Rhodium-catalyzed intramolecular formation of N-sulfamoyl 2,3-aziridino-γ-lactones and their use for the enantiospecific synthesis of α,β-diamino acid derivatives

Article abstract of DOI:10.1021/jo300468j

4-Hydroxymethylbutenolide 4 was transformed into its sulfamoyl derivative 5, which upon treatment with iodosobenzene diacetate and magnesium oxide in the presence of a rhodium catalyst afforded the product of intramolecular aziridination 6. Reaction of 6 with primary or secondary amines in DMA led to regioselective opening of the aziridine ring at C2 to give the corresponding bicyclic derivatives 7a-7g in good to excellent yields. Methanolysis of the lactone ring of the N-benzyl-N-methyl derivative 7c followed by protection of the resulting secondary hydroxy group and treatment of the product with Boc anhydride provided the activated cyclic sulfamates 13 and 14. The latter then reacted with a second nucleophile (azide or thiophenol) to give the corresponding difunctionalized α,β-diamino methyl esters 15-18, 20.

Full text of DOI:10.1021/jo300468j

Article
pubs.acs.org/joc
Rhodium-Catalyzed Intramolecular Formation of N-Sulfamoyl 2,3-
Aziridino-γ-lactones and Their Use for the Enantiospecific Synthesis
of α,β-Diamino Acid Derivatives
Marcelo Siqueira Valle,†,§,⊥ Mauricio Frota Saraiva,†,∥,⊥ Pascal Retailleau,† Mauro V. de Almeida,‡
and Robert H. Dodd*,†
†Centre de recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse,
91198 Gif-sur-Yvette, France
‡Departamento de Química, Instituto de Cien
̂
cias Exatas, Universidade Federal de Juiz de Fora, 36036-330, Juiz de Fora, MG, Brazil
S
* Supporting Information
ABSTRACT: 4-Hydroxymethylbutenolide 4 was transformed
into its sulfamoyl derivative 5, which upon treatment with
iodosobenzene diacetate and magnesium oxide in the presence
of a rhodium catalyst afforded the product of intramolecular
aziridination 6. Reaction of 6 with primary or secondary
amines in DMA led to regioselective opening of the aziridine ring at C2 to give the corresponding bicyclic derivatives 7a−7g in
good to excellent yields. Methanolysis of the lactone ring of the N-benzyl-N-methyl derivative 7c followed by protection of the
resulting secondary hydroxy group and treatment of the product with Boc anhydride provided the activated cyclic sulfamates 13
and 14. The latter then reacted with a second nucleophile (azide or thiophenol) to give the corresponding difunctionalized α,β-
diamino methyl esters 15−18, 20.
thorough methodological study of the reaction, showing that
copper(I) and (II) salts were the most efficient catalysts for
generating the reactive nitrene species from the iminoiodanes
and that the aziridination could be made stereoselective by
including chiral ligands in the reaction mixture (Figure 3).
The advent of one-pot procedures whereby the arylsulfony-
liminoiodanes are generated in situ by reaction of the
arylsulfonamide and iodosylbenzene PhIO or iodosophenyl
diacetate PhI(OAc)2 circumvented the necessity of preparing
these sensitive reagents beforehand.16 This procedure also
allowed extension of the aziridination reaction to its intra-
molecular version starting from olefinic sulfonamides. Besides
being more reactive, replacement of the sulfonamide by a
sulfamate in these intramolecular reactions introduces another
electrophilic center, which after nucleophilic aziridine opening
and sulfamate activation, allows further chemical trans-
formations of the substrate (Figure 4).17 In this regard, we
have recently described a copper-catalyzed stereocontrolled
version of this intramolecular olefin aziridination starting from
sulfamates17b as well as its application to the synthesis of
neuroactive steroid analogues.18
INTRODUCTION
■
2,3-Aziridino-γ-lactones have been shown to be valuable
starting materials for the preparation of α- and β-amino
acids.1−5 Unlike the well-documented aziridino-2-carboxylic
esters, known to react with nucleophiles almost always at the C-
3 position to give the corresponding α-amino acids,6 2,3-
aziridino-γ-lactones show different reactivity depending on the
type of nucleophile used. Thus, while hard nucleophiles (e.g.,
alcohols) also react exclusively at the C-3 position in SN2
fashion to afford optically pure α-amino acids, soft nucleophiles
(e.g., thiols, azide, indole, halides) attack only at the C-2
position, leading to the formation of α-substituted β-amino
acids (Figure 1).
This particular reactivity of aziridino-γ-lactones has been
successfully applied to the enantiospecific synthesis of the α-
amino acids (2S,3S,4S)-dihydroxyglutamic acid (1)7,8 and
(−)-polyoxamic acid (2)9 as well as to a protected form of
APTO (3),10 the β-amino acid component of the marine cyclic
depsipeptide, microsclerodermin D (Figure 2).
Several methodologies have been developed that allow access
to 2,3-aziridino-γ-lactones. All of these are multistep procedures
starting from D-ribose (or D-lyxose)1,2 or from a butenone
derivative.10,11 The synthesis of 2,3-aziridino-γ-lactones from β-
lactams has also been described.12
The direct aziridination of olefins by nitrenes generated from
metal-catalyzed formation of metallanitrenes from hypervalent
iodine reagents such as arylsulfonyliminoiodanes PhI
NSO2Ar is a subject of considerable current synthetic interest.13
The initial premises of the reaction having been established by
Mansuy and co-workers,14 it was Evans15 who conducted a
In this paper then, we wish to report the adaptation of this
procedure to the intramolecular aziridination of the sulfamate 5
derived from commercially available butenolide 4, the reactivity
of the product toward nucleophiles, and application of the
procedure to the synthesis of α,β-diamino acids (Figure 5).
Many examples of the latter are found in nature or as
Received: April 9, 2012
Published: June 5, 2012
© 2012 American Chemical Society
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Figure 1. Reactivity of aziridino-γ-lactones.
RESULTS AND DISCUSSION
■
Butenolide 4 was first treated with chlorosulfonylisocyanate and
formic acid in DMA to give the corresponding 5-O-sulfamate 5
in 62% yield.17 Surprisingly, attempted aziridination of
sulfamate 6 using the standard conditions shown to be
successful for intramolecular aziridination of olefinic sulfamates
(10 mol % Cu(CH3CN)4PF6, 1.2 equiv of PhIO, molecular
sieves in CH3CN)17 resulted only in complete recovery of
starting material despite prolonged reaction times. The use of
different copper salts and solvents had no visible effects on this
outcome. We thus decided to resort to rhodium catalysts to
effect this reaction. The use of rhodium complexes for
aziridination of olefins by sulfonamides and sulfamates (usually
in the presence of PhI(OAc)2) has been well described.20
However, in contrast to copper catalysis, rhodium catalysts tend
to favor C−H insertion at allylic or benzylic carbons if this
possibility exists on the substrate rather than aziridination.13a,21
This is indeed the case with butenolide 5, the allylic C-4
position being in principle susceptible to C−H amination by
the sulfamate. Du Bois and co-workers have described a highly
effective rhodium complex, Rh2(esp)2 (esp = α,α,α′,α′-
tetramethyl-1,3-benzenedipropionic acid), useful for the
aziridination of olefins.22 We thus decided to apply Du Bois’
reaction conditions (5 mol % Rh2(esp)2, 1.2 equiv of
PhI(OAc)2 and MgO in CH3CN at rt for 4 h) to substrate
5, and we were pleased to obtain the desired aziridine-lactone 6
in 50% yield with no trace by NMR of the competing product
of C−H allylic amination (Scheme 1).
Figure 2. α- and β-amino acids prepared from 2,3-aziridino-γ-lactones.
