Synthesis of Highly Enantioenriched Propelladienes and their Application as Ligands in Asymmetric Rh-Catalyzed 1,4-Additions

Article abstract of DOI:10.1021/acs.orglett.8b02204

The first synthesis of highly enantioenriched [4.3.3]propelladienes is reported. The novel bridged bicyclo[3.3.0] dienes were applied as steering ligands in the rhodium-catalyzed asymmetric arylation of cyclic enones. The catalytic system showed high catalytic activity, and the 1,4-adducts were obtained in good to excellent yields (46-99%) with enantioselectivities up to 96% ee.

Full text of DOI:10.1021/acs.orglett.8b02204

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Highly Enantioenriched Propelladienes and their
Application as Ligands in Asymmetric Rh-Catalyzed 1,4-Additions
Tommaso Pecchioli and Mathias Christmann*
Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, 14195 Berlin, Germany
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S
* Supporting Information
ABSTRACT: The first synthesis of highly enantioenriched [4.3.3]-
propelladienes is reported. The novel bridged bicyclo[3.3.0] dienes
were applied as steering ligands in the rhodium-catalyzed
asymmetric arylation of cyclic enones. The catalytic system showed
high catalytic activity, and the 1,4-adducts were obtained in good to
excellent yields (46−99%) with enantioselectivities up to 96% ee.
hiral dienes have recently emerged as powerful new
Scheme 1. Approaches to the Propelladienes
C
ligands in asymmetric catalysis.1 Since the pioneering
works of the groups of Hayashi2 and Carreira,3 a variety of
olefin ligands have been used successfully in asymmetric
transition-metal-catalyzed transformations.4 So far, their
structural diversity has been limited to planar chiral,5 acyclic,6
and bicyclic dienes,7 with the latter ones leading to the best
performance. We speculated that the presence of transannular
bonds in rigid polycyclic ligands could have a beneficial
influence on the catalytic behavior of the active metal complex.
Nevertheless, access to polycyclic chiral dienes in enantiomeri-
cally enriched form is still limited,8 probably due to synthetic
challenges.
Among polycyclic molecules, propellanes consist of a
tricyclo[m.n.o.0] architecture9 that embeds three rings
cojoined by a central C−C bond.10 Paquette et al. prepared
and demonstrated the utility of achiral [4.4.2]propella-3,11-
diene as a chelating diene by the formation of a molybdenum
complex (Scheme 1a).11 Recently, our group developed a
general asymmetric route to carbocyclic propellanes.12 Inspired
by the work of Paquette, we decided to implement our
approach in the preparation of enantiomerically enriched
[4.3.3]propelladienes (PPDs) (Scheme 1b).
The use of bicycloocta-2,6-dienes as steering ligands in
rhodium-catalyzed arylations was introduced by the groups of
Hayashi,7c Lin,13 and Laschat.14 In order to design more
efficient ligands, variations on length of the transannular
connection and on topology of the diene substitution were
extensively investigated (Scheme 2). A comparative DFT
analysis, carried out by Kantchev,15 rationalized the effect on
enantioselectivity of such modifications. The study finally led
to the synthesis of highly selective 3,7-disubstituted
bicyclo[3.3.0]octa-2,6-dienes.16 This type of diene induces
the best cooperation between crossed coordination to the
metal center and steric repulsion of the substituents.15a On the
other hand, the effect of an additional alkyl bridge on
bicycloocta-2,6-dienes has not been examined. In this work,
we expand the diversity of this family of steering ligands by the
disclosure of novel tricyclic representatives. The impact of the
geometrical features of PPDs on catalysis was then
experimentally evaluated for the first time using the Rh-
catalyzed 1,4-arylations of cyclic enones.
Our synthesis of the PPDs commenced with the preparation
of the Hajos−Parrish ketone derivative 2 in three steps from
commercially available cyclopentane-1,3-dione (1) (Scheme
3a).12a Enone 2 was obtained in >99% ee after a simple
recrystallization on gram scale. Conjugate addition of a high-
order vinyl cuprate to 2 forged the second quaternary center of
3 in 49% yield. Subsequent ring-closing metathesis furnished
propellenedione 4 in nearly quantitative yield. The less
hindered C3 carbonyl was sequentially reduced to investigate
the influence of the oxygen function on the bridge of the final
ligands. The C3-carbonyl group of 4 was selectively reduced to
alcohol 5 in 83% yield using L-Selectride (Scheme 3b).12a
Received: July 15, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02204
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Family of the Octa-2,6-diene Ligands17
symmetric tricycle 13 by application of a Clemmensen
reduction. The reaction proceeds via in situ acetal cleavage
and subsequent carbonyl reduction to deliver tricycle 13,
which to the best of our knowledge, represents the first
example of an enantiomerically enriched PPD hydrocarbon.
