Organocatalyzed Diastereo- and Enantioselective Conjugate Addition of Nitroalkanes to β-Silylmethylene Malonates: Direct Access to Enantioenriched Organosilanes

Article abstract of DOI:10.1002/ejoc.202000306

Cinchona-alkaloid derived bifunctional thiourea catalyzed conjugate addition reaction of nitroalkanes to β-silylmethylene malonates is reported for direct access of densely functionalized enantioenriched organosilanes in good yields (up to 86 %) with exce

Full text of DOI:10.1002/ejoc.202000306

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Organocatalyzed Diastereo- and Enantioselective Conjugate
Addition of Nitroalkanes to β-Silylmethylene Malonates: Direct
Access to Enantioenriched Organosilanes
Authors: Raghunath Chowdhury, Akhil K. Dubey, and Sunil K. Ghosh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000306
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01/2020

10.1002/ejoc.202000306
European Journal of Organic Chemistry
Organocatalyzed Diastereo- and Enantioselective Conjugate Addition of
Nitroalkanes to β-Silylmethylene Malonates: Direct Access to
Enantioenriched Organosilanes
Raghunath Chowdhury,*a Akhil K. Dubey,a Sunil K. Ghosha,b
aBio-Organic Division, bHomi Bhabha National Institute,
Bhabha Atomic Research Centre, Trombay, Mumbai 400085
Fax: +91-22-25505151
E-mail: raghuc@barc.gov.in
Abstract Cinchona-alkaloid derived bifunctional thiourea catalysed conjugate addition
reaction of nitroalkanes to β-silylmethylene malonates is reported for direct access of densely
functionalized enantioenriched organosilanes in good yields (up to 86%) with excellent
stereoselectivities (up to 98:2 dr and 90% ee). Using pseudoenantiomeric catalyst, both the
enantiomers of the conjugate addition products were easily accessible. Preparative scale
synthesis of two conjugate addition products confirmed the practical applicability of the current
methods. Furthermore, synthetic potential of these organosilanes was demonstrated by
employing one of the products in the formal asymmetric synthesis of nootropic drug (R)-
oxiracetam, synthesis of sila-analogue of PAR-2 agonist AC-264613 and synthesis of (R)- N-
benzyl-4-hydroxy-pyrrolidin-2-one, intermediate for the synthesis of several pharmaceuticals.
Introduction
Chiral organosilanes are valuable substrates in organic synthesis,[1] materials science,[2] and
agroscience.[3] Suitably substituted silicon groups attached to carbon atom can be converted to
a hydroxyl group by Tamo-Fleming oxidation. [4] Chiral organosilanes (Figure 1, A[5] and B[6]
) and silicon-containing organic molecules are attractive targets owing to their impressive
application in medicinal chemistry. The replacement of carbon with silicon or introduction of
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silyl group in organic molecules can improve the pharmacological properties.[7] Several elegant
transition metal catalysed enantioselective methods[8] have been developed for the synthesis of
enantioenriched organosilanes whereas the organocatalyzed methods for their direct synthesis
are limited.
Figure 1. Selected examples of medicinally important chiral organosilanes.
In the realm of chiral organosilanes synthesis under organocatalytic conditions,
Jørgensen and co-workers demonstrated an organocatalyzed Michael addition reaction of β-
ketoesters with silicon-substituted α,β-unsaturated aldehydes followed by acid-catalysed
decarboxylation and aldol condensation for the synthesis of 5-(trialkylsilyl)cyclohex-2-enones
(Scheme 1 A).[9] Ghosh and co-workers developed asymmetric organocatalyzed direct
conjugate addition of alkyl methyl ketones and aldehydes to a β-silylmethylene malonate to
form β-silyl carbonyl compounds (Scheme 1 B). [10] In 2011, Hoveyda and co-workers reported
a NHC catalysed silyl conjugate addition to α,β-unsaturated carbonyl compounds for the
synthesis of β-silyl carbonyl compounds (Scheme 1 C). [11] More recently, Fu, Huang and co-
workers developed carbene- catalysed formal [4+2] annulation of enals with β-silyl enones to
form enantiopure organosilanes (Scheme 1 D). [12] As part of our recent interest on catalytic
enantioselective synthesis of organic molecules bearing a silyl substituted asymmetric
carbon[13] and in general development of bifunctional thio(urea) catalysed reactions,[14,15] we
envisaged that organocatalyzed conjugate addition of nitroalkanes to β-silylmethylene
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European Journal of Organic Chemistry
malonates would be the most straightforward approach to rapid access of enantioenriched
organosilanes (Scheme 1 E).
Scheme 1. Selected state-of-the-art strategies for the synthesis of enantioenriched
organosilanes under organocatalytic conditions and present work.
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Literature survey reveals that there are two details studies[16,17]on organocatalyzed
asymmetric conjugate addition of homologous nitroalkanes to aryl/alkylidene malonates and
only one report[18] on organocatalyzed nitromethane addition to aryl/alkylidene malonates. The
reported[18] conjugate addition of nitromethane to aryl/alkylidene malonates took place with
moderate yields and long reaction time (3-5 days) in presence of 10 mol% catalyst and
nitromethane as a solvent. In addition, bifunctional iminophosphorane catalysed Michael
addition of nitroalkanes to enone diesters is also reported. [19] However, to the best of our
knowledge, organocatalytic asymmetric conjugate addition reaction of nitroalkanes to β-
silylmethylene malonates has not been studied so far. In this paper, we disclose the first
catalytic conjugate addition of nitroalkanes including nitromethane to β-silylmethylene
malonates for the diastereo- and enantioselective synthesis of organosilanes (Scheme 1 E). The
important feature of these conjugate addition products is the presence of different functional
groups which could be useful for downstream synthetic transformation.
RESULTS AND DISCUSSION
Initially, we started the optimization studies by screening readily available bifunctional
hydrogen-bonding organocatalysts[20] I-XII (Figure 2) for the Michael addition reaction
between β-silylmethylene malonate1a and nitromethane 2a in toluene as a solvent. To our
delight, quinidine derived thiourea catalyst I furnished the desired conjugate addition product
3a with 82% yield and 76% ee at 30°C. Whereas the quinidine derived urea catalysts II
delivered the product 3a with similar enantioselectivity but with lower yield (Table 1, entry 2)
due to incomplete reaction. Both the quinine and hydroquinine derived thiourea catalysts III
and IV also delivered the desired product 3a, with opposite configuration, in good yields but
with slight erosion of enantioselectivity compared to quinidine derived catalysts I and II
(Table1, entries 3-4). Cinchonidine derived thiourea catalyst V also produced the product 3a
with slightly better enantioselectivity as compared to catalysts III and IV (Table 1, entry 5).
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European Journal of Organic Chemistry
Interestingly, quinidine derived thiourea catalyst VI bearing a 4-nitrophenyl group afforded the
conjugated addition product 3a with 86% ee (Table 1, entry 6) in good yield 84%. Catalyst
VII, the pseudoenantiomer of catalyst VI, lead to product ent-3a with 79% ee (Table 1, entry
7). The quinidine derived squaramide catalyst VIII provided 3a in 79% yield with 72% ee
(Table 1, entry 8). On the other hand, the quinine derived squaramide catalyst IX furnished the
desired product ent-3a in 78% yield with 60% ee (Table 1, entry 9). Squaramide catalyst X
also yielded the product 3a in 54% yield with 40% ee (Table 1, entry 10). Bifunctional urea
catalyst XI derived from trans-1,2-diaminocyclohexane was not effective as lower ee was
recorded on employment of the catalyst (Table 1, entry 11). Hydroquinine derivative
(DHQ)2PHAL XII was also screened (not included in the Table 1) for the model reaction and
found to be inefficient as 42% consumption (determined from1H NMR of the crude reaction
mixture) of the β-silylmethylene malonate 1a was observed in 24 h at 30°C. From the above
studies, catalyst VI exhibited the best catalytic performance in terms of reaction rate, yield and
enantioselectivity and therefore was chosen for further optimization experiments. With the
optimal catalyst VI, subsequently, solvent screening studies were carried out. Solvent
screening revealed that toluene and dichloromethane (DCM) were the choice of solvents (Table
1, entries 6 and 13). To avoid halogenated solvents, toluene was selected as the reaction
medium for further studies. When the catalyst loading was changed from 10 mol% to 5 mol%,
the enantioselectivity of the 3a and yield almost remained the same (Table 1, entry 6 vs 15).
