Synthesis of Enantiomerically Pure N-Acyl Amino Nitriles via Catalytic Dehydration of Oximes and Application in a de Novo Synthesis of Vildagliptin

Article abstract of DOI:10.1021/acs.oprd.7b00169

An alternative route toward enantiomerically highly enriched N-acyl amino nitriles based on the Cu(OAc)₂-catalyzed dehydration of aldoximes, which are readily available from N-acyl l- or d-α-amino aldehydes through condensation with hydroxylamine, has been developed. The desired products were obtained with high conversion and in enantiomeric excesses of 97-99% ee. Furthermore, this method has been applied in the synthesis of an N-chloroacetylated 2-cyanopyrrolidine, which represents a building block for the synthesis of Vildagliptin.

Full text of DOI:10.1021/acs.oprd.7b00169

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Full Paper
Synthesis of Enantiomerically Pure N-Acyl Amino Nitriles via Catalytic
Dehydration of Oximes and Application in a de novo-Synthesis of Vildagliptin
Philipp Rommelmann, Tobias Betke, and Harald Gröger
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00169 • Publication Date (Web): 12 Jul 2017
Downloaded from http://pubs.acs.org on July 13, 2017
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Synthesis of Enantiomerically Pure NꢀAcyl Amino
Nitriles via Catalytic Dehydration of Oximes and
Application in a de novoꢀSynthesis of Vildagliptin
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Philipp Rommelmann, Tobias Betke, and Harald Gröger*
Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitätsstr. 25,
33615 Bielefeld, Germany
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Table of Contents Graphic and Synopsis
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KEYWORDS: αꢀAmino nitriles; Catalysis; Dehydration; Nitriles; Oximes; Vildagliptin.
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ABSTRACT: An alternative route towards enantiomerically highly enriched Nꢀacyl amino
nitriles based on the Cu(OAc)2ꢀcatalyzed dehydration of aldoximes, which are readily available
from Nꢀacyl
Lꢀ or
D
ꢀαꢀamino aldehydes through condensation with hydroxylamine, has been
developed. The desired products were obtained with high conversion and in enantiomeric
excesses of 97ꢀ99% ee. Furthermore, this method has been applied in the synthesis of an Nꢀ
chloroacetylated 2ꢀcyanopyrrolidine, which represents a building block for the synthesis of
Vildagliptin.
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A major interest in current fine chemicals research centers on the discovery and development of
novel synthetic routes towards pharmaceuticals or key building blocks thereof. One of such key
building blocks gaining increasing attention in recent years are enantiomerically pure Nꢀacylated
αꢀamino nitriles of type 1 since such chiral nitrile structures can be found as key fragments in
pharmaceuticals (Scheme 1).1 Representative examples of active pharmaceutically ingredients in
this field are Vildagliptin (2),2 which has been developed and commercialized by Novartis, NVPꢀ
DPPꢀ728 (3) and Saxagliptin (4) as a drug from BMS (Scheme 1).3,4 Vildagliptin is a drug
against diabetes type II, and sales with this drug were 1.2 billion USꢀ$ in 2013. It turned out that
the drug interaction with the target protein is related to the presence of the nitrile moiety in such
drugs.1
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Scheme 1. General structure of a chiral Nꢀacylꢀαꢀamino nitrile and pharmaceutically relevant
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representatives thereof (Vildagliptin, NVPꢀDPPꢀ728, Saxagliptin).
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Thus, efforts have been made to develop efficient synthetic routes towards enantiomerically pure
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αꢀamino nitriles or derivatives thereof, in particular those being derived from Lꢀproline and
substituted derivatives due to their application in the preparation of Vildagliptin (2), NVPꢀDPPꢀ
728 (3) and Saxagliptin (4).2,4 As
attractive starting material (with a price reported to be in the range of 40 $/Kg)5 synthetic routes
Lꢀproline represents a readily available and commercially
starting from this Lꢀamino acid as an enantiomerically pure raw material from the chiral pool
were developed. First, an Nꢀacylation and amide formation gives the intermediate (S)ꢀ6.
Subsequent dehydration utilizing the Vilsmeier reagent 7 then furnishes the chiral nitrile (S)ꢀ5,
which can be regarded as a nitrile analogue of the corresponding Nꢀacylated L
ꢀproline.2 For the
final step of the Vildagliptin synthesis, Novartis researchers developed an elegant approach
based on the use of this Nꢀprotected pyrrolidine 2ꢀnitrile of type (S)ꢀ5 by means of a substitution
reaction (Scheme 2).
