A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine)

Article abstract of DOI:10.1021/jacs.8b05043

The hetisine-type natural products exhibit one of the most complex carbon skeletons within the diterpenoid alkaloid family. The use of network analysis has enabled a synthesis strategy to access alkaloids in this class with hydroxylation on the A-ring. Key transformations include a benzyne acyl-alkylation to construct a key fused 6-7-6 tricycle, a chemoselective nitrile reduction, and sequential C-N bond formations using a reductive cyclization and a photochemical hydroamination to construct an embedded azabicycle. Our strategy should enable access to myriad natural and unnatural products within the hetisine-type.

Full text of DOI:10.1021/jacs.8b05043

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Communication
A Benzyne-Insertion Approach to Hetisine-Type Diterpenoid
Alka-loids: Synthesis of Cossonidine (Davisine)
Kevin G. M. Kou, Jason J Pflueger, Toshihiro Kiho, Louis Christian Morrill, Ethan
L. Fisher, Kyle Clagg, Terry P Lebold, Jessica K Kisunzu, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05043 • Publication Date (Web): 11 Jun 2018
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A Benzyne-Insertion Approach to Hetisine-Type Diterpenoid Alkaloids:
Synthesis of Cossonidine (Davisine)
Kevin G. M. Kou,†,‡ Jason J. Pflueger,†,‡,§ Toshihiro Kiho,†,﬩ Louis C. Morrill,†,‖ Ethan L. Fisher,†,¶ Kyle
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Clagg,†,∇ Terry P. Lebold,†,° Jessica K. Kisunzu,ꢀ,* and Richmond Sarpong†,*
ꢀDepartment of Chemistry & Biochemistry, Colorado College, Colorado Springs, Colorado 80903, United States
†Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
ABSTRACT: The hetisine-type natural products exhibit one of the
most complex carbon skeletons within the diterpenoid alkaloid
family. The use of network analysis has enabled a synthesis strat-
egy to access alkaloids in this class with hydroxylation on the A-
ring. Key transformations include a benzyne acyl-alkylation to
construct a key fused 6-7-6 tricycle, a chemoselective nitrile re-
duction, and sequential C–N bond formations using a reductive
cyclization and a photochemical hydroamination to construct an
embedded azabicycle. Our strategy may enable access to myriad
natural and unnatural products within the hetisine-type.
Voltage-gated sodium (Nav), calcium (Cav), and potassium (Kv)
channels regulate a wide variety of biophysical responses in the
Figure 1. Representative diterpenoid alkaloids.
nervous, circulatory, and muscular systems.1 As a result, the se-
lective targeting of ion channels holds great promise for treating
a number of channelopathies, including Alzheimer’s disease,
epilepsy, and chronic pain.2 One of the greatest challenges in the
discovery of small molecule modulators of ion channels, particu-
larly Nav channels, is to achieve high selectivity in targeting one
isoform over another.3 For example, targeting Nav1.7 or 1.8 may
prove useful in combating chronic pain, but off-target interac-
tions with other isoforms leads to serious cognitive, cardiac, or
muscular complications.3a The identification, synthesis, and study
of isoform-selective ion channel modulators will facilitate a bet-
ter understanding of the interactions responsible for selectivity.
The diterpenoid alkaloids, a collection of over 1200 natural
products isolated from numerous plants in the Aconitum, Del-
phinium, and Consolida genera, show strong affinities for various
Nav and Kv channels, functioning as either agonists or antago-
nists.4 This
Figure 2. Biosynthetic relationships between selected C20-
diterpenoid alkaloids.
