Synthesis of racemic δ,δ-dimethylproline derivatives

Article abstract of DOI:10.1002/ejoc.201201420

A versatile methodology for the preparation of racemic δ,δ- dimethylproline derivatives has been developed. Methyl N-Boc-δ,δ- dimethylprolinate was synthesized from a β-amino acid in six steps and 55 % overall yield. The route is amenable to the preparation of a broad range of δ,δ-disubstituted prolines by starting with the adequate β-amino acids. In addition, one of the intermediate compounds in the synthetic route has been used for the preparation of a δ,δ- dimethylproline derivative that is substituted at the β-position with a phenyl group. This has been achieved by coupling phenylboronic acid with a regioselectively generated vinyl triflate followed by a stereoselective hydrogenation. δ,δ-Dimethylproline derivatives have been efficiently synthesized by employing a β-amino acid as the starting material. The methodology is amenable to the preparation of other δ,δ- disubstituted prolines. Copyright

Full text of DOI:10.1002/ejoc.201201420

Job/Unit: O21420
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FULL PAPER
DOI: 10.1002/ejoc.201201420
Synthesis of Racemic δ,δ-Dimethylproline Derivatives
Isabel Rodríguez,[a] M. Isabel Calaza,[a] and Carlos Cativiela*[a]
Keywords: Synthetic methods / Amino acids / Nitrogen heterocycles / Regioselectivity / Proline analogues
A versatile methodology for the preparation of racemic δ,δ-
dimethylproline derivatives has been developed. Methyl N-
Boc-δ,δ-dimethylprolinate was synthesized from a β-amino
acid in six steps and 55% overall yield. The route is amena-
ble to the preparation of a broad range of δ,δ-disubstituted
prolines by starting with the adequate β-amino acids. In ad-
dition, one of the intermediate compounds in the synthetic
route has been used for the preparation of a δ,δ-dimethylpro-
line derivative that is substituted at the β-position with a
phenyl group. This has been achieved by coupling phenyl-
boronic acid with a regioselectively generated vinyl triflate
followed by a stereoselective hydrogenation.
proteins,[4d,7,8] the mechanism of important receptors
in neuroscience,[9] and the bioactive conformations of
peptides.[7,10]
Introduction
Proline is the only coded amino acid that exhibits a re-
stricted conformational flexibility due to its cyclic structure.
This unique structural feature explains its tendency to act
as a β-turn inductor in peptides and proteins[1] as well as
its ability to form cis peptide bonds.[2] These properties are
the basis for the important role of proline in biology. In-
deed, peptide turns are known to be propitious sites for
molecular recognition,[3] and the cis/trans isomerization of
a prolyl peptide bond is considered to be a molecular switch
that controls important biological processes.[4]
Figure 1. The cis/trans isomerism of the amide bond, which in-
volves the pyrrolidine nitrogen, when δ,δ-dimethylproline is incor-
porated into a peptide chain.
Among proline analogues,[5] those that incorporate sub-
stituents at the δ-carbon atom are receiving increasing at-
tention. Such analogues are able to stabilize the cis state
of the peptide bond that involves the pyrrolidine nitrogen
atom.[6] The cis/trans equilibrium of prolyl peptide bonds
is governed by the different steric interactions established
between the acyl substituent on the nitrogen atom and the
α- or δ-positions of the pyrrolidine ring (see Figure 1). In
the case of proline, the α-position is sterically more crowded
than the δ-position, and, therefore, the trans prolyl amide
geometry is preferred. Increasing the steric hindrance
around the δ-carbon atom translates into a higher prefer-
ence for the prolyl peptide bond to accommodate the cis
arrangement. Thus, δ,δ-dimethylproline was reported to
generate peptides with the prolyl amide bond locked in the
cis geometry (see Figure 1).[7] Accordingly, δ,δ-dimethyl-
proline is being used as a probe to explore the three-
dimensional structure and folding pathways of therapeutic
For example, the rational replacement of a proline resi-
due in bovine pancreatic ribonuclease A by δ,δ-dimeth-
ylproline led to faster folding and enhanced conformational
stability of the protein.[8] Additionally, δ,δ-dimethylproline
has been shown to be an excellent probe to build an experi-
mental model of ion-channel gating for the 5-HT3 receptor,
which belongs to a cys-loop superfamily of neurotransmit-
ter-gated ion channels.[9] The mutagenesis of a proline resi-
due in a receptor loop with different analogues revealed
that only modified prolines that favor the cis amide geome-
try produced functional channels.[9d] Remarkably, a ca. 60-
fold increase in receptor activation was achieved with δ,δ-
dimethylproline.[9d] Accordingly, the authors proposed that
the trans-to-cis isomerization of a single proline residue pro-
vides the switch to interconvert the closed and open states
of the channel. Moreover, some applications of δ,δ-dimeth-
ylproline have been reported such as in the design of bioac-
tive compounds for the treatment of pain,[11] neurodegener-
ative disorders,[12] or bacterial infections.[13]
[a] Departamento de Química Orgánica, Instituto de Síntesis
Química y Catálisis Homogénea (ISQCH), CSIC – Universidad
de Zaragoza,
Despite its remarkable value, only few synthetic strategies
have been developed for the preparation of δ,δ-dimeth-
ylproline (see Scheme 1). Some procedures make use of di-
methyl-substituted pyrrolidine precursors, in which the
carboxylic acid moiety is further installed. Thus, this strat-
egy provides access to a racemic amino acid. In particular,
50009 Zaragoza, Spain
Fax: +34-976-761210
E-mail: cativiela@unizar.es
Homepage: http://www.unizar.es/aminoacidosypeptidos
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201420.
