A post-modification strategy for the synthesis of uniform, hydrophilic/hydrophobic patterned a-hydroxy acid oligomers

FULL PAPER

DOI: 10.1002/ejoc.200900663

A Post-Modification Strategy for the Synthesis of Uniform, Hydrophilic/

Hydrophobic Patterned α-Hydroxy Acid Oligomers

Nadja Franz,^[a]Laure Menin,^[b]and Harm-Anton Klok*^[a]

Keywords: Oligomerization / Protecting groups / Hydroxy acids / Post-modification / Mass spectrometry

Hydrophilic/hydrophobic patterning is a well-established de-

sign strategy to guide secondary structure formation of both

natural as well as non-natural oligomers and polymers. This

contribution explores the feasibility of a new approach for

the synthesis of uniform, sequence-defined, hydrophilic/

hydrophobic patterned oligo(α-hydroxy acid)s. The proposed

strategy is based on post-modification of a reactive oligoester

scaffold composed of an alternating sequence of hydrophobic

ates the need for additional protective group chemistry dur-

ing chain extension. In a subsequent post-modification step,

the allyl side chains can be quantitatively modified via free-

radical addition of different ω-functional thiols to afford hy-

drophilic/hydrophobic patterned oligoesters. The proposed

synthetic strategy provides an interesting alternative to

rapidly generate libraries of foldamers with identical chain

length and monomer sequence but different side-chain func-

[(2S)-2-hydroxy-4-methylpentanoic acid] and masked hydro- tionalities.

philic [(2S)-2-hydroxypent-4-enoic acid] α-hydroxy acids.

The use of (2S)-2-hydroxypent-4-enoic acid instead of a com- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

plex side-chain-protected hydrophilic building block obvi- Germany, 2009)

are α-hydroxy acids. Oligo(α-hydroxy acid) foldamers, how-

ever, are of potential interest for a number of reasons. First

Introduction

Foldamers are synthetic oligomers that can fold into con-

formationally ordered states akin to those of peptides, nu-

cleic acids or polysaccharides.^[1–3]Foldamers represent an

attractive tool to probe and understand the basic sequence-

structure-function relationships that govern protein folding.

In addition, many foldamers have been reported with inter-

esting properties that could be useful for a variety of appli-

cations. Amongst others, foldamers have been prepared that

possess host-guest properties,^[4–6]display antimicrobial^[7–10]

or enzymatic activities,^[11]act as antagonists to inhibit the

anticoagulant function of heparin^[12]or as HIV fusion in-

hibitor,^[13]modify the growth of calcite crystals^[14]or can

be used as thermal sensors.^[15]

of all, oligo(α-hydroxy acid)s are structurally related to pep-

tides, but lack amide bonds in their main chain. As a result,

a comparison of the folding properties of oligo(α-hydroxy

acid)s to those of the corresponding peptide analogues

could provide insight into the role of hydrogen bonding in

the formation of peptide/protein secondary structures.

Furthermore, in contrast to many of the other foldamers

reported so far, oligo(α-hydroxy acid)s are potentially hy-

drolytically degradable, which could be advantageous for

future medical or biological applications.

In the literature, two strategies for the synthesis of uni-

form, sequence-defined oligo(α-hydroxy acid)s have been

reported.^[16]Huang and Hermes described a convergent/di-

vergent solution approach for the preparation of perfectly

alternating -lactic acid-co-glycolic acid oligomers contain-

ing up to 16 structural units.^[17]These oligomers were pre-

pared from an orthogonally protected -lactic acid-co-gly-

colic acid dimer containing a methoxyethoxymethyl ether

(MEM) and a benzyl ester group to selectively block the

The foldamers that have been reported so far are ex-

tremely diverse with regards to the nature of the building

blocks from which they have been constructed.^[1–3]A class

of building blocks that has received only limited attention

[a] École Polytechnique Fédérale de Lausanne (EPFL), Institut des hydroxy and the carboxylic acid functional groups, respec-

Matériaux, Laboratoire des Polymères, Bâtiment MXD, Station

tively, and were generated using 1,3-dicyclohexylcarbodiim-

12,

ide (DCC)/4-(dimethylamino)pyridine (DMAP) coupling

chemistry for chain extension. Kuisle et al. have developed

a solid phase strategy for the preparation of uniform, se-

quence-specific oligo(α-hydroxy acid)s based on tetra-

hydropyranyl (THP) ether-protected building blocks.^[18,19]

Synthesis was carried out on a Wang resin and oligomers

containing up to eight α-hydroxy acid units were obtained

1015 Lausanne, Switzerland

Fax: +41-21-693-5650

E-mail: harm-anton.klok@epfl.ch

[b] École Polytechnique Fédérale de Lausanne (EPFL), Institut des

Sciences et Ingénierie Chimiques, Service de Spectrométrie de

Masse,

1015 Lausanne, Switzerland

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200900663.

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

via repetitive sequences of N,NЈ-diisopropylcarbodiimide

(DIC)/DMAP mediated coupling reactions and deprotec-

tion steps. As the work by Huang and Hermes and Kuisle

et al. was not aimed at the preparation of oligomers with

defined monomer sequences that can induce folding into

specific secondary structures, the conformational properties

of the oligo(α-hydroxy acid)s were not investigated. Related

work by Seebach and co-workers has focused on the synthe-

sis and structure of oligo(3-hydroxyalkanoate)s, i.e. oligo(β-

hydroxy acid)s.^[20–22]Following a convergent/divergent solu-

tion phase strategy that involved the use of (tert-butyl)di-

phenylsilyl (TBDPS) and benzyl ester protecting group

chemistry and acid chloride/pyridine mediated chain exten-

sion, Lengweiler et al. were able to prepare uniform oligo-

mers containing up to 128 repeat units. Circular dichroism

and NMR spectroscopy studies on oligo(3-hydroxyalkano-

ate) analogues of helix forming β-peptides, however, did not

provide evidence for the formation of conformationally or-

dered solution states.^[23–25]

In this contribution, we report a novel synthetic strategy

for the preparation of uniform, sequence-defined α-hydroxy

acid oligomers that are designed to fold into regular β-sheet

secondary structures. To guide secondary structure forma-

tion, the α-hydroxy acid oligomers are patterned with an

alternating sequence of hydrophilic and hydrophobic sub-

stituents. This concept of hydrophilic/hydrophobic

patterning has already been successfully applied to direct

folding of de novo designed peptides as well as non-natural

oligomers and polymers and it has been shown that alter-

nating sequences of hydrophilic (P) and hydrophobic (NP)

residues can promote the formation of β-sheet struc-

tures.^{[8,9,26–44]}The synthesis of uniform hydrophilic/hydro-

phobic patterned oligomers typically involves a repetitive

sequence of coupling and deprotection reactions using a

hydrophobic and an appropriate side-chain-protected hy-

Results and Discussion

Synthesis of the Oligoester Scaffold

Starting compounds for the synthesis of the targeted oli-

goester scaffolds were -leucine and -allylglycine. -Allyl-

glycine was prepared in three steps from (R,R)-(–)-pseudoe-

phedrine and glycine methyl ester according to a procedure

published by Myers et al.^[48]Subsequently, via a one step

diazotization reaction, -leucine and -allylglycine were

converted into the corresponding α-hydroxy acids

(Scheme 1). (2S)-2-Hydroxy-4-methylpentanoic acid (2) was

readily obtained in 88% yield following a literature pro-

cedure, by diazotization of -leucine using NaNO₂in an

aqueous solution of H₂SO₄.^[49]Application of this pro-

cedure to the synthesis of (2S)-2-hydroxypent-4-enoic acid

(4), however, did not yield satisfactory results. Compound

4 was obtained in 69% yield according to another literature

procedure that involved reaction of -allylglycine with

NaNO₂in a 8:2 (v/v) mixture of water and acetic acid, fol-

lowed by quenching the reaction with methylamine.^[50]

Scheme 1. Synthesis of α-hydroxy acids 2 and 4.

