Heterogeneous Dipeptide-Catalyzed α-Amination of Aldehydes in a Continuous-Flow Reactor: Effect of Residence Time on Enantioselectivity

Article abstract of DOI:10.1002/adsc.201500375

A solid-supported dipeptide-catalyzed continuous-flow process was developed for the direct enantioselective α-amination of aldehydes with dibenzyl azodicarboxylate as the electrophilic nitrogen source. With residence time control as an efficient tool for

Full text of DOI:10.1002/adsc.201500375

UPDATES
DOI: 10.1002/adsc.201500375
Heterogeneous Dipeptide-Catalyzed a-Amination of Aldehydes
in a Continuous-Flow Reactor: Effect of Residence Time on
Enantioselectivity
Sµndor B. Ötvçs,a,b Aliz Szloszµr,a Istvµn M. Mµndity,a and Ferenc Fülçpa,b,*
a
Institute of Pharmaceutical Chemistry, University of Szeged, Eçtvçs u. 6, H-6720 Szeged, Hungary
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eçtvçs u. 6, H-6720 Szeged, Hungary
b
Fax: (+36)-62-545-705; phone: (+36)-62-545-562; e-mail: fulop@pharm.u-szeged.hu
Received: May 16, 2015; Revised: July 29, 2015; Published online: October 27, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500375.
Abstract: A solid-supported dipeptide-catalyzed
continuous-flow process was developed for the
direct enantioselective a-amination of aldehydes
with dibenzyl azodicarboxylate as the electrophilic
nitrogen source. With residence time control as an
efficient tool for the fine-tuning of the enantioselec-
tivity, synthetically useful a-hydrazino alcohols
were achieved with excellent ees. The packed-bed
system proved to be highly robust: no decrease in
catalyst activity or selectivity was detected through-
out 20 h of continuous-flow operation.
lysts extremely attractive as compared with organo-
metallic counterparts,[5] and the organocatalytic a-
amination strategy has therefore recently grown into
a powerful and promising methodology for the enan-
tioselective synthesis of complex molecules and opti-
cally active precursors.[6] Countless applications have
emerged for the asymmetric synthesis of natural prod-
ucts,[7] bioactive amino acids[8] and amino acid deriva-
tives,[9] and the strategy has also proved useful for the
production of highly functionalized chiral heterocy-
cles (Scheme 1).[10]
The immobilization of organocatalysts on solid sup-
ports allows more sustainable chemical synthesis, as
such materials can be reused and recycled several
times, and the product isolation is greatly simpli-
Keywords: asymmetric a-amination; continuous-
flow reactor; organocatalysis; peptides; supported
catalysts
Introduction
The great importance of optically active a-amino
acids, a-amino aldehydes and a-amino alcohols has
led to intense efforts to develop catalytic asymmetric
approaches for the a-amination of carbonyl com-
pounds with azodicarboxylate esters as electrophiles.[1]
Up to the end of the 20th century, this field had been
completely dominated by chiral transition metal cata-
lysts.[2] In 2002, Jørgensen and List almost simultane-
ously reported the first metal-free approach for the
enantioselective a-amination of aldehydes with azodi-
carboxylate esters, utilizing l-proline as a readily
available organocatalyst.[3] Subsequently, a wide array
of proline-derived catalysts have been designed that
offer improved catalytic activity and an extended sub-
strate scope, including ketones as well as a-branched
and a,b-unsaturated aldehydes.[4] Beneficial features,
such as their high stability, availability, non-toxicity
Scheme 1. Organocatalytic asymmetric a-amination of alde-
hydes with azodicarboxylate esters, and examples of bioac-
tive products obtained from the corresponding chiral a-hy-
drazino aldehydes: (a) a cell adhesion inhibitor,[8b] (b) a cer-
nuane-type Lycopodium alkaloid,[7a] and (c) a metabotropic
and low cost, make the use of such metal-free cata- glutamate receptor ligand.[8a]
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Sµndor B. Ötvçs et al.
