Design and Synthesis of Novel Chiral Dirhodium(II) Carboxylate Complexes for Asymmetric Cyclopropanation Reactions

Article abstract of DOI:10.1002/chem.201504817

A novel approach to the design of dirhodium(II) tetracarboxylates derived from (S)-amino acid ligands is reported. The approach is founded on tailoring the steric influences of the overall catalyst structure by reducing the local symmetry of the ligand's N-heterocyclic tether. The application of the new approach has led to the uncovering of [Rh₂(S-^tertPTTL)₄] as a new member of the dirhodium(II) family with extraordinary selectivity in cyclopropanation reactions. The stereoselectivity of [Rh₂(S-^tertPTTL)₄] was found to be comparable to that of [Rh₂(S-PTAD)₄] (up to >99 % ee), with the extra benefit of being more synthetically accessible. Correlations based on X-ray structures to justify the observed enantioinduction are also discussed.

Full text of DOI:10.1002/chem.201504817

DOI: 10.1002/chem.201504817
Full Paper
&
Cyclopropanation Catalyst
Design and Synthesis of Novel Chiral Dirhodium(II) Carboxylate
Complexes for Asymmetric Cyclopropanation Reactions**
Frady G. Adly,[b] Michael G. Gardiner,[c] and Ashraf Ghanem*[a]
Abstract: A novel approach to the design of dirhodium(II)
tetracarboxylates derived from (S)-amino acid ligands is re-
ported. The approach is founded on tailoring the steric influ-
ences of the overall catalyst structure by reducing the local
symmetry of the ligand’s N-heterocyclic tether. The applica-
tion of the new approach has led to the uncovering of
[Rh2(S-tertPTTL)4] as a new member of the dirhodium(II) family
with extraordinary selectivity in cyclopropanation reactions.
The stereoselectivity of [Rh2(S-tertPTTL)4] was found to be
comparable to that of [Rh2(S-PTAD)4] (up to >99% ee), with
the extra benefit of being more synthetically accessible. Cor-
relations based on X-ray structures to justify the observed
enantioinduction are also discussed.
Introduction
ers revealed a trend between the steric bulk at the a position
and the enantioselectivity of the catalyst.[3] The enantioselec-
tivity increases with increasing steric bulk and the highest
enantioselectivity was observed with [Rh2(S-PTTL)4], which
carries a tert-butyl group (Figure 1).
Dirhodium(II) complexes have been used as effective catalysts
for highly stereoselective inter- and intramolecular cyclopropa-
nation reactions.[1] Their superior level of stereoselectivity is
such that they can serve as powerful tools for the construction
of molecules with complex structures.
Aside from instances in which catalysis optimisation is
mapped onto specific structural features of the substrate, de-
velopment in the field of dirhodium(II) chiral catalysis is related
to either electronic or steric modifications within the complex
framework.[2] However, researchers in this field rely on explor-
ing and amending the steric profiles and conformations adapt-
ed by bridging ligands for the discovery of new catalysts, pre-
diction of transition states, and justification for the observed
selectivity.[2] In contrast, the strategy of electronic modification
is generally limited to the fine-tuning of the selectivity of a
particular catalyst when used in a particular reaction towards
the preparation of a particular class of products.[2b]
Figure 1. Available highly stereoselective dirhodium(II) carboxylates.
Later, Davies and co-workers extended the idea and
assumed that a catalyst carrying the more bulky adamantyl
moiety at the a-carbon atom would surpass those carrying the
standard PTTL ligands (Figure 1).[4] [Rh2(S-PTAD)4] demonstrated
enhanced levels of enantioselectivity and acted as a comple-
mentary catalyst when [Rh2(S-DOSP)4] failed to give high asym-
metric induction with some of donor–acceptor systems.[5] In
addition, [Rh2(S-PTAD)4] was reported to be the optimal chiral
catalyst when the acceptor group in the donor–acceptor sub-
strates is a phosphonate ester,[4] nitrile,[6] trifluoromethyl[7] or
keto[8] group, giving better enantioselectivities than [Rh2(S-
PTTL)4]. In fact, the emergence of [Rh2(S-PTAD)4] circumvented
to a great extent the limitations of selectivity associated with
[Rh2(S-DOSP)4]. However, the synthesis of the (S)-PTAD ligand is
based on (S)-a-adamantylglycine, which is not commercially
available and its asymmetric synthesis is very tedious and tire-
some.[4] These problems associated with ligand preparation
have blemished the overall interest in this catalyst.[9]
The most obvious example is Hashimoto and co-workers’
phthalimide-based catalytic series. Careful analysis of this
series in various reactions reported by Hashimoto and co-work-
[a] Dr. A. Ghanem
Biomedical science department
University of Canberra
ACT, 2601 (Australia)
E-mail: ashraf.ghanem@canberra.edu.au
[b] Dr. F. G. Adly
University of Canberra
ACT, 2601 (Australia)
[c] Dr. M. G. Gardiner
School of Physical Sciences, ChemistryUniversity of Tasmania
Hobart, TAS, 7001 (Australia)
[**] The catalyst ([Rh2(S-tertPTTL)4]; patent PCT/AU2015/000557) is now available
at STREM Chemicals.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/chem.201504817.
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In the same context, symmetry is believed to be an impor-
tant concept that plays an extensive role in chiral catalysis. The
use of high-symmetry catalysts is assumed to minimise the
number of possible substrate trajectories in the catalytic steps
of the reaction in question. This, in turn, can afford a predicta-
ble, more precise, 3D transition-state structure. So, generally, in
the field of chiral catalyst design, the use of ligands with the
highest possible symmetry is usually preferred to generate
high-symmetry catalysts. The use of such ligands can signifi-
cantly simplify the prediction of stereoinduction mechanisms.
Moreover, the synthesis of such ligands, in most cases, is much
simpler.[10]
For dirhodium(II) carboxylate complexes, the paddlewheel
framework provides a distinguishable scaffolding for achieving
higher-symmetry chiral complexes through what is called
a “modular approach”.[2a] In this approach, several identical C1-
symmetric ligands surround the inherently high-symmetry core
to afford a far superior symmetrical homochiral molecule com-
pared with the individual ligand itself. It was believed that
chiral dirhodium(II) complexes exhibit exceptionally high ste-
reoselectivities because of this interesting attribute.[2a] Howev-
er, Fox[11] and Charette[12] and their co-workers independently
explored the interruption of this high-symmetry framework.
They replaced one of the ligands with an achiral ligand, which
led to the generation of lower-symmetry heteroleptic com-
plexes. The results of screening tests revealed that lowering
the global symmetry of the catalysts had a beneficial impact
on their asymmetric induction.
Figure 2. Comparison of the backbone structure of the ligands in
dirhodium(II) complexes.
quence, two more approaches were investigated as improved
methods for reducing the local symmetry of the ligand’s
heterocyclic tether.
Guided by previous findings relating to the nature of the
chiral crown cavity in dirhodium(II) complexes,[13b,16] we have
continued to modify the N-heterocyclic tether of ligands
derived from l-tert-leucine as a pivotal part of this type of li-
gands. The aim of the study reported herein was to explore in
depth the effect of reducing the local symmetry of the N-het-
erocyclic tether and to trace its effect on the mechanism of
stereoselection in asymmetric cyclopropanation reactions.
For dirhodium(II) catalysts derived from N-protected amino
acid ligands, it has long been held (based on the enantioselec-
tivities achieved with these systems) that N-aryl tethers can act
as steric blockers. The role of these tethers is considered pivo-
tal in controlling the trajectory of the incoming substrates
during catalysis. Following the classical catalyst design
described above, all the reported dirhodium(II) complexes
belonging to this family have a C2v-symmetric N-heterocyclic
tether for the construction of the chiral ligands.
In 2004, Müller and Ghanem[13] reported several [Rh2(S-
NTTL)4] analogues in which only one hydrogen in the heterocy-
clic tether is substituted, generating ligands carrying Cs-sym-
metric N-protecting groups (Figure 2). Their results revealed
that the [Rh2(S-4-Br-NTTL)4]-catalysed cyclopropanation of sty-
rene with dimethyl malonate proceeded with far improved
levels of enantioselectivity (82% ee) compared with its parent
complex [Rh2(S-NTTL)4] (37% ee).[13a,14] The same catalyst was
also effective in olefin cyclopropanation with Meldrum’s acid
giving 92% ee with styrene and 87% ee with pent-1-ene.
Very recently, our group explored this further and reported
[Rh2(S-1,2-NTTL)4] as a new member of the chiral dirhodium(II)
family derived from Cs-symmetric N-protected tert-leucine
(Figure 2). The idea was to reduce the local symmetry of the li-
gand’s heterocyclic tether in [Rh2(S-1,2-NTTL)4] by fusing a ring
at one side of the N-heterocyclic tether. The results demon-
strated that [Rh2(S-1,2-NTTL)4] is a promising catalyst for the
cyclopropanation reactions involving donor–acceptor phos-
phonate carbenoids, however, the results did not show a clear
advantage of the “lower-symmetry“ approach.[15] As a conse-
Results and Discussion
New ligands 1–4 carrying N-protecting groups of reduced Cs
symmetry were prepared as illustrated in Scheme 1. Standard
ligand-exchange conditions between the prepared ligands and
[Rh2(OAc)4] generated [Rh2(S-1-Ph-BPTTL)4] (5), [Rh2(S-tertPTTL)4]
(6), [Rh2(S-BOTL)4] (7) and [Rh2(S-BHTL)4] (8) as green solids in
yields of 67, 71, 92 and 83%, respectively (Scheme 2). These
four catalysts emerged as a result of applying alternative strat-
egies for lowering the symmetry of the N-heterocyclic tether.
Similar to the case of the N-1,2-NTTL ligand reported earli-
er,[15] partial substitution of the ring can reduce the symmetry
of the N-protecting group, as in the case of [Rh2(S-1-Ph-
BPTTL)4] (5) and [Rh2(S-tertPTTL)4] (6). This is due to the removal
of the mirror planes lying both in the heterocyclic plane and
perpendicular to this plane. The planarity of the heterocyclic
section is maintained in these two complexes, but the local
symmetry of the N-protecting group is reduced from C2v to Cs
by virtue of the substituents; tert-butyl and phenyl substitu-
ents were chosen for their bulk.[17]
As illustrated in Figure 3a, introducing a substituent at either
position 3 (3’) or 4 (4’) in the PTTL-derived catalyst 6 will
reduce the symmetry of the phthalimide protecting group. But
to gain the advantage of the “cavity rim steric impedance ef-
fect“,[13b] introduction of the substituent at position 4 (4’) was
favoured over position 3 (3’). For the BPTTL-derived catalyst 5
(Figure 3b), positions 4 (4’) and 5 (5’) are far away from the
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Figure 3. Suitable positions for the introduction of substituents into com-
plexes a) 6 and b) 5. The favoured positions of substitution are represented
by black arrows.
rhodium reactive centre and the introduction of the substitu-
ent at any of these two spots is expected to exert minimal in-
fluence on the stereoselectivity of the catalyst. As a conse-
quence, introduction of the substituent at position 3 (3’) was
favoured. However, the expected “lean“ of the nitrogen tether
by its clockwise twist will render inequivalent positions 4 and
4’ in 6 (Figure 3a) and positions 3 and 3’ in 5 (Figure 3b). Thus,
the anticipated “best” orientation of the substituent was
difficult to predict at this stage.
