Modular hemisyntheses of boronato- and trifluoroborato-substituted L -NHBoc amino acid and peptide derivatives

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FULL PAPER

DOI: 10.1002/ejoc.201301084

Modular Hemisyntheses of Boronato- and Trifluoroborato-Substituted

-NHBoc Amino Acid and Peptide Derivatives

L

Hassib Audi,^[a]Emmanuelle Rémond,^[a]Marie-Joëlle Eymin,^[a]Arnaud Tessier,^[a][‡]

Raluca Malacea-Kabbara,^[a]and Sylvain Jugé*^[a]

Keywords: Wittig reactions / Amino acids / Phase-transfer catalysis / Boron / Iridium / Trifluoroborates

Modular hemisyntheses of boronato- and trifluoroborato-

substituted amino acid and peptide derivatives by using Wit-

tig and C–H iridium-catalyzed borylation as key reactions,

are described. Amino ester precursors bearing an aromatic

moiety on a lateral chain were prepared by reaction of a new

performed with a dipeptide in 78% yield. Finally, reaction of

the boronato amino acids with KHF₂or NaI in the presence

of chloramine led to the corresponding trifluoroborato or iodo

derivatives in good to excellent yields. A study of the hydrol-

ysis of the trifluoroborates in buffer solution by using ¹⁹F

NMR monitoring, showed an excellent stability for the 3-

methylthien-2-yl amino acid derivative. Consequently, this

hemisynthesis offers an efficient route for the modular prepa-

ration of boron amino acid derivatives that are useful for the

synthesis of modified peptides and the fluoride labelling of

peptides.

L-NHBoc-amino acid Wittig reagent with the corresponding

aromatic aldehydes. After esterification and hydrogenation,

the borylation of amino esters was achieved with yields up

to 82% by using the catalysed reaction of bis(pinacolato) di-

borane reagent (B₂Pin₂) in the presence of an iridium com-

plex. Interestingly, this iridium-catalyzed borylation was also

tential. In this context, compounds 1–8 are representative

examples of various classes of boron amino acid derivatives

that are commonly used for enzyme inhibition,^[6c,19]medical

imaging,^[17]or BNCT,^[7,12]or as simple building blocks for

the synthesis of nonproteogenic amino acids and modified

peptides (Figure 1).^[11–18]

Introduction

Organoboron derivatives are useful compounds in or-

ganic synthesis as Lewis acids^[1]or reagents for transition-

metal-catalyzed cross-coupling reactions, allowing straight-

forward formation of carbon–carbon bonds, particularly by

using palladium complexes.^[2]Organoboron compounds,

which are easily obtained by hydroboration^[2,3]or bo-

rylation reactions,^[4,5]can be used as pharmaceutical agents,

in boron neutron capture therapy (BNCT) for cancer treat-

ment, and also for drug delivery.^[6–8]Moreover, these com-

pounds are of great interest as building blocks for incorpo-

rating short and long-lived carbon, nitrogen, oxygen and

halogens isotopes, in compounds with biological or thera-

peutic uses.^[9]Recently, organoboron compounds were in-

vestigated to design radiolabelled trifluoroborate derivatives

from reactions with ¹⁸F^–radioisotopes, which are useful for

medical imaging by Positron Emission Tomography

(PET).^[10]

So far, enantiomerically pure boron amino acids have

been prepared from enzymatic resolution of racemic mix-

tures,^[12b,20]nucleophilic α-amination of pinanediol

boronates,^[11]functionalization of glycine or alanine equiva-

lents with a substituent bearing a boron group,^[12]or by

rhodium-catalyzed asymmetric hydrogenation.^[12b]On the

other hand, direct borylation of the l-amino acid moiety

can be achieved either by hydroboration,^[13]by reaction of

boron reagent with an alanine equivalent,^[14]or by palla-

dium-catalysed cross-coupling processes.^[15]However, the

described boron amino acids are mainly derived from ala-

nine, phenylalanine, vinyl- or allylglycine, and their design

is still hampered by the lack of a general synthetic route.

In connection with our ongoing investigation on the

stereoselective synthesis of heterosubstituted amino

acids,^[21,22]we recently reported the use of phosphonium

salt 9 as a convenient Wittig reagent, affording γ,δ-unsatu-

rated amino acids from aldehydes or activated ketones

(Scheme 1).^[22]This new, efficient reaction, which proceeds

under phase-transfer conditions, leads to the corresponding

amino acids by C=C bond formation on the lateral chain

without racemization. Interestingly, the amino acid Wittig

reagent 9 reacts with functionalized aldehydes bearing vari-

ous substituents, such as trifluoromethyl, cyano, nitro,

Relatively few examples of boron amino acid derivatives

have been described so far. However, their use in the synthe-

sis of modified peptides^[11–17]and their labelling by radio-

elements or use as cold-probes,^[16,18]have considerable po-

[a] Institut de Chimie Moléculaire de l’Université de Bourgogne,

ICMUB-StéréochIM, UMR 6302,

9 av. A. Savary, BP 47870, 21078 Dijon Cedex, France

E-mail: sylvain.juge@u-bourgogne.fr

[‡] Present address: UFR des Sciences et des Techniques

2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,

France

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201301084.

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Figure 1. Representative examples of boron-containing amino acids and derivatives.^[11–19]

Scheme 1. Direct stereoselective synthesis of boronato- and trifluoroborato-substituted amino acid derivatives 11a and 12a, respectively,

by using the Wittig reagent 9.

ferrocenyl or azido to afford the corresponding γ,δ-unsatu- and ¹⁹F NMR spectra show broad signals at 2.9 and

rated amino acids. Our interest in this chemistry led us to –138.9 ppm, respectively, that are characteristic of the

the stereoselective synthesis of boron-containing amino BF₃K substituent.^[23]Moreover, two sets of ethylenic pro-

1

acid derivatives supported by aromatic or heteroaromatic tons in 20:80 ratio were observed in the H NMR spectra,

substituents.

due to the presence of the Z/E mixture.^[24]

We now report an efficient and modular synthesis of

Due to the short lifetime of the [¹⁸F^–] radioisotope

boronate amino acids derivatives based on tandem Wittig (110 min),^[10e]the kinetics of the trifluoroborate moiety for-

reaction and catalyzed borylation. The boronate amino ac- mation and its stability under physiological conditions are

ids were used for the preparation of trifluoroborate deriva- crucial for the suitable design of boron amino acid deriva-

tives, for which only one example has been described so tives for PET medical imaging, so that good quality images

far,^[15b]and their stability under hydrolysis conditions was can be expected regardless of their bioavailability.^[25]Re-

investigated.

lated to the first point, the formation of the trifluoroborate

is sufficiently fast (30 min at room temp.) to allow work up

and purification of the labelled products. However, because

trifluoroborate 12a is completely hydrolyzed after 10 min,

Results and Discussion

When the phosphonium amino acid derivative 9 reacts this compound is of minimal interest for [¹⁸F^–] labelling.^[26]

with 4-(pinacolatoboronato)benzaldehyde (10a), the γ,δ-un- Recently, it has been shown that the hydrolysis of aryltri-

saturated boron amino acid derivative 11a is obtained in fluoroborate compounds depends on the substituents borne

57% yield as a mixture of (Z,E)-isomers in 25:75 ratio by the aromatic moiety.^[26a]Basically, electron-withdrawing

(Scheme 1). Based on fluorination conditions reported in (EW) substituents could retard the hydrolysis, whereas their

literature,^[1c]the corresponding trifluoroborato derivative electron-donating (ED) counterparts or trifluoroborate-

12a was obtained from 11a by reaction with KHF₂in a based heteroaromatics could enhance it.^[26b]To develop the

methanol/water (10:8) mixture. After 30 min reaction at synthesis of new trifluoroborato-aryl amino acids, which

room temperature, the desired compound 12a was obtained are notably more robust with regard to hydrolysis, we inves-

in 67% yield and was characterised by ¹H, ¹³C, ¹¹B and ¹⁹

NMR analysis in [D₆]dimethyl sulfoxide (DMSO). The ¹¹B cially available (pinacolato)boronato aromatic aldehydes

F

tigated the reaction of the Wittig reagent 9 with commer-

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Boron-Substituted Amino Acid and Peptide Derivatives

Scheme 2. Wittig reaction of (pinacolato)boronato aldehydes 10b–d with phosphonium salt 9.

10b–d, bearing either fluoro substituents or furanyl-, or thi- Table 1. Preparation of methyl amino esters 14 from aromatic alde-

hydes 10e–k.

enyl-based heteroaromatics (Scheme 2).

Using the conditions of the Wittig reaction, phosphon-

ium salt 9 reacted with (pinacolato)boronato aromatic alde-

hydes 10b–d to afford γ,δ-unsaturated amino acid deriva-

tives 11b–d in 74–82% yields. Unfortunately, the boronate

moiety was eliminated (Scheme 2). This unexpected side-

reaction can be explained by cleavage of the carbon–boron

bond under basic conditions, as the aromatic residue is a

better leaving group and the carbanion, i.e., difluorophenyl,

furanyl or thienyl moiety, is more stabilized than in com-

pounds 10a and 11a. To circumvent this side-reaction, the

borylation on the aromatic substituent of amino acid deriv-

atives was studied.

Over the past decade, the borylation of aromatic com-

pounds catalyzed by palladium or iridium complexes has

emerged as a powerful method for the preparation of useful

boron derivatives.^[5,15]Interestingly, the catalyzed bo-

rylation could be achieved by direct C–H bond activation

of aromatic or heteroaromatic compounds,^[5b,5e,5f]using

iridium complexes as catalysts, even when the substrate is a

phenylalanine derivative.^[15]Therefore, the catalyzed bo-

rylation was studied for a series of methyl amino esters 14,

which are substituted in the δ-position of the lateral chain

by an aromatic substituent bearing various EW or ED

by column chromatography. [d] Reactions were performed at room

groups (Table 1).

[a] The reactions were performed at 90 °C for 15 h in chlorobenzene

and with a 9/10/base ratio of 1:2:6. [b] Determined on the basis of

¹H NMR spectroscopic analysis. [c] Isolated yield after purification

temp. with a 11/TMSCHN₂ratio of 1:1.2. [e] The Hydrogenations

were performed in methanol at room temp. by using Pd/C (5%) as

catalyst under 10 bar H₂. [f] Overall yield from the Wittig reagent

9.

Using aldehydes 10e–k, methyl amino esters 14a–g could

be conveniently prepared in three steps in 53–87% overall

yield (Table 1). First, aldehydes 10e–k reacted with the Wit-

tig reagent 9 to afford the desired γ,δ-unsaturated amino

acid derivatives 11c–i in 66–93% isolated yields (Table 1). procedure drawn from the pioneering works of Miyaura,

These compounds were obtained as Z/E mixtures in 13:87 Hartwig, Smith and others (Scheme 3).^[5,15d,15e]Under these

to 25:75 ratios. Because of the side-reactions that occur dur- conditions, the use of thienyl substrate 14a led to a mixture

ing the catalyzed borylation due to the presence of the of mono- and bis(pinacolato)boronato-substituted amino

double bond and the free carboxylic acid function,^[27]the esters 15a and 15b in 82% yield and in 30:70 ratio (Table 2,

amino acid derivatives 11c–i were converted into methyl es- entry 1). However, when the reaction was performed at

ter intermediates 13a–g by reaction with TMSCHN₂, and 60 °C, monoboronate 15a was obtained, but in lower yield

then hydrogenated into products 14a–g by using Pd/C (5%) (31%; entry 2). In the case of 3-methylthienyl substrate 14b,

as catalyst (Table 1).

the catalyzed borylation afforded 5-(pinacolato)boronato

The borylation of substrates 14a–g was achieved through derivative 15c in 71% isolated yield (entry 3). When the bor-

known C–H activation methodologies by using bis(pinacol- ylation was performed with amino esters 14d, 14e or 14g,

ato)diboron (B₂pin₂) in the presence of an iridium catalyst, the corresponding m-boronato derivatives 15f, 15g, or 15i

by heating at 90 °C in hexane in a closed flask, following a were obtained in 60, 57 and 47% yields, respectively (entries

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Scheme 3. Catalyzed borylation of amino esters derivatives 14 and their use to afford iodo- or trifluoroboronato amino acid derivatives

16 and 17.

