Asymmetric Catalysis with a Mechanically Point-Chiral Rotaxane

Article abstract of DOI:10.1021/jacs.6b00303

Mechanical point-chirality in a [2]rotaxane is utilized for asymmetric catalysis. Stable enantiomers of the rotaxane result from a bulky group in the middle of the thread preventing a benzylic amide macrocycle shuttling between different sides of a prochi

Full text of DOI:10.1021/jacs.6b00303

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Asymmetric Catalysis with a Mechanically Point-Chiral Rotaxane
Yusuf Cakmak, Sundus Erbas-Cakmak, and David A. Leigh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00303 • Publication Date (Web): 02 Feb 2016
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Asymmetric Catalysis with a Mechanically Point-Chiral Ro-
taxane
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Yusuf Cakmak,‡ Sundus Erbas-Cakmak,‡ David A. Leigh*
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
Supporting Information Placeholder
chiral centers through mechanical bonding is rare10 and
ABSTRACT: Mechanical point-chirality in a [2]rotaxane is
chiral systems of this type have not previously been investi-
gated for potential applications.
utilized for asymmetric catalysis. Stable enantiomers of the
rotaxane result from a bulky group in the middle of the
thread preventing a benzylic amide macrocycle shuttling
between different sides of a prochiral center, creating point
chirality in the vicinity of a secondary amine group. The
resulting mechanochirogenesis delivers enantioselective
organocatalysis via both enamine (up to 71:29 er) and imini-
um (up to 68:32 er) activation modes.
Distinctive features imparted by the mechanical bonding
in rotaxanes1 (such as their dynamic properties and the abil-
ity of the ring to mask regions of the thread) are beginning to
be investigated in various aspects of catalysis.2-7 The position
of the macrocycle on rotaxane threads has been used to
conceal or expose amine groups that can promote different
aminocatalysis activation modes3 and threaded molecular
structures have been exploited in processive4 and sequence-
specific5 catalysis. A rotaxane has been demonstrated to be
an effective chiral ligand in nickel-catalyzed Michael addi-
tion reactions6 and a rotaxane complex was recently em-
ployed7 in a gold-mediated cyclopropanation. In both of the
latter two cases embedding the coordinated metal ion within
the well-defined binding pocket of the rotaxane resulted in
higher stereoselectivity of the products than when using the
non-interlocked components as ligands (enantioselectivity in
the case of the chiral rotaxane-nickel catalyst;6 diastereose-
lectivity with the achiral rotaxane-gold catalyst7). However,
to date asymmetric catalysis with rotaxanes has only utilized
conventional chiral elements.2b,2f,3b,6,7 Here we report on the
use of a previously unexplored feature of rotaxane architec-
tures in catalysis, that of chirality induced by the mechanical
bond.8,9
Figure 1. Chemical structures of rotaxane (S)-1 and thread T1, show-
ing the mechanically induced chirality of the rotaxane. The carbon
labelled C11 is a prochiral center in the non-interlocked thread (T1)
but a chiral center in the rotaxane ((S)-1) as the 4-tolylamine group
blocks shuttling of the macrocycle to the other side of the thread.
Two rotaxanes, (S)-1 with the 4-tolylamine group and (S)-2
bearing an analogous 3,5-bis(trifluoromethyl)benzylamine
barrier, were prepared in enantioenriched form (84 % ee in
each case, as indicated by chiral HPLC, see Supporting In-
formation) by unambiguous synthetic routes (see Supporting
Information). In each rotaxane synthesis the key steps in-
volve the five-component macrocyclization about a chiral
succinamide thread (e.g. 3) to form a [2]rotaxane intermedi-
ate (e.g. 4), followed by extension of the stopper (with 5) to
form the second, inaccessible, succinamide group of the axle,
shown in Scheme 1 for the synthesis of (S)-1.
Scheme 1. Synthesis of mechanically point-chiral rotaxane
(S)-1.a
The chemical structures of the rotaxane, (S)-1, and its par-
ent thread, T1, are shown in Figure 1. Thread T1 is achiral,
possessing a mirror place through the prochiral center la-
beled C11. In the rotaxane, however, the bulky 4-tolylamine
group (shown in red, Figure 1) prevents macrocycle shuttling
between the two succinamide stations (shown in green)
resulting in a loss of symmetry. Accordingly, rotaxane (S)-1
has a center of point chirality (C11) with the two succinamide
groups of the thread in different chemical environments, one
accessible to the macrocycle and one not. Establishing point
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aReagents and conditions: (i) Isophthaloyl chloride, p-
xylylenediamine, NEt3, CHCl3, RT, 20 h, 33 %; (ii) Pd/C, H2, CH2Cl2,
MeOH, RT, 16 h, 91 %; (iii) 5, N,N′-dicyclohexylcarbodiimide, dime-
thylaminopyridine, THF:CH2Cl2, RT, 16 h, 81 %; (iv) CF3CO2H,
CH2Cl2, RT, 12 h, 73 %.
