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Dearomative Synthetic Entry into the Altemicidin Alkaloids

Claire S. Harmange Magnani and Thomas J. Maimone*
Cite This: J. Am. Chem. Soc. 2021, 143, 7935−7939 Read Online

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ABSTRACT: Altemicidin and related Streptomyces-derived monoterpene alkaloids possess dense, highly polar azaindane cores as
well as potent cytotoxic and tRNA synthetase inhibitory properties. The congested α-amino acid motif decorating their presumed
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iridoid-like core structure has proven to be both a synthetic challenge and a biosynthetic mystery to date. Herein, we report a
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distinct, abiotic strategy to these alkaloids resulting in a concise synthesis of altemicidin from simple chemical feedstocks. Key
chemical findings include the exploitation of a dearomative pyridinium addition and dipolar cycloaddition sequence to
stereospecifically install the quaternary amine moiety, and a chemoselective molybdenum-mediated double reduction to establish the
fully functionalized azaindane nucleus with minimal redox manipulations.

I n a screening effort to identify novel acaricidal and

insecticidal natural products, Takahashi and co-workers
isolated (−)-altemicidin (1) from Streptomyces sioyaensis in
1989 (Figure 1A).1−4 Following this report, researchers at
SmithKline Beecham identified the related alkaloids SB-
203207 (2) and SB-203208 (3) while searching for novel
microbial tRNA synthetase inhibitors.5,6 Preliminary medicinal
chemistry work involving modification of natural 1 supports
the speculation that the sulfonamide side chains of 2 and 3
may mimic natural aminoacyl adenosine monophosphate
(AMP) substrates.7,8 This is notable given the importance of
tRNA synthetase inhibitors as antibiotic and antimalarial drug
leads.9 The cytotoxic mechanism of the action of 1, which lacks
the presumed tRNA synthetase-anchoring isoleucyl side chain,
has not been vetted, but we are intrigued by the possibility that
1 serves as an AMP (4) mimic owing to its complementary size
and electronic distribution (Figure 1A). Notably, nucleotide
mimics have touched many areas of modern drug discovery
from antivirals to cancer immunotherapeutics.10
To date, the enzymatic origins of 1 remain unverified with
the exception of the sulfonamide side chain, which Abe has
shown originates from cysteine (Figure 1B).11 While an
iridoid-like monoterpene is a likely source of the 10-carbon
core of 1, we were compelled to use simple feedstock
chemicals in a net reductive dearomative assembly of 1,12
rather than a nature-inspired oxidative approach (Figure 1B).13
We recognized the latent tetrahydropyridine harbored in
altemicidin and envisioned this motif arising from the
hypothetical annulation shown involving nicotinamide and an
oxime derivative. In contrast to fully synthetic routes to 1 and
2, which proceed in approximately 30 steps,14,15 this strategy
could potentially introduce differentiated polar functionality
rapidly, construct the synthetically challenging α-tertiary amine
stereocenter,16 and reduce reliance on protecting group
chemistry and redox manipulations. Herein, we describe a
short route to (±)-1 guided by this blueprint.

Received: April 21, 2021

Published: May 21, 2021

Figure 1. Altemicidin monoterpene alkaloids. (A) Members and

electrostatic potential surfaces. (B) Potential biosynthesis of 1 and
retrosynthetic plan.

© 2021 American Chemical Society https://doi.org/10.1021/jacs.1c04147

7935 J. Am. Chem. Soc. 2021, 143, 7935−7939
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Scheme 1. Total Synthesis of Altemicidin (1)a

