A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth-Rhodium Paddlewheel Catalysts

Article abstract of DOI:10.1021/jacs.1c01972

Heterobimetallic bismuth-rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents.

Full text of DOI:10.1021/jacs.1c01972

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A New Ligand Design Based on London Dispersion Empowers Chiral
Bismuth−Rhodium Paddlewheel Catalysts
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Santanu Singha, Michael Buchsteiner, Giovanni Bistoni, Richard Goddard, and Alois Furstner*
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ABSTRACT: Heterobimetallic bismuth−rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the
meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor
carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous
generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new
catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD)
interactions of the peripheral silyl substituents.
dirhodium core; this chiral calyx is maintained in solu-
he first chiral dirhodium carbene characterized by X-ray
Tcrystallography was derived from diazoester 4a and tion.1,27,28 Under the premise that the enantiodetermining
[Rh2(PTTL)4] (1a) (Figure 1).1−4 This particular paddle-
transition state features a similar overall structure, the data
allowed the sense of induction in the cyclopropanation of
styrene to be explained;1 the moderate level of induction (78%
ee) can also be rationalized by the fairly wide aperture of the
chiral binding site, as observed in the solid state. Moreover, the
two Rh atoms reside in notably different ligand environments:
the tert-butyl groups form a narrow but essentially “achiral”
pore about Rh2: any competing background reaction at this site
will reduce the optical purity of the product.1
wheel complex had been chosen not only for its excellent
pedigree in asymmetric catalysis5−26 but also because the
reasons for its efficiency had been subject to debate.27−33
Interestingly, the four N-phthalimido substituents on the tert-
leucine ligands were found to adopt an α,α,α,α-conformation
about the carbene ligand occupying an axial site on the
In a first foray to translate these insights into an improved
catalyst design, the Rh2 center of 1a was formally replaced by
Bi(+2).34−46 For its larger radius, this main group element
imparts a conical shape onto the ligand sphere, which, in turn,
tightens the chiral pocket at the Rh-site. Since Bi(+2) does not
decompose the diazo ester, the racemic background reaction is
essentially shut off. These effects are thought to synergize; they
explain why the heterobimetallic complex [BiRh(PTTL)4]
(2a) led to much improved ee’s in many cases.34 Limitations
were encountered with less electron-rich donor/acceptor diazo
derivatives, which gave rather poor results (see below).34
Initial attempts to remedy this issue by tailoring the
phthalimido groups largely met with failure. Although
perhalogenated phthalimides have proven advantageous in
many cases,47−50 the heterobimetallic complex 2b gave almost
racemic product. The X-ray structure revealed the likely cause:
2b features an inverted calyx, in which the “chiral” environment
envelopes the unreactive Bi(+2) site, whereas the Rh-atom
sees the tert-butyl substituents.34 The substituted phthalimido
Received: February 19, 2021
Published: April 8, 2021
Figure 1. Prior art. The “paddles” in the schematic drawing represent
the (substituted) phthalimido groups, R = tBu.
© 2021 The Authors. Published by
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groups are more encumbered and hence flank the Bi(+2)
center, simply because the larger cation provides more space.34
An improved design needs to provide rigorous control over
the directionality of the chiral ligand sphere while allowing the
substitution pattern to be fine-tuned. To this end, we planned
to employ London dispersion as a noncovalent but attractive
interaction to lock the desirable conformation in place. It is
increasingly clear that multiple intramolecular contacts can
outweigh steric repulsion and be structure-determining;51,52
although this effect might be more prevalent in (organo-
metallic) catalysis than commonly appreciated,51,53−56 exam-
ples of deliberate use of London dispersion (LD) as a key
design principle for the development of new catalysts with
improved application profiles are exceedingly rare.57−59
Outlined below we present such a case.
