Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis

Article abstract of DOI:10.1021/jacs.8b07125

1,1′-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1′-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α′-bis(arylidene)ketones and TiCl₄ promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1S,2S,2′S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1S,2S,2′S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a-c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.

Full text of DOI:10.1021/jacs.8b07125

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Article
Chiral Cyclohexyl-Fused Spirobiindanes: Practical
Synthesis, Ligand Development, and Asymmetric Catalysis
Zhiyao Zheng, Yuxi Cao, Qinglei Chong, Zhaobin Han, Jiaming Ding,
Chenguang Luo, Zheng Wang, Dongsheng Zhu, Qi-Lin Zhou, and Kuiling Ding
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07125 • Publication Date (Web): 23 Jul 2018
Downloaded from http://pubs.acs.org on July 23, 2018
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Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand
Development, and Asymmetric Catalysis
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Zhiyao Zheng,a† Yuxi Cao,a,b† Qinglei Chong,a,d Zhaobin Han,a Jiaming Ding,a Chenguang Luo,a
Zheng Wang,a* Dongsheng Zhu,b QiꢀLin Zhou,c,d and Kuiling Dinga,d,e*
a. State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032 (China);
kding@mail.sioc.ac.cn.
b. Department of Chemistry, Northeast Normal University, Changchun 130024 (China).
c. State Key Laboratory and Institute of ElementoꢀOrganic Chemistry, Nankai University, Tianjin 300071 (China)
d. Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071
(China)
e. University of Chinese Academy of Sciences, Beijing 100049 (China)
ABSTRACT: 1,1’ꢀSpirobiindane has been one type of privileged skeleton for chiral ligand design and 1,1’ꢀ
spirobiindaneꢀbased chiral ligands have demonstrated outstanding performance in various asymmetric catalysis.
However, the access to enantiopure spirobiindane is quiet tedious, which obstructs its practical application. In the
present article, a facile enantioselective synthesis of cyclohexylꢀfused chiral spirobiindanes has been accomplished, in
high yields and excellent stereoselectivities (up to > 99% ee), via a sequence of Irꢀcatalyzed asymmetric hydrogenation
of α,α’ꢀbis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The
protocol can be performed in oneꢀpot and is readily scalable, and has been utilized in a 25ꢀgram scale asymmetric
synthesis of cyclohexylꢀfused spirobiindanediol (1S,2S,2'S)ꢀ5, in >99% ee and 67% overall yield for four steps without
chromatographic purification. Facile derivations of (1S,2S,2'S)ꢀ5 provided straightforward access to chiral monodentate
phosphoramidites 6a-c and a tridentate phosphorusꢀamidopyridine 11, which were evaluated as chiral ligands in
several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2+2] reaction) catalyzed by
transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic
performances of these ligands, with a competency essentially equal to the corresponding wellꢀestablished privileged
ligands bearing a regular spirobiindane backbone. Xꢀray crystallography revealed a close resemblance between the
structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical
stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindaneꢀderived ligands with or without a
fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily
accessible skeletons in development of chiral ligands and functional molecules.
chemical innovation can provide access to more
diversified and creative catalyst design through ligand
INTRODUCTION
The sterically constrained features of the spiro structures
make them excellent frameworks in construction of
R
R
OH
OH
X
Y
OH
OH
chiral ligands,1 and remarkable achievements have been
made in this area since the late 1990s.2 In this context, a
class of chiral ligands and organocatalysts featuring a
1,1’ꢀspirobiindane3
extraordinarily
outstanding performance in
backbone
successful,
(Chart
which demonstrated
a host of asymmetric
1)
are
spirobiindane-based
chiral ligands
cyclohexyl-fused
chiral spirobiindanes
cyclohexyl-fused
SPINOL
SPINOL
Chart 1. Selected chiral spiro skeletons and
ligands
catalytic reactions.1,4ꢀ6 Currently, most synthetic
approaches to this type of privileged ligands/catalysts4
