Optically active N- and C-terminal building blocks for the synthesis of peptidyl olefin peptidomimetics

FULL PAPER

DOI: 10.1002/ejoc.201000539

Optically Active N- and C-Terminal Building Blocks for the Synthesis of

Peptidyl Olefin Peptidomimetics

Sima Mirilashvili,^[a]Naama Chasid-Rubinstein,^[a]and Amnon Albeck*^[a]

Keywords: Asymmetric synthesis / Enzymes / Olefination / Stereocontrol / Peptidomimetics

Peptidyl olefin peptidomimetics serve as biologically active

compounds or as intermediates for other peptidyl isosteres.

of reactions. They include an electrophilic aldehyde and nu-

cleophilic sulfone, phosphonium salt, phosphonate, and dis-

The N-terminal side of the C=C bond could be easily pre- elenide. Key enzymatic hydrolysis of prochiral diesters to the

pared in an optically pure form from α-amino acids. Synthesis

of C-terminal building blocks in an optically pure form is

more challenging. We developed a chemoenzymatic stereo-

corresponding hydroxy esters introduces optical activity. The

sequence of the subsequent chemical reactions, either pro-

tection–hydrolysis–functionalization or functionalization–hy-

selective approach to such optically active C-terminal build- drolysis–protection, determines the absolute stereochemistry

ing blocks to be assembled into peptidyl olefins by a variety

of the final building blocks.

Introduction

Peptides function in biological systems as neurotransmit-

ters, hormones, process modulators, toxins, and so on. Pep-

tides are also used as drugs for various diseases (diabetes,

growth disorders). However, their pharmaceutical use is

limited due to low bioavailability, low metabolic stability,

and conformational flexibility that enables binding to sev-

eral biological targets and, hence, side effects.^[1]The poten-

tial pharmaceutical applications of peptides on one hand,

and their limitations on the other, have led to the develop-

ment of peptidomimetic analogs. Among these, peptide

isosteres containing a replacement of a specific amide bond

in the peptide have been extensively used as protease and

other enzyme inhibitors. Of special interest among these are

peptidyl olefin isosteres, in which a specific peptide bond is

replaced by a C=C bond (Figure 1). Peptidyl olefins were

used as protease inhibitors,^[2]as biologically active com-

pounds,^[3]as mechanistic probes,^[4]or as intermediates for

the synthesis of other peptidyl isosteres such as ethylene-,

diol-, epoxide-, and hydroxyethylene-containing peptides

(Figure 1).^{[2b–2d,3h,5]}

Figure 1. Peptidyl olefins and peptidyl olefin derived peptidyl

isosteres.

mimetic (= CCH₂CO), which is not chiral, at this posi-

tion^{[2a–2d,3c,3d,4a,6]}or a substitution (= CCHRCO) in a non-

stereoselective manner to produce a diastereomeric mixture

of the peptidyl olefin product.^{[2a–2c,3c–3e,5a–5c,7]}Some meth-

ods provide optically active products after separation of ra-

cemic or diastereomeric intermediates.^[8]Only a handful of

chiral methods have been introduced, which are based on

alkylation in the presence of a chiral auxiliary,^[4b]S_N2 or-

ganocuprate addition,^{[3a,3b,3f–3h,9]}sigmatropic rearrange-

ment,^[10]ring-closing metathesis,^[11]and Julia or Wittig re-

action between chiral N-terminal nucleophile and C-ter-

minal aldehyde.^[2g,12]These methods require long pro-

cedures for the preparation of optically pure starting mate-

rials, and they provide the products in low overall yields.

Thus, efficient stereoselective synthesis of peptidyl olefins

still poses a synthetic challenge and an important target.

We recently described a new synthetic approach for op-

tically active γ-hydroxy sulfones to serve as C-terminal nu-

cleophilic building blocks for the synthesis of peptidyl ole-

It is relatively straightforward to control the stereochem-

istry of the chiral center of the P₁residue of the peptidyl

olefin (the chiral center adjacent to the olefin at its N-ter-

minal side), as it may originate directly from an optically

active α-amino acid. The situation is much different at the

other side of the double bond (the C-terminal end, or the

P₁Ј residue replacement). The vast majority of the synthetic

procedures for peptidyl olefins introduce either a glycine

[a] The Julius Spokojny Bioorganic Chemistry Laboratory,

Department of Chemistry, Bar Ilan University,

Ramat Gan 52900, Israel

Fax: +972-3-7384053

E-mail: albecka@mail.biu.ac.il

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S. Mirilashvili, N. Chasid-Rubinstein, A. Albeck

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fins.^[13]Here we extend our study and describe asymmetric e, derived from the amino acids alanine, ethylglycine, valine,

syntheses of both the N-terminal and C-terminal building leucine, and phenylalanine, were prepared in high yields

blocks for the synthesis of peptidyl olefins and other op- either by direct reduction (DIBAL) of the corresponding

tically active olefins.

methyl ester or Weinreb amide or by a reduction (LAH)–

oxidation (Swern) sequence. Condensation of nucleophiles

with such α-amino aldehydes N-protected as carbamates

(Cbz or Boc) is hampered by side reactions due to the acid-

ity of the carbamate proton. This problem could be over-

come by protection with the trityl protecting group, which

keeps the amino proton not acidic.^[14]Therefore, we demon-

strated the formation of both N-Cbz- and N-trityl-protected

α-amino aldehydes.^[14,15]

Results and Discussion

Analysis of the existing methods for the synthesis of pep-

tidyl olefins reveals that most polar reactions between a nu-

cleophile and an electrophile to directly form the new C=C

bond are not stereoselective. Most of the chiral methods,

on the other hand, are based on a key rearrangement of a

pre-existing, sterically well-defined C=C bond. We explored

the former, polar approach. We applied standard synthetic

protocols for the synthesis of both nucleophilic and electro-

philic N-terminal building blocks, utilizing optically active

α-amino acids as starting materials. We developed a chemo-

enzymatic procedure to prepare optically active C-terminal

building blocks with various electrophilic and nucleophilic

functional groups. These N-terminal and C-terminal com-

pounds could then be condensed into dipeptidyl olefins, fol-

lowed by peptide extension by standard coupling pro-

cedures on both their N-terminal and C-terminal sides ac-

cording to the desired amino acid sequence. The retrosyn-

thetic analysis of this approach is described in Scheme 1.

Scheme 2. The synthesis of N-terminal electrophilic and nucleo-

philic building blocks.

β-Amino sulfones 5 and β-amino phosphonium salts 7

were synthesized as nucleophilic N-terminal building blocks

(Scheme 2). They can interact with C-terminal aldehyde

building blocks through the Julia and Wittig reactions,

respectively.

Sulfone N-terminal building blocks 5a–e, derived from

the α-amino acids alanine, ethylglycine, valine, leucine, and

phenylalanine, were prepared according to a published pro-

cedure.^[12d]They carry either Cbz- or Boc-protecting groups

and either thiophenol, for the classical Julia reagent or 1-

phenyl-1H-tetrazole-5-thiol for the Julia–Kocienski rea-

gent.^[16]

Scheme 1. Retrosynthetic analysis for peptidyl olefin peptidomi-

metics.

Phosphonium salt building blocks 7a–e were prepared by

bromination of α-amino alcohols 1a–e,^[17]followed by sub-

stitution of the bromide by triphenylphosphane. The mod-

est yields of the latter reactions are due to a competing

The N-Terminal Building Blocks

The synthesis of the various N-terminal (P₁) building intramolecular reaction that yields, in addition to the de-

blocks starts from optically active α-amino acids or their sired phosphonium salt product 7, also a cyclic carbamate

derivatives (Scheme 2). N-Protected α-amino aldehydes 2a– and benzyl bromide. This problem could be overcome by

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Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

replacing the N-protecting group with trifluoroacetyl.^[4a,12a]acylase in organic solvents. The hydroxy ester product of

The carbonyl oxygen of this amide is much less electron the enzymatic reaction would then be further manipulated

rich because of the electron-withdrawing character of the chemically towards the desired C-terminal building blocks.

trifluoromethyl substituent, and therefore, it is not nucleo-

Synthesis of the Enzyme Substrates

philic enough to compete with the intermolecular nucleo-

This protocol was applied to five different diethyl malon-

philic reactions.

ate compounds substituted with methyl, isopropyl, isobutyl,

benzyl, and ethyl groups. When incorporated into peptidyl

olefins, these building blocks would mimic the natural

amino acids alanine, valine, leucine, and phenylalanine, and

the unnatural amino acid ethylglycine, respectively

(Scheme 3).^[13]Racemic monoacetates were synthesized

separately by partial chemical acetylation of the corre-

sponding diols. These compounds were used as references

for chiral HPLC analysis of the enzymatic reaction.

The C-Terminal Building Blocks

The synthesis of the C-terminal building blocks (both

nucleophilic and electrophilic, Scheme 1) is based on a

chemoenzymatic protocol that provides a common optically

active intermediate, which could then be further chemically

manipulated to the various desired compounds.

The key step that provides optical activity in the product

is a stereoselective hydrolysis of a prochiral diester, cata-

lyzed by the enzyme lipase. This enzyme can either hy-

drolyze a prochiral diester to an optically active hydroxy

ester in aqueous medium or acylate the corresponding diol

to the enantiomeric hydroxy ester in organic solvents

(Scheme 3).^[18]This approach presents a few advantages:

(i) Facile entry to almost any possible substitution by alk-

ylation of diethyl malonate, followed by reduction to the

corresponding diol 8 and subsequent diacetylation to 9

(Scheme 3). (ii) Full conversion to the desired optically

active product, which stems from the reaction of the en-

zyme on a homogeneous prochiral compound rather than

enzymatic resolution of a racemic mixture. (iii) Control of

the stereoselectivity by the mode of the application of the

enzyme – either as a hydrolase in aqueous solution or as an

The Enzymatic Reaction

We then proceeded to the enzymatic reaction. As dis-

cussed above, lipase can act both as a hydrolase in aqueous

medium and as an acylase in organic solvents. We studied

both directions. Lipases from nine different sources were

studied for the acetylation of the five diols 8a–e: from wheat

germ, porcine pancreas, candida rugosa, candida cylindra-

cea, candida lipolytica, rhizopus niveus, rhizopus arrhizus,

pseudomonas cepacia, and mucor javanicus. We examined

acetylation by vinyl acetate in chloroform^[19]and by acetic

anhydride in ether.^[20]The best enzyme in our hands was

the lipase from pseudomonas sepacia, which converted the

substrate 2-benzyl-1,3-propanediol (8e) into monoacetate

product (R)-10e in only 40–60%ee. The other substrates

were turned over more slowly and with poorer enantio-

selectivity.

For the opposite enzymatic reaction, the hydrolysis of

diacetyl substrates 9a–e by the pseudomonas cepacia lipase

under various aqueous conditions was evaluated. The best

results in terms of conversion and enantioselectivity were

obtained with 40 m NaCl, 5 m CaCl₂, and 0.07% BSA,

with 12.5–40 mg of the enzyme and 100–1000 mg of the

substrate. Chiral HPLC analysis identified a single isomer

of the products at 50% conversion. The absolute S configu-

ration of the products was assigned by comparison to litera-

ture data.^[18b,21]When carried out further, the hydrolysis of

benzyl derivative 9e at 65% conversion yielded 94%ee of

desired monoester product 10e, and hydrolysis of ethyl de-

rivative 9b at 90% conversion provided product 10b in

72%ee.

Some racemization was observed upon standing of hy-

droxy ester derivatives 10 in the NMR test tube. This could

be explained in terms of migration of the acetyl group be-

tween the two prochiral hydroxy groups, through a six-

membered ring transition state (Figure 2). This reaction

was catalyzed by the very mildly acidic CDCl₃solvent.

Scheme 3. Lipase hydrolysis of prochiral diacetates and lipase

acetylation of the corresponding prochiral diols produce enantio-

meric hydroxy esters.

Figure 2. The hydroxy ester racemization mechanism.

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Scheme 4. Stereoselective synthesis of C-terminal electrophilic and nucleophilic building blocks of R absolute configuration.

Further Chemical Manipulations to the C-Terminal

Building Blocks

the base afforded the corresponding hydroxy sulfide 13Ј.

Oxidation of sulfides 13 by m-CPBA afforded target

sulfones 14.

Optically active (S configuration) hydroxy ester 10 was

further chemically modified into one electrophilic and three

nucleophilic C-terminal building blocks (Scheme 4). Paral-

lel synthesis with racemic 10 was also carried out to have

the necessary standards for chiral HPLC analysis of the ste-

reochemistry of the products. We applied the following pro-

tocols to two hydroxy esters 10: benzyl derivative 10e, repre-

senting the natural amino acid phenylalanine with a large

hydrophobic aromatic side chain, and ethyl derivative 10b,

representing the unnatural amino acid ethylglycine with a

small aliphatic side chain.

The first C-terminal building block to be synthesized was

electrophilic aldehyde 11. An attempt to apply Swern oxi-

dation to 10e (the butyryl ester derivative) afforded the eli-

mination product 2-benzyl acrolein. Milder Dess–Martin

oxidation afforded desired butyryl ester aldehyde 11e in

good yield and optical purity (95%ee).

Three nucleophilic C-terminal building blocks were syn-

thesized, bearing a sulfone (14), a phosphonium salt (16),

or a phosphonate (17) as an electron-withdrawing group.

These could then be interacted with an N-terminal α-amino

aldehyde by the Julia, Wittig, or Emmons–Horner reaction,

respectively, to form a precursor of a dipeptidyl olefin.

Sulfone building blocks 14b and 14e were prepared by

a short and efficient sequence of chemical transformations

(Scheme 4).^[5e,13]It involved mesylation of hydroxy esters 10

to yield mesylates 12, substitution with an aromatic thiol

to sulfides 13, and m-CPBA oxidation of the latter to the

corresponding sulfones 14. The S_N2 reaction of mesylate

12 with aromatic thiols (either thiophenol or 1-phenyl-1H-

tetrazole-5-thiol), activated by NaH yielded either ester

sulfide 13 (X = Ac) or the corresponding hydroxy sulfide (X

= H). The product identity was controlled by the amount of

the added base: one equivalent of NaH (relative to the

thiol) afforded ester sulfide 13, whereas two equivalents of

Scheme 5. Stereoselection of final C-terminal building blocks by

the sequence of chemical reactions from a common optically active

intermediate.

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Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

In addition to their application in peptidyl olefin synthe- rity (in comparison with the corresponding racemic mix-

sis,^[13]optically active β-alkyl-γ-hydroxy sulfones are useful tures). The results demonstrated at least 90% retention of

Julia reagents for the synthesis of various natural products steric integrity in all of the synthetic transformations.

and their analogs.^[22]

The enzymatic hydrolytic reaction determined the abso-

Phosphonium salt (Wittig reagent) C-terminal building lute stereochemistry of its hydroxy ester product 10. Enzy-

blocks could also be prepared from mesylates 12 matic acetylation in organic medium would yield the enan-

(Scheme 4).^[18c]Attempts to transform the mesylates di- tiomeric hydroxy ester, but the latter did not proceed in sat-

rectly into phosphonium salts 16 failed. Therefore, they isfactory enantioselectivity. Alternatively, the order of fur-

were first transformed into bromides 15. The acetoxy group ther chemical manipulations could provide a second oppor-

of bromides 15 was reduced by DIBAL-H to hydroxy tunity to control the stereochemistry of the final C-terminal

bromides 15Ј, followed by displacement of the bromide by building blocks. Thus, as shown in Scheme 4, transforma-

triphenylphosphane to afford the desired Wittig reagent tion of the original free hydroxy group into the desired elec-

building blocks 16Ј. Such phosphonium salts were pre- trophilic and nucleophilic functional groups yielded the R

viously used in the synthesis of natural products.^[18c,22l,23]enantiomer of the aldehyde, sulfone, phosphonium salt, and

Bromide 15e also underwent Arbuzov reaction with triethyl phosphonate building blocks. On the other hand, protec-

phosphite to yield the corresponding phosphonate 17e.

tion (silylation) of the free hydroxy group of 10, followed

All of the benzyl derivatives along the various synthetic by acetyl hydrolysis and transformation of the new free hy-

routes were analyzed by chiral HPLC for their optical pu- droxy group into the desired electrophilic and nucleophilic

Scheme 6. Stereoselective synthesis of the two enantiomers of the C-terminal building blocks. Aldehyde (R)-11e was prepared from the

corresponding butyryl ester.

