A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs

Article abstract of DOI:10.1016/j.tet.2018.04.022

Solid support-enabled site isolation has previously allowed to use paraldehyde as an acetaldehyde surrogate in aldol reactions. However, only electron-poor aldehydes were tolerated by the system. Herein, we show that the temporary conversion of benzaldehyde into η⁶-benzaldehyde Cr(CO)₃ circumvents this limitation. Asymmetric synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrate the benefits of this strategy.

Full text of DOI:10.1016/j.tet.2018.04.022

Accepted Manuscript
A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol
drugs
Shoulei Wang, Carles Rodríguez-Escrich, Xinyuan Fan, Miquel A. Pericàs
PII:
S0040-4020(18)30401-0
10.1016/j.tet.2018.04.022
TET 29437
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 February 2018
Revised Date: 5 April 2018
Accepted Date: 7 April 2018
Please cite this article as: Wang S, Rodríguez-Escrich C, Fan X, Pericàs MA, A site isolation-enabled
organocatalytic approach to enantiopure γ-amino alcohol drugs, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.04.022.
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A site isolation-enabled organocatalytic
approach to enantiopure γ-amino alcohol
drugs
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Shoulei Wang, Carles Rodríguez-Escrich, Xinyuan Fan and Miquel A. Pericàs*
Institute of Chemical Research of Catalonia (ICIQ). The Barcelona Institute of Science and Technology, Av.
Països Catalans, 16, 43007 Tarragona (Spain)

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Tetrahedron
journal homepage: www.elsevier.com
A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs
Shoulei Wang,a Carles Rodríguez-Escrich,a Xinyuan Fana and Miquel A. Pericàsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans, 16, 43007 Tarragona (Spain).
Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB), 08028 Barcelona (Spain).
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Solid support-enabled site isolation has previously allowed to use paraldehyde as an
acetaldehyde surrrogate in aldol reactions. However, only electron-poor aldehydes were
tolerated by the system. Herein, we show that the temporary conversion of benzaldehyde into η6-
benzaldehyde Cr(CO)3 circumvents this limitation. Asymmetric synthesis of (R)-Phenoperidine,
as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrate the benefits of this
strategy.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
Solid-supported catalysts
Site Isolation
η6-Arene chromium complexes
γ-Amino alcohol drugs
Phenoperidine
1. Introduction
The direct cross-aldol reaction represents one of the most
important carbon-carbon bond forming processes since it can
provide an efficient approach to both naturally occurring and
synthetically important building blocks.1-5 During the past
decade, a variety of enamine-mediated aminocatalytic processes
have been developed and successfully applied in asymmetric
cross-aldol reaction.6-9 However, most of these examples are not
efficient with acetaldehyde as the donor due to its high reactivity
unavoidably leading to a variety of by-products arising from its
oligomerization and self-aldolization.10-11 Ten years ago, the
Hayashi group reported the first organocatalytic direct cross-aldol
reaction of acetaldehyde with aromatic aldehydes using a
diarylprolinol as the catalyst.12 Later, the use in the same
reactions of chiral primary amine catalysts under neat
conditions13 and of suitably modified diarylprolinol catalysts in
aqueous media,14 have also been reported. More recently, we
have disclosed a highly enantioselective version of the reaction
promoted by a dual catalytic system (polystyrene-bound sulfonic
acid 1 and polystyrene-supported diarylprolinol catalyst 2, Figure
1), which enabled the use of paraldehyde as a convenient source
of acetaldehyde.15 Compared to acetaldehyde, paraldehyde is less
expensive, easier to handle (b.p. 123 °C) and can be
deoligomerized in situ by polystyrene-bound sulfonic acid 1. The
site isolation scenario generated under these conditions16-19
enabled catalyst 1 to work compatibly with 2 in one pot in a
highly recyclable manner, furnishing the aldol products in good
yields and excellent enantioselectivities. This methodology
granted access to enantioenriched 1-arylpropane-1,3-diols, a
privileged core structure occurring in a variety of drugs and
natural products.20
Figure 1. Cascade deoligomerization and cross-aldol reaction mediated
by 1/2 operating under site isolation.
However, the drawback of this method was the fact that only
electron-poor benzaldehydes could be used as effective substrates
(Scheme 1, top). Considering the importance of 3-phenyl-3-
hydroxypropanal as a key building block in the synthesis of many
active pharmaceutical ingredients, we analyzed methods allowing
the reversible electronic modification of benzaldehyde that could
favor its participation in the cross-aldol reaction.
It is known that the formation of η6-arene-Cr(CO)3 complexes
importantly decreases the electron density of the parent arene and
modifies accordingly its reactivity.21-22 From
a practical
perspective, these complexes are easily formed upon reaction of
Cr(CO)6 with aromatic substrates, and the metal moiety can be
later removed in quantitative yield by exposure to visible light.23-
24
Thus, the complexation/decomplexation process has normally
low impact on the efficiency of the overall process. In 2011,
Walsh et al. exploited this approach to favour the generation of
nucleophiles for allylic substitution reaction,25-26 and the same
strategy has been recently applied by Larrosa et al. for enhancing