Figure 3. Copper-catalyzed iminoiodane-mediated aziridination of
olefins.
The structure of compound 6 was confirmed by X-ray
Figure 4. Intramolecular aziridination of olefinic sulfamates and
reaction with nucleophiles.
crystallography (see the Supporting Information).23
We then proceeded to study the reactivity of cyclic
sulfonamide 6 toward various amines. Compound 6 being
quite poorly soluble in apolar organic solvents, the first
experiments using benzylamine as nucleophile were run in
DMF at room temperature. As shown in Table 1 (entry 1), the
only product isolated after 24 h from the complicated reaction
mixture was compound 8a, obtained in only 22% yield, the
result of lactone opening by the amine to give the benzylamide
followed by attack at the C-3 position. The structure of
compound 8a was unambiguously determined by an X-ray
crystallographic study (see the Supporting Information).24
Similarly, the more reactive o,p-dimethoxybenzylamine pro-
vided 8b, obtained in only 23% yield (Table 1, entry 3). More
satisfactory results were obtained when DMA was used as the
solvent. Thus, both benzylamine and o,p-dimethoxybenzyl-
amine now provided only the products of C-2 attack of
aziridine 6, that is, compounds 7a and 7b, in 70 and 58% yields,
respectively, after only 1−1.5 h reaction times (Table 1, entries
2 and 4). Using DMA as solvent, secondary amines also gave
the products of type 7, though reaction times increased and
yields decreased as the steric bulk of the nucleophile increased.
N-Methyl-, N-ethyl-, and N-benzyl-benzylamine thus furnished
products 7c, 7d, and 7e in 80, 55, and 35% yields after 1, 48,
and 120 h reaction times, respectively (Table 1, entries 5−7).
Figure 5. Proposed synthesis of aziridino-γ-lactones via intramolecular
aziridination by a sulfamate and use for preparation of α,β-diamino
acids.
components of natural products. Moreover, α,β-diamino acids
form the core structure of a wide variety of therapeutically
useful drugs.19
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Scheme 1
Table 1. Reaction of Cyclic Sulfonamide 6 with Various Amines
a
entry
R
R′
solvent
time (h)
cpd no.
yield (%)
70
cpd no.
yield (%)
1
2
3
4
5
6
7
8
9
Bn
Bn
H
DMF
DMA
DMF
DMA
DMA
DMA
DMA
DMA
DMA
24
1
7a
7a
7b
7b
7c
7d
7e
7f
8a
8a
8b
8b
8c
8d
8e
8f
22
23
H
o,p-(MeO)2Bn
H
24
1.5
1
o,p-(MeO)2Bn
H
58
80
55
35
60
20
Bn
Bn
Bn
Ph
Et
Me
Et
48
120
48
1
Bn
Me
Et
7g
8g
a
Yields reported are after purification by column chromatography.
N-Phenyl-N-methylamine also provided a satisfactory yield of
C-2 ring-opened product 7f (60%; Table 1, entry 8), while
diethylamine gave product 7g in only 20% yield (Table 1, entry
9).
Opening of the aziridine ring of compound 6 by a hard
nucleophile, methanol, proved surprisingly difficult. After 2
days of reflux in a 1:1 mixture of methanol and THF (the latter
added to ensure solubility) and in the presence of 1 equiv of
boron trifluoride etherate, a 51% yield of the expected product
of C-3 attack, compound 9, was obtained, accompanied by 14%
of the product corresponding to methanolysis of the lactone
function of 9, that is, compound 10 (Scheme 2).25
pyridine to give 12. Transformation of the sulfamate 12 into its
activated N-Boc derivative 13 was then accomplished by
reaction with Boc anhydride and DMAP in DMF. The overall
yield of 13 was 85% for the 3 steps.
Alternatively, the secondary OH group of compound 11
could be benzylated using benzyl trichloroacetimidate and TFA
in CH2Cl2/cyclohexane to give, after treatment with Boc
anhydride, compound 14 (Scheme 4). The overall yield for the
three steps was in this case slightly lower (60%).
Reaction of the activated sulfamates with nucleophiles was
then investigated. Gratifyingly, reaction of the O-acetyl
derivative 13 with sodium azide in DMA provided the 5-
azido α,β-diamino ester 15, the product of sulfamate ring-
opening followed by loss of SO3. The O-benzyl derivative 14
provided, under the same reaction conditions, the analogous 5-
azido product 16 in 65% yield. Similarly, phenylthiolate reacted
with 13 to give the 5-thiophenyl analogue 17 in 77% yield
(Scheme 5).
Scheme 2
The advantage of the O-benzyl versus the O-acetyl protecting
group in 16 and 15, respectively, became apparent during initial
attempts at deprotection of these compounds. Thus, treatment
of 15 with TFA in CH2Cl2 effectively removed the Boc group,
but this was accompanied by O- to N-migration of the acetyl
group, affording 18 in 66% yield accompanied by 19, the
product of lactonization, isolated in 25% yield (Scheme 6). On
the other hand, similar treatment of the O-Bn derivative 16
with TFA allowed smooth conversion to the free β-amino
compound 20 in 80% yield.
Our primary objective being the preparation of α,β-diamino
acids, we next studied the reactivity of the cyclic sulfamate after
amine-promoted aziridine opening of 6. For this model study,
the N-benzyl-N-methyl derivative 7c was chosen as starting
material. Reaction of the latter with methanol at room
temperature for 4 days provided the methyl ester 11 (Scheme
3). In order to avoid relactonization, the free hydroxy function
of 11 was immediately acetylated using acetic anhydride in
In conclusion, we have developed an efficient intramolecular
rhodium-catalyzed, iminoiodane-mediated aziridination of 4-
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Scheme 3
Scheme 4
Scheme 6
sulfamoylmethylbutenolide to give the corresponding aziridino-
γ-lactone. Regioselective opening of the aziridine ring with
amines followed by cyclic sulfamate activation and nucleophilic
opening then gives access to α,β-diamino acids. The procedure
allows for the stereospecific preparation of highly substituted
derivatives, which can be useful for the preparation of natural
products or therapeutic agents. Studies in this direction are
presently being pursued.
organic phase was collected, and the aqueous layer was extracted with
EtOAc (2 × 15 mL). The organic extracts were combined, washed
with saturated aqueous NaCl solution (2 × 30 mL), dried over
MgSO4, and concentrated under reduced pressure. Purification of the
resulting residue by flash chromatography on silica gel (EtOAc/
heptane 9:1) afforded sulfamic ester 5 (521 mg, 2.7 mmol) in 62%
yield as a white amorphous solid: Rf 0.2 (EtOAc/heptane 7:3); IR
(film) 3354, 3204, 3098, 1737, 1726, 1567, 1365, 1276, 1163, 1092,
1051, 987, 928 cm−1; 1H NMR (500 MHz, (CD3)2CO) δ 4.31 (dd, J =
5.1 Hz, J = 11.3 Hz, 1H), 4.52 (dd, J = 11.3 Hz, J = 3.2 Hz, 1H), 5.44
(m, 1H), 6.26 (dd, J = 2.1 Hz, J = 11.3 Hz, 1H), 6.84 (br s, 2H), 7.74
(dd, J = 1.5 Hz, J = 5.7 Hz, 1H); 13C NMR (75 MHz, (CD3)2CO) δ
68.3, 81.4, 126.3, 154.1, 172.9; HREIMS m/z calcd for
[C5H7NO5SNa]+ 215.9943, found 215.9946.
EXPERIMENTAL SECTION
■
General Methods. Melting points, measured in capillary tubes, are
uncorrected. IR spectra were recorded on an FT-IR spectrometer.
