Thiol-Ene Click Reactions - Versatile Tools for the Modification of Unsaturated Amino Acids and Peptides

FULL PAPER

DOI: 10.1002/ejoc.201300672

Thiol-Ene Click Reactions – Versatile Tools for the Modification ofUnsaturated Amino Acids and Peptides

Lisa Karmann[a] and Uli Kazmaier*[a]

Dedicated to Professor Wolfgang Steglich on the occasion of his 80th birthday

Keywords: Amino acids / Peptides / Click chemistry / Allylation / Thiols

Terminal γ,δ-unsaturated amino acids, easily available byClaisen rearrangement or palladium-catalysed allylic alkyl-ation, are excellent substrates for radical thiol additions.These click reactions allow the introduction of highly func-

Introduction

Since the introduction of “click chemistry” by Sharplessin 2001,[1] click reactions have become extremely popular inmany fields of advanced chemistry.[2] Besides polymer andmaterials synthesis,[3] also the life sciences benefit enor-mously from such reactions.[4] Typical characteristics ofclick reactions are their generally high yields (almost noside-reactions), their high regio- and stereoselectivities, theirhigh tolerance of oxygen and water, and their orthogonalitytowards a wide range of other important functional groups.Many of the reactions can even be carried out in aqueoussystems, and this makes them highly suitable for the modifi-cation of biomolecules.[4] Although some of the popularclick reactions are “relatively old”, new and very mild ver-sions have been developed in recent years, and this hasmade them applicable to sensitive systems. Probably thebest example of this is the copper-free azide–alkyne cyclo-addition,[2b,5] based on the [3+2]-cycloadditions[6] reportedby Huisgen in the early 1960’s.[7] The omission of the toxiccopper allows these click reactions to be carried out in liv-ing cells.[8] Another popular and extremely mild click reac-tion is the addition of thiols to alkenes (and alkynes),[9]

known as thiol-ene click chemistry.[10] These reactions alsogive almost quantitative yields in many cases, and they findwidespread application in polymer chemistry[11] and chemi-cal biology.[12] Although the nucleophilic thiol addition isrestricted to electron-poor alkenes, the radical versionworks well with both electron-poor and electron-rich

[a] Institute for Organic Chemistry, Saarland University,P. O. Box 151150, 66041 Saarbrücken, GermanyE-mail: [email protected]://www.uni-saarland.de/lehrstuhl/kazmaier.htmlSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201300672.

Eur. J. Org. Chem. 2013, 7101–7109 © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 7101

tionalized side-chains into a given amino acid or peptide.This protocol is suitable for the modification of all kinds ofterminal alkenes, such as allyl protecting groups.

double bonds, as long as they are not too sterically hin-dered.[8,9]Therefore, in general, the best results are obtainedwith terminal alkenes. These reactions also work well withalkynes to produce 1,2-dithiolated alkanes.[13] The radicalthiol addition proceeds under completely neutral conditionsand allows the regioselective modification of, for example,unsaturated carbohydrates[14] and amino acids.[15] With thelatter class of compounds, in some cases, a partial racemiza-tion of the chiral α-centre is observed, as a result of aninternal radical hydrogen shift.[16]

Results and Discussion

Our group is involved in the development of methods forthe synthesis of unnatural amino acids, especially unsatu-rated ones.[17] γ,δ-Unsaturated amino acids can easily beobtained either by chelate Claisen rearrangement[18] or bytransition-metal-catalysed allylic alkylation.[19] Besides Pdcatalysts, complexes of Rh[20] and Ru[21] can be used in theallylic alkylations. The two protocols, the Claisen rearrange-ment and the allylic alkylation, complement each othernicely, and give access to both stereoisomers (if β-substi-tuted amino acids are formed) in a highly stereoselectivefashion.[22] If stannylated substrates are used, the metallatedamino acid formed can be subjected to subsequent cross-coupling reactions to generate libraries of structurally re-lated amino acids and peptides.[23] To increase the potentialof γ,δ-unsaturated amino acids even more, we became inter-ested in their thiol-ene click reactions. Depending on thethiol used, the new substituent could be used to introducespecific properties (polarity, water solubility, etc.) or labels(fluorescence, photoaffinity, biotin, etc.) into a given aminoacid or peptide. Therefore, we started to investigate thethiol-ene click reaction of protected allyl-glycine 1 with awide range of thiols (Table 1).

L. Karmann, U. KazmaierFULL PAPERTable 1. Thiol-ene click reactions of protected allyl-glycine 1.

[a] Yield of pure compound 2. [b] Contaminated with the corre-sponding cystine derivative (2%). [c] Contaminated with thiol(9%). Boc = tert-butoxycarbonyl.

Initial experiments were carried out in CH2Cl2 usingstoichiometric amounts of tBuSH as the thiol component.Irradiation using an ultravitalux lamp provided the productin 44 % yield after irradiation for 3 h. The reaction couldbe optimized by using a threefold excess of the thiol andprolonging the irradiation time to 6 h. Ethanol was foundto be the solvent of choice. Under these conditions, a yieldof 73% could be obtained with tBuSH (Table 1, entry 1).To obtain comparable results, the conditions were kept con-stant for the addition reactions of further thiols. The rela-tively moderate yield obtained with tBuSH can probablybe explained as being due to the reversibility of the thioladdition,[24] which led to a mixture of the starting materialand the addition product. An even more dramatic effectwas observed in the addition reaction of thiophenol. Here,a product yield of only 12% could be obtained, probablybecause of the relative stability of the thiophenol radicaland an unfavourable equilibrium. But these problems canbe overcome completely if sterically less demanding ali-phatic thiols are used. With linear primary thiols, an almostquantitative yield of the addition product was obtained(Table 1, entries 2 and 3). Such nonpolar substituents canbe used to decrease the polarity of amino acids and pept-ides. On the other hand, the polarity can be significantlyincreased by the addition of hydroxylated or carboxylatedthiols (Table 1, entries 4–6). These substituents should in-crease the water solubility of a given peptide. In addition,the introduction of a free carboxylic acid directly into anamino acid (Table 1, entry 6) would allow it to be coupleddirectly with other amino acids or labels. Amine functional-

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ities can be introduced, e.g., by the addition of N-protectedcysteamine derivatives (Table 1, entry 7). The almost quan-titative addition of thioacetic acid (Table 1, entry 8) is espe-cially interesting, because saponification of the thioestergives rise to higher homologues of cysteine. In principle,such thiolated amino acids could be subjected to furtherthiol-ene click reactions, as illustrated by the addition ofprotected cysteine (Table 1, entry 9). The diamino acidsformed are suitable candidates for the synthesis of cross-linked or cyclic peptides.[25] The introduction of a trime-thoxysilane side-chain (Table 1, entry 10) should allow theimmobilization of amino acids and peptides on solid sup-ports.[26]

To test the scope and limitations of this protocol, we nextinvestigated the addition of thiols to substituted allyl-glycine derivatives (Scheme 1). Starting from cinnamylalcohol, β-phenylated amino acid 3 could easily be obtainedby a chelated Claisen rearrangement,[27] while δ-phenylatedderivative 4 was obtained by allylic alkylation.[20]

Scheme 1. Thiol-ene click reactions of substituted allyl-glycines.TFA = trifluoroacetyl.

Branched amino acid 3, with a terminal double bond,reacted nicely, and gave results comparable to those ob-tained with unsubstituted allyl-glycine 1. However, no reac-tion was observed with linear amino acid 4, with an internaldouble bond. Even though a well-stabilized benzyl radicalcan be formed from compound 4, probably for stericreasons the thiol-ene click reaction proceeds selectively atterminal double bonds.

Bearing in mind that Broxterman et al. observed a slightdecrease of the enantiomeric purity of the amino acids incomparable studies,[16] we also investigated the addition of athiol to enantiomerically enriched allyl-glycine (Scheme 2),easily accessible by asymmetric Claisen rearrangement.[28]

And indeed, a slight drop in the ee was observed followingthe addition of mercaptopropanoate, confirming the pre-viously reported results. This effect might be explained asbeing due to a competitive 1,3-hydrogen shift of the radicalintermediate.[16]

Scheme 2. Thiol-ene click reaction of enantiomerically enrichedallyl-glycine 1.

