Stereocontrolled ring-opening of a hindered sulfamidate with nitrogen-containing aromatic heterocycles: Synthesis of chiral quaternary imidazole derivatives

Article abstract of DOI:10.1021/jo200479y

This paper explores the role of a hindered cyclic sulfamidate derived from α-methylisoserine as an electrophile in a nucleophilic displacement reaction with nitrogen-containing aromatic heterocycles. Several imidazoles and pyrazole were tested as nucleoph

Full text of DOI:10.1021/jo200479y

ARTICLE
pubs.acs.org/joc
Stereocontrolled Ring-Opening of a Hindered Sulfamidate with
Nitrogen-Containing Aromatic Heterocycles: Synthesis of Chiral
Quaternary Imidazole Derivatives
Lara Mata,† Gonzalo Jimꢀenez-Osꢀes,‡ Alberto Avenoza,*,† Jesꢀus H. Busto,*,† and Jesꢀus M. Peregrina†
†Departamento de Química, Universidad de La Rioja, Centro de Investigaciꢀon en Síntesis Química, UA-CSIC, E-26006 Logro~no, Spain
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States
S Supporting Information
b
ABSTRACT: This paper explores the role of a hindered cyclic
sulfamidate derived from R-methylisoserine as an electrophile
in a nucleophilic displacement reaction with nitrogen-contain-
ing aromatic heterocycles. Several imidazoles and pyrazole were
tested as nucleophiles in the absence of an additional base to
give the corresponding ring-opening compounds. We show that
the process takes place by inversion of the configuration of the
quaternary electrophilic center, retaining the enantiomeric
excess of the starting sulfamidate. This reaction opens the way
to obtain important quaternary imidazole derivatives such as an
innovative type of bis-amino acid related to histidinoalanine and a novel R,R-disubstituted β-amino acid (β2,2-amino acid).
’ INTRODUCTION
The main roles that cyclic sulfamidates have played in organic
synthesis, as well as the recent developments in their chemistry,
have profusely been described in the recent literature.1 These
systems can compete with epoxides and aziridines in terms
of reactivity and selectivity in ring-opening reactions with
nucleophiles.
Recently, we focused our interest on five-membered cyclic R-
methylisoserine-derived sulfamidates as excellent chiral building
blocks for the synthesis of several β-amino acids by nucleophilic
ring-opening reactions (Figure 1).2 In this context, a thorough
study has been carried out using S-nucleophiles,2aꢀf demonstrat-
ing in all cases the inversion of configuration at the electrophilic
center by a SN2 mechanism. Later, we studied their behaviors
toward O-nucleophiles in acidic and neutral media. The most
important outcome of this last study was the development of a
Figure 1. Cyclic sulfamidates and hindered chiral imidazole derivatives.
simple and practical method for the ring-opening reaction of
hindered sulfamidates using alcohols as O-nucleophiles2g,h under
in their chiral version have been employed in the synthesis of
mild conditions, at a quaternary carbon and with total inversion
imidazolium-based chiral ionic liquids6 and chiral N-heterocyclic
of the configuration.
carbeneꢀtransition metal complexes.7 On the other hand, the
However, the only N-nucleophile introduced in these systems
1H-imidazol-1-yl moiety incorporated in quaternary systems
was the sodium azide through the corresponding SN2 mechanism.2a
shows good oral bioavailability and increased GH secretion.8
In this context, the incorporation of nitrogen aromatic hetero-
cycles such as the imidazole or pyrazole systems into certain
’ RESULTS AND DISCUSSION
chiral molecules could provide new chiral ligands, since the
potential utility of imidazoles and pyrazoles as efficient coordi-
nating ligands is well-established in chemistry (Figure 1).
The ring-opening reactions of epoxides,3 aziridines,4 and
sulfamidates5 with imidazoles and pyrazoles as nucleophiles have
been used to prepare new diazole derivatives. These compounds
Sulfamidate (R)-1 (scheme of Table 1) was obtained in a gram
scale using a methodology previously published by us.2a We first
Received: March 4, 2011
Published: April 14, 2011
r
2011 American Chemical Society
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Table 1. Reaction of Sulfamidate (R)-1 with Imidazole
Table 2. Reaction of Sulfamidate (R)-1 with Benzimidazole
entry
equiv
solvent
T (°C)
time (h)
(S)-3b
entry
equiv
solvent
T (°C)
time (h)
(S)-2b
1
2
3
4
5
2
2
2
2
3
DMF
rt
48
24
24
48
48
30%c
9%c
1
2
3
4
5
2
2
3
2
2
CH3CN
CH3CN
CH3CN
DMSO
DMF
rt
48
48
24
8
52%
24%
67%
33%
79%c
DMF
50
50
reflux
rt
CH3CN
CH3CN
CH3CN
50
38%
47%
60%
reflux
reflux
a Hydrolysis conditions: 20% H2SO4 (aq)/CH2Cl2 (1:1). b Yields after
column chromatography purification. c Yield of product (S)-3 after
separation from the side products.
rt
36
a Hydrolysis conditions: 20% H2SO4 (aq)/CH2Cl2 (1:1). b Yields after
column chromatography purification. c Yield of product (S)-2 after
separation from the side product (S)-20 (10%).
presence of side products. Taking into account that the increase
of temperature in DMF did not give good results (Table 2, entry
2), the solvent was changed to CH3CN, the best yield being
obtained when 3 equiv of benzimidazole at reflux for 48 h was
used (Table 2, entry 5).
Taking into account the previous experiments, we carried out
the ring-opening reaction with different substituted imidazoles
using 3 equiv of nucleophile at reflux of CH3CN for 48 h. As a
result, 2-methyl-1H-imidazole, 2-ethyl-1H-imidazole and 2-iso-
propyl-1H-imidazole were found to operate as nucleophiles with
moderate yields in the same conditions (Table 3, entries 1, 2, and
3). The structures for compounds (S)-4 and (S)-5 were un-
ambiguously determined by X-ray diffraction analyses (see
Supporting Information).
