Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

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 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.


Condensation of aldehydes with Ellman's chiral sulfinamide to form imines 5
GP-1: tert-Butylsulfinamide (S)-1 or (R)-1 (1 equiv) was dissolved in freshly distilled aldehyde (1 equiv) and Ti(OEt) 4 (2 equiv) was added in one portion. The slightly yellow suspension turned brightly orange upon heating for 40 min (approximately 60 °C) under reflux conditions. After cooling to rt, the suspension was diluted with EtOAc (40 mL) and brine (1 mL) was added dropwise leading to the formation of a colourless precipitate. The solid was filtered through a pad of celite and washed with EtOAc (200 mL). Evaporation of the solvent in vacuo yielded the aldimine (5b, 5c, 5h, 5i, 5t) in pure form to be converted without further purification. Typical reactions were carried out on a scale of 1-3 g of tert-Butylsulfinamide (S)-1 or (R)-1. Analogous reaction conditions have already been described by Ellman et al. and Yus et al. [3][4][5].
GP-2: tert-Butylsulfinamide (S)-1 or (R)-1 (1 equiv) was dissolved in CH 2 Cl 2 (1 M solution) and freshly prepared aldehyde (1.2 equiv), as well as dried CuSO 4 (1.5-2.0 equiv) was added in one portion. The colourless reaction mixture was stirred for 72 h at rt. After complete conversion of the sulfinamide (monitored by TLC), the suspension was diluted with a KHSO 4 solution (5%). The aqueous layer was separated, extracted twice with CH 2 Cl 2 and the combined organic layers were dried over Na 2 SO 4 . Evaporation of the solvent in vacuo yielded the desired sulfinylimines (5d-g, 5j-l, 5n-q, 5s, 5v, 5w). In some cases, purification by column chromatography was necessary. Typical reactions were carried out on a scale of 0.2-3 g of tert-Butylsulfinamide (S)-1 or (R)-1. Analogous reaction conditions have already been described by Ellman et al. [6]. of NH 4 Cl was added until no further precipitate was formed. The colourless solid was filtered through a pad of celite, and the pad was washed with EtOAc (200 mL). The filtrate was dried over Na 2 SO 4 and the solvent evaporated under reduced pressure. The crude product was directly applied for desilylation. This method was applied for the synthesis of 6a-d, 6n and 6t.
Typical reactions were carried out on a scale of 0.5-3 g of imine 5. Analogous reaction conditions have already been described by Ellman et al. and Tartakovski et al. [7][8][9]. Analogous reaction conditions have already been described by Vasella et al. [18]. were isolated by recrystallization. These reaction conditions were only used for the synthesis of 7i (typically 0.3-3 g). Analogous reaction conditions have already been described by Vasella et al. [17].

Swern Oxidation
GP-8: DMSO (50 mmol) was added dropwise to a solution of oxalylchloride (25 mmol) in DCM (60 mL) at −78 °C. After 2 min, a solution of the alcohol (23 mmol) in DCM (30 mL) was added over a period of 5 min. The reaction mixture was stirred for 30 min, before NEt 3 (115 mmol) was added. The resulting slurry was stirred for further 30 min at −78 °C and then warmed up to rt. The suspension was washed with water (50 mL) and a solution of KHSO 4 (5 %, 30 mL). The aqueous layers were extracted with DCM (2 × 30 mL) and the combined organic layers were washed with brine (20 mL) and dried over Na 2 SO 4 before the solvent was evaporated under reduced pressure. The prepared aldehyde was directly converted or purified S10 by column chromatography or distillation. Typical reactions were carried out on a scale of 0.5-10 g of alcohol. The synthesis was carried out as described by Swern et al. [19].
Sonogashira cross coupling of propargylamine 7 to peptidomimetic 11 GP-9: DIPEA (6 equiv) was added to a solution of propargylamine 7 (1 equiv) and the methyl iodo-benzoate derivative (1.6 equiv) in THF (THF/DIPEA = 3:1). The reaction mixture was degassed by freeze pump thaw method, until no more gas atmosphere could be detected by the manometer. The catalysts, Cl 2 Pd(PPh 3 ) 2 (2 mol %) and CuI (1 mol %) were added to the frozen reaction mixture and the solution slowly warmed to room temperature. After 30-120 min, a colourless precipitate formed in the clear solution, indicating the progress of the reaction. At least 2-8 h later, the suspension was diluted with a saturated aqueous NH 4 Cl solution and KHSO 4 (aq, 5 %) was added, until the organic layer started to turn faintly red (pH 5-6). The emulsion was diluted with Et 2 O, the organic layer separated and the organic layer extracted to more times with Et 2 O. The combined organic layers were dried over Na 2 SO 4 and the solvent was evaporated in vacuum. The crude product was purified by column chromatography. Typical reactions were carried out on a scale of 0.1-0.5 g of propargylamine 7. Similar reactions have already been described by Hashmi [20], Ishida [21] and Wong et al. [22].

