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Diterpenoids from Isodon species: An update
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DOI: 10.1039/C7NP00027H
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Volume 34 Number 9 September 2017 Pages 1039–1174
Natural Product
Reports
rsc.li/npr
ISSN 0265-0568
REVIEW ARTICLE
Jian-Xin Pu et al.
Diterpenoids from Isodon species: an update
Natural Product
Reports
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REVIEW View Journal | View Issue
Diterpenoids from Isodon species: an update†

ab a a *a
Cite this: Nat. Prod. Rep., 2017, 34, Miao Liu, Wei-Guang Wang, Han-Dong Sun and Jian-Xin Pu
1090
Covering: December 2005 to June 2016. Previous review: Nat. Prod. Rep., 2006, 23, 673–698
Over the last decade, great efforts have been made to conduct phytochemistry research on the genus
Published on 31 July 2017. Downloaded on 04/09/2017 16:10:31.
Received 21st April 2017

Isodon, which have led to the isolation and identification of a number of diterpenoids. At the same time,
these newly reported diterpenoids with diverse structures have led to new findings on their biological
DOI: 10.1039/c7np00027h
functions and chemical synthesis research. In this update, we review more than 600 new diterpenoids,
rsc.li/npr including their structures, classifications, biogenetic pathways, bioactivities, and chemical synthesis.
1 Introduction 2.9 Other tricyclic diterpenoids

2 Structures, classications, and distributions 2.10 Bicyclic diterpenoids
2.1 C-20 non-oxygenated ent-kauranes 2.10.1 Labdanes
2.2 C-20 oxygenated ent-kauranes 2.10.2 ent-Clerodanes
2.2.1 Monoepoxy-ent-kauranes 2.10.3 ent-Halimanes
2.2.1.1 7,20-Epoxy-ent-kauranes 2.11 Meroditerpenoids
2.2.1.2 3,20-Epoxy-ent-kauranes 3 Biological activities
2.2.1.3 11,20-Epoxy-ent-kauranes 3.1 Cytotoxic activity and structure-activity relationship
2.2.2 Diepoxy-ent-kauranes 3.2 Anti-tumor mechanism
2.2.2.1 3,20:7,20-Diepoxy-ent-kauranes 3.3 Anti-inammatory activity
2.2.2.2 7,20:14,20-Diepoxy-ent-kauranes 3.4 Antibiosis
2.2.3 7,20-Lactone-ent-kauranes 3.5 Anti-virus
2.2.4 C-20 oxygenated non-epoxy ring ent-kauranes 3.6 Other activities
2.2.5 19,20-Lactone-ent-kauranes 4 Total synthesis
2.3 Seco-ent-kaurane 4.1 Total synthesis of maoecrystal V
2.3.1 1,10-Seco-ent-kauranes 4.1.1 Approaches by Yang’s group
2.3.2 6,7-Seco-ent-kauranes 4.1.2 Approaches by Baran’s group
2.3.2.1 Enmein type (1,7-lactone type) 4.1.3 Approaches by Danishefsky’s group
2.3.2.2 Spiro-lactone type (7,20-lactone type) 4.1.4 Approaches by Zakarian’s group
2.3.2.2.1 Spiro-lactone type (6,7-seco-7,20-lactone type) 4.1.5 Approaches by Thomson’s group
2.3.2.2.2 Spiro-lactone type (6,7:8,15-diseco-7,20-lactone type) 4.1.6 Approaches by Nicolaou’s group
2.3.2.2.3 Spiro-lactone type (6,7:8,15-diseco-6,8-cyclo-7,20-lactone type) 4.1.7 Approaches by Chen’s group
2.3.3 8,15-Seco-ent-kauranes 4.1.8 Approaches by Trauner’s group
2.3.4 15,16-Seco-ent-kauranes 4.1.9 Approaches by Chisholm’s group
2.4 7,20-Cyclo-ent-kauranes 4.1.10 Approaches by Mobin’s group
2.5 Diterpene dimers 4.1.11 Approaches by Jeremy’s group
2.6 Miscellaneous ent-kauranes (diterpene alkaloids with 4.2 Total synthesis of maoecrystal Z
an aza-ent-kaurane skeleton) 4.3 Total synthesis of sculponeatin N
2.7 ent-Atisanes 4.3.1 Approaches by Zhai’s group
2.8 Abietanes and ent-abietanes 4.3.2 Approaches by Thomson’s group
4.4 Total synthesis of trichorabdal A
a
4.5 Total synthesis of longikaurin E
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming
Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, P. R.
4.6 Total synthesis of S-trans-12E,14-labdadien-20,8b-olide
China. E-mail: pujianxin@mail.kib.ac.cn; Tel: +86 871 65223616 5 Conclusions
b
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China 6 Acknowledgements
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7np00027h 7 References
1090 | Nat. Prod. Rep., 2017, 34, 1090–1140 This journal is © The Royal Society of Chemistry 2017
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Review Natural Product Reports
During this time, some mini reviews have summarized studies

1 Introduction on diterpenoids from the genus Isodon and exclusively focused
The genus Isodon, which contains approximately 150 species on reviewing partial studies with limited references, such as
worldwide, is mainly distributed in tropical and subtropical studies on chemical constituents,21–29 biological activi-
Asia. Some plants from this genus have been used in traditional ties,22,24–28,30–33 or synthesis34–36 aspects of diterpenoids from the
Chinese folk medicine, including I. rubescens, I. xerophilus, I. genus Isodon. To obtain a more comprehensive perspective, it is
serra, etc.1 The genus Isodon is abundant in diterpenoids with necessary to publish a review focusing on the “diterpenoids
diverse structural scaffolds and important pharmaceutical from the genus Isodon” and covering extensive aspects of these
functions.2,3 Among these compounds, the unique structures compounds. In this review, we intend to cover prior studies
include maoecrystal V,4–8 maoecrystal Z,9,10 trichorabdal A,9,11 conducted between December 2005 and June 2016. More than
longikaurin E,9,11 and sculponeatin N,12,13 which have been 600 new diterpenoids will be described, including their isola-
totally synthesized, and some compounds have been repeatedly tion, structures and classications, distributions, biogenetic
synthesized by different groups. At the same time, as one of the pathways, biological activities and structure-activity relation-
important groups of diterpenoids, ent-kaurane diterpenoids, ships, and total synthesis.
such as oridonin,14,15 eriocalyxin B,16,17 adenanthin,18 and
pharicins A19 and B,20 have received much attention due to their
potential antitumor properties. 2 Structures, classifications, and

In the last decade, there has been a dramatic increase in the distributions
number of new diterpenoids, and there has been new progress
in the total synthesis of some Isodon diterpenoids, as well as In 1984, due to the limited number of diterpenoids from the
substantial research progress into their biological activity. Isodon species, E. Fujita classied Isodon diterpenoids into four
groups: ent-kauranes, 6,7-seco-ent-kauranes, 8,9-seco-ent-
Miao Liu obtained his Master’s Han-Dong Sun received his PhD
Degree in Natural Product degree from Kyoto University,
Chemistry in 2013 from the West Japan, in 1988. In 2003, he was
China School of Pharmacy, elected to the Chinese Academy
Sichuan University. In 2013, he of Sciences. He has conducted
joined Prof. Han-Dong Sun’s phytochemical studies of more
group to obtain his PhD degree than 260 plants and published
in Medicinal Chemistry at over 720 scientic papers. He
Kunming Institute of Botany holds over 30 patents. His
(KIB), Chinese Academy of research interests have focused
Sciences. His doctoral research on: (1) innovative studies of
focused on biologically active novel triterpenoids from the
diterpenoids from the genus Schisandraceae family; (2)
Isodon and structurally interesting triterpenoids from the genus systemic studies of endemic Isodon species in China; (3) research
Schisandra. and development of new drugs.
Wei-Guang Wang obtained his Jian-Xin Pu joined Prof. Han-

PhD degree in Medicinal Chem- Dong Sun’s group in 2004 at
istry in 2013 from Kunming the Kunming Institute of Botany,
Institute of Botany (KIB), Chinese Academy of Sciences,
Chinese Academy of Sciences, where he received his PhD
under the supervision of Prof. degree in 2007. He is currently
Han-Dong Sun and Jian-Xin Pu. a professor of natural products
His doctoral research focused on chemistry and his research is
the structures and biological focused on the chemical constit-
activity of diterpenoids from uents of the plants in the genus
plants of the genus Isodon. Since Isodon and the Schisandraceae
2013, he has worked as an family as well as the bioactivity
assistant professor at KIB, where of these constituents. He has
his research is focused on discovering bioactive natural products also investigated secondary metabolites from the endophytic fungi
from the endophytic fungus. He is currently an associate professor of these plants.
at KIB.
This journal is © The Royal Society of Chemistry 2017 Nat. Prod. Rep., 2017, 34, 1090–1140 | 1091
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kauranes and other species.2 When more diterpenoids were In our previously published review from 2006, we maintained
isolated and identied from the genus Isodon, Y. Takeda and H. this nomenclature, and classied Isodon diterpenoids into
Otsuka divided Isodon diterpenoids into nine groups in 1995.37 eleven groups including ve subgroups.3 During the last
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decade, a large number of new diterpenoids was discovered, K562, A549, and HepG2 human cell lines.56 In studies of the
including some novel skeletons. Based on the category princi- constituents of I. pharicus by our group, we reported the
ples previously described, the structures, distributions and structures of pharicinins B and C (37, 38),57 pharicinins D and
classications will be introduced. Furthermore, the plausible E (77, 78),58 pharicinin D acetal (79),58 and pharicunins N–R
biogenetic relationships of different types of diterpenoids are (39–43),59 along with 21 other new ent-kauranes (44–5660 and
also proposed in this review (Schemes 1–5). 88–9561). From the same species, two new ent-kaurane diter-
penoids, pseuratas H (85)62 and I (103),63 were also isolated by
two other groups (I. pharicus was previously named I. pseu-
2.1 C-20 non-oxygenated ent-kauranes doirrorata). Nine ent-kauranoids, isoscoparins D–L (57–65),
Based on 212 C-20 non-oxygenated ent-kauranes that were were reported from I. scoparius.64 From I. sculponeata, two new
previously reported, another 134 new ones were identied from ent-kaurane derivatives, sculponeatins N (74) and O (75), were
the genus Isodon over the last ten years. As one of the largest isolated.65 Because 74 had the same name as 420, we renamed
groups of ent-kauranes, the number of compounds in this type 74 as sculponeatin N1 and maintained 420 as sculponeatin N.
represents approximately 28 percent of all diterpenoids from A new ent-kaurane, maoesin E (76), was isolated from I. erio-
the genus Isodon. calyx.66 3a,17-dihydroxy-15(16)-ene-ent-kaur-7-one (86) was
Excisusin F (1), which is a new diterpenoid connected with obtained from I. eriocalyx var. laxiora, which is a variant of
a pyrrolidinone at C-19, was isolated from the aerial parts of I. I. eriocalyx.67 Isoleuconins A–C (80–82) were identied from
excisus. 1 showed potent inhibitory effects on LPS-induced the leaves of I. leucophyllus,68 and showed no obvious cyto-
nitric oxide production in RAW264.7 cells with an IC50 value toxicity against the SK-OV-3, Bel-7402, and HT-29 cell lines.
at 10.4 mM.38 Excisusins A–E (19–23), which are ve new ent- The chemical investigation into the aerial parts of I. adeno-
kauranes isolated from the aerial parts of I. excisus, showed lomus collected in the Shangri-La region of Yunnan Province
inhibitory effects on NF-kB activation and NO production led to the identication of two new cytotoxic ent-kauranoids,
except for excisusin C (21).39 Among albopilosins B–J40 (2–10), specically isoleuconins B and C (83, 84).69 Jianshirubesin G
which were identied from the aerial parts of I. albopilosus, (87), which is a new diterpenoid without cytotoxic activity, and
albopilosin J (10) is an ent-kauranoid connected to a b-D-glu- hubeirubesins A and B (100, 101) were isolated from
copyranoside moiety at C-18. Phyllostachysins D–H (11–15) I. rubescens.70,71 Among them, the absolute conguration of 87
were discovered from the aerial parts of I. phyllostachys, and was determined by single-crystal X-ray diffraction analysis.70 A
were tested for their cytotoxic effects against K562 cells.41 new ent-kaurane diterpenoid, 3a,14b,16a-trihydroxy-ent-
Reinvestigation into I. parvifolia by two groups led to the kaurane (102), was isolated from the leaves of I. japonica. Its
isolation of parvifoline Z (16)42 and 2b,3b,6b,11b-tetraacetoxy- structure was elucidated by spectroscopic methods and was
kaur-16b-methy-15-one (121).43 Compound 16 exhibited further conrmed by X-ray crystallography.72 Phytochemical
signicant cytotoxicity against A549, HT-29 and K562 cell investigation of EtOAc extracts from the aerial parts of
lines with IC50 values ranging from 1.89 0.23, 2.45 0.11 to I. wikstroemioides led to the discovery of 15 new ent-kaurane
1.24 0.12 mM.42 Compound 121 should be named as diterpenoids (wikstroemioidins E–S, 104–118). The absolute
2b,3b,6b,11b-tetraacetoxy-ent-kauran-16aH-15-one. Race- conguration of 104 was conrmed by single-crystal X-ray
mosin A (17), which is a diterpenoid from I. racemosa, showed diffraction analysis.73 The isolates were screened against ve
cytotoxicity against Bel-7402 and HO-8910 with IC50 values of human tumor cell lines. As a result, compounds 106, 107, 112,
1.56 1.17 and 3.72 2.55 mM, respectively.44 Chemical and 114–116 showed signicant cytotoxic activity with IC50
investigations of I. excisoides (collected from two different values ranging from 0.8 to 5.1 mM. In addition, compounds
regions) resulted in the isolation and identication of exci- 104–107, 112, and 114–116 inhibited NO production in LPS-
soidesin A (18)45 and taihangexcisoidesin A (73).46,47 Glauco- activated RAW264.7 macrophages.73 Two new ent-kaurane
calyxins F (24) and X (25) were reported in 2008 from the diterpenoids (119 and 120) were isolated from the ethyl
whole plant of I. japonica var. glaucocalyx, whereas the acetate fraction of the 70% acetone extract of the roots from
stereochemistry of these compounds were not determined.48 I. adenantha.74 None of these compounds showed signicant
In 2009, the stereochemistry of 24 and 25 was conrmed cytotoxic or antibacterial activity. Thirteen new ent-kaur-
based on ROESY spectra.49 Glaucocalyxins H–J (96–98) were anoids, tenuifolins A–M (122–134), along with four known
isolated from the leaves of I. japonica var. glaucocalyx. Their kauranoids were isolated from I. tenuifolius. Their structures
structures were elucidated by spectroscopic analysis, and the were established based on detailed spectroscopic analysis.
structures of 97 and 98 were further conrmed by X-ray crys- The absolute congurations of 133 and 134 were conrmed by
tallography.50,51 Glaucocalyxin G (99) was reported from the single-crystal X-ray diffraction.75
n-butanol-soluble fraction of the dried whole plants of
I. japonica var. glaucocalyx in 2013.52,53 Minheryins H and I (26
and 27)54 and minheryins A–G (66–72)55 were isolated from the
leaves of I. henryi. Among them, minheryin I (27) is a D-glu- 2.2 C-20 oxygenated ent-kauranes
cose-ent-kaurane glycoside. Among nervonins B–J (28–36), This type of compound represents another large group of ent-
which were obtained from the aerial parts of I. nervosus, kauranes, which can be further classied into some subgroups.
nervonin B (28) exhibited signicant cytotoxicity towards 2.2.1 Monoepoxy-ent-kauranes
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Scheme 1 Proposed major biogenetic pathways and classifications of diterpenoids from the Isodon species.
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Scheme 2 Proposed major biogenetic pathways and classifications of ent-kauranes.
Scheme 3 Proposed biogenetic relationships of different types of ent-kauranes.
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2.2.1.1 7,20-Epoxy-ent-kauranes. Repeated chemical investi- ability against human A549, HT-29, and K562 cell lines. Among
gation into I. eriocalyx led to the isolation of six new ent-kaur- them, hebeirubescensins B and C exhibited signicant cyto-
anoids: maoecrystals X (135) and Y (136),76 3-acetylmaoecrystal S toxicity with IC50 values < 2.0 mM.
(137),77 Maoesins B–D (138–140),66 and a new natural product, 6- Xerophilusins III–XIII (176–186)85 and xerophinoid B (187)86
acetylmaoecrystal B (141).78 For the ent-kaurane diterpenoids were identied from the leaves of I. xerophilus. Some of these
with a 7,20-epoxy structure, the hydroxyl at C-6 was always b- compounds exhibited cytotoxic activity against several human
oriented, but 138 was an exception. The hydroxyl at C-6 in 138 tumor cell lines. Xerophinoid B reduced the nitrite production
was a-oriented instead. Among these compounds, maoesin D in RAW264.7 murine macrophages with an IC50 value of 0.24
(140) showed cytotoxicity towards the HT-29 cell line with an mM. In addition, xerophinoid B inhibited TNF-a production
IC50 value of 7.3 mM. Dayecrystal B (142) was isolated from the with an IC50 value larger than 1 mM. Finally, xerophinoid B also
leaves of I. macrophyllus.79 Eighteen new 7,20-epoxy-ent-kaur- decreased the IL-b production with an IC50 value less than
anes, parvifolines C–K (143–151)80 and parvifolines O–W (152– 50 nM. Phyllostacins C and D (188 and 189)87 and phyllostacins
160),81 were reported from I. parvifolia. The compounds were F and G (190 and 191)88 were isolated from the aerial parts of
tested for their cytotoxicity against three human tumor cell I. phyllostachys. They were evaluated for their inhibitory activity
lines. Among these isolates, 143, 154, 158, and 159 showed against several cell lines. Ten 7a,20-epoxy-ent-kauranes, iso-
cytotoxic activity. An extensive study of the diterpenoids of dojaponins A and B (192 and 193),89 isojaponin C (194),90 and
I. rubescens by several groups led to the isolation of 15 new ent- hikiokoshins D–I (195–200),91 along with maoyecrystal L (201),92
kaurane diterpenoids: hebeirubescensins A–L (161–172),82 were isolated from I. japonica. The absolute conguration of
11,15-O,O-diacetyl-rabdoternin D (173) and 16,17-exo-epoxide- maoyecrystal L was determined by X-ray crystallography.
oridonin (174),83 as well as jiyuanoridonin A (175).84 Compounds 192 and 193 inhibited LPS-induced production of
Compounds 167 and 168 were an inseparable mixture of two nitric oxide in murine macrophage RAW264.7 cells at 6.3 0.22
isomers. Select compounds were assayed for their inhibitory and 10.2 0.25 mM, respectively. Compounds 195–200 were
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tested against murine lymphoma L1210 and human epider- and B (229) exhibited cytotoxic activity against some of the
moid carcinoma KB cells and showed no cytotoxicity (IC50 > 10 tested human tumor cell lines. In addition, the absolute
mg mL1) in vitro. 6b,7b,13a-trihydroxy-1a-acetoxy-7a,20-epoxy- conguration of sinuolatin A (235) at C-16 was not explained in
ent-kaur-16-en-15-one (202),93,94 rabdonervosin D (223),95 rab- the original literature. Taihangexcisoidesin C (236)104,105 and 1a-
donervosin G (224),96 and 7b,12a-dihydroxy-6b,15b-diacetoxy- acetoxy-14b-hydroxy-7a,20-epoxy-ent-kaur-16-en-15-one (246)106
7a,20-epoxy-ent-kaur-2,16-dien-1-one (225)97 were isolated from were isolated from the leaves of I. excisoides. Compound 246
I. nervosus. Further investigation on the chemical constituents exhibited selective cytotoxic activity against HCT-116, HepG2,
of I. eriocalyx var. laxiora led to the isolation of twenty 7,20- A2780, NCI-H1650, and BGC-823 cell lines. Among rubluanins
epoxy-ent-kauranes, including laxiorin T (203)98 and neo- A–D (240–242 and 237),107 which were obtained from I. rubescens
laxiorins G–Y (204–222).99,100 Compounds 204–222 were tested var. lushanensis, rubluanin D (237) showed weak cytotoxic
for in vitro cytotoxicity against A-549, HL-60, MCF-7, SMMC- activity towards selective tumor cell lines. From I. rubescens var.
7721, and SW-480 human cancer cell lines using the MTT lushiensis, the other variety from I. rubescens, isolushinins B–F
method. Compounds 208–210, 213–214, and 220 showed (238, 239, and 243–245),108 were identied. Isolushinin D (243)
inhibitory activity. From I. sculponeata, six 7,20-epoxy-ent-kaur- showed cytotoxic activity towards HL-60, SMMC-7721, A-549,
anes were reported, including sculponins K and L (226 and SK-BR-3, and PANC-1 human tumor cell lines. A new 7,20-
233),101 as well as sculponins W–Z (232, 234, 227, and 228).102 epoxy-ent-kaurane diterpenoid, 15-acetyldemethylkamebacetal
Among all these compounds, only sculponin Y (227) showed A (247) from I. inexus, was evaluated for inhibitory effects on
weak cytotoxic activity against HL-60, SMMC-7721, MCF-7, and TNF-a-induced NF-kB activation with an IC50 value of 20.15
SW-480 cell lines, and 227 also inhibited NO production in LPS- mM.109 Eight new diterpenoids, isoadenolins D–K (248–255),
stimulated RAW264.7 cells with an IC50 value of 13.8 mM. Four were isolated from the aerial parts of I. adenolomus. Select
7,20-epoxy-ent-kauranes, specically sinuolatins A–D (235 and compounds were evaluated for their in vitro cytotoxicity against
229–231), were reported from I. sinuolata.103 Sinuolatins A (235) human tumor HL-60, SMMC-7721, A-549, MCF-7, and SW480
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cell lines. Compounds 253 and 255 showed inhibitory effects in tumor cell lines. Compounds 268–271 exhibited signicant
all ve cell lines.110 Isorosthins F–I (258–261) and K–O (256–257 activity with IC50 values ranging from 0.9 to 7.0 mM. In addition,
and 262–264), as well as nine new ent-kauranes, were discovered compounds 268–271 and 274 exhibited inhibitory activity
from I. rosthornii. Several of these compounds exhibited cyto- against nitric oxide production in LPS-activated RAW264.7
toxicity against ve human tumor lines. Furthermore, some macrophages.115 Nine new diterpenoids, 15-acetylmegathyrin B
compounds also showed inhibitory activity against nitric (275), serrin E (276), 14b-hydroxyrabdocoestin A (277), serrin F
oxide production in LPS-activated RAW264.7 macrophages.111 (278), serrin G (279), 11-epi-rabdocoestin A (280), serrin H (281),
6b,14a-dihydroxy-1a,7b-diacetoxy-7a,20-epoxy-ent-kaur-16-en- serrin I (282), and 15-acetylenanderianin N (283), were isolated
15-one (265)112 and effusanin F (266)113 are new diterpenoids from I. serra.116 The absolute conguration of 275 was deter-
isolated from I. serra. The orientation of H-14 in 265 needs to be mined by single-crystal X-ray diffraction analysis. All
questioned. A new ent-kaurane diterpenoid, isodonhenrin D compounds were evaluated for their cytotoxic activity against
(267), was isolated from the aerial parts of I. henryi.114 Seven new ve human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7,
diterpenoids from I. wikstroemioides, Isowikstroemins A–G and SW480). Compound 278 showed cytotoxic activity against
(268–274), were evaluated for cytotoxicity against ve human all cell lines, with IC50 values ranging from 0.7 to 3.7 mM.
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2.2.1.2 3,20-Epoxy-ent-kauranes. This type of ent-kaurane is trione (285),67 6-hydroxy-15b-acetoxy-3a,20-epoxy-16b,17-

