Regio- and stereocontrol in the michael-initiated ring-closure reactions of γ,δ-epoxy-α,β-unsaturated esters, ketones, sulfones, and amides

Article abstract of DOI:10.1021/jo402075d

Organozincates or Grignard reagents in the presence of zinc catalysts undergo Michael initiated ring closure (MIRC) reactions with γ,δ-epoxy-α,β-enoates, enones, enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of dias

Full text of DOI:10.1021/jo402075d

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Article
Regio- and Stereocontrol in the Michael Initiated Ring
Closure (MIRC) Reactions of gamma,delta-Epoxy-alpha,beta-
unsaturated Esters, Ketones, Sulfones, and Amides
Ramesh C. Dhakal, and R. Karl Dieter
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Nov 2013
Downloaded from http://pubs.acs.org on November 17, 2013
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Regio- and Stereocontrol in the Michael Initiated Ring Closure (MIRC) Reactions of γ,δ-
Epoxy-α,β-unsaturated Esters, Ketones, Sulfones, and Amides
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Ramesh C. Dhakal and R. Karl Dieter*
Hunter Laboratory, Department of Chemistry, Clemson University, Clemson, SC 29634-0973
R1
R1
1
R MgX (1.2 equiv)
R MgX
(1.2 equiv)
1
ZnX (0.1 equiv)
O
2
ZnX (0.1 equiv)
2
Z
HO
HO
30 to 25 oC, 12 hr
-30 to 25 oC, 12 hr
-
Z
Z
CH Cl2 or PhMe
THF or Et O
2
2
Z = -CO Et, -SO Ph, c-C H10NCO-
i
2
2
5
Z = -CO Et, -COPh, -COPr,-SO Ph, c-C H10NCO-
2 2 5
R1 = Me, Et, nBu, Pr, Ph
i
R1 = Me, Et, nBu, Pr, Bu, Ph
i
t
5
2-90% (73:27 - 100:0 dr)
51-88% (50:50 - 100:0 dr)
dieterr@clemson.edu
Abstract: Organozincates or Grignard reagents in the presence of zinc catalysts undergo
Michael Initiated Ring Closure (MIRC) reactions with γ,δ-epoxy-α,β-enoates, enones,
enesulfones, and enamides to afford 1,2,3-trisubstituted cyclopropanes. The direction of
diastereoselectivity is solvent dependent for alkyl Grignard reagents reacting with epoxy enoates,
ensulfones, and enamides but solvent independent for the enones. Excellent diastereoselectivity
can be achieved for the epoxy enoates, enones, and ensulfones, while the enamides afford
modest diastereoselectivity under optimal conditions. The MIRC reaction can be achieved with
phenylmagnesium chloride and these substrates under reaction conditions designed to minimize
biphenyl formation.
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Introduction
The rich functionality of γ,δ-epoxy-α,β-enoates (e.g., 1) provides opportunities for
nucleophilic attack at the epoxide, alkene, and ester functionalities. We, and others, have
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N
examined copper reagents for preferential S 2’-allylic substitution on these substrates with the
1
,2
aim of controlling the variable regio- and stereoselectivity of the reaction. The modest to good
regio- and stereoselectivities observed with the epoxyenoate led us to examine the reactions of 5-
acetoxy-4-halo-2-enoates with copper reagents where good to excellent regio- and
3
stereoselectivities were observed. However, a variety of heteroatom nucleophiles, particularly
4
metal halides, effect direct S
N
2-substitution on the epoxide at the allylic position of
epoxyenoates, and in an effort to extend this regiochemistry to carbon nucleophiles we examined
N
the possibility of using zinc reagents that were reported to be S 2-regioselective on simple allylic
5
epoxides. Recently, an effective iron catalyzed protocol for S
N
2-selectivity on these substrates
6
7
has been reported. Our studies, have uncovered a Michael Initiated Ring Closure (MIRC)
reaction involving organozincates and γ,δ-epoxy-α,β-unsaturated substrates.
Little and Dawson coined the term Michael Initiated Ring Closure (MIRC) to describe
the addition of lithium thiolate or amide nucleophiles to α,β-unsaturated carbonyl systems
containing an appended electrophile, which upon reaction with the resultant carbonyl enolate
8
anion formed a ring. Application of this strategy of nucleophilic conjugate addition-cyclization
7
has been tabulated in a number of reviews with the principal approach relying on conjugate
9
10
11a-b
11c-d
12
addition of phosphonium, sulfonium, arsonium
or telluronium
ylides where the
7
a
leaving group is attached to the nucleophile effecting conjugate addition. Conjugate addition of
1
3
enolates generated from α,α-dichloroimines represent another example of this tactic.
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The protocol has been successfully applied for the construction of three, four, five, six,
and seven membered rings. Michael acceptors containing a leaving group in the γ-position are
7b,15-16
15-16
15,17
largely limited to γ-halo-α,β-unsaturated esters,
ketones,
sulfones,
and
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1
5
nitroalkenes since participation of γ,δ-epoxy-α,β-unsaturated substrates in MIRC reactions
14b,18
19
have been limited to bis-activated alkenes
or use of dithianyl anions as other organolithium
and Grignard reagents failed. Cyclopropane formation has been achieved by conjugate addition
2
0
of organolithium reagents to γ-chloro-α,β-unsaturated acylphosphanes, and an efficient MIRC
1
6
enantioselective synthesis of trans-1,2-disubstituted cyclopropyl esters and ketones appears
limited to 4-halocrotonates and 4-haloketones given our recent work on γ,δ-epoxy-α,β-enonates,
2-3
which undergo allylic substitution in the presence of Grignard reagents and Cu(I) salts.
Zinc
1
4a,21
14a,21
glycinate enolates participate
in MIRC reactions and γ-phosphoryl enoates
have been
employed. MIRC reactions leading to five- and six-membered rings have been observed with
cuprate mediated conjugate addition reactions and have been the subject of recent
2
2
investigations.
Although compatible with a wide range of functional groups, monoalkyl and dialkylzinc
2
3
24
reagents are generally unreactive towards common electrophiles in the absence of additives or
transmetallation to transition metals (e.g., Pd, Cu, Ni, Ti, Zr) that can mediate a variety of
2
3,25
transformations.
involve radical mediated pathways promoted by molecular oxygen. Organozincates (i.e.,
ZnM, R ZnM ), readily prepared by transmetallation from organolithium and Grignard
reagents or by halogen-zinc exchange, effect halogen-metal exchange, open epoxides, and
2
Reported 1,4-conjugate additions of RZnX or R Zn to enoates appear to
2
6
27
R
3
4
2
2
8
2
9
undergo 1,4-conjugate addition reactions with sterically unhindered enones. Zincate conjugate
26b
additions to enoates are limited to two examples involving a β-unsubstituted enoate and an
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3 2
intramolecular ring closure involving a tetracoordinate zincate (i.e., R R ZnLi ). The more
reactive silyl- and stannylorganozincates transfer the heteroatom ligand to enals, enones, enoates,
2
7,31
32,33
and enamides in conjugate addition reactions.
Zincate structural studies
and mechanistic
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studies on conjugate addition reactions have been reported. Difficult conjugate additions of
3
5
organozincates to vinyl pyridines have been effected with Ni catalysis, which have also been
3
6
utilized to promote asymmetric conjugate additions of dialkylzinc reagents to chalcones and to
3
7
effect 1,4-additions of trialkylindium reagents to enones, enoates and ennitriles.
We now report a general MIRC methodology for the regio- and stereoselective
preparation of 1,2,3-trisubstituted cyclopropanes from γ,δ-epoxy-α,β-unsaturated ketones, esters,
sulfones, and amides involving unprecedented zincate mediated conjugate additions.
Results and Discussion
Treatment of the epoxide of ethyl sorbate (1) with either lithium trimethyl- or tri-n-
butylzincate in THF afforded clean conjugate addition-epoxide opening to give 2a-b with high
regioselectivity and diastereoselectivity (Table 1, entries 1-2), although lithium trimethylzincate
required higher temperatures and longer reaction times (entry 1). The only other product
3
8
observed was the known lactone 3b arising from the hydroxy ester via intramolecular trans-
esterification either under the reaction conditions or during work-up. Similar results were
n
obtained with mixed lithium tri-alkylzincate reagents where two of the Bu-ligands were
t
replaced with methyl or Bu ligands (entries 3-5). In all cases, the latter two ligands functioned as
n
non-transferable ligands relative to the Bu-ligand when used in various combinations. Transfer
n
of the Bu group generally gave two cyclopropane products, as evidenced by DEPT NMR
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studies, with very high diastereoselectivity (entries 2-3 & 5). The relative stereochemistry of the
major isomer 2 was established by X-ray crystallography of a derivative (vida infra) and the
minor isomer is unlikely to be the diastereomer leading to 3 since we could not convert 3 to the
hydroxy ester via trans-esterification procedures.
