Rhodium-catalyzed enantioselective intramolecular [4+2] cycloaddition using a chiral phosphine-phosphite ligand: Importance of microwave-assisted catalyst conditioning

Article abstract of DOI:10.1002/adsc.201100658

The use of modular α,α,α′,α′-tetraaryl- 1,3-dioxolane-4,5-dimethanol (TADDOL)- and 1,1′-bi-2-naphthol (BINOL)-derived phosphine-phosphite ligands (L₂) in the asymmetric rhodium-catalyzed intramolecular [4+2] cycloaddition ("neutral" Diels-Alder

Full text of DOI:10.1002/adsc.201100658

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DOI: 10.1002/adsc.201100658
Rhodium-Catalyzed Enantioselective Intramolecular [4+2]
Cycloaddition using a Chiral Phosphine-Phosphite Ligand:
Importance of Microwave-Assisted Catalyst Conditioning
Anna Falk,a Lukas Fiebig,a Jçrg-Martin Neudçrfl,a Andreas Adler,a
and Hans-Gꢀnther Schmalza,*
a
Department fꢀr Chemie, Universitꢁt zu Kçln, Greinstraße 4, 50939 Kçln, Germany
Fax : (+49)-221-470-3064; phone: (+49)-221-470-3063; e-mail: schmalz@uni-koeln.de
Received: August 18, 2011; Published online: December 6, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100658.
Abstract: The use of modular a,a,a’,a’-tetraaryl-
1,3-dioxolane-4,5-dimethanol (TADDOL)- and 1,1’-
bi-2-naphthol (BINOL)-derived phosphine-phos-
phite ligands (L2*) in the asymmetric rhodium-cata-
lyzed intramolecular [4+2]cycloaddition (“neutral”
Diels–Alder reaction) of (E,E)-1,6,8-decatriene de-
rivatives (including a 4-oxa and a 4-aza analogue)
was investigated. Initial screening of a small ligand
library led to the identification of a most promising,
TADDOL-derived ligand bearing a phenyl group
adjacent to the phosphite moiety at the arene back-
bone. In the course of further optimization studies,
the formation of a new, more selective catalyst spe-
cies during the reaction time was observed. By irra-
diating the pre-catalyst with microwaves prior to
substrate addition high enantioselectivities (up to
93% ee) were achieved. The new cyclization proto-
col was successfully applied to all three substrates
investigated to give the bicyclic products in good
yield and selectivity. 31P NMR and ESI-MS
and even “uncommon” types of (formal) cycloaddi-
tions, such as [2+2+2],[3] [2+2+1],[4] or [5+2][5]
processes have been developed and applied as strate-
gic key steps in natural product synthesis.[6]
Transition metal catalysis also allows one to over-
come certain limitations of the classical Diels–Alder
reaction. For instance, so-called “neutral” Diels–
Alder reactions, involving non-activated dienes and
dienophiles, often cannot be achieved under thermal
(or Lewis acid-catalyzed) conditions. However, it has
been shown that certain transition metal complexes
are able to efficiently catalyze such transformations,
in particular in cases where an alkyne (or allene) acts
as the dienophile.[7]
Intramolecular [4+2]cycloadditions of trienes of
type 1 represent an interesting challenge, as the re-
sulting hexahydroindenes (or their hetero analogues)
of type 2 resemble relevant substructures of natural
products (Scheme 1). As an important breakthrough,
Livinghouse and co-workers reported in 1990 that the
conversion of 1a to rac-2a could be achieved in high
yield using [(i-C3HF6O)3P]2RhCl as a catalyst.[8]
The chirogenic nature of this Rh-catalyzed transfor-
mation opens the possibility to perform it in an asym-
metric fashion by using chiral ligands. A first enantio-
selective version was disclosed by Livinghouse who
used DIOP in the synthesis of 2a (73% ee)[9] and 2b
measurements indicated the formation of
[Rh
(L2*)2]+ species as the more selective (pre-) cat-
alyst.
a
ACHTUNGTRENNUNG
Keywords: asymmetric catalysis; chiral P,P ligands;
ACHTUNGTRENNUNG[4+2]cycloaddition; Diels–Alder reaction; enantio-
selectivity; rhodium(I) complexes
Cycloadditions, such as the most prominent Diels–
Alder reaction,[1] open particularly powerful options
for the construction of polycyclic systems in an atom-
economical fashion.[2] With the emergence of transi-
tion metal catalysis, the toolset of classical (pericyclic)
Scheme 1. Rh-catalyzed intramolecular [4+2]cycloadditions
cycloaddition chemistry has been greatly expanded of trienes of type 1.