With the five new PPD ligands, [4.3.3]propella-7,10-dienes
or tricyclo[4.3.3.0]dodeca-7,10-dienes9 (7, 9, 10, 12, and 13)
in hand, we tested their performance as chiral ligands in the
rhodium-catalyzed asymmetric 1,4-addition of arylboronic acid
to cyclic enones. We selected cyclohex-2-enone (14) as a
model acceptor for the conjugate addition. The desired diene−
rhodium catalyst was prepared in situ starting from the readily
available [Rh(C2H4)2Cl]2. An initial loading of 3.0 mol %
(with respect to Rh) was chosen to evaluate the performance
of the synthesized PPDs (Table 1).2
All of the prepared ligands led to excellent yields for 15a
(complete conversion within 5 min as indicated by thin-layer
chromatography control). The ligands with unsubstituted
diene moiety provided excellent enantioselectivities (93% ee;
Table 1, entries 1, 3−5), whereas substituted 10 (entry 2) was
clearly inferior. The oxygen function on the bridge and the
chosen protecting groups had a minor influence on the
catalytic performance. Ligand (1R,6S)-12 was then selected for
our studies due to its shorter preparation (three steps from 9).
The rhodium−ethylene precatalyst [Rh(C2H4)2Cl]2 was
submitted to an olefin-exchange reaction with diene 12 to yield
the PPD−Rh complex (see the Supporting Information (SI)).
At this point, the catalyst loading was decreased to assess the
activity of our catalytic system in the 1,4-arylation of 14 (Table
2).
Subsequently, the hydroxyl group of 5 was silylated using
TBSOTf or the more sterically demanding TIPSOTf in good
yields. The second alkene was introduced by conversion of the
C7-carbonyl groups of 6 and 8 to the corresponding enol
triflates, followed by palladium-catalyzed reductions to yield
dienes 7 and 9. Suzuki coupling of the triflate derived from
ketone 8 with phenylboronic acid gave substituted diene 10.
Thus, O-silylated dienols 7, 9, and 10 were obtained in four
steps starting from propellendione 4.
Alternatively, diketone 4 was transformed into dioxolane 11
(Scheme 3c). The diene moiety was generated using the
above-discussed triflation/reduction sequence to give PPD 12.
All reactions toward diene 12 could be performed on a gram
scale and resulted in the isolation of more than 800 mg of the
final material. Finally, PPD 12 was converted into the C2-
Scheme 3. Synthesis of Highly Enantioenriched PPDs 7, 9, 10, 12, and 13
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DOI: 10.1021/acs.orglett.8b02204
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Organic Letters
Letter
a
Table 1. PPD Ligand Screening in the Rhodium-Catalyzed
Asymmetric Arylation of Cyclohex-2-enone (14) with
Phenylboronic Acid To Give 15a
Table 3. Substrate Scope
a
b
c
entry
enone
Ar−B(OH)2
C6H5
4-OMe−C6H4
4-F−C6H4
4-Br−C6H4
4-CO2Me−C6H4
4-Me−C6H4
3-Br−C6H4
3-CF3−C6H4
2-Cl−C6H4
2-Me−C6H4
C6H5
prod
yield (%)
ee (%)
b
c
entry
ligand
yield (%)
ee (%)
d
1
14
14
14
14
14
14
14
14
14
14
16
16
16
16
15a
15b
15c
15d
15e
15f
15g
15h
15i
99
>99
96
93
90
79
83
95
93
92
46
>99
96
76
93
94
93
94
96
93
96
96
84
38
74
68
70
63
1
2
3
4
5
9
10
7
12
13
97
94
97
98
96
93
21
93
93
93
2
3
4
5
6
e
e
a
Reaction conditions: enone 14 (0.350 mmol, 1.0 equiv), PhB(OH)2
7
8
9
10
11
12
13
14
(0.700 mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv).
b
c
Isolated yield. Determined by GC analysis on a chiral column.
