Bioinspired Diversification Approach Toward the Total Synthesis of Lycodine-Type Alkaloids

Article abstract of DOI:10.1021/jacs.1c00457

Nitrogen heterocycles (azacycles) are common structural motifs in numerous pharmaceuticals, agrochemicals, and natural products. Many powerful methods have been developed and continue to be advanced for the selective installation and modification of nitrogen heterocycles through C-H functionalization and C-C cleavage approaches, revealing new strategies for the synthesis of targets containing these structural entities. Here, we report the first total syntheses of the lycodine-type Lycopodium alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine A through bioinspired late-stage diversification of a readily accessible common precursor, N-desmethyl-β-obscurine. Key steps in the syntheses include oxidative C-C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-selective C-H borylation of a pyridine nucleus to enable cross-coupling reactions.

Full text of DOI:10.1021/jacs.1c00457

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Article
Bioinspired Diversification Approach Toward the Total Synthesis of
Lycodine-Type Alkaloids
Hannah M. S. Haley,⊥ Stefan E. Payer,⊥ Sven M. Papidocha, Simon Clemens, Jonathan Nyenhuis,
and Richmond Sarpong*
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ABSTRACT: Nitrogen heterocycles (azacycles) are common
structural motifs in numerous pharmaceuticals, agrochemicals, and
natural products. Many powerful methods have been developed and
continue to be advanced for the selective installation and
modification of nitrogen heterocycles through C−H functionaliza-
tion and C−C cleavage approaches, revealing new strategies for the
synthesis of targets containing these structural entities. Here, we
report the first total syntheses of the lycodine-type Lycopodium
alkaloids casuarinine H, lycoplatyrine B, lycoplatyrine A, and
lycopladine F as well as the total synthesis of 8,15-dihydrohuperzine
A through bioinspired late-stage diversification of a readily accessible
common precursor, N-desmethyl-β-obscurine. Key steps in the
syntheses include oxidative C−C bond cleavage of a piperidine ring in the core structure of the obscurine intermediate and site-
selective C−H borylation of a pyridine nucleus to enable cross-coupling reactions.
expanded the processes available for such structural alterations,
typically elaborating around the periphery of a molecule.13
Alternatively, C−C bond cleavage and functionalization
strategies represent a key complementary approach which
can be applied to remodel not only the periphery but also the
core carbon skeleton of organic compounds.14 Although C−C
cleavage tactics typically result in a decrease in molecular
complexityin contrast to Corey’s retrosynthetic para-
digm15they can lead to the identification of new
retrosynthetic disconnections. In turn, such methods could
enable rapid access to a diverse range of natural products or
bioactive agents from a single compound, which, albeit more
structurally complex, is easily obtained through chemical
synthesis, biosynthesis, or synthetic biology.
INTRODUCTION
■
The Lycopodium alkaloids are a diverse group of natural
products found in plants of the widely distributed Lycopodium
genus, commonly known as clubmosses.1,2 Since the isolation
of the first of these alkaloids, lycopodine, in 1881,3 a wealth of
biosynthetically related alkaloids have also been isolated and
characterized. These natural products are organized into four
main classes (lycodine, lycopodine, fawcettimine, and a
miscellaneous class) on the basis of their distinct carbon
backbones, which arise as a consequence of C−C bond
formation and rearrangement events during their putative
biosyntheses.2 Many Lycopodium alkaloids possess intriguing
and complex molecular architectures, and also display
promising bioactivity profiles. The archetypical lycodine
alkaloid huperzine A (1, Figure 1a), for example, is a potent
and selective acetylcholinesterase (AChE) inhibitor and also
demonstrates noncholinergic neuroprotective effects.4−6 This
bioactivity is of interest for the symptomatic treatment of
Alzheimer’s disease and other neurodegenerative disor-
ders.2,4−6 The combination of interesting structural features
and noteworthy bioactivity continue to drive synthetic studies
toward Lycopodium alkaloids and their analogues.7−12
The ubiquity of nitrogen heterocycles in pharmaceuticals,16
agrochemicals, and alkaloids17 render them attractive structural
motifs for diversification to efficiently access underexplored
chemical space.18 Therefore, a variety of methods for both the
introduction and selective functionalization of azacycles
continue to be reported.19−21 Inspired by these contributions,
we envisioned nitrogen heterocycles as versatile synthetic
Received: January 14, 2021
Published: March 17, 2021
Synthetic strategies that enable late-stage structural mod-
ification and diversification of a common advanced inter-
mediate can provide versatility that facilitates efficient access to
a range of products that might otherwise each require
significant synthetic investment. A rapidly growing catalog of
C−H bond functionalization technologies has powerfully
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Figure 1. Bioinspired plans for the synthesis of lycodine alkaloids.
