Stereoselective isoxazolidine synthesis via copper-catalyzed alkene aminooxygenation

Article abstract of DOI:10.1021/jo3013226

Isoxazolidines are useful in organic synthesis, drug discovery, and chemical biology endeavors. A new stereoselective synthesis of methyleneoxy-substituted isoxazolidines is disclosed. The method involves copper-catalyzed aminooxygenation/cyclization of N

Full text of DOI:10.1021/jo3013226

Note
pubs.acs.org/joc
Stereoselective Isoxazolidine Synthesis Via Copper-Catalyzed Alkene
Aminooxygenation
Shuklendu D. Karyakarte, Thomas P. Smith, and Sherry R. Chemler*
Department of Chemistry, The State University of New York at Buffalo, Buffalo, New York, 14260, United States
S
* Supporting Information
ABSTRACT: Isoxazolidines are useful in organic synthesis, drug discovery, and
chemical biology endeavors. A new stereoselective synthesis of methyleneoxy-
substituted isoxazolidines is disclosed. The method involves copper-catalyzed
aminooxygenation/cyclization of N-sulfonyl-O-butenyl hydroxylamines in the
presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) and O2
and provides substituted isoxazolidines in excellent yields and diastereoselectiv-
ities. We also demonstrate selective mono N−O reduction followed by
oxidation of the remaining N−O bond to reveal a 2-amino-γ-lactone. Reduction of the γ-lactone reveals the corresponding
aminodiol.
soxazolidines have demonstrated a range of biological
activities including antibiotic,1 gene expression regulation2
to its high solubility in nonpolar organic solvents.]8b,d Substrate
1a is significantly more reactive than the γ-pentenyl
sulfonamide substrates we had previously examined in this
aminooxygenation reaction8 and 1a actually suffered substantial
decomposition at 110 and 120 °C, the temperatures previously
examined substrates reacted best at.8 The oxygen source in this
aminooxygenation reaction is (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl radical (TEMPO) and the stoichiometric oxidant is O2
(1 atm, balloon). We initially used 3 equiv of TEMPO based on
our previously reported aminooxygenation reactions,8 but we
found midway during these studies that 1.2 equiv of TEMPO is
sufficient for excellent conversion. We also found that a 10% O2
in N2 atmosphere (1 atm, balloon) is sufficient for good
conversion (Table 1, entry 6), thereby enabling a safer process.
Substrates with α-substituents (1b, R1 = Me and 1c, R1 = Ph)
provided moderate 3,5-cis isoxazolidine diastereoselectivity with
the Cu(OTf)2•3 catalyst and higher diastereoselectivity with
Cu(eh)2 as catalyst (Table 1, entries 8−12). The relative
configuration of the major diastereomers were assigned by
NOE.
I
and cancer cell cytotoxicity.3 While [3 + 2] dipolar cyclo-
addition reactions are most frequently used to synthesize
isoxazolidines,4,5 the intramolecular addition of hydroxylamines
onto alkenes and allenes has emerged as an important
alternative strategy.6,7 These two synthetic strategies are largely
complementary: the former is usually an entirely intermolecular
process while the latter is intramolecular in the first step of the
addition to the alkene. Because of these different aspects,
different stereocontrolling elements are involved in each.
Herein we report a copper-catalyzed addition of a nitrogen
and oxygen across the alkene, resulting in methyleneoxy-
functionalized isoxazolidines.
Our lab has recently disclosed that copper(II) salts can be
used to efficiently promote and catalyze intramolecular alkene
aminooxygenation.8 This reaction has been used to synthesize
methyleneoxy functionalized indolines, pyrrolidines and cyclic
ureas. The present contribution broadens the scope of the
copper-catalyzed alkene aminooxygenation reaction to the
synthesis of isoxazolidines. The resulting methyleneoxy
functionalized isoxazolidines might serve directly as pharmaco-
logical leads or alternatively N−O bond reduction/oxidation
could lead to synthetically useful 2-amino-γ-lactones and 1,3-
aminoalcohols (vide infra).
The N-sulfonyl-O-butenyl hydroxyl amine substrates 1 were
synthesized via aldehyde allylation, subsequent Mitsunobu
reaction with N-hydroxyphthalimide, N-deprotection and N-
sulfonylation, as previously reported.6,7 Substrates 1a−c were
then subjected to various copper(II)-catalyzed aminooxygena-
tion conditions to determine the optimal protocol (Table 1).
We found the reaction of N-tosyl-O-butenyl hydroxyl amine 1a
to be very efficient at 60 °C when Cu(OTf)2 was used with the
2,2-isopropylidinebis(oxazoline) ligand 3 or when Cu(2-
ethylhexanoate)2 [Cu(eh)2] was used as the catalyst (Table 1,
entries 3 and 4). [We generally prefer Cu(2-ethylhexanoate)2 in
our copper-carboxylate promoted and catalyzed reactions due
A series of N-sulfonyl-O-butenylamines 1 were subjected to
the optimal conditions (Table 1, entries 4 and 5) to establish
the substrate scope (Scheme 1). A number of functional groups
(aryl-Br, aryl-Cl, thiophene, Ns, SES, allyl) were stable to the
reaction conditions. α-Substituted hydroxylamines provided the
corresponding isoxazolidines 2d−j and 2l with good to
excellent 3,5-cis diastereoselectivity while a β-phenyl substrate
provided the 3,4-trans diastereomer 2k selectively (stereo-
chemistry assigned by NOE). Substrates with internal alkenes
and ones that could potentially form 6-membered rings were
not examined in this limited study.
