Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

Article abstract of DOI:10.3762/bjoc.13.240

The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at C^α, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman's chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the C^α of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the C^α-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.

Full text of DOI:10.3762/bjoc.13.240

Asymmetric synthesis of propargylamines as amino acid
surrogates in peptidomimetics
Matthias Wünsch, David Schröder, Tanja Fröhr, Lisa Teichmann, Sebastian Hedwig,
Nils Janson, Clara Belu, Jasmin Simon, Shari Heidemeyer, Philipp Holtkamp,
Jens Rudlof, Lennard Klemme, Alessa Hinzmann, Beate Neumann,
Hans-Georg Stammler and Norbert Sewald*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2428–2441.
Organic and Bioorganic Chemistry, Department of Chemistry,
Bielefeld University, Universitätsstraße 25, D-33615 Bielefeld,
Germany
doi:10.3762/bjoc.13.240
Received: 08 August 2017
Accepted: 19 October 2017
Published: 15 November 2017
Email:
Norbert Sewald* - norbert.sewald@uni-bielefeld.de
Associate Editor: S. Flitsch
* Corresponding author
© 2017 Wünsch et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amino acid analogous side chains; desilylation; Ellman’s chiral
sulfinamide; intramolecular Huisgen reaction; peptidomimetics;
propargylamines; rearrangement to α,β-unsaturated imines
Abstract
The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore,
the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As
most amino acids have a chiral center at Cα, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a
set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides
chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl
propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Cα of amino
acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional
groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to
remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Cα-position facilitate a base induced
rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild condi-
tions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional
groups is accessible for the use as precursors of peptidomimetics.
Introduction
Terminal alkynes display an intriguing versatility as building tions, e.g., [3 + 2] cycloadditions with azides and isoelectronic
blocks in organic and medicinal chemistry, as their reactivity is functional groups (among them the copper or ruthenium-cata-
unique. Their chemistry involves several highly selective reac- lyzed azide–alkyne cycloaddition, CuAAC and RuAAC), the
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thiol–yne reaction, Diels–Alder reactions and the Sonogashira converted into acids, alcohols [12] or olefins in order to obtain
cross-coupling. While amino acids with a terminal alkyne in the natural products like angustureine and cuspareine [13].
side chain are well-known, the synthesis of their correlates
where the carboxy group is replaced by a terminal alkyne is still Intramolecular Pauson–Khand reaction [14], Diels–Alder reac-
tedious. Nevertheless, these propargylamines have been tion [15], gold-catalyzed azetidin-3-one formation [16], as well
frequently used as precursors for the synthesis of diverse bioac- as various transition metal-mediated additions and cross-coup-
tive compounds. Their conversion into triazoles is best investi- ling reactions [17] represent further important reactions of
gated, since triazoles as amide bond surrogates are found in propargylamines, providing the potential to form innovative
several inhibitors of proteases such as cathepsin S [1-6], peptidomimetics (Figure 2).
cysteine proteases [7], cruzain 20 [8,9], caspases [10] and
peptidyl aminopeptidases [11]. These protease inhibitors show Our attention has been focused on the synthesis of amino acid
potential for the treatment of Chagas disease [2,9], Huntington’s analogous propargylamines, furnished with Cα-substituents
disease [10], malaria [11], autoimmune diseases [6] and the imitating various amino acid side chains.
imaging of tumor associated macrophages [2]. Whereas the
carboxylic acid function of amino acids can be easily converted The direct conversion of amino acids into propargylamines by
into amides or esters (Figure 1), propargylamines have been the Corey–Fuchs or the Seyferth–Gilbert homologation has
Figure 1: Concept of carboxylic acid or amide bond replacement on the basis of an alkyne moiety.
Figure 2: Selection of reactions based on propargylamines as precursors. a) Intramolecular Pauson–Khand reaction, R = (S)-tert-butylsulfinyl,
R’ = CH2CH2OTBDPS [14]. b) Diels–Alder reaction, R = pTs, R’ = H, R’’ = Me [15]. c) Gold-catalyzed intramolecular reaction to azetidin-3-ones,
R = tert-butylsulfonyl, R’ = aromatics, aliphatics [16]. d) Sonogashira cross-coupling, R = tert-butylsulfinyl, R’ = Me, CHMe2, CH2CHMe2, cyclohexyl
[17]. e,f) CuI or RuII-catalyzed [3 + 2] cycloadditions (CuAAC, RuAAC) [18-21]. e) R = Boc, R’ = Bn [19]. f) R = Boc, R’ = Me, CHMe2, CH2CHMe2,
R’’ = Me, CHMe2, CH2Ph [21].
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been successfully used for the preparation of several natural phile is transferring the amino acid side chain, in approach II,
amino acid analogues [22,23]. However, epimerization in the the amino acid side chain comes from the aldehyde incorporat-
α-position frequently occurs under the alkaline reaction condi- ed in the imine.
tions of the Seyferth–Gilbert and the Corey–Fuchs reaction. In
Results and Discussion
order to access propargylamines with modified side chains, we
Synthesis of propargylamines, general
strategies
chose a de novo synthesis strategy, using Ellman’s chiral sulfin-
amide auxiliary to produce diastereomerically pure amines [7].
