Exploring structural diversity in ligand design: The aminoindanol case

Article abstract of DOI:10.1002/adsc.200800420

A series of enantiopure ligands based on the aminoindanol scaffold, but differing in regio-and stereochemistry has been synthesized. These ligands have been conveniently derivatized and their catalytic efficiency in different enantioselective reactions has been screened to determine privileged candidates with respect to regio- and stereochemistry for each considered process. The nature of the amino substituent has been optimized for specific applications and this has led to the development of an efficient method for the preparation of bulky bicyclic amines by reductive amination.

Full text of DOI:10.1002/adsc.200800420

FULL PAPERS
DOI: 10.1002/adsc.200800420
Exploring Structural Diversity in Ligand Design:
The Aminoindanol Case
Sergi Rodríguez-Escrich,a Lluís Solà,a Ciril Jimeno,a Carles Rodríguez-Escrich,a
and Miquel A. Pericàsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Fax : (+34)-977-920-222; phone: (+34)-977-920-200; e-mail: mapericas@iciq.es
Departament de Química Orgànica, Universitat de Barcelona, 08028 Barcelona, Spain
b
Received: July 7, 2008; Published online: September 24, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800420.
Abstract: A series of enantiopure ligands based on substituent has been optimized for specific applica-
the aminoindanol scaffold, but differing in regio- and tions and this has led to the development of an effi-
stereochemistry has been synthesized. These ligands cient method for the preparation of bulky bicyclic
have been conveniently derivatized and their catalyt- amines by reductive amination.
ic efficiency in different enantioselective reactions
has been screened to determine privileged candi- Keywords: addition to carbonyl compounds; allylic
dates with respect to regio- and stereochemistry for substitution; amino alcohols; asymmetric catalysis;
each considered process. The nature of the amino N,O ligands; reductive amination
Introduction
by regioselective ring-opening of this epoxide with ni-
trogen nucleophiles.[2] From the point of view of struc-
The ever growing field of enantioselective catalysis is tural diversity, a recent analysis of chemical databas-
in permanent search for new chiral ligands. However, es[3] has shown a repetitive pattern in the scaffolds
the quest for these ligands is sometimes restricted to more commonly found in organic molecules. Accord-
molecules obtained from the chiral pool, either direct- ing to the results reported in this study, half of the in-
ly or after derivatization. While this strategy has clear dexed compounds (more than 24 million) can be de-
advantages in terms of price and enantiomeric purity, scribed by as little as 143 frameworks, and the indane
the obvious drawbacks are that the choice is limited scaffold represents one of the most widespread. Nev-
and often only one of the enantiomers is readily avail- ertheless, despite the prevalence of its corresponding
able. Thus, there is an interest for developing new framework and the application of some chiral amino-
methods for the preparation of optically pure ligands indanols as ligands in asymmetric catalysis, the full
in both enantiomeric forms. One of the most practical potential of this substructure has been usually ne-
approaches to fulfill this goal consists in the prepara- glected, as efforts in this field have been mostly re-
tion of the target ligands or their precursors through stricted to cis-1-amino-2-indanol (1a).[4]
catalytic highly enantioselective processes that can
While this compound is commercially available in
afford products of both enantiomeric series. Within both enantiomeric forms, the aminoindanol scaffold
this approach, enantiomerically pure epoxides are offers a wider range of possibilities based on the
ideal relays for the preparation of modular 1,2-difunc- simple variation of the regio- and stereochemistry of
tional compounds suitable for catalytic application the two functional groups. As depicted in Figure 1,
through ring-opening processes. Over a decade ago, the aminoindanol family encompasses four different
we and others started the exploration of this strat- members, each one of them with its corresponding en-
egy.[1]
antiomer. It must be mentioned that, in the present
Indene oxide is probably one of the most readily work, the letters a, b, c or d used in Figure 1 refer to
available enantiopure epoxides. On this basis, we each one of these isomers or their derivatives.