Optical rotations were determined at 20 °C. Proton (1H) and carbon
(13C) NMR spectra were recorded in CDCl3 unless otherwise stated.
Chemical shifts (d) are reported in parts per million with reference to
CDCl3 (1H, 7.27; 13C, 77.00), CD3OD (1H, 3.31; 13C, 49.00), D2O
(1H, 4.79) or DMSO-d6 (1H, 2.50; 13C, 39.51). The following
abbreviations are used for the proton spectra multiplicities: s, singlet;
d, doublet; t, triplet; q, quartet; qu, quintuplet; m, multiplet; br, broad.
Coupling constants (J) are reported in Hertz (Hz). Mass spectra were
obtained using electrospray ionization and a time of flight analyzer
(ESI-MS) for high resolution mass spectra (HRMS). Thin-layer
chromatography was performed on silica gel-coated aluminum plates
and visualized under a UV lamp (254 nm) and with a solution of p-
anisaldehyde (5%) in ethanol/H2SO4/AcOH (90/5/1) or a solution
of ninhydrin (2% in ethanol). Flash chromatography was performed
on silica gel at medium pressure (300 mbars). All solvents were freshly
distilled when required. Rh2(esp)2 was purchased from Sigma-Aldrich.
(S)-(5-Oxo-2,5-dihydrofuran-2-yl)methyl Sulfamate (5).
HCO2H (331 mL, 8.76 mmol) was added dropwise to neat
OCNSO2Cl (658 mL, 8.76 mmol) at 0 °C with vigorous stirring.26
Gas evolved during addition. The resulting viscous suspension was
stirred for 18 h at rt. The mixture was cooled to 0 °C, DMA (2 mL)
was added, and the solution was stirred for 5 min. A solution of alcohol
4 (500 mg, 4.38 mmol) in DMA (2 mL) was added dropwise, the
reaction was allowed to warm to rt, and stirring was continued until
the reaction was complete (2−3 h) as determined by TLC. The
reaction was quenched by the successive addition of EtOAc (30 mL)
and saturated aqueous NaCl solution (15 mL). The mixture was
poured into a mixture of EtOAc (40 mL) and H2O (15 mL). The
(1R,6S,9S)-2-Aza-4,7-dioxa-3-thiatricyclo[4.3.0.0]nonan-8-
one (6). To a suspension of sulfamate 5 (585 mg, 3.03 mmol) in
CH3CN (15 mL) were added successively MgO (40.3 mg, 281 mmol),
PhI(OAc)2 (1.07 g, 3.33 mmol), and Rh2(esp)2 (46 mg, 0.06 mmol).
The reaction mixture was refluxed during 2 h, cooled, and filtered
through a pad of Celite, which was washed with acetone. The filtrate
was concentrated under reduced pressure, and the crude product was
taken up in methanol. A white precipitate formed, which was collected
by filtration and washed with methanol affording aziridine 6 (274 mg,
1.56 mmol) in 52% yield: Rf 0.30 (EtOAc/heptane 7:3); [α]D20 = −7.0
(c 1.71, acetone); mp 185 °C (decomp.); IR (film) 1785, 1379, 1076,
1
985, 774, 678 cm−1; H NMR (300 MHz, (CD3)2CO) δ 3.99 (d, J =
3.7 Hz), 4.59 (m, 1H), 4.65 (dd, J = 2.7 Hz, J = 12.4 Hz, 1H), 5.00
(dd, J = 0.6 Hz, J = 12.4 Hz), 5.17 (m, 1H); 13C NMR (75 MHz,
(CD3)2CO) δ 45, 51.8, 68.6, 74.3, 167.1; HRESMS m/z calcd for
[C5H4NO5S]− 189.9810, found 189.9808. The structure of compound
6 was confirmed by single-crystal X-ray crystallography (see the
Supporting Information).
(4aS,7R,7aR)-7-(Benzylamino)tetrahydrofuro[3,2-d][1,2,3]-
oxathiazin-6(1H)-one 2,2-Dioxide (7a). To a solution of aziridine 6
(20 mg, 0.1 mmol) in DMA (1 mL) under argon at room temperature
was added benzylamine (14 μL, 0.12 mmol, 1.2 equiv). The reaction
mixture was stirred for 1 h and diluted with EtOAc (3 mL) and
Scheme 5
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saturated aqueous NaCl (3 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 3 mL). The organic
extracts were combined, dried over MgSO4, and evaporated to dryness
under vacuum. The residue obtained was purified by chromatography
on silica gel (EtOAc/heptane 7:3) to furnish compound 7a (20.1 mg,
0.07 mmol, 70% yield) as a colorless oil: 1H NMR (300 MHz, CDCl3)
δ 3.59 (s, J = 2.0 Hz, 1H), 3.90 (s, 2H), 4.29 (dd, J = 1.9 Hz, J = 4.1
Hz, 1H), 4.65 (m, 1H), 4.82 (dd, J = 1.6 Hz, J = 13.6 Hz, 1H), 4.89
(dd, J = 2.5 Hz, J = 13.6 Hz, 1H), 7.24−7.44 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 52.2, 59.9, 62.3, 70.2, 71.2, 127.9, 128.3, 128.8, 137.9,
173.3; IR 3165, 3013, 2924, 2853, 2746, 1737, 1633, 1552, 1430, 1360,
1060; HRESMS m/z calcd for [C14H18N2O5SNa]+ 349.0834, found
349.0834.
(4aS,7R,7aR)-7-[Dibenzylamino]tetrahydrofuro[3,2-d][1,2,3]-
oxathiazin-6(1H)-one 2,2-Dioxide (7e). To a solution of aziridine
6 (20 mg, 0.1 mmol) in DMA (1 mL) under argon at room
temperature was added N,N-dibenzylamine (28 μL, 0.18 mmol; 1.4
equiv). The reaction mixture was stirred for 5 days and diluted with
EtOAc (1 mL) and saturated aqueous NaCl (3 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 3
mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 7:3) to
furnish compound 7e (13.5 mg, 0.03 mmol, 35% yield) as a colorless
oil: 1H NMR (300 MHz, (CD3)2CO) δ 3.83 (s, 4H), 3.96 (d, 1H, J =
3.4 Hz), 4.75−4.80 (m, 2H), 4.87 (dd, 1H, J = 13.5 Hz, J = 2.8 Hz),
4.90 (m, 1H), 7.05 (d, 1H, J = 5.8 Hz), 7.23−7.43 (m, 10H); 13C
NMR (75 MHz, (CD3)2CO) δ 55.8, 57.0, 64.7, 71.8, 72.2, 128.3,
129.3, 129.7, 139.1, 173.7; HRESMS m/z calcd for
[C19H20N2O5SNa]+ 411.0991, found 411.0987.
(4aS,7R,7aR)-7-[Phenyl(methyl)amino]tetrahydrofuro[3,2-d]-
[1,2,3]oxathiazin-6(1H)-one 2,2-Dioxide (7f). To a solution of
aziridine 6 (20 mg, 0.1 mmol) in DMA (1 mL) under argon at room
temperature was added N,N-methylphenylamine (20 μL, 0.13 mmol,
1.3 equiv). The reaction mixture was stirred for 2 days and diluted
with EtOAc (3 mL) and saturated aqueous NaCl (3 mL). The layers
were separated, and the aqueous layer was extracted with EtOAc (2 ×
3 mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 6:4) to
1181, 1024, 941, 749 cm−1
; HRESMS m/z calcd for
[C12H14N2O5SNa]+ 321.0521, found 321.0532.
