A novel multistep mechanism for the stereocontrolled ring opening of hindered sulfamidates: Mild, green, and efficient reactivity with alcohols

Article abstract of DOI:10.1002/chem.200900710

Cyclic hindered sulfamidates exhibited an outstanding performance in their ring-opening reactions with alcohols and in the absence of any external activator. The mechanism of this unprecedented transformation was thoroughly studied both experimentally and

Full text of DOI:10.1002/chem.200900710

DOI: 10.1002/chem.200900710
A Novel Multistep Mechanism for the Stereocontrolled Ring Opening of
Hindered Sulfamidates: Mild, Green, and Efficient Reactivity with Alcohols
Gonzalo Jimꢀnez-Osꢀs, Alberto Avenoza,* Jesffls H. Busto, Fernando Rodríguez, and
Jesffls M. Peregrina*[a]
Abstract: Cyclic hindered sulfamidates
exhibited an outstanding performance
in their ring-opening reactions with al-
cohols and in the absence of any exter-
nal activator. The mechanism of this
unprecedented transformation was
thoroughly studied both experimentally
and theoretically. As a result, a nontri-
vial stepwise pathway involving sol-
vent-induced conversion of the sulfami-
dates to activated aziridinium and then
to oxazolinium cations, which are final-
ly opened at their 5-position with inver-
sion of configuration, is proposed. The
presence of the SO3 moiety in the sul-
famidate was revealed as a “built-in ac-
tivator”. In fact, the spontaneous SO3
cleavage takes place under the reaction
conditions and avoids the subsequent
step of hydrolysis after the ring open-
ing of the sulfamidates. This is another
important improvement of this meth-
odology with respect to the standard
basic conditions, allowing greater
a
compatibility with other functional
groups. Furthermore, the carbamate
group plays a key role in this mecha-
nism. Briefly, a highly chemoselective
and stereoespecific formal solvolysis of
hindered sulfamidates with alcohols
without further activation is described.
This reaction takes place exclusively at
the quaternary center with inversion of
configuration, providing a new straight-
forward synthetic route to O-substitut-
ed a-methylisoserines.
Keywords: alcohols · neighboring-
group effects · nucleophilic substitu-
tion · reaction mechanisms · sulfa-
midates
Introduction
tivity in ring-opening reactions with nucleophiles. Moreover,
the chemical properties of these heterocycles are tightly
connected since the epoxides/sulfates and aziridines/sulfami-
dates interconversions have previously been described[4]
(Scheme 1).
Although the reactivity of epoxides, aziridines, sulfates,
and sulfamidates towards sulfur, halogen, nitrogen, and
carbon nucleophiles has been widely studied, procedures for
Epoxides and aziridines are valuable intermediates in organ-
ic synthesis because they can undergo a great number of
transformations.[1] Nucleophilic ring-opening reactions of
these systems are especially important for the synthesis of
many biologically interesting compounds,[1] such as amino
acids, heterocycles, and alkaloids. As a result, several meth-
ods have been reported for the regioselective ring opening
of epoxides and aziridines with various nucleophiles.[2] On
the other hand, the importance of five-membered cyclic sul-
fates and sulfamidates in organic synthesis has profusely
been described in the literature.[3] These systems compete
with epoxides and aziridines in terms of reactivity and selec-
[a] Dr. G. Jimꢀnez-Osꢀs, Dr. A. Avenoza, Dr. J. H. Busto,
Dr. F. Rodrꢁguez, Dr. J. M. Peregrina
Departamento de Quꢁmica, Universidad de La Rioja
Grupo de Sꢁntesis Quꢁmica de La Rioja.
UA-CSIC 26006 LogroÇo (Spain)
Fax : (+34)941-299-621
E-mail: alberto.avenoza@unirioja.es
jesusmanuel.peregrina@unirioja.es
Scheme 1. Interconversions of epoxides–sulfates and aziridines–sulfami-
dates. The reactive positions of each substrate (apart from sulfur atom)
are shown with arrows.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900710.
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Chem. Eur. J. 2009, 15, 9810 – 9823

FULL PAPER
their opening with oxygenated nucleophiles (O nucleo-
philes) are scarce.[1g,2] This is mainly caused by the basic
character of these reagents in their anionic form (alkoxides,
phenoxides, carboxylates, etc.), which very often leads to
competitive reactions (i.e., eliminations). In addition, O nu-
cleophiles, such as alkoxides, are very hard and, as a conse-
quence, incompatible with a broad range of functional
groups (i.e., carbonyl compounds). As an alternative to the
basic conditions, ring-opening reactions with O nucleophiles
(i.e., alcohols or water) are frequently carried out in the
presence of activating Lewis/Brønsted acids,[5] which in
some cases interfere with other basic groups in the substrate.
However, recently the ring opening of epoxides or aziridines
under milder conditions (catalyst-free) with various nucleo-
philes has received particular attention.[6]
The reaction conditions (basic or acidic) play a key role in
the regio- and stereochemical outcome of the ring-opening
reaction, which allows for the direction of the nucleophilic
attack to any of the different reactive positions of the heter-
ocyclic substrates.[1g] As an example, and in connection with
the results discussed later in this work, the nucleophilic ring
opening of a 2-substituted aziridine-2-carboxylic acid deriva-
tives has been carried out regioselectively at both the secon-
dary and the quaternary carbon atoms depending on the in-
coming nucleophile and the reaction conditions.[7] However,
the use of alcohols as O nucleophiles in a neutral medium
(without acidic or basic additives) has not yet been explored
in these reactions. To the best of our knowledge, only one
example has been reported, which describes the regioselec-
tive ring opening in methanol of two aziridines activated by
a strong electron-withdrawing group, such as the N-(p-tolue-
nesulfonyl)-p-toluenesulfonimidoyl group.[8] However, no
discussion on the regioselectivity and the stereochemical
course of the reaction with these two substrates was done.
Given the importance of chiral compounds with quaterna-
ry carbon stereocenters[9] in the field of b-amino acids,[10]
particularly of chiral a,a-disubstituted b-amino acids
(namely b2,2-amino acids[11]), we have focused our attention
on the synthesis of isoserine derivatives[12] due to their impli-
cations as peptidomimetic units.[13] In this sense, and follow-
ing our previously published protocol,[14] one attractive
access to these b2,2-amino acids with the isoserine skeleton
involves the ring-opening reaction of hindered sulfamidates
(R)-1a,b with O nucleophiles (Scheme 2).
therefore, the SN2 reactivity with several nucleophiles in a
basic medium was explored and further hydrolysis of ring-
opening products allowed us to obtain interesting chiral
compounds.[15] In this context, although chemoselectivity
problems (elimination vs. substitution) with these substrates
are well-known, we have recently published a highly chemo-
selective ring-opening reaction of sulfamidates (R)-1a,b
with O nucleophiles in a basic medium.[16] Nevertheless, this
method is limited to O-aryl or O-acyl-substituted a-methyli-
soserines (Scheme 2) and the use of alcohols as nucleophiles
in acid or neutral media has not yet been explored in hin-
dered sulfamidates. To the best of our knowledge, there is
only one precedent in the literature dealing with the ring
opening of a prolinol-derived sulfamidate with methanol as
a solvent in the presence of one drop of trifluoroacetic
acid.[17] Our previous results, together with the lack of ante-
cedents on the ring opening of three- and five-membered
cyclic systems with O nucleophiles in neutral media, encour-
aged us to undertake a study on the behavior of hindered
sulfamidates (R)-1a,b towards alcohols.
Results and Discussion
Reactivity of hindered sulfamidates: Firstly, and with the
aim of fully inspecting the reactivity of these substrates, we
started our study with the evaluation of alcohol-compatible
Lewis acids. With this is mind, sulfamidates (R)-1a,b[14] were
treated with stoichiometric amounts of several Lewis acids
in methanol (Scheme 3). With Sm
(TfO)3 only deprotection of the carbamate group was ob-
served, giving compounds (R)-2a,b, whereas reaction with
Sc(TfO)3 and In(TfO)3 did not progress and all of the start-
ACHUTGTNERN(NGU TfO)3, HoCAHTUNGTERN(NGUN TfO)3, or Yb-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ing material was recovered. These results are similar to
those previously reported with MeONa as the nucleo-
phile.[16] As will be discussed later on, the carbamate cleav-
age under these conditions has a decisive influence on the
observed reactivity. Therefore, this strategy was abandoned
because the desired ring-opening reaction was not observed
at any extent.
Scheme 3. Reaction of sulfamidates (R)-1a,b with MeOH by using vari-
ous Lewis acids. a) MeOH, 688C, 2 h (94–99%).
Scheme 2. Retrosynthesis of isoserine derived b2,2-amino acids.
In the next stage of our study, we tested the reaction of
(R)-1a with methanol as a solvent in the presence of varia-
ble amounts of different Brønsted acids such as p-toluene-
sulfonic acid (pTsOH), Dowex 50W-X8, and triflic acid
(TfOH). In all cases, the reactions quantitatively gave, as de-
The quaternary carbon atom of these chiral building
blocks (R)-1a,b is activated for nucleophilic displacement;
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9811

J. M. Peregrina et al.
sired and in “one-pot”, the product (S)-3b, arising from the
amide–ester exchange, the subsequent ring opening with in-
version of the configuration, and further sulfamic acid sol-
volysis reactions (Scheme 4). The amide–ester exchange to
give (R)-1b occurs before the ring-opening reaction of this
sulfamidate. This fact was demonstrated by carrying out the
same reaction with (R)-1a at a lower temperature (408C),
which only gave (R)-1b in good yield (Scheme 4).
Scheme 5. Determination of the absolute configuration of (S)-3b. a) HCl
9m, reflux, 12 h (100%); b) i) AcCl, MeOH, reflux, 10 h; ii) iPr2EtN,
CH2Cl2, 258C, 14 h; iii) column chromatography (61% of (S,S)-6, 32% of
(S,S)-7); c) and d) the same conditions as b) (91% of (S,S)-7, 87% of
(S,R)-7).
Scheme 4. Sequential and one-pot ring-opening reactions of sulfamidate
(R)-1a (optimized conditions). a) MeOH, TfOH (1.5 equiv), 408C, 24 h
(98%); b) MeOH, TfOH (1.5 equiv), 688C, 48 h (98%).