a
Reagents and conditions: (a) 5 (1.0 equiv), 6 (1.5 equiv), phenyl chloroformate (1.3 equiv), TMSOTf (0.10 equiv), MeCN, 23 °C, 3 h, 77%; (b)
Pd(PPh3)4 (1 mol %), NDMBA (0.5 equiv), DCM, 23 °C, 16 h, 92%; (c) NaBH4 (4.0 equiv), 2% MeOH/THF, −50 °C, 8 h, 65% (1.7:1 dr); (d)
trifluorotoluene, BHT (5 mg/mL), MWI, 130 °C, 8 h then add LiBr (5.0 equiv), DBU (1.0 equiv), 3 Å mol. sieves, MeOH, 0 °C, 3 h, 45%; (e)
Ac2O (0.2 M), 65 °C, 89%, 12 h; (f) NaH (90%, 20 equiv), MeI (40 equiv), 3 Å mol. sieves, DCM/DMF (4:1), −30 to −10 °C, 2 h, 98%; (g)
Mo(CO)6 (1.05 equiv), MeCN, 87 °C, 4 h then add 11, NaBH3CN (10 equiv), 6 h, 82%; (h) Pd(OAc)2 (10 mol %), acetaldoxime (10 equiv), 1,4-
dioxane, 105 °C, 12 h, 82%; (i) AcCl (1.5 M in EtOH), 100 °C (pressurized tube), 1.5 h, 63%; (j) 2-sulfamoyl acetic acid (1.1 equiv), DCC (1.1
equiv), DMAP (1.1 equiv), DMF, 23 °C, 12 h, 73%; (k) LiI (12 equiv), pyridine, 130 °C, 9 h, 67%. TMSOTf = trimethylsilyl
trifluoromethanesulfonate, TBS = tert-butyldimethylsilyl, NDMBA = 1,3-dimethylbarbituric acid, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, MWI
= microwave irradiation, BHT = 2,6-di-tert-butyl-4-methylphenol, DCC = N,N′-dicyclohexylcarbodiimide, DMAP = 4-dimethylaminopyridine.

