Synthesis of C14-Desmethylene Corialactone D and Discovery of Inhibitors of Nerve Growth Factor Mediated Neurite Outgrowth

Article abstract of DOI:10.1021/acs.orglett.9b00921

An asymmetric synthesis of C14-desmethylene corialactone D is described on the basis of strategic application of a metallacycle-mediated annulative cross-coupling reaction, a Still [2,3]-Wittig rearrangement, and Morken's hydroxyl-directed diboration reac

Full text of DOI:10.1021/acs.orglett.9b00921

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of C14-Desmethylene Corialactone D and Discovery of
Inhibitors of Nerve Growth Factor Mediated Neurite Outgrowth
Robert M. Leon,† Divya Ravi,‡ Jennifer S. An,‡ Carmen L. del Genio,‡ Arnold L. Rheingold,§
Arti B. Gaur,*,‡ and Glenn C. Micalizio*,†
†Department of Chemistry, Dartmouth College, Burke Laboratory, Hanover, New Hampshire 03755, United States
‡Dartmouth College, Geisel School of Medicine, Lebanon, New Hampshire 03756, United States
§Department of Chemistry, University of CaliforniaSan Diego, La Jolla, California 92093, United States
S
* Supporting Information
ABSTRACT: An asymmetric synthesis of C14-desmethylene
corialactone D is described on the basis of strategic application of
a metallacycle-mediated annulative cross-coupling reaction, a Still
[2,3]-Wittig rearrangement, and Morken’s hydroxyl-directed dibora-
tion reaction. While representing a convenient approach to access
novel compositions of matter inspired by the sesquiterpenoid natural
product class (including classic natural product synthesis targets
including the picrotaxanes and dendrobine), these studies have led to the discovery of natural product-inspired agents that
inhibit nerve growth factor (NGF)-mediated neurite outgrowth in PC-12 cells.
mall molecule modulators of nerve growth factor (NGF) are
1
Sof great current interest in biology and medicine. While
neurotrophic agents that promote regeneration and growth of
neurons in the presence of NGF are thought to be of value in
chronic neurodegenerative disease (conditions marked by axon
degeneration and neuronal atrophy) and in acute spinal cord
injury,1a,b,2 inhibitors of NGF are currently thought to be of
potential value as nonopiate analgesic agents.1c,d As such, rare
natural products shown to possess NGF-modulating properties
have been the subject of much investigation in laboratories
engaged in natural product synthesis efforts, including our own.3
Recently, neurotrophic sesquiterpenoid natural products
represented by the corialactones (Figure 1A) have become of
interest to our laboratory because of their structural similarity to
classic targets in natural product synthesis (Figure 1B),4 and an
interest in exploring the value of recently developed synthetic
methods in target-oriented synthesis and the biological
properties associated with compositions of matter in this class.
Corialactones have been found in terrestrial Himalayan shrubs
(Coriaria nepalensis) that have been used as a Chinese herbal
medicine for the treatment of numbness, toothache, traumatic
injury, and acute conjunctivitis, among other ailments.5 Notably,
two sesquiterpenes identified from this terrestrial source have
been claimed to be clinically useful for the treatment of
schizophrenia.5,6 Despite the structural similarity of corialactone
sesquiterpene natural products to the potent GABA antagonist
picrotoxinin (described as one of the most toxic agents of plant
origin)7 and the modestly analgesic alkaloid dendrobine (Figure
1B),7,8 sesquiterpenes from the roots of Coriaria nepalensis
Figure 1. Introduction to the corialactones and structurally related
natural products.
Received: March 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00921
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Retrosynthetic strategy for C14-desmethylene corialactone D.
