Total Synthesis of (±)-Pestalachloride C and (±)-Pestalachloride D through a Biomimetic Knoevenagel/Hetero-Diels-Alder Cascade

Article abstract of DOI:10.1021/acs.orglett.9b00323

A concise total synthesis of (±)-pestalachloride C and (±)-pestalachloride D was achieved through a Knoevenagel/hetero-Diels-Alder cascade reaction to test the nonenzymatic biosynthetic hypothesis of Shao, Wang, and co-workers. The cascade reaction generates a mixture of racemic indano[2,1-c]chromans like those found in the natural products.

Full text of DOI:10.1021/acs.orglett.9b00323

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of ( )-Pestalachloride C and ( )-Pestalachloride D
through a Biomimetic Knoevenagel/Hetero-Diels−Alder Cascade
Vanessa Arredondo,† Daniel E. Roa,† Songyuan Yan,† Feng Liu-Smith,‡
and David L. Van Vranken*,†
†Department of Chemistry, University of California, Irvine, 1102 Natural Sciences II, Irvine, California 92697, United States
‡Department of Medicine, School of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine,
California 92697, United States;
S
* Supporting Information
ABSTRACT: A concise total synthesis of ( )-pestalachloride C and ( )-pestalachloride D was achieved through a
Knoevenagel/hetero-Diels−Alder cascade reaction to test the nonenzymatic biosynthetic hypothesis of Shao, Wang, and co-
workers. The cascade reaction generates a mixture of racemic indano[2,1-c]chromans like those found in the natural products.
ndano[2,1-c]chromans have unknowingly held the attention
In 2008, a new indano[2,1-c]chroman, ( )-pestalachloride
C, was isolated from an endophytic plant fungus Pestalotiopsis
adusta (L416).7 The congested structure was distinct from that
of other natural indano[2,1-c]chromans and is further
distinguished by its occurrence in nature as a racemate.8
Shao, Wang, and co-workers later isolated ( )-pestalachloride
C, along with its epimer ( )-pestalachloride D, in a 3.6:1 ratio,
from cultures of the marine fungus Pestalotiopsis sp., obtained
from the soft coral Sarcophyton sp.9 The syn isomer,
pestalachloride D, exhibited no teratogenicity up to the assay
limit of 50 μg/mL, whereas the anti isomer, pestalachloride C,
exhibited teratogenic effects in zebrafish embryos at multiple
stages, including egg coagulation, nonspontaneous movements,
abnormal heartbeat, organ malformation, delayed hatching,
and embryonic death.9 A variety of selective teratogens such as
retinoic acid, thalidomide, lenalidomide, pomalidomide,
apremilast, vismodegib, and sodidegib have found use as
drugs against cancer and other diseases.10 A concise route to
pestalachlorides C and D would facilitate assessment of their
therapeutic potential.
I
of humans for over two millennia (Figure 1).1 The red
Figure 1. Naturally occurring indano[2,1-c]chromans.
In 2014, our group developed a palladium-catalyzed carbene
insertion reaction to construct 1-arylindanes that contain three
of the four rings found in indano[2,1-c]chromans in high
yield.11 The palladium-catalyzed reaction creates a central
point of disconnection to access these 1-arylindanes, and we
envisioned utilizing the method to develop a convergent
synthesis of indano[2,1-c]chromans. A model reaction
involving a highly substituted aryl iodide and N-tosylhydrazone
extracts of sappanwood were mentioned in writings from as
early as the second century. Crystals of the key constituent of
these extracts, brazilin, were reported in 1808, but the
indano[2,1-c]chroman structure was not deduced until
1901.2 Plant-based indano[2,1-c]chromans, including (+)-bra-
zilin,3a (+)-3′-O-methylbrazilin,3 (+)-4′-O-methylbrazilin,3
(+)-brazilane,3b caesalpiniaphenol E,3b (+)-hematoxylin (still
used as a common cell stain), isohematoxylin,4 and the
protosappanins5 are widely believed to arise from the C15
chalcone biosynthetic pathway.6
Received: January 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
gave modest yields of the desired arylindane 3 even when 2
equiv of the N-tosylhydrazone were used (Scheme 1). Given
the inefficiency of this chemistry we sought inspiration from
nature.