To extend this methodology to other nitrogen heteroaromatic
nucleophiles, we attempted the ring-opening reaction with
pyrazole, obtaining in standard conditions a good yield (69%)
for compound (S)-9 (Table 3, entry 6). To test that these
reactions take place by the conventional SN2-type mechanism
similar to the cases of S-nucleophiles,2aꢀf with inversion of the
configuration at the stereogenic center, we carried out the
reaction with 2-bromo-1H-imidazole. The reaction (Table 3,
entry 7) proceeded with a low yield of compound (S)-10, but we
were able to obtain a single crystal suitable to be analyzed by
X-ray diffraction (see Supporting Information) with refinement
of the Flack parameter,9 by which it was possible to determine an
absolute S-configuration.
When the alkyl substituent of imidazole derivatives is located
at position 5, two isomers are possible in the nucleophilic starting
material due to the tautomerism,10 and they could give two
different reaction compounds (Scheme 1). In this context, two
imidazole derivatives, 4(5)-methyl-1H-imidazole (Table 3, entry 4)
and 2,4(5)-dimethyl-1H-imidazole (Table 3, entry 5), were
tested. In the first case, only one ring-opening compound (S)-7a
was obtained, which corresponded to the nucleophilic attack of the
4-methyl-1H-imidazole isomer, which has a less hindered nucleo-
philic nitrogen. When the reaction with 2,4(5)-dimethyl-1H-imida-
zole was carried out, two compounds (S)-8a and (S)-8b in a 2:1
ratio were obtained. Again, the attack is favored for the isomer in
which the nitrogen electron density is more accessible to give mainly
the isomer (S)-8a. This compound was isolated and characterized
by NMR experiments (COSY, HSQC, and HMBC).
explored the reactivity of this sulfamidate (R)-1 with imidazole as
a nucleophile using basic conditions. We observed that the
nucleophilic opening reaction did not progress satisfactorily in
any tested conditions [DBU in DMF or acetonitrile, and Cs2CO3
in DMF] yielding decomposition products, principally carba-
mate cleavage product, but not elimination product.
However, when the reaction was carried out in the absence
of a base, we could obtain some positive results. As a conse-
quence, mixing both reagents, sulfamidate and imidazole, in
acetonitrile (CH3CN) as a solvent at room temperature for
48 h, we obtained the sulfamate ring-opening product, which
provided compound (S)-2 (Table 1, entry 1) after acid hydro-
lysis with 20% H2SO4 (aq)/CH2Cl2 (1:1). The best conditions
using CH3CN were found at reflux with 3 equiv of imidazole to
give 67% of (S)-2 (Table 1, entry 3). The change to other more
polar solvents such as DMSO provided lower yields (Table 1,
entry 4). When we used DMF as a solvent at room tempera-
ture, the yield increased to 79%, but unexpectedly, the required
opening product (S)-2 was accompanied with side prod-
ucts (Table 1, entry 5). The possible attack of the DMF car-
bonyl oxygen as a nucleophile has been considered. After
hydrolysis, we could isolate the corresponding alcohol (S)-20
in a 10% yield, after column chromatography. To confirm the
structure and the configuration of this new product, we carried
out an alternative synthesis from (S)-R-methylisoserine, pre-
viously obtained following the procedure described in the
literature2a (see Experimental Section). The optical rotation
for this compound was [R]20D = þ45, identical to that obtained
as a side product in the ring-opening reaction with imidazol
in DMF.
To explore the scope of this reaction, other imidazole deriva-
tives were tested as nucleophiles. Therefore, the reaction with the
less nucleophilic benzimidazole was carried out under the best
conditions described above (Table 2, entry 1). However, we had
to try other conditions because of the low conversion and the
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Table 3. Reaction of Sulfamidate (R)-1 with Nitrogen Aro-
matic Heterocycles
Scheme 1. Tautomerism of Substituted Imidazoles and Re-
activity as Nucleophiles
(R)-1 in different orientations were considered. In sum, up to 40
and 34 different reaction pathways were calculated for the mono-
and disubstituted imidazoles, respectively (see Supporting In-
formation). The minimum energy structures of these calculated
reaction pathways are depicted in Figure 2. As can be seen on this
plot, a very similar activation barrier (ΔGq) was observed when
one methyl group was appended to the heterocyclic nucleophile;
on the contrary, the presence of a second methyl group increases
the energy barrier by ca. 2ꢀ3 kcal molꢀ1. These computational
kinetic data agree quite well with the slight decrease in reactivity
observed experimentally when we shifted from unsubstituted and
monomethylated to dimethylated imidazole. Moreover, and as
experimentally demonstrated, complete selectivity toward the
nucleophilic attack of the less sterically hindered N atom was
obtained as a result of the great difference between the lowest
energies of activation calculated for both reaction pathways,
labeled as ts9 and ts10 (4.2 kcal molꢀ1).11 As can be seen in
ts10 (Figure 2), steric interactions occurring between methyl
group of imidazole and methylene, methyl ester, and methyl
groups of sulfamidate at the most crowded TS are most likely at
the origin of this high site selectivity. The same tendency,
although somewhat overestimated, was observed with dimethy-
lated imidazole. In this case, the lowest activation barriers leading
to both site isomers (ts11 and ts12) differ by 5.5 kcal molꢀ1, the
attack of the most accessible nitrogenated position being favored
again. This energy gap is too big to account for the experimental
decrease of selectivity to a 2:1 mixture of isomers when carrying
out the SN2 reaction with dimethylated imidazole; the major
reaction product is predicted correctly. Again, steric repulsions
between the methyl groups of the incoming nucleophile and the
substituents located at the quaternary position of the electrophile
determine the energy distribution of all calculated TS.
a Hydrolysis conditions: 20% H2SO4 (aq)/CH2Cl2 (1:1). b Yields after
column chromatography purification. c Yield for both isomers. Yield for
compound (S)-8a was 36%. d Yield obtained by using 6 equiv of
nucleophile for 4 days of reaction time.
To gain insight into the reactivity and selectivity of these
processes, we have carried out theoretical calculations. First,
genuine SN2 transition states (TS), in which a total inversion of
configuration takes place at the quaternary carbon atom, were
located and characterized at the B3LYP/6-31Gþ(d,p) level
starting from sulfamidate (R)-1 and neutral imidazole. Every
structure (for example ts2) comprised several carbonyl rotamers
(for both the ester and carbamate groups) and sulfamidate ring
conformers, as well as distinct imidazole approximations. Overall,
up to 18 TS were calculated with the simplest imidazole (see
Supporting. Information). Counterpoise-corrected gas-phase
energy barriers were recalculated in solution through single-
point energy calculations with implicit continuous solvation in
acetonitrile (see Computational Details).