relied heavily on functional group manipulation of
enantiopure 1,1’ꢀspirobiindaneꢀ7,7’ꢀdiol (SPINOL) and
analogues,2c,3ꢀ5 which was generally obtained by optical
resolution using substoichiometric resolving agents in
the past decades.3,7 The asymmetric catalytic
construction of SPINOL and related spirobiindanes,
though challenging in the broad context of chiral
spirocycle synthesis,8 is highly attractive from the
viewpoint of practical synthesis.9 In addition, such a
design and total synthesis.10 In this respect, a recent
report by Tan and coworkers is especially noteworthy,
who disclosed the only example so far on the successful
catalytic enantioselective synthesis of SPINOL and its
analogues.11 In this elegant work, chiral phosphoric acids
were
used
as
catalysts
for
enantioselective
spirocyclization of achiral acetone derivatives, providing
a variety of SPINOLs in good yields with excellent ee
values. Previously in our efforts towards the
development of chiral spiro ligands,2fꢀh,12 we have
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reported the first asymmetric synthesis of chiral
Page 2 of 10
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aromatic spiroketals, based on a oneꢀpot Ir(I)ꢀcatalyzed
hydrogenation and spiroketalization of α,α’ꢀbis(2ꢀ
hydroxyarylidene)ketones.2h We envisioned that this
strategy might also work for synthesis of chiral
cyclohexylꢀfused spirobiindanes, e.g., via asymmetric
hydrogenation13 of α,α’ꢀbisꢀ(arylidene)cyclohexanones
and stereoselective spiroannulation of the resulting
chiral ketones. In this case, the carbonyl group in the
hydrogenation product would be flanked by two vicinal
chiral carbon centers, which may induce good
stereochemical control in the ensuing spirocyclization. It
is interesting to note that in addition to axial spiro
Entr
y
Ar
R
Product
Yield (%)b
Ee
(%)c
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
1
2
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
(S, S)ꢀ2a
(S, S)ꢀ2b
(S, S)ꢀ2c
(S, S)ꢀ2d
(S, S)ꢀ2e
(S, S)ꢀ2f
(S, S)ꢀ2g
(S, S)ꢀ2h
(S, S)ꢀ2i
(S, S)ꢀ2j
(S, S)ꢀ2k
(S, S)ꢀ2l
(S, S)ꢀ2m
90
94
82
90
97
95
95
97
97
95
90
89
94
2ꢀMeC6H4
9
3
3ꢀMeC6H4
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4
4ꢀMeC6H4
5
3ꢀMeOC6H4
4ꢀMeOC6H4
2ꢀNaphthyl
chirality, such
a reaction sequence can effectively
6
establish two more chiral centers in the cyclohexylꢀfused
spirobiindanes. Such spirocycles are also expected to be
conformationally more constrained than their regular
spirobiindane analogues, and hence might provide an
excellent platform for chiral ligand development and
structureꢀreactivity relationship assessment. Herein, we
report a scalable asymmetric synthesis of cyclohexylꢀ
fused chiral spirobiindanes, preparation of ligands with
this new chiral scaffold, comparative studies in
enantioselective catalysis, as well as structural
characterization of some precatalysts.
7
8
2ꢀBrꢀ5ꢀMeOC6H3
3,4ꢀ(MeO)2C6H3
2,5ꢀMe2C6H3
2ꢀMeꢀ5ꢀMeOC6H3
2,5ꢀ(MeO)2C6H3
9
10
11
12
13
>99
>99
2,3,4ꢀ
(MeO)3C6H2
14
15
16
2ꢀBrꢀ5ꢀMeOC6H3
2ꢀBrꢀ5ꢀMeOC6H3
2ꢀBrꢀ5ꢀMeOC6H3
Me
tBu
Ph
(S, S)ꢀ2n
(S, S)ꢀ2o
(S, S)ꢀ2p
95
93
90
>99
>99
>99
RESULTS AND DISCUSSION
Cyclohexyl-fused chiral spirobiindanes: efficient and
scalable synthesis
aConditions: 1 (0.2 mmol), Ir(I)/(S)ꢀtBuꢀPHOX (0.002
mmol), H2 (30 atm), CH2Cl2 (5 mL), rt, 6 h. In each case, the
dr value of hydrogenation product 2 (transꢀ2/cisꢀ2) was
The α,α’ꢀbisꢀ(arylidene)cyclohexanone substrates 1aꢀp
were readily prepared by condensation of cyclohexanone
with the corresponding aromatic aldehydes (for details,
see SI). Since chiral Ir(I)/phosphineꢀoxazoline
complexes have been demonstrated particularly effective
in the asymmetric hydrogenation of less functionalized
alkenes,14 including α,βꢀunsaturated ketones,15 we
surveyed some chiral Ir(I) precatalysts for asymmetric
hydrogenation of 1a, and Ir(I)/(S)ꢀtBuꢀPHOX turns out
to be the best under the optimized reaction conditions
(SI). Thus, the asymmetric hydrogenations of 1aꢀp were
performed under 30 atm of H2 in dichloromethane at rt
with 1.0 mol% Ir(I)/(S)ꢀtBuꢀPHOX as the catalyst. In all
cases, the chiral α,α’ꢀbis(benzyl)ketones (S,S)ꢀ2aꢀp were
obtained in high yields (≥ 82%) with excellent
1
b
determined to be >20/1 by H NMR analysis. Yields of the
c
isolated products. Determined by HPLC analysis on chiral
columns.