We were very fortunate to find 4-tert-butylphthalic an-
hydride and 1-phenylnaphthalene-2,3-dicarboxylic anhydride
to be commercially available, and these were chosen for pro-
tection of the tert-leucine amino group. Using a commercially
available anhydride definitely simplifies the preparation pro-
cess and makes the final catalyst more synthetically accessible.
In contrast, the reduction of symmetry achieved in [Rh2(S-
BOTL)4] (7) and [Rh2(S-BHTL)4] (8) complexes was quite interest-
ing. The N-protecting group again has Cs symmetry, which
means that all four N-protecting groups could be equivalently
positioned around the extremity of the chiral crown cavity and
not reduce the C4 symmetry of the final complex. To the best
of our knowledge, no catalyst structure has been reported in
which the rotation of ligand rings results in a different size
chiral cavity (Figure 4).
Scheme 1. Preparation of chiral ligands 1–4.
With these four catalysts in hand, their efficiencies were ex-
amined in the standard reaction between styrene and dimethyl
a-diazobenzylphosphonate with 2,2-dimethylbutane (2,2-DMB)
as the reaction solvent. In all cases, the cyclopropylphospho-
nate product 9 was generated in good-to-excellent yields (84–
92%) and with levels of diastereoselectivity of >20:1 E/Z d.r.
In terms of enantioselectivity, the results indicate that the in-
troduction of a substituent into the heterocyclic tether leads
to a significant improvement in enantioselectivity. For example,
[Rh2(S-BPTTL)4] generated the cyclopropane product with 86%
ee, whereas the introduction of an extra phenyl group into the
protecting group in [Rh2(S-1-Ph-BPTTL)4] (5) resulted in the
generation of the product with 90% ee under the same
reaction conditions (Table 1, entries 5 vs 7).
Moreover, the effect of introducing a tert-butyl group at the
4-position of the phthalimido group in [Rh2(S-tertPTTL)4] was
Scheme 2. Synthesis and structures of the complexes 5–8.
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Figure 4. Two possible orientations for the N-protecting group in [Rh2(S-BOTL)4] (7) and [Rh2(S-BHTL)4] (8).
with an enantioselectivity of 66% ee (Table 1, entry 2). At this
Table 1. Asymmetric cyclopropanation of styrene with dimethyl diazo-
benzylphosphonate (donor–acceptor substrate).[a]
point, and based on the results obtained, it was realised that
a
much more synthetically accessible alternative to
[Rh2(S-PTAD)4] might have been discovered.
Unfortunately, the bicyclic complexes [Rh2(S-BOTL)4] (7) and
[Rh2(S-BHTL)4] (8) did not return the expected success. The
cyclopropanation reactions proceeded successfully giving the
cyclopropane product with moderate enantioselectivities of 66
and 74% ee, respectively (Table 1, entries 9 and 10).
Catalyst
Catalyst
code
Reaction
temp. [8C]
Yield
[%]
ee [%]
The carbenoid cyclopropanation reaction of dimethyl a-di-
azobenzylphosphonate was applied to a range of olefins using
[Rh2(S-1-Ph-BPTTL)4] (5) and [Rh2(S-tertPTTL)4] (6) as catalysts and
the results are presented in Table 2. All the reactions involving
[Rh2(S-tertPTTL)4] (6) were carried out at room temperature,
whereas the reactions involving [Rh2(S-1-Ph-BPTTL)4] (5) were
carried out at 598C. In all cases, the reactions proceeded
smoothly resulting in the formation of the corresponding
cyclopropylphosphonate products in very high yields (82–
93%) and diastereoselectivities (>20:1 E/Z d.r.). In terms of
enantioselectivity, [Rh2(S-tertPTTL)4] (6) was the best catalyst
giving the corresponding cyclopropane products with very
high levels of enantioselectivity (>98–99% ee).
1
[Rh2(S-PTAD)4]
[Rh2(S-PTAD)4]
[Rh2(S-PTTL)4]
–
–
–
–
–
–
5
6
7
8
59
86
49
85
87
83
93
87
92
89
84
94
66
92
91
86
92
90
98
66
74
2
3
4
5
6
7
8
9
10
23[b]
59
[Rh2(S-NTTL)4]
59
59
59
59
23[b]
59
[Rh2(S-BPTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-BOTL)4]
[Rh2(S-BHTL)4]
59
[a] Heated at reflux, unless stated otherwise, until TLC indicated complete
consumption of the diazo starting material. Diastereomeric ratios (d.r.)
were determined by 1H NMR analysis of the crude reaction mixtures.
Enantiomeric excesses (ee) were determined by chiral HPLC using a Chiral-
cel OJ column, 2% 2-propanol in n-hexane (v/v%), 1 mLminÀ1, 220 nm,
t1 =18 min, t2 =21 min. [b] Stirring overnight. [c] Stirring for 5 h.
Table 2. Scope of the catalysts with respect to the alkene.[a]
dramatic. [Rh2(S-tertPTTL)4] (6) is fully soluble in 2,2-DMB at
room temperature and, generally, it provided improved levels
of enantioinduction compared with [Rh2(S-PTTL)4] and
[Rh2(S-NTTL)4] (Table 1, entries 8 vs 3 and 4). In the presence of
[Rh2(S-PTTL)4] and [Rh2(S-NTTL)4], cyclopropane 9 was generat-
ed with 92 and 91% ee, respectively, whereas, after stirring for
5 h at room temperature, the [Rh2(S-tertPTTL)4]-catalysed
reaction proceeded smoothly to generate the cyclopropane
product 9 with 98% ee (Table 1, entry 8).
This result is superior to that obtained when [Rh2(S-PTAD)4]
was used as catalyst in the same reaction carried out at reflux
(598C) for 13 h.[4] The [Rh2(S-PTAD)4]-catalysed cyclopropana-
tion reaction performed with stirring at room temperature
overnight gave the cyclopropane product in a yield of 49%
R
Product [Rh2(S-1-Ph-BPTTL)4] (5) [Rh2(S-tertPTTL)4][b] (6)
Yield [%]
ee [%]
Yield [%]
ee [%]
1
2
3
4
p-ClPh
p-MeOPh
p-MePh
10
11
12
13
89
86
88
82
84
93
90
90
94
90
93
85
>98
99
>99
>98
1-naphthyl
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC. See the Experimental Section for chromatographic conditions
and details. [b] Stirring at room temperature.
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The relative and absolute configuration of dimethyl 1-
phenyl-2-(p-methylphenyl)cyclopropylphosphonate (12) was
determined by X-ray crystallographic analysis to be (1S,2R),
which is in agreement with the predicted assignment. The
structures of all the other cyclopropylphosphonate derivatives
were tentatively assigned the same relative and absolute
configuration by analogy to 12 and based on the assumption
that all reactions occur through similar transition states.
The effect of the size of the diazophosphonate ester groups
on the enantioselectivity of the cyclopropanation reaction per-
formed with catalysts 5 and 6 was next examined by using
a series of diazophosphonate derivatives. The results are sum-
marised in Table 3 and reveal that the diastereoselectivity is in-
dependent of the size of the phosphonate group and not
greatly influenced by the size of the ester groups. However, in
all cases, increasing the size of the ester group caused a drastic
decrease in both the yield and enantioselectivity, with the
highest yield and enantioselectivity observed with dimethyl
a-diazobenzylphosphonate (Table 3, entry 1).
Crystallographic studies on [Rh2(S-1-Ph-BPTTL)4] (5),
[Rh2(S-tertPTTL)4] (6), [Rh2(S-BOTL)4] (7) and [Rh2(S-BHTL)4] (8)
were carried out to clarify the nature of the observed
enhancement effect exhibited by lowering the symmetry of
the N-protecting group on the enantioinduction.
In the published structure of the mono-EtOAc adduct of
[Rh2(S-PTTL)4],[18] the flow of the ligand based chirality can be
seen to give rise to a “chiral binding pocket” or “chiral crown
cavity”. The nature of the chirality of this binding pocket is
based on two important features (Figure 5a): 1) the CaÀCO2
single bond torsion (carboxylate carbon to a-carbon bond),
which causes the CaÀN bond to twist clockwise towards the
carbene binding pocket (when viewed along the Rh–Rh axis in
the chiral cavity) and 2) the NÀCa bond torsion, which allows
docking of the adjacent N-phthaloyl units featuring O···CH clos-
est contacts. Figure 5b,c schematically depict the “daisy chain”
manner in which the binding pocket is constructed.[16]
Figure 5. a) Features that determine the chirality to binding pocket of
[Rh2(S-PTTL)4] and its analogues. b,c) Schematic illustration of the “daisy-
chain” manner in which the rectangular binding pocket of [Rh2(S-PTTL)4] is
constructed.
adducts reveal a chiral crown conformation in which all four N-
protecting groups are equivalently positioned around the ex-
tremity of the chiral crown cavity without reducing the C4 sym-
metry of the catalyst (Figure 6). The tert-butyl substituents are
similarly disposed towards the “corner” of the square-shaped
cavity. The chiral cavity is rigorously C4-symmetrical in the solid
state (in both the bis(ACN) and bis(THF) adducts), whereas the
four N-(4-tert-butylphthaloyl) groups maintain the chiral nature
of the crown cavity surrounding the axial rhodium coordina-
tion site through the clockwise twist of these groups.
The X-ray crystal structures of both bis(ACN) and bis(THF)
adducts of [Rh2(S-tertPTTL)4] (6) were obtained from samples
recrystallised from acetonitrile and THF, respectively. Both
Table 3. Effect of the size of the a-diazophosphonate ester groups on
the enantioselectivity of the catalysts.[a]
The square cavity of [Rh2(S-tertPTTL)4] (6) contrasts with the
rectangular conformer originally reported for the mono-EtOAc
adduct of [Rh2(S-PTTL)4] (Figure 7).[18] The additional substitu-
tion on the N-phthaloyl group in [Rh2(S-tertPTTL)4] can be seen
to extend the width of each of the cavity walls to the point
that adjacent ligands are nearly in van der Waals contact. Fur-
thermore, from a comparison of the space-filling representa-
tions of [Rh2(S-tertPTTL)4] and [Rh2(S-PTTL)4], it is clear that the
extra tert-butyl substituents in [Rh2(S-tertPTTL)4] lead to greater
ligand conformational rigidity through CaÀCO2 and NÀCa bond
torsions of the ligands. On the other hand, this is not the case
for the unsubstituted [Rh2(S-PTTL)4] and various other contort-
R
Product
[Rh2(S-1-Ph-BPTTL)4] (5)
[Rh2(S-tertPTTL)4][b] (6)
Yield [%]
ee [%]
Yield [%]
ee [%]
1
2
3
Me
Et
iPr
9
14
15
87
66
38
92
54
48[c]
92
74
40
99
92
64[c]
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC. See the Experimental Section for chromatographic conditions
and details. [b] Stirring at room temperature. [c] Heated at reflux for
3 days.
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Therefore, if this geometry is also relevant to the solution
structures adopted during catalysis, it may be linked to the
observed enhanced enantioinduction relative to the parent
catalyst [Rh2(S-PTTL)4].
