Evolution of a synthetic strategy for complex polypyrrole alkaloids: Total syntheses of curvulamine and curindolizine

Article abstract of DOI:10.1021/jacs.0c13465

Structurally unprecedented antibacterial alkaloids containing multiple electron-rich pyrrole units have recently been isolated from Curvularia sp. and Bipolaris maydis fungi. This article documents the evolution of a synthetic program aimed at accessing the flagship metabolites curvulamine and curindolizine which are presumably a dimer and trimer of a C₁₀N biosynthetic building block, respectively. Starting with curvulamine, we detail several strategies to merge two simple, bioinspired fragments, which while ultimately unsuccessful, led us toward a pyrroloazepinone building block-based strategy and an improved synthesis of this 10π-aromatic heterocycle. A two-step annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C₁₀N fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive heterocycle.

Full text of DOI:10.1021/jacs.0c13465

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Evolution of a Synthetic Strategy for Complex Polypyrrole Alkaloids:
Total Syntheses of Curvulamine and Curindolizine
Jun Xuan,‡ Karl T. Haelsig,‡ Michael Sheremet, Paulo A. Machicao, and Thomas J. Maimone*
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ABSTRACT: Structurally unprecedented antibacterial alkaloids containing
multiple electron-rich pyrrole units have recently been isolated from Curvularia
sp. and Bipolaris maydis fungi. This article documents the evolution of a
synthetic program aimed at accessing the flagship metabolites curvulamine and
curindolizine which are presumably a dimer and trimer of a C10N biosynthetic
building block, respectively. Starting with curvulamine, we detail several
strategies to merge two simple, bioinspired fragments, which while ultimately
unsuccessful, led us toward a pyrroloazepinone building block-based strategy
and an improved synthesis of this 10π-aromatic heterocycle. A two-step
annulation process was then designed to forge a conserved tetracyclic bis-pyrrole architecture and advanced into a variety of late-
stage intermediates; unfortunately, however, a failed decarboxylation thwarted the total synthesis of curvulamine. By tailoring our
annulation precursors, success was ultimately found through the use of a cyanohydrin nucleophile which enabled a 10-step total
synthesis of curvulamine. Attempts were then made to realize a biomimetic coupling of curvulamine with an additional C10N
fragment to arrive at curindolizine, the most complex family member. Although unproductive, we developed a 14-step total synthesis
of this alkaloid through an abiotic coupling approach. Throughout this work, effort was made to harness and exploit the innate
reactivity of the pyrrole nucleus, an objective which has uncovered many interesting findings in the chemistry of this reactive
heterocycle.
The chemical structures of 1 and 2 (and 5−10) bear little
resemblance to known alkaloids and suggest the involvement
of unique biosynthetic machinery. Initial isotopic feeding
experiments in Curvularia sp. pointed to a mixed polyketide/
amino acid origin for 1, wherein two molecules of alanine and
eight acetyl-CoA units serve as building blocks.3 Recently, Tan
and co-workers discovered the biosynthetic gene cluster
responsible for the synthesis of C10N fragment 16, a potential
monomeric building block for this family, in Bipolaris maydis
(Figure 2).5 A Pyridoxal phosphate (PLP)-dependent enzyme
CuaB merges polyketide fragment 11 with alanine/PLP
condensation product 12 resulting in intermediate 13 after
C−C bond formation. CuaB also possesses oxygenase activity,
catalyzing the decarboxylative oxygenation of 13 to 14 and
ultimately 15 following cofactor release and hydroperoxide
reduction. Aminodiketone 15 then undergoes spontaneous
cyclo-condensation to produce isolable vinylogous lactam 16.
Two enzymes, an oxidase CuaD and a reductase CuaC, are
then assumed to process this material into hypothetical
INTRODUCTION
■
Owing to a variety of disparate chemical architectures and
often unique chemical reactivity, pyrrole-containing alkaloids
have captivated practitioners of total synthesis for many
decades.1 The high acid sensitivity and oxidative fragility
inherent to electron-rich pyrroles, however, places many
additional constraints on the employable tactics used to access
these fascinating natural products.2 In 2014, Tan and co-
workers discovered the unusual, electron-rich bis-pyrrole-
containing natural product curvulamine (1) from Curvularia
sp. IFB-Z10 fungus isolated from the intestinal tract of the
white croaker fish (Figure 1).3 The white croaker can feed on
dead and decaying prey, suggesting its gut flora may harbor
unique antimicrobial producing organisms, and indeed 1 was
reported to possess notable antibacterial activity against a small
panel of both Gram-positive and negative pathogens including
V. parvula, B. Vulgatus, and Streptococcus and Peptostreptococcus
sp. Serendipitously, when scaling up the fungal fermentation of
1, a new, even more complex alkaloid, namely curindolizine
(2), was subsequently isolated.4 Interestingly, 2 did not possess
the antibiotic activity of 1, but instead demonstrated anti-
inflammatory properties in lipopolysaccharide-induced macro-
phages. More recently, genome mining efforts have culminated
in the discovery of additional curvulamine-type secondary
metabolites known as bipolamines (see 3−10), all produced by
the fungal strain Bipolaris maydis (Figure 1).5
Received: December 31, 2020
Published: February 11, 2021
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© 2021 American Chemical Society
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alkaloid natural products.7 Our successful route to 1, while
concise, required intensive experimentation as we navigated
multiple strategic dead-ends and detours, unanticipated
chemical reactivity, and unpredictable compound stability.
Herein we document the evolution of a synthetic strategy
toward (−)-curvulamine as well as the first total synthesis of
the most complex family member (+)-curindolizine.
RESULTS AND DISCUSSION
■
Initial Synthetic Planning. In 2015, we began our
synthetic investigations with little information regarding the
biosynthesis of these alkaloids, although we found it highly
plausible that a building block similar to 17 might merge with a
linear C10N fragment to forge the carbocyclic core of 1. We
initially devised a hypothetical annulation between dianion 18
and dication 19 to construct the 7-membered ring present in
higher order members (see inset, Scheme 1). In this coupling,
which we evaluated in sequential fashion, the innate
nucleophilicity of the pyrrole anion and an enolate would be
leveraged directly. We also anticipated that dication-like
reactivity could be accessible via 2-fold activation of a suitable
indolizidine diol intermediate.
We began our bioinspired approach by first developing a
robust route to an indolizidine coupling partner (Scheme 1).
Enol ether 20 and aldehyde 21 were merged via a
diastereoselective magnesium bromide-mediated Mukaiyama
aldol reaction generating oxonium ion 22 that was immediately
attacked by the pendant electron-rich pyrrole leading to 23 in
40% yield (10:1 dr).8 Diol 24 was obtained after sequential
functional group interconversions in which the secondary
alcohol was protected (SEMCl, DIPEA), the TIPS group
removed (TBAF), and the allyl group cleaved (Pd0, K2CO3,
MeOH). As testament to the high reactivity of this pyrrole-
containing nucleus, simple diol activation with carbon-
yldiimidazole (CDI) generated noticeable quantities of
imidazole 26. Presumably, benzylic ionization generated an
azafulvene structure which was attacked by imidazole and
further rearomatized to 26 via loss of water. This deleterious
process could be averted though by first brominating the
pyrrole ring (NBS) prior to activation with CDI. Through this
sequence cyclic carbonate 25, whose structure was confirmed
Figure 1. Fungal-derived polypyrrole alkaloids.
indolizidine 17, via an epoxidation of the polyene (via CuaD)
and a postulated C−N bond-forming reductive cyclization
which opens the epoxide (via CuaC).6 The latter step also
requires trans to cis isomerization of the central alkene. While
the structural resemblance between 17 and bipolamines A (3)
and B (4) is clear, the enzymology behind the conversion of
this C10N unit into higher order (C10N)2- and (C10N)3-
containing natural products such as 1, 2, and 5−10 remains
mysterious. Presumably 17 merges with 16 (or an oxidized
variant) to produce (C10N)2 metabolites and a further reaction
with 17 generates 2, the lone (C10N)3-level structure.
We recently reported a chemical synthesis of (−)-curvul-
amine, the first reported synthetic work toward any of these
Figure 2. Tan’s investigations into the early stages of polypyrrole alkaloid biosynthesis in Bipolaris maydis.