Lowering the reaction temperature to 0 °C lead to improvement in enantioselectivity of 3a
without much affecting the chemical yield (Table 1, entry 16). When the amount of
nitromethane was reduced from 20 equivalents to 10 equivalents, the chemical yield and
enantioselectivity of 3a remained the almost the same (Table 1, entry 16 vs 17). However, when
the reaction was performed at -10°C with prolonged reaction time, erosion in yield and no
improvement of ee value was observed (Table 1, entry 18). In additional attempt, at 0 °C, upon
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European Journal of Organic Chemistry
decrease of the loading of catalyst VI from 5 mol% to 2.5 mol%, the product 3a still could be
obtained in high yield and enantioselectivity but drop in reaction rate was observed. (Table 1,
entry 19). From the above studies, we set the optimized reaction conditions as: 1a (0.2 mmol,
1 equiv), 2a (2 mmol, 10 equiv), VI (5 mol%) in toluene (0.4 mL) at 0 °C (Table 1, entry 17).
Figure 2. Structures of screened bifunctional organocatalysts.
Table 1. Catalysts Screening and Optimization of Reaction Conditions.[a]
Entry Cat. (mol%)
Solvent
toluene
toluene
toluene
toluene
toluene
Time (h) Yield (%)[b] of 3a %ee[c] of 3a
1
2[d]
3
I (10)
II (10)
III (10)
IV (10)
V (10)
18
48
4
82
74
84
82
81
76
76
73[e]
73[e]
76[e]
4
4
5
6
6
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6
7
VI (10)
VII (10)
VIII (10)
IX (10)
X (10)
toluene
toluene
toluene
toluene
toluene
toluene
THF
6
6
84
83
79
78
54
77
79
82
81
83
83
83
86
79[e]
72
8
10
14
17
12
18
6
9
60[e]
40[e]
52[e]
81
10[f]
11
12
13
14
15
16[g]
17[h]
XI (10)
VI (10)
VI (10)
VI (10)
VI (5)
DCM
86
nitromethane
toluene
toluene
toluene
5
80
9
86
VI (5)
22
24
90
VI (5)
90
18[i]
19[j]
VI (5)
toluene
toluene
48
48
80
77
90
90
VI (2.5)
[a]Reaction conditions: 1a (0.2 mmol), 2a (4 mmol), catalyst (0.02 mmol, 10 mol%) in solvent
0.3mL) at 30 °C. [b] Isolated yield of 3a after column chromatography. [c] Determined by
(
̴
HPLC using chiralpak AD-H column. [d] 90% conversion of the starting material 1a,
1
determined by H NMR analysis of the crude reaction mixture. [e] Opposite enantiomer. [f]
1
75% conversion of the starting material 1a, determined by H NMR analysis of the crude
reaction mixture. [g] The reaction was performed at 0°C, 20 equiv of nitromethane 2a and 0.3
mL of toluene were used. [h] The reaction was performed at 0°C, 10 equiv of nitromethane 2a
and 0.4 mL of toluene were used. [i] The reaction was performed at -10°C, 10 equiv of
nitromethane 2a and 0.4 mL of toluene were used. [j] The reaction was performed at 0°C, 10
equiv of nitromethane 2a and 0.4 mL of toluene were used.
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___________________________________________________________________________
After establishing the optimized conditions, the Michael addition reactions of
nitromethane 2a with different β-silylmethylene malonates 1a-1h (Table 2) were explored. The
β-silylmethylene malonates 1a-1d with the silyl group from dimethylphenylsilyl to methyl-
diphenylsilyl groups, the conjugate addition reactions proceeded smoothly and the
corresponding products 3a-3d were formed with good to excellent yields (72-83%) and good
enantioselectivities (80-90% ee) (Table 2). The β-silylmethylene malonate 1e with the bulky
tert-butyldiphenylsilyl group also participated in the conjugate addition reaction in presence of
20 mol% of catalyst VII at room temperature and the corresponding product 3e was isolated in
67% yield with 65% ee. Furthermore, β-silylmethylene malonate 1f having triphenylsilyl
group also furnished the desired product 3f in 80% yield with 85.5% ee. These results suggest
that as the steric bulk of the silyl group increases the reactivity of β-silylmethylene malonates
decreases. Notably, the β-silylmethylene malonates 1g and 1h with pentamethyldisiloxanyl
group as the silyl moiety also afforded the corresponding products 3g and 3h with excellent
yield (Table 2). In addition, dimethylphenylsilyl allylidine malonate 1i and β-
dimethylphenylsilyl-acrylate 1j remained unreactive under the optimized reaction conditions
(see the supporting information for details). Accessing both the antipode products with similar
level of enantioselectivity is challenging specially the reactions catalysed by Cinchona
alkaloids or their derivatives due to their existence as a single enantiomer.[21] When the Michael
addition reaction of nitromethane 2a with β-silylmethylene malonates 1a was performed in the
presence of 5 mol% of quinine derived catalyst VII, (pseudoenantiomer of the catalyst VI)
under optimized conditions the enantiomeric product ent-3a was obtained in 80% yield with
good enantioselectivity (81% ee). Lowering the reaction temperature offered slight
improvement of enantioselectivity (83% ee) of ent-3a. Therefore, catalyst VII in dry toluene
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at -10°C yielded ent-3a, ent-3b, ent-3c and ent-3f (Table 2) in good yields (77-83%) and
enantioselectivities (76-84.5%).
Table 2. Scope of β-Silylmethylene Malonates.[a]
________________________________________________________________________________
[a]Reaction conditions: For 3a, 3c, 3d, 3g and 3h, 1 (0.2 mmol), 2a (2 mmol), catalyst VI (0.01
mmol, 5 mol%) in dry toluene (0.4 mL) at 0°C. For 3b, 1b (0.2 mmol), 2a (4 mmol), catalyst VI
(0.01 mmol, 5 mol%) in dry toluene (0.3 mL) at 0°C. For ent-3b, 1b (0.2 mmol), 2a (4 mmol),
catalyst VII (0.01 mmol, 5 mol%) in dry toluene (0.3 mL) at -10°C. For ent-3a and ent-3c, 1
(0.2 mmol), 2a (2 mmol), catalyst VII (0.01 mmol, 5 mol%) in dry toluene (0.4 mL) at -10°C.
For 3e, 1 (0.2 mmol), 2a (4 mmol), catalyst VI (0.04 mmol, 20 mol%) in dry toluene (0.3 mL)
at 28-30°C. For 3f, 1f (0.2 mmol), 2a (4 mmol), catalyst VI (0.02 mmol, 10 mol%) in dry toluene
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(0.3 mL) at 0°C. For ent-3f, 1f (0.2 mmol), 2a (4 mmol), catalyst VII (0.02 mmol, 10 mol%) in
dry toluene (0.3 mL) at -10°C. [b]Isolated yield of 3 after column chromatography, 1-5%
̴
substrate 1 was recovered, [c]Determined by HPLC using chiral stationary phase. [d]ee of 3g and
3h could not be determined.
