Darzens reaction rate enhancement using aqueous media leading to a high level of kinetically controlled diastereoselective synthesis of steroidal epoxyketones

Article abstract of DOI:10.1021/jo501500v

Darzens reactions between halocarbonyls and aldehydes have been carried out in water in the presence of a Li⁺-containing base, a phase-transfer catalyst, and granular polytetrafluoroethylene under mechanical stirring. Reactions using both aromatic and aliphatic aldehydes produced epoxides stereoselectively in good to excellent yields. This is the first time that aliphatic aldehydes with α-H have been used in aqueous Darzens reactions. The Darzens reactions were much faster in water than in organic solvents. This aqueous rate enhancement occurred for Darzens reactions between enantiopure steroidal haloketones and aldehydes, yielding enantiopure spiroepoxides with a high level of kinetically controlled diastereoselectivity. Chromatography was avoided in the purifications of the steroidal spiroepoxides. This is an example of preparing enantiopure epoxyketones via aqueous Darzens reaction using chiral α-haloketone substrates.

Full text of DOI:10.1021/jo501500v

Subscriber access provided by BOSTON COLLEGE
Article
Darzens Reaction Rate Enhancement via Using Aqueous
Media Leading to a High Level of Kinetically Controlled
Diastereoselective Synthesis of Steroidal Epoxyketones
Bo Li, and Chunbao Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501500v • Publication Date (Web): 13 Aug 2014
Downloaded from http://pubs.acs.org on August 14, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Darzens Reaction Rate Enhancement via Using Aqueous Media
Leading to a High Level of Kinetically Controlled
7
8
9
Diastereoselective Synthesis of Steroidal Epoxyketones
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
Bo Li and Chunbao Li*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072 (China).
Fax: (+86) 2227403475. Eꢀmail: lichunbao@tju.edu.cn
ABSTRACT
Darzens reactions between halocarbonyls and aldehydes have been carried out in water in the
presence of a Li+ꢀcontaining base, a phaseꢀtransfer catalyst and granular polytetrafluoroethylene
under mechanical stirring. Reactions using both aromatic and aliphatic aldehydes produced
epoxides stereoselectively in good to excellent yields. This is the first time that aliphatic aldehydes
with αꢀH have been used in aqueous Darzens reactions. The Darzens reactions were much faster in
water than in organic solvents. This aqueous rate enhancement occurred for Darzens reactions
between enantiopure steroidal haloketones and aldehydes, yielding enantiopure spiroepoxides in a
high level of kinetically controlled diastereoselectivity. Chromatography was avoided in the
purifications of the steroidal spiroepoxides. This is an example of preparing enantiopure
epoxyketones via aqueous Darzens reaction using chiral αꢀhaloketone substrates.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
1
2
3
4
5
Introduction
6
7
8
9
Darzens reaction is a nonꢀoxidative method in the construction of epoxycarbonyls and related
compounds.1 Classically, this reaction is performed in the presence of a halocarbonyl, an aldehyde
and a base in organic solvents. To achieve high yield, stereoselectivity and enantioselectivity and
to ensure the survival of the substrates bearing baseꢀliable groups, the reaction needs to be
performed under mild conditions at the cost of reaction rates.2 It is quite often that the reactions
take one or two days or even ten days.2 In some cases, a twoꢀstep procedure (an aldolꢀtype
reaction and an intramolecular cyclization) was used to achieve better results.3 The asymmetric
version of Darzens reaction has been realized by using chiral catalysts or auxiliaries.2a For
example, enantiopure camphorꢀbased αꢀbromoketones were used in the asymmetric Darzens
reaction.4 However, the ketones with the camphorꢀbased auxiliary and the chiral epoxyacids were
produced instead of chiral epoxyketones without auxiliary. To the best of our knowledge, there
have been no reports of asymmetric Darzens reaction using chiral αꢀhaloketone leading to
α,βꢀepoxyketones.
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
The advantages of waterꢀmediated reactions over organic solventꢀmediated ones include
better yields, better stereoselectivities and faster speeds.5 Especially, we have noted the
neighboring heteroatom effect unique to aqueous aldol reactions.5g In this work, our goal was to
investigate whether this effect could be extended to aqueous Darzens reactions to yield the
products diastereoselectively.
Results And Discussion
Initially, comparison Darzens reactions promoted by LiOH or Li2CO3 were carried out in water
and in organic solvents (Table 1). In accordance with our previous work,5eꢀg the aqueous reactions
involving waterꢀinsoluble highꢀmeltingꢀpoint organic substrates were accelerated by adding
granular polytetrafluoroethylene (granular PTFE, or PTFE sand, see Supporting Information, page
S2ꢀS3) and agitating with a modified stirring rod. Mechanically stirring a mixture of chloroketone
1a (500 mg), Li2CO3 (1.2 equiv), benzaldehyde 2a (1.05 equiv), Aliquat 336 (50 mg), water (4 mL)
and granular PTFE (5 g) at 60 oC produced epoxyketone 3a in 86% yield and in a short time (0.3
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
h). However, no reactions took place for either the homogeneous (Table 1, entries 2ꢀ4) or
heterogeneous (Table 1, entries 5ꢀ7) organic solvent systems even after a longer period (1 h). The
reactions for chloroamides 1b and 1c with 2a were achieved in the aqueous system and failed in
methanol (Table 1, entries 8ꢀ11). The reaction between 1a and aliphatic aldehyde 2b had a faster
reaction rate and a higher yield than those in the control experiment in methanol (Table 1, entries
12ꢀ13).
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
Table 1. Comparison of Aqueous and Organic SolventꢀMediated Darzens Reactionsa
Yield
entry
carbonyl
aldehyde
solvent
base
t (h)
(%)c,d
86, 3a
NRe
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
H2O
EtOH
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
LiOH
0.3
1
3
DMF
1
NRe
4
CH3CN
1
NRe
5
THFꢀH2O (3:1)
PhMeꢀH2O (3:1)
tBuOHꢀH2O (3:1)
H2O
1
trace
NRe
6
1
7
1
NRe
8
5.5
5
52, 3b
trace
44, 3c
trace
53, 3d
32, 3d
9
MeOH
LiOH
10
11
12
13
H2O
LiOH
3
MeOH
LiOH
5
H2O
Li2CO3
Li2CO3
1
MeOH
12
aReaction conditions in water: 1aꢀ1c (500 mg, 1.0 equiv.), base (1.2 equiv), aldehyde (1.05 equiv
for 2a, 1.2 equiv for 2b), Aliquat 336 (50 mg), water (4 mL) and granular PTFE (5 g), mechanical
o
stirring (400 rmp) at 60 C. Reaction conditions in organic solvents: 1aꢀ1c (500 mg, 1.0 equiv),
base (1.2 equiv), aldehyde (1.05 equiv for 2a, 1.2 equiv for 2b) and organic solvent (4 mL),
magnetic stirring at 60 oC. bCy=cyclohexyl. cIsolated yield. d3a and 3d were transꢀisomers, 3b and
3c were a mixture of cisꢀ and transꢀisomers (1:1). eNR, no reaction.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
1
2
3
4
5
6
7
8
9
These improved performances in aqueous media encouraged us to investigate a series of
aqueous Darzens reactions between chlorocarbonyls and aromatic and aliphatic aldehydes with
αꢀH. The results are summarized in Scheme 1. For the reactions with aromatic aldehydes and
formaldehyde, Aliquat 336 was used as the phaseꢀtransfer catalyst (PTC) to produce epoxides
3eꢀ3k (Scheme 1) in excellent yields. For the aliphatic aldehydes, sodium dodecyl sulfate (SDS)
was used as the PTC because it gave higher yields (Scheme 1, 3lꢀ3p) than Aliquat 336 did. Some
of the aqueous reactions occurred instantly (Scheme 1, 3l and 3m), and most of the reaction times
were less than 1 h. With the exception of 3h and 3k, antiꢀepoxides were stereoselectively obtained
for all reactions.
