Proline-catalyzed sequential syn-Mannich and [4 + 1]-annulation cascade reactions to form densely functionalized pyrrolidines

Article abstract of DOI:10.1021/jo5028886

A highly efficient one-pot [4 + 1]-annulation process for the asymmetric synthesis of densely functionalized pyrrolidine derivatives is described. The in situ generated syn-Mannich adduct obtained via proline catalysis acts as a four-atom component, and Corey's sulfur ylide or ethyl bromoacetate acts as a one-atom carbon source to construct pyrrolidine units in a highly enantio- and diastereoselective manner.

Full text of DOI:10.1021/jo5028886

Note
pubs.acs.org/joc
Proline-Catalyzed Sequential syn-Mannich and [4 + 1]-Annulation
Cascade Reactions To Form Densely Functionalized Pyrrolidines
Ravindra D. Aher, B. Senthil Kumar, and Arumugam Sudalai*
Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune,
Maharashtra, India 411008
*
S Supporting Information
ABSTRACT: A highly efficient one-pot [4 + 1]-annulation
process for the asymmetric synthesis of densely functionalized
pyrrolidine derivatives is described. The in situ generated
syn-Mannich adduct obtained via proline catalysis acts as a
four-atom component, and Corey’s sulfur ylide or ethyl
bromoacetate acts as a one-atom carbon source to construct
pyrrolidine units in a highly enantio- and diastereoselective
manner.
he derivatives of functionalized pyrrolidines are structural
[4 + 1]-annulation strategy with well-defined stereochemistry
and derivatizable functional groups has not been reported.
Thus, we envisioned that a new synthesis of pyrrolidines via a
1
T
components of many bioactive natural products and
2
pharmaceutically important substances. Figure 1 shows some
[
4 + 1]-annulation approach should be feasible by employing
15
β-amino aldehyde 4 as a four-atom precursor and sulfur ylide
or ethyl bromoacetate as a one-carbon source (Scheme 1).
Scheme 1. Reaction of β-Amino Aldehydes with Sulfur Ylide
and Wittig Olefination/N-Alkylation/Michael Reaction
Figure 1. Bioactive pyrrolidine-containing natural products.
of the examples of bioactive natural products containing densely
substituted pyrrolidine units. In particular, anisomycin 1 is a basic
2f
antibiotic, while domoic acid 2 and kainic acid 3 are potent
2
g
neuroexcitatory amino acids. Due to their biological
importance and structural complexity, several methods for
construction of pyrrolidine units have been reported recently,
which mainly include [3 + 2]-cycloadditions of azomethine ylides
Accordingly, when β-amino aldehyde 4 was treated with CH 
2
16
SOMe (Corey’s ylide) in DMSO/THF at 25 °C, the desired
2
hydroxypyrrolidine derivative 5 was obtained in 95% yield.
Additionally, when 4 was treated with Ph PCHCO Et for
3
3
2
with alkenes or nitrones with cyclopropanes, transition-
1
.5 h at 25 °C followed by addition of ethyl bromoacetate in
metal-catalyzed carboamination, hydroamination or allylic
4
the presence of Cs CO at 50 °C for 6 h, the corresponding
2 3
amination protocol, intramolecular cyclization of epoxy and
5
pyrrolidine dicarboxylate derivative 6 was obtained in 90% yield
with moderate diastereoselectivity (dr = 7:3).
halogenated sulfones under basic conditions, acid-catalyzed
6
cyclization of vinylsilanes, intramolecular carbolithiation of
7
8
Encouraged by initial results, we became interested in
investigating the feasibility of this new diastereoselective
homoallylic amines, radical cyclizations, catalytic intramolecular
9
hydroamination of alkenylamines, manipulations of sugars from
the chiral pool resources, various metal-catalyzed cyclizations,
ring-closing metathesis of allylic amines, and 5-endo-trig
cyclization of N-allylic-substituted α-amino nitriles. In recent
years, proline-catalyzed sequential reactions have gained more
applicability for the asymmetric synthesis of structurally diverse
1
7
10
11
[4 + 1]-annulation strategy with chiral Mannich aldehydes A
18
12
or δ,δ′-diamino α,β-unsaturated esters 10 (Scheme 2) and
CH SOMe or ethyl bromoacetate, respectively, which can
13
2
2
furnish chiral-substituted pyrrolidines. In this communication,
we describe a one-pot sequential [4 + 1]-annulation approach
14
molecular architectures.
Although many strategies for the synthesis of substituted
pyrrolidines have been described, a transition-metal-free
Received: December 20, 2014
©
XXXX American Chemical Society
A
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Probable Mechanistic Pathway for Pyrrolidine
Carboxylate Formation
Table 2. L-Proline-Catalyzed Sequential syn-Mannich/Wittig
Olefination/N-Alkylation/Michael Addition Reaction for
Synthesis of Pyrrolidine Carboxylate 9a−h
a
b
imines 7a−h
product 9a−h
c
d
entry
Ar
yield (%)
ee (%)
1
2
3
4
5
6
7
8
phenyl (7a)
4-Cl-ph (7b)
80
67
68
78
79
76
71
60
96
94
99
93
92
99
92
92
involving the reaction of in situ generated syn-Mannich
aldehydes A with sulfur ylide or δ,δ′-diamino α,β-unsaturated
ester 10 formed in situ with ethyl bromoacetate that provides
for the construction of densely substituted pyrrolidine units 8
and 9 in a highly enantio- and diastereoselective manner
4-CF -ph (7c)
3
4-tolyl (7d)
2-napth (7e)
4-Br-ph (7f)
4-F-ph (7g)
2-furyl (7h)
(
Tables 1 and 2).
a
Imine (2.5 mmol), aldehyde (2.75 mmol), L-proline (10 mol %),
Table 1. L-Proline-Catalyzed Sequential syn-Mannich/
Corey−Chaykovsky Reaction for the Synthesis of
Ph PCHCO Et (3.75 mmol), 0 °C, 1.5 h then, ethyl bromoacetate
3
2
b
(3 mmol), Cs
CO (6.25 mmol), 50 °C, 6 h. Single diastereoisomer
3
c
2
a
(
dr >99:1) was obtained. Isolated yield with respect to imine.
Hydroxypyrrolidines 8a−k
d
Percent enantioselectivity was determined from chiral HPLC analysis.
such as THF, CHCl , and DMF for the tandem protocol
3
resulted in a sluggish reaction with low product yields. With
these optimized reaction conditions (Table 1, footnote a), we
next examined the scope of the annulation protocol. Substrates
having fluoro, chloro, bromo, methoxy, methyl, trifluoromethyl,
and thiomethyl groups on the aromatic nucleus and
heteroaromatic compounds such as thiophenyl and furfuryl
were well-tolerated under the reaction conditions (Table 1,
entries 2−11).
b
imines 7a−k
products 8a−k
c
d
entry
Ar
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
phenyl (7a)
4-Cl-ph (7b)
72
66
70
70
63
61
66
64
65
63
74
99
96
95
94
99
98
94
90
88
86
99
4-CF -ph (7c)
3
Next, it was of interest to extend the utility of the syn-
Mannich adduct for the asymmetric synthesis of densely
functionalized pyrrolidine dicarboxylates 9a−h (Table 2).