crystallographic standards was obtained (see the Supporting
Information (SI)). As expected, complex 3a adopts an α,α,α,α-
conformation, in which the silylated aryl rings envelope the Bi-
center whereas the phthalimides form a narrow chiral pocket
about Rh (Figure 2). The steric demand of the TIPS groups is
To reach this goal, the tert-leucine-derived ligands of 2a,b,
which are too far apart for any LD among them,34 were
replaced by phenylglycine derivatives carrying TIPS-groups at
the meta-positions of the aromatic ring; the latter were
expected to mediate a sufficient number of intramolecular
contacts to entail stabilization via dispersion interactions
(Scheme 1).60−62 Commercial benzyl alcohol 6 was O-silylated
a
Scheme 1
Figure 2. Structure of complex 3a in the solid state; disordered parts
are shown with dashed bonds, H atoms omitted for clarity; for further
information, see the SI.
manifested in innumerous short H···H and H···C contacts in
the periphery. The crystallographic data, however, do not allow
us to decide whether these contacts mediate LD and are hence
stabilizing, or whether they are repulsive as a consequence of
steric hindrance.
This aspect was addressed by DFT calculations.66,67 To this
end, the structures of 3a,b were computed with and without
D3 (BJ) dispersion correction at the PBE level of theory (see
the SI).68,69 Details apart, the computations are unambiguous
in that dispersion renders the structures notably more
compact. In energetic terms, it entails stabilization of 3a and
3b by no less than −9.9 and −11.6 kcal·mol−1, respec-
tively.70,71 LD is therefore clearly a major structure
determinant.72 Deconvolution validates the original design
a
Reagents and conditions: (a) TIPSCl, DBU, CH2Cl2, 99%; (b)
tBuLi, THF, −78 °C → rt, then TIPSCl, −20 °C → rt; (c) TBAF,
THF, −20 °C → rt, 74% (over both steps); (d) PCC, CH2Cl2, 94%;
(e) (R)-tBuS(O)NH2, Ti(OEt)4, THF, 70 °C, 84%; (f) vinyl-
magnesium bromide, Me2Zn (50 mol %), THF, −78 °C, 87% (dr =
99:1); (g) (i) HCl/1,4-dioxane, MeOH; (ii) aq. NaOH, 90% (iii)
(substituted) phthalic anhydride, Et3N, toluene, reflux, 75% (10a),
73% (10b); (h) RuCl3·H2O (5 mol %), NaIO4, CCl4, MeCN, H2O,
74% (11a, 96% ee), 69% (11b, 98% ee); (i) [BiRh(OCOCF3)4],
toluene, reflux, 81% (3a), 94% (3b).
concept:73 the TIPS-groups account for ∼32% of ΔEdisp
,
whereas the contribution of the tBu groups in 3b is smaller but
still appreciable (∼12%); in structural terms, however, this
extra factor visibly tightens the chiral binding site on the Rh-
face in 3b (Figure 3).
To explore the catalytic performance of the new
heterobimetallic complexes, the cyclopropanation of styrene
with the fluorinated diazo derivative 4b was chosen as a test
reaction (Table 1). Neither [Rh2(PTTL)4] (1a) nor [BiRh-
(PTTL)4] (2a) gave good results,34 whereas the new complex
3b furnished product 5b (R = Me) with 90% ee. The
corresponding trichloroethyl ester proved even more success-
ful:74,75 once again, replacement of 2a by either of the new
complexes led to massive improvements. The fact that 3a and
3b both perform very well but 3b is the better of the two is in
excellent accord with the conclusions drawn from the DFT
calculations: the peripheral −TIPS groups make the larger
contribution to the stabilization of the chiral ligand sphere, but
the tBu− substituents on the phthalimide residues pay an
additional dividend. This notion is further supported by a
prior to metal/halogen exchange and quenching of the dilithio
species with TIPSCl. Product 7 was elaborated into tert-
butylsulfinyl imine 8,63 which reacted with vinylmagnesium
bromide in the presence of ZnMe2 to give 9 as a single isomer
(dr ≈ 99:1). The auxiliary was removed and the phthalimide of
choice64 introduced before the double bond of 10 was cleaved
with RuCl3 cat./NaIO4 to avoid racemization. The resulting
acids 1165 were reacted with [BiRh(OCOCF3)4] in boiling
toluene and the released trifluoroacetic acid trapped with
K2CO3 in a Soxhlet apparatus to furnish complexes 3 in
excellent yield.
