Synthesis of Ent Kauranes

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Recent advances in the synthesis of ent-kaurane

Cite this: DOI: 10.1039/d1np00028d
diterpenoids
Published on 15 July 2021. Downloaded by Goteborgs Universitet on 9/1/2021 3:18:35 AM.
Xiangbo Zhao,† Bastien Cacherat,† Qifei Hu and Dawei Ma *
Covering: 2015 to 2020
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,
Received 28th April 2021
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
DOI: 10.1039/d1np00028d
products. The purpose of this review is to describe the recent advances in the total synthesis of ent-
rsc.li/npr 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)
1 Introduction
State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for
In 1961, the simplest ent-kaurane diterpenoid, ent-kaurene (1),
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 was detected for the rst time in New Zealand in the leaf
Lingling Road, Shanghai 200032, China. E-mail: madw@sioc.ac.cn essential oil in Agathis, a member of Araucariaceae, a conifer
† Both authors contributed equally to this article. family (Fig. 1).1 The plant being locally called kauri pine, this
This journal is © The Royal Society of Chemistry 2021 Nat. Prod. Rep.
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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
Fig. 1 ent-Kaurene skeleton.
the Labiatae (or Lamiaceae) family, feature numerous ent-
kauranoids, but other families, for example Asteraceae (or
Compositae), Annonaceae, Pteridaceae, Euphorbiaceae, as well
type of diterpene with negative optical rotation was conse- as liverworts and microbial metabolites, are also a source of
quently called ent-kaurene, “ent” meaning enantiomeric.
a plethora of ent-kauranoids.2c Sun and co-workers notably

As a family composed of structurally diverse and biologically achieved the separation, the identication as well as biological
active natural products of terrestrial plants, ent-kaurane diter- activity testing of more than 300 diterpenoids from the Isodon
penoids, with their 20 C-atoms, account to date for more than species.2a,b In recent years, more and more studies have shown
Xiangbo Zhao was born and Qifei Hu was born in Xi'an,

raised in Xuzhou, China and China and graduated from
obtained his BSc degree at Nankai University (Tianjin,
Northwest University (Xi'an, China) in 2015. Then, he
China) in 2012. Then, he went to continued his education under
Shanghai Institute of Organic the supervision of Prof. Dawei
Chemistry (SIOC) to pursue his Ma at Shanghai Institute of
PhD degree in Professor Dawei Organic Chemistry (Shanghai,
Ma's group, working on the total China), working on the total
synthesis of ent-kaurane diter- synthesis of rearranged ent-
penoids and napelline alkaloids. kaurane diterpenoids. In 2020,
Aer graduation in 2017, he he received his PhD and joined
continued his work in the same Pharmaron Inc. as a R&D Senior
group for one year and then joined the Macmillan group as a post- Scientist in the same year. His research interest includes total
doc at Princeton University in 2019, where he mainly focused on synthesis of natural products with signicant bioactivities and
the development of new cross-coupling methods using metal- efficient methodologies in drug research and development.
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 Dawei Ma received his PhD in