Figure 3. Asymmetric synthesis of (+)-C14-desmethylene corialactone D.
appear to have a unique and nontoxic pharmacological profile in
vitro at concentrations up to 10 μM [PC-12 (neuro), HCT-8
(colon), HepG2 (liver), BGC-823 (gastric), A549 (lung
epithelia), and SKOV3 (ovarian) - MTT assays].5a Piquing
our interest in corialactones as synthetic targets, glycosides of
sesquiterpenes in this class, as well as semisynthetic variants (1−
3; Figure 1A), have been reported as neurotrophic agents,
despite a variable nature of C14 (i.e., active agents are reported
that contain an allylic alcohol, allylic halide, or an electrophilic
enone in this region of the natural product structure).5b Due to
this apparent tolerability of disparate functionality at this
location of the tricyclic corialactone nucleus, we opted to pursue
the construction of novel compositions of matter that simply
lack the C14 carbon altogether. These efforts have led to
establishing an asymmetric synthesis of C14-desmethylene
corialactone D and the discovery of several new natural product-
inspired compositions of matter that have distinct and opposite
activity to that reported for semisynthetic agents 1−3; they
significantly inhibit NGF-promoted nerve outgrowth in PC-12
cells at concentrations as low as 3 μM. The synthetic chemistry
that fueled these advances was based on strategic application of
an alkoxide-directed metallacycle-mediated annulative cross-
coupling reaction,9 a Still [2,3]-Wittig reaction,10 and Morken’s
hydroxyl-directed diboration reaction.11
It was reasoned that C14-desmethylene corialactone (Figure
2) could be prepared from an intermediate of general structure V
through sequential deprotection of the C12 alcohol and
reductive cleavage of the C−X bond at C4. It was then thought
that V could be accessed by way of intermediate IV through
oxidation of C15 and lactonization. Finally, IV was reasoned to
be accessible by Still [2,3]-Wittig rearrangement of the
secondary allylic alcohol III, a structure that was reasoned to
be derived from a sequence of stereoselective metallacycle-
mediated annulative cross-coupling of a suitably silylated alkyne
II and the chiral enyne I, a substrate ultimately available through
simple functionalization of (R)-(−)-epichlorohydrin.
As illustrated in Figure 3A, titanium alkoxide-mediated and
hydroxyl-directed coupling of enyne 4 with the silylated alkyne 5
delivered hydrindane 6 as a single regio- and stereoisomer in
68% yield (i.e., BnMe2Si− located at C3, i-Pr at C4, and
establishment of the C1 quaternary center).12 Next oxidation of
the C−Si bond at C3 and base-mediated equilibration delivered
the cis-fused biyclic ketone 7 in a modest 46% yield over the two-
step sequence. Protection of the secondary alcohol as its
corresponding p-methoxybenzyl (PMB) ether and diastereose-
lective CBS13 reduction of the C3 ketone then delivered the
stereodefined secondary allylic alcohol 9 in 57% yield over two
steps (ds = 9:1). Still [2,3]-Wittig rearrangement then
B
DOI: 10.1021/acs.orglett.9b00921
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Evaluation of synthetic corialactones for NGF-modulating properties: (A) panel of natural product inspired tricyclic lactones prepared by the
synthetic route presented in Figure 3. (B, C) Compounds 11−17 inhibit NGF-induced neurotrophic properties. Number of differentiated PC-12 cells
(B) and neurite length in PC-12 cells (C) treated with 25 μM of compounds 11−17 or vehicle control DMSO for 72 h in the presence of 50 ng/mL of
NGF. (D) NGF-induced neurite outgrowth is inhibited in a dose-dependent manner by 12: PC-12 cells were treated with 12 or DMSO at various
concentrations in the presence of 50 ng/mL of NGF. The number of differentiated cells and neurite lengths were measured after 72 h. (E) NGF-
induced neurite outgrowth is inhibited by 12: Phase-contrast images of PC-12 cells treated with 3.125 μM of 12 and DMSO in the presence of 50 ng/
mL of NGF.
proceeded smoothly to deliver the stereodefined homoallylic
alcohol 10 as a single stereoisomer.
confirmed through X-ray crystallography. Finally, deprotection
of the PMB ether with DDQ delivered C14-desmethylene
corialactone D (13), surprisingly as a 9:1 mixture of isomers.
While not reported in the isolation and characterization of
corialactone D, we note that compound 13 was formed as a
mixture of lactone isomers. Notably, oxidation of this mixture
with Dess−Martin periodinane delivered a single tricyclic
ketone 14 (Figure 3B).