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functional groups would provide the S enantiomer of the the same Julia–Kocienski reaction was carried out in a more

final products (Scheme 5). This was demonstrated in the polar solvent, namely, 10% HMPA in THF, only the trans

stereoselective preparation of the S enantiomer of one elec- isomer of olefin 24e was obtained as a pure single dia-

trophilic (aldehyde) and two nucleophilic (sulfone and di- stereomer, though at a lower 31% yield.^[18c]Similarly, the

selenide) C-terminal building blocks of both the benzyl and pure trans isomer (2S,5S)-1-(tert-butyldimethylsilyloxy)-2-

the ethyl derivatives.

ethyl-5-tritylamino-hex-3-ene (24b) was obtained in 22%

We demonstrated above the direct oxidation of hydroxy yield from R sulfone 23b₁and N-tritylalaninal. Further

ester 10e to the corresponding R ester aldehyde 11e. Alter- studies for the optimization of this reaction are currently in

natively, hydroxy esters 10b and 10e were silylated (18), fol- progress.

lowed by ester hydrolysis under mild basic conditions (18Ј),

and oxidation of the newly exposed alcohols under either

Swern or Dess–Martin conditions provided the correspond-

ing S aldehydes 19 (Scheme 6). Thus, aldehydes of both R

and S configuration were prepared in high optical purity

from the same enzymatic product 10.

Aldehyde (S)-19e was further transformed into new

nucleophilic C-terminal building block diselenide 20e

(Scheme 6).^[24]This transformation demonstrates the sim-

plicity of the approach in controlling the absolute configu-

ration of a C-terminal nucleophilic building block by the

order of the chemical transformations from single isomer

starting material 10.

We further applied the control of product stereochemis-

try by modification of the sequence of chemical reactions

from optically active hydroxy ester 10, either functionaliza-

tion–hydrolysis–protection or protection–hydrolysis–func-

Scheme 7. The Julia–Kocienski reaction of C-terminal (P₁Ј) sulfone

building blocks towards dipeptidyl olefins.

tionalization (Scheme 5), to the synthesis of the two stereo-

isomers of sulfone C-terminal building blocks (Scheme 6).

We described above the synthesis of the R enantiomer of

sulfone compounds 14 on the basis of the functionalization-

first sequence (Scheme 6, left branch). Sulfone 14Јe was also

silylated to give the R enantiomer of protected sulfone 23e.

Alternatively, benzyl hydroxy ester 10e was silylated on the

free hydroxy group in quantitative yield, providing orthogo-

nally doubly protected diol 18e. Selective hydrolysis to acet-

Conclusions

In this study we developed a new efficient approach for

ate 18Јe, followed by the short set of functionalization reac- the preparation of optically active nucleophilic and electro-

tions used above (mesylation to 21e, formation of sulfide philic C-terminal (P₁Ј) building blocks for the synthesis of

22e₁, and oxidation) afforded the S enantiomer of sulfone peptidyl olefin peptidomimetics. The nucleophilic func-

23e₁(subscript “1” denotes the 1-phenyl-1H-tetrazol-5-yl tional groups include sulfones, phosphonium salts, phos-

derivatives).

phonates, and diselenides. Aldehydes serve as the electro-

philic group. This approach is based on a key enzymatic

reaction: stereoselective hydrolysis of prochiral diesters to

optically active hydroxy esters. The role of the enzymatic

reaction is only to provide high optical purity, rather than

Peptidyl Olefins

To demonstrate the utility of the C-terminal building to define the stereochemistry of the final C-terminal build-

blocks, we used two such units, with different side chains ing block products. The absolute configuration is eventually

(ethyl and benzyl) and two opposite stereoisomers (R and determined by the sequence of the subsequent chemical re-

S, respectively) for the synthesis of peptidyl olefin precur- actions towards the final building block: either protection–

sors. We treated the lithium salt of S sulfone 23e₁with N- hydrolysis–functionalization (yielding the S configuration)

tritylalaninal^[14]in THF (Julia–Kocienski reaction, or functionalization–hydrolysis–protection (yielding the R

Scheme 7).^[25]The desired product (2R,5S)-2-benzyl-1-(tert- configuration). A set of electrophilic (aldehyde) and nucleo-

butyldimethylsilyloxy)-5-tritylamino-hex-3-ene (24e), the philic (sulfone, phosphonium salts, and phosphonate) N-

olefin isoster of N-trityl-alanylphenylalaninol, was obtained terminal building blocks complements the C-terminal

as a 1:1 mixture of E/Z isomers (which were separated by building blocks for the synthesis of peptidyl olefins peptido-

chromatography) in 68% yield. No racemization at the chi- mimetics. We demonstrated formation of two precursors of

ral centers was detected. The product could then be trans- dipeptidyl olefin isosteres in pure enantiomeric form by the

formed into the dipeptidyl olefin by alcohol deprotection Julia–Kocienski reaction between optically active C-ter-

and oxidation, as previously demonstrated.^[3f,5c,7b]When minal sulfones and an N-terminal α-amino aldehyde.

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Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

8.3, 4.2 Hz, 1 H), 1.73 (non., J = 6.3 Hz, 1 H), 1.63 (ddd, J = 14.1,

8.7, 5.1 Hz, 1 H), 1.38 (ddd, J = 14.1, 9.3, 5.1 Hz, 1 H), 0.95 (d, J

= 6.3 Hz, 3 H), 0.93 (d, J = 6.3 Hz, 3 H) ppm. ¹³C NMR: δ =

200.1, 156.3, 136.2, 128.5, 128.2, 128.0, 67.0, 58.8, 37.8, 24.5, 23.0,

21.8 ppm. MS: m/z (%) = 250 (4) [M + H]⁺, 220 (13), 176 (14), 91

(100). HRMS: calcd. for C₁₄H₂₀NO₃[M + H]⁺250.1443; found

250.1437.

Experimental Section

General: Anhydrous solvents were dried and freshly distilled (THF,

DME, ether, and toluene from sodium/benzophenone, DMF from

molecular sieves, and CH₂Cl₂from CaCl₂). Chromatography refers

to flash column chromatography carried out on silica gel 60 (230–

400 mesh ASTM, E. Merck) by using analytical-grade solvents.

TLC was performed on E. Merck 0.2 mm percolated silica gel F-

254 plates. Compounds were detected by UV light (254 nm) and/

or by staining with vanillin, Cl₂/KI-tolidine,^[26]or phosphomolyb-

dic acid. ¹H and ¹³C NMR spectra were recorded at 600 or

300 MHz and 150 or 75 MHz, respectively, in CDCl₃, unless other-

wise indicated. Chemical shifts are reported in ppm relative to TMS

in CDCl₃or relative to solvent resonance in other solvents. Most

¹H NMR assignments were supported by 2D homonuclear COSY

experiments. ¹³C NMR assignments were supported by DEPT or

2D heteronuclear COSY (HMQC) and heteronuclear multiple

bond connectivity (HMBC) experiments. Mass spectra were re-

corded in DCI mode with methane as the reagent gas. HPLC was

carried out on CHIRALCEL_ROD-H 250ϫ10 mm or CHIRA

1

Cbz-Phenylalaninal (2e): Yield: 1.09 g, 80%. H NMR: δ = 9.57 (s,

1 H), 7.37–7.09 (m, 10 H), 5.40 (d, J = 6.6 Hz, 1 H), 5.07 (s, 2 H),

4.46 (q, J = 6.7 Hz, 1 H), 3.12 (dd, J = 13.8, 6.8 Hz, 1 H), 3.05

(dd, J = 13.8, 6.8 Hz, 1 H) ppm. ¹³C NMR: δ = 199.0, 156.0, 136.2,

135.5, 129.3, 128.8, 128.6, 128.3, 128.2, 127.2, 67.1, 61.1, 35.3 ppm.

MS: m/z (%) = 284 (4) [M + H]⁺, 254 (13), 210 (15), 91 (100).

HRMS: calcd. for C₁₇H₁₈NO₃[M + H]⁺284.1287; found 284.1276.

The syntheses of trityl-alaninal (2Јa), trityl-leucinal (2Јd), and tri-

tyl-phenylalaninal (2Јe) were described previously.^[14]

Methanesulfonates 3: Prepared from the corresponding alcohols 1

according to a published procedure.^[12d]

Cbz-Alaninol Methanesulfonate (3a): Yield: 93%. ¹H NMR: δ =

7.34–7.33 (m, 5 H), 5.09 (obscured, 1 H), 5.09 (s, 2 H), 4.22 (dd, J

= 10.1, 4.5 Hz, 1 H), 4.13 (dd, J = 9.9, 4.5 Hz, 1 H), 4.02 (m, 1 H),

2.94 (s, 3 H), 1.22 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR: δ = 155.7,

136.3, 128.6, 128.3, 128.2, 71.8, 66.9, 46.1, 37.2, 10.1 ppm. MS: m/z

(%) = 287 [M]⁺, 178 (7), 108 (30), 91 (100). HRMS: calcd. for

C₁₂H₁₈NO₅S [M + H]⁺288.0906; found 288.0905.

GROM 250x2 mm chiral columns, at flow rates of

1 and

0.3 mLmin^–1, respectively.

Synthesis of N-Terminal Building Blocks

Cbz-α-Amino Aldehydes (2): A solution of DMSO (0.83 mL,

11.7 mmol) in dry CH₂Cl₂(3 mL) was added to a stirred solution

of oxalyl chloride (0.46 mL, 5.26 mmol) in dry CH₂Cl₂(13 mL),

under an argon atmosphere at –60 °C. After 10 min, a solution of

Cbz-amino alcohol (4.8 mmol) in dry CH₂Cl₂(7 mL) was added,

and the reaction mixture was stirred for 15 min at –60 °C. Et₃N

(3.3 mL, 23.9 mmol) was added, and the cooling bath was removed,

allowing the solution to reach room temperature. The mixture was

stirred for an additional 20 min. Water was added, and the aqueous

phase was re-extracted with CH₂Cl₂(2ϫ20 mL). The combined

organic layer was washed successively with water, 0.5  HCl solu-

tion (2ϫ), water, and saturated NaCl solution. The organic layer

was dried with MgSO₄, filtered, and concentrated. Purification by

chromatography (hexane/EtOAc, 3:1) afforded the clean aldehyde

as a yellow oil.

Cbz-Ethylglycinol Methanesulfonate (3b): Yield: 100%. ¹H NMR:

δ = 7.33–7.27 (m, 5 H), 5.30 (d, J = 8.4 Hz, 1 H), 5.10 (d, J =

11.4 Hz, 1 H), 5.06 (d, J = 11.4 Hz, 1 H), 4.21 (dd, J = 10.2, 4.2 Hz,

1 H), 4.15 (dd, J = 10.2, 4.5 Hz, 1 H), 3.79 (tdt, J = 8.4, 6.3, 4.4 Hz,

1 H), 2.90 (s, 3 H), 1.57 (dqd, J = 13.5, 7.3, 6.3 Hz, 1 H), 1.51

(ddq, J = 13.5, 8.4, 7.3 Hz, 1 H), 0.94 (t, J = 7.3 Hz, 3 H) ppm.

¹³C NMR: δ = 156.0, 136.3, 128.4, 128.1, 127.9, 70.6, 66.6, 51.6,

37.0, 24.0, 10.2 ppm. MS: m/z (%) = 302 (93) [M + H]⁺, 258 (60),

206 (65), 192 (99), 108 (80), 92 (97), 79 (32). HRMS: calcd. for

C₁₃H₂₀NO₅S [M + H]⁺302.1062; found 302.1065.

1

Cbz-Valinol Methanesulfonate (3c): H NMR: δ = 7.35–7.30 (m, 5

Cbz-Alaninal (2a): Yield: 670 mg, 67%. ¹H NMR: δ = 9.48 (s, 1

H), 7.34–7.25 (m, 5 H), 5.70 (br. d, 1 H), 5.09 (s, 2 H), 4.23 (quint.,

J = 7.2 Hz, 1 H), 1.29 (d, J = 7.5 Hz, 3 H) ppm. ¹³C NMR: δ =

199.5, 156.0, 136.1, 128.5, 128.2, 128.1, 67.0, 55.8, 14.5 ppm. MS:

m/z (%) = 208 (12) [M + H]⁺, 178 (18), 91 (100). HRMS: calcd.

for C₁₁H₁₄NO₃[M + H]⁺208.0974; found 208.0989.

H), 5.12 (obscured, 1 H), 5.12 (d, J = 12.3 Hz, 1 H), 5.08 (d, J =

12.3 Hz, 1 H), 4.25 (d, J = 4.5 Hz, 2 H), 3.70 (ddt, J = 9.3, 6.9,

4.5 Hz, 1 H), 2.93 (s, 3 H), 1.87 (oct., J = 6.8 Hz, 1 H), 0.97 (d, J

= 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR: δ =

156.2, 136.4, 128.6, 128.2, 128.1, 69.5, 66.9, 55.6, 37.2, 29.1, 19.3,

18.5 ppm. MS: m/z (%) = 316 (9) [M + H]⁺, 206 (31), 181 (12), 108

(58), 91 (100). HRMS: calcd. for C₁₄H₂₂NO₅S [M + H]⁺316.1219;

found 316.1208.

1

Cbz-Ethylglycinal (2b): Yield: 1.01 g, 95%. H NMR: δ = 9.56 (s,

1 H), 7.37–7.31 (m, 5 H), 5.44 (br. d, 1 H), 5.12 (s, 1 H), 4.28 (q,

J = 6.6 Hz, 1 H), 1.97 (dqd, J = 14.4, 7.5, 5.7 Hz, 1 H), 1.69

(dquint., J = 14.4, 7.2, Hz, 1 H), 0.95 (t, J = 7.5, Hz, 3 H) ppm.

¹³C NMR: δ = 199.4, 156.2, 136.3, 128.7, 128.3, 128.2, 67.2, 61.3,

22.4, 9.4 ppm. MS: m/z (%) = 222 (4) [M + H]⁺, 192 (27), 148 (20),

91 (100). HRMS: calcd. for C₁₂H₁₆NO₃[M + H]⁺222.1130; found

222.1108.

1

Cbz-Leucinol Methanesulfonate (3d): H NMR: δ = 7.38–7.27 (m,

5 H), 5.01 (d, J = 12.2 Hz, 1 H), 4.97 (d, J = 12.2 Hz, 1 H), 4.94

(d, J = 8.4 Hz, 1 H), 4.15 (dd, J = 10.2, 3.9 Hz, 1 H), 4.03 (dd, J

= 10.2, 4.5 Hz, 1 H), 3.88 (tq, J = 9.2, 4.6 Hz, 1 H), 2.93 (s, 3 H),

1.57 (doct., J = 8.7, 6.5 Hz, 1 H), 1.35 (ddd, J = 14.1, 9.6, 5.7 Hz,

1 H), 1.23 (ddd, J = 14.1, 8.7, 5.4 Hz, 1 H), 0.93 (d, J = 6.6 Hz, 6

H) ppm. ¹³C NMR: δ = 155.9, 136.4, 128.6, 128.2, 128.1, 71.4, 66.9,

48.5, 39.9, 37.2, 24.6, 23.0, 21.9 ppm. MS: m/z (%) = 329 (9) [M]⁺,

220 (12), 176 (22), 108 (17), 91 (100). HRMS: calcd. for

C₁₅H₂₃NO₅S [M]⁺329.1297; found 329.1293.

1

Cbz-Valinal (2c): Yield: 1.09 g, 96%. H NMR: δ = 9.38 (s, 1 H),

7.18–7.09 (m, 5 H), 5.78 (d, J = 8.1 Hz, 1 H), 4.94 (s, 2 H), 4.10

(dd, J = 8.1, 4.5 Hz, 1 H), 2.07 (dsept., J = 6.9, 4.5 Hz, 1 H), 0.84

(d, J = 6.9 Hz, 3 H), 0.74 (dd, J = 6.9, 0.6 Hz, 3 H) ppm. ¹³C

NMR: δ = 200.0, 156.3, 136.1, 128.2, 127.8, 127.7, 66.6, 64.8, 28.5,

18.7, 17.2 ppm. MS: m/z (%) = 236 (10) [M + H]⁺, 206 (21), 162

(32), 91 (100). HRMS: calcd. for C₁₃H₁₈NO₃[M + H]⁺236.1287;

found 236.1256.

