Sequential enantiodivergent organocatalysis: Reversibility in enantioswitching controlled by a conformationally flexible guanidine/bisthiourea organocatalyst

Article abstract of DOI:10.1039/c3ob27479a

Here we describe our studies on solvent-dependent enantiodivergent Mannich-type reactions utilizing conformationally flexible guanidine/bisthiourea organocatalyst (S,S)-1. Our mechanistic investigations revealed that the stereo-determining steps in both t

Full text of DOI:10.1039/c3ob27479a

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Sequential enantiodivergent organocatalysis:
reversibility in enantioswitching controlled by a
conformationally flexible guanidine/bisthiourea
organocatalyst†‡
Cite this: DOI: 10.1039/c3ob27479a
Yoshihiro Sohtome,§* Takahisa Yamaguchi, Shinji Tanaka and Kazuo Nagasawa*
Here we describe our studies on solvent-dependent enantiodivergent Mannich-type reactions utilizing
conformationally flexible guanidine/bisthiourea organocatalyst (S,S)-1. Our mechanistic investigations
revealed that the stereo-determining steps in both the (R)- and (S)-selective Mannich-type reactions are
governed by the cooperative effect of guanidine and thiourea in the inherently monomeric structure of
(S,S)-1. Based on the mechanistic similarity between the (R)- and (S)-selective Mannich-type reactions, we
discovered that (S,S)-1-catalyzed reactions show unique reversibility in mixed solvent systems. We high-
light the development of sequential enantiodivergent organocatalysis using (S,S)-1, which allows
enantio-switching with single-flask operation and high in situ tunability.
Received 21st December 2012,
Accepted 26th February 2013
DOI: 10.1039/c3ob27479a
www.rsc.org/obc
single flask. Thus, construction of dynamically switchable
catalytic systems from a single chiral molecular framework is
Introduction
Asymmetric bifunctional catalysis, in which discrete functional an important goal. Such studies may also contribute to a
groups on the same catalyst can simultaneously activate both convergence of molecular catalysts and enzymes, which can
nucleophile and electrophile, is a powerful synthetic strategy display diverse functions in living cells.9
to generate optically active compounds through catalytic
A simple model to examine the feasibility of constructing
bond-forming reaction.1–3 Asymmetric bifunctional catalysts enantiomerically distinct chiral environments utilizing
a
obtained by designing suitable combinations of catalytic active single chiral catalyst is enantiodivergent catalysis, in which
sites and chiral ligand(s)/spacer(s) have been used for vast each enantiomer can be catalytically formed (Fig. 1a).5 Since
numbers of asymmetric catalytic transformations over the last the seminal work on enantioswitching in the reduction of
two decades. In sharp contrast, dynamic bifunctional catalysis, unsymmetric ketones with stoichiometric chiral alkoxyalumi-
based on the use of a single chiral source, has only recently nium hydrides in 1972,10 various types of enantioswitching
emerged.4 The methodology is potentially applicable to not induced by metal catalysts have been sporadically reported.5
only stereodivergent catalysis,5,6 but also programmed cascade Broadly speaking, the preparation of different sets of metal
reactions with a single chiral catalyst.7,8 Because efficient dis-
sociation of the catalyst/product complex results in high cata-
lyst turnover, in situ generation of another active species with a
single chiral catalyst to promote the second catalytic reaction
is feasible, enabling such programmed-cascade reactions in a
Department of Biotechnology and Life Science, Faculty of Technology,
Tokyo University of Agriculture and Technology, 2-24-26 Naka-cho, Koganei, Tokyo,
Japan. E-mail: knaga@cc.tuat.ac.jp, sohtome@riken.jp;
Fax: (+81) 42-388-7295(+81) 48-462-4666;
Tel: (+81) 42-388-7295, (+81) 48-467-9374
†Dedicated to Professor Andrew D. Hamilton on the occasion of his 60th
birthday.
‡Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob27479a
§Present address: Synthetic Organic Laboratory, Advanced Science Institute,
RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Fig. 1 (a) Enantiodivergent organocatalysis and (b) sequential enantiodiver-
gent organocatalysis with a single organocatalyst.