2
Tetrahedron
ACCEPTED MANUSCRIPT
the reactivity of C-H bonds in arylation reactions.27 With these
precedents in mind, we assumed that the η6-benzaldehyde
complex 3 could be used as an activated benzaldehyde surrogate
in the cross-aldol reaction with paraldehyde mediated by the 1/2
dual catalytic system (Scheme 1, bottom).
A screening of additives including benzoic acid, p-
nitrobenzoic acid and water revealed the latter as the most
convenient one (entries 4-6). When raising the temperature,
either with conventional heating or using the microwave, the
enantioselectivity was maintained but the yield slightly decreased
(entries 7 and 8). In order to evaluate the effect of different
reaction times on the yield and enantioselectivity, we carried out
a series of comparative experiments§ which showed that after 72
hours the reduced aldol product 4 could be obtained in 38% yield
and 93% ee (entry 9). Subsequently, the use of different amounts
of paraldehyde was examined (entries 10-12). The improvement
was not significant, but 5 equiv. seemed to be a bit better.
Finally, increasing the loading of polystyrene-supported catalyst
2 led to a major yield improvement (up to 61%) when 40 mol%
of this catalyst was used (entry 15).
O
O
OH
O
O
O
H
Cat. 1, Cat. 2
O
Cr(CO)6
O
O
"Cr(CO)3"
O
H
Cr(CO)3
3
Cat. 1, Cat. 2
It is to be noted that such a high catalyst loading can only be
justified if the dual catalytic system is amenable to recycling.28-30
In this regard, it is worth mentioning that the recovery of the two
different polystyrene-supported catalysts can be achieved by
simple filtration without separating the two resins. Gratifyingly,
the mixture of the two catalysts can be reactivated by briefly
washing with AcOH after each reaction cycle. The role of the
acid is presumably to hydrolyse the parasite oxazolidine formed
by catalyst 2 and acetaldehyde, thus increasing the effective
amount of catalytic species.15 Using this strategy, the 1/2 dual
catalytic system could be reused for five cycles with essentially
the same results. On the sixth cycle, the aldol product was still
obtained in high enantioselectivity (90% ee), albeit with slightly
decreased yield (Table 2).
Scheme 1. Deoligomerization/cross-aldol reaction of paraldehyde with
complex 3 mediated by the 1/2 dual catalytic system.
2. Results and discussion
Initially, we investigated the cross-aldol reaction of the
tricarbonyl (η6-benzaldehyde) chromium (0) with paraldehyde
mediated by the dual catalytic system 1/2 in DMF (Table 1, entry
1) but the target aldol product was not formed at all in this
solvent. A subsequent solvent screening showed that when
acetonitrile was employed the product can be isolated in 18%
yield and 93% ee (entry 3).
Table 1. Tandem deoligomerization plus asymmetric cross-
aldol reaction of tricarbonyl (η6-benzaldehyde) chromium (0)
with paraldehyde catalyzed by 1/2.a
Table 2. Recycling in the tandem deoligomerization/
asymmetric cross-aldol reaction of tricarbonyl (η6-
benzaldehyde) chromium (0) with paraldehyde catalyzed by
1/2.
Paraldehyde
(equiv.)
Yield
(%)b
ee
Entry
Time (h)
Solvent
(%)c
1
2
24
24
24
24
24
24
24
24
72
72
72
72
72
72
72
DMF
2
2
0
–
CH3NO2
15
18
12
17
20
17
19
38
41
33
30
20
49
61
92
93
92
93
93
93
93
93
93
93
92
92
93
93
Run
1
Yield (%)
ee (%)
93
3
MeCN
2
58
60
54
53
50
38
4d
5e
6
MeCN
2
2
93
MeCN
2
3
92
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
Paradehyde
MeCN/H2O
MeCN/H2O
2
4
93
7f
2
5
92
8g
2
6
90
9
2
10
11
12
13
14h
15i
5
As already mentioned, enantiomerically enriched 1,3-diols
and β-hydroxyaldehydes are versatile building blocks for the
synthesis of a wide variety of natural products and commercially
important drugs.31-33 For instance, enantioenriched diol 4 is a key
intermediate in the preparation of the selective serotonin reuptake
inhibitor (R)-fluoxetine (Prozac®) and the norepinephrine
reuptake inhibitor (R)- atomoxetine (Strattera®), which are
important drugs for the treatment of important psychiatric
disorders.20, 34
10
20
–
5
5
aThe reaction was carried out with 3 (0.1 mmol), paraldehyde, 1 (10 mol%), 2
(20 mol%) and H2O (0.5 mmol) in 0.3 mL solvent. bDetermined by 1H NMR
using mesitylene as internal standard. cBy HPLC. d0.01 mmol PhCO2H added.
e0.01 mmol p-NO2C6H4CO2H added. fAt 40 °C. gUsing microwave at 40 °C.
h30 mol% of 2 was used. i40 mol% of 2 was used.

