Synthesis of cyclic γ-amino acids for foldamers and peptide nanotubes

FULL PAPER

DOI: 10.1002/ejoc.201201565

Synthesis of Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

Nuria Rodríguez-Vázquez,^[a]Stephan Salzinger,^[a]Luis F. Silva,^[a]Manuel Amorín,*^[a]and

Juan R. Granja*^[a]

Keywords: Amino acids / Peptides / Carbocycles / Foldamers / Secondary structure / Self-assembly

Cyclic γ-amino acids are molecular building blocks of great

interest in peptide and foldamer chemistry, as they allow the

preparation of new structures that are not found in Nature.

In this paper, we describe the synthesis of cyclic γ-amino

acids that have a cis relationship between the amino and the

carboxylic acid groups. This arrangement, in most cases, in-

duces the resulting peptides to adopt a flat conformation,

which makes them appropriate for the design of foldamers

that adopt β-sheet-type structures.

and amino groups.^[9]Finally, γ-amino acids have been pre-

pared and studied because of their biological applications

as GABA mimics or antiviral agents.^[10]

Introduction

Peptides and proteins are essential components of living

organisms and are responsible for, amongst other things,

catalytic activity and structural or mechanical functions. In

order to carry out these functions, they fold into specific

and characteristic three-dimensional structures.^[1]These

structures and functions arise mainly from the combination

of the 20 proteinogenic amino acids (Aas). The synthesis of

non-natural amino acids has attracted interest from chem-

ists and materials scientists, due to the envisaged large

number of possible applications.^[2,3]In addition, in recent

years, chemists have started to develop oligomeric struc-

tures made from non-natural monomers, called folda-

mers,^[4]in the search for new molecules that can adopt spe-

cial and unique structures with new properties for materials

or therapeutical sciences.^[5]The search for new monomers

that can be used in the synthesis of foldamers is still of great

interest. In addition to β-amino acids,^[6]γ-amino acids are

powerful building blocks due to their unique structural

properties derived from the additional carbon atoms be-

tween the carbonyl and amino groups.^[7]The preparation of

a large variety of derivatives of these compounds is possible,

because a range of side-chains can be introduced at the α-,

β- and/or γ-positions.^[8]Cyclic amino acids are of particular

interest in foldamer synthesis, due to their conformational

restrictions, and the particular orientation of the carbonyl

In the last few years, we have focussed on the design and

synthesis of supramolecular structures derived from cyclic

peptides (CPs) that contain γ-aminocycloalkanecarboxylic

acids (γ-Acas).^[11,12]We have shown that peptides of α- and

γ-amino acids, and more recently, peptides of all γ-amino

acids,^[13]of alternating chirality can adopt a flat conforma-

tion that allows stacking to form dimers or nanotubes. The

main characteristic of these CPs is the projection of the β-

carbon of each γ-amino acid towards the cavity, a situation

that modifies the properties of the ensemble. In this paper,

we present our results on the preparation of a variety of γ-

Acas that may be of interest for the design not only of

nanotubes but also of foldamers. A common feature of the

compounds is the cis-relationship between the carboxylic

acid and amino groups, which would make then particularly

appropriate for β-strand conformations (Figure 1). The

strand, because of the rigidity of the cyclic ring, would be

bent by an angle φ that would depend on the ring size (n =

0, 1, 2, etc.). Such a structure would give rise to coiled

[a] Departamento de Química Orgánica, Centro Singular de

Investigación en Química Biológica y Materiales Moleculares

(CIQUS) y Unidad Asociada al CSIC, Campus Vida,

Universidad de Santiago de Compostela,

15782 Santiago de Compostela, Spain

Fax: +34-881-815704

E-mail: juanr.granja@usc.es

Figure 1. General structure of cyclic γ-amino acids (γ-Aca) for use

in foldamer synthesis described in this article, and proposed prop-

erties of the oligomer β-strand derived from the γ-Aca (SPPS =

solid-phase peptide synthesis, LPPS = liquid-phase peptide synthe-

sis).

manuel.amorin@usc.es

Homepage: http://ww w .usc.es/ciqus/es/investigacion/

grupos-de-investigacion/granja-guillan

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201201565.

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strands in which the properties of the major arc would de- mation and self-assemble into dimers that resemble the

pend on the properties of the longer chain (C-4, C-5 and characteristic β-sheet structure present in nanotubes.^[11,12]

so on) of the cyclic moiety, while the internal part, i.e., the

The partially hydrophobic character of the cavity of the

minor arc, would depend on the properties of the β-carbon ensemble provided by the γ-Ach residue led us to study the

(C-2) and its functionalization (X ϶ H).

preparation of the β-methylated derivative using a similar

procedure. Thus, the 2-methyl-3-nitrobenzoic acid was

treated under similar conditions to give a mixture of the

four possible diastereomers in a 3:3:3:1 ratio. Unfortunately,

these compounds could not be separated by flash

chromatography, but selective washes of the Boc-protected

amino acids with dichloromethane allowed the separation

of the most soluble fractions, i.e., trans,trans isomer 2b and

minor isomer 2d, while the insoluble solid was enriched in

2a and 2c. Crystallization of this solid mixture from meth-

anol gave pure 2c, while the mother liquors contained

mainly diastereomer 2a (9:1 ratio). Crystallization of the

dichloromethane-soluble fraction from chloroform/hexane

gave pure isomer 2b. Interestingly, sometimes under these

conditions, crystals with a different form, which corre-

sponded to the minor stereoisomer (i.e., 2d), were observed,

which allowed the purification and characterization of this

compound. The initial structural assignment was carried

out by NMR spectroscopy, particularly ¹³C NMR spec-

troscopy, and the structure was later confirmed by X-ray

crystallography. In the ¹³C NMR spectra, we considered

that an axial orientation of a substituent would induce an

upfield shift of the carbon bearing the axial substituent (see

Table 1).^[18]We reasoned that only one of the four dia-

stereomers would have the most stable conformation in

which all of the substituents would be equatorially orien-

tated (2b), and that the other three would each have only

one axially orientated group (Scheme 2): the carboxylic acid

in 2a, whose Cα appears at δ = 42.9 ppm, the methyl group

in isomer 2c, in which the Cβ signal is at δ = 33.7 ppm, and

the amino group in 2d, with the Cγ at δ = 49.1 ppm. The

axial orientation of the methyl group in compound 2c can

also be inferred from its own upfield shift (δ = 8.2 ppm).

On the other hand, the downfield shift observed for each

of the three methine ring-carbons in compound 2b also

confirms the expected all-equatorial orientation.

Results and Discussion

The first γ-Aca prepared in this study was 3-aminocyclo-

hexanecarboxylic acid (γ-Ach-OH), which was obtained in

three steps from 3-nitrobenzoic acid (Scheme 1).^[11a]The

first step was the simultaneous reduction of the nitro group

and aromatic ring with Raney Nickel under hydrogen pres-

sure (100 bar) at 150 °C. These conditions gave the cis iso-

mer of the 3-aminocyclohexanecarboxylic acid.^[11,14]The re-

sulting amino acid was treated with Boc anhydride, and the

racemic Boc-γ-Ach-OH (Boc = tert-butoxycarbonyl) was

resolved by crystallization in the presence of (+)-1-phenyl-

ethanamine, an inexpensive commercial chiral amine (both

enantiomers are available at similar prices). This amine has

proved to be very useful, and most of the chiral Boc-pro-

tected γ-Acas that we have prepared were resolved in a sim-

ilar manner. In general, the R isomer, (+)-1-phenylethan-

amine, crystallized together with the 1R,3S enantiomer (l-

Boc-γ-Ach-OH, 1a), while the S enantiomer provided the

1S,3R-configured amino acid (d-Boc-γ-Ach-OH).^[15]At

least two co-crystallizations were generally required to ob-

tain the Boc-Aca with an enantiomeric excess higher than

97%.

Table 1. ¹³C NMR chemical shifts of Cα, Cβ, and Cγ, and of the

methyl group corresponding to the cyclohexanecarboxylic acid de-

rivatives (in 1 and 2a–d), which were used to assign their relative

configurations. The lowest values for each carbon are shown in

bold and the highest are in italics.

Scheme 1. Reagents and conditions: (a) H₂(100 atm), Raney Ni,

NaOH, H₂O, 150 °C, 80%; (b) (Boc)₂O, DIEA (diisopropylethyl-

amine), H₂O/dioxane, 80%; (c) (R)-phenylethanamine, CHCl₃/hex-

anes; (d) NaH, MeI, THF, 88%.

δ (Cα)

δ (Cβ)

δ (Cγ)

δ (Me)

1

43.5

42.9

50.0

45.8

44.2

50.2

49.9

54.0

51.9

49.1

The Boc-protected amino acid can be transformed into

other derivatives, such as N-alkylated compounds. N-

Methyl amino acids are known to increase membrane per-

meability and enhance other biologically relevant proper-

ties.^[16]In addition, the self-assembling properties of cyclic

peptides have been studied in organic solvents by selective

2a

2b

2c

2d

36.4

39.4

33.7

36.0

14.7

16.5

8.2

15.9

The structures of the most relevant isomers (2b and 2c)

homochiral N-alkylation.^[11,12,17]Thus, the N-methylated were confirmed by X-ray crystallography (Scheme 2). We

derivative (1b) was prepared by treatment of Boc-Ach-OH also resolved 2b by co-crystallization in the presence of S-

with NaH in the presence of iodomethane. The use of these phenylethanamine to give the dextrorotatory isomer with

amino acids in cyclic peptides of alternating α- and γ-Aas 98% ee. Although the hydrogenation gave rise to a complex

confirmed that the resulting peptides adopt the flat confor- mixture of the four diastereomers, the two most interesting

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Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

amine. Finally, the N-methyl derivative (i.e., 7) was obtained

by alkylation of 6 with sodium hydride and iodomethane in

THF.

Scheme 3. Reagents and conditions: (a) H₂, Pd/C, MeOH, 98%;

(b) HCl (10%), 90%; (c) (Boc)₂O, DIEA, H₂O/dioxane, 89%;

(d) (R)-phenylethylamine, CHCl₃/hexanes; (e) NaH, MeI, THF,

88%; (f) i) 10% HCl, Δ; ii) Boc₂O, DIEA, H₂O/dioxane (80% over

two steps); (g) H₂, Pd/C, EtOH, 98%.

Scheme 2. Reagents and conditions: (a) NaOMe, MeOH, Δ. The

most stable chair conformations of the 2-methyl derivatives. The

proposed equilibrium between chair conformations is represented

for 2a. The isomerization of methyl ester 3a with sodium methoxide

in methanol provided a mixture enriched in isomer 2b. Bottom,

single-crystal X-ray structures of compounds 2b and 2c.^[19]

The unsaturated derivative, 4-aminocyclopent-2-enecarb-

oxylic acid (γ-Ace-OH), was also prepared by simple hy-

drolysis under acidic conditions, and this was followed by

isomers (i.e., 2b and 2c) could be obtained by isomerization amine protection with Boc anhydride. Once again, the reso-

of the methyl esters of the other two isomers. For example, lution was carried out with phenylethanamine to provide

a mixture enriched in the thermodynamically more stable the enantiopure form of the Ace. Once more, the levorota-

isomer 2b (3:1) was obtained on heating 3a (9:1 mixture tory enantiomer (R) of the phenylethanamine gave rise to

with 3b) in methanol in the presence of sodium methoxide, the 1S,4R-configured stereoisomer, l-Boc-γ-Ace-OH (8),

in a reaction in which isomerization and hydrolysis took while the S isomer provided the d form (1R,4S). This reso-

place simultaneously.

lution could be carried out on a multi-gram scale and in a

The next targets were the cyclopentyl derivatives. The more reproducible manner than for the saturated derivative.

simplest example, 3-aminocyclopentanecarboxylic acid (γ- In this way, an improved synthesis of Boc-γ-Acp-OH can

Acp-OH), was obtained from the commercially available be carried out by simply hydrogenating the corresponding

Vince lactam (4). Hydrogenation, followed by hydrolysis enantiomers of Boc-γ-Ace-OH. The potential applications

with HCl, and reaction with Boc anhydride gave Boc-γ- of the γ-Ace residue in foldamer chemistry were studied

Acp-OH (Scheme 3). The resulting protected γ-amino acid with the dimer-forming cyclic peptide c-[Aib-l-γ-Ace-]₃

was also resolved by co-crystallization with S-phenylethan- (Scheme 4).^[12b]The Aib residue was introduced to examine

amine to give the 1S,3R enantiomer (d-Boc-γ-Acp-OH, the steric effect on the self-assembling properties of the CP

6).^[15,20]l-Boc-γ-Acp-OH was obtained from the mother ring when a methyl substituent is axially orientated at the

liquors and by using the other enantiomer of the chiral α-position of every second residue. This peptide did self-

Scheme 4. Representation of the self-assembling properties of cyclic peptides containing Acp and Ace residues alternated with Aib,

showing their different tendencies to adopt the flat conformation.

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assemble into dimers with a β-sheet-type interaction, but

the reduced analogue (i.e., c-[Aib-l-γ-Acp-]₃) was folded as

a consequence of the steric interactions between the axially

orientated α-methyl and carbonyl groups of the γ-Acp. This

difference between the two cyclic peptides must be related

to the higher degree of flexibility of the 1,3-cyclopentylene

moiety of γ-Acp compared to the 1,4-cyclopent-2-enylene

ring, which might prevent the CP from adopting the flat

conformation required for dimerization in the β-strand

form. Unfortunately, the Ace was configurationally un-

stable and, under the typical basic or acidic conditions used

in peptide synthesis, epimerization or isomerization took

place, thus making its implementation in foldamer chemis-

try difficult.

Interestingly, Vince lactam (4) can also be used for the

preparation of other γ-amino acids with functional groups

in other positions.^[10]Some work has already been carried

out in this area, but it focussed on the synthesis of GABA

analogues. As mentioned above, we were interested in the

introduction of functional groups at C-2, but trans-orien-

tated with respect to the amino and carboxylic acid groups.

Such a configuration would not interfere with the folding

and assembling properties of the resulting peptide. Our ini-

tial target was the N-Boc-protected 2-fluoro derivative (i.e.,

Boc-2-F-γ-Acp-OH, 10), which would then be used in pept-

ide synthesis. We followed a similar strategy to that pre-

viously described for the preparation of (1r,2s,3s,4s)-3-

amino-4-bromo-2-fluorocyclopentanecarboxylic acid, al-

though this approach was reported to give the cis,cis iso-

mer.^[21]Thus, treatment of the p-methoxybenzyl-protected

Vince lactam with m-CPBA (m-chloroperbenzoic acid) pro-

vided the epoxide. This was transformed into 8b by reaction

with hydrogen bromide followed by treatment of the crude

mixture with trimethylsilyl triflate (TMSOTf; Scheme 5).

TMS protection facilitated separation of the 7-hydroxy de-

rivative (8a) from its regioisomer [6-bromo-5-hydroxy-2-(4-

methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one],^[21]which

was also generated under these conditions in 12% yield.

Radical debromination carried out with tributyltin hydride

in the presence of initiator 2,2Ј-azobis(isobutyronitrile)

(AIBN) was followed by TMS deprotection with tetrabut-

ylamonium fluoride and treatment of the resulting alcohol

with one equivalent of (diethylamino)sulfur trifluoride

(DAST) in dichloromethane at –78 °C. This sequence gave

bicyclic fluoride 9b in 60% yield. It has been reported that

this transformation takes place by an S_N2 mechanism,^[21]

Scheme 5. Reagents and conditions: (a) NaH, PMBCl, TBAI (tetra-

butylammonium iodide), DMF, 91%; (b) m-CPBA, CHCl₃, 91%;

(c) HBr (45%), CH₃CN; (d) TMSOTf, Pyridine, DMAP (4-dimeth-

ylaminopyridine), CH₂Cl₂, Δ, 75% (two steps); (e) Bu₃SnH, AIBN,

benzene, Δ, 97%; (f) TBAF (tetrabutylammonium fluoride), THF,

88%; (g) DAST, CH₂Cl₂, –78 °C – room temp., 60%; (h) CAN,

CH₃CN; (i) HCl (4 m)/AcOH; (j) (Boc)₂O, DIEA, H₂O/dioxane

(1:1), 53% (three steps).

Figure 2. Top, HOESY spectra of fluoride derivative 9b, in which

the cross-peaks are between fluoride and protons H-5 and H-6.^[22]

Bottom, single-crystal X-ray structures of compounds 10, 12a, 12b,

and 13.^[19]

but two-dimensional NMR experiments showed that the apical proton and the methylene protons of the PMB (para-

fluoride substitution took place with retention of configu- methoxybenzyl) group, which confirmed their spatial prox-

ration. The cross-peak in the HOESY (heteronuclear imity. Replacement of the PMB group by benzyl protection

NOESY)^[22]spectra between the fluoride and the lactam (11) did not change the stereochemistry of the fluoride sub-

protons at C-5 and C-6 suggests a cis orientation (Figure 2). stituent, and lactam 12b was formed in 60% yield with re-

Some additional experiments were carried out to study tention of configuration (Scheme 6). The relative configura-

the fluorination reaction. DAST treatment was also carried tion of lactams 12a and 12b, and of the final amino acid

out on bromide derivative 8a to ascertain whether the reten- (i.e., 10) was confirmed by X-ray diffraction, as shown in

tion of configuration was due to steric congestion. Treat- Figure 2. The retention of configuration can be explained

ment of this lactam with DAST again provided the corre- in terms of an amide-assisted intermediate (Figure 2) in

sponding fluoride derivative with retention of configuration which the nitrogen stabilizes the carbocation generated

(9a). NOe experiments revealed a cross-peak between the upon activation of the hydroxy group by DAST. The

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Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

fluoride ion would react with the apical carbon to regener- chloride (MEMCl) in the presence of diisopropylethyl-

ate the five-membered lactam instead of the β-lactam, and amine, followed by radical debromination with tributyltin

so provide the fluoride derivative with retention of configu- hydride and AIBN. Debenzylation of 15a was carried out

ration.

with sodium and liquid ammonia in THF at –78 °C, and

the lactam was hydrolysed under basic conditions. For this

purpose, the resulting lactam (i.e., 15b) was treated with

Boc anhydride in the presence of DMAP, and the resulting

tert-butylcarbamate (i.e., 15c) was stirred in a mixture of

methanol and water (3:1) in the presence of potassium car-

bonate to give 16 in 78% yield.

