michael-type cyclization as the key steps at the
early stage, making this strategy remarkably convergent.
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As outlined in Scheme 2, the authors started the synthesis
from enone 16, which was transformed into ester 17 in two
steps. This ester was subjected to a Pd-catalyzed intramolecular
allylation to create a quaternary carbon center in 82% yield and
87% ee.12 Aer reduction and isomerization of the chiral ketone
18, the resulting enone 19 was subsequently converted into
Scheme 2 The first asymmetric total synthesis of 1a,6a-diacetoxy-
ent-kaura-9(11),16-dien-12,15-dione by the Ma group.
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[3.2.1] bicyclic enone 20 through a Pd-catalyzed cyclo-
alkenylation. Ketone protection of 20, followed by silyl ether
cleavage and Ley–Griffith oxidation delivered the designed
aldehyde building block 21.
In a parallel procedure, asymmetric reduction of a-methyl-
cyclohexenone 22 with (R)-CBS gave allylic alcohol 23 in 90%
yield and 99% ee. NaH-mediated condensation of 23 with N,N-
diisopropylcarbamoyl chloride provided the desired cyclo-
hexenyl carbamate 24. Aer condensation of 24 with the alde-
hyde 21 under typical Hoppe homoaldol reaction conditions,13
an unprecedented intramolecular Mukaiyama–Michael cycliza-
tion reaction was conducted under the action of boron tri-
uoride diethyl etherate, successfully yielding a diastereomeric
mixture 26 aer quenching the reaction with aqueous sodium
bicarbonate. Next, hydrolysis of the ester group in 26 and
subsequent oxidation furnished a ketone, which was treated
with DBU to afford C-5 epimerization product 27.
Using 27 as a key intermediate, total synthesis of (+)-1a,6a-
diacetoxy-ent-kaura-9(11),16-dien-12,15-dione was achieved
rst. The two carbonyl groups in 27 were subsequently reduced
with L-selectride and DIBAL-H to produce diol 28 stereo-
selectively. Acetylation of 28 followed by ketal deprotection and
oxidation state adjustment of the [3.2.1] bicyclic fragment
delivered the target molecule. In order to convert the interme-
diate 27 into the pentacyclic ent-kaurane diterpenoid lung-
shengenin D, an additional hydroxyl group should be
introduced to create the requisite ether linkage (Scheme 3). To
this end, Ma and coworkers transformed two ketone groups in
27 into the disilyl enol ether, which was subjected to selective
oxidation of less hindered A-ring with DDQ and then cleavage of
the silyl ether and ketal protecting groups to deliver trione 30.
Through this operation the more reactive C-2 position was
blocked and now C-11 became the more reactive one. Aer
installing a hydroxyl group at this position to form 31,
Scheme 3 The first asymmetric total synthesis of lungshengenin D by
the Ma group.
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intramolecular etherication was carried out under the assis-
tance of HCl to afford pentacyclic intermediate 32. Next, deox-
ygenation of C-12 was achieved via a selective reduction of C-12
carbonyl group, mesylation of the resultant alcohol, and
subsequent reduction with LAH. The resultant diol was oxidized
with IBX to give 33, which was converted into lungshengenin D
aer 4 steps.
2.2 Asymmetric total syntheses of (
)-pharicin A,
(+)-pharicinin B, (+)-7-O-acetylpseurata C and (+)-pseurata C
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(Ding)
In 2017, the Ding group developed a new strategy to forge the
highly oxygenated bicyclo[3.2.1]octane core unit of ent-kaurane
diterpenoids bearing a b-OH at C-14.7b This new strategy
featured an oxidative dearomatization-induced [5+2]
cycloaddition/pinacol-type 1,2-acyl migration cascade to
construct the core structure. The implementation of this
strategy with subsequent retro-aldol/aldol reaction and singlet
oxygen ene reaction allowed for the rst asymmetric total
syntheses of the natural products pharicin A, pharicinin B, 7-O-
acetylpseurata C and pseurata C in a rather convergent way.
As depicted in Scheme 4, conversion of the Wieland–
Miescher ketone 35 into the bicyclic ketone 36 via the formation
of corresponding chiral alcohol was performed in 6 steps. The
resulting epoxide 36 underwent Eschenmoser–Tanabe cleavage
to deliver the acetylene aldehyde 37 with the side chains at C-10
Scheme 4 The first asymmetric total syntheses of (
)-pharicin A,
(+)-pharicinin B, (+)-7-O-acetylpseurata C and (+)-pseurata C by the
Ding group.
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and C-5 positions. A couple of reaction sequences allowed the
access to a 2 : 1 mixture of vinylphenols at C-7, which was
further transformed to tetracyclic diketone 42 upon treatment
with PIFA. The ODI (oxidative dearomatization-induced) [5+2]
cycloaddition rst connected C-9 to C-8 and C-11 to C-12, and
then a pinacol-type 1,2-acyl migration reaction occurred to
cause C14–C12 cleavage and subsequent creation of a C14–C13
linkage. Finally, a retro-aldol/aldol process and a singlet oxygen
reaction were employed to adjust the oxidation state,7b which
allowed the total syntheses of several natural products, namely
pharicin A, pharicinin B, 7-O-acetylpseurata C and pseurata C
aer a few steps.
2.3 Total syntheses of ()-11b-hydroxy-16-kaurene, ()-11a-
hydroxy-16-kaurene, ()-liangshanin G and ()-gesneroidin B
(Ma)
In 2019, the Ma group reported the total syntheses of four
kaurane diterpenoids by using a twisted and extremely reactive
enone, 6-methylenebicyclo[3.2.1]oct-1-en-3-one (46) (Scheme 5),
as a Diels–Alder reaction dienophile.7c The [3.2.1] bridgehead
enone, prepared through bromide elimination, enabled the
construction of the tricyclic or tetracyclic adducts through
Diels–Alder cycloaddition at the early stage of a synthesis.
The synthesis of the [3.2.1] bridgehead enone started with the
preparation of bicyclic carboxylic acid 44 from methyl 3-
methoxybenzoate 43 in 75% yield over three steps (Scheme 5).14
The carboxylic acid group was exchanged with a bromide through
Barton halodecarboxylation with halothane as a bromide source.
As proof of concept, the resulting bromide 45 underwent Cs2CO3-
mediated bromide elimination to form the desired dienophile
46, which spontaneously underwent Diels–Alder reactions with
some dienes, namely 2,3-dimethyl-1,3-butadiene, Danishefsky's
Scheme 5 The total syntheses of ()-11b-hydroxy-16-kaurene,
()-11a-hydroxy-16-kaurene, ()-liangshanin G and ()-gesneroidin B
by the Ma group.
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diene, furan and a diene derived from 1-(cyclohex-1-en-1-yl)
ethan-1-one, to provide the corresponding cycloadducts.7c
However, under the same conditions the diene 47 did not give
a satisfactory result. The authors then found that when using
another inorganic base, K3PO4, instead, at 100  C and in neat
conditions, the desired product 48 could be formed in 48% yield
as a 1 : 1 diastereomeric mixture. The slow addition of the
dienophile to the diene/K3PO4 mixture appeared to be critical.
Then, the ketone at C-11 was reduced with DIBAL-H to form
alcohol 49 in 47% yield, together with its separable C-10 epimer.
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With the alcohol 49 in hand, four kaurane diterpenoids, namely
()-11b-hydroxy-16-kaurene, ()-11a-hydroxy-16-kaurene,