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Scheme 2. Phenol-derived phosphine-phosphite ligands of
type 4.
(79% ee).[10] An important advance was reported by
Gilbertson and co-workers who succeeded in convert-
ing 1a to 2a with >98% ee (64% yield) using pre-
formed [(RhACHTUNGTRENNUNG(NBD)BINAP)SbF6] as a pre-catalyst,
which was activated by hydrogenation prior to sub-
strate addition.[11] In the course of another study, the
synthesis of 2b was achieved in 91% ee using a rather
specialized sila-bridged P-chirogenic diphosphine.[12]
Still, in contrast to the structurally related diene-
yne substrates, diene-enes of type 1 represent rather
difficult substrates for enantioselective Diels–Alder-
type transformations challenging the development of
a generally applicable catalyst system.
Figure 1. Phophine-phosphite ligands of type 4 used in the
present study.
Table 1. Screening of different ligands of type 4 in the Rh-
catalyzed [4+2]cycloaddition of substrate 1a.[a]
A few years ago, we elaborated an efficient modu-
lar synthesis of phenol-derived phosphine-phosphites
of type 4 using chiral diols such as TADDOL or
BINOL as a source of chirality (Scheme 2).[13]
This new class of readily available chiral ligands
was then shown to possess a promising potential for
asymmetric metal catalysis (especially Cu- and Rh-
catalyzed transformations).[14] We therefore envi-
sioned that such ligands could also serve in the Rh-
catalyzed [4+2] cycloaddition of tethered diene-enes
of type 1. We here report on the successful realization
of this idea and the elaboration of an optimized pro-
tocol for such transformations.
We started our investigation with a primary ligand
screening. For this purpose, we used the reaction of
substrate 1a in CH2Cl2 as a solvent under the condi-
tions developed by Gilbertson[11] with the difference
that the Rh complexes were formed in situ (without
isolation). The tested ligands of type 4 (Figure 1)
were prepared as previously reported.[13] As the only
new ligand the 4-fluorophenyl-TADDOL derivative
4j was synthesized along the established route.[13a]
The results of the initial ligand testing are summar-
ized in Table 1. Firstly, it was found that the ligands
(despite their seemingly structural similarity) behaved
quite differently. Most importantly, a tremendous
effect of the phenolic backbone substitution pattern
on the activity and selectivity of the catalyst was ob-
Entry Ligand
(L2*)
Conversion[b] ee
[%][c] mer[d]
Major enantio-
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
+
–
–
– –
–
–
–
+
6
6
5
–
48
7
8
62
25
62
ent-2a
ent-2a
ent-2a
–
2a
ent-2a
ent-2a
2a
9
–
+
ent-2a
2a
10
4j
[a]
Conditions: 6 mol% of catalyst prepared from
[Rh(NBD)Cl]2, AgSbF6, L2* (0.5:1:1.2) and activation
AHCTUNGTRENNUNG
with H2; reaction carried out in CH2Cl2 at room tempera-
ture.
Complete (+), incomplete (–), or no (– –) conversion
after 3 days.
The enantiomeric excess (ee) of 2a/ent-2a was deter-
mined by GC analysis after 3 days.
The absolute configuration was assigned by GC compari-
son with a reference sample of ent-2a prepared according
to ref.[11] using (S,S)-DIOP as a ligand.
