Ag(I)-Fesulphos-Catalyzed Enantioselective Synthesis of 3-Silylproline Derivatives

Article abstract of DOI:10.1021/acs.joc.8b02412

An efficient catalytic asymmetric 1,3-dipolar cycloaddition of N-benzylidineiminoglycinate-derived azomethine ylides to β-silylmethylene malonates catalyzed by a Ag(I)-Fesulphos complex has been developed, affording fully substituted 3-silylproline derivatives with an all carbon quaternary center. The silylproline derivatives were obtained in moderate-to-good yields (up to 81%) in high diastereoselectivities and enantioselectivities (dr up to 95:5; er up to 96:4). Tamao-Fleming oxidation of selected 3-silylproline derivatives provided not only an efficient route but also the shortest route to 3-hydroxyproline derivatives, which are not accessible by direct 1,3-dipolar cycloadditions of azomethine ylide with frequently used arylidene/alkylidene malonates.

Full text of DOI:10.1021/acs.joc.8b02412

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Article
Ag(I)-Fesulphos Catalyzed Enantioselective
Synthesis of 3-Silylproline Derivatives
Raghunath Chowdhury, Akhil Kumar Dubey, and Sunil K. Ghosh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02412 • Publication Date (Web): 30 Jan 2019
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Ag(I)-Fesulphos Catalyzed Enantioselective Synthesis of 3-Silylproline
Derivatives
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Raghunath Chowdhury,*a Akhil K. Dubey,a Sunil K. Ghosha,b
Bio-Organic Division,a bHomi Bhabha National Institute,
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Bhabha Atomic Research Centre, Trombay, Mumbai 400085
Fax: +91-22-25505151
E-mail: raghuc@barc.gov.in
Abstract: An efficient catalytic asymmetric 1,3-dipolar cycloaddition of N-
benzylidineiminoglycinate derived azomethine ylides to β-silylmethylene malonates catalysed
by a Ag(I)-Fesulphos complex has been developed, affording fully substituted 3-silylproline
derivatives with an all carbon quaternary center. The silylproline derivatives were obtained in
moderate-to-good yields (up to 81%) in high diastereo- and enantioselectivities (dr up to 95:5;
er up to 96:4). Tamao-Fleming oxidation of selected 3-silylproline derivatives provided
efficient and shortest route to 3-hydroxyproline derivatives which are not accessible by direct
1,3-dipolar cycloadditions of azomethine ylide with frequently used arylidene/alkylidene
malonates.
Ag2O (10 mol%)
L8 (11 mol%)
or
StBu
SiR2R3R4
CO2Et
EtO2C
EtO2C
EtO2C
EtO2C
OH
CO2Me
SiR2R3R4
CO2Me
Ag2O (5.0 mol%)
L8 (5.5 mol%)
O
2 steps
PPh2
+
R1
N
R1
R1
DABCO (20 mol%)
toluene, -40 °C
OMe
Fe
N
N
CO2Et
H
Ts
L8
up to 81% yield
dr up to 95:5
er up to 96:4
INTRODUCTION
Organosilicon compounds are known to have enormous applicability starting from protecting
group to intermediates in natural product synthesis.1,2 In recent time, silicon-containing amino
acids (Figure 1) are getting considerable attention because they are well-suited to provide the
protein structure and also can act as a structural probes for finding drug-protein binding
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interaction.3,4 In addition, many silicon-containing molecules and peptides are known for their
inhibitory activity towards certain enzymes (Figure 1) and some of them are in the final stage
of clinical trials.3,4 Silicon is considered as a bioisostere of carbon since both belong to the same
group in the periodic table. Incorporation of the silicon into the amino acid or peptide enhances
the lipophilicity due to unique properties of the silyl group.5 Enhancement of lipophilicity may
ease membrane permeability and cellular uptake.5 It has also been found that the integration of
silicon-containing amino acids into peptide changes the properties of these biomolecules such
as conformational freedom, enhanced stability, hydrophobicity, and increase in resistance to
enzymatic degradation and bioavailability.3 Despite their alluring medicinal and biological
applications, only a handful of methods are available for synthesis of silicon-containing amino
acids and their derivatives.3,4 The use of stoichiometric reagents, auxiliaries and resolution of
intermediates are still common protocols for their synthesis.3,4The catalytic methods for their
preparation is rare in literature.6 Therefore, development of new catalytic methods for synthesis
of novel silicon-containing amino acid derivatives is a pre-requisite and at the same time
challenging.
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Me
CO2H
NH2
CO2H
NH2
Me Si
Me3Si
CO2H
Me3Si
TMS-phenylalanine
N
H
Silaproline (Sip)
-Trimethylsilylalanine
CO2H
O
Me
OH
Si
HO
Me3Si
N
NH
NH
TAC101
in clinical trial
for lung cancer
CO2H
O
O
Ph
SiMe3
ACE inhibitor
Figure 1. Representative examples of silicon-containing amino acids and medicinally
important silicon-containing molecules.
To understand the mechanism of conformational stability of protein triple helix
structures and development of novel peptide-based drug molecules, new 3-hydroxyproline
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derivatives and 3-silylproline derivatives are likely to play significant roles. 3-hydroxyproline
is known to induce β-turn in peptide and is also present in many bioactive peptides including
important structural protein collagen.7 Furthermore, 3-hydroxypyrrolidines are privileged
substructures widespread in numerous biologically active natural products (Figure 2) and also
crucial intermediates for variety of natural products and drug molecules.8
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OH
OH
OH
AcO
Bn
CO2H
N
N
N
C9H19
MeO
H
H
Me
(+)-Preussin
Anisomycine
trans-3-Hydroxy-L-proline
Figure 2. 3-Hydroxypyrrolidine based natural products and amino acid.
The catalytic asymmetric1,3-dipolar cycloadditions of azomethine ylides to variety of electron-
deficient alkenes as dipolarophiles is the most explored route for the construction of
enantioenriched densely substituted pyrrolidines because of its efficacy, straightforwardness
and atom economy.9,10 Research groups of Zhang11 and Jørgensen12 independently reported
first examples of metal catalyzed asymmetric1,3-dipolar cycloaddition of azomethine ylides
derived from iminoesters with activated alkenes. Since then, diverse electron deficient alkenes
including aryl- and alkylidene malonates (Scheme 1 A) and different variety of azomethine
ylides have been enrolled in catalytic asymmetric1,3-dipolar cycloadditions affording
pyrrolidines with diverse substitution patterns.9,10However, presumably β-silylmethylene
malonate 2 has not so far been employed as a dipolarophile in 1,3-dipolar cycloaddition with
azomethine ylide.13 Considering the importance of 3-silylproline derivatives and 3-
hydroxypyrrolidine derivatives, we envisaged that 1,3-dipolar cycloaddition reaction of N-
benzylideneiminoglycinates derived azomethine ylides with β-silylmethylene malonates14
would lead to 3-silylproline derivatives. Subsequent conversion of dimethyl(phenyl)silyl group
to a hydroxy group following the Tamao–Fleming oxidation15 would lead to 3-hydroxyproline
derivatives. Several methods16 have been reported for the preparation of enantiopure 3-
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hydroxyproline whereas the synthetic routes for the substituted 3-hydroxyproline derivatives
are in dearth. To best of our knowledge, there are only two reports for the enantioselective
synthesis of substituted 3-hydroxyproline derivatives wherein Rh or Ru catalyzed
intramolecular carbenoid N-H insertion reaction of appropriately designed chiral δ-amino β-
ketoester based diazo compounds followed by stereoselective reduction have been used
(Scheme 1 B).17 Herein, we report a straightforward synthetic route for the asymmetric
synthesis of fully substituted 3-silylproline derivatives and 3-hydroxyproline derivatives
starting from simple and easily accessible achiral starting materials (Scheme 1C).
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Scheme 1. Asymmetric 1,3-dipolar cycloadditions of azomethine ylides with arylidene-/
alkylidene-/ β-silylmethylene malonates and synthesis of 3-hydroxyproline derivatives.
A. Prevoius work: 1,3 -dipolar cycloaddtion of azomethine ylides with arylidene-/alkylidene malonates
Ag-salt or Cu
R3O2C
Chiral ligand
R2
R2
salt, Base
R3O2C
R1
O
CO2R3
CO2R3
R2 = Aryl/alkyl
*
+
R1
N
*
*
CO2Me
Solvent
exo-selective
ref 10a,b,c
OMe
N
H
B. Prevoius strategies for 3-hydroxyproline derivatives
Boc
OH
CO2Me
O
HN
Ph
O
Rh-catalyzed
OMe
Ph
ref 17a
N
H
N2
(1 example)
cis, cis
OH
R1HN
R2
O
O
Ru-catalyzed
ref 17b
R2
OMe
CO2Me
N
H
N2
(3 examples)
cis, cis
This work:
C.