()-liangshanin G and ()-gesneroidin B, were rapidly prepared
through simple oxidation state adjustments.
2.4 Total synthesis of (
)-glaucocalyxin A (Jia)
In 2020, the Jia group reported the asymmetric total synthesis of
(
)-glaucocalyxin A, a highly oxidized ent-kaurane diterpe-
noid.7d The synthesis featured a Mn(III)-mediated radical cycli-
zation to form a C-14 oxygenated bicyclo[3.2.1]octane ring at the
early stage and an intramolecular Diels–Alder reaction to form
the key tetracyclic core.
The synthesis started with a highly enantioselective conju-
gate addition of Grignard reagent 50 onto the cyclic a,b-
Scheme 6 The total synthesis of (
)-glaucocalyxin A by the Jia group.
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unsaturated ketone 51 followed by enolate ethoxycarbonylation
with Mander's reagent (Scheme 6). The resulting ketoester 52
and its corresponding enol were alkylated with 3-bromo-1-
trimethylsilyl-1-propyne (53) in a diastereoselective fashion to
result in b-ketoester 54. The alkynyl ketone 55 was then
prepared aer selective C(sp3)–Si bond cleavage, followed by
a Mn(III)-mediated oxidative cyclization to deliver C14-
oxygenated bicycle 55 in 45% yield. Next, desilylation followed
by reduction of the ketone and TBS protection of the resulting
alcohol yielded ester 56. The ester was then converted to alde-
hyde 57 before a Yamamoto aldol reaction achieved the
formation of 58 as major diastereoisomer together with the
undesired epimer at C-7 (3 : 1 dr). Aer MOM protection of the
resulting alcohol, the ester was successively converted to
a Weinreb amide, to a ketone upon Grignard addition and
nally to silyl enol ether 59. An intramolecular Diels–Alder
reaction then delivered the tetracyclic compound 60 in excellent
yield but under pretty harsh reaction conditions. The key tet-
racyclic core was obtained aer the gem-dimethyl group at C-4
was installed upon addition of “anhydrous” TBAF and concen-
trated MeI, leading to the formation of ketone 61 in 86% yield.
Aer installations of the desired alcohol at C-14 and ketone at C-
15, the total synthesis of (
)-glaucocalyxin A was nally
achieved.
2.5 Total synthesis of (
)-euphoranginol C and
(
)-euphoranginone D (Lou)
In 2020, the Lou group completed the asymmetric total
synthesis of (
)-euphoranginol C and (
)-euphoranginone D.7e
The synthesis featured a notable De Mayo reaction to rapidly
generate the bicyclic [3.2.1]octane moiety in the target
molecules.
The synthesis commenced with the preparation of polyenoid
62 over four steps, which was used in a BF3$Et2O-induced
biomimetic cationic cyclization to afford halogenated decalin
63 (Scheme 7). Benzyl protection of the newly formed secondary
alcohol in 63, followed by formylation and reduction, provided
an allylic alcohol, which was further converted to allylic
bromide 64 with PBr3. Next, treatment of 64 with the enolate of
65 generated coupling products 66 and epi-66, which both
underwent the De Mayo reaction under irradiation with 254 nm
light, triggering a smooth [2+2] photocycloaddition. ent-
Kaurene-type 70 and ent-phyllocladene 71 were obtained from
the intermediates 67 and 68 aer acidic work-up, respectively. It
is noteworthy that the treatment of intermediate 67 with BF3-
$2AcOH resulted in its C9 epimerization via an oxonium inter-
mediate to give ent-kaurene-type 70. In parallel, the De Mayo
reaction was attempted on substrate epi-66, nally affording C9-
epi-kaurane-type 72 as a single isomer. With the desired inter-
mediate 70 in hand, several transformations were carried out to
accomplish the total synthesis. Hydrolysis of vinyl ether 70 with
3 N HCl and regioselective methenylation in the presence of
phosphine salts produced olen 73. Next, a radical reduction,
acid-promoted esterication and removal of the benzyl group
afforded euphorangiol C, which was transformed into euphor-
anginone D upon further oxidation.
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Scheme 7 The total synthesis of (
)-euphoranginol C and
(
)-euphoranginone D by the Lou group.
2.6 Total synthesis of ()-1a-hydroxykauran-12-one, ()-12-
oxo-9,11-dehydrokaurene and ()-12a-hydroxy-9,11-
dehydrokaurene (Lei)
In 2020, the Lei group developed a concise approach for
assembling the core structure of ent-kaurane diterpenoids,7f
which relied on a rhodium-catalyzed [3+2+1] cycloaddition to
furnish the B ring and C ring in one step, as well as a palladium-
mediated cycloalkenylation to construct the key [3.2.1] ring
system. Based on this synthetic strategy they achieved the rst
total syntheses of ()-1a-hydroxykauran-12-one, ()-12-oxo-
9,11-dehydrokaurene and ()-12a-hydroxy-9,11-
dehydrokaurene in a protecting-group-free manner.
The synthesis started with commercially available enone 74
that underwent Michael addition and alkynylation in two steps to
yield 77 (Scheme 8). Aer a brief optimization, the key Rh(I)-
catalyzed [3+2+1] cycloaddition of 77 and CO occurred smoothly
to deliver the desired 78 in 52% yield with a diastereomeric ratio
of 5.8 : 1 at C8. It is noteworthy that two rings, three carbon–
carbon bonds, and one quaternary stereogenic center were
created in this step through a remarkable [3+2+1] cycloaddition.15
Next, Pd-mediated 5-endo oxidative cyclization of a 5-vinyl silyl
enol ether generated from the tricyclic 78 produced 79 in 79%
yield. The success in creating the requisite [3.2.1] ring in this step
relied on increasing the equivalents of Pd(OAc)2 and conducting
the reaction at a relatively low temperature. Next, regioselective
Mukaiyama hydration of the diene 79 occurred at the less
hindered part and the resultant tertiary alcohol was subjected to
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Scheme 8 The total synthesis of ()-1a-hydroxykauran-12-one,
()-12-oxo-9,11-dehydrokaurene and ()-12a-hydroxy-9,11-dehy-
drokaurene by the Lei group.
dehydration to provide a terminal alkene, which was reduced
with NaBH4 leading to the formation of two isomers, 80 and 81.
Due to the undesired C16 stereochemistry provided by hydroge-
nation of the terminal double bond in 81, a hydroxyl-directed
reduction strategy was then studied to overcome this drawback.
As a result, face-selective Luche reduction of 81 afforded C12-b-
OH 82, which underwent hydroxyl-directed reduction with
RANEY® Ni and H2 to give enone 83 with the desired C16
stereochemistry upon a MnO2-mediated oxidization. Reduction
of 83 under Birch conditions enabled the rst total synthesis of
()-1a-hydroxykauran-12-one. In a parallel procedure, Barton–
McCombie deoxygenation of the isomer 80 delivered ()-12-oxo-
9,11-dehydrokaurene. Luche reduction of 84 furnished C12-b-OH
85, which was treated with 2 N HCl at 50  C to give a mixture of
unreacted 85 and the desired ()-12a-hydroxy-9,11-
dehydrokaurene.
3 Total syntheses of C-20
oxygenated ent-kauranoids
In contrast to unoxidized C-20 ent-kaurane diterpenoids, these
types of diterpenes usually feature either an oxidized methylene
group, an aldehyde group or a carbonyl group at C-20. Conse-
quently, they can form additional oxygen bridges, such as
acetal, hemiketal, ketone, lactone or ether with carbons at the C-
3, C-4, C-7, C-11 or C-14 position. Three papers about the total
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syntheses of this subgroup have been published during the past