became interested in the preparation of aminoinda-
The rigidity associated with the indane scaffold
nol-derived ligands to be used in asymmetric catalysis limits the set of conformers accessible to these struc-
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Exploring Structural Diversity in Ligand Design
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selectivity. An additional point to take into account
refers to the availability of the five-membered che-
lates derived from trans structures. Thus, when long
À
metal O,N bonds are involved in the chelate, like in
the methylzinc alkoxides represented in Figure 2, a
trans stereochemistry in the indane skeleton introdu-
ces an affordable level of strain (some 11.3 kcalmolÀ1
according to PM3 calculations on the 2-amino-1-inda-
nol system). On the other hand, the energetic cost as-
sociated to the formation of a trans chelate could be
À
unaffordable when short element O,N bonds are in-
volved in the process (some 29 kcalmolÀ1, according
to PM3 calculations, for each diastereomeric pair of
the regioisomeric 2-methyl-1,3,2-oxazaborolidines
that can be constructed on the indane structure). Fi-
nally, it is important to recall that the pair of atoms
Figure 1. Structural diversity of the aminoindanol isomers.
tures with respect to their acyclic analogues. When metal,O or metal,N involved in the catalytic event
the chelated metal complexes usually involved in cat- varies from one process to another (see Figure 2,
alysis are considered, it can be seen that this fact gen- structures b and c) so that, according to steric consid-
erates a rather flat geometry for the trans regioisom- erations, the optimal ligand regioisomer can also vary
ers and a bent disposition for their cis counterparts from one process to another.
(Figure 2). Needless to say, these changes are expect-
According to this, we decided to study the use in
ed to have a significant impact on the catalytic profile catalysis of the four possible derivatives bearing in
of the considered amino alcohols or of their deriva- common the aminoindanol structure, which would
tives. Thus, it can be expected a priori that the cis de- eventually allow us to find the ideal candidate for
rivatives will present a more marked facial preference each reaction studied. In the cases where strain con-
for the coordination of substrates and reagents and, siderations make unlikely the participation of trans
hence, that they will induce higher degrees of enantio- diastereomers, this study will be restricted to the cis
selectivity. However, it is important to recall that ones.
rather flat species derived from trans disubstituted
It is also worth noting that 1- and 2-aminoindanols
scaffolds, like those involved in the Jacobsen epoxida- can be considered as constrained surrogates of phe-
tion,[5] are able to induce very high levels of enantio- nylglycinol and the members of the ephedrine family,
Figure 2. PM3 optimized molecular structures of metal chelates [methylzinc (green) and methylboron (golden)] of aminoin-
danols showing the flat structure of trans derivatives (a) and the bent nature of the cis ones (b and c). Arrows in structures b
and c indicate both the preferred face for substrate and reagent coordination and the atoms in the metal chelates involved
in reference catalytic processes (aldehyde alkylation and ketone reduction with borane).
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respectively. Indeed, the stereochemical diversity of
the latter has been explored in several studies[6] con-
cerning, for instance, CBS reduction,[6a] Et2Zn addi-
tion to aldehydes[6b] or asymmetric transfer hydroge-
nation,[6c] to name but a few.
Scheme 2. Preparation of 1b by resolution of a racemate.
Results and Discussion
Preparation of a Family of Aminoindanol-Derived
Ligands
As previously mentioned, cis-1-amino-2-indanol (1a)
is commercially available. As for the rest of the li-
gands, they were prepared in a few steps either by
chemical resolution of racemates or by de novo syn-
thesis starting from achiral compounds.[7] The amino
Scheme 3. Preparation of dialkyl derivatives of 1b.
alcohols obtained in this manner were transformed Preparation of 1c and Derivatives
into their dimethylamino or piperidino[8] derivatives
to ensure sufficient steric diversity in the amino The preparation of 1c (trans-1-amino-2-indanol,
moiety.
Scheme 4) started with the asymmetric epoxidation of
indene[13] using Jacobsenꢁs method.[5] The correspond-
ing indene oxide was obtained in 93% ee, and after
several trials the best method found to attain optical
purity consisted in the transformation of this scalemic
Preparation of Derivatives of 1a
The dialkylamino derivatives were obtained from indene oxide into the corresponding hydroxycarba-
commercially available 1a following methods de- mate by regioselective ring-opening with ammonia
scribed in the literature. Reductive amination with and protection of the amine as a carbamate.[14] This
formaldehyde[9] or nucleophilic substitution with 1,5- intermediate could be recrystallized to attain 100%
dibromopentane[10] afforded the dialkylamino deriva- enantiomeric purity, after which acid hydrolysis of the
tives in a straightforward manner (Scheme 1).
carbamate afforded 1c in quantitative yield. Again,
the dialkylamino derivatives 2c and 3c were synthe-
sized without any problem.