Scheme 6. Reagents and conditions: (a) KOH, BnBr, TBAI,

DMSO, 96%; (b) m-CPBA, CHCl₃, 88%; (c) i) 45% HBr, CH₃CN;

ii) TMSOTf, Py, DMAP, CH₂Cl₂, Δ, 53% (two steps); (d) TBAF,

THF, 93%; (e) DAST, CH₂Cl₂, –78 °C – room temp., 62%;

(f) Bu₃SnH, AIBN, benzene, Δ, 88%; (g) Na/NH₃, tBuOH, –78 °C,

78%; (h) HCl (4 m)/AcOH; (i) (Boc)₂O, DIEA, H₂O/dioxane (1:1),

93% (two steps).

Scheme 8. Reagents and conditions: (a) MEMCl, DIEA, CH₂Cl₂,

80%; (b) Bu₃SnH, AIBN, benzene, Δ, 85%; (c) Na, NH₃, THF,

–78 °C, 74%; (d) (Boc)₂O, DMAP, CH₂Cl₂, 91%; (e) K₂CO₃,

MeOH/H₂O (3:1), 78%.

The synthesis of the amino acid was completed by both

approaches. Fluoride 9b was treated with ceric ammonium

nitrate (CAN) to remove the protecting group. The lactam

was then hydrolysed by treatment with HCl, and the re-

sulting amino acid was protected as its tert-butylcarbamate

by reaction with Boc anhydride. Similarly, compound 12a

was treated with tributyltin hydride in the presence of

AIBN to remove the bromide, and the resulting lactam was

treated with sodium in liquid ammonia to remove the

benzyl protecting group. The resulting fluoride-substituted

lactam was treated as before to provide compound 10.

Alkylation of the resulting lactam did not give rise to

N-methyl-substituted amino acid 14 (Boc-2-F-^MeN-γ-Acp-

OH). Under typical basic conditions (NaH) we only ob-

served decomposition of the starting material. For this

reason, compound 14 was prepared following a strategy

(see Scheme 7) similar to that described for 10, starting

from lactam 4. Perhaps the main differences are the lower

yields observed in the fluoride-substitution reaction (only

40% yield) and in the lactam hydrolysis and protection of

the secondary amide (only 36% yield for both steps). Once

again, the fluorination reaction took place with retention

of configuration, as inferred from the X-ray diffraction

pattern of a crystal of compound 13 (Figure 2).

The efficiency of the processes presented are remarkable.

Most of the reactions could be carried out on a multigram

scale, and the transformations took place in good to excel-

lent yields. However, final resolution steps were still re-

quired, as all of the methods described above provided the

corresponding N-Boc protected amino acids as racemic

mixtures. In an effort to overcome this drawback, we evalu-

ated other synthetic strategies using the chiral pool. With

this idea in mind, the preparation of a 3-substituted tetra-

hydrofuran [γ-Ahf(Bn)-OH] starting from d-xylose was at-

tempted (Scheme 9).^[23]Although we have previously de-

scribed the synthesis of several such derivatives, some of

the key steps have been improved recently.^[24]Xylose was

dissolved in a mixture of sulfuric acid in acetone under con-

trolled conditions followed by neutralization with sodium

hydrogen carbonate. The resulting 1,2-monoacetonide was

treated with excess methanesulfonyl chloride to provide the

bismesylate, the isopropylidene protecting group was re-

moved by treatment with trifluoroacetic acid (TFA), and

then epoxide 17 was formed by reaction with potassium

carbonate. Epoxide 17 was ring-opened with sodium azide,

and the resulting alcohol was protected by treatment with

benzyl bromide. In this step, a variety of substituents can

be introduced at this position by using different alkylating

electrophiles. Compound 18b was transformed into methyl

ester 19a by a sequence of hydrolysis of the dimethyl acetal

with TFA/water, followed by oxidation of the resulting alde-

hyde with N-bromosuccinide (NBS) in the presence of po-

tassium carbonate. This fully protected amino acid can be

used in the synthesis of any kind of peptide using orthogo-

nal or N-deprotection conditions. Treatment of the ester

with lithium hydroxide produced the corresponding acid

(19b), while reduction with triphenylphosphane in THF or

Scheme 7. Reagents and conditions: (a) NaH, MeI, THF, 87%;

(b) m-CPBA, CH₂Cl₂, 75%; (c) i) 45% HBr, CH₃CN; ii) TMSOTf,

Py, DMAP, CH₂Cl₂, Δ, 52% (two steps); (d) TBAF, THF, 98%;

(e) DAST, CH₂Cl₂, –78 °C – room temp., 40%; (f) Bu₃SnH, AIBN,

benzene, Δ, 93%; (g) HCl (4 m)/AcOH; (h) (Boc)₂O, DIEA, H₂O/

dioxane (1:1), 36% (two steps).

Finally, 2-hydroxy derivative 16 was also prepared by a hydrogenation with 10% palladium on carbon provided the

similar strategy (Scheme 8). The starting material was inter- free amine derivative 20a. Compound 19b could be ob-

mediate 11, which was transformed into MEM-protected tained in one pot from acetal 18a by hydrolysis with TFA

compound 15a by treatment with methoxyethoxymethyl and subsequent oxidation with chromium trioxide in a mix-

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ture of THF and water in the presence of acetone. Although

the yield was slightly lower than that of the previously de-

scribed method (67 vs. 80%), the process is simpler, and

the acid (i.e., 19b) was sufficiently pure to be used without

chromatographic purification. The Boc-protected amino

acid (i.e., 20b) for use in solid phase synthesis could be ob-

tained by the reaction of 20a with tert-butoxycarbonyl an-

hydride in dichloromethane, followed by hydrolysis with

lithium hydroxide in a water/methanol mixture.

Scheme 10. A cyclic peptide containing Ahf that forms a dimer

with large association constant. In the dimer, the hydroxy groups

participate in an inter-peptide hydrogen bond that favours the for-

mation of only one dimer, instead of the previously reported γ-

turn.^[25]

treated with o-nosyl chloride (NsCl, o-nitrobenzene-1-sulf-

onyl chloride) to give compound 22. Sulfonamide 22 was

treated with potassium carbonate in the presence of methyl

iodide to give the N-methylated derivative (i.e., 23) in 77%

yield. This fully protected amino acid can be used directly

in solid phase or solution synthesis by orthogonal deprotec-

tion of the carboxylic acid (LiOH in methanol) or the

Scheme 9. Reagents and conditions: (a) i) H₂SO₄/acetone, room

temp., 30 min; ii) H₂SO₄(0.15 m), iii) NaHCO₃, acetone/H₂O,

room temp., 95%; (b) MsCl, Et₃N, CH₂Cl₂, 96%; (c) i) TFA/

MeOH; ii) K₂CO₃, 93%; (d) NaN₃, NH₄Cl, H₂O, EtOH, 83%;

(e) NaH, BnBr, NBu₄I, THF, 87%; (f) TFA/H₂O (4:1), 95%; amino group (thiophenol/potassium carbonate), or it could

(g) NBS, K₂CO₃, MeOH, CH₃CN, 90%; (h) LiOH, MeOH/H₂O,

94%; (i) Ph₃P, THF, 77%; (j) Boc₂O, DIEA, CH₂Cl₂, 85%.

simply be transformed into the more conventional Boc de-

rivative (i.e., 24b). Thus, the reaction of 23 with PhSH and

K₂CO₃in DMF, followed by reaction with tert-butyloxy-

carbonyl anhydride gave Boc-protected amino acid 24a,

which was treated with lithium hydroxide in methanol to

provide 24b in 60% yield over the three steps.

It has been shown previously that this amino acid tends

to adopt a conformation in which the three substituents

are in pseudoaxial orientations, due to the stereoelectronic

influence of the hydroxy substituent and the furan oxygen,

assisted by a hydrogen bond between the NH and carbonyl

moieties (Scheme 10).^[25]As a result, this amino acid adopts

a γ-turn-type conformation. More recent work in our group

has shown that the use of this compound in a conforma-

tionally restricted cyclic peptide, such as tetrapeptide 21, led

the amino acid to adopt a β-strand-like conformation that

allowed the peptide to self-assemble into the corresponding

dimer with a large association constant.^[24]It should be

mentioned that the presence of the hydroxy group pro-

Scheme 11. Reagents and conditions: (a) H₂, 10% Pd/C, CH₂Cl₂,

jecting towards the cavity of the dimer is responsible not

only for the large association constant, but also for dis-

crimination in dimer formation. CP 21 can form two non-

equivalent dimers (D21_synand D21_anti), but computational

calculations suggest that the presence of the hydroxy group

shifts the equilibrium towards the one in which both of the

hydroxy groups participate in hydrogen-bonding interac-

tions (D21_syn).

96%; (b) NsCl, DIEA, CH₂Cl₂, 73%; (c) MeI, K₂CO₃, DMF, 77%;

(d) C₆H₅SH, K₂CO₃, DMF, 72%; (e) Boc₂O, DIEA, CH₂Cl₂, 90%;

(f) LiOH, MeOH/H₂O, 94 %.

Conclusions

The synthesis of various protected cyclic γ-amino acids

suitable for use in peptide synthesis is described. A common

Finally, attempts to obtain N-methylated amino acid 24b feature of all of these amino acids is the cis-orientation of

[Boc-^MeN-γ-Ahf(Bn)-OH] by alkylation of 20a or its methyl the substituents, which makes them especially suitable for

ester with NaH and methyl iodide were unsuccessful. Under the formation of β-strand conformations in non-natural

all the conditions we tested, we observed decomposition of oligomers. In addition, in some derivatives, the β-carbon

the starting material. As an alternative, we decided to use substituent is in a trans disposition with respect to the carb-

Fukuyama’s method (Scheme 11)^[26]and, after the re- onyl and amino groups. This configuration allows the com-

duction of the azide group of 19a, the resulting amine was pounds to modify the properties of internal part, i.e., the

3482

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Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

a second crystallization, 80 %, R_f= 0.85 (MeOH), m.p. 136–

138 °C]. The resulting racemic Boc-γ-Ach-OH was resolved by

crystallization from CHCl₃/hexane (2:1) in the presence of (+)-1-

phenylethanamine (1 equiv.). The resulting white crystals were

washed with CHCl₃/hexane (2:1), poured into a separating funnel,

dissolved in CH₂Cl₂(500 mL), and washed with citric acid (10%

aq.; 3ϫ 150 mL). The combined organic extracts were dried with

anhydrous Na₂SO₄, filtered, and concentrated, and the resulting oil

was crystallized from CH₂Cl₂/hexane (2:1).^{[11b] 1}H NMR

(250 MHz, CDCl₃, 25 °C): δ = 5.56 (m, 1 H, NH), 4.47 (m, 1 H,

3-H), 3.44 (m, 1 H, 1-H), 1.42 (s, 9 H, Boc) ppm.

minor arc, of the coiled peptide structure, induced by the

rigidity of the cycloalkyl moiety. The DAST induced fluo-

ride-substitution reaction of [2.2.1] bicyclic lactams at the

apical carbon took place with retention of configuration,

probably via a carbocation stabilized by the amide group.

Experimental Section

General: d-(+)-Xylose Ͼ98% was acquired from Lancaster. All rea-

gents obtained from commercial suppliers were used without fur-

ther purification unless otherwise noted. CH₂Cl₂, DIEA, and tert-

butyl alcohol to be used as reaction solvents were distilled from

CaH₂under argon immediately before use. Tetrahydrofuran (THF)

was dried and distilled from sodium/benzophenone.^[27]Analytical

thin-layer chromatography was performed on E. Merck silica gel

60 F254 plates. Compounds that were not UV-active were visual-

ized by dipping the plates into a ninhydrin solution and heating.

Silica gel flash chromatography was performed using E. Merck sil-

ica gel (type 60SDS, 230–400 mesh). Solvent mixtures for

(1R,3S)-3-[(tert-Butyloxycarbonyl)methylamino]cyclohexanecarb-

oxylic Acid (L

-Boc-^MeN-γ-Ach-OH, 1b): A solution of l-Boc-γ-

Ach-OH (1.38 g, 5.68 mmol) in dry THF (50 mL) was treated with

NaH (60% in mineral oil; 680 mg, 28.33 mmol). The resulting mix-

ture was stirred at 0 °C for 30 min, and then methyl iodide

(1.06 mL, 17.03 mmol) was added. The mixture was stirred over-

night at room temp., and an additional 3 equiv. NaH (680 mg,

28.33 mmol) and methyl iodide (1.06 mL, 17.03 mmol) were added

at 0 °C (as starting material was detected by TLC), and the re-

sulting mixture was stirred for a further 3 h at room temp. After

quenching with water, the solution was concentrated to remove the

THF. The resulting aqueous solution was washed with diethyl

ether, acidified to pH = 3 by addition of HCl (10% aq.), and finally

extracted with CH₂Cl₂(3ϫ 50 mL). The combined organic extracts

were dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. The crude material was crystallized from

CH₂Cl₂/hexane to give l-Boc-^MeN-γ-Ach-OH (1b; 1.29 g, 88%) as

a white solid.^[11b]R_f= 0.58 (10 % MeOH/CH₂Cl₂). m.p. 141–

143 °C. ¹H NMR (250 MHz, CDCl₃, 25 °C, TMS): δ = 4.01 and

3.77 (m, 1 H, 3-H), 2.69 (s, 3 H, MeN), 2.42 (m, 1 H, 1-H), 1.42

(s, 9 H, Boc) ppm. [α]²_D⁰= –47.2 (c = 0.80 in MeOH).

1

chromatography are reported as v/v ratios. H NMR spectra were

recorded with Varian Inova 500 MHz, Varian Inova 400 MHz, Var-

ian Mercury 300 MHz, or Bruker DPX 250 MHz spectrometers.

Chemical shifts (δ) are reported in parts per million (ppm) and

were calibrated to tetramethylsilane (δ = 0.00 ppm) or to the resid-

ual solvent signals. ¹H NMR splitting patterns are designated as

singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint). First-

order splitting patterns were assigned on the basis of the appear-

ance of the multiplet. Splitting patterns that could not be easily

interpreted are designated as multiplet (m) or broad (br). Carbon

nuclear magnetic resonance (¹³C NMR) spectra were recorded with

Varian Inova 500 MHz, Varian Inova 400 MHz, Varian Mercury

300 MHz or Bruker DPX 250 MHz spectrometers. Carbon reso-

nances were assigned using distortionless enhancement by polariza-

tion transfer (DEPT) spectra obtained with a phase-angle of 135°.

¹⁹F NMR spectra were recorded with a Varian Mercury 300 MHz

spectrometer. Fast Atom Bombardement (FAB⁺) and Chemical

Ionization (CI⁺) mass spectra were recorded with a Micromass Au-

tospec mass spectrometer. Electrospray (ESI) mass spectra were re-

corded with a Bruker BIOTOF II mass spectrometer. FTIR mea-

surements were made with a JASCO FTIR-400 spectrophotometer

with the sample placed on a CaF₂pellet.

3-[(tert-Butyloxycarbonyl)amino]-2-methylcyclohexanecarboxylic

Acids 2a–d: A mixture of 2-methyl-3-nitrobenzoic acid (10 g,

0.055 mol), NaOH (3.0 g, 0.075 mol), and Raney Ni (6.5 g) in water

(150 mL) was placed in a Parr reactor (0.5 L capacity). The mixture

was stirred at 150 °C for 12 h under hydrogen (100 atm). After cool-

ing and releasing the pressure, the mixture was filtered through

Celite, acidified to pH = 2 with HCl (10% aq.), and then concen-

trated. The mixture was passed through an ion-exchange column,

and the salts were removed with Dowex 50 WX 8 to yield the hy-

drochloride mixture (8.0 g, 75%). R_f= 0.60 (MeOH).

cis-3-Aminocyclohexanecarboxylic Acid Hydrochloride (HCl·H-γ-

Ach-OH): Raney Ni (7.0 g) was added to a solution of 3-nitroben-

zoic acid (11.3 g, 67.61 mmol) and NaOH (3.3 g, 82.50 mmol) in

H₂O (200 mL) in a pressure bottle. The resulting mixture was hy-

drogenated (90–100 atm) at 150 °C for 12 h in a Parr apparatus.

The mixture was filtered through Celite, and the catalyst was

washed with H₂O. The resulting solution was acidified to pH = 2

with HCl (10% aq.) and then concentrated under vacuum. The

residue was desalted by passing through a Dowex AG50W-X4 col-

The resulting mixture (2.0 g, 0.010 mol) was treated with Boc₂O

(2.62 g, 0.012 mol) and DIEA (5.5 mL, 0.031 mol) in H₂O/dioxane

(1:1, 25 mL). The mixture was stirred for 3 h at room temp. The

the mixture was acidified to pH = 2 with HCl (10% aq.) and ex-

tracted with CH₂Cl₂(4ϫ 20 mL). The combined organic extracts

were dried with anhydrous Na₂SO₄and concentrated under re-

duced pressure to give N-Boc-3-amino-2-methylcyclohexanecar-

boxylic acid (2.2 g, 80%) as a mixture of four diastereomers whose

NMR spectra showed a 2a:2b:2c:2d ratio of 3:3:3:1. R_f= 0.35

umn (1 m pyridine) to provide γ-Ach-OH (9.73 g, 80%) as a white

solid.^[11b]R_f= 0.48 (MeOH). H NMR (250 MHz, D₂O, 25 °C): δ (MeOH). The product was washed with CH₂Cl₂(2 mL) and fil-

1

= 3.04 (m, 1 H, 3-H), 2.20–1.70 (m, 5 H), 1.30–0.90 (m, 4 H) ppm.

tered. The mother liquors were enriched in 2b and 2d, while the

solid portion was enriched in isomers 2a and 2c. A portion of the

filtrate fraction (50 mg) was dissolved in CH₂Cl₂(20 mL) and

equilibrated by vapour-phase diffusion in hexane to give crystals

of isomer 2b. Also, a portion of the solid fraction (50 mg), which

contained mainly 2a and 2c, was dissolved in methanol and equili-

brated by vapour-phase diffusion in a hexane atmosphere to give

crystals of 2c.