The aforementioned results encouraged us to discover syn-
thetic applications of the ring-opening reaction of sulfamidates
with nitrogen aromatic heterocycles described above. In this way,
we wanted to explore the utility of this methodology for the
synthesis of both the β-amino acids and the bis-amino acids, also
named cross-linking amino acids. Thus, although bis-amino acids
are non-natural amino acids, they appear naturally as protein
linkers in certain proteins and antibiotic peptides. Moreover,
they can be formed on exposure of proteins to certain processing
Once the concerted nature of the nucleophilic ring-opening
reaction was demonstrated, the high site selectivity exhibited by
nonsymmetric substituted imidazoles was tested theoretically.
To this aim, both tautomeric forms of 4(5)-methyl-1H-imidazole
and 2,4(5)-dimethyl-1H-imidazole approximating to sulfamidate
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Figure 2. Minimum energy TS calculated at the B3LYP/6-31Gþ(d,p)
level for all the proposed pathways starting from sulfamidate (R)-1 and
mono-, di-, and unsubstituted imidazoles. Distances are given in Å and
activation energies (ΔGq) in kcal molꢀ1
.
conditions, resulting in adverse effects especially in nutritional
proteins related to food science.12 In this sense, lanthionine
(LAN) and histidinoalanine (HAL) are two of the most relevant
bis-amino acids. Lanthionine consists of two alanines (Ala)
covalently linked by a sulfur atom (Ala-S-Ala), which is con-
sidered a thioether analogue of cystine (AlaꢀSꢀSꢀAla). LAN is
found in an important class of antibiotic peptides known as
lantibiotics.13 Because of this, several synthetic efforts14 have
been made to develop both lanthionine and their mimetics,
methyllanthionine (MeLAN), norlanthionine (norLAN), and
methylnorlanthionine (MenorLAN), whose structures can be
seen in Figure 3.14
HAL is derived from a covalent linkage of nitrogen of the
imidazol of a histidine (His) to β-carbon of an Ala.15 Depending
on which nitrogen of the imidazole is linked to the Ala, two
regioisomers can appear (τ-HAL and π-HAL). Both regioi-
somers have been detected in different sources: (1) protein-
containing foods that have been treated with alkali, (2) tissue
proteins such as bone, dentin, and eye cataracts, where their
formation may be related to the aging process, (3) phosphopro-
teins of bivalve mollusks, and (4) the theonellamides, which are a
family of bicyclic dodecapeptides characterized by a bridging τ-
HAL (Figure 3). A number of biological activities have been
described for theonellamides, but the role of HAL is unclear, and
several authors suggest that they are the histidine analogues of
the lantibiotics.
Taking into account the importance of cross-linking amino
acids, the development of synthetic methods that allow the
preparation of bis-amino acids has attracted significant interest.
Nevertheless, while several derivatives of LAN have been
described,13,14 the synthesis of HAL and derivatives has been
scarcely explored because of the problem of regioisomers and the
low yield. To the best of our knowledge, four syntheses of HAL
Figure 3. Structures of several bis-amino acids and Theonellamide F.
have been reported.16 The first three syntheses16aꢀc,f give a
mixture of τ-HAL and π-HAL regioisomers, both as distereomeric
mixtures arising from the conjugate addition of the nucleophilic
side chain (nitrogens of imidazole) of His to dehydroamino acid
derivatives (2-acetamidoacrylic acid or methyl 2-acetamido-
acrylate). There is only one methodology16d,e described in which
the configurations of both stereocenters are controlled, and it
involves the nucleophilic attack of the His on a β-lactone derived
from D-serine. Although a mixture of regioisomers again ap-
peared, they could be separated, giving 40% of τ-HAL derivative
and 21% π-HAL derivative. During the preparation of this
manuscript, we became aware of related work on the synthesis
of τ-HAL via a cyclic sulfamidate.16g
Therefore, we decided to carry out the ring-opening reaction
of cyclic sulfamidate (R)-1 using as a nucleophile the imidazole
heterocycle incorporated in the adequately protected amino acid
His. Thus, the Fmoc-L-His-OMe was prepared from commercial
Fmoc-L-His-OH using acetyl chloride (AcCl) in MeOH. The ring-
opening reaction was carried out with 3 equiv of Fmoc-L-His-OMe
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Scheme 2. Synthesis of Protected Menor-τ-HAL
Scheme 3. Synthesis of a Novel β2,2-Amino Acid
Scheme 4. Synthesis of Mosher Derivatives
in acetonitrile at reflux and proceeded with moderate yield, but
we could isolate, after column chromatography, compound 11 in
a 32% yield as a sole regioisomer (Scheme 2), recovering some
quantities of unreacted starting material and affording some
traces of a new product corresponding to the cleavage of the
carbamate group. This compound 11 can be regarded as a
protected derivative of τ-HAL that involves the covalent linking
of nitrogen of the imidazole of the R-amino acid His with the R-
carbon of the β-amino acid β-alanine (β-Ala), with the peculiar-
ity of bearing a quaternary stereocenter, whose configuration is
controlled in the nucleophilic substitution. Therefore, this deri-
vative can be named as Menor-τ-HAL compared with their
lanthionine partner (MenorLAN).14d Taking into account that,
from a conformational viewpoint, the role of τ-HAL in theonel-
lamides is not clear,17 probably the future inclusion of other
derivatives like Menor-τ-HAL will allow the exploration of
conformational space that is not available with the bis-amino
acids that appear naturally as protein linkers.