The proposed reaction mechanism is outlined in Scheme 2.8
cis-Aminocupration via the seven-membered chairlike transition
Received: July 3, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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Note
a
a
Table 1. Optimization of the Aminooxygenation
Scheme 1. Isoxazolidine Scope
entry
R1
CuX2
ligand
yield (%)
cis:trans
b
c
1
H
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(eh)2
Cu(eh)2
Cu(eh)2
Cu(eh)2
Cu(OTf)2
Cu(eh)2
Cu(OTf)2
Cu(eh)2
Cu(eh)2
60
b
c
2
H
Bipy
55
c
3
H
3
>95
b
4
H
83
81
70
5
H
d
6
H
e
c
7
H
65 (90 )
c
b
8
Me
Me
Ph
Ph
Ph
3
3
95
3:1
10:1
8:1
b
9
75
b
c
10
95
b
11
83
82
10:1
10:1
12
a
Reaction conditions: 1 (0.165 mmol), K2CO3 (0.165 mmol) and
TEMPO (0.198 mmol, 1.2 equiv) was added to a solution of CuX2
(0.033 mmol, 20 mol %) [Cu(OTf)2 and ligands (25 mol %) were
complexed at 60 °C for 2 h prior to substrate addition] and the
reaction mixture was heated at 60 °C under O2 (1 atm, balloon) for 24
h. Yields are of product isolated after flash chromatography on SiO2
b
unless otherwise noted. 3 equiv of TEMPO was used in this reaction.
a
R3 = 2,2,6,6-tetramethylpiperidinyl.
c
d
1
% Conversion based on crude H NMR analysis. 10% O2 in N2 (1
e
atm, balloon) was used. 15 mol % Cu(eh)2 was used.
Scheme 2. Proposed Reaction Mechanism
state A gives the unstable organocopper(II) intermediate. For
the diastereoselective reactions, placement of the substituent in
a less sterically demanding pseudoequatorial position leads to
the major diasteromer. Homolysis of the carbon−copper bond
gives Cu(I) and the carbon radical intermediate then undergoes
rapid trapping with TEMPO radical to provide isoxazolidine 2.
Reoxidation of Cu(I) to Cu(II) by TEMPO/O2 completes the
catalytic cycle.
While isoxazolidines are useful in their own right, they can
also be easily converted to 1,3-amino alcohols.9 The ring N−O
bond of isoxazolidine 2c was selectively cleaved via hydro-
genation, catalyzed by 20 mol % Pearlman’s catalyst [20% (by
weight) Pd(OH)2 on carbon] to provide the acyclic 1,3-amino
alcohol 4 in 70% yield along with 10% recovered 2c (Scheme
3).9c We initially anticipated that oxidation of amino alcohol 4
with m-CPBA8a,b would provide the corresponding lactol.
Instead, γ-lactone 5 was obtained exclusively. Lactone 5 could
be reduced to the corresponding 1,4-diol 6 with NaBH4. Such
γ-lactones and 3-amino-1,4-diols are important intermediates in
the synthesis of HPA-12, a CERT antagonist that can be used
as a treatment for sphingolipid misregulation which in turn can
cause autoimmune disorders.10
and organic synthesis endeavors. This method could provide
access to disubstituted chiral isoxazolidines if the synthetic
route to the hydroxylamine substrate involved an enantiose-
lective step,6f,g for example, an enantioselective aldehyde
allylation reaction.6j,11 Sequential N−O reduction and N−O
oxidation reactions as shown in Scheme 3 can provide
unnatural amino acid synthons such as γ-lactone 5 and
structures related to CERT antagonists such as aminodiol 6.
EXPERIMENTAL SECTION
■
SUMMARY AND CONCLUSIONS
■
General Experimental Information. Reagents were used as
supplied unless otherwise noted. m-CPBA was 70−75% composition
by weight. 1H NMR spectra were recorded in CDCl3, C6D6 or
CD3OD (referenced at 7.26 ppm, residual CHCl3, 7.16 ppm, residual
A very concise, efficient and diastereoselective method for the
synthesis of variously functionalized isoxazolidines has been
presented. Such compounds may prove useful in drug discovery
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Note
2.65−2.58 (m, 1H), 2.45 (s, 3H), 2.45−2.41 (m, 1H); 13C NMR (75.5
MHz, CDCl3) δ 144.9, 138.1, 133.9, 133.5, 133.2, 129.6, 128.6, 128.6,
128.5, 117.9, 87.2, 39.5, 21.6; IR (thin film) 3189, 1643, 1592, 1333,
1158, 913 cm− 1 ; HRMS (ESI) calcd for [M + Na]+
C17H18O3N1S1Cl1Na1: 374.0588, found 374.0586.
Scheme 3. N−O Bond Reduction and Oxidation
( )-N-(1-(4-Chlorophenyl)but-3-enyloxy)-2-(trimethylsilyl)-
ethanesulfonamide (1e). 1-(4-Chlorophenyl)-but-3-en-1-ol12 was
converted to 1e (104 mg, 26% yield, white solid) as above except
with 2-trimethylsilylethanesulfonyl chloride. mp = 92−94 °C; 1H
NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.4 Hz, 2H), 7.30 (d, J= 8.8
Hz, 2 H), 6.72 (s, 1H), 5.83−5.76 (m, 1H), 5.12−5.06 (m, 2H), 5.00
(dd, J = 6.4 Hz, J = 7.6 Hz, 1 H), 3.15−3.08 (m, 2H), 2.68−2.64 (m,
1H), 2.49−2.46 (m, 1H), 1.05−0.89 (m, 2H), 0.07 (s, 9H); 13C NMR
(75.5 MHz, CDCl3) δ 137.9, 134.1, 133.2, 128.6, 128.5, 117.9, 86.9,
45.5, 39.5, 9.7, 0.0, IR (thin film) 3223, 2923, 2852, 1597, 1338, 1167,
1091, 919, 813, 705; HRMS (ESI) calcd for [M + Na]+
C15H24Cl1NO3S1Si1Na1: 384.0827, found 384.0832.
