Total Syntheses of (?)-Minovincine and (?)-Aspidofractinine through a Sequence of Cascade Reactions

Article abstract of DOI:10.1002/anie.202004769

We report 8-step syntheses of (?)-minovincine and (?)-aspidofractinine using easily available and inexpensive reagents and catalyst. A key element of the strategy was the utilization of a sequence of cascade reactions to rapidly construct the penta- and hexacyclic frameworks. These cascade transformations included organocatalytic Michael-aldol condensation, a multistep anionic Michael-S_N2 cascade reaction, and Mannich reaction interrupted Fischer indolization. To streamline the synthetic routes, we also investigated the deliberate use of steric effect to secure various chemo- and regioselective transformations.

Full text of DOI:10.1002/anie.202004769

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Accepted Article
Title: Total Syntheses of (–)-Minovincine and (–)-Aspidofractinine Using
Chain of Cascade Reactions
Authors: Tibor Soós, Szilárd Varga, Péter Angyal, Gábor Martin,
Orsolya Egyed, and Tamás Holczbauer
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10.1002/anie.202004769
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Total Syntheses of (–)-Minovincine and (–)-Aspidofractinine Using
a Sequence of Cascade Reactions
Szilárd Varga,[a] Péter Angyal,[a] Gábor Martin,[a] Orsolya Egyed,[b] Tamás Holczbauer,[a,b] Tibor Soós*[a]
To the memory of Prof. Dr. Georg Fráter
Abstract: We report eight-step syntheses of (–)- minovincine and (–
)-aspidofractinine using easily available and inexpensive reagents
and catalyst. A key element of the strategy was the utilization of the
chain of cascade reactions to rapidly construct the penta- and
hexacyclic frameworks. These cascade transformations included
organocatalytic Michael-aldol condensation, a multistep anionic
Michael-SN2 cascade reaction and Mannich reaction interrupted
Fischer indolization. To streamline the synthetic routes, we also
investigated the deliberate use of steric effect to secure various
chemo- and regioselective transformations.
methodologies, only two enantioselective approaches have been
reported by MacMillan[8] and Nishida[9]. One rationale for this
relative paucity in synthetic routes is the shortcomings in the
existing repository of asymmetric protocols that can concisely
deliver the aspidosperma skeleton with oxidized exocyclic
functionality in position C-5.
Stimulated by the synthetic challenges of (–)-minovincine
(1), with its added (bio)synthetic potential, we devoted ourselves
to develop a concise and scalable route of (–)-minovincine (1).
Our hope was also to expand our synthetic strategy toward
topologically different, but minovincine derived natural products.
Therefore, a refractine type alkaloid was also targeted, the
hexacyclic (–)-aspidofractinine (6). As an overarching goal, we
aimed to devise streamlined synthetic routes that would
collaterally achieve greater level of “ideality”[10] and synthetic
practicality[11]. Thus, three interwoven guidelines directed our
synthetic design: (1) to implement sequence of cascade
reactions[12] for the rapid construction of the penta- and
hexacyclic frameworks (2) to minimize protecting group
manipulations and steer the selectivity of reactions by steric
effect[13] (3) to avoid exotic, toxic and expensive reagents or
catalysts.
The aspidosperma family of alkaloids continues to attract
enhanced interest owing to their medical potential and intriguing
chemical structure.[1] Their stereochemical complexities present
an intrinsic synthetic challenge and their polycyclic, cage-like
structures provide much latitude for advancing different synthetic
strategies. As a result, this class of compounds has frequently
served as a benchmark target for the development of innovative
synthetic methodologies and strategies.[2] In particular,
aspidospermanes have often provided inspiration for the
synthetic community to devise efficient catalytic approaches that
allow the stereoselective construction of quaternary carbon
stereocenters (C-5 and C-12 in Figure 1). The emerging thrust-
power of these asymmetric methodologies has not only enriched
the aspidosperma chemistry, but also enabled to pursuit concise
synthetic strategies and collective synthesis of structurally
related aspidosperma alkaloids.[3]
There is a distinct aspidosperma alkaloid, (–)-minovincine
(1), possessing a C-20 oxygenation that is not common within
this class of alkaloids. With this subtle, but remarkable structural
modification, this alkaloid is evolved into a biogenetic turntable
toward more complex pleiocarpine-refractine classes of alkaloids
(e.g. 2, 3 in Figure 1). Additionally, this unique aspidospermane
derivative can be transformed to pauciflorine[4] and eburnane[5]
type alkaloids (4, 5 in Figure 1) in few chemical steps. Owing to
the apparent synthetic significance of minovincine (1), it has
been an attractive research target since its isolation[6] in 1962.[7]
Interestingly, and despite the advances of catalytic asymmetric
Figure 1. Structure of (–)-minovincine (1), (–)-aspidofractinine (6) and
related alkaloids.