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I. Rodríguez, M. I. Calaza, C. Cativiela
FULL PAPER
the pyrrolidone depicted in Scheme 1a was reported to un-
dergo a selective reduction to form a Δ1-pyrroline that was
cyanated and hydrolyzed to the corresponding proline.[14]
Alternatively, the substituted nitrone in Scheme 1b under-
went an acid-catalyzed addition of cyanide to yield the N-
hydroxy nitrile, which was further hydrolyzed and reduced
to the amino acid,[15] along with the concomitant genera-
tion of a byproduct arising from an acid-catalyzed methyl
migration from the δ-carbon atom to the pyrrolidine nitro-
gen atom.[10b,12] The racemic δ,δ-dimethylproline obtained
in this manner was chemically resolved[7] by fractional
crystallization of the diastereomeric tartrates. The resolu-
tion process delivered δ,δ-dimethyl-l-proline with Ͼ 98%
enantiomeric purity. Additionally, the synthesis of
enantioenriched δ,δ-dimethylproline has been achieved
through an intramolecular cyclization procedure that in-
volves the N–Cδ bond formation.[16] Specifically, a chiral
prenylglycine intermediate, which was generated from two
different precursors (see Scheme 1c and d), rendered δ,δ-
dimethylproline in 98% ee upon heating under acidic condi-
tions.[16]
Scheme 2. Structure of the β-amino acid selected as a precursor of
δ,δ-dimethylproline.
As this compound exhibits a geminal substitution
pattern at the β-carbon atom (C-3), it belongs to the family
of β3,3-amino acids. These amino acids are targets of inter-
est for the preparation of structurally defined oligomers as
well as building blocks for bioactive molecules. Therefore,
a variety of methods have been described for their prepara-
tion.[18]
The synthesis of 3-amino-3-methylbutanoic acid with the
amino moiety protected by a tert-butoxycarbonyl (Boc)
group could be attempted by the homologation of α-amino-
isobutyric acid (Aib). However, the generation and re-
arrangement of the diazo ketones implicated in the homolo-
gation of α,α-disubstituted α-amino acids are reported to
proceed with poor yields.[18] For this reason, we undertook
an alternative three-step procedure (see Scheme 3) that
started with the conjugate addition of sodium azide to 3-
methyl-2-butenoic acid under acidic conditions.[19] The re-
duction of the azido group in 1 was then accomplished by
hydrogenation at atmospheric pressure using palladium on
carbon as the catalyst.[19] The introduction of the Boc pro-
tecting group at the amino functionality was carried out
by treatment of the crude β-amino acid with di-tert-butyl
dicarbonate under standard conditions. In this way,
multigram quantities of 2 were prepared in 68% overall
yield without purification of the intermediate compounds.
Scheme 1. Reported strategies for the synthesis of δ,δ-dimethyl-
proline.
Herein, we report an alternative preparation for δ,δ-di-
methylproline through an intramolecular cyclization pro-
cedure that involves the formation of the N–Cα bond and tions: (a) NaN3, H2O/AcOH, 95 °C; (b) H2, Pd/C, EtOAc, room
makes use of a β-amino acid as the starting material.
Scheme 3. Synthesis of the β-amino acid 2. Reagents and condi-
temp.; (c) Boc2O, KOH, dioxane/H2O, room temp.
Once the β-amino acid precursor was obtained, it was
converted into β-oxo ester 3 (see Scheme 4).[17] Thus, the
carbonyl group in 2 was activated by treatment with N,NЈ-
Results and Discussion
We have recently shown that a β-amino acid can be used carbonyldiimidazole, and the resulting imidazolide was
as a suitable precursor to build the proline skeleton. Specifi- treated with a magnesium enolate that was generated from
cally, the proline analogue that contains a phenyl substitu- the potassium salt of monomethyl malonate. Upon sponta-
ent attached to the pyrrolidine β-carbon atom was prepared neous decarboxylation, the nucleophilic addition provided
from β-alanine in a highly efficient manner.[17] The starting 3. Next, the crude β-oxo ester 3 was submitted to a diazo-
β-amino acid was converted into an α-diazo-β-oxo ester de- transfer reaction by treatment with 4-(acetamido)benz-
rivative that underwent an intramolecular N–H insertion enesulfonyl azide.[20] The diazo group of the resulting α-
reaction upon generation of a metal carbenoid. The re- diazo-β-oxo ester 4 successfully underwent decomposition,
sulting oxoproline was further modified at the β-carbon upon treatment with rhodium diacetate in toluene at 85–
atom to incorporate the desired aromatic functionality.[17]
90 °C.[21] The intramolecular N–H insertion of the metal
We decided to explore whether δ,δ-dimethylproline could carbenoid generated in situ cleanly delivered δ,δ-dimethyl-
be synthesized by applying the aforementioned approach. oxoproline 5, which was readily purified by column
In this case, the required β-amino acid (i.e., 3-amino-3- chromatography. The overall sequence in Scheme 4 pro-
methylbutanoic acid; see Scheme 2) is not as readily avail- vided this oxoproline in 82% yield from the starting β-
able as β-alanine.
