Immobilization of cis-4-Hydroxydiphenylprolinol Silyl Ethers onto Polystyrene. Application in the Catalytic Enantioselective Synthesis of 5-Hydroxyisoxazolidines in Batch and Flow

Article abstract of DOI:10.1002/adsc.201800572

A new family of polystyrene-supported cis-4-hydroxydiphenylprolinol silyl ethers has been prepared, and the resulting polymers have been evaluated as organocatalysts to promote the tandem reaction between N-protected hydroxylamines and α,β-unsaturated aldehydes in batch and flow. The new PS-supported catalysts compare favorably with well-established immobilized J?rgensen-Hayashi catalysts, affording 5-hydroxyisoxazolidines as single diastereoisomers with high enantioselectivities and good yields (up to 83% yield, up to 99% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.201800572

Title: Immobilization of cis-4-Hydroxydiphenylprolinol Silyl Ethers
onto Polystyrene. Application in the Catalytic Enantioselective
Synthesis of 5-Hydroxyisoxazolidines in Batch and Flow
Authors: Junshan Lai, Sonia Sayalero, Alessandro Ferrali, Laura
Osorio-Planes, Fernando Bravo, Carles Rodríguez-Escrich,
and Miquel Àngel Pericàs
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800572
Link to VoR: http://dx.doi.org/10.1002/adsc.201800572

10.1002/adsc.201800572
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Immobilization of cis-4-Hydroxydiphenylprolinol Silyl Ethers onto
Polystyrene. Application in the Catalytic Enantioselective Synthesis of
5-Hydroxyisoxazolidines in Batch and Flow
Junshan Lai,a,c Sonia Sayalero,a Alessandro Ferrali,a Laura Osorio-Planes,a Fernando
Bravo,a Carles Rodríguez-Escrich*a and Miquel A. Pericàs*a,b
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països
Catalans, 16, 43007 Tarragona (Spain). crodriguez@iciq.es; mapericas@iciq.es; (+34) 977-920-200.
Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB), 08028 Barcelona (Spain).
Universitat Rovira i Virgili, Departament de Química Analítica i Química Orgànica, c/Marcel·lí Domingo, 1, 43007
b
c
Tarragona, Spain
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new family of polystyrene-supported cis-4- immobilized Jørgensen-Hayashi catalysts, affording 5-
hydroxydiphenylprolinol has been prepared, and the hydroxyisoxazolidines as single diastereoisomers with high
resulting polymers have been evaluated as organocatalysts to enantioselectivities and good yields (up to 83% yield, up to
promote the tandem reaction between N-protected 99% ee).
hydroxylamines and α,β-unsaturated aldehydes in batch and
Keywords: supported catalysts; organic catalysis; flow
flow. The new PS-supported catalysts compare favorably
chemistry; asymmetric catalysis; isoxazolidines
with well-established
techniques and Design of Experiments (DoE) we
were able identify the most promising catalysts for
Introduction
the aza-Michael addition and fine-tune the reaction
The development of asymmetric catalysis has
conditions to optimize yield and enantioselectivity.[6c]
significantly expanded the toolkit of synthetic
Encouraged by the behavior of the cis-derivatives,
chemists when tackling the preparation of optically
which performed better than their trans analogues,
enriched compounds.[1] The advent of organocatalysis,
we decided to study the immobilization of cis-4-
that arrived to complement biocatalysis and transition
hydroxyprolinol derivatives and establish a direct
metal-based approaches, has provided new
comparison with the trans series we have previously
opportunities to activate very reactive intermediates
reported (Figure 1).
in generally mild conditions. -Diarylprolinols,
generally known as Jørgensen-Hayashi catalysts, are
amongst the most successful aminocatalysts.[2] Their
HO
O
linker
main drawback is the high catalyst loadings usually
required as a consequence of unfavourable equilibria
and the formation of off-cycle species.[3] To address
this issue, our research group, as well as others, have
studied their immobilization in an attempt to increase
their lifespan.[4] In the cases where the anchoring
strategy has proven successful, the resulting solid-
supported Jørgensen-Hayashi catalysts display high
catalytic activity and selectivity, while being
recyclable and even amenable to application in
continuous flow.[5]
Ar
Ar
COOH
N
N
H
previous work
OSiR3
PG
trans-1
O
O
linker
O
Ar
Ar
N
N
H
this work
PG
OSiR3
cis-1
Recently, we reported the preparation of a family
of 37 modular cis-4-hydroxyprolinol derivatives
starting from trans-4-hydroxyproline. The synthesis
relied on the intermediacy of the bicyclic lactone
depicted in Figure 1 (previously described by
Joullié[6a]) to invert the stereochemistry at C4. With
the help of high-throughput-experimentation (HTE)
Figure 1. Immobilized cis- and trans-diarylprolinols.
Isoxazolidines[7] are valuable chiral building blocks
that can be easily converted to γ-amino alcohols,[8] β-
lactams[9] and β-amino acids,[10,7e,f] important
scaffolds for chemical and biological applications.
1
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10.1002/adsc.201800572
Advanced Synthesis & Catalysis
This has prompted several authors to develop novel
asymmetric methods for their preparation. For
instance, in 2000, MacMillan and co-workers were
the first to report an imidazolidinone-catalyzed
enantioselective synthesis of isoxazolidines that
relied on 1,3-dipolar cycloaddition reactions of an
iminium ion intermediate.[11] In 2007, Cόrdova
reported the preparation of 5-hydroxyisoxazolidines
mediated by -diarylprolinol TMS ether via an
asymmetric domino Michael reaction pathway
between N-protected hydroxylamines and enals,[12]
for which Wang later employed a spiranic catalyst[13]
(Scheme 1). In 2010, Zlotin and co-workers used
recoverable α,α-diarylprolinol-derived chiral ionic
liquids which could be easily recycled and reused
more than four times in this domino reaction.[14]
However, to the best of our knowledge, the
asymmetric organocatalytic synthesis of 5-
hydroxyisoxazolidines in flow remains unexplored.
mechanical stability of non-properly selected
supports can counterbalance the putative advantages
of easy recycling and reuse.[15] In our experience,
polystyrene resins have proven reliable in terms of
thermal and mechanical stability. In this context, the
implementation of flow processes entails a further
advantage because, once the resin is packed, the
beads are not shaken nor stirred. In light of the above-
mentioned, we thought the addition of hydroxylamine
derivatives to enals catalyzed by immobilized
diarylprolinol derivatives would be
a
good
benchmark to assess the relative merits of the cis and
trans series both in batch and flow.
Results and Discussion
In order to establish the catalytic behavior of the
supported cis-diarylprolinols, we prepared two
members of this family, bearing TMS and TBDMS
protecting groups, according to the sequence outlined
in Scheme 2. First, lactone 5[6] was treated with
phenylmagnesium chloride to generate the 2,4-cis
diphenylprolinol derivative 6. Propargylation of the
secondary alcohol took place with concomitant
oxazolidinone formation and the product 7 was then
hydrolyzed to the amino alcohol 8. This intermediate
was protected as a TMS (9) or TBS (10) ether which,
after immobilization via azide-alkyne cycloaddition
with azidomethyl-polystyrene, gave rise to resins 1b
and 1c, respectively with full functionalization.