École Nationale Supérieure de 1989 from Shanghai Institute of
Chimie de Mulhouse from 2011 Organic Chemistry and did his
to 2014, earning a M.Sc. in postdoctoral studies at the
sciences, technologies, health University of Pittsburgh and
and research, together with Mayo Clinic. He returned to
a Diplôme d’Ingénieur in chem- SIOC in 1994 and was appoin-
istry. As a doctoral student sup- ted as research professor in
ported by a Max-Planck- 1995. His research interests
Gesellscha fellow-ship in the currently focus on the develop-
laboratory of Prof. Bill Morandi ment of new synthetic method-
at the Max-Planck-Institut für ologies, the total synthesis of
Kohlenforschung, he then devel- complex natural products, and
oped new strategies in organic synthesis, using either transition their SAR and action mode studies, as well as the discovery of
metals or Brønsted acids. Subsequently, he moved to Shanghai, small modulators for target proteins and special biological
China to undertake a postdoctoral fellowship with Prof. Dawei Ma processes.
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.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2021
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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
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
Fig. 2 Structures of related ent-kauranes.
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- attracted extensive attention from synthetic chemists and
cyclic beyeranyl-13-cation intermediate PB (5), with a secondary a tremendous amount of total syntheses were disclosed over the
carbocation at C-13. A 1,2-alkyl migration then occurs, forming past decade.4–6 To the best of our knowledge, there have been
the ent-kaurenyl-16-cation intermediate PE (6) with a more several elegant reviews focusing on the total synthesis of these
stable tertiary carbocation. Alternatively, Tantillo's calculation diterpenoids between 1962 (the rst total synthesis of ent-
work on the ent-kaurene biosynthetic pathway indicates that kaurane diterpenoids by Ireland and co-workers)5a and 2014,
secondary carbocations can be avoided by combining two or published by the Thomson, Hong, Lei, and Schindler groups.4a–d
more mechanistic steps into concerted processes that lead to Many of the classic methods that were invented for total
tertiary carbocations.3c,d Therefore, the tertiary carbocation PE synthesis of these natural products in this period, such as
(6) is also expected to be formed from PA (4) via a concerted Mori's fragmentation of unique cyclopropane intermediate,5f
cyclization/alkyl shi process. Finally, ent-kaurene is generated Corey's cationic cyclization,5h,i and Yang's oxidative
through proton removal which quenches the tertiary carboca- dearomatization/intramolecular Diels–Alder reaction,6g remain
tion, yielding the desired exocyclic olen. effective in this eld and continue as fruitful resources to
For this parent ent-kaurene carboskeleton, oxidation, C–C inspire total synthesis and method development to this day.4e
bond cleavage, fragmentation or rearrangement within these During the past seven years, rapid development of new
diterpenoids are incredibly common and lead to a variety of synthetic strategies and methodologies, particularly unprece-
additional structures. Based on structural features, ent-kaurane dented C–C bond formation reactions, has offered numerous
diterpenoids were classied into different sub-classes: the C-20 new opportunities for the total synthesis of ent-kaurane and
non-oxygenated ent-kauranoids (such as pharicin A, 7), the C-20 related diterpenoids. Dozens of unique synthetic strategies have
oxygenated ent-kauranoids (such as xerophilusin I, 8), the seco- been developed towards accessing the more recently isolated,
ent-kauranoids (such as sculponeatin N, 12), nor- or rearranged- highly oxidized, and unusual members of this family.7–11 In this
ent-kauranoids (such as maoecrystal V, 14), and grayananes review, we cover the recent total syntheses of the ent-kauranoids
(such as principinol D, 15) (Fig. 2).2 ent-Kauranoids exhibit from 2015 to date.
numerous frameworks and oxidation patterns, as well as
a variety of bioactivities, and so these molecules have naturally
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
Scheme 1 Biosynthesis of ent-kaurene. assemble these natural products, which are summarized below.
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2.1 Asymmetric total syntheses of (+)-lungshengenin D and [3.2.1] bicyclic enone 20 through a Pd-catalyzed cyclo-
(+)-1a,6a-diacetoxy-ent-kaura-9(11),16-dien-12,15-dione (Ma) alkenylation. Ketone protection of 20, followed by silyl ether
cleavage and Ley–Griffith oxidation delivered the designed
In 2017 the Ma group completed the rst asymmetric total
aldehyde building block 21.
syntheses of two highly oxidized ent-kaurane diterpenoids,
In a parallel procedure, asymmetric reduction of a-methyl-
lungshengenin D and 1a,6a-diacetoxy-ent-kaura-9,16-dien-
cyclohexenone 22 with (R)-CBS gave allylic alcohol 23 in 90%
12,15-dione,7a in which a [3.2.1] bicyclic unit was designed as
yield and 99% ee. NaH-mediated condensation of 23 with N,N-
a common intermediate. This unit was established by using
a Hoppe homoaldol reaction and a Lewis acid-mediated diisopropylcarbamoyl chloride provided the desired cyclo-
Mukaiyama–Michael-type cyclization as the key steps at the hexenyl carbamate 24. Aer condensation of 24 with the alde-
hyde 21 under typical Hoppe homoaldol reaction conditions,13
early stage, making this strategy remarkably convergent.
an unprecedented intramolecular Mukaiyama–Michael cycliza-

As outlined in Scheme 2, the authors started the synthesis
tion reaction was conducted under the action of boron tri-
from enone 16, which was transformed into ester 17 in two
uoride diethyl etherate, successfully yielding a diastereomeric
steps. This ester was subjected to a Pd-catalyzed intramolecular
mixture 26 aer quenching the reaction with aqueous sodium
allylation to create a quaternary carbon center in 82% yield and
bicarbonate. Next, hydrolysis of the ester group in 26 and
87% ee.12 Aer reduction and isomerization of the chiral ketone
18, the resulting enone 19 was subsequently converted into 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 2 The first asymmetric total synthesis of 1a,6a-diacetoxy- Scheme 3 The first asymmetric total synthesis of lungshengenin D by
ent-kaura-9(11),16-dien-12,15-dione by the Ma group. the Ma group.
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intramolecular etherication was carried out under the assis- and C-5 positions. A couple of reaction sequences allowed the
tance of HCl to afford pentacyclic intermediate 32. Next, deox- access to a 2 : 1 mixture of vinylphenols at C-7, which was
ygenation of C-12 was achieved via a selective reduction of C-12 further transformed to tetracyclic diketone 42 upon treatment
carbonyl group, mesylation of the resultant alcohol, and with PIFA. The ODI (oxidative dearomatization-induced) [5+2]
subsequent reduction with LAH. The resultant diol was oxidized cycloaddition rst connected C-9 to C-8 and C-11 to C-12, and
with IBX to give 33, which was converted into lungshengenin D then a pinacol-type 1,2-acyl migration reaction occurred to
aer 4 steps. 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
2.2 Asymmetric total syntheses of ()-pharicin A, allowed the total syntheses of several natural products, namely
(+)-pharicinin B, (+)-7-O-acetylpseurata C and (+)-pseurata C
pharicin A, pharicinin B, 7-O-acetylpseurata C and pseurata C