Thiol-Ene Click Reactions

To test whether this is an issue of allyl-glycine in particu-lar, or whether it might be generally found in thiol-ene clickreactions of amino acids and peptides, we also synthesizedsome allylated dipeptides and subjected them to thiol ad-dition reactions. Allylated dipeptides can easily be obtainedby Pd-catalysed allylic alkylation in a highly stereoselectivefashion.[29] Diastereomeric product ratios of �90:10 aregenerally obtained, especially if substituted allylic sub-

Scheme 3. Synthesis of allylated peptides 6 and 7. LHMDS = lith-ium hexamethyldisilazide.

Scheme 4. Synthesis of allylated peptide 6.

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strates are used. Only with unsubstituted allyl acetates andcarbonates are significantly worse selectivities obtained(Scheme 3).

To tackle this issue, we decided to evaluate the allylationreaction with a substituted allylic substrate that could laterbe cleaved to reveal a terminal double bond. The synthesisand application of a suitable substrate is shown inScheme 4. Starting from commercially available glycerolallyl ether, oxidative cleavage, using NaIO4 immobilized onsilica,[30] gave rise to the corresponding aldehyde, which wasdirectly (without further purification) subjected to a vinylGrignard addition. The allylic alcohol obtained was con-verted into the corresponding allyl carbonate (i.e., 8), thesubstrate for the desired allylic alkylation reaction. And in-deed, with this substituted allylic substrate, the diastereo-selectivity in the allylation step could be increased to�90 %. (The term “% ds” describes the percentage of themajor diastereomer formed.) Unfortunately, the reactivityof this allylic substrate seemed to be lower than that ofother substrates such as the methallyl carbonate used pre-viously. A lower yield was obtained, even when the dipept-ide was used in slight excess, and therefore the product (i.e.,9) was contaminated with the peptide starting material,which could not be removed by flash chromatography. Nev-ertheless, impure allylated peptide 9 was subjected to ring-closing metathesis, which resulted in the cleavage of the all-ylic substituent and the formation of the allyl-glycine sub-unit (i.e., 6).

With allylated peptides 6 and 7 in hand, we subjectedthem to the thiol-ene click reactions (Table 2). The yields

L. Karmann, U. KazmaierFULL PAPERobtained were slightly worse than those obtained in the re-actions of the amino acid, but they were still in the prepara-tively useful range. Interestingly, no epimerization of thestereogenic centres was observed in these cases.

Table 2. Addition of thiols to allylated dipeptides 6 and 7.

[a] Determined by 1H NMR spectroscopy. [b] 1:1 (R/S) mixture inthe side-chain.

To further examine the substrate scope, we also subjectedsome tetrapeptides such as 12 to the thiol-ene click reac-tions. Due to the high polarity of the tetrapeptide, the ex-periments were carried out in a 2:1 mixture of ethanol andTHF (Table 3). Based on the results of the irradiations withthe dipeptides, the excess of the thiol was increased to6 equiv. Under these conditions, the yields of compounds13a–c were in the same range as those obtained with thedipeptides (i.e., of 10 and 11) (Table 3, entries 1–3).

Table 3. Addition of thiols to tetrapeptide 12 containing an allyl-glycine subunit.

[a] Contaminated with the corresponding thiol (5%).


To demonstrate the broad scope of this reaction, anothertetrapeptide with an O-allyl group instead of a C-allyl unitwas prepared by standard methods and subjected to thethiol addition reaction conditions (Table 4). Also with thistetrapeptide (i.e., 14), excellent yields were obtained underthe same conditions (Table 4, entries 1–3).

Table 4. Thiol-ene click reactions of O-allylated tyrosine peptide14.

[a] Contaminated with the corresponding thiol (6%). [b] Contami-nated with starting material 14 (6%).

Conclusions

In conclusion, we have shown that the thiol-ene click re-action can be used to introduce a wide range of side chains(polar, nonpolar, or functionalized) into unsaturated aminoacids and peptides. Further applications of this protocol arecurrently under investigation.

Experimental SectionGeneral Remarks: All air- and moisture-sensitive reactions werecarried out in dried glassware under a nitrogen atmosphere. THFwas distilled from sodium benzophenone. LHMDS solutions wereprepared from freshly distilled HMDS (hexamethyldisilazane) andcommercially available n-butyllithium solution (1.6 m in hexane) inTHF before use. In the thiol-ene click reactions, an ultravitaluxlamp (280–740 nm; 300 W) served as light source. The radiationswere carried out in quartz tubes under a nitrogen atmosphere. Theproducts were purified by flash chromatography on silica gel col-umns (40–63 μm). Mixtures of hexanes and ethyl acetate or dichlo-romethane and methanol were generally used as eluents. 1H and13C NMR spectra were recorded in CDCl3 or D4[methanol] (1H:400 and 500 MHz, 13C: 100 and 125 MHz). Chemical shifts arereported in ppm (δ), and tetramethylsilane or CHCl3 were used asinternal standards. Mass spectra were recorded on a quadrupole


spectrometer using the CI technique. In case of compounds con-taining non-removable impurities, the yield was calculated accord-ing to the 1H NMR spectrum.

General Procedure for the Thiol-Ene Click Reactions (GP): A solu-tion of the ene component (1.0 equiv.) and the thiol (3.0–6.0 equiv.)in a suitable solvent (EtOH, MeOH, or EtOH/THF; 0.17–0.33 m)was irradiated until no further consumption of the starting materialwas observed (TLC). During irradiation, the internal temperaturerose to 70 °C. After cooling to room temperature, the solvent wasevaporated under reduced pressure, and the residue was purified byflash chromatography.

Methyl 2-(tert-Butoxycarbonylamino)-5-(tert-butylthio)pentanoate(2a): According to GP, tert-butylthiol (151 mg, 1.67 mmol) and 1[31]

(128 mg, 556 μmol) were subjected to the thiol-ene click reactionin ethanol. After evaporation of the solvent and purification (silica,hexanes/ethyl acetate, 98:2), compound 2a (130 mg, 407 μmol,73%) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):δ = 1.31 (s, 9 H), 1.44 (s, 9 H), 1.54–1.78 (m, 3 H), 1.92 (m, 1 H),2.54 (m, 2 H), 3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 6.8 Hz, 1H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.7, 27.8, 28.3, 31.0,32.2, 42.0, 52.3, 53.1, 79.9, 155.3, 173.2 ppm. HRMS (CI): calcd.for C15H30NO4S [M + H]+ 320.1890; found 320.1893.

Methyl 2-(tert-Butoxycarbonylamino)-5-(butylthio)pentanoate (2b):Following GP, n-butylthiol (145 mg, 1.61 mmol) and 1 (123 mg,537 μmol) were subjected to the thiol-ene click reaction in ethanol.After evaporation and purification (silica, hexanes/ethyl acetate,85:15), compound 2b (171 mg, 535 μmol, 99%) was isolated as apale yellow oil. 1H NMR (CDCl3, 400 MHz): δ = 0.91 (t, J =7.3 Hz, 3 H), 1.40 (m, 2 H), 1.44 (s, 9 H), 1.55 (m, 2 H), 1.60–1.77(m, 3 H), 1.92 (m, 1 H), 2.49 (t, J = 7.4 Hz, 2 H), 2.52 (m, 2 H),3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 7.1 Hz, 1 H) ppm. 13CNMR (CDCl3, 100 MHz): δ = 13.7, 22.0, 25.4, 28.3, 31.5, 31.7,31.8, 31.9, 52.3, 53.1, 79.9, 155.3, 173.2 ppm. C15H29NO4S(319.46): C 56.40, H 9.15, N 4.38; found C 57.11, H 9.32, N 4.71.HRMS (CI): calcd. for C15H30NO4S [M + H]+ 320.1890; found320.1896.