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
Scheme 1. Aqueous Darzens Reactions Using Aromatic and Aliphatic Aldehydes.a
aReaction conditions for 3eꢀ3k: haloketone (500 mg), base (1.2 equiv, Li2CO3 for 3eꢀ3j or LiOH
for 3k), aldehyde (5.0 equiv for 3k and 1.05 equiv for the others), Aliquat 336 (50 mg), granular
PTFE (5 g) and water (4 mL), mechanical stirring (400 rmp) for 3eꢀ3i or magnetic stirring (400
rmp) for 3j and 3k. Reaction conditions for 3lꢀ3p: haloketone (500 mg), LiOH (2.0 equiv), 20%
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
1
2
3
4
5
b
(w/w) aqueous SDS (500 mg), aldehyde (2.0 equiv), magnetic stirring (400 rmp) Without the
granular PTFE, the conversion was only 37% in 1 h.
6
7
8
9
Aqueous Darzens reactions have been reported by Tanaka et al and Shi et al.6 The differences
between literature works and this work are in the following aspects. Firstly, weak bases Li2CO3
and LiOH were used in this work, which ensures the survivals of ester and amide groups (Table 1,
entries 8 and 10; Scheme 1, 3h; Table 3, entry 16; and Table 4, entry 9). Strong base NaOH was
used in the literature works. Secondly, lipophilic Aliquat 336 used in this work functions as both a
PTC and a reaction medium for waterꢀinsoluble highꢀmeltingꢀpoint organic substrates. Thirdly,
granular PTFE used in this work was especially useful in the promotion of aqueous reactions for
waterꢀinsoluble highꢀmeltingꢀpoint organic substrates. In the presence of the granular PTFE, the
reaction took 10 min to produce 3g in 98% yield (Scheme 1). In the control experiment for
preparing 3g in the absence of granular PTFE, the reaction ended in only 37% conversion in 1 h.
Finally, haloamides, both aliphatic and aromatic haloketones and aldehydes were used in this work.
In the literature works, only ωꢀchloroacetophenones and aromatic aldehydes were used.
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
Previously, Darzens reactions using aliphatic aldehydes have only been performed in organic
solvents. The literature results of Darzens reactions using aliphatic aldehydes in organic solvents
are compared with the aqueous reaction results from this work in Table 2. All the reactions
performed in organic solvents were sluggish7ꢀ9 with reaction times from 5 to 134 h (Table 2,
entries 1, 2, 4, 5, 7 and 9). However, in our aqueous system, the reactions were much faster (1 min
to 0.5 h, Table 2, entries 3, 6, 8 and 10). In addition, most of the yields were excellent (Scheme 1).
Obviously, Darzens reactions can be dramatically accelerated by using an aqueous medium, which
is probably because that the high concentrations of the substrates in the PTC phase, the
neighboring heteroatom effect5g of the halocarbonyls in the aqueous system, and the acceleration
effect of granular PTFE for the aqueous reaction for waterꢀinsoluble highꢀmeltingꢀpoint organic
substrates. The ratio of substrate to granular PTFE is 10:1 (w/w). The latter functions as hundreds
of coꢀstirrers to smash the former.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
1
2
3
Table 2. Darzens Reaction Performances Using Aliphatic Aldehydes in Organic Solvents versus
4
5
Water.
entry
1a
2b
3c
4a
5d
6c
7a
8c
product
3l
solvent
nBu2O
CHCl3
H2O
temperature
4 oC
rt
time
yield (%)
32
6
7
8
9
117 h
5 h
3l
49
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
3l
rt
1 min
60 h
98
3m
3m
3m
3n
nBu2O
CH2Cl2
H2O
4 oC
ꢀ20 oC
0 oC
4 oC
0 oC
4 oC
0 oC
82
72 h
93
3 min
134 h
30 min
60 h
72
nBu2O
H2O
73
3n
55
9a
10c
3o
nBu2O
H2O
80
3o
15 min
81
aSee reference 7. bSee reference 8. cThis work. dSee reference 9.
With this fast reactionꢀrate procedure in hand, we proceeded to test if the high reaction rates
can lead to a kinetically controlled diastereoselective synthesis of epoxyketones. Enantiopure
bromoketone 4a (16αꢀBr) and chloroketone 4b (16βꢀCl) were chosen to react with formaldehyde
or benzaldehyde and the results are summarized in Table 3. Mechanically stirring a mixture of
haloketone 4a (500 mg), formaldehyde (5.0 equiv), LiOH (1.2 equiv), water (4 mL), Aliquat 336
(50 mg) and granular PTFE (5 g) at room temperature for 1 h gave (16R)ꢀspiroepoxide 5a as the
only product in 95% yield (Table 3, entry 1). In contract, the stereoselectivies were poor in organic
solventꢀmediated reaction and the ratios of the diastereoisomers (5a:6a) ranged from 11.3:1 to
0.5:1 with much longer reaction times (Table 3, entries 2 to 7). The aqueous condensation of 4a
o
and benzaldehyde at 65 C promoted by Li2CO3 or Na2CO3 led to the stereospecific and
quantitative production of (16R)ꢀspiroepoxide 5b (Table 3, entries 8 and 13). However, in the
o
presence of K2CO3 or Cs2CO3, no reaction took place at 65 C (Table 3, entries 14 and 15). This
indicates that hard ions Li+ and Na+ can chelate with the bidentate haloenolate and soft ions K+
and Cs+ cannot. Another explanation for the better performance of Li2CO3 than other carbonates
are an appropriate size of Li+ allowing its incorporation in a chelated fiveꢀmembered ring without
strain. In the control experiments in methanol, the diastereoselectivity was poor (Table 3, entries
16ꢀ19). In terms of reaction rate, yield and diastereoselectivity, the Cs2CO3ꢀpromoted reaction
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(Table 3, entry 19) was the best among the four carbonateꢀpromoted reactions mediated by
methanol. This is because that Cs2CO3 is the strongest base among the four carbonates and the
chelations between M+ and the haloenolates are not important in methanol.
9
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
Three sets of control experiments were carried out to test the effects of the amount of water,
the stirring speed and the nature of PTC on the reactions of 4a. Only a slight change in the
reaction times was observed when the amount of water was decreased from 4 mL (Table 3, entry 8,
5 h) to 2 mL (Table 3, entry 9, 5.5 h). The reaction time (5 h) was almost the same after doubling
the amount of water from 4 mL (Table 3, entry 8) to 8 mL (Table 3, entry 10). The possible reason
is that Li2CO3 is slightly soluble in water (solubility at 60 oC: 10 mg/mL). If the amount of water
is not enough, a less amount of Li2CO3 gets dissolved to take part in the reaction. Raising the
stirring speed from 400 rmp (Table 3, entry 8) to 800 rmp (Table 3, entry 11) did not change the
reaction time. The reaction time was 1 h longer by decreasing the stirring speed to 200 rmp (Table
3, entry 12). Stirring rate 400 rmp was appropriate. Without lipophilic Aliquat 336 or replacing it
with waterꢀsoluble tetrabutylammonium bromide or SDS, the aqueous reactions for steroidal
haloketones 4a did not occur.
