Stitching Oxindoles and Ynones in a Domino Process: Access to Spirooxindoles and Application to a Short Synthesis of Spindomycin B

Article abstract of DOI:10.1021/acs.orglett.7b03030

A general, transition-metal-free, one-pot, domino Michael-S_NAr or Ad_NE substitution protocol was devised for spiroannulation of oxindoles with ortho-bromoaryl ynones, β-bromoalkenyl ynones, and β-bromoalkenyl enones in a convenient a

Full text of DOI:10.1021/acs.orglett.7b03030

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Stitching Oxindoles and Ynones in a Domino Process: Access
to Spirooxindoles and Application to a Short Synthesis of
Spindomycin B
Ramesh Samineni,†,§ Jaipal Madapa,†,§ Srihari Pabbaraja,*,† and Goverdhan Mehta*,‡
†Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
‡School of Chemistry, University of Hyderabad, Hyderabad 500046, India
*
S Supporting Information
ABSTRACT: A general, transition-metal-free, one-pot, dom-
ino Michael−S Ar or Ad E substitution protocol was
N
N
devised for spiroannulation of oxindoles with ortho-bromoaryl
ynones, β-bromoalkenyl ynones, and β-bromoalkenyl enones
in a convenient and efficient manner. As an application, a short
synthesis of tetracyclic alkaloid spindomycin B was accom-
plished.
pirooxindoles, embodying spiroannulation of a carbo- or
chemical space around the 3-spirocyclohexanyl-2-oxindole
scaffolds. Several methods developed in this context that involve3
Pd-catalyzed intramolecular Heck cyclization (9 → 10),
S
heterocyclic rings at the 3-position of oxindoles, are generally
perceived as privileged structures through their three-dimen-
sional architecture with variegated and generous distribution
of functionalities. They are found as core substructures in many
bioactive natural products and pharmacologically relevant
4
5a,b
α-arylation (11 → 12), C−H activation (13 → 14), Lewis
6a,f
acid mediatedcyclizations (15 →16), Diels−Alder cycloadditions
7
a,e
8a,d
(17 → 18), radical cyclizations (19 → 20), organocatalytic
1
9a,j
synthetic compounds. Among the spirooxindoles, those with
reactions (21 → 22), and other catalytic/domino processes
10a,g
3
,3′-fused six-membered rings with additional appendages, both
(23 → 24),
among many others, are captured in Figure 2.
of natural and synthetic origin and displaying promising bio-
2
activity attributes, have drawn considerable interest from the
3
−10
synthetic organic and medicinal chemistry community.
Representative examples of natural products spindomycin A 1
2a
and B 2 (tyrosine kinase inhibitor), gelsemine 3, gelseverine 4
2
d,c
2d
(
antidepressant), maremycin F 5 and synthetic compounds
2e 2f
satavaptan6(hyponatremia), 7(MDM2-p53inhibitor), and8
aprogesteronereceptoragonist) depictingthediversityamong
-spirocyclohexanyl-2-oxindole based scaffolds are displayed in
2g
(
3
Figure 1.
Figure 2. Previous approaches for six-membered spirooxindoles
Although the previous methods are useful in their own right,
some require considerable effort toward the acquisition of
precursors or deployment of metal catalysts and less accessible
reagents, underscoring the need for a general, simple to execute
Figure 1. Representative six-membered spirooxindoles
A confluence of complex structural features and wide range
Received: September 27, 2017
bioactivities has aroused considerable interest in exploring
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03030
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
approach employing readily available precursors to access these
Scheme 2. Reaction of Various Substituted Oxindoles with
valuable pharmacophoric scaffolds. As part of our ongoing
o-Bromoaryl Ynones
1
1
research, we recently demonstrated an approach to 3,3′-cyclo-
11a
pentaspirooxindoles (27, 29) through aryne 26 and ynone
8 insertion into 3-oxindole acetic acid ester 25 (Figure 3).
2
Figure 3. Our approach to carbocyclic spirooxindoles
We report here an interesting transition-metal-free, “one-pot”
domino reaction between readily available oxindole 30 and
o-bromoaryl ynones 31 and β-bromoalkenylynones 33 via
12,13
14
domino Michael−S Ar
or AdNE reactions to deliver vari-
N
ously embellished 3-spirocyclohexanyl-2-oxindole scaffolds 32
and 34, respectively (Figure 3). This conceptualization was
successfully extended to accomplish the first total synthesis of
bioactive alkaloid spindomycin B (2).