The synthesis of oligoester scaffolds consisting of 2, 4 or

drophilic building block followed by a deprotection step to 8 alternating repeat units of 2 and 4 is shown in Scheme 2.

remove the side-chain protective groups from the hydrophi- The oligomers were prepared via a convergent/divergent

lic repeat units. This contribution explores the feasibility of growth process, which required orthogonal protection of

an alternative synthetic strategy, which is based on post- both chain ends. The synthetic route outlined in Scheme 2

modification of a reactive oligoester scaffold. The hydrophi- is based on a protective group strategy that uses tetra-

lic/hydrophobic patterned oligomers that will be discussed hydropyran (THP) ether and allyl ester groups to mask the

here are based on an oligoester scaffold composed of (2S)- hydroxy and carboxylic terminal groups, respectively. The

2-hydroxy-4-methylpentanoic acid (a leucine analogue) as hydroxy group of 4 was protected by reacting the hydroxy

the hydrophobic (NP) and (2S)-2-hydroxypent-4-enoic acid acid with an excess of dihydropyran (1.4 equiv.) in the pres-

as a masked hydrophilic (P) building block. The use of (2S)- ence of a catalytic amount of pTosOH (0.02 equiv.) to give

2-hydroxypent-4-enoic acid obviates the need for additional 6 as a mixture of diastereoisomers.^[51]The carboxylic acid

protective group chemistry to block side chain functional group of 2 was masked as an allyl ester and was prepared

groups that could interfere with the chain extension. It also using allyl bromide in the presence of tetrabutyl ammonium

facilitates the access to libraries of hydrophilic/hydrophobic bromide and potassium carbonate to afford 5 in 89% yield.

patterned oligomers with diverse hydrophilic functional According to ¹H NMR spectroscopy, 5 was obtained in ca.

groups since the allyl side chains can be smoothly converted 90% purity (see Supporting Information, Figure S3). The

into a variety of functional groups via radical addition of ESI-TOF mass spectrum of 5 revealed the presence of allyl

appropriate ω-functional thiols.^[45–47]The focus of the pres- ester-protected (2S)-2-hydroxy-4-methylpentanoic acid

ent contribution is on establishing the feasibility of the pro- oligomers byproducts (Supporting Information, Figure S4).

posed post-modification strategy and the structural charac- These side products, which are probably the result of trans-

terization of the resulting oligomers. The conformational esterification reactions that accompany the protection reac-

properties and self-assembling behavior of these materials tion, could not be separated with column chromatography.

will be subject of forthcoming publications.

It was found, however, that the coupling products of these

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N. Franz, L. Menin, H.-A. Klok

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Scheme 2. Synthetic route for the preparation of oligo(α-hydroxy acid)s 7, 10 and 13.

dimeric and trimeric (2S)-2-hydroxy-4-methylpentanoic allyl ester-protected (2S)-2-hydroxy-4-methylpentanoic acid

acid impurities could be easily removed after the esterifica- dimers and trimers with 6. As the integrals of the ¹H NMR

tion/chain extension step so that the desired oligomers spectrum of 7 were in good agreement with the expected

could be isolated as the pure tetra- or octamers (vide infra). values, the level of these trace impurities is thought not to

Chain extension was carried out by reacting 1.1 equiv. exceed ca. 5%. The carboxylic acid function of 7 could be

of the monoprotected carboxylic acid building block and deprotected via Pd⁰-catalyzed allyl transfer to morpholine

1 equiv. of the monoprotected hydroxy building block in (1.05 equiv.)

using

tetrakis(triphenylphosphane)palla-

CH₂Cl₂in the presence of 1.1 equiv. DCC as a coupling dium(0) [Pd(PPh₃)₄] (0.1 equiv.) to give building block 8 in

agent and a catalytic amount of DMAP (0.1 equiv.). In this 64% yield after purification. Selective removal of the THP

way, the double-protected dimer 7 was obtained in 84% protecting group could be achieved by treating 7 with a

yield after column chromatography. Compound 7 was char- catalytic amount of pTosOH (1 mgmL^–1) in dry methanol

acterized by ¹H and ¹³C NMR spectroscopy, as well as ESI- yielding intermediate 9 in good yield. The acid 8 and the

1

TOF mass spectrometry. H NMR and ¹³C NMR spectra alcohol 9 were subsequently coupled using 0.1 equiv.

of 7 are included in the Supporting Information (Figure DMAP and a slightly higher excess of DCC (1.4 equiv.) to

S5 and S6). Within the experimental accuracy (ca. 5%), the favor the formation of the O-acylisourea intermediate. Col-

1

experimentally determined integrals in the H NMR spec- umn chromatography using a mixture of diethyl ether and

trum agreed with the expected values, indicating that com- pentane as the eluent allowed to successfully remove by-

pound 7 was isolated with a purity of Ն 95%. The ESI- products that were generated due to reaction of the impuri-

TOF mass spectrum of 7 is shown in Figure 1 (A). The ties present in 7 and afforded tetramer 10 in 74% yield. The

signals at m/z 355.2130, 377.1741 and 393.1598 represent ESI-TOF mass spectrum of 10 in Figure 1 (B) shows signals

the [M + H]⁺, [M + Na]⁺and [M + K]⁺ions of the desired at m/z 589.3011 and 605.3306 corresponding to [M + Na]⁺

compound 7, respectively. In addition, Figure 1 (A) reveals and [M + K]⁺ions, respectively. The ¹H and ¹³C NMR

signals at m/z 491.2036 and 605.2910, which were assigned spectra of 10 are included in the Supporting Information

to sodium adducts of side-products due to coupling of the (Figure S7 and S8). Selective deprotection of 10 using the

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

same reaction conditions that were also used for dimer 7

afforded carboxylic acid 11 and alcohol 12 in 66% and 94%

yield, respectively. Subsequent coupling of 11 and 12 at

0 °C, finally gave the octamer 13 in 82% isolated yield after

1

column chromatography. H and ¹³C NMR spectra of 13

are included in the Supporting Information (Figure S9 and

S10). The ESI-TOF mass spectrum shown in Figure 1 (C)

reveals two major peaks at m/z 1013.5056 and 1029.5895,

which can be assigned to the sodium ([M + Na]⁺) and po-

tassium ([M + K]⁺) adducts of 13.

While an accurate mass (Ͻ 5 ppm) could be obtained by

ESI-TOF-MS for each of the compounds 7, 10 and 13 (see

Table 1), mass measurements alone do not provide infor-

mation about the primary structure, i.e. hydroxy acid se-

quence, of these oligomers. To verify the alternating pri-

mary structure, oligomers 10 and 13 were analyzed by ESI

tandem mass spectrometry. Collision-induced dissociation

(CID) relies on the dissociation of a precursor ion upon

collision with neutral gas molecules to induce fragmenta-

tion of the molecule along the most labile bonds. Following

the nomenclature that is used to describe peptide fragmen-

tation patterns, the fragment ions generated after dissoci-

ation of the ester bonds are named b- or y-ions if they origi-

nate from the O-terminal or C-terminal part of the oligo-

mer, respectively.^[52,53]Figure 2 shows the fragmentation

patterns observed for the sodium adducts of tetramer 10

and octamer 13. The losses of 98 and 114 Da correspond

to the fragmentation of C₅H₆O₂[(2S)-2-hydroxypent-4-en-

oic acid residue] and C₆H₁₀O₂[(2S)-2-hydroxy-4-methyl-

pentanoic acid residue], respectively. The dominant peaks

in the MS/MS spectra, located at m/z 505.3624 and

929.5825 for tetramer 10 and octamer 13 respectively, are

due to the loss of the O-terminal THP group. Signals at

m/z 463.3110 and 887.5460 for tetramer 10 and octamer 13,

respectively, correspond to subsequent loss of the allyl ester

protecting group. The fragment ions of the [M + Na]⁺ad-

duct of the tetramer 10 and octamer 13 have been assigned

to c_n/z_nthat are formed after loss of the protecting groups

(series are annotated in the full spectrum). These MS/MS

data confirm the strictly alternating structure of (2S)-2-

hydroxy-4-methylpentanoic acid and (2S)-2-hydroxypent-4-

enoic acid residues.

Figure 1. ESI-TOF mass spectra of (A) dimer 7; (B) tetramer 10;

(C) octamer 13.

Table 1. Summary of theoretical and experimental masses of H⁺/Na⁺adducts of the different oligo(α-hydroxy acid)s as measured by ESI-

TOF-MS.