For the double intramolecular FC reactions of chiral
ketones (S,S)ꢀ2a-p, both Brønsted and Lewis acids can
in principle be utilized to control the stereochemical
outcomes of the products. Therefore, a variety of acids,
including Brønsted and Lewis type, were examined for
their efficiency in promoting the asymmetric
spiroannulation using (S,S)ꢀ2h (>99% ee). As shown in
Table 2, a large excess of polyphosphoric acid (PPA)
worked well in promoting the reaction to give 3h in 72%
isolated yield, nevertheless the resultant product 3h was
essentially racemic (entry 1), probably due to the protonꢀ
promoted ketoenol tautomerization and racemisation of
(S,S)ꢀ2h.18 On the other hand, the use of H3[W12PO40] as
the promoter did not afford any expected product 3h
(entry 2), instead a slightly racemized (S,S)ꢀ2h (56%,
enantiopurity lowered from >99% ee to 95% ee) and
mesoꢀ2h (44%) were observed in the recovered
materials. Moreover, most of the tested Lewis acidic salts
are completely inactive for the reaction in CH2Cl2 at 40°C
(entries 3ꢀ9). Gratifyingly, the strongly oxophilic Lewis
acid titanium chloride turns out to be a valuable
exception, affording the spirocycle 3h in 51% yield with
99% ee (entry 10). Further variations in temperature
(entries 11ꢀ13), solvent polarity, and substrate
concentration resulted in a substantial improvement in
the outcome of transformation (for details, see SI). The
spiroannulation of (S,S)ꢀ2h (0.05 M) was best conducted
in CH2Cl2 at 0ꢀ25°C for 6 h with 2.0 equivalents of TiCl4
(entry 14), to afford excellent yield (93%) of spirocycle
3h as a single enantiomer (>99% ee). The absolute
1
diastereoselectivities (trans/cis > 20 by H NMR) and
extremely high enantiopurities ( ≥ 99% ee) (Table 1),
thus laying a good basis for ensuing transformations.
Subsequently, a variety of acidic catalysts and reaction
parameters were screened for diastereoselective
spiroannulation of the resulting enantiopure ketones,
using (S,S)ꢀ2h as the model substrate. Mechanistically,
the acid promoted spiroannulation would involve
electrophilic activation of the carbonyl group by
protonation, followed by two successive intramolecular
FriedelꢀCrafts (FC) reactions of the nucleophilic phenyl
groups leading to stereogenic formation of the spiro
carbon center, and concomitant loss of an equivalent of
water.16,17
Table 1. Ir(I)/(S)-tBu-PHOX catalyzed
asymmetric hydrogenation of 1a-pa
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exhibited less
configuration of 3h was established as (1S,2S,2'S) by Xꢀ
d
significant
effect
on
the
1
2
3
4
5
6
7
8
ray crystallographic analysis of its demethylated diol
derivative (4, see SI), indicating that the stereochemistry
of the spiroannulation was completely substrateꢀ
controlled by the chirality of the transꢀhydrogenated
intermediate (S,S)ꢀ2h.
enantioselectivities of the reactions, giving the relevant
products [(1S,2S,2'S)ꢀ3bꢀd] in excellent ee values. The
substrate (S,S)ꢀ2g bearing 2ꢀnaphthyl groups underwent
a
smooth spirocyclization to give benzoꢀannulated
spirobiindane (1S,2S,2'S)ꢀ3g with 99% ee. Finally,
ketone substrates (S,S)ꢀ2nꢀp with alkyl (Me and tꢀBu) or
phenyl groups on the cyclohexyl backbones were also
transformed to (1S,2S,2'S)ꢀ3nꢀp with 97ꢀ>99% ees.
Table
2.
Survey
of
conditions
for
spiroannulation of (S, S)-2h a
Br
Br
O
Br
Table 3. TiCl4-promoted spiroannulation of 2a-p
9
a-c
OMe
OMe
conditions
10
11
12
13
14
15
16
17
18
19
20
21
22
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25
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MeO
OMe
Br
(S,S)-2h, >99% ee
(1S,2S,2'S)-3h
Yield
ee
Entry Acid (equiv.)