broad range of activity and selectivity arises from relatively sub-
tle changes on scaffolds consisting of 18, 19, and 20 carbon at-
oms. For example, despite their overwhelming similarities, the
C19-diterpenoid alkaloid aconitine (1, Figure 1) is a potent Nav
channel activator, whereas the related C18-diterpenoid alkaloid
lappaconitine (2) is a Nav channel blocker.5 The C20-diterpenoid
alkaloid Guan-fu base A (3), another Nav channel blocker, is ap-
proved and marketed in China for the treatment of arrhythmia.6
Within this family, there exist other oxygenated congeners with
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unexplored activity.7 Therefore, the ability to access myriad oxy-
biosynthetically related atisine-, denudatine-, hetidine-, hetisine-
and vakognavine-type natural products (Figure 2), the carbon
framework of the hetisine-type diterpenoid alkaloids (exempli-
fied by cossonidine (8)) is considered to be the most complex,
featuring a C14–C20 bond and an N–C6 bond, which results in a
tertiary amine embedded within a heptacyclic skeleton. Strate-
gies for the syntheses of atisine- and hetidine-type diterpenoid
alkaloids have been advanced;11–15 however, to date, only mono-
hydroxylated hetisine-
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genated diterpenoid alkaloid natural products and their associat-
ed derivatives would enable studies to deepen our understand-
ing of the structure-activity relationships across all classes and
types.
Our group’s interest in this class of molecules has culminated
in the syntheses of several C18- and C19-aconitine-type, as well as
C20-denudatine-type natural products.8,9 Within the C20 family,
the hetisine-type molecules are the most prevalent, with more
than 120 known members, including Guan-fu base A (3).10 Of the
Scheme 1. Network-Analysis-Guided Retrosynthesis of Cossonidine
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type alkaloids have been accessed by total synthesis: nominine
(4) by Muratake/Natsume16a–c as well as by Gin/Peese,16e,f and
spirasine IV/XI by Zhang and coworkers.17 The relatively few
number of hetisine syntheses can, in part, be attributed to the
challenge in forming the N-C6 bond at a late stage through chem-
ical synthesis.11a,13
Hydrindanone 13, prepared on multi-gram scale in two steps
from dienophile 14 and diene 15 according to our previously
reported procedures,8,9 served as the starting point for our stud-
ies (see Scheme 2). LiAlH4-mediated reduction of both the ester
and ketone groups in 13, followed by Ley oxidation,20 provided a
ketoaldehyde intermediate (not shown). While olefination of the
aldehyde under standard Wittig conditions led to poor yields of
the desired alkene, application of Lebel’s Rh-catalyzed methyle-
nation21 effected selective formation of terminal alkene 16 in
71% yield over 3 steps. Acylation using allyl cyanoformate (17)22
proceeded in 88% yield to provide β-ketoester 12, the substrate
for the aryne insertion reaction. Following the precedent of
Stoltz and coworkers,23 treatment of a mixture of β-ketoester 12
and aryne precursor 1824 with CsF in MeCN at 70 °C provided
tricycle 19 in 38–45% yields. The brom-
Cognizant of the fact that most hetisine-type diterpenoid alka-
loids, including the medicinally relevant Guan-fu base A (3), pos-
sess additional oxygenation on the A ring, our group set out to
develop a synthesis route to the hetisine framework that would
introduce A ring oxygenation, while obviating the challenge asso-
ciated with a late-stage installation of the N-C6 bond. In this
Communication, we report a validation of our approach, which
has resulted in the first synthesis of cossonidine (8), a hetisine-
type alkaloid isolated independently in 1996 by de la Fuente7b
and Pelletier7c (who termed this natural product davisine).
ine atom on the aryne was required to obtain high regioselectivi-
ty in the acyl-alkylation process, in accordance with studies by
Garg and Houk.25 This transformation represents one of the most
complex applications of the benzyne acyl-alkylation reaction
reported to date.26
By constraining our analysis to a maximum ring size of seven in
our network-analysis of cossonidine (8),18,19 we identified two
maximally-bridged ring systems: a carbocyclic 7-membered ring
and a nitrogen-containing 7-membered ring (highlighted in blue,
Scheme 1), both of which contain 6 bridging atoms. To achieve
maximal simplification of the highlighted bridged ring systems,
we envisioned a bicyclization transform that would alleviate
bridging atoms in both ring systems, thus leading back to penta-
cycle 9 containing an alkene and arene functional groups. Net-
work analysis of 9 revealed the F ring to be maximally-bridged,
with 5 bridging atoms. Disconnecting the two C–N bonds in 9
using two amination transforms effectively simplified the target
structure to fused tricycle 10, which exhibits no bridging ele-
ments. Forging the seven-membered ring motif in 10 was envi-
sioned to occur through an acyl-alkylation annulation between
functionalized benzyne derivative 11 and β-ketoester 12, which
in turn could arise from literature-reported hydrindanone 13.8,9
We next sought to install a functional handle in the form of an
Scheme 2. Synthesis and Elaboration of the 6-7-6 Tricycle
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Scheme 3. Assembly of the Heptacyclic Core of the Hetisine-type Alkaloids and Completion of Cossonidine
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alkene group at C6 to aid in the formation of the N–C6 bond at a
photochemical hydroamination furnished tertiary amine 9 in 71%
later stage of the synthesis. Thus, deallylation using catalytic
Pd(PPh3)4 and PhSiH3 provided carboxylic acid 20 in 97–99%
yield,27 which was characterized by X-ray crystallography. Subse-
quent treatment with 1,3-diiodo-5,5-dimethylhydantoin (DIH)
under photochemical conditions effected oxidative decarboxyla-
tion28 to furnish styrenyl derivative 21 in 71–74% yield.