o
In the aqueous reactions of 4b and benzaldehyde at 65 C (Table 3, entries 20ꢀ23), Li2CO3
was the base that produced the epoxides (6c:5c = 20:1) in the highest rate among the four
carbonates because Li+ is harder than Na+, K+ and Cs+. This is in agreement with the neighboring
heteroatom effect unique to aqueous reactions.5g The ester group of 4b survived the basic
conditions. If the water is replaced by organic solvents, the ester group becomes hydrolyzed.10
Other advantages of the aqueous reaction over the organic solventꢀmediated ones are that the
isomerization11 of 4a (16αꢀBr) to 7 (16βꢀBr) (Table 3, entries 3ꢀ7 and 16), the hydrolysis11 of 4a to
side product 8 (Table 3, entries 3ꢀ7), lower conversions and reaction rates (Table 3, entries 3ꢀ7 and
12) occurred in organic solventꢀmediated reactions were not observed in the aqueous reactions. All
these results indicate that faster reaction rates result in better diastereoselectivities in both the
aqueous (Table 3, entries 1, 8ꢀ15, and 20ꢀ23) and organic solventꢀmediated (Table 3, entries 2ꢀ7
and 16ꢀ19) reactions.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
1
2
3
4
5
Table 3. Comparison of the Diastereoselectivity in Aqueous and Organic Solventꢀmediated
Darzens Reactionsa
6
7
8
9
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
yield (%)c
t
conv.
(%)c
entryb ketone
solvent
base
epoxide (d.r.c)
95d (5a only)
7
0
0
7
4
5
8
0
(h)
1
2
3
4
5
6
4a
4a
4a
4a
4a
4a
H2O
MeOH
EtOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
1
100
100
94
10
10
10
10
10
91d(5a:6a=11.3:1)
63 (5a:6a=8.1:1)
69 (5a:6a=8.1:1)
65 (5a:6a=3.3:1)
19 (5a:6a=1.5:1)
0
24
15
13
DMF
88
iPrOH
CH3CN
82
75
10 46
PhMeꢀH2O
(3:1)
7
4a
LiOH
10
28
12 (5a:6a=0.5:1)
5
11
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
H2O
H2O
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Na2CO3
K2CO3
Cs2CO3
Li2CO3
Na2CO3
K2CO3
Cs2CO3
Li2CO3
Na2CO3
K2CO3
Cs2CO3
5
5.5
5
100
100
100
100
100
100
trace
trace
73
>99d (5b only)
>99d (5b only)
>99d (5b only)
>99d (5b only)
>99d (5b only)
>99d (5b only)
trace
0
0
0
0
0
0
0
0
35
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
9e
10e
11f
12f
13
14
15
16
17
18
19
20
21
22
23
H2O
H2O
5
H2O
6
H2O
8
H2O
5
H2O
5
trace
MeOH
MeOH
MeOH
MeOH
H2O
24
5
38 (5b:6b=0.3:1)
91d (5b:6b=0.5:1)
93d (5b:6b=0.8:1)
93d (5b:6b=1.3:1)
>99d (6c:5c=20:1)
>99d (6c:5c=17:1)
>99d (6c:5c=15:1)
>99d (6c:5c=18:1)
100
100
100
100
100
100
100
1
0.5
1
H2O
1.5
5
H2O
H2O
10
aAqueous reaction conditions: haloketone (4a or 4b, 500 mg), aldehyde (5.0 equiv for entries 1ꢀ7,
1.05 equiv for entries 8ꢀ23), base (1.2 equiv), water (4 mL), Aliquat 336 (50 mg) and granular
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
1
2
3
PTFE (5 g), mechanical stirring (400 rmp). Organic solventꢀmediated reaction conditions: ketone
4
5
6
7
8
9
(4a or 4b, 500 mg), aldehyde (5.0 equiv for entries 2ꢀ7, 1.05 equiv for entries 16ꢀ19), base (1.2
b
equiv), organic solvent (4 mL), mechanical stirring (400 rmp). Reaction temperatures: 25 oC for
o
c
1
d
e
entries 1ꢀ7, 65 C for entries 8ꢀ23. Determined by H NMR. Isolated yield. The amounts of
f
water were 2 mL for entry 9 and 8 mL for entry 10. The stirring rates were 800 rmp for entry 11
and 200 rmp for entry 12.
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
The reaction conditions were further applied to the preparations of nine enantiopure
epoxyketones (Table 4 entries 1ꢀ9, 5dꢀ5k and 6d) from four haloketones (4aꢀ4d) and five
aldehydes with good isolated yields (53ꢀ77%) in water at 65ꢀ80 oC. At the end of the reactions, the
granular PTFE precipitated on the bottom of the flask. The purifications of the products were
performed only by filtration and crystallization and the granular PTFE was collected and reused.
The organic solvent extractions in the workup and chromatography were avoided. The
configurations at Cꢀ16 for 5 (5a, 5b and 5dꢀ5k) and 6 (6c and 6d) are 16R and 16S respectively,
which originate from (16αꢀBr)ꢀsteroidal ketones 4a, 4c and 4d for 5 and (16βꢀCl)ꢀsteroidal ketone
4b for 6, and are complementary to each other stereochemically.
Table 4. Aqueous Diastereoselective Darzens Reactions for Spiroepoxyketones.a
C5ꢀ6 or
C5ꢀH
yieldd
(%)
entry
substrate
R
T
t (h)
product
Ar
1
2
3
4
5
6
4a
4a
4a
4a
4c
4c
H
H
H
H
H
H
db
db
5d
5e
5f
4ꢀNO2C6H4
4ꢀMeOC6H4
4ꢀClC6H4
4ꢀBrC6H4
Ph
67
77
63
65
60
65
65 oC
80 oC
70 oC
70 oC
65 oC
80 oC
3
5
db
10.5
10
5
db
5g
5h
5i
sc, α
sc, α
4ꢀMeOC6H4
2.5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
1
2
3
4
5
6
7
8
9
65 oC
80 oC
65 oC
8
5.5
1
7
8
9
4d
4d
4b
Bn
Bn
ꢀ
db
db
ꢀ
5j
5k
6d
Ph
76
67
53
4ꢀMeOC6H4
4ꢀNO2C6H4
aReaction conditions: haloketone (4aꢀ4d, 500 mg), aldehyde (1.05 equiv), Li2CO3 (1.2 equiv),
b
water (4 mL), Aliquat 336 (50 mg) and granular PTFE (5 g), mechanical stirring. Double bond.
cSingle bond. dIsolated yield after crystallization.
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
In summary, the reaction rates of Darzens reactions were greatly enhanced by using aqueous
media because of the neighboring heteroatom effect of the halocarbonyls and the acceleration
effects of granular PTFE for waterꢀinsoluble highꢀmeltingꢀpoint organic substrates. The yields and
stereoselectivities were good to excellent for both aromatic and aliphatic aldehydes in the aqueous
reactions. This is the first time that aliphatic aldehydes have been used in aqueous Darzens
reactions. As weak bases were used, esters and amides could survive the reactions. Altogether 12
enantiopure (16R)ꢀ and (16S)ꢀsteroidal spiroepoxyketones were produced in good to excellent
yields in a high level of kinetically controlled diastereoselectivity.
Experimental Section
General Information. Steroidal haloketones 4aꢀ4c11b and 4d12 were prepared according to the
literatures. Other halocarbonyls were obtained from commercial sources or prepared according to
standard methods.13 1H NMR, NOESY (400 or 600 MHz) and 13C{1H} NMR (100 or 151 MHz)
spectra were recorded with a 400 or 600 MHz spectrometer using TMS as an internal standard.