Recently, our laboratory developed a strategy for the
concise and diastereoselective synthesis of cis- and trans-
decaline subunits of terpenoids.[14] Key to the strategy was an
organocatalyzed Robinson annulation reaction that afforded a
chiral enone building block with quaternary stereogenic center.
As an outgrowth of these studies, we were intrigued to develop
an analogous chiral building block 7 that might confer synthetic
practicality in aspidospermane chemistry. Our retrosynthetic
plan adopted in this investigation is illustrated in Scheme 1. We
envisioned tricyclic 8, a modified Stork’s tricyclic ketone[15], to
serve as an advanced intermediate en route to 1 and 6. We also
expected that the C-5 ester functionality of 8 can be selectively
transformed into the requisite exocyclic keto group to establish
the correct functionality in minovincine (1). Furthermore, on the
grounds of proposed biosynthetic pathway of aspidofractinine
(6),[16] our hope was that its “supercaged” skeleton might be
[a]
[b]
Dr. Sz. Varga, P. Angyal, G. Martin, Dr. T. Holczbauer and Dr. T.
Soós
Institute of Organic Chemistry
Research Centre for Natural Sciences
2 Magyar tudósok krt., Budapest, Hungary, H-1117
E-mail: tibor.soos@ttk.hu
Dr. O. Egyed
Instrumentation Center
Research Centre for Natural Sciences
2 Magyar tudósok krt., Budapest, Hungary, H-1117
Supporting information and the ORCID identification number of the
authors for this article can be found:
http:
.
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secured through the interception of C-2 carbon atom of the
transient iminium ion of 9 by its acetyl functionality. Finally, we
aspired to construct the desired tricyclic ketone 8 in a concise
way to provide opportunity for a scalable process of this
advanced intermediate. So, we devised a short synthetic route
through the organocatalytic Robinson annulation reaction of 10
and 11 to give multifunctional enone 7 followed by a multistep
nucleophilic cascade reaction of aziridine (12). Thus, we aimed
the early introduction of the C-5 quaternary center and used that
center to direct the relative configuration of further
functionalization around the C ring.
chiral building block 7 was constructed in 71% yield and 90% ee
(Scheme 2). Notably, the catalyst tolerated the presence of
primary alkyl chloride functional group, the alkylative inhibition of
the catalyst was not detected. This method proved also to be
amenable for scale up, ultimately allowing access to 80 g of
enone 7.
With a robust approach to 7 in hand, we were poised to
examine the feasibility of the nucleophilic cascade strategy
toward the tricyclic ketone 8. Pleasingly, the envisioned
multistep reaction occurred smoothly and delivered the tricyclic
ketone 8 with the correct configuration in high efficiency and
diastereoselectivity (Scheme 2: 8, X-ray)[17]
. Although the
diastereoselectivity of the cascade was excellent, the exact
mechanism by which this is achieved is not unequivocal. To
begin with, the product of the first aziridine adduct could not be
detected by NMR, suggesting that the rate of the subsequent
cyclization is relatively fast. Thus, the reaction started either by
the aza-Michael addition of aziridine (12) on the double activated
enone 7 or by the nucleophilic substitution of aziridine (12) on
the alkyl halide part of the enone 7. Regardless of the reaction
sequence, the stereochemical outcome is determined by the -
facial diastereoselectivity of the aza-Michael addition. This type
of Michael-SN2 or SN2-Michael annulation thus establishes a
preference for trans addition with the C-5 carboxylic substituents
of 14.[18] As a 5-endo-tet cyclization is less probable,[19] the
presumed zwitterionic aziridinium intermediate 14 was expected
to undergo a ring opening with halogenides. This mechanistic
manifold was corroborated by the isolation of 15 from the
reaction mixture.[20] Once generated, the arising ethyl halogenide
moiety was then quenched by the enolate, closing the cascade
process and generating a quaternary stereogenic center and the
E ring in parallel. As a less harmful and hazardous synthetic
precursor of aziridine (12), 2-chloroethylamine (16) was also
probed. To our delight, the intriguing nucleophilic cascade
proceeded also well with 2-chloroethylamine (16) in the
presence of DIPEA, which allowed us to conduct the process in
a batch of 80 g with a 72% yield.
Scheme 1. Retrosynthetic analysis of (–)-minovincine (1) and (–)-
aspidofractinine (6).