The optical purity of O-methyl-a-methylisoserine deriva-
tive (S)-3b was determined by GC analysis (>93% ee), a
result that is equal to that measured for the starting materi-
al, sulfamidate (R)-1a, by the same methodology[14] (see the
Supporting Information). To demonstrate that the nucleo-
philic attack of methanol proceeded with inversion of con-
figuration at the quaternary sterogenic center of the sulfami-
date, we carried out the hydrolysis of compound (S)-3b with
an aqueous solution of 9m HCl at reflux to give a mixture
of compounds (S)-4 and (S)-5 (Scheme 5). Due to the im-
possibility of separating this mixture of b2,2-amino acids,
they were derivatized to the corresponding peptides (S,S)-6
and (S,S)-7 by reaction with (S)-N-(p-tosyl)phenylalaninyl
chloride, with previous esterification. Once both compounds
were separated by column chromatography, the spectroscop-
ic data and optical activity of dipeptide (S,S)-7 were com-
pared to those measured for the diastereomers (S,S)-7 and
(S,R)-7, prepared separately from each enantiomer of a-
methylisoserine (S)-5 and (R)-5, which were synthesized by
other published methodologies.[12c,14,16] This comparison al-
lowed us to confirm the absolute configuration of (S)-3b
(Scheme 5 and Supporting Information) and verify the high
configurational stability of a-methylisoserine derivatives in
strongly acidic aqueous media.
To expand the scope of these reactions, several alcohols
were assayed, firstly under controlled-temperature condi-
tions and then at higher temperatures. Therefore, a pool of
the corresponding amide–ester exchange products (R)-1c–k
were obtained in good yields (Table 1, entries conditions A).
Both, the linear and branched primary alcohols gave good
yields. In the case of a secondary alcohol, prolonged heating
at 808C was necessary (Table 1, entry 17). The structure of
(R)-1c was confirmed by X-ray analysis and the ORTEP
structure is shown in Figure 1. To expand this methodology
to other high boiling point alcohols, we optimized the
amide–ester exchange reaction of (R)-1a by using toluene
Figure 1. X-ray structure of sulfamidate (R)-1c.
as the solvent and only three equivalents of alcohol in the
presence of more practical pTsOH. For example, a good
yield of (R)-1k was obtained in the case of benzylic alcohol
(Table 1, entry 19).
Once the ester sulfamidates (R)-1b–k were prepared, and
to avoid possible transesterification products, we initially as-
sayed the ring-opening reaction on these substrates with the
same alcohol that was used to get the amide–ester exchange.
Surprisingly, we found that this reaction could be accom-
plished simply by heating each substrate in the correspond-
ing alcohol at 68–808C (the reaction progresses smoothly
above 458C) in the absence of acid additives (conditions B
in Table 1); this cleanly gave the corresponding ring-opening
products (S)-3b–j with both linear and branched alcohols in
excellent yields. It must be noted that even a secondary al-
cohol (isopropanol, Table 1, entry 18) reacted after pro-
longed heating at 808C (5 days) to give the corresponding
ring-opening product in a good yield (65%) and without
secondary reactions. Moreover, this methodology also al-
lowed us to carry out the reactions with alcohols sensitive to
acid medium, such as the allylic alcohol (Table 1, entry 12).
The enantiomeric purity values of these ring-opening prod-
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Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
Table 1. Reactions of (R)-1a,b and (R)-1b–j in acidic or neutral conditions.
transesterification, ring open-
ing, both processes simultane-
ously, or carbamate deprotec-
tion.
It is important to note that,
to the best of our knowledge,
this is the first time that a ring-
opening reaction of sulfami-
dates has been reported with al-
cohols as nucleophiles in neu-
tral and mild conditions. There-
fore, this methodology is syn-
thetically useful and highly en-
vironmentally friendly, given
that a full atom economy is
achieved and no extra disposals
apart from the alcoholic solvent
are generated in the reaction.
Once the synthetic scope of
the ring-opening reaction was
explored, we were intrigued by
the high enantioselectivity ach-
ieved in the process, which was
confirmed to take place with in-
version of the configuration of
the quaternary carbon atom.
Alcohols have been traditional-
ly considered as poor nucleo-
philes, especially when reacting
Entry
Substrate
Alcohol
R
Conditions[a]
Products
Yield [%][b]
1
2
3
4
5
6
7
8
(R)-1a
(R)-1b
(R)-1a
(R)-1c
(R)-1a
(R)-1d
(R)-1a
(R)-1e
(R)-1a
(R)-1 f
(R)-1a
(R)-1g
(R)-1a
(R)-1h
(R)-1a
(R)-1i
(R)-1a
(R)-1j
(R)-1a
methanol
methanol
ethanol
ethanol
propanol
propanol
butanol
butanol
pentanol
Me
Me
Et
Et
Pr
Pr
Bu
Bu
Bu
Bu
allyl
allyl
iBu
iBu
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
(R)-1b
(S)-3b
(R)-1c
(S)-3c
(R)-1d
(S)-3d
(R)-1e
(S)-3e
(R)-1 f
(S)-3 f
(R)-1g
(S)-3g
(R)-1h
(S)-3h
(R)-1i
(S)-3i
98
93
94
94
93
91
89
93
90
88
86
84
91
90
93
92
79[c]
65[d]
89
9
G
10
11
12
13
14
15
16
17
18
19
pentanol
ACHTUNGTRENNUNG
allylic alcohol
allylic alcohol
isobutanol
isobutanol
isopentanol
isopentanol
isopropanol
isopropanol
benzylic alcohol
iBu
iBu
iPr
iPr
Bn
N
AHCTUNGTRENNUNG
A
B
A*
(R)-1j
(S)-3j
(R)-1k
[a] Conditions: A) alcohol, TfOH (1.5 equiv), 408C, 24 h; B) alcohol, 68–808C, 48 h; A*) alcohol (3.0 equiv),
pTsOH·H2O (1.5 equiv), toluene, reflux, 24 h. [b] Yield determined after column chromatography. [c] To carry
out the amide–ester exchange it was necessary to heat at 808C for 48 h. [d] To carry out the ring-opening reac-
tion it was necessary to heat at 808C for 120 h.
ucts were the same as those obtained for (S)-3b (ee>93%)
even in the most problematic cases with less nucleophilic,
bulkier, or more branched alcohols (see the Supporting In-
formation for a thorough study on enantioselectivity).
The possibility of acid traces present in the alcohols as the
true activators was discarded by carrying out the reaction
with HPLC-grade MeOH distilled over CaH2. Under these
conditions, the same results in terms of yield and enantiose-
lectivity were obtained.
Scheme 6. Chemoselective ring-opening reaction of sulfamidate (R)-1b.
a) nPrOH, 558C, 4 d (82%); b) HCl 6m, 908C, 48 h (95%).
Moreover, and according to our previous results,[14] we
confirmed that the presence of an ester group is required to
accomplish the ring opening of sulfamidate, since the reac-
tion of (R)-1a at reflux in methanol for 48 h did not prog-
ress at all. On the other hand, we carried out the reaction in
different solvents, obtaining good results only with neat al-
cohols.[18]
As an important synthetic advantage, the absence of
acidic promotors allowed us the chemoselective synthesis of
O-substituted a-methylisoserine derivatives bearing differ-
ent groups in ester or ether substituents (i.e., avoiding trans-
esterification). Indeed, the treatment of sulfamidate (R)-1b
with propanol as the solvent at 558C gave a good yield of
compound (S)-8, which could be easily converted into the
corresponding b2,2-amino acid (S)-9 (Scheme 6). Thus, de-
pending on the reaction conditions (presence or absence of
acidic activators), the reactivity of these hindered sulfami-
dates with alcohols can be completely directed towards
towards sterically hindered electrophiles like quaternary
carbon atoms. Therefore, and although the ring opening of
sulfamidates (R)-1a,b has been demonstrated, by both ex-
perimental and theoretical studies, to take place by means
À
of a SN2 process with strong nucleophiles (RSÀ, N3 , CNÀ,
FÀ),[14,15a] such a mechanism is, a priori, highly unfeasible
with alcohols. In turn, terms like “solvolysis” easily come to
mind when looking at the aforementioned reaction condi-
tions. But, how does this solvolysis really take place? Is the
commonly referred formation of ion pairs after heterolytic
cleavage enough to explain the observed enantioselectivity
and the inversion of configuration? To shed some light on
these questions, we performed a thorough study combining
experimental studies and theoretical calculations, which al-
lowed us to confidently propose a mechanism to explain the
enantioselective ring-opening reaction of hindered sulfami-
dates with alcohols.
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J. M. Peregrina et al.
The ring-opening mechanism: Despite of their small size,
a big number of reaction channels starting from sulfamidates
(R)-1a,b can be expected because of their high functionali-
zation. Indeed, methods to carry out many of these reactions
selectively (nucleophilic substitution, elimination, deprotec-
tion, and functional-group interconversions) have been pre-
viously described.[14–16] Moreover, a great dependence on ap-
parently expectant neighboring groups, such as the ester or
amide substituents, on some reactions (i.e., SN2 vs. E2 with
basic nucleophiles) has been observed and studied.[14] Re-
garding the ring-opening reaction of substrates (R)-1a,b
with alcohols described in this work, the presence of both
an ester group and a carbamate group has been observed to
be mandatory for the reaction to take place. Leaving aside
the activating effect of the ester groups towards nucleophilic
substitution at the quaternary position with respect to
amides, which has been exten-
3) After carrying out the ring-opening reaction of sulfami-
date (R)-1b in [D4]MeOH, residual signals in the 13C
spectra (Figure 3b) were tentatively assigned to traces of
[D6]dimethyl sulfate or [D6]dimethylether (multiplet at
d=60 ppm)[19] and the [D3]methoxysulfonate anion (mul-
Scheme 7. Deprotection/protection of hindered sulfamidates under basic
conditions. a) MeOH, 688C, 48 h (81–93% conv.); b) Boc2O, Et3N,
CH2Cl2, 258C, 32 h (76%); c) MeOH, 688C, 48 h (72% conv.).
sively studied for both cyclic
sulfates and sulfamidates in our
previous works,[3h,14] the unex-
pected key role of the carba-
mate in the ring-opening reac-
tion of (R)-1b–k with alcohols
is challenging and points to a
nontrivial mechanism. With this
in mind, some experimental
findings must be taken into ac-
count:
1) The
methyl
carbamate
Figure 2. Reaction of sulfamidate (R)-10 with methanol after 48 h at reflux. The 1H NMR spectrum of the
crude mixture shows the clean cleavage of the carbamate group in the sulfamidate together with a small
amount of the N-protected ring-opening product (the conformational isomerism of the Boc group is revealed
in some duplicated signals).
group is required to achieve
the ring-opening reaction
(i.e., sulfamidate (R)-2b
does not react at all) and it
remains unaltered irrespec-
tive of the alcohol used as the nucleophile.
tiplet at d=55 ppm), which would be in agreement with
the aforementioned generation of acidic species from
SO3 and [D4]MeOH.
2) When the ring-opening reaction was assayed on the tert-
butyloxycarbonyl (Boc)-derived sulfamidate (R)-10,
(Scheme 7 and Figure 2), only a small amount of the
ring-opening product (~20%, not isolated) could be de-
4) Sulfamidate (R)-1b is stable when heated in neat non-
nucleophilic solvents (i.e., toluene, chloroform, and ace-
tonitrile) both in neutral and acidic (stoichiometric
pTsOH) conditions. Therefore, the role of the generated
acid mentioned above is not clear at this point. Con-
versely, the presence of a protic solvent like methanol,
and not an initial activation with an “exogen acid” seems
to be required for the reaction to take place.