PG
O
O
PG
OH
cat.
N
+
N
H
OH
R
R
2
3
4
Ph
Ph
Córdova
2007
Wang
2016
N
HN
H
OTMS
TBDPSO
Scheme 1. Organocatalytic isoxazolidine formation.
When dealing with supported catalysts, besides the
type of monomer and the immobilization strategy, the
choice of solid phase is crucial because poor
Scheme 2. Synthetic sequence for the preparation of resins 1b and 1c.
For the sake of comparison, we decided to evaluate
as well the activity of supported diarylprolinol
catalysts previously reported in our group, either
having a 2,4-trans array[5c] (1d) or prepared by co-
2
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10.1002/adsc.201800572
Advanced Synthesis & Catalysis
polymerization of a distyrylprolinol derivative[5e,16]
(1e,f). Finally, homogeneous cis-1g would also tested
in an attempt to assess the impact of the triazole
linker.
(entry 4). A direct comparison between 1c and 1d,
which differ only on the relative stereochemistry of
the pyrrolidine 2,4 substituents allows to establish the
superiority of the cis-derivatives over the trans ones
in terms of yield and enantioselectivity, at least for
this reaction. Although the catalytic activity of 1c is
only slightly better than that of 1d, as indicated by the
kinetics of comparative experiments (see SI), 1c has
the definitive advantage of its stereochemical
integrity, secured by the fixed configurational
arrangement of the pyrrolidine 2,4 substituents in
5.[6c-d] In addition, two catalysts prepared by co-
polymerization of a distyrylprolinol were submitted
to the reaction conditions: 1e (with a fluorine; entry
5) gave moderate enantioselectivity, whereas 1f,
bearing a silyl ether (entry 6), matched the ee’s of 1c,
albeit with a slightly lower activity. Finally, an
homogeneous analogue of 1c, without the triazole
(1g[6c] entry 7) was shown to behave similarly in
terms of yield and selectivity, which points out to a
steric rather than electronic effect of the linker. In
summary, the catalyst of choice for this reaction is 1c,
with a cis-2,4 arrangement and a TBS group.
Thus, the stage was set to run a comparative study
of catalysts 1a-1g (Table 1), placing special emphasis
on the stereochemistry at C4. The model reaction
selected was the addition of protected hydroxylamine
3a to cinnamaldehyde 2a, which afforded chiral 5-
hydroxyisoxazolidine 4aa via a tandem sequence
consisting of aza-Michael addition followed by
hemiacetalization. Preliminary tests run with 1b
established CHCl3 and rt as a good starting point to
optimize reaction conditions (see SI for details).
Table 1. Solid-supported catalyst screening for the
enantioselective formation of isoxazolidines.
During the investigation of this tandem reaction,
we found that the addition of acid had a significant
impact on the reaction rate and selectivity, leading in
most cases to full conversions in shorter times
(Scheme 3).[17] While strong acids like TFA or TsOH
completely shut down the catalytic activity, with less
acidic co-catalysts the ee value increased (acids 11c-
e) and full conversion was reached in 6 h. Among all
carboxylic acids tested, cinnamic acid turned out to
give the best enantioselectivity in CHCl3. Because of
the toxicity of CHCl3 which may limit the utilization
of the immobilized diarylprolinol in flow, we carried
out a similar screening in CH2Cl2 (see SI). In this
solvent, benzoic and cinnamic acid behave similarly;
given that the former is inexpensive, we established a
second set of conditions involving CH2Cl2 and
benzoic acid as an additive.
N
N
N
N
N
N
cis
cis
O
O
Ph
Ph
Ph
Ph
Ph
Ph
N
N
H
N
H
H
OTMS
OTBS
OTMS
1b
1c
1a
N
N
N
trans
O
BnO
Ph
Ph
Ph
Ph
N
H
N
N
H
H
OTBS
X
OTBS
1d
1e X = F
1f X = OTBS
1g
time
(h)
Conv.
(%)
Yield
(%)
ee
(%)
Entrya)
Cat.
1c
Cbz
O
O
(20 mol %)
Cbz
OH
N
1
2
3
4
5
6
7
6
6
7
99
99
100
98
100
97
98
65
80
76
71
74
68
89
90
95
92
76
95
93
1a
1b
1c
1d
1e
1f
N
H
OH
+
Ph
acid co-cat.
(20 mol %)
CHCl3, rt, 6 h
COOH
Ph
2a
3a
4aa
7
COOH
18
18
6
CF3COOH
p-TolSO3H
11a
11b
11c
11d
Me2N
70
1g
no conv.
no conv.
98% ee
96% ee
a)
1
Conversion and yield determined by H NMR using
mesitylene as an internal standard; for the functionalization
level of catalysts, see SI.
COOH
COOH
COOH
11e
93% ee
11g
97% ee
11f
95% ee
O2N
Br
NO2
According
to
literature
precedents,[12]
OMe
COOH
diarylprolinol TMS ether 1a proved competent in this
reaction (entry 1). In comparison, the supported
catalysts from the novel 2,4-cis series 1b and 1c
(bearing a TMS and a TBS group, respectively;
entries 2 and 3) displayed improved activity and
enantioselectivity. Interestingly, the results were also
better than those recorded for the trans analog 1d
COOH
COOH
no co-cat
N
Boc
11j
94% conv. in
30 h, 93% ee
11h
91% ee
11i
>99% ee
92% ee
a)
Scheme 3. Screening of the acidic co-catalyst.
Conv.
determined by 1H NMR using mesitylene as internal
3
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10.1002/adsc.201800572
Advanced Synthesis & Catalysis
standard; full conversion recorded with acids 11c-11j in 6
h.
be run for 10 consecutive cycles after simply filtering
and recovering the resin. As shown in Table 2, the
results obtained in the tenth cycle match those
recorded in the initial one, which bears witness of the
catalyst robustness. Indeed, the accumulated TON in
these ten runs was 36.5.
Thus, we decided to investigate the scope of the
catalytic asymmetric tandem reaction in batch using
immobilized diarylprolinol 1c with cinnamic acid as
additive in CHCl3 (Scheme 4, conditions A) or
benzoic acid as additive in CH2Cl2 (Scheme 4,
conditions B), in both cases at room temperature.
Encouraged by the robustness of the supported
catalyst, a family of α,β-unsaturated aldehydes was
submitted to the flow process with 3a or 3b as
reaction partners (Scheme 5). To this end, a packed
bed reactor was filled with catalyst 1c (1.00 g, 0.41
mmol) and two channels were used to feed the
reagents through the system. Due to compatibility
issues, the first contained a solution of 2 while the
second had a mixture of hydroxylamine 3 and
benzoic acid (11d); the use of a single syringe pump
equipped with two syringe slots ensured that both
flow rates were equal. For each experiment, 9.84
mmol of 2 were passed through the packed bed
reactor, at a combined flow rate of 100 μL min–1.
When the solutions of starting materials were
consumed, the column was rinsed with CH2Cl2 to
remove all organic products.
Indeed,
β-substituted
enals
provided
the
corresponding 5-hydroxyisoxazolidines 4 as single
diastereoisomers with high enantioselectivities and
moderate to good yields (34-83% yield, 71–99% ee).