Although 3a crystallizes well, the many degrees of rotational
freedom of the eight peripheral TIPS groups cause disorder.
This complication notwithstanding, a data set meeting good
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24% ee (see the SI). The fact that the outcome is fairly
independent of the medium (pentane versus CH2Cl2) can be
taken as additional indirect evidence for LD being operative in
solution.76 Under the optimized conditions, product 5b′ was
formed in essentially quantitative yield with 98% ee as a single
diastereomer.
Formal replacement of a Rh(+2) center by Bi(+2) usually
entails a loss in reactivity.34−38 When seen against this
backdrop, the rate with which cyclopropane 5a was formed
by 3 even at −10 °C is truly remarkable (Figure 4): conversion
Figure 4. Kinetic profiling: Formation of 5a using different BiRh-
paddlewheel complexes (0.25 mol %, pentane, −10 °C).
was complete within 10 min at 0.25 mol % catalyst loading,
whereas it took >3 h with the parent complex 2a.77 The fact
that the visibly more crowded catalysts lead to notably higher
ratesin contrast to what one would expect from a confined
spaceindicates stabilizing LD interactions with the incoming
substrate. The new design hence entails excellent selectivity
and reactivity at the same time. The high solubility of 3a,b in
the common solvents even at low temperatures is an additional
asset.
These rewarding results suggested that it should be possible
to reduce the loading to partly compensate for the high
molecular weights of 3a,b. Indeed, no drop in productivity or
optical purity was noticedwithout any further optimization
of the conditionswhen the reaction was performed with only
0.005 mol % of 3b on a mmol scale (Table 1, entry 10).78 The
robustness of these conditions was confirmed by the additional
example shown in Table 2 (entry 6, 1.3 g scale).79
Figure 3. Side-view of the structure of 3b as computed at the PBE/
def2-SVP level of theory without (top) and with (bottom) D3 (BJ)
dispersion correction
a
Table 1. Screening
The scope is broad, the level of induction is invariably
excellent, and the reactions are typically very clean; therefore,
basically quantitative yields were obtained in most cases (Table
2). α-Aryl-α-diazo esters comprising a strong donor substituent
perform so well with the parent complex [BiRh(S-PTTL)4]
(2a) that there was no real need to resort to 3a,b (entries 1−
4).34 However, diazoesters comprising less electron-rich aryl
groups strongly benefitted from their use: in all cases
investigated, 3b led to significantly higher levels of induction,
with ee’s often approaching 99% (entries 5−21). This striking
invariance of the results upon substantial modulation of the
diazo compound is deemed another favorable distinguishing
feature of the new catalyst.80
Excellent results were also obtained with donor/acceptor α-
diazo ketones (entries 24, 25), which previously required
forcing conditions and recourse to special media.81 With
catalyst 3b, these challenging substrates react even at −10 °C.
Likewise, donor/donor carbenes are well behaved,2,82,83 again
furnishing the corresponding cyclopropanes with outstanding
levels of enantio- and diastereoselectivity (entries 26−28).
Entry
R
Catalyst
Mol %
ee
b
1
2
3
4
5
6
7
8
Me
Me
Me
1a
2a
3b
2a
3a
3b
3b
3b
3b
3b
3b
1
1
1
1
1
1
1
1
32%
35%
90%
58%
91%
95%
94%
98%
98%
97%
b
b
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
c
b
b e
,
9
10
11
0.1
0.005
0.001
b e
,
d
n.d.
a
All reactions were performed in pentane at RT; the yield of product
(NMR) was ≥90%. At −10 °C. In CH2Cl2. Incomplete conversion
after 24 h. 1 mmol scale
b
c
d
e
control experiment with a catalyst analogous to 3a but lacking
the peripheral TIPS-groups, which gave product 5b′ with only
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a b
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,
thylsilane, and allyl(pinacol)boronate, some of which have
been rarely used before. Even allyl bromide reacts cleanly
(entry 14): we are unaware of any prior use in asymmetric
cyclopropanation. The same is true for exo-methylenecyclobu-
tane and -hexane, which furnish spirocyclic products (entries
22, 23); in these cases, the superiority of 3b is particularly
evident.