rarely reported, and eight in total were found in Isodon epoxy-5(6)-ene-ent-kaur-1,7-dione (286),67 laxiorin R (287),117
species. Five new ent-kaurane diterpenoids, including and laxiorol B (291),118 were isolated from the leaves of I.
6b,13a,15b-trihydroxy-16-ene-3a,20-epoxy-ent-kaur-1,7-dione eriocalyx var. laxiora. Jianshirubesin H (288) was a 3, 20-epoxy-
(284),67 6-hydroxy-3a,20-epoxy-5(6)-ene-ent-kaur-1,7,15- ent-kaurane isolated from I. rubescens with a hemiketal at C-3.70
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Isorosthornin F (289, from I. rosthornii) is a 3, 20-epoxy-ent-

kaurane with an acetal at C-20.119 Together with rabdonervosin J
(290), rabdonervosin I was also reported as a new compound
from I. nervosus in 2013. In fact, rabdonervosin I is the
same compound as 285, which was reported in 2012. In addi-
tion, rabdonervosin I exhibited cytotoxicity against HepG2 and
CNE2 cell lines with IC50 values of 8.64 and 9.77 mM,
respectively.96
2.2.1.3 11,20-Epoxy-ent-kauranes. Only ten 11,20-epoxy-ent-

kauranes, specically jianshirubesins D–F (292–294),120 iso-
rosthornin E (295),119 and isowikstroemins H–M (296–301),121
were discovered from three Isodon species. Among all the
compounds, 296 and 298–300 exhibited cytotoxic activity
against HL-60, SMMC-7721, A-549, MCF-7 and SW-480 cell lines,
whereas the others showed no inhibitory activity in those cell
lines.
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2.2.2 Diepoxy-ent-kauranes
2.2.2.1 3,20:7,20-Diepoxy-ent-kauranes. Only two
compounds belong to this type of ent-kaurane. The rst example
of this subgroup was found in I. xerophilus.122,123 The other one
from the genus Isodon was named isolushinin A (302, from
I. rubescens var. lushiensis). Compound 302 exhibited no obvious
inhibitory activity against the HL-60, SMMC-7721, A-549, SK-BR-
3, and PANC-1 human cancer cell lines with IC50 values larger
than 10 mM.108
2.2.4 C-20 oxygenated non-epoxy ring ent-kauranes. Iso-

lushinins G–J (319–322) were isolated from the aerial parts of I.
rubescens var. lushiensis.108 Wikstroemioidins T–V (323–325)
came from the aerial parts of I. wikstroemioides.73 A phyto-
2.2.2.2 7,20:14,20-Diepoxy-ent-kauranes. In our last review chemical study on the leaves of I. xerophilus led to the isolation
published in 2006, six ent-kauranes with a 7,20:14,20-diepoxy of xerophinoid A (326)86 and xerophilusins I and II (327 and
structure were summarized.3 Over the last ten years, another ten 328).85 Their structures were determined using spectroscopic
7,20:14,20-diepoxy-ent-kauranes were identied from ve Isodon methods including 1D and 2D NMR analyses. Repeated chem-
species: phyllostacins H and I (303 and 304, from I. phyllos- ical investigation into I. excisoides by two groups resulted in the
tachys),88 isoadenolins A–C (305–307, from I. adenolomus),110 discovery of three new diterpenoids: ent-7a,14b-dihydroxykaur-
isorosthornins A–C (308–310, from I. rosthornii),124 jianshir- 16-en-15-one-20-oic acid (329),125 1a,7a,14b-trihydroxy-20-ace-
ubesin I (311, from I. rubescens),70 and isodonhenrin C (312, toxy-ent-kaur-15-one (330),106 and 1a,7a,14b,18-tetrahydroxy-20-
from I. henryi).114 The absolute conguration of 305 was deter- acetoxy-ent-kaur-15-one (331).106 Compounds 330 and 331
mined using single-crystal X-ray diffraction. None of the exhibited cytotoxic activity against several tested tumor cell
selected compounds showed cytotoxic activity against tested lines. Two new compounds, specically ent-1a,7a,14b,20-
human tumor cell lines. tetrahydroxy-11,16-kauradien-15-one (332)126 and dayecrystal A
(333),79 were isolated from I. serra and I. macrophyllus, respec-
tively. Among these compounds, 329 and 332 were named
incorrectly. Compound 329 and 332 should be named as ent-
7b,14a-dihydroxy-15-oxo-kaur-16-en-20-oic acid and ent-
1b,7b,14a,20-tetrahydroxy-11,16-kaur-dien-15-one, respectively.
2.2.3 7,20-Lactone-ent-kauranes. During the last decade,

only six 7,20-lactone-ent-kaurane diterpenoids were reported
from ve Isodon species: rabdonervosin E (313, from I. nerv-
osus),95 isorosthin J (314, from I. rosthornii),111 sculponins U
and V (315 and 316, from I. sculponeata),102 isoadenolin L (317,
from I. adenolomus),110 and isodonhenrin E (318, from I. hen- 2.2.5 19,20-Lactone-ent-kauranes. Lophanthodin G (334,
ryi).114 The absolute conguration of 315 was determined using from I. lophanthoides var. geradianus) is the only example of
single-crystal X-ray diffraction. Among some selected a 19,20-lactone-ent-kaurane.127
compounds, none showed cytotoxic activity against tested
human tumor cell lines. 2.3 Seco-ent-kaurane
2.3.1 1,10-Seco-ent-kauranes. Only two compounds with
a novel 1,10-seco-ent-kaurane skeleton were reported from the
Isodon species. Luanchunin B (335), which was isolated from
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bonds of 7,20-epoxy-ent-kauranes. Before 2006, there were 105

6,7-seco-ent-kauranes reported from the Isodon species. This
group was formerly classied into two subgroups: enmein type
(1,7-lactone) and spiro-lactone (7,20-lactone). With the
discovery of new ent-kauranes, spiro-lactone can be further
classied into another two subgroups: 6,7:8,15-diseco-ent-
kauranes and 6,7:8,15-diseco-6,8-cyclo-ent-kauranes. Newly
discovered compounds belonging to the latter two subgroups
have been very rarely reported.
2.3.2.1 Enmein type (1,7-lactone type). In our previous review
published in 2006, only 29 enmein-type ent-kauranes were
summarized. In this review, 65 new compounds belonging to
this group are included.
Thirty-nine new 6,20-epoxy-enmein type ent-kauranes were
discovered from the Isodon species in the past ten years. Among
them, phyllostacin A (337) and phyllostacin B (338) were iso-
lated from I. phyllostachys. Both 337 and 338 were found as

diastereoisomers. To illustrate the tautomerism of 337 and 338,
the corresponding diastereoisomeric diacetates of 337 were
prepared and separated. Thus, 337 was shown to be a pair of
epimers at C-20.129 Interestingly, in pyridine-d5 solution, the two
epimers of 337 were present in equal amounts, but in CDCl3 or
CD3OD, the (S)-epimer predominates in the mixture of
hemiacetals.
I. rubescens var. lushanensis in 2010 by our group, was the rst Other new 6,20-epoxy-enmein type ent-kauranes reported in
example of this type of ent-kaurane. Compound 335 showed the last decade are listed below: 15a,20b-dihydroxy-6b-methoxy-
potent cytotoxic activity against HL-60 with an IC50 value of 3.52 6,7-seco-6,20-epoxy-ent-kaur-16-en-1,7-olide (339, from
mM.128 Plausible pathways for biosynthesis from kamebakaurin I. serra),130,131 isojaponin A (the same as 11a,15a-dihydroxy-6b-
to luanchunin B were also postulated (Scheme 6). The other methoxy-6,7-seco-6,20-epoxy-1a,7-olide-ent-kaur-16-ene, 340,
example, 1,7a,12b,14b-tetrahydroxy-1,10-seco-ent-kaur-10,16- from I. japonica),132,133 Macrocalyxin J (341, from I. macro-
dien-15-one (336), was identied in 2014 from I. excisoides.125 calyx),134 sinuolatin E (342, from I. sinuolata),103 dayecrystals D
Compound 336 should be named as 1,7a,12b,14b-tetrahydroxy- and E (343 and 374, from I. macrophyllus),135 sculponin F (344,
1,10-seco-ent-kaur-10(20),16-dien-15-one. from I. sculponeata),101 sculponeatin R (345, from I. sculpo-
neata),136 rabdonervosin F (346, from I. nervosus),95 iso-
donhenrin B (347, from I. henryi),114 6b-butyroxy-3b-hydroxy-6,7-
seco-6,20-epoxy-7,1a-olide-ent-kaur-16-en-15-one (348, from I.
japonica),137 serrin D (349, from I. serra),138 rabdonervosin H
(350, from I. nervosus),96 isorothornin G (351, from I. ros-
thornii)119 and isorosthins C–E (352–354, from I. rosthornii),111
rabdosins F–J (363–367, from I. serra),139 sculponins M, N, P,
and Q (372, 373, 368, and 369, from I. sculponeata),140 jianshir-
ubesins B and C (370 and 371, from I. rubescens),141 and scul-
2.3.2 6,7-Seco-ent-kauranes. The 6,7-Seco-ent-kauranes ponin B (375, from I. sculponeata).142 Additionally, eight new
were regarded as the oxidative cleavage products of the C-6-C-7 compounds, including phyllostacin M, 20-epiphyllostacin M,
11-epitaibaijaponicain A, 11,17-diepitaibaijaponicain A, phyl-
lostacin N, 20-epiphyllostacin N, 17-epidihydroisodocarpin, and
20-episerrin C (355–362), were identied from I. phyllostachys
recently.143 It is worth noting that 372 and 374 were different
from the others due to their rare ethylene oxide fragment. For
375, a unique furan ring was formed between C-12 and C-17.
Repeated investigation of I. sculponeata led to the isolation of
eight new 6,19:6,20-diepoxy-enmein type ent-kauranes: sculpo-
nin O (376),140 sculponins G–J (377–380),101 sculponeatin S
(381),136 Phyllostacin O, and 20-epiphyllostacin O (382 and
383).143 ent-Kauranes with 6,11:6,20-diepoxy fragments were
really rare. In the last decade, only two new ent-kauranes of this
Scheme 6 Proposed biogenetic pathway for luanchunin B (335). subgroup were identied: phyllostacin L (384)143 and 15b-
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hydroxy-6,7-seco-6,11b:6,20-diepoxy-1a,7-olide-ent-kaur-16-ene Another example of this subgroup is isorosthin B (395), which

