Review

Cite This: Chem. Rev. XXXX, XXX, XXX−XXX pubs.acs.org/CR

Research Progress of Polycyclic Polyprenylated Acylphloroglucinols

Xing-Wei Yang,† Robert B. Grossman,‡ and Gang Xu*,†
†
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of
Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People’s Republic of China
‡
Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, United States
*
S Supporting Information

ABSTRACT: Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid

natural products sharing the mevalonate/methylerythritol phosphate and polyketide
biosynthetic pathways and showing considerable structure and bioactivity diversity. This
review discusses the progress of research into the chemistry and biological activity of 421
natural PPAPs in the past 11 years as well as in-depth studies of biological activities and
total synthesis of some PPAPs isolated before 2006. We created an online database of all
PPAPs known to date at http://www.chem.uky.edu/research/grossman/PPAPs. Two
subclasses of biosynthetically related metabolites, spirocyclic PPAPs with octahydrospiro-
[cyclohexan-1,5′-indene]-2,4,6-trione core and complicated PPAPs produced by intra-
molecular [4 + 2] cycloadditions of MPAPs, are brought into the PPAP family. Some
PPAPs’ relative or absolute configurations are reassigned or critically discussed, and the confusing trivial names in PPAPs inves-
tigations are clarified. Pharmacologic studies have revealed a new molecular mechanism whereby hyperforin and its derivatives
regulate neurotransmitter levels by activating TRPC6 as well as the antitumor mechanism of garcinol and its analogues. The
antineoplastic potential of some type B PPAPs such as oblongifolin C and guttiferone K has increased significantly. As a result of
the recent appearances of innovative synthetic methods and strategies, the total syntheses of 22 natural PPAPs including
hyperforin, garcinol, and plukenetione A have been accomplished.

CONTENTS 6.1.1. Hyperforin and Its Synthetic Derivatives Y

1. Introduction
2. Classification of Diverse PPAPs
2.1. Bicyclic Polyprenylated Acylphloroglucinols
(BPAPs)
2.1.1. Type A BPAPs
2.1.2. Type B BPAPs
2.1.3. seco-BPAPs
2.2. Caged PPAPs with Adamantane and Homo-
adamantane Skeletons
2.2.1. Adamantane-Type PPAPs
2.2.2. Homoadamantane-Type PPAPs
2.3. Other PPAPs
2.3.1. Spirocyclic PPAPs with Octahydrospiro-
[cyclohexan-1,5′-indene] Core
2.3.2. Complicated PPAPs via Intramolecular
[4 + 2] Cycloadditions from MPAPs
3. Investigation of Certain PPAPs’ Configurations
3.1. Relative Configuration of C-7 for Certain
BPAPs
3.2. Reassignment of Some PPAPs’ Relative
Configuration on Other Locations
3.3. Investigation of the Absolute Configurations
of Certain PPAPs
4. Consolidation of Some PPAPs’ Trivial Names
5. Living Database of PPAPs
6. Biological Activities of PPAPs
6.1. Biological Activities of Type A BPAPs
6.1.2. Nemorosone and 7-epi-Nemorosone Z
B 6.1.3. Garcinielliptone FC Z
B 6.2. Biological Activities of Type B BPAPs Z
6.2.1. Garcinol and Its Derivatives Z
H 6.2.2. Clusianone and 7-epi-Clusianone Z
H 6.2.3. Guttiferone A and Its Derivatives Z
H 6.2.4. Oblongifolin C and Guttiferone K AA
H 6.3. Biological Activities of Other PPAPs AB
7. Synthetic Chemistry of PPAPs AB
N 7.1. Shibasaki’s Total Syntheses of ent-Hyper-
N forin and Garsubellin A AB
O 7.2. Shair’s Enantioselective Total Syntheses of
Q (+)-Hyperforin and (−)-Nemorosone AB
7.3. Barriault’s Total Syntheses of Hyperforin and
Q Papuaforins A−C AD
7.4. Maimone’s Total Synthesis of Hyperforin AF
Q 7.5. Nakada’s Syntheses of Hyperforin, Nemor-
Q osone, Garsubellin A, and Clusianone AG
7.6. Danishefsky’s Total Syntheses of Nemoro-
Q sone, Clusianone, and Garsubellin A AH
7.7. Simpkins’s Total Syntheses of Nemorosone
W and Clusianone AH
7.8. Plietker’s Total Syntheses of a Series of Type
X B PPAPs AI
X
X
X
Y Received: September 12, 2017

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7.8.1. Oblongifolin A, 7-epi-Clusianone, Hyper-
ibone L, and Hyperpapuanone AI
7.8.2. Hyperibone I, Sampsonione P, (+)-Clu-
sianone, Garcinol, and Isogarcinol AI
7.8.3. Guttiferone A AJ
7.9. Porco’s Total Syntheses of PPAPs Using
Alkylative Dearomatization Strategy AJ
7.9.1. (−)-Hyperibone K and Clusianone AJ
7.9.2. Plukenetione A and 7-epi-Nemorosone AK
7.9.3. Asymmetric Syntheses of (−)-Clusia-
none and Non-natural PPAPs AK
7.10. Biomimetic Syntheses of PPAPs Using
Radical Cyclization AL
8. Summary and Future Directions AL
Associated Content AM
Supporting Information AM
Author Information AM
Corresponding Author AM
ORCID AM
Notes AM
Biographies AM
Acknowledgments AM
References AM
1. INTRODUCTION
Polycyclic polyprenylated acylphloroglucinols (PPAPs), pos-
sessing highly oxygenated acylphloroglucinol-derived cores deco-
rated with isoprenyl or geranyl side chains, are a group of struc-
turally fascinating and synthetically challenging natural products
that collectively exhibit a broad range of biological activities.
Biogenetically, PPAPs are derived from a “mixed” mevalonate/
methylerythritol phosphate and polyketide biosynthetic path-
way.1 Their acylphloroglucinol cores are produced by a charac-
teristic polyketide-type biosynthesis involving the condensation
of one acyl-CoA and three malonyl-CoA units.2−5 Prenylation of
this core moiety affords monocyclic polyprenylated acylphlor-
oglucinols (MPAPs), which may be further cyclized to PPAP-
type metabolites with diverse carbon skeletons.2−5 The type of
acyl groups, the number and position of isoprenyl substituents,
the degree of oxidation of isoprenyl side chains and corre-
sponding locations of ether rings, and different types of sec-
ondary cyclization (such as aldol, Diels−Alder, etc.) create PPAPs’
structural diversity and complexity. Interestingly, this special
class of hybrid natural products has been exclusively isolated
from the plants of family Guttiferae (Clusiaceae) and mainly
from the genera Hypericum and Garcinia with only a few excep-
tions, discussed later.
The first PPAP to be identified, hyperforin, was isolated in
1971 from H. perforatum (St. John’s wort) and is now consid-
ered to be the main constituent of the medicinal herb respon-
sible for its antidepressant activity.6,7 The separation and struc-
tural identification of PPAPs were difficult because their physical
and chemical properties were similar to each other, which hin-
dered the progress of comprehensive research into this type of
metabolite. Up to 2005, only 119 members belong to the PPAP
family had been reported according to Ciochina and Gross-
man’s review in 2006.8 With the development of techniques of
separation and structural identification, a total of 421 natural
PPAPs with various skeletons were reported in the past decade.
Two new classes of biosynthetically related metabolites, spirocyclic
PPAPs with octahydrospiro[cyclohexan-1,5′-indene]-2,4,6-tri-
one core and complicated PPAPs via intramolecular [4 + 2]
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cycloadditions of MPAPs, emerged in large numbers. Mean-
while, the structures of all of the type C PPAPs were revised to
the corresponding type A structures,9 and several other PPAPs’
skeletons and configurations were also clarified. Furthermore,
pharmacologic studies revealed a new molecular mechanism of
hyperforin and its derivatives whereby they regulate neurotrans-
mitters by activating transient receptor potential channel 6
(TRPC6)10 as well as the antitumor mechanism of garcinol and
its analogues. The antineoplastic potential of some recently iso-
lated type B PPAPs such as oblongifolin C and guttiferone K is
increasing significantly. In addition, as a result of the recent appear-
ances of innovative synthetic methods and strategies, the total
syntheses of 22 complex natural molecules, such as hyperforin,
clusianone, and plukenetione A, have been achieved. In partic-
ular, the remarkable contributions from the research groups of
Plietker, Porco, Jr., and Maimone et al. ushered in the peak
period of PPAPs synthesis.
Some minireviews related to partial aspects of PPAPs have
been presented. Prenylated acylphloroglucinols and their bioac-
tivities from genera Hypericum and Garcinia, respectively, have
been summarized in different years.11−14 It is noteworthy that
some reviews emphasized the well-known hyperforin and garcinol
and aspects of their chemistry and bioactivities, including anti-
depressant and antitumor activities.10,15−22 The organic synthe-
sis progress of PPAPs has also been reviewed before 2013.23−25
In addition, some reviews about the chemistry and bioactivities
of natural phloroglucinol derivatives and benzophenones, which
involved some of the PPAPs, have been published.26−28 How-
ever, none of them gave general insight into the chemistry and
biological activities of PPAPs.
During our investigations on the biologically active PPAPs
from Guttiferae, we noticed confusion and ambiguity about PPAPs
in the literature. (i) Some PPAPs’ relative configurations were
assigned incorrectly, perhaps because the key NOE signals were
deficient or overlapped in their NOESY spectra. (ii) Certain
PPAPs’ absolute configurations as assigned by their optical rota-
tions or determined by comparison of their experimental and
calculated ECDs were not reliable. (iii) Some PPAPs were given
the same nomenclature but had different structures, while some
PPAPs had the same structure but different names.
This review summarizes the progress of research into the
chemistry and biological activity of 421 natural PPAPs in the
past 11 years (from 2006 to June 30, 2017) as well as the in-depth
studies of biological activities and total synthesis of some prom-
ising PPAPs reported before 2006. Some PPAPs’ relative or abso-
lute configurations are reassigned or critically commented upon.
Furthermore, we try to clarify the confusing trivial names in
PPAPs investigations. In addition, we created a freely accessible
Web site at http://www.chem.uky.edu/research/grossman/
PPAPs that shows structures, names, plant sources, specific
rotations, and hyperlinked references to the original literature
for all PPAPs known to date. We will continue to add new
PPAPs to the database as they are discovered and to modify the
entries as new information comes to light.
2. CLASSIFICATION OF DIVERSE PPAPS
Previously, the various PPAPs have been divided into types A,
B, and C depending on the relative position of the acyl group
on the phloroglucinol core.8,29 However, the structural assign-
ments of type C PPAPs were problematic and doubtful. In fact,
the investigations before 2003 involved the structural revisions
of three type C PPAPs, nemorosone, hydroxynemorosone, and
7-epi-nemorosone.8,29,30 In 2017, the structures of all of the
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remaining type C PPAPs, garcinielliptones K−M,31 were revised
to corresponding type A structures (24, 23, and 18) by our team
via NMR spectroscopic and quantum computational chemistry
methods (Scheme 1).9 The positions of the bridgehead
Scheme 1. Skeleton Reassignment of Type C PPAPs
substituents (the acyl and isoprenyl groups) in these com-
pounds and the enolic β-diketone system in 18, 23, and 24
were all switched from their originally assigned positions. There-
fore, only type A and B PPAPs are likely present in plants of the
family Guttiferae.9
In this review, we provide a new classification of PPAPs; and
Cuesta-Rubio and Grossman’s classification into types A and B
will continue to be used as subclassification.29 Biogen-
etically, PPAPs are all derived from a common biosynthetic
pathway via different cyclizations of the less complex mono-
cyclic polyprenylated acylphloroglucinols (MPAPs).1−5,8 All of
the PPAP profiles are generated via three major biosynthetic path-
ways and may be divided into three groups (I−III) according to
their different scaffolds (Scheme 2).1 The bicyclic polyprenylated
acylphloroglucinols (BPAPs) with major bicyclo[3.3.1]nonane-
2,4,9-trione core (1−243, Tables 1 and 2) and related seco-
BPAPs (244−263, Table 3) are classified as group I and com-
prise approximate 60% of PPAPs. The caged PPAPs with
adamantane (tricyclo[3.3.1.1]decane) (264−296, Table 4) and
homoadamantane (tricyclo[4.3.1.1]undecane) (297−345, Table 5)
Scheme 2. Proposed Biosynthetic Pathways to the PPAPs: from Polyketides to Acylphloroglucinols to Diverse PPAP-Type
Derivatives
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skeletons, derived via the enolic C-3 cyclizing onto C-27 and
C-28 of normal endo-BPAPs, respectively, are included in group II
and consist of 82 members. Other biosynthetically related metab-
olites, derived from direct cyclizations of MPAPs rather than via
formation of the BPAPs, are also brought into the PPAP family
and assigned to group III. This group contains two subclasses:
spirocyclic PPAPs with an octahydrospiro[cyclohexan-1,5′-
indene]-2,4,6-trione core (346−391, Table 6) and complicated
PPAPs (392−421, Table 7) derived from intramolecular [2 + 4]
cycloadditions of MPAPs.
Interestingly, 18 BPAPs, hyperibine J (2) from H. perforatum
and H. triquetrifolium,32,33 hypermongones A−J (21, 28, 20, 27,
44, 54, 43, 53, 45, 46) from H. monogynum,34 hyperscabrones
C (110), D (111), and G (98) from H. scabrum,35 and
ascyronones A−D (259, 260, 255, 100) from H. ascyron36 as
well as some spirocyclic PPAPs from genus Hypericum37−42
feature a methyl substituent at C-5 rather than a prenyl or geranyl
group in most of other PPAPs. It suggests that not only
prenylation but also methylation may occur in the acylphlor-
oglucinol cores to form the MPAP intermediates in these
plants, which enriches the structural diversity of PPAPs.
In literature surveys, many PPAPs have been classified into
the benzophenone family.28 However, the benzoyl or hydroxy-
lated benzoyl group in many PPAPs is just a substituent acyl
group rather than part of the PPAPs’ basic phloroglucinol
architecture. The acyl group in PPAPs can also be an isobutyryl,
2-methylpentanoyl, or 3-methylpentanoyl (isovaleryl) group.
To date, this special class of hybrid natural products has been
almost exclusively isolated from the plants of family Guttiferae.
However, there are two exceptions in recent years. Two BPAPs
(101 and 134) have been isolated from Spiranthera odoratissima
(Rutaceae),43 and five spirocyclic PPAPs (353, 354, 376−378)
obtained from Harrisonia perforate (Simaroubaceae) have been
reported.44 These findings expand plant resources for diverse
PPAPs.
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Table 1. Type A BPAPs

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Table 1. continued

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Table 1. continued

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Table 1. continued

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Table 1. continued

a
C. = Clusia, G. = Garcinia, H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, e = EtOH, m = MeOH).
c
The absolute configuration is known to be as shown. dThe C-7 relative configuration was reassigned according to the method of Grossman and
Jacobs. eThe absolute configurations of C-1 and C-5 are assigned by comparison of its experimental and calculated ECD. fNot all of the
stereocenters’ configurations have been assigned. gThe original structures were incorrectly drawn by mistake and reassigned as shown. hTwo
compounds with identical NMR data were reported almost simultaneously (The other name, hypersampsone S, has been used previously88), but
opposite configurations were assigned in the cyclohexane substituent. iThe original assignment of the C-7 relative configuration is probably incorrect
according to the rule of Grossman and Jacobs.

