Chapter 7
Copper Catalyzed Asymmetric
Conjugate Addition of Grignard
Reagents to Į-Methyl Cyclic
Enones
In this chapter the first catalytic enantioselective Grignard addition to Į-methyl
substituted cyclic enones is described.
Parts of this chapter will be submitted for publication: Madduri, A. V. R.; Feringa, B.
L.; Minnaard, A. J.; Harutyunyan, S. R. 2012.
Chapter 7
7.1 Introduction
The stereoselective formation of two chiral centers in one step is a rewarding
process in synthetic organic chemistry. In principle, asymmetric conjugate addition
reactions, such as the copper-catalyzed addition of organometallics, are suitable
for this goal.1-4
A logic approach in this regard is to trap the enolate, resulting from the addition
reaction, with an electrophile to create two stereocenters in one step. For cyclic
enones, like cyclohexenone, this reaction is known for a long time, and leads to
reasonable, though not excellent, stereoselectivities (Scheme 1).5-8 More recently,
also linear substrates have been used with success, a special mention deserves
the conjugate addition-aldol reaction to Į,ȕ-unsaturated thioesters by Howell et al.9
Scheme 1: Enolate trappings with electrophiles
An obvious alternative is the asymmetric conjugate addition to substrates that
already have a substituent ( H) at the Į-position. This has turned out, however, to
be a remarkably difficult reaction to achieve.10-13 The copper-catalyzed asymmetric
conjugate addition to unsaturated malonates is known,14 as well as scattered
reports on other doubly activated Michael acceptors.15,16 Only recently, however,
the first report on the successful conjugate addition to 2-methyl cyclohexenone
appeared from the group of Alexakis, using trialkylaluminum reagents (Scheme
2).17,18 The reason for the reluctant behavior of 2-methyl cyclohexenone, compared
178
Conjugate addition of Grignard to Į-substituted enones
O
+
R3Al
CuTC 2 mol%
Ligand 2 4 mol%
Et2O, -30 oC, 18 h
R = Et and Me
O
R
dr's = up to 77:23
ee's up to 93%
O
P N
O
(Ra,Sc,Sc)-Phosphoramidite 2
Scheme 2: Cu-catalyzed asymmetric 1,4-addition of trialkylaluminium reagents with a copperphosphoramidite catalyst
to cyclohexenone, in asymmetric conjugate addition reactions could be the
attenuated coordination of the copper catalyst to the enone.19 Moreover, the
formed enolate during the conjugate addition reaction of 2-methyl cyclic enones
can result in two diastereomeric products, trans and cis, upon electrophilic
quenching, in this case protonation. In most cases the thermodynamically favored
trans product was observed as a major product.17 Very importantly, when the
enolate is quenched with electrophiles other than a proton this leads to valuable
quaternary stereo centers in the resulting product.
Next to the Cu-catalyzed conjugate addition of diorganozinc and
triorganoaluminum reagents, the use of Grignard reagents in this reaction is
important, mainly because of the availability of the latter. A representative example
uses Cu-TaniaPhos as the catalyst, as depicted in Scheme 3.20 This reaction is
especially suited for the addition of alkyl Grignard reagents, leading to the
corresponding chiral conjugate addition products in high yields and with excellent
enantiomeric excess.
179
Chapter 7
Scheme 3: Cu-catalyzed asymmetric 1,4-addition of Grignard reagents with TaniaPhos
The advantage of using Grignard reagents, prompted us to study whether this
reaction could be used for the conjugate addition to D-alkyl substituted
cyclohexenone as well.2 As shown in the previous chapters, the combination of
CuBr with rev-JosiPhos catalyzes the 1,2-addition of Grignard reagents to Įmethyl-substituted acyclic enones providing tertiary allylic alcohols with
enantioselectivities up to 96% (Scheme 4).21 Surprisingly, in the course of this
study, we found that the corresponding Į-methyl-substituted cyclic enones gave
conjugate addition products with promising stereoselectivities.