phthalaldehyde 4 to generate a benzhydrol 6 with two
potential fates. Dehydration of the benzhydrol 6 produces a
highly reactive quinone methide 7 which could undergo an
inverse-electron-demand hetero-Diels−Alder cycloaddition to
afford the anti isomer pestalachloride C or the syn isomer
pestalachloride D (Figure 2). Alternatively, oxidation of the
Scheme 1. Palladium-Catalyzed Carbene Insertion To
Construct 1-Arylindanes
Figure 2. Depiction of transition states leading to pestalachlorides C
and D.
benzhydrol 6 would directly generate pestalone and then
( )-pestalachloride A in the presence of ammonia. The
involvement of aldiminium intermediates in the biosynthesis of
( )-pestalachloride A suggests a potential role for iminium
intermediates in the formation of ( )-pestalachlorides C and
D through a nonenzymatic biosynthetic process.
Shao and Wang’s hypothesis is related to the Knoevenagel/
hetero-Diels−Alder cascade reactions developed by Tietze and
co-workers.14 In 2001, Tietze and co-workers published a
Knoevenagel/hetero-Diels−Alder cascade catalyzed by the
diamine catalyst ethylenediammonium diacetate (10 mol %
EDDA), presumably via an iminium ion. The reaction
generates two types of fused barbituric acid derivatives: the
allyl substrate 8a afforded bridged tetralin 9, whereas the
prenyl-substituted substrate 8b afforded the cis-fused indane 10
(Scheme 3).15 Lee and co-workers have applied the Tietze
The biosyntheses of pestalone and the pestalachlorides seem
to be connected. Schmalz and co-workers demonstrated that
pestalone12 readily generated the lactam ( )-pestalachloride A
in the presence of ammonia (Scheme 2).13 In their isolation
Scheme 2. Shao, Wang, and Co-workers’ Proposed
Biosynthesis of Pestalachlorides and Pestalone
Scheme 3. Types of the Products Generated by the Tietze
Knoevenagel/Hetero-Diels−Alder Cascade Reaction That
Are Sensitive to the Structure of the Starting Materials
conditions to aromatic nucleophiles to generate cannabinoids
and related ring systems.16 The facile generation of tetracycles
related to indano[2,1-c]chromans under organocatalytic
conditions strongly supports Shao and Wang’s proposed
biosynthesis, but the stereoselectivity and sensitivity to
substituents left us uncertain that it could be applied to a
total synthesis of both the syn isomer pestalachloride D and the
anti isomer pestalachloride C. Other workers have shown that
quinone methide intermediates derived from benzylic alcohols
can undergo intramolecular hetero-Diels−Alder reactions to
paper, Shao, Wang and co-workers proposed a compelling
hypothesis for the biosynthesis of pestalone, ( )-pestala-
chloride C, and the new stereoisomeric natural product
( )-pestalachloride D (Scheme 2).9
The proposed biosynthesis involved a cascade reaction
starting with condensation of the resorcinol 5 with the o-
B
DOI: 10.1021/acs.orglett.9b00323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generate mixtures of cis-fused and trans-fused cyclopenta[c]-
chromans.17 Conflicted by the strong precedent and lingering
questions, we set out to test the cascade reaction underlying
the Shao and Wang biosynthetic hypothesis as an approach to
pestalachlorides C and D.