Moreover, the reactions with N-Boc-NHOH 3b gave
the corresponding products in 51–74% yield and in
71–99% ee. Cinnamaldehyde and its derivatives
containing halogen atoms (F or Cl) or a nitro group at
the para-position of the aromatic ring afforded the
desired isoxazolidines in a short time. Introduction of
a group in the ortho-position or the presence of a
methoxy group at the para-position slowed down the
reaction.
Cond. A: 1c, 11i
Table 2. Study of the catalyst recyclability.
R2
O
O
R2
CHCl3, rt
OH
N
N
OH
+
H
R1
R1
Cond. B: 1c, 11d
2a-g
3a R2 = Cbz
3b R2 = Boc
4aa-4ha
4ab-4gb
CH2Cl2, rt
Cbz
Boc
O
Cbz
O
O
N
N
N
OH
OH
OH
Run
1
2
3
4
5
6
7
8
Conv. (%)
Yield (%)
ee (%)
94
95
95
96
95
96
96
96
98
97
97
97
96
97
97
96
92
91
73
79
89
80
71
68
65
72
64
69
Cl
4aa
4ab
4ba
a 6 h, 82%, 99% ee
b 7 h, 73%, 97% ee
a 6 h, 74%, 99% ee
b 7 h, 74%, 99% ee
a 6 h, 82%, 96% ee
b 7 h, 71%, 98% ee
Cbz
Boc
O
Cbz
Boc
O O
N
O
N
N
N
OH
OH
OH
OH
O2N
Cl
F
F
4bb
4ca
4cb
4da
a 6 h, 79%, 99% ee a 6 h, 82%, 97% ee a 16 h, 51%, 94% ee
b 7 h, 76%, 99% ee b 7 h, 72%, 93% ee b 16 h, 75%, 87% ee
a 6 h, 82%, 95% ee
b 7 h, 63%, 96% ee
Boc
Cbz
O
O
Cbz
Boc
N
O
O
N
N
N
9
10
96
96
OH
OH
OH
OH
O2N
NO2
MeO
MeO
4db
4ea
4eb
4fa
a 16 h, 55%, 96% ee
b 16 h, 68%, 94% ee
a 16 h, 83%, 86% ee a 16 h, 76%, 96% ee
b 16 h, 60%, 86% ee b 16 h, 51%, 71% ee
With this sequential approach, up to ten different
5-hydroxyisoxazolidines were prepared with
a 16 h, 34%, 95% ee
b 16 h, 55%, 94% ee
Boc
O
Cbz
Boc
Cbz
O
O
O
N
N
N
N
excellent enantioselectivities and moderate to good
yields. As shown in Scheme 5, cinnamaldehyde and
its electron poor derivatives afforded the
corresponding products in good yields and excellent
ee’s working at 100 μL min–1. On the other hand, the
slower kinetics observed for 2e forced us to lower the
flow rate to 50 μL min–1; under these conditions, even
if the yields were not fully satisfactory, the
enantioselectivities remained excellent. Overall, the
accumulated TON in these flow processes was of 134.
Remarkably, the same packed bed reactor was used
for all the flow experiments (preliminary runs and
scope), carried out within a period of 2 months
without apparent decrease in performance.
OH
OH
OH
OH
Me
Me
NO2
O
O
Me
4ga
4gb
4fb
4ha
a 16 h, 40%, 96% ee a 24 h, 60%, 98% ee a 24 h, 43%, 96% ee
b 7 h, 72%, 92% ee
b 16 h, 64%, 95% ee
b 24 h, 66%, 92% ee b 24 h, 65%, 80% ee
a)
Scheme 4. Scope of the catalytic reaction in batch.
Reaction conditions: 2 (0.05 mmol, 1 eq.), 3 (10 mg, 0.06
mmol, 1.2 eq.), 1c (23 mg, 20 mol %), 11i (1.5 mg, 20
mol %), CHCl3 (0.25 mL), rt. Reactions run in CH2Cl2
(0.5 mmol of 2) with 11d (12 mg, 20 mol %) as co-catalyst.
b
The good results recorded prompted us to study the
recyclability of the catalyst in batch. To our delight,
the reaction between 2a and 3a catalyzed by 1c could
4
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10.1002/adsc.201800572
Advanced Synthesis & Catalysis
50 µL min-1
O
R1
R2
O
N
Two-channel
syringe pump
cat. 1c
OH
R2
OH
R1
N
H
Cat. 1c
(1.0 g, 0.41 mmol)
+
PhCOOH
50 µL min-1
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Cbz
Cbz
Cbz
Cbz
O
O
O
O
N
N
N
N
OH
OH
OH
OH
4da
67%, 95% ee
4aa
67%, 95% ee
4ba
65%, 95% ee
4ca
57%, 95% ee
Cl
F
O2N
Boc
Cbz
Boc
Boc
Cbz
O
O
O
O
O
N
N
N
N
N
OH
OH
OH
OH
OH
MeO
Cl
O2N
4ea
21%, 90% ee
4ab
59%, 99% ee
4bb
61%, 99% ee
4db
55%, 94% ee
4aa
36%, 95% ee
Scheme 5. Set-up and results of the continuous flow reaction promoted by 1c.
In summary, a solid-supported organocatalyst has
been applied to the enantioselective domino reaction
between α,β-unsaturated aldehydes and N-protected
hydroxylamines in batch and flow. Immobilized
diarylprolinol 1c, has afforded the best results while
proving remarkably stable under the reaction
conditions. This has allowed to run ten consecutive
cycles of the same reaction, providing the same
enantioselectivity and without significant loss of
yield. In addition, eleven flow experiments involving
nine different substrates have been carried out over a
period of 2 months with the same packed column.
Finally, a sequence consisting of oxidation and
continuous flow hydrogenation allowed the
preparation of β-amino acids, thus proving the
synthetic potential of this methodology.
The synthetic versatility of the products was
demonstrated by taking the crude mixture from one
of the reactions and submitting it to oxidation to
furnish isoxazolidinone 12 (Scheme 6). Even more
interestingly, this could be reduced to a -amino acid
in a continuous flow experiment carried out with a H-
cube reactor (90 atm of H2, 0.5 mL min–1, 50 °C) that
involved N-O bond reduction and hydrogenolysis of
the Cbz protecting group. Remarkably, this allows the
generation of enantioenriched -amino acids in only
three steps, two of which are carried out in a
continuous flow manner. Moreover, the use of the H-
cube enables to carry out the reduction without a
bottle of gaseous hydrogen (it is generated in situ
from water), which greatly improves the safety
profile of the procedure.
Experimental Section
Preparation of immobilized 2,4-cis-diarylprolinols
1b,1c
A solution of the lactone 5[6] (1.377 g, 6.46 mmol) in dry
THF (38 ml) under Ar was cooled to 0 °C and PhMgCl
(2.0 M in THF, 6.5 ml, 12.92 mmol) was added dropwise.
The mixture was stirred for 2 h (conversion was checked
by TLC). Then, the reaction mixture was quenched with aq.
sat. NH4Cl (50 mL), the layers were separated, the aqueous
phase was extracted with TBME (3 x 40 mL) and dried
Scheme 6. Derivatization of Product 4aa.
