Two-stage optimization of a supramolecular catalyst for catalytic asymmetric hydroboration

Article abstract of DOI:10.1039/c1cc16146f

Systematic changes, first to the structure of the catalyst scaffold and then to the ligating groups, are used to fine tune supramolecular catalysts to achieve high regioselectivity (95-98%) and high enantioselectivity (94-97% ee) across a series of meta-substituted styrenes varying in electronic character.

Full text of DOI:10.1039/c1cc16146f

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COMMUNICATION
Two-stage optimization of a supramolecular catalyst for catalytic
asymmetric hydroborationwz
Shin A. Moteki,ya Kazuya Toyama,a Zeyu Liu,b Jing Ma,b Andrea E. Holmesc and
James M. Takacs*a
Received 3rd October 2011, Accepted 2nd November 2011
DOI: 10.1039/c1cc16146f
Systematic changes, first to the structure of the catalyst scaffold
and then to the ligating groups, are used to fine tune supramolecular
catalysts to achieve high regioselectivity (95–98%) and high
enantioselectivity (94–97% ee) across a series of meta-substituted
styrenes varying in electronic character.
principally due to the recent development of stereospecific methods
for their use in C–C bond construction.10
A series of 64 SALs Zn(SXa,RYa) (2), each bearing the parent
TADDOL-derived phosphite a, were prepared in situ via
S
combination of the appropriate subunits Xa and RYa. These
were evaluated under a standard set of reaction conditions for
the rhodium-catalyzed CAHB of 3-methylstyrene (3a, X = Me)
by pinacolborane (PinBH). Enantioselectivity is determined by
chiral GC analysis after oxidative workup. The catalysts
screened exhibit enantioselectivities that vary over a wide range,
distributing rather smoothly from near racemic to greater than
90% ee (Fig. 1). The catalyst derived from SAL Zn(SAa,RAa) is
among the better ones, effecting CAHB of 3a to (S)-4a in
91% ee and with excellent regiocontrol (98%) (Table 1, entry 1).11
The data in entries 2–4 of Table 1 highlight the results of
some key control experiments. Adding the complementary SAa
and RAa subunits but omitting zinc (entry 2) gives lower yield,
enantioselectivity and regioselectivity than SAL Zn(SAa,RAa).
Using two equivalents of a truncated SAL containing the zinc
complex but lacking one of the two phosphite moieties (i.e.,
Zn(SAa,RD), entry 3) gives similar results. The results obtained
in these latter two cases are very similar to those obtained using
two equivalents of the chiral monophosphite (TADDOL)POPh
(entry 4). These experiments show the positive effect of the
Combining bisoxazoline subunits 1 of complementary chirality
with Zn(II) affords the thermodynamically favored heteroleptic
zinc complex 2. By virtue of the modular design, a series of
bifunctional subunits bearing a chiral monophosphite connected
to the bisoxazoline moiety via a phenyl or biphenyl tether can be
used to create dozens of distinct self-assembled ligands (SALs)
2, each possessing a slightly different ligand scaffold. When
combined with metal catalysts, these SALs afford closely related,
but structurally unique, heterobimetallic supramolecular catalysts
differing subtly in the catalyst scaffold.1
While great strides have been made toward mimicking catalytic
behaviours of enzymes using supramolecular coordination
catalysts,2 other than efficient screening methods,3 the protocol
for optimizing the performance of a supramolecular catalyst is
not as well developed as those for traditional homogeneous
catalysts.4 The present study focuses on using a two-step
optimization strategy, first ligand/catalyst scaffold and then
ligating group optimization, to identify catalysts that rival or
exceed the best selectivity previously reported for the catalytic
asymmetric hydroboration (CAHB)5 of a series of meta-substituted
styrenes.6 Methods for catalytic asymmetric synthesis of chiral
organoboranes and related derivatives are of renewed interest,7–9
a Department of Chemistry, University of Nebraska-Lincoln, Lincoln,
Nebraska, USA. E-mail: jtakacs1@unl.edu; Fax: +1 402 472 9402;
Tel: +1 402 472 6232
b School of Chemistry and Chemical Engineering, Institute of
Theoretical and Computational Chemistry, Key Laboratory of
Mesoscopic Chemistry of MOE, Nanjing University, Nanjing,
Jiangsu 210093, People’s Republic of China
c Department of Chemistry, Doane College, Crete, Nebraska 68333,
USA
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: Detailed
procedures and compound characterization. See DOI: 10.1039/
c1cc16146f
Fig. 1 A subset of chiral bisphosphite SALs, Zn(SXn,RYm) (2),
prepared via chirality directed self-assembly of subunits SXn and
RYm using combinations of tethers (e.g., X and Y = A–B) bearing
chiral phosphite ligating groups (TDL)P from among a–d.