Scheme 5. Synthesis of Oxygenated Benzaldehyde 19 and
4,6-Dichloroorcinol 15
The Shao and Wang biosynthetic hypothesis requires a
regioselective Knoevenagel condensation with just one of the
two aldehydes of o-phthalaldehyde 4. To ensure condensation
with the correct aldehyde, we opted to introduce the second
formyl group at a later stage into the fully formed indane ring
system (Scheme 4). We anticipated the need for a functional
Scheme 4. Premature Intramolecular Carbonyl Ene Process
Competes with the Knoevenagel Reaction
11 by monobromination and protection of the aldehyde as an
acetal. As before, aryl bromide 17 was converted to the
cyanocuprate and coupled with prenyl bromide to afford
dioxolane 18.13 This time, we were able to remove the acetal
under mildly acidic conditions at incomplete conversion. The
desired aldehyde 19 could be obtained in 71% yield.
handle like bromine to allow installation of the aldehyde into a
crowded position. To that end, we converted aldehyde 11 into
an o,o′-dibromoaldehyde and masked the aldehyde to give
acetal 12. One of the two bromines was converted to the
cyanocuprate through lithium−halogen exchange with 1.2
equiv of phenyllithium, and the cuprate was then coupled with
prenyl bromide to afford acetal 13a. The juxtaposition of
aldehyde and prenyl group in 13a is precarious. All attempts to
deprotect the acetal led to complex mixtures arising from Prins
reactions. We found it expedient to carry out the cuprate
coupling with allyl bromide to afford allylbenzene derivative
13b. After revealing the aldehyde, we gently converted the allyl
group to a prenyl group using Grubbs metathesis.
4,6-Dichloroorcinol 15 was available through the regiose-
lective chlorination of orcinol.18 Sadly, we were unable to
engage the dichloroorcinol in the Knoevenagel cascade due to
the competing intramolecular carbonyl ene process. Under
some conditions, the undesired indane 16 was formed
stereoselectively in high yield. A syn orientation of the
substituents on indane 16 has been tentatively assigned on
the basis of the 5 Hz vicinal coupling constant19 and is based
on the preference for intramolecular carbonyl ene reactions to
afford syn-cyclopentanols in saturated systems.20
Under base-catalyzed conditions (Et3N) aldehyde 19 and
resorcinol 20 generated a complex mixture containing less than
6% of indano[2,1-c]chromans 20. In the presence of EDDA,
which promotes iminium ion formation, the reaction is much
more efficient. With some optimization, the Knoevenagel/
hetero-Diels−Alder cascade generated the indano[2,1-c]-
chromans 20 in 85−90% yields in about 90% purity. The
anti and syn isomers are formed in a 1.4−1.6:1 ratio, depending
on the equivalents of 4,6-dichloroorcinol and reaction time.
The ratio was 1.8:1 after chromatographic purification,
probably due to slight chromatographic loss of the syn isomer.
The inseparable mixture was carried on through the synthetic
route. The success of this cascade reaction is consistent with a
biosynthetic route that involves a nonenzymatic cascade
reaction, although the solvents and temperatures are abiotic.
We were pessimistic that an aldehyde could be introduced at
the more hindered position of the indane aromatic ring.
Fortunately, Vilsmeier−Haack reaction of phenol 20 was
found to introduce the formyl group at the desired position,
but the resulting mixture of seven-membered ring hemiacetals
and hydroxyaldehydes proved unwieldy. The fortuitous and
surprising regioselectivity in the formylation was initially
attributed to a directing effect from the phenolic hydroxyl
group on the dichloroorcinol ring. We were surprised to find
that O-methylation of the dichlorochroman phenol 20 was still
followed by a highly regioselective Vilsmeier formylation at the
hindered position to afford carbaldehyde 21. Attempts to
We hypothesized that the o-bromo group of aldehyde 14
might be accelerating the undesired carbonyl ene reaction and
set out to test the cascade on a less crowded substrate (Scheme
5). The desired monobromide 17 was prepared from aldehyde
C
DOI: 10.1021/acs.orglett.9b00323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Absolute Configurations of 3,4-Dihydroxylated Homoisoflavans and
Brazilins from Caesalpinia Sappan L. Chem. Pharm. Bull. 1987, 35,
2761. (b) Min, B. S.; Cuong, T. D.; Hung, T. M.; Min, B. K.; Shin, B.