Ellman’s chiral sulfinamide can be readily synthesized on a lab-
oratory scale [24]. Moreover, sulfinamides can be cleaved
easily under acidic conditions [1,25,26] and the produced
sulfinic acid can even be recycled [25,27]. However, the sulfin-
amide auxiliary has to be treated with care, as it tends to dispro-
portionate quickly in solution at elevated temperature or in
chloroform at room temperature [28]. Furthermore, sulfin-
amides are unstable upon sonication [28]. Sulfinamides are also
reported to decompose in the presence of low concentrations of
acid under pressure, typical conditions of HPLC analysis.
Consequently, the application of the tert-butylsulfinyl as protec-
tive group for the amine is restricted to very mild conditions.
However, it can be easily cleaved from N-sulfinyl propargyl-
To avoid side reactions of the terminal alkyne in approach I,
internal alkynes were applied. Benzoate substituents were
chosen as they are comparatively inert and convertible to
peptidomimetics. At first, iodobenzene derivatives with an ester
moiety in p- or m-position were reacted with propargyl alcohol
in a Sonogashira reaction to give the phenylpropargyl alcohols
1a and 1b (Figure 4) [42,43], which were transformed in a
Swern oxidation to afford the aldehydes 2a and 2b [44]. Con-
densation of the aldehydes 2a and 2b with (R)-configured tert-
butyl sulfinamide led to the enantiomerically pure sulfinylim-
ines 3a and 3b, which were reacted with a variety of organome-
tallic compounds, including iPrMgBr, MeMgBr and BnMgBr.
amines by acidic methanolysis and subsequent Boc protection The reaction of the enantiomerically pure N-sulfinylimines 3a
[21]. Here we report on the diastereoselective synthesis of chiral and 3b with aliphatic organometallic nucleophiles resulted in
N-sulfinyl propargylamines with amino acid type “side chains” low yields and diastereoselectivity. The reaction of sulfinyl-
attached to the propargylic position mediated by Ellman’s auxil- imine 3a with isopropylmagnesium bromide provided the
iary.
sulfinamide 4a in only 13% yield with a ratio of diastereomers
of 99:1. Only 10% of the addition product 4b were obtained by
Enantiomerically pure amines can be obtained by condensation addition of methylmagnesium bromide to the N-sulfinylimine
of aldehydes or ketones with Ellman’s chiral sulfinamide, medi- 4b (dr 51:49). In order to prepare phenylalanine analogoues,
ated by KHSO4 [29], Cs2CO3 [30], Ti(OEt)4 [31-33], or CuSO4 N-sulfinylimines 3a and 3b were reacted with benzylmagne-
[34], followed by either reduction [35-40] or addition of a sium bromide. However, only traces of the desired addition
nucleophile to the imine [41]. In general, there are two options products could be detected by LC–MS analysis of the crude
(Figure 3) for the synthesis of enantiomerically pure propargyl- products.
amines by nucleophilic addition. The synthesis of propargyl-
amines by diastereoselective reductive amination requires Approach II starts with the condensation of an aldehyde with
alkynyl ketones, which are difficult to prepare and are unstable Ellman’s chiral sulfinamide to provide a sulfinylimine [29-34],
towards reductive conditions.
which was reacted with (trimethylsilyl)ethynyllithium [1,14,45-
48]. The terminal TMS group was cleaved off after the addition
In approach I, organometallic nucleophiles are added to reaction [49,50] (Table 1).
N-sulfinyl propargylimines, derived from aldehydes. According
to approach II, a metallated terminal alkyne is added to an Several conditions for the condensation of aldehydes with
N-sulfinylaldimine. In approach I, the organometallic nucleo- Ellman’s chiral sulfinamide (S)-1 have been described. Cataly-
Figure 3: Two different approaches for the stereoselective de novo synthesis of propargylamines using Ellman’s chiral sulfinamide. (a) tert-Butyl
sulfinamide, Lewis acid, CH2Cl2. (b) Organometallic compound. (c) (Trimethylsilyl)ethynyllithium.
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Figure 4: Synthesis of propargylamines 4a and 4b by introducing the side chain as nucleophile. (a) HC≡CCH2OH, Cl2Pd(PPh3)2 (1 mol %), CuI
(2 mol %), THF/piperidine (3:1), rt, 2 h. (b) (COCl)2, DMSO, NEt3, −78 °C, DCM. (c) (R)-tert-Butyl sulfinamide ((R)-1), CuSO4, DCM, rt, 3 d (see
GP-2). (d) iPrMgBr, THF, −38 °C, AlMe3 in n-hexane (4a, 13%, dr 99:1). (e) MeLi in Et2O, toluene, −30 °C, AlMe3 in n-hexane (4b, 4%, dr 52:48).
(f) MeMgBr in Et2O, toluene, −35 °C (4b, 10%, dr 51:49).
