Continuous flow synthesis of β-amino acids from α-amino acids via Arndt-Eistert homologation

Article abstract of DOI:10.1039/c4ra08113g

A fully continuous four step process for the preparation of β-amino acids from their corresponding α-amino acids utilizing the Arndt-Eistert homologation approach is described. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra08113g

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Continuous flow synthesis of b-amino acids from
a-amino acids via Arndt–Eistert homologation†
Cite this: RSC Adv., 2014, 4, 37419
*
Vagner D. Pinho, Bernhard Gutmann and C. Oliver Kappe
Received 2nd July 2014
Accepted 12th August 2014
DOI: 10.1039/c4ra08113g
www.rsc.org/advances
A fully continuous four step process for the preparation of b-amino uniform irradiation of the reaction mixture for a well-dened
acids from their corresponding a-amino acids utilizing the Arndt– time, controlled by the pump ow rate.6
Eistert homologation approach is described.
The major drawback of the Arndt–Eistert homologation
sequence is related to safety concerns associate with the use of
diazomethane (CH2N2), a highly volatile, irritating, poisonous
and carcinogenic compound. Furthermore, diazomethane is
exceedingly heat-, light- and shock sensitive, and tends to
decompose explosively.8 Recently, our group and others have
developed strategies where generation, extraction and
consumption of diazomethane were integrated in a continuous
ow systems.9,10 Key to these protocols was the use of a semi-
permeable, micro-porous, hydrophobic membrane, which
selectively allows gases but not liquids to cross, to accomplish
the selective separation of anhydrous CH2N2 from an aqueous
feed.9 This approach was recently used by our group for the
preparation of a-halo ketones, chiral building blocks for the
synthesis of HIV protease inhibitors.9b
Less abundant than a-amino acids, b-amino acids represent an
important class of bioactive compounds.1,2 The presence of an a
methylene in b-amino acids gives b-amino acids higher
conformational exibility compared to their a-amino
analogues, strongly affecting the structural and biological
properties of b-peptides, such as secondary structure and the
rate of enzymatic degradation.1,2 Many secondary metabolites
found in nature have b-amino acids incorporated in their
structure, and the biological activities of these compounds are
frequently connected to the b-amino acid moiety, which makes
them potential lead structures for the development of new
drugs.1
Despite the plethora of interesting approaches for the
preparation of b-amino acids,1,3 the use of readily available
N-protected a-amino acids as starting materials for an Arndt–
Eistert homologation sequence4b is particularly attractive, since
the stereogenic center of the a-amino acids is retained in the
homologated product without signicant racemization (Scheme
1).1,2c,3b,4,5c The last step in this sequence, the Wolff rearrange-
ment,5 can be performed thermally under silver catalysis, or
photochemically induced,5b,c the latter approach being envi-
ronmentally more friendly and suitable to continuous ow
processing.6,7 Photochemical transformations in continuous
ow have several advantages compared to their batch counter-
parts, since common problems associated with photochemistry,
such as scalability and over irradiation can be overcome.6 The
relatively small channel diameters and the high surface-to-
volume ratio of capillary ow reactors assure efficient and
Herein we report a fully continuous four step synthesis of
b -amino acids from the respective protected a -amino acids. For
the synthesis of b -amino acids 4, four successive reactions have
to be accomplished (Scheme 1): activation of the amino acid 1 to
the mixed anhydride 2, acylation of diazomethane by the mixed
anhydride 2 to form the a-diazoketone 3, and nally the Wolff
rearrangement of the diazoketone with accompanying inter-
ception of the intermediate ketene with water to form the
b -amino acids 4.
To achieve the continuous four-step synthesis of b-amino
acids, we envisaged to couple the continuous ow preparation
Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010
Graz, Austria. E-mail: oliver.kappe@uni-graz.at
† Electronic supplementary information (ESI) available: Experimental procedures,
reaction optimization, and characterization of all compounds. See DOI:
10.1039/c4ra08113g
Scheme 1 Preparation of b-amino from a-amino acids.