Cbz-Phenylalaninol Methanesulfonate (3e): ¹H NMR: δ = 7.32–7.20

(m, 10 H), 5.25 (d, J = 8.1 Hz, 1 H), 5.05 (s, 2 H), 4.22 (dd, J =

9.3, 3.3 Hz, 1 H), 4.15 (qt, J = 7.5, 3.7 Hz, 1 H), 4.09 (dd, J = 9.3,

3.9 Hz, 1 H), 2.90 (s, 3 H), 2.89 (dd, J = 13.8, 7.2 Hz, 1 H), 2.84

(dd, J = 13.8, 7.2 Hz, 1 H) ppm. ¹³C NMR: δ = 155.8, 136.5, 136.3,

129.2, 128.8, 128.6, 128.2, 128.1, 127.0, 69.7, 66.8, 51.4, 37.1,

Cbz-Leucinal (2d): Yield: 1.17 g, 97%. ¹H NMR: δ = 9.52 (s, 1 H),

7.36–7.25 (m, 5 H), 5.53 (br. d, 1 H), 5.09 (s, 2 H), 4.27 (td, J =

Eur. J. Org. Chem. 2010, 4671–4686

www.eurjoc.org

4677

S. Mirilashvili, N. Chasid-Rubinstein, A. Albeck

FULL PAPER

37.0 ppm. MS: m/z (%) = 364 (1) [M + H]⁺, 272 (17), 228 (17), 176

Sulfones 5: Prepared from the corresponding sulfides 4 according

(7), 132 (6), 91 (100). HRMS: calcd. for C₁₈H₂₂NO₅S [M + H]⁺to a published procedure.^[12d]

364.1219; found 364.1203.

(N-Cbz-2-amino)propyl Phenyl Sulfone (5a): Yield: 84% (overall

from 1a). ¹H NMR: δ = 7.86 (d, J = 7.8 Hz, 2 H), 7.55 (tt, J = 7.5,

1.4 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.31–7.25 (m, 5 H), 5.61 (d,

J = 7.2 Hz, 1 H), 4.97 (s, 2 H), 4.09 (dqdd, J = 7.2, 6.9, 6.6, 4.8 Hz,

1 H), 3.47 (dd, J = 13.8, 6.6 Hz, 1 H), 3.15 (dd, J = 14.1, 4.8 Hz,

1 H), 1.27 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR: δ = 155.1, 139.4,

136.2, 133.6, 129.1, 128.3, 127.9, 127.8, 127.7, 66.3, 60.2, 43.2,

20.5 ppm. MS: m/z (%) = 334 (64) [M + H]⁺, 290 (93), 226 (12),

108 (34), 91 (100). HRMS: calcd. for C₁₇H₂₀NO₄S [M + H]⁺

334.1113; found 334.1110.

Sulfides 4: Prepared from the corresponding methanesulfonates 3

according to a published procedure.^[12d]

(N-Cbz-2-amino)propyl Phenyl Sulfide (4a): ¹H NMR: δ = 7.35–

7.11 (m, 10 H), 5.07 (d, J = 12.3 Hz, 1 H), 5.03 (d, J = 12.3 Hz, 1

H), 5.03 (obscured, 1 H), 3.94 (m, 1 H), 3.12 (dd, J = 13.5, 5.1 Hz,

1 H), 2.93 (dd, J = 13.5, 6.0 Hz, 1 H), 1.20 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR: δ = 155.6, 136.5, 136.0, 129.4, 129.0, 128.5,

128.1, 128.1, 126.2, 66.6, 46.7, 40.1, 19.8 ppm. MS: m/z (%) = 301

(100) [M]⁺, 192 (15), 178 (7), 150 (20), 124 (23), 91 (60). HRMS:

calcd. for C₁₇H₁₉NO₂S [M]⁺301.1137; found 301.1095.

(N-Cbz-2-amino)butyl Phenyl Sulfone (5b): Yield: 77% (overall

from 1b). ¹H NMR: δ = 7.88 (d, J = 7.5 Hz, 2 H), 7.59 (tt, J = 7.4,

1.2 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.37–7.26 (m, 5 H), 5.30 (d,

J = 8.1 Hz, 1 H), 5.01 (d, J = 12.6 Hz, 1 H), 4.98 (d, J = 12.6 Hz,

1 H), 3.92 (dquint., J = 7.5, 4.8 Hz, 1 H), 3.47 (dd, J = 14.4, 7.5 Hz,

1 H), 3.23 (dd, J = 14.4, 4.2 Hz, 1 H), 1.71 (dqd, J = 13.5, 7.5,

6.0 Hz, 1 H), 1.66 (dquint., J = 13.5, 7.5 Hz, 1 H), 0.88 (t, J =

7.5 Hz, 3 H) ppm. ¹³C NMR: δ = 155.6, 139.7, 136.4, 133.8, 129.3,

128.5, 128.1, 128.0, 127.9, 66.6, 59.0, 49.1, 27.4, 10.2 ppm. MS: m/z

(%) = 348 (36) [M + H]⁺, 304 (21), 240 (13), 108 (100), 91 (64).

HRMS: calcd. for C₁₈H₂₂NO₄S [M + H]⁺348.1270; found

348.1262.

(N-Cbz-2-amino)butyl Phenyl Sulfide (4b): ¹H NMR: δ = 7.35–7.13

(m, 10 H), 5.07 (d, J = 12.6 Hz, 1 H), 5.03 (d, J = 12.6 Hz, 1 H),

4.99 (d, J = 9.6 Hz, 1 H), 3.78 (ddq, J = 9.6, 7.5, 5.6 Hz, 1 H), 3.09

(dd, J = 13.5, 5.7 Hz, 1 H), 3.01 (dd, J = 13.5, 5.7 Hz, 1 H), 1.66

(dqd, J = 14.1, 7.5, 5.4 Hz, 1 H), 1.46 (dquint., J = 14.1, 7.5 Hz, 1

H), 0.88 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR: δ = 156.0, 136.5,

136.3, 129.4, 129.0, 128.5, 128.0, 128.0, 126.2, 66.6, 52.3, 38.6, 26.6,

10.3 ppm. MS: m/z (%) = 315 (26) [M]⁺, 192 (25), 164 (23), 124

(32), 91 (100). HRMS: calcd. for C₁₈H₂₁NO₂S [M]⁺315.1293;

found 315.1311.

1

(N-Cbz-2-amino)-3-methylbutyl Phenyl Sulfide (4c): H NMR: δ =

(N-Cbz-2-amino)butyl (1-phenyl-1H-tetrazole-5-yl) Sulfone (5b₁):

Yield: 53% (overall from 1b). ¹H NMR: δ = 7.66–7.52 (m, 5 H),

7.36–7.26 (m, 5 H), 5.14 (br. s, 1 H), 4.99 (s, 2 H), 4.18 (m, 1 H),

4.02 (dd, J = 15.0, 7.8 Hz, 1 H), 3.88 (dd, J = 15.0, 4.2 Hz, 1 H),

1.74 (quint., J = 6.5 Hz, 2 H), 0.96 (t, J = 7.4 Hz, 3 H) ppm. ¹³C

NMR: δ = 155.6, 153.9, 136.2, 133.1, 131.6, 129.7, 128.6, 128.3,

128.1, 125.5, 67.0, 59.4, 48.7, 27.7, 10.3 ppm. MS: m/z (%) = 416

(5) [M + H]⁺, 308 (11), 147 (14), 108 (14), 91 (100). HRMS: calcd.

for C₁₉H₂₂N₅O₄S [M + H]⁺416.1393; found 416.1348.

7.35–7.10 (m, 10 H), 5.06 (s, 2 H), 5.01 (d, J = 9.3 Hz, 1 H), 3.72

(dq, J = 9.0, 6.2 Hz, 1 H), 3.02 (d, J = 6.0 Hz, 2 H), 1.90 (oct., J

= 6.8 Hz, 1 H), 0.89 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR: δ = 156.2, 136.6, 136.2, 129.6, 128.9, 128.4,

126.0, 126.2, 66.6, 55.8, 37.2, 30.8, 19.4, 17.7 ppm. MS: m/z (%) =

329 (41) [M]⁺, 220 (9), 206 (43), 178 (21), 123 (28), 91 (50). HRMS:

calcd. for C₁₉H₂₃NO₂S [M]⁺329.1450; found 329.1446.

(N-Cbz-2-amino)-4-methylpentyl Phenyl Sulfide (4d): ¹H NMR: δ =

7.38–7.14 (m, 10 H), 5.05 (s, 2 H), 4.89 (d, J = 7.8 Hz, 1 H), 3.95

(tq, J = 8.0, 5.4 Hz, 1 H), 3.10 (dd, J = 13.4, 5.1 Hz, 1 H), 3.04

(dd, J = 13.4, 5.7 Hz, 1 H), 1.61 (non., J = 6.6 Hz, 1 H), 1.44 (ddd,

J = 13.7, 8.1, 5.1 Hz, 1 H), 1.37 (ddd, J = 13.7, 8.7, 6.0 Hz, 1 H),

0.87 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR:

δ = 155.8, 136.5, 136.4, 129.6, 129.0, 128.5, 128.1, 128.1, 126.2,

66.7, 49.1, 42.9, 39.6, 24.9, 23.1, 22.1 ppm. MS: m/z (%) = 344 (36)

[M + H]⁺, 343 (51) [M]⁺, 234 (21), 220 (44), 192 (15), 176 (71), 124

(29), 91 (100). HRMS: calcd. for C₂₀H₂₆NO₂S [M + H]⁺344.1684;

found 344.1699.

(N-Cbz-2-amino)-3-methylbutyl Phenyl Sulfone (5c): Yield: 43%

(overall from 1c). ¹H NMR: δ = 7.89 (d, J = 7.5 Hz, 2 H), 7.59 (tt,

J = 7.5, 1.2 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.39–7.28 (m, 5 H),

5.14 (d, J = 8.7 Hz, 1 H), 5.03 (d, J = 12.5 Hz, 1 H), 5.00 (d, J =

12.5 Hz, 1 H), 3.88 (tdd, J = 8.7, 6.5, 3.3 Hz, 1 H), 3.38 (dd, J =

14.7, 8.6 Hz, 1 H), 3.24 (dd, J = 14.7, 3.3 Hz, 1 H), 2.01 (oct., J =

6.6 Hz, 1 H), 0.87 (d, J = 6.9 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR: δ = 155.7, 139.2, 136.4, 133.6, 129.1, 128.3,

127.9, 127.8, 66.4, 57.3, 52.1, 32.1, 18.6, 17.6 ppm. MS: m/z (%) =

362 (55) [M + H]⁺, 319 (24), 254 (68), 108 (100). HRMS: calcd. for

C₁₉H₂₄NO₄S [M + H]⁺362.1426; found 362.1422.

1

(N-Cbz-2-amino)-3-phenylpropyl Phenyl Sulfide (4e): H NMR: δ =

7.33–7.08 (m, 15 H), 5.04 (d, J = 12.8 Hz, 1 H), 5.01 (d, J =

12.8 Hz, 1 H), 4.94 (d, J = 7.8 Hz, 1 H), 4.10 (sext., J = 6.5 Hz, 1

H), 3.04 (d, J = 5.4 Hz, 2 H), 2.92 (d, J = 6.6 Hz, 2 H) ppm. ¹³C

NMR: δ = 155.7, 137.3, 136.5, 135.9, 129.7, 129.46, 129.1, 128.7,

128.6, 128.2, 128.1, 126.8, 126.4, 66.7, 51.9, 39.3, 37.6 ppm. MS:

m/z (%) = 377 (1) [M]⁺, 135 (100), 133 (96). HRMS: calcd. for

C₂₃H₂₃NO₂S [M]⁺377.1450; found 377.1423.

(N-Cbz-2-amino)-4-methylpentyl Phenyl Sulfone (5d): Yield: 68%

(overall from 1d). ¹H NMR: δ = 7.89 (d, J = 7.5 Hz, 2 H), 7.60 (tt,

J = 7.5, 1.2 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 2 H), 7.38–7.28 (m, 5 H),

5.23 (d, J = 8.4 Hz, 1 H), 5.02 (d, J = 12.2 Hz, 1 H), 4.97 (d, J =

12.2 Hz, 1 H), 4.05 (tdt, J = 9.1, 6.9, 4.8 Hz, 1 H), 3.48 (dd, J =

14.5, 6.8 Hz, 1 H), 3.24 (dd, J = 14.5, 4.4 Hz, 1 H), 1.61 (non., J

= 6.0 Hz, 1 H), 1.52 (ddd, J = 15.0, 8.7, 4.6 Hz, 1 H), 1.46 (ddd, J

= 15.0, 9.9, 7.8 Hz, 1 H), 0.85 (d, J = 6.0 Hz, 6 H) ppm. ¹³C NMR:

δ = 155.5, 139.9, 136.4, 133.8, 129.3, 128.6, 128.2, 128.0, 127.9,

66.7, 59.6, 46.1, 43.2, 24.8, 22.8, 21.8 ppm. MS: m/z = 376 [M +

H]⁺, 332, 240, 91. HRMS (MALDI-TOF): calcd. for C₂₀H₂₆NO₄S

[M + H]⁺376.1577; found 376.1587.

(N-Cbz-2-amino)butyl (1-Phenyl-1H-tetrazole-5-yl) Sulfide (4b₁): ¹H

NMR: δ = 7.51 (s, 5 H), 7.27 (s, 5 H), 5.31 (d, J = 8.7 Hz, 1 H),

5.03 (s, 2 H), 3.95 (dquint., J = 7.8, 4.2 Hz, 1 H), 3.64 (dd, J =

13.5, 4.2 Hz, 1 H), 3.47 (dd, J = 13.8, 8.7 Hz, 1 H), 1.67 (dquint.,

J = 14.1, 7.0 Hz, 1 H), 1.58 (dquint., J = 14.1, 7.4 Hz, 1 H), 0.96

(t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR: δ = 156.2, 154.5, 136.5, 133.5,

130.2, 129.8, 128.5, 128.0, 127.8, 123.9, 66.6, 52.6, 37.8, 27.5,

(N-Cbz-2-amino)-3-phenylpropyl Phenyl Sulfone (5e): Yield: 44%

(overall from 1e). ¹H NMR: δ = 7.87 (d, J = 7.5 Hz, 2 H), 7.63 (tt,

10.4 ppm. MS: m/z (%) = 384 (21) [M + H]⁺, 276 (7), 192 (8), 148 J = 7.5, 1.2 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.42–7.12 (m, 10

(14), 118 (15), 91 (100). HRMS: calcd. for C₁₉H₂₂N₅O₂S [M +

H), 5.19 (d, J = 6.9 Hz, 1 H), 5.05 (d, J = 12.2 Hz, 1 H), 4.98 (d,

J = 12.2 Hz, 1 H), 4.21 (dquint., J = 7.2, 4.8 Hz, 1 H), 3.49 (dd, J

H]⁺384.1494; found 384.1460.

4678

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4671–4686

Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

= 14.4, 7.8 Hz, 1 H), 3.29 (dd, J = 14.4, 4.8 Hz, 1 H), 3.09 (dd, J

10.7 ppm. MS: m/z = 468 [M]⁺, 317. HRMS (MALDI-TOF):

= 13.8, 6.9 Hz, 1 H), 3.02 (dd, J = 13.8, 7.2 Hz, 1 H) ppm. ¹³C calcd. for C₃₀H₃₁NO₂P [M]⁺468.2086; found 468.2074.

NMR: δ = 155.4, 139.7, 136.3, 136.4, 133.9, 129.5, 129.4, 128.9,

128.6, 128.3, 128.2, 128.0, 127.1, 66.8, 57.9, 49.2, 39.9 ppm. MS

(N-Cbz-2-amino)-3-methylbutyltriphenylphosphonium Bromide (7c):

Yield: 440 mg, 26%. H NMR: δ = 7.94–7.20 (m, 20 H), 5.16 (dt,

1

(ESI): m/z = 432 (100) [M + Na]⁺, 410 (2) [M + H]⁺, 366 (38), 298

J = 15.3, 11.4 Hz, 1 H), 4.77 (d, J = 12.6 Hz, 1 H), 4.54 (d, J =

(16), 236 (21), 229 (26), 214 (54), 158 (68). HRMS (MALDI-TOF):

12.6 Hz, 1 H), 4.00 (dtd, J = 13.8, 10.2, 7.2 Hz, 1 H), 2.94 (br. t, J

calcd. for C₂₃H₂₄NO₄S [M + H]⁺410.1420; found 410.1520.