( )-N-(1-(4-Chlorophenyl)but-3-enyloxy)-4-nitrobenzenesulfona-
mide (1f). 1-(4-Chlorophenyl)-but-3-en-1-ol12 was converted to 1f
(126 mg, 30% yield, yellow solid) as above except with 4-
nitrobenzenesulfonyl chloride. mp = 127−129 °C; 1H NMR (400
MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H),
7.32 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8 Hz, 2H), 6.95 (s, 1H), 5.78−
5.69 (m, 1H), 5.14−5.04 (m, 3H), 2.66−2.58 (m, 1H), 2.49−2.42 (m,
1H); 13C NMR (75.5 MHz, CDCl3), δ 150.8, 142.2, 137.5, 134.5,
133.1, 130.0, 128.8, 128.5, 124.2, 118.3, 88.9, 39.4; IR (thin film) 3224,
1606, 1531, 1348, 1312, 1173, 1089, 1013, 854, 744 cm−1; HRMS (EI)
calcd for [M − C3H5]+ C13H10N2O5Cl1S1: 340.9977, found 340.9993.
( )-4-Nitro-N-(pent-4-en-2-yloxy)benzenesulfonamide (1g).
Pent-4-en-2-ol was converted to sulfonamide 1g (1.20 g, 64% yield,
white solid) as above except with 4-nitrobenzenesulfonyl chloride. mp
= 72−75 °C; 1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 8.5 Hz, 2H),
8.12 (d, J = 9.0 Hz, 2H), 7.14 (s, 1H), 5.79−5.74 (m, 1H), 5.10−5.06
(m, 2H), 4.27−4.23 (m, 1H), 2.36−2.32 (m, 1H), 2.28−2.24 (m, 1H),
1.21 (d, J = 6.5 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 150.7,
142.3, 133.7, 129.9, 124.1, 117.8, 82.6, 39.1, 30.9, 18.2; IR (thin film)
3212, 1608, 1535, 1445, 1348, 1167 cm−1; HRMS (EI) calcd for [M]+
C11H14O5N2S1: 286.0625, found 286.0618.
C6H6 and 3.34 ppm, residual CH3OH) at 300, 400, or 500 MHz. 13C
NMR spectra were recorded in CDCl3 (77.0 ppm as internal
reference) at 75.5 MHz. Characteristic peaks in the IR spectra are
reported in wave numbers, cm−1. Melting points are reported as
uncorrected. Reactions were run in oven-dried glassware under Argon
unless otherwise noted. Solvents were dried under Argon using a
commercial purification system involving filtration through alumina.
N-(But-3-enyloxy)-4-methylbenzenesulfonamide (1a) (Represen-
tative Procedure).6,7 A 0 °C solution of 3-butene-1-ol (500.0 mg, 6.9
mmol), triphenylphosphine (2.2 g, 8.3 mmol) and N-hydroxyph-
thalimide (1.3 g, 8.3 mmol) in THF (56 mL) was treated with
diethylazodicarboxylate (3.6 mL, 8.3 mmol, 40 wt % in toluene),
added over 30 min. The reaction was warmed to rt and stirred for 4 h,
then hydrazine monohydrate (0.77 mL, 15.8 mmol) was added
dropwise. After 2 h, the mixture was filtered through Celite and
concentrated in vacuo. The resulting hydroxylamine was dissolved in
CH2Cl2 (69 mL), treated with pyridine (1.7 mL, 20.8 mmol) and p-
TsCl (1.6 g, 8.3 mmol) and stirred for 16 h at rt. The mixture was
quenched with water and extracted with CH2Cl2 (2 × 30 mL). The
organics were washed with 1 M HCl (20 mL), brine (20 mL), dried
over Na2SO4 and concentrated in vacuo. Flash chromatography on
SiO2 (10−30% EtOAc in hexanes) gave N-tosyl hydroxylamine 1a
(
)-4-methyl-N-(1-(thiophen-2-yl)but-3-enyloxy)-
benzenesulfonamide (1h).7 1-(Thiophen-2-yl)but-3-en-1-ol12 was
converted to 1h (90 mg, 44% yield, yellow solid). mp = 80−82 °C;
1H NMR (400 MHz, CDCl3), δ 7.72 (d, J = 8.4 Hz, 2H), 7.24 (d, J =
1
(600 mg, 30% yield, yellow oil). H NMR (400 MHz, CDCl3) δ 7.83
(d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.78−5.74 (m, 1 H),
5.13−5.05 (m, 2 H), 4.05 (t, J = 12.0 Hz, 2 H), 2.46 (s, 3 H), 2.46−
2.34 (m, 2 H); 13C NMR (75.5 MHz, CDCl3) δ 144.7, 134.1, 133.4,
129.5, 128.5, 116.9, 76.1, 32.4, 21.5; IR (thin film) 3222, 2946, 1642,
1598, 1335, 1164 cm−1; HRMS (ESI) calcd for [M + Na]+
C11H15O3N1Na1S1: 264.0666, found 264.0665.
( )-4-Methyl-N-(pent-4-en-2-yloxy)benzenesulfonamide (1b).
Pent-4-en-2-ol was converted to 1b (326 mg, 22% yield, clear oil).
1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 8.1 Hz, 2H), 7.32 (d, J =
8.1 Hz, 2H), 6.99 (s, 1H), 5.80−5.68 (m, 1H), 5.08−5.03 (m, 2H),
4.21−4.15 (m, 1H), 2.43 (s, 3H), 2.39−3.30 (m, 1H), 2.25−2.18 (m,
1H), 1.18 (d, J = 9.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 144.7,
133.9, 133.6, 129.5, 128.5, 117.4, 81.8, 39.1, 21.6, 18.2; IR (thin film)
3222, 1314, 1167, 1091 cm−1; HRMS (EI) calcd for [M]+
C12H17O3N1S1: 255.09152, found 255.0924.
( )-4-Methyl-N-(1-phenylbut-3-enyloxy)benzenesulfonamide
(1c).7 1-Phenyl-but-3-en-1-ol12 was converted to 1c (481.2 mg, 42%
yield, white solid). mp = 105 °C; 1H NMR (500 MHz, CDCl3) δ 7.80
(d, J = 8.4 Hz, 2 H), 7.36−7.28 (m, 5H), 7.28−7.25 (m, 2H), 6.67 (s,
1H), 5.80−5.71 (m, 1H), 5.10−5.01 (m, 3H), 2.68−2.60 (m, 1H),
2.49 (s, 3H), 2.48−2.45 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ
144.8, 139.6, 133.8, 133.7, 129.6, 128.7, 128.4, 128.2, 127.1, 117.6,
88.0, 39.6, 21.6; IR (thin film) 3224, 1642, 1598, 1339, 1166 cm−1;
HRMS (ESI) calcd for [M + Na]+ C17H19O3N1S1: 340.0978, found
340.0975.
