Stereocontrolled [11C]Alkylation of N-Terminal Glycine Schiff Bases To Obtain Dipeptides

Article abstract of DOI:10.1002/ejoc.201701129

The use of various quaternary ammonium salts as chiral phase-transfer catalysts allowed effective and stereoselective radiochemical [¹¹C]alkylation to obtain functionalized dipeptides. We herein report a broadly applicable procedure for the asymmetric [¹¹C]alkylation of dipeptides to give labeled N-terminal peptides by using different [¹¹C]alkyl halides. Contended stereoselectivities of the reactions were observed by using ¹¹C-labeled alkyl halides, [¹¹C]methyl iodide and [¹¹C]benzyl iodide, and diastereomeric ratios with different specialized catalysts of 95:5 and 90:10 were achieved, respectively. Accordingly, the straightforward synthesis of enantioenriched compounds should play a vital role in peptide-based radiopharmaceutical development and positron emission tomography imaging.

Full text of DOI:10.1002/ejoc.201701129

A Journal of
Accepted Article
Title: Stereocontrolled 11C-Alkylation of N-terminal Glycine Schiff
Bases to Obtain Dipeptides
Authors: Ulrike Filp, Aleksandra Pekošak, Alex J Poot, and Albert D
Windhorst
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701129
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701129
Supported by

10.1002/ejoc.201701129
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Stereocontrolled 11C-Alkylation of N-terminal Glycine Schiff Bases
to Obtain Dipeptides
Ulrike Filp§*, Aleksandra Pekošak§, Alex J. Poot, Albert D. Windhorst
Abstract: The use of various quaternary ammonium salts as chiral phase-transfer catalysts allows the effective and stereoselective
radiochemical 11C-alkylation to obtain functionalized dipeptides. The here reported asymmetric 11C-alkylation of dipeptides allows a broadly
applicable procedure to obtain labeled N-terminal peptides using different 11C-alkyl halides. Contended stereoselectivities of the reactions were
observed using 11C-labeled alkyl halides, [11C]methyl iodide and [11C]benzyl iodide, achieving diastereomeric ratio with different specialized
catalayst of 95:5 and 90:10, respectively. Accordingly, straightforward synthesis of enantioenriched compounds should play a vital role in peptide
based radiopharmaceutical development and PET imaging.
Positron emission tomography[1] (PET) is a non-invasive imaging technique enabled by the administration of trace amounts of
biochemically active compounds labeled with positron-emitting radioisotope. In recent years, PET has proven itself in disease diagnosis,
drug efficacy testing and treatment monitoring.[2,3] The presence of carbon in all biological and organic compounds makes positron
emitting isotope carbon-11 (100 % β+, Emax=0.96 MeV, t1/2=20.4 min)[4] an attractive radionuclide for PET tracer development. In theory,
carbon-11 can be incorporated in all molecules of biological interest without changing the lead structure. For native peptide-based PET
tracers however, carbon-11 remains almost unexplored compared to well established approaches like radiometal chelation (e.g.
gallium-68) or the addition of a prosthetic group (e.g. 4-[18F]fluorobenzaldehyde). These strategies of peptide radiolabeling lead to
molecular changes resulting in different physico-chemical properties compared to the lead peptide. As a result, clinical translation of
these peptides requires additional research for the validation of the tracer, which delays the development of peptide based PET
tracers.[5–7]
Recently, more progress has been made in the radiolabeling of peptides with carbon-1.1[8–10] In addition, the high molar activity, low
radiation dose to the human subject and the option of doing multiple scans per day, offers unique possibilities of carbon-11 labeled
peptides as PET tracers. Nevertheless, carbon-11 has its challenges, mainly caused by its short half-live, meaning that reactions and
work-up procedures must be fast (typically minutes) with a complete synthesis time of 60 minutes including purification and formulation.
With respect to reaction kinetics, an advantage of the high molar activity is that the carbon-11 labeled reagent is typically present in
low nanomolar amounts whereas other reagents are present in micromolar amounts. This distorted stoichiometry leads to fast reactions,
since radiochemical yields are based only upon the carbon-11 labeled reagent.
Asymmetric alkylation of Schiff base glycine derivatives, utilizing phase-transfer catalysts (PTC), is a highly efficient and generally
applicable method to synthesize natural and unnatural amino acids under mild reaction conditions.[11] Nevertheless, a careful selection
of reaction conditions and catalysts needs to be performed based upon the peptidic backbone.