S.; Woo, M. H. Compounds from the Heartwood of Caesalpinia
Sappan and Their Anti-Inflammatory Activity. Bioorg. Med. Chem.
Lett. 2012, 22, 7436.
(4) Lin, L.-G.; Xie, H.; Li, H.-L.; Tong, L.-J.; Tang, C.-P.; Ke, C.-Q.;
Liu, Q.-F.; Lin, L.-P.; Geng, M.-Y.; Jiang, H.; et al. Naturally
Occurring Homoisoflavonoids Function as Potent Protein Tyrosine
Kinase Inhibitors by C-Src-Based High-Throughput Screening. J. Med.
Chem. 2008, 51, 4419.
(5) (a) Masuda, H.; Ohtani, K.; Mizutani, K.; Ogawa, S.; Kasai, R.;
Tanaka, O. Chemical Study on Haematoxylon Campechianum: A
Sweet Principle and New Dibenz[b,d]Oxocin Derivatives. Chem.
Pharm. Bull. 1991, 39, 1382. (b) Nguyen, M. T. T.; Awale, S.; Tezuka,
Y.; Tran, Q. L.; Kadota, S. Xanthine Oxidase Inhibitors from the
Heartwood of Vietnamese Caesalpinia Sappan. Chem. Pharm. Bull.
2005, 53, 984.
(6) (a) Dewick, P. M. Biosynthesis of the 3-Benzylchroman-4-One
Eucomin in Eucomis bicolor. Phytochemistry 1975, 14, 983. (b) Nagai,
M.; Nagumo, S.; Eguchi, I.; Lee, S.; Suzuki, T. Sappanchalcone from
Caesalpinia Sappan L., the Proposed Biosynthetic Precursor of
Brazilin. Yakugaku Zasshi 1984, 104, 935. (c) Nagai, M.; Nagumo,
S.; Lee, S.-M.; Eguchi, I.; Kawai, K.-I. Protosappanin A, a Novel
Biphenyl Compound from Sappan Lignum. Chem. Pharm. Bull. 1986,
34, 1. (d) Lin, L.-G.; Liu, Q.-Y.; Ye, Y. Naturally Occurring
Homoisoflavonoids and Their Pharmacological Activities. Planta
Med. 2014, 80, 1053 and references cited therein .
cleave the benzyl ethers of carbaldehyde 21 under typical
hydrogenolysis conditions with hydrogen gas were accom-
panied by concomitant reduction of the benzaldehyde moiety
of 21 to a methyl group, but when formate was used as the
reductant, deprotection proceeded cleanly to afford a mixture
of ( )-pestalachloride C and ( )-pestalachloride D in a 1.6:1
ratio in 83−90% yield. The isomers were readily separable by
reversed-phase HPLC.
Hydroxylated flavonoids are known to exert weak terato-
genic effects, exhibit antimelanogenic activity, and inhibit
proliferation of melanoma.21 We tested ( )-pestalachlorides C
and D against the A375 melanoma cell lines and found
pestalachloride D to be slightly more potent with IC50s of 12.4
2.4 and 7.1 0.6 μM, respectively.
The ready formation of pestalachlorides C and D through a
Tietze cascade reaction, involving Knoevenagel reactions of
dienophiles tethered to aldehydes followed by hetero Diels−
Alder cycloaddition of a quinone methide intermediate,
supports the Shao and Wang biosynthetic hypothesis for
these racemic natural products. It adds to the growing list of
related Knoevenagel/hetero-Diels−Alder cascade reactions
that parallel biosynthetic pathways.22,23 Late-stage introduction
of the formyl group allows one to assemble ( )-pestala-
chlorides C and D in a facile and concise manner utilizing a
Knoevenagel/hetero-Diels−Alder cascade cyclization reaction.