fied.[11] Continuous-flow processes involving the use of aldehyde and acetic acid as an additive with the
of supported organocatalysts have attracted consider- resin-bound diphenylprolinol-type catalyst prior to
able attention in recent years,[12] and now comprise the addition of the azodicarboxylate component.[13p]
a powerful methodology for the synthesis of enan-
Inspired by the above literature findings and limita-
tioenriched products.[13] This is not merely due to the tions, we set out to develop a robust flow chemistry-
ease of use of such heterogeneous materials. In filled based approach for the a-amination of aldehydes
reaction columns, the continuous substrate stream in- through use of a highly reusable heterogeneous orga-
teracts with a superstoichiometric amount of catalyst nocatalyst, and also to investigate the role of resi-
molecules, thereby allowing unprecedented reaction dence time control as a tool for the fine-tuning of the
rates;[12] and if catalyst deactivation can be ruled out, enantioselectivity.
the scale of production and the catalyst loading
become straight functions of the process time.[14]
One of the most important benefits of packed-bed Results and Discussion
flow systems is that the contact time of the reactants
with the catalyst bed (i.e., the residence time) can The use of synthetic peptides as on-demand organoca-
readily be fine-tuned through the flow rate, so that talysts is highly beneficial in consequence of their
optimization of the conversion and throughput be- modular nature, readily designable structure and in-
comes simple and easy.[14] Systematic tuning of the herent chirality.[19] Peptides bearing an N-terminal
residence time affects not only the reaction rate, but secondary amine unit and an acidic side-chain can be
also the product selectivity.[15] The importance of regarded as mimetics of proline,[20] with the additional
making use of the flow conditions to improve the benefits of higher structural diversity and simple cata-
enantioselectivity was realized first in dialkylzinc ad- lyst immobilization by means of well-established
ditions and later in chiral transition metal complex- solid-phase peptide synthesis (SPPS).[13n,o] We there-
mediated cyclopropanations.[16] The dependence of ee fore investigated the catalytic activity of various N-
on the residence time was also noted in continuous- terminal prolyl-peptides in the asymmetric a-amina-
flow organocatalytic alkylations and Diels–Alder re- tion of aldehydes. At the C-terminus of the peptides,
actions.[13e,f,k] With regard to the observation that the aspartic acid or the homologous glutamic acid served
enantioselectivity of the proline-mediated a-amina- as sources for the carboxylic acid side-chain. The cata-
tion of aldehydes is time-dependent due to partial lysts were prepared by means of SPPS, with Fmoc/t-
racemization,[3b] heterogeneous catalysis in combina- Bu protocols (see the Experimental Section and
tion with precise residence time control appears to be Scheme S1 in the Supporting Information for details).
a reasonable strategy to overcome racemization and The solid support in the peptide synthesis also served
to achieve valuable a-aminated products with high as a catalyst carrier without the need for further syn-
ees.
thetic steps, which eliminated the otherwise laborious
In spite of the obvious benefits, there are very few peptide work-up and purification steps. The catalysts
precedents for heterogeneous organocatalytic asym- were initially supported on a polystyrene resin with
metric a-aminations.[13a,p,t,17] As an example, Tanaka a 4-methylbenzhydrylamine linker (PS-MBHA, with
et al. employed a heterogeneous tetrapeptide for re- a loading of 0.59 mmolgÀ1), and were used as ob-
actions of aldehydes with azodicarboxylate esters,[17] tained, as salts of trifluoroacetic acid (TFA) after the
while Pericàs and co-workers developed a resin-sup- SPPS.