Table 2. Asymmetric [2 + 1] Cycloadditions
Although less comprehensive, the foray into the cyclo-
propenation of terminal alkynes was no less gratifying (entries
29−32). Most notable is the use of propargyl chloride, which
leads to a multifunctional building block that promises rich
downstream chemistry. Equally remarkable and largely
unprecedented is the fact that cyclopropenation of a terminal
alkyne is faster than insertion of the carbene intermediate into
an unprotected alcohol (entry 32).84−87 To put these results
into perspective, one has to note that [Rh2(esp)2]88 or
[Rh2(OTpa)4] (OTpa = triphenylacetate) as some of the most
proficient achiral catalysts known to date furnished only
complex mixtures on reaction with these functionalized
alkynes.89
Finally, the new catalysts were briefly examined in reactions
other than [2 + 1] cycloadditions. Although a more systematic
foray has to await further studies, the preliminary data obtained
for prototype C−H and Si−H insertion reactions are
promising (Table 3). When compared with the current state-
a
Table 3. C−H and Si−H Insertion Reactions
a
Color code as shown in Table 2; pentane, −10 °C, 1 mol % catalyst
loading. In cyclohexane. With [Rh2(R-PTAD)4]: 56% ee (49%).90
b
c
of-the-art,90 the formation of a benzodihydrofuran by intra-
molecular insertion of a donor/donor carbene into a methyl
ether makes a particularly compelling case (entry 2). Whereas
2a performed poorly in the particularly taxing reaction of 4a
with Et3SiH, 3b resulted in clean conversion and an excellent
overall result.11,91−98
In summary, a new class of heterobimetallic paddlewheel
complexes is presented, which take advantage of LD to
stabilize the shape and directionality of the calyx that forms the
chiral binding pocket. 3a,b as the parent complexes of this
series excel in cyclopropanation, cyclopropenation, and certain
insertion reactions; as many variations of the conceptually new
design can be envisaged, one may have high expectations for
future generations of catalysts of this type. Opportunities along
these and related lines99,100 are actively pursued in our
laboratory.
a
b
Color code: black, 2a; red, 3b. Pentane, −10 °C, 1 mol % catalyst
c
d
e
loading. In CH2Cl2/pentane. At rt. In CH2Cl2
In addition to (substituted) styrenes, many other terminal
alkenes proved suitable, including vinyl benzoate, allyltrime-
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̀
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01972.
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Experimental Section containing supporting crystallo-
graphic data, computational data, characterization data,
and NMR spectra of new compounds (PDF)
Accession Codes
CCDC 2063745−2063748 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Alois Fu
45470 Mu
0098-3417; Email: fuerstner@kofo.mpg.de
̈
rstner − Max-Planck-Institut fu
̈
r Kohlenforschung,
̈
lheim/Ruhr, Germany; orcid.org/0000-0003-
Authors
Santanu Singha − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0003-
4236-4366
Michael Buchsteiner − Max-Planck-Institut fu
Kohlenforschung, 45470 Mulheim/Ruhr, Germany;
orcid.org/0000-0001-5169-3458
Giovanni Bistoni − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0003-
4849-1323
Richard Goddard − Max-Planck-Institut fu
45470 Mulheim/Ruhr, Germany; orcid.org/0000-0003-
0357-3173
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01972
Author Contributions
§S.S. and M.B. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Max-Planck-Gesellschaft is
gratefully acknowledged. We thank Dr. L. Collins and Mr. S.
Auris for exploratory studies, Dr. M. Leutzsch for help with the
kinetic experiments, and the Analytical Departments of this
Institute for excellent support.
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