Asymmetric Synthesis of γ-Lactones through Koga Amine-Controlled Addition of Enediolates to α,β-Unsaturated Sulfoxonium Salts

Article abstract of DOI:10.1021/acs.joc.6b02622

A chiral Koga amine-controlled asymmetric synthesis of cis-γ-lactones through a formal [3 + 2] cycloaddition of enediolates with α,β-unsaturated sulfoxonium salts is described. The desired structural motif was formed in moderate to good yields (50-71% for 13 examples), with good to very good diastereoselectivity (dr 5:1 to 10:1 for 20 examples), favoring the cis-isomer, and good to excellent enantioselectivity (70-91% ee for 13 examples).

Full text of DOI:10.1021/acs.joc.6b02622

Subscriber access provided by UNIVERSITY OF SOUTH CAROLINA LIBRARIES
Article
Asymmetric synthesis of gamma-lactones through Koga amine-controlled
addition of enediolates to alpha,beta-unsaturated sulfoxonium salts
Nicholas J Peraino, Sven H. Kaster, Kraig A. Wheeler, and Nessan Joseph Kerrigan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02622 • Publication Date (Web): 02 Dec 2016
Downloaded from http://pubs.acs.org on December 2, 2016
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 21
The Journal of Organic Chemistry
1
2
3
4
Asymmetric synthesis of γ-lactones through Koga amine-controlled addition of enediolates to α,β-
5
6
7
unsaturated sulfoxonium salts
8
9
Nicholas J. Perainoa, Sven H. Kastera, Kraig A. Wheelerb and Nessan J. Kerrigana,*
aDepartment of Chemistry, Oakland University, 2200 N. Squirrel Road, Rochester, MI 48309-4477, USA.
bDepartment of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, IL 61920-3099, USA.
kerrigan@oakland.edu
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
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
A chiral Koga amine-controlled asymmetric synthesis of cis-γ-lactones through a formal [3 + 2] cycloaddition of enediolates
with α,β-unsaturated sulfoxonium salts is described. The desired structural motif was formed in moderate to good yields (50-
71% for 13 examples), with good to very good diastereoselectivity (dr 5:1 to 10:1 for 20 examples), favoring the cis-isomer,
and good to excellent enantioselectivity (70-91% ee for 13 examples).
Introduction
The development of methods facilitating the asymmetric synthesis of -lactones has attracted attention from many research
groups due to their intriguing biological activity and their potential as synthetic intermediates.1,2 Notwithstanding the recent
achievements of the Johnson group in developing an elegant catalytic asymmetric approach to 4,5-substituted -lactones,
enantioselective approaches to -lactones are often characterized by limitations in substitution patterns accommodated,
inconvenient/unwieldy procedures or variable levels of asymmetric induction.1,2 Indeed enantioselective entries to 3,4-substituted,
especially α-arylsubstituted, -lactones have been rare.2d We recently reported a diastereoselective and convergent method for the
assembly of 3,4-substituted -lactones through the reaction of lithium enediolates with α,β-unsaturated sulfoxonium salts (Scheme
1).3a The desired product was obtained with excellent diastereoselectivity in most cases, with the trans-isomer being favored as the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
5
major isomer. Given the prevalence of γ-lactone or γ-lactone-derived motifs in natural products we were motivated to develop an
6
7
asymmetric variant of our diastereoselective methodology.1
8
9
Scheme 1. Our previous work.
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
We were attracted to the idea of utilizing chiral amine ligands as a means of controlling enantioselectivity in the desired reaction
manifold.4 Interestingly, Zakarian’s group had described the use of chiral Koga amine ligands in the enantioselective alkylation of
enediolates, and more recently in the conjugate addition of enediolates to acrylates.5 Inspired by Zakarian’s work, we proceeded to
evaluate the use of chiral Koga amine ligands in the addition of enediolates to α,β-unsaturated sulfoxonium salts. Herein, we
describe the results of our study which demonstrate that chiral Koga amine ligands can be used to affect an interesting switch in
product diastereoselectivity (to the cis-isomer), as well as facilitate an enantioselective entry to 3,4-disubstituted γ-lactones.
Results and Discussion
We began our studies by investigating the reaction of 2-methoxyphenylacetic acid 1a with phenyl-substituted sulfoxonium salt
2a at 78 C, using n-BuLi as the base for enediolate generation and chiral Koga amines 4-7 (Table 1).5-7 Sulfoxonium salt 2a and
all related racemic salts in this study were prepared by procedures previously described by Johnson and co-workers, while
enantioenriched salts were prepared through an additional step, involving a resolution procedure described by Gais and co-
workers.6,7
The reaction conditions previously developed by us for the diastereoselective synthesis of trans--lactones proved ineffective in
the context of developing an asymmetric variant (Table 1, entry 1).3a Specifically, the use of excess carboxylic acid-derived
enediolate (2 equiv), and an elevated quench temperature proved counterproductive for satisfactory yield (trace) (Table 1, entry 1).
In addition, the use of excess mole equivalents of sulfoxonium salt proved ineffective here. Investigation of conditions described
by Zakarian’s group for asymmetric alkylations also proved unsuccessful (36%, dr 1:1).5 However, keeping the reaction at 25 C,
rather than warming up to room temperature, prior to quenching led to improved yield and diastereoselectivity (Table 1, entries 2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
and 3). Limiting the amount of time at 25 C to 5 min (instead of 1-12h) gave significantly improved product yield (entry 7 vs
5
6
7
entry 2).
8
9
Table 1. Optimization of enantioselective [3 + 2] cycloaddition of enediolates with sulfoxonium salts.
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
entry
chiral
quench
quench temp
%
yieldb
drc
% eed
reaction conditions (C for temp)
aminea
(C)
1
2
4
4
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
HCl (0.1 M)
AcOH
50
-25
-25
-25
-25
-25
-25
-25
-25
-25
trace
43
-78 for 4h  rt o/n
-78 for 1h  -25 for 12h
-78 for 1h  -25 for 12h
-78 for 1h  -25 for 12h
-78 for 1h  -25 for 12h
-78 for 1h  -25 for 1h
-78 for 1h  -25 for 5 min
-78 for 1h  -25 for 5 min
-78 for 1h  -25 for 5 min
-78 for 1h  -25 for 5 min
13:1
10:1
10:1
nd
74
68
52
46
78
72
78
77
-18
3
5
41
4
6
43
5
7
28
6
4
30
7:1
7
4
51
6:1
8e
9e
10e,f
4
60
6:1
4
63
61
6:1
1:1
none
AcOH
a Reaction conditions: 1.03 equiv of Koga amine 4-7 and 1.0 equiv of ()-2a. b % yield = isolated yield for both diastereomers. c dr determined
by GC-MS or 1H NMR analysis. ee determined by chiral HPLC analysis. Enediolate generated over 30 min. Entries 1-7 involved 15 min
d
e
enediolate generation. f (R)-2a was used. (3R,4S)-3b formed as major enantiomer of cis-isomer.
Adjusting enediolate generation time to 30 min from 15 min contributed to a further elevation in yield of 3a (entry 8). The
acidity of the quenching agent was also an important consideration – acetic acid afforded a slightly superior yield compared to
dilute HCl (entry 9 vs entry 8). Pyrrolidine-substituted Koga amines (6 and 7) resulted in significantly lower levels of
enantioselectivity (entries 4 and 5). Ultimately it was found that the reaction gave optimal yield, diastereoselectivity and
enantiomeric excess of the desired -lactone 3a when the enediolate reactant (1 equiv), generated through treatment of the
carboxylic acid (1 equiv) and Koga amine 4 (1.03 equiv) with n-BuLi (4 equiv), was added to 2a (1 equiv) in THF at 78 C.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
5
Keeping the reaction at 78 C for 1 h, followed by warming the reaction to 25 C for 5 min, and quenching the reaction at 25
6
7
C with glacial acetic acid provided best results (entry 9).
8
9
When enantioenriched 2a (rather than racemate) was used as substrate, in the absence of any Koga amine, the desired product 3a
was obtained in a modest ee of 18% (entry 10). Nonetheless, this result opened up the possibility of investigating a match of
chirality between that of the Koga amine and that of the sulfoxonium salt (Table 2).8 Interestingly, in all experiments conducted in
the presence of Koga amines 4-7, the cis-isomer of lactone 3a was favored (as determined by comparison of NMR data with that
for trans-3a and X-ray crystal structure analysis of recrystallized lactone 3g).3a In addition, the absolute stereochemistry of 3a was
determined to be (3S,4R) by analogy with the assignment for 3g (see cif 3g).
