A rapid and efficient one-pot method for the reduction of N-protected α-amino acids to chiral α-amino aldehydes using CDI/DIBAL-H

Article abstract of DOI:10.1039/c5ob01838b

N-Protected amino acids can be easily converted into chiral α-amino aldehydes in a one-pot reaction by activation with CDI followed by reduction with DIBAL-H. This method delivers Boc-, Cbz- and Fmoc-protected amino aldehydes from proteinogenic amino acids in very good isolated yields and complete stereointegrity.

Full text of DOI:10.1039/c5ob01838b

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A rapid and efficient one-pot method for the reduction of N-
protected α-amino acids to chiral α-amino aldehydes using
CDI/DIBAL-H
Received 00th January 20xx,
Accepted 00th January 20xx
Jakov Ivkovic,a Christian Lembacher-Faduma and Rolf Breinbauer*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
N-Protected amino acids can be easily converted into chiral α-
amino aldehydes in a one-pot reaction by activation with CDI
followed by reduction with DIBAL-H. This method delivers Boc-,
Cbz- and Fmoc protected amino aldehydes from proteinogenic
amino acids in very good isolated yields and complete
stereointegrity.
Introduction
Chiral N-protected
α-amino aldehydes are tremendously
valuable building blocks,1 which have seen numerous
applications in the synthesis of biologically active molecules.2
Typically their synthesis starts from the chiral pool with readily
accessible N-protected amino acids following two distinct
routes (Scheme 1).3 In the first (Route A), the amino acid
converted into an activated carboxylic acid derivative , such
as an ester4 or a Weinreb amide,5 and then directly reduced to
the corresponding aldehyde . The second (Route B) starts
from the same N-protected amino acid , which is first fully
reduced to the corresponding amino alcohol and selectively
reoxidized to the desired The major
-amino aldehyde B 6
challenge for both routes is the intrinsic lability of the
stereogenic centre of -amino aldehydes, which is prone to
epimerization especially in the presence of acid or base.7
In the course of an ongoing project in our group to design
and synthesize transition state mimetics as inhibitors for a
peptidase target protein, we required a scalable access to Boc-
valinal. In our first attempt we synthesized the aldehyde
following the procedure of Morwick by converting Boc-valine
into the corresponding Weinreb amide using activation by
Staab’s reagent (CDI, 1,1’-carbonyldiimidazole).8 The Weinreb
amide was isolated and converted to Boc-valinal by reduction
with LiAlH4 in 85% yield under complete retention of
stereoconfiguration. While this two-step method delivered the
A is
C
Scheme 1 Two distinct routes for the synthesis of α-amino aldehydes and conversion
of amino acids to amino aldehydes using CDI/DIBAL-H.
B
desired product, we regarded the necessity to isolate the
intermediate Weinreb-amide as a time-consuming nuisance,
and reasoned that this step could be avoided if the
intermediate acyl imidazolide9 would serve as a substrate for
the DIBAL-H reaction. Stammer et al. have already reported in
A
D
α
.
α
1979 such
a
method,10 which despite its apparent
attractiveness has seen little application,11 very likely because
in the original paper optical rotation studies, which have been
pursued for only one product in detail (Cbz-leucinal), indicated
that this product was produced in only 60% ee. Despite this
caveat we were encouraged by this literature precedence and
can now report that through optimization of reaction
parameters the one-pot production and reduction of acyl
imidazolides provides an attractive rapid and efficient access
to chiral α-amino aldehydes.
Results and Discussion
As a test substrate we chose Boc-valine to establish a suitable
protocol for the CDI/DIBAL-H method. After considerable
optimization in which we varied solvent, temperature, reaction
time and workup conditions in comparison to the literature
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Table 1 Selection of α-amino aldehydes obtained via CDI/DIBAL-H reduction.
Entry
Product
Yield
84%
ee
>99% a
1
3a
3b
2
3
87%
96%
-
>99% a
Scheme 2 One-pot synthesis of α-amino aldehydes using CDI and DIBAL-H.
