Me2AlSEt-promoted domino dieckmann cyclization enables the total synthesis of polycyclic polyprenylated acylphloroglucinols

Article abstract of DOI:10.1021/acs.orglett.9b03078

A bioinspired, Me₂AlSEt-promoted domino Dieckmann cyclization via an 8-membered ring intermediate to construct bicyclo[3.3.1]nonanes was developed, and the divergent syntheses of nine complex polycyclic polyprenylated acylphloroglucinols were a

Full text of DOI:10.1021/acs.orglett.9b03078

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Me2AlSEt-Promoted Domino Dieckmann Cyclization Enables the
Total Synthesis of Polycyclic Polyprenylated Acylphloroglucinols
Liping Wang,†,∥ Lian Sun,†,∥ Xueying Wang,†,§ Rong Wu,† Hua Zhou,‡ Changwu Zheng,*,†,§
and Hongxi Xu*,†,‡
†School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
‡Institute of Cardiovascular Disease of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
§Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A bioinspired, Me2AlSEt-promoted domino Die-
ckmann cyclization via an 8-membered ring intermediate to
construct bicyclo[3.3.1]nonanes was developed, and the
divergent syntheses of nine complex polycyclic polyprenylated
acylphloroglucinols were achieved. This novel domino cycliza-
tion tolerates a series of congested substrates, providing a very
efficient way to construct diverse polycyclic structures. The
selectivity and the advantages of the domino cyclization were
studied. Moreover, the structure−activity relationship study
leads to the identification of three simplified potent antitumor
agents.
olycyclic polyprenylated acylphloroglucinols (PPAPs),
which are generally characterized by highly oxygenated
their unnatural analogues (6, 8) feature different substituents
at C1, C5, and C7 (Scheme 1, b).
P
bicyclo[3.3.1] nonane-2,4,9-trione cores that are densely
substituted with prenyl and geranyl groups, have been isolated
from plants of the Guttiferae (Clusiaceae) family.1 So far,
hundreds of natural PPAPs with diverse skeletons have been
identified. The promising bioactivities2 and synthetic chal-
lenges of the PPAPs have initiated a significant interest to
synthetic chemists,3,4 with the molecules such as clusianone,5
hyperforin,6 and garcinol7 achieved from several research
groups.8
The use of domino reaction sequences has emerged as a
particularly attractive avenue in total synthesis for the
diastereoselective formation of multiple carbon−carbon
bonds.9 Studies into the biosynthesis of PPAPs describe the
efficient construction of 1,3-polyketides by enzyme-promoted
cascading Dieckmann reactions and further affording the
acylphloroglucinols (Scheme 1, a).1 When these cascade
sequences are incorporated into organic synthesis, powerful
strategies for the one-pot production of bicyclo[3.3.1]nonanes
I may be achieved with the linear precursor II, which can be
prepared from the easily accessible starting materials. In order
to verify this bioinspired strategy, a series of bioactive PPAPs
as well as their analogues diversely decorated with prenyl and
geranyl groups10 are set as the targets and their total syntheses
are investigated. The PPAPs epi-clusianone (1) and garcimulti-
florones H and I (2 and 3),11 all bearing three prenyl groups,
are differentiated with acyl groups at C3 and C2, while
guttiferone I (4)12 and oblongifolins A (5) and D (7)13 and
The synthesis was started with the diesters 9, which
underwent a sequence of transformations such as alkylation,
reduction, and oxidation to afford the linear precursors 14a in
gram scale as an inseparable mixture of cis- and trans-isomers
(3:1) in seven steps (Scheme 2). The crucial intramolecular
domino Dieckmann cyclization was then investigated with 14a
(Table 1). Although the Dieckmann reaction is well
established and has been widely used for preparing 1,3-
dicarbonyl compounds, we are not aware of examples of its use
in cascades to construct complex molecules. Evaluation of the
commonly used basic conditions, such as those involving t-
BuOK, NaH, and LiHMDS,14 at room temperature gave no
reactions (see the Supporting Information for details).