Table 2. Preparation of boronato- and trifluoroborato-substituted amino acid derivatives 15 and 17 from methyl amino esters 14.^[a]

[a] Reaction conditions: [Ir(OMe)COD]₂, dtbpy, B₂pin₂, hexane, 90 °C, 16 h. [b] Isolated yield. [c] Reaction with KHF₂for compounds

15c–g. [d] Yield of the mixture 15a and 15b. [e] 99% ee checked by HPLC analysis on Chiralpak IB. [f] Catalyzed borylation, then

treatment by LiOH. [g] Overall yield from 14c.

6, 7 and 9). The regioselectivity of the borylation of amino

Moreover, 3,5-difluoro-4-(pinacolato)boronatophenyl-

acids 14d, 14e, and 14g, was fully consistent with the steric substituted amino ester 15d could be hydrolyzed at room

hindrance induced by the aromatic moiety, as described pre- temperature by using LiOH in a mixture of methanol/water

viously in aromatic series.^[5i]Unfortunately, borylation of (2:1), to afford the corresponding carboxylic acid derivative

the 3,5-bis(trifluoromethyl)phenyl substrate 14f did not oc- 15e in 44% overall yield from substrate 14c (entry 5).

cur under these conditions. This is probably due to the ste-

The (pinacolato)boronato compounds 15c–g could be

ric hindrance by the substituents placed at the meta-posi- used in the preparation of iodo- or trifluoroborato-amino

tion of the aromatic moiety (entry 8). Conversely, when the acid derivatives 16 or 17, according to conditions described

catalyzed borylation was performed with 3,5-difluoro- in the literature^[1c,3,9,28](Scheme 3). For example, boronato

phenyl substrate 14c, the corresponding target p-(pinac- amino acid derivative 15c reacted with NaI during 30 min,

olato)boronato amino acid derivative 15d was afforded in in the presence of chloramine T, to provide 5-iodo-3-meth-

74% isolated yield (entry 4). The enantiomeric purity of 15d ylthienyl amino acid derivative 16 in 68% yield (Scheme 3,

was readily checked by HPLC analysis on the chiral column a). On the other hand, (pinacolato)boronato derivatives

Chiralpak IB, by comparison with a racemic sample pre- 15c–g reacted with KHF₂in a methanol/water (10:8) mix-

pared from the Wittig reagent (Ϯ)-9, hence demonstrating ture for 30 min to form the corresponding trifluoroborate

the enantiospecificity of the process.

compounds 17a–e in 65–88% yield (Table 2, entries 3–7). It

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Boron-Substituted Amino Acid and Peptide Derivatives

Scheme 4. Iridium-catalyzed borylation of dipeptide 20.

is noteworthy that this method allows the preparation of (entry 3). Interestingly, the best result was obtained with 3-

boronato- and trifluoroborato-amino acid derivatives fea- methyl-5-trifluoroboratothienyl derivative 17a, even though

turing a free carboxylic function (i.e., 15e and 17c, respec- its hydrolysis time exceeded one month (entry 2). In fact,

tively), and is convenient for peptide synthesis. Moreover, the integration values of the ratio [17a (–136 ppm)]/[17a +

the borylation reaction could also be performed with di-

peptide 20 (Scheme 4). The preparation of this substrate

Table 3. Hydrolysis of trifluoroborato-substituted amino acid de-

was performed by coupling amino acid 11e with methyl al-

aninate (S)-18, following hydrogenation of the unsaturated

intermediate 19. In this case, the catalyzed borylation of

dipeptide 20 in the presence of an iridium complex led to

the formation of boronato dipeptide 21 in 78% yield

(Scheme 4).

rivatives.

Finally, bearing in mind that trifluoroborato-substituted

amino acid derivatives 17 could be potentially used in PET

medical imaging, their relative stability during hydrolysis

was studied (Table 3).^[26]The hydrolysis assays were under-

taken in phosphate buffer at pH 7 and were monitored by

¹⁹F NMR analysis of the BF₃K signal, showing different

rates in comparison with the previously observed rates for

compound 12a (entry 1). Under these conditions, trifluoro-

borato compounds 17d and 17e, bearing a trifluoromethyl

or a methoxy substituent, respectively, were fully hydrolyzed

in 30 min and 2 h to their corresponding boronic acids 22d

and 22e (entries 4 and 5). Conversely, the total hydrolysis of

[a] The chemical shifts in ppm are referenced to CFCl₃. [b] For full

3,5-difluoro-4-trifluoroborate derivative 17b required 24 h hydrolysis.

Figure 2. Graph reporting the variation of the resonance intensity of the ¹⁹F NMR signal at –136 ppm during hydrolysis of trifluoroborate

amino ester derivative 17a at pH 7.

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the corresponding commercially boronic acid, according to the

standard procedure.^[29]The (S)-2-(tert-butyloxycarbonyl)amino-4-

triphenylphosphonio-butanoic acid 9 was prepared according to

the published procedure.^[22]

free fluoride (–119 ppm)] fits with an exponential curve in-

dicating a pseudo-first-order reaction (Figure 2).

Surprisingly, during the hydrolysis of trifluoroborate 17a,

the ¹⁹F NMR spectra showed the formation of a new signal

at –129 ppm. This signal was attributed to the formation of

difluoroborate intermediate 23, resulting from the loss of

KF (Figure 2). The ¹¹B NMR spectra of the reaction mix-

ture shows a triplet overlapping with the quadruplet of tri-

fluoroborate 17a. This observation is consistent with the

formation of difluoroborate intermediate 23. Finally, these

results indicate that the hydrolysis of difluoroborate com-

pound 23 is much slower than its trifluoroborate precursor

17a (Figure 2).

Flash chromatography was performed with the indicated solvents

1

by using silica gel 60 (60AAC, 35–70 μm; SDS). H, ¹³C, ¹⁹F and

¹¹B NMR spectra were recorded with 600, 500 or 300 MHz spec-

trometers at ambient temperature with TMS as internal reference

1

for H and ¹³C NMR, CCl₃F for ¹⁹F NMR, and BF₃·OEt₂for ¹¹B

NMR spectroscopy. Data are reported as s = singlet, d = doublet,

t = triplet, q = quartet, m = multiplet, br. s = broad signal, coupling

constant(s) in Hertz, integration. HPLC analyses were performed

with a chromatograph equipped with a UV detector at λ = 210 nm

and λ = 254 nm. The IR spectra were recorded with an FTIR in-

strument. Melting points were measured with an electrothermal

9100 melting point apparatus. Optical rotation values were mea-

sured with a polarimeter at 589 nm (sodium lamp). High-resolution

mass spectra were obtained under (ESI) conditions with a micro

Q-TOF detector.

Conclusions

We have developed a new stereoselective synthesis of

boronato-substituted amino acid derivatives by using Wittig

and C–H iridium-catalyzed borylation as key reactions.

First, a range of amino ester precursors bearing an aro-

matic moiety at the δ-position of the lateral chain were ob-

tained in 53–87% overall yield; the reaction involved a se-

quence of Wittig reaction of amino acid phosphonium salt

with the corresponding aromatic aldehydes, followed by es-

terification and hydrogenation. Borylation of the amino es-

ters was achieved by reacting amino esters with the bis-

(pinacolato)diborane reagent (B₂Pin₂), in the presence of an

iridium complex as catalyst, leading to the corresponding

monoboronato derivatives in yields up to 82%. The

boronate compounds are easily converted into their corre-

sponding iodide- or trifluoroborate-amino acid derivatives

in 65–88% yields, by reaction with either NaI in the pres-

ence of chloramine or with KHF₂, respectively. The aque-

ous stability of the trifluoroborato-substituted amino acid

derivatives is strongly dependent of the substituent pattern

of the aromatic or heteroaromatic moiety. An investigation

¹⁹F NMR Spectroscopic Kinetic Analyses: A small quantity of the

trifluoroborate salt (5 mg) was added to an NMR tube. At the start

of the solvolysis reaction (t = 0 min), the trifluoroborate salt was

dissolved in 0.5 mL of a 200 mm buffer solution, and the decompo-

sition was monitored by ¹⁹F NMR spectroscopy. The buffer solu-

tions with 200 mm strength were prepared by mixing in 100 mL

H₂O with AcOH (1.1 g) and NaOAc·3H₂O (48 mg) for pH 3,

Na₂HPO₄·7H₂O (5.3 g) and NaH₂PO₄·H₂O (40 mg) for pH 8.6, or

Na₂HPO₄·7H₂O (5.3 g) and NaH₂PO₄·H₂O (40 mg) for pH 7. ¹⁹F

NMR spectra were acquired at different times, and the integration

was calculated from the spectra. Integrals corresponding to the tri-

fluoroborate peak were divided by the sum of the trifluoroborate

and the free fluoride integrations, to calculate the fraction of ¹⁹F

existing as the trifluoroborate salt. The ratio of ¹⁹F signal existing

as the trifluorborate salt to the total ¹⁹F signal was plotted against

time to determinate the kinetics of the hydrolysis. The kinetic

curves reported in Figure 2 and in the Supporting Information are

the result of nonlinear regression analyses of the cumulative plot

of all data sets for identical experiments, using Excel version 14.1.3.

General Procedure for the Preparation of Unsaturated Amino Acid

of trifluoroborate hydrolysis in buffer solution indicates an 11 from the Wittig Reagent 9: To a solution of phosphonium amino

acid 9 (120 mg, 0.2 mmol) in chlorobenzene (1.5 mL) were added

aldehyde 10 (0.4 mmol or 0.2 mmol for 10k) and K₃PO₄

(1.2 mmol). After 16 h at 90 °C, the reaction was quenched by the

addition of distilled water (5 mL) then extracted with diethyl ether

(3ϫ 5 mL). The aqueous phase was acidified with KHSO₄(1 m)

solution to pH 3 then extracted with ethyl acetate (3ϫ 5 mL) and

dried on MgSO₄. Following removal of residual solvent in vacuo,

the residue was purified on SiO₂(PE/EtOAc, 90:10 to 70:30) to

afford pure amino acid derivative 11.

excellent stability of the 3-methylthienyl-substituted amino

acid derivative. Consequently, this hemisynthesis offers an

efficient route for the modular preparation of boron amino

acid derivatives that are useful for the synthesis of modified

peptides and fluoride labelling of peptides.