1
tected by H NMR spectroscopy at short reaction times
(12 h), with the deprotection product (R)-2b the major
product when the reaction was completed. Bearing in
mind the high lability of the Boc group in acidic media,
this result points to the generation of “acid” to some
extent at the early stages of the reaction. Indeed, a varia-
tion in the pH of the reaction mixture was observed
qualitatively by using an indicator paper from neutral to
slightly acid upon the completion of the reaction. This
acidification could be the result of the reaction of SO3
(released in some way along the reaction pathway) with
methanol to produce methoxysulfonic acid and/or di-
methyl sulfate. Unfortunately, any attempt to inhibit the
ring-opening reaction of sulfamidate (R)-1b in the pres-
ence of variable amounts of base (triethylamine or
sodium bicarbonate) resulted in rapid transformation to
(R)-2b (Scheme 7).
À
+
À
5) Markedly, the sulfamic acid ( NSO3 H ) generated
after the ring opening of sulfamidates, which must be
cleaved before isolating the final products (commonly by
acid hydrolysis or treatment with BF3·Et2O/thiol), ap-
pears to be spontaneously lost without observing any in-
termediate along the whole reaction pathway. This is an
unprecedented finding which, apart from being useful
synthetically, points to a somewhat different mechanism
in which the SO3 moiety is removed very quickly after
(or maybe at the same time) the ring-opening reaction
occurs.
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Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
is a common strategy in organic
synthesis,[22] which has been
studied both experimentally
and theoretically.[23] Finally,
there are many examples in the
literature describing the regio-
selective ring opening of oxazo-
lines with nucleophiles at the 5-
position in acidic media (in
competition with the usual re-
activity at the 2-position).[24]
Therefore, a stepwise mecha-
nism involving the ring contrac-
tion of sulfamidate (R)-1b into
the corresponding aziridine de-
rivative and its subsequent re-
gioselective ring expansion to
an oxazolinium, followed by the
regioselective
nucleophilic
attack at the 5-position with in-
version of the quaternary
carbon atom (Scheme 8), is a
reasonable pathway to be con-
sidered together with the direct
SN2 ring opening of the sulfami-
date. This novel mechanism
could explain the key role of
the neighboring carbamate
group in the stereoselective
ring-opening reaction of hin-
dered sulfamidates with alco-
hols (i.e., by forming an oxazo-
linic intermediate).
Figure 3. Reaction of sulfamidate (R)-1b with CD3OD monitored by NMR spectroscopy. a) The stacked
1H NMR spectra show the clean and direct conversion of (R)-1b into (S)-3b’ and the simultaneous (but faster)
disappearance of the ester signals in both the reactant and the product (CO2Me, d=3.89 and 3.75 ppm, respec-
tively) due to transesterification with CD3OD (with the subsequent evolution of MeOH). As a consequence, a
slight growing of the ether signal (OCH3, d=3.31 ppm) arising from the competitive ring opening with the
The regioselective nucleo-
philic ring opening of the sulfa-
generated MeOH is also appreciated. b) The 13C NMR spectrum shows the presence of small amounts of deu- midate-derived aziridine is an-
terated dimethyl ether and sulfonic derivatives at the end of the reaction.
other possibility that must be
taken into account. With this in
mind, 2-methylaziridine (R)-
12,[25] which was prepared by in-
6) The pseudo-first-order kinetics of the ring-opening reac-
tion of (R)-1b with methanol (measured by GC analysis)
and [D4]MeOH (measured by 1H NMR spectroscopy,
Figure 3a) were studied at different initial concentrations
of substrate and effective (also called “apparent”) kinetic
constants were obtained (see the Supporting Informa-
tion).[20,21]
tramolecular ring closure of bromide (S)-11 in the presence
of tBuOK as a base, was treated with methanol at reflux
under different conditions. Noticeably, and according to pre-
vious results reported for analogue 2-aziridinecarboxylic
acids,[5i] this substrate remained unaltered under neutral con-
ditions, but when an equimolecular amount of pTsOH was
added a full conversion into (S)-3b, as a single regioisomer
with a high enantiomeric purity, was observed (Scheme 9).
It must be noted that, as mentioned in the Introduction, 2-
methylaziridine-2-carboxilic acid derivatives have been
opened regioselectively at both the secondary (mainly with
hard nucleophiles and/or in basic conditions[7a–c]) and the
quaternary (mostly with soft nucleophiles and/or with acid
activation[7c–f]) positions. Therefore, these results are in good
agreement with those previously reported for similar sub-
strates and reinforce the possibility of acid-activated aziri-
dine (R)-12 (i.e., its related aziridinium cation) as an inter-
In view of all these experimental results, and despite the
nondetection of any intermediates along the reaction path-
way, the possibility of a stepwise mechanism was considered.
The spontaneous conversion of sulfamidates into aziridines
with release of SO3 in neutral media has been previously re-
ported,[4g,h] being also a common secondary reaction in the
preparation of sulfamidates.[4i,j] In addition, the thermal, nu-
cleophilic, or acid-catalyzed ring expansion of N-acylaziri-
dines into oxazolines to obtain protected 1,2-aminoalcohols
Chem. Eur. J. 2009, 15, 9810 – 9823
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9815

J. M. Peregrina et al.
Scheme 8. Possible reaction channels calculated from sulfamidate (R)-1b. The minimum-energy pathway is depicted in red and relative energies (DG, in
parentheses) are given in kcalmolÀ1
.
mediate involved in the ring-opening reaction of sulfamidate
(R)-1b.
ble continuum model by using methanol parameters. In ad-
dition, and given that the methoxide anion failed experi-
mentally to achieve the ring opening of sulfamidate (R)-1b,
all nucleophilic displacements were calculated by using
methanol as the nucleophile. Apart from the ring-opening
reaction mechanism (SN2 and stepwise pathways), other pos-
sible reactions (although not observed experimentally) were
theoretically explored (Scheme 8 and Supporting Informa-
tion). Figure 4 shows the most remarkable geometrical fea-
tures of selected minimum-energy transition states (TSs)
and intermediates, with a detailed description of all the cal-
culated structures available in the Supporting Information.
In view of the experimental results, the rate-determining
step of the global reaction should be the first one starting
from sulfamidate (R)-1b. This point was confirmed theoreti-
cally by inspecting all the reaction barriers involved in the
whole process. Thus, the activation energy calculated for the
ring contraction of sulfamidate into aziridine (tsRC, DG° =
42.1 kcalmolÀ1) was lower than those associated with the
SN2 reaction (tsSN2s, DG° =46.3 kcalmolÀ1), elimination
Scheme 9. Synthesis and ring-opening reaction of sulfamidate-derived
aziridine (R)-12. a) i) Bu4NBr, CH3CN, 258C, 20 h; ii) 20% H2SO4/
CH2Cl2 1:1, 258C, 8 h (76%); b) tBuOK, THF, 08C, 12 h (43%, unopti-
mized conditions); c) MeOH, 688C, 48 h; d) MeOH, pTsOH·H2O
(1.0 equiv), 688C, 48 h (86% conv., ee>93% determined by GC analysis,
see the Supporting Information).
(tsE, DG° =44.9 kcalmolÀ1), and much lower than the meth-
°
À
À
Theoretical calculations: To evaluate the experimentally
based mechanistic hypothesis mentioned above, several re-
action pathways starting from sulfamidate (R)-1b were cal-
culated by using DFT methods (see the Supporting Informa-
tion). Solvent effects were envisaged to have a decisive in-
fluence on the relative stability of the calculated species,
particularly of those charged; hence, bulky solvent effects
were considered for all the structures through the polariza-
anolysis of the S O (tsM1) and S N (tsM2) bonds (DG =
68.9 and 67.7 kcalmolÀ1, respectively). This first step of the
mechanism could provide a useful explanation to sulfami-
date/aziridine ring contraction, a reaction observed for a
long time, the mechanism of which had not been described
previously.[4g,h]
To test the influence of the carbamate group on the acti-
vation energy of both the ring contraction and SN2 process-
9816
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Chem. Eur. J. 2009, 15, 9810 – 9823

Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
molÀ1, favored) positions by means of a SN2 mechanism.
Theoretical calculations on regioselective ring-opening reac-
tions of aziridinium systems have been extensively stud-
ied.[27] Thus, and according to previous theoretical studies,[24]
the formation of the oxazolinium derivative (ox) by means
of a SNi mechanism was more favorable than the substitu-
tion with a poor nucleophile like methanol by 3.2 kcalmolÀ1.
It is worth mentioning that no transition structure for the
ring-expansion of this aziridinium cation, by means of attack
of the carbonyl group at the less-hindered b-position could
be located, which means that this process could only have
taken place at the more substituted a-position. This prefer-
ence of the incoming nucleophile to react at the most-hin-
dered carbon atom could be a consequence of the well-
known ability of quaternary carbon atoms to stabilize the
partial positive charge generated in the transition structures.
A point to note is that the formation of a “naked” planar
carbocation (c+) through a barrierless SN1 process was also
detected in this region of the PES, although this structure
was found to be much less stable (27.1 kcalmolÀ1 higher in
energy) than the oxazolinium cation, which appeared to be
exceedingly stable in the calculations. The final nucleophilic
attack of methanol at the 5-position of this derivative, by
means of a SN2 mechanism (tsSN2o, DG° =35.1 kcalmolÀ1)
led to the final product (S)-3b as a single regioisomer and
with inversion of configuration at the quaternary carbon
atom.
In summary, the theoretical calculations carried out in this
work suggest a multistep mechanism for the ring opening of
sulfamidate (R)-1b with methanol as the nucleophile.
Hence, the minimum-energy pathway of this process in-
volves the ring contraction of sulfamidate into an aziridine–
SO3 complex as the rate-determining step (highest activation
energy), followed by the fast (lower activation barriers) re-
lease of SO3 to form an aziridinium cation, its subsequent
ring-expansion into an oxazolinium cation, and, finally, the
regio- and stereoselective opening of this derivative at the
quaternary position with inversion of configuration. In this
mechanism, the SO3 moiety of sulfamidate acts as an “acid
reservoir” in the presence of methanol, producing increasing
amounts of sulfonic acid(s) at the sulfamidate–aziridine in-
terconversion step and promoting the ring-opening reaction.
These computational results are in good agreement with the
aforementioned experimental observations.