Methyl 2-(tert-Butoxycarbonylamino)-5-(dodecylthio)pentanoate(2c): According to GP, dodecanthiol (607 mg, 3.00 mmol) and 1(229 mg, 1.00 mmol) were subjected to the thiol-ene click reactionin ethanol. After evaporation of the solvent and purification (silica,hexanes/ethyl acetate, 9:1), compound 2c (406 mg, 0.94 mmol,94%) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.26 (s, 16 H), 1.36 (m, 2 H), 1.44 (s,9 H), 1.52–1.76 (m, 5 H), 1.91 (m, 1 H), 2.48 (m, 2 H), 2.52 (m, 2H), 3.74 (s, 3 H), 4.31 (m, 1 H), 5.02 (d, J = 7.2 Hz, 1 H) ppm. 13CNMR (CDCl3, 100 MHz): δ = 14.1, 22.7, 25.4, 28.3, 28.9, 29.3,29.3, 29.5, 29.6, 29.6, 29.6, 29.6, 31.5, 31.9, 31.9, 32.1, 52.3, 53.1,79.9, 155.3, 173.1 ppm. C23H45NO4S (431.67): calcd. C 63.99, H10.51, N 3.24; found C 63.93, H 10.09, N 2.96. HRMS (CI): calcd.for C23H46NO4S [M + H]+ 432.3142; found 432.3161.

Methyl 2-(tert-Butoxycarbonylamino)-5-(2-hydroxyethylthio)pent-anoate (2d): According to GP, 2-mercaptoethanol (116 mg,1.48 mmol) and 1 (113 mg, 493 μmol) were subjected to the thiol-ene click reaction in ethanol. After evaporation of the solvent andpurification (silica, hexane/ethyl acetate, 1:1), compound 2d(138 mg, 449 μmol, 91%) was isolated as a colourless oil. 1H NMR(CDCl3, 400 MHz): δ = 1.44 (s, 9 H), 1.57–1.77 (m, 3 H), 1.92 (m,1 H), 2.20 (t, J = 5.9 Hz, 1 H), 2.56 (m, 2 H), 2.71 (t, J = 5.9 Hz,2 H), 3.72 (td, J = 5.8 Hz, 2 H), 3.75 (s, 3 H), 4.32 (m, 1 H), 5.04(d, J = 7.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.4,28.3, 30.9, 31.9, 35.2, 52.4, 52.8, 60.3, 80.0, 155.3, 173.1 ppm.


HRMS (CI): calcd. for C13H26NO5S [M + H]+ 308.1526; found308.1540.

Methyl 2-(tert-Butoxycarbonylamino)-5-(2,3-dihydroxypropylthio)-pentanoate (2e): Following GP, thioglycerin (361 mg, 3.00 mmol,90% in water) and 1 (230 mg, 1.00 mmol) were subjected to thethiol-ene click reaction in ethanol. After evaporation and purifica-tion (silica, dichloromethane/methanol, 9:1), compound 2e(328 mg, 972 μmol, 97%) was isolated as a colourless oil. 1H NMR(CDCl3, 400 MHz): δ = 1.44 (s, 9 H), 1.58–1.78 (m, 3 H), 1.91 (m,1 H), 2.22 (br. s, 1 H), 2.51–2.72 (m, 4 H), 2.92 (br. s, 1 H), 3.56(m, 1 H), 3.74 (s, 3 H), 3.79 (m, 2 H), 4.31 (m, 1 H), 5.10 (d, J =7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.3, 28.3,31.6, 31.9, 35.6, 52.4, 52.8, 65.3, 70.0, 80.1, 155.4, 173.0 ppm.C14H27NO6S (337.43): calcd. C 49.83, H 8.07, N 4.15; found C50.07, H 7.84, N 3.94. HRMS (CI): calcd. for C14H28NO6S [M +H]+ 338.1632; found 338.1637.

2-[4-(tert-Butoxycarbonylamino)-5-methoxy-5-oxopentylthio]prop-anoic Acid (2f): According to GP, thiolactic acid (318 mg,3.00 mmol) and 1 (229 mg, 1.00 mmol) were subjected to the thiol-ene click reaction in ethanol. After evaporation of the solvent andpurification (silica, hexanes/ethyl acetate/acetic acid 70:29:1), com-pound 2f (265 mg, 0.79 mmol, 79%) was isolated as a colourlessoil. 1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 9 H), 1.44 (d, J =6.9 Hz, 3 H), 1.56–1.80 (m, 3 H), 1.90 (m, 1 H), 2.68 (m, 2 H), 3.39(q, J = 7.1 Hz, 1 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.12 (d, J =7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 16.9, 25.0,28.3, 30.8, 31.7, 40.8, 52.4, 53.0, 80.2, 155.5, 173.2, 177.6 ppm.C14H25NO6S (335.42): calcd. C 50.13, H 7.51, N 4.18; found C50.17, H 7.08, N 3.67. HRMS (CI): calcd. for C14H26NO6S [M +H]+ 336.1476; found 336.1473.

Methyl 5-(2-Acetamidoethylthio)-2-(tert-butoxycarbonylamino)-pentanoate (2g): Following GP, N-acetylcysteamine (221 mg,1.85 mmol; 98%, contaminated with 2% of the corresponding di-sulfide) and 1 (134 mg, 585 μmol) were subjected to the thiol-eneclick reaction in ethanol. After evaporation of the solvent and puri-fication (silica, ethyl acetate), compound 2g (195 mg, 561 μmol,96 %) was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz):δ = 1.45 (s, 9 H), 1.57–1.77 (m, 3 H), 1.92 (m, 1 H), 2.00 (s, 3 H),2.55 (m, 2 H), 2.65 (t, J = 6.4 Hz, 2 H), 3.43 (td, J = 6.1 Hz, 2 H),3.75 (s, 3 H), 4.32 (m, 1 H), 5.06 (d, J = 6.5 Hz, 1 H), 5.93 (br. s,1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.3, 25.3, 28.3, 31.0,31.8, 31.9, 38.4, 52.4, 64.6, 80.0, 155.2, 167.6, 170.1 ppm. HRMS(CI): calcd. for C15H29N2O5S [M + H]+ 349.1787; found 349.1783.

Methyl 5-(Acetylthio)-2-(tert-butoxycarbonylamino)pentanoate (2h):According to GP, thioacetic acid (228 mg, 3.00 mmol) and 1(229 mg, 1.00 mmol) were subjected to the thiol-ene click reactionin ethanol. After evaporation of the solvent and purification (silica,hexanes/ethyl acetate, 8:2), compound 2h (303 mg, 992 μmol, 99%)was isolated as a colourless oil. 1H NMR (CDCl3, 400 MHz): δ =1.44 (s, 9 H), 1.58–1.72 (m, 3 H), 1.87 (m, 1 H), 2.32 (s, 3 H), 2.88(t, J = 7.0 Hz, 2 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.01 (d, J =7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.5, 28.3,28.5, 30.6, 31.8, 52.3, 53.0, 80.0, 155.3, 173.0, 195.6 ppm.C13H23NO5S (305.39): calcd. C 51.13, H 7.59, N 4.59; found C50.84, H 7.18, N 4.13. HRMS (CI): calcd. for C13H24NO5S [M +H]+ 306.1370; found 306.1393.

(6R)-Dimethyl 2,2,16,16-Tetramethyl-4,14-dioxo-3,15-dioxa-8-thia-5,13-diazaheptadecane-6,12-dicarboxylate (2i): According to GP,starting from (R)-methyl 2-(tert-butoxycarbonylamino)-3-mercap-topropanoate (468 mg, 1.99 mmol) and 1 (140 mg, 611 μmol) inethanol, after evaporation and purification (silica, hexanes/ethylacetate, 8:2), compound 2i (263 mg, 566 μmol, 93%) was obtained,

L. Karmann, U. KazmaierFULL PAPERcontaminated with the corresponding disulfide of the protected cys-teine (7.97 mg, 17.0 μmol), as a colourless oil. 1H NMR (CDCl3,400 MHz): δ = 1.44 (s, 9 H), 1.45 (s, 9 H), 1.59–1.75 (m, 3 H), 1.89(m, 1 H), 2.55 (m, 2 H), 2.94 (m, 2 H), 3.74 (s, 3 H), 3.76 (s, 3 H),4.30 (m, 1 H), 4.52 (m, 1 H), 5.05 (br. s, 1 H), 5.33 (br. s, 1 H)ppm. 13C NMR (CDCl3, 100 MHz): δ = 25.3, 28.3, 28.3, 31.8, 32.2,34.6, 52.3, 52.5, 53.0, 53.3, 80.0, 80.2, 155.1, 155.3, 171.1,171.5 ppm. HRMS (CI): calcd. for C20H37N2O8S [M + H]+

465.2265; found 465.2258.