(Ding) aer a few steps.
In 2017, the Ding group developed a new strategy to forge the
highly oxygenated bicyclo[3.2.1]octane core unit of ent-kaurane 2.3 Total syntheses of ()-11b-hydroxy-16-kaurene, ()-11a-
diterpenoids bearing a b-OH at C-14.7b This new strategy hydroxy-16-kaurene, ()-liangshanin G and ()-gesneroidin B
featured an oxidative dearomatization-induced [5+2] (Ma)
cycloaddition/pinacol-type 1,2-acyl migration cascade to In 2019, the Ma group reported the total syntheses of four
construct the core structure. The implementation of this kaurane diterpenoids by using a twisted and extremely reactive
strategy with subsequent retro-aldol/aldol reaction and singlet enone, 6-methylenebicyclo[3.2.1]oct-1-en-3-one (46) (Scheme 5),
oxygen ene reaction allowed for the rst asymmetric total as a Diels–Alder reaction dienophile.7c The [3.2.1] bridgehead
syntheses of the natural products pharicin A, pharicinin B, 7-O- enone, prepared through bromide elimination, enabled the
acetylpseurata C and pseurata C in a rather convergent way. construction of the tricyclic or tetracyclic adducts through
As depicted in Scheme 4, conversion of the Wieland– Diels–Alder cycloaddition at the early stage of a synthesis.
Miescher ketone 35 into the bicyclic ketone 36 via the formation The synthesis of the [3.2.1] bridgehead enone started with the
of corresponding chiral alcohol was performed in 6 steps. The preparation of bicyclic carboxylic acid 44 from methyl 3-
resulting epoxide 36 underwent Eschenmoser–Tanabe cleavage methoxybenzoate 43 in 75% yield over three steps (Scheme 5).14
to deliver the acetylene aldehyde 37 with the side chains at C-10 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 4 The first asymmetric total syntheses of ()-pharicin A, Scheme 5 The total syntheses of ()-11b-hydroxy-16-kaurene,
(+)-pharicinin B, (+)-7-O-acetylpseurata C and (+)-pseurata C by the ()-11a-hydroxy-16-kaurene, ()-liangshanin G and ()-gesneroidin B
Ding group. by the Ma group.
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diene, furan and a diene derived from 1-(cyclohex-1-en-1-yl) unsaturated ketone 51 followed by enolate ethoxycarbonylation
ethan-1-one, to provide the corresponding cycloadducts.7c with Mander's reagent (Scheme 6). The resulting ketoester 52
However, under the same conditions the diene 47 did not give and its corresponding enol were alkylated with 3-bromo-1-
a satisfactory result. The authors then found that when using trimethylsilyl-1-propyne (53) in a diastereoselective fashion to
another inorganic base, K3PO4, instead, at 100 C and in neat result in b-ketoester 54. The alkynyl ketone 55 was then
conditions, the desired product 48 could be formed in 48% yield prepared aer selective C(sp3)–Si bond cleavage, followed by
as a 1 : 1 diastereomeric mixture. The slow addition of the a Mn(III)-mediated oxidative cyclization to deliver C14-
dienophile to the diene/K3PO4 mixture appeared to be critical. oxygenated bicycle 55 in 45% yield. Next, desilylation followed
Then, the ketone at C-11 was reduced with DIBAL-H to form by reduction of the ketone and TBS protection of the resulting
alcohol 49 in 47% yield, together with its separable C-10 epimer. alcohol yielded ester 56. The ester was then converted to alde-
With the alcohol 49 in hand, four kaurane diterpenoids, namely hyde 57 before a Yamamoto aldol reaction achieved the
()-11b-hydroxy-16-kaurene, ()-11a-hydroxy-16-kaurene, formation of 58 as major diastereoisomer together with the
()-liangshanin G and ()-gesneroidin B, were rapidly prepared undesired epimer at C-7 (3 : 1 dr). Aer MOM protection of the
through simple oxidation state adjustments. 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
2.4 Total synthesis of ()-glaucocalyxin A (Jia) reaction then delivered the tetracyclic compound 60 in excellent
In 2020, the Jia group reported the asymmetric total synthesis of yield but under pretty harsh reaction conditions. The key tet-
()-glaucocalyxin A, a highly oxidized ent-kaurane diterpe- racyclic core was obtained aer the gem-dimethyl group at C-4
noid.7d The synthesis featured a Mn(III)-mediated radical cycli- was installed upon addition of “anhydrous” TBAF and concen-
zation to form a C-14 oxygenated bicyclo[3.2.1]octane ring at the trated MeI, leading to the formation of ketone 61 in 86% yield.
early stage and an intramolecular Diels–Alder reaction to form Aer installations of the desired alcohol at C-14 and ketone at C-
the key tetracyclic core. 15, the total synthesis of ()-glaucocalyxin A was nally
The synthesis started with a highly enantioselective conju- achieved.
gate addition of Grignard reagent 50 onto the cyclic a,b-
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-
Scheme 6 The total synthesis of ()-glaucocalyxin A by the Jia group. anginone D upon further oxidation.
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Scheme 7 The total synthesis of ()-euphoranginol C and Scheme 8 The total synthesis of ()-1a-hydroxykauran-12-one,
()-euphoranginone D by the Lou group. ()-12-oxo-9,11-dehydrokaurene and ()-12a-hydroxy-9,11-dehy-
drokaurene by the Lei group.
2.6 Total synthesis of ()-1a-hydroxykauran-12-one, ()-12-