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2
3
4
5
6
Table 1. Enantioselective Michael addition of 1,3-
diphenyl-1,3-propanedione to α,β-unsaturated alde-
hydes via iminium catalysis using rotaxanes (S)-1, (S)-
2, and the parent threads T1 or T2 as catalysts.
1
Comparison of the H NMR spectrum of rotaxane (S)-1
with that of the component thread, T1, in CD2Cl2 shows an
upfield shift of one set of succinamide CH2CH2 protons (ΔδH
= −1.25 ppm) in the rotaxane due to shielding by the aromatic
rings of the encapsulating macrocycle (Figure 2, H7,8 in the
thread splits into two sets of protons, H7,8 and H7',8', in the
rotaxane). This is a result of the amine group being too bulky
for the macrocycle to pass.
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conv. (%)
(24/48 h)b
63/95
er of 8
(S:R)c
50:50
entrya
cat.
R (6)
1
T1
Me
2
3
4
5
6
7
(S)-1d
(S)-1d
(S)-1d
(S)-1d
T2
Me
50/77
-/58
68:32
58:42
55:45
57:43
50:50
67:33
Et
Pr
Figure 2. 1H NMR Spectra (600 MHz, CD2Cl2, 298 K) of (a) rotaxane
(S)-1 and (b) thread T1. The letter, number and color assignments
correspond to those shown in Figure 1.
-/36
CH2CH2Ph
Me
90/-
29/44e
Desymmetrization of the rotaxane axle through the me-
chanically locked location of the macrocycle creates point
chirality at carbon C11. The circular dichroism (CD) spectrum
of (S)-1 in CHCl3 confirms this mechanical chirogenesis (Fig-
ure S3). In contrast, the achiral thread, T1, does not display a
CD response.
(S)-2d
Me
70/95
aReactions were run with 12.5 ꢀmol 7, 25.0 ꢀmol unsaturated alde-
o
hyde (6a-d) in 50 ꢀl of CH2Cl2 at -20 C with 20 % catalyst loading.
1
c
bConversions estimated by H NMR. er values determined by HPLC
after 24 h. d84 % ee. Low conversions with the T2 catalyst may be
e
Space-filling models of rotaxane (S)-1 suggest that the
presence of the macrocycle on one side of the axle should
create a well-expressed chiral environment around the amine
group (Figure S4). We therefore investigated the efficacy of
the chiral rotaxane in asymmetric organocatalysis, firstly
through iminium activation with the Michael addition of 1,3-
diphenyl-1,3-propanedione to α,β-unsaturated aldehydes
due to the poor solubility of this compound in the reaction medium.
Table 2. Enantioselective enamine catalysis by (S)-1
or T1: Asymmetric α-amination of aldehydes with
dibenzyl azodicarboxylate.
o
(Table 1). At -20 C in CH2Cl2 using 20 mol% of the achiral
threads as catalyst (T1 and T2), we obtained a racemic mix-
ture of products (entries 1 and 6, Table 1). In contrast, using
(S)-1 as catalyst, we obtained an excess of the (S)-Michael
adducts (entries 2-5, Table 1). Aldehydes with smaller alkyl
substituents (e.g. 6) gave the best enantiomeric ratios, the
best being 68:32 (R = Me) in favor of (S)-product (entry 2,
Table 1). Rotaxane (S)-2, which possesses a different aryl
substituent, gave similar enantioselectivities (entry 7, Table
1). Decreasing the polarity of the reaction solvent (CH2Cl2) by
adding less polar solvents (CCl4, Et2O, PhCH3) had no signifi-
cant effect on the enantiomeric ratio of the products (Table
er of 12
entrya
cat.
R (9)
conv. (%)b
(S:R)c
o
S1). Decreasing the reaction temperature below -20 C led to
1
2
3
4
T1
Me
Me
Et
>95
>95
>95
>95
50:50
modest increases in enantioselectivity (69:31 er for 8a),
whereas at room temperature racemic mixtures of products
were obtained (Table S2).
(S)-1d
(S)-1d
(S)-1d
70:30
71:29
67:33
i-Pr
aReactions were run with 12.5 ꢀmol 10, 25.0 ꢀmol unsaturated alde-
hyde (9a-c) in 50 ꢀl of CH2Cl2 at -20 oC with 20% catalyst loading.