In order to facilitate the following analysis and discussion, we
unified the numbering of the bicyclo[3.3.1]nonane core for
both type A and type B BPAPs, as shown in Scheme 2.
2.1. Bicyclic Polyprenylated Acylphloroglucinols (BPAPs)
2.1.1. Type A BPAPs. As shown in Table 1, this subclass
includes 114 BPAPs in which the acyl group is located at
the C-1 position. Interestingly, the majority of the type A
BPAPs (102 members) are obtained from the genus Hyper-
icum.62,69,70,73,75,79,80,82 The vast majority, compounds 1−112,
share a common bicyclo[3.3.1]nonane-2,4,9-trione core. By con-
trast, hypercohin A (113) possesses an unusual bicyclo[5.3.1]-
hendecane core. Compound 113, isolated from H. cohaerens, is
the first PPAP featured with an eight-membered ring B, and its
absolute configuration was determined by single-crystal X-ray
diffractions of its p-bromobenzoate ester.45 Takaneone C (114),
reported by Tanaka et al.,46 is the first type A BPAP that pos-
sesses a basic bicyclo[3.2.1]octane-2,4,8-trione core, and further
cyclization of the C-5 and C-6 side chains makes it bear a more
complicated tricyclic carbon system. It is noteworthy that the
BPAPs that keep an enolic β-diketone system in their struc-
tures, such as 1−5, are usually obtained as keto−enol tau-
tomeric mixtures, doubling the signals present in their 1H and
13
C NMR spectra.33,47−49 The prenyl or geranyl side chains at
C-3 and C-5 as well as the prenylmethyl group at C-8 are prone
to be oxidized and further cyclized with O-2 or O-4 to form
furan, pyran, etc., substructures in 6−96 and 105−113, which
thereby hinders keto−enol tautomerism of these BPAPs.
In addition, C-3 of type A structures are also easily oxidized
and further generate 3,9-hemiketal form, as exemplified by
97−104.
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2.1.2. Type B BPAPs. This subclass, whose acyl groups
are located at the C-3 position, comprises 129 members
(Table 2).95,96,111,112,120,122,124−128,132,134,135 Most of the type B
BPAPs are obtained from the genus Garcinia, and the majority
of them share a characteristic hydroxylated benzoyl group.
It has been found that the enolic β-diketone system and 3,
4-dihydroxybenzoyl substituents in the structures of type B
BPAPs are important for their anticancer activities.89,90 Com-
pounds 115−236 possess the same bicyclo[3.3.1]nonane-2,4,
9-trione core, whereas 241−243 feature a rare bicyclo[4.3.1]-
decane-2,4,9-trione core. Yezo’otogirins E (237) and F (238),
isolated from H. yezoense and takaneones A (239) and B (240)
obtained from H. sikokumontanum, share a basic bicyclo[3.2.1]-
octane-2,4,8-trione core; further cyclization of the C-1 and C-7
side chains gives them a more complicated tricyclic carbon sys-
tem.46,91 It is noteworthy that in only three BPAPs, oblongifolin
M (170),92 garciesculentone A (191),93 and paucinone C (207),94
an oxygen atom is inserted between C-3 and the acyl group
to form an ester moiety. Type B BPAPs that possess a 3,
4-dihydroxybenzoyl substituent are prone to be oxidized (C-6
position of benzene) and further cyclized with O-2 or O-4 to
form a fused tetracyclic system, as shown in 218−236.
2.1.3. seco-BPAPs. Twenty seco-BPAPs are listed in
Table 3.139 Among them, compounds 244−261 are type A deriv-
atives, whereas 262 and 263 are type B derivatives. Compounds
244−260 are suggested to be 1,9-seco-BPAPs, which are derived
from 3,9-hemiketal precursors such as 97, and 261−263 are
considered to be 1,2-seco-BPAPs. In fact, 244 was isolated from
H. perforatumin and named perforatumone early in 2004138 but
assigned an incorrect skeleton with a seven-membered carbon
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Table 2. Type B BPAPs

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Table 2. continued

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Table 2. continued

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Table 2. continued

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Table 2. continued

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Table 2. continued

a
C. = Clusia, G. = Garcinia, H. = Hypericum, M. = Moronobea, S. = Symphonia. bThe values in parentheses are the concentration and the solvent
(a = acetone, c = CHCl3, e = EtOH, m = MeOH). cNot all of the stereocenters’ configurations have been assigned. dThe absolute configuration is
known to be as shown. eThe C-7 configuration was reassigned (see text). fThe original assignment of the C-7 relative configuration is probably
incorrect according to the rule of Grossman and Jacobs. gThe original name, guttiferone I, has been used previously, and we rename as 13-deoxy-
guttiferone J. hThe absolute configurations of C-1 and C-5 are assigned by comparison of its experimental and calculated ECD. iPairs of isolates with
positive and negative optical values, respectively, may be enantiomers. jIt may be an enantiomer of (+)-cycloxanthochymol according to its negative
optical value. kThe original absolute configuration was reassigned. lIts C-4 stereocenter was not assigned, and the C-7 relative configuration was
incorrectly drawn by mistake in the original paper; hence, it may be enantiomeric to symphonone I. mThe original name, guttiferone O, has been
used previously, and we rename as oxy-oblongifolin A.

core. In 2015, the structure was revised to hyphenrone A (244)
by NMR spectroscopic analysis and biomimetic synthesis from
3-hydroxyhyperforin-3,9-hemiketal via 244 into hyphenrone
F (254) (Scheme 3).1 The final single-crystal X-ray diffraction
analysis of 254 suggested that the structure of perforatumone
was identical or enantiomeric to that of hyphenrone A (244).
Also, the structure of its derivative, attenuatumione B (249),60
was revised to share the same eight-membered carbon core fused
by a γ-lactone ring as that of 244.87 The structures of hyphenrone
N DOI: 10.1021/acs.chemrev.7b00551
C and I (256 and 257), featuring a 5/8/5 fused ring system, and
hyphenrone D (258), with an unprecedented 6/6/5/8/5 fused
ring system, are suggested to be derived from the less compli-
cated 1,9-seco-BPAP precursors 244−246 via aldol condensation
and intermolecular Diels−Alder cycloaddition, respectively.1,85
2.2. Caged PPAPs with Adamantane and
Homoadamantane Skeletons
2.2.1. Adamantane-Type PPAPs. It was once assumed
that living organisms could not synthesize adamantane derivatives,
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Table 3. seco-BPAPs

a
H. = Hypericum. bThe values in parentheses are the concentration and the solvent (a = acetone, c = CHCl3, e = EtOH, m = MeOH). cThe absolute
configuration is known to be as shown. dNot all of the stereocenters’ configurations have been assigned.

whose synthesis was considered purely abiotic.141 However, this
view was finally refuted in 1996 when plukenetione A, the first
adamantane-type PPAP, was isolated from the Clusia plukenetii.142
As shown in Table 4,146 this subclass includes 33 PPAPs with a
“diamond-like” caged core (264−282 and 288−295) or related
seco-scaffolds (283−287 and 296). Among them, compounds
264−287 and 288−296 are derived from corresponding type A
and B BPAP precursors, respectively. Two secondary skeletons
with tetracyclo[7.3.1.13,11.03,8]tetradecane (276 and 277) and
tetracyclo[6.3.1.13,10.03,7]tridecane (278−282) cores are derived
by the further cyclization of C-18/C-29 and C-18/C-28, respec-
tively, from the normal adamantane-type PPAP precursors.1
2.2.2. Homoadamantane-Type PPAPs. As shown in
Table 5,152,154,157,162 49 members of the homoadamantane-type
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PPAPs, which share a common tricyclo[4.3.1.1]undecane core
(except for 345 with its tricyclo[4.2.1.1]decane skeleton),
all have type A structures. Compounds with a tetracyclo-
[7.3.1.13,11.03,7]tetradecane core (320−344) are secondarily
derived from C-18/C-29 cyclization in the homoadamantane-
type PPAPs. Lathrophytoic acid A (345), isolated from
Kielmeyera lathrophyton, is the first 4-nor-homoadamantane
PPAP with loss of C-4 carbonyl and followed by the formation
of a C-3/C-5 carbon−carbon bond.66 It is noteworthy that
H. sampsonii, a traditional Chinese medicine to treat blood stasis
and swelling reduction, is the richest source of caged PPAPs, and
over 50 adamantane- and homoadamantane-type derivatives have
been reported from this plant thus far. In 2017, the relative
configurations of cowabenzophenone B (344) and an unnamed
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Table 4. Caged PPAPs with Adamantane Skeleton

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Table 4. continued

a
G. = Garcinia, H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute
configuration is known to be as shown. dThe original name, garcimultiflorone D, has been used previously, and we rename as isosampsonione J.
e
The configuration of the oxirane unit was reassigned according to the rule established by Xu et al.144 fPairs of isolates with positive and negative
optical value, respectively, may be enantiomers.

one were revised to the same as those of hyperattenin H and
pseudohenone E (343), respectively.143
2.3. Other PPAPs
2.3.1. Spirocyclic PPAPs with Octahydrospiro-
[cyclohexan-1,5′-indene] Core. This subclass comprises
46 PPAPs (Table 6164) that are considered to be the further
intramolecular cyclization products of the less complicated MPAPs,
such as hypercalin C (Scheme 4). Interestingly, these spirocyclic
PPAPs are all isolated from the genus Hypericum, except for five
compounds (353, 354, 376−378), sharing a distinct acetyl
group, that are obtained from H. perforate, a plant of family
Simaroubaceae. Oxidative ring opening of the phloroglucinol
core of these PPAPs affords derivatives with a bicyclo[4.3.0]-
nonane skeleton (385−391), which might recyclize to a spiro-
skeleton metabolite with a cyclopentane-1,3-dione moiety (384).
This type of PPAP was first reported in 2008, when tomoeones
A−H (348, 350−352, 370, 372, 374, and 375) were isolated
from the leaves of H. ascyron by Hashida and co-workers.160
In 2015, Zhu et al. revised the hydroxyl substituent of C-13
in tomoeones C, D, G, and H (372, 350, 375, and 352) to a
hydroperoxyl group as well as the relative configuration of C-13
by analysis of their MS and NMR spectroscopic data.161
2.3.2. Complicated PPAPs via Intramolecular [4 + 2]
Cycloadditions from MPAPs. As mentioned above, the com-
plicated PPAPs are derived from intramolecular [4 + 2] cyclo-
additions of MPAPs rather than via formation of the BPAPs
(Scheme 4) and have been neglected in all of the previous
reviews about PPAPs. As shown in Table 7,171 this subclass
includes 30 PPAPs with complicated ring systems that share a
basic tricyclo[4.3.1.03,7]decane-2,9-dione moiety (except for 421),
as exemplified by (+)-nemorosonol (400), the first member of
Q DOI: 10.1021/acs.chemrev.7b00551
this subclass reported early in 1988.165 Compounds 392−399,
which have a fused hexacyclic system, represent the most com-
plex PPAPs thus far and are likely derived from tetraprenylated
MPAPs (such as weddellianone A) via successive intramolec-
ular [4 + 2] radical cycloadditions (Scheme 4).166 Interestingly,
racemic mixtures such as (±)-garmultin A (406 and 407) and
optically pure analogues such as garmultin B (408) have been
coisolated from G. multif lora.167 The authors presume that
different MPAP precursors (with chiral or achiral center) before
the biosynthetic Diels−Alder reactions may be the main reason
for this special phenomenon.167 Hypatulin A (421), obtained
from H. patulum, is also presumed to be generated from an
MPAP with four isoprene units via [3 + 2] intramolecular
cyclization, oxidative ring cleavage, and further cyclization.168
It is noteworthy that the previous C-5 configurations of doit-
unggarcinone A (393) and doitunggarcinone B (402) were
incorrectly drawn by mistake, even though the authors had
provided correct NOE correlations.133 In 2012, George’s team
accomplished the synthesis of 393 and suggested the structural
revision for 393 and its biosynthetic precursor 402.166,169
3. INVESTIGATION OF CERTAIN PPAPS’
CONFIGURATIONS
3.1. Relative Configuration of C-7 for Certain BPAPs
In the structural determination of BPAPs, the assignment of the
C-7 relative configuration by NOE experiments is problematic
and sometimes leads to an erroneous conclusion, because the
key signals, such as the two H-6 protons and H-7, usually overlap
in the upfield region of the 1H NMR spectrum. Furthermore,
the NOE correlations of the protons of adjacent carbons are
Chem. Rev. XXXX, XXX, XXX−XXX
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Table 5. Caged PPAPs with Homoadamantane Skeleton

R DOI: 10.1021/acs.chemrev.7b00551
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Chemical Reviews Review

Table 5. continued

a
C. = Clusia, G. = Garcinia, H. = Hypericum. bOMe indicates the rotation was measured for its methylated derivative. The values in parentheses are
the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known to be as shown. dPairs of isolates with positive
and negative optical value, respectively, may be enantiomers. eThe C-8 configuration was reassigned, see text.

not reliable for the determination of the corresponding stereo-
chemistry, especially in conformationally variable molecules.
Fortunately, Grossman and Jacobs formulated a rule for easily
determining the orientation of the C-7 substituent in BPAPs
(endo or exo) by examining the 1H and 13C NMR spectro-
scopic data.8,173 When the C-7 substituent is exo, the difference
in chemical shifts of the two H-6 atoms is 0.3−1.2 ppm and the
chemical shift of C-7 is 41−44 ppm, whereas when the C-7
substituent is endo, either the difference in chemical shifts of
the two H-6 atoms is 0.0−0.2 ppm or the chemical shift of C-7
is 45−49 ppm.8,173 Since this rule was formulated in the early
2000s, dozens more BPAPs have been isolated and charac-
terized. Remarkably, the rule holds very consistently across all
of these newly discovered BPAPs, regardless of NMR solvent
and BPAP type. Hence, we strongly suggest that researchers use
Grossman and Jacobs’ rule to determine the C-7 configuration
of BPAPs in the future. Meanwhile, the conformational analysis
of the B ring of the bicyclo[3.3.1]nonane system and the
coupling constant of H-7/H-6ax can also be used to make the
S DOI: 10.1021/acs.chemrev.7b00551
assignment. Rastrelli et al. have shown that the coupling con-
stant of H-7/H-6ax is 6−8 Hz when the C-7 substituent is in the
axial position (endo), while the coupling constant of H-7/H-6ax
is 10−13 Hz when the C-7 substituent is equatorial (exo).174
After survey of all of the NMR data of BPAPs reported in
this period, some PPAPs’ C-7 relative configurations need
reevaluation.
• In 2012, Kaur et al. reported an unnamed BPAP (231),121
and they used the method of Grossman and Jacobs to
assign C-7 an exo configuration, but they drew the struc-
ture with the endo configuration. On the basis of the
NMR data in the paper, the exo configuration appears to
be correct.
• Hyperscabrone K (8) was reported to have a C-7 endo
substituent, but the chemical shifts of C-7 (δ 43.0) and
H-6 (δ 1.98 and 1.48) match those of exo BPAPs.55
Analysis of the process of configuration assignment indicates
that the authors misused the Grossman and Jacobs’ rule,
and the meaning of endo/exo was mistaken for α/β.55
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Chemical Reviews Review

Table 6. Spirocyclic PPAPs with Octahydrospiro[cyclohexan-1,5′-indene] Core

T DOI: 10.1021/acs.chemrev.7b00551
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Chemical Reviews Review

Table 6. continued

a
H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known
to be as shown. dThe original assignment of the C-4 relative configuration is probably incorrect according to its NMR data, and it may be a C-6 or
C-18 epimer of sampsonol A. eThe absolute configuration is known and is opposite to what is shown.