Scheme 4: Catalytic asymmetric 1,2-additon to Į-substituted Į,ȕ-unsaturated ketones
7.2 Results and Discussion
With this result in hand, we further explored this reaction by varying the ligand and
the Grignard reagent. The first step was to identify the influence of the structure of
180
Conjugate addition of Grignard to Į-substituted enones
the ligand, and the preference for 1,4-addition over 1,2-addition (Table 1). In
addition to the formation of the desired 1,4-product 3 via conjugate addition, the
Grignard reagent can enolise the substrate 1, form via ȕ-hydride transfer the
corresponding secondary alcohol 5, or lead to the 1,2-product 4 via direct
addition.22 Literature precedent shows that the ligand as well as the substitution
pattern of the substrate plays a decisive role in the preference for these
pathways.23 Therefore, the substrate 2-methylcyclohex-2-enone 1 was studied in
the copper catalyzed addition of ethylmagnesium bromide with a range of
ferrocenyl diphosphine ligands24 and other chiral ligands. By using the established
copper-catalyzed 1,2-addition conditions we were pleased to find that in the
presence of 5 mol% CuBr•SMe2/L1, the reaction proceeded with excellent 1,4regioselectivity and an ee of 40% for product 2 (Table 1, entry 1). In the presence
of 5 mol% of a copper(I) salt only, the reaction proceeded with complete lack of
chemoselectivity providing a mixture of products (Table 1, entry 2). This shows the
influence of the chiral ligand on the chemo- and regioselectivity. Subsequently,
ligands and copper precursors were varied, the results of which are presented in
Table 1. Ligand L2 in combination with copper iodide showed to be promising in
asymmetric conjugate addition reactions. This catalyst in the present conjugate
reaction proceeds with moderate selectivities (entry 3). Further, L3/CuCl has
shown excellent results in the asymmetric conjugate addition of Grignard reagents
to cyclic enones.20 However, L3/CuCl and L3/CuBr•SMe2 at different reaction
temperatures gave only modest regioselectivities and racemic product (entries 47). The reaction performed with ligand L5 (Josiphos)/CuBr·SMe2 proceeded with
good regioselectivity and poor enantioselectivities for the both 1,2 and 1,4 adducts
(Table 1, entries 8). As phosphoramidite ligands had shown to be successful in the
conjugate addition of trialkylaluminum reagents by Alexakis and coworkers,17,25
also these were incorporated in the screening but without success (entries 9 and
10). A further screening of several other ligands L7-L10 (entries 11 and 14) did not
show good results as well, compared to rev-JosiPhos L1. It is clear that both in
terms of 1,4-selectivity and stereoinduction, ligand L1/CuBr•SMe2 is remarkably
effective compared to other members of the ferrocenyl ligand family as well as to
biaryl-based chiral ligands L2, and L8.
181
Chapter 7
EtMgBr
Copper salt 5 mol%
Ligand 6 mol%
O
O
OH
HO
+
+
tBuOMe, -78 oC
3a
1,4-product
1
4
1,2-product
5
1,2-reduction
Table 1: 1,4-addition of Grignard reagents to 2-methylcyclohex-2-enone 1 with various ligands
Ligands
Ph2P
Me2N
Ph2P
Cy2P
Rev-Josiphos
(S,RFe)-L1
PCy2
Ph2P
(Tol)2P
(Tol)2P
Fe
Fe
Fe
JosiPhos
(R,SFe)-L4
TaniaPhos
(R,RFe)-L3
(R)-TolBinap
L2
PPh2
P(tBu)2
O
P N
O
O
P N
O
(Sa,Sc,Sc)-Phosphoramidite
L5
PPh2
Fe
(Ra,Sc,Sc)-Phosphoramidite
L6
Josiphos-type
(R,SFe)-L7
F3C
Me2N
Ph2P
Ph2P
PPh2
PPh2
MeO
MeO
Meo-Biphep-type
R-L8
Entrya
Ligand
CF3
Fe
Fe
P
CF3
Me2N Ph P
2
Walphos-type
(R,RFe)-L10
Mandyphos-type
(R,SFe)-L9
Copper salt
3a:4:5
F3C
trans/cis ratio, ee of major
trans isomer 3ab,c
1
182
L1
CuBr•SMe2
96:3:1
81/19, 40%
Conjugate addition of Grignard to Į-substituted enones
2
-
CuBr•SMe2
38:56:6
-
3
L2
CuI
73:26:1
80/20, 21%
4
L3
CuCl
29:62:9
59/41, 0%
5d
L3
CuCl
42:56:2
66/44, 0%
6
L3
CuBr•SMe2
35:64:1
79/21, 0%
7d
L3
CuBr•SMe2
21:79:0
74/26, 0%
8
L4
CuBr•SMe2
61:37:2
79/21, 9%
9
L5
CuBr•SMe2
94:5:1
80/20, 4%
10
L6
CuBr•SMe2
91:9:0
81/21, 10%
11
L7
CuBr•SMe2
65:32:3
80/20, 8%
12
L8
CuBr•SMe2
91:6:3
80/20, 25%
13
L9
CuBr•SMe2
94:4:2
80/20, 3%
14
L10
CuBr•SMe2
95:5:0
79/21, 6%
15e
L1
CuBr•SMe2
96:3:1
81/19, 36%
a
Conditions: 5 mol% copper salt, 6 mol% Ligand, 1.3 eq of RMgBr (3 h addition time), 0.1 M in tBuOMe,
b
c
All conversions determined by (GC-MS). Regio- and enantioselectivities were
–78 °C, 5-10 h.