Thus, Mannich adduct A (Ar = Ph) was trapped in situ with
Ph PCHCO Et for 1.5 h, followed by addition of ethyl
4-tolyl (7d)
2-naph (7e)
4-Br-ph (7f)
4-F-ph (7g)
furyl (7h)
e
e
e
3
2
bromoacetate in the presence of Cs CO as base, which
4-SMe-ph (7i)
thienyl (7j)
p-anisyl (7k)
2
3
facilitated in situ intramolecular Michael addition to produce
the expected pyrrolidine dicarboxylate derivative 9a. Com-
pound 9a was indeed obtained in 80% yield with 96% ee and
>99% diastereoselectivity when carried out at 50 °C for 6 h
(Table 2, entry 1). Further, increase of temperature (70 °C),
with an overall aim to improve the rate of the reaction and
product yield, however, resulted in low yields. With optimized
reaction conditions (Table 2, footnote a), other substrates
bearing a fluoro, chloro, bromo, methyl, and trifluoromethyl
substituent on the aromatic nucleus including heteroaryl units
underwent this [4 + 1]-annulation cascade smoothly, affording
the corresponding pyrrolidine dicarboxylates 9b−h in high
yields with excellent enantio- and diastereoselectivities (Table 2,
entries 2−8).
1
0
1
1
a
Imine (2.5 mmol), aldehyde (2.75 mmol), L-proline (10 mol %),
b
CH SOMe (3.75 mmol), DMSO/THF (1:1), −10 °C, 2 h. Single
2
2
c
diastereoisomer (dr >99:1) was obtained. Isolated yield with respect
d
to imine. Percent enantioselectivity was determined from chiral
HPLC analysis. Corresponding oxazolidinones were isolated by using
e
7
.5 mmol of ylide for 12 h at 25 °C.
Thus, β-amino aldehyde 4 was treated with aryl imine 7a as a
17
model substrate under List protocol that produced the
corresponding chiral syn-Mannich aldehyde A in situ. This was
followed by the addition of a solution of CH SOMe in
2
2
DMSO/THF (1.5 equiv) at 25 °C, which gave the desired
chiral hydroxypyrrolidine 8a in 68% yield with 92% ee and
moderate diastereoselectivity (dr = 4:1). An improvement in
diastereoselectivity (dr = 9:1) was realized by performing the
reaction at 0 °C for 2 h. Finally, when the addition of ylide was
conducted at −10 °C, 8a was indeed obtained in 72% yield
with 99% ee and >99 dr (Table 1, entry 1). However, further
lowering of temperature for the annulation protocol had a
deleterious effect on the yield (60%). Use of other solvents
The absolute configuration of the newly generated syn-
Mannich adduct A was assigned on the basis of the previously
17
established configuration of amino aldehydes. The relative
19
stereochemistry of substituted pyrrolidine derivatives 8a−k and
9a−h is proven unambiguously from COSY, NOESY studies,
and X-ray crystallographic analysis (Figure 2, CCDC 1036949).
The formation of hydroxypyrrolidines 8a−k can be readily
14c
understood on the basis of our previously established study.
B
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
quenched by the addition of aq NH Cl solution. The mixture was
4
concentrated in vacuum to remove acetonitrile, and concentrate was
extracted with EtOAc (3 × 30 mL). The combined organic layers were
washed with brine, dried over anhyd Na SO , and concentrated under
2
4
reduced pressure to give the crude products, which were then purified
by silica gel column chromatography (230−400 mesh) using
petroleum ether and ethyl acetate as eluents to afford the pure
products 8a−k.
Figure 2. ORTEP diagram of 9e.
Sequential syn-Mannich/Wittig Olefination/N-Alkylation/
Michael Addition. To a cooled solution of N-Boc imines (7a−h,
A probable mechanistic pathway for the formation of pyrrolidine
20
2.5 mmol) and L-proline (10 mol %) in dry CH CN (20 mL) at 0 °C
3
dicarboxylates 9a−h is, however, shown in Scheme 2. Initially,
was added β-amino aldehyde 4 (568 mg, 2.75 mmol), and the mixture
was stirred for 8−12 h at 0 °C. This was followed by the addition of a
syn-Mannich aldehyde A in Wittig olefination forms δ,δ′-diamino
1
13
α,β-unsaturated ester 10 ( H and C NMR analysis) in situ,
5
ethyl 2-(triphenyl-λ -phosphanylidene)acetate (1.306 g, 3.75 mmol) at
which undergoes N-alkylation with ethyl bromoacetate in the
0
°C and allowed to stir for 2 h at the same temperature; ethyl
presence of Cs CO to form the anionic species B. This is
2
3
bromoacetate (501 mg, 3.455 mL, 3 mmol) and Cs CO (2.037 g,
2
3
followed by the intramolecular distereoselective Michael addition
to produce pyrrolidine dicarboxylates 9a−h. The high
distereoselectivity can be explained by the formation of favorable
6
.25 mmol) were added, and reaction temperature increased to 50 °C
and was allowed to stir for 6−8 h at the same temperature. The
progress of the reaction can be monitored by TLC. It was then
(
E)-enolate (species C), in which the cesium ion coordinates to
quenched by the addition of an aq NH Cl solution. The mixture was
4
then extracted with EtOAc (3 × 30 mL). The combined organic layers
both of the ester carbonyls.
were washed with brine, dried over anhyd Na SO , and concentrated
In summary, we have described, for the first time, a novel
4 + 1]-annulation strategy which includes syn-Mannich/
2
4
under reduced pressure to give the crude products, which were then
purified by flash silica gel column chromatography (230−400 mesh)
using petroleum ether and ethyl acetate as eluents to afford the pure
products 9a−h.
Corey−Chaykovsky Reaction of β-Amino Aldehyde. To a cooled
solution of β-amino aldehyde 4 (568 mg, 2.5 mmol) in dry THF (5 mL)
at 25 °C was added a solution of dimethyloxosulfonium methylide
(2.5 mmol) in DMSO (10 mL), and the reaction mixture was allowed
to stir for 2 h at the same temperature. It was then quenched by the
[
Corey−Chaykovsky or Wittig olefination/N-alkylation/Michael
addition cascade that leads to the asymmetric synthesis of
substituted pyrrolidine derivatives 8a−k and 9a−h, respec-
tively, with good yields and excellent enantio- and diaste-
reoselectivities. The present approach thus provides for ready
access to a large number of kainoid amino acids and their
congeners that can be utilized for SAR studies. The salient
features of the methodology are as follows: (1) metal-free
pyrrolidine synthesis; (2) one-pot 3 or 4 reactions; (3)
functional group tolerance and milder reaction conditions;
and (4) high yields with excellent enantio- and diastereose-
lectivity to obtain densely functionalized chiral pyrrolidines.
addition of aq NH Cl solution. The mixture was then extracted with
4
EtOAc (3 × 30 mL). The combined organic layers were washed with
brine, dried over anhyd Na SO , and concentrated under reduced
2
4
pressure to give the crude products, which were then purified by silica
gel column chromatography (100−200 mesh) using petroleum ether
and ethyl acetate as eluents (6:4) to afford the pure products 5 (570 mg,
9
5% yield).
EXPERIMENTAL SECTION
■
Sequential Wittig Olefination/N-Alkylation/Michael Addition of
General Information. Solvents were purified and dried by
standard procedures before use; petroleum ether in the boiling
range of 60−80 °C was used. Melting points are uncorrected. Optical
rotations were measured using sodium D line on a polarimeter.
β-Amino Aldehyde. To a cooled solution of β-amino aldehyde 4
(568 mg, 2.5 mmol) in dry CH CN (20 mL) at 25 °C was added ethyl
2-(triphenyl-λ -phosphanylidene)acetate (1.045 g, 3 mmol), and the
reaction mixture was allowed to stir for 1.5 h at the same tempera-
ture; ethyl bromoacetate (501 mg, 3.455 mL, 3.0 mmol) and
Cs CO (1.956 g, 6.0 mmol) were then added, and reaction
temperature increased to 50 °C and was allowed to stir for 6 h at
the same temperature. It was then quenched by the addition of an
aq NH Cl solution. The mixture was then extracted with EtOAc
(3 × 30 mL). The combined organic layers were washed with brine,
dried over anhyd Na SO , and concentrated under reduced pressure to
give the crude products, which were then purified by flash silica gel
column chromatography (230−400 mesh) using petroleum ether
and ethyl acetate as eluents (8:2) to afford the products 6 (860 mg,
3
5
1
13
H NMR and C NMR were recorded on 200, 400, and 500 MHz
NMR spectrometers. HRMS data for new compounds were recorded
using an Orbitrap mass analyzer associated with an Accela 1250 pump.
