Chemoselectivity control in the reactions of 1,2-cyclic sulfamidates with amines

Article abstract of DOI:10.1002/chem.201204392

Although 1,2-cyclic sulfamidates derived from α-methylisoserine undergo nucleophilic displacement at the quaternary center, to the best of our knowledge their behavior with amines as nucleophiles has never been explored. We have found that a broad range of amines can be used, demonstrating the scope of the reaction, and that excellent control of the chemoselectivity can be achieved. Application of this methodology for the synthesis of a chiral α,β-diamino acid and an important piperazinone heterocycle is also presented. Additionally, we have found that DMF and DMSO behave not only as polar aprotic solvents but also as O-nucleophilic reagents, allowing the incorporation of an oxygen atom at a quaternary center of the electrophile, with inversion of configuration. Copyright

Full text of DOI:10.1002/chem.201204392

FULL PAPER
DOI: 10.1002/chem.201204392
Chemoselectivity Control in the Reactions of 1,2-Cyclic Sulfamidates with
Amines
Lara Mata, Alberto Avenoza, Jesffls H. Busto,* and Jesffls M. Peregrina*[a]
Abstract: Although 1,2-cyclic sulfami-
dates derived from a-methylisoserine
undergo nucleophilic displacement at
the quaternary center, to the best of
our knowledge their behavior with
amines as nucleophiles has never been
explored. We have found that a broad
range of amines can be used, demon-
strating the scope of the reaction, and
that excellent control of the chemose-
lectivity can be achieved. Application
of this methodology for the synthesis
of a chiral a,b-diamino acid and an im-
portant piperazinone heterocycle is
also presented. Additionally, we have
found that DMF and DMSO behave
not only as polar aprotic solvents but
also as O-nucleophilic reagents, allow-
ing the incorporation of an oxygen
atom at a quaternary center of the
electrophile, with inversion of configu-
ration.
Keywords: amines · amino acids ·
chemoselectivity · nucleophilic sub-
stitution · ring-opening reactions
Introduction
termediates to epoxides and aziridines,[8] has received less
attention. To the best of our knowledge, very few examples
have been reported,[8a,9] and in most cases the amine attacks
at a secondary carbon, because when more hindered sulfa-
midates have been employed the substitution reaction has
been difficult to accomplish.[9c]
In this field, we have reported the use of 1,2-cyclic sulfa-
midates derived from a-methylisoserine as outstanding
chiral building blocks to obtain a variety of important com-
pounds,[10] especially a,a-disubstituted b-amino acids, named
as b2,2-amino acids. The key step involves nucleophilic attack
on the tertiary carbon with inversion of configuration. We
examined the use of several sulfur, oxygen, and nitrogen nu-
cleophiles, obtaining excellent results. As nitrogen nucleo-
philes, we used azide and aromatic nitrogen-heterocycles,
such as imidazole, pyrazole, pyridine, and their derivatives.
However, as far as we are aware, the particular case of treat-
ing this substrate with amines has never been explored.
Moreover, it is important to note that these cyclic sulfami-
date-based building blocks have several reaction sites and
that amines can act both as nucleophiles and as bases.
The amino group is an integral feature of compounds impor-
tant to life, such as a-amino acids. Amines of great rele-
vance (histamine, dopamine, tyramine, and so on) are
formed by decarboxylation of amino acids.[1] In the pharma-
ceutical industry, such amine moieties are present in a large
number of drugs and have a wide variety of functions. In
many cases, only specific chiral forms show the desired bio-
logical activity.[2] Due to the abundance of amino groups in
natural compounds such as peptides, alkaloids, nucleosides,
and so on, and their importance in relation to the properties
and biological functions of these molecules, a large number
À
of synthetic methodologies for the formation of C N bonds
have been developed.[3] In this context, the use of amines as
nucleophiles (Hofmann alkylation, for instance) is very lim-
ited because the degree of alkylation is difficult to control
and so, in general, amines are prepared by alternative meth-
ods. There are, however, some exceptions and some exam-
ples in which amines serve as nucleophiles in substitution re-
actions have been described. Among them, ring-opening re-
actions of epoxides[4] and aziridines[5] have great significance
because the products obtained, 1,2-amino alcohols[6] and 1,2-
diamines,[7] are of interest in medicinal chemistry and the
pharmaceutical industry. Nevertheless, the use of amines as
nucleophiles in ring-opening reactions of 1,2-cyclic sulfami-
dates, which represent alternative heterocyclic synthetic in-
Results and Discussion
To study the issue of regioselective ring opening, we have
explored the reactivity of a-methylisoserine-derived sulfami-
dates with amines. We started our study with propylamine
as a representative primary amine because it is readily avail-
able and liquid at room temperature. Following a protocol
similar to that described for other reactions of sulfamidates
with various nucleophiles,[9a] we carried out the reaction of
sulfamidate (R)-1 with propylamine (4.0 equiv) in the pres-
ence of Cs2CO3 in THF as solvent at room temperature
(Table 1, entry 1). After 8 h of reaction, we obtained a 42%
yield of compound (R)-2 derived from N-deprotection of
[a] Dr. L. Mata, Prof. A. Avenoza, Dr. J. H. Busto, Prof. J. M. Peregrina
Departamento de Quꢀmica, Universidad de La Rioja
Centro de Investigaciꢁn en Sꢀntesis Quꢀmica
Madre de Dios, 51, 26006 LogroÇo (Spain)
Fax : (+34)941299620
E-mail: jesusmanuel.peregrina@unirioja.es
hector.busto@unirioja.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204392.