Scheme 2. NꢀAcylꢀαꢀamino nitrile (S)ꢀ5 as key intermediate in the synthesis of Vildapliptin.
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Typically the access towards Nꢀacylated chiral nitriles of type (R)ꢀ und (S)ꢀ1 is achieved through
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a multiꢀstep synthesis starting from (i) either prochiral imines or (ii) Lꢀamino acids as “chiral
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pool molecules”.2,6,7 The first approach (i) is based on an asymmetric Strecker reaction as a key
step, and recently a range of efficient asymmetric Strecker reactions by means of suitable chiral
chemocatalysts have been developed.6 Although high conversion and enantioselectivity can be
achieved in many cases with different types of (metal or organoꢀ) catalysts, limitations exist.
Typically these reactions are carried out with acyclic, Nꢀsubstituted imines, which would not
enable a (direct) synthetic access towards prolineꢀbased nitriles nor towards αꢀamino nitriles
bearing a primary amino group (as nitrileꢀanalogues of natural α–amino acids). Furthermore, the
need of highly toxic cyanide represents another disadvantage. An alternative method (ii), which
has been applied by Novartis researchers for the preparation of Vildagliptin, represents the
activation and subsequent dehydration of an Nꢀacylated enantiomerically pure Lꢀamino acid
amide (here: Nꢀchloroacetyl
Lꢀproline amide, (S)ꢀ6) under formation of the desired αꢀamino
nitrile in Nꢀprotected form (according to the reaction shown in Scheme 2).2,3 As a starting
material in the synthesis of Vildagliptin,
Lꢀproline amide is used, which is accessible through
amidation of the readily available natural amino acid
Lꢀproline. In addition, the Vilsmeier reagent
is utilized for the „formal dehydration“ step. The efficient synthesis of nonꢀsubstituted, primary
amides, however, still often represents a challenge, and the soꢀcalled „Vilsmeier reagent“ and its
application is causing formation of a significant amount of waste as well as tedious unit
operation steps for such a desired dehydration process. In order to overcome major hurdles of
this process Novartis Pharma researchers found an elegant solution based on flow chemistry.2c
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Addressing the challenge to develop an efficient and sustainable alternative cyanideꢀfree general
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approach towards Nꢀacyl αꢀamino nitriles, which is also applicable to a de novoꢀaccess towards
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Vildagliptin, we studied a twoꢀstep approach consisting of an initial transformation of Nꢀacyl αꢀ
amino aldehydes to the corresponding oximes and their catalytic dehydration under formation of
the desired chiral nitrile products. This synthetic concept is shown in Scheme 3 exemplified for
the formation of an acyclic as well as a cyclic Nꢀacyl αꢀamino nitrile, namely the transformation
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of NꢀBoc Lꢀ and Dꢀphenylalanineꢀ and NꢀBoc Lꢀ and Dꢀprolineꢀderived aldehydes (S)ꢀ and (R)ꢀ9
and (S)ꢀ and (R)ꢀ12, respectively, into their corresponding nitriles (S)ꢀ and (R)ꢀ11 and (S)ꢀ and
(R)ꢀ14, respectively. The first transformation is a simple, nonꢀcatalytic and spontaneous
condensation of the aldehyde moiety into the oxime, whereas the second reaction consists of a
dehydration of the oximes. Although in general a range of methods are known for the
dehydration of acyclic oximes, our attention was in particular driven to a copperꢀcatalyzed
dehydration with acetonitrile serving as both, reagent and solvent.7 The byꢀproduct in this
transformation is acetamide, which is formed from acetonitrile in this catalytic dehydration of the
oxime. The overall process appears to be economical and sustainable under the prerequisite that
racemization of the enantiomerically pure starting material can be suppressed. An advantage of
this method is the avoidance of highly toxic cyanide as a reagent, which is not required for this
synthetic sequence. Furthermore, this process runs under smooth conditions, thus avoiding harsh
reaction conditions. Another advantage is that the starting materials are readily accessible from
the chiral pool, in particular when intending to prepare nitriles derived from proteinogenic amino
acids such as Lꢀproline. In addition, hydroxylamine used as reagent and nitrogen component is a
raw material being readily available in bulk quantities due to its use in the manufacture of εꢀ
caprolactam with an annual production volume on a multiꢀmillion tons scale.8
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Scheme 3. Synthetic concept for the twoꢀstep conversion of NꢀBoc αꢀamino aldehydes into the
corresponding nitriles.