Hence, we reassign the C-7 relative configuration of
hyperscabrone K, and it should share the same relative
structure with scrobiculatone B.56
• The exo BPAP hyperibrin D,61 reported by the same
team, possesses identical 1H and 13C NMR spectroscopic
data to those of endo BPAP hyperattenin E (199),71 indi-
cating the original assignment of C-7 relative configuration
for hyperibrin D was incorrect. Their C-7 (δ 46.4) value
and coupling constant of H-7/H-6ax (6.0 Hz) are con-
sistent with those of other endo BPAPs. Therefore, we
reassign the C-7 configuration of hyperibrin D to be the
same as that of hyperattenin E (199).
• We also reassign the C-7 configuration of a pair of
C-7 epimers, oblongifolins L (161) and AA (164),92,119
according to their chemical shifts of C-7 (δ 42.4 for 161
and 45.5 for 164) and two H-6 protons (δ 2.02, 1.47 for
161 and δ 2.21, 2.18 for 164). The original assignment
of one H-6 proton (δ 1.99, m) in 161 was incorrect;
it should be located at 1.47 ppm (t, J = 12.9 Hz)
after examining its HSQC spectrum.92 Therefore, both
the difference in chemical shifts of two H-6 atoms
(0.55 ppm) and the large coupling constant of H-7/H-6ax
(12.9 Hz) support the equatorial (exo) substituent of
C-7 in 161.
U DOI: 10.1021/acs.chemrev.7b00551
• Similarly, the structures of hypersampsone H (7)54 and
oblongifolin T (149)119 were reassigned to be 7-endo
BPAPs, according to their chemical shifts of H-6 (Δ = 0.12
and 0.09) and C-7 (48.7 and 47.7). The authors did not rec-
ognize that a 7-endo substituent could cause the H-7 to have
a NOESY interaction with either methyl group on C-8.119
According to the rules mentioned above, the original assign-
ments of the C-7 relative configuration of the following 14
BPAPs are questionable (their C-7 configuration is not assigned
in Tables 1 and 2) and need to be further investigated.
Spiranthenone A (101),43 spiranthenone B (134),43 semsinone
A (135),104 oblongifolins M−O, Q−S, and Z (170, 166, 169,
167, 203, 190, and 168, respectively),92,119 13,14-didehydroxy-
isogarcinol (187),77 and garcinialone (232)130 are all reported
to have C-7 endo substituents; however, their C-7 δ values
(40.2−44.3 ppm, 37.5 for 169) are not consistent with those of
other endo BPAPs but match those of exo BPAPs. Also, the
C-7 δ values (47.0−47.5 ppm) of exo BPAPs 32-hydroxy-ent-
guttiferone M (148)110 and garciesculentone A (191)93 suggest
that they are endo BPAPs.
It is important to note that Grossman and Jacobs’ rule can be
widely used for determination of the C-7 relative configuration
of those BPAPs with two methyl groups at C-8, but caution
should be exercised when a prenylmethyl group is present at
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Chemical Reviews Review