Figure 4. Most relevant minimum-energy structures and TSs at the
B3LYP/6-31+GACHTUNGTRENNUNG(d,p) level calculated for all the proposed pathways start-
ing from sulfamidate (R)-1b. Distances are given in ꢃ.
es, the energy barriers of these pathways were calculated
from sulfamidate (R)-2b (tsRC’ and tsSN2s’, DG° =41.2 and
47.6 kcalmolÀ1, respectively), and were very similar to those
calculated from (R)-1b. Therefore, the carbamate group
does not confer an extra inductive activation to the sulfami-
date moiety, although the ring-opening reaction does not
take place experimentally in the absence of the former. This
result indicates that a direct SN2 is not the most feasible
ring-opening mechanism of sulfamidate (R)-1b, and encour-
aged us to further explore its energy surface to gain insights
into the whole mechanism.
À
Markedly, the heterolytic cleavage of the C O bond in
the ring-contraction process did not result in any stable
“naked” carbocationic structure, or in any ionic pair be-
À
tween the quaternary carbon atom and the NSO3 moieties.
In contrast, as demonstrated by IRC calculations, the N
atom attacks at the quaternary position at the same time
À
that the C O bond is breaking to form the corresponding
aziridine (az) in a concerted way.
It is important to note that, after formation of the aziri-
dine–SO3 complex, the SO3 moiety lies greatly separated
from the molecule (dNÀS =2.23 ꢃ), which is in agreement
with the experimental spontaneous cleavage of the sulfamic
acid. Therefore, the next calculated step was the conversion
of the aziridine–SO3 complex (az) into the corresponding
aziridinium cation az+ (13.1 kcalmolÀ1 lower in energy)
after protonation with the sulfonic acid generated in the re-
action of methanol with SO3 (tsM3). The activation energy
of this process calculated from the aziridine–SO3 complex
was DG° =34.3 kcalmolÀ1.
Conclusions
The thorough study on the reactions of hindered ester or
amide-derived sulfamidates with O nucleophiles in acidic
and neutral media has given us a greater insight into the re-
activity of these systems. Thus, it is possible to fully direct
the chemoselectivity of the reactions towards ring opening,
amide–ester exchange, or carbamate deprotection depend-
ing on the experimental conditions. The most important out-
come of this study is the development of a conceptually
new, simple, and self-promoted practical method for the
This activated aziridinium cation[26] could undergo a regio-
selective ring-expansion reaction into the corresponding ox-
azolinium cation (tsRE, DG° =11.7 kcalmolÀ1) together
with the ring-opening reaction with methanol at both the
secondary (tsSN2ab, b-attack, DG° =21.8 kcalmolÀ1, disfa-
vored) and quaternary (tsSN2aa, a-attack, DG° =14.9 kcal
Chem. Eur. J. 2009, 15, 9810 – 9823
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9817

J. M. Peregrina et al.
rified by silica-gel column chromatography (hexane/AcOEt 7:3) to give
compound (R)-4b (74 mg, 99%) as a colorless oil. [a]2D5 =À24.4 (c=1.30
in CHCl3); 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); 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; ESI+: m/z: 196.2.
ring-opening reaction of hindered sulfamidates by using al-
cohols as O nucleophiles, allowing the synthesis of interest-
ing enantiopure b2,2-amino acids. This methodology over-
comes one of the most reported drawbacks in the chemistry
of cyclic sulfamidates: the ring-opening reaction of these
substrates with alcohols. In addition, this is carried out in
the absence of external activators and under mild condi-
tions, at a quaternary carbon atom and with inversion of
configuration. Moreover, the cleavage of sulfamic acid de-
rived intermediates is totally suppressed within this proto-
col, which allows a greater compatibility with other func-
tional groups present on the molecule. This observed reac-
tivity has been explained by means of a multistep mecha-
nism involving aziridinium and oxazolinium intermediates
as found by theoretical calculations. We think that this new
strategy broadens the chemistry of sulfamidates and will be
useful for a number of synthetic organic chemists in the
future.
General procedure for amide–ester exchange in cyclic sulfamidates (con-
ditions A in Table 1): Sulfamidate (R)-1a (1.0 equiv) was dissolved in the
corresponding alcohol (20 mL) (see Table 1) and the solution was cooled
to 08C, then TfOH (1.5 equiv) was added dropwise. The temperature of
the reaction was slowly increased to 408C and the mixture was stirred for
24 h (48 h and 808C in the case of iPrOH). The solvent was evaporated
and the residue was dissolved in CH2Cl2 (30 mL). The acid was then neu-
tralized by addition of a saturated solution of NaHCO3 (20 mL). The or-
ganic phase was separated and the aqueous phase was extracted with
CH2Cl2 (3ꢅ30 mL). The combined organic phases were dried (Na2SO4),
concentrated, and the residue was purified by flash silica-gel column
chromatography, to give the corresponding sulfamidates (R)-1b–j.
Methyl (R)-5-ethoxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxathiazoli-
dine-3-carboxylate ((R)-1c): Compound (R)-1c (120 mg, 94%) was ob-
tained as
a white solid, starting from sulfamidate (R)-1a (135 mg,
0.48 mmol), after purification by column chromatography (hexane/
AcOEt 8:2). M.p. 72–748C; [a]2D5 =À59.1 (c=1.33 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.35 (t, 3H, J=7.2 Hz; CH2CH3), 1.82 (s, 3H;
CCH3), 3.88–3.97 (m, 4H; CH2N+CO2CH3), 4.27–4.42 (m, 2H;
CH2CH3), 4.59 ppm (d, 1H, J=10.4 Hz; CH2N); 13C NMR (75 MHz,
CDCl3): d=13.9 (CH2CH3), 22.7 (CCH3), 53.0 (CH2N), 54.8 (CO2CH3),
63.3 (CH2CH3), 83.4 (CCH3), 150.0 (NCO), 167.7 ppm (CO2); elemental
analysis calcd (%) for (C8H13NO7S): C 35.95, H 4.90, N 5.24, S 12.00;
found: C 35.81, H 4.92, N 5.26, S 12.04; ESI+: m/z: 268.3.
Experimental Section
General procedures: All manipulations with air-sensitive reagents were
carried out under a dry argon atmosphere by using standard Schlenk
techniques. Solvents were purified according to standard procedures. The
chemical reagents were purchased from Aldrich Chemical Co. Analytical
TLC was performed by using Polychrom SI F254 plates. Column chroma-
tography was performed by using Kieselgel 60 (230–400 mesh). Organic
solutions were dried over anhydrous Na2SO4 and, when necessary, con-
centrated under reduced pressure by using a rotary evaporator. NMR
spectra were recorded on Bruker ARX 300 and Bruker Avance 400 spec-
trometers at 300 or 400 MHz (1H) and at 75 or 100 MHz (13C) and signals
are reported in ppm downfield from TMS. The value of coupling con-
stants (J) is reported in Hz. Mass spectra were obtained by electrospray
ionization (ESI). Melting points were determined on a Bꢄchi B-545 melt-
ing point apparatus and are uncorrected. Optical rotations were mea-
sured on a Perkin–Elmer 341 polarimeter in a 1 dm cell of 1 mL capacity.
Microanalyses were carried out on a CE Instruments EA-1110 analyzer
and are in good agreement with the calculated values.
Methyl
(R)-5-methyl-5-(n-propoxy)carbonyl-2,2-dioxo-2l6-[1,2,3]oxa-
thiazolidine-3-carboxylate ((R)-1d): Compound (R)-1d (135 mg, 93%)
was obtained as a colorless oil, by starting from sulfamidate (R)-1a
(145 mg, 0.51 mmol), after purification by column chromatography
(hexane/AcOEt 8:2). [a]2D5 =À59.1 (c=1.64 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.98 (t, 3H, J=7.4 Hz; CH2CH2CH3), 1.67–1.79
(m, 2H; CH2CH2CH3), 1.83 (s, 3H; CCH3), 3.89–3.96 (m, 4H; CH2N+
CO2CH3), 4.16–4.31 (m, 2H; CH2CH2CH3), 4.59 ppm (d, 1H, J=10.4 Hz;
CH2N); 13C NMR (75 MHz, CDCl3): d=10.1 (CH2CH2CH3), 21.7
(CH2CH2CH3), 22.8 (CCH3), 53.0 (CH2N), 54.8 (CO2CH3), 68.8
(CH2CH2CH3), 83.5 (CCH3), 150.0 (NCO), 167.8 ppm (CO2); elemental
analysis calcd (%) for (C9H15NO7S): C 38.43, H 5.38, N 4.98, S 11.40;
found: C 38.31, H 5.36, N 5.00, S 11.43; ESI+: m/z: 282.3.
(R)-5-Methyl-5-(N-methoxy-N-methylcarbamoyl)-2,2-dioxo-2l6-[1,2,3]ox-
athiazolidine ((R)-2a): SmACHTUNTRGNEUNG(TfO)3 (238 mg, 0.39 mmol) was added to a so-
Methyl
(R)-5-(n-butoxycarbonyl)-5-methyl-2,2-dioxo-2l6-[1,2,3]oxa-
lution of sulfamidate (R)-1a (110 mg, 0.39 mmol) in MeOH (10 mL), and
the mixture was stirred at room temperature for 2 h. The solvent was
evaporated and the residue was dissolved in a mixture of CH2Cl2 (15 mL)
and an aqueous 2m HCl solution (10 mL). Then, the organic phase was
separated and the aqueous phase was extracted with CH2Cl2 (3ꢅ15 mL).
The combined organic phases were dried (Na2SO4), concentrated, and
the residue was purified by silica-gel column chromatography (hexane/
AcOEt 7:3) to give compound (R)-2a (82 mg, 94%) as a colorless oil.
thiazolidine-3-carboxylate ((R)-1e): Compound (R)-1e (118 mg, 89%)
was obtained as a colorless oil, by starting from sulfamidate (R)-1a
(127 mg, 0.45 mmol), after purification by column chromatography
(hexane/AcOEt 8:2). [a]2D5 =À58.7 (c=1.62 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.95 (t, 3H, J=7.4 Hz; CH2CH2CH2CH3), 1.33–
1.50 (m, 2H; CH2CH2CH2CH3), 1.62–1.78 (m, 2H; CH2CH2CH2CH3),
1.82 (s, 3H; CCH3), 3.87–3.97 (m, 4H; CH2N+CO2CH3), 4.19–4.34 (m,
2H; CH2CH2CH2CH3), 4.58 ppm (d, 1H, J=10.4 Hz; CH2N); 13C NMR
(75 MHz, CDCl3): d=13.5 (CH2CH2CH2CH3), 18.8 (CH2CH2CH2CH3),
22.7 (CCH3), 30.2 (CH2CH2CH2CH3), 53.0 (CH2N), 54.8 (CO2CH3), 67.1
(CH2CH2CH2CH3), 83.5 (CCH3), 150.0 (NCO), 167.8 ppm (CO2); ele-
mental analysis calcd (%) for (C10H17NO7S): C 40.67, H 5.80, N 4.74, S
10.86; found: C 40.81, H 5.82, N 4.72, S 10.82; ESI+: m/z: 296.3.