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of a-diazoketones9 with a subsequent photochemically induced tributylamine (1.0 equivalent; feed C) in dry THF and a 2 mL
Wolff rearrangement. The initial optimization of the contin- solution of ethyl chloroformate (0.96 mmol, 1.5 equivalents;
uous photochemical Wolff rearrangement was performed with feed D) in dry THF were loaded into the sample loops of the two
the pure a-diazoketone derived from phenylalanine (3a). Several injection valves. When the ow reaction was started, the injec-
compact uorescent lights (CFL) were tested as light sources,6,11 tion valves were switched to connect the sample loop in line
and different reactor congurations and residence times were with the carrier stream (dry THF). The two reaction solutions
investigated (for details see the ESI†). The nal photochemical were pumped with ow rates of 75 mL minÀ1 into the T-mixer
reactor consisted of a commercial germicide compact uores- (TM1) and the merged stream then went through the tube
cent UV light (254 nm) surrounded by 3 mL of an UV-trans- reactor RT1 at room temperature. The mixture subsequently
parent peruoroalkoxy alkane (PFA) tubing with an outer passed through the outer chamber of the TiT reactor where the
diameter of 1.5 mm. The heat generated by the lamp was activated acid reacted with the dry diazomethane generated in
dissipated from the reactor by air cooling with a fan. To ensure a the inner tube (Fig. 1).9 Diazoketone formation was completed
stable ow rate, a back-pressure regulator (BPR, 6.9 bar) was in a second residence loop (RT2) attached downstream to the
attached at the downstream side of the photoreactor. For the outer tube of the tube-in-tube reactor. Finally, a solution of
ow reaction, a 0.16 M solution of the diazoketone 3a in THF THF/H2O 1 : 1 was fed into the system at a ow rate of 150 mL
was combined with a second feed of H2O/THF 1 : 1 in a T-mixer minÀ1 using a h pump and a further T-piece (TM3). The
and the combined stream passed through the photoreactor. reaction stream then went through the photoreactor at a
Complete conversion of the diazo compound 3a was obtained combined theoretical ow rate of 300 mL minÀ1 (Fig. 1).
with ow rates of 150 mL minÀ1 for both feeds (residence time in Formation of the diazoketone from the activated acid liberates
the photo reactor: 10 min) and the pure b-amino acid 4a was one equivalent of an acid and thus sequesters one equivalent of
isolated in 57% yield by column chromatography.
CH2N2 with an accompanying release of N2 gas. Furthermore,
With the optimized conditions for the photochemical step in due to photochemical and/or thermal decomposition of exces-
hand, we then evaluated the fully continuous synthesis of sive CH2N2 and diazoketone downstream of the TiT reactor, a
b-amino acids starting directly from a-amino acids. Therefore, considerable volume of nitrogen was generated. Therefore, the
the diazoketone was synthesized as reported previously from reaction mixture was driven through the photoreactor at
the respective activated a-amino acid in a commercially avail- considerably higher ow rates, resulting in relatively short
able tube-in-tube (TiT) reactor.9,12 The inner tube of that device residence times and incomplete rearrangement of the diazo-
is made of a hydrophobic, gas-permeable Teon AF-2400 ketone. Moreover, the presence of excess of diazomethane
membrane (0.8 mm inner diameter, 1 mm outer diameter, 4 m during the photochemical Wolf rearrangement could cause
length).12 For the generation of the anhydrous diazomethane, a side-reactions and could adversely affect the purity of the
0.6 M methanolic solution of N-methyl-N-nitroso-p-toluene- photochemical reaction step. Thus, in order to remove the
sulfonamide (Diazald) and a 1.2 M solution of KOH in MeOH/ generated nitrogen and any excess of diazomethane a 2 mL
H2O 1 : 1 were pumped at ow rates of 200 mL minÀ1 into a tubing of gas-permeable Teon AF-2400 was attached between
T-mixer by two syringe pumps. The combined stream passed the RT2 and TM3 units (RT3; Fig. 1).13 The permeable tubing
through a short residence tube and then further through the was immersed in an alcoholic solution of acetic acid to imme-
inner tube of the TiT reactor (Fig. 1). Diazomethane is formed in diately quench any diazomethane diffused through it. This
the inner tube and subsequently diffuses through the hydro- approach was successful in degassing the stream coming from
phobic, permeable wall into the outer chamber. The activation the RT2, providing a stable and diazomethane-free ow stream
of the N-protected a-amino acid was accomplished by means of to the photoreactor. The b-amino acid 4a was nally collected
a 1 mL residence loop (RT1), a T-mixer (TM1), two injection and isolated by chromatography in 40% product yield aer the
valves (SL1, SL2) and two further syringe pumps attached continuous ow four-step reaction sequence. The continuous
upstream to the outer tube of the TiT reactor (Fig. 1). A 2 mL ow setup was then used to prepare a variety of b-amino acids
solution of N-cbz-L-phenylalanine (0.64 mmol) and from the corresponding N-protected a-amino acids in yields
Fig. 1 Flow set-up for the continuous four-step Arndt–Eistert homologation of a-amino acids.