The field of the β-amino acids is a matter of continuous
interest due to the remarkable structures displayed by the
corresponding β-peptides that they can generate.18 Particularly
attractive are the chiral β2,2-amino acids,19 since they bear a
quaternary stereocenter at the R-position. In this context, with
the aim of exploring the synthetic utility of this reaction, we
carried out the synthesis of a new β2,2-amino acid from methyl
ester (S)-2 (Scheme 3). The first step involved the deprotection
of methyl carbamate from amino group. When we attempted the
hydrolysis under several acids conditions, we could not release
the amino group and a rather complex mixture of compounds
was obtained. However, the more specific deprotection method
for methyl carbamates, using trimethylsilyl iodide (TMSI) in
CH2Cl2,20 allowed us to obtain hydroiodide (S)-12 in a 73%
yield. In the next step, the hydrolysis of methyl ester in an
aqueous solution of 2 N HCl gave the β2,2-amino acid hydro-
chloride (S)-13 in an excellent yield. An aliquot of this com-
pound was treated with propylene oxide to obtain the free amino
acid (S)-14 in a 92% yield.
first from hydroiodide (S)-12 and second with a known ratio of
both enantiomers. In accordance with the protocol described in
the literature,21 amine (S)-12 was coupled with (R)-(þ)-meth-
oxytrifluorophenylacetic acid [(R)-(þ)-MTPA], in the pre-
sence of dicyclohexylcarbodiimide (DCC) and 4-dimethylami-
nopyridine (DMAP), to give the Mosher amide 15. The
mixture of (S)-12 and (R)-12 (3:1) was treated in the same
way to obtain amides 15 and 16 (Scheme 4). Analysis of the 1H
NMR and 19F NMR spectra of amides in both reactions (see
Supporting Information) showed that the enantiomeric excess
of starting sulfamidate (previously established by us in several
works2b,22 as 93% ee) was maintained in the ring-opening
reaction, and racemization has not been observed in these
new reactions.
’ CONCLUSION
We have obtained a new family of imidazole and pyrazole-
derived quaternary systems. Interestingly, the starting material
sulfamidate (R)-1 shows a tertiary electrophilic center with high
reactivity able to react with nitrogen-containing aromatic hetero-
cycles in the absence of additional base through a ring-opening
process and with simple experimental conditions. Starting from
nucleophilic ring-opening products, we have gained in a good
yield a novel β2,2-amino acid, and we could access an interesting
bis-amino acid derived from histidine.
To confirm that the enantiomeric excess (93%) of sulfamidate
(R)-1 is kept in the nucleophilic ring-opening process, we
repeated the reaction starting from sulfamidate (S)-1 and with
imidazole as a nucleophile to give compound (R)-2. The deprotec-
tion of methyl carbamate with TMSI allowed us to obtain
hydroiodide (R)-12. With compounds (S)-12 and (R)-12 in
our hands, we synthesized the corresponding Mosher amides,
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’ EXPERIMENTAL SECTION
(NCO2CH3), 175.9 (CO2CH3). HRMS (ESIþ): calcd for C7H14NO5
(M þ H) 192.0866, found (M þ H) 192.0862.
General Procedures. Solvents were purified according to standard
(S)-Methyl 2-(1H-Benzo[d]imidazol-1-yl)-3-(methoxycarbonylamino)-
2-methylpropanoate (S)-3. Starting from (R)-1 and using CH3CN as a
solvent, compound (S)-3 was isolated in a 60% yield as a white solid. Mp:
126ꢀ128 °C. [R]26D (c 0.96, CHCl3): ꢀ95.1. 1H NMR (CDCl3) δ 1.94
(s, 3H, CH3), 3.56 (s, 3H, NCO2CH3), 3.65 (s, 3H, CO2CH3), 3.79 (dd,
1H, J = 14.5 Hz, J = 6.1 Hz, CH2NH), 4.08 (dd, 1H, J = 14.5 Hz, J = 7.3
Hz, CH2NH), 4.94 (s, 1H, NH), 7.09ꢀ7.24 (m, 3H, arom), 7.67ꢀ7.77
(m, 1H, arom), 7.98 (m, 1H, arom). 13C NMR (CDCl3) δ 21.2 (CH3),
45.4 (CH2NH), 52.5 (NCO2CH3), 53.2 (CO2CH3), 64.0 (CCH3),
110.6, 120.9, 122.7, 123.4, (arom), 157.4 (NCO2CH3), 171.6
(CO2CH3). HRMS (ESIþ): calcd for C14H18N3O4 (M þ H)
292.1292, found (M þ H) 292.1296.
procedures. Column chromatography was performed using silica gel
1
60 (230ꢀ400 mesh). H and 13C NMR spectra were recorded on a
400 MHz spectrometer, using CDCl3 as a deuterated solvent with TMS
as an internal reference (chemical shifts are reported in ppm on the δ
scale, and coupling constants are in Hz). Assignment of all separate
1
signals in the H NMR spectra was made on the basis of coupling
1
1
1
13
constants and gradient enhanced Hꢀ H COSY and Hꢀ C HSQC
2D NMR experiments recorded on a 400 MHz spectrometer. Melting
points were determined on a melting point apparatus and are uncor-
rected. Optical rotations were measured on a polarimeter in 1.0 dm cells
of 1.0 and 0.3 mL capacity, respectively. Electrospray mass spectra were
recorded on a spectrometer; accurate mass measurements were achieved
using sodium formate as an external reference.
(S)-Methyl 3-(Methoxycarbonylamino)-2-methyl-2-(2-methyl-1H-
imidazol-1-yl)propanoate (S)-4. Starting from (R)-1 using CH3CN as a
solvent, compound (S)-4 was isolated in a 62% yield as a white solid. Mp:
122ꢀ124 °C. [R]26D (c 1.07, CHCl3): ꢀ62.2. 1H NMR (CDCl3) δ 1.81
(s, 3H, CH3), 2.25 (s, 3H, CH3imi), 3.65ꢀ3.70 (m, 4H, CO2CH3,
CH2NH), 3.79 (s, 3H, CO2CH3), 3.92 (dd, 1H, J = 14.3 Hz, J = 6.8 Hz,
CH2NH), 5.70ꢀ5.74 (s, 1H, NH), 6.87 (s, 1H, arom), 6.95 (s, 1H,
arom). 13C NMR (CDCl3) δ 15.0 (CH3imi), 22.7 (CH3), 46.6 (CH2NH),
52.5 (NCO2CH3), 53.2 (CO2CH3), 63.7 (CCH3), 117.4, 126.8, 144.3
(arom), 157.6 (NCO2CH3), 172.3 (CO2CH3). HRMS (ESIþ): calcd
for C11H18N3O4 (M þ H) 256.1292, found (M þ H) 256.1294.