Methyl 3,3-Dimethoxy-15,15-dimethyl-13-oxo-2,14-dioxa-7-thia-12-aza-3-silahexadecane-11-carboxylate (2k): Following GP, 3-(trime-thoxysilyl)propane-1-thiol (589 mg, 3.00 mmol) and 1 (230 mg,1.00 mmol) were subjected to the thiol-ene click reaction in drymethanol. After evaporation, compound 2k (424 mg, 995 μmol,99%) was isolated, contaminated with the corresponding thiol(53 mg, 270 μmol, 9 %). 1H NMR (CDCl3, 400 MHz): δ = 0.75 (m,2 H), 1.44 (s, 9 H), 1.61–1.97 (m, 6 H), 2.46–2.57 (m, 4 H), 3.57 (s,9 H), 3.74 (s, 3 H), 4.30 (m, 1 H), 5.03 (d, J = 7.7 Hz, 1 H) ppm.13C NMR (CDCl3, 100 MHz): δ = 8.5, 22.9, 25.4, 28.2, 31.3, 31.8,34.9, 50.5, 52.2, 53.0, 79.9, 155.3, 173.1 ppm. HRMS (CI): calcd.for C17H36NO7SSi [M + H]+ 426.1971; found 426.1969.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-ethoxy-3-oxopropyl-thio)pentanoate (2l): According to GP, ethyl-3-thiopropionate(199 mg, 1.48 mmol) and (S)-1 (114 mg, 495 μmol, 86% ee) weresubjected to the thiol-ene click reaction in ethanol. After evapora-tion of the solvent and purification (silica, hexane/ethyl acetate,8:2), compound (S)-2l (160 mg, 440 μmol, 89%) was isolated as apale yellow oil. [α]D20 = –11.2 (c = 1.0, CHCl3; 81% ee). 1H NMR(CDCl3, 400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.44 (s, 9 H),1.56–1.77 (m, 3 H), 1.91 (m, 1 H), 2.56 (m, 2 H), 2.58 (t, J = 7.2 Hz,2 H), 2.77 (t, J = 7.2 Hz, 2 H), 3.74 (s, 3 H), 4.16 (q, J = 7.1 Hz,2 H), 4.31 (m, 1 H), 5.03 (d, J = 7.9 Hz, 1 H) ppm. 13C NMR(CDCl3, 100 MHz): δ = 14.2, 25.3, 26.9, 28.3, 31.6, 31.8, 34.9, 52.3,53.0, 60.7, 80.0, 155.3, 171.9, 173.1 ppm. GC (Chirasil-l-Val): T0

= 80 °C [10 min], 1 °C/min to 180 °C [100 min], (S)-2l: tR =153.93 min, (R)-2l: tR = 154.80 min. C16H29NO6S (363.47): calcd.C 52.87, H 8.04, N 3.85; found C 52.85, H 8.04, N 4.34. HRMS(CI): calcd. for C16H30NO6S [M + H]+ 364.1788; found 364.1772.

(2S,3S)-Methyl 5-(Acetylthio)-2-(tert-butoxycarbonylamino)-3-phenylpentanoate (5): According to GP, thioacetic acid (356 mg,4.68 mmol) and 3[27] (310 mg, 1.02 mmol) were subjected to thethiol-ene click reaction in ethanol. After evaporation of the solventand purification (silica, hexanes/ethyl acetate, 95:5), compound 5(362 mg, 0.95 mmol, 95%) was isolated as a pale yellow solid, m.p.61–65 °C. 1H NMR (CDCl3, 400 MHz): δ = 1.39 (s, 9 H), 2.00 (m,1 H), 2.08 (m, 1 H), 2.28 (s, 3 H), 2.65 (ddd, J = 13.7, 7.9, 7.9 Hz,1 H), 2.83 (ddd, J = 13.9, 8.5, 5.7 Hz, 1 H), 3.29 (dt, J = 9.8,5.2 Hz, 1 H), 3.65 (s, 3 H), 4.60 (dd, J = 9.4, 4.7 Hz, 1 H), 4.82 (d,J = 9.3 Hz, 1 H), 7.10–7.32 (m, 5 H) ppm. 13C NMR (CDCl3,100 MHz): δ = 27.0, 28.2, 30.5, 31.3, 47.0, 52.1, 57.3, 79.9, 127.6,128.2, 128.7, 137.8, 155.5, 171.8, 195.4 ppm. HRMS (CI): calcd.for C19H28NO5S [M + H]+ 382.1677; found 382.1670.

(R)-tert-Butyl 2-[(S)-3-Phenyl-2-(2,2,2-trifluoroacetamido)propan-amido]pent-4-enoate (6): Compound 9 (197 mg, 0.41 mmol) con-taminated with dipeptide TFA-Phe-Gly-OtBu (80 mg, 0.21 mmol)was dissolved in dichloromethane (0.1 m), and Grubbs catalyst I(8.4 mg, 10.3 μmol) was added. The mixture was stirred at roomtemperature overnight. The solvent was evaporated, and the residuewas purified (silica, hexanes/ethyl acetate, 9:1 to 8:2) to give com-pound 6[29] (157 mg, 0.38 mmol, 92%; 91% ds, determined by 1HNMR spectroscopy) as a colourless solid, m.p. 80–83 °C. [α]20 =–7.9 (c = 1.0, CHCl3, 91% ds). Data for the major diastereomer:


1H NMR (CDCl3, 400 MHz): δ = 1.43 (s, 9 H), 2.34 (m, 1 H), 2.40(m, 1 H), 3.03 (dd, J = 13.6, 8.6 Hz, 1 H), 3.17 (dd, J = 13.6,5.5 Hz, 1 H), 4.44 (ddd, J = 7.5, 5.5, 5.5 Hz, 1 H), 4.65 (ddd, J =7.9, 7.9, 5.6 Hz, 1 H), 4.97 (ddt, J = 17.0, 1.5, 1.5 Hz, 1 H), 5.04(dd, J = 10.3, 1.4 Hz, 1 H), 5.41 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.96 (br. s, 1 H), 7.20–7.35 (m, 6 H) ppm. 13C NMR (CDCl3,100 MHz): δ = 27.9, 36.4, 38.7, 52.2, 54.8, 82.7, 115.6 (J = 288 Hz),119.2, 127.4, 128.8, 129.3, 131.7, 135.3, 156.6 (J = 38.0 Hz), 168.7,169.9 ppm. Selected data for the minor diastereomer: 1H NMR(CDCl3, 400 MHz): δ = 1.46 (s, 9 H), 2.50 (m, 2 H), 3.08 (dd, J =13.8, 7.8 Hz, 1 H), 4.41 (ddd, J = 7.2, 5.6, 5.6 Hz, 1 H), 5.56 (ddt,J = 17.3, 10.2, 7.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ= 36.4, 52.3, 119.5, 128.8, 129.3 ppm.