Table 1: Preparation of N-sulfinyl propargylamines 7 with aliphatic side chains.a
R
(a)
Yield (5)
(b), (c)
Yield (7)b
dr
Me
GP-1c
GP-1
GP-1
GP-2
GP-2
GP-2
GP-2c
81% (5a)
90% (5b)
92% (5c)
96% (5d)
18% (5e)
42% (5f)
89% (5g)
GP-3, GP-5
GP-3, GP-5
GP-3, GP-5
GP-3, GP-5
GP-4, GP-5
GP-4, GP-5
GP-4, GP-6
47% (7a)
61% (7b)
53% (7c)
59% (7d)
41% (7e)
15% (7f)
34% (7g)d
100:0
97:3
iPr
CH2-iPr
C6H11
t-Bu
97:3
97:3
80:20
100:0
96:4
adamantyl
CH2CH2SMe
a(a) GP-1: Auxiliary (S)-1, aldehyde, Ti(OiPr)4, 70 °C, 40 min. GP-2: Auxiliary (S)-1, aldehyde, CuSO4, DCM, rt, 3 d. (b) GP-3: (Trimethylsilyl)ethynyl-
lithium, Ti(OiPr)4, THF, −78 °C to rt. GP-4: (Trimethylsilyl)ethynyllithium, AlMe3, toluene, −78 °C to rt. (c) GP-5: TBAF, THF, 0 °C, 3 h. GP-6: KF,
18-crown-6, THF/H2O (98:2), 0 °C. bIsolated yields are given, referring to 5 (over two steps (b) and (c)). cGP-1 had to be modified for the synthesis of
5a: acetaldehyde (5 equiv), MgSO4 (5 equiv), 30 °C, 12 h [51]. d(R)-configured Ellman’s sulfinamide (R)-1 was applied. Hence, the mirror images of
5–7g were obtained.
sis by Brønstedt acids has been reported [29], but was not method, leading to high yields of sulfinylimines 5. (Trimethyl-
considered here due to the lability of the tert-butyl sulfinamide silyl)ethynylmagnesium bromide has already been successfully
moiety towards acids [1,25,26]. Strongly alkaline conditions added to sulfinylimines to produce various N-sulfinyl
[30] were also avoided. Liquid aldehydes were readily propargylamines in excellent yields and diastereomeric excesses
condensed with tert-butyl sulfinamide (S)-1 in the presence of [13,16]. Several N-sulfinyl propargylamines (analogoues of
Ti(OEt)4 as Lewis acid and water scavenger [31-33]. However, valine, phenylglycine and tyrosine) have been prepared using a
the removal of precipitated TiO2 was tedious and time large excess (4 equivalents) of [(trimethylsilyl)ethynyl]di-
consuming. Therefore, dry CuSO4 as Lewis acid and water methylaluminum as the nucleophile [14,48,52]. The reaction of
scavenger at ambient temperature [34] represented a versatile the sulfinylimines 5 with (trimethylsilyl)ethynyllithium provi-
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ded the crude intermediates 6, which were converted into the The cleavage of the TMS groups of the addition products 6
N-sulfinyl propargylamines 7 in high yields and satisfactory could be accomplished with TBAF in THF [49,50,56]. Basic
diastereomeric ratios by cleaving off the TMS protecting group conditions, like K2CO3 as described in the literature [50,57] did
with TBAF. In previous investigations, the choice of solvent not lead to the desired N-sulfinyl propargylamines 7. We
and Lewis acid were controversially discussed [13,14,45-50,52- assume that strong bases do not only lead to desilylation, but
55]. Nonpolar solvents (DCM < THF < Et2O < toluene) have also induce decomposition of the propargylamine system
been described to enhance the stability of the transition state, (see below). Kracker et al. recently demonstrated the substitu-
improving the diastereomeric ratio, as well as the reactivity of tion of the labile tert-butylsulfinyl group of compounds 7a–c by
the nucleophile, resulting in an improved yield [45]. As the more versatile Boc protective group in yields of 56–94%
aldimines have been reported to be rather unreactive electro- [21].
philes [53], hard Lewis acids (AlMe3 > AlR3 > Ti(OiPr)4 [14] >
Synthesis of propargylamines containing
BF3 > MgBr2 > ZnCl2 > ZnEt2) have been recommended for
activation [45]. However, the Lewis acid BF3 was shown to electron-withdrawing substituents
give products with inverted configuration of the newly formed Aromatic and carbonyl substituents in the Cβ-position of
chiral center [47]. While several authors obtained increased propargylamines (occurring in analogoues of the amino acids
yields upon addition of AlMe3 [1,45,46], others advised against phenylalanine, tyrosine, histidine, tryptophan, aspartic acid and
its use as activation agent of aldimines, because side reactions asparagine) increase the acidity of the adjacent protons consid-
were observed [13,54,55], which will also be further discussed erably. In the precursor sulfinylimines 5 of the target propargyl-
below. We used THF or toluene as solvents and AlMe3 or amines the acidity of the protons of the methylene moiety is
Ti(OiPr)4 as activation agent. According to Ellman et al., the further increased by the electron-withdrawing effect of the adja-
diastereoselectivity of the addition to sulfinylimines is con- cent sulfinyl imino moiety. Thus, the nucleophilic addition of
trolled by the formation of a cyclic, six-membered, chair-like (trimethylsilyl)ethynyllithium is competing with deprotonation
transition state, which is formed by precoordination of the of the methylene moiety giving rise to the formation of the
organometallic reagent to aldimine 5 [45]. This cyclic transi- azaenolate (Figure 5). The resulting anion is reprotonated
tion state accounts for the preferred re-face attack of the nucleo- during aqueous work-up, leading to the starting sulfinylimine 5.
