Journal of the American Chemical Society
Article
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 heterocyclesare 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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J. Am. Chem. Soc. 2021, 143, 2970−2983