Next, a collection of synthetic agents bearing the central
tricyclic lactone resident in the corialactones (Figure 4A) was
assembled and advanced for evaluation in vitro. Specifically, an
established neuronal cell model16 was employed to investigate
the impact that these novel natural product-inspired agents have
on nerve growth factor (NGF)-induced neurite outgrowth in
PC-12 cells.16 Based on both differentiation (Figure 4B) and
neurite length (Figure 4C), compounds 11−17 did not
demonstrate NGF-induced neurotrophic properties compared
to the vehicle control17 (i.e., these synthetic agents did not
enhance NGF-promoted neurite outgrowth). Interestingly, and
A variety of strategies were considered for conversion of 10 to
the tricyclic lactone skeleton common to the corialactones,
including oxidation to the β,γ-unsaturated carboxylic acid and 5-
endo halonium ion-induced lactonization.14 Ultimately, it was
found that Morken’s hydroxyl-directed diboration was partic-
ularly well suited to convert 10 to an intermediate of value for
this synthesis campaign. As depicted, treatment of 10 with
bis(pinacolato)diboron and cesium carbonate followed by
oxidation with basic hydrogen peroxide delivered the formal
product of directed dihydroxylation in 52% yield. Selective
oxidation of the primary alcohol at C15 was then accomplished
by treatment with Dess−Martin periodinane (88%), and
subsequent oxidation of the intermediate lactol with TPAP
and NMO delivered the lactone intermediate in 74% yield. Next
deoxygenation at C4 of 11 was achieved through standard
Barton−McCombie conditions15 to deliver the protected
corialactone intermediate 12, the structure of which was
C
DOI: 10.1021/acs.orglett.9b00921
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Accession Codes
distinct from reports describing the biological activity of
sesquiterpenoids related to the corialactones, all p-methox-
ybenzyl (PMB)-functionalized compounds 11, 12, and 15 had a
significant inhibitory effect on NGF-induced neurite outgrowth.
While exposure to 25 μM concentrations of these agents
resulted in a significant decrease in number of differentiated cells
(i.e., up to a 63% reduction; Figure 4B), by 72 h the small
subpopulation of cells that could be observed as having some
neurite outgrowth were markedly shorter than vehicle control
(decrease in neurite length by 21.8%, 26.2%, and 16.3%; Figure
4C). A second treatment of compounds administered at 72 h
further inhibited NGF-induced neurite outgrowth, and at 96 h
from initial dosing a complete retraction of neurites was observed
in cells treated with compounds 12 and 15 (Supplementary
Figure 1A); importantly, none of the tricyclic lactones tested
(11−17) had a cytotoxic effect on PC-12 cells at 25 μM after 96
h of treatment (Supplementary Figure 1B).
CCDC 1869261 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: glenn.c.micalizio@dartmouth.edu.
*E-mail: arti.b.gaur@dartmouth.edu.
ORCID
Glenn C. Micalizio: 0000-0002-3408-5570
Notes
The authors declare no competing financial interest.
Further analyses of 12 revealed dose-dependent inhibition of
NGF-induced neurite outgrowth. As illustrated in Figures 4D,E,
concentrations as low as 3.1 μM of 12 result in a substantial
decrease in the number of NGF-induced differentiated cells and
length of neurites observed. Importantly, these actions are not
due to a cytotoxic effect, as toxicity was not observed even at
concentrations up to 100 μM (Supplementary Figure 2).
Overall, we report the development of an asymmetric
synthesis of C14-desmethylene corialactone that proceeds by
way of strategic application of an alkoxide-directed metallacycle-
mediated annulative cross-coupling reaction, a Still [2,3]-Wittig
rearrangement process, and strategic application of Morken’s
hydroxyl-directed diboration reaction. The tricyclic picrotoxane
skeleton of the corialactones was forged in 13 steps from the
chiral enyne 4, and the synthetic route was employed to access a
collection of tricyclic natural product-inspired agents for
evaluation as potential modulators of nerve growth factor.
While none of the unique compositions of matter prepared and
evaluated here were found to have neurotrophic properties, our
studies have led to the discovery that the p-methoxybenzyl-
substituted species 11, 12, and 15 have activity as inhibitors of
NGF-mediated neurite outgrowth in PC-12 cellsa biological
profile that is opposite to what has been reported for some
corialactone natural products and related semisynthetic agents.