1-(Allyloxy)but-3-en-2-yl Acetate (8): 1-(Allyloxy)but-3-en-2-ol(990 mg, 7.72 mmol) was dissolved in dichloromethane (0.5 m), anddry pyridine (918 mg, 11.6 mmol, 0.93 mL) was added. The mix-ture was cooled to 0 °C, and then ethyl chloroformate (1.00 g,9.26 mmol, 0.88 mL) was slowly added dropwise. The ice-bath wasremoved, and the mixture was stirred overnight at room tempera-ture. The resulting solution was diluted with dichloromethane andthen washed with CuSO4 (1 m aq.) until the excess pyridine wasremoved. The organic phase was dried with Na2SO4, and the sol-vent was evaporated under reduced pressure. The crude productwas purified by flash chromatography (silica, hexanes/ethyl acetate,9:1) to give 8 (1.39 g, 6.94 mmol, 90 %) as a colourless liquid. 1HNMR (CDCl3, 400 MHz): δ = 1.31 (t, J = 7.1 Hz, 3 H), 3.54 (dd,J = 9.8, 3.5 Hz, 1 H), 3.58 (dd, J = 9.7, 5.7 Hz, 1 H), 4.00 (ddt, J

= 13.0, 5.6, 1.5 Hz, 1 H), 4.05 (ddt, J = 12.9, 5.6, 1.5 Hz, 1 H),4.20 (q, J = 7.1 Hz, 2 H), 5.18 (ddt, J = 10.4, 1.3, 1.3 Hz, 1 H),5.24–5.30 (m, 3 H), 5.39 (ddd, J = 17.2, 1.2, 1.2 Hz, 1 H), 5.84(ddd, J = 17.4, 10.4, 6.4 Hz, 1 H), 5.88 (ddt, J = 17.3, 10.5, 5.6 Hz,1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.2, 64.0, 71.2, 72.2,77.1, 117.3, 118.6, 132.9, 134.4, 154.5 ppm. C10H16O4 (200.23):calcd. C 59.98, H 8.05; found C 59.96, H 7.55. HRMS (CI): calcd.for C10H17O4 [M + H]+ 201.1122; found 201.1116.

(R,E)-tert-Butyl 6-(Allyloxy)-2-[(S)-3-phenyl-2-(2,2,2-trifluoroacet-amido)propanamido]hex-4-enoate (9): n-Butyllithium (1.6 m

1.64 mL, 2.63 mmol) was added dropwise to a solution of HMDS(460 mg, 2.85 mmol, 4.22 mL) in THF (0.6 m) at –78 °C. The mix-ture was stirred for 5 min, then it was allowed to warm up to roomtemperature. A solution of dipeptide TFA-(S)-Phe-Gly-OtBu(281 mg, 0.75 mmol) and dried zinc chloride (113 mg, 0.83 mmol)in THF (0.15 m) was prepared and then cooled to –78 °C. Thefreshly prepared LHMDS solution was also cooled to –78 °C, andthen the dipeptide/ZnCl2 solution was slowly added. A solution ofallylpalladium chloride dimer (3.7 mg, 10.1 μmol), PPh3 (10.5 mg,40.0 μmol), and ethyl carbonate 8 (105 mg, 0.52 mmol) was pre-pared in THF (1.5 mL). The catalyst/substrate solution was stirredfor 5 min, and then it was added slowly to the chelated enolate at–78 °C. The dry ice was removed from the cooling bath, and themixture was allowed to warm to room temperature overnight. Thesolution was diluted with diethyl ether, and then HCl (1 m aq.)was added. After separation of the phases, the aqueous phase wasextracted three times with diethyl ether, and the combined organicextracts were dried with Na2SO4. The solvent was removed invacuo, and the residue was purified by flash chromatography (silicagel, hexanes/ethyl acetate, 8:2) to give a mixture of 9 (210 mg,0.43 mmol, 83%; 91% ds, determined by 1H NMR spectroscopy)and the original dipeptide (87 mg, 0.23 mmol). Data for the majordiastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.42 (s, 9 H), 2.33(m, 1 H), 2.41 (m, 1 H), 3.03 (dd, J = 13.6, 8.6 Hz, 1 H), 3.16 (dd,J = 13.6, 5.6 Hz, 1 H), 3.86 (d, J = 5.8 Hz, 2 H), 3.94 (dt, J = 5.6,1.4 Hz, 2 H), 4.44 (ddd, J = 7.5, 5.5, 5.5 Hz, 1 H), 4.65 (ddd, J =


8.0, 8.0, 5.8 Hz, 1 H), 5.18 (ddt, J = 10.4, 1.4, 1.4 Hz, 1 H), 5.23–5.33 (m, 2 H), 5.52 (dtt, J = 15.4, 5.9, 1.2 Hz, 1 H), 5.89 (ddt, J =17.2, 10.5, 5.6 Hz, 1 H), 5.99 (br. s, 1 H), 7.19–7.36 (m, 6 H) ppm.13C NMR (CDCl3, 100 MHz): δ = 28.0, 35.0, 38.8, 52.3, 54.8, 70.0,71.2, 82.8, 115.6 (J = 288 Hz), 117.0, 126.5, 127.5, 128.9, 129.3,131.2, 134.6, 135.3, 156.7 (J = 37.8 Hz), 168.4, 169.8 ppm. Selecteddata for the minor diastereomer: 1H NMR (CDCl3, 400 MHz): δ= 1.43 (s, 9 H), 2.53 (m, 2 H), 4.41 (m, 1 H), 5.76 (m, 1 H) ppm.13C NMR (CDCl3, 100 MHz): δ = 27.9, 117.0, 126.4, 128.8, 129.3,131.2, 134.4 ppm. HRMS (CI): calcd. for C24H31N2O5F3 [M]+

484.2180; found 484.2139.

(R)-tert-Butyl 5-(2-Hydroxyethylthio)-2-[(S)-3-phenyl-2-(2,2,2-tri-fluoroacetamido)propanamido]pentanoate (10a): According to GP,2-mercaptoethanol (48.8 mg, 624 μmol) and 6 (85.7 mg, 208 μmol)were subjected to the thiol-ene click reaction in ethanol (1.5 mL).After evaporation of the solvent and purification (silica, hexanes/ethyl acetate, 6:4), compound 10a (70.4 mg, 143 μmol, 69%; 91%ds, determined by 1H NMR spectroscopy) was isolated as a colour-less solid, m.p. 74–79 °C. [α]20 = +2.1 (c = 1.0, CHCl3, 91% ds).Data for the major diastereomer: 1H NMR (CDCl3, 400 MHz): δ= 1.36 (m, 2 H), 1.43 (s, 9 H), 1.66 (m, 2 H), 2.26 (br. s, 1 H, OH),2.44 (dt, J = 12.8, 6.1 Hz, 1 H), 2.50 (dt, J = 10.4, 5.9 Hz, 1 H),2.70 (t, J = 5.9 Hz, 2 H), 3.03 (dd, J = 13.6, 8.9 Hz, 1 H), 3.19 (dd,J = 13.5, 5.4 Hz, 1 H), 3.73 (m, 2 H), 4.37 (m, 1 H), 4.67 (ddd, J

= 8.5, 5.8, 5.8 Hz, 1 H), 6.08 (br. s, 1 H), 7.19–7.36 (m, 6 H) ppm.13C NMR (CDCl3, 100 MHz): δ = 24.9, 27.9, 31.1, 31.3, 35.2, 38.6,52.4, 54.8, 60.5, 82.8, 115.6 (J = 288 Hz), 127.5, 128.9, 129.2, 135.3,156.7 (J = 37.9 Hz), 168.7, 170.5 ppm. Selected data for the minordiastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 9 H), 2.67(t, J = 5.9 Hz, 2 H), 3.11 (dd, J = 14.6, 6.2 Hz, 1 H), 6.21 (br. s, 1H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 27.9, 60.4 ppm.C22H31F3N2O5S (492.55): calcd. C 53.65, H 6.34, N 5.69; found C54.10, H 6.43, N 5.19. HRMS (CI): calcd. for C22H32F3N2O5S [M+ H]+ 493.1979; found 493.1995.

