Memory of Chirality in a Flow-Based System: Enantioselective Synthesis of Quaternary α-Amino Acids Using Flow Microreactors

Article abstract of DOI:10.1002/ejoc.201801305

Enantioselective synthesis of quaternary α-amino acids based on alkylation of a conformationally unstable enolate according to a memory-of-chirality strategy was successfully adapted to a flow-based system. This allows for the scale-up of this enantioselective process with reaction residence times of less than three minutes. The enantiomeric excess values are similar to those obtained in the batch process.

Full text of DOI:10.1002/ejoc.201801305

A Journal of
Accepted Article
Title: Memory of chirality in a flow-based system: enantioselective
synthesis of quaternary α-amino acids using flow microreactors
Authors: Antonin Mambrini, Didier Gori, Cyrille Kouklovsky, Heijin Kim,
Jun-ichi Yoshida, and Valérie Alezra
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801305
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10.1002/ejoc.201801305
European Journal of Organic Chemistry
COMMUNICATION
Memory of chirality in a flow-based system: enantioselective
synthesis of quaternary -amino acids using flow microreactors
Antonin Mambrini,[a] Didier Gori, [a] Cyrille Kouklovsky, [a] Heejin Kim, [b] Jun-ichi Yoshida, [c] and Valérie
Alezra*[a]
Abstract: Enantioselective synthesis of quaternary -amino acids
based on alkylation of a conformationally unstable enolate according
to a Memory of Chirality strategy was successfully adapted to a flow-
based system. This allows for the scale up of this enantioselective
process with reaction residence times of less than 3 minutes. The
enantiomeric excesses are similar to those obtained in batch
process.
referring to very fast reactions conducted in a highly controlled
manner using microflow reactors. Flash chemistry is very
promising as it allows transformations that are difficult even
impossible to perform in batch. Highly unstable intermediates
can be used for the next reaction before they decompose or
isomerize by virtue of extremely short reaction times. It is also
really interesting in the field of labile organometallic anion
chemistry.[34–38] This concept of flash chemistry seemed thus to
be perfectly adapted to our MOC reactions and it has never
been tried before for enantioselective synthesis by MOC. We
describe here our results on L-alanine in this field, which consist
in the very first application of MOC in a flow-based system, as
well as a large scale synthesis of a quaternary -amino acid
derivative.
Introduction
Memory of Chirality (MOC)[1–10] is an original strategy in
asymmetric synthesis based on the chiral pool but in which the
initial stereogenic center is temporarily destroyed and recovered
in an enantioselective fashion. The principle relies on a
memorization of the initial chirality by
a
global chiral
conformation of the intermediate. Therefore this strategy is very
sensitive to reaction conditions in particular reaction rate and
temperature, and many MOC reactions are either
intramolecular[11–15] or performed at low temperature[16–20] or
both.[21,22] We have already developed a 3-step asymmetric
synthesis of quaternary -amino acids based on MOC.[23–26] The
key step is an intermolecular alkylation of an enolate and the
initial chirality of the starting -amino acid is “memorized” at only
low temperatures by a chiral conformation of a tertiary aromatic
amide (Scheme 1). This reaction is very efficient and
enantioselective but not scalable because strict temperature
control (and consequently the pre-cooling of the base,
transferred by cannulation) is essential to achieve high
enantioselectivity. Thus, we thought that we could use
continuous flow chemistry[27,28] to optimize the heat exchange
and to be able to access to large quantities of quaternary -
amino acids.
Continuous flow chemistry has been recently found as an
attractive method for organic chemistry as it increases the safety
(by better heat and mass transfer) and it is easy to adapt to
scale-up.[29,30] Among flow chemistry, flash chemistry,[31–33] is
[a]
Pr. Dr. C. Kouklovsky, Dr. V. Alezra, Laboratoire de Méthodologie,
Synthèse et Molécules Thérapeutiques, ICMMO, UMR 8182, CNRS,
Univ. Paris-Sud, Université Paris-Saclay,
Scheme 1. Previous work on L-Ala alkylation and adaptation to flow process.
Faculté des Sciences d’Orsay Bât 410, Orsay, F-91405 France
E-mail: valerie.alezra@u-psud.fr
http://www.icmmo.u-psud.fr/Labos/MSMT/
Dr. H. Kim, Department of Synthetic and Biological Chemistry
Graduate School of Engineering,
Results and Discussion
[b]
[c]
Kyoto University,
Nishikyo-ku, Kyoto, 615-8510, Japan.
Pr. Dr. J.-i. Yoshida, National Institute of Technology, Suzuka
College, Suzuka, Mie, 510-0294, Japan.