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active species, including monomers or oligomers, by tuning
the coordination ability of metals to chiral ligands, substrates,
solvents and additives is considered to be a key requirement
for developing metal-based stereodivergent reactions. On the
other hand, organocatalytic enantiodivergent reactions exploit-
ing inorganic salt- or additive-dependent strategies were rarely
reported11,12 before our methodology was developed.13 As
various types of transition state-mode switching induced by
the coordination of achiral additives to a chiral catalyst and/or
substrate have been investigated, the substrate scope and
enantioselectivity in enantiodivergent organocatalysis have
been gradually improved.12,14–16 While these approaches
provide the capability to toggle the enantioselectivity con-
trolled by a single chiral organocatalyst, the development of a
strategy that can be reversibly applied to a variety of catalytic
stereodivergent reactions is highly desirable. Here, we describe
our studies to gain insight into the molecular mechanism of
solvent dependence in the Mannich-type reaction17–19 by utiliz-
ing guanidine/bisthiourea organocatalyst (S,S)-1.13,20 In par-
ticular, we highlight the reversibility of the solvent-dependent
stereo-discrimination as a new aspect of this conformationally
flexible organocatalyst, enabling the development of sequen-
tial enantiodivergent organocatalysis (Fig. 1b).6a,b
Fig. 2 (a) Solvent-dependent enantiodivergent Mannich-type reaction of 2
with 3 utilizing (S,S)-1 under optimized conditions; (b) Eyring plots of (S,S)-1-
catalyzed Mannich-type reactions of 2a (Ar1 = Ph) with 3a (R2 = Me) in various
solvents. (b-1) (R)-Selective reactions in EtOAc (open circle), THF (open triangle),
EtCN (open square) and MeCN (open diamond); (b-2) (S)-selective reactions in
toluene (closed circle), m-xylene (cross), chlorobenzene (closed triangle) and
CH2Cl2 (closed diamond).
Results and discussion
Our research group previously explored the solvent-dependent
Mannich-type reactions of aromatic N-Boc aldimines 2 with
malonates 317–19 based on the mechanistic hypothesis that the
population of the conformers of 1, in which the relative
arrangements of guanidine and thiourea functional groups are
enantiomerically distinct, can be altered by tuning the reaction
conditions (Fig. 2).13 This simple methodology has a broad
applicability to aromatic N-Boc imines and it displays extra-
ordinary high reactivity (maximum catalyst turnover frequency:
66 h−1) and dual enantioselectivity, giving the (S)-products
(87–97% ee) in m-xylene and the (R)-products (80–89% ee) in
acetonitrile. We also established that the stereoselectivity of
(S)-selective Mannich-type reactions in non-polar solvents is
governed by the difference in entropies of activation (ΔΔS‡S–R),21
while the stereo-discrimination in (R)-selective reactions is
based on the difference in enthalpies of activation (ΔΔH‡R).22
The design of guanidine/bisthiourea bifunctional organo-
catalysts23,24 was originally inspired by the differences of
chemoselectivity between guanidinium and thiourea
functionalities reported by Hamilton’s group.25,26 We aimed to
activate a nucleophilic anion with a guanidine base, and a
Lewis basic electrophile with a thiourea functionality in order
to develop catalytic asymmetric bond-forming reactions by uti-
Fig. 3 Studies on the relationship between structure and catalytic activity in
enantiodivergent Mannich-type reactions.
lizing proximity effects.1–3 However, in (R)-selective reactions the structure–activity relationship of the catalytic active sites
using (S,S)-1, Lewis-basic acetonitrile might coordinate with by using structural variants of (S,S)-1 (Fig. 3).27 When the opti-
the thiourea functionality in (S,S)-1. Thus, the possibility that mized reaction conditions for (S,S)-1-catalyzed reactions were
only guanidine in (S,S)-1 exerts inherent activity as a Brønsted employed for (S,S)-5, in which the guanidine moiety of (S,S)-1
base through functional masking of the thiourea by aceto- is replaced with a thiourea group, no reaction occurred due to
nitrile could not be excluded. Therefore, we set out to examine the loss of Brønsted basicity. In contrast, the chiral
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monofunctional guanidine obtained by removal of the thiourea chirality in the product, despite the existence of an enormous
group from (S,S)-1 showed drastically decreased enantioselec- number of interconvertible conformers. This is a unique
tivity (for compound (S,S)-6: 97% yield, 1% ee in acetonitrile, feature of the solvent-dependent stereo-discrimination process
99% yield, 0% ee in toluene). These results are not consistent controlled by (S,S)-1 through enthalpy–entropy compensation-
with the idea that solvent coordination with thiourea in the mode switching: the inherent conformation of (S,S)-1 is dyna-
catalyst can explain the origin of solvent-dependent enantio- mically changed to hold the nucleophilic anion and electro-
divergence. It can be concluded that (1) the guanidine base in phile in a suitable proximity.