3
ACCEPTED MANUSCRIPT
Ph
OH
O
O
HN
OH
OH
CO2Et
Cat. 1/2
hv
N
O
+
O
Ph
NaBH(OAc)3
THF
MeCN/H2O
RT, 72 h
Et2O
Cr(CO)3
O
H
O
CO2Et
8
6
5
Phenoperidine
Cr(CO)3
99% ee
NaBH(OAc)3
THF
MeNH2
36% overall yield
3
H3C
O
CF3
OH
ref. 20
Me
N
ref. 20
O
H
NHMe·HCl
NHMe·HCl
(R)-Fluoxetine hydrochloride
7
95% ee
35% overall yield
(R)-Atomoxetine hydrochloride
Scheme 2 Synthesis of drugs and intermediates with the present methodology.
According to previous literature procedures, the reduced
cross-aldol product 4 can be converted into amino alcohol 7, a
common precursor to both drugs, in four steps and 36% overall
yield.20 We have now found (Scheme 2) that crude aldol 6,
obtained by decomplexation of 5 in ether solution on exposure to
visible light, can be converted into 7 (95% ee) in a single step by
reductive amination with MeNH2 (35％ overall yield). The
possibility of applying a reductive amination greatly facilitates
the introduction of an amine moiety in this position.
Phenoperidine 8,35-37 another well-known drug can also be
synthesized in a single step from crude 6 upon treatment with
ethyl 4-phenylpiperidine-4-carboxylate and NaBH(OAc)3 in 36%
overall yield and 99% ee.
in Et2O (5 mL) and this solution was exposed to air and light
until a colorless solution with a green or brown precipitate
resulted. Filtration through celite, concentration and purification
of the crude product by column chromatography on silica gel
(hexane/ethyl acetate 1:1), provided the pure product 412 (0.11
mmol, 18 mg) as a colorless oil in 58% yield and 93% ee.
(R)-1-phenylpropane-1,3-diol (4). 1H NMR (300 MHz,
CDCl3): δ = 1.85-2.04 (m, 2H), 2.88 (brs, 1H), 3.34 (brs, 1H),
3.81 (t, J = 5.4 Hz, 2H), 4.92 (dd, J = 3.9, 8.4 Hz, 1H), 7.23-7.35
(m, 5H); 13C NMR (75 MHz, CDCl3): δ = 40.5, 61.5, 74.4, 125.6
(×2), 127.6, 128.5 (×2), 144.3; HPLC (Chiralcel AD-H,
Hexane/i-propanol (97:3), flow rate = 1.0 mL min-1, λ = 210 nm):
tmajor = 35.0 min, tminor = 37.2 min.
3. Conclusions
In conclusion, we have developed an efficient approach for
enhancing the reactivity of benzaldehyde in the cross-aldol
reaction with acetaldehyde resulting from the deoligomerization
of paraldehyde. The tandem process is mediated by the dual
polymer-supported catalytic system 1/2, which operates under
site isolation conditions in a recyclable manner. The strategy
reported herein, involving η6-coordination to Cr(CO)3, has been
applied to overcome the challenges and limitation of cross-aldol
reaction of acetaldehyde with benzaldehyde, affording 1-
phenylpropane-1,3-diol in high yield and excellent
enantioselectivity. The crude, enantioenriched aldol 6 has been
applied to the development of very short formal syntheses of the
important drugs (R)-Fluoxetine and (R)-Atomoxetine.
4.2. General procedure for catalyst recycling
Catalyst 1 (10 mol%, 0.02 mmol, 6.7 mg), catalyst 2 (40
mol%, 0.08 mmol, 170.4 mg) and tricarbonyl (η6-benzaldehyde)
chromium (0) (0.2 mmol, 51.4 mg) were mixed in a brown vial
with acetonitrile (0.6 mL). Then paraldehyde (137 µL, 5.0 eq.,
1.0 mmol) and deionized water (1.8 µL, 0.1 mmol) were added
and the brown vial was sealed and shaken at room temperature.
After 72 h, the mixture was filtered and washed with acetonitrile
(3 × 1 mL), the filtrate being treated as described above to isolate
the desired compound. As for the mixed catalysts recovered, they
were washed with acetic acid (0.5 mL) and acetonitrile (4 × 1
mL), repeating this procedure several times until the solvent was
colorless. After that, the mixed catalysts were dried at 40 ºC
under vacuum for 6 h and then used in the next reaction.
4. Experimental
4.3. Synthesis and characterization of 7 and 815
4.1. Procedure for the cross-aldol reaction and decomplexation28
Catalyst 2 (40 mol%, 0.12 mmol, 255.6 mg), catalyst 1 (10
mol%, 0.03 mmol, 10.1 mg) and the tricarbonyl (η6-
benzaldehyde) chromium (0) (0.3 mmol, 77 mg) were mixed in a
brown vial with acetonitrile (0.9 mL). Then, paraldehyde (5.0 eq.,
206 µL, 1.5 mmol) and deionized water (2.7 µL, 0.15 mmol)
were added and the brown vial was sealed and shaken at room
temperature for 72 hours. After that, the reaction mixture was
filtered and washed with acetonitrile (3 × 1.2 mL) and AcOH
(15% in THF, 3 × 1.2 mL). The filtrates were combined and
crude product 5 was obtained after removal of the solvent under
vacuum. Then, this was dissolved in Et2O (25 mL) and the
resulting solution was exposed to air and light until a colorless
solution with a green or brown precipitate resulted. Filtration
through celite and concentration gave the crude product 6.
Catalyst 1 (10 mol%, 0.02 mmol, 6.7 mg), catalyst 2 (40
mol%, 0.08 mmol, 170.4 mg) and tricarbonyl (η6-benzaldehyde)
chromium (0) (0.2 mmol, 51.4 mg) were mixed in a brown vial
with acetonitrile (0.6 mL). Then paraldehyde (137 µL, 5.0 eq.,
1.0 mmol) and deionized water (1.8 µL, 0.1 mmol) were added
and the brown vial was sealed and shaken at room temperature
for 72 hours. After that the reaction mixture was filtered and
washed with methanol (3 × 0.8 mL). The filtrates were combined
and cooled to 0 ºC, then NaBH4 (37.8 mg, 1.0 mmol) was added
and the mixture was stirred for 20 minutes. After that, the
reaction was quenched with aqueous NH4Cl (2 mL) and extracted
with ethyl acetate (3 × 5 mL). The organic layer was then washed
with brine (2 mL), dried with anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The residue was dissolved