In the following we report our results on the development of such a synthesis of Nꢀacyl αꢀamino
nitrile and its application towards a de novoꢀmulti step synthesis of Vildagliptin.
Our initial investigations addressed the question which catalytic system would be appropriate for
an economically attractive nitrile synthesis with utilization of ideally nonꢀtoxic reagents and a
broad applicability in terms of substrate range. While numerous methods for the synthesis of
nitriles from aldoximes have been developed in recent years, many of them rely on the use of
hazardous reagents like oxalyl chloride9, trifluoroacetic anhydride10, ethyl dichlorophosphate11 or
hexamethyldisilazane (HMDS)12 and the utilization of bases like diazabicycloundecene (DBU),
triethylamine or pyridine. Oneꢀpot procedures which allow nitrile syntheses starting from
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aldehydes have also been developed, but those methods are based on the use of either HMDS in
combination with a catalyst12 or a nitrogen source which has to be synthesized beforehand.13 The
mildest methods so far have been metal catalyzed nitrile syntheses, utilizing e.g. Cu7, Pd14 or
other metal catalysts. Very recently, an interesting approach has been developed by Kyodo et al.
synthesizing nitriles from oximes via iron catalysis under nitrileꢀfree conditions.15 They were
inspired by the mechanism of aldoxime dehydratases, which utilize a heme group containing FeII
to dehydrate oximes into nitriles in aqueous medium.16 However, the methodology disclosed by
Kyodo et al. operates at low substrate concentrations (50 mM) in order to achieve good
selectivity and needs high reaction temperatures (refluxing toluene) as well as long reaction
times (24 hours).
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Taking into account the advantages and drawbacks of the various methodologies, for our study
on the development of a synthesis of enantiomerically enriched Nꢀacyl amino nitriles from
aldoximes we decided to apply the method based on the utilization of Cu(OAc)2 as a catalyst7
because it benefits from low cost reagents, short reaction times (usually 1ꢀ2 hours) and easy
work up (filtration over silica).17 In addition, copper represents an abundant and economically
attractive metal component, offering advantages also from the perspective of toxicity. As a
starting material for our synthetic approach towards enantiomerically pure Nꢀacylated amino
nitriles we synthesized the
D
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Lꢀenantiomeric form of NꢀBocꢀprotected aldoximes (10 and
13) starting from the ꢀ and
D
Lꢀamino aldehydes of proline (9) and phenylalanine (12). Simple
condensation with readily available hydroxylamine then furnished the aldoximes (R)ꢀ and (S)ꢀ10
as well as (R)ꢀ and (S)ꢀ13 with complete conversions and in high yields of up to 92% (see
Supporting Information).
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A subsequent Cuꢀcatalyzed dehydration then gave successfully the corresponding nitriles (R)ꢀ
and (S)ꢀ11 as well as (R)ꢀ and (S)ꢀ14 (Table 1). For this dehydration step, a catalytic loading of
the copper catalyst Cu(OAc)2 being in the range of 2ꢀ10 mol% was used in combination with
acetonitrile as a solvent. We were pleased to find that under these conditions the NꢀBocꢀ
protected αꢀamino nitriles of proline ((S)ꢀ11 and (R)ꢀ11) and phenylalanine ((S)ꢀ14 and (R)ꢀ14)
could be synthesized in high yields ranging from 83 to 92% and with excellent enantiomeric
excesses (>99% ee). Thus, these multiꢀstep transformations of enantiomerically highly enriched
Nꢀacyl amino aldehydes 9 and 12 (which are accessible from the corresponding amino acids as
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chiral pool molecules in case of the Lꢀenantiomers) to the nitriles of type 11 and 14 via the
aldoxime intermediates 10 and 13 proceed under formation of the products with still high
enantiomeric excess. Thus, in spite of enolizable aldehydes as starting materials being in
principle prone to racemization, no or only a negligible loss of enantiomeric excess takes place
during the twoꢀstep transformation into the desired nitrile products (as confirmed via chiral GC
or HPLC, see Supporting Information), which is crucial for the implementation of the process for
the synthesis of pharmaceutically relevant enantiomerically pure compounds such as, for
example, Vildagliptin (Table 1).