(385).93,133 Re-analysis of the NMR data and a computer-modeled was isolated from I. rosthornii.111 Among these new diterpe-
3D structure of 384 revealed that H-6 in 384 was b-oriented noids, H-1 in 388 and 389 were determined to be a-oriented. It is
instead. worth noting that they represent the only examples of the H-1 as
Sculponin A (386) was an enmein-type ent-kaurane with an a-oriented compound for enmein-type ent-kauranes. The
a unique 6,19:6,11:19,20-triepoxy fragment, and was the only absolute congurations of 393 and 394 were both determined
example of triepoxy-ent-kauranes until now. Compound 386 by single-crystal X-ray diffraction. Compound 393 was also iso-
displayed signicant cytotoxic activity against K562, A549, and lated as a new compound from I. henryi and was conrmed by
HepG2 human tumor cell lines.142 6,20,15a-trihydroxy-6,7-seco- single-crystal X-ray diffraction analysis.114 Additionally, aer
1a,7-olide-ent-kaur-16-ene (387) was an enmein-type ent-kaur- a careful analysis of 1H NMR spectra of all 6,11-epoxy and
ane that did not form an extra oxygen ring between C-6 and 6,11:6,20-diepoxy-enmein-type ent-kauranes, we found that the
other carbon atoms.97 orientation of H-11 could be deduced from the coupling
Seven new 6,11-epoxy-enmein-type ent-kauranes were re- constant (J3 value) between H-9 and H-11. If the J3 value equals
ported from ve Isodon species: maoesin A and 3a-acetoxy- approximately 3.2 Hz, these two protons will be homolateral.
maoesin A (388 and 389, from I. eriocalyx),66 6a,15a-dihydroxy- However, H-9 and H-11 will be on opposite sides if the J3 value is
20-aldehyde-6,7-seco-6,11a-epoxy-ent-kaur-16-en-1,7-olide (390, approximately 11.6 Hz.
from I. serra),130,131 15a,20-dihydroxy-6,7-seco-ent-kaur-16-ene- There are three 3,6:6,20-diepoxy-enmein-type ent-kauranes

7,1a(6,11a)-diolide (391, from I. japonica),137 15a-hydroxy-6,7- reported from the genus Isodon. Jianshirubesin A (396), which
seco-1a,7:11a,6-diolide-ent-kaur-16-ene (392, from I. coetsa),144 was isolated from I. rubescens, was the rst example of this
and 15a-acetoxyl-6,11a-epoxy-6a-hydroxy-20-oxo-6,7-seco-ent- subgroup.141 The other two compounds in this subgroup came
kaur-16-en-1,7-olide and 15a-hydroxy-20-oxo-6,7-seco-ent-kaur- from the investigation of I. sculponeata140 and were named
16-en-1,7a(6,11a)-diolide (393 and 394, from I. rubescens).145 sculponins R and S (397 and 398).140 The absolute
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congurations of 396 and 397 were both determined by single- olide (406), and 6-aldehyde-1a,19-diacetoxy-6,7-seco-ent-kaur-
crystal X-ray diffraction analysis. 16-en-15-one-7,20-olide (407) from I. japonica,89 isorubesins
Phyllostacins J and K (399 and 400, from I. phyllostachys)143 A–D (408–411) discovered in I. rubescens,146 parvifoline AB (412)
and rabdosin E (401, from I. serra)139 were the only examples of from I. parvifolia,42 isojaponin B (413) identied in I. japonica,132
a rare 3,20:6,20-diepoxy-enmein-type ent-kaurane from the taihangexcisoidesin B (414) isolated from I. excisoides,46,47
genus Isodon. The absolute congurations of 399 and 401 were maoesin F (415) found in I. eriocalyx,66 ternifolide C (416) ob-
determined using single-crystal X-ray diffraction. All these tained from I. ternifolius,147 sculponin T (417) isolated from I.
compounds were inactive in tested human tumor cell lines. sculponeata,148 hikiokoshin C (418) reported in I. japonica,91
2.3.2.2 Spiro-lactone type (7,20-lactone type) rabdosin K (419) isolated from I. serra,139 sculponeatins N–P
2.3.2.2.1 Spiro-lactone type (6,7-seco-7,20-lactone type). Over (420–422) discovered in I. sculponeata,136 and laxiorolides H
the last decade, there were a total of 39 spiro-lactone type-ent- and I, K and L, N–R, and T (423–432), which were obtained from
kauranes isolated from the Isodon species. According to the I. eriocalyx var. laxiora.149 Compared to the other analogs, 416
classication principle proposed in our previous review, ent- is very special because it exhibited two stable conformations at
kauranes from this group were further divided into three sets 30 C.147 Among these diterpenoids, compounds 405–407
with four-ring, ve-ring or six-ring skeletons based on whether should be named as 6-hydroxy-1a,19-diacetoxy-15-oxo-6,7-seco-
C-6–O–C-19, C-6–O–C-20, or C-6–O–C-1 was formed or not.3 ent-kaur-16-en-7,20-olide, 19-hydroxy-1a,6-diacetoxy-15-oxo-6,7-
ent-Kaurane diterpenoids with a four-ring substructure seco-ent-kaur-16-en-7,20-olide, and 6-aldehyde-1a,19-diacetoxy-

account for a majority of this group. These new compounds 15-oxo-6,7-seco-ent-kaur-16-en-7,20-olide, respectively.
include epi-maoecrystal N (402), eriocalyxin G (403), and According to our last review, spiro-lactone type-ent-kauranes
maoecrystal W (404) isolated from I. eriocalyx,76 6-hydroxy- with a ve-ring skeleton were mainly of the 6,19-epoxy type.3
1a,19-diacetoxy-6,7-seco-ent-kaur-16-en-15-one-7,20-olide (405), Over the past ten years, no new compound of this type was re-
19-hydroxy-1a,6-diacetoxy-6,7-seco-ent-kaur-16-en-15-one-7,20- ported in the Isodon species. Enanderinanin F, which is a ve-
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ring spiro-lactone type-ent-kauranes isolated from I. enander- 2.3.2.2.2 Spiro-lactone type (6,7:8,15-diseco-7,20-lactone
ianus in 2001 by our group, was not included in our last type). The rst examples of 6,7:8,15-diseco-7,20-lactone-ent-
review.150 Laxiorolide J (433) was isolated from I. eriocalyx var. kauranes were laxiorins F and G.151 Then, two other ent-kaur-
laxiora with a rare oxirane fragment.149 Laxiorolides E–G anes belonging to this skeleton, laxiorolides C and D (441 and
(434–436), which were also isolated from I. eriocalyx var. laxi- 442), were reported.149 All of these compounds with a novel
ora, represented the rst examples of ve-ring spiro-lactone 6,7:8,15-diseco skeleton were discovered in I. eriocalyx var. lax-
type-ent-kauranes with a unique oxygen bridge between C-6 iora. Among these compounds, the absolute conguration of
and C-3.149 Laxiorolide S (437, from I. eriocalyx var. laxi- laxiorolide C was determined by single-crystal X-ray diffraction
ora)149 and phyllostacin E (438, from I. phyllostachys)87 were the analysis.
only 6,20-epoxy ve-ring spiro-lactone-type ent-kauranes ob-
tained from Isodon species over the last decade. Repeated
chemical investigation on I. sculponeata resulted in the identi-
cation of two rare spiro-lactone type-ent-kauranes. Sculponin C
(440)142 was a 19,20-epoxy ve-ring spiro-lactone, whereas scul-
poneatin Q (439)136 was the only 6,1:6,19-diepoxy-spiro-lactone
obtained from the genus Isodon over the last ten years. Among
these compounds, the absolute congurations of 423 and 436

were both determined by single-crystal X-ray diffraction 2.3.2.2.3 Spiro-lactone type (6,7:8,15-diseco-6,8-cyclo-7,20-lactone
analysis. type). The rst ent-kaurane diterpenoid from a natural resource with
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15,16-seco-ent-kaurane found aer the identication of rubes-

censin S and gesneroidin G.154,157 It is worth noting that the
chemical structure of rubescensin S was revised to a C-13
epimer of the original structure aer total synthesis and
chemical transformation, combined with single-crystal X-ray
diffraction analysis.158
Scheme 7 Proposed biogenetic pathway for maoecrystal Z (443).
a novel 6,7:8,15-diseco-6,8-cyclo skeleton was reported in I. eriocalyx by

our group in 2006, and it was named maoecrystal Z (443). It exhibited
an inhibitory effect against K562, MCF-7, and A2780 tumor cell lines
with IC50 values of 2.90, 1.63, and 1.45 mg mL1, respectively. A plau-
sible biogenetic pathway showed that it might be derived from a 7,20-
epoxy-ent-kaurane that becomes a spiro-lactone-type ent-kaurane, and
then maoecrystal Z (Scheme 7).152 The transformation from trichor-

abdal B to a novel rearrangement through retro-Claisen condensation
followed by an Aldol condensation was accomplished by E. Fujita, et al.
in 1981.153 Thus, the proposed biogenetic pathway of maoecrystal Z is
reasonable to some extent. Hikiokoshin B (444) is the second example
of this group derived from a natural resource.91
2.4 7,20-Cyclo-ent-kauranes
Until now, only ve 7,20-cyclo-ent-kauranes were found in the
Isodon species. Phyllostachysin A, which was the rst diterpe-
noid with a 7,20-cyclo-ent-kaurane skeleton, was isolated from
I. phyllostachys in 1985 by T. Fujita, et al.159 Rubescensin D from
I. rubescens is the second one that was found in this group.160
Xerophilusin F from I. xerophilus is another example of this
skeleton.122 A newly reported 7,20-cyclo-ent-kaurane diterpe-
noid, parvifoline AA (447), was isolated by our group in 2006,
and it exhibited signicant cytotoxicity against A549, HT-29,
and K562 cell lines with IC50 values of 4.12 0.25, 12.78
0.89, and 5.26 0.31 mM, respectively.42 From I. rosthornii, a C-1
epimer of rubescensin D was discovered, and it was named
isorosthin P (448).111 It is worth noting that the congurations
2.3.3 8,15-Seco-ent-kauranes. A previous chemical investi- of C-20 for all these compounds were “R”.
gation of the Isodon species resulted in the discovery of only two
8,15-seco-ent-kauranes: rubescensins T and U.154,155 Parvifoline
Y (445), which was isolated from I. parvifolia, is the only example
of this group that has been reported over the last ten years.156
2.3.4 15,16-Seco-ent-kauranes. Neolaxiorin F (446),99
which was isolated from I. eriocalyx var. laxiora, was the third
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2.5 Diterpene dimers

In our last review, only ten diterpene dimers were summarized.
In this review, we are introducing diterpene dimers discovered
from the genus Isodon during the last decade. The isolated
diterpene dimers were mainly formed in three different
patterns: Diels–Alder cycloaddition, [2 + 2] cycloaddition, and
Michael addition. Diterpene dimers derived from two diterpene
monomers by linkage of carbon–oxygen–carbon bonds were not
included in this part.
Repeated phytochemical investigation of I. rubescens led to
the discovery of bisrubescensins A–E (449–451, 454, and
467).161–163 Bisrubescensin A is an ent-kaurane dimer with an
unprecedented C23-kaurane unit. The plausible biosynthetic
pathway of 449 was proposed as shown in Scheme 8. Bisjapo-
nins A and B (452 and 453, from I. japonica) were formed by
a [2 + 2] cycloaddition reaction based on two monomers.164 Two

diterpene moieties of pseurata F were linked through C-17 and
C-110 with a Michael addition reaction as the key step to form
a novel ent-kaurane dimer, bispseurata F (455, from I. phar-
icus)57 (Scheme 9). Sculponins D and E (456 and 457, from
I. sculponeata)101 were both Diels–Alder reaction products
between enmein-type ent-kauranes. Four ent-kaurane dimers,
bisleuconins A–D (458–461), were isolated from I. leucophyllus.
Compounds 458 and 459 are a pair of epimers at C-160 . Both of
them were formed via Michael addition as a key step.165 Among
biexcisusins A–E (462–466, from I. excisus), compounds 464–466
were specialized as a rare macrolide. The formation of
compounds 464–466 is supposed to involve two key steps, one is
an intermolecular Diels–Alder addition reaction, and the other Scheme 10 Proposed biogenetic pathways for hispidanins A–D (481–
484).
is oxidative cleavage of the bond between C-150 and C-160 .166

Thirteen ent-kaurane dimers, bistenuifolins A–M (468–480),
were discovered in I. tenuifolius. This was the rst time that such
a large number of ent-kaurane dimers was identied from
a single Isodon species.167 Hispidanins A–D (481–484, from the
roots of I. hispida) have unique asymmetric structures formed
by the bond between totarane and labdane diterpenoids.168
Compounds 481–484 represent the only dimeric diterpenoids
Scheme 8 Proposed biogenetic pathway for bisrubescensin A (449). that are not derived from ent-kauranes. Hypothetical biosyn-
thetic pathways for 481–484 have been proposed (Scheme 10).
Scheme 9 Proposed biogenetic pathway for bispseurata F (455).
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2.6 Miscellaneous ent-kauranes (diterpene alkaloids with an

aza-ent-kaurane skeleton)
Miscellaneous ent-kauranes are a series of ent-kauranoids that
do not belong in any of the aforementioned groups. In this
review, 23 novel diterpenoids will be introduced.
Parvifoline X (485, from I. parvifolius) is a novel 15(8/11)-
abeo-7a,20-epoxy-ent-kaurane diterpenoid.156 Compound 485
was supposed to be derived from lasiodonin (which is a major
known diterpenoid from this plant) by an 1,3-alkyl shi as the
key step. It was the rst time that an ent-kaurane with this
skeleton was found in the genus Isodon.
Nervonin A (486), a pentacyclic ent-kauranoid with an
unprecedented cyclobutane moiety, was isolated from
I. nervosus.56
The hypothetical biogenetic pathways for 485 and 486 are
shown in Schemes 11 and 12, respectively.
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Scheme 11 Proposed biogenetic pathway for parvifoline X (485).