However, under heating, the reaction with LiHMDS generated
two products, 16 and 17 (3:1), which featured a rare 8-
membered ring structure (entries 1−3). Further attempts to
obtain bicyclo[3.3.1]nonanes 15a or promote the transannular
cyclization of 16/17 under basic conditions failed. At this
point, we assumed that the domino Dieckmann cyclization
might be hindered by the methoxy groups, which are poor
leaving groups, and thus this group was changed to SEt to
facilitate the cyclization. In the following transthioesterification
of 14a under Me3Al/EtSH conditions, we surprisingly found
Received: August 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Bioinspired Strategies for Synthesis of PPAPs
and Their Analogues with Diverse Side Chains
Table 1. Conditions for the Domino Dieckmann
Cyclizations
a
entry
conditions
t-BuOK, THF, reflux
NaH, toluene, reflux
results
1
2
3
no reaction
no reaction
16/17 (48%, 3:1)
16/17 (73%, 6:1)
15a (60%)
15a (75%)
no reaction
decomposition
LiHMDS, toluene, reflux
b
4
Al(Me)3/EtSH, DCM/heptane, rt
Al(Me)3/EtSH, DCM/heptane, reflux
Al(Me)3/EtSH, DCM/heptane, reflux
TiCl4/Et3N, Cl(CH2)2Cl, reflux
p-TsOH, toluene, reflux
b
5
c
6
7
8
a
For reaction details, please see the Supporting Information.
CH2Cl2/heptane = 1:1 (v/v). CH2Cl2/heptane = 10:1 (v/v).
b
c
Scheme 3. Selectivity and Advantages of the Domino
Cyclization toward 15a
Scheme 2. Synthesis of Congested Linear Precursors
the previous 8-membered ring products (16 and 17, 6:1) were
obtained instead of the predicted products 18 (entry 4). As we
know, the combination of Me3Al and EtSH generates
Me2AlSEt in situ and has never been used as a Lewis acid
promoter in the reactions before.15 These unexpected results
prompted us to further investigate these conditions, and after
optimization, we obtained the desired [3.3.1] bicyclic product
15a in 75% yield. Notably, the ratio of CH2Cl2 and heptane in
the reaction is crucial for obtaining good results. The
cyclization was more successful in CH2Cl2/heptane (10/1),
and 5 equiv of Me3Al/EtSH were needed (entries 5−6). Under
the optimal conditions, the domino reaction of 14a has been
run in 0.5 mmol scale (0.23 g) to afford 15a in 72% yield.
Other Lewis acids that have been reported to promote
Dieckmann reactions were also evaluated. However, no
positive effects on the reaction outcomes were observed
(entries 7−8).
through an 8-membered ring intermediate (A and B), the
diastereoselectivity of which was controlled by steric repulsion
between the ester and prenyl groups to give 16 as the major
product. For the second transannular cyclization, a Lewis acid
as the promoter (C to 15a) is crucial to its proceeding, as the
enolization under base is more likely to occur at C3, which
hampers further conversion to 15a (D to 15a). The advantages
of the domino Dieckmann condensation were also demon-
strated by its unusual cyclization pathway. With the
diastereoselectivity controlled by the steric hindrance, the
cyclization via the 8-membered ring with the favored
intermediate could successfully give desired bicyclo[3.3.1]
The regioselectivity of the cyclization from 14a to 16 and 17
rather than the transthioesterification could be attributed to
the presence of a methyl ketone, which is more active than the
ester, and the loss of EtSH is more favorable than the loss of
Me2AlOMe (Scheme 3). Apparently, the cyclization went
B
DOI: 10.1021/acs.orglett.9b03078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nonanes 15a, while the cyclization via the 6-membered ring
gave a trans-intermediate that could not be converted to 15a
(E to 15a).
Table 2. Domino Dieckmann Cyclization in the Total
Synthesis of PPAPs 4−8 Bearing Diverse Substituents
The total synthesis was then continued by treating 15a with
benzoyl cyanide in the presence of t-BuOK, which proceeded
smoothly to give epi-clusianone (1) in 46% yield (Scheme 4).