Product

Composition

M_theor.[Da]

M_exp.[Da]

Mass accuracy [ppm]

7

10

13

C₁₉H₃₀O₆+ H⁺

C₃₀H₄₆O₁₀+ Na⁺

C₅₂H₇₈O₁₈+ Na⁺

355.2121

589.2989

1013.5086

355.2130

589.3011

1013.5056

2.53

3.73

2.96

14

15

16

C₁₈H₃₀O₉S₂+ H⁺

C₂₃H₄₂O₈S₂+ H⁺

C₁₈H₃₆N₂O₅S₂+ H⁺

455.1410

511.2399

425.2144

455.1394

511.2414

425.2122

3.52

2.93

5.17

17

18

C₃₁H₅₀O₁₅S₃+ H⁺

759.2390

714.3492

759.2385

714.3477

0.66

2.10

C₃₁H₅₉N₃O₉S₃+ H⁺

19

20

C₅₇H₉₀O₂₇S₅+ H⁺

1367.4352

646.8133

1367.4371

646.8143

1.39

1.55

[C₅₇H₁₀₅N₅O₁₇S₅+ 2H]²⁺

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Figure 2. ESI-MS/MS spectra of (A) tetramer 10 and (B) octamer 13.

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

Post-Modification

allyl groups was necessary. The quantitative post-modifica-

tion is apparent by comparison of the H NMR spectra in

1

The allyl side group of the (2S)-2-hydroxypent-4-enoic

acid repeat units in oligomers 7, 10 and 13 provides a

unique chemical handle that can be converted into a wide

variety of polar functional groups via radical addition of

appropriate ω-functional thiols. In this contribution, the

modification of the allyl side groups of the (2S)-2-hy-

droxypent-4-enoic acid repeat units with thioglycolic acid,

mercaptoethanol and cysteamine hydrochloride was ex-

plored in order to convert these masked hydrophilic repeat

units into carboxylic acid, hydroxy and amine groups and

generate oligo(α-hydroxy acid)s with an alternating hydro-

philic/hydrophobic monomer sequence (Scheme 3).

Figure 3 (A, C). The appearance of the methylene proton

peaks adjacent to the sulfur atom (cЈ, fЈ, gЈ, hЈ), the disap-

pearance of the olefin protons (b, e, c, f) and the shift of

proton d to dЈ from 4.7–4.5 ppm to 4.4–4.2 ppm indicate a

1

complete conversion of the allyl groups. H NMR analysis

of the crude reaction mixture of entry #1 in Table 2, which

was carried out with an excess of allyl groups relative to

thioglycolic acid, reveals that the post-modification reaction

is not regioselective. Comparison of the spectra in Figure 3

(A, B) suggests that half of the (2S)-2-hydroxypent-4-enoic

acid repeat units (intensity of the signal a) and half of the

allyl protecting groups (intensity of the signal d) have been

modified.

Whereas a 2.5-fold molar excess of thiol relative to

double bonds was sufficient to allow a quantitative post-

modification of 7 with thioglycolic acid, these reaction con-

ditions resulted only in the modification of 75% of the allyl

groups when mercaptoethanol was used (entry #9 in

Table 2). By using a 10-fold excess of mercaptoethanol,

however, 90% of the allyl groups of 7 could be modified

(entry #10 in Table 2). In contrast to thioglycolic acid and

mercaptoethanol, cysteamine hydrochloride is only poorly

soluble in toluene. Post-modification of 7 with cysteamine

hydrochloride in toluene was carried out under hetero-

geneous conditions and resulted in incomplete double bond

conversion (entry #11 in Table 2). When DMF instead of

Scheme 3. Post-modification of dimer 7, tetramer 10 and octamer

13.

In a first series of experiments, the conditions for the toluene was used as the solvent, a homogeneous reaction

free-radical addition of the different thiols were optimized mixture was obtained and the allyl group conversion was

using dimer 7 as the substrate. These reactions were carried quantitative under the same reaction conditions (entry #12

1

out at 70 °C for 18 h in toluene or DMF, under nitrogen in Table 2). H NMR spectra and ESI-TOF mass spectra

atmosphere and using different amounts of thiol and of the post-modified analogues of 7 (14, 15 and 16) are

AIBN. The progress of the reaction was monitored with ¹H shown in Figures 4 and 5, respectively. The H NMR spec-

1

NMR spectroscopy and mass spectrometry and the results tra illustrate the quantitative allyl group conversion upon

of these experiments are summarized in Table 2.

post-modification of 7 with thioglycolic acid and cyste-

1

Figure 3 compares the H NMR spectrum of 7 with H amine hydrochloride and reveal the presence of residual un-

NMR spectra of the crude reaction mixtures obtained after reacted allyl groups (ca. 10%) in the mercaptoethanol-

1

modification of 7 with thioglycolic acid under different con- modified dimer 15. Further analysis of the H NMR spec-

ditions. To obtain a quantitative conversion of the allyl tra also reveals that the thiol radical addition in some cases

groups, a 2.5-fold excess of thioglycolic acid with respect to is accompanied by partial or complete loss of the THP pro-

Table 2. Summary of reaction conditions that were evaluated to optimize the radical addition of various thiols to 7.

Entry

Thiol

Solvent

[C=C]₀/[RSH]₀/[AIBN]₀

Product

Conversion

[% of modified C=C^[a]

]

1

2

3

4

5

Thioglycolic acid

toluene

1:0.5:0.02

1:1.5:0.02

1:1.5:0.2

1:2.5:0.2

1:10:0.33

14

50

90

98

100

6

7

8

9

Mercaptoethanol

toluene

1:0.5:0.02

1:1.5:0.02

1:1.5:0.2

1:2.5:0.2

1:10:0.33

15

35–37

60–70

50

75

90

10

11

12

Cysteamine hydrochloride

toluene

DMF

1:10:0.33

16

50

100

1

[a] Based on H NMR analysis of the crude reaction mixture.

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Figure 3. ¹H NMR spectra (CDCl₃) of (A) dimer 7; (B) the crude reaction mixture obtained after modification of 7 using [C=C]₀/[RSH]₀/

[AIBN]₀= 1:0.5:0.02 (≈ 50% conversion) (entry #1, Table 2); (C) the crude reaction mixture obtained after modification of 7 using

[C=C]₀/[RSH]₀/[AIBN]₀= 1:2.5:0.2 (quantitative) (entry #4, Table 2).

1

tecting group. According to the H NMR spectra of the tecting groups in case of thioglycolic acid and cysteamine

crude reaction mixtures of entries #5, #10 and #12 from hydrochloride and that post-modification with mercapto-

Table 2, THP cleavage was quantitative for dimer 14, partial ethanol does not affect the THP group. The peak at m/z

for 16 and absent for the radical addition of mercapto- 509.2753 in the mass spectrum of 16 represents the [M +

ethanol (compound 15). The ¹H NMR spectra further indi- H]⁺signal of the THP-protected, post-modified dimer.

cate that the radical addition of the different thiols to 7

The results summarized in Table 2 provided the starting

proceeded in the expected anti-Markovnikov fash- point for the post-modification of the longer oligomers 10

ion.^[46,54–59]Markovnikov addition products should have and 13. A first attempt to post-modify tetramer 10 with a

produced a multiplet at 1.2–1.3 ppm due to the additional 2.5-fold excess of thioglycolic acid only resulted in partial

methyl groups and one or two quartets between 2.7– conversion of the double bonds (ca. 70%). When the reac-

3.0 ppm due to additional methylene groups adjacent to the tion was carried out with a 10-fold excess of thioglycolic

sulfur atoms, which are absent in the spectra in Figure 4. acid, however, i.e. [C=C]₀/[RSH]₀/[AIBN]₀= 1:10:0.3,

The ESI-TOF mass spectra of the post-modified dimers 14, quantitative allyl group conversion was obtained. These re-

15 and 16 are shown in Figure 5. The major peaks in the action conditions were subsequently also successfully used

mass spectra at [M + H]⁺455.1394, 511.2414 and 425.2122 for the post-modification of 10 with cysteamine hydrochlo-

correspond to the quantitatively post-modified dimers. The ride as well as for the post-modification of 13 with thiogly-

mass spectra further confirm that the thiol radical addition colic acid and cysteamine hydrochloride. In all cases, the

is accompanied by complete or partial loss of the THP pro- ¹H NMR spectra of the crude reaction mixtures indicated

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

Figure 4. ¹H NMR spectra of crude mixtures after radical additions of various thiols to 7 using [C=C]₀/[RSH]₀/[AIBN]₀= 1:10:0.33. (A)

thioglycolic acid-modified dimer (14) (entry #5, Table 2); (B) mercaptoethanol-modified dimer (15) (entry #10, Table 2); (C) cysteamine

hydrochloride-modified dimer (16) (entry #12, Table 2).

quantitative allyl group conversion. To remove the excess of signals due to the allyl side chains confirms the quantitative

thiol, the crude products were purified with RP-HPLC to post-modification. Furthermore, the absence of any reso-

afford the pure post-modified oligomers 17, 18, 19 and 20. nances due to the THP protecting group that is present in

As a representative example, Figure 6 shows the ¹H the starting oligomers 10 and 13 indicates that also for these

NMR spectra of the purified post-modified oligomers 19 longer oligomers, post-modification is accompanied by loss

and 20 (¹H NMR spectra of 17 and 18 are included in the of the THP protective group. The ¹H NMR spectra are sup-

Supporting Information Figure S11). The absence of any ported by the results of ESI-TOF mass spectrometry experi-

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N. Franz, L. Menin, H.-A. Klok

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presence of both the unprotected 20 as well as the THP-

protected cysteamine hydrochloride-modified octamer.