(S)-Methyl 2-(2-Ethyl-1H-imidazol-1-yl)-3-(methoxycarbonylamino)-
2-methylpropanoate (S)-5. Starting from (R)-1 using CH3CN as a
solvent, compound (S)-5 was isolated in a 42% yield as white solid. Mp:
123ꢀ125 °C. [R]20D (c 1.17, CHCl3): ꢀ63.3. 1H NMR (CDCl3) δ 1.33
(t, 3H, J = 7.38 Hz, CH3imi), 1.81 (s, 3H, CH3), 2.35ꢀ2.55 (m, 2H,
CH2imi), 3.56ꢀ3.75 (m, 4H, CH2NH, CO2CH3), 3.79 (s, 3H,
CO2CH3), 3.87ꢀ3.92 (m, 1H, CH2NH), 5.13 (s, 1H, NH), 6.95 (s,
1H, arom), 7.00 (s, 1H, arom). 13C NMR (CDCl3) δ 12.2 (CH3imi),
21.5 (CH2imi), 22.9 (CH3), 41.7 (CH2NH), 52.6 (NCO2CH3), 53.3
(CO2CH3), 63.6 (CCH3), 116.9, 126.8, 149.3 (arom), 157.4 (NCO2-
CH3), 172.6 (CO2CH3). HRMS (ESIþ): calcd for C12H20N3O4 (M þ H)
270.1448, found (M þ H) 270.1449.
General Procedure for Ring-Opening Reactions of Cyclic Sulfamidates.
Sulfamidate (R)-1 or (S)-1 (1 equiv) and the corresponding nitrogen-
containing aromatic heterocycle (3 equiv) were dissolved in DMF at rt
or CH3CN under reflux, and the mixture was stirred for 48 h. After evapora-
tion of the solvent, the residue was dissolved in a mixture of aqueous 20%
H2SO4/CH2Cl2 (1:1), and the mixture was stirred at room temperature
for 12 h. Sodium hydrogen carbonate was added to the biphasic system
(until effervescence ceased). Once the phases were separated, the
aqueous layer was extracted with EtOAc. The combined organic phases
were dried over Na2SO4 and evaporated to give a residue, which was
purified by a silica gel column chromatography (CH2Cl2/MeOH, 9:1).
(S)-Methyl 2-(1H-Imidazol-1-yl)-3-(methoxycarbonylamino)-2-methyl-
propanoate (S)-2. Starting from (R)-1 using DMF as a solvent,
compound (S)-2 was isolated in a 79% yield as a white solid. Mp:
67ꢀ69 °C. [R]20D (c 1.02, CHCl3): ꢀ53.9. 1H NMR (CDCl3) δ 1.85 (s,
3H, CH3), 3.66 (s, 3H, NCO2CH3), 3.72 (dd, 1H, J = 14.4 Hz, J = 6.2
Hz, CH2NH), 3.78 (s, 3H, CO2CH3), 3.91 (dd, 1H, J = 14.4 Hz, J = 7.3
Hz, CH2NH), 5.05 (s, 1H, NH), 7.00 (s, 1H, arom), 7.11 (s, 1H, arom),
7.61 (s, 1H, arom). 13C NMR (CDCl3) δ 20.8 (CH3), 48.0 (CH2NH),
52.5 (NCO2CH3), 53.3 (CO2CH3), 64.0 (CCH3), 117.0, 129.7, 135.4
(arom), 157.1 (NCO2CH3), 171.2 (CO2CH3). HRMS (ESIþ): calcd
for C10H16N3O4 (M þ H) 242.1135, found (M þ H) 242.1131.
(R)-Methyl 2-(1H-Imidazol-1-yl)-3-(methoxycarbonylamino)-2-methyl-
propanoate (R)-2. Starting from (S)-1 using DMF as a solvent, com-
pound (R)-2 was isolated in a 79% yield as a white solid. [R]20D (c 1.03,
CHCl3): þ54.4. HRMS (ESIþ): calcd for C10H16N3O4 (M þ H)
242.1135, found (M þ H) 242.1141.
(S)-Methyl 2-(2-Isopropyl-1H-imidazol-1-yl)-3-(methoxycarbonyl-
amino)-2-methylpropanoate (S)-6. Starting from (R)-1 using CH3CN
as a solvent, compound (S)-6 was isolated in a 48% yield as colorless oil.
[R]20D (c 0.99, CHCl3): ꢀ39.8. 1H NMR (CDCl3) δ 1.24 (d, 3H, J =
6.62 Hz, CH3imi), 1.27 (d, 3H, J = 6.62 Hz, CH3imi), 1.82 (s, 3H, CH3),
2.55ꢀ2.63 (m, 1H, CHimi), 3.59ꢀ3.66 (m, 4H, CH2NH, CO2CH3),
3.79 (s, 3H, CO2CH3), 3.92ꢀ3.97 (m, 1H, CH2NH), 5.01ꢀ5.04 (m,
1H, NH), 6.89 (s, 1H, arom), 7.01 (s, 1H, arom). 13C NMR (CDCl3) δ
22.3 (CH3imi), 22.8 (CH3), 22.9 (CH3), 27.5 (CHimi), 47.5 (CH2NH),
52.5 (NCO2CH3), 53.1 (CO2CH3), 63.1 (CCH3), 115.6, 127.2, 153.5
(arom), 157.2 (NCO2CH3), 172.8 (CO2CH3). HRMS (ESIþ): calcd
for C13H22N3O4 (M þ H) 284.1610, found (M þ H) 284.1599.
(S)-Methyl 3-(Methoxycarbonylamino)-2-methyl-2-(4-methyl-1H-
imidazol-1-yl)propanoate (S)-7a. Starting from (R)-1 using CH3CN
as a solvent, compound (S)-7a was isolated in a 66% yield as colorless oil.
[R]20D (c 1.15, CHCl3): ꢀ50.5. 1H NMR (CDCl3) δ 1.74 (s, 3H, CH3),
2.11 (s, 3H, CH3imi), 3.59ꢀ3.64 (m, 4H, NCO2CH3, CH2NH), 3.69 (s,
3H, CO2CH3), 3.82ꢀ3.87 (m, 1H, CH2NH), 5.77 (s, 1H, NH), 6.62 (s,
1H, arom), 7.42 (s, 1H, arom). 13C NMR (CDCl3) δ 13.1 (CH3imi),
20.1 (CH3), 47.4 (CH2NH), 51.9 (NCO2CH3), 52.7 (CO2CH3), 63.4
(CCH3), 113.1, 134.0, 137.9 (arom), 157.0 (NCO2CH3), 170.8 (CO2CH3).
HRMS (ESIþ): calcd for C11H18N3O4 (M þ H) 256.1292, found
(M þ H) 256.1290.