2-(Benzylthio)acetaldehyde
Benzyl(2,2-dimethoxyethyl)sulfane (5.00 g, 23.5 mmol, 1 equiv) was dissolved in H 2 SO 4 (0.5 M, 21 mL) and the solution was heated for 5.5 h to 60 °C. After cooling down to rt, a solution of saturated NaHCO 3 was added until the pH was neutral. Afterwards, the solution was extracted with DCM (4 × 15 mL). The combined organic layers were dried over Na 2 SO 4 and the solvent was evaporated under reduced pressure to yield 2-(benzylthio)acetaldehyde in pure form. The synthesis of the title compound has been first described by Zhdanko, Gulevich and Nenajdenko [40].
A solution of iodine (7.650 g, 30.14 mmol) in THF (50 mL) was added dropwise at 0 °C to a rigorously stirred suspension of NaBH 4 (0.568 g, 15.01 mmol) in THF (80 mL) over a period of 2 h. The reaction mixture was allowed to warm up to rt overnight.

5-Hydroxypentanenitrile
To a solution of 5-iodobutan-1-ol (16.5 g, 82.5 mmol, 1 equiv) in dry DMSO (75 mL), solid NaCN (6.06 g, 124 mmol, 1.5 equiv) was added in small portions at 0 °C. The reaction progress was surveilled by NMR spectroscopy. It is instant and the title compound as well as THF (6 : 5) are formed. After complete conversion, the reaction mixture was diluted with water (75 mL) and extracted with Et 2 O (5 × 100 mL). The combined organic layers were washed with brine and dried over Na 2 SO 4 . Evaporation of the solvent yielded the title compound in pure form.

TMS protected propargylamines 6
In most cases, compound 6 was not isolated. The crude product of the described synthesis was directly converted to propargylamine 7, without further purification. was not purified. The crude product was directly converted to 7a. 1  Colourless crystals, yield: 2.45 g, 8.18 mmol, 33 % (referred to sulfinamide (S)-1). 1  When hemiaminal 8k was used instead of imine 5k, the yield was considerably reduced to 24.2 mg, 106 mol, 5 %. When imine 5k was used, and AlMe 3 was added as a Lewis acid, as Yellow oil, yield not determined. 1

Propargylamines 7
When compound 6 was not isolated, the yield of propargylamine 7 usually refers to imine 5 (2 steps, mentioned in parentheses).

X-ray structure analysis
Details of crystal and refinement data can be found in Table S1. CCDC 1566791 -CCDC 1566804 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Single crystals of C 8 H 15 NOS (7a) were achieved out of a saturated solution in n-hexane.      Single crystals of C 13 H 12 F 5 NOS (7k) were achieved out of a saturated solution in EtOAc. One C(CCH)(CF 3 ) unit is disordered in ratio 51:49. The anisotropic displacement parameters of these atoms were constrained to be same pairwisely. The N-H distances were restrained to a value of 0.86 Å.    Single crystals of C 11 H 18 N 2 OS (7q) were achieved out of a saturated solution in EtOAc.

S94
Single crystals of C 11 H 7 F 3 O 3 (12k) were achieved out of a saturated solution in CHCl 3 .