handles that would enable the expedient preparation of a
collection of lycodine-type alkaloids (2−4, 8, 9, Figure 1a)
from a common, readily prepared, precursor through a series of
programmed oxidation and C−C bond cleavage events in
analogy to their biosynthesis.2,22
Although the complete biosynthetic pathways to the
Lycopodium alkaloids remain to be fully elucidated,23
biochemical studies have suggested that these compounds
derive from phlegmarine (13), which arises from the coupling
of pelletierine (11) and 4-(2-piperidyl) acetoacetate (12), both
of which originate from L-lysine (10, Figure 1b).2
Subsequent closure of ring B through bond formation
between C13 and C4 furnishes the characteristic [3.3.1]-
bicyclic scaffold of the lycodine class. A series of oxidative
modifications, which include oxidation of the A-ring to the
corresponding pyridone (e.g., in N-desmethyl-β-obscurine, 6)
or pyridine (e.g., in lycodine, 7), C-ring cleavage, and excision
of C9 further diversifies the parent scaffold, yielding a range of
alkaloids including 1−6 (Figure 1b, blue arrows).
On the basis of these presumed biosynthetic events, we
envisioned a retrosynthesis (Figure 1c) in which 8,15-
dihydrohuperzine A (3)24 could arise from casuarinine H
(2)25 through olefin isomerization, whereas lycoplatyrine B
(4)26 could be accessed from 2 through semireduction of the
pyridone. Casuarinine H (2) was traced back to functionalized
tricyclic intermediate A through decarboxyolefination. In turn,
A could be formed from the readily accessible key precursor N-
desmethyl-β-obscurine (6) through oxidative functionalization
and cleavage of the C9−N bond.
Another small set of structurally unique lycodine alkaloids
bearing substitution at the C2 position of the pyridine A-ring
(e.g., lycoplatyrine A,26 8, and lycopladine F,27 9) is proposed
to arise biosynthetically through electrophilic substitution on
lycodine (7) or the corresponding dihydropyridine by a Δ1-
piperidinium or Δ1-pyrrolinium cation (or the corresponding
imines; Figure 1b, green arrows).26,27 Subsequent oxidative
cleavage of the pyrrolidine ring in 14 is suggested to provide
lycopladine F (9), analogous to the oxidative ring cleavage
pathway that leads to metabolic products of nicotine.28
Overall, we envisioned lycoplatyrine A (8) and lycopladine F
(9) could be accessed through cross-coupling of appropriate
C(sp3) nucleophiles with a functionalized lycodine analog (B),
which again would be prepared from the key obscurine scaffold
6. The required deoxygenation of precursor 6 and site-selective
functionalization at C2 would rely upon precedent demon-
strated by our laboratories in the total synthesis of the dimeric
lycodine alkaloids complanadine A and B.29,30
RESULTS AND DISCUSSION
■
Preparation of the Key Diversifiable Precursor. Our
investigations commenced with the development of a robust
synthesis of N-desmethyl-β-obscurine (6), the late-stage
common intermediate for the synthesis of all of the alkaloids
described here. A convergent route featuring a diastereose-
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a
Scheme 1. Synthesis of the Bicyclo[3.3.1]nonane Core in N-Desmethyl-α-obscurine through Formal (3 + 3)-Cycloaddition
a
Reagents and conditions: (a) NaOEt, EtOH, 21 °C, then acrylonitrile, 0 to 21 °C, then TsOH, 145 °C (38%, > 13 g scale); (b) Zn(NO3)2·6H2O,
acetone oxime, H2O, 90 °C, then vacuum, 120 °C (46%, > 2 g scale); (c) aq. H2O2, LiOH·H2O, MeOH, H2O, 21 °C (90%, 30 g scale); (d) PhSH,
Na, THF, 21 °C, then 19, 85 °C; (e) NaBO3·H2O, AcOH, 40 °C (65%, 2 steps, > 17 g scale); (f) DBU, iPrOH, 0 °C, then acrylonitrile, 0 to 40 °C
(60%, > 7 g scale); (g) ethylene glycol, p-TsOH, HC(OEt)3, 75 °C (97%); (h) LiAlH4, Et2O, 0 °C (84%, > 2 g scale); (i) aq. HClO4, 1,4-dioxane,
105 °C; (j) Boc2O, Et3N, THF, 60 °C (54%, 2 steps); (k) Pb(OAc)4, CHCl3, 21 °C (90%); (l) Tf2O, pyridine, CH2Cl2, −78 to 21 °C (78%).