(R)-tert-Butyl 5-(3-Ethoxy-3-oxopropylthio)-2-[(S)-3-phenyl-2-(2,2,2-trifluoroacetamido)propanamido]pentanoate (10b): Accordingto GP, ethyl-3-thiopropionate (201 mg, 1.50 mmol) and 6 (207 mg,0.50 mmol) were subjected to the thiol-ene click reaction in ethanol(1.5 mL). After evaporation of the solvent and purification (silica,hexanes/ethyl acetate, 7:3), compound 10b (244 mg, 0.44 mmol,88%; 91% ds, determined by 1H NMR spectroscopy) was isolatedas a colourless solid, m.p. 61–65 °C. [α]20 = +3.7 (c = 1.0, CHCl3,91% ds). Data for the major diastereomer: 1H NMR (CDCl3,400 MHz): δ = 1.27 (t, J = 7.2 Hz, 3 H), 1.35 (m, 2 H), 1.43 (s, 9H), 1.65 (m, 2 H), 2.42 (dt, J = 12.9, 7.3 Hz, 1 H), 2.51 (dt, J =12.5, 6.8 Hz, 1 H), 2. 58 (m, 2 H), 2.75 (m, 2 H), 3.02 (dd, J =13.6, 8.9 Hz, 1 H), 3.20 (dd, J = 13.6, 5.4 Hz, 1 H), 4.17 (q, J =7.2 Hz, 2 H), 4.35 (ddd, J = 7.2, 7.2, 5.4 Hz, 1 H), 4.67 (ddd, J =8.2, 8.2, 5.5 Hz, 1 H), 6.01 (d, J = 7.1 Hz, 1 H), 7.19–7.36 (m, 6H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1, 24.7, 26.9, 27.9,31.2, 31.5, 34.8, 38.7, 52.5, 54.8, 60.7, 82.6, 115.6 (J = 288 Hz),127.4, 128.8, 129.2, 135.5, 156.6 (J = 37.7 Hz), 168.7, 170.5,172.0 ppm. Selected data for the minor diastereomer: 1H NMR(CDCl3, 400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H), 1.47 (s, 9 H),4.16 (q, J = 7.2 Hz, 2 H), 6.22 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR(CDCl3, 100 MHz): δ = 14.2, 27.9, 34.5, 60.8, 82.8, 135.4 ppm.C25H35F3N2O6S (548.62): calcd. C 54.73, H 6.43, N 5.11; found C54.97, H 6.32, N 4.76. HRMS (CI): calcd. for C25H36F3N2O6S [M+ H]+ 549.2241; found 549.2239.

(2R)-tert-Butyl 5-(2-Hydroxyethylthio)-4-methyl-2-[(S)-3-phenyl-2-(2,2,2-trifluoroacetamido)propanamido]pentanoate (11a): Accordingto GP, 2-mercaptoethanol (59.0 mg, 756 μmol) and 7[29] (108 mg,


252 μmol) were subjected to the thiol-ene click reaction in ethanol(0.75 mL). After evaporation of the solvent and purification (silica,hexanes/ethyl acetate, 1:1), compound 11a (89.3 mg, 176 μmol,70%) was isolated as a colourless oil. [α]20 = +8.7 (c = 1.0, CHCl3;90% ds, determined by 1H NMR spectroscopy, 1:1 mixture in theside-chain). Data for the major diastereomers: 1H NMR (CDCl3,400 MHz): δ = 0.97 (d, J = 6.3 Hz, 1.5 H), 0.99 (d, J = 6.7 Hz, 1.5H), 1.43 (s, 4.5 H), 1.43 (s, 4.5 H), 1.55–1.73 (m, 2 H), 2.34–2.51(m, 2 H), 2.59 (m, 1 H), 2.68 (t, J = 5.9 Hz, 2 H), 2.89 (br. s, 0.5H), 2.99 (m, 1 H), 3.16 (dd, J = 13.2, 5.7 Hz, 0.5 H), 3.19 (dd, J =13.4, 5.7 Hz, 0.5 H), 3.73 (m, 2 H), 3.92 (br. s, 0.5 H), 4.37 (ddd,J = 8.2, 8.2, 4.9 Hz, 0.5 H), 4.39 (ddd, J = 8.0, 8.0, 5.8 Hz, 0.5 H),4.68 (ddd, J = 8.2, 8.2, 5.7 Hz, 1 H), 6.12 (d, J = 8.0 Hz, 0.5 H),6.17 (d, J = 8.0 Hz, 0.5 H), 7.15–7.35 (m, 6 H) ppm. 13C NMR(CDCl3, 100 MHz): δ = 19.2, 19.7, 27.9, 27.9, 30.0, 30.1, 35.5, 35.6,38.1, 38.3, 38.5, 38.5, 38.9, 39.1, 51.2, 51.3, 54.8, 54.8, 60.7, 60.8,82.5, 82.8, 115.6 (J = 288 Hz), 115.6 (J = 288 Hz), 127.4, 127.4,128.8, 128.8, 129.2, 129.3, 135.3, 135.4, 156.8 (J = 37.8 Hz), 156.8(J = 37.8 Hz), 168.9, 169.1, 170.8, 171.1 ppm. Selected data for theminor diastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 4.5H), 1.47 (s, 4.5 H), 1.01 (d, J = 6.4 Hz, 1.5 H), 1.03 (d, J = 6.5 Hz,1.5 H) ppm. HRMS (CI): calcd. for C23H34F3N2O5S [M + H]+

507.2130; found 507.2156.

(2R)-tert-Butyl 5-(3-Ethoxy-3-oxopropylthio)-4-methyl-2-[(S)-3-phenyl-2-(2,2,2-trifluoroacetamido)propanamido]pentanoate (11b):According to GP, ethyl-3-thiopropionate (201 mg, 1.50 mmol) and7[29] (214 mg, 0.50 mmol) were subjected to the thiol-ene click reac-tion in ethanol (1.5 mL). After evaporation of the solvent and puri-fication (silica, hexanes/ethyl acetate, 8:2), compound 11b (229 mg,0.41 mmol, 82%) was isolated as a pale yellow oil. [α]20 = +11.8 (c= 1.0, CHCl3; 90% ds, determined by 1H NMR spectroscopy, 1:1mixture in the side-chain). Data for the major diastereomers: 1HNMR (CDCl3, 400 MHz): δ = 0.95 (d, J = 6.4 Hz, 1.5 H), 0.99 (d,J = 6.6 Hz, 1.5 H), 1.27 (t, J = 7.1 Hz, 1.5 H), 1.29 (t, J = 7.2 Hz,1.5 H), 1.35 (m, 0.5 H), 1.42 (s, 4.5 H), 1.43 (s, 4.5 H), 1.55–1.72(m, 2 H), 1.81 (ddd, J = 13.7, 10.9, 3.4 Hz, 0.5 H), 2.27 (dd, J =13.3, 8.2 Hz, 0.5 H), 2.36 (dd, J = 12.8, 7.2 Hz, 0.5 H), 2.46 (dd, J

= 13.3, 5.5 Hz, 0.5 H), 2.52–2.80 (m, 4.5 H), 3.02 (dd, J = 13.6,8.7 Hz, 0.5 H), 3.07 (dd, J = 13.6, 8.7 Hz, 0.5 H), 3.16 (dd, J =13.6, 5.7 Hz, 0.5 H), 3.21 (dd, J = 13.7, 5.7 Hz, 0.5 H), 4.16 (q, J

= 7.1 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 1 H), 4.31 (ddd, J = 10.8, 7.8,4.0 Hz, 0.5 H), 4.39 (ddd, J = 7.8, 7.8, 6.5 Hz, 0.5 H), 4.67 (ddd, J

= 8.0, 8.0, 5.9 Hz, 0.5 H), 4.75 (ddd, J = 8.0, 8.0, 5.7 Hz, 0.5 H),5.92 (d, J = 7.9 Hz, 0.5 H), 6.46 (d, J = 7.6 Hz, 0.5 H), 7.19–7.36(m, 6 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.1, 14.1, 19.0,19.3, 27.1, 27.5, 27.8, 27.8, 29.3, 29.9, 34.5, 34.9, 37.6, 38.4, 38.5,38.8, 38.9, 39.5, 51.0, 51.2, 54.6, 54.7, 60.6, 60.9, 82.1, 82.5, 115.6(J = 287 Hz), 115.6 (J = 287 Hz) 127.2, 127.3, 128.6, 128.7, 129.2,129.2, 135.4, 135.5, 156.6 (J = 37.7 Hz), 156.7 (J = 37.8 Hz), 168.8,169.4, 170.8, 171.0, 171.9, 172.3 ppm. Selected data for the minordiastereomer: 1H NMR (CDCl3, 400 MHz): δ = 1.46 (s, 4.5 H),1.48 (s, 4.5 H), 4.47 (m, 0.5 H), 6.21 (d, J = 8.2 Hz, 0.5 H, NH),6.61 (d, J = 8.3 Hz, 0.5 H) ppm. C26H37F3N2O6S (562.64): calcd.C 55.60, H 6.46, N 4.99; found C 55.10, H 6.38, N 4.60. HRMS(CI): calcd. for C22H30N2O6F3S [M – tBu + 2H]+ 507.1771; found507.1789.