For a superior understanding of the enhanced selectivity,
the structure obtained for [Rh2(S-tertPTTL)4] was also compared
with the X-ray structure of [Rh2(S-PTAD)4]. The X-ray structure
of the former resembles to a large extent the X-ray crystal
structure of the latter catalyst (Figure 8). [Rh2(S-PTAD)4] was ob-
served to form a bis(EtOAc) adduct with an a,a,a,a conforma-
tion in the solid state when crystallised from an ethyl acetate/
n-hexane solvent mixture. All four N-phthaloyl protecting
groups sit evenly around the edge of a fairly square cavity to
afford a C4-symmetric catalyst molecule (Figure 8). The width
across the cavity faces was found to be between 14.1 and
16.0 Š. From the space-filling representation of [Rh2(S-PTAD)4],
it can be anticipated that the bulkier adamantyl groups intro-
duce a greater conformational rigidity through only CaÀCO2
bond torsions of the ligands, whereas the NÀCa bond torsions
remain flexible. Therefore, [Rh2(S-PTAD)4] is expected to have
a more rigid chiral cavity than its parent [Rh2(S-PTTL)4], but less
rigid than [Rh2(S-tertPTTL)4] (6). In addition, [Rh2(S-PTAD)4] retains
the same gaps at the corners of the chiral cavity as found in
[Rh2(S-PTTL)4].
Figure 6. Molecular structure of the bis(THF) adduct of [Rh2(S-tertPTTL)4] (6).
Space-filling representations: a) top view, b) bottom view and c,d) side
views. A second similar molecule as well as axial ligands have been omitted
for clarity.
Another important feature to note is that the crystal struc-
ture of [Rh2(S-PTAD)4] has an ethyl acetate molecule coordinat-
ed to each rhodium centre, which confirms that there is still
enough room for a Lewis basic ligand to coordinate to the
“achiral” axial rhodium coordination site (the site shrouded by
adamantyl substituents). This observation confirms that both
Figure 7. Space-filling structure comparison of the EtOAc adduct of
[Rh2(S-PTTL)4] and the bis(THF) adduct of [Rh2(S-tertPTTL)4] (6). a,c) Top views
of [Rh2(S-PTTL)4] and [Rh2(S-tertPTTL)4], respectively, b,d) side views of [Rh2(S-
PTTL)4] and [Rh2(S-tertPTTL)4], respectively.
ed chiral cavities that have been crystallographically observ-
ed.[13b,16,18] The gaps at the corners of these cavities allow sub-
stantial variation around the CaÀCO2 and NÀCa bond torsions.
Therefore, the additional tert-butyl substitution in [Rh2(S-
tertPTTL)4] relieves the overall chiral twist of the cavity without
introducing additional steric hindrance at the axial positions.
Figure 8. Molecular structure of the bis(EtOAc) adduct of [Rh2(S-PTAD)4]
a) viewed from above the chiral crown cavity and b) general view. All hydro-
gen atoms, a second similar molecule and lattice solvent have been omitted
for clarity. Space-filling representations viewed along the Rh–Rh axis c) from
above the chiral crown cavity d) onto the axial rhodium coordination site
shrouded by the adamantyl groups.
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rhodium atoms are still accessible to the diazo substrates, even
after the introduction of the more bulky adamantyl groups.
This observation contrasts with the hypothesis of Fox and
co-workers[18] in relation to the full chiral crown conformer in
the Hashimoto-type dirhodium catalysts and the foundation
for the development of the [Rh2(S-PTAD)4] catalyst.[4]
The X-ray crystal structure of the bis(EtOAc) adduct of
[Rh2(S-1-Ph-BPTTL)4] (5; Figure 9) was also determined and
shows that the complex also adopts the a,a,a,a conformation
in the solid state with all four N-protected amino acid ligands
being directed towards the same axial coordination site of the
C4-symmetric chiral paddlewheel complex. The molecule exhib-
its a perfectly regular cavity, with each of the four aryl units
comprising the cavity walls having a clockwise twisted ar-
rangement with a cavity width of 13.4 Š between opposite
faces. Although retaining the same clockwise twist, the phenyl
substituents point towards the opposite side of the protecting
group rings compared with the tert-butyl substituents in
[Rh2(S-tertPTTL)4] (6). The substituents are ordered with respect
to the C4 axis of the catalyst. This again widens the walls of the
cavity relative to its parent [Rh2(S-BPTTL)4][16] structure creating
significantly smaller gaps at the corners of the cavity and
significantly less variation in the CaÀCO2 and NÀCa bond
rotations.
Figure 10. Molecular structure of the bis(ACN) adduct of [Rh2(S-BHTL)4] (8).
Space-filling representations (ACN removed except in b): a) top view, b) pro-
late-shaped ACN axial ligand entirely shrouded by cavity walls, c) bottom
view and d,e) side views.
The X-ray crystal structures of [Rh2(S-BOTL)4] (7) and [Rh2(S-
BHTL)4] (8) were also obtained; both revealed crown structures,
as described above for [Rh2(S-PTTL)4], [Rh2(S-PTAD)4], [Rh2(S-
tertPTTL)4] and [Rh2(S-1-Ph-BPTTL)4]. The N-protecting groups in
[Rh2(S-BHTL)4] (8) are all directed in the same way with the syn-
annulated cyclopentene extremities pointing into the cavity
and the axially bonded prolate-shaped ACN ligand entirely
shrouded by the cavity walls (Figure 10). This does not reduce
the overall higher-order chirality of the complex as each ligand
is similarly disposed and the ligand extremities contribute to
the overall C4 symmetry of the chiral cavity. The top of the
cavity is “square” and it is very congested for the binding of
substrates during catalysis, apparent in the space-filling repre-
sentation of the complex (Figure 10a,b). For this catalyst to be
functional, it is anticipated that some of the N-protecting
groups need to rotate (flip with respect to NÀCa bond rota-
tion) and/or lose the crown conformation to provide enough
room for the binding of larger substrates (Figure 4). Otherwise,
the crown cavity will remain too crowded for the substrate to
bind and possibly lead to the other “achiral” rhodium centre
competing to play a greater role. If the latter is the case, this
could justify the observed relatively low enantioselectivity of 8.
The X-ray structure of [Rh2(S-BOTL)4] (7) reveals an a,a,a,a
crown conformer with one ligand orientated differently to that
normally seen in other a,a,a,a analogues and with all four
amino acid derived ligands maintaining their S-stereogenic
carbon centres (Figure 11). The examination of several crystals
indicated the same morphology. This is in contrast to the
clockwise twist observed for [Rh2(S-BHTL)4] (8) discussed
above. For [Rh2(S-BOTL)4] (7) crystallised from MeOH, the posi-
tioning of the non-rhodium-bound MeOH lattice molecule,
which forms hydrogen bonds with the MeOH bonded to the
rhodium in the chiral cavity, is influential. In the catalyst, one
of the S-BOTL ligands is forced, unusually, to shift to create
room for the hydrogen-bonded MeOH molecule (Figure 11a,b).
It is also important to highlight that the extremities of the N-
Figure 9. Molecular structures of the bis(EtOAc) adduct of [Rh2(S-1-Ph-
BPTTL)4] (5) a) viewed along the axis of the chiral crown cavity and b) side
view. All hydrogen atoms, a second similar molecule and lattice solvent
have been omitted for clarity. Space-filling representations viewed along the
Rh–Rh axis c) from above the chiral crown cavity, d) onto the axial rhodium
coordination site shrouded by the tert-butyl groups.
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Table 4. Asymmetric cyclopropanation of styrene with 2,2,2-triflurometh-
yl-1-phenyldiazoethane (donor–acceptor substrate).[a]
Catalyst
[Rh2(S-PTAD)4]
[Rh2(S-PTTL)4]
[Rh2(S-NTTL)4]
[Rh2(S-4-Br-NTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-tertPTTL)4]
Catalyst code Solvent
Yield [%] ee [%]
1
2
3
4
5
6
7
8
–
–
–
–
–
5
6
6
TFT
TFT
TFT
TFT
TFT
TFT
TFT
95
96
95
83
85
69
99
88
82
79
78
82
42
88
88
2,2-DMB 97
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC using a Chiralcel OJ column, 1% 2-propanol in n-hexane
(v/v%), 0.8 mLminÀ1, 220 nm, t1 =5.5 min, t2 =6.8 min.
Figure 11. Molecular structures of the bis(MeOH) adduct of [Rh2(S-BOTL)4]
(7). Space-filling structures: a,b,c) three pictures of the complex in various
states of “undressing” of the MeOH ligands around the cavity.
With respect to enantioselectivity, the results show that the
product was generated in 88% ee with [Rh2(S-tertPTTL)4] (6) as
catalyst (Table 4, entry 7), and that changing the reaction sol-
vent to 2,2-DMB did not impact on its enantioselectivity
(Table 4, entry 8). The enantioselectivity observed with [Rh2(S-
tertPTTL)4] was analogous to that observed when [Rh2(S-PTAD)4]
was applied in the same reaction under the same reaction
conditions (Table 4, entry 1) whereas in the [Rh2(S-PTTL)4]-,
[Rh2(S-NTTL)4]- and [Rh2(S-1,2-NTTL)4]-catalysed reactions, the
cyclopropane product 16 was generated in lower enantioselec-
tivities of 82, 79 and 82% ee, respectively. [Rh2(S-1-Ph-BPTTL)4]
(5) was found to be unsuitable for this reaction, generating the
cyclopropane in 42% ee. The relative and absolute stereo-
chemistry of the product was again unambiguously assigned
to be (1S,2R) by means of X-ray crystallography analysis.
The next series of experiments were carried out on diazoace-
tates as another example of donor–acceptor diazo-substrates.
The new catalysts were evaluated in the cyclopropanation re-
action of styrene with methyl p-methoxyphenyldiazoacetate,
which generates methyl 1,2-diphenylcyclopropanecarboxylate
17; the results are summarised in Table 5. All the catalysts
afforded the cyclopropane product 17 with excellent dia-
stereoselectivity (>18:1 E/Z d.r.).
protecting group do not face in towards the top of the cavity
but outwards, which is opposite to the related complex 8
described above.
The structural features of complexes 7 and 8 are very impor-
tant as they strongly indicate that these two complexes lack
the conformational rigidity through both CaÀCO2 and NÀCa
bond torsions of the ligands. It can be speculated that the
flexibility of the ligands in both [Rh2(S-BOTL)4] (7) and
[Rh2(S-BHTL)4] (8) could have led to irregular cavities similar to
that observed in 7 when substrates binds to it. This, in turn,
may lead to different selectivities, accounting for the relatively
low enantioselectivities observed in the reactions with these
complexes.
More extensive structural investigations need to be under-
taken before any generalities should be drawn regarding the
effects of axial-bound ligands on the conformational
preference of this class of complexes.
The scope of the new catalysts was also investigated by
studying cyclopropanation reactions involving donor–acceptor
carbenoid intermediates containing CF3 as an electron-with-
drawing group using the reported optimised reaction condi-
tions.[7] The fluoro functionality impacts profoundly on the
chemical, physical and biological properties of organic com-
pounds[19] and is generally used to tune the pharmacokinetic,
electronic,[20] steric[21] and lipophilic[22] properties of different
pharmaceutical agents.