Solvent T (°C)
(%)b
72
0
(%)c
1
PPA (30)
none
80
110
40
40
40
40
40
40
40
40
25
0
2
H3[W12PO40] (2)
Sc(OTf)3 (2)
In(OTf)3 (2)
Cu(OTf)2 (2)
AlCl3 (2)
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀꢀ
3
0
ꢀꢀ
4
0
ꢀꢀ
5
0
ꢀꢀ
6
0
ꢀꢀ
7
SnCl4 (2)
0
ꢀꢀ
8
FeCl3 (2)
Ti(OiPr)4 (2)
0
ꢀꢀ
9
0
ꢀꢀ
10
11d
12e
13f
14f,g
TiCl4 (2)
51
55
62
84
93
99
>99
>99
>99
>99
TiCl4 (2)
TiCl4 (2)
0
TiCl4 (2)
0ꢀ25
0ꢀ25
TiCl4 (2)
a Conditions: (S,S)ꢀ2h (0.2 mmol), solvent (2 mL), 12 h. b
The yield of isolated 3h. c The ee value of (1S,2S,2'S)ꢀ3h was
d-f
determined by HPLC on chiral stationary phase.
The
reaction time was 2 h, 20 h, and 6 h (0°C for 1 h, 25 °C for 5
h), respectively. g [(S,S)ꢀ2h] = 0.05 M.
Having established the optimal conditions for the
asymmetric spiroannulation, we proceeded to examine
the adaptability of the protocol. As shown in Table 3,
analogous reactions of chiral ketones (S,S)ꢀ2a-p
proceeded smoothly in the presence of two equivalents of
TiCl4, affording the corresponding chiral spirobiindanes
(1S,2S,2'S)ꢀ3aꢀp in moderate to high yields (45ꢀ93%)
with generally excellent enantiomeric excesses (up to
>99% ee). The reaction of the prototype substrate 2a (R
= R' = H) gave its corresponding product (1S,2S,2'S)ꢀ3a
in 83% yield with 96% ee. The presence of activating
groups, e.g., electronꢀdonating methoxy and/or methyl
groups on the phenyl rings, were found beneficial for the
FCꢀtype ring closure processes of ketones (S,S)ꢀ2bꢀf and
(S,S)ꢀ2hꢀm. The spiroannulations proceeded efficiently
a Conditions: (S, S)ꢀ2 (0.2 mmol), TiCl4 (0.4 mmol), CH2Cl2
(4 mL),0ꢀ25°C, 6 h. [b] Yields of the isolated products. [c]
Ee values were determined by HPLC on a chiral stationary
phase.
These results set the stage for facile access to an
enantiopure cyclohexylꢀfused SPINOL
derivative
under
the
mild
conditions,
providing
the
(1S,2S,2'S)ꢀ5, a new building block for synthesis of
various chiral ligands and catalysts. In fact, asymmetric
hydrogenation and spiroannulation can be combined in
oneꢀpot without purification and isolation of the
hydrogenated intermediate. As shown in Scheme 1, using
this procedure (1S,2S,2'S)ꢀ3h was readily prepared in a
scale of tens grams in 84% yield.19 The target cyclohexylꢀ
fused SPINOL (1S,2S,2'S)ꢀ5 was readily synthesized in
80% overall yield from (1S,2S,2'S)ꢀ3h, via BBr3 mediated
enantioenriched spirobiindanes (1S,2S,2'S)ꢀ3bꢀf and
(1S,2S,2'S)ꢀ3hꢀm in 45ꢀ93% yields. The stereochemistry
of the spirocyclization was wellꢀcontrolled in most cases
(90ꢀ>99% ee), albeit partial racemization occurred in the
reactions of (S,S)ꢀ2f and (S,S)ꢀ2m (both bearing paraꢀ
methoxy groups) by an unknown pathway which led to
somehow lowered ee values in the corresponding
products (1S,2S,2'S)ꢀ3f and (1S,2S,2'S)ꢀ3m. The orthoꢀ,
metaꢀ, or paraꢀmethyl groups on the phenyl rings of 2bꢀ
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Page 4 of 10
a) Proposed mechanism
demethylation
and
Pdꢀcatalyzed
hydrogenolytic
[Ti]
[Ti]
O
O
1
2
3
4
debromination. It is especially noteworthy that the whole
synthetic sequence was accomplished on a large scale
without resorting to any chromatographic workup, and
purification of 5 was readily effected by crystallization,
thus further attesting the practicality and scalability of
the protocol (for details, see SI).
- H+
+ [Ti]
(S,S)-2a
A
B
5
- H+
+ [Ti]
6
7
8
9
- [Ti-O-Ti]
Scheme 1. Practical preparation of an
enantiopure cyclohexyl-fused SPINOL derivative
(1S,2S,2'S)-5.