Preparation of 1b and Derivatives
Racemic cis-2-Amino-1-indanol (1b)[11] was obtained Preparation of 1d and Derivatives
from the commercially available bromohydrin by con-
version of the bromide into an azide and subsequent Finally, 2d and 3d were prepared from 2c and 3c
reduction to the amine. Resolution of the racemic through the intermediacy of an aziridinium ion,[15]
mixture by crystallization of the corresponding tar- which was regioselectively ring-opened at the benzylic
trate allowed access to optically pure 1b in both enan- position with sodium p-nitrobenzoate. The corre-
tiomeric forms (Scheme 2).[12]
sponding ester was reduced with DIBALH to furnish
The procedures described for the dialkylation of 1a the desired trans-2-dialkylamino-1-indanols
were applied to 1b as depicted in Scheme 3, which al- (Scheme 5).
lowed us to isolate the dimethylamino and piperidino
derivatives in 100% and 70% yields, respectively.
With this whole set of molecules sharing the amino-
indanol scaffold in hand (2a–d, 3a–d) the stage was
set to analyze their performance as ligands in a series
of catalytic enantioselective reactions.
Enantioselective Ethylation of Benzaldehyde
Given the successful application of modular amino al-
cohols in the alkyl- and arylzinc additions to alde-
hydes,[1a–c,16,17] we decided to use these reactions as
benchmarks to test the catalytic profile of the synthe-
sized aminoindanol ligands. It is worth noting that
Scheme 1. Preparation of dialkyl derivatives of 1a.
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Scheme 4. Preparation of dialkyl derivatives of 1c from scalemic indene oxide.
In nearly all cases the ligands containing the piperi-
dino subunit (3a–d) displayed superior catalytic activi-
ty than their dimethylamino counterparts (2a–d) both
in terms of conversion and enantioselectivity. Among
ligands 3, the cis-2-piperidino derivative 3b exhibited
the best activity/selectivity profile (entry 4). These re-
sults corroborated our working hypothesis that
changes in the regio- and stereochemistry of the ami-
noindanol scaffold, as well as the steric hindrance
around the amino group, can have a dramatic effect
on the outcome of a given reaction.
Based on our results[1a–b] and Umani-Ronchiꢁs,[18]
there seemed to be a clear correlation between the
bulkiness of the amino substituent and the enantiose-
lectivity of the addition process. Consequently, we de-
cided to carry out a fine-tuning involving this sub-
Scheme 5. Preparation of dialkyl derivatives of 1d from 2–
3c.
Umani-Ronchi et al. had described the catalytic activ- structure, focusing on the array that had proven to
ity of aminoindanol ligands in this reaction with the provide better results: the cis-2-amino series. Hence,
dibutyl and diallyl derivatives of 1a,[18] but their ees different ligands derived from 1b with structural di-
did not exceed 50%. The results obtained using 6 versity in the dialkylamino moiety were synthesized
mol% ligand in toluene at 08C are summarized in by nucleophilic substitution or reductive amination.
Table 1.
The pyrrolidino (4b)[10] and a,a’-dimethylpyrrolidino
(5b)[19] derivatives were prepared as shown in
Scheme 6.
Attempts to generate the dimethylpiperidino ana-
logue of 5b resulted in a mixture of diastereomers
which could not be separated. Finally, we set our
Table 1. Catalytic profile displayed by ligands 2a–d and 3a–d
in the Et2Zn addition to benzaldehyde.
Entry Ligand Conversion [%] ee [%] Configuration
1
2
3
4
5
6
7
8
2a
3a
2b
3b
2c
3c
2d
3d
91
95
56
99
45
98
12
91
15
19
38
85
47
33
11
44
R
R
S
S
R
R
S
S
Scheme 6. Synthesis of bicyclic amines by alkyaltion of 1b.
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Figure 3. X-ray structure of hemiaminal 6b.
sights on the bulkier bicyclic amine 7b, which we tried preparation of bulky tertiary amines involving the 9-
to prepare by reductive amination of 1b with 1,5-cy- azabicyclo[3.3.1]nonane system.
clooctanedione. However, under the standard condi- The catalytic activity of these bulky amines, togeth-
tions a compound which was identified as the hemi- er with that of the hemiaminal 6b, was then tested in
aminal 6b was obtained. This assignment was con- the same reaction and the results (displayed in
AHCTREUNG
ACHTREUNG
firmed
by
single-crystal
X-ray
diffraction Table 2) were compared with the best candidate aris-
(Figure 3).[20]
ing from the first screening: 3b.
