Exploiting a novel size exclusion phenomenon for enantioselective acid/base cascade catalysis

Article abstract of DOI:10.1039/c2cc32258g

A novel size exclusion phenomenon between PS-BEMP and sterically bulky BPAs, has been discovered and exploited in a one-pot base-catalysed Michael addition/acid-catalysed enantioselective N-acyliminium cyclisation cascade, allowing the preparation of structurally complex β-carbolines with moderate to good enantiocontrol.

Full text of DOI:10.1039/c2cc32258g

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COMMUNICATION
Exploiting a novel size exclusion phenomenon for enantioselective
acid/base cascade catalysisw
a
Michael E. Muratore,a Lei Shi,z Adam W. Pilling,b R. Ian Storerc and Darren J. Dixon*a
Received 28th March 2012, Accepted 27th April 2012
DOI: 10.1039/c2cc32258g
A novel size exclusion phenomenon between PS-BEMP and
sterically bulky BPAs, has been discovered and exploited in a
one-pot base-catalysed Michael addition/acid-catalysed enantio-
selective N-acyliminium cyclisation cascade, allowing the prepara-
tion of structurally complex b-carbolines with moderate to good
enantiocontrol.
Strong chiral organic Brønsted acids such as the BINOL
phosphoric acids (BPA) pioneered by Terada1 and Akiyama2
have found widespread use in asymmetric catalysis. As acid
Scheme 1 Concept of an acid/base catalysed enantioselective Michael
catalysts they have been successfully applied in asymmetric
transformations ranging from the Mannich reaction1–3 to
addition, N-acyliminium cyclisation cascade.
complex multi-component reactions.4 Their conjugate bases,
as chiral counter anions, have also been exploited in asymmetric
However, to develop catalytic cascade reactions involving
iminium ion catalysis5 as well as in transition metal catalysis.6
the simultaneous use of both strongly basic and strongly acidic
reagents the problem of annihilation (catalyst quenching) had to
be overcome. We and others have demonstrated that site isolation
Together with other compatible catalytically active species they
have also been shown to engage in dual catalysis.7,8
In a continuation of our work in the field of tandem base and
acid catalysis9 we were interested in developing reaction
of acid and base functionalities by employment of separate
insoluble polymeric analogues can effectively prevent annihilation
and reaction products resulting from distinct base-catalysed and
cascades involving the strong Schwesinger base 2-tert-butylimino-
acid-catalysed steps can be readily obtained.13–16 To date however,
enantioselective cascade catalysis involving BPA derivatives
site-isolated from what would otherwise be a mutually destruc-
tive catalyst (or reagent), such as a strong base, has not been
reported despite the wealth of untapped synthetic opportunities
that such a combination would create.
2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine,10,11
polymer supported (PS-BEMP 1) and (R)-BPA 2 or bulky deriva-
tives such as (R)-3,30-bis(triphenylsilyl)-BPA [(R)-TPS-BPA 3]
and (R)-3,30-bis(triphenylsilyl)-[H8]BPA [(R)-TPS-H8-BPA 4]
(pKa B 1).12 We believed a Michael addition/N-acyliminium
ion cyclisation cascade would be an ideal platform since it is
known to require distinct base-catalysed and acid-catalysed
steps.7,9 Not only would it showcase our concept but it would
also allow the rapid construction of complex enantioenriched
polycyclic products III from readily available starting materials I
(Scheme 1).
Initially, we considered the possibility of attaching the BPA
to suitably functionalised polymeric supports or polymerising
appropriate BPA monomers,17,18 however the added step
count and potentially detrimental effect of immobilisation on
enantioselectivity relative to the soluble monomeric catalyst
was unattractive. Accordingly, and as an exciting and practical
alternative, we considered whether size exclusion (molecular
sieving) could be exploited to provide the necessary site isolation
of mutually destructive acidic and basic functional groups.
