A convenient C–H functionalization platform for pyrroloiminoquinone alkaloid synthesis

Article abstract of DOI:10.1016/j.tet.2019.05.009

Pyrroloiminoquinone alkaloids represent a structurally intriguing class of natural products that display an array of useful biological properties. Here, we present a versatile and scalable platform for the synthesis of this diverse family – and in particular the antitumor discorhabdins – built upon sequential selective C–H functionalization of tryptamine. The utility of this strategy is showcased through short formal syntheses of damirones A–C, makaluvamines D and I, and discorhadbin E. Additionally, we describe efforts to develop the first catalytic asymmetric entry to the discorhabdin subclass.

Full text of DOI:10.1016/j.tet.2019.05.009

Accepted Manuscript
A convenient C–H functionalization platform for pyrroloiminoquinone alkaloid
synthesis
Myles W. Smith, Isaac D. Falk, Hideya Ikemoto, Noah Z. Burns
PII:
S0040-4020(19)30516-2
https://doi.org/10.1016/j.tet.2019.05.009
TET 30330
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2019
Revised Date: 1 May 2019
Accepted Date: 2 May 2019
Please cite this article as: Smith MW, Falk ID, Ikemoto H, Burns NZ, A convenient C–H functionalization
platform for pyrroloiminoquinone alkaloid synthesis, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2019.05.009.
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ACCEPTED MANUSCRIPT
Graphical Abstract:
[O]
O
Br
HN
O
NH2
HN
C–H Oxidation
[6 steps]
[gram scale]
N
H
N
O
N
[O]
N
H
Ts
H
O
[O]
tryptamine
Ts-damirone C
discorhabdin E

ACCEPTED MANUSCRIPT
A Convenient C–H Functionalization Platform for Pyrroloiminoquinone Alkaloid Synthesis
Myles W. Smith, Isaac D. Falk, Hideya Ikemoto and Noah Z. Burns*
Department of Chemistry, Stanford University, Stanford, California 94305, United States
Abstract: Pyrroloiminoquinone alkaloids represent a structurally intriguing class of natural products that
display an array of useful biological properties. Here, we present a versatile and scalable platform for the
synthesis of this diverse family – and in particular the antitumor discorhabdins – built upon sequential
selective C–H functionalization of tryptamine. The utility of this strategy is showcased through short
formal syntheses of damirones A–C, makaluvamines D and I, and discorhadbin E. Additionally, we
describe efforts to develop the first catalytic asymmetric entry to the discorhabdin subclass.
Alkaloids have long captured the imagination of synthetic chemists and medical practitioners alike due to
the challenge their intricate structures present and the wide array of useful biological properties often
encoded therein.1 Among this large collection of natural products, the pyrroloiminoquinone alkaloids
represent a unique subset of structural complexity. These compounds are typically isolated from marine
sources and encompass many diverse classes, such as the discorhabdins, makaluvamines, and damirones
(Figure 1), displaying antitumor, antimalarial, antiviral, antifeedant and antibacterial properties.2 Within
this larger group of alkaloids, arguably the most complex and interesting biologically are the
discorhabdins, a family of over 50 members isolated from various species of marine sponge.3 The
discorhabdins display noteworthy anticancer activities, with nanomolar cytotoxicity (IC50 often <50 nM)
being observed in vitro against a range of cancer cell lines; however, in vivo studies have proven less
promising, either due to compound instability or nonspecific cytotoxicity.3,4,5 For this reason, a flexible de
novo synthetic entry to the family would be desirable for detailed SAR studies,5 ideally allowing their
selectivity profile to be fine-tuned while
also
providing
access
to
related
pyrroloiminoquinone targets.
Structurally, the discorhabdins contain a
unique polycyclic framework, comprising a
tricyclic pyrroloiminoquinone ring system
fused to a spirodienone fragment via a
quaternary stereogenic spirocenter, as
exemplified in discorhabdin E6 (1, Figure
1). More complex members feature
additional ring systems (e.g., 4, 5) and the
class as a whole contains an impressive
array of heteroatoms, with nitrogen, sulfur,
bromine and oxygen substituents all
commonly found within the same molecule.
Of note is the particularly challenging
arrangement
of
N-atoms
in
the
pyrroloiminoquinone portion of the
molecules, which results in a highly basic
doubly vinylogous guanidinine (i.e. 7); in
fact, such substructures have typically
required more than 10 steps to construct.3
Biosynthetically, these natural products are
postulated to arise from the combination of
two amino acid-derived fragments:
tryptamine (9) and tyramine (10), which
1