lective formal (3 + 3)-cycloaddition to form the three
contiguous stereocenters and two C−C bonds in ring B of
631 was adapted from literature protocols by Schuster,32
Caine,33 Dake,34 and Jung35 as well as our own previous
studies.29
The coupling partner that would lead to ring A,
dihydropyridone 17, was prepared from β-ketoester 15
through a Michael addition into acrylonitrile followed by
decarboxylation to give nitrile 16. Subsequent nitrile hydration
and cyclization in vacuo delivered 17 in 18% overall yield
(Scheme 1a).29,31
The C/D ring cycloaddition partner 22 was prepared from
(+)-pulegone (18) in six steps and 28% overall yield (Scheme
1b).32,33 The sequence was initiated by Weitz−Scheffer-type
epoxidation of the exocyclic olefin group of 18, which provided
a 1:2 mixture of epoxide isomers (19).38,39 Subsequent
nucleophilic opening of the epoxide with sodium thiopheno-
late and concomitant retro-aldol reaction delivered the
phenylthioether,33 which was selectively oxidized to sulfoxide
20 with sodium perborate.34 α-Alkylation of 20 with
acrylonitrile, followed by thermal syn-elimination of phenyl-
sulfenic acid gave enone 21,35,36 which was protected as the
ethylene glycol ketal and reduced with LiAlH4 to deliver
primary amine 22.32 The two building blocks (17 and 22)
were ultimately coupled upon heating with perchloric acid
(Scheme 1c). Under these conditions, oxygen-sensitive α,β-
unsaturated iminium ion 22a and the open-chain enolamide
17a are presumably formed in situ and undergo the desired
formal cycloaddition to furnish N-desmethyl-α-obscurine
(5).29,31,37 Boc-protection of the piperidine nitrogen in 5 and
dehydrogenation of the dihydropyridone ring using lead(IV)
acetate provided N-Boc-β-obscurine (23) in 49% yield over
three steps.
As an alternative to the oxidation of Boc-protected 5 using
stoichiometric lead(IV) acetate, we investigated a photo-
catalytic dehydrogenation protocol.40,41 Our preliminary
results demonstrated that N-Boc-5 was readily oxidized to 23
(57% yield) in the presence of an iridium(III) photoredox
catalyst (Ir[dF(CF3)ppy]2(dtbbpy)PF6) with potassium per-
sulfate as the terminal oxidant upon irradiation with blue light
(λ = 450 nm) under anoxic conditions. In the absence of light
or the photoredox catalyst, only traces of product (6%) were
formed in the best case, whereas under aerobic conditions
complete decomposition of the substrate was noted (see
Section S3.1 in the Supporting Information, SI). Despite
attempts to optimize this reaction, we were unable to obtain
yields comparable with those achieved with lead(IV) acetate
(90%). Therefore, the latter conditions were employed for the
preparation of large quantities of material. Finally, pyridone O-
triflation of 23 delivered fully protected β-obscurine scaffold
24 in 78% yield.29
Synthesis of (−)-Casuarinine H, (−)-8,15-Dihydrohu-
perzine A, and (+)-Lycoplatyrine B. Our envisioned route
toward the lycodine alkaloids casuarinine H (2), 8,15-
dihydrohuperzine A (3), and lycoplatyrine B (4) required
the identification of suitable conditions to effect the
bioinspired oxidative cleavage of the C9−N bond in protected
tetracycle 24 or a related obscurine congener. To this end, we
pursued several conditions for C−N cleavage and functional-
ization that included biocatalytic and transition metal-mediated
approaches.