8.0 Hz, 2H), 7.19 (t, J = 5.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.88
(dd, J = 3.4 Hz, 5.0 Hz, 1H), 6.75 (s, 1H), 5.76−5.66 (m, 1H), 5.18 (t,
J = 7.0 Hz, 1H), 5.07−5.01 (m, 2H), 2.70−2.63 (m, 1H), 2.54−2.46
(m, 1H), 2.36 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 144.8, 142.2,
133.6, 133.2, 129.6, 128.6, 127.1, 126.6, 125.8, 118.0, 83.2, 39.6, 29.6,
21.6; IR (thin film) 3223, 2923, 1339, 1167, 1091, 920, 813, 705 cm−1;
HRMS (ESI) calcd for [M + Na]+ C15H17O3N1Na1S2: 346.0542, found
346.0526.
( )-N-(1-(4-Bromophenyl)but-3-enyloxy)-4-methylbenzenesulfo-
namide (1i). 1-(4-Bromophenyl)-but-3-en-1-ol12 was converted to 1i
1
(1.2 g, 70% yield, white solid). mp = 115−118 °C; H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H),
7.32 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 6.75 (s, 1H), 5.76−
5.69 (m, 1H), 5.08−5.04 (m, 2H), 5.00 (t, J = 5.6 Hz, 1H), 2.62−2.58
(m, 1H), 2.45 (s, 3H), 2.45−2.39 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 144.9, 138.6, 133.5, 133.2, 131.6, 129.6, 128.9, 128.6, 122.2,
118.0, 87.3, 39.4, 21.7; IR (thin film) 3213, 1597, 1166, 1091, 732
cm−1; HRMS (ESI) calcd for [M + Na]+ C17H18O3N1S1Br1Na1:
420.0063, 418.0088, found 420.0051; 418.0109.
( )-N-(Hepta-1,6-dien-4-yloxy)-4-methylbenzenesulfonamide
(1j). Hepta-1,6-dien-4-ol13 was converted to 1j (162 mg, 26% yield,
white solid). mp = 52−54 °C; 1H NMR (400 MHz, CDCl3), 7.81 (d, J
= 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 5.84−5.73 (m,
1H), 5.10−5.05 (m, 4H), 4.20−4.16 (t, J = 6.0 Hz, 1H), 2.44 (s, 3H),
2.35−2.32 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 144.8, 133.9,
133.6, 129.6, 128.4, 117.6, 85.0, 41.0, 36.6, 21.7; IR (thin film), 3220,
2929, 1642, 1334, 1168, 1091, 1019, 918, 814, 731 cm−1; HRMS (ESI)
calcd. for [M + Na]+ C14H19O3N1Na1S1: 304.0987, found 304.0978.
( )-N-(1-(4-Chlorophenyl)but-3-enyloxy)-4-methylbenzenesulfo-
namide (1d). 1-(4-Chlorophenyl)-but-3-en-1-ol12 was converted to 1d
1
(1.5 g, 81% yield, white solid). mp = 107−110 °C; H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2 H), 7.33−7.28 (m, 4H), 7.19 (d,
J = 8.5 Hz, 2H), 6.77 (s, 1H), 5.76−5.68 (m, 1H), 5.08−4.99 (m, 3H),
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Note
( )-4-Methyl-N-(2-phenylbut-3-enyloxy)benzenesulfonamide
8.4 Hz, 2H), 7.32−7.21 (m, 6H), 5.21 (dd, J = 6.6 Hz, 9.8 Hz, 1H),
4.55−4.48 (m, 1 H), 4.04 (dd, J= 6.0 Hz, 9.2 Hz, 1H), 3.89 (dd, J= 6.6
Hz, 8.4 Hz, 1H), 2.79 (ddd, J= 6.6 Hz, 8.2 Hz, 12.6 Hz, 1H), 2.43 (s,
3H), 2.12 (ddd, J = 7.2 Hz, 10.0 Hz, 12.2 Hz, 1H), 1.55−1.41(m, 4H),
1.28−1.07 (m, 12H); 13C NMR (75.5 MHz, CDCl3) δ 144.9, 135.7,
134.4, 133.1, 129.2, 128.7, 128.2, 82.3, 78.0, 60.1, 58.6, 40.4, 39.6, 33.0,
30.9, 21.7, 20.1, 17.0; IR (thin film) 1596, 1492, 1360, 1166, 817 cm−1;
HRMS (ESI) calcd for [M + H]+ C26H36O4N2S1Cl1: 507.2085, found
507.2088.
(1k). 2-Phenyl-but-3-en-1-ol14 was converted to 1k (120 mg, 56%
1
yield, clear oil). H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.0 Hz,
2H), 7.37−7.19 (m, 7H), 6.93 (s, 1 H), 6.02−5.90 (m, 1 H), 5.16−
5.07 (m, 2H), 4.31 (d, J= 10.0 Hz, 2H), 3.76−3.68 (m, 1H), 2.42 (s,
3H); 13C NMR (75.5 MHz, CDCl3) δ 144.7, 140.3, 137.8, 133.3,
129.5, 128.5, 128.4, 128.0, 126.8, 116.5, 79.7, 48.2, 21.6; IR (thin film)
3223, 2960, 1453, 1336, 1167, 1091, 918, 757 cm−1; HRMS (ESI)
calcd for [M + Na]+ C17H19O3N1Na1S1: 340.0969, found 340.0978.