Scheme 13 Proposed biogenetic pathway for luanchunin A (487).
Luanchunin A (487) is a novel ent-kaurane obtained from the

aerial parts of I. rubescens var. lushanensis with a 6/7/6/5 fused
ring system.128 A plausible biogenetic pathway of 487 was
proposed and is shown in Scheme 13.
Laxiorin S (488, from I. eriocalyx var. laxiora)98 is an ent-
kaurane derivative with a unique C24 carbon framework. The
acetonide of rabdoloxin A64 (489) and taihangexcisoidesin
D104,105 (490), which were isolated from I. scoprius and I. exci-
soides, respectively, are ent-kaurane derivatives composed of
a C23 carbon skeleton. Compounds 488–490 are similar to tai-
hangjaponicain B,169 which was a known compound reported in
the genus Isodon and was supposed to be an artifact formed by
a Michael addition between the olen group at C-17 and
Scheme 12 Proposed biogenetic pathway for nervonin A (486). acetone.
In 2012, ternifolide A (491), which is a new diterpenoid-
based macrolide, was isolated from the leaves of I. ternifolius.
Specically, a unique 10-membered lactone ring formed
between C-6 and C-15. The absolute conguration of 491 was
conrmed by an X-ray diffraction study.147 Compound 491 was
classied as a new diterpene type called ternifonane. Hikio-
koshin A (493), which is an analogue of ternifolide A, was iso-
lated from I. japonica in 2014.91
Ternifolide B (492), which is a novel 6,7:8,15-diseco-6-nor-
ent-kaurane, was also isolated along with ternifolide A. A
Scheme 14 Proposed biogenetic pathways for ternifolides A and B

(491 and 492).
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plausible biogenetic pathway from 416 to 416b and then to 492

was proposed.147 It seems that the plausible biogenetic pathway
from 416a directly to 492 (Scheme 14) is much more sensible.
Laxiorolide M (494, from I. eriocalyx var. laxiora) is the rst
naturally occurring 6-nor-6,7-seco-ent-kaurane with an absolute
conguration that was determined by single-crystal X-ray
diffraction analysis.149
Scheme 17 Proposed biogenetic pathways for neolaxiflorins A and B

(496 and 497).
Neoadenoloside A (495) is an unprecedented ent-kaurane C-

were identied from I. eriocalyx var. laxiora.117 From I. eriocalyx
glycoside. It was discovered from I. adenolomus by our group in
var. laxiora, another three novel caged ent-kauranoids, neo-
2012. The stereochemistry of 495 was determined using single-
laxiorins D and E (500 and 501)99 and laxiorin U (502),98 were
crystal X-ray diffraction analysis of the 8,15-cleavage product
reported. Among them, 500 and 502 were the rst examples of
(495a, Scheme 15) of 495.170 A hypothetical biogenetic pathway
a 15,16-seco-16,17-dinor-ent-kaurane diterpenoid. Compound
for 495 was proposed (Scheme 16).
501 was the rst 15,16-seco-17-homo-ent-kauranoid. The abso-
Neolaxiorin A (496), which is an ent-kaurane diterpenoid
lute congurations of 500 and 501 were determined by single-
with an unprecedented bicyclo[3.1.0]hexane unit, and its seco-
crystal X-ray diffraction analysis. Hypothetical biogenetic path-
derivative, neolaxiorin B (497), were isolated from I. eriocalyx
ways of 500 and 501 were proposed as shown in Scheme 18.
var. laxiora. The absolute conguration of 496 was determined
Isorosthin A (503, from I. rosthornii) was the rst 20-nor-
by single-crystal X-ray diffraction analysis.171 Plausible bioge-
enmein-type diterpenoid.111 This is the second time that 20-
netic pathways from laxiorin A to 496 and 497 were proposed
nor-ent-kaurane was found in the Isodon species aer the
(Scheme 17).
identication of rubescensin N.172
A pair of epimeric bishomoditerpene lactones with a unique
C22 framework, specically laxiorolides A (498) and B (499),
Scheme 15 Transformation from neoadenoloside A (495) to a 8,15-

cleavage product (495a).
Scheme 16 Proposed biogenetic pathway for neoadenoloside A Scheme 18 Proposed biogenetic pathways for neolaxiflorins D–E
(495). (500 and 501).
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chemical computational 13C NMR and ECD data analysis. These

alkaloids were presumably biosynthesized from ent-kaurane
diterpenoids.173
2.7 ent-Atisanes
Over the last ten years, chemical investigation of Isodon species
resulted in the discovery of six new ent-atisane diterpenoids. ent-

Atisanes from the Isodon species were supposed to be bioge-
netically derived from ent-kauranes.174,175
Alboatisins A–C (508–510, from I. albopilosus) were the rst
examples of ent-atisanes reported from the genus Isodon.174
Other examples include eriocatisin A (511, from I. eriocalyx),66
isorosthornin D (512, from I. rosthornii),119 and isorubesin E
(513, from I. rubescens).146 Among them, 512 was conrmed by
single-crystal X-ray diffraction analysis.
Laxiorol A (504) is an unprecedented 7,8:15,16-di-seco-15-

nor-21-homo-ent-kauranoid discovered in I. eriocalyx var. laxi-
ora. The absolute conguration was determined by spectral
methods and quantum chemical calculations.118 A plausible
biogenetic pathway was also proposed and is shown in
Scheme 19.
A new group of diterpene alkaloids, kauranes A–C (505–507),
were obtained from I. rubescens. Their structures and absolute
congurations were determined by spectroscopy and quantum-
2.8 Abietanes and ent-abietanes
Except for ent-kauranes, abietanes and ent-abietanes are the
other largest group of diterpenoids from Isodon species. Thirty-
two diterpenoids belonging to abietanes or ent-abietanes were
reported from the genus Isodon previously. In this review,
another 64 new ones will be introduced.
Repeated chemical investigation into I. xerophilus led to the
identication of a new diterpene glycoside (xerophinoid C,
514)176 and three new ent-abietanes (xerophilusins XIV–XVI,
515–517).177 Macrophynins E and F (518 and 519)178 and day-
ecrystal C (520)179 were isolated from I. macrophyllus by two
groups. An attempt to use an advanced Mosher’s method to
determine the absolute conguration of 519 failed. The
congurations of 518 and 519 were deduced mainly by bioge-
netic considerations. Furthermore, the conguration of C-8 in
Scheme 19 Proposed biogenetic pathway for laxiflorol A (504). 519 was not nally determined.
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Scheme 20 Proposed biogenetic pathways for rubesanolides A and B

(521 and 522).
Rubesanolides A and B (521 and 522),180 with an unprece-

dented b-lactone group formed between C-9 and C-20, were
identied in I. rubescens. For both of them, the rings between A
and B, as well as those between B and C, were trans-fused, and
rings A, B and C were in the chair, boat, and twist-chair
conformations, respectively, which was the rst time that
a diterpene had such conformations in the skeleton. In addi-
tion, 521 was conrmed by single-crystal X-ray diffraction.
Together with 521 and 522, rubesanolides C–E (523–525)181 were
also discovered. These diterpenoids contained a unique g-
lactone subgroup formed between C-8 and C-20. Their struc-
tures were determined by spectroscopic data and were further
conrmed by the X-ray crystallographic data for 523 and 525 as
well as a comparison of the CD spectrum of 524 to that of 523.
The postulated biogenetic pathways for 521–525 are shown in
Schemes 20 and 21.
From the same species collected from Hubei Province, ve

new ent-abietanes, ent-abierubesins A–E (526–530), were iso-
lated.71 The absolute stereochemistry of 526 was determined by
a single-crystal X-ray diffraction experiment.
A study of the chemical constituents of I. rubescens var.
rubescens (a variant of I. rubescens) led to the isolation of
hebeiabinins A–E (531–535). Both 534 and 535 were novel
Scheme 21 Proposed biogenetic pathways for rubesanolides C–E dimeric diterpenoids linked by an ether group between the C-20
(523–525).
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of the ent-kaurane unit and the C-18 of the ent-abietane frag- the abietane nucleus and acetone. 11,12-dihydroxyabieta-7-oxo-
ment.182 Rubescensin M was the only dimeric diterpenoid of 8,11,13-trien-15-ol (559) was another example from I. lophan-
this type previously reported in the Isodon species.183 thoides var. geradianus.191 Compound 559 should be named as
Four abietane diterpenoids, inexanins A–D (536–539), were 11,12,15-trihydroxy-abieta-5,8,11,13-tetraen-15-one. Addition-
isolated from I. inexus. Their structures were established ally, compound 559 was insufficiently deduced to be an ent-
mainly by NMR analysis, and by comparison of CD spectra with abietane by the evidence that “abietane diterpenoids isolated
similar compounds. The sugar unit was shown to be glucose by from the genus Isodon possess an ent-conguration”.191 In fact,
paper chromatography aer the hydrolysis of 536.184 From two both ent-abietane and abietane diterpenoids were reported for
Isodon species, 3a,6b-dihydroxy-7,17-dioxo-ent-abieta-15(16)- the genus Isodon.3 Six new abietanes were obtained from
ene (540, from I. inexus)185 and laxiorin P (541, I. eriocalyx I. lophanthoides var. graciliorus,192 specically 16-acetoxylsugiol
var. laxiora)117 were isolated. Compound 541 was a new natural (560), graciliorin E (561), graciliorin F (562), 15-O-methyl-
product that had been synthesized from maoecrystal A.186 graciliorin F (563), 15-hydroxy-20-deoxocarnosol (564), and 15-
Additionally, along with 541, two novel ent-abietanes, laxiorins hydroxy-1-oxosalvibretol (565). Graciliorin D (566)193 is another
Q (542)117 and V (543),98 were also discovered. Compound 542 is new abietane diterpenoid found in the same species as 565.
a unique 16,17-bisnor-ent-abietane diterpenoid. Compound 543 They are both rearranged abietane diterpenoids and are
is the rst 3,4-seco-ent-abietane diterpenoid obtained from the supposed to be formed in a similar way as 551, except that a C–C
genus Isodon. Six new ent-abietanoids, eriocasins B–E (544–546 bond is formed between C-4 and C-11 in 565 and 566 instead of
and 549), 3-acetyleriocasin C (547), and 3b-acetoxyeriocasin D the C–O–C bonds in 551.
(548), were reported by our group from I. eriocalyx.66 From From I. coetsa collected in Singapore, two new 17(15/16)-
I. lophanthoides var. geradianus, which is a species abundant in abietane diterpenoids, sincoetsins A and B (567 and 568), were
abietane diterpenoids, a series of new abietane diterpenoids isolated.194 Their congurations at C-16 were not determined.
was obtained, including gerardianin A (550),187 rabdosin D Other ent-abietane diterpenoids include parvifolines L–N (569–
(551), (+)-15-hydroxysalvinolone (552), and rabdosiacoside A 571, from I. parvifolia),195 ent-abienervonins A–C (572–574, from
(553),188 isolophanthins A, B and D (554–556),189 and ger- I. nervosus),196 and isoadenolin M (575, from I. adennolmus).69
ardianins B and C (557 and 558).190 Among them, 550 was The conguration of 575 was conrmed by single-crystal X-ray
conrmed by single-crystal X-ray diffraction analysis. analysis. Isoabietenins A–C (576–578), which were three new
Compound 551 was supposed to be formed by three key steps: abietane diterpenoids obtained from I. tenuifolius, were evalu-
(1) the oxidative cleavage of the carbon–carbon bond between C- ated for their cytotoxic activity against ve human tumor cell
4 and C-5; (2) 1,2-methyl shi; (3) the cyclization between C-4 lines. As a result, isoabietenin C exhibited selective cytotoxic
and C-11 to form an eight-membered oxygen ring. Compound activity against an HL-60 cell line with an IC50 value of 4.7 mM.
553 is a rare 20(10/9)-abietane-type diterpenoid. Compound Additionally, isoabietenin A had a rare 1,11-epoxy unit.75
556 may be an artifact formed by a Michael addition between
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2.9 Other tricyclic diterpenoids Sempervirane is a type of diterpenoid that has never been
reported in the genus Isodon. Now, three semperviranes are
Pimaranes from the genus Isodon are supposed to be bioge-
isolated from two species. 3b-hydroxysempervirol (586, from
netically related to kauranes, and ent-pimaranes were consid-
ered to be the precursors of ent-kauranes. Thus, pimaranes I. lophanthoides var. graciliorus) was the rst example of sem-
isolated from the Isodon species were deduced to share an ent- pervirane from the genus Isodon.192 Hispidanols A and B (587
and 588, from I. hispida) are other semperviranes that were
pimarane conguration.3 However, avidusins A and B and
discovered. Compound 587 is a 17-nor-sempervirane, and 588 is
glutinosin B were exceptions.197 It is difficult to distinguish
a 9(10/20)abeo-sempervirane with a 3,10-epoxy unit.198
whether the isolates are ent-pimaranes or not. Under these
Totara-8,11,13-triene-13/16-hemiacetal (589, from I. his-
circumstances, in fact, most of the pimaranes (ent-pimaranes,
pida) was isolated as the only totarane diterpenoid from the
isopimaranes or ent-isopimaranes) were determined based on
genus Isodon.198 But, the congurations of compounds 588 and
a relative conguration or through biogenetical consideration.
Over the last ten years, an ent-isopimarane (Pharicinin A, 579, 589 have yet to be determined.
from I. pharicus),57 two ent-isopimarane glycosides (ent-iso-
pimanervosides A and B, 581 and 582, from I. nervosus),196 and
an isopimarane (Graciliorin C, 580, from I. lophanthoides var.
graciliorus)193 were reported. For 581 and 582, the congura-
tion of C-8 was not determined.
Three podocarpanes were discovered from the genus Isodon,
including isolophanthin C (583)189 and graciliorins A and B
(584 and 585).193
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2.10 Bicyclic diterpenoids

2.10.1 Labdanes. Only nine labdanes were discovered in
the Isodon species. Two new labdane diterpenoids, S-trans-
8(17),12E,14-labdatrien-20-oic acid (590) and S-trans-12E,14-
labdadien-20,8b-olide (591), were isolated from the roots of
I. yuennanensis.199 Chemical investigation of I. adenantha led to
the isolation of seven labdane diterpenoids: 14b-hydroxy-
8(17),12-labdadien-(15/16)-lactone-19-oic acid (592),74
13x,14b-dihydroxy-8(17)-labdaen-(15/16)-lactone-19-oic acid
(593),74 adenanthic acids A and B (594 and 595),200 and ade-
nanthosides A–C (596–598).200 For 593 and 596, the congura-
tion of C-13 was not determined. Compounds 596–598 are 2.10.3 ent-Halimanes. Scopariusins A–C (602–604), which
labdane glycoside derivatives. Compounds 592 and 593 should are three novel rearranged ent-halimanoids with a bicycle [5.4.0]
be named as 14b-hydroxy-16,15-olid-8(17),12-labdadien-19-oic undecane ring system, along with another two new normal ent-
acid and 13x,14b-dihydroxy-16,15-olid-8(17)-labdaen-19-oic halimanoids (605 and 606), were isolated from I. scoparius.
acid, respectively. Because the crystals of these novel rearranged ent-halimanoids
2.10.2 ent-Clerodanes. In the last decade, isoscoparins O–Q
were not obtained, the determination of their absolute cong-
(599–601)201–203 were the only examples of ent-clerodanes re- urations was a challenge. Fortunately, a biomimetic trans-
ported from the Isodon species. Their absolute congurations formation from the ent-clerodanoid (599) to the normal (606)
were determined by single-crystal X-ray diffraction analysis.
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2.11 Meroditerpenoids
Scopariusic acid (607), which is a new ent-clerodane-based
meroditerpenoid with a unique cyclobutane ring and
a 1-octen-3-ol substituent, was isolated from I. scoparius. Sco-
pariusic acid might be biosynthetically formed via an intermo-
lecular [2 + 2] cycloaddition between the acyclic side chains of
two absolutely different units, with one moiety possessing an
ent-clerodane diterpenoid nucleus, and the other derived from
10 -octen-30 -yl-4-hydroxycinnamate, which is an ester of trans-4-
hydroxycinnamic acid and (3R)-1-octen-3-ol. Compound 607
showed weak cytotoxicity and moderate immunosuppressive
activity. A single-crystal X-ray diffraction analysis was success-
fully performed to provide the relative conguration of 603. To
further determine the absolute conguration of 607, it was
hydrolyzed with concentrated aq NaOH in MeOH to yield
1-octen-3-ol, which was examined using spectroscopy methods.