Conclusion
over
Na2SO4.
Purification
by
flash
column
chromatography (Cy/EtOAc 80:20 - 70:30 - 65:35 - 60:40)
gave 2.11 g of product 6 (88% yield).
5
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10.1002/adsc.201800572
Advanced Synthesis & Catalysis
tert-Butyl
(2S,4S)-4-hydroxy-2-(hydroxydiphenylme-
layer was extracted with EtOAc (3 x 20 mL). The
combined organic extracts were dried over Na2SO4 and
thyl)pyrrolidine-1-carboxylate (6). White solid. Melting
25
point: 197.3-199.5. Rf: 0.30 (Cy/EtOAc 60:40). [α]D
=
concentrated
under
reduced
pressure.
Flash
1
+122.3 (c 1.00, DCM). H NMR (400, CDCl3): δ = 7.52-
7.48 (m, 2H), 7.41-7.35 (m, 4H), 7.33-7.28 (m, 1H), 7.26-
7.17 (m, 3H), 4.92 (d, J = 9.1 Hz, 1H), 4.54 (br s, 1H),
4.35 (br s, 1H), 4.20-3.70 (br s, 2H), 3.33 (br s, 1H), 2.30
(ddd, J = 14.6, 9.3, 7.6 Hz, 1H), 1.82 (d, J = 14.6 Hz, 1H),
1.14 (br s, 9H). 13C NMR (100.4, CDCl3): δ = 154.8, 145.0,
144.7, 128.2 (2C), 127.8 (2C), 127.2, 127.1 (3C), 126.9
(2C), 81.4, 79.7, 70.1, 64.7, 57.1, 38.2, 27.9 (3C). HRMS
(ESI+): calcd for C22H27NNaO4 [M+Na]+: 392.1832,
found: 392.1840.
chromatography on silica gel with 2.5% Et3N (Cy/EtOAc
50:50) afforded 282 mg of the silylated product 9 (91%
yield, 0.813 mmol).
(2S,4S)-2-(Diphenyl((trimethylsilyl)oxy)methyl)-4-
(prop-2-yn-1-yloxy)pyrrolidine (9). Colourless oil. Rf:
25
1
0.42 (Cy/EtOAc 80:20). [α]D = −50.0 (c 1.00, DCM). H
NMR (400 MHz, CDCl3): δ = 7.51-7.47 (m, 2H), 7.35-
7.31 (m, 2H), 7.29-7.18 (m, 6H), 4.14 (dtd, J = 6.7, 5.2, 3.0
Hz, 1H), 3.98 (dd, J = 15.8, 2.4 Hz, 1H), 3.92 (dd, J = 15.8,
2.4 Hz, 1H), 3.89 (dd, J = 9.3, 6.9 Hz, 1H), 3.01 (ddd, J =
12.0, 3.1, 1.0 Hz, 1H), 2.94 (dd, J = 12.0, 5.6 Hz, 1H), 2.34
(t, J = 2.4 Hz, 1H), 1.82 (br s, 1H), 1.74 (dt, J = 13.5, 6.9
Hz, 1H), 1.58 (dddd, J = 13.5, 9.4, 4.9, 1.0 Hz, 1H), −0.08
(s, 9H). 13C NMR (100.4 MHz, CDCl3): δ = 146.8, 145.2,
128.7 (2C), 127.7 (2C), 127.6 (2C), 127.2 (2C), 127.1,
126.8, 82.4, 80.0, 78.6, 73.8, 65.8, 55.8, 53.2, 34.6, 2.1
(3C). HRMS (ESI+): calcd. for C23H30NO2Si [M+H]+:
380.2040, found: 380.2050.
A suspension of NaH (60% in mineral oil, 0.200 g, 5.0
mmol) in 9 mL of anhydrous DMF under N2 was cooled to
–25 °C (internal temperature) and a solution of alcohol 6
(0.924 g, 2.5 mmol) in 7 mL of DMF was added dropwise.
The mixture was stirred at this temperature for 20 min and
then propargyl bromide (80% in toluene, 0.28 mL, 2.5
mmol) was added dropwise. The resulting mixture was
stirred at 0 °C for 1 h and then brought to RT. When TLC
analysis showed complete conversion of the starting
material, 35 mL of NH4Cl were added and it was extracted
with EtOAc (3 × 60 mL). the combined organic phases
were dried over Na2SO4 and concentrated in vacuo.
Purification by flash column chromatography (Cy/EtOAc
90:10 to 60:40) gave the propargylated derivative 7 in 80%
yield (0.668 g, 2.00 mmol) as a white solid.
Azidomethylpolystyrene (f = 0.60, 5.90 g, 3.52 mmol) was
suspended in DMF (53 ml) and THF (53 ml). Then,
DIPEA (6.1 ml, 35.2 mmol) and copper(I) iodide (34 mg,
0.176 mmol) were added, followed by a solution of the
alkyne 9 (1.61 g, 4.23 mmol) in the same solvent mixture
(via cannula). The resulting mixture was shaken overnight
at 40 ºC. The next morning, after checking a small aliquot
by IR to confirm full conversion, the resin 1b was filtered
and washed with water, water/MeOH, MeOH,
MeOH/CH2Cl2 and CH2Cl2. Then, it was dried overnight in
the vacuum oven at 40 °C.
(6S,7aS)-1,1-Diphenyl-6-(prop-2-yn-1-yloxy)tetrahy-
dro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (7). White solid.
Melting point: 140.0-141.8. Rf: 0.27 (Cy/EtOAc 70:30).
25
1
[α]D = −209.8 (c 1.00, DCM). H NMR (400, CDCl3): δ
= 7.53-7.48 (m, 2H), 7.38-7.25 (m, 8H), 4.64 (dd, J = 9.0,
7.1 Hz, 1H), 4.41 (qd, J = 5.9, 3.2 Hz, 1H), 4.04 (dd, J =
16.1, 2.4 Hz, 1H), 3.96 (dd, J = 16.1, 2.4 Hz, 1H), 3.89 (dd,
J = 12.6, 3.2 Hz, 1H), 3.30 (dd, J = 12.6, 5.9 Hz, 1H), 2.39
(t, J = 2.4 Hz, 1H), 2.09 (ddd, J = 13.4, 7.1, 6.2 Hz, 1H),
1.42 (dddd, J = 13.5, 9.1, 5.4, 0.8 Hz, 1H). 13C NMR
(125.0, CDCl3): δ = 160.3, 143.2, 139.9, 128.6 (2C), 128.4
(2C), 128.3, 127.8, 126.0 (2C), 125.7 (2C), 86.2, 79.0, 78.0,
74.9, 67.4, 56.3, 52.0, 35.5. HRMS (ESI+): calcd. for
C21H19NNaO3 [M+Na]+: 356.1257, found: 356.1251.
fmax = 0.49; f = 0.49 (based on N Elemental Analysis).
Complete functionalization.