Chem. Eur. J. 2013, 19, 6831 – 6839
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6831

Table 1. Reactivity of cyclic sulfamidate (R)-1 with propylamine.
Therefore, we have verified that the chemoselectivity in
the reaction of propylamine with cyclic sulfamidate (R)-1 is
mainly controlled by the choice of solvent. Acetonitrile
favors N-deprotection of the sulfamidate, in THF there is
not only N-deprotection, but also conversion of the methyl
ester to propylcarboxamide, whereas in DMF there is nucle-
ophilic attack at the quaternary center of the sulfamidate
with inversion of configuration, circumventing the need for
a second step for hydrolysis of the sulfamic moiety. In all
cases, no elimination products were detected.[11]
Several attempts were made to increase the yield of com-
pound (S)-4 by using DMF as solvent, but we observed the
formation of a new product, the tertiary alcohol (S)-5, along
with compounds (S)-4 and (R)-2. To confirm the structure of
this compound, we prepared it from (S)-methylisoserine,
which was obtained according to a previously published
methodology.[10f] (S)-Methylisoserine was first transformed
to the corresponding methyl ester derivative by treatment
with acetyl chloride in methanol, and then the amino group
was protected as a methyl carbamate by reaction with di-
methyl dicarbonate (DMDC) in the presence of diisopropy-
lethylamine (DIEA) with THF as solvent (Scheme 1. The
Entry PrNH2 Base
[equiv]
Solvent
T
[8C]
t
(R)-2 (R)-3 (S)-4
G
[h]
[%][a] [%][a] [%][a]
1
2
3
4
5
6
7
8
9
4.0
4.0
1.0
neat
neat
4.0
2.0
1.0
Cs2CO3 THF
RT
8
1
48
7
0.5
48
5
42
60
81
–
–
–
–
–
–
94
93
92
–
–
–
–
–
–
–
–
–
23
14
49
–
CH3CN reflux
BuLi
THF
RT
RT
48
RT
reflux
reflux
reflux
–
–
–
–
–
–
PrNH2
PrNH2
THF
THF
THF
52
45
6
2.0
DMF
0.5 35
[a] Yield after column chromatography.
the sulfamidate (cleavage of methyl carbamate). We were
able to improve the yield of this reaction to 60% by using
acetonitrile (CH3CN) as solvent and increasing the tempera-
ture without addition of a supplementary base (Table 1,
entry 2). We even achieved an 81% yield by using only
1.0 equivalent of propylamine in THF in conjunction with
1.2 equivalents of BuLi at À788C and allowing the reaction
to proceed at room temperature for 48 h (Table 1, entry 3).
When propylamine was used as the solvent and the reac-
tion was allowed to proceed for 7 h at room temperature,
the only product obtained, in an excellent yield of 94%, was
the sulfamidate (R)-3. Hence, not only N-deprotection oc-
curred, but also a concomitant amidation reaction that in-
volved conversion of the methyl ester into propylcarboxa-
mide (Table 1, entry 4). A similar yield of (R)-3 (93%) was
obtained when this reaction was carried out for 30 min at
488C (Table 1, entry 5). Finally, the best conditions for ob-
taining compound (R)-3 (92% yield) were identified as the
use of only 4.0 equivalents of propylamine in THF as sol-
vent, with a reaction time of 48 h at room temperature
(Table 1, entry 6). An increase in temperature, even with
control of the number of equivalents of amine, led to cleav-
age of the carbamate to generate compound (R)-2, along
with a small quantity of compound (S)-4 arising from ring
opening of the cyclic sulfamidate by propylamine (Table 1,
entries 7 and 8).