Chemical shifts (δ
) are reported relative to TMS (1H) or CDCl3 (13C) and multiplicities are
reported as follows: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). Infrared
analyses (KBr pellet) were performed on a FTꢀIR spectrometer. Elemental analyses for C, H and N
were performed on an elemental analyzer. High resolution mass spectra (HRMS) were recorded on
a QTOF mass analyzer with electrospray ionization (ESI). Melting points were recorded with a
micro melting point apparatus. The aqueous reactions for insoluble high meltingꢀpoint organic
substrates were conducted in 100 mL flasks and agitated by the modified stirring rod.3g The
polytetrafluoroethylene (PTFE) plate (Supporting Information, Page S2) was cut into granular
PTFE (70 pieces/g, Supporting Information, Pages S2 and S3).
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
General Procedures for the Aqueous Darzens Reactions Using Aliquat 336 as Phase
Transfer Catalyst.
7
8
9
Procedure A: a mixture of halocarbonyl (500 mg, 1.0 equiv), Aliquat 336 (50 mg), aldehyde
(1.2 equiv for aliphatic one, 1.05 equiv for aromatic one, 5.0 equiv for formaldehyde), granular
PTFE (5 g), base (Li2CO3 or LiOH, 1.2 equiv) and water (4 mL) were mechanically stirred (400
rmp). After TLC indicated completion of the reaction, the crude product suspended in water was
filtrated, leaving the granular PTFE precipitating on the bottom to be recovered. For products 3a,
3d, 3f, 5dꢀ5i and 6d, the crude product was crystallized in methanol (2 mL) to give the desired
product. For products 5j and 5k, the crude product was crystallized in ethyl acetate (2 mL). For
products 3b, 3c and 3i, chromatography was used. For products 3e, 3g, 3h, 5a, 5b and 6c, the
desired product were obtained after washing the crude product with 1.5 mL of cold aqueous
acetone (75% v/v). For 3j and 3k, the reaction was magnetically stirred. After extraction (ethyl
acetate, 5 mL x 3), drying (Na2SO4) and concentration under reduced pressure, the crude product
was purified via bulbꢀtoꢀbulb distillation under reduced pressure.
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
General Procedures for the Darzens Reactions Using Aqueous Sodium Dodecyl Sulfate as
the Reaction Medium.
Procedure B: After magnetically stirring (400 rmp) a mixture of halocarbonyl (500 mg, 1.0
equiv), aliphatic aldehyde (2.0 equiv), and 20% (w/w) aqueous SDS (500 mg) for 15 min, LiOH
(2.0 equiv) was added. The reaction mixture was stirred for an additional period of time. After
TLC indicated completion of the reaction, 1.0 equiv of acetic acid was added. The water and
excess aldehyde were removed under reduced pressure. Crude product 3l was purified via
bulbꢀtoꢀbulb distillation under reduced pressure. For products 3mꢀ3p, chromatography was used.
transꢀ1ꢀ(4ꢀBromophenyl)ꢀ2,3ꢀepoxyꢀ3ꢀphenylꢀ1ꢀpropanone (3a). Procedure A: 469 mg, 86% yield;
white solid; mp 134ꢀ135 oC; 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.5 Hz, 2H), 7.64 (d, J =
7.6 Hz, 2H), 7.42ꢀ7.36 (m, 5H), 4.22 (s, 1H), 4.08 (s, 1H); 13C NMR (151 MHz, CDCl3): δ 192.3,
135.3, 134.1, 132.3, 129.9, 129.4, 129.2, 128.8, 125.8, 61.1, 59.4; Product 3a is a known
compound.14
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
1
2
3
4
5
6
7
8
9
NꢀBenzylꢀ3ꢀphenylꢀ2,3ꢀepoxyꢀ1ꢀpropanamide (3b). Procedure A: 359 mg, 52% yield; white solid;
1H NMR (600 MHz, CDCl3): 7.35ꢀ7.16 (m, 9H), 6.70 (d, J = 7.2 Hz, 1H), 6.64 (s, 0.5H), 6.19 (s,
0.5H), 4.45ꢀ4.41 (m, 1H), 4.31 (d, J = 4.6 Hz, 0.5H, transꢀisomer), 4.28 (dd, J = 14.9, 6.9 Hz, 0.5H),
4.04 (dd, J = 15.0, 5.0 Hz, 0.5H), 3.88 (d, J = 1.3 Hz, 0.5H, cisꢀisomer), 3.81 (d, J = 4.7 Hz, 0.5H,
transꢀisomer), 3.55 (d, J = 1.5 Hz, 0.5H, cisꢀisomer); 13C NMR (151 MHz, CDCl3): δ 166.2, 137.0,
133.1, 128.6, 128.5, 127.5, 127.3, 126.6, 58.3, 56.4, 42.7, 29.7; Product 3b is known
compounds.15
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
NꢀCyclohexylꢀ3ꢀphenylꢀ2,3ꢀepoxyꢀ1ꢀpropanamide (3c). Procedure A: 307 mg, 44% yield; white
1
solid; H NMR (600 MHz, CDCl3): δ 7.36ꢀ7.26 (m, 5H), 6.14 (d, J = 6.3 Hz, 0.5H), 5.71 (d, J =
6.0 Hz, 0.5H), 4.31 (d, J = 4.7 Hz, 0.5H, transꢀisomer), 3.85 (s, 0.5H, cisꢀisomer), 3.82ꢀ3.77 (m,
1H), 3.76 (d, J = 4.8 Hz, 0.5H, transꢀisomer), 3.51 (s, 0.5H, cisꢀisomer), 1.96ꢀ1.89 (m, 1H),
1.76ꢀ1.72 (m, 1.5H), 1.64ꢀ1.60 (m, 1H), 1.49ꢀ1.47 (m, 0.5 H), 1.41ꢀ1.33 (m, 1.5 H), 1.28ꢀ0.99 (m,
4H), 0.49ꢀ0.43 (m, 0.5 H);13C NMR (151 MHz, CDCl3): δ 165.0, 133.3, 128.4, 128.3, 126.6, 58.1,
56.2, 47.2, 32.7, 32.2, 29.7, 25.3, 24.6, 24.4;
Product 3c is known compounds.17
transꢀ1ꢀ(4ꢀBromophenyl)ꢀ2,3ꢀepoxyꢀ5ꢀmethylꢀ1ꢀhexanone (3d). Procedure A: 316 mg, 53% yield;
white solid; mp 44ꢀ45 oC; 1H NMR (600 MHz, CDCl3): δ 7.90 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5
Hz, 2H), 3.94 (d, J = 1.7 Hz, 1H), 3.16 (ddd, J = 6.7, 4.9, 1.9 Hz, 1H), 1.95ꢀ1.85 (m, 1H), 1.66
(ddd, J = 12.1, 7.3, 4.8 Hz, 1H), 1.61ꢀ1.55 (m, 1H), 1.01 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.4 Hz,
3H); 13C NMR (151 MHz, CDCl3): δ 193.7, 134.1, 132.0, 129.8, 128.9, 59.1, 57.2, 40.8, 26.4,
22.7, 22.4; IR (KBr): v 3069, 2960, 2870, 1683, 1583, 1435, 1393, 1233, 1068, 1003, 909, 832,
736, 512 cmꢀ1; elemental analysis calcd (%) for C13H15BrO2: C 55.14, H 5.34; found, C 55.01, H
5.30.