Experimental Section

General Methods: All reactions were carried out by using standard

Schlenk techniques under an inert atmosphere. Solvents were dried

and purified by conventional methods prior to use. Chlorobenzene

(PhCl), toluene, diethyl ether (Et₂O), n-hexane, ethyl acetate

(EtOAc), petroleum ether (PE), and methyl alcohol (MeOH) were

purchased in anhydrous form. The reagents bis(pinacolato)dibor-

ane (B₂pin₂), [Ir(OMe)COD]₂, 4,4Ј-di-tert-butyl-2,2Ј-bipyridine

(dtbpy), KHF₂, K₃PO₄, trimethylsilyldiazomethane (2 m in hex-

anes), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium

hexafluorophosphate (HATU), 4-[(pinacolato)boronato]-3,5-di-

fluorobenzaldehyde (10d) and aromatic aldehydes 10e–k, were pur-

chased from commercial sources. The (pinacolato)boronato-substi-

tuted aldehydes 10a–c were prepared by reaction of pinacol with

(S)-2-(tert-Butoxycarbonylamino)-5-{4-[4,4,5,5-tetramethyl(1,3,2-di-

oxaborolan-2-yl)]phenyl}pent-4-enoic Acid (11a):^[22]Under the

above conditions, phosphonium salt 9 (120 mg, 0.2 mmol) and 4-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

10a

(93 mg, 0.4 mmol), afforded unsaturated amino acid 11a (48 mg,

57%) as a colorless uncrystallized compound with a cis/trans ratio

of 25:75. R_f= 0.40 (EtOAc/PE, 3:7 + 1% acetic acid). ¹H NMR

(300 MHz, CDCl₃): δ = 1.36 (s, 12 H), 1.44 (s, 9 H), 2.67–2.80 (m,

2 H), 4.45–5.14 (m, 1 H), 5.16–6.18 (m, 1 H), 5.61–5.73 (m, 0.25

H), 6.10–6.25 (m, 0.75 H), 6.51 (d, J = 15.6 Hz, 0.75 H), 6.63 (d, J

= 12.3 Hz, 0.25 H), 7.17–7.77 ppm (m, 4 H). ¹³C NMR (75.5 MHz,

CDCl₃): δ = 24.8, 28.3, 31.2, 35.9, 53.1, 54.4, 80.4, 81.7, 83.8, 116.0,

124.8, 125.3, 125.6, 126.4, 128.0, 128.2, 129.0, 129.4, 131.6, 132.5,

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Boron-Substituted Amino Acid and Peptide Derivatives

134.2, 134.8, 135.1, 137.9, 139.5, 155.6, 176.1 ppm. ¹¹B NMR

6.75 (d, J = 5.1 Hz, 0.75 H), 6.83 (d, J = 5.1 Hz, 0.25 H), 7.01 (d,

J = 5.1 Hz, 0.75 H), 7.17 (d, J = 5.1 Hz, 0.25 H), 10.59 (br. s, 1 H)

ppm; ¹³C NMR (75 MHz, CDCl₃): δ = 13.8, 14.1, 28.3, 35.8, 36.4,

53.1, 54.6, 80.4, 81.8, 122.5, 122.8, 123.5, 123.6, 123.8, 125.7, 129.8,

130.5, 132.8, 134.6, 135.4, 136.3, 151.3, 176.4 ppm. HRMS (ESI-

Q-TOF): calcd. for C₁₅H₂₁NO₄S [M⁺– H] 310.11076; found

310.11304.

(96.3 MHz, CDCl ): δ = +30.75 ppm. FTIR (neat): ν = 3346, 2979–

˜

3

2931, 1714, 1608, 1515, 1496, 1455, 1397, 1358, 1321, 1270, 1214,

1143, 1089, 1052, 1019, 963, 859, 787, 696, 656, 607, 546, 540, 535,

524, 517 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₂₂H₃₂BNO₆Na

[M + Na⁺] 440.2219; found 440.2215. The enantiomeric excess

Ͼ 99% was determined by HPLC analysis after esterification with

TMSCHN₂(Lux 5μ cellulose-2; hexane/iPrOH, 90:10; 1 mLmin^–1;

λ = 210 nm; 20 °C): t_R= 6.9 (E,S), 7.8 (Z,S), 10.2 (E,R), 12.7

(Z,R) min.

(S)-2-(tert-Butoxycarbonylamino)-5-[3-(trifluoromethyl)phenyl]-

pent-4-enoic Acid (11f): Under the above conditions, phosphonium

amino acid 9 (100 mg, 0.17 mmol) and 3-trifluoromethyl benzalde-

(S)-2-(tert-Butyloxycarbonylamino)-5-(fur-2-yl)pent-4-enoic

Acid hyde (10h; 58.9 mg, 0.34 mmol), led to product 11f (50 mg,

(11b):^[22]Under the above conditions, phosphonium salt 9 (100 mg,

0.17 mmol) and 5-(pinacolato)dioxaboronato-2-furaldehyde (10b;

56 mg, 0.26 mmol) afforded unsaturated amino acid 11b (35 mg,

0.13 mmol, 74%) as a colorless uncrystallized compound with a

cis/trans ratio 25:75. R_f= 0.40 (EtOAc/PE, 3:7 + 1% acetic acid).

The characterization data are identical to the Wittig product 11b

previously obtained by Wittig reaction of 9 with the 2-fural-

dehyde.^[22]

0.14 mmol, 82%) as a colorless uncrystallized compound, with

cis/trans ratio 13:87. R_f= 0.71 (EtOAc/PE, 1:1 + 1% acetic acid).

¹H NMR (300 MHz, CDCl₃): δ = 1.42 (s, 9 H), 2.64–2.83 (m, 2

H), 4.3–4.51 (m, 1 H), 5.08–5.10 (m, 1 H), 5.69–5.77 (m, 0.13 H),

6.15–6.25 (m, 0.87 H), 6.51 (d, J = 15.5 Hz, 0.87 H), 6.60 (d, J =

12 Hz, 0.13 H), 7.37–7.55 (m, 4 H) ppm; ¹³C NMR (75 MHz,

CDCl₃): δ = 28.2, 35.9, 36.3, 53.0, 54.5, 80.6, 122.9 (q, J = 4 Hz),

123.8 (q, J = 4 Hz), 124.0 (q, J = 4 Hz), 125.4 (q, J = 4 Hz), 125.8,

125.9, 127.4, 128.8, 129.0, 129.4, 131.0 (q, J = 32 Hz), 131.8, 132.8,

137.6, 155.5, 176.25 ppm.^{[30a] 19}F NMR (282 MHz, CDCl₃): δ =

–62.71 (s, 0.39 F), –62.79 (s, 2.61 F) ppm. HRMS (ESI-Q-TOF):

calcd. for C₁₇H₂₀F₃NO₄Na [M + Na⁺] 382.12366; found

382.12244.

(S)-2-(tert-Butoxycarbonylamino)-5-(thien-2-yl)pent-4-enoic

Acid

(11c): Under the above conditions, the reaction of phosphonium

amino acid 9 (250 mg, 0.42 mmol) with 2-thienylcarbaldehyde (10e;

94.3 mg, 0.84 mmol), led to the unsaturated amino acid 11c

(93.5 mg, 0.31 mmol, 75%) as a pale-yellow uncrystallized com-

pound, with cis/trans ratio 25:75. R_f= 0.57 (EtOAc/PE, 4:6 + 1%

acetic acid). H NMR (300 MHz, CDCl₃): δ = 1.44 (s, 9 H), 2.63– Acid (11g): Under the above conditions, phosphonium amino acid

(S)-2-(tert-Butoxycarbonylamino)-5-(3-methoxyphenyl)pent-4-enoic

1

2.74 (m, 2 H), 4.43–4.45 (m, 1 H), 5.04 (m, 1 H), 5.49–5.57 (m,

0.25 H), 5.89–5.99 (m, 0.75 H), 6.52 (d, J = 15.6 Hz, 0.75 H), 6.69 0.33 mmol), led to the product 11g (40 mg, 0.13 mmol, 73%) as a

(d, J = 11.7 Hz, 0.25 H), 6.90–7.29 (3H), 10.25 (br. s, 1 H) ppm; colorless uncrystallized compound, with cis/trans ratio 24:76. R_f=

¹³C NMR (125 MHz, CDCl₃): δ = 28.3, 32.0, 35.5, 53.2, 80.4, 0.37 (EtOAc/PE, 3:7 + 1 % acetic acid); ¹H NMR (500 MHz,

9 (100 mg, 0.17 mmol) and 3-methoxybenzaldehyde (10i; 45.4 mg,

123.4, 123.7, 124.1, 125.1, 125.4, 125.5, 126.9, 127.2, 127.3, 127.9,

139.7, 141.9, 155.5, 176.1 ppm. HRMS (ESI-Q-TOF): calcd. for

C₁₄H₁₉NO₄SNa [M + Na⁺] 320.0901; found 320.0927.

CDCl₃): δ = 1.43 (s, 9 H), 2.59–2.96 (m, 2 H), 3.80 (s, 3 H), 4.26–

4.48 (m, 1 H), 5.04–5.12 (m, 1 H), 5.60–5.65 (m, 0.24 H), 6.09–6.14

(m, 0.76 H), 6.46 (d, J = 16 Hz, 0.76 H), 6.58 (d, J = 11.5 Hz, 0.24

H), 6.77–7.26 (m, 4 H), 9.54 (br. s, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 28.3, 31.2, 35.7, 53.1, 55.2, 80.4, 111.8, 112.6, 113.2,

114.3, 119.0, 121.2, 124.0, 125.9, 129.3, 129.5, 132.7, 134.1, 138.3,

138.3, 155.5, 159.6, 159.8, 176.4 ppm. HRMS (ESI-Q-TOF): calcd.

for C₁₇H₂₃NO₅[M + Na⁺] 344.14684; found 344.14616.

(S)-2-(tert-Butoxycarbonylamino)-5-(3,5-difluorophenyl)pent-4-enoic

Acid (11d): Under the above conditions, the reaction of phosphon-

ium amino acid 9 (200 mg, 0.34 mmol) with 3,5-difluorobenzalde-

hyde (10g; 96 mg, 0.5 mmol), led to unsaturated amino acid 11d

(91 mg, 0.28 mmol, 82%) as a colorless uncrystallized compound,

with cis/trans ratio 14:86. R_f= 0.37 (EtOAc/PE, 1:1 + 1% acetic

acid); ¹H NMR (500 MHz, CDCl₃): δ = 1.35 (s, 9 H), 2.51–2.85

(m, 2 H), 4.21–4.44 (m, 1 H), 5.08–5.14 (m, 1 H), 5.61–5.66 (m,

(S)-2-(tert-Butoxycarbonylamino)-5-[3,5-bis(trifluoromethyl)phen-

yl]pent-4-enoic Acid (11h): Under the above conditions, phosphon-

ium amino acid 9 (100 mg, 0.17 mmol) and 3,5-bis(trifluorometh-

0.14 H), 6.06–6.09 (m, 0.86 H), 6.31 (d, J = 15.7 Hz, 0.86 H), 6.41 yl)benzaldehyde (10j; 82 mg, 0.34 mmol), led to product 11h

(d, J = 11.7 Hz, 0.14 H), 6.56–7.18 (m, 3 H), 10.95 (br. s, 1 H) (52 mg, 0.16 mmol, 93%) as a colorless uncrystallized compound,

ppm; ¹³C NMR (75 MHz, CDCl₃): δ = 28.3, 35.9, 36.1, 53.0, 54.5,

80.6, 102.8 (t, J = 25 Hz), 109.0 (dd, J = 19.7, 6 Hz), 111.5 (dd, J

= 19.7, 6 Hz), 126.9, 128.2, 130.8, 132.1, 140.4 (t, J = 9 Hz), 155.6,

163.6 (dd, J = 247.8, 13.8 Hz), 164.1 (dd, J = 247.8, 13.8 Hz),

175.7, 176.1 ppm. ¹⁹F NMR (470 MHz, CDCl₃): δ = –110.31 (s,

with cis/trans ratio 10:90. R_f= 0.25 (EtOAc/PE, 1:9 + 1% acetic

acid); ¹H NMR (300 MHz, CDCl₃): δ = 1.42 (s, 9 H), 2.62–2.92

(m, 2 H), 4.25–4.59 (m, 1 H), 5.07–6.64 (m, 1 H), 5.82–5.90 (m,

0.14 H), 6.26–6.36 (m, 0.86 H), 6.53 (d, J = 16 Hz, 0.86 H), 6.62

(d, J = 12 Hz, 0.14 H), 7.66–7.83 (m, 3 H), 9.17 (br. s, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 28.2, 31.2, 36.1, 54.3, 80.6, 121.0,

1.72 F), –109.99 (s, 0.28 F) ppm. IR (neat): ν = 3500–2500, 3371,

˜

2924–2866, 1711, 1588, 1159, 838, 480, 509 cm^–1. HRMS (ESI-Q- 121.4, 123.4 (q, J = 273 Hz), 126.1, 126.7, 128.4, 129.6, 131.3, 131.9

TOF): calcd. for C₁₆H₁₉F₂NO₄Na [M + Na⁺] 350.11744; found

350.11749.