Scheme 4. Completion of the Synthesis of epi-Clusianone
(1) and Garcimultiflorones H and I (2 and 3)
However, when the reaction was run with bulky 4-
(cyanocarbonyl)-1,2-phenylene diacetate (20), only a trace
amount of the C-acylated product was observed. Other
reagents, such as Et3N and LiHMDS, did not afford the
desired products. Fortunately, we found that the acylation
could be smoothly promoted by the Lewis acid SmCl3 under
modified conditions reported by Zhou,16 which afforded
garcimultiflorone H (2) in 62% yield after quenching with
K2CO3. The Lewis acid SmCl3 has indeed substantially
promoted the reaction not only with benzoyl chloride but
also with benzoyl cyanide. Under the current set of conditions,
the reactions with the cyclic sterically hindered substrates
proceeded very smoothly and were complete in 2 h. The
subsequent oxidative cyclization was then conducted with high
regioselectivity under different oxidative conditions to give
garcimultiflorone I (3) in 58% yield17 and regio-garcimulti-
florone I (21) in 27% yield.18
With the novel Me2AlSEt-promoted domino Dieckmann
cyclization and SmCl3-promoted C-acylation well established,
the scope of the domino Dieckmann cyclization was then
demonstrated in the total synthesis of complex PPAPs with a
series of congested linear precursors. As indicated in Table 2,
the cyclization precursor 14b (5.9 g) was prepared in one step
from 13a as a mixture (cis:trans = 3:1), while precursors 14c−
14f (1.5−6.2 g) were prepared as cis-isomers in a similar
sequence to 14a (see Supporting Information for details).
These linear precursors bearing bulky geranyl groups and
prenyl groups at either C1, C5, or C7 feature diverse
substituents, and herein their successful cyclization provides
general strategy for the synthesis of PPAPs with various
substituents. Under the standard conditions, bicyclo[3.3.1]-
nonanes 15b, 15c, 15d, 15e, and 15f were obtained via the
domino cyclization in good yields from 58% to 73% at about
0.1 g scale. Following C-acylation and subsequent treatment
with K2CO3, the natural products guttiferone I, oblongifolin A,
oblongifolin D, and their analogues regio-guttiferone I and epi-
guttiferone O (4−8) were obtained in a very divergent and
efficient way (Table 2). It should be noted that the 8-
membered ring intermediates could also be detected during
the reactions. When these reactions are conducted at room
temperature, a high yield of 8-membered ring intermediate
such as 16′ from 14f can be isolated in 73% yield. Apparently
from these examples, the newly developed domino Dieckmann
cyclization has demonstrated its significant application with the
sterically hindered substrates for the synthesis of complex
polycyclic molecules.
Although many PPAPs have been reported to exhibit
cytotoxicity against cancer cell lines, limited studies have
been performed to elucidate their SARs.19 Following the
synthesis, the cytotoxicities of the synthesized PPAPs (1−8
and 21) and bicyclo[3.3.1]nonanes 15 against the HeLa
(cervical cancer), SGC7901 (gastric cancer), and HCT116
(colorectal carcinoma) cell lines were studied (Figure 1, see
Supporting Information for the cytotoxicity data). The
C
DOI: 10.1021/acs.orglett.9b03078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (81602990), Fok Ying-Tong Education Foundation
(161039), A Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning and
Shanghai Sailing Program (17YF1419500) for financial
support. We appreciate Professor Regan Thomson at North-
western University for helpful discussions and writing
assistance. We also thank Dr. Longhui Yu at SIOC and Dr.
Dan Zheng at SHUTCM for assistance in acquiring part of the
NMR spectra and high-resolution mass spectra, respectively.
Figure 1. SARs study against three tested cell lines.
biological evaluation revealed a set of structure−activity
relationships that could facilitate further optimization. The
most notable results were provided by bicyclo[3.3.1]nonanes
15b, 15e, and 15f, which were synthesized for the first time in
this study and possess geranyl group at C5. These three
simplified compounds showed activity profiles similar to those
of PPAPs. The capacity to delete the large acyl group, which is
supposed to be crucial to the activity,20 is both intriguing and
unexpected.
In summary, a bioinspired, Me2AlSEt-promoted domino
Dieckmann cyclization via an 8-membered ring was developed
in the total synthesis of nine PPAPs. Most of these PPAPs are
decorated with the less explored geranyl groups and are
synthesized herein for the first time in short steps. The
reactions can be run on large scales to give several PPAPs in
one sequence. Significantly, both the domino Dieckmann
reactions and the C-acylation reactions are applicable to the
sterically hindered substrates, providing novel strategies for the
synthesis of complex molecules. The selectivity and the
advantages of the domino cyclization were also studied.