EtO2C
EtO2C
SiMe2R2
CO2Me
OH
CO2Me
SiMe2R2
CO2Et
EtO2C
EtO2C
Ag-salt, Base
Chiral ligand
2 steps
O
+
R1
N
R1
N
Solvent
R1
OMe
N
CO2Et
H
PG
cis, trans
Fully substituted 3-silylproline derivatives
Precursor of 3-hydroxyproline derivatives
RESULTS AND DISCUSSION
Our investigation began with the optimization studies of the 1,3-dipolar cycloaddition reaction
of azomethine ylide, derived in-situ from N-(4-chlorobenzylidene)glycine methyl ester 1a and
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β-silylmethylene malonate 2a. When the reaction between 1a and 2a was performed in toluene
without addition of silver salt, ligand and base at 27 °C, the conversion to desired pyrrolidine
derivative 3a was very slow as judged by 1H NMR spectroscopy.18 Then, we investigated the
catalytic version of the reaction using the cinchona alkaloid derived tertiary amino-(thio)urea
derivatives and trans-1,2-diaminocyclohexane based-(thio)urea derivatives. We found that
these (thio)urea derivatives were not promising for this 1,3-dipolar cycloaddition reaction (see
Supporting Information). Subsequently, we switched to commercially available axially chiral
bisphosphine ligands. When the reaction between model substrates1a and 2a was carried out
in the presence of (R)-BINAP ligand L1 in combination with Ag2O as the catalyst system and
DABCO as the base in toluene at 27 °C, the reaction proceeded smoothly and to our delight,
the exo-3a was formed with moderate yield and enantioselectivity (Table 1, entry 1).
Encouraged by this preliminary result, an array of bisphosphine ligands L2-L7 were screened
(Table 1, entries 2-7). In all the cases, the desired exo-3a was obtained without any
improvement of enantioselectivity. The next series of attempts were performed with ligands
L8 and L9 having ferrocene backbone. (R)-Fesulphos ligand L8/Ag2O catalyst system was
found to be more promising, furnishing the exo-product 3a in 74% yield, with high
diastereoselectivity (96:4 dr) and moderate enantioselectivity (86:14 er) (Table 1, entry 8).
Therefore, Fesulphos L8 was selected as the ligand for further studies. Exploration of the
reaction with silver carbonate (Table 1, entry 10), silver acetate (Table 1, entry 11), and cupric
acetate (Table 1, entry 12) did not give superior result compared to Ag2O.
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Table 1. Screening of the ligand and metal salt a
Metal salt (10 mol%)
L (11 mol%)
DABCO (20 mol%)
EtO2C
EtO2C
SiMe2Ph
CO2Me
SiMe2Ph
CO2Et
Cl
O
+
N
toluene, 27 °C
40 min
Ar
OMe
N
H
CO2Et
1a
2a
3a
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________________________________________________________
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PPh2
PPh2
PPh2
PPh2
PAr2
PAr2
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(R)-Tol BINAP, Ar = 4-CH3C6H4
L1
L2
L3
O
O
H3C
P
CH3
PPh2
PPh2
O
O
O
O
PAr2
PAr2
CH3
P
H3C
O
O
(R)-DTBM-Segphos
Ar = 4MeO-3,5-tBu2C6H2
L5
L4
L6
Ph
StBu
PPh2
CH3
CH3
O
Cy2P
PCy2
P
N
O
Fe
CH3
Fe
Ph
(S, R, R)
(R)-Fesulphos
L7
L8
L9
entry
1
metal salt
Ag2O
ligand
L1
L2
L3
L4
L5
L6
L7
L8
L9
L8
L8
% conv.b
>98
drc
yieldd (%)
ere
ND
62
65
19:81
77:23
28:72
76:24
45:55
25:75
66:34
86:14
52:48
85:15
82:18
2
Ag2O
>98
90:10
NDf
3
Ag2O
NDf
>98
67
4
Ag2O
90:10
88:12
88:12
95:5
95:5
85:15
94:6
94:6
65
5
Ag2O
>98
66
6
Ag2O
>99
73
7
Ag2O
>97
61
8
Ag2O
>99
74
9
Ag2O
>98
ND f
74
10g
11
Ag2CO3
AgOAc
>96
>99
75
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12g
Cu(OAc)2
L8
>42
ND
ND
ND
5
6
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8
aUnless otherwise stated, reactions were carried out with 0.2 mmol of 1a and 0.1 mmol of 2a
b
9
in 1 mL of toluene at 27 °C. Indicate percentage of conversion of the starting material 2a,
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1
c
determined by H NMR analysis of the crude reaction mixture. The dr19 was determined by
1H NMR analysis of the crude reaction mixture. Yield of the major diastereomer. The
enantiomeric ratio (er) was determined by HPLC analysis using a chiral stationary phase. f Not
determined. gReaction time 2h.
d
e
___________________________________________________________________________
Subsequently different organic bases were surveyed (Table 2, entries 1-3) in the
reaction but found inferior than DABCO. A solvent screening (Table 2, entries 2 and 4-6)
revealed that toluene remained the best choice of solvent in terms of yield, diastereo-and
enantioselectivity. Dilution of the reaction did no effect on the enantioselectivity of 3a.
Lowering the temperature had a beneficial effect on enantioselectivity. When the reaction was
carried out at 0 °C, the exo-adduct 3a was obtained with excellent diastereoselectivity and
improved enantioselectivity (Table 2, entry 8). Lowering of the temperature to -40 °C lead to
improvement in enantioselectivity of 3a while the yield and diastereoselectivity remained
unchanged (Table 2, entry 10). Further enhancement of enantioselectivity of 3a could not be
achieved by performing the reaction at -60 °C (Table 2, entry 11). Lowering in the loading of
catalyst system viz. Ag2O (5 mol%), and ligand L8 (5.5 mol%), resulted in slightly reduced
yield without much change in selectivities (Table 2, entry 12). From the above studies, we
chose two sets of optimized reaction conditions: Conditions A: 1a (0.2 mmol), 2a (0.1 mmol),
Ag2O (0.01mmol), L8 (0.011mmol) and DABCO (0.02 mmol) in 1mL of toluene at -40 °C
(Table 2, entry 10) and Conditions B: 1a (0.4 mmol), 2a (0.2 mmol), Ag2O (0.01mmol), L8
(0.011mmol) and DABCO (0.04 mmol) in 2 mL of toluene at -40 °C (Table 2, entry 12).
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Table 2. Reaction optimizationsa
5
6
7
8
9
Ag2O(10 mol%)
L8(11 mol%)
Base (20 mol%)
EtO2C
EtO2C
SiMe2Ph
CO2Me
SiMe2Ph
CO2Et
Cl
O
+
N
toluene, 27 °C
40 min
Ar
OMe
N
H
CO2Et
10
11
12
13
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19
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1a
2a
3a
entry
base
Et3N
solvent
% conv.b
90
drc
yieldd (%)
58
er (%)e
81:19
1
2
C6H5CF3
C6H5CF3
toluene
Et2O
90:10
90:10
70:30
82:18
75:25
NDf
iPr2NEt2
DBU
86
54
85:15
3
>40
>90
>99
90
NDf
57
NDf
4g
5
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
85:15
THF
55
85:15
6
MTBE
toluene
toluene
toluene
toluene
toluene
toluene
58
85:15
7h
8 i
9 j
10k
11l
12m
NDf
>99
>99
>99
>98
>98
95:5
96:4
95:5
95:5
95:5
95:5
62
85:15
76
89.5:10.5
90.5:9.5
94.5:5.5
94:6
75
77
70
74
94.5:5.5
a Reactions were carried out with 0.2 mmol of 1a and 0.1 mmol of 2a, Ag2O (0.01 mmol), L8
(0.011 mmol) and DABCO (0.02 mmol) in 1 mL of solvent at 27°C. b Determined by 1H NMR
analysis of the crude reaction mixture. The dr19 was determined by H NMR analysis of the
crude reaction mixture. d Yield of the major diastereoisomer. eThe enantiomeric ratio (er) was
determined by HPLC analysis using a chiral stationary phase. f Not determined. gReaction time
c
1
h
was 2 h. 2 mL of toluene was used. iThe reaction was carried out at 0°C, reaction time 5 h,
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j
10 mol% of L8 was used. The reaction was performed at -20°C and reaction time 10 h, 10
mol% L8 was used. k The reaction was performed at -40 °C and reaction time was 10 h. lThe
reaction was performed at -60°C and reaction time 12 h. mReactions was carried out with 0.4
mmol of 1a and 0.2 mmol of 2a, Ag2O (0.01mmol), L8 (0.011 mmol) and DABCO (0.04
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mmol) in
2
mL of toluene at -40 °C, reaction time was 12 h.
__________________________________________________________________________
With the established optimization reaction conditions in hand, we explored the reaction of β-
silylmethylene malonate 2a with various imino esters 1. The results are summarised in Table
3. Imino esters 1 with the aryl group substituted at para position with electron withdrawing or
donating groups were well tolerated and afforded desired exo-products 3a, 3c-3f in moderate
to high yield and high diastereo - and enantioselectivity. The imino esters with substituent at
meta and ortho position on the aromatic ring was also equally effective and provided the exo-
cycloadducts 3g-3k in high yield, diastereo- and enantioselectivity. It is noteworthy that the
reaction worked well with heteroaromatic-substituted imino ester and the product 3l was
formed in high yield and enantioselectivity. The scope of this methodology was further
extended to exploring the reaction of azomethine ylide derived from N-(4-
chlorobenzylidene)glycine methyl ester 1a with alkyl substituted β-silylmethylene malonate
2b. The desired product 3m was obtained in high yield and excellent stereoselectivity.