Additionally, the absolute conguration of 1-octen-3-ol was
determined by comparing its optical rotation value with that of
an authentic sample.202
Scopariusicides A (608) and B (609), two novel immunosup-
pressive unsymmetrical cyclobutane derivatives, were isolated
from Isodon scoparius. Additionally, a concise stereocontrolled
Scheme 22 Proposed biogenetic pathway for scopariusins A–C synthesis of scopariusicide A was efficiently achieved using 601
(602–604). as a starting material. A crossed intermolecular [2 + 2] photo-
cycloaddition and a Pd-catalyzed sp3 C–H bond b-arylation were
used synergistically to access the highly congested unsymmet-
and the rearranged (602) ent-halimane diterpenoids was rical cyclobutane core with four contiguous stereocenters.203
successfully accomplished. In addition, the absolute congu-
rations of 599 and 605 were determined by single-crystal X-ray
diffraction analysis. Thus, the accomplishment of the biomi-
metic transformation not only validated the biogenetic
hypothesis in this plant but also conrmed the absolute
congurations of 602 and 606.201 The biogenetic pathways for
602–604 were proposed and are shown in Scheme 22.
In summary, 609 new diterpenoids were isolated and iden-

tied from the Isodon species during the period reviewed for
this update. The resources of these compounds are listed in
Table S1.†
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3 Biological activities onto the a,b-unsaturated ketone moiety, which leads to the
deactivation of SH enzymes or SH coenzymes.18,204,206,207
3.1 Cytotoxic activity and structure-activity relationship Nuclear transcription factor-kB (NF-kB) plays a crucial role in
Due to the anti-tumor activity of some plants from the genus inammation, cell proliferation, apoptosis, and immunity. The
Isodon, the cytotoxicity of the isolated diterpenoids is the most activation of NF-kB is known to be related to cancer, arthritis,
commonly studied bioactivity. Among those types of diterpe- asthma, and inammation.208 The mechanisms of the inhibi-
noids, ent-kauranes were the representative cytotoxic compo- tion of NF-kB signaling of some ent-kauranoids such as erio-
nents (Fig. 1). The cytotoxic activities of the isolated calyxin B (610), oridonin (611), ponicidin (612), and
diterpenoids from the Isodon species are listed in Table S2.† kamebakaurin (613) have been studied.209–211 Excisusins A–E
Most of the active ent-kauranes share an a,b-unsaturated (19–23) were evaluated for inhibitiing NF-kB activation. They
ketone moiety. The presence of a hydroxyl group on the C ring exhibited inhibition activity against NF-kB activation, except for
increases the activity, while the methyl oxidation at C-4 excisusin C (21) (Table 1). The a,b-unsaturated ketone unit in
decreases the toxicity.204 For 7,20-epoxy-ent-kauranes, the 7,20- the ent-kauranoids appeared to be indispensable for inhibiting
epoxy moiety and hydroxyls at C-6 and C-7 were benecial for NF-kB signaling in previously published research. Neolaxiorin
the cytotoxic activity.205 Oxidation of the CHO at C-6 in spiro- Q (214), an ent-kaurane with a 15-oxo-16-aH-17-ethoxy unit,
lactone ent-kauranes to COOH could destroy the cytotoxic exhibited cytotoxicity towards HL-60, SMMC-7721, A-549, MCF-
activity despite the presence of an a,b-unsaturated ketone 7, and SW-480 cell lines with IC50 values of 4.40, 2.99, 3.62, 5.25,
moiety.205 and 1.97 mM, respectively. The effect of neolaxiorin Q on TNF-
During our attempt to search for new diterpenoids with a induced NF-kB activation in HEK293T cells was also exam-
interesting biological effects, we found an interesting ined. As a result, neolaxiorin Q showed inhibitory effects
phenomenon. The ent-kauranes with a 15-oxo-16-aH-17- against NF-kB activation with an IC50 value of 9.4 mM.100 15-
methoxy or 15-oxo-16-aH-17-ethoxy fragment also exhibited acetyldemethylkamebacetal A (247) contained only the exo-
cytotoxic activity.100 The mechanisms underlying the cytotox- methylene group without a conjugated carbonyl group, and it
icity of these ent-kauranes are still unknown, and need to be exhibited weak inhibitory effects on TNF-a induced NF-kB
studied further. activation with an IC50 value of 20.15 0.95 mM.109
Eriocalyxin B (610) inhibited lymphoma cell proliferation
and induced apoptosis through multiple signal transduction
3.2 Anti-tumor mechanism
pathways, including inhibition of NF-kB and AKT pathways, as
Numerous studies have reported anti-tumor mechanisms of well as the activation of the extracellular signal-related kinase
Isodon diterpenoids over the past few decades. In this section, (ERK) pathway.210 Eriocalyxin B induced SMMC-7721 hepato-
only a small portion of these studies will be briey introduced. cellular carcinoma cell apoptosis by interfering with the
As many ndings have shown, the a,b-unsaturated ketone binding between NF-kB and the response elements by targeting
was the active center for cytotoxic activity. The widely accepted cysteine 62 of p50, which is the critical residue of p50 for erio-
mechanism for the active ent-kaurane is the Michael addition of calyxin B binding through a,b-unsaturated ketones.16 Erioca-
so nucleophiles, such as thiols and protein sulydryl groups, lyxin B suppressed the glutathione and thioredoxin antioxidant
systems, thus increasing the intracellular ROS levels and regu-
lating the MAPK and NF-kB pathways. Treatment with erioca-
lyxin B depleted the intracellular thiol-containing proteins in
pancreatic adenocarcinoma CAPAN-2 cells. The thiol-
containing antioxidants, N-acetylcysteine (NAC) or dithio-
threitol (DTT), inhibited eriocalyxin B-induced cytotoxicity and
apoptosis.212
Oridonin (611) induced apoptosis and G(2)/M phase arrest in
human laryngeal carcinoma HEp-2 cells decient in functional
Table 1 Inhibition of NF-kB activation of ent-kauranoids from the

Isodon species
Compound Activity Ref.
Excisusin A (19) 0.90 0.01 mM 20

Excisusin B (20) 0.26 0.01 mM 20
Excisusin C (21) >10 mM 20
Excisusin D (22) 3.21 0.05 mM 20
Excisusin E (23) 1.02 0.16 mM 20
15-Acetyldemethylkamebacetal A (247) 20.15 0.95 mM 90
Fig. 1 Representative examples of ent-kauranes that have been Neolaxiorin Q (214) 9.4 mM 81
studied for anti-tumor mechanisms.
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Table 2 Inhibition of LPS induced NO production activity of ent- Table 2 (Contd. )

kauranoids from the Isodon species
Compound Activity (IC50) Ref.
Compound Activity (IC50) Ref.
Isorosthin D (353) 1.5 mM 111
Excisusin F (1) 10.4 0.3 mM 38 Isorosthin E (354) 6.3 mM 111
Excisusin A (19) 0.67 0.01 mM 39 20-Episerrin C (362) 1.36 mM 143
Excisusin B (20) 0.56 0.01 mM 39 Phyllostacin L (384) 4.93 mM 143
Excisusin C (21) >10 mM 39 Isorosthin B (395) >25 mM 111
Excisusin D (22) 2.89 0.17 mM 39 6-Hydroxy-1a,19-diacetoxy-6,7- 8.2 0.12 mM 89
Excisusin E (23) 1.36 0.07 mM 39 seco-ent-kaur-16-en-15-one-7,
Wikstroemioidin E (104) 16.8 mM 73 20-olide (405)
Wikstroemioidin F (105) 16.5 mM 73 19-Hydroxy-1a,6-diacetoxy-6,7- 8.7 0.27 mM 89
Wikstroemioidin G (106) 5.0 mM 73 seco-ent-kaur-16-en-15-one-7,
Wikstroemioidin H (107) 3.5 mM 73 20-olide (406)
Wikstroemioidin M (112) 4.7 mM 73 6-Aldehyde-1a,19-diacetoxy-6,7- 20.3 0.33 mM 89
Wikstroemioidin O (114) 2.5 mM 73 seco-ent-kaur-16-en-15-one-7,
Wikstroemioidin P (115) 1.1 mM 73 20-olide (407)
Wikstroemioidin Q (116) 1.9 mM 73 Sculponin T (417) 18.6 mM 148
Wikstroemioidin R (117) 23.9 mM 73 Laxiorolide C (441) 1.5 0.3 mM 149

Tenuifolin A (122) 6.9 mM 75 Biexcisusin A (462) >50 mM 166
Tenuifolin B (123) >25 mM 75 Biexcisusin B (463) >50 mM 166
Tenuifolin C (124) >25 mM 75 Biexcisusin C (464) >50 mM 166
Tenuifolin D (125) >25 mM 75 Biexcisusin D (465) >50 mM 166
Tenuifolin E (126) >25 mM 75 Biexcisusin E (466) >50 mM 166
Tenuifolin F (127) >25 mM 75 3a,6b-Dihydroxy-7,17-dioxo- 1.3 mM 185
Tenuifolin G (128) >25 mM 75 ent-abieta-15(16)-ene (540)
Tenuifolin H (129) >25 mM 75 Isoabietenin A (576) >25 mM 75
Tenuifolin I (130) 5.8 mM 75 Isoabietenin B (577) >25 mM 75
Tenuifolin J (131) 8.8 mM 75 Isoabietenin C (578) 10.8 mM 75
Tenuifolin L (133) >25 mM 75
Tenuifolin M (134) >25 mM 75
Xerophinoid B (187) 0.24 mM 86
Isodojaponin A (192) 6.3 0.22 mM 89
Isodojaponin B (193) 10.2 0.25 mM 89
p53. Oridonin triggered the mitochondrial apoptotic pathway
Neolaxiorin P (213) 0.29 mM 100 via a caspase-9-independent pathway. These results suggested
Neolaxiorin Q (214) 1.95 mM 100 that G(2)/M phase arrest and apoptosis mediated by oridonin
Neolaxiorin W (220) >25 mM 100 occurred via a p53-independent but p21/WAF1-dependent
Sculponin Y (227) 13.8 mM 102 manner in HEp-2 cells. In addition, the generation of reactive
Isorosthin K (256) >25 mM 111
Isorosthin L (257) 2.0 mM 111
oxygen species (ROS) was found to be a critical mediator in
Isorosthin F (258) >25 mM 111 growth inhibition induced by oridonin.15
Isorosthin G (259) >25 mM 111 Ponicidin (612) suppressed HT29 cell growth by inducing G1
Isorosthin H (260) >25 mM 111 cell cycle arrest and apoptosis. The AKT and MEK signaling
Isorosthin I (261) >25 mM 111 pathways were also suppressed. However, the p38 signaling
Isorosthin M (262) 3.9 mM 111
Isorosthin O (264) 1.5 mM 111
Isowikstroemin A (268) 1.34 0.11 mM 115
Isowikstroemin B (269) 2.28 0.17 mM 115
Isowikstroemin C (270) 1.49 0.08 mM 115
Isowikstroemin D (271) 1.13 0.14 mM 115
Isowikstroemin F (273) 23.6 0.41 mM 115
Isowikstroemin G (274) 2.50 0.37 mM 115
Serrin E (276) 1.4 mM 116
14b-hydroxyrabdocoestin A (277) 7.6 mM 116
Serrin F (278) 0.6 mM 116
11-Epi-rabdocoestin A (280) 2.1 mM 116
Serrin H (281) 5.9 mM 116
Serrin I (282) 4.6 mM 116
Isowikstroemin H (296) 2.05 0.21 mM 121
Isowikstroemin J (298) 1.09 0.06 mM 121
Isowikstroemin K (299) 8.32 0.19 mM 121
Isowikstroemin L (300) 20.91 2.98 mM 121
Wikstroemioidin U (324) 9.9 mM 73
Wikstroemioidin V (325) 2.8 mM 73
Xerophinoid A (326) 2.1 mM 86
Isorosthin C (352) >25 mM 111 Fig. 2 Representative examples of ent-kauranes that have been
studied for synthesis.
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Scheme 23 Reagents and conditions: (a) Pb(OAc)4, Hg(OAc)2, CHCl3, 60 C; (b) Pyridine, CHCl3, then H+ (70%); (c) TMSCl, imdazole, CH2Cl2,
0 C; (d) DIBAL-H, CH2Cl2, 70 C to rt, then HCl (3 N) (85% for c and d); (e) EDCl, DMAP (70%); (f) Pb(OAc)4, AcOH (92%); (g) toluene, 130 C; (h)

Pd/C, H2; (i) SmI2, THF, t-BuOH, rt.
pathway was signicantly activated. The expression levels of Studies of the anti-tumor mechanism indicated that ade-
caspase 3 and Bax protein were markedly upregulated following nanthin (614) induced differentiation of acute promyelocytic
treatment with ponicidin.213 leukemia (APL) cells by targeting peroxiredoxins (Prx) I and
II.18,214 Further study to explore the potential activity of 614 in
solid tumor cells demonstrated that Prx I protein was essential
for the survival of hepatocellular carcinoma (HCC) cells, and
614 could kill the malignant liver cells in vitro and in xenogras.
Compound 614 induced HCC cell death mediated by the
increased reactive oxygen species (ROS) levels. Furthermore,
silencing of Prx I or Prx II enhanced the cytotoxic activity of 614
on HCC signicantly, whereas the ectopic expression of Prx I
and Prx II, rather than mutations of adenanthin-bound cyste-
ines, can rescue adenanthin-induced cytotoxicity in Prxs-
Scheme 24 Reagents and conditions: (a) dimethyl carbonate, NaH,