Moreover, biological evaluation of the synthesized compounds
against three cancer cell lines led to the identification of
simplified potent antitumor agents (15b, 15e, and 15f) from
PPAPs for the first time, and a set of SARs that could facilitate
further optimization studies was identified.
REFERENCES
■
(1) For reviews, see: (a) Ciochina, R.; Grossman, R. B. Polycyclic
polyprenylated acylphloroglucinols. Chem. Rev. 2006, 106, 3963.
(b) Richard, J. A.; Pouwer, R. H.; Chen, D. Y. K. The chemistry of the
polycyclic polyprenylated acylphloroglucinols. Angew. Chem., Int. Ed.
2012, 51, 4536. (c) Richard, J. A. Chemistry and biology of the
polycyclic polyprenylated acylphloroglucinol Hyperforin. Eur. J. Org.
Chem. 2014, 2014, 273. (d) Yang, X. W.; Grossman, R. B.; Xu, G.
Research progress of polycyclic polyprenylated acylphloroglucinols.
Chem. Rev. 2018, 118, 3508.
(2) (a) Garnsey, M. R.; Matous, J. A.; Kwiek, J. J.; Coltart, D. M.
Asymmetric total synthesis of (+)- and (−)-clusianone and (+)- and
(−)-clusianone methyl enol ether via ACC alkylation and evaluation
of their anti-HIV activity. Bioorg. Med. Chem. Lett. 2011, 21, 2406.
(b) Zhao, J.; Liu, W.; Wang, J. C. Recent advances regarding
constituents and bioactivities of plants from the genus Hypericum.
Chem. Biodiversity 2015, 12, 309. (c) Guo, Y.; Zhang, N.; Chen, C.;
Huang, J.; Li, X.-N.; Liu, J.; Zhu, H.; Tong, Q.; Zhang, J.; Luo, Z.;
Xue, Y.; Zhang, Y. Tricyclic polyprenylated acylphloroglucinols from
St John’s Wort, Hypericum perforatum. J. Nat. Prod. 2017, 80, 1493.
(d) Bridi, H.; Meirelles, G. d. C.; von Poser, G. L. Structural diversity
and biological activities of phloroglucinol derivatives from Hypericum
species. Phytochemistry 2018, 155, 203.
(3) For reviews, see: (a) Njardarson, J. T. Synthetic efforts toward
[3.3.1] bridged bicyclic phloroglucinol natural products. Tetrahedron
2011, 67, 7631. (b) Simpkins, N. S. Adventures in bridgehead
substitution chemistry: synthesis of polycyclic polyprenylated
acylphloroglucinols (PPAPs). Chem. Commun. 2013, 49, 1042.
(4) For asymmetric synthesis of PPAPs, see: (a) Rodeschini, V.;
Simpkins, N. S.; Wilson, C. Kinetic resolution in a bridgehead
lithiation mediated by a chiral bis-lithium amide: assignment of the
absolute configuration of clusianone. J. Org. Chem. 2007, 72, 4265.
(b) Qi, J.; Beeler, A. B.; Zhang, Q.; Porco, J. A., Jr. Catalytic
enantioselective alkylative dearomatization−annulation: total syn-
thesis and absolute configuration assignment of hyperibone K. J. Am.
Chem. Soc. 2010, 132, 13642. (c) Uetake, Y.; Uwamori, M.; Nakada,
M. Enantioselective approach to polycyclic polyprenylated acylphlor-
oglucinols via catalytic asymmetric intramolecular cyclopropanation. J.
Org. Chem. 2015, 80, 1735. (d) Horeischi, F.; Guttroff, C.; Plietker, B.
The enantioselective total synthesis of (+)-clusianone. Chem.
Commun. 2015, 51, 2259. (e) Boyce, J. H.; Eschenbrenner-Lux, V.;
Porco, J. A., Jr. Syntheses of (+)-30-epi-, (−)-6-epi-, ( )-6,30-epi-
13,14-didehydroxyisogarcinol and ( )-6,30-epi-garcimultiflorone A
utilizing highly diastereoselective, Lewis acid-controlled cyclizations. J.