few years, which are discussed below.
3.1 Total synthesis of ()-maoecrystal P (Luo)
In 2018, the Luo group completed the racemic total synthesis of
maoecrystal P, an ent-kaurene diterpenoid oxygenated at C-20.8a
The synthesis featured a highly regioselective and diaster-
eoselective intermolecular Diels–Alder cycloaddition for
creating a tetracyclic system from an enone-aldehyde and
a diene embedded in a substituted bicyclo[4.1.0] skeleton.
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Another key point in this synthesis was a SmI2-mediated
carbonyl–alkene reductive coupling to install the key [3.2.1] ring
system.
As shown in Scheme 9, BF3$OEt2-mediated intermolecular
Diels–Alder cycloaddition between the enone-aldehyde 86 and
the diene 87 quickly produced tetracyclic compound 88. The
subsequent reduction, acetyl protection and allylic oxidation
afforded the desired enone 90, which underwent Pd-catalyzed
Scheme 9 The first total synthesis of maoecrystal P by the Luo group.
Nat. Prod. Rep.
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hydrogenolysis of the cyclopropane ring to give a pair of dia-
stereoisomers 91 at C-16. Decarboxylation of 91 and acetonide
protection led to the formation of 92, which was converted into
aldehyde 93 through two-step redox manipulations. Carbonyl–
alkene reductive cyclization of 93 with the assistance of SmI2
proceeded smoothly to afford tetracyclic intermediate 94, which
successively underwent DMP oxidation of the hydroxyl group at
C-15 and introduction of a methylene group at C-16 to produce
96. Oxidation of the enol ether moiety in 96 followed by
deprotection furnished triol 97. TBAF-mediated ketal formation
of 97 provided acetonide 98, which was converted into maoe-
crystal P aer 5 steps.
3.2 Total syntheses of ()-eriocalyxin B, ()-neolaxiorin L
and ()-xerophilusin I (Lee)
In 2018, the Lee group completed the racemic total syntheses of
three diterpenoids, namely eriocalyxin B, neolaxiorin L and
xerophilusin I.8b These natural products are oxidized at C-20
and are named 7,20-epoxy-ent-kauranoids aer forming the C-
7,20 hemiketal bridge. The syntheses relied on an intra-
molecular Diels–Alder cycloaddition to install the AB ring
system, and a cascade Lewis acid-mediated intramolecular
Mukaiyama–Michael/carbocyclization reaction to set up the CD
ring system. Aer construction of the requisite tetracyclic core,
the authors planned that a redox relay would successively
undergo (1) selective reduction of C-12 ketone; (2) a-oxygenation
at C-6 thanks to the residual ketone at C-7; (3) C-7,20 hemiketal
bridge formation through cis-AB to trans-AB ring equilibrium;
(4) OH-directed allylic C–H oxidation at C-15 and H-bonding
controlled reduction of the carbonyl at C-6; and nally (5)
selective oxidation at C-1.
The linear synthesis mainly started with an intermolecular
Diels–Alder cycloaddition between the a-formylcyclohexenone
101 and the enone 100 aer conversion of the latter to silyl enol
ether (Scheme 10). With the AB ring system now formed, the
subsequent reduction, diol protection and oxidation yielded the
enone 104. Aer strong Lewis acids screening, it was found that
dimethyl aluminum chloride, in the presence of lithium
bromide, could be used for realizing the expected tandem
Mukaiyama–Michael/carbocyclization reaction. With the
desired tetracyclic core 105 in hand, the authors carried out C-
12 deoxygenation through mesylate 106 and introducing
a hydroxyl group at the C-6 position to afford ketone 107, whose
free hydroxyl group was oxidized and then silyl ether cleavage
was conducted to produce hemiketal 108. During this course
the cis-AB ring had been equilibrated to the trans-AB ring. A
Riley oxidation then introduced a hydroxyl group at C-15, LAH
reduced the carbonyl group at C-6 and other oxidation state
adjustments led to the formation of the three C-20 oxygenated
diterpenoids eriocalyxin B, neolaxiorin L and xerophilusin I.
3.3 Total synthesis of (
)-oridonin (Luo)
In 2019, the Luo group reported the asymmetric total
synthesis of the highly oxidized (
)-oridonin. 8c It features an
interrupted Nazarov/Hosomi–Sakurai reaction cascade to
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Scheme 10 The first total syntheses of ()-eriocalyxin B,
()-neolaxiflorin L and ()-xerophilusin I by the Lee group.
build the key tetracyclic core and an important stereogenic
center at C-8.
The synthesis commenced with the preparation of two key
building blocks, 112 and 114, over several simple transformations
(Scheme 11). With these two fragments in hand, Li–Br exchange
between 112 and t-BuLi yielded the corresponding vinyl lithium,
and the addition onto the rst fragment 114 afforded secondary
alcohols, which were converted to ketone 115 upon addition of
Cornforth reagent PDC. For the key interrupted Nazarov/
Hosomi–Sakurai reaction, the authors discovered that excess
EtAlCl2 was effective, and ring closing yielded the interme-
diate 116 as a major product, in which the stereogenic center
at C-8 was established through anti-addition of the allyl
silane to the hydrogen at C-9. Next, subjecting 116 to singlet
oxygen ene reaction followed by acetate anhydride treatment
provided aldehyde 117. A Rh(I)-catalyzed deformylation
delivered the ketone 118, which underwent 1,2-addition to
form an allylic alcohol, and then selective epoxidation of the
C13–C14 alkene with mCPBA to form 119 in 70% overall yield.
The desired B-ring was then formed through ring expansion
via bromination of the C]C double bond with NBS and
subsequent semipinacol rearrangement. The resultant
bromide was oxidized with RuCl3/NaIO4 to convert two benzyl
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Scheme 11 The total synthesis of (
)-oridonin by the Luo group.
ether moieties to the corresponding benzoyl esters, and then
treated with DBU to eliminate HBr to give enone 120, which
underwent Upjohn dihydroxylation to form diol 121. The
desired C/D ring system was then implemented upon addi-
tion of EtAlCl2 which induced the key rearrangement. The
product was then treated with excess LAH to reduce the
ketone at C-6 and cleavage of the two benzoyl protecting
groups to form the polyol 122. The hemiketal 123 was then
formed aer oxidative cleavage of the less sterically hindered
vicinal diol with NaIO4. Now the stage was set for inversion of
the C-1 and C-6 stereogenic centers. The authors envisioned
that oxidation/reduction operation at these positions might
give the desired results. Accordingly, acetonide protection of
the 1,3-diol unit in 123 followed by DMP oxidation produced
diketone 124. Aer some tries, they found that sequentially
reducing C-1 ketone with DIBAL-H and C-6 ketone with Red-
Al could gave the desired stereochemistry at both positions,
and the resultant diol was subjected to acidic work-up and
another singlet oxygen ene reaction, and treatment with
Boc2O and HCl sequentially to furnish (
)-oridonin.
4 Total syntheses of seco-ent-
kauranoids
The seco-ent-kaurane diterpenoids can be generated through
oxidative cleavage of the C–C bond of their biogenetic prototype
Nat. Prod. Rep.
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and this phenomenon occurs naturally. This class of diterpenes