oxo-9,11-dehydrokaurene and ()-12a-hydroxy-9,11- dehydration to provide a terminal alkene, which was reduced
dehydrokaurene (Lei) with NaBH4 leading to the formation of two isomers, 80 and 81.
In 2020, the Lei group developed a concise approach for Due to the undesired C16 stereochemistry provided by hydroge-
assembling the core structure of ent-kaurane diterpenoids,7f nation of the terminal double bond in 81, a hydroxyl-directed
which relied on a rhodium-catalyzed [3+2+1] cycloaddition to reduction strategy was then studied to overcome this drawback.
furnish the B ring and C ring in one step, as well as a palladium- As a result, face-selective Luche reduction of 81 afforded C12-b-
mediated cycloalkenylation to construct the key [3.2.1] ring OH 82, which underwent hydroxyl-directed reduction with
system. Based on this synthetic strategy they achieved the rst RANEY® Ni and H2 to give enone 83 with the desired C16
total syntheses of ()-1a-hydroxykauran-12-one, ()-12-oxo- stereochemistry upon a MnO2-mediated oxidization. Reduction
9,11-dehydrokaurene and ()-12a-hydroxy-9,11- of 83 under Birch conditions enabled the rst total synthesis of
dehydrokaurene in a protecting-group-free manner. ()-1a-hydroxykauran-12-one. In a parallel procedure, Barton–
The synthesis started with commercially available enone 74 McCombie deoxygenation of the isomer 80 delivered ()-12-oxo-
that underwent Michael addition and alkynylation in two steps to 9,11-dehydrokaurene. Luche reduction of 84 furnished C12-b-OH
yield 77 (Scheme 8). Aer a brief optimization, the key Rh(I)- 85, which was treated with 2 N HCl at 50 C to give a mixture of
catalyzed [3+2+1] cycloaddition of 77 and CO occurred smoothly unreacted 85 and the desired ()-12a-hydroxy-9,11-
to deliver the desired 78 in 52% yield with a diastereomeric ratio dehydrokaurene.
of 5.8 : 1 at C8. It is noteworthy that two rings, three carbon–
carbon bonds, and one quaternary stereogenic center were 3 Total syntheses of C-20
created in this step through a remarkable [3+2+1] cycloaddition.15
Next, Pd-mediated 5-endo oxidative cyclization of a 5-vinyl silyl
oxygenated ent-kauranoids
enol ether generated from the tricyclic 78 produced 79 in 79% In contrast to unoxidized C-20 ent-kaurane diterpenoids, these
yield. The success in creating the requisite [3.2.1] ring in this step types of diterpenes usually feature either an oxidized methylene
relied on increasing the equivalents of Pd(OAc)2 and conducting group, an aldehyde group or a carbonyl group at C-20. Conse-
the reaction at a relatively low temperature. Next, regioselective quently, they can form additional oxygen bridges, such as
Mukaiyama hydration of the diene 79 occurred at the less acetal, hemiketal, ketone, lactone or ether with carbons at the C-
hindered part and the resultant tertiary alcohol was subjected to 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 hydrogenolysis of the cyclopropane ring to give a pair of dia-
few years, which are discussed below. stereoisomers 91 at C-16. Decarboxylation of 91 and acetonide
protection led to the formation of 92, which was converted into
3.1 Total synthesis of ()-maoecrystal P (Luo) aldehyde 93 through two-step redox manipulations. Carbonyl–
alkene reductive cyclization of 93 with the assistance of SmI2
In 2018, the Luo group completed the racemic total synthesis of
proceeded smoothly to afford tetracyclic intermediate 94, which
maoecrystal P, an ent-kaurene diterpenoid oxygenated at C-20.8a
successively underwent DMP oxidation of the hydroxyl group at
The synthesis featured a highly regioselective and diaster-
C-15 and introduction of a methylene group at C-16 to produce
eoselective intermolecular Diels–Alder cycloaddition for
96. Oxidation of the enol ether moiety in 96 followed by
creating a tetracyclic system from an enone-aldehyde and
deprotection furnished triol 97. TBAF-mediated ketal formation
a diene embedded in a substituted bicyclo[4.1.0] skeleton.
of 97 provided acetonide 98, which was converted into maoe-