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Utilization of 1-hexyne as a potentially residual non-transferable ligand altered the course
N
of the reaction pathway. Here, S 2-epoxide opening afforded 4b as the major product along with
significant amounts of the S
N
2’-allylic substitution product 5b (entry 6) in a 76:24 ratio. The
i
mixed isopropyldimethylzincate selectively transferred the Pr group but gave significant
amounts of 4c and 5c as a 1:1 mixture of regioisomers (entry 7). These products (i.e., 4b-c and
2
5
b-c) were identified by comparison of the NMR spectra with the known compounds. The
mixed phenyldimethylzincate gave poor yields of conjugate addition-epoxide opening
accompanied by substantial amounts of biphenyl (entry 8), while the 2-furyldimethylzincate gave
epoxide opening without conjugate addition (entry 9). The formation of biphenyl could not be
suppressed by changing the solvent or reaction temperature.
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Table 1. Reaction of Tri-orgnozincate Reagents with Ethyl
4
,5-Epoxy-2,3-hexenoate (1).
R1
O
1 2 3
O
R R R ZnLi
+
0
1
2
3
4
5
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9
0
1
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0
OEt
+
THF, -20 to 25 °C
HO
CO Et
2
1
2
O
H
OH
O
OH
O
R1
H
+
O
OEt
OEt
R1
H
R1
3
4
5
a R1 = Me
b R1 = nBu
c R1 = iPr
d R1 = Ph
e R1 = 2-Furyl
b
Temp
°C (hr)
25
-20 (2)
-20 (3)
-20 (3)
-20 (4)
-20 to 25
-20 (6)
-20 to 25 32
-20 to 25
% yield
1
2
3
a
c
entry R
R
R
2
3
-
5
5
-
4:5 dr 2
1
2
3
4
5
6
7
8
9
Me
Me
Bu
Me
Bu
65
74
71
83
70
-
-
-
-
-
-
100:0
96:4
98:2
100:0
97:3
-
n
n
n
Bu
Bu
Bu
Bu
n
Me
Me
Me
n
t
Bu
Bu
n
t
t
Bu
-
n
d
d
e
Bu
C
6
H
9
C
6
H
9
56
i
f
g
Pr
Ph
Me
Me
Me
Me
Me
61
-
-
-
18 100:0
-
57
h
100:0
-
i
2-Furyl Me
-
a
Reactions were run in THF at the indicated temperature and
b
quenched at that temperature unless otherwise noted.
Yields are
c
based upon isolated products purified by column chromatography.1
Diastereomeric ratios were determined from integration of the H
NMR carbinol CH-hydrogen absorptions or via peak heights of the
1
3
C-NMR carbinol carbon absorptions. The minor diasteromer is either
n
d
e
2
5 or 26 (Scheme 1, R = Bu). C
6
H
9
= 1-hexynyl. Isomer ratio of
f
g
4:5 = 76:24. The magnesium zincate was employed. An inseparable
1
was obtained in 37% yield. The ratio of 4:5 > 95:5 and was not
h
2
:1 mixture of regioisomers 4:5 was obtained. Run in Et O. Biphenyl
i
detected in the NMR spectrum.
In an effort to isolate the conjugate addition reaction from the ring-closing reaction, the
temperature profile of the reactions was examined (Table 2). Although conjugate addition and
o
epoxide opening did not occur at -78 C (entry 1), both reactions occurred slowly at -55 °C
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(
entries 2-3) and rapidly at -20 °C (entries 5-7). In no instance, could the conjugate addition
reaction be disentangled from the epoxide opening reaction suggesting that cyclopropane
formation is competitive with or faster than the conjugate addition reaction. The reaction was
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also facile in Et
2 2 2
O and CH Cl , although in the latter solvent the diastereoselectivity was
reversed leading subsequently to formation of lactone 3b.
Table 2. Temperature and Solvent Dependence in the
Reaction of Bu
n
3
ZnLi with Ethyl 4,5-Epoxy-2,3-enoate (1).
temp
time
(hr) 1:2b:3b
dr
2b
%
yield
a
b
c
d
entry °C
1
2
3
4
5
6
7
8
9
-78
-55
-55
-35
-20
-20
-20
-20
-20
3
2
4
3
100:0:0
60:40:0
45:55:0
0:94:6
-
-
-
-
0.5 16:72:12
1
2
3
3
0:95:5
0:95:5
0:98:2
0:0:100
-
96:4
97:3
-
82
81
82
e
f
a
The reaction was carried out at this
temperature for the specified time in THF unless
otherwise noted. The ratio was determined by
integration of H-NMR absorptions. The dr of
2b was determined by integration of H-NMR
b
1
c
1
absorptions of the carbinol methine proton.
DEPT NMR experiments established the
cyclopropane composition for each diasteromer.
d
Yields are based upon isolated products
e
purified by column chromatography.
reaction was carried out in Et
was carried out in CH Cl
The
f
2
O. The reaction
2
2
.
In an effort to minimize the amount of organometallic reagent required, procedures
n
catalytic in zinc(II) salts were employed. Treatment of 1 with BuMgCl in the presence of
2
TMSCl and with no added ZnBr gave a complex mixture of products along with complete
3
9
2
consumption of starting epoxide. However, utilization of 0.1 equivalents of ZnBr gave the
cyclopropane products in yields comparable to those obtained with stoichiometric amounts of
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zincate reagents (Tables 2 and 3) with the exception of MeMgCl which gave 65% yield of 2a
under stoichiometric conditions and only recovered starting material under conditions catalytic in
ZnBr
2
(Table 2, entry 1 vs. Table 3, entry 1).
Table 3. Zinc Bromide Catalyzed Reaction of
0
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2
3
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9
0
1
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Grignard Reagents with Ethyl 4,5-Epoxy-2,3-
hexenoate (1).
R1
1
R MgX (X = Cl, Br)
O
O
(1.2-2.0 equiv)
HO
CO Et
OEt
2
ZnBr (0.1 equiv)
2
1
THF, -20 to 25 °C
2b-c,f
1
R MgX
%
1
a
b
entry R
equiv
2.0
2.0
product yield
c
1
2
3
4
5
6
7
Me
Et
2a
2f
-
73
85
85
85
80
82
n
d
Bu
Bu
Bu
Pr
Pr
2.0
2b
2b
2b
2c
2c
n
n
i
2.0
1.2
2.0
1.2
i
a
Reactions were carried out from -20 °C
to room temperature unless otherwise
b
noted.
material
Yields are based upon isolated
purifiedc by column
Only recovered
chromatography.
starting material was obtained. TMSCl
(2.0 equiv) was added.
d
The reactions of γ,δ-epoxy-α,β-unsaturated ketones, sulfones and amides with Grignard
2
reagents and catalytic amounts of ZnBr were examined to explore the generality and scope of
this MIRC methodology (Table 4). Reaction of γ,δ-epoxy-α,β-unsaturated phenyl ketone 6 with
methyl-, ethyl-, n-butyl-, and i-propyl magnesium halides in the presence of catalytic amounts of
zinc bromide (10 mol %) in THF gave good yields of MIRC products 10a-d with excellent
diastereoselectivities (entries 1-7). The direction of diastereoselectivity was unaffected by
2 2
solvent polarity affording the same major diastereomer in both THF and CH Cl (entries 2 vs. 4,
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&
5 vs. 6). Although epoxy isopropyl enone 7 gave cyclopropanes in excellent yields and
n
i
t
diasteoselectivities upon reaction with BuMgCl (entries 9-11), PrMgCl (entry 12), or BuMgCl
entry 13) in the presence of catalytic amounts of ZnBr , MeMgCl failed to react with 7 upon
stirring at room temperature for 36 hours (entry 8) while reaction in toluene gave recovered
starting material or, in one instance, S 2-opening of the epoxide at the allylic position.