(1R,3S)-3-[(tert-Butyloxycarbonyl)amino]cyclohexanecarboxylic

Acid (L-Boc-γ-Ach-OH, 1a): Boc₂O (7.0 g, 32.06 mmol) and DIEA

(14.7 mL, 84.19 mmol) were added to a solution of cis-3-aminocy-

clohexanecarboxylic acid (4.0 g, 27.93 mmol) in water (25 mL) and

dioxane (25 mL). The mixture was stirred at room temp. for 3 h

and acidified to pH = 2. The product was extracted with CH₂Cl₂.

The combined organic extracts were dried with anhydrous Na₂SO₄,

filtered, and concentrated, and the resulting oil was crystallized

from CH₂Cl₂/hexane (2:1) to give the product [3.4 g, and 2.1 g from

Data for 2a: ¹H NMR (300 MHz, CDCl₃): δ = 12.01 (br., 1 H,

COOH), 4.55 (m, 1 H, NH), 3.77 (m, 1 H, 3-H), 2.71 (m, 1 H, 1-

Eur. J. Org. Chem. 2013, 3477–3493

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3483

M. Amorín, J. R. Granja et al.

FULL PAPER

H), 1.97 (m, 1 H, 2-H), 1.48 (s, 9 H, Boc), 1.03 (d, J = 6.8 Hz, 3

Methyl 3-[(tert-Butyloxycarbonyl)amino]-2-methylcyclohexanecarb-

oxylate (3b): A solution of 2b (50 mg, 0.19 mmol) in MeOH (2 mL)

H, Me) ppm. ¹³C NMR (125.7 MHz, DMSO): δ = 175.5 (CO),

155.0 (CO), 77.2 (C), 50.0 (CH), 43.0 (CH), 36.4 (CH), 29.3 (CH₂), was treated with EDC·HCl (93.5 mg, 0.49 mmol), HOBt (65.8 mg,

28.2 (Boc), 25.4 (CH₂), 20.2 (CH₂), 14.7 (CH₃) ppm. MS (ESI): 0.49 mmol), and DMAP (59.4 mg, 0.49 mmol). The resulting mix-

m/z (%) = 280 (100) [M + Na]⁺, 258 (1) [M + H]⁺, 222 (55) [M

+ Na – tBu]⁺, 202 (8) [M + H – tBu]⁺. HRMS (ESI): calcd. for

C₁₃H₂₃NNaO₄280.1519; found 280.1516.

ture was stirred at room temp. for 4 h, then the solution was con-

centrated to remove the MeOH. The resulting oil was dissolved in

EtOAc and washed with HCl (5% aq.; 3ϫ 10 mL) and NaHCO₃

(satd. aq.; 2ϫ 10 mL). The combined organic extracts were dried

with anhydrous Na₂SO₄, filtered, and concentrated under reduced

pressure. The residue was purified by flash chromatography (25%

EtOAc/hexane) to give 3b (45.5 mg, 86%) as a white solid. R_f=

Data for 2c: ¹H NMR (250 MHz, CDCl₃): δ = 4.67 (d, J = 6.3 Hz,

1 H, NH), 3.66 (br. s, 1 H, 3-H), 2.55 (m, 2 H, 2-H, 1-H), 1.44 (s,

9 H, Boc), 0.84 (d, J = 6.9 Hz, 3 H, Me) ppm. ¹³C NMR

(62.9 MHz, CDCl₃): δ = 179.9 (CO), 155.3 (CO), 79.4 (C), 52.1

(CH), 45.9 (CH), 33.8 (CH), 28.5 (Boc), 26.6 (CH₂), 23.4 (CH₂),

21.3 (CH₂), 8.2 (CH₃) ppm. MS (ESI): m/z (%) = 280 (100) [M +

Na]⁺, 258 (5) [M + H]⁺, 222 (28) [M + Na – tBu]⁺, 202 (15) [M +

H – tBu]⁺. CCDC-909273.

1

0.56 (25% EtOAc/hexane). H NMR (300 MHz, CDCl₃): δ = 4.39

(d, J = 9.1 Hz, 1 H, 3-H), 3.64 (s, 3 H, OMe), 3.16 (m, 1 H, 1-H),

2.09 (td, J = 11.1 and 3.4 Hz, 1 H, 2-H), 1.94 (m, 1 H), 1.77 (m, 2

H), 1.40 (s, 9 H, Boc), 0.88 (d, J = 6.4 Hz, 3 H, Me) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 175.8 (CO), 155.7 (CO), 79.2 (C),

54.2 (CH), 51.6 (CH₃), 50.4 (CH), 40.03 (CH), 3.7 (CH₂), 29.6

(CH₂), 28.5 (CH₃), 24.5 (CH₂), 16.6 (CH₃) ppm. MS (ESI-TOF⁺):

m/z (%) = 294 (18) [M + Na]⁺, 272 (1) [M + H]⁺, 256 (5), 238 (10),

216 (36) [M + H – tBu]⁺, 156 (100) [M + H – Boc – Me]⁺.

Data for 2d: ¹H NMR (250 MHz, DMSO): δ = 6.72 (d, J = 9.5 Hz,

1 H, NH), 3.64 (m, 1 H, H-3), 2.32 (td, J = 10.7 and 3.4 Hz, 1 H,

H-1), 1.38 (s, 9 H, Boc), 0.76 (d, J = 6.6 Hz, 3 H, Me). ¹³C NMR

(62.9 MHz, DMSO): δ = 176.9 (CO), 155.7 (CO), 77.5 (C), 49.2

(CH), 44.3 (CH), 36.1 (CH), 30.7 (CH₂), 28.5 (CH₂), 28.4 (Boc),

19.2 (CH₂), 15.9 (CH₃). MS (ESI): m/z (%) = 280 (100)

[M + Na]⁺, 258 (3) [M + H]⁺, 222 (64) [M + Na – tBu]⁺, 202 (12)

[M + H – tBu]⁺.

2-Azabicyclo[2.2.1]heptan-3-one: A solution of 2-Azabicyclo[2.2.1]-

hept-5-en-3-one (4; 25.0 g, 0.23 mol) in EtOAc (1 L) was treated

with Pd/C (10%; 7.3 g, 6.88 mmol), and hydrogenated at balloon

pressure for 1–2 d. The insoluble material was removed by filtration

through Celite, which was rinsed with EtOAc, and the filtrate was

concentrated to give 2-azabicyclo[2.2.1]heptan-3-one (25.2 g, 99%)

as a white solid.^[20a]R_f= 0.20 (EtOAc). ¹H NMR (CDCl₃,

250 MHz): δ = 7.08 (br., 1 H), 3.72 (m, 1 H, 3-H), 2.53 (m, 1 H,

1-H) ppm.

(1S,2R,3R)-3-[(tert-Butyloxycarbonyl)amino]-2-methylcyclo-

hexanecarboxylic Acid (2b): The racemic mixture of 2b was resolved

by crystallization from CHCl₃/hexane (2:1) in the presence of

(–)-1-phenylethanamine (1 equiv.). The resulting white crystals were

washed with CHCl₃/hexane (2:1), poured into a separating funnel,

dissolved in CH₂Cl₂, and washed with citric acid (10%). This oper-

ation was repeated 2–3 times. The combined organic extracts were

dried (Na₂SO₄), filtered, and concentrated to give 2b. ¹H NMR

(250 MHz, CDCl₃): δ = 10.6 (br. s, 1 H, COOH), 6.28 (d, J =

7.2 Hz, 1 H, NH), 4.41 (d, J = 9.0 Hz, 1 H, 3-H), 3.19 (m, 1 H, 1-

H), 3.00 (m, 1 H, 2-H), 1.42 (s, 9 H, Boc), 0.98 (d, J = 5.4 Hz, 3

H, Me) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 180.8 (CO), 155.8

(CO), 79.4 (C), 54.1 (CH), 50.6 (CH), 39.8 (CH), 33.7 (CH₂), 29.7

(CH₂), 28.5 (Boc), 24.6 (CH₂), 16.7 (CH₃) ppm. MS (ESI-TOF⁺):

m/z (%) = 280 (100) [M + Na]⁺, 258 (2) [M + H]⁺, 222 (36) [M

+ Na – tBu]⁺, 202 (4) [M + H – tBu]⁺. HRMS (ESI): calcd. for

C₁₃H₂₃NNaO₄280.1519; found 280.1524. [α]²_D⁰= +20.4 (c = 1.0 in

MeOH). CCDC-909272.

cis-3-Aminocyclopentanecarboxylic Acid Hydrochloride (HCl·H-

Acp-OH): A solution of 2-Azabicyclo[2.2.1]heptan-3-one (10.50 g,

94.60 mmol) in HCl (10% aq.; 500 mL) was stirred for 2 d at room

temperature, and then concentrated in vacuo. Addition of acetone

to the yellow oil gave a white solid, which was filtered and washed

with acetone to give cis-3-aminocyclopentanecarboxylic acid hy-

drochloride (14.61 g, 93 %).^[20a]R_f= 0.32 (MeOH)]. ¹H NMR

(D₂O, 250 MHz): δ = 3.70 (m, 1 H, 3-H), 2.95 (quint, J = 8.0 Hz,

1 H, 1-H), 2.35 (m, 1 H, 2-H) ppm.

(1R,3S)-3-[(tert-Butyloxycarbonyl)amino]cyclopentanecarboxylic

Acid (L-Boc-γ-Acp-OH, 6): Boc₂O (28.65 g, 131.42 mmol) and

DIEA (45.9 mL, 262.84 mmol) were added to a solution of cis-3-

aminocyclopentanecarboxylic acid hydrochloride (14.50 g,

87.61 mmol) in a mixture of water and dioxane (1:1; 600 mL). After

stirring at room temp. for 3 h, the solution was acidified to pH =

3 by the addition of aqueous HCl, and then it was extracted with

CH₂Cl₂(3ϫ 150 mL). The combined organic extracts were dried

with Na₂SO₄, filtered, and concentrated. The resulting yellow oil

was crystallized from CHCl₃/hexanes (1:1) to give racemic cis-Boc-

3-aminocyclopentanecarboxylic acid (13.38 g, and 3.91 g in a sec-

ond crystallization). The racemate was resolved by crystallization

from CHCl₃/hexane (1:1) in the presence of with (+)-1-phenyl-

ethanamine (0.7–1 equiv.). The resulting white crystals were washed

with CHCl₃/hexane (2:1), poured into a separating funnel, dis-

Methyl 3-[(tert-Butyloxycarbonyl)amino]-2-methylcyclohexanecarb-

oxylate (3a): A solution of 2a (50 mg, 0.19 mmol) in MeOH (2 mL)

was treated with EDC·HCl (93.5 mg, 0.49 mmol), HOBt (65.8 mg,

0.49 mmol), and DMAP (59.4 mg, 0.49 mmol). The resulting mix-

ture was stirred at room temp. for 4 h and the solution was concen-

trated to remove the MeOH. The resulting oil was dissolved in

EtOAc (25 mL) and washed with HCl (5% aq.; 3ϫ 10 mL) and

NaHCO₃(satd. aq.; 2ϫ 10 mL). The combined organic extracts

were dried with Na₂SO₄, filtered, and concentrated under reduced

pressure. The residue was purified by flash chromatography (25%

EtOAc/hexane) to give 3a (40 mg, 76%) as a white solid. R_f= 0.56

1

(25% EtOAc/hexane). H NMR (300 MHz, CDCl₃): δ = 4.57 (br.,

1 H, NH), 3.71 (m, 1 H, 3-H), 3.65 (s, 3 H, OMe), 2.65 (dt, J = solved in CH₂Cl₂, and washed with citric acid (5% aq.; 3ϫ 50 mL).

8.2 and 4.3 Hz, 1 H, 1-H), 1.96 (m, 1 H, 2-H), 1.42 (s, 9 H, Boc),

This operation was repeated 2–3 times. The combined organic ex-

tracts were dried with anhydrous Na₂SO₄, filtered, and concen-

0.93 (d, J = 7.1 Hz, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 175.3 (CO), 155.5 (CO), 79.2 (C), 51.4 (CH₃), 51.0 (CH), 43.4 trated, and the resulting oil was crystallized from CHCl₃/hexane

(CH), 36.9 (CH), 28.5 (Boc), 28.2 (CH₂), 24.3 (CH₂), 20.6 (CH₂),

14.6 (CH₃) ppm. MS (ESI-TOF⁺): m/z (%) = 294.2 (18) [M +

Na]⁺, 272.2 (1) [M + H]⁺, 256.3 (5), 238.1 (15), 216.1 (23) [M +

H – tBu]⁺, 184.1 (9), 156.1 (100) [M + H – Boc – Me]⁺. HRMS

(ESI): calcd. for C₁₄H₂₅NNaO₄294.1676; found 294.1677.

(1:1) to give 6 (17.2 g, 86%) as white crystals. R_f= 0.82 (MeOH).^[28]

¹H NMR (CDCl₃, 250 MHz): δ = 6.34 and 5.03 (m, 1 H, NH),

4.15–3.73 (m, 1 H, 3-H), 2.81 (m, 1 H, 1-H), 2.18 (m, 1 H, 3-H),

1.39 (s, 9 H, Boc) ppm. ¹³C NMR (CDCl₃, 62.9 MHz): δ = 181.7

(CO₂H), 155.4 (CO), 79.2 (C), 51.9 (CH), 41.7 (CH), 36.0 (CH₂),

3484

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Eur. J. Org. Chem. 2013, 3477–3493

Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

33.0 (CH₂), 28.3 (CH₃), 27.9 (CH₂) ppm. MS (CI⁺): m/z (%) = 230 The resulting mixture was filtered through a Celite pad, which was

(42) [M + H]⁺, 174 (89), 156 (66), 130 (100) [M + H – Boc]⁺, 112

(74), 95 (10), 84 (11). HRMS: calcd. for C₁₁H₂₀NO₄[M + H]⁺

230.1392; found 230.1402. [α]²_D⁰= –16.8 (c = 1.0 in MeOH).

rinsed with EtOH, and the filtrate was concentrated to give l-Boc-

γ-Acp-OH (2.60 g, 99%) as a white solid. R_f= 0.60 (10% MeOH/

CH₂Cl₂).

(1R,3S)-3-[(tert-Butyloxycarbonyl)methylamino]cyclopentane-

(؎)-(1r,4s,7r)-2-(4-Methoxybenzyl)-7-(trimethylsilyloxy)-2-azabicy-

clo[2.2.1]heptan-3-one: Tributyltin hydride (8.1 mL, 0.030 mol) and

AIBN (200 mg, 1.22 mmol) were added to a solution of 8b^[21]

(10.0 g, 25.10 mmol) in dry benzene (300 mL). The mixture was

heated at reflux for 12 h, and then concentrated under reduced

pressure. The residue was purified by flash chromatography (15–

30% EtOAc/hexane) to give the desired product (7.8 g, 97%) as a

colourless oil. R_f= 0.46 (30 % EtOAc/hexane). ¹H NMR

(300 MHz, CDCl₃): δ = 7.15 (d, J = 8.7 Hz, 2 H, Ar), 6.84 (d, J =

8.7 Hz, 2 H, Ar), 4.49 (d, J = 14.7 Hz, 1 H, Bn), 4.06 (d, J =

14.7 Hz, 1 H, Bn), 3.85 (m, 1 H, 7-H), 3.78 (s, 3 H, MeO), 3.33

(m, 1 H, 1-H), 2.60 (m, 1 H, 4-H), 1.99 (m, 1 H, 5-H), 1.78 (ddd,

J = 10.3, 7.2, and 4.2 Hz, 1 H, 6-H), 1.48 (ddd, J = 11.8, 8.0, and

3.6 Hz, 1 H, 5-H), 1.33 (m, 1 H, 6-H), 0.05 (s, 9 H, TMS) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 175.2 (CO), 159.2 (C), 129.5

(CH), 129.3 (C), 114.1 (CH), 75.8 (CH), 61.8 (CH), 55.3 (CH₃),

50.6 (CH), 43.8 (CH₂), 25.1 (CH₂), 22.1 (CH₂), 0.03 (CH₃) ppm.

carboxylic Acid (L

-Boc-^MeN-γ-Acp-OH, 7): A solution of l-Boc-γ-

Acp-OH (750 mg, 3.27 mmol) in dry THF (25 mL) was treated

with NaH (60% in mineral oil; 390 g, 9.82 mmol), and the mixture

was stirred at 0 °C for 30 min. Then, iodomethane (610 μL,

9.82 mmol) was added, and the resulting mixture was stirred over-

night at room temp. After quenching with water (50 mL), the solu-

tion was concentrated to remove the THF. The resulting aqueous

solution was washed with Et₂O (3ϫ 25 mL), then acidified to pH

= 3 by the addition of HCl (10% aq.), and finally extracted with

CH₂Cl₂(3ϫ 25 mL). The combined organic extracts were dried

with anhydrous Na₂SO₄, filtered, and concentrated under reduced

pressure. The crude material was crystallized from Et₂O/hexanes to

give l-Boc-^MeN-γ-Acp-OH (7; 0.78 g, 98%) as colourless crystals.