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 2. Substrate scope of enantioselective -lactone formation.a
entry
chiral
amine
sulfoxonium
salt
R1
R2
%
yieldb
63
drc
% eed
product
1
2
4
4
5
5
4
4
5
4
4
4
4
5
5
4
5
4
5
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-MePh
2-MePh
2-MePh
Ph
Ph
Ph
6:1
7:1
77
91
68
3a
3a
3b
3b
3c
3c
3d
3e
3e
3f
()-2a
(S)-2a
66
41
55
66
50
48
65
45
67
64
45
58
50
56
34
31
3
Ph
10:1
()-2a
(R)-2a
()-2a
(S)-2a
(R)-2a
4
Ph
4:1 (6:1)e 78 (83)e
5
Ph
6:1
5:1
5:1
5:1
4:1
8:1
5:1
7:1
6:1
5:1
4:1
7:1
7:1
70
82
76
76
81
50
53
50
61
78
72
75
68
6
Ph
7
Ph
8
Ph
()-2a
(S)-2a
9
Ph
Ph
10
11
12
13
14
15
16
17
1-Naph
1-Naph
1-Naph
1-Naph
2-FPh
Ph
()-2a
(S)-2a
()-2a
(R)-2a
(S)-2a
(R)-2a
()-2b
()-2b
Ph
3f
Ph
3g
3g
3h
3i
Ph
Ph
2-FPh
Ph
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
3j
3k
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
18
19
20
21
22f
4
4
4
5
4
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-Naph
3-MeOPh
4-ClPh
4-ClPh
4-ClPh
i-Pr
46
71
55
58
39
7:1
5:1
6:1
5:1
7:1
nd
64
85
57
80
3l
3m
3m
3n
3o
()-2c
()-2d
(S)-2d
()-2d
()-2e
a Reaction conditions: 1.03 equiv of Koga amine 4 or 5 and 1.0 equiv 2. b % yield = isolated yield for both diastereomers. c dr determined by
GC-MS analysis. d ee determined by chiral HPLC analysis. e reaction carried out on 1 mmol scale. f using procedure of Table 1 entry 1 (ref. 3a).
The scope with respect to both acid and sulfoxonium salt structure was then systematically evaluated (Table 2). A variety of
acids, including those possessing electron donating (e.g. MeO or Me) or electron withdrawing substituents (e.g. F) at the 2-position
on the aryl ring were tolerated well for all vinyl sulfoxonium salts investigated. Other aryl-substituted α,β-unsaturated sulfoxonium
salts also worked well, with R2 = 4-ClPh providing the desired lactones in good yields (entries 19-21), and with only slightly lower
diastereoselectivity and enantioselectivity relative to the styrenyl salt (entries 1-3). The presence of a more electron donating and
sterically demanding 2-MeOPh substituent at the β-position led to lower reaction efficiency (yields: 30-40%), but with retention of
good diastereoselectivity and enantioselectivity (entries 16 and 17) compared to the styrenyl examples (entries 1 and 3). Alkyl-
substitution at the β-position also led to moderate yield of the desired γ-lactone, albeit with good diastereoselectivity and
enantioselectivity (entry 22). Overall, good to very good diastereoselectivity favoring formation of the cis-diastereomer as the
major isomer was achieved in most cases (dr 5:1 to 10:1 for 20 examples).
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
An intriguing aspect of our studies was the finding that when enantioenriched sulfoxonium salts were employed in combination
with the appropriate enantiomer of Koga amine (4 or 5), that a significant amplification of asymmetric induction could be obtained
through a match of the chirality associated with the sulfoxonium salt and that of the chiral amine.8 This improvement in
enantioselectivity ranged from 10-21% ee compared to the result obtained with racemic sulfoxonium salt, e.g. an increase from 77
to 91% ee for entries 1 and 2, and from 64 to 85% ee for entries 19 and 20. In the future, improvements in enantioselectivity may
be achieved through careful modification of substituents at the sulfur center on the sulfoxonium salt as well as on the Koga amine.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
5
6
7
8
Scheme 2. Asymmetric synthesis of all stereoisomers of 3a.
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
The synthetic potential of the methodology was demonstrated by the facile conversion of enantioenriched 3a and 3b into the
corresponding trans-isomers (3aa and 3bb) through employment of an isomerization procedure (Scheme 2). In this way, all four
stereoisomers of the γ-lactone could be readily accessed with good to excellent diastereoselectivity (dr 6:1 to 24:1) and good to
excellent enantioselectivity (75-91% ee).
X-ray crystal structure analysis of 3g revealed that its major diastereomer is the cis-isomer (see cif 3g). By analogy the relative
stereochemistry of all other lactones (3a-3o) produced by the Koga amine-controlled reaction was assigned to be cis. In addition,
the absolute stereochemistry of 3g was revealed to be (3R,4S). By analogy, the lactone products 3a-3o of all (S)-Koga amine 5-
controlled reactions were assigned the (3R,4S)-configuration, while the products of all (R)-Koga amine 4-controlled reactions were
assigned the (3S,4R)-configuration. The major diastereomer of 3aa and 3bb was confirmed to be trans by comparison of their GC-
MS and 1H NMR data with those for starting materials, cis-3a and cis-3b respectively, and with previously prepared trans-3aa.3a
Reaction Mechanism. We propose that the reaction proceeds through a conjugate addition-ylide protonation-cyclization
mechanism (Scheme 3). Ylide intermediate I is formed through conjugate addition of lithium enediolate 1 to the -position of
vinyl sulfoxonium 2a.5 Protonation of ylide I by added acetic acid leads to the formation of Intermediate II, followed by cyclization
providing access to -lactone 3. The dramatic change in the sense of diastereoselectivity to favor the cis-isomer, in contrast to our
earlier studies (in the absence of Koga amine), may be explained by the conjugate addition step proceeding through an open
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
antiperiplanar transition state (see inset of Scheme 3).3a,9 This differs from our previously proposed transition state for the reaction
conducted in the absence of Koga amine where a closed transition state, involving lithium chelation of the sulfoxonium oxygen and
enediolate, leads to the trans-isomer dominating (Scheme 3).3a The use of equilibrating conditions (78 C to rt overnight, heating
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
to 50 C, and 2 equiv of enediolate) and quenching at an elevated temperature (50 C) could also explain the pronounced trans-
selectivity of our previously reported system.3a In contrast, the low temperature (78 C to 25 C) at which the present reaction is
conducted and quenched, the use of only 1 equiv of enediolate, and the short reaction time (1.5-2 h) limits the possibility of
intermediates or cis-3 undergoing equilibration.
Scheme 3. Proposed reaction mechanism.
Conclusion
In conclusion, we report that the Koga amine-controlled reaction of lithium enediolates with vinyl sulfoxonium salts provides a
convenient, diastereoselective, and enantioselective route to cis--lactones. Future studies will focus on the development of a
catalytic asymmetric variant of the reported reaction and other [3 + 2]-cycloadditions.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
7
Experimental Section
General
8
9
All reactions were carried out in flame-dried glassware under a nitrogen atmosphere using standard inert atmosphere techniques
unless otherwise stated. THF was freshly distilled from a sodium benzophenone ketyl still under nitrogen prior to use.10 Acetone
was distilled from CaSO4. 2-Phenylacetic acid, 2-methoxyphenylacetic acid, 2-methylphenylacetic acid, 1-naphthylacetic acid, 2-
fluorophenylacetic acid, 2-naphthylacetic acid, 2-methoxybenzaldehyde, methylphenyl sulfoxide, sodium azide, formaldehyde,
formic acid, trimethyloxonium tetrafluoroborate, (1S)-(+)-10-camphorsulfonic acid, (1R)-(–)-10-camphorsulfonic acid, and n-
butyllithium (2.5 M in hexane) were purchased and used as received. Benzaldehyde, 3-methoxybenzaldehyde, and
isobutyraldehyde were purchased and distilled prior to use. 4-Chlorobenzaldehyde was washed with NaHCO3 (satd.), extracted
into ether, and crystallized. Iatrobeads (neutral silica, 60μM particle size), and TLC plates (UV254, 250μM) were used as received.
Ethenyl sulfoximine precursors and sulfoxonium salts 2a-2e were prepared as previously described by the groups of Johnson and
Gais.6,7 Koga amines (R,R)-4, (S,S)-5, (R,R)-6, and (S,S)-7 were synthesized by previously reported methods.5
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
1
NMR spectra were recorded on a 200 spectrometer (200 MHz for H and 50 MHz for 13C) and 400 spectrometer (400 MHz for
1
1H and 100 MHz for 13C). NMR chemical shifts were reported relative to TMS (0 ppm) for H and to CDCl3 (77.23 ppm) for 13C
spectra. High resolution mass spectra were obtained on an Accurate Mass Q-TOF LC-MS instrument with ESI as ionization
method. Low resolution mass spectra were recorded on a GC-MS instrument equipped with a mass selective detector, and using a
GC column (30 m, 0.25 mm ID). IR spectra were recorded on an IR spectrometer. Optical rotations were measured on an
automatic polarimeter in dichloromethane at 598 nm. Chiral high performance liquid chromatography analysis (chiral HPLC) was
performed using OD-H or AD-H columns (0.46 cm  25 cm) on a HPLC instrument attached with a diode array detector
(deuterium lamp, 190-600 nm) with HPLC-grade isopropanol and hexanes as the eluting solvents. Enantiomeric excesses were
determined at  = 254 or 225 nm (details given for each compound). Diastereoselectivity for γ-lactone formation was determined
by GC-MS analysis of the crude product.
Method A for preparation of γ-lactones
Two 10 mL flame-dried flasks were equipped with septa and stir bars. One was charged with α,β-unsaturated sulfoxonium salt 2
(0.25 mmol, 1.0 equiv) and the other with the Koga tetraamine 4 or 5 (115.5 mg, 0.258 mmol, 1.03 equiv) and arylacetic acid (0.25
mmol, 1.0 equiv). Both were placed under high vacuum for 30 min and subjected to vacuum/nitrogen fill cycles ( 3). The salt
was suspended in THF (1.0 mL) and the tetraamine and arylacetic acid were dissolved in THF (3.0 mL). The acid and amine
solution was cooled to 0 °C and n-butyllithium (2.5 M in hexane, 0.4 mL, 1.00 mmol, 4.0 equiv) was added dropwise, and the
solution was stirred for 30 min. The two flasks were immersed in a dry ice/acetone bath (−78 °C) and cooled for 5 min. A
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
cannula was bridged across the two flasks and the nitrogen line removed from the enediolate flask. The enediolate flask was
pressurized with a syringe and dry nitrogen to transfer the enediolate complex to the α,β-unsaturated sulfoxonium salt suspension.