transꢀ2,3ꢀEpoxyꢀ3ꢀ(nitrophenyl)ꢀ1ꢀphenylꢀ1ꢀpropanone (3e). Procedure A: 852 mg, 98% yield;
white solid; mp 149ꢀ151 oC; 1H NMR (600 MHz, CDCl3): δ 8.27 (d, J = 8.7 Hz, 2H), 8.01 (d, J =
7.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.52 (t, J = 7.8 Hz, 2H), 4.28 (d, J =
1.7 Hz, 1H), 4.21 (d, J = 1.4 Hz, 1H); 13C NMR (151 MHz, CDCl3): δ 192.1, 148.3, 142.8, 135.2,
134.3, 129.0, 128.4, 126.7, 124.0, 60.8, 58.0; Product 3e is a known compound.17
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
transꢀ2,3ꢀEpoxyꢀ1,3ꢀdiphenylꢀ1ꢀpropanone (3f). Procedure A: 442 mg, 61% yield; white solid; mp
89ꢀ90 oC; 1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 7.3 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t,
J = 7.7 Hz, 2H), 7.45ꢀ7.38 (m, 5H), 4.33 (d, J = 1.7 Hz, 1H), 4.10 (d, J = 1.4 Hz, 1H); 13C NMR
(151 MHz, CDCl3): δ 193.1, 135.6, 134.0, 129.1, 128.9, 128.8, 128.4, 125.9, 61.0, 59.4; Product
3f is a known compound.18
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
transꢀ1ꢀ(4ꢀBromophenyl)ꢀ2,3ꢀepoxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀpropanone (3g). Procedure A: 731 mg,
o
1
98% yield; white solid; mp 164ꢀ165 C; H NMR (600 MHz, DMSOꢀd6): δ 8.24 (d, J = 7.7 Hz,
2H), 7.90 (d, J = 7.5 Hz, 2H), 7.66ꢀ7.59 (m, 4H), 4.41 (d, J = 2.4 Hz, 1H), 4.23 (d, J = 2.4 Hz, 1H);
13C NMR (151 MHz, CDCl3): δ 191.3, 148.4, 142.5, 133.9, 132.4, 129.9, 126.7, 124.1, 60.9, 58.0;
Product 3g is a known compound.19
N,NꢀDiphenylꢀ2,3ꢀepoxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀpropanamide (3h). Procedure A: 697 mg, 95% yield;
white solid; 1H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.64 (d,
J = 7.8 Hz, 1H), 7.64ꢀ6.99 (m, 11H), 4.33 (s, 0.5H, cisꢀisomer), 4.05 (d, J = 4.3 Hz, 0.5H,
transꢀisomer), 3.84 (d, J = 4.3 Hz, transꢀisomer), 3.30 (s, 0.5H, cisꢀisomer); 13C NMR (151 MHz,
CDCl3): δ 165.5, 163.9, 148.1, 142.7, 140.9, 130.0, 129.0, 128.4, 128.1, 126.7, 126.5, 125.9, 125.3,
123.8, 123.4, 58.7, 58.2, 57.9, 57.4; Product 3h is known compounds.20
transꢀ2ꢀEthylꢀ2,3ꢀepoxyꢀ3ꢀ(4ꢀnitrophenyl)ꢀ1ꢀphenylꢀ1ꢀpropanone (3i). Procedure A: 300 mg of
2ꢀchloroꢀ1ꢀphenylꢀ1ꢀbutanone and 1 mL of water were used; 454 mg of 3i was obtained, 93%
yield; yellow solid; mp 85ꢀ87 oC; 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 8.7 Hz, 2H), 7.98 (d,
J = 8.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 4.15 (s,
1H), 1.88 (dq, J = 15.0, 7.6 Hz, 1H), 1.38 (dq, J = 14.8, 7.5 Hz, 1H), 0.87 (t, J = 7.5 Hz, 3H); 13C
NMR (151 MHz, CDCl3): δ 197.2, 147.9, 141.5, 134.4, 133.8, 129.3, 128.7, 127.5, 123.6, 70.8,
60.8, 21.7, 9.2; IR (KBr): v 3110, 3085, 3065, 2971, 2934, 1685, 1599, 1582, 1517, 1448, 1340,
1267, 1238, 1177, 841, 798, 717, 688 cmꢀ1; HRMS calcd for C17H15NO4Na [M+Na+]: 320.0899,
found: 320.0905.
transꢀ2,3ꢀEpoxyꢀ2ꢀethylꢀ1,3ꢀdiphenylꢀ1ꢀpropanone (3j). Procedure A: 587 mg, 85% yield;
1
colorless oil; H NMR (600 MHz, CDCl3): δ 8.11 (d, J = 7.6 Hz, 2H), 8.01 (d, J = 7.7 Hz, 2H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
7
8
9
7.59 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H),
6.06 (dd, J = 8.0, 4.4 Hz, 1H), 2.14ꢀ1.99 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz,
CDCl3): δ 198.3, 134.9, 134.1, 133.5, 129.3, 128.6, 128.4, 128.2, 126.6, 70.5, 61.8, 21.6, 9.2;
Product 3j is a known compound. 21
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
2,3ꢀEpoxyꢀ2ꢀethylꢀ1ꢀphenylꢀ1ꢀpropanone (3k). Procedure A: 424 mg, 88% yield; colorless oil; 1H
NMR (600 MHz, CDCl3): δ 8.03 (d, J = 7.8 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz,
2H), 2.96 (d, J = 5.0 Hz, 1H), 2.89 (d, J = 5.0 Hz, 1H), 2.28 (dq, J = 15.0, 7.5 Hz, 1H), 1.83 (dq, J
= 14.8, 7.5 Hz, 1H), 1.02 (t, J = 7.5 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ 198.3, 134.8, 133.3,
129.2, 128.4, 64.0, 50.5, 25.9, 8.8; Product 3k is a known compound.21
transꢀ2,3ꢀEpoxyꢀ3ꢀethylꢀ1ꢀphenylꢀ1ꢀpropanone (3l). Procedure B: 559 mg, 98% yield; colorless
oil; 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.50 (t, J =
7.5 Hz, 2H), 4.02 (s, 1H), 3.14 (t, J = 5.2 Hz, 1H), 1.88ꢀ1.71 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H); 13C
NMR (151 MHz, CDCl3): δ 194.7, 135.6, 133.8, 128.8, 128.3, 60.9, 57.2, 25.0, 9.6; Product 3l is a
known compound.7
transꢀ2,3ꢀEpoxyꢀ3ꢀpropanylꢀ1ꢀphenylꢀ1ꢀpropanone (3m). Procedure B: 443 mg, 72% yield;
corless oil; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.49
(t, J = 7.4 Hz, 2H), 4.01 (s, 1H), 3.15 (t, J = 5.4 Hz, 1H), 1.81ꢀ1.50 (m, 4H), 1.01 (t, J = 7.3 Hz,
3H); 13C NMR (151 MHz, CDCl3): δ 194.7, 135.6, 133.8, 128.8, 128.3, 59.8, 57.4, 34.0, 19.2,
13.8; Product 3m is a known compound.7
transꢀ2,3ꢀEpoxyꢀ3ꢀ(2ꢀmethylpropanyl)ꢀ1ꢀphenylꢀ1ꢀpropanone (3n). Procedure B: 364 mg, 55%
yield; corless oil; 1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 7.9 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H),
7.50 (t, J = 7.6 Hz, 2H), 3.99 (d, J = 1.4 Hz, 1H), 3.17 (t, J = 4.7 Hz, 1H), 1.99ꢀ1.82 (m, 1H), 1.67
(ddd, J = 12.1, 7.0, 4.9 Hz, 1H), 1.63ꢀ1.56 (m, 1H), 1.01 (t, J = 6.1 Hz, 6H); 13C NMR (151 MHz,
CDCl3): δ 194.7, 135.6, 133.8, 128.8, 128.3, 59.0, 57.4, 41.1, 26.5, 22.8, 22.5; Product 3n is a