ported diphenylprolinol silyl ether as catalyst for
The immobilized peptidic catalysts were screened
batch and continuous-flow a-aminations.[13p] The main under conventional batch conditions, the electrophilic
limitation of such reactions is that the possibility of a-amination of propanal with dibenzyl azodicarboxy-
catalyst reuse is strongly limited by the azodicarboxy- late (DBAD) serving as a model reaction. The mix-
late component, which can contribute considerably to ture for each reaction contained 1 equivalent of
off-cycle catalyst deactivation.[18] To suppress such DBAD, 1.5 equivalents of aldehyde and 0.1 equiva-
a deactivation pathway and to facilitate enamine for- lent of the corresponding catalyst, in CHCl3 as solvent
mation, Pericàs, for example, premixed a large excess (Scheme 2), and was stirred at ambient temperature
Scheme 2. Solid-supported peptide-catalyzed a-amination of propanal with DBAD as electrophilic nitrogen source, and re-
duction of the resulting a-hydrazino aldehyde to the corresponding alcohol.
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Heterogeneous Dipeptide-Catalyzed a-Amination of Aldehydes
until the yellow color of the azodicarboxylate had dis- dramatically (Table 1, entries 5–8), presumably be-
appeared (or for 24 h at most). As the resulting a-hy- cause of base-promoted racemization.
drazino aldehydes are prone to racemization, the cor-
responding stereochemically stable alcohols were iso- leading to a conversion of 86% and an ee of 59%
lated after reduction with NaBH4.[21]
without NMM (Table 1, entry 2). However, as these
Catalyst 2 performed best among the tripeptides,
Tripeptides with the general formula H-l/d-Pro- results were far below optimal, we next focused on
Pro-Xaa-NH2, where Xaa is aspartic or glutamic acid, the role of the central proline unit. Heterogeneous di-
were recently reported to be effective organocatalysts peptides were prepared consisting of a C-terminal as-
for asymmetric reactions of aldehydes involving en- partic or glutamic acid and an N-terminal proline
amine intermediates in batch and in continuous-flow moiety (Figure 1b). After the omission of the central
systems.[13n,o,20] We therefore tested H-Pro-Pro-Asp- proline residue, the resulting dipeptides proved more
NH-PS-MBHA,
H-d-Pro-Pro-Asp-NH-PS-MBHA, suitable for asymmetric catalysis. Besides high activi-
H-Pro-Pro-Glu-NH-PS-MBHA and H-d-Pro-Pro- ties, most of the novel catalysts exhibited improved
Glu-NH-PS-MBHA (catalysts 1–4) as heterogeneous enantioselectivities (ee 52–76%, with quantitative
organocatalysts for the a-amination of propanal (Fig- conversion in each case after 20–22 h) as compared
ure 1a). Although most of these peptides proved with the corresponding tripeptides (Table 1, entries 9–
highly active in the model reactions (conversion 86– 12 vs. entries 1–4). H-Pro-Asp-NH-PS-MBHA (cata-
100% after 19–24 h), only low or moderate enantiose- lyst 5a) was found to be most promising, yielding
lectivities were observed (ee 6–59%, Table 1, en- quantitative conversion after 22 h, a productivity of
tries 1–4). The effects of N-methylmorpholine 0.46 mmol product”mmol catalystÀ1 ”hÀ1 and a satis-
(NMM) base were next investigated, to liberate the factory ee of 76%, with the (R)-hydrazino alcohol as
catalysts from their TFA salt form and to check the the major product (Table 1, entry 9). The absolute
efficacy of the desalted peptides. It emerged that, fol- configuration of the product was predominantly con-
lowing addition of the base, the rates of the reactions trolled by the N-terminus of the catalyst. Peptides
increased significantly (complete conversion was ob- with an N-terminal d-proline residue (catalysts 2, 4, 6
tained with each peptide in shorter reaction times), and 8) gave the (S)-alcohol.
but at the same time the enantioselectivity decreased
Figure 1. Immobilized peptides utilized as catalysts for the a-amination reactions: (a) tripeptides known from previous stud-
ies,[13n,o,20] and (b) novel dipeptides.