(S,S,S)-3a
C
b) Reactivity of meso-2h and rac-2h
10
11
12
13
14
15
16
17
18
19
20
21
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OMe
[Ti]
O
Br
CH2Cl2
6 hr, 0oC-rt
meso-2h
rac-3h
OMe
<1% by 1H NMR
98% meso-2h recovered
H
H
Br
OMe
[Ti]
O
Br
CH2Cl2
6 hr, 0oC-rt
rac-3h
rac-2h
H
OMe
H
90%
Br
This dramatic reactivity difference between racꢀ and
mesoꢀdiastereomers suggests that a proper orientation of
phenyl groups is a prerequisite for the cyclization to
occur, which provides a rational basis for the viability of
Although the exact mechanistic pathway of the TiCl4
mediated spiroannulation of (S,S)ꢀ2 to (1S,2S,2'S)ꢀ3 is
not completely clear at the present stage, a plausible
mechanism was proposed on the basis of the
stereochemical relationship between the synthetic
precursor (S,S)ꢀ2 and the annulation product
(1S,2S,2'S)ꢀ3 (Scheme 2a). Initially, the carbonyl oxygen
of (S,S)ꢀ2 is coordinated to Lewis acidic TiCl4 to generate
an intermediate A20 that is activated towards
nucleophilic attack. Owing to the steric constraints of the
α,α’ꢀchirality on the cyclohexanone moiety, the first
intramolecular FC reaction of A occurs through delivery
of the phenyl group to one face (upper or lower) of the
cyclohexanone, leading to the formation of titanium
alkoxide B. The alkoxide B might undergo a Ti(IV)ꢀ
assisted deoxygenation21 to generate a tertiary carbon
cation C, which is immediately trapped by the other
phenyl group via a second FC reaction, thus affording
(1S,2S,2'S)ꢀ3 with retention of stereochemistries at both
2,2’ꢀpositions. In order to shed some light on the origin
of extremely high ee values of most annulation products
3 even in the case using hydrogenated intermediates 2
containing small amount of mesoꢀdiastereomer (oneꢀpot
procedure), the control experiments were carried out to
compare the reactivity of racꢀ2h and its mesoꢀ
diastereomer. As shown in Scheme 2b, the reaction of
mesoꢀ2h was very sluggish under the otherwise identical
conditions, while the reaction of racꢀ2h gave racꢀ3h in
90% yield.
oneꢀpot
tandem
hydrogenationꢀspiroannulation
procedure in the presence of mesoꢀ2h byproduct
mentioned above. The conformational analysis of mesoꢀ
2h clearly showed that both benzyl groups should
occupy equatorial α,α’ꢀpositions of cyclohexone (Scheme
2b), which renders the delivery of the phenyl group to
one face (upper or lower) of the activated C=O moiety
virtually impossible. In contrast, the axial orientation of
one benzyl group in racꢀ2h fulfills the spatial
requirement for the interaction of phenyl ring with the
activated C=O group, hence allowing for the
intramolecular FC reaction to occur.
Synthesis of chiral Ligands from (1S,2S,2'S)ꢀ5
Having established an efficient and scalable route to
access enantiopure cyclohexylꢀfused SPINOL analogue
(1S,2S,2'S)ꢀ5, we ventured into using this compound as a
building block for construction of some new chiral
ligands. In this context, chiral monodentate
phosphoramidite ligands, which have found numerous
catalytic applications with transition metals,22 came up
as an appealing goal by virtue of their straightforward
synthesis and structural variability. Hence, treatment of
the
diol
(1S,2S,2'S)ꢀ5
with
an
appropriate
aminophosphorous dichloride (Cl2PNR2) in the presence
of triethylamine, led to ready access to the corresponding
chiral spiro phosphoramidite ligands (1S,2S,2'S)ꢀ6a, (1S,
2S, 2’S, RN, RN)ꢀ6b, and (1S, 2S, 2’S, SN, SN)ꢀ6c,
respectively, in good yields (Scheme 3, see SI for details).
The structures of 6a and 6c were characterized by single
crystal Xꢀray diffractional studies (Scheme 3, inset
figures). Notably, a strongly twisted eightꢀmembered
phosphadioxa ring was formed in both structures, at a
cost of conformational change in the shape of cyclohexyl
ring, which isomerized from chair in 5 into twistꢀboat in
6 during OꢀP bond formation in phosphoramidite
synthesis.
Scheme 2. Proposed mechanism for TiCl4-
mediated spiroannulation (a), and comparison
of reactivity for meso- and rac-2h (b)
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basis of the literature precedents, using SIPHOS or
Scheme 3. Synthesis of mono-phosphoramidites
1
2
3
4
6a-c
SpiroPAP as the references. The results of these
comparative studies are presented in Scheme 5, which
showcased the outstanding characteristics of prepared
ligands for asymmetric catalysis.
Scheme 5. Comparative studies
5
6
7
8
9
(a)
[Rh(COD)2]BF4 (1 mol%)
CO2Me
NHAc
CO2Me
NHAc
6a or SIPHOS-Me (2 mol%)
H2 (20 atm), CH2Cl2, r.t., 1 h
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ref [23b]
Me
Me
P N
O
O
O
O
vs
P N
Me
Me
>99% conv.