Considering the enantioselectivity of the reaction, generally,
the results reveal that [Rh2(S-tertPTTL)4] (6) is a better catalyst
than [Rh2(S-PTAD)4] at a catalyst loading of 0.01 equivalents
and similar to [Rh2(S-PTTL)4]. In contrast, [Rh2(S-1-Ph-BPTTL)4]
(5) and [Rh2(S-NTTL)4] are totally incompatible with this class of
substrate with quite poor enantioselectivities (10 and 42% ee,
respectively). Increasing the [Rh2(S-tertPTTL)4] (6) catalyst loading
from 0.01 to 0.05 equivalents had a minimal effect on both
yield and enantioselectivity (Table 5, entries 7 and 8). Further-
more, changing the reaction solvent to 2,2-DMB slightly en-
hanced the enantioselectivity of [Rh2(S-tertPTTL)4] (6) to 78% ee
(Table 5, entries 7 and 9).
The results summarised in Table 4 reveal a similar enhance-
ment in enantioselectivity for the cyclopropanation of styrene
with 2,2,2-trifluromethyl-1-phenyldiazoethane. Generally, the
product 16 was generated in high yields and with high levels
of diastereoselectivity (>20:1 E/Z d.r.) by using a,a,a-trifluoro-
toluene (TFT) as solvent.
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Table 5. Asymmetric cyclopropanation of styrene with methyl p-
methoxyphenyldiazoacetate (donor–acceptor substrate).[a]
Table 6. Asymmetric cyclopropanation of styrene with a-phenyldiazo-
acetate (donor–acceptor substrate).[a]
Catalyst
[Rh2(S-PTAD)4][5]
[Rh2(S-PTTL)4]
[Rh2(S-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-BOTL)4]
Catalyst code
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
–
–
–
5
6
–
7
8
87
87
88
90
87
89
66
58
21[b]
20
8
30[c]
46
30
38
17
Catalyst
Catalyst Solvent
code
Catalyst Yield ee
loading
[equiv]
[%]
[%]
1
2
3
4
5
6
7
8
9
[Rh2(S-PTAD)4]
[Rh2(S-PTTL)4]
[Rh2(S-NTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-tertPTTL)4]
–
–
–
–
5
5
6
6
6
pentane 0.01
pentane 0.01
96
84
83
84
80
83
80
83
85
73
78
42
70
8
10
76
76
78
pentane 0.01
pentane 0.01
pentane 0.01
2,2-DMB 0.01
pentane 0.01
pentane 0.05
2,2-DMB 0.01
[Rh2(S-BHTL)4]
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC using a Chiralcel OJ column, 1% 2-propanol in n-hexane
(v/v%), 0.8 mLminÀ1
, 220 nm, t1 =5.5 min, t2 =6.8 min. [b] In toluene.
[c] The opposite enantiomer was observed.
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC using a Chiralcelꢁ OD-H column, 0.7% 2-propanol in n-hexane
(v/v%), 1 mLminÀ1, 220 nm, t1 =13 min, t2 =23 min.
Table 7. Asymmetric cyclopropanation of styrene with methyl 2-diazo-4-
phenylbut-3-enoate (donor–acceptor substrate).[a]
Catalyst screening was further extended by removing the p-
methoxy group from the diazoacetate. The cyclopropanation
reaction of styrene with methyl 2-diazo-2-phenylacetate was
carried out with a catalyst loading of 0.01 equivalents. As illus-
trated in Table 6, all the catalysts afforded the cyclopropane
product 18 in good-to-excellent yields (65–89%) and with high
diastereoselectivities (>18:1 E/Z d.r.). However, the asymmetric
induction was dramatically reduced upon removal of the
p-methoxy group. The best enantiomeric induction was 46%
ee with [Rh2(S-tertPTTL)4] (6; Table 6, entry 5).
It is important to note that although [Rh2(S-1-Ph-BPTTL)4] (5)
is derived from protected l-tert-leucine, like the rest of com-
plexes screened, its use in this reaction resulted in the forma-
tion of the corresponding cyclopropane product 18 in 30% ee,
but with the opposite absolute configuration (Table 6, entry 4).
This may be related to the opposite alignment of the phenyl
substituents on the N-protecting group rings. Further investi-
gations are still required regarding this point.
Catalyst
[Rh2(S-PTTL)4]
[Rh2(S-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-BOTL)4]
Catalyst code Solvent
Yield [%] ee [%]
1
2
3
4
5
6
7
8
–
–
5
6
–
–
7
8
CH2Cl2
CH2Cl2
2,2-DMB 86
2,2-DMB 86
83
82
40
16
19[b]
44
10
10
4
CH2Cl2
88
pentane 87
pentane 69
2,2-DMB 77
[Rh2(S-BHTL)4]
2
1
[a] Diastereomeric ratios (d.r.) were determined by H NMR analysis of the
crude reaction mixtures. Enantiomeric excesses (ee) were determined by
chiral HPLC using a Chiralcel OJ column, 1.5% 2-propanol in n-hexane
(v/v%), 1 mLminÀ1
, 254 nm, t1 =15 min, t2 =21 min. [b] The opposite
enantiomer was observed.
A series of experiments were also carried out with methyl
(E)-2-diazo-4-phenylbut-3-enoate (Table 7). In all cases, excel-
lent levels of diastereoselectivity were observed, however, the
best enantiomeric induction was 44% ee when [Rh2(S-tertPTTL)4]
(6) was used as the catalyst (Table 7, entry 4). Similar behaviour
to that discussed above was witnessed with [Rh2(S-1-Ph-
BPTTL)4] (5); this catalyst gave the cyclopropane product 19 in
19% ee, but with the opposite absolute configuration (Table 7,
entry 3).
ported by Davies and co-workers.[6] The results are illustrated
in Table 8.
The cyclopropane product 20 was generated in high yields
for all catalysts. In terms of diastereoselectivity, although
[Rh2(S-PTTL)4] and [Rh2(S-tertPTTL)4] (6) offered an acceptable
diastereoselectivity of >20:1 (E/Z) d.r., [Rh2(S-PTAD)4] was the
best among the screened complexes with a diastereomeric
ratio of 64:1 (E/Z). The diastereoselectivity of the cyclopropane
product generated by [Rh2(S-1,2-NTTL)4] did not exceed 11:1
(E/Z) d.r.. This system has been studied previously and it was
proposed that the variable diastereoselectivity observed was
due to the small size of the nitrile acceptor group.[6]
The scope of the new catalysts was further investigated by
performing cyclopropanation reactions involving donor–ac-
ceptor carbenoid intermediates containing CN as an electron-
withdrawing group using the optimised reaction conditions re-
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Table 8. Asymmetric cyclopropanation of styrene with a-phenyl-a-diazoacetonitrile (donor–acceptor substrate).[a]
Catalyst
Catalyst code
Catalyst loading [equiv]
Solvent
Yield [%][b]
d.r. (E/Z)
ee [%]
Major diastereomer
Minor diastereomer
1
2
3
4
5
6
7
8
9
[Rh2(OAc)4]
[Rh2(S-PTAD)4]
[Rh2(S-PTTL)4]
–
–
–
–
–
5
6
6
6
0.02
0.02
0.02
0.02
0.02
0.02
0.02
0.01
0.02
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
2,2-DMB
82
85
84
84
80
84
83
81
83
4:1[c]
64:1
27:1
13:1
11:1
7:1
25:1
26:1
16:1
–
80
86
90
83
30
82
82
82
–
74
78
92
76
78
84
86
82
[Rh2(S-NTTL)4]
[Rh2(S-1,2-NTTL)4]
[Rh2(S-1-Ph-BPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-tertPTTL)4]
[Rh2(S-tertPTTL)4]
[a] Diastereomeric ratios (d.r.) were determined by 1H NMR analysis of the crude reaction mixtures. Enantiomeric excesses (ee) were determined by chiral
HPLC using a Chiralcel OD column, 0.8% 2-propanol in n-hexane (v/v%), 1 mLminÀ1, 220 nm, t1 =19 min, t2 =29 min. [b] Yield for both diastereomers.
[c] Carried out at room temperature.
With regards to enantioselectivity, [Rh2(S-tertPTTL)4] (6), [Rh2(S-
1,2-NTTL)4], [Rh2(S-PTTL)4] and [Rh2(S-PTAD)4] revealed compa-
rable enantioselectivity for the major diastereomer (80–86%
ee). Erosion of neither the diastereo- nor enantioselectivity was
observed when the [Rh2(S-tertPTTL)4] loading was reduced from
0.02 to 0.01 equivalents. Also, changing the reaction solvent to
2,2-DMB did not affect the enantioselectivity of the major
diastereomer, however, the diastereoselectivity was reduced to
16:1 (E/Z) d.r..
prepared in more than 13 steps and takes around 2 weeks. In
the synthesis of the cyclopropylphosphonate derivatives,
[Rh2(S-tertPTTL)4] (6) proved to offer an extra advantage over
[Rh2(S-PTAD)4]; [Rh2(S-tertPTTL)4] (6) generated the correspond-
ing cyclopropane products in high yields, diastereoselectivities
and enantioselectivities after stirring at room temperature for
5 h, whereas similar reactions catalysed by [Rh2(S-PTAD)4] were
performed at reflux over 10 h.[4] Our results have also
demonstrated that [Rh2(S-tertPTTL)4] (6) is compatible with some
donor–acceptor diazaoacetate substrates. This reflects its
ability to complement the currently known flagship catalyst
[Rh2(S-DOSP)4] and broadens the range of available catalysts
for the asymmetric synthesis of chiral cyclopropanecarboxylate
derivatives.
Regardless of its relatively low diastereoselectivity, [Rh2(S-
NTTL)4] was the best catalyst in terms of enantioselectivity for
this catalytic system. The catalyst gave the major and minor
diastereomers of the cyclopropane products with enantiomeric
excesses of 90 and 92%, respectively. On the other hand,
[Rh2(S-1-Ph-BPTTL)4] (5) was completely incompatible with this
reaction; the cyclopropane product was generated with a 7:1
(E/Z) d.r. and with 30% ee for the major diastereomer (Table 8,
entry 6).
X-ray crystallography studies revealed that the structures of
[Rh2(S-tertPTTL)4] (6) and [Rh2(S-PTAD)4] are different to the X-ray
crystal structure of [Rh2(S-PTTL)4] determined by Fox and co-
workers, who suggested that [Rh2(S-PTTL)4] and related
complexes are in a C2-symmetric arrangement in the solid
state.[18,23] From the comparison of the solid-state structures, it
is evident that the extra tert-butyl groups introduced into
[Rh2(S-tertPTTL)4] (6) generate similar structural effects to the
adamantyl groups in [Rh2(S-PTAD)4] as a result of the increase
in the size of the substituents at the a positions. This was fur-
ther confirmed by the comparable enantioselectivity observed
for [Rh2(S-tertPTTL)4] (6) and [Rh2(S-PTAD)4]. Through the study
of the halogen bond rigidification effect observed in chlorinat-
ed complexes, Charette and co-workers[12,24] highlighted the
effect of chiral cavity rigidity on the enhancement of enantio-
selectivity. Herein, and based on the enantioselectivities ach-
ieved along with crystallographic observations of the new cat-
alytic systems, it can be confirmed that the partial substitution
of the ligand’s N-heterocyclic tether is another factor towards
reinforcing the rigidity of the cavity and enhancing the catalyst
stereoselectivity.