(q, J = 32.7 Hz), 138.9, 155.5, 176.2, 177.2 ppm. ¹⁹F NMR

(282 MHz, CDCl₃): δ = –63.1 (s, 0.84 F), –63.0 (s, 5.28 F) ppm. IR

(neat): ν = 3500–2500, 3392, 2981–2866, 1713, 1381, 1275, 1125,

˜

(S)-2-(tert-Butoxycarbonylamino)-5-(3-methylthien-2-yl)pent-4-

enoic Acid (11e): Under the above conditions, the reaction of phos-

phonium amino acid 9 (100 mg, 0.17 mmol) with 3-methyl-2-thien-

ylcarbaldehyde (10f; 36.1 mg, 0.28 mmol), led to unsaturated

amino acid 11e (34.9 mg, 0.11 mmol, 66%) as a pale-yellow uncrys-

tallized compound, with cis/trans ratio 25:75. R_f= 0.47 (EtOAc/

895, 681 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₁₈H₁₉F₆NO₄Na

[M + Na⁺] 450.1105; found 450.10980.

1,3-Bis[(S)-1-(carboxy)-1-(tert-butoxycarbonylamino)but-3-en-4-

yl]benzene (11i): Under the above conditions, phosphonium amino

acid 9 (120 mg, 0.2 mmol) and m-phthaldialdehyde (10k; 85.7 mg,

0.1 mmol), led to the product 11i (97.2 mg, 0.17 mmol, 85%) as

1

PE, 3:7 + 1% acetic acid). H NMR (300 MHz, CDCl₃): δ = 1.43

(s, 9 H), 2.20 (s, 3 H), 2.21 (s, 3 H), 2.54–3.06 (m, 2 H), 4.24–4.47 a colorless uncrystallized compound and as an indistinguishable

(m, 1 H), 5.10–6.39 (m, 1 H), 5.55–5.59 (m, 0.25 H), 5.81–5.94 (m,

mixture of major isomers E,E and E,Z. R_f= 0.23 (EtOAc/PE, 3:7

0.75 H), 6.53 (d, J = 15 Hz, 0.25 H), 6.61 (d, J = 16 Hz, 0.75 H),

+ 1% acetic acid). The characterization data were identical to the

Eur. J. Org. Chem. 0000, 0–0

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7

Job/Unit: O31084

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Date: 16-10-13 17:18:20

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S. Jugé et al.

FULL PAPER

Wittig product 11i previously obtained by reaction of the Wittig

reagent 9 with m-phthaldialdehyde 10k.^[22]

(ESI-Q-TOF): calcd. for C₁₇H₂₁F₂NO₄Na [M + Na⁺] 364.13309;

found 364.13251.

General Procedure for the One-Pot Preparation of Methyl Amino

Esters 13 from the Wittig Reagent 9: Using the above procedure for

the preparation of amino acid 11, the esterification then occurred

without further purification, following subsequent removal of re-

sidual solvent in vacuo. To a solution of the residue in a toluene/

methanol mixture (3:2, 2 mL), TMSCHN₂(1.2 equiv.) was added

at room temperature whilst stirring for 30 min. After removal of

residual solvent in vacuo, the residue was purified on SiO₂(PE/

EtOAc, 90:10) to afford ester product 13.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3-(trifluorometh-

yl)phenyl]pent-4-enoate (13d): Under the above conditions, phos-

phonium amino acid 9 (150 mg, 0.25 mmol) and 3-trifluoromethyl

benzaldehyde (10h; 88.3 mg, 0.5 mmol), led to product 13d (after

esterification with TMSCHN₂) as a colorless uncrystallized com-

pound (81 mg, 0.218 mmol, 87%), with a cis/trans ratio 13:87. R_f

1

= 0.45 (EtOAc/PE, 2:8). H NMR (300 MHz, CDCl₃): δ = 1.42 (s,

9 H), 2.58–2.89 (m, 2 H), 3.70 (s, 0.4 H), 3.76 (s, 2.6 H), 4.28–4.49

(m, 1 H), 4.93–5.16 (m, 1 H), 5.67–5.75 (m, 0.13 H), 6.13–6.19 (m,

0.87 H), 6.47 (d, J = 15.5 Hz, 0.87 H), 6.59 (d, J = 12 Hz, 0.13 H),

7.38–7.56 (m, 4 H) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ =

28.2, 36.3, 52.3, 52.3, 53.1, 80.0, 122.9 (q, J = 4 Hz), 123.7 (q, J =

4 Hz), 123.9 (q, J = 273 Hz), 124.0 (q, J = 4 Hz), 125.31 (q, J =

4 Hz), 125.5, 126.2, 127.5, 128.8, 129.0, 129.4, 130.9 (q, J = 32 Hz),

131.3, 132.4, 137.5, 137.7, 155.2, 172.4 ppm. ¹⁹F NMR

(282.4 MHz, CDCl₃): δ = –62.8 (s, 2.61 F), –62.7 (s, 0.39 F) ppm.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(thien-2-yl)pent-4-eno-

ate (13a): Under the above conditions, phosphonium amino acid 9

(300 mg, 0.5 mmol) and 2-thienylcarbaldehyde (10e; 113.8 mg,

1 mmol), led to the product 13a (after esterification with

TMSCHN₂) as a yellow uncrystallized compound (120 mg,

0.38 mmol, 77%), with cis/trans ratio 25:75. R_f= 0.66 (EtOAc/PE,

3:7). ¹H NMR (300 MHz, CDCl₃): δ = 1.43 (s, 9 H), 2.54–3.02 (m,

2 H), 3.73 (s, 0.75 H), 3.75 (s, 2.25 H), 4.43–4.45 (m, 1 H), 4.8–5.1

(m, 1 H), 5.45–5.54 (m, 0.25 H), 5.84–5.94 (m, 0.75 H), 6.57 (d, J

= 15.6 Hz, 0.75 H), 6.65 (d, J = 11.7 Hz, 0.25 H), 6.89–7.27 (m, 3

H) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 28.3, 32.2, 36.0, 52.3,

52.4, 53.2, 80.0, 123.4, 123.7, 124.1, 124.9, 125.3, 125.5, 126.9,

127.0, 127.2, 127.9, 139.7, 141.9, 155.2, 155.2, 172.4, 172.4 ppm.

IR (neat): ν = 3373, 2934–2867, 1713, 1437, 1160, 788, 661,

˜

476 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₁₈H₂₂F₃NO₄Na [M +

Na⁺] 396.13931; found 396.13928.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-methoxyphenyl)pent-

4-enoate (13e): Under the above conditions, phosphonium amino

acid 9 (150 mg, 0.25 mmol) and 3-methoxybenzaldehyde (10i;

IR (neat): ν = 3367, 2977–2878, 1709, 1499, 1159, 779, 495 cm^–1. 68.1 mg, 0.5 mmol), led to product 13e (after esterification with

˜

HRMS (ESI-Q-TOF): calcd. for C₁₅H₂₁NO₄SNa [M + Na⁺] TMSCHN₂) as a colorless uncrystallized compound (70 mg,

334.10835; found 334.10749.

0.21 mmol, 84%), with a cis/trans ratio 24:76. R_f= 0.53 (EtOAc/

PE, 2:8). ¹H NMR (500 MHz, CDCl₃): δ = 1.45 (s, 9 H), 2.63–2.87

(m, 2 H), 3.72 (s, 0.72 H), 3.77 (s, 2.28 H), 3.82 (s, 3 H), 4.29–4.48

(m, 1 H), 4.86–5.13 (m, 1 H), 5.59–5.64 (m, 0.24 H), 6.05–6.11 (m,

0.76 H), 6.45 (d, J = 16 Hz, 0.76 H), 6.59 (d, J = 11.5 Hz, 0.24 H),

6.79–7.28 (m, 4 H) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ =

28.3, 31.5, 36.1, 52.3, 53.2, 55.2, 80.0, 111.7, 112.5, 113.1, 114.3,

118.9, 121.1, 124.1, 126.0, 129.3, 129.5, 132.5, 133.8, 138.3, 138.4,

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-methylthien-2-

yl)pent-4-enoate (13b): Under the above conditions, phosphonium

amino acid 9 (200 mg, 0.34 mmol) and 3-methyl-2-thienylcarbal-

dehyde (10f; 72.1 mg, 0.57 mmol), led to product 13b (after esterifi-

cation with TMSCHN₂) as a yellow uncrystallized compound

(97.2 mg, 0.3 mmol, 88%), with a cis/trans ratio 25:75; R_f= 0.33

1

(EtOAc/PE, 1:9). H NMR (300 MHz, CDCl₃): δ = 1.42 (s, 9 H),

155.2, 159.5, 159.1, 172.5 ppm. FTIR (neat): ν = 3372, 2924–2865,

˜

2.20 (s, 3 H), 2.55–2.98 (m, 2 H), 3.72 (s, 0.75 H), 3.74 (s, 2.25 H),

4.20–4.45 (m, 1 H), 4.80–5.1 (m, 1 H), 5.46–5.55 (m, 0.25 H), 5.76–

5.86 (m, 0.75 H), 6.56 (d, J = 16.2 Hz, 0.75 H), 6.63 (d, J = 11.4 Hz,

0.25 H), 6.75 (d, J = 5.1 Hz, 0.75 H), 6.83 (d, J = 5.1 Hz, 0.25 H),

7.01 (d, J = 5.1 Hz, 0.75 H), 7.16 (d, J = 5.1 Hz, 0.25 H) ppm. ¹³C

NMR (75.5 MHz, CDCl₃): δ = 13.8, 14.1, 28.3, 36.2, 52.2, 52.3,

53.3, 80.0, 122.5, 122.8, 123.5, 123.6, 123.8, 125.6, 129.8, 130.5,

1712, 1491, 1155, 774, 688, 456 cm^–1. HRMS (ESI-Q-TOF): calcd.

for C₁₈H₂₅NO₅Na [M + Na⁺] 358.16249; found 358.16299.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3,5-bis(trifluorometh-

yl)phenyl]pent-4-enoate (13f): Under the above conditions, phos-

phonium amino acid 9 (150 mg, 0.25 mmol) and 3,5-bis(trifluoro-

methyl)benzaldehyde (10j; 122.9 mg, 0.5 mmol), led to product 13f

(after esterification with TMSCHN₂) as a colorless uncrystallized

compound (108 mg, 0.24 mmol, 98%), with a cis/trans ratio 14:86.

132.8, 134.5, 135.4, 136.3, 155.2, 172.4, 172.6 ppm. IR (neat): ν =

˜

3371, 2923–2861, 1710, 1499, 1160, 702, 452 cm^–1. HRMS (ESI-

Q-TOF): calcd. for C₁₆H₂₃NO₄SNa [M + Na⁺] 348.12135; found

348.12238.