amino acid 2.
2
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Synthesis of Racemic δ,δ-Dimethylproline Derivatives
presence of palladium on carbon (see Scheme 5b). This
transformation, which has been proposed[24] to occur
through a concerted hydrogenolysis of the C–O bond by
a PdH2 species followed by hydrogenation of the alkene,
provided 7 in 64% yield, when the reaction was carried out
on approximately a gram scale. However, concomitant de-
protection of the amino group occurred upon scale-up as
the reaction progressed, and the isolation of 7 became
troublesome. To circumvent this inconvenience, we under-
took the reduction of 6 through a two-step procedure that
involved a palladium-catalyzed reductive removal of the
triflate group by employing triethylsilane as the hydride
source,[25] which was followed by hydrogenation of the re-
sulting Δ2-pyrroline 8 (see Scheme 5c and b). This pro-
cedure cleanly furnished 7 in 73% yield from 6, without any
isolation difficulties. Consequently, these transformations
seem to be preferable for the preparation of 7.
Scheme 4. Synthesis of δ,δ-dimethyl-oxoproline 5 from the β-amino
acid 2. Reagents and conditions: (a) N,NЈ-carbonyldiimidazole,
MgCl2, tetrahydrofuran (THF), room temp.; (b) 4-(acetamido)-
benzenesulfonyl azide, Et3N, CH3CN, room temp.; (c) Rh2(OAc)4,
toluene, 85–90 °C.
Therefore, we developed a methodology that renders ra-
cemic methyl N-Boc-δ,δ-dimethylprolinate (7) in a 55%
overall yield through a six-step sequence that uses a β-
amino acid as the starting material. The procedure seems
to be a well-suited approach for the preparation of a
broader range of δ,δ-disubstituted prolines, as the required
β-amino acids should be accessible through a wide variety
of methods.[18]
An alternative synthesis of a similar oxoproline, with N-
acetyl protection, has previously been reported.[22] The
strategy described by Sato et al. involved an intramolecular
Dieckmann condensation reaction with the corresponding
β3,3-amino methyl ester. However, the process suffered from
a low overall yield (26% yield of N-acetylated oxoproline
from the β-amino ester). Therefore, the sequence reported
herein (see Scheme 4) that involves the intramolecular N–H
insertion of a metal carbenoid as the cyclization step repre-
sents a substantial improvement, in terms of efficiency, in
comparison to the previous procedure.[22]
After the preparation of δ,δ-dimethyl-oxoproline 5, we
addressed its transformation into the desired δ,δ-dimeth-
ylproline derivative (see Scheme 5). First, the deprotonation
of 5 with potassium hexamethyldisilazide (KHMDS) at
room temperature gave an enolate that was then trapped
with N-(5-chloro-2-pyridyl)triflimide to generate a vinyl
triflate.[23] This combination of base and triflating agent,
which proved optimal for achieving regiocontrol when
working with 3-oxoproline,[17] rendered 6 in high yield as a
single regioisomer.
In addition, this synthetic route provides access to valu-
able intermediate compounds, namely, vinyl triflate 6 and
Δ2-pyrroline 8. Thus, the latter could be used for the prepa-
ration of enantiopure or enantioenriched δ,δ-dimethylpro-
line derivatives by means of asymmetric catalytic hydrogen-
ations, as already tested for a 2,3-dehydroprolinate.[26]
Moreover, both 8 and 6 could act as precursors of δ,δ-di-
methylproline derivatives functionalized at the β-position.