(S)-Methyl 2-Hydroxy-3-(methoxycarbonylamino)-2-methylpro-
panoate (S)-20. This experimental procedure describes an alternative
synthesis for the side product (S)-20, which was obtained when
sulfamidate (R)-1 was opened with imidazole, using DMF as a solvent
(Table 1, entry 5). (S)-R-Methylisoserine (119 mg, 1.00 mmol), previously
obtained following the method described in the literature,2a was suspended
in a mixture of MeOH/HCl, previously prepared by the addition of AcCl
(4 mL) over MeOH (16 mL) at 0 °C. After refluxing for 10 h, the solvent
was evaporated, the hydrochloride derivative was dissolved in water
(5mL), andNa2CO3 10H2O (0.57 g, 2.00 mmol) was added. A solution of
3
dimethyl dicarbonate (174 mg, 1.3 mmol) in THF (20 mL) was added
to the mixture. The mixture was vigorously stirred at rt for 15 h, and a
saturated aqueous NaCl solution (40 mL) was then added. The resulting
mixture was extracted with EtOAc (3 ꢁ 20 mL). The organic layer was
dried, filtered, and evaporated to give a residue, which was purified by
column chromatography, eluting with hexane/EtOAc (1:1), to give (S)-
20 (76 mg, 40%) as an oil. [R]20 (c 0.99, CHCl3): þ45.0. H NMR
1
D
(CDCl3) δ 1.39 (s, 3H, CH3), 3.26 (dd, 1H, J = 13.9, J = 5.0 Hz,
CH2NH), 3.57ꢀ3.65 (m, 4H, NCO2CH3, CH2NH), 3.79 (s, 3H,
CO2CH3), 5.10 (s, 1H, NH). 13C NMR (CDCl3) δ 23.2 (CH3), 48.7
(CH2NH), 52.3 (NCO2CH3), 53.1 (CO2CH3), 74.5 (CCH3), 157.3
(S)-Methyl 2-(2,4-Dimethyl-1H-imidazol-1-yl)-3-(methoxycarbonyl-
amino)-2-methylpropanoate (S)-8a and (S)-Methyl 2-(2,5-Dimethyl-
1H-imidazol-1-yl)-3-(methoxycarbonylamino)-2-methylpropanoate
(S)-8b. (S)-8a: Starting from (R)-1 using CH3CN as a solvent, compound
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The Journal of Organic Chemistry
ARTICLE
(S)-8a was isolated in a 36% yield as colorless oil. [R]26 (c 0.94,
3.79ꢀ3.87 (m, 1H, CH2NH), 4.21ꢀ4.30 (m, 2H, CH2Fmoc), 4.35ꢀ4.39
(m, 1H, CHFmoc), 4.62ꢀ4.67 (m, 1H, CHHis), 5.10ꢀ5.14 (m, 1H, NH),
6.34ꢀ6.36 (m, 1H, NH), 6.79 (s, 1H, arom), 7.30 (t, 2H, J = 7.43 Hz,
arom), 7.39 (t, 2H, J = 7.43 Hz, arom), 7.52 (s, 1H, arom), 7.60ꢀ7.64
(m, 2H, arom), 7.75 (d, 2H, J = 7.52 Hz, arom). 13C NMR (CDCl3) δ
20.9 (CH3), 30.7 (CH2His), 47.3 (CHFmoc), 48.2 (CH2), 52.5 (CO2CH3),
52.7 (CO2CH3), 53.5 (CO2CH3), 54.3 (CHHis), 64.4 (CCH3), 67.3
(CH2Fmoc), 115.3, 120.1, 125.4, 125.5, 127.1, 127.2, 127.8, 135.6, 137.9,
141.4, 144.0, 144.2 (arom), 156.4, 157.3 (NCO2), 171.2, 172.4 (CO2CH3).
HRMS (ESIþ): calcd for C29H33N4O8 (M þ H) 565.2293, found
(M þ H) 565.2298.
D
CHCl3): ꢀ40.3. 1H NMR (CDCl3) δ 1.78 (s, 3H, CH3), 2.16 (s, 3H,
CH3imi), 2.23 (s, 3H, CH3imi), 3.62ꢀ3.71 (m, 4H, NCO2CH3,
CH2NH), 3.79 (s, 3H, CO2CH3), 3.86ꢀ3.91 (m, 1H, CH2NH), 5.41
(s, 1H, NH), 6.66 (s, 1H, arom). 13C NMR (CDCl3) δ 12.9 (CH3imi),
14.3 (CH3imi), 22.1 (CH3), 46.3 (CH2NH), 52.1 (NCO2CH3), 52.8
(CO2CH3), 63.2 (CCH3), 113.3, 134.8, 143.0 (arom), 157.0 (NCO2CH3),
171.9 (CO2CH3). HRMS (ESIþ): calcd for C12H20N3O4 (M þ H)
270.1448, found (M þ H) 270.1451.
1
NMR data of (S)-8b extracted from a mixture of regioisomers: H
NMR (CDCl3) δ 1.81 (s, 3H, CH3), 2.08 (s, 3H, CH3imi), 2.21 (s, 3H,
CH3imi), 3.60ꢀ3.63 (m, 1H, CH2NH), 3.77 (s, 3H, NCO2CH3), 3.74
(s, 3H, CO2CH3), 4.08ꢀ4.14 (m, 1H, CH2NH), 5.19 (s, 1H, NH), 6.69
(s, 1H, arom). 13C NMR (CDCl3) δ 13.6 (CH3imi), 14.7 (CH3imi), 22.5
(CH3), 46.6 (CH2NH), 52.4 (NCO2CH3), 53.2 (CO2CH3), 63.8
(CCH3), 113.3, 134.8, 143.0 (arom), 157.2 (NCO2CH3), 171.3
(CO2CH3).
(S)-Methyl 3-Amino-2-(1H-imidazol-1-yl)-2-methylpropanoate Hy-
droiodide (S)-12. To a solution of (S)-2 (35 mg, 0.07 mmol) in dry
CH2Cl2 (3 mL) under argon was added TMSI (17 μL, 0.14 mmol). The
reaction mixture was stirred at room temperature for 12 h, then it was
quenched with MeOH (5 mL), and the solvent was evaporated in vacuo.