Methyl (R)-5-methyl-5-(n-pentyloxy)carbonyl-2,2-dioxo-2l6-[1,2,3]oxa-
thiazolidine-3-carboxylate ((R)-1 f): Compound (R)-1 f (130 mg, 90%)
was obtained as a colorless oil, by starting from sulfamidate (R)-1a
(132 mg, 0.47 mmol), after purification by column chromatography
(hexane/AcOEt 8:2). [a]2D5 =À54.5 (c=2.43 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.82–1.03 (m, 3H; CH2CH2CH2CH2CH3), 1.24–
1
[a]2D5 =À46.3 (c=1.04 in CHCl3); H NMR (300 MHz, CDCl3): d=1.77 (s,
3H; CH3), 3.12–3.42 (m, 4H; CH2N+NCH3), 3.80 (s, 3H; NOCH3),
4.35–4.51 (m, 1H; CH2N), 5.01 ppm (brs, 1H; NH); 13C NMR (75 MHz,
CDCl3) d=21.8 (CH3), 33.7 (NCH3), 52.5 (CH2N), 61.7 (NOCH3), 90.7
(CCH3), 167.8 ppm (CON); elemental analysis calcd (%) for
(C6H12N2O5S): C 32.14, H 5.39, N 12.49, S 14.30; found: C 32.26, H 5.41,
N 12.52, S 14.27; ESI+: m/z: 225.2.
Methyl (R)-5-methyl-2,2-dioxo-2l6-[1,2,3]oxathiazolidine-5-carboxylate
((R)-2b): SmACHTUNGTRENNUNG(TfO)3 (232 mg, 0.38 mmol) was added to a solution of sul-
famidate (R)-1b (97 mg, 0.38 mmol) in MeOH (10 mL) and the mixture
was stirred at room temperature for 2 h. The solvent was evaporated and
the residue was dissolved in a mixture of CH2Cl2 (15 mL) and an aqueous
2m HCl solution (10 mL). Then, the organic phase was separated and the
aqueous phase was extracted with CH2Cl2 (3ꢅ15 mL). The combined or-
ganic phases were dried (Na2SO4), concentrated, and the residue was pu-
1.45
(m,
4H;
CH2CH2CH2CH2CH3),
1.61–1.79
(m,
2H;
CH2CH2CH2CH2CH3), 1.82 (s, 3H; CCH3), 3.83–4.02 (m, 4H; CH2N+
CO2CH3), 4.17–4.36 (m, 2H; CH2CH2CH2CH2CH3), 4.58 ppm (d, 1H, J=
9818
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Chem. Eur. J. 2009, 15, 9810 – 9823

Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
10.4 Hz;
CH2N);
13C NMR
(75 MHz,
CDCl3):
d=13.8
(hexane/AcOEt 8:2), to give compound (R)-1k (144 mg, 89%) as a color-
less oil. [a]2D5 =À42.3 (c=1.11 in CHCl3); 1H NMR (300 MHz, CDCl3):
d=1.80 (s, 3H; CH3), 3.80–4.00 (m, 4H; CH2N+CO2CH3), 4.57 (d, 1H,
J=10.5 Hz; CH2N), 5.27 (s, 2H; CH2Ph), 7.31–7.49 ppm (m, 5H; Ph);
13C NMR (75 MHz, CDCl3): d=22.6 (CH3), 52.9 (CH2N), 54.8 (CO2CH3),
68.8 (CH2Ph), 83.4 (CCH3), 128.3, 128.7, 128.8, 134.1 (Ph), 149.9 (NCO),
167.6 ppm (CO2); elemental analysis calcd (%) for (C13H15NO7S): C
47.41, H 4.59, N 4.25, S 9.74; found: C 47.52; H 4.61, N 4.27, S 9.71;
ESI+: m/z: 330.3.
(CH2CH2CH2CH2CH3), 22.1 (CH2CH2CH2CH2CH3), 22.7 (CCH3), 27.6,
27.8 (CH2CH2CH2CH2CH3), 53.0 (CH2N), 54.7 (CO2CH3), 67.3
(CH2CH2CH2CH2CH3), 83.5 (CCH3), 149.9 (NCO), 167.7 ppm (CO2); el-
emental analysis calcd (%) for (C11H19NO7S): C 42.71, H 6.19, N 4.53, S
10.37; found: C 42.59, H 6.16, N 4.56, S 10.41; ESI+: m/z: 310.3.
Methyl (R)-5-allyloxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxathiazoli-
dine-3-carboxylate ((R)-1g): Compound (R)-1g (101 mg, 86%) was ob-
tained as a colorless oil, by starting from sulfamidate (R)-1a (119 mg,
0.42 mmol), after purification by column chromatography (hexane/
AcOEt 8:2). [a]2D5 =À54.7 (c=2.52 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.84 (s, 3H; CCH3), 3.87–4.00 (m, 4H; CH2N+CO2CH3),
4.59 (d, 1H, J=10.4 Hz; CH2N), 4.76 (ddd, 2H, J=6.2, 2.6, 1.3 Hz;
CH2CH=CH2), 5.29–5.47 (m, 2H; CH2CH=CH2), 5.94 ppm (tdd, 1H, J=
17.6, 10.5, 5.9 Hz; CH2CH=CH2); 13C NMR (75 MHz, CDCl3): d=22.7
(CCH3), 52.9 (CH2N), 54.7 (CO2CH3), 67.5 (CH2CH=CH2), 83.4 (CCH3),
119.9 (CH2CH=CH2), 130.4 (CH2CH=CH2), 149.9 (NCO), 167.4 ppm
(CO2); elemental analysis calcd (%) for (C9H13NO7S): C 38.71, H 4.69, N
5.02, S 11.48; found: C 38.55, H 4.67, N 5.04, S 11.52; ESI+: m/z: 280.3.
General procedure for the ring opening of cyclic sulfamidates with alco-
hols (conditions B in Table 1): The corresponding sulfamidate (R)-1b–j
was dissolved in the corresponding alcohol (see Table 1) and the solution
was heated at 70–808C for 48 h (120 h in the case of iPrOH). The reac-
tions were monitored by TLC. After evaporating the solvent, the corre-
sponding ring-opening products (S)-3b–j were cleanly obtained as color-
less oils. Moreover, the products were purified by flash silica-gel column
chromatography.
Methyl (S)-2-methoxy-2-methoxycarbonylaminomethylpropanoate ((S)-
3b)
Methyl (R)-5-isobutoxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxathiazo-
lidine-3-carboxylate ((R)-1h): Compound (R)-1h (142 mg, 91%) was ob-
tained as a colorless oil, by starting from sulfamidate (R)-1a (149 mg,
0.53 mmol), after purification by column chromatography (hexane/
AcOEt 8:2). [a]2D5 =À56.6 (c=2.24 in CHCl3); 1H NMR (300 MHz,
Method 1 (conditions B in Table 1): Following the general procedure de-
scribed for the ring opening of sulfamidates with alcohols, compound (S)-
3b (97 mg, 93%) was obtained by starting from sulfamidate (R)-1b
(145 mg, 0.51 mmol), after purification by flash silica-gel column chroma-
tography (hexane/AcOEt 7:3).
CDCl3): d=0.79–1.00 (m, 6H; CH2CH
2.03 (m, 1H; CH2CH
4.05 (m, 2H; CH2CH
13C NMR (75 MHz, CDCl3): d=18.7 (CH2CH
(CH2CH(CH3)2), 53.0 (CH2N), 54.7 (CO2CH3), 73.0 (CH2CHACHTGNUTRENNUNG
ACHTUNGTRENNUNG
Method 2 (one-pot): TfOH (0.2 mL, 1.74 mmol) was added dropwise t o a
precooled (08C) solution of sulfamidate (R)-1a (327 mg, 1.16 mmol) in
MeOH (10 mL). The temperature of the reaction was slowly increased to
70–808C and the mixture was stirred for 48 h. The solvent was evaporat-
ed and the residue was dissolved in CH2Cl2 (30 mL). The acid was then
neutralized by addition of a saturated solution of NaHCO3 (20 mL). The
organic phase was separated and the aqueous phase was extracted with
CH2Cl2 (3ꢅ30 mL). The combined organic phases were dried (Na2SO4),
concentrated, and the residue was purified by flash silica-gel column
chromatography (hexane/AcOEt 7:3) to give compound (S)-3b as a col-
orless oil (232 mg, 98%). [a]2D5 =À4.6 (c=1.33 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.37 (s, 3H; CCH3), 3.28 (s, 3H; COCH3), 3.38
(dd, 1H, J=13.9, 5.9 Hz; CH2N), 3.52 (dd, 1H, J=13.8, 6.5 Hz; CH2N),
3.63 (s, 3H; CO2CH3), 3.72 (s, 3H; CO2CH3), 4.87–5.27 ppm (m, 1H;
NH); 13C NMR (75 MHz, CDCl3): d=18.6 (CCH3), 47.1 (CH2N), 52.1,
52.2, 52.3, (COCH3 +CO2CH3 +CO2CH3), 79.5 (CCH3), 157.0 (NCO),
172.8 (CO2); elemental analysis calcd (%) for (C8H15NO5): C 46.82, H
7.37, N 6.83; found: C 47.00, H 7.39, N 6.81; ESI+: m/z: 206.2.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
83.5 (CCH3), 149.9 (NCO), 167.7 ppm (CO2); elemental analysis calcd
(%) for (C10H17NO7S): C 40.67, H 5.80, N 4.74, S 10.86; found: C 40.82,
H 5.78, N 4.76, S 10.90; ESI+: m/z: 296.3.
Methyl
(R)-5-isopentoxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxa-
thiazolidine-3-carboxylate ((R)-1i): Compound (R)-1i (135 mg, 93%)
was obtained as a colorless oil, by starting from sulfamidate (R)-1a
(132 mg, 0.47 mmol), after purification by column chromatography
(hexane/AcOEt 8:2). [a]2D5 =À56.6 (c=1.90 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=0.77–1.07 (m, 7H; CH2CH2CHCAHTUNGTRENNUNG
(m, 5H; CCH3 +CH2CH2CHACHTNUGTRENNNUG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(CH2CH2CH
(CH2CH2CHACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Ethyl (S)-2-ethoxy-2-methoxycarbonylaminomethylpropanoate ((S)-3c):
Compound (S)-3c (96 mg, 94%) was obtained as a colorless oil, by start-
ing from sulfamidate (R)-1c (117 mg, 0.44 mmol), after purification by
column chromatography (hexane/AcOEt 9:1). [a]2D5 =0.0 (c=1.03 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.18 (t, 3H, J=7.0 Hz;
CH2CH3), 1.26 (t, 3H, J=7.2 Hz; CH2CH3), 1.38 (s, 3H; CCH3), 3.33–
3.58 (m, 4H; COCH2 +CH2N), 3.64 (s, 3H; CO2CH3), 4.12–4.24 (m, 2H;
CO2CH2), 4.82–5.22 ppm (m, 1H; NH); 13C NMR (75 MHz, CDCl3): d=
14.1 (CH2CH3), 15.6 (CH2CH3), 19.3 (CCH3), 47.5 (CH2N), 52.1
(CO2CH3), 60.1 (COCH2), 61.2 (CO2CH2), 79.2 (CCH3), 157.0 (NCO),
172.7 ppm (CO2); elemental analysis calcd (%) for (C10H19NO5): C 51.49,
H 8.21, N 6.00; found: C 51.62, H 8.18, N 6.02; ESI+: m/z: 234.3.
mental analysis calcd (%) for (C11H19NO7S): C 42.71, H 6.19, N 4.53, S
10.37; found: C 42.58, H 6.23, N 4.55, S 10.40; ESI+: m/z: 310.3.