Due to the current pharmaceutical interest in developing NGF-
inhibitors as nonopioid analgesics and the reality that current
clinical agents are biologics (monoclonal antibodies), this
discovery of a unique class of natural product-inspired inhibitors
of NGF could be of interest for further clinical evaluation.18
Certainly, there remains great uncertainty associated with the
mechanism of action of corialactone congeners previously
reported as neurotrophic agents, as well as the manner in which
the structurally unique tricyclic lactone 12 discovered in this
program inhibits NGF-mediated neurite outgrowth in PC-12
cells. We look forward to future advances and discoveries that
grow from the foundation of science described here.
ACKNOWLEDGMENTS
■
We acknowledge financial support from Dartmouth College,
Mr. Don Bell, and the National Institutes of Health
(GM080266). We also acknowledge the Irradiation, Preclinical
Imaging and Microscopy Shared Resource (IPIMSR) in the
Norris Cotton Cancer Center at Dartmouth College with NCI
Cancer Center Support Grant 5P30 CA023108-37.
REFERENCES
■
(1) (a) Koliatsos, V. E.; Price, D. L.; Clatterbuck, R. E.; Markowska, A.
L.; Olton, D. S.; Wilcox, B. J. Neurotrophic Strategies for Treating
Alzheimer’s Disease: Lessons from Basic Neurobiology and Animal
Models. Ann. N. Y. Acad. Sci. 1993, 695, 292−299. (b) Akagi, M.;
Matsui, N.; Akae, H.; Hirashima, N.; Fukuishi, N.; Fukuyama, Y.; Akagi,
R. Nonpeptide neurotrophic agents useful in the treatment of
neurodegenerative diseases such as Alzheimer’s disease. J. Pharmacol.
Sci. 2015, 127, 155−163. (c) Chang, D. S.; Hsu, E.; Hottinger, D. G.;
Cohen, S. P. Anti-nerve growth factor in pain management: current
evidence. J. Pain Res. 2016, 9, 373−383. (d) Seidel, M. F.; Wise, B. L.;
Lane, N. E. Nerve growth factor: an update on the science and therapy.
Osteoarthr. Cartilage 2013, 21, 1223−1228.
(2) (a) Price, R. D.; Milne, S. A.; Sharkey, J.; Matsuoka, N. Advances
in small molecules promoting neurotrophic function. Pharmacol. Ther.
̈
̈
2007, 115, 292−306. (b) Dakas, P.-Y.; Parga, J. A.; Hoing, S.j; Scholer,
H. R.; Sterneckert, J.; Kumar, K.; Waldmann, H. Discovery of
Neuritogenic Compound Classes Inspired by Natural Products.
Angew. Chem., Int. Ed. 2013, 52, 9576−9581. (c) Burch, P.; Binaghi,
M.; Scherer, M.; Wentzel, C.; Bossert, D.; Eberhardt, L.; Neuburger,
M.; Scheiffele, P.; Gademann, K. Total Synthesis of Gelsemiol. Chem. -
Eur. J. 2013, 19, 2589−2591.
(3) Cheng, X.; Micalizio, G. C. Synthesis of Neurotrophic Seco-
prezizaane Sesquiterpenes (1R,10S)-2-Oxo-3,3-dehydroneomajucin,
(2S)-Hydroxy-3,4,-dehydroneomajucin, and (−)-Jiadifenin. J. Am.
Chem. Soc. 2016, 138, 1150−1153.
(4) (a) Yamada, K.; Suzuki, M.; Hayakawa, Y.; Aoki, K.; Nakamura,
H.; Nagase, H.; Hirata, Y. Total synthesis of ( )-dendrobine. J. Am.
Chem. Soc. 1972, 94, 8278−8280. (b) Inubushi, Y.; Kikuchi, T.; Ibuka,
T.; Tanaka, K.; Saji, I.; Tokane, K. Total synthesis of the alkaloid
( )-dendrobine. J. Chem. Soc., Chem. Commun. 1972, 1252−1253.
(c) Inubushi, Y.; Kikuchi, T.; Ibuka, T.; Tanaka, K.; Saji, I.; Tokane, K.
Total Synthesis of the Alkaloid ( )-Dendrobine. Chem. Pharm. Bull.
1974, 22, 349−367. (d) Kende, A. S.; Bentley, T. J.; Mader, R. A.;
Ridge, D. Simple total synthesis of (+)-dendrobine. J. Am. Chem. Soc.