The residue was dissolved in H2O (5 mL) and was extracted with
CHCl3/iPrOH (3:1) (2 ꢁ 5 mL). The combined aqueous phases were
concentrated, and the residue was dissolved in H2O (2 mL) and eluted
through a reverse-phase Sep-pak C18 cartridge to obtain, after evapora-
(S)-Methyl 3-(Methoxycarbonylamino)-2-methyl-2-(1H-pyrazol-1-
yl)propanoate (S)-9. Starting from (R)-1 using CH3CN as a solvent,
compound (S)-9 was isolated in a 69% yield as colorless oil. [R]20
D
(c 1.15, CHCl3): ꢀ46.9. 1H NMR (CDCl3) δ 1.75 (s, 3H, CH3), 3.57
(s, 3H, CO2CH3), 3.66 (s, 3H, CO2CH3), 3.93ꢀ4.05 (m, 2H, CH2NH),
5.35 (s, 1H, NH), 6.25 (s, 1H, arom), 7.48 (s, 2H, arom). 13C NMR
(CDCl3) δ 21.2 (CH3), 47.2 (CH2NH), 52.2 (NCO2CH3), 52.9 (CO2-
CH3), 67.3 (CCH3), 105.9, 128.1, 139.7 (arom), 157.1 (NCO2CH3),
171.4 (CO2CH3). HRMS (ESIþ): calcd for C10H15N3O4Na (M þ Na)
264.0955, found (M þ Na) 264.0962.
tion of the H2O, compound (S)-12 as a yellow oil (33 mg, 73%). [R]20
D
(c 1.02, CH3OH): þ2.7. 1H NMR (CD3OD) δ 2.19 (s, 3H, CH3), 3.91
(s, 3H, CO2CH3), 4.03 (s, 2H, CH2NH), 7.75 (s, 1H, arom), 8.00 (s,
1H, arom), 9.38 (s, 1H, arom). 13C NMR (CD3OD) δ 21.9 (CH3), 46.0
(CH2NH), 55.6 (CO2CH3), 66.1 (CCH3), 122.5, 122.6, 137.4 (arom),
169.6 (CO2CH3). HRMS (ESIþ): calcd for C8H14N3O2 (M þ H)
184.1081, found (M þ H) 184.1071.
(S)-Methyl 2-(2-Bromo-1H-imidazol-1-yl)-3-(methoxycarbonylamino)-
2-methylpropanoate (S)-10. Starting from (R)-1 using CH3CN as a
solvent, compound (S)-10 was isolated in a 29% yield as a white solid.
Mp: 136ꢀ138 °C. [R]20D (c 1.01, CHCl3): ꢀ69.1. 1H NMR (CDCl3) δ
1.92 (s, 3H, CH3), 3.67 (s, 3H, CO2CH3), 3.78ꢀ3.84 (m, 4H, CO2CH3,
CH2NH), 4.04 (dd, 1H, J = 14.5 Hz, J = 6.9 Hz, CH2NH), 5.04 (s, 1H,
NH), 7.03 (s, 1H, arom), 7.11 (s, 1H, arom). 13C NMR (CDCl3) δ 22.7
(CH3), 46.6 (CH2NH), 52.8 (NCO2CH3), 53.5 (CO2CH3), 65.1 (CCH3),
117.9, 120.5, 129.6 (arom), 157.5 (NCO2CH3), 171.7 (CO2CH3).
HRMS (ESIþ): calcd for C10H15BrN3O4 (M þ H) 320.0240, found
(M þ H) 320.0238.
(R)-Methyl 3-Amino-2-(1H-imidazol-1-yl)-2-methylpropanoate Hy-
droiodide (R)-12. Following the same procedure described above for
compound (S)-12, but starting from (R)-2, the enantiomer (R)-12 was
obtained. [R]20 (c 1.01, CH3OH): ꢀ2.9. HRMS (ESIþ): calcd for
D
C8H14N3O2 (M þ H) 184.1081, found (M þ H) 184.1074.
(S)-3-Amino-2-(1H-imidazol-1-yl)-2-methylpropanoic Acid Hydro-
chloride (S)-13. Compound (S)-12 (55 mg) was suspended in aqueous
2 N HCl (4 mL), and the mixture was heated at 50 °C for 48 h. After that,
the solvent was evaporated, and the residue was dissolved in H2O
(2 mL) and then eluted through a reverse-phase Sep-pak C18 cartridge
to obtain, after evaporation of the H2O, the corresponding compound
(S)-13 as a colorless oil (39 mg, 91%). [R]20D (c 1.06, H2O): þ15.7. 1H
NMR (D2O) δ 2.01 (s, 3H, CH3), 3.52ꢀ3.58 (m, 1H, CH2NH),
3.62ꢀ3.73 (m, 1H, CH2NH), 7.60 (s, 1H, arom), 7.70 (s, 1H, arom),
9.01 (s, 1H, arom). 13C NMR (D2O) δ 20.8 (CH3), 45.4 0 (CH2NH),
65.3 (CCH3), 120.4, 120.7, 134.8 (arom), 175.0 (CO2H). HRMS
(ESIþ): calcd for C7H12N3O2 (M þ H) 170.0924, found (M þ H)
170.0928.
(S)-Methyl 2-(4-((S)-2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-
3-methoxy-3-oxopropyl)-1H-imidazol-1-yl)-3-(methoxycarbonylamino)-
2-methylpropanoate 11
Synthesis of Nucleophile: Fmoc-His-OH (218 mg, 0.57 mmol) was
dissolved in a mixture of MeOH/HCl, previously prepared by the
addition of AcCl (0.12 mL) over MeOH (4 mL) at 0 °C. The mixture
was stirred at room temperature for 24 h. After evaporation of the
solvent, the crude product was treated with saturated NaHCO3 solution
(5 mL) and extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic
phases were dried over Na2SO4, concentrated, and the residue was
purified by a silica gel column chromatography (CH2Cl2/MeOH, 95:5)
to give compound Fmoc-His-OMe (174 mg, 77%) as a white solid. Mp:
113ꢀ115 °C. [R]20D (c 1.00, CHCl3): þ12.1. 1H NMR (CDCl3) δ 3.15
(s, 2H, CH2), 3.71 (s, 3H, CO2CH3), 4.23 (t, 1H, J = 7.09 Hz, CH),
4.37ꢀ4.39 (m, 2H, CH2), 4.62ꢀ4.64 (m, 1H, CH), 6.19ꢀ6.23 (m, 1H,
NH), 6.79 (s, 1H, arom), 7.31 (t, 2H, J = 7.45 Hz, arom), 7.39 (t, 2H, J =
7.40 Hz, arom), 7.57ꢀ7.62 (m, 3H, arom), 7.76 (d, 2H, J = 7.54 Hz,
arom). 13C NMR (CDCl3) δ 29.6 (CH2), 47.2 (CH), 52.5 (CO2CH3),
54.1 (CH), 67.1 (CH2), 120.0, 125.2, 127.1, 127.7, 135.1, 141.3, 143.9,
144.0 (arom), 156.2 (NCO2CH2), 172.2 (CO2CH3). HRMS (ESIþ):
calcd for C22H22N3O4 (M þ H) 392.1605, found (M þ H) 392.1617.