(
2
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60
N
The chemical yields and diastereoselectivities in the reactions of γ,δ-epoxy-α,β-
unsaturated phenyl sulfone 8 with Grignard reagents was dependent upon the solvent employed
(Table 4, entries 14-21). Ensulfone 8 failed to react with MeMgCl and ZnBr
2
(10 mol %) in THF
(entry 14) but did afford cyclopropane 16a diastereoselectively and in good yield (entry 15)
n
when toluene was employed. Reaction of 8 with BuMgCl and catalytic amounts of zinc bromide
10 mol %) in THF gave cyclopropane 12c with poor diastereoselectivity (i.e., 58:42 dr, entry
(
1
6), while reaction in dichloromethane or toluene completely reversed the diastereoselectivity
i
affording 16c as a single diastereomer (entries 17-18). Although reaction of 8 with PrMgCl in
THF gave trace amounts of product 12d along with recovered starting material (entry 19), use of
toluene gave the cyclopropane 16d in excellent yield and diastereoselectivity (entry 20-21). The
reactions of epoxy enamide 9 gave modest yields and poor to modest diastereoselectivities of
cyclopropanes 13c and 17c under all reaction conditions examined (entries 22-25). Reaction of 9
i
with PrMgCl gave a complex mixture of reaction products when run in either THF (entry 26) or
2 2
CH Cl .
9
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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4
4
4
4
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5
5
5
6
Table 4. Reaction of 4,5-Epoxy-2,3-hexenyl Ketones 6-7, Sulfone 8, and Amide 9.
R1
R1
1
R MgX (X = Cl, Br)
O
(1.2 equiv)
Z
HO
HO
Z
Z
ZnBr (0.1 equiv)
2
-30 to 25 oC, 12 hr
6-9
14-17
1
0-13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f R = tBu
6
, 10, 14 Z = PhCO-
a R = Me
i
b R = Et
7, 11, 15 Z = PrCO-
c R = nBu
8, 12, 16 Z = PhSO2-
i
9, 13, 17 Z = c-C H10NCO-
d R = Pr
5
major
% a
1
b
entry epoxide R
solvent ROH yield
dr
1
2
3
4
5
6
7
8
9
6
6
6
6
6
6
6
7
7
7
7
7
7
Me
Et
Et
THF
THF
10a
10b
10b
10b
10c
10c
10d
11a
11c
11c
11c
11d
11f
12a
16a
12c
16c
16c
12d
16d
16d
13c
17c
17c
17c
13d
57
63
63
61
67
66
63
-
100:0
100:0
100:0
100:0
100:0
100:0
100:0
-
100:0
100:0
100:0
95:5
100:0
-
7:93
58:42
0:100
0:100
-
0:100
0:100
50:50
47:53
36:64
27:73
-
Et
2
O
Et
CH
2
Cl
2
n
Bu THF
Bu CH Cl
2
n
i
2
Pr
THF
THF
c
Me
n
Bu THF
Bu THF
Bu CH Cl
2 2
88
n
n
i
d
1
0
69
85
82
11
12
Pr
Bu
THF
THF
THF
PhMe
t
e
1
1
1
1
3
4
5
6
82
-
8
Me
Me
8
8
8
8
8
8
8
9
9
9
9
9
78
78
83
90
trace
83
82
73
51
63
5f2
n
Bu THF
Bu CH
Bu PhMe
n
n
i
17
2 2
Cl
1
1
2
2
8
9
0
1
Pr
Pr
Pr
THF
PhMe
PhMe
i
i
n
n
n
n
i
22
23
Bu THF
Bu Et
Bu PhMe
Bu CH Cl
THF
2
O
2
2
2
4
5
6
2
2
Pr
a
Yields are based upon isolated products purified by column
b
chromatography. Diastereomeric ratios (i.e., 10-13:14-17)
were determined from integration of the H NMR of the
carbinol proton absorptions or via peak heights in the C-
1
13
NMR spectra corresponding to the carbinol carbon peak
c
absorptions. Stirred at room temperature for 30 h with no
d
observation of product formation.
The reaction was
o
e
conducted at 25 C for 12 hr. The reaction was conducted at
1
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8
9
o
t
0
C for 12 hr. In a separate experiment, the reagent Bu
3
ZnLi
o
f
gave 11f in 73% yield (0-25 C, 12 hr). A complex mixture
of products was obtained in both THF and CH Cl
2
2
.
Although the MIRC reactions of trialkylzincates with epoxyenoate 1 gave good product
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yields under either stoichiometric or catalytic protocols, the utilization of arylzincates gave low
4
0
yields of cyclopropane 2d and considerable quantities of biphenyl (Table 1, entry 8). Initial
attempts to suppress biphenyl formation in the reaction of lithium phenyldimethylzincate by
using a variety of solvents failed with both coordinating (e.g, THF, Et
(e.g. CH Cl , toluene) solvents. However, significant product formation (i.e., 2d) was obtained
by reverse addition of phenyl magnesium bromide to a solution of epoxyenoate 1 and catalytic
amounts of ZnX (X = Br, Cl, I, OAc) in less polar solvents (Table 5, entries 2-10), although
only trace amounts of 2d were obtained in THF (entry 1). Addition of Ni(acac) had little, if any,
effect on product yield (entry 5). The lowest yields of undesired biphenyl were obtained with
Zn(CN) (entries 11-14) and lower yields of 2d were obtained as the temperature was lowered
entries 13-14) with concomitant increase in the yield of 3d. Utilization of higher temperatures
and inverse addition of the Grignard reagent allows competitive conjugate addition of the in situ
2
O) and non-coordinating
2
2
2
2
2
(
generated zincate reagent to the Michael acceptors with the ZnX
2
catalyzed coupling reaction
o
leading to biphenyl. Conducting these reactions at higher temperatures (i.e., 25 C, entries 11-12)
to maximize product yield resulted in higher diastereoselectivity in the addition process leading
to mixtures of 2d:3d with modest selectivity in comparison to the excellent diastereoselectivity
2
obtained with the alkyl Grignard reagents (Tables 1-2). Utilizing Zn(CN) and reverse addition,
modest to good yields of cyclopropanes could be obtained from enones 6-7 at lower reaction
temperatures (entries 15-18), enesulfone 8 (entries 19-21), and enamide 9 (entries 22-23).
Diastereoselectivity mirrored prior observations with the ketones 6-7 giving largely diastereomer
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A and sulfone 8 and amide 9 giving diasteromer B as the major product in non-coordinating
solvents (Table 5). Grignard reagents derived from 4-bromo-N,N-dimethylaniline or 4-
iodoanisole gave only bi-aryl coupling products.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Zinc Catalyzed Reaction of Phenyl
Magnesium Bromide with 4,5-Epoxy Enoate
1, Enones 6-7, Ensulfone 8 and Enamide 9.
Ph
Ph
O
PhMgX
Z
+
HO
HO
Z
Z
ZnX (0.1)
2
A
B
14e-17e
H
1
, 6-9
1
,
2, 3 Z = CO Et
2d, 10e-13e
2
6, 10, 14 Z = PhCO-
O
i
7
, 11, 15 Z = PrCO-
, 12, 16 Z = PhSO2-
, 13, 17 Z = c-C H10NCO-
Ph
H
H
or
O
8
9
5
3d
o
T C
A, %c
B or 3d,c
2d:3d or d % yield
c
a
b
entry epoxide catalyst
solvent
THF
(t)
A
yield % yield
A:B/range Ph-Ph
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
1
1
6
6
6
7
8
8
8
9
9
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
ZnBr
2
2
2
2
2
2
2
A
A
A
B
A
A
A
A
A
A
A
C
D
E
F
F
F
E
G
G
G
G
G
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
2d
10e
10e
10e
11e
12e
16e
16e
17e
17e
-
-
5
4
5
3
31
17
7
3
5
7
3
17
33
-
-
42
37
22
30
17
26
27
28
31
25
6
5
3
11
11
9
e
f
Et
Et
Et
Et
2
2
2
2
O
O
O
O
48
46
59
63
32
45
57
59
52
61
61
49
37
63
68
64
84
42
17
05
-
80:20/07
83:17/11
58:42/16
86:14/01
68:39/15
68:32/09
70:30/08
82:16/03
84:16/03
86:14/06
78:22/03
63:37/05
44:46/05
88:12
g
CH
PhMe
2
Cl
2
ZnCl
ZnI
Zn(OAc)
2
Et
Et
Et
Et
Et
Et
Et
Et
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
2
1
1
1
0
1
2
2
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
Zn(CN)
2
2
2
2
2
2
2
2
2
2
2
2
2
h
13
i
1
1
1
1
4
5
6
7
j
j
j
j
CH
PhMe
CH Cl
Et
CH
PhMe
CH Cl
PhMe
2
Cl
2
2
2
2
-
90:10
-
92:8
8
18
19
2
-
100:0
3
2
O
Cl
30
64
82
62
66
55:45
22:78
7:93
22:78
13
8
7
14
13
2
2
2
2
0
1
2
3
2
j
2
j
-
19:81b
a
The Grignard reagent was added to the mixture of ZnX
2
and epoxide. Temperature,
o
o
o
o
(
time = hrs): A = 25 C (12). B = 0 to 25 C (12). C = 25 C (1.5). D = 0 to 25 C (2). E
1
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9
o
o
o
c
=
-20 to 25 C (4). F = -30 to 25 C (3). G = 25 C (4). Yields are based upon isolated
products purified by column chromatography. All reactions involved inverse addition of
d
the Grignard reagent to the substrate and zinc salt. Diastereomeric ratios were
1
determined by averaging values from integration of the H NMR absorptions of the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
methyl attached to the carbinol carbon, the benzyl methine proton, and the C-NMR
peak heights of the carbonyl carbon absorption. The range between the high and low
1
13
value for the major diastereomer determined from several H and C absorptions is also
given and ranges between 3 and 16 (e.g., 80:20/83:17 to 70:30/86:14) for the sets of
e
measurements. The Grignard reagent was added to the substrate at room temperature
f
over 15 min. The Grignard reagent was diluted with 3.0 mL of Et
2
O and added to the
g
substrate over 15 min at room temperature. Ni(acac)
2
(0.1 equiv) was added to the zinc
h
salt before adding the Grignard reagent. LiCl (0.2 equiv) was added to the mixture of
o
i
zinc salt and epoxyenoate 1 before adding the Grignard reagent at 0 C. The Grignard
reagent was diluted with anhydrous Et O and added to the zinc salt/epoxide mixture
2
o
j
over 30 min at -20 C. The minor isomer was also present.