A solution of the diphenylprolinol derivative 8 (350 mg,
1.139 mmol) in DCE (5.5 mL) under Ar was cooled to
0 °C and treated with 2,6-lutidine (1.05 mL, 9.11 mmol)
and TBSOTf (1.05 mL, 4.55 mmol). Then, it was heated at
reflux overnight under vigorous stirring. The next morning,
the reaction mixture was quenched with sat. aq. NH4Cl (25
mL) and the aqueous layer was extracted with CH2Cl2 (3 ×
25 mL). The combined organic extracts were dried over
Na2SO4 and concentrated under reduced pressure.
Purification by flash chromatography on silica gel with
2.5% Et3N (Cy/EtOAc 90:10) gave silyl ether 10 in 63%
yield (302 mg, 1.14 mmol).
A solution of the oxazolidinone 7 (503 mg, 1.51 mmol) in
EtOH (11 mL) was treated with a solution of KOH (423
mg, 7.54 mmol) in water (0.8 M). The mixture was heated
at reflux overnight turning from a slurry to a clear
yellowish solution. The next morning, TLC analysis
(Cy/EA 50:50) shows that the starting material has
disappeared, so the reaction mixture is concentrated in
vacuo. The resulting slurry is diluted with water, extracted
with EtOAc (3 × 25 mL), dried over Na2SO4 and
evaporated. Purification by flash column chromatography
gave 456 mg (1.51 mmol) of the amino alcohol 8 (98%).
(2S,4S)-2-(((tert-Butyldimethylsilyl)oxy)diphenylme-
thyl)-4-(prop-2-yn-1-yloxy)pyrrolidine (10). yellow oil.
Rf: 0.28 (Cy/EtOAc 80:20). [α]D25 = −33.3 (c 1.00, DCM).
1H NMR (400 MHz, CDCl3): δ = 7.61-7.55 (m, 2H), 7.38-
7.32 (m, 2H), 7.32-7.22 (m, 6H), 4.13 (dtd, J = 6.8, 5.0, 3.2
Hz, 1H), 3.95 (dd, J = 15.8, 2.4 Hz, 1H), 3.89 (dd, J = 15.8,
2.4 Hz, 1H), 3.88 (dd, J = 9.5, 7.0 Hz, 1H), 2.99-2.89 (m,
2H), 2.34 (t, J = 2.4 Hz, 1H), 1.92 (br s, 1H), 1.77 (dt, J =
13.6, 6.9 Hz, 1H), 1.56 (ddd, J = 13.6, 9.7, 4.7 Hz, 1H),
0.99 (s, 9H), −0.12 (s, 3H), −0.51 (s, 3H). 13C NMR (100.4
MHz, CDCl3): δ = 146.5, 144.8, 129.5, 127.7 (2C), 127.6
(2C), 127.4 (2C), 127.3 (2C), 126.9, 82.2, 80.0, 78.5, 73.7,
66.1, 55.7, 53.2, 35.0, 26.3 (3C), 19.1, −2.5, −3.6. HRMS
(ESI+): calcd for C26H36O2 [M+H]+: 422.2510, found:
422.2513.
Diphenyl((2S,4S)-4-(prop-2-yn-1-yloxy)pyrrolidin-2-
25
yl)methanol (8). Colourless oil. [α]D = −44.5 (c 1.00,
1
DCM). H NMR (400 MHz, CDCl3): δ = 7.62-7.56 (m,
2H), 7.53-7.47 (m, 2H), 7.32-7.25 (m, 4H), 7.20-7.14 (m,
2H), 4.32 (dd, J = 8.2, 7.1 Hz, 1H), 4.23 (dddd, J = 6.1, 5.1,
3.7, 2.3 Hz, 1H), 4.15 (dd, J = 15.9, 2.4 Hz, 1H), 4.08 (dd,
J = 15.9, 2.4 Hz, 1H), 3.16 (ddd, J = 10.9, 2.3, 1.4 Hz, 1H),
3.04 (dd, J = 10.9, 5.1 Hz, 1H), 2.38 (t, J = 2.4 Hz, 1H),
1.90 (ddd, J = 14.4, 8.2, 6.3 Hz, 1H), 1.80 (dddd, J = 14.1,
7.1, 3.7, 1.4 Hz, 1H). 13C NMR (100.4 MHz, CDCl3): δ =
147.2, 145.4, 128.2 (2C), 128.0 (2C), 126.5, 126.4, 125.9
(2C), 125.5 (2C), 79.7, 77.6, 76.9, 74.2, 63.8, 55.8, 51.9,
32.6. HRMS (ESI+): calcd for C20H22NO2 [M+H]+:
308.1645, found: 308.1641.
Azidomethylpolystyrene (f = 0.509, 6 g, 3.05 mmol) was
suspended in DMF (46 ml) and THF (46 ml). Then,
DIPEA (5.3 ml, 30.5 mmol) and copper(I) iodide (29 mg,
0.153 mmol) were added, followed by a solution of the
alkyne (1.545 g, 3.66 mmol) in the same solvent mixture
(via cannula). The resulting mixture was shaken overnight
at 40 ºC. The next morning, after checking a small aliquot
by IR to confirm full conversion, the resin 1c was filtered
and washed with water, water/MeOH, MeOH,
MeOH/CH2Cl2 and CH2Cl2. Then, it was dried overnight in
the vacuum oven at 40 °C.
A solution of the amino alcohol 8 (250 mg, 0.813 mmol) in
CH2Cl2 (8133 µl) was cooled to 0 °C. Then, imidazole
(166 mg, 2.440 mmol) and chlorotrimethylsilane (258 µl,
2.033 mmol) were sequentially added. The solution was
then allowed to reach 0 °C and stirred at this temperature
for 3 h. Then, it was quenched with water and the aqueous
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800572
Advanced Synthesis & Catalysis
fmax = 0.42; f = 0.41 (based on N Elemental Analysis).
(ddd, J = 12.6, 8.2, 4.5 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 159.3, 141.4, 135.6, 128.6 (x2), 128.4 (x2), 128.1,
127.7 (x2), 127.4, 126.0 (x2), 98.8, 68.1, 61.3, 45.3. IR
(neat): 3362, 3063, 3032, 2860,1707, 1496, 1453, 1390,
Complete functionalization.
General Procedures for the Batch Experiments
Conditions A
25
1301, 1238, 1027, 902, 754, 696 cm–1. [α]D = –29.5 (c =
1.0, CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-
PrOH = 90:10, flow rate 1.0 mL/min, λ = 210 nm): major
isomer: tR = 13.2 min; minor isomer: tR = 15.3 min.
