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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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Organic Process Research & Development

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* Chair of Organic Chemistry I, Faculty of Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany

ACS Paragon Plus Environment

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Table of Contents Graphic and Synopsis


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KEYWORDS: α-Amino nitriles; Catalysis; Dehydration; Nitriles; Oximes; Vildagliptin.

ABSTRACT: An alternative route towards 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 Nchloroacetylated 2-cyanopyrrolidine, 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 N-acylated α-amino 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, NVPDPP-728 (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 US-$ 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 N-acyl-α-amino nitrile and pharmaceutically relevant representatives thereof (Vildagliptin, NVP-DPP-728, Saxagliptin). Thus, efforts have been made to develop efficient synthetic routes towards enantiomerically pure α-amino nitriles or derivatives thereof, in particular those being derived from L-proline and substituted derivatives due to their application in the preparation of Vildagliptin (2), NVP-DPP728 (3) and Saxagliptin (4).2,4 As L-proline represents a readily available and commercially attractive starting material (with a price reported to be in the range of 40 $/Kg)5 synthetic routes starting from this L-amino acid as an enantiomerically pure raw material from the chiral pool were developed. First, an N-acylation 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 N-acylated L-proline.2 For the final step of the Vildagliptin synthesis, Novartis researchers developed an elegant approach based on the use of this N-protected pyrrolidine 2-nitrile of type (S)-5 by means of a substitution reaction (Scheme 2).

Scheme 2. N-Acyl-α-amino nitrile (S)-5 as key intermediate in the synthesis of Vildapliptin.


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Typically the access towards N-acylated chiral nitriles of type (R)- und (S)-1 is achieved through a multi-step synthesis starting from (i) either prochiral imines or (ii) L-amino acids as “chiral 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 organo-) catalysts, limitations exist. Typically these reactions are carried out with acyclic, N-substituted imines, which would not enable a (direct) synthetic access towards proline-based nitriles nor towards α-amino nitriles bearing a primary amino group (as nitrile-analogues 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 N-acylated enantiomerically pure L-amino acid amide (here: N-chloroacetyl L-proline amide, (S)-6) under formation of the desired α-amino nitrile in N-protected form (according to the reaction shown in Scheme 2).2,3 As a starting material in the synthesis of Vildagliptin, L-proline amide is used, which is accessible through amidation of the readily available natural amino acid L-proline. In addition, the Vilsmeier reagent is utilized for the „formal dehydration“ step. The efficient synthesis of non-substituted, primary amides, however, still often represents a challenge, and the so-called „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 cyanide-free general approach towards N-acyl α-amino nitriles, which is also applicable to a de novo-access towards Vildagliptin, we studied a two-step approach consisting of an initial transformation of N-acyl αamino 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 N-acyl α-amino nitrile, namely the transformation of N-Boc L- and D-phenylalanine- and N-Boc L- and D-proline-derived 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, non-catalytic 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 copper-catalyzed dehydration with acetonitrile serving as both, reagent and solvent.7 The by-product 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 L-proline. 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 εcaprolactam with an annual production volume on a multi-million tons scale.8


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Scheme 3. Synthetic concept for the two-step conversion of N-Boc α-amino aldehydes into the corresponding nitriles.

In the following we report our results on the development of such a synthesis of N-acyl α-amino nitrile and its application towards a de novo-multi 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 non-toxic 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. One-pot 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 nitrile-free 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). Taking into account the advantages and drawbacks of the various methodologies, for our study on the development of a synthesis of enantiomerically enriched N-acyl 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 1-2 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 N-acylated amino nitriles we synthesized the D- and L-enantiomeric form of N-Boc-protected aldoximes (10 and 13) starting from the D- and L-amino 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 Cu-catalyzed 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 2-10 mol% was used in combination with acetonitrile as a solvent. We were pleased to find that under these conditions the N-Bocprotected α-amino 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 multi-step transformations of enantiomerically highly enriched N-acyl amino aldehydes 9 and 12 (which are accessible from the corresponding amino acids as chiral pool molecules in case of the L-enantiomers) 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 two-step 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. Two-step synthesis of proline-derived nitrile 11 and phenylalanine-derived nitrile 14 utilizing dehydration catalyzed by Cu(OAc)2 as a key step


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entrya

substrate

product

catalyst

yield [%]

ee-value

loading

the

[mol%]