Biocatalytic methods were explored as a means to achieve a
protecting group-free oxidation of the C9−N bond, reminis-
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cent of the proposed biosynthetic tailoring process. Although
the requisite biosynthetic enzymes have not been identified, we
posited that other established biocatalysts capable of oxidizing
C-heteroatom bonds could accept the bicyclo[3.3.1]nonane
scaffold of 5 as a substrate while retaining site-selectivity. A
screening set composed of 14 commercial and in-house
heterologously expressed copper-42,43 and flavin-dependent
oxidases,44−46 a pyrroloquinoline (PQQ) dependent dehydro-
genase,47 a horseradish peroxidase (HRP),48 and a laccase/
TEMPO redox mediator system49 was assembled. However,
overview screenings under representative conditions did not
identify any oxidation activity with unprotected substrate 5
(see SI Section S3.2 for details).
Scheme 2. Synthesis of C-Ring Cleaved Lycodine Alkaloids
from Protected β-Obscurine.
a
We therefore sought to examine other established chemical
conditions for the oxidation of carbamate-protected saturated
nitrogen heterocycles. While methods employing iron50 and
copper51 redox mediators in combination with peroxides failed
to generate the anticipated enamine or enamide products, we
observed that substoichiometric quantities of RuO2 with
sodium periodate as stoichiometric oxidant in a mixture of
tBuOH and water resulted in piperidine oxidation to yield 25
(Scheme 2a).52,53 Although oxidation under these conditions
by the presumed in situ generated RuO4 catalyst was expected
to give the corresponding amino acid (i.e., following hydrolysis
of an intermediate C-ring iminium ion and oxidation of the
resulting aldehyde), cyclic imide 25 was obtained in 86% yield.
Additional experiments demonstrated that the electronically
deactivating triflyl group on the pyridone oxygen was critical to
the success of the piperidine oxidation−oxidation of derivatives
of 25 bearing methyl, benzyl, or SEM groups instead of the
triflyl moiety proved unsuccessful under identical conditions.
We envisioned that hydrolysis of imide 25 followed by
decarboxyolefination of the resulting carboxylic acid could
offer an attractive strategy to excise C9 and install the required
unsaturation at C10−C11. Treatment of 25 with aqueous
LiOH at the elevated temperatures required for imide
hydrolysis resulted in undesired concomitant triflate cleavage.
Therefore, a methyl ether was introduced in place of the triflate
prior to imide hydrolysis to yield carboxylic acid 26.
Unfortunately, subjecting 26 to classic Kochi oxidative
decarboxylation conditions54 failed to deliver alkene 27.
Additionally, an attempted Hunsdiecker-type decarboxyhalo-
genation55 resulted in the C-ring contracted pyrrolidine 28
(Scheme 2b), presumably the result of an SN2 displacement of
the intermediate alkyl halide. While more recently developed
decarboxyolefination conditions using metallo-organo-56 or
organo-photocatalysts57 in combination with cobalt-based
dehydrogenation catalysts furnished olefin 27 in 50% yield, a
competing protodemetalation pathway leading to ethyl
derivative 29 hindered further optimization of this process.
Alternatively, desired terminal olefin 27 was obtained in higher
yield (65%) through a Pd(0)-catalyzed decarbonylative
elimination of an in situ-generated mixed anhydride of 26.58
Deprotection of 27 using TMSI12 completed the first total
synthesis of the neuroprotective compound (−)-casuarinine H
(2, Scheme 2c).25 Semireduction of the pyridone moiety in 2
with samarium metal in aqueous HCl59 cleanly yielded
(+)-lycoplatyrine B (4)26 in 84% yield, also constituting the
first total synthesis of this Lycopodium alkaloid. Furthermore,
treatment of terminal olefin 27 with an in situ-generated
palladium hydride catalyst effected isomerization to the
internal (E)-alkene in 81% yield.60 A subsequent TMSI-
a
Reagents and conditions: (a) RuO2·H2O, NaIO4, H2O, 21 °C, then
24, tBuOH, 60 °C (86%); (b) aq. 1 M LiOH, THF, 30 °C; (c) MeI,
Ag2CO3, CHCl3, 75 °C (86%, 2 steps); (d) aq. 1 M LiOH, THF, 65
°C (97%); (e) PdBr2, DPE-Phos, Piv2O, Et3N, DMPU, 130 °C
(65%); (f) TMSI, CHCl3, 65 °C (89%); (g) Sm, aq. 3 M HCl, 0 to 21
°C (84%); (h) Pd(dba)2, P(tBu)3, PrCOCl, toluene, 90 °C (81%);
i
(i) TMSI, CHCl3, 65 °C (41%).
mediated deprotection delivered (−)-8,15-dihydrohuperzine A
(3).24,61
The spectroscopic data for synthetic (−)-casuarinine H (2),
(+)-lycoplatyrine B (4), and (−)-8,15-dihydrohuperzine A (3)
were in full agreement with those reported upon isolation of
these natural products from the producing organisms.24−26
Taking advantage of this late-stage diversification approach, the
target alkaloids 2−4 were prepared in 16 to 17 steps (longest
linear sequence, LLS) and 1.7−4.5% overall yield from
(+)-pulegone.