To a 2 mL glass vial were sequentially added PS-catalyst
1c (f = 0.41 mmol/g, 0.01mmol, 23 mg, 20 mol % loading),
0.25 mL CHCl3 and 11i (1.5 mg, 20 mol %), followed by 2
(1 eq., 0.05 mmol) and 3 (1.2 eq., 0.06 mmol) at room
temperature. The reaction mixture was shaken until TLC
analysis showed consumption of the enal (for reaction
times, see Scheme 4). Then, it was filtered and the resin
beads were washed with DCM (5 x 0.25 mL). The solvent
was concentrated under reduced pressure and the product
was isolated after purification by column chromatography
on silica gel with cyclohexane/ethyl acetate (EtOAc/c-Hex
= 1:5) to yield 4.
tert-Butyl (3S,5S)-5-hydroxy-3-phenylisoxazolidine-2-
carboxylate (4ab).[12] 1H NMR (400 MHz, CDCl3) δ 7.34
(d, J = 4.4 Hz, 4H), 7.26 (dd, J = 8.2, 4.5 Hz, 1H), 5.92 (d,
J = 4.0 Hz, 1H), 5.29 (dd, J = 8.9, 7.7 Hz, 1H), 2.76 (dd, J
= 12.5, 8.3 Hz, 1H), 2.33-2.21 (m, 1H), 1.42 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 158.8, 142.1, 128.5 (x2), 127.2,
126.1 (x2), 98.6, 82.5, 61.4, 45.3, 28.1 (x3). IR (neat):
3347, 2977, 2933, 1703, 1456, 1367, 1346, 1316, 1247,
25
1162, 1070, 911, 848, 758, 697 cm–1. [α]D = –15.2 (c =
1.0, CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-
PrOH = 90:10, flow rate 1.0 mL/min, λ = 210 nm): major
isomer: tR = 6.3 min; minor isomer: tR = 7.5 min.
Conditions B
Benzyl (3S,5S)-3-(4-chlorophenyl)-5-hydroxyisoxazoli-
1
To a 5 mL glass vial were sequentially added PS-catalyst
1c (f = 0.41 mmol/g, 0.1 mmol, 232 mg, 20 mol %
loading), 2.5 mL CH2Cl2 and 11d (12 mg, 0.1mmol, 20
mol %), followed by 2 (1 eq., 0.5 mmol) and 3 (1.2 eq., 0.6
mmol) at room temperature. The reaction mixture was
shaken until TLC analysis showed consumption of the enal
(for reaction times, see Scheme 4). Then, it was filtered
and the resin beads were washed with DCM (8 x 1.5 mL).
The solvent was concentrated under reduced pressure and
the product was isolated after purification by column
chromatography on silica gel with cyclohexane/ethyl
acetate (EtOAc/c-Hex = 1:5) to yield 4.
dine-2-carboxylate (4ba). H NMR (400 MHz, CDCl3) δ
7.40-7.21 (m, 9H), 5.94-5.83 (m, 1H), 5.38 (t, J = 8.2 Hz,
1H), 5.21 (s, 2H), 2.80 (dd, J = 12.6, 8.4 Hz, 1H), 2.33-
2.21 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 159.1, 139.9,
135.5, 133.2, 128.8 (x3), 128.4 (x2), 128.2, 127.8, 127.4
(x2), 98.7, 68.2, 60.8, 45.2. IR (neat): 3356, 3033, 2961,
1707, 1492, 1391, 1296, 1237, 1087, 1014, 903, 825, 736,
696 cm–1. HRMS (ESI): m/z: [M+Na]+ (C17H16ClNNaO4),
calcd.: 356.0660; found: 356.0660. [α]D25 = –33.2 (c = 1.0,
CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
90:10, flow rate 1.0 mL/min, λ = 210 nm): major isomer:
tR = 14.911 min; minor isomer: tR = 17.611 min.
General Procedure for the Flow Experiments
tert-Butyl (3S,5S)-3-(4-chlorophenyl)-5-hydroxyisoxa-
zolidine-2-carboxylate (4bb).[12] 1H NMR (400 MHz,
CDCl3) δ 7.36-7.22 (m, 4H), 5.91 (d, J = 4.4 Hz, 1H), 5.27
(t, J = 8.3 Hz, 1H), 2.76 (dd, J = 12.4, 8.3 Hz, 1H), 2.22
(ddd, J = 12.6, 8.5, 4.4 Hz, 1H), 1.43 (s, 9H). 13C NMR
(126 MHz, CDCl3) δ 158.7, 140.6, 133.1, 128.7 (x2), 127.5
(x2), 98.6, 82.8, 60.9, 45.3, 28.1 (x3). IR (neat): 3378,
2979, 2931, 2854, 1702, 1491, 1351, 1325, 1249, 1163,
1089, 1014, 956, 907, 847, 821, 769 cm–1. [α]D25 = –14.6 (c
= 1.0, CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-
PrOH = 98:2, flow rate 1.0 mL/min, λ = 210 nm): minor
isomer: tR = 22.3 min; major isomer: tR = 24.7 min.
Using the set-up depicted in Scheme 5, the packed bed
reactor (Omnifit glass column, 10 mm Ø) was filled with
1.0 g of catalyst 1c, which was swollen by pumping
CH2Cl2 at 0.1 mL min–1 for one hour. The reagents were
then introduced in the system in two separate streams (50
µL min–1 each unless otherwise stated) using a dual syringe
pump: (a) containing 2 (0.4 M, 1.0 eq) in 21.5 mL of
CH2Cl2 and (b) containing a mixture of 3 (0.48 M, 1.2 eq.)
and PhCOOH in 21.5 mL of CH2Cl2. When the solutions
of reagents were consumed, the packed bed reactor was
rinsed with CH2Cl2 at 0.1 mL min–1 for 2 h. The collected
outstream was concentrated under reduced pressure and
purified by column chromatography on silica gel with
cyclohexane/ethyl acetate (EtOAc/c-Hex 1:5) to yield the
corresponding product 4.
Benzyl (3S,5S)-3-(4-fluorophenyl)-5-hydroxyisoxazoli-
1
dine-2-carboxylate (4ca). H NMR (400 MHz, CDCl3) δ
7.35-7.15 (m, 7H), 7.00 (t, J = 8.7 Hz, 2H), 5.84 (d, J = 4.2
Hz, 1H), 5.34 (t, J = 8.2 Hz, 1H), 5.17 (s, 2H), 2.76 (dd, J
= 12.6, 8.4 Hz, 1H), 2.24 (ddd, J = 12.6, 8.1, 4.5 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 162.1 (d, J = 245.8 Hz),
159.2, 137.1 (d, J = 3.1 Hz), 135.5, 128.4 (x2), 128.2,
127.8 (x2), 127.7 (x2, d, J = 8.0 Hz), 115.5 (x2, d, J = 21.6
Hz), 98.7, 68.2, 60.8, 45.3. 19F NMR (376 MHz, CDCl3) δ
–115.1. IR (neat): 3367 (s), 3035, 2962, 1709, 1605, 1509,
1454, 1390, 1297, 1224, 1070, 905, 835, 736, 697 cm–1.