The use of N,N-dimethylformamide (DMF) as an aprotic
and polar solvent favored this third type of reaction between
sulfamidate (R)-1 and propylamine. By using only 2.0 equiv-
alents of propylamine in DMF at reflux for 30 min, com-
pound (S)-4 was obtained in 49% yield, accompanied by a
35% yield of compound (R)-2 (Table 1, entry 6). Compound
(S)-4 arose from nucleophilic ring opening of the cyclic
sulfamidate with inversion of configuration. In general, reac-
tions of this type require a second step for hydrolysis of the
sulfamic moiety. In the present case, however, this step was
not necessary, which may be considered as an advantage.
Scheme 1. Synthesis of (S)-5 from (S)-methylisoserine.
optical rotation measured for alcohol (S)-5 derived from
sulfamidate (R)-1 was identical to that measured for the (S)-
5 derived from methylisoserine, confirming the absolute
configuration at the quaternary stereocenter (Scheme 1).
DMF is an excellent polar solvent and has also been used
as an effective ligand in metallic compounds. Moreover,
DMF can react as either an electrophilic or a nucleophilic
agent, as has recently been reviewed.[12] In fact, DMF has
been described as a precursor of different units (e.g., an
oxygen atom, or carbonyl, dimethylamino, dimethylamino-
carbonyl, or methyl groups). To the best of our knowledge,
only a few reports have been published concerning the use
of DMF as an O-nucleophile and source of an oxygen
atom.[13]
In view of the above, we propose DMF as the source of
the hydroxyl oxygen atom in the formation of compound
(S)-5. A possible mechanism that would account for the for-
mation of (S)-5 involves nucleophilic attack of the oxygen of
DMF followed by aminolysis by propylamine to cleave the
sulfamic moiety (Scheme 2 and the Supporting Informa-
tion).
To confirm this proposal, we carried out the reaction of
sulfamidate (R)-1 with DMF at room temperature and at
708C in the absence of propylamine, obtaining in both cases
compound (S)-5 in yields of 36 and 96%, respectively
(Table 2, entries 1 and 2). To demonstrate that residual
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Chem. Eur. J. 2013, 19, 6831 – 6839

Versatile Reactivity of a 1,2-Cyclic Sulfamidate with Amines
FULL PAPER
sulfamidate structure. To this end, sulfamidate (R)-2 was
transformed into the benzyl derivative (R)-1’ (99% yield;
Scheme 3) by treatment with benzyl bromide in diethyl
Scheme 2. Mechanism of the generation of (S)-5 from DMF.
Table 2. Reactivity of cyclic sulfamidate (R)-1 with polar solvents.
Scheme 3. Synthesis of (R)-3’ and quaternary chiral 1,2-diamine (S)-4’
(Bn=benzyl).
Entry
Solvent
T
[8C]
t
(S)-5
[h]
[%][a]
1
2
3
4
5
6
DMF[b]
RT
70
70
70
RT
RT
48
6
6
6
30
48
36
96
97
95
98
–
DMF[b]
ether at room temperature for 24 h by using Cs2CO3 as a
base. When benzyl derivative (R)-1’ was treated with propyl-
amine in DMF at reflux for 30 min, the corresponding ring-
opened product (S)-4’, a chiral quaternary 1,2-diamine, was
obtained in 84% yield. Interestingly, when compound (R)-1’
was treated with propylamine in the absence of DMF, only
ester–amide exchange was observed, furnishing compound
(R)-3’ in excellent yield (Scheme 3).
anhyd. DMF[c]
DMF/H2O[d]
DMSO
CH3CN
[a] Yield after column chromatography. [b] The reaction was carried out
in air. [c] The reaction was carried out under an inert atmosphere with
anhydrous DMF (<0.005% water, Aldrich 227056-100 mL). [d] The reac-
tion was carried out in air with using 100 equivalents of H2O.
The reactions of cyclic sulfamidate (R)-1 were extended
to other amines besides propylamine in order to achieve
both N-deprotection of the sulfamidate and conversion of
the methyl ester group to different amides. We carried out
the reactions of (R)-1 with methylamine, allylamine, benzyl-
amine, and isopropylamine under the optimal conditions es-
tablished as described above, that is, by using 4.0 equivalents
of the amine in THF as solvent or by using only the corre-
sponding amine neat (as the solvent), always at room tem-
perature. In all cases, we obtained excellent yields of the
corresponding amide derivatives (R)-6, (R)-7, (R)-8, and
(R)-9, respectively. These results are gathered in Table 3.