Specifically, vinyl triflate 6 and Δ2-pyrroline 8 should be
suitable substrates to carry out cross-coupling reactions and
1,4-conjugate additions, respectively. In fact, applying these
strategies, we[17] and others[27] have successfully employed
analogous compounds derived from proline in the synthesis
of β-substituted prolines. The β-functionalization of δ,δ-di-
methylproline is expected to render analogues that are able
to combine the propensity of the parent amino acid to lock
the prolyl amide bond in the cis geometry with the presence
of new side chains. Such analogues are anticipated to be
highly valuable for the development of pharmacologically
active compounds. Until now, only few attempts have been
made to access δ,δ-dimethylproline analogues with ad-
ditional substituents at the β-carbon atom.[28]
We exemplified the value of these precursors (i.e., 6 and
8) in the synthesis of a β-substituted δ,δ-dimethylproline
derivative using vinyl triflate 6. Specifically, we carried out
the preparation of the analogue that has a phenyl substitu-
ent attached to the β-carbon atom, given the demonstrated
utility of β-phenylproline in improving the pharmacological
profile of biologically active peptides.[29] The incorporation
Scheme 5. Synthesis of methyl N-Boc-δ,δ-dimethylprolinate (7)
from δ,δ-dimethyl-oxoproline 5. Reagents and conditions:
(a) KHMDS, N-(5-chloro-2-pyridyl)triflimide, THF, room temp.;
(b) H2, Pd/C, MeOH, room temp.; (c) Pd(PPh3)4, Et3SiH, LiCl,
Et3N, N,N-dimethylformamide (DMF), 60 °C.
Although vinyl triflate 6 proved stable when stored at of the aromatic substituent into the δ,δ-dimethylproline
–20 °C, it was submitted to hydrogenation directly after its scaffold was achieved by means of a palladium-mediated
chromatographic purification. Thus, it was reduced to an cross-coupling reaction (see Scheme 6).[30] Treatment of
alkane under atmospheric pressure of hydrogen gas in the vinyl triflate 6 with phenylboronic acid in the presence of
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I. Rodríguez, M. I. Calaza, C. Cativiela
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raphy (TLC) was performed with Macherey–Nagel Polygram® SIL
G/UV254 precoated silica gel polyester plates. The products were
visualized by exposure to UV light or iodine vapor or by submer-
sion in ninhydrin stain or an ethanolic solution of phosphomolyb-
dic acid. Column chromatography was performed using 60 M
(0.04–0.063 mm) silica gel from Macherey–Nagel. Melting points
were determined with a Gallenkamp apparatus. IR spectra were
potassium carbonate, and
a
catalytic amount of
dichlorido[1,1Ј-bis(diphenylphosphanyl)ferrocene]palla-
dium(II) rendered Δ2-pyrroline 9 in moderate yield. The
presence of a double bond that connects the α- and β-car-
bon atoms in 9 ensured the relative cis disposition of the
substituents upon reduction of the pyrroline. Thus, catalytic
hydrogenation of 9 under standard conditions furnished 10
in high yield. This result emphasizes the importance of the
regioselectivity previously attained in the generation of
registered with a Nicolet Avatar 360 FTIR spectrophotometer, and
1
ν
values are given for the main absorption bands. The H and
˜
max
13C NMR spectroscopic data were recorded with a Bruker AV-400
vinyl triflate 6 (see Scheme 5), which was not significant or AV-500 instrument at room temperature with the residual sol-
vent signal as the internal standard. The chemical shifts (δ) are
expressed in parts per million, and the coupling constants (J) in
Hertz. High-resolution mass spectra were obtained with a Bruker
Microtof-Q spectrometer.
for the preparation of the parent δ,δ-dimethylproline, but
becomes a key issue in a stereocontrolled synthesis of the
β-substituted analogues. A copper-mediated 1,4-addition of
a phenyl Grignard reagent to 8 would most probably render
10 as mixture of cis/trans isomers, as observed in the case
of the Δ2-pyrroline derived from proline.[27]
3-Amino-N-(tert-butoxycarbonyl)-3-methylbutanoic Acid (2):
A
solution of sodium azide (13.00 g, 199.97 mmol) in water (25 mL)
was added dropwise by syringe to a solution of 3-methyl-2-butenoic
acid (5.00 g, 49.94 mmol) in acetic acid (13 mL). After stirring of
the mixture for 1 h, the temperature was raised to 95 °C, and the
solution was stirred for an additional 2 d. The reaction mixture was
diluted with water, and the resulting solution was extracted with
diethyl ether (5ϫ50 mL). The combined organic layers were dried
with MgSO4 and filtered. The solvent was concentrated in vacuo
to afford a white solid (7.10 g) that was used without purification.
A mixture of the solid and 10% Pd/C (700 mg) in ethyl acetate
(100 mL) was stirred under an atmospheric pressure of hydrogen
gas at room temperature for 24 h. The catalyst was removed by
filtration and washed with ethyl acetate (100 mL). The resulting
solution was washed with water (100 mL), and the aqueous phase
was extracted with ethyl acetate (2ϫ100 mL). The aqueous phase
was lyophilized to afford 3-amino-3-methylbutanoic acid (4.80 g,
40.97 mmol) as a white solid. The crude compound was dissolved
in dioxane (95 mL), and di-tert-butyl dicarbonate (17.80 g,
81.94 mmol) was added. The mixture was treated with potassium
hydroxide (1 m aqueous solution, 42 mL), and the resulting mixture
was stirred for 36 h. The reaction mixture was diluted with water
and then basified with lithium hydroxide. After extraction with di-
ethyl ether (3ϫ50 mL), the aqueous phase was acidified by the
Scheme 6. Synthesis of the cis-β-substituted δ,δ-dimethylproline
analogue 10. Reagents and conditions: (a) PhB(OH)2, PdCl2(dppf),
K2CO3, toluene/MeOH, 80 °C; (b) H2, Pd/C, MeOH, room temp.