Table 7. Complicated PPAPs via Intramolecular [4 + 2] Cycloadditions of MPAPs

V DOI: 10.1021/acs.chemrev.7b00551
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Chemical Reviews
Table 7. continued
a
C. = Clusia, G. = Garcinia, H. = Hypericum, T. = Triadenum. bThe values in parentheses are the concentration and the solvent (c = CHCl3,
m = MeOH). cThe absolute configuration is known to be as shown. dThe absolute configuration is known and is opposite to what is shown.
Scheme 3. Biomimetic Transformation of
3-Hydroxyhyperforin-3,9-hemiketal to 254
Scheme 4. Proposed Biosynthetic Pathways to
Representative Spirocyclic and Complicated PPAPs
C-8, as in some endo BPAPs, such as guttiferone A, 2,16-
oxyguttiferone A (230), and 4,16-oxyguttiferone A (235).129,175
The difference in chemical shifts of the two H-6 atoms for
guttiferone A, 230, and 235 indeed conform to the rule, but
their chemical shifts of C-7 (39−42 ppm) do not match with
endo BPAPs (45−49 ppm), which could be resulted from the
prenylmethyl group’s participation ultimately leading to the
conformational change of these molecules. Nevertheless, the
C-8 prenylmethyl group in BPAPs was proposed to be trans
to the C-7 prenyl group, as expected from the postulated
mechanism of cyclization of MPAPs to BPAPs (C-8 pre-
nylmethyl may adjust to be trans to the C-7 prenyl group to
W DOI: 10.1021/acs.chemrev.7b00551
Review
avoid steric hindrance, when cationic C-8 cyclized to the
phloroglucinol core).8
3.2. Reassignment of Some PPAPs’ Relative Configuration
on Other Locations
We suggest that some PPAPs’ relative configurations on other
locations (beside C-7) should be reassigned after detailed
investigation of their NMR data.
• The Z configuration of the geranyl group (should
be E-configuration) in androforin A (36)68 as well as
the C-18 configuration in 18-epifurohyperforin isomer
1 (40), furohyperforin isomer 1 (49), and furoadhy-
perforin isomers A and B (50 and 41),65,72 were drawn
incorrectly by mistake; the correct structures are given in
Table 1.
• We have revised the C-18 configuration of hypercohin
J (57) because of its similar NOE correlations to those of
hyperforatin K (59).63,67
• The use of NOE experiments to determine the C-28
configuration of adamantane-type PPAPs with a 28,29-
epoxide moiety is not reliable due to the rotational free-
dom about the C-27/C-28 bond. A more reliable solu-
tion,144 examining the chemical shifts of C-27 and C-28,
that was proposed in 2016 suggests the reassignment
of the epoxide moiety’s configuration in hyperandrone
A (272).68
• The homoadamantane-type PPAP, attenuatumione A,60
shares identical 1H and 13C NMR spectroscopic data
to those of hypercohone A (333)158 but bears different
relative configuration at C-18. Examination of their
original NOESY spectra suggests that the C-18 relative
configuration of attenuatumione A was incorrectly assigned
and that it should possess the same relative structure with
hypercohone A (333).
Interestingly, hypersampsonone A (64) and another com-
pound (its name, hypersampsone S, has been used and reserved
for Lin’s isolate, 30288) with identical NMR data were reported
almost simultaneously.53,76 However, opposite configurations
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Chemical Reviews
were assigned in the cyclohexane substituent, which remains to
be further confirmed.
3.3. Investigation of the Absolute Configurations of
Certain PPAPs
In the last 11 years, over 100 PPAPs’ absolute configurations
have been determined by X-ray diffraction, comparison of their
experimental and calculated ECDs, and synthetic methods. Zhu
et al. established a useful method to determine the absolute con-
figuration of C-1 for benzoyl-substituted adamantane/homoada-
mantane PPAPs by examining the Cotton effect around 330 nm
(negative and positive Cotton effects, indicating the R and S
configuration of C-1, respectively).149 Although ECD methods
have been widely used to determine the absolute configuration
of many PPAPs in recent years, especially for the BPAPs and
adamantane- and homoadamantane-type PPAPs, this method
needs to be used cautiously. The type B BPAPs hyperscabrone L
(196) and hyperibrin D (199),55,61 two C-23 epimers isolated
from the same plant (H. scabrum), possess identical experimental
ECD, but opposite absolute configurations of C-1 and C-5 were
assigned by quantum chemical computation. Comparison of the
ECD of hyperscabrone L with those of other structures with
known absolute configurations (such as oblongifolin X, 201119)
and similar chromophores indicated that the computational pro-
cess of hyperscabrone L must have gone wrong;55 so, we reas-
signed the absolute configuration of hyperscabrone L. In addition,
the authors also used the calculated ECD method to determine
the absolute configuration of hyperscabrone J (12),55 which
bears a stereocenter (C-23) in a flexible side chain. However,
this method may be not fessible to assign the absolute config-
uration of a stereocenter located far away from the chromo-
phore, such as C-23 in 12.
Some PPAPs have been isolated as racemic mixtures (406
and 407,167 409 and 410,167 411 and 412,167 414 and 415,167
417 and 418172), further chiral separations and quantum chem-
ical computation methods revealed their absolute configura-
tions. Moreover, seven pairs of isolatesscrobiculatone B (8)/
hyperscabrone K,55,56 guttiferone Q (160)/cowanone,116,117
garcicowin C (192)/garcinialiptone B,49,101 hyphenrone A (244)/
perforatumone,1,138 hypercohone A (333)/attenuatumione
A,60,158 hypercohone C (342)/cowabenzophenone A,159,144
and cowabenzophenone B (344)/hyperattenin H71,159have
been found to have the same relative stereochemistry but spe-
cific rotations opposite in sign, suggesting that they are enantio-
mers. However, optical rotations are notoriously sensitive to
the presence of impurities, and more reliable evidence, such as
X-ray diffraction and ECD data, is not available to support their
enantiomeric relationships, so it is too early to judge whether
they are enantiomers or homomers, especially for those with
small optical values. Nevertheless, when a compound’s absolute
configuration is known and the compound is isolated again
from a different source, the new isolate’s specific rotation can
reveal whether it is enantiomeric or homomeric to the original
isolate, so we include each PPAP’s specific rotation in the tables.
Kuo’s team has made the remarkable claim that they have
successively isolated the enantiomeric PPAPs, (+)-garcinialip-
tone A (289) in June 2005, and (−)-garcinialiptone A,
(+)-cycloxanthochymol, and (−)-cycloxanthochymol (172) in
June 2007, from G. subelliptica collected from the same moun-
tain, and that they were able to separate the enantiomers by
HPLC without using any chiral HPLC columns.49 It is likely that
either one of the plant materials was misidentified or the mea-
sured optical rotations of certain compounds were inaccurate.
X DOI: 10.1021/acs.chemrev.7b00551
Review
4. CONSOLIDATION OF SOME PPAPS’ TRIVIAL
NAMES
Some PPAPs were isolated simultaneously by different groups
working independently, who then gave the PPAP different names.
The structures of adhyperfirin and garcinielliptone K were initially
misassigned;31,32 later revision showed them to be identical to the
already known hyperibine J (2)33 and propolone C (24).9,64
Furthermore, the structures of hyperibine J (2) and hyper-
polyphyllirin,50,51 hypersampson R (88) and hyperattenin
B,71,83 hypercohone F (107) and uralione H,57,86 guttiferone
J (137) and garciyunnanin A,105,106 oblongifolin C (141) and
(+)-guttiferone G,100,108 cowanone (160) and chamuan-
gone,117,118 sampsonione P (196) and hyperscabrone L,55,59
hyperattenin E (199) and hyperibrin D,61,71 pyramidatone
A (365) and chipericumin E,40,163 and hypelodin B (394)78
and hyphenrone L1 were reported repeatedly and given two
different names. In the tables, we arrange these names according
to the order of publication.
On the contrary, some PPAPs were given the same name but
had different structures. The original name of 136, guttiferone I,176
has been used in 2005 for another PPAP, so we rename 136
as 13-deoxy-guttiferone J.105 Also, the original names of 234
and 271 were reserved for earlier reported isolates, 132
(guttiferone O) and 126 (garcimultiflorone D),102,103 respec-
tively, and new names were given to 234 (oxy-oblongifolin A)131
and 271 (isosampsonione J).148 Hypersampsone S, another
name of hypersampsonone A (64),53,76 has been reserved for
Lin’s isolate, 302.88 In addition, the names of 7 pairs of PPAPs
with uncertain enantiomeric relationship mentioned above are
all retained along with their optical rotations in the corre-
sponding tables.
5. LIVING DATABASE OF PPAPS
One of the coauthors of the current paper (RBG) has created
an online, freely accessible database of PPAPs that users can
find at http://www.chem.uky.edu/research/grossman/PPAPs/.
The database groups PPAPs according to the structure and
stereochemistry of their cores, much like the tables in this
review. Both this review and the database list each PPAP’s
name(s), plant origin, reported optical rotation, and hyperlinks
to the literature articles describing the determination of the
PPAP’s structure, but the database also includes two-dimensional
MOL representations, which users can copy and paste into their
own structure-drawing programs. Furthermore, the database
provides a simple sorting tool, which a user can use to display a
subset of PPAPs that have particular structural characteristics.
The database will be updated as new compounds are dis-
covered and as the structures of already discovered compounds
are revised as new information is acquired. Readers are encour-
aged to submit additions and corrections to RBG.
6. BIOLOGICAL ACTIVITIES OF PPAPS
Significant progress has been made over the past decade in
elucidating the biological activities of PPAPs. The pharmaco-
logic activities and corresponding mechanisms of some prom-
ising PPAPs isolated before 2006, such as hyperforin, garcinol,
nemorosone, 7-epi-clusianone, and guttiferone A, are summar-
ized. Recent studies revealed a new molecular mechanism of
hyperforin and its synthetic derivatives for regulating neuro-
transmitters by activating transient receptor potential channel
6 (TRPC6), and the antitumor mechanism of garcinol and its
analogues has been studied in depth. The limitations of the
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Chemical Reviews
clinical application of the two most studied molecules (hyperforin
and garcinol) are also evaluated. It has become obvious that the
antineoplastic potential of type B PPAPs, especially for some
recently isolated ones such as oblongifolin C and guttiferone K,
is increasing significantly. In addition, many PPAPs have been
reported to show anti-HIV, anti-inflammatory, antiplasmodial,
and antimicrobial potential in recent years.
6.1. Biological Activities of Type A BPAPs
6.1.1. Hyperforin and Its Synthetic Derivatives. Hyper-
forin (422), present in great amounts in Hypericum perforatum
(St. John’s wort), is the most famous molecule in the PPAP
family (Figure 1).6,7 Substantial studies make clear that
Figure 1. Structures of hyperforin and its synthetic derivatives
(422−425).
hyperforin is mainly responsible for the antidepressant effects
of this medicinal plant.177,178 It has been described as an inhib-
itor of the reuptake of many neurotransmitters such as serotonin,
dopamine, norepinephrine, L-glutamate, and γ-aminobutyric acid
(GABA).15,179,180 In addition, it is also an antagonist of many
receptors such as the N-methyl-D-aspartate (NMDA) receptor.15
To date, the molecular mechanisms underlying the modulation
of neurotransmitter uptake by hyperforin mainly include its
protonophoric properties and activation of transient receptor
potential channel 6 (TRPC6).10,18
Recently, it has been discovered that hyperforin integrates
the inhibition of neurotransmitter uptake and neurotrophism
by specifically activating TRPC6, a Ca2+-conducting channel of
the plasma membrane, without activating the other isoforms
(TRPC1, TRPC3, TRPC4, TRPC5, and TRPC7). Due to this
specific property, it is now used as a convenient pharmaco-
logical tool to investigate the functions and properties of native
TRPC6 in various cell types.18,181−185 Leuner has shown that
hyperforin induces neurite outgrowth in PC12 cells and spine
morphology changes in CA1 and CA3 hippocampal neurons via
activation of TRPC6,186,187 which was further mediated by
several mechanisms comprising Ras, ERK, PI3K, and Ca2+/
calmodulin-dependent protein kinase IV (CAMKIV) activation,
finally resulting in cAMP-dependent response element binding
protein (CREB) phosphorylation.188 The cAMP-dependent
protein kinase A and the transcription factor CREB triggered by
hyperforin could increase the expression of the brain-derived
neurotrophic factor (BDNF) receptor neurotrophic tyrosine
kinase (TrkB) and TRPC6.189
However, some other researchers presume that the anti-
depressant activity is mediated by hyperforin-dependent indirect
inhibition of transmitter reuptake and vesicular transmitter
loading based on the protonophoric activity of hyperforin with-
out activating TRPC6 channel.190 Further investigations are
needed to clarify the interesting discrepancy that the antidepressant
activity of hyperforin is dependent or independent of TPRC6.10
In fact, hyperforin (422) is a multitarget drug influencing the
cellular homeostatic mechanisms of H+, Na+, Ca2+, and Zn2+
due to its effects on their influx and/or release from internal
Y DOI: 10.1021/acs.chemrev.7b00551
Review
stores.18,191−193 Although there have been recent studies in the
characterization of cellular responses to hyperforin, it remains
unclear what pharmacological aspects of hyperforin functions
are relevant in vivo.18 Nevertheless, hyperforin has been shown
to have cognition-enhancing and memory-facilitating proper-
ties.15 It possesses neuroprotective effects against Alzheimer’s
disease (AD) neuropathology, including the ability to disas-
semble amyloid-β (Aβ) aggregates in vitro, decrease astrogliosis
and microglia activation, as well as improve spatial memory
in vivo.15,194,195
Besides its antidepressant activity, hyperforin (422) also
exerts potent anti-inflammatory effects.196,197 It is shown to be
a novel type of 5-lipoxygenase inhibitor, apparently acting by
interference with the C2-like domain,198 and induces Ca2+-
independent arachidonic acid release in human platelets by
facilitating cytosolic phospholipase A2 activation through select
phospholipid interactions.199 It also blocks several proinflam-
matory functions of leukocytes in vitro such as chemotaxis and
chemoinvasion200,201 and downregulates effector functions of
activated T lymphocytes.202 In microglia and macrophages,
hyperforin is a modulator of inducible nitric oxide synthase and
phagocytosis.203 In addition, it exerts protective effects by
inhibiting multiple phosphorylation steps along the STAT1,
NF-κB, and MAPK signaling pathways and consequent
restriction of inflammatory and apoptotic gene expression in
pancreatic β cells.204 In vivo, hyperforin impaired acute neu-
trophil recruitment and enhanced resolution in a pulmonary
bleomycin-induced inflammation model reducing consequent
fibrosis,201 and it suppressed carrageenan-induced rat pleurisy
when given intraperitoneally.198 In addition, it was shown to
inhibit microsomal prostaglandin E2 synthase-1 and suppress
prostaglandin E2 formation in vivo.205
Meanwhile, recent studies have shown that hyperforin is a
potential anticancer agent,206,207 especially in the treatment of
chronic lymphoid leukemia (CLL) and acute myeloid leukemia
(AML).16 Hyperforin targets molecules involved in signaling
pathways that control leukemic cell proliferation, survival, apo-
ptosis, migration, and angiogenesis.208−210 It can also down-
regulate the expression of P-glycoprotein, a protein that is
involved in the resistance of leukemia cells to chemotherapeutic
agents.211 In primary CLL cells, hyperforin stimulates the
expression of the pro-apoptotic Noxa, a BH3-only protein of
the Bcl-2 family.212,213 In AML cell lines and primary AML
cells, it directly inhibits the kinase activity of the serine/threonine
protein kinase B/AKT1, leading to activation of the pro-apoptotic
Bcl-2 family protein Bad through its nonphosphorylation by
AKT1.214 Despite these in vitro observations, further studies
in vivo involving the evaluation of hyperforin’s therapeutic
potential in CLL or AML are needed.
Hyperforin (422) has been also shown to display antibac-
terial,207,215,216 antioxidant,217 antimalarial,218 larvicidal,219 and
estrogenic220 activities in the time range of this review.197
Unfortunately, hyperforin’s chemical instability and poor solu-
bility in aqueous solutions,10,16,17 its ability to increase expression
levels of cytochrome P450 enzymes (particularly CYP3A4) by
binding to the pregnane X receptor,221−227 and its other side
effects228,229 limit its potential clinical application. Nevertheless,
synthetic derivatives of hyperforin with increased stability and
solubility (Figure 1), such as aristoforin (423), tetrahydrohy-
perforin (424, IDN5706), and octahydrohyperforin (425), have
also recently been studied for their potential antidepressant and
antitumor uses both in vitro and in vivo.10,16,17 Among these
modified molecules, tetrahydrohyperforin has been shown to be
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Chemical Reviews
a promising neuroprotective agent against AD.230−237 Further
studies about the structure−activity relationship (SAR) of these
modified molecules are urgently needed to enhance corre-
sponding antidepressant or antitumor activity with simulta-
neously eliminating the therapy-limiting pregnane X receptor-
dependent side effects.
6.1.2. Nemorosone and 7-epi-Nemorosone. Nemor-
osone (426), the major constituent of the floral resin of Clusia
species and also present in Cuban propolis,29 has been described
as a potent antimicrobial agent (Figure 2).238 In recent years,
Figure 2. Structures of nemorosone (426) and 7-epi-nemorosone (427).
nemorosone has also been proven to show antitumor potential.
It blocks proliferation and induces apoptosis in leukemia cells
partly by targeting the Akt/PKB signal transducer, affecting
protein levels and cell cycle progression.239 Low concentrations
(0.03−1.0 μM) of nemorosone inhibited the cell viability of
estrogen receptor positive (ERα+) MCF-7 human breast can-
cer cells.240 Further mechanistic study has shown that it induced
discrete cell cycle arrest in the G1 phase and significant deplet-
ion in the G2 phase and altered the expression of genes linked to
the cell cycle, apoptosis, and hormone receptors.241 Nemorosone
also affects the cell cycle and unfolded protein response (UPR)
regulatory pathways in pancreatic cancer cells but not in fibro-
blasts.242 It exerts antiproliferative activity in neuroblastoma
cells possibly via inhibition of upstream kinase MEK1/2 and
targeting Akt/PKB kinase.243 In addition, nemorosone was
suggested to be a potent protonophoric mitochondrial uncoupler,
which is potentially involved in its toxicity on cancer cells.244
Meanwhile, its isomer, 7-epi-nemorosone (427), was also
found to be a potent antilentiviral agent in the employed system,
inhibiting viral infection at concentrations below 1 μM.245 It also
exerts cytotoxicity in an androgen-dependent prostate carcinoma
entity by targeting the MEK1/2 signal transducer.246
6.1.3. Garcinielliptone FC. Garcinielliptone FC (5) was
obtained from G. subelliptica and Platonia insignis and identified
as a type A structure.48,52 It has been shown to be an anti-
tumor,247−249 antioxidant,48,52,250 and antiparasitic247,251 agent.
It also decreases the frequency of pilocarpine-induced seizures
and increases survival rate in mice,252 and it promotes a
vasorelaxant effect on rat mesenteric artery.253 An acute toxicity
study indicated that it was well tolerated in animals, suggesting
that it is safe for further investigation.254
6.2. Biological Activities of Type B BPAPs
6.2.1. Garcinol and Its Derivatives. Garcinol (428),
obtained from Garcinia indica and several other Garcinia plants
(Figure 3),255 was shown to be an antibacterial and antioxidant
agent in earlier studies.8,19,256 Recent investigations have revealed
that garcinol has excellent cytotoxicity and antitumorigenesis
activities.20−22,257−261 It has been found to be an effective inhib-
itor of various key signaling pathways, such as NF-κB and
STAT3, in cancer cells (Table 8). In vitro as well as some
in vivo studies have shown the potential of garcinol in controlling
malignant growth of several cancer types including head and
Z DOI: 10.1021/acs.chemrev.7b00551
Review
Figure 3. Structures of garcinol (428) and its derivatives (429−431).
neck, breast, prostate, colon, hepatocellular, pancreatic, and leu-
kemia.22 The anticarcinogenic properties of garcinol appear to
be moderated via its antioxidative, anti-inflammatory, antiangio-
genic, proliferation, and proapoptotic activities (Table 8).20,262,263
In addition, garcinol displays an effective epigenetic influence
by inhibiting histone acetyltransferases (p300-HAT) and by
possible post-transcriptional modulation via miRNA profiles
involved in carcinogenesis.20,264,265
Despite its high potential as an antineoplastic modulator of
several cancer types, garcinol (428) is still in the preclinical
stage due to a lack of a systematic and conclusive evaluation of
pharmacological parameters. Meanwhile, recent studies on its
effectiveness in ameliorating other chronic diseases, such as car-
diovascular diseases, diabetes, allergy, neurodegenerative diseases,
etc.,286−289 are promising and require more detailed and in-depth
investigations.22,290
Its cyclization product, isogarcinol (429), also exerts antipro-
liferative and proapoptotic effects on breast cancer cells through
modulating different pathways.291,292 Cen’s investigation sug-
gested that it could be a new immunosuppressant that binds
directly to calcineurin in vitro, unlike the classical calcineurin
inhibitors cyclosporin A and tacrolimus.293 In addition, the
enantiomeric forms of garcinol and isogarcinol, guttiferone
E (430)294,295 and isoxanthochymol (431),296 also showed
promising anticancer activities (Figure 3).
6.2.2. Clusianone and 7-epi-Clusianone. Clusianone
(432) and 7-epi-clusianone (433), a pair of C-7 epimers
(Figure 4), were first isolated from different Clusia species,174
and recent investigations have shown their wide range of bio-
activities. Clusianone induces HepG2 cell death by promoting
the dissipation of rat liver mitochondrial membrane potential
via a protonophoric uncoupling mechanism.297 In the assay of
HIV-1 infection, both (+)- and (−)-clusianone exhibited potent
inhibitory activity with IC50 values of 1.5 and 1.1 μM,
respectively, in the 3T3 system.298
7-epi-Clusianone (433) showed good antimicrobial activity
against Streptococcus mutans at low concentrations (MIC 1.25−
2.5 μg/mL),299,300 and it could be an agent to prevent and
control dental caries disease.301 A further mechanistic study
showed that it acts by inhibiting glucan synthesis, particularly
those synthesized by glucosyltransferases C, and disrupting the
development and acidogenicity of S. mutans biofilms.302 Up to
10 μM, 7-epi-clusianone induces an endothelium-dependent
vasodilator effect in rat aortic rings, while at higher concen-
trations (higher than 10 μM) and in conditions where NO
synthase was inhibited, it induces a vasocontractile effect.303
7-epi-Clusianone was shown to relax airway smooth muscle
through activation of epithelium-, nitric oxide-, and cGMP-
dependent pathways.304 7-epi-Clusianone also showed potential
antitumor,305−308 anti-inflammatory,309,310 antianaphylactic,311
and leishmanicidal312 activities.
6.2.3. Guttiferone A and Its Derivatives. Guttiferone A
(434), initially obtained from Symphonia globulifera and
Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews Review

breast, HCC, HNSCC, pancreatic,

breast, HNSCC, oral, pancreatic,

breast, colon, HCC, leukemia,

types of cancer

lung, pancreatic
prostate, skin

breast, colon

colon, skin
prostate

lung, skin
Figure 4. Structures of clusianone (432) and 7-epi-clusianone (433).

G. livingstonei in 1992, is a type B structure bearing a pre-

inhibition of proliferation and inflammation; induction of apoptosis;

nylmethyl group at C-8 (Figure 5).175 The biologic studies of
inhibition of proliferation; induction of apoptosis; inhibition of the
progression; induction of apoptosis; reversal of EMT phenotype

guttiferone A (434) investigated antitumor,313 antimicrobial,238

inhibition of inflammation, proliferation, angiogenesis, cell cycle

antiparasitic,314 and neuroprotective315,316 properties. More

radiosensitization; suppression of oncogenic properties
importantly, guttiferone A was able to inhibit or increase silent
reversal of EMT phenotype; inhibition of inflammation

information regulator 1 (SIRT1) catalytic activity, depending

on protein concentration and presence of detergent.317 Unfor-
tunately, though, guttiferone A produced genotoxic effects in
inhibition of proliferation and inflammation

leukocytes, liver, bone marrow, brain, and testicle cells of mice.318

function

Its derivatives, guttiferone F (435) and xanthochymol (436)

(Figure 5),294,295,319 also showed promising anticancer
invasive capacity of cancer cells

inhibition of inflammation
downregulation: uPA, VEGF, MMP-9, cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, VEGF
downregulation: vimentin, ZEB-1, ZEB-2, β-catenin, cyclin D1, Bcl-2, Bcl-xL, survivin,

downregulation: the nicotinic receptor, cyclin D3, NHEJ, PGE2, 5-LO, COX, survivin,
biomarkers (Ki-67, CD31) upregulation: E-cadherin, miR-200, let-7s, cleaved PARP,

Figure 5. Structures of guttiferone A (434), guttiferone F (435), and

upregulation: DR4, DR5, GADD153, Bax, cytosolic cytochrome c, tBid, caspase-3,
Mcl-1, VEGF, iNOS, COX-2, MMP-9, IL-8, PGE 2, XIAP cIAP, proliferative

xanthochymol (436).
downregulation: vimentin, ZEB-1, ZEB-2, β-catenin, COX-2, cyclin D1, VEGF

activities, and further SAR, toxicological, and metabolic studies

of these agents are required.
Bcl-2, XIAP, cFLIP, Bid, Notch1, Mcl-1, EZH2, ABCG2, Gli-1

6.2.4. Oblongifolin C and Guttiferone K. Oblongifolin C

Table 8. Summary of Different Cellular Pathways Regulated by Garcinol
downstream targets/related molecules