are numerous, mainly dominated by 6,7-seco-ent-kaurane
diterpenoids that can be divided into two types according to
different structures: enmein-type and spirolactone-type. Some
total syntheses toward this subgroup are listed below.

4.1 Total synthesis of ()-trichorabdal A and

()-maoecrystal Z (Liang)
In 2018, the Liang group disclosed their total syntheses of tri-
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chorabdal A and maoecrystal Z.9a Both natural products were

prepared from the same [3.2.1] bicyclic intermediate 135, whose
oxidation at C-15 would lead to trichorabdal A whereas a retro-
aldol/aldol tandem reaction would feature concomitant C6–C8
bond formation and C8–C15 bond cleavage to afford maoe-
crystal Z. Their common synthetic route featured several intra-
molecular radical cyclizations, including a cross-ring radical
cyclization to forge the C9–C10 bond together with the spi-
rocyclic quaternary carbon center at C-10; a Ueno–Stork radical
cyclization to connect C-15 to C-8 and establish an all-carbon
quaternary carbon center at C-8; and a reaction between cyclo-
hexenone and terminal alkyne in 132 to forge the bicyclo[3.2.1]
octane ring in diketone 133. The lactone ring in 135 was con-
structed by oxidative cleavage of the ve-membered ring a-
hydroxyketone.
The synthetic route towards the key intermediate 135 star-
ted with compound 125 whose g-position was added onto the
aldehyde 126 upon n-BuLi deprotonation (Scheme 12). Once
the two structures united together, in situ TBS deprotection
with TBAF yielded the desired lactone 127 in 83% yield. The
rst radical cyclization was initiated with AIBN, and its Scheme 12 The total syntheses of ()-trichorabdal A and ()-maoe-
crystal Z by the Liang group.
combination with Bu3SnH afforded spirocyclic compound 128.
Subjecting 128 to subsequent reduction and dearomatization
and introducing two more carbons delivered the designed
precursor 129 for key Ueno–Stork cyclization. In this particular preparation of maoecrystal Z, the authors designed a reverse
case, the Ueno–Stork cyclization reaction appeared chal- aldol/aldol reaction. To that end, the TBS group in the key
lenging, and numerous attempts led to either decomposition, intermediate 135 was rst replaced with an acetate group to
deiodination or aromatization. The authors addressed this give 136. Next, the allylic alcohol resulting from Riley oxida-
challenge through 1,4-addition of thiophenol to break the 1,6- tion at C-15 underwent the expected reverse aldol/aldol reac-
enone system that was apparently preventing the formation of tion under basic conditions, furnishing the natural product
the C8–C15 bond. In such case the desired product 131 was maoecrystal Z.
obtained in 89% yield under standard conditions. Aer a few
simple transformations, the desired terminal alkyne and 4.2 Asymmetric total syntheses of (
)-enmein,
cyclization precursor 132 was obtained. Another radical cycli- (
)-isodocarpin and (
)-sculponin R (Dong)
zation occurred under the action of AIBN and Bu3SnH to In 2018, the Dong group reported the total syntheses of
produce bicyclo[3.2.1]octane 133 with the connection of C-13 (
)-enmein, (
)-isodocarpin and (
)-sculponin R,9b which were
to C-16.16 Next, the stereogenic center at C-5 was xed prepared from the same tetracyclic intermediate. At the early
through redox reactions, and protecting group manipulations stage of the synthetic route, a Diels–Alder reaction was utilized
allowed the nal formation of 134. Aer a hydroxyl group was to quickly construct the A/B ring system. Next, a one-pot
introduced at C-20, at the a-position of a carbonyl group, an acylation/alkylation/lactonization reaction was employed to
oxidative cleavage occurred under the action of aqueous construct both the C ring and the quaternary carbon center at C-
orthoperiodic acid to form a lactol intermediate. Treatment of 8. Finally, a reductive alkenylation was used to achieve the
the lactol with LAH to remove the benzoate protecting group construction of the D/E rings.
and subsequent oxidation of the resulting primary alcohol The asymmetric synthesis started with a Diels–Alder
with PCC provided the key intermediate 135. Trichorabdal A reaction between the chiral diene 137 and the maleic anhy-
was prepared in a few steps through introduction of an addi- dride 138 (Scheme 13). Aer aqueous hydrochloric acid
tional carbonyl group and TBS deprotection. Concerning the quenching, the desired addition product 139 was obtained in