1

R_f= 0.36 (EtOAc/PE, 1:9). H NMR (500 MHz, CDCl₃): δ = 1.41

(s, 9 H), 2.58–2.87 (m, 2 H), 3.70 (s, 0.42 H), 3.76 (s, 2.58 H), 4.30–

4.49 (m, 1 H), 5.03–5.21 (m, 1 H), 5.8–5.86 (m, 0.14 H), 6.24–6.3

(m, 0.86 H), 6.51 (d, J = 16 Hz, 0.86 H), 6.61 (d, J = 12 Hz, 0.14

H), 7.50–7.82 (m, 3 H) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ =

28.2, 36.4, 52.5, 53.0, 80.3, 120.8, 122.2, 123.3 (q, J = 273 Hz),

126.1, 126.5, 128.7, 129.6, 131.53, 131.8 (q, J = 32.7 Hz), 139.0,

155.3, 172.2 ppm. ¹⁹F NMR (470.59 MHz, CDCl₃): δ = –63.01 (s,

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3,5-difluorophen-

yl)pent-4-enoate (13c): Under the above conditions, phosphonium

amino acid 9 (200 mg, 0.34 mmol) and 3,5-difluorobenzaldehyde

(10g; 96 mg, 0.5 mmol), led to product 13c (after esterification with

TMSCHN₂) as a colorless uncrystallized compound (100 mg,

0.292 mmol, 87%), with a cis/trans ratio 14:86; R_f= 0.46 (EtOAc/

PE, 2:8). ¹H NMR (500 MHz, CDCl₃): δ = 1.41 (s, 9 H), 2.56–2.84

(m, 2 H), 3.70 (s, 0.42 H), 3.74 (s, 2.58 H), 4.25–4.46 (m, 1 H),

4.93–5.15 (m, 1 H), 5.65–5.70 (m, 0.14 H), 6.07–6.13 (m, 0.86 H),

6.35 (d, J = 15.7 Hz, 0.86 H), 6.47 (d, J = 11.7 Hz, 0.14 H), 6.61–

6.83 (m, 3 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 28.2, 36.2,

52.4, 53.1, 80.1, 102.6 (t, J = 25 Hz), 108.9 (dd, J = 19.8, 6 Hz),

111.4 (dd, J = 19.8, 6 Hz), 127.0, 128.2, 130.5, 131.8, 140.3 (t, J =

9 Hz), 140.9 (t, J = 9 Hz), 155.1, 162.9 (dd, J = 247.8, 13.8 Hz),

163.2 (dd, J = 247.8, 13.8 Hz), 172.3 ppm. ¹⁹F NMR (470.59 MHz,

CDCl₃): δ = –110.4 (s, 1.72 F), –110.1 (s, 0.28 F) ppm. IR (neat):

0.84 F), –63.13 (s, 5.26 F) ppm. IR (neat): ν = 3392, 2981–2866,

˜

1659, 1504, 1275, 1124, 702, 681, 479 cm^–1. HRMS (ESI-Q-TOF):

calcd. for C₁₉H₂₁F₆NO₄Na [M + Na⁺] 464.12670; found

464.12893.

1,3-Bis[(S)-1-(methoxycarbonyl)-1-(tert-butoxycarbonylamino)but-

3-en-4-yl]benzene (13g): Under the above conditions, phosphonium

amino acid 9 (200 mg, 0.34 mmol) and m-phthaldialdehyde (10k;

22.7 mg, 0.17 mmol), followed by esterification with TMSCHN₂

afford diester 13g (97.2 mg, 0.17 mmol, 96%) as a colorless oil and

as a mixture of major isomers E,E/Z,E (6:4). R_f= 0.79 (EtOAc/

PE, 2:8). ¹H NMR (300 MHz, CDCl₃): δ = 1.43 (s, 18 H), 2.59–

ν = 3373, 2934–2867, 1708, 1588, 1162, 857, 480, 510 cm^–1. HRMS

˜

8

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Pages: 14

Boron-Substituted Amino Acid and Peptide Derivatives

2.84 (m, 4 H), 3.70 (s, 2.5 H), 3.75 (s, 3.5 H), 4.23–4.45 (m, 2 H),

(EtOAc/PE, 1:9); [α]²_D⁰= +40.8 (c = 0.8 in CHCl₃). ¹H NMR

4.84–5.16 (m, 2 H), 5.56–5.65 (m, 0.80 H), 6.02–6.12 (m, 1.20 H), (500 MHz, CDCl₃): δ = 1.43 (s, 9 H), 1.63–1.84 (m, 4 H), 2.62–

6.44 (d, J = 17 Hz, 1.20 H), 6.59 (d, J = 11.7 Hz, 0.80 H), 7.09–

7.27 (m, 4 H) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 28.3, 31.5,

36.2, 52.2, 52.3, 52.3, 52.4, 80.0, 124.1, 124.4, 124.8, 125.3, 125.4,

126.4, 126.7, 127.7, 128.2, 128.50, 128.7, 129.0, 132.3, 133.7, 137.0,

2.75 (m, 2 H), 3.72 (s, 3 H), 4.13–4.35 (m, 1 H), 4.80–5.04 (m, 1

H), 7.32–7.44 (m, 4 H) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ =

27.0, 28.4, 32.4, 35.1, 52.4, 53.2, 80.1, 123.0 (q, J = 4 Hz), 124.1

(q, J = 273 Hz), 125.15 (q, J = 4 Hz), 128.9, 130.8 (q, J = 32.7 Hz),

131.9, 142.7, 155.5, 173.3 ppm. ¹⁹F NMR (470.7 MHz, CDCl₃): δ

137.1, 155.2, 172.5, 172.5 ppm. IR (neat): ν = 3381, 2992–2980,

˜

1699, 1496, 1365, 1160, 1021, 731, 695, 470 cm^–1. HRMS (ESI-

Q-TOF): calcd. for C₂₈H₄₀N₂O₈Na [M + Na⁺] 555.26769; found

555.27005.

= –62.59 (s) ppm. IR (neat): ν = 3367, 2929–2856, 1712, 1327, 1158,

˜

7 0 2 , 4 3 1 , 4 0 8 c m^{– 1}. HRMS (ESI-Q-TOF) : c al cd . for

C₁₈H₂₄F₃NO₄Na [M + Na⁺] 398.15496; found 398.15345.

General Procedure for the Hydrogenation of Amino Esters: In an

autoclave, to a solution of unsaturated amino ester 13 (0.2 mmol)

in methanol (2 mL), was added 20% weight of Pd/C (5%). After

flushing with H₂, the mixture was stirred for 16 h under 10 bar H₂,

then filtered off and washed with EtOAc and concentrated in

vacuo. The residue was purified by chromatography on silica gel

(PE/EtOAc, 9:1) to afford amino ester 14.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-methoxyphen-

yl)pentanoate (14e): According to the above procedure, starting

from 13e (100 mg, 0.30 mmol), amino ester 14e (87 mg, 0.26 mmol,

86%) was obtained as colorless uncrystallized compound. R_f= 0.43

(EtOAc/PE, 1:9); [α]²_D⁰= +32.5 (c = 0.8 in CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 1.33 (s, 9 H), 1.59–1.82 (m, 4 H), 2.52–

2.68 (m, 2 H), 3.71 (s, 3 H), 3.78 (s, 3 H), 4.12–4.32 (m, 1 H), 4.70–

5.03 (m, 1 H), 6.70–6.75 (m, 3 H), 7.15–7.20 (m, 1 H) ppm. ¹³C

NMR (75.5 MHz, CDCl₃): δ = 27.0, 28.3, 32.3, 35.1, 52.2, 53.3,

55.1, 79.8, 111.2, 114.2, 120.8, 129.3, 143.3, 155.4, 159.7,

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(thien-2-yl)pentanoate

(14a): According to the above procedure, starting from 13a

(155 mg, 0.50 mmol), amino ester 14a (150 mg, 0.48 mmol, 96%)

was obtained as a pale-yellow uncrystallized compound. R_f= 0.70

(EtOAc/PE, 3:7); [α]²_D⁰= +19.5 (c = 0.4 in CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 1.44 (s, 9 H), 1.65–1.87 (m, 4 H), 2.82–

2.88 (m, 2 H), 3.73 (s, 3 H), 4.15–4.33 (m, 1 H), 4.7–5.1 (m, 1 H),

6.76–6.78 (m, 1 H), 6.89–6.92 (m, 1 H), 7.11 (dd, J = 5.1, 1 Hz, 1

H) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 27.6, 28.5, 29.5, 32.3,

52.4, 53.3, 80.1, 123.3, 124.5, 126.7, 144.6, 155.5, 173.4 ppm. IR

173.3 ppm. IR (neat): ν = 3367, 2923–2854, 1710, 1365, 1159, 736,

˜

446, 403 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₁₈H₂₇NO₅Na [M

+ Na⁺] 360.17814; found 360.17703.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3,5-bis(trifluorometh-

yl)phenyl]pentanoate (14f): According to the above procedure, start-

ing from 13f (110 mg, 0.25 mmol), amino ester 14f (106 mg,

0.24 mmol, 96%) was obtained as a colorless uncrystallized com-

pound. R_f= 0.59 (EtOAc/PE, 2:8); [α]²_D⁰= +16.5 (c = 0.8 in CHCl₃).

¹H NMR (500 MHz, CDCl₃): δ = 1.44 (s, 9 H), 1.61–1.86 (m, 4

H), 2.7–2.83 (m, 2 H), 3.71 (s, 3 H), 4.12–4.39 (m, 1 H), 4.79–5.06

(m, 1 H), 7.61 (s, 2 H), 7.70 (s, 1 H) ppm. ¹³C NMR (125.75 MHz,

CDCl₃): δ = 26.9, 28.4, 32.6, 35.0, 52.5, 52.9, 80.3, 120.3, 123.5 (q,

J = 273 Hz), 128.7, 131.8 (q, J = 32.7 Hz), 144.3, 155.6, 173.2 ppm.

¹⁹F NMR (470.6 MHz, CDCl₃): δ = –62.87 (s) ppm. HRMS (ESI-

Q-TOF): calcd. for C₁₉H₂₃F₆NO₄Na [M + Na⁺] 466.14235; found

466.14383.

(neat): ν = 3367, 2923–2854, 1710, 1502, 1159, 850, 693 cm^–1

.

˜

HRMS (ESI-Q-TOF): calcd. for C₁₅H₂₃NO₄SNa [M + Na⁺]

336.1240; found 336.1244.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-methylthien-2-

yl)pentanoate (14b): According to the above procedure, starting

from 13b (120 mg, 0.37 mmol), amino ester 14b (118 mg,

0.36 mmol, 98 %) was obtained as a pale-yellow uncrystallized

compound. R_f= 0.33 (EtOAc/PE, 1:9); [α]²_D⁰= +44.1 (c = 0.7 in

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.43 (s, 9 H), 1.56–1.99

(m, 4 H), 2.13 (s, 3 H), 2.66–2.89 (m, 2 H), 3.72 (s, 3 H), 4.12–4.33

(m, 1 H), 4.77–5.02 (m, 1 H), 6.75 (d, J = 5.1 Hz, 1 H), 6.99 (d, J

= 5.1 Hz, 1 H) ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.5, 27.3,

27.4, 28.4, 32.9, 52.3, 53.3, 80.0, 121.2, 130.0, 132.9, 137.6, 155.4,

1,3-Bis[(S)-1-(methoxycarbonyl)-1-(tert-butoxycarbonylamino)but-

4-yl]benzene (14g): According to the above procedure, starting from

13g (88 mg, 0.16 mmol), amino ester 14g (84 mg, 0.157 mmol,

98%) was obtained as a colorless uncrystallized compound. R_f=

0.72 (EtOAc/PE, 2:8); [α]²_D⁰= +74 (c = 0.5 in CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 1.46 (s, 18 H), 1.52–1.85 (m, 8 H), 2.59–