(
)-4-Methyl-N-(3-methyl-1-phenylbut-3-enyloxy)-
(
)-1-(((3S,5R)-5-(4-Chlorophenyl)-2-(2-(trimethylsilyl)-
benzenesulfonamide (1l). 3-Methyl-1-phenylbut-3-en-1-ol15 was
converted to 1l (105 mg, 51% yield, yellow solid). mp = 83−85 °C;
1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.33−7.27
ethylsulfonyl)isoxazolidin-3-yl)methoxy)-2,2,6,6-tetramethylpiperi-
dine (2e). 1e was converted to 2e (35.2 mg, 62% yield, white solid) in
1
>20:1 d.r. mp = 88−90 °C; H NMR (400 MHz, CDCl3) δ 7.35 (s,
4H), 5.47 (dd, J = 7.2 Hz, 1H), 4.59−4.55 (m, 1H), 4.00 (dd, J = 6.4
Hz, 9.2 Hz, 1H), 3.88 (dd, J = 6.4 Hz, 8.8 Hz, 1H), 3.29−3.13 (m,
2H), 2.85 (ddd, J = 7.2 Hz, 12.0 Hz, 17.8 Hz, 1H), 2.15 (ddd, J = 6.8
Hz, 9.8 Hz, 12.5 Hz, 1H), 1.54−1.44 (m, 4H), 1.19−1.09 (m, 12H),
0.03 (s, 9H); 13C NMR (75.5 MHz, CDCl3) δ 135.8, 134.4, 128.8,
128.3, 82.9, 77.8, 60.1, 56.9, 47.1, 40.0, 39.6, 33.0, 20.1, 16.9, 9.5, 0.0;
IR (thin film) 2930, 1599, 1493, 1469, 1333, 1251, 1172, 1148, 1091,
1056, 1015, 860, 830, 736, 701 cm−1; HRMS (ESI) calcd for [M + H]+
C24H42O4N2Cl1S1Si1: 517.2318, found 517.2335.
(m, 7H), 6.62 (s, 1H), 5.15 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 4.83 (s, 1H),
4.73 (s, 1H), 2.59 (dd, J = 8.4 Hz, 14.4 Hz, 1H), 2.41 (s, 3 H), 2.35
(dd, J = 5.2 Hz, 14.4 Hz, 1H), 1.81 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 144.7, 141.3, 140.0, 133.7, 129.6, 128.7, 127.1, 113.5, 88.2,
44.1, 23.4, 21.7; IR (thin film) 3223, 2923, 1597, 1454, 1339, 1167,
812, 727 cm−1; HRMS (ESI) calcd for [M + Na]+ C18H21O3N1Na1S1:
354.1134, found 354.1134.
( )-2,2,6,6-Tetramethyl-1-((2-tosylisoxazolidin-3-yl)methoxy)-
piperidine (2a) (Representative Procedure). N-Tosyl hydroxylamine
1a (40 mg, 0.165 mmol), copper(II) 2-ethylhexanoate (11.5 mg, 0.033
mmol), TEMPO (30.9 mg, 0.198 mmol) and K2CO3 (22.8 mg, 0.165
mmol) were placed in a 100 mL flask (14/20 neck) and dissolved in
toluene (1.65 mL). O2 (1 atm) was introduced via balloon attached to
a short vacuum hose, that in turn was attached to an adapter (14/20).
The solution was heated to 60 °C and stirred for 24 h, then was
diluted with EtOAc, filtered through Celite and concentrated. Flash
chromatography on SiO2 (10−30% EtOAc:hexanes) afforded 51.6 mg
of isoxazolidine 2a as a white solid in 79% yield. mp = 101−102 °C;
1H NMR (500 MHz, C6D6) δ 7.98 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.5
( )-1-(((3S,5R)-5-(4-Chlorophenyl)-2-(4-nitrophenylsulfonyl)-
isoxazolidin-3-yl)methoxy)-2,2,6,6-tetramethylpiperidine (2f). 1f
was converted (at 70 °C) to 2f (36.6 mg, 65% yield, white solid,
1
>20:1 d.r.). mp = 158−160 °C; H NMR (400 MHz, CDCl3) δ 8.36
(d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),
7.25 (d, J = 8.8 Hz, 2H), 5.41 (dd, J = 6.8 Hz, 1H), 4.69−4.67 (m, 1
H), 4.04 (dd, J = 6.4 Hz, 9.2 Hz, 1H), 3.94 (dd, J = 5.4 Hz, 9.4 Hz,
1H), 2.88 (ddd, J= 8.4 Hz, 12.6 Hz, 17.1 Hz, 1H), 2.16 (ddd, J= 7.2
Hz, 10.0 Hz, 12.6 Hz, 1H), 1.46−1.43 (m, 4H), 1.25−1.14 (m, 12H);
13C NMR (75.5 MHz, CDCl3) δ 150.7, 142.5, 135.1, 134.7, 130.3,
128.9, 128.2, 124.1, 83.0, 77.6, 60.1, 58.3, 39.9, 39.6, 39.9, 32.9, 20.1,
17.0; IR (thin film), 2973, 2930, 1607, 1533, 1493, 1469, 1348, 1310,
1261, 1167, 1132, 1091, 1048, 1014, 955, 910, 854, 739, 622, 620
cm−1; HRMS (ESI) calcd for [M + H]+ C25H33O6N3Cl1S1: 538.1773,
found 538.1759.
Hz, 2 H), 4.58−4.56 (m, 1H), 4.07−4.04 (m, 1H), 4.00 (dd, J = 7.5
Hz, 15.7 Hz, 1H), 3.85 (dd, J = 6.5 Hz, 9.0 Hz, 1H), 3.55−3.51 (m,
1H), 1.97−1.94 (m, 1H), 1.79 (s, 3H), 1.69−1.66 (m, 1H), 1.42−1.40
(m, 4H), 1.28−1.15 (m, 12H); 13C NMR (75.5 MHz, CDCl3) δ 144.8,
133.1, 129.6, 129.1, 77.7, 69.8, 59.9, 57.6, 39.5, 33.0, 31.9, 30.8, 21.6,
20.0, 16.9 ; IR (thin film) 1361, 1329, 1162, 1088 cm−1; HRMS (ESI)
calcd for [M + H]+ C20H33O4N2S1: 397.2156, found 397.2159.