_________________________________________________________________________________________________________________
The conjugate addition product 3f was isolated as a white solid with ee 85.5%. The
optical purity of 3f was improved to >93% ee by single recrystallization. The absolute
configuration of the stereogenic center bearing the silyl group in compound 3f was determined
to be (R) by single crystal X-ray crystallographic analysis (Figure 3).[22] The absolute
configuration of other products 3a-3h were assigned to be (R) in analogy with 3f.
Figure 3. The ORTEP diagram of single crystal X-ray of product 3f (CCDC 1983892).
Next, the scope of the developed conjugate addition reaction was tested with
homologous nitroalkanes. Performing the reaction between β-silylmethylene malonates 1a and
nitroethane 2b (20 equiv) using 5 mol% of the catalyst VI in toluene at 0°C, the product 3ab
was isolated in 64% yield and good enantioselectivity (78%) as well as excellent
diastereoselectivity23(Table 3, entry 1). When the same reaction was carried out at low
temperature (-20°C) in presence of 10 mol% of the catalyst VI, the product 3ab was isolated
in 70% yield with improvement of enantioselectivity (Table 3, entry 2). Under the same
reaction conditions, the nitropropane addition product 3ac was obtained in 75% yield with
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European Journal of Organic Chemistry
excellent diastereoselectivity[23] (98:2) and with 74% ee for the major diastereoisomer 3ac
(Table 3, entry 3).
Table 3. Scope of Nitroalkanes[a]
Entry
Cat.
(mol%)
5
Temp. Nitroalkane Yield (%) of 3 [b]
dr[c]
96:4
96:4
98:2
%ee[d]
78
1
2
3
0 oC
2b
2b
2c
64 (96%)[e]
70 (>99%) [e]
75 (>98%)[e]
10
10
-20 oC
-20 oC
80
74
[a]Reaction conditions: 1a (61 mg, 0.2 mmol), 2 (4 mmol), catalyst VI in toluene. [b] Isolated
yield of both the diastereoisomer after column chromatography. [c]Determined by 1H NMR of
the crude reaction mixture. [d]The ee of major diastereoisomer was determined by HPLC using
a Daicel Chiralcel OD-H column. [e] Conversion of the starting material 1a given in the
parentheses, determined by 1H NMR analysis of the crude reaction mixture.
_________________________________________________________________________
To demonstrate the scalability of the above developed catalytic protocol, large scale
synthesis of 3a and 3ab were carried out. In both the cases the product 3a and 3ab were
obtained with similar level of stereoselectivity (Scheme 2) as compared to small scale reaction.
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Scheme 2. Preparative Scale Synthesis of 3a and 3ab
The practical value of the synthesized organosilanes was exemplified in the asymmetric
total formal synthesis of (R)-oxiracetam, a nootropic drug used in the treatment of Alzheimer’s
diseases,[24] synthesis of (R)-N-benzyl-4-hydroxy-pyrrolidin-2-one, versatile intermediates for
the synthesis of several pharmaceuticals[25] and Sila-analogue of the PAR-2 agonist AC-
264613. [26]
Asymmetric formal total Synthesis of (R)-oxiracetam 7 started with the sodium
borohydride reduction of nitro group of conjugate addition product 3a followed by concomitant
lactamization which yielded the lactam 4 (Scheme 3). The relative trans configuration of the
1
major product 4 was determined from H,1H-NOESY spectrum (details, see supporting
information). Subsequent hydrolysis of the lactam 4 with sodium hydroxide followed by
acidification with 6(N) HCl provided the corresponding acid 5 in 92% yield (Scheme 3). The
decarboxylation of the acid 5 afforded the lactam 6 with 75% isolated yield and 87% ee
(Scheme 3). The absolute stereochemistry of the chiral center at C(4) in 6 was assigned to be
(R) by comparing the specific optical rotation value of 6 with that reported in the
literature[27] ([α]D25 = +11.4 (c =0.8; CHCl3, ee = 87%), lit.[25] [α]D28 = +17.9 (c = 1.00, CHCl3).
Therefore, the absolute configuration of its progenitor 3a was also assigned to be (R). With the
lactam 6 as the advanced intermediate in hand, (R)-oxiracetam 7 could be easily accessed in
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two steps using commercially available reagents following the synthetic route developed by
the Procter group. [27]
Scheme 3. Asymmetric Formal Total Synthesis of (R)-Oxiracetam 7.
Chiral 4-hydroxy-pyrrolidin-2-one and its N-substituted derivatives are key
intermediate for the synthesis of many pharmaceuticals[25,27] and alkaloids. [28] Lactam 6 can be
easily transformed to N-substituted derivatives of 4-hydroxy-pyrrolidin-2-one. N-alkylation of
lactam 6 by benzyl bromide furnished 8 with 82% yield (Scheme 4). [29] Subsequently, the
dimethyl(phenyl)silyl group in 8 was converted to a hydroxy group (Scheme 4) following the
Tamao–Fleming oxidation[4] with retention of configuration at C(4) chiral center and provided
(R)- N-benzyl-4-hydroxy-pyrrolidin-2-one 9 which can be transformed to (R)-GABOB
10.[25,30] In addition, the opposite enantiomer of 9 is the known intermediate for the preparation
1
of alkaloid (1S,8aS)-octahydroindolizidin-1-ol 11. [28]The H and 13C NMR and specific
rotation value for 9 were in close agreement with those reported values. [30]
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Scheme 4. Asymmetric transformation of lactam 6 to (R)- N-benzyl-4-hydroxy-pyrrolidin-2-
one 9 is shown.
After accomplishing the formal synthesis of (R)-oxiracetam 7 and synthesis of (R)- N-
benzyl-4-hydroxy-pyrrolidin-2-one 9, next, we targeted the asymmetric synthesis of sila-
analogue 13 of the proteinase-activated receptor-2 (PAR-2) agonist AC-264613 (Scheme 5).
The small-molecule 14 was identified as a PAR-2 agonist by a high-throughput screening
process. [26] Incorporation of silicon into drug or bio-active molecules has beneficial effect as
it enhances their lipophilicity, ease membrane permeability and hence bio-availability. [7] The
synthesis of sila-analogue 13 of AC264613 was achieved in two steps starting from the acid 5
(Scheme 5). The reaction of 5 with N-hydroxysuccinimide (NHS) and diisopropylcarbodiimide
(DIPC) produced in situ NHS ester which upon reaction with hydrazine hydrate yielded
hydrazide 12. [31] Subsequent condensation of 12 with 3′-bromoacetophenone in presence of
catalytic amount of acetic acid in methanol furnished the sila-analogue 13 of AC264613
(Scheme 5).
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Scheme 5. Asymmetric transformation of acid 5 to a Sila-analogue 13 of AC264613 is shown.
CONCLUSION
In summary, we have developed the conjugate addition reactions of nitroalkanes to β-
silylmethylene malonates for the straightforward synthesis of enantioenriched organosilanes
with multiple functional handles under mild organocatalytic conditions. The chiral
organosilanes were obtained in good yields and stereoselectivities. To showcase the synthetic
potential of the developed methodology, one of the conjugate addition products was exploited
for the asymmetric formal synthesis of medicinally important molecules such as (R)-
Oxiracetam, synthesis of (R)- N-benzyl-4-hydroxy-pyrrolidin-2-one and Sila-analogue of the
PAR-2 agonist AC-264613.