Elemental analysis was carried on a CHNS-O analyzer. HPLC was
performed with a variable wavelength detector. Column chromatog-
raphy was carried out by using silica gel with the selected particle size
of 100−200 mesh or 230−400 mesh. D-Proline and L-proline were
purchased from Sigma-Aldrich. Racemic proline was prepared by
2
3
4
2
4
16
mixing both enantiomers before use. Imines 7a−k and β-amino
15
aldehyde 4 were freshly prepared prior to use following reported
methods.
9
0% yield).
General Experimental Procedure. Preparation of Sulfur Ylide.
NaH (90 mg, 3.75 mmol, previously washed with petroleum ether to
remove oil) was taken in an oven-dried three-necked flask, followed by
the addition of dry DMSO/THF (5 mL each) through a septum to it,
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(phenyl)methyl)
carbamate (8a):
and the whole slurry was stirred at 25 °C under N atmosphere. Then
2
trimethyloxosulfonium iodide (835 mg, 3.75 mmol) was added to the
slurry over a period of 5 min via a solid addition funnel until it became
a homogeneous solution.
D
Sequential syn-Mannich/Corey−Chaykovsky Reaction. To a
Yield 807 mg, 72%; colorless solid; mp 197−200 °C; [α]25 +10.4 (c 0.2,
CHCl ); 99% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/i-PrOH,
80:20, 0.5 mL/min, 254 nm), t = 11.3 min (minor), t = 10.1 min
, cm ) νmax 763, 1014, 1296, 1418, 1575, 1652,
cooled solution of N-Boc imines (7a−k, 2.5 mmol) and L-proline
3
(
10 mol %) in dry CH CN (20 mL) at 0 °C was added β-amino
r
r
3
−
1
aldehyde 4 (568 mg, 2.75 mmol), and the mixture was stirred for
−12 h at 0 °C. This was followed by the addition of a solution of
dimethyloxosulfonium methylide in DMSO/THF (3.75 mmol) at
10 °C and allowed to stir for 2 h at the same temperature. The
progress of the reaction can be monitored by TLC. It was then
(major); IR (CHCl
1669, 1720, 2917, 3366; H NMR (400 MHz, CDCl ) δ 1.40 (s, 9H),
3
2.35−2.40 (m, 1H), 2.44 (s, 3H), 2.84 (t, J = 11.5 Hz, 1H), 2.96 (t, J =
8.8 Hz, 1H), 3.44 (d, J = 11.5 Hz, 1H), 3.57 (d, J = 11.5 Hz, 1H),
4.24 (br s, 1H), 4.53 (dd, J = 8.1, 10.8 Hz, 1H), 4.73 (br s, 1H), 4.88
3
1
8
−
C
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
7
d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H),
.35−7.40 (m, 3H), 7.65 (d, J = 8.1 Hz, 2H); C NMR (100 MHz,
(4R,4aR,7aS)-4-(Naphthalen-2-yl)-6-tosylhexahydropyrrolo[3,4-e]-
[1,3]oxazin-2(3H)-one (8e):
13
CDCl ) δ 21.5, 28.2 (3), 48.3, 52.2, 53.2, 55.9, 69.9, 81.1, 126.7 (2),
3
1
27.4 (2), 128.7, 129.4, 129.5, 134.1, 139.1, 143.3, 156.7; HRMS (ESI)
+
calcd for C H N O S [M + Na] 469.1772; found 469.1761.
23
30
2
5
tert-Butyl ((R)-(4-Chlorophenyl)((3R,4S)-4-hydroxy-1-tosylpyrrolidin-
-yl)methyl)carbamate (8b):
3
D
Yield 667 mg, 63%; colorless solid; mp 153−156 °C; [α]25 +14.7
(
c 0.3, CHCl ); 99% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/
3
i-PrOH, 90:10, 0.5 mL/min, 254 nm), t = 100.7 min (minor), t =
r
r
−1
8
2
(
(
(
0.1 min (major); IR (CHCl , cm ) ν 740, 1154, 1268, 1718,
3 max
D
Yield 800 mg, 66%; colorless solid; mp 203−205 °C; [α]25 +15.4 (c 0.2,
1
286, 2390, 3010, 3053, 3290; H NMR (500 MHz, CDCl ) δ 2.44
3
CHCl ); 96% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
s, 3H), 2.57 (d, J = 3.3 Hz, 1H), 3.30 (t, J = 9.1 Hz, 1H), 3.47−3.50
m, 1H), 3.58 (d, J = 11.9 Hz, 1H), 3.69 (t, J = 9.46 Hz, 1H), 4.56
s, 1H), 4.67 (d, J = 2.44 Hz, 1H), 6.07 (s, 1H), 7.26 (d, J = 8.54 Hz,
8
(
0:20, 0.5 mL/min, 254 nm), t = 15.1 min (minor), t = 12.5 min
r
r
−
1
1
major); IR (CHCl , cm ) ν 1089, 1158, 1317, 1390, 1696; H NMR
400 MHz, CDCl ) δ 1.38 (s, 9H), 1.98 (s, 1H), 2.38 (br s, 1H), 2.45
s, 3H), 3.28 (s, 1H), 3.33 (t, J = 10.0 Hz, 1H), 3.40 (s, 1H), 3.65 (t, J =
.8 Hz, 1H), 3.77 (s, 1H), 4.78 (s, 1H), 5.0 (s, 1H), 7.23 (dd, J = 8.2,
.0 Hz, 4H), 7.32 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H); C NMR
125 MHz, CDCl , CD OD) δ 21.3, 28.1 (3), 48.8, 49.9, 52.5, 56.9, 69.5,
3 max
(
3
1
7
H), 7.32 (d, J = 8.54 Hz, 2H), 7.49 (d, J = 8.24 Hz,2H), 7.65 (s, 1H),
(
13
.68 (d, J = 6.71 Hz,2H), 7.69−7.70 (m, 3H); C NMR (100 MHz,
8
8
13
CDCl ) δ 21.5, 42.2, 48.4, 53.9, 54.1, 75.8, 123.1, 124.9, 126.7, 127.0,
3
1
27.4 (2), 127.7, 127.9, 129.5, 129.9 (2), 133.1, 133.4, 137.4, 144.1,
(
3
3
7
9.8, 127.3 (2), 128.1 (2), 128.5 (2), 129.6 (2), 133.0, 134.0, 139.9, 143.4,
151.9; HRMS (ESI) calcd for C23
found 423.1379.
H N O
22 2 4
S [M + H]+ 423.1378;
+
155.4; HRMS (ESI) calcd for C H ClN O S [M + Na] 503.1383;
23
29
2
5
found 503.1391.