( )-2,2,6,6-Tetramethyl-1-(((3S,5S)-5-methyl-2-tosylisoxazolidin-
3-yl)methoxy)piperidine (2b). 1b was converted to (48 mg, 75% yield,
white solid, d.r. = 10:1) 2b as above (except 3 equiv of TEMPO was
used). The diastereomers were separated by HPLC (5% EtOAc in
(
)-2,2,6,6-Tetramethyl-1-(((3S,5S)-5-methyl-2-(4-
nitrophenylsulfonyl)isoxazolidin-3-yl)methoxy)piperidine (2g). 1g
was converted to 2g (49 mg, 69% yield, white solid, >20:1 d.r.)
using the above conditions except at 70 °C with 3 equiv TEMPO. mp
1
= 146−147 °C; H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.5 Hz,
2H), 8.17 (d, J = 8.5 Hz, 2H), 4.52−4.45 (m, 2H), 3.95 (dd, J= 6.7 Hz,
9.2 Hz, 1H), 3.83 (dd, J = 5.7 Hz, 9.2 Hz, 1H), 2.60 (ddd, J = 6.5 Hz,
8.0 Hz, 12.2 Hz, 1H), 1.72 (ddd, J = 7.0 Hz, 10.0 Hz, 12.2 Hz, 1H),
1.52−1.43 (m, 4H), 1.25 (s, 3H), 1.22−1.10 (m, 12H); 13C NMR
(75.5 MHz, CDCl3) δ 150.6, 142.8, 130.2, 124.0, 78.4, 77.8, 60.0, 58.2,
39.5, 39.0, 33.0, 32.8, 30.9, 18.0, 16.9; IR (thin film) 1607, 1534, 1349,
1263, 1172 cm−1; HRMS (ESI) calcd for [M + H]+ C20H31O6N3S1:
441.1928, found 441.1932.
1
hexanes). Major diastereomer: mp = 111−113 °C; H NMR (400
MHz, C6D6) δ 8.01 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H),
4.65−4.61 (m, 1H), 4.51−4.46 (m, 1H), 4.20 (dd, J = 6.4 Hz, 9.2 Hz,
1H), 3.96 (dd, J = 6.4 Hz, 9.0 Hz, 1H), 2.12 (ddd, J = 6.0 Hz, 8.0 Hz,
11.1 Hz, 1H), 1.81 (s, 3H), 1.48−1.18 (m, 5H), 1.14−1.13 (m, 12H),
0.91 (d, J = 6.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 144.7,
133.4, 129.6, 129.1, 78.3, 77.8, 59.9, 58.4, 39.5. 30.9, 21.6, 18.1, 17.0;
IR (film) 1598, 1359, 1333, 1166, 813 cm−1; HRMS (ESI) calcd for
( )-2,2,6,6-Tetramethyl-1-(((3S,5R)-5-(thiophen-2-yl)-2-tosylisox-
azolidin-3-yl)methoxy)piperidine (2h). 1h was converted to 2h (43.6
mg, 76% yield, white solid, 5.5:1 d.r.). Major diastereomer: mp = 95−
97 °C; 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 8.1 Hz, 2 H), 7.33
(d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1 H), 7.06 (d, J = 3.0 Hz, 1H),
6.95 (t, J = 5.4 Hz, 1H), 5.57 (dd, J = 6.3 Hz, 7.8 Hz, 1H), 4.60−4.56
(m, 1H), 4.08 (dd, J = 6.3 Hz, 8.7 Hz, 1H), 3.93 (dd, J = 6.8 Hz, 9.0
Hz, 1H), 2.92−2.82 (m, 1H), 2.43 (s, 1H), 2.28 (ddd, J = 7.0 Hz, 10.0
Hz, 12.4 Hz, 1H), 1.52−1.38 (m, 4H), 1.25−1.11 (m, 12H); 13C
NMR (75.5 MHz, CDCl3) δ 144.8, 139.4, 133.2, 129.6, 129.2, 127.2,
126.7, 126.5, 78.8, 77.9, 60.0, 58.5, 40.3, 39.6, 33.1, 32.9, 21.6, 20.1,
17.0 ; IR (thin film) 2927, 1451, 1359, 1332, 1162, 1092, 1048, 812,
705, 671; HRMS (ESI) calcd for [M + H]+ C24H35O4N2S2: 479.2026,
found 479.2033.
+
[M + H] C21H35O4N2S1: 411.2312, found 411.2310.
( )-2,2,6,6-Tetramethyl-1-(((3S,5R)-5-phenyl-2-tosylisoxazolidin-
3-yl)methoxy)piperidine (2c). 1c was converted to 2c (49.4 mg, 83%
yield, 10:1 dr). The diastereomers were separated by HPLC (5%
EtOAc in hexanes). Major diastereomer: white solid, mp = 131−133
1
°C; H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.28−
7.21 (m, 7H), 5.16 (dd, J = 6.4 Hz, 10.0 Hz, 1H), 4.50−4.46 (m, 1H),
4.11−4.08 (dd, J = 6.0 Hz, 9.2 Hz, 1H), 3.88 (dd, J = 6.6 Hz, 9.4 Hz,
1H), 2.76 (ddd, J = 6.4 Hz, 8.2 Hz, 12.4 Hz, 1H), 2.38 (s, 3H), 2.13
(ddd, J = 7.2 Hz, 10.2 Hz, 12.8 Hz, 1H), 1.51−1.39 (m, 4H), 1.15−
1.09 (m, 12H); 13C NMR (75.5 MHz, CDCl3) δ 144.8, 137.1, 133.3,
129.6, 129.3, 128.63, 128.57, 126.9, 83.1, 78.2, 60.1, 58.7, 40.5, 39.6,
33.9, 21.7, 20.1, 17.1 ; IR (thin film) 1598, 1360, 1333, 1164, 813
cm−1; HRMS (ESI) calcd for [M + H]+ C26H37O4N2S1: 473.2469,
found 473.2474.
( )-1-(((3S,5R)-5-(4-Bromophenyl)-2-tosylisoxazolidin-3-yl)-
methoxy)-2,2,6,6-tetramethylpiperidine (2i). 1i was converted to 2i
(51.1 mg, 92% yield, white solid, >20:1 d.r.) using the method for 2b.
