Expeditious and Divergent Total Syntheses of Aspidosperma Alkaloids Exploiting Iridium(I)-Catalyzed Generation of Reactive Enamine Intermediates

Article abstract of DOI:10.1002/anie.201605503

A new approach for the divergent total syntheses of (±)-vincaminorine, (±)-N-methylquebrachamine, (±)-quebrachamine, (±)-minovine and (±)-vincadifformine, each in less than 10 linear steps starting from a single δ-lactam building block, is reported. Key to our route design is the late-stage generation of reactive enamine functionality from stable indole-linked δ-lactams via a highly chemoselective iridium(I)-catalyzed reduction. The efficiently formed secodine intermediates subsequently undergo either a formal Diels–Alder cycloaddition or a competitive Michael addition/reduction to access aspidosperma-type alkaloids in excellent diastereoselectivities. Product selectivity could be controlled by changing the indole N-protecting group in the reductive cyclization precursors. An asymmetric variant of this synthetic strategy for the synthesis of (+)-20-epi-ibophyllidine is also described.

Full text of DOI:10.1002/anie.201605503

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605503
German Edition: DOI: 10.1002/ange.201605503
Alkaloid Synthesis
Expeditious and Divergent Total Syntheses of Aspidosperma Alkaloids
Exploiting Iridium(I)-Catalyzed Generation of Reactive Enamine
Intermediates
Peng Wen Tan, Jayasree Seayad,* and Darren J. Dixon*
Abstract: A new approach for the divergent total syntheses of
(Æ)-vincaminorine, (Æ)-N-methylquebrachamine, (Æ)-que-
brachamine, (Æ)-minovine and (Æ)-vincadifformine, each in
less than 10 linear steps starting from a single d-lactam building
block, is reported. Key to our route design is the late-stage
generation of reactive enamine functionality from stable
indole-linked d-lactams via a highly chemoselective iridium-
(I)-catalyzed reduction. The efficiently formed secodine inter-
mediates subsequently undergo either a formal Diels–Alder
cycloaddition or a competitive Michael addition/reduction to
access aspidosperma-type alkaloids in excellent diastereose-
lectivities. Product selectivity could be controlled by changing
the indole N-protecting group in the reductive cyclization
precursors. An asymmetric variant of this synthetic strategy for
the synthesis of (+)-20-epi-ibophyllidine is also described.
skeletally distinct scaffolds.[4] Similarly, Movassaghi et al.
demonstrated a versatile double-cyclization strategy that
generated a complex diiminium ion intermediate that could
be readily converted into a series of related aspidosperma
alkaloids.[5] Furthermore, MacMillan et al. developed an
organocatalytic route to access an enantioenriched tetracyclic
spiroindoline molecular scaffold, and from it elegantly
diversified to a series of common alkaloid natural products.[6]
Stimulated by these well-designed and well-executed
approaches, we set out to devise a synthetic route that could
furnish a range of related, yet structurally diverse, mono-
terpene indole alkaloid natural products from easily acces-
sible substrates in a concise fashion. In particular, we were
attracted to the possibility of generating and trapping reactive
enamine intermediates from stable lactam substrates via
a chemoselective partial reduction/elimination sequence. Our
hope was that the enamine could act as an electron-rich
nucleophile/dienophile and be readily intercepted by a strate-
gically placed diene to afford pentacyclic natural products
such as minovine and vincadifformine via a formal Diels–
Alder reaction. Recent work from our group had indeed
demonstrated the feasibility of generating and trapping
reactive iminium ions—via enamine intermediates—from
nitroalkyl-linked lactam starting materials in a reductive
nitro-Mannich cyclization cascade using Vaskaꢀs catalyst in
the presence of a silane terminal reductant.[7,8]
Our synthetic plan was well-founded; employing enamine
derivatives as synthetic intermediates towards alkaloid natu-
ral product target molecules has been of great interest to the
synthetic community.[9] In the early 1960s, Wenkert and Scott
proposed that aspidosperma and iboga alkaloids were bioge-
netically derived from enamine intermediates, via intramo-
lecular Diels–Alder type reactions.[10] This hypothesis was
subsequently supported by labelling experiments and various
synthetic approaches that employed the high reactivity of the
secodine intermediate (Int 1, Figure 1) formed in situ from
acyclic precursors to obtain the aspidosperma alkaloids such
as vincadifformine.[11]
M
onoterpene indole alkaloids are a diverse class of natural
products that is comprised of at least 2000 members. They
possess inherent structural complexity and a range of
important biological activities that qualifies a number of
them to be ideal candidates for anti-cancer, anti-malarial and
anti-arrhythmic agents.[1] As a result, these natural products
have inspired the synthetic community to devise innovative
and elegant approaches that allow their efficient synthesis.[2]
Interestingly, and despite the many successful synthetic
approaches already reported, recent efforts have shifted
towards demonstrating unified, general and concise strategies
that enable collective syntheses of a range of structurally
related natural products. For example, Zhu and co-workers
reported an elegant approach that involved the synthesis of
cyclopentene intermediates which would then undergo an
integrated oxidation/reduction/cyclization (iORC) sequence
to access a range of monoterpene indole alkaloids.[3] Oguri
and co-workers established an artificial divergent synthesis
that allowed access to ene-yne substrates that underwent
a dihydropyridine (DHP) cyclization to a key intermediate
that could be transformed into terpenoid indole alkaloids of
Herein we wish to report a new strategy which provides
a short and divergent synthetic route to several vincadiffor-
mine-type, quebrachamine-type and iboga-type alkaloids.