(S,S)-1 is essential for promoting the reaction, and (2) both
The observed mechanistic similarities between (R)- and
guanidine and thiourea functionalities in (S,S)-1 cooperatively (S)-selective Mannich-type reactions, in which a cooperative
govern the stereo-discrimination processes in solvent-depen- effect of guanidine and thiourea in monomeric (S,S)-1 operates
dent enantiodivergent Mannich-type reactions.
to control the stereo-determining steps, stimulated us to
Another important consideration in the solvent-dependent examine the Mannich-type reaction in an acetonitrile/m-xylene
enantiodivergent reaction using (S,S)-1 is the aggregation mixed solvent system in order to evaluate the tunability of the
mode of the catalyst. In general, the assembly state is an catalyst 1. In the previously developed solvent-dependent
important determinant of ordered conformation of acyclic enantiodivergent reactions, we had used two distinct reaction
compounds.28 For example, we observed a non-linear relation- flasks, containing a polar solvent or a non-polar solvent, to
ship29 between ee of the catalyst and ee of the product in the selectively obtain the (R)- or (S)-enantiomer, respectively. In
nitroaldol reaction30 and the phospha-Michael reaction31 the (S,S)-1-catalyzed Mannich-type reaction of 2a with 3a,
under water-containing biphasic conditions, suggesting the acetonitrile gave the best (R)-selectivity, while m-xylene or
importance of catalyst assembly in those stereo-discrimination toluene gave the best (S)-selectivity. As shown in Fig. 5, the (S)-
processes. Interestingly, when we examined the (S,S)-1-cata- selectivity was gradually decreased as the content of m-xylene
lyzed Mannich-type reactions, the relationship between the % in the mixed solvent was decreased. The major enantiomer
ee of (S,S)-1 and that of Mannich adduct 4 was linear in both switched from (S)- to (R)-4aa beyond the equipodal content
acetonitrile and toluene (Fig. 4), suggesting that the stereo- ratio, and the (R)-selectivity increased as the ratio of aceto-
discrimination process in the solvent-dependent enantio- nitrile was further increased. Thus, the ee value of 4aa is
divergent Mannich-type reaction is controlled not by dimer or highly responsive to, and well correlated with, the solvent
oligomers, but by the monomeric form of the catalyst.32,33
content, giving a sigmoid-like relationship between ee of the
Because the ee values in both acetonitrile and toluene are product and the solvent ratio in the solvent-dependent enantio-
independent of percentage conversion, the stereoselectivities divergent catalysis.19c Considering the difficulty of removing
of both (R)- and (S)-products are kinetically governed. Thus, generally employed switching triggers, such as metal or addi-
the stereo-discrimination processes are apparently different tive,5,6,12 from the reaction medium, the observed fine-tunabil-
from those seen in other stereodivergent catalytic reactions ity of the solvent-dependent enantiofacial switching using
that utilize statically stable conformers of the catalyst.6,14,15 (S,S)-1 is expected to provide a potentially useful strategy for
Specifically, the relative arrangement between guanidine and reversibly modulating chiral environments with the use of a
thiourea in (S,S)-1 seems to be kinetically transferred to the single organocatalyst.
Fig. 4 Relationships between the ee value of (S,S)-1 and 4aa in the Mannich-
type reaction of 2a with 3a.
Fig. 5 Relationship between the ee of 4aa and m-xylene/acetonitrile content
in (S,S)-1-catalyzed Mannich-type reaction of 2a with 3a.
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Scheme 1 Sequential organocatalytic enatiodivergent Mannich-type reactions in a single flask.