= 14.4 Hz, 1 H), 2.15 (oct., J = 6.8 Hz, 1 H), 0.93 (d, J = 6.9 Hz,

3 H), 0.90 (d, J = 6.6 Hz, 3 H) ppm. ¹³C NMR: δ = 156.2, 136.6,

134.8 (d, J = 2.3 Hz), 134.1 (d, J = 9.8 Hz), 130.2 (d, J = 12.0 Hz),

128.3, 127.7, 127.6, 118.3 (d, J = 85.5 Hz), 66.0, 51.4 (d, J =

5.0 Hz), 34.9 (d, J = 13.2 Hz), 26.3 (d, J = 50.6 Hz), 19.4, 18.7 ppm.

MS: m/z = 482 [M]⁺, 374, 331. HRMS (MALDI-TOF): calcd. for

C₃₁H₃NO₂P [M]⁺482.2243; found 482.2110.

Bromides 6: Prepared from the corresponding alcohols 1 according

to a published procedure.^[17]

(N-Cbz-2-amino)-3-methylbutyl Bromide (6c): Yield: 77%. ¹H

NMR: δ = 7.37–7.25 (m, 5 H), 5.12 (d, J = 12.6 Hz, 1 H), 5.09 (d,

J = 12.6 Hz, 1 H), 4.98 (d, J = 8.7 Hz, 1 H), 3.64 (tt, J = 8.4,

4.2 Hz, 1 H), 3.55 (d, J = 3.9 Hz, 2 H), 1.88 (oct., J = 6.8 Hz, 1

H), 0.96 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H) ppm. ¹³C

NMR: δ = 156.1, 136.4, 128.6, 128.3, 128.1, 67.0, 56.7, 37.0, 30.6,

19.4, 18.6 ppm. MS: m/z (%) = 300 (22) [M + H]⁺, 162 (7), 108

(19), 91 (100). HRMS: calcd. for C₁₃H₁₉NO₂⁸¹Br [M + H]⁺

302.0579; found 302.0590. HRMS: calcd. for C₁₃H₁₉NO₂⁷⁹Br [M

+ H]⁺300.0599; found 300.0624.

(N-Cbz-2-amino)-4-methylpentyltriphenylphosphonium

Bromide

1

(7d): Yield: 503 mg, 29%. H NMR: δ = 7.93–7.07 (m, 20 H), 7.34

(d, J = 10.5 Hz, 1 H), 5.00 (dt, J = 15.6, 11.0 Hz, 1 H), 4.75 (d, J

= 12.6 Hz, 1 H), 4.48 (d, J = 12.6 Hz, 1 H), 4.35 (dquint., J = 10.5,

5.4 Hz, 1 H), 2.96 (br. t, J = 13.7 Hz, 1 H), 2.02 (m, 1 H), 1.60

(ddd, J = 13.6, 6.9, 6.0 Hz, 1 H), 1.49 (ddd, J = 13.6, 8.1, 5.4 Hz,

1 H), 0.77 (d, J = 6.3 Hz, 3 H), 0.69 (d, J = 6.3 Hz, 3 H) ppm. ¹³C

NMR: δ = 155.6, 136.3, 134.6 (d, J = 3.0 Hz), 133.7 (d, J =

10.5 Hz), 129.9 (d, J = 12.0 Hz), 128.1, 127.4, 127.2, 117.9 (d, J =

85.5 Hz), 65.7, 46.7 (d, J = 13.3 Hz), 44.0 (d, J = 4.8 Hz), 28.6 (d,

J = 49.1 Hz), 24.5, 22.1, 21.6 ppm. MS: m/z = 496 [M]⁺, 388, 345,

262. HRMS (MALDI-TOF): calcd. for C₃₂H₃₅NO₂P [M]⁺

496.2399; found 496.2389.

Phosphonium Salts 7:

A three-necked round-bottomed flask,

equipped with a reflux condenser, was flushed with dry nitrogen

and LiBr (0.45 g, 5.2 mmol) was added. The flask was heated a

little and then charged slowly with dry CH₃CN (4.2 mL). The solu-

tion was stirred for 15 min with gentle heating till all the LiBr was

dissolved. The flask was loaded dropwise over 15 min with a solu-

tion of mesylate 3 (3.5 mmol) in dry CH₃CN (1.5 mL) under an

argon atmosphere. The reaction mixture was heated at reflux for

4 h, and TLC (hexane/EtOAc, 3:1) indicated that the starting mate-

rial was fully consumed. The mixture was cooled to room tempera-

ture, diluted with diethyl ether, washed with saturated NaHCO₃

and saturated NaCl solutions. The organic layer was dried with

MgSO₄, filtered, and concentrated. The residue was purified by

chromatography to yield clean bromide 6 in 33–77% yield. A cyclic

carbamate byproduct (12–30% yield) and benzyl bromide (0.1 g,

15–30% yield) were also isolated from the column. Bromide 6

(1.0 mmol) in dry CHCl₃(6.5 mL), under an argon atmosphere was

treated with Ph₃P (0.66 g, 2.5 mmol). The mixture was stirred at

60 °C for 4 d, cooled to room temperature, and stirred for an ad-

ditional 2 d. After evaporation of the solvent, phosphonium salt 7

was purified by chromatography (EtOAc/MeOH, 97:3) to yield a

clean product (0.21 g, 38% yield). A cyclic carbamate byproduct

(20–31% yield) was also isolated.

(N-Cbz-2-amino)-3-phenylpropyltriphenylphosphonium

Bromide

1

(7e): Yield: 370 mg, 20% (overall). H NMR: δ = 7.68–7.18 (m, 25

H), 5.27 (dt, J = 15.6, 11.1 Hz, 1 H), 4.75 (d, J = 12.5 Hz, 1 H),

4.70 (d, J = 12.5 Hz, 1 H), 4.36 (dquint., J = 9.5, 4.8 Hz, 1 H),

3.25 (dt, J = 13.5, 4.9 Hz, 1 H), 3.13 (dd, J = 13.5, 9.8 Hz, 1 H),

2.92 (dd, J = 15.6, 13.0 Hz, 1 H) ppm. ¹³C NMR: δ = 155.8, 137.5,

136.6, 134.8 (d, J = 2.3 Hz), 133.8 (d, J = 10.5 Hz), 130.2 (d, J =

12.8 Hz), 129.7, 128.9, 128.3, 128.0, 127.8, 126.9, 117.9 (d, J =

85.5 Hz), 66.1, 48.4 (d, J = 4.5 Hz), 43.9 (d, J = 14.3 Hz), 25.2 (d,

J = 51.2 Hz) ppm. MS: (ESI) m/z 530 (100) [M]⁺, 379 (31), 277

(19). HRMS (MALDI-TOF): calcd. for C₃₅H₃₃NO₂P [M]⁺

530.2243; found 530.2279.

Synthesis of C-Terminal Building Blocks

Diols 8: A three-necked round-bottomed flask equipped with a

pressure equalizing addition funnel, reflux condenser, and drying

tube was flushed with argon and LiAlH₄(5.7 g, 0.15 mol) was

added. The flask was loaded dropwise with dry THF (100 mL).

Diethyl alkylmalonate (0.1 mol) in dry THF (50 mL) was added

dropwise over 1 h at room temperature by the pressure equalizing

addition funnel, and the reaction mixture was heated at reflux for

3 d. The mixture was cooled to 0 °C and quenched with 0.5  HCl

(50 mL). The white suspension was diluted with water (100 mL)

and its pH was adjusted to 7 with concentrated HCl. The aqueous

solution was extracted with CH₂Cl₂(3ϫ300 mL). The volume of

the combined organic layers was partially reduced to 100 mL under

vacuum and washed with saturated NaHCO₃and saturated NaCl

solutions. The organic layer was dried with MgSO₄, filtered, and

concentrated. The aqueous solution was further extracted in a con-

tinuous extraction apparatus for 5 d to give a cleaner product.

(N-Cbz-2-amino)propyltriphenylphosphonium Bromide (7a): Yield:

604 mg, 38% (crystallized from hexane/EtOAc, 9:1). ¹H NMR: δ =

7.91–7.08 (m, 20 H), 4.93 (dt, J = 15.3, 11.1 Hz, 1 H), 4.73 (d, J =

12.6 Hz, 1 H), 4.54 (d, J = 12.6 Hz, 1 H), 4.43 (m, 1 H), 3.28 (br.

t, J = 13.8 Hz, 1 H), 1.52 (dd, J = 6.3, 2.1 Hz, 3 H) ppm. ¹³C

NMR: δ = 155.2, 136.2, 134.6 (d, J = 2.3 Hz), 133.8 (d, J = 9.8 Hz),

130.0 (d, J = 12.8 Hz), 128.0, 127.4, 127.3, 117.8 (d, J = 85.5 Hz),

65.6, 42.2 (d, J = 4.7 Hz), 29.4 (d, J = 49.4 Hz), 24.2 (d, J =

14.8 Hz) ppm. MS: m/z = 454 [M]⁺, 346, 303, 262. HRMS

(MALDI-TOF): calcd. for C₂₉H₂₉NO₂P [M]⁺454.1930; found

454.1817.

(N-Cbz-2-amino)butyltriphenylphosphonium Bromide (7b): Yield:

147 mg, 9%. ¹H NMR: δ = 7.93–7.18 (m, 20 H), 5.03 (dt, J = 15.3,

11.4 Hz, 1 H), 4.75 (d, J = 12.6 Hz, 1 H), 4.51 (d, J = 12.6 Hz, 1

H), 4.15 (dquint., J = 10.0, 5.0 Hz, 1 H), 3.13 (br. t, J = 14.1 Hz,

1 H), 2.07 (dquint., J = 13.7, 7.4 Hz, 1 H), 1.77 (dqd, J = 13.7,

7.4, 5.0 Hz, 1 H), 0.83 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR: δ =

156.2, 136.6, 134.8 (d, J = 2.3 Hz), 134.1 (d, J = 10.5 Hz), 130.2

(d, J = 12.8 Hz), 128.3, 127.7, 127.6, 118.3 (d, J = 85.5 Hz), 66.0,

47.9 (d, J = 5.3 Hz), 31.2 (d, J = 14.6 Hz), 28.7 (d, J = 49.6 Hz),

1

2-(Hydroxymethyl)butanol (8b): Yield: 9.98 g, 95%. H NMR: δ =

3.79 (dd, J = 10.8, 3.9 Hz, 2 H), 3.63 (dd, J = 10.8, 7.5 Hz, 2 H),

3.49 (br. s, 2 H, OH), 1.67 (tquint., J = 7.0, 4.2 Hz), 1.29 (quint.,

J = 7.2 Hz, 2 H), 0.94 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR: δ =

64.7, 43.8, 20.6, 11.6 ppm. MS: m/z = 105 [M + H]⁺, 103, 86.

HRMS: calcd. for C₅H₁₃O₂[M + H]⁺105.0916; found 105.0895.

Eur. J. Org. Chem. 2010, 4671–4686

www.eurjoc.org

4679

S. Mirilashvili, N. Chasid-Rubinstein, A. Albeck

FULL PAPER

2-Hydroxymethyl-3-methylbutanol (8c): Yield: 11.20 g, 94%. ¹H m/z (%) = 251 (0.9) [M + H]⁺, 190 (33), 131 (39), 117 (28), 104

NMR: δ = 3.83 (dd, J = 10.8, 3.9 Hz, 2 H), 3.75 (obscured, 2 H),

(12), 91 (44). HRMS: calcd. for C₁₄H₁₉O₄[M + H]⁺251.1283;

3.73 (dd, J = 10.8, 8.1 Hz, 2 H), 1.72 (oct., J = 6.8 Hz, 1 H), 1.53 found 251.1272.

(qt, J = 7.6, 3.8 Hz, 1 H), 0.93 (d, J = 6.6 Hz, 6 H) ppm. ¹³C NMR:

Enzymatic (Chiral) Synthesis of (S)-Monoacetates 10: To a stirred

δ = 64.2, 47.9, 26.4, 20.3 ppm. MS: m/z (%) = 119 (7) [M + H]⁺,

101 (9), 83 (16). HRMS: calcd. for C₆H₁₅O₂[M + H]⁺119.1072;

found 119.1071.

suspension of diester 9 (0.1–1 g) in aqueous solution containing

40 m NaCl, 5 m CaCl₂, and 0.07% BSA at pH 7.5 (2–5 mL) at

37 °C was added the enzyme lipase (from Pseudomonas Cepacia,

2-Hydroxymethyl-4-methylpentanol (8d): Yield: 12.25 g, 92%. ¹H 50 u/mg, 12.5–40 mg). The pH of the suspension was kept constant

NMR: δ = 4.24 (br. s, 2 H), 3.65 (dd, J = 10.5, 3.9 Hz, 2 H), 3.49

(dd, J = 10.5, 7.5 Hz, 2 H), 1.80 (tquint., J = 7.4, 3.6 Hz, 1 H),

1.62 (non., J = 6.7 Hz, 1 H), 1.07 (t, J = 7.2 Hz, 2 H), 0.90 (d, J

= 6.6 Hz, 6 H) ppm. ¹³C NMR: δ = 65.3, 39.6, 36.9, 25.3, 22.8 ppm.

MS: m/z (%) = 133 (10) [M + H]⁺, 115 (10), 97 (52). HRMS: calcd.

for C₇H₁₇O₂[M + H]⁺133.1229; found 133.1232.

by the continuous addition of a 0.2  aqueous NaOH solution by

using an automatic titrator. The reaction was monitored by TLC

(hexane/EtOAc, 3:1) and NMR spectroscopy. When the desired de-

gree of conversion was reached, the reaction was quenched by the

addition of ether (8 mL), and the layers were separated. The aque-

ous layer was further extracted with diethyl ether (3ϫ15 mL), and

the combined extracts were washed with saturated NaCl solution,

dried with MgSO₄, and concentrated to give a mixture of diester

starting material, the monoester product, and diol, which was sepa-

rated by chromatography (hexane/EtOAc, 3:1) to give the optically

active monoester product as a yellow oil. The compounds were

characterized by chiral HPLC analysis.

2-Benzyl-1,3-propanediol (8e): Yield: 16.21 g, 97%. ¹H NMR: δ =

7.29–7.13 (m, 5 H), 3.72 (dd, J = 10.8, 3.9 Hz, 2 H), 3.59 (dd, J =

10.8, 6.9 Hz, 2 H), 3.41 (s, 2 H), 2.56 (d, J = 7.5 Hz, 2 H), 2.00

(tquint., J = 7.4, 3.7 Hz, 1 H) ppm. ¹³C NMR: δ = 139.9, 129.1,

128.5, 126.2, 64.9, 43.9, 34.3 ppm. MS: m/z (%) = 167 (0.2) [M +

H]⁺, 148 (65), 130 (32), 104 (20), 91 (71). HRMS: calcd. for

C₁₀H₁₅O₂[M + H]⁺167.1072; found 167.1063.

Chemical (racemic) Synthesis of Monoacetates 10: AcCl (0.75 mL,

10.6 mmol) was slowly added by syringe to a solution of 2-alkyl-

1,3-propanediol 8 (10.6 mmol) in CHCl₃(8 mL), and the solution

was stirred at room temperature for 30 min. Then, the mixture was

diluted with water (75 mL) and extracted with CH₂Cl₂

(3ϫ100 mL). The combined organic layer was washed with satu-

rated NaHCO₃and saturated NaCl solutions, dried with MgSO₄,

filtered, and concentrated. Chromatography (hexane/EtOAc, 4:1)

separated desired monoacetate 10 (major product) from diacetate

9 (minor product) and some diol 8 starting material.

Diacetates 9: AcCl (2.6 mL, 36 mmol) was added dropwise to a

stirred solution of 2-alkyl-1,3-propanediol 8 (12 mmol) in CHCl₃

(15 mL). After stirring at room temperature for 24 h, water (30 mL)

was added, and the solution was extracted with CH₂Cl₂

(3ϫ40 mL). The combined organic layer was washed with satu-

rated NaHCO₃and saturated NaCl solutions, dried with MgSO₄,

filtered, and concentrated to give the clean product as a yellow oil.

2-(Acetoxymethyl)propyl Acetate (9a): Yield: 1.98 g, 94%. ¹H

NMR: δ = 4.01 (d, J = 6.0 Hz, 4 H), 2.17 (oct., J = 6.3 Hz, 1 H),

2.07 (s, 6 H), 0.99 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR: δ = 171.2,

66.0, 32.4, 21.0, 14.0 ppm. MS: m/z (%) = 175 (12) [M + H]⁺, 133

(22), 115 (100). HRMS: calcd. for C₈H₁₅O₄[M + H]⁺175.0970;

found 175.0970.

