Exploiting Sm(ii) and Sm(iii) in SmI2-initiated reaction cascades: Application in a tag removal-cyclisation approach to spirooxindole scaffolds

Article abstract of DOI:10.1039/c1ob05710c

A tag removal-cyclisation sequence is described that is initiated by reduction using a Sm(ii) species and completed by a Sm(iii) Lewis acid that is formed in an earlier stage. Therefore, the reaction cascade utilises both oxidation states of a samarium reagent in discrete steps and allows access to privileged, pyrrolidinyl-spirooxindole scaffolds and analogues inspired by the anti-cancer natural product spirotryprostatin A. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05710c

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PAPER
Exploiting Sm(II) and Sm(III) in SmI2-initiated reaction cascades: application
in a tag removal–cyclisation approach to spirooxindole scaffolds†
Susannah C. Coote, Seidjolo Quenum and David J. Procter*
Received 14th February 2011, Accepted 4th May 2011
DOI: 10.1039/c1ob05710c
A tag removal–cyclisation sequence is described that is initiated by reduction using a Sm(II) species and
completed by a Sm(III) Lewis acid that is formed in an earlier stage. Therefore, the reaction cascade
utilises both oxidation states of a samarium reagent in discrete steps and allows access to privileged,
pyrrolidinyl-spirooxindole scaffolds and analogues inspired by the anti-cancer natural product
spirotryprostatin A.
tag removal–cyclisation sequence initiated by reduction of tagged
oxindoles 1 using a Sm(II) species and completed by a Sm(III) Lewis
Introduction
acid that is formed in an earlier step. The fluorous3 approach
would allow access to the biologically significant pyrrolidinyl-
spirooxindoles 3, with purification being conveniently carried out
using fluorous solid-phase extraction (FSPE)4 (Scheme 2). The
pyrrolidinyl-spirooxindole unit forms the core of an extensive
family of alkaloid natural products, many of whose members
possess bioactivity.5 For example, spirotryprostatins A and B6
Cascade reactions in which multiple synthetic tasks are carried
out selectively in a single reaction flask represent the holy grail
for the synthetic chemist. The lanthanide reagent, samarium
diiodide (SmI2),1 is one of the most important chemical reductants
and is often the reagent of choice for the orchestration of
reductive reaction cascades due to the high chemo-, regio- and
stereoselectivity it exhibits.2
Here we describe an example of a sequence that utilises both
oxidation states of a samarium reagent in discrete steps. In contrast
to reduction-only cascades, the exploitation of additional Lewis
acid-mediated processes to terminate reaction sequences, mediated
by Sm(III) species formed in earlier reductive steps, greatly expands
the chemical space that can be accessed. In the new reaction
cascades, Sm(II)-mediated reduction of A generates an otherwise
stable product B that is then transformed by the Lewis acidic
Sm(III) by-product to give C (Scheme 1).
Scheme 1 Exploiting Sm(II) and Sm(III) in SmI2-initiated cascades.
To evaluate the feasibility of exploiting both oxidation states
of a samarium reagent in cascade reactions we designed a phase
School of Chemistry, University of Manchester, Oxford Road, Manchester,
UK M13 9PL. E-mail: david.j.procter@manchester.ac.uk; Fax: +44 (0)161
275 4939; Tel: +44 (0)161 2751425
† Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and 1H and 13C spectra, X-ray crys-
tallographic data. CCDC reference numbers 780379–780382 and 791298.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob05710c
Scheme 2 A Sm(II)/Sm(III)-mediated approach to the pyrrolidinyl-
spirooxindole scaffold.
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exhibit anti-cancer activity and analogues of spirotryprostatin
A 6 have improved activity against breast cancer cell lines.6b
Furthermore, simplified analogues such as 7 are promising MDM2
inhibitors.7 We proposed that manipulation of 3 could give natural
product analogues 5 via intermediates 4, which are related to
MDM2 inhibitors 7 (Scheme 2).
expulsion of the fluorous tag and intramolecular Sm(III)-enolate13
alkylation to give vinylcyclopropane 17 (cf. 2) in 53% isolated yield
as a single diastereoisomer (Scheme 3).