Conclusions
In this work a series of dirhodium(II) tetracarboxylates derived
from (S)-amino acid ligands were prepared. A number of differ-
ent approaches were explored to reduce the local symmetry of
the ligand’s heterocyclic tether. Four dirhodium(II) complexes
were then prepared from these ligands, of which [Rh2(S-
tertPTTL)4] (6) proved to be an exceptional catalyst with extra-
ordinary enantioselectivity (up to 99% ee). Screening of
a number of different donor–acceptor diazo systems revealed
that, generally, [Rh2(S-tertPTTL)4] (6) is a much more enantio-
selective catalyst than [Rh2(S-PTTL)4] and [Rh2(S-NTTL)4], with
a comparable enantioselectivity to [Rh2(S-PTAD)4]. This is in ad-
dition to overcoming the synthetic limitations associated with
[Rh2(S-PTAD)4] as it is much more synthetically accessible;
[Rh2(S-tertPTTL)4] (6) was prepared in high yield by a two-step
procedure, whereas [Rh2(S-PTAD)4] is reported to have been
Chem. Eur. J. 2016, 22, 3447 – 3461
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TripleTOF 5600 and AB MDS Sciex 4800 MALDI-TOF-TOF mass
spectrometers.
It is also tempting to infer that the binding of identical
MeOH axial ligands to each rhodium centre in [Rh2(S-BOTL)4]
(7) does not result in a major a,a,a,a to a,a,b,b or a,b,a,b con-
formational flip. However, the C4 symmetry of the chiral cavity
was lost although the a,a,a,a conformation of the catalyst still
exists.
HPLC analysis
All HPLC analyses were carried out at 258C by using a Prominence
Shimadzu System equipped with an LC-20AD solvent delivery unit,
SPD-M20A photodiode array detector, SIL-20AHT auto-sampler and
CTO-20A column oven. For instrument control and data process-
ing, LabSolutions data managing software (version 5.54 SP2) was
utilised. Chiralpak AD (0.46 mm”250 mm) and Chiralcel OJ
(0.46 mm”250 mm) columns were obtained from Daicel Chiral
Technologies. HPLC-grade n-hexane and 2-propanol were obtained
from Scharlau Chemie SA. Chiral HPLC separation conditions were
determined by obtaining a separation of a standard racemic
sample and by applying previously reported parameters if any.
All in all, and in the light of the results achieved, it is strong-
ly believed that the “reduction of symmetry” approach devel-
oped here is an excellent new way to enhance the enantiose-
lectivity of asymmetric dirhodium(II)-catalysed transformations.
Further explorations related to this new trend are crucial to
further confirm the impact of the lowering of local symmetry
of the N-protecting group on the final enantioselectivity of the
catalyst.
X-ray crystallography of the dirhodium(II) complexes
Experimental Section
X-ray-quality crystals of the dirhodium(II) complexes were obtained
by dissolving the pure complex in the appropriate solvent (for 5,
green prisms from ethyl acetate/n-hexane (1:1); for 6, green prisms
from THF that were violet at the data collection temperature of
100 K; for 7, green needles from MeOH; for 8, violet prisms from
ACN). The resulting solutions were subjected to sonication and
Pasteur pipette filtration followed by slow evaporation of the sol-
vent to yield crystals of the complexes (for [Rh2(S-PTAD)4], green
prisms were obtained by using the “vapour-diffusion crystallisa-
tion” method of n-hexane into an EtOAc solution that had been
subjected to sonication and Pasteur pipette filtration). Data were
collected at À1738C on crystals mounted on a Hampton Scientific
cryoloop at the MX1 (5, 8 and [Rh2(S-PTAD)4]) or MX2 (6 and 7)
beamlines (Australian Synchrotron, Victoria).[27] The structures were
solved by direct methods with SHELXS-97, refined by using full-
matrix least-squares methods against F2 with SHELXL-97[28] and vi-
sualised by using X-SEED.[29] Unless described in specific detail
below, all non-hydrogen atoms were anisotropically refined, where-
as all hydrogen atoms were positioned in calculated locations and
refined by using a riding model with fixed CÀH distances of 0.95
(sp2CH), 1.00 (sp3CH), 0.99 (CH2) and 0.98 Š (CH3). The thermal
parameters of all hydrogen atoms were estimated as Uiso(H)=
1.2Ueq(C) except for CH3, for which Uiso(H)=1.5Ueq(C).
Chemicals
All starting materials and reagents were purchased from Sigma–Al-
drich, Acros Organics and Tokyo Chemical Industry Co. (TCI) and
used without any further purification. All solvents were HPLC-
grade and solvents used in dirhodium(II) carbenoid reactions were
dried, distilled and degassed immediately prior to use: DCM over
calcium hydride, n-pentane and toluene over sodium wire and
chlorobenzene over potassium hydroxide. Anhydrous 2,2-DMB, TFT
and THF were purchased from Sigma–Aldrich and degassed prior
to use. All reactions were performed using oven-dried glassware
and were flame-dried under vacuum prior to use. TLC was per-
formed by using Sigma–Aldrich pre-coated silica gel 60 F254 alu-
minium supports (20”20 cm, 0.2 mm layer thickness) and spots
were visualised by UV light (254 nm) or by using either 10%
KMNO4 or phosphomolybdic acid (PMA) as visualising agents. Prep-
arative TLC purification was performed by using Sigma–Aldrich
pre-coated silica gel 60 F254 glass supports (20”20 cm, 0.25 mm
layer thickness). Column chromatography was carried out on silica
gel 60 (130–270 mesh ASTM, Sigma–Aldrich) using the specified
eluent compositions. The [Rh2(S-PTTL)4],[25] [Rh2(S-NTTL)4],[14] [Rh2(S-
BPTTL)4],[26] and [Rh2(S-1,2-NTTL)4][15] catalysts were prepared ac-
cording to reported procedures. [Rh2(OAc)4] and [Rh2(S-PTAD)4]
were purchased from Strem Chemicals.
In addition to the general X-ray crystallographic conditions de-
scribed earlier for data collection and refinement, for 5 and 6 dif-
fuse lattice solvent areas (ethyl acetate for 5 and THF for 6) were
treated with SQUEEZE.[30] For 5, the rhodium-bound ethyl acetate
solvent was apparent in difference maps, which was extensively
disordered around the rotational axis. The isotropic refinement
model for these solvent molecules required a number of positional
and thermal parameter restraints. For 6, refinement in P21212 is
presented. A similarly disordered refinement was established in tet-
ragonal P4, but this is inconsistent with the systematic absences.
Refinement in P4212, which has the same systematic absences as
P21212, resulted in disordered rhodium centres along the C2 axis
and was not pursued. The rhodium-bound THF molecules were
also badly disordered over four sites. Each rhodium axial coordina-
tion site featured a similar disorder that was modelled through the
use of carbon atoms with 50 and 25% occupancies and EXYZ,
EADP and FREE cards to handle the location of hydrogen atoms.
All the carbon atoms of the THF molecules were modelled
isotropically.
Instruments
Melting points were measured on a Stuart-SMP10 melting point
apparatus and are uncorrected. Optical rotations were measured
by using a Perkin–Elmer 341 polarimeter at the sodium D line
(589 nm) and are reported as [a]2D5 in g/100 mL concentration (c) in
the solvents indicated. IR spectra were recorded on a Perkin–Elmer
TravelIR FT-IR spectrometer. NMR spectra were recorded on Varian
400-MR and Varian Inova-500 spectrometers at room temperature
in the solvents given. Chemical shifts are expressed in parts per
million (ppm) and reported either relative to an internal tetrame-
thylsilane standard (TMS: d=0.0 ppm) or relative to solvent peaks
(1H NMR: CDCl3 d=7.2 ppm, [D6]DMSO d=2.5 ppm, HOD d=
3.3 ppm; 13C NMR: CDCl3 d=77.0 ppm, [D6]DMSO d=39.5 ppm).
Multiplicities are denoted as follows: s=singlet, d=doublet, t=
triplet, q=quartet, dd=doublet of doublets, ddd=doublet of
doublet of doublets, td=triplet of doublets, qd=quartet of dou-
blets, m=multiplet, br=broad and apt=apparently. Coupling con-
stants (J) are reported in Hertz (Hz). Mass spectrometric analyses
were recorded on Finnigan MAT LCQ MS/MS ESI, AB Sciex
Crystals of 12 suitable for single-crystal X-ray crystallography were
obtained by dissolving the compound prepared from [Rh2(S-
tertPTTL)4] (6) in ethyl acetate/n-hexane (1:3). The resulting solution
Chem. Eur. J. 2016, 22, 3447 – 3461
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3457
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Full Paper
was subjected to sonication and Pasteur pipette filtration. Colour-
less crystals were obtained by the slow evaporation of the solvent
and were used directly for measurement. Single-crystal X-ray
diffraction data were collected at 200 K on a Nonius–KappaCCD
diffractometer equipped with graphite-monochromatised MoKa
radiation (l=0.71073 Š).
Synthesis of the new dirhodium(II) carboxylate complexes[25]
General procedure for the preparation of ligands: Triethylamine
(TEA; 0.1 equiv) was added to a mixture of the acid anhydride
(1.1 equiv) and the l-amino acid (1 equiv) in anhydrous toluene,
and the mixture was heated at reflux for 12 h under nitrogen. After
that time, the reaction mixture was diluted with ethyl acetate,
washed twice with 0.1m hydrochloric acid solution, dried over an-
hydrous Na2SO4, filtered and concentrated in vacuo. The residue
was then purified by silica gel column chromatography using ethyl
acetate/n-hexane as eluent to afford the corresponding desired
product. The amounts of acid anhydride and l-amino acid used
are given below.
Crystals of 16 suitable for single-crystal X-ray crystallography were
obtained by dissolving the compound prepared from [Rh2(S-
tertPTTL)4] (6) in IPA. Colourless crystals were obtained by the slow
evaporation of the solvent which was used directly for measure-
ment. Single-crystal X-ray diffraction data were collected at 150 K
on an Agilent SuperNova Dual diffractometer equipped with
mirror-monochromatised CuKa radiation (l=1.54180 Š).
(S)-N-(1-Phenylnaphthalene-2,3-dicarboximido)-tert-leucine (S-1-
Ph-BPTTL, 1): 1-Phenylnaphthalene-2,3-dicarboxylic anhydride
(0.47 g, 1.7 mmol), l-tert-leucine (0.2 g, 1.6 mmol); colourless oil
(0.6 g, 99%). [a]2D5 =À0.35 (c=1 in CHCl3); Rf =0.59 (ethyl acetate/
n-hexane, 1:1); 1H NMR (400 MHz, CDCl3): d=8.30 (s, 1H; Ar-H),
7.98 (d, J=7.8 Hz, 1H; Ar-H), 7.70 (d, J=8.2 Hz, 1H; Ar-H), 7.62–
7.37 (m, 5H; Ar-H), 7.30 (m, 2H; Ar-H), 4.65 (s, 1H; CHN), 1.08 ppm
(s, 9H; C(CH3)3); 13C NMR (100 MHz, CDCl3): d=172.9 (COOH), 167.6,
166.9 (2”CON), 140.6, 135.5, 134.2, 130.3, 129.9, 129.2, 129.0,
128.6, 128.5, 128.2, 128.1, 127.2, 124.7, 123.1 (16”Ar-C), 60.0 (NCH),
35.1 (C(CH3)3), 28.1 ppm (C(CH3)3); IR (film): n˜ =2962, 1709, 1368,
1241, 1114, 767, 699 cmÀ1; MS (ESI): m/z: calcd for [C24H21NO4+H]+:
388.15; found: 388.16; calcd for [C24H20NO4ÀCO2]À: 342.15; found:
342.15.