phile at (S)-configured N-sulfinylimines, which leads to amines
with the same configuration as the proteinogenic (S)-config- Benzyl-substituted N-sulfinyl propargylamine 6h was prepared
ured amino acids. This stereoselection was confirmed by by the addition of (trimethylsilyl)ethynyllithium to N-sulfinyl-
various X-ray crystal structures of propargylamines obtained imine 5h. The starting material 5h and the addition product 6h
during our investigations like 7a, 7c–e, 7s, 7i–k, 7q and tri- were isolated in a 7:3 ratio indicating deprotonation to be the
azole 13w (see Supporting Information File 1). Independent on predominant reaction. The phenylalanine analogous N-sulfinyl
the substituent, solvent and Lewis acid used, the direction of the propargylamine 7h was isolated in only 12% yield (over two
nucleophilic attack of (trimethylsilyl)ethynyllithium was always steps, referring to imine 5h) after desilylation with TBAF
the same, forming the new centers of chirality of all N-sulfinyl (Table 2). As the benzylic proton of sulfinylimine 5h is quite
propargylamines 7 configured as expected. As already de- acidic, approach II was not pursued for the synthesis of
scribed by Ellman et al. [45], the size of the side chain corre- propargylamines analogous to tyrosine, histidine, tryptophan,
lates with the result of the reaction. The diastereomeric excesses and aspartate.
increased in a size-dependent manner in the order 6a (alanine) <
6c (leucine) < 6d (cyclohexylglycine) (compare Table 1). The Proteinogenic amino acids do not contain substituents, which
yield of the tert-leucine derivative 6e was reduced due to steri- additionally increase the acidity of the α-proton. Nevertheless,
cally shielding of the imino moiety by the tert-butyl group.
glycine derivatives with electron-withdrawing substituents like
Figure 5: Reaction of N-sulfinylimine 5h with (trimethylsilyl)ethynyllithium. (a) GP-3 or GP-4. (b) Aqueous work-up, H2O/H+. Deprotonation in benzylic
position competes with nucleophilic attack (5h/6h, 7:3).
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Table 2: Synthesis of propargylamines 7 with electron-withdrawing substituents in the side chain.a
R
(a)
Yield (5)
(b)
Yield (6)
(c)
Yield (7)
dr
CH2Ph
Ph
GP-2
GP-1
GP-2
GP-2b
GP-2b
64% (5h)
99% (5i)
88% (5j)
n.i. (5k)
GP-4
GP-4
GP-4
GP-4
GP-4
34% (6h)
54% (6i)
41% (6j)
33%c (6k)
10% (6l)
GP-5
GP-7
GP-6
GP-6
GP-6
35% (7h)
66% (7i)
52% (7j)
29% (7k)
57% (7l)
97:3
95:5
C6F5
CF3
100:0
93:7
CCl3
87% (5l)
100:0
a(a) GP-1: Auxiliary (S)-1, aldehyde, Ti(OiPr)4, 70 °C, 40 min. GP-2: Auxiliary (S)-1, aldehyde, CuSO4, DCM, rt, 3 d. (b) GP-4: (Trimethylsilyl)ethynyl-
lithium, AlMe3, toluene, −78 °C to rt. (c) GP-5: TBAF, THF, 0 °C, 3 h. GP-6: KF, 18-crown-6, THF/H2O (98:2), 0 °C. GP-7: 1. AgNO3, EtOH, 0 °C;
2. KCN, EtOH, HCl. bFor the synthesis of 5k, procedure GP-2 was modified: The aldehyde was distilled under argon atmosphere, condensed onto a
mixture of sulfinamide (S)-1 and molecular sieves 4 Å. Toluene was added and the solution was stirred for 48 h. 5k was directly applied for subse-
quent reactions and could not be isolated (n.i.). cYield refers to Ellman’s chiral sulfinamide (S)-1.
formylglycine [58,59], phenylglycine [60,61] and fluorinated extremely high electrophilicity. Instead, immediate hydrolysis
alanine [62-64] have attracted great attention as peptido- occurs upon contact with water forming hemiaminal 8k
mimetics, drugs or in the bioorthogonal functionalization of (Figure 6), as already observed by Truong et al. [94]. This
larger peptides.
frequently observed hemiaminal was isolated by column chro-
matography and recrystallized from EtOAc.
The trifluoromethyl moiety has been reported to enhance the ac-
tivity, stability and selectivity of various pharmacologically Distillation of imine 5k has been reported to provide a very low
active compounds [65,66], e.g., trifluridine [67-70], efavirenz yield (22% [94]). The reaction of hemiaminal 8k with (tri-
[71-73], fluoxetine [74-76] and fluozolate [77]. As the general methylsilyl)ethynyllithium in the presence of the strong Lewis
structure of fluorinated propargylamines occurs in important acid AlMe3 has been proposed by Truong et al. [94], but was re-
drugs, like HIV protease inhibitor DPC 961 and its analogues ported to give very poor yields and low diastereoselectivity. In
[78-83], particular effort was put on the synthesis of N-sulfinyl contrast to the argumentation of Xiao et al., who strongly
propargylamine 7k. Because of the poor electrophilicity of recommended hard Lewis acids for the reaction of sulfinylim-
imines 5, the nucleophilic addition of trifluoromethyl nucleo- ines with various ethynyllithium reagents [95], the crude imine
philes, such as TMS–CF3 [84,85] has been described to be inef- 5k predominantly reacted with the Lewis acids Ti(OiPr)4 and
ficient. Still, the asymmetric synthesis of CF3-substituted AlMe3 and gave only low yields of the desired N-sulfinyl
propargylamines has been described, using (R)-2-methoxy-1- propargylamine 6k. The reaction of crude 5k in the presence of
phenylethan-1-amine as chiral auxiliary [86-88]. However, the Lewis acid Ti(OiPr)4 afforded the N/O-acetal 9k, whereas
cleavage of the protective group requires reductive conditions, the attempt of activation with AlMe3 provided the methylated
which also affects the CF3 group and the alkyne [86-88].