Synthesis of Lycoplatyrine A and Lycopladine F. For
the synthesis of Lycopodium alkaloids bearing substituents at
C2 (i.e., 8−9), we envisioned a cross-coupling approach in
which the key β-obscurine intermediate 24 would be
elaborated to a selectively C2-functionalized lycodine deriva-
tive to serve as a common coupling partner. Accordingly,
protected β-obscurine 24 was deoxygenated in the presence of
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a
Scheme 3. Couplings of a Site-Selectively Functionalized Lycodine Congener in the Syntheses of C2-Substituted Alkaloids
a
Reagents and Conditions: (a) HCO2NH4, Pd(OAc)2, dppf, Et3N, DMF, 60 °C (99%); (b) B2 pin2, [Ir(COD)(OMe)]2, dtbbpy, THF, 80 °C; (c)
CuBr2, MeOH, H2O, 80 °C (74%, 2 steps); (d) RuPhos Pd G4, Cs2CO3, toluene, 70 °C [(2′S)-33: 65%, (2′R)-33: 65%, 33 as epimeric mixture at
C2′ with rac-32: 72%]; (e) NaOH, MeOH, 1,4-dioxane, 70 °C (f) aq. 6 M HCl, 70 °C [(2′S)-8: 90%, (2′R)-8: 68%; 2 steps]; (g) sBuLi, (+)- or
(−)-sparteine, MTBE, −78 °C, then ZnCl2, THF, −78 to 21 °C, then 31, Pd(OAc)2, tBu3PHBF4, MTBE, 60 °C [(2′S)-36: 55%, (2′R)-36: 88%];
(h) aq. 6 M HCl, 21 °C [(2′S)-14: quantitative, (2′R)-14: 70%]; (i) 31, NiCl2‑glyme, dtbbpy, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Cs2CO3, DMF, 450
nm LED, 21 °C (84%); (j) PhOH, TMSCl, CH2Cl2, 21 °C; (k) 500 psi H2, Pd/C, CF3CO2H, MeOH, 21 °C (71%, 2 steps).
a palladium catalyst and ammonium formate as reductant to
deliver N-Boc lycodine (30). Subsequent iridium-catalyzed
meta-selective C−H borylation29,62 of the pyridine A-ring and
bromodeborylation63 furnished 2-bromolycodine (31)
(Scheme 3a).
Lycoplatyrine A (8) features a C2 piperidine substituent as
an epimeric mixture of undetermined absolute configuration,26
which we anticipated could be installed through the coupling
of 31 with an α-functionalized piperidine derivative (Scheme
3b). We specifically envisioned the application of a method
recently disclosed by our laboratory in which α-hydroxy-β-
lactams such as 32 serve as surrogates for α-metalated N-
heterocycles in a palladium-catalyzed coupling with aryl
halides.20 This method was particularly attractive due to the
mild and stereospecific nature of the cross-coupling, although
the use of pyridyl bromides had not been previously
demonstrated. As proposed, the coupling of 31 with racemic
lactam 32, prepared from the corresponding piperidine-derived
2-oxophenylacetamide through a Norrish-Yang reaction,20
delivered 33 as a mixture of epimers at C2′. Cleavage of the
2-oxophenylacetamide and Boc-protecting groups under
sequential basic and acidic conditions yielded lycoplatyrine A
(8) as a 1:1.5 mixture of the anticipated C2′ epimers.
According to the previously proposed mechanism for this
coupling, the hydroxy group of the lactam coordinates to the
palladium center before irreversible C−C bond cleavage (β-
carbon elimination) driven by the release of ring strain in 32
delivers a C2′-palladated species in a stereoretentive manner
(Scheme 3b, gray box).20,64 We therefore anticipated that the
use of enantiomerically pure lactams (2′S)- and (2′R)-32
would enable the stereospecific piperidinylation of the lycodine
scaffold at C2, and thus allow the assignment of absolute
configurations at C2′ in naturally occurring alkaloid 8.