(141), also known as (+)-guttiferone G, was first isolated from

the bark of Garcinia oblongifolia100 and was later found to be
present in a greater amount in the pericarp of G. yunnanensis.106
downregulation: cyclin D1, VEGF, iNOS, COX-2

caspase-8, caspase-9, PARP, DFF-45, miR-200c

Oblongifolin C was found to exhibit inhibitory activity against a

wide spectrum of cancer cell lines,98,101,106,320,321 with IC50 values
upregulation: E-cadherin, miR-200, let-7s

less than 1.5 nM in SW620 colon cancer cell line.321 Recent

investigations have revealed that oblongifolin C significantly
inhibits tumor proliferation and metastasis320,322 and promotes
downregulation: iNOS, COX-2

apoptosis320,323,324 by modulating different pathways, indicating

cleaved caspases-3 and -9

upregulation: P21Waf1/Cip1

its therapeutic potential in several solid tumors. Moreover,

oblongifolin C is found to be a novel autophagic flux inhibitor
and might be useful in anticancer therapy.323,325 Oblongifolin C
not only triggers DNA double-strand breaks and DNA damage
response but also inhibits repair of DNA damage, suggesting its
use to treat apoptosis-efficient tumors.326 In addition, oblongifolin
C is an inhibitor of human silent information regulator 1 and 2
(SIRT1 and SIRT2), with SIRT1 being more greatly affected
than SIRT2.108 Therefore, it may be a valuable tool in the area of
downregulation of Wnt signaling

p-mTOR, 5-LO, NHEJ279−285

suppression of NF-κB signaling

inhibition of STAT3 signaling

inhibition of PI3K/Akt267,278

epigenetics and could also be used to reveal the biological role of

dwonregulation of MAPK

sirtuins in processes such as cancer, neurodegenerative diseases,

cellular pathways

others, such as Notch1,

and diabetes.108,327 Oblongifolin C was also shown to inhibit

pathway271,276,277

allergic inflammation through the suppression of mast cell acti-

pathway266−275

signaling260,267
pathway275,278

vation.328 However, metabolic research of oblongifolin C suggested

that it is a broad inhibitor of UDP-glucuronosyltransferase iso-
forms in human liver and intestine microsomes, indicating a
potential side effect of drug−drug interactions.329
AA DOI: 10.1021/acs.chemrev.7b00551
Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews
Guttiferone K (138) was first obtained from the fruits of
Rheedia calcicola107 and was later coisolated with oblongifolin
C from G. yunnanensis and G. cowa.101,106 It shows similar anti-
tumor activities to oblongifolin C by activating apoptosis, arresting
the cell cycle, and promoting autophagy.266,324,330,331 Guttiferone K
effectively suppresses the motility and metastasis of hepatocel-
lular carcinoma cells mainly by restoration of aber-
rantly reduced PFN1 protein expression.332
6.3. Biological Activities of Other PPAPs
Besides garcinielliptone FC (5), oblongifolin C (141), and
guttiferone K (138), the biological activities of the other PPAPs
reported since 2006 are summarized below. PPAPs possessing
cytotoxicities and other activities at the cellular level are listed
in Tables 9 and 10, respectively.
Hyperibrins C (16) and D (199), hypermongone D (27)
and G (43), and hyperscabrones D (111), E (200), F (213),
and G (98), isolated from H. scabrum, exhibited neuropro-
tective effects on glutamate-induced toxicity in SK-N-SH cells
at 10 μM.35,61 Uralodins A (68), B (51), and C (42) and
uraliones A−E (9, 13, 11, 14, and 78) and H−J (107, 108, and
106) from H. uralum showed potent protective effects against
corticosterone-induced injury in PC12 cells within the
concentration range tested (0.1−10.0 μM).57 Uralodin A (68),
orally administered in doses of 13 and 26 mg/kg, exhibited anti-
depressant-like activity in tail suspension and forced swimming
tests in mice.57
Hyperibrins C (16) and D (199), hypermongone H (53),
and hyperscabrones C (110), D (111), G (98), K (8), and
M (77) showed moderate hepatoprotective activities against
paracetamol-induced HepG2 cell damage at 10 μM.35,55,61
Oblongifolin M (170), isolated from G. oblongifolia, potently
inhibits enterovirus 71 reproduction through downregulation of
ERp57.333
Dioxasampsone B (308) and hypersampsone N (312),
obtained from H. sampsonii, showed mild RXRα transcriptional
inhibitory activities in a dose-dependent manner (5−20 μM).83,153
(+)-Garmultin C (409), (−)-garmultin C (410), and
(+)-garmultin D (414) from G. multif lora were shown to be
capable of inhibiting oncogene (Fli-1) expression and inducing
apoptosis in human erythroleukemia cells.167 Garcimultiflorone
I (218) exhibited anticancer activity targeting the cell cycle
through apoptosis signaling pathways.99 Garcimulin B (419) at
20 μM exhibited strong suppression of lysosomal acidification
in HeLa cells.172
7. SYNTHETIC CHEMISTRY OF PPAPS
With their fascinating biological profiles and intriguing complex
molecular architectures, PPAPs have long provided a fertile
playing field for synthetic organic chemists.24 The recent appear-
ances of innovative synthetic methods and strategies together
with asymmetric catalysis have vitalized this field tremen-
dously.23−25 Although many synthetic efforts had been made in
earlier period, it was not until 2005 that the first synthesis of a
PPAP, namely, garsubellin A, was realized.335 Now, a total of
22 natural PPAPs have been successfully synthesized, of which
hyperforin, nemorosone, clusianone, and garsubellin A are the
most common targets. In particular, the recent remarkable
contributions from the research groups of Plietker, Porco, Jr.,
and Maimone ushered in a peak period of PPAPs synthesis.
This review aims to highlight the recent achievements in the
total synthesis of PPAPs as well as notable methods developed
for construction of the core structures of these molecules.
AB
Review
7.1. Shibasaki’s Total Syntheses of ent-Hyperforin and
Garsubellin A
As mentioned above, the first total synthesis of (±)-garsubellin
A (446) was achieved by Shibasaki and co-workers in 2005.335
The synthesis began with the preparation of enone 438 from
commercially available 437 (Scheme 5). The keys for success
are the stereo- and regioselective introduction of the C-5 vinyl
group from 439 to 440 via aldol condensation, the stereo-
selective allylation at C-1 of 441 via Claisen rearrangement to
afford 442, and further ring-closing metathesis for construction
of the bicyclo[3.3.1]nonane system of 444 in the presence of
the Hoveyda−Grubbs catalyst 443. Finally, bridged bicycle 444
was successfully transformed into (±)-garsubellin A (446) in
seven steps via a key intermediate 445. The authors further
demonstrated that enantiomerically enriched cyclohexenone
438 could be prepared using the asymmetric alkylation method,
thus paving the way for an asymmetric synthesis of garsubellin A.335
The first catalytic asymmetric total synthesis of hyperforin
(422) was also accomplished by Shibasaki’s research group in
2010,336,337 nearly 30 years after its initial isolation, standing as
the most recognizable achievement (Scheme 6). Their synthe-
sis began with an asymmetric Diels−Alder reaction between
TIPS enol ether 447 (diene) and the oxazolidinone acrylamide
derivative 448 (dienophile), promoted by cationic iron−pybox
complex 449, to produce substituted cyclohexane 450 with
contiguous C-7 and C-8 stereocenters in excellent yield and
isomeric purity (96% ee, dr > 33:1). The thermal Claisen rear-
rangement of allyl enol ether 451 proceeded with remarkable
efficiency (>99% yield) and high diastereoselectivity (dr = 12:1)
to afford 452 bearing the bridgehead quaternary carbon (C-1).338
The key bicyclic intermediate 454 was synthesized uneventfully
from 452 through a selective hydroboration at the terminal
olefin using (Sia)2BH, Dess−Martin oxidation, intramolecular
aldol cyclization of resulting aldehyde 453, and oxidation.
Under their optimized conditions and using the bulky base 2,6-di-
tert-butylpyridine, a vinylogous Pummerer rearrangement of
allylic sulfoxide 455 took place preferentially to the normal
Pummerer rearrangement (4:1) and smoothly provided allylic
alcohol 456 in 65% yield. A palladium-promoted Claisen
rearrangement of 457 presumably proceeded through the
intermediacy of a π-allyl−palladium species, with the resulting
enolizable 1,3-diketone temporarily masked as its enol acetate
458 in 50% yield. Finally, cross-metathesis to introduce the
prenyl group at C-3 and methanolysis of the acetate under basic
conditions completed the total synthesis of ent-hyperforin
(422), the antipode of the naturally occurring substance, as
confirmed by optical rotation measurements. The authors claim
that these basic methods are also applicable to the asymmetric
synthesis of other PPAPs and analogues of hyperforin.24,336,337
7.2. Shair’s Enantioselective Total Syntheses of
(+)-Hyperforin and (−)-Nemorosone
Shair and co-workers reported a modular, 18-step enantioselective
total synthesis of (+)-hyperforin, starting from geraniol.339 As
shown in Scheme 7, the key intermediate 465 possessing a
bicyclo[3.3.1]nonane core with C-7 and C-8 quaternary stereo-
centers was accessed from cyclohexadiene 463 via a group-
selective, Lewis acid-mediated epoxide-opening cyclization.
Cyclohexadiene 463 would be synthesized in two steps through
the regioselective coupling of 1,5-dimethoxy-1,4-cyclohexadiene
461 with prenyl chloride and epoxygeranyl bromide 460.
Exposure of 463 to TMSOTf and 2,6-lutidine via a favored
chair transition state 464 gave the ketal 465 in 79% yield as the
DOI: 10.1021/acs.chemrev.7b00551
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Chemical Reviews Review
a
Table 9. Cytotoxicity of Selected PPAPs Table 9. continued
compounds cell lines IC50 values compounds cell lines IC50 values
garcinialiptone D (1)49 A549 human lung carcinoma 4.4 μM BT474 human breast cancer 7.4 μM
DU145 prostate cancer 3.3 μM HepG2 human hepatocellular carcinoma 1.1 μM
KB nasopharyngeal carcinoma 3.9 μM KATO-III human gastric cancer 5.6 μM
KBvin (vincristine-resistant KB subline) 4.6 μM CHaGo human lung cancer 1.1 μM
attenuatumione H (10)58 HepG2 human hepatocellular carcinoma 9.1 μM HeLa human cervical carcinoma 7.3 μM
garcinialiptone C (17)49 A549 human lung carcinoma 4.3 μM guttiferone L (142)107 A2780 human ovarian carcinoma 4.9 μM
DU145 prostate cancer 4.3 μM garcimultiflorone E MCF-7 human breast adenocarcinoma 9.8 μM
KB nasopharyngeal carcinoma 3.4 μM (145)93
KBvin (vincristine-resistant KB subline) 4.9 μM thorelione A (155)114 MCF-7 human breast adenocarcinoma 7.4 μM
hyperforatin I (48)63
SMMC7721 human hepatocarcinoma 9.1 μM HeLa human cervical carcinoma 9.3 μM
dihroxuralodin (52)74 MCF-7 human breast adenocarcinoma 8.9 μM schomburgkianone A HeLa human cervical carcinoma 9.8 μM
(157)109
hyperforatin F (69)63 SMMC7721 human hepatocarcinoma 10.0 μM
schomburgkianone B HeLa human cervical carcinoma 9.9 μM
hyphenrone X (80)81 HL-60 acute myeloid leukemia 4.3 μM
(158)109
MCF-7 human breast adenocarcinoma 2.1 μM
guttiferone Q (160)116 MCF-7 human breast adenocarcinoma 5.5 μM
hypercohin B (84)67 HL-60 acute myeloid leukemia 5.8 μM
Hela human cervical carcinoma 6.0 μM
hypercohin C (85)67 SMMC-7721 human hepatocarcinoma 8.2 μM
NCI-H460 human lung cancer 8.0 μM
SW480 human colon cancer 9.2 μM
garciniaphenone (163)307 UACC-62 human melanoma cancer 6.1 μM
hypercohin D (86)67 HL-60 acute myeloid leukemia 8.8 μM
OVCAR human ovarian cancer 6.4 μM
SMMC-7721 human hepatocarcinoma 9.5 μM
PC03 human prostate cancer 6.6 μM
A-549 human lung carcinoma 5.6 μM
786-0 human kidney cancer 5.1 μM
MCF-7 breast adenocarcinoma 9.3 μM
NCI-460 human lung cancer 8.3 μM
SW480 human colon cancer 7.4 μM
(−)-cycloxanthochymol A549 human lung carcinoma 4.5 μM
hyperattenin A (87)71 HL-60 acute myeloid leukemia 9.6 μM (172)49
SMMC-7721 human hepatocarcinoma 9.9 μM DU145 prostate cancer 4.7 μM
attenuatumione C (89)60 MCF-7 human breast adenocarcinoma 5.7 μM KB nasopharyngeal carcinoma 4.9 μM
hyperisampsin J (93)84 HL-60 acute myeloid leukemia 0.56 μM KBvin (vincristine-resistant KB subline) 5.2 μM
SMMC-7721 human hepatocarcinoma 0.58 μM coccinone C (174)97 MRC-5 human diploid embryonic 9.3 μM
A-549 human lung carcinoma 0.53 μM lung cells
MCF-7 human breast adenocarcinoma 0.88 μM coccinone E (176)97 MRC-5 human diploid embryonic 9.1 μM
SW480 human colon cancer 2.5 μM lung cells
BEAS-2B human bronchial epithelial 1.5 μM 7-epi-isogarcinol (178)97 MRC-5 human diploid embryonic 2.3 μM
cells lung cells
NB4 acute myeloid leukemia 0.63 μM symphonone A (185)123 MRC-5 human diploid embryonic 5.8 μM
lung cells
hyperisampsin K (94) 84
HL-60 acute myeloid leukemia 1.7 μM
garcinialiptone B (192)49 A549 human lung carcinoma 6.7 μM
SMMC-7721 human hepatocarcinoma 2.2 μM
DU145 prostate cancer 7.3 μM
A-549 human lung carcinoma 2.1 μM
KB nasopharyngeal carcinoma 5.7 μM
MCF-7 human breast adenocarcinoma 2.7 μM
KBvin (vincristine-resistant KB subline) 6.6 μM
SW480 human colon cancer 3.0 μM
garcicowin D (193)101 HT-29 human colon adenocarcinoma <5 μM
BEAS-2B human bronchial epithelial 2.7 μM
cells coccinone A (195)97 MRC-5 human diploid embryonic 3.3 μM
lung cells
hyperisampsin L (95) HL-60 acute myeloid leukemia 3.0 μM
paucinone D (204)94 HeLa human cervical carcinoma 5.8 μM
hyperisampsin M (96) HL-60 acute myeloid leukemia 1.4 μM
paucinone A (205)94 HeLa human cervical carcinoma 10.0 μM
SMMC-7721 human hepatocarcinoma 2.3 μM
paucinone B (206)94 HeLa human cervical carcinoma 8.2 μM
A-549 human lung carcinoma 1.9 μM
symphonone F (211)123 MRC-5 human diploid embryonic 6.9 μM
MCF-7 human breast adenocarcinoma 1.7 μM lung cells
SW480 human colon cancer 2.9 μM symphonone G (212)123 MRC-5 human diploid embryonic 3.7 μM
BEAS-2B human bronchial epithelial 3.0 μM lung cells
cells schomburgkianone D HeLa human cervical carcinoma 6.5 μM
hyphenrone U (104)81 HL-60 acute myeloid leukemia 6.1 μM (215)109
MCF-7 human breast adenocarcinoma 5.5 μM schomburgkianone E HeLa human cervical carcinoma 5.9 μM
hyphenrone E (105)85 HL-60 acute myeloid leukemia 4.7 μM (216)109
13-deoxy-guttiferone J KB nasopharyngeal carcinoma 8.3 μM garcimultiflorone I (218)99 HeLa human cervical carcinoma 7.7 μM
(136)105 SGC7901 human gastric cancer 4.2 μM
guttiferone J (137)105 KB nasopharyngeal carcinoma 8.5 μM TE1 esophageal cancer 8.1 μM
guttiferone K SW620 human colon cancer 0.0017 μM HCT-116 colon carcinoma 6.0 μM
(138)101,107,321
HL-7702 human normal hepatic cells 5.4 μM
BT474 human breast cancer 9.9 μM
oblongifolin F (221)334 HeLa human cervical carcinoma 4.2 μM
HepG2 human hepatocellular carcinoma 0.13 μM
HepG2 human hepatocellular 7.7 μM
KATO-III human gastric cancer 0.13 μM carcinoma
CHaGo human lung cancer 0.10 μM MCF-7 human breast adenocarcinoma 3.0 μM
HeLa human cervical carcinoma 9.7 μM MCF7-HER2 (HER2-overexpressed) 5.1 μM
A2780 human ovarian carcinoma 6.0 μM HCT-116 colon carcinoma 2.9 μM
HT-29 human colon adenocarcinoma 5.4 μM HCT-15 (P-glycoprotein-overex- 4.9 μM
oblongifolin C (141)101,321 SW620 human colon cancer <0.0015 μM pressed)