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a
Scheme 1. First-Generation Approach to Curvulamine via the Merger of Bioinspired Fragments
a
Reagents and conditions: (a) 20 (1.5 equiv), 21 (1.0 equiv), MgBr2·OEt2 (3.0 equiv), 2,6-DTBP (1.1 equiv), DCM, 0 °C, 12 h, 43% (10:1 dr);
(b) SEMCl (2.0 equiv), EtN(i-Pr)2 (4.0 equiv), DCE, 40 °C, 12 h, 91%; (c) TBAF (1.0 M in THF, 1.1 equiv), THF, 50 °C, 12 h, 89%; (d)
Pd(PPh3)4 (0.05 equiv), K2CO3 (2.0 equiv), MeOH, 100 °C, 4 h, 53%; (e) NBS (1.05 equiv), DMF, 0 °C, 1 h, used without purification; (f) NaH
(4.0 equiv), DMF, 0 °C, 5 min, then add CDI (3.0 equiv), 25 °C, 30 min, 82% (2 steps); (g) NaH (4.0 equiv), DMF, 0 °C, 30 min then add CDI
(1.1 equiv), 0 °C, 1 h, 23%; (h) 25 (1.0 equiv), 27 (1.5 equiv), SnCl4 (1.0 equiv), DCM, −78 °C, 3 h, 45% (10.6:3.4:1.5:1.0 dr); (i) MsCl (1.1
equiv), Et3N (1.2 equiv), DCM, 0 °C, 1 h, 81%; (j) NaOMe (5.0 equiv), MeOH, 0 °C, 1 h, 53%. TIPS = triisopropylsilyl, DTBP = di-tert-
butylpyridine, SEM = 2-(trimethylsilyl)ethoxymethyl, DCE = 1,2-dichloroethane, TBAF = tetrabutylammonium fluoride, NBS = N-
bromosuccinimide, DMF = dimethylformamide, CDI = 1,1′-carbonyldiimidazole, TES = triethylsilyl.
by X-ray crystallographic analysis, could be obtained in good
yield.
intermolecular coupling and the 7-membered ring assembled
via a 7-endo radical cyclization (see inset, Scheme 2A). We
believed the reactivity of hypothetical vinylcation 33 could be
replicated by a vinyl triflate (or halide) precursor.
With indolizidine 25 in hand, attempts were then made to
realize the designed annulation process (Scheme 1). We found
that 25 could be coupled with pyrrole-containing silyl enol
ether 27 (prepared in 3-steps)9 via SnCl4-mediated activation
of the cyclic carbonate (25) which delivered 28 as an
inseparable mixture of diastereomers in 55% yield.10,11 With
the first crucial bond formed, effort was directed toward
intramolecular C−N bond formation to close the seven-
membered ring. While 28, could be activated (MsCl, Et3N)
and the pyrrole anion unveiled (NaOMe, MeOH), we have
never elucidated a productive cyclization transformation to
afford 30. In many instances, unwanted reactivity stemming
from the methyl ketone was observed. For instance, treating 29
with TBAF in THF generated cyclopropane 31 and products
of O-alkylation of the methyl ketone enolate. While this
reactivity could be potentially averted by reduction or
protection of the carbonyl, attempts to realize seven-
membered ring closure of ketone analogs was also
unsuccessful. Moreover, the conversion of 29 to alkene 32
also occurred under mild conditions (Cs2CO3, MeCN, 0
°C).12
Efforts to realize this revised plan were facilitated by the
observation that previously employed diol 24 underwent a
facile redox-neutral isomerization to generate ketone 34 under
mildly acidic conditions via an ionization/1,2-hydride shift
pathway (Scheme 2A). The ketone formed (34), could then be
converted to vinyl triflate 35 (NaHMDS, PhNTf2) setting up
the key pyrrole C−N bond-forming event. While a model
pyrrole (i.e 2,5-dimethylpyrrole) successfully coupled with 35
under Pd-catalyzed cross-coupling conditions to generate 36,13
we could not extend this transformation to more complex
pyrroles featuring extended side chains such as 37−39.14
Undeterred by these findings, we retooled our initial aldol-
based synthesis of the indolizidine core to incorporate a
fragment that already contains a pyrrole C−N bond (Scheme
2B). Deprotonation of pyrrole ester 40 (NaHMDS) followed
by addition of aldehyde 41 generated adduct 42 in good yield
(82%). Careful DIBAL reduction of this material then
furnished an intermediate aldehyde, which underwent
cyclization and dehydration to produce 43 when exposed to
silica gel. Finally, ruthenium-catalyzed cross metathesis of this
material with methyl vinyl ketone generated cyclization
precursor 44.
A Revised Indolizidine-Based Approach. Our inability
to form a carbon−nitrogen bond via intramolecular displace-
ment led us to consider a revised orchestration of events,
wherein the C−N bond would be constructed through an
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a
Scheme 2. Revised Indolizidine-Based Route to 1
a
Reagents and conditions: (a) 2,6-lutidine (1.0 equiv), AcOH (1.0 equiv), PhMe, 150 °C, 15 min, 50%; (b) NaHMDS (2.0 equiv), THF, −78 °C,
30 min, then add PhNTf2 (1.2 equiv), −78 °C, 1 h, 90%; (c) 2,6-dimethylpyrrole (1.5 equiv), Pd2(dba)3 (0.05 equiv), t-BuXPhos (0.1 equiv),
NaOt-Bu (1.4 equiv), PhMe, 60 °C, 12 h, 60%; (d) 40 (1.0 equiv), NaHMDS (1.1 equiv), THF, −78 °C, 30 min, then add 41 (1.1 equiv), −78 °C,
1 h, 82%; (e) DIBAL (5.0 equiv), PhMe, −78 °C, 1 h, then add SiO2, DCM, 25 °C, 30 min, 31%; (f) MVK (3.0 equiv), GII (0.01 equiv), CuI (0.02
equiv), DCM, 50 °C, 1 h, 93%; (g) 1 M NaOH (2.0 equiv), 50% H2O2 (2.0 equiv), MeOH, 0 to 25 °C, 3 h, 81%; (h) Cp2TiCl2 (1.0 equiv), Zn0
(8.0 equiv), THF, 25 °C, 30 min, 88%; (i) (Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.01 equiv), PhSH (1.1 equiv), p-toluidine (0.5 equiv), MeCN, blue
LED irradiation, 25 °C, 3 h, 74% (46:47 ≈ 1:1). Tf = trifluoromethanesulfonyl, NaHMDS = sodium 1,1,1-trimethyl-N-(trimethylsilyl)silanaminide,
MVK = methyl vinyl ketone, TMS = trimethylsilyl, dba = dibenzylideneacetone, t-BuXPhos = 2-di-tert-butylphosphino-2′,4′,6′-
triisopropylbiphenyl, GII cat. = Grubbs second generation catalyst = (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-
(phenylmethylene)(tricyclohexylphosphine)ruthenium, (Ir[dF(CF3)ppy]2(dtbpy))PF6 = [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]
bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate.
a
Scheme 3. Towards a Pyrroloazepinone-Based Route to 1
a
Reagents and conditions: (a) Et3N (1.5 equiv), TMSOTf (1.1 equiv), DCM, 0 °C, 30 min, used without purification; (b) Pd(dba)2 (0.05 equiv),
Pt-Bu3 (0.1 equiv), ZnF2 (1.5 equiv), CsF (1.5 equiv), DMF, 70 °C, 5 h, 29% (1:1 dr) (40% BRSM); (c) LiHMDS (1.2 equiv), THF, −78 °C, 30
min, then add 56 (1.1 equiv), −78 °C, 3 h, 62%; (d) nBu3SnLi (1.2 equiv), THF, −78 °C, 1 h, then add 56 (1.1 equiv), −78 °C, 3 h, 44%; (e) 57
(1.1 equiv), 58 (1.0 equiv), Pd2dba3 (0.05 equiv), TFP (0.2 equiv), CuDPP (1.1 equiv), THF, 60 °C, 1.5 h, 67% or 57 (1.1 equiv), 59 (1.0 equiv),
Pd2dba3 (0.05 equiv), TFP (0.2 equiv), CuDPP (1.1 equiv), THF, 60 °C, 1.5 h, 37%; (f) 60 (1.0 equiv), PPTS (0.5 equiv), PhMe, 60 °C, 1.5 h,
91% (4:1 dr) or 61 (1.0 equiv), (TMS)3SiH (1.5 equiv), BEt3 (1.1 equiv), O2, DCM, −78 °C, 2 h, 43% (6:1 dr). LiHMDS = lithium 1,1,1-
trimethyl-N-(trimethylsilyl)silanaminide, dba = dibenzylideneacetone, TFP = tri(2-furyl)phosphine, DPP = diphenylphosphinate.