Another key point in this synthesis was a SmI2-mediated
crystal P aer 5 steps.
carbonyl–alkene reductive coupling to install the key [3.2.1] ring
system.
As shown in Scheme 9, BF3$OEt2-mediated intermolecular 3.2 Total syntheses of ()-eriocalyxin B, ()-neolaxiorin L
Diels–Alder cycloaddition between the enone-aldehyde 86 and and ()-xerophilusin I (Lee)
the diene 87 quickly produced tetracyclic compound 88. The
In 2018, the Lee group completed the racemic total syntheses of
subsequent reduction, acetyl protection and allylic oxidation
three diterpenoids, namely eriocalyxin B, neolaxiorin L and
afforded the desired enone 90, which underwent Pd-catalyzed
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
Scheme 9 The first total synthesis of maoecrystal P by the Luo group. interrupted Nazarov/Hosomi–Sakurai reaction cascade to
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Scheme 11 The total synthesis of ()-oridonin by the Luo group.
Scheme 10 The first total syntheses of ()-eriocalyxin B, ether moieties to the corresponding benzoyl esters, and then
()-neolaxiflorin L and ()-xerophilusin I by the Lee group.
treated with DBU to eliminate HBr to give enone 120, which
underwent Upjohn dihydroxylation to form diol 121. The
build the key tetracyclic core and an important stereogenic desired C/D ring system was then implemented upon addi-
center at C-8. tion of EtAlCl2 which induced the key rearrangement. The
The synthesis commenced with the preparation of two key product was then treated with excess LAH to reduce the
building blocks, 112 and 114, over several simple transformations ketone at C-6 and cleavage of the two benzoyl protecting
(Scheme 11). With these two fragments in hand, Li–Br exchange groups to form the polyol 122. The hemiketal 123 was then
between 112 and t-BuLi yielded the corresponding vinyl lithium, formed aer oxidative cleavage of the less sterically hindered
and the addition onto the rst fragment 114 afforded secondary vicinal diol with NaIO4. Now the stage was set for inversion of
alcohols, which were converted to ketone 115 upon addition of the C-1 and C-6 stereogenic centers. The authors envisioned
Cornforth reagent PDC. For the key interrupted Nazarov/ that oxidation/reduction operation at these positions might
Hosomi–Sakurai reaction, the authors discovered that excess give the desired results. Accordingly, acetonide protection of
EtAlCl2 was effective, and ring closing yielded the interme- the 1,3-diol unit in 123 followed by DMP oxidation produced
diate 116 as a major product, in which the stereogenic center diketone 124. Aer some tries, they found that sequentially
at C-8 was established through anti-addition of the allyl reducing C-1 ketone with DIBAL-H and C-6 ketone with Red-
silane to the hydrogen at C-9. Next, subjecting 116 to singlet Al could gave the desired stereochemistry at both positions,
oxygen ene reaction followed by acetate anhydride treatment and the resultant diol was subjected to acidic work-up and
provided aldehyde 117. A Rh(I)-catalyzed deformylation another singlet oxygen ene reaction, and treatment with
delivered the ketone 118, which underwent 1,2-addition to Boc2O and HCl sequentially to furnish ()-oridonin.
form an allylic alcohol, and then selective epoxidation of the
C13–C14 alkene with mCPBA to form 119 in 70% overall yield. 4 Total syntheses of seco-ent-
The desired B-ring was then formed through ring expansion
via bromination of the C]C double bond with NBS and
kauranoids
subsequent semipinacol rearrangement. The resultant The seco-ent-kaurane diterpenoids can be generated through
bromide was oxidized with RuCl3/NaIO4 to convert two benzyl oxidative cleavage of the C–C bond of their biogenetic prototype
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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-
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 formation. With the oxidation at C-11 xed, compound 146
with LAH to selectively reduce more sterically hindered underwent reduction to allylic alcohol at C-14. The [3.2.1] bridge
carbonyl group in the anhydride and the ketone to afford ring was then implemented through a radical cyclization reac-
lactone 140. tion and a few simple transformations yielded the natural
Under the action of Li/NH3, the 1,4-cyclohexadiene was ob- product ()-sculponin R. Back to the key intermediate 144, its
tained through Birch reduction of 140, whose lactone was reduction with L-selectride generated a lithium enolate, which
reduced to hemiacetal and the benzyl ether protecting group at underwent a palladium-catalyzed alkenylation reaction under
C-1 underwent smooth cleavage. Aer acidic work-up, the 1,4- the action of Cs2CO3 and Pd(PPh3)4 to construct the [3.2.1]
cyclohexadiene was converted to cyclohexenone, while the bicyclic ring in 145. From that point, simple transformations
hemiacetal was transformed to the caged acetal, nally yielding led to the total syntheses of both ()-enmein and
caged compound 141. TMS protection at C-1 prior to hydroge- ()-isodocarpin.

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 4.3 Asymmetric total syntheses of (+)-longirabdiol,
acylation/alkylation/lactonization reaction could now be per- ()-longirabdolactone and ()-effusin (Li)
formed to install the quaternary center at C-8. For that purpose, In 2019, the Li group described their asymmetric total syntheses
the b-ketoester was formed rst, and 2,3-dibromopropene was of (+)-longirabdiol, ()-longirabdolactone and ()-effusin
then introduced at the alpha position. The C ring in the through late-stage redox modication of a common key inter-
advanced key intermediate 144 was nally obtained aer acidic mediate oxygenated at C-19.9c The key steps towards these target
work-up to remove the TMS group. In order to prepare sculpo- molecules included several free-radical-based reactions, namely
nin R, LiHMDS/TBSCl treatment of the key intermediate 144 a copper-catalyzed tandem decarboxylative radical cyclization/
yielded the corresponding silyl enol ether, which was subse- alkenylation reaction to build the cis-g-lactone; an intra-
quently transformed into g-hydroxyenone via epoxide 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
Scheme 13 The asymmetric total syntheses of ()-enmein, ()-iso- reaction with allyl iodide introduced two side chains, and then
docarpin and ()-sculponin R by the Dong group. an intramolecular RCM reaction occurred, yielding compound
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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
Scheme 14 The asymmetric total syntheses of (+)-longirabdiol, and interesting structures. Some synthetic efforts towards this
()-longirabdolactone and ()-effusin by the Li group. class of natural products are introduced below.
5.1 Total syntheses of ()-jungermannenone B and