sulfinamide 10k. Both side products were isolated as colorless
crystalline solids. It is assumed, that the undesired side prod-
Various trifluoromethyl-substituted ketones have been con- ucts 9k and 10k were formed by a ligand transfer from the
verted into N-sulfinylimines, which were subsequently trans- Lewis acids to imine 5k. Nucleophilic substitution of N/O-
formed into sulfinamides attached to a tertiary C-atom by acetal 9k with two equivalents of (trimethylsilyl)ethynyllithium,
addition of nucleophiles [89-92]. N-Sulfinyl propargylamine 7k in analogy to the conversions reported by Kuduk et al. [96],
was prepared, following approach II under varying conditions remained unsuccessful. The (S)-configuration of the newly
(Table 2). Fluoral hydrate was dehydrated with concentrated generated chiral center of amine 10k was determined by X-ray
sulfuric acid to give trifluoroacetaldehyde by distillation [93]. structure analysis (Figure 7), suggesting two possible transition
states for the ligand transfer.
The reaction of trifluoroacetaldehyde with tert-butyl sulfin-
amide (S)-1 in the presence of molecular sieves 4 Å provided Whereas transition state TII requires only one equivalent of
the sulfinylimine 5k, which could not be isolated due to its AlMe3, two equivalents of AlMe3 are involved in transition
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Figure 6: Side reactions observed in the course of the conversion of highly electrophilic sulfinylimines 5. (a) Sulfinamide (S)-1, molecular sieves 4 Å,
toluene. (b) 1. Dilution with H2O, 2. Extraction with DCM. (c) Addition of Ti(OiPr)4 prior to the conversion with (trimethylslyl)ethynyllithium [94]. (d) Ad-
dition of AlMe3 prior to the conversion with (trimethylsilyl)ethynyllithium.
Figure 7: a) Possible transition states TI and TII for the transfer of the methyl moiety from AlMe3 to the imino moiety. b) X-ray crystal structure analy-
sis of the methyl transfer product 10k.
state TI. As in this case almost quantitative conversion of desilylation procedure was required. Therefore, AgNO3 and
AlMe3 was observed, transition state TII seems to be more KCN (GP-7) were used for the desilylation of 6i to afford the
probable. Still, more complex coordination geometry (hexago- free alkyne 7i in 66% yield. N-Sulfinyl propargylamines 6k and
nal or dinuclear complexes) of the Lewis acid are probable as 6j, with perfluorinated side chains, required even milder desilyl-
well and hardly depend on the stoichiometry. In the conversion ation conditions. KF in the presence of 18-crown-6 (GP-6) pro-
of highly reactive sulfinylimines like 5k, best results were ob- vided the free alkynes 7k and 7j in 29% and 52% yield, respec-
tained in the absence of a Lewis acid. Analogous investigations tively (results are collected in Table 2).
with chloral hydrate instead of fluoral hydrate showed that the
trichloromethylimine 5l also forms a hemiaminal 8l upon con- Desilylation of alkynes 6k and 6j under alkaline conditions with
tact with water, but does not undergo comparable side reactions K2CO3, in analogy to the description of Vasella et al. [57] leads
with Ti(OiPr)4 or AlMe3. Sulfinylimine 5l appears to be a to instant decomposition of the starting material in a base-
weaker electrophile, which is attributed to the lower electroneg- promoted propargyl–allenamide isomerization. According to
ativity of Cl compared to F and to the larger size of the CCl3 our hypothesis, basic fluoride leads to deprotonation in the
group compared to the CF3 moiety, sterically shielding imine 5 Cα-position of 6i, 6k and 6j, inducing an alkyne rearrangement
against nucleophilic attack.
to form an allene, which rearranges further to provide an α,β-
unsaturated imine (Figure 8) [97].
Desilylation of N-sulfinyl propargylamine 6i with TBAF (GP-5)
resulted in decomposition instead of formation of the free One target application of propargylamines 7 is the Sonogashira
alkyne 7i. In order to obtain the free terminal alkyne 7i, a milder cross-coupling with halogenated benzoates, forming the scaf-
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Beilstein J. Org. Chem. 2017, 13, 2428–2441.
Figure 8: Base-induced rearrangement of propargylamines bearing electron-withdrawing substituents.
fold of versatile peptidomimetics 11. According to the pro- understanding of the reactivity of propargylamines, the stability
posed rearrangement of alkyne 7 (Figure 9), the choice of base and propensity for base induced rearrangement of 11 were in-
is crucial for such cross-coupling reactions. To get a better vestigated (Figure 9).