With 44 secured, we commenced attempts to construct the
key 7-membered ring via radical cyclization.15 Reductive
radical cyclizations initiated at the pendant enone with M/
HSiR3 (M = Fe, Co)-based systems led to reduction without
cyclization.16 While an epoxide (see 45) could be generated
from 44 (H2O2, NaOH), attempted titanocene-mediated
cyclizations only returned enone 44.17 The addition of a
thiyl radical to initiate radical cyclization was also explored
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under photoredox conditions,18 but these conditions instead
promoted a rather facile, yet unselective, [2 + 2] cycloaddition
to generate cyclobutanes 46 and 47 in 74% combined yield.19
Initial Forays Into a Pyrroloazepinone Fragment-
Based Synthesis. Faced with an inability to form both of the
key bonds needed for a successful indolizidine annulation-
based approach, we adjusted our retrosynthesis to include a
pre-existing 7-membered ring (see inset, Scheme 3).
Specifically, we considered the convergence of a 5,7-fused
pyrrole-containing synthetic unit (see 48) with fragment 49, an
alternative retrosynthetic strategy for carbocyclic construction
of curvulamine’s core, lending to a potentially more facile six-
membered ring-forming annulation. Nevertheless, the precise
oxidation state of 48 and the reaction types capable of realizing
this annulation remained open questions; ultimately, only
through significant experimentation and reactivity reconnais-
sance gathering did a successful route to 1 emerge along these
lines.
from only ∼20−25% and large quantities of reagent 56 was
also required to produce 55.24
Given this backdrop, we investigated alternatives routes to
this class of heterocycles (Figure 3). Inspired by the work of
We initiated our investigations using enone 50, a known
Robinson annulation product of 2-formylpyrrole and methyl
vinyl ketone.20 To construct one of the two key C−C bonds in
the revised annulation, we turned toward Pd-catalyzed enolate
arylation. Enone 50 could be converted to sensitive
trimethylsilyl enol ether 51 and merged with pyrrole iodide
52 to generate 53.21 However, further manipulation of this
material proved challenging; we were unable to produce
dienone 54 through Saegusa-Ito or related enolate oxidation
processes.
Given these setbacks, we found it prudent to investigate
installation of the alternative key C−C bond first (Scheme 3).
Unlike 54, enone 50 could be oxidized to pyrroloazepinone 55
using Mukaiyama’s desaturation reagent N-tert-Butylbenzene-
sulfinimidoyl chloride (56). Pyrroloazepinones such as 55
uncommon 10π-aromatic heterocyclesare infrequently used
in synthesis and their reactivity is largely unexplored.22 While
we did not know it at the time, this heteroaromatic proved key
in the development of a concise route to 1.
Pyrroloazepinone 55 underwent productive conjugate
addition with a variety of nucleophiles (vide infra). Initially
we found that tributylstannyllithium (LDA, HSnBu3) was
readily added and that the resulting enolate could be directly
oxidized with 56 to produce stannane 57 (Scheme 3). We
envisioned that this fragment could be merged with a pyrrole-
containing thioester via Liebeskind-Srogl coupling. Exper-
imentally, we discovered that 56 reacted with thioester 58 and
iodo-variant 59 in 67% and 37% yield, respectively.23 The
products formed, namely enediones 60 and 61, lacked only a
single C−C bond for advancement into the tetracyclic scaffold
of 1. However, upon treating dienone 60 with a variety of
Lewis acids, we observed exclusive formation spirocycle 62 as a
mixture of diastereomers. Attempts to elicit direct, palladium-
catalyzed dehydrogenative coupling of 60 were also
complicated by this Lewis-acid catalyzed background reaction.
Employing iodide 61 and changing the reaction manifold to
one based on free radicals (i.e., Bu3SnH/AIBN or
(TMS)3SiH/Et3B/O2) did not change the outcome as
spirocyclic enone 62 was again generated.
Figure 3. Two-step synthesis of novel pyrroloazepinones.
Flitsch,22 we developed a straightforward synthesis using Boc-
protected 2-formylpyrroles, ubiquitous Vilsmeier−Haack for-
mylation products, as starting materials (Figure 3). The
enolate of vinylogous ester 64 was first added to pyrrole 63
resulting in direct formation of dienone 65 through an aldol
addition/Boc-migration/E1cB elimination pathway. With
access to dienone 65 we evaluated cyclization conditions to
produce the 10π aromatic nucleus (see Table, Figure 3). We
sought to avoid flash vacuum pyrolysis and other low-yielding
cyclization conditions observed in the cyclization of related
vinylogous amides.22
Dienone 65 formed pyrroloazepinone 66 under mild
conditions (Cs2CO3, 25 °C), but the yield of this cyclization
was low (<20%, see entries 1−2). Microwave-induced thermal
cyclizations employing amine bases proved more efficient, and
utilizing DBU we were able to prepare 66 in 60% yield (entry
5)notably these conditions were also scalable and enabled
multigram procurement of this key building block.25,26
Next, we surveyed these cyclization conditions for the
synthesis of novel, substituted pyrroloazepinones (see 67−73,
Figure 3). Previously prepared heteroaromatic 55 was
produced in comparable yield to 66 (64% cyclization yield)
as was isomeric methyl-containing substrate 67. Importantly,
67 also demonstrates that ketones, and not just aldehydes, can
be used in this methodology. Indole (see 68) and
tetrahydroindole (see 69) units could also be incorporated
although cyclization yields were somewhat diminished (40−
43%). Aryl substituents were also tolerated on the pyrrole ring,
leading to products 70−73.
While the two strategies in Scheme 3 were ultimately dead-
ends, we were keen to survey additional nucleophilic partners
in the coupling with a pyrroloazepinone heterocycle. An initial
impediment to such endeavors was the difficulty in preparing
large quantities of 55. Specifically, enone 50 (prepared using a
two-step Robinson annulation), was produced in yields ranging
Exploring a Dearomative Approach. With a robust
synthesis of pyrroloazepinone 66 in hand, we proceeded to
evaluate a carbon-based nucleophile in the dearomative
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Scheme 4. Successful Dearomative C−C Bond Formation Leads to Unexpected Pyrrole Reactivity
a
Reagents and conditions: (a) ( )-74 (1.4 equiv), KHMDS (1.4 equiv), THF, −78 °C, 30 min, then add HMPA (5.0 equiv), 66 (1.0 equiv), −78
°C, 2 h, 54% (5:1 dr); (b) ethyl vinyl ether (7.5 equiv), t-BuLi (7.0 equiv), THF, −78 to 0 °C, 30 min; 75 (1.0 equiv), CeCl3 (1.0 equiv), LiCl (2.0
equiv), 0 °C, 30 min, then add lithiated ethyl vinyl ether, −78 °C, 1 h, then add 1 M HCl, 25 °C, 30 min, 72% (2.6:1 dr); (c) 5 M NaOH (2.0
equiv), THF, 60 °C, 1 h, used without purification; (d) MsCl (5.0 equiv), Et3N (10.0 equiv), DCM, 0 °C, 15 min, then add N-hydroxyphthalimide
(2.2 equiv), 0 °C, 30 min, 35% (2 steps); (e) Cu(acac)2 (2.0 equiv), B2Pin2 (1.5 equiv), LiOH·H2O (15.0 equiv), MgCl2 (1.2 equiv), Dioxane/
DMF = 5:1 (v:v), 25 °C, 2 h, used without purification; (f) NaBO3·H2O (5.0 equiv), THF/H2O = 1/1, 25 °C, 30 min, 17% for 2 steps; (g) p-TsOH
(0.5 equiv), DCM, 25 °C, 85%. KHMDS = potassium bis(trimethylsilyl)amide, HMPA = hexamethylphosphoramide, acac = acetylacetonate,
B2Pin2 = 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane.
conjugate addition reaction (Scheme 4). Much to our delight,
we observed that the potassium enolate of pyrrole-containing
ester 74 could be prepared, and in the presence of HMPA,
added to 66 to yield coupled product 75 in 54% yield and with
5:1 diastereoselectivity at C-3. While 66 possesses several sites
for Michael-type attack (see C1, C9, and C5), under these
conditions selectivity for the C5 position was observed.27
Notably the stereochemical relationship between the methyl
group and the stereocenter on the 7-membered ring are correct
for advancement to 1 as well. We assumed (albeit incorrectly)
that the C-3 ester could be easily removed later in the synthesis
by decarboxylative methods (vide infra).
forming an extended azafulvenium ion (80). Interestingly, this
electrophile was attacked by the second pyrrole at a substituted
carbon center leading to pyrrole dearomatization and
formation of a quaternary center. While related enamines are
highly unstable,2 conjugation to the electron-withdrawing
ketone stabilizes this structure. Conversion of 81 to NHPI
ester 82 (MsCl, Et3N, N-Hydroxyphthalimide) then allowed
for a copper-mediated decarboxylative borylation and
oxidation furnishing alcohol 83 whose structure was confirmed
by single crystal X-ray diffraction.29 While these unoptimized
transformations were low-yielding, this work suggested that the
extraneous carbon atom added in the dearomative conjugate
addition could be removed to yield a hydroxyl group.