We postulated that 17 would react with an imine in the
presence of a Sm(III) Lewis acid, formed during tag removal, to
give an iminium ion intermediate (cf. 18) that would undergo
subsequent Mannich-type cyclisation. Carreira has previously
employed oxindole cyclopropanes in analogous cycloadditions
mediated by MgX2.6h,6j,14
We were pleased to find that treatment of 11 with SmI2 in
THF (2 equiv) at room temperature followed by addition of N-
allylphenylimine and heating to 80 ◦C resulted in removal of the
fluorous tag and cyclisation to give pyrrolidinyl-spirooxindole 19
as a separable 4 : 1 mixture of diastereoisomers in 77% yield after
purification by FSPE. The relative stereochemistry of diastereoiso-
mers 19a and 19b was confirmed by X-ray crystallographic
analysis15 (Scheme 4).
New tagging strategies8 continue to play a key role in the
quest for more efficient synthesis. In particular, the use of
fluorous tags and associated purification technologies3 now enjoys
widespread use in chemistry and chemical biology. In addition
to the development of new Sm-mediated cascade processes, our
studies will show how the unavoidable tag introduction and tag
removal steps can be used to trigger important synthetic events in
a route and thus the use of a phase tag to assist purification need
not lengthen a synthesis.
Results and discussion
Development and scope of Sm(II)/Sm(III)-mediated reaction
cascades
To investigate our proposal to exploit a Sm(II)/Sm(III)-mediated
reaction cascade, tagged oxindoles 10–16 were prepared using a
modification of our tag introduction–cyclisation process based
on a Pummerer-type9 reaction, and were purified conveniently
using fluorous solid-phase extraction (FSPE).4 For example,
tag introduction–cyclisation10,11 involving glyoxamide 8 followed
by removal of the DMB protection and alkylation with cis-
1,4-dichlorobut-2-ene gave 10. N-Alkyl substrates 11–16 were
prepared in two steps from substrates analogous to 8. FSPE was
used to purify products in all steps en route to 10–16 (Scheme 3).
12
Pleasingly, treatment of tagged substrate 11 with SmI2 triggered
Scheme 4 Mechanism and proposed origin of diastereoselectivity in the
Sm(II)/Sm(III)-mediated reaction cascade.
The intermediacy of spirocyclopropyloxindole 17 was con-
firmed by monitoring the reaction by 1H NMR spectroscopy
and by the observation that heating 17 at 80 ◦C with N-
allylphenylimine in the presence of SmI3 gave 19 in 68% yield
and a similar diastereoisomeric ratio to that obtained from the
sequential reaction. The evolution of the reagent was crucial to
Scheme
-CH2CH2C8F17).
3
Substrates for Sm(II)/Sm(III)-mediated cascades (RF
=
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the success of the cascade, as heating 17 with the imine in the
absence of Sm(III) led to the recovery of starting materials.
The diastereoselectivity observed in the reaction cascade to
give 19 can be explained by considering transition structures 18
(Scheme 4).16 Transition structure 18b is disfavoured due to steric
interactions arising from the syn relationship between the Sm(III)-
enolate and its associated ligands and the substituent on the imine.
The syn relationship between the substituents a to nitrogen in the
pyrrolidine ring in both products appears to result from rapid
epimerisation of the stereocentre a to nitrogen bearing the vinyl
group (C9 in Scheme 4), post cyclisation.
The approach to oxindole cyclopropanes embedded in our new
cascade reaction has several advantages over literature routes:
mild, reductive conditions are used, thereby avoiding the use of
strong bases and low temperatures or diazocompounds.6h,6j,14 In
addition, the in situ generation of these relatively unstable species
renders their isolation and purification unnecessary.
The scope of the Sm(II)/Sm(III)-mediated reaction cascade was
explored using oxindole substrates 10–16 and a range of imines.
Pyrrolidinyl-spirooxindoles 19–30 were obtained in good overall
yield (58–77%) (Fig. 1). The moderate to good diastereoselectivity
(3 : 1 dr to 11 : 1 dr) observed is comparable to that reported for the
related stepwise process mediated by Mg(II).17 The process is com-
patible with some imines bearing a-hydrogens (e.g. preparation of
27 and 28) and oxindoles bearing a free N–H (e.g. preparation of
29 and 30). In all cases, FSPE can be used to purify products
by removing any unreacted starting material and the fluorous
disulfide by-product resulting from removal of the fluorous tag.
Pleasingly, the fluorous disulfide can be recovered from these
cascades in ~70% yield using FSPE and can be reduced to the
fluorous thiol (nBu3P, H2O, THF, 70%) and reused.18
Manipulation of products from the Sm(II)/Sm(III)-mediated
reaction cascades
In our route to pyrrolidinyl-spirooxindoles, the introduction (see
8 to 9 in Scheme 3) and removal of the tag are used to trigger key
cyclisation events in the fluorous synthesis and no additional steps
result from the use of a tag as a purification handle.