1974, 96, 4332−4334. (e) Roush, W. R. Total Synthesis of
( )-Dendrobine. J. Am. Chem. Soc. 1978, 100, 3599−3601.
(f) Corey, E. J.; Pearce, H. L. Total Synthesis of Picrotoxinin. J. Am.
Chem. Soc. 1979, 101, 5841−5843. (g) Roush, W. R. Total Synthesis of
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00921.
Procedures and spectroscopic data (PDF)
Cell line data (PDF)
D
DOI: 10.1021/acs.orglett.9b00921
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
( )-Dendrobine. J. Am. Chem. Soc. 1980, 102, 1390−1404. (h) Corey,
E. J.; Pearce, H. L. Total Synthesis of Picrotin. Tetrahedron Lett. 1980,
21, 1823−1824. (i) Tanaka, K.; Uchiyama, F.; Sakamoto, K.; Inubushi,
Y. Stereocontrolled Total Synthesis of ( )-Coriamyrtin. J. Am. Chem.
Soc. 1982, 104, 4965−4967. (j) Tanaka, K.; Uchiyama, F.; Sakamoto,
K.; Inubushi, Y. Synthetic Studies on a Picrotoxane Sesquiterpene,
Coriamyrtin. III. Completion of the Stereocontrolled Total Synthesis of
( )-Coriamyrtin. Chem. Pharm. Bull. 1983, 31, 1972−1979. (k) Niwa,
H.; Wakamatsu, K.; Hida, T.; Niiyama, K.; Kigoshi, H.; Yamada, M.;
Nagase, H.; Suzuki, M.; Yamada, K. Stereocontrolled Total Synthesis of
(−)-Picrotoxinin and (+)-Coriamyrtin via a Common Isotwistane
Intermediate. J. Am. Chem. Soc. 1984, 106, 4547−4552. (l) Connolly, P.
J.; Heathcock, C. H. An Approach to the Total Synthesis of
Dendrobine. J. Org. Chem. 1985, 50, 4135−4144. (m) Wakamatsu,
K.; Kigoshi, H.; Niiyama, K.; Niwa, H.; Yamada, K. Stereocontrolled
Total Syntheses of (+)-Tutin and (+)-Asteromurin A, Toxic
Picrotoxane Sesquiterpenes. Tetrahedron 1986, 42, 5551−5558.
(n) Miyashita, M.; Suzuki, T.; Yoshikoshi, A. Stereoselective Total
Synthesis of (−)-Picrotoxinin and (−)-Picrotin. J. Am. Chem. Soc. 1989,
111, 3728−3734. (o) Martin, S. F.; Li, W. Application of Intramolecular
Diels−Alder Reactions to Alkaloid Synthesis. A Formal Total Synthesis
of ( )-Dendrobine. J. Org. Chem. 1991, 56, 642−650. (p) Lee, C. H.;
Westling, M.; Livinghouse, T.; Williams, A. C. Acylnitrilium Ion
Initiated Heteroannulations in Alkaloid Synthesis. An Efficient,
Stereocontrolled, Total Synthesis of the Orchidaceae Alkaloid
( )-Denrobine. J. Am. Chem. Soc. 1992, 114, 4089−4095. (q) Mori,
M.; Uesaka, N.; Shibasaki, M. Novel Synthesis of Nitrogen Hetero-
cycles Using Zirconium-Promoted Reductive Coupling. Formal Total
Synthesis of Dendrobine. J. Org. Chem. 1992, 57, 3519−3521. (r) Mori,
M.; Saitoh, F.; Uesaka, N.; Shibasaki, M. Formal Total Synthesis of
(−)-Dendrobine Using Zirconium Promoted Cyclization. Determi-
nation of the Absolute Configuration of the Intermediary Tricyclic
Ketone. Chem. Lett. 1993, 22, 213−216. (s) Uesaka, N.; Saitoh, F.;
Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. Formal Total Synthesis
of (−)-Dendrobine Using Zirconium-Promoted Reductive Cyclization.
J. Org. Chem. 1994, 59, 5633−5642. (t) Sha, C.-K.; Chiu, R.-T.; Yang,
C.-F.; Yao, N.-T.; Tseng, W.-H.; Liao, F.-L.; Wang, S.-L. Total
Synthesis of (−)-Dendrobine via α-Carbonyl Radical Cyclization. J.