2.64 (m, 4 H), 3.71 (s, 6 H), 4.13–4.35 (m, 2 H), 4.74–5.02 (m, 2

H), 6.97–7.28 (m, 4 H) ppm. ¹³C NMR (125.75 MHz, CDCl₃): δ =

27.1, 28.3, 32.4, 37.1, 52.2, 53.3, 79.9, 125.9, 128.4, 128.6, 141.7,

173.3 ppm. IR (neat): ν = 3315, 2930–2850, 1711, 1503, 1160, 780,

˜

475 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₁₆H₂₅NO₄SNa [M +

Na⁺] 350.13812; found 350.13803.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3,5-difluorophen-

yl)pentanoate (14c): According to the above procedure, starting

from unsaturated amino ester 13c (100 mg, 0.17 mmol) and 20 mg

of Pd/C (5%), amino ester 14c (99.5 mg, 0.17 mmol, 99%) was ob-

tained as a colorless uncrystallized compound. R_f= 0.34 (EtOAc/

PE, 2:8); [α]²_D⁰= +26 (c = 0.7 in CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.42 (s, 9 H), 1.54–1.86 (m, 4 H), 2.53–2.66 (m, 2 H),

3.71 (s, 3 H), 4.08–4.36 (m, 1 H), 4.77–5.05 (m, 1 H), 6.60 (t, J =

9 Hz, 1 H), 6.66 (d, J = 7 Hz, 2 H) ppm. ¹³C NMR (125.75 MHz,

CDCl₃): δ = 26.5, 28.3, 32.2, 34.9, 52.3, 53.0, 80.0, 101.4 (t, J =

25 Hz), 111.2 (dd, J = 19, 5 Hz), 145.6 (t, J = 9.5 Hz), 155.4, 163.0

(dd, J = 13, 248 Hz), 173.1 ppm. ¹⁹F NMR (470.6 MHz, CDCl₃):

155.4, 173.3 ppm. IR (neat): ν = 2961–2986, 1711, 1633, 1563,

˜

1496, 1425, 1345, 1273, 1212, 1163, 1075, 962, 853, 669, 559, 489,

411 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₂₈H₄₄N₂O₈Na [M +

Na⁺] 559.29899; found 559.29883. The enantiomeric excess Ͼ 99%

was determined by HPLC (Lux 5μ cellulose-2; hexane/iPrOH,

90:10; Flow: 1 mLmin^–1; UV detection: λ = 254 nm; T: 20 °C): t_R

= 14.3 (S,S), 21.7 [(R,S) + (S,R)], 32.2 (R,R) min.

General Procedure for the Borylation of Aromatic Amino Esters: A

10 mL round-bottomed flask equipped with a magnetic stirrer, was

charged with methyl amino ester 14 (0.5 mmol), bis(pinacolato)di-

boron (B₂pin₂; 152 mg, 0.6 mmol), 4,4Ј-di-tert-butyl-2,2Ј-bipyridine

(dtbpy; 2.7 mg, 0.01 mmol), [Ir(OMe)COD]₂(3.3 mg, 0.005 mmol)

and n-hexane (2.5 mL) were added. After heating at 90 °C whilst

stirring for 16 h in the closed flask, the reaction mixture was filtered

δ = –110.66 (s) ppm. IR (neat): ν = 3368, 2931–2857, 1714, 1591,

˜

1150, 855, 433, 407 cm^–1. HRMS (ESI-Q-TOF): calcd. for

C₁₇H₂₃F₂NO₄Na [M + Na⁺] 366.14874; found 366.14853.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-trifluoromethyl-

phenyl)pentanoate (14d): According to the above procedure, starting

from 13d (93 mg, 0.25 mmol), amino ester 14d (90 mg, 0.24 mmol, through a short plug of Celite (Et₂O). Following subsequent re-

96%) was obtained as colorless uncrystallized compound. R_f= 0.48 moval of residual solvent in vacuo, the residue was purified by

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S. Jugé et al.

FULL PAPER

chromatography on silica gel (PE/EtOAc, 90:10), to give pure prod-

uct 15.

cording to a literature procedure,^[15d]boron amino acid derivative

15e was obtained by hydrolysis of ester 15d (70 mg, 0.149 mmol) in

methanol/water (2:1, 3 mL) and LiOH (125 mg, 0.3 mmol).

Boronate 15e (0.041 g, 0.089 mmol, 60%) was obtained as a color-

less uncrystallized compound. R_f= 0.60 (EtOAc/PE, 3:7 + 1% ace-

tic acid); [α]²_D⁰= +21.1 (c = 0.3 in CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.36 (s, 12 H), 1.43 (s, 9 H), 1.59–1.93 (m, 4 H), 2.55–

2.70 (m, 2 H), 4.12–4.33 (m, 1 H), 5.01–6.34 (m, 1 H), 6.66 (d, J

= 8.2 Hz, 2 H), 7.54 (br. s, 1 H) ppm. ¹³C NMR (75.46 MHz,

CDCl₃): δ = 24.7, 26.3, 28.3, 31.9, 35.0, 53.0, 80.3, 84.1, 111.0 (dd,

J = 19.4, 6.5 Hz), 148.5 (t, J = 9.8 Hz), 155.4, 166.7 (dd, J = 252.4,

14.8 Hz), 176.6 ppm. ¹¹B NMR (96.29 MHz, CDCl₃): δ =

+29.8 (br. s) ppm. ¹⁹F NMR (282.4 MHz, CDCl₃): δ = –101.07 (s)

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-{5-(4,4,5,5-tetramethyl-

[1,3,2]dioxaborolan-2-yl)thien-2-yl}pentanoate (15a) and (S)-Methyl

2-(tert-Butoxycarbonylamino)-5-{3,5-bis(4,4,5,5-tetramethyl-

[1,3,2]dioxaborolan-2-yl)thien-2-yl}pentanoate (15b): According to

the above procedure, starting from amino ester 14a (37 mg,

0.118 mmol), a mixture of mono- and diboronated compounds 15a

and 15b (3:7 ratio), respectively, was obtained as a pale-yellow

uncrystallized compound (56 mg, 82% yield). When the reaction

was performed at 60 °C, boronate 15a was mainly obtained (16 mg,

31%); R_f= 0.70 (EtOAc/PE, 3:7).

Monoboronate 15a: ¹H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 12

H), 1.43 (s, 9 H), 1.60–1.86 (m, 4 H), 2.85–2.91 (m, 2 H), 3.72 (s,

3 H), 4.12–4.31 (m, 1 H), 4.7–4.8 (m, 1 H), 6.84 (d, J = 3.6 Hz, 1

H), 7.45 (d, J = 3.6 Hz, 1 H) ppm. ¹³C NMR (75.7 MHz, CDCl₃):

δ = 24.8, 27.3, 28.4, 29.7, 31.8, 52.1, 53.4, 79.8, 83.8, 126.2, 137.4,

152.2, 155.3, 173.3 ppm.^[30b]HRMS (ESI-Q-TOF): calcd. for

C₂₁H₃₄BNO₆SNa [M + Na⁺] 462.20959; found 462.20866.

ppm. IR (neat): ν = 3345 (N–H), 2912–2815 (C-H), 1710 (C=O),

˜

1345, 1150, 850 cm^{– 1}. HRMS (ESI-Q-TOF): calcd. for

C₂₂H₃₁BF₂NO₆[M^–– H] 454.22219; found 454.22008.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3-trifluoromethyl-5-

(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanoate

(15f): According to the above procedure, starting from amino ester

14d (50 mg, 0.133 mmol), boronate 15f (37 mg, 0.08 mmol, 60%)

Diboronate 15b: H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 12 H),

was obtained as a colorless oil. R_f= 0.46 (EtOAc/PE, 2:8); [α]²_D⁰

+32.1 (c = 0.4 in CHCl₃). H NMR (300 MHz, CDCl₃): δ = 1.35

=

1

1.31 (s, 12 H), 1.43 (s, 9 H), 1.60–1.86 (m, 4 H), 3.10–3.20 (m, 2

H), 3.71 (s, 3 H), 4.12–4.31 (m, 1 H), 4.70–4.80 (m, 1 H), 7.85 (s,

(s, 12 H), 1.44 (s, 9 H), 1.61–1.85 (m, 4 H), 2.60–2.77 (m, 2 H),

1 H) ppm. ¹³C NMR (75.7 MHz, CDCl₃): δ = 24.7, 27.3, 28.3, 3.73 (s, 3 H), 4.25–4.39 (m, 1 H), 4.75–5.08 (m, 1 H), 7.48 (s, 1 H),

29.6, 32.1, 52.2, 53.2, 79.9, 83.9, 144.8, 152.2, 155.3, 173.3 ppm.

HRMS (ESI-Q-TOF): calcd. for C₂₇H₄₅B₂NO₈SNa [M + Na⁺]

588.29538; found 588.29747.

Mixture 15a,15b: ¹¹B NMR (96.3 MHz, CDCl₃): δ = +28.22 (br.

7.76 (s, 1 H), 7.88 (s, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

= 25.0, 27.1, 28.5, 32.5, 35.1, 52.4, 53.2, 80.1, 84.4, 126.1 (q, J =

273 Hz), 127.8 (q, J = 4 Hz), 129.2 (q, J = 4 Hz), 130.4 (q, J =

32 Hz), 138.2, 142.0, 155.6, 173.4 ppm. ¹¹B NMR (96.3 MHz,

CDCl₃): δ = +30.2 (br. s) ppm. ¹⁹F NMR (282.4 MHz, CDCl₃): δ

s) ppm. IR (neat): ν = 3367, 2923–2854, 1710, 1502, 1159, 850,

˜

= –62.5 (s) ppm. IR (neat): ν = 3367, 2929–2856, 1714, 1298, 1121,

˜

693 cm^–1.

847, 480 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₂₄H₃₅BF₃NO₆Na

[M + Na⁺] 524.24061; found 524.24243.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-{3-methyl-5-(4,4,5,5-

tetramethyl[1,3,2]dioxaborolan-2-yl)thien-2-yl}pentanoate (15c): Ac-

cording to the above procedure, starting from amino ester 14b

(50 mg, 0.15 mmol), boronate 15c (48.2 g, 0.11 mmol, 71%) was

obtained as a pale-yellow uncrystallized compound. R_f= 0.43

(EtOAc/PE, 2:8); [α]²_D⁰= +33.1 (c = 0.6 in CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 1.31 (s, 12 H), 1.43 (s, 9 H), 1.58–1.89 (m,

4 H), 2.13 (s, 3 H), 2.74–2.79 (m, 2 H), 3.72 (s, 3 H), 4.07–4.31 (m,

1 H), 4.74–4.99 (m, 1 H), 7.32 (s, 1 H) ppm. ¹³C NMR (96.29 MHz,

CDCl₃): δ = 13.4, 24.8, 26.9, 27.7, 28.3, 32.2, 52.2, 53.2, 79.9, 83.8,

134.7, 140.4, 145.7, 155.3, 173.2 ppm. ¹¹B NMR (96.3 MHz,

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3-methoxy-5-(4,4,5,5-

tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]pentanoate (15g): Ac-

cording to the above procedure, starting from amino ester 14e

(47 mg, 0.131 mmol), boronate 15g (35 mg, 0.075 mmol, 57%) was

obtained as colorless uncrystallized compound. R_f= 0.37 (EtOAc/

PE, 2:8); [α]²_D⁰= +32 (c = 0.9 in CHCl₃). ¹H NMR (300 MHz,

CDCl₃): δ = 1.34 (s, 12 H), 1.43 (s, 9 H), 1.54–1.86 (m, 4 H), 2.51–

2.67 (m, 2 H), 3.71 (s, 3 H), 3.81 (s, 3 H), 4.1–4.31 (m, 1 H), 4.68–

4.97 (m, 1 H), 6.79–6.81 (s, 1 H), 7.14–7.15 (s, 1 H), 7.25 (s, 1 H)

ppm. ¹³C NMR (75.5 MHz, CDCl₃): δ = 24.8, 27.0, 28.3, 32.4,

35.2, 52.2, 53.3, 55.4, 79.9, 83.8, 116.1, 118.2, 127.4, 142.7, 155.4,

159.2, 173.3 ppm. ¹¹B NMR (96.3 MHz, CDCl₃): δ = +30.75 (br.