THF (0.5 mL) was used to rinse the flask and cooled for a minute before a second transfer was performed. The reaction was stirred
for 1 h at −78 °C, and then placed in a −25 °C isopropanol/cryocool bath for 5 minutes, before quenching with glacial acetic acid
(0.1 mL). The flask was swirled by hand in the bath 4 or 5 times until the color was white and immediately extracted into ethyl
acetate (30 mL), using additional portions to rinse the flask. The mixture was washed vigorously with HCl (1M, 10 mL), brine (10
mL), NaHCO3 (10 mL), and brine (10 mL). Ethyl acetate (30 mL) was brought through each wash 2 more times for a total of ~100
mL of ethyl acetate collected. The collected organics were dried over MgSO4 and filtered through cotton. The crude product was
concentrated to an oil/solid and quickly purified over neutral silica (10 g) eluting with 8% EtOAc:hexane to prevent isomerization
and decomposition. Note: The crude product was observed to isomerize to the trans-isomer when left at the crude stage overnight
(at room temperature), or when left to stir for an hour after quenching.
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
Method B for preparation of γ-lactones
Two 10 mL flame-dried flasks were equipped with septa and stir bars. One was charged with α,β-unsaturated sulfoxonium salt 2
(0.27 mmol, 1.1 equiv) and the other with tetraamine 4 or 5 (115.5 mg, 0.258 mmol, 1.03 equiv) and arylacetic acid (0.25 mmol,
1.0 equiv). Both flasks were placed under high vacuum for 30 min and filled with N2. The salt was suspended in THF (0.5 mL)
and the tetraamine and arylacetic acid were dissolved in THF (1.5 mL). The flask containing the acid and amine was cooled to 0 °C
and n-butyllithium (2.5 M in hexane, 0.4 mL, 1.00 mmol, 4.0 equiv) was added dropwise and stirred for 30 min. The two flasks
were immersed in a dry ice/acetone bath (−78 °C) and cooled for 5 min. A cannula was bridged across the two flasks and the
nitrogen line removed from the enediolate flask. The enediolate flask was pressurized with a syringe and dry nitrogen to transfer
the enediolate complex to the α,β-unsaturated sulfoxonium salt suspension. THF (0.5 mL) was used to rinse the flask and cooled
for a minute before a second transfer. The reaction was stirred for 1 h at −78 °C, and then placed in a −25 °C isopropanol/cryocool
bath for 16 h, before quenching with HCl (0.1 M, ~5 mL). The product was extracted into ethyl acetate (30 mL), using excess to
rinse the flask. The product mixture was washed vigorously with HCl (1 M, 10 mL), brine (10 mL), NaHCO3 (10 mL), and brine
(10 mL) in that order, saving each wash. Ethyl acetate (30 mL) was brought through each wash 2 more times for a total of ~100
mL of ethyl acetate collected. The collected organics were dried with MgSO4 and filtered through cotton. The crude product was
concentrated to an oil/solid and quickly purified over neutral silica (10 g) eluting with 8% EtOAc:hexane.
Method C for preparation of γ-lactones
One 10 mL flame-dried flask equipped with a septum and a stir bar was charged with tetraamine 4 or 5 (115.5 mg, 0.258 mmol,
1.03 equiv) and arylacetic acid (0.25 mmol, 1.0 equiv). The α,β-unsaturated sulfoxonium salt (0.27 mmol, 1.1 equiv) was added
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
6
7
8
9
to another 10 mL flame-dried flask and the flask was fitted with a septum. Both flasks were placed under high vacuum for 30 min
and filled with N2. The salt was dissolved in THF (0.4 mL) and the tetraamine and arylacetic acid were dissolved in THF (1.7 mL).
The flask containing the acid and amine was cooled to 0 °C and n-butyllithium (2.5 M in hexane, 0.4 mL, 1.00 mmol, 4.0 equiv)
was added dropwise to the solution, and stirred for 15 min. The enediolate flask was immersed in a dry ice/acetone bath and
cooled for 5 min to −78 °C. A syringe was used to transfer the α,β-unsaturated sulfoxonium salt solution, still at room temperature,
over 10 min to the enediolate solution. The reaction was stirred for 4 h at −78 °C and allowed to warm to room temperature
overnight. The next morning, the reaction was heated to 50 °C for 30 min and quenched with HCl (0.1 M, ~5 mL). The product
mixture was extracted with dichloromethane (3  10 mL), using excess to rinse the flask. The collected organics were washed with
HCl (1 M, 10 mL), brine (10 mL), dried with Na2SO4, and filtered through cotton. The crude product was concentrated to an
oil/solid and quickly purified over neutral silica (10 g) eluting with 8% EtOAc:hexane.
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
Isomerization Procedure
The lactone (1 equiv) was placed in a flame-dried flask fitted with a septum and a stir bar. THF (0.11 M) was added and the
reaction cooled to 0 °C. KOtBu (1 M in hexane, 0.25 equiv) was added dropwise and the mixture was heated to 50 °C for 30 min.
The reaction was quenched with HCl (0.1 M, ~5 mL) added dropwise, and extracted into dichloromethane. The mixture was
purified by column chromatography using neutral silica eluting with 8% EtOAc:hexane to yield the pure trans-lactone. Chiral
HPLC analysis was carried out using an AD-H column, eluting with 95:5 hexane:isopropanol system at 1.5 mL/min.
(3S,4R)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3a): The reaction was performed following Method A using
sulfoxonium salt (±)-2a, (R)-Koga amine 4, and 2-methoxyphenylacetic acid 1a. 3a was isolated as a colorless oil (42.3 mg, 63%)
with a dr = 6:1 as determined by GC-MS analysis of the isolated product. HPLC analysis: 77% ee [Daicel Chiralpak OD-H
column; 1.0 mL/min; solvent system: 5% isopropanol in hexane; retention time: 25.3 min (major), 41.3 min (minor)]; IR (thin
film): 1770, 1495, 754 706 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.11-7.06 (m, 4H), 6.87-6.84 (m, 2H),
6.75-6.64 (m, 3H), 4.74-4.66 (m, 2H), 4.57 (d, J = 8.9 Hz, 1H), 4.08 (ddd, J = 8.9, 6.6, 4.6 Hz, 1H), 3.69 (s, 3H); 13C NMR (100
MHz, CDCl3) for the major diastereomer: δ 177.2, 157.2 137.9, 130.3, 128.8, 128.3, 127.9, 127.3, 122.4, 120.5, 110.2, 71.8, 55.4,
+
46.4, 46.3; MS (EI 70eV): 268, 223, 193, 165, 148, 91, 77 m/z; (M + H)+ HRMS m/z calcd for C17H17O3 : 269.1178; found:
269.1167.
(‒)-(3S,4R)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3a): The reaction was performed following Method A
using sulfoxonium salt (S)-2a, (R)-Koga amine 4, and 2-methoxyphenylacetic acid 1a. (‒)-3a was isolated as a colorless oil (44.0
mg, 66%) with a dr = 7:1 as determined by GC-MS analysis of the crude. HPLC analysis: 91% ee [Daicel Chiralpak OD-H column;
1.0 mL/min; solvent system: 5% isopropanol in hexane; retention time: 24.3 min (major), 39.4 min (minor)];
= ‒255.2
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(c = 2.21, CH2Cl2); IR (thin film): 1768, 1495, 753, 705 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.12-7.06
(m, 4H), 6.87-6.84 (m, 2H), 6.75-6.64 (m, 3H), 4.74-4.66 (m, 2H), 4.57 (d, J = 8.9 Hz, 1H), 4.08 (ddd, J = 9.0, 6.6, 4.6 Hz, 1H),
3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 177.2, 157.2 137.9, 130.3, 128.8, 128.3, 127.9, 127.3,
122.4, 120.6, 110.2, 71.8, 55.4, 46.4, 46.4; MS (EI 70eV): 268, 223, 193, 165, 148, 91, 77 m/z; (M + H)+ HRMS m/z calcd for
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
+
C17H17O3 : 269.1178; found: 269.1171.
(+)-(3R,4S)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3b): The reaction was performed following Method B
using sulfoxonium salt (±)-2a, (S)-Koga amine 5, and 2-methoxyphenylacetic acid 1a. (+)-3b was isolated as a colorless oil (41.0
mg, 41%) with a dr = 10:1 as determined by GC-MS analysis of the crude. HPLC analysis: 68% ee [Daicel Chiralpak OD-H
column; 1.0 mL/min; solvent system: 5% isopropanol in hexane; retention time: 23.8 min (minor), 36.9 min (major)];
=
+123.1 (c = 1.80, CH2Cl2); IR (thin film): 1768, 1495, 753, 705 cm-1; H (400 MHz, CDCl3, TMS) for the major diastereomer: δ
7.12-7.06 (m, 4H), 6.87-6.84 (m, 2H), 6.75-6.64 (m, 3H), 4.74-4.66 (m, 2H), 4.57 (d, J = 8.9 Hz, 1H), 4.08 (ddd, J = 8.9, 6.6, 4.6
Hz, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 177.2, 157.2 137.9, 130.3, 128.8, 128.3, 127.9,
127.3, 122.4, 120.5, 110.2, 71.8, 55.4, 46.4, 46.3; MS (EI 70eV): 268, 223, 193, 165, 148, 91, 77 m/z; (M + H)+ HRMS m/z calcd
1
+
for C17H17O3 : 269.1178; found: 269.1172.