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Table 1. Screening of solid-supported peptidic catalysts in
the batch reaction of propanal with DBAD (see Scheme 2
for the reaction conditions).
Entry Catalyst Reaction
time [h]
Conv.
[%][a]
ee
Abs.
[%][b] config.
1
2
3
4
1
2
3
4
1
2
3
4
5a
6
7
8
19
24
23
22
2
97
86
24
59
31
6
R
S
R
S
R
S
R
–
R
S
R
S
R
R
Figure 2. Experimental set-up for continuous-flow a-amina-
tion reactions. The resulting a-hydrazino aldehyde was re-
duced to the corresponding alcohol with NaBH4.
100
100
100
100
100
100
100
100
100
100
100
100
5[c]
6[c]
7[c]
8[c]
9[d]
10
11
12
18
17
26
rac.
76
53
66
52
79
75
2
3
ous stream of the reactants was passed by a single
HPLC pump. The a-hydrazino aldehydes obtained in
the continuous-flow reactions were immediately re-
duced to the corresponding alcohols with NaBH4 in
order to avoid racemization.
3.5
22
22
22
20
20
22
13[e,f] 5b
14[d] 5c
The effects of the aldehyde excess were first inves-
tigated under flow conditions utilizing the propanal–
DBAD model reaction (Figure 3). It emerged that
high aldehyde amounts pushed the reaction to com-
[a]
Determined by 1H NMR spectroscopic analysis of the
crude material.
Determined by chiral-phase HPLC analysis after reduc-
tion with NaBH4.
[b]
[c]
[d]
0.1 equivalent of NMM was used as basic additive.
Productivity was 0.46 mmol product”mmol catalystÀ1
”
”
hÀ1.
[e]
[f]
Productivity was 0.5 mmol product”mmol catalystÀ1
hÀ1.
CHCl3:i-PrOH 9:1 was used as solvent.
It is noteworthy that the performance of the opti-
mized heterogeneous peptide (catalyst 5a) was com-
parable to that observed with its non-supported coun-
terpart. Thus, the peptide H-Pro-Asp-NH2 (catalyst
5b) afforded an ee of 79% and a marginally improved
reaction rate, which involved a reaction time of 20 h
for completion and a slightly better productivity of
0.5 mmol product”mmol catalystÀ1 ”hÀ1 (Table 1,
entry 9 vs. 13).
With an optimized catalyst in hand, we turned our
attention to continuous-flow operation. The catalyst
carrier was changed from PS-MBHA to the polystyr-
ene-polyethylene glycol grafted copolymer TentaGel
(with a loading of 0.48 mmolgÀ1), which is a more
robust and pressure stable resin, ideally suited for
flow chemistry-based applications.[13o] It was verified
that the exchange of the solid support had no effects
on the catalytic activity or selectivity, as the peptide
H-Pro-Asp-NH-TentaGel (catalyst 5c) performed
comparably to its PS-MBHA-bound counterpart (cat-
alyst 5a) in the batch model reaction between propa-
nal and DBAD (Table 1, entry 9 vs. 14). A simple and
cheap instrument was assembled for the flow reac-
tions (Figure 2). 200 mg of catalyst 5c were encom-
passed in a cylindrical PEEK column (with internal
Figure 3. Investigation of the dependence of (a) the conver-
sion and (b) ee on the aldehyde excess in the continuous-
flow a-amination of propanal with DBAD. An aldehyde
dimensions of 100”4 mm), through which a continu- amount of 3 equivalents was chosen as optimum.