Our new approach features a key late-stage generation of
reactive enamine functionality from stable indole-linked d-
lactams via a highly chemoselective iridium(I) catalyzed
reduction.
(Æ)-Minovine (4) was chosen as our initial synthetic
target. The synthesis of the key lactam intermediate 16 began
with alkylation of 3-ethyl-2-piperidone 6 with 1,4-dibromo-
butane to furnish lactam 7 (Scheme 1). The N-linked alkyl-
[*] P. W. Tan, Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
12 Mansfield Road, Oxford (UK)
E-mail: darren.dixon@chem.ox.ac.uk
P. W. Tan, Dr. J. Seayad
Organic Chemistry, Institute of Chemical and Engineering Sciences
8 Biomedical Grove, Neuros, #07-01, Singapore 138665 (Singapore)
E-mail: jayasree_seayad@ices.a-star.edu.sg
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201605503.
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bromide was then readily converted to its corresponding
aldehyde 8 via a Kornblum oxidation.[12] The construction of
the indole functionality proceeded successfully by Storkꢀs
modification of the Fischer indole synthesis[13] of aldehyde 8
with phenylhydrazine·HCl. After methylating the indolyl
nitrogen to afford 10, Stephensonꢀs photoredox-catalyzed
À
direct C H functionalization at C2 of the indole adduct 10
with benzyl methyl bromomalonate occurred smoothly to
obtain 13 in 82% yield.[14] Finally, debenzylation of the benzyl
ester via Pd-catalyzed hydrogenolysis, followed by a decar-
boxylative Mannich reaction gave the desired enamine
precursor—stable lactam 16—in 55% yield over two steps.
With the desired indole-linked lactam 16 in hand, the key
Ir-catalyzed reduction–cycloaddition sequence was investi-
gated. To our delight, the chemoselective Ir-catalyzed reduc-
tion of the lactam moiety in the presence of the a,b-
unsaturated ester occurred smoothly to give the correspond-
ing enamine (Int B), via presumed siloxy intermediate (Int
A),[15] as confirmed by 1H NMR spectroscopy. On the basis of
Wenkertꢀs hypothesis, this reactive secodine intermediate was
expected to undergo a formal Diels–Alder reaction via a two-
stage intramolecular enamine conjugate addition on the
acrylate moiety followed by a transannular Mannich reaction
of the iminium species (Int C) to form (Æ)-minovine (4)
(Scheme 2).[16] However, during our initial attempts no
observable (Æ)-minovine (4) was detected under ambient
reaction conditions. We anticipated that the addition of
a Lewis acid or hydrogen bond-donor promoter would
enhance the electrophilicity of the acrylate moiety to
facilitate the nucleophilic addition step (see the Supporting
Information for details). Pleasingly, it was observed that the
addition of silica gel[17] facilitated the direct formation of the
target alkaloid, (Æ)-minovine (4). Serendipitously, another
skeletally distinct alkaloid, (Æ)-vincaminorine (1) was also
formed as a single diastereomer in the reaction vessel (4:1 =
1.7: 1.0, combined yield = 83%). Presumably (Æ)-vincami-
norine (1) was formed by a competing Ir-catalyzed reduction
of the iminium intermediate (Int C) resulting from the initial
Michael addition of the enamine to the a,b-unsaturated ester.
In 1968, Wigfield and co-workers[18] postulated a biosynthetic
sequence that invoked a common secodine type enamine
intermediate as the source of quebrachamine-type and
vincadifformine-type alkaloids via independent pathways.