(3R,4S)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3b): The reaction was performed following Method A using
sulfoxonium salt (R)-2a, (S)-Koga amine 5 and 2-methoxyphenylacetic acid 1a. 3b was isolated as a colorless oil (36.6 mg, 55%)
with a dr = 4:1 as determined by GC-MS analysis of the crude. HPLC analysis: 78% ee [Daicel Chiralpak OD-H column; 1.0
mL/min; solvent system: 5% isopropanol in hexane; retention time: 25.7 min (minor), 40.1 min (major)]; IR (thin film): 1768,
1495, 753, 705 cm-1; H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.12-7.06 (m, 4H), 6.87-6.84 (m, 2H), 6.75-6.64
1
(m, 3H), 4.74-4.67 (m, 2H), 4.57 (d, J = 8.9 Hz, 1H), 4.08 (ddd, J = 9.0, 6.6, 4.6 Hz, 1H), 3.69 (s, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer: δ 177.2, 157.2 137.9, 130.3, 128.8, 128.3, 127.9, 127.3, 122.4, 120.6, 110.2, 71.8, 55.4, 46.4,
46.4; MS (EI 70eV): 268, 223, 193, 165, 148, 91, 77 m/z; (M + H)+ HRMS m/z calcd for C17H17O3 : 269.1178; found: 269.1173.
+
(3S,4R)-3-(2-methylphenyl)-4-phenyldihydrofuran-2(3H)-one (3c): The reaction was performed following Method A,
quenching with HCl (0.1 M) instead of acetic acid, using sulfoxonium salt (±)-2a, (R)-Koga amine 4, and 2-methylphenylacetic
acid 1b. 3c was isolated as a colorless oil (41.5 mg, 66%) with a dr = 6:1 as determined by GC-MS analysis of the crude. HPLC
analysis: 70% ee [Daicel Chiralpak AD-H column; 1.5 mL/min; solvent system: 1% isopropanol in hexane; retention time: 15.0
min (minor), 17.4 min (major)]; IR (thin film): 1770, 1494, 1024, 757, 704 cm-1; H (400 MHz, CDCl3, TMS) for the major
1
diastereomer: δ 7.14-6.93 (m, 6H), 6.81-6.78 (m, 2H), 6.75-6.73 (m, 1H), 4.74-4.64 (m, 2H), 4.39 (d, J = 8.9 Hz, 1H), 4.05 (ddd, J
= 8.9, 6.6, 5.6 Hz, 1H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 177.3, 137.0, 136.7, 132.0,
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
130.3, 129.0, 128.5, 128.2, 127.7, 126.1, 71.6, 48.9, 46.7, 19.8; MS (EI 70eV): 252, 207, 193, 178, 132, 104, 91 m/z; (M + H)+
6
7
+
HRMS m/z calcd for C17H17O2 : 253.1229; found: 253.1225.
8
9
(3S,4R)-3-(2-methylphenyl)-4-phenyldihydrofuran-2(3H)-one (3c): The reaction was performed following Method A using
sulfoxonium salt (S)-2a, (R)-Koga amine 4, and 2-methylphenylacetic acid 1b. 3c was isolated as a colorless oil (31.6 mg, 50%)
with a dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 82% ee [Daicel Chiralpak AD-H column; 1.5
mL/min; solvent system: 1% isopropanol in hexane; retention time: 15.0 min (minor), 17.5 min (major)]; IR (thin film): 1771,
1496, 1024, 757, 704 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.14-6.94 (m, 6H), 6.80-6.78 (m, 2H), 6.75-
6.73 (m, 1H), 4.74-4.64 (m, 2H), 4.39 (d, J = 8.6 Hz, 1H), 4.05 (ddd, J = 8.6, 6.6, 5.6 Hz, 1H), 2.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer: δ 177.3, 137.0 136.7, 132.0, 130.3, 129.0, 128.5, 128.2, 127.7, 126.1, 71.6, 48.9, 46.7, 19.8;
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
+
MS (EI 70eV): 252, 207, 193, 178, 132, 104, 91 m/z; (M + H)+ HRMS m/z calcd for C17H17O2 : 253.1229; found: 253.1228.
(3R,4S)-3-(2-methylphenyl)-4-phenyldihydrofuran-2(3H)-one (3d): The reaction was performed following Method A using
sulfoxonium salt (R)-2a, (S)-Koga amine 5, and 2-methylphenylacetic acid 1b. 3d was isolated as a colorless oil (30.4 mg, 48%)
with a dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 76% ee [Daicel Chiralpak AD-H column; 1.5
mL/min; solvent system: 1% isopropanol in hexane; retention time: 15.2 min (major), 17.9 min (minor)]; IR (thin film): 1767,
1
1022, 754, 703 cm-1; H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.14-6.94 (m, 6H), 6.80-6.78 (m, 2H), 6.74-6.73
(m, 1H), 4.74-4.65 (m, 2H), 4.39 (d, J = 8.9 Hz, 1H), 4.05 (ddd, J = 8.9, 6.6, 5.6 Hz, 1H), 2.08 (s, 3H) 13C NMR (100 MHz,
CDCl3) for the major diastereomer: δ 177.3, 137.0 136.7, 132.0, 130.3, 129.0, 128.5, 128.2, 127.7, 126.1, 71.6, 48.9, 46.7, 19.8;
+
MS (EI 70eV): 252, 207, 193, 178, 132, 104, 91 m/z; (M + H)+ HRMS m/z calcd for C17H17O2 : 253.1229; found: 253.1224.
(3S,4R)-3,4-diphenyldihydrofuran-2(3H)-one (3e): The reaction was performed following Method A using sulfoxonium salt (±)-
2a, (R)-Koga amine 4, and phenylacetic acid 1c. 3e was isolated as a white solid (38.9 mg, 65%, mp 140-142 °C) with a dr = 5:1
as determined by GC-MS analysis of the crude. HPLC analysis: 76% ee [Daicel Chiralpak OD-H column; 1 mL/min; solvent
system: 10% isopropanol in hexane; retention time: 19.0 min (major), 29.1 min (minor)]; IR (thin film): 1764, 1038, 710, 698 cm-1;
1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.15-7.08 (m, 6H), 6.86-6.81 (m, 4H), 4.75-4.68 (m, 2H), 4.25 (d, J =
8.5 Hz, 1H), 4.00 (ddd, J = 8.5, 6.1, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.6, 137.0 133.3,
129.6, 128.6, 128.4, 128.1, 127.6, 127.5, 71.5, 52.2, 48.0; MS (EI 70eV): 238, 193, 179, 118, 104, 77 m/z; (M + H)+ HRMS m/z
+
calcd for C16H15O2 : 239.1072; found: 239.1066.
(3S,4R)-3,4-diphenyldihydrofuran-2(3H)-one (3e): The reaction was performed following Method A using sulfoxonium salt (S)-
2a, (R)-Koga amine 4, and phenylacetic acid 1c. 3e was isolated as a white solid (26.8 mg, 45%, mp 136-138 °C) with a dr = 4:1
as determined by GC-MS analysis of the crude. HPLC analysis: 81% ee [Daicel Chiralpak OD-H column; 1 mL/min; solvent
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
system: 10% isopropanol in hexane; retention time: 18.7 min (major), 28.4 min (minor)]; IR (thin film): 1767, 1039, 697 cm-1; 1H
(400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.15-7.09 (m, 6H), 6.86-6.80 (m, 4H), 4.74-4.67 (m, 2H), 4.25 (d, J = 8.5
Hz, 1H), 4.00 (ddd, J = 8.5, 6.1, 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.7, 137.0 133.2,
129.6, 128.6, 128.4, 128.1, 127.6, 127.5, 71.5, 52.2, 48.0; MS (EI 70eV): 238, 193, 179, 118, 104, 77 m/z; (M + H)+ HRMS m/z
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
+
calcd for C16H15O2 : 239.1072; found 239.1071.
(‒)-(3S,4R)-3-(naphthalen-1-yl)-4-phenyldihydrofuran-2(3H)-one (3f): The reaction was performed following Method A
quenching with HCl (0.1 M) using sulfoxonium salt (±)-2a, (R)-Koga amine 4, and 1-naphthylacetic acid 1d. (‒)-3f was isolated as
a white solid (47.4 mg, 67%, mp 139-140 °C) with a dr = 8:1 as determined by GC-MS analysis of the crude. HPLC analysis: 50%
ee [Daicel Chiralpak AD-H column; 1 mL/min; solvent system: 10% isopropanol in hexane; retention time: 15.4 min (major), 24.1
1
min (minor)];
= ‒354.1 (c = 1.43, CH2Cl2); IR (thin film): 1771, 1145, 703 cm-1; H (400 MHz, CDCl3, TMS) for the
major diastereomer: δ 7.86 (d, J = 8.2 Hz, 1H), 7.80-7.78 (m, 1H), (d, J = 8.2 Hz, 1H), 7.50-7.42 (m, 2H), 7.20-6.89 (m, 4H), 6.99-
6.89 (m, 4H), 6.67-6.65 (m, 2H), 5.02 (d, J = 8.6 Hz, 1H), 4.87-4.76 (m, 2H), 4.26-4.22 (m, 1H); 13C NMR (100 MHz, CDCl3) for
the major diastereomer: δ 176.8, 137.4, 133.6, 132.2, 129.3, 129.2, 128.3, 128.2, 127.6, 127.4, 126.5, 125.6, 125.2, 122.5, 71.7,
48.2, 47.2; MS (EI 70eV): 288, 243, 229, 168, 153, 77 m/z; (M + H)+ HRMS m/z calcd for C20H17O2 : 289.1229; found: 289.1224.