d
o
e
determined by GC-MS and chiral GC of the crude Reaction performed at 10 C. RMgBr (15 min
addition time).
The influence of the solvent on the selectivity of the 1,4-addition was studied with
the CuBr•SMe2/L1 catalyst. This revealed that ethereal solvents were superior both
in terms of regio- and stereoselectivity of the reaction. tBuOMe was the solvent of
choice for further studies, as in the asymmetric 1,2-additions in the previous
chapters. A small gain in chemo- and enantioselectivity was obtained by switching
from direct to slow addition of the Grignard reagent (Table 1, entry 15). With these
183
Chapter 7
optimized conditions in hand (Table 1, entries 1), the scope of this new reaction
was explored.
Both 2-methyl-cyclohexenone 1, and 2-methyl-cyclopentenone 2 were investigated
in the CuBr•SMe2/L1 catalyzed 1,4-addition reaction (Table 2). In this study we
relied on conversions rather than on isolated yields because of the volatility of the
products, that makes accurate determination of the yields very difficult.
Interestingly, conjugate addition of ethylmagnesium bromide to 2 proceeds with an
excellent conversion, a high regioselectivity in favor of the 1,4-addition and a
rewarding enantioselectivity of 84% ee (Entry 2). When the reaction was performed
at higher temperatures a drastic decrease in regio and enantioselectivity of the
reaction was observed (Entry 3). With this promising result we further explore the
scope of the reaction. 2-Bromo-cyclopentenone underwent conjugate addition
reaction very smoothly but in very poor enantioselectivities (Entry 4).26 The addition
of pentylmagnesium bromide proceed with a good regioselectivity of 88/12 and an
excellent enantiomeric excess of 93% (Entry 5).
Table 2: Conjugate addition of Grignard reagents to 2-methyl-cyclopentenone and 2-methylcyclohexenone
a
Entry
n
RMgBr
3:4:5 (%)
trans/cis, ee of
major trans
isomer ee,
(conversion)
b,c,d
of 3
1
1
96:3:1
3a 81/19,
40(94)
2
184
0
98:1:1
3b 90/10,
Conjugate addition of Grignard to Į-substituted enones
84(96)
3e
99:0:1
0
3b 80/20,
70(98)
4f
0
95:3:2
3c 76/24, 8(95)
5e
0
99:0:1
3d 88/12,
93(98)
MgBr
6
0
96:2:2
3e 87/13,
68(96)g
7
0
99:0:1
3f 84/16, 86(98)
8
1
89:11:0
3g 66/34, 0(81)
9
0
76:24:0
3h 82/18,
55(86)
a
b
Conditions: 5 mol% CuBr•SMe2, 6 mol% L1, 1.3 eq of RMgBr, 0.1 M in tBuOMe, –78 °C, 5-10 h.
c
Conversions were determined by GC-MS. The high volatility of the products did not allow to completely
remove the solvents after the chromatography, frustrating the determination of an accurate isolated
d
e
yield. Regio and enantioselectivities were determined by GC-MS and chiral GC of the crude. Reaction
o
f
g
performed at –60 C. Reaction performed on 2-bromo-cyclopentenone. Isolated yield.