known compound.7
transꢀ2,3ꢀEpoxyꢀ3ꢀ(2ꢀpropanyl)ꢀ1ꢀphenylꢀ1ꢀpropanone (3o). Procedure B: 498 mg, 81% yield;
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
corless oil;1H NMR (600 MHz, CDCl3): δ 8.02 (d, J = 7.9 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.50
(t, J = 7.6 Hz, 2H), 3.99 (d, J = 1.4 Hz, 1H), 3.18ꢀ3.15 (m, 1H), 1.96ꢀ1.85 (m, 1H), 1.71ꢀ1.64 (m,
1H), 1.64ꢀ1.55 (m, 2H), 1.01 (t, J = 6.1 Hz, 3H);13C NMR (151 MHz, CDCl3): δ 194.8, 135.6, 133.7,
128.8, 128.2, 65.0, 56.6, 30.6, 18.9, 18.2; Product 3o is a known compound.7
3
4
5
6
7
8
9
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
transꢀ3ꢀcyclopentanylꢀ2,3ꢀepoxyꢀ1ꢀphenylꢀ1ꢀpropanone (3p). Procedure B: 678 mg, 97% yield;
corless oil; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.3 Hz, 1H), 7.50
(t, J = 7.5 Hz, 2H), 4.04 (s, 1H), 3.08 (d, J = 6.4 Hz, 1H), 2.10ꢀ2.00 (m, 1H), 1.91ꢀ1.82 (m, 2H),
1.69ꢀ1.45 (d, 5H); 13C NMR (151 MHz, CDCl3): δ 194.7, 135.6, 133.8, 128.8, 128.2, 63.2, 57.0,
41.4, 29.1, 28.8, 25.4; Product 3p is a known compound. 22
(16R)ꢀ3βꢀHydroxyꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone (5a). Procedure A: 409 mg, 95% yield;
o
1
white solid; mp 200ꢀ201 C; H NMR (400 MHz, CDCl3): δ 5.39 (d, J = 4.7 Hz, 1H), 3.59ꢀ3.52
(m, 1H), 3.12 (d, J = 6.3 Hz, 1H), 2.97 (d, J = 6.3 Hz, 1H), 2.35 (dd, J = 12.8, 3.6 Hz, 1H), 2.26 (t,
J = 12.2 Hz, 1H), 1.94ꢀ1.87 (m, 4H), 1.77ꢀ1.41 (m, 9H), 1.07 (s, 3H), 1.05 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 215.8, 141.1, 120.6, 71.5, 59.5, 51.6, 50.0, 49.3, 48.1, 42.1, 37.0, 36.6, 31.5, 31.3,
31.2, 30.6, 28.4, 20.1, 19.5, 13.9; IR (KBr): v 3474, 2925, 2899, 1744, 1463, 1435, 1378, 1066,
1002, 934, 729 cmꢀ1; elemental analysis calcd (%) for C20H28O3: C 75.91, H 8.92; found: C 75.83,
H 9.01.
(3´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀphenylꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone (5b). Procedure A: 539
o
1
mg, quantitative yield; white solid; mp 253ꢀ254 C; H NMR (400 MHz, CDCl3): δ 7.47 (d, J =
7.2 Hz, 2H), 7.37ꢀ7.29 (m, 3H), 5.41 (d, J = 5.0 Hz, 1H), 4.24 (s, 1H), 3.60ꢀ3.52 (m, 1H),
2.39ꢀ2.23 (m, 3H), 2.09 (dd, J = 14.1, 6.8 Hz, 2H), 1.87 (d, J = 10.3 Hz, 2H), 1.06 (s, 3H), 0.93 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 211.6, 141.2, 133.3, 128.2, 127.8, 126.5, 120.6, 71.5, 66.3,
65.4, 50.0, 48.6, 48.0, 42.2, 37.0, 36.6, 31.5, 31.4, 31.0, 30.5, 29.6, 20.0, 19.4, 13.0; IR (KBr): v
3387, 2936, 2903, 2861, 1746, 1454, 1376, 1058, 998, 751, 698, 616 cmꢀ1; elemental analysis
calcd (%) for C26H32O3: C 79.56, H 8.22; found: C 79.48, H 8.29.
(3´R,16S)ꢀ3βꢀAcetoxyꢀ3´ꢀphenylꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone (6c). Procedure A: 601
mg (with 5% amount of 5c), quantitative yield; white solid; mp 176ꢀ178 oC; 1H NMR (600 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
1
2
3
4
5
6
7
8
9
CDCl3): δ 7.38 (t, J = 7.3 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 7.1 Hz, 2H), 5.35 (d, J =
5.2 Hz, 1H), 4.63ꢀ4.57 (m, 1H), 4.15 (s, 1H), 2.38ꢀ2.25 (m, 1H), 2.03 (s, 3H), 1.01 (s, 3H), 0.96 (s,
3H); 13C NMR (150 MHz, CDCl3): δ 214.5, 170.5, 139.9, 134.6, 128.5, 128.4, 126.2, 121.6, 66.7,
62.8, 49.9, 48.5, 47.5, 38.0, 36.8, 36.7, 31.2, 30.9, 30.6, 27.7, 25.7, 21.4, 20.0, 19.3, 13.8; IR
(KBr): v 3350, 2930, 2885, 2859, 1748, 1457, 1377, 1352, 1056, 1010, 978, 921, 853, 766, 746,
699 cmꢀ1; elemental analysis calcd (%) for C28H34O4: C 77.39, H 7.89; found: C 77.48, H 7.84.
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´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀ(4ꢀnitrophenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone
(5d).
o
1
Procedure A: 399 mg, 67% yield; white solid; mp 218ꢀ221 C; H NMR (600 MHz, CDCl3): δ
8.20 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 4.8 Hz, 1H), 4.29 (s, 1H), 3.58ꢀ3.50
(m, 1H), 2.37ꢀ2.22 (m, 3H), 2.14ꢀ2.05 (m, 2H), 1.85 (d, J = 10.4 Hz, 2H), 1.04 (s, 3H), 0.90 (s,
3H); 13C NMR (151 MHz, CDCl3): δ 211.4, 147.8, 141.2, 140.5, 127.6, 123.1, 120.5, 71.5, 66.4,
64.0, 49.9, 48.5, 48.1, 42.1, 37.0, 36.6, 31.5, 31.4, 30.9, 30.5, 29.5, 19.9, 19.5, 13.0; IR (KBr): v
3406, 2934, 2861, 1749, 1604, 1517, 1436, 1350, 1057, 1046, 865, 733 cmꢀ1; elemental analysis
calcd (%) for C26H31NO5: C 71.37, H 7.14, N 3.20; found: C 71.23, H 7.19, N 3.15.
(3´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone
(5e).
o
1
Procedure A: 443 mg, 63% yield; white solid; mp 210ꢀ212 C; H NMR (600 MHz, CDCl3): δ
7.39 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 4.6 Hz, 1H), 4.18 (s, 1H), 3.79 (s,
3H), 3.62ꢀ3.48 (m, 1H), 2.33 (dd, J = 12.9, 3.3 Hz, 1H), 2.30ꢀ2.21 (m, 2H), 2.11ꢀ2.02 (m, 2H),
1.85 (d, J = 10.7 Hz, 2H), 1.76ꢀ1.61 (m, 6H), 1.55ꢀ1.33 (m, 3H), 1.11ꢀ1.05 (m, 2H), 1.03 (s, 3H),
0.91 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 212.1, 159.5, 141.1, 127.8, 125.3, 120.7, 113.3, 71.5,
66.4, 65.5, 55.2, 49.9, 48.5, 48.0, 42.1, 37.0, 36.6, 31.5, 31.4, 31.0, 30.5, 29.5, 20.0, 19.5, 13.0; IR
(KBr): v 3230, 2933, 2861, 1743, 1613, 1515, 1250, 1173, 1035, 921, 733 cmꢀ1; elemental analysis
calcd (%) for C27H34O4: C 76.74, H 8.11; found: C 76.63, H 8.20.