The structures of these new carboxamides were confirmed
by X-ray analyses of single crystals obtained by slow evapo-
ration of the solvent (Figure 1). Because of the importance
of sulfamidates of this type as interesting chiral building
blocks, this methodology could be considered as an excellent
means of obtaining carboxamides from a methyl ester
group, especially in cases in which other reactive sites are
present in the molecule.
In addition, we explored the scope of ring-opening reac-
tions of sulfamidate (R)-1 with primary alkylamines. To this
end, we carried out reactions of cyclic sulfamidate (R)-1
with methylamine, allylamine, and benzylamine under the
optimal conditions established for propylamine, which in-
volved the use of DMF at reflux. With methylamine and al-
lylamine, the starting material (R)-1 was consumed, generat-
ing, in both cases, an almost equimolecular mixture of two
products: (R)-2 as a result of carbamate deprotection, and
the tertiary alcohol (S)-5, arising from the behavior of DMF
as an O-nucleophile (Table 3, entries 6 and 7). The use of
water does not participate as a nucleophile in the ring-open-
ing reaction, we carried out the reaction under the same
conditions as those in Table 2 entry 2 but by using an-
ACHTUNGTRENNUNGhydrous DMF and an inert atmosphere. The results (yield
and optical rotation) matched those obtained previously
(Table 2, entry 3). Moreover, no effects were observed when
the reaction was carried out by using a mixture of DMF/
water (Table 2, entry 4). When we carried out the same re-
action for 30 h at room temperature in DMSO as an alterna-
tive polar aprotic solvent, compound (S)-5 was obtained in
excellent yield (Table 2, entry 5). In all cases, an additional
hydrolysis step was needed to cleave the sulfamate group.
For this, as in other nucleophilic ring-opening reactions of
sulfamidates, an equimolecular mixture of 20% aqueous
H2SO4 and dichloromethane was used. When we attempted
the same reaction with acetonitrile as solvent and without
propylamine, the starting material (R)-1 was recovered
(Table 2, entry 6). This chemistry is important because, to
the best of our knowledge, this is the first report of DMF
and DMSO serving as O-nucleophiles, leading, in a clean
and straightforward way, to the incorporation of an oxygen
atom at a quaternary carbon of an electrophile system with
inversion of configuration. This fact could also be the most
logical justification for the observed decrease in yield in this
type of reaction when DMF was used as solvent.[9b]
Considering that it was not possible to use polar solvents
of this type to carry out the ring-opening reaction of sulf-
ACHTUNGTRENNUNG
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6833

J. H. Busto, J. M. Peregrina et al.
Table 3. Reactivity of cyclic sulfamidate (R)-1 with amines.
only 15 min at 508C, a good yield of compound
(S)-10, derived from nucleophilic ring opening of
the cyclic sulfamidate (Table 4, entry 1). We were
also able to isolate from this reaction a white solid
that corresponded to the subproduct of aminolysis
of the sulfamic moiety, which was analyzed by
HRMS (see the Supporting Information). In order
to reduce the number of equivalents of aniline, we
carried out the reaction by using DMF as solvent.
The use of 2.0 equivalents of aniline in DMF at
508C gave, after 18 h of reaction, compound (S)-10
in 90% yield (Table 4, entry 2). When the same re-
action was carried out with only 1.0 equivalent of
aniline, compound (S)-10 was again obtained, but
in only 45% yield along with a 32% yield of terti-
ary alcohol (S)-5 (Table 4, entry 3). At least one
equivalent of aniline was needed to open the cyclic
sulfamidate and a further equivalent for aminolysis
of the sulfamic moiety. To extend this reactivity to
other primary arylamines, we selected the optimal
conditions and examined the reactions with para-
bromoaniline and para-(methylthio)aniline, obtain-
Entry Amine
[equiv]
R
Solvent
THF
T
t
Products
ACHTUNGTRENNUNG
[h] ([%])[a]
1
2
3
4
5
6
methylamine (4.0)
allylamine (neat)
benzylamine (4.0)
isopropylamine (neat) iPr
isopropylamine (4.0)
methylamine (2.0)
Me
RT
RT
RT
24
4
18
6
(R)-6 (94)
Allyl allylamine
Bn THF
(R)-7 (96)
(R)-8 (82)
(R)-9 (97)
(R)-9 (77)
isopropylamine RT
THF
DMF
iPr
Me
RT
72
reflux 0.5 (R)-2 (47)
(S)-5 (51)
reflux 0.5 (R)-2 (41)
(S)-5 (48)
reflux 0.5 (R)-2 (23)
(S)-5 (31)
7
8
allylamine (2.0)
Allyl DMF
Bn DMF
benzylamine (2.0)
(S)-8’ (37)
[a] Yield after column chromatography.
ing excellent yields of compounds (S)-11 and (S)-12, respec-
tively (Table 4, entries 4 and 5).