Am. Chem. Soc. 2016, 138, 14789. (f) Wen, S.; Boyce, J. H.;
Kandappa, S. K.; Sivaguru, J.; Porco, J. A., Jr. Regiodivergent
photocyclization of dearomatized acylphloroglucinols: asymmetric
syntheses of (−)-nemorosone and (−)-6-epi-garcimultiflorone A. J.
Am. Chem. Soc. 2019, 141, 11315.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03078.
Full experimental procedures, characterization data,
copies of the NMR spectra for all new compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhengcw@shutcm.edu.cn.
*E-mail: xuhongxi88@gmail.com.
ORCID
Changwu Zheng: 0000-0002-0869-8314
Hongxi Xu: 0000-0001-6238-4511
Author Contributions
∥L.P.W. and L.S. contributed equally.
(5) (a) Rodeschini, V.; Ahmad, N. M.; Simpkins, N. S. Synthesis of
( )-clusianone: high-yielding bridgehead and diketone substitutions
by regioselective lithiation of enol ether derivatives of bicyclo[3.3.1]-
nonane-2,4,9-triones. Org. Lett. 2006, 8, 5283. (b) Qi, J.; Porco, J. A.,
Jr. Rapid access to polyprenylated phloroglucinols via alkylative
dearomatization−annulation: total synthesis of ( )-clusianone. J. Am.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b03078
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́
Chem. Soc. 2007, 129, 12682. (c) Ahmad, N. M.; Rodeschini, V.;
Simpkins, N. S.; Ward, S. E.; Blake, A. J. Synthesis of polyprenylated
acylphloroglucinols using bridgehead lithiation: the total synthesis of
racemic clusianone and a formal synthesis of racemic garsubellin A. J.
Org. Chem. 2007, 72, 4803. (d) Tsukano, C.; Siegel, D. R.;
Danishefsky, S. J. Differentiation of nonconventional “carbanions”
the total synthesis of nemorosone and clusianone. Angew. Chem., Int.
Ed. 2007, 46, 8840. (e) Nuhant, P.; David, M.; Pouplin, T.; Delpech,
B.; Marazano, C. α,α’-Annulation of 2,6-prenyl-Substituted cyclo-
hexanone derivatives with malonyl chloride: application to a short
synthesis of ( )-clusianone. Formation and rearrangement of a
biogenetic-like intermediate. Org. Lett. 2007, 9, 287. (f) Garnsey, M.
R.; Lim, D.; Yost, J. M.; Coltart, D. M. Development of a strategy for
the asymmetric synthesis of polycyclic polyprenylated acylphloroglu-
cinols via N-amino cyclic carbamate hydrazones: application to the
total synthesis of (+)-clusianone. Org. Lett. 2010, 12, 5234.
(g) Uwamori, M.; Nakada, M. Collective total synthesis of PPAPs:
total synthesis of clusianone via intramolecular cyclopropanation. Nat.
Prod. Commun. 2013, 8, 955. (h) Boyce, J. H.; Porco, J. A., Jr.
Asymmetric stereodivergent synthesis of (−)-clusianone utilizing a
biomimetic cationic cyclization. Angew. Chem., Int. Ed. 2014, 53, 7832.
(i) Garnsey, M. R.; Uteuliyev, M. M.; Coltart, D. M. Asymmetric
synthesis of structural analogues of (+)-clusianone via enantioselective
ACC alkylation. Tetrahedron Lett. 2015, 56, 3183.
(6) (a) Shimizu, Y.; Shi, S. L.; Usuda, H.; Kanai, M.; Shibasaki, M.
Catalytic asymmetric total synthesis of ent-hyperforin. Angew. Chem.,
Int. Ed. 2010, 49, 1103. (b) Uwamori, M.; Nakada, M. Stereoselective
total synthesis of ( )-hyperforin via intramolecular cyclopropanation.
Tetrahedron Lett. 2013, 54, 2022. (c) Sparling, B. A.; Moebius, D. C.;
Shair, M. D. Enantioselective total synthesis of hyperforin. J. Am.
Chem. Soc. 2013, 135, 644. (d) Bellavance, G.; Barriault, L. Total
syntheses of hyperforin and papuaforins A−C, and formal synthesis of
nemorosone through a gold(I)-catalyzed carbocyclization. Angew.