Since the ¹H NMR spectrum in Figure 7 (C) does not reveal

any resonances that can be attributed to the THP group,

the THP-protected derivative of 20 is assumed to be present

only in trace amounts (Ͻ 5%).

To confirm the alternating, hydrophilic/hydrophobic pat-

terned monomer sequence, the post-modified oligomers

were analyzed by tandem mass spectrometry. As a represen-

tative example, Figure 8 shows ESI-MS/MS spectra of

oligomers 17 and 19. Fragmentation of the protonated olig-

oesters 17 and 19 (m/z 759.2390 and 1367.4351, respec-

tively) generally occurred through reactions that involved

cleavage of the ester bonds along the oligoester backbone

and produced b_nand z_nseries of ions. The losses of 114

and 190 Da correspond to the fragmentation of (2S)-2-hy-

droxy-4-methylpentanoic acid and (2S)-5-[(carboxymethyl)-

thio]-2-hydroxypentanoic acid residues, respectively. Strictly

alternating sequences of (2S)-2-hydroxy-4-methylpentanoic

acid and (2S)-5-[(carboxymethyl)thio]-2-hydroxypentanoic

acid residues could be observed for both oligoesters. The

peak located at m/z 741.2367 for 17 corresponds to the loss

of a water molecule from the parent ion. Water loss was

observed on most of the a and b-ions. The peak at m/z

695.2334 corresponds to the loss of a carboxylic acid

HCOOH (CH₂O₂) group. This loss of ca. 46 Da is also ob-

served for b₁, b₃, z₁, z₂and z₃ions, giving the peaks at

m/z 145.0431, 449.1481, 201.1094, 391.1441 and 505.2131,

respectively. In the same manner for the octamer 19, the

main peaks at m/z 1349.4305 and 1303.4187 correspond to

the loss of a water molecule from the parent ion and the

additional loss of a carboxylic acid CH₂O₂group, respec-

tively. The additional signal at m/z 1257.4177 corresponds

to the subsequent loss of ca. 46 Da. The product ion at m/z

133.0543 observed for both oligomers correspond to the

C₅H₉O₂S group and could be either the z₀ion, or the O-

terminal or the lateral C₅H₉O₂S chains.

Conclusion

In this contribution, we have explored the feasibility of

a novel strategy for the preparation of uniform, hydrophilic/

hydrophobic patterned α-hydroxy acid oligomers. To avoid

complex protective group strategies and side-chain-pro-

tected building blocks, the synthetic strategy presented in

this report involves post-modification of a reactive oligoes-

ter scaffold with a precisely defined length and a strictly

alternating sequence of hydrophobic [(2S)-2-hydroxy-4-

Figure 5. ESI-TOF mass spectra of (A) thioglycolic acid-modified

dimer (14); (B) mercaptoethanol-modified dimer (15); (C) cyste-

amine hydrochloride-modified dimer (16).

ments, which are shown in Figure 7 for 19 and 20 (and in methylpentanoic acid] and masked hydrophilic [(2S)-2-

Figure S12 for 17 and 18). In the ESI mass spectra of oligo- hydroxypent-4-enoic acid] α-hydroxy acids. Oligomers con-

mers 17, 18 and 19 protonated molecular ions [M + H]⁺taining up to 8 α-hydroxy acid repeat units could be pre-

could be detected at m/z 759.2385, 714.3477 and 1367.4371 pared via a straightforward convergent/divergent growth

with a mass accuracy better than 5 ppm (Table 1). The cor- process without the need for protective group chemistry to

responding doubly [M + 2H]²⁺and triply [M + 3H]³⁺pro- block the allyl groups of the (2S)-2-hydroxypent-4-enoic

tonated species were also detected for 18 at m/z 357.6840 acid residues during the chain growth process. In a subse-

and 238.8021, and for 20 at m/z 646.8143 and 431.5513, quent post-modification step, the allyl side chain functional

respectively. The ESI-TOF mass spectrum of 20 reveals the groups of these oligoesters could be quantitatively modified

5398

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

Figure 6. ¹H NMR spectra of (A) octamer (13); (B) thioglycolic acid-modified octamer (19); (C) cysteamine hydrochloride-modified

octamer (20).

via free-radical addition of various ω-functional thiols to quence could be confirmed using ESI tandem mass spec-

afford hydrophilic/hydrophobic patterned oligoesters. The trometry experiments. The proposed synthetic strategy may

chemical composition of these oligomers was confirmed by be an interesting alternative approach to generate libraries

¹H NMR spectroscopy and ESI-TOF mass spectrometry of foldamers and study the effect of side-chain functionality

and the alternating hydrophilic/hydrophobic monomer se- on folding properties.

Eur. J. Org. Chem. 2009, 5390–5405

www.eurjoc.org

5399

N. Franz, L. Menin, H.-A. Klok

FULL PAPER

KMnO₄solutions. Allylglycine was prepared in three steps from

(R,R)-(–)-pseudoephedrine and glycine methyl ester according to a

procedure published by Myers et al.^[48]

Analytical Methods: ¹H and ¹³C NMR spectra were recorded using

an AVANCE-400 spectrometer (Bruker). Chemical shift values (δ)

are reported in ppm and CDCl₃(solvent) (¹H, δ = 7.25 ppm; ¹³C,

δ = 77.0 ppm) or [D₆]DMSO (solvent) (¹H, δ = 2.49 ppm; ¹³C, δ =

39.50 ppm) was used as internal standard.

Semi-preparative reverse-phase high-pressure liquid chromatog-

raphy (RP-HPLC) was performed using a Waters Delta 600 instru-

ment equipped with a Waters Atlantis^®dC₁₈column (OBD^TM

5 µm, 30ϫ150 mm). Modified oligomers obtained after radical ad-

dition of thioglycolic acid or cysteamine hydrochloride were dis-

solved in acetonitrile/water (1:1) and DMSO, respectively. The

solutions were injected onto the HPLC column and subsequently

eluted with linear gradients from 100% ammonium acetate buffer

(pH = 7) to 100% acetonitrile, over 30 min. For samples injected

in DMSO, an isocratic flow of ammonium acetate (6 min) preceded

the gradient elution with ammonium acetate and acetonitrile. The

flow rate was 20 mLmin^–1. Elution was monitored with a UV-de-

tector with dual wavelength detection at 214 nm and 220 nm.

Electrospray ionization mass spectrometry experiments (ESI-MS

and ESI-MS/MS) were performed on a quadrupole time-of-flight

mass spectrometer (Q-TOF) Ultima API (Waters) fitted with a

standard Z-spray source and operated in the positive ionization

mode. The lockSpray interface was employed for more accurate

mass analysis (Ͻ 5 ppm). Single MS analyses were followed by MS/

MS experiments on the selected precursor ions. The collision en-

ergy was manually adjusted for the most efficient and informative

fragmentation. The samples were first dissolved in an appropriate

solvent and acidified (0.1% HCOOH). Then, 5 µL of the sample

solution was introduced into the mass spectrometer by infusion at

a flow rate of 10 µLmin^–1with a solution of MeOH/H₂O/HCOOH,

50:49.9:0.1 (v/v/v). Data analysis was performed using

MassLynx^TM4.1 software. External calibration was carried out

with 0.05% phosphoric acid.

Procedures

General Procedure for the Ester Coupling Reaction (GP1): A mix-

ture of carboxylic acid (1.1 equiv.), alcohol (1 equiv.) and DMAP

(0.1 or 0.05 equiv.) was dissolved in CH₂Cl₂(0.3  solution) and

cooled to 0 °C. DCC (1.1 equiv. or 1.4 equiv.) was added to the

reaction mixture, which was stirred 5 min at 0 °C and then at room

temperature. The reaction was followed by TLC and stopped when

no more alcohol could be detected. Precipitated urea was filtered

off over Celite, the filtrate evaporated to half of its volume and, if

necessary, filtered again to remove any residual urea. The CH₂Cl₂

solution was washed twice with 0.5  HCl, once with a saturated

aqueous solution of NaHCO₃, dried with MgSO₄, concentrated un-

der reduced pressure and dried under high vacuum. The crude

product was purified by silica gel column chromatography (CH₂Cl₂

or diethyl ether/pentane, 1:4).