THF, D, 92%; (b) 2-((methoxymethoxy)-3-ethylphenyl)triacetoxy-
plumbane, pyridine, CHCl3, 60 C, 88%; (c) LiAlH4, THF, rt, 640a (12%)
and 640b (72%); (d) (Bu4N)BH4, MeOH, 40 C, 65% (89% brsm); (e) Scheme 25 Reagents and conditions: (a) NBS, (PhCO2)2, CCl4, reflux,
LiAlH4, THF, rt, 88%; (f) 2-(diethoxyphosphoryl)acetic acid, EDCI, 2 h, 90%; (b) Bu3SnH, TEMPO, PhH, reflux, 2 h, 75%; (c) Zn, AcOH, THF,
DMAP, CH2Cl2, rt, 82%; (g) TsN3, DBU, 0 C, 81%; (h) Rh2(OAc)4, PhH, D, H2O, 70 C, 2 h, 85%; (d) SmI2, THF, MeOH, rt, 10 min, 88%; (e) Lindlar
60%; (i) tBuOK, (HCHO)n, THF, 0 C, 95%; (j) TFA, CH2Cl2, rt, 90%; (k) cat. MeOH, THF, rt, 2 h, 92%; (f) DMP, CH2Cl2, rt, 1 h, 88%; (g) DBU,
Pb(OAc)4, AcOH, 0 C, then PhMe, 145 C, 24 h, 36%. toluene, 100 C, 1 h, 48% (90% brsm).
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mitochondrial cytochrome c-dependent activation of the

caspase-9 and caspase-3 cascade pathway in esophageal squa-
mous cell carcinoma cell lines.217
Pharicin A (616) induced mitotic arrest in leukemia and solid
tumor-derived cells, which were associated with unaligned
chromosomes, aberrant BubR1 localization and deregulated
spindle checkpoint activation. Pharicin A was not only directly
bound to BubR1 in vitro but also induced mitotic arrest in
paclitaxel-resistant Jurkat and U2OS cells. In other words, 616
perturbed mitotic progression and initiated a mitotic
catastrophe.19
Pharicin B (617) can rapidly stabilize the retinoic acid
receptor-a (RAR-a) protein in various acute myeloid leukemia
(AML) cell lines and primary leukemic cells from AML patients,
even in the presence of ATRA, which is known to induce the loss
of RAR-a protein. Compound 617 also enhanced the ATRA-
dependent transcriptional activity of the RAR-a protein in the

promyelocytic leukemia-RARa-positive APL cell line NB4 cells.
When it was used in combination with ATRA in several AML cell
lines, 617 demonstrated either a synergistic or additive
Scheme 26 Reagents and conditions: (a) NaBH4, MeOH, 77%; (b)
MsCl, Et3N, CH2Cl2, 96%; (c) DBU, CH2Cl2, rt, 80%; (d) LiAlH4, THF, rt, differentiation-enhancing effect.20
95%; (e) ()-DIPET, Ti(OiPr)4, TBHP, 30 C, 92% (99% ee); (f) DMP, Longikaurin A (618) induced cell cycle arrest and apoptosis
CH2Cl2, 92%; (g) n-BuLi, Et2O 90% (dr. ¼ 1.8 : 1); (h) Et2AlCl (2 eq.) 4 Å in human hepatocellular carcinoma cell lines by reducing Skp2
MS (200 wt%), THF; (i) LiAlH4, THF, 78 C to rt; (j) pyridine, CH2Cl2, expression and activating the ROS/JNK/c-Jun signaling path-
(Cl3CO)2CO, 85%; (k) MOMCl, NaOH, TBAI, THF, rt, 30 min; (l) K2CO3,
ways. Compound 618 also suppressed tumor growth in SMMC-
MeOH, 92% for (k) and (l).
7721 xenogra models without inducing any notable major
organ-related toxicity.218 The other study to examine the anti-
tumor effects of 618 in nasopharyngeal carcinoma in vitro and
silenced HCC cells.215 Compound 614 also targets additional
in vivo showed that 618 inhibited cell growth by inducing
proteins including the thioredoxin–thioredoxin reductase
apoptosis and cell cycle arrest. Interestingly, 618 induced S
system as well as a protein disulde isomerase (PDI) that
phase arrest at low concentrations and caspase-dependent
contains a characteristic structural motif, which is referred to as
apoptosis by regulating apoptotic molecules at higher
a thioredoxin fold. Compound 614 inhibited the activity of the
concentrations.219
Trx-TR system and PDI in vitro in the insulin reduction assay
and decreased the activity of Trx in cultured cells.216
Xerophilusin B (615) inhibited the tumor growth of a human 3.3 Anti-inammatory activity
esophageal tumor xenogra in BALB/c nude mice without Given the folk use of some Isodon plants, and since NO is an
signicant secondary adverse effects. Additionally, 615 induced essential component of the host innate immune and inam-
G2/M cell cycle arrest and promoted apoptosis through matory responses for a variety of pathogens, new diterpenoids
Scheme 27 Reagents and conditions: (a) Ar3BiCl2, DBU, PhMe, 67%, dr ¼ 7 : 3; (b) Li(t-BuO)3AlH, THF, 78 C, 72%; (c) acryloyl chloride, DIEPA,
DMAP, DCM, 78 C, 69%; (d) TFA, DCM, 0 C, 65%; (e) Pb(OAc)4, AcOH, 81%, dr ¼ 3 : 7; (f) 165 C, o-DCB, BHT 79% for 667a from 666a, 69% for
667b from 666b; (g) H2, Pd/C, EtOAc, 97% for 668 from 667a; (h) SmI2, MeOH, THF, 0 C, 76%, dr ¼ 17 : 3.
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are usually evaluated based on their inhibition effects for NO The antibacterial activity-guided isolation of I. serra led to
production in LPS-stimulated RAW264.7 cells. In this section, the discovery of a new diterpenoid, specically effusanin F
we provide a table to display the inhibition of the NO produc- (253). Compound 253 exhibited higher inhibition effects
tion activity of ent-kauranoids from the Isodon species (Table 2). against Staphylococcus. aureus, L. monocytogenes and P. aerugi-
nosa with IC50 values of 16 mg mL1 and lower inhibition
3.4 Antibiosis effects against Bacillus. subtilis and B. cereus with IC50 values of
32 mg mL1.113
In this section, the antibiotic activity of Isodon diterpenoids
The antimicrobial activity of hikiokoshins A (493) and B (444)
which were reported as new compounds over the last ten years
against Escherichia coli, S. aureus, B. subtilis, Micrococcus luteus,
will be introduced.
Scheme 28 Reagents and conditions: (a) Pd(OAc)2, 2-di-t-butylphosphino-20 -methylbiphenyl, K3PO4, THF, 80 C, 12 h, 91%; (b)TMSCHN2,
Hünig’s base, CH3CN/MeOH ¼ 9 : 1, 6 h, 100%; (c) Bu3SnCH2OMOM, BuLi, THF, 78 C to 40 C, 30 min, 0.5% HCl work-up, 75%; (d) HCl/
MeOH, 50 C, 75%; (e) PivCl, Py, DCM, 12 h, 96%; (f) NaBH4, CeCl3, MeOH, 0 C, 2 h, 93%; (g) MOMCl, Hünig’s base, DCM, 12 h, 95%; (h) DIBAL-H,
78 C, DCM, 30 min, 95%; (i) KH, 18-crown-6, ICH2SnBu3, 0 C, THF, 6 h, 90%; (j) n-BuLi, 78 C to 20 C, THF, 6 h, 88%; (k) Li, NH3(l), t-BuOH/
THF, 78 C, 20 min, 33 C, 40 min; (l) 1 N HCl, 0 C, THF/MeOH (10 : 1), 8 h, 2 steps, 78%; (m) acid chloride, Py, DCM, 0 C, 72%; (n) TBSOTf,
TEA, DCM, 0 C, 15 h, 81%; (o) 180 C, sealed tube, toluene, 12 h; (p) TBAF, 0 C, THF, 48% over 2 steps from 679.
Scheme 29 Reagents and conditions: (a) LDA, 78 C, THF, 40%; (b) (1) DIBAL-H, 78 C, DCM, 2 h; (2) MnO2, rt, DCM, 40 min, two steps, 68%;
(c) (1) 686, Py, 0 C, DCM, 30 min, 86%; (2) TBSOTf, TEA, DCM, 78 C, 12 h, 91%; (d) toluene, sealed tube, 166 C, 1 h, then TBAF, THF, 62%; (e)
PhSiH3, Mn(dpm)3, O2, DCM/iPrOH, 0 C, 80%; (f) H2O2, NaOH, MeOH, 0 C, 95%; (g) m-CPBA, DCM, rt, 18 h, 72%; (h) p-TsOH-H2O, DCM, rt, 12 h,
90%; (i) ethanedithiol, BF3$OEt2, DCM; RANEY®-Ni, ethanol, 75 C, 8 h; DMP, DCM, rt, 12 h, three steps, 70%; (j) NaBH4, DCM/MeOH, 78 C to
50 C, 96%; (k) (1) MsCl, DMAP, DCM, 50 C, 12 h, 58%, 95% brsm; (2) DBU, toluene, 128 C, 4 h, 90%; (l) DMSO, DCM, 0 C, then ether, BF3, 75%;
(m) NaBH4, 78 C to 50 C, 95%.
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Aspergillus niger, Trichophyton mentagrophytes, Candida albicans, Scopariusicide A (608) and isoscoparin Q (601) were screened
and Cryptococcus neoformans was evaluated. Hikiokoshin A for immunosuppressive activity arising from the inhibition of
exhibited antifungal activity against A. niger and C. neoformans human T cell proliferation in vitro with BD750 as a positive
(IC50 values of 16 mg mL1 each), whereas hikiokoshin B did not control (IC50 ¼ 1.1 mM). Their cytotoxicity against human
show such activity against any strains with IC50 values > 32 mg resting PBMCs was also tested. Overall, they exhibited weak
mL1.91 immunosuppressive activity at non-toxic concentrations with
14b-hydroxy-8(17),12-labdadien-(15/16)-lactone-19-oic acid IC50 values of 20.7 and 49.3 mM, respectively.203
(592) and adenanthoside C (598) were subjected to in vitro
antibacterial activity tests against Staphylococcus aureus, 4 Total synthesis
Candida albicans, Pseudomonas aeruginosa, Shigella dysenteriae,
Escherichia coli, Salmonella typhi H901, Bacillus subtilis, and Due to their structural complexity and interesting biological
Proteusbacillus vulgaris using the lter paper disk agar diffusion activity, the synthesis of some interesting diterpenoids from the
method. As a result, these compounds showed no obvious genus Isodon has received much attention from synthetic
inhibition activity against the bacterial strains.74,200 chemists. The total synthesis of popular molecules, such as
maoecrystal V (619), maoecrystal Z (443), sculponeatin N (420),
and trichorabdal A (621), has already been successfully accom-
3.5 Anti-virus
plished (Fig. 2). Among these molecules, maoecrystal V (619) is
Only limited anti-virus activity for Isodon diterpenoids has been undoubtedly the shining star. More recently, three reviews have
reported. Isolophanthin D (556) was subjected to an evaluation focused on the total synthesis of Isodon diterpenes.34–36 In this
of anti-HBV activity in the HBV-transfected Hep G 2.2.15 cell part of our review, we introduce approaches to the total
line. Compound 556 showed high inhibitory potential against synthesis of Isodon diterpenoids that were conducted over the
HBsAg and HBeAg with IC50 values of < 0.02 and 0.44 mg mL1, last ten years.
respectively.189
4.1 Total synthesis of maoecrystal V
3.6 Other activities Maoecrystal V (619), which was discovered in I. eriocalyx by our
Scopariusic acid (607) and isoscoparin P (600) were evaluated group in 2004, is a novel diterpenoid with a C19 skeleton that
for immunosuppressive activity mediated through inhibition of possesses an unprecedented and highly congested pentacyclic
mouse T cell proliferation in vitro using BD750 as a positive framework with six stereocenters.220 This structure was
control (IC50 ¼ 1.5 mM). The non-toxic concentrations of sco- conrmed by X-ray crystallography. Given its fascinating struc-
pariusic acid exhibited moderate immunosuppressive activity ture and distinct biological activity, maoecrystal V has received
(IC50 ¼ 2.6 mM), while isoscoparin P showed no activity.202 much attention from synthetic chemists around the world.
Scheme 30 Reagents and conditions: (a) (1) Ac2O, Py, DCM; (2) NaBH4, DCM/EtOH, 85% over 2 steps; (b) (1) MOMCl, i-Pr2NEt; (2) K2CO3, MeOH,
90% over 2 steps; (c) m-CPBA, rt, 95%; (d) (1) DMP, NaHCO3, DCM, 0 C, 85%; (2) Ac2O, Py, DCM, 90%; (e) PhSH, Et3N; then NaBH4, EtOH/DCM,
78%; (f) (1) RANEY®-Ni; (2) MsCl, DMAP, 65% over two steps; (3) K2CO3/MeOH, rt, 95%; (g) DMDO; then BF3$OEt2, 82%. (h) Lombardo reagent,
DCM, rt, 85%; (i) CH2I2, Zn/Ag, Et2O, 36 C, 88%; (j) PCC, DCM, rt, 76%; (k) H2, PtO2, AcOH, 40%; (l) Lombardo reagent, DCM, 0 C, 80%; (m) p-
TsOH$H2O, benzene, 76 C, 85%; (n) (1) LDA, TMSCl, THF, 78 C, 90%; then Pd(TFA); (2) CH3CN, 80%; (o) TFDO, CH2Cl2, 78 C to 0 C, dr ¼
1 : 1, 90%; (p) BF3$OEt2, DCM, rt, 85%.
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Scheme 31 Reagents and conditions: (a) 716, Ph3P, (EtO2C)2N2, THF, toluene, reflux, 63%; (b) n-BuLi, THF, rt; ZnCl2, ClCOCO2Me, 46% (brsm
71%); (c) (1) TsNHNH2, TsOH, PhH; (2) DBU, CH2Cl2, rt, 75% over 2 steps; (d) Rh2(OAc)4, 4 Å MS, CH2Cl2, rt, 86%, dr ¼ 10 : 1; (e) Li(SiMe3)2, ZnEt2,
MeI, DMPU, THF, 100%; (f) LiAlH4, THF, 63%; (g) MeMgBr, PhH, 80 C, 100%; (h) PhI(OCOCF3)2, NaHCO3, EtOH, 95%; (i) 725, i-Pr2NEt, DMAP, 73%;
(j) BHT, o-DCB, 140 C, 2.5 h, 160 C, 16 h, 98%; (k) 728, Et3N, DMAP, CH2Cl2, 0 C, 82%; (l) BHT, i-Pr2NEt, toluene, 60%.
Scheme 32 Reagents and conditions: (a) 2 eq. sesamol (i-PrO2C)2N2, Ph3P, THF-PhMe, reflux, 18 h, 79%; (b) n-BuLi, THF, ZnCl2, ClCOCO2Me,
47% (96% brsm); (c) TsNHNH2, PhH, DBU, CH2Cl2, 82%; (d) 1 mol% Rh2(OAc)4, CH2Cl2, 23 C, 74%, dr ¼ 10 : 1; (e) LDA, THF, Et2Zn, BnOCH2Cl,
76%, dr ¼ 9 : 1; (f) LiAlH4, THF, 23 C, 88%; (g) CH3MgBr, PhH, 80 C, 95%; (h) (1) Phl(O2CCF3)2, EtOH; (2) CH2 ¼ CHSi(Me)2Cl, 85% for two steps; (i)
toluene, 110 C, 24 h, (10 mol% BHT), 95%; (j) SmI2, MeOH-THF, 90%; (k) n-Bu4NF, DMPU, 0 C, 1 h, 50%; (l) (1) Im2CO, THF; (2) Ph2Se2, NaBH4,
68% over 2 steps; (m) (Me3Si)3SiH, AlBN, PhH, 80 C, 12 h, 55%; (n) (1) DDQ, aq. CH2Cl2; (2) DMP, CH2Cl2; (3) Ph3P ¼ CH2, 68% over 2 steps; (o)
LiN(SiMe3)2, CH3I, THF, 40 C, 90%, dr ¼ 7 : 1; (p) (1) DDQ, aq. CH2Cl2; (2) DMP, CH2Cl2; (3) CH2 ¼ CHMgBr, CeCl3, THF, 71% over 3 steps; (q) (1)
20 mol% HGII (CH2Cl)2, 80 C; (2) DMP, CH2Cl2, 86% over 2 steps.
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Scheme 33 Reagents and conditions: (a) (1) NaOH, aq. MeOH, 0 C; (2) C6H5COCl, Et3N, toluene, then 748; (b) (1) TsNHNH2, PhH; (2) Et3N,
CH2Cl2; (c) 2 mol% catalyst, 4 Å MS solvent, 23 C, 24 h; (d) CH3ONa, CH3OH, 23 C, 5 min; (e) LDA, THF, Et2Zn, BnOCH2Cl, DMPU, 15 C, 1 h;
23 C 1 h; (f) LiAlH4, THF, 0 C, 80% over 2 steps from 752, dr > 30 : 1; (g) CH3MgBr, Et2O, PhH, 80 C, 8 h, 91%; (h) Phl(O2CCF3)2, NaHCO3, EtOH,
23 C, 15 min, 99%; (i) 757, ImH, CH2Cl2, 0 C, 30 min, 87%; (j) PhMe, 110 C, 24 h, 97%; (k) SmI2, MeOH, THF, 23 C, 85%; (l) Bu4NF, DMPU, 0 C,
1 h, 40–50%; (m) (1) Im2CO, THF, 23 C, 14 h; (2) (PhSe)2, NaBH4, DMF, 23 C, 87% over 2 steps; (n) (MeSi)3SiH, AlBN, PhH, 80 C, 12 h, 40–55%; (o)
(1) DDQ, CH2Cl2–H2O; (2) DMP, CH2Cl2; (3) Ph3P ¼ CH2, THF, 55% over 3 steps; (p) LiN(SiMe3)2, CH3I, THF, 40 C, 5 h, 90%, dr ¼ 7 : 1; (q) (1)
DDQ, CH2Cl2-H2O; (2) DMP, CH2Cl2; (3) CH2 ¼ CHMgBr, 65% over 3 steps, dr > 10 : 1; (r) (1) 20 mol% HGII (CH2Cl)2, 80 C; (2) DMP, CH2Cl2, 88%
over 2 steps. For 749–751, R ¼ Me or Ph.
Scheme 34 Reagents and conditions: (a) (1) LDA, TMSCl, m-CPBA; (2) TBSCl, imid, 70% over 2 steps; (b) (1) 769, NaH; (2) 770; 73% over 2 steps; (c)
FeCl3, 72%; (d) (1) DABAL-H; (2) 773, 44% over 2 steps; (e) (1) KOH; (2) Jones ox. 86% over 2 steps; (f) TMSI/HMDS, m-CPBA, 88%; (g) Pd/C, H2,
71%; (h) (1) H5IO6, MeOH; (2) NaBH4, 75% over 2 steps. (P ¼ TBS).
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4.1.1 Approaches by Yang’s group. In 2009, the rst successful total synthesis of ()-maoecrystal V. The synthesis
approach for the construction of the core structure of featured a Wessely oxidative dearomatization of a phenol (643),
maoecrystal V was developed by Yang and co-workers. First, the an IMDA reaction to produce 644, and a Rh-catalyzed O–H bond
starting material, 621, was made from commercially available 2- insertion from 641 to 642 as the key steps (Schemes 24 and 25).8
hydroxy-3-methylphenyl boronic acid. Then, the key interme- In 2015, Yang and colleagues nished the asymmetric total
diate 625 was prepared from 621 via the lead-mediated arylation synthesis of ()-maoecrystal V. They used a different strategy
of b-ketoesters as a key step. The other key steps involved with an early-stage semipinacol rearrangement reaction for the
oxidative dearomatization from 627 to 628 and 629 as well as construction of the key intermediate 640a, followed by the
the intramolecular Diels–Alder (IMDA) reaction from 628 and aforementioned strategy reported in 2010 to accomplish asym-
629 to 630 and 631, respectively (Scheme 23).221 metric total synthesis of ()-maoecrystal V (Scheme 26).4
Yang’s successful attempt to construct the core structure of 4.1.2 Approaches by Baran’s group. Baran and colleagues
maoecrystal V paved the way for the total synthesis of this described the enantioselective synthesis of the carbon skeleton
fascinating natural product. In 2010, they reported the rst of maoecrystal V in 2009. The key transformations included
Scheme 35 Reagents and conditions: (a) TNSI, NaH, DMSO, 86%; (b) 781, Cp2Ti(III)Cl, 33–54%; (c) (1) LiHMDS, MoOPH, 61%; (2) TBSOTf, 2,6-
lutidine, 83%; (d) TsOH, 99%; (e) (1) LDA, TMSCl; (2) Pd(OAc)2, 75%, dr ¼ 1 : 1; (f) TBAF/AcOH, THF.
Scheme 36 Reagents and conditions: (a) CH2O, sodium dodecyl sulfate, DMAP, H2O, 71%; (b) 1.5 eq. of ()-diisopropyltartrate, 1.45 eq. of
Ti(iPrO)4, tBuOOH, 4 Å MS, 74%, 94% ee; (c) TfOH, 790, 87%; (d) NaBH4, 87%; (e) Ph3P, I2, imidazole, 76%; (f) Zn, NH4Cl, 0 C, 93%; (g) TESCl,
imidazole, 92%; (h) 3 mol% Pd(Ph3P)4, PMP, 125 C; TBAF, 52% of 793; (i) PhI(OAc)2, NaHCO3, (CF3)2CHOH-DCM, 95%; (j) 3 mol% Stryker’s cat.,
PhSiH3, 92%; (k) LDA, TMSCl; (l) 797, BHT, PhH; HCl/THF, 55% from 795; (m) 1,2-ethanedithiol, BF3$Et2O, then Zn/HCl, 89%; (n) IBX, DMSO; 1 N
HCl, 87%; (o) K2CO3, (CH2O)n, DMF, 97%; (p) NaBH4, MeOH, then RANEY® Ni, reflux, 95%, dr > 15 : 1; (q) NBS, benzoylperoxide, CCl4, 80 C, then
AgBF4, DMSO, 73%; (r) CrO3/AcOH, DCM, reflux, 28% maoecrystal V and 47% 804.
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Scheme 37 Reagents and conditions: (a) 806 (1.6 eq.), Pd(TFA)2 (0.2 eq.), Ag2CO3 (2.0 eq.), DMF/DMSO (20 : 1), 80 C, 3 h, 89%; (b) BBr3 (1.8 eq.),
CH2Cl2, 15 C, 2.5 h, 70%; (c) NaH (2.1 eq.), THF, 0 C to 23 C, 1 h; then 809 (5.0 eq.) 0 C to 23 C, 16 h; (d) Na2CO3 (5.0 eq.), MeI (10.0 eq.),
MeOH, reflux, 2 h, 80% over the two steps; (e) TBSOTf (1.5 eq.), Et3N (3.0 eq.), CH2Cl2, 0 C, 1.5 h; (f) K2CO3 (4.8 eq.), hydroquinone (1.2 eq.),
toluene, reflux, 16 h; then 1.0 N aq. HCl, 1 h, 23 C, 64% over the two steps; (g) NaOH (1.0 N aq.)/EtOH (1 : 1), 60 C, 5 h; (h) (COCl)2 (5.0 eq.), DMF
(1 drop), CH2Cl2, reflux, 1 h; (i) TMSCHN2 (5.0 eq.), THF-CH3CN (1 : 1), 0 C, 2 h, 79% over the three steps; (j) Rh2(OAc)4 (0.1 eq.), CH2Cl2, 23 C, 1 h,
75%; (k) 10% Pd/C (0.26 eq.), H2, EtOAc, 23 C, 24 h, 87%.
Barton arylation (660 to 661), Wessely oxidative dearomatiza- as the key step, the total synthesis of racemic maoecrystal V was
tion of a phenol (665 to 666a and 666b), and a subsequent IMDA successfully accomplished. The other key step included the
reaction (Scheme 27).222 At the same time, Baran’s group and creation of the A–C ring trans-fusion through intramolecular
Yang’s group nished construction of the core structure of delivery of a hydrogen to the hindered b-face of the ring system
maoecrystal V using similar, but separate strategies. More (Scheme 30).7 This was the second total synthesis of
recently, Baran’s group reported 11 steps for the enantiose- maoecrystal V.
lective total synthesis of maoecrystal V at a 2.7% yield.223 The 4.1.4 Approaches by Zakarian’s group. A strategy that also
details about this new study are not included in this review. involved an IMDA reaction was designed to address the unique
4.1.3 Approaches by Danishefsky’s group. Danishefsky and strained tetrahydrofuran ring at the center of maoecrystal V
co-workers investigated two strategies for the synthesis of (Scheme 31).226
maoecrystal V, which both involved an intramolecular Diels– Zakarian reported the total synthesis of maoecrystal V in 24
Alder reaction (Schemes 28 and 29).224,225 steps with about a 1.5% overall yield from sesamol in 2013. The
Based on a former attempt to construct the core structure of synthesis strategy involved a counterintuitive early disconnec-
maoecrystal V using an intramolecular Diels–Alder cyclization tion of the lactone subunit to a polycyclic enol ether
Scheme 38 Reagents and conditions: (a) BBr3 (3.5 eq.), CH2Cl2, 78 to 0 C, 2 h, 98%; (b) NaH (1.1 eq.), MOMCl (1.2 eq.), THF, 0 C, 2 h, 56%; (c)
NaH (2.1 eq.), THF, 0 C to 23 C, 1 h; then 809 (4.0 eq.), THF, 0 C to 23 C, 8 h; (d) Na2CO3 (2.6 eq.), MeI (11 eq.), MeOH, reflux, 2 h, 57% over two
steps; (e) TBSOTf (1.5 eq.), Et3N (3.0 eq.), CH2Cl2, 0 C, 2 h; (f) K2CO3 (4.8 eq.), hydroquinone (1.2 eq.), toluene, reflux, 18 h; then 1.0 N aq. HCl,
23 C, 1 h, 50% over two steps; (g) HCl (6.0 N aq.)/EtOH-CHCl3 (1 : 1 : 1), reflux, 3 h, 83%; (h) PIFA (2.0 eq.), KHCO3 (2.2 eq.), MeOH, 0 C to 23 C,
0.5 h, 83%; (i) 10% Pd/C (0.33 eq.), H2, EtOH, 23 C, 10 h, 23: 66%, 24: 33%; (j) 1.0 N aq. NaOH (7.0 eq.), EtOH, reflux, 5 h; then 1.0 N aq. HCl; (k)
ClCH2I (11 eq.), KOtBu (5.0 eq.), 18-crown-6 (5.5 eq.), THF, 23 C, 3 h, 42% over two steps.
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Scheme 39 Reagents and conditions: (a) NiCl2 (0.05 eq.), NaBH4 (5.0 eq.), MeOH, 0 C, 1 h, 63%; (b) l-selectride (1.0 M in THF, 3.0 eq.), THF,
30 C, 1 h, 80%; (c) PPTS (0.1 eq.), acetone/H2O (20 : 1), 40 C, 1 h, 87%; (d) Pd/C (10% wt/wt, catalyst), H2, EtOH, 25 C, 16 h, 72%; (e) Ph3PMeBr
(5.0 eq.), LHMDS (1.0 M in THF, 5.0 eq.), THF, 0 C, 3 h, 42%; (f) Et2Zn (1.0 M in hexane, 5.0 eq.), CH2I2 (5.0 eq.), toluene, 40 C, 2 h, 54%; (g) DMP
(5.0 eq.), CH2Cl2, 25 C, 1 h, 91%; (h) PtO2 (1.5 eq.), H2, AcOH, 40 C, 1 h, 76%.
intermediate to preserve the central tetrahydrofuran ring until Based on previous attempts to construct the core structure of
the beginning stages of the synthesis. During the construction maoecrystal V, the enantioselective synthesis of maoecrystal V
of a dihydrobenzo-furan intermediate, C–H functionalization at was eventually nished. Key reactions in the synthesis included
the early phase of the synthesis was applied (Scheme 32).6 an intramolecular Heck reaction (from 791 to 793), an oxidative
The rst asymmetric total synthesis of the natural enantiomer cycloetherication (794), and an intermolecular Diels–Alder
of maoecrystal V was successfully achieved by Zakarian’s group in reaction (from 796 and 797 to 798) that formed the carbocyclic
2014. An early stage chiral auxiliary-directed asymmetric C–H core in a concise and stereoselective manner. Late-stage amine
functionalization for the construction of a key benzofuran and C–H oxidation were used to install the nal functional
intermediate facilited this total synthesis (Scheme 33).227 groups required to complete the synthesis (Scheme 36).5
4.1.5 Approaches by Thomson’s group. Construction of the 4.1.6 Approaches by Nicolaou’s group. Two strategies for
tetracyclic core structure of the complex polycyclic the construction of core structures of maoecrystal V were
maoecrystal V was achieved in 13 steps from 3,3-dimethylcy- described by K. C. Nicolaou and colleagues. The rst route to
clohexanone by employing a stereoselective Nazarov cyclization 816 used an IMDA reaction and intramolecule
followed by a Diels–Alder reaction to form the two contiguous cyclopropanation/dearomatization/ring opening (Scheme 37).
quaternary stereocenters (Scheme 34).228 The other strategy to obtain 826 utilized the same type of
An evaluation of “east-to-west” ether-forming strategies for intramolecule Diels–Alder reaction but used a different dear-
the total synthesis of maoecrystal V was performed by Thomson omatization process (Scheme 38).230
et al., which revealed numerous complications for the “east-to- 4.1.7 Approaches by Chen’s group. As a continuation of
west” ether bond construction strategy (Scheme 35).229 earlier synthetic efforts to construct the pentacyclic core
Scheme 40 Reagents and conditions: (a) O3, Me2S, 94%; (b) TBSCl, 73%; (c) TMSA, BULi, 75%; (d) NaH, 40 C, 82%; (e) H2, Pd/CaCO3, Py, 96%; (f)
LDA, CH2O, 40 C, 92%; (g) DMP, 90%; (h) NaBH4, 92%; (i) LDA, CH2O, 40 C, 65%; (j) O3, Me2S, 46%.
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Scheme 41 Reagents and conditions: (a) neat reflux, 91%; (b) PCC, silica gel, CH2Cl2; (c) H2, Pd/C, Et2O/EtOH; (d) KOH, THF/H2O, reflux, 46%
over 3 steps from 847 and 848; (e) BF3$OEt2, CH2Cl2, 98%; (f) NaH, PMBCl, DMF, 99%; (g) BuLi, HMPA, THF, 78 C, then 851, 24%; (h) (1) LiHMDS,
THF, 78 C, then PhSeBr; (2) 857, NaHCO3, CH2Cl2/H2O, 48% over 2 steps; (i) (1) DDQ, CH2Cl2/H2O; (2) Dess Martin periodinane.
Scheme 42 Reagents and conditions: (a) p-TsOH, dimethoxypropane, acetone, rt, 72.5%; (b) OsO4, NMO, aq. acetone, 90%; (c) NaIO4, aq.
MeCN, 0 C, 2 h, 81%; (d) NaBH4, aq. MeOH, 99%; (e) acrolyl chloride, CH2Cl2, diisopropyl ethyl amine, DMAP, 95%; (f) aq. HCl, THF, rt, 91.8%; (g)
aq, NaIO4, CH3CN, 0 C to rt; (h) Zn–NH4Cl, aq, MeOH, 93%; (i) Jones’ox, aq. THF, 100 C, 66%; (j) H2, Pd/C, EtOH, 90%.
Scheme 43 Reagents and conditions: (a) 869, EtAlCl2, PhMe, 0 C, 3 h;