We used a simple flow-based system composed of 3 syringe
pumps, stainless steel tubing and T-mixers. We first tried to
perform alkylation of compound 1 under the conditions similar to
the batch reaction, with KHMDS as a base at -78 °C. It
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801305
European Journal of Organic Chemistry
COMMUNICATION
completely failed as formation of insoluble potassium salt (KBr
or KI) occurred in situ and thus clogged the system. Attempts to
use an ultrasonic bath led also to overpressure at low
temperatures (at 0°C, no overpressure was observed but the
alkylated compound was racemic). Therefore, we decided to use
and 6). Deprotonation was complete at -50 °C in 35 seconds but
we had also high conversion with higher enantiomeric excesses
at lower temperatures (entries 1 and 2). Use of 10 equivalents of
electrophile did not improve the yield (entry 4). The best
compromise seemed thus deprotonation at -55 °C for 35 s (entry
2).
LDA as
a base to produce soluble lithium salts and
reinvestigated batch experiments.
We first conducted the reaction with LDA under batch
conditions, and the results are shown in Table 1. Several
reaction conditions were modified according to the experimental
requirements of the flow mode. In particular, the reaction
solution was a bit more diluted (0.10 M) than the experiments in
our previous reports (0.27 M), because highly concentrated
solution having high viscosity is easy to clog in flow (in aldol
reaction, use of even higher concentration improved the
enantiomeric excess). The enantiomeric excesses obtained with
LDA (entries 1–3 Table 1) were a bit lower than with KHMDS
(entries 4–6) but are acceptable. Unexpectedly, DME, which was
the best additive for KHMDS, gave very disappointing results
with LDA but DMPU was a convenient additive for this reaction
(reaction was not possible without it for allyl iodide). And the
reaction with ethyl iodoacetate gave better yield and
enantiomeric excess, probably because of high reactivity (entry
7).
Table 2. Optimization of deprotonation time and temperature in a flow-based
system – alkylation with ethyl iodoacetate
Entry
t1 (s)
T1 (°C)
Conv. (%)[a]
ee (%)[a]
1
35
35
7.7
35
17
35
-50
-55
-55
-60
-65
-78
100
88
83
75
72
61
62
75
77
72
78
78
2
3
4[b]
5
6
[a] Determined by chiral stationary-phase HPLC. [b] 10 equiv. of electrophile
were used.
Table 1. Batch tests
Entry
R
Additive
Base
Yield (%)
ee (%)[a]
1
2
3
4
5
6
7
Allyl
-
LDA
NR[b]
81
NR[b]
64
We then optimized the alkylation step and used allyl iodide as
electrophile because it was less reactive. The length of tubing
reactor for alkylation was extended to 20 m to improve the
conversion (longer tubing induced overpressure). We fixed the
deprotonation temperature (-60 °C) and time (35 s), then varied
the temperature of the reaction with allyl iodide. We also
investigated the role of DMPU as it improved the yield in batch.
We first added this additive with the base but it systematically
induced clogging. We thus added it with the electrophile. The
results are gathered in table 3. DMPU improved the conversion
(entries 3 and 4). Increasing temperature from -78 °C to -55 °C
does not affect the enantiomeric excess but improved the
conversion (entries 1 and 3). At -30°C, the conversion was
complete, but the enantiomeric excess completely dropped
(entry 5). Finally, at -60 °C, the isolated yield was 74% with an
enantiomeric excess of 57% (entry 6). This result was a bit
inferior to the batch experiment but acceptable, probably
because of the lower concentration or of the temperature
increase.
Allyl
DMPU
DME
-
LDA
Allyl
LDA
33
59
Allyl
KHMDS
KHMDS
KHMDS
LDA
81
65
Allyl
DMPU
DME
-
81
65
Allyl
75
70
CH2CO2Et
74
65
[a] Determined by chiral stationary-phase HPLC. [b] No reaction
We then decided to investigate alkylation with LDA in a flow-
based system. We first conducted reactions using ethyl
iodoacetate as an electrophile, because it was a better reactant
as confirmed in Table 1. We optimized the reaction time for
deprotonation (t1) by changing the length of the tubing as well as
the deprotonation temperature (T1; Table 2). This reaction led
successfully to the expected compound 2b with, not surprisingly,
the same absolute configuration as in batch. Temperature
variations showed that the enantiomeric excess is pretty stable
below -55 °C whereas the conversion drops at -78 °C (entries 2
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10.1002/ejoc.201801305
European Journal of Organic Chemistry
COMMUNICATION
dependent of the nature of the electrophile, much more than in
our previous batch reactions. This may be due either to a lower
conformational stability of the lithium enolate in flow than of the
potassium enolate in batch, or to a reduced reactivity of a lithium
enolate, compared to our former potassium enolate, rendering
the reactivity of the electrophile more important for the control of
the racemization.