Encouraged by these results, we further assessed the feasi- way to improve the catalytic efficiency in the sequential
bility of dynamic enantioswitching with single-flask opera- enantiodivergent reaction.
tion.6a,b Since removal and exchange of the reaction solvent
are easy, we examined the sequential catalytic enantiodivergent
reactions shown in Scheme 1. In the designed protocol, the
solvent was evacuated after completion of the first Mannich-
Conclusions
type reaction of 2a with 3a. Subsequently, the second Here, we have described our studies on solvent-dependent
Mannich-type reactions were performed using a different reac- enantiodivergent Mannich-type reaction, focusing on its appli-
tion medium. In protocol (a), after the initial generation of (R)- cation to sequential enantiodivergent organocatalysis. Our
4aa (99% yield, 88% ee) in the reaction conducted in aceto- mechanistic investigations revealed that the bifunctionality in
nitrile, reversal of enantioselectivity in the second Mannich- the inherently monomeric (S,S)-1 plays a crucial role in govern-
type reactions was induced by using m-xylene as the reaction ing the unique stereo-discrimination processes in the
solvent, affording the corresponding Mannich adducts (S)-4ba Mannich-type reaction. By exploiting the ease of tuning of
and (S)-4ca, in 99% yield with 94% ee (run 1) and 90% yield solvent-dependent enantio-differentiation, we successfully
with 93% ee (run 2), respectively.34 The preference of the enantio- developed sequential enantiodivergent reactions using (S,S)-1,
selectivity in the newly developed sequential enantio-diver- demonstrating its in situ tunability in a single flask. We believe
gent Mannich-type reaction can be bidirectional. As shown in that the reaction design criteria suggested by this work will be
protocol (b), (S)-4aa (99% yield, 92% ee) in the first Mannich- applicable to other dynamic asymmetric organocatalysis reac-
type reaction using m-xylene was produced, followed by gener- tions with high predictability and dual selectivity. Further
ation of (R)-4ba (87% yield, 80% ee), was generated in the efforts to apply sequentially switchable organocatalysis to
second reaction that was carried out in acetonitrile (run 3).35 other classes of asymmetric transformation are ongoing in our
These experiments described in Scheme 1 demonstrated for research group.
the first time that the enantioselectivity preference of a single
organocatalyst can be switched in a single flask. This in situ
tunability of “enantio-divergence” is different from sequential
Experimental
1. General details
diastereodivergent reactions reported with rare earth metal6a
or diphenyl hydrogen phosphate (DPP)6b as a diastereo-switch-
ing trigger, in which orthogonal mechanisms are operating for Flash chromatography was performed using silica gel 60
the generation of anti- and syn-products. Further work is under (spherical, particle size 0.040–0.100 mm; Kanto Co., Inc.,
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Japan). Optical rotations were measured on a JASCO P-2200 major: 31.2 min),13,36 (+)-(S)-4ba (Chiralpak OD–H, 0.46 cm (ϕ)
1
polarimeter. H and 13C NMR spectra were recorded on JEOL × 25 cm (L), n-hexane–2-propanol = 90/10, 1.0 mL min−1
,
EX300 and ECA/ECX400 instruments. Chemical shifts in major: 8.3 min, minor: 7.8 min).13
chloroform-d were reported relative to the chloroform-d signal
Spectral data of 4aa.13,36 1H NMR (400 MHz, CDCl3) δ
at 7.26 ppm for H NMR. For 13C NMR, chemical shifts were 7.34–7.23 (m, 5H), 6.14 (br s, 1H), 5.49 (br s, 1H), 3.92 (br s,
reported relative to the chloroform-d signal at 77.0 ppm as an 1H), 3.74 (s, 3H), 3.63 (s, 3H), 1.42 (s, 9H). 13C NMR (100 MHz,
internal reference. Mass spectra were recorded on JEOL CDCl3) δ 168.4, 167.5, 155.1, 139.3, 128.6, 127.6, 126.1, 79.8,
1
JMS-T100LC and JEOL JMA-HX110 spectrometers.
56.6, 53.3, 52.8, 52.5, 28.2. HRMS (ESI, M + Na) calcd for
C17H23N1Na1O6 360.1423, found 360.1444.
2. Typical procedure for Mannich-type reaction (Fig. 5)
Spectral data of 4ba.13 1H NMR (400 MHz, CDCl3) δ 7.21 (d,
To a mixture of (S,S)-1 (7.7 mg, 0.01 mmol) and N-Boc ald- J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.07 (br, 1H), 5.42 (br,
imine 2a (20.5 mg, 0.1 mmol) in m-xylene (1.0 mL) was added 1H), 3.88 (br, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 3.64 (s, 3H), 1.41
dimethyl malonate (0.014 mL, 0.12 mmol) at −10 °C. After stir- (s, 9H). 13C NMR (100 MHz, CDCl3) δ 168.4, 167.5, 158.9,
ring for 24 h at −10 °C, the reaction was quenched by the 155.0, 131.43, 127.3, 113.9, 79.7, 56.8, 55.2, 52.9, 52.8, 52.5,
addition of saturated NH4Cl aq. The resulting mixture was 28.2. HRMS (ESI, M + Na+) calcd for C18H25N1Na1O7 390.1529,
diluted with EtOAc and poured into water. The aqueous layer found 390.1526.