( )-1-(((3S,5R)-5-(4-Chlorophenyl)-2-tosylisoxazolidin-3-yl)-
methoxy)-2,2,6,6-tetramethylpiperidine (2d). 1d was converted to
2d (50.8 mg, 64% yield, white solid, >20:1 d.r.) using the conditions
for 2b. mp = 128−129 °C; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J =
1
mp = 137−138 °C; H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.0
Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.0, 2H), 7.18 (d, J =
8.4 Hz, 2H), 5.21 (dd, J = 6.4 Hz, 9.4 Hz, 1H), 4.55−4.52 (m, 1H),
7758
dx.doi.org/10.1021/jo3013226 | J. Org. Chem. 2012, 77, 7755−7760

The Journal of Organic Chemistry
Note
4.06 (dd, J = 6.0 Hz, 8.8 Hz, 1H), 3.91 (dd, J = 6.6 Hz, 9.0 Hz, 1H),
2.81 (ddd, J = 6.8 Hz, 8.0 Hz, 12.5 Hz, 1H), 2.43 (s, 3H) 2.13 (ddd, J
= 7.2 Hz, 9.8 Hz, 11.7 Hz, 1H), 1.45−1.43 (m, 4H), 1.18−1.09 (m,
12H); 13C NMR (75.5 MHz, CDCl3) δ 144.9, 136.3, 133.1, 131.7,
129.6, 129.2, 128.5, 122.5, 82.4, 77.9, 60.1, 58.6, 40.4, 39.6, 33.1, 30.1,
21.7, 20.1, 17.1; IR (thin film) 1596, 1360, 1334, 1163, 671 cm−1;
HRMS (ESI) calcd for [M + H]+ C26H36O4N2S1Br1: 551.1574, found
551.1583.
77% pure material, 2 equiv), added over 5 min. After being stirred for
5 h, the mixture was quenched with Na2SO3 (aq) and extracted with
CH2Cl2 (3 × 10 mL). The organic extracts were washed with brine,
dried over Na2SO4 and concentrated in vacuo. Flash chromatography
on SiO2 (20−80% EtOAc in hexanes) afforded lactone 5 (6.8 mg, 64%
yield) as a waxy solid. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0
Hz, 2H), 7.41−7.21 (m, 7H), 5.69 (d, J = 8.0 Hz, 1H), 5.14 (d, J = 3.2
Hz, 1H), 4.02−3.96 (m, 1H), 2.83 (dd, J = 2.0 Hz, 8.6 Hz, 1H), 2.80
(dd, J = 2.0 Hz, 8.0 Hz, 1H) 2.42 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) 173.9, 144.3, 138.1, 135.8, 129.9, 129.0, 128.6, 127.2, 124.7,
78.6, 50.7, 37.6, 21.6; IR (thin film) 3264, 2924, 1786, 1597, 1496,
1452, 1333, 1254, 1161, 1092, 1009, 916 cm−1; HRMS (ESI) calcd for
[M + Na]+ C17H17O4N1Na1S1: 354.0757, found 354.0771.
( )1-(((3R,5R)-5-Allyl-2-tosylisoxazolidin-3-yl)methoxy)-2,2,6,6-
tetramethylpiperidine (2j). 1j was converted to 2j (42.5 mg, 65%
yield, colorless oil, 15:1 d.r.). The diastereomers were separated by
1
HPLC (10% EtOAc in hexanes). Major diastereomer: H NMR (400
MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.1, Hz, 2H),
5.77−5.63 (m, 1H), 5.08−5.05 (m, 2H), 4.42−4.25 (m, 2H), 3.97 (dd,
J = 8.0 Hz, 12.2 Hz, 1H), 3.80 (dd, J = 8.0 Hz, 12.2 Hz, 1H), 2.48
(ddd, J = 6.4 Hz, 8.4 Hz, 12.2 Hz, 1H), 2.45 (s, 3H), 2.39−2.33 (m,
1H), 2.28−2.20 (m, 1H), 1.80 (ddd, J = 6.4 Hz, 9.4 Hz, 12.3 Hz, 1H),
1.45−1.43 (m, 4H), 1.16−1.09 (m, 12H); 13C NMR (75.5 MHz,
CDCl3) δ 144.7, 133.4, 133.0, 129.6, 129.1, 117.8, 80.8, 78.2, 60.0,
58.1, 39.6, 37.2, 33.1, 32.8, 21.7, 20.1, 17.0; IR (thin film) 2928, 1451,
1334, 1359, 1164, 1056, 918, 813, 671 cm−1; HRMS (ESI) calcd for
[M + H]+ C23H37O4N2S1: 437.2455, found 437.2469.
N-((2S,4R)-1,4-Dihydroxy-4-phenylbutan-2-yl)-4-methylbenzene-
sulfonamide (6). Crude 5 [obtained from 4 (58.5 mg, 0.12 mmol) as
above] in EtOH (5 mL) and NaBH4 (22.7 mg, 0.6 mmol) were stirred
at rt. After 6 h, the mixture was quenched with 5% K2CO3 (aq) (8 mL)
and EtOH was removed in vacuo. The mixture was extracted with Et2O
(4 × 20 mL) and the organic extracts were dried over Na2SO4 and
concentrated. Flash chromatography on SiO2 (30−90% EtOAc in
hexanes) provided amino-diol 6 (22.8 mg) in 56% yield (white solid).
1
mp = 125−127 °C; H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 8.0
Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.31−7.23 (m, 3H), 7.18 (d, J = 8.4
Hz, 2H) 4.60 (t, J = 6.8 Hz, 1H), 3.52 (dd, J = 4.0 Hz, 11.2 Hz, 1H),
3.41 (dd, J = 5.6 Hz, 11.2 Hz, 1H), 3.24−3.22 (m, 1H), 2.48 (s, 1H),
1.98−1.95 (m, 1H), 1.81−1.75 (m, 1H); 13C NMR (75.5 MHz,
CD3OD) δ 145.7, 144.6, 139.9, 130.7, 129.2, 128.3, 128.1, 127.3, 72.0,
64.9, 54.2, 41.8, 21.5; IR (thin film) 3461, 3288, 2924, 2853, 1454,
1323, 1156, 1093, 1051, 815 cm−1; HRMS ESI calcd for [M + Na]+
C17H21O4N1Na1S1: 358.1091, found 358.1084.