Table 3. Scope of substratesa,b
Ag2O (10 mol%)
L8 (11 mol%)
or
SiMe2R2
SiMe2R2
EtO2C
Ag2O (5 mol%)
O
EtO2C
L8 (5.5 mol%)
+
CO2Et
R1
N
R1
DABCO (20 mol%)
toluene, -40 °C
CO2Me
OMe
N
H
CO2Et
1a
2
3
2a; R2 = Ph
2b; R2 = OTMS
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entry
1a
R1/R2
3
drc
95:5
94:6
94:6
95:5
94:6
90:10
94:6
92:8
95:5
92:8
91:9
95:5
94:6
yieldd (%)
77
er (%)e
94.5:5.5
93:7
4-ClC6H4/Ph
Ph/Ph
3a
3b
3c
3d
3e
3f
2b
73
3b
4-BrC6H4/Ph
4-FC6H4/Ph
4-CF3C6H4/Ph
4-EtC6H4/Ph
3-BrC6H4/Ph
3-ClC6H4/Ph
3-FC6H4/Ph
2-ClC6H4/Ph
2-FC6H4/Ph
2-thienyl/Ph
77
95:5
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4b
74
94.5:5.5
95:5
5a
74
6a,f
7
66
91.5:8.5
92:8
3g
3h
3i
76
8a
75
93:7
9a
78
92:8
10a
11a
12a
3j
71
95:5
3k
3l
71
95:5
81g
72
93.5:6.5
96:4
13a 4-ClC6H4/OTMS 3m
aReaction conditions A: 1 (0.2 mmol), 2a (0.1 mmol), Ag2O (0.01 mmol), L8 (0.011 mmol),
DABCO (0.02 mmol) in 1.0 mL toluene at -40 °C for 10-16 h. bReaction conditions B: 1 (0.4
mmol), 2a (0.2 mmol), Ag2O (0.01 mmol), L8 (0.011 mmol) and DABCO (0.04 mmol) in 2.0
mL of toluene at -40 °C for 10-14 h. cThe dr18 was determined by 1H NMR of the crude reaction
mixture. dIsolated yield of the major diastereomer. eEnantiomeric ratio (er) was determined by
HPLC analysis using a chiral stationary phase. fThe reaction was performed at 0 °C, 2.3 equiv
of imino ester was used. gCombined yield of two diastereomers.
___________________________________________________________________________
To demonstrate the practicality of the above developed method, the asymmetric 1,3-dipolar
cycloaddition between 1a and 2a was conducted on a 1 mmol scale under the optimized
conditions, affording 3a with 80% yield and with >95:5 er (Scheme 2).
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Scheme 2. Scale-up synthesis of 3a
5
6
7
8
9
EtO2C
EtO2C
SiMe2Ph
CO2Me
Ag2O (5 mol%)
L8 (5.5 mol%)
Cl
SiMe2Ph
CO2Et
O
+
N
DABCO (20 mol%)
toluene, -40 °C
OMe
N
H
CO2Et
Cl
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1a
2 mmol
(2.0 equiv)
2a
1 mmol
3a
0.415 g, 80 % yield
>95:5 er, 94:6 dr19
Next, we turned our attention to extend the scope for other dipolarophiles. Thus the reaction
between N-(4-chlorobenzylidene)glycine methyl ester 1a and β-dimethylphenylsilyl-acrylate 4
was performed under optimized reaction conditions (Conditions B), which provided the exo-
product 5 in good yield but with poor enantioselectivity (Scheme 3). The configuration of 5
was confirmed by comparison with literature data.13
Scheme 3. 1,3-Dipolar cycloaddition reaction of β-dimethylphenylsilyl acrylate
MeO2C
SiMe2Ph
CO2Me
Ag2O (5 mol%)
L8 (5.5 mol%)
Cl
O
CO2Me
+
PhMe2Si
N
DABCO (20 mol%)
toluene, -40 °C
N
H
OMe
Cl
1a
4
5
64% yield
56:44 er, 82:18 dr
The asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylide derived from N-(4-
chlorobenzylidene)glycine methyl ester 1a to benzylidene-malonate 6 was examined under the
optimized reaction conditions (Conditions A), the cycloadduct exo-7 was obtained in good
yield and excellent diastereoselectivity but in moderate enantioselectivity (Scheme 5). The
relative stereochemistry of 7 was confirmed from literature report.10c
Scheme 4. 1,3-Dipolar cycloaddition reaction of benzylidene malonate 6
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Ag2O (10 mol%)
L8 (11 mol%)
EtO2C
EtO2C
Ph
CO2Me
Ph
Cl
O
CO2Et
+
N
DABCO (20 mol%)
toluene, -40 °C
OMe
N
H
CO2Et
Cl
1a
6
7
7
8
9
72% yield
75:25 er, 97:3 dr
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The relative and absolute configuration of 3j was established by single crystal X-ray
crystallography as shown in Figure 4 which confirmed the cycloaddition took place in exo
fashion. The configurations of the other products were assigned in analogy as exo products.
CCDC 1868102
Figure 4. ORTEP diagram of 3j, ellipsoids show 50% probability levels.
The observed high stereoselectivity in the above developed 1,3-dipolar cycloaddition
reaction could be explained by the proposed transition state (Figure 5).10g The azomethine ylide
coordinates with Ag(I)–Fesulphos preferably in the orientation where the carbonyl oxygen
atom of azomethine ylide and sulphur atom of Fesulphos ligand are trans to each other.10c The
t
“bottom” face of the azomethine ylide is shielded by the bulky Bu group of the Fesulphos
ligand. Therefore, the dipolarophile 2 would preferably approach from the less hindered “top”
face. Between the two faces of the dipolarophile 2, a Si-face attack would lead to less stable
transition state I due to steric repulsion between bulky silicon group of dipolarophile and PPh2
group of the Fesulphos ligand while Re-face attack would lead to favourable transition state II.
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Cl
4
5
6
7
8
9
Cl
E
E
E
E
EtO2C
EtO2C
SiMe2Ph
CO2Me
N
Ag
S
N
i
Ph
Ag
S
Me
S
S
i
P
O
Ph
N
H
Ph
Me
Me
P
Me
Ph
O
O
Ph
Fe
Ph
Cl
Me
E= E= CO2Et
TS I
O
3j
Fe
Me
E= E= CO2Et
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TS-II
Figure 5. Proposed transition states
After successfully demonstrating the synthesis of fully substituted 3-silylproline
derivative with an all carbon quaternary centre, we focussed our efforts to the synthesis of 3-
hydroxyproline derivatives. Treatment of 3 with p-toluene sulfonyl chloride in presence of
Et3N in dichloromethane furnished the products 8. Subsequently, the dimethyl(phenyl)silyl
group in 8 was converted to hydroxy group (Table 4) with retention of configuration following
the Tamao–Fleming oxidation.15
Table 4. Synthesis of 3-hydroxyproline derivativesa,b
EtO2C
EtO2C
EtO2C
EtO2C
SiMe2Ph
CO2Me
OH
CO2Me
EtO2C
EtO2C
SiMe2Ph TsCl, Et3N
DMAP
KBr, AcOOH
30 °C
Ar
Ar
N
N
CO2Me
Ar
CH2Cl2, 30 °C, 22h
N
H
Ts
Ts
3
8
9
entry
3, Ar
8, yieldc (%) 9, yieldd (%)
1
2
3
4
3a, 4-ClC6H4
3b, C6H5
8a, 90
8b, 88
8c, 92
8i, 84
9a, 72
9b,70
9c, 71
9i, 65
3c, 4-BrC6H4
3i, 3-FC6H4
a Step1: Reactions were carried out with 0.15 mmol of 3, 0.45 mmol of TsCl, 0.6 mmol of Et3N
b
and 20 mol% of DMAP in 3 mL of CH2Cl2. Step 2: Reactions were carried out with 0.12
mmol of 8, 0.16 mmol of potassium bromide, 0.1 mL of H2O2, 3 mL of peroxyacetic acid (35%
solution in acetic acid). c Isolated yield of 8. d Isolated yield of 9.
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Conclusion
7
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9
In summary, we have developed an efficient Ag(I)-Fesulphos catalytic system for asymmetric
1,3-dipolar cycloaddition reaction of azomethine ylides with β-silylmethylene malonates,
affording 3-silylproline derivatives in good yield and excellent stereoselectivities. Notably, β-
silylmethylene malonates has been introduced for the first time as dipolarophiles in the 1,3-
dipolar cycloaddition reactions of azomethine ylides. The usefulness of the developed reaction
has been demonstrated by converting four cyclo-adducts into 3-hydoxyproline derivatives in
two steps.
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EXPERIMENTAL SECTION
General information. Solvent removal was performed with a rotary evaporator that was
connected to a dry ice condenser. TLC (0.5 mm) was carried out using homemade silica gel
plates with fluorescence indicator. Column chromatography was performed on silica gel (230-
400 mesh). The 1H and 13C NMR spectroscopic data were recorded with 500 MHz (1H NMR:
500 MHz, 13C NMR: 125 MHz) Varian spectrometer and 200 MHz (1H NMR: 200 MHz, 13C
NMR: 50 MHz) Bruker spectrometer. The 1H and 13C chemical shifts are given in ppm (δ scale)
and are measured relative to CHCl3 (7.27 ppm) and CDCl3 (77.0 ppm), respectively, as internal
standards. High resolution mass spectra were recorded at 60-70 eV with a Waters Micromass
Q-TOF spectrometer (ESI, Ar). Enantiomeric ratio (er) values were determined by HPLC
analysis with a JASCO (JASCOPU-2080) instrument fitted with a Daicel Chiralpak AD-H
column, Daicel Chiralcel OD-H column and Daicel Chiralpak AS-H with UV-2075 detector (λ
fixed at 254 nm). Melting points (mp) were measured in a Büchi B-540 apparatus. N-
Benzylideneiminoglycinates 1 were prepared according to previously reported procedure.20 β-
Silylmethylene malonate 2a and 2c was prepared according to reported procedure.9,21 Ag (I)-
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salts, DABCO and chiral ligands were purchased from the commercial source and used as
received without further purification. Et3N, iPr2EtN, DBU and TMG were dried over CaH2 and
stored over it. All the solvents were dried according to standard procedures.