(4R,4aR,7aS)-4-(4-Bromophenyl)-6-tosylhexahydropyrrolo[3,4-e]-
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(4-(trifluoro-
methyl)phenyl)methyl)carbamate (8c):
[1,3]oxazin-2(3H)-one (8f):
D
D
Yield 905 mg, 70%; colorless solid; mp 202−204 °C; [α]25 +27.3 (c 0.3,
Yield 690 mg, 61%; colorless solid; mp 210−213 °C; [α]25 +12.3
CHCl ); 95% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
(c 0.3, CHCl ); 98% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/
3
8
(
2
0:20, 0.5 mL/min, 254 nm), t = 93.6 min (minor), t = 86.0 min
r
r
i-PrOH, 80:20, 0.5 mL/min, 254 nm), t = 34.5 min (minor), t = 40.9
r
r
−1
major); IR (CHCl , cm ) ν 1249, 1418, 1506, 1621, 1653, 1683,
979, 3366; H NMR (500 MHz, CDCl ) δ 1.40 (s, 9H), 2.36−2.41
m, 1H), 2.44 (s, 3H), 2.83 (t, J = 9.7 Hz, 1H), 2.94 (t, J = 7.9 Hz,
−1
3
max
min (major); IR (CHCl , cm ) ν 742, 1160, 1271, 1705, 2286,
350, 2999, 3290; H NMR (500 MHz, CDCl , CD OD) δ 2.45
3 3
s, 3H), 2.48−2.49 (m, 1H), 3.25 (t, J = 9.7 Hz, 1H), 3.50 (dd, J = 4.2,
.6 Hz,1H), 3.62 (d, J = 11.9 Hz 1H), 3.70 (t, J = 8.1 Hz, 2H) 4.43 (d,
J = 2.7 Hz, 1H), 4.67 (t, J = 3.9 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.37
(t, J = 8.2 Hz, 2H), 7.50 (d, J = 7.5 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H);
C NMR (125 MHz, CDCl , CD OD) δ 21.2, 41.8, 48.1, 52.4, 54.1,
3 max
1
3
1
2
(
(
7
1
4
7
4
5
H),3.42 (d, J = 11.6 Hz, 1H), 3.56 (d, J = 10.3 Hz, 1H), 4.23 (s, 1H),
.43 (br s, 1H), 4.64 (t, J = 8.8 Hz, 1H), 4.93 (d, J = 7.6 Hz, 1H),
.29 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.64 (t, J = 7.6 Hz,
H); 13C NMR (125 MHz, CDCl ) δ 21.6, 28.2 (3), 48.0, 51.7, 52.8,
3
13
5.9, 70.0, 81.3, 122.6 (q, J = 272.8 Hz) 126.4 (2), 127.2 (2), 127.5
2), 129.6 (2),130.1 (q, J = 32.4 Hz), 134.2, 143.1, 143.3, 156.5;
HRMS (ESI) calcd for C H F N O S [M + Na] 537.1646; found
3
3
(
75.5, 122.2, 127.1 (2), 127.2 (2), 129.7 (2), 132.0 (2), 133.1, 139.6,
+
S [M + Na]+
144.0, 152.4; HRMS (ESI) calcd for C19
473.0141; found 473.0133.
H19BrN O
24
29
3
2
5
2 4
537.1648.
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(p-tolyl)-
methyl)carbamate (8d):
(4R,4aR,7aS)-4-(4-Fluorophenyl)-6-tosylhexahydropyrrolo[3, 4-e]
[1,3]oxazin-2(3H)-one (8g):
D
Yield 810 mg, 70%; colorless solid; mp 187−190 °C [α]
+25.1
25
D
(
c 0.2, CHCl ); 94% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/
3
Yield 646 mg, 66%; colorless solid; mp 207−211 °C; [α]25 +12.3
i-PrOH, 80:20, 0.5 mL/min, 254 nm), t = 19.8 min (minor), t =
r
r
(c 1.0, CHCl ); 94% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/
3
−1
1
1
4.3 min (major); IR (CHCl , cm ) ν 884, 1091, 1248, 1339,
366, 1472, 1507, 1558, 1653, 1683, 2977, 3366; H NMR (400 MHz,
3 max
i-PrOH, 80:20, 0.5 mL/min, 254 nm), t = 29.1 min (minor), t = 24.0
r
r
1
−1
min (major); IR (CHCl , cm ) ν 740, 1158, 1267, 1713, 2293,
356, 3059, 3282; H NMR (500 MHz, CDCl ) δ 2.45 (s, 3H), 2.48−
.50 (m, 1H), 3.26 (t, J = 8.54 Hz, 1H), 3.56 (q, J = 8.2 Hz, 2H), 3.64
3
max
CDCl ) δ 1.40 (s, 9H), 2.31−2.34 (m, 1H), 2.36 (s, 3H), 2.44 (s, 3H),
1
3
2
2
3
2.80 (dd, J = 9.8, 11.5 Hz, 1H), 2.96 (dd, J = 7.6, 9.3 Hz, 1H), 3.43
(
d, J = 11.5 Hz, 1H), 3.57 (dd, J = 3.7, 12.9 Hz, 1H), 4.22 (s, 1H),
(
5
dd, J = 7.9, 9.7 Hz, 1H), 4.42 (t, J = 3.0 Hz, 1H), 4.69−4.71 (m, 1H),
4
1
8
.49 (dd, J = 8.1, 11.0 Hz, 1H), 4.75 (br s, 1H), 4.83 (d, J = 7.8 Hz,
H), 7.09 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.29 (d, J =
.1 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl3)
.76 (d, J = 1.5 Hz,1H), 7.08 (t, J = 8.5 Hz, 2H), 7.20 (q, J = 8.5 Hz,
1
3
13
2H), 7.35 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H); C NMR
100 MHz, CDCl ) δ 21.6, 42.6, 48.4, 53.3, 54.0, 75.8, 116.3, 116.5,
(
δ 21.1, 21.6, 28.2 (3), 48.3, 52.3, 52.9, 55.9, 69.9, 80.9, 126.6 (2),
27.4 (2), 129.5 (2), 130.0 (2), 134.1, 136.1, 138.5, 143.3, 156.7;
3
1
127.5,127.6, 127.7, 129.9 (2), 133.5, 136.0, 144.1, 151.7, 161.5 (d, J =
+
+
HRMS (ESI) calcd for C H N O S [M + Na] 483.1930; found
250 Hz); HRMS (ESI) calcd for C19
found 413.0929.
H19FN
2
O
4
S [M + Na] 413.0942;
24
32
2
5
483.1926.
D
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
D
tert-Butyl ((R)-Furan-2-yl((3R,4S)-4-hydroxy-1-tosylpyrrolidin-3-yl)-
methyl)carbamate (8h):
Yield 883 mg, 74%; colorless solid; mp 199−202 °C; [α]2 +33.4 (c 0.3,
5
CHCl ); 99% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
−1
9
8
0:10, 0.5 mL/min, 254 nm), t = 70.7 min; IR (CHCl , cm ) ν
r 3 max
1
87, 1094, 1341, 1369, 1469, 1510, 1561, 1656, 1679, 2974, 3365; H
NMR (500 MHz, CDCl ) δ 1.41 (s, 9H), 2.29−2.40 (m, 1H), 2.45
3
(s, 3H), 2.78 (dd, J = 9.2, 11.6 Hz, 1H), 2.95 (dd, J = 7.8, 9.2 Hz, 1H),
3
4
2
8
.44 (d, J = 11.5 Hz, 1H), 3.59 (dd, J = 3.7, 12.9 Hz, 1H), 3.83 (s, 3H),
.18−4.25 (m, 1H), 4.47 (dd, J = 7.8,10.7 Hz, 1H), 4.73−4.75 (m,
H), 6.88 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.30 (d, J =
D
Yield 695 mg, 64%; colorless solid; mp 136−139 °C; [α]
−16.3
2
5
(
c 0.5, CHCl ); 90% ee (Chiracel OD-H (250 × 4.6 mm), n-hexane/
i-PrOH, 80:20, 0.5 mL/min, 254 nm), t = 19.8 min (minor), t =
4.3 min (major); IR (CHCl , cm ) ν 887, 1341, 1366, 1467,
514, 1558, 1654, 1682, 3365; H NMR (400 MHz, CDCl ) δ 1.43
13
3
.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H); C NMR (125 MHz, CDCl3)
r
r
δ 21.6, 28.2 (3), 48.3, 52.4, 52.5, 55.3, 55.9, 70.0, 81.0, 114.8, 127.5
−
1
1
1
(
1
(
3 max
(
(
2), 127.9 (2), 129.5 (2), 131.3 (2), 134.4, 143.1, 156.6, 159.7; HRMS
ESI) calcd for C H N O S[M + Na] 499.1873; found 499.1861.