We also briefly explored the reactivity of intermediates
stemming from the minor diastereomer of 75 (see inset,
Scheme 4). Compound 84 could be formed analogously to 76.
Interestingly, treatment of 84 with para-toluenesulfonic acid
generated putative azafulvenium ion 85 which was also
quenched through intermolecular attack from the pendant
pyrrole to afford 86. Fascinatingly, the sole product formed (in
85%) in this cyclization, however, was tetracycle 86 whose
notable diazabicyclo[4.4.1]undecane core was confirmed
crystallographically.30
Adopting the conditions of Knochel,28 a cerium-mediated
1,2-addition of lithiated ethyl vinyl ether into enone 75
produced methyl ketone 76 as a mixture of diastereomers
(72%, 2.6:1 dr) after acidic hydrolysis (aq. HCl) of the enol
ether (Scheme 4). We had hoped that treating compound 76
with base would transiently generate lactone 77 which in turn
might undergo an E2 elimination, thus generating enone 78.
An intramolecular addition of the pyrrole to this newly
generated Michael acceptor would then produce 79, the key
tetracyclic core of all (C10N)2 members. Subjecting 76 to
sodium hydroxide at slightly elevated temperature followed by
an acidic quench led to a markedly different outcome,
however, wherein a rather remarkable dearomatized enamine
(81) containing a 5,7,5,7-fused ring system was produced. We
speculate that 77 was indeed formed, but the electron-rich
vinyl pyrrole nucleus expelled the carboxylate leaving group
While neither of these two pathways yielded the desired
tetracyclic core of 1, we felt that the initial conjugate addition
reaction with heterocycle 66 was a promising route for further
exploration and that a decarboxylation reaction could be
employed late-stage. In reality, these assumptions proved
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Scheme 5. Successful Synthesis of the Curvulamine Core
a
Reagents and conditions: a) ( )-74 (1.4 equiv), KHMDS (1.4 equiv), THF, −78 °C, 30 min then add HMPA (5.0 equiv), 66 (1.0 equiv), −78
°C, 2 h, then add I2 (1.1 equiv), −78 °C, 30 min, 49% (5:1 dr); (b) Na2CO3 (5.0 equiv), MeOH, Kessil Lamp KSPR160 (390 nm, 40 W), 25 °C, 1
h, 70%; (c) 88 (1.0 equiv), CeCl3 (2.0 equiv), THF, 0 °C, 30 min, then add vinylMgBr (2.5 equiv), 30 min, −78 °C, 1 h, 37%; (d) 88 (1.0 equiv),
CeCl3 (2.0 equiv), THF, 0 °C, 30 min, then add EtMgBr (1.05 equiv), −78 °C, 1 h, 60%; (e) KHMDS (2.0 equiv), 18-crown-6 (2.0 equiv), THF,
−78 °C, 30 min, then add Davis oxaziridine (1.2 equiv), −78 °C, 30 min, 45%; (f) DIBAL (1.2 equiv), DCM, −78 °C, 30 min, 52%; (g) Me3OBF4
(1.5 equiv), proton sponge (3.0 equiv), DCE, 90 °C, 12 h, 50%; (h) 1 M KOH (3.0 equiv), MeOH, 90 °C, 12 h, 15%; (i) DIBAL (2.5 equiv),
DCM, −78 °C, 30 min, 82%; (j) Cu[MeCN]4OTf (0.1 equiv), MeObpy (0.1 equiv), NMI (0.1 equiv), ABNO (0.05 equiv), O2, MeCN, 25 °C, 30
min, 75%; (k) MeMgBr (1.1 equiv), THF, −15 °C, 30 min, 71%; (l) Cu[MeCN]4OTf (0.1 equiv), MeObpy (0.1 equiv), NMI (0.1 equiv), ABNO
(0.05 equiv), O2, MeCN, 25 °C, 30 min, 55%. 18-crown-6 = 1,4,7,10,13,16-Hexaoxacyclooctadecane, MeObpy = 4−4′-dimethoxy-2−2′-bipyridine,
NMI = 1-methylimidazole, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl.
partially correct and significant experimentation remained to
clarify a workable pathway forward.
(Scheme 5). Initially, we added excess vinyl magnesium
bromide to 88 producing double addition product 89. We had
hoped that the array of known methods to generate alkoxy
radicals would allow for facile C−C bond β-cleavage of the
desired bond shown in green and further radical functionaliza-
Successful Synthesis of the Curvulamine Core Leads
to a Difficult Decarboxylation. Our inability to close the
six-membered ring via polar, pyrrole cyclization approaches led
us to consider radical-based methods (Scheme 5). Specifically,
our dearomative conjugate addition furnished an enolate which
we believed could be oxidized to a radical. Unfortunately, the
addition of common single-electron oxidants to this coupling
reaction did not lead to pyrrole C-2 functionalization despite
literature precedent suggesting its feasibility.31 We could
however quench the anionic coupling of 66 and 74 with NIS
or I2 leading to iodide 87 (49% combined yield), thus allowing
for a broader survey of reaction conditions to be explored
(Scheme 5).32 While photoredox chemistry was explored with
some success,7 control experiments found that simple
irradiation of 87 (390 nm light) forged compound 88 in
good yield (70%) thus accomplishing our first successful
synthesis of the curvulamine tetracycle. While unknown at the
time, substantial challenges awaited.
́
tion. Unfortunately, Suarez conditions (PIDA, I2, hv) single-
electron oxidants (FeCl3, AgNO3/K2S2O8/NIS), and a variety
of other reagents (Ir(III)/hv, CeBr3/O2/hv) failed to provide
detectable quantities of C−C bond cleaved productsonly
decomposition was typically observed. Attempts to convert the
tertiary alcohol into a hydroperoxide for iron-induced C−C
bond cleavage were also unproductive.33,34
To promote the C−C cleavage process, we reasoned that
introduction of an additional hydroxyl group (thus construct-
ing a 1,2-diol motif) might allow for a wider reactivity window
to be explored. Carefully controlled addition of ethyl-
magnesium bromide mediated by CeCl3 allowed for the
conversion of 88 into lactone 90. Remarkably, this material
could be deprotonated (KHMDS, 18-crown-6) at the bridge-
head position allowing for hydroxylation with Davis’
oxaziridine. The α-hydroxylactone formed (91) could then
be reduced with DIBAL to generate α-hydroxy acetal 92.
Much to our dismay, however, standard diol cleavage
With tetracyclic enone 88 in hand, a variety of endgames
were envisioned all of which required a C−C bond cleavage
event to excise the extraneous C-3 carbon atom of the ester
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conditions (NaIO4, Pb(OAc)4, H5IO6) were all incompatible
with this sensitive substrate leading only to intractable
mixtures.
We then decided to explore the chemistry of a conforma-
tionally distinct ester intermediate, finding that alkylative
lactone opening of 90 (Me3OBF4, proton sponge, Δ) furnished
methyl ester 93 in moderate yield.35 Given the breadth and
renaissance in decarboxylative functionalization chemistry, we
first looked toward hydrolysis of methyl ester to prepare
carboxylic acid 94. The hydrolysis of this quite hindered ester
proved challenging, resulting in only 15% yield of acid 94 along
with extensive decomposition.36 Nevertheless, we were able to
explore several strategies with this limited amount of material.
Similar to substrate 89, direct decarboxylative functionalization
́
of the free acid under radical generating conditions (i.e., Suarez
chemistry, AgI salts, Pb(OAc)4, photoredox catalysis) did not
lead to isolable products. We had hoped that Barton’s
decarboxylative oxygenation might allow for a peroxidation
cascade an analogy to our prior work on terpene scaffolds;37,38
while a Barton ester could be formed in trace quantities,
instant decomposition was observed during its activation in the
presence of oxygen. Finally, decarboxylative borylation/
oxidation, which had been used to construct 83 in low yield
(Scheme 4), was unsuccessful in this setting under a variety of
conditions.29,39
As a last-ditch effort, we attempted to remove this
recalcitrant carbon atom from multiple different carbonyl
bearing intermediates (Scheme 5). Ester 93 was reduced
cleanly with DIBAL to generate a primary alcohol which could
be oxidized to an aldehyde using Stahl’s mild copper-catalyzed
conditions.40 Unfortunately, attempts at performing Iwasawa’s
cobalt salen-catalyzed cleavage reaction of an in situ generated
hydroperoxide led to extensive decomposition.41 In our final
foray, we turned to the tried-and-true Baeyer−Villiger
oxidation. While methyl ketone 96 could be synthesized
from aldehyde 95 in two steps, this substrate was not
compatible with peracids likely as a result of the vinyl pyrrole
nucleus (vide infra).