R_f= 0.43 (5% MeOH/CH₂Cl₂).^{[28] 1}H NMR (CDCl₃, 250 MHz): δ

= 4.53 (m, 1 H, 3-H), 2.82 (m, 1 H, 1-H), 2.76 (s, 3 H, MeN), 1.46

(s, 9 H, Boc) ppm. ¹³C NMR (CDCl₃, 62.9 MHz): δ = 181.2 (CO),

155.8 (CO), 79.6 (C), 55.8 (CH), 41.2 (CH), 31.7 (CH₂), 28.3 (CH₃),

28.2 (CH₃), 27.3 (CH₂), 27.2 (CH₂) ppm. MS (CI⁺): m/z (%) = 244

(3) [M + H]⁺, 188 (36), 170 (30), 144 (100) [M + H – Boc]⁺, 126

(85), 112 (9). HRMS: calcd. for C₁₂H₂₂NO₄[M + H]⁺244.1549;

found 244.1553. [α]²_D⁰= –23.0 (c = 0.80 in MeOH).

FTIR (293 K, CHCl ): ν = 2954, 2910, 2832, 1699, 1613, 1513,

˜

3

1459, 1416, 1361, 1250, 1173, 1125 cm^–1. MS (ESI-TOF⁺): m/z (%)

= 121.1 (100), 140.1 (17), 212.1 (19), 248.1 (10) [M + H – TMS]⁺,

270.1 (18) [M + Na – TMS]⁺, 320 (15) [M + H]⁺, 342 (9)

[M + Na]⁺. HRMS (ESI): calcd. for C₁₇H₂₆NO₃Si 320.1676; found

320.1674.

cis-4-Aminocyclopent-2-enecarboxylic Acid Hydrochloride (HCl·H-

Ace-OH): A solution of 2-azabicyclo[2.2.1]hept-5-en-3-one (25.0 g,

229.08 mmol) in HCl (10% aq.; 1.3 L) was stirred for 24 h at room

temperature, and then the mixture was concentrated in vacuo. Ad-

dition of acetone to the resulting yellow oil gave a white solid, cis-

4-aminocyclopent-2-enecarboxylic acid hydrochloride, which was

filtered off and washed with acetone to give the product (29.08 g,

100 %).^[12a]R_f= 0.46 (50 % MeOH/CH₂Cl₂). ¹H NMR (D₂O,

250 MHz): δ = 6.18 (d, J = 5.6 Hz, 1 H), 6.04–5.79 (m, 1 H), 4.36

(m, 1 H), 3.81–3.60 (m, 1 H), 2.63 (dt, J = 14.6 and 8.5 Hz, 1 H),

2.03 (dt, J = 14.6 and 4.9 Hz, 1 H) ppm.

(؎)-(1r,4s,7r)-7-Hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-

heptan-3-one: TBAF (1 m in THF; 30 mL) was added to a stirred

solution of (1r,4s,7r)-2-(4-methoxybenzyl)-7-(trimethylsilyloxy)-2-

azabicyclo[2.2.1]heptan-3-one (7.8 g, 0.024 mol) in THF (210 mL).

The mixture was stirred for 30 min, and then the solvent was re-

moved under reduced pressure. The resulting residue was diluted

with EtOAc (750 mL), and the solution was washed with HCl (10%

aq.; 300 mL), NaHCO₃(satd. aq.; 2 ϫ 300 mL), and brine

(200 mL). The organic phase was dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (EtOAc) to give the desired prod-

(1S,4R)-4-[(tert-Butyloxycarbonyl)amino]cyclopent-2-enecarboxylic

Acid (L-Boc-γ-Ace-OH, 8): Boc₂O (74.02 g, 339.55 mmol) and

1

uct (5.3 g, 88%) as a colourless oil. R_f= 0.48 (EtOAc). H NMR

(300 MHz, CDCl₃): δ = 7.11 (d, J = 8.6 Hz, 2 H, Ar), 6.82 (d, J =

8.6 Hz, 2 H, Ar-H), 4.48 (d, J = 14.7 Hz, 1 H, Bn), 3.98 (d, J =

14.7 Hz, 1 H, Bn), 3.92 (m, 1 H, 7-H), 3.88 (br. s, 1 H, OH), 3.77

(s, 3 H, MeO), 3.41 (br. s, 1 H, 1-H), 2.60 (m, 1 H, 4-H), 2.05 (m,

1 H, 5-H), 1.85 (ddd, J = 13.6, 5.6, and 2.9 Hz, 1 H, 6-H), 1.41

(m, 2 H, 5-H and 6-H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ =

175.6 (CO), 159.2 (C), 129.5 (CH), 128.9 (C), 114.2 (CH), 75.3

(CH), 61.5 (CH), 55.3 (CH₃), 50.2 (CH), 43.8 (CH₂), 24.9 (CH₂),

DIEA (118.6 mL, 679.29 mmol) were added to a solution of cis-4-

aminocyclopent-2-enecarboxylic acid hydrochloride (37.0 g,

163.45 mmol) in water (750 mL) and dioxane (750 mL). After stir-

ring at room temp. for 3 h, the solution was acidified to pH = 3 by

the addition of HCl (10%), and then it was extracted with CH₂Cl₂.

The combined organic extracts were dried (Na₂SO₄), filtered, and

concentrated. The resulting yellow oil was crystallized from 1:1

CHCl₃/hexanes to give Boc-γ-Ace-OH (41.9 g and 11.3 g in suc-

cessive crystallizations). The racemic product was resolved by

crystallization from CHCl₃/hexane (1:1) in the presence of (+)-1-

phenylethanamine (0.7–1 equiv.). The resulting white crystals were

washed with hexane, poured into a separating funnel, dissolved in

CH₂Cl₂(150 mL), and washed with HCl (5% aq.; 3ϫ 100 mL).

The organic extracts were dried with Na₂SO₄, filtered, and concen-

trated. The resulting oil was crystallized from CHCl₃/hexane (1:1)

to give 8 (99 %) as white crystals].^[12a]R_f= 0.60 (10 % MeOH/

CH₂Cl₂). ¹H NMR (CDCl₃, 250 MHz): δ = 10.8 (s, 1 H), 6.30 and

4.98 (s, 1 H), 5.90 (s, 2 H), 4.80–4.51 (m, 1 H), 3.51 (s, 1 H), 2.54

(m, 1 H), 1.94 (m, 1 H), 1.46 (s, 9 H) ppm.

21.9 (CH ) ppm. FTIR (293 K, CHCl ): ν = 2995, 2951, 2837,

˜

2

3

1674, 1513, 1464, 1247, 1176, 1116, 1034 cm^–1. MS (ESI-TOF⁺):

m/z (%) = 270 (8) [M + Na]⁺, 248 (31) [M + H]⁺, 245 (100), 149

(81) [M + H – PMB]⁺. HRMS (ESI): calcd. for C₁₄H₁₇NO₃Na

270.1101; found 270.1102.

(؎)-(1r,4s,7r)-7-Fluoro-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]-

heptan-3-one (9b): A stirred solution of (Ϯ)-(1r,4s,7r)-7-hydroxy-2-

(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (2.0 g,

8.08 mmol) in anhydrous CH₂Cl₂(60 mL) was cooled to –80 °C,

and DAST (2.1 mL, 0.016 mol) was added. The resulting mixture

was stirred for 2 h at –80 °C, then it was allowed to warm to room

temperature, and stirred at that temperature for 12 h. NaHCO₃

(satd. aq.; 20 mL) was slowly added, and the mixture was extracted

(1R,3S)-3-[(tert-Butoxycarbonyl)amino]cyclopentanecarboxylic Acid

(L-Boc-γ-Acp-OH, 6): A solution of l-Boc-γ-Ace-OH (2.58 mg,

11.36 mmol) in EtOH (40 mL) was treated with Pd/C (10 %; with CH₂Cl₂(3ϫ 20 mL). The combined organic extracts were

121 mg, 1.36 mmol) and hydrogenated at balloon pressure for 12 h. dried with anhydrous Na₂SO₄, filtered, and concentrated under re-

Eur. J. Org. Chem. 2013, 3477–3493

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3485

M. Amorín, J. R. Granja et al.

FULL PAPER

duced pressure. The residue was purified by flash chromatography

(30% EtOAc/hexane) to give 9b (1.2 g, 60%) as a colourless oil. R_f

= 0.47 (50% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ =

7.09 (d, J = 8.6 Hz, 2 H, Ar), 6.78 (d, J = 8.6 Hz, 2 H, Ar), 4.60

(d, J = 57.9 Hz, 1 H, 7-H), 4.45 (dd, J = 14.7 and 2.1 Hz, 1 H),

4.02 (d, J = 14.7 Hz, 1 H, Bn), 3.72 (s, 3 H, MeO), 3.56 (br. s, 1

H, 1-H), 2.80 (m, 1 H, 4-H), 1.98 (m, 1 H, 5-H), 1.76 (dddd, J =

16.7, 10.4, 6.5, and 3.8 Hz, 1 H, 6-H), 1.51 (m, 2 H, 5-H and 6-H)

ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 172.3 (d, J = 11.7 Hz,

CO), 159.1 (C), 129.3 (CH), 128.5 (C), 114.0 (CH), 91.6 (d, J =

208.3 Hz, CH), 59.3 (d, J = 19.7 Hz, CH), 55.1 (CH₃), 48.5 (d, J =

15.9 Hz, CH), 43.5 (CH₂), 24.7 (CH₂), 21.5 (CH₂) ppm. ¹⁹F NMR

(282.3 MHz, CDCl₃): δ = –193.2 (d, J = 57.9 Hz) ppm. FTIR

calcd. for C₁₄H₁₇NNaO₃270.1112; found 270.1110. CCDC-

909274.

(؎)-(1s,4r)-2-Benzyl-2-azabicyclo[2.2.1]hept-5-en-3-one: A solution

of KOH (37 g, 0.66 mol) in dry DMSO (200 mL) was added to a

solution of 4 (18 g, 0.16 mol) in dry DMSO (100 mL), and the re-

sulting mixture was stirred for 30 min at room temp. TBAI (0.76 g,

2.06 mmol) was added, and the solution was stirred for 15 min.

The mixture was cooled to 0 °C, and then benzyl bromide (40 mL,

0.33 mol) was slowly added. The mixture was stirred for 15 min at

0 °C, and then for 5 h at room temp. The resulting mixture was

diluted with CHCl₃(400 mL) and washed with NH₄Cl (satd. aq.;

160 mL). The aqueous solution was extracted with CHCl₃(5ϫ

150 mL), and the combined organic extracts were washed with H₂O

(150 mL) and brine (150 mL). The combined aqueous phases were

extracted with CHCl₃(2ϫ 80 mL). The combined organic extracts

were dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. The residue was purified by flash chromatog-

raphy (60 % EtOAc/hexane) to give the desired product (31.6 g,

96 %). R_f= 0.46 (50 % EtOAc/hexane). ¹H NMR (500 MHz,

CDCl₃): δ = 7.31 (m, 3 H, Ar), 7.20 (m, 2 H, Ar), 6.56 (s, 2 H, 5-

H and 6-H), 4.45 (d, J = 14.8 Hz, 1 H, Bn), 4.02 (br. s, 1 H, 1-H),

3.96 (d, J = 14.8 Hz, 1 H, Bn), 3.39 (br. s, 1 H, 4-H), 2.30 (dt, J =

7.7 and 1.6 Hz, 1 H, 7-H), 2.06 (dt, J = 7.7 and 1.5 Hz, 1 H, 7-H)

ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 180.1 (CO), 139.5 (CH),

137.3 (CH), 136.5 (C), 128.6 (CH), 128.3 (CH), 127.5 (CH), 62.6

(CH), 58.3 (CH₂), 53.8 (CH), 48.0 (CH₂) ppm. MS (ESI-TOF⁺):

m/z (%) = 222 (73) [M + Na]⁺, 200 (86) [M + H]⁺, 123 (100) [M –

Ph]⁺. HRMS (ESI): calcd. for C₁₃H₁₄NO 200.1070; found

200.1073.

(؎)-(1r,2s,4r,5s)-6-Benzyl-3-oxa-6-azatricyclo[3.2.1.0^2,4]octan-7-

one: An excess of m-CPBA (70%; 53 g, 0.31 mol) was added to a

solution of (؎)-(1s,4r)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-one

(30 g, 0.15 mol) in CHCl₃(500 mL), and the resulting solution was

heated at reflux for 6 h. After cooling down to room temp., the

mixture was diluted with chloroform (1 L), and washed with

Na₂SO₃(satd. aq.; 600 mL) and Na₂CO₃(2ϫ 500 mL). The com-

bined aqueous phases were extracted with CHCl₃(2ϫ 500 mL),

and the combined organic extracts were dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure. The

residue was purified by flash chromatography (30% EtOAc/hexane)

to give the desired product (29.4 g, 91%). R_f= 0.42 (50% EtOAc/

hexane). ¹H NMR (500 MHz, CDCl₃): δ = 7.32 (m, 3 H, Ar), 7.25

(m, 2 H, Ar), 4.44 (AB, J = 14.8 Hz, 1 H, Bn), 4.33 (AB, J =

14.8 Hz, 1 H, Bn), 3.77 (br. s, 1 H, 1-H), 3.54 (br. s, 1 H, 6-H),

3.26 (br. s, 1 H, 5-H), 3.00 (m, 1 H, 4-H), 1.80 (d, J = 9.7 Hz, 1 H,

7-H), 1.63 (d, J = 9.4 Hz, 1 H, 7-H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 177.0 (CO), 137.3 (C), 128.8 (CH), 128.3 (CH), 128.0

(CH), 59.6 (CH), 55.3 (CH), 51.7 (CH), 47.2 (CH), 46.0 (CH₂),

30.2 (CH₂) ppm. MS (ESI-TOF⁺): m/z (%) = 216 (100) [M + H]⁺,

238 (40) [M + Na]⁺. HRMS (ESI): calcd. for C₁₃H₁₄NO₂216.1019;

found 216.1019.

(293 K, CHCl ): ν = 2991, 2956, 2838, 1707, 1613, 1513, 1413,

˜

3

1353, 1248, 1176, 1058, 1034 cm^–1. MS (ESI-TOF⁺): m/z (%) = 273

(17) [M + Na]⁺, 250 (33) [M + H]⁺, 245 (100). HRMS (ESI): calcd.

for C₁₄H₁₇FNO₂250.1238; found 250.1238.

(؎)-(1r,4r,7r)-7-Fluoro-2-azabicyclo[2.2.1]heptan-3-one: A solution

of CAN (3.8 g, 6.93 mmol) in water (5 mL) was added to a stirred

solution of 9b (600 mg, 2.41 mmol) in acetonitrile (20 mL). After

stirring for 5 h, the reaction mixture was diluted with EtOAc

(200 mL), and the resulting solution was washed with water (4ϫ

10 mL) and brine (30 mL). The organic phase was dried with anhy-

drous Na₂SO₄, filtered, and concentrated under reduced pressure.

The resulting crude material (650 mg) was used in the following

transformation without further purification. R_f= 0.41 (50 %

EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ = 7.21 (br. s, 1 H,

NH), 4.74 (d, J = 57.6 Hz, 1 H, 7-H), 3.80 (m, 1 H, 1-H), 2.77 (m,

1 H, 4-H), 2.01 (m, 2 H, 5-H and 6-H), 1.63 (m, 2 H, 5-H and 6-

H) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 175.9 (d, J = 11.5 Hz,

CO), 92.6 (d, J = 207.6 Hz, CH), 56.3 (d, J = 20.2 Hz, CH), 48.0

(d, J = 16.0 Hz, CH), 27.0 (CH₂), 20.6 (CH₂) ppm. ¹⁹F NMR

(282.3 MHz, CDCl₃): δ = –191.4 (d, J = 57.6 Hz) ppm. FTIR

(293 K, CHCl ): ν = 3187, 3089, 2924, 2853, 1698, 1462, 1344,

˜

3

1248, 1120, 1054 cm^–1. MS (ESI-TOF⁺): m/z (%) = 152 (7) [M +

Na]⁺, 130 (100) [M + H]⁺. HRMS (ESI): calcd. for C₆H₉FNO:

130.0663; found 130.0665.

(؎)-(1s,2s,3s)-3-[(tert-Butyloxycarbonyl)amino]-2-fluorocyclo-

pentanecarboxylic Acid (Boc-2-F-γ-Acp-OH, 10): A solution of (Ϯ)-

(1r,4r,7r)-7-fluoro-2-azabicyclo[2.2.1]heptan-3-one in acetic acid

(12 mL) and HCl (4 n; 12 mL) was stirred at 70 °C for 5 h. After

this time, the mixture was concentrated under reduced pressure.

The residue was dissolved in a mixture of dioxane and water (1:1;

16 mL), and then treated with DIEA (1.4 mL, 8.02 mmol) and

Boc₂O (880 mg, 4.03 mmol). The mixture was stirred at room tem-

perature for 12 h. The resulting aqueous solution was carefully

acidified with HCl (5% aq.) to pH = 3. The acidified aqueous

solution was extracted with CH₂Cl₂(2ϫ 100 mL), and the com-

bined organic extracts were dried with anhydrous Na₂SO₄, filtered,

and concentrated under reduced pressure. The residue was purified

by flash chromatography (50–100% EtOAc/hexane) to give the de-

sired product (310 mg, 53%) as a white foam. R_f= 0.52 (EtOAc).

(؎)-(1s,4s,6s,7r)-2-Benzyl-6-bromo-7-(trimethylsilyloxy)-2-azabi-

cyclo[2.2.1]heptan-3-one: HBr (48%; 40 mL) was added to a stirred

solution of (1r,2s,4r,5s)-6-benzyl-3-oxa-6-azatricyclo[3.2.1.0^2,4]-

octan-7-one (30.0 g, 0.14 mol) in acetonitrile (1.2 L) at 0 °C. After

stirring for 2 h at this temperature, the resulting reaction mixture

was washed with saturated NaHCO₃(500 mL), and the aqueous

layer was extracted with EtOAc (2ϫ 500 mL). The combined or-

ganic extracts were dried with anhydrous Na₂SO₄, filtered, and

concentrated under reduced pressure to give a mixture (32.2 g,

73%). R_f= 0.39 (5% methanol/CH₂Cl₂).