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General Procedure A for the preparation of rac-3-silyl proline derivatives 3a-3m
In an oven and vacuum-dried round-bottom flask, Ag2O (2.3 mg, 0.01 mmol) and DABCO (2.3
mg, 0.02 mmol) were taken with 0.5 mL of freshly distilled toluene under argon. The reaction
mixture was stirred at 30 ºC for 30 min. A solution of N-benzylideneiminoglycinates 1 (0.2
mmol, 2.0 equiv) in toluene (0.25 mL) was added slowly to the reaction mixture followed by
the addition of a solution of β-silylmethylene malonate 2 (0.1 mmol, 1 equiv) in toluene (0.25
mL) and the reaction mixture was stirred at 30 ºC for 40 min-24 h. Once starting material was
consumed (monitored by TLC), the reaction mixture was passed through a small pad of Celite
and flushing with 100 mL of 50% EtOAc/hexane. The solvent was removed under reduced
pressure and the residue was directly subjected to column chromatography on silica gel to
afford the corresponding products rac 3a-3m.
General Procedure B for the preparation of chiral 3-silylproline derivatives 3a, 3e-3m
Condition A. Under Argon atmosphere, Ag2O (2.3 mg, 0.01 mmol), DABCO (2.3 mg, 0.02
mmol) and ligand L8 (5.0 mg, 0.011 mmol) were dissolved in 0.5 mL of freshly distilled
toluene and stirred at room temperature for about 50 min. Then, the reaction mixture was
cooled to -40 °C and a solution of N-benzylideneiminoglycinates 1 (0.2 mmol, 2.0 equiv) in
toluene (0.25 mL) was added slowly to the reaction mixture followed by the addition of a
solution of β-silylmethylene malonate 2 (0.1 mmol, 1 equiv) in toluene (0.25 mL). The reaction
mixture was stirred at this temperature and once the β-silylmethylene malonate 2 was
consumed (monitored by TLC), the reaction mixture was passed through a small pad of silica
and flushing with 100 mL of 50% EtOAc/hexane. The solvent was removed under reduced
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pressure and the residue was directly subjected to column chromatography on silica gel to
5
6
afford the corresponding products 3a, 3e-3m.
7
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9
General Procedure C for the preparation of chiral 3-silylproline derivatives 3a-3d
Condition B. Under Argon atmosphere, Ag2O (2.3 mg, 0.01 mmol), DABCO (~4.5 mg, 0.04
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mmol) and ligand L8 (5.0 mg, 0.011 mmol) were dissolved in 1.0 mL of freshly distilled
toluene and stirred at room temperature for about 50 min. Then, the reaction mixture was
cooled to -40 °C and a solution of N-benzylideneiminoglycinates 1 (0.4 mmol, 2.0 equiv) in
toluene (0.5 mL) was added slowly to the reaction mixture followed by the addition of a
solution of β-silylmethylene malonate 2 (0.2 mmol, 1 equiv) in toluene (0.5 mL). The reaction
mixture was stirred at this temperature and once the β-silylmethylene malonate 2 was
consumed the reaction mixture (monitored by TLC), was passed through a small pad of silica
and flushing with 150 mL of 50% EtOAc/hexane. The solvent was removed under reduced
pressure and the residue was directly subjected to column chromatography on silica gel to
afford the corresponding products 3a-3d.
(2R,3S,5S)-4,4-diethyl 2-methyl 5-(4-chlorophenyl)-3-(dimethylphenylsilyl)pyrrolidine-2,4,4-
tricarboxylate (3a). The title compound was prepared according to the general procedure C
1
(Condition B). Yield : 77 mg (74 %); colorless liquid; H NMR (500 MHz, CDCl3): δ 7.54-
7.52 (m, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.37-7.35 (m, 3H), 7.27-7.26 (m, 2 H), 5.05 (s, 1 H),
4.21 (dq, J = 10.8, 7.2 Hz, 1 H), 3.88 (d, J = 10.5 Hz, 1 H), 3.87-3.82 (m, 1 H), 3.80-3.76 (m,
1 H), 3.56 (dq, J = 10.8, 7.2 Hz, 1 H), 3.30 (s, 3 H), 2.86 (d, J = 10.5 Hz, 1 H), 1.21 (t, J = 7.5
Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H), 0.40 (s, 3 H), 0.33 (s, 3 H); 13C{1H} NMR (125 MHz,
CDCl3): δ 174.2, 170.4, 168.6, 139.6, 137.7, 134.0 (3 C), 133.5, 129.5 (2 C), 129.1, 128.0 (2
C), 127.6, 69.0, 67.7, 62.1, 61.7, 61.3, 51.8, 36.4, 13.7, 13.5, -1.6, -4.8; The er was determined
by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min;
27
τmajor = 9.54 min, τminor = 13.37 min, [α]D = +3.22 (c 4.16, CHCl3, ee>89%); HRMS (ESI)
m/z: [M+H]+Calcd for C26H33ClNO6Si 518.1760; Found 518.1761.
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(2R,3S,5S)-4,4-diethyl
2-methyl
3-(dimethylphenylsilyl)-5
phenylpyrrolidine-2,4,4-
5
6
tricarboxylate (3b). The title compound was prepared according to the general procedure C
7
8
9
1
(Condition B). Yield: 71 mg (73 %); colorless liquid; H NMR (200 MHz, CDCl3): δ 7.57-
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7.46 (m, 4 H), 7.38-7.33 (m, 3 H), 7.29-7.25 (m, 3 H), 5.08 (s, 1 H), 4.21 (dq, J = 11.0, 7.0,
Hz, 1 H), 3.90 (d, J = 10.5 Hz, 1 H), 3.92-3.79 (m, 1 H), 3.76-3.63 (m, 1 H), 3.48 (dq, J = 10.5,
6.5, Hz, 1 H), 3.28 (s, 3 H), 2.88 (d, J = 10.5 Hz, 1 H), 2.45(bs, 1 H), 1.20 (t, J = 7.5 Hz, 3 H),
0.87 (t, J = 7.0 Hz, 3 H), 0.41 (s, 3 H), 0.33 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ 174.1,
170.6, 168.8, 140.7, 137.9, 134.0 (2 C), 129.0, 128.0 (2 C), 127.9 (2 C), 127.7, 127.6 (2 C),
69.1, 68.5, 62.1, 61.6, 61.1, 51.8, 36.8, 13.7, 13.4, -1.5, -4.9; The er was determined by HPLC
using a Daicel Chiralpak AD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 9.07
min, τminor = 11.60 min, [α]D26 = +3.0 (c 1.1, CHCl3, ee >84%); HRMS (ESI) m/z: [M+H]+Calcd
for C26H34NO6Si 484.2150; Found 484.2143.
(2R,3S,5S)-4,4-diethyl 2-methyl 5-(4-bromophenyl)-3-(dimethylphenylsilyl)pyrrolidine-2,4,4-
tricarboxylate (3c). The title compound was prepared according to the general procedure C
(Condition B). Yield: 87 mg (77 %); colorless liquid; 1H NMR (200 MHz, CDCl3): δ 7.55-
7.51 (m, 2 H), 7.41(s, 4 H), 7.38-7.33 (m, 3 H), 5.04 (s, 1 H), 4.21 (dq, J = 10.9, 7.2 Hz, 1 H),
3.89 (d, J = 11.0 Hz, 1 H), 3.87-3.71 (m, 2 H), 3.61-3.47 (m, 1 H), 3.29 (s, 3 H), 2.86 (d, J =
10.5 Hz, 1 H), 2.63 (bs, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.5 Hz, 3 H), 0.40 (s, 3 H),
0.33 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ 174.2, 170.3, 168.5, 140.0, 137.6, 134.0 (2
C), 131.0 (2 C), 129.8 (2 C), 129.1, 127.6 (2 C), 121.6, 68.8, 67.6, 61.9, 61.7, 61.3, 51.9, 36.2,
13.7, 13.5, -1.6, -4.8; The er was determined by HPLC using a Daicel Chiralpak AD-H
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[hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 9.67 min, τminor = 13.32 min, [α]D
=
+5.6 (c 4.9, CHCl3, ee = 90%); HRMS (ESI) calcd for C26H33BrNO6Si [M + H]+: 562.1255,
found 562.1258.
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(2R,3S,5S)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-(4-fluorophenyl)-pyrrolidine-2,4,4-
tricarboxylate (3d). The title compound was prepared according to the general procedure C
(Condition B). Yield: 74 mg (74 %); colorless liquid; 1H NMR (200 MHz, CDCl3): δ 7.56-7.46
(m, 4 H), 7.38-7.34 (m, 3 H), 7.02-6.94 (m, 2 H), 5.07 (s, 1 H), 4.21 (dq, J = 11.0, 7.2 Hz, 1
H), 3.89 (d, J = 10.6 Hz, 1 H), 3.89-3.70 (m, 2 H), 3.59-3.49 (m, 1 H), 3.29 (s, 3 H), 2.87 (d, J
= 10.5 Hz, 1 H), 2.68 (bs, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.2 Hz, 3 H), 0.41 (s, 3
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H), 0.34 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3): δ 174.2, 170.5, 168.7, 162.4 (d, JC-F
=
244.6 Hz), 137.7, 136.7 (d, JC-F = 3.2 Hz), 134.0 (3 C), 129.7 (d, JC-F = 8.0 Hz), 129.1, 127.7
(3 C), 114.7 (d, JC-F = 21.0 Hz), 68.9, 67.6, 62.1, 61.7, 61.3, 51.9, 36.3, 13.8, 13.5, -1.5, -4.9;
The er was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (90:10)];
26
flow rate 1.0 mL/min; τmajor = 8.96 min, τminor = 14.58 min, [α]D = +8.2 (c 2.2, CHCl3, ee
>89%); HRMS (ESI) m/z: [M+H]+Calcd for C26H33FNO6Si 502.2079; Found 502.2072.