Am. Chem. Soc. 1997, 119, 4130−4135. (u) Trost, B. M.; Krische, M. J.
Palladium-Catalyzed Enyne Cycloisomerization Reaction in an
Asymmetric Approach to the Picrotoxane Sesquiterpenes. 2. Second-
Generation Total Syntheses of Coranin, Picrotoxinin, Picrotin, and
Methyl Picrotoxate. J. Am. Chem. Soc. 1999, 121, 6131−6142.
(v) Trost, B. M.; Haffner, C. D.; Jebaratnam, D. J.; Krische, M. J.;
Thomas, A. P. The Palladium-Catalyzed Enyne Cycloisomerization
Reaction in a General Approach to the Asymmetric Syntheses of the
Picrotoxane Sesquiterpenes. Part I. First-Generation Total Synthesis of
Corianin and Formal Syntheses of Picrotoxinin and Picrotin. J. Am.
Chem. Soc. 1999, 121, 6183−6192. (w) Kreis, L. M.; Carreira, E. M.
Total Synthesis of (−)-Dendrobine. Angew. Chem., Int. Ed. 2012, 51,
3436−3439. (x) Guo, L.; Frey, W.; Plietker, B. Catalytic Enantiose-
lective Total Synthesis of the Picrotoxane Alkaloids (−)-Dendrobine,
(−)-Mubironine B, and (−)-Dendroxine. Org. Lett. 2018, 20, 4328−
4331.
(8) Chen, K. K.; Chen, A. L. The Pharmacological Action of
Denrobine. The Alkaloid of Chin-Shih-Hu. J. Pharmacol. Exp. Ther.
1935, 55, 319−325.
(9) Greszler, S. N.; Reichard, H. A.; Micalizio, G. C. Asymmetric
Synthesis of Dihydroindanes by Convergent Alkoxide-Directed Metal-
lacycle-Mediated Bond Formation. J. Am. Chem. Soc. 2012, 134, 2766−
2774.
(10) Still, W. C.; Mitra, A. A Highly Stereoselective Synthesis of Z-
Trisubstituted Olefins via [2,3]-Sigmatropic Rearrangement. Prefer-
ence for a Pseudoaxially Substituted Transition State. J. Am. Chem. Soc.
1978, 100, 1927−1928.
(11) Blaisdell, T. P.; Caya, T. C.; Zhang, L.; Sanz-Marco, A.; Morken,
J. P. Hydroxyl-Directed Stereoselective Diboration of Alkenes. J. Am.
Chem. Soc. 2014, 136, 9264−9267.
(12) Micalizio, G. C.; Mizoguchi, H. The Development of Alkoxide-
Directed Metallacycle-Mediated Annulative Cross-Coupling Chem-
istry. Isr. J. Chem. 2017, 57, 228−238.
(13) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. Highly Enantioselective
Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines.
Mechanism and Syntehtic Implications. J. Am. Chem. Soc. 1987, 109,
5551−5553. (b) Corey, E. J.; Helal, C. J. Reduction of Carbonyl
Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm
for Enantioselective Catalysis and a Powerful New Synthetic Method.
Angew. Chem., Int. Ed. 1998, 37, 1986−2012.
(14) For an example of 5-endo halo-lactonization, see: (a) Schultz, A.
G.; Kirincich, S. J. Asymmetric Total Synthesis of the Caribbean Fruit
Fly Pheromone (+)-Epianastrephin. J. Org. Chem. 1996, 61, 5626−
5630. For reported challenges associated with the control of
regioselection in hydroboration reactions of homoallylic alcohols
bearing a similarly substituted trisubstituted alkene, see: (b) Paquette,
L. A.; Peng, X.; Yang, J.; Kang, H.-J. The CarbohydrateSesquiterpene
Interface. Directed Synthetic Routes to Both (+)- and ()-Fomanno-
sin from D-Glucose. J. Org. Chem. 2008, 73, 4548−4558. (c) Funk, R.
L.; Bolton, G. L.; Daggett, J. U.; Hansen, M. M.; Horcher, L. H. M.
Intramolecular Cycloaddition Reactions of Exocyclic Nitrones.