Boc-L-Ala-(rac)-2-amino-5-(2-hydroxyethylthio)pentanoic-acid-L-Phe-GlyOMe (13a): According to GP, 2-mercaptoethanol (234 mg,3.00 mmol) and 12 (252 mg, 0.50 mmol) were subjected to thethiol-ene click reaction in a mixture of ethanol (2 mL) and THF(1 mL). After evaporation of the solvent, purification (silica,CH2Cl2/MeOH, 98:2, 95:5), and lyophilization (acetonitrile/water),13a (277 mg, 475 μmol, 95 %; 1:1 mixture of diastereomers) was

L. Karmann, U. KazmaierFULL PAPERisolated as a colourless solid, contaminated with the correspondingthiol (11 mg, 0.14 mmol), m.p. 136–139 °C. 1H NMR (CDCl3,500 MHz): δ = 1.25 (d, J = 6.9 Hz, 1.5 H), 1.32 (d, J = 7.1 Hz, 1.5H), 1.37–1.55 (m, 2 H), 1.42 (s, 4.5 H), 1.42 (s, 4.5 H), 1.56–1.86(m, 2 H), 2.40–2.55 (m, 3 H), 2.63 (t, J = 6.1 Hz, 1 H), 2.65 (t, J

= 6.0 Hz, 1 H), 2.97 (dd, J = 14.3, 8.9 Hz, 0.5 H), 3.00 (dd, J =14.6, 7.6 Hz, 0.5 H), 3.17 (dd, J = 14.0, 6.2 Hz, 0.5 H), 3.23 (dd, J

= 14.1, 5.6 Hz, 0.5 H), 3.69 (m, 2 H), 3.70 (s, 1.5 H), 3.71 (s, 1.5H), 3.89–4.06 (m, 2 H), 4.23 (m, 0.5 H), 4.30 (m, 0.5 H), 4.41 (m,0.5 H), 4.50 (m, 0.5 H), 4.84 (m, 1 H), 5.43 (m, 0.5 H) 5.48 (m, 0.5H), 7.17–7.48 (m, 8 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =18.6, 18.7, 24.8, 25.1, 28.3, 28.3, 30.8, 31.1, 31.2, 31.4, 34.7, 34.9,37.8, 38.1, 41.1, 41.3, 50.0, 50.1, 52.2, 52.3, 52.5, 52.9, 54.1, 54.3,60.8, 61.0, 80.2, 80.2, 126.8, 126.8, 128.5, 128.6, 129.2, 129.3, 136.5,136.7, 155.6, 155.8, 169.9, 170.3, 171.4, 171.4, 171.5, 171.7, 173.3,173.3 ppm. HRMS (CI): calcd. for C27H42N4O8S [M]+ 582.2717;found 582.2718.

Boc-L-Ala-(rac)-2-amino-5-(3-ethoxy-3-oxopropylthio)pentanoic-acid-L-Phe-GlyOMe (13b): According to GP, ethyl-3-thiopropion-ate (402 mg, 3.00 mmol) and 12 (252 mg, 0.50 mmol) were sub-jected to the thiol-ene click reaction in a mixture of ethanol (2 mL)and THF (1 mL). After evaporation of the solvent, purification(silica, CH2Cl2/MeOH, 98:2, 95:5), and lyophilization (acetonitrile/water), 13b (298 mg, 0.47 mmol, 94 %; 1:1 mixture of dia-stereomers) was isolated as a colourless solid, m.p. 123–127 °C.[α]20 = –27.7 (c = 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ =1.25 (t, J = 7.1 Hz, 3 H), 1.27 (d, J = 7.1 Hz, 1.5 H), 1.31 (d, J =7.1 Hz, 1.5 H), 1.41 (s, 4.5 H), 1.42 (s, 4.5 H), 1.35–1.51 (m, 2 H),1.52–1.83 (m, 2 H), 2.37 (m, 2 H), 2.55 (t, J = 7.3 Hz, 1 H), 2.56(t, J = 7.3 Hz, 1 H), 2.71 (t, J = 7.2 Hz, 1 H), 2.71 (t, J = 7.5 Hz,1 H), 2.98 (dd, J = 13.9, 8.7 Hz, 0.5 H), 3.01 (dd, J = 13.7, 8.4 Hz,0.5 H), 3.23 (dd, J = 14.1, 5.6 Hz, 1 H), 3.10 (s, 1.5 H), 3.71 (s, 1.5H), 3.89–4.08 (m, 2 H), 4.14 (q, J = 7.2 Hz, 1 H), 4.14 (q, J =7.1 Hz, 1 H), 4.22 (m, 1 H), 4.35 (m, 1 H), 4.82 (m, 1 H), 5.31 (d,J = 6.7 Hz, 0.5 H), 5.44 (d, J = 7.4 Hz, 0.5 H), 7.11–7.32 (m, 8 H)ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.2, 14.2, 18.1, 18.6, 24.8,24.9, 26.8, 26.8, 28.3, 28.3, 30.8, 30.8, 31.5, 31.5, 34.7, 34.8, 37.7,37.7, 41.1, 41.1, 50.0, 50.3, 52.2, 52.3, 52.7, 53.3, 53.8, 54.2, 60.7,60.7, 80.0, 80.3, 126.7, 126.9, 128.4, 128.5, 129.1, 129.2, 136.6,136.7, 155.6, 155.8, 169.9, 170.2, 171.2, 171.2, 171.3, 171.5, 172.0,172.1, 173.3, 173.5 ppm. C30H46N4O9S (638.77): calcd. C 56.41, H7.26, N 8.77; found C 56.09, H 7.18, N 8.60. HRMS (CI): calcd.for C30H46N4O9S [M]+ 638.2980; found 638.2997.

Boc-L-Ala-(rac)-5-(acetylthio)-2-aminopentanoic-acid-L-Phe-Gly-OMe (13c): According to GP, thioacetic acid (228 mg, 3.00 mmol)and 12 (252 mg, 0.50 mmol) were subjected to the thiol-ene clickreaction in a mixture of ethanol (2 mL) and THF (1 mL). Afterevaporation of the solvent, purification (silica, CH2Cl2/MeOH,98:2, 95:5), and lyophilisation (acetonitrile/water), 13c (287 mg,0.49 mmol, 98%; 1:1 mixture of diastereomers) was isolated as acolourless solid, m.p. 151–159 °C. [α]20 = –30.5 (c = 1.0, CHCl3).1H NMR (CDCl3, 500 MHz): δ = 1.25 (d, J = 7.1 Hz, 1.5 H), 1.29(d, J = 7.1 Hz, 1.5 H), 1.32–1.53 (m, 2 H), 1.39 (s, 4.5 H), 1.40 (s,4.5 H), 1.55–1.76 (m, 2 H), 2.27 (s, 3 H), 2.68–2.88 (m, 2 H), 2.95(dd, J = 14.3, 8.9 Hz, 0.5 H), 2.98 (dd, J = 14.3, 8.4 Hz, 0.5 H),3.17 (m, 0.5 H), 3.22 (dd, J = 14.2, 5.6 Hz, 0.5 H), 3.68 (s, 3 H),3.96 (m, 2 H), 4.23 (m, 1 H), 4.37 (m, 0.5 H), 4.45 (m, 0.5 H), 4.81(m, 1 H), 5.26 (d, J = 7.0 Hz, 0.5 H), 5.43 (d, J = 7.5 Hz, 0.5 H),7.13–7.30 (m, 8 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 18.4,18.7, 25.2, 25.5, 28.2, 28.3, 28.3, 28.4, 30.6, 30.6, 30.9, 31.0, 37.8,37.9, 41.1, 41.1, 50.0, 50.2, 52.2, 52.3, 52.5, 52.8, 54.0, 54.1, 80.0,80.2, 126.8, 126.9, 128.4, 128.5, 129.2, 129.2, 136.7, 136.7, 155.6,155.6, 169.9, 170.2, 171.2, 171.2, 171.3, 171.4, 173.0, 173.3, 195.9,