The results in Scheme 5 were both encouraging and
frustrating as is often the case during a total synthesis. While a
viable strategy to the elusive curvulamine tetracycle had
emerged, it was clear that alternative nucleophiles in the
conjugate addition would need to be examined if we were to
synthesize 1 by this strategy.
Reactivity of Alternative Nucleophiles in the Dear-
omative Conjugate Addition. We undertook a fairly
comprehensive study of various carbanions and their reactivity
with our key pyrroloazepinone (see 66 + 97 → 98, Figure 4).
Although we had not succeeded in decarboxylating acid 94, the
extremely low yield in preparing this material from ester 93
compelled us to examine free carboxylic acid 99 in the
dearomative coupling (Figure 4). We attempted to generate
the dianion of 99 using an excess of strong base (KHMDS)
and found that a new product was formed after the addition of
66. Much to our surprise the structure of the “coupled
product” turned out to be dimer 100 whose structure was
secured by X-ray crystallography. Excess base apparently
deprotonated the acidic methyl group of 66, forming an
anion which added in a conjugate fashion to another molecule
of 66 resulting in a formal annulation after a second,
intramolecular Michael addition.
Figure 4. Examination of alternative nucleophiles in the conjugate
addition to pyrroloazepinone 66.
the desired position.42 Deprotonation of 101 (s-BuLi)
followed by addition of 66 generated several new products
which were most easily analyzed following lithium aluminum
hydride reduction of the carbamate. To our surprise we found
that tetracycle 102, formed as a mixture of diastereomeric
spirocycles, was the major product. This product ostensibly
stems from lithiate 1,2-addition followed by ionization of the
highly labile tertiary alcohol to form an aromatic carbocation
which is trapped by the electron-rich pyrrole.
Next, we considered the use of a metalated nitrile owing to
the possibility for downstream reductive decyanation/
functionalization.43 The anion derived from 103 underwent
coupling with 66 to generate coupled product 104 (40%)
whose structure was confirmed by X-ray crystallographic
analysis. Notably the stereochemical configuration of the
methyl group (C2) is opposite to that found in curvulamine
and would have to be corrected at some point. In addition to
104, we also observed substantial amounts (38%) of spirocycle
105 in analogy to 102. In addition to these “successful”
experiments, a number of other pyrrole-containing nucleo-
philes (see 106−108) were examined but did not lead to C−C
bond formation with 66. In addition, we attempted to generate
the ketyl radical of 41 in the presence of 66, but did not
observe any productive coupling.
A lithiated carbamate strategy was also briefly explored as
this would correctly incorporate a masked hydroxyl group at
Total Synthesis of Curvulamine. Given the successful
coupling of nitrile 103, we chose to evaluate one final
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Scheme 6. Total Synthesis of Curvulamine
a
Reagents and conditions: (a) 110 (1.5 equiv), LiCl (5.0 equiv), NaHMDS (1.6 equiv), THF, −78 °C, 30 min then add 66 (1.0 equiv), THF, −78
°C, 1 h then add NIS (1.5 equiv), THF, −78 °C, 5 min (64%); (b) NaHCO3 (5.0 equiv), MeCN/t-BuOH (4:1), Kessil Lamp KSPR160 (390 nm,
40W), 23 °C, ∼2 h (55%); (c) Na2CO3 (2.0 equiv), MeOH, 23 °C, 5 min (96%); (d) ethyl vinyl ether (5.5 equiv), t-BuLi (5.0 equiv), THF, −78
°C, 30 min then add 113 (1.0 equiv), −78 °C, 1 h (52%); (e) ethyl vinyl ether (5.5 equiv), t-BuLi (5.0 equiv), THF, −78 °C, 30 min then add 112
(1.0 equiv), −78 °C, 1 h (55%); (f) NaOMe (5.0 equiv), MeOH, 90 °C, 4 h (85%); (g) KHMDS (1.6 equiv), −78 °C, 30 min; then add phenyl
chlorothionoformate (2.0 equiv), DMAP (2.0 equiv), THF, −78 to 0 °C, 20 min (50% 117 + 21% 118); (h) HSnBu3 (2.0 equiv), BEt3 (1.0 equiv),
O2, THF, 45 °C, 1 h then add aq. HCl, 0 °C, 5 min (40%); (i) (R)-2-methyl-CBS-oxazaborolidine (1.0 equiv), BH3·DMS (2.0 equiv), DCM, 23
°C, 1 h (45% (−)-1 + 45% (+)-12-epi-1; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DMAP = 4-dimethylaminopyridine, NIS = N-
iodosuccinimide.
nucleophilea cyanohydrinwhich are known to undergo
1,4-addition reactions.44 Ultimately this decision proved
critical in enabling the first total synthesis of curvulamine
(Scheme 6).7 Unlike 74, deprotonation of cyanohydrin 110
using KHMDS in the presence of HMPA lead to E1cB of the
pyrrole anion, producing a variety of undesired products when
reacted with 66.45 A stable carbanion could be made however
using NaHMDS in the presence of LiCl; this species added to
66, giving a 64% yield of coupled product 111 (∼6:1 dr) after
quenching with N-iodosuccinimide. As noted when forming
104, the C2 stereocenter was incorrectly set during this
process. From 111, our previously developed photochemical
cyclization generated tetracyclic ketone in moderate yield
(55%). The cyanohydrin could be easily removed by basic
methanolysis to give diketone 113. Interestingly, this
compound reacted with lithiated ethyl vinyl ether to give
114, the product of nucleophilic addition at the incorrect
carbonyl group. Satisfyingly, however, treatment of 112 with
an excess of the same nucleophile produced lactol 115 bearing
the correct connectivity in 55% isolated yield.
2.3:1 mixture of lactols favoring the epimerized isomer (116)
in 85% combined yield.
The next obstacle in the synthesis of curvulamine entailed
removal of the bridgehead hydroxyl group comprising the
lactol motif. The inseparable, thermodynamic mixture of
lactols (115/116) was activated (KHMDS, pyridine,
ClCSOPh) generating a mixture of thiocarbonate epimers
117 and 118 (71% yield) which could be separated
chromatographically. Of practical importance, the undesired
isomer (i.e., 118) could be recycled by one-pot, base-mediated
methanolysis/epimerization (NaOMe, MeOH, Δ) redelivering
the equilibrium mixture of 115 and 116. Finally, reductive
deoxygenation (HSnBu3, BEt3/O2) with concomitant enol
ether hydrolysis of intermediate 119 during acidic workup (aq.
HCl) afforded methyl ketone ( )-120 in 40%.
To complete the synthesis of racemic 1 we simply needed to
reduce ( )-120 diastereoselectively. A variety of reducing
agents (DIBAL, NaBH4, LiBH(Et)3, LiAlH4, and other simple
hydrides) afforded primarily the undesired secondary alcohol
diastereomer, namely ( )-12-epi-1. Intrigued by a possible
reagent controlled solution, we exposed our methyl ketone to
CBS reduction conditions ((R)-2-Methyl-CBS-oxazaboroli-
dine, BH3·DMS, DCM).46 Interestingly, a near perfect
stereodivergent reduction ensued wherein ( )-120 was
converted into an easily separable 1:1 mixture of (−)-(1)
and (+)-12-epi-1 with 97% and 94% ee respectively (90%
With 115 in hand we proceeded to investigate epimerization
of the C2 methyl group. We found it plausible that allylic 1,3-
strain minimization between the two methyl groups (C1 and
C10) might favor the desired stereochemistry. Gratifyingly,
basic treatment of 115 (NaOMe, MeOH, Δ) established a
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Figure 5. Tan’s biosynthetic hypothesis regarding the origins of curindolizine.
overall yield).47,48 Our journey to 1, which was filled with
numerous roadblocks and unexpected surprises, was finally
complete.
curvulamine (1) under acidic conditions have not yielded
coupled products to date (Figure 6). Moreover, reacting 1 with
other activated α,β-unsaturated carbonyls such as acylate
systems or cyclohexenone has not demonstrated the feasibility
of productive Michael addition chemistry at the desired pyrrole
positiononly recovered starting material or decomposition is
observed in the presence of Brønsted or Lewis acids. Similarly,
attempts at coupling 17 with 1 have only led to aromatization
of 17 forming 3,5-dimethylindolizine. Against this backdrop,
we investigated nonbiomimetic strategies to access this
complex family member (Scheme 7).