185
Chapter 7
Phenylethylmagnesium bromide was also employed in conjugate addition to 2 and
proceeded with complete conversion and in good regioselectivity but a decreased
enantioselectivity (Entry 6). As this product was less volatile, the isolated yield
could be determined. This showed that the reactions go in virtually quantitative
yield. Butenylmagnesium bromide was also employed successfully, installing a
convenient handle for further functionalization, in high regio and enantioselectivity
(entry 7). Addition of methylmagnesium bromide to 1 proceeded with a complete
lack of enantioselectivity (Entry 8). Interestingly, however, the addition of
methylmagnesium bromide to 2 resulted in the desired conjugate addition product
in 55% ee (Entry 9). Probably due to the lower reactivity of MeMgBr, the reaction
did not go to full conversion. As a comparable jump in ee is observed for the
addition of ethylmagnesium bromide to 2, the conclusion is justified that L1 is
especially suited for conjugate additions to the latter substrate. In the conjugate
addition to cyclohexenone and cyclopentenone, according to literature mostly the
opposite trend is observed.
7.3 Summary and concluding remarks
The results obtained so far point at a remarkable regioselectivity in the conjugate
addition of Grignard reagents to 2-methyl-cyclohexenone and 2-methylcyclopentenone using CuBr/L1, somewhat attenuated in the addition of MeMgBr.
What is unique as well, are the synthetically useful enantioselectivities obtained for
the addition of several Grignard reagents to 2-methyl-cyclohexenone and 2-methylcyclopentenone.
Further research on this reaction should obviously aim at the expansion of the
substrate scope. Also trapping of the enolate formed with an electrophile, not
studied yet due to time constraints, will be very interesting as (all-carbon)quaternary stereocenters can be formed in this way. The current good-but-notexcellent preference for the trans isomer will be difficult to change as it fully
depends on substrate control during the protonation of the enolate. The ratios
observed in this study are comparable to those found in literature.17
7.4 Experimental section
General
Flash chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck
silica gel 60, 0.25 mm. Components were visualized by UV and Seebach’s reagent,
186
Conjugate addition of Grignard to Į-substituted enones
a mixture of phosphomolybdic acid (25 g), cerium (IV) sulfate (7.5 g), H2O (500 mL)
and H2SO4 (25 mL) or potassium permanganate staining. Progress and conversion
of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an
HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). High resolution mass
spectra (HRMS) were recorded on a AEI-MS-902 and FTMS orbitrap (Thermo
Fisher Scientific) mass spectrometer. 1H- and 13C-NMR were recorded on a Varian
AMX400 (400 and 100.59 MHz, respectively) or a Varian Gemini 200, using CDCl3
as solvent. Chemical shift values are reported in ppm with the solvent resonance
as the internal standard (CHCl3: G 7.26 for 1H, G 77.0 for 13C). Data are reported as
follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet), coupling constants (Hz), and integration. Carbon
assignments are based on APT 13C-NMR experiments. Optical rotations were
measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell
(c given in g/100 mL). Enantiomeric excesses were determined by HPLC analysis
using a Shimadzu LC-10ADVP HPLC equipped with a Shimadzu SPD-M10AVP
diode array detector or by capillary GC analysis (HP 6890, CP-Chiralsil-Dex-CB
column (25 m x 0.25 mm) or Chiraldex B-PM (30 m x 0.25 mm x 0.25 ȝm)) using a
flame ionization detector.
All reactions were carried out under a nitrogen atmosphere using oven dried
glassware and using standard Schlenk techniques. tBuOMe and dichloromethane
were dried and distilled from calcium hydride; toluene, THF and n-hexane were
dried and distilled from sodium. All copper salts were purchased from Aldrich, and
used without further purification. All Starting materials and EtMgBr, PentylMgBr
Grignard reagents were purchased from Aldrich. All other Grignard reagents were
prepared from the corresponding alkyl bromides and Mg activated with I2 in Et2O.