Methyl
(R)-5-isopropoxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxa-
thiazolidine-3-carboxylate ((R)-1j): Compound (R)-1j (122 mg, 79%)
was obtained as a colorless oil, by starting from sulfamidate (R)-1a
(155 mg, 0.55 mmol), after purification by column chromatography
(hexane/AcOEt 8:2); [a]2D5 =À59.2 (c=1.09 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.17–1.48 (m, 6H; CHACTHUNGTRNEUNG(CH3)2), 1.79 (s, 3H;
CCH3), 3.80–4.02 (m, 4H; CH2N+CO2CH3), 4.57 (d, 1H, J=10.2 Hz;
CH2N), 5.01–5.25 ppm (m, 1H; CH
(CH3)2); 13C NMR (75 MHz, CDCl3):
d=21.4 (CH(CH3)2), 22.7 (CCH3), 53.0 (CH2N), 54.8 (CO2CH3), 71.7
(CH(CH3)2), 83.4 (CCH3), 150.0 (NCO), 167.2 ppm (CO2); elemental
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
n-Propyl (S)-2-methoxycarbonylaminomethyl-2-(n-propoxy)propanoate
((S)-3d): Compound (S)-3d (109 mg, 91%) was obtained as a colorless
oil, by starting from sulfamidate (R)-1d (129 mg, 0.46 mmol), after purifi-
cation by column chromatography (hexane/AcOEt 9:1). [a]2D5 =À2.3 (c=
1.19 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.86–0.99 (m, 6H;
CH2CH2CH3 +CH2CH2CH3), 1.39 (s, 3H; CCH3), 1.50–1.76 (m, 4H;
CH2CH2CH3 +CH2CH2CH3), 3.30–3.46 (m, 3H; COCH2 +CH2N), 3.53
(dd, 1H, J=13.7, 6.2 Hz; CH2N), 3.65 (s, 3H; CO2CH3), 4.08 (t, 2H, J=
6.7 Hz; CO2CH2), 4.81–5.17 ppm (m, 1H; NH); 13C NMR (75 MHz,
CDCl3): d=10.3, 10.5 (CH2CH2CH3 +CH2CH2CH3), 19.3 (CCH3), 21.9,
23.3 (CH2CH2CH3 + CH2CH2CH3), 47.6 (CH2N), 52.1 (CO2CH3), 66.2
(COCH2), 66.8 (CO2CH2), 79.0 (CCH3), 157.0 (NCO), 172.8 ppm (CO2);
elemental analysis calcd (%) for (C12H23NO5): C 55.16, H 8.87, N 5.36;
found: C 55.31, H 8.90, N 5.34; ESI+: m/z: 262.3.
ACHTUNGTRENNUNG
analysis calcd (%) for (C9H15NO7S): C 38.43, H 5.38, N 4.98, S 11.40;
found: C 38.52, H 5.36, N 4.96, S 11.44; ESI+: m/z: 282.3.
Methyl (R)-5-benzyloxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxathiazo-
lidine-3-carboxylate ((R)-1k): TsOH·H2O (141 mg, 0.74 mmol) and ben-
zylic alcohol (159 mg, 1.47 mmol) were added to a solution of sulfamidate
(R)-1a (139 mg, 0.49 mmol) in toluene (10 mL) and the mixture was
stirred at reflux for 24 h. After evaporating the solvent, the residue was
dissolved in CH2Cl2 (30 mL) and the acid was neutralized by addition of
an aqueous saturated solution of NaHCO3 (20 mL). The organic phase
was separated and the aqueous phase was extracted with CH2Cl2 (3ꢅ
30 mL). The combined organic phases were dried (Na2SO4), concentrat-
ed, and the residue purified by silica-gel column chromatography
Chem. Eur. J. 2009, 15, 9810 – 9823
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9819

J. M. Peregrina et al.
n-Butyl
(S)-2-(n-butoxy)-2-methoxycarbonylaminomethylpropanoate
CH2CH2CHACHTUGNTERNNU(G CH3)2 +CH2CH2CHACHTUGNTREN(NUNG CH3)2), 3.04–3.52 (m, 4H; CH2N+
((S)-3e): Compound (S)-3e (104 mg, 93%) was obtained as a colorless
oil, by starting from sulfamidate (R)-1e (114 mg, 0.39 mmol), after purifi-
cation by column chromatography (hexane/AcOEt 9:1). [a]2D5 =À1.7 (c=
1.04 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.84–0.96 (m, 6H;
CH2CH2CH2CH3 +CH2CH2CH2CH3), 1.27–1.44 (m, 7H; CCH3 +
COCH2), 3.59 (s, 3H; CO2CH3), 3.79–4.19 (m, 2H; CO2CH2), 4.73–
5.13 ppm (m, 1H; NH); 13C NMR (75 MHz, CDCl3): d=11.1, 11.3, 16.3,
16.5 (CH2CH2CH
N
ACHTUNGTRENNUNG
22.6, (CH2CH2CH
G
+
ACHTUNGTRENNUNG
(CH2CH2CH
(CH2CH2CH
U
+
ACHTUNGTRENNUNG
CH2CH2CH2CH3 +CH2CH2CH2CH3),
1.46–1.67
(m,
4H;
ACHTUNGTRENNUNG
CH2CH2CH2CH3 +CH2CH2CH2CH3), 3.30–3.44 (m, 3H; COCH2 +
CH2N), 3.51 (dd, 1H, J=13.6, 6.2 Hz; CH2N), 3.64 (s, 3H; CO2CH3),
4.10 (t, 2H, J=6.6 Hz; CO2CH2), 4.80–5.15 ppm (m, 1H; NH); 13C NMR
(75 MHz, CDCl3): d=13.6, 13.9 (CH2CH2CH2CH3 +CH2CH2CH2CH3),
19.1, 19.2, 19.3 (CCH3 +CH2CH2CH2CH3 +CH2CH2CH2CH3), 30.5, 32.2
(CH2CH2CH2CH3 +CH2CH2CH2CH3), 47.6 (CH2N), 52.1 (CO2CH3), 64.3
(COCH2), 65.0 (CO2CH2), 79.1 (CCH3), 157.0 (NCO), 172.8 ppm (CO2);
elemental analysis calcd (%) for (C14H27NO5): C 58.11, H 9.40, N 4.84;
found: C 58.29, H 9.43, N 4.82; ESI+: m/z: 290.4.
62.9, 69.3 (COCH2), 63.8, 69.7 (CO2CH2), 79.0 (CCH3), 157.0 (NCO),
172.7 ppm (CO2); elemental analysis calcd (%) for (C16H31NO5): C,
60.54; H, 9.84; N, 4.41; found: C 60.71, H 9.87, N 4.39; ESI+: m/z: 318.4.
Isopropyl (S)-2-isopropoxy-2-methoxycarbonylaminomethylpropanoate
((S)-3j): Compound (S)-3j (71 mg, 65%) was obtained as a colorless oil,
by starting from sulfamidate (R)-1j (119 mg, 0.42 mmol), after purifica-
tion by column chromatography (hexane/AcOEt 9:1); [a]2D5 =+2.6 (c=
1.13 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.08 (d, 3H, J=6.1 Hz;
CH
CH
N
ACHTUNGTREN(NNUG CH3)2), 1.19 (d, 6H, J=6.2 Hz;
n-Pentyl
(S)-2-methoxycarbonylaminomethyl-2-(n-pentoxy)propanoate
((S)-3 f): Compound (S)-3 f (113 mg, 88%) was obtained as a colorless
oil, by starting from sulfamidate (R)-1 f (125 mg, 0.40 mmol), after purifi-
cation by column chromatography (hexane/AcOEt 9:1). [a]2D5 =À1.8 (c=
1.10 in CHCl3); 1H NMR (300 MHz, CDCl3) d=0.75–1.02 (m, 6H;
CH2CH2CH2CH2CH3 +CH2CH2CH2CH2CH3), 1.16–1.45 (m, 11H;
CCH3 +CH2CH2CH2CH2CH3 +CH2CH2CH2CH2CH3), 1.46–1.74 (m, 4H;
3.42 (dd, 1H, J=13.5, 6.4 Hz; CH2N), 3.59 (s, 3H; CO2CH3), 3.69 (sept,
1H, J=12.2, 6.1 Hz; COCH), 4.75–5.09 ppm (m, 2H; CO2CH+NH);
13C NMR (100 MHz, CDCl3): d=20.0 (CCH3), 21.6, 21.7, 23.9, 24.7 (CH-
ACHUTNGRENNU(G CH3)2)+(CHACHUTTGNRENN(GUN CH3)2), 48.4 (CH2N), 52.1 (CO2CH3), 68.0 (COCH), 68.8
(CO2CH), 79.6 (CCH3), 157.0 (NCO), 172.7 ppm (CO2); elemental analy-
sis calcd (%) for (C12H23NO5): C 55.16, H 8.87, N 5.36; found: C 55.05, H
8.84, N 5.38; ESI+: m/z: 262.3.
CH2CH2CH2CH2CH3 +CH2CH2CH2CH2CH3),
3.26–3.43
(m,
3H;
COCH2 +CH2N), 3.50 (dd, 1H, J=13.6, 6.2 Hz; CH2N), 3.63 (s, 3H;
CO2CH3), 4.09 (t, 2H, J=6.7 Hz; CO2CH2), 4.80–5.13 ppm (m, 1H; NH);
(S)-N-(Tosyl)phenylalaninyl-(S)-O-methyl-a-methylisoserine methyl ester
((S,S)-6) and (S)-N-(tosyl)phenylalaninyl-(S)-a-methylisoserine methyl
ester ((S,S)-7): Compound (S)-3b (202 mg, 0.98 mmol) was suspended in
aqueous 9m HCl (5 mL) and the mixture was heated at reflux for 12 h.