TOTAL SYNTHESIS OF CURINDOLIZINE
■
With a 10-step route to curvulamine in place, we turned our
attention toward curindolizine (2), the most complexand
only trimeric (C10N)3member in the family (Figure 5).
When scaling up a 300 L fermentation of Curvularia sp. IFB-
Z10, Tan and co-workers found that 2 was formed in
preference to 1.4 It was proposed that curindolizine is
produced from the Michael addition reaction of 1 and enone
122, which could be derived from procuramine (123), a simple
C10N member present in the fermentation broth. Additionally,
when 1 and 123 were exposed to cell lysate containing the
intracellular protein fractions, 2 could be detected implicating
enzymatic assistance in this coupling. The direct coupling of 1
and 123 still requires a reduction step to generate curindolizine
and thus it was not clear to us if nature’s pathway involves the
sequence shown in Figure 5 or one involving allylic alcohol 17,
the previously speculated biosynthetic intermediate from B.
maydis and a possible Friedel−Crafts (rather than Michael)
coupling partner (Figure 6). We developed simple chemistry to
While a logical solution to the coupling problem would be to
simply halogenate 1 and explore various C−C bond-forming
reactions, the locus of reactivity with electrophilic reagents in
this multiheterocyclic system lies at the vinyl pyrrole group.49
Fortunately, previously prepared tetracycle 112 (prepared in 5
steps on a gram scale) underwent very clean iodination to yield
iodide 124 in 88% yield (Scheme 7). Presumably this is the
least-hindered position on the more electron-rich pyrrole ring.
A Ce(III)-mediated addition of lithiated ethyl vinyl ether to
this material then gave 125 after in situ silylation (TMSCl).
Iodide 125 could be converted into an organozinc reagent (t-
BuLi then ZnCl2) and subjected to Pd-catalyzed Negishi
coupling with racemic triflate 126 to yield a separable mixture
of diastereomeric products (see 127 and 128) in 80%
combined yield.50 The desired isomer (128) could then be
stereoselectively reduced by samarium iodide to generate ester
129 as essentially a single compound. Gratifyingly the relative
relationship between this newly formed stereocenter and the
adjacent methyl group is as found in 2.51 A similar four-step
sequence as the one employed in the synthesis of 1, namely (i)
thermodynamic equilibration of the methyl-containing stereo-
center, (ii) thiocarbamate formation, (iii) deoxygenation, and
(iv) CBS reduction proceeded uneventfully in this setting,
thereby advancing ( )-129 into (−)-130. In the final step of
the synthesis, and in analogy to the preparation of 17, careful
DIBAL reduction of this material generated an aldehyde which
cyclized directly to (+)-curindolizine (2) in 70% yield, thus
completing the first synthesis of this complex trimeric alkaloid
in 14 steps.
Figure 6. Preparation and reactivity of candidate biosynthetic
coupling partners.
DISCUSSION
■
access both 17 and 123 based largely on our unsuccessful
initial attempts to synthesize 1 via bioinspired strategies. An
aldol reaction between methyl tert-butyl acetate and aldehyde
41 first generated 124 (82%, 6:1 dr). Mild Friedel−Crafts
acylation of this material (TMSOTf) then generated
procuramine (123) in 50% yield. Alternatively, 124 could be
reduced with DIBAL generating an aldehyde which cyclized
and dehydrated in the presence of silica gel to yield 17 (44%).
Unfortunately attempts to merge either 17 or 123 with
In this article, we have chronicled the evolution of a total
synthetic strategy toward complex polypyrrole alkaloids from
Curvularia sp. fungi resulting in a 10-step total synthesis of
curvulamine (1) and 14-step route to curindolizine (2). Given
their unprecedented chemical structures and mysterious
biosynthetic origins, a variety of approaches were brought to
bear on this synthetic problem. Throughout each planning
stage though, effort was made to explore and exploit the innate
reactivity of the electron-rich pyrrole nucleus.52 Indeed, we
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Scheme 7. Total Synthesis of Curindolizine
a
Reagents and conditions: (a) NIS (1.05 equiv), acetone, 0 °C, 30 min, 88%; (b) ethyl vinyl ether (5.5 equiv), t-BuLi (5.0 equiv), THF, −78 to 0
°C, 30 min, then add CeCl3 (5.0 equiv), 25 °C, 1 h, then add 124, −78 °C, 1 h, then add TMSCl (5.0 equiv), −78 °C, 30 min, 79%; (c) 125 (1.0
equiv), t-BuLi (2.5 equiv), THF, −78 °C, 30 min, then add ZnCl2 (3.0 equiv), −78 °C, 1 h, then add Pd(PPh3)4 (0.03 equiv), ( )-126 (2.0 equiv),
25 °C, 6 h, 80% (127:128 = 1:1); (d) SmI2 (2.0 equiv), THF/MeOH = 9/1, 0 °C, 30 min, then add TBAF (2.0 equiv), 25 °C, 30 min, 80%; (e)
NaOMe (5.0 equiv), MeOH, 90 °C, 1 h, 57% (80% BRSM); (f) KHMDS (1.2 equiv), −78 °C, 30 min; then add DMAP (2.0 equiv), Phenyl
chlorothionoformate (2.0 equiv), THF, −78 °C, 1 h, 83%; (g) HSnBu3 (2.0 equiv), BEt3 (1.0 equiv), O2, THF, 45 °C, 1 h, then add aq. HCl, 0 °C,
30 min, 41%; (h) (R)-2-methyl-CBS-oxazaborolidine (1.0 equiv), BH3·DMS (2.0 equiv), DCM, 23 °C, 1 h, 42% (−)-130 + 42% (+)-12-epi-130;
(i) DIBAL (5.0 equiv), DCM, −78 °C, 30 min, then add silica gel, 5 min, 70%.
have observed the pyrrole as a nucleophile, radical acceptor,
and electrophile (as part of several azafulvenium ions
encountered) in the course of our studies. While many of
the synthetic intermediates described herein proved challeng-
ing to work with from a technical perspective (i.e., air and acid
sensitivity), we were rewarded by beholding their interesting
and unexpected reactivity in a novel chemical architecture.
During our studies we also developed an improved synthesis of
pyrroloazepinones, which should find broader use in
heterocyclic chemistry, as well as expanded the knowledge
base surrounding the reactivity of this exotic 10π-electron
heteroaromatic. Finally, we developed a route to curindolizine,
despite being unable to elicit a direct, biomimetic coupling of
(C10N)2 and C10N fragments. While not demonstrated herein,
we believe our finding can also enable routes to bipolamine-
type metabolites as well as facilitate a greater understanding of
the antibacterial properties of these alkaloids. Such inves-
tigations are underway and will be reported in due course.
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
Authors
Jun Xuan − Department of Chemistry, University of California,
Berkeley, Berkeley, California 94720, United States
Karl T. Haelsig − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Michael Sheremet − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Paulo A. Machicao − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13465
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13465.
Author Contributions
‡These authors contributed equally to this work.
Notes
Experimental procedures and spectroscopic data (PDF)
The authors declare no competing financial interest.
Accession Codes
ACKNOWLEDGMENTS
■
CCDC 2059551−2059556 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, U.K.; fax: +44 1223 336033.
Financial support is acknowledged from the NIH NIGMS
(R01GM136945 to T.J.M. and a diversity supplement to
P.A.M.). T.J.M. acknowledges unrestricted financial support
from Novartis, Bristol-Myers Squibb, Amgen, and Eli Lilly.
M.S. thanks the German Research Foundation for a DFG
Postdoctoral fellowship. We are grateful to Dr. Hasan Celik
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(13) Movassaghi, M.; Ondrus, A. E. Enantioselective Total Synthesis
of Tricyclic Myrmicarin Alkaloids. Org. Lett. 2005, 7, 4423.
(14) The iodo variant of 35 could be prepared, but this compound
also failed to undergo C−N cross-coupling with these more complex
pyrroles under Ullman-type conditions.
(15) For recent reviews on radical cyclizations in total synthesis, see:
(a) Romero, K. J.; Galliher, M. S.; Pratt, D. A.; Stephenson, C. R. J.
Radicals in Natural Product Synthesis. Chem. Soc. Rev. 2018, 47, 7851.
(b) Hung, K.; Hu, X.; Maimone, T. J. Total Synthesis of Complex
Terpenes Employing Radical Cascade Processes. Nat. Prod. Rep.
2018, 35, 174.
(16) For a review on this type of chemistry, see: Matos, J. L. M.;
Green, S. A.; Shenvi, R. A. Chapter 7. Markovnikov Functionalization
by Hydrogen Atom Transfer. Organic Reactions 2019, 100, 383.