yield over 3 steps.31
At this stage, formation of the [2.2.2] bicycle was explored fol-
lowing the Birch reduction/intramolecular Diels–Alder sequence
utilized in the Gin synthesis of nominine.17 Notably, while the cy-
cloaddition performed by Gin and Peese (on an intermediate
analogous to 24 but lacking the C1-methoxy substituent) pro-
ceeded in high yield at only 60 °C, the cycloaddition of 24 re-
quired significantly elevated temperatures. The best results were
achieved using microwave irradiation at 110 °C in 9:1
MeOH/pyrrolidine for 2 h, forging the heptacyclic product (25)
after hydrolysis in 54% yield over 2 steps. We postulate that the
steric influence of the equatorial C1-methoxy substituent in 24
preferentially orients the vinyl group away from the diene, a
penalty which is avoided in the Gin substrate lacking the meth-
oxy group.
The next challenge was to introduce the methyl group (C18) at
the C4-position, which is present not only in the hetisine-type,
but in all the C20-diterpenoid alkaloid natural products. Efforts to
introduce this methyl group at earlier stages in the synthesis
were unsuccessful, resulting in recovered starting material or
nonspecific decomposition. Ultimately, the primary hydroxyl
group resulting from TBAF-mediated desilylation of 21 (95%
yield) was directly converted into nitrile 22 in 96% yield,29 and
diastereoselective methylation of 22 was accomplished in 58%
yield by deprotonation with LiHMDS followed by addition of me-
thyl iodide. Access to tricyclic intermediate 10, bearing functional
handles at C6 and C20, set the stage for the subsequent C–N
bond-forming reactions.
With the heptacyclic core assembled, we investigated reaction
conditions for selective cleavage of the C1 methyl ether. While
an evaluation of standard Lewis acid-mediated conditions for the
cleavage of aliphatic methyl ethers proved unsuccessful, expo-
sure of ether 25 to HBr in AcOH9,32 and ensuing treatment with
K2CO3 in methanol provided secondary alcohol 26 in 60% yield
over 2 steps. Under these conditions, a Wagner-Meerwein rear-
rangement product (27), which was umambiguously character-
ized by X-ray crystallography, is also formed in 5% yield over 2
steps (see the SI for details). Wittig methylenation converted the
ketone group of 26 into the terminal alkene (28) in 85% yield,
thereby introducing the final carbon atom of the hetisine-type
skeleton. An oxidation/re-duction sequence was then explored to
invert the C1-stereocenter. Application of Stahl’s aerobic oxida-
tion conditions33 gave the ketone 29 in 81% yield. In a reversal of
the typical stereoselectivity trend observed in cyclohexanone
reductions,34 reacting this ketone with LiAlH4 resulted in a dia-
stereoselective reduction (6.6:1 dr) in favor of the desired alco-
hol (30) with the axially-disposed hydroxyl group, which was
isolated in 81% yield. Subjecting 30 to selenium dioxide produced
cossonidine (8) and enone 31 in 39% and 19% yields, respective-
To construct the azabicycle moiety, we sought to first form the
N–C20 bond through a global reduction of 10, which we envi-
sioned would convert the nitrile to a primary amine, the ketone
to a hydroxyl group, and effect removal of the bromine atom. At
this stage, displacement of the C20-hydroxyl group by the result-
ant primary amine through a Mitsunobu reaction or via an inter-
mediate alkyl chloride was expected to forge the piperidine ring
(the N–C20 bond).12b Treatment of 10 with LiAlH4, however, re-
sulted in a complex mixture of products, presumably due to in-
complete reduction of the nitrile group. We posited that a poten-
tial solution would be to first chemoselectively reduce the nitrile
group in the presence of the ketone carbonyl and two alkene
groups. This was achieved with cobalt boride (Co2B) and borane
t-butylamine complex (Scheme 3).30 Gratifyingly, upon subjecting
the resulting primary amine to LiAlH4 in THF at reflux, ketone
reduction, protodebromination, and cyclization to form the N–
C20 bond occurred to deliver directly secondary amine 23. A
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catalyzed olefination, and Dr. Pamela Tadross (Caltech) Prof.