(4aS,7R,7aR)-7-[(2,4-Dimethoxybenzyl)amino]-
tetrahydrofuro[3,2-d][1,2,3]oxathiazin-6(1H)-one 2,2-Dioxide
(7b). To a solution of aziridine 6 (20 mg, 0.1 mmol) in DMA (1
mL) under argon at room temperature was added 2,4-dimethox-
ybenzylamine (20 μL, 0.13 mmol, 1.3 equiv). The reaction mixture
was stirred for 1.5 h and diluted with EtOAc (3 mL) and saturated
aqueous NaCl (3 mL). The layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 3 mL). The organic extracts were
combined, dried over MgSO4, and evaporated to dryness under
vacuum. The residue obtained was purified by chromatography on
silica gel (EtOAc/heptane 7:3) to furnish compound 7b (20.7 mg,
0.058 mmol, 58% yield) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 3.42 (s, 1H), 3.79 (s, 3H), 3.84 (s, 3H), 3.85 (s, 2H), 4.47
(dd, J = 6.4 Hz, J = 3.6 Hz, 1H), 4.80 (m, 1H), 4.91 (dd, J = 13.9 Hz, J
= 1.4 Hz, 1H), 4.98 (dd, J = 13.9 Hz, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3
Hz, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H),
7.22 (d, J = 8.3 Hz); 13C NMR (75 MHz, CDCl3) δ 46.7, 55.6, 55.8,
60.7, 62.7, 71.1, 72.4, 99.2, 105.0, 119.8, 131.6, 159.7, 161.6, 174.1; IR
(film, ν, cm−1) 3211, 2939, 2839, 1784, 1515, 1368, 1261, 1204, 766
cm−1; HRESMS m/z calcd for [C14H18N2O7SNa]+ 381.0733, found
381.0698.
(4aS,7R,7aR)-7-[Benzyl(methyl)amino]tetrahydrofuro[3,2-d]-
[1,2,3]oxathiazin-6(1H)-one 2,2-Dioxide (7c). To a solution of
aziridine 6 (20 mg, 0.1 mmol) in DMA (1 mL) under argon at room
temperature was added N-methylbenzylamine (17 μL, 0.13 mmol, 1.3
equiv). The reaction mixture was stirred for 1 h and diluted with
EtOAc (3 mL) and saturated aqueous NaCl (3 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 3
mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 7:3) to
furnish compound 7f (17.8 mg, 0.06 mmol, 60% yield) as a white
1
amorphous solid: [α]20 = +56.8 (c 1.0. (CH3)2CO); H NMR (300
D
MHz, (CD3)2CO) δ 2.93 (s, 3H), 4.71 (m, 1H), 4.89 (m, 2H), 5..05−
5.09 (m, 2H), 6.82 (m, 1H), 6.97 (m, 2H), 7.26 (m, 2H), 7.38 (br s,
1H); 13C NMR (75 MHz, (CD3)2CO) δ 35.6, 57.6, 64.4, 72.1, 72.5,
115.5, 120.0, 130.1, 150.0, 171.8; HRESMS m/z calcd for
[C12H14N2O5SNa]+ 321.0521, found 321.0535.
(4aS,7R,7aR)-7-[Diethylamino]tetrahydrofuro[3,2-d][1,2,3]-
oxathiazin-6(1H)-one 2,2-Dioxide (7g). To a solution of aziridine
6 (30 mg, 0.15 mmol) in DMA (1 mL) under argon at room
temperature was added N,N-diethylamine (19.6 μL, 0.18 mmol; 1.2
equiv). The reaction mixture was stirred for 1 h and diluted with
EtOAc (3 mL) and saturated aqueous NaCl (3 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 3
mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 1:1) to
furnish compound 7g (7.9 mg, 0.03 mmol, 20% yield) as a colorless
furnish compound 7c (24.1 mg, 0.08 mmol, 80% yield) as a white
1
amorphous solid: [α]26 = +49.9 (c 1.0, (CH3)2CO); H NMR (300
D
oil: [α]21 = +47.4 (c 1.0, (CH3)2CO); 1H NMR (500 MHz,
MHz, (CD3)2CO) δ 2.34 (s, 3H), 3.80 (d, 1H, J = 3.2 Hz), 3.82 (s,
2H), 4.71 (dd, 1H, J7a‑7 = 5.5 Hz, J7a‑4a= 3.4 Hz), 4.81−4.92 (m, 2H),
4.93−4.95 (m, 1H), 7.14 (br s, 1H), 7.23−7.39 (m, 5H); 13C NMR
(75 MHz, (CD3)2CO), 75 MHz) δ 39.2, 57.5, 59.8, 68.2, 71.8, 72.5,
128.2, 129.2, 129.7, 139.1, 172.9; HRESMS m/z calcd for
[C13H15N2O5]− 311.0702, found 311.0703.
D
(CD3)2CO) δ 1.05 (t, 6H, J = 7.1 Hz), 2.71 (q, 4H, J = 7.1 Hz), 3.90
(d, 1H, J = 3.9 Hz), 4.53 (m, 1H), 4.80−4.87 (m, 2H), 4.90 (m, 1H),
7.22 (br s, 1H); 13C NMR (125 MHz, (CD3)2CO) δ 13.2, 45.4, 57.9,
65.2, 71.7, 72.5, 173.4; HRESMS m/z calcd for [C9H16N2O5SNa]+
287.0678, found 287.0681.
(4aS,7R,7aR)-7-[Benzyl(ethyl)amino]tetrahydrofuro[3,2-d]-
[1,2,3]oxathiazin-6(1H)-one 2,2-Dioxide (7d). To a solution of
aziridine 6 (20 mg, 0.1 mmol) in DMA (1 mL) under argon at room
temperature was added N-ethylbenzylamine (14 μL, 0.13 mmol; 1.3
equiv). The reaction mixture was stirred for 48 h and diluted with
EtOAc (3 mL) and saturated aqueous NaCl (3 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 3
mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 6:4) to
(4S,5S,6S)-N-(2-Benzyl)-5-[(2-benzyl)amino]-6-hydroxy-
1,2,3-oxathiazepane-4-carboxamide 2,2-Dioxide (8a). To a
solution of aziridine 6 (40 mg, 0.21 mmol) in DMF (2 mL) under
argon at room temperature was added benzylamine (34 μL, 0.31
mmol, 1.5 equiv). The reaction mixture was stirred for 24 h and
diluted with EtOAc (3 mL) and saturated aqueous NaCl (3 mL). The
layers were separated, and the aqueous layer was extracted with EtOAc
(2 × 3 mL). The organic extracts were combined, dried over MgSO4,
and evaporated to dryness under vacuum. The residue obtained was
purified by chromatography on silica gel (EtOAc/heptane 7:3) to
furnish compound 8a (14 mg, 0.047 mmol, 22% yield) as an
amorphous white solid: 1H NMR (300 MHz, (CD3)2CO) δ 3.39, 3.48
(2× d, 2H, 2J = 12.8 Hz), 3.88 (br s, 3H), 4.06 (ddd, 1H, J = 10.7 Hz, J
= 3.7 Hz, J = 3.6 Hz), 4.22 (dd, 1H, J = 12.3 Hz, J = 10.7 Hz), 4.30 (m,
3H), 4.42 (2× d, 2H, J = 14.6 Hz), 7.06−7.25 (m, 11H); 13C NMR
(75 MHz, (CD3)2CO) δ 43.9, 53.2, 56.4, 60.2, 67.7, 69.5, 127.8, 127.9,
128.7, 129.1, 129.2, 139.9, 169.3; HRESMS m/z calcd for
furnish compound 7d (17.9 mg, 0.055 mmol, 55% yield) as a white
1
amorphous solid: [α]23 = +51.6 (c 1.0. (CH3)2CO); H NMR (300
D
MHz, (CD3)2CO) δ 1.08 (t, 3H, J = 7.1 Hz), 2.74 (q, 2H, J = 7.1 Hz),
3.81 (s, 2H), 4.06 (d, 1H, J = 4.5 Hz), 4.65 (m, 1H), 4.85 (m, 2H),
4.94 (m, 1H), 7.17 (d, 1H, J = 6.1 Hz), 7.22−7.41 (m, 5H); 13C NMR
(75 MHz, (CD3)2CO) δ 13.0, 46.3, 55.6, 57.6, 64.9, 71.9, 72.5, 128.0,
129.2, 129.4, 139.9, 173.5. IR (film) 3204, 1771, 1449, 1362, 1188,
5596
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The Journal of Organic Chemistry
Article
[C19H23N3O5SNa]+ 428.1256, found 428.1246. The structure of
compound 8a was confirmed by single-crystal X-ray crystallography
(see the Supporting Information).
furnish compound 13 (80 mg, 0.16 mmol, 85% yield after 3 steps) as a
colorless oil.