After several trials, we succeeded in reducing the
Somewhat surprisingly, as illustrated in this table,
hemiaminal to the desired amine 7b upon treatment variations on the amine leading to increased steric
with triethylsilane in the presence of trifluoroacetic bulk (entries 3 and 5) did not have a positive impact
acid (Scheme 7).[21] In the scarce precedents involving on the outcome of the reaction, and 3b remained the
construction of bulky amines by reductive amination, best catalyst for this particular reaction.
the hemiaminal intermediate was reduced by a two-
Next, we turned our attention to the enantioselec-
step procedure consisting in conversion of the alcohol tive methylation of benzaldehyde. This time, the
[22]
into a chloride followed by reduction with LiAlH4
screening was limited to the best ligands as regards
or radical-involving methods (Bu3SnH/AIBN).[23] In- ethylation of aldehydes, along with 2b as an example
terestingly, in the last case the authors report that re- of acyclic amine. The results clearly show that increas-
duction of a bicyclic hemiaminal with the Et3SiH/TFA ing the steric bulk of the amino substituent leads to
combination is sluggish, which they attribute to the an important improvement of the enantioselectivity
inability to form the bridgehead iminium intermedi- of the methylation, although this is accompanied with
ate[23] (Bredtꢁs rule). However, in our system this re- some decrease in the catalytic activity (Table 3).
action worked well and the amine was generated
In light of these results, 2b was ruled out as a candi-
from the hemiaminal in a single step with moderate date for screening the catalytic activity of the amino-
yields. This approach represents a novel and efficient indanols in the phenylation of p-tolualdehyde. This
alternative to the protocols described so far for the
Table 2. Catalytic activity of ligands 3–7b in the Et2Zn addi-
tion to benzaldehyde.
Entry
Ligand
Conversion [%]
ee [%]
1
2
3
4
5
3b
4b
5b
6b
7b
>99
93
>99
4
85
73
79
–
Scheme 7. Synthesis of bicyclic amine 7b by reductive ami-
nation of 1b.
61
81
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Table 3. Catalytic activity of ligands 2–3b and 7b in the
Me2Zn addition to benzaldehyde.
Palladium-Catalyzed Asymmetric Allylic Alkylation
Our efforts to expand the scope of the comparison
began by preparing the bis(oxazoline) (BOX) deriva-
tives of the aminoindanol scaffold. Since their intro-
duction in 1989 based on Pfaltzꢁs preliminary studies
with the semicorrin platform,[27] BOX have been
found to successfully catalyze several metal-mediated
processes such as asymmetric allylic alkylation,[27] al-
lylic oxidation, aziridination of olefins and imines, cy-
clopropanation and Mukaiyama aldol reactions, just
to quote a few.[28]
Entry
Ligand
Conversion [%]
ee [%]
1
2
3
2b
3b
7b
74
73
45
27
70
87
The synthesis of the aminoindanol-derived BOX li-
gands was carried out following a reported protocol[29]
which furnished 8a and 8b in good to excellent yields
(Scheme 8). Worthy of note is the profound effect on
the shape of the bis(oxazoline) exerted by the regio-
chemistry of the aminoindanol building block. It must
be mentioned that although the preparation of bis(ox-
azoline) 8a has been reported,[30] its use in asymmetric
catalysis remains virtually unexplored.[31]
Table 4. Enantioselective addition of PhZnEt catalyzed by
3b and 7b.
Entry
Ligand
Conversion [%]
ee [%]
With these bis(oxazolines) in hand, we were ready
to perform a comparison of their activity in asymmet-
ric allylic alkylation. Several allylic acetates were al-
kylated with dimethyl malonate using 1.1 mol% of
ligand, and the results are presented in Table 5.
It is interesting to observe (entries 1 and 2) that
1
2
3b
7b
>99
>99
60
86
time 7b matched complete conversion with a high both BOX ligands are able to induce the alkylation of
enantioselectivity, much better than the one obtained 1-acetoxy-1,3-diphenyl-2-propene with high enantiose-
with 3b (Table 4). Clearly, in this case steric factors lectivity. In this reaction, the U-shaped bis(oxazoline)
were crucial to achieve high enantioselectivity and 8a behaves slightly better than the less sterically de-
this tends to indicate that, under the studied reaction manding 8b. Noteworthy, with less bulky substrates
conditions, the higher reactivity towards the carbonyl (entries 3, 4 and 5, 6) 8b is more enantioselective than
group of the ethylphenylzinc species[24,25] compensates 8a, although the performance of both ligands with
any possible decrease in catalytic activity of the bulky these substrates is far from optimal.