Table 1. Twoꢀstep synthesis of prolineꢀderived nitrile 11 and phenylalanineꢀderived nitrile 14
utilizing dehydration catalyzed by Cu(OAc)2 as a key step
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entrya
substrate
product
catalyst
loading
[mol%]
yield [%]
eeꢀvalue
of
the
product
[%]b
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3
(S)ꢀ10
(R)ꢀ10
(S)ꢀ13
(R)ꢀ13
(S)ꢀ11
(R)ꢀ11
(S)ꢀ14
(R)ꢀ14
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The purity of the commercially available aldehydes 9 and 12 was 97% (according to the
b
information of the supplier, see Experimental Section). The enantiomeric excess (ee) was
determined via chiral GC (entries 1 and 2) and chiral HPLC (entries 3 and 4); see Supporting
Information.
Based on these results, next we were interested in minimizing the required amount of acetonitrile
(which was used as both, reagent and solvent before, see Table 1) and getting an insight into the
impact of other solvents on the course of the dehydration reaction. Toward this end, we
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synthesized (S)ꢀ11 in different mixtures of widely applied solvents with acetonitrile. To decide
how much acetonitrile in relation to the amount of oxime (S)ꢀ10 is necessary for an efficient
conversion, we firstly used ethyl acetate as major solvent and added different amounts of
acetonitrile. The use of only one equivalent of acetonitrile already led to the desired nitrile (S)ꢀ11
with more than 50% conversion (Figure 1a). This positive result with only one equivalent of
acetonitrile was encouraging for further process development, and additionally it can be regarded
as a support for the proposed reaction mechanism.7b,14 According to this proposed reaction
mechanism,7b,14 only one equivalent of acetonitrile is theoretically needed for this metal ion
catalyzed dehydration, since one equivalent of water is transferred from the oxime to acetonitrile
under formation of nitrile and acetamide. The reaction is proposed to proceed through a
copper(II)ꢀoximeꢀacetonitrile complex.7b,14 In order to increase the reaction rate of this process,
next we investigated the impact of an increasing amount of acetonitrile of up to ten equivalents.
We were pleased to observe a beneficial effect of elevated amount of acetonitrile. For example,
the use of 10 equivalents of acetonitrile resulted in a conversion of 80% for the reaction of (S)ꢀ10
to (S)ꢀ11. The use of 15 or more equivalents of acetonitrile then gave results comparable to the
ones in pure acetonitrile without additional ethyl acetate. In these cases, a high conversion of
92% was achieved (Figure 1a).
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a) varying amounts of acetonitrile
(solvent: ethyl acetate)
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(amount of acetonitrile: 10 equivalents)
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Figure 1. a) Conversion to nitrile (S)ꢀ11 in dependency on varying amounts of acetonitrile in
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ethyl acetate, determined by HꢀNMR measurements. b) Conversion to nitrile (S)ꢀ11 in
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dependency on varying solvents with ten equivalents of acetonitrile, determined by HꢀNMR
measurements.
As the use of ten equivalents of acetonitrile appeared to be the best compromise between
yielding a high conversion and minimized use of reagent, we conducted a study of other solvents
besides ethyl acetate with this stoichiometric amount of acetonitrile (Figure 1b). This solvent
study revealed that highly polar, protic solvents as methanol and ethanol give comparable good
results with conversions of up to 80%. However, when utilizing water as a major solvent, the
conversion decreases to a value below 50%. In this case, water can be expected to serve as a
competitive ligand, which is binding to the copper center ion instead of the desired oxime, thus
suppressing the catalytic cycle under formation of the desired nitrile product and the stable
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acetamide byꢀproduct from the oxime and acetonitrile. This type of negative impact of water has
also been reported earlier for related copperꢀcatalyzed dehydration reactions with other oxime
substrates.7b In addition we were pleased to find that with apolar, aprotic solvents, like
cyclohexane and toluene, slightly increased conversions of up to 90% were obtained. The best
result emerged from the reaction using the green solvent dimethyl carbonate. In this case, the
desired nitrile (S)ꢀ11 was produced with an excellent conversion of 94%.
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With this synthetic tool in hand, we implemented the aldehydeꢀoximeꢀnitrile sequence in the
total synthesis of Vildagliptin, which represents a new, alternative approach to this
pharmaceutically active compound (Scheme 4). As a starting material for this synthetic route we
chose
Lꢀprolinate, 15, as an easily accessible derivative of the inexpensive chiral pool molecule
Lꢀproline.
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Scheme 4. New synthetic approach towards Vildagliptin (2) based on Cuꢀcatalyzed dehydration
of an Lꢀprolineꢀderived aldoxime intermediate as a key step.