+
(‒)-(3S,4R)-3-(naphthalen-1-yl)-4-phenyldihydrofuran-2(3H)-one (3f): The reaction was performed following Method A,
quenching with HCl (0.1 M), using sulfoxonium salt (S)-2a, (R)-Koga amine 4, and 1-naphthylacetic acid 1d. 3f was isolated as a
white solid (46.0 mg, 64%, mp 138-139 °C) with a dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 53%
ee [Daicel Chiralpak AD-H column; 1 mL/min; solvent system: 10% isopropanol in hexane; retention time: 15.0 min (major), 23.5
min (minor)]; IR (thin film): 1766, 1143, 702 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.85 (d, J = 8.3 Hz,
1H), 7.79-7.77 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.49-7.41 (m, 2H), 7.19-7.15 (m, 1H), 6.98-6.88 (m, 4H), 6.66-6.64 (m, 2H), 5.01
(d, J = 8.6 Hz, 1H), 4.86-4.75 (m, 2H), 4.25-4.21 (m, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.8, 137.4,
133.6, 132.2, 129.3, 129.2, 128.3, 128.2, 127.6, 127.4, 126.5, 125.6, 125.3, 122.5, 71.7, 48.2, 47.2; MS (EI 70eV): 288, 243, 229,
168, 153, 77 m/z; (M + H)+ HRMS m/z calcd for C20H17O2 : 289.1229; found: 289.1224.
+
(+)-(3R,4S)-3-(naphthalen-1-yl)-4-phenyldihydrofuran-2(3H)-one (3g): The reaction was performed following Method A,
quenching with HCl (0.1 M), using sulfoxonium salt (±)-2a, (S)-Koga amine 5, and 1-naphthylacetic acid 1d. (+)-3g was isolated
as a white solid (32.3 mg, 45%, mp 133-135 °C) with a dr = 7:1 as determined by GC-MS analysis of the crude. 15.2 mg of the
major isomer was crystallized from isopropanol to >99% optical purity as shown by chiral HPLC analysis. X-ray crystal analysis
determined the stereochemistry of the major isomer to be (3R,4S) (see cif-3g in supporting information); HPLC analysis: 50% ee
[Daicel Chiralpak AD-H column; 1 mL/min; solvent system: 10% isopropanol in hexane; retention time: 15.1 min (minor), 23.6
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
4
5
min (major)];
= +69.7 (c = 0.67, CH2Cl2); IR (thin film): 1770, 1146, 703 cm-1; 1H (400 MHz, CDCl3, TMS) for the major
6
7
8
9
diastereomer: δ 7.86 (d, J = 8.4 Hz, 1H), 7.80-7.77 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.50-7.42 (m, 2H), 7.20-7.16 (m, 1H), 6.99-
6.89 (m, 4H), 6.67-6.65 (m, 2H), 5.02 (d, J = 8.6 Hz, 1H), 4.88-4.76 (m, 2H), 4.27-4.22 (m, 1H); 13C NMR (100 MHz, CDCl3) for
the major diastereomer: δ 176.8, 137.4, 133.7, 132.2, 129.3, 129.2, 128.4, 128.2, 127.6, 127.5, 126.5, 125.7, 125.3, 122.5, 71.8,
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
+
48.3, 47.2; MS (EI 70eV): 288, 243, 168, 153, 77 m/z; (M + H)+ HRMS m/z calcd for C20H17O2 : 289.1229; found: 289.1221.
(+)-(3R,4S)-3-(naphthalen-1-yl)-4-phenyldihydrofuran-2(3H)-one (3g): The reaction was performed following Method A using
sulfoxonium salt (R)-2a, (S)-Koga amine 5, and 1-naphthylacetic acid 1d. 3g was isolated as a white solid (41.6 mg, 58%, mp 139-
140 °C) with a dr = 6:1 as determined by GC-MS analysis of the crude. HPLC analysis: 61% ee [Daicel Chiralpak AD-H column;
1 mL/min; solvent system: 10% isopropanol in hexane; retention time: 15.3 min (minor), 24.3 min (major)]; IR (thin film): 1768,
1145, 702 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.86 (d, J = 8.4 Hz, 1H), 7.80-7.78 (m, 1H), 7.64 (d, J =
8.2 Hz, 1H), 7.50-7.42 (m, 2H), 7.20-7.16 (m, 1H), 7.00-6.89 (m, 4H), 6.67-6.65 (m, 2H), 5.02 (d, J = 8.6 Hz, 1H), 4.88-4.77 (m,
2H), 4.27-4.22 (m, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.8, 137.4, 133.7, 132.2, 129.3, 129.2,
128.4, 128.2, 127.6, 127.5, 126.5, 125.7, 125.3, 122.5, 71.8, 48.3, 47.2; MS (EI 70eV): 288, 243, 168, 153, 77 m/z; (M + H)+
+
HRMS m/z calcd for C20H17O2 : 289.1229; found: 289.1220.
(3S,4R)-3-(2-fluorophenyl)-4-phenyldihydrofuran-2(3H)-one (3h): The reaction was performed following Method A using
sulfoxonium salt (S)-2a, (R)-Koga amine 4, and 2-fluorophenylacetic acid 1e. 3h was isolated as a clear oil (32.1 mg, 50%) with a
dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 78% ee [Daicel Chiralpak OD-H column; 1 mL/min;
solvent system: 10% isopropanol in hexane; retention time: 14.1 min (major), 18.4 min (minor)]; IR (thin film): 1770, 1493, 1455,
754, 697 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.13-7.08 (m, 4H), 6.94-6.89 (m, 3H), 6.84-6.74 (m, 2H),
4.81-4.73 (m, 2H), 4.57 (d, J = 8.7 Hz, 1H), 4.11-4.06 (m, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 175.8,
161.2 (d, J = 244 Hz, 1C), 137.6, 130.8 (d, J = 3 Hz, 1C), 129.4 (d, J = 8 Hz, 1C), 128.7, 127.7, 127.7, 124.1 (d, J = 3 Hz, 1C),
121.1 (d, J = 14 Hz, 1C), 114.9 (d, J = 21 Hz, 1C), 71.9, 46.5, 45.5 (d, J = 3 Hz, 1C); MS (EI 70eV): 256, 211, 197, 136, 108, 77
+
m/z; (M + H)+ HRMS m/z calcd for C16H14FO2 : 257.0978; found: 257.0969.
(3R,4S)-3-(2-fluorophenyl)-4-phenyldihydrofuran-2(3H)-one (3i): The reaction was performed following Method A using
sulfoxonium salt (R)-2a, (S)-Koga amine 5, and 2-fluorophenylacetic acid 1e. 3i was isolated as a clear oil (35.7 mg, 56%) with a
dr = 4:1 as determined by GC-MS analysis of the crude. HPLC analysis: 72% ee [Daicel Chiralpak OD-H column; 1 mL/min;
solvent system: 10% isopropanol in hexane; retention time: 13.9 min (minor), 17.8 min (major)]; IR (thin film): 1768, 1493, 1455,
755, 704 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.14-7.08 (m, 4H), 6.94-6.89 (m, 3H), 6.84-6.74 (m, 2H),
4.81-4.73 (m, 2H), 4.57 (d, J = 8.7 Hz, 1H), 4.11-4.07 (m, 1H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
175.8, 161.1 (d, J = 244 Hz, 1C), 137.5, 130.8 (d, J = 4 Hz, 1C), 129.4 (d, J = 9 Hz, 1C), 128.7, 127.7, 127.7, 124.1 (d, J = 4 Hz,
1C), 121.0 (d, J = 14 Hz, 1C), 115.0 (d, J = 21 Hz, 1C), 71.9, 46.5, 45.5 (d, J = 2 Hz, 1C); MS (EI 70eV): 256, 211, 197, 136, 108,
7
8
9
+
77 m/z; (M + H)+ HRMS m/z calcd for C16H14FO2 : 257.0978; found: 257.0966.