Tetrahedron 1985, 41, 3479−3495.
(15) (a) Barton, D. H. R.; McCombie, S. W. A New Method for the
Deoxygenation of Secondary Alcohols. J. Chem. Soc., Perkin Trans. 1
1975, 1574−1585. For a procedure that is catalytic in BusSnH, see:
(b) Lopez, R. M.; Hays, D. S.; Fu, G. C. Bu3SnH-Catalyzed Barton−
McCombie Deoxygenation of Alcohols. J. Am. Chem. Soc. 1997, 119,
6949−6950.
(16) Harrill, J. A.; Mundy, W. R. Quantitative Assessment of Neurite
Outgrowth in PC12 Cells. Methods Mol. Biol. 2011, 758, 331−348.
(17) For the control, dimethyl sulfoxide (DMSO) was used at final
volumes that were identical to those used to attain all concentrations
tested.
(18) For examples of structurally unrelated small molecules and
natural products that have been shown to inhibit NGF, see:
(a) Owolabi, J. B.; Rizkalla, G.; Tehim, A.; Ross, G. M.; Riopelle, R.
J.; Kamboj, R.; Ossipov, M.; Bian, D.; Wegert, S.; Porreca, F.; Lee, D. K.
H. Characterization of Antiallodynic Actions of ALE-0540, a Novel
Nerve Growth Factor Receptor Antagonist, in the Rat. J. Pharmacol.
Exp. Ther. 1999, 289, 1271−1276. (b) Koizumi, S.; Contreras, M. L.;
Matsuda, Y.; Hama, T.; Lazarovici, P.; Guroff, G. K-252a: A Specific
Inhibitor of the Action of Nerve Growth Facton on PC 12 Cells. J.
Neurosci. 1988, 8, 715−721. (c) Miller, R. E.; Malfait, A.-M.; Block, J. A.
Current Status of Nerve Growth Factor Antibodies for the Treatment
of Osteoarthritis Pain. Clin. Exp. Rheumatol. 2017, 35 (Suppl 107), 85−
87. (d) Liu, L.; Shi, X.-W.; Zong, S.-C.; Tang, J.-J.; Gao, J.-M.
Scabronine M, a novel inhibitor of NGF-induced neurite outgrowth
from PC12 cells from the fungus Sarcodon scabrosus. Bioorg. Med. Chem.
Lett. 2012, 22, 2401−2406. (e) Kennedy, A. E.; Laamanen, C. A.; Ross,
M. S.; Vohra, R.; Boreham, D. R.; Scott, J. A.; Ross, G. M. Nerve Growth
Factor Inhibitor with Novel-Binding Domain Demonstrates Nano-
molar Efficacy in Both Cell-Based and Cell-Free Assay Systems.
Pharmacol. Res. Perspect. 2017, 5, No. e00339.
(5) (a) Zhao, F.; Liu, Y.-B.; Ma, S.-G.; Qu, J.; Yu, S.-S.; Fang, Z.-F.; Li,
L.; Si, Y.-K.; Zhang, J.-J. New sesquiterpenes from the roots of Coriaria
nepalensis. Tetrahedron 2012, 68, 6204−6210. (b) Wang, Y.-Y.; Tian, J.-
M.; Zhang, C.-C.; Luo, B.; Gao, J.-M. Picrotoxane Sesquiterpene
Glycosides and a Coumarin Derivative from Coriaria nepalensis and
Their Neurotrophic Activity. Molecules 2016, 21, 1344. Notably, the
enone-containing semisynthetic variant reported in ref 5b was
described as being toxic to PC-12 cells at 20 μM.
(6) Okuda, T.; Yoshida, T.; Chen, X.-M.; Xie, J.-X.; Fukushima, M.
Corianin from Coriaria japonica A. GRAY, and Sesquiterpene Lactones
from Loranthus parasiticus MERR. Used for Treatment of Schizo-
phrenia. Chem. Pharm. Bull. 1987, 35, 182−187.
(7) For a review of picrotoxinin and related substances, see: Porter, L.
E. Picrotoxinin and Related Substances. Chem. Rev. 1967, 67, 441−464.
E
DOI: 10.1021/acs.orglett.9b00921
Org. Lett. XXXX, XXX, XXX−XXX