(S)-N-(4-tert-Butylphthalimido)-tert-leucine (S-tertPTTL, 2): 4-tert-
Butylphthalic anhydride (0.514 g, 2.52 mmol), l-tert-leucine (0.3 g,
2.29 mmol); colourless oil (0.7 g, 96%); [a]2D5 =À0.35 (c=1 in
CHCl3); Rf =0.7 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz,
CDCl3): d=7.88–7.71 (m, 3H; Ar-H), 4.69 (s, 1H; NCH), 1.34 (s, 9H;
C(CH3)3), 1.15 ppm (s, 9H; C(CH3)3); 13C NMR (100 MHz, CDCl3): d=
173.3 (COOH), 168.4, 168.0 (2”CON), 158.9, 131.8, 131.3, 128.9,
123.4, 120.8 (6”Ar-C), 59.8 (NCH), 35.7, 35.6 (2”C(CH3)3), 31.1,
27.9 ppm (2”C(CH3)3); IR (film): n˜ =2963, 1711, 1372, 1101, 908,
729 cmÀ1; MS (ESI): m/z: calcd for [C18H23NO4+H]+ 318.17; found:
318.17; calcd for [C18H22NO4ÀCO2]À 272.17; found: 272.17.
(S)-N-(endo-Bicyclo[2.2.1]hept-5-ene-2,3-dicarboximido)-tert-leu-
cine (S-BHTL, 3): endo-cis-5-Norbornene-2,3-dicarboxylic anhydride
(0.413 g, 2.52 mmol), l-tert-leucine (0.3 g, 2.29 mmol); white solid
(0.57 g, 90%); [a]2D5 =À0.55 (c=1 in CHCl3); Rf =0.30 (ethyl acetate/
n-hexane, 1:1); 1H NMR (400 MHz, CDCl3): d=6.13–6.09 (ddd, 2H;
CH=CH), 4.34 (s, 1H; CHN), 3.40 (brs, 2H; 2”CH), 3.35–3.30 (m, 2H;
2”CH), 1.63 (dd, J=74.8, 8.8 Hz, 2H; CH2), 1.02 ppm (s, 9H;
C(CH3)3); 13C NMR (100 MHz, CDCl3): d=177.4, 177.3 (2”CON),
172.4 (COOH), 135.2 (=CH), 134.5 (=CH), 60.2 (NCH), 52.5 (CH2),
46.0, 45.7 (2”CH), 45.3, 44.9 (2”CH), 35.4 (C(CH3)3), 27.8 ppm
(C(CH3)3); IR (film): n˜ =3294, 2960, 2870, 1739, 1687, 1380, 1339,
1169, 1145, 713 cmÀ1; MS (ESI): m/z: calcd for [C15H19NO4+H]+;
278.13; found: 278.13. Recrystallised from hot MeOH.
Crystal data for 5: C104H96N4O20Rh2, M=1927.66, tetragonal,
a=21.4840(18), c=11.661(5) Š, V=5382(2) Š3, T=100 K, space
group I4 (no. 79), Z=2, 40745 reflections measured, 6413 unique
(Rint =0.0247), 6289>4s(F), R=0.0416 (observed), Rw =0.1143 (all
data).
.
Crystal data for 6: C72H92N4O16Rh2 2(C4H8O), M=1619.52, ortho-
rhombic, a=19.0510(12), b=19.0440(10), c=11.599(3) Š, V=
4208.2(12) Š3, T=100 K, space group P21212 (no. 18), Z=2, 93973
reflections measured, 15027 unique (Rint =0.0528), 13223>4s(F),
R=0.0421 (observed), Rw =0.1160 (all data).
.
Crystal data for 7: C66H94N4O18Rh2 2(CH4O), M=1501.35,
orthorhombic, a=8.8180(18), b=13.414(3), c=57.659(12) Š, V=
6820(2) Š3, T=100 K, space group P212121 (no. 19), Z=4, 52260 re-
flections measured, 15296 unique (Rint =0.0981), 11 459>4s(F), R=
0.0880 (observed), Rw =0.2100 (all data).
Crystal data for 8: C64H86N6O16Rh2, M=1401.20, monoclinic,
a=12.765(5), b=21.453(4), c=12.932(3) Š, b=112.262(12)8, V=
3277.4(16) Š3, T=100 K, space group P21 (no. 4), Z=2, 53135 re-
flections measured, 19812 unique (Rint =0.0509), 17763>4s(F), R=
0.0348 (observed), Rw =0.0798 (all data).
Crystal data for [Rh2(S-PTAD)4]: 2(C88H96N4O20Rh2).C6H14.C4 H8O2,
M=3645.28, monoclinic, a=19.5350(14), b=14.2510(15), c=
30.592(2) Š, b=90.6030(10)8, V=8516.1(12) Š3, T=100 K, space
group P21 (no. 4), Z=2, 128848 reflections measured, 39729
unique (Rint =0.0324), 38005>4s(F), R=0.0389 (observed), Rw =
0.1017 (all data).
Crystal data for 12: C18H21O3P, M=316.34, orthorhombic, a=
6.6766(1), b=15.6794(3), c=16.3174(3) Š, V=1708.19(5) Š3, T=
200 K, space group P212121 (no. 19), Z=4, 30661 reflections mea-
sured, 3918 unique (Rint =0.034), 3605>4s(F), R=0.0345 (ob-
served), Rw =0.0918 (all data).
Crystal data for 16: C16H13F3, M=262.27, monoclinic, a=9.2411(3),
b=5.7885(2), c=12.0746(5) Š, b=94.319(3)8, V=644.06(4) Š3, T=
150 K, space group P21 (no. 4), Z=2, 11 761 reflections measured,
2530 unique (Rint =0.066), 2502>4s(F), R=0.0814 (observed),
Rw =0.2014 (all data).
CCDC 1063700 (5),
1063701 (6),
1433479 (7),
1433480 (8),
(S)-N-(endo-Bicyclo[2.2.2]oct-5-ene-2,3-dicarboximido)-tert-leu-
cine (S-BOTL, 4): endo-Bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic an-
hydride (0.5 g, 2.8 mmol), l-tert-leucine (0.3 g, 2.3 mmol); white
solid (0.65 g, 98%); [a]D25 =À0.45 (c=1 in CHCl3); Rf =0.31 (ethyl
1433481 ([Rh2(S-PTAD)4]), 1433482 (12), and 1433483 (16) contain
the supplementary crystallographic data for this paper. These data
are provided free of charge by The Cambridge Crystallographic
Data Centre.
1
acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl3): d=6.19 (m, 2H;
CH=CH), 4.43 (s, 1H; CHN), 3.17 (s, 2H; 2”CH), 2.90 (qd, J=8.4,
2.9 Hz, 2H; 2”CH), 1.61 (d, J=7.7 Hz, 2H; CH2), 1.39 (d, J=8.8 Hz,
2H; CH2), 1.05 ppm (s, 9H; C(CH3)3); 13C NMR (100 MHz, CDCl3): d=
178.8, 178.6 (2”CON), 172.3 (COOH), 132.8 (=CH), 132.4 (=CH),
60.2 (NCH), 44.3, 43.9 (2”CH), 35.6 (C(CH3)3), 31.8, 31.5 (2”CH),
27.8 (C(CH3)3), 23.7, 23.6 ppm (2”CH2); IR (film): n˜ =3294, 2958,
2870, 1746, 1683, 1389, 1366, 1166, 1145, 701 cmÀ1; MS (ESI): m/z:
calcd for [C16H21NO4+H]+ 292.15; found: 292.15; calcd for
Synthetic procedures
Preparation of racemic cyclopropane derivatives: All racemic
cyclopropane standards for chiral HPLC analysis were synthesised
following the same synthetic procedures designated below with
[Rh2(OAc)4] employed as catalyst. Analytical samples were obtained
by purification by preparative TLC.
Chem. Eur. J. 2016, 22, 3447 – 3461
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3458
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[C16H20NO4ÀCO2]À 246.15; found: 246.15. Recrystallised from hot
83%); Rf =0.22 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz,
CDCl3): d=6.32–5.86 (m, 8H; 4 CH=CH), 4.70–3.96 (m, 4H; 4 CHN),
3.38–3.10 (m, 16H; 16 CH), 1.79–1.41 (m, 8H; 4 CH2), 0.87 ppm
(brs, 36H; 4 C(CH3)3); 13C NMR (100 MHz, CDCl3): d=186.0 (COO),
176.4, 175.2 (CON), 135.1, 132.0 (CH=CH), 60.9 (NCH), 50.7 (CH2),
45.5, 44.4 (CH), 43.9 43.7 (CH), 34.2 (C(CH3)3), 26.8 ppm (C(CH3)3); IR
(film): n˜ =2961, 1703, 1610, 1398, 1372, 1345, 1172, 1039, 803, 778,
692 cmÀ1; MS (ESI): m/z: calcd for [C60H80N4O16Rh2+6H]+: 1316.3;
found: 1315.9; calcd for [C60H80N4O16Rh2+5HÀC5H6]+: 1249.3;
found: 1249.6; calcd for [C60H80N4O16Rh2+5HÀ2C5H6]+: 1183.2;
found: 1183.2; calcd for [C60H80N4O16Rh2+4HÀC15H20NO4]+: 1038.2;
found: 1037.5; calcd for [C60H80N4O16Rh2+3HÀC15H20NO4ÀC5H6]+:
971.1; found: 971.1; calcd for [C60H80N4O16Rh2+HÀ2C15H20NO4]+:
759.0; found: 759.1.
MeOH.
General procedure for ligand exchange: A mixture of the carbox-
ylic acid ligand (6 equiv) and dirhodium(II) tetraacetate
([Rh2(OAc)4], 1 equiv) in dry chlorobenzene was heated at reflux for
24 h under nitrogen using a Soxhlet extractor fitted with a thimble
containing a dry mixture of Na2CO3 and sand (1:1) for trapping the
eliminated acetic acid molecules. After that time, the solvent was
evaporated in vacuo and the residue was redissolved in DCM,
washed with a saturated solution of NaHCO3, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The green residue was
then purified by silica gel column chromatography using ethyl ace-
tate/n-hexane as eluent. The pure products were dried overnight
under vacuum at 508C before analysis. The amounts of carboxylic
acid ligand and [Rh2(OAc)4] are given below.