Accordingly, 6 (and 8) are suitable precursors to generate
proline analogues with the prolyl amide bond stabilized in
the cis geometry that incorporate additional functionality
at the β carbon.[31]
Conclusions
A simple route for the preparation of methyl N-Boc-δ,δ-
dimethylprolinate in racemic form has been developed. The
procedure involves the construction of the pyrrolidine ring
through an intramolecular cyclization reaction to form the addition of HCl (2 m solution), and the resulting solution was ex-
tracted several times with ethyl acetate. The combined organic ex-
tracts were concentrated to dryness to afford pure 2 (7.42 g,
34.15 mmol, 68% overall yield) as a white solid; m.p. 98 °C. IR
N–Cα bond and makes use of a β-amino acid as the start-
ing material. The methodology can adequately be extended
to the preparation of other δ,δ-disubstituted prolines by
using different starting β-amino acids. In addition, it pro-
vides access to valuable intermediates for the preparation
of δ,δ-dimethylproline derivatives that are functionalized at
the β-carbon atom. In particular, the cis stereoisomer of
methyl N-Boc-δ,δ-dimethyl-β-phenylprolinate was obtained
through a cross-coupling reaction of a vinyl triflate interme-
diate that was regioselectively generated. Such δ,δ-disubsti-
tuted prolines that are functionalized at the β-position com-
bine the ability to stabilize the cis geometry of the prolyl
amide bond with the presence of additional side-chain func-
(Nujol): ν = 3313, 3260, 3100–2500, 1701, 1652 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.39 (s, 6 H, Cβ-CH3), 1.44 (br. s, 9 H, tBu
CH3), 2.72 (br. s, 2 H, Hα), 4.96 (br. s, 1 H, NHBoc), 10.08 (br. s,
1 H, CO2H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.88 (Cβ-
CH3), 28.50 (tBu CH3), 44.33 (Cα), 51.24 (Cβ), 79.74 (tBu C),
155.14 (tBuOCO), 176.50 (CO2H) ppm. HRMS (ESI): calcd. for
C10H19NNaO4 [M + Na]+ 240.1206; found 240.1213.
Methyl
N-(tert-Butoxycarbonyl)-5,5-dimethyl-3-oxopyrrolidine-2-
carboxylate (5): A solution of 2 (6.00 g, 27.62 mmol) in anhydrous
tetrahydrofuran (120 mL) under argon was treated with N,NЈ-car-
bonyldiimidazole (5.40 g, 33.30 mmol). After stirring at room tem-
tionality. Efforts to obtain pure enantiomers of δ,δ-dimeth- perature for 1 h, a mixture of previously combined magnesium
chloride (2.00 g, 21.00 mmol) and monopotassium monomethyl
malonate (6.50 g, 41.62 mmol) was added. The resulting mixture
was stirred at room temperature for an additional 18 h. The solvent
was evaporated, and the residue was dissolved in ethyl acetate
(100 mL). The resulting solution was washed with 5% aqueous
KHSO4 (2ϫ50 mL), 5% aqueous NaHCO3 (2ϫ50 mL), and then
brine (2ϫ50 mL). The organic layer was dried with MgSO4, fil-
tered, and concentrated under reduced pressure to afford a pale
ylproline by HPLC resolution on a chiral column are un-
derway.[32]
Experimental Section
General Methods: All reagents were used as received from commer-
cial suppliers without further purification. Thin layer chromatog-
4
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Synthesis of Racemic δ,δ-Dimethylproline Derivatives
orange oil (7.50 g, 27.43 mmol). The crude compound was dis-
solved in anhydrous acetonitrile (100 mL) under argon, and 4-
(acetamido)benzenesulfonyl azide (6.90 g, 28.72 mmol) was added
in one portion, which was followed by the addition of triethylamine
purified by column chromatography (hexanes/ethyl acetate, 5:1) to
afford 7 (94 mg, 0.37 mmol, 94% yield) as an oil. IR (neat): ν =
˜
1752, 1706, 1686 cm–1. 1H NMR (500 MHz, CDCl3, mixture of
rotamers, 1.2:1): δ = 1.31 and 1.38 (2 s, 3 H, Cδ-CH3), 1.39 and
(10.90 mL, 78.15 mmol). The resulting mixture was stirred at room 1.48 (2 s, 9 H, tBu CH3), 1.49 and 1.53 (2 s, 3 H, Cδ-CH3), 1.69–
temperature for 2 h. The solvent was concentrated in vacuo, and
the residue was dissolved in diethyl ether (100 mL). The resulting
solution was washed with saturated aqueous NaHCO3 (2ϫ50 mL),
saturated aqueous NH4Cl (2ϫ50 mL), and brine. The organic layer
was dried with MgSO4, filtered, and concentrated under reduced
pressure to afford an oil (7.80 g, 26.06 mmol) that was used in the
next step without purification. The oil was dissolved in anhydrous
toluene (300 mL) under argon, and Rh2(OAc)4 (56 mg,
0.127 mmol) was added. In a preheated oil bath, the reaction mix-
ture was heated at 85–90 °C for approximately 40 min. The solvent
was evaporated to dryness, and the residue was purified by column
chromatography (hexanes/ethyl acetate, 2:1) to afford pure 5
(6.15 g, 22.67 mmol, 82% overall yield) as a white solid; m.p.