1

m.p. 109.4–111.9 °C. H NMR (300 MHz, CDCl₃): δ = 6.64 (br. s,

1 H, NH), 5.20 (d, J = 49.6 Hz, 1 H, 2-H), 4.06 (m, 1 H, 3-H),

3.05 (m, 1 H, 1-H), 2.30–2.00 (m, 3 H, 5-H and 6-H), 1.68 (m, 1

H, 6-H), 1.48 (s, 9 H, Boc) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ

= 175.9 (d, J = 58.4 Hz, CO), 157.4 (CO), 99.9 (d, J = 181.8 Hz,

CH), 81.9 (CH₃), 57.8 (d, J = 30.8 Hz, CH), 49.5 (CH), 29.9 (CH₂),

28.4 (CH ), 25.9 (CH ) ppm. FTIR (293 K, CHCl ): ν = 3092,

˜

3

2

3

2977, 2937, 2876, 2684, 2525, 1869, 1699, 1663, 1522, 1409, 1369,

1167, 1062 cm^–1. MS (ESI-TOF⁺): m/z (%) = 148 (100) [M + H –

Boc]⁺, 192 (47) [M + H – tBu]⁺, 270 (82) [M + Na]⁺. HRMS (ESI):

The previously prepared mixture and pyridine (5.3 mL,

65.80 mmol) were dissolved in CH₂Cl₂(100 mL). The solution was

3486

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Eur. J. Org. Chem. 2013, 3477–3493

Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

cooled down to 0 °C, and trimethylsilyl triflate (12 mL,

66.14 mmol) was added. After 10 min, DMAP (800 mg,

6.55 mmol) was added, and the mixture was stirred overnight at

reflux. The resulting solution was allowed to cool, diluted with

CH₂Cl₂(200 mL), and washed with HCl (2% aq.; 50 mL). The

aqueous solution was extracted with CH₂Cl₂(2ϫ 100 mL), and

the combined organic extracts were dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (25% EtOAc/hexane) to provide

(Ϯ)-(1s,4s,6s,7r)-2-benzyl-6-bromo-7-(trimethylsilyloxy)-2-azabi-

cyclo[2.2.1]heptan-3-one [4.2 g, 52%; R_f= 0.54 (25% EtOAc/hex-

ane)] together with the other regioisomer (Ϯ)-(1s,4r,5s,6s)-2-benzyl-

6-bromo-5-(trimethylsilyloxy)-2-azabicyclo[2.2.1]heptan-3-one

[1.0 g, 13%; R_f= 0.26 (25% EtOAc/hexane)]. ¹H NMR (500 MHz,

CDCl₃): δ = 7.29 (m, 3 H, Ar), 7.21 (m, 2 H, Ar), 4.58 (d, J =

14.8 Hz, 1 H, Bn), 4.07 (d, J = 14.8 Hz, 1 H, Bn), 4.06 (s, 1 H, 7-

H), 3.70 (m, 1 H, 6-H), 3.55 (s, 1 H, 1-H), 2.69 (t, J = 1.9 Hz, 1

H, 4-H), 2.44 (dt, J = 13.4 and 4.2 Hz, 1 H, 5-H), 2.36 (dd, J =

13.4 and 8.0 Hz, 1 H, 5-H), 0.10 (s, 9 H, TMS) ppm. ¹³C NMR

(125.7 MHz, CDCl₃): δ = 173.7 (CO), 136.2 (C), 129.0 (CH), 128.0

(CH), 76.2 (CH), 66.2 (CH), 51.3 (CH), 44.4 (CH₂), 41.5 (CH),

34.0 (CH₂), 0.03 (CH₃) ppm. MS (ESI-TOF⁺): m/z (%) = 392 (5)

[M + Na]⁺, 390 (5) [M + Na]⁺, 370 (9) [M + H]⁺, 368 (9)

[M + H]⁺, 320 (34) [M + Na – TMS]⁺328 (35) [M + Na –

TMS]⁺, 298 (89) [M + H – TMS]⁺, 296 (100) [M + H – TMS]⁺.

HRMS (ESI): calcd. for C₁₆H₂₃⁷⁹BrNO₂Si 368.0676; found

368.0676; calcd. for C₁₆H₂₃⁸¹BrNO₂Si 370.0657; found 370.0661.

17.6 Hz, CH), 49.1 (d, J = 17.6 Hz, CH), 44.5 (CH₂), 40.2 (CH),

33.9 (CH₂) ppm. CCDC-909275.

(؎)-(1r,4s,7r)-2-Benzyl-7-fluoro-2-azabicyclo[2.2.1]heptan-3-one

(12b): Tributyltin hydride (1.6 mL, 5.95 mmol) and AIBN (25 mg,

0.15 mmol) were added to a solution of 12a (1.3 g, 4.36 mmol) in

dry benzene (45 mL), and the resulting stirred solution was heated

at reflux overnight. The mixture was concentrated under reduced

pressure, and the residue was purified by flash chromatography

(50% EtOAc/hexane) to give 12b (850 mg, 88%). R_f= 0.57 (50%

EtOAc/hexane). A crystal for X-Ray diffraction was obtained from

a solution of this compound in CH₂Cl₂. ¹H NMR (500 MHz,

CDCl₃): δ = 7.33 (m, 3 H, Ar), 7.22 (m, 2 H, Ar), 4.71 (d, J =

57.7 Hz, 1 H, 7-H), 4.64 (d, J = 14.8 Hz, 1 H, Bn), 4.09 (d, J =

14.8 Hz, 1 H, Bn), 3.64 (m, 1 H, 1-H), 2.92 (m, 1 H, 4-H), 2.06 (m,

1 H, 5-H), 1.86 (m, 1 H, 6-H), 1.66–1.52 (m, 2 H, 5-H and 6-H)

ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 172.7 (d, J = 12.5 Hz,

CO), 136.5 (C), 128.8 (CH), 128.1 (CH), 127.9 (CH), 91.7 (d, J =

208.7 Hz, CH), 59.6 (d, J = 20.1 Hz, CH), 48.6 (d, J = 16.3 Hz,

CH), 44.2 (CH₂), 24.7 (CH₂), 21.6 (CH₂) ppm. MS (ESI-TOF⁺):

m/z (%) = 258 (1) [M + K]⁺, 242 (63) [M + Na]⁺, 220 (100)

[M + H]⁺. HRMS (ESI): calcd. for C₁₃H₁₅FNO 220.1132; found

220.1139. CCDC-909276.

(؎)-(1r,4s,7r)-7-Fluoro-2-azabicyclo[2.2.1]heptan-3-one: Freshly cut

sodium metal (0.32 g, 0.014 mol) was added to a stirred solution

of liquid NH₃(5 mL) and tert-butanol (1.5 mL) at –78 °C to form

a deep blue solution. Then, a solution of 12b (440 mg, 1.99 mmol)

in THF (6 mL) was added portionwise to the stirred solution at

–78 °C. The resulting solution was stirred for 20 min at this tem-

perature, then the mixture was warmed to –30 °C, and stirring was

continued for 4 min. The mixture was then cooled back to –78 °C,

and solid NH₄Cl (1.1 g, 20.56 mmol) was slowly added. NH₄Cl

(satd. aq.; 10 mL) was then added, and the aqueous phase was

extracted with CH₂Cl₂(3ϫ 10 mL). The combined organic extracts

were dried with anhydrous Na₂SO₄, filtered, and concentrated un-

der reduced pressure. The resulting residue was purified by flash

chromatography (75% EtOAc/hexane) to give the desired product

(200 mg, 78%). R_f= 0.41 (EtOAc).

(؎)-(1s,4s,6s,7r)-2-Benzyl-6-bromo-7-hydroxy-2-azabicyclo[2.2.1]-

heptan-3-one (11): TBAF (1 m in THF; 23 mL) was added to a

stirred solution of (؎)-(1s,4s,6s,7r)-2-benzyl-6-bromo-7-(trimethyl-

silyloxy)-2-azabicyclo[2.2.1]heptan-3-one (5.3 g, 0.014 mol) in dry

THF (140 mL). The mixture was stirred for 35 min at room temp.,

and then the solvent was removed under reduced pressure. The re-

sulting residue was purified by flash chromatography (EtOAc) to

give the desired product (3.9 g, 93%) R_f= 0.61 (EtOAc). ¹H NMR

(500 MHz, CDCl₃): δ = 7.35 (m, 3 H, Ar), 7.23 (m, 2 H, Ar), 4.61

(d, J = 14.8 Hz, 1 H, Bn), 4.19 (s, 1 H, 7-H), 4.04 (d, J = 14.8 Hz,

1 H, Bn), 3.78 (t, J = 6.0 Hz, 1 H, 1-H), 3.69 (s, 1 H, 6-H), 2.83

(br. s, 1 H, 4-H), 2.48 (m, 2 H, 5-H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 173.6 (CO), 136.0 (C), 129.0 (CH), 128.1 (CH), 128.2

(CH), 76.7 (CH), 65.6 (CH), 50.7 (CH), 44.5 (CH₂), 42.1 (CH),

34.0 (CH₂) ppm.

(؎)-(1s,2s,3s)-3-tert-Butoxycarbonylamino-2-fluorocyclopentane-

carboxylic Acid (Boc-2-F-γ-Acp-OH, 10): (Ϯ)-(1r,4s,7r)-7-Fluoro-2-

azabicyclo[2.2.1]heptan-3-one (50 mg, 0.39 mmol) was dissolved in

acetic acid (1.5 mL) and HCl (4 n aq.; 1.5 mL). The resulting mix-

ture was stirred at 70 °C for 4.5 h, and then it was concentrated

under reduced pressure. The residue was dissolved in a mixture of

dioxane and water (1:1; 3 mL), and DIEA (270 μL, 1.55 mmol) and

Boc₂O (130 mg, 0.58 mmol) were successively added. The resulting

mixture was stirred at room temperature overnight, and then it was

carefully acidified with HCl (5% aq.) to pH = 3. The acidified

aqueous solution was extracted with CH₂Cl₂(3ϫ 10 mL), and the

combined organic extracts were dried with anhydrous Na₂SO₄, fil-

tered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (0.5% AcOH/EtOAc) to give 10

(93 mg, 97%) as a white foam. R_f= 0.56 (0.5% AcOH/EtOAc).

(؎)-(1s,4s,6s,7r)-2-Benzyl-6-bromo-7-fluoro-2-azabicyclo[2.2.1]-

heptan-3-one (12a): DAST (2.4 mL, 0.018 mol) was added to a

stirred solution of (Ϯ)-(1s,4s,6s,7r)-2-benzyl-6-bromo-7-hydroxy-2-

azabicyclo[2.2.1]heptan-3-one (3.7 g, 0.012 mol) in anhydrous

CH₂Cl₂(100 mL) at –78 °C. The resulting mixture was stirred for

2 h at this temperature, and then it was allowed to warm to room

temperature and stirred overnight. After this time, NaHCO₃(satd.

aq.; 100 mL) was slowly added, and the mixture was extracted with

CH₂Cl₂(3ϫ 50 mL). The combined organic extracts were dried

with anhydrous Na₂SO₄, filtered, and concentrated under reduced

pressure. The resulting residue was purified by flash chromatog-

raphy (50 % EtOAc/hexane) to give the desired product (2.2 g,

62 %). R_f= 0.65 (50 % EtOAc/hexane). This product was crys-

(؎)-(1s,4r)-2-Methyl-2-azabicyclo[2.2.1]hept-5-en-3-one: A solution

of lactam 4 (10 g, 0.092 mol) in dry THF (350 mL) was cooled to

0 °C and then treated with NaH (60% dispersion in mineral oil;

tallized from a solution in EtOAc by vapour-phase equilibration

1

with hexane. H NMR (500 MHz, CDCl₃): δ = 7.37 (m, 3 H, Ar), 20 g, 0.46 mol). The reaction mixture was stirred at 0 °C for 30 min,

7.22 (m, 2 H, Ar), 4.85 (d, J = 55.7 Hz, 1 H, 7-H), 4.60 (d, J =

14.8 Hz, 1 H, Bn), 4.11 (d, J = 14.8 Hz, 1 H, Bn), 3.87 (s, 1 H, 1-

H), 3.80 (m, 1 H, 6-H), 3.01 (s, 1 H, 4-H), 2.54 (m, 1 H, 5-H), 2.44

and then methyl iodide (28.6 mL, 0.46 mol) was slowly added. The

mixture was stirred for 3 d at room temperature under Ar. Then

the mixture was cooled to 0 °C and quenched with water. The THF

(dt, J = 13.8 and 4.1 Hz, 1 H, 5-H) ppm. ¹³C NMR (125.7 MHz, was removed under reduced pressure. The residue was passed

CDCl₃): δ = 171.2 (d, J = 10.1 Hz, CO), 135.7 (C), 129.1 (CH),

128.3 (CH), 128.1 (CH), 91.7 (d, J = 214.9 Hz, CH), 64.6 (d, J =

though a silica gel pad eluting with methanol/chloroform (10%).

The filtrate was dried with anhydrous Na₂SO₄, filtered, and con-

Eur. J. Org. Chem. 2013, 3477–3493

www.eurjoc.org

3487

M. Amorín, J. R. Granja et al.

FULL PAPER

centrated under reduced pressure. The residue was purified by flash

chromatography (75% EtOAc/hexane) to give the desired product

(9.8 g, 87%). R_f= 0.45 (65% EtOAc/hexane). ¹H NMR (250 MHz,

CDCl₃): δ = 6.62 (m, 1 H, 6-H), 6.40 (m, 1 H, 5-H), 3.89 (m, 1 H,

1-H), 3.08 (m, 1 H, 4-H), 2.45 (s, 3 H, MeN), 2.13 (m, 1 H, 7-H),

1.91 (d, J = 7.5 Hz, 1 H, 7-H) ppm. ¹³C NMR (62.5 MHz, CDCl₃):

δ = 181.0 (CO), 138.9 (CH), 137.9 (CH), 65.0 (CH), 58.0 (CH),

53.4 (CH₃), 31.3 (CH₂) ppm. HRMS (CI⁺): calcd. for C₇H₁₀NO

124.0762; found 124.0763.

(br. s, 1 H, OH), 2.76 (s, 3 H, MeN), 2.45 (m, 2 H, 5-H) ppm. ¹³C

NMR (100.6 MHz, CDCl₃): δ = 174.3 (CO), 76.2 (CH), 68.1 (CH),

50.5 (CH), 41.4 (CH), 34.0 (CH₂), 27.7 (CH₃) ppm. MS (ESI-

TOF⁺): m/z (%) = 245 (100), 222 (14) [M + H]⁺, 220 (13) [M + H]⁺.

HRMS (ESI): calcd. for C₇H₁₁⁷⁹BrNO₂219.9968; found 219.9965;

calcd. for C₇H₁₁⁸¹BrNO₂221.9948; found 221.9946.

(؎)-(1s,4s,6s,7r)-6-Bromo-7-fluoro-2-methyl-2-azabicyclo[2.2.1]-

heptan-3-one (13): DAST (1.2 mL, 9.08 mmol) was added to a

stirred solution of (1s,4s,6s,7r)-6-bromo-7-hydroxy-2-methyl-2-aza-

bicyclo[2.2.1]heptan-3-one (1.0 g, 4.55 mmol) in anhydrous CH₂Cl₂

(35 mL) at –80 °C. The resulting mixture was stirred for 2 h at that

temperature, and then it was allowed to warm to room temperature.

After stirring for 14 h, NaHCO₃(satd. aq.; 15 mL) was slowly

added, and the mixture was extracted with CH₂Cl₂(2ϫ 15 mL).

The combined organic extracts were dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (70% EtOAc/hexane) to give the

desired product (440 mg, 40%). R_f= 0.36 (50% EtOAc/hexane).

¹H NMR (500 MHz, CDCl₃): δ = 4.92 (d, J = 55.7 Hz, 1 H, 7-H),

3.96 (m, 1 H, 6-H), 3.90 (s, 1 H, 1-H), 2.94 (br. s, 1 H, 4-H), 2.81

(s, 3 H, MeN), 2.53 (dd, J = 14.5 and 7.8 Hz, 1 H, 5-H), 2.45 (dt,

J = 13.9 and 4.0 Hz, 1 H, 5-H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 171.8 (d, J = 10.1 Hz, CO), 91.4 (d, J = 214.1 Hz,

CH), 66.9 (d, J = 17.1 Hz, CH), 48.8 (d, J = 16.6 Hz, CH), 39.6

(CH), 33.9 (CH₂), 27.6 (CH₃) ppm. ¹⁹F NMR (282.3 MHz,

CDCl₃): δ = –188.1 (d, J = 57.6 Hz) ppm. MS (ESI-TOF⁺): m/z

(%) = 245 (100), 223 (23) [M + H]⁺, 221 (25) [M + H]⁺. HRMS

(ESI): calcd. for C₇H₁₀⁷⁹BrFNO 221.9924; found 221.9923; calcd.

for C₇H₁₀⁸¹BrFNO 223.9904; found 223.9903. CCDC-909277.

(؎)-(1r,2s,4r,5s)-6-Methyl-3-oxa-6-azatricyclo[3.2.1.0^2,4]octan-7-

one: A solution of (1s,4r)-2-methyl-2-azabicyclo[2.2.1]hept-5-en-3-

one (9.8 g, 0.080 mol) in CH₂Cl₂(1 L) was treated with NaHCO₃

(10 g, 0.12 mol). After 15 min, m-CPBA (70%; 42 g, 0.24 mol) was

added, and the mixture was stirred for 12 h. The solvent was re-

moved under reduced pressure, and the residue was purified by

flash chromatography (50 % EtOAc/hexane) to give the desired

product (8.3 g, 75 %). R_f= 0.43 (EtOAc). ¹H NMR (250 MHz,

CDCl₃): δ = 3.58 (m, 1 H, 1-H), 3.51 (m, 1 H, 6-H), 3.32 (m, 1 H,

2-H), 2.72 (m, 1 H, 5-H), 2.60 (s, 3 H, MeN), 1.58 (d, J = 9.4 Hz,

1 H, 8-H), 1.40 (d, J = 9.4 Hz, 8-H) ppm. ¹³C NMR (62.5 MHz,

CDCl₃): δ = 177.7 (CO), 61.4 (CH), 54.9 (CH), 51.7 (CH), 47.0

(CH), 29.7 (CH₃), 28.9 (CH₂) ppm. HRMS (ESI): calcd. for

C₇H₁₀NO₂140.0706; found 140.0702.