HRMS (ESI): m/z: [M+Na]+ (C17H16FNNaO4), calcd.:
Preparation of -Amino Acid Hydrochloride 13
To a 25 mL round-bottom flask were sequentially added
4aa (1.50 g, 5 mmol), tert-butanol (8 mL), H2O (4 mL), 2-
methylbut-2-ene (2 mL), KH2PO4 (1088 mg, 8 mmol),
NaClO2 (720 mg, 8 mmol). The reaction mixture was
stirred at room temperature for 16 h and then it was
washed with saturated Na2SO3 and concentrated under
reduced pressure. The residue obtained was dissolved in
MeOH (200 mL), filtered to remove insoluble material and
circulated through the H-Cube at 0.5 mL min–1 flow rate
25
340.0956; found: 340.0961. [α]D = –33.2 (c = 1.0,
CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
90:10, flow rate 1.0 mL/min, λ = 210 nm): major isomer:
tR = 13.3 min; minor isomer: tR = 15.8 min.
o
(90 atm, 50 C). The outstream collected was concentrated
tert-Butyl (3S,5S)-3-(4-fluorophenyl)-5-hydroxyisoxazo-
lidine-2-carboxylate (4cb). 1H NMR (400 MHz, CDCl3) δ
7.37-7.26 (m, 2H), 7.10-6.99 (m, 2H), 5.93-5.82 (m, 1H),
5.29 (t, J = 8.3 Hz, 1H), 2.77 (dd, J = 12.5, 8.3 Hz, 1H),
2.26 (dddd, J = 12.6, 8.3, 4.4, 1.7 Hz, 1H), 1.45 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 162.1 (d, J = 245.41),
158.6, 137.8 (d, J = 3.2), 127.7 (x2, d, J = 8.1), 115.4 (x2,
d, J = 21.5), 98.5, 82.6, 60.8, 45.4, 28.1 (x3). 19F NMR
(376 MHz, CDCl3) δ –115.52. IR (neat): 3395, 2979, 2935,
1714, 1604, 1367, 1321, 1248, 1221, 1155, 1069, 910, 833,
766, 551 cm–1. HRMS (ESI): m/z: [M+Na]+
(C14H18FNO4Na), calcd.: 306.1112; found: 306.1112.
in vacuo and the residue was washed with 2 M HCl in
diethyl ether (10 mL), then with diethyl ether (5 x 10 mL),
to give hydrochloride 13 in 67% yield (673 mg, 3.35
mmol).
Compound Characterization Data
Benzyl
(3S,5S)-5-hydroxy-3-phenylisoxazolidine-2-
carboxylate (4aa).[12] 1H NMR (400 MHz, CDCl3) δ 7.37-
7.17 (m, 10H), 5.91 (d, J = 4.4 Hz, 1H), 5.38 (t, J = 8.2 Hz,
1H), 5.17 (s, 2H), 2.79 (dd, J = 12.6, 8.4 Hz, 1H), 2.30
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800572
Advanced Synthesis & Catalysis
25
[α]D = –10.7 (c = 1.0, CHCl3). HPLC (Daicel Chiralpak
[M+Na]+ (C172H5 16N2NaO6), Calcd.: 367.0901. Found:
367.0910. [α]D = +67.7 (c = 1.0, CHCl3). HPLC (Daicel
Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate 1.0
mL/min, λ = 210 nm): major isomer: tR = 11.3 min; minor
isomer: tR = 14.7 min.
AD-H, hexane/i-PrOH = 90:10, flow rate 1.0 mL/min, λ =
210 nm): major isomer: tR = 9.3 min; minor isomer: tR =
11.3 min.
Benzyl
(3S,5S)-5-hydroxy-3-(4-nitrophenyl)isoxazoli-
dine-2-carboxylate (4da).[12] 1H NMR (400 MHz, CDCl3)
δ 8.17 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.37-
7.16 (m, 5H), 5.94 (d, J = 4.2 Hz, 1H), 5.48 (t, J = 8.3 Hz,
1H), 5.18 (s, 2H), 2.87 (dd, J = 12.5, 8.5 Hz, 1H), 2.25
(ddd, J = 12.5, 8.2, 4.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 159.1, 148.6, 147.2, 135.1, 128.4 (x2), 128.3,
127.8 (x2), 126.8 (x2), 123.9 (x2), 98.7, 68.5, 60.8, 45.0.
tert-Butyl (3S,5S)-5-hydroxy-3-(2-nitrophenyl)isoxazoli-
1
dine-2-carboxylate (4fb). H NMR (400 MHz, CDCl3) δ
7.89 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.60-
7.50 (m, 1H), 7.42-7.28 (m, 1H), 5.92-5.76 (m, 2H), 3.01
(dd, J = 12.7, 8.4 Hz, 1H), 2.10 (ddd, J = 7.9, 4.6, 2.1 Hz,
1H), 1.32 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 158.1,
147.6, 138.2, 133.9, 128.1(x2), 124.4, 98.8, 83.1, 58.4,
IR (neat): 3363, 2958, 2837, 1706, 1612, 1513, 1455, 1392, 45.3, 28.0 (x3). IR (neat): 3348, 2977, 2927, 2854, 1707,
1319, 1290, 1243, 1113, 1029, 903, 849, 747, 695 cm–1.
1345, 1244, 1138, 1066, 958, 913, 848, 788, 744 cm–1.
HRMS (ESI): m/z: [M+Na]+ (C17H16N2NaO6), calcd.:
HRMS (ESI): m/z: [M+Na]+ (C14H18N2NaO6), calcd.:
25
25
367.0901; found: 367.0903. [α]D = –40.5 (c = 1.0,
333.1057; found: 333.1059. [α]D = +83.4 (c = 1.0,
CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 210 nm): minor isomer:
tR = 19.7 min; major isomer: tR = 22.1 min.
CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
95:5, flow rate 1.0 mL/min, λ = 210 nm): minor isomer: tR
= 19.0 min; major isomer: tR = 20.2 min.
tert-Butyl (3S,5S)-5-hydroxy-3-(4-nitrophenyl)isoxazoli-
dine-2-carboxylate (4db).[12] 1H NMR (400 MHz, CDCl3)
Benzyl (3S,5S)-5-hydroxy-3-(2-methoxyphenyl)isoxazo-
lidine-2-carboxylate (4ga). 1H NMR (400 MHz, CDCl3) δ
δ 8.22 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 5.94 (d, 7.42 (d, J = 7.6 Hz, 1H), 7.32-7.18 (m, 6H), 6.94 (t, J = 7.5
J = 4.3 Hz, 1H), 5.40 (t, J = 8.4 Hz, 1H), 2.85 (dd, J = 12.4, Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.81 (s, 1H), 5.72 (t, J =
8.4 Hz, 1H), 2.23 (ddd, J = 12.6, 8.5, 4.4 Hz, 1H), 1.44 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 158.6, 149.4, 147.25,
126.9 (x2), 123.9 (x2), 98.5, 83.3, 61.0, 45.1, 28.0 (x3). IR
(neat): 3329, 2960, 2931, 2840, 1702, 1614, 1514, 1455,
1368, 1336, 1299, 1246, 1159, 1088, 1064, 1032, 965, 913,
868, 835, 807 cm–1. [α]D25 = –26.9 (c = 1.0, CHCl3). HPLC
(Daicel Chiralpak AD-H, hexane/i-PrOH = 90:10, flow
rate 1.0 mL/min, λ = 210 nm): minor isomer: tR = 12.1
min; major isomer: tR = 14.1 min.
7.8 Hz, 1H), 5.19 (s, 2H), 3.80 (s, 3H), 2.89 (dd, J = 12.7,
8.4 Hz, 1H), 2.13 (ddd, J = 12.4, 7.2, 4.8 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 159.3, 156.1, 135.9, 129.9,
128.3 (x2), 128.2, 128.1, 127.7 (x2), 125.8, 120.6, 110.3,
98.8, 67.9, 56.8, 55.3, 44.2. IR (neat): 3360, 2960, 2838,
1707, 1601, 1491, 1460, 1389, 1339, 1285, 1239, 1068,
1025, 908, 751, 696 cm–1. HRMS (ESI): m/z: [M+Na]+
25
(C18H19NNaO5), calcd.: 352.1155; found: 352.1154. [α]D
= –42.0 (c = 1.0, CHCl3). HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 210
nm): major isomer: tR = 7.8 min; minor isomer: tR = 13.2
min.