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To obtain α-hydroxy-β-lactam 32 in enantioenriched form,
we first investigated enzymatic resolution methods. Despite
extensive reaction engineering, selectivity for an enzymatic
hydrolytic kinetic resolution65,66 of acetylated tertiary alcohol
32 with pig liver esterase (PLE) and lipase A from C. antarctica
(CalA) was poor and therefore not synthetically useful (E ≤ 7)
(see SI Section S3.5). Alternatively, enantiomerically resolved
lactams (2′S)- and (2′R)-32 were obtained from preparative
chiral supercritical fluid chromatography (SFC).20 Coupling of
lactams (2′S)- and (2′R)-32 with lycodine bromide 31 gave
single epimers of 33 in 65% yield, which were deprotected to
provide single epimers of lycoplatyrine A (8) in 4.7% overall
yield over 16 steps from (+)-pulegone (LLS). Comparison of
the spectral data of single epimers of synthetic 8 with data for
naturally derived 8 revealed a slight excess of the (2′S)-8
epimer in material isolated from natural sources (d.r. 1.3:1).26
The cross-coupling product obtained using racemic 32 was
also enriched in the same epimer (d.r. 1.5:1, vide supra),
suggesting that the chiral lycodine scaffold exerts a low level of
enantiodiscrimination and enantiotopic face discrimination in
both the synthetic and natural coupling processes.
Indeed, our success in preparing single epimers of
lycoplatyrine A (8) rested on the stereospecific coupling of
α-hydroxy-β-lactams as surrogates for α-metalated piperidines,
which otherwise typically suffer from low yields and poor
stereoselectivities in the metalation step.67,68 Although an
analogous β-lactam-based cross-coupling for five-membered
nitrogen heterocycles is precluded due to the inaccessibility of
the five-membered analogues of 32 with established photo-
chemical methods,69 α-metalated pyrrolidines are excellent
stereoselective coupling partners. These reagents set the stage
for the preparation of the pyrrolidine analog of lycoplatyrine A
(“pyrrolo-lycoplatyrine A”, 14), which is hypothesized to be an
intermediate in the biosynthesis of other lycodine-derived
congeners including lycopladine F (9).27 For the synthesis of
N-Boc pyrrolo-lycoplatyrine A (36), we turned to a method by
Campos and co-workers70 for the stereoselective α-arylation of
N-Boc-pyrrolidine (34) (Scheme 3c). Enantioselective ortho-
lithiation of 34 in the presence of either (+)- or
(−)-sparteine,71 transmetalation to form the corresponding
organozinc species (35), and subsequent palladium-catalyzed
coupling to lycodine bromide (31) delivered single C2′-
epimers of the desired product (36) in high yield (88%).
Subsequent deprotection provided each of the two C2′-
epimers of pyrrolo-lycoplatyrine A (14) in 15 steps from
(+)-pulegone (7% overall, LLS).
from Lycopodium complanatum as a 3.5:1 mixture of (2′S):
(2′R)-epimers.27 We expect access to pyrrolo-lycoplatyrine A
(14) and lycopladine F (9) to set the stage for studies into the
biosynthesis of the latter natural product.27
CONCLUSIONS
■
In summary, we have developed the first total syntheses of
lycodine alkaloids casuarinine H (2), lycoplatyrine B (4),
lycoplatyrine A (8), and lycopladine F (9) and a total synthesis
of 8,15-dihydrohuperzine A (3) employing the readily
accessible tetracycle N-desmethyl-β-obscurine (6) as a
common intermediate. A series of bioinspired modifications
of the piperidine C-ring in 6, including oxidative ring cleavage,
C−C bond scission with carbon atom excision, and olefin
isomerization delivered tricyclic congeners 2−4. Conversion of
the pyridone A-ring in 6 to the corresponding pyridine (7) and
site-selective C−H functionalization to ultimately afford
bromopyridine 31 enabled direct cross-couplings with
saturated azacycles or an amino acid to complete the syntheses
of C2-derivatized lycodine alkaloids lycoplatyrine A (8) and
lycopladine F (9). The general late-stage peripheral derivatiza-
tion and C−C functionalization strategies outlined herein may
provide a basis for synthetic access to an even wider range of
Lycopodium alkaloids. Our synthetic studies toward these
compounds should also set the stage for a broader, more
systematic assessment of their biosynthesis and bioactiv-
ity.25,26,61 Biological activities exerted by these natural products
may include a range of neuroprotective effects such as those
observed for huperzine A,4,5 for example the attenuation of
both glutamate-induced neurotoxicity and free radical-medi-
ated oxidative stress.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00457.