196.4 ppm. C27H40N4O8S (580.69): calcd. C 55.85, H 6.94, N 9.65;foun d C 55 .21 , H 6 .82 , N 9 .37 . HRMS (CI) : c a l cd . forC27H41N4O8S [M + H]+ 581.2640; found 581.2670.

Boc-L-2-Amino-3-{4-[3-(2-hydroxyethylthio)propoxy]phenyl}-propanoic-acid-Gly-L-Phe-Gly (15a): According to GP, 2-mercapto-ethanol (234 mg, 3.00 mmol) and 14 (298 mg, 0.50 mmol) were sub-jected to the thiol-ene click reaction in a mixture of ethanol (2 mL)and THF (1 mL). After evaporation of the solvent, purification(silica, CH2Cl2/MeOH, 98:2, 95:5), and lyophilisation (acetonitrile/water), compound 15a (325 mg, 0.48 mmol, 96%) was isolated as acolourless solid, contaminated with the corresponding thiol (14 mg,0.18 mmol), m.p. 109–112 °C. 1H NMR ([D4]methanol, 500 MHz):δ = 1.37 (s, 9 H), 2.01 (tt, J = 6.9, 6.1 Hz, 2 H), 2.66 (t, J = 6.8 Hz,2 H), 2.71 (t, J = 7.2 Hz, 2 H), 2.77 (dd, J = 13.9, 9.1 Hz, 1 H),2.93 (dd, J = 13.8, 9.5 Hz, 1 H), 3.03 (dd, J = 13.9, 5.6 Hz, 1 H),3.22 (dd, J = 14.0, 5.2 Hz, 1 H), 3.63 (m, 1 H), 3.68 (t, J = 6.8 Hz,2 H), 3.71 (s, 3 H), 3.90 (m, 3 H), 4.04 (t, J = 6.1 Hz, 2 H), 4.21(dd, J = 9.1, 5.6 Hz, 1 H), 4.66 (dd, J = 9.1, 5.2 Hz, 1 H), 6.83 (d,J = 8.6 Hz, 2 H), 7.12 (d, J = 8.6 Hz, 2 H), 7.17–7.21 (m, 1 H),7.22–7.28 (m, 4 H) ppm. 13C NMR ([D4]methanol, 125 MHz): δ =28.8, 29.5, 30.7, 35.3, 38.2, 38.7, 42.0, 42.2, 52.7, 56.0, 57.9, 62.5,67.4, 80.8, 115.6, 127.8, 129.5, 130.4, 130.6, 131.4, 138.5, 157.8,159.3, 171.4, 171.5, 173.9, 175.1 ppm. HRMS (CI): calcd. forC28H39N4O7S [M + H]+ 575.2534; found 575.2547.

Boc-L-2-Amino-3-{4-[3-(3-ethoxy-3-oxopropylthio)propoxy]phenyl}-propanoic-acid-Gly-L-Phe-Gly (15b): According to GP, ethyl-3-thio-propionate (403 mg, 3.00 mmol) and 14 (298 mg, 0.50 mmol) weresubjected to the thiol-ene click reaction in a mixture of ethanol(2 mL) and THF (1 mL). After evaporation of the solvent, purifica-tion (silica, CH2Cl2/MeOH, 98:2, 95:5) and lyophilisation (acetoni-trile/water), compound 15b (355 mg, 0.49 mmol, 98%) was isolatedas a colourless solid, m.p. 96–102 °C. [α]20 = +0.9 (c = 1.0, CHCl3).1H NMR (CDCl3, 500 MHz): δ = 1.26 (t, J = 7.1 Hz, 3 H), 1.37(s, 9 H), 2.02 (m, 2 H), 2.59 (t, J = 7.4 Hz, 2 H) 2.69 (t, J = 7.2 Hz,2 H), 2.78 (t, J = 7.4 Hz, 2 H), 2.90 (m, 1 H), 2.98–3.04 (m, 2 H),3.17 (dd, J = 5.6, 13.7 Hz, 1 H), 3.69 (s, 3 H), 3.74 (m, 1 H), 3.87–4.03 (m, 5 H), 4.14 (q, J = 7.1 Hz, 2 H), 4.36 (m, 1 H), 4.77 (m, 1H), 5.26 (m, 1 H), 6.79 (d, J = 8.5 Hz, 2 H), 7.01–7.27 (m, 10 H)ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.2, 27.0, 28.2, 28.6, 29.2,34.8, 37.3, 37.8, 41.4, 43.2, 52.3, 54.3, 55.9, 60.7, 66.1, 80.3, 114.6,126.9, 128.5, 128.5, 129.2, 130.3, 136.5, 155.7, 157.8, 168.9, 170.1,171.1, 171.9, 172.5 ppm. C36H50N4O10S (730.87): calcd. C 59.16, H6.90, N 7.67; found C 59.10, H 6.87, N 7.66. HRMS (CI): calcd.for C36H51N4O10S [M + H]+ 731.3320; found 731.3338.

Boc-L-3-{4-[3-(Acetylthio)propoxy]phenyl}-2-aminopropanoic-acid-Gly-L-Phe-Gly (15c): According to GP, thioacetic acid (228 mg,3.00 mmol) and 14 (298 mg, 0.50 mmol) were subjected to thethiol-ene click reaction in a mixture of ethanol (2 mL) and THF(1 mL). After evaporation of the solvent, purification (silica,CH2Cl2/MeOH, 98:2, 95:5) and lyophilisation (acetonitrile/water),compound 15c (318 mg, 0.47 mmol, 94%) was isolated as a colour-less solid, contaminated with 14 (18 mg, 0.03 mmol), m.p. 88–92 °C. 1H NMR (CDCl3, 500 MHz): δ = 1.35 (s, 9 H), 2.00 (m, 2H), 2.30 (s, 3 H), 2.87 (m, 1 H), 2.96–3.01 (m, 4 H), 3.15 (dd, J =13.8, 6.1 Hz, 1 H), 3.67 (s, 3 H), 3.73 (m, 1 H), 3.85–4.00 (m, 5 H),4.35 (m, 1 H), 4.76 (ddd, J = 9.4, 6.1, 6.1 Hz, 1 H), 5.26 (d, J =8.8 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 2 H), 7.03–7.08 (m, 4 H), 7.15–7.25 (m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 25.8, 28.3,29.2, 30.6, 37.4, 37.9, 41.1, 43.2, 52.3, 54.3 55.9, 66.1, 80.3, 114.6,126.9, 128.5, 128.5, 129.2, 130.3, 136.5, 155.7, 157.8, 168.9, 170.1,171.2, 172.5, 195.8 ppm. HRMS (CI): calcd. for C33H45N4O9S [M+ H]+ 673.2902; found 673.2908.


Supporting Information (see footnote on the first page of this arti-cle): Copies of the NMR spectra of all new compounds.

Acknowledgments

Financial support from the Deutsche Forschungsgemeinschaft(DFG) (DFG) is gratefully acknowledged. The authors also wishto thank Ms. Nadja Klippel for her valuable contributions.

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Received: May 7, 2013Published Online: September 13, 2013

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