Ligand L1-L4 and L7-L10 were purchased from Solvias ligand kit Phosphoramidite
ligand L5 and L6 were prepared as reported in the literature.25 Racemic products
were synthesized by reaction of the ketones 1 with the corresponding Grignard
reagent, copper salt 10 mol% and 20 miol% triphenyl phosphine at rt in Et2O.
Whenever the absolute configuration is indicated, the assignment was based on
comparison with literature data on similar compounds.
General procedures for the copper-catalyzed conjugate addition of Grignard
reagents.
Procedure A:
A Schlenk tube equipped with septum and stirring bar was charged with
CuBr•SMe2 (0.015 mmol, 3.08 mg, 5 mol%) and ligand L1 (0.018 mmol, 6 mol%).
Dry tBuOMe (3 mL) was added and the solution was stirred under nitrogen
atmosphere at rt for 15 min. Then, 1 or 2 (0.3 mmol in 1 mL tBuOMe) was added
and the resulting solution was cooled to –78 °C. The corresponding Grignard
reagent (0.36 mmol, 1.3 eq in Et2O) was diluted with tBuOMe (combined volume of
1 mL) under nitrogen and added to the reaction mixture over 3 h. Once the addition
was complete, the reaction mixture was analyzed by TLC and GC-MS. The
reaction was quenched by the addition of MeOH (1 mL) and saturated aqueous
187
Chapter 7
NH4Cl (2 mL) and the mixture was warmed to rt, diluted with Et2O and the layers
were separated. The aqueous layer was extracted with Et2O (3 x 5 mL) and the
combined organic layers were dried with anhydrous Na2SO4, filtered and the
solvent was evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel using mixtures of n-pentane and Et2O as the eluent.
Note: GC analysis was carried out to determine the 1,4-addition, 1,2-addition and
1,2-reduction ratio on a sample obtained after aqueous workup and extraction with
Et2O, which was passed through a short plug of silica gel to remove copper
residues.
Procedure B:
A Schlenk tube equipped with septum and stirring bar was charged with
CuBr•SMe2 (0.015 mmol, 3.08 mg, 5 mol%) and ligand L1 (0.018 mmol, 6 mol%).
Dry tBuOMe (3 mL) was added and the solution was stirred under nitrogen at room
temperature for 15 min. Then, 1 or 2 (0.3 mmol in 1 mL tBuOMe) was added and
the resulting solution was cooled to –60 °C. The corresponding Grignard reagent
(0.36 mmol, 1.3 eq, in Et2O) was diluted with tBuOMe (combined volume of 1 mL)
under nitrogen and added to the reaction mixture over 3h. Once the addition was
complete, the reaction mixture was analyzed by TLC and GC-MS. The reaction
was quenched by the addition of MeOH (1 mL) and saturated aqueous NH4Cl (2
mL) and the mixture was warmed to room temperature, diluted with Et2O and the
layers were separated. The aqueous layer was extracted with Et2O (3 x 5 mL) and
the combined organic layers were dried with anhydrous Na2SO4, filtered and the
solvent was evaporated in vacuo. The crude product was purified by flash
chromatography on silica gel using mixtures of n-pentane and Et2O as the eluent.
Assignment of absolute configurations:
The absolute configuration of all products was assigned by comparing the sign of
the optical rotation to that of (+)-(2S,3R)-2,3-dimethylcyclopentanone (5)27-29 and
(í)-(2S,3R)-3-ethyl-2-methylcyclohexanone
(6)17
with
known
absolute
configuration.
Chiral GC conditions:
The enantiomeric excess was determined by chiral GC (chiraldex G-TA Grace
Alltech nt. 4139, 30 m, 0,25 mm, 0,125 μm), Detector FID. Temperature programs
were as follows: initial temperature 95 oC, temperature gradient 4 oC/min 5 min
hold time, 125 oC (1 oC/min) 7 min hold time, final temperature (130 oC (0.5 oC/min)
50 min hold time); retention time (RT) are given in min.
188
Conjugate addition of Grignard to Į-substituted enones
(í)-(2S,3R)-3-ethyl-2-methylcyclohexanone (3a):
Using method A: Reaction was performed with (S,RFe)ligand L1 and
EtMgBr. Product 3a was obtained as a colorless oil 96:3:1 mixture of 3a, 4a, and
5a after column chromatography (SiO2, n-pentane:Et2O 90:10), [94% conversion,
trans/cis 81/19, 40% ee major trans diastereomer, 38% ee minor cis diastereomer].