[b]
[c]
[d]
served. While a methyl substituent in the R4 position (62% ee) was found only for the phenyl-substituted li-
of the ligand 4 strongly reduced the activity (reaction gands 4h and 4j (Table 1, entries 8 and 10). Exchang-
rate), the variation of the substituent R1 (ortho to the ing the TADDOL unit for BINOL (4h!4i) led to a
phosphite moiety) had a great impact on the enantio- dramatic decrease in enantioselectivity (entry 9). The
selectivity. Ligands 4a, 4h and 4j led to full conversion fluorophenyl-TADDOL-based ligand 4j performed
within 3 days,[15] while a promising enantioselectivity similar to its non-fluorinated congener 4h (entry 10).
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Rhodium-Catalyzed Enantioselective Intramolecular [4+2]Cycloaddition
Table 2. Influence of different solvents on the rate and selec-
tivity of the Rh-catalyzed reaction of 1a to 2a in the pres-
ence of ligand 4h.[a]
Entry
Solvent
Conversion[b]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
EtOAc
THF
2-Me-THF
Et2O
MTBE
toluene
DCE
DMSO
HFIP
+
+
–
–
–
–
–
+
– –
–
62
72
44
40
36
52
72
54
–
9
10
11
32
60
ethyl formate
+
Figure 2. Increase of the enantioselectivitiy during the reac-
tion of 1a to 2a in EtOAc at room temperature according to
Table 3, entry 1 (>95% conversion after 44 h).
[a]
Conditions: 6 mol% of catalyst prepared from
[Rh(NBD)Cl]2, AgSbF6, 4h (0.5:1:1.2) and activation
ACHTUNGTRENNUNG
with H2; room temperature.
Complete (+), incomplete (–), or no (– –) conversion
after 3 days.
The enantiomeric excess (ee) of 2a was determined by propanol (HFIP) were less effective. We therefore
GC analysis after full conversion of substrate 1a or after
7 days.
[b]
[c]
polar solvents such as ethyl formate or hexafluoro-2-
used EtOAc as a solvent of choice for all further ex-
periments (see below).
At this point, we probed the conditions developed
so far (using ligand 4h in EtOAc at room tempera-
ture) also on a preparative scale. We found that all
three substrates (1a–c) afforded the expected prod-
ucts (2a–c) with at least significant selectivity
(Table 3, entries 1, 3, and 5). In the case of 2a the
rather low isolated yield reflects the high volatility of
the product. In the case of 2b a higher catalyst load
(10 mol%) was used to accelerate the very slow reac-
tion.[15] Noteworthy is the fact that 2c formed at all,
because substrate 1c is known to yield a different
(monocyclic) product under related conditions in the
presence of other ligands.[17] Nevertheless, the moder-
ate yields and enantioselectivities as well as the rather
long reaction times required further optimization ef-
forts.
Table 3. Rh-catalyzed [4+2]cycloadditions according to
Scheme 1 using ligand 4h with and without catalyst pre-con-
ditioning.[a]
Entry Substrate Conditions Reaction time Yield
ee
[%]
[days]
[%][b]
1
2
1a
1a
1b
1b
1c
1c
A
B
A
B
A
B
3
1
8
1
7
1
54c)
44c)
69
83
11
72
90
51
90
31
68
3[d]
4[d]
5
6
79
[a]
Conditions A: 6 mol% of catalyst prepared from
[Rh(NBD)Cl]2, AgSbF6, 4h (0.5:1:1.2) and activation
ACHTUNGTRENNUNG
with H2; EtOAc; room temperature. Conditions B:
A surprising observation was made when we moni-
tored the enantioselectivity during the conversion of
1a (Table 3, entry 1). As depicted in Figure 2, the
enantioselectivity strongly improved within the first
20 h (from 30% to 70% ee).
We assumed that this phenomenon resulted from
the slow formation of a secondary catalyst species
that is far more selective than the initial one. To
6 mol% of microwave-conditioned catalyst prepared
from [RhACHTUNGTRENNUNG(NBD)Cl]2, AgSbF6, 4h (0.5:1:1.6) and subse-
quent activation with H2; the reaction was then carried
out in EtOAc at 508C in the microwave reactor.
Isolated yield after purification.
Reduced yield because of a high volatility of the product.
10 mol% of catalyst used.