General experimental
Solvent removal was performed with a rotary evaporator that was connected to a dry ice
condenser. TLC (0.5 mm) was carried out using Merck TLC plate. Column chromatography
1
13
was performed on silica gel (230-400 mesh). The H and C NMR spectroscopic data were
recorded with 500 MHz (1H NMR: 500 MHz, 13C NMR: 125 MHz) Varian spectrometer. The
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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 OJ-H with UV-2075 detector (λ fixed at 254 nm or 220 nm). Melting
points (mp) were measured in a Büchi B-540 apparatus. FTIR was recorded in Bruker tensor
II. All the solvents were dried according to standard procedures and stored over activated
molecular sieves (4 Å) before use. Nitromethane, nitroethane and nitropropane were purchased
from commercial source and used without any purification or drying. The detail procedure for
synthesis of β-silylmethylene malonates 1a-1h, synthesis of catalysts I-XI and procedure for
the preparation of racemic samples 3a-3ac are available in supporting information.
General procedure
General Procedure for the preparation of enantioenriched organosilanes 3a-3d, 3g, 3h
and ent-3a-ent-3c
Under Argon atmosphere, in an oven dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, β-Silylmethylene malonate 1 (0.2 mmol, 1 equiv) and catalyst VI (5 mg,
0.01mmol, 5 mol%) or catalyst VII (5 mg, 0.01mmol, 5 mol%) were dissolved in 0.4 mL of
dry toluene and stirred at room temperature for about 5 min. The reaction mixture was cooled
to 0°C (for 3a-3d and 3g, 3h) or -10 °C (for ent-3a-ent-3c) and stirred for 5 min. Nitromethane
(105 µl, 2 mmol, 10 equiv) was added to the reaction mixture and stirred for 6-24 h. Once the
β-silylmethylene malonate 1 was consumed (monitored by TLC/1HNMR), the reaction mixture
was quenched by addition of saturated aqueous solution of NH4Cl and diluted with
CH2Cl2. The reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel (5% petroleum ether/EtOAc-8%
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petroleum ether/EtOAc) to afford the corresponding products 3a-3d, 3g, 3h and ent-3a- ent-
3c. [It should be noted for 3b and ent-3b, 210 µl (4 mmol, 20 equiv) of nitromethane and 0.3
mL of dry toluene were used.]
(R)-diethyl2-(1-dimethyl(phenyl)silyl)-2-nitroethyl)malonate 3a
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-8% petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (61 mg, 83%). 1H
NMR (500 MHz, CDCl3): δ 7.54-7.52 (m, 2 H), 7.43-7.37 (m, 3 H), 4.76 (dd, J = 15.0, 9.0
Hz, 1 H), 4.47 (dd, J = 14.7, 4.0 Hz, 1 H), 4.14-4.05 (m, 4 H), 3.54 (d, J = 4.5 Hz, 1 H), 2.60
(pent, J = 4.5 Hz, 1 H), 1.25-1.21 (m, 6 H), 0.42 (s, 3 H), 0.41 (s, 3 H); 13C{1H} NMR (125
MHz, CDCl3): δ 168.8, 168.5, 135.4, 134.0 (2 C), 129.9, 128.0 (2 C), 74.6, 61.8, 61.7, 50.3,
25.2, 13.9 (2 C), -3.38, -3.79; The ee was determined by HPLC using a Daicel Chiralpak AD-
H [hexane/i-PrOH (97/3)]; flow rate 1.0 mL/min; λ = 254 nm; τminor = 8.05 min, τmajor = 10.77
24
min, [α]D = -6.5 (c 1.56, CHCl3, ee = 90%); HRMS (ESI) calcd for C17H25NNaO6Si [M +
Na]+: 390.1343, found: 390.1337.
(S)-diethyl2-(1-dimethyl(phenyl)silyl)-2-nitroethyl)malonate ent-3a
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-8% petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (59 mg, 80%). The
ee was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (97/3)]; flow rate
1.0 mL/min; λ = 254 nm; τmajor = 7.89 min, τminor = 10.58 min, [α]D24 = +8.2 (c 2.32, CHCl3, ee
= 83 %).
(R)-diethyl 2-(1-methyldiphenylsilyl)-2-nitroethyl)malonate 3b
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-8%petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (62 mg, 72%).1H
NMR (500 MHz, CDCl3): δ 7.61-7.56 (m, 4 H), 7.46-7.37 (m, 6 H), 4.93 (dd, J = 14.9, 9.6,
Hz, 1 H), 4.50 (dd, J = 14.9, 3.2 Hz, 1 H), 4.05-3.92 (m, 4 H), 3.57 (d, J = 4.3 Hz, 1 H), 3.16-
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3.13 (m, 1 H), 1.20 (t, J = 7.5 Hz, 3 H), 1.16 (t, J = 7.5 Hz, 3 H), 0.73 (s, 3 H); 13C{1H} NMR
(125 MHz, CDCl3): δ 168.7, 168.4, 134.9 (2 C), 134.7 (2 C), 133.3, 133.27, 130.1, 130.0,
128.2 (2 C), 128.1 (2 C), 74.4, 61.8, 61.6, 50.0, 23.5, 13.8, 13.7, -5.0; The ee was determined
by HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (97/3)]; flow rate 1.0 mL/min; λ =
254 nm; τminor = 8.78 min, τmajor = 9.46 min, [α]D26 = -26.9 (c 2.38, CHCl3, ee = 86.5%); HRMS
(ESI) calcd for C22H27NNaO6Si [M + Na]+: 452.1500, found: 452.1492.
(S)-diethyl 2-(1-methyldiphenylsilyl)-2-nitroethyl)malonate ent-3b
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-8%petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (66 mg, 77%). The
ee was determined by HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (97/3)]; flow rate
1.0 mL/min; λ = 254 nm; τmajor = 8.20 min, τminor = 9.12 min, [α]D24 = +30.0 (c 2.37, CHCl3, ee
= 84.5%).
(R)-dimethyl 2-(1-dimethyl(phenyl)silyl)-2-nitroethyl)malonate 3c
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-10% petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (54 mg, 79%).1H
NMR (500 MHz, CDCl3): δ 7.53-7.51 (m, 2 H), 7.42-7.38 (m, 3 H), 4.76 (dd, J = 14.7, 9.2
Hz, 1 H), 4.46 (dd, J = 14.7, 4.0 Hz, 1 H), 3.66 (s, 3 H), 3.64 (s, 3 H), 3.58 (d, J = 4.5 Hz, 1
H), 2.61 (pent, 1 H), 0.42 (s, 3 H), 0.41 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.2,
168.9, 135.1, 134.0 (2 C), 130.0, 128.1 (2 C), 74.5, 52.7, 52.6, 49.8, 25.4, -3.5, -3.9; The ee
was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (97/3)]; flow rate
1.0 mL/min; λ = 220 nm; τminor = 9.75 min, τmajor = 12.32 min; [α]D25 = -4.4 (c 1.23, CHCl3, ee
= 81%); HRMS (ESI) calcd for C15H21NNaO6Si [M + Na]+: 362.1030, found: 362.1034.
(S)-dimethyl 2-(1-dimethyl(phenyl)silyl)-2-nitroethyl)malonate ent-3c
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-10% petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (56 mg, 82%). The
18
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ee was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (97/3)]; flow rate
1.0 mL/min; λ = 220 nm; τmajor = 8.60 min, τminor = 10.35 min; [α]D26 = +5.8 (c 1.66, CHCl3, ee
= 76%).
(R)-dimethyl 2-(1-methyldiphenylsilyl)-2-nitroethyl)malonate 3d
Purified by column chromatography on silica gel (first petroleum ether, then 8% petroleum
1
ether/EtOAc). The above titled compound was isolated as colourless liquid (62 mg, 77 %). H
NMR (500 MHz, CDCl3): δ 7.60-7.55 (m, 4 H), 7.45-7.37 (m, 6 H), 4.94 (dd, J = 14.9, 9.7 Hz,
1 H), 4.50 (dd, J = 14.9, 3.1 Hz, 1 H), 3.62 (d, J = 4.4 Hz, 1 H), 3.57 (s, 3 H), 3.52 (s, 3 H), 3.16-
3.12 (m, 1 H), 0.73 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.0, 168.7, 134.9 (2 C),
134.7 (2 C), 133.1, 133.0, 130.2, 130.1, 128.3 (2 C), 128.2 (2 C), 74.4, 52.6, 52.5, 49.6, 23.8, -
5.1; The ee was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (97/3)];
flow rate 1.0 mL/min; λ = 220 nm; τminor = 12.32 min, τmajor = 15.47 min; [α]D25 = -32.7 (c 1.86,
CHCl3, ee = 80%); HRMS (ESI) calcd for C20H23NNaO6Si [M + Na]+: 424.1187, found:
424.1175.