The high volatility of the product 3a did not allow complete removal of the solvents
after the chromatography, hampering the determination of an accurate isolated
yield. The spectral data were identical in all respects to those previously reported.17
[Į]D20 = +5.2 (c = 1.3, CHCl3), [lit.17 (82% ee): [Į]D20 = í12.7 (c = 1.29, CHCl3) for
trans 2R,3S]. Retention times on chiral GC for the major trans diastereomer: 4.4
min (major), 4.6 min (minor)].
(+)-(2S,3R)-3-ethyl-2-methylcyclopentanone (3b):
Using method A: Reaction was performed with (S,RFe)ligand L1 and
EtMgBr. The product was isolated as a colorless oil in a 98:1:1 mixture of 3b, 4b,
and 5b after column chromatography (SiO2, n-pentane:Et2O 90:10), [96%
conversion, trans/cis 90/10, 84% ee major trans diastereomer, 81% ee minor cis
diastereomer]. The high volatility of the product 3b did not allow to completely
remove the solvents after the chromatography, hampering the determination of an
accurate isolated yield. Traces of Et2O were present in the NMR spectra. 1H NMR
(400 MHz, CDCl3) mixture of diastereomers į 2.23 – 2.07 (m, 1H), 2.04 – 1.87 (m,
2H), 1.66 – 1.47 (m, 2H), 1.46 – 1.29 (m, 1H), 1.23 – 1.09 (m, 2H), 0.88 (dd, J =
6.9, 2.5, 3H), 0.80 (t, J = 7.4, 3H). 13C NMR (101 MHz, CDCl3) trans diastereomer
including Et2O į 220.53, 49.94, 46.19, 37.02, 26.85, 26.45, 12.34, 11.13. 13C NMR
(101 MHz, CDCl3) cis diastereomer į 220.56, 49.07, 46.65, 35.81, 24.89, 21.82,
11.91, 9.29. [Į]D20 = +84.1 (c = 2.5, CHCl3). HRMS (ESI+, m/z): calcd for C8H14ONa
[M+Na]+: 149.09369; found: 149.09371. Retention times on chiral GC for the major
trans diastereomer 2.8 min (major), 2.9 min (minor)].
(+)-(2S,3R)-2-methyl-3-pentylcyclopentanone (3d):
Using method A: Reaction was performed with (S,RFe)ligand L1
and pentylmagnesium bromide. Product 3d was obtained as a colorless oil in a
99:0:1 mixture of 3d, 4d, and 5d after column chromatography (SiO2, pentane:Et2O
90:10), [98% conversion, trans/cis 88/12, 93% ee for the major trans diastereomer].
The high volatility of the product 3d did not allow complete removal of the solvents
after chromatography, hampering the determination of an accurate isolated yield
and traces of Et2O are present in NMR spectra. 1H NMR (400 MHz, CDCl3) mixture
189
Chapter 7
of diastereomers į 2.38 – 2.27 (m, 1H), 2.09 (m, 2H), 1.72 – 1.52 (m, 3H), 1.36 –
1.21 (m, 8H), 1.04 (d, J = 6.7, 3H), 0.88 (t, J = 8.1, 3H). 13C NMR (101 MHz,
CDCl3) major trans diastereomer į 221.51, 50.49, 44.82, 37.40, 34.40, 32.05,
27.23, 26.75, 22.60, 14.03, 12.67. [Į]D20 = +27.7 (c = 1.1, CHCl3). HRMS (ESI+,
m/z): calcd for C11H20O+Na [M+Na]+: 191.14064; found: 191.14069. Retention
times on chiral GC for the major trans diastereomer 34.5 min (major), 36.6 min
(minor)].