We previously reported on the successful asymmetric synthesis of [11C]alanine[12], [11C]phenylalanine[13], and two small 11C-
peptides[10] applying this methodology. We postulate that the stereoselective synthesis of dipeptides will have implications in the
development of asymmetric chemical transformations in the radiosynthesis of functionalized small peptides (Figure 1A) to be used as
PET tracers.[14] In this study the aim was to investigate the influence of the peptidic backbone and catalyst induction on stereoselectivity.
To achieve this, mild PTC conditions were transferred towards various dipeptides with two different alkylating agents, [11C]methyl iodide
([11C]MeI) and [11C]benzyl iodide[15] ([11C]BnI), to evaluate efficacy and chiral induction of direct alkylation. Generally applicable
conditions were identified by screening and optimizing the reagent conditions with the amount of precursor and base, the catalyst,
reaction time and temperature to obtain high diastereomeric ratios (dr) and radiochemical conversion yields.
U. Filp, A. Pekošak, Dr. A. J. Poot, Prof. Dr. A. D. Windhorst
Department of Radiology and Nuclear Medicine
VU University Medical Center
De Boelelaan 1085c, 1081HV Amsterdam, the Netherlands
*Correspondence to: u.filp@vumc.nl
§: Authors contributed equally to this work.
Supporting Information for this article is given via a link at the end of
the document.
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Figure 1. (A) Radiochemical synthesis scheme by alkylation of precursor 1 - 8
with [11C]MeI or [11C]BnI; (B) HPLC profiles of the UV and radioactive signal of
the crude alkylation mixture of [11C]9; (C) Radiochemical yield of the crude
reaction mixture, determined by analytical HPLC and defined as radiochemicall
conversion (RCC) of asymmetric alkylation to compound [11C]9-20.
The first aim here was to optimize the concentration of the Schiff base precursor for 11C-alkylation reactions. Due to higher
reactivity of [11C]MeI only 30-40 mM of precursor were necessary, whereas for [11C]benzylation concentrations between 50-60 mM
were required (see Supporting Information). With the acquired knowledge, protected 11C-dipeptides as alkylated product were
successfully obtained in high radiochemical yields, determined by analytical HPLC and expressed as radiochemical conversion (RCC).
The results were also dependent upon the amount of base - CsOH·H2O, which was assessed to be optimal between 80-110 equivalents
compared to precursor. This excess provides adequate effective surface area for phase-transfer alkylations. To attain sufficient
exchange between solid-liquid system[16] efficient stirring was of paramount importance. The vigorous mixing of the reaction mixture
was achieved with a helium flow of 20-50 mL·min-1 which enlarges the interfacial area, as experiments without vigorous reagent mixing
showed little to no product formation (see Supporting Information). From experience, solvent toluene was optimal.[17] Next, the reaction
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has been set to 5 min with satisfactory RCC of > 75 % overall. Finally, Figure 1C illustrates that the optimized conditions yielded product
for all mentioned dipeptides in excellent RCC, exemplified by a representative radiochromatogram in Figure 1B.
In general, [11C]methylation reactions that were performed at 10 ºC had slightly higher outcome than 0 ºC, while for the [11C]benzylation
reactions 0 ºC proved to be favorable.[10] We also observed that the adjacent amino acid (1 - 2 compared to 3 - 4) has no influence on
the conversion to racemic 11C-dipeptides.
Gratified by the excellent conversion rates, the stereoselectivity of the 11C-alkylations was examined. Table 1 presents the results
of the analysis of alkylation reactions comparing the situation without catalyst and with an achiral catalyst TBAB (tetrabutyl ammonium
bromide). The results are high-yielding and RCCs are comparable with results employing CsOH·H2O as deprotonating agent and base.
Hereby, the application of a catalyst was confirmed not to influence the RCC. Remarkably, the influence of the second amino acid was
larger in the reactions with [11C]MeI, resulting in a ratio of approx. 60:40 (Table 1, Entry 1-4), whereas in the reactions with [11C]BnI the
outcome was 50:50 (Table 1,Entry 5-8). Without catalyst, we assume the dipeptides are in a slightly bended position in the apolar
organic medium, therefore favoring one diastereomer, whereas the bulkiness of Phenyl group imparts a stronger effect resulting in a
racemic mixture. The influence of TBAB is clearly shown in decreasing the ratio for [11C]MeI due to ion-stabilization of Schiff base
enolate, whilst for [11C]BnI no influence on the dr is observed.