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and destroyed in a quench solution. A subsequent photo-Wolff
rearrangement provided the b-amino acids in reasonable over-
all yields. The on-demand generation–purication–consump-
tion of diazomethane, as described herein, eliminates all
human exposure to this hazardous reagent and reduces the risk
of explosive decomposition. The use of membranes to separate
and purify hazardous gases may allow a plethora of other
synthetic chemistry to be explored and performed in the future.
Fig. 2 b-amino acids prepared in continuous flow (Fig. 1).
Table 1 Continuous flow silver-catalyzed Wolff rearrangement
Acknowledgements
V.D.P. thanks CAPES for a postdoctoral scholarship (PGCI 5502-
13-6).
Notes and references
Flow
rate (mL)
T
(
Residence
time (min)
Conversiona
(%)
1 For a discussion of the synthesis and biology of b -amino
acids see: in Juaristi and V. A. Soloshonok, Enantioselective
Synthesis of Beta-Amino Acids, Wiley-VCH, Hoboken, N.J.,
2nd edn 2005.
ꢁ
Entry
C)
1
2
3
400
400
200
r.t
60
60
5
5
10
76
93
100 (71)
¨
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a
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U. Hommel and H. Widmer, Helv. Chim. Acta, 1997, 80,
Conversion determined by HPLC analysis.
¨
2033; (c) D. Seebach, M. Overhand, F. N. M. Kuhnle,
comparable to those reported for conventional batch proce-
dures (Fig. 2).14
B. Martinoni, L. Oberer, U. Hommel and H. Widmer, Helv.
Chim. Acta, 1996, 79, 13; (d) R. P. Cheng, S. H. Gellman
and W. F. DeGrado, Chem. Rev., 2001, 101, 3219.
As an alternative to the photochemical Wolff rearrangement,
we briey also explored the silver-catalyzed rearrangement
using reaction cartridges packed with silver oxide.5c,15 Accord-
ingly, 2 mL of a 0.16 M solution of diazoketone 3a in THF/EtOH
1 : 1 was pumped through a column packed with 1 g of silver
oxide/charcoal 1 : 1 (Table 1). Applying a ow rate of 400 mL
minÀ1 at room temperature a conversion of 76% to the
homologated ester was obtained. Full conversion was achieved
with a residence time of ꢀ10 min at a reaction temperature of
60 ꢁC. The pure homologated product was isolated in 71% yield
by chromatography (Table 1). ICPMS analysis of the processed
samples indicated that the catalyst is highly stable and does not
leach under the investigated reaction conditions (ꢀ0.05 ppm Ag
were detected in the samples; see ESI†). These preliminary
results suggest the participation of a heterogeneous silver
species in the catalytic cycle. Further investigations on mecha-
nistic aspects of the silver catalyzed rearrangement are ongoing
in our laboratories.
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¨
In conclusion, we have demonstrated a fully continuous four-
step synthesis of b-amino acids from a-amino acids following
the Arndt–Eistert homologation approach. For this process the
diazomethane was generated on-demand in a microreactor
environment and directly extracted from the aqueous feed using
a gas-permeable membrane. The anhydrous CH2N2 thus
generated was consumed by acylation with the activated amino
acid. Any excess of CH2N2 was immediately removed from the
reaction stream employing a second gas-selective membrane
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