[%]b

1

(S)-10

(S)-11

2

86

97

2

(R)-10

(R)-11

2

88

99

3

(S)-13

(S)-14

10

92

98

4

(R)-13

(R)-14

10

83

97

a

of

product

The purity of the commercially available aldehydes 9 and 12 was 97% (according to the

information of the supplier, see Experimental Section).

b

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)-oxime-acetonitrile 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).

a) varying amounts of acetonitrile (solvent: ethyl acetate)

b) varying solvents (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 ethyl acetate, determined by 1H-NMR measurements. b) Conversion to nitrile (S)-11 in dependency on varying solvents with ten equivalents of acetonitrile, determined by 1H-NMR 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 by-product from the oxime and acetonitrile. This type of negative impact of water has also been reported earlier for related copper-catalyzed 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%.

With this synthetic tool in hand, we implemented the aldehyde-oxime-nitrile 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 L-prolinate, 15, as an easily accessible derivative of the inexpensive chiral pool molecule L-proline.


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Scheme 4. New synthetic approach towards Vildagliptin (2) based on Cu-catalyzed dehydration of an L-proline-derived 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 Takasago-catalyst Ru-MACHO18, leading to L-prolinol, (S)-16, with excellent conversion of >99% and a non-optimized yield of 25%. Next, acylation of the amino moiety in (S)-16 with chloroacetyl chloride proceeds selectively19 and gave the desired N-acyl L-prolinol (S)-17 in 71% yield. We also tried to hydrogenate the ester after successful N-chloroacetylation 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 copper-catalysis 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 work-up 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 N-acyl amino nitrile (S)-5 (which represents a Vildagliptin precursor) was obtained within five simple chemical transformations with a copper-catalyzed aldoxime dehydration as a key step when starting from the chiral pool compound L-proline methyl ester (15).

In conclusion, an alternative route towards enantiomerically highly enriched N-acyl α-amino nitriles based on a 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 with enantiomeric excesses of 97-99% ee. Furthermore, this method has been applied in a novel, alternative total synthesis of N-chloroacetylated (S)-2-cyanopyrrolidine, 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 N-acyl prolinal, increase of space-time-yield and downstream-processing.


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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

EXPERIMENTAL SECTION Materials and Methods. The N-Boc-protected 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 (N-Boc-L-prolinal, N-Boc-D-prolinal, N-Boc-Lphenylalaninal, N-Boc-D-phenylalaninal) was 97%. Other reagents were purchased from Alfa Aesar, from fluorochem and from Acros Organics and also used without further purification. 1H- and

13

C-NMR 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). IRspectra were recorded on a Thermo Nicolet 380 FT-IR. GC-chromatograms were recorded on a Shimadzu GC-2010 using the column Agilent CP-Chirasil-Dex CB with different temperature programs. Melting points were determined with a Büchi Melting Point B-540 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. RP-HPLC-chromatograms 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). NP-HPLC-chromatograms


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were recoreded on a JASCO system utilizing a Daicel Chiracel AD-H column with different ratios of supercritical CO2/Isopropanol as mobile phase.

N-Boc L-E/Z-prolinal oxime ((S)-E/Z-10). Hydroxylamine hydrochloride (104 mg, 1.50 mmol) 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 N-Boc-L-prolinal (L-9, 199 mg, 1.00 mmol) the resulting 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/Z-10 (143 mg, 67%) as a colorless oil with an E/Z ratio of 65:35 (determined by 1H-NMR spectroscopy in CDCl3). 1H-NMR (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, E-CHNOH), 6.74 + 6.69 (2 s, 1H, Z-CHNOH), 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, Boc-H). 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). N-Boc (S)-E/Z-L-prolinal oxime ((S)-E/Z-10, 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. Removal of the solvent yielded nitrile (S)-11 (97 mg, 86%) as a colorless oil with an enantiomeric excess of 97%. 1H-NMR (500 MHz, CDCl3) δ 4.57 + 4.45 (2 d, 1H, CHCN), 3.51 + 3.37 (2 m, 2H, BocNCH2), 2.25 – 2.02 (m, 4H, BocNCH2CH2CH2), 1.51 + 1.48 (2 s, 9H, BocH). 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, 13C-NMR 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 * E-mail: [email protected] 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 The authors thank Laura Bernhard and Alessa Hinzmann for experimental assistance.

ABBREVIATIONS ACN, acetonitrile; HPLC, high performance liquid chromatography; NMR, nuclear magnetic resonance; OAc, acetate.

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Synthesis of Enantiomerically Pure N-Acyl Amino ... - ACS Publications

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