The next challenge was to achieve high dr making use of commercially available chiral phase-transfer catalysts. The reaction
mixtures of the protected dipeptides 9-10 and 15-16 could not be separated efficiently on C18 reversed-phase or normal-phase HPLC.
However, the separation with dipeptides 11-14 and 17-20 was successful on RP-C18 (see Supporting Information), thus our efforts
focused on achieving the best dr for these dipeptides with the catalysts specified in Figure 2. In all likelihood, the diastereomeric
separation is possible due to the configuration of the second amino acid, which enables stronger van der Waals bonds of the sterically
more hindered dipeptide to the C18 column. Henceforth, we moved on with precursor 3 and counterpart 7, as well as 4 and 8, to be able
to examine the backbone influence in particular.
Table 1. Diasteriomeric ratio of 11C-dipeptides without catalyst and with an achiral phase-transfer catalyst TBAB.
[a]
#
11C-Product
11 Ala-L-Val
13 Ala-D-Val
12 Ala-L-Leu
14 Ala-D-Leu
No Cat[b]
TBAB[b,c]
n.d.[d]
60:40
(DL:LL)
60:40
(LD:DD)
62:38
(DL:LL)
67:33
(LD:DD)
54:46
(DL:LL)
47:53
(LD:DD)
50:50
(DL:LL)
51:49
(LD:DD)
1
2
3
4
5
6
7
8
n.d.
47:53
(DL:LL)
57:43
(LD:DD)
17 Phe-L-Val
19 Phe-D-Val
18 Phe-L-Leu
20 Phe-D-Leu
n.d.
n.d.
52:48
(DL:LL)
56:44
(LD:DD)
[a]Reactions performed with 40-60 mM of precursor 3-4, 7-8 and 80-110 eq CsOH·H2O , compared to precursor, at 0-10 ºC for 5 min; [b] 40-60 mM TBAB
(c)Reported as dr; [d]n.d. = not determined.
In organic asymmetric synthesis lower temperatures (-40 to 0 ºC) are preferred to obtain better dr of the product, however considering
the short half-life of carbon-11, ambient temperatures are preferable for reaction kinetics to accomplish higher conversion rates. Indeed,
the temperature had significant influence on the dr as shown in Table 2 (Entry 3-5), while maintaining slightly lower but acceptable
conversion rates (Table 2, Entry 1-2; 3-5). Surprisingly, the lower temperature reduced the dr negatively presumably due to the enolate-
catalyst complex not forming properly in distorted radiochemistry conditions and also due to less time to react. This unexpected result
has also been observed in other organic chemistry experiments implementing a derivative of Cat 4.[18] Furthermore, the amount of
catalyst (Table 2, Entry 6-8) used in the reactions hardly influenced the diastereoselectivity of the formed product.
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Table 2. Evaluation of catalyst amount (Cinchona-derived) and temperature influence with precursor 4.
[a]
#
11C-alkyl halide
Cat
1
Eq Cat[b]
Temp (ºC)
DL:LL
42:52
40:60
79:21
62:38
50:50
28:72
23:77
27:73
RCC (%)
94
1
[
11C]MeI
11C]MeI
1
1
10
-10
0
2
3
4
5
6
7
8
[
1
35
[
11C]BnI
11C]BnI
11C]BnI
11C]BnI
11C]BnI
11C]BnI
2
1
97
[
2
1
-20
-40
0
62
[
[
[
[
2
1
32
3
0.5
1
82
3
0
97
3
2
0
79
[a]Reactions performed with 40-60 mM of precursor 4 and 80-110 eq of CsOH·H2O for 5 min; [b]Compared to 4; Entry 1-2 yielding product 12 and Entry 3-8
yielding product 18; in general: DL+LL=100.
For the asymmetric alkylation reactions further on, the amount of catalyst used ranged from 0.5 to 1 eq, compared to the amount of
Schiff base precursor. The first set of experiments was performed with Schiff base glycine-L/D-valine tert-butylester 3 / 7 yielding L/D-
alanine-L/D-valine tert-butylester 11 / 13 and L/D-phenylalanine-L/D-valine tert-butylester 17 / 19 with results summarized in Table 3.