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Heterogeneous Dipeptide-Catalyzed a-Amination of Aldehydes
pletion, but also dramatically decreased the enantio- plained by the secondary amine moiety of the organo-
À
selectivity. With 1.5 equivalents of propanal, for ex- catalyst, which is able not only to aid asymmetric C
ample, a conversion of only 40% was achieved, N bond formation through an enamine-based catalytic
whereas the ee was as high as 94%. In contrast, the cycle, but also to promote the enolization and hence
use of 10 equivalents of aldehyde led to complete the racemization of the resulting chiral a-hydrazino
conversion, but at the expense of a significant fall in aldehyde in an undesired off-cycle pathway.[3b,13n] Ac-
ee to 62%. Thus, 3 equivalents of aldehyde were cordingly, it was found that enhancement of the flow
found to be optimal, affording a high conversion and rate led to an increase in ee. At 0.05 mLminÀ1, for ex-
an excellent ee at the same time.
ample, the ee was 85%, whereas at 0.5 mLminÀ1, the
To investigate the role of the residence time on the ee improved to 97%. A flow rate of 0.1 mLminÀ1,
catalyst bed, the dependence of the a-amination on which corresponded to a residence time on the cata-
the flow rate was next tested. At 0.05 mLminÀ1 a con- lyst bed of 8 min, offered the best compromise be-
version of 89% was achieved, and at 0.1 mLminÀ1 tween the conversion (86%) and the enantioselectivi-
only a slight conversion decrease to 86% was ob- ty (90%), and was thus selected as an optimum value.
served (Figure 4a). However, it turned out that the re-
Conventional batch-based operations do not allow
action is very sensitive to further reduction of the res- such easy and precise control over the reaction time.
idence time, as any higher flow rate resulted in a sig- In batch reactions with the same heterogeneous di-
nificant fall in the conversion (at 0.2 mLminÀ1, for ex- peptide (catalyst 5c) or with its non-supported deriva-
ample, the conversion was only 44%). Importantly, tive (catalyst 5b), much lower ees of 75% and 79%
the residence time proved to influence not only the were found after reaction times of 22 and 20 h, re-
conversion, but also the enantioselectivity of the flow spectively, in spite of the lower propanal excess uti-
process (Figure 4b). This phenomenon can be ex- lized (Table 1, entries 13 and 14). We believe that this
significant contrast results from the fundamental dif-
ferences between a classical batch experiment and
a packed-bed flow system. The well-defined short
contact time of the starting materials with the high
local catalyst concentration in the packed bed ensures
efficient enamine catalysis, but can reduce enolization
upon strict residence time control. Whereas in batch,
there is a broad reaction window where both process-
es can occur more or less simultaneously. These re-
sults highlight the importance of strategic residence
time control, and illustrate the feasibility of continu-
ous-flow processing for asymmetric syntheses involv-
ing configurationally labile products.
Study of the pressure dependence of the continu-
ous-flow reaction demonstrated that enhancement of
the pressure from atmospheric to 60 bar significantly
improved the rate of the reaction, but further eleva-
tion was not beneficial, possibly because of erosion of
the resin (Figure 5). The enantioselectivity did not
change in response to pressurizing: the ee was in the
interval 89–91% in all cases. It was established earlier
that, when swellable resins are used as heterogeneous
catalyst carrier, the continuous reactions are diffu-
sion-controlled, and the role of pressure is to aid the
diffusion of the reactants into the swollen polymer
matrix toward the active catalyst sites.[13n,o,22]
Since catalyst deactivation is an important limit of
heterogeneous catalytic approaches toward a-aminat-
ed products,[13p,17] the reaction of propanal with
DBAD was scaled up in order to investigate the sta-
bility and preparative capability of the immobilized
Figure 4. Investigation of the dependence of (a) conversion
catalyst. The large-scale experiment was run under
and (b) ee on the flow rate in the continuous-flow a-amina-
the previously optimized conditions (0.1 mLminÀ1
flow rate and 60 bar), with a fresh portion of catalyst
5c packed into the catalyst bed. The concentration
tion of propanal with DBAD. A flow rate of 0.1 mLminÀ1
was chosen as optimum, which corresponds to a residence
time on the catalyst bed of 8 min.