ASSOCIATED CONTENT
* Supporting Information
■
(7) Li, E.; Jiang, L.; Guo, L.; Zhang, H.; Che, Y. Pestalachlorides A−
C, Antifungal Metabolites from the Plant Endophytic Fungus
Pestalotiopsis Adusta. Bioorg. Med. Chem. 2008, 16, 7894.
(8) Zask, A.; Ellestad, G. Biomimetic Syntheses of Racemic Natural
Products. Chirality 2018, 30, 157 and references cited therein .
(9) Wei, M.-Y.; Li, D.; Shao, C.-L.; Deng, D.-S.; Wang, C.-Y.
( )-Pestalachloride D, an Antibacterial Racemate of Chlorinated
Benzophenone Derivative from a Soft Coral-Derived Fungus
Pestalotiopsis Sp. Mar. Drugs 2013, 11, 1050.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00323.
1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all compounds (PDF)
(10) Blagosklonny, M. V. Teratogens as Anticancer Drugs. Cell Cycle
2005, 4, 1518.
(11) Gutman, E. S.; Arredondo, V.; Van Vranken, D. L. Cyclization
of η3-Benzylpalladium Intermediates Derived from Carbene Insertion.
Org. Lett. 2014, 16, 5498.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.vv@uci.edu.
ORCID
(12) Cueto, M.; Jensen, P. R.; Kauffman, C.; Fenical, W.; Lobkovsky,
E.; Clardy, J. Pestalone, a New Antibiotic Produced by a Marine
Fungus in Response to Bacterial Challenge. J. Nat. Prod. 2001, 64,
1444.
Vanessa Arredondo: 0000-0001-6567-4549
Feng Liu-Smith: 0000-0003-3963-0651
David L. Van Vranken: 0000-0001-5964-7042
Notes
̌
̈
(13) Slavov, N.; Cvengros, J.; Neudorfl, J.-M.; Schmalz, H.-G. Total
Synthesis of the Marine Antibiotic Pestalone and Its Surprisingly
Facile Conversion into Pestalalactone and Pestalachloride A. Angew.
Chem., Int. Ed. 2010, 49, 7588.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(14) (a) Tietze, L. F.; Kettschau, G. Hetero Diels-Alder Reactions in
Organic Chemistry. In Stereoselective Heterocyclic Synthesis I; Metz, P.,
Ed.; Springer: Berlin, 1997; 1−120. (b) Tietze, L. F.; Beifuss, U.
Sequential Transformations in Organic Chemistry: A Synthetic
Strategy with a Future. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(c) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem. Rev.
1996, 96, 115. (d) Tietze, L. F.; Lieb, M. E. Domino Reactions for
Library Synthesis of Small Molecules in Combinatorial Chemistry.
Curr. Opin. Chem. Biol. 1998, 2, 363. (e) Tietze, L. F.; Modi, A.
Multicomponent Domino Reactions for the Synthesis of Biologically
Active Natural Products and Drugs. Med. Res. Rev. 2000, 20, 304.
(f) Tietze, L. F.; Haunert, F. Domino Reaction in Organic Synthesis.
An Approach to Efficiency, Elegance, Ecological Benefit, Economic
Advantage and Preservation of Our Resources in Chemical Trans-
This work was supported by the School of Physical Sciences.
V.A. acknowledges support from a fellowship from the
National Science Foundation. D.R. acknowledges support
from the Allergan Summer Undergraduate Research Program.
D.R. and S.Y. acknowledge support from the UCI University
Research Opportunities Program.
REFERENCES
■
(1) Dapson, R.; Bain, C. Brazilwood, Sappanwood, Brazilin and the
Red Dye Brazilein: From Textile Dyeing and Folk Medicine to
Biological Staining and Musical Instruments. Biotech. Histochem. 2015,
90, 401.