In our initial synthetic studies, we attempted to add various
keto-oxime enolates to N-methylpyridinium salts with the
hopes of trapping the unstable dihydropyridine adduct in a [3
+ 2] cycloaddition, but these reactions proved fruitless.17 After
extensive experimentation, we found that phenyl chloroformate
activation of commercially available and inexpensive nicotino-
nitrile (5) allowed for addition of silylenol ether 6 (prepared
from commercially available ethyl-2-(hydroxyimino)-3-oxobu-
tanoate) in 77% on large scales (Scheme 1).18 In addition to
the identification of 6 as a suitable nucleophile for this process,
and the optimal chloroformate activator (PhOCOCl), the use
of catalytic TMSOTf as a coactivator and polar solvent
acetonitrile were key to engendering greater yields and
selectivity for addition at the desired C-4 position over those
of C-6.19,20 Notably, even slight variations to these coupling
conditions were highly detrimental: lithium, potassium,
sodium, and titanium enolates afforded no product, and
enolates containing larger oxime protecting groups generated
only trace amounts of product.21,22
Our efforts were next directed toward forging the key α-
tertiary amine stereocenter. Attempts to utilize the dihydropyr-
idine as a nucleophilic enamine in an addition reaction to the
7936
oxime π-bond failed and led us to the realization that a dipolar
cycloaddition strategy was required. Efforts to generate a 1,3-
dipole from the allyl oxime through reported palladium-
mediated O → N allyl migration were appealing but
unsuccessful.23 The allyl group could, however, be removed
(cat. Pd(PPh3)4, NDMBA) to cleanly afford free oxime 7 in a
high yield (92%). Gratifyingly, microwave heating of this
compound induced the requisite [3 + 2] dipolar cycloaddition
in 30% isolated yield. Improving the yield of this trans-
formation was challenging, because 7 had a propensity to
revert to nicotinonitrile at elevated temperatures. Additionally,
the general instability of the tricyclic product hampered efforts
to reduce the ketone. We reasoned that reduction of the
ketone prior to the cycloaddition could potentially alleviate
these problems, and that the incorporation of an additional sp3
center might provide a more optimal transition state for the
dipolar cycloaddition. Low-temperature sodium borohydride
reduction of 7 produced alcohol 8 as a mixture of alcohol
epimers (1.7:1 dr) in 65% yield.24 Compared to 7, the mixture
of 8/epi-8 was indeed a superior cyclization substrate,
undergoing the thermal [3 + 2] cyclization in over 80%
combined yield. Microwave heating and the addition of the
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J. Am. Chem. Soc. 2021, 143, 7935−7939
Journal of the American Chemical Society
radical scavenger (BHT) were essential to this process.
Interestingly, through careful chromatography, we isolated an
isomer of 7 in 5% yield after the palladium-mediated
deallylation, which we suspect is the (E)-oxime geometric
isomer. Upon reduction (NaBH4) of this material and workup
with aqueous acid, we found that the material had directly
cyclized to the tricyclic product suggesting that the depicted
(Z)-oxime isomer is carried through the initial steps of the
synthesis as the major product and that oxime isomerization is
a significant component of the activation barrier for the
thermal cycloaddition process. Given the clean reaction profile
for the cycloaddition of 8, we were able to telescope this
process with phenyl carbamate cleavage by simply adding
methanol and LiBr-DBU.25 From this one-pot transformation,
diastereomerically pure tricyclic isoxazolidine 9, whose
structure was confirmed by X-ray crystallography, could be
isolated in 45% yield. Of note, we have easily generated
multigram quantities of 9 through this process.
While our route to the carbocyclic core of altemicidin
proceeded efficiently (i.e., 4 steps from 5 and 6), we were
cognizant that managing the correct oxidation states and
orchestrating the reactivity of the several polar functional
groups would be critical to realizing an overall concise route to
1. Particularly, direct and chemoselective reduction of the C−
O and N−O bonds in isoxazolidine 9 stood as a primary
hurdle. While reduction efforts began with tricycle 9, we
quickly realized that incorporation of an electron-withdrawing
acetyl group was required to activate the N−O bond (vide
infra). Accordingly, acylated tricycle 10 was cleanly generated
by heating 9 in neat acetic anhydride at 65 °C (Scheme 1).
Other activating groups such as carbamates, trifluoro- and
trichloroacetates, and even a protected form of the natural
sulfonamide side chain were ineffective in downstream
chemistry. Compound 10 could be methylated on nitrogen
(NaH, MeI) producing intermediate 11 whose structure was
also verified crystallographically.
With both 10 and 11 accessible, we proceeded to examine
the reduction of these compounds (Table 1). Canonical
reducing and hydrogenation conditions were first examined,
and representative examples are shown. In methanol, samarium
diiodide reduction of 10 gave only N−O reduction product 21.
When water was added as a cosolvent (entry 2), extensive
reduction of the cyclopentane ring occurred (see 22).
Hydrogenolysis conditions (H2, Pd/C) completely reduced
the amino acrylonitrile to methylpiperidine 23 leaving the N−
O bond untouched (entry 3). In contrast, molybdenum
hexacarbonyl in wet acetonitrile at reflux produced dihydro-
pyridine 20 (entry 4), indicating that N−O reduction was