1
3
+
24
32
2
6
s, 9H), 2.28 (s, 1H), 2.44 (s, 4H), 2.99 (t, J = 9.4 Hz, 1H), 3.13 (t, J =
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(phenyl)methyl)-
0.0 Hz, 2H), 3.33−3.40 (m, 1H), 3.56 (q, J = 9.7 Hz, 1H), 3.91−4.04
3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-carboxylate (9a):
m, 1H), 4.94−5.03 (m, 2H), 6.15−6.19 (m,1H), 6.30 (s, 1H), 7.31
(
d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ) δ 21.6, 28.2 (3), 47.0 (2), 50.5, 52.2,
3
7
1
4
0.9, 80.8, 106.7, 110.5, 126.5, 127.6 (2), 129.8 (2), 142.3, 143.6,
+
52.0, 156.3; HRMS (ESI) calcd for C H N O S [M + Na]
2
1
28
2
6
59.1560; found 459.1551.
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(4-(meth-
D
Yield 1.17 g, 80%; colorless solid; mp 150−151 °C; [α] +34.3 (c 0.5,
25
ylthio)phenyl)methyl)carbamate (8i):
CHCl
); 96% ee (Chiracel AS-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
8
0:20, 0.5 mL/min, 254 nm), t = 10.2 min (minor), t = 11.1 min
r
r
−1
1
(
major); IR (CHCl , cm ) ν 1162, 1214, 1345, 1499, 1736; H
3 max
NMR (400 MHz, CDCl ) δ 1.22−1.26 (m, 6H), 1.41 (s, 9H), 1.89
3
(
(
(
dd, J = 5.7 and 11.8 Hz, 1H), 2.44 (s, 3H), 2.51−2.63 (m, 3H), 3.17
t, J = 9.0 Hz, 1H), 3.43 (t, J = 8.5 Hz, 1H), 4.0−4.13 (m, 4H), 4.61
d, J = 7.7 Hz, 1H), 4.80 (br s, 1H), 4.99 (d, J = 8.0 Hz, 1H), 7.14 (d,
D
Yield 801 mg, 65%; colorless solid; mp 209−211 °C; [α]
+1.6
13
25
J = 7.2 Hz, 2H), 7.26−7.33 (m, 5H), 7.68 (d, J = 8.0 Hz, 2H); C
NMR (100 MHz, CDCl ) δ 14.0, 14.2, 21.6, 28.2, 29.7, 33.2, 40.5,
(
c 0.1, CHCl ); 88% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/
3
3
i-PrOH, 80:20, 0.5 mL/min, 254 nm), t = 34.0 min (minor),
r
46.9, 48.3, 53.0, 60.6, 61.2, 63.2, 80.0, 125.9,127.4, 128.9, 129.6, 135.6,
140.2, 143.4, 155.3, 170.4, 170.6; HRMS (ESI) C H N O S [M +
Na] 611.2402; found 611.2395.
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(4-chloro-
phenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-car-
boxylate (9b):
−1
t = 30.4 min (major); IR (CHCl , cm ) ν 886, 1096, 1339, 1371,
r
3
max
30
40
2
8
1
1467, 1512, 1559, 1658, 1684, 2969, 3366; H NMR (500 MHz,
+
CDCl ) δ 1.41 (s, 9H), 2.19−2.40 (m, 1H), 2.45 (s, 3H), 2.51 (s, 3H),
3
2
3
4
1
7
.77 (dd, J = 9.6,11.8 Hz, 1H),), 2.96 (dd, J = 7. 5, 9.1 Hz, 1H),
.43 (d, J = 11.4 Hz, 1H), 3.55−3.64 (m, 1H), 4.20−4.26 (m, 1H),
.50 (dd, J = 7.9, 10.7 Hz, 1H), 4.61 (br s, 1H), 4.77 (d, J = 7.8 Hz,
H), 7.13 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.30 (d, J =
13
.9 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H); C NMR (125 MHz, CDCl3)
δ 15.7, 21.6, 28.3 (3), 48.3, 52.2, 52.8, 56.0, 70.0, 81.1, 127.2 (2), 127.3
(
(
2), 127.6 (2), 129.5 (2), 134.4, 135.8, 139.5, 143.1, 156.6; HRMS
+
ESI) calcd for C H N O S [M + Na] 515.1650; found 515.1645.
24
32
2
5
2
D
Yield 1.04 g, 67%; colorless solid; mp 155−156 °C; [α]2 +23.4 (c 0.6,
5
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(thiophen-
-yl)methyl)carbamate (8j):
CHCl ); 94% ee (Chiracel AS-H (250 × 4.6 mm), n-hexane/i-PrOH,
2
3
9
(
(
0:10, 0.5 mL/min, 254 nm), t = 27.2 min (minor), t = 30.6 min
r
r
−
1
1
major); IR (CHCl , cm ) ν 1156, 1238, 1512, 1711; H NMR
500 MHz, CDCl ) δ 1.20 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H),
3 max
3
1
.40 (s, 9H), 1.96 (dd, J = 6.1, 10.9 Hz, 1H), 2.42 (s, 3H), 2.54−2.63
(
4
m, 3H), 3.14 (t, J = 8.5 Hz, 1H), 3.41 (br s,1H), 3.99−4.03 (m, 1H),
.06−4.15 (m, 3H), 4.65 (d, J = 7.6 Hz, 1H), 4.79 (br s, 1H), 4.95
D
Yield 710 mg, 63%; colorless solid; mp 186−189 °C; [α]25 +37.3 (c 0.3,
(br s,1H), 7.11 (d, J = 8.5 Hz, 2H), 7.30 (dd, J = 2.4, 7.9 Hz, 4H), 7.69
(d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl ) δ 13.9, 14.1, 21.5,
CHCl ); 86% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
3
8
0:20, 0.5 mL/min, 254 nm), t = 18.0 min (minor), t = 20.9 min
28.1, 33.2, 40.4, 46.7, 48.0, 52.5, 60.7, 61.3, 63.1, 80.3, 127.3, 129.0,
129.6, 133.5, 135.3, 138.8, 143.7, 155.3, 170.3, 170.6; HRMS (ESI)
r
r
−1
(
major); IR (CHCl , cm ) ν 1345, 1370, 1472, 1521, 1565, 1655,
3 max
1
+
1
2
8
6
(
(
685, 3369; H NMR (200 MHz, CDCl ) δ 1.42 (s,9H), 1.77 (s, 1H),
calcd for C H ClN O S [M + Na] 645.2013; found 645.2001.
3
30 39
2
8
.36 (br s, 1H), 2.44 (s, 3H), 2.96−3.14 (m, 2H), 3.42 (t, J =
.3 Hz,1H), 3.47−3.62 (m,1H), 4.0 (br s, 1H), 5.08 (br s, 2H), 6.87−
.96 (m, 2H), 7.21 (t, J = 5.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.69
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(4-(trifluoro-
methyl)phenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-
2
-carboxylate (9c):
d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl ) δ 21.6, 28.3
3
3),47.2, 49.4, 51.8, 53.0, 71.3, 80.6, 124.5, 124.7, 127.1, 127.6 (2),
1
29.7 (2), 133.4, 134.1, 143.5, 156.0; HRMS (ESI) calcd for
+
C H N O S [M + Na] 475.1332; found 475.1320.