96% ee
>99% conv.
96% ee
(1S,2S,2'S)-6a
SIPHOS-Me
A new tridentate phosphorusꢀaminopyridine ligand (11),
with the cyclohexylꢀfused spirobiindane backbone, was
also prepared by following an analogous procedure for
preparation of SpiroPAP,24 via further derivatization of
the OH groups in the key intermediate (1S,2S,2'S)ꢀ5. As
shown in Scheme 4, Pd/racꢀBINAP catalyzed coupling of
bistriflate (1S,2S,2'S)ꢀ7 with diphenylmethanimine
furnished the monoꢀaminated triflate (1S,2S,2'S)ꢀ8,
which underwent a phosphinylation in the presence of
catalytic Pd(OAc)2/dppb. The resulting compound
(1S,2S,2'S)ꢀ9, bearing a sterically bulky P(O)R2ꢀtype
moiety (R = 3,5ꢀtBu2C6H3), was reduced by PhSiH3 to
give the aminophosphine (1S,2S,2'S)ꢀ10. Finally,
reductive amination using 3ꢀmethylpicolinaldehyde and
NaBH(OAc)3 afforded the target ligand (1S,2S,2'S)ꢀ11 in
a satisfactory overall yield for five steps (61%) (for details,
see SI).
(c)
OH
O
OH
O
[Rh(COD)Cl]2 (2.5 mol%)
H
SPh
6c or SIPHOS-PE (6 mol%)
+
K3PO4 (5 mol%), DCM
0 °C,18 h
SPh
(+)- or (-)-17
16
Scheme 4. Synthesis of tridentate P^N^N ligand
11
Ph
ref [27]
Ph
O
O
P N
Ph
vs
91% yield
P N
O
O
diphenylmethanimine
OTf Pd(OAc)2/rac-BINAP
97% yield
92% ee
Ph
OH
OTf
Tf2O, pyridine
CH2Cl2
92% ee
OH
Cs2CO3, toluene
OTf
NH2
b/l > 20/1
b/l > 20/1
80°C
(1S,2S,2'S,SN,SN)-6c
(R,RN,RN)-SIPHOS-PE
(d)
(1S,2S,2'S)-5
(1S,2S,2'S)-7
(1S,2S,2'S)-8
O
OH
(DTB)2P(O)H
[Ir(COD)Cl]2/Ligand
H2
+
Pd(OAc)2/dppb
P(O)(DTB)2
NH2
P(DTB)2
NH2
PhSiH3
tBuOK, EtOH, rt
50 atm
DMSO, iPr2NEt
140 °C
100 o
C
(1S,2S,2'S)-9
(1S,2S,2'S)-10
But
N
CHO
tBu
P(DTB)2
P(DTB)2
H
H
vs
P(DTB)2
H
N
N
N
N
where DTB
NaBH(OAc)3
CH2Cl2, r.t.
N
N
3,5-tBu2C6H3
61% overall yield for five steps
(1S,2S,2'S)-11
(S)-
SpiroPAPref. [24]
(1S,2S,2'S)-11
S/C = 1000000, 1 d
100% conv., 98% ee
S/C = 5000000, 15 d
91% conv., 98% ee
Enantioselective catalyses: a comparative study
Since 6aꢀc and 11 can be viewed as structural analogues
of privileged SIPHOS5a,23 and SpiroPAP24 ligands, it
was tempting for us to seek a comparison of their
catalytic performances. As an exhaustive study of the
relevant catalyses would be impractical, we have
surveyed ligands 6aꢀc and 11 in a cursory way for some
benchmark metalꢀcatalyzed reactions, selected on the
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Finally, we moved on to examine the catalytic efficiency
1
2
3
4
5
6
of the iridium complex of tridentate spiro P^N^N ligand
(1S,2S,2'S)ꢀ11 in the asymmetric hydrogenation of
acetophenone (Scheme 5d). In an recent work, an
extremely efficient chiral iridium catalyst bearing the
tridentate ligand SpiroPAP has been developed for
asymmetric hydrogenation of ketones.24
A recordꢀ
breaking TON value up to 4,550,000 (in a reaction time
of 15 days) has been achieved in the hydrogenation of
acetophenone, attesting the extraordinarily high stability
and activity of the catalyst. From this perspective, we
were intrigued whether the use of ligand (1S,2S,2'S)ꢀ11,
structurally analogous to SpiroPAP, may lead to
catalytic performance comparable to the latter in this
reaction. The reactions were conducted under 10 atm H2
at a catalyst loading of 0.02 mol%, and both catalysts
conveyed excellent enantioselectivity (98% ee, Scheme
5d). In fact, up to 1,000,000 of TON (in 24 hr) has been
obtained in the hydrogenation of acetophenone with
Ir/(1S,2S,2'S)ꢀ11 without any loss of enantioselectivity
(98% ee). The utility of Ir/(1R,2R,2'R)ꢀ11 has also been
demonstrated in the catalytic asymmetric hydrogenation
of key intermediate (3R,4S)ꢀ18 for synthesis of chiral
drug Ezetimibe,28 affording (3R,4S,3’S)ꢀ19 in 95% yield
and 99:1 diastereoselectivity under a catalyst loading of
0.01 mol% (Scheme 5e).