(2R,3S,5S)-4,4-diethyl
2-methyl
3-(dimethylphenylsilyl)-5-(4-(trifluoromethyl)phenyl)-
pyrrolidine-2,4,4-tricarboxylate (3e). The title compound was prepared according to the
general procedure B (Condition A). Yield: 41 mg (74 %); colorless liquid;1H NMR (500 MHz,
CDCl3): δ 7.68-7.66 (m, 2 H), 7.56-7.52 (m, 4 H), 7.38-7.35 (m, 3 H), 5.15 (s, 1 H), 4.22 (dq,
J = 11.0, 7.0 Hz, 1 H), 3.92 (d, J = 10.5 Hz, 1 H), 3.83 (dq, J = 11.0, 7.0 Hz, 1 H), 3.74 (dq, J
= 10.5, 7.0 Hz, 1 H), 3.53 (dq, J = 11.0, 7.0, Hz 1 H), 3.32 (s, 3 H), 2.89 (d, J = 10.0 Hz, 1 H),
1.21 (t, J = 7.0 Hz, 3 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.42 (s, 3 H), 0.35 (s, 3H); 113C{1H} NMR
(125 MHz, CDCl3): δ 174.2, 170.3, 168.4, 145.2, 137.5, 134.0 (3 C), 129.8 (q, Jc-F = 32.0 Hz),
129.1, 128.5 (2 C), 127.6 (2 C), 124.7 (q, JC-F = 3.8 Hz), 124.1 (q, JC-F = 270.5 Hz), 68.8, 67.6,
62.0, 61.8, 61.3, 51.9, 36.1, 13.7, 13.3, -1.7, -4.9; The er was determined by HPLC using a
Daicel Chiralcel OD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 4.99 min, τminor
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= 6.79 min, [α]D = +2.3 (c 2.1, CHCl3, ee = 90%); HRMS (ESI) m/z: [M+H]+Calcd for
C27H33F3NO6Si 552.2052; Found 552.2046.
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(2R,3S,5S)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-(4-ethylphenyl)-pyrrolidine-2,4,4-
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tricarboxylate (3f). The title compound was prepared according to the general procedure B
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(Condition A). Yield: 34 mg (66 %); colorless liquid; H NMR (500 MHz, CDCl3): δ 7.56-
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7.54 (m, 2 H), 7.38-7.34 (m, 5 H), 7.12 (d, J = 8.0 Hz, 2 H), 5.06 (s, 1 H), 4.21 (dq, J = 7.0,
10.5 Hz, 1 H), 3.88 (d, J = 10.5 Hz, 1 H), 3.87-3.81 (m, 1 H), 3.72 (dq, J = 10.5, 7.0 Hz, 1 H),
3.50 (dq, J = 10.5, 7.0 Hz, 1 H), 3.28 (s, 3 H), 2.87 (d, J = 10.5 Hz, 1 H), 2.61 (q, J = 7.5 Hz,
2 H), 1.20 (m, 6 H), 0.87 (t, J = 7.0 Hz, 3 H), 0.41 (s, 3 H), 0.33 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 174.1, 170.6, 168.9, 143.8, 138.0, 137.8, 134.0 (2 C), 128.9, 127.9 (2 C), 127.6
(2 C), 127.4 (2 C), 69.1, 68.4, 62.2, 61.5, 61.1, 51.8, 36.9, 28.5, 15.6, 13.7, 13.4, -1.5, -4.9; The
er was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (90:10)]; flow
rate 1.0 mL/min; τmajor = 11.65 min, τminor = 13.93 min, [α]D26 = +4.4 (c 1.27, CHCl3, ee >83%,
mixture of 3f and ~ 4% of minor isomer); HRMS (ESI) m/z: [M+H]+Calcd for C28H38NO6Si
512.2463; Found 512.2463.
(2R,3S,5S)-4,4-diethyl 2-methyl 5-(3-bromophenyl)-3-(dimethylphenylsilyl)-pyrrolidine-2,4,4-
tricarboxylate (3g). The title compound was prepared according to the general procedure B
(Condition A).Yield: 43 mg (76 %); colorless liquid; 1H NMR (500 MHz, CDCl3): δ 7.62 (brs,
1 H), 7.55-7.53 (m, 3 H), 7.38-7.35 (m, 4 H), 7.19 (t, J = 7.0 Hz, 1 H), 5.04 (s, 1 H), 4.22 (dq,
J = 10.5, 7.0 Hz, 1 H), 3.89 (d, J = 10.5 Hz, 1 H), 3.88-3.78 (m, 2 H), 3.61 (dq, J = 11.0, 7.0
Hz, 1 H), 3.30 (s, 3 H), 2.86 (d, J = 10.5 Hz, 1 H), 1.22 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.5 Hz,
3 H), 0.40 (s, 3 H), 0.33 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 174.0, 170.3, 168.4,
143.5, 137.6, 134.0 (2 C), 131.3, 130.6, 129.6, 129.1, 127.6 (2 C), 126.6, 121.8, 68.8, 67.5,
62.0, 61.7, 61.4, 51.8, 36.0, 13.7, 13.5, -1.6, -4.9; The er was determined by HPLC using a
Daicel Chiralcel OD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 5.53 min, τminor
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= 7.05 min, [α]D = +6.51 (c 1.2, CHCl3, ee ~84 %); HRMS (ESI) m/z: [M+H]+Calcd for
C26H33BrNO6Si 562.1255; Found 562.1257.
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(2R,3S,5S)-4,4-diethyl 2-methyl 5-(3-chlorophenyl)-3-(dimethylphenylsilyl)-pyrrolidine-2,4,4-
tricarboxylate (3h). The title compound was prepared according to the general procedure B
(Condition A). Yield: 39 mg (75%); colorless liquid; 1H NMR (500 MHz, CDCl3): δ 7.55-7.53
(m, 2 H), 7.47 (bs 2 H), 7.37-7.35 (m, 3 H), 7.25-7.22 (m, 2 H), 5.06 (s, 1 H), 4.21 (dq, J =
11.0, 7.0 Hz, 1 H), 3.91 (d, J = 10.5 Hz, 1 H), 3.88-3.78 (m, 2 H), 3.60 (dq, J = 10.5, 7.0 Hz, 1
H), 3.32 (s, 3 H), 2.87 (d, J = 10.5 Hz, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 0.97 (t, J = 7.0 Hz, 3 H),
0.41 (s, 3 H), 0.34 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.9, 170.2, 168.5, 142.9,
137.7, 134.1 (2 C), 133.8, 129.3, 129.1, 128.5, 127.8, 127.6 (2 C), 126.1, 69.0, 67.7, 62.1, 61.8,
61.4, 51.9, 36.3, 13.7, 13.5, -1.6, -4.7; The er was determined by HPLC using a Daicel Chiralcel
OD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 5.75 min, τminor = 7.93 min,
[α]D22 = +4.1 (c 1.8, CH2Cl2, ee = 86%); HRMS (ESI) m/z: [M+H]+Calcd for C26H33ClNO6Si
518.1760; Found 518.1779.
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(2R,3S,5S)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-(3-fluorophenyl)-pyrrolidine-2,4,4-
tricarboxylate (3i). The title compound was prepared according to the general procedure B
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(Condition A). Yield: 39 mg (78 %); colorless liquid; H NMR (500 MHz, CDCl3): δ 7.55-
7.53 (m, 2 H), 7.38-7.35 (m, 3 H), 7.30-7.23 (m, 3 H), 6.96-6.92 (m, 1 H), 5.08 (s, 1 H), 4.22
(dq, J = 11.5, 7.5 Hz, 1 H), 3.89 (d, J = 10.0 Hz, 1 H), 3.87-3.76 (m, 2 H), 3.59 (dq, J = 10.5,
7.0 Hz, 1 H), 3.30 (s, 3 H), 2.87 (d, J = 11.0 Hz, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 0.94 (t, J = 7.0
Hz, 3 H), 0.41 (s, 3 H), 0.34 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 174.0, 170.4,
168.5, 162.5 (d, JC-F = 244.0 Hz), 143.8 (d, JC-F = 6.8 Hz), 137.8, 134.1 (2 C), 129.3 (d, JC-F
8.0 Hz), 129.1, 127.6 (2 C), 123.6 (d, JC-F = 2.9 Hz), 115.3 (d, JC-F = 21.8 Hz), 114.5 (d, JC-F
=
=
21.8 Hz), 69.1, 67.8 (d, JC-F = 1.74 Hz), 62.2, 61.7, 61.3, 51.8, 36.4, 13.7, 13.5, -1.5, -4.7; The
er was determined by HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (90:10)]; flow
rate 1.0 mL/min; τmajor = 5.35 min, τminor = 6.94 min; [α]D22 = -3.1 (c 3.42, CHCl3, ee = 84%);
HRMS (ESI) m/z: [M+H]+Calcd for C26H33FNO6Si 502.2079; Found 502.2074.