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52% yield as a major isomer. The anhydride 139 was treated
with LAH to selectively reduce more sterically hindered
carbonyl group in the anhydride and the ketone to afford
lactone 140.
Under the action of Li/NH3, the 1,4-cyclohexadiene was ob-
tained through Birch reduction of 140, whose lactone was
reduced to hemiacetal and the benzyl ether protecting group at
C-1 underwent smooth cleavage. Aer acidic work-up, the 1,4-
cyclohexadiene was converted to cyclohexenone, while the
hemiacetal was transformed to the caged acetal, nally yielding
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caged compound 141. TMS protection at C-1 prior to hydroge-
nation of the a,b-unsaturated ketone 141 furnished the desired
C-9 stereocenter. Newhouse's procedure was then applied,
yielding the a,b-unsaturated ketone 142.17 The one-pot
acylation/alkylation/lactonization reaction could now be per-
formed to install the quaternary center at C-8. For that purpose,
the b-ketoester was formed rst, and 2,3-dibromopropene was
then introduced at the alpha position. The C ring in the
advanced key intermediate 144 was nally obtained aer acidic
work-up to remove the TMS group. In order to prepare sculpo-
nin R, LiHMDS/TBSCl treatment of the key intermediate 144
yielded the corresponding silyl enol ether, which was subse-
quently transformed into g-hydroxyenone via epoxide
Scheme 13 The asymmetric total syntheses of (
)-enmein, (
)-iso-
docarpin and (
)-sculponin R by the Dong group.
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formation. With the oxidation at C-11 xed, compound 146
underwent reduction to allylic alcohol at C-14. The [3.2.1] bridge
ring was then implemented through a radical cyclization reac-
tion and a few simple transformations yielded the natural
product (
)-sculponin R. Back to the key intermediate 144, its
reduction with L-selectride generated a lithium enolate, which
underwent a palladium-catalyzed alkenylation reaction under
the action of Cs2CO3 and Pd(PPh3)4 to construct the [3.2.1]
bicyclic ring in 145. From that point, simple transformations
led to the total syntheses of both (
)-enmein and
(
)-isodocarpin.
4.3 Asymmetric total syntheses of (+)-longirabdiol,
(
)-longirabdolactone and (
)-effusin (Li)
In 2019, the Li group described their asymmetric total syntheses
of (+)-longirabdiol, (
)-longirabdolactone and (
)-effusin
through late-stage redox modication of a common key inter-
mediate oxygenated at C-19.9c The key steps towards these target
molecules included several free-radical-based reactions, namely
a copper-catalyzed tandem decarboxylative radical cyclization/
alkenylation reaction to build the cis-g-lactone; an intra-
molecular Giese reaction to transform a carboxylic acid to
a precursor for forming an unsaturated spirolactone; and a vinyl
radical cyclization to install the required bicyclo[3.2.1]octane
ring.
The synthesis started with commercially available 2-cyclo-
hexanonecarboxylate 148 that underwent a 5-step procedure to
yield compound 149 in 87% ee and 35% overall yield (Scheme
14). The carboxylic acid in 149 was converted to the redox-
active ester 151 in 3 steps and 85% overall yield. Next, the
free-radical decarboxylative cyclization/olenation reaction
was carried out to form the C5–C6 bond and introduce the side
chain at C-10. The authors found that the reaction of 151 with
b-bromostyrene proceeded best with copper(II) chloride and
DavePhos as a catalyst system to yield the desired g-lactone
152. The use of both 2-bromopropanoic acid as an additive and
zinc powder proved essential to the reaction. Aer the styrene
group in 152 underwent oxidative cleavage to form the desired
carboxylic acid 153 in 46% yield, construction of the C-10
quaternary stereocenter continued with the esterication
using Takeda's conditions.18 Although a mixture of diastereo-
isomers was obtained, LDA treatment followed by BOMCl
addition yielded a single diastereomer through 1,3-diaxial
interaction. Upon reduction of the lactone, TBS protection of
the resulting diol, and removal of the t-butyl ester protecting
group, acid 154 was obtained in 54% overall yield. The acid
was then converted into a redox active ester and was then
exposed to 2,2,2-triuoroethyl acrylate through decarbox-
ylative Giese reaction19 to produce the desired product 155,
which was subjected to benzyl ether deprotection and subse-
quent oxidation with benzeneseleninic acid anhydride to give
spirolactone 156. Aer that, the strategy of the Li group to
build the C ring resembles that of the Thomson team.6f The
1,4-addition of the allyl cuprate species followed by the in situ
reaction with allyl iodide introduced two side chains, and then
an intramolecular RCM reaction occurred, yielding compound
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Scheme 14 The asymmetric total syntheses of (+)-longirabdiol,
(
)-longirabdolactone and (
)-effusin by the Li group.
157 in 65% overall yield. LDA was then used to deprotonate
compound 157 prior to allylation with 2,3-dibromopropene
which yielded compound 158 as single diastereomer. The
bicyclo[3.2.1]octane ring was then formed through a 5-exo
radical annulation and subsequent allylic oxidation and DMP
oxidation at C-15 yielded the ketone 159. The natural product
(+)-londirabdiol was nally obtained aer global deprotection
using LiBF4. Another DMP oxidation of (+)-londirabdiol would
furnish (
)-longirabdolactone, whereas a regioselective acet-
ylation of the C-19 hydroxyl group prior to DMP oxidation
would furnish (
)-effusin.
5 Total syntheses of nor- or
rearranged-ent-kauranoids
With a unique skeleton structure, the classication of this group of
the ent-kaurane diterpenoids is challenging. They are usually the
results of either the formation of one or several new C–C bonds, or
of one or several C–C bond rearrangements, bonds that are usually
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Scheme 15 The total synthesis of ()-jungermannenone B and
()-jungermannenone C by the Lei group.
connected to the ent-kaurene framework. The degradation of one
or several C-atoms can also lead to new compounds with different
and interesting structures. Some synthetic efforts towards this
class of natural products are introduced below.
5.1 Total syntheses of ()-jungermannenone B and
()-jungermannenone C (Lei)
In 2015, the Lei group reported the scalable racemic total
syntheses of the rearranged ent-kaurene jungermannenones B
and C.10a The protecting-group-free synthesis featured an
intramolecular electrophilic hydroarylation to construct the
tricyclic system and an unprecedented regioselective 1,6-dien-
yne reductive cyclization reaction to close the rearranged bicy-
clo[3.2.1]octane bridged ring.
The authors started the synthesis with inexpensive and readily
available geraniol (160) that underwent substitution reaction to
yield the aromatic diene 162 (Scheme 15), which in turn under-
went a Ru(III)-catalyzed tandem cyclization followed by chromium
trioxide oxidation to afford tricyclic ketone 164. Birch reduction of
164 followed by acid hydrolysis yielded dienone 167. A propargyl
group was then selectively introduced, and an allylic alcohol was
formed through Luche reduction of the enone to afford a precursor
for the key radical cyclization. Upon n-Bu3SnH/AIBN treatment, the
expected intramolecular 1,6-dienyne reductive radical cyclization
proceeded smoothly to create the key bicyclo[3.2.1]octane bridged
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ring in tetracyclic intermediate 170. From that point, selective

oxidative cleavage of exocyclic double bond provided the ketone
171 in 83% yield. Finally, the racemic syntheses of jungermanne-
nones B and C were both completed aer nal installation of exo-
enone by a-methylenation.

5.2 Asymmetric total synthesis of (
)-maoecrystal V (Baran)

The combination of striking structural features and exciting
bioactivity exhibited by the ent-kaurane diterpenoid
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maoecrystal V has attracted extensive interest within the

organic community since 2004.6g–k In 2016, the Baran group
developed a new strategy for asymmetric total synthesis of
(
)-maoecrystal V in 11 steps.10b In the synthesis, the chirality
was introduced through an asymmetric 1,4-addition of an
enone. A pinacol rearrangement together with a double bond
isomerization was used to convert the [3.2.1] bridged ring to the
required [2.2.2] bridged ring.
Starting from cyclohexanone (172), an alkenyl fragment was
smoothly introduced through asymmetric copper-catalyzed 1,4-
Michael addition of an allyl silane using a TADDOL-derived
phosphine-phosphite ligand L2 in toluene/MeTHF (Scheme
16). The resulting product 174 underwent a-acetoxylation aer
successive deprotonation with LiTMP, oxygen atom transfer
with Davis' oxaziridine followed by acetylation to nally yield
compound 175. An intramolecular Hosomi–Sakurai reaction
catalyzed by EtAlCl2 was then performed, which successfully
installed the [3.2.1] bridged ring of alcohol 176 through an anti-
Baldwin cyclization. Aer successive methylation, hydrolysis
and oxidation, the resulting ketone 177 underwent addition of
the corresponding Grignard reagent of 178 that was generated
aer Mg/I exchange in the presence of turbo Grignard.20 Aer
heating the resultant alcohol 179 under acidic conditions, both
a pinacol rearrangement and olen isomerization took place to
Scheme 16 The asymmetric total synthesis of (
)-maoecrystal V by
produce diketone 180 in 45% isolated yield. The next chal- the Baran group.
lenging step was introducing a hydroxymethyl group regiose-
lectively at C-10. With this aim in mind, the authors extended
180 to its sodium enolate form, added a LaCl3$2LiCl solution 5.3 Asymmetric total syntheses of (+)-jungermatrobrunin A,
and quenched the resulting thermodynamically stable enolate (
)-1a,6a-diacetoxyjungermannenone C and (+)-12-hydroxy-
with a formaldehyde gas to achieve the construction of the all- 1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one (Lei)
carbon quaternary carbon center and yielded 181. The regiose-
lective reduction of the ketone at C-5 was made possible In 2019, the Lei team completed the asymmetric total synthesis
through protection of the carbonyl at C-8 by means of ketal of the rearranged ent-kaurene (+)-jungermatrobrunin A in 13
formation. Subsequent treatment of the ketal 182 with LiBH4/ steps, along with the syntheses of (
)-1a,6a-diacetox-
Zn(OTf)2 reduced the carbonyl at C-5 to the desired hydroxyl yjungermannenone C and (+)-12-hydroxy-1a,6a-diacetoxy-ent-
with the required conguration. The resulting alcohol 183 kaura-9(11),16-dien-15-one.10c Interestingly, the natural product
underwent a few protecting group adjustments prior to the (+)-jungermatrobrunin A contains a scarcely observed peroxide
introduction of a cyano group at C-8. The d-valerolactone 186 bridge in the ent-kaurene diterpenoid family. The synthesis
was then formed upon saponication, therefore installing the featured a 1,4-asymmetric addition catalyzed by a chiral Cu(I)
last ring of the pentacyclic core. Aer DMDO epoxidations, both complex to introduce the chirality and a radical-mediated
the epoxides were opened upon InI3/MgI2 treatment to form 188 reductive 1,6-dienyne cyclization to construct the bicyclo[3.2.1]
aer DMP oxidation. In this case an iodohydrin resulted from octene ring. The key peroxide bridge of (+)-jungermatrobrunin A
one of the epoxides, whereas the other epoxide underwent 1,2- was implemented at the last step through a Schenck ene reac-
hydride shi, installing the desired stereochemistry at C-16. tion upon exposure of the intermediate (
)-1a,6a-diacetox-
Finally, upon oxidation of 188 with oxone followed by the yjungermannenone C to irradiation with a 24 W white LED.
spontaneous elimination of the a-iodoso species, the 11-step Interestingly, the authors observed that (
)-1a,6a-diacetox-
total synthesis of maoecrystal V was successfully completed. yjungermannenone C is in equilibrium with (+)-12-hydroxy-