Figure 9: Base-catalyzed rearrangement of propargylamines 11 to α,β-unsaturated imines 12. A) Reaction scheme: (a) methyl 4-iodobenzoate (for
the conversion of 7i to 11i, 1.6 equiv) or methyl 3-iodobenzoate (for the conversion of 7k to 11k), DIPEA (6 equiv), THF, Cl2Pd(PPh3)2, CuI, room
temperature, 2 h (GP-9). (b) Piperidine/THF (1:3), 0 °C, 30 min (conversion of 11i to 12i). Or LiOH (3 equiv), MeOH/H2O (2:1), 0 °C, 30 min.
B) UV–vis spectra of propargylamines 11 and α,β-unsaturated imines 12. C) X-ray crystal structure analysis of propargylamine 11i and α,β-unsatu-
rated imine 12i.
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Beilstein J. Org. Chem. 2017, 13, 2428–2441.
The ester substituted compounds 11i and 11k were obtained by are not reversible. Reversibility of the rearrangement would be
Sonogashira cross-coupling of the terminal alkynes 7i and 7k fundamental for racemization of propargylamines, which is
with methyl 4- and 3-iodobenzoate, respectively. As the tert- consequently improbable. However, even in the presence of
butylsulfinyl group can be cleaved off under mild, acidic condi- strong bases like KOt-Bu or LDA, the propargylamide–allenyl-
tions [1,25,26], it provides a versatile protective group for the amide rearrangement could never be observed for propargyl-
amine during the conversion of the alkyne. Additionally, it’s amines without an acidifying Cα-substituent.
chirality indicates epimerization and, for example in the
Synthesis of propargylamines containing
Pauson–Khand reaction [14], allows the determination of the
stereoselectivity of asymmetric conversions by simple 1H NMR polar or acidic functional groups
experiments. Consequently it was not removed prior to the rear- The synthesis of propargylamines with polar substituents to
rangement experiments.
mimic polar amino acids such as serine (alcohol), cysteine
(thiol) or glutamine (carboxamide) requires special protective
Treatment of 11i and 11k with the mild base piperidine led to groups (Table 3).
the formation of α,β-unsaturated sulfinylimines 12i and 12k.
The structures of the rearranged products were proven unequiv- The cyano moiety was used as precursor of the carboxamide
ocally by 1H and 13C NMR spectroscopy and X-ray crystal moiety of glutamine, since the cyano group is stable in the pres-
structure analysis.
ence of nucleophiles and strong bases. The synthesis started
with the Kolbe nitrile synthesis of 4-iodobutan-1-ol with NaCN.
Due to the extended π-system of the α,β-unsaturated imines 12i Performing this transformation in DMSO provided the desired
and 12k, the progress of the propargylamide–allenylamide rear- 5-hydroxypentanenitrile and THF in the ratio 5:2 (monitored by
rangement that eventually leads to the formation of the α,β- 1H NMR spectroscopy, see Supporting Information File 1).
unsaturated imines by tautomerism could be easily monitored Next, 4-cyanobutan-1-ol was oxidized in a Swern oxidation and
by UV–vis spectroscopy. The reaction mixture turned brightly the resulting aldehyde was condensed with tert-butylsulfi-
yellow when treated with bases like piperidine. The X-ray namide (S)-1, according to GP-2. The reaction of sulfinimine 5q
crystal structures of 11i and 12i confirm unequivocally the with (trimethylsilyl)ethynyllithium led to sulfinamide 6q. In this
structure of the products and thus the postulated two-step rear- case, the Lewis acid AlMe3, which could also react with the
rangement. Both, the rearrangement of the alkyne to the allene cyano moiety, was omitted. Finally, cleavage of the TMS group
and the subsequent tautomerism to the α,β-unsaturated imine was achieved under mild conditions with KF and 18-crown-6
Table 3: Preparation of N-sulfinyl propargylamines 7 with polar and acidic functional groups in the side chains.a
R
(a)
Yield (5)
(b), (c)
Yield (7)b
dr
CH2OCPh3
CH2OBn
GP-2
GP-2
GP-1
GP-2
GP-2
GP-2
GP-2
GP-1
GP-1
GP-2
GP-2
47% (5m)
81% (5n)d
24% (5o)
83% (5p)d
80% (5q)
79% (5r)
64% (5s)
90% (5t)
85% (5u)
52% (5v)
84% (5w)
GP-4, GP-6
GP-3, GP-5
GP-4, GP-5
GP-3, GP-5
GP-4, GP-6
GP-4, GP-5
GP-4, GP-6
GP-3, GP-5
GP-4, GP-5
f
0% (7m)c
4% (7n)e
31% (7o)
31% (7p)f
43% (7q)
0% (7r)c
47% (7s)
27% (7t)
0% (7u)c
n.d.
95/5
93/7
93/7
95/5
n.d.
CH2OAll
CH2SBn
(CH2)3CN
(CH2)2CO2Bn
(CH2)2CO2t-Bu
(CH2)3OXf
(CH2)3Cl
93/7
93/7
n.d.