accompanied by loss of water and tautomerization rather than
further reduction. With the hypothesis that the addition of a
hydride source might intercept the presumed imine
intermediate, phenylsilane, which has reported orthogonality
to Mo0, was included.26 Gratifyingly, these conditions (entry
5) favored formation of tetrahydropyridine 19 over dihy-
dropyridine 20. Resubjecting 20 to the reaction conditions did
not result in conversion to the desired product, suggesting that
20 is not an intermediate under these conditions. Increasing
phenylsilane equivalents improved the formation of 19 relative
to 20, but yields remained below 50%. Reductants such as
sodium triacetoxyborohydride and sodium cyanoborohydride
were examined and showed some desired reactivity (entries 6
and 7); however, these reactions suffered from significant
production of 20 in the former and poor conversion in the
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pubs.acs.org/JACS Communication
Table 1. Studies on the Chemoselective Reduction of the
Tricyclic Isoxazolidine
latter. Despite the low conversion, we noted that NaBH3CN
cleanly intercepted the transient imine without concomitant
formation of 20. A report that NaBH3CN reacts with
Mo(CO)6 illuminated a potential problem,27 which was
remedied by preforming the active Mo(CO) 3(MeCN)3
complex in situ before introducing 10 and NaBH3CN (entry
8). Under these conditions, 19 was delivered in 78% yield on
half-gram scales. While earlier attempts to achieve this
reduction with the corresponding N-methyl derivative 11
using the phenylsilane reductant were met with single N−O
bond reduction, we were gratified to observe that 11
undergoes the desired double reductions under the Mo(0)/
NaBH3CN conditions to give 12 in 82% yield as an
inconsequential mixture of O-acylated and deacylated products
(entry 9).
To complete the total synthesis, the nitrile moiety was
carefully converted to its corresponding amide using Pd(OAc)2
and acetaldoxime in refluxing dioxane (Scheme 1).28 Extensive
experimentation revealed that the N-acetyl group of 13 could
only be removed under strongly acidic conditions at elevated
temperatures (AcCl, EtOH, 100 °C).29 Following this
transformation, the sulfonamide side chain could be attached
via a DCC/DMAP-mediated coupling with acid 15 to provide
ethyl altemicidin (16). With 1 within reach, we found 16 to be
robustly resistant to saponification conditions. Despite the
challenges associated with dealkylating an ethyl group,
subjecting 16 to lithium iodide in refluxing pyridine provided
the free carboxylic acid. We believe that this challenging ethyl
dealkylation is facilitated by the formation of isolable oxazoline
intermediates (see 17 and 18) which sterically disencumber
the ethyl ester to permit dealkylation. Hydration of oxazoline
18 occurs during concentration of the aqueous, reverse-phase
column fractions at elevated temperatures. Overall, altemicidin
is generated in 67% yield from 16 and in 11 steps from 5 and
6.
Our synthesis of 1 leverages a dearomative approach to
install the core heteroatoms convergently and rapidly and is
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J. Am. Chem. Soc. 2021, 143, 7935−7939
Journal of the American Chemical Society
strategically distinct to past syntheses of these compact, polar
alkaloids. A chemo- and diastereoselective dipolar cyclo-
addition forges the challenging α-tertiary amine stereocenter,
which is ultimately converted into altemicidin through a
carefully orchestrated reduction/functionalization sequence. As
a result of the robust chemistry described herein, ample
opportunity exists to make deep-seated changes to the cores of
these biologically active natural products as well as procure
sufficient quantities for further target identification and
mechanism of action studies.
■
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04147.
Experimental procedures and spectroscopic data for all
compounds (PDF)
Accession Codes
CCDC 2078779−2078780 contain the supplementary crys-
tallographic 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 Author
Thomas J. Maimone − Department of Chemistry, University
of CaliforniaBerkeley, Berkeley, California 94720, United
States; orcid.org/0000-0001-5823-692X;
Email: maimone@berkeley.edu
Author
Claire S. Harmange Magnani − Department of Chemistry,
University of CaliforniaBerkeley, Berkeley, California
94720, United States; orcid.org/0000-0003-0334-2535
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04147
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Financial support was provided by the NIH (R01GM136945).
C.S.H.M. thanks the NSF (DGE-1106400) for predoctoral
fellowship support. We acknowledge José R. Hernández-
Meléndez for contributions to the optimization of the
pyridinium addition reaction and thank the UC-Berkeley
Amgen Scholars Program for their support. We are
appreciative for spectroscopic assistance from Dr. Hasan
Celik under NIH grant S10OD024998 and Dr. Jeff Pelton
under NIH grant GM68933. Dr. Nicholas Settineri is
acknowledged for X-ray crystallographic analysis wherein
support from NIH Shared Instrument Grant (S10-
RR027172) is also acknowledged. We also thank Dr. Ulla
Andersen for mass spectrometry analysis and Prof. Wenjun
Zhang and Dr. Zhijuan Hu for HPLC assistance. Finally, we
are grateful to Prof. Ikuro Abe (University of Tokyo) for
providing an authentic sample of altemicidin and helpful
discussions.
7938
■
pubs.acs.org/JACS Communication
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