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1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one upon UV irradi-
ation or sunlight exposure of either one or the other.
The synthesis started with the 1,4-asymmetric addition of
styrene-derived 190 onto the a,b-unsaturated ketone 189 cata-
lyzed by both a chiral copper(I) complex and Schwartz's reagent
(Scheme 17).21 The desired chiral adduct 191 was obtained in
78% yield and 88% ee. Subsequent a-arylation under the action
of a palladium(II)/NHC catalytic system completed the ring
closure to afford 192 aer simple methylation, whose benzylic
carbon was then oxidized by chromium trioxide yielding the
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diketone 193. Aer Luche reduction, the resulting triol 194
underwent a Birch reduction followed by an acidic work-up to
deliver 2,4-dienone 195. The propargyl side chain was stereo-
selectively introduced at C-13 aer the TMS protection of the
diol 195 was carried out. Next, Luche reduction of the new 2,4-
dienone followed by MOM protection of the resultant alcohol
afforded the key intermediate 196. The free radical reductive
cyclization of 196 proceeded smoothly to install bicyclo[3.2.1]
octane unit and lead to the formation of 197.10a A Lemieux–
Johnson oxidation then delivered the ketone 198 upon oxidative
cleavage, whose TMS protecting groups were exchanged for
acetates to deliver the natural product (
)-1a,6a-
Scheme 17 The asymmetric total syntheses of (+)-jungermatrobrunin
A, (
)-1a,6a-diacetoxyjungermannenone C and (+)-12-hydroxy-
1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one by the Lei group.
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diacetoxyjungermannenone C aer a methylene group was
introduced. The last task was exposure of this compound to
24 W white LED light to furnish (+)-jungermatrobrunin A
through a Schenck ene reaction and singlet oxygen participa-
tion. The interconversion of the rearranged [3.2.1] bridged ring
structure to the ent-kaurane [3.2.1] bridged ring structure was
also noted upon UV irradiation or upon sunlight exposure of
either one or the other. The synthesis of (+)-12-hydroxy-1a,6a-
diacetoxy-ent-kaura-9(11),16-dien-15-one was therefore also
completed.
5.4 Asymmetric total syntheses of (+)-ent-kauradienone and
(
)-jungermannenone C (Lei)
In 2019, the Lei team also completed the total syntheses of two
other diterpenoids.10d The rst one, (+)-ent-kauradienone, was
prepared in 12 steps and its reduction and subsequent photo-
induced skeletal rearrangement delivered a rearranged ent-
kaurane diterpenoid, jungermannenone C.
Based on their previous results,10a,c the authors embarked on
the preparation of other natural products knowing that a skel-
etal rearrangement of the bicyclo[3.2.1]octene ring system of
ent-kaurane diterpenoids can be induced at a late stage by the
action of light. With jungermannenone C as main target
molecule, the authors started the synthesis from 6-heptyn-1-ol
(199) (Scheme 18). The formation of the (alkenyl)dimethyla-
lane through carboalumination with zirconocene dichloride
followed by iodination resulted in compound 200 that under-
went Suzuki–Miyaura cross-coupling to form 202. Next, a Swern
oxidation was performed, allowing for an enantioselective
organo-SOMO cycloaddition using MacMillan's catalyst 203.22
The resulting chiral compound 204 was obtained in 72% yield
and 85% ee. The subsequent C-4 methylation of 205, aldehyde
deoxygenation, benzylic oxidation, Birch reduction and acidic
hydrolysis delivered the desired 2,4-dienone 206. The dienyne
207 was then prepared through a-propargylation and a radical-
mediated reductive cyclization to install the key bicyclo[3.2.1]
octene ring. A Lemieux–Johnson oxidation followed by a-
methylenation smoothly delivered the rst compound, (+)-ent-
kauradienone, in an excellent overall yield. The asymmetric
total synthesis of jungermannenone C was completed aer
Luche reduction and a late-stage rearrangement of the ent-
kaurane-type skeleton upon UV irradiation at 254 nm or
sunlight exposure. These results in turn implied that photoin-
duced skeletal rearrangement may occur in the biosynthesis of
ent-kaurane-type diterpenoids.
5.5 Total synthesis of (+)-farnesin (Gao)
In 2020, the Gao team completed the asymmetric total synthesis
of farnesin, an acafamane-type diterpenoid.10e This natural
product features a cis-fused tetracyclic structure (syn-syn-syn
hydrouorenol ABC ring) and an extra lactone A0 ring. Farnesin
and, in a broader context, all acafamane-type diterpenoids are
biosynthetically derived from ent-kaurene derivatives through
B-ring cleavage followed by ring regeneration.23 To prepare the
highly strained ABC ring system, a stereocontrolled excited-
state Nazarov cyclization was implemented by the authors.
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Scheme 18 The asymmetric total syntheses of (+)-ent-kauradienone

and (+)-jungermannenone C by the Lei group.