(17) Morcillo, S. P.; Miguel, D.; Campana, A. G.; Alvarez de
Cienfuegos, L.; Justicia, J.; Cuerva, J. M. Recent applications of
Cp2TiCl in natural product synthesis. Org. Chem. Front. 2014, 1, 15.
(18) (a) Tyson, E. L.; Ament, M. S.; Yoon, T. P. Transition Metal
Photoredox Catalysis of Radical Thiol-Ene Reactions. J. Org. Chem.
2013, 78, 2046. (b) Guerrero-Corella, A.; Martinez-Gualda, A. M.;
and Dr. Jeffrey Pelton for NMR spectroscopic assistance and
NIH grant GM68933 as well as Bella Germek for technical
assistance. Mr. Edward Miller is acknowledged for assistance
with chiral HPLC. Dr. Nicholas Settineri and Jeffrey Derrick
are acknowledged for X-ray crystallographic analysis wherein
support from NIH Shared Instrument Grant (S10-RR027172)
is also acknowledged.
REFERENCES
■
(1) For a general review, see: (a) Young, I. S.; Thornton, P. D.;
Thompson, A. Synthesis of natural products containing the pyrrolic
ring. Nat. Prod. Rep. 2010, 27, 1801. (b) Mal, D.; Shome, B.; Dinda,
B. K. Pyrrole and Its Derivatives. In Heterocycles in Natural Product
Synthesis; Majumdar, K. C., Chattopadhyay, S. K., Ed.; Wiley: New
York, 2011; Ch. 6, p 187.
(2) For examples on the extreme end of the pyrrole reactivity scale,
̈
see: (a) Schroder, F.; Franke, S.; Francke, W.; Baumann, H.; Kaib, M.;
Pasteels, J. M.; Daloze, D. A New Family of Tricyclic Alkaloids from
Myrmicaria Ants. Tetrahedron 1996, 52, 13539. (b) Ondrus, A. E.;
Movassaghi, M. Total synthesis and study of myrmicarin alkaloids.
Chem. Commun. 2009, 4151. (c) Snyder, S. A.; Elsohly, A. M.; Kontes,
F. Synthetic and Theoretical Investigations of Myrmicarin Biosyn-
thesis. Angew. Chem., Int. Ed. 2010, 49, 9693.
́
Ahmadi, F.; Ming, E.; Fraile, A.; Aleman, J. Thiol-ene/oxidation
tandem reaction under visible light photocatalysis: synthesis of alkyl
sulfoxides. Chem. Commun. 2017, 53, 10463. (c) Xu, J.; Boyer, C.
Visible Light Photocatalytic Thiol−Ene Reaction: An Elegant
Approach for Fast Polymer Postfunctionalization and Step-Growth
Polymerization. Macromolecules 2015, 48, 520. (d) For an example in
synthesis, see: Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang,
Z. Enantioselective Total Synthesis of (−)-Pavidolide B. J. Am. Chem.
Soc. 2017, 139, 13989.
(3) Han, W. B.; Lu, Y. H.; Zhang, A. H.; Zhang, G. F.; Mei, Y. N.;
Jiang, N.; Lei, X.; Song, Y. C.; Ng, S. W.; Tan, R. X. Curvulamine, a
New Antibacterial Alkaloid Incorporating Two Undescribed Units
from a Curvularia Species. Org. Lett. 2014, 16, 5366.
(4) Han, W. B.; Zhang, A. H.; Deng, X. Z.; Lei, X.; Tan, R. X.
Curindolizine, an Anti-Inflammatory Agent Assembled via Michael
Addition of Pyrrole Alkaloids Inside Fungal Cells. Org. Lett. 2016, 18,
1816.
(5) Dai, G. Z.; Han, W. B.; Mei, Y. N.; Xu, K.; Jiao, R. H.; Ge, H. M.;
Tan, R. X. Pyridoxal-5′-phosphate−dependent bifunctional enzyme
catalyzed biosynthesis of indolizidine alkaloids in fungi. Proc. Natl.
Acad. Sci. U. S. A. 2020, 117, 1174.
(6) The nature of the nitrogen nucleophile which opens the epoxide
is unclear. Whether the pyrrole is made before or after this event is
not known. Compound 17 also represents a postulate, not isolated,
intermediate.
(19) Compounds 43−45 were also prone to aromatization, forming
an indolizine heterocycle under slightly acidic conditions.
(20) Jones, G.; Radley, P. M. Azonia-azulene salts. Part 5. Synthesis
of 5H-pyrrolo[1,2-a]azepine and of 7H-pyrrolo[1,2-a]azepin-7-one. J.
Chem. Soc., Perkin Trans. 1 1982, 1123.
(21) Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Pd-
Catalyzed α-Arylation of Trimethylsilyl Enol Ethers with Aryl
Bromides and Chlorides: a Synergistic Effect of Two Metal Fluorides
as Additives. Angew. Chem., Int. Ed. 2006, 45, 5852.
(22) Flitsch, W.; Hohenhorst, M. Eine einfache Synthese des 3a-
Azaazulen-6-ons. Liebigs Ann. Chem. 1988, 1988, 275.
(23) Wittenberg, R.; Srogl, J.; Egi, M.; Liebeskind, L. S. Ketone
Synthesis Under Neutral Conditions. Cu(I) Diphenylphosphinate-
Mediated, Palladium-Catalyzed Coupling of Thiol Esters and
Organostannanes. Org. Lett. 2003, 5, 3033.
(24) The Robinson annulation favors 5-membered (pyrrolizine) ring
formation as shown below:
(7) Haelsig, K. T.; Xuan, J.; Maimone, T. J. Total Synthesis of
(−)-Curvulamine. J. Am. Chem. Soc. 2020, 142, 1206.
(8) For inspiration, see: (a) Northrup, A. B.; Macmillan, D. W. C.
Two-step Synthesis of Carbohydrates by Selective Aldol Reactions.
Science 2004, 305, 1752−5. (b) Gati, W.; Yamamoto, H. A highly
diastereoselective “super silyl” governed aldol reaction: synthesis of α,
β-dioxylaldehydes and 1,2,3-triols. Chem. Sci. 2016, 7, 394.
(9) See the Supporting Information for synthetic preparation
(10) These compounds were quite sensitive to silica gel purification
and the individual isomers could not be separated by careful
chromatography.
(11) For the addition of a silyl ketene thioacetal to an azafulvenium
ion, see ref 2b.
(12) In a model study lacking the pyrrole C2 methyl group, we
advanced compound 25 along similar lines as 28 (see SI for synthetic
details). Upon unveiling the free pyrrole nitrogen, we found the
product (see F1 below) exists as a stable hemiaminal that also
thwarted cyclization attempts.
(25) Several plausible mechanisms can be envisioned for the
cyclization of 65 to 66 including conjugate addition/elimination of
the pyrrole anion of (Z)-65 or a 10π-electrocyclization as show below.
We note that (Z)-65 has been isolated from many of the cyclization
reaction mixtures.
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(26) While 63 and 64 could be directly converted into 66 in a single
step using NaOt-Bu in THF (∼30% yield on 0.5 mmol scale), this
reaction afforded only ∼10% yield on a gram scale.
(27) This selectivity was only observed under conditions employing
a weakly bound potassium counterion (KHMDS) and highly polar
additive (HMPA). Although somewhat unstable, products tentatively
arising from C9 attack were observed in initial experiments using
LHMDS as base in THF (without HMPA). C5 selectivity (over C9)
cannot be rationalized by the LUMO orbital coefficients of 66, or
steric effects, but the natural charge (and Mulliken charge) of C5 is
positive, while the C1 and C9 carbons are negative, suggesting the
importance of Coulombic factors in this process.
(28) Krasovskiy, A.; Kopp, F.; Knochel, P. Soluble Lanthanide Salts
(LnCl3•2LiCl) for the Improved Addition of Organomagnesium
Reagents to Carbonyl Compounds. Angew. Chem., Int. Ed. 2006, 45,
497.
(35) (a) Hung, K.; Condakes, M. L.; Morikawa, T.; Maimone, T. J.
Oxidative Entry into the Illicium Sesquiterpenes: Enantiospecific
Synthesis of (+)-Pseudoanisatin. J. Am. Chem. Soc. 2016, 138, 16616.
(b) Hung, K.; Condakes, M. L.; Novaes, L. F. T.; Harwood, S. J.;
Morikawa, T.; Yang, Z.; Maimone, T. J. Development of a Terpene
Feedstock-based Oxidative Synthetic Approach to the Illicium
Sesquiterpenes. J. Am. Chem. Soc. 2019, 141, 3083.