CDCl ): δ = +28.82 (br. s) ppm. IR (neat): ν = 3367, 2976–2834,

˜

3

1713, 1367, 1141, 853, 465 cm^–1. HRMS (ESI-Q-TOF): calcd. for

C₂₂H₃₆BNO₈SNa [M + Na⁺] 476.22486; found 476.22412.

s) ppm. IR (neat): ν = 3367, 2923–2854, 1710, 1365, 1159, 736,

˜

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3,5-difluoro-4-(4,4,5,5- 446 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₂₄H₃₈BNO₇Na [M +

tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl)pentanoate (15d): Ac-

cording to the above procedure, starting from the amino ester 14c

(71 mg, 0.206 mmol), boronate 15d (0.072 g, 0.153 mmol, 74%) was

obtained as a colorless uncrystallized compound. R_f= 0.45

(EtOAc/PE, 2:8); [α]²_D⁰= +26.3 (c = 0.5 in CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 1.35 (s, 12 H), 1.42 (s, 9 H), 1.54–1.82 (m,

4 H), 2.53–2.67 (m, 2 H), 3.71 (s, 3 H), 4.12–4.34 (m, 1 H), 4.75–

5.01 (m, 1 H), 6.63 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR

(125.75 MHz, CDCl₃): δ = 24.7, 26.2, 28.3, 32.2, 34.9, 52.3, 53.0,

80.0, 84.0, 111.0 (dd, J = 22.1, 6.6 Hz), 148.5 (t, J = 9.8 Hz), 155.4,

166.7 (dd, J = 251.3, 13.8 Hz), 173.1 ppm. ¹¹B NMR (160.5 MHz,

CDCl₃): δ = +29.65 (br. s) ppm. ¹⁹F NMR (470.6 MHz, CDCl₃): δ

Na⁺] 486.26335; found 486.26361.

1,3-Bis[(S)-1-(methoxycarbonyl)-1-(tert-butoxycarbonylamino)but-

4-yl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzene (15i):

According to the above procedure, starting from amino ester 14g

(40 mg, 0.075 mmol), boronate 15i (23 mg, 0.035 mmol, 47%) was

obtained as a colorless uncrystallized compound. R_f= 0.52

(EtOAc/PE, 2:8); [α]²_D⁰= +69 (c = 0.5 in CHCl₃). ¹H NMR

(600 MHz, CDCl₃): δ = 1.34 (s, 12 H), 1.43 (s, 18 H), 1.62–1.82

(m, 8 H), 2.57–2.62 (m, 4 H), 3.72 (s, 6 H), 4.12–4.32 (m, 2 H),

4.86–5.01 (m, 2 H), 7.04 (s, 1 H), 7.43 (s, 2 H) ppm. ¹³C NMR

(75.46 MHz, CDCl₃): δ = 24.9, 27.2, 28.3, 32.4, 35.2, 52.2, 53.3,

79.9, 83.7, 125.3, 128.4, 128.5, 141.1, 155.4, 173.3 ppm. ¹¹B NMR

(96.3 MHz, CDCl₃): δ = +30.6 (br. s) ppm. HRMS (ESI-Q-TOF):

calcd. for C₃₄H₅₅BN₂O₁₀Na [M + Na⁺] 685.38480; found

685.38423.

= –101.12 (s) ppm. IR (neat): ν = 3368, 2929–2855, 1714, 1345,

˜

1150, 850, 550 cm^{– 1}. HRMS (ESI-Q-TOF): calcd. for

C₂₃H₃₄BF₂NO₆Na [M + Na⁺] 492.23435; found 492.23507.

(S)-2-(tert-Butoxycarbonylamino)-5-{3,5-difluoro-4-(4,4,5,5-tetra- (S)-Methyl 2-(tert-Butoxycarbonylamino)-5-(3-methyl-5-iodothien-

methyl[1,3,2]dioxaborolan-2-yl)phenyl}pentanoic Acid (15e): Ac- 2-yl)pentanoate (16): To a solution of boronate 15c (23 mg,

10

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Boron-Substituted Amino Acid and Peptide Derivatives

0.05 mmol) in 50 % aqueous THF (2 mL) contained in a 5 mL

round-bottomed flask, which was protected from light, was added

chloramine-T (12.5 mg, 0.055 mmol) and sodium iodide (8.99 mg,

0.06 mmol). The resulting mixture was stirred for 30 min at room

temperature. When the reaction was complete, 10% aqueous so-

dium thiosulfate (2 mL) was added to decompose the excess iodine.

The mixture was extracted with EtOAc (3ϫ 10 mL) and the com-

bined organic extracts were washed with water (10 mL), brine

(20 mL), dried with MgSO₄, and concentrated under reduced pres-

sure. The crude product was purified by column chromatography

over silica gel (PE/EtOAc, 80:20) to afford iodo amino ester deriva-

tive 16 (15.4 mg, 0.034 mmol, 68%) as a pale-yellow uncrystallized

compound. R_f= 0.35 (EtOAc/PE, 2:8); [α]²_D⁰= +21 (c = 0.2 in

CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.44 (s, 9 H), 1.57–1.88

(m, 4 H), 2.10 (s, 3 H), 2.67–2.78 (m, 2 H), 3.73 (s, 3 H), 4.1–4.33

(m, 1 H), 4.7–5 (m, 1 H), 6.9 (s, 1 H) ppm. ¹³C NMR (125 MHz,

CDCl₃): δ = 13.2, 27.3, 28.3, 28.4, 32.1, 52.3, 53.1, 68.1, 79.9, 135,

139.6, 143.9, 155.3, 173.2 ppm. HRMS (ESI-Q-TOF): calcd. for

C₁₆H₂₄INO₄SNa [M + Na⁺] 476.03629; found 476.03661.

0.06 mmol, 88%) was obtained as a white solid; m.p. 57–58 °C;

[α]²_D⁰= +39.4 (c = 0.7 in DMSO). ¹H NMR (500 MHz, [D₆]-

DMSO): δ = 1.38 (s, 9 H), 1.55–1.66 (m, 4 H), 2.84 (m, 2 H), 3.85

(s, 3 H), 3.98 (m, 1 H), 5.76 (m, 0.1 H), 6.48 (d, J = 7 Hz, 2 H),

7.26 (d, J = 8.1 Hz, 0.9 H) ppm. ¹³C NMR (125.75 MHz, DMSO):

δ = 27.2, 28.6, 30.7, 34.2, 52.2, 53.7, 78.6, 110.4 (dd, J = 22.2,

7.5 Hz), 142.3 (t, J = 10 Hz), 156.0, 166.7 (dd, J = 242, 20 Hz),

173.6 ppm. ¹⁹F NMR (470.6 MHz, DMSO): δ = –103.12 (m),

–131.95 (s) ppm. ¹¹B NMR (160.5 MHz, DMSO): δ = +1.82 (br. s)

ppm. HRMS (ESI-Q-TOF): calcd. for C₁₇H₂₂BF₅NO₄[M^–– K]

410.15597; found 410.15753.

(S)-2-(tert-Butoxycarbonylamino)-5-[3,5-difluoro-4-(potassio-tri-

fluoroborato)phenyl]pentanoic Acid (17c): According to the above

procedure, starting from the boronate 15e (40 mg, 0.088 mmol), tri-

fluoroborate 17c (25 mg, 0.057 mmol, 65 %) was obtained as a

white solid; m.p. 57–58 °C; [α]²_D⁰= +37 (c = 0.7, in DMSO). ¹H

NMR (500 MHz, [D₆]DMSO): δ = 1.36 (s, 9 H), 1.41–1.66 (m, 4

H), 2.35–2.44 (m, 2 H), 3.42–3.49 (m, 1 H), 5.63–5.9 (m, 1 H),

6.43 (d, J = 7.5 Hz, 2 H) ppm. ¹³C NMR (125.7 MHz, DMSO): δ

= 27.2, 28.7, 33.2, 34.9, 55.3, 77.5, 110.3 (dd, J = 22.6, 7.4 Hz),

143.2 (t, J = 10 Hz), 155.2, 166.3 (dd, J = 241, 19 Hz), 173.5 ppm.

¹⁹F NMR (470.6 MHz, DMSO): δ = –104.1 (s), –131.95 (m) ppm.

¹¹B NMR (160.5 MHz, DMSO): δ = +2.1 (br. s) ppm. HRMS

(ESI-Q-TOF): calcd. for C₁₆H₂₀BF₅NO₄[M^–– K] 396.14030;

found 396.14175.

General Procedure for the Preparation of Trifluoroborato-Substi-

tuted Amino Acid Derivatives: To boronate 11a or 15 (0.5 mmol) in

MeOH (1 mL), a solution of KHF₂(156 mg, 2 mmol) in H₂O

(0.8 mL) was added dropwise. The mixture was stirred for 30 min,

then dried under high vacuum. The residual solid was extracted

with four portions of 20% MeOH in acetone. The combined ex-

tracts were concentrated close to the saturation point, then Et₂O

was added until no more precipitation was observed. The solid was

filtered off, washed with two portions of Et₂O, and dried under

high vacuum to give the corresponding trifluoroborato product 12a

or 17.

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3-trifluoromethyl-5-

(potassio-trifluoroborato)phenyl]pentanoate (17d): According to the

above procedure, starting from the boronate 15f (78 mg,

0.153 mmol), trifluoroborate 17d (56 mg, 0.116 mmol, 75%) was

obtained as a white solid; m.p. 57–58 °C; [α]²_D⁰= +25.4 (c = 0.3 in

(S)-2-(tert-Butoxycarbonylamino)-5-[4-(potassio-trifluoroborato)- DMSO). ¹H NMR (500 MHz, [D₆]DMSO): δ = 1.39 (s, 9 H), 1.51–

phenyl]pent-4-enoic Acid (12a): According to the above procedure, 1.67 (m, 4 H), 2.54–2.64 (m, 2 H), 3.62 (s, 3 H), 3.93–4.01 (m, 1

starting from boronate 11a (140 mg, 0.335 mmol, cis/trans, 25:75), H), 7.16 (s, 1 H), 7.28 (d, J = 7 Hz, 1 H), 7.41 (s, 2 H) ppm. ¹³C

the corresponding trifluoroborate 12a (0.09 g, 0.226 mmol, 67%,

cis/trans, 20:80) was obtained as a white solid;^[24]m.p. 55–56 °C;

[α]²_D⁰= +21.4 (c = 0.8 in DMSO). ¹H NMR (300 MHz, [D₆]-

DMSO): δ = 1.35 (s, 9 H), 2.53–2.75 (m, 2 H), 3.58 (m, 1 H), 5.49–

NMR (125.7 MHz, DMSO): δ = 25.4, 28.0, 28.6, 35.0, 52.1, 53.7,

78.6, 121.7, 125.5, 127.3, 128.2, 135.9, 156.0, 173.6 ppm. ¹⁹F NMR

(470.6 MHz, DMSO): δ = –60.5 (s), –139.87 (m) ppm. ¹¹B NMR

(160.5 MHz, DMSO): δ = +2.8 (br. s) ppm. HRMS (ESI-Q-TOF):

5.51 (m, 0.20 H), 5.60–5.90 (m, 1 H), 5.98–6.02 (m, 0.80 H), 6.19 calcd. for C₁₈H₂₃BF₆NO₄[M^–– K] 442.16222; found 442.16199.