157 in 65% overall yield. LDA was then used to deprotonate
()-jungermannenone C (Lei)
compound 157 prior to allylation with 2,3-dibromopropene
which yielded compound 158 as single diastereomer. The In 2015, the Lei group reported the scalable racemic total
bicyclo[3.2.1]octane ring was then formed through a 5-exo syntheses of the rearranged ent-kaurene jungermannenones B
radical annulation and subsequent allylic oxidation and DMP and C.10a The protecting-group-free synthesis featured an
oxidation at C-15 yielded the ketone 159. The natural product intramolecular electrophilic hydroarylation to construct the
(+)-londirabdiol was nally obtained aer global deprotection tricyclic system and an unprecedented regioselective 1,6-dien-
using LiBF4. Another DMP oxidation of (+)-londirabdiol would yne reductive cyclization reaction to close the rearranged bicy-
furnish ()-longirabdolactone, whereas a regioselective acet- clo[3.2.1]octane bridged ring.
ylation of the C-19 hydroxyl group prior to DMP oxidation The authors started the synthesis with inexpensive and readily
would furnish ()-effusin. 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
5 Total syntheses of nor- or trioxide oxidation to afford tricyclic ketone 164. Birch reduction of
rearranged-ent-kauranoids 164 followed by acid hydrolysis yielded dienone 167. A propargyl
group was then selectively introduced, and an allylic alcohol was
With a unique skeleton structure, the classication of this group of formed through Luche reduction of the enone to afford a precursor
the ent-kaurane diterpenoids is challenging. They are usually the for the key radical cyclization. Upon n-Bu3SnH/AIBN treatment, the
results of either the formation of one or several new C–C bonds, or expected intramolecular 1,6-dienyne reductive radical cyclization
of one or several C–C bond rearrangements, bonds that are usually 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
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- diacetoxyjungermannenone C aer a methylene group was

ation or sunlight exposure of either one or the other. introduced. The last task was exposure of this compound to
The synthesis started with the 1,4-asymmetric addition of 24 W white LED light to furnish (+)-jungermatrobrunin A
styrene-derived 190 onto the a,b-unsaturated ketone 189 cata- through a Schenck ene reaction and singlet oxygen participa-
lyzed by both a chiral copper(I) complex and Schwartz's reagent tion. The interconversion of the rearranged [3.2.1] bridged ring
(Scheme 17).21 The desired chiral adduct 191 was obtained in structure to the ent-kaurane [3.2.1] bridged ring structure was
78% yield and 88% ee. Subsequent a-arylation under the action also noted upon UV irradiation or upon sunlight exposure of
of a palladium(II)/NHC catalytic system completed the ring either one or the other. The synthesis of (+)-12-hydroxy-1a,6a-
closure to afford 192 aer simple methylation, whose benzylic diacetoxy-ent-kaura-9(11),16-dien-15-one was therefore also
carbon was then oxidized by chromium trioxide yielding the completed.
diketone 193. Aer Luche reduction, the resulting triol 194