y Present address: Laboratory for Specially-Promoted Research on
Organocatalytic Chemistry, Kyoto University, Kyoto, Japan.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 263–265 263

Table 1 Rhodium-catalyzed CAHB of 3a using SAL Zn(SAa,RAa)a
Table 2 Subtle variation of the ligating group further optimizes the
(SAL)Rh-catalyzed CAHB of 3a–ea
SXn
RXn
4a
4b
4c
4d
4e
1
2
3
4
Aa
Ab
Ac
Ad
Ab
Ab
Ac
Bc
Bc
Bc
Aa
Ab
Ac
Ad
Ac
Ac
Bc
Ac
Bc
Cc
91
91
84
57
94
94
88
90
92
88
90
90
92
70
95
93
95
95
93
90
91
90
96
75
94
94
92
92
94
90
92
91
95
78
94
93
92
90
96
90
90
91
95
83
94
93
97
95
95
90
5b
6c
7
% ee of 4a
(% a-isomer 4a)
Entry
RhX
Ligand
8
9
10
1
BF4
BF4
BF4
BF4
Zn(SAa,RAa)
SAa + RAa
91 (98)
73 (90)
73 (85)
70 (81)
2b
3c
4c
Zn(SAa,RD)
(TADDOL)POPh
Screening conditions: 2% Rh(nbd)2BF4, 2.1% SAL, 1.2 PinBH, THF, rt,
14 h. Data reported as % ee of 4. b 0.8 mol% catalyst. c 1.0 mmol
substrate, 0.05% Rh(nbd)2BF4, 0.05% SAL, 1.2 PinBH, THF, rt, 5 h.
a
a
Reaction conditions: 2% Rh(nbd)2BF4, 2% SAL, 1.2 equiv. of Pin BH,
b
THF, rt, 14 h; yields are essentially quantitative. Only subunits SAa and
RAa, no zinc present. Two equivalents of monophosphite.
c
the enantioselectivity for 4 of the 5 substrates. The tert-butyl
derivative (TADDOL d, entry 4) gives only moderate enantio-
selectivity. Incorporating two different ligating groups into the SAL
can further tune catalyst performance. For example, the catalyst
derived from the heterocombination SAL Zn(SAb,RAc) (entry 5)
shows better performance than either Zn(SAb,RAb) or Zn(SAc,RAc)
and is effective at rather low catalyst loading (0.05 mol%, entry 6).
Combining different tethers can be effective. Diastereomeric
SALs Zn(SAc,RBc) and Zn(SBc,RAc) are particularly effective
for the methoxy-(3b) and trifluoromethyl-derivatives (3e). The
highest enantioselectivity for the fluoro-derivative (3d) is
obtained with the catalyst derived from Zn(SBc,RBc). Overall,
systematic changes in the structure of the TADDOL ligating
group permit fine tuning of the supramolecular catalyst to achieve
high enantioselectivity (94–97% ee) and high regioselectivity
(95–98%; see ESIz, Table S2 for details) across the series 3a–e.