2-(Acetoxymethyl)propanol (10a): Yield: 395 mg, 28%. ¹H NMR: δ

= 4.08 (dd, J = 11.1, 5.7 Hz, 1 H), 4.03 (dd, J = 11.1, 6.9 Hz, 1

H), 3.56 (dd, J = 11.1, 5.4 Hz, 1 H), 3.52 (dd, J = 11.1, 5.7 Hz, 1

H), 2.21 (qquint., J = 6.9, 5.5 Hz, 1 H), 2.07 (s, 3 H), 1.06 (d, J =

6.9 Hz, 3 H) ppm. ¹³C NMR: δ = 171.0, 65.9, 47.3, 35.1, 20.9,

14.8 ppm. MS: m/z (%) = 133 (20) [M + H]⁺, 115 (34), 73 (60).

HRMS: calcd. for C₆H₁₃O₃[M + H]⁺133.0865; found 133.0867.

1

2-(Acetoxymethyl)Butyl Acetate (9b): Yield: 2.0 g, 88%. H NMR:

δ = 4.03 (dd, J = 11.1, 5.4 Hz, 2 H), 3.98 (dd, J = 11.1, 6.3 Hz, 2

H), 1.99 (s, 6 H), 1.86 (ttt, J = 7.2, 6.3, 5.4 Hz, 1 H), 1.35 (quint.,

J = 7.4 Hz, 2 H), 0.90 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR: δ =

171.1, 64.0, 38.8, 21.1, 20.9, 11.2 ppm. MS: m/z (%) = 189 (9) [M

+ H]⁺, 129 (100), 103 (16), 86 (53). HRMS: calcd. for C₉H₁₇O₄[M

+ H]⁺189.1127; found 189.1165.

1

2-(Acetoxymethyl)butanol (10b): Yield: 560 mg, 36%. H NMR: δ

= 4.07 (dd, J = 11.1, 5.1 Hz, 1 H), 4.01 (dd, J = 11.1, 6.3 Hz, 1

H), 3.51 (dd, J = 11.1, 4.8 Hz, 1 H), 3.44 (dd, J = 11.1, 6.3 Hz, 1

H), 2.81 (br. s, 1 H), 1.98 (s, 3 H), 1.64 (ttt, J = 6.9, 6.3, 5.1 Hz, 1

H), 1.32 (dqd, J = 13.8, 7.8, 6.9 Hz, 1 H), 1.27 (dqd, J = 13.8, 7.8,

6.9 Hz, 1 H), 0.87 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR: δ = 171.7,

64.4, 62.1, 41.9, 20.8, 20.6, 11.3 ppm. MS: m/z (%) = 147 (100) [M

+ H]⁺, 129 (73), 103 (15), 87 (43), 69 (73). HRMS: calcd. for

C₇H₁₅O₃[M + H]⁺147.1021; found 147.1033.

2-Acetoxymethyl-3-methylbutyl Acetate (9c): Yield: 2.12 g, 87%. ¹H

NMR: δ = 4.18 (dd, J = 11.1, 4.5 Hz, 2 H), 4.06 (dd, J = 11.1,

6.3 Hz, 2 H), 2.06 (s, 6 H), 1.81 (m, 2 H), 0.97 (d, J = 6.0 Hz, 6

H) ppm. ¹³C NMR: δ = 171.2, 63.0, 43.0, 26.9, 21.0, 20.0 ppm.

MS: m/z (%) = 203 [M + H]⁺, 143 (8), 114 (15). HRMS: calcd. for

C₁₀H₁₉O₄[M + H]⁺203.1283; found 203.1268.

2-Acetoxymethyl-3-methylbutanol (10c): Yield: 547 mg, 32%. ¹H

NMR: δ = 4.25 (dd, J = 11.1, 4.8 Hz, 1 H), 4.13 (dd, J = 11.1,

2-Acetoxymethyl-4-methylpentyl Acetate (9d): Yield: 2.35 g, 90%. 6.3 Hz, 1 H), 3.68 (dd, J = 11.1, 4.8 Hz, 1 H), 3.57 (dd, J = 11.1,

¹H NMR: δ = 4.08 (dd, J = 11.1, 5.1 Hz, 2), 4.01 (dd, J = 11.1,

6.3 Hz, 2 H), 2.08 (obscured, 1 H), 2.06 (s, 6 H), 1.67 (non., J =

6.7 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 2 H), 0.91 (d, J = 6.6 Hz, 6

H) ppm. ¹³C NMR: δ = 170.7, 64.3, 37.3, 34.9, 25.0, 22.5,

20.6 ppm. MS: m/z (%) = 217 (3) [M + H]⁺, 216 (3) [M]⁺, 173 (6),

157 (40), 114. HRMS: calcd. for C₁₁H₂₁O₄[M + H]⁺217.1440;

found 217.1474.

6.6 Hz, 1 H), 3.03 (br. s, 1 H), 2.07 (s, 3 H), 1.81 (oct., J = 6.9 Hz,

1 H), 1.61 (qt, J = 6.6, 4.8 Hz, 1 H), 0.96 (d, J = 6.9 Hz, 3 H), 0.95

(d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR: δ = 171.6, 63.4, 60.9, 46.1,

26.3, 20.9, 20.2, 19.8 ppm. MS: m/z = 161 [M + H]⁺, 143, 101.

HRMS: calcd. for C₈H₁₇O₃[M + H]⁺161.1178; found 161.1174.

2-Acetoxymethyl-4-methylpentanol (10d): Yield: 683 mg, 41%. ¹H

NMR: δ = 4.13 (dd, J = 11.1, 4.5 Hz, 1 H), 4.01 (dd, J = 11.1,

6.3 Hz, 1 H), 3.54 (dd, J = 11.1, 4.5 Hz, 1 H), 3.44 (dd, J = 11.1,

6.3 Hz, 1 H), 2.56 (br. s, 1 H), 2.02 (s, 3 H), 1.84 (tquint., J = 6.8,

4.5 Hz, 1 H), 1.62 (non., J = 6.8 Hz, 1 H), 1.17 (dt, J = 14.1,

7.2 Hz, 1 H), 1.08 (dt, J = 14.1, 7.2 Hz, 1 H), 0.86 (d, J = 6.6 Hz,

6 H) ppm. ¹³C NMR: δ = 171.8, 64.9, 62.8, 38.1, 37.1, 25.2, 22.8,

2-(Benzyl)-1,3-propanediol Diacetate (9e): Yield: 2.89 g, 96%. ¹H

NMR: δ = 7.30–7.12 (m, 5 H), 4.07 (dd, J = 11.1, 5.4 Hz, 2 H),

4.00 (dd, J = 11.1, 6.0 Hz, 2 H), 2.68 (d, J = 7.5 Hz, 2 H), 2.31

(ttt, J = 7.4, 6.0, 5.3 Hz, 1 H), 2.03 (s, 6 H) ppm. ¹³C NMR: δ =

170.8, 138.7, 128.9, 128.5, 126.4, 63.7, 39.1, 34.5, 20.8 ppm. MS:

4680

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4671–4686

Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

22.7, 21.0 ppm. MS: m/z (%) = 174 [M]⁺, 157 (100), 114 (15).

HRMS: calcd. for C₉H₁₇O₂[M + H – H₂O]⁺157.1229; found

157.1253.

the white suspension was stirred at room temperature for 15 min.

A solution of mesylate 12 (0.83 mmol) in dry THF (1.5 mL) was

added, and the mixture was stirred overnight at 50 °C. The mixture

was cooled to room temperature, diluted with CH₂Cl₂(15 mL), and

washed with 10% NaOH solution (20 mL). The aqueous phase was

re-extracted with CH₂Cl₂(3ϫ20 mL), and the volume of the com-

bined organic phase was washed with saturated NaCl solution,

dried with MgSO₄, filtered, and evaporated to provide a yellow oil.

Chromatography (hexane/EtOAc, 9:1) afforded the clean product.

2-Benzyl-1,3-propanediol Monoacetate (10e): Yield: 1.04 g, 47%. ¹H

NMR: δ = 7.32–7.16 (m, 5 H), 4.14 (dd, J = 11.4, 5.0 Hz, 1 H),

4.06 (dd, J = 11.4, 6.3 Hz, 1 H), 3.58 (dd, J = 11.1, 4.8 Hz, 1 H),

3.49 (dd, J = 11.1, 6.0 Hz, 1 H), 2.69 (dd, J = 13.8, 7.5 Hz, 1 H),

2.61 (dd, J = 13.8, 6.3 Hz, 1 H), 2.59 (s, 1 H), 2.13 (dqt, J = 7.5,

6.2, 5.0 Hz, 1 H), 2.05 (s, 3 H) ppm. ¹³C NMR: δ = 171.6, 139.4,

129.0, 128.4, 126.1, 64.0, 61.8, 42.3, 34.2, 20.8 ppm. MS: m/z (%)

2-Hydroxymethylbutyl Phenyl Sulfide (13Јb): Yield: 140 mg, 86%.

= 208 [M]⁺, 190 (5), 148 (56), 130 (55), 117 (100), 91 (30). HRMS: ¹H NMR: δ = 7.34 (d, J = 8.4 Hz, 2 H), 7.26 (t, J = 8.1 Hz, 2 H),

calcd. for C₁₂H₁₇O₃[M + H]⁺209.1178; found 209.1175.

7.14 (tt, J = 7.2, 1.5 Hz, 1 H), 3.70 (dd, J = 11.0, 4.7 Hz, 1 H),

3.61 (dd, J = 11.0, 5.9 Hz, 1 H), 3.01 (dd, J = 12.9, 6.9 Hz, 1 H),

2.96 (dd, J = 12.9, 5.7 Hz, 1 H), 2.16 (s, 1 H), 1.70 (dsext., J = 6.4,

4.8 Hz, 1 H), 1.46 (quint., J = 7.2 Hz, 2 H), 0.91 (t, J = 7.5 Hz, 3

H) ppm. ¹³C NMR: δ = 137.0, 128.9, 125.8, 64.0, 41.8, 35.3, 23.3,

11.3 ppm. MS: m/z (%) = 197 (19) [M + H]⁺, 196 (100) [M]⁺, 123

(27), 110 (64). HRMS: (DCI/CH₄): calcd. for C₁₁H₁₆OS [M]⁺

196.0922; found 196.0899.

Ester Aldehyde 11: Dess–Martin reagent (0.3 g, 0.68 mmol) was

added to a stirred solution of 2-benzyl-1,3-propanediol monobutyr-

ate (0.107 g, 0.45 mmol) in dry CH₂Cl₂(40 mL) under an argon

atmosphere at 0 °C. The ice bath was removed, and the reaction

mixture was allowed to proceed at room temperature for 3.5 h.

CH₂Cl₂(30 mL) was added, and the mixture was washed with satu-

rated Na₂S₂O₅solution (50 mL). The layers were separated, and

the organic layer was washed with saturated NaHCO₃(2ϫ) and

(2-Acetoxymethylbutyl) 1-Phenyl-1H-tetrazole-5-yl Sulfide (13b₁):

1

saturated NaCl solutions, dried with MgSO₄, and filtered. Evapo- Yield: 227 mg, 89%. H NMR: δ = 7.60–7.51 (m, 5 H), 4.19 (dd,

ration of the solvent afforded the clean aldehyde as a yellow oil

(90 mg, 85% yield). H NMR: δ = 9.74 (d, J = 1.5 Hz, 1 H), 7.30– J = 13.2, 5.7 Hz, 1 H), 3.44 (dd, J = 13.2, 7.2 Hz, 1 H), 2.14 (tqd,

J = 11.3, 4.8 Hz, 1 H), 4.09 (dd, J = 11.3, 6.0 Hz, 1 H), 3.55 (dd,

1

7.15 (m, 5 H), 4.32 (dd, J = 11.7, 4.5 Hz, 1 H), 4.24 (dd, J = 11.4,

6.2 Hz, 1 H), 3.09 (dd, J = 13.5, 6.3 Hz, 1 H), 2.910 (qdd, J = 6.0,

J = 7.2, 6.0, 4.8 Hz, 1 H), 2.06 (s, 3 H), 1.56 (dqd, J = 14.1, 7.2,

6.3 Hz, 1 H), 1.50 (dquint., J = 14.1, 7.2 Hz, 1 H), 0.99 (t, J =

4.5, 1.5 Hz, 1 H), 2.78 (dd, J = 13.5, 8.1 Hz, 1 H), 2.27 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR: δ = 171.0, 154.3, 133.6, 130.2, 129.8,

7.2 Hz, 2 H), 1.63 (sext., J = 7.5 Hz, 2 H), 0.94 (t, J = 7.5 Hz, 3

H) ppm. ¹³C NMR: δ = 201.5, 173.4, 137.7, 129.0, 128.8, 126.8,

61.4, 52.6, 36.0, 31.8, 18.4, 13.7 ppm.

127.9, 64.7, 39.0, 34.9, 23.5, 20.9, 11.1 ppm. MS: m/z (%) = 307

(100) [M + H]⁺, 129 (21), 118 (25). HRMS: calcd. for C₁₄H₁₉N₄O₂S

[M + H]⁺307.1229; found 307.1242.

Acetyl Mesylates 12: A solution of monoacetate 10 (6.0 mmol) and

Et₃N (1.25 mL, 8.9 mmol) in dry CH₂Cl₂(10 mL) under an argon

atmosphere was cooled to 0 °C. The solution was stirred for

15 min, followed by slow addition (10 min) of MsCl (0.7 mL,

9.0 mmol) in dry CH₂Cl₂(2 mL). Stirring was continued at 0 °C

under an argon atmosphere for 3 h. The solution turned yellow.

Ether was added, and the solution was washed with 1  HC1, satu-

rated NaHCO₃, and saturated NaCl solutions. The organic phase

was dried with MgSO₄, filtered, and concentrated to give the clean

product.

(2-Hydroxymethylbutyl) 1-Phenyl-1H-tetrazole-5-yl Sulfide (13Јb₁):

Yield: 207 mg, 94%. H NMR: δ = 7.63–7.56 (m, 5 H), 3.72 (dd,

1

J = 11.9, 3.9 Hz, 1 H), 3.60 (dd, J = 14.1, 4.7 Hz, 1 H), 3.56 (dd,

J = 11.9, 6.9 Hz, 1 H), 3.49 (dd, J = 14.1, 6.6 Hz, 1 H), 3.38 (br.

s, 1 H), 1.94 (tquint., J = 6.9, 4.2 Hz, 1 H), 1.51 (dquint., J = 14.0,

7.5 Hz, 1 H), 1.44 (dquint., J = 14.0, 7.0 Hz, 1 H), 0.97 (t, J =

7.5 Hz, 3 H) ppm. ¹³C NMR: δ = 155.7, 133.6, 130.4, 129.9, 124.0,

62.3, 43.1, 34.9, 23.0, 11.6 ppm. MS: m/z (%) = 265 (100) [M +

H]⁺, 118 (45). HRMS: calcd. for C₁₂H₁₇N₄OS [M + H]⁺265.1123;

found 265.1109.

2-(Acetoxymethyl)butanol Methanesulfonate (12b): Yield: 1.27 g,

94%. H NMR: δ = 4.25 (dd, J = 9.9, 5.1 Hz, 1 H), 4.21 (dd, J =

9.9, 5.7 Hz, 1 H), 4.15 (dd, J = 11.4, 5.1 Hz, 1 H), 4.06 (dd, J =

11.4, 6.6 Hz, 1 H), 3.03 (s, 3 H), 2.07 (s, 3 H), 2.01 (qq, J = 6.9,

3-Acetoxy-2-benzylpropyl Phenyl Sulfide (13e): Yield: 187 mg, 78%

yield (crystallized from hexane/EtOAc, 9:1). ¹H NMR: δ = 7.27–

7.10 (m, 10 H), 4.14 (dd, J = 11.1, 5.1 Hz, 1 H), 4.05 (dd, J = 11.1,

5.4 Hz, 1 H), 2.94 (d, J = 6.6 Hz, 2 H), 2.81 (dd, J = 13.8, 7.2 Hz,

1

5.1 Hz, 1 H), 1.49 (dqd, J = 13.8, 7.8, 6.3 Hz, 1 H), 1.43 (ddq, J = 1 H), 2.72 (dd, J = 13.8, 7.5 Hz, 1 H), 2.21 (ttt, J = 7.2, 6.6, 5.3 Hz,

13.8, 9.3, 6.9 Hz, 1 H), 0.99 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR:

δ = 170.9, 69.0, 63.1, 39.3, 37.2, 20.9, 20.6, 11.2 ppm. MS: m/z (%)

1 H), 2.02 (s, 3 H) ppm. ¹³C NMR: δ = 171.0, 139.1 136.4, 129.3,

129.2, 129.0, 128.6, 126.5, 126.1, 65.3, 39.7, 37.0, 34.9, 21.0 ppm.