(R)-dimethyl 2-(1-(tert-butyldiphenylsilyl)-2-nitroethyl)malonate 3e
Under Argon atmosphere, in an oven dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, β-Silylmethylene malonate 1e (76.5 mg, 0.2 mmol, 1 equiv) and catalyst VI (20 mg,
0.04 mmol, 20 mol%) were dissolved in 0.3 mL of dry toluene and stirred at 28°C for about 5
min. Nitromethane (210 µl, 4 mmol, 20 equiv) was added to the reaction mixture and stirred for
72 h at 28-30°C. The reaction mixture was subjected to column chromatography on silica gel(first
petroleum ether, then 5%petroleum ether/EtOAc) to afford the corresponding product 3e as
colourless liquid (60 mg, 67%).1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 6.9 Hz, 2 H), 7.56
(d, J = 7.0 Hz, 2 H), 7.47-7.37 (m, 6 H), 5.34 (dd, J = 15.3, 10.2 Hz, 1 H), 4.67 (dd, J = 15.3,
1.95 Hz, 1 H), 3.81 (d, J = 2.55 Hz, 1 H), 3.67 (s, 3 H), 3.43-3.40 (m, 1 H), 3.23 (s, 3 H), 1.19
(s, 9 H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.3, 168.1, 136.3 (2 C), 136.2 (2 C), 131.4,
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131.0, 130.05, 130.03, 128.01 (2 C), 127.96 (2 C), 74.1, 52.7, 52.0, 48.9, 28.6 (3 C), 22.1, 18.9;
The ee was determined by HPLC using a Daicel Chiralpak AD-H [hexane/i-PrOH (97/3)]; flow
rate 1.0 mL/min; λ = 254 nm; τminor = 8.52 min, τmajor = 9.63 min; [α]D25 = -4.0 (c 2.19, CHCl3,
ee = 65%); HRMS (ESI) calcd for C23H29NNaO6Si [M + Na]+: 466.1656, found: 466.1668.
General Procedure for the preparation of enantioenriched organosilanes 3f and ent-3f
Under Argon atmosphere, in an oven dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, β-Silylmethylene malonate 1f (81 mg, 0.2 mmol, 1 equiv) and catalyst VI (10 mg,
0.02mmol, 10 mol%) or catalyst VI (10 mg, 0.02mmol, 10 mol%) were dissolved in 0.3 mL of
dry toluene and stirred at room temperature for about 5 min. The reaction mixture was cooled to
0°C (for 3f) or -10 °C (for ent-3f) and stirred for 5 min. Nitromethane (210 µl, 4 mmol, 20 equiv)
was added to the reaction mixture and stirred for 72 h. Once the β-silylmethylene malonate 1f
was consumed (monitored by TLC/1HNMR), the reaction mixture was quenched by addition of
saturated aqueous solution of NH4Cl and diluted with CH2Cl2. The reaction mixture was
extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (5% petroleum ether/EtOAc-9% petroleum ether/EtOAc) to afford
the corresponding products as white solid.
(R)-dimethyl 2-(2-nitro-1-(triphenylsily)ethyl)malonate 3f
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-9% petroleum
ether/EtOAc). The above titled compound was isolated as white solid (74 mg, 80%). Mp: 106-
107 °C (EtOAc/petroleum ether); 1H NMR (500 MHz, CDCl3): δ 7.60 (d, J = 7.0 Hz, 6 H), 7.49-
7.46 (m, 3 H), 7.44-7.41 (m, 6 H), 5.27 (dd, J = 15.2, 9.8 Hz, 1 H), 4.64 (dd, J = 15.2, 2.5 Hz, 1
H), 3.85 (d, J = 3.9 Hz, 1 H), 3.59 (s, 3 H), 3.53-3.50 (m, 1 H), 3.28 (s, 3 H); 13C{1H} NMR
(125 MHz, CDCl3): δ 169.1, 168.5, 136.1 (6 C), 131.2 (3 C), 130.4 (3 C), 128.3 (6 C), 74.2,
52.7, 52.2, 49.3, 23.5; The ee was determined by HPLC using a Daicel Chiralpak OD-H
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[hexane/i-PrOH (97/3)]; flow rate 1.0 mL/min; λ = 220 nm; τminor = 10.63 min, τmajor = 13.07
25
min; [α]D = -34.1 (c 0.99, CHCl3, ee = >93.0%); After single recrystallization, the ee of 3f
improved to >93.0%; HRMS (ESI) calcd for C25H25NNaO6Si [M + Na]+: 486.1343, found:
486.1336.
(S)-dimethyl 2-(2-nitro-1-(triphenylsily)ethyl)malonate ent-3f
Purified by column chromatography on silica gel (5% petroleum ether/EtOAc-9% petroleum
ether/EtOAc). The above titled compound was isolated as white solid (77 mg, 83%). mp: 104-
105.5 °C (IPA/n-hexane); The ee was determined by HPLC using a Daicel Chiralpak OD-H
[hexane/i-PrOH (97/3)]; flow rate 1.0 mL/min; λ = 220 nm; τmajor = 9.96 min, τminor = 12.06 min;
[α]D20 = +33.8 (c 1.22, CHCl3, ee = 90%); After single recrystallization, the ee of ent-3f improved
to 90%.
(R)-diethyl 2-(2-nitro-1-(1,1,3,3,3-pentamethyldisiloxanyl)ethyl)malonate 3g
Purified by column chromatography on silica gel (first petroleum ether, then 4% petroleum
1
ether/EtOAc). The above titled compound was isolated as colourless liquid (65 mg, 86%). H
NMR (500 MHz, CDCl3): δ 4.74 (dd, J = 14.8, 8.2 Hz, 1 H), 4.54 (dd, J = 14.8, 4.7 Hz, 1 H),
4.23-4.12 (m, 4 H), 3.63 (d, J = 5.0 Hz, 1 H), 2.30 (dt, J = 8.1, 4.9 Hz, 1 H), 1.27 (td, J = 7.1,
2.6 Hz, 6 H), 0.19 (s, 3 H), 0.17 (s, 3 H), 0.07 (s, 9 H); 13C{1H} NMR (125 MHz, CDCl3): δ
169.0, 168.7, 74.2, 61.8, 61.6, 49.9, 26.8, 13.93, 13.91, 1.7 (3 C), 0.34, 0.21; [α]D25 = +2.48 (c
1.21, CHCl3); HRMS (ESI) calcd for C14H29NNaO7Si2 [M + Na]+: 402.1375, found: 402.1378.
(R)-dimethyl 2-(2-nitro-1-(1,1,3,3,3-pentamethyldisiloxanyl)ethyl)malonate 3h
Purified by column chromatography on silica gel (first petroleum ether, then 7% petroleum
ether/EtOAc). The above titled compound was isolated as colourless liquid (54 mg, 77%).1H
NMR (500 MHz, CDCl3): δ 4.74 (dd, J = 14.8, 8.4 Hz, 1 H), 4.54 (dd, J = 14.8, 4.6 Hz, 1 H),
3.74 (s, 3 H), 3.73 (s, 3 H), 3.69 (d, J = 4.95 Hz, 1 H), 2.32 (pent, J = 4.8 Hz, 1 H), 0.19 (s, 3 H),
0.18 (s, 3 H), 0.08 (s, 9 H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.4, 169.1, 74.2, 52.7, 52.6,
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25
49.5, 27.0, 1.7 (3 C), 0.20, 0.198; [α]D = +5.75 (c 1.4, CHCl3); HRMS (ESI) calcd for
C12H25NNaO7Si2 [M + Na]+: 374.1062, found: 374.1068.