1
Compound 12: H NMR (300 MHz, CDCl3) δ 1.87 (s, 3H), 2.21
(s, 3H), 3.23 (d, 1H, J = 10.6 Hz), 3.53, 3.70 (2× d, 2H, 2J = 12.8 Hz),
( 4 S , 5 S , 6 S ) - N - ( 2 , 4 - D i m e t h o x y b e n z y l ) - 5 - [ ( 2 , 4 -
dimethoxybenzyl)amino]-6-hydroxy-1,2,3-oxathiazepane-4-
carboxamide 2,2-Dioxide (8b). To a solution of aziridine 6 (20 mg,
0.1 mmol) in DMF (2 mL) under argon at 0 °C was added 2,4-
dimethoxybenzylamine (22.5 μL, 0.15 mmol, 1.5 equiv). The reaction
mixture was stirred for 24 h and diluted with EtOAc (3 mL) and
saturated aqueous NaCl (3 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 3 mL). The organic
extracts were combined, dried over MgSO4, and evaporated to dryness
under vacuum. The residue obtained was purified by chromatography
on silica gel (EtOAc/heptane 7:3) to furnish 8b (12 mg, 0.02 mmol,
23% yield) as a colorless oil: 1H NMR (300 MHz, (CD3)2CO) δ 3.30
(d, 1H, 2J = 12.5 Hz), 3.48 (d, 1H, 2J = 12.5 Hz), 3.72, 3.78, 3.79, 3.81
(4x s, 12H), 3.84 (s, 1H), 3.86 (d, 1H,J = 3.7 Hz), 3.92 (ddd, 1H, 2J =
3.71 (s, 3H), 4.22 (dd, 1H, J = 10.6 Hz, J = 3.9 Hz), 4.40 (dd, 1H, 2J =
2
12.9 Hz, JH6−H5 = 1.7 Hz), 4.70 (dd, 1H, J = 12.9 Hz, JH6′‑H5 = 1.5
Hz), 4.76 (dd, 1H, JH5−H4 = 3.2 Hz, JH5−H6′ = 1.5 Hz), 4.84 (b, 1H),
7.16−7.29 (m, 5H) 13C NMR (75 MHz, CDCl3) δ 20.6, 37.8, 52.1,
55.5, 59.6, 62.1, 63.0, 74.1, 127.9, 128.8, 129.5, 137.7, 169.1, 170.1;
HRESMS m/z calcd for [C16H22N2O7SNa]+ 409.1045, found
409.1053.
Compound 13: [α]20 = +17.5 (c 1.0, CHCl3); IR (neat, cm−1)
D
1744, 1708, 1221, 1156, 749; 1H NMR (300 MHz, (CD3)2CO) δ 1.46
2
(s, 9H), 1.93 (s, 3H), 2.05 (s, 3H), 3.69, 3.79 (2× d, 2H, J = 12.5
2
Hz), 3.84 (s, 3H), 4.03 (d, 1H, JH2′−H4 = 11.5 Hz), 4.67 (d, 1H, J =
2
12.8 Hz), 4.96 (d, 1H, J = 13.2 Hz), 5.45 (b, 1H), 5.72 (b, 1H),
7.22−7.54 (m, 5H); 13C NMR (75 MHz, (CD3)2CO) δ 20.6, 27.9,
37.0, 51.6, 56.5, 62.4, 67.2, 67.3, 74.8, 85.7, 128.0, 128.9, 130.2, 139.9,
151.4, 169.5, 169.9; HRESMS m/z calcd for [C21H30N2O9SNa]+
509.1570, found 509.1580.
12.2 Hz, JH7−H6 = 3.2 Hz, JH7−OH = 0.8 Hz), 4.12 (ddd, 1H, JH6−H7′
=
2
10.6 Hz, J
= 3.5 Hz, J
= 3.5 Hz), 4.28 (dd, 1H, J = 12.0
H6−H7
H6−H5
2
Hz, J H6−H7′ = 10.7 Hz), 4.30 (dd, 1H, J = 14.3 Hz, J = 5.2 Hz), 4.50
(dd, 1H, 2J = 14.3 Hz, J = 6.3 Hz), 6.35−6.55 (m, 4H) 6.95 (d, 1H, J =
8.2 Hz), 7.19 (d, 1H, J = 8.2 Hz), 7.84 (b, 1H); 13C NMR (75 MHz,
(CD3)2CO) δ 39.3, 47.8, 55.6, 55.7, 55.9, 56.2, 59.1, 67.5, 69.6, 99.1,
99.2, 104.7, 105.1, 119.4, 121.0, 130.7, 131.6, 159.4, 159.8, 161.5,
169.1; HRESMS m/z calcd for [C23H31N3O9SNa]+ 548.1679, found
548.1715.
(2R)-Methyl 2-[(4R,5S)-(5-Benzyloxy-3-tert-butoxycarbonyla-
mino-2,2-dioxide-1,2,3-oxathiazine-tetrahydro-4-yl)-2-benzyl-
(methyl)amino) Acetate (14). Crude compound 11 (66 mg, 0.192
mmol) was dissolved in CH2Cl2/cyclohexane 2:1 (6 mL), and benzyl
2,2,2-trichloroacetimidate (215 μL, 1.14 mmol) and trifluorometha-
nosulfonic acid (33 μL, 0.38 mmol) were added. After 4 h of stirring,
the solvents were evaporated under vacuum, and the resulting solid
was dissolved in ethyl acetate. Celite was added, and the suspension
was transferred to a silica gel chromatography column, which was
eluted with CH2Cl2/heptane/CH3OH (1:1:0.2). The product
obtained was immediately dissolved in DMF (1 mL) and treated
with Boc2O (34.8 mg, 0.16 mmol, 1.2 equiv), triethylamine (11.6 μL,
0.16 mmol, 1.2 equiv), and DMAP (2 mg, 0.1 equiv). The reaction
mixture was stirred for 4 h at rt, saturated aqueous NaHCO3 was
added, and the phases were separated. The aqueous phase was
extracted with EtOAc (2 × 3 mL), and the organic extracts were
combined, dried over MgSO4, and evaporated to dryness under
vacuum. The oil obtained was purified by flash chromatography on
silica gel (EtOAc/heptane 1:1) to furnish compound 14 (60.9 mg,
(1R,6S,9S)-9-Methoxy-4,7-dioxa-3-thia-2-azabicyclo[4.2.1]-
nonan-8-one 3,3-Dioxide (9) and Methyl (4S,5R,6R)-6-Hy-
droxy-5-methoxy-1,2,3-oxathiazepane-4-carboxylate 2,2-Di-
oxide (10). To a suspension of aziridine 6 (50 mg, 0.26 mmol) in
MeOH (1.5 mL) was added BF3·OEt2 (0.036 mL, 0.29 mmol) at rt.