As for the nature of the catalyst, several lines of evidence in
addition to those experiments discussed above in the context
of Table 1 suggest that 1 : 1 SAL : Rh chelated structures are
relevant. For example, there are major changes in the circular
dichroic (CD) spectra upon complexation to rhodium (Fig. 3).
The CD spectrum of SAL Zn(SBc,RAc) in dichloromethane
exhibits a bisignate couplet with a zero-crossing at around
316 nm. The bisignate couplet indicates exciton coupling
with negative chirality.14 In contrast, its rhodium complex
(i.e., [Zn(SBc,RAc)Rh(nbd)]BF4) shows a new negative Cotton
effect in the region around 243 nm15 but no bisignate CD is
apparent. In rigid systems, this type of negative bisignate
CD is associated with a negative absolute twist between the
electric transition moments of interacting chromophores.16
The disappearance of this signal indicates a loss of a helical
arrangement in conjunction with a conformational change
ligand scaffold on catalyst performance and suggest that a
chelated SAL–Rh complex is important to the success of entry 1.
Fig. 2 compiles the results obtained for the 64 catalysts with
3-methylstyrene (3a) and four other meta-substituted styrenes
(i.e., 3b–e). Enantioselectivity is expressed in terms of DDGz for
the competing pathways leading to (R)- and (S)-4 and ordered
from the most to the least enantioselective catalyst based on
results obtained for 3a. While the different catalyst scaffolds
effect CAHB with different degrees of efficiency, it is noteworthy
that the enantioselectivity exhibited by a given catalyst often
varies little across the series of substrates; this is especially seen
for the more selective catalysts, e.g., Zn(SAa,RAa) (90–92% ee,
Table 2, entry 1). The data indicate that the substituent does not
strongly influence enantioselectivity in a systematic way.12
Catalyst scaffolds derived from tethers A and B exhibit high
selectivity. These were used in a second stage of catalyst
optimization focusing on varying the shape of the TADDOL
ligating group by employing different aryl substituents.13 Entries
1–4 in Table 2 use tether A with each of the TADDOL-phosphites
a–d. The 3,5-dimethyl-derivative, TADDOL b (entry 2), did not
significantly impact enantioselectivity but did lower regioselectivity
(see ESIz). The 4-methylphenyl derivative, TADDOL c (entry 3),
exhibits the high regioselectivity seen for TADDOL a and improves
Fig. 2 Enantioselectivity (expressed in terms of DDGz) for CAHB
leading to (R)- and (S)-4a–e with 64 supramolecular catalysts.
Fig. 3 CD spectra (230–350 nm in CH2Cl2) of SAL Zn(SBc,RAc)
(black trace) and [Zn(SBc,RAc)Rh(nbd)]BF4 (gray).
c
264 Chem. Commun., 2012, 48, 263–265
This journal is The Royal Society of Chemistry 2012

Notes and references
1 J. M. Takacs, P. M. Hrvatin, J. M. Atkins, D. S. Reddy and J. L. Clark,
New J. Chem., 2005, 29, 263–265; J. M. Takacs, D. S. Reddy,
S. A. Moteki, D. Wu and H. Palencia, J. Am. Chem. Soc., 2004, 126,
4494–4495; J. M. Takacs, K. Chaiseeda, S. A. Moteki, D. S. Reddy,
D. Wu and K. Chandra, Pure Appl. Chem., 2006, 78, 501–509.
2 (a) M. J. Weister, P. A. Ulmann and C. A. Mirkin, Angew. Chem., Int.
Ed., 2011, 50, 114–137; (b) S. Carboni, C. Gennari, L. Pignataro and
U. Piarulli, Dalton Trans., 2011, 40, 4355–4373; (c) J. Meeuwissen and
J. N. H. Reek, Nat. Chem., 2010, 2, 615–621; (d) G. Gasparini,
M. D. Molin and L. J. Prins, Eur. J. Org. Chem., 2010, 2429–2440;
(e) P. W. N. M. van Leeuwen, Supramolecular Catalysis, Wiley-VCH,
Weinhem, 2008; (f) S. J. Reyes and K. Burgess, Chem. Soc. Rev., 2006,
35, 416–423; (g) B. Breit, Angew. Chem., Int. Ed., 2005, 44, 6816–6825;
(h) E. A. Karakhanov, A. L. Maksimiov and E. A. Runova,
Russ. Chem. Rev., 2005, 74, 97–111.