The synthesis commenced with the preparation of 2,4-dienol

212 over three steps, which was used in an asymmetric Diels–
Alder reaction with methyl acrylate 211 (Scheme 19). The
resulting bicyclic compound 213 was obtained in 87% yield
thanks to an optimized chiral ZnII/MgII bimetallic system with
(R)-octahydrobinaphthol L3 as a ligand.24 Aer methylation at
C-4 to afford 214, acetonide protecting group was removed prior
to oxidative cleavage of the resulting diol to provide aldehyde
215.
The synthesis of the second fragment started from diaster-
eoselective alkylation of 217 with allyl bromide 216, and the
resultant diene 218 was subjected to Ru-catalyzed RCM reaction
to afford bromocyclohexene 219 in 75% yield. Reductive
removal of the chiral auxiliary in 219 and oxidation generated
an aldehyde, which was subjected to a NHC-catalyzed hydrox-
ymethylation and subsequent TBS protection to produce 220. A
Wittig olenation nally delivered the second fragment 221,
which underwent an intermolecular addition onto the rst
fragment 215 aer treatment with t-BuLi. Aer IBX oxidation of
the resulting alcohol, dienone 222 was obtained in 67% yield
over two steps. The key Nazarov reaction was then implemented
since non-aromatic dicylic divinyl ketone can engage in cycli-
zation under acidic conditions or by photolysis.25 The latter
apparently allowed the formation of the desired product
through disrotatory cyclization via an excited-state Nazarov
Scheme 19 The total synthesis of (+)-farnesin by the Gao group.
reaction, which resulted in the formation of the desired highly
strained tetracyclic intermediate 223 in 68% yield using ow
chemistry. TBS deprotection followed by SmI2-mediated radical
reaction then reduced the enone in 223. Although the ketone at
C-7 was reduced in the meantime, it was recovered through
DMP-oxidation, which ultimately delivered the aldehyde 224.
The formation of the C8–C15 bond through NaOMe-mediated
intramolecular aldol condensation achieved the construction
of the bicyclo[3.2.1]octane unit. Oxidation of the resulting
alcohol then delivered the methyl ether 225, which underwent
demethylation followed by dehydration through sulfonate ester
formation to afford the acafamane-type framework 226. The
total synthesis of (+)-farnesin was fullled aer oxidation state
adjustments at C-6, C-7 and C-15 over 7 steps.

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6 Total syntheses of grayananes

Grayananes are among a broader class of rearranged kaurane
diterpenoids and their tetracyclic framework is formed through
rearrangement of the kaurane 6,6-A/B ring system to the 5,7-
ring system.26 They feature a central seven-membered ring in
a characteristic [5,7,6,5]-tetracyclic carbon skeleton decorated
with 7–10 stereogenic centers, as well as a dense arrangement of
hydroxyl groups. Before 2019, only two total syntheses of these
family members had been disclosed. One was reported by
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Matsumoto and co-workers more than forty years ago, in which

a relay total synthesis (>39 steps) of grayanotoxin II based on
a key biomimetic photo-santonin rearrangement was describe-
d.27a,b Another one was disclosed by Shirahama and co-workers
in 1994, in which an enantioselective total synthesis of graya-
notoxin III was accomplished in 38 steps.27c Very recently, three
more synthetic studies on these family members were reported,
which are briey summarized below.

6.1 Total synthesis of (+)-principinol D (Newhouse)

In 2019, the Newhouse group developed a convergent route
towards the total synthesis of (+)-principinol D.11a This synthesis
featured a 1,2-addition to couple the two designed fragments,
a SmI2-mediated reductive cyclization to form the central seven-
membered ring of the grayanane skeleton, and a Ni-catalyzed a-
vinylation reaction to install the requisite bicyclo[3.2.1]octane
ring.
As outlined in Scheme 20, the synthesis started with a vicinal
difunctionalization of 1-cyclohex-2-enone 227. The addition of
a vinyl Grignard reagent onto the enone was performed using
a catalytic amount of CuBr–DMS complex together with excess
DMPU. The following ethoxycarbonylation with Mander's
reagent resulted in the formation of the b-ketoester 228. Aer
allylation with 2,3-dibromopropene, reduction of the ester
using LiBH3NMe2 through enolate formation with the weak
base Zn(TMP)2 yielded the primary alcohol 229. A TBS protec-
tion of the alcohol 229 was performed prior to the a-vinylation
using a Ni(II) precatalyst and LiHMDS as base. The TBS group of
the resulting bicyclo[3.2.1]octane ring was then cleaved under
acidic conditions to afford 230. The ketone was then reduced
with SmI2 in the presence of HMPA and PhSH, presumably
acting as H-atom donor.28 The desired diol 231 was obtained in
both high yield and diastereoselectivity, and the primary
alcohol was converted into alkyl iodide through Appel reaction,
whereas the secondary alcohol was MOM-protected to nally
yield the rst key fragment 232. The treatment of 232 with t-
BuLi enabled addition onto the enantioenriched aldehyde 233,
and the resulting secondary alcohol was MOM-protected to
form the desired adduct 234 in 23% overall yield. TBS depro-
tection followed by DMP oxidation rstly formed an enone, and
its terminal alkene then underwent Lemieux–Johnson oxidation
to nally yield the aldehyde 235. The key seven-membered ring
and therefore 236 was now formed in 63% yield upon SmI2/H2O
treatment. With the aim of installing exocyclic olen at C-10,
the secondary alcohol was rst oxidized to ketone using DMP
and then treated with Me3SiCH2Li to form b-hydroxysilane 237.
Scheme 20 The total synthesis of (+)-principinol D by the Newhouse
group.
The tertiary alcohol at C-16 was rstly installed through
Mukaiyama hydration. Then, the secondary alcohol at C-3 was
formed upon reduction of the ketone with LiEt3BH at 65  C.
Upon heating, the b-hydroxysilane was eliminated to deliver the
alkene at C-10 through Peterson olenation. Global MOM
deprotection nally delivered (+)-principinol D in a total of 19
steps.
6.2 Total syntheses of ()-rhodomolleins XX and XXII (Ding)
In 2019, the Ding group reported the total syntheses of
()-rhodomolleins XX and XXII, two highly oxidized grayanoids
that were prepared in 23 and 22 steps, respectively.11b Notably, it
features a Ti(III)-mediated reductive ring opening of a [2.2.1]-
bicyclic ketoepoxide and a Dowd–Beckwith rearrangement to
establish the bicyclo[3.2.1]octane ring system.
The synthesis started with the 7-step preparation of b-
ketoester 239 from 3-hydroxy-2-methoxybenzaldehyde 238
(Scheme 21). A Regitz diazo transfer delivered an a-diazo-b-
ketoester, which then gave the cyclopropanation product 240
under the catalysis of a Cu(II) salen analogue. Treatment of 240
with TMSOTf and (TMSOCH2)2 resulted in protection of the C-2
ketone together with ring opening of the cyclopropane to deliver
the styrene 241, which was subjected to selective epoxidation of
the alkene and subsequent Pd-catalyzed hydrogenation to
produce alcohol 242. The ethyl ester 242 was then converted to
vinyl ketone 243 through subsequent b-keto phosphonate
formation, followed by a HWE olenation. Aer the depro-
tection of silyl ether in 243 with TBAF, PIDA-mediated intra-
molecular ODI Diels–Alder cycloaddition smoothly occurred to