Determination of Stereochemistry
The inability to convert cyclopropyl ester 2b into lactone 3b in the presence of base or
acid suggested the trans disposition of the carbinol and carboalkoxy substitutents and this
tentative assignment was reinforced as lactone 3b was obtained when the reaction was performed
2 2
in CH Cl (Table 2, entry 9). The relative stereochemistry of the 1,2,3-trisubstituted cyclopropyl
esters was confirmed by reduction of 2b to the diol whose bis-3,5-dinitrobenzoyl derivative
provided suitable crystals for X-ray crystallography, which could not be obtained for the 3,5-
dinitrobenzoyl derivative of the secondary alcohol 2b. X-ray structural determinations were also
obtained on the 3,5-dinitrobenzoyl derivatives derived from the major (12c) and minor (16c)
diastereomers of cyclopropyl sulfone 12c and for amides 13e and the 3,5-dinitrobenzoyl
derivative of 17e.
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R
Hb
Z
Hc
Ha
d OH
H
2
d Z = CO Et, R = Ph
2
0b Z = COPh, R = Et
11e Z = CO Pr, R = Ph
1
i
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In order to determine the relative stereochemistry of the substituents present in the
cyclopropyl ketone derivatives, NOESY NMR spectra were obtained for ketones 10b and 11e
and compared with spectra for ester 2d. The presence of phenyl substitutents on the ring or
attached to the acyl group dispersed the cyclopropyl proton absorptions necessary for performing
a
b
c
d
NOESY experiments. The H , H , H and H proton assignments for 2d, 10b, and 11e were
determined from COSY NMR experiments. In the NOESY spectra of these compounds, strong
a
d
b
c
coupling was observed between H and H and H and H , while weak coupling was observed
a
b
a
c
c
d
between H and H , H and H and H and H confirming the assigned stereochemistry. Thus,
both alkyl and aryl Grignard reagents react with epoxy enones and enoates in THF to give the
same relative stereochemistry about the cyclopropane ring.
Diastereoselectivity and Solvent Effects
2 2
Intriguingly, ester 1 affords only diastereomer 2b in THF and only lactone 3b in CH Cl
n
upon reaction with Bu
3
ZnLi (Table 2). A plausible rationalization invokes minimization of
1
,3
2,41
A -strain in the transition state structures arising from conformers 18-20 (Scheme 1) where
stability of the conformers is expected to be 18 > 20 > 19 and the solvent dependent nature of the
zincate reagent involving solvent separated ion pairs (SSIP) in THF and contact ion pairs in
CH
2
Cl
2
(CIP). Recent X-ray crystal structures and solution NMR studies have elucidated mixed
(X = Cl, Br) or ZnR
bimetallic reagents obtained upon mixing Grignard reagents with ZnX
2
2
1
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33
+
-
compounds in THF and have implicated [(THF)
6
Mg(η-Cl)
3 2 5 2
] [Zn Et ] in ZnCl mediated
3
3b
addition of EtMgCl to benzophenone. The structures of these mixed Mg-Zn complexes is
t
33
dependent upon the alkyl ligand (e.g., Bu vs. Et) and are in dynamic equilibrium with a variety
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
3a
of zinc species depending upon concentration. The composition and structures of mixed Mg-
Zn complexes in solvents other than THF are unknown but if similar to those shown in Figure 1,
2
it would be reasonable to expect SSIP in THF and tight CIP in PhMe and CH Cl2.
S
Cl
S
tBu
tBu Zn
Mg
Mg
Cl
Cl
(a)
tBu
S
S
S
S
S = THF
S
Cl
S
Et
Et
Zn Zn
Et
Mg
Mg
(b)
Cl
Cl
S
S
Et Et
S
S
Figure 1. Mixed bimetallic Mg-Zn complexes
+
t
-
(a) [(THF)
6
Mg(η-Cl)
3
]
[Zn Bu
3
]
(
see 33a) and (b) [(THF)
6
Mg(η-
+
-
3 2 5
Cl) ] [Zn Et ] (see 33b).
Due to electrostatic dipole-dipole repulsion, the SSIP approaches from the side opposite
the polar heteroatom substituent (i.e., the epoxide in 18) to give conformers 21 and/or 22, while
the CIP approaches from the same side as the epoxide oxygen perhaps enhanced by
complexation with the magnesium counter-ion (i.e., from either 18 or 20) to give conformers 23
and/or 24. It should be noted that the bimetallic magnesium cations should be more effective
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
27b
2
Lewis acids than neutral MgX salts that may be present in a dynamic equilibrium.
Conformers 21-22 and 23-24 can arise directly from the conjugate addition process or by rotation
about C-C bond a prior to cyclopropane formation. The initial formation of configurational
diastereomers arising from zincate attack on the enoate either syn or anti to the epoxide
determines the stereochemical outcome during cyclopropane formation. Zincate attack anti to the
epoxide leads to conformational diasteromers 21-22 with proper orientation to afford
cyclopropanes 25 and 2b, respectively. In conformer 21 the R-group and the enolate are eclipsed
about bond a, while in conformer 22 they are oriented anti and this anticipated lower energy
conformer in the transtition state leads to the observed product 2b. Similarly, in the transition
states corresponding to conformers 23 and 24 arising from zincate syn attack, conformer 24 has
the R-enolate eclipsed arrangement about bond a, while 23 has the lower energy anti
arrangement leading to the observed product 3b. This analysis implies that the R-group (from the
zincate reagent) and the EWG will always be trans to each other. Previous rationalizations
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
invoking a carbanionic lithium enolate seem unlikely given computational studies on enolate
42
anions.
1
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Scheme 1. Stereochemical models for cyclopropane formation from intermediate enolates .
XMgRZnR contact ion pair
2
(CIP)
H
O
CO Et
H
CO2Et
2
Me
?