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
(‒)-(3S,4R)-3,4-bis(2-methoxyphenyl)dihydrofuran-2(3H)-one (3j): The reaction was performed following Method A using
sulfoxonium salt (±)-2b, (R)-Koga amine 4, and 2-methoxyphenylacetic acid 1a. (‒)-3j was isolated as a clear oil (25.5 mg, 34%)
with a dr = 7:1 as determined by GC-MS analysis of the crude. HPLC analysis: 75% ee [Daicel Chiralpak AD-H column; 1
mL/min; solvent system: 2% isopropanol in hexane; retention time: 32.6 min (major), 45.3 min (minor)];
= ‒202.4 (c =
1
0.17, CH2Cl2); IR (thin film): 1770, 1493, 1455, 754, 697 cm-1; H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.08-
7.02 (m, 2H), 6.96 (dd, J = 7.6, 1.6 Hz, 1H), 6.81 (dd, J = 7.8, 1.7 Hz, 1H), 6.73 (dt, J = 7.5, 1.0 Hz, 1H), 6.66-6.62 (m, 2H), 6.55
(d, J = 8.2 Hz, 1H), 4.69-4.67 (m, 2H), 4.53 (d, J = 9.7 Hz, 1H), 4.47-4.41 (m, 1H), 3.72 (s, 3H), 3.55 (s, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer: δ 177.8, 157.4, 157.3, 130.3, 128.6, 128.5, 127.9, 126.7, 123.1, 120.3, 120.1, 110.0, 109.8,
+
71.0, 55.4, 55.0, 45.4, 40.5; MS (EI 70eV): 298, 280, 223, 148, 119, 91 m/z; (M + H)+ HRMS m/z calcd for C18H19O4 : 299.1283;
found: 299.1278.
(+)-(3R,4S)-3,4-bis(2-methoxyphenyl)dihydrofuran-2(3H)-one (3k): The reaction was performed following Method A using
sulfoxonium salt (±)-2b, (S)-Koga amine 5, and 2-methoxyphenylacetic acid 1a. (+)-3k was isolated as a clear oil (23.0 mg, 31%)
with a dr = 7:1 as determined by GC-MS analysis of the crude. HPLC analysis: 68% ee [Daicel Chiralpak AD-H column; 1
mL/min; solvent system: 2% isopropanol in hexane; retention time: 33.8 min (minor), 46.6 min (major)];
= +22.8 (c = 0.80,
CH2Cl2); IR (thin film): 1768, 1494, 1462, 750 cm-1; 1H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.08-7.02 (m, 2H),
6.96 (dd, J = 7.6, 1.6 Hz, 1H), 6.81 (dd, J = 7.9, 1.7 Hz, 1H), 6.73 (dt, J = 7.5, 1.0 Hz, 1H), 6.66-6.62 (m, 2H), 6.55 (dd, J = 8.2,
0.6 Hz, 1H), 4.69-4.67 (m, 2H), 4.53 (d, J = 9.7 Hz, 1H), 4.47-4.41 (m, 1H), 3.72 (s, 3H), 3.55 (s, 3H); 13C NMR (100 MHz,
CDCl3) for the major diastereomer: δ 177.8, 157.4, 157.3, 130.3, 128.5, 128.5, 127.9, 126.7, 123.0, 120.2, 120.1, 110.0, 109.8,
+
71.0, 55.4, 55.0, 45.4, 40.5; MS (EI 70eV): 298, 280, 223, 148, 119, 91m/z; (M + H)+ HRMS m/z calcd for C18H19O4 : 299.1283;
found: 299.1283.
(‒)-(3S,4R)-3-(2-methoxyphenyl)-4-(3-methoxyphenyl)dihydrofuran-2(3H)-one (3l): The reaction was performed following
Method B, but left to stir for 72 h at ‒25 °C instead of overnight, using sulfoxonium salt (±)-2c, (R)-Koga amine 4, and 2-
methoxyphenylacetic acid 1a. (‒)-3l was isolated as a yellow oil (34.6 mg, 46%) with a dr = 7:1 as determined by GC-MS analysis
1
of the crude;
= ‒87.3 (c = 1.79, CH2Cl2); IR (thin film): 1770, 1495, 1463, 1251, 755 cm-1; H NMR (400 MHz, CDCl3,
TMS) for the major diastereomer: δ 7.13-7.09 (m, 1H), 7.03-6.99 (m, 1H), 6.79-6.77 (m, 1H) 6.73-6.61 (m, 2H), 6.62 (dd, J = 8.2,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
5
6
7
8
9
2.1 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), 4.72-4.64 (m, 2H), 4.55 (d, J = 8.8 Hz, 1H), 4.05 (ddd, J = 8.9, 6.7, 4.8 Hz,
1H), 3.71 (s, 3H), 3.59 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 177.2, 159.5, 157.3, 139.4, 130.3,
129.3, 128.9, 122.5, 120.6, 120.3, 113.5, 113.1, 110.3, 71.8, 55.5, 55.3, 46.4; MS (EI 70eV): 298, 253, 223, 148, 121, 91 m/z ; (M
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
+
+ H)+ HRMS m/z calcd for C18H19O4 : 299.1283; found: 299.1275.
(3S,4R)-4-(4-chlorophenyl)-3-(2-methoxyphenyl)dihydrofuran-2(3H)-one (3m): The reaction was performed following Method
A using sulfoxonium salt (±)-2d, (R)-Koga amine 4, and 2-methoxyphenylacetic acid 1a. 3m was isolated as a clear oil (53.5 mg,
71%) with a dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 64% ee [Daicel Chiralpak AD-H column; 1
mL/min; solvent system: 2% isopropanol in hexane; retention time: 30.1 min (major), 32.6 min (minor)]; IR (thin film): 1773,
1494, 1247, 753 cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.14-7.10 (m, 1H), 7.06-7.03 (m, 2H), 6.80-
6.76 (m, 3H), 6.72-6.69 (m, 2H), 4.69 (dd, J = 9.4, 6.8 Hz, 1H), 4.60 (dd, J = 9.4, 4.6 Hz, 1 H), 4.54 (d, J = 8.9 Hz, 1 H), 4.06
(ddd, J = 8.9, 6.8, 4.6 Hz, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.8, 157.1, 136.4,
133.1, 130.2, 129.2, 129.0, 128.4, 122.1, 120.7, 110.3, 71.5, 55.4, 46.3, 45.7; MS (EI 70eV): 302, 257, 223, 165, 148, 121, 91, 77
m/z; (M + H)+ HRMS m/z calcd for C17H16ClO3 : 303.0788; found: 303.0777.
+
(3S,4R)-4-(4-chlorophenyl)-3-(2-methoxyphenyl)dihydrofuran-2(3H)-one (3m): The reaction was performed following Method
A using sulfoxonium salt (S)-2d, (R)-Koga amine 4, and 2-methoxyphenylacetic acid 1a. 3m was isolated as a clear oil (41.9 mg,
55%) with a dr = 6:1 as determined by GC-MS analysis of the crude. HPLC analysis: 85% ee [Daicel Chiralpak AD-H column; 1
mL/min; solvent system: 2% isopropanol in hexane; retention time: 29.6 min (major), 32.1 min (minor)]; IR (thin film): 1771,
1494, 1246, 753 cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.15-7.10 (m, 1H), 7.06-7.03 (m, 2H), 6.80-
6.76 (m, 3H), 6.73-6.69 (m, 2H), 4.70 (dd, J = 9.4, 6.8 Hz, 1H), 4.61 (dd, J = 9.4, 4.6 Hz, 1 H), 4.54 (d, J = 8.9 Hz, 1 H), 4.06
(ddd, J = 8.9, 6.8, 4.6 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.8, 157.1, 136.4,
133.1, 130.2, 129.2, 129.1, 128.4, 122.1, 120.8, 110.3, 71.5, 55.4, 46.3, 45.8; MS (EI 70eV): 302, 257, 223, 165, 148, 121, 91, 77
m/z; (M + H)+ HRMS m/z calcd for C17H16ClO3 : 303.0788; found: 303.0779.
+
(3R,4S)-4-(4-chlorophenyl)-3-(2-methoxyphenyl)dihydrofuran-2(3H)-one (3n): The reaction was performed following Method
A using sulfoxonium salt (±)-2d, (S)-Koga amine 5, and 2-methoxyphenylacetic acid 1a. 3n was isolated as a clear oil (44.2 mg,
58%) with a dr = 5:1 as determined by GC-MS analysis of the crude. HPLC analysis: 57% ee [Daicel Chiralpak AD-H column; 1
mL/min; solvent system: 2% isopropanol in hexane; retention time: 30.2 min (minor), 32.6 min (major)]; IR (thin film): 1770,
1493, 1245, 752 cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.15-7.10 (m, 1H), 7.06-7.03 (m, 2H), 6.80-
6.76 (m, 3H), 6.73-6.69 (m, 2H), 4.70 (dd, J = 9.4, 6.8 Hz, 1H), 4.60 (dd, J = 9.4, 4.6 Hz, 1 H), 4.54 (d, J = 8.9 Hz, 1 H), 4.06
(ddd, J = 8.9, 6.8, 4.6 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 176.8, 157.1, 136.4,
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
133.1, 130.2, 129.2, 129.1, 128.4, 122.1, 120.8, 110.3, 71.5, 55.4, 46.3, 45.8; MS (EI 70eV): 302, 257, 223, 165, 148, 121, 91, 77
5
6
7
+
m/z; (M + H)+ HRMS m/z calcd for C17H16ClO3 : 303.0788; found: 303.0784.