7b ligand.
So far we have seen that the catalytic performance
of aminoindanol ligands in diorganylzinc additions to
aldehydes critically depends on the regio- and the ste-
reochemistry of the ligands, and that simple modifica-
tion of the steric environment of the amino group can
also lead to very significant improvements in enantio-
selectivity. Not surprisingly if the nature of the atoms
involved in the catalytic process is considered (see
structures b and c in Figure 2), the optimal aminoin-
danol ligands for this process derive from the cis-2-
amino-1-indanol isomer rather than from its more
commonly used regioisomer, i.e., cis-1-amino-2-inda-
nol.
A high number of catalytic systems use ligands
which are not amino alcohols, but that can be readily
prepared from this class of molecules. To explore the
behaviour of the indane scaffold in processes of these
types, we decided to extend the study of the regioiso-
meric and diastereomeric aminoindanols to reactions
catalyzed by their derivatives.
Scheme 8. Preparation of the bis(oxazoline) derivatives 8a, b
from 1a, b.
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Table 5. Pd-catalyzed asymmetric allylic alkylation mediated by ligands 8a and 8b [BSA=N,O-bis(trimethylsilyl)acetamide].
Entry
Ligand
Substrate
Time [h]
Conversion [%]
ee [%]
Configuration
1
2
8a
8b
20
20
>99%
>99%
98
93
S
R
3
4
8a
8b
48
48
19
17
<1
9
–
–
5
6
8a
8b
48
48
16
18
8
47
S
R
7
8
8a
8b
48
48
–
–
–
–
–
–
Trimethylsilyl Cyanide Addition to Aldehydes
The formation of cyanohydrins is a classical transfor-
mation in organic synthesis. However, the develop-
ment of catalytic enantioselective variants using chiral
Lewis acids[32] and the versatility of the nitrile group
have given this reaction a second youth.
In particular, imines have become a very interesting
group of modular ligands to perform this reaction. In
1991, Oguni et al.[33] reported the use of an imino al-
cohol as the chiral ligand for the titanium-catalyzed
silylcyanation of aldehydes. More recently, Walsh Scheme 9. Preparation of imines 9a and 9b.
et al.[34] reported the use of imines derived from com-
mercially available 1a in combination with titanium
Table 6. Silylcyanation of benzaldehyde catalyzed by 9a, b.
Entry Ligand Conversion [%] ee [%] Configuration
tetraisopropoxide with moderate yields and enantio-
selectivities. Thus, we decided to extend this study to
other aminoindanols with the aim of finding the best
candidate isomer for this application.[35] In view of the
results recorded in the addition of diorganozinc spe-
cies to aldehydes, only the cis type regioisomers were
studied.
Both imines were prepared quantitatively by simply
treating a solution of the aminoindanol and salicylal-
dehyde with anhydrous sodium sulfate (Scheme 9).
1
2
9a
9b
69
27
70
16
S
R
This method allowed the isolation of Walshꢁs imine transition states when imines derived from cis-1-
9a[34] and of its analogue derived from cis-2-amino-1- amino-2-indanol are employed in the reaction.
indanol: 9b.
The study of the behaviour of 9a and 9b was car-
ried out using the same conditions as described by Asymmetric Borane Reduction of Prochiral Ketones
Walsh et al.[34] These involved a 20 mol% loading of
ligand and Ti
ACHTREUNG
sults are summarized in Table 6.
As exemplified in this table, and according to the borolidines. These species have proven to be an excel-
results described by Walsh, the results were only mod- lent option in the enantioselective reduction of ke-
erate for 9a. As for the new ligand 9b, it performed tones with borane for the production of enantioen-
poorly. It is thus clear that, for this particular process, riched secondary alcohols. The use of oxazaboroli-
the discriminating effect of the phenyl substituent is dines in asymmetric ketone reduction was introduced
more efficiently transmitted to the diastereomeric by Itsuno et al.[36] although it was Corey who pro-
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posed the mechanism, which allowed for a rational tion of acetophenone using 10a, b and 11a, b are illus-
development of the catalytic system.[37]
trated in Table 7.