AC DOI: 10.1021/acs.chemrev.7b00551
Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews Review

Table 9. continued Table 9. continued

compounds cell lines IC50 values compounds cell lines IC50 values
symphonone H (226)123 MRC-5 human diploid embryonic lung 4.9 μM garmultin B (408)167 HL-60 acute myeloid leukemia 2.5 μM
cells SW480 human colon cancer 7.8 μM
oblongifolin G (227)334 HeLa human cervical carcinoma 3.9 μM (+)-garmultin C (409)167 HL-60 acute myeloid leukemia 2.4 μM
HepG2 human hepatocellular 7.7 μM SW480 human colon cancer 5.5 μM
carcinoma
(−)-garmultin C (410)167 HL-60 acute myeloid leukemia 3.2 μM
MCF-7 human breast adenocarcinoma 2.6 μM
SMMC-7721 human hepatocarcinoma 5.6 μM
MCF7-HER2 (HER2-overexpressed) 2.9 μM
A-549 human lung carcinoma 4.4 μM
HCT-116 colon carcinoma 2.9 μM
MCF-7 human breast adenocarcinoma 5.9 μM
HCT-15 (P-glycoprotein-overex- 4.0 μM
pressed) SW480 human colon cancer 3.0 μM
2,16-oxyguttiferone A HCT-116 colon carcinoma 8.0 μM human erythroleukemia (HEL) cells 2.5 μM
(230)129 (+)-garmultin F (411)167 HL-60 acute myeloid leukemia 5.4 μM
4,16-oxyguttiferone A HCT-116 colon carcinoma 3.0 μM A-549 human lung carcinoma 9.5 μM
(235)129 SW480 human colon cancer 4.3 μM
xerophenone C (242)136 KB nasopharyngeal carcinoma 1.5 μM (−)-garmultin F (412)167 HL-60 acute myeloid leukemia 2.6 μM
thoreliolide B (263)140 MCF-7 human breast adenocarcinoma 9.7 μM SW480 human colon cancer 3.4 μM
hypersubone C (265)145 HepG2 human hepatocellular carcinoma 9.7 μM (+)-garmultin D (414)167 HL-60 acute myeloid leukemia 2.4 μM
human esophageal cancer (Eca109) 6.7 μM MCF-7 human breast adenocarcinoma 3.1 μM
HeLa human cervical carcinoma 9.3 μM SW480 human colon cancer 1.5 μM
hyperisampsin C (278)149 HL-60 acute myeloid leukemia 9.5 μM human erythroleukemia (HEL) cells 4.7 μM
hyperisampsin D (279)149 HL-60 acute myeloid leukemia 9.4 μM (−)-garmultin D (415)167 HL-60 acute myeloid leukemia 3.5 μM
A-549 human lung carcinoma 6.0 μM SMMC-7721 human hepatocarcinoma 3.8 μM
hypersubone B (280)145 HepG2 human hepatocellular carcinoma 1.6 μM A-549 human lung carcinoma 3.0 μM
human esophageal cancer (Eca109) 0.07 μM MCF-7 human breast 3.2 μM
HeLa human cervical carcinoma 3.5 μM adenocarcinoma
A549 human lung carcinoma 7.5 μM SW480 human colon cancer 2.0 μM
garcinialiptone A (289)49 A549 human lung carcinoma 4.2 μM human erythroleukemia (HEL) cells 2.2 μM
DU145 prostate cancer 4.1 μM garmultin E (416)167 A-549 human lung carcinoma 10.0 μM
KB nasopharyngeal carcinoma 5.7 μM SW480 human colon cancer 5.8 μM
KBvin (vincristine-resistant KB subline) 5.6 μM (+)-garcimulin A (417)172 HL-60 acute myeloid leukemia 3.4 μM
garciniagifolone A (290) 150
GC7901 human gastric cancer 9.7 μM SMMC-7721 human hepatocarcinoma 4.2 μM
garcixanthochymone A HepG2 human hepatocellular carcinoma 8.3 μM A-549 human lung carcinoma 4.5 μM
(291)151 MCF-7 human breast adenocarcinoma 4.2 μM
SGC7901 human gastric cancer 7.3 μM SW480 human colon cancer 7.2 μM
MCF-7 human breast adenocarcinoma 5.8 μM garcimulin B (419)172 SMMC-7721 human hepatocarcinoma 7.6 μM
garcixanthochymone B HepG2 human hepatocellular carcinoma 5.8 μM A-549 human lung carcinoma 7.1 μM
(292)151 hyperuralone A (420)170 HL-60 acute myeloid leukemia 7.1 μM
SGC7901 human gastric cancer 5.2 μM SMMC-7721 human hepatocarcinoma 8.1 μM
garcixanthochymone C HepG2 human hepatocellular carcinoma 6.6 μM A-549 human lung carcinoma 4.6 μM
(295)151
SW480 human colon cancer 5.6 μM
SGC7901 human gastric cancer 6.8 μM
MCF-7 human breast adenocarcinoma 9.8 μM
a
Other PPAPs with IC50 > 10 μM for all cell lines are not listed.
sampsonione R (297) 153
Hela human cervical carcinoma <5 μM
pseudohenone F (299)143 human esophageal cancer (Eca109) 9.5 μM
only isolated product. After extensive optimization, allylic oxi-
HeLa human cervical carcinoma 6.2 μM dation of 465 was accomplished using TBHP, PhI(O2CCF3)2,
pseudohenone G (300)143 human esophageal cancer (Eca109) 9.6 μM and O2 to afford vinylogous ester 466. Hydrolysis of the C-9
hyperisampsin O (319)155 HL-60 acute myeloid leukemia 3.8 μM ketal present in 466 to yield alcohol 467 was performed via
hypersampsonone F HL-60 acute myeloid leukemia 4.2 μM treatment of 466 with BrBMe2, followed by LiTMP-mediated
(320)76 methanol extrusion from the intermediate hemiketal. After
A-549 human lung carcinoma 9.4 μM surveying various methods, a radical Keck allylation approach
hyperattenin K (331)147 HL-60 acute myeloid leukemia 4.6 μM was introduced to install the C-7 prenyl group from 467 to 468
A-549 human lung carcinoma 5.4 μM in three steps. After silylation at the C-3 position, sequential
hyperattenin I (335)71 HL-60 acute myeloid leukemia 2.0 μM bridgehead deprotonation−acylation using LiTMP and i-PrCOCN
A-549 human lung carcinoma 3.3 μM yielded ketone 469, which could be converted to (+)-hyperforin
tomoeone F (351)160 KB nasopharyngeal carcinoma 6.2 μM (422) in three steps.339 This strategy was also applied to the total
harrisotone A (353)44 P-388 leukemia 1.6 μM syntheses of hyperforin’s analogue, (−)-nemorosone (426),
hyperascyrone C (361)161 HL-60 acute myeloid leukemia 4.2 μM and the nonnatural compound (+)-secohyperforin by starting
harrisotone C (376)44 P-388 leukemia 2.4 μM with isoprenyl alcohol instead of geraniol (Scheme 7).340
hyphenrone R (395)81 HL-60 acute myeloid leukemia 3.3 μM
7.3. Barriault’s Total Syntheses of Hyperforin and
garcixanthochymone E HepG2 human hepatocellular carcinoma 9.0 μM
(398)151 Papuaforins A−C
A549 human lung carcinoma 8.2 μM The concise total syntheses of hyperforin (422) and its ana-
garcixanthochymone D HepG2 human hepatocellular carcinoma 9.1 μM logues, papuaforins A−C (478−480), were accomplished in
(399)151
17 steps by Barriault and Bellavance (Scheme 8).341 They
A549 human lung carcinoma 7.5 μM
provided a strategy of short and scalable synthesis of densely
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a
Table 10. Other Activities of PPAPs
compounds subject results activities
hyperforatin D (22)63 acetylcholinesterase (AChE) 7.2 μM (IC50) neural activity
15-epi-hyperforatin D (31)63 AChE 4.0 μM
hyperforatin B (32)63 AChE 8.8 μM
hyperforatin F (69)63 AChE 8.8 μM
32-epi-hyperforatin E (73)63 AChE 9.1 μM
hyperuralone C (247)87 AChE 9.6 μM
hyperuralone D (250)87 AChE 7.1 μM
hypermongone G (43)34 NO production in RAW264.7 cells 9.5 μM (IC50) anti-inflammatory
garcimultiflorone A (63)77 superoxide anion (·O2−) generation and elastase release 5.6 μM
4.7 μM
13,14-didehydroxy-isogarcinol (187)77 superoxide anion (·O2−) generation and elastase release 0.88 μM
1.2 μM
garcimultiflorone B (208)77 superoxide anion (·O2−) generation and elastase release 0.11 μM
0.14 μM
13-hydroxygarcimultiflorone B (209)77 superoxide anion (·O2−) generation and elastase release 0.40 μM
0.86 μM
isosampsonione J (271)148 superoxide anion (·O2−) generation and elastase release 7.2 μM
6.0 μM
garcimultiflorone G (317)156 superoxide anion (·O2−) generation 7.0 μM
hyperattenin C (61)71 HIV on C8166 cells 8.1 μM (EC50) anti-HIV
1.65 (SI)
hyperattenin B (88)71 HIV on C8166 cells 9.9 μM, 0.97
hyperisampsin D (279)149 HIV-1 in MT-4 cells 0.97 μM, 7.7
hyperisampsin A (281)149 HIV-1 in MT-4 cells 3.0 μM, 4.8
hyperattenin K (331)147 HIV-1 in MT-4 cells 3.4 μM, 3.5
hyperascyrone E (349)161 HIV-1 in MT-4 cells 3.6 μM, 2.1
hyperascyrone B (360)161 HIV-1 in MT-4 cells 4.2 μM, 0.36
hyperascyrone C (361)161 HIV-1 in MT-4 cells 2.4 μM, 0.23
hyperascyrone F (373)161 HIV-1 in MT-4 cells 2.4 μM, 5.6
coccinone C (174)97 FcB1 (P. falciparum) 9.0 μM (IC50) antiplasmodial
coccinone D (175)97 FcB1 (P. falciparum) 7.0 μM
coccinone E (176)97 FcB1 (P. falciparum) 4.9 μM
7-epi-isogarcinol (178)97 FcB1 (P. falciparum) 5.1 μM
14-deoxy-7-epi-isogarcinol (179)97 FcB1 (P. falciparum) 2.5 μM
symphonone B (180)123 FcB1 (P. falciparum) 3.3 μM
7-epi-coccinone B (181)123 FcB1 (P. falciparum) 3.3 μM
symphonone D (182)123 FcB1 (P. falciparum) 2.1 μM
symphonone E (183)123 FcB1 (P. falciparum) 2.7 μM
symphonone A (185)123 FcB1 (P. falciparum) 2.8 μM
symphonone C (186)123 FcB1 (P. falciparum) 2.6 μM
coccinone A (195)97 FcB1 (P. falciparum) 4.3 μM
symphonone F (211)123 FcB1 (P. falciparum) 3.2 μM
symphonone H (226)123 FcB1 (P. falciparum) 3.0 μM
symphonone I (231)123 FcB1 (P. falciparum) 6.7 μM
guttiferone K (138)113 DPPH 2.3 μg/mL (IC50) antioxidant
acuminophenone A (154)113 DPPH 1.1 μg/mL
ABTS 2.0 μg/mL
compounds subject results activities
kielmeyeracin (156)115 S. aureus SA-1199B 2 μg/mL (MIC) antimicrobial
S. aureus XU-212 0.25 μg/mL
S. aureus ATCC-25923 1 μg/mL
S. aureus RN-4220 0.25 μg/mL
S. aureus EMRSA-15 1 μg/mL
S. aureus EMRSA-16 0.5 μg/mL
cowanone (160)117,118 S. aureus 2 μg/mL
S. pyogenes 7.8 μg/mL
S. aureus (methicillin resistant) 0.5 μg/mL
Yezo’otogirin E (237)91 E. coli 4.0 μg/mL
S. aureus 8.0 μg/mL
trijapin D (243)137 C. albicans 8.0 μg/mL

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Table 10. continued

compounds subject results activities
(−)-nemorosonol (401)137 E. coli 8 μg/mL
T. mentagrophytes 8 μg/mL
otogirinin D (39)76 phosphodiesterase-4 (PDE4D2) 2.7 μM (IC50) PDE4 inhibitor
hyperattenin C (61)76 PDE4D2 0.64 μM
hypersampsonone A (64)76 PDE4D2 8.1 μM
hyperisampsin I (92)76 PDE4D2 3.1 μM
hyperisampsin J (93)76 PDE4D2 1.9 μM
hypersampsone N (312)76 PDE4D2 1.6 μM
hyperattenin G (339)76 PDE4D2 3.5 μM
guttiferone J (137)109 DNA polymerases α and λ 6.5, 5.7 μM (IC50) DNA polymerases inhibitor
guttiferone K (138)109 DNA polymerases α and λ 6.2, 5.4 μM
oblongifolin C (141)109 DNA polymerases α and λ 5.7, 5.2 μM
schomburgkianone F (143)109 DNA polymerases α and λ 8.6, 8.8 μM
schomburgkianone A (157)109 DNA polymerases α and λ 6.3, 5.0 μM
schomburgkianone B (158)109 DNA polymerases α and λ 6.4, 5.8 μM
schomburgkianone C (159)109 DNA polymerases α and λ 8.8, 5.6 μM
schomburgkianone D (215)109 DNA polymerases α and λ 5.6, 7.4 μM
schomburgkianone E (216)109 DNA polymerases α and λ 5.4, 6.9 μM
furohyperforin isomer 1 (49)65 CYP3A4 enzyme 0.079 μM (IC50) side effects
furoadhyperforin (67)65 CYP3A4 enzyme 0.072 μM
a
Other PPAPs with IC50 > 10 μM (or 10 μg/mL) are not listed.