8
9
(+)-(3R,4R)-4-isopropyl-3-(naphthalen-2-yl)dihydrofuran-2(3H)-one (3o): The reaction was performed following Method C
using sulfoxonium salt (±)-2e, (R)-Koga amine 4, and 2-naphthylacetic acid 1f. (+)-3o was isolated as a white solid (24.8 mg, 39%,
mp 118-120 °C) with a dr = 7:1 as determined by GC-MS analysis of the crude. HPLC analysis: 80% ee [Daicel Chiralpak OD-H
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
column; 1 mL/min; solvent system: 10% isopropanol in hexane; retention time: 14.5 min (minor), 20.2 min (major)];
=
1
+23.9 (c = 0.51, CH2Cl2); IR (thin film): 1769, 1011, 749 cm-1; H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ
7.85-7.80 (m, 3H), 7.72 (d, J = 1.3 Hz, 1H), 7.51-7.48 (m, 2H), 7.30 (dd, J = 8.5, 1.9 Hz, 1H), 4.54-4.52 (m, 1H), 4.32 ( t, J = 9.5
Hz, 1H), 4.00 (d, J = 8.7 Hz, 1H), 2.61 (d, J = 9.4 Hz, 1H), 1.38-1.27 (m, 1H), 0.09 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H);
13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 178.0, 133.6, 132.8, 131.8, 128.8, 128.5, 128.1, 127.8, 126.9, 126.7,
+
126.5, 70.9, 49.8, 48.5, 26.9, 21.8; MS (EI 70eV): 254, 186, 167, 141, 69 m/z; (M + H)+ HRMS m/z calcd for C17H19O2 :
255.1385; found: 255.1376.
(3R,4R)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3aa): The reaction was performed following the isomerization
procedure using (‒)-(3S,4R)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one 3a (42.8 mg, 0.16 mmol). 3aa was isolated as
a colorless oil (37.4 mg, 87%), with a dr = 1:14 (favoring the trans-isomer), as determined by chiral HPLC analysis of the purified
product. HPLC analysis: 78% ee [Daicel Chiralpak AD-H column; 1.5 mL/min; solvent system: 5% isopropanol in hexane;
retention time: 15.7 min (major), 19.2 min (minor)];
= ‒146.5 (c = 0.55, CH2Cl2); IR (thin film): 1774, 1496, 755, 699
1
cm-1; H (400 MHz, CDCl3, TMS) for the major diastereomer: δ 7.34-7.19 (m, 6H), 7.01 (dd, J = 7.5, 1.7 Hz, 1H), 6.90-6.85 (m,
2H), 4.76-4.72 (m, 1H), 4.38-4.29 (m, 1H), 4.03-3.94 (m, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major
diastereomer: δ 177.0, 157.4 138.8, 131.0, 129.5, 129.2, 127.8, 127.4, 124.7, 121.2, 111.8, 72.4, 55.8, 50.8, 48.6; MS (EI 70eV):
+
268, 223, 193, 165, 148, 115, 91, 77 m/z; (M + H)+ HRMS m/z calcd for C17H17O3 : 269.1178; found: 269.1167.
(3S,4S)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one (3bb): The reaction was performed following the isomerization
procedure using (+)-(3R,4S)-3-(2-methoxyphenyl)-4-phenyldihydrofuran-2(3H)-one 3b (27.4 mg, 0.10 mmol). 3bb was isolated as
a colorless oil (27.4 mg, >99%) with a dr = 1:24 (favoring the trans-isomer) as determined by GC-MS analysis of the crude. The
HPLC analysis: 75% ee [Daicel Chiralpak AD-H column; 1.5 mL/min; solvent system: 5% isopropanol in hexane; retention time:
1
15.4 min (minor), 18.6 min (major)];
= +175.0 (c = 2.74, CH2Cl2); IR (thin film): 1771, 1495, 754, 699 cm-1; H (400
MHz, CDCl3, TMS) for the major diastereomer: δ 7.33-7.19 (m, 6H), 7.01 (dd, J = 7.5, 1.7 Hz, 1H), 6.91-6.85 (m, 2H), 4.75-4.71
(m, 1H), 4.37-4.28 (m, 1H), 4.02-3.94 (m, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 177.0,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
4
5
157.4, 138.8, 130.9, 129.5, 129.1, 127.8, 127.4, 124.7, 121.1, 111.7, 72.4, 55.8, 50.8, 48.6; MS (EI 70eV): 268, 223, 193, 165,
6
7
+
148, 115, 91, 77 m/z; (M + H)+ HRMS m/z calcd for C17H17O3 : 269.1178; found: 269.1175.
8
9
General procedure for preparation of Ethenyl-Sulfoxonium Salts
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-(N,N-dimethyl-S-phenylsulfonimidoyl)-1-substituted ethenyl tetrafluoroborate: Ethenyl sulfoximines were prepared as
previously described by the groups of Johnson and Gais.6,7 The appropriate ethenyl sulfoximine (~5 mmol, 1 equiv) was dissolved
in dichloromethane (16.6 mL, 0.3 M) and cooled to 0 °C. Me3O+BF4‒ (1.1-1.8 equiv) was added all at once and the reaction was
stirred vigorously for 4 h. The reaction was analyzed by TLC (20% EtOAc:hexane) for consumption of starting material and
quenched with deionized water (~30 mL) if complete. If not complete, the reaction was stirred at room temperature overnight.
After quenching, the organic layer was collected and the aqueous layer was extracted with dichloromethane (2  100 mL). The
combined organics were dried with sodium sulfate and filtered. For crystallization: To minimize exposure to water, vapor liquid
diffusion was carried out by placing a beaker containing the crude dichloromethane solution inside a screw cap chamber filled with
ether, to give a final mixture of ether:dichloromethane (2:1). The crystallization was allowed to proceed over several days. The
crystals were then collected by decanting the filtrate and drying under high vacuum. Amorphous solids would oil out of solution
and were dried under high vacuum to yield a foam which could be ground into a powder. Oils were placed under reduced pressure
(rotovap) and heated to 50 °C for ~6 h and then placed in a vacuum desiccator overnight.
(Dimethylamino)-phenyl-(2-phenylvinyl)-oxosulfonium fluoroborate ((±)-2a). Performed at (5.10 g, 19.7 mmol) scale using
1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h and then warmed to room temperature overnight. Isolated as white crystals (5.45 g,
77%, mp 131-132 °C).6c IR (thin film): 1054 (BF stretch), 753 cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer:
δ 8.34-8.32 (m, 2H), 7.98 (d, J = 15.1 Hz, 1H), 7.90-7.79 (m, 6H), 7.56-7.46 (m, 3H), 3.14 (s, 6H); 13C NMR (100 MHz, CDCl3)
for the major diastereomer: δ 154.0, 137.2, 134.2, 131.6, 131.0, 130.9, 130.3, 129.8, 129.4, 115.7, 38.0; (M+) HRMS m/z calcd for
C16H18NOS+: 272.1109; found: 272.1110.
(S,E)-(Dimethylamino)-phenyl-(2-phenylvinyl)-oxosulfonium fluoroborate ((S)-2a). Performed at (1.94 g, 7.0 mmol) scale
using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h. Isolated as a hygroscopic white amorphous solid which resisted crystallization
1
(1.69 g, 67%).
= ‒1.32 (c = 7.65, CH2Cl2); IR (thin film): 1055 (BF stretch), 753 cm-1; H NMR (400 MHz, CDCl3,
TMS) for the major diastereomer: δ 8.34-8.32 (m, 2H), 7.99 (d, J = 15.1 Hz, 1H), 7.90-7.79 (m, 6H), 7.56-7.46 (m, 3H), 3.14 (s,
6H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 154.0, 137.2, 134.2, 131.6, 131.0, 130.9, 130.3, 129.8, 129.4,
115.7, 38.0; (M+) HRMS m/z calcd for C16H18NOS+: 272.1109; found: 272.1113.
(R,E)-(Dimethylamino)-phenyl-(2-phenylvinyl)-oxosulfonium fluoroborate ((R)-2a). Performed at (1.91 g, 6.9 mmol) scale
using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h. Isolated as a hygroscopic white amorphous solid which resisted
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
4
1
crystallization (2.19 g, 88%).
= +4.35 (c = 6.85, CH2Cl2)6c; IR (thin film): 1057 (BF stretch), 753 cm-1; H NMR (400
5
6
7
8
9
MHz, CDCl3, TMS) for the major diastereomer: δ 8.34-8.32 (m, 2H), 7.98 (d, J = 15.08 Hz, 1H), 7.90-7.79 (m, 6H), 7.57-7.46 (m,
3H), 3.14 (s, 6H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 154.0, 137.2, 134.2, 131.6, 131.0, 130.9, 130.3,
129.8, 129.4, 115.7, 38.0; (M+) HRMS m/z calcd for C16H18NOS+: 272.1109; found: 272.1111.
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
(Dimethylamino)-phenyl-(2-methoxyphenyl-2-vinyl)-oxosulfonium fluoroborate ((±)-2b). Performed at (1.88 g, 6.56 mmol)
scale using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h, and then warmed to room temperature overnight. A portion of (±)-2b was
crystallized by dissolving in minimal hot EtOAc and adding to ether (50 mL), open to air. The resulting solid was dissolved in
minimal dichloromethane, dried with sodium sulfate, and re-crystallized through vapor liquid diffusion of ether into
dichloromethane to yield a pale yellow solid (1.97 g, >95%, 25% recrystallized, mp 123-124 °C) IR (thin film): 1051 (BF stretch),
1
757 cm-1; H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 8.35-8.32 (m, 2H), 8.07-7.98 (m, 2H), 7.87-7.77 (m,
3H), 7.68 (dd, J = 7.8, 1.6 Hz, 1H), 7.53-7.49 (m, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.02 (s, 3H), 3.14 (s, 6H);
13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 160.4, 149.0, 136.8, 135.9, 133.4, 131.5, 130.8, 129.4, 121.4, 120.1,
115.6, 111.7, 56.1, 37.9; (M+) HRMS m/z calcd for C17H20NO2S+: 302.1215; found: 302.1212.