(36) A possible mechanism for decomposition under basic
conditions initiates with α-deprotonation of the ester followed by
E1cB elimination of the pyrrole. The first step is supported by the
observation that isolated acid 94 has underwent epimerization.
(37) Barton, D. H. R.; Crich, D.; Motherwell, W. B. The Invention
of New Radical Chain Reactions. Part VIII. Radical Chemistry of
Thiohydroxamic Esters; A New Method for the Generation of Carbon
Centered Radicals from Carboxylic Acids. Tetrahedron 1985, 41,
3901.
(38) (a) Hu, X.; Maimone, T. J. Four-step Synthesis of the
Antimalarial Cardamom Peroxide via an Oxygen Stitching Strategy. J.
Am. Chem. Soc. 2014, 136, 5287. (b) Hu, X.; Lim, P.; Fairhurst, R.;
Maimone, T. J. Synthesis and Study of the Antimalarial Cardamom
Peroxide. Tetrahedron 2018, 74, 3358. (c) Hu, X.; Musacchio, A.;
Shen, X.; Tao, Y.; Maimone, T. J. Allylative Approaches to the
Synthesis of Complex Guaianolide Sesquiterpenes from Apiaceae and
Asteraceae. J. Am. Chem. Soc. 2019, 141, 14904.
(39) (a) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, D.
S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, M.;
Baran, P. S. Decarboxylative Borylation. Science 2017, 356, eaam7355.
(b) Candish, L.; Teders, M.; Glorius, F. Transition-Metal-Free,
Visible-Light Enabled Decarboxylative Borylation of Aryl N-
Hydroxyphthalimide Esters. J. Am. Chem. Soc. 2017, 139, 7440.
(c) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.;
Aggarwal, V. K. Photoinduced decarboxylative borylation of
carboxylic acids. Science 2017, 357, 283.
(29) Wang, J.; Shang, M.; Lundberg, H.; Feu, K. S.; Hecker, S. J.;
Qin, T.; Blackmond, D. G.; Baran, P. S. Cu-Catalyzed Decarboxylative
Borylation. ACS Catal. 2018, 8, 9537.
(30) It would appear this stereocenter enforces distinct precycliza-
tion conformations.
(31) (a) Baran, P. S.; Richter, J. M.; Lin, D. W. Direct coupling of
pyrroles with carbonyl compounds: short enantioselective synthesis of
(S)-ketorolac. Angew. Chem., Int. Ed. 2005, 44, 609. (b) Maimone, T.
J.; Ishihara, Y.; Baran, P. S. Scalable total syntheses of (−)-hapalindole
U and (+)-ambiguine H. Tetrahedron 2015, 71, 3652. (c) Richter, J.
M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.;
Baran, P. S. Scope and Mechanism of Direct Indole and Pyrrole
Couplings Adjacent to Carbonyl Compounds: Total Synthesis of
Acremoauxin A and Oxazinin 3. J. Am. Chem. Soc. 2007, 129, 12857.
(32) For related transformations, see: (a) Artis, D. R.; Cho, I.-S.;
Muchowski, J. M. Radical-based syntheses of 5-benzoyl-1,2-dihydro-
3H-pyrrolo[l,2-a]pyrrole-l-carboxylic acid (ketorolac)1 Can. J. Chem.
1992, 70, 1838. (b) Baciocchi, E.; Muraglia, E.; Sleiter, G. Homolytic
Substitution Reactions of Electron-Rich Pentatomic Heteroaromatics
by Electrophilic Carbon-Centered Radicals. Synthesis of α-Hetero-
arylacetic Acids. J. Org. Chem. 1992, 57, 6817. (c) Baciocchi, E.;
Muraglia, E. Homolytic Aromatic Substitutions of Pentatomic
Heteroaromatics with Electrophilic Carbon Radicals Generated by
Alkyl Halides and Triethylborane. Tetrahedron Lett. 1993, 34, 5015.
(d) Byers, J. H.; Duff, M. P.; Woo, G. W. A one-step radical synthesis
of pyrrol-2-acetic acids. Tetrahedron Lett. 2003, 44, 6853. (e) Byers, J.
H.; DeWitt, A.; Nasveschuk, C. G.; Swigor, J. E. Tandem radical-
electrophilic annulations to pyrrole. Tetrahedron Lett. 2004, 45, 6587.
(f) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Enantioselective Organocatalysis Using
SOMO Activation. Science 2007, 316, 582. (g) Furst, L.; Matsuura,
B. S.; Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Visible
Light-Mediated Intermolecular C−H Functionalization of Electron-
Rich Heterocycles with Malonates. Org. Lett. 2010, 12, 3104.
(h) Tucker, J.W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson,
C. R. J. Electron Transfer Photoredox Catalysis: Intramolecular
Radical Addition to Indoles and Pyrroles. Org. Lett. 2010, 12, 368.
(i) Boubertakh, O.; Goddard, J.-P. Construction and Functionaliza-
tion of Heteroarenes by Use of Photoredox Catalysis. Eur. J. Org.
Chem. 2017, 2017, 2072.
(40) Steves, J. E.; Stahl, S. S. Copper(I)/ABNO-Catalyzed Aerobic
Alcohol Oxidation: Alleviating Steric and Electronic Constraints of
Cu/TEMPO Catalyst Systems. J. Am. Chem. Soc. 2013, 135, 15742.
(41) Watanabe, E.; Kaiho, A.; Kusama, H.; Iwasawa, N. Cobalt−
Salen Complex-Catalyzed Oxidative Generation of Alkyl Radicals
from Aldehydes for the Preparation of Hydroperoxides. J. Am. Chem.
Soc. 2013, 135, 11744.
(42) Beak, P.; Reitz, D. B. Dipole-Stabilized Carbanions: Novel and
Useful Intermediates. Chem. Rev. 1978, 78, 275.
(43) For a recent review, see: Mattalia, J.-M. R. The reductive
decyanation reaction: an overview and recent developments. Beilstein
J. Org. Chem. 2017, 13, 267.
(44) For seminal work on the generation of cyanohydrin anions and
their use in conjugate addition chemistry, see: (a) Stork, G.;
Maldonado, L. Anions of Protected Cyanohydrins as Acyl Carbanion
Equivalents and Their Use in a New Synthesis of Ketones. J. Am.
Chem. Soc. 1971, 93, 5286. (b) Stork, G.; Maldonado, L. Conjugate
Addition of Acyl Carbanion Equivalents via the Protected
Cyanohydrin Method. J. Am. Chem. Soc. 1974, 96, 5272.
(45) Interestingly, the liberated pyrrole anion was found to add to
66. In addition, dimer 100 was also formed under these conditions.
(46) For reviews, see: (a) 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. (b) Helal,
C. J.; Meyer, M. P. The Corey−Bakshi−Shibata Reduction:
Mechanistic and Synthetic ConsiderationsBifunctional Lewis Base
Catalysis with Dual Activation. In Lewis Base Catalysis in Organic
Synthesis; Vedejs, E., Denmark, S. E., Eds.; Wiley: New York, 2016;
Ch. 11, p 387.
(33) Hawkins, E. G. E.; Young, D. P. Reactions of Organic
Peroxides. Part V. Reaction of Ferrous Sulphate with Methylcyclo-
pentyl and Methylcyclohexyl Hydroperoxides. J. Chem. Soc. 1950,
2804.
(34) We also explored the use of the minor diastereomer of 87.
While this compound could be advanced to diast-88 and then F2 (see
below), we were unable to forge the bridging ether shown below by
direct C−H etherification.
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(47) For a review on stereodivergent reactions of racemic mixtures,
see: Miller, L. C.; Sarpong, R. Chem. Soc. Rev. 2011, 40, 4550.
(48) For a closely related example in total synthesis, see: Kurosu, M.;
Kishi, Y. A Novel Example for Optical Resolution of Racemic Ketones
Originating from Batrachotoxin Synthesis. J. Org. Chem. 1998, 63,
6100.
(49) Treating 1 with NBS for example leads to dibromination of the
alkene and not bromination of the desired pyrrole. These addition
products are also highly unstable and could not be manipulated
further.
(50) A number of additional reaction manifolds, including cuprate
conjugate addition, Heck reaction, and Hayashi−Miyaura coupling,
were explored to couple the fragments below but were uniformly
unsuccessful.
(51) In addition to successfully completing the total synthesis of 2,
an X-ray crystal structure of the samarium iodide reduction product of
isomer 127 was obtained (see diast-129 below) and allowed us to
deduce which isomer to carry forward.
(52) Baran, P. S.; Maimone, T. J.; Richter, J. M. Total Synthesis of
Marine Natural Products Without Using Protecting Groups. Nature
2007, 446, 404.
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