After 24 h, reactions were quenched with MeOH and excess NaBH4
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values determined by HPLC after 24 h. d84 % ee.
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7
8
To investigate the effectiveness of these mechanically
point-chiral catalysts using a different activation mode, we
examined the efficacy of (S)-1 in an enamine-mediated α-
amination reaction (Table 2). Dibenzyl azodicarboxylate (10)
was employed as a nitrogen electrophile and reacted with
aldehydes possessing various substituents (9a-c, Table 2).
Due to the configurational instability of the α-aminated
products (11a-c), the enantioselectivity of the rotaxane-
catalyzed reaction was assessed after reduction to the corre-
sponding alcohol (12a-c).11 The result was enantiomeric ratios
of up to 71:29 er (entry 3, Table 2), similar to those obtained
in the iminium activation mode catalyzed reaction (Table 1).
The point chirality previously exploited in asymmetric ca-
talysis has invariably arisen from four different covalent
groups attached to the tetrahedral center. Our results show
that point chirality induced by mechanical bonding between
an achiral macrocycle and an achiral thread can also be used
to generate a chiral space suitable for asymmetric catalysis.
We anticipate that the expression of mechanically generated
chirality for asymmetric catalysis, either by ligated metals or
through organocatalysis, may be further enhanced through
the structural optimization of the rotaxane components.
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ASSOCIATED CONTENT
Supporting Information
Additional figures and tables, experimental details, synthetic
procedures and characterization data are available in The
Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) (a) Galli, M.; Lewis, J. E. M.; Goldup, S. M. Angew. Chem. Int.
Ed. 2015, 54, 13545. (b) Lee, A.-L.; Nature Chem. 2016, 8, 8.
(8) For examples of rotaxanes that are mechanically chiral by vir-
tue of the two ends of the axle being inequivalent and the macrocy-
cle rotationally unsymmetrical (‘mechanical planar chirality’ or
‘cyclochirality’), see: (a) Yamamoto, C.; Okamoto, Y.; Schmidt, T.;
Jäger, R.; Vögtle, F. J. Am. Chem. Soc. 1997, 119, 10547. (b) Schmieder,
R.; Hübner, G.; Seel, C.; Vögtle, F. Angew. Chem., Int. Ed. 1999, 38,
3528. (c) Reuter, C.; Seel, C.; Nieger, M.; Vögtle, F. Helv. Chim. Acta
2000, 83, 630. (d) Kishan, M. R.; Parham, A.; Schelhase, F.; Yoneva,
A.; Silva, G.; Chen, X.; Okamoto, Y.; Vögtle, F. Angew. Chem., Int. Ed.
2006, 45, 7296. (e) Kameta, N.; Nagawa, Y.; Karikomi, M.; Hiratani,
K. Chem. Commun. 2006, 3714. (f) Makita, Y.; Kihara, N.; Nakakoji,
N.; Takata, T.; Inagaki, S.; Yamamoto, C.; Okamoto, Y. Chem. Lett.
2007, 36, 162. (g) Glen, P. E.; O’Neill, J. A. T.; Lee, A.-L. Tetrahedron
2013, 69, 57. (h) Bordoli, R.; Goldup, S. M. J. Am. Chem. Soc. 2014,
136, 4817. For rotaxanes that exhibit mechanical sequence isomerism,
see: (i) Fuller, A.-M. L.; Leigh, D. A.; Lusby, P. J. J. Am. Chem. Soc.
2010, 132, 4954.
(9) Stereoisomerism that arises through the restriction of compo-
nent dynamics in mechanically interlocked structures, as opposed to
that arising through sequence information in the constitution of the
components (see ref (8a-h)), is conceptually similar to atropisomer-
ism, which formally only refers to restricted rotation about single
bonds.
(10) (a) Chatterjee, M. N.; Kay, E. R.; Leigh, D. A. J. Am. Chem. Soc.
2006, 128, 4058. (b) Alvarez-Pérez, M.; Goldup, S. M.; Leigh, D. A.;
Slawin, A. M. Z. J. Am. Chem. Soc. 2008, 130, 1836. (c) Carlone, A.;
Goldup, S. M.; Lebrasseur, N.; Leigh, D. A.; Wilson, A. J. Am. Chem.
Soc. 2012, 134, 8321.
AUTHOR INFORMATION
Corresponding Author
david.leigh@manchester.ac.uk
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Y.C. and S.E.-C are grateful to the EU for Marie Curie Action
Intra-European Postdoctoral Fellowships. We thank the ERC
and the EPSRC for funding and the EPSRC National Mass
Spectrometry Centre (Swansea, UK) for high resolution mass
spectrometry.
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