Figure 7. ESI-TOF mass spectra of (A) octamer (13); (B) thiogly-

colic acid-modified octamer (19); (C) cysteamine hydrochloride-

modified octamer (20).

General Procedure for the Allyl Ester Cleavage (GP2): To a solution

of allyl ester (1 equiv.) in THF at 0 °C were added Pd(PPh₃)₄

(0.1 equiv.) and dropwise morpholine (1.05 equiv.). The reaction

mixture was stirred at this temperature until it was judged to be

complete as monitored by TLC. The solvent was removed under

reduced pressure (30 °C), the remaining residue dissolved in

CH₂Cl₂, washed three times with 1  HCl, dried with MgSO₄and

concentrated. The resulting oil was dissolved in diethyl ether, fil-

Experimental Section

Materials: All reagents were purchased from Fluka or Sigma–

Aldrich and used as received. All reactions were carried out under

nitrogen atmosphere in oven-dried glassware (150 °C, for 12 h). Sol-

vents were purified through a PureSolv^®System from Innovative

Technology under nitrogen prior to use. Column chromatography

was performed by using silica gel 60. Thin layer chromatography

(TLC) was performed on precoated aluminum sheets (TLC Silica tered through Celite, concentrated and dried under high vacuum.

gel 60 F254). Thin layer chromatograms were visualized either un-

der a 254 nm UV light or with iodine, bromocresol, ninhydrin or

The crude product was purified by silica gel column chromatog-

raphy (diethyl ether/pentane, 4:1).

5400

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Eur. J. Org. Chem. 2009, 5390–5405

Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

Figure 8. ESI-MS/MS spectra of (A) thioglycolic acid-modified tetramer (17) and (B) thioglycolic acid-modified octamer (19).

Eur. J. Org. Chem. 2009, 5390–5405

www.eurjoc.org

5401

N. Franz, L. Menin, H.-A. Klok

FULL PAPER

General Procedure for the THP Ether Cleavage (GP3): The THP-

protected oligomer (1 equiv.) was treated with a solution of p-tolu-

enesulfonic acid (pTosOH) (0.07 or 0.4 equiv.) in methanol and the

reaction was followed by TLC. After completion of the reaction,

the mixture was concentrated under vacuum. The residue was taken

up in diethyl ether, washed with a saturated aqueous solution of

NaHCO₃and NaCl, dried with MgSO₄, concentrated under re-

duced pressure and dried under high vacuum. Purification by silica

gel column chromatography (diethyl ether/pentane, 1:4) afforded

the deprotected compound.

bined organic phases were washed twice with 5% NaHCO₃

(2ϫ100 mL) and saturated NaCl (2ϫ100 mL) solutions, dried

with MgSO₄, concentrated under reduced pressure and dried under

high vacuum. Purification by silica gel column chromatography (di-

ethyl ether/pentane, 1:4) afforded 5 (30.67 g, 177.1 mmol, 89%) as

a light yellow, oily liquid. R_f= 0.43 (diethyl ether/pentane, 1:4). ¹H

NMR (400 MHz, CDCl₃): δ = 5.93–5.87 (m, 1 H, CH=CH₂), 5.34–

5.24 (m, 2 H, CH=CH₂), 4.65–4.59 (m, 2 H, O-CH₂), 4.22–4.19

(m, 1 H, CH-OH), 1.93–1.82 (m, 1 H, CH₂-CH), 1.57–1.53 (m, 2

H, CH-CH₂-CH), 0.96–0.91 (m, 6 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 175.51, 131.47, 118.92, 69.05, 66.02, 43.46,

24.38, 23.21, 21.50 ppm. EI-MS: m/z (%) = 190 (7) [M + NH₃]⁺,

173 (100) [M + H]⁺, 145 (11), 127 (11), 113 (14), 98 (14), 87 (62),

85 (30), 71 (16). ESI-MS: m/z: calcd. for C₉H₁₆O₃+ H⁺: 173.1178;

found 173.1170.

General Procedure for the Radical Addition of Thiols (GP4): A care-

fully dried 5 mL round-bottomed flask was charged with oligomer

7, 10 or 13 (1 equiv. of allyl groups), AIBN (0.02 to 0.33 equiv.)

and thiol (0.5 to 10 equiv.). The flask was evacuated and flushed

with nitrogen three times. A minimal amount of nitrogen-saturated

solvent (toluene or DMF) was added to the mixture which was

then allowed to react 18 h at 70 °C. The reaction product was then

evaporated to dryness.

(2S)-2-(Tetrahydro-2H-pyran-2-yloxy)pent-4-enoic Acid (6):

4

(14.55 g, 125.4 mmol) and pTosOH (479.2 mg, 2.52 mmol) were

dissolved in CH₂Cl₂(260 mL) and cooled to 4 °C. Dihydropyran

(16.3 mL, 179.8 mmol) was added dropwise. After 5 min, the ice

bath was removed and the mixture warmed to room temperature.

The reaction was followed by TLC. After 2.5 h, the reaction mix-

ture was extracted twice with 0.2  KOH (2 ϫ300 mL). The com-

bined KOH layers were acidified to pH 3–4 with 6  HCl and ex-

tracted three times with CH₂Cl₂(3ϫ300 mL). The pH of the aque-

ous layer was controlled between extractions and adjusted with

more HCl if necessary. The combined CH₂Cl₂extracts were washed

with water, dried with MgSO₄, concentrated under reduced pres-

sure and dried under high vacuum. The crude product was purified

by silica gel column chromatography using a gradient mixture of

100% CH₂Cl₂to 100% CH₃CN to give 6 as a mixture of diastereo-

isomers as a sticky oil (15.35 g, 76.8 mmol, 61%). R_f= 0.61

(2S)-2-Hydroxy-4-methylpentanoic Acid (2): To a stirred solution of

-leucine 1 (7.87 g, 60 mmol) in an aqueous solution of 0.5 

H₂SO₄(240 mL, 120 mmol) was added dropwise a solution of

NaNO₂(24.84 g, 360 mmol) in water (90 mL) at 0 °C over 3 h. The

reaction was warmed to room temperature and stirred for ad-

ditional 24 h. Once the reaction was finished as shown by TLC, the

reaction mixture was extracted three times with diethyl ether

(1ϫ150 and 2ϫ100 mL). The combined organic layers were

washed twice with saturated brine (2ϫ30 mL), dried with MgSO₄

and concentrated under reduced pressure. The sticky yellow oil was

recrystallized from diethyl ether to give 2 (6.95 g, 52.6 mmol, 88%)

as a white powder. ¹H NMR (400 MHz, CDCl₃): δ = 4.30–4.26 (m,

1 H, CH-OH), 1.93–1.86 (m, 1 H, CH₂-CH), 1.64–1.60 (m, 2 H,

CH₂), 0.96–0.95 (m, 6 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 180.53, 68.89, 43.19, 24.45, 23.18, 21.41 ppm. EI-MS:

m/z (%) = 150 (49) [M + NH₃]⁺, 133 (16) [M + H]⁺, 99 (100), 81

(15), 71 (93) for C₆H₁₂O_3.

1

(CH₂Cl₂/CH₃CN, 2:0.75). H NMR (400 MHz, CDCl₃): δ = 5.85–

5.66 (m, 1 H, CH=CH₂), 5.09–5.00 (m, 2 H, CH=CH₂), 4.69–4.68

and 4.60–4.58 [m, 1 H, O-CH(CH₂)-O], 4.31–4.28 and 4.09–4.06

(m, 1 H, CH-CO), 3.91–3.74 and 3.46–3.39 (m, 2 H, O-CH₂-CH₂),

2.55–2.38 (m, 2 H, CH-CH₂-CH), 1.82–1.42 [m, 6 H, (CH₂)₃] ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 176.41, 175.38, 132.94, 132.38,

118.21, 117.82, 99.94, 96.94, 76.57, 73.02, 63.11, 61.83, 36.94,

36.40, 30.05, 29.91, 25.03, 24.77, 19.25, 18.47 ppm. EI-MS: m/z (%)

= 218 (29) [M + NH₃]⁺, 201 (62) [M + H]⁺, 155 (36), 102 (28), 85

(100); 71 (10). ESI-MS: m/z: calcd. for C₁₀H₁₆O₄+ H⁺: 201.1127;

found 201.1144.