To study the steric and electronic effects of the substitu-
ents on the aniline derivatives, we initially tested the elec-
tron-withdrawing substituent -CO2Me at the para- and meta-
positions of aniline, by using DMF as solvent at 508C. In
both cases, the starting material was not consumed and we
only observed small quantities of the ring-opened product
(S)-5, arising from the action of DMF as an O-nucleophile.
We then proceeded to explore the presence of the electron-
withdrawing substituent -OMe at the para-, ortho-, and
meta-positions of aniline, under the same conditions. Fortu-
nately, the reaction worked very well in the case of para-ani-
sidine, furnishing compound (S)-12a in good yield (Table 4,
entry 6). In the other two cases, decreased yields of the ring-
opened products (S)-12b and (S)-12c were observed, partic-
ularly when ortho-anisidine was used as the nucleophile
(Table 4, entries 7 and 8). Moreover, in these two
cases, the formation of compound (S)-5 was again
observed.
Figure 1. ORTEP structures of cyclic sulfamidates (R)-6, (R)-7, and (R)-
9. Ellipsoids are drawn at the 50% probability level.
benzylamine afforded a mixture of three products, (R)-2 in
23% yield, (S)-5 in 31% yield, and the new ring-opened
product (S)-8’ in 37% yield (Table 3, entry 8).
Primary arylamines are another important class of amines
that we tested in the reaction with sulfamidate (R)-1. The
use of aniline as both solvent and nucleophile gave, after
Table 4. Reactivity of cyclic sulfamidate (R)-1 with primary arylamines.
The next step was to explore the reactivity of
sulfamidate (R)-1 with secondary and tertiary al-
kylamines. In the case of diethylamine, which also
served as the solvent, N-deprotection was observed
at room temperature, furnishing compound (R)-2
in 60% yield after 24 h (Scheme 4). When triethyl-
amine was used under the same conditions, no re-
action occurred, but when the temperature was in-
creased to 898C (reflux) for 2 h, compound (R)-2
was obtained in an almost equimolecular ratio
with a known compound (13) arising from a b-
elimination reaction[10a] (Scheme 4).
Entry Arylamine
[equiv]
R
Solvent
t
Products
[%][a]
N
[h]
1
2
3
4
5
6
7
8
aniline (neat)
aniline (2.0)
aniline (1.0)
para-bromoaniline (2.0)
Ph
Ph
Ph
p-BrC6H4-
aniline 0.25 (S)-10 (89)
DMF
DMF
DMF
DMF
18
24
18
18
18
18
18
(S)-10 (90)
(S)-10 (45)[b]
(S)-11 (83)
para-(methylthio)aniline (2.0) p-MeSC6H4
(S)-12 (72)
para-anisidine (2.0)
meta-anisidine (2.0)
ortho-anisidine (2.0)
p-MeOC6H4 DMF
m-MeOC6H4 DMF
o-MeOC6H4 DMF
(S)-12a (85)
(S)-12b (57)[b]
(S)-12c (16)[b]
To conclude this study of reactivity, we exam-
ined the reaction of sulfamidate (R)-1 with a rep-
resentative of the most important class of com-
[a] Yield after column chromatography. [b] Ring-opened products (S)-10, (S)-12b, and
(S)-12c were obtained along with 32, 15, and 21% yields of (S)-5, respectively.
6834
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Versatile Reactivity of a 1,2-Cyclic Sulfamidate with Amines
FULL PAPER
One of the most attractive features of this class of 1,2-
cyclic sulfamidates is their use as a synthetic tool allowing
easy access to new acyclic chiral quaternary b2,2-amino
acids.[10] In the present study, the products obtained bear an
additional amino substituent at the a-position, and so they
can be regarded not only as important b2,2-amino acids,[16]
but also as a,b-diamino acids. a,b-Diamino acids and their
derivatives have attracted a great deal of attention due to
their ubiquitous nature as key structural fragments of bio-
logically active compounds. An excellent review has recently
been published,[17] dealing with their biological significance,
therapeutic uses, and synthetic approaches for obtaining
them. Their syntheses can be divided into two principal
Scheme 4. Reactions of sulfamidate (R)-1 with secondary and tertiary
amines.