To the best of our knowledge, this here is the first evidence
demonstrating the feasibility of such a sequence to form
divergently these alkaloids from a common enamine inter-
mediate. Furthermore, from a synthetic viewpoint, such an
enamine Michael addition/reduction sequence in a single pot
is also the first example of its kind. Thus the results of this
intriguing one-pot reaction sequence not only support the
hypothesis of the secodine intermediate undergoing a formal
Diels–Alder cycloaddition reaction pathway to give vincadif-
formine-type alkaloids but also provide invaluable insights
into its stepwise nature and the potential biogenesis of
skeletally distinct quebrachamine-type alkaloids. Due to the
lack of full characterization data available in the literature,
the stereochemical configuration of the (Æ)-vincaminorine
(1) was unambiguously determined by single-crystal X-ray
diffraction. (Æ)-Vincaminorine (1) was further treated with
Figure 1. Divergent synthesis of aspidosperma-type alkaloids via Ir-
catalyzed reductive generation of reactive enamine intermediates from
lactams.
Scheme 1. Synthesis of lactam 16, 17 and 18: a) NaH, 1,4-dibromobu-
tane, THF:DMF (5:1), RT, 18 h, 80%; b) NMO, DMSO, RT, 18 h, 60%;
c) Phenylhydrazine, HCl, 4% H2SO4(aq)/DMA (1:1), 1108C, 2 h, 62%;
d) MeI, NaH, THF, RT, 3 h, 95%; e) MOMCl, NaH, THF:DMF (2:1),
08C, 2 h, 89%; f) Boc2O, NEt3, DMAP, CH2Cl2, RT, 1.5 h, 95%; g) [Ru-
(bpy)3]Cl2, 1-benzyl-3-methyl-2-bromomalonate, 4-methoxyphenylamine,
blue LEDs, DMF, RT, 12 h, 13: 82%; 14: 66%; 15: 89%; h) Pd/C, H2,
=
EtOH, RT, 1 h; i) CH2 O, HNMe2. HCl, NaOAc, AcOH, RT, 4 h, 16:
55%; 17: 55%; 18: 82% (over 2 steps).
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Scheme 3. Divergent synthesis of (Æ)-quebrachamine (3) and (Æ)-
vincadifformine (5): l) IrCl(CO)(PPh3)2 (1 mol%), TMDS (2 equiv),
toluene, RT, 10 min, subsequent addition of SiO2, À788C to 08C to RT,
2 h, (20): 14%, (19): 52%; m) 3n HCl, MeOH, 558C, 48 h, 71%;
n) 1n HCl, MeOH, RT, 20 min, 84%; o) TFA, Me2S, CH2Cl2, RT, 1 h;
p) IrCl(CO)(PPh3)2 (1 mol%), TMDS (2 equiv), toluene, RT, 1 h, 44%
(over 2 steps).
Scheme 2. Divergent synthesis of (Æ)-vincaminorine (1), (Æ)-minovine
(4) and (Æ)-N-methylquebrachamine (2): j) IrCl(CO)(PPh3)2 (1 mol%),
TMDS (2 equiv), toluene, RT, 10 min, subsequent addition of SiO2,
À788C to RT, 1 h, (4): 52%, (1): 31%; k) 6n HCl, 908C, 2 h, 61%.
examine if the absence of a protecting group (P) on the
indolyl nitrogen would also influence the outcome of the
reaction.[19] Consequently, the unprotected precursor 21 was
synthesized from 18 by treatment with trifluoroacetic acid.
(Scheme 3). As the lactam 21 was relatively unstable towards
attempted chromatographic purification, it was then imme-
diately subjected to the Ir-catalyzed reduction conditions. In
this case however, the reaction proceeded directly—without
the addition of any silica gel mediator—to give exclusively the
formal Diels–Alder product, (Æ)-vincadifformine (5), with
a yield of 44% over 2 steps. Overall, this study demonstrated
that manipulation of the intrinsic electron density of the
indole moiety through varying the substituent on the indolyl
nitrogen atom could influence the selectively of the reductive
cyclization cascade towards either the vincadifformine-type
alkaloids or quebrachamine-type alkaloids.