15j
a
Table 2. Catalyst Loading Investigation
17a
17b
17c
17d
4-OMe−C6H4
4-F−C6H4
4-Br−C6H4
a
Reaction conditions: 14 or 16 (0.350 mmol, 1.0 equiv), ArB(OH)2
(0.700 mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv).
b
c
b
c
entry
Rh (mol %)
yield (%)
ee (%)
Isolated yields. Determined by GC analysis on a chiral column.
Performed on 1.00 mmol scale. (ArBO)3 (0.66 mmol, 2.0 equiv B)
d
e
1
2
3
1
>99
98
96
93
93
93
93
was used as donor.
0.5
0.25
0.1
d
4
33
a
Reaction conditions: 14 (0.350 mmol, 1.0 equiv), PhB(OH)2 (0.700
In summary, we have accomplished the first synthesis of a
series of enantiomerically enriched [4.3.3]PPDs possessing a
bicycloocta-2,6-diene moiety. The PPD ligands showed
excellent catalytic efficiency in the rhodium-catalyzed asym-
metric arylation of cyclic enones. In the substrate scope, good
to excellent levels of asymmetric induction typical for the use
of unsubstituted bicyclo[3.3.n] dienes were maintained.
Application in catalysis of the tricyclic PPD ligands revealed
a substantial beneficial effect on turnover frequency when
compared to previous systems based on bicyclic analogues. We
hope that our findings will promote future computational and
experimental investigations on the effects of rigid polycyclic
scaffolds in asymmetric catalysis. Further studies will be
focused on understanding the active rhodium complex and
potential catalyst deactivation pathways in molecular detail.
b
mmol, 2.0 equiv), aq KOH (1.5 M; 0.175 mmol, 0.5 equiv). Isolated
yield. Determined by GC analysis on a chiral column. The reaction
was conducted for 2 h.
c
d
The complex loading was reduced from 1 to 0.25 mol %
(Table 2, entries 1−3) without affecting reaction time, yield,
and selectivity (complete conversion for 14 was achieved
within 5 min as indicated by thin-layer chromatography
control). Further decrease of the catalyst loading (0.1 mol %)
gave a reduced yield of 33% for the arylated product 15a
(Table 2, entry 4). Our system showed a turnover frequency
(TOF of 2.3 × 103 h−1 at 25 °C) superior to those exhibited by
the reported catalytic systems based on bicyclo[3.3.n] ligands
(see the SI for a detailed comparison).
Finally, the scope of the asymmetric arylation was
investigated by the addition of different phenylboronic acids
to 6- and 5-membered cyclic enones (Table 3).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02204.
■
S
Cyclohex-2-enone (14) gave good to excellent yields for the
desired products 15a−j (Table 3, entries 1−10). The presence
of para- and meta-substituents on the boronic acids was well
tolerated and the adducts were isolated in high enantiose-
lectivities (93−96% ee; Table 3, entries 2−8). The use of
sterically hindered ortho-substituted donors led to decreased
selectivity (Table 3, entries 9 and 10). In particular, addition of
2-tolylboronic acid to 14 furnished ketone 15j in 38% ee.
Arylations with cyclopent-2-enone (16) occurred more
sluggish in terms of yields and asymmetric inductions (Table
Experimental procedures and characterization for PPD
ligands and rhodium−12 complex. General procedures
for the 1,4-addition and NMR data for adducts 15a−j
and 17a−d. NMR spectra and GC chromatograms
(PDF)
AUTHOR INFORMATION
■
3, entries 11−14). The latter effect is in accordance with those
Corresponding Author
*E-mail: mathias.christmann@fu-berlin.de.
ORCID
17e
observed by Lin18 and Stoncius in the use of unsubstituted
̌
bicyclo[3.3.0] and [3.3.1] dienes as steering ligands. In our
hands, cyclohept-2-enone failed to react even with electron-
rich boronic acids.
Mathias Christmann: 0000-0001-9313-2392
C
DOI: 10.1021/acs.orglett.8b02204
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Umicore for donation of the metathesis catalyst.
Professors C. Tzschucke and P. Heretsch (Freie Universitat
̌
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B.; Ivsic, T.; Strand, D. ACS Omega 2018, 3, 3622−3630.
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thank C. Groneberg (Freie Universitat Berlin) for assistance
with the quantitative GC analysis.
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DOI: 10.1021/acs.orglett.8b02204
Org. Lett. XXXX, XXX, XXX−XXX