1.80 (m, 1 H, Hγ), 1.81–1.99 (m, 2 H, Hβ and Hγ), 2.06–2.20 (m, 1
H, Hβ), 3.71 and 3.72 (2 s, 3 H, OCH3), 4.30 (dd, J = 8.8, 3.3 Hz,
0.54 H, Hα), 4.41 (dd, J = 8.7, 2.9 Hz, 0.46 H, Hα) ppm. 13C NMR
(125 MHz, CDCl3, duplicate signals observed for all carbon
atoms): δ = 26.07/26.92 (Cδ-CH3), 26.34/26.90 (Cγ), 26.46/27.58
(Cδ-CH3), 28.51/28.66 (tBu CH3), 40.19/41.02 (Cβ), 52.00/52.16
(OCH3), 60.90/61.67 (Cδ), 61.51/61.52 (Cα), 79.52/80.05 (tBu C),
152.75/154.48 (tBuOCO), 173.85/174.25 (CO2CH3) ppm. HRMS
(ESI): calcd. for C13H23NNaO4 [M + Na]+ 280.1519; found
280.1528.
Methyl N-(tert-Butoxycarbonyl)-5,5-dimethyl-Δ2-pyrroline-2-carb-
oxylate (8): Triethylsilane (0.55 mL, 3.45 mmol) and triethylamine
(0.97 mL, 6.95 mmol) were added dropwise to a solution of 6
(0.70 g, 1.74 mmol), lithium chloride (221 mg, 5.21 mmol), and
Pd(PPh3)4 (27 mg, 0.17 mmol) in anhydrous DMF (28 mL). The
reaction mixture was stirred at 60 °C for 1 h, and then the solvent
was removed under reduced pressure. The solid residue was puri-
fied by column chromatography (hexanes/ethyl acetate, 5:1) to af-
112 °C. IR (Nujol):
ν =
˜
1767, 1744, 1714 cm–1. 1H NMR
(400 MHz, CDCl3, mixture of rotamers, 2:1): δ = 1.39 (br. s, 6 H,
tBu CH3) overlapped with 1.46–1.72 (m, 9 H, tBu CH3 and Cδ-
CH3), 2.51–2.73 (m, 2 H, Hγ), 3.79 (s, 3 H, OCH3), 4.58 and 4.66
(2 br. s, 1 H, Hα) ppm. 13C NMR (100 MHz, CDCl3, duplicate
signals observed for most carbon atoms, * = signal corresponding
to minor rotamer): δ = 26.84, 27.48, and 27.87* (Cδ-CH3), 28.30/
28.52* (tBu CH3), 53.01/53.16* (OCH3), 53.34/53.96* (Cγ), 58.72*/
59.22 (Cδ), 68.28/68.42* (Cα), 80.87/81.58* (tBu C), 152.59/154.33*
(tBuOCO), 166.92*/167.25 (CO2CH3), 203.03*/203.72 (Cβ=O)
ppm. HRMS (ESI): calcd. for C13H21NNaO5 [M + Na]+ 294.1312;
found 294.1301.
ford pure 8 (347 mg, 1.36 mmol, 78% yield) as an oil. IR (neat): ν
˜
= 1741, 1705, 1627 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.43
(s, 9 H, tBu CH3), 1.47 (s, 6 H, Cδ-CH3), 2.52 (d, J = 3.0 Hz, 2 H,
Hγ), 3.78 (s, 3 H, OCH3), 5.43 (t, J = 3.0 Hz, 1 H, Hβ) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.28 (Cδ-CH3), 28.27 (tBu CH3),
45.82 (Cγ), 52.09 (OCH3), 64.81 (Cδ), 80.92 (tBu C), 113.36 (Cβ),
136.33 (Cα), 151.46 (tBuOCO), 163.42 (CO2CH3) ppm. HRMS
(ESI): calcd. for C13H21NO4 [M + H]+ 256.1543; found 256.1538.