Compound 11: Starting from (R)-1 using CH3CN as a solvent,
(S)-3-Amino-2-(1H-imidazol-1-yl)-2-methylpropanoic Acid (S)-14.
Compound (S)-13 (39 mg) was dissolved in ethanol/propylene oxide
(3:1, 4 mL), and the solution was refluxed for 1 h. After that, (S)-14
precipitated as a white solid (25 mg, 92%). [R]20D (c 1.08, H2O): þ16.5.
1H NMR (D2O) δ 1.89 (s, 3H, CH3), 3.46 (q, 2H, J = 13.62 Hz,
CH2NH), 7.24 (s, 1H, arom), 7.35 (s, 1H, arom). 13C NMR (D2O) δ
21.2 (CH3), 46.4 0 (CH2NH), 63.8 (CCH3), 126.1 (arom), 175.0
(CO2H). HRMS (ESIþ): calcd for C7H12N3O2 (M þ H) 170.0924,
found (M þ H) 170.0920.
(S)-Methyl 2-(1H-Imidazol-1-yl)-2-methyl-3-((R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanamido)propanoate 15. A solution of (R)-(þ)-
MTPA (24 mg, 0.10 mmol) in CH3CN (1 mL) was added to a solution
of (S)-12 (29 mg, 0.09 mmol), DCC (21 mg, 0.10 mmol), and DMAP
(12 mg, 0.10 mmol) in CH3CN (1.0 mL), under an inert atmosphere.
The mixture was stirred at room temperature for 24 h. The resulting
white suspension was filtered to remove the N,N0-dicyclohexylurea and
then concentrated to give the crude product, which was purified by silica gel
compound 11 was isolated in a 32% yield as a white solid. Mp:
1
61ꢀ63 °C. [R]20 (c 1.00, CH3OH): ꢀ15.9. H NMR (CDCl3) δ
D
1.79 (s, 3H, CH3), 3.08ꢀ3.09 (m, 2H,CH2His), 3.57ꢀ3.68 (m, 4H,
CO2CH3, CH2NH), 3.73 (s, 3H, CO2CH3), 3.75 (s, 3H, CO2CH3),
column chromatography (CH2Cl2/MeOH, 95:5) to give compound 15
1
(9 mg, 25%), as a yellow oil. [R]20 (c 0.96, CHCl3): ꢀ4.1. H NMR
D
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The Journal of Organic Chemistry
ARTICLE
(CDCl3) δ 1.82 (s, 3H, CH3), 3.31 (s, 3H, CH3O), 3.77 (s, 3H, CO2CH3),
3.88 (dd, 1H, J = 14.2 Hz, J = 6.2 Hz, CH2NH), 4.08 (dd, 1H, J = 14.2 Hz,
J = 7.2 Hz, CH2NH), 7.02 (s, 2H, arom), 7.15 (s, 1H, arom), 7.40
(s, 5H, arom), 7.71 (s, 1H, arom). 13C NMR (CDCl3) 20.6 (CH3),
46.1 (CH2NH), 53.7 (CO2CH3), 63.8 (CCH3), 127.7, 128.9, 128.9,
132.1 (arom þ CF3), 167.1 (NCO2C), 169.4 (CO2CH3). HRMS
(ESIþ): calcd for C18H21F3N3O4 (M þ H) 400.1479, found (M þ H)
400.1460.
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W. D. Org. Lett. 2001, 3, 2965–2968. (j) Jamieson, A. G.; Boutard, N.;
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Computational Details. All calculations were carried out with the
B3LYP hybrid functional23 and 6-31Gþ(d,p) basis set. Full geometry
optimizations and transition structure (TS) searches were carried out
with the Gaussian 03 package.24 The possibility of different conforma-
tions and nucleophile approximations was taken into account for all
structures. Basis set superposition errors (BSSE) were corrected by the
BoysꢀBernardi counterpoise method.25 Frequency analyses were car-
ried out at the same level used in the geometry optimizations, and the
nature of the stationary points was determined in each case according to
the appropriate number of negative eigenvalues of the Hessian matrix.
Scaled frequencies were not considered since significant errors in the
calculated thermodynamic properties are not found at this theoretical
level.26 Mass-weighted intrinsic reaction coordinate (IRC) calculations
were carried out by using the Gonzalez and Schlegel scheme27 in order
to ensure that the TSs indeed connected the appropriate reactants and
products. Solvent effects were taken into account through the polarized
continuum model (IEF-PCM)28 using UAHF radii, as implemented in
Gaussian 03. The internally stored parameters for acetonitrile (ɛ = 35.7)
were used to calculate solvation free energies (ΔGsolv). Gibbs free
energies (ΔG) were used for the discussion on the relative stabilities of
the considered structures. Cartesian coordinates, electronic energies,
entropies, enthalpies, Gibbs free energies, lowest frequencies of the
different conformations of all structures considered are available as
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’ ASSOCIATED CONTENT
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S
Supporting Information. Spectroscopic characterization
b
of all new compounds, crystal structure data, computational data,
and complete ref 24 (Gaussian). This material is available free of
charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: alberto.avenoza@unirioja.es; hector.busto@unirioja.es.
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’ ACKNOWLEDGMENT
We are grateful to the Ministerio de Ciencia e Innovaciꢀon
(project CTQ2009-13814/BQU), the Universidad de La Rioja
(project EGI10/65), the Gobierno de La Rioja (Colabora 2010/
05), and the CSIC (predoctoral fellowship of L.M).
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