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(2R,3S,5R)-4,4-diethyl 2-methyl 5-(2-chlorophenyl)-3-(dimethylphenylsilyl)-pyrrolidine-
2,4,4-tricarboxylate (3j). The title compound was prepared according to the general procedure
B (Condition A). Yield: 37 mg (71 %);white solid; mp: 92-94 °C; 1H NMR (200 MHz, CDCl3):
δ 7.93 (dd, J = 1.5, 7.8 Hz, 1 H), 7.57-7.52 (m, 2 H), 7.37-7.26 (m, 5 H), 7.23-7.13 (m, 1 H),
5.79 (s, 1 H), 4.29 (dq, J = 10.8, 7.1 Hz, 1 H), 4.09 (dq, J = 10.8, 7.1, Hz, 1 H), 3.94 (d, J =
12.3 Hz, 1 H), 3.78 (dq, J = 10.8, 7.2 Hz, 1 H), 3.53 (dq, J = 10.7, 7.1, Hz, 1 H), 3.20 (s, 3 H),
2.91 (d, J = 12.4 Hz, 1 H), 2.80 (bs, 1 H), 1.29 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 3 H),
0.42 (s, 3 H), 0.30 (s, 3 H); 13C{1H}NMR (50 MHz, CDCl3): δ 173.8, 170.6, 168.3, 139.2,
137.9, 134.0 (2 C), 133.7, 130.1, 129.0, 128.8, 128.7, 127.6 (2 C), 127.0, 69.0, 63.4, 62.2, 61.9,
61.4, 51.8, 37.2, 13.8, 13.4, -1.1, -5.4; The er was determined by HPLC using a Daicel Chiralcel
OD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor = 5.85 min, τminor = 12.55 min;
[α]D29 = +29.4 (c 2.8, CHCl3, ee >90%); HRMS (ESI) m/z: [M+H]+Calcd for C26H33ClNO6Si
518.1760; Found 518.1764. After recrystallization from petroleum ether at - 20 ºC, a suitable
crystal for X-ray diffraction was obtained.
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(2R,3S,5S)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-(2-fluorophenyl)-pyrrolidine-2,4,4-
tricarboxylate (3k). The title compound was prepared according to the general procedure B
(Condition A). Yield: 36 mg (71 %); colorless liquid; 1H NMR (500 MHz, CDCl3): δ 7.88-7.85
(m, 1 H), 7.55-7.54 (m, 2 H), 7.38-7.35 (m, 3 H), 7.24-7.20 (m, 1 H), 7.18-7.15 (m, 1 H), 6.94
(t, J = 9.0 Hz, 1 H), 5.49 (s, 1 H), 4.23 (dq, J = 10.5, 7.0 Hz, 1 H), 3.96 (dq, J = 10.5, 7.0 Hz,
1 H), 3.92 (d, J = 11.5 Hz, 1 H), 3.82 (dq, J = 10.5, 7.0 Hz, 1 H), 3.58 (dq, J = 10.5, 7.0 Hz, 1
H), 3.24 (s, 3 H), 2.90 (d, J = 12.0 Hz, 1 H), 1.25 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.0 Hz, 3 H),
0.41 (s, 3 H), 0.32 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.8, 170.4, 168.5, 160.2
(d, JC-F = 245.8Hz), 137.7, 134.0 (2 C), 130.2 (d, JC-F = 3.4 Hz), 129.3 (d, JC-F = 8.4 Hz), 129.0,
128.1 (d, JC-F = 11.2 Hz), 127.6 (2 C), 124.3 (d, JC-F = 3.5 Hz), 114.6 (d, JC-F = 22.5 Hz), 68.7,
62.1, 61.8, 61.4, 60.8 (d, JC-F = 4.0 Hz), 51.9, 36.7, 13.8, 13.4, -1.3, -5.1; The er was determined
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by HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min; τmajor
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= 5.30 min, τminor = 9.41 min; [α]D = +6.83 (c 3.14, CHCl3, ee >90%); HRMS (ESI) m/z:
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[M+H]+Calcd for C26H33FNO6Si 502.2079; Found 502.2072.
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(2R,3S,5R)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-(thiophen-2-yl)-pyrrolidine-2,4,4-
tricarboxylate (3l). The title compound was prepared according to the general procedure B
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(Condition A). Yield: 40 mg (81%); colorless liquid; H NMR (500 MHz, CDCl3): δ 7.56-7.54
(m, 2 H), 7.37-7.34 (m, 3 H), 7.21-7.20 (m, 1 H), 7.10 (d, J = 3.5 Hz, 1 H), 6.94 (dd, J = 3.5,
5.5 Hz 1 H), 5.30 (s, 1 H), 4.25 (dq, J = 10.5, 7.0 Hz, 1 H), 3.94-3.86 (m, 2 H), 3.85 (d, J =
11.0 Hz, 1 H), 3.72 (dq, J = 10.5, 7.0 Hz, 1 H), 3.26 (s, 3 H), 2.94 (d, J = 10.5 Hz, 1 H), 1.23
(t, J = 7.0 Hz, 3 H), 1.02 (t, J = 7.0 Hz, 3 H), 0.42 (s, 3 H), 0.34 (s, 3 H); 13C{1H} NMR (125
MHz, CDCl3): δ 173.7, 170.3, 168.4, 144.8, 138.1, 134.0 (2 C), 128.9, 127.6 (2 C), 126.4,
125.6, 124.9, 69.2, 64.1, 62.0, 61.7, 61.4, 51.7, 35.8, 13.7, 13.5, -1.4, -4.7;The er was
determined by HPLC using a Daicel Chiralcel AD-H [hexane/i-PrOH (90:10)]; flow rate 1.0
mL/min; τmajor = 9.44 min, τminor = 15.20 min; [α]D28 = -7.2 (c 2.4, CHCl3, ee = 87%); HRMS
(ESI) m/z: [M+H]+Calcd for C24H32NO6SSi 490.1740; Found 490.1738.
(2R,3S,5S)-4,4-diethyl2-methyl5-(4-chlorophenyl)-3-(1,1,3,3-
pentamethyldisiloxanyl)pyrrolidine-2,4,4-tricarboxylate (3m). The title compound was
prepared according to the general procedure B (Condition A).Yield: 38 mg (72 %); colorless
liquid;1H NMR (500 MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2 H), 7.26-7.25 (m, 2 H), 5.03 (s, 1
H), 4.38 (dq, J = 11.0, 7.4 Hz, 1 H), 4.06 (dq, J = 10.8, 7.2 Hz, 1 H), 3.91 (d, J = 11.0 Hz, 1
H), 3.82-3.76 (m, 1 H), 3.80 (s, 3 H), 3.56 (dq, J = 10.8, 7.2 Hz, 1 H), 2.53 (d, J = 11.0 Hz, 1
H), 1.28 (t, J = 7.2 Hz, 3 H), 0.95 (t, J = 7.2 Hz, 3 H), 0.16 (s, 3 H), 0.12 (s, 3 H), 0.87 (s, 9 H);
13C{1H} NMR (125 MHz, CDCl3): δ 174.6, 170.5, 168.3, 139.7, 133.4, 129.5 (2 C), 127.9 (2
C), 68.5, 67.3, 61.6, 61.4, 61.2, 52.2, 37.7, 13.8, 13.5, 1.90 (3 C), 1.41, 0.60; The er was
determined by HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (90:10)]; flow rate 0.5
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mL/min; τmajor = 8.25 min, τminor = 9.30 min; [α]D28 = -39.02 (c 1.68, CH2Cl2, ee = 92%); HRMS
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(ESI) m/z: [M+H]+Calcd for C23H37ClNO7Si2 530.1792; Found 530.1793.
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dicarboxylate 5: Under Argon atmosphere, Ag2O (2.3 mg, 0.01 mmol), DABCO (~4.5 mg,
0.04 mmol) and ligand L8 (5.0 mg, 0.011 mmol) were dissolved in 1.0 mL of freshly distilled
toluene and stirred at room temperature for about 50 min. Then, the reaction mixture was
cooled to -40 °C and a solution of (4-chlorobenzylidene)glycine methyl ester 1a (~85 mg, 0.4
mmol) in toluene (0.5 mL) was added slowly to the reaction mixture followed by the addition
of a solution of β-dimethylphenylsilyl-acrylate 4 (44 mg, 0.2 mmol) in toluene (0.5 mL). The
reaction mixture was stirred at this temperature overnight and then reaction mixture was passed
through a small pad of silica and flushing with 100 mL EtOAc. The solvent was removed under
reduced pressure and the residue was directly subjected to column chromatography on silica
gel to afford the product 513as a colourless liquid in 64% yield (55 mg, combined yield of two
diastereomers); Data of Major isomer 1H NMR (500 MHz, CDCl3): δ 7.54-7.52 (m, 2 H), 7.39-
7.38 (m, 3 H), 7.25 (d, J = 8.3 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H), 4.14 (d, J = 8.2 Hz, 1 H),
3.79 (d, J = 9.7 Hz, 1 H), 3.65 (s, 3 H), 3.18-3.15 (m, 4 H), 2.21 (dd, J = 9.5, 7.9 Hz, 1 H), 0.40
(s, 3 H), 0.39 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.4, 173.1, 137.3, 135.9, 134.0
(2 C), 133.2, 129.6, 128.2 (2 C), 128.15 (2 C), 127.9 (2 C), 65.2, 62.5, 53.0, 52.1, 51.4, 34.6, -
4.1, -4.3; The er was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH
(90:10)]; flow rate 0.8 mL/min, λ = 220 nm; τmajor = 14.18 min, τminor = 29.25 min.