Methyl
N-(tert-Butoxycarbonyl)-5,5-dimethyl-3-(trifluoromethyl-
sulfonyl)-Δ2-pyrroline-2-carboxylate (6): A solution of KHMDS
(0.5 m in toluene, 12.4 mL, 6.20 mmol) was added by syringe to a
stirred solution of 5 (1.40 g, 5.16 mmol) in anhydrous tetra-
hydrofuran (16 mL) at room temperature. After stirring for 40 min,
N-(5-chloro-2-pyridyl)triflimide (2.43 g, 6.20 mmol) was added,
and the resulting solution was stirred for an additional 4 h. The
solvent was evaporated to dryness, and the residue was purified by
column chromatography (hexanes/ethyl acetate, 5:1) to afford pure
6 (1.90 g, 4.70 mmol, 91% yield) as an oil that solidified in the
Methyl N-(tert-Butoxycarbonyl)-5,5-dimethyl-3-phenyl-Δ2-pyrroline-
2-carboxylate (9): To a solution of 6 (350 mg, 0.87 mmol) and
phenylboronic acid (212 mg, 1.74 mmol) in a mixture of toluene/
methanol (10:1, 5.5 mL) were added potassium carbonate (180 mg,
1.30 mmol) and dichlorido[1,1Ј-bis(diphenylphosphanyl)ferrocene]-
palladium(II) (32 mg, 0.044 mmol). The reaction mixture was
stirred at 80 °C for 1 h. The solvent was evaporated in vacuo, and
the resulting residue was purified by silica gel column chromatog-
raphy (hexanes/ethyl acetate, 5:1) to afford pure 9 (185 mg,
freezer. IR (neat): ν = 1750, 1716, 1429, 1387, 1370 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.44 (s, 9 H, tBu CH3), 1.56 (s, 6 H, Cδ-
CH3), 2.82 (s, 2 H, Hγ), 3.85 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.30 (Cδ-CH3), 28.19 (tBu CH3), 45.40
(Cγ), 52.68 (OCH3), 64.64 (Cδ), 82.38 (tBu C), 118.41 (q, J =
320.4 Hz, CF3), 128.38 (Cα), 133.55 (Cβ), 150.97 (tBuOCO), 160.03
(CO2CH3) ppm. HRMS (ESI): calcd. for C14H20F3NNaO7S [M +
Na]+ 426.0805; found 426.0795.
0.56 mmol, 64% yield) as a white solid; m.p 108 °C. IR (Nujol): ν
˜
1
= 1734, 1697 cm–1. H NMR (400 MHz, CDCl3): δ = 1.50 (s, 9 H,
tBu CH3), 1.59 (s, 6 H, Cδ-CH3), 2.93 (s, 2 H, Hγ), 3.82 (s, 3 H,
OCH3), 7.20–7.41 (m, 5 H, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.29 (Cδ-CH3), 28.42 (tBu CH3), 49.41 (Cγ), 52.46
(OCH3), 63.23 (Cδ), 81.44 (tBu C), 126.48 (Ar), 127.38 (Ar), 128.49
(Ar), 128.58 (Cβ), 129.86 (Cα), 134.16 (Ar), 151.26 (tBuOCO),
164.75 (CO2CH3) ppm. HRMS (ESI): calcd. for C19H25NO4 [M +
H]+ 332.1856; found 332.1837; calcd. for C19H25NNaO4 [M +
Na]+ 354.1676; found 354.1660.
Methyl
N-(tert-Butoxycarbonyl)-5,5-dimethylpyrrolidine-2-carb-
oxylate (7)
Procedure A: A mixture of 6 (1.90 g, 4.70 mmol) and 10% Pd/C
(0.19 g) in methanol (40 mL) was stirred under an atmospheric
pressure of hydrogen gas at room temperature for 18 h. The catalyst
was removed by filtration and then washed with methanol. The
solvent was concentrated in vacuo, and the crude residue was puri-
fied by column chromatography (hexanes/diethyl ether, 5:1) to af-
ford 7 (0.77 g, 3.00 mmol, 64% yield) as an oil.
Methyl cis-N-(tert-Butoxycarbonyl)-5,5-dimethyl-3-phenylpyrrolid-
ine-2-carboxylate (10): A mixture of 9 (166 mg, 0.50 mmol) and
10% Pd/C (17 mg) in methanol (5 mL) was stirred under an atmo-
spheric pressure of hydrogen gas at room temperature overnight.
The catalyst was removed by filtration and then washed with meth-
anol. The solvent was evaporated in vacuo, and the crude residue
was purified by column chromatography (hexanes/ethyl acetate,
5:1) to afford 10 (155 mg, 0.46 mmol, 93% yield) as an oil. IR
Procedure B: A mixture of 8 (100 mg, 0.39 mmol) and 10% Pd/
C (10 mg) in methanol (10 mL) was stirred under an atmospheric
pressure of hydrogen gas at room temperature overnight. The cata-
lyst was removed by filtration and then washed with methanol.