= 225 (100) [M + H]⁺, 129 (57). HRMS: calcd. for C₈H₁₇O₅S [M MS: m/z (%) = 300 (48) [M]⁺, 191 (9), 149 (45), 110 (47), 91 (94).

+ H]⁺225.0797; found 225.0781.

HRMS: calcd. for C₁₈H₂₀O₂S [M]⁺300.1184; found 300.1189.

3-Acetoxy-2-benzyl-1-propyl Methanesulfonate (12e): Yield: 1.72 g,

100%. ¹H NMR: δ = 7.33–7.16 (m, 5 H), 4.20 (dd, J = 9.8, 5.0 Hz,

1 H), 4.14 (dd, J = 9.8, 5.6 Hz, 1 H), 4.13 (dd, J = 11.4, 5.1 Hz, 1

2-Benzyl-3-hydroxypropyl Phenyl Sulfide (13Јe): Yield: 212 mg,

99%. ¹H NMR: δ = 7.27–7.05 (m, 10 H), 3.62 (dd, J = 11.0, 4.8 Hz,

1 H), 3.53 (dd, J = 11.0, 5.4 Hz, 1 H), 2.94 (dd, J = 13.5, 6.6 Hz,

H), 4.02 (dd, J = 11.4, 6.6 Hz, 1 H), 2.97 (s, 3 H), 2.74 (dd, J = 1 H), 2.89 (dd, J = 13.5, 6.6 Hz, 1 H), 2.70 (d, J = 7.2 Hz, 2 H),

14.3, 7.9 Hz, 1 H), 2.70 (dd, J = 14.3, 7.2 Hz, 1 H), 2.39 (qq, J =

7.2, 5.2 Hz, 1 H), 2.06 (s, 3 H) ppm. ¹³C NMR: δ = 170.7, 137.9,

128.9, 128.6, 126.6, 68.6, 62.8, 39.5, 37.0, 33.8, 20.7 ppm. MS: m/z

(%) = 287 (1.4) [M + H]⁺, 226 (3), 190 (18), 130 (100), 91 (4).

HRMS: calcd. for C₁₃H₁₉O₅S [M + H]⁺287.0953; found 287.0957.

2.30 (br. s, 1 H), 2.01 (sept., J = 6.1 Hz, 1 H) ppm. ¹³C NMR: δ =

139.7, 136.5, 129.2, 128.9, 128.7, 128.4, 126.1, 125.7, 63.6, 42.3,

36.7, 34.4 ppm.

(3-Acetoxy-2-benzylpropyl) 1-Phenyl-1H-tetrazole-5-yl Sulfide

(13e₁): Yield: 260 mg, 85%. ¹H NMR: δ = 7.59–7.53 (m, 5 H),

7.32–7.15 (m, 5 H), 4.15 (dd, J = 11.4, 4.8 Hz, 1 H), 4.00 (dd, J =

11.4, 5.7 Hz, 1 H), 3.54 (dd, J = 13.2, 6.0 Hz, 1 H), 3.45 (dd, J =

13.2, 6.9 Hz, 1 H), 2.86 (dd, J = 13.8, 6.6 Hz, 1 H), 2.75 (dd, J =

13.8, 7.8 Hz, 1 H), 2.54 (qtd, J = 7.1, 5.7, 4.7 Hz, 1 H), 2.07 (s, 3

Sulfides 13: Thiophenol or 1-phenyl-1H-tetrazole-5-thiol

(2.5 mmol) was dissolved in dry THF (4 mL). NaH (60% in min-

eral oil, either 1 or 2 equiv. relative to the thiol to provide either

the acetoxy or hydroxy sulfide, respectively) was added slowly, and

Eur. J. Org. Chem. 2010, 4671–4686

www.eurjoc.org

4681

S. Mirilashvili, N. Chasid-Rubinstein, A. Albeck

FULL PAPER

H) ppm. ¹³C NMR: δ = 170.9, 154.1, 138.3, 133.6, 130.3, 129.9,

13.8, 7.8 Hz, 1 H), 2.76 (obscured, 1 H), 2.72 (dd, J = 13.8, 7.2 Hz,

1 H), 2.37 (qq, J = 7.3, 4.8 Hz, 1 H) ppm. ¹³C NMR: δ = 139.3,

129.1, 128.7, 126.7, 123.9, 64.3, 39.4, 36.9, 34.8, 20.9 ppm. MS: m/z

(%) = 369 (100) [M + H]⁺, 327 (13), 222 (16), 191 (95), 163 (66), 138.4, 133.6, 129.3, 129.1, 128.5, 127.6, 126.4, 62.9, 56.1, 37.8,

131 (53), 91 (23). HRMS: calcd. for C₁₉H₂₁N₄O₂S [M + H]⁺

369.1385; found 369.1351.

36.1 ppm. MS: m/z (%) = 291 (13) [M + H]⁺, 273 (13), 131 (100),

117 (26), 104 (6), 91 (43). HRMS: calcd. for C₁₆H₁₉O₃S [M + H]⁺

291.1055; found 291.1058.

(2-Benzyl-3-hydroxypropyl) 1-Phenyl-1H-tetrazole-5-yl Sulfide

(13Јe₁): Yield: 230 mg, 85%. ¹H NMR: δ = 7.55 (s, 5 H), 7.26–7.15

(m, 5 H), 3.95 (br. s, 1 H), 3.71 (dd, J = 12.0, 3.9 Hz, 1 H), 3.55

(dd, J = 12.0, 6.3 Hz, 1 H), 3.52 (dd, J = 14.1, 4.5 Hz, 1 H), 3.41

(dd, J = 14.1, 6.9 Hz, 1 H), 2.79 (dd, J = 13.8, 7.2 Hz, 1 H), 2.68

(dd, J = 13.8, 7.8 Hz, 1 H), 2.32 (m, 1 H) ppm. ¹³C NMR: δ =

155.4, 139.0, 133.3, 130.3, 129.8, 129.0, 128.5, 126.3, 123.8, 61.9,

43.2, 36.3, 34.4 ppm. MS: m/z (%) = 327 (43) [M + H]⁺, 236 (13),

180 (77), 163 (15), 131 (26), 118 (34), 91 (100). HRMS: calcd. for

C₁₇H₁₉N₄OS [M + H]⁺327.1279; found 327.1253.

(3-Acetoxy-2-benzylpropyl) 1-Phenyl-1H-tetrazole-5-yl Sulfone

(14e₁): Yield: 183 mg, 91%. ¹H NMR: δ = 7.63–7.12 (m, 10 H),

4.20 (dd, J = 11.4, 4.2 Hz, 1 H), 4.02 (dd, J = 11.4, 4.8 Hz, 1 H),

3.94 (dd, J = 15.0, 6.0 Hz, 1 H), 3.73 (dd, J = 15.0, 5.4 Hz, 1 H),

2.96 (dd, J = 16.8, 9.6 Hz, 1 H), 2.84 (m, 1 H), 2.83 (dd, J = 16.8,

8.1 Hz, 1 H), 2.06 (s, 3 H) ppm. ¹³C NMR: δ = 170.6, 153.7, 137.2,

132.9, 131.5, 129.7, 129.2, 128.8, 127.0, 125.2, 64.0, 56.5, 37.1, 34.7,

20.7 ppm. MS: m/z (%) = 401 (28) [M + H]⁺, 359 (7), 208 (23), 118

(62), 91 (100). HRMS: calcd. for C₁₉H₂₁N₄O₄S [M + H]⁺401.1284;

found 401.1285.

Sulfones 14: m-CPBA (75%, 0.28 g, 1.6 mmol) was added to a

stirred solution of sulfide 13 (0.5 mmol) in dry CH₂Cl₂(4 mL) at

0 °C. The ice bath was removed, and the reaction mixture was al-

lowed to proceed at room temperature for 3 h. CH₂Cl₂(10 mL) was

added, and the mixture was washed with saturated Na₂S₂O₅/10%

NaOH solution (1:1, 10 mL). The layers were separated, and the

aqueous phase was further extracted with CH₂Cl₂(3ϫ20 mL). The

combined organic layer was washed with saturated NaHCO₃and

saturated NaCl solutions, dried with MgSO₄, filtered, and concen-

trated to give a yellow oil, which was purified by chromatography

(hexane/EtOAc, 4:1) to afford the clean product.

Acetyl Bromides 15: Prepared as described above for N-terminal

bromides 6.

2-Acetoxymethylbutyl Bromide (15b): Yield: 79%. ¹H NMR: δ =

4.15 (dd, J = 11.1, 5.1 Hz, 1 H), 4.03 (dd, J = 11.1, 7.2 Hz, 1 H),

3.53 (dd, J = 10.4, 4.8 Hz, 1 H), 3.48 (dd, J = 10.4, 5.1 Hz, 1 H),

2.07 (s, 3 H), 1.92 (qq, J = 7.0, 4.9 Hz, 1 H), 1.49 (dquint., J =

13.8, 7.4 Hz, 1 H), 1.43 (dquint., J = 13.8, 7.2 Hz, 1 H), 0.96 (t, J

= 7.5 Hz, 3 H) ppm. ¹³C NMR: δ = 170.6, 64.7, 40.7, 34.9, 22.4,

20.7, 10.9 ppm. MS: m/z (%) = 211, 209 (9, 6) [M + H]⁺, 149 (11),

129 (8), 85 (82), 71 (100). HRMS: calcd. for C₇H₁₄O₂⁸¹Br

[M

+

H]⁺211.0157; found 211.0122. HRMS: calcd. for

2-Hydroxymethylbutyl Phenyl Sulfone (14Јb): Yield: 102 mg, 89%.

¹H NMR: δ = 7.93 (d, J = 7.2 Hz, 2 H), 7.66 (tt, J = 7.4, 1.5 Hz,

1 H), 7.57 (tt, J = 7.4, 1.5 Hz, 2 H), 3.80 (dd, J = 11.1, 4.5 Hz, 1

H), 3.59 (dd, J = 11.1, 5.4 Hz, 1 H), 3.33 (dd, J = 14.1, 7.2 Hz, 1

H), 3.03 (dd, J = 14.1, 4.8 Hz, 1 H), 2.56 (br. s, 1 H), 2.08 (qq, J

= 6.8, 5.1 Hz, 1 H), 1.51 (dqd, J = 13.8, 7.2, 6.3 Hz, 1 H), 1.46

(dqd, J = 13.8, 6.6, 5.7 Hz, 1 H), 0.86 (t, J = 7.4 Hz, 3 H) ppm.

¹³C NMR: δ = 139.8, 133.8, 129.4, 127.8, 63.3, 57.4, 37.7, 24.1,

11.0 ppm. MS: m/z (%) = 229 (100) [M + H]⁺, 211 (22), 171 (8),

143 (64), 125 (22). HRMS: calcd. for C₁₁H₁₇O₃S [M + H]⁺

229.0898; found 229.0883.

C₇H₁₄O₂⁷⁹Br [M + H]⁺209.0177; found 209.0126.

3-Acetoxy-2-benzylpropyl Bromide (15e): Yield: 93%. ¹H NMR: δ

= 7.35–7.15 (m, 5 H), 4.14 (dd, J = 11.1, 5.4 Hz, 1 H), 4.04 (dd, J

= 11.1, 6.9 Hz, 1 H), 3.46 (dd, J = 10.2, 4.5 Hz, 1 H), 3.34 (dd, J

= 10.2, 5.1 Hz, 1 H), 2.74 (dd, J = 14.2, 7.8 Hz, 1 H), 2.69 (dd, J

= 14.2, 6.6 Hz, 1 H), 2.28 (tdq, J = 7.5, 6.9, 5.0 Hz, 1 H), 2.05 (s,

3 H) ppm. ¹³C NMR: δ = 170.7, 138.3, 129.1, 128.6, 126.6, 64.8,

41.1, 35.6, 34.8, 20.8 ppm. MS: m/z (%) = 273, 271 (5, 4)

[M + H]⁺, 212, 210 (9, 11), 131 (100), 91 (26). HRMS: calcd. for

C₁₂H₁₆O₂⁸¹Br [M + H]⁺273.0313; found 273.0403. HRMS: calcd.

for C₁₂H₁₆O₂⁷⁹Br [M + H]⁺271.0334; found 271.0330.

(3-Acetoxybutyl) 1-Phenyl-1H-tetrazole-5-yl Sulfone (14b₁): ¹H

NMR: δ = 7.69–7.59 (m, 5 H), 4.26 (dd, J = 11.4, 4.8 Hz, 1 H),

4.14 (dd, J = 11.4, 5.4 Hz, 1 H), 3.95 (dd, J = 14.4, 6.6 Hz, 1 H),

3.76 (dd, J = 14.4, 5.7 Hz, 1 H), 2.48 (sept., J = 6.0 Hz, 1 H), 2.08

(s, 3 H), 1.69 (dqd, J = 14.6, 7.8, 5.9 Hz, 1 H), 1.60 (dquint., J =

14.6, 7.3 Hz, 1 H), 0.99 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR: δ =

170.8, 153.9, 133.1, 131.6, 129.8, 125.2, 64.3, 57.0, 34.4, 24.2, 20.9,

10.9 ppm.

Hydroxy Bromides 15Ј: Acetyl bromide 15 (4.0 mmol) was dis-

solved in dry THF (18 mL) and cooled to –78 °C under an argon

atmosphere. DIBAL-H (1  in hexane, 20 mL) was added dropwise

over 15 min. After an additional 1.5 h at –78 °C, the reaction was

quenched with EtOAc (5 mL) and water (3 mL). The mixture was

filtered through Celite, washed with diethyl ether and EtOAc, dried

with MgSO₄, and filtered. Evaporation of the solvent afforded the

clean product as a brownish oil.

2-Hydroxymethylbutyl Bromide (15Јb): Yield: 670 mg, 100%. ¹H

NMR: δ = 3.69 (dd, J = 11.0, 5.0 Hz, 1 H), 3.61 (dd, J = 9.9,

4.2 Hz, 1 H), 3.58 (dd, J = 11.0, 7.1 Hz, 1 H), 3.52 (dd, J = 9.9,

5.4 Hz, 1 H), 3.31 (s, 1 H), 1.73 (qq, J = 6.9, 4.9 Hz, 1 H), 1.41

(quint., J = 7.3 Hz, 2 H), 0.94 (t, J = 7.4 Hz, 3 H) ppm. ¹³C NMR:

δ = 63.0, 43.7, 35.9, 22.1, 11.2 ppm. MS: m/z (%) = 169 and 167 (6

and 5) [M + H]⁺, 151 and 149 (7 and 8), 87 (11). HRMS: calcd.

for C₅H₁₂O⁸¹Br [M + H]⁺169.0051; found 169.0027. HRMS:

calcd. for C₅H₁₂O⁷⁹Br [M + H]⁺167.0072; found 167.0090.

3-Acetoxy-2-benzylpropyl Phenyl Sulfone (14e): Yield: 127 mg,

76%. ¹H NMR: δ = 7.84 (d, J = 7.8 Hz, 2 H), 7.64 (tt, J = 7.5,

1.4 Hz, 1 H), 7.53 (tt, J = 7.5, 1.4 Hz, 2 H), 7.27–7.03 (m, 5 H),

4.12 (dd, J = 11.3, 5.0 Hz, 1 H), 4.03 (dd, J = 11.3, 5.0 Hz, 1 H),

3.23 (dd, J = 14.6, 6.5 Hz, 1 H), 3.09 (dd, J = 14.6, 5.6 Hz, 1 H),

2.83 (dd, J = 13.8, 7.2 Hz, 1 H), 2.74 (dd, J = 13.8, 7.5 Hz, 1 H),

2.54 (tdq, J = 7.4, 6.5, 5.1 Hz, 1 H), 2.01 (s, 3 H) ppm. ¹³C NMR:

δ = 170.7, 139.4, 137.7, 133.8, 129.4, 129.1, 128.7, 127.9, 126.7,

64.8, 56.3, 37.2, 35.1, 20.8 ppm. MS: m/z (%) = 333 (2) [M + H]⁺,

273 (5), 131 (100), 117 (10), 91 (30). HRMS: calcd. for C₁₈H₂₁O₄S

[M + H]⁺333.1161; found 333.1139.