underwent a Birch reduction followed by an acidic work-up to 5.4 Asymmetric total syntheses of (+)-ent-kauradienone and
deliver 2,4-dienone 195. The propargyl side chain was stereo- ()-jungermannenone C (Lei)
selectively introduced at C-13 aer the TMS protection of the
In 2019, the Lei team also completed the total syntheses of two
diol 195 was carried out. Next, Luche reduction of the new 2,4-
other diterpenoids.10d The rst one, (+)-ent-kauradienone, was
dienone followed by MOM protection of the resultant alcohol
prepared in 12 steps and its reduction and subsequent photo-
afforded the key intermediate 196. The free radical reductive
induced skeletal rearrangement delivered a rearranged ent-
cyclization of 196 proceeded smoothly to install bicyclo[3.2.1]
kaurane diterpenoid, jungermannenone C.
octane unit and lead to the formation of 197.10a A Lemieux–
Based on their previous results,10a,c the authors embarked on
Johnson oxidation then delivered the ketone 198 upon oxidative
the preparation of other natural products knowing that a skel-
cleavage, whose TMS protecting groups were exchanged for
etal rearrangement of the bicyclo[3.2.1]octene ring system of
acetates to deliver the natural product ()-1a,6a-
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
Scheme 17 The asymmetric total syntheses of (+)-jungermatrobrunin
B-ring cleavage followed by ring regeneration.23 To prepare the
A, ()-1a,6a-diacetoxyjungermannenone C and (+)-12-hydroxy- highly strained ABC ring system, a stereocontrolled excited-
1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one by the Lei group. 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 Scheme 19 The total synthesis of (+)-farnesin by the Gao group.
215.
The synthesis of the second fragment started from diaster-
eoselective alkylation of 217 with allyl bromide 216, and the reaction, which resulted in the formation of the desired highly
resultant diene 218 was subjected to Ru-catalyzed RCM reaction strained tetracyclic intermediate 223 in 68% yield using ow
to afford bromocyclohexene 219 in 75% yield. Reductive chemistry. TBS deprotection followed by SmI2-mediated radical
removal of the chiral auxiliary in 219 and oxidation generated reaction then reduced the enone in 223. Although the ketone at
an aldehyde, which was subjected to a NHC-catalyzed hydrox- C-7 was reduced in the meantime, it was recovered through
ymethylation and subsequent TBS protection to produce 220. A DMP-oxidation, which ultimately delivered the aldehyde 224.
Wittig olenation nally delivered the second fragment 221, The formation of the C8–C15 bond through NaOMe-mediated
which underwent an intermolecular addition onto the rst intramolecular aldol condensation achieved the construction
fragment 215 aer treatment with t-BuLi. Aer IBX oxidation of of the bicyclo[3.2.1]octane unit. Oxidation of the resulting
the resulting alcohol, dienone 222 was obtained in 67% yield alcohol then delivered the methyl ether 225, which underwent
over two steps. The key Nazarov reaction was then implemented demethylation followed by dehydration through sulfonate ester
since non-aromatic dicylic divinyl ketone can engage in cycli- formation to afford the acafamane-type framework 226. The
zation under acidic conditions or by photolysis.25 The latter total synthesis of (+)-farnesin was fullled aer oxidation state
apparently allowed the formation of the desired product adjustments at C-6, C-7 and C-15 over 7 steps.
through disrotatory cyclization via an excited-state Nazarov
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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
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, Scheme 20 The total synthesis of (+)-principinol D by the Newhouse
a SmI2-mediated reductive cyclization to form the central seven- group.
membered ring of the grayanane skeleton, and a Ni-catalyzed a-
vinylation reaction to install the requisite bicyclo[3.2.1]octane
ring. The tertiary alcohol at C-16 was rstly installed through
As outlined in Scheme 20, the synthesis started with a vicinal Mukaiyama hydration. Then, the secondary alcohol at C-3 was
difunctionalization of 1-cyclohex-2-enone 227. The addition of formed upon reduction of the ketone with LiEt3BH at 65 C.
a vinyl Grignard reagent onto the enone was performed using Upon heating, the b-hydroxysilane was eliminated to deliver the
a catalytic amount of CuBr–DMS complex together with excess alkene at C-10 through Peterson olenation. Global MOM
DMPU. The following ethoxycarbonylation with Mander's deprotection nally delivered (+)-principinol D in a total of 19
reagent resulted in the formation of the b-ketoester 228. Aer steps.
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- 6.2 Total syntheses of ()-rhodomolleins XX and XXII (Ding)
tion of the alcohol 229 was performed prior to the a-vinylation In 2019, the Ding group reported the total syntheses of
using a Ni(II) precatalyst and LiHMDS as base. The TBS group of ()-rhodomolleins XX and XXII, two highly oxidized grayanoids
the resulting bicyclo[3.2.1]octane ring was then cleaved under that were prepared in 23 and 22 steps, respectively.11b Notably, it
acidic conditions to afford 230. The ketone was then reduced features a Ti(III)-mediated reductive ring opening of a [2.2.1]-
with SmI2 in the presence of HMPA and PhSH, presumably bicyclic ketoepoxide and a Dowd–Beckwith rearrangement to
acting as H-atom donor.28 The desired diol 231 was obtained in establish the bicyclo[3.2.1]octane ring system.
both high yield and diastereoselectivity, and the primary The synthesis started with the 7-step preparation of b-
alcohol was converted into alkyl iodide through Appel reaction, ketoester 239 from 3-hydroxy-2-methoxybenzaldehyde 238
whereas the secondary alcohol was MOM-protected to nally (Scheme 21). A Regitz diazo transfer delivered an a-diazo-b-
yield the rst key fragment 232. The treatment of 232 with t- ketoester, which then gave the cyclopropanation product 240
BuLi enabled addition onto the enantioenriched aldehyde 233, under the catalysis of a Cu(II) salen analogue. Treatment of 240
and the resulting secondary alcohol was MOM-protected to with TMSOTf and (TMSOCH2)2 resulted in protection of the C-2
form the desired adduct 234 in 23% overall yield. TBS depro- ketone together with ring opening of the cyclopropane to deliver
tection followed by DMP oxidation rstly formed an enone, and the styrene 241, which was subjected to selective epoxidation of
its terminal alkene then underwent Lemieux–Johnson oxidation the alkene and subsequent Pd-catalyzed hydrogenation to
to nally yield the aldehyde 235. The key seven-membered ring produce alcohol 242. The ethyl ester 242 was then converted to
and therefore 236 was now formed in 63% yield upon SmI2/H2O vinyl ketone 243 through subsequent b-keto phosphonate
treatment. With the aim of installing exocyclic olen at C-10, formation, followed by a HWE olenation. Aer the depro-
the secondary alcohol was rst oxidized to ketone using DMP tection of silyl ether in 243 with TBAF, PIDA-mediated intra-
and then treated with Me3SiCH2Li to form b-hydroxysilane 237. molecular ODI Diels–Alder cycloaddition smoothly occurred to
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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
Scheme 21 The total synthesis of ()-rhodomolleins XX and XXII by subsequent NaBH4 reduction to yield the desired epimer 258 at
the Ding group.
C-7. Aer THP protection of the alcohol 258, an ODI (5+2)
cycloaddition/pinacol-type 1,2-acyl migration cascade was
afford desired tetracyclic product 244 in 70% yield. The SmI2- carried out to form tetracyclic intermediate 259 as a single
mediated reductive demethoxylation of 244 followed by selec- diastereomer aer THP deprotection with TFA. Treatment of
tive epoxidation of the alkene with DMDO provided the exo- 259 with TMSOTf and 1,2-bis(trimethylsiloxy)ethane allowed
epoxide 245 as a single diastereomer in 83% yield over two the formation of enone 260 through retro-Dieckmann
steps. The key Ti(III)-mediated reductive epoxide opening then fragmentation/vinylogous Dieckmann cyclization. With 260 in
took place in a rather regioselective fashion thanks to the free hand, the alcohol at C-7 was converted into xanthate ester,
alcohol at C-6. The resulting radical intermediate 246 then which was subjected to Barton–McCombie deoxygenation to
underwent a Dowd–Beckwith rearrangement reaction. In this furnish 261. DIBAL-H treatment of 261 to cleave the benzoyl
case the subsequent selective cleavage of the C12–C16 bond was protecting group and reduce the enone formed allylic alcohol
supposedly enabled by the titanoxy group at C-14, which might 262, in which the hydroxyl group was then critical to direct the
slow down the rate of radical quenching at C-13, resulting in the vanadyl acetylacetonate-catalyzed epoxidation through
reversible formation of the cyclopropoxy radical 247 prior to the hydrogen bonding. The resulting b-epoxide 263 underwent
construction of the key bicyclo[3.2.1]octane ring in 248 through (PhSeO)2O-mediated oxidation and Luche reduction to afford a-
C13–C16 bond linkage.29 alcohol 265. As mentioned by the authors, TMS group protec-
Moving on to the total syntheses of ()-rhodomolleins XX tion of the alcohol was necessary to efficiently perform the
and XXII, the acetylation of the two free hydroxyl groups in 248 subsequent photo-Nazarov cyclization/intramolecular ring-
and subsequent regioselective methylenation of the C-16 ketone opening cycloetherication cascade reactions. As a result, the
produced enol 249. Aer treatment of 249 with PhSeCl and desired product 266 was ultimately formed in 56% yield.
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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
Scheme 22 The total synthesis of ()-rhodomollanol A by the Ding
group. 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
To continue the synthesis, ketone 267 was obtained through
those synthesized. Additionally, the biological activities of most
deprotonation of the enone 266 with dimsyl sodium32 and
isolated ent-kauranoids have not been systematically evaluated
methylation with methyl iodide in extremely anhydrous solvent.
because sufficient material was not available. With the progress in
The D (ref. 5 and 6) double bond in compound 267 underwent
total synthesis of ent-kauranoids, researchers should pay more
dihydroxylation with OsO4-pyridine complexes followed by
attention to obtaining more material, particularly those with
hydrolysis of the osmate ester with NaHSO3. The resulting cis-
unique structural features, and testing the biological activities of
diol was then efficiently protected as an acetonide 268 upon
the corresponding natural products. Such studies will be of benet
PPTs and 2-methoxypropene treatment. Inversion of the ster-
for detailed investigations of the mechanism of action and thera-
eogenic center at C-1 was then performed through successive
peutic potential of ent-kauranoids.
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 8 Conflicts of interest
Ti(III)-mediated reductive ring opening of the epoxide, Chugaev
There are no conicts to declare.
View Article Online
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Synthesis of Ent Kauranes