(2S,3S,5S)-4,4-diethyl 2-methyl5-(4-chlorophenyl)-3phenylpyrrolidine-2,4,4-tricarboxylate 7:
Under Argon atmosphere, Ag2O (2.3 mg, 0.01 mmol), DABCO (2.3 mg, 0.02 mmol) and ligand
L8 (5.0 mg, 0.011 mmol) were dissolved in 0.5 mL of freshly distilled toluene and stirred at
room temperature for about 50 min. Then, the reaction mixture was cooled to -40 °C and a
solution of (4-chlorobenzylidene)glycine methyl ester 1a (42 mg, 0.2 mmol) in toluene (0.25
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mL) was added slowly to the reaction mixture followed by the addition of a solution of
benzylidene malonate 6 (0.1 mmol, 1 equiv) in toluene (0.25 mL). The reaction mixture was
stirred at this temperature overnight and then the reaction mixture was passed through a small
pad of silica and flushing with 100 mL EtOAc. The solvent was removed under reduced
pressure and the residue was directly subjected to column chromatography on silica gel to
afford the product 710c as a white solid in 72% yield (33 mg). mp 106-108 °C; 1H NMR (500
MHz, CDCl3): δ 7.46 (d, J = 8.4 Hz, 2 H), 7.33-7.26 (m, 7 H), 5.33 (s, 1 H), 4.41 (d, J = 6.6
Hz, 1 H), 4.21 (d, J = 6.6 Hz, 1 H), 3.88-3.79 (m, 2 H), 3.77 (s, 3 H), 3.48-3.40 (m, 2 H), 0.82-
0.77 (m, 6 H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.0, 169.3, 168.6, 138.7, 136.9, 133.8,
129.0 (2 C), 128.9 (2 C), 128.4 (2 C), 128.2 (2 C), 127.6, 70.6, 67.2, 66.2, 61.4, 61.1, 55.8,
52.5, 13.3, 13.2; [α]D26 = -39.5 (c 1.88, CHCl3); The er was determined by HPLC using a Daicel
Chiralpak AS-H [hexane/i-PrOH (80:20)]; flow rate 1.0 mL/min; τmajor = 4.84 min, τminor = 6.07
min.
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Scale up procedure for the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylide1a with β-silylmethylene malonate 2a
Under an Argon atmosphere, Ag2O (11.5 mg, 0.05 mmol), ligand L8 (25 mg, 0.055 mmol,
mmol), and DABCO (22.5 mg, 0.2 mmol) were dissolved in toluene (5.0 mL) and stirred at
room temperature for approximately 1h. Then, the reaction mixture was cooled to -40 °C and
a solution of imino ester 1a (423 mg, 2.0 mmol) in toluene (2.5 mL) was added slowly over a
period of 5 min and the resulting mixture was stirred for 5 min followed by addition of a
solution of β-silylmethylene malonate 2 (306 mg, 1.0 mmol) in toluene (2.5 mL) over a period
of 5 min. Once the starting material was consumed (monitored by TLC), then the mixture was
filtered through a small pad of silica flushing with 150 mL of CH2Cl2 and 250 mL of 50%
EtOAc/hexane. The filtrates were concentrated and purified by column chromatography to give
3a as a colorless liquid in 80% yield (415 mg).
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General Procedure D for the preparation of N-tosyl-3-silylyproline derivatives 8
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Under nitrogen atmosphere, compound 3 (0.15 mmol, 1.0 equiv) was dissolved in 3 mL of dry
CH2Cl2. TsCl (0.45 mmol, 3.0 equiv), Et3N (0.6 mmol, 4.0 equiv) and DMAP (0.03 mmol, 20
mol%) were added sequentially and the reaction mixture was stirred for 22 h at 27 ºC. The
solvent was evaporated and the residue was purified by column chromatography to give the
corresponding product 8a-8c and 8i.
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(2R,3S,5S)-4,4-diethyl
2-methyl
5-(4-chlorophenyl)
3-(dimethylphenylsilyl)
-1-
tosylpyrrolidine-2,4,4-tricarboxylate 8a. The title compound was prepared according to the
general procedure D. Yield: 91mg (90 %); colorless liquid, 1H NMR (500 MHz, CDCl3): δ
7.50-7.49 (m, 3 H), 7.45-7.43 (m, 4 H), 7.34-7.33 (m, 3 H), 7.16 (d, J = 8.5 Hz, 1 H), 7.08 (d,
J = 8.5 Hz, 2 H), 5.65 (s, 1 H), 4.29 (d, J = 12.4 Hz, 1 H), 4.15-4.04 (m, 2 H), 3.76-3.70 (m, 1
H), 3.63-3.56 (m, 1 H), 3.14 (s, 3 H), 2.93 (d, J = 12.4 Hz, 1 H), 2.33 (s, 3 H), 1.27 (t, J = 7.0
Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H), 0.46 (s, 3 H), 0.24 (s, 3 H); 13C{1H} NMR (125 MHz,
CDCl3): δ 171.7, 168.9, 166.4, 143.6, 137.4, 136.5, 135.4, 133.9 (2 C), 133.88, 129.7 (2 C),
129.2, 128.9 (2 C), 128.0 (2 C), 127.9 (2 C), 127.7 (2 C), 67.9, 67.3, 63.1, 62.5, 61.9, 52.1,
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35.0, 21.4, 13.8, 13.5, -0.84, -5.4; [α]D = +11.4 (c 3.37, CHCl3); HRMS (ESI) m/z:
[M+Na]+Calcd for C33H38ClNNaO8SSi 694.1668; Found 694.1662.
(2R,3S,5S)-4,4-diethyl 2-methyl 3-(dimethylphenylsilyl)-5-phenyl-1-tosylpyrrolidine-2,4,4-
tricarboxylate 8b.The title compound was prepared according to the general procedure D.
Yield: 84 mg (88 %); colorless liquid, 1H NMR (500 MHz, CDCl3): δ 7.52-7.48 (m, 4 H), 7.44
(d, J = 8.2 Hz, 2 H), 7.34-7.32 (m, 3 H), 7.19-7.18 (m, 3 H), 7.05 (d, J = 8.0 Hz, 2 H), 5.70 (s,
1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.13-4.06 (m, 2 H), 3.68-3.63 (m, 1 H), 3.59-3.53 (m,1 H),
3.13 (s, 3 H), 3.00 (d, J = 12.4 Hz, 1 H), 2.30 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H), 0.95 (t, J = 7.2
Hz, 3 H), 0.47 (s, 3 H), 0.24 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 171.6, 169.2,
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166.5, 143.3, 137.8, 137.6, 135.7, 134.0 (2 C), 129.1, 128.8 (2 C), 128.3 (2 C), 128.0, 127.9 (3
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C), 127.8, 127.6 (2 C), 68.1, 68.0, 63.2, 62.4, 61.8, 52.0, 35.0, 21.4, 13.8, 13.5, -0.7, -5.4; [α]D
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= +10.3 (c 2.5, CHCl3); HRMS (ESI) m/z: [M+Na]+Calcd for C33H39NNaO8SSi 660.2058;
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Found 660.2056.
(2R,3S,5S)-4,4-diethyl
2-methyl
5-(4-bromophenyl)
3-(dimethylphenylsilyl)
-1-
tosylpyrrolidine-2,4,4-tricarboxylate 8c The title compound was prepared according to the
general procedure D. Yield: 99 mg (92 %); colorless liquid;1H NMR (200 MHz, CDCl3): δ
7.52-7.40 (m, 5 H), 7.35-7.28 (m, 7 H), 7.08 (d, J = 8.0 Hz, 2 H), 4.29 (d, J = 12.3 Hz, 1 H),
4.15-4.01 (m, 2 H), 3.78-3.51 (m, 2 H), 3.15 (s, 3 H), 2.91(d, J = 12.3 Hz, 1 H), 2.33 (s, 3 H),
1.27 (t, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.0 Hz, 3 H), 0.46 (s, 3 H), 0.24 (s, 3 H); 13C{1H} NMR
(50 MHz, CDCl3): δ 171.6, 168.8, 166.3, 143.6, 137.3, 137.0, 135.4, 133.9 (2 C), 130.9 (2 C),
130.0 (2 C), 129.1, 128.9 (2 C), 127.8 (2 C), 127.6 (2 C), 122.1, 67.9, 67.4, 63.1, 62.5, 61.9,
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52.0, 35.0, 21.4, 13.7, 13.4, -0.91, -5.4; [α]D = +11.3 (c 2.0, CHCl3); HRMS (ESI) m/z:
[M+Na]+Calcd for C33H38BrNNaO8SSi 738.1163; Found 738.1161.