Reaction between N-methyl oxindole 30a and 1-(2-bromo-
phenyl)-3-phenylprop-2-yn-1-one 31a was probed. Under
and oxindole 30f smoothly delivered the corresponding spiro-
oxindoles 32i−o, respectively, in moderate yields (Scheme 2).
The formation of spirooxindoles 32a−o was secured through
consistent and complementary spectral data and single crystal
X-raystructuredeterminationofoneofthem(32k,Scheme1and2).
However, ynone 31f bearing an alkyl substituent did not undergo
spirocyclization to yield the desired 32p but afforded only the
Michael product 35a (see SI).
optimized conditions [Cs CO (2.0 equiv), DMF, 100 °C, 6 h;
2
3
see Supporting Information (SI)], 32a and 35 (∼13:1) were
realized (Scheme 1). While the major spiroannulated product
Scheme 1. Initial experiment
Our experimental observations and scrutiny of related
12,13
precedence, gleaned from the literature,
are suggestive of
a plausible reaction mechanism (Scheme 3) for this domino
Scheme 3. Proposed Reaction Mechanism
3
2a (63%) could be envisioned to arise through tandem Michael
addition−nucleophilic aromatic substitution(S Ar), theorigin of
N
the minor product 35 (5%) could be traced to Michael addition
andbasemediateddouble bondrelocation (Scheme3). Whenthe
reaction was conducted at ambient temperature, 35 was the only
product observed. In a control experiment it was observed that
3
2a and 35 originated independently, as 35 under the optimized
reaction conditions remained unaltered (Scheme 1).
We proceeded to demonstrate the generality and scope of this
dominoMichael−S Arreactionemployingvariousoxindolesand
N
o-bromoaryl ynones under the optimized conditions. Reaction
between ynone 31a and various 5-substituted oxindoles (30b−e)
led to the formation of spirooxindoles 32b−e, respectively, as the
main products with the minor products similar to 35 formed only
in <5% yield and were not isolated (Scheme 2). Oxindoles with
N-phenyl 30f and N-benzyl 30g,h also engaged ynone 31a to
furnish the corresponding spirooxindoles 32f−h. It was also
felt appropriate to investigate this domino process with diverse
ynone partners 31b−e which upon reaction with oxindole 30a
process. It would be reasonable to assume that the oxindole
derived anion 30a adds to ynone 31a in Michael fashion to afford
intermediate A which tautomerizes to olefin B. At higher
temperature (∼100 °C) the anion derived from B displaces the
B
DOI: 10.1021/acs.orglett.7b03030
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
aromatic bromide in a nucleophilic aromatic substitution (S Ar)
partners for oxindole and target recently isolated natural products 1
and 2 as a total synthesis objective. These tetracyclic alkaloids
were isolated from rhizosphere strain Streptomycessp. xzqh-9, and
their structures and absolute configurations were determined
N
reaction to deliver the spiro product 32a via intermediate C.
On the other hand, at ambient temperature the anion B only
undergoes double bond isomerization to furnish alkylidene
oxindole product 35.
2a
through 2D NMR and calculated electronic circular dichroism.
In this facile and apparently general S Ar reaction of oxindoles
Among the two sibling alkaloids, 2 displayed weak (30 μM)
inhibitory activity against tyrosine kinase Bcr-Abl implicated in
chronic myeloid leukemia and was chosen as the initial target.