(CH2)4N3
f
(CH2)3N3
a(a) GP-1: Auxiliary (S)-1, aldehyde, Ti(OiPr)4, 70 °C, 40 min. GP-2: Auxiliary (S)-1, aldehyde, CuSO4, DCM, rt, 3 d. (b) GP-4: (Trimethylsilyl)ethynyl-
lithium, AlMe3, toluene, −78 °C to rt. (c) GP-5: TBAF, THF, 0 °C, 3 h. GP-6: KF, 18-crown-6, THF/H2O (98:2), 0 °C. bYields of 7 refer to imine 5 (two
steps). cCompounds 7m, 7r and 7u could not be isolated and the diastereoselectivity could not be determined (n.d.). dFurther reactions in Table 4.
e(R)-Configured Ellman’s sulfinamide (R)-1 was applied. Hence, the mirror images of 5–7n,p were obtained. f5t, X = TBDMS. 7t, X = H.
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(GP-6), to yield N-sulfinyl propargylamine 7q as an analogue of transformed into an aminoalkyl group by Staudinger reduction
the non-proteinogenic amino acid 5-cyano-L-norvaline. Forma- [16]. In order to follow a more convergent approach and to
tion of a glutamine analogous side chain by hydrolysis of the avoid nucleophilic substitution of the halide at a late stage, we
nitrile function to an amide remained unsuccessful so far.
decided to start the synthesis with 4-azidobutanal, which was
prepared by opening THF with iodine and NaBH4, nucleophilic
Propargylamines with diversely protected alcohol functionali- substitution by sodium azide and Swern oxidation of the
ties in the side chain were obtained by approach II. The applica- alcohol.
tion of an allyl ether, starting from 2-allyloxyacetaldehyde to
form 7o and a benzoate, starting from formylmethyl benzoate to 4-Azidobutanal was converted with chiral sulfinamide (S)-1
form 7n (Table 3) turned out to be most convenient. In contrast into N-sulfinylimine 5w, which was reacted with (trimethyl-
to labile TMS ethers, the sterically more demanding tert-butyl silyl)ethynyllithium. However, following the usual procedure
dimethylsilyl ether was successfully applied as protective group GP-4 with warming up the reaction mixture to room tempera-
to obtain the homologated serine analogous propargylamine 7t ture before quenching with water led to the formation of tri-
similar to the description by Verrier et al. [47,55], starting from azole 13w, which was isolated in 56% yield (Table 4). The
TBDMS-protected oxybutanal. Treatment of alkyne 6t with target propargylamine 6wx was obtained in only 19% yield.
TBAF leads to simultaneous cleavage of both silyl groups. Al- Cleavage of the TMS group with KF and 18-crown-6 at 0 °C
though sterically shielding protective groups have proven con- provided azide 7wx in only 22% yield, because triazole 14w
venient, the trityl group turned out to be inefficient to generate a was formed in a side reaction. Compound 7wx was converted
serine-analogous propargylamine. Trityl-protected imine 5m into triazole 14w even upon standing at room temperature in
immediately decomposed, when treated with (trimethyl- CDCl3 (monitored by 1H NMR spectroscopy, see Supporting
silyl)ethynyllithium.
Information File 1). Formation of triazoles 13w and 14w was
unexpected, because the uncatalyzed Huisgen reaction usually
The preparation of glutamic acid-analogous propargylamines requires higher temperature or activation by electron-with-
failed when the acid functionality was protected as a benzyl drawing substituents at the alkyne or electron-donating substitu-
ester. Fortunately, the sterically more demanding tert-butyl ents at the azide, respectively [105,106]. As none of these
ester was stable and gave high yields of 7s. The synthesis requirements are met in the case of 6wx and 7wx, it is assumed,
started from the aldehyde tert-butyl-4-oxobutanoate, which that the preorientation of the azide and the alkyne together with
could be easily obtained from succinic anhydride [44,98,99]. the formation of an energetically favored six-membered ring are
Selective cleavage of the tert-butyl group was not yet accom- the driving forces. As hexose scaffolds similar to 13w and 14w
plished without affecting the tert-butyl sulfinamide protection have been successfully applied as inhibitors of β-glucosidases
group of the amine.
[107] and hexosamidases [108], this intramolecular Huisgen
reaction could be exploited to develop novel enzyme inhibitors.
A cysteine-analogous alkyne could be synthesized starting from
benzylmercaptan. Unfortunately, only extremely low yields In order to get access to propargylamines with the side chains of
were achieved and N-sulfinyl propargylamine 7p is not stable lysine, ornithine and arginine, azide 7wx should be reduced.
under the conditions, which are necessary to cleave the However, all attempts to reduce the isolated azide 7wx with
thioether [100,101].
NaBH4 or PPh3 failed, due to the competing triazole formation.
Therefore, instant reduction of in situ prepared 6wy was envis-
aged. The nucleophilic addition of (trimethylsilyl)ethynyl-
lithium to N-sulfinylimine 5w was monitored by analytical
Synthesis of propargylamines with basic
functional groups in the side chain
Very often, basic amino acids, like lysine or arginine are found HPLC. After complete conversion, PPh3 was added directly to
in the catalytic center of enzymes. Therefore, propargylamines the reaction mixture at −78 °C. After addition of water and stir-
mimicking these basic amino acids are of particular interest to ring for two hours, the primary amine 7wy was isolated in 86%
be incorporated in peptidomimetics. The exchange of basic yield. This procedure led to the ornithine analogous propargyl-
amino acids has already been performed to develop potent en- amine 7wy, which was reacted with Boc-protected
zyme inhibitors [102-104]. In order to introduce side chains S-methylisothiourea to yield the arginine analogous propargyl-
with basic amino moieties into propargylamines, these have to amine 7x in a yield of 79%. During the decomposition of the
be protected against nucleophiles, bases and deprotonation.
azide in the Staudinger reaction, the TMS group at the alkyne
was cleaved off simultaneously. Cleavage of TMS groups with
According to the approach of Ye et al., a 3-bromopropyl side PPh3 under similar conditions has not been reported so far.
chain was used, which was converted to the azide and further Therefore, an intramolecular mechanism is postulated, in which
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Beilstein J. Org. Chem. 2017, 13, 2428–2441.