Scheme 5. Shibasaki’s Total Synthesis of Garsubellin A Scheme 6. Shibasaki’s Total Synthesis of (−)-Hyperforin

substituted PPAP scaffolds with a bicyclo[3.3.1]-nonane core

through a gold(I)-catalyzed 6-endo-dig carbocyclization of cyclic
enol ethers for late-stage functionalization.342−345 First, a selec-
tive 6-endo-dig carbocyclization of silyl enol ethers to alkynes
was achieved by modulating the steric and electronics prop-
erties of the ancillary ligand on the cationic gold complex.
Starting from commercially available ketone 470, a careful
orchestration of stereospecific allylation, alkylation, and aldol
reactions (from 471 to 474) installed the functional groups at
C-5, C-7, and C-8. Then a rapid and scalable synthesis of
bicyclo[3.3.1]nonadione 475 was realized through an efficient
gold(I)-catalyzed carbocyclization, which served as a pivotal
intermediate for the assembly of various PPAPs, such as
(±)-hyperforin (422) and (±)-papuaforins A−C (478−480),
through late-stage functionalization at C-1 and C-3 on inter-
mediate 476. In addition, a formal synthesis of (±)-nemor-
osone (426) from 476 in 6 steps was also suggested.341 This
modular approach serves as a platform to quickly assemble PPAPs
for further synthetic studies.341
AF
7.4. Maimone’s Total Synthesis of Hyperforin
Maimone and Ting developed a route of a 10-step total syn-
thesis of hyperforin (422) from 2-methylcyclopent-2-en-1-one
(481).346,347 This route was enabled by a novel diketene annu-
lation reaction and an oxidative ring expansion strategy designed
to complement the presumed biosynthesis of complex PPAPs.
First, highly substituted cyclopentanone 482 with contiguous
C-7 and C-8 stereocenters was prepared (Scheme 9), which
could be further alkylated to afford ketone 483, setting the
stage for a key annulation reaction. After careful experimenta-
tion, it was found that the LiTMP-mediated deprotonation of
483 engaged simple diketene in a formal C-acylation/ring
annulation process leading to complex 5/6-fused bicycle 484 as
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Scheme 7. Shair’s Enantioselective Total Syntheses of Scheme 9. Maimone’s Total Synthesis of Hyperforin
(+)-Hyperforin and (−)-Nemorosone

422 is consistent with the naturally occurring substance. The

described work enables the preparation of a highly substituted
Scheme 8. Barriault’s Total Syntheses of Hyperforin and bicyclo[3.3.1]nonane-2,4,9-trione motif (488) in only six steps
Papuaforins A−C and thus serves as a platform for the construction of easily synthe-
sized, highly diverse PPAPs modifiable at every position.346,347
7.5. Nakada’s Syntheses of Hyperforin, Nemorosone,
Garsubellin A, and Clusianone
Nakada and co-workers established a novel synthetic approach
to bicyclo[3.3.1]nonane derivative 494 and achieved the total
synthesis of (±)-hyperforin starting from methyl 2,6-dimethox-
ybenzoate 489 in 35 steps (Scheme 10).348 Their route involved