Chem., Int. Ed. 2014, 53, 6701. (e) Ting, C. P.; Maimone, T. J. Total
synthesis of hyperforin. J. Am. Chem. Soc. 2015, 137, 10516. (f) Ting,
C. P.; Maimone, T. J. The total synthesis of hyperforin. Synlett 2016,
27, 1443. (g) Bellavance, G.; Barriault, L. Modular total syntheses of
hyperforin, papuaforins A, B, and C via gold(I)-catalyzed carbocyc-
lization. J. Org. Chem. 2018, 83, 7215.
(9) (a) Poulin, J.; Grise-Bard, C. M.; Barriault, L. Pericyclic domino
reactions: concise approaches to natural carbocyclic frameworks.
Chem. Soc. Rev. 2009, 38, 3092. (b) Bonne, D.; Coquerel, Y.;
Constantieux, T.; Rodriguez, J. 1,3-Dicarbonyl compounds in
stereoselective domino and multicomponent reactions. Tetrahedron:
́
Asymmetry 2010, 21, 1085. (c) Ruiz, M.; Lopez-Alvarado, P.; Giorgi,
G.; Menendez, J. C. Domino reactions for the synthesis of bridged
́
bicyclic frameworks: fast access to bicyclo[n.3.1]alkanes. Chem. Soc.
Rev. 2011, 40, 3445.
(10) Limited examples with geranyl group have been reported, see:
Biber, N.; Mows, K.; Plietker, B. The total synthesis of hyper-
papuanone, hyperibone L, epi-clusianone and oblongifolin A. Nat.
Chem. 2011, 3, 938.
(11) Fu, W. W.; Wu, M.; Zhu, L. L.; Lao, Y. Z.; Wang, L. P.; Tan, H.
S.; Yuan, Q. H.; Xu, H. X. Prenylated benzoylphloroglucinols and
biphenyl derivatives from the leaves of Garcinia multiflora Champ.
RSC Adv. 2015, 5, 78259.
(12) Gao, X. M.; Yu, T.; Lai, F. S. F.; Zhou, Y.; Liu, X.; Qiao, C. F.;
Song, J. Z.; Chen, S. L.; Luo, K. Q.; Xu, H. X. Identification and
evaluation of apoptotic compounds from Garcinia paucinervis. Bioorg.
Med. Chem. 2010, 18, 4957.
(13) Hamed, W.; Brajeul, S.; Mahuteau-Betzer, F.; Thoison, O.;
Mons, S.; Delpech, B.; Hung, N. V.; Sevenet, T.; Marazano, C.
Oblongifolins A−D, polyprenylated benzoylphloroglucinol derivatives
from Garcinia oblongifolia. J. Nat. Prod. 2006, 69, 774.
(14) Zheng, C. W.; Wang, X. Y.; Fu, W. W.; Lu, Y.; Tan, H. S.; Xu,
H. X. Total synthesis of norsampsones A and B, garcinielliptones N
and O, and hyperscabrin A. J. Nat. Prod. 2018, 81, 2582.
(15) 1H NMR spectroscopic analysis in CD2Cl2 verified the
generation of Me2AlSEt. Please see the Supporting Information for
details, and also see: (a) Cohen, T.; Gapinski, R. E. The conversion of
esters to phenyl thioesters by boron thiophenoxide and aluminum
thiophenoxide. Tetrahedron Lett. 1978, 19, 4319. (b) Usuda, H.;
Kanai, M.; Shibasaki, M. Studies toward the total synthesis of
garsubellin A: synthesis of 8-deprenyl-garsubellin A. Tetrahedron Lett.
2002, 43, 3621.
(16) Shen, Q. S.; Huang, W.; Wang, J. L.; Zhou, X. G. SmCl3-
Catalyzed C-Acylation of 1,3-Dicarbonyl Compounds and Malononi-
trile. Org. Lett. 2007, 9, 4491.
́
(17) Menelle, P.; Cottet, K.; Fromentin, Y.; Gaslonde, T.; Poree, F.-
(7) Socolsky, C.; Plietker, B. Total synthesis and absolute
configuration assignment of MRSA active garcinol and isogarcinol.