(3´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀ(4ꢀchlorophenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone
(5f).
o
1
Procedure A: 366 mg, 52% yield; white solid; mp 264ꢀ267 C; H NMR (600 MHz, CDCl3): δ
7.40 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.39 (d, J = 5.2 Hz, 1H), 4.18 (s, 1H), 3.57ꢀ3.51
(m, 1H), 2.33 (ddd, J = 13.1, 4.8, 1.8 Hz, 1H), 2.07 (dt, J = 14.1, 5.9 Hz, 1H), 1.85 (d, J = 9.8 Hz,
1H), 1.03 (s, 3H), 0.90 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 211.6, 141.1, 134.1, 131.8, 128.1,
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
128.0, 120.6, 71.5, 66.3, 64.7, 49.9, 48.5, 48.0, 42.2, 37.0, 36.6, 31.5, 31.4, 31.0, 30.5, 29.5, 20.0,
19.5, 13.0; IR (KBr): v 2945, 2900, 2861, 2835, 1745, 1492, 1449, 1379, 1093, 1062, 1013, 1000,
921, 866, 789 cmꢀ1; elemental analysis calcd (%) for C26H31ClO3: C 73.14, H 7.32; found: C 73.23,
H 7.25.
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´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀ(4ꢀbromophenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone
(5g).
o
1
Procedure A: 417 mg, 65% yield; white solid; mp 253ꢀ256 C; H NMR (600 MHz, CDCl3): δ
7.46 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.39 (d, J = 5.1 Hz, 1H), 4.18 (s, 1H), 3.59ꢀ3.50
(m, 1H), 2.33 (dd, J = 13.0, 3.2 Hz, 1H), 2.30ꢀ2.21 (m, 1H), 2.07 (dd, J = 14.2, 7.0 Hz, 1H), 1.85
(d, J = 10.1 Hz, 1H), 1.03 (s, 3H), 0.90 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 211.8, 141.1,
132.2, 131.0, 128.3, 122.4, 120.6, 71.5, 66.2, 64.8, 49.8, 48.5, 48.0, 42.1, 37.0, 36.6, 31.5, 31.4,
30.9, 30.5, 29.4, 20.0, 19.5, 13.0; IR (KBr): v 3470, 2943, 2898, 2859, 1745, 1489, 1449, 1422,
1140, 1062, 1009, 921, 865, 786, 619, 525 cmꢀ1; elemental analysis calcd (%) for C26H31BrO3: C
66.24, H 6.63; found: C 66.12, H 6.65.
(3´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀphenylꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀandrostanone (5h). Procedure A: 321mg,
1
60% yield; white solid; mp 237ꢀ240oC; H NMR (600 MHz, CDCl3): δ 7.44 (d, J = 7.3 Hz, 2H),
7.33 (t, J = 7.2 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 4.21 (s, 1H), 3.63ꢀ3.58 (m, 1H), 2.25 (t, J = 13.3
Hz, 1H), 2.04 (dd, J = 14.2, 6.8 Hz, 1H), 1.81 (d, J = 11.7 Hz, 1H), 0.88 (s, 3H), 0.83 (s, 3H); 13
C
NMR (151 MHz, CDCl3): δ 212.0, 133.2, 128.3, 127.8, 126.5, 71.1, 66.3, 65.4, 54.1, 48.2, 48.2,
44.7, 38.0, 36.7, 35.7, 35.0, 31.4, 31.1, 30.6, 29.5, 28.3, 20.1, 13.2, 12.3; IR (KBr): v 3680, 3388,
2929, 2857, 1748, 1628, 1450, 1374, 1338, 1155, 1042, 990, 915, 868, 750, 699 cmꢀ1; elemental
analysis calcd (%) for C26H34O3: C 79.15, H 8.69; found: C 79.08, H 8.65.
(3´R,16R)ꢀ3βꢀHydroxyꢀ3´ꢀ(4ꢀmethoxyphenyl)ꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀandrostanone (5i). Procedure
o
1
A: 374 mg, 65% yield; white solid; mp 194ꢀ196 C; H NMR (600 MHz, CDCl3): δ 7.38 (d, J =
8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.15 (s, 1H), 3.79 (s, 3H), 3.64ꢀ3.55 (m, 1H), 3.48 (s, 1H),
2.27ꢀ2.19 (m, 1H), 2.02 (dd, J = 14.2, 7.1 Hz, 1H), 1.81 (d, J = 12.5 Hz, 1H), 0.88 (s, 3H), 0.83 (s,
3H); 13C NMR (151 MHz, CDCl3): δ 212.1, 159.5, 127.8, 125.4, 113.3, 71.1, 66.5, 65.5, 55.2,
54.1, 48.3, 48.2, 44.7, 38.0, 36.8, 35.7, 34.9, 31.4, 31.1, 30.6, 29.5, 28.3, 20.1, 13.2, 12.3; IR
(KBr): v 3473, 3293, 2932, 2858, 1744, 1615, 1515, 1451, 1252, 1173, 1037, 992, 871, 834, 816,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
1
2
790 cmꢀ1; elemental analysis calcd (%) for C27H36O4: C 76.38, H 8.55; found: C 76.30, H 8.57.
3
4
5
6
7
(3´R,16R)ꢀ3βꢀ(Benzyloxy)ꢀ3´ꢀphenylꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone (5j). Procedure A:
8
9
o
401 mg, 76% yield; white solid; mp 260ꢀ262 C; 1H NMR (600 MHz, CDCl3): δ 7.45 (d, J = 7.4
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
Hz, 2H), 7.37ꢀ7.27 (m, 8H), 5.38 (d, J = 5.0 Hz, 1H), 4.57 (s, 2H), 4.23 (s, 1H), 3.33ꢀ3.26 (m, 1H),
2.46 (dd, J = 13.2, 2.3 Hz, 1H), 2.29 (t, J = 13.5 Hz, 2H), 2.07 (dd, J = 14.3, 7.1 Hz, 2H), 1.98 (d,
J = 12.6 Hz, 1H), 1.04 (s, 3H), 0.91 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 211.7, 141.3, 139.0,
133.3, 128.4, 128.2, 127.8, 127.6, 127.5, 126.5, 120.5, 78.3, 70.0, 66.3, 65.4, 50.0, 48.6, 48.0, 39.2,
37.0, 37.0, 31.4, 31.0, 30.5, 29.6, 28.3, 20.0, 19.5, 13.0; IR (KBr): v 3033, 2970, 2930, 2906, 2892,
2866, 1744, 1495, 1455, 1370, 1249, 1208, 1108, 1023, 1001, 918, 863, 744, 698 cmꢀ1; elemental
analysis calcd (%) for C33H38O3: C 82.12, H 7.94; found: C 82.17, H 7.89.
(3´R,16R)ꢀ3βꢀ(Benzyloxy)ꢀ3´ꢀ(methoxyphenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone
(5k).
o
1
Procedure A: 376 mg, 67% yield; white solid; mp 221ꢀ223 C; H NMR (600 MHz, CDCl3): δ
7.39 (d, J = 8.6 Hz, 2H), 7.37ꢀ7.27 (m, 5H), 6.86 (d, J = 8.7 Hz, 2H), 5.38 (d, J = 5.1 Hz, 1H),
4.57 (s, 2H), 4.18 (s, 1H), 3.79 (s, 3H), 3.33ꢀ3.26 (m, 1H), 2.46 (ddd, J = 13.2, 4.3, 2.1 Hz, 1H),
2.33ꢀ2.23 (m, 2H), 1.04 (s, 3H), 0.91 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 211.8, 159.6, 141.3,
139.0, 128.4, 127.9, 127.6, 127.5, 125.3, 120.6, 113.3, 78.3, 70.0, 66.4, 65.5, 55.2, 50.0, 48.6, 48.0,
39.2, 37.0, 37.0, 31.4, 31.0, 30.5, 29.5, 28.3, 20.0, 19.5, 13.0; IR (KBr): v 3030, 2933, 2903, 2843,
1744, 1613, 1517, 1458, 1252, 1179, 1032, 1003, 919, 868, 840, 783 cmꢀ1; elemental analysis
calcd (%) for C34H40O4: C 79.65, H 7.86; found: C 79.53, H 7.91.