Finally, the versatility of our synthetic strategy was further
demonstrated by expanding its scope towards the synthesis of
enantiomerically pure monoterpene indole alkaloid, (+)-20-
epi-ibophyllidine,[11e,h,k] beginning with the g-lactam derivative
(S)-5-ethylpyrrolidin-2-one, 23 (Scheme 4). Thus, 23 was
converted into the stable lactam intermediate 29 by similar
synthetic steps to those described in Scheme 1 (see the
Supporting Information for details). Subsequent N-Boc
deprotection of 29 to the precursor 30 followed by the Ir-
catalyzed reduction proceeded smoothly without the aid of
any silica gel promoter, to generate the formal Diels–Alder
product, (+)-20-epi-ibophyllidine as a single diastereomer.
6n HCl (aq) to undergo acid hydrolysis/ decarboxylation to
furnish (Æ)-N-methylquebrachamine (2).
Thereafter, our attention shifted to generating non-
methylated aspidosperma-type alkaloids by applying the
same synthetic strategy to MOM-protected lactam intermedi-
ate 17 (Scheme 3). The synthesis of 17 was straightforward
and although the key transformation, the Ir-catalyzed reduc-
tion to attain the secodine intermediate, proceeded without
incident, it is interesting to note that the Michael addition/
iminium reduction product 19 was obtained in larger propor-
tion than the formal Diels–Alder cycloaddition product 20
(19:20 = 3.7:1.0) (Scheme 3). Subsequent treatment of prod-
uct 19 and 20 with dilute hydrochloric acid generated (Æ)-
quebrachamine (3) and (Æ)-vincadifformine (5) with 71%
and 84% yields, respectively.
The changing selectivity between the formal Diels–Alder
product and the Michael addition/ reduction product as
a result of the nature of substituent on the indolyl nitrogen
was interesting and synthetically relevant. The results sug-
gested that decreasing the electron density of the indole
moiety reduced the rate of second cyclization relative to
reduction by hydride. To probe this further, we proceeded to
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Scheme 4. Synthesis of (+)-20-epi-ibophyllidine: q) TFA, Me2S, CH2Cl2,
RT, 1 h; r) IrCl(CO)(PPh3)2 (1 mol%), TMDS (2 equiv), toluene, RT,
1 h, 40% (over 2 steps).
In conclusion, we have developed an expeditious and
divergent reaction sequence to aspidosperma-type alkaloids
(Æ)-vincaminorine, (Æ)-N-methylquebrachamine, (Æ)-que-
brachamine, (Æ)-minovine and (Æ)-vincadifformine in excel-
lent diastereoselectivities. Strategically, the route relied on
the late-stage generation of reactive enamine functionality
from stable indole-linked delta lactams via a highly chemo-
selective iridium(I)-catalyzed reduction. This secodine inter-
mediate could subsequently undergo either a formal Diels–
Alder cycloaddition or Michael addition/reduction to provide
the target products. This study demonstrated that subtle
modifications of the indole lactam precursors could control
the preference of the secodine intermediate to undergo either
of the two reaction pathways. Furthermore, we have demon-
strated the versatility of our synthetic approach by applying it
to an asymmetric synthesis of iboga-type alkaloid (+)-20-epi-
ibophyllidine, starting from g-lactam, (S)-5-ethylpyrrolidin-2-
one 23. Investigations into the development of an enantiose-
lective variant of this iridium(I)-catalyzed reductive cycliza-
tion sequence are currently ongoing and will be disclosed in
due course.
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Acknowledgements
We acknowledge the University of Oxford and the Agency for
Science, Technology and Research (A*STAR) Singapore for
a predoctoral fellowship.
Keywords: aspidosperma alkaloid · enamine ·
iridium catalyzed reduction · lactam · total synthesis
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same Ir-catalyzed reduction conditions (see the Supporting
Information for details). In this case only 13% of reductive
cyclization product 22 was obtained; the remainder of the mass
was largely over-reduced lactam and importantly no formal
Diels–Alder product was observed.
[16] Concerted Diels–Alder reaction pathway cannot be ruled at this
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Received: June 6, 2016
Revised: August 18, 2016
Published online: && &&, &&&&
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Communications
Alkaloid Synthesis
Which way to go? A novel synthetic
strategy for the divergent synthesis of
different classes of aspidosperma alka-
loids is described. Key step is the highly
chemoselective iridium(I)-catalyzed
reduction of cyclic lactams to enamine
intermediates, followed by either a highly
diastereoselective formal Diels–Alder
reaction or a competitive Michael addi-
tion/reduction (see scheme; two exam-
ples shown).
P. W. Tan, J. Seayad,*
D. J. Dixon*
&&&& — &&&&
Expeditious and Divergent Total
Syntheses of Aspidosperma Alkaloids
Exploiting Iridium(I)-Catalyzed
Generation of Reactive Enamine
Intermediates
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!