After evaporation of the solvent, the residue was dissolved in water
(2 mL) and was eluted through a C18 reverse-phase Sep-pak cartridge to
give, after evaporation, the corresponding mixture of b-amino acids (S)-
O-methyl-a-methylisoserine and (S)-a-methylisoserine as hydrochloride
derivatives (S)-4 and (S)-5, respectively, as white solids. This residue was
dissolved in a mixture of MeOH/HCl, previously prepared by addition of
AcCl (4 mL) over MeOH (16 mL) at 08C. After refluxing for 10 h, the
solvent was evaporated, the residue was suspended in CH2Cl2 (10 mL)
under an inert atmosphere, and (S)-N-(p-tosyl)phenylalaninyl chloride
(432 mg, 1.26 mmol) and ethyldiisopropylamine (DIEA) (508 mL,
2.91 mmol) were added. The resulting solution was stirred at room tem-
perature for 14 h. The reaction was quenched by addition of aqueous
0.5m HCl (4 mL), the organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (3ꢅ15 mL). The combined organic
phases were dried (Na2SO4), concentrated, and the crude reaction was
purified by silica-gel column chromatography (hexane/AcOEt 6:4) to
give dipeptides (S,S)-6 (268 mg, 61%) and (S,S)-7 (156 mg, 32%) as oils.
Compound (S,S)-6: [a]D25 =À31.5 (c=1.12 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.24 (s, 3H; CCH3), 2.33 (s, 3H; PhCH3), 2.69–
2.94 (m, 2H; CH2Ph), 3.19 (s, 3H; COCH3), 3.28–3.50 (m, 2H; CH2N),
3.64 (s, 3H; CO2CH3), 3.67–3.83 (m, 1H; CH), 4.95–5.11 (m, 1H;
NHSO2), 6.59 (brs, 1H; NHCO), 6.78–6.92 (m, 2H; PhCH3), 6.95–7.15
(m, 5H; Ph), 7.35–7.52 ppm (m, 2H; PhCH3); 13C NMR (75 MHz,
CDCl3): d=18.5 (CCH3), 21.5 (PhCH3), 38.4 (CH2Ph), 45.4 (CH2N), 52.1
(COCH3), 52.3 (CO2CH3), 58.0 (CH), 79.2 (CCH3), 127.0, 127.1, 128.8,
129.0, 129.7, 135.3, 135.7, 143.6 (Ph), 170.3 (CON), 172.7 ppm (CO2); ele-
mental analysis calcd for (C22H28N2O6S): C 58.91, H 6.29, N, 6.25, S 7.15;
found: C 58.74, H 6.27, N 6.23, S 7.17; ESI+: m/z: 449.5.
13C NMR (75 MHz, CDCl3) d=13.6, 14.0 (CH2CH2CH2CH2CH3
CH2CH2CH2CH2CH3), 19.3 (CCH3), 22.2, 22.5 (CH2CH2CH2CH2CH3
+
+
+
CH2CH2CH2CH2CH3),
28.0,
28.2
(CH2CH2CH2CH2CH3
CH2CH2CH2CH2CH3), 29.8 (CH2CH2CH2CH2CH3), 47.5 (CH2N), 52.1
(CO2CH3), 64.6 (COCH2), 65.3 (CO2CH2), 79.1 (CCH3), 157.0 (NCO),
172.8 ppm (CO2); elemental analysis calcd (%) for (C16H31NO5): C 60.54,
H 9.84, N 4.41; found: C 60.71, H 9.87, N 4.39; ESI+: m/z: 318.4.
Allyl (S)-2-allyloxy-2-methoxycarbonylaminomethylpropanoate ((S)-3g):
Compound (S)-3g (66 mg, 84%) was obtained as a colorless oil, by start-
ing from sulfamidate (R)-1g (85 mg, 0.30 mmol), after purification by
column chromatography (hexane/AcOEt 9:1). [a]2D5 =+4.9 (c=1.01 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=1.38 (s, 3H; CCH3), 3.38 (dd,
1H, J=13.7, 5.6 Hz; CH2N), 3.52 (dd, 1H, J=13.7, 6.3 Hz; CH2N), 3.59
(s, 3H; CO2CH3), 3.81–4.04 (m, 2H; COCH2), 4.46–4.67 (m, 2H;
CO2CH2), 4.94–5.35, (m, 5H; CH2CH=CH2 +CH2CH=CH2 +NH), 5.72–
5.97 ppm (m, 2H; CH2CH=CH2 +CH2CH=CH2); 13C NMR (100 MHz,
CDCl3): d=19.3 (CCH3), 47.6 (CH2N), 52.2 (CO2CH3), 65.8 (COCH2),
66.0 (CO2CH2), 79.6 (CCH3), 116.8, 118.8 (CH2CH=CH2 +CH2CH=CH2),
131.6, 134.5 (CH2CH=CH2 +CH2CH=CH2), 157.0 (NCO), 172.2 ppm
(CO2); elemental analysis calcd (%) for (C12H19NO5): C 56.02, H 7.44, N
5.44; found: C 56.20, H 7.42, N 5.46; ESI+: m/z: 258.3.
Isobutyl
(S)-2-isobutoxy-2-methoxycarbonylaminomethylpropanoate
((S)-3h): Compound (S)-3h (116 mg, 90%) was obtained as a colorless
oil, by starting from sulfamidate (R)-1h (131 mg, 0.44 mmol), after purifi-
cation by column chromatography (hexane/AcOEt 9:1). [a]2D5 =À5.0 (c=
1.18 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.72–0.99 (m, 12H;
CH2CHACHTUNGTRENNUNG(CH3)2 +CH2CHACHTUNGTRENNUNG
CH2CH(CH3)2 +CH2CHACHTUNGTRENNUNG
G
1H, J=13.6, 5.8 Hz; CH2N), 3.47 (dd, 1H, J=13.6, 6.2 Hz; CH2N), 3.59
(s, 3H; CO2CH3), 3.84 (d, 2H, J=6.6 Hz; CO2CH2), 4.76–5.11 ppm (m,
1H; NH); 13C NMR (75 MHz, CDCl3) d=19.0 (CH2CH
ACHTUNGTRENNUNG
1
Compound (S,S)-7: [a]2D5 =À23.4 (c=1.12 in CHCl3); H NMR (300 MHz,
A
N
ACHTUNGTRENNUNG
(CH2N), 52.1 (CO2CH3), 70.9 (COCH2), 71.2 (CO2CH2), 79.0 (CCH3),
157.0 (NCO), 172.7 ppm (CO2); elemental analysis calcd (%) for
(C14H27NO5): C 58.11, H 9.40, N 4.84; found: C 58.02, H 9.43, N 4.82;
ESI+: m/z: 290.4.
CDCl3): d=1.39 (s, 3H; CCH3), 2.41 (s, 3H; PhCH3), 2.79 (dd, 1H, J=
14.1, 8.6 Hz; CH2Ph), 3.01 (dd, 1H, J=14.1, 5.4 Hz; CH2Ph), 3.36 (dd,
1H, J=13.7, 5.8 Hz; CH2N), 3.62–3.95 (m, 5H; CH2N+CO2CH3 +CH),
5.28 (d, 1H, J=6.3 Hz; NHSO2), 6.83–7.03 (m, 3H; PhCH3 +NHCO),
7.06–7.22 (m, 5H; Ph), 7.38–7.55 ppm (m, 2H; PhCH3); 13C NMR
(75 MHz, CDCl3): d=21.5 (PhCH3), 23.2 (CCH3), 38.2 (CH2Ph), 47.2
(CH2N), 53.1 (CO2CH3), 58.1 (CH), 74.5 (CCH3), 127.0, 128.8, 129.0,
129.1, 129.7, 135.2, 135.3, 143.7 (Ph), 171.1 (CON), 175.6 ppm (CO2); ele-
mental analysis calcd (%) for (C21H26N2O6S): C 58.05, H 6.03, N 6.45, S
7.38; found: C 58.22, H 6.05, N 6.47, S 7.36; ESI+: m/z: 435.5.
Isopentyl
(S)-2-isopentoxy-2-methoxycarbonylaminomethylpropanoate
((S)-3i): Compound (S)-3i (121 mg, 92%) was obtained as a colorless oil,
by starting from sulfamidate (R)-1i (128 mg, 0.41 mmol), after purifica-
tion by column chromatography (hexane/AcOEt 9:1). [a]2D5 =À0.6 (c=
1.23 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.72–0.98 (m, 12H;
CH2CH2CHACHTUNGTRENNUNG(CH3)2 +CH2CH2CHACHTUGNTREN(NGUN CH3)2), 1.29–1.71 (m, 9H; CCH3 +
9820
www.chemeurj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9810 – 9823

Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
(S)-N-(Tosyl)phenylalaninyl-(S)-a-methylisoserine methyl ester ((S,S)-7):
(S)-a-Methylisoserine hydrochloride (S)-5[12c,14,16] (78 mg, 0.34 mmol) was
dissolved in a mixture of MeOH/HCl, previously prepared by addition of
AcCl (4 mL) over MeOH (16 mL) at 08C. After refluxing for 10 h, the
solvent was evaporated, the residue was suspended in CH2Cl2 (10 mL)
under an inert atmosphere, and (S)-N-(p-tosyl)phenylalaninyl chloride
(150 mg, 0.44 mmol) and DIEA (176 mL, 1.00 mmol) were added. The re-
sulting solution was stirred at room temperature for 14 h. The reaction
was quenched by addition of aqueous 0.5m HCl (4 mL), the organic
phase was separated, and the aqueous phase was extracted with CH2Cl2
(3ꢅ15 mL). The combined organic phases were dried (Na2SO4), concen-
trated, and the crude reaction was purified by silica-gel column chroma-
tography (hexane/AcOEt 6:4), to give dipeptide (S,S)-7 (134 mg, 91%)
as an oil. [a]2D5 =À24.2 (c=1.15 in CHCl3); NMR spectroscopic data
agree with those described above; elemental analysis calcd (%) for
(C21H26N2O6S): C 58.05, H 6.03, N 6.45, S 7.38; found: C 58.43, H 6.11, N
6.51, S 7.40; ESI+: m/z: 435.5.
another 16 h. The solvent was evaporated and the residue was purified
directly by silica-gel column chromatography (hexane/AcOEt 8:2) to give
compound (R)-10 as a colorless oil (104 mg, 76%). [a]2D5 =À35.2 (c=1.34
in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.54 (s, 9H; C
ACTHNUGTRNEUGN(CH3)3), 1.80
(s, 3H; CCH3), 3.82–3.93 (m, 4H; CH2N+CO2CH3), 4.48 ppm (d, 1H,
J=10.2 Hz; CH2N); 13C NMR (75 MHz, CDCl3): d=23.0 (CCH3), 27.9,
29.7 (CACTHNUTRGENNG(U CH3)3), 52.8 (CH2N), 53.8 (CO2CH3), 82.7, 86.0 (CCH3, CACHTUNGTRENNUNG(CH3)3),
148.2 (NCO), 168.6 ppm (CO2); elemental analysis calcd (%) for
(C10H17NO7S): C 40.67, H 5.80, N 4.74, S 10.86; found: C 40.95, H 5.84, N
4.77, S 10.94; ESI+: m/z: 296.3.