H
CO Et
2
H
18
H
O
H
H
H
O
19
2
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
R Zn MgX
CIP and
SSIP
3
Me
solvent separated
ion pair (SSIP)
2
CH Cl2
THF
H
H
OMgX
OEt
R
OMgX
OEt
R
a
a
a
H
a
R
R
H
H
O
H
H
O
O
H
O
H
O
H
H
H
O
H
H
OEt
OEt
H
MeMgX
Me
Me
H
MeMgX
21
22
23
24
R
R
R
R
HO
HO
HO
CO Et
CO Et
CO Et
2
2
2
O
Me
Me
Me
O
Me
H
2b R = nBu (85%)
2
5
b R = nBu (82%)
26
3
not observed
only product in THF
only product in CH Cl2
not observed
2
If the solvent affects the syn:anti ratio (i.e., the initial 1,4-addition occurring syn or anti to
the epoxide), why is there no solvent effect for the epoxyenones, clean reversal of
diastereoselectivity for the epoxyenoates, and poor to no diastereoselectivity for the epoxy
ensulfones and enamides in THF to excellent (i.e., 8) to modest (i.e., 9) reversal of
2 2
distereoselectivity in CH Cl ? To probe this question, we performed several competition
experiments with one equivalent of Grignard reagent and 0.5 equivalents each of two
n
electrophiles. Treatment of 0.5 equivalents of enone 7 and enoate 1 with BuMgCl [CH
2
Cl
2
or
o
THF, ZnBr
2
(0.1 equiv), -40 to 25 C, 12 h)] gave complete conversion of 7 to 11c with complete
2 2
recovery of 1, while reaction of 1 and 8 under the same conditions in CH Cl gave a 35:65 ratio
of recovered 1:8 along with the cyclopropanes 3b and 12c. Similarly, reaction of 8 and 9 gave a
1
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
3% recovery of 8 and 27% of 9. These competition experiments establish that the relative rate
factors for reaction of 7: 9: 1: 8 are >20:2.7:1.9:1 in CH
2
2
Cl .
+
The relative basicities of the EWGs (i.e., pKBH ) in 1 and 6-9 can be estimated from
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reported values for similar compounds where PhSO
(-7) < RCO R (-6.5) < ROR (-3.5) < THF (-2.05) < RCONH
Similarly, the relative electron withdrawing power of the carbonyl and sulfonyl groups can be
estimated from Hammett σ -substitutent constants decreasing in power with –COMe (0.16) ≈ -
CO Me (0.16) > -SO Me (0.12) > -CONH
an order of -SO Me (0.73) > –COMe (0.47) > -CO
2
Ph (-12.37) < MeSO
2
Me (-12.27) < RCOR
4
3-44
2
2
[pKBH+(O) = -0.5] in basicity.
R
4
5
2
2
2
(0.00). The Hammett σ
p
-substituent constants give
(0.31) correctly
2
2
Me (0.44) > -CONH
2
predicting a greater reactivity for the enone than the enoate but incorrectly predicting the greatest
45
reactivity for the sulfone. Although these parameters specifically measure proton acceptor and
donor properties (i.e., the acidity of substituted benzoic acids), respectively, they should
qualitatively reflect magnesium complexation and Michael acceptor susceptibility, respectively.
+
From this analysis the sulfone, ketone, and ester are less basic than the epoxide, while the σ
R
substitutent constants correlate with the relative rates measured by competition experiments with
> 1 > 8 but not with 9, with 9 > 1 > 8 in reactivity. Thus, the most reactive epoxy ketones 6-7
7
show no solvent dependent diastereoselectivity, while the less reactive ester 1 and sulfone 8
substates do, with the more reactive ester giving excellent but different diastereoselectivity in
THF and CH
Michael acceptor and shows excellent diastereoselectivity in CH
diastereoselectivity in THF. Epoxy amide 9 is expected to be the poorest Michael acceptor based
upon Hammett σ -substitutent constants but is the most basic substrate and its relative reactivity
i.e., 9 > 1 > 8) suggests amide-magnesium ion complexation is facilitating the conjugate
2
Cl
2
. The least reactive epoxy sulfone 8 is also the least basic, the second poorest
2
Cl and poor
2
R
(
1
8
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9
addition reaction. The correlation of reactivity with diastereoselectivity is clearly seen in the
reactions of PhMgCl with epoxy ester 1 (Table 5, entries 11-14) where the less reactive putative
o
phenyl zincate reagent gives poor diastereoselective at -20 to 0 C and better diastereoselectivity
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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35
36
37
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
at 25 C that is in turn lower than those obtained with the more reactive alkylzincate reagents
(Tables 1-3).
Although the details remain to be elucidated, the observed solvent dependent
diastereoselectivity of the epoxy ketones, ester, sulfone and amide appears to reflect a complex
interplay between functional group basicity and electron withdrawing capacity and may also
involve structural variation of the mixed Mg-Zn complexes in different solvents. The more
reactive epoxy ketones 6-7 show no solvent dependent diastereoselectivity, while the most basic
epoxy amide 13 never gives a single diastereomer under any reaction conditions. The epoxy ester
1
and sulfone 12 display intermediate behavior.
Summary
In summary, tri-alkylzincates or Grignard reagents and catalytic amounts of Zn(II) salts
react with γ,δ-epoxy-α,β-unsaturated ketones, esters, sulfones, and amides to afford trans-cis-
trans-1,2,3-trisubstituted cyclopropanes via a MIRC process. These unprecedented zincate
mediated conjugate addition reactions display excellent cyclopropane diastereoselectivity for the
ketone and ester substrates in THF that can be reversed to the 1,2-cis-2,3-trans-isomer for the
latter by changing to CH
diastereoselectivity in THF, while excellent 1,2-cis-2,3-trans distereoselectivity is achieved for
the sulfone in CH Cl and modest selectivity with the amide. The diastereoselectivity established
2 2
Cl . The sulfone and amide substrates afford poor cyclopropane
2
2
1
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1
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1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
during the conjugate addition reaction appears to control the subsequent cyclopropane
distereoselectivity arising from the epoxide opening-ring closure event. The reaction of
triarylzincates or aryl Grignard reagents and Zn(II) salts is complicated by biaryl formation that
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
can be suppressed by inverse addition of the Grignard reagent and use of Zn(CN) .
The high regio- and diastereoselectivity observed in these reactions provides useful
synthetic routes to highly substituted cyclopropane derivatives. The stereo- and regio-controlled
7
a,46-56
48
synthesis of cyclopropane derivatives,
is important in both synthesis and medicinal
5
3-56
47
49
chemistry.
This is illustrated by recent reviews on enantioenriched , fluorinated-
50
51
52
53
alkylidene-, silylmethyl-substituted-, spiroannulated-, and aryl- cyclopropanes, and the
5
4
preparation and biological activity of cyclopropyl phosphonates, cyclopropane derived
5
5a
56
peptidomimetics, and cyclopropyl-containing α-amino acids.
Experimental
General. NMR spectra were recorded as CDCl
3
or C
6
D
6
solutions on a 500 MHz NMR
1
instrument. The H NMR chemical shifts are reported as δ values in parts per million (ppm)
3 6 6
relative to tetramethylsilane (TMS, δ = 0.00) / CHCl (δ = 7.28) or C H (δ = 7.16) as internal
13
standard. The C NMR chemical shifts are reported as δ values in parts per million (ppm)
downfield from TMS and referenced with respect to the CDCl
3
signal (triplet, centerline δ = 77.0
ppm) or C signal (multiplet, centerline δ = 128.4 ppm). Infrared (IR) spectra were recorded as
6
D
6
neat samples (liquid films on NaCl plates). Gas chromatography-mass spectrometry
measurements were performed on a GC coupled to a quadrupole detector at 70 eV. Analytical
thin layer chromatography (TLC) was performed on silica gel plates, 200 mesh with F254
indicator. Visualization was accomplished by UV light (254 nm), and/or a 10 % ethanol solution
2
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of phosphomolybdic acid. Flash column chromatography was performed with 230-400 silica.
The yields are of materials isolated by column chromatography.
Materials. Anhydrous tetrahydrofuran (THF), diethyl ether (Et
CH Cl ) were distilled from sodium benzophenone ketyl. Toluene was dried over molecular
sieves and used for the reactions. BuLi (2.5 M in hexane), MeLi (1.6 M in Et
2
O) and dichloromethane
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2
2
n
t
2
O), and BuLi (1.7
M in pentane) were commercially available and were titrated using sec-butyl alcohol and 1,10-
n
phenanthroline monohydrate in THF. BuMgCl (2.50 M in THF), EtMgCl (2.0 M in Et
2
O),
O), BuMgCl (1.7 M in THF) and PhMgCl
O) were commercially available and titrated using menthol and 1,10-
i
t
MeMgCl (3.0 M in Et
2.80 M in Et
phenanthroline monohydrate in THF.
corresponding lithium or magnesium reagents and flame dried ZnBr
2 2
O), PrMgBr (2.0 M in Et
(
2
4
5
Zincate reagents were synthesized from the
. All glassware was flamed-
2
dried under high vacuum and purged with argon and then cooled under a dry nitrogen
o
atmosphere. Low temperature baths (up to -78 C) were prepared using thermo flasks using dry
o
ice-iso-propanol slush bath mixtures or an ice-NaCl (-23 C) mixture. All reactions were
conducted under a positive, dry argon atmosphere in anhydrous solvents in flasks fitted with a
rubber septum.