Table 4: Synthesis of lysine, ornithine and arginine-analogous propargylamines 7vy, 7wy and 7x and discovery of an unexpected intramolecular low-
temperature Huisgen reaction.
Starting
material
Reaction conditions
Product
Yield
dr
5v
(a) (trimethylsilyl)ethynyllithium, Ti(OiPr)4, THF, −78 °C (GP-3)
(a) (trimethylsilyl)ethynyllithium, Ti(OiPr)4, THF, −78 °C. (GP-3)
(b) (trimethylsilyl)ethynyllithium, AlMe3, toluene, −78 °C (GP-4)
(c) TBAF (2 equiv), THF, 0 °C, 4 h (GP-5)
(c) TBAF (2 equiv), THF, 0 °C, 4 h (GP-5)
(d) CDCl3, 7 d, rt.
6v
58%
14%
56%
58%
19%
66%
0%
100:0
n.d.
5w
6v
6w
13w
7vx
7wx
14w
7vy
7wy
7vy
7wy
7vy
100:0
74:26
96:4
96:4
n.d.
6v
6w
7wx
7vx
7wx
6v
(e) 1. PPh3, CuSO4, THF; 2. H2O.
(e) 1. PPh3, CuSO4, THF; 2. H2O.
0%
n.d.
(f) 1. NaBH4, CuSO4, THF; 2. H2O.
0%
n.d.
6w
5v
(f) 1. NaBH4, CuSO4, THF; 2. H2O.
0%
n.d.
(g) 1. (trimethylsilyl)ethynyllithium, toluene, −78 °C, 3 h; 2. PPh3
(4 equiv), THF, −78 °C; 3. H2O, rt, 2 h.
68%
91:9
5w
(g) 1. (trimethylsilyl)ethynyllithium, toluene, −78 °C, 3 h; 2. PPh3
(4 equiv), THF, −78 °C; 3. H2O, rt, 2 h.
7wy
7vz
7wz
7x
86%
45%
63%
79%
80:20
91:9
7vy
7wy
7wy
(h) 1. Boc2O (2 equiv), THF/H2O (1:1), NaHCO3 (3 equiv);
2. imidazole, 4 h.
(h) 1. Boc2O (2 equiv), THF/H2O (1:1), NaHCO3 (3 equiv);
2. imidazole, 4 h.
90:10
93:7
(i) BocHN-C(=NBoc)SMe (1 equiv), DCM, rt, 3 d.
the iminophosphorane, formed by the reaction of PPh3 with protected with a Boc group to give propargylamines 7wz and
azide 6wy, coordinates to the silyl group. This intramolecular 7vz.
coordination facilitates the fast hydrolytic cleavage of the silyl
group during aqueous work-up. This PPh3-induced TMS Conclusion
cleavage could also be successfully applied in the synthesis of Ellman’s chiral sulfinamide has been successfully used for the
the lysine analogous propargylamine 7vy from 5v but could asymmetric synthesis of enantiomerically pure propargyl-
never be reproduced in the formation of other propargylamines, amines. An array of 24 diastereomerically pure N-sulfinyl
like the tert-butyl-substituted compound 7e, under identical propargylamines has been prepared, bearing side chains in
reaction conditions. The amine groups of 7wy and 7vy were α-position, which are analogous or similar to amino acid side
2438

Beilstein J. Org. Chem. 2017, 13, 2428–2441.
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versible alkyne–allene-α,β-unsaturated imine rearrangement
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Supporting Information File 1
Details about the experiments, methods and materials, the
X-ray crystal structures and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
16. Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50,
3236–3239. doi:10.1002/anie.201007624
The authors gratefully acknowledge Deutsche Forschungs-
gemeinschaft for financial support of the project (SE 609/10-1).
17. Wünsch, M.; Senger, J.; Schultheisz, P.; Schwarzbich, S.;
Michalek, C.; Klaß, M.; Goskowitz, S.; Borchert, P.; Jung, M.;
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ORCID® iDs
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2010, 12, 1064–1067. doi:10.1021/ol1000473
Matthias Wünsch - https://orcid.org/0000-0002-3244-8374
David Schröder - https://orcid.org/0000-0002-7249-4156
Nils Janson - https://orcid.org/0000-0002-9681-5698
Jasmin Simon - https://orcid.org/0000-0002-8309-2267
Shari Heidemeyer - https://orcid.org/0000-0002-9254-7796
Alessa Hinzmann - https://orcid.org/0000-0002-1893-7892
Hans-Georg Stammler - https://orcid.org/0000-0002-0918-7057
Norbert Sewald - https://orcid.org/0000-0002-0309-2655
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