Chem. - Eur. J. 2015, 21, 3053.
H.; Buisson, D.; Lallemand, M.-C. Progress on PPAPs cyclization:
Guttiferone A as a case study. Tetrahedron Lett. 2017, 58, 4876.
(18) Marteau, C.; Guitard, R.; Penverne, C.; Favier, D.; Nardello-
Rataj, V.; Aubry, J.-M. Boosting effect of ortho-propenyl substituent
on the antioxidant activity of natural phenols. Food Chem. 2016, 196,
418.
(19) (a) Zhu, L.; Qi, J.; Chiao, C. Y.-C.; Zhang, Q.; Porco, J. A., Jr;
Faller, D. V.; Dai, Y. Identification of a novel polyprenylated
acylphloroglucinol-derived SIRT1 inhibitor with cancer-specific anti-
proliferative and invasion-suppressing activities. Int. J. Oncol. 2014, 45,
2128. (b) SARs studies for antibiotic activities, see: Guttroff, C.;
Baykal, A.; Wang, H.; Popella, P.; Kraus, F.; Biber, N.; Krauss, S.;
Gotz, F.; Plietker, B. Polycyclic polyprenylated acylphloroglucinols: an
emerging class of non-peptide-based MRSA- and VRE-active
antibiotics. Angew. Chem., Int. Ed. 2017, 56, 15852.
(20) Wang, L. P.; Wu, R.; Fu, W. W.; Lao, Y. Z.; Zheng, C. W.; Tan,
H. S.; Xu, H. X. Synthesis and biological evaluation of oblongifolin C
derivatives as c-Met inhibitors. Bioorg. Med. Chem. 2016, 24, 4120.
(8) (a) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.;
Shibasaki, M. Total synthesis of ( )-garsubellin A. J. Am. Chem. Soc.
2005, 127, 14200. (b) Siegel, D. R.; Danishefsky, S. J. Total synthesis
of garsubellin A. J. Am. Chem. Soc. 2006, 128, 1048. (c) Ahmad, N.
M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.; Wilson, C. Synthetic
studies towards garsubellin A: synthesis of model systems and
potential mimics by regioselective lithiation of bicyclo[3.3.1]nonane-
2,4,9-trione derivatives from catechinic acid. Org. Biomol. Chem. 2007,
5, 1924. (d) Simpkins, N. S.; Taylor, J. D.; Weller, M. D.; Hayes, C. J.
Synthesis of nemorosone via a difficult bridgehead substitution
reaction. Synlett 2010, 2010, 639. (e) Zhang, Q.; Mitasev, B.; Qi, J.;
Porco, J. A., Jr. Total synthesis of plukenetione A. J. Am. Chem. Soc.
2010, 132, 14212. (f) Uwamori, M.; Saito, A.; Nakada, M.
Stereoselective total synthesis of nemorosone. J. Org. Chem. 2012,
77, 5098. (g) Zhang, Q.; Porco, J. A., Jr. Total synthesis of ( )-7-epi-
nemorosone. Org. Lett. 2012, 14, 1796. (h) Lindermayr, K.; Plietker,
B. The Bidirectional total synthesis of sampsonione P and hyperibone
I. Angew. Chem., Int. Ed. 2013, 52, 12183. (i) Uwamori, M.; Nakada,
M. Stereoselective total synthesis of garsubellin A. J. Antibiot. 2013,
66, 141. (j) Grenning, A. J.; Boyce, J. H.; Porco, J. A., Jr. Rapid
synthesis of polyprenylated acylphloroglucinol analogs via dearoma-
tive conjunctive allylic annulation. J. Am. Chem. Soc. 2014, 136,
11799. (k) Horeischi, F.; Biber, N.; Plietker, B. The total syntheses of
guttiferone A and 6-epi-guttiferone A. J. Am. Chem. Soc. 2014, 136,
4026. (l) Sparling, B. A.; Tucker, J. K.; Moebius, D. C.; Shair, M. D.
Total synthesis of (−)-nemorosone and (+)-secohyperforin. Org. Lett.
2015, 17, 3398.
̈
E
DOI: 10.1021/acs.orglett.9b03078
Org. Lett. XXXX, XXX, XXX−XXX