Asymmetric synthesis of 3ab
Under Argon atmosphere, in an oven dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, β-Silylmethylene malonate 1a (61 mg, 0.2 mmol, 1 equiv) and catalyst VI (10 mg,
0.02mmol, 10 mol%) were dissolved in 220 µl of dry toluene and stirred at room temperature
for about 5 min. The reaction mixture was cooled to -20 °C and stirred for 5 min. Nitroethane
(285 µl, 4 mmol, 20 equiv) was added to the reaction mixture and stirred for 48 h at -20 °C.
1
Once the β-silylmethylene malonate 1a was consumed (monitored by HNMR), the reaction
mixture was quenched by addition of saturated aqueous solution of NH4Cl and diluted with
CH2Cl2. The reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude
1
product was analysed by H NMR spectroscopy to determine the diastereomeric ratio (by
integration of 1H-NMR signal: δmajor 0.53 ppm. s, δminor 0.49 ppm. s), then the residue was
purified by column chromatography on silica gel (first petroleum ether, then 3% petroleum
ether/EtOAc) to afford 3ab (almost as a single diastereomer) in 70% (53 mg) yield, colourless
liquid. Data of major diastereomer: 1H NMR (500 MHz, CDCl3): δ 7.64-7.62 (m, 2 H), 7.38-
7.37 (m, 3 H), 4.79-4.72 (m, 1 H), 4.27-4.20 (m, 2 H), 4.18-4.08 (m, 2 H), 3.38 (d, J = 3.6 Hz,
1 H), 2.56 (dd, J = 11.0, 3.6 Hz, 1 H), 1.41 (d, J = 6.6 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.27
(t, J = 7.2 Hz, 3 H), 0.53 (s, 3 H), 0.34 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 169.0,
168.7, 138.5, 134.0 (2 C), 129.3, 128.0 (2 C), 85.3, 62.0, 61.7, 51.5, 31.9, 20.4, 14.0, 13.9, -
0.7, -3.1; The ee of major diastereomer was determined by HPLC using a Daicel Chiralcel OD-
H [hexane/i-PrOH (97/3)]; flow rate 0.5 mL/min; λ = 220 nm; τminor = 10.18 min, τmajor = 21.68
min; [α]D25 = -39.0 (c 2.67, CHCl3, ee = 80%); HRMS (ESI) calcd for C18H27NNaO6Si [M +
Na]+: 404.1500, found: 404.1509.
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Asymmetric synthesis of 3ac
Under Argon atmosphere, in an oven dried 5 mL round-bottom flask equipped with a magnetic
stirring bar, β-Silylmethylene malonate 1a (61 mg, 0.2 mmol, 1 equiv) and catalyst VI (10 mg,
0.02mmol, 10 mol%) were dissolved in 140 µl of dry toluene and stirred at room temperature
for about 5 min. The reaction mixture was cooled to -20 °C and stirred for 5 min. Nitropropane
(356 µl, 4 mmol, 20 equiv) was added to the reaction mixture and stirred for 144 h. Once the
β-silylmethylene malonate 1a was consumed (monitored by 1HNMR), the reaction mixture was
quenched by addition of saturated aqueous solution of NH4Cl and diluted with CH2Cl2. The
reaction mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was
analysed by 1H NMR spectroscopy to determine the diastereomeric ratio (by integration of 1H-
NMR signal: δmajor 0.51 ppm. s, δminor 0.48 ppm. s and δmajor 0.32 ppm. s, δminor 0.41
ppm. s), and % of conversion of 1a (> 99% conversion of 1a after 144h as measured by 1HNMR
of the crude reaction mixture). The reaction mixture was subjected to column chromatography
on silica gel (first petroleum ether, then 3% petroleum ether/EtOAc) to afford the
corresponding product (almost as a single diastereomer) 3ac, colourless liquid 3ac (59 mg, 75
1
%). Data of major diastereomer: H NMR (500 MHz, CDCl3): δ 7.64-7.63 (m, 2 H), 7.38-
7.37 (m, 3 H), 4.51 (td, J = 10.7, 3.0 Hz, 1 H), 4.32-4.22 (m, 2 H), 4.20-4.08 (m, 2 H), 3.39 (d,
J = 3.3 Hz, 1 H), 2.51 (dd, J = 11.0, 3.3 Hz, 1 H), 1.77-1.64 (m, 2 H), 1.32 (t, J = 7.1 Hz, 3 H),
1.27 (t, J = 7.2 Hz, 3 H), 0.76 (t, J = 7.3 Hz, 3 H), 0.51 (s, 3 H), 0.32 (s, 3 H); 13C{1H} NMR
(125 MHz, CDCl3): δ 169.1, 168.8, 138.8, 134.0 (2 C), 129.2, 127.9 (2 C), 92.4, 62.0, 61.7,
51.4, 30.9, 27.4, 14.0, 13.9, 10.7, -0.5, -3.5; The ee of major diastereomer was determined by
HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (97/3)]; flow rate 1.0 mL/min; λ = 220
24
nm; τminor = 4.50 min, τmajor = 10.47 min; [α]D = -34.0 (c 1.93, CHCl3, ee =74%); HRMS
(ESI) calcd for C19H29NO6SiK [M + K]+: 434.1401, found: 434.1413.
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Preparative Scale Synthesis of 3a
Under Argon atmosphere, in an oven dried 25 mL round-bottom flask equipped with a
magnetic stirring bar, β-Silylmethylene malonate 1a (612 mg, 2 mmol, 1 equiv) and catalyst
VI (50 mg, ~0.10 mmol, 5 mol%) were dissolved in 4 mL of dry toluene and stirred at room
temperature for about 5 min. Then, the reaction mixture was cooled to 0°C and stirred for 5
min. Then nitromethane 2a (1.1 mL, 20 mmol, 10 equiv) was added to the reaction mixture
and stirred for 24 h. the reaction mixture was quenched by addition of saturated aqueous
solution of NH4Cl and diluted with CH2Cl2. The reaction mixture was extracted with CH2Cl2
(3 × 70 mL). The combined organic layers were dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was purified by column
chromatography on silica gel (5% petroleum ether/EtOAc-8% petroleum ether/EtOAc) to
afford the corresponding products 3a in 0.61 g (83% yield).
Preparative Scale Synthesis of 3ab
Under Argon atmosphere, in an oven dried 25 mL round-bottom flask equipped with a
magnetic stirring bar, β-Silylmethylene malonate 1a (306 mg, 1.0 mmol, 1 equiv) and catalyst
VI (50 mg, 0.1mmol, 10 mol%) were dissolved in 1.1mL of dry toluene and stirred at room
temperature for about 10 min. The reaction mixture was cooled to -20 °C and stirred for 5 min.
Nitroethane (1.4 mL, ~20 mmol, 20 equiv) was added to the reaction mixture and stirred for
48 h at -20 °C. Once the β-silylmethylene malonate 1a was consumed (monitored by 1HNMR),
the reaction mixture was quenched by addition of saturated aqueous solution of NH4Cl and
diluted with CH2Cl2. The reaction mixture was extracted with CH2Cl2 (3 × 40 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced
1
pressure. The crude product was analysed by H NMR spectroscopy to determine the
diastereomeric ratio (by integration of 1H-NMR signal: δmajor 0.53 ppm. s, δminor 0.49 ppm.
s), then the residue was purified by column chromatography on silica gel (first petroleum ether,
24
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European Journal of Organic Chemistry
then 3% petroleum ether/EtOAc) to afford 3ab (almost as a single diastereomer) in 68% (260
mg) yield, colourless liquid.