(Dimethylamino)-phenyl-(3-methoxyphenyl-2-vinyl)-oxosulfonium fluoroborate ((±)-2c). Performed at (1.45 g, 5.0 mmol)
scale using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h, and then warmed to room temperature overnight. Isolated as yellow
1
crystals (1.55 g, 80%, mp 164-165 °C) IR (thin film): 1057 (BF stretch) cm-1; H NMR (400 MHz, CDCl3, TMS) for the major
diastereomer: δ 8.34-8.31 (m, 2H), 8.01 (d, J = 15.0 Hz, 1H), 7.91-7.79 (m, 4H), 7.49-7.48 (m, 1H), 7.37-7.33 (m, 1H), 7.24-7.22
(m, 1H), 7.11-7.08 (m, 1H), 3.92 (s, 3H), 3.14 (s, 6H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ 160.8, 154.0,
137.2, 132.2, 131.6, 130.5, 130.3, 129.4, 124.7, 122.4, 115.5, 112.4, 56.1, 38.0; (M+) HRMS m/z calcd for C17H20NO2S+:
302.1215; found: 302.1208.
(Dimethylamino)-phenyl-(4-chlorophenyl-2-vinyl)-oxosulfonium fluoroborate ((±)-2d). Performed at (1.75 g, 6.0 mmol) scale
using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h, and then warmed to room temperature overnight. Isolated as pale yellow
1
crystals (1.93 g, 78%, mp 174-175 °C); IR (thin film): 1032 (BF stretch) cm-1; H NMR (400 MHz, CDCl3, TMS) for the major
diastereomer: δ 8.33-8.31 (m, 2H), 8.00 (d, J = 15.1 Hz, 1H), 7.90-7.75 (m, 6H), 7.47-7.45 (m, 2H), 3.14 (s, 6H); 13C NMR (100
MHz, CDCl3) for the major diastereomer: δ 152.4, 140.6, 137.3, 132.1, 131.6, 130.2, 130.0, 129.4, 129.4, 116.3, 38.0; (M+) HRMS
m/z calcd for C16H17ClNOS+: 306.0719; found: 306.0718.
(S,E)-(Dimethylamino)-phenyl-(4-chlorophenyl-2-vinyl)-oxosulfonium fluoroborate ((S)-2d). Performed at (2.28 g, 7.8 mmol)
scale using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h, and then warmed to room temperature overnight. Isolated as a
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
4
5
hygroscopic pale yellow amorphous solid which resisted crystallization (2.38 g, 78%);
= +47.9 (c = 3.05, CH2Cl2); IR
6
7
8
9
(thin film): 1032 (BF stretch) cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 8.32-8.30 (m, 2H), 8.00 (d, J =
15.1 Hz, 1H), 7.92-7.75 (m, 6H), 7.46-7.44 (m, 2H), 3.14 (s, 6H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ
152.4, 140.6, 137.3, 132.1, 131.6, 130.2, 130.1, 129.5, 129.4, 116.3, 38.0; (M+) HRMS m/z calcd for C16H17ClNOS+: 306.0719;
found: 306.0718.
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
(R,E)-(Dimethylamino)-phenyl-(4-chlorophenyl-2-vinyl)-oxosulfonium fluoroborate ((R)-2d). Performed at (2.34 g, 8.0 mmol)
scale using 1.8 equiv Me3O+BF4‒, stirred at 0 °C for 4 h, and then warmed to room temperature overnight. Isolated as a
hygroscopic pale yellow amorphous solid which resisted crystallization (2.35 g, 75%);
= ‒27.4 (c = 2.58, CH2Cl2); IR
(thin film): 1032 (BF stretch) cm-1; 1H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 8.33-8.31 (m, 2H), 8.00 (d, J =
15.1 Hz, 1H), 7.89-7.75 (m, 6H), 7.47-7.45 (m, 2H), 3.14 (s, 6H); 13C NMR (100 MHz, CDCl3) for the major diastereomer: δ
152.4, 140.6, 137.3, 132.1, 131.7, 130.2, 130.1, 129.5, 129.4, 116.3, 38.0; (M+) HRMS m/z calcd for C16H17ClNOS+: 306.0719;
found: 306.0715.
(Dimethylamino)-phenyl-(2-isopropylvinyl)-oxosulfonium fluoroborate ((±)-2e). Performed at (1.25 g, 5.6 mmol) scale using
1.1 equiv Me3O+BF4‒, stirred at 0 °C for 4 h. Isolated as a clear yellow oil (1.83 g, >95%). Occasionally, a plug column was used
to purify by removing impurities with ether, and collecting the pure salt using dichloromethane. IR (thin film): 1031 (BF stretch),
1
947 cm-1; H NMR (400 MHz, CDCl3, TMS) for the major diastereomer: δ 8.27-8.24 (m, 2H), 7.93-7.88 (m, 1H), 7.83-7.79 (m,
2H), 7.42-7.32 (m, 2H), 3.09 (s, 6H), 2.89-2.81 (m, 1H), 1.18 (dd, J = 12.0, 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) for the
major diastereomer: δ 166.4, 137.3, 131.6, 129.8, 129.4, 37.9, 32.7, 20.8, 20.8; (M+) HRMS m/z calcd for C13H20NOS+: 238.1266;
found: 238.1266.
Determination of relative and absolute stereochemistry: 3g, from an (S)-Koga amine 5-controlled reaction, was crystallized
from isopropanol to provide a sample suitable for X-ray crystallographic analysis.
Acknowledgment. Support has been provided by the National Science Foundation and the National Institutes of Health: Grant Nos. CHE-
1463728 to N.J.K. and CHE-0722547 to K.A.W., and R15GM107800 to N.J.K.
Supporting Information Available: Spectroscopic data, X-ray crystallographic data (cif-3g), and chromatograms for all new compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
References:
1.
(a) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285-292. (b) Hoffman, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1985, 24, 94-110. (c) Koch,
S. S. C.; Chamberlain, A. R. In Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier Science: New York, 1995; Vol. 16, pp 687-725.
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2.
Enantioselective approaches to γ-lactones: (a) Goodman, C. G.; Walker, M. M.; Johnson, J. S. J. Am. Chem. Soc. 2015, 137, 122-125. (b) Steward, K.
M.; Gentry, E. C.; Johnson, J. S. J. Am. Chem. Soc. 2012, 134, 7329-7332. (c) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem.
Soc. 2010, 132, 3298-3300. (d) Cao, P.; Zhang, X. J. Am. Chem. Soc. 1999, 121, 7708-7709. (e) Kerrigan, N. J.; Hutchison, P. C.; Heightman, T. D.;
Procter, D. J. Chem. Commun. 2003, 1402-1403. (f) Fukuzawa, S.-i.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem. Soc. 1997, 119, 1482-1483.
(a) Peraino, N. J.; Wheeler, K. A.; Kerrigan, N. J. Org. Lett. 2015, 17, 1735-1737. (b) Mondal, M.; Ho, H.-J.; Peraino, N. J.; Gary, M. A.; Wheeler, K.
A.; Kerrigan, N. J. J. Org. Chem. 2013, 78, 4587-4593. (c) Peraino, N. J.; Ho, H.-J.; Mondal, M.; Kerrigan, N. J. Tetrahedron Lett. 2014, 55, 4260-4263.
(a) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem. Soc. 1994, 116, 8829-8830. (b) Yamashita, Y.; Emura, Y.; Odashima, K.;
Koga, K. Tetrahedron Lett. 2000, 41, 209-213.
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.
4.
5.
(a) Lu, P.; Jackson, J. J.; Eickhoff, J. A.; Zakarian, A. J. Am. Chem. Soc. 2015, 137, 656-659. (b) Ma, Y; Stivala, C. E.; Wright, A. M.; Hayton, T.;
Liang, J.; Keresztes, I.; Lobkovsky, E.; Collum, D. B.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 16853-16864. (c) Stivala, C. E.; Zakarian, A. J. Am.
Chem. Soc. 2011, 133, 11936-11939. (d) Frizzle, M. J.; Caille, S.; Marshall, T. L.; McRae, K.; Nadeau, K.; Guo, G.; Wu, S.; Martinelli, M. J.; Moniz, G.
A. Org. Process Res. Dev. 2007, 11, 215-222.
6.
7.
(a) Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970, 92, 6594-6598. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973,
95, 7418-7423. (c) Johnson, C. R.; Lockard, J. P.; Kennedy, E. R. J. Org. Chem. 1980, 45, 264-271.
(a) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 6, 909-912. (b) Gais, H.-J.; Hainz, R.; Müller, H.; Bruns, P.; Giesen, N.; Raabe, G.; Runsink,
J.; Nienstedt, S.; Decker, J.; Schleusner, M.; Hachtel, J.; Loo, R.; Woo, C.-W.; Das, P. Eur. J. Org. Chem. 2000, 3973-4009.
Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1-30.
8.
9.
(a) Oare, D. A.; Heathcock, C. J. Org. Chem. 1990, 55, 157-172. (b) Kwan, E. E.; Evans, D. A. Org. Lett. 2010, 12, 5124-5127.
10. Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th Ed. Butterworth Heinemann, 2002.
21
ACS Paragon Plus Environment