(3´R,16S)ꢀ3βꢀAcetoxyꢀ3´ꢀ(4ꢀnitrophenyl)ꢀ5ꢀandrosteneꢀ16ꢀspiroꢀ2´ꢀoxiranꢀ17ꢀone (6d). Procedure
o
1
A: 349 mg, 53% yield; white solid, mp 268ꢀ270 C; H NMR (600 MHz, CDCl3): δ 8.25 (d, J =
8.7 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 5.36 (d, J = 5.0 Hz, 1H), 4.64ꢀ4.55 (m, 1H), 4.26 (s, 1H),
2.36ꢀ2.26 (m, 2H), 2.03 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 213.3,
170.5, 148.0, 142.0, 140.0, 127.0, 123.9, 121.4, 73.6, 66.9, 61.5, 49.8, 48.5, 47.6, 38.0, 36.7, 36.7,
31.2, 30.8, 30.5, 27.6, 25.6, 21.4, 19.9, 19.3, 13.8; IR (KBr): v 3064, 3037, 2943, 2908, 2869,
1738, 1495, 1374, 1251, 1034, 997, 922, 904, 748, 697, 615 cmꢀ1; elemental analysis calcd (%) for
C28H33NO6: C 70.13, H 6.94, N 2.92; found: C 70.01, H 6.88, N 2.99.
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
Stereochemistry for 3i, 5a, 5b and 6c. The configurations of the epoxide groups for 3i, 5a, 5b
and 6c were indicated by the NOESY spectra.
7
8
9
Supporting Information
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
The pictures of the granular PTFE. Copies of 1H NMR spectra for known compounds. Copies of
1H NMR, 13C NMR and NOESY spectra for new compounds. This material is available free of
charge via the Internet at http: //pubs.acs.org
References
(1) (a) Newmann, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413ꢀ441; (b) Ballester, M. Chem.
Rev. 1955, 55, 283ꢀ300; (c) Berti, G. Top. Stereochem. 1973, 7, 93ꢀ251.
(2) For an review of asymmetric Darzens reaction, see: (a) Bakó, P.; Rapi, Z.; Keglevich, G.
Curr. Org. Syn. 2014, 11, 361ꢀ376. For represented reports, see: (b) Arai, S.; Tokumaru, K.;
Aoyama, T. Tetrahedron Lett. 2004, 45, 1845ꢀ1848; (c) Achard, T. R. J.; Belokon, Y. N.;
Ilnyin, M.; Moskalenko, M.; North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2965ꢀ2969;
(d) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301ꢀ1304.
(3) Concellón, J. M.; Bardales, E. Org. Lett. 2003, 5, 4783ꢀ4785.
(4) Palomo, C.; Oiarbide, M.; Sharma, A. K.; GonzálesꢀRego, C.; Linden, A.; García, J. M.;
González, A. J. Org. Chem. 2000, 65, 9007ꢀ9012.
(5) For reviews, see: (a) Li, C.ꢀJ.; Chan T.ꢀH Comprehensive organic reactions in aqueous
media, WILEY, New York, 2007; (b) Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110,
6302ꢀ6337; (c) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725ꢀ748. For represented
reports, see: (d) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2005, 44, 3275ꢀ3279; (e) Cui, X.; Li, B.; Liu, T.; Li, C. Green
Chem. 2012, 14, 668ꢀ672; (f) He, G.; Li, B.; Li, C. J. Agric. Food Chem. 2013, 61,
2913ꢀ2918; (g) Li, B.; Li, C. J. Org. Chem. 2014, 79, 2242ꢀ2254.
(6) (a) Tanaka, K.; Shiraishi, R. Green Chem., 2001, 3, 135ꢀ136; (b) Shi, D.ꢀQ.; Zhang. S.;
Zhuang, Q.ꢀY.; Wang, X.ꢀS.; Tu, S.ꢀJ.; Hu, H.ꢀW. Chinese J. Chem. 2003, 21, 680ꢀ682.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
1
2
3
4
5
6
7
8
(7) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55, 6375ꢀ6386.
(8) Watanabe, S.; Hasebe, R.; Ouchi, J.; Nagasawa, H.; Kataoka, T. Tetrahedron Lett. 2010, 51,
5778ꢀ5780.
9
(9) Liu, Y.; Provencher, B. A.; Bartelson, K. J.; Deng, L. Chem. Sci. 2011, 2, 1301ꢀ1304.
(10) For examples, see: (a) Shing, T. K. M.; Yeung, Y.ꢀY.; Su, P. L. Org. Lett. 2006, 8, 3149ꢀ3151;
(b) Huang, Y.; Cui, J.; Zhong, Z.; Gan, C.; Zhang, W.; Song, H. Bioorg. Med. Chem. Lett.
2011, 21, 3641ꢀ3643; (c) Zhang, H.ꢀX.; Liu, Y. Steroids 2014, 80, 30ꢀ36.
(11) (a) Numazawa, M.; Osawa, Y. J. Am. Chem. Soc. 1980, 102, 5402ꢀ5404; (b) Numazawa, M.;
Nagaoka, M. J. Org. Chem. 1982, 47, 4024ꢀ4029; (c) Numazawa, M.; Nagaoka, M. Steroids
1982, 39, 345ꢀ356; (d) Numazawa, M.; Ogata, M.; Abiko, K.; Nagaoka, M. Steroids 1985,
45, 403ꢀ410.
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
(12) Ellis, B.; Patel, D.; Pretrow, V. J. Chem. Soc. 1958, 800ꢀ804.
(13) Maji, T.; Karmakar, A.; Reiser, O. J. Org. Chem. 2011, 76, 736ꢀ739.
(14) Konduru, N. K.; Ahmed, N. Synth. Comm. 2013, 43, 2008ꢀ2018.
(15) Liu, P.; Wong, E. L.ꢀM.; Yuen, A. W.ꢀH.; Che, C.ꢀM. Org. Lett. 2008, 10, 3275ꢀ3278.
(16) Bhatia, B.; Jain, S.; De, A.; Bagchi, I.; Iqbal, J. Tetrahedron Lett. 1996, 37, 7311ꢀ7314.
(17) Yan, P.; Tan, X.; Jing, H. J. Org. Chem. 2011, 76, 2459ꢀ2464.
(18) Geng, X. L.; Wang, Z.; Li, X. Q.; Zhang, C. J. Org. Chem. 2005, 70, 9610ꢀ9613.
(19) Sipos, Gy.; Schöbel, Gy.; Baláspiri, L. J. Chem. Soc. (C) 1970, 9, 1154ꢀ1156.
(20) Belokon, Y. N.; Hunt, J. Tetrahedron: Asymmetry 2008, 19, 2804ꢀ2815.
(21) House, H. O.; Reif, D. J. J. Am. Chem. Soc. 1957, 79, 6491ꢀ6495.
(22) Treves, G. R.; Stange, H.; Olofson, R. A. J. Am. Chem. Soc.1967, 89, 6257ꢀ6260.
ACS Paragon Plus Environment