21
28
2
5 2
tert-Butyl ((R)-((3R,4S)-4-Hydroxy-1-tosylpyrrolidin-3-yl)(4-metho-
xyphenyl)methyl)carbamate (8k):
D
Yield 1.11 g, 68%; colorless solid; mp 169−170 °C; [α]2 +12.1 (c 0.4,
5
CHCl ); 99% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
9
0:10, 0.5 mL/min, 254 nm), t = 18.9 min (minor), t = 27.9 min
r
r
−1
1
(major);IR (CHCl , cm ) ν 1159, 1319, 1513, 1599, 1735; H
3 max
NMR (500 MHz, CDCl ) δ 1.23 (dd, J = 7.3, 9.1 Hz, 6H), 1.40
3
(s, 9H), 1.99 (dd, J = 5.4, 10.6 Hz, 1H), 2.43 (s, 3H), 2.54−2.60 (m, 2H),
E
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2
4
8
.67 (s, 1H), 3.20 (t, J = 8.5 Hz, 1H), 3.37 (t, J = 7.6 Hz, 1H), 4.02−
.14 (m, 4H), 4.64 (d, J = 7.3 Hz, 1H), 4.88 (s, 1H), 5.26 (d, J =
.8 Hz, 1H), 7.31 (t, J = 8.2 Hz, 4H), 7.57(d, J = 7.9 Hz, 2H), 7.68 (d,
(125 MHz, CDCl ) δ 13.8, 14.1, 21.5, 28.2, 33.2, 40.4, 46.6, 48.1, 52.6,
3
60.7, 61.3, 63.1, 80.2, 121.5, 127.2, 127.4, 127.6, 129.6, 131.9, 132.1,
135.3, 139.3, 143.7, 155.3, 170.3, 170.6; HRMS (ESI) calcd for
13
+
J = 8.2 Hz, 2H); CNMR (125 MHz, CDCl ) δ 13.9, 14.1, 21.6,
C H BrN O S [M + Na] 689.1507; found 689.1517.
3
30 39
2
8
2
2
8.2, 33.2, 40.5, 46.7, 47.9, 52.7, 60.7, 61.3, 63.0, 80.3, 122.8 (q, J =
71.8 Hz), 125.9, 126.4, 127.1 (q, J = 28.3 Hz), 127.4, 129.6, 130.1
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(4-fluoro-
phenyl)methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-car-
boxylate (9g):
(
q, J = 33.3 Hz), 135.5, 143.6 (d, J = 271.8 Hz), 155.3, 170.3, 170.5;
+
HRMS (ESI) calcd for C H F N O S [M + Na] 679.2271; found
31
39
3
2
8
679.2271.
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(p-tolyl)methyl)-
-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-carboxylate (9d):
3
D
5
Yield 1.07 g, 71%; colorless solid; mp 148−150 °C; [α]2 +13.2 (c 0.5,
CHCl ); 92% ee (Chiracel AS-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
9
0:10, 0.5 mL/min, 254 nm), t = 17.5 min (minor), t = 22.7 min
r
r
−1
1
(major); IR (CHCl , cm ) ν 1161, 1214, 1344, 1510, 1736; H
3 max
Yield 1.17 g, 78%; colorless solid; mp 177−178 °C; [α]25D +10.9 (c 0.7,
CHCl ); 93% ee (Chiracel AS-H (250 × 4.6 mm), n-hexane/i-PrOH,
NMR (500 MHz, CDCl ) δ 1.20 (d, J = 7.0 Hz, 3H), 1.24 (d, J =
3
3
7.0 Hz, 3H), 1.40 (s, 9H), 1.93 (dd, J = 5.9, 11.0 Hz, 1H), 2.43 (s,
3H), 2.50−2.58 (m, 2H), 2.63 (br s, 1H), 3.15 (t, J = 8.5 Hz, 1H),
3.45 (s,1H), 4.0−4.12 (m, 4H), 4.64 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H),
9
0:10, 0.5 mL/min, 254 nm), t = 27.2 min (minor), t = 39.4 min
r
r
−1
1
(
major); IR (CHCl , cm ) ν 1162, 1214, 1344, 1499, 1734; H
3 max
NMR (500 MHz, CDCl ) δ 1.22 (quint, J = 7.0 Hz, 6H), 1.39 (s, 9H),
3
4.91 (s, 1H), 7.01 (t, J = 8.5 Hz, 2H), 7.13 (dd, J = 2.7, 8.5 Hz, 2H),
1
.88 (dd, J = 4.5, 11.6 Hz, 1H), 2.31 (s, 3H), 2.43 (s, 3H), 2.49−2.62
13
7
.30 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H); C NMR
(
(
m, 3H), 3.17 (t, J = 8.8 Hz, 1H), 3.46 (t, J = 7.6 Hz, 1H), 3.98−4.13
m, 4H), 4.60 (d, J = 7.6 Hz, 1H), 4.74 (s, 1H), 5.02 (d, J = 8.5 Hz,
(
125 MHz, CDCl ) δ 13.9, 14.1, 21.6, 28.2, 28.3, 33.2, 40.6, 46.8, 48.3,
3
5
1
2.6, 60.6, 61.2, 63.2, 80.1, 115.7, 115.9, 127.3, 127.6, 127.7, 129.6,
1
H), 7.02 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.9
35.5, 136.2, 143.5, 155.3, 161.0 (d, J = 247 Hz), 170.4, 170.5; HRMS
13
Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H); C NMR (125 MHz, CDCl3)
δ 13.9, 14.1, 21.0, 21.5, 28.2, 33.2, 40.5, 46.9, 48.4, 52.8, 60.5, 61.1,
+
(ESI) calcd for C H FN O S [M + Na] 629.2303; found 629.2307.
30
39
2
8
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(furan-2-yl)-
methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-carboxylate (9h):
6
3.2, 79.8, 125.8, 127.3, 129.6, 135.5, 137.2, 143.3, 155.3, 170.4, 170.6;
+
HRMS (ESI+, m/z) calcd for C H N O S [M + Na] 625.2554;
31
42
2
8
found 625.2558.