General procedure for the preparation of cyclopropylphospho-
Dirhodium(II,II)
tetrakis[(S)-N-(1-phenylnaphthalene-2,3-dicar-
nate derivatives:
A
solution of a-diazobenzylphosphonate
boximido)-tert-leucinate] ([Rh2(S-1-Ph-BPTTL)4], 5): Ligand
(0.621 g, 1.60 mmol), [Rh2(OAc)4] (0.12 g, 0.27 mmol); green solid
(0.31 g, 67%); Rf =0.77 (ethyl acetate/n-hexane, 1:1); 1H NMR
(400 MHz, CDCl3): d=8.07 (s, 4H; Ar-H), 7.60 (d, J=8.2 Hz, 8H; Ar-
H), 7.51–7.30 (m, 24H; Ar-H), 7.12 (d, J=6.9 Hz, 4H; Ar-H), 4.92 (s,
4H; 4”CHN), 1.19–1.16 ppm (m, 36H; 4”C(CH3)3); 13C NMR
(100 MHz, CDCl3): d=186.2 (COO), 166.3, 165.5 (CON), 138.2, 134.5,
134.1, 133.8, 129.6, 129.2, 128.9, 127.4, 127.2, 127.0, 126.8, 126.6,
123.4, 122.9 (Ar-C), 60.4 (NCH), 34.7 (C(CH3)3), 27.0 ppm (C(CH3)3); IR
(film): n˜ =2962, 1709, 1617, 1397, 1365, 1340, 1260, 1109, 1030,
801, 761, 696 cmÀ1; MS (ESI): m/z: calcd for [C96H80N4O16Rh2+7H]+:
(1 equiv) in 2,2-DMB (10 mL) was added dropwise through a syringe
pump to a stirred solution of alkene (5 equiv) and dirhodium(II)
catalyst (0.01 equiv) in 2,2-DMB (3 mL) heated at reflux (598C)
under nitrogen for 10 min. After the addition, the reaction was fur-
ther heated at reflux until TLC indicated complete consumption of
the diazo starting material. The diastereomeric ratio (d.r.) of the
generated product was determined by 1H NMR analysis of the
crude mixture. The product was purified by preparative TLC (ethyl
acetate/n-hexane) and the enantiomeric excess (ee%) of the prod-
uct was determined by chiral HPLC analysis.
General procedure for the preparation of cyclopropylphospho-
nate derivatives using [Rh2(S-tertPTTL)4] (6): A solution of a-diazo-
benzylphosphonate (1 equiv) in 2,2-DMB (10 mL) was added drop-
wise through a syringe pump to a stirred solution of alkene
(5 equiv) and [Rh2(S-tertPTTL)4] (6; 0.01 equiv) in 2,2-DMB (3 mL)
under nitrogen over a period of 10 min. After the addition, the re-
action was stirred at room temperature until TLC indicated a com-
plete consumption of the diazo starting material. The diastereo-
meric ratio (d.r.) of the generated product was determined by
1H NMR analysis of the crude mixture. The product was purified by
preparative TLC (ethyl acetate/n-hexane) and the enantiomeric
excess (ee%) of the product was determined by chiral HPLC analy-
sis.
1758.4; found: 1758.1; calcd for [C96H80N4O16Rh2+5HÀC24H20NO4]+:
+
1369.2; found: 1369.1; calcd for [C96H80N4O16Rh2+2HÀ2C24H20NO4]
:
980.1; found: 980.1; calcd for [C96H80N4O16Rh2À3C24H20NO4ÀH]+:
608.9; found: 608.9; calcd for [C24H20NO4ÀCO2]À: 342.1) found:
341.7.
Dirhodium(II) tetrakis[(S)-N-(4-tert-butylphthalimido)-tert-leuci-
nate] ([Rh2(S-tertPTTL)4], 6): Ligand (0.645 g, 2.032 mmol),
[Rh2(OAc)4] (0.150 g, 0.339 mmol); green solid (0.35 g, 71%); Rf =
0.50 (ethyl acetate/n-hexane, 1:2); 1H NMR (400 MHz, CDCl3): d=
7.85 (brs, 4H; Ar-H), 7.67–7.62 (m, 8H; Ar-H), 4.88 (s, 4H; 4 NCH),
1.35 (s, 36H; 4 C(CH3)3), 1.11 ppm (s, 36H; 4 C(CH3)3); 13C NMR
(100 MHz, CDCl3): d=187.1 (COO), 172.1, 168.2 (CON), 158.0, 132.1,
130.5, 129.4, 122.9, 120.5 (Ar-C), 61.26 (NCH), 35.6, 35.5 (2 C(CH3)3),
31.1, 27.9 ppm (2 C(CH3)3); IR (film): n˜ =2959, 1713, 1612, 1366,
1103, 752, 693 cmÀ1; MS (ESI): m/z: calcd for [C72H88N4O16Rh2+6H]+:
1476.4; found: 1476.8; calcd for [C72H88N4O16Rh2+4HÀC18H22NO4]+:
1158.3; found: 1158.1; calcd for [C72H88N4O16Rh2+2HÀ2”
C18H22NO4]+: 840.1; found: 839.5.
Dimethyl (E)-1,2-diphenylcyclopropylphosphonate (9):[31] Colour-
less oil; [a]2D5 =À0.25 (c=0.53 in CHCl3, 98% ee); Rf =0.15 (ethyl
1
acetate/n-hexane, 1:1); H NMR (400 MHz, CDCl3): d=7.00 (m, 3H;
Ar-H), 6.99 (m, 5H; Ar-H), 6.68 (m, 2H; Ar-H), 3.67 (d, JHP =10.5 Hz,
3H; OCH3), 3.62 (d, JHP =10.5 Hz, 3H; OCH3), 2.95 (ddd, JHP =16.5,
J=8.8, 6.7 Hz, 1H; CH), 1.99 (ddd, JHP =17.3, J=8.8, 5.1 Hz, 1H;
CH2), 1.66 ppm (ddd, JHP =12.2, J=6.7, 5.1 Hz, 1H; CH2). The spec-
troscopic data are consistent with previously reported data.[31] The
enantiomeric excess was determined by chiral HPLC (Chiralcel OJ
column, 25”0.46 cm, 2% 2-propanol in n-hexane (v/v%);
1 mLminÀ1, 220 nm, t1 =18 min, t2 =21 min).
Dirhodium(II,II) tetrakis[(S)-N-(endo-bicyclo[2.2.2]oct-5-ene-2,3-
dicarboximido)-tert-leucinate] ([Rh2(S-BOTL)4], 7): Ligand (0.53 g,
1.82 mmol), [Rh2(OAc)4] (0.13 g, 0.30 mmol); green solid (0.38 g,
92%); Rf =0.34 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz,
CDCl3): d=6.15 (brs, 8H; CH=CH), 4.41 (brs, 4H; 4 CHN), 3.11 (brs,
8H; 8 CH), 2.73 (brs, 8H; 8 CH), 1.56 (brs, 8H; 4 CH2), 1.36 (brs,
8H; 4 CH2), 1.05 ppm (s, 36H; 4 C(CH3)3); 13C NMR (100 MHz,
CDCl3): d=185.5, 185.3 (COO), 177.8, 176.2 (CON), 132.9, 132.0,
131.8, 129.6, 128.7, 127.6, 127.0, 125.3 (CH=CH), 60.7 (NCH), 43.77,
43.15, 42.9, 42.7, 42.5 (CH), 34.4 (C(CH3)3), 30.6 (CH), 26.8 (C(CH3)3),
22.8 ppm (CH2); IR (film): n˜ =2953, 2868, 1703, 1612, 1375, 1174,
781, 695 cmÀ1; MS (ESI): m/z: calcd for [C64H86N4O16Rh2+6H]+:
1372.4; found: 1372.3; calcd for [C64H86N4O16Rh2+4HÀC16H20NO4]+:
1080.2; found: 1079.7; calcd for [C64H86N4O16Rh2+HÀ2C16H20NO4]+:
787.1; found: 787.2.
Dimethyl
(E)-1-phenyl-2-(p-chlorophenyl)cyclopropylphospho-
nate (10):[31b] Colourless oil; [a]D25 =À0.54 (c=0.87 in CHCl3, 98%
ee); Rf =0.11 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz,
CDCl3): d=7.14–7.11 (m, 3H; Ar-H), 7.04 (m, 2H; Ar-H), 7.01 (d, J=
8.5 Hz, 2H; Ar-H), 6.64 (d, J=8.4 Hz, 2H; Ar-H), 3.70 (d, JHP
10.6 Hz, 3H; OCH3), 3.66 (d, JHP =10.6 Hz, 3H; OCH3), 2.96 (ddd,
HP =16.5, J=8.8, 6.7 Hz, 1H; CH), 2.06 (ddd, JHP =17.4, J=9.0,
=
J
5.3 Hz, 1H; CH2), 1.66 (ddd, JHP =12.4, J=6.5, 5.3 Hz, 1H; CH2). The
spectroscopic data are consistent with previously reported data.[31b]
The enantiomeric excess was determined by chiral HPLC (Chiralcel
OJ column, 25”0.46 cm, 8% 2-propanol in n-hexane (v/v%);
1 mLminÀ1, 220 nm, t1 =10 min, t2 =12 min).
Dirhodium(II,II) tetrakis[(S)-N-(endo-bicyclo[2.2.1]hept-5-ene-2,3-
dicarboximido)-tert-leucinate] ([Rh2(S-BHTL)4], 8): Ligand (0.49 g,
1.77 mmol), [Rh2(OAc)4] (0.13 g, 0.29 mmol); green solid (0.32 g,
Chem. Eur. J. 2016, 22, 3447 – 3461
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Full Paper
Dimethyl (E)-1-phenyl-2-(p-methoxyphenyl)cyclopropylphospho-
nate (11):[31b] Colourless oil; [a]D25 =À0.57 (c=1 in CHCl3, 99% ee);
Rf =0.11 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz, CDCl3):
d=7.12–7.10 (m, 3H; Ar-H), 7.05 (m, 2H; Ar-H), 6.62 (dd, J=23.0,
8.9 Hz, 4H; Ar-H), 3.71 (d, JHP =10.6 Hz, 3H; OCH3), 3.68 (s, 3H;
OCH3), 3.66 (d, JHP =10.6 Hz, 3H; OCH3), 2.96 (ddd, JHP =16.1, J=
9.1, 6.6 Hz, 1H; CH), 2.03 (ddd, JHP =17.5, J=9.1, 5.2 Hz, 1H; CH2),
1.64 ppm (ddd, JHP =12.4, J=6.5, 5.3 Hz, 1H; CH2). The spectro-
scopic data are consistent with previously reported data.[31b] The
enantiomeric excess was determined by chiral HPLC (Chiralcel OJ
column, 25”0.46 cm, 3% 2-propanol in n-hexane (v/v%);
1 mLminÀ1, 220 nm, t1 =37 min, t2 =42 min).
a syringe pump. The reaction was stirred for another hour, after
which time the reaction solvent was removed under reduced pres-
sure. The diastereomeric ratio (d.r.) of the generated product was
1
determined by H NMR analysis of the crude mixture. The product
was purified by preparative TLC using n-hexane as eluent. White
1
solid; Rf =0.29 (n-hexane); H NMR (400 MHz, CDCl3): d=7.13–6.99
(m, 8H; Ar-H), 6.71–6.69 (m, 2H; Ar-H), 2.77 (dd, J=9.6, 7.0 Hz, 1H;
CH), 1.81 (dd, J=9.6, 5.9 Hz, 1H; CH2), 1.61 ppm (m, 1H; CH2). The
spectroscopic data are consistent with previously reported data.[7]
The enantiomeric excess was determined by chiral HPLC (Chiralcel
OJ column, 25”0.46 cm, 1% 2-propanol in n-hexane (v/v%);
0.8 mLminÀ1, 220 nm, t1 =6.5 min, t2 =7.8 min).