2-Benzyl-3-hydroxypropyl Bromide (15Јe): Yield: 916 mg, 100%. ¹H

2-Benzyl-3-hydroxypropyl Phenyl Sulfone (14Јe): Yield: 138 mg, NMR: δ = 7.32–7.17 (m, 5 H), 3.69 (dd, J = 11.1, 5.1 Hz, 1 H),

1

95%. H NMR: δ = 7.81 (d, J = 7.8 Hz, 2 H), 7.56 (t, J = 7.5 Hz,

1 H), 7.47 (t, J = 7.8 Hz, 2 H), 7.25–7.02 (m, 5 H), 3.76 (dd, J =

11.1, 4.5 Hz, 1 H), 3.57 (dd, J = 11.1, 5.1 Hz, 1 H), 3.33 (dd, J =

14.4, 7.2 Hz, 1 H), 3.03 (dd, J = 14.4, 5.4 Hz, 1 H), 2.77 (dd, J =

3.62 (dd, J = 11.1, 6.9 Hz, 1 H), 3.55 (dd, J = 10.1, 4.4 Hz, 1 H),

3.40 (dd, J = 10.1, 5.3 Hz, 1 H), 2.71 (dd, J = 13.7, 7.2 Hz, 1 H),

2.66 (dd, J = 13.7, 7.5 Hz, 1 H), 2.19 (s, 1 H), 2.11 (qq, J = 7.1,

4.9 Hz, 1 H) ppm. ¹³C NMR: δ = 139.1, 129.2, 128.6, 126.5, 63.3,

4682

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4671–4686

Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

44.2, 35.8, 35.6 ppm. MS: m/z (%) = 230 and 228 (14 and 16)

[M]⁺, 212 and 210 (48 and 51), 131 (95), 117 (12), 91 (100). HRMS:

calcd. for C₁₀H₁₃O⁸¹Br [M]⁺230.0129; found 230.0058. HRMS:

calcd. for C₁₀H₁₃O⁷⁹Br [M]⁺228.0150; found 228.0117.

H), 2.75 (dd, J = 13.7, 7.7 Hz, 1 H), 2.64 (dd, J = 13.7, 7.1 Hz, 1

H), 2.14 (sept., J = 6.1 Hz, 1 H), 2.06 (s, 3 H), 0.95 (s, 9 H), 0.07

(s, 6 H) ppm. ¹³C NMR: δ = 171.0, 139.8, 129.1, 128.4, 126.1, 64.3,

61.8, 42.2, 34.2, 25.9, 20.9, 18.3, –5.5, –5.6 ppm. MS: m/z (%) =

323 (7) [M + H]⁺, 265 (22), 263 (21), 191 (21), 131 (100), 117 (92),

91 (27). HRMS: calcd. for C₁₈H₃₁O₃Si [M + H]⁺323.2042; found

323.2082.

Phosphonium Salts 16: Ph₃P (0.34 g, 1.31 mmol) under an argon

atmosphere was heated to 120 °C. Bromide 15 (1.31 mmol) was

added to the melted Ph₃P, and the reaction mixture was stirred at

120 °C for 2 d. The mixture was cooled to room temperature, and

the brownish residue was chromatographed (EtOAc/hexane, 1:1

and then EtOAc/MeOH, 97:3) to give the clean phosphonium salt

as a yellowish solid.

Hydroxysilanes 18Ј: Na₂CO₃(1.5 g) was added to a stirred solution

of acetate 18 (3.0 mmol) in dry MeOH (60 mL). The suspension

was stirred vigorously at room temperature for 1.5 h and was

stopped when TLC (hexane/EtOAc, 5:1) indicated that the starting

material was fully consumed. The mixture was filtered off by suc-

tion filtration to remove the Na₂CO₃and washed with methanol

and ether. The filtrate was evaporated to dryness, and the residue

was dissolved in ether. The ether phase was washed with acidic

water (pH 2.5, 3ϫ80 mL) until the pH of the aqueous layer was

neutral. Then the ether phase was washed with saturated NaCl

solution, dried with MgSO₄, filtered, and concentrated to give the

desired product as a yellow oil.

(2-Benzyl-3-hydroxypropyl)triphenylphosphonium Bromide (16Јe):

Yield: 323 mg, 60% (20% recovery of starting material). ¹H NMR:

δ = 7.83–6.88 (m, 20 H), 4.48 (ddd, J = 16.1, 13.9, 5.0 Hz, 1 H),

3.53 (dd, J = 11.4, 5.7 Hz, 1 H), 3.47 (dd, J = 11.4, 6.0 Hz, 1 H),

2.90 (ddd, J = 16.1, 13.2, 5.6 Hz, 1 H), 2.67 (dd, J = 13.3, 8.3 Hz,

1 H), 2.37 (dd, J = 13.3, 6.3 Hz, 1 H), 2.25 (m, 1 H) ppm. ¹³C

NMR: δ = 138.2, 134.7 (d, J = 2.3 Hz), 133.3 (d, J = 10.5 Hz),

130.2 (d, J = 12.8 Hz), 128.8, 128.3, 126.2, 118.2 (d, J = 84.8 Hz),

62.4 (d, J = 7.2 Hz), 38.4 (d, J = 6.5 Hz), 37.8 (d, J = 3.6 Hz), 23.1

(2-Hydroxymethylbutoxy) tert-Butyldimethylsilane (18Јb): Yield:

(d, J = 50.3 Hz) ppm. MS: m/z (%) = 411 (8) [M]⁺, 393 (100), 277 540 mg, 82%. H NMR: δ = 3.61 (dd, J = 9.9, 4.5 Hz, 1 H), 3.53

1

(7). HRMS: calcd. for C₂₈H₂₈OP [M]⁺411.1878; found 411.1876.

(dd, J = 10.8, 4.2 Hz, 1 H), 3.48 (dd, J = 9.9, 6.9 Hz, 1 H), 3.46

(dd, J = 10.8, 6.9 Hz, 1 H), 3.33 (br. s, 1 H), 1.47 (tquint., J = 6.8,

4.4 Hz, 1 H), 1.20 (dqd, J = 13.8, 7.8, 5.7 Hz, 1 H), 1.15 (ddq, J =

13.8, 8.1, 6.9 Hz, 1 H), 0.79 (t, J = 7.4 Hz, 3 H), 0.76 (s, 9 H),

–0.07 (s, 6 H) ppm. ¹³C NMR: δ = 65.7, 64.9, 43.9, 25.7, 20.4, 18.0,

11.5, –5.7, –5.8 ppm. MS: m/z (%) = 219 (26) [M + H]⁺, 201 (7),

189 (38), 161 (24), 87 (7), 73 (22). HRMS: calcd. for C₁₁H₂₇O₂Si

[M + H]⁺219.1780; found 219.1741.

Diethyl 3-Acetoxy-2-benzylpropylphosphonate (17e): A mixture of

P(OEt)₃(1.9 mL, 10.9 mmol) and bromide 15e (1.5 g, 5.4 mmol)

under an argon atmosphere was heated to 140 °C under Hickman

condenser for 20 h. The mixture was cooled to room temperature,

and the residue was chromatographed (EtOAc/hexane, 1:1 and then

EtOAc/MeOH, 97:3) to afford the desired product as a yellowish

oil (0.89 g, 50% yield; 20% recovery of starting material). ¹H

NMR: δ = 7.35–7.16 (m, 5 H), 4.18–3.98 (m, 6 H), 2.84 (dd, J =

13.5, 6.9 Hz, 1 H), 2.75 (dd, J = 13.5, 7.1 Hz, 1 H), 2.42 (sept., J

= 7.0 Hz, 1 H), 2.06 (s, 3 H), 1.84 (ddd, J = 22.8, 15.6, 7.2 Hz, 1

2-Benzyl-3-hydroxypropoxy tert-Butyldimethylsilane (18Јe): Yield:

743 mg, 92%. ¹H NMR: δ = 7.35–7.16 (m, 5 H), 3.77 (dd, J = 9.9,

4.2 Hz, 1 H), 3.75 (dd, J = 10.7, 3.8 Hz, 1 H), 3.65 (dd, J = 10.7,

H), 1.78 (ddd, J = 21.9, 15.6, 6.9 Hz, 1 H), 1.31 (t, J = 7.2 Hz, 3 6.5 Hz, 1 H), 3.65 (dd, J = 9.9, 6.3 Hz, 1 H), 2.93 (br. s, 1 H), 2.68

H), 1.30 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR: δ = 170.9, 138.9,

129.3, 128.5, 126.5, 66.1 (d, J = 8.9 Hz), 61.6 (d, J = 6.3 Hz), 38.4

(d, J = 10.4 Hz), 34.9 (d, J = 3.8 Hz), 26.8 (d, J = 140.1 Hz), 20.9,

16.44 (d, J = 6.1 Hz) ppm. MS: m/z = 329 [M + H]⁺, 287, 269, 283,

328.

(dd, J = 13.5, 7.8 Hz, 1 H), 2.63 (dd, J = 13.5, 5.4 Hz, 1 H), 2.02

(ttt, J = 7.5, 6.5, 3.9 Hz, 1 H), 0.95 (s, 9 H), 0.09 (s, 3 H), 0.09 (s,

3 H) ppm. ¹³C NMR: δ = 140.2, 129.1, 128.4, 126.0, 65.6, 65.2,

44.2, 34.2, 25.9, 18.2, –5.5 ppm. MS: m/z (%) = 269 [M + H]⁺, 131

(100), 117 (10), 105 (21), 91 (46). HRMS: calcd. for C₁₅H₂₉O₂Si

[M + H]⁺269.1937; found 269.1936.

Silyl Acetates 18: 2-(Alkyl)-1,3-propanediol monoacetate 10

(27 mmol) in dry DMF (20 mL) was added to a solution of imid-

azole (2.7 g, 39.5 mmol) and tert-butylchlorodimethylsilane (6.0 g,

39.5 mmol) in dry DMF (60 mL). After stirring overnight at room

temperature, the mixture was diluted with diethyl ether (100 mL)

and water (50 mL) and the layers were separated. The aqueous

phase was further extracted with CH₂Cl₂(3ϫ75 mL), and the com-

bined organic layer was washed with water and brine, dried with

MgSO₄, and filtered. Evaporation of the solvent afforded the clean

product as a yellow oil.

Silyl Aldehydes 19

(2-Formylbutoxy) tert-Butyldimethylsilane (19b): Dess–Martin rea-

gent (0.6 g, 1.37 mmol) was added to a stirred solution of alcohol

18Јb (0.2 g, 0.92 mmol) in dry CH₂Cl₂(70 mL) under an argon at-

mosphere at 0 °C. The ice bath was removed, and the reaction mix-

ture was allowed to proceed at room temperature for 3.5 h. CH₂Cl₂

(60 mL) was added, and the mixture was washed with saturated

Na₂S₂O₅solution (60 mL). The layers were separated, and the or-

ganic layer was washed with saturated NaHCO₃(2ϫ) and saturated

NaCl solutions, dried with MgSO₄, and filtered. Evaporation of

the solvent afforded the clean aldehyde as a yellow oil (0.11 g, 55%

yield). ¹H NMR: δ = 9.70 (d, J = 2.4 Hz, 1 H), 3.86 (d, J = 5.4 Hz,

2 H), 2.34 (ttd, J = 7.0, 5.4, 2.4 Hz, 1 H), 1.72 (dquint., J = 14.5,

7.3 Hz, 1 H), 1.53 (dquint., J = 14.5, 7.2 Hz, 1 H), 0.94 (t, J =

(2-Acetoxymethylbutoxy) tert-Butyldimethylsilane (18b): Yield:

1

6.77 g, 96%. H NMR: δ = 4.04 (dd, J = 11.1, 6.0 Hz, 1 H), 4.01

(dd, J = 11.1, 5.7 Hz, 1 H), 3.56 (dd, J = 9.9, 4.8 Hz, 1 H), 3.51

(dd, J = 9.9, 5.7 Hz, 1 H), 2.00 (s, 3 H), 1.66 (ttt, J = 6.9, 6.0,

5.1 Hz, 1 H), 1.36 (dqd, J = 13.8, 7.8, 6.9 Hz, 1 H), 1.29 (dquint.,

J = 13.8, 7.1 Hz, 1 H), 0.88 (t, J = 7.5 Hz, 3 H), 0.84 (s, 9 H), –0.01 7.5 Hz, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H) ppm. ¹³C NMR: δ = 204.9,

(s, 6 H) ppm. ¹³C NMR: δ = 171.2, 64.5, 62.3, 41.9, 25.9, 21.0,

61.7, 55.9, 25.9, 18.7, 18.3, 11.5, –5.4, –5.5 ppm. MS: m/z (%) =

20.8, 18.3, 11.5, –5.5 ppm. MS: m/z (%) = 261 (4) [M + H]⁺, 201 217 (11) [M + H]⁺, 201 (33), 159 (100), 84 (42), 71 (25). HRMS:

(9), 129 (8). HRMS: calcd. for C₁₃H₂₉O₃Si [M + H]⁺261.1886;

found 261.1880.

calcd. for C₁₁H₂₅O₂Si [M + H]⁺217.1624; found 217.1575.

(2-Benzyl-3-oxopropoxy) tert-Butyldimethylsilane (19e): A solution

of DMSO (1.86 mL, 26.2 mmol) in dry CH₂Cl₂(6.5 mL) was added

to a stirred solution of oxalyl chloride (1.0 mL, 11.8 mmol) in dry

CH₂Cl₂(28 mL) under an argon atmosphere and cooled to –60 °C.

(3-Acetoxy-2-benzylpropoxy) tert-Butyldimethylsilane (18e): Yield:

8.64 g, 99%. ¹H NMR: δ = 7.35–7.19 (m, 5 H), 4.10 (d, J = 6.0 Hz,

2 H), 3.62 (dd, J = 9.9, 4.8 Hz, 1 H), 3.55 (dd, J = 9.9, 5.1 Hz, 1

Eur. J. Org. Chem. 2010, 4671–4686

www.eurjoc.org

4683

S. Mirilashvili, N. Chasid-Rubinstein, A. Albeck

FULL PAPER

After 10 min, a solution of alcohol 18Јe (3.0 g, 10.7 mmol) in dry

CH₂Cl₂(15 mL) was added, and the reaction mixture was stirred

for 15 min at –60 °C. Et₃N (7.4 mL, 54.2 mmol) was added, and

the cooling bath was removed, allowing the solution to reach room

temperature, and the mixture was stirred for an additional 20 min.

Water was added, and the aqueous phase was re-extracted with

CH₂Cl₂(2ϫ40 mL). The combined organic layer was washed suc-

cessively with water, 0.5  HCl solution (2ϫ), water, and saturated

NaCl solution. The organic layer was dried with MgSO₄, filtered,

and concentrated to yield the product, which was further purified

by chromatography (hexane/EtOAc, 3:1) to afford the clean alde-

stirred at room temperature for 15 min. A solution of mesylate 21e

(1.5 g, 4.2 mmol) in dry THF (6 mL) was added, and the mixture

was stirred overnight at 50 °C. The mixture was cooled to room

temperature, diluted with CH₂Cl₂(30 mL), and washed with 10%

NaOH solution (50 mL). The aqueous phase was re-extracted with

CH₂Cl₂(3ϫ50 mL), and the volume of the combined organic

phase was partially reduced to 50 mL under vacuum. The organic

layer was washed with saturated NaCl solution, dried with MgSO₄,

filtered, and concentrated to provide a yellow oil, which was chro-

matographed (hexane/EtOAc, 5:1) to give the clean product (1.34 g,

1

73% yield). H NMR: δ = 7.59–7.50 (m, 5 H), 7.30–7.16 (m, 5 H),

1

hyde as a yellow oil (2.87 g, 97% yield). H NMR: δ = 9.82 (d, J

3.64 (dd, J = 10.2, 3.9 Hz, 1 H), 3.52 (dd, J = 13.0, 6.4 Hz, 1 H),

3.50 (dd, J = 10.2, 4.5 Hz, 1 H), 3.47 (dd, J = 13.0, 6.8 Hz, 1 H),

2.78 (d, J = 7.2 Hz, 2 H), 2.30 (ttt, J = 7.8, 6.6, 4.3 Hz, 1 H), 0.90

(s, 9 H), 0.01 (s, 3 H), 0.01 (s, 3 H) ppm. ¹³C NMR: δ = 154.7,

139.5, 133.9, 130.2, 129.9, 129.3, 128.5, 126.3, 124.0, 62.7, 42.3,

36.6, 35.3, 26.0, 18.3, –5.40, –5.44 ppm. MS: m/z (%) = 441 (76)

[M + H]⁺, 383 (61), 237 (46), 163 (25), 131 (36), 117 (24), 91 (100).