The use of Cinchona-based[19] pseudo-enantiomers Cat 1 and Cat 2, which were most promising for [11C]BnI (Table 3, Entry 3-4),
showed less selective results for [11C]MeI. The yield and dr of the obtained product 15 was clearly dependent on the starting material
and catalyst used, which can be called a match and mismatch situation for precursor and catalyst (Table 3, Entry 3-4). We have also
observed a substantial improvement in stereochemical control with Cat 3 – Park’s two cinchona alkaloid unit catalyst[19] (Table 2, Entry
6-8) compared to Cat 1 – a single unit catalyst in the [11C]benzylation reaction. They have both resulted in more LL-product with Gly-L-
AA Schiff base precursors. As shown in Table 3 (Entry 1-2, Cat 1 and 2), the outcome in [11C]methylation reactions with Cinchona
catalysts were leading to lower dr, henceforth the use of Cat 3 was abandoned. Closer inspection of Table 3 specifically Maruoka’s first
generation catalysts[20], Cat 4 and 5, which performed outstandingly in the synthesis of amino acids [11C]alanine and [11C]phenylalanine,
unfortunately yielded unfavorable results for the diastereoselective synthesis of [11C]alanine-based dipeptides (Table 3, Entry 1-2) and
were therefore discarded for the use with [11C]BnI. The tartrate-derived Cat 6 and Cat 7, (TaDiAs) published by Shibuguchi et al.[15,16]
did not result in a decent stereochemical control, however gave different ratios compared to no catalyst (Table 3, Entry 1-2) and as
these were insignificant differences, the use with [11C]BnI was discarded. Likewise, Cat 4 and Cat 5 did not increase the
diastereoselectivity of the reaction and were thus not further investigated during this study.
Figure 2. Chiral phase-transfer catalysts explored for the radiosynthesis of 11C-dipeptides with (A) Cinchona-based catalysts; (B) Maruoka’s quaternary ammonium
based and (C) tartrate-derived catalysts.
Table 3. Diastereoselective N-terminal 11C-alkylation with precursor 3 and 7.
[a]
#
11C-Product
Cat 1
41:59
62:38
37:63
77:23
Cat 2
69:31
27:73
79:21
22:78
Cat 4
66:37
68:32
Cat 5
38:62
58:42
Cat 6
63:37
63:37
Cat 7
46:54
39:61
11 Ala-L-Val
(DL:LL)
13 Ala-D-Val
(LD:DD)
17 Phe-L-Val
(DL:LL)
19 Phe-D-Val
(LD:DD)
1
2
3
4
n.d.
[a]Reactions performed with 40-60 mM of 3 or 7 with 80-110 eq of CsOH·H2O, compared to precursor, at 0-10 ºC for 5 min; in general: DL+LL=100.
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To differentiate the results for the [11C]methylations on a precursor with a bigger adjacent side chain, namely leucine, best results
were obtained for precursor 4 with Cat 1 summarized in Table 4 (Entry 1). In contrast, the best result for [11C]benzylation reactions
were achieved with Cat 2, also here we observed a match/mismatch situation with Cat 1 (Table 4, Entry 3). A significant difference is
clearly obtained with Cat 2 and the two chiral precursors 4 and 8. Here, depending upon which chiral precursor is preferred, the favored
catalyst can be successfully employed. Here as well, the bigger sidechain did not yield better dr with the other catalysts employed.
Table 4. Diastereoselective N-terminal 11C-alkylation with precursor 4 and 8.
[a]
#
11C-Product
Cat 1
22:78
64:36
35:65
54:46
Cat 2
61:39
33:67
79:21
12:88
Cat 4
57:43
63:37
71:29
48:52
Cat 5
54:46
67:33
48:52
59:41
Cat 6
Cat 7
12 Ala-L-Leu
(DL:LL)
14 Ala-D-Leu
(LD:DD)
18 Phe-L-Leu
(DL:LL)
20 Phe-D-Leu
(LD:DD)
1
57:43
43:57
2
3
4
n.d.
n.d.
52:48
34:66
[a]Reactions performed with 40-60 mM of 4 or 8 with 80-110 eq CsOH·H2O compared to precursor, at 0-10 ºC for 5 min; in general: DL+LL=100.
Figure 3. (A) Diastereomeric ratio of Cat 8 with Schiff base precursor 4 to product
12 and 18; (B) Exemplified radioactive HPLC of a reaction with 4 to 18 using Cat
8; (C) Exemplified radioactive HPLC of a reaction with 8 to 20 using Cat 9; (D)
Diastereomeric ratio of Cat 9 with Schiff base precursor 8 to product 14 and 20.