(d, J = 15.6 Hz, 0.80 H), 6.29 (d, J = 12 Hz, 0.20 H), 7.01–7.65 (m,

(S)-Methyl 2-(tert-butoxycarbonylamino)-5-(3-methoxy-5-(potassio-

4 H) ppm. ¹³C NMR (150.9 MHz, DMSO): δ = 28.2, 35.7, 54.6,

trifluoroborato)phenyl)pentanoate (17e): According to the above

77.5, 124.0, 124.4, 126.7, 127.3, 127.8, 131.1, 131.5, 132.2, 133.9,

procedure, starting from boronate 15g (44 mg, 0.095 mmol), tri-

154.1, 173.5 ppm. ¹⁹F NMR (470.6 MHz, DMSO): δ = –138.96 (m)

fluoroborate 17e (35 mg, 0.079 mmol, 83 %) was obtained as a

ppm. ¹¹B NMR (192.5 MHz, DMSO): δ = +2.87 (br. s) ppm.

white solid; m.p. 53–54 °C; [α]²_D⁰= +33.4 (c = 1 in DMSO). ¹H

HRMS (ESI-Q-TOF): calcd. for C₁₆H₁₉BF₃KNO₄[M^–– H]

NMR (300 MHz, [D₆]DMSO): δ = 1.38 (s, 9 H), 1.57–1.64 (m, 4

396.1005; found 396.1019.

H), 2.25–2.27 (m, 2 H), 3.61 (s, 3 H), 3.66 (s, 3 H), 3.86–4.12 (m,

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3-methyl-5-(potassio-

trifluoroborato)thien-2-yl]pentanoate (17a): According to the above

procedure, starting from boronate 15c (63 mg, 0.139 mmol), tri-

1 H), 6.39 (s, 1 H), 6.69 (d, J = 2.4 Hz, 1 H), 6.75 (s, 1 H), 7.27 (d,

J = 7.5 Hz, 1 H) ppm. ¹³C NMR (125.75 MHz, DMSO): δ = 27.6,

28.2, 30.5, 35.0, 51.6, 53.4, 54.3, 78.1, 110.7, 113.6, 124.1, 140.4,

fluoroborate 17a (47 mg, 0.108 mmol, 78%) was obtained as a yel- 155.5, 158.0, 173.2 ppm. ¹⁹F NMR (470.6 MHz, DMSO): δ =

low solid; m.p. 61–62 °C; [α]²_D⁰= +29 (c = 0.6 in DMSO). ¹H NMR

(500 MHz, [D₆]DMSO): δ = 1.37 (s, 9 H), 1.48–1.70 (m, 4 H), 1.98

(s, 3 H), 2.65–2.89 (m, 2 H), 3.60 (s, 3 H), 3.93–4.04 (m, 1 H), 6.45–

6.76 (s, 1 H), 7.24 (d, J = 8.1 Hz, 1 H) ppm. ^{1 3}C NMR

(125.75 MHz, DMSO): δ = 13.8, 27.3, 28.3, 28.6, 30.7, 52.1, 53.7,

78.6, 130.7, 131.7, 135.7, 156.0, 173.6 ppm. ¹⁹F NMR (282.4 MHz,

DMSO): δ = –134.11 (m) ppm. ¹¹B NMR (96.29 MHz, DMSO): δ

= +2. 49 (br. s) ppm. HRMS (ESI-Q-TOF): calcd. for

C₁₆H₂₄BF₃NO₄S [M^–– K] 394.14657; found 394.14658.

–139.05 (m) ppm. ¹¹B NMR (160.5 MHz, DMSO): δ = +3.42 (br.

s) ppm. HRMS (ESI-Q-TOF): calcd. for C₁₈H₂₆BF₃NO₅[M^–– K]

404.18569; found 404.18540.

Preparation of Dipeptide 20: Prepared according to a modified pro-

cedure described in the literature.^[31]To a solution of amino acid

derivative 11e (57 mg, 0.16 mmol) in DMF (1.5 mL), was added

methyl l-alaninate hydrochloride 18 (28.13 mg, 0.176 mmol) and

2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexa-

fluorophosphate (HATU; 76.43 mg, 0.176 mmol). The mixture was

cooled in an ice bath, then diisopropylethylamine (DIPEA; 0.1 mL)

was added. The resulting mixture was stirred for 3 d at 65 °C. When

the reaction was complete, a solution of HCl 1M (3 mL) was

added. The mixture was extracted with EtOAc (3ϫ5 mL), washed

(S)-Methyl 2-(tert-Butoxycarbonylamino)-5-[3,5-difluoro-4-(pot-

assio-trifluoroborato)phenyl]pentanoate (17b): According to the

above procedure, starting from the boronate 15d (32 mg,

0.068 mmol), the corresponding trifluoroborate 17b (27 mg,

Eur. J. Org. Chem. 0000, 0–0

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S. Jugé et al.

FULL PAPER

with water (10 mL), brine (20 mL), dried with MgSO₄, and concen-

trated under reduced pressure. The crude product was purified by

column chromatography over silica gel (PE/EtOAc, 8:2 + 1% acetic

acid), leading to the corresponding unsaturated dipeptide 19

(37.4 mg, 0.09 mmol, 59%) as a yellow uncrystallized compound,

with a cis/trans ratio 28:72. R_f= 0.38 (PE/EtOAc, 7:3 + 1% acetic

acid); [α]²_D⁰= +38 (c = 0.5 in CHCl₃). ¹H NMR (500 MHz, CDCl₃):

δ = 1.4 (d, J = 7 Hz, 3 H), 1.43 (s, 9 H), 2.20 (s, 0.72 H), 2.21 (s,

0.28 H), 2.62–2.96 (m, 2 H), 3.71 (s, 0.72 H), 3.72 (s, 0.28 H), 4.10–

4.12 (m, 1 H), 4.57 (q, J = 7 Hz, 1 H), 5.05–5.13 (m, 1 H), 5.55–

5.57 (m, 0.28 H), 5.87–5.9 (m, 0.72 H), 6.51 (d, J = 16 Hz, 0.72

H), 6.64 (d, J = 12 Hz, 0.28 H), 6.73 (m, 1 H), 6.75 (d, J = 5.1 Hz,

0.72 H), 6.82 (d, J = 5.1 Hz, 0.28 H), 6.99 (d, J = 5.1 Hz, 0.72 H),

7.15 (d, J = 5.1 Hz, 0.28 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

= 13.7, 14.1, 18.3, 28.2, 32.0, 36.1, 48.1, 48.1, 52.4, 54.1, 80.1,

122.5, 123.4, 123.5, 123.7, 124.2, 125.6, 129.8, 130.5, 134.5, 135.5,

D. Harvey (Sherbrooke) for his help in the preparation of this ma-

nuscript.

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2861, 1710, 1657, 1158, 701, 461 cm^–1.

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Hydrogenation of unsaturated dipeptide 19 (100 mg, 0.23 mmol) in

methanol (2 mL) in the presence of Pd/C 5% (20 mg), led to satu-

rated derivative 20 (89.6 mg, 0.225 mmol, 98%), which was ob-

tained in as a pale-yellow uncrystallized product. R_f= 0.42 (PE/

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EtOAc, 7:3); [α]²_D⁰= +29 (c = 0.4 in CHCl₃). H NMR (500 MHz,

1

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CDCl₃): δ = 1.41 (d, J = 7 Hz, 3 H), 1.43 (s, 9 H), 1.6–1.9 (m, 4

H), 2.13 (m, 3 H), 2.69–2.80 (m, 2 H), 3.73 (s, 1 H), 4.11–4.22 (m,

1 H), 4.56 (q, J = 7 Hz, 1 H), 4.8–5 (m, 1 H), 6.55 (m, 1 H), 6.75

(d, J = 5.1 Hz, 1 H), 6.99 (d, J = 5.1 Hz, 1 H) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 13.6, 18.3, 27.3, 27.4, 28.3, 31.9, 48.0, 52.4,

54.2, 80.1, 121.1, 129.9, 132.8, 137.5, 155.6, 171.5, 173.0 ppm. IR

(neat): ν = 3303, 2913–2858, 1746, 1656, 1525, 1454, 1363, 1159,

˜

865, 697, 464 cm^–1. HRMS (ESI-Q-TOF): calcd. for

C₁₉H₃₀N₂O₅SNa [M + Na⁺] 421.17676; found 421.17763.

Borylation of the Dipeptide 20: According to the general procedure

for the borylation of amino esters 14, described above, saturated

dipeptide 20 (37 mg, 0.093 mmol) led to boronate 21 (38 mg,

0.072 mmol, 78%) as a pale-yellow uncrystallized compound. R_f=

0.43 (PE/EtOAc, 4:6); [α]²_D⁰= +32 (c = 0.5 in CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 1.31 (s, 12 H), 1.4 (d, J = 7 Hz, 3 H), 1.43

(s, 9 H), 1.60–1.93 (m, 4 H), 2.13 (m, 3 H), 2.69–2.83 (m, 2 H),

3.73 (s, 1 H), 3.97–4.09 (m, 1 H), 4.50–4.59 (m, J = 7.2 Hz, 1 H),

4.97–4.99 (m, 1 H), 6.55 (d, J = 6.5 Hz, 1 H), 7.32 (s, 1 H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 13.4, 18.3, 24.7, 27.1, 27.8, 28.3,

31.8, 48.0, 52.4, 54.2, 80.1, 83.8, 134.7, 140.4, 145.7, 155.6, 171.4,

173.0 ppm. ¹¹B NMR (160 MHz, CDCl₃): δ = +29.37 (br. s) ppm.

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466 cm^–1. HRMS (ESI-Q-TOF): calcd. for C₂₅H₄₁BN₂O₇SNa [M

+ Na⁺] 547.26243; found 547.26035.

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1

cle): H, ¹³C, ¹⁹F NMR spectra of all compounds and kinetic hy-

drolysis data.

Acknowledgments

This research was supported by the (Centre National de la Recher-

che Scientifique (CNRS)), the Ministère de l’Education Nationale

et de la Recherche, and the Conseil Regional de Bourgogne (grant

number 3MIM). H. A. is grateful for the JCE fellowship provided

by the Conseil Regional de Bourgogne with the sponsorship of

Synthelor S.A. (Nancy). The authors would also like to thank M.

J. Penouilh, M. and F. Picquet at the Welience/Pôle Chimie Molé-

culaire, for the NMR and mass spectrometry analyses, and Pr. P.

12

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Published Online: ᭿

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Job/Unit: O31084

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Date: 16-10-13 17:18:20

Pages: 14

S. Jugé et al.

FULL PAPER

Boron Amino Acids

H. Audi, E. Rémond, M.-J. Eymin,

A. Tessier, R. Malacea-Kabbara,

S. Jugé* .......................................... 1–14

Modular Hemisyntheses of Boronato- and

Trifluoroborato-Substituted

Amino Acid and Peptide Derivatives

l-NHBoc

Modular hemisyntheses of new boron-con-

taining l-amino acid derivatives by using

Wittig and C–H Ir-catalyzed borylation as

key reactions, are reported. Reaction of the

boronato amino acids with KHF₂or NaI

in the presence of chloramine led to the

iodo or trifluoroborato derivatives. An

investigation of trifluoroborates hydrolysis

in buffer solution (¹⁹F NMR) shows an

excellent stability for the 3-methylthienyl

amino acid derivative.

Keywords: Wittig reactions / Amino acids /

Phase-transfer catalysis / Boron / Iridium /

Trifluoroborates

14

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Article Doi

Modular hemisyntheses of boronato- and trifluoroborato-substituted L -NHBoc amino acid and peptide derivatives

DOI: 10.1002/ejoc.201301084

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Full text of DOI:10.1002/ejoc.201301084

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