(2R,3S,5S)-4,4-diethyl
2-methyl
3-(dimethylphenylsilyl)
5-(3-fluorophenyl)
-1-
tosylpyrrolidine-2,4,4-tricarboxylate 8i. The title compound was prepared according to the
general procedure D. Yield: 83 mg (84 %); colorless liquid, 1H NMR (500 MHz, CDCl3): δ
7.50-7.46 (m, 4 H), 7.34-7.33 (m, 3 H), 7.26 (bs, 2 H), 7.16 (q, J = 7.8 Hz, 1 H), 7.09 (d, J =
8.1 Hz, 2 H), 6.91-6.87 (m, 1 H), 5.67 (s, 1 H), 4.28 (d, J = 12.4 Hz, 1 H), 4.14-4.03 (m, 2 H),
3.76-3.69 (m, 1 H), 3.66-3.60 (m, 1 H), 3.15 (s, 3 H), 2.93 (d, J = 12.4 Hz, 1 H), 2.32 (s, 3 H),
1.27 (t, J = 7.2 Hz, 3 H), 0.99(t, J = 7.2 Hz, 3 H), 0.46 (s, 3 H), 0.24 (s, 3 H); 13C{1H} NMR
(125 MHz, CDCl3): δ 171.5, 168.8, 166.3, 162.3 (d, JC-F = 244.5 Hz), 143.6, 140.6 (d, JC-F
=
7.0 Hz), 137.4, 135.4, 133.9 (2 C), 129.3 (d, JC-F = 8.0 Hz), 129.2, 128.9 (2 C), 127.9 (2 C),
127.6 (2 C), 123.8 (d, JC-F = 2.8 Hz), 115.3 (d, JC-F = 22.7 Hz), 114.7 (d, JC-F = 21.0 Hz), 68.0,
67.4 (d, JC-F = 1.8 Hz), 63.2, 62.5, 61.9, 52.1, 35.0, 21.4, 13.8, 13.4, -0.86, -5.3; [α]D25 = +5.3
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(c 1.71, CHCl3); HRMS (ESI) m/z: [M+Na]+Calcd for C33H38FNNaO8SSi 678.1964; Found
5
6
678.1964.
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General Procedure E for the preparation of 3-hydroxyproline derivatives
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Potassium bromide (0.16 mmol, 1.2 equiv) was added to a stirred solution of 8 (0.12 mmol, 1.0
equiv) and peracetic acid (35% solution in acetic acid, 3 mL) at 0 °C followed by H2O2 (30%,
0.1 mL). The reaction mixture was warmed slowly to room temperature and stir for 2d. Sodium
thiosulphate was added to the reaction mixture and stirred until (approx. 10 min) the clear
solution became turbid. Solvent was removed under reduced pressure and the residue was
dissolved in dichloromethane and passed through Na2SO4. The organic solvent was evaporated
under reduced pressure. The residue was purified by column chromatography to give 9a-9c
and 9i.
(2S,3S,5S)-4,4-diethyl2-methyl5-(4-chlorophenyl)3-hydroxy-1-tosylpyrrolidine-2,4,4-
tricarboxylate 9a. The title compound was prepared according to the general procedure E.
Yield: 48 mg (72 %); white amorphous solid; 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 8.1
Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 5.57 (s,
1 H), 5.10 (s, 1 H), 4.59 (d, J = 4.8 Hz, 1 H), 4.26-4.21 (m, 1 H), 4.17-4.13 (m, 1 H), 3.88 (s, 3
H), 3.82-3.76 (m, 1 H), 3.49 (dq, J = 10.7, 7.2 Hz, 1 H), 3.01 (d, J = 5.0 Hz, 1 H), 2.37 (s, 3
H), 1.23 (t, J = 7.1 Hz, 3 H), 0.81 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ
170.5, 166.72, 166.70, 143.9, 135.4, 135.0, 133.8, 129.8 (2 C), 129.0 (2 C), 128.2 (2 C), 127.9
(2 C), 76.4, 69.5, 67.0, 65.7, 62.5, 62.0, 52.9, 21.5, 13.9, 13.2; [α]D26 = -23.0 (c 0.7, CHCl3);
[M+H]+Calcd for C25H29ClNO9S 554.1246; Found 554.1241.
(2S,3S,5S)-4,4-diethyl 2-methyl 3-hydroxy-5-phenyl-1-tosylpyrrolidine-2,4,4-tricarboxylate
9b. The title compound was prepared according to the general procedure E. Yield = 44 mg (70
1
%); white amorphous solid; H NMR (500 MHz, CDCl3): δ 7.51 (d, J = 8.0 Hz, 2 H), 7.38-
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7.37 (m, 2 H), 7.14-7.13 (m, 3 H), 7.09 (d, J = 8.0 Hz, 2 H), 5.60 (s, 1 H), 5.17 (d, J = 5.5 Hz,
1 H), 4.53 (d, J = 5.8 Hz, 1 H), 4.28-4.14 (m, 2 H), 3.88 (s, 3 H), 3.75 (dq, J = 10.6, 7.1 Hz, 1
H), 3.45 (dq, J = 10.5, 7.2 Hz, 1 H), 2.98 (bs, 1 H), 2.34 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.78
(t, J = 7.2 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.6, 167.1, 166.8, 143.6, 136.8,
135.2, 128.9 (3 C), 128.4, 128.2 (2 C), 127.9, 127.8 (2 C), 76.4, 69.1, 66.4 (2 C), 62.5, 61.8,
52.9, 21.5, 13.9, 13.2; [α]D26 = -23.2 (c 1.4, CHCl3); [M+H]+Calcd for C25H30NO9S 520.1636;
Found 520.1631.
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(2S,3S,5S)-4,4-diethyl
2-methyl
5-(4-bromophenyl-3-hydroxy-1-tosylpyrrolidine-2,4,4-
tricarboxylate 9c. The title compound was prepared according to the general procedure E.
1
Yield: 51 mg (71 %); colorless liquid, H NMR (500 MHz, CDCl3): δ 7.50 (d, J = 8.5 Hz, 2
H), 7.25-7.20 (m, 4 H), 7.12 (d, J = 8.0 Hz, 2 H), 5.55 (s, 1 H), 5.09 (d, J = 4.3 Hz, 1 H), 4.61
(d, J = 4.3 Hz, 1 H), 4.26-4.18 (m, 1 H), 4.17-4.09 (m,1 H), 3.88 (s, 3 H), 3.79 (dq, J = 10.8,
7.2 Hz, 1 H), 3.48 (dq, J = 10.7, 7.2 Hz, 1 H), 3.17 (bs, 1 H), 2.32 (s, 3 H), 1.22 (t, J = 7.1 Hz,
3 H), 0.80 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 170.5, 166.73, 166.66,
144.0, 135.8, 135.0, 130.8, 130.2, 129.0 (3 C), 128.2 (3 C), 122.0, 76.4, 69.6, 67.2, 65.8, 62.4,
62.0, 52.9, 21.5, 13.9, 13.2; [α]D25 = -20.1 (c 3.0, CHCl3); HRMS (ESI) m/z: [M+H]+Calcd for
C25H29BrNO9 598.0741; Found 598.0742.
(2S,3S,5S)-4,4-diethyl
2-methyl
5-(3-fluorophenyl-3-hydroxy-1-tosylpyrrolidine-2,4,4-
tricarboxylate 9i. The title compound was prepared according to the general procedure E.
1
Yield: 42 mg (65 %); colorless liquid, H NMR (500 MHz, CDCl3): δ 7.54 (d, J = 8.2 Hz, 2
H), 7.21 (d, J = 7.5 Hz, 1 H), 7.13-7.10 (m, 4 H), 6.84 (dd, J = 2.0, 8.0 Hz, 1 H), 5.59 (s, 1 H),
5.10 (d, J = 4.9 Hz, 1 H), 4.59 (d, J = 4.9 Hz, 1 H), 4.26-4.19 (m, 1 H), 4.18-4.12 (m, 1 H),
3.88 (s, 3 H), 3.78 (dq, J = 10.7, 7.1 Hz, 1 H), 3.51 (dq, J = 10.8, 7.2 Hz, 1 H), 3.11 (bs, 1 H),
2.35 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 0.81 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (125 MHz,
CDCl3): δ 170.4, 166.7, 166.66, 162.2 (d, JC-F = 244.5 Hz), 143.9, 139.4 (d, JC-F = 7.2 Hz),
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134.9, 129.3 (d, JC-F = 8.0 Hz), 129.0 (2 C), 128.2 (2 C), 124.1 (d, JC-F = 2.8 Hz), 115.4 (d, JC-
F = 22.8 Hz), 114.7 (d, JC-F = 21.0 Hz), 76.4, 69.5, 67.0, 65.8 (d, JC-F = 1.84 Hz), 62.5, 61.9,
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52.9, 21.5, 13.9, 13.2; [α]D = -21.6 (c 2.35, CHCl3); HRMS (ESI) m/z: [M+H]+Calcd for
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C25H29BrNO9S 538.1542; Found 538.1540.
"Supporting Information:”
The Supporting Information is available free of charge on the
ACS Publications website:
X-ray crystallographic information of 3j (PDF)
X-ray crystallographic data for 3j (CIF)
1H and 13C spectra for 3a-3m, 5, 7, 8a-8c, 8i, 9a-9c and 9i (PDF)
HPLC trace of 3a-3m, 5 and 7(PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: raghuc@barc.gov.in
ORCID: Raghunath Chowdhury: 0000-0002-0395-7014
Notes and references
(1) Selected reviews (a) Fleming, I. In Science of Synthesis; Fleming, I., Ed.; Thieme: Stuttgart,
2002; Vol. 4, p 927. (b) Fleming, I.; Barbero, A.; Walter, D. Stereochemical Control in Organic
Synthesis Using Silicon-Containing Compounds. Chem. Rev. 1997, 97, 2063. (c) Denmark S.
E.; Regens, C. S. Palladium-Catalyzed Cross-Coupling Reactions of Organosilanols and Their
Salts: Practical Alternatives to Boron- and Tin-Based Methods. Acc. Chem. Res., 2008, 41,
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