The solvent was concentrated in vacuo, and the crude residue was
(neat): ν = 1745, 1705, 1684 cm–1. 1H NMR (400 MHz, CDCl3,
˜
mixture of rotamers, 1.2:1): δ = 1.37 and 1.49 (2 s, 9 H, tBu CH3),
1.43 and 1.47 (2 s, 3 H, Cδ-CH3), 1.67 and 1.73 (2 s, 3 H, Cδ-CH3),
1.89–2.02 (m, 1 H, Hγ), 2.48–2.73 (m, 1 H, Hγ), 3.22 and 3.25 (2 s,
Eur. J. Org. Chem. 0000, 0–0
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I. Rodríguez, M. I. Calaza, C. Cativiela
FULL PAPER
3 H, OCH3), 3.61–3.79 (m, 1 H, Hβ), 4.53 (d, J = 8.8 Hz, 0.55 H,
Hα), 4.62 (d, J = 8.7 Hz, 0.45 H, Hα), 7.16–7.36 (m, 5 H, Ar) ppm.
13C NMR (100 MHz, CDCl3, duplicate signals observed for all car-
bon atoms): δ = 26.04/26.90 (Cδ-CH3), 27.16/28.20 (Cδ-CH3),
28.44/28.62 (tBu CH3), 43.07/43.62 (Cβ), 43.71/44.51 (Cγ), 51.20/
51.34 (OCH3), 60.52/61.18 (Cδ), 66.70/66.84 (Cα), 79.68/80.24 (tBu
C), 127.45/127.51 (Ar), 127.96/128.00 (Ar), 128.38/128.41 (Ar),
136.74/136.77 (Ar), 152.47/154.26 (tBuOCO), 172.15/172.23
(CO2CH3) ppm. HRMS (ESI): calcd. for C19H27NO4 [M + H]+
334.2013; found 334.1993; calcd. for C19H27NNaO4 [M + Na]+
356.1832; found 356.1828.
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Acknowledgments
The authors thank Dr. A. I. Jiménez for helpful discussions and
comments on the manuscript. Financial support from the Minis-
terio de Ciencia e Innovación – FEDER (grant CTQ2010-17436;
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6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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Date: 10-01-13 15:44:07
Pages: 8
Synthesis of Racemic δ,δ-Dimethylproline Derivatives
[29] P. Fatás, A. I. Jiménez, M. I. Calaza, C. Cativiela, Org. Biomol.
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the enantioseparation) and subsequently extending them to a
preparative scale would provide access to significant amounts
of enantiopure δ,δ-dimethylproline (both enantiomers). For
previous work from our group that describes the isolation of
(multi)gram quantities of enantiomerically pure amino acids
through the preparative HPLC resolution of racemic precur-
sors, see: a) P. Fatás, A. M. Gil, M. I. Calaza, A. I. Jiménez, C.
Cativiela, Chirality 2012, 24, 1082–1091; b) F. J. Sayago, M. J.
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iela, Chirality 2005, 17, 22–29; g) C. Cativiela, M. Lasa, P.
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Received: October 24, 2012
[31] We confirmed that β-substituted analogue 10 exhibited a ca-
pacity to stabilize the cis state of the amide bond that involves
the pyrrolidine nitrogen atom. To this end, we synthesized N-
acetyl derivatives of 7 and 10 by acidic treatment followed by
a reaction with acetic anhydride. Analysis of the two sets of
1
resonances in the H NMR spectra of 7 and 10 in CDCl3 re-
vealed a 67 and 70% cis-amide ratio, respectively, that is, a
slightly superior tendency for the β-phenyl derivative to stabi-
lize the cis amide geometry. Note that the remaining ca. 30%
trans amide bond is a result of the small size of the methyl
group in the N-acyl substituent. When δ,δ-dimethylproline is
within a peptide chain, an amino acid is linked to the pyrrolid-
ine nitrogen atom (instead of the acetyl group), and the higher
steric hindrance prevents the trans arrangement of the prolyl
peptide bond.
[32] Analytical assays have shown that benzyl N-benzyloxycarb-
onyl-δ,δ-dimethylprolinate (obtained by deprotection and fur-
ther protection of the amino and carboxylic acid groups in 7
by following standard procedures) is well resolved by HPLC
on a cellulose-derived Chiralpak® IB column (tR = 4.6 and
6.7 min; n-hexane/2-propanol, 95:5; 150ϫ4.6 mm column;
flow rate 1.0 mL/min). Optimization of these preliminary re-
sults (mainly by testing the effect of other mobile phases on
Published Online: ᭿
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Job/Unit: O21420
/KAP1
Date: 10-01-13 15:44:07
Pages: 8
I. Rodríguez, M. I. Calaza, C. Cativiela
FULL PAPER
Amino Acids
I. Rodríguez, M. I. Calaza,
C. Cativiela* ..................................... 1–8
Synthesis of Racemic δ,δ-Dimethylproline
Derivatives
δ,δ-Dimethylproline derivatives have been
efficiently synthesized by employing a β-
amino acid as the starting material. The
methodology is amenable to the prepara-
tion of other δ,δ-disubstituted prolines.
Keywords: Synthetic methods
/ Amino
acids / Nitrogen heterocycles / Regioselec-
tivity / Proline analogues
8
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