Benzyl (3S,5S)-5-hydroxy-3-(4-methoxyphenyl)isoxazo-
1
lidine-2-carboxylate (4ea). H NMR (400 MHz, CDCl3) δ
7.35-7.17 (m, 7H), 6.86 (d, J = 8.7 Hz, 2H), 5.90 (d, J =
4.2 Hz, 1H), 5.33 (t, J = 8.2 Hz, 1H), 5.17 (s, 2H), 3.79 (s,
3H), 2.75 (dd, J = 12.6, 8.3 Hz, 1H), 2.29 (ddd, J = 12.6,
8.3, 4.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 159.2,
159.0, 135.7, 133.4, 128.4 (x2), 128.1, 127.7 (x2), 127.3
(x2), 114.0 (x2), 98.7, 68.0, 60.9, 55.3, 45.2. IR (neat):
3475, 3120, 2960, 2850, 1707, 1610, 1513, 1396, 1346,
1324, 1261, 1124, 1012, 962, 833, 758, 694, 518 cm–1.
HRMS (ESI): m/z: [M+Na]+ (C18H19NNaO5), calcd.:
tert-Butyl (3S,5S)-5-hydroxy-3-(2-methoxyphenyl)isoxa-
zolidine-2-carboxylate (4gb). 1H NMR (400 MHz,
CDCl3) δ 7.43 (dd, J = 7.6, 1.5 Hz, 1H), 7.29-7.16 (m, 1H),
6.94 (td, J = 7.5, 0.9 Hz, 1H), 6.86 (dd, J = 8.2, 0.7 Hz,
1H), 5.84 (dd, J = 4.2, 2.8 Hz, 1H), 5.64 (t, J = 7.9 Hz, 1H),
3.84 (s, 3H), 2.85 (dd, J = 12.7, 8.4 Hz, 1H), 2.14-2.03 (m,
1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 158.8,
156.1, 130.6, 128.0, 126.0, 120.6, 110.2, 98.7, 82.1, 56.7,
55.3, 44.2, 28.1 (x3). IR (neat): 3356, 2976, 2930, 2850,
1703, 1602, 1491, 1461, 1348, 1315, 1239, 1160, 1066,
1027, 916, 848, 806, 751 cm–1. HRMS (ESI): m/z:
[M+Na]+ (C1255H21NNaO5), calcd.: 318.1312; found:
318.1312. [α]D = –22.0 (c = 1.0, CHCl3). HPLC (Daicel
Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate 1.0
mL/min, λ = 210 nm): major isomer: tR = 7.9 min; minor
isomer: tR = 11.1 min.
25
352.1155; found: 352.1152. [α]D = –51.7 (c = 1.0,
CHCl3). HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
85:15, flow rate 1.0 mL/min, λ = 210 nm): major isomer:
tR = 16.1 min; minor isomer: tR = 19.8 min.
tert-Butyl
(3S,5S)-5-hydroxy-3-(4-methoxyphenyl)-
1
isoxazolidine-2-carboxylate (4eb). H NMR (400 MHz,
CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H),
5.93-5.82 (m, 1H), 5.23 (t, J = 8.2 Hz, 1H), 3.79 (s, 3H),
2.71 (dd, J = 12.5, 8.3 Hz, 1H), 2.26 (dddd, J = 12.6, 8.3,
4.5, 2.0 Hz, 1H), 1.42 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ 158.8, 158.7, 134.1, 127.4 (x2), 113.9 (x2), 98.6,
82.3, 60.9, 55.3, 45.3, 28.1 (x3). IR (neat): 3329, 2960,
2931, 1702, 1613, 1514, 1455, 1336, 1299, 1246, 1159,
1088, 1064, 1032, 965, 91, 807 cm–1. HRMS (ESI): m/z:
[M+Na]+ (C1255H21NNaO5), calcd.: 318.1312; found:
318.1311. [α]D = –33.8 (c = 1.0, CHCl3). HPLC (Daicel
Chiralpak AD-H, hexane/i-PrOH = 90:10, flow rate 1.0
mL/min, λ = 210 nm): major isomer: tR = 9.1 min; minor
isomer: tR = 10.0 min.
(S)-3-Amino-3-phenylpropanoic acid hydrochloride
(13).[18] 1H NMR (400 MHz, Deuterium Oxide) δ 7.38 (s,
5H), 4.69 (m, 5 H), 3.10 (dd, J = 17.2, 7.7 Hz, 1H), 2.98
(dd, J = 17.2, 6.6 Hz, 1H). 13C NMR (101 MHz, D2O) δ
173.4, 135.1, 129.7, 129.4 (x2), 127.1 (x2), 51.5, 37.7.
[α]D25 = +2.8 (c = 0.28, H2O).
Acknowledgements
Financial support from CERCA Programme/Generalitat de
Catalunya, MINECO (CTQ2015-69136-R, AEI/MINECO/
FEDER, UE and Severo Ochoa Excellence Accreditation 2014–
2018, SEV-2013-0319) and the CELLEX Foundation [CELLEX-
ICIQ High Throughput Experimentation (HTE) platform] is
gratefully acknowledged.
Benzyl
(3S,5S)-5-hydroxy-3-(2-nitrophenyl)isoxazoli-
1
dine-2-carboxylate (4fa). H NMR (400 MHz, CDCl3) δ
8.04 (dd, J = 8.2, 1.2 Hz, 1H), 7.79 (dd, J = 8.0, 1.3 Hz,
1H), 7.65 (td, J = 7.8, 1.2 Hz, 1H), 7.49 – 7.41 (m, 1H),
7.35-7.20 (m, 5H), 6.09 (t, J = 7.8 Hz, 1H), 5.91 (d, J = 4.3
Hz, 1H), 5.24-5.15 (m, 2H), 3.17 (dd, J = 12.9, 8.6 Hz, 1H),
2.28-2.16 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 158.8,
147.3, 137.7, 135.3, 134.1 (x2), 128.5 (x2), 128.3 (x2),
127.9, 127.8, 124.8, 98.9, 68.4, 58.7, 45.2. IR (neat): 3366,
3067, 3035, 2961, 1710, 1609, 1578, 1523, 1446, 1391,
1339, 1292, 1067, 907, 738, 676 cm–1. HRMS (ESI): m/z:
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Advanced Synthesis & Catalysis
FULL PAPER
Immobilization of 2,4-cis-Diarylprolinol Silyl
Ethers and Their Application in the Catalytic
Enantioselective Synthesis of 5-
Hydroxyisoxazolidines in Batch and Flow
Adv. Synth. Catal. Year, Volume, Page – Page
Junshan Lai, Sonia Sayalero, Alessandro Ferrali,
Laura Osorio-Planes, Fernando Bravo, Carles
Rodríguez-Escrich* and Miquel A. Pericàs*
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