Commercially available PS-BEMP 1 is a microporous 1–2%
cross-linked polystyrene-based polymer19 with pore sizes
that vary significantly depending on the reaction solvent
employed.20 We hypothesised that in an appropriate
solvent and with the appropriate 3,30-substituents, BPAs could
be made sufficiently large (Fig. 1) so as to prevent full
penetration of the microporous lattice,21 thus leaving
unquenched both the internal basic residues and the BPA in
solution.
a Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
E-mail: Darren.dixon@chem.ox.ac.uk; Fax: +44 (0)1865 285002;
Tel: +44 (0)1865 275648
b School of Chemistry, The University of Manchester, Oxford Road,
Manchester M13 9PL, UK
c Pfizer Neusentis, The Portway Building, Granta Park, Cambridge,
CB21 6GS, UK
w Electronic supplementary information (ESI) available: Character-
isation and NMR spectra for all compounds. See DOI: 10.1039/
c2cc32258g
z Current address: The Academy of Fundamental and Interdisciplinary
Science, Harbin Institute of Technology, Harbin, 150080, People’s
Republic of China.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6351–6353 6351

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Table 1 Proof of principle and optimisation study
Entry Basea
Acida Time
Result
1b
2b
3b
4b
5b
6b
7c
—
(R)-3 24 h
no conversion
93% yield of 8a
89% yield of 8a
no conversion
88% yield of 8a
no conversion
no conversion
PS-BEMP
BEMP
BEMP
PS-BEMP (R)-3 57 h
PS-BEMP DPP 5 24 h
PS-BEMP (R)-2 24 h
PS-BEMP (R)-3d 57 h
—
—
6 h
2 h
(R)-3 24 h
Fig. 1 3D models of (R)-BPA 2, (R)-TPS-BPA 3 and (R)-TPS-H8-
BPA 4 and corresponding calculated dimensions.22
8b
9e,f
10f
79.5% conv. of 6a
PS-BEMP (R)-3d 16 hg + 36 hh 25% yield of 9a–51% ee
PS-BEMP (R)-4d 24 hg + 24 hh 81% yield of 9a–57% ee
Provided that the smaller substrates/reagents could penetrate
through to the internal catalytically active basic sites, this size
exclusion phenomenon could allow both strong base and strong
chiral acid catalysts to co-exist and function simultaneously in the
same vessel. If viable, this strong base and strong acid site isolation
concept would not only be general to numerous asymmetric
reactions and cascades but would also be technically simple to
carry out and negate the challenging and resource-consuming
preparation of immobilised BPA derivatives. Herein we report
our investigations leading to a new and potentially powerful
discovery in the field of enantioselective BPA catalysis.
a
b
10 mol% unless otherwise stated; performed in NMR tube at
c
room temperature (r.t.) at 600 rpm; performed in CH2Cl2 at r.t.;
d
e
20 mol% of (R)-3; 1.5 eq. of MVK; toluene as solvent; time at r.t.;
f
g
h
time at reflux.
Michael/N-acyliminium cyclisation cascade were then performed
to assess the catalytic competence of both the PS-BEMP 1 and
TPS-BPA 3 components when present in the same pot. We chose
pro-nucleophile 6a and methyl vinylketone (MVK 7a) as our
model system and the results are presented in Table 1.
To probe whether a size exclusion phenomenon could exist at
1
all, a series of H NMR titration experiments were performed
At room temperature in CD2Cl2, (R)-TPS BPA 3 did not
catalyse the Michael addition of 6a with MVK (Table 1, entry 1).
However, and as expected, good reactivity was observed when
10 mol% of soluble BEMP or PS-BEMP 1 were used as the
sole catalyst (Table 1, entries 2–3).23 Combining soluble BEMP
(10 mol%) with (R)-TPS-BPA 3 (10 mol%) (not unexpectedly)
rendered the BEMP catalytically incompetent (Table 1, entry 4).
In contrast and very pleasingly, when both PS-BEMP 1
(10 mol%) and (R)-TPS-BPA 3 (10 mol%) were employed
simultaneously, the Michael addition product 8a was isolated in
88% yield, albeit after an extended reaction time (Table 1,
entry 5). Significantly, no reactivity was observed when a
combination of PS-BEMP and DPP or a combination of
PS-BEMP and 3,30-unsubstituted (R)-BPA 2 were evaluated
(Table 1, entries 6–7). The use of excess acid (R)-3 (two equivalents
relative to PS-BEMP 1) did not have a significant deleterious effect
on the catalytic activity of PS-BEMP (Table 1, entry 8).
using PS-BEMP 1 as the insoluble base and either (R)-TPS-BPA 3
(a large BPA) or diphenyl phosphate 5 (DPP, a significantly
smaller phosphoric acid) as the soluble acid. The amount of free
acid remaining in solution was measured by 1H NMR against an
internal standard over time. The results shown in Fig. 2 strongly
suggested that site isolation through size exclusion was in opera-
tion with (R)-TPS-BPA 3 but was not with DPP. For example,
whereas DPP was quenched rapidly and fully by an equimolar
quantity of PS-BEMP 1, 24% TPS-BPA 3 remained in solution
after B4 days. Even with excess PS-BEMP 1, (R)-TPS-BPA 3 was
removed from solution only slowly. When the titration was
performed with 50 mol% of PS-BEMP 1, the amount of acid in
solution stabilised at around 80% after 17 h. In other words,
approximately 40% of the base was annihilated while 60% was
still unquenched even after B4 days.