( )-2,2,6,6-Tetramethyl-1-(((3S,4R)-4-phenyl-2-tosylisoxazolidin-
3-yl)methoxy)piperidine (2k). 1k was converted to 2k (48.8 mg, 82%
yield), clear oil, 10:1 d.r. The diastereomers were separated by HPLC
1
(5% EtOAc in hexanes). Major diastereomer: H NMR (400 MHz,
C6D6) δ 8.05 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.2 Hz, 2H), 7.08 (t, J =
7.2 Hz, 2H), 6.99 (t, J = 5.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 2H), 4.78−
4.73 (m, 1H), 4.39−4.36 (m, 1H), 4.32 (dd, J = 6.0 Hz, 10.0 Hz, 1H),
4.24 (dd, J = 6.4 Hz, 10.2 Hz, 1H), 3.84 (t, J = 8.0 Hz, 1H), 3.57−3.50
(m, 1H), 1.81 (s, 3H), 1.44−1.42 (m, 4H), 1.26−1.03 (m, 12H); 13C
NMR (75.5 MHz, CDCl3) δ 144.9, 136.4, 133.2, 129.7, 129.3, 128.8,
128.0, 127.6, 65.1, 59.9, 52.3, 39.6, 32.9, 21.7, 20.0, 17.0; IR (thin film)
2919, 1458, 1360, 1338, 1164, 1092, 1052, 908, 732 cm−1; HRMS
(ESI) calcd for [M + H]+ C26H37O4N2S1: 473.2484, found 473.2469.
( )-2,2,6,6-Tetramethyl-1-(((3S,5S)-3-methyl-5-phenyl-2-tosyli-
soxazolidin-3-yl)methoxy)piperidine (2l). 1l was converted to 2l
(49.5 mg, 85% yield, white solid, 12:1 d.r.) using the conditions for 2f.
Major diastereomer: mp = 120−122 °C; 1H NMR (400 MHz, CDCl3)
δ 7.84 (d, J = 8.4 Hz, 2H), 7.37−7.23 (m, 7H), 5.54 (t, J = 8.4 Hz,
1H), 3.88 (ABq, ΔνAB = 88.6 Hz, JAB = 8.6 Hz, 2H), (dd, J = 8.0 Hz,
12.2 Hz, 1H), 2.42 (dd, J = 8.0 Hz, 12.2 Hz, 1H), 2.37 (s, 3H), 1.93 (s,
3H), 1.48−1.42 (m, 4H), 1.20−1.16 (m, 12H); 13C NMR (75.5 MHz,
CDCl3) δ 144.1, 137.7, 135.9, 129.2, 128.7, 128.4, 128.3, 126.6, 81.5,
70.5, 60.2, 48.5, 39.7, 21.5, 21.3, 20.2, 16.9; IR (thin film) 2926, 1597,
1452, 1331, 1160, 1091, 812, 756; HRMS (ESI) calcd for [M + H]+
C27H39O4N2S1: 487.2623, found 487.2623.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for all new compounds, NMR spectra supporting
stereochemical assignments. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*schemler@buffalo.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The National Institutes of Health (GM 078383) is gratefully
acknowledged for support of this research.
■
( )-N-((2S,4R)-4-Hydroxy-4-phenyl-1-(2,2,6,6-tetramethylpiperi-
din-1-yloxy)butan-2-yl)-4-methylbenzenesulfonamide (4). A solu-
tion of isoxazolidine 2c (40 mgs, 0.08 mmol) and Pearlman’s catalyst
[Pd(OH)2 on carbon, wet. Degussa type, 20% (wt.)] (6 mg, 0.017
mmol, 10 mol %) in EtOH (8 mL) was shaken under 3 atm H2
pressure (hydrogenator) for 18 h.9c Additional catalyst (6 mg, 10 mol
%) was added and the mixture was shaken for 4 h. The mixture was
diluted with EtOAc, filtered through Celite and concentrated under
reduced pressure. Flash chromatography (10−60% EtOAc in hexanes)
afforded 28 mg (70%) of amino-alcohol 4 (colorless oil). 2c (4 mg,
REFERENCES
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1
10%) was recovered. H NMR (CDCl3, 400 MHz) δ 7.73 (d, J = 8.0
Hz, 2H), 7.32−7.23 (m, 7H), 5.08 (d, J = 8.0 Hz, 1H), 4.68 (t, J = 6.4
Hz, 1H), 3.71 (dd, J = 4.4 Hz, 8.8 Hz, 1H), 3.61 (dd, J = 5.6 Hz, 9.2
Hz, 1H), 3.50−3.46 (m, 1H), 2.39 (s, 3H), 1.98 (t, J = 8.0 Hz, 2H),
1.42−1.35 (m, 4H), 1.03−0.95 (m, 12H); 13C NMR (CDCl3, 75.5
MHz) δ 144.1, 143.4, 137.4, 129.6, 128.5, 127.7, 127.2, 125.8, 77.5,
72.1, 59.9, 51.8, 41.7, 39.6, 32.9, 21.4, 20.1, 16.9; IR (thin film) 3484
(br), 3279, 2928, 1598, 1494, 1453, 1374, 1330, 1159, 1093, 1047,
972, 910, 814, 732, 700, 665 cm−1; HRMS (ESI) calcd for [M + H]+
C26H39N2O4S1: 475.2625; found 475.2636.
( )-4-Methyl-N-((3S,5R)-2-oxo-5-phenyl-tetrahydrofuran-3-yl)-
benzenesulfonamide (5). Sulfonamide 4 (15 mg, 0.032 mmol) in
CH2Cl2 (0.3 mL) was treated with m-CPBA (14.3 mg, 0.083 mmol of
7759
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