(b) m-CPBA, benzene or pentane, 20 C, 24 h, 77% over 2 steps; (c)
DIBAL-H, PhMe, 78 C, 1 h; or K2CO3, MeOH/H2O, 20 C, 3 h; (d)
Scheme 44 Reagents and conditions: (a) LiTMP (4.0 eq.), THF, 78 C;
LiTMP, 78 C to 20 C, then TMSCl; (e) selectfluor (1.05 eq.), then
(b) TBSCl, imid, CH2Cl2, 20 C, 68% over 2 steps; (c) Na, D2O, 1,4-
TBAF (1.05 eq.); (f) TBSOTf, Et3N, 0 C to 20 C, 55% over 4 steps; (g)
dioxane, 50 C, 24 h; (d) MeLi, CeCl3, 78 C; (e) 876, Me2NPh, CH2Cl2,
LDA, 78 C, then HCl/MeOH; (h) MeLi, CeCl3, 78 C; (i) xylene,
0 C, 15 min, then Et3N, 0 C to 20 C; (f) Rh2(esp)2, (0.5 mol%), slow
100 C, 872; (j) p-ABSA, Et3N, 0 C to 20 C, then aq. LiOH, 55 C, 70%
addition with 4 Å MS CH2Cl2, 20 C, 0.01 M, 32% over 4 steps; (g) i-
over 4 steps; (k) Rh2(esp)2, (0.5 mol%), slow addition with 4 Å MS
Pr2NLi, 78 C, then CH3CHO; (h) Dess Martin periodinane, CH2Cl2,
CH2Cl2, 20 C, 0.02 M; (l) KHMDS, DMPU, PhN(Tf)2; (m) Pd(OAc)2,
0 C; (i) LiHMDS, 20 C, then BOM-Cl, 73% over 3 steps.
PPh3, HCOOH, Et3N, DMF, 55 C, 28% over 3 steps.
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Scheme 45 Reagents and conditions: (a) (1) TBSCl, imid, CH2Cl2; (2) m-CPBA, NaHCO3, CH2Cl2, 91% over 2 steps; (b) Cp2TiCl2, Zn (1.5 eq.),
2,4,6-collidine$HCl (3 eq.), THF, 23 C, 74%; (c) PivCl, Et3N, THF, then S,S-pseudoephedrine, 82%; (d) LDA, LiCl, THF, ICH2CH2OTBS, 92%; (e) (1)
BH3 NH3, LDA, THF; (2) I2, PPh3, imid, CH2Cl2, 85% over 2 steps; (f) LHMDS, 4 : 1 THF/HMPA, 0 C to 23 C, 74%; (g) KHMDS, 78 C, PhSeBr, then
H2O2, 81%; (h) (1) H2SiF6, MeCN; (2) DMP, CH2Cl2, 86% over 2 steps; (i) SmI2, LiBr, t-BuOH, THF, 78 C, 54%; (j) Ac2O, TMSOTf, CH2Cl2, 74%; (k)
(1) O3, CH2Cl2, Et3N; (2) Et3N, CH2Cl2, 80% over 2 steps; (l) 1 : 1 MeOH/H2O, 1 M NaOH, 38%.
structures (816 and 826), an advanced structure that contained oen necessary for intermolecular Diels–Alder reactions with
additional functionality and the stereochemical elements (833) aldehydes (Scheme 41).233
of maoecrystal V was prepared (Scheme 39).231 4.1.10 Approaches by Mobin’s group. An approach for
4.1.8 Approaches by Trauner’s group. A synthetic strategy creating a tricyclic ring system containing bridged bicyclo[2.2.2]
for the establishment of contiguous quaternary stereocenters of octanone annulated with a lactone ring in maoecrystal V was
maoecrystal V was explored. It was shaped by the necessity to described. The key features of this approach involved the in situ
manoeuvre in sterically hindered molecular environments generation of spiro-epoxy-cyclohexa-2,4-dienone (863) and
(Scheme 40).232 intramolecular cycloaddition (from 863 to 864) (Scheme 42).234
4.1.9 Approaches by Chisholm’s group. An intramolecular 4.1.11 Approaches by Jeremy’s group. An alternative
Diels–Alder route employing an aldehyde dienophile was synthetic strategy that formed the central bond of maoecrystal V
explored for the synthesis of maoecrystal V. The intramolecular (874) through a bridgehead C–H bond insertion was described
nature of this reaction allowed the use of aldehydes as dien- (Scheme 43). The vicinal quaternary carbon was also
ophiles without the use of highly activated dienes, which is
Scheme 46 Reagents and conditions: (a) LDA, (CHO)n, THF, 78 C to 0 C, 72%; (b) NaBH4, THF/H2O, 25 C; (c) DMP, NaHCO3, CH2Cl2, 25 C,
84% over 2 steps from 895; (d) n-BuLi, HMPA, THF, 78 C to 25 C, 75%; (e) LiAlH4, THF, 0 C; (f) acryloyl chloride, DIPEA, CH2Cl2, 78 C, 84%
over 2 steps from 898; (g) BHT, toluene, sealed tube, 190 C; (h) TsOH, 120 C, sealed tube, (i) K2CO3, MeOH, 25 C, 80% over 3 steps from 899; (j)
TBSCl, imidazole, DMF, 25 C, 95%; (k) LDA, THF, 78 C, HMPA; (l) 904, 0 C, 88% over 2 steps from 903; (m) Et3B, (TMS)3SiH, PhH, 25 C, 68%;
(n) SeO2, TBHP, CH2Cl2, 25 C; (o) DMP, NaHCO3, CH2Cl2, 25 C; (p) 1 M HCl, THF, 25 C, 80% over 3 steps from 906.
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Scheme 47 Reagents and conditions: (a) MeMgBr (1.2 eq.), CuI (5 mol%), LiCl (10 mol%); then CH2O, 88%; (b) TBDPSCl (1.1 eq.), Im (2.1 eq.), 98%;
(c) TMSCH2CO2Et (2.0 eq.), LDA (2.0 eq.), 57% (87% brsm); (d) Me(OMe)NH$HCl (2.0 eq.), iPrMgCl (4.0 eq.), 85%; (e) 909 (1.2 eq.), 95%; (f) (1) AlCl3
(2.0 eq.); (2) TBSCl (1.1 eq.), Im (2.1 eq.), 80%; (g) 912 (4.0 eq.), tBuLi (8.0 eq.), (2-thiophene)-Cu(CN)Li (4.0 eq.), BF3$Et2O (4.0 eq.), 78%; (h) (1) 10%
HF, acetonitrile; (2) Grieco reagent (2.5 eq.), Bu3P (3.0 eq.); then H2O2 (50 eq.), 71%; (i) (1) TMSOTf (6.0 eq.), NEt3 (8.0 eq.); (2) MeLi (1.2 eq.), allyl
iodide (5.0 eq.) 57%; (j) Grubbs II (5 mol%), 91%; (k) PdCl2 (25 mol%), CuCl (1.5 eq.), O2; (l) KHMDS (1.5 eq.), Comins reagent (4.0 eq.); (m) (1) TMSOTf
(15 eq.), NEt3 (20 eq.); (2) MeLi (3.0 eq.) MoO5, Py, HMPA (5.0 eq.), 67%; (n) SeO2 (2.0 eq.), tBuOOH (1.2 eq.); (o) TMSOTf (15 eq.), NEt3 (20 eq.); (p)
O3, methanol; (q) LiBH4, 50 C, 47%; (r) TBAF (5.0 eq.), 38%; (s) MnO2 (5.0 eq.).
successfully constructed (879) by enolate functionalization a diastereoselective SmII-mediated reductive cascade cyclization
(Scheme 44).235 reaction (from 890 to 891) (Scheme 45).9,10
4.2 Total synthesis of maoecrystal Z