was extracted with EtOAc (×3) and the combined organic layer
Spectral data of 4ca.13,36 1H NMR (400 MHz, CDCl3) δ
was washed with brine, and then dried over MgSO4. Solvent 7.21–7.18 (m, 1H), 6.94–6.90 (m, 2H), 6.11 (br, 1H), 5.71 (br,
was removed under reduced pressure, and the residue was pur- 1H), 4.00 (br, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 1.43 (s, 9H). 13C
ified by flash column chromatography (neutral SiO2, n-hexane– NMR (100 MHz, CDCl3) δ 168.3, 167.2, 154.9, 143.5, 126.9,
EtOAc = 20/1 to 10/1 and CHCl3–MeOH = 9/1) to afford (+)-(S)- 124.8, 124.4, 80.0, 56.6, 53.0, 52.7, 49.9, 28.2. HRMS (ESI,
4aa (32.7 mg, 97% yield) and (S,S)-1·HCl (8.1 mg, 99% recov- M + Na) calcd for C15H21N1Na1O7 350.1216, found 350.1242.
ery). The enantiomeric excess of (+)-(S)-4aa (92% ee) was deter-
mined by means of chiral HPLC analysis (Chiralpak AD-H,
0.46 cm (ϕ) × 25 cm (L), n-hexane–2-propanol = 90/10, 1.0 mL
min−1, major; 23.3 min, minor; 31.2 min). The absolute stereo-
chemistry of (+)-(S)-4aa was determined based on the retention
time and optical rotation reported previously.13,36 The reac-
tions were performed in m-xylene–acetonitrile = 90/10, 80/20,
50/50, 20/80, 10/90 and 0/100, respectively. The ee value of 4aa
is plotted against the m-xylene–acetonitrile solvent ratio
in Fig. 5.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scienti-
fic Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan.
3. A procedure for sequential organocatalytic
enantiodivergent Mannich-type reaction (Scheme 1, run 1)
Notes and references
To a mixture of (S,S)-1 (7.7 mg, 0.01 mmol) and N-Boc ald-
imine 2a (20.5 mg, 0.1 mmol) in acetonitrile (1.0 mL) was
added dimethyl malonate (0.014 mL, 0.12 mmol) at −30 °C.
After stirring for 24 h at −30 °C, the reaction solvent was
removed under reduced pressure. Then, a solution of 2b
(23.6 mg, 0.1 mmol) in m-xylene and additional dimethyl malo-
nate (0.014 mL, 0.12 mmol) were added at −10 °C. After stir-
ring for 24 h at −10 °C, the reaction was quenched by the
addition of saturated NH4Cl aq. The resulting mixture was
diluted with EtOAc and poured into water. The aqueous layer
was extracted with EtOAc (×3) and the combined organic layer
was washed with brine, and then dried over MgSO4. Solvent
was removed under reduced pressure, and the crude residue
was purified by flash column chromatography (neutral SiO2,
n-hexane–EtOAc = 10/1, 5/1, 1/1 and CHCl3–MeOH = 9/1) to
afford the (−)-(R)-4aa (33.7 mg, 99% yield), (+)-(S)-4ba
(36.7 mg, 99% yield) and 1a·HCl (8.1 mg, 99% recovery). The
enantiomeric excess values of (−)-(R)-4aa (88% ee) and (+)-(S)-
4ba (81% ee) were determined by means of chiral HPLC ana-
lysis; (−)-(R)-4aa (Chiralpak AD-H, 0.46 cm (ϕ) × 25 cm (L),
n-hexane–2-propanol = 90/10, 1.0 mL min−1, minor: 23.3 min,
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29 A recent review, see: T. Satyanarayana, S. Abraham and 33 NMR studies also support this idea, because the C2-sym-
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various reaction temperatures, in contrast to ref. 32a
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31 Y. Sohtome, N. Horitsugi, R. Takagi and K. Nagasawa, Adv. 34 In the absence of (R)-4aa, (S)-4ba was obtained in 99%
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32 (a) G. Tárkányi, P. Király, V. Szilárd, B. Vakulya and T. Soós,
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97% ee.13
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This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.