(2S)-2-Hydroxypent-4-enoic Acid (4): To a stirred solution of -al-

lylglycine 3 (14.97 g, 130 mmol) in water/acetic acid 8:2 (v/v)

(1300 mL) was added dropwise a solution of NaNO₂(17.94 g,

260 mmol) in water (260 mL) at 0 °C over 3 h. Once the reaction

was finished as shown by TLC, the reaction was quenched with 2 

methylamine solution in THF (130 mL, 260 mmol). The solvent

was removed under reduced pressure. The residual aqueous solu-

tion was acidified to pH = 2 with 6  HCl and extracted with ethyl

acetate (2ϫ2000 and 1ϫ1000 mL). The solvent was evaporated

and the residue purified by silica gel column chromatography

(CHCl₃/MeOH/acetic acid, 90:9:1) to give 4 (10.31 g, 88.8 mmol,

69%) as a light yellow oil. R_f= 0.58 (CHCl₃/MeOH/acetic acid

90:9:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.83–5.73 (m, 1 H,

CH=CH₂), 5.17–5.12 (m, 2 H, CH=CH₂), 4.34–4.32 (m, 1 H, CH-

OH), 2.62–2.56 and 2.49–2.42 (m, 2 H, CH-CH₂-CH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 178.37, 131.95, 119.15, 69.77,

38.16 ppm. ESI-MS: m/z: calcd. for C₅H₈O₃+ Na⁺: 139.0371;

found 139.0346.

Double-Protected Dimer 7: According to GP1,

6 (11.23 g,

56.1 mmol) and 5 (8.78 g, 51 mmol) were reacted in the presence

of DMAP (0.62 g, 5.1 mmol) and DCC (11.57 g, 56.1 mmol) in

CH₂Cl₂(170 mL) for 3.5 h. Purification by silica gel column

chromatography (CH₂Cl₂) yielded 7 (mixture of diastereoisomers;

15.44 g, 43.6 mmol, 84%) as a colorless oil. R_f= 0.44 (CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 5.91–5.74 (m, 2 H, CH=CH₂),

5.30–5.03 (m, 5 H, CH=CH₂, CO-O-CH), 4.72–4.56 [m, 3 H, O-

CH₂-CH, O-CH(CH₂)-O], 4.40–4.37 and 4.10–4.06 [m, 1 H, O-

CH(CH₂)-CO], 3.88–3.77 and 3.49–3.34 (m, 2 H, CH₂-CH₂-O),

2.66–2.42 (m, 2 H, CH₂=CH-CH₂), 1.84–1.44 [m, 9 H, CH-

(CH₂)₃-CH₂, (CH₃)₂-CH-CH₂], 0.91–0.87 (m, 6 H, CH₃) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 171.86, 169.81, 133.29, 131.42,

118.80, 117.85, 96.89, 73.16, 70.85, 65.74, 61.93, 39.66, 36.83,

30.10, 25.28, 24.47, 21.36, 18.72 ppm. ESI-MS: m/z: calcd. for

C₁₉H₃₀O₆+ H⁺: 355.2121; found 355.2130.

Allyl (2S)-2-Hydroxy-4-methylpentanoate (5): Tetrabutyl ammo-

nium bromide (6.45 g, 20.0 mmol) and K₂CO₃(33.12 g, 240 mmol)

were suspended in DMF (400 mL). Then, allyl bromide (20.3 mL,

240 mmol) and 2 (26.43 g, 200 mmol) were added and the reaction

was followed by TLC. After 4 h stirring at room temperature, the

reaction mixture was concentrated to a quarter of its initial volume

and diethyl ether (620 mL), 5% aq. citric acid solution (400 mL)

and water (100 mL) were added. The aqueous phase was separated

and extracted three times with diethyl ether (3ϫ200 mL). The com-

THP-Protected Dimer 8: According to GP2, 7 (3.59 g, 10.1 mmol)

was treated with Pd(PPh₃)₄(1.155 g, 1.00 mmol) and morpholine

(916.3 mg, 10.52 mmol) at 0 °C in 40 mL of THF for 2 h. The crude

product was purified by silica gel column chromatography (diethyl

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Hydrophilic/Hydrophobic Patterned α-Hydroxy Acid Oligomers

ether/pentane, 4:1) to yield 8 (mixture of diastereoisomers; 2.04 g,

6.50 mmol, 64%) as a colorless oil. R_f= 0.78 (diethyl ether/pentane,

pTosOH in methanol (1 mgmL^–1) and the reaction mixture was

stirred at room temperature for 1.25 h. The crude product was puri-

4:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.94–5.75 (m, 1 H, fied by silica gel column chromatography (diethyl ether/pentane,

CH=CH₂), 5.19–5.08 (m, 3 H, CH=CH₂, CH-COOH), 4.75–4.58 1:4) to give 12 (405.5 mg, 0.84 mmol, 94%) as a colorless oil. R_f=

[m, 1 H, O-CH(CH₂)-O], 4.44–4.41 and 4.12–4.09 [m, 1 H, O- 0.29 (diethyl ether/pentane, 1:4). ¹H NMR (400 MHz, CDCl₃): δ =

CH(CH₂)-CO], 3.96–3.81 and 3.52–3.40 (m, 2 H, CH₂-CH₂-O),

2.66–2.50 (m, 2 H, CH-CH₂-CH), 1.86–1.49 [m, 9 H, (CH₂)₃, CH₂- CH(CH₂)-CO], 4.65–4.64 (m, 2 H, O-CH₂-CH), 4.36–4.32 (m, 1 H,

CH-(CH₃)₂]; 0.96–0.91 (m, 6 H, CH₃) ppm. ¹³C NMR (100 MHz,

OH-CH), 2.80–2.54 (m, 4 H, CH-CH₂-CH), 1.91–1.64 [m, 6 H,

CDCl₃): δ = 175.58, 171.93, 133.23, 118.07, 97.11, 73.33, 70.67, CH₂-CH-(CH₃)₂], 0.99–0.94 (m, 12 H, CH₃) ppm. ¹³C NMR

5.95–5.81 (m, 3 H, CH=CH₂), 5.37–5.13 [m, 9 H, CH=CH₂, O-

62.15, 39.51, 37.10, 30.15, 25.35, 24.59, 22.94, 21.40, 18.83 ppm.

ESI-MS: m/z: calcd. for C₁₆H₂₆O₆+ Na⁺: 337.1627; found

337.1631.

(100 MHz, CDCl₃): δ = 173.95, 169.62, 169.44, 168.66, 132.38,

131.42, 131.35, 119.15, 119.06, 118.97, 71.93, 71.72, 71.46, 69.66,

65.96, 39.59, 39.39, 38.75, 35.10, 24.54, 24.52, 22.96, 22.92, 21.47,

21.39 ppm. ESI-MS: m/z: calcd. for C₂₅H₃₈O₉+ Na⁺: 505.2414;

found 505.2428.

Allyl Ester-Protected Dimer 9: According to GP3, 7 (3.55 g,

10 mmol) was treated with 133 mL of a solution of pTosOH in

methanol (1 mgmL^–1) and the reaction mixture was stirred at room

temperature for 3 h. The crude product was purified by silica gel

column chromatography (diethyl ether/pentane, 1:4) to give 9

(1.98 g, 7.32 mmol, 73%) as a colorless oil. R_f= 0.37 (diethyl ether/

pentane, 1:4). ¹H NMR (400 MHz, CDCl₃): δ = 5.98–5.82 (m, 2

H, CH=CH₂), 5.37–5.16 [m, 5 H, CH=CH₂, O-CH(CH₂)-CO],

4.66–4.63 (m, 2 H, O-CH₂-CH), 4.35–4.32 (m, 1 H, OH-CH), 2.69–

2.53 (m, 2 H, CH-CH₂-CH), 1.86–1.69 [m, 3 H, CH₂-CH-(CH₃)₂],

0.98–0.94 (m, 6 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

173.98, 169.69, 132.36, 131.31, 119.07, 118.99, 71.74, 69.64, 65.96,

39.63, 38.72, 24.55, 22.92, 21.42 ppm. ESI-MS: m/z: calcd. for

C₁₄H₂₂O₅+ H⁺: 271.1545; found 271.1575.