4
Tetrahedron
ACCEPTED MANUSCRIPT
Crude product 6 was dissolved in anhydrous THF (3 mL)
Appendix A. Supplementary Data
and methylamine (33 wt% in EtOH, 1.5 mmol, 140 mg) and
anhydrous Na2SO4 (2.1 mmol, 0.3 g) were added. The mixture
was stirred for 5 hours and then NaBH(OAc)3 (2.0 eq., 0.6 mmol,
127 mg) was added in portions. After stirring overnight, the
solution was quenched with saturated aqueous sodium
bicarbonate and extracted with ethyl acetate (3 × 8 mL). The
organic layer was washed with brine (2 mL) and dried with
anhydrous Na2SO4. Evaporation of the solvent under reduced
pressure gave the crude mixture, which was purified by fast
column chromatography on silica gel, with CH2Cl2/MeOH/
NH4OH mixtures as eluent. In this manner, 20 mg of 7 (0.12
mmol, 35% overall yield for three steps) were obtained as a
colorless oil with 95% ee (determined by chiral HPLC analysis of
their N-acetyl derivative according to a reported procedure34; see
ESI).
Supplementary data related to this article can be found at...
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Acknowledgments
Financial support from CERCA Programme/Generalitat de
Catalunya, MINECO (CTQ2015-69136-R and Severo Ochoa
Excellence Accreditation 2014–2018, SEV-2013-0319) and the
CELLEX Foundation is gratefully acknowledged.