Conclusions
To conclude, we successfully adapted our MOC reaction to a
flow-based system. In particular, we were able to synthesize a
large amount of quaternary amino acid derivative 2b in high
yield and high enantiomeric excess, at a temperature slightly
superior than in batch and mostly in a very short time, with
reaction residence time of less than 3 minutes. We thus showed
for the first time that MOC synthesis of quaternary amino acids
could be adapted to the concept of flash chemistry allowing
larger scale synthesis.
Table 3. Optimization of alkylation in a flow-based system alkylation with allyl
iodide, benzyl bromide, ethyl iodoacetate and aldol reaction with
benzaldehyde
Entry
Electrophile
Additive[a]
T2 (°C)
Conv. (%)[b]
ee (%)[b]
1
2
3
4
5
6
7
8
9
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
Allyl iodide
-
-78
-78
-55
-55
-30
-60
-60
-60
-70
37
50
Experimental Section
DMPU
-
56
44
46
49
Flow alkylation general procedure
DMPU
-
99
52
97
18
DMPU
DMPU
DMPU
-
74[c]
68[c]
42[c],[d]
82[c],[e]
57
BnBr
75
67/90[d]
PhCHO
ICH2CO2Et
89
[a] 6 equiv. of DMPU was mixed with an electrophile and used for flow
reaction. [b] Determined by chiral stationary-phase HPLC. [c] isolated yield. [d]
de = 74%, ee(major dia) = 67%, ee(minor dia) = 90%. [e] reaction performed
on 1.33 g of compound 1; 1.20 g of 2b was obtained.
We then applied these conditions (entry 6, table 3) to benzyl
bromide (10 equiv.) and obtained the expected compound 2c (E
= Bn) in 68% yield and 75% enantiomeric excess (entry 7). We
also performed aldol reaction with benzaldehyde and get a
separable mixture of diastereomers (de= 74%, yield = 42%) in
67% (major diastereomer) and 90% (minor diastereomer)
enantiomeric excess.
As our goal was to demonstrate that thanks to flow chemistry,
we would be able to access large quantities of quaternary amino
acids, we launched the alkylation on a larger quantity of
A microfluidic system consisting of two T-shaped micromixers (M1 and
M2), four microtubes reactors (R1, R2, R3 and R4) and three tubes pre-
temperature-retaining units (1000 μm of inner diameter (ø) and 100 cm of
length (L)) were used at temperature T1 for P1 and P2 and T2 for P3. A
solution of (S)-3-(1-naphthoyl)-2,2,4-trimethyloxazolidin-5-one (1; 0.10 M
in THF) and a solution of lithium diisopropylamine (0.80 M in hexane/THF
(1.4/1.0) were individually introduced to M1 (ø:500 μm) by syringe
pumps. The resulting solution was passed through R1 (various lenghts, ø:
1000 μm, temperature: T1), R2 (10 cm, ø: 1000 μm, temperature: room
temperature), R3 (5 cm, ø: 1000 μm, temperature : T2) and was mixed
oxazolidinone
1 with ethyl iodoacetate. For experimental
reasons (temperature control) we chose to perform the large-
scale reaction at -70 °C, which is possible thanks to the high
reactivity of ethyl iodoacetate. When using 1.33 g of 1, we were
pleased to get 1.20 g of the final compound 2b in 82% yield and
89% enantiomeric excess (entry 9, table 3), which is very close
to our previous batch result. Obviously, larger quantities are
reachable by just increasing the collecting time. Unexpectedly,
these flow results show that the enantiomeric excess is highly
with
a solution of electrophile (various electrophiles and various
concentration in THF) in M2 (ø: 500 μm). The resulting solution was
passed through R4 (various sizes, ø: 1000 μm, temperature: T2). The flow
rates for (S)-3-(1-naphthoyl)-2,2,4-trimethyloxazolidin-5-one 1, LDA and
the electrophile were 4 mL/min, 1.2 mL/min and 2 mL/min respectively.
After a steady state was reached, the product solution was collected for 1
min while being quenched with saturated aqueous NH4Cl solution (2 mL).
Then, DCM (6 mL) and brine (2 mL) were added, and then the organic
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10.1002/ejoc.201801305
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This research was supported by the Ministère de
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Keywords: Flash chemistry • Asymmetric synthesis • Amino
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10.1002/ejoc.201801305
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The first Memory of Chirality
reaction in flash chemistry is
reported: it allows enantioselective
synthesis of quaternary -amino
acid derivatives with reaction
residence times of less than 3
minutes. This proof of concept
shows that larger quantities of
compound can be synthesized in
short reaction time.
Asymmetric synthesis
Antonin Mambrini, Didier Gori, Cyrille
Kouklovsky, Heejin Kim, Jun-ichi
Yoshida, Valérie Alezra*
Page No. – Page No.
Memory of chirality in a flow-
based system: enantioselective
synthesis of quaternary -amino
acids using flow microreactors
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