Starting from this carboxylic acid ester (S)ꢀ15, the initial chemical key transformation consisted
in the reduction of the ester to the aldehyde moiety. Since a direct selective reduction would
involve industrially unfavorable reaction conditions, e.g., expensive reagents and very low
temperature when utilizing diisobutylaluminium hydride at ꢀ78 °C, we decided to reduce the
ester to the alcohol first. This reduction was carried out by means of a hydrogenation with the
commonly used Takasagoꢀcatalyst RuꢀMACHO18, leading to
Lꢀprolinol, (S)ꢀ16, with excellent
conversion of >99% and a nonꢀoptimized yield of 25%. Next, acylation of the amino moiety in
(S)ꢀ16 with chloroacetyl chloride proceeds selectively19 and gave the desired Nꢀacyl
Lꢀprolinol
(S)ꢀ17 in 71% yield. We also tried to hydrogenate the ester after successful Nꢀchloroacetylation
of the amine functionality, but this reaction sequence was not fruitful as we could not find any
conversion to the desired alcohol (S)ꢀ17. For the subsequent selective oxidation of alcohol (S)ꢀ17
to the corresponding aldehyde (S)ꢀ18, two different methods were investigated. However, the
Swern oxidation led to a decomposition of the substrate without product formation. Thus, as an
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alternative method we applied the smooth TEMPO mediated oxidation20, which yielded the
desired aldehyde (S)ꢀ18 in 54% yield. Finally, we incorporated the established synthetic
aldehyde – aldoxime – nitrile pathway by means of copperꢀcatalysis into the total synthesis of
Vildagliptin: the aldoxime (S)ꢀ19 was generated by condensation of the aldehyde (S)ꢀ18 with
hydroxylamine. The reaction proceeds very efficient with 99% conversion. Since workꢀup was
not optimized so far, the yield of (S)ꢀ19 did not exceed 45%. Subsequent dehydration of the
aldoxime (S)ꢀ19 led to the key intermediate (S)ꢀ5 with >99% conversion and in 61% yield. This
chiral nitrile (S)ꢀ5 can then serve as a precursor for the synthesis of the target compound 2, and
this reaction step has already been described in literature.2 Thus, by means of this novel synthetic
pathway the Nꢀacyl amino nitrile (S)ꢀ5 (which represents a Vildagliptin precursor) was obtained
within five simple chemical transformations with a copperꢀcatalyzed aldoxime dehydration as a
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key step when starting from the chiral pool compound Lꢀproline methyl ester (15).
In conclusion, an alternative route towards enantiomerically highly enriched Nꢀacyl αꢀamino
nitriles based on a Cu(OAc)2ꢀcatalyzed dehydration of aldoximes, which are readily available
from Nꢀacyl
Lꢀ or
D
ꢀαꢀamino aldehydes through condensation with hydroxylamine, has been
developed. The desired products were obtained with high conversion and with enantiomeric
excesses of 97ꢀ99% ee. Furthermore, this method has been applied in a novel, alternative total
synthesis of Nꢀchloroacetylated (S)ꢀ2ꢀcyanopyrrolidine, which represents a key building block
for the synthesis of Vildagliptin. Further process development on the various steps of the total
synthesis of Vildagliptin are a task of current and future work, comprising improvement of the
synthetic access to the Nꢀacyl prolinal, increase of spaceꢀtimeꢀyield and downstreamꢀprocessing.
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With respect to the latter issue, besides high yields of the intermediates and final nitrile product
also removal of the copper component from the nitrile product represents a challenge.21
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EXPERIMENTAL SECTION
Materials and Methods. The NꢀBocꢀprotected amino aldehydes of phenylalanine and proline
were purchased from Sigma-Aldrich and used without further purification. According to the
supplier, the purity of these compounds (NꢀBocꢀ
Lꢀprolinal, NꢀBocꢀDꢀprolinal, NꢀBocꢀLꢀ
phenylalaninal, NꢀBocꢀ ꢀphenylalaninal) was 97%. Other reagents were purchased from
D
Alfa Aesar, from fluorochem and from Acros Organics and also used without further
1
purification. Hꢀ and 13CꢀNMR spectra were recorded on a Bruker Avance 500 at 500 MHz
(1H) or 125 MHz (13C) in deuterated dichloromethane (CD2Cl2) or deuterated chloroform
(CDCl3) without the usage of an internal standard. Chemical shifts are reported in ppm.