HRMS data on compounds 2b’, 2d, 2f, 3d, 10a-e, 11e, 12e, 13c, 16a, 16d-e and 17c were
analyzed with a Q-TOF detector (hybrid quadrupole time of flight MS). Compounds 1, 3b, 4b,
2
, 57-60
4
c, 4e, 5b, 5c, 6 and 9 have been fully characterized and reported.
General Procedure A: Reaction of lithium trialkylzincates (R
2,3-hexenoate(1). To an ice cold solution of flame dried ZnBr (225 mg, 1.0 mmol) in THF (4.0
3
ZnLi) with ethyl 4,5-epoxy-
2
mL) under argon was added alkyllithium (3.0 mmol) and the reaction mixture was stirred for 30
o
minutes at 0 C. Ethyl 4,5-epoxy-2,3-hexenoate (156 mg, 1.0 mmol) was added and the resulting
2
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mixture was stirred for 2-12 hours at the indicated temperature range. The reaction mixture was
quenched with NH
extracted with Et O (3 x 15.0 mL). The combined organic phase was washed with water (10.0
mL), brine (10.0 mL) and then dried over anhydrous MgSO , filtered, concentrated in vacuo, and
4 4
Cl-NH OH aqueous buffer (pH = 7.0, 10.0 mL), filtered and the filtrate was
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
purified by flash column chromatography (silica, 10-20% EtOAc in petroleum ether, v/v) to give
pure compounds.
1
2
3
General Procedure B: Reaction of mixed lithium organozincates (R R R ZnLi) with ethyl
γ,δ-epoxy-α,β-hexenoate. To an ice cold solution of flame dried ZnBr
2
(225 mg, 1.0 mmol) in
1
2
3
THF (4.0 mL) under argon was added R Li (1.0 mmol), R Li (1.0 mmol) and R Li (1.0 mmol)
o
o
and the mixture was stirred for 30 min at 0 C. The flask was then transferred to a -20 C bath,
ethyl 4,5-epoxy-2,3-hexenoate (156 mg, 1.0 mmol) was added and the mixture was stirred for the
indicated time and temperature range. The reaction mixture was quenched with NH
aqueous buffer (pH = 7.0, 10.0 mL), filtered and the filtrate was extracted with Et
mL). The combined organic phase was washed with water (10.0 mL), brine (10.0 mL) and then
dried over anhydrous MgSO , filtered, concentrated in vacuo, and purified by flash column
4
4
Cl-NH OH
2
O (3 x 15.0
4
chromatography (silica, 10-20% EtOAc in petroleum ether, v/v) to give pure compounds.
General Procedure C: Reaction of alkyl Grignard reagents with ethyl 4,5-epoxy-2,3-
unsaturated ester 1, ketones 6-7, sulfone 8 and amide 9 in the presence of catalytic amounts
2
of zinc bromide. To an ice cold solution of flame dried ZnBr (23 mg, 0.1 mmol) in THF or
Et O or CH Cl or toluene (4.0 mL) under argon was added the Grignard reagent (1.2 mmol) and
2
2
2
o
o
the mixtures was stirred for 5 min at 0 C. The flask was then cooled in a -20 to -30 C bath,
epoxide (1.0 mmol) was added and the mixture was stirred for 2-12 hours with gradual warming
4
to room temperature. The reaction was quenched with saturated aqueous NH Cl, filtered and the
2
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filtrate was extracted with Et
2
O (3 x 15.0 mL). The combined organic phase was washed with
4
water (10.0 mL), brine (10.0 mL) and then dried over anhydrous MgSO , filtered, concentrated
in vacuo, and purified by flash column chromatography( silica, 10-20% EtOAc in petroleum
ether, v/v) to give pure compounds.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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53
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56
57
58
59
60
General Procedure D for Reverse Addition: Reaction of phenyl magnesium bromide with
ethyl 4,5-epoxy-2,3-unsaturated ester 1, ketone 6-7, sulfone 8 and amide 9 in the presence of
catalytic amounts of zinc (II) salt. To an ice cold solution of flame dried Zn(II) salts (0.1
2 2 2
mmol) in Et O or CH Cl or toluene (4.0 mL) under argon was added epoxide (1.0 mmol) and
then the phenyl magnesium bromide (1.2 mmol) was added dropwise over 15 minutes and the
mixture was stirred for indicated hours at given temperature range. The reaction mixture was
quenched with saturated aqueous NH
4
Cl, filtered and the filtrate was extracted with Et
2
O (3 x
1
5.0 mL). The combined organic phase was washed with water (10.0 mL), brine (10.0 mL) and
4
then dried over anhydrous MgSO , filtered, concentrated in vacuo, and purified by flash column
chromatography (silica, 10-20% EtOAc in petroleum ether, v/v) to give pure compounds.
General Procedure E for Competition Experiments: Reaction of Grignard reagent (1.0
equiv) with a 1:1 mixture of ethyl 4,5-epoxy-2,3-unsaturated ester 1 (0.5 equiv) and other
epoxides (0.5 equiv) such as 4,5-epoxy-2,3-unsaturated ketone 7, 4,5-epoxy-2,3-unsaturated
sulfone and 1:1 mixture of 4,5-epoxy-2,3-unsaturated sulfone (0.5 equiv) with 4,5-epoxy-
2,3-unsaturated amide (0.5 equiv) in the presence of catalytic amounts of ZnBr
2
. To the
flame dried solution of ZnBr (23 mg, 0.1 mmol) in CH Cl (4.0 mL) under argon was added
2 2 2
n
o
BuMgCl (1.0 mmol) at -40 C. To this solution was added the 1:1 mixture of two epoxides
Cl (2.0 mL) and the reaction mixture was allowed to wam up to room
temperature over 12 hrs. The reaction was quenched with saturated aqueous NH Cl, filtered and
under study in CH
2
2
4
2
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1
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1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the filtrate was extracted with CH
2
Cl
2
(3 x 15.0 mL). The combined organic phase was washed
, filtered,
with water (10.0 mL), brine (10.0 mL) and then dried over anhydrous MgSO
4
concentrated in vacuo. The crude product was subjected to NMR and GC/MS analysis and the
ratio of each component was calculated from the corresponding data.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
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5
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7
8
9
0
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2
3
4
5
6
7
8
9
0
(1R*,2R*,3S*,1’R*) Ethyl 2-(1-hydroxyethyl)-3-methylcyclopropane carboxylate (2a).
Employing General Procedure A and using MeLi (1.88 mL, 1.6 M in Et
2
O, 3.0 mmol), flame
dried ZnBr (225 mg, 1.0 mmol) and ethyl 4,5-epoxy-2,3-hexenoate (156 mg, 1.0 mmol) at room
2
temperature gave after purification by flash column chromatography (silica, 20-30%
EtOAc:petroleum ether, v/v) 2a (113 mg, 65 %, dr 100:0) as a colorless oil: IR (neat) 3432 (br s),
-
1 1
2
1
1
3
967 (s), 2921 (s), 1715 (s), 1434 (s), 1361 (s), 1181 (s) cm ; H NMR (500 MHz, CDCl ) δ
.24 (d, J = 6.4 Hz, 3H),1.24-1.14 (m, 1H), 1.25 (t, J = 7.3 Hz, 3H), 1.35 (d, J = 7.8 Hz, 3H),
13
.54-1.58 (m, 2H), 1.81 (s, 1H), 3.49-3.61 (m, 1H), 4.11 (q, J = 5.5 Hz, 2H); C NMR (125
MHz, CDCl
3
) δ 12.1, 14.2, 21.3, 23.3, 26.2, 34.4, 60.5, 66.9, 173.6; mass spectrum m/z (relative
+
intensity) EI 172 (0. 2, M ), 154 (12), 127 (81), 98 (69), 83 (100), 69 ( 57), 59 (93), 55 (76).
9 16 3
Anal.Calcd for C H O : C, 62.77; H, 9.36 %; found: C, 62.56; H, 9.24 %.