À
Since their use was first described by Didierꢁs
These results show that B OMe oxazaborolidines
group for the borane reduction of ketones,[38] the ami- (11) perform slightly better than their B H counter-
noindanol scaffold has been employed by other au- parts (10). As for the regiochemistry, the cis-1-amino-
À
thors[18,39] in this reaction, either as the B H, the B
2-indanol (a series) tends to provide better ees than
À
À
À
Me or B OMe derivative. Nevertheless, this work has its 2-amino regioisomer (b) and this observation
been restricted to derivatives of 1a. Therefore, our stands for both methods.
aim was to compare the results obtained for the com-
mercially available aminoindanol with those of its re-
gioisomer. According to the strain considerations set Asymmetric Transfer Hydrogenation
up above (Figure 2), the use of the trans diastereo-
mers 1c and d was not considered for this application. The reduction of ketones by hydrogen transfer has
À
À
Thus, the B H and the B OMe oxazaborolidines de- emerged as a powerful alternative to the use of mo-
rived from 1a and 1b were prepared by Methods A lecular hydrogen. In this method, alternative hydro-
and B (Table 7) and tested in the reaction. In Method gen sources (usually isopropyl alcohol – IPA – or
À
A, the B H oxazaborolidine was generated in situ by formic acid/triethylamine) involving less potential
reaction between the amino alcohol and borane, risks are used. The process is normally mediated by
while Method B involved pre-formation of the B
OMe derivative and subsequent addition of the through the use of enantiopure monotosylated 1,2-di-
À
ruthenium catalysts, enantiocontrol being secured
borane and the ketone to be reduced.
amines as ligands.[41] Enantiopure amino alcohols
Since it is well known that oxazaborolidine-mediat- have also found regular application as ligands for this
ed reductions tend to be very sensitive to reaction process,[42] and we have shown that when these mole-
temperature,[40] the reactions were performed at sev- cules are modularly constructed it is possible to opti-
eral temperatures in order to establish the optimal mize their structures for high enantiocontrol.[43] Ac-
conditions for the process with this set of ligands. The cording to these facts, we thought it would be inter-
results obtained for the catalytic asymmetric reduc- esting to apply the aminoindanols to this reduction as
an alternative to oxazaborolidines. The use of 1a in
this field was pioneered by Wills et al. in 1997.[44] The
same authors have described the comparative use of
1a, 1c and several N-alkyl derivatives in this reac-
tion.[14] Therefore, the effect of the stereochemistry
had been studied, but the consequences of a change
in the regiochemistry remained unexplored, so we de-
cided to undertake the comparative study of the cata-
lytic activity of 1a and 1b in the asymmetric reduction
of acetophenone with a ruthenium catalyst. The re-
sults are summarized in Table 8.
Table 7. Asymmetric reduction of acetophenone by in situ
generation of oxazaborolidines.
Table 8 clearly indicates that when 1b is used the
reaction is slowed down, and its enantioselectivity
drops, so that 1a proved to be the best option. It is
also worth mentioning that, with the studied ligands,
the application of longer reaction times can be trou-
Table 8. Transfer hydrogenation of acetophenone employing
1a, b as ligands.
Entry
Ligand
T
Conversion [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
10b
10a
10b
10b
11a
11b
11a
11b
11a
11b
08C
r.t.
r.t.
408C
08C
08C
r.t.
r.t.
408C
408C
74
68
94
84
81
92
78
93
82
92
81
>99
>99
>99
>99
93
>99
>99
>99
>99
Entry Ligand t
Conversion
ee
[%]
Configuration
[h] [%]
1
2
3
4
1a
1b
1a
1b
2
2
4
4
90
33
91
36
84
77
76
76
R
S
R
S
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Sergi Rodríguez-Escrich et al.
FULL PAPERS
1
1211, 1059, 1018, 975, 760, 739, 670 cmÀ1; H NMR (CDCl3,
blesome due to the reversibility of the reaction which
can gradually erode the enantiomeric purity of the
product as verified when comparing entries 1–3 and
2–4.
400 MHz): d=7.55–7.42 (1H, m, ArH), 7.30–7.15 (3H, m,
ArH), 4.74 (1H, d, J=5.5 Hz, CHOH), 3.47 (1H, ddd, J=
4.9 Hz, J=7.1 Hz, J=12.3 Hz, CHNR2), 3.2–2.9 (4H, m,
CHHCHN, CHHCHN, 2CHCH3), 1.93 (2H, m, CH2), 1.53
(2H, m, CH2), 1.24 (3H, d, J=6.4 Hz, CH3), 1.02 (3H, d,
J=6.4 Hz, CH3); 13C NMR (CDCl3, 100.6 MHz): d=143.5
(C), 141.5 (C), 128.4 (CH), 126.8 (CH), 125.4 (CH), 124.5
(CH), 73.5 (CH), 67.9 (CH), 63.0 (CH), 56.4 (CH), 33.8
(CH2), 32.9 (CH2), 32.5 (CH2), 25.3 (CH3), 22.7 (CH3); HR-
MS (ESI+): m/z=232.1693, calcd. for C15H22NO [M+H]+:
232.1696.