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form makaluvamine-type structures (e.g., 2, Figure 1) that are in turn spirocyclized to the discorhabins
(e.g., discorhabdin C 11, Scheme 1A).3 Indeed, while there have been many creative approaches to these
molecules,7 the majority of successful synthetic efforts have followed this biomimetic blueprint. For
example, notable work from the Kita and
Heathcock groups involved synthesizing
makaluvamine-type structures 12 from simple
aromatic building blocks which are then
oxidatively spirocyclized under hypervalent
iodine(III) or aerobic copper-mediated
conditions en route to discorhabdins
C
(11),8,9,10 E (1),10 and A (4)11 (Scheme 1A).
In planning our own bioinspired approach to
these important targets, we noted two key
areas in these prior studies where significant
improvement might be possible: first, while
highly
effective
in
their
sequential
transformation of oxidized tryptamine
fragments to makaluvamine-type intermediates
to spirocyclic compounds, these routes
invested the majority of their synthetic effort
in preparation of such tryptamine frameworks,
typically via lengthy de novo sequences from
simple aromatics (Scheme 1A).8-11 Second, no
enantioselective approach to the family has
been described to date,12 meaning that a
catalytic asymmetric entry to the class could
prove especially enabling. Given our lab’s
interest in both catalytic asymmetric
halofunctionalization transformations13 and
novel synthetic strategies enabled by C–H
functionalization,14 we formulated a plan
towards one of the prototypical chiral
members of the discorhabdin family,
discorhabdin E (1). As outlined in Scheme 1B,
we hoped to set the chirality of its lone
stereocenter through the development of either
an asymmetric spirocyclization of
brominated makaluvamine-type precursor 13
(X Br) or via brominative
a
=
a
desymmetrization of achiral spirodienone 14,
also available from a similar precursor (13, X
= H). We postulated that 13 could be formed
through a condensation reaction between an
appropriate tyramine partner 10A and an
orthoquinone tricycle 3A, encompassing the
framework of the natural product damirone C15 (3). In contrast to the relatively lengthy prior syntheses of
tricycles of type 3A,16 we sought to streamline our preparation of this key fragment by beginning with the
readily available, unsubstituted tryptamine scaffold, and simply installing the necessary carbon–
heteroatom bonds through selective C–H oxidations. Importantly, 3A could also serve as a versatile
intermediate for accessing other classes of pyrroloiminoquinone alkaloids (see Figure 1). Herein, we
2

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report the execution of this plan, resulting in convenient, scalable access to such an intermediate, along
with our efforts to develop the first catalytic asymmetric entry to the discorhabdins as a prelude to
optimizing their antitumor properties.
Our route began with the quantitative N-Boc-protection of tryptamine (9), followed by the application of a
modified one-pot C–H diborylation/monodeborylation procedure under Ir- and Pd-catalysis, developed by
Movassaghi and co-workers (Scheme 2).17 This process proceeds via diborylated intermediate 15 and
achieves the net installation of a C-7 Bpin substituent, which could be easily transformed to the
corresponding phenol through treatment with alkaline H2O2 to deliver 17 in 56% overall yield from
tryptamine. This sequence proved highly scalable and was reliably conducted on decagram quantities of
17 with little variation in yield. With a C-7 phenol in place, selective oxidation to the corresponding
orthoquinone 18A with IBX proceeded effectively,18 with this being the first demonstration of this
process in an indole setting to the best of our knowledge. Although precedent exists for cyclization of
tryptamine orthoquinones similar to 18A under basic aerobic conditions,16b-d,f our efforts to cyclize the
corresponding amine salts (available from acidic N-Boc deprotection), routinely resulted in extensive
decomposition, with no damirone C (3) being isolated. We found, however, that protection of the indole
nitrogen of 18A with a tosyl group (62% over two steps from phenol 17) gave a material (18B) that could
be cleanly converted to tricycle 19 in 48% yield by treatment with TFA, evaporation of the volatiles, and
exposure to Et3N in MeOH under air.19 This protocol can reliably be conducted on gram scale, and to date
we have prepared over 2.5 g of 19. Indeed, the synthesis of 19 in 6 steps and 15% overall yield from
tryptamine represents the shortest preparation of this material to date (15 steps previously),16a and also
constitutes the formal synthesis of several pyrroloiminoquinone alkaloids including damirones A–C and
makaluvamines D and I.16 Furthermore, we found that 19 could be condensed with tyramine fragments 10
and 10A under mild conditions to give makaluvamine-type compounds 2A and 20 in 71 and 29% yield,
respectively (Scheme 3). In these reactions, careful control of reaction time and purification was
important for maximizing material throughput; even so, achieving high conversions in the brominated
series proved unexpectedly challenging. We observed that longer reaction times led to competitive
degradation of both 20 and its condensation product. One such identified pathway was transfer of the
toluenesulfonyl group from the indole nitrogen to the primary amine.20
While the preparation of 20 constituted a racemic formal synthesis of discorhabdin E (1),10 we aimed to
provide an asymmetric entry to the family. It should be noted, however, that the properties of compounds
post condensation rendered the development of such a process challenging, with the basic and
heteroatom-rich scaffolds limiting the choice of strategies or, in the case of polar salt forms of 20 (and
3