The reaction mixture was refluxed during 48 h, cooled, and washed
successively with saturated aqueous solutions of NaHCO3 (2 × 1 mL)
and NaCl (2 × 1 mL). The organic layers were combined, dried over
MgSO4, filtered, and evaporated to dryness. The resulting oil was
purified by flash chromatography on silica gel (EtOAc/heptane 7:3) to
furnish compounds 9 (32.2 mg, 0.14 mmol) in 51% yield and 10 (10.6
mg, 0.04 mmol) in 14% yield. Data for 9: Rf 0.40 (EtOAc/heptane
7:3); [α]20 = −8.07 (c 0.5, MeOH); IR (neat, cm−1) 3281, 2997,
D
0.11 mmol, 60% yield) as a colorless oil: [α]22 = +23.1 (c 1.0,
1
2922, 2850, 1785, 1430, 1369, 1259, 1171, 1075, 932, 744, 634; H
D
CHCl3); IR (neat, cm−1) 2927, 2359, 1808, 1731, 1259, 1146, 778; 1H
NMR (300 MHz, CDCl3) δ 3.47 (s, 3H), 3.78 (s, 1H), 4.48 (dd, J =
2.7 Hz, J = 13.1 Hz), 4.56 (dd, J = 1.0 Hz, J = 13.1 Hz, 1H), 4.75 (s,
1H), 4.90 (m, 1H), 5.51 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ
54.1, 57.5, 70.4, 78.6, 82.3, 172.8; HRESMS m/z calcd for
[C6H8NO6S]− 222.0072, found 222.0067.
NMR (300 MHz, (CD3)2CO) δ 1.43 (s, 9H), 1.93 (s, 3H), 3.45 (s,
2
2
3H) 3.64 (d, 1H, J = 12.6 Hz), 3.74 (d, 1H, J = 12.6 Hz), 3.98 (d,
2
1H, JH2′‑H4 = 11.5 Hz), 4.50 (d, 1H, J = 11.3 Hz), 4.54 (ddd, 1H,
JH5−H4 = 7.8 Hz, JH5−H6 = 4.6 Hz, JH5−H6′ = 3.2 Hz), 4.64 (d, 1H, 2J =
11.3 Hz), 4.74 (dd, 1H, JH6−H6′ = 12.5 Hz, JH6−H5 = 3.2 Hz), 4.82 (dd,
Data for 10: Rf 0.45 (EtOAc/heptane 7:3); [α]20 = +28.97 (c 0.8,
D
2
2
MeOH); IR (neat, cm−1) 3491, 3269, 2955, 1741, 1633, 1434, 1360,
1H, J = 12.5 Hz, JH6′‑H5 = 4.6 Hz), 5.53 (dd, 1H, JH4−H7 = 11.5 Hz,
JH4−H5 = 7.8 Hz), 7.21−7.49 (m, 10H); 13C NMR (75 MHz,
(CD3)2CO) δ 28.0, 37.2, 51.1, 57.2, 62.5, 67.0, 73.2, 73.8, 74.4, 85.4,
127.9, 128.7, 128.9, 129.2, 130.2, 138.6, 140.2, 151.7, 169.3; HRESMS
m/z calcd for [C26H34N2O8SNa]+ 557.1934, found 557.1952.
1
1179, 1092, 989, 967, 791, 622; H NMR (300 MHz, CDCl3) δ 2.36
(d, J = 10.4 Hz, 1H), 3.50 (s, 3H), 3.85 (s, 3H), 4.05 (m, 2H), 4.12
(m, 1H), 4.15 (d, J = 3.5 Hz), 4.35 (dd, J = 1.7 Hz, J = 10.7 Hz); 13C
NMR (75 MHz, CDCl3) δ 53.4, 55.0, 61.4, 66.6, 70.0, 80.6, 168.7;
HRESMS m/z calcd for [C7H13NO7SNa]+ 278.0310, found 278.0307.
(2R)-Methyl 2-[(4R,5S)-(5-Acetyloxy-2,2-dioxide-1,2,3-oxa-
thiazine-tetrahydro-4-yl)-2-benzyl(methyl)amino) Acetate
(12) and (2R)-Methyl 2-[(4R,5S)-(5-Acetyloxy-3-tert-butoxycar-
bonylamino-2,2-dioxide-1,2,3-oxathiazine-tetrahydro-4-yl)-2-
benzyl(methyl)amino) acetate (13). Compound 7c (80 mg, 0.42
mmol) was dissolved in methanol (10 mL), and the solution was
stirred for 96 h at rt. The solvent was then removed under vacuum to
furnish a white residue (11, 85 mg, 0.25 mmol). The latter (66 mg,
0.19 mmol), unstable and used without further purification, was
dissolved in pyridine (2 mL), and acetic anhydride (181 μL, 1.92
mmol, 10 equiv) was added. The solution was stirred for 4 h at rt, and
the solvents were evaporated in vacuo affording 12 as a homogeneous
white solid by TLC (73 mg, 0.19 mmol, 99% yield). This crude
product was dissolved in DMF (1 mL) and Boc2O (50 mg, 0.23 mmol,
1.2 equiv), and triethylamine (31.6 μL, 1.2 equiv) and DMAP (3 mg,
0.023 mmol, 0.12 equiv) were added. The reaction mixture was stirred
for 4 h, and the solvent was removed under vacuum. The residue was
purified by flash chromatography on silica gel (EtOAc/heptane 1:1) to
(2R,3R,4R)-Methyl 4-Acetoxy-5-azido-2-(benzyl(methyl)-
amino)-3-(tert-butoxycarbonylamino)pentanoate (15). To a
solution of 13 (32 mg, 0.048 mmol) in DMA (0.6 mL) was added
NaN3 (4.3 mg, 0.048 mmol). The reaction mixture was stirred for 1 h
and then partitioned between EtOAc (2 mL) and saturated aqueous
NaCl (2 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 2 mL). The organic extracts were
combined, dried over MgSO4, and evaporated to dryness under
vacuum, affording compound 15 (14 mg, 0.03 mmol, 66% yield) as a
1
colorless oil: [α]24 = +40.5 (c 1.0, CHCl3); H NMR (300 MHz,
D
(CD3)2CO) δ 1.45 (s, 9H), 2.00 (s, 3H), 2.09 (s, 3H), 3.42 (d, 1H,
2
JH2−H3 = 11.3 Hz), 3.50 (dd, 1H, J = 15.7 Hz, JH−H4 = 8.1 Hz), 3.54
(dd, 1H, 2J = 15.7 Hz, JH−H4 = 7.0 Hz), 3.55, 3.75 (2× d, 2H, 2J = 13.5
Hz), 4.34 (m, 1H), 5.09 (ddd, 1H, JH4−H = 8.1 Hz, J = 5.1 Hz, J = 1.5
Hz), 5.90 (d, 1H, J = 9.6 Hz), 7.20−7.37 (m, 5H); 13C NMR (75
MHz, (CD3)2CO) δ 20.7, 28.6, 37.8, 51.1, 51.5, 52.7, 60.1, 67.2, 72.2,
79.5, 127.9, 129.0, 129.5, 140.4, 157.2, 170.7; FTIR (film, ν cm−1)
2975, 2098, 1729, 1713, 1496, 1218, 1047, 699; HRESMS m/z calcd
for [C21H31N5O6Na]+ 472.2172, found 472.2177.