[b]
[c]
[d]
In all cases, the cis-bicyclic products (2a/ent-2a) were probe this assumption we performed an experiment
obtained as pure diastereomers (GC-MS). using a catalyst solution in EtOAc which was “pre-
Having identified 4h as a promising ligand, the next conditioned” at 808C for 2 h. And indeed, an im-
goal was to further optimize the reaction conditions. proved enantioselectivity was observed in this case
For this purpose, we tested a series of different sol- (60% ee after 3 h; 78% ee after 90% conversion). An
vents, again using the transformation of 1a to 2a as a even more efficient conditioning was achieved under
standard (Table 2). While both EtOAc and toluene rather harsh microwave conditions (1208C in EtOAc,
gave rise to an improved enantioselectivity of 72% ee, 5.0 bar, 45 min). While the resulting brownish-orange
the reaction was much faster in EtOAc.[11,16] Notewor- catalyst solution was poorly active at room tempera-
thy, no conversion was observed in DMSO, and other ture, it performed very well at elevated temperatures.
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Figure 3. 31P NMR spectra (in EtOAc/C6D6): (a) free ligand 4h (L2*); (b) freshly prepared pre-catalyst, i.e.,
[Rh
(NBD)L2*]+SbF6ꢀ; (c) aged pre-catalyst after 24 h at room temperature, and (d) conditioned pre-catalyst (microwave,
ACHTUNGTRENNUNG
1208C, 45 min).
Best results were obtained at 508C in a microwave re- Table 4. 31P NMR data of different species in EtOAc (com-
pare Figure 3).
actor. Under these conditions, the intramolecular
ACHTUNGTRENNUNG[4+2]cycloaddition of all three substrates (1a–c) was
achieved in good yield within 20 h and with a remark-
able level of selectivity (Table 3, entries 2, 4 and 6).
Noteworthy, the microwave-assisted reactions pro-
ceeded also much more cleanly than those performed
at the same temperature in an oil bath.
Of course, we were curious about the chemical
nature of the “more selective” catalyst species. In a
first attempt to shed some light on the molecular
changes occurring during the conditioning we investi-
Species
d [ppm] (coupling)
4h (free ligand)
144.4 (d, J=88 Hz), 17.4 (d,
J=88 Hz)
(NBD)L2*]+SbF6 113.2 (dd, J=269/85 Hz), 20.4 (dd,
ACHTUNGTRENNUNG
ꢀ
[Rh
[Rh
J=142/85 Hz)
116.2 (ddd, J=238/60/58 Hz), 22.3
(ddd, J=130/60/58 Hz)
ꢀ
(L2*)2]+SbF6
gated different solutions by means of 31P NMR spec- which is also connected to a signal splitting resulting
troscopy. Figure 3 shows the 31P NMR spectra (in from P Rh (J1) coupling. The additional couplings
ꢀ
EtOAc) of (a) the free ligand (L2*, that is, 4h), (b) within the species formed during the conditioning
the
[RhACHTUNGTRENNUNG
standard
cꢀatalyst
solution,
that
is, process indicate the presence of an additional L2*
(NBD)L2*]+SbF6 , (c) the “aged” catalyst solution ligand at the Rh center, that is, the formation of a
after 24 h at room temperature containing small [Rh
amounts of a different complex, and (d) the catalyst
solution after microwave treatment (45 min, 1208C). [Rh
ACHTUNGTRENNUNG
+
The NMR-based proposal of a RhL4 species (i.e.
ꢀ
A
Obviously, the original complex was completely con- spectrometric measurements. The ESI (+) mass spec-
verted into a new species in the course of the condi- trum showed a signal at m/z=1800.473 corresponding
tioning process.
to the [Rh(4h)2]+ ion (see the Supporting Informa-
The NMR data (see Table 4) nicely show the tion). The identity of this signal was confirmed by a
changes of the chemical shifts of both the phosphine collision-induced dissociation (CID) experiment
and the phosphite teeth of 4h on Rh-complexation, (LTQ-MS2) where a main product ion showed up at
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Rhodium-Catalyzed Enantioselective Intramolecular [4+2]Cycloaddition
ed catalyst conditioning) was identified and suggested
to act as a more selective (pre-)catalyst.