As a first foray, we sought to develop an efficient synthesis
of the desired enone 7 with the requisite quaternary stereogenic
center. Specifically, we strived to merge the easily available
Nazarov reagent 10 and -chloro-formylpentenoate 11 using the
previously reported quinine-squaramide organocatalyst 13[14]
(Scheme 2). Gratifyingly, this Michael addition-aldol
condensation organocascade reaction afforded the envisioned
enone 7 as a sole product. Using the optimized reaction
condition (dioxane, room temperature, 2 mol% catalyst) the
Scheme 2. Rapid construction of key intermediate 8 via relay cascade reactions. Reaction conditions: aa) 10+11 (1.13:1.0) (2 mol% 13) dioxane, r.t.; ab) 10+11
(1.1:1.0) (3 mol% 13), dioxane, r.t.; ba) KI, CH2Cl2, rt.; bb) DIPEA, KI, CH2Cl2, r.t.; DIPEA= diisopropylethylamine.
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Scheme 3. Syntheses of (–)-minovincine (1) and (–)-aspidofractinine (6). Reaction conditions: aa) aq. H2SO4 (50 V/V%), dioxane, r.t.; ab) PhNHNH2 then
i
BF3•OEt2, MeOH, 70 oC; ac) Pr2NH, LDA, CNCOOMe, THF, -78 oC; ad) AliBu3, THF, -78 oC to r.t. then TMSCH2Li; ba) TMSCH2Li, THF, r.t.; bb) aq. H2SO4 (50
V/V%), dioxane, r.t.; bc) PhNHNH2 then BF3•OEt2, EtOH, 85 oC; bd) N2H4•H2O, KOH, DEG, 130 to 210 oC, LDA= lithium diisopropylamide, TMS= trimethylsilyl,
THF= tetrahydrofuran, DEG= diethyleneglycol.
Given the ready availability of tricyclic ketone 8, the
scalable synthesis of (–)-minovincine (1) was addressed by
using the classical Fischer indole synthesis[21] (Scheme 3). The
synthesis of indolenine 17 was straightforward, proceeded
without incident. Thus, following selective deprotection of tBu-
ester, the resulting -oxo carboxylic acid spontaneously
reaction as a transient protecting group with dual roles. This
strong base would not only exert a charge control over C-3
methoxycarbonyl via N-H deprotonation, but the di-isobutyl
aluminium adduct 22 would secure an enhanced steric shielding
around the C-3 methoxycarbonyl moiety.[20] Gratifyingly, by
employing TRIBAL additive, a 52% yield (for two steps) of (–)-
decarboxylated, affording ketone 18 in 95% yield in 7 gram scale. minovincine (1) could be obtained on a 1.10 gram scale. Overall,
Subsequent treatment of product 18 with phenylhydrazine
generated aspidospermane-type indolenine 17 and its structural
isomer 19 in 50% and 31% yields, respectively. Having achieved
the construction of pentacyclic 17, what remained for completing
the synthesis of minovincine was the installation of C-3
methoxycarbonyl and C-5 acetyl groups. During these
endeavors, our priority was to minimize the functional group
manipulations to shorten the synthetic route and enhance its
practicality. First, methyl cyanoformate, also known as Mander
reagent, was used to append the methoxycarbonyl group into C-
the gram-scale synthesis of (–)-minovincine (1) was
accomplished in an overall yield of 11% by an eight-step
sequence. By virtue of (bio)synthetic potential of minovincine,
this scalable route seems to provide a rapid access toward
structurally related, more complex indole alkaloids.
Aspidofractinine is thought to originate from 9 that is
derived from minovincine via an ester hydrolysis followed by
decarboxylation (Scheme 1).[1,16] While several routes have been
developed to construct racemic aspidofractinine,[23,24] its only
asymmetric synthesis was reported by Spino[25] in 2009. The
relative ease of our minovincine synthesis served us an impetus
for developing a biosynthetically inspired synthesis of (–)-
aspidofractinine (6). Specifically, we envisioned an interrupted
Fischer indolization[26] by the pendant acetyl nucleophile.