(2) Gilbody, A. W.; Perkin, W. H.; Yates, J. CXLVI.Brazilin and
Hœmatoxylin. Part I. J. Chem. Soc., Trans. 1901, 79, 1396.
(3) (a) Namikoshi, M.; Nakata, H.; Yamada, H.; Nagai, M.; Saitoh,
T. Homoisoflavonoids and Related Compounds. II. Isolation and
̈
formations. In Stimulating Concepts in Chemistry; Vogtle, F., Stoddart,
J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2005; Chapter 4, pp
39−64.
D
DOI: 10.1021/acs.orglett.9b00323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) Tietze, L. F.; Ott, C.; Haunert, F. Efficient and Regioselective
Synthesis of Bridged Ring Systems by Domino Knoevenagel - Hetero-
Diels-Alder Reaction. Can. J. Chem. 2001, 79, 1511.
(f) Lam, H. C.; Phan, Q. D.; Sumby, C. J.; George, J. H. Biomimetic
Synthesis of Hyperjapones F-I. Aust. J. Chem. 2018, 71, 649.
(g) Dethe, D. H.; Kumar, V. B.; Maiti, R. Biomimetic Total Syntheses
of Chromane Meroterpenoids, Guadials B and C, Guapsidial A and
Psiguajadial D. Org. Biomol. Chem. 2018, 16, 4793. (h) Takao, K.;
Noguchi, S.; Sakamoto, S.; Kimura, M.; Yoshida, K.; Tadano, K. Total
Synthesis of (+)-Cytosporolide A via a Biomimetic Hetero-Diels−
Alder Reaction. J. Am. Chem. Soc. 2015, 137, 15971. (i) Chapman, L.
M.; Beck, J. C.; Lacker, C. R.; Wu, W.; Reisman, S. E. Evolution of a
Strategy for the Enantioselective Total Synthesis of (+)-Psiguadial B.
J. Org. Chem. 2018, 83, 6066.
(16) (a) Lee, Y. R.; Xia, L. Efficient One-Pot Synthetic Approaches
for Cannabinoid Analogues and Their Application to Biologically
Interesting (−)-Hexahydrocannabinol and (+)-Hexahydrocannabinol.
Tetrahedron Lett. 2008, 49, 3283. (b) Lee, Y. R.; Kim, Y. M.; Kim, S.
H. Efficient One-Pot Synthesis of Benzopyranobenzopyrans and
Naphthopyranobenzopyrans by Domino Aldol-Type Reaction/
Hetero Diels−Alder Reaction of Resorcinols and Naphthols.
Tetrahedron 2009, 65, 101.
(17) (a) Shrestha, K. S.; Honda, K.; Asami, M.; Inoue, S. Facile
Synthesis of the Fused 6−6−5 Ring System Containing Chroman
Ring from 2-(1-Hydroxy-5-Alkenyl)Phenol Derivatives via Intra-
molecular Inverse-Electron-Demand Diels−Alder Reaction. Bull.
Chem. Soc. Jpn. 1999, 72, 73. (b) Hug, R.; Hansen, H.-J.; Schmid,
H. Thermische Cyclodehydratisierung von Salicylalkoholen; Eine
Einfache Synthese von 4-Substituierten 2H-Chromenen. Helv. Chim.
Acta 1972, 55, 1675.
(18) Kaiser, F.; Schmalz, H.-G. Synthetic Analogues of the Antibiotic
Pestalone. Tetrahedron 2003, 59, 7345.
(19) (a) Agrawal, P. K.; Schneider, H.-J.; Malik, M. S.; Rastogi, S. N.
13C NMR Shifts and Conformations of Substituted Indans. Org. Magn.