3 J. Wieland and B. Breit, Nat. Chem., 2010, 2, 832–837.
4 J. M. Brown and R. J. Deeth, Angew. Chem., Int. Ed., 2009, 48,
4476–4479, and references cited therein.
5 Reviews: A. M. Carroll, T. P. O’Sullivan and P. J. Guiry, Adv.
Synth. Catal., 2005, 347, 609–631; C. M. Vogels and S. A. Westcott,
Curr. Org. Chem., 2005, 9, 687–699; C. M. Crudden and
D. Edwards, Eur. J. Org. Chem., 2003, 4695–4712; I. Beletskaya
and A. Pelter, Tetrahedron, 1997, 53, 4957–5026; K. Burgess and
M. J. Ohlmeyer, Chem. Rev., 1991, 91, 1179–1191.
6 A previous study on the CAHB of ortho-substituted styrenes showed
the effectiveness of ligand/catalyst scaffold optimization. See:
S. A. Moteki and J. M. Takacs, Angew. Chem., Int. Ed., 2008, 47,
894–896. The two-step optimization protocol described herein has
subsequently been used to further improve catalyst performance.
7 For recent examples of catalyzed hydroborations of 1,3-dienes, see:
R. J. Ely and J. P. Morken, J. Am. Chem. Soc., 2010, 132,
2534–2535; Y. Sasaki, C. Zhong, M. Sawamura and H. Ito,
J. Am. Chem. Soc., 2010, 132, 1226–1227; J. Y. Wu, B. Morequ
and T. Ritter, J. Am. Chem. Soc., 2009, 131, 12915–12917.
8 For recent examples of enantioselective b-borations of a,b-unsaturated
carbonyls, see: A. Guzman-Martinez and A. H. Hoveyda, J. Am.
Chem. Soc., 2010, 132, 10634–10637; I. Chen, M. Kanai and
M. Shibasaki, Org. Lett., 2010, 12, 4098–4101; D. Noh, H. Chea,
J. Ju and J. Yun, Angew. Chem., Int. Ed., 2009, 48, 6062–6064.
9 For recent examples of enantioselective diboration, see: C. H. Schuster,
B. Li and J. P. Morken, Angew. Chem., Int. Ed., 2011, 50, 7906–7909;
L. T. Kliman, S. N. Mlynarski and J. P. Morken, J. Am. Chem. Soc.,
2009, 131, 13210–13211; H. E. Burks and J. P. Morken,
Chem. Commun., 2007, 4717–4725 and references cited therein.
10 D. L. Sandrock, L. Jean-Gerard, C.-Y. Chen, S. D. Dreher and
G. A. Molander, J. Am. Chem. Soc., 2010, 132, 17108–17110;
T. Ohmura, T. Awano and M. Suginome, J. Am. Chem. Soc., 2010,
132, 13191–13192; A. Ros and V. K. Aggarwal, Angew. Chem., Int.
Ed., 2009, 48, 6289–6292; D. Imao, B. W. Glasspoole,
V. S. Laberge and C. M. Crudden, J. Am. Chem. Soc., 2009,
131, 5024–5025; C. M. Crudden, B. W. Glasspoole and C. J. Lata,
Chem. Commun., 2009, 6704–6716 and references cited therein.
11 For CAHB of 3a in as high as 91% ee, see: S. Demay, F. Volant
and P. Knochel, Angew. Chem., Int. Ed., 2001, 40, 1235–1238.