Double-Protected Octamer 13: According to GP1, 11 (232.4 mg,

0.44 mmol) and 12 (205.9 mg, 0.43 mmol) were reacted in the pres-

ence of DMAP (2.9 mg, 0.024 mmol) and DCC (123 mg, 0.6 mmol)

in CH₂Cl₂(5 mL) for 2.5 h at 0 °C. Purification by silica gel column

chromatography (diethyl ether/pentane, 1:4) yielded 13 (mixture of

diastereoisomers; 345.6 mg, 0.35 mmol, 82%) as a colorless oil. R_f

1

= 0.61 (diethyl ether/pentane, 1:4). H NMR (400 MHz, CDCl₃): δ

= 5.93–5.76 (m, 5 H, CH=CH₂), 5.32–5.08 (m, 17 H, CH=CH₂,

CO-O-CH), 4.74–4.61 [m, 3 H, O-CH₂-CH, O-CH(CH₂)-O], 4.43–

4.39 and 4.12–4.09 [m, 1 H, O-CH(CH₂)-CO], 3.90–3.80 and 3.50–

3.38 (m, 2 H, CH₂-CH₂-O), 2.73–2.49 (m, 8 H, CH₂=CH-CH₂),

1.84–1.49 [m, 18 H, CH-(CH₂)₃-CH₂, (CH₃)₂-CH-CH₂], 0.95–0.90

(m, 24 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.95,

169.78, 169.59, 169.56, 169.34, 169.31, 168.67, 168.59, 133.34,

133.05, 131.45, 131.37, 131.33, 118.99, 118.95, 118.90, 118.03,

117.93, 96.97, 76.20, 73.22, 71.87, 71.74, 71.64, 71.30, 70.77, 70.53,

65.89, 61.99, 39.55, 39.42, 39.34, 39.31, 37.13, 36.87, 35.03, 34.85,

30.15, 25.39, 24.50, 24.48, 24.46, 24.43, 22.95, 22.93, 22.92, 22.88,

21.42, 21.34, 21.35, 21.28, 18.79 ppm. ESI-MS: m/z: calcd. for

C₅₂H₇₈O₁₈+ Na⁺: 1013.5086; found 1013.5056.

Double-Protected Tetramer 10: According to GP1, 8 (2.66 g,

8.45 mmol) and 9 (2.08 g, 7.68 mmol) were reacted in the presence

of DMAP (95.7 mg, 0.78 mmol) and DCC (2.23 g, 10.83 mmol) in

CH₂Cl₂(25 mL) for 2 h. Purification by silica gel column

chromatography (diethyl ether/pentane, 1:4) yielded 10 (mixture of

diastereoisomers; 3.22 g, 5.68 mmol, 74%) as a colorless oil. R_f=

0.71 (diethyl ether/pentane, 1:4). ¹H NMR (400 MHz, CDCl₃): δ =

5.94–5.75 (m, 3 H, CH=CH₂), 5.32–5.06 (m, 9 H, CH=CH₂, CO-

O-CH), 4.75–4.59 [m, 3 H, O-CH₂-CH, O-CH(CH₂)-O], 4.42–4.39

and 4.12–4.09 [m, 1 H, O-CH(CH₂)-CO], 3.90–3.80 and 3.49–3.38

(m, 2 H, CH₂-CH₂-O), 2.75–2.45 (m, 4 H, CH₂=CH-CH₂), 1.87–

1.48 [m, 12 H, CH-(CH₂)₃-CH₂, (CH₃)₂-CH-CH₂], 0.95–0.90 (m,

12 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.98, 169.79,

169.62, 168.71, 133.37, 133.07, 131.46, 118.91, 118.04, 117.94,

96.99, 73.24, 71.65, 70.80, 70.56, 65.90, 62.02, 39.59, 39.37, 37.16,

35.09, 30.10, 25.37, 24.51, 22.90, 21.46, 18.81 ppm. ESI-MS: m/z:

calcd. for C₃₀H₄₆O₁₀+ Na⁺: 589.2989; found 589.3011.

(9S,12S)-12-Hydroxy-9-isobutyl-8,11-dioxo-7,10-dioxa-3,16-dithia-

octadecane-1,18-dioic Acid (14): The synthesis of this compound

was optimized in a number of reactions, which are summarized in

Table 2. The following protocol describes the optimal conditions

(Entry 5 in Table 2). According to GP4, 7 (35.4 mg, 0.1 mmol,

0.2 mmol allyl groups) was treated with AIBN (10.8 mg,

0.066 mmol) and thioglycolic acid (138.9 µL, 2 mmol) in 4 mL of

toluene at 70 °C for 18 h. The reaction product was then evapo-

rated to dryness, dissolved in CH₂Cl₂and washed twice with a

saturated solution of NaCl. The organic phase was dried with

MgSO₄, concentrated under reduced pressure and dried under high

vacuum to give 14 (42.1 mg, 0.093 mmol, 92.7%) as a light yellow

oil. ¹H NMR (400 MHz, CDCl₃): δ = 5.10–4.97 (m, 2 H, CH-CO),

4.23–4.15 (m, 2 H, O-CH₂), 3.20 (s, 4 H, CH₂-COOH), 2.67–2.64

(m, 4 H, CH₂-S), 1.95–1.49 [m, 9 H, CH₂-CH-(CH₃)₂, O-CH₂-CH₂,

CH-(CH₂)₂], 0.91–0.79 (m, 6 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 176.19, 175.80, 174.62, 170.01, 71.97, 69.90, 63.83,

39.48, 33.37, 33.12, 33.00, 31.85, 30.48, 28.86, 25.26, 24.52, 22.86,

21.45 ppm. ESI-MS: m/z: calcd. for C₁₈H₃₀O₉S₂+ H⁺: 455.1410;

found 455.1394.

THP-Protected Tetramer 11: According to GP2, 10 (504.7 mg,

0.89 mmol) was treated with Pd(PPh₃)₄(102.8 mg, 0.09 mmol) and

morpholine (79.7 mg, 0.91 mmol) at 0 °C in 15 mL of THF for 1 h.

The crude product was purified by silica gel column chromatog-

raphy (diethyl ether/pentane, 4:1) to yield 11 (mixture of diastereo-

isomers; 311.4 mg, 0.59 mmol, 66%) as a colorless oil. R_f= 0.54

(diethyl ether/pentane, 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 5.95–

5.76 (m, 2 H, CH=CH₂), 5.19–5.09 (m, 7 H, CH=CH₂, CO-O-CH),

4.75–4.68 [m, 1 H, O-CH(CH₂)-O], 4.43–4.40 and 4.14–4.12 [m, 1

H, O-CH(CH₂)-CO], 3.86–3.84 and 3.51–3.39 (m, 2 H, CH₂-CH₂-

O), 2.73–2.52 (m, 4 H, CH-CH₂-CH), 1.82–1.52 [m, 12 H,

(CH₂)₃, CH₂-CH-(CH₃)₂], 0.96–0.91 (m, 12 H, CH₃) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 174.86, 172.08, 169.72, 168.70,

133.35, 131.33, 119.11, 118.03, 97.05, 73.30, 71.78, 71.18, 70.89,

62.08, 39.47, 39.40, 37.18, 35.06, 30.19, 25.37, 24.56, 22.90, 21.43,

18.80 ppm. ESI-MS: m/z: calcd. for C₂₇H₄₂O₁₀+ Na⁺: 549.2676;

found 549.2651.

3-[(2-Hydroxyethyl)thio]propyl (2S)-2-{[(2S)-5-[(2-Hydroxyethyl)-

thio]-2-(tetrahydro-2H-pyran-2-yloxy)pentanoyl]oxy}-4-methylpen-

tanoate (15): The synthesis of this compound was optimized in a

number of reactions, which are summarized in Table 2. The follow-

ing protocol corresponds to the optimized conditions (Entry 10 in

Table 2). According to GP4, 7 (35.2 mg, 0.1 mmol, 0.2 mmol allyl

groups) was treated with AIBN (10.8 mg, 0.066 mmol) and mercap-

toethanol (140.6 µL, 2 mmol) in 4 mL of toluene at 70 °C for 18 h.

Allyl Ester-Protected Tetramer 12: According to GP3, 10

(504.3 mg, 0.89 mmol) was treated with 9 mL of a solution of

Eur. J. Org. Chem. 2009, 5390–5405

www.eurjoc.org

5403

N. Franz, L. Menin, H.-A. Klok

FULL PAPER

The reaction product was then evaporated to dryness, dissolved in

CH₂Cl₂and washed twice with a saturated solution of NaCl. The

organic phase was dried with MgSO₄, concentrated under reduced

pressure and dried under high vacuum to give 15 (mixture of dia-

stereoisomers; 45.7 mg, 0.090 mmol, 89.5%) as a light yellow oil.