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Rhꢀcatalyzed asymmetric hydrogenation (AH) of various
dehydroamino acid derivatives has been extensively
investigated for the synthesis of optically enriched chiral
chemicals.13 Especially, cationic Rhꢀcatalyzed AH of
aminocinnamic acid derivative 12, owing to its
mechanistically wellꢀdefined nature, has often served as
a standard for test of chiral phosphorus ligands. In 2004,
spinolꢀderived chiral monodentate phosphoramidite,
SIPHOS-Me, has been demonstrated to be a highly
enantioselective ligand for Rh catalyzed asymmetric
hydrogenation of a range of functionalized olefins, and
hydrogenation of 12 under 20 atm H2 at rt afforded 13 in
96% ee.23b Given these facts, we begin by examining
ligand 6a in this model reaction. Gratifyingly, equally
excellent results (full conversion, 96% ee) were achieved
using 6a under otherwise identical conditions (Scheme
5a).
Characterization of precatalyst structures
The results from the comparative reaction studies clearly
indicated that, in enantioselective catalysis, the efficiency
and asymmetryꢀinducing ability of chiral ligands with a
cyclohexylꢀfused spirobiindane backbone are essentially
parallel to their regular Spinolꢀderived analogues in
conveying asymmetry and efficiency. To probe the origin
of such a close resemblance in reaction behavior, we
conducted further comparative structural studies for
some selected precatalysts. Accordingly, we have
characterized the crystal structures of the precatalysts
Catalytic asymmetric cycloadditions play a key role in
asymmetric synthesis, since such transformations result
in simultaneous formation of two or more new bonds
with stereochemical control.25 In a recent publication,
González group has demonstrated the utility of
(S,RN,RN)ꢀSIPHOS-PE in the Auꢀcatalyzed asymmetric
[2+2] reaction of Nꢀallenylsulfonamides with vinylarenes
for the facile synthesis of alkylidenecyclobutanes.26
Under otherwise identical conditions as optimized in this
work, we have found that with (1S, 2S, 2’S, RN, RN)ꢀ6b as
ligand, equally satisfactory results could be on the model
reaction of Nꢀallenylsulfonamide 14 with 4ꢀ
methoxystyrene, generating excelent yield (93%) and
enantioselectivity (93% ee) for the fourꢀmembered ring
15 (Scheme 5b).
[Rh(cod){(1S,2S,2’S)ꢀ6a}2](BF4)·(CH2Cl2)2
(20)and
[Rh(COD)Cl((1S,2S,2’S,SN,SN)ꢀ6c)] (21) (for details, see
SI). Figure 1 showed the Xꢀray crystal structures of 20
and 21 along with their counterparts, [Rh(cod){(S)ꢀ
SIPHOS-Me}2](OH)·CH2Cl2 (CSD refcode: MORSIV)5a
and
[Rh(COD)Cl((R,RN,RN)ꢀSIPHOS-PE)]
(CSD
refcode: EDEMEH)29, respectively, retrieved from the
CSD database. A close inspection of the structure of 20,
as shown in Figure 1a, revealed that RhꢀP bond lengths
[2.2901(19) and 2.261(2) Å] and P2ꢀRh1ꢀP1 bite angle
[93.80(7)º] are within the expected values. Similar to
that
in
(1S,2S,2’S)ꢀ6a,
the
eightꢀmembered
Subsequently, we undertook
ligand evaluation in Rhꢀcatalyzed
a
further comparative
asymmetric
phosphadioxa ring in 20 is strongly twisted. While the
coordination geometry about the P atoms are pseudoꢀ
tetrahedral, the N atoms of the two ligands are trigonal
planar. Most interestingly, an overlay of structures 20
and MORSIV revealed striking similarities between the
two precatalysts (Figure 1b). Whereas the presence of
two monodentate Pꢀligands might in principle render
considerable structural flexibility for 20 and MORSIV,
nonetheless both precatalysts assume almost the same
geometries, especially in the vicinity of the active Rh site.