Maoecrystal Z (443) was the rst ent-kaurane diterpenoid with 4.3 Total synthesis of sculponeatin N
a novel 6,7:8,15-di-seco-6,8-cyclo skeleton from the genus Iso- As mentioned before, due to the repetition of the name, 74 was
don. It exhibited a signicant inhibitory effect against K562, renamed sculponeatin N1, and 420 is still named sculponeatin
MCF-7, and A2780 tumor cell lines.152 Due to the intriguing N. Sculponeatin N is a 6,7-seco-ent-kaurane diterpenoid from I.
structure and interesting biological activity, maoecrystal Z was sculponeata, and it comprises a spiro- and bridged-ring system
attractive to synthetic chemists. as well as ve stereogenic centers. Additionally, sculponeatin N
The rst total synthesis of ()-maoecrystal Z was accom- exhibited cytotoxicity against K562 and HepG2 human tumor
plished in 12 steps from ()-g-cyclogeraniol in 2011. The key cell lines with IC50 values of 0.21 and 0.29 mM, respectively.136
steps included a diastereoselective TiIII-mediated reductive The fascinating structure and interesting bioactivity of 420
epoxide coupling reaction (from 881 to 883) and encouraged synthetic chemists to pursue its total synthesis.
Scheme 48 Reagents and conditions: (a) (1) n-Bu4NHSO4, p-TsOH, MeOH, 0 C; (2) DMP, DCM, 77% over 2 steps; (b) SmI2, LiBr, t-BuOH, THF,
78 C, 57%; (c) MOMCl, n-Bu4NI, DIPEA, DMF, 45 C, 91%; (d) KHMDS, TBSCl, DMPU, THF, 78 C, 85%; (e) PdII, DMSO, 45 C, air; (f) O3, DCM,
94 C; then PPh3, 69%; (g) Me2NCH2NMe2, Ac2O, DMF, 95 C, 82%; (h) (1) 6 M aq. HCl, dioxane, 45 C; (2) TEMPO, Phl(OAc)2, DCM, 73% over 2
steps.
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used to generate an all-carbon quaternary center and the

bicyclo[3.2.1]octane framework was one of the key steps
(Scheme 48).9,11
4.5 Total synthesis of longikaurin E

The total synthesis of longikaurin E, along with trichorabdal A,
has also been reported. The synthetic strategy is similar to that
of ()-trichorabdal A (Scheme 49).9,11
Scheme 49 Reagents and conditions: (a) 6 M aq. HCl, dioxane, 45 C, 4.6 Total synthesis of S-trans-12E,14-labdadien-20,8b-olide
89%; (b) (1) TEMPO, PhI(OAc)2; (2) Ac2O, DMAP, 58% over 2 steps; (c)
SmI2, THF, 23 C, 55% (75% brsm); (d) (1) O3, DCM, 94 C; then PPh3; S-trans-12E,14-labdadien-20,8b-olide (591) was reported as
(2) Me2NCH2NMe2, Ac2O, DMF, 95 C, 44% over 2 steps. a new labdane diterpenoid from I. yuennanensis in 2015 by Jiang
Bei et al.199
The rst total synthesis of S-trans-12E,14-labdadien-20,8b-
Recently, two groups accomplished the total synthesis of scul- olide (591) was achieved in 14 steps from (+)-sclareolide. The
poneatin N. synthesis features a Barton nitrite ester reaction to introduce

4.3.1 Approaches by Zhai’s group. A 13-step total synthesis oxime at the angular methyl group and Jones oxidation to
of ()-sculponeatin N was achieved by Zhai and co-workers. The construct the lactone segment (Scheme 50). With the total
strategy included a regio- and stereo-selective aldol reaction to synthesis achieved, the absolute stereochemistry of this natural
form a lactone (from 894 to 895), an intramolecular Diels–Alder diterpenoid was determined by comparing the optical rotation
reaction to install B and C rings (from 899 to 900) simulta- of a synthetic sample to a natural sample.236
neously, and a radical cyclization (from 905 to 906) to create the
D ring (Scheme 46).12 5 Conclusions
4.3.2 Approaches by Thomson’s group. The other total
synthesis of ()-sculponeatin N was reported at the same time as The rst review on diterpenoids from Isodon species was pub-
Zhai’s study. Key features of the synthesis include diaster- lished by E. Fujita et al. in 1984 and introduced 108 new diter-
eoselective Nazarov and ring-closing metathesis reactions as well penoids.2 Since then, 518 new diterpenoids were summarized in
as a highly efficient formation of the bicyclo[3.2.1]octane ring our previous review from 2006.3 Including the 609 new diter-
system through a reductive radical cyclization (Scheme 47).13 penoids discussed in this review, more than 1200 diterpenoids
have been isolated and identied from the genus Isodon. Well-
known molecules with interesting biological activity, such as
4.4 Total synthesis of trichorabdal A eriocalyxin B (610), oridonin (611), ponicidin (612), and ade-
With 889 in hand, which is an intermediate product in the nantin (614), along with some compounds that have fascinating
process of the total synthesis of maoecrystal Z, the total structures, such as maoecrystals V (619) and Z (443), have
synthesis of ()-trichorabdal A was accomplished. A Pd- attracted substantial attention from pharmacologists and
mediated oxidative cyclization of a silyl ketene acetal was synthetic chemists all over the world. The efforts to discover
Scheme 50 Reagents and conditions: (a) LiAlH4, THF, 0 C; (b) Ac2O, Py, DMAP, DCM, 0 C, quant. over two steps; (c) SO2Cl2, Py, DCM, 78 C;
(d) K2OsO4$H2O, NMO, then NaIO4, acetone/H2O, rt, 62% over two steps; (e) MeLi, THF, 78 C; (f) Ac2O, Py, DMAP, 83% over two steps; (g)
NOCl, Py, 40 C; (h) 450 W Hg lamp, acetone, rt, 43% over two steps; (i) Jones reagent, acetone, 0 C, 69%; (j) K2CO3, MeOH, rt, 95%; (k) IBX,
ethyl acetate, 80 C, 98%; (l) Ph3P ¼ CH2, THF, 0 C, 83%; (m) 2nd Grubbs cat. DCM, reflux, 73%; (n) Ph3P ¼ CH2, THF, 0 C, 91%.
View Article Online
novel diterpenoids with interesting biological activity and 17 Y. Lu, B. Chen, J. H. Song, T. Zhen, B. Y. Wang, X. Li, P. Liu,
intriguing structures from Isodon species have long been a hot X. Yang, Q. L. Zhang, X. D. Xi, S. D. Chen, J. P. Zuo, Z. Chen
topic in natural products chemistry. The current research on and S. J. Chen, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 2258–
Isodon species is still going strong.31 The increasing interest in 2263.
diterpenoids from the plants of the genus Isodon may promote 18 C. X. Liu, Q. Q. Yin, H. C. Zhou, Y. L. Wu, J. X. Pu, L. Xia,
new progress in nding and developing lead compounds. W. Liu, X. Huang, T. Jiang, M.-X. Wu, L. C. He,
Additionally, accompanied by new achievements in biosyn- Y. X. Zhao, X. L. Wang, W. L. Xiao, H. Z. Chen, Q. Zhao,
thesis, the biosynthetic pathways for some diterpenoids from A. W. Zhou, L. S. Wang, H. D. Sun and G. Q. Chen, Nat.
the genus Isodon will also be disclosed. Chem. Biol., 2012, 8, 486–493.
19 H. Z. Xu, Y. Huang, Y. L. Wu, Y. Zhao, W. L. Xiao, Q. S. Lin,
H. D. Sun, W. Dai and G. Q. Chen, Cell Cycle, 2010, 9, 2897–
6 Acknowledgements 2907.
20 Z. M. Gu, Y. L. Wu, M. Y. Zhou, C. X. Liu, H. Z. Xu, H. Yan,
Related work in our laboratory was nancially supported by the
Y. Zhao, Y. Huang, H. D. Sun and G. Q. Chen, Blood, 2010,
NSFC-Joint Foundation of Yunnan Province (Grant U1302223),
116, 5289–5297.
and the National Natural Science Foundation of China (Grants
21 Z. B. Xiang, X. Y. Liu and X. H. Li, Pharm. Chem. J., 2015, 48,
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Diterpenoids from Isodon species: An update

Article in Natural Product Reports · July 2017

Miao Liu Wei-Guang Wang

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Diterpenoids from Isodon species: an update†

Received 21st April 2017

1 Introduction 2.9 Other tricyclic diterpenoids

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During this time, some mini reviews have summarized studies

potential antitumor properties. 2 Structures, classiﬁcations, and

Wei-Guang Wang obtained his Jian-Xin Pu joined Prof. Han-

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Scheme 2 Proposed major biogenetic pathways and classiﬁcations of ent-kauranes.

Scheme 3 Proposed biogenetic relationships of diﬀerent types of ent-kauranes.

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Scheme 4 Proposed biogenetic relationships of diﬀerent types of ent-kauranes.

Scheme 5 Proposed biogenetic relationships of diﬀerent types of ent-kauranes.

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2.2.1.2 3,20-Epoxy-ent-kauranes. This type of ent-kaurane is trione (285),67 6-hydroxy-15b-acetoxy-3a,20-epoxy-16b,17-

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Isorosthornin F (289, from I. rosthornii) is a 3, 20-epoxy-ent-

2.2.1.3 11,20-Epoxy-ent-kauranes. Only ten 11,20-epoxy-ent-

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2.2.4 C-20 oxygenated non-epoxy ring ent-kauranes. Iso-

2.2.3 7,20-Lactone-ent-kauranes. During the last decade,

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bonds of 7,20-epoxy-ent-kauranes. Before 2006, there were 105

lated from I. phyllostachys. Both 337 and 338 were found as

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hydroxy-6,7-seco-6,11b:6,20-diepoxy-1a,7-olide-ent-kaur-16-ene Another example of this subgroup is isorosthin B (395), which

from I. serra),130,131 15a,20-dihydroxy-6,7-seco-ent-kaur-16-ene- There are three 3,6:6,20-diepoxy-enmein-type ent-kauranes

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ent-Kaurane diterpenoids with a four-ring substructure seco-ent-kaur-16-en-7,20-olide, and 6-aldehyde-1a,19-diacetoxy-

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these compounds, the absolute congurations of 423 and 436

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15,16-seco-ent-kaurane found aer the identication of rubes-

a novel 6,7:8,15-diseco-6,8-cyclo skeleton was reported in I. eriocalyx by

then maoecrystal Z (Scheme 7).152 The transformation from trichor-

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2.5 Diterpene dimers

a [2 + 2] cycloaddition reaction based on two monomers.164 Two

is oxidative cleavage of the bond between C-150 and C-160 .166

Scheme 9 Proposed biogenetic pathway for bispseurata F (455).

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2.6 Miscellaneous ent-kauranes (diterpene alkaloids with an

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Scheme 11 Proposed biogenetic pathway for parvifoline X (485).

Luanchunin A (487) is a novel ent-kaurane obtained from the

Scheme 14 Proposed biogenetic pathways for ternifolides A and B

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plausible biogenetic pathway from 416 to 416b and then to 492

Scheme 17 Proposed biogenetic pathways for neolaxiﬂorins A and B