With these data in hand, a series of quantitative control
and optimisation studies on a base then acid catalysed
These findings, in addition to the results of the NMR
titration experiments, clearly demonstrate that an effective site
isolation phenomenon, attributable to size exclusion of the
bulky 3,30-disubstituted BPA from the internal catalytically active
sites of PS-BEMP 1, was occurring with (R)-TPS-BPA 3. Exploiting
this discovery, optimisation studies for the tandem reaction were
performedw and revealed that (R)-TPS-H8-BPA 4 gave the highest
ee of product 9a (57% ee) in good chemical yield (81%) when the
Michael addition with MVK (3 eq) was performed at room
temperature for 24 h and the enantioselective N-acyliminium
cyclisation at reflux in toluene for 24 h (Table 1, entry 10).
In order to demonstrate that this cascade was general, a
set of malonamate nucleophiles 6 was reacted with MVK 7a
and/or ethyl vinylketone (EVK 7b) in the presence of our
newly developed PS-BEMP 1 and (R)-4 catalyst system
(Scheme 2).
Fig. 2 Titration of DPP 5 and (R)-TPS-BPA 3 against various amounts
of PS-BEMP 1 over time.
c
6352 Chem. Commun., 2012, 48, 6351–6353
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3 Q.-X. Guo, H. Liu, C. Guo, S.-W. Luo, Y. Gu and L.-Z. Gong,
J. Am. Chem. Soc., 2007, 129, 3790.
4 (a) X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun and L.-Z. Gong,
J. Am. Chem. Soc., 2006, 128, 14802; (b) T. Yue, M.-X. Wang,
D.-X. Wang, G. Masson and J. Zhu, Angew. Chem., Int. Ed., 2009,
48, 6717.
5 For selected examples see: (a) S. Mayer and B. List, Angew.
Chem., Int. Ed., 2006, 45, 4193; (b) X. Wang and B. List, Angew.
Chem., Int. Ed., 2008, 47, 1119.
6 For selected examples see: (a) S. Liao and B. List, Angew. Chem.,
Int. Ed., 2010, 49, 628; (b) G. L. Hamilton, E. J. Kang, M. Mba
and F. D. Toste, Science, 2007, 317, 496.
7 M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer,
G. Trevitt and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 10796.
8 For selected examples see: (a) C. Wang, Z.-Y. Han, H.-W. Luo and
L.-Z. Gong, Org. Lett., 2010, 12, 2266; (b) W. Hu, X. Xu, J. Zhou,
W.-J. Liu, H. Huang, J. Hu, L. Yang and L.-Z. Gong, J. Am.
Chem. Soc., 2008, 130, 7782; (c) M. Rueping, A. P. Antonchick and
C. Brinkmann, Angew. Chem., Int. Ed., 2007, 46, 6903.
9 (a) A. W. Pilling, J. Boehmer and D. J. Dixon, Angew. Chem., Int.
Ed., 2007, 46, 5428; (b) A. W. Pilling, J. Boehmer and D. J. Dixon,
Chem. Commun., 2008, 832.
10 pKa (BEMP-H+
) in DMSO = 16.2 see M. J. O’Donnell,
F. Delgado, C. Hostettler and R. Schwesinger, Tetrahedron Lett.,
1998, 39, 8775.
Scheme 2 Scope of the enantioselective base- and acid-catalysed
11 R. Schwesinger, J. Willaredt, H. Schlemper, M. Keller, D. Schmitt
and H. Fritz, Chem. Ber., 1994, 127, 2435.
cascade with MVK and EVK.