HRMS: calcd. for C₂₃H₃₃N₄OSiS [M + H]⁺441.2144; found

441.2130.

= 1.5 Hz, 1 H), 7.35–7.20 (m, 5 H), 3.93 (dd, J = 10.5, 4.2 Hz, 1

H), 3.78 (dd, J = 10.5, 5.4 Hz, 1 H), 3.09 (dd, J = 13.8, 6.0 Hz, 1

H), 2.86 (dd, J = 13.8, 8.1 Hz, 1 H), 2.72 (dtdd, J = 8.1, 5.9, 4.4,

1.5 Hz, 1 H), 0.94 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. ¹³C

NMR: δ = 203.9, 139.0, 129.1, 128.6, 126.4, 60.8, 55.7, 31.3, 25.9,

18.3, –5.4 ppm. MS: m/z (%) = 279 (12) [M + H]⁺, 278 (8) [M]⁺,

277 (40), 221 (28), 191 (7), 145 (34), 117 (45), 105 (12), 91 (95).

HRMS: calcd. for C₁₆H₂₆O₂Si [M]⁺278.1702; found 278.1647.

(2-Benzyl-3-diphenylselenoacetalpropoxy) tert-Butyldimethylsilane

(20e): A solution of aldehyde 19e (0.28 g, 1.0 mmol) in dry CCl₄

(0.5 mL) was slowly added under an argon atmosphere with stirring

to a suspension of anhydrous zinc chloride (0.07 g, 0.5 mmol) in a

solution of selenophenol (0.31 g, 2.0 mmol) in dry CCl₄(1 mL).

The reaction mixture was stirred at room temperature for 3.5 h and

then diluted with diethyl ether (5 mL). The ether phase was washed

with water and saturated NaCl solution, dried with MgSO₄, fil-

tered, concentrated, and purified by chromatography (petroleum

ether 40–60 °C) to give the clean selenoacetal (0.14 g, 24% yield).

2-Benzyl-3-(tert-butyldimethylsilyloxy)propyl (1-Phenyl-1H-tetraz-

ol-5-yl) Sulfone (23e₁): m-CPBA (75%, 1.68 g, 9.7 mmol) was added

to a stirred solution of sulfide 22e₁(1.34 g, 3.0 mmol) in dry

CH₂Cl₂(24 mL) at 0 °C. The ice bath was removed, and the reac-

tion mixture was allowed to proceed at room temperature over-

night. CH₂Cl₂(10 mL) was added, and the mixture was washed

with saturated Na₂S₂O₅/10% NaOH solution (1:1, 30 mL). The

layers were separated, and the aqueous phase was further extracted

with CH₂Cl₂(3ϫ30 mL). The combined organic layer was washed

with saturated NaHCO₃and saturated NaCl solutions, dried with

¹H NMR: δ = 7.62–7.00 (m, 15 H), 4.84 (d, J = 2.7 Hz, 1 H), 3.81 MgSO₄, filtered, and concentrated to give a yellow oil (1.43 g, 98%

(dd, J = 10.2, 7.2 Hz, 1 H), 3.68 (dd, J = 10.2, 4.8 Hz, 1 H), 3.11

(dd, J = 13.7, 6.0 Hz, 1 H), 2.63 (dd, J = 13.7, 8.4 Hz, 1 H), 2.25

(ddddd, J = 8.5, 6.9, 6.0, 4.8, 2.7 Hz, 1 H), 0.84 (s, 9 H), –0.04 (s,

3 H), –0.07 (s, 3 H) ppm. ¹³C NMR: δ = 140.1, 133.7, 133.5, 129.2,

128.4, 127.7, 127.6, 126.2, 63.1, 48.4, 47.8 (d, J = 85.3 Hz), 35.5,

26.0, 18.3, –5.3, –5.4 ppm. MS: m/z (%) = 576 (4) [M]⁺, 461 (2),

yield), which was crystallized (hexane/EtOAc, 3:1) to afford a white

crystalline product. ¹H NMR: δ = 7.47–7.60 (m, 5 H), 7.13–7.28

(m, 5 H), 3.96 (dd, J = 14.9, 6.9 Hz, 1 H), 3.74 (dd, J = 10.2,

3.9 Hz, 1 H), 3.63 (dd, J = 14.9, 5.1 Hz, 1 H), 3.53 (dd, J = 10.2,

3.2 Hz, 1 H), 2.91 (dd, J = 13.5, 6.2 Hz, 1 H), 2.84 (dd, J = 13.5,

8.7 Hz, 1 H), 2.62 (dtq, J = 8.7, 6.6, 4 Hz, 1 H), 0.91 (s, 9 H), 0.04

419 (5), 261 (100), 145 (51). HRMS: calcd. for C₂₈H₃₆O⁸⁰Se₂Si (s, 6 H) ppm. ¹³C NMR: δ = 153.8, 138.3, 133.0, 131.3, 129.6,

[M]⁺576.0866; found 576.0855.

128.5, 126.6, 125.2, 62.0, 56.4, 37.5, 36.7, 25.9, 18.2, –5.6 ppm. MS:

m/z (%) = 473 (3) [M + H]⁺, 269 (11), 175 (35), 131 (54), 117 (96),

91 (100). HRMS: calcd. for C₂₃H₃₃N₄O₃SiS [M + H]⁺473.2043;

found 473.2019.

2-Benzyl-3-(tert-butyldimethylsilyloxy)propylmethane

Sulfonate

(21e): A solution of alcohol 18Јe (1.2 g, 4.3 mmol) and Et₃N

(0.9 mL, 6.4 mmol) in dry CH₂Cl₂(7 mL) under an argon atmo-

sphere was cooled to 0 °C. The solution was stirred for 30 min,

followed by the slow addition (10 min) of MsCl (0.5 mL, 6.6 mmol)

in dry CH₂Cl₂(1.5 mL). Stirring was continued at 0 °C under an

argon atmosphere for 3 h. The solution turned yellow. Ether was

added, and the solution was washed with 1  HC1 and saturated

NaHCO₃and saturated NaCl solutions. The organic phase was

dried with MgSO₄, filtered, and concentrated to give the clean

product (1.51 g, 98% yield). ¹H NMR: δ = 7.31–7.16 (m, 5 H), 4.21

(dd, J = 9.6, 5.1 Hz, 1 H), 4.17 (dd, J = 9.6, 6 Hz, 1 H), 3.63 (dd,

J = 10.2, 4.5 Hz, 1 H), 3.53 (dd, J = 10.2, 6 Hz, 1 H), 2.93 (s, 3

H), 2.70 (dd, J = 13.7, 7.8 Hz, 1 H), 2.64 (dd, J = 13.7, 7.2 Hz, 1

H), 2.16 (tquint., J = 7.5, 5.4 Hz, 1 H), 0.91 (s, 9 H), 0.04 (s, 6

H) ppm. ¹³C NMR: δ = 138.9, 129.1, 128.5, 126.3, 69.4, 61.1, 42.7,

36.8, 33.5, 25.9, 18.2, –5.5 ppm. MS: m/z (%) = 359 (3) [M + H]⁺,

263 (11), 153 (51), 131 (100), 91 (86). HRMS m/z for C₁₇H₃₁O₄SiS

[M + H]⁺359.1712; found 359.1721.

2-Benzyl-3-(tert-butyldimethylsilyloxy)propyl Phenyl Sulfone (23e):

Prepared from alcohol 14Јe according to the procedure described

1

for 18e. Yield: 84%. H NMR: δ = 7.85 (d, J = 7.8 Hz, 2 H), 7.65

(t, J = 7.8 Hz, 1 H), 7.53 (t, J = 7.8 Hz, 2 H), 7.30–7.06 (m, 5 H),

3.65 (dd, J = 9.9, 4.2 Hz, 1 H), 3.50 (dd, J = 9.9, 4.2 Hz, 1 H), 3.37

(dd, J = 14.4, 6.6 Hz, 1 H), 3.01 (dd, J = 14.4, 5.1 Hz, 1 H), 2.80

(dd, J = 13.8, 6.6 Hz, 1 H), 2.76 (dd, J = 13.8, 7.5 Hz, 1 H), 2.33

(qq, J = 6.9, 4.8 Hz, 1 H), 0.89 (s, 9 H), 0.02 (s, 3 H), 0.01 (s, 3

H) ppm. ¹³C NMR: δ = 139.8, 138.8, 133.6, 129.3, 129.2, 128.5,

127.9, 126.4, 62.8, 56.2, 38.0, 36.9, 25.9, 18.2, –5.5 ppm. MS: m/z

(%) = 405 (2) [M + H]⁺, 347 (100), 131 (42), 91 (42). HRMS: calcd.

for C₂₂H₃₃O₃SiS [M + H]⁺405.1920; found 405.1952.

2-(tert-Butyldimethylsilyloxy)methylbutyl (1-Phenyl-1H-tetrazol-5-

yl) Sulfone (23b₁): Hydroxy sulfide 13Јb₁was silylated according to

the procedure described for 18e, followed by m-CPBA oxidation as

described for 14. Yield: 86% (overall). ¹H NMR: δ = 7.70–7.55 (m,

5 H), 3.98 (dd, J = 14.7, 6.5 Hz, 1 H), 3.79 (dd, J = 10.2, 4.2 Hz,

1 H), 3.65 (dd, J = 14.7, 5.1 Hz, 1 H), 3.65 (dd, J = 10.2, 4.4 Hz,

1 H), 2.24 (ttt, J = 6.5, 5.8, 4.4 Hz, 1 H), 1.61 (quint., 2 H), 0.94

(t, J = 7.4 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s, 6 H) ppm. ¹³C NMR: δ

2-Benzyl-3-(tert-butyldimethylsilyloxy)propyl (1-Phenyl-1H-tetraz-

ol-5-yl) Sulfide (22e₁): 1-Phenyl-1H-tetrazol-5-thiol (2.46 g,

13.8 mmol) was dissolved in dry THF (29 mL). NaH (60% in min-

eral oil, 0.54 g) was added slowly, and the white suspension was

4684

www.eurjoc.org

Eur. J. Org. Chem. 2010, 4671–4686

Building Blocks for the Synthesis of Peptidyl Olefin Peptidomimetics

Terakubo, J. O. Trent, S. C. Peiper, N. Yamamoto, H. Nakash-

ima, A. Otaka, N. Fujii, J. Med. Chem. 2005, 48, 380; c) K.

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Kennewell, J. B. Taylor, J. Chem. Soc. Perkin Trans. 1 1982,

307; e) P. Wipf, J. Xiao, J. Jiang, N. Belikova, V. A. Tyurin,

M. P. Fink, V. E. Kagan, J. Am. Chem. Soc. 2005, 127, 12460;

f) K. Fujimoto, R. Doi, R. Hosotani, M. Wada, J.-U. Lee, T.

Koshiba, T. Ibuka, H. Habashita, K. Nakai, N. Fujii, M. Im-

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ani, S. Higashide, T. Ibuka, H. Habashita, K. Nakai, N. Fujii,

M. Imamura, Pancreas 1995, 10, 301; h) J. S. Wai, D. L. Bam-

berger, T. E. Fisher, S. L. Graham, R. L. Smith, J. B. Gibbs,

S. D. Mosser, A. I. Oliff, D. L. Pompliano, E. Rands, N. E.

Kohl, Bioorg. Med. Chem. 1994, 2, 939; i) M. T. Cox, J. J.

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= 154.1, 133.2, 131.5, 129.7, 125.2, 62.6, 56.8, 37.2, 25.9, 23.8, 18.3,

11.0, –5.5, –5.6 ppm. MS: m/z (%) = 411 (49) [M + H]⁺, 353 (70),

325 (30), 265 (79), 175 (99), 145 (35), 117 (100). HRMS: calcd. for

C₁₈H₃₁N₄O₃SiS [M + H]⁺411.1886; found 411.1859.

trans-Dipeptidyl Olefin Precursors 24: LiHMDS (1  in THF,

0.23 mL, 0.23 mmol) was slowly added to a stirring solution of

sulfone 23 (0.23 mmol) in dry THF (1 mL) and HMPA (0.2 mL)

under an argon atmosphere at –78 °C. After 20 min, a solution

of N-trityl-alaninal (104 mg, 0.33 mmol) in dry THF (0.8 mL) was

added slowly. After 3 h at –78 °C, the reaction mixture was further

stirred at room temperature for 15 h. Ether (50 mL) and water

(35 mL) were added, and the organic phase was washed with brine

(30 mL), dried with MgSO₄, filtered, concentrated, and chromato-

graphed (hexane/EtOAc, 19:1) to yield the clean product as a clear

oil.

[4]

[5]

a) I. E. Andersson, B. Dzhambazov, R. Holmdahl, A. Linus-

son, J. Kihlberg, J. Med. Chem. 2007, 50, 5627; b) Y. Fu, J.

Bieschke, J. W. Kelly, J. Am. Chem. Soc. 2005, 127, 15366.

N-Trityl-5-amino-1-(tert-butyldimethylsilyloxy)-2-ethyl-3-hexene

(24b): Yield: 25 mg, 22%. H NMR: δ = 7.55–7.11 (m, 15 H), 5.28

1

(dd, J = 15.6, 6.3 Hz, 1 H), 5.14 (dd, J = 15.6, 8.1 Hz, 1 H), 3.40

(dd, J = 9.8, 6.0 Hz, 1 H), 3.35 (dd, J = 9.8, 6.8 Hz, 1 H), 3.02 (br.

quint., J = 6.3 Hz, 1 H), 1.90 (m, 1 H), 1.45 (m, 1 H), 1.10 (m, 1

H), 0.86 (s, 9 H), 0.80 (t, J = 7.5 Hz, 3 H), 0.59 (d, J = 6.0 Hz, 3

H), 0.00 (s, 6 H) ppm. ¹³C NMR: δ = 147.2, 144.7, 137.5, 129.7,

129.2, 129.1, 128.4, 128.0, 127.8, 127.5, 126.9, 126.7, 126.3, 71.8,

66.7, 50.8, 46.7, 26.1, 24.0, 23.8, 18.5, 15.4, –5.2 ppm. MS: m/z (%)

= 500 [M + H]⁺, 484 (1), 422 (10), 258 (12), 243 (100). HRMS:

calcd. for C₃₃H₄₆NOSi [M + H]⁺500.3349; found 500.3305.

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N-Trityl-5-amino-2-benzyl-1-(tert-butyldimethylsilyloxy)-3-hexene

1

(24e): Yield: 40 mg, 31%. H NMR: δ = 7.82–7.08 (m, 20 H), 5.28

(ddd, J = 15.8, 7.7, 0.9 Hz, 1 H), 5.13 (dd, J = 15.8, 6.2 Hz, 1 H),

3.40 (dd, J = 9.9, 5.4 Hz, 1 H), 3.35 (dd, J = 9.9, 6.3 Hz, 1 H), 2.97

(br. quint., J = 6.1 Hz, 1 H), 2.76 (dd, J = 13.5, 6.3 Hz, 1 H), 2.42

(dd, J = 13.5, 7.2 Hz), 2.27 (br. sext., J = 6.6 Hz, 1 H), 0.88 (s, 9

H), 0.57 (d, J = 6.0 Hz, 3 H), 0.06 (s, 6 H) ppm. ¹³C NMR: δ =

147.0, 144.6, 140.6, 137.1, 125.6, 129.0, 128.3, 71.5, 65.3, 50.5, 46.1,

37.5, 25.9, 23.4, 18.3, –5.3, –5.4 ppm. HRMS: calcd. for

C₃₈H₄₈NOSi [M + H]⁺562.3505; found 562.3519.

[6]

[7]

[8]

Acknowledgments

This research was partially supported by the Israel Science Founda-

tion (grant no. 1115/04) and by the Marcus Center for Pharmaceu-

tical and Medicinal Chemistry, Bar Ilan University.

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Received: April 18, 2010

Published Online: July 13, 2010

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Article Doi

Optically active N- and C-terminal building blocks for the synthesis of peptidyl olefin peptidomimetics

DOI: 10.1002/ejoc.201000539

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