3c
precedence of Stammer,10a we arrived at the following
protocol in which a solution of N-protected amino acid in DCM
was treated with 1.1 eq of CDI at 0 °C for 60 min. Subsequently
2.1 eq of DIBAL-H were added dropwise to the resulting
solution at -78 °C (Scheme 2). In the course of our studies we
recognized that the outcome of this process depended on the
quality of the used CDI and we recommend the use of CDI
recrystallized from dry THF,12 which can be stored in nitrogen
or argon atmosphere at 4 °C for at least 8 weeks. Special
attention had to be paid for the workup of the DIBAL-H
reduction reaction. In order to avoid basic conditions and
prolonged workup, which could cause loss of chiral integrity of
the resulting amino aldehyde,7 we have devised a quick
method of quenching and aluminium complexation using a
solution of tartaric acid instead of the commonly used
Rochelle-salt solution.13 This method provided slightly acidic
quenching conditions, and dramatically shortened the
dissolution times of aluminium salts to less than 20 min even
on multigram scale reactions compared to 2 h when using
Rochelle-salt. We were pleased to see that by this extractive
workup we could isolate Boc-valinal (3a) already in pure form
as judged by NMR and chiral GC, thereby avoiding purification
via flash chromatography on silica.
4
5
3d
3e
97%
92%
>99% b
>99% a
6
7
3f
91%
>99% a,c
3g
62% d
-
8
9
3h
3i
87%
>98% a
99%
94%
>97% b
>99% b
With the optimized protocol in hands, a selection of
proteinogenic amino acids with different N-protecting groups
was converted to the corresponding aldehydes in excellent
yields and high purity based on NMR and gas chromatography
analysis (Table 1). The data on enantiomeric purity were
determined by gas chromatography using prepared reference
racemic samples, while for substrates which could not be
separated via chiral GC optical rotations are reported in the
ESI. Boc-valine was converted to the corresponding aldehyde
in 84% yield and >99% ee on a 10 gram-scale (Entry 1), as well
as other Boc-protected amino acids (Entries 2-6) were
obtained in excellent yields. An informative test substrate for
our method was phenylalanine, known as the most
racemisation-prone proteinogenic amino acid in peptide
synthesis.14 In the event Boc-phenylalaninal (3c) was produced
with the CDI/DIBAL-H method in >99% ee as judged by chiral
GC (Entry 3), and Cbz-phenylalaninal (3i) with >97% ee
measured by chiral HPLC after reduction of the isolated
aldehyde with NaBH4 (Entry 9).15 This result allows us to expect
that our method can generally cover the conversion of
proteinogenic amino acids to chiral amino aldehydes without
10
11
3j
3k
72% d, e >99% b
12
3l
52% d, f
-
83%
(72%) a, g
13
3m
88%
a
b
Chiral-GC-FID based measurement;
Chiral HPLC-based measurement;
c
d
diastereomeric excess; Isolated by flash chromatography on silica due to
lower purity of the crude material, to determine the abundance of the desired
aldehyde; e 3.35 eq DIBAL-H used; f 4.00 eq DIBAL-H used; g 83% ee obtained by
adding 0.5 eq CuCl2 during the activation step, and 72% ee when no additive was
used under the same conditions.
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racemization (Entried 4-6, 10-11) – even in the cases in which
no suitable ee-determination method with chiral GC or HPLC is
currently available. In order to compare our improved protocol
with the original one by Stammer10a we investigated the
reduction of Cbz-leucine to Cbz-leucinal (3h) (Entry 8) and
could determine >98% ee via chiral GC (compared to the
reported 60 % ee in their publication, which had been
determined via optical rotation). This confirms that by our
modifications the one-pot strategy of CDI-activation/DIBAL-H
reduction could be developed into a feasible and useful
no additive
0.5 eq Cu(II) chloride
90.0
80.0
70.0
60.0
50.0
40.0
30.0
20.0
method for the synthesis of N-protected α-amino aldehydes.
0.50
1.00
1.50
2.00
2.50
3.00
In terms of functional groups in the side chain, we could
notice that this method reduces acyl imidazolide significantly
faster than methyl ester, as exemplified for protected
aspartate aldehyde 3g (Entry 7). Notably Fmoc-protection was
orthogonal to the reaction conditions, although at least one
more equivalent of DIBAL-H had to be added to complete the
conversion to the aldehydes 3k and 3l (Entries 11-12).