(؎)-(1s,4s,6s,7r)-6-Bromo-2-methyl-7-(trimethylsilyloxy)-2-azabicy-

clo[2.2.1]heptan-3-one: HBr (48%; 1.5 mL) was added to a stirred

solution of (1r,2s,4r,5s)-6-methyl-3-oxa-6-azatricyclo[3.2.1.0^2,4]-

octan-7-one (1.0 g, 7.19 mmol) in acetonitrile (50 mL) at 0 °C. Af-

ter stirring for 2 h at this temperature, the reaction mixture was

diluted with EtOAc (150 mL) and washed with NaHCO₃(satd. aq.;

100 mL). The organic phase was dried with anhydrous Na₂SO₄,

filtered, and concentrated under reduced pressure to give a mixture

(1.2 g, 76%). R_f= 0.30 (3% methanol/CH₂Cl₂).

(؎)-(1r,4s,7r)-7-Fluoro-2-methyl-2-azabicyclo[2.2.1]heptan-3-one:

Tributyltin hydride (450 μL, 1.67 mmol) and AIBN (10 mg,

0.061 mmol) were added to a solution of 13 (310 mg, 1.38 mmol)

in dry benzene (10 mL). The resulting solution was heated at reflux

with stirring overnight. The reaction mixture was concentrated un-

der reduced pressure, and the residue was purified by flash

chromatography (50% EtOAc/hexane) to give the desired product

(190 mg, 93 %). R_f= 0.37 (60 % EtOAc/hexane). ¹H NMR

(500 MHz, CDCl₃): δ = 4.75 (d, J = 57.9 Hz, 1 H, 7-H), 3.66 (s, 1

H, 1-H), 2.83 (m, 1 H, 4-H), 2.78 (s, 3 H, MeN), 2.05 (m, 1 H, 5-

H), 1.92 (m, 1 H, 6-H), 1.72 (m, 1 H, 5-H), 1.64 (m, 1 H, 6-H)

ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 173.2 (d, J = 11.3 Hz,

CO), 91.4 (d, J = 207.3 Hz, CH), 62.0 (d, J = 19.9 Hz, CH), 48.4

(d, J = 15.9 Hz, CH), 27.3 (CH₃), 24.2 (CH₂), 21.6 (CH₂) ppm.

MS (ESI-TOF⁺): m/z (%) = 144 (100) [M + H]⁺.

A stirred solution of the previously prepared mixture in CH₂Cl₂

(50 mL) was succesively treated with pyridine (880 μL,

10.92 mmol), trimethylsilyl triflate (2.0 mL, 11.02 mmol), and

DMAP (150 mg, 1.23 mmol). After stirring overnight at reflux, the

resulting solution was cooled, diluted with CH₂Cl₂(100 mL), and

washed with H₂O (2ϫ 50 mL). The organic phase was dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. The residue was purified by flash chromatography (50 %

EtOAc/hexane) to give (Ϯ)-(1s,4s,6s,7r)-6-bromo-2-methyl-7-(tri-

methylsilyloxy)-2-azabicyclo[2.2.1]heptan-3-one [610 mg, 52%; R_f

= 0.63 (50 % EtOAc/hexane)], and the other regioisomer (Ϯ)-

(1s,4r,5s,6s)-6-bromo-2-methyl-5-(trimethylsilyloxy)-2-azabicyclo-

[2.2.1]heptan-3-one [120 mg, 10%; R_f= 0.38 (50% EtOAc/hexane)].

¹H NMR (500 MHz, CDCl₃): δ = 4.13 (s, 1 H, 7-H), 3.86 (m, 1 H,

6-H), 3.59 (s, 1 H, 1-H), 2.77 (s, 3 H, MeN), 2.63 (s, 1 H, 4-H),

2.47 (m, 1 H, 5-H), 2.36 (dd, J = 13.4 and 8.4 Hz, 1 H, 5-H), 0.17

(s, 9 H, TMS) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 174.3

(CO), 75.7 (CH), 68.5 (CH), 51.1 (CH), 40.9 (CH), 34.0 (CH₂),

27.5 (CH₃), –0.16 (CH₃) ppm. MS (ESI-TOF⁺): m/z (%) = 292

(100) [M + H]⁺, 294 (84) [M + H]⁺.

(؎)-(1s,2s,3s)-3-[(tert-Butyloxycarbonyl)methylamino]-2-fluoro-

cyclopentanecarboxylic Acid (Boc-2-F-^MeN-γ-Acp-OH, 14): (Ϯ)-

(1r,4s,7r)-7-Fluoro-2-methyl-2-azabicyclo[2.2.1]heptan-3-one

(80 mg, 0.60 mmol) was dissolved in acetic acid (1.5 mL) and HCl

(4 n aq.; 1.5 mL). The resulting mixture was stirred at 70 °C for

8 h, and then it was concentrated under reduced pressure. The resi-

due was dissolved in a mixture of dioxane and water (1:1; 4 mL)

and treated with DIEA (490 μL, 2.81 mmol) and Boc₂O (170 mg,

(؎)-(1s,4s,6s,7r)-6-Bromo-7-hydroxy-2-methyl-2-azabicyclo[2.2.1]- 0.78 mmol). The resulting mixture was stirred at room temperature

heptan-3-one: TBAF (1 m in THF; 2 mL) was added to a stirred for 12 h, after which it was acidified carefully with HCl (5% aq.)

solution of (1s,4s,6s,7r)-6-bromo-2-methyl-7-(trimethylsilyloxy)-2- to pH = 3. The acidified aqueous solution was extracted with

azabicyclo[2.2.1]heptan-3-one (1.1 g, 3.76 mmol) in dry THF

(30 mL). The mixture was stirred for 10 min, and then the solvent

was concentrated under reduced pressure. The resulting residue was

purified by flash chromatography (50% EtOAc/hexane) to give the

desired product (870 mg, 98%). R_f= 0.40 (70% EtOAc/hexane).

¹H NMR (400 MHz, CDCl₃): δ = 4.22 (m, 1 H, 7-H), 3.91 (m, 1

H, 6-H), 3.71 (s, 1 H, 1-H), 2.84 (d, J = 5.2 Hz, 1 H, 4-H), 2.74

CH₂Cl₂(3ϫ 10 mL), and the combined organic extracts were dried

with anhydrous Na₂SO₄, filtered, and concentrated under reduced

pressure. The residue was purified by flash chromatography (70%

EtOAc/hexane) to give 14 (54 mg, 36%). R_f= 0.38 (EtOAc). ¹H

NMR (300 MHz, CDCl₃): δ = 5.23 (dt, J = 54.0 and 7.2 Hz, 1 H,

2-H), 4.49 (m, 1 H, 3-H), 3.01 (m, 1 H, 1-H), 2.82 (s, 3 H, MeN),

2.22–1.64 (m, 4 H, 4-H and 5-H), 1.44 (s, 9 H, Boc) ppm. ¹³C

3488

www.eurjoc.org

Eur. J. Org. Chem. 2013, 3477–3493

Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

NMR (75.4 MHz, CDCl₃): δ = 176.9 (CO), 155.9 (C=O), 91.6 (d,

J = 186.5 Hz, CH), 80.5 (C), 61.7 (CH), 47.2 (d, J = 21.5 Hz, CH),

15b (34 mg, 0.16 mmol) in dry CH₂Cl₂(1.5 mL) was treated with

Boc₂O (130 mg, 0.58 mmol) and DMAP (7.7 mg, 0.63 mmol), and

30.5 (CH₃), 28.5 (CH₃), 24.2 (CH₂), 24.1 (CH₂) ppm. ¹⁹F NMR the mixture was stirred at room temperature for 20 h. The resulting

(282.3 MHz, CDCl₃): δ = –186.3 (d, J = 52.3 Hz) ppm. FTIR

solution was diluted with CH₂Cl₂(5 mL), and washed with HCl

(5% aq.; 5 mL). The aqueous phase was extracted with CH₂Cl₂

(2ϫ 5 mL), and the combined organic extracts were dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. The residue was purified by flash chromatography (75 %

EtOAc/hexane) to give 15c (50 mg, 91%) as a white foam. R_f=

(293 K, CHCl ): ν = 3480, 2976, 2932, 2884, 1693, 1671, 1482,

˜

3

1368, 1251, 1160, 1011 cm^–1. MS (ESI-TOF⁺): m/z (%) = 284 (35)

[M + Na]⁺, 245 (100) [M + H – OH]⁺, 162 (13) [M + H – Boc]⁺.

HRMS (ESI): calcd. for C₁₂H₂₀FNO₄Na 284.1269; found

284.1263.

1

0.50 (75% EtOAc/hexane). H NMR (500 MHz, CDCl₃): δ = 4.78

(؎)-(1s,4s,6s,7r)-2-Benzyl-6-bromo-7-[(2-methoxyethoxy)methoxy]-

2-azabicyclo[2.2.1]heptan-3-one: A solution of 11 (500 mg,

1.69 mmol) in dry CH₂Cl₂(17 mL) was succesively treated with

DIEA (3.0 mL, 0.017 mol) and methoxyethoxymethyl chloride

(1.0 mL, 8.76 mmol). The resulting mixture was stirred overnight

at room temp. Then CH₂Cl₂(50 mL) was added, and the solution

was washed with NH₄Cl (satd. aq.; 50 mL). The aqueous phase

was extracted with CH₂Cl₂(3ϫ 25 mL), and the combined organic

extracts were dried with anhydrous MgSO₄, filtered, and concen-

trated under reduced pressure. The residue was purified by flash

chromatography (50% EtOAc/hexane) to give the desired product

(s, 2 H, MEM), 4.42 (m, 1 H, 1-H), 4.01 (m, 1 H, 7-H), 3.70 (m, 2

H, MEM), 3.59 (m, 2 H, MEM), 3.41 (s, 3 H, MEM), 2.81 (m, 1

H, 4-H), 2.05 (m, 2 H, 5-H and 6-H), 1.75 (m, 2 H, 5-H and 6-H),

1.48 (s, 9 H, Boc) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 172.5

(CO), 148.9 (CO), 94.6 (CH₂), 83.1 (CH₃), 78.4 (CH), 71.6 (CH₂),

67.6 (CH₂), 60.0 (CH₃), 59.1 (CH), 50.0 (CH), 28.0 (CH₃), 25.9

(CH₂), 21.5 (CH₂) ppm. MS (ESI-TOF⁺): m/z (%) = 338 (21) [M

+ Na]⁺, 316 (1) [M + H]⁺, 238 (100) [M + Na – Boc]⁺, 216 (2) [M

+ H – Boc]⁺. HRMS (ESI): calcd. for C₁₅H₂₅NO₆Na 338.1574;

found 338.1579.

1

(620 mg, 80%). R_f= 0.50 (EtOAc). H NMR (500 MHz, CDCl₃):

(؎)-(1r,2s,3r)-3-[(tert-Butyloxycarbonyl)amino]-2-[(2-methoxyeth-

oxy)methoxy]cyclopentanecarboxylic Acid (16): A solution of 15c

(25 mg, 0.79 mmol) and K₂CO₃(43 mg, 0.32 mmol) in a mixture

of methanol and water (3:1; 1 mL) was stirred at room temperature

for 18 h. The resulting aqueous solution was carefully acidified

with HCl (5% aq.) to pH = 4, and then the acidified aqueous solu-

tion was extracted with CH₂Cl₂(3ϫ 5 mL). The combined organic

extracts were dried with anhydrous Na₂SO₄, filtered, and concen-

trated under reduced pressure. The resulting solid residue was puri-

fied by flash chromatography (EtOAc) to give 16 (20 mg, 78%). R_f

= 0.25 (EtOAc). ¹H NMR (300 MHz, CDCl₃): δ = 5.12 (br. s, 1 H,

NH), 4.78 (s, 2 H, MEM), 4.12 (br. s, 1 H, 3-H), 3.87 (br. s, 1 H,

2-H), 3.71 (m, 2 H, MEM), 3.58 (m, 2 H, MEM), 3.39 (s, 3 H,

MEM), 2.86 (m, 1 H, 1-H), 2.23–1.52 (m, 3 H, 5-H and 6-H), 1.61

(m, 1 H, 6-H), 1.44 (s, 9 H, Boc) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 179.2 (CO), 155.9 (CO), 95.1 (CH₂), 79.6 (C), 85.0

(CH), 71.7 (CH₂), 67.1 (CH₂), 59.1 (CH₃), 57.4 (CH), 48.9 (CH),

δ = 7.37 (m, 3 H, Ar), 7.21 (m, 2 H, Ar), 4.82 (s, 2 H, MEM), 4.75

(d, J = 7.0 Hz, MEM), 4.69 (d, J = 7.0 Hz, MEM), 4.56 (d, J =

14.9 Hz, 1 H, Bn), 4.14 (q, J = 1.5 Hz, 1 H, 6-H), 4.10 (d, J =

14.9 Hz, 1 H, Bn), 3.78 (m, 1 H, 7-H), 3.72 (m, 3 H, 1-H and

MEM), 3.56 (m, 2 H, MEM), 3.36 (s, 3 H, MEM), 2.86 (m, 1 H,

4-H), 2.43 (m, 2 H, 5-H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

= 173.3 (CO), 136.0 (C), 129.0 (CH), 128.1 (CH), 94.0 (CH₂), 79.4

(CH), 71.7 (CH₂), 67.6 (CH₂), 64.5 (CH), 59.0 (CH₃), 49.5 (CH),

44.5 (CH₂), 41.5 (CH), 34.3 (CH₂) ppm.

(؎)-(1r,4s,7r)-7-[(2-Methoxyethoxy)methoxy]-2-azabicyclo[2.2.1]-

heptan-3-one (15b): Tributyltin hydride (840 μL, 3.12 mmol) and

AIBN (13 mg, 0.079 mmol) were successively added to a solution

of (Ϯ)-(1s,4s,6s,7r)-2-benzyl-6-bromo-7–2-methoxyethoxymethoxy-

2-azabicyclo[2.2.1]heptan-3-one (870 mg, 2.26 mmol) in dry benz-

ene (24 mL). The resulting solution was heated at reflux and stirred

overnight under argon. The mixture was then allowed to cool, and

concentrated under reduced pressure, and the residue was purified

by flash chromatography (50% EtOAc/hexane) to give 15a (590 mg,

85%), which was used immediately in the next step.

30.0 (CH ), 28.5 (CH ), 25.7 (CH ) ppm. FTIR (293 K, CHCl ): ν

˜

2

3

2

3

= 3521, 3354, 2975, 2928, 2890, 1696, 1482, 1523, 1367, 1168,

1041 cm^–1. MS (ESI-TOF⁺): m/z (%) = 356 (81) [M + Na]⁺, 334

(2) [M + H]⁺, 300 (79) [M + K – tBu]⁺, 256 (6) [M + Na – Boc]⁺,

234 (7) [M + H – Boc]⁺, 202 (56), 172 (100), 154 (54), 128 (66),

110 (40). HRMS (ESI): calcd. for C₁₅H₂₇NO₇Na 356.1680; found

356.1683.

Freshly cut sodium metal (350 mg, 0.015 mol) was added to a

stirred solution of liquid NH₃(25 mL) at –78 °C to form a deep

blue solution. Then a solution of previously prepared lactam 15a

(590 mg, 1.93 mmol) in THF (30 mL) was added portionwise to

the stirred reaction mixture at –78 °C. The resulting solution was

stirred for 30 min at –78 °C, then solid NH₄Cl (1.9 g, 35.51 mmol)

was slowly added. NH₄Cl (satd. aq.; 60 mL) was then added, and

the aqueous phase was extracted with CH₂Cl₂(3ϫ 60 mL). The

combined organic extracts were dried with anhydrous Na₂SO₄, fil-

tered, and concentrated under reduced pressure. The residue was

purified by flash chromatography (75% EtOAc/hexane) to give 15b

1,2-O-Isopropylidene-α-D-xylofuranose: Powdered d-xylose (32.5 g,

0.22 mol) was dissolved in a solution of H₂SO₄(0.66 m) in acetone

(780 mL), and the mixture was stirred at room temp. until the solid

was fully dissolved (at least 30 min). A solution of sodium carbon-

ate (39.0 g, 0.37 mol) in water (340 mL) was added, and the mixture

was stirred for a further 2.5 h. Sodium carbonate was added until

the mixture was neutralized (pH = 6–7). The mixture was filtered,

and the salts were rinsed with acetone. The solvent was removed

completely from the filtrate under reduced pressure, and the re-

sulting residue was purified by flash chromatography over silica

(10% MeOH/CH₂Cl₂) to give the desired product (39.3 g, 95%) as

1

(320 mg, 74%). H NMR (500 MHz, CDCl₃): δ = 6.02 (br. s, 1 H,

NH), 4.78 (s, 2 H, MEM), 3.99 (m, 1 H, 1-H), 3.80 (m, 1 H, 7-H),

3.70 (m, 2 H, MEM), 3.60 (m, 2 H, MEM), 3.42 (s, 3 H, MEM),

2.72 (m, 1 H, 4-H), 2.03 (m, 2 H, 5-H and 6-H), 1.60 (m, 2 H, 5-

H and 6-H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 177.2 (CO),

94.7 (CH₂), 81.3 (CH), 71.6 (CH₂), 67.5 (CH₂), 59.1 (CH₃), 56.8

(CH), 48.0 (CH), 27.6 (CH₂), 21.2 (CH₂) ppm. MS (ESI-TOF⁺):

m/z (%) = 238 (100) [M + Na]⁺, 216 (7) [M + H]⁺. HRMS (ESI):

calcd. for C₁₀H₁₇NO₄Na 238.1050; found 238.1046.