As a result of conformational constraints by cyclohexyl
ring in 20, the spirobiindane rings in the two structures
adopt slightly different spatial orientations. The
cyclohexyls in 20 are far removed from the Rh center,
hydroacylation, with homoallylic sulfide 16 and
salicylaldehyde as the model substrates (Scheme 5c). The
prototype study was reported by Dong and coworkers,
who
have
discovered
that
Spinolꢀderived
phosphoramidte (R,RN,RN)ꢀSIPHOS-PE was superior
in effecting such transformations.27 As anticipated, our
phosphoramidite (1S, 2S, 2’S, SN, SN)ꢀ6c was found
equally potent in regioꢀ and stereocontrol of this
reaction, affording the hydroacylation product 17 in 91%
yield with >20:1 branched/linear regioselectivity and
92% ee (Scheme 5c).
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and hence unlikely to exert significant steric effects on asymmetric spiroannulation of the hydrogenated chiral
1
2
3
4
5
6
7
8
the catalysis. The close structural resemblance suggested
that a reaction catalyzed by 20 or MORSIV is much
likely to follow the same stereochemical course, hence
giving almost identical results in the reaction (Scheme
5a). Figure 1c shows the crystal structures of 21 and its
analogue EDEMEH, which help understanding the
reaction outcomes of the asymmetric hydroacylation
catalyzed by these complexes (Scheme 5c). Ignoring the ꢀ
(CH2)3ꢀ linkage at the backbone C2 and C2’ centers, 21
and EDEMEH can approximately be viewed as the
mirror image of each other, with considerable
similarities in their structural details. As a result, it is no
wonder that using these two catalysts, almost the same
ee values were obtained in the asymmetric
hydroacylation (Scheme 5c).
ketones, afforded a variety of cyclohexylꢀfused chiral
spirobiindanes in excellent stereoselectivities (up to
>99% ee). The protocol can be accomplished in oneꢀpot
and is readily scalable, hence paving the way to practical
utility of the skeletons. Some new chiral ligands bearing
the cyclohexylꢀfused spirobiindane backbone were easily
accessed via further synthetic manipulations, and were
evaluated in several asymmetric catalytic reactions.
Results from comparative studies revealed that the
catalytic competency of these ligands can largely rival the
corresponding Spinolꢀderived privileged ligands.
Crystallographic studies provided strong evidences for
the overall structural similarities between precatalysts
bearing spirobiindane backbone with or without the
fused cyclohexyl rings, which ultimately help to
rationalize the largely identical stereochemical outcomes
of reactions catalyzed by these complexes. This work is
expected to trigger further applications of this type of
readily accessible skeletons in development of chiral
ligands and functional molecules.
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(a)
ASSOCIATED CONTENT
Supporting Information.
Detailed synthetic, crystallographic, and characterization
data. Crystallographic data (CIF files) for (2E,6E)ꢀ1l (CCDC
1406103), (1S,2S,2'S)ꢀ3g (CCDC 1406101), (1S,2S,2'S)ꢀ4
(CCDC 1406102), [(1S,2S,2'S)ꢀ5]2·Et3N (CCDC 1556728),
(1S,2S,2'S)ꢀ6a (CCDC 1556898), (1S,2S,2'S, SN, SN)ꢀ6c
(CCDC 1556899), 20 (CCDC 1556900), 21 (CCDC 1556901)
and {[(1S, 2S, 2S’, RN, RN)ꢀ6b]AuCl} (CCDC 1853631) have
been deposited at the Cambridge Crystallographic Data
Center. This material is available free of charge via the
Internet at http://pubs.acs.org.
(b)
AUTHOR INFORMATION
Corresponding Author
(c)
* kding@sioc.ac.cn
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by Ministry of Science and Techꢀ
nology of China (grant no. 2016YFA0202900), NSFC (grant
nos. 21232009, 21421091), CAS (XDB20000000) and the
Science and Technology Commission of Shanghai
Municipality.
Figure 1. (a) Crystal structure of [Rh(cod){(1S,2S,2’S)ꢀ
6a}2](BF4)·(CH2Cl2)2 (20). (b) Structural overlay of
[Rh(cod){(1S,2S,2’S)ꢀ6a}2](BF4)·(CH2Cl2)2
[Rh(cod){(S)ꢀSIPHOS-Me}2](OH)·CH2Cl2
(20)
(MORSIV),
and
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R'
O
CHO
OH
X
Y
(a) NaOH
R
+
OH
(b) [Ir], H2;
TiCl4
2 R'
R
catalytic efficiency
equal to
priviledged ligands
25-g scale, >99% ee
without chromatographic
purification
R = H, Me, Ph, t-Bu
R'
16 examples
up to >99% ee
R' = Me, MeO or Br
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