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21), solvents. While our initial
efforts focusing on an
asymmetric spirocyclization
of 2A and 20 were largely
unfruitful, explorations of a
brominative desymmetrization
approach on spirodienone 21
proved more rewarding. This
material was reliably prepared
in 74% yield by treatment of
2A under conditions of Kita et
al. employing PIFA and
Montmorillonite K-10 clay in
2,2,2-trifluoroethanol.11
Although the aerobic Cu-
based
Heathcock
conditions10
and
of
Aubart
provided high yields of 21 on
small scale (<50 mg of 2A), in
our hands their method proved
much less effective on scale-
up. Initial attempts at effecting
the desired bromination of 21
showed that this could be
readily accomplished in a
racemic sense using n-
Bu4NBr3 (66% yield of rac-
1A). In contrast, achieving an analogous enantioselective transformation proved challenging. For
example, while explorations in a model system showed organocatalytic methods to be viable, the
complications inherent to the structure of 21 (either as its TFA salt or free base) led to no productive
reactivity. Efforts to condense chiral auxiliaries such as (S)-1-amino-2-methoxymethylpyrrolidine
(SAMP) onto the ketone were unfortunately unsuccessful. Similarly, attempted bromination of chiral salt
forms of 21 (formed from 21 and an equivalent amount of chiral phosphoric acid) delivered the desired
product in poor yield and with no enantioselectivity.
Given these failures, we then proceeded to explore Baylis–Hillman-type brominations with an appropriate
combination of nucleophile and brominating reagent. Inspired by a recent report by Feng and co-workers
on the asymmetric haloazidation of acyclic enones,21 we found in initial trials that the combination of
TMS azide and NBS as nucleophile and bromonium source, respectively, in the presence of a catalytic
amount of Sc(OTf)3 delivered rac-1A directly (34%, 43% 21 recovered) without isolation of the
intermediate bromoazide. We then proceeded to test various combinations of Lewis acidic metals and
chiral ligands (see SI for details) in this process. Among the many systems screened, we ultimately found
that treatment of 21 with TMS azide and NBS in the presence of a combination of Sc(OTf)3 and chiral
N,N’-dioxide ligand 2222 (30 mol% of each) in CH2Cl2 at –30 °C with 4Å MS provided the desired
bromoenone 1A in 23% yield and 33% ee. The use of other Br+ sources (e.g. NBA, DBDMH, TBCHD,
BsNMeBr; for a complete list, see Supporting Information), nucleophiles (TsNH2, p-NsNH2)23 and
various solvents did not improve the enantioinduction (see SI for full details). While the selectivity
achieved to date is admittedly moderate, it is important to note that this nevertheless represents the first
catalytic asymmetric inroad towards the discorhabdin family, hinting at the challenge posed by their
unique scaffolds.
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In summary, we have described a short and scalable entry to the pyrroloiminoquinone alkaloids via a key
tricyclic intermediate, available through a series of selective C–H functionalization reactions on the parent
tryptamine framework. Through this synthetic platform we have achieved concise formal syntheses of
damirones A–C, makaluvamines D and I, and discorhadbin E. Finally, we have disclosed our preliminary
efforts toward a catalytic asymmetric solution to the discorhabdin alkaloids, providing the key spirocycle
of discorhadbin E with moderate enantioselectivity. It is our hope that the tools and strategies presented
herein will prove useful in future synthetic endeavors toward this broad class of bioactive alkaloids.
Acknowledgments: This work was supported by Stanford University and the National Institutes of Health
(R01 GM114061). We are grateful to Dr. S. Lynch (Stanford University) for assistance with NMR
spectroscopy.
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1
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chromatogaphed 17 performed better in the subsequent condensation reactions.
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7