1

a pale yellow syrup.^[29]R_f= 0.5 (10% MeOH/CH₂Cl₂). H NMR

(250 MHz, CDCl₃): δ = 5.93 (d, J = 3.7 Hz, 1 H, 1-H), 4.47 (d, J

= 3.7 Hz, 1 H, 2-H), 4.45 (s, 1 H, -OH), 4.25 (m, 1 H, 3-H), 4.12

(m, 1 H, 4-H), 3.96 (m, 2 H, 5-H), 3.74 (s, 3 H, -OH), 1.44 (s, 3 H,

Me), 1.28 (s, 3 H, Me) ppm.

(؎)-(1r,4s,7r)-2-[(tert-Butyloxycarbonyl)amino]-7-[(2-methoxyeth-

oxy)methoxy]-2-azabicyclo[2.2.1]heptan-3-one (15c): A solution of

1,2-O-Isopropylidene-3,5-di-O-methanesulfonyl-α-

1,2-O-Isopropylidene-α-d-xylofuranose (33.2 g, 0.17 mol) was dis-

D-xylofuranose:

Eur. J. Org. Chem. 2013, 3477–3493

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3489

M. Amorín, J. R. Granja et al.

FULL PAPER

solved in dry CH₂Cl₂(1.25 L), and triethylamine (61.0 mL,

0.44 mol) was added. The reaction mixture was cooled to 0 °C.

Methanesulfonyl chloride (34.0 mL, 0.44 mol) was added slowly,

and the reaction mixture was warmed to room temp. and stirred at

that temperature for 1 h. The solution was washed with NaHCO₃

(satd. aq.; 3ϫ 250 mL) and brine (500 mL), and the combined or-

ganic extracts were dried with anhydrous Na₂SO₄and filtered. The

filtrate was evaporated under reduced pressure to give the product

(58 g, 96%) as an orange solid that was used without further purifi-

cation.^[29]R_f= 0.85 (4% MeOH/CH₂Cl₂). ¹H NMR (250 MHz,

CDCl₃): δ = 5.98 (d, J = 3.6 Hz, 1 H, 1-H), 5.09 (d, J = 2.8 Hz, 1

(9.45 g, 87%) as a yellow liquid. R_f= 0.55 (25% EtOAc in hexane).

¹H NMR (250 MHz, CDCl₃): δ = 7.35 (m, 5 H, Ar), 4.54 (AB, J

= 11.8 Hz, 1 H, Bn), 4.48 (AB, J = 11.8 Hz, 1 H, Bn), 4.35 [d, J =

6.2 Hz, 1 H, CH(OMe)₂], 3.35 (s, 3 H, MeO), 3.95–3.84 (m, 5 H,

2-H, 3-H, 4-H, and 5-H), 3.34 (s, 3 H, MeO) ppm. ¹³C NMR

(62.9 MHz, CDCl₃): δ = 137.2 (C), 128.4 (CH), 127.9 (CH), 127.8

(CH), 103.6 (CH), 84.4 (CHO), 84.0 (CH), 72.0 (CH₂), 70.8 (CH₂),

65.6 (CH), 55.4 (CH₃), 54.0 (CH₃) ppm. MS (CI⁺): m/z (%) = 234

(27) [M + H – (OMe) – N₂]⁺, 204 (27) [M + H – (OMe)₂– N₂]⁺,

128 (39), 107 (89). HRMS (CI⁺): calcd. for C₁₂H₁₆N₃O₂234.12425;

found 234.12471. FTIR (293 K, CHCl ): ν = 2935 (CH ), 2831

˜

3

2

H, 3-H), 4.82 (d, J = 3.6 Hz, 1 H, 2-H), 4.58 (dt, J = 6.1, and (CH), 2104 (N=N), 1454, 1363, 1257, 1192, 1138, 1099, 943 cm^–1.

2.8 Hz, 1 H, 4-H), 4.41 (d, J = 6.1 Hz, 2 H, 5-H), 3.12 (s, 3 H,

SO₂Me), 3.08 (s, 3 H, SO₂Me), 1.51 (s, 3 H, Me), 1.32 (s, 3 H, Me)

ppm.

[α]²_D⁰= +14.3 (c = 0.84 in MeOH).

(2R,3R,4S)-4-Azido-3-(benzyloxy)tetrahydrofuran-2-carbaldehyde:

Compound 18b (950 mg, 4.06 mol) was stirred in a mixture of TFA

(1R,2R,5R)-2-(Dimethoxymethyl)-3,6-dioxabicyclo[3.1.0]hexane and water (4:1; 100 mL) for 2 h at room temp. The mixture was

(17): 1,2-O-Isopropylidene-3,5-di-O-methanesulfonyl-α-d-xylofur-

anose (70.0 g, 0.20 mol) was dissolved in dry methanol (1.25 L),

and TFA (12.5 L) was added. The reaction mixture was heated un-

der reflux for 40 h. Then it was cooled to room temp., K₂CO₃

(84.0 g, 0.60 mol) was added, and the mixture was stirred over-

diluted with water (50 mL), and the aqueous phase was extracted

with CH₂Cl₂(3ϫ 50 mL). The combined organic extracts were

washed with NaHCO₃(satd. aq.; 3ϫ 25 mL), dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure to give

the product (750 mg, 95%) as an orange oil that was used without

night. Water was added to dissolve the K₂CO₃fully, and the prod- further purification. R_f= 0.33 (30 % EtOAc/hexane). ¹H NMR

uct was extracted with CH₂Cl₂(500 mL). The organic phase was

washed with water (3 ϫ 50 mL). The combined aqueous phases

were extracted with CH₂Cl₂(3ϫ 50 mL). The organic extracts were

dried with anhydrous Na₂SO₄, filtered, and concentrated under re-

duced pressure. The resulting crude product was purified by flash

chromatography (50% EtOAc in hexane) to give 17 (29.7 g, 93%)

(250 MHz, CDCl₃): δ = 9.54 (br. s, 1 H, CHO), 7.29 (m, 5 H, Ar),

4.58 (AB, J = 11.5 Hz, 1 H, Bn), 4.49 (AB, J = 11.5 Hz, 1 H, Bn),

4.26 (br. s, 1 H, 2-H), 4.13–3.76 (s, 4 H, 3-H, 4-H, and 5-H) ppm.

¹³C NMR (62.9 MHz, CDCl₃): δ = 201.4 (CO), 136.7 (CH), 128.8

(CH), 128.4 (CH), 128.0 (CH), 87.6 (CH), 85.3 (CH), 72.3 (CH₂),

71.7 (CH), 64.5 (CH) ppm. FTIR (293 K, CHCl ): ν = 3421, 3060,

˜

3

as an orange liquid.^[29]R_f= 0.4 (50% EtOAc in hexane). ¹H NMR 3031, 2929, 2873, 2106, 1718, 1496, 1454, 1259, 1079 cm^–1. MS

(250 MHz, CDCl₃): δ = 4.23 [d, J = 4.5 Hz, 1 H, CH(OMe)₂], 4.01

(d, J = 4.5 Hz, 1 H, 2-H), 3.92 (d, J = 10.1 Hz, 1 H, 4-H), 3.78 (d,

(CI⁺): m/z (%) = 248 (7) [M + H]⁺, 220 (46) [M + H – CHO]⁺, 133

(22), 107 (100). HRMS (CI⁺): calcd. for C₁₂H₁₄N₃O₃248.10352;

J = 10.1 Hz, 1 H, 4-H), 3.76 (d, J = 3.0 Hz, 1 H, 5-H), 3.72 (d, J found 248.10408. [α]²_D⁰= +9.8 (c = 0.67 in MeOH).

= 3.0 Hz, 1 H, 1-H), 3.40 (s, 3 H, MeO), 3.38 (s, 3 H, MeO) ppm.

Methyl (2R,3R,4S)-4-Azido-3-(benzyloxy)tetrahydrofuran-2-carb-

(2R,3R,4S)-4-Azido-2-dimethoxymethyl-3-hydroxytetrahydrofuran

(18a): Compound 17 (29.7 g, 0.18 mol) was dissolved in a mixture

of ethanol and water (4:1; 1 L). Sodium azide (24.0 mL, 0.37 mol)

and ammonium chloride (24.6 g, 0.46 mol) were added, and the

reaction mixture was heated under reflux for 24 h. The mixture was

allowed to cool down to room temp., and the solvent was removed

under reduced pressure. The residue was washed with CH₂Cl₂(5ϫ

30 mL), and the combined organic extracts were dried (Na₂SO₄)

and concentrated on a rotary evaporator. The crude product was

purified by flash chromatography (40% EtOAc in hexane) to give

18a (31.3 g, 83%) as a yellow-orange liquid.^[29]R_f= 0.33 (40%

oxylate (19a): (2R,3R,4S)-4-Azido-3-(benzyloxy)tetrahydrofuran-2-

carbaldehyde (1.7 g, 6.85 mmol) was dissolved in acetonitrile

(20 mL) and methanol (8 mL). NBS (6.3 g, 35.40 mmol) and potas-

sium carbonate (4.9 g, 35.45 mmol) were added, and the mixture

was stirred in the dark for 24 h at room temp. Water was added,

and the remaining NBS was quenched with portions of Na₂S₂O₅.

The yellow solution was extracted with a mixture of EtOAc and

hexane (1:1; 3ϫ 30 mL). The combined organic extracts were dried

with anhydrous Na₂SO₄, filtered, and concentrated under reduced

pressure. The crude product was purified by flash chromatography

(25% EtOAc in hexane) to give pure 19a (1.77 g, 90%) as a yellow

liquid. R_f= 0.50 (25% EtOAc in hexane). ¹H NMR (250 MHz,

CDCl₃): δ = 7.25 (m, 5 H, Ar), 4.60 (AB, J = 11.8 Hz, 1 H, Bn),

4.52 (AB, J = 11.8 Hz, 1 H, Bn), 4.43 (d, J = 2.4 Hz, 1 H, 2-H),

4.12 (t, J = 1.9 Hz, 1 H, 2-H), 4.06 (dd, J = 10.5 and 5.8 Hz, 1 H,

5-H), 3.99–3.92 (m, 2 H, 4-H and 5-H), 3.69 (s, 3 H, MeO) ppm.

¹³C NMR (62.9 MHz, CDCl₃): δ = 170.5 (CO), 136.8 (CH), 128.7

(CH), 128.3 (CH), 128.0 (CH), 86.4 (CH), 81.9 (CH), 72.3 (CH₂),

1

EtOAc in hexane). H NMR (250 MHz, CDCl₃): δ = 4.33 [d, J =

6.3 Hz, 1 H, CH(OMe)₂], 4.17 (m, 1 H, 3-H), 3.99 (dd, J = 9.4 and

5.4 Hz, 1 H, 5-H), 3.94 (m, 1 H, 4-H), 3.84 (dd, J = 9.4 and 3.5 Hz,

1 H, 5-H), 3.73 (dd, J = 6.3 and 4.8 Hz, 1 H, 2-H), 3.43 (s, 3 H,

MeO), 3.40 (s, 3 H, MeO), 3.24 (br., 1 H, OH) ppm.

(2R,3R,4S)-4-Azido-3-benzyloxy-2-(dimethoxymethyl)tetrahydro-

furan (18b): A solution of 18a (7.5 g, 36.91 mmol) in dry THF

(400 mL) under argon was treated with NaH (60% dispersion in

mineral oil; 1.26 g, 52.50 mmol), and the reaction mixture was

stirred for 30 min at room temp. Tetrabutylammonium iodide

(6.8 g, 18.41 mmol) and benzyl bromide (6.6 g, 38.59 mmol) were

added, and the mixture was stirred for 3 h. The reaction was

quenched with water, and the THF was removed under reduced

pressure. The residue was extracted with CH₂Cl₂(3ϫ 30 mL), and

the combined organic extracts were washed with NaHCO₃(satd.

aq.; 3ϫ 20 mL), dried with anhydrous Na₂SO₄, and filtered. After

concentration under reduced pressure, the crude product was puri-

fied by flash chromatography (25% EtOAc in hexane) to give 18b

71.4 (CH), 64.9 (CH), 52.6 (MeO) ppm. FTIR (293 K, CHCl ): ν

˜

3

= 3028, 2954, 2877, 2108, 1757, 1496, 1456, 1437, 1255, 1213, 1105,

1028 cm^–1. MS (FAB⁺): m/z (%) = 300 (25) [M + Na]⁺, 278 (31)

[M + H]⁺, 154 (97), 137. HRMS (FAB⁺): calcd. for C₁₃H₁₆N₃O₄

278.11408; found 278.11329. [α]²_D⁰= –16.6 (c = 1.6 in MeOH).

(2R,3R,4S)-4-Azido-3-(benzyloxy)tetrahydrofuran-2-carboxylic Acid

(19b): Compound 19a (6.5 g, 23.37 mmol) was dissolved in TFA

(72 mL) and water (18 mL), and the mixture was stirred for 2 h at

room temp. The resulting brown solution was diluted with water

(200 mL), and THF was added until a one-phase system was

formed (approx. 600 mL). Acetone (5 mL) and CrO₃(6.66 g,

3490

www.eurjoc.org

Eur. J. Org. Chem. 2013, 3477–3493

Cyclic γ-Amino Acids for Foldamers and Peptide Nanotubes

66.60 mmol) were added, and the solution was stirred overnight at

room temp., which resulted in an intensely blue-coloured solution.

The THF was removed on a rotary evaporator, and the residue was

extracted with CH₂Cl₂(5ϫ 150 mL). The solution was concen-

trated, and the organic solution was washed with NaOH (1 m aq.;

3ϫ 50 mL). The aqueous phases were combined and acidified to

pH = 2 with HCl (10% aq.) and washed with CH₂Cl₂(3ϫ 50 mL).

The organic extracts were combined, dried with anhydrous

Na₂SO₄, and filtered. The solvent was removed under reduced pres-

sure to give 19b (3.89 g, 67%) as a brown syrup. R_f= 0.15 (5%

MeOH/CH₂Cl₂). ¹H NMR (250 MHz, CDCl₃): δ = 8.70 (br. s, 1

H, COOH), 7.26 (m, 5 H, Ar), 4.65 (AB, J = 11.7 Hz, 1 H, Bn),

4.54 (AB, J = 11.7 Hz, 1 H, Bn), 4.47 (br. s, 1 H, 2-H), 4.20 (br. s,

1 H, 3-H), 4.08 (m, 1 H, 5-H), 4.02 (m, 2 H, 4-H and 5-H) ppm.

¹³C NMR (62.9 MHz, CDCl₃): δ = 173.8 (CO), 136.6 (CH), 128.7

(CH), 128.4 (CH), 128.1 (CH), 86.2 (CH), 82.3 (CH), 72.4 (CH₂),

C₁₈H₂₅NO₆Na 374.1586; found 374.1574. [α]²_D⁰= –78.3 (c = 0.80 in

MeOH).

(2R,3R,4S)-3-(Benzyloxy)-4-(tert-butyloxycarbonylamino)tetra-

hydrofuran-2-carboxylic Acid [Boc-γ-Ahf(Bn)-OH, 20b]: A solution

of (2R,3R,4S)-methyl 3-(benzyloxy)-4-(tert-butoxycarbonylamino)-

tetrahydrofuran-2-carboxylate (100.0 mg, 0.91 mmol) in a mixture

of MeOH and water (3:1; 5 mL) was treated with LiOH·H₂O

(33.5 mg, 1.40 mmol), and the resulting mixture was stirred at room

temp. for 4 h. After removal of the solvent, the residue was diluted

with water (25 mL), and washed with CH₂Cl₂(3ϫ 10 mL), and the

resulting aqueous solution was acidified to pH = 3 with HCl (10%

aq.). The acidic solution was extracted with CH₂Cl₂(3ϫ 10 mL),

and the combined organic extracts were dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure to give

20b (90 mg, 94%) as a colourless oil. R_f= 0.6 (4% CH₂Cl₂/MeOH).

¹H NMR (300 MHz, C₂D₂Cl₄, 353 K):^[30]δ = 8.00 (br. s, 1 H,

COOH), 7.31 (m, 5 H, Ar), 4.70 (s, 2 H, Bn), 4.52 (s, 1 H, 2-H),

4.23 (m, 3 H, 3-H, 5-H), 4.02 (d, J = 9.0 Hz, 1 H, 4-H), 1.47 (s, 9

H, Boc) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 173.8 (CO), 157.2

(CO), 137.2 (C), 128.6 (CH), 128.0 (CH), 127.8 (CH), 87.9 (CH),

82.5 (C), 81.0 (CH), 72.4 (CH₂), 71.6 (CH₂), 56.8 (CH), 28.4 (CH₃)

71.9 (CH ), 64.7 (CH) ppm. FTIR (293 K, CHCl ): ν = 3400, 3029,

˜

2

3

2943, 2108, 1749, 1456, 1255, 1205, 1101, 1028, 931 cm^–1. MS (ESI-

TOF⁺): m/z (%) = 286 [M + Na]⁺264 [M + H]⁺. HRMS (ESI):

calcd. for C₁₃H₁₃N₃O₄Na 286.0798; found 286.0796. [α]²_D⁰= –0.81

(c = 0.80 in MeOH).

ppm. FTIR (293 K, CHCl ): ν = 3331, 2977, 2931, 2875, 1714,

˜

3

(2R,3R,4S)-Methyl 4-Amino-3-(benzyloxy)tetrahydrofuran-2-carb-

oxylate [H-γ-Ahf(Bn)-OMe, 20a]: A solution of methyl ester 19a

(5.08 g, 18.33 mmol) in dry THF (50 mL) was treated with tri-

phenylphosphane (6.70 g, 25.67 mmol), and the resulting mixture

was stirred for 3 h. After the addition of water (5.6 mL), the mix-

ture was heated at reflux for 1 h. The solvent was removed under

reduced pressure, and the residue was purified by flash chromatog-

raphy (4% MeOH/CH₂Cl₂) to give amine 20a (1.88 g, 41%). R_f=

1518, 1455, 1368, 1250, 1166, 1096 cm^–1. MS (FAB⁺): m/z (%) =

337 [M + H]⁺. HRMS (ESI): calcd. for C₁₇H₂₃NO₆Na 360.1424;

found 360.1418. [α]²_D⁰= –46.5 (c = 0.80 in MeOH).