5597
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The Journal of Organic Chemistry
Article
(2R,3R,4R)-Methyl 5-Azido-2-(benzyl(methyl)amino)-4-
(benzyloxy)-3-(tert-butoxycarbonylamino)pentanoate (16). To
a solution of 14 (35 mg, 0.065 mmol) in DMA (0.6 mL) was added
NaN3 (10 mg, 0.154 mmol). The reaction mixture was stirred for 1 h
and then partitioned between EtOAc (2 mL) and saturated aqueous
NaCl (2 mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 2 mL). The organic extracts were
combined, dried over MgSO4, and evaporated to dryness under
pound 16 (13.5 mg, 0.027 mmol) in CH2Cl2 (40 μL) was added TFA
(4.2 μL, 0.054 mmol, 2 equiv). The reaction mixture was stirred for 1
h and then evaporated to dryness under vacuum. The resulting residue
was taken up in EtOAc (2 mL) and washed with saturated aqueous
NaCl (2 mL). The aqueous layer was extracted with EtOAc (2 × 2
mL), and the organic phases were combined and dried over MgSO4.
Removal of the solvent under vacuum provided compound 20 (8.5 mg
0.02 mmol, 80% yield) as a yellow pale oil: [α]27 = +38.5 (c 1.0,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 2.23 (s, 3H), 3.13, 3.26 (2×
d, 2H, J = 10.3 Hz), 3.47 (m, 1H), 3.51−3.66 (m, 3H), 3.68 (s, 3H),
3.76 (d, 1H, J = 13.3 Hz), 4.35, 4.61 (2× d, 2H, J = 10.9 Hz), (d,1H, J
= 10.9 Hz), 7.14−7.33 (m, 10H). FTIR (film, cm−1) 2946, 2097, 1724,
1433, 741; HRESMS m/z calcd for [C21H27N5O3Na]+ 420.2012,
found 420.2001.
vacuum affording compound 16 (21 mg, 0.04 mmol, 65% yield) as a
1
colorless oil: [α]25 = +41.0 (c 1.0, CHCl3); H NMR (500 MHz,
D
(CD3)2CO) δ 1.43 (s, 9H), 2.16 (s, 3H), 3.42−3.66 (m, 5H), 3.69 (s,
3H), 3.79 (d, 1H, J = 12.2 Hz), 4.30 (m, 1H) 4.48, 4.68 (2× d, 2H, 2J
= 11.2 Hz), 5.55 (d, J = 8.2 Hz), 7.19−7.39 (m, 10H); 13C NMR (125
MHz, (CD3)2CO) δ 28.7, 38.4, 51.4, 52.8, 59.7, 66.8, 73.8, 78.4, 79.3,
127.9, 128.5, 129.1, 129.7, 138.9, 140.4, 157.0, 170.9; FTIR (film, ν
cm−1) 2928, 2099, 1727, 1713, 1495, 1164, 697; HRESMS m/z calcd
for [C26H35N5O5Na]+ 520.2536, found 520.2528.
ASSOCIATED CONTENT
■
S
* Supporting Information
(2R,3R,4S)-Methyl 4-Acetoxy-2-(benzyl(methyl)amino)-3-
(tert-butoxycarbonylamino)-5-(phenylthio)pentanoate (17).
To a solution of thiophenol (11.8 μL, 0.11 mmol, 1.3 equiv) in
THF (1 mL) was added a suspension of NaH in mineral oil (5 mg,
0.12 mmol, 1.4 equiv). A solution of compound 13 (43 mg, 0.088
mmol) in THF (0.4 mL) was added, and the reaction mixture was
stirred for 1.5 h at rt. The mixture was then partitioned between
EtOAc (2 mL) and saturated aqueous NaCl (2 mL), the layers were
separated, and the aqueous layer was extracted with EtOAc (2 × 2
mL). The organic extracts were combined, dried over MgSO4, and
evaporated to dryness under vacuum, affording compound 17 (43.7
mg, 0.08 mmol, 77%) as a colorless oil: [α]26D = +52.8 (c 1.0. CHCl3);
1H and 13C NMR spectra of compounds 5, 6, 7a−7g, 8a, 8b, 9,
1
10, 12−19 and H NMR spectrum of compound 20. ORTEP
drawings of compounds 6 and 8a and X-ray data of 6 and 8a in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: robert.dodd@icsn.cnrs-gif.fr.
■
Present Addresses
1
IR (neat, cm−1) 2952, 2927, 1730, 1497, 1221, 1023, 738; H NMR
§Departamento de Cien
̂
cias Naturais, Universidade Federal de
Sao Joao del Rei, UFSJ, Campus Dom Bosco, CDB, Praca Dom
ricas, 36301-160, Sao Joao del Rei, MG, Brazil.
(300 MHz, (CD3)2CO) δ 1.46 (s, 9H), 1.90 (s, 3H), 2.11 (s, 3H),
3.15−3.18 (m, 2H), 3.39 (d, 1H, JH2−H3 = 11.3 Hz), 3.54, 3.76 (2× d,
2H, 2J = 13.3 Hz), 3.65 (s, 3H), 4.53 (m, 1H), 5.06 (m, 1H), 5.83 (d,
1H, JNH‑H3 = 9.4 Hz), 7.18−7.44 (m, 10H); 13C NMR (75 MHz,
(CD3)2CO) δ 20.6, 28.7, 35.9, 38.0, 51.4, 51.8, 60.1, 67.6, 72.5, 79.4,
127.0, 127.8, 129.0, 129.6, 129.8, 130.1, 137.0, 140.5, 157.3, 170.5,
170.6; HRESMS m/z calcd for [C27H36N2O6SNa]+ 539.2192, found
539.2202.
̧
̃
̃
Helvec
́
io, 74 Fab
Departamento de Fisica e Quimica, Instituto de Cien
Exatas, Universidade Federal de Itajuba, 37500-903, Itajuba,
́
̃
̃
∥
́
́
̂
cias
́
́
MG, Brazil.
Author Contributions
⊥M.S.V. and M.F.S. contributed equally to this work
(2R,3R,4R)-Methyl 3-Acetamido-5-azido-2-(benzyl(methyl)-
amino)-4-hydroxypentanoate (18) and Compound 19. To a
solution of compound 15 (29 mg, 0.064 mmol) in CH2Cl2 (2 mL) was
added TFA (99 μL, 0.128 mmol, 2 equiv). The reaction mixture was
stirred for 1 h and then evaporated to dryness under vacuum. The
crude product was taken up in EtOAc (1 mL) and washed with a
saturated aqueous solution of NaHCO3 (2 × 1 mL). The combined
aqueous layers were extracted with EtOAc (1 mL), and the organic
extracts were combined, dried over MgSO4, and evaporated to dryness
under vacuum. The residual oil was purified by preparative
chromatography on silica gel (EtOAc/heptane 1:1) furnishing
compounds 18 (14.7 mg, 0.04 mmol) and 19 (5 mg, 0.016 mmol)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank CAPES and CNPq (Brazil) for fellowships and the
ICSN for a postdoctoral fellowship (M.S.V.).
■
REFERENCES
■
(1) Dubois, L.; Mehta, A.; Tourette, E.; Dodd, R. H. J. Org. Chem.
1994, 59, 434−441.
(2) Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd, R. H. J. Org.
Chem. 1995, 60, 2035−2043.
in 66 and 25% yield, respectively.
1
Compound 18. Colorless oil: [α]25 = +45.0 (c 1.0, CHCl3); H
D
(3) Dauban, P.; Chiaroni, A.; Riche, C.; Dodd, R. H. J. Org. Chem.
1996, 62, 2488−2496.