Conclusions
A systematic study of the catalytic profile of the
regio- and stereoisomers of the aminoindanol struc-
ture has been carried out for the first time, and the
isomers depicting optimal properties as ligands for a
variety of important catalytic enantioselective pro-
cesses have been identified. The results have demon-
strated that, whilst for most reactions commercially
available cis-1-amino-2-indanol 1a and/or its deriva-
tives represent the best possible option, that is more a
general tendency than a rule, as demonstrated in the
addition of diorganozinc reagents to aldehydes, where
this tendency is completely reversed and cycloalkylat-
ed derivatives of cis-2-amino-1-indanol 1a bearing
bulky amino substituents afford the highest enantiose-
lectivities. According to the results recorded for the
reactions involving cyclic chelates studied here, it ap-
pears that internal delivery of the reagent from the
heteroatom occupying the benzylic position in a cis-
aminoindanol structure (see structures b and c in
Figure 2) fulfills the requirements for highest enantio-
selectivity. From a synthetic point of view, we have
shown that very bulky tertiary amines, involving the
Preparation of Hemiaminal 6b
The experimental procedure was the same as for 5b with the
following quantities: (1S,2R)-2-amino-1-indanol 1b (298 mg,
2.0 mmol) in MeOH (2 mL), 0.13 mL from a methanolic so-
lution containing KOH (33 mg, 0.5 mmol) and acetic acid
(0.125 mL, 2.2 mmol), 1,5-cyclooctanedione (280 mg,
2.0 mmol) in MeOH (1 mL), and NaBH3CN (127 mg,
2.0 mmol) in MeOH (1 mL). The viscous oil obtained was
purified by column chromatography (from hexanes/EtOAc
1:1 to 1:3) to afford 9-[(1S,2R)-1-hydroxy-2,3-dihydro-1H-
inden-2-yl]-9-azabicyclo[3.3.1]nonan-1-ol (6b); yield: 227 mg
A
(42%); [a]23: À61.4 (c 1.02, CHCl3); IR (neat, ATR): n=
3385, 2917,D2873, 1432, 1371, 1175, 1034, 974, 876, 832, 743,
714 cmÀ1 1H NMR (CDCl3, 400 MHz): d=7.40–7.48 (1H,
;
m, ArH), 7.18–7.27 (3H, m, ArH), 4.83 (1H, d, J=5.5 Hz,
CHOH), 3.56 (1H, dd, J=7.1 Hz, J=13.3 Hz, CHNR2), 3.04
(1H, dd, J=7.1 Hz, J=15.5 Hz, CHH), 2.86 (1H, dd, J=
7.5 Hz, J=15.5 Hz, CHH), 2.80 (1H, m, CHNCH2CH2), 2.50
(1H, br s, OH), 2.42 [1H, m, CHHC(OH)N], 2.26 [2H, m,
CH2C(OH)N], 2.12 [1H, m, CHHC(OH)N], 1.94 [4H, m,
9-azabicyclo[3.3.1]nonane system can be readily pre-
A
pared by a two-step procedure consisting in the for-
mation of an intermediate hemiaminal and its subse-
quent reduction under acidic conditions.
2CH2(CH2)CH2], 1.70 [4H, m, 2CH2(CH)CH2CH2];
C
Experimental Section
Synthesis of 5b by Reductive Amination[19]
Reduction of Hemiaminal 6b to (1S,2R)-2-(9-Aza-
bicyclo
(7b)
[3.3.1]nonan-9-yl)-2,3-dihydro-1H-inden-1-ol
(1S,2R)-2-Amino-1-indanol 1b (298 mg, 2.0 mmol) was dis-
solved under argon in 2 mL of MeOH. An aliquot of
0.13 mL of a methanolic solution containing KOH (33 mg,
0.5 mmol) and acetic acid (0.125 mL, 2.2 mmol) were added.