12 A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713.
13 See ref. 9 and references cited therein.
Malonamates 6 bearing various substituents at the 5, 6 and
7-position on the indole p-nucleophile successfully took part in
the cascade. 5-Bromo substituted and 7-alkyl substituted indole-
14 Selected example: V. Gembus, J.-J. Bonnet, F. Janin, P. Bohn,
V. Levacher and J.-F. Briere, Org. Biomol. Chem., 2010, 8, 3287.
15 For selected examples of methods employing star polymers to
create site isolated base and acid see: (a) B. Helms, S. J. Guillaudeu,
Y. Xie, M. McMurdo, C. J. Hawker and J. M. J. Frechet, Angew.
Chem., Int. Ed., 2005, 44, 6384; (b) Y. Chi, S. T. Scroggins and
J. M. J. Frechet, J. Am. Chem. Soc., 2008, 130, 6322.
16 For reviews on site isolation see and polymer-supported
reagents: (a) B. Voit, Angew. Chem., Int. Ed., 2006, 45, 4238;
(b) M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003,
103, 3401.
17 For polymer-supported binol derivatives see: (a) D. Jayaprakash
and H. Sasai, Tetrahedron: Asymmetry, 2001, 12, 2589;
(b) S. Kobayashi, K.-I. Kusakabe and H. Ishitani, Org. Lett.,
2000, 2, 1225 and references therein.
18 For polymer-supported BPA see: M. Rueping, E. Sugiono,
A. Steck and T. Theissmann, Adv. Synth. Catal., 2010, 352, 281.
19 PS-BEMP (2.2 mmol gꢀ1 loading) was purchased from Sigma-
Aldrich (product number 20026) and used without further
treatment.
derived malonamates
6 showed higher selectivities in the
N-acyliminium cyclisation compared to the unsubstituted counter-
part. Methyl and ethyl malonamates could be used with identical
reactivity and similar selectivity in the cascade. Although the
EVK-derived Michael adducts cyclised slowly, the desired
tetracycles were obtained in good yield and moderate to good
enantioselectivities (57–82% ee). Substituted vinylketones (such as
3-methyl-3-buten-2-one) did not partake in the reaction and only
degradation of the malonamate substrate was observed after
prolonged heating. The absolute stereochemistry of all products
was assigned by analogy with our previous studies.7,24b
To our knowledge, this is the first report of the steric
properties of bulky 3,30-disubstituted BPAs being exploited
to gain site isolation. Taking advantage of a novel size
exclusion phenomenon between PS-BEMP and sterically
bulky BPAs, we have been able to develop a one-pot base-
catalysed Michael addition followed by an acid-catalysed
enantioselective N-acyliminium cyclisation cascade that has
allowed the preparation of structurally complex b-carbolines
with moderate to good enantiocontrol. We believe this
approach is a viable and efficient alternative to the use of
polymer supported BPAs in situations where site isolation is a
necessity. Developments and further applications of this concept
are currently under investigation in our laboratory and will be
disclosed in due course.
20 For recent examples of the use of PS-BEMP and swelling issues
associated see: (a) A. Zvagulis, S. Bonollo, D. Lanari, F. Pizzo and
L. Vaccaro, Adv. Synth. Catal., 2010, 352, 2489; (b) T. Angelini,
F. Fringuelli, D. Lanari, F. Pizzo and L. Vaccaro, Tetrahedron
Lett., 2010, 51, 1566.
21 For a supporting study see: J. A. Greig and D. C. Sherrington,
Polymer, 1978, 19, 163.
22 The structure of (R)-2, (R)-3 and (R)-4 were drawn in ChemBio3D
and the geometry optimised by minimisation of energy (MM2,
minimum RMS gradient = 0.05). The dimensions were calculated
from the atom coordinates of the optimised structures.
23 For selected examples of PS-BEMP catalysed Michael additions
see: (a) D. Bensa, T. Constantieux and J. Rodriguez, Synthesis,
2004, 6, 923; (b) R. Ballini, L. Barboni, L. Castrica, F. Fringuelli,
D. Lanari, F. Pizzo and L. Vaccaro, Adv. Synth. Catal., 2008,
350, 1218.
24 For our previous work on N-acyliminium cyclisations see ref. 7
and: (a) T. Yang, L. Campbell and D. J. Dixon, J. Am. Chem. Soc.,
2007, 129, 12070; (b) C. A. Holloway, M. E. Muratore, R. I. Storer
and D. J. Dixon, Org. Lett., 2010, 12, 4720.
Notes and references
1 D. Uraguchi and M. Terada, J. Am. Chem. Soc., 2004, 126, 5356.
2 T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem.,
Int. Ed., 2004, 43, 1566.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6351–6353 6353