A retrosynthetic perspective aimed at a short synthesis of 2 is
N
withβ-bromoarylynones, wewerecurioustofindoutifthesimilar
protocol could be implemented on β-bromoalkenyl ynones to
advance the potentiality of our domino reaction. Accordingly,
when 30a was engaged with readily obtainable 1-(2-bromocyclo-
pent-1-en-1-yl)-3-phenylprop-2-yn-1-one 33a (for the prepara-
tion of bromoalkenylynones 33a−d, see SI) under optimized
conditions (Cs CO , DMF, 100 °C), the reaction afforded the
depicted in Scheme 6. Thus, a Michael−Ad E protocol between
N
Scheme 6. Retrosynthetic Analysis of Spindomycin B
2
3
tetracyclic spirooxindole 34a in 75% yield, along with the minor
product 36 in <5% yield. Once again, it was observed that 34a
and 36 were formed independently and the latter did not convert
to the former under the reaction regime. Furthermore, to demon-
strate the generality and scope of this reaction, various substituted
oxindoles (30e/f/h) readily engaged with diverse cyclic β-bro-
moalkenyl ynones 33a/b/c/e to afford the corresponding
tetracyclic spiroannulated compounds 34b−g, respectively, in
good yields, Scheme 4. However, the alkyl-substituted ynone 33d
3
0a and 38 would deliver the tetracyclic framework 37, well
geared for functional group amplification to deliver the target
natural product in a few steps.
The reaction between 30a and cross-conjugated 38 under
optimized conditions (Cs CO , DMF, 100 °C) afforded the
expected spiroannulated tetracyclic oxindole 37 as a mixture of
inseparable diastereomers and was elaborated to diastereomeric
α-hydroxyketones39followingtheRubottomoxidationprotocol.
2
3
Scheme 4. Michael−Ad E Reaction of Oxindoles with
N
β-Bromoalkenylynones
15
Thus, 37 with LiHMDS and TMSCl afforded silyl-enol ether,
which upon further epoxidation with mCPBA and TBAF exposure
16
led to 39 as a mixture of diastereomers. Dess-Martin periodinane
oxidationof39andconcomitantenolizationafforded2in82%yield.
The spectral data of the synthetic spindomycin B were found to
be identical with those reported for the natural product. Moreover,
we also determined its single crystal X-ray structure (Scheme 7).
Scheme 7. Total Synthesis of Alkaloid Spindomycin B (2)
like 31f (Scheme 2) did not lead to 34h but provided only 36a
(
see SI) under the reaction conditions.
A plausible mechanism for the above transformation can be
through a tandem Michael addition followed by addition−
elimination (Ad E) reactions (D → E→F → 34a), Scheme 5.
N
Scheme 5. Proposed Reaction Mechanism
In conclusion, we outlined a one-pot, metal-free spiroannula-
tion strategy to conveniently access the 3-spirocyclohexanyl-2-
oxindole motif from oxindoles and β-bromoaryl ynones and
further extended this domino protocol to β-bromoalkenyl ynones
and enones. As an application of this new method, the first syn-
thesis of tetracyclic alkaloid spindomycin B was accomplished in
five steps with an overall yield of 53%.
ASSOCIATED CONTENT
Supporting Information
■
*
S
To further evaluate the scope and efficacy of our one-pot
β-bromoalkenylynonemediatedoxindolespiroannulationmethod-
ology, we ventured to extend it to β-bromoalkenyl enones as
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03030.
C
DOI: 10.1021/acs.orglett.7b03030
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Detailed experimental procedures and spectral data for all
Letter
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(
new compounds (PDF)
Crystallographic data for compound 32k (CIF)
Crystallographic data for compound 2 (CIF)
AUTHOR INFORMATION
Corresponding Authors
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*
E-mail: srihari@iict.res.in.
*E-mail: gmehta43@gmail.com.
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Srihari Pabbaraja: 0000-0002-1708-6539
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§
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R.S. and J.M. contributed equally.
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Notes
adsc.201701059. (b) Huang, J.-R.; Sohail, M.; Taniguchi, T.; Monde, K.;
Tanaka, F. Angew. Chem., Int. Ed. 2017, 56, 5853. (c) Sun, Q.-S.; Lin, H.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was initiated under the Indo-French “Joint
Laboratory for Natural Products and Synthesis towards Affordable
Health (NPSAH)” and supported jointly by the Council of
Scientific and Industrial Research (CSIR) and Department of
Science and Technology (DST), New Delhi under Project Code
GAP-584. J.M. thanks CSIR for the Fellowship. G.M. wishes to
thank Dr. Reddy’s Laboratory (DRL) for the award of the
Dr.KallamAnjiReddyChairProfessorship.WethankMr.Showkat
Rashid for his help in X-ray analysis.
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