¹H NMR (400 MHz, CDCl₃): δ = 5.28–4.96 (m, 1 H, CO-O-CH),

4.65–4.55 [m, 1 H, O-CH(CH₂)-O], 4.36–4.33 and 4.06–4.01 (m, 1

H, CH-CO), 4.22–4.14 (m, 2 H, O-CH₂-CH₂), 3.83–3.74 and 3.48–

3.33 (m, 2 H, CH-O-CH₂), 3.67–3.64 (m, 4 H, CH₂-OH), 2.67–2.47

(m, 8 H, CH₂-S-CH₂), 1.96–1.47 [m, 15 H, CH₂-CH-(CH₃)₂, O-

(100 MHz, DMSO): δ = 173.72, 169.39, 168.83, 158.12, 71.82,

71.37, 70.02, 68.99, 63.70, 38.42, 38.37, 38.32, 32.78, 32.78, 30.35,

29.93, 29.44, 27.95, 27.95, 27.80, 27.74, 26.76, 24.56, 24.13, 24.01,

22.79, 22.79, 22.63, 22.63, 21.38, 21.38 ppm. ESI-MS: m/z: calcd.

for C₃₁H₅₉N₃O₉S₃+ H⁺: 714.3492; found 714.3477.

19: According to GP4, 13 (10.3 mg, 0.0104 mmol, 0.052 mmol allyl

groups) was treated with AIBN (2.82 mg, 0.017 mmol) and thiogly-

colic acid (36.13 µL, 0.52 mmol) in 2 mL of toluene at 70 °C for

18 h. The reaction product was then evaporated to dryness and

purified by RP-HPLC (t_R= 24.30 min) to give 19 (11.2 mg,

0.008 mmol, 78.8%) as a light yellow oil. ¹H NMR (400 MHz,

CDCl₃): δ = 5.19–5.01 (m, 7 H, CH-CO), 4.32–4.15 (m, 3 H, CH-

OH, O-CH₂), 3.31–3.21 (m, 10 H, CH₂-COOH), 2.73–2.64 (m, 10

H, CH₂-S), 2.09–1.71 [m, 30 H, CH₂-CH-(CH₃)₂, O-CH₂-CH₂,

CH-(CH₂)₂], 0.97–0.91 (m, 24 H, CH₃) ppm. ESI-MS: m/z: calcd.

for C₅₇H₉₀O₂₇S₅+ H⁺: 1367.4352; found 1367.4371.

CH₂-CH₂, CH-(CH₂)₂, (CH₂)₃], 0.90–0.86 (m, 6 H, CH₃) ppm. ¹³

C

NMR (100 MHz, CDCl₃): δ = 172.50, 170.29, 97.28, 72.94, 71.34,

63.68, 62.39, 60.59, 60.39, 39.54, 35.07, 34.84, 31.73, 31.49, 31.20,

30.20, 27.89, 25.31, 25.11, 24.57, 22.90, 21.53, 18.97 ppm. ESI-MS:

m/z: calcd. for C₂₃H₄₂O₈S₂+ H⁺: 511.2399; found 511.2414.

3-[(2-Aminoethyl)thio]propyl (2S)-2-({(2S)-5-[(2-Aminoethyl)thio]-2-

hydroxypentanoyl}oxy)-4-methylpentanoate (16): The synthesis of

this compound was optimized in two reactions, which are summa-

rized in Table 2. The following protocol corresponds to the opti-

mized conditions (Entry 12 in Table 2). According to GP4, 7

(35.8 mg, 0.1 mmol, 0.2 mmol allyl groups) was treated with AIBN

(10.8 mg, 0.066 mmol) and cysteamine hydrochloride (227.2 mg,

2 mmol) in 4 mL of DMF at 70 °C for 18 h. The reaction product

was then evaporated to dryness, dissolved in CH₂Cl₂and washed

twice with a saturated solution of NaCl. The organic phase was

dried with MgSO₄, concentrated under reduced pressure and dried

under high vacuum to give 16 (33.1 mg, 0.078 mmol, 78.1%) as a

light yellow oil. ¹H NMR (400 MHz, DMSO): δ = 5.16–4.91 (m, 2

H, CH-CO), 4.31–4.10 (m, 2 H, O-CH₂), 3.25–3.20 (m, 4 H, CH₂-

NH₂), 2.74–2.70 (m, 4 H, S-CH₂), 2.59–2.49 (m, 4 H, CH₂-S), 1.87–

1.40 [m, 9 H, CH₂-CH-(CH₃)₂, O-CH₂-CH₂, CH-(CH₂)₂], 0.95–

0.84 (m, 6 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO): δ =

162.32, 161.13, 72.72, 70.82, 69.78, 41.88, 40.70, 35.82, 33.98,

33.88, 30.78, 27.82, 25.43, 23.44, 22.68, 21.28 ppm. ESI-MS: m/z:

calcd. for C₁₈H₃₆N₂O₅S₂+ H⁺: 425.2144; found 425.2122.

20: According to GP4, 13 (19.8 mg, 0.02 mmol, 0.1 mmol allyl

groups) was treated with AIBN (5.42 mg, 0.033 mmol) and cyste-

amine hydrochloride (113.6 mg, 1.0 mmol) in 4 mL of DMF at

70 °C for 18 h. The reaction product was then evaporated to dry-

ness and purified by RP-HPLC (t_R= 18.80 min) to give 20

(17.3 mg, 0.013 mmol, 67.0%) as a light yellow oil. ¹H NMR

(400 MHz, DMSO): δ = 7.88 (s, 10 H, NH₂), 5.17–4.99 (m, 7 H,

CH-CO), 4.29–4.10 (m, 3 H, CH-CO, O-CH₂), 3.03–2.91 (m, 10

H, CH₂-NH₂), 2.70–2.66 (m, 10 H, S-CH₂), 2.58–2.53 (m, 10 H,

CH₂-S), 2.03–1.62 [m, 30 H, CH₂-CH-(CH₃)₂, O-CH₂-CH₂, CH-

(CH₂)₂], 0.93–0.87 (m, 24 H, CH₃) ppm. ESI-MS: m/z: calcd. for

[C₅₇H₁₀₅N₅O₁₇S₅+ 2H]²⁺: 646.8133; found 646.8143.

Supporting Information (see also the footnote on the first page of

this article): Additional NMR and mass spectra of compounds 2,

4–7, 10, 13.

Acknowledgments

This research was supported by the Swiss National Science Foun-

dation. The authors are thankful to Prof. Yury O. Tsybin for his

help and discussions regarding the mass spectrometry studies.

17: According to GP4, 10 (16.5 mg, 0.029 mmol, 0.087 mmol allyl

groups) was treated with AIBN (4.73 mg, 0.029 mmol) and thiogly-

colic acid (60.65 µL, 0.873 mmol) in 3.3 mL of toluene at 70 °C for

18 h. The reaction product was then evaporated to dryness and

purified by RP-HPLC (t_R= 24.34 min) to give 17 (21.2 mg,

0.028 mmol, 96.3%) as a light yellow oil. ¹H NMR (400 MHz,

DMSO): δ = 5.14–5.11 (m, 1 H, CH-CO), 5.05–4.99 (m, 2 H, CH-

CO), 4.20–4.09 (m, 3 H, CH-OH, O-CH₂), 3.22–3.19 (d, J =

13.74 Hz, 6 H, CH₂-COOH), 2.64–2.54 (m, 6 H, CH₂-S), 2.02–1.56

[m, 16 H, CH₂-CH-(CH₃)₂, O-CH₂-CH₂, CH-(CH₂)₂], 0.92–0.86

(m, 12 H, CH₃) ppm. ¹³C NMR (100 MHz, DMSO): δ = 173.65,

171.50, 171.47, 171.45, 169.45, 169.37, 168.81, 71.83, 71.40, 69.98,

69.01, 63.66, 33.05, 32.96, 32.92, 32.88, 32.84, 31.36, 30.97, 29.35,

27.98, 27.48, 24.12, 24.05, 24.01, 23.56, 23.56, 22.78, 22.63, 21.37,

21.35 ppm. ESI-MS: m/z: calcd. for C₃₁H₅₀O₁₅S₃+ H⁺: 759.2390;

found 759.2385.

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Received: June 16, 2009

Published Online: September 18, 2009

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5405

Article Doi

A post-modification strategy for the synthesis of uniform, hydrophilic/hydrophobic patterned a-hydroxy acid oligomers

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