12 The efficiency, regioselectivity and enantioselectivity of vinyl arene
CAHB are thought to depend upon both steric and electronic
influences of aryl substituents, see: A. M. Segarra, E. Daura-Oller,
C. Claver, J. M. Poblet, C. Bo and E. Fernandez, Chem.–Eur. J.,
2004, 10, 6456–6467; D. R. Edwards, Y. B. Hleba, C. J. Lata,
L. A. Calhoun and C. M. Crudden, Angew. Chem., Int. Ed., 2007,
46, 7799–7802; A. C. Maxwella, S. P. Flanagana, R. Goddard and
P. J. Guiry, Tetrahedron: Asymmetry, 2010, 21, 1458–1473 and
references therein.
Fig. 4 Modeled structure of the cis-[Zn(SBc,RBc)Rh(cod)]+ complex.
in going from the free SAL, Zn(SBc,RAc), to the rhodium
complex, [Zn(SBc,RAc)Rh(nbd)]BF4.
The rhodium complex of Zn(SBc,RCc) (Table 2, entry 10),
while not as efficient as the Zn(SBc,RBc) catalyst, is amenable to
structural characterization. HRFAB mass spectrometry finds a
peak at 2363.8108 m/z, consistent with the heterobimetallic
complex, [Zn(SBc,RCc)Rh(nbd)]BF4 (calculated 2363.8009 m/z).
The 31P NMR spectrum of the complex is simple and clean,
exhibiting peaks at 107.7 and 113.6 ppm with Rh–P couplings of
249 and 254 Hz, respectively, and P–P coupling of 38.8 Hz.
DFT calculations at the B3LYP/6-31G (non-metal atoms) and
B3LYP/LanL2DZ (metal atoms) levels were carried out to explore
the possible conformations of cis-[Zn(SBc,RBc)Rh(cod)]+. Fig. 4
presents the predicted most stable conformer from among several
possible configurations (see ESIz). Its structure gives some
preliminary indications of ways in which the ligand/catalyst
scaffold and ligating group substituents influence the topography
around rhodium.
In summary, a series of SALs, each bearing the parent
TADDOL-derived ligating group, was used in the CAHB of
five meta-substituted styrenes varying in steric and electronic
character. The results show that enantioselectivity as a function
of catalyst scaffold varies similarly for all five substrates. This
suggests that enantioselectivity is not strongly correlated with the
nature of the substituent in this series. Scaffolds incorporating
tethers A and B prove to be among the most efficient catalysts.
These were further optimized by varying the aryl substituents on
the TADDOL moiety. In some cases, the most efficient catalyst
combines two different ligating groups in the SAL. Overall,
systematic changes in the structures of the scaffold and ligating
groups permit fine tuning of the supramolecular catalyst to
achieve high regioselectivity (95–98%) and high enantioselectivity
(94–97% ee) across the series of five substrates, 3a–e. The results
rival or exceed the best selectivity previously reported for
each substrate. Computational modelling gives a picture of the
presumed 1 : 1 chelated structure and provides a starting point for
probing structure activity relationships in future studies.
13 D. Seebach, A. K. Beck and A. Heckel, Angew. Chem., Int. Ed.,
2001, 40, 92–138.
14 N. Harada and K. Nakanishi, Circular Dichroic Spectroscopy.
Exciton Coupling in Organic Stereochemistry, University Science
Books, Mill Valley, CA, 1983.
15 A similar peak is seen in the CD upon the addition of Rh(nbd)2BF4
to (TADDOL)POPh in 1 : 2 stoichiometry.
16 I. Akritopoulou-Zanze, K. Nakanishi, H. Stepowska, B. Grzeszczyk,
A. Zamojski and N. Berova, Chirality, 1997, 9, 699–712.
Financial support for this research from the NSF
(CHE-0809637) is gratefully acknowledged. We thank A. Vidol
(ICREA) for preliminary studies modeling the CD spectra,
N. C. Thacker for assistance in the preparation of this manu-
script, the NSF (CHE-0091975, MRI-0079750) and NIH
(SIG-1-510-RR-06307) for the NMR spectrometers used in these
studies carried out in facilities renovated under NIH RR016544.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 263–265 265