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Sµndor B. Ötvçs et al.
Table 2. Investigation of the large-scale synthetic capability
of catalyst 5c in continuous-flow mode.
Entry[a]
Time [h]
Conv. [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
0–2
2–4
4–6
6–8
8–10
10–12
12–14
14–16
16–18
18–20
84
88
88
91
83
85
90
88
86
87
92
90
90
88
89
91
90
90
91
88
Figure 5. Pressure dependence of the a-amination of propa-
nal with DBAD in continuous-flow mode. 60 bar was found
optimal. The enantioselectivity was independent of the pres-
sure: ee was in the interval 89–91% in all cases.
[a]
After reduction with NaBH4, 3.49 g of a-hydrazino alco-
hol were collected in the whole experiment. The overall
yield was 81%.
[b]
[c]
Determined by 1H NMR spectroscopic analysis of the
crude material.
and ratio of the starting materials were not changed
for the scaling-up, and the eluting product solution
was collected for 20 h in 2 h fractions, the conversion
and ee being determined for each fraction separately.
Determined by chiral-phase HPLC analysis after reduc-
tion with NaBH4.
We were delighted to find that the packed-bed flow Table 3. Investigation of the scope and applicability of the
continuous-flow a-amination with catalyst 5c.
system proved highly robust, as no decrease in cata-
lyst activity or selectivity was detected in the moni-
tored reaction window. The conversion and ee were
virtually constant throughout the 20 h, at around 83–
91% and 88–92%, respectively, and after reduction
with NaBH4, 3.49 g of the corresponding a-hydrazino
alcohol was isolated, which gave an overall yield of
81% (Table 2). In this case, the catalyst loading in the
continuous reaction became a direct function of the
process time; the large-scale flow synthesis permitted
an almost 13-fold reduction of the catalyst loading rel-
ative to the corresponding batch reactions utilizing
the same heterogeneous dipeptide (catalyst 5c) or its
non-supported analogue (catalyst 5b).
To investigate the scope and applicability of the de-
scribed methodology, the a-amination of various alde-
hydes was next investigated with DBAD as the elec-
trophilic nitrogen source utilizing catalyst 5c under
the previously optimized reaction conditions (a 3-fold
excess of aldehyde, a flow rate of 0.1 mLminÀ1 and
60 bar). As shown in Table 3, short linear aldehydes
(propanal, butanal and pentanal) gave conversions of
86–96% and excellent ees of 90–99% (entries 1–3).
Aldehydes with longer linear carbon chains (hexanal
Entry R1
R2 Conv. [%][a] ee [%][b] Prod.[c]
1
2
3
4
5
6
7
8
Me
Et
n-Pr
n-Bu
CH2=CH(CH2)7
Bn
i-Pr
Me
H
H
H
H
H
H
H
86
93
96
100
100
100
92
90
99
93
90
90
95
98
–
5.38
5.81
6.00
6.25
6.25
6.25
5.75
–
Me trace
[a]
[b]
[c]
Determined by 1H NMR spectroscopic analysis of the
crude material.
Determined by chiral-phase HPLC analysis after reduc-
tion with NaBH4.
Productivity in mmol product”mmol catalystÀ1 ”hÀ1.
and undecylenic aldehyde) were converted quantita- a key intermediate for the synthesis of (À)-bestatin
tively to the desired adducts with ees of 90% (en- (Scheme 3), a naturally occurring aminopeptidase in-
tries 4 and 5). Quantitative conversion and an excel- hibitor that exhibits immunostimulatory and cytotoxic
lent ee of 95% were achieved in the reaction of activities.[9c,23] After it had been established that cata-
DBAD with 3-phenylpropanal (entry 6), affording lyst 5c is a highly robust system, this flow reaction
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Heterogeneous Dipeptide-Catalyzed a-Amination of Aldehydes
enantioselectivity in asymmetric syntheses involving
configurationally labile products.