Therefore, we set out to prepare a C-5 acetyl substituted tricyclic
ketone 23 from the previously synthesized advanced
intermediate 8. We reasoned that the steric hindrance
embedded in this key intermediate 8 can be exploited for
chemo- and regioselective transformation, thus, obviating the
need of protecting group manipulation. This scenario proved to
be viable, affording a simple route to 24. Thus, treatment of 8
3
position of the indolenine 20. Importantly, some N-
carboxylated isomer 21 also formed that cannot be separated by
chromatography (20:21 ratio was 6:1). Then, we turned our
attention to the regioselective transformation of the C-5
methoxycarbonyl group to the requisite acetyl moiety. While
conversion of the methyl ester 20 to a methyl ketone was not
successful
with
standard
reagents
(MeLi•LiBr
and
TMSCH2MgCl), TMSCH2Li proved to be a competent reagent to
effect the desired transformation[22] Although our initial attempts
with TMSCH2Li resulted in poor yields, we anticipated that the
addition of TRIBAL to 20 would improve the selectivity of the
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[1]
[2]
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Chemistry and Biology, Vol 51., (Ed.: G. A. Cordell), Academic Press,
San Diego, 1998, pp. 1–197.
with TMSCH2Li (rt, 1h) followed by ester hydrolysis and
decarboxylation resulted in the selective generation of 23 with
80% overall yield. Corroborating the importance of steric effect,
the decarboxylated, thus sterically less crowded analog 18 was
also reacted with TMSCH2Li under the same condition.
Importantly, that reaction resulted in a complex mixture.[20]
Next, the feasibility of the interrupted Fischer indolization
was investigated to construct the “supercaged” aspidofractinine
framework. To our delight, the Fischer indole-Mannich cascade
reaction occurred smoothly to afford the corresponding oxo-
aspidofractinine 25 in a 55% yield (alongside with its isomer 26)
via a presumed indolenine intermediate 9. Several significant
features of the reactions shown in Scheme 3 should be noted.
Though there are scattered examples of interrupted Fischer
indolization in the literature, a Mannich reaction coupled strategy
has not been utilized, to best of our knowledge. Furthermore, the
successful implementation of the trans annular Mannich-Fischer
indolization process led to the formation of three new bonds and
two additional quaternary stereogenic centers. Moreover, based
on the notion that C-20 derived indole formation was not
detected we surmised that the steric effect secured again the
regioselectivity. As the final step of the synthetic route, the
substrate 25 was exposed to hydrazine to furnish (–)-
aspidofractinine (6) in 89% yield.
Reviews on Synthesis of Aspidosperma and related alkaloids a) J. E.
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[3]
In conclusion, we have developed eight-step synthetic
routes toward (–)-minovincine (1) and (–)-aspidofractinine (6)
with 11% and 19% overall yields, respectively. Key to the
success was the strategic implementation of a chain of cascade
reactions, including organocatalytic Michael-aldol condensation,
multistep anionic Michael-SN2 cascade reactions and Mannich
reaction interrupted Fischer indolization. Importantly, four
contiguous stereogenic centers were created in those steps with
excellent absolute and relative stereochemical control. Both the
employed chain of cascade reactions and the steric effect
steered chemo- and regioselective reactions contributed
immeasurably for bringing not only synthetic brevity but also
improved practicality. Thus, the advanced building block 8
having a quaternary stereogenic center could be synthesized in
60 g scale. The (–)-minovincine (1) was delivered in gram scale
and the “supercaged” (–)-aspidofractinine (6) has become
accessible via excessively short manner. Furthermore, the
synthetic convenience to utilize easily available, inexpensive
reagents adds further practical appeal. We are currently
pursuing this synthetic strategy in the total synthesis of
structurally related members of aspidospermanes, the results
will be reported in due course.
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Acknowledgements
Authors are grateful for the supports of the National Research,
Development and Innovation Office-NKFIH (K 125385, FK
124863, PD 128504) and the János Bolyai Research
Scholarship of the HAS (T.H.).
Keywords: alkaloids • asymmetric catalysis • biomimetic
synthesis • total synthesis • organocatalysis
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via
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[20] For details see Supporting Information.
[21] Recent review on Fischer indole reaction: M. M. Heravi, S. Rohani, V.
Zadsirjan, N. Zahedi, RSC Adv. 2017, 7, 52852–52887.
[22] M. Demuth, Helv. Chim. Acta 1978, 61, 3136–3138.
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10.1002/anie.202004769
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Szilárd Varga, Péter Angyal, Gábor
Martin, Orsolya Egyed, Tamás
Holczbauer, Tibor Soós*
Page No. – Page No.
Total Syntheses of (–)-Minovincine
and (–)-Aspidofractinine Using a
Sequence of Cascade Reactions
Cl
OtBu
O
MeO
O
NH
O
O
NH
N
O
tBuO
O
O
OHC
O
2 cascade
reactions
4 steps
O
OMe
N
N
Key intermediate
(-)-Aspidofractinine
19% (8 steps)
[59 g]
(-)-Minovincine
11% (8 steps)
[1.1 g]
HN
[59 g]
Excessively concise syntheses of (–)-minovincine and (–)-aspidofractinine were
accomplished via the strategic use of chain of cascade reactions and steric control.
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