Methyl (S)-2-bromo-3-methoxycarbonylamino-2-methylpropanoate ((S)-
11): Et4NBr (404 mg, 1.25 mmol) was added to a solution of sulfamidate
(R)-1b (289 mg, 1.14 mmol) in CH3CN (20 mL) and the mixture was
stirred at 258C for 20 h. The solvent was evaporated and the residue dis-
solved into a mixture of 20% H2SO4/CH2Cl2 1:1 and stirred for 8 h to hy-
drolize the sulfamic acid intermediate. The organic phase was separated
and the aqueous phase was extracted with AcOEt (3ꢅ15 mL). The com-
bined organic phases were dried (Na2SO4), concentrated, and the residue
was purified by silica-gel column chromatography (hexane/AcOEt 8:2),
to give compound (S)-11 as a colorless oil (194 mg, 76%). [a]2D5 =À11.0
(S)-N-(Tosyl)phenylalaninyl-(R)-a-methylisoserine methyl ester ((S,R)-
7): Following the same protocol described for diastereomer (S,S)-7, di-
peptide (S,R)-7 was prepared from (R)-a-methylisoserine hydrochloride
(R)-5[12c„16] (54 mg, 0.24 mmol) as an oil (91 mg, 87%). [a]2D5 =À32.2 (c=
1.23 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.36 (s, 3H; CCH3),
2.40 (s, 3H; PhCH3), 2.80 (ddd, 1H, J=8.4, 14.2, 17.3 Hz; CH2Ph), 2.98
(ddd, 1H, J=5.7, 9.7, 13.8 Hz; CH2Ph), 3.32 (ddd, 1H, J=5.4, 13.7,
17.0 Hz; CH2N), 3.67 (dd, 1H, J=6.9, 13.7 Hz; CH2N), 3.73–3.93 (m, 4H;
CO2CH3 +CH), 5.29 (d, 1H, J=6.6 Hz; NHSO2), 6.84–7.03 (m, 3H;
PhCH3 +NHCO), 7.05–7.24 (m; 5H; Ph), 7.39–7.62 ppm (m, 2H;
PhCH3); 13C NMR (75 MHz, CDCl3): d=21.5 (PhCH3), 23.2, 23.3
(CCH3), 38.2 (CH2Ph), 47.2, 47.4 (CH2N), 53.1 (CO2CH3), 57.9, 58.1
(CH), 74.3, 74.5 (CCH3), 127.0, 127.1, 128.4, 128.8, 129.0, 129.5, 129.6,
129.7, 135.2, 135.3, 135.4, 143.7 (Ph), 171.2, 171.3 (CON), 175.4,
175.5 ppm (CO2); elemental analysis calcd (%) for (C21H26N2O6S): C
58.05, H 6.03, N 6.45, S 7.38; found: C 58.61, H 6.13, N 6.53, S 7.40;
ESI+: m/z: 435.5.
1
(c=1.65 in CHCl3); H NMR (300 MHz, CDCl3): d=1.86 (s, 3H; CCH3),
3.54–3.87 (m, 8H; COCH3 +CH2N+COCH3), 5.10–5.46 ppm (m, 1H;
NH); 13C NMR (75 MHz, CDCl3): d=25.5 (CCH3), 49.8 (CH2N), 52.3,
53.3, (COCH3 +CO2CH3), 58.4 (CCH3), 157.0 (NCO), 171.0 ppm (CO2);
elemental analysis calcd (%) for (C7H12BrNO4): C 33.09, H 4.76, N 25.19;
found: C 33.32, H 4.79, N 25.37; ESI+: m/z: 255.1.
(R)-Dimethyl 2-methylaziridine-1,2-dicarboxylate ((R)-12): Potassium
tert-butoxide (1m in THF, 0.2 mL, 0.22 mmol) was added dropwise to a
solution of compound (S)-11 (62 mg, 0.24 mmol) in THF (5 mL) under
an argon atmosphere at 08C. The mixture was stirred at 08C for 12 h and
the resulting white suspension was filtered and washed with cold THF
and AcOEt to obtain aziridine (R)-12 as a white solid (18 mg, 43%). The
spectroscopic data obtained for this compound are in accordance with
those reported in the literature.[25]
Methyl
(S)-2-methoxycarbonylaminomethyl-2-(n-propoxy)propanoate
Computational details: All calculations were carried out with the B3LYP
((S)-8): Sulfamidate (R)-1b (116 mg, 0.46 mmol) was dissolved in nPrOH
and the solution was heated at 558C for 96 h at which point total con-
sumption of starting material was observed by TLC. After evaporating
the solvent, the residue was purified by silica-gel column chromatography
(hexane/AcOEt 9:1) to give the ring-opening product (S)-8 (88 mg, 82%)
as a colorless oil. [a]2D5 =À11.8 (c=0.90 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=0.85 (t, 3H, J=7.4 Hz; CH2CH2CH3), 1.34 (s, 3H; CCH3),
1.44–1.58 (m, 2H; CH2CH2CH3), 3.23–3.40 (m, 3H; COCH2 +CH2N),
3.47 (dd, 1H, J=13.7, 6.5 Hz; CH2N), 3.54–3.71 (m, 6H; CO2CH3 +
CO2CH3), 4.73–5.07 ppm (m, 1H; NH); 13C NMR (100 MHz, CDCl3): d=
10.5 (CH2CH2CH3), 19.3 (CCH3), 23.3 (CH2CH2CH3), 47.6 (CH2N), 52.2
hybrid functional[28] and 6-31+G
ACTHUNRTGNE(GNU d,p) basis set. Full geometry optimiza-
tions and transition structure searches were carried out with the Gaussi-
an 03 package.[29] The possibility of different conformations was taken
into account for all structures. Basis set superposition errors (BSSE)
were corrected by the Boys–Bernardi counterpoise method.[30] Frequency
analyses were carried out at the same level used in the geometry optimi-
zations, 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.[31] Where necessary, mass-weighted intrinsic reaction co-
ordinate (IRC) calculations were carried out by using the Gonzalez and
Schlegel scheme[32] to ensure that the TSs indeed connected the appropri-
ate reactants and products. Solvent effects were taken into account
through the polarized continuum model (IEF-PCM)[33] by using UAHF
radii, as implemented in Gaussian 03. The internally stored parameters
for methanol were used to calculate solvation free energies (DGsolv).
Gibbs free energies (DG) were used for the discussion on the relative sta-
bilities of the considered structures. Cartesian coordinates, electronic en-
ergies, entropies, enthalpies, Gibbs free energies, and lowest frequencies
of the different conformations of all structures considered are available
as Supporting Information.
(CO2CH3
+ CO2CH3), 66.2 (COCH2), 79.1 (CCH3), 157.1 (NCO),
173.2 ppm (CO2); elemental analysis calcd (%) for (C10H19NO5): C 51.49,
H 8.21, N 6.00; found: C 51.61, H 8.23, N 6.02; ESI+: m/z: 234.3.
(S)-2-Aminomethyl-2-(n-propoxy)propanoic acid hydrochloride ((S)-9):
Compound (S)-8 (71 mg, 0.30 mmol) was suspended in aqueous 6m HCl
(5 mL) and the mixture was heated at 908C for 48 h. After evaporation
of the solvent, the residue was dissolved in water (2 mL) and was eluted
through a C18 reverse-phase Sep-pak cartridge to give, after evaporation,
the corresponding hydrochloride (S)-9 as a white solid (57 mg, 95%).
1
[a]2D5 =À4.8 (c=1.01 in H2O); H NMR (300 MHz, D2O): d=0.87 (t, 3H,
J=7.4 Hz; CH2CH2CH3), 1.49 (s, 3H; CH3), 1.51–1.66 (m, 2H;
CH2CH2CH3), 3.11–3.54 ppm (m, 4H; COCH3 +CH2N); 13C NMR
(75 MHz, D2O): d=12.0 (CH2CH2CH3), 21.3 (CH3), 25.0 (CH2CH2CH3),
46.7 (CH2N), 69.1 (COCH2), 79.1 (CCH3), 177.2 ppm (CO2); elemental
analysis calcd (%) for (C7H16ClNO3): C 42.54, H 8.16, N 7.09; found: C
42.71, H 8.19, N 7.11; ESI+: m/z: 162.2.
X-ray diffraction analysis
Crystal data for (R)-1c: C8H13NO7S; Mw =267.25; colorless prism of
0.40ꢅ0.20ꢅ0.05 mm; T=100 K; orthorhombic; space group; P212121; Z=
4; a=8.2030(5), b=9.3790(7), c=14.9320(10) ꢃ; a=b=g=908; V=
1148.81(13) ꢃ3; 1calcd =1.545 gcmÀ3; F
m=0.306 mmÀ1
ACHTUNGTRENNUNG
tert-Butyl
(R)-5-methoxycarbonyl-5-methyl-2,2-dioxo-2l6-[1,2,3]oxa-
;
q
thiazolidine-3-carboxylate ((R)-10): Boc2O (123 mg, 0.56 mmol) and
Et3N (71 mL, 0.52 mmol) were added to a solution of sulfamidate (R)-2b
(91 mg, 0.47 mmol) in CH2Cl2 (10 mL), and the mixture was stirred at
258C for 16 h. A second portion of Boc2O (123 mg, 0.56 mmol) and Et3N
(71 mL, 0.52 mmol) was added and the mixture was stirred at 258C for
27.468; 14787 collected reflections, 2620 unique; full-matrix least-squares
(SHELXL97[34]), R1 =0.0825, wR2 =0.0752 (R1 =0.0731, wR2 =0.0830 all
data); goodness-of-fit=1.084; residual electron density=0.272-(À0.320)
eꢃÀ3; absolute structure parameter (Flack)=0.04(10); hydrogen atoms
Chem. Eur. J. 2009, 15, 9810 – 9823
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9821

J. M. Peregrina et al.
were located by mixed methods (electron-density maps and theoretical
positions).
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CCDC-691617 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We thank the Ministerio de Ciencia e Innovaciꢆn (project CTQ2006–
05825/BQU), the CSIC (JAE-doc program contract of F.R.) and the Uni-
versidad de La Rioja (doctoral fellowship of G.J.-O.). We also thank J.I.
Garcꢁa for his helpful comments and CESGA and IUCH for computer
support.
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9810 – 9823

Stereocontrolled Ring Opening of Hindered Sulfamidates
FULL PAPER
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Received: March 18, 2009
Revised: June 23, 2009
Published online: August 13, 2009
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9823