Experimental Section
Scheme 3. (À)-Bestatin, a naturally occurring aminopepti-
dase inhibitor, and the corresponding a-hydrazino alcohol
as its key intermediate.[9c,23]
General Information
All the materials and reagents were of analytical grade and
were used as received without purification. Flash column
chromatography was performed on Merck silica gel 60, par-
ticle size 63–200 mm, and analytical thin-layer chromatogra-
phy (TLC) on Merck silica gel 60 F254 plates. Compounds
were visualized by means of UV or KMnO4. 1H and
13C NMR spectra were recorded on a Bruker Avance DRX
400 spectrometer at ambient temperature, in CDCl3 as sol-
vent, with TMS as internal standard, at 400.1 and
100.6 MHz, respectively. HPLC analyses were performed on
an analytical instrument with a diode array detector from
JASCO. MS analyses were carried out with a Thermo Scien-
tific LCQ Fleet/Thermo Scientific Dionex Ulimate 3000 LC/
MSD.
was repeated on a larger scale, resulting in 1.20 g
(92% yield) of the desired a-aminated key product
after NaBH4 reduction (the ee was 95%, similarly as
in the small-scale experiment). Isovaleraldehyde, a b-
branched aldehyde, also served as a good reaction
partner of DBAD (92% conversion and 98% ee,
entry 7), but isobutyraldehyde proved to be a poor
substrate because of the a-branch (entry 8).
These results compare well with those of literature
procedures involving the use of various homogeneous
or heterogeneous catalysts; detailed comparison with
literature batch and continuous-flow experiments are
to be found in the Supporting Information (Tables S1
and S2).[3b,4k–m,13p,t,17] The chemical efficacy of the con-
tinuous reactions utilizing catalyst 5c was found to be
Catalyst Synthesis
The heterogeneous peptidic catalysts were prepared manual-
ly by means of SPPS, utilizing Fmoc/t-Bu chemistry (Fmoc=
9H-fluoren-9-ylmethoxycarbonyl).
Amino-functionalized
markedly high. For example, in the propanal–DBAD non-TFA-labile resins were utilized as solid supports for the
SPPS: PS-MBHA (with a loading of 0.59 mmolgÀ1) and Ten-
reaction, the productivity of the flow process proved
taGel (with a loading of 0.48 mmolgÀ1). With respect to the
to be 11–12 times higher than that of the correspond-
different swelling properties of the applied resins, DMF was
used as solvent in the case of TentaGel, and DMF/CH2Cl2
1:1 for couplings with PS-MBHA. Before any synthetic
steps, the resin was swollen thoroughly for 1 h in the appro-
priate solvent. Further treatment with 5% N,N-diisopropyle-
thylamine (DIEA) solution was carried out in the case of
PS-MBHA to liberate the amino function from the HCl salt
ing batch processes in which the same supported pep-
tide or its resin-free analogue (catalyst 5b) was used.
Moreover, the productivities achieved (5.38–
6.25 mmol product”mmol catalystÀ1 ”hÀ1, Table 3)
exceeded our previous continuous-flow organocatalyt-
ic findings.[13n,o]
form. For the couplings, 3 equivalents of Fmoc-protected
amino acid and 3 equivalents of 1-[bis(dimethylamino)me-
thyliumyl]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide (HATU)
were dissolved, and 6 equivalents of DIEA were added. The
Conclusions
solution of the activated amino acid was then poured onto
In summary, a simple resin-supported dipeptide con-
the swollen resin, and the coupling was fulfilled by agitation
taining an N-terminal proline unit and an acidic side-
for 3 h. The incorporation of the amino acid was monitored
chain at the C-terminus was developed as an effective
by means of the ninhydrin or isatin test. If the test revealed
organocatalyst for the direct enantioselective a-ami-
nation of aldehydes with DBAD as electrophilic ni-
trogen source. The heterogeneous catalyst was readily
synthetized and immobilized in the same step by
unreacted amino groups, the coupling was repeated. Fmoc
deprotection was performed in a solution of 2% 1,8-diazabi-
cyclo[5.4.0]undec-7-ene and 2% piperidine with agitation for
2”15 min, and the peptide chain was then elongated with
SPPS without cleavage of the peptide from the resin. repetition of the coupling and deprotection steps. After each
step, the resin was washed 3 times with CH2Cl2, once with
MeOH and 3 times with CH2Cl2. Finally, the carboxyl side-
chain was deprotected without cleavage of the peptide from
the solid support by means of agitation for 3 h in a mixture
of TFA and H2O (9:1 v/v). After filtration and washing with
the same solvents as described previously, the resin-bound
peptide was kept at ambient temperature for 6 h to dry. The
immobilized catalysts were obtained in TFA salt form after
the SPPS.