Dimethyl (E)-1-phenyl-2-(p-methylphenyl)cyclopropylphospho-
nate (12): White solid; [a]2D5 =À0.57 (c=0.93 in CHCl3, 99% ee);
Rf =0.17 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz, CDCl3):
d=7.13–7.10 (m, 3H; Ar-H), 7.07–7.04 (m, 2H; Ar-H), 6.85 (d, J=
General procedure for the preparation of cyclopropanecarboxy-
lates: The diazo compound (1.0 equiv) dissolved in the same dry
and degassed solvent was added dropwise through a syringe
pump to a solution of styrene (5.0 equiv) and dirhodium(II) catalyst
(0.01 equiv) in dry and degassed solvent under nitrogen over
a period of 10 min. After the addition, the mixture was stirred for
at least 1 h. When the diazo compound was fully consumed, as in-
dicated by TLC, the reaction solvent was removed in vacuo. The
diastereomeric ratio (d.r.) of the generated product was deter-
7.8 Hz, 2H; Ar-H), 6.61 (d, J=8.2 Hz, 2H; Ar-H), 3.72 (d, JHP
10.6 Hz, 3H; OCH3), 3.66 (d, JHP =10.6 Hz, 3H; OCH3), 2.97 (ddd,
HP =16.1, J=9.1, 6.6 Hz, 1H; CH), 2.19 (s, 3H; CH3), 2.03 (ddd, JHP
=
J
=
17.5, J=9.0, 5.1 Hz, 1H; CH2), 1.67 ppm (ddd, JHP =12.5, J=6.6,
5.1 Hz, 1H; CH2). The enantiomeric excess was determined by
chiral HPLC (Chiralcel OJ column, 25”0.46 cm, 3% 2-propanol in n-
hexane (v/v%); 1 mLminÀ1, 220 nm, t1 =12 min, t2 =15 min).
1
mined by H NMR analysis of the crude mixture. The product was
purified by preparative TLC using ethyl acetate/n-hexane and the
enantiomeric excess (ee%) of the product was determined by
chiral HPLC analysis.
Dimethyl
(E)-1-phenyl-2-(1-naphthyl)cyclopropylphosphonate
(13): Colourless oil; [a]D25 =À0.24 (c=0.5 in CHCl3, 98% ee); Rf =
0.14 (ethyl acetate/n-hexane, 1:1); 1H NMR (400 MHz, CDCl3): d=
7.72–7.53 (m, 2H; Ar-H), 7.50 (d, J=7.50 Hz, 1H; Ar-H), 7.35 (m, 2H;
Ar-H), 7.29 (s, 1H; Ar-H), 7.07 (m, 4H; Ar-H), 6.76 (dd, J=8.5, 1.8 Hz,
1H; Ar-H), 3.75 (d, JHP =10.6 Hz, 3H; OCH3), 3.70 (d, JHP =10.6 Hz,
3H; OCH3), 3.16 (ddd, JHP =16.1, J=9.1, 6.6 Hz, 1H; CH), 2.14 (ddd,
Methyl (E)-1-(p-methoxyphenyl)-2-phenylcyclopropanecarboxy-
late (17):[5] Colourless oil; Rf =0.52 (ethyl acetate/n-hexane, 1:4);
1H NMR (400 MHz, CDCl3): d=7.10–7.07 (m, 3H; Ar-H), 6.95 (d, J=
8.8 Hz, 2H; Ar-H), 6.80–6.77 (m, 2H; Ar-H), 6.68 (d, J=8.8 Hz, 2H;
Ar-H), 3.74 (s, 3H; CH3), 3.68 (s, 3H; CH3), 3.09 (dd, J=9.2, 7.6 Hz,
1H; CH), 2.14 (dd, J=9.2, 4.8 Hz, 1H; CH2), 1.84 ppm (dd, J=7.2,
4.8 Hz, 1H; CH2). The spectroscopic data are consistent with previ-
ously reported data.[5] The enantiomeric excess was determined by
chiral HPLC (Chiralcel OD-H column, 25”0.46 cm, 0.7% 2-propanol
in n-hexane (v/v%); 1 mLminÀ1, 220 nm, t1 =13 min, t2 =23 min).
J
HP =17.5, J=9.0, 5.3 Hz, 1H; CH2), 1.85 ppm (ddd, JHP =12.5, J=
6.6, 5.1 Hz, 1H; CH2). The enantiomeric excess was determined by
chiral HPLC (Chiralpak AD column, 25”0.46 cm, 1% 2-propanol in
n-hexane (v/v%); 2 mLminÀ1, 220 nm, t1 =36 min, t2 =42 min).
Diethyl (E)-1,2-diphenylcyclopropylphosphonate (14):[31b] Colour-
less oil; [a]2D5 =À0.11 (c=0.4 in CHCl3, 92% ee); Rf =0.26 (ethyl ace-
tate/n-hexane, 1:1); 1H NMR (400 MHz, CDCl3): d=7.11–7.07 (m,
4H; Ar-H), 7.06–7.01 (m, 4H; Ar-H), 6.72 (m, 2H; Ar-H), 4.11–3.95
(m, 4H; 2 OCH2CH3), 2.98 (ddd, JHP =16.5, J=8.8, 6.5 Hz, 1H; CH),
1.99 (ddd, JHP =17.5, J=9.0, 5.1 Hz, 1H; CH2), 1.68 (ddd, JHP =12.2,
J=6.7, 5.1 Hz, 1H; CH2), 1.26 (td, J=7.0, 0.4 Hz, 3H; OCH2CH3),
1.22 ppm (td, J=7.0, 0.5 Hz, 3H; OCH2CH3). The spectroscopic data
are consistent with previously reported data.[31b] The enantiomeric
excess was determined by chiral HPLC (Chiralpak AD column, 25”
Methyl (E)-1,2-diphenylcyclopropanecarboxylate (18):[5,32] White
solid; m.p. 60–628C; Rf =0.30 (ethyl acetate/n-hexane, 1:10);
1H NMR (400 MHz, CDCl3): d=7.13–6.75 (m, 10H; Ar-H), 3.66 (s, 3H;
CH3), 3.11 (dd, J=9.3, 7.3 Hz, 1H; CH), 2.13 (dd, J=9.3, 4.9 Hz, 1H;
CH2), 1.88 ppm (dd, J=7.3, 4.9 Hz, 1H; CH2). The spectroscopic
data are consistent with previously reported data.[5,32] The enantio-
meric excess was determined by chiral HPLC (Chiralcel OJ column,
25”0.46 cm, 0.5% 2-propanol in n-hexane (v/v%); 1 mLminÀ1
220 nm, t1 =14 min, t2 =20 min).
,
0.46 cm, 0.6% 2-propanol in n-hexane (v/v%); 0.8 mLminÀ1
220 nm, t1 =69 min, t2 =76 min).
,
Methyl
(E)-2-phenyl-1-[(Z)-styryl]cyclopropane-1-carboxylate
(19):[33] White solid; m.p. 58–618C; Rf =0.63 (ethyl acetate/n-
Diisopropyl (E)-1,2-diphenylcyclopropylphosphonate (15):[31b]
Colourless oil; Rf =0.40 (ethyl acetate/n-hexane, 1:1); 1H NMR
(400 MHz, CDCl3): d=7.08 (m, 5H; Ar-H), 7.02 (m, 3H; Ar-H), 6.73
hexane, 1:3); H NMR (400 MHz, CDCl3): d=7.17–7.04 (m, 10H; Ar-
1
H), 6.26 (d, J=Hz, 1H; CH=CH), 6.05 (d, J=Hz, 1H; CH=CH), 3.68
(s, 3H; CH3), 2.93 (dd, J=9.0, 7.5 Hz, 1H; CH), 1.94 (dd, J=9.2,
5.0 Hz, 1H; CH2), 1.75 ppm (dd, J=9.2, 5.0 Hz, 1H; CH2). The spec-
troscopic data are consistent with previously reported data.[33] The
enantiomeric excess was determined by chiral HPLC (Chiralcel OJ
column, 25”0.46 cm, 1.5% 2-propanol in n-hexane (v/v%);
1 mLminÀ1, 254 nm, t1 =15 min, t2 =21 min).
(E)-1,2-Diphenylcyclopropanecarbonitrile (20):[6,34] a-Diazo-2-phe-
nylacetonitrile (1 equiv) dissolved in dry and degassed toluene
(2 mL) was added dropwise through a syringe pump to a stirred
solution of styrene (5 equiv) and dirhodium(II) catalyst (0.02 equiv)
in dry and degassed toluene (3 mL) maintained at À788C and
under nitrogen over a period of 10 min . The orange reaction mix-
ture was allowed to slowly warm up to ~208C, during which time,
the colour of the mixture returned back to green. The solvent was
then removed in vacuo and the diastereomeric ratio (d.r.) of the
(m, 2H; Ar-H), 4.67–4.56 (m, 2H; 2 CH(CH3)2), 2.95 (ddd, JHP
=
16.8 Hz, J=8.9, 6.5 Hz, 1H; CH), 2.02 (ddd, JHP =17.5, J=8.9, 5.1 Hz,
1H; CH2), 1.67 (ddd, JHP =12.4 Hz, J=6.5, 5.0 Hz, 1H; CH2), 1.27 (d,
J=2.0 Hz, 3H; CH(CH3)2), 1.25 (d, J=2.0 Hz, 3H; CH(CH3)2), 1.23 (d,
J=6.2 Hz, 3H; CH(CH3)2), 1.19 ppm (d, J=6.2 Hz, 3H; CH(CH3)2).
The spectroscopic data are consistent with previously reported
data.[31b] The enantiomeric excess was determined by chiral HPLC
(Chiralpak AD column, 25”0.46 cm, 0.6% 2-propanol in n-hexane
(v/v%); 0.8 mLminÀ1, 220 nm, t1 =49 min, t2 =54 min).
(E)-1-Trifluoromethyl-1,2-diphenylcyclopropane (16):[7] 1-Phenyl-
2,2,2-trifluorodiazoethane (1.0 equiv) dissolved in dry and degassed
TFT (2 mL) was added dropwise to a solution of the styrene
(5.0 equiv) and dirhodium(II) catalyst (0.02 equiv) in dry and de-
gassed TFT (3 mL) under nitrogen over a period of 10 min by using
Chem. Eur. J. 2016, 22, 3447 – 3461
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1
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due. The product was purified by preparative TLC using diethyl
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8H; Ar-H), 6.82–6.80 (m, 2H; Ar-H), 3.09 (t, J=8.6 Hz, 1H; CH),
2.14–2.00 ppm (m, 2H; CH2). The enantiomeric excess was deter-
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propanol in n-hexane (v/v%); 1 mLminÀ1, 220 nm, t1 =19 min, t2 =
29 min).
(Z)-1,2-Diphenylcyclopropanecarbonitrile: White solid; Rf =0.32
(diethyl ether/n-hexane, 1:9); 1H NMR (400 MHz, CDCl3): d=7.34–
7.23 (m, 10H; Ar-H), 2.72 (t, J=8.4 Hz, 1H; CH), 2.06–1.91 ppm (m,
2H; CH2). The enantiomeric excess was determined by chiral HPLC
(Chiralcel OD column, 25”0.46 cm, 0.8% 2-propanol in n-hexane
(v/v%); 1 mLminÀ1, 220 nm, t1 =22 min, t2 =36 min).
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Acknowledgements
The authors gratefully acknowledge the W. J. Weeden Scholar-
ships Program at the University of Canberra, Australia, for the
Ph. D. scholarship offered to Dr. Frady Gamal Adly Gouany. The
authors acknowledge the role of Dr. Tony Willis from the Aus-
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graphic data of some of the prepared cyclopropane products.
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Keywords: asymmetric synthesis
catalysis · cyclopropanation · rhodium
·
carbenoids
·
chiral
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Received: November 30, 2015
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Published online on February 2, 2016
Chem. Eur. J. 2016, 22, 3447 – 3461
www.chemeurj.org
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