Ethyl (2S,3R,4R)-4-((R)-((tert-Butoxycarbonyl)amino)(naphthalen-2-
yl)methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-carboxylate (9e):
Yield 0.861 g, 60%; gum; [α]25D +34.0 (c 0.9, CHCl ); 92% ee (Chiracel
3
AS-H (250 × 4.6 mm), n-hexane/i-PrOH, 80:20, 0.5 mL/min, 254 nm),
−
1
t = 17.0 min (minor), t = 20.7 min (major); IR (CHCl , cm ) ν
1
r
r
3
max
1
162, 1344, 1513, 1599, 1735; H NMR (200 MHz, CDCl ) δ 1.22 (t,
3
D
Yield 1.26 g, 79%; colorless solid; mp 160−161 °C; [α]25 +22.7 (c 0.5,
J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.40 (s, 9H), 1.95 (q, J =
11.1, 5.9 Hz, 1H), 2.44 (s, 4H), 2.58 (s, 1H), 2.68 (m, 1H), 3.20 (t, J =
9.3 Hz, 1H), 3.56 (t, J = 8.4 Hz, 1H), 4.04−4.17 (m, 4H), 4.58 (d, J =
7.9 Hz, 1H), 4.87 (s, 2H), 6.13 (d, J = 3.1 Hz, 1H), 6.28 (br s, 1H),
CHCl ); 92% ee (Chiracel AS-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
8
(
(
0:20, 0.5 mL/min, 254 nm), t = 17.8 min (minor), t = 26.9 min
r
r
−
1
1
major); IR (CHCl , cm ) ν 1163, 1214, 1514, 1738; H NMR
400 MHz, CDCl ) δ 1.21 (t, J = 7.0 Hz, 6H), 1.41 (s, 9H), 1.95 (dd,
J = 4.8, 11.9 Hz, 1H), 2.41 (s, 3H), 2.60 (d, J = 11 Hz, 2H), 2.78
s, 1H), 3.25 (t, J = 8.8 Hz, 1H), 3.45 (t, J = 7.5 Hz, 1H), 3.99−4.13
m, 4H), 4.65 (d, J = 7.5 Hz, 1H), 4.98 (s, 1H), 5.19 (s, 1H), 7.26 (d,
J = 8.0 Hz, 3H), 7.46 (t, J = 3.9 Hz, 2H), 7.60 (s, 1H), 7.67 (d, J =
.8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 3H); C NMR (100 MHz, CDCl3)
3 max
1
3
3
7.33 (d, J = 7.7 Hz, 3H), 7.69 (d, J = 8.2 Hz, 2H); C NMR
(125 MHz, CDCl ) δ 14.0, 14.2, 21.6, 28.2, 33.0, 40.2, 45.5, 47.4, 48.4,
3
(
(
60.6, 61.2, 63.0, 80.2, 106.6, 110.5, 127.4, 129.6, 135.8, 142.2, 143.3,
152.6, 155.3, 170.4, 170.7; HRMS (ESI+, m/z) calcd for
+
C H N O S) [M + Na] 601.2195; found 601.2197.
28
38
2
9
13
7
1-Tosylpyrrolidin-3-ol (5):
δ 13.9, 14.1, 21.5, 28.2, 33.3, 40.6, 46.8, 48.3, 53.2, 60.5, 61.2, 63.2,
8
1
0.0, 123.9, 124.6, 126.1, 126.4, 127.3, 127.6, 127.9, 128.9, 129.6,
32.7, 133.2, 135.5, 137.5, 143.4, 155.4, 170.4, 170.6; HRMS (ESI)
+
calcd for C H N O S [M + Na] 661.2559; found 661.2555.
34
42
2
8
Ethyl (2S,3R,4R)-4-((R)-(4-Bromophenyl)((tert-butoxycarbonyl)-
amino)methyl)-3-(2-ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-car-
boxylate (9f):
1
Yield 570 mg, 95%; gum; H NMR (200 MHz, CDCl
) δ1.81−1.95
3
(m, 2H), 2.16 (d, J = 4.0 Hz, 1H), 2.43 (s, 3H), 3.25 (d, J = 11.0 Hz,
H), 3.30−3.40 (m, 3H), 4.35 (s, 1H), 7.29 (d, J = 7.9 Hz, 2H), 7.68
d, J = 8.2 Hz, 2H); 13C NMR (50 MHz, CDCl ) δ 21.4, 33.8, 45.9,
1
(
3
5
5.8, 70.29, 127.4, 129.5, 133.4, 143.3. Anal. Calcd for C H NO S:
11 15 3
C, 54.75; H, 6.27; N, 5.80; S, 13.29. Found: C, 54.66; H, 6.19; N, 5.70;
S, 13.22.
Ethyl 3-(2-Ethoxy-2-oxoethyl)-1-tosylpyrrolidine-2-carboxylate (6):
D
Yield 1.27 g, 76%; colorless solid; mp 161−163 °C; [α]25 +17.4 (c 0.5,
CHCl ); 99% ee (Chiracel OJ-H (250 × 4.6 mm), n-hexane/i-PrOH,
3
−1
8
1
0:20, 0.5 mL/min, 254 nm), t = 24.0 min; IR (CHCl , cm ) ν
r 3 max
1
155, 1237, 1737, 1511, 1718; H NMR (200 MHz, CDCl ) δ 1.21 (q,
3
J = 7.2, 7.33 Hz, 6H), 1.40 (s, 9H), 1.96 (dd, J = 6.9, 10.48 Hz, 1H),
−
1
2.44 (s, 3H), 2.52−2.60 (m, 3H), 3.15 (t, J = 8.9 Hz, 1H), 3.39 (t, J =
8.4 Hz, 1H), 4.0−4.17 (m, 4H), 4.62 (d, J = 7.0 Hz, 1H), 4.78 (s, 1H),
5.04 (d, J = 9.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 8.0 Hz,
2
H), 7.42 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H); 13C NMR
Yield 860 mg, 90%; gum; IR (CHCl , cm ) ν 1162, 1344, 1513,
3 max
1
1735; H NMR (200 MHz, CDCl ) δ 1.22−1.31 (m, 6H), 1.72−2.32
(m, 4H), 2.43 (s, 3H), 2.50−2.74 (m,1H), 3.02−3.30 (m, 1H), 3.62
(t, J = 8.4 Hz, 1H), 3.96−4.22 (m, 4H), 4.35 (d, J = 8.3 Hz, 1H),
3
F
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7
.29 (d, J = 8.0 Hz, 2H),7.70 (d, J = 8.2 Hz, 2H); 13C NMR (50 MHz,
CDCl ) δ 14.0, 21.3, 29.6, 34.2, 38.5, 43.0, 60.5, 61.0, 62.3, 65.1, 127.2,
4, 844. (g) Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005, 61,
5713.
(3) (a) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1997, 38, 7669.
3
1
29.5, 135.2, 143.2, 170.1, 170.6. Anal. Calcd for C H NO S: C,
18
25
6
5
6.38; H, 6.57; N, 3.65; S, 8.36. Found: C, 56.30; H, 6.50; N, 3.61;
(b) Bashiardes, G.; Safir, I.; Mohamed, A. S.; Barbot, F.; Laduranty, J.
S, 8.30.
Ethyl (4R,5R,E)-5-((tert-Butoxycarbonyl)amino)-5-(4-fluorophenyl)-
-(((4-methylphenyl)sulfonamido)methyl)pent-2-enoate (10):
Org. Lett. 2003, 5, 4915. (c) Galliford, C. V.; Beenen, M. A.; Nguyen,
S. T.; Scheidt, K. A. Org. Lett. 2003, 5, 3487. (d) Young, I. S.; Williams,
J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953. (e) Pearson, W. H.; Dietz, A.;
Stoy, P. Org. Lett. 2004, 6, 1005. (f) Ayan, S.; Dogan, O.; Ivantcova, P.
M.; Datsuk, N. G.; Shulga, D. A.; Chupakhin, V. I.; Zabolotnev, D. V.;
Kudryavtsev, K. V. Tetrahedron: Asymmetry 2013, 24, 838.
4
(g) Randjelovica, J.; Simica, M.; Tasica, G.; Husinecb, S.; Savic, V.
−
1
Curr. Org. Chem. 2014, 18, 1073. (h) Li, J.; Wang, J.; Xu, Z.; Zhu, S.
ACS Comb. Sci. 2014, 16, 506. (i) Guo, C.; Song, J.; Gong, L.-Z. Org.
Lett. 2013, 15, 2576.
Yield 75%; gum; IR (CHCl , cm ) ν 1161, 1214, 1344, 1510,
1
(
(
3
max
1
736; H NMR (500 MHz, CDCl ) δ 1.23 (t, J = 7.0 Hz, 3H), 1.37
3
s, 9H), 2.42 (s, 3H), 2.79−2.82 (m, 1H), 2.85−2.90 (m, 1H), 3.18
s,1H), 4.08 (q, J = 8.5 Hz, 2H), 4.68 (s, 1H), 5.14 (s, 1H), 5.64 (d,
(4) (a) Nakhla, J. S.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc.