■
sı
Experimental procedures, additional experimental re-
sults, and compound characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Richmond Sarpong − Department of Chemistry, University of
California, Berkeley, California 94720, United States;
orcid.org/0000-0002-0028-6323; Email: rsarpong@
berkeley.edu
We sought to similarly access lycopladine F (9) via a direct
coupling approach where the necessary amino acid moiety is
appended at C2 of lycodine bromide (31, Scheme 3d). To this
end, iridium-catalyzed photoredox conditions effected activa-
tion of bis-protected glutamic acid 37 through single-electron
oxidation of the cesium carboxylate, followed by decarbox-
ylative C−C bond scission and nickel-catalyzed C(sp3)−C(sp2)
coupling with aryl bromide 31 to deliver protected lycopladine
F (38) in 84% yield.72 A low nickel loading (1 mol %) was
necessary to attenuate consumption of bromide 31 in a
nonproductive protodehalogenation pathway and achieve good
yields of 38. Removal of both Boc protecting groups followed
by hydrogenolytic cleavage of the benzyl ester in the presence
of trifluoroacetic acid yielded lycopladine F (9) in 71% yield as
a 1:1 mixture of epimers (4.8% yield over 16 steps LLS). The
analytical data obtained for the synthetic material matched
those reported for the natural material, which was isolated
Authors
Hannah M. S. Haley − Department of Chemistry, University
of California, Berkeley, California 94720, United States
Stefan E. Payer − Department of Chemistry, University of
California, Berkeley, California 94720, United States
Sven M. Papidocha − Department of Chemistry, University of
California, Berkeley, California 94720, United States
Simon Clemens − Department of Chemistry, University of
California, Berkeley, California 94720, United States
Jonathan Nyenhuis − Department of Chemistry, University of
California, Berkeley, California 94720, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00457
Author Contributions
⊥These authors contributed equally to this work.
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(13) Hartwig, J. F. Catalyst-Controlled Site-Selective Bond
Activation. Acc. Chem. Res. 2017, 50, 549−555.
Notes
The authors declare no competing financial interest.
(14) Wang, B.; Perea, M. A.; Sarpong, R. Transition Metal-Mediated
Cleavage of C−C Single Bonds: Making the Cut in Total Synthesis.
Angew. Chem., Int. Ed. 2020, 59, 18898−18919.
ACKNOWLEDGMENTS
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This research was funded in part by the Austrian Science Fund
(FWF) [J 4227-B21]. S.E.P. acknowledges funding by the
Austrian FWF through an Erwin Schrödinger fellowship. J.N.
and S.C. acknowledge funding through a PROMOS-scholar-
ship by the DAAD (Deutscher Akademischer Austausch-
dienst). Financial support for this research was provided to
R.S. by the National Institutes of General Medical Sciences
(NIGMS R35 GM130345A). Prof. Nick Turner (University of
Manchester), Prof. Marco Fraaje (University of Groningen),
Prof. Kurt Faber (University of Graz), and Prof. Wolfgang
Kroutil (University of Graz) are thanked for the donation of
plasmids for various oxidase enzymes. We are grateful to Prof.
John F. Hartwig (UC Berkeley) and Prof. Jon Rittle (UC
Berkeley) for generously sharing their equipment for the
preparation of biocatalysts. We are grateful to Frederick M.
Tomlin and James N. Newton (UC Berkeley) for early
contributions on the RuO4 oxidation chemistry. We thank Dr.
Charles Yeung and colleagues at Merck Research Laboratories
for the chiral SFC separation of the enantiomers of 32. We
thank Dr. Hasan Celik and UC Berkeley’s NMR facility in the
College of Chemistry (CoC-NMR) for spectroscopic assis-
tance. Instruments in CoC-NMR are supported in part by NIH
S10OD024998. We are also grateful to Dr. Miao Zhang (DOE
Catalysis Facility, UC Berkeley) for support with the
acquisition of HRMS and IR data.
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