(1R*,2R*,3S*,1’R*) Ethyl 2-(1-hydroxyethyl)-3-n-butylcyclopropane carboxylate (2b).
n
Employing General Procedure A and using BuLi (1.2 mL, 2.5 M in hexane, 3.0 mmol), flame
dried ZnBr
after purification by flash column chromatography (silica, 10-20 % EtOAc:petroleum ether, v/v)
b and 2b’ (177 mg, 82 %, dr 96:4) as a colorless oil (the application of General procedure C
gave 182 mg, 85%, 100:0 dr). Major (2b): IR (neat) 3457 (br s), 2961 (s), 2932 (s), 1724 (s),
2
(225 mg, 1.0 mmol) and ethyl γ,δ-epoxy-α,β-hexanoate (156 mg, 1.0 mmol) gave
2
-
1 1
1
450 (s), 1374 (s), 1176 (s) cm ; H NMR (500 MHz, CDCl
3
) δ 0.91 (t, J = 7.3 Hz, 3H), 1.22 (t,
J = 4.6 Hz, 1H), 1.26 ( t, J = 6.8 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.35-1.39 (m, 2H), 1.42-1.48
2
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(
m, 4H), 1.59-1.71 (m, 2H), 2.01 (s, 1H), 3.52 (dq, J = 3.2, 9.6 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H);
1
3
C NMR (125 MHz, CDCl
3
) δ 13.9, 14.1, 22.4, 23.4, 25.1, 27.0, 27.6, 31.8, 34.4, 60.4, 67.0,
+
1
1
73.7; mass spectrum m/z (relative intensity) EI 214 (0.04, M ), 196 (2), 169 (100), 157 (43),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
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49
50
51
52
53
54
55
56
57
58
59
60
22 3
41 (12), 128 (52), 123 (15), 99 (59), 81 (66), 55 (59). Anal. Calcd for C12H O : C, 67.26; H,
10.35 %; found: C, 67.63; H, 10.59 %. Minor (2b’): IR (neat) 3457 (br s), 2956 (s), 2932 (s),
-
1 1
2
7
850 (s), 1730 (s), 1468 (s), 1374 (s), 1176 (s) cm ; H NMR (500 MHz, CDCl
3
) δ 0.91 (t, J =
.3 Hz, 3H), 1.27 (t, J = 6.9 Hz, 3H), 1.30-1.38 (m, 4H), 1.34 (d, J = 6.4 Hz, 3H), 1.40-1.67 (m,
1
3
6H), 3.15 (dq, J = 3.2, 6.4 Hz, 1H), 4.13 (q, J = 7.3 Hz, 2H); C NMR (125 MHz, CDCl
3
) δ
1
3.9, 14.2, 22.4, 23.4, 25.7, 27.2, 27.5, 31.8, 35.3, 60.5, 67.4, 173.8; mass spectrum m/z (relative
+
intensity) EI 214 (0. 1, M ), 197(13), 169 (100), 157 (26), 141 (14), 99 (82), 81 (77), 55 (83);
+
HRMS (ESI) calculated for [C12
H
22
O
3
Na] : 237.1461, found 237.1458.
(1R*, 2R*, 3S*, 1’R*) Ethyl 2-(1-hydroxyethy)-3-(1-methylethyl)cyclopropane carboxylate
o
i
(
2c). Employing General Procedure B, at -20 C, PrMgBr (0.50 mL, 2.0 M in Et
2
O, 1.0 mmol),
MeLi (1.25 mL, 1.6 M in diethyl ether, 2.0 mmol), flame dried ZnBr
2
(225 mg, 1.0 mmol) and
ethyl 4,5-epoxy-2,3-hexenoate (156 mg, 1.0 mmol) gave after purification by flash column
chromatography (silica, 10-20 % EtOAc:petroleum ether, v/v) 2c (138 mg, 69 %, dr 100:0) as a
colorless oil (the application of General procedure C gave 160 mg, 80%, 100:0 dr): IR (neat)
-
1
1
3
448 (br s), 2941 (br s), 2868 (s), 1727 (s), 1471 (s), 1370 (s), 1179 (s) cm ; H NMR (500
MHz, CDCl ) δ 1.10 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 1.19 (t, J = 4.6 Hz, 1H), 1.27
t, J = 6.8 Hz, 3H), 1.31-1.34 (m, 1H), 1.35 (d, J = 9.6 Hz, 3H), 1.36-1.42 (m, 1H), 1.10 (s, 1H),
3
(
1
3
1
.65 (dt, J = 5.0, 9.6 Hz, 1H), 3.53 (dq, J = 3.2, 6.4 Hz, 1H), 4.12 (q, J = 6.9 Hz, 2H); C NMR
(125 MHz, CDCl
3
) δ 14.2, 22.8, 23.0, 23.9, 24.4, 27.4, 35.2, 36.1, 60.5, 67.1, 173.8; mass
2
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6
+
spectrum m/z (relative intensity) EI 200 (0.3, M ), 155 (55), 32 (128), 110 (98), 99 (100), 69
(
35), 56 (54). Anal.Calcd for C11
1R*,2R*,3S*,1’R*) Ethyl 2-(1-hydroxyethyl)-3-phenylcyclopropane carboxylate (2d).
O, 1.0 mmol), MeLi
(225 mg, 1.0 mmol) and ethyl 4,5-
O gave after purification by flash column
20 3
H O : C, 65.97; H, 10.07 %; found: C, 65.87; H, 10.2 %.
(
0
1
2
3
4
5
6
7
8
9
0
1
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0
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9
0
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5
6
7
8
9
0
Employing General Procedure B and using PhMgBr (0.36 mL, 2.8 M in Et
(1.25 mL, 1.6 M in Et O, 2.0 mmol), flame dried ZnBr
epoxy-2,3-hexenoate (156 mg, 1.0 mmol) in Et
2
2
2
2
chromatography (silica, 15-20 % EtOAc:petroleum ether, v/v) 2d (74 mg, 32 %, dr 100:0) as a
colorless oil. Utilization of General Procedure D gave 2d (157 mg, 61 %) as a major product: IR
-1
1
(
neat) 3425 (br s), 2976 (s), 2890 (s), 1724 (s), 1447 (s), 1180 (s), 699 (s) cm ; H NMR (500
MHz, CDCl ) δ 1.22 (d, J = 6.4 Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H), 1.41 (s, 1H), 1.82-1.87 (m,
H), 1.99 (t, J = 4.3 Hz, 1H), 2.80 (dd, J = 4.1, 9.2 Hz, 1H), 3.14 (dq, J = 6.4, 9.6 Hz, 1H), 4.12
3
1
13
(
q, J = 6.9 Hz, 2H), 7.17-7.30 (m, 5H); C NMR (125 MHz, CDCl
3
) δ 14.2, 22.5, 23.3, 30.7,
3
5.9, 60.9, 66.4, 127, 128.5, 128.7, 135.4, 172.9; mass spectrum m/z (relative intensity) EI 234
+
(
0.16, M ), 216 (0.1), 189 (100), 177 (28), 161 (21), 144 (49), 143 (32), 133 (42), 128 (85), 117
+
(
84), 115 (95), 107 (28), 91 (44), 77 (23), 55 (8); HRMS (ESI) calculated for [C14
H18NaO
3
] :
257.1154, found 257.1148.
-endo-(Phenyl)-4-methyl-3-oxabicyclo-[3.1.0]-hexen-2-one (3d). Employing General
Procedure D and using PhMgBr (0.43 mL, 2.8 M in Et O, 1.0 mmol), flame dried Zn(CN) (12
mg, 0.1 mmol) and ethyl 4,5-epoxy-2,3-hexenoate (156 mg, 1.0 mmol) in Et O gave after
6
2
2
2
purification by flash column chromatography (silica, 15-20 % EtOAc:petroleum ether, v/v) 3d
1
(
13 mg, 7 %) as a minor product. H NMR (500 MHz, CDCl
3
) δ 1.39 (d, J = 5.9 Hz, 3H), 2.26
(
dd, J = 2.3, 5.5 Hz, 1H), 2.30 (t, J = 2.7 Hz, 1H), 2.40-2.43 (m, 1H), 4.80 (dq, J = 1.4, 5.9 Hz,
13
1
3
H), 6.99-7.24 (m, 5H) C NMR (125 MHz, CDCl ) δ 17.7, 25.7, 28.7, 30.9, 76.6, 125.9, 127.1,
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1
28.7, 137.2, 174.7; mass spectrum m/z (relative intensity) EI 188 (40, M ), 144 (100), 143 (65),
29 (95), 117 (36), 115 (97), 91 (26), 89 (20), 77 (16), 65 (15), 55 (17); HRMS (ESI) calculated
for [C12
H
12
O
2
Na]
1R*,2R*,3S*,1’R*) Ethyl 2-(1-hydroxyethyl)-3-ethylcyclopropane carboxylate (2f).