We have also successfully evaluated the use of Maruoka’s dedicated di- and tetrapeptide catalysts for alkylation,[22,23] Cat 8 and
Cat 9, with results summarized in Figure 3. The (S,S) version, Cat 8, worked highly successful especially with precursor 4 yielding
preferably DL-dipeptide (Figure 3A, 3C). Whereas for complexes of 4 with Cat 9 the dr for methylated product 12 and benzylated product
18 was 50:50. In contrast, the formation of precursor-catalyst complex of 8 with (R,R)-Cat 9 (see Figure 3D) is preferred to yield
preferably LD-dipeptide, whereas with Cat 8 it has the reversed outcome yielding for [11C]benzylation 31:69 and for [11C]methylation
resulted in 52:48. Moreover, as outlined in Table 5 outstanding results have been obtained with [11C]MeI and 3 supporting our previous
findings. To summarize, (S,S)-Cat 8 yielded high diastereoselectivities with precursor 3 and 4, whereas with the (R,R)-Cat 9 better
results were obtained with D-dipeptide precursor 7 and 8. Furthermore, from these results we concluded that the configuration and
confirmation of Cat 8 is more favorable for a good outcome, which might be explained by the more bulky character of the catalyst whit
the two –CF3 groups instead of single fluorine atoms (such as for Cat 4, 5 and 9). Nonetheless, these catalysts are favorable for good
enantioselectivities due to the strengthened internal hydrogen-bonding by the F atoms involving water which leads to more rigid
conformations of catalysts.[25,26] Furthermore, Kamachi et al. performed density functional theory (DFT) calculations, which provided
lowest energy transition structures leading to preferred products and is in accordance with our findings.[27] The slightly lower dr obtained
with bigger catalysts for the 11C-benzylation in comparison with [11C]MeI we believe is due to the steric hindrance of penetrating
effectively the enolate-catalyst system.
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Table 5. Diastereomeric ratio of reactions with glycine-D/L-valine Schiff base with [11C]MeI.
[a]
#
11C-Product
Cat 8
95:5
Cat 9
57:43
79:21
11 Ala-L-Val
(DL:LL)
13 Ala-D-Val
1
2
61:39
(LD:DD)
[a]Reactions performed with 40-60 mM of 3 or 7 with 80-110 eq of CsOH·H2O compared to precursor, at 0-10 ºC for 5 min; in
general: DL+LL=100.
The acidic cleavage of obtained protected dipeptides is achieved conveniently. The obtained radioactive alkylated products have
been quantitatively deprotected in short time with 6M HCl at elevated temperatures yielding the free 11C-dipeptide (see Supporting
Information). In light of molar activity, where the present work was focused on radiochemistry method development, that is established
to be dependent upon the starting alkylation agent and is estimated to be 50[12] to 135[13] GBq·µmol-1 of tracer ready for biological studies
based on similar publications. As soon as an authentic PET tracer candidate is achieved by implementing this methodology, the molar
activity will be determined.
In conclusion, the best dr was obtained using Cat 8 with [11C]MeI and [11C]BnI resulting in 95:5 and 90:10 diastereomeric ratio
with RCC of > 80 %, respectively. Hence, the herein presented radiosynthetic method enables a reliable and reproducible strategy to
obtain pure diastereomerically enriched carbon-11 labeled dipeptides. This methodology provides a general and versatile procedure to
be applied for peptide-based PET tracer development, stimulating their application and translation towards preclinical and potentially
also clinical studies.
Experimental Section
Full experimental details are presented in Supporting Information.
Acknowledgements
This study received funding from the European Union, Marie Curie actions RADIOMI under project reference no. 316882. We gratefully
acknowledge the Cyclotron BV for [11C]CO2 production that was used to synthesize [11C]MeI and [11C]BnI.
Keywords: C-C coupling • Small peptides • Radiochemistry • Asymmetric synthesis • Positron Emission
Tomography
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Entry for the Table of Contents
Layout 1:
COMMUNICATION
Diastereoselective
synthesis of carbon-11
Ulrike Filp, Aleksandra Pekošak
Page No. – Page No.
labeled
dipeptides
towards favored (red) or
unfavored (blue) product
for alkylation of Ph2Gly-L-
Val-OtBu Schiff base
precursor.
Stereocontrolled
Alkylation of
Glycine Schiff Bases to
Obtain Dipeptides
11C-
N-terminal
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