Methyl (2R,3R,4S)-3-(Benzyloxy)-4-(2-nitrophenylsulfonamido)-

tetrahydrofuran-2-carboxylate (22): A solution of 19a (1.0 g,

3.59 mmol) in CH₂Cl₂(50 mL) containing Pd/C (96.0 mg,

0.90 mmol) was stirred at room temp. for 2 h under a hydrogen

atmosphere. The mixture was filtered through a Celite pad, the

residue was washed with CH₂Cl₂, and the washings were concen-

trated under reduced pressure. The resulting material was dissolved

in CH₂Cl₂(20 mL) and treated with DIEA (4.1 mL, 23.48 mmol)

and 2-nitrobenzene-1-sulfonyl chloride (1.3 g, 5.87 mmol). The

mixture was stirred at room temp. for 5 h under argon, after which

it was washed with HCl (5% aq.; 2ϫ 20 mL) and with NaHCO₃

(satd. aq.; 2ϫ 20 mL). The organic phase was dried with anhydrous

Na₂SO₄, filtered, and concentrated under reduced pressure. The

crude product was purified by flash chromatography (CH₂Cl₂) to

1

0.29 (4% MeOH/CH₂Cl₂). H NMR (500 MHz, CDCl₃): δ = 7.30

(m, 5 H, Ar), 4.67 (AB, J = 11.9 Hz, 1 H, Bn), 4.57 (AB, J =

11.9 Hz, 1 H, Bn), 4.47 (d, J = 2.0 Hz, 1 H, 2-H), 4.12 (dd, J = 9.0

and 4.7 Hz, 1 H, 5-H), 3.96 (br. s, 1 H, 3-H), 3.84 (dd, J = 9.0 and

2.5 Hz, 1 H, 5-H), 3.76 (s, 3 H), 3.49 (br. s, 1 H, 4-H) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 172.0 (CO), 137.5 (C), 128.6 (CH),

128.0 (CH), 127.8 (CH), 89.8 (CH), 81.9 (CH), 75.6 (CH₂), 71.8

(CH ), 57.3 (CH), 52.4 (CH ) ppm. FTIR (293 K, CHCl ): ν =

˜

2

3

3367, 2945, 2833, 1670, 1541, 1456, 1271, 1219, 1095, 1028 cm^–1.

MS (CI⁺): m/z (%) = 252 (100) [M + H]⁺, 237 (79) [M + H –

Me]⁺. HRMS (CI⁺): calcd. for C₁₃H₁₈NO₄252.1236; found

252.1235. [α]²_D⁰= –62.3 (c = 0.87 in MeOH).

1

give 22 (1.1 g, 73%) as a yellow oil. R_f= 0.52 (CH₂Cl₂). H NMR

(250 MHz, CDCl₃): δ = 7.95 (dd, J = 7.5 and 1.6 Hz, 1 H, Ar),

7.76 (dd, J = 7.5 and 1.6 Hz, 1 H, Ar-H), 7.64 (dt, J = 7.5 and

1.6 Hz, 1 H, Ar-H), 7.26 (m, 5 H, Ar), 6.02 (br. d, J = 5.0 Hz, 1

H, NH), 4.54 (AB, J = 11.9 Hz, 1 H, Bn), 4.47 (AB, J = 11.9 Hz,

1 H, Bn), 4.39 (s, 1 H, 4-H), 4.03 (m, 3 H, 5-H, 2-H), 3.82 (d, J =

8.8 Hz, 1 H, 5-H), 3.66 (s, 3 H, MeO) ppm. ¹³C NMR (62.9 MHz,

CDCl₃): δ = 171.3 (CO), 147.8 (C), 136.8 (C), 134.1 (CH), 134.0

(CH), 133.1 (CH), 130.6 (CH), 128.6 (CH), 128.2 (CH), 127.8

(CH), 125.5 (CH), 86.7 (CH), 81.8 (CH), 72.8 (CH₂), 71.9 (CH),

(2R,3R,4S)-Methyl 3-(Benzyloxy)-4-(tert-butoxycarbonylamino)-

tetrahydrofuran-2-carboxylate: A solution of 20a (250 mg,

0.99 mmol) in CH₂Cl₂(20 mL) was successively treated with DIEA

(520 μL, 2.98 mmol) and Boc₂O (325 mg, 1.49 mmol), and the mix-

ture was stirred at room temp. for 6 h. The solution was washed

with HCl (5% aq.; 3ϫ 20 mL), the organic phase was dried with

anhydrous Na₂SO₄, filtered, and concentrated under reduced pres-

sure. The resulting crude product was purified by flash chromatog-

raphy (20% EtOAc/hexane) to give the desired product (296 mg,

59.1 (CH ), 52.8 (CH) ppm. FTIR (293 K, CHCl ): ν = 3310, 3094,

˜

3

2954, 2886, 1754, 1541, 1440, 1363, 1205, 1170, 1097 cm^–1. MS

(ESI-TOF⁺): m/z (%) = 475 (9) [M + K]⁺, 459 (100) [M + Na]⁺.

HRMS (ESI): calcd. for C₁₉H₂₀N₂O₈SNa 459.0833; found

459.0813. [α]²_D⁰= –85.1 (c = 0.8 in MeOH).

1

85%) as a white solid. R_f= 0.70 (50% EtOAc/hexane). H NMR

(300 MHz, CDCl₃): δ = 7.24 (m, 5 H, Ar), 5.02 (d, J = 6.4 Hz, 1

H, NH), 4.66 (AB, J = 11.8 Hz, 1 H, Bn), 4.57 (AB, J = 11.8 Hz,

1 H, Bn), 4.59 (m, 1 H, 4-H), 4.36 (d, J = 1.6 Hz, 1 H, 2-H), 4.16

(br. s, 1 H, 3-H), 4.06 (dd, J = 9.5 and 4.8 Hz, 1 H, 5-H), 3.86 (d,

J = 8.7 Hz, 1 H, 5-H), 3.65 (s, 3 H, MeO), 1.35 (s, 9 H, Boc) ppm.

Methyl (2R,3R,4S)-3-(Benzyloxy)-4-[(2-nitrophenylsulfon)methyl-

amido]tetrahydrofuran-2-carboxylate (23): A solution of 22

¹³C NMR (75.4 MHz, CDCl₃): δ = 171.6 (CO), 155.0 (CO), 137.3 (650 mg, 1.42 mmol) in dry DMF (15 mL) was treated with K₂CO₃

(C), 128.4 (CH), 127.8 (CH), 87.2 (CH), 82.0 (CH), 79.8 (C), 73.1 (2.5 g, 18.09 mmol) and MeI (740 μL, 11.88 mmol), and the mix-

(CH₂), 71.7 (CH₂), 55.8 (CH), 52.4 (CH₃), 28.3 (CH₃) ppm. FTIR ture was stirred at room temp. for 4 h under argon. NaHCO₃(satd.

(293 K, CHCl ): ν = 3390, 2956, 2925, 2854, 1716, 1674, 1520,

aq.; 25 mL) was slowly added, and the residue was extracted with

CH₂Cl₂(3ϫ 25 mL). The combined organic extracts were washed

˜

3

1456, 1367, 1265, 1095 cm^–1. MS (ESI-TOF⁺): m/z (%) = 374 (100)

[M + Na⁺], 352 (20) [M + H⁺]. HRMS (ESI): calcd. for with NaCl (satd. aq.; 100 mL), dried with anhydrous Na₂SO₄, fil-

Eur. J. Org. Chem. 2013, 3477–3493

www.eurjoc.org

3491

M. Amorín, J. R. Granja et al.

FULL PAPER

tered, and concentrated under reduced pressure. The resulting ma-

(3) [M + H]⁺, 332 (100). HRMS (ESI): calcd. for C₁₉H₂₇NO₆Na

terial was purified by flash chromatography (CH₂Cl₂) to give 23

388.1731; found 388.1733. [α]²_D⁰= –63.8 (c = 1.1 in MeOH).

1

(520 mg, 77%) as a yellow oil. R_f= 0.62 (2% MeOH/CH₂Cl₂). H

(2R,3R,4S)-3-(Benzyloxy)-4-[N-(tert-butoxycarbonyl)methyl-

amino]tetrahydrofuran-2-carboxylic Acid [Boc-^MeN-γ-Ahf(Bn)-OH,

24b]: A solution of (2R,3R,4S)-methyl 3-(benzyloxy)-4-(meth-

ylamino)tetrahydrofuran-2-carboxylate (200 mg, 0.55 mmol) in a

mixture of MeOH and water (3:1; 12 mL) was treated with LiOH

(65.6 mg, 2.74 mmol). The solution was stirred at room temp. for

2 h, and then the solvent was removed under reduced pressure. The

resulting residue was diluted with water (25 mL) and washed with

CH₂Cl₂(1ϫ 10 mL), and the resulting aqueous solution was acidi-

fied to pH = 3 with HCl (5% aq.). The acidic solution was ex-

tracted with CH₂Cl₂(3ϫ 10 mL), and the combined organic ex-

tracts were dried with anhydrous Na₂SO₄, filtered, and concen-

trated under reduced pressure to give 24b (190 mg, 98%) as a pale

yellow oil. R_f= 0.4 (5% MeOH/CH₂Cl₂). ¹H NMR (300 MHz,

CDCl₃): δ = 9.18 (br., 1 H, COOH), 7.21 (m, 5 H, Ar), 4.64 (AB,

J = 12.1 Hz, 1 H, Bn), 4.59 (AB, J = 11.9 Hz, 1 H, Bn), 4.61 (m,

1 H, 4-H), 4.37 (d, J = 4.3 Hz, 1 H, 2-H), 4.18 (t, J = 3.7 Hz, 1 H,

3-H), 4.03 (dd, J = 9.9 and 7.1 Hz, 1 H, 5-H), 3.94 (dd, J = 9.9

and 5.3 Hz, 1 H, 5-H), 2.67 (s, 3 H, MeN), 1.38 (s, 9 H, Boc) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 174.3 (CO), 155.5 (CO), 137.2

(C), 128.2 (CH), 127.9 (CH), 127.8 (CH), 85.2 (CH), 82.0 (CH),

80.9 (C), 71.9 (CH₂), 69.2 (CH₂), 62.5 (CH), 30.9 (CH₃), 28.4 (CH₃)

NMR (250 MHz, CDCl₃): δ = 7.98 (dd, J = 6.9 and 2.6 Hz, 1 H,

Ar), 7.59 (m, 3 H, Ar), 7.29 (m, 5 H, Ar), 4.57 (m, 1 H, 4-H), 4.53

(s, 2 H, Bn), 4.31 (d, J = 4.7 Hz, 2 H, 2-H), 4.22 (dd, J = 4.7 and

3.0 Hz, 3-H), 4.08 (dd, J = 10.4 and 6.9 Hz, 1 H, 5-H), 3.91 (dd, J

= 10.4 and 4.4 Hz, 1 H, 5-H), 3.65 (s, 3 H, MeO), 2.75 (s, 3 H,

MeN) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 170.4 (CO), 147.8

(C), 136.8 (CH), 134.0 (CH), 131.8 (CH), 131.7 (CH), 131.1 (CH),

128.3 (CH), 127.9 (CH), 127.8 (CH), 124.2 (CH), 84.6 (CH), 81.8

(CH), 72.0 (CH₂), 68.9 (CH), 63.5 (CH), 52.4 (CH₃), 30.5 (CH₃)

ppm. FTIR (293 K, CHCl ): ν = 3092, 3029, 2953, 2897, 1749,

˜

3

1544, 1460, 1363, 1198, 1190 cm^–1. MS (ESI-TOF⁺): m/z (%) =

473 (100) [M + Na]⁺, 489 (2) [M + K]⁺. HRMS (ESI): calcd. for

C₂₀H₂₂N₂NaO₈S 473.0989; found 473.1002. [α]²_D⁰= –222.3 (c = 0.80

in MeOH).

Methyl (2R,3R,4S)-3-(Benzyloxy)-4-(methylamino)tetrahydrofuran-

2-carboxylate: A solution of 23 (500 mg, 1.06 mmol) in dry DMF

(14 mL) was treated with K₂CO₃(760 g, 5.50 mmol) and thi-

ophenol (450 μL, 4.41 mmol), and the mixture was stirred at room

temp. for 3 h under argon. NaHCO₃(satd. aq.; 10 mL) was added,

and the residue was extracted with CH₂Cl₂(4ϫ 10 mL). The com-

bined organic extracts were washed with NaCl (satd. aq.; 2 ϫ

25 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated

under reduced pressure. The remaining DMF was removed by dis-

tillation under vacuum. The crude product was purified by flash

chromatography (2–5% MeOH/CH₂Cl₂) to give the desired prod-

uct (210 g, 72%) as a yellow oil. R_f= 0.47 (5% MeOH/CH₂Cl₂).

¹H NMR (250 MHz, CDCl₃): δ = 7.24 (m, 5 H, Ar), 4.54 (AB, J

= 11.9 Hz, 1 H, Bn), 4.47 (AB, J = 11.9 Hz, 1 H, Bn), 4.42 (d, J =

1.9 Hz, 1 H, 2-H), 4.02 (m, 2 H, 5-H), 3.82 (dd, J = 9.2 and 2.7 Hz,

1 H, 5-H), 3.66 (s, 3 H, MeO), 3.12 (m, 1 H, 4-H), 2.26 (s, 3 H,

MeN) ppm. ¹³C NMR (62.9 MHz, CDCl₃): δ = 171.6 (CO), 137.3

(C), 128.2 (CH), 127.7 (CH), 127.6 (CH), 86.1 (CH), 81.6 (CH),

72.9 (CH₂), 71.4 (CH), 65.6 (CH), 52.1 (OMe), 34.2 (MeN) ppm.

ppm. FTIR (293 K, CHCl ): ν = 3505, 3011, 2978, 2932, 2875,

˜

3

1746, 1686, 1455, 1368, 1163, 1109 cm^–1. MS (ESI-TOF⁺): m/z (%)

= 390.1 (1) [M + K]⁺, 374.1 (100) [M + Na]⁺, 352.0 (3) [M + H]⁺,

318.1 (36) [M + Na – tBu]⁺, 296.1 (8) [M + H – tBu]⁺, 274.1 (19)

[M + Na – Boc]⁺, 252.1 (70) [M + H – Boc]⁺. HRMS (ESI): calcd.

for C₁₈H₂₅NO₆Na 374.1574; found 374.1565. [α]²_D⁰= –42.0 (c =

0.80 in MeOH).

CCDC-909272 (for 2b), -909273 (for 2c), -909274 (for 10), -909275

(for 12a), -909276 (for 12b), and -909277 (for 13) contain the sup-

plementary crystallographic data for this paper. These data can be

obtained free of charge from the Cambridge Crystallographic Data

Centre via www.ccdc.cam.ac.uk/data request/cif.

FTIR (293 K, CHCl ): ν = 3330, 3064, 3030, 2950, 2881, 2797,

˜

3

1750, 1455, 1276, 1207, 1098 cm^–1. MS (ESI-TOF⁺): m/z (%) =

288 (3) [M + Na]⁺, 266 (100) [M + H]⁺. HRMS (ESI): calcd. for

C₁₄H₂₀NO₄266.1387; found 266.1393. [α]²_D⁰= –32.6 (c = 0.85 in

MeOH).

Supporting Information (see footnote on the first page of this arti-

1

cle): Copies of the H and ¹³C NMR spectra of new compounds.

Acknowledgments

Methyl (2R,3R,4S)-3-(Benzyloxy)-4-[N-(tert-butoxycarbonyl)meth-

ylamino]tetrahydrofuran-2-carboxylate (24a): A solution of

(2R,3R,4S)-methyl 3-(benzyloxy)-4-(methylamino)tetrahydrofuran-

2-carboxylate (20 mg, 0.75 mol) in CH₂Cl₂(15 mL) was success-

ively treated with DIEA (520 μL, 2.98 mmol) and Boc₂O (410 mg,

1.88 mmol), and the mixture was stirred at room temp. for 7 h. The

solution was washed with HCl (5% aq.; 3ϫ 15 mL), and the or-

ganic phase was dried with anhydrous Na₂SO₄, filtered, and con-

centrated under reduced pressure. The resulting crude product was

purified by flash chromatography (2% MeOH/CH₂Cl₂) to give the

desired product (250 mg, 90 %) as a yellow oil R_f= 0.61 (5 %

This work was supported by the Spanish Ministry of Education

and Competitivity (MEC) and the European Regional Develop-

ment Fund (ERDF) (grant number CTQ2010-15725), by the Con-

solider Ingenio 2010 (grant number CSD2007-00006), by the Xunta

de Galicia (grant number GRC2006/132), and European project

Magnifyco (grant number NMP4-SL-2009-228622). N. R.-V. and

M. A. thanks the Spanish Ministry of Education and Competitivity

(MEC) for a FPU fellowship grant and RyC contract.

1

MeOH/CH₂Cl₂). H NMR (250 MHz, CDCl₃): δ = 7.25 (m, 5 H,

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Received: November 20, 2012

Published Online: March 13, 2013

Eur. J. Org. Chem. 2013, 3477–3493

www.eurjoc.org

3493

Article Doi

Synthesis of cyclic γ-amino acids for foldamers and peptide nanotubes

DOI: 10.1002/ejoc.201201565

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