(+)-(2S,3R)-2-methyl-3-phenethylcyclopentanone (3e):
Using method A: Reaction was performed with (S,RFe)ligand
L1 and phenethylmagnesium bromide. Product 3e was obtained as a colorless oil
in a 96:2:2 mixture of 3e, 4e, and 5e after column chromatography (SiO2, npentane:Et2O 97:03), [96% yield, trans/cis 87/13, 68% ee major trans
diastereomer, 67% ee minor cis diastereomer]. 1H NMR (400 MHz, CDCl3) mixture
of diastereomers į 7.31 – 7.25 (m, 2H), 7.18 (dd, J = 11.6, 4.3, 3H), 2.84 – 2.56
(m, 2H), 2.36 (dd, J = 18.8, 8.6, 1H), 2.27 – 2.17 (m, 1H), 2.06 (m, 2H), 1.80 – 1.54
(m, 3H), 1.50 – 1.38 (m, 1H), 1.06 (d, J = 6.7, 3H). 13C NMR (101 MHz, CDCl3)
trans diastereomer į 220.94, 142.13, 128.87, 126.10, 50.43, 44.36, 37.39, 36.36,
33.46, 27.17, 12.58. 13C NMR (101 MHz, CDCl3) cis diastereomer į 221.39,
128.48, 128.27, 125.91, 46.64, 39.51, 36.31, 34.02, 31.36, 25.57, 9.82. [Į]D20 =
+8.5 (c = 1, CHCl3). HRMS (ESI+, m/z): calcd for C14H18O+H [M+H]+: 203.1430;
found: 203.1430. Retention times on chiral GC for the major trans diastereomer
43.3 min (major), 44.2 min (minor)].
(+)-(2S,3R)-3-(but-3-en-1-yl)-2-methylcyclopentanone (3f):
Using method A: Reaction was performed with (S,RFe)ligand L1
and but-3-en-1-ylmagnesium bromide. Product 3f was obtained as a colorless oil in
a 99:0:1 mixture of 3f, 4f, and 5f after column chromatography (SiO2, npentane:Et2O 90:10), [98% conversion, trans/cis 84/16, 86% ee major trans
diastereomer, 84% ee minor cis diastereomer]. The high volatility of the product 3f
did not allow complete removal of the solvents after the chromatography,
hampering the determination of an accurate isolated yield and traces of Et2O were
present in NMR spectra. 1H NMR (400 MHz, CDCl3) mixture of diastereomers į
5.76 – 5.58 (m, 1H), 4.99 – 4.73 (m, 2H), 2.26 – 2.16 (m, 1H), 2.12 – 1.92 (m, 4H),
1.73 – 1.45 (m, 3H), 1.24 (m, 2H), 0.93 (d, J = 6.6, 3H). 13C NMR (101 MHz,
CDCl3) trans diastereomer į 220.40, 138.28, 114.58, 50.21, 44.05, 37.10, 33.63,
31.17, 26.92, 12.41. 13C NMR (101 MHz, CDCl3) cis diastereomer į 221.22,
138.09, 114.58, 46.49, 39.33, 35.95, 31.71, 28.40, 25.21, 9.57. [Į]D20 = +72.1 (c =
190
Conjugate addition of Grignard to Į-substituted enones
2.7, CHCl3). HRMS (ESI+, m/z): calcd for C10H16O+Na [M+Na]+:175.1093; found:
175.1093. Retention times on chiral GC for the retention time (RT) are given in min,
major trans diastereomer 5.5 min (major), 5.7 (minor)].
(+)-(2S,3R)-2,3-dimethylcyclopentanone (3h):
Using method B: Reaction was performed with (S,RFe)ligand L1
and MeMgBr. Product 3h was obtained as a colorless oil in a 76:24:0 mixture of
3h, 4h, and 5h after column chromatography (SiO2, n-pentane:Et2O 90:10), [86%
conversion, trans/cis 89/11, 55% ee major trans diastereomer, 42% ee minor cis
diastereomer]. The high volatility of the product 3g did not allow complete removal
the solvents after the chromatography, hampering the determination of an accurate
isolated yield. The spectral data were identical in all respects to those reported.
27,28
[Į]D20 = +81.6 (c = 1.8, CHCl3), [lit.
(99% ee): [Į]D20 = +152 (c = 2, CHCl3)].
Retention times on chiral GC for the major trans diastereomer 1.8 min (major), 1.9
min (minor)].
7.5 References
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
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Chapter 7
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192