À
pounds that bear an amino group, namely a-amino acid de-
rivatives. Specifically, we examined the reaction with phenyl-
alanine methyl ester[14] under different conditions (solvent,
temperature, and number of equivalents). The best yield
(78%) of the ring-opened product (S,S)-14 was obtained
after heating at reflux for 12 h with 3.0 equivalents of the a-
amino ester in acetonitrile (Scheme 5). It is noteworthy that
groups, those involving C C bond formation and those in-
À
volving C N bond formation. The methodology proposed
herein, based on the ring-opening of cyclic sulfamidates with
amines, belongs to the second group.
On the other hand, N-aryl a-amino acids have been syn-
thesized by various methodologies, such as nucleophilic ring
opening of aziridines,[18] N-arylation by using palladium or
copper catalysts,[19] and Michael additions of aniline deriva-
tives to acrylates.[20] In view of the fact that both N-aryl a-
amino acids and a,b-diamino acids have attracted considera-
ble attention, we selected the reaction of sulfamidate (R)-1
with aniline in order to synthesize a new amino acid with an
arylated a-amino group. Initially, we carried out the same
reaction but starting from the enantiomer of sulfamidate
(R)-1, compound (S)-1 (Scheme 6), and obtained a similar
Scheme 5. Reaction of sulfamidate (R)-1 with phenylalanine methyl
ester.
in this case the use of DMF as a polar solvent was not neces-
sary. As in the reactions with arylamines, we were able to
isolate a new white solid compound, which was character-
ized by HRMS as a phenylalanine sulfamate derivative,
formed by aminolysis of the sulfamic moiety.
Scheme 6. Reaction of sulfamidate (S)-1 with aniline.
In conclusion, sulfamidate (R)-1 reacts differently with
different types of amines. Arylamines and a-amino acid de-
rivatives, and even propylamine under certain conditions,
give a ring-opening reaction with inversion of configuration
at the tertiary carbon (quaternary stereocenter), and a
second step for hydrolysis of the sulfamic moiety is not re-
quired. In general, primary alkylamines give rise to two con-
comitant reactions: N-deprotection and ester–amide conver-
sion. Secondary alkylamines give only N-deprotection of the
cyclic sulfamidate. The use of tertiary alkylamines produces
a mixture of N-deprotection and b-elimination products. In
an attempt to rationalize the experimental observations, we
compared the reactivities of the amines with their basici-
ties.[15] Thus, less basic amines (arylamines and amino esters
have pKaH values of 3.89 to 7.11) behave as excellent nucle-
ophiles in the ring-opening reaction of the cyclic sulfami-
date, whereas more basic amines (alkylamines have pKaH
values of 9.33 to 10.84) are disfavored for this reaction, pro-
moting instead N-deprotection or even the concomitant con-
version of ester to amide, depending on steric hindrance.
result to that in Table 4, entry 2. The next step was to deter-
mine the enantiomeric excess of the ring-opened products
(S)-10 and (R)-10 by chiral HPLC (see the Supporting Infor-
mation). From these data, we concluded that the enantio-
meric excess of the starting sulfamidate (which we previous-
ly established as 93%ee)[10b] was maintained in the ring-
opening reactions, and that there was no racemization.
Selective deprotection of the carbamate group in the ring-
opened product (S)-10 by using iodotrimethylsilane
(TMSI)[21] under an inert atmosphere gave diamino ester
(S)-15 (Scheme 7).. Subsequent acid hydrolysis of (S)-15
with aqueous 2n HCl at 508C for 24 h gave the a,b-diamino
acid (S)-16 as a hydrochloride derivative (Scheme 7).
In looking for synthetic applications of the ring-opening
reaction of sulfamidate (R)-1 with a-amino esters, we fo-
cused our attention on the piperazinone substructure be-
cause it is a constituent of various natural products extract-
ed from marine sponges, such as the phakellins group,
(À)-agelastine A, and pseudoteonamides A1 and A2.[22]
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J. H. Busto, J. M. Peregrina et al.
with TMSI[21] to afford compound (S,S)-17 as a hydroiodide
derivative. The subsequent lactamization, accomplished by
the action of aqueous 2n HCl solution at 508C for 12 h, fol-
lowed by neutralization with saturated aqueous NaHCO3,
afforded the required piperazinone derivative (S,S)-18 in
good yield (Scheme 8). This piperazinone can be regarded
as a “chimera” of the a-amino acids phenylalanine and ala-
nine. In particular, the phenylalanine substructure shows a
huge conformational restriction, with phi and psi dihedral
angles typical of folded conformations. In contrast, the ala-
nine substructure shows only a restriction in the phi dihedral
angle. Moreover, it is important to note that compound
(S,S)-18 incorporates the substructure of the above-cited
PCA amino acid (Scheme 8).