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Scheme 21 The total synthesis of ()-rhodomolleins XX and XXII by
the Ding group.
afford desired tetracyclic product 244 in 70% yield. The SmI2-
mediated reductive demethoxylation of 244 followed by selec-
tive epoxidation of the alkene with DMDO provided the exo-
epoxide 245 as a single diastereomer in 83% yield over two
steps. The key Ti(III)-mediated reductive epoxide opening then
took place in a rather regioselective fashion thanks to the free
alcohol at C-6. The resulting radical intermediate 246 then
underwent a Dowd–Beckwith rearrangement reaction. In this
case the subsequent selective cleavage of the C12–C16 bond was
supposedly enabled by the titanoxy group at C-14, which might
slow down the rate of radical quenching at C-13, resulting in the
reversible formation of the cyclopropoxy radical 247 prior to the
construction of the key bicyclo[3.2.1]octane ring in 248 through
C13–C16 bond linkage.29
Moving on to the total syntheses of ()-rhodomolleins XX
and XXII, the acetylation of the two free hydroxyl groups in 248
and subsequent regioselective methylenation of the C-16 ketone
produced enol 249. Aer treatment of 249 with PhSeCl and
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pyridine to afford enone 250 through a-selenylation and
subsequent spontaneous elimination of the resultant selenide,
regioselective Mukaiyama hydration was conducted to deliver
triol 251. Both the hydroxyl groups at C-2 and C-14 were pro-
tected as TBS-ethers prior to Grignard addition to the C-10
ketone that delivered 252. Without further purication, the
synthesis of ()-rhodomollein XXII was achieved aer acidic
work-up in 77% yield over two steps. For the synthesis of
()-rhodomollein XX, the intermediate 252 was converted into
a-hydroxyketone 253 (d.r. > 20 : 1) through a MeReO3-catalyzed
Rubottom oxidation. TBS group deprotection nally yielded
()-rhodomollein XX in 64% yield over three steps.
6.3 Total synthesis of (
)-rhodomollanol A (Ding)
Rhodomollanol A is a highly oxidized hexacyclic diterpenoid
that was isolated by Yao and co-workers from the leaves of
Rhododendron molle G. in 2017.30 Unlike typical grayanoids,
rhodomollanol A possesses an unusual [3,5,7,5,5,5] hexacyclic
carbon framework, which features a 7-oxabicyclo[4.2.1]nonane
core. Biosynthetically, this target molecule was proposed to be
derived from grayananes via a set of biochemical trans-
formations.31 In 2020, the Ding group reported the asymmetric
total synthesis of (
)-rhodomollanol A.11c The key elements in
their synthesis include an oxidative dearomatization-induced
(5+2) cyclo-addition/pinacol-type 1,2-acyl migration cascade to
construct the bicyclo[3.2.1]octane skeleton, a retro-Dieckmann
fragmentation/vinylogous Dieckmann cyclization cascade to
forge the bicyclo[3.3.0]octane ring, and a photo-Nazarov
cyclization/intramolecular cycloetherication cascade to
assemble the 7-oxabicyclo[4.2.1]nonane core structure of the
natural product.
The synthesis started with the 1,2-addition of the corre-
sponding aryllithium reagent of 256 to the aldehyde 255 that
was prepared in 7 steps from bicyclic enone 254 (Scheme 22).
The resulting alcohols 257 underwent PDC oxidation and
subsequent NaBH4 reduction to yield the desired epimer 258 at
C-7. Aer THP protection of the alcohol 258, an ODI (5+2)
cycloaddition/pinacol-type 1,2-acyl migration cascade was
carried out to form tetracyclic intermediate 259 as a single
diastereomer aer THP deprotection with TFA. Treatment of
259 with TMSOTf and 1,2-bis(trimethylsiloxy)ethane allowed
the formation of enone 260 through retro-Dieckmann
fragmentation/vinylogous Dieckmann cyclization. With 260 in
hand, the alcohol at C-7 was converted into xanthate ester,
which was subjected to Barton–McCombie deoxygenation to
furnish 261. DIBAL-H treatment of 261 to cleave the benzoyl
protecting group and reduce the enone formed allylic alcohol
262, in which the hydroxyl group was then critical to direct the
vanadyl acetylacetonate-catalyzed epoxidation through
hydrogen bonding. The resulting b-epoxide 263 underwent
(PhSeO)2O-mediated oxidation and Luche reduction to afford a-
alcohol 265. As mentioned by the authors, TMS group protec-
tion of the alcohol was necessary to efficiently perform the
subsequent photo-Nazarov cyclization/intramolecular ring-
opening cycloetherication cascade reactions. As a result, the
desired product 266 was ultimately formed in 56% yield.
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Scheme 22 The total synthesis of (
)-rhodomollanol A by the Ding
group.
To continue the synthesis, ketone 267 was obtained through
deprotonation of the enone 266 with dimsyl sodium32 and
methylation with methyl iodide in extremely anhydrous solvent.
The D (ref. 5 and 6) double bond in compound 267 underwent
dihydroxylation with OsO4-pyridine complexes followed by
hydrolysis of the osmate ester with NaHSO3. The resulting cis-
diol was then efficiently protected as an acetonide 268 upon
PPTs and 2-methoxypropene treatment. Inversion of the ster-
eogenic center at C-1 was then performed through successive
enone formation, conversion to hydrazine, stereoselective
reduction and allylic diazene rearrangement to yield 269. The
epoxy compound 269 was then reduced to alkene 270 upon
Ti(III)-mediated reductive ring opening of the epoxide, Chugaev
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elimination, and acetal and acetonide deprotections. Finally, C-
5 hydroxyl group-directed epoxidation through hydrogen
bonding and reduction of the ketone at C-12 achieved the
asymmetric total synthesis of rhodomollanol A.
7 Conclusion and outlook
As mentioned above, we have witnessed great progress in the
total synthesis of ent-kaurane and related diterpenoids during
the past seven years. Around 43 diverse target molecules have
been synthesized during this period, which were demonstrated
in 20 published articles. The total number of nished molecules
is probably higher than what was done from 1962 to 2014. These
achievements are highly reliant on using many concise retro-
synthetic disconnections and innovative synthetic strategies,
particularly those unprecedented C–C bond formation reac-
tions such as novel radical-triggered cyclization, metal-
mediated cascade cyclization, unusual Diels–Alder cycloaddi-
tion, and photoinduced skeletal rearrangement. These inven-
tive ideas have been well demonstrated to overcome key
challenges associated with the constitution of bicyclo[3.2.1]
octane skeleton and its embedded ring system of ent-kaurane-
type diterpenoids. It is interesting that some synthetic strate-
gies are quite general to some extent for diversely synthesizing
ent-kaurane and related diterpenoids, which are exemplied by
the unied approach utilizing dearomatizative cycloaddition
that the Ding group took to access three different kinds of target
molecules. Other remarkable progress is that many of the re-
ported synthetic routes to the same (or closely similar) target
molecules have been regularly updated and simplied. The
striking case is Baran's synthetic routes towards maoecrystal V
only needing about 11 steps, which would have been unthink-
able a decade ago. One can expect that in this eld more
recently isolated and highly unusual target molecules of this big
family will be synthesized in the near future.
Nevertheless, a large part of the already isolated and charac-
terized ent-kauranoids still represent an unsolved challenge for the
synthetic community, as they remain inaccessible by the reported
strategies. Moreover, there is undoubtedly a plethora of ent-kaur-
anoids that have been neither isolated nor characterized from their
natural source. Consequently, new, more divergent and efficient
strategies remain highly desirable, particularly unied strategies to
efficiently access a subgroup of ent-kaurenes, which will help to
close the gap between the number of ent-kaurenes isolated and
those synthesized. Additionally, the biological activities of most
isolated ent-kauranoids have not been systematically evaluated
because sufficient material was not available. With the progress in
total synthesis of ent-kauranoids, researchers should pay more
attention to obtaining more material, particularly those with
unique structural features, and testing the biological activities of
the corresponding natural products. Such studies will be of benet
for detailed investigations of the mechanism of action and thera-
peutic potential of ent-kauranoids.
8 Conflicts of interest
There are no conicts to declare.
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9 Acknowledgements
Financial support of this research from Chinese Academy of
Sciences (supported by the Strategic Priority Research Program,
grants XDB20020200 and QYZDJ-SSW-SLH029) and the
National Natural Science Foundation of China (grants
21621002, 21831009 and 21991110) is acknowledged.
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