Brian Stoltz (Caltech) and Prof. Neil Garg (UCLA) for discusꢁ
sions regarding the benzyne acylꢁalkylation.
ly. Reduction of enone 31 under Luche conditions resulted in 90%
yield of 3:1 mixture of diastereomers favoring 15-epi-
cossonidine (32).
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In summary, our work has provided access to the complete he-
tisine-type skeleton bearing key functional group handles on
both the A ring and the [2.2.2] bicycle for further derivatization.
This route proceeds in 21 steps from known hydrindanone 13
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and features
a benzyne acyl-alkylation ring expansion, a
chemoselective nitrile reduction, a light-mediated hydroamina-
tion, and an intramolecular Diels–Alder cycloaddition as key
steps. With the complex hetisine skeleton assembled, future
studies will be directed toward generating more highly oxygen-
ated congeners.7 Furthermore, by starting with enantioenriched
hydrindanone 13, which was recently reported by our group,8,9
this synthesis should be readily rendered enantioselective.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge on the ACS Publications Website at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*jkisunzu@coloradocollege.edu
*rsarpong@berkeley.edu
Present Addresses
§Department of Chemistry, Rose-Hulman Institute of Technology,
5500 Wabash Avenue, Terre Haute, IN 47803
﬩Modality Laboratories, Daiichi-Sankyo Co. Ltd., 1-2-58 Hiroma-
chi, Shinagawa-ku, Tokyo 140-8710, Japan
‖School of Chemistry, Cardiff University, Main Building, Park
Place, Cardiff, CF10 3AT, UK
¶Pfizer Worldwide Research and Development, Eastern Point
Road, Groton, Connecticut 06340, USA
∇Department of Small Molecule Process Chemistry, Genentech,
1 DNA Way, South San Francisco, California 94080, USA
°Janssen Research & Development, LLC, 3210 Merryfield Row,
San Diego, California 92121, USA
Author Contributions
‡ These authors contributed equally.
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gew. Chem. Int. Ed. 2013, 52, 4854–4857. (b) Hamlin, A. M.; Lapointe, D.;
Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79, 6783–6800.
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Chem. Soc. 2014, 136, 12592–12595.
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cepted. DOI: 10.1021/jacs.8b03712.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to the NIH (NIGMS R01 GM084906) and Daiichi
Sankyo (T.K.) for financial support. K.G.M.K. and T.P.L.
acknowledge NSERC for post-doctoral fellowships. We are thank-
ful to the NSF for a graduate fellowship to J.J.P. and to Eli Lilly for
graduate fellowships to J.J.P. and J.K.K. We thank A. DiPasquale
(UC Berkeley) for solving the crystal structure of 20 and N. Set-
tineri (UC Berkeley) for the crystal structure of 27, supported by
the NIH Shared Instrumentation Grant (S10RR027172). We thank
the Central California 900 MHz NMR Facility and the College of
Chemistry NMR Facilities for their help with NMR experimenta-
tion. Funds for the 900 MHz NMR spectrometer were provided
by the NIH through grant GM68933. We thank Prof. Hélène Lebel
(U. de Montréal) for insightful conversations regarding the Rhꢁ
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