Compound (S,S)-18 was also used to corroborate the con-
figuration at the stereocenter created in the nucleophilic
attack. Thus, in 2D NOESY experiments, observation of a
clear NOE signal between Ha of the phenylalanine substruc-
ture and the methyl group attached to the quaternary
stereocenter allowed us to conclude that the quaternary
center had an (S)-configuration, indicating that the nucleo-
philic attack of this amine had proceeded with total inver-
sion of configuration (Figure 2).
Scheme 7. Synthesis of b2,2-amino acid (S)-16.
Moreover, the piperazinone ring is also found in compounds
of great interest to the pharmaceutical industry; for instance,
in the family of renieramycins,[23] which show antitumor ac-
tivity, and in some antihelmintic derivatives (marcfortine B
and praziquantel).[24] The piperazinone substructure has also
been incorporated into new peptidomimetics, with a view to
generating structural modifications in the backbone due to
the limited conformational flexibility of this cycle. In fact,
the amino acid 5-oxopiperazine-2-carboxylic acid (abbreviat-
ed as PCA) is able to induce different turns when it is incor-
porated into tetrapeptides.[25] In general, the piperazinone
substructure is obtained by cyclization reactions generating
the C N bond,[26] although other syntheses involving
À
tandem reactions have been reported.[27] To synthesize N,N-
disubstituted piperazinones, Gallagher and co-workers used
a strategy that involved nucleophilic ring-opening reactions
of cyclic sulfamidates with N-tosyl-a-amino esters in the
presence of a base (NaH or Cs2CO3), followed by lactamiza-
tion in an acid medium.[28] It is important to note that al-
though this is the most closely related example of sulfami-
date ring-opening to the work reported herein, there are
two important differences. First, in the published report, the
nucleophilic agent was not the amino group but the tosyl-
Conclusion
The reactivity of different amines with the 1,2-cyclic sulfami-
date (R)-1 derived from a-methylisoserine, which has previ-
ously provided a flexible and generally efficient entry to a
range of b2,2-amino acids, has been studied. Although this
type of cyclic electrophile incorporates several reactive sites,
we have found conditions that allowed us to control the che-
moselectivity of the reaction. The reactivity of propylamine
is controlled by the solvent: acetonitrile favors N-deprotec-
tion of the sulfamidate, in THF there is also N-deprotection,
but this is accompanied by conversion of the methyl ester
into a carboxamide, and DMF favors nucleophilic attack of
propylamine (also observed with benzylamine) at the qua-
ternary center of the sulfamidate with inversion of configu-
ration, avoiding the use of a second step for sulfamic moiety
hydrolysis. The chemoselectivity of the reaction is also con-
trolled by the type of amine used. The use of arylamines
and a-amino acid derivatives also led to ring opening of the
sulfamidate with inversion of configuration, whereas, in gen-
eral, primary alkylamines led to two concomitant reactions,
N-deprotection and ester–amide conversion. Secondary al-
kylamines led to exclusive N-deprotection of the cyclic
sulfamidate in a clean and simple manner. Additionally, we
have found that DMF and DMSO behave not only as polar
solvents, but also as nucleophilic reagents, allowing the in-
corporation of an oxygen atom in the electrophile.
ACHTUNGTRENNUNG
amide derivative (TsNÀ), a much more efficient nucleophile,
which attacked an achiral secondary carbon atom. Second,
in our case, the attack of the amino group occurs on a hin-
dered system, a chiral quaternary center (tertiary carbon
atom), with inversion of configuration.
Taking into account the importance of the piperazinone
heterocycle, we synthesized compound (S,S)-18, a chiral
3,5,5-trisubstituted piperazinone derivative by starting from
(S,S)-14, which was obtained by nucleophilic ring-opening of
sulfamidate (R)-1 with phenylalanine methyl ester
(Scheme 8). The methylcarbamate group of compound
(S,S)-14 was transformed into an amino group by treatment
As a synthetic application of this reactivity study, and
taking into account the biological significance of a,b-diami-
no acids, we have developed the synthesis of a new type of
chiral a,b-diamino acid with an arylated a-amino group.
Since this sulfamidate readily undergoes a nucleophilic dis-
Scheme 8. Synthesis of a chiral 3,5,5-trisubstituted piperazinone.
6836
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Chem. Eur. J. 2013, 19, 6831 – 6839

Versatile Reactivity of a 1,2-Cyclic Sulfamidate with Amines
FULL PAPER
Figure 2. NOE NMR study of compound (S,S)-18.
quired by using z-filter and selection before t1 removing the decoupling
during acquisition by use of the invigpndph pulse program with CNST2
(JHC)=145. Phase-sensitive ge-2D NOESY experiments were per-
formed. NOE intensities were normalized with respect to the diagonal
peak at zero mixing time.