Afterwards, at 08C, 2,5-hexanedione (0.2 mL, 2.0 mmol), fol-
lowed by NaBH3CN (127 mg, 2.0 mmol) dissolved in MeOH
(1.0 mL) were successively added. The temperature rose
spontaneously to room temperature and the miyture was
stirred overnight (20 h). The reaction was monitored by
TLC and quenched with 4N HCl (5 mL). MeOH was re-
moved under vacuum and the remaining solution was
washed with CH2Cl2. The aqueous solution was basified by
careful addition of K2CO3 until pH 9–10, and extracted with
CH2Cl2 (3”10 mL). The xtract was then dried with Na2SO4
and solvent evaporated under vacuum to yield a white solid,
which was further purified by column chromatography (hex-
anes/EtOAc from 1:1 to 1:3) to afford 5b as a white solid;
yield: 325 mg (71%); mp 758C; [a]23: À47.3 (c 0.85, CHCl3);
IR (neat, ATR): n=3245, 3065, 297D2, 2927, 2869, 1456, 1328,
Hemiaminal 6b (112 mg, 0.41 mmol) was dissolved in anhy-
drous CH2Cl2 (3 mL) under argon. Triethylsilane (1.15 mL,
7.0 mmol) and TFA (0.83 mL, 6.6 mmol) (dried over 4 Š ac-
tivated MS for 1 h before using it) were added dropwise,
and the mixture was stirred at room temperature for 60 h.
Then, the reaction was quenched with 10 mL of a saturated
solution of NaHCO3 and basified to pH 11–12 with 30%
aqueous NaOH. It was extracted with CH2Cl2 (3”15 mL)
and allowed to stir over MgSO4. An orange spot appeared
in the TLC when stained with ninhydrin, which evolved
throughout 8 h. After that, it was filtered off and purified by
column chromatography in neutral alumina with hexane/
EtOAc (from 9:1 to 1:3) to afford the desired product;
yield: 49 mg (47%). mp 958C; [a]2D3: +64.8 (c 1.04, CHCl3);
IR (neat, ATR): n=3238, 2923, 2849, 1735, 1561, 1477, 1308,
1
1274, 1178, 1139, 1072, 1034, 942, 834, 724 cmÀ1; H NMR
(CDCl3, 400 MHz): d=7.50–7.42 (1H, m, ArH), 7.17–7.30
2258
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Exploring Structural Diversity in Ligand Design
FULL PAPERS
(3H, m, ArH), 4.78 (1H, d, J=4.9 Hz, CHOH), 3.75 (1H,
ddd, J=4.9 Hz, J=7.1 Hz, J=12.3 Hz, CHNR2), 3.10 (2H,
bs, CHNCH2CH2), 2.99 (1H, dd, J=11.6 Hz, J=14.6 Hz,
CHH), 2.89 (1H, dd, J=7.1 Hz, J=14.6 Hz, CHH), 2.07
(6H, m, 3 CH2), 1.64 (6H, m, 3 CH2), 1.6 (1H, br s, OH);
13C NMR (CDCl3, 100.6 MHz): d=142.9 (C), 141.9 (C),
128.8 (CH), 126.9 (CH), 125.9 (CH), 124.8 (CH), 71.5 (CH),
62.5 (CH), 49.3 (CH), 33.8 (CH2), 28.5 (CH2), 27.0 (CH2),
20.5 (4 CH2); HR-MS (ESI+): m/z=258.1863, calcd. for
C17H24NO [M+H]+: 258.1852.
prehensive Asymmetric Catalysis, Vol. II, (Eds.: E. N.
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Supporting Information
Detailed experimental procedures for the preparation of the
enantiopure aminoindanol precursors and ligands derived
from them, as well as the application of these compounds in
asymmetric catalysis are available in the Supporting Infor-
mation.
[9] Y. Hirata, I. Yanagisawa, M. Takeda, H. Ino, K. Taka-
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Acknowledgements
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Pierce, J. R. Moore, Org. Synth. 2000, 77, 12.
This work was funded by MEC (Grant CTQ2005–02193/
BQU), DIUE (Grant 2005SGR225), Consolider Ingenio
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[20] Crystals of 6b could be obtained by slow evaporation
of a solution of the compound in a mixture of ethanol
and ethyl acetate. Crystal data for 6b at 100 K:
2·(C17H23NO2), 546.73 gmolÀ1, orthorhombic, P212121,
a=6.7084(3) Š, b=19.3348(9) Š, c=22.5361(10) Š,
V=2923.1(2 Š3, Z=4, 1calcd. =1.242 Mg/m3, R1 =0.0420
(0.0470), wR2=0.1144 (0.1196), for 16172 reflections
with I>2s(I) (for 17104 reflections [Rint: 0.0250] with a
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