Experimental Section
Pre-catalyst Preparation and Conditioning
In
a
Schlenk flask under an atmosphere of argon
[Rh
N
Figure 4. Structure of 2b in the crystalline state confirming
drous CH2Cl2 (0.5 mL) and AgSbF6 (8.3 mg, 0.024 mmol)
was added in one portion. After stirring for 10 min, the red
solution was carefully needled off the precipitated AgCl
(which was washed twice with 1 mL of anhydrous CH2Cl2)
and the Rh-containing CH2Cl2 solutions were combined
with a solution of the ligand (0.038 mmol) in anhydrous
CH2Cl2 (0.5 mL). The resulting orange solution was allowed
to stir for 45 min at room temperature before the solvent
was removed under vacuum. The obtained pre-catalyst
(0.024 mmol) was dissolved in anhydrous EtOAc (4.0 mL)
and the solution was transferred into a septum-sealed micro-
wave vial under argon. The solution was then heated in a
CEM microwave reactor at 300 W until a pressure of 5.0 bar
was reached. The stirred solution was then kept for 45 min
at 1208C with a maximum power of 300 W and 5.0 bar pres-
sure.
the relative and absolute configuration.
m/z=951.187 resulting from dissociation of one mole-
cule of ligand 4h.
+
The formation of a Rh(L2)2 complex as the only
major phosphorus-containing species in our catalyst
solutions (after conditioning) was initially rather sur-
prising to us. However, a literature search revealed
that related complexes had been identified in certain
hydrogenation reactions and found to be less active
+
but more enantioselective in comparison to the RhL2
systems.[18] Under our optimized conditions (compare
Table 3, conditions B) an excess of the chiral ligand
was employed (Rh/L2*=1:1.6) to suppress any achiral
background catalysis. After we had realized that two
ligand (L2*) molecules are actually required per rho-
dium atom to generate the selective catalyst, we per-
formed a control experiment employing an increased
General Cyclization Procedure (Table 3, Conditions
B)
Under an atmosphere of argon, a Schlenk flask was filled
with the conditioned pre-catalyst (0.024 mmol) in EtOAc
(4.0 mL) prepared as described above. To activate the cata-
lyst, H2 was bubbled through the solution for 2 min, fol-
lowed by argon for 2 min. Then, a solution of the substrate
(1a–c) (0.40 mmol) in EtOAc (2.0 mL) was added and the
mixture was degassed (3 freeze-pump-thaw cycles) before it
was stirred at 508C in the microwave for 20 h. The reaction
progress could be monitored by TLC or GC.
amount of the ligand 4h {[RhACHTUNTRGNEUNG(NBD)Cl]2:AgSbF6:4h=
0.5:1:2}. In this case the product (2b) was indeed ob-
tained with a slightly improved enantioselectivity
(93% ee).
Throughout the study, the enantiomeric analyses of
the products of type 2 were performed by means of
chiral GC (2a), chiral HPLC (2b) or chiral NMR shift
reagents (2c) using racemic reference samples. For
this purpose, the heteroatom-tethered substrates 1a
and 1b were cyclized using dppe as an achiral ligand
to give rac-2a[19] and rac-2b, respectively. To obtain a
sample of rac-2c, however, the ligand rac-4h (derived
from rac-TADDOL) was employed. The absolute
configuration of 2a was assigned according to Gilbert-
son.[11] In the case of 2b the relative and absolute con-
figuration was unambiguously confirmed by means of
X-ray crystal structure analysis (Figure 4).[20] We
therefore assume that all products (2a–c) prepared
using ligand 4h belong to the same stereochemical
series.
Acknowledgements
This work was performed in the context of COST D40 and
supported by the Fonds der Chemischen Industrie (fellowship
to A. F.) and the Cusanuswerk (fellowship to L. F.). We are
grateful to Daniela Naumann for assistance with 600 MHz
NMR measurements.
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COMMUNICATIONS
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Adv. Synth. Catal. 2011, 353, 3357 – 3362