Scheme 10. Nakada’s Syntheses of Hyperforin, Nemorosone,

Garsubellin A, and Clusianone

a single diastereomer in 45% yield. Diketone 484 then reacted

smoothly with trimethylsilyldiazomethane (96%) to obtain an
easily separable 1:1 mixture of regioisomeric vinylogous esters
485 and 486. Regioisomer 485 was ultimately discovered to be
crucial in completing the total synthesis of hyperforin, while
486 could be recycled to 484 via basic hydrolysis. After opti-
mization, it was discovered that simply stirring 485 with
PhI(OAc)2 in basic methanol at room temperature effected a
very clean (92%) rearrangement to give 488, presumably via an
intermediate similar to 487 (Scheme 9). The isobutyryl and
prenyl groups at C-1 and C-3, respectively, were further
installed in four steps to accomplish the total synthesis of a three-step sequence: ingenious intramolecular cyclopropanation
hyperforin (422). Single-crystal X-ray analysis of intermediate of 491, which was prepared from 489 by 7 steps, followed by
486 indicated the absolute configuration of the final product stereoselective alkylation of the cyclopropane 492 to afford 493
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Chemical Reviews
with a C-8 quaternary stereogenic center, and, finally, regio-
selective ring opening of the cyclopropane moiety to afford
494.349−351 Chemo- and stereoselective hydrogenation of the
versatile intermediate 495 generated 496 with a C-7 stereo-
genic center, from which (±)-hyperforin (422) could be further
obtained in several steps. The authors also used this ingenious
route to accomplish the total syntheses of hyperforin’s ana-
logues (±)-nemorosone (426) and (±)-garsubellin A (446) as
well as a type B BPAP, (±)-clusianone (432).348,352−354
However, the catalytic asymmetric intramolecular cyclo-
propanation of the α-diazo ketone 491, a common synthetic
intermediate for the above four PPAPs, exhibited low enan-
tioselectivity.348,355 Later, the improved α-diazo β-keto sulfone
497 was found to be catalyzed by a chiral ligand 498 in the
presence of H2O to directly afford bicyclo[3.3.1]nonane
derivative 499 with 84% ee and in 79% yield without isolation
of the cyclopropane intermediate (Scheme 11).355 The PhSO2
Scheme 11. Nakada’s Formal Syntheses of (+)-Hyperforin,
Nemorosone, Garsubellin A, and (−)-Clusianone
group of 499 was removed by successive treatment with alu-
minum amalgam and (TBS)OTf to obtain 500, which expe-
rienced a Mukaiyama aldol reaction with benzaldehyde and
further elimination of TBSOH to afford 501. Dimethylation of
the C-8 position of 501 gave 502, while first allylation and
then methylation could afford 504. The benzylidene groups in
502 and 504 were removed using n-Bu4NOH in acetonitrile
and THF, respectively, to afford the respective synthetic inter-
mediates 503 and 505 that were previously reported, accom-
plishing the formal enantioselective total syntheses of nemorosone
(426), garsubellin A (446), (−)-clusianone (432), and
(+)-hyperforin (422).355
7.6. Danishefsky’s Total Syntheses of Nemorosone,
Clusianone, and Garsubellin A
Danishefsky and co-workers devised a divergent synthetic strategy
that ultimately enabled the total syntheses of (±)-nemorosone
(426), (±)-clusianone (432), and (±)-garsubellin A (446)
(Scheme 12).356,357 The common intermediate 514 that served
as the branching point toward (±)-nemorosone (426) and
(±)-clusianone (432) was constructed by utilizing the allylative
dearomatization and iodinative cyclization methods. First, 3,5-
dimethoxyphenol (506) underwent a π-allylpalladium trans-
formation in the presence of allyl alcohol, Ti(Oi-Pr)4, and
Pd(OAc)2 to afford the dearomatized doubly allylated product
507 in 50% yield. With the stage set for the construction of the
bicyclo[3.3.1] system, doubly prenylated dione 508 was
AH
Review
Scheme 12. Danishefsky’s Total Syntheses of Nemorosone,
Clusianone, and Garsubellin A
subjected to iodinative cyclization to afford the desired bicycle
511 (32% yield), accompanied by fused bicyclic byproducts
509 and 510 (29% and 24% yield, respectively), which could be
conveniently recycled to cyclohexadione 508 under reductive
conditions (Zn) in 78% and 87% yields, respectively. Diiodide
511 was converted into monoiodide 513 through the inter-
mediacy of cyclopropane 512 in a two-step operation that
involved i-PrMgBr and TMSI. The subsequent alkylation of
513 generated key intermediate 514 (84% yield) with a
bicyclo[3.3.1]nonane core to further accomplish the total
syntheses of (±)-nemorosone (426) and (±)-clusianone (432)
in several steps.356 In addition, the elegant and instructive syn-
thesis of (±)-garsubellin A (446) was also achieved using a
similar strategy starting from a protected phloroglucinol
derivative 515.357 Their synthesis involved key steps of pre-
nylation and dearomatization of 515 to afford 516, iodinative
cyclization of the prenylated diketone 517 to obtain diiodide
518, and further allylation to generate intermediate 519 to
access the target natural product.356,357
7.7. Simpkins’s Total Syntheses of Nemorosone and
Clusianone
Simpkins’ research group published a series of reports that doc-
umented the preparation of racemic and optically pure clus-
ianone (432),358−361 in which an Effenberger annulation was at
the center of their synthetic strategy for the construction of the
bicyclo[3.3.1]nonane core structure 526 (Scheme 13).362−364
Their synthesis began with preparation of substituted cyclo-
hexenone 521 from cyclohexadione derivative 520 in 88% yield
over the two steps. 1,4-Addition of the methyl group to 521 led
to an inconsequential mixture of diastereomers 522 and 523
(85:15), which were converted into methyl enol ethers 524 and
525 in preparation for the proposed Effenberger cyclization.
Treatment of compounds 524 and 525 with malonyl dichloride
under phase-transfer conditions (KOH, BnEt3NCl) led to the
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Scheme 13. Simpkins’s Total Syntheses of Nemorosone and
Clusianone
anticipated bicyclic system 526 being obtained as a single
isomer. The versatile intermediate 526 was successfully trans-
formed into (±)-clusianone (432) and (±)-nemorosone (426)
as well as 519, a key intermediate to accomplish the formal
synthesis of (±)-garsubellin A (446).358−361 Interestingly, kinetic
resolution of an advanced intermediate (±)-527 in a bridgehead
lithiation mediated by a chiral bis-lithium amide 528 gave
(+)-527 (98% ee) and prenylated product (−)-529 (50% ee),
which enabled access to natural product (+)-clusianone (432)
in optically pure form.361 X-ray diffraction analysis of its deriv-
ative 530 allowed the absolute configuration of (+)-clusianone
to be assigned.24,361
In addition, Marazano and Coltart’s research groups also
accomplished the total synthesis of clusianone (432) in 2007
and 2010, respectively.365,366 Their synthetic routes were
generally similar to that of Simpkins’, and Effenberger annu-
lation was utilized as the key step for the construction of the
bicyclo[3.3.1]nonane core.298,365−367
7.8. Plietker’s Total Syntheses of a Series of Type B PPAPs
7.8.1. Oblongifolin A, 7-epi-Clusianone, Hyperibone L,
and Hyperpapuanone. In 2011, Plietker and co-workers
reported an excellent 7-step high-yielding synthetic approach
toward four natural endo type B PPAPs: oblongifolin A (120),
7-epi-clusianone (433), hyperibone L (537), and hyper-
papuanone (538) (Scheme 14).368 The concept of a strict
separation between framework construction and framework
decoration proved to be the key for successful synthesis of
these natural products, which differ in their substituents R1−R4.
Acetylacetone (531) serves as a common starting material and
was allylated in the first step using sodium hydride (NaH) and
the corresponding allylating agent R1X.368 The α,β-unsaturated
ketone 532 was employed in a subsequent tandem Michael
addition−Knoevenagel condensation to give the cyclohexenone
core 533. A regioselective 1,2-addition of methyllithium to 533
followed by α-allylation or methylation led to cyclohexenone
534 with a high level of control of the relative stereochemistry
AI
Review
Scheme 14. Plietker’s Syntheses of Oblongifolin A, 7-epi-
Clusianone, Hyperibone L, and Hyperpapuanone
in favor of the desired trans diastereomers. Subsequent addi-
tion of methylcopper in the presence of lithium chloride
and Me3SiCl allowed a 1,4-methylation to yield 535, which
underwent a diastereoselective alkylation to produce the densely
substituted cyclohexanone 536. With this material available,
they used a Dieckmann condensation to prepare the strained
bicyclo[3.3.1]nonatrione core that was successfully converted
to natural products (±)-oblongifolin A (120), (±)-7-epi-
clusianone (433), (±)-hyperibone L (537), and (±)-hyper-
papuanone (538) in 6%, 22%, 22%, and 21% overall yield,
respectively. In addition, non-natural BPAP regio-hyperpapua-
none, a 1,5-regioisomer of hyperpapuanone (538), was also
designed to confirm the originally proposed structure of 538.368
7.8.2. Hyperibone I, Sampsonione P, (+)-Clusianone,
Garcinol, and Isogarcinol. Soon afterward, Plietker’s research
group accomplished the first total syntheses of (±)-hyperibone
I (546) and (±)-sampsonione P (547) in 9 and 10 steps,
respectively, using a similar strategy to that mentioned above
(Scheme 15).369 The key step of the two syntheses is the
introduction of the last prenyl or allyl substituent by either a
Fe-catalyzed allylation (from 539 to 540) or a decarboxylative
Tsuji−Trost allylation (from 539 to 541). Selectively
prenylated cyclohexanones 540 and 541 successfully underwent
a Dieckmann condensation to generate structures 542 (47% yield)
and 543 (34% yield) with a bicyclo[3.3.1]nonatrione core.
Owing to the different rates in the epoxidation of prenyl and
allyl groups, the tetrahydrofuran motif (544 and 545) could
be formed at a late stage in the synthesis. The final cross-
metathesis provided the desired remaining prenyl side chains in
good overall yield (71% and 65%). Both the total syntheses and
the in-depth spectroscopic investigations confirmed the
structure of sampsonione P (547) and the previously proposed
revised structure of hyperibone I (546).369 In addition, Plietker
and co-workers also provided a short and concise enantiose-
lective total synthesis of the exo-type B PPAP, (+)-clusianone
(432), in 11 steps with 97% ee.370 As shown in Scheme 15, an
asymmetric Tsuji−Trost allylation from 548 to 550 and a
sequence of Ru-catalyzed ring-closing metathesis from 550 to
551 and subsequent diastereoselective Tsuji−Trost allylation
from 551 to 552 represent the key steps in this synthetic route.
The successful application of this method on (+)-clusianone
(432) enabled the authors to extend the PPAP-synthesis algo-
rithm to the exo-type B PPAPs without alteration of the syn-
thetic operations.370
Plietker’s synthetic strategy is widely used in the total
syntheses of other endo type B PPAPs, such as the first access
of (±)-garcinol (428) and (±)-isogarcinol (429).371 The syn-
thetic route is similar to that of (±)-sampsonione P (547)
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Scheme 15. Plietker’s Total Syntheses of Hyperibone I,
Sampsonione P, and (+)-Clusianone
(Scheme 16),369 in which key intermediates 554 and 555 share
a 4-acetoxylated prenyl group at C-5 rather than a prenyl group.
Scheme 16. Plietker’s Total Syntheses of Garcinol and
Isogarcinol
A subsequent diastereoselective Pd-catalyzed allyl−allyl cross-
coupling led to a clean formation of 556 by using bis-diphe-
nylphosphinoethane (dppe) as a ligand and addition of CsF as
activator. Upon completion of the synthesis of (±)-garcinol
(428), it could be further transformed into (±)-isogarcinol
(429) by treatment of a concentrated HCl solution. After
separation of the enantiomers, the absolute configurations
of the four natural products were assigned based on ECD
spectroscopy.371
7.8.3. Guttiferone A. In 2014, Plietker and co-workers
achieved the first total synthesis of (±)-guttiferone A (434) in
10 steps starting from 1,8-nonadien-5-one (557) (Scheme 17)
AJ
Review
Scheme 17. Plietker’s Total Synthesis of Guttiferone A
by strictly separating framework-decorating operations from
framework-constructing ones.372 Compared to the endo type B
PPAPs accessed above, guttiferone A (434) possesses an
additional chiral center at C-8 (trans relationship of C-7/C-8);
therefore, the full control of four adjacent stereocenters within a
central cyclohexanone motif turned out to be a synthetic
challenge. Plietker’s team developed a synthetic algorithm that
allowed full control of the diastereoselective course for total
syntheses of endo type B PPAPs. The trans stereochemistry at
C-5 was mainly directed by the C-7 substituent, as in the
formation of 558. The addition of the organocopper reagent to
C-8 occurs cis with respect to the C-7 substituent, as in the
generation of 559. The sterically more demanding substituent
at C-8 directs the final allylation at C-1 into the trans position,
but this stereochemical course is not applicable for synthesis of
guttiferone A (434).372 A ring-closing metathesis (from 559 to
560) and the resulting conformational change make a full
inversion of the C-8 stereochemistry using a Pd-catalyzed
decarboxylative Tsuji−Trost allylation (from 561 and 562 to
563). In addition, the authors also accomplished the total
synthesis of a non-natural PPAP, (±)-8-epi-guttiferone A, whose
synthetic route is similar to that of sampsonione P (547).369,372
7.9. Porco’s Total Syntheses of PPAPs Using Alkylative
Dearomatization Strategy
7.9.1. (−)-Hyperibone K and Clusianone. Inspired by
biosynthetic considerations,373 Porco’s research group devised
an ingenious and highly instructive approach to the PPAPs that
ultimately enabled the total synthesis of (±)-clusianone (432)
and the first asymmetric synthesis of the type B adamantane
PPAP (−)-hyperibone K (575) (Scheme 18).374,375 In this
approach, an alkylative dearomatization−annulation strategy
was developed to access the bicyclic core structure of the
PPAPs.374,375 Commencing from acylphloroglucinol 565,
double C-prenylation gave clusiaphenone B (566) in 45%
yield. Treatment of 566 with KHMDS and α-acetoxy enal 567
led to the annulation product with bicyclo[3.3.1]nonane
framework. To facilitate isolation and further characterization,
enol methylation afforded 568 as a mixture of regioisomers
in 54% overall yield. Addition of a vinyl Grignard reagent to
aldehyde 568, followed by acetylation of the intermediate allylic
alcohol, afforded allylic acetate 569, which was successfully
converted to (±)-clusianone (432) in three steps. 375
Remarkably, the enantioselective dearomatization/alkylation
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Scheme 18. Porco’s Total Syntheses of (−)-Hyperibone
K and Clusianone
of phloroglucinol precursor 566 with enal 570 could form an
adamantane core 572 with four carbon quaternary centers in
one step using dimeric chiral phase-transfer (ion pair) catalysts
571. Treatment of 572 with LDA, followed by addition of
2-methyl-1-propenylmagnesium bromide, afforded allylic alcohol
574 which was produced from the retro-aldol intermediate 573.
Intramolecular cation cyclization of 574 catalyzed by Sc(OTf)3
successfully afforded (−)-hyperibone K (575) in 50% yield
(two steps) with high diastereoselectivity (dr > 20:1). Successful
completion of the total synthesis also served to confirm the
absolute configuration of the naturally occurring substance.374
7.9.2. Plukenetione A and 7-epi-Nemorosone. As an
extension of their synthetic studies toward the PPAPs through
an alkylative dearomatization−annulation strategy, they later
demonstrated an acid-mediated site-selective alkylation that
allows facile access to the type A adamantane PPAP plukenetione
A (583), a regioisomer of hyperibone K (575) (Scheme 19).376
Scheme 19. Porco’s Total Syntheses of Plukenetione A and
7-epi-Nemorosone
In this context, protected acylphloroglucinol methyl ether 576
was employed with the intention that the alkylative dear-
omatization would take place at the C-1 and C-5 positions
AK
Review
rather than at the C-3 and C-5 positions to approach the type B
PPAPs. Treatment of 576 with LiHMDS in the presence of
α-acetoxy enal 567 afforded the monoalkylated dearomatized
product 577 (90% yield) instead of the expected annulation
product. Interestingly, treatment of dearomatized substrate 577
with lithium chloride in DMSO unexpectedly led to formation
of the type B adamantane 578. However, silylative cyclization
of 577 with TBSOTf and N,N-diisopropylethylamine yielded
bicyclic product 579, which was exposed to concentrated HCl
(4 equiv) to afford adamantane alcohol 580 in 69% yield as a
single diastereomer. In contrast, treatment of 577 with concen-
trated HCl in THF led directly to adamantane alcohol 580
(75%). Then CeCl3-promoted addition of 2-methyl-2-prope-
nylmagnesium bromide followed by acidic workup afforded the
undesired adamantane 582 (13% yield) and the corresponding
desired diastereomer. A solution to address this late-stage set-
back was ultimately secured through the isolation of the alkenyl
addition product 581, which could be smoothly converted to
adamantane 582 as a single diastereomer in 32% yield. Olefin
cross-metathesis of 582 using isobutylene in the presence of
the Grubbs II metathesis catalyst afforded (±)-plukenetione A
(583) in 74% yield.376 In addition, starting from adamantane
580, tandem retro-aldol/vinyl Grignard addition followed by
sequential acylation led to the formation of 584, which was
successfully transformed into (±)-7-epi-nemorosone (427) in
three steps.377
7.9.3. Asymmetric Syntheses of (−)-Clusianone and
Non-natural PPAPs. Later, Porco’s research group developed
a scalable, asymmetric, and stereodivergent synthesis of
(−)-clusianone (432) in only six steps from commercial starting
materials (Scheme 20).378 They implemented a challenging
biomimetic cationic cyclization forging a bond between two
sterically encumbered quaternary carbon atoms (from 586 to
587). Mechanistic studies underscore the ability of formic
acid to mediate a unique biomimetic cyclization to access allyl
clusianone 587. After accessing (−)-clusianone (432), the gram-
scale synthesis of (±)-clusianone (432) was achieved by changing
the triflate (−)-585 to (±)-585 from the beginning.378
The biomimetic cationic cyclization strategy was also utilized
to accomplish the first asymmetric total syntheses of four non-
natural PPAPs in six steps.379 In this context, regioselective bis-
alkylation of acylphloroglucinol 584 using the triflate (−)-585
provided dearomatized adduct (+)-(S,S)-588 (Scheme 20).
Diastereoselective oxycyclization of (+)-(S,S)-588 utilized
novel SnCl4 and BF3−OEt2 LBA systems to induce stereo-
selective, intramolecular protonation resulting in selective for-
mation of either pyranodienone (−)-589 or (+)-590. Asymmetric
syntheses of (+)-7-epi-13,14-didehydroxyisogarcinol (593) and
(+)-23-epi-13,14-didehydroxyisogarcinol (594) were completed
by treating allylated products 591 and 592 with 1:1 H2O/TFA
followed by Grubbs II catalyst. In addition, a similar strategy
enabled production of the meso-dervied isomers (±)-7,23-epi-
13,14-didehydroxyisogarcinol and (±)-7,23-epi-garcimultiflor-
one A.379 Finally, the authors developed a gram-scale strategy
to enable production of ample quantities of each isomer in a
single synthetic sequence, which minimized step count and
purification events.379
In the process of the syntheses of diverse PPAPs, Porco and
co-workers developed a biosynthesis-inspired, diversity-ori-
ented synthesis approach to rapid construction of both type
A and B PPAP scaffolds (596 and 597) via the use of two
consecutive Pd-catalyzed reactions, double-decarboxylative
allylation (DcA)/Claisen rearrangement (from 595 to 576),
DOI: 10.1021/acs.chemrev.7b00551
Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews
Scheme 20. Porco’s Asymmetric Syntheses of
(−)-Clusianone and Non-natural PPAPs
and a dearomative conjunctive allylic alkylation (DCAA)
(Scheme 21).380
Scheme 21. Porco’s Synthesis Approach to PPAPs Using
Double-DcA/Claisen Rearrangement and DCAA
7.10. Biomimetic Syntheses of PPAPs Using Radical
Cyclization
George’s research group accomplished the biomimetic
syntheses of four PPAPs, ialibinones A and B,381 garcibractea-
tone (392), and doitunggarcinone A (393) in 4 steps,166,169
using a key radical cyclization reaction of MPAPs (Schemes 22
and 23). Independently, Simpkins and co-workers also reported
similar biomimetic syntheses of ialibinones A and B in 2010
through a Mn(OAc)3-mediated domino radical cyclization.382
As shown in Scheme 22, the proposed biosynthetic precursor
600 was synthesized from phloroglucinol (598) via acylphlor-
oglucinol 599 in three steps. Oxidative radical cyclization of
600 with PhI(OAc)2 gave (±)-ialibinones A (601) and B (602)
AL
Review
Scheme 22. George’s Biomimetic Syntheses of Ialibinones
A and B
in 58% yield (1:1) via a selective radical cascade reaction to
install the bicyclo[3.2.1]octane ring system.381 Using a similar
strategy, George et al. also provided four-step syntheses of the
highly complex PPAPs (+)-garcibracteatone (392) and
(±)-doitunggarcinone A (393) (Scheme 23). The key
Scheme 23. George’s Biomimetic Syntheses of
Garcibracteatone and Doitunggarcinone A
biomimetic transformation is a cascade of 7-endo-trig and
5-exo-trig radical cyclizations followed by a terminating aromatic
substitution reaction.166,169 The synthesis of doitunggarcinone
A (393) confirmed its C-5 relative configuration and also led to
a structural revision for doitunggarcinone A (393) and its
biosynthetic precursor doitunggarcinone B (402).166,169
The success of the strategy highlights the power of biomi-
metic synthesis as applied to the rapid generation of molecular
complexity. Furthermore, the efficiency and inherent selectivity
of the radical cascade reactions strongly suggest that a similar
process is involved in the biosynthesis of the natural products.166,169
In addition to total synthesis studies of PPAPs, other teams
such as Couladouros,383,384 Marazano,385−387 Mehta,388−394
Takagi,395,396 and Chen,397 et al., have also made efforts to
develop synthetic methodologies and strategies toward con-
struction of the bicyclo[3.3.1]nonane core of these complicated
natural products.398−402 This work has been summarized in
other reviews and hence is not elaborated in detail here.23−25
8. SUMMARY AND FUTURE DIRECTIONS
In summary, this review presents general insight into the
chemistry and biological activities of PPAPs in the past 11
years. As chemists discover and report new PPAPs and as they
correct errors in the literature, we will update the online data-
base in real time. Our hope is that the tables will serve as a
continuing resource both for natural products chemists and for
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Chem. Rev. XXXX, XXX, XXX−XXX
Chemical Reviews
synthetic chemists looking both to clarify structural assignments
and to prepare new compounds.
The presence of multiple prenyl groups and the derived
complex ring systems in the diverse structures of PPAPs are
distinctive among plant secondary metabolites. Generally,
polyketide and prenylation synthases are widespread in plants
and often coexist in certain species, as evidenced by the
presence of natural prenylated flavones and xanthones. Notably,
complex PPAPs are hitherto restricted to plants in the family
Guttiferae, which indicated the prenyltransferase in these plants
should possess high activity and selectivity. Furthermore, the
intriguing structures of PPAPs and their biogenetic relationship
also suggest there are complex postmodification processes
including oxidation, rearrangement, and cyclization in plants.
Only a few studies on the biosynthesis of PPAPs were reported
before 2007; more in-depth research is still needed to elucidate
the interesting biosynthetic pathway of this special group of
metabolites. Systematic SAR evaluation of pharmacological
parameters, especially in vivo studies using suitable higher
animal species, are urgently demanded so that the limitations of
the clinical application of some promising molecules, such as
garcinol, oblongifolin C, and hyperforin’s synthetic derivatives,
can be overcome. Moreover, more investigations into the
bioactivities and corresponding molecular mechanisms of other
types of PPAPs (besides BPAPs) are also needed. In the aspect
of organic synthesis, these complex and fascinating chemical
structures of PPAPs continue to be a challenging task for
chemists, although much progress has been made in recent
years. The currently accomplished molecules are mainly type A
and B BPAPs with a bicyclo[3.3.1]nonane core, and only total
syntheses of two adamantane-type PPAPs, plukenetione A and
hyperibone K, and the biomimetic syntheses of four PPAPs
using radical cyclization strategy have been achieved. The total
syntheses of other PPAPs including adamantane/homoada-
mantane and spirocyclic types, as well as some structurally
complex PPAPs with unprecedented carbon skeletons reported
in recent years remain to be achieved.
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.chemrev.7b00551.
Complete author list of references with more than
10 authors (PDF)
AUTHOR INFORMATION
Corresponding Author
*Phone/Fax: (86) 871-65217971. E-mail: xugang008@mail.
kib.ac.cn.
ORCID
Xing-Wei Yang: 0000-0002-9578-2986
Gang Xu: 0000-0001-7561-104X
Notes
The authors declare no competing financial interest.
Biographies
Xing-Wei Yang was born in Sichuan province, China, in 1985. He
received his Ph.D. degree in Pharmaceutical Chemistry from the
University of Chinese Academy of Sciences in 2015. Now he is an
associate professor in the State Key Laboratory of Phytochemistry and
AM
Review
Plant Resources in West China, Kunming Institute of Botany, CAS.
His research interests include the structures and bioactivities of natural
PPAPs and other secondary metabolites in traditional Chinese
medicines.
Robert B. Grossman, a native of Long Island, NY, earned his A.B.
degree at Princeton University, where he carried out research under
the direction of Robert A. Pascal. After graduating in 1987, he moved
to MIT and worked under the direction of Stephen L. Buchwald to
develop zirconium- and titanium-mediated and -catalyzed organic
synthetic methodology. He earned his Ph.D. degree in 1992 and
moved from Steve’s lab in Cambridge, MA, to Steve’s lab in
Cambridge, England, where he worked in the Ley group on various
aspects of the chemistry of azadirachtin. In 1994 he left the United
Kingdom to join the faculty at the University of Kentucky in
Lexington, KY. His research interests are currently focused on
synthetic methodology, total synthesis, and biosynthetic pathways. He
is the author of The Art of Writing Reasonable Organic Reaction
Mechanisms, 2nd ed. (Springer, 2002), and one of the cocreators of
ACE Organic, a Web-based organic chemistry homework program that
provides response-specific feedback to structures drawn by students.
Gang Xu is a professor of natural products chemistry at the State Key
Laboratory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, CAS. He received his Ph.D. degree in
Phytochemistry from the Kunming Institute of Botany, CAS (2005).
He worked at the Chinese Medicine Laboratory, Hong Kong Jockey
Club Institute of Chinese Medicine (2007). His interests focus on the
systematic chemical studies of natural PPAPs as well as research of the
exploration and utilization of traditional medicinal herbs in the west of
China.
ACKNOWLEDGMENTS
The work was financially supported by the Natural Sciences
Foundation of Yunnan Province (No. 2015FA032, 2016FB017),
foundation from the Youth Innovation Promotion Association
CAS to X.W.Y. (No. 2016350), and foundation from Kunming
Institute of Botany (KIB2017001). The authors thank Prof.
Hong-Xi Xu, Drs. Juan Huang and Liang-Qun Li, and Mr. Yao-
Tao Duan for their valuable suggestions during the preparation
of this review. Thanks also to Dr. Helen Jacobs for her
contributions to this project.
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AY DOI: 10.1021/acs.chemrev.7b00551
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