X-ray diffraction analysis:[29] A summary of crystal data for (R)-6, (R)-7,
and (R)-9 is presented in the Supporting Information. The SHELXL97
program[30] was used for the refinement of crystal structures and hydro-
gen atoms were fitted at theoretical positions.
placement by a-amino esters, application of this chemistry
provided an example of an important class of chiral N-
ACHTUNGTRENNUNGheterocycles based on the piperazinone ring, which can be
regarded as a restricted scaffold that is suitably predisposed
for use in peptide chemistry.
(R)-5-Methyl-2,2-dioxo-2l6-[1,2,3]-oxathiazolidine-5-carboxylic
acid
Experimental Section
methyl ester ((R)-2): Propylamine (73 mg, 1.24 mmol) was added to a
solution of sulfamidate (R)-1 (87 mg, 0.31 mmol) in acetonitrile (10 mL)
and the mixture was stirred at reflux for 1 h. The solvent was evaporated
and the residue was purified by column chromatography on silica gel,
eluting with hexanes/ethyl acetate (7:3), to give compound (R)-2 (36 mg,
60%) as a colorless oil. The physical properties of the product were
found to be identical to those reported previously.[8f] Elemental analysis
calcd (%) for C5H9NO5S: C 30.77, H 4.65, N 7.18, S 16.43; found: C
30.89, H 4.63, N 7.16, S 16.45; [a]2D0 (c=1.30 in CHCl3): À24.4; MS
(ESI+): m/z: 196.2; 1H NMR (400 MHz, CDCl3): d=1.75 (s, 3H; CH3),
3.44–3.58 (m, 1H; CH2N), 3.87 (s, 3H; CO2CH3), 3.94–4.09 (m, 1H;
CH2N), 4.91 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3): d=22.5
(CH3), 52.1 (CH2N), 53.7 (CO2CH3), 88.0 (CCH3), 169.8 ppm (CO2).
General procedures: Solvents were purified according to standard proce-
dures. Column chromatography was performed by using silica gel 60
(230–400 mesh). 1H and 13C NMR spectra were recorded on a Bruker
400 MHz spectrometer by using CDCl3, CD3OD, or D2O as solvents
(chemical shifts are reported in ppm on the d scale, coupling constants in
Hz). All resolved signals in the 1H NMR spectra were assigned on the
basis of coupling constants and ge-COSY and ge-HSQC experiments per-
formed on the 400 MHz spectrometer. The results of these experiments
were processed with MestReC and MestreNova software (Mestrelab Re-
search, Spain). Melting points were determined on a Bꢃchi melting-point
apparatus and are uncorrected. Optical rotations were measured on a
Perkin–Elmer polarimeter from solutions in 1.0 dm cells of capacity 1.0
or 0.3 mL. Electrospray mass spectra were recorded on a micrOTOF-Q
Bruker spectrometer; accurate mass measurements were achieved by
using sodium formate as an external reference. Full experimental details
and physical data for all new compounds are provided in the Supporting
Information.
General procedure for the synthesis of carboxamides from sulfamidate
(R)-1: Sulfamidate (R)-1 and the requisite amine were dissolved in THF
(or the amine was used as the solvent). The reaction mixture was stirred
at room temperature for the time indicated in Table 3. After evaporation
of the solvent, the residue was purified by column chromatography on
silica gel eluting with hexanes/ethyl acetate (3:7).
NMR experiments: NMR experiments were performed on a Bruker
Avance 400 spectrometer at 298 K. Magnitude-mode ge-2D COSY spec-
tra were acquired with gradients by using the cosygpqf pulse program
with a pulse width of 908. Phase-sensitive ge-2D HSQC spectra were ac-
Chem. Eur. J. 2013, 19, 6831 – 6839
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6837

J. H. Busto, J. M. Peregrina et al.
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Acknowledgements
We are grateful to the Ministerio de Economꢀa y Competitividad (proj-
ects CTQ2009–13814 and CTQ2012–36365), the Universidad de La Rioja
(project EGI11/62), the Gobierno de La Rioja (COLABORA 2010/05),
and the CSIC (predoctoral fellowship to L.M.).
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Versatile Reactivity of a 1,2-Cyclic Sulfamidate with Amines
FULL PAPER
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Received: December 10, 2012
Revised: February 19, 2013
Published online: April 10, 2013
Chem. Eur. J. 2013, 19, 6831 – 6839
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6839