Rate of addition of DIBAL-H [mL/h]
conversion, accompanied by lower reaction concentrations to
avoid gelation that occurred otherwise. A similar degree of
epimerization was found for both peptide aldehydes (Entries
1-2). We reasoned that epimerization occurs already at the
activation step with CDI via an oxazolone intermediate,
according to a mechanism well known in peptide coupling.22
Consequently, we attempted to suppress epimerization by
using additives developed for peptide coupling14,23 and mild
acidic buffering with pyridinium p-toluenesulfonate during the
activation step (Entries 4-8). Among these only the addition of
1.0 eq of HOBt or HOAt led to an increase in
diastereoselecitivity to 90% de, which still reflects the
limitation of this method that the rather slow formation of
peptide-imidazolides at lower temperatures is accompanied by
epimerization presumably via oxazolone formation.
After having established the scope of this robust protocol
for the conversion of proteinogenic amino acids, we wanted to
check the limitations of our method and apply it to
phenylglycine – a very challenging substrate, which racemizes
very easily and for which only few stereoselective
transformations are known.16 Myers et al. have successfully
accessed Fmoc-phenylglycinal via oxidation of Fmoc-
phenyglycinol
with
Dess-Martin-periodinane,17
while
Wroblewski and Piotrowska demonstrated the same with Boc-
and Bz-phenylglycine.18 When we tested our CDI/DIBAL-H
method for Boc-Phg we received the product in good 88%
yield, but disappointing enantiopurity of 72% ee. We
rationalized that the second equivalent of DIBAL-H is necessary
to complete the conversion of the acyl imidazolide
intermediate due to the presence of one equivalent of
imidazole byproduct from the activation step. Thus imidazole
deprotonated by the hydride reagent is thought to be a base
contributing to racemization of the product. We hypothesized
that by addition of complexing metal salts we could scavenge
deprotonated imidazole. Copper(II) salts were found to
produce complexes with imidazole in DCM (in 60 min vs >24 h
in case of nickel salts) based on visual observation.19
Consequently, we performed a series of experiments adding
copper(II) chloride as a scavenging agent additive after CDI
activation and prior to the addition of DIBAL-H. The addition of
0.5 eq CuCl2 enhanced the ee of produced Boc-phenylglycinal
Table 2 Synthesis of peptide aldehydes using the CDI/DIBAL-H procedure.
Entry
1
Product
Additive
DIBAL-H yield de
Boc-Val-L-Phe-H
(4a)
-
3.1 eq
3.1 eq
4.0 eq
3.5 eq
4.5 eq
89% 79%
95% 77%
52% 81%
99% 69%
93% 90%
Boc-Val-D-Phe-H
(4b)
2
3
4
5
-
4b
4b
4b
CuCl2, 1.0 eq
PPTS, 1.0 eq
HOBt, 1.0 eq
HOBt, 1.5 eq
(
3m) in each experiment, in contrast to parallel experiments
with no additives (Figure 1). Adding more than 0.5 eq of CuCl2
did not further increase the enantiomeric purity. Additional
factors that improve ee of the resulting Boc-phenylglycinal are
precise rate of addition of DIBAL-H and temperatures lower
than -50 °C, which are also beneficial for the yield.20
6
7
4b
4b
4.5 eq quant. 79%
4.5 eq 84% 85%
4.5 eq quant. 90%
HOBt, 1.5 eq,
4Å mol. sieves
Another test case which could define the limits of our
method, was the synthesis of peptide aldehydes,21 in particular
with the epimerization prone Phe at the C-terminus.14 From
the corresponding dipeptide acids, the CDI/DIBAL-H procedure
furnished two epimeric aldehydes, 4a and 4b, in good yields
8
4b
HOAt, 1.0 eq
Due to instability of aldehydes in HPLC conditions, de was measured after
reduction15 to the corresponding alcohols, which were readily separated by
and purities (Table 2). In these cases increased amounts of reverse phase HPLC; PPTS: pyridinium p-toluenesulfonate; HOBt: 1-
hydroxybenzotriazole; HOAt: 1-hydroxy-7-azabenzotriazole.
DIBAL-H (3.1–4.5 eq in total) were necessary to complete the
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In summary, we have presented an efficient one-pot method
for the conversion of N-protected amino acids into chiral N-
7
protected
α-amino aldehydes by in situ activation with CDI
followed by reduction with DIBAL-H. The advantages of this
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Acknowledgements
This work was supported by the doctoral program W901-B05
DK Molecular Enzymology, funded by the Austrian Science
Fund (FWF) and by NAWI Graz.
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