Mass spectra were recorded on an Esquire 3000 using electron spray ionization (ESI). IRꢀ
spectra were recorded on a Thermo Nicolet 380 FTꢀIR. GCꢀchromatograms were recorded
on a Shimadzu GCꢀ2010 using the column Agilent CPꢀChirasilꢀDex CB with different
temperature programs. Melting points were determined with a Büchi Melting Point Bꢀ540
and are uncorrected. Optical rotation angles were measured on a Perkin Elmer Polarimeter
Model 341. Column chromatography was performed either manually or using an automatic
column chromatography system Isolera One by Biotage. RPꢀHPLCꢀchromatograms were
recorded on a JASCO system utilizing a Macherey-Nagel Nucleodur C18 HTec column with
different ratios of water/acetonitrile as mobile phase (listed below). NPꢀHPLCꢀchromatograms
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were recoreded on a JASCO system utilizing a Daicel Chiracel ADꢀH column with different
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ratios of supercritical CO2/Isopropanol as mobile phase.
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N-Boc
and sodium carbonate (159 mg, 1.50 mmol) were diluted in H2O (3 mL) and ethanol (2 mL) at
room temperature. After the addition of NꢀBocꢀ ꢀprolinal ( ꢀ9, 199 mg, 1.00 mmol) the resulting
L-E/Z-prolinal oxime ((S)-E/Z-10). Hydroxylamine hydrochloride (104 mg, 1.50 mmol)
L
L
solution was stirred for 20 hours, upon which complete conversion was achieved according to
TLC analysis. The solution was extracted three times with ethyl acetate (each 5 mL) and the
combined organic phases were washed with H2O (5 mL). Drying over MgSO4 and evaporation
of the solvent gave a crude product, which was purified by silica column chromatography
(cyclohexane:ethyl acetate 3:1, v/v) to obtain oxime (S)ꢀE/Zꢀ10 (143 mg, 67%) as a colorless oil
1
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with an E/Z ratio of 65:35 (determined by HꢀNMR spectroscopy in CDCl3). HꢀNMR (500
MHz, CDCl3) δ 8.36 + 8.21 (2 s, 1H, Z-NOH), 8.01 + 7.90 (2 s, 1H, E-NOH), 7.40 + 7.31 (2 s,
1H, EꢀCHNOH), 6.74 + 6.69 (2 s, 1H, ZꢀCHNOH), 4.88 + 4.83 (2 s, 1H, Z-BocNCH), 4.46 +
4.31 (2 s, 1H, E-BocNCH), 3.41 (m, 2H, BocNCH2), 2.26 – 1.75 (m, 4H, BocNCH2CH2CH2),
1.46 + 1.44 (2 s, 9H, BocꢀH). These data are in accordance with literature.22
N-Boc (S)-pyrrolidine 2-carbonitrile ((S)-11). Copper(II) acetate (2.58 mg, 11.5 µmol) was
dissolved in acetonitrile (7 mL). NꢀBoc (S)ꢀE/ZꢀLꢀprolinal oxime ((S)ꢀE/Zꢀ10, 123 mg,
570 µmol) was added and the reaction mixture was heated to reflux for 7 hours and stirred for
another 16 hours. After removal of the acetonitrile in vacuum, the crude product, containing one
equivalent of acetamide, was dissolved in cyclohexane/ethyl acetate (2:1, v/v) and filtered over a
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small silica column (4 cm), effectively removing acetamide and residual copper(II) acetate.
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Removal of the solvent yielded nitrile (S)ꢀ11 (97 mg, 86%) as a colorless oil with an
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enantiomeric excess of 97%. HꢀNMR (500 MHz, CDCl3) δ 4.57 + 4.45 (2 d, 1H, CHCN), 3.51
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+ 3.37 (2 m, 2H, BocNCH2), 2.25 – 2.02 (m, 4H, BocNCH2CH2CH2), 1.51 + 1.48 (2 s, 9H, Bocꢀ
H). These data are in accordance with literature.23
For detailed experimental procedures of all experiments and full characterization of all
compounds, see Supporting Information.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and characterization (1H, 13CꢀNMR data and
spectra, HPLC chromatograms) for all compounds. The Supporting Information is available free
of charge via the Internet at DOI: 10.1021/acs.oprd.xxxxx.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: harald.groeger@uniꢀbielefeld.de
Author Contributions
All authors contributed to the conceptual development of this process. P.R. and T.B. planned and
conducted the experiments. The manuscript was written through contributions of all authors. All
authors have given approval to the final version of the manuscript.
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ACKNOWLEDGMENT
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The authors thank Laura Bernhard and Alessa Hinzmann for experimental assistance.
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ABBREVIATIONS
ACN, acetonitrile; HPLC, high performance liquid chromatography; NMR, nuclear magnetic
resonance; OAc, acetate.
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