The benefits of continuous-flow processing in combi-
nation with strategic control over the residence time
were exploited to achieve both high enantioselectivity
and high reaction rates. Thus, synthetically useful a-
hydrazino alcohols were obtained with high produc-
tivities and excellent ees (90–99%). The heterogene-
ous peptidic catalyst proved prominently robust: no
deactivation occurred during 20 h continuous-flow op-
eration. Strategic residence time control has therefore
H-Pro-Asp-NH2 was synthesized manually on Tentagel R
proved to be an efficient tool for the improvement of RAM resin (0.20 mmolgÀ1). The peptide chain was elongat-
Adv. Synth. Catal. 2015, 357, 3671 – 3680
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UPDATES
Sµndor B. Ötvçs et al.
ed through repetition of the coupling and deprotection steps
Acknowledgements
given in the previous paragraph. The peptide was cleaved
from the resin by agitation for 3 h in a mixture of TFA and
H2O (95:5 v/v). The TFA was then removed under vacuum,
and the free peptide was precipitated in dried diethyl ether,
filtered off, dissolved in 10% aqueous acetic acid and
lyophilized.
We are grateful to the Hungarian Research Foundation
(OTKA NK81371 and OTKA PD103994) and TMOP-
4.2.2A-11/1/KONV-2012-0035 for financial support. S.B.Ö.
acknowledges the award of a fellowship from the Postdoctor-
al Research Program of the Hungarian Academy of Sciences.
S.B.Ö and I.M.M. acknowledge the award of Jµnos Bolyai
scholarships from the Hungarian Academy of Sciences.
General Procedure for the Batch Reactions
Propanal (0.375 mmol, 1.5 equivalents), DBAD (0.25 mmol,
1 equivalent) and the corresponding catalyst (0.025 mmol,
0.1 equivalent) were combined in CHCl3 (2.5 mL). In some
cases, NMM (0.025 mmol, 0.1 equivalent) was also added.
The reaction mixture was stirred at ambient temperature
until the yellow color of the azodicarboxylate had disap-
peared or for 24 h at most (the progress of the reaction was
also followed by TLC). The catalyst was then filtered off
and the solvent was removed under vacuum. EtOH
(2.5 mL) and NaBH4 (0.275 mmol, 1.1 equivalents) were
added to the filtrate, and the mixture was stirred for 15 min
at 08C. After completion of the reduction, the mixture was
concentrated under vacuum. Brine (10 mL) was next added,
and the resulting mixture was extracted with ethyl acetate
(3”10 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure, affording
the corresponding a-hydrazino alcohol.
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Continuous-Flow Reactions
The continuous-flow experiments were conducted in a modu-
lar instrument consisting of a cylindrical PEEK column
(with internal dimensions of 100”4 mm) filled with catalyst
5c (200 mg), an HPLC pump (a Watersꢁ 600 pump
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similarly as given for the batch reactions. In the cases of vol-
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the reduction process through a simple extractive work-up
and evaporation. If necessary, column chromatographic pu-
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