NMR (300 MHz, CDCl3) δ 2.01 (s, 3H), 2.24 (s, 3H), 3.30 (d, 1H, J
= 3.6 Hz), 3.32 (s, 1H), 3.57 (d, 1H, 2J = 13.4 Hz), 3.66 (d, 1H, JH2−H3
= 9.9 Hz), 3.72 (d, 1H, JHD‑HC = 13.4 Hz), 3.74 (m, 1H), 3.77 (s, 3H),
4.29 (m, 1H), 5.75 (d, 1H, J = 8.5 Hz), 7.21−7.34 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 23.5, 38.7, 50.3, 51.7, 55.0, 65.4, 70.3, 127.6,
128.6, 128.8, 138.8, 170.5, 171.2. FTIR (film, cm−1) 3289, 2926, 2098,
1778, 1726, 1649, 1260, 740; HRESMS m/z calcd for
[C16H23N5O4Na]+ 372.1648, found 372.1636.
(4) Dauban, P.; Dodd, R. H. J. Org. Chem. 1997, 62, 4277−4284.
(5) Siqueira Valle, M.; Tarrade-Matha, A.; Dauban, P.; Dodd, R. H.
Tetrahedron 2008, 64, 419−432.
(6) For reviews, see: (a) Tanner, D. Angew. Chem., Int. Ed. 1994, 33,
599−619. (b) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247−258.
(c) Mc Coull, W.; Davis, F. A. Synthesis 2000, 1347−1365.
(7) Dauban, P.; De Saint-Fuscien, C.; Dodd, R. H. Tetrahedron 1999,
55, 7589−7600.
Compound 19. Colorless oil: 1H NMR (500 MHz, CDCl3) δ 2.00
(s, 3H), 2.44 (s, 3H), 3.41, 3.64 (2× d, 2H, J = 13.3 Hz), 3.77 (d, 1H, J
2
́
(8) Dauban, P.; De Saint-Fuscien, C.; Acher, F.; Prezeau, L.; Brabet,
= 10.2 Hz), 3.83, 3.89 (2× d, 2H, J = 13.0 Hz), 4.70−4.81 (m, 2H),
5.52 (sl, 1H), 7.26−7.35 (m, 5H); 13C NMR (125 MHz, CDCl3) δ
23.1, 37.8, 49.5, 51.5, 59.0, 64.0, 75.9, 127.9, 128.7, 129.1, 138.6, 171.1,
171.8. FTIR (film, cm−1) 3282, 2928, 2111, 1777, 1658, 1538, 1453,
1290, 742; HRESMS m/z calcd for [C15H19N5O3Na]+ 340.1386,
found 340.1370.
I.; Pin, J. -P.; Dodd, R. H. Bioorg. Med. Chem. Lett. 2000, 10, 129−133.
(9) Tarrade, A.; Dauban, P.; Dodd, R. H. J. Org. Chem. 2003, 68,
9521−9524.
(10) Tarrade-Matha, A.; Siqueira Valle, M.; Tercinier, P.; Dauban, P.;
Dodd, R. H. Eur. J. Org. Chem. 2009, 673−686.
(11) de Saint-Fuscien, C.; Tarrade, A.; Dauban, P.; Dodd, R. H.
Tetrahedron Lett. 2000, 41, 6393−6396.
(2R,3R,4R)-Methyl 3-Amino-5-azido-2-(benzyl(methyl)-
amino)-4-(benzyloxy)pentanoate (20). To a solution of com-
5598
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The Journal of Organic Chemistry
Article
(12) Kale, A. S.; Deshmukh, A. R. A. S. Synlett 2005, 2370−2372.
(13) For reviews, see: (a) Muller, P.; Fruit, C. Chem. Rev. 2003, 103,
̈
2905−2919. (b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571−1586.
(c) Halfen, J. A. Curr. Org. Chem 2005, 9, 657−669. (d) Pellissier, H.
Tetrahedron 2010, 66, 1509. (e) Karila, D.; Dodd, R. H. Curr. Org.
Chem. 2011, 15, 1507−1538.
(14) (a) Mansuy, D.; Mahy, J.-P.; Dureault, A.; Bedi, G.; Battioni, P.
Chem. Commun. 1984, 1161−1162. (b) Mahy, J.-P.; Battioni, P.;
Mansuy, D. J. Am. Chem. Soc. 1986, 108, 1079−1080. (c) Mahy, J.-P.;
Bedi, G.; Battioni, P.; Mansuy, D. J. Chem. Soc., Perkin Trans. 2 1988,
1517−1524.
(15) (a) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Org. Chem.
1991, 56, 6744−6746. (b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.;
Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328−
5329. (c) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc.
1994, 116, 2742−2753.
(16) (a) Yu, X. Q.; Huang, J.-S.; Zhou, X.-G.; Che, C.-M. Org. Lett.
2000, 2, 2233−2236. (b) Espino, C. G.; Du Bois, J. Angew. Chem., Int.
Ed. 2001, 40, 598−601. (c) Espino, C. G.; Wehn, P. M.; Chow, J.; Du
Bois, J. J. Am. Chem. Soc. 2001, 123, 6935−6936. (d) Dauban, P.;
̀
Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123,
7707−7708.
(17) (a) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.;
́
Dodd, R. H. Org. Lett. 2002, 4, 2481−2483. (b) Esteoule, A.; Duran,
F.; Retailleau, P.; Dodd, R. H.; Dauban, P. Synthesis 2007, 1251−1260.
(18) (a) Duran, F. J.; Ghini, A. A.; Dauban, P.; Dodd, R. H.; Burton,
G. J. Org. Chem. 2005, 70, 8613−8616. (b) Duran, F. J.; Edelsztein, V.
C.; Ghini, A. A.; Rey, M.; Coirini, H.; Dauban, P.; Dodd, R. H.;
Burton, G. Bioorg. Med. Chem. 2009, 17, 6526−6533.
(19) For a review, see: Viso, A.; Fernandez de la Pradilla, R.; Garcia,
A.; Flores, A. Chem. Rev. 2005, 105, 3167−3196.
(20) (a) Padwa, A.; Flick, A. C.; Leverett, C. A.; Stengel, T. J. Org.
Chem. 2004, 69, 6377−6386. (b) Guthikonda, K.; Wehn, P. M.;
Caliando, B. J.; Du Bois, J. Tetrahedron 2006, 62, 11331−11342.
(21) (a) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; p
379. (b) Dauban, P.; Dodd, R. H. In Amino Group Chemistry, from
Synthesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim,
2008; p 55. (c) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun.
2009, 5061−5074.
(22) (a) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124,
13672−13673. (b) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J.
Am. Chem. Soc. 2004, 126, 15378−15379.
(23) X-ray crystallographic data for compound 6 have been deposited
at the Cambridge Crystallographic Data Centre, Lensfield Road,
Cambridge CB2 1EW, U.K. (deposition number CCDC 837575).
(24) X-ray crystallographic data for compound 8a have been
deposited at the Cambridge Crystallographic Data Centre, Lensfield
Road, Cambridge CB2 1EW, U.K. (deposition number CCDC
837577).
(25) We previously explained the C-2 vs C-3 selectivity of opening of
N-acetylaziridine-γ-lactones by soft and hard nucleophiles, respectively,
using MNDO calculations (see refs 1 and 2). While we have not
repeated these calculations on the tricyclic N-sulfamoylaziridine-γ-
lactone 6 in order to corroborate the regioselectivity of aziridine
opening by the amines at C-2 and of methanol at C-3, a reviewer has
pointed out that our results can be rationalized by NBO analysis. In
this case, attack of the amines at C-2 would correspond to simple
nucleophilic addition at this more electrophilic center compared to C-
3, while for methanol, the situation is reversed because of the
coordination of boron trifluoride etherate (modeled as a protonated
N-sulfamoyl function). We thank the reviewer for this insight.
(26) Okada, M.; Iwashita, S.; Koizumi, N. Tetrahedron Lett. 2000, 41,
7047−7051.
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