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Natural Product

Recent advances in the synthesis of ent-kaurane

Xiangbo Zhao,† Bastien Cacherat,† Qifei Hu and Dawei Ma *

Covering: 2015 to 2020

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

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1000 varieties of natural enantiomers that have been either

a plethora of ent-kauranoids.2c Sun and co-workers notably

Xiangbo Zhao was born and Qifei Hu was born in Xi'an,

Bastien Cacherat studied at the Dawei Ma received his PhD in

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that most of these natural products showcase excellent prop-

transformation. It depends whether the enzyme is ent-CPP

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an unprecedented intramolecular Mukaiyama–Michael cycliza-

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pharicin A, pharicinin B, 7-O-acetylpseurata C and pseurata C

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2.6 Total synthesis of ()-1a-hydroxykauran-12-one, ()-12-

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of 97 provided acetonide 98, which was converted into maoe-

3.3 Total synthesis of ()-oridonin (Luo)

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Scheme 11 The total synthesis of ()-oridonin by the Luo group.

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and this phenomenon occurs naturally. This class of diterpenes

4.1 Total synthesis of ()-trichorabdal A and

chorabdal A and maoecrystal Z.9a Both natural products were

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caged compound 141. TMS protection at C-1 prior to hydroge- ()-isodocarpin.

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Scheme 15 The total synthesis of ()-jungermannenone B and

connected to the ent-kaurene framework. The degradation of one

5.1 Total syntheses of ()-jungermannenone B and

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ring in tetracyclic intermediate 170. From that point, selective

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

maoecrystal V has attracted extensive interest within the

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1a,6a-diacetoxy-ent-kaura-9(11),16-dien-15-one upon UV irradi- diacetoxyjungermannenone C aer a methylene group was

diketone 193. Aer Luche reduction, the resulting triol 194

5.5 Total synthesis of (+)-farnesin (Gao)

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Scheme 18 The asymmetric total syntheses of (+)-ent-kauradienone

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

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6 Total syntheses of grayananes

Matsumoto and co-workers more than forty years ago, in which

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

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pyridine to aﬀord enone 250 through a-selenylation and

()-rhodomollein XX in 64% yield over three steps.

6.3 Total synthesis of ()-rhodomollanol A (Ding)

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elimination, and acetal and acetonide deprotections. Finally, C-

7 Conclusion and outlook

been synthesized during this period, which were demonstrated

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9 Acknowledgements 133, 14964; (d) J. T. S. Yeoman, V. W. Mak and