J = 15.5 Hz, 1H), 5.78 (s, 1H), 6.53 (dd, J = 9.1, 14.9 Hz, 1H), 6.96 (d,
J = 8.24 Hz, 2H), 7.13 (dd, J = 5.1, 3.0 Hz, 2H), 7.27 (d, J = 7.9 Hz,
2006, 128, 2893 and references cited therein. (b) Zhu, S.; Ye, L.; Wu,
W.; Jiang, H. Tetrahedron 2013, 69, 10375. (c) Barber, D. M.; Duris,
A.; Thompson, A. L.; Sanganee, H. J.; Dixon, D. J. ACS Catal. 2014, 4,
2
2
1
H), 7.69 (d, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl ) δ 14.1,
3
1.4, 28.2, 43.8, 47.9, 54.9, 60.3, 80.1, 115.5, 115.7, 125.1, 127.0, 128.7,
29.6, 134.9, 136.8, 143.2, 144.4, 155.3, 161.1 (d, J = 247 Hz),165.3.
6
34. (d) Natori, Y.; Kikuchi, S.; Kondo, T.; Saito, Y.; Yoshimura, Y.;
Takahata, H. Org. Biomol. Chem. 2014, 12, 1983.
(5) (a) Wang, Q.; Sasaki, N. A.; Potier, P. Tetrahedron Lett. 1998, 39,
Anal. Calcd for C H FN O S: C, 59.98; H, 6.39; N, 5.38; S, 6.16.
26
33
2
6
Found: C, 60.0; H, 6.40; N, 5.36; S, 6.18.
5
755 and references cited therein. (b) Back, T. G.; Parvez, M.; Zhai, H.
J. Org. Chem. 2003, 68, 9389.
(6) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A.
ASSOCIATED CONTENT
■
*
S
Supporting Information
Org. Lett. 2000, 2, 385 and references cited therein.
(
7) Coldham, I.; Hufton, R.; Price, K. N.; Rathmell, R. E.; Snowden,
D. J.; Vennall, G. P. Synthesis 2001, 10, 1523.
8) (a) Besev, M.; Engman, L. Org. Lett. 2002, 4, 3023.
b) Aurrecoechea, J. M.; Fernandez, A.; Gorgojo, J. M.; Saornil, C.
Tetrahedron 1999, 55, 7345 and references cited therein.
9) (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471.
b) Dion, I.; Vincent Rocan, J.-F.; Zhang, L.; Cebrowski, P. H.;
Full compound characterization and spectral data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
(
AUTHOR INFORMATION
■
(
Corresponding Author
(
*Tel.: +91 20 25902547. Fax: +91 20 25902676. E-mail: a.
Lebrun, M.-E.; Pfeiffer, J. Y.; Bedard, A.-C.; Beauchemin, A. M. J. Org.
Chem. 2013, 78, 12735. (c) Shigehisa, H.; Koseki, N.; Shimizu, N.;
Fujisawa, M.; Niitsu, M.; Hiroya, K. J. Am. Chem. Soc. 2014, 136,
13534.
sudalai@ncl.res.in.
Notes
The authors declare no competing financial interest.
(10) (a) Sletten, E. M.; Liotta, L. J. J. Org. Chem. 2006, 71, 1335.
(
b) De Raadt, A.; Ekhart, C. W.; Ebner, M.; Stutz, A. E. Top. Curr.
ACKNOWLEDGMENTS
■
Chem. 1997, 187, 157. (c) Buchanan, J. G.; Edgar, A. R.; Hewitt, B. D.;
Jigajinni, V. B.; Singh, G.; Wightman, R. H. ACS Symp. Ser. 1989, 386,
1
We sincerely thank CSIR, New Delhi, India (Indus MAGIC
project CSC-0123) and DST (No. SR/S1/OC-67/2010) for
financial support. R.D.A. and B.S.K. thank CSIR, New Delhi,
India for research fellowships. We thank Dr. Rajesh G. Gonnade
and Mr. Shridhar Thorat (Center for Materials Characterization,
CSIR-NCL) for assistance with X-ray crystallography.
07. (d) Zhao, H.; Cheng, S.; Mootoo, D. R. J. Org. Chem. 2001, 66,
761. (e) Ansaria, A. A.; Vankar, Y. D. RSC Adv. 2014, 4, 12555.
1
(11) (a) Ohno, H.; Takeoka, Y.; Kadoh, Y.; Miyamura, K.; Tanaka, T.
J. Org. Chem. 2004, 69, 4541. (b) Apte, S.; Radetich, B.; Shin, S.;
RajanBabu, T. V. Org. Lett. 2004, 6, 4053.
(
12) (a) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay,
REFERENCES
■
K. B.; Machan, T.; Tang, M. Synlett 2004, 15, 2670. (b) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (c) Cren, S.; Wilson, C.;
Thomas, N. R. Org. Lett. 2005, 7, 3521.
(
1) (a) Pearson, W. H. In Studies in Natural Product Chemistry; Atta-
Ur-Rahman, Ed.; Elsevier: New York, 1988; Vol. 1, pp 323−358.
b) Bindra, J. S. In The Alkaloids; Manske, R. H. F., Ed.; Academic
(
(13) En, D.; Zou, G.-F.; Guo, Y.; Liao, W.-W. J. Org. Chem. 2014, 79,
Press: New York, 1973; Vol. 14, pp 84121. (c) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213. (d) Antonchick, A. P.; Gerding-Reimers,
C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.;
Waldmann, H. Nat. Chem. 2010, 2, 735.
4
(
456.
14) (a) List, B. Tetrahedron 2002, 58, 5573. (b) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
c) Kumar, B. S.; Venkataramasubramanian, V.; Sudalai, A. Org. Lett.
012, 14, 2468.
15) Jui, N. T.; Garber, J. A. O.; Finelli, F. G.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2012, 134, 11400.
(
2
(
(
2) (a) Stocker, B. L.; Dangerfield, E. M.; Win-Mason, A. L.; Haslett,
G. W.; Timmer, M. S. M. Eur. J. Org. Chem. 2010, 1615. (b) Agbodjan,
A. A.; Cooley, B. E.; Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.;
Glover, B. N.; Guidetti, R.; Haigh, D.; Howes, P. D.; Jackson, M. M.;
Matsuoka, R. T.; Medhurst, K. J.; Millar, A.; Sharp, M. J.; Slater, M. J.;
(
(
16) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
17) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007, 46,
Toczko, J. F.; Xie, S. J. Org. Chem. 2008, 73, 3094. (c) Naj
Retamosa, M. G.; Sansano, J. M.; de Cozar, A.; Cossío, F. P. Eur. J.
Org. Chem. 2007, 5038. (d) Bellina, F.; Rossi, R. Tetrahedron 2006, 62,
213. (e) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.;
́
era, C.; de
6
09.
18) See general experimental procedure.
19) The relative stereochemistry of 8f was confirmed by COSY and
NOESY studies. A significant NOESY correlation was observed
́
(
(
7
Lin-Goerke, J.; Baker, A.; Earnshaw, D. L.; Hofmann, G. A.; Keenana,
R. M.; Dhanaka, D. Bioorg. Med. Chem. Lett. 2005, 15, 1553. (f) Lynch,
J. E.; English, A. R.; Bank, H.; Deligianis, H. Antibiot. Chemother. 1954,
between H
H , H , and H .
−H
and H
−H
, confirming a syn relationship between
6
5
5
4
6
5
4
G
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
20) Kwan, E. E.; Scheerer, J. R.; Evans, D. A. J. Org. Chem. 2013, 78,
1
2
75. (b) Yokoyama, Y.; Tsuchikura, K. Tetrahedron Lett. 1992, 33,
823.
H
DOI: 10.1021/jo5028886
J. Org. Chem. XXXX, XXX, XXX−XXX