The products of the Sm(II)/Sm(III)-mediated reaction cascade
can be readily converted to compounds related to MDM2 in-
hibitors 7 and spirotryprostatin A 6. In the latter case, Danishefsky
has shown that analogues of spirotryprostatin A bearing different
sidechains at C18 can have activity greater than that exhibited
by the natural products.6b Attractively, our approach allows the
synthesis of a wide range of analogues by introducing diversity at
C18 and on the oxindole ring, and by manipulation of the terminal
alkene in the pyrrolidinyl-spirooxindoles.
Oxidative cleavage of the alkenes in pyrrolidinyl-spirooxindoles
25/29 gave aldehydes 31/32 in good yield (Scheme 5). Subsequent
oxidation, esterification and debenzylation gave methyl esters
35/36 (cf. MDM2 inhibitors 7). The relative stereochemistry of
35 was confirmed by X-ray crystallographic analysis.15 Coupling
with Troc-(S)-proline chloride allowed a late-stage resolution to
be exploited for the introduction of stereochemical diversity in
our library approach. Removal of the Troc protecting group from
37/38 triggered cyclisation to give 39/40a,b (Scheme 5). The
stereochemistry of the four analogues was confirmed by X-ray
crystallographic analysis of 40b15 and NOE studies on 39a,b.
Fig. 1 Scope of the Sm(II)/Sm(III)-mediated reaction cascade.
The Sm(II)/Sm(III)-mediated reaction cascade has also been ex-
ploited in a tag handover–cyclisation strategy for the preparation
of compounds related to MDM2 inhibitors 7 and spirotryprostatin
A 6. A reaction cascade employing tagged oxindole 10 and
an imine bearing a fluorous benzyl protecting group19 allowed
tags to be exchanged during the cascade to generate 41 thus
avoiding the need to remove an old tag and introduce a new
tag in a stepwise fashion. The fluorous tag that is removed can
be recovered and recycled as before (vide supra) as the RFSSRF
elutes more slowly than 41 on fluorous silica gel due to its
higher fluorine content.18 Straightforward manipulation of 41 gave
42, after purification by FSPE. Finally, removal of the fluorous
benzyl group under acidic hydrogenolysis conditions gave 36
(Scheme 6). The conversion of 36 to 40a,b has been illustrated in
Scheme 5.
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Scheme 6 A tag handover–cyclisation strategy (BnF = –CH2(4-C6H4CH2-
CH2C8F17).
analogues such as 36 display levels of activity similar to that of
spirotryprostatin A.20
Acknowledgements
We thank the EPSRC (S. C. C and project studentship to S. Q)
and the University of Manchester for financial support. We also
thank Sylvia Gang for preliminary studies.
Notes and references
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Scheme 5 Manipulation of pyrrolidinyl-spirooxindoles.
Conclusions
SmI2-initiated reaction cascades have been developed in which the
samarium reagent’s change from reductant to Lewis acid is ex-
ploited. The concept has been exemplified in a phase tag removal–
cyclisation process which is initiated by reduction using a Sm(II)
species and completed by a Sm(III) Lewis acid formed during the
reductive step. Thus, the sequence utilises both oxidation states
of a samarium reagent in discrete steps. The sequence has been
exploited in a fluorous synthesis of pyrrolidinyl-spirooxindoles in
which the introduction and removal of the fluorous tag are used to
trigger key cyclisation events and thus no additional steps result
from the use of a tag as a purification handle. The route has been
extended to prepare analogues inspired by the anti-cancer natural
product spirotryprostatin A. The biological evaluation of these
compounds is underway and preliminary studies have shown that
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15 See the Supporting Information for CCDC numbers and X-ray
crystallographic data†.
16 The ratio of the product diastereoisomers 19a and 19b remains constant
throughout the course of the reaction, suggesting epimerisation at
the quaternary stereocentre in the products is not taking place.
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8 J. Yoshida and K. Itami, Chem. Rev., 2002, 102, 3693.
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18 See the Supporting Information for details of the recycling of the
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20 MTT assays assessing cytotoxicity in MDA-468 cells. Spirotryprostatin
A (110 mM ref. 6b), 36 (95 mM). The synthesis and biological evaluation
of more active spirooxindoles is currently underway.
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