Employing General Procedure C and using EtMgCl (0.6 mL, 2.0 M in Et O, 1.2 mmol), ZnBr
23 mg, 0.1 mmol) and ethyl γ,δ-epoxy-α,β-hexanoate (156 mg, 1.0 mmol) gave after
+
: 211.0730, found 211.0731.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2
2
(
purification by flash column chromatography (silica, 15-25 % EtOAc:petroleum ether, v/v) 2f
(136 mg, 73 %, dr 100:0) as a colorless oil: IR (neat) 3437 (br s), 2957 (s), 2921(s), 1717 (s),
-1
1
1
427 (s), 1364 (s), 1130 (s) cm ; H NMR (500 MHz, CDCl
3
) δ 1.08 (t, J = 7.3 Hz, 3H), 1.22 (t,
J = 4.6 Hz, 1H), 1.26 (t, J = 6.9 Hz, 3H), 1.35 (d, J = 6.4 Hz, 3H), 1.38-1.45 (m, 1H), 1.48-1.53
(
m, 1H), 1.61 (s, 1H), 1.62-1.69 (m, 2H), 3.15 (dq, J = 5.9, 12.3 Hz, 1H), 4.13 (q, J = 7.3 Hz,
13
2
H); CNMR (125 MHz, CDCl
3
) 14.0, 14.2, 20.7, 23.5, 25.0 29.3, 34.8, 60.5, 67.2, 173.7; mass
+
spectrum m/z (relative intensity) EI 186 (0.04, M ), 170 (0.1), 141 (68), 129 (52), 113 (28), 101
+
(
62), 83 (36), 67 (26), 43 (100); HRMS (ESI) calculated for [C10
09.1140.
(E) (4S*,5R*) Ethyl 4-(2-furyl)-5-hydroxy-2-hexenoate (4e). In a first flask, furan (0.08 mL,
H
18
O
3
Na] : 209.1148, found
2
o
n
1
.0 mmol) was deprotonated at 0 C using BuLi (0.4 mL, 2.5 M in hexane, 1.0 mmol) in THF
(
2.0 mL) under argon for 3 hours. In the second flask, to a solution of flame dried ZnBr (225
2
mg, 1.0 mmol) in THF (2.0 mL) under argon was added MeLi (1.25 mL, 1.6 M in Et
2
O, 2.0
o
mmol), 2-lithiofuran from flask 1 and the resulting mixture was stirred for 30 minutes at 0 C.
o
The flask was then transferred to a -20 C bath, nitro-methane (2.0 mL) and ethyl 4,5-epoxy-2,3-
hexenoate (156 mg, 1.0 mmol) was added and the resulting mixture was gradually warmed to
4 4
room temperature over 12 hours. The reaction was quenched with NH Cl-NH OH aqueous
2
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buffer (pH = 7.0, 10.0 mL), filtered and the filtrate was extracted with Et O (3 x15.0 mL). The
combined organic phase was washed with water (10.0 mL), brine (10.0 mL) and then dried over
anhydrous MgSO , filtered, concentrated in vacuo, and purified by flash column chromatography
silica, 10-20% EtOAc in petroleum ether, v/v) to give pure compounds 4e (128 mg, 57%, dr
4
0
1
2
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0
1
2
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9
0
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8
9
0
(
6
0
100:0) as a colorless liquid. IR (neat) 3423 (br, s), 2921 (s), 2852 (s), 1718 (s), 1458 (s), 1262
-
1 1
(
s), 1143 (s), 799 (s) cm ; H NMR (500 MHz, CDCl
3
) δ 1.11 (d, J = 5.9 Hz, 3H), 1.23 (t, J =
7
.3 Hz, 3H), 1.92 (s, 1H), 3.48 (dd, J = 8.7, 5.9 Hz, 1H), 4.06-4.14 (m, 3H), 5.85 (d, J = 15.6
Hz, 1H), 6.25-6.27 (m, 1H), 7.06 (dd, J = 8.7, 15.6 Hz, 1H), 6.08 (d, J = 2.7 Hz, 1H), 7.30 (d, J =
13
1
1
1
.8 Hz, 1H); C NMR (125 MHz, CDCl
3
) δ 14.3, 20.9, 49.9, 60.6, 69.2, 107.3, 110.5, 124.6,
+
42.1, 144.5, 152.9, 166.2; mass spectrum m/z (relative intensity) EI 224 (0.12, M ), 206 (57),
78 (100), 139 (39), 133 (73), 128 (56), 111(71), 84 (63), 67 (44), 56 (17).
General Procedure F: Synthesis of Ketodiene Ketodienes used for the epoxidation reactions
were synthesized by using the following procedure. To a solution of LDA (12.0 mL 1.0 M in
o
THF) was added ketone (10.0 mmol in 10.0 mL THF) over 10 minutes at -78 C. After 75
minutes, the mixture of crotonaldehyde (0.70 g, 10.0 mmol) with TMSCl (1.08 gm, 10.0 mmol)
in THF (5.0 mL) was added drop wise. The solution was removed from the cooling bath, stirred
at room temperature for one hour before refluxing for 4 hours. The reaction was quenched with
saturated NH
combined organic phase was washed with water (15.0 mL), brine (15.0 mL) and then dried over
anhydrous MgSO , filtered, concentrated in vacuo. The NMR of the product was identical with
the one reported in the literature.
2E,4R*,5R*)-4,5-Epoxy-1-phenylhex-2-en-1-one (6). Employing General Procedure F and
using LDA (18.0 mL 1.0 M in THF), acetophenone (1.8 gm, 15.0 mmol), crotonaldehyde (1.05
4
Cl solution, diluted with water, extracted with dichloromethane (3 x 15 mL). The
4
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gm, 15.0 mmol) and TMSCl (1.62 gm, 15.0 mmol) gave (2E, 4E)-1-phenyl-2,4-hexadien-1-one
(1.73 gm, 12.5 mmol) as a colorless oil. To the solution of 2E,4E-1-phenyl-2,4-hexadien-1-one
o
(
10.0 mmol) was added m-CPBA (3.0 gm, 1.3 equiv, 75 % wt. in water) at 0 C in CH
2
Cl
2
and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the resulting mixture was warmed to room temperature over 12 hours. The reaction mixture was
quenched with Me S (1.0 mL), diluted with water (10.0 mL) and extracted with CH Cl (3 x 20.0
mL). The organic layer was washed with saturated aqueous NaHCO (5 x 20.0 mL), brine (20.0
mL), dried over anhydrous MgSO and concentrated in vacuo. The purification of product using
2
2
2
3
4
flash column chromatography (silica, 10-15% EtOAc: petroleum ether, v/v) gave pure 6 (1.52
1
gm, 81%) as a colorless oil: H NMR (500 MHz, CDCl
3
) δ 1.43 (d, J = 5.0 Hz, 3H), 3.01-3.04
(m, 1H), 3.31 (dd, J = 6.8, 1.9 Hz, 1H), 6.82 (dd, J = 6.9, 15.5 Hz, 1H), 7.20 (d, J = 14.6 Hz,
1
3
1
1
H), 7.47-7.96 (m, 5H); C NMR (125 MHz, CDCl
3
) δ 17.6, 57.7, 57.9, 126.9, 128.6, 128.7,
+
33.1, 137.3, 144.6, 189.6; mass spectrum m/z (relative intensity) EI 188 (M , 2), 172 (31), 120
(15), 105 (100), 77 (93), 65 (2), 55 (29).
(
2E,4R*,5R*)-4,5-Epoxy-1-(1-methylethyl)-hex-2-en-1-one (7). Employing General Procedure
F and using LDA (18.0 mL 1.0 M in THF), 3-methyl-2-butanone (1.29 gm, 15.0 mmol),
crotonaldehyde (1.05 gm, 15.0 mmol) and TMSCl (1.62 gm, 15.0 mmol) gave (2E, 4E)-1-
methylethyl-2,4-hexadien-1-one (1.73 gm, 12.5 mmol) as a colorless oil. To the solution of (2E,
4
2 2
E)-1-(1-methylethyl)-2,4-hexadien-1-one (1.38 gm, 10.0 mmol) in CH Cl was added m-CPBA
o
(1.3 equiv, 3.0 gm, 75 % wt. in water) at 0 C and the resulting mixture was warmed to room
temperature over 4 hours. The reaction mixture was quenched with Me
water and extracted with CH Cl (3 x 20.0 mL). The organic layer was washed with saturated
aqueous NaHCO (5 x 20.0 mL), brine (20.0 mL), dried over anhydrous MgSO , filtered and
concentrated in vacuo after purification by flash column chromatography (silica, 10-15 %
2
S (1.0 mL), diluted with
2
2
3
4
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