(3R,4R)-ethyl 4-(dimethyl(phenyl)silyl)-2-oxopyrrolidine-3 carboxylate 4
Under Argon atmosphere, to a suspension of 3a (632 mg, 1.72 mmol) and NiCl2•6H2O (450
mg, 1.89 mmol) in MeOH (8.0 mL) was added NaBH4 (780 mg, 20.6 mmol) carefully at 0 °C.
The reaction mixture was stirred at 0 °C for 5 h. The reaction mixture was passed through a
pad of Celite and silica gel and flushing with 150 mL of 5% MeOH/CH2Cl2. The solvent was
removed under reduced pressure and the residue was directly subjected to column
chromatography on silica gel (first CH2Cl2 then 3% MeOH/ CH2Cl2) to afford 4 as a red liquid
(346 mg, 69%). It should be noted that diastereomer ratio of the crude could not be determined
1
but after column chromatography the product 4 was isolated as a single diastereomer. H
NMR (500 MHz, CDCl3): δ 7.48-7.46 (m, 2 H), 7.39-7.36 (m, 3 H), 6.74 (bs, 1 H), 4.15-4.10
(m, 2 H), 3.43 (t, J = 9.5 Hz, 1 H), 3.22-3.17 (m, 2 H), 2.40 (q, J = 9.5 Hz, 1 H), 1.23 (t, J =7.2
Hz, 3 H), 0.33 (s, 6 H); 13C{1H} NMR (125 MHz, CDCl3): δ 174.5, 170.3, 135.2, 133.8 (2
27
C), 129.7, 128.1 (2 C), 61.6, 49.9, 42.5, 26.0, 14.0, -5.0, -5.2; [α]D = +30.9 (c 1.0, CHCl3);
HRMS (ESI) calcd for C15H22NO3Si [M + H]+: 292.1369; found: 292.1371
(3R,4R)-4-(dimethyl(phenyl)silyl)-2-oxopyrrolidine-3 carboxylic acid 5
To a stirred solution of 4 (330 mg, 1.13 mmol) in EtOH (5.0 mL) was added aq. NaOH 1N (1.5
mL, 1.32 equiv) dropwise at 0 °C. After completion of addition, the cold bath was removed.
The reaction mixture was stirred at room temperature for 90 min. The reaction mixture
concentrated, acidified with HCl (6N) and extracted with EtOAc (4 x 20 mL). The combined
organic phases were dried over sodium sulfate, filtered and concentrated under reduced
pressure. The acid 5 was isolated as a light-brown solid (272 mg, 92% yield). 1H NMR (500
MHz, CD3OD): δ 7.54-7.52 (m, 2 H), 7.38-7.37 (m, 3 H), 4.89 (bs, 2 H), 3.43 (t, J = 9.6 Hz, 1
25
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H), 3.22 (t, J = 9.7 Hz, 1 H), 3.18 (d, J = 10.5 Hz, 1 H), 2.34 (q, J = 10.2 Hz, 1 H), 0.36 (s, 3
H), 0.35 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3): δ 176.7, 173.8, 136.8, 135.0 (2 C),
130.7, 129.1(2 C), 51.6, 43.7, 27.4, -4.7, -5.2; IR (ATR): 3280, 1719, 1663,1285, 1251, 1110,
852, 829 cm-1; HRMS (ESI) calcd for C13H17NO3Si [M - H]-: 262.0898; found: 262.0898.
(R)-4-(dimethyl(phenyl)silyl)pyrrolidine-2-one 6
The acid 5 (263 mg, 1.0 mmol), without any further purification, was dissolved in toluene (10
mL) and refluxed for 16h. The reaction mixture was brought to room temperature and then
concentrated under reduced pressure. The residue was directly subjected to column
chromatography on silica gel (first 50% EtOAc/petroleum ether then EtOAc) to afford 6 as a
1
white solid (165 mg, 75%). Mp: 89-90 °C (EtOAc/petroleum ether); H NMR (500 MHz,
CDCl3): δ 7.48-7.47 (m, 2 H), 7.39-7.36 (m, 3 H), 6.61 (bs, 1 H), 3.41 (t, J = 9.3 Hz, 1 H),
3.27 (t, J = 9.6 Hz, 1 H), 2.35 (dd, J = 16.9, 9.8 Hz, 1 H), 2.18 (dd, J = 16.9, 11.0 Hz, 1 H),
1.93 (pent, , J = 9.5 Hz, 1 H), 0.33 (s, 3 H), 0.32 (s, 3 H); 13C{1H} NMR (125 MHz, CDCl3):
δ 179.7, 136.2, 133.7 (2 C), 129.5, 128.0 (2 C), 44.1, 32.0, 21.2, -4.9, -5.2; [α]D25 = +11.4 (c
28
0.8, CHCl3, ee = 87%) lit.27 [α]D = +17.9 (c = 1.00, CHCl3); The ee of was determined by
HPLC using a Daicel Chiralcel OD-H [hexane/i-PrOH (80/20)]; flow rate 1.0 mL/min; λ = 220
nm; τmajor = 8.51 min, τminor = 10.63 min; HRMS (ESI) calcd for C12H18NOSi [M + H]+:
220.1152, found: 220.1152.
(R)-1-benzyl-4-(dimethyl(phenyl)silyl)pyrrolidine-2-one 8
Under Argon atmosphere, in an oven dried 25 mL round-bottom flask equipped with a
magnetic stirring bar, sodium hydride (52 mg, 50% in oil, 1.1 mmol, 1.5 equiv.) was made oil
free by washing with dry hexane and then 2 mL of dry THF was added. To this stirred
suspension of sodium hydride solution sequentially, a solution of 18-crown-6 in 0.5 mL of dry
THF, lactam 6 (160 mg, 0.73 mmol, 1 equiv) in 2.0 mL of dry THF and benzyl bromide (96
26
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10.1002/ejoc.202000306
European Journal of Organic Chemistry
µl, 0.80 mmol, 1.1 equiv) in 1.0 mL of dry THF were added at 0 °C. After the addition, the
cold bath was removed and then the reaction mixture was stirred at 32 °C for 2h. The reaction
mixture was quenched with water (8 mL) and extracted with CHCl3 (3× 15 mL). The combined
extract was washed with brine, dried over anhydrous magnesium sulphate, filtered and
concentrated under reduced pressure. The residue was directly subjected to column
chromatography on silica gel (10% EtOAc/petroleum ether to 25% EtOAc/petroleum ether) to
afford 8 (185 mg, 82%) as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.44-7.43 (m, 2
H), 7.40-7.26 (m, 6 H), 7.19 (d, J = 7.2 Hz, 2 H), 4.56 (d, J = 14.8 Hz, 1 H), 4.25 (d, J = 14.8
Hz, 1 H), 3.31 (t, J = 9.5 Hz, 1 H), 3.15 (t, J = 9.4 Hz, 1 H), 2.55 (dd, J = 17.0, 10.0 Hz, 1 H),
2.34 (dd, J = 16.9, 10.6 Hz, 1 H), 1.76 (pent, J = 9.8 Hz, 1 H), 0.29 (3 H), 0.28 (3 H); 13C{1H}
NMR (125 MHz, CDCl3): δ 175.1, 136.5, 136.1, 133.6 (2 C), 129.5, 128.6 (2 C), 128.0 (2 C),
127.9 (2 C), 127.4, 48.4, 46.6, 39.9, 17.7, -4.9, -5.3; [α]D25= -4.3 (c = 3.1, CHCl3); HRMS
(ESI) calcd for C19H24NOSi [M + H]+: 310.1633, found: 310.1627.