Reson. 1983, 21, 146. (b) Guo, X.-X.; Sawano, T.; Nishimura, T.;
Hayashi, T. Rhodium-Catalyzed Enantioselective Alkynylative Cycli-
zation of Allenyl Aldehydes with Terminal Alkynes. Tetrahedron:
Asymmetry 2010, 21, 1730. (c) Wu, A.; Cremer, D.; Auer, A. A.;
Gauss, J. Extension of the Karplus Relationship for NMR Spin−Spin
Coupling Constants to Nonplanar Ring Systems: Pseudorotation of
Cyclopentane. J. Phys. Chem. A 2002, 106, 657.
(20) Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Enantioselective
Catalytic Carbonyl−Ene Cyclization Reactions. Angew. Chem., Int. Ed.
2008, 47, 1469.
(21) (a) Liu-Smith, F.; Meyskens, F. L. Molecular Mechanisms of
Flavonoids in Melanin Synthesis and the Potential for the Prevention
and Treatment of Melanoma. Mol. Nutr. Food Res. 2016, 60, 1264.
́
́
(b) Veselinovic, J. B.; Kocic, G. M.; Pavic, A.; Nikodinovic-Runic, J.;
́
́
Senerovic, L.; Nikolic, G. M.; Veselinovic, A. M. Selected 4-Phenyl
Hydroxycoumarins: In Vitro Cytotoxicity, Teratogenic Effect on
Zebrafish (Danio rerio) Embryos and Molecular Docking Study.
Chem. Biol. Interact. 2015, 231, 10.
(22) (a) Yang, B.; Gao, G. Recent advances in the application of
Diels-Alder reactions involving o-quinodimethanes, aza-o-quinone
methides and o-quinone methides in natural product total synthesis.
Chem. Soc. Rev. 2018, 47, 7926. (b) Nielsen, C. D. -T.; Abas, H.;
Spivey, A. C. Stereoselective Reactions of ortho-Quinone Methide and
ortho-Quinone Methide Imines and Their Utility in Natural Product
Synthesis. Synthesis 2018, 50, 4008. (c) Ai, W.-Y.; Liao, D.-H.; Lei, X.-
G. Applications of ortho-Quinone Methides in the Synthesis of
Natural Products. Chin. J. Org. Chem. 2015, 35, 1615. (d) Willis, J.;
Bray, C. D. ortho-Quinone Methides in Natural Product Synthesis.
Chem. Eur. J. 2012, 18, 9160. (e) Tietze, L. F.; Rackelmann, N. The
Domino-Knoevenagel-hetero-Diels−Alder Reaction and Related
Transformations. In Multicomponent Reactions; Zhu, J., Hugues, B.,
Eds.; Wiley-VCH: Weinheim, 2005; Chapter 5, pp 121−168.
(23) (a) Casiraghi, G.; Cornia, M.; Casnati, G.; Fava, G. G.; Belicchi,
M. F. A one-step highly stereocontrolled synthesis of (−)- and
(+)-hexahydrocannabinol and related compounds. J. Chem. Soc.,
Chem. Commun. 1986, 271. (b) Lawrence, A. L.; Adlington, R. M.;
Baldwin, J. E.; Lee, V.; Kershaw, J. A.; Thompson, A. L. A Short
Biomimetic Synthesis of the Meroterpenoids Guajadial and Psidial A.
Org. Lett. 2010, 12, 1676. (c) Newton, C. G.; Tran, D. N.; Wodrich,
M. D.; Cramer, N. One-Step Multigram-Scale Biomimetic Synthesis
of Psiguadial B. Angew. Chem., Int. Ed. 2017, 56, 13776. (d) Spence, J.
T. J.; George, J. H. Structural Reassignment of Cytosporolides A−C
via Biomimetic Synthetic Studies and Reinterpretation of NMR Data.
Org. Lett. 2011, 13, 5318. (e) Spence, J. T. J.; George, J. H. Total
Synthesis of Peniphenones A−D via Biomimetic Reactions of a
Common o-Quinone Methide Intermediate. Org. Lett. 2015, 17, 5970.
E
DOI: 10.1021/acs.orglett.9b00323
Org. Lett. XXXX, XXX, XXX−XXX