(R)-1-benzyl-4-hydroxypyrrolidine-2-one 9
Potassium bromide (32 mg, 0.32 mmol, 1.2 equiv), sodium acetate (33 mg, 0.41 mmol, 1.5
equiv) and lactam 8 (84 mg, 0.27 mmol, 1 equiv) were stirred at 0 °C. To this mixture was
dropwise added peracetic acid (̴ 32% solution in acetic acid, 3 mL). The reaction mixture was
warmed slowly to room temperature and stir for overnight. Sodium thiosulphate (solid) 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 a pad of Na2SO4. The organic solvent was evaporated
under reduced pressure. The residue was directly subjected to column chromatography on silica
gel (EtOAc) to afford 9 (33 mg, 64%) as a white solid. mp: 103-104°C; lit.[30] for (S)-enatiomer,
1
107.5–109°C; H NMR (500 MHz, CDCl3): δ 7.33-7.30 (m, 2 H), 7.28-7.25 (m, 1 H), 7.22
(d, J = 7.3 Hz, 2 H), 4.48 (d, J = 14.8 Hz, 1H), 4.45-4.42 (m, 1 H), 4.40 (d, J = 14.8 Hz, 1H),
27
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10.1002/ejoc.202000306
European Journal of Organic Chemistry
3.48 (dd, J = 10.9, 5.6 Hz, 1H), 3.36 (bs, 1 H), 3.19 (d, J = 10.9 Hz, 1H), 2.70 (dd, J = 17.4,
6.6 Hz, 1H), 2.43 (dd, J = 17.4, 1.7 Hz, 1H), 13C{1H} NMR (125 MHz, CDCl3): δ 173.2,
135.9, 128.7 (2 C), 127.9 (2 C), 127.6, 64.1, 55.7, 46.3, 41.1; [α]D25= +38.0 (c = 1.22, CHCl3),
lit.[30] for (S)-enatiomer [α]D20 = -35.2 (c = 1.30, CHCl3); IR (ATR): 3287, 1651, 1482, 1442,
1422, 1406, 1285, 1212, 1084, 974, 737 cm-1; HRMS (ESI) calcd for C11H14NO2 [M + H]+:
192.1026, found: 192.1025.
(3R,4R)-4-(dimethyl(phenyl)silyl)-2-oxopyrrolidine-3-carbohydrazide 12
The solution of DIPC (124 µl, 0.79 mmol, 1 equiv) in dry THF (2mL) was added dropwise to
a stirred solution of the acid 5 (208 mg, 0.79 mmol) and N-hydroxysuccinimide (109 mg, 0.95
mmol, 1.2 equiv) in dry THF (6.0 mL) at 0 °C under Argon atmosphere. The reaction mixture
was slowly brought to room temperature and stirred for overnight. The suspension was filtered
and residue was washed with diethyl ether (2 x 0.5 mL). The filtrate was added dropwise at
0°C to a solution of hydrazine hydrate (130 µl) in THF (0.5 mL) and the mixture was stirred
for 2 h at 5°C. The reaction mixture was filtered and residue was washed with diethyl ether (2
× 0.5 mL). The solvent was removed under reduced pressure and the residue was directly
subjected to column chromatography on silica gel (CH2Cl2 to 7% MeOH/ CH2Cl2) to afford 12
1
(120 mg, 55%) as thick liquid. H NMR (500 MHz, CDCl3): δ 8.36 (bs, 1 H), 7.48-7.47 (m,
2 H), 7.36-7.35 (m, 3 H), 6.71-6.67 (m, 1 H), 3.40 (t, J = 9.7 Hz, 1 H), 3.17 (t, J = 9.4 Hz, 1
H), 2.99 (d, J = 10.5 Hz, 1 H), 2.48 (q, J = 9.5 Hz, 1 H), 0.35 (s, 3 H), 0.34 (s, 3 H); 13C{1H}
NMR (125 MHz, CDCl3): δ 175.8, 169.2, 135.7, 133.9 (2 C), 129.7, 128.1 (2 C), 48.3, 42.7,
23.0, -4.5, -5.0; IR (ATR): 3232, 1691, 1654, 1424, 1253, 1112, 882, 735 cm-1; HRMS (ESI)
calcd for C13H19N3NaO2Si [M + Na]+: 300.1147, found: 300.1147.
28
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10.1002/ejoc.202000306
European Journal of Organic Chemistry
(3R, 4R, E)-N′-(1-(3-bromophenyl)ethylidene)-4-(dimethyl(phenyl)silyl)-2oxopyrrolidine-3-
carbohydrazide 13
3′-bromoacetophenone (49 µl, 0.37 mmol, 1 equiv) was added drop wise to a stirred solution
of 12 (103 mg, 0. 37 mmol, 1 equiv) and acetic acid (2 drops) in 2 mL dry ethanol. The reaction
mixture was stirred at 30 °C for 48h. The solvent was removed under reduced pressure and the
residue was directly subjected to column chromatography on silica gel (CH2Cl2 to 3% MeOH/
CH2Cl2) to afford 13 (144 mg, 85%) as a white solid. [The product 13 exists as a E/Z
mixture31and could not be separated in column chromatography or by crystallization]. (The
product was contaminated with small amount of inseparable unidentified impurities which
could be separated by single recrystallization). Mp: 174-175 °C (EtOAc/petroleum ether); 1H
NMR (500 MHz, CDCl3, E/Z mixture): δ 10.8 (s, 1H, major), 9.0 (bs, 1 H, minor), 7.97 (s, 1
H, major), 7.85 (s, minor), 7.73 (d, J = 8.0 Hz, 1 H, major), 7.59 (d, J = 7.8 Hz, 1 H, minor),
7.54-7.51 (m, 2 H, major), 7.48 (d, J = 7.8 Hz, 1 H, major), 7.43 (d, J = 7.0 Hz, 1 H, major),
7.38-7.36 (m, 3 H, major), 7.38-7.36 (m, 1 H, minor), 7.28-7.21 (m, 6 H, minor), 6.37 (bs, 1
H, minor), 6.23 (bs, 1 H, minor), 4.48 (d, J = 11.7 Hz, 1 H, minor), 3.49 (t, J = 9.2 Hz, 1 H,
minor), 3.39 (t, J = 10.0 Hz, 1 H, major), 3.30 (t, J = 9.9 Hz, 1 H, minor), 3.25-3.20 (m, 2 H,
major), 2.59 (q, J = 10.4 Hz, 1 H, minor), 2.51 (q, J = 9.9 Hz, 1 H, major), 2.26 (s, 3 H, major),
2.16 (s, 3 H, minor), 0.48 (s, 3 H, major), 0.44 (s, 3 H, major), 0.34 (s, 3 H, minor), 0.33(s, 3
H, minor); 13C{1H} NMR (125 MHz, CDCl3, E/Z mixture): 176.3 (major), 175.7 (minor),
172.7 (minor), 164.3 (major), 150.7 (major), 146.7 (minor), 139.83 (major), 139.78 (minor),
135.8 (major), 135.4 (minor), 134.0 (2 C, major), 133.9 (2 C, minor), 132.3 (major), 132.2
(minor), 129.9 (minor), 129.7 (major), 129.5 (2 C, major), 129.2 (minor), 128.0 (2 C, major),
127.9 (2C, minor), 125.2 (major), 124.9 (minor), 122.6 (minor), 122.5 (major), 48.2 (major),
46.2 (minor), 42.7 (major), 26.3 (minor), 22.4 (major), 13.6 (major), 13.0 (minor), -3.9 (major),
-4.